EA047300B1 - SUBSTITUTED PYRIDAZINONES AS HERBICIDES - Google Patents

Abstract

The present invention relates to herbicidal substituted phenylpyridazinediones and substituted phenylpyridazinone derivatives of formula (I). The present invention further extends to herbicidal compositions containing such derivatives, as well as to the use of such compounds and compositions in providing control of the growth of undesirable plants, in particular to the use in providing control of weeds, such as broadleaf dicotyledonous weeds, in agricultural crops of useful plants.

Description

The present invention relates to herbicidal substituted phenylpyridazinediones and substituted phenylpyridazinone derivatives of formula (I), as well as methods and intermediates used for the preparation of such derivatives. The present invention further extends to herbicidal compositions containing such derivatives, as well as the use of such compounds and compositions in providing control of the growth of undesirable plants, in particular, use in providing control of weeds, such as broadleaf dicotyledonous weeds, in crops of beneficial plants.

Herbicidal pyridazinones are known from WO2009/086041. In addition, herbicidal 5/6-membered heterocyclyl-substituted pyridazinones are known from WO 2011/045271. Moreover, WO2013/160126 describes indolylpyridazinone derivatives that exhibit herbicidal activity.

The present invention is based on the discovery that substituted phenylpyridazinediones and substituted phenylpyridazinone derivatives of formula (I) exhibit unexpectedly good herbicidal activity.

Thus, in the first aspect there is provided a compound of formula (I),

or a salt or N-oxide thereof, where

R ¹ is selected from the group consisting of methyl, ethyl, n-propyl, cyclopropyl, propargyl and C ₁ haloalkyl;

R ² is selected from the group consisting of hydrogen, halogen, CrCzalkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl and C ₂ -C ₆ haloalkenyl;

G is hydrogen or C(O)R ³ where R ³ is isopropyl, tert-butyl, methyl, ethyl, propargyl, methoxy, ethoxy or tert-butoxy;

X represents hydrogen, halogen or C ₁ haloalkyl;

Y represents hydrogen, C _g Czalkyl, cyclopropyl, C ₁ -C ₃ haloalkyl or halogen;

D is either a substituted or unsubstituted naphthalene ring system, or a substituted or unsubstituted 8-10 membered bicyclic saturated, partially saturated or unsaturated heterocyclic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein, if D is substituted, then it is substituted at least one carbon atom in the ring with R ⁸ and/or at least one nitrogen atom in the ring with R ⁹ ;

each R ⁸ independently represents oxygen, hydroxyl, halogen, cyano, C ₁ -C ₆ alkyl, CpC^haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ haloalkoxy-C ₁ -C ₃ alkyl-, C ₁ - With ₆ alkoxy,

C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ hydroxyalkyl-, C ₁ -C ₆ alkylcarbonyl-, Cg^alkyl^O^-, amino, C ₁ -C ₆ alkylamino, C ₁ - C ₆ dialkylamino, -C(T _g C ₃ alkyl) ^(')-C|-C ₃ a.p<i.1 or

C ₂ -C ₆ haloalkynyl;

m is an integer equal to 0, 1 or 2;

each R ⁹ independently represents C ₁ -C ₄ alkyl, C ₁ -C ₄ alogenalkyl, hydroxyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylthio;

W represents

where a is the point of attachment to the phenylpyridazinone/phenylpyridazinedione moiety, b is the point of attachment to ring D, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen; and R ¹⁴ and R ¹⁵ are each hydrogen.

The compounds of formula (I) may contain asymmetric centers and may be present as a single enantiomer, pairs of enantiomers in any proportion or, if more than one asymmetric center is present, contain diastereoisomers in all possible proportions. Typically, one of the enantiomers is characterized by increased biological activity compared to other options.

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Likewise, in the case of disubstituted alkenes, they can be present in the E- or Z-form or as mixtures of both in any proportion.

Moreover, the compounds of formula (I) can be in equilibrium with alternative tautomeric forms. For example, a compound of formula (Ii), i.e. a compound of formula (I) wherein R ² is hydrogen and G is hydrogen may be represented in at least three tautomeric forms:

(l-i)

It should be understood that all tautomeric forms (single tautomer or mixtures thereof), racemic mixtures and individual isomers are included within the scope of the present invention.

Each alkyl moiety, either on its own or as part of a larger group (such as alkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl, etc.) can be straight chain or branched. Typically, alkyl is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl or ngexyl. Alkyl groups are typically C1- _C6 alkyl groups (unless already more narrowly defined), but are preferably C1- _C4 alkyl or Q-C alkyl groups, and more preferably are C1- _C2 alkyl groups (such as methyl).

Alkenyl and alkynyl moieties can be in straight or branched chain form, and the alkenyl moieties can be in either the (E) or (Z) configuration if desired. Alkenyl or alkynyl moieties are typically C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl, more particularly vinyl, allyl, ethynyl, propargyl or prop-1-ynyl. Alkenyl and alkynyl moieties may contain one or more double and/or triple bonds in any combination; but preferably they contain only one double bond (for alkenyl) or only one triple bond (for alkynyl).

Preferably, the term cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term aryl preferably means phenyl. The term heteroaryl as used herein means a monocyclic or bicyclic aromatic ring system containing at least one heteroatom in the ring. Preferably, monocyclic ring systems will contain 1, 2 or 3 heteroatoms per ring, and bicyclic ring systems will contain 1,2,3 or 4 heteroatoms per ring, each heteroatom being independently selected from nitrogen, oxygen and sulfur.

Typically, the monocyclic heteroaryl ring is selected from the group consisting of furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,4oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl or 1,3,5triazinyl ring.

Typically, the bicyclic heteroaryl ring system is selected from the group consisting of indolizine, indole, isoindole, 3-H-indole, benzofuran, benzothiophene, 1Hindazole, benzimidazole, benzthiazole, purine, 4H-quinolysine, quinoline, isoquinoline, cinnoline, phthalazine, ova , 1-8-naphthyridine or pteridine ring system.

Heterocyclyl groups and heterocyclic rings (either by themselves or as part of a larger group such as heterocyclyl-alkyl-) are ring systems containing at least one heteroatom and may be in mono- or bicyclic form and may also be partially saturated or fully saturated. Heterocyclyl groups will preferably contain up to two heteroatoms, which will preferably be selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include oxetanyl, thietanyl, azetidinyl and 7-oxabicyclo[2.2.1]hept-2-yl.

Heterocyclyl groups containing one oxygen atom as a heteroatom are most preferred.

Halogen (or halogeno) covers fluorine, chlorine, bromine or iodine. The same thing, respectively, accept

- 2 047300 nimo to halogen in the context of other definitions such as haloalkyl or halophenyl.

Haloalkyl groups with a chain length of 1 to 6 carbon atoms are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1,1-difluoro-2 ,2,2-trichloroethyl, 2,2,3,3-tetrafluoroethyl and 2,2,2trichloroethyl, heptafluoro-n-propyl and perfluoro-n-hexyl.

Alkoxy groups preferably have a chain length of 1 to 6 carbon atoms. Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy or an isomer of pentyloxy or hexyloxy, preferably methoxy and ethoxy. It should also be understood that two alkoxy substituents can be present on the same carbon atom.

Halogenoalkoxy is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy or 2,2,2-trichloroethoxy, preferably difluoromethoxy, 2-chloroethoxy or trifluoromethoxy.

C1- _C6 alkyl-8-(alkylthio) is, for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio or tert-butylthio, preferably methylthio or ethylthio.

C1-Cbalkyl-8(O)-(alkylsulfinyl) is, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl or tert-butylsulfinyl, preferably methylsulfinyl or ethylsulfinyl.

C1- _C6 alkyl^(O) ₂ - (alkylsulfonyl) is, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl or ethylsulfonyl.

Group Q.

referred to herein as a pyridazinedione/pyridazinone moiety, where B represents the point of attachment to the rest of the molecule (ie, the optionally substituted phenyl-W-D moiety).

The present invention also includes the agriculturally acceptable salts that the compounds of formula (I) can form with amines (eg, ammonia, dimethylamine and triethylamine), alkali metal and alkaline earth metal bases or quaternary ammonium bases. Among the hydroxides, oxides, alkoxides, and bicarbonates and carbonates of alkali metals and alkaline earth metals used as salt formers, special attention should be paid to the hydroxides, alkoxides, oxides and carbonates of lithium, sodium, potassium, magnesium and calcium, but especially to the hydroxides, alkoxides, oxides and carbonates of sodium, magnesium and calcium. The corresponding trimethylsulfonium salt may also be used. The compounds of formula (I) according to the present invention also include hydrates which may be formed during salt formation.

Preferred values for R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , W, D, G, X, Y, Z and m are set out below , and the compound of formula (I) in accordance with the present invention may include any combination of the above values. One skilled in the art will appreciate that values for any specified group of embodiments can be combined with values for any other group of embodiments as long as such combinations are not mutually exclusive.

Preferably R ¹ is selected from the group consisting of methyl, ethyl, propyl (in particular n- or cyclopropyl), propargyl or C ₁ haloalkyl. More preferably, R ¹ is methyl, ethyl, cyclopropyl, propargyl or C1fluoroalkyl. Even more preferably, R ¹ is methyl, ethyl, cyclopropyl or propargyl. Most preferably, R ¹ is methyl.

Preferably R ² is selected from the group consisting of hydrogen, halogen, ^-C ^ alkyl, C 1 -C ₆ haloalkyl, C 1 -C ₆ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl and C ₂ -C ₆ haloalkynyl. More preferably, R ² is selected from the group consisting of chlorine, fluorine, methyl, ethyl, cyclopropyl, trifluoromethyl and methoxymethyl, even more preferably chlorine, cyclopropyl, trifluoromethyl or methyl, most preferably chlorine or methyl. In one set of embodiments of the present invention, R ² is hydrogen. In a further group of embodiments, R ² is cyclopropyl, in a third group of embodiments, R ² is methyl, in a fourth group of embodiments, R ² is trifluoromethyl, and in a fifth group of embodiments, R ²

- 3 047300 represents chlorine. As described herein, G can be hydrogen or C(O)-R ³ and R ³ is isopropyl, t-butyl, methyl, ethyl, propargyl, methoxy, ethoxy or t-butoxy.

In a further set of embodiments, G is hydrogen or -C(O)-R ³ where R ³ is isopropyl, tert-butyl, methyl, ethyl, propargyl or methoxy. However, it is particularly preferred that G is hydrogen or -C(O)-R ³ where R ³ is isopropyl.

X is preferably hydrogen, halogen or C-haloalkyl, more preferably hydrogen, fluorine, chlorine, bromo or C-fluoroalkyl, and even more preferably hydrogen, fluorine, chlorine or trifluoromethyl. In one group of embodiments, it is preferred that X is in the ortho position (6-position) relative to the pyridazinone/pyridazinedione moiety (Q group). It is particularly preferred that X is fluorine, chlorine or Ci-haloalkyl (in particular C|fluoroalkyl) and is in the ortho position (6-position) relative to the pyridazinone/pyridazinedione moiety (Q group). Most preferably, X is fluorine and is in the ortho position (6-position) relative to the pyridazinone/pyridazinedione moiety.

Y is preferably hydrogen, C ₁ -C ₃ alkyl, cyclopropyl, C ₁ -C ₃ haloalkyl or halogen. More preferably, Y is hydrogen, chlorine, fluorine or bromine.

In one group of embodiments, it is preferred that Y is in the ortho position (3-position) relative to the -W-D moiety. In a further set of embodiments, Y is in the para position relative to the pyridazinone/pyridazinedione moiety (Q group).

It is particularly preferred that Y is in the ortho position (3-position) relative to the -W-D moiety and is a halogen, in particular chlorine or fluorine; more preferably chlorine.

In one particularly preferred group of embodiments, X is fluorine and is ortho (6-position) relative to the pyridazinone/pyridazinedione moiety and Y is chlorine and is ortho (3-position) relative to the -W-D moiety.

As described herein, D is a substituted or unsubstituted naphthalene ring system or a substituted or unsubstituted 8-10 membered bicyclic saturated, partially saturated or unsaturated heterocyclic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein, if D is substituted, then it is substituted at least one ring carbon atom with R ⁸ and/or, as appropriate, one ring nitrogen atom with R ⁹ . In one group of preferred embodiments, the ring system D is attached to the rest of the molecule via a carbon atom in the ring.

Preferably D is a substituted or unsubstituted naphthalene ring system or is a substituted or unsubstituted 8-10 membered bicyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. More preferably, D is substituted (by at least one R ⁸ and/or R ⁹ as described herein) or unsubstituted naphthalene, indolizine, indole, isoindole, indoline, isoindoline, 3-H-indole, benzofuran, benzothiophene , 1H-indazole, benzimidazole, benzthiazole, benzoxazole, benzodioxole, purine, 4H-quinolysine, quinoline, isoquinoline, tetrahydroquinoline, cinnoline, phthalazine, quinoxaline, 1-8-naphthyridine, pteridine, 1H-pyrrolo[2,3b]pyri dinovu, imidazo [1,2-a]pyrazine or 1H-benzotriazole ring system.

Even more preferably, D is substituted (by at least one R ⁸ and/or R ⁹ as described herein) or unsubstituted naphthalene, indolizine, indole, isoindole, 3-H-indole, benzofuran, benzothiophene, 1H- indazole, benzimidazole, benzthiazole, benzoxazole, purine, 4H-quinolysine, quinoline, isoquinoline, tetrahydroquinoline, cinnoline, phthalazine, quinoxaline, 1-8naphthyridine or pteridine ring system.

More preferably, in such embodiments, D is a substituted (as described herein) or unsubstituted naphthalene, quinoline, tetrahydroquinoline, indole, or benzoxazole ring.

Preferably, each R ⁸ independently represents oxygen, hydroxyl, halogen, cyano, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy, C ₁ -C ₃ haloalkoxy-C ₁ -C ₃ alkyl- , C ₁ -C ₆ alkoxy, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl-, C ₃ -C ₆ cycloalkyl , C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ hydroxyalkyl-, C ₁ -C ₆ alkylcarbonyl-, C^-Cbalkyl-BSO^-, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ dialkylamino, -CfS/-C>,alkyl)=H-O-C/-C ₃ alkyl or

C2-C6haloalkynyl.

Even more preferably, each R ⁸ independently represents hydroxyl, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy. Even more preferably, each R ⁸ independently represents C1- _C3 alkyl, _C1 - _C3 haloalkyl, chlorine, fluorine, hydroxyl or _C1 - _C3 alkoxy.

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Preferably, each R ⁹ is independently C1-C4 alkyl, C1-C4 haloalkyl, hydroxyl, C1-C4 alkoxy or C1-C4 alkylthio. More preferably, each R ⁹ independently represents C1-C4 alkyl or C1-C ₄ alkoxy. Even more preferably, each R ⁹ is independently C1- _C4 alkyl. Most preferably, each R ⁹ is methyl.

m is an integer equal to 0, 1 or 2. Preferably m is 0 or 2.

W functions as a linker moiety linking ring system D to the rest of the molecule (ie, the phenylpyridazinone/phenylpyridazinedione moiety). Compounds of formula (I) where the linker is W1 and W3 have herbicidal activity, and compounds of formula (I) where the linker is W2 may not only have herbicidal activity, but also be useful intermediates in the preparation of compounds of formula ( I) containing W1 linkers. Thus, in the first group of embodiments, W is W1 or W3 (preferably W1), while in the second group of embodiments, W is W2.

In preferred embodiments, W is either -CH2-CH2-, -CH=CH-, or -OC-.

Preferably, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen.

Preferably, R ¹⁴ and R ¹⁵ are each hydrogen.

In one preferred group of embodiments, in a compound of formula (I):

R ¹ is methyl, ethyl, cyclopropyl, propargyl or C1fluoroalkyl;

R ² represents chlorine, cyclopropyl, trifluoromethyl or methyl;

G is hydrogen or -C(O)-R ³ where R ³ is isopropyl, t-butyl, methyl, ethyl, propargyl, methoxy, ethoxy or t-butoxy;

X represents fluorine, chlorine or C1haloalkyl and is in the ortho position relative to the pyridazinone/pyridazinedione moiety;

Y is hydrogen, chlorine, fluorine or bromine and is in the ortho position relative to the -W-D moiety;

D is either a substituted or unsubstituted naphthalene ring system, or a substituted or unsubstituted 8-10 membered bicyclic saturated, partially saturated or unsaturated heterocyclic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein, if D is substituted, then it is substituted at least one carbon atom in the ring with R ⁸ and/or at least one nitrogen atom in the ring with R ⁹ ;

each R ⁸ independently represents hydroxyl, halogen, C1- _C6 alkyl, C1- _C6 haloalkyl or C1- _C6 alkoxy;

each R ⁹ is independently C1- _C4 alkyl or C1- _C4 alkoxy;

W represents W1; and R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are all hydrogen.

In an even more preferred group of embodiments, in a compound of formula (I):

R ¹ represents methyl; R ² represents methyl;

G is hydrogen or -C(O)-R ³ where R ³ is isopropyl, t-butyl, methyl, ethyl, propargyl, methoxy, ethoxy or t-butoxy;

X represents fluorine and is in the ortho position relative to the pyridazinone/pyridazinedione moiety;

Y is chlorine and is in the ortho position relative to the -W-D moiety;

D is substituted or unsubstituted naphthalene, indolizine, indole, isoindole, indoline, isoindoline, 3-H-indole, benzofuran, benzothiophene, N-indazole, benzimidazole, benzthiazole, benzoxazole, benzodioxole, purine, 4H-quinolysine, isoquinoline, , tetrahydroquinoline, cinnoline, phthalazine, quinoxaline, 1-8-naphthyridine, pteridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrazine or 1H-benzotriazole ring system, and if D is substituted, then it is substituted on one or two carbon atoms in the ring with R ⁸ and/or one nitrogen atom in the ring with R ⁹ ;

each R ⁸ independently represents C1- _C3 alkyl, C1- _C3 haloalkyl, chlorine, fluorine, hydroxyl or C'i-CvItkokch;

R ⁹ represents C1- _C4 alkyl;

W represents W1; and R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are all hydrogen.

In table 1-4 below illustrate 2752 specific examples of compounds of formula (I) of the present invention.

Herbicidal compounds of the present invention. The numbering system used to describe the X and Y positions is shown for clarity only.

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In table 1 shows 688 compounds A-1.001 to A-1.688 of formula (I) as shown above, where G is hydrogen, W is -CH2-CH2-, and ^R1 , ^R2 , X, Y, D are as follows: as determined for compounds Nos. 1.001-1.688, respectively, in Table. And lower.

Table A

Definitions of substituents R ¹ , R ² , X, Y and D for compounds of formula (I)_______

Connection no. R ¹ R ² X Y D 1.001 -Me -Me 6-F 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1.002 -Me -Me 6-F 3-F 1H-indol-4-yl- 1.003 -Me -Me 6-F 3-F 1H-indol-5-yl- 1.004 -Me -Me 6-F 3-F lH-indol-b-yl- 1.005 -Me -Me 6-F 3-F 1 -methylindol-4-yl- 1.006 -Me -Me 6-F 3-F 1-methylindol-5-yl- 1.007 -Me -Me 6-F 3-F 1 -methylindol-6-yl- 1.008 -Me -Me 6-F 3-F 1-naphthyl- 1.009 -Me -Me 6-F 3-F 2-(trifluoromethyl)-4-quinolyl- 1.010 -Me -Me 6-F 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1.011 -Me -Me 6-F 3-F 2-methyl-1,3-benzoxazol-6-yl- 1.012 -Me -Me 6-F 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.013 -Me -Me 6-F 3-F 2-methyl-6-quinolyl- 1.014 -Me -Me 6-F 3-F 2-methyl-6-quinolyl- 1.015 -Me -Me 6-F 3-F 2-methyl-6-quinolyl- 1.016 -Me -Me 6-F 3-F 2-methyl-6-quinolyl- 1.017 -Me -Me 6-F 3-F 2-naphthyl- 1.018 -Me -Me 6-F 3-F 4-quinolyl- 1.019 -Me -Me 6-F 3-C1 1,2,3,4-tetrahydroquinolin-6-yl- 1,020 -Me -Me 6-F 3-C1 1H-indol-4-yl- 1.021 -Me -Me 6-F 3-C1 1H-indol-5-yl- 1.022 -Me -Me 6-F 3-C1 lH-indol-b-yl- 1.023 -Me -Me 6-F 3-C1 1 -methylindol-4-yl- 1.024 -Me -Me 6-F 3-C1 1-methylindol-5-yl- 1.025 -Me -Me 6-F 3-C1 1 -methylindol-6-yl- 1.026 -Me -Me 6-F 3-C1 1-naphthyl- 1.027 -Me -Me 6-F 3-C1 2-(trifluoromethyl)-4-quinolyl- 1.028 -Me -Me 6-F 3-C1 2-ethyl-1,3-benzoxazol-6-yl- 1.029 -Me -Me 6-F 3-C1 2-methyl-1,3-benzoxazol-6-yl- 1,030 -Me -Me 6-F 3-C1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.031 -Me -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.032 -Me -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.033 -Me -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.034 -Me -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.035 -Me -Me 6-F 3-C1 2-naphthyl-

- 6 047300

1.036 -Me -Me 6-F 3-C1 4-quinolyl- 1.037 -Me -Me 6-C1 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1.038 -Me -Me 6-C1 3-F Sh-indol-4-yl- 1.039 -Me -Me 6-C1 3-F 1H-indol-5-yl- 1,040 -Me -Me 6-C1 3-F lH-indol-b-yl- 1,041 -Me -Me 6-C1 3-F 1 -methylindol-4-yl- 1,042 -Me -Me 6-C1 3-F 1-methylindol-5-yl- 1,043 -Me -Me 6-C1 3-F 1 -methylindol-6-yl- 1,044 -Me -Me 6-C1 3-F 1-naphthyl- 1.045 -Me -Me 6-C1 3-F 2-(trifluoromethyl)-4-quinolyl- 1,046 -Me -Me 6-C1 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1.047 -Me -Me 6-C1 3-F 2-methyl-1,3-benzoxazol-6-yl- 1,048 -Me -Me 6-C1 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1,049 -Me -Me 6-C1 3-F 2-methyl-6-quinolyl- 1,050 -Me -Me 6-C1 3-F 2-methyl-6-quinolyl- 1.051 -Me -Me 6-C1 3-F 2-methyl-6-quinolyl- 1.052 -Me -Me 6-C1 3-F 2-methyl-6-quinolyl- 1.053 -Me -Me 6-C1 3-F 2-naphthyl- 1.054 -Me -Me 6-C1 3-F 4-quinolyl- 1.055 -Me -Me 6-C1 3-C1 1,2,3,4-tetrahydroquinolin-6-yl- 1.056 -Me -Me 6-C1 3-C1 1H-indol-4-yl- 1.057 -Me -Me 6-C1 3-C1 1H-indol-5-yl- 1.058 -Me -Me 6-C1 3-C1 lH-indol-b-yl- 1.059 -Me -Me 6-C1 3-C1 1 -methylindol-4-yl- 1,060 -Me -Me 6-C1 3-C1 1-methylindol-5-yl- 1.061 -Me -Me 6-C1 3-C1 1 -methylindol-6-yl- 1,062 -Me -Me 6-C1 3-C1 1-naphthyl- 1,063 -Me -Me 6-C1 3-C1 2-(trifluoromethyl)-4-quinolyl- 1,064 -Me -Me 6-C1 3-C1 2-ethyl-1,3-benzoxazol-6-yl- 1.065 -Me -Me 6-C1 3-C1 2-methyl-1,3-benzoxazol-6-yl- 1,066 -Me -Me 6-C1 3-C1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.067 -Me -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1.068 -Me -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1,069 -Me -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1,070 -Me -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1,071 -Me -Me 6-C1 3-C1 2-naphthyl- 1,072 -Me -Me 6-C1 3-C1 4-quinolyl- 1,073 -Me -Cl 6-F 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1,074 -Me -Cl 6-F 3-F 1H-indol-4-yl- 1.075 -Me -Cl 6-F 3-F 1H-indol-5-yl- 1.076 -Me -Cl 6-F 3-F 1H-indol-6-yl- 1.077 -Me -Cl 6-F 3-F 1 -methylindol-4-yl- 1.078 -Me -Cl 6-F 3-F 1-methylindol-5-yl- 1,079 -Me -Cl 6-F 3-F 1 -methylindol-6-yl- 1,080 -Me -Cl 6-F 3-F 1-naphthyl- 1,081 -Me -Cl 6-F 3-F 2-(trifluoromethyl)-4-quinolyl-

- 7 047300

1,082 -Me -Cl 6-F 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1,083 -Me -Cl 6-F 3-F 2-methyl-1,3-benzoxazol-6-yl- 1,084 -Me -Cl 6-F 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.085 -Me -Cl 6-F 3-F 2-methyl-6-quinolyl- 1,086 -Me -Cl 6-F 3-F 2-methyl-6-quinolyl- 1,087 -Me -Cl 6-F 3-F 2-methyl-6-quinolyl- 1,088 -Me -Cl 6-F 3-F 2-methyl-6-quinolyl- 1,089 -Me -Cl 6-F 3-F 2-naphthyl- 1,090 -Me -Cl 6-F 3-F 4-quinolyl- 1,091 -Me -Cl 6-F 3-C1 1,2,3,4-tetrahydroquinolin-6-yl- 1,092 -Me -Cl 6-F 3-C1 1H-indol-4-yl- 1,093 -Me -Cl 6-F 3-C1 1H-indol-5-yl- 1,094 -Me -Cl 6-F 3-C1 1N-IDOL-6-IL- 1.095 -Me -Cl 6-F 3-C1 1 -methylindol-4-yl- 1,096 -Me -Cl 6-F 3-C1 1-methylindol-5-yl- 1,097 -Me -Cl 6-F 3-C1 1 -methylindol-6-yl- 1,098 -Me -Cl 6-F 3-C1 1-naphthyl- 1,099 -Me -Cl 6-F 3-C1 2-(trifluoromethyl)-4-quinolyl- 1,100 -Me -Cl 6-F 3-C1 2-ethyl-1,3-benzoxazol-6-yl- 1.101 -Me -Cl 6-F 3-C1 2-methyl-1,3-benzoxazol-6-yl- 1.102 -Me -Cl 6-F 3-C1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.103 -Me -Cl 6-F 3-C1 2-methyl-6-quinolyl- 1.104 -Me -Cl 6-F 3-C1 2-methyl-6-quinolyl- 1.105 -Me -Cl 6-F 3-C1 2-methyl-6-quinolyl- 1.106 -Me -Cl 6-F 3-C1 2-methyl-6-quinolyl- 1.107 -Me -Cl 6-F 3-C1 2-naphthyl- 1.108 -Me -Cl 6-F 3-C1 4-quinolyl- 1.109 -Me -Cl 6-C1 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1.110 -Me -Cl 6-C1 3-F 1H-indol-4-yl- 1.111 -Me -Cl 6-C1 3-F 1H-indol-5-yl- 1.112 -Me -Cl 6-C1 3-F 1N-IDOL-6-IL- 1.113 -Me -Cl 6-C1 3-F 1 -methylindol-4-yl- 1.114 -Me -Cl 6-C1 3-F 1-methylindol-5-yl- 1.115 -Me -Cl 6-C1 3-F 1 -methylindol-6-yl- 1.116 -Me -Cl 6-C1 3-F 1-naphthyl- 1.117 -Me -Cl 6-C1 3-F 2-(trifluoromethyl)-4-quinolyl- 1.118 -Me -Cl 6-C1 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1.119 -Me -Cl 6-C1 3-F 2-methyl-1,3-benzoxazol-6-yl- 1.120 -Me -Cl 6-C1 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.121 -Me -Cl 6-C1 3-F 2-methyl-6-quinolyl- 1.122 -Me -Cl 6-C1 3-F 2-methyl-6-quinolyl- 1.123 -Me -Cl 6-C1 3-F 2-methyl-6-quinolyl- 1.124 -Me -Cl 6-C1 3-F 2-methyl-6-quinolyl- 1.125 -Me -Cl 6-C1 3-F 2-naphthyl- 1.126 -Me -Cl 6-C1 3-F 4-quinolyl- 1.127 -Me -Cl 6-C1 3-C1 1,2,3,4-tetrahydroquinolin-6-yl-

- 8 047300

1.128 -Me -Cl 6-C1 3-C1 1H-indol-4-yl- 1.129 -Me -Cl 6-C1 3-C1 1H-indol-5-yl- 1.130 -Me -Cl 6-C1 3-C1 lH-indol-b-yl- 1.131 -Me -Cl 6-C1 3-C1 1 -methylindol-4-yl- 1.132 -Me -Cl 6-C1 3-C1 1-methylindol-5-yl- 1.133 -Me -Cl 6-C1 3-C1 1 -methylindol-6-yl- 1.134 -Me -Cl 6-C1 3-C1 1-naphthyl- 1.135 -Me -Cl 6-C1 3-C1 2-(trifluoromethyl)-4-quinolyl- 1.136 -Me -Cl 6-C1 3-C1 2-ethyl-1,3-benzoxazol-6-yl- 1.137 -Me -Cl 6-C1 3-C1 2-methyl-1,3-benzoxazol-6-yl- 1.138 -Me -Cl 6-C1 3-C1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.139 -Me -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1,140 -Me -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1.141 -Me -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1.142 -Me -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1.143 -Me -Cl 6-C1 3-C1 2-naphthyl- 1,144 -Me -Cl 6-C1 3-C1 4-quinolyl- 1.145 -CH ₂ C=CH -Me 6-F 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1.146 -CH ₂ C=CH -Me 6-F 3-F 1H-indol-4-yl- 1.147 -CH ₂ C=CH -Me 6-F 3-F 1H-indol-5-yl- 1.148 -CH ₂ C=CH -Me 6-F 3-F lH-indol-b-yl- 1.149 -CH ₂ C=CH -Me 6-F 3-F 1 -methylindol-4-yl- 1,150 -CH ₂ C=CH -Me 6-F 3-F 1-methylindol-5-yl- 1.151 -CH ₂ C=CH -Me 6-F 3-F 1 -methylindol-6-yl- 1.152 -CH ₂ C=CH -Me 6-F 3-F 1-naphthyl- 1.153 -CH ₂ C=CH -Me 6-F 3-F 2-(trifluoromethyl)-4-quinolyl- 1.154 -CH ₂ C=CH -Me 6-F 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1.155 -CH ₂ C=CH -Me 6-F 3-F 2-methyl-1,3-benzoxazol-6-yl- 1.156 -CH ₂ C=CH -Me 6-F 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.157 -CH ₂ C=CH -Me 6-F 3-F 2-methyl-6-quinolyl- 1.158 -CH ₂ C=CH -Me 6-F 3-F 2-methyl-6-quinolyl- 1.159 -CH ₂ C=CH -Me 6-F 3-F 2-methyl-6-quinolyl-

- 9 047300

1,160 -dn ₂ s = dn -Me 6-F 3-F 2-methyl-6-quinolyl- 1.161 -dn ₂ s = dn -Me 6-F 3-F 2-naphthyl- 1.162 -dn ₂ s = dn -Me 6-F 3-F 4-quinolyl- 1.163 -dn ₂ s = dn -Me 6-F 3-C1 1,2,3,4-tetrahydroquinolin-6-yl- 1.164 -dn ₂ s = dn -Me 6-F 3-C1 1H-indol-4-yl- 1.165 -dn ₂ s = dn -Me 6-F 3-C1 1H-indol-5-yl- 1.166 -dn ₂ s = dn -Me 6-F 3-C1 1N-IDOL-6-IL- 1.167 -dn ₂ s = dn -Me 6-F 3-C1 1 -methylindol-4-yl- 1.168 -dn ₂ s = dn -Me 6-F 3-C1 1-methylindol-5-yl- 1.169 -dn ₂ s = dn -Me 6-F 3-C1 1 -methylindol-6-yl- 1,170 -dn ₂ s = dn -Me 6-F 3-C1 1-naphthyl- 1.171 -dn ₂ s = dn -Me 6-F 3-C1 2-(trifluoromethyl)-4-quinolyl- 1.172 -dn ₂ s = dn -Me 6-F 3-C1 2-ethyl-1,3-benzoxazol-6-yl- 1.173 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-1,3-benzoxazol-6-yl- 1.174 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.175 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.176 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.177 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.178 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-6-quinolyl- 1.179 -dn ₂ s = dn -Me 6-F 3-C1 2-naphthyl- 1,180 -dn ₂ s = dn -Me 6-F 3-C1 4-quinolyl- 1.181 -dn ₂ s = dn -Me 6-C1 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1.182 -dn ₂ s = dn -Me 6-C1 3-F 1H-indol-4-yl- 1.183 -dn ₂ s = dn -Me 6-C1 3-F 1H-indol-5-yl-

- 10 047300

1,184 -dn ₂ s = dn -Me 6-C1 3-F ΙΗ-indol-b-yl- 1.185 -dn ₂ s = dn -Me 6-C1 3-F 1 -methylindol-4-yl- 1.186 -dn ₂ s = dn -Me 6-C1 3-F 1-methylindol-5-yl- 1,187 -dn ₂ s = dn -Me 6-C1 3-F 1 -methylindol-6-yl- 1,188 -dn ₂ s = dn -Me 6-C1 3-F 1-naphthyl- 1,189 -dn ₂ s = dn -Me 6-C1 3-F 2-(trifluoromethyl)-4-quinolyl- 1,190 -dn ₂ s = dn -Me 6-C1 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1.191 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-1,3-benzoxazol-6-yl- 1,192 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.193 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-6-quinolyl- 1,194 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-6-quinolyl- 1.195 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-6-quinolyl- 1,196 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-6-quinolyl- 1,197 -dn ₂ s = dn -Me 6-C1 3-F 2-naphthyl- 1,198 -dn ₂ s = dn -Me 6-C1 3-F 4-quinolyl- 1,199 -сн ₂ С=сн -Me 6-C1 3-C1 1,2,3,4-tetrahydroquinolin-6-yl- 1,200 -dn ₂ s = dn -Me 6-C1 3-C1 1H-indol-4-yl- 1.201 -dn ₂ s = dn -Me 6-C1 3-C1 1H-indol-5-yl- 1,202 -dn ₂ s = dn -Me 6-C1 3-C1 1H-indol-6-yl- 1.203 -dn ₂ s = dn -Me 6-C1 3-C1 1 -methylindol-4-yl- 1.204 -dn ₂ s = dn -Me 6-C1 3-C1 1-methylindol-5-yl- 1.205 -сн ₂ С=сн -Me 6-C1 3-C1 1 -methylindol-6-yl- 1.206 -dn ₂ s = dn -Me 6-C1 3-C1 1-naphthyl- 1.207 -dn ₂ s = dn -Me 6-C1 3-C1 2-(trifluoromethyl)-4-quinolyl-

- 11 047300

1.208 -dn ₂ s = dn -Me 6-C1 3-C1 2-ethyl-1,3-benzoxazol-6-yl- 1,209 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-1,3-benzoxazol-6-yl- 1.210 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.211 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1.212 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1.213 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1.214 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-6-quinolyl- 1.215 -dn ₂ s = dn -Me 6-C1 3-C1 2-naphthyl- 1.216 -dn ₂ s = dn -Me 6-C1 3-C1 4-quinolyl- 1.217 -dn ₂ s = dn -Cl 6-F 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1.218 -dn ₂ s = dn -Cl 6-F 3-F 1H-indol-4-yl- 1.219 -dn ₂ s = dn -Cl 6-F 3-F 1H-indol-5-yl- 1,220 -dn ₂ s = dn -Cl 6-F 3-F 1N-IDOL-6-IL- 1.221 -dn ₂ s = dn -Cl 6-F 3-F 1 -methylindol-4-yl- 1.222 -dn ₂ s = dn -Cl 6-F 3-F 1-methylindol-5-yl- 1.223 -сн ₂ С=сн -Cl 6-F 3-F 1 -methylindol-6-yl- 1.224 -dn ₂ s = dn -Cl 6-F 3-F 1-naphthyl- 1.225 -dn ₂ s = dn -Cl 6-F 3-F 2-(trifluoromethyl)-4-quinolyl- 1.226 -dn ₂ s = dn -Cl 6-F 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1.227 -dn ₂ s = dn -Cl 6-F 3-F 2-methyl-1,3-benzoxazol-6-yl- 1.228 -dn ₂ s = dn -Cl 6-F 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.229 -сн ₂ С=сн -Cl 6-F 3-F 2-methyl-6-quinolyl- 1,230 -dn ₂ s = dn -Cl 6-F 3-F 2-methyl-6-quinolyl- 1.231 -dn ₂ s = dn -Cl 6-F 3-F 2-methyl-6-quinolyl-

- 12 047300

1.232 -dn ₂ s = dn -C1 6-F 3-F 2-methyl-6-quinolyl- 1.233 -dn ₂ s = dn -C1 6-F 3-F 2-naphthyl- 1.234 -dn ₂ s = dn -C1 6-F 3-F 4-quinolyl- 1.235 -dn ₂ s = dn -C1 6-F 3-S1 1,2,3,4-tetrahydroquinolin-6-yl- 1.236 -dn ₂ s = dn -C1 6-F 3-S1 1H-indol-4-yl- 1.237 -dn ₂ s = dn -C1 6-F 3-S1 1H-indol-5-yl- 1.238 -dn ₂ s = dn -C1 6-F 3-S1 1H-INDOL-6-IL- 1.239 -dn ₂ s = dn -C1 6-F 3-S1 1 -methylindol-4-yl- 1,240 -dn ₂ s = dn -C1 6-F 3-S1 1-methylindol-5-yl- 1.241 -dn ₂ s = dn -C1 6-F 3-S1 1 -methylindol-6-yl- 1,242 -dn ₂ s = dn -C1 6-F 3-S1 1-naphthyl- 1.243 -CH ₂ s=dn -C1 6-F 3-S1 2-(trifluoromethyl)-4-quinolyl- 1,244 -dn ₂ s = dn -C1 6-F 3-S1 2-ethyl-1,3-benzoxazol-6-yl- 1.245 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-1,3-benzoxazol-6-yl- 1,246 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1,247 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-6-quinolyl- 1,248 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-6-quinolyl- 1,249 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-6-quinolyl- 1,250 -сн ₂ С=сн -C1 6-F 3-S1 2-methyl-6-quinolyl- 1.251 -dn ₂ s = dn -C1 6-F 3-S1 2-naphthyl- 1.252 -dn ₂ s = dn -C1 6-F 3-S1 4-quinolyl- 1.253 -dn ₂ s = dn -C1 6-S1 3-F 1,2,3,4-tetrahydroquinolin-6-yl- 1.254 -dn ₂ s = dn -C1 6-S1 3-F 1H-indol-4-yl- 1.255 -dn ₂ s = dn -C1 6-S1 3-F 1H-indol-5-yl-

- 13 047300

1.256 -dn ₂ s = dn -C1 6-S1 3-F 1H-indol-6-yl- 1.257 -dn ₂ s = dn -C1 6-S1 3-F 1 -methylindol-4-yl- 1.258 -dn ₂ s = dn -C1 6-S1 3-F 1-methylindol-5-yl- 1.259 -dn ₂ s = dn -C1 6-S1 3-F 1 -methylindol-6-yl- 1,260 -dn ₂ s = dn -C1 6-S1 3-F 1-naphthyl- 1.261 -dn ₂ s = dn -C1 6-S1 3-F 2-(trifluoromethyl)-4-quinolyl- 1.262 -dn ₂ s = dn -C1 6-S1 3-F 2-ethyl-1,3-benzoxazol-6-yl- 1.263 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-1,3-benzoxazol-6-yl- 1,264 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1.265 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-6-quinolyl- 1,266 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-6-quinolyl- 1.267 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-6-quinolyl- 1.268 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-6-quinolyl- 1,269 -dn ₂ s = dn -C1 6-S1 3-F 2-naphthyl- 1,270 -dn ₂ s = dn -C1 6-S1 3-F 4-quinolyl- 1.271 -CH ₂ C=CH -C1 6-S1 3-S1 1,2,3,4-tetrahydroquinolin-6-yl- 1.272 -dn ₂ s = dn -C1 6-S1 3-S1 1H-indol-4-yl- 1.273 -dn ₂ s = dn -C1 6-S1 3-S1 1H-indol-5-yl- 1.274 -dn ₂ s = dn -C1 6-S1 3-S1 1N-IDOL-6-IL- 1.275 -dn ₂ s = dn -C1 6-S1 3-S1 1 -methylindol-4-yl- 1.276 -dn ₂ s = dn -C1 6-S1 3-S1 1-methylindol-5-yl- 1.277 -сн ₂ С=сн -C1 6-S1 3-S1 1 -methylindol-6-yl- 1.278 -dn ₂ s = dn -C1 6-S1 3-S1 1-naphthyl- 1,279 -dn ₂ s = dn -C1 6-S1 3-S1 2-(trifluoromethyl)-4-quinolyl-

- 14 047300

1,280 -dn ₂ s = dn -Cl 6-C1 3-C1 2-ethyl-1,3-benzoxazol-6-yl- 1.281 -dn ₂ s = dn -Cl 6-C1 3-C1 2-methyl-1,3-benzoxazol-6-yl- 1,282 -dn ₂ s = dn -Cl 6-C1 3-C1 2-methyl-1,2,3,4tetrahydroquinolin-6-yl- 1,283 -dn ₂ s = dn -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1,284 -dn ₂ s = dn -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1.285 -dn ₂ s = dn -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1,286 -dn ₂ s = dn -Cl 6-C1 3-C1 2-methyl-6-quinolyl- 1,287 -dn ₂ s = dn -Cl 6-C1 3-C1 2-naphthyl- 1,288 -dn ₂ s = dn -Cl 6-C1 3-C1 4-quinolyl- 1,289 -Me -Me 6-F 3-F 2-methyl-5-1,3-benzothiazolyl- 1,290 -Me -Me 6-F 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1,291 -Me -Me 6-F 3-F 2-methyl-6-1,3-benzoxazolyl- 1,292 -Me -Me 6-F 3-F 2,2-d iforo-5 -1,3-benzodioxolyl- 1,293 -Me -Me 6-F 3-F 3-methyl-5-benzotriazolyl- 1,294 -Me -Me 6-F 3-F 1 -methyl-3-indazolyl- 1.295 -Me -Me 6-F 3-F 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1,296 -Me -Me 6-F 3-F 5-benzofuranyl- 1,297 -Me -Me 6-F 3-F 6-benzothiophenyl- 1,298 -Me -Me 6-F 3-F 5-benzothiophenyl- 1,299 -Me -Me 6-F 3-F 6-1,3-benzothiazolyl- 1,300 -Me -Me 6-F 3-F 5-1,3-benzothiazolyl- 1,301 -Me -Me 6-F 3-F 3-methyl-6-1,2-benzoxazolyl- 1,302 -Me -Me 6-F 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.303 -Me -Me 6-F 3-F 6-1 -methylindazolyl- 1,304 -Me -Me 6-F 3-F 5-1 -methylindazolyl- 1.305 -Me -Me 6-F 3-F 6-1 -methylindolyl- 1,306 -Me -Me 6-F 3-F 5-1 -methylindolyl- 1,307 -Me -Me 6-F 3-F 5 -2-oxoindolinyl- 1,308 -Me -Me 6-F 3-F 2-methyl-1,3-dioxoisoindolin-5 yl 1,309 -Me -Me 6-F 3-F 2-1,3-benzoxazolyl- 1,310 -Me -Me 6-F 3-F 2-1,3-benzothiazolyl 1.311 -Me -Me 6-F 3-F 5-2,2-dimethyl-1,3benzodioxolyl- 1.312 -Me -Me 6-F 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1.313 -Me -Me 6-F 3-F 6-imidazo[1,2-a]pyrazinyl- 1.314 -Me -Me 6-F 3-C1 2-methyl-5-1,3-benzothiazolyl- 1.315 -Me -Me 6-F 3-C1 2,2-dimethyl-6-3H-benzofuranyl- 1.316 -Me -Me 6-F 3-C1 2-methyl-6-1,3-benzoxazolyl-

- 15 047300

1.317 -Me -Me 6-F 3-C1 2,2-d iforo-5 -1,3-benzodioxolyl- 1.318 -Me -Me 6-F 3-C1 3-methyl-5-benzotriazolyl- 1.319 -Me -Me 6-F 3-C1 1-methyl-3-indazolyl- 1,320 -Me -Me 6-F 3-C1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.321 -Me -Me 6-F 3-C1 5-benzofuranyl- 1.322 -Me -Me 6-F 3-C1 6-benzothiophenyl- 1.323 -Me -Me 6-F 3-C1 5-benzothiophenyl- 1.324 -Me -Me 6-F 3-C1 6-1,3-benzothiazolyl- 1.325 -Me -Me 6-F 3-C1 5-1,3-benzothiazolyl- 1.326 -Me -Me 6-F 3-C1 3-methyl-6-1,2-benzoxazolyl- 1.327 -Me -Me 6-F 3-C1 5-2-oxo-3N-1,3-benzoxazolyl- 1.328 -Me -Me 6-F 3-C1 6-1 -methylindazolyl- 1.329 -Me -Me 6-F 3-C1 5-1 -methylindazolyl- 1,330 -Me -Me 6-F 3-C1 6-1 -methylindolyl- 1.331 -Me -Me 6-F 3-C1 5-1 -methylindolyl- 1.332 -Me -Me 6-F 3-C1 5 -2-oxoindolinyl- 1.333 -Me -Me 6-F 3-C1 2-methyl-1,3-dioxoisoin olin-5 yl 1.334 -Me -Me 6-F 3-C1 2-1,3-benzoxazolyl- 1.335 -Me -Me 6-F 3-C1 2-1,3-benzothiazolyl 1.336 -Me -Me 6-F 3-C1 5-2,2-dimethyl-1,3benzodioxolyl- 1.337 -Me -Me 6-F 3-C1 6-2,2-dimethyl-3N-benzofuranyl- 1.338 -Me -Me 6-F 3-C1 6-imidazo[1,2-a]pyrazinyl- 1.339 -Me -Me 6-C1 3-F 2-methyl-5-1,3-benzothiazolyl- 1,340 -Me -Me 6-C1 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1.341 -Me -Me 6-C1 3-F 2-methyl-6-1,3-benzoxazolyl- 1,342 -Me -Me 6-C1 3-F 2,2-d iforo-5 -1,3-benzodioxolyl- 1,343 -Me -Me 6-C1 3-F 3-methyl-5-benzotriazolyl- 1,344 -Me -Me 6-C1 3-F 1 -methyl-3-indazolyl- 1.345 -Me -Me 6-C1 3-F 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1,346 -Me -Me 6-C1 3-F 5-benzofuranyl- 1,347 -Me -Me 6-C1 3-F 6-benzothiophenyl- 1,348 -Me -Me 6-C1 3-F 5-benzothiophenyl- 1,349 -Me -Me 6-C1 3-F 6-1,3-benzothiazolyl- 1,350 -Me -Me 6-C1 3-F 5-1,3-benzothiazolyl- 1.351 -Me -Me 6-C1 3-F 3-methyl-6-1,2-benzoxazolyl- 1.352 -Me -Me 6-C1 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.353 -Me -Me 6-C1 3-F 6-1 -methylindazolyl- 1.354 -Me -Me 6-C1 3-F 5-1 -methylindazolyl- 1.355 -Me -Me 6-C1 3-F 6-1 -methylindolyl- 1.356 -Me -Me 6-C1 3-F 5-1 -methylindolyl- 1.357 -Me -Me 6-C1 3-F 5 -2-oxoind olinyl- 1.358 -Me -Me 6-C1 3-F 2-methyl-1,3-dioxoisoindolin-5yl 1.359 -Me -Me 6-C1 3-F 2-1,3-benzoxazolyl- 1,360 -Me -Me 6-C1 3-F 2-1,3-benzothiazolyl

- 16 047300

1,361 -Me -Me 6-C1 3-F 5-2,2-dimethyl-1,3benzodioxolyl- 1,362 -Me -Me 6-C1 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1,363 -Me -Me 6-C1 3-F 6-imidazo[1,2-a1pyrazinyl- 1,364 -Me -Me 6-C1 3-C1 2-methyl-5-1,3-benzothiazolyl- 1.365 -Me -Me 6-C1 3-C1 2,2-dimethyl-6-3H-benzofuranyl- 1,366 -Me -Me 6-C1 3-C1 2-methyl-6-1,3-benzoxazolyl- 1,367 -Me -Me 6-C1 3-C1 2,2-d iforo-5 -1,3-benzodioxolyl- 1,368 -Me -Me 6-C1 3-C1 3-methyl-5-benzotriazolyl- 1,369 -Me -Me 6-C1 3-C1 1-methyl-3-indazolyl- 1,370 -Me -Me 6-C1 3-C1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.371 -Me -Me 6-C1 3-C1 5-benzofuranyl- 1.372 -Me -Me 6-C1 3-C1 6-benzothiophenyl- 1.373 -Me -Me 6-C1 3-C1 5-benzothiophenyl- 1,374 -Me -Me 6-C1 3-C1 6-1,3-benzothiazolyl- 1.375 -Me -Me 6-C1 3-C1 5-1,3-benzothiazolyl- 1.376 -Me -Me 6-C1 3-C1 3-methyl-6-1,2-benzoxazolyl- 1.377 -Me -Me 6-C1 3-C1 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.378 -Me -Me 6-C1 3-C1 6-1 -methylindazolyl- 1.379 -Me -Me 6-C1 3-C1 5-1 -methylindazolyl- 1,380 -Me -Me 6-C1 3-C1 6-1 -methylindolyl- 1.381 -Me -Me 6-C1 3-C1 5-1 -methylindolyl- 1,382 -Me -Me 6-C1 3-C1 5 -2-oxoindolinyl- 1,383 -Me -Me 6-C1 3-C1 2-methyl-1,3-dioxoisoin olin-5 yl 1,384 -Me -Me 6-C1 3-C1 2-1,3-benzoxazolyl- 1.385 -Me -Me 6-C1 3-C1 2-1,3-benzothiazolyl 1,386 -Me -Me 6-C1 3-C1 5-2,2-dimethyl-1,3benzodioxolyl- 1,387 -Me -Me 6-C1 3-C1 6-2,2-dimethyl-3N-benzofuranyl- 1,388 -Me -Me 6-C1 3-C1 6-imidazo[1,2-a1pyrazinyl- 1,389 -Me -Cl 6-F 3-F 2-methyl-5-1,3-benzothiazolyl- 1,390 -Me -Cl 6-F 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1,391 -Me -Cl 6-F 3-F 2-methyl-6-1,3-benzoxazolyl- 1,392 -Me -Cl 6-F 3-F 2,2-d iforo-5 -1,3-benzodioxolyl- 1,393 -Me -Cl 6-F 3-F 3-methyl-5-benzotriazolyl- 1,394 -Me -Cl 6-F 3-F 1-methyl-3-indazolyl- 1.395 -Me -Cl 6-F 3-F 1-methyl-5-pyrrolo[2,3b1pyridinyl- 1,396 -Me -Cl 6-F 3-F 5-benzofuranyl- 1,397 -Me -Cl 6-F 3-F 6-benzothiophenyl- 1,398 -Me -Cl 6-F 3-F 5-benzothiophenyl- 1,399 -Me -Cl 6-F 3-F 6-1,3-benzothiazolyl- 1,400 -Me -Cl 6-F 3-F 5-1,3-benzothiazolyl- 1.401 -Me -Cl 6-F 3-F 3-methyl-6-1,2-benzoxazolyl- 1,402 -Me -Cl 6-F 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.403 -Me -Cl 6-F 3-F 6-1 -methylindazolyl- 1,404 -Me -Cl 6-F 3-F 5-1 -methylindazolyl-

- 17 047300

1.405 -Me -Cl 6-F 3-F 6-1 -methylindolyl- 1.406 -Me -Cl 6-F 3-F 5-1 -methylindolyl- 1,407 -Me -Cl 6-F 3-F 5 -2-oxoindolinyl- 1,408 -Me -Cl 6-F 3-F 2-methyl-1,3-dioxoisoindolin-5 yl 1,409 -Me -Cl 6-F 3-F 2-1,3-benzoxazolyl- 1,410 -Me -Cl 6-F 3-F 2-1,3-benzothiazolyl 1.411 -Me -Cl 6-F 3-F 5-2,2-dimethyl-1,3benzodioxolyl- 1.412 -Me -Cl 6-F 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1.413 -Me -Cl 6-F 3-F 6-imidazo[1,2-a]pyrazinyl- 1.414 -Me -Cl 6-F 3-C1 2-methyl-5-1,3-benzothiazolyl- 1.415 -Me -Cl 6-F 3-C1 2,2-dimethyl-6-3H-benzofuranyl- 1.416 -Me -Cl 6-F 3-C1 2-methyl-6-1,3-benzoxazolyl- 1.417 -Me -Cl 6-F 3-C1 2,2-d iforo-5 -1,3-benzodioxolyl- 1.418 -Me -Cl 6-F 3-C1 3-methyl-5-benzotriazolyl- 1.419 -Me -Cl 6-F 3-C1 1-methyl-3-indazolyl- 1,420 -Me -Cl 6-F 3-C1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.421 -Me -Cl 6-F 3-C1 5-benzofuranyl- 1.422 -Me -Cl 6-F 3-C1 6-benzothiophenyl- 1.423 -Me -Cl 6-F 3-C1 5-benzothiophenyl- 1.424 -Me -Cl 6-F 3-C1 6-1,3-benzothiazolyl- 1.425 -Me -Cl 6-F 3-C1 5-1,3-benzothiazolyl- 1.426 -Me -Cl 6-F 3-C1 3-methyl-6-1,2-benzoxazolyl- 1.427 -Me -Cl 6-F 3-C1 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.428 -Me -Cl 6-F 3-C1 6-1 -methylindazolyl- 1.429 -Me -Cl 6-F 3-C1 5-1 -methylindazolyl- 1,430 -Me -Cl 6-F 3-C1 6-1 -methylindolyl- 1.431 -Me -Cl 6-F 3-C1 5-1 -methylindolyl- 1.432 -Me -Cl 6-F 3-C1 5 -2-oxoindolinyl- 1.433 -Me -Cl 6-F 3-C1 2-methyl-1,3-dioxoisoindolin-5 yl 1.434 -Me -Cl 6-F 3-C1 2-1,3-benzoxazolyl- 1.435 -Me -Cl 6-F 3-C1 2-1,3-benzothiazolyl 1.436 -Me -Cl 6-F 3-C1 5-2,2-dimethyl-1,3benzodioxolyl- 1.437 -Me -Cl 6-F 3-C1 6-2,2-dimethyl-3N-benzofuranyl- 1.438 -Me -Cl 6-F 3-C1 6-imidazo[1,2-a]pyrazinyl- 1.439 -Me -Cl 6-C1 3-F 2-methyl-5-1,3-benzothiazolyl- 1,440 -Me -Cl 6-C1 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1.441 -Me -Cl 6-C1 3-F 2-methyl-6-1,3-benzoxazolyl- 1,442 -Me -Cl 6-C1 3-F 2,2-d iforo-5 -1,3-benzodioxolyl- 1.443 -Me -Cl 6-C1 3-F 3-methyl-5-benzotriazolyl- 1,444 -Me -Cl 6-C1 3-F 1-methyl-3-indazolyl- 1.445 -Me -Cl 6-C1 3-F 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1,446 -Me -Cl 6-C1 3-F 5-benzofuranyl- 1.447 -Me -Cl 6-C1 3-F 6-benzothiophenyl-

- 18 047300

1,448 -Me -Cl 6-C1 3-F 5-benzothiophenyl- 1,449 -Me -Cl 6-C1 3-F 6-1,3-benzothiazolyl- 1,450 -Me -Cl 6-C1 3-F 5-1,3-benzothiazolyl- 1.451 -Me -Cl 6-C1 3-F 3-methyl-6-1,2-benzoxazolyl- 1.452 -Me -Cl 6-C1 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.453 -Me -Cl 6-C1 3-F 6-1 -methylindazolyl- 1.454 -Me -Cl 6-C1 3-F 5-1 -methylindazolyl- 1.455 -Me -Cl 6-C1 3-F 6-1 -methylindolyl- 1.456 -Me -Cl 6-C1 3-F 5-1 -methylindolyl- 1.457 -Me -Cl 6-C1 3-F 5 -2-oxoindolinyl- 1.458 -Me -Cl 6-C1 3-F 2-methyl-1,3-dioxoisoindolin-5 yl 1.459 -Me -Cl 6-C1 3-F 2-1,3-benzoxazolyl- 1,460 -Me -Cl 6-C1 3-F 2-1,3-benzothiazolyl 1.461 -Me -Cl 6-C1 3-F 5-2,2-dimethyl-1,3benzodioxolyl- 1.462 -Me -Cl 6-C1 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1.463 -Me -Cl 6-C1 3-F 6-imidazo[1,2-a]pyrazinyl- 1,464 -Me -Cl 6-C1 3-C1 2-methyl-5-1,3-benzothiazolyl- 1.465 -Me -Cl 6-C1 3-C1 2,2-dimethyl-6-3H-benzofuranyl- 1,466 -Me -Cl 6-C1 3-C1 2-methyl-6-1,3-benzoxazolyl- 1.467 -Me -Cl 6-C1 3-C1 2,2-d iforo-5 -1,3-benzodioxolyl- 1.468 -Me -Cl 6-C1 3-C1 3-methyl-5-benzotriazolyl- 1,469 -Me -Cl 6-C1 3-C1 1-methyl-3-indazolyl- 1,470 -Me -Cl 6-C1 3-C1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.471 -Me -Cl 6-C1 3-C1 5-benzofuranyl- 1.472 -Me -Cl 6-C1 3-C1 6-benzothiophenyl- 1.473 -Me -Cl 6-C1 3-C1 5-benzothiophenyl- 1.474 -Me -Cl 6-C1 3-C1 6-1,3-benzothiazolyl- 1.475 -Me -Cl 6-C1 3-C1 5-1,3-benzothiazolyl- 1.476 -Me -Cl 6-C1 3-C1 3-methyl-6-1,2-benzoxazolyl- 1.477 -Me -Cl 6-C1 3-C1 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.478 -Me -Cl 6-C1 3-C1 6-1 -methylindazolyl- 1.479 -Me -Cl 6-C1 3-C1 5-1 -methylindazolyl- 1,480 -Me -Cl 6-C1 3-C1 6-1 -methylindolyl- 1.481 -Me -Cl 6-C1 3-C1 5-1 -methylindolyl- 1.482 -Me -Cl 6-C1 3-C1 5 -2-oxoindolinyl- 1.483 -Me -Cl 6-C1 3-C1 2-methyl-1,3-dioxoisoindolin-5 yl 1,484 -Me -Cl 6-C1 3-C1 2-1,3-benzoxazolyl- 1.485 -Me -Cl 6-C1 3-C1 2-1,3-benzothiazolyl 1,486 -Me -Cl 6-C1 3-C1 5-2,2-dimethyl-1,3benzodioxolyl- 1,487 -Me -Cl 6-C1 3-C1 6-2,2-dimethyl-3N-benzofuranyl- 1,488 -Me -Cl 6-C1 3-C1 6-imidazo[1,2-a]pyrazinyl- 1,489 -CH ₂ C=CH -Me 6-F 3-F 2-methyl-5-1,3-benzothiazolyl-

- 19 047300

1,490 -dn ₂ s = dn -Me 6-F 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1,491 -dn ₂ s = dn -Me 6-F 3-F 2-methyl-6-1,3-benzoxazolyl- 1,492 -dn ₂ s = dn -Me 6-F 3-F 2,2-d iforo-5 -1,3 -benzode ioxolyl- 1,493 -dn ₂ s = dn -Me 6-F 3-F 3-methyl-5-benzotriazolyl- 1,494 -dn ₂ s = dn -Me 6-F 3-F 1 -methyl-3 -indazol yl- 1.495 -dn ₂ s = dn -Me 6-F 3-F 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1,496 -dn ₂ s = dn -Me 6-F 3-F 5-benzofuranyl- 1,497 -dn ₂ s = dn -Me 6-F 3-F 6-benzothiophenyl- 1,498 -dn ₂ s = dn -Me 6-F 3-F 5-benzothiophenyl- 1,499 -dn ₂ s = dn -Me 6-F 3-F 6-1,3-benzothiazolyl- 1,500 -dn ₂ s = dn -Me 6-F 3-F 5-1,3-benzothiazolyl- 1,501 -dn ₂ s = dn -Me 6-F 3-F 3-methyl-6-1,2-benzoxazolyl- 1,502 -dn ₂ s = dn -Me 6-F 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1,503 -dn ₂ s = dn -Me 6-F 3-F 6-1 -methylindazolyl- 1,504 -dn ₂ s = dn -Me 6-F 3-F 5-1 -methylindazolyl- 1.505 -dn ₂ s = dn -Me 6-F 3-F 6-1 -methylindolyl- 1,506 -dn ₂ s = dn -Me 6-F 3-F 5-1 -methylindolyl- 1,507 -dn ₂ s = dn -Me 6-F 3-F 5 -2-oxoindolinyl- 1,508 -dn ₂ s = dn -Me 6-F 3-F 2-methyl-1,3-dioxoisoindolin-5 yl 1,509 -dn ₂ s = dn -Me 6-F 3-F 2-1,3-benzoxazolyl- 1,510 -dn ₂ s = dn -Me 6-F 3-F 2-1,3-benzothiazolyl 1,511 -dn ₂ s = dn -Me 6-F 3-F 5-2,2-dimethyl-1,3benzodioxolyl- 1.512 -dn ₂ s = dn -Me 6-F 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1,513 -сн ₂ С=сн -Me 6-F 3-F 6-imidazo[1,2-a]pyrazinyl-

- 20 047300

1,514 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-5-1,3-benzothiazolyl- 1.515 -dn ₂ s = dn -Me 6-F 3-C1 2,2-dimethyl-6-3H-benzofuranyl- 1.516 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-6-1,3-benzoxazolyl- 1.517 -dn ₂ s = dn -Me 6-F 3-C1 2,2-d iforo-5 -1,3-benzodioxolyl- 1.518 -dn ₂ s = dn -Me 6-F 3-C1 3-methyl-5-benzotriazolyl- 1,519 -dn ₂ s = dn -Me 6-F 3-C1 1-methyl-3-indazolyl- 1,520 -dn ₂ s = dn -Me 6-F 3-C1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.521 -сн ₂ С=сн -Me 6-F 3-C1 5-benzofuranyl- 1.522 -dn ₂ s = dn -Me 6-F 3-C1 6-benzothiophenyl- 1.523 -dn ₂ s = dn -Me 6-F 3-C1 5-benzothiophenyl- 1.524 -dn ₂ s = dn -Me 6-F 3-C1 6-1,3-benzothiazolyl- 1.525 -dn ₂ s = dn -Me 6-F 3-C1 5-1,3-benzothiazolyl- 1.526 -dn ₂ s = dn -Me 6-F 3-C1 3-methyl-6-1,2-benzoxazolyl- 1.527 -dn ₂ s = dn -Me 6-F 3-C1 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.528 -dn ₂ s = dn -Me 6-F 3-C1 6-1 -methylindazolyl- 1.529 -dn ₂ s = dn -Me 6-F 3-C1 5-1 -methylindazolyl- 1,530 -dn ₂ s = dn -Me 6-F 3-C1 6-1 -methylindolyl- 1.531 -dn ₂ s = dn -Me 6-F 3-C1 5-1 -methylindolyl- 1.532 -dn ₂ s = dn -Me 6-F 3-C1 5 -2-oxoindolinyl- 1.533 -dn ₂ s = dn -Me 6-F 3-C1 2-methyl-1,3-dioxoisoindolin-5 yl 1.534 -dn ₂ s = dn -Me 6-F 3-C1 2-1,3-benzoxazolyl- 1.535 -dn ₂ s = dn -Me 6-F 3-C1 2-1,3-benzothiazolyl 1.536 -dn ₂ s = dn -Me 6-F 3-C1 5-2,2-dimethyl-1,3benzodioxolyl- 1.537 -dn ₂ s = dn -Me 6-F 3-C1 6-2,2-dimethyl-3N-benzofuranyl-

- 21 047300

1.538 -dn ₂ s = dn -Me 6-F 3-C1 6-imidazo[1,2-a]pyrazinyl- 1.539 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-5-1,3-benzothiazolyl- 1,540 -dn ₂ s = dn -Me 6-C1 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1,541 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-6-1,3-benzoxazolyl- 1,542 -dn ₂ s = dn -Me 6-C1 3-F 2,2-d iforo-5 -1,3 -benzode ioxolyl- 1,543 -dn ₂ s = dn -Me 6-C1 3-F 3-methyl-5-benzotriazolyl- 1,544 -dn ₂ s = dn -Me 6-C1 3-F 1-methyl-3-indazolyl- 1.545 -dn ₂ s = dn -Me 6-C1 3-F 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1,546 -dn ₂ s = dn -Me 6-C1 3-F 5-benzofuranyl- 1,547 -dn ₂ s = dn -Me 6-C1 3-F 6-benzothiophenyl- 1,548 -dn ₂ s = dn -Me 6-C1 3-F 5-benzothiophenyl- 1,549 -dn ₂ s = dn -Me 6-C1 3-F 6-1,3-benzothiazolyl- 1,550 -dn ₂ s = dn -Me 6-C1 3-F 5-1,3-benzothiazolyl- 1.551 -dn ₂ s = dn -Me 6-C1 3-F 3-methyl-6-1,2-benzoxazolyl- 1.552 -dn ₂ s = dn -Me 6-C1 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.553 -dn ₂ s = dn -Me 6-C1 3-F 6-1 -methylindazolyl- 1.554 -dn ₂ s = dn -Me 6-C1 3-F 5-1 -methylindazolyl- 1.555 -dn ₂ s = dn -Me 6-C1 3-F 6-1 -methylindolyl- 1.556 -dn ₂ s = dn -Me 6-C1 3-F 5-1 -methylindolyl- 1.557 -dn ₂ s = dn -Me 6-C1 3-F 5 -2-oxoindolinyl- 1.558 -dn ₂ s = dn -Me 6-C1 3-F 2-methyl-1,3-dioxoisoindolin-5 yl 1.559 -dn ₂ s = dn -Me 6-C1 3-F 2-1,3-benzoxazolyl- 1,560 -dn ₂ s = dn -Me 6-C1 3-F 2-1,3-benzothiazolyl 1,561 -сн ₂ С=сн -Me 6-C1 3-F 5-2,2-dimethyl-1,3benzodioxolyl-

- 22 047300

1,562 -dn ₂ s = dn -Me 6-C1 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1,563 -dn ₂ s = dn -Me 6-C1 3-F 6-imidazo[1,2-a]pyrazinyl- 1,564 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-5-1,3-benzothiazolyl- 1.565 -dn ₂ s = dn -Me 6-C1 3-C1 2,2-dimethyl-6-3H-benzofuranyl- 1,566 -dn ₂ s = dn -Me 6-C1 3-C1 2-methyl-6-1,3-benzoxazolyl- 1,567 -dn ₂ s = dn -Me 6-C1 3-C1 2,2-d iforo-5 -1,3-benzodioxolyl- 1,568 -dn ₂ s = dn -Me 6-C1 3-C1 3-methyl-5-benzotriazolyl- 1,569 -dn ₂ s = dn -Me 6-C1 3-C1 1-methyl-3-indazolyl- 1,570 -dn ₂ s = dn -Me 6-C1 3-C1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.571 -dn ₂ s = dn -Me 6-C1 3-C1 5-benzofuranyl- 1,572 -dn ₂ s = dn -Me 6-C1 3-C1 6-benzothiophenyl- 1.573 -dn ₂ s = dn -Me 6-C1 3-C1 5-benzothiophenyl- 1,574 -dn ₂ s = dn -Me 6-C1 3-C1 6-1,3-benzothiazolyl- 1.575 -dn ₂ s = dn -Me 6-C1 3-C1 5-1,3-benzothiazolyl- 1.576 -dn ₂ s = dn -Me 6-C1 3-C1 3-methyl-6-1,2-benzoxazolyl- 1.577 -сн ₂ С=сн -Me 6-C1 3-C1 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.578 -dn ₂ s = dn -Me 6-C1 3-C1 6-1 -methylindazolyl- 1,579 -dn ₂ s = dn -Me 6-C1 3-C1 5-1 -methylindazolyl- 1,580 -dn ₂ s = dn -Me 6-C1 3-C1 6-1 -methylindolyl- 1,581 -dn ₂ s = dn -Me 6-C1 3-C1 5-1 -methylindolyl- 1,582 -dn ₂ s = dn -Me 6-C1 3-C1 5 -2-oxoindolinyl- 1,583 -сн ₂ С=сн -Me 6-C1 3-C1 2-methyl-1,3-dioxoisoindolin-5 yl 1,584 -dn ₂ s = dn -Me 6-C1 3-C1 2-1,3-benzoxazolyl- 1.585 -dn ₂ s = dn -Me 6-C1 3-C1 2-1,3-benzothiazolyl

- 23 047300

1,586 -dn ₂ s = dn -Me 6-C1 3-C1 5-2,2-dimethyl-1,3benzodioxolyl- 1,587 -dn ₂ s = dn -Me 6-C1 3-C1 6-2,2-dimethyl-3N-benzofuranyl- 1,588 -dn ₂ s = dn -Me 6-C1 3-C1 6-imidazo[1,2-a]pyrazinyl- 1,589 -dn ₂ s = dn -Cl 6-F 3-F 2-methyl-5-1,3-benzothiazolyl- 1,590 -dn ₂ s = dn -Cl 6-F 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1,591 -dn ₂ s = dn -Cl 6-F 3-F 2-methyl-6-1,3-benzoxazolyl- 1,592 -dn ₂ s = dn -Cl 6-F 3-F 2,2-d iforo-5 -1,3-benzodioxolyl- 1,593 -dn ₂ s = dn -Cl 6-F 3-F 3-methyl-5-benzotriazolyl- 1,594 -dn ₂ s = dn -Cl 6-F 3-F 1-methyl-3-indazolyl- 1,595 -dn ₂ s = dn -Cl 6-F 3-F 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1,596 -dn ₂ s = dn -Cl 6-F 3-F 5-benzofuranyl- 1,597 -dn ₂ s = dn -Cl 6-F 3-F 6-benzothiophenyl- 1,598 -dn ₂ s = dn -Cl 6-F 3-F 5-benzothiophenyl- 1,599 -dn ₂ s = dn -Cl 6-F 3-F 6-1,3-benzothiazolyl- 1,600 -dn ₂ s = dn -Cl 6-F 3-F 5-1,3-benzothiazolyl- 1.601 -сн ₂ С=сн -Cl 6-F 3-F 3-methyl-6-1,2-benzoxazolyl- 1.602 -dn ₂ s = dn -Cl 6-F 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.603 -dn ₂ s = dn -Cl 6-F 3-F 6-1 -methylindazolyl- 1,604 -dn ₂ s = dn -Cl 6-F 3-F 5-1 -methylindazolyl- 1.605 -dn ₂ s = dn -Cl 6-F 3-F 6-1 -methylindolyl- 1.606 -dn ₂ s = dn -Cl 6-F 3-F 5-1 -methylindolyl- 1.607 -сн ₂ С=сн -Cl 6-F 3-F 5 -2-oxoindolinyl- 1,608 -dn ₂ s = dn -Cl 6-F 3-F 2-methyl-1,3-dioxoisoindolin-5 yl 1,609 -dn ₂ s = dn -Cl 6-F 3-F 2-1,3-benzoxazolyl-

- 24 047300

1,610 -dn ₂ s = dn -C1 6-F 3-F 2-1,3-benzothiazolyl 1.611 -dn ₂ s = dn -C1 6-F 3-F 5-2,2-dimethyl-1,3benzodioxolyl- 1.612 -dn ₂ s = dn -C1 6-F 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1.613 -dn ₂ s = dn -C1 6-F 3-F 6-imidazo[1,2-a]pyrazinyl- 1.614 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-5-1,3-benzothiazolyl- 1.615 -dn ₂ s = dn -C1 6-F 3-S1 2,2-dimethyl-6-3H-benzofuranyl- 1.616 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-6-1,3-benzoxazolyl- 1.617 -dn ₂ s = dn -C1 6-F 3-S1 2,2-d iforo-5 -1,3-benzodioxolyl- 1.618 -dn ₂ s = dn -C1 6-F 3-S1 3-methyl-5-benzotriazolyl- 1.619 -dn ₂ s = dn -C1 6-F 3-S1 1 -methyl-3-indazolyl- 1,620 -dn ₂ s = dn -C1 6-F 3-S1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.621 -dn ₂ s = dn -C1 6-F 3-S1 5-benzofuranyl- 1.622 -dn ₂ s = dn -C1 6-F 3-S1 6-benzothiophenyl- 1.623 -dn ₂ s = dn -C1 6-F 3-S1 5-benzothiophenyl- 1.624 -dn ₂ s = dn -C1 6-F 3-S1 6-1,3-benzothiazolyl- 1.625 -сн ₂ С=сн -C1 6-F 3-S1 5-1,3-benzothiazolyl- 1.626 -dn ₂ s = dn -C1 6-F 3-S1 3-methyl-6-1,2-benzoxazolyl- 1.627 -dn ₂ s = dn -C1 6-F 3-S1 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.628 -dn ₂ s = dn -C1 6-F 3-S1 6-1 -methylindazolyl- 1.629 -dn ₂ s = dn -C1 6-F 3-S1 5-1 -methylindazolyl- 1,630 -dn ₂ s = dn -C1 6-F 3-S1 6-1 -methylindolyl- 1.631 -сн ₂ С=сн -C1 6-F 3-S1 5-1 -methylindolyl- 1.632 -dn ₂ s = dn -C1 6-F 3-S1 5 -2-oxoindolinyl- 1.633 -dn ₂ s = dn -C1 6-F 3-S1 2-methyl-1,3-dioxoisoindolin-5 yl

- 25 047300

1.634 -dn ₂ s = dn -C1 6-F 3-S1 2-1,3-benzoxazolyl- 1.635 -dn ₂ s = dn -C1 6-F 3-S1 2-1,3-benzothiazolyl 1.636 -dn ₂ s = dn -C1 6-F 3-S1 5-2,2-dimethyl-1,3benzodioxolyl- 1.637 -dn ₂ s = dn -C1 6-F 3-S1 6-2,2-dimethyl-3N-benzofuranyl- 1.638 -dn ₂ s = dn -C1 6-F 3-S1 6-imidazo[1,2-a]pyrazinyl- 1.639 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-5-1,3-benzothiazolyl- 1,640 -dn ₂ s = dn -C1 6-S1 3-F 2,2-dimethyl-6-3H-benzofuranyl- 1.641 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-6-1,3-benzoxazolyl- 1.642 -dn ₂ s = dn -C1 6-S1 3-F 2,2-d iforo-5 -1,3-benzodioxolyl- 1.643 -dn ₂ s = dn -C1 6-S1 3-F 3-methyl-5-benzotriazolyl- 1,644 -dn ₂ s = dn -C1 6-S1 3-F 1-methyl-3-indazolyl- 1.645 -dn ₂ s = dn -C1 6-S1 3-F 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.646 -dn ₂ s = dn -C1 6-S1 3-F 5-benzofuranyl- 1.647 -dn ₂ s = dn -C1 6-S1 3-F 6-benzothiophenyl- 1,648 -dn ₂ s = dn -C1 6-S1 3-F 5-benzothiophenyl- 1,649 -dn ₂ s = dn -C1 6-S1 3-F 6-1,3-benzothiazolyl- 1,650 -dn ₂ s = dn -C1 6-S1 3-F 5-1,3-benzothiazolyl- 1.651 -dn ₂ s = dn -C1 6-S1 3-F 3-methyl-6-1,2-benzoxazolyl- 1.652 -dn ₂ s = dn -C1 6-S1 3-F 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.653 -dn ₂ s = dn -C1 6-S1 3-F 6-1 -methylindazolyl- 1.654 -dn ₂ s = dn -C1 6-S1 3-F 5-1 -methylindazolyl- 1.655 -dn ₂ s = dn -C1 6-S1 3-F 6-1 -methylindolyl- 1.656 -dn ₂ s = dn -C1 6-S1 3-F 5-1 -methylindolyl- 1.657 -сн ₂ С=сн -C1 6-S1 3-F 5 -2-oxoindolinyl-

- 26 047300

1.658 -dn ₂ s = dn -C1 6-S1 3-F 2-methyl-1,3-dioxoisoindolin-5 yl 1.659 -dn ₂ s = dn -C1 6-S1 3-F 2-1,3-benzoxazolyl- 1,660 -dn ₂ s = dn -C1 6-S1 3-F 2-1,3-benzothiazolyl 1.661 -dn ₂ s = dn -C1 6-S1 3-F 5-2,2-dimethyl-1,3benzodioxolyl- 1.662 -dn ₂ s = dn -C1 6-S1 3-F 6-2,2-dimethyl-3N-benzofuranyl- 1.663 -dn ₂ s = dn -C1 6-S1 3-F 6-imidazo[1,2-a]pyrazinyl- 1.664 -dn ₂ s = dn -C1 6-S1 3-S1 2-methyl-5-1,3-benzothiazolyl- 1.665 -dn ₂ s = dn -C1 6-S1 3-S1 2,2-dimethyl-6-3H-benzofuranyl- 1.666 -dn ₂ s = dn -C1 6-S1 3-S1 2-methyl-6-1,3-benzoxazolyl- 1.667 -dn ₂ s = dn -C1 6-S1 3-S1 2,2-d iforo-5 -1,3-benzodioxolyl- 1.668 -dn ₂ s = dn -C1 6-S1 3-S1 3-methyl-5-benzotriazolyl- 1,669 -dn ₂ s = dn -C1 6-S1 3-S1 1-methyl-3-indazolyl- 1,670 -dn ₂ s = dn -C1 6-S1 3-S1 1-methyl-5-pyrrolo[2,3b]pyridinyl- 1.671 -dn ₂ s = dn -C1 6-S1 3-S1 5-benzofuranyl- 1.672 -dn ₂ s = dn -C1 6-S1 3-S1 6-benzothiophenyl- 1.673 -dn ₂ s = dn -C1 6-S1 3-S1 5-benzothiophenyl- 1.674 -dn ₂ s = dn -C1 6-S1 3-S1 6-1,3-benzothiazolyl- 1.675 -dn ₂ s = dn -C1 6-S1 3-S1 5-1,3-benzothiazolyl- 1.676 -dn ₂ s = dn -C1 6-S1 3-S1 3-methyl-6-1,2-benzoxazolyl- 1.677 -dn ₂ s = dn -C1 6-S1 3-S1 5 -2-oxo-ZN-1,3-benzoxazolyl- 1.678 -dn ₂ s = dn -C1 6-S1 3-S1 6-1 -methylindazolyl- 1.679 -dn ₂ s = dn -C1 6-S1 3-S1 5-1 -methylindazolyl- 1,680 -dn ₂ s = dn -C1 6-S1 3-S1 6-1 -methylindolyl- 1.681 -dn ₂ s = dn -C1 6-S1 3-S1 5-1 -methylindolyl-

- 27 047300

1.682 -CH ₂ s=dn -C1 6-S1 3-S1 5 -2-oxoindolinyl- 1.683 -CH ₂ s=dn -C1 6-S1 3-S1 2-methyl-1,3-dioxoisoindolin-5 yl 1.684 -CH ₂ s=dn -C1 6-S1 3-S1 2-1,3-benzoxazolyl- 1.685 -CH ₂ dc -C1 6-S1 3-S1 2-1,3-benzothiazolyl 1.686 -CH ₂ s=dn -C1 6-S1 3-S1 5 -2,2-dimethyl-1,3benzodioxolyl- 1.687 -dn ₂ CCII -C1 6-S1 3-S1 6-2,2-dimethyl-3N-benzofuranyl- 1.688 -SN ₂ - CCII -C1 6-S1 3-S1 6-imidazo[1,2-a]pyrazinyl-

In table 2 shows 688 compounds A-2.001 - A-2.688 of formula (I), as shown above, where G represents hydrogen, W represents (E)-CH=CH-, and R ¹ , R ² , X, Y, D are as defined for compounds Nos. 1.001-1.688, respectively, in Table. And higher.

In table 3 shows 688 compounds A-3.001 - A-3.688 of formula (I), as shown above, where G represents -(C=O)iPr, W represents -CH2-CH2-, and R ¹ , R ² , X, Y, D are as defined for compounds Nos. 1.001-1.288, respectively, in table. And higher.

In table 4 shows 688 compounds A-4.001 - A-4.688 of formula (I), as shown above, where G represents -(C=O)iPr, W represents (E)-CH=CH-, and R ¹ , R ² , X, Y, D are as defined for compounds Nos. 1.001-1.288, respectively, in table. And higher.

The compounds of the present invention can be prepared in accordance with the following schemes, in which the substituents R ¹ , R ² , R ³ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , W, D, G, X, Y, Z and m have (unless expressly stated otherwise) the definitions described above herein.

Some compounds (I-ii) of the present invention can be prepared from compounds (2) as shown in Reaction Scheme 1. Compounds (I-ii) are compounds of formula (I) in which W is -CH2-CH2-.

Reaction scheme 1.

Compounds (I-ii) can be prepared by catalytic hydrogenation of compounds (2) with hydrogen gas in a suitable solvent [such as tetrahydrofuran, methanol, ethanol, acetic acid or ethyl acetate] in the presence of a suitable catalyst [such as Pd/C, Pd/CaCO ^ Rh/Al ₂ CO ₃ or sponge nickel] at temperatures from -10 to 100°C.

Alternatively, compounds (I-ii) can also be prepared by catalytic transfer hydrogenation of compounds (2) by treatment with a suitable source of hydrogen in a suitable solvent in the presence of a suitable catalyst at a temperature of -10 to 100°C. Examples of suitable systems are tetrahydroxydiboron in dichloromethane/water or dichloromethane/methanol mixtures in the presence of Pd/C, Pd(OAc)2 or Pd(OH) ₂ /C (J. Am. Chem. Soc, 2016, 138, 6107-6110 ) or diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate in ethanol in the presence of Pd/C (Tetrahedron Letters, 2009, 50, 1026).

Alternatively, compounds (I-ii) can also be prepared by reduction with a diimide prepared in-situ from a suitable precursor in a suitable solvent at a temperature of -10 to 200°C. Examples of suitable reagents for preparing the diimide include substituted arylsulfonylhydrazides such as 2,4,6-triisopropylbenzenesulfonylhydrazide, optionally in the presence of a suitable base. Examples of suitable bases include triethylamine, diisopropylethylamine, potassium carbonate and sodium carbonate. Suitable solvents include tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetonitrile and dimethylformamide.

Compounds (2) can be prepared from compounds (3) and compounds (4) as shown in Reaction Scheme 2, according to either the described Suzuki reaction protocol or the described Heck reaction protocol. When using the Suzuki reaction protocol, compounds (4) are organoboron compounds such as boronic acids, boronic esters or salts representing

- 28 047300 is potassium trifluoroborate. Using the Heck reaction protocol, compounds (4) are styrenes.

Reaction scheme 2.

Suzuki reaction protocol.

Compounds (2) can be prepared by treating compounds (3) with compounds (4) in the presence of a suitable base and a suitable catalyst in a suitable solvent at a temperature of from 10 to 150°C. Examples of suitable bases are potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate and potassium fluoride. Examples of suitable catalysts are the complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane [PdCl2(dppf)-DCM], tetrakis(triphenylphosphine)palladium(0) [Pd(PPh ₃ ) ₄ ] and the catalyst system , formed in situ from a mixture of palladium(II) acetate and triphenylphosphine. Examples of suitable solvents are water, 1,4dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile and toluene. Many compounds (4) are commercially available [such as 4,4,5,5-tetramethyl-2-[(E)-2-(2-naphthyl)vinyl]-1,3,2dioxaborolane] or can be prepared using known methods. Examples of compounds (3) that are particularly useful in the Suzuki reaction protocol are the isobutyryl esters (3-i) wherein G is isobutyryl.

One skilled in the art will appreciate that the conditions of the Suzuki reaction protocol may allow for the cleavage of ester groups, therefore Reaction Scheme 2 may also describe a reaction where starting material (3) contains an ester moiety [so G is an acyl group] but the product (2) does not contain [so G represents hydrogen].

Heck reaction protocol.

Compounds (2) can be prepared by treating compounds (3) with compounds (4) in the presence of a suitable base and a suitable catalyst at a temperature of from 10 to 150°C. Optionally, additional solvent may be included. Examples of suitable bases are triethylamine, morpholine, N-methylmorpholine, diisopropylethylamine and pyridine. Examples of suitable catalysts are tetrakis(triphenylphosphine)palladium(0) [Pd(PPh ₃ ) ₄ ], a catalyst system formed in-situ from a mixture of palladium(II) acetate and triphenylphosphine, a catalytic system formed in-situ from a mixture of tris(dibenzylideneacetone )dipalladium(0) and tri-tert-butylphosphonium tetrafluoroborate, and a catalyst system formed in-situ from a palladium cyclic precatalyst such as chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(P). Examples of optional additional solvent are 1,4-dioxane, tetrahydrofuran, acetonitrile and toluene. Many compounds (4) are commercially available [such as 2-vinylnaphthalene] or can be prepared using known methods. Examples of compounds (3) with particular utility in the Heck reaction protocol are the isobutyryl esters (3-i), where G is isobutyryl.

Compounds (3-i) can be prepared from compounds (5) as shown in Reaction Scheme 3.

Reaction scheme 3.

- 29 047300

Compounds (3-i) can be prepared by treating compounds (5) with isobutyryl chloride in a suitable solvent [such as dichloromethane, acetonitrile and toluene] in the presence of a suitable base [such as triethylamine, diisopropylethylamine or pyridine] at a temperature of -10 to 60° WITH. Optionally, a catalyst [such as 4-(dimethylamino)pyridine] may be included.

Compounds (5) can be prepared from compounds (6) as shown in Reaction Scheme 4 by heating compounds (6) with a base (such as 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hexamethyldisilazide or hexamethyldisilazide lithium) in a solvent [such as acetonitrile, H,H-dimethylformamide or toluene] at a temperature of 50 to 200°C. Traditional heating or microwave heating may be used.

Reaction scheme 4.

Compounds (6) can be prepared from phenylacetic acids (7) as shown in Reaction Scheme 5.

Reaction scheme 5.

ethanol

For Reaction Scheme 5, example hydrazines (8) is methylhydrazine, and example ketoesters (10) is ethyl pyruvate. An example of hydrazones (9) is ethyl (2E^)-2-(methylhydrazono)propanoate, prepared in accordance with the methods described in the patent application according to PCT WO 2016/008816. An example of phenylacetic acids (7) is (2-bromo-6-fluorophenyl)acetic acid, which can be synthesized according to reaction scheme 10. An additional example of phenylacetic acids (7) is (2-bromo-3-chloro-6fluorophenyl)acetic acid, which can be synthesized according to reaction scheme 11.

Some compounds (I-iii) of the present invention can be prepared from compounds (11) as shown in Reaction Scheme 6, or from compounds (I-iv) as shown in Reaction Scheme 12. Compounds (I-iii) are compounds formula (I) in which W represents -CH ₂ -CH ₂ - and G represents hydrogen.

- 30 047300

Reaction scheme 6.

Compounds (I-iii) can be prepared by heating compounds (11) with a base (such as 1,8diazabicyclo[5.4.0]undec-7-ene, sodium hexamethyldisilazide or lithium hexamethyldisilazide) in a solvent [such as acetonitrile, N,N- dimethylformamide or toluene] at temperatures from 50 to 200°C. Traditional heating or microwave heating may be used.

Compounds (11) can be prepared from compounds (12) as shown in Reaction Scheme 7 below.

Reaction scheme 7.

ethanol

Compounds (12) can be prepared from compounds (13) as shown in Reaction Scheme 8. A variety of compounds (13) are commercially available [such as methyl 2-phenylacetate and methyl 2-(2fluorophenyl) acetate].

- 31 047300

Reaction scheme 8.

When applied to reaction scheme 8, phosphoranes (15) can be prepared according to reaction scheme 9.

Reaction scheme 9.

With respect to Reaction Scheme 9, examples of suitable bases are sodium hydride, sodium hexamethyldisilazide and potassium tert-butoxide. Compounds (16) are electrophiles where LG represents a leaving group [such as chloride, bromide, iodide, tosylate or mesylate]. A variety of compounds (16) are commercially available [such as 4-chlorobenzyl bromide or 2-chloro-5-chloromethylthiazole].

Reaction scheme 10.

For Reaction Scheme 10, (2-bromo-6-fluorophenyl)acetic acid ethyl ester can be prepared as described in Lundgren et al., JACS 2016, 138, 13826-13829.

- 32 047300

Reaction scheme 11. i)

2-methylbut~2-ene NaH ₂ PO ₄ tert-butanol water

For reaction scheme 11, 2-bromo-1-chloro-4-fluorobenzene is commercially available. Reaction scheme 12.

Compounds (I-iii) can be prepared by treating compounds (I-iv) with a metal hydroxide [such as sodium hydroxide, lithium hydroxide or potassium hydroxide] in a mixture of water and a suitable solvent [such as methanol, ethanol or tetrahydrofuran]; or by treating compounds (I-iv) with a metal carbonate [such as sodium carbonate or potassium carbonate] in an alcoholic solvent [such as methanol or ethanol] at a temperature of from 0°C to 100°C. Compounds (I-iv) are compounds of formula (I) in which W is -CH ₂ -CH ₂ - and G is C(O)R ³ .

Compounds (2) can be prepared from compounds (14) and compounds (15) as shown in reaction scheme 13, in accordance with either the described Suzuki reaction protocol or the described Heck reaction protocol. When using the Suzuki reaction protocol, compounds (14) are organoboron compounds such as boronic acids, boronic esters or potassium trifluoroborate salts, and compounds (15) are halide or pseudohalide compounds such as chlorides, bromides, iodides or triflates. When using the Heck reaction protocol, compounds (14) are styrenes, and compounds (15) are halide or pseudohalide compounds such as chlorides, bromides, iodides or triflates.

Reaction scheme 13.

Suzuki reaction protocol.

Compounds (2) can be prepared by treating compounds (14) with compounds (15) in the presence of a suitable base and a suitable catalyst in a suitable solvent at a temperature of from 10 to 150°C. Examples of suitable bases are potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate and potassium fluoride. Examples of suitable catalysts are

- 33 047300 complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(P) and dichloromethane [PdCl2(dppf)-DCM], tetrakis(triphenylphosphine)palladium(0) [Pd(PPh ₃ ) ₄ ] and catalytic system, formed in situ from a mixture of palladium(II) acetate and triphenylphosphine. Examples of suitable solvents are water, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile and toluene. Many compounds (15) are commercially available or can be prepared using known methods. Examples of compounds (14) with particular utility in the Suzuki reaction protocol are isobutyryl esters (14-i), where G is isobutyryl.

One skilled in the art will appreciate that the conditions of the Suzuki reaction protocol can provide cleavage of ester groups, therefore, reaction scheme 13 can also describe a reaction where starting material (14) contains an ester moiety [so that G is an acyl group] but the product (2) does not contain [so G represents hydrogen].

Heck reaction protocol.

Compounds (2) can be prepared by treating compounds (14) with compounds (15) in the presence of a suitable base and a suitable catalyst at a temperature of from 10 to 150°C. Optionally, additional solvent may be included. Examples of suitable bases are triethylamine, morpholine, N-methylmorpholine, diisopropylethylamine and pyridine. Examples of suitable catalysts are tetrakis(triphenylphosphine)palladium(0) [Pd(PPh ₃ ) ₄ ], a catalyst system formed in-situ from a mixture of palladium(II) acetate and triphenylphosphine, a catalytic system formed in-situ from a mixture of tris(dibenzylideneacetone )dipalladium(0) and tri-tert-butylphosphonium tetrafluoroborate, and a catalyst system formed in-situ from a palladium cyclic precatalyst such as chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(P). Examples of optional additional solvent are 1,4-dioxane, tetrahydrofuran, acetonitrile and toluene. Many compounds (15) are commercially available or can be prepared using known methods. Examples of compounds (14) with particular utility in the Heck reaction protocol are isobutyryl esters (14-i), where G is isobutyryl.

Compounds (14-ii), where J is an organoboron compound such as a boronic ester, can be prepared from compounds (3) and compounds (16), as shown in reaction scheme 14.

Reaction scheme 14.

Compounds (14-ii) can be prepared by treating compounds (3) with compounds (16) in the presence of a suitable base and a suitable catalyst at a temperature of from 10 to 150°C. Optionally, additional solvent may be included. Examples of suitable bases are triethylamine, morpholine, N-methylmorpholine, diisopropylethylamine and pyridine. Examples of suitable catalysts are tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4], a catalyst system formed in-situ from a mixture of palladium(II) acetate and triphenylphosphine, and a catalyst system formed in-situ from a mixture of tris(dibenzylideneacetone )dipalladium(0) and tri-tert-butylphosphonium tetrafluoroborate. Examples of optional additional solvent are 1,4-dioxane, tetrahydrofuran, acetonitrile and toluene. A variety of compounds (16) are commercially available, such as vinyl boronic acid MIDA ester or vinyl boronic acid pinacol ester, or can be prepared by known methods. Examples of compounds (3) with particular utility in the Heck reaction protocol are the isobutyryl esters (3-i), where G is isobutyryl.

- 34 047300

Reaction scheme 15.

Compounds (14-iii), where J represents hydrogen, can be prepared from compounds (3) as shown in reaction scheme 15 above.

Compounds (14-iii) can be prepared by treating compounds (3) with tributyl(vinyl)stannane, optionally in the presence of a suitable base, in the presence of a suitable catalyst at a temperature of from 10 to 150° C. in a suitable solvent. Examples of optional bases are triethylamine, morpholine, N-methylmorpholine, diisopropylethylamine and pyridine. Examples of suitable catalysts are the complex of 1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(P) and dichloromethane [PdCl2(dppf)-DCM], tetrakis(triphenylphosphine)palladium(0) [Pd(PPh ₃ ) ₄ ], catalytic system, formed in-situ from a mixture of palladium(II) acetate and triphenylphosphine, a catalytic system formed in-situ from a mixture of tris(dibenzylideneacetone)dipalladium(0) and tri-tert-butylphosphonium tetrafluoroborate, and a catalytic system formed in-situ from a palladium cyclic precatalyst , such as chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(P). Examples of suitable solvents are 1,4dioxane, tetrahydrofuran, acetonitrile and toluene. Examples of compounds (3) having particular applicability are the isobutyryl esters (3-i) wherein G represents isobutyryl.

Compounds (18) can be prepared from compounds (3) via the Sonogashira reaction as shown in Reaction Scheme 16.

Reaction scheme 16.

Compounds (18) can be prepared by treating compounds (3) with compounds (17) in the presence of a suitable base and suitable catalyst(s) at a temperature of from 10 to 150°C. Optionally, additional solvent may be added. Examples of suitable bases are triethylamine, morpholine, N-methylmorpholine, diisopropylamine, diisopropylethylamine and pyridine. Examples of suitable catalysts are bis(triphenylphosphine)palladium(II) dichloride [Pd(PPh ₃ )Cl ₂ ], a catalyst system formed in-situ from a mixture of palladium(II) acetate and triphenylphosphine, a catalyst system formed in-situ from a mixture of Tris (dibegoylideneacetone)dipalladium(0) and tri-tert-butylphosphonium tetrafluoroborate, and a catalyst system formed in-situ from a palladium cyclic precatalyst such as chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(P). Optionally, copper catalysts such as copper(T) iodide can also be added. Examples of suitable additional solvents are 1,4-dioxane, tetrahydrofuran, acetonitrile, toluene and N-dimethylformamide. Examples of compounds (3) having particular applicability are the isobutyryl esters (3-i) wherein G represents isobutyryl.

One skilled in the art will appreciate that the Sonogashira reaction conditions can provide cleavage of ester groups, hence reaction scheme 16 may also describe a reaction where starting material (3) contains an ester moiety [so G is an acyl group] but product (18 ) does not contain [so G represents hydrogen].

Compounds (19) can be prepared from compounds (3) and compounds (20), as shown in Reaction Scheme 17, via a Suzuki reaction, where compound (20) is a suitable organoboron compound such as boric acid, boronate ester or salt, which is potassium trifluoroborate.

- 35 047300

Reaction scheme 17.

J

Compounds (19) can be prepared by treating compounds (3) with compounds (20) in the presence of a suitable base and a suitable catalyst in a suitable solvent at a temperature of from 10 to 150°C. Examples of suitable bases are potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate and potassium fluoride. Examples of suitable catalysts are the complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane [PdCl2(dppf)-DCM], a catalytic system formed in situ from a mixture of tris(dibenzylideneacetone)dipalladium(0) and tetrafluoroborate tri -tert-butylphosphonium, a catalyst system formed in situ from a mixture of tris(dibenzylideneacetone)dipalladium(0) and tricyclohexylphosphine, a catalyst system formed in situ from a palladium cyclic precatalyst such as chloro[(tri-tert-butylphosphine)-2-(2aminobiphenyl )]palladium(P), and a catalyst system formed in situ from a palladium cyclic precatalyst such as chloro[(tricyclohexylphosphine)-2-(2'-aminobiphenyl)]palladium(P). Examples of suitable solvents are water, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile and toluene. Some compounds (20) are commercially available or can be prepared using known methods (see, for example, the methods described in Org. Process Res. Dev. 2012, 16, 87-95). Examples of compounds (3) having particular applicability in the Suzuki reaction are benzyl esters (3-ii), where G represents benzyl.

Reaction scheme 18.

Compounds (I9-ii) can be prepared by catalytic hydrogenation of compounds (19-i) with hydrogen gas in a suitable solvent [such as tetrahydrofuran, methanol, ethanol, acetic acid or ethyl acetate] in the presence of a suitable catalyst [such as Pd/C,

Pd/CaCO ₃ , Rh/Al ₂ CO ₃ or sponge nickel] at temperatures from -10 to 100°C.

Certain compounds (I-ii) of the present invention can be prepared from compounds (21) as shown in Reaction Scheme 19. Compounds (I-ii) are compounds of formula (I) in which W is -CH2-CH2-.

Reaction scheme 19.

Compounds (I-ii) can be prepared by treating compounds (21), wherein [B] may be a trialkylborane, an alkylboronic acid, an alkylboronic ester or a trifluoroborate salt

- 36 047300 alkylpotassium, compounds (15) in the presence of a suitable base and a suitable catalyst in a suitable solvent at a temperature of from 10 to 150°C. Examples of suitable bases are potassium carbonate, potassium phosphate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium fluoride. Examples of suitable catalysts are the complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane [PdCl2(dppf)-DCM], [1,3-bis(2,6-di-3-pentylphenyl)imidazole- 2-ylidene](3chloropyridyl)dichloropalladium(H) [Pd-PEPPSI™-IPent], a catalyst system formed in-situ from a palladium cyclic precatalyst such as chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy1,1'- biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(P) [RuPhos-Pd-G2], [dicyclohexyl[2',4',6'-tris(1methylethyl)[1, 1'-biphenyl]-2-yl]phosphine](methanesulfonato-kO)[2'-(methylamino-kK)[1,1'-biphenyl]-2-ylkC]palladium [XPhos-Pd-G4] and [( 4-(Ndimethylamino)phenyl)di-tert-butylphosphine](methanesulfonateO)[2'-(methylamino-kK)[1,1'-biphenyl]-2-yl-kC]palladium [APhos-Pd-G4] . Examples of suitable solvents are water, 1,4-dioxane, 2-methyltetrahydrofuran, tetrahydrofuran, acetonitrile and toluene. Many compounds (15) are commercially available or can be prepared using known methods. Examples of compounds (21) with particular utility in the Suzuki reaction protocol are isobutyryl esters (21-i), where G is isobutyryl.

One skilled in the art will appreciate that the conditions of the Suzuki reaction protocol may allow cleavage of ester groups, whereby reaction scheme 19 may also describe a reaction where starting material (21) contains an ester moiety [so that G is an acyl group] but the product (I-ii) does not contain [so G represents hydrogen].

Reaction scheme 20.

(14-111) (21)

Compounds (21) can be prepared by hydroborating alkenes (14-iii) using a suitable hydroborating reagent (22) in a suitable solvent with the optional addition of a suitable catalyst at temperatures between 0°C and 100°C. Examples of hydroborating reagents include borane, dichloroborane, dibromoborane, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane [pinacolborane], 1,3,2-benzodioxaborole [catecholborane], or 9-borylbicyclo[3.3.1] nonane [9-BBN]. Examples of suitable solvents include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, 2-methoxy-2-methylpropane [MTBE] and diethyl ether. Examples of suitable catalysts include a catalyst system formed in situ from bisCE-cyclooctadiene-cyridium dichloride[[Ir(COD)Cl] ₂ ], and 4diphenylphosphanylbutyl(diphenyl)phosphane [DPPB] [J. Am. Chem. Soc, 2004, 126, 9200-9201].

If [B] is an alkyl boronic ester, it can be converted to the corresponding boronic acid by treatment with methyl boronic acid [MeB(OH) ₂ ] and trifluoroacetic acid in a suitable solvent such as dichloromethane [DCM] at temperatures from 0 to 40° From [Org. Lett., 2019, 21, 3048-3052]. If [B] is an alkyl boronic acid or an ester thereof, they can be converted to the corresponding alkyl potassium trifluoroborate salt by treatment with potassium hydrofluoride in a suitable solvent such as methanol or acetone at temperatures from 0 to 40°C.

The compounds of the present invention can be used as herbicidal agents in unmodified form, but are typically formulated in various ways using formulation auxiliaries such as carriers, solvents and surfactants. The compositions may be present in various physical forms, for example, sprayable powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent tablets, emulsifiable concentrates, microemulsion concentrates, oil-in-water emulsions, oil-based pourable formulations, aqueous dispersions, oil dispersions, suspoemulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as a carrier), impregnated polymer films or in other forms known, for example, from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, First Edition, Second Revision (2010). Such formulations can either be applied directly or diluted before use. Dilutions can be carried out, for example, with water, liquid fertilizers, nutrients

- 37 047300 microelements, biological organisms, oils or solvents.

The compositions can be prepared, for example, by mixing the active ingredient with formulation auxiliaries to obtain compositions in the form of fine solids, granules, solutions, dispersions or emulsions. The active ingredients may also be formulated with other excipients, for example, fine solids, mineral oils, vegetable or animal oils, modified vegetable or animal oils, organic solvents, water, surfactants, or combinations thereof.

The active ingredients may also be contained in very small microcapsules. Microcapsules contain active ingredients in a porous carrier. This allows the active ingredients to be released into the environment in controlled quantities (eg slow release). Microcapsules are typically characterized by a diameter ranging from 0.1 to 500 microns. They contain active ingredients in amounts ranging from approximately 25 to 95% by weight of the capsule. The active ingredients may be in the form of a monolithic solid, in the form of fine particles in a solid or liquid dispersion, or in the form of a suitable solution. Encapsulating membranes may contain, for example, natural and synthetic rubbers, cellulose, styrene-butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to one skilled in the art. Alternatively, very fine microcapsules can be prepared in which the active ingredient is contained as fine particles in a solid matrix of the base material, but the microcapsules are not themselves encapsulated.

Formulation auxiliaries that are suitable for preparing the compositions according to the present invention are known per se. Liquid carriers that can be used include water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, KH-dimethylformamide. dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerin, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, , mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol, propionic acid, propyl lactate, propylene carbonate, glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylene sulfonic acid, paraffin, mineral oil, trichlorethylene, perchlorethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol and high molecular weight alcohols such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, etc.

Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, diatomaceous earth, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed hulls, wheat flour, soya flour, pumice, wood flour, ground shells walnuts, lignin and similar substances.

A large number of surfactants can be used successfully in both solid and liquid formulations, especially in those formulations that can be diluted with a vehicle before use. Surfactants may be anionic, cationic, nonionic, or polymeric, and may be used as emulsifiers, wetting agents, or suspending agents, or for other purposes. Typical surfactants include, for example, alkyl sulfate salts such as diethanolammonium lauryl sulfate, alkyl aryl sulfonate salts such as calcium dodecyl benzene sulfonate, alkyl phenol/alkylene oxide adducts such as nonylphenol ethoxylate, alcohol/alkylene oxide adducts such as tridecyl alcohol ethoxylate, soaps, such as sodium stearate, alkyl naphthalene sulfonate salts such as sodium dibutyl naphthalene sulfonate, dialkyl ester sulfosuccinate salts such as sodium di(2ethylhexyl) sulfosuccinate, sorbitol esters such as sorbitoleate, quaternary amines such as lauryl trimethyl ammonium chloride, polyethylene glycol fatty acid esters, such as polyethylene glycol stearate, ethylene oxide-propylene oxide block copolymers and mono- and dialkyl phosphate ester salts, as well as additional substances described, for example, in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).

- 38 047300

Additional excipients that may be used in pesticide formulations include crystallization inhibitors, viscosity modifiers, suspending agents, colorants, antioxidants, foaming agents, light absorbers, mixing aids, antifoams, complexing agents, neutralizing or pH-modifying agents, and buffers. corrosion inhibitors, fragrances, wetting agents, absorption enhancers, micronutrients, plasticizers, glidants, lubricants, dispersants, thickeners, antifreeze, microbicides, and liquid and solid fertilizers.

The compositions of the present invention may include an additive containing a vegetable or animal oil, mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives. The amount of oil additive in the composition according to the present invention is usually from 0.01 to 10% based on the mixture to be used. For example, an oil additive can be added to the sprayer reservoir at the required concentration after preparing the spray mixture. Preferred oil additives contain mineral or vegetable oils, such as canola oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of vegetable oils, such as methyl derivatives, or an animal oil, such as fish oil or beef tallow. . Preferred oil additives contain alkyl esters of C ₈ -C 22 fatty acids, especially methyl derivatives of C ₁₂ -C ₁₈ fatty acids, for example, methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively). Many oil derivatives are known from Compendium of Herbicide Adjuvants, ^10th Edition, Southern Illinois University, 2010.

Herbicidal compositions generally contain from 0.1 to 99% by weight, in particular from 0.1 to 95% by weight, of the compounds of formula (I) and from 1 to 99.9% by weight of a formulation aid which preferably includes from 0 to 25% by weight of surfactant. The compositions of the present invention generally contain from 0.1 to 99% by weight, in particular from 0.1 to 95% by weight, of the compounds of the present invention and from 1 to 99.9% by weight of the formulation excipient, which preferably includes from 0 to 25% by weight of surfactant. Since commercial products may preferably be formulated as concentrates, the end user will typically use diluted formulations.

Application rates vary widely and depend on soil properties, application method, crop plant, pest being controlled, prevailing climatic conditions and other factors determined by application method, time of application and target crop. As a general guide, the compounds can be applied at rates of 1 to 2000 l/ha, in particular 10 to 1000 l/ha.

Preferred compositions may be characterized by the following compositions (wt.%).

Emulsifiable concentrates:

active ingredient: 1-95%, preferably 60-90%;

surfactant: 1-30%, preferably 5-20%;

liquid carrier: 1-80%, preferably 1-35%. Dust preparations: 0.1-10%, preferably 0.1-5%; active ingredient:

solid carrier: 99.9-90%, preferably 99.9-99%.

Suspension concentrates: active ingredient: 5-75%, preferably 10-50%; water: 94-24%, preferably 88-30%;

surfactant: 1-40%, preferably 2-30%.

Wettable powders:

active ingredient: 0.5-90%, preferably 1-80%;

surfactant: 0.5-20%, preferably 1-15%;

solid carrier: 5-95%, preferably 15-90%. Granules:

active ingredient: 0.1-30%, preferably 0.1-15%;

solid carrier: 99.5-70%, preferably 97-85%.

The composition of the present invention may further comprise at least one

- 39 047300 additional pesticide. For example, the compounds of the present invention may also be used in combination with other herbicides or plant growth regulators. In a preferred embodiment, the additional pesticide is a herbicide and/or a herbicide antidote.

Thus, the compounds of formula (I) can be used in combination with one or more other herbicides to provide various herbicide mixtures. Specific examples of such mixtures include (wherein I is a compound of formula (I)): I + acetochlor; I + acifluorfen (including acifluorfen sodium); I + aclonifen; I + ametrine; I + amicarbazone; I + aminopyralide; I + aminotriazole; I + atrazine; I + beflubutamide-M; I + benquitrion; I + bensulfuron (including bensulfuron-methyl); I + bentazone; I + bicyclopyrone; I + bilanaphos; I + bispiribac sodium; I + bixlozone; I + bromacil; I + bromoxynil; I + butachlor; I + butafenacil; I + carfentrazone (including carfentrazone-ethyl); I + cloransulam (including cloransulam-methyl); I + chlorimuron (including chlorimuronethyl); I + chlortoluron; I + chlorsulfuron; I + cinmethylin; I + clacifos; I + clethodim; I + clodinafop (including clodinafop-propargyl); I + clomazone; I + clopyralid; I + cyclopyranil; I + cyclopyrimorate; I + cyclosulfamuron; I + cyhalofop (including cyhalofop-butyl); I + 2,4-D (including its choline salt and 2-ethylhexyl ester); I + 2,4-DB; I + desmedipham; I + dicamba (including its aluminum, aminopropyl, bis-aminopropylmethyl, choline, dichlorprop, diglycolamine, dimethylamine, dimethylammonium, potassium and sodium salts); I + diclosulam; I + diflufenican; I + diflufenzopyr; I + dimethachlor; I + dimethenamid-P; I + diquat dibromide; I + diuron; I + epirifenacil; I + ethalfluralin; I + ethofumesate; I + fenoxaprop (including fenoxaprop-R-ethyl); I + phenoxasulfone; I + phenquinotrione; I + phentrazamide; I + flazasulfuron; I + florasulam; I + florpyrauxifen (including florpyrauxifen-benzyl); I + fluazifop (including fluazifop-R-butyl); I + flucarbazone (including flucarbazone sodium); I + flufenacet; I + flumetsulam; I + flumioxazin; I + fluometuron; I + flupirsulfuron (including flupirsulfuron-methyl-sodium); I + fluroxypyr (including fluroxypyr-meptyl); I + fomesafen; I + foramsulfuron; I + glufosinate (including its ammonium salt); I + glyphosate (including its diammonium, isopropylammonium and potassium salts); I + halauxifen (including halauxifen-methyl); I + haloxyfop (including haloxyfop-methyl); I + hexazinone; I + hydantocidin; I + imazamox; I + imazapic; I + imazapyr; I + imazethapyr; I + indaziflam; I + iodosulfuron (including iodosulfuron-methyl-sodium); I + iofensulfuron (including iofensulfuron sodium); I + ioxynil; I + isoproturon; I + isoxaflutole; I + lancotrione; I + MSPA; I + MSRP; I + mecoprop-P; I + mesosulfuron (including mesosulfuron-methyl); I + mesotrione; I + metamitron; I + metazachlor; I + methiozoline; I + metolachlor; I + methosulam; I + metribuzin; I + metsulfuron; I + napropamide; I + nicosulfuron; I + norflurazon; I + oxadiazone; I + oxasulfuron; I + oxyfluorfen; I + paraquat dichloride; I + pendimethalin; I + penoxulam; I + phenmedipham; I + pichloram; I + pinoxaden; I + pretilachlor; I + primisulfuron-methyl; I + prometrin; I + propanil; I + propaquizafop; I + propyrisulfuron; I + propyzamide; I + prosulfocarb; I + prosulfuron; I + pyraclonil; I + pyraflufen (including pyraflufen-ethyl); I + pyrasulfotol; I + pyridate; I + pyrifthalide; I + pyrimisulfan; I + pyroxasulfone; I + pyroxulam; I + quinclorac; I + quinmerac; I + quizalofop (including quizalofopR-ethyl and quizalofop-R-tefuryl); I + rimsulfuron; I + saflufenacil; I + methoxydim; I + simazine; I + S-metallochlorine; I + sulfentrazone; I + sulfosulfuron; I + tebuthiuron; I + tefuryltrione; I + tembotrione; I + terbutylazine; I + terbutryn; I + tetflupyrolymet; I + thiencarbazone; I + thifensulfuron; I + thiaphenacyl; I + tolpyralate; I + topramesone; I + tralkoxydim; I + triafamon; I + triallate; I + triasulfuron; I + tribenuron (including tribenuron-methyl); I + trichloropyr; I + trifloxysulfuron (including trifloxysulfuron sodium); I + trifludimoxazine; I + trifluralin; I + triflusulfuron; I + ethyl ester 3-(2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-3,6dihydropyrimidin-1(2H)-yl)phenyl)-5-methyl -4,5-dihydroisoxazole-5-carboxylic acid; I + 4hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one; I + 4-hydroxy-1,5dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one; I + 5-ethoxy-4-hydroxy-1-methyl-3-[4(trifluoromethyl)-2-pyridyl]imidazolidin-2-one; I + 4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2pyridyl]imidazolidin-2-one; I + 4-hydroxy-1,5-dimethyl-3-[1-methyl-5-(trifluoromethyl)pyrazol-3yl]imidazolidin-2-one; I + (4R)1-(5-tert-butylisoxazol-3-yl)-4-ethoxy-5-hydroxy-3-methylimidazolidin2-one; I + 3-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione; I + 2-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]-5-methyl-cyclohexane-1,3-dione; I + 2[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]cyclohexane-1,3-dione; I + 2-[2-(3,4dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]-5,5-dimethylcyclohexane-1,3-dione; I + 6-[2-(3,4dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]-2,2,4,4-tetramethylcyclohexane-1,3,5-trione; I + 2[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]-5-ethylcyclohexane-1,3-dione; I + 2-[2-(3,4dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]-4,4,6,6-tetramethylcyclohexane-1,3-dione; I + 2-[6cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxopyridazine-4-carbonyl]-5-methylcyclohexane-1,3-dione; I + 3-[6cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxopyridazine-4-carbonyl]bicyclo[3.2.1]octane-2,4-dione; I + 2-[6cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxopyridazine-4-carbonyl]-5,5-dimethylcyclohexane-1,3-dione; I + 6-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxopyridazine-4-carbonyl]-2,2,4,4-tetramethylcyclohexane - 40 047300

1,3,5-trione; I + 2-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxopyridazine-4-carbonyl]cyclohexane-1,3dione; I + 4-[2-(3,4-dimethoxyphenyl)-6-methyl-3-oxopyridazine-4-carbonyl]-2,2,6,6-tetramethyltetrahydropyran-3,5-dione; I + 4-[6-cyclopropyl-2-(3,4-dimethoxyphenyl)-3-oxopyridazine-4-carbonyl]2,2,6,6-tetramethyltetrahydropyran-3,5-dione; I + 4-amino-3-chloro-5-fluoro-6-(7-fluoro-1H-indol-6-yl)pyridin-2-carboxylic acid (including its agrochemically acceptable esters, for example methyl-4amino - 3 -chloro-5 -fluoro-6 -(7 -fluoro- 1H-indol-6 -yl)pyridin-2-carboxylate, prop-2 -inyl-4 -amino -3 -chloro-5 fluoro-6-(7 -fluoro-1H-indol-6-yl)pyridin-2-carboxylate and cyanomethyl-4-amino-3-chloro-5-fluoro-6-(7-fluoro-Shindol-6-yl)pyridin-2-carboxylate) ; I + 3-ethylsulfanyl-H-(1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine-8-carboxamide; I + 3-(isopropylsulfanylmethyl)-N-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine -8-carboxamide; 1 + 3-(isopropylsulfonylmethyl)-H-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine -8-carboxamide; I + 3-(ethylsulfonylmethyl)-H-(5-methyl-1,3,4-oxadiazol-2-yl)-5-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine -8-carboxamide; I + ethyl 2-[[3-[[3-chloro-5-fluoro-6-[3-methyl-2,6-dioxo-4-(trifluoromethyl)pyrimidin-1yl]-2-pyridyl]oxy]acetate ; I + 6-chloro-4-(2,7-dimethyl-1-naphthyl)-5-hydroxy-2-methylpyridazin-3-one; I + 1[2-chloro-6-(5-chloropyrimidin-2-yl)oxyphenyl]-4,4,4-trifluorobutan-1-one and I + 5-[2-chloro-6-(5-chloropyrimidin- 2-yl)oxyphenyl]-3-(difluoromethyl)isoxazole. The components mixed with the compound of formula (I) may also be in the form of esters or salts, as mentioned, for example, in The Pesticide Manual, Fourteenth Edition, British Crop Protection Council, 2006.

The compound of formula (I) can also be used in mixtures with other agrochemicals, such as fungicides, nematicides or insecticides, examples of which are given in The Pesticide Manual.

The mixture ratio of the compound of formula (I) and the component to be mixed is preferably from 1:100 to 1000:1.

The mixtures can advantageously be used in the above-mentioned formulations (in which case the active ingredient refers to a corresponding mixture of the compound of formula (I) with the component to be mixed).

The compounds of formula (I) of the present invention can also be combined with herbicide safeners. Preferred combinations (where I is a compound of formula (I)) include: I + benoxacor, I + cloquintocet (including cloquintocet-mexyl); I + cyprosulfamide; I + dichlormide; I + fenchlorazole (including fenchlorazole-ethyl); I + fenclorim; I + fluxofenim; 1+ furilazole I + isoxadifen (including isoxadifen-ethyl); I + mefenpyr (including mefenpyr-diethyl); I + metcamifene; I + Na(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide and I + oxabetrinyl.

Particularly preferred are mixtures of the compound of formula (I) with cyprosulfamide, isoxadifen (including isoxadifen-ethyl), cloquintoset (including cloquintosetmexil) and/or Na(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide .

Antidotes for the compound of formula (I) may also be in the form of esters or salts, as mentioned, for example, in The Pesticide Manual, 14 Edition (BCPC), 2006. Reference to cloquintocet-mexyl also refers to its lithium, sodium, potassium, calcium, magnesium, aluminum, iron, ammonium, quaternary ammonium, sulfonium or phosphonium, as disclosed in WO 02/34048, and reference to fenchlorazole-ethyl also refers to fenchlorazole, etc.

Preferably, the mixture ratio of the compound of formula (I) and the antidote is from 100:1 to 1:10, in particular from 20:1 to 1:1.

The mixtures can advantageously be used in the above-mentioned formulations (in which case the expression active ingredient refers to a corresponding mixture of a compound of formula (I) with an antidote).

The compounds of formula (I) of the present invention are useful as herbicides. Therefore, the present invention further provides a method for controlling unwanted plants, comprising applying to said plants or a growing location containing them an effective amount of a compound of the present invention or a herbicidal composition containing the same. Control means killing, reducing or retarding growth or preventing or reducing germination. Typically the plants to be controlled are unwanted plants (weeds). Habitat means the area in which plants grow or will grow.

The rates of application of compounds of formula (I) can vary widely and depend on the properties of the soil, the method of application (pre-emergence; post-emergence; application in relation to the seed furrow; application in no-tillage, etc.), the crop plant , the weed(s) to be controlled, prevailing climatic conditions and other factors determined by the method of application, timing of application and target crop. The compounds of formula (I) according to the present invention are generally used at a rate of 10 to 2000 g/ha, in particular 50 to 1000 g/ha.

Application is usually carried out by spraying the composition, usually using a tractor-mounted sprayer for large areas, but others can also be used

- 41 047300 methods such as pollination (for powders), drip irrigation or irrigation.

Beneficial plants to which the composition of the present invention can be applied include agricultural crops such as cereals, for example barley and wheat, cotton, oilseed rape, sunflower, maize, rice, soybeans, sugar beets, sugar cane and turf. cover.

Cultivated plants may also include trees such as fruit trees, palm trees, coconut trees or other nut crops.

Also included are climbing plants such as grapes, fruit bushes, fruit plants and vegetables.

It should be understood that crops also include those crops that have been made tolerant to herbicides or classes of herbicides (e.g., ALS, GS, EPSPS, PPO, ACCase, and HPPD inhibitors) through conventional breeding techniques or through genetic engineering. An example of a crop that has been made tolerant of imidazolinones, such as imazamox, through traditional breeding techniques is Clearfield® canola. Examples of crops that have been genetically engineered to tolerate herbicides include, for example, glyphosate- and glufosinate-resistant maize varieties commercially available under the trademarks RoundupReady® and LibertyLink®.

Crop crops also include those that have been genetically engineered to be resistant to harmful insects, such as Bt maize (resistant to the corn borer), Bt cotton (resistant to the cotton weevil), and varieties of Bt potatoes ( resistant to the Colorado potato beetle). Examples of Bt maize are the Bt 176 NK® maize hybrids (Syngenta Seeds). Bt toxin is a protein that is naturally produced by the soil bacteria Bacillus thuringiensis. Examples of toxins or transgenic plants capable of synthesizing such toxins are described in EP-A-451878, EP-A-374753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427529. Examples of transgenic plants containing one or more genes encoding insect resistance and expressing one or more toxins include KnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard® (cotton), NewLeaf® (potato varieties), NatureGard® and Protexcta®. Plant crops or their seed material can be resistant to herbicides and at the same time resistant to eating by insects (transgenic objects with packaged genes). For example, a seed may have the ability to express the insecticidal protein Cry3 while at the same time being tolerant to glyphosate.

It should also be understood that crop crops include those produced by traditional breeding methods or genetic engineering that have so-called introduced traits (eg, improved storage stability, higher nutritional value, and improved flavor).

Other useful plants include turf grass, such as on golf courses, lawns, parks and roadsides or commercially grown for lawns, and ornamental plants such as flowers or shrubs.

The compounds of formula (I) and the compositions of the present invention can generally be used to control a wide variety of monocotyledonous and dicotyledonous weed species. Examples of monocot species that can usually be controlled include Alopecurus myosuroides, Avena fatua, Brachiaria plantaginea, Bromus tectorum, Cyperus esculentus, Digitaria sanguinalis, Echinochloa crus-galli, Lolium perenne, Lolium multiflorum, Panicum miliaceum, Poa annua, Setaria viridis, Setaria faberi and Sorghum bicolor. Examples of dicotyledonous species that can be controlled include Abutilon theophrasti, Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Euphorbia heterophylla, Galium aparine, Ipomoea hederacea, Kochia scoparia, Polygonum convolvulus, Sida spinosa, Sinapis arvensis, Solarium nigrum, Stellaria media, Veronica persica and Xanthium strumarium. Weeds can also include plants that may be considered crops but that grow outside the crop area (escapers), or that grow from seeds left over from a previous planting of another crop (self-seeding plants). Such self-seeding or escape plants may be tolerant of some other herbicides.

Various aspects and embodiments of the present invention will now be illustrated in more detail by way of example. It should be understood that modifications in certain details may be made without departing from the scope of the present invention.

Examples of receiving

Example 1. Preparation of [5-[3-chloro-6-fluoro-2-[2-(2-methyl-6-quinolyl)ethyl]phenyl]-1,3-dimethyl-6oxopyridazin-4-yl]-2- methylpropanoate (A-3.034).

- 42 047300

1.1. 3-Allyl-2-bromo-1-chloro-4-fluorobenzene.

A solution of lithium diisopropylamide (2M In tetrahydrofuran, 3.6 ml, 7.2 mmol) was cooled to -78°C under N2. A solution of 2-bromo-1-chloro-4-fluorobenzene (1.0 g, 4.8 mmol) in tetrahydrofuran was added dropwise at -78°C. The mixture was stirred for 45 min at the same temperature before treatment with allyl bromide (0.3 ml, 5.7 mmol). The reaction was allowed to continue at -78°C for 2 hours, then warmed to room temperature. The reaction was extinguished with our help. NH4Cl (aq) solution and extracted with ethyl acetate. The organic matter was separated and left, then washed with saline. The organics were dried over sodium sulfate and concentrated under reduced pressure to give 3-allyl-2-bromo-1-chloro-4-fluorobenzene (1.2 g, 100%) as an oil.

¹ H NMR (400 MHz, CDCl ₃ ) 0 _H : 7.34-7.30 (m, 1H), 7.01-6.96 (m, 1H), 5.94-5.83 (m, 1H ), 5.10-5.00 (m, 2H), 3.64-3.58 (m, 2H).

1.2. 2-(2-Bromo-3-chloro-6-fluorophenyl)acetic acid.

A solution of 3-allyl-2-bromo-1-chloro-4-fluorobenzene (15.0 g, 60.1 mmol) in dichloromethane (200 ml) in a 2-neck flask was cooled to -78°C. The throat on one side was connected to a trap containing an aqueous solution of KI. Ozone was bubbled through the solution until the starting material was completely consumed (5 hours). Air was bubbled through the solution for 10 min to remove excess ozone. Dimethyl sulfide (44 ml, 601 mmol) was added and the mixture was allowed to warm to room temperature. The reaction was allowed to continue for 16 hours at room temperature.

The mixture was washed with brine (2x100 ml) and the organic layer was left. The organics were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give crude 2-(2-bromo-3-chloro-6-fluorophenyl)acetaldehyde (15.3 g), which was used for the next step without further purification.

Crude 2-(2-bromo-3-chloro-6-fluorophenyl)acetaldehyde (15.3 g, 60.8 mmol) was dissolved in a mixture of tert-butanol (92 ml) and water (46 ml), then cooled to 0° WITH. 2-Methylbut-2-ene (64.5 mL, 608 mmol), sodium dihydrogen phosphate (34.6 g, 243 mmol) and sodium chlorite (16.5 g, 163 mmol) were added. The mixture was stirred for 2 hours, then diluted with saline (150 ml) and 2M hydrochloric acid (150 ml). The mixture was extracted with ethyl acetate (3x100 ml). The combined organic extracts were washed with saturated aqueous sodium metabisulfite (100 ml), then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a pale yellow solid. The crude solid was dissolved in a mixture of water (100 ml) and 2.0 M NaOH (30 ml). The aqueous solution was washed with ethyl acetate (100 ml) and the organics were removed. The aqueous layer was acidified by adding concentrated hydrochloric acid (20 ml), which resulted in the formation of a white suspension. The mixture was extracted with ethyl acetate (3x200 ml). The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated to give 2-(2-bromo-3-chloro-6-fluorophenyl)acetic acid (8.0 g, 49%) as a white solid. .

1H NMR (400 MHz, DMSO-d6) _δΗ : 12.79 (br.s, 1H), 7.67-7.59 (m, 1H), 7.39-7.31 (m, 1H), 3.82(s,2H).

- 43 047300

1.3. 2-(2-Bromo-3-chloro-6-fluorophenyl)-N-methylacetohydrazide.

To a stirred solution of 2-(2-bromo-3-chloro-6-fluorophenyl)acetic acid (2.0 g, 7.5 mmol) in dichloromethane (20 ml) at 0°C was added No. -ethylcarbodiimide hydrochloride [EDC-HCl] (1.4 g, 9.0 mmol) followed by dropwise addition of methylhydrazine (0.4 ml, 7.5 mmol). The temperature of the reaction mixture was maintained at 0°C for 3 hours. The reaction was then quenched with water and extracted into dichloromethane. Organic matter was separated, washed with brine and dried over Na ₂ SO ₄ . Concentration under reduced pressure provided crude 2-(2-bromo-3-chloro-6-fluorophenyl)-N-methylacetohydrazide (1.8 g, 81%), which was used in the next step without further purification.

1H NMR (400 MHz, DMSO-d ₆ ) 6H 7.59 (dd, J=8.9 and 5.4, 1H), 7.30 (t, J=8.9, 1H), 4.91 ( s, 2H), 4.10 (br. s, 2H), 3.02 (s, 3H).

1.4. Ethyl ester of 2-{[2-(2-bromo-3-chloro-6-fluorophenyl)-acetyl]-methylhydrazono}propionic acid.

Ethyl pyruvate (0.7 mL, 6 .7 mmol). The reaction mixture was heated at 80°C for 4 hours. Then the reaction mixture was cooled to room temperature. and evaporated it under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane gradient elution) to give the desired compound, 2-{[2-(2-bromo-3-chloro-6-fluorophenyl)-acetyl]-methylhydrazono}-propionic ethyl ester acid (1.8 g, 75%) - as an off-white solid.

GT

N ΛΛ o ¹ H NMR (400 MHz, CDCl ₃ ) 6H 7.40-7.35 (m, 1H), 7.04-6.98 (m, 1H), 4.32 (q, J=7, 1, 2H), 4.24 (s, 2H), 3.41 (s, 3H), 2.32 (s, 3H), 1.36 (t, J=7.1, 3H).

1.5. 4-(2-Bromo-3-chloro-6-fluorophenyl)-5-hydroxy-2,6-dimethylpyridazin-3-one.

2-{[2-(2-bromo-3-chloro-6-fluorophenyl)-acetyl]-methylhydrazono}propionic acid ethyl ester (500 mg, 1.27 mmol) was dissolved in acetonitrile (2.5 ml) and treated 1,8diazabicyclo[5.4.0]undec-7-ene [DBU] (0.47 ml, 3.2 mmol). The mixture was heated to 125°C using microwave radiation for 1 hour. The reaction mixture was then evaporated under reduced pressure. The residue was dissolved in water and acidified to pH 1 with 2N. hydrochloric acid. The mixture was extracted with DCM and the organics were separated and washed with brine. The organic solution was dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (ethyl acetate/hexane gradient elution) to give 4-(2-bromo-3chloro-6-fluorophenyl)-5-hydroxy-2,6-dimethylpyridazin-3-one (340 mg, 77 .1%) as an off-white solid.

- 44 047300

1H NMR (400 MHz, DMSO-d6) δΗ 11.01 (s, 1H), 7.77-7.73 (m, 1H), 7.39 (t, J=8.7, 1H), 3, 58 (s, 3H), 2.24 (s, 3H).

1.6. [5 -(2-Bromo-3-chloro-6-fluorophenyl)-1,3-dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate.

To a stirred solution of 4-(2-bromo-3-chloro-6-fluorophenyl)-5-hydroxy-2,6-dimethylpyridazin-3one (1.4 g, 4.02 mmol) in dichloromethane (32 ml) at room temperature. T. triethylamine (1.1 mL, 8.06 mmol), 4(dimethylamino)pyridine [DMAP] (49 mg, 0.40 mmol), and isobutyryl chloride (0.6 mL, 4.83 mmol) were added.

Once the reaction was considered complete, the reaction mixture was diluted with dichloromethane and water. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product. The crude material was purified by silica gel column chromatography (gradient elution with ethyl acetate/hexane) to give [5-(2bromo-3-chloro-6-fluorophenyl)-1,3-dimethyl-6-oxopyridazin-4-yl]-2- methyl propanoate (1.47 g, 87%).

1H NMR (400 MHz, CDCl ₃ ) δ^ 7.51-7.47 (m, 1H), 7.10-7.05 (m, 1H), 3.82 (s, 3H), 2.60- 2.55 (m, 1H), 2.25 (s, 3H), 1.02-0.98 (m, 6H).

1.7. 2-Methyl-6-[(E)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl]quinoline.

4,4,5,5-Tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.73 ml, 4.32 mmol) and N-diisopropylethylamine (1.25 ml, 7.20 mmol) were added to the stirred a solution of 6-bromo-2-methylquinoline (800 mg, 3.6 mmol) and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(P) (92 mg, 0.18 mmol) in toluene (14 ml). The reaction mixture was heated to 95°C under a nitrogen atmosphere for 4 hours.

Once complete, the reaction mixture was allowed to cool to room temperature and then filtered through Celite® (eluting with DCM). The filtrate was concentrated in vacuo then purified by flash column chromatography (silica, ethyl acetate/isohexane gradient) to give 2-methyl-6-[(E)-2-(4,4,5,5-tetramethyl-1 ,3,2dioxaborolan-2-yl)vinyl]quinoline (886 mg, 83% yield).

1H NMR (400 MHz, solvent) δ ppm 1.34 (s, 12H) 2.74 (s, 3H) 6.29 (d, J=18.46 Hz, 1H) 7.26 - 7.29 (m , 1H) 7.55 (d, J=18.4 Hz, 1H) 7.77 (d, J=1.47 Hz, 1H) 7.85 - 7.92 (m, 1H) 7.94 - 7 .99 (m, 1H) 8.02 (d, J=8.4 Hz, 1H).

1.8. [5-[3-Chloro-6-fluoro-2-[(E)-2-(2-methyl-6-quinolyl)vinyl]phenyl]-1,3-dimethyl-6-oxopyridazin-4yl]-2- methyl propanoate (A-4.034).

Stirred solution of [5-(2-bromo-3-chloro-6-fluorophenyl)-1,3-dimethyl-6-oxopyridazin-4-yl]-2methylpropanoate (1.03 g, 2.47 mmol), Cs ₂ CO ₃ (2.43 g, 7.40 mmol), 2-methyl-6-[(E)-2-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)vinyl]quinoline (0.874 g, 2.96 mmol) and Pd(dppf)Cl ₂ -DCM (0.101 g, 0.123 mmol) in 1,4-dioxane (21 ml) and water (6 ml) were refluxed.

After 16 h, the reaction mixture was concentrated in vacuo to remove most of the dioxane, then diluted with water and EtOAc. The organic layer was separated and the aqueous phase was extracted portionwise with EtOAc (x2). The aqueous phase was then adjusted to pH 2 with 2 M HCl (aq), then extracted with additional EtOAc.

The crude product was purified by flash column chromatography (silica, ethyl acetate/isohexane gradient) to give [5-[3-chloro-6-fluoro-2-[(E)-2-(2methyl-6-quinolyl)vinyl ]phenyl]-1,3-dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate (86 mg, 7% yield, A-4.034) and 4-[3-chloro-6-fluoro-2-[( E)-2-(2-methyl-6-quinolyl)vinyl]phenyl]-5-hydroxy-2,6dimethylpyridazin-3-one (51 mg, 5% yield, A-2.034).

- 45 047300

1H NMR (400 MHz, CDCl ₃ ) δ ppm 1.11 (apparent t, J=7.1 Hz, 6 H) 2.23 (s, 3H) 2.63 - 2.71 (m, 1H) 2, 74 (s, 3H) 3.69 (s, 3H) 6.81 (d, J=16.4 Hz, 1H) 7.04 (t, J=8.7 Hz, 1H) 7.15 (d, J=16.5 Hz, 1H) 7.27 (s, 1H) 7.45 (dd, J=8.9, 5.07 Hz, 1H) 7.63 (d, J=1.7 Hz, 1H ) 7.75 - 7.81 (m, 1H) 7.94 (d, J=8.8 Hz, 1H) 8.01 (d, J=8.3 Hz, 1H).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 2.24 (s, 3H) 2.66 (s, 3H) 3.66 (s, 3H) 6.72 (d, J=16.4 Hz, 1H) 6.93 7.07 (m, 2H) 7.26 (s, 1H) 7.38 (dd, J=8.9, 5.14 Hz, 1H) 7.55 (d, J=1.7 Hz, 1H) 7.66 (dd, J=8.8, 2.0 Hz, 1H) 7.84 (d, J=8.8 Hz, 1H) 7.99 (d, J=8.4 Hz , 1H).

1.9. [5-[3-Chloro-6-fluoro-2-[2-(2-methyl-6-quinolyl)ethyl]phenyl]-1,3-dimethyl-6-oxopyridazin-4-yl]-2methylpropanoate (A- 3.034).

[5-[3-Chloro-6-fluoro-2-[(E)-2-(2-methyl-6-quinolyl)vinyl]phenyl]-1,3-dimethyl-6-oxopyridazin-4-yl]2 -Methylpropanoate (56 mg, 0.12 mmol, 4.034) was subjected to catalytic hydrogenation in tetrahydrofuran (0.3 ml) in the presence of 5% Pd/C catalyst (24 mg) at a pressure of H ₂ 3 bar.

Once complete, the reaction mixture was filtered through a pad of Celite® eluting with DCM. The filtrate was concentrated in-vacuo to obtain a crude residue.

The residue was adsorbed onto silica and purified by flash column chromatography (silica, eluting with ethyl acetate/isohexane) to give [5-[3-chloro-6fluoro-2-[2-(2-methyl-6-quinolyl)ethyl]phenyl] -1,3-dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate (15 mg, 27% yield, A-3.034) and a mixture of further concentrated products, which was further purified by mass directed preparative reverse phase HPLC to give [5-[3-chloro-6-fluoro-2-[2-(2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)ethyl]phenyl]-1,3-dimethyl-6oxopyridazine -4-yl]-2-methylpropanoate (6 mg, yield 11%, A-3.030).

1H NMR (400 MHz, CDCl3) δ ppm 0.97 (dd, J=7.0, 4.4 Hz, 6 H) 2.24 (s, 3H) 2.47-2.57 (m, 1H) 2.73 (s, 3H) 2.79 - 3.09 (m, 4H) 3.84 (s, 3H) 7.00 (t, J=8.6 Hz, 1H) 7.25 (d, J =8.3 Hz, 1H) 7.49 (apparent d, J=1.1 Hz, 3H) 7.90 (d, J=8.4 Hz, 1H) 7.96 (d, J=8.3 Hz, 1H).

1H NMR (400 MHz, CDCl ₃ ) δ ppm 0.96 (dd, J=7.03, 2.02 Hz, 6 H) 1.25 (d, J=6.24 Hz, 3 H) 1.58 - 1.69 (m, 1H) 1.90-1.98 (m, 1H) 2.24 (s, 3H) 2.54 (dt, J=13.94, 6.97 Hz, 1H) 2, 63-2.84 (m, 6 N) 3.39 (td, J=6.51, 3.12 Hz, 1H) 3.83 (s, 3H) 6.52 (br d, J=6.48 Hz, 1H) 6.72-6.79 (m, 2 H) 6.96 (t, J=8.62 Hz, 1H) 7.40 (dd, J=8.80, 5.14 Hz, 1H ).

- 46 047300

Example 2. Preparation of 4-[3-chloro-6-fluoro-2-[2-(1H-indol-5-yl)ethyl]phenyl]-5-hydroxy-2,6dimethylpyridazin-3-one (A-1.021) .

2.1. 5-Benzyloxy-4-(2-bromo-3-chloro-6-fluorophenyl)-2,6-dimethylpyridazin-3-one.

Benzyl bromide (0.19 ml, 1.58 mmol) was added to a stirred suspension of 4-(2-bromo-3-chloro-6fluorophenyl)-5-hydroxy-2,6-dimethylpyridazin-3-one (500 mg, 1.44 mmol) and K ₂ CO ₃ (0.22 g, 1.58 mmol) in acetone (2.9 ml), and the mixture was refluxed for 2 hours.

Once complete, the reaction mixture was cooled to room temperature and then filtered (eluting with acetone). The filtrate was concentrated in vacuo then purified by flash column chromatography (silica, ethyl acetate/isohexane gradient) to give 5-benzyloxy-4-(2-bromo-3-chloro-6-fluorophenyl)-2,6-dimethylpyridazine -3-one (560 mg, 89% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.29 (s, 3H) 3.77 (s, 3H) 4.59 - 4.76 (m, 2 H) 7.09 (dd, J=8 .93, 7.95 Hz, 1H) 7.13-7.20 (m, 2 H) 7.29-7.36 (m, 3H) 7.52 (dd, J=8.93, 5.38 Hz, 1H).

2.2. 2-[(E)-2-[2-(5-Benzyloxy-2,6-dimethyl-3-oxopyridazin-4-yl)-6-chloro-3-fluorophenyl]vinyl]-6methyl-1,3,6 ,2-dioxazaborocane-4,8-dione.

Stirred solution of 5-benzyloxy-4-(2-bromo-3-chloro-6-fluorophenyl)-2,6-dimethylpyridazin-3-one (1.00 g, 2.28 mmol), chloro[(tri-tert- butylphosphine)-2-(2-aminobiphenyl)]palladium(P) (59 mg, 0.11 mmol), U,U-diisopropylethylamine (0.80 ml, 4.57 mmol) and 6-methyl-2-vinyl- 1,3,6,2-dioxazaborocane-4,8-dione (0.50 g, 2.74 mmol) in THF (23 ml) was heated at 90°C for 5 hours, then at 70°C for additional 16 hours

The reaction mixture was allowed to cool to room temperature, then diluted with DCM and filtered through Celite®, eluting with additional DCM. The filtrate was concentrated in vacuo then purified by flash column chromatography (silica, ethyl acetate/methanol gradient) to give 5-benzyloxy-4-(2bromo-3-chloro-6-fluorophenyl)-2,6-dimethylpyridazin-3 -He; 2-[(E)-2-[2-(5-benzyloxy-2,6-dimethyl-3oxopyridazin-4-yl)-6-chloro-3-fluorophenyl]vinyl]-6-methyl-1,3,6 ,2-dioxazaborocane-4,8-dione (904 mg, 74% yield).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.26 (s, 3H) 2.79 (s, 3H) 3.73 (s, 7H) 4.60 (s, 2H) 5.97 (d, J=18.6 Hz, 1H) 6.76 (d, J=18.5 Hz, 1H) 7.02 (t, J=8.6 Hz, 1H) 7.09 (dd, J=6.7 , 3.00 Hz, 2H) 7.29-7.34 (m, 3H) 7.44 (dd, J=8.9, 5.1 Hz, 1H).

2.3. 5-Behuyloxy-4-[3-chloro-6-fluoro-2-[(E)-2-(1H-indol-5-yl)vinyl]phenyl]-2,6-dimethylpyridazin-3one.

2-[(E)-2-[2-(5-benzyloxy-2,6dimethyl-3-oxopyridazin-4-yl)-6-chloro-3-fluorophenyl]vinyl]-6- was added to the vial for microwave treatment. methyl 1,3,6,2-dioxazaborocane-4,8-dione (300 mg, 0.56 mmol), 5-bromo-III-indole (163 mg, 0.84 mmol), Pd(dppf)Cl ₂ -DCM (23 mg, 0.028 mmol) and

- 47 047300

K3PO4-H2O (512 mg, 2.22 mmol). The vial was then sealed and purged with N2 before adding THF (5.6 ml) and water (0.2 ml). The reaction mixture was then heated to 90°C for 30 min under microwave irradiation.

The reaction mixture was cooled to room temperature, then partitioned between water (20 ml) and EtOAc (20 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x20 ml). The combined organic layers were collected, dried (MgSO ₄ ), filtered and concentrated in vacuo to give the crude product.

The crude product was purified by mass directed preparative reverse phase HPLC to give 5-benzyloxy-4-[3-chloro-6-fluoro-2-[(E)-2-(III-indol-5-yl)vinyl]phenyl ]-2,6dimethylpyridazin-3-one (45 mg, 16% yield).

¹ H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 3H) 3.76 (s, 3H) 4.70 (d, J=5.3 Hz, 2 H) 6.53 (t, J =2.1 Hz, 1H) 6.78-6.86 (m, 1H) 6.88-6.94 (m, 1H) 7.01 (t, J=8.6 Hz, 1H) 7.12 -7.17 (m, 2H) 7.19 (t, J=2.8 Hz, 1H) 7.21-7.25 (m, 1H) 7.29-7.35 (m, 4H) 7 .47 (dd, J=8.9, 5.3 Hz, 1H) 7.55 (s, 1H) 8.25-8.44 (m, 1H).

2.4. 4-[3-Chloro-6-fluoro-2-[2-(1H-indol-5-yl)ethyl]phenyl]-5-hydroxy-2,6-dimethylpyridazin-3-one (A1.021).

5-Benzyloxy-4-[3-chloro-6-fluoro-2-[(E)-2-(1H-indol-5-yl)vinyl]phenyl]-2,6-dimethylpyridazin-3-one (45 mg , 0.09 mmol) was subjected to catalytic hydrogenation in tetrahydrofuran (0.23 ml) in the presence of 5% Pd/C catalyst (38 mgx2) at a pressure of H ₂ 3 bar.

Once complete, the reaction mixture was filtered through a pad of Celite® eluting with DCM. The filtrate was concentrated in-vacuo to obtain a crude residue.

The residue was adsorbed onto silica and purified by flash column chromatography (silica, eluting with ethyl acetate/isohexane) to give 4-[3-chloro-6fluoro-2-[2-(1H-indol-5-yl)ethyl]phenyl]- 5-hydroxy-2,6-dimethylpyridazin-3-one (24 mg, 65% yield, A1.021).

¹ H NMR (400 MHz, CDCh) δ ppm 2.18 (s, 3H) 2.70-2.96 (m, 4H) 3.69 (s, 3H) 6.44 (ddd, J=3.0 , 2.0, 0.7 Hz, 1H) 6.78 (dd, J=8.3, 1.6 Hz, 1H) 6.89 (t, J=8.6 Hz, 1H) 7.14- 7.18 (m, 1h) 7.18-7.26 (m, 2 h) 7.37 (dd, J=8.8, 5.14 Hz, 1H) 8.21 (brs, 1H).

Example 3 Preparation of 4-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-5-hydroxy2,6-dimethylpyridazin-3-one (1.343).

3.1. [5-[3-Chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl] 1,3-dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate.

[5-(2-Bromo-3-chloro-6-fluorophenyl)-1,3-dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate (5.00 g, 11.97 mmol, 1.0 eq .), 6-methyl-2-vinyl-1,3,6,2-dioxazaborocane-4,8-dione (2.63 g, 14.36 mmol, 1.2 eq.) and chloro[(tri-tert -Butylphosphine)-2-(2-aminobiphenyl)]palladium(P) (307 mg, 0.60 mmol, 0.05 eq.) was loaded

- 48 047300 in a 250 ml round bottom flask equipped with a condenser, magnetic stir bar and nitrogen bubbler. THF (100 mL) was added followed by N-diisopropylethylamine (4.2 mL, 23.94 mmol, 2.0 eq.) against a stream of nitrogen and the mixture was heated to reflux for 3 hours.

The reaction mixture was allowed to cool to room temperature, then diluted in DCM and filtered through Celite®, washing with additional DCM. The eluent was then concentrated to dryness.

The crude product was purified by flash column chromatography to give [5[3-chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocane -2-yl)vinyl]phenyl]-1,3-dimethyl-6oxopyridazin-4-yl]-2-methylpropanoate (5.91 g, 11.4 mmol, 95% yield) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.63 (dd, J=5.1, 8.9 Hz, 1H), 7.31 (t, J= 8.9 Hz, 1H), 6.65 (d, J=18.3 Hz, 1H), 5.68 (d, J=18.3 Hz, 1H), 4.24 (dd, J=11.9, 17.2 Hz, 2H ), 3.95-3.83 (m, 2H), 3.70 (s, 3H), 2.66 (spt, J=7.0 Hz, 1H), 2.16 (s, 3H), 0 .90 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H)

3.2. [5-[3-Chloro-6-fluoro-2-[(E)-2-(3-methylbenzotriazol-5-yl)vinyl]phenyl]-1,3-dimethyl-6-oxopyridazin-4-yl]- 2-methylpropanoate (4.343).

[5-[3-Chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl] -1,3dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate (700 mg, 1.35 mmol), complex of 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(P) and dichloromethane [PdCl ₂ (dppf) -DCM] (55 mg, 0.067 mmol), 6-bromo-1methylbenzotriazole (371 mg, 1.75 mmol) and potassium phosphate (1.17 mg, 5.39 mmol) were added to a 10-20 mL microwave vial . 2-Methyltetrahydrofuran (10 ml) and water (0.5 ml) were added, then the reaction mixture was degassed by pumping and filling with nitrogen (x3). The reaction mixture was heated to 120°C for 60 min under microwave irradiation.

The reaction mixture was filtered through a pad of Celite®, washing with EtOAc and EtOH. The filtrate was concentrated under reduced pressure to give a brown gum (853 mg). The crude material was purified by automated silica gel flash chromatography system eluting with cyclohexane/ethyl acetate to give [5-[3-chloro-6-fluoro-2-[(E)-2-(3methylbenzotriazol-5-yl)vinyl] phenyl]-1,3-dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate (4.343) as an orange gum (622 mg, 87% yield).

The purified material was dissolved in acetonitrile (10 ml) and treated with SiliCycle SiliaMetS® thiol (SH) metal absorption resin (622 mg) at room temperature. The suspension was stirred at room temperature for 1.5 hours, then filtered to remove the resin, washing with additional acetonitrile. The filtrate was concentrated in vacuo to give [5-[3chloro-6-fluoro-2-[(E)-2-(3-methylbenzotriazol-5-yl)vinyl]phenyl]-1,3-dimethyl-6-oxopyridazin-4 -yl]-2methylpropanoate (4.343) as a white solid (583 mg, 87% yield).

^1H NMR(400 MHz, chloroform) 7.96 (d, J=9.0 Hz, 1H), 7.39 - 7.49 (m, 3H), 7.15 (d, J=16.3 Hz , 1H), 7.05 (t, J=8.7 Hz, 1H), 6.81 (d, J=16.3 Hz, 1H), 4.29 (s, 3H), 3.68 (s , 3H), 2.67(spt, J=7.0 Hz, 1H), 2.23 (s, 3H), 1.13 (d, J=7.0 Hz, 3H), 1.09 (d , J=7.0 Hz, 3H)

3.3. [5-[3-Chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-1,3-dimethyl-6-oxopyridazin4-yl]-2-methylpropanoate

[5-[3-Chloro-6-fluoro-2-[(E)-2-(3-methylbenzotriazol-5-yl)vinyl]phenyl]-1,3-dimethyl-6-oxopyridazin-4yl]-2- Methyl propanoate (496 mg, 1.00 mmol) was catalytically hydrogenated in EtOAc (10 ml) in

- 49 047300 in the presence of 5% Pd/C catalyst (50% humidity) (0.21 g) at a pressure of H ₂ 3 bar for 18 hours.

The reaction mixture was filtered through a pad of Celite®, washing with ethyl acetate. The filtrate was concentrated in-vacuo to give a crude residue (503 mg), which was purified by reverse phase mass directed HPLC to give [5-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5yl)ethyl] phenyl]-1,3-dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate as a colorless gum (332 mg, 67% yield).

^1H NMR (400 MHz, chloroform) δ=7.92 (d, J=8.6 Hz, 1H), 7.43 (dd, J=5.1, 8.7 Hz, 1H), 7.24 (br s, 1H), 7.17 (dd, J=1.3, 8.6 Hz, 1H), 7.01 (t, J=8.7 Hz, 1H), 4.26 (s, 3H ), 3.81 (s, 3H), 3.11-2.91 (m, 3H), 2.86-2.72 (m, 1H), 2.54 (spt, J=7.0 Hz, 1H), 2.25 (s, 3H), 0.98 (d, J=7.1 Hz, 3H), 0.96 (d, J=7.0 Hz, 3H)

3.4. Preparation of 4-[3-chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-5-hydroxy-2,6dimethylpyridazin-3-one (1.343).

[5-[3-Chloro-6-fluoro-2-[2-(3-methylbenzotriazol-5-yl)ethyl]phenyl]-1,3-dimethyl-6-oxopyridazin-4yl]-2-methylpropanoate (332 mg , 0.67 mmol) was stirred in ethanol (5 ml) at room temperature. A solution of lithium hydroxide monohydrate (85 mg, 2.00 mmol) in water (2 mL) was added dropwise and the reaction mixture was stirred at room temperature for 21 hours.

The ethanol solvent was removed under reduced pressure, then the residue was diluted with water (20 ml). The aqueous phase was acidified to pH ~3-4 by adding 2 M HCl (aq), then extracted with EtOAc (3x10 ml). The combined organic extracts were concentrated under reduced pressure to give a white solid (240 mg). The crude residue was purified by automated flash silica chromatography system with cyclohexane/ethyl acetate gradient elution to give 4-[3-chloro-6-fluoro-2-[2-(3methylbenzotriazol-5-yl)ethyl]phenyl]-5 -hydroxy-2,6-dimethylpyridazin-3-one (1.343) as a white solid (196 mg, 69%).

¹ H NMR (400 MHz, acetonitrile) δ ppm 7.83 (d, J=8.6 Hz, 1H), 7.57 (dd, J=5.2, 8.8 Hz, 1H), 7.33 (s, 1H), 7.10-7.18 (m, 2H), 4.22 (s, 3H), 3.64 (s, 3H), 2.84-3.07 (m, 4H) 2 .21 (s, 3H).

Example 4 Preparation of 4-[2-[2-(1,3-benzothiazol-5-yl)ethyl]-3-chloro-6-fluorophenyl]-5-hydroxy-2,6dimethylpyridazin-3-one (1.350).

4.1. 4-[2-[(E)-2-(1,3-Benzothiazol-5-yl)vinyl]-3-chloro-6-fluorophenyl]-5-hydroxy-2,6-dimethylpyridazin-3-one.

[5-[3-Chloro-6-fluoro-2-[(E)-2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl]phenyl] -1,3dimethyl-6-oxopyridazin-4-yl]-2-methylpropanoate (500 mg, 0.96 mmol), 5-bromo-1,3-benzothiazole (309 mg, 1.44 mmol), complex 1,1 -bis(diphenylphosphino)ferrocene]dichloropalladium(P) and dichloromethane

[PdCl ₂ (dppf)-DCM] (4 mg, 0.05 mmol) and POTASSIUM CARBONATE (403 mg, 2.89 mmol) were added to a 10-20 ml microwave vial under nitrogen atmosphere. Degassed aceto was added

- 50 047300 nitrile (8 ml) and water (2 ml), and the mixture was heated to 150°C for 30 minutes under microwave irradiation.

The reaction mixture was concentrated to dryness. The residue was treated with water (10 ml) and the aqueous phase was acidified to pH 4 by adding 1 M HCl (aq). DCM (20 ml) was added and the layers were separated. The aqueous phase was further extracted with DCM/MeOH (8:1) (2x10 ml), then the combined organic extracts were dried and concentrated to give a brown oil. The crude material was purified by automated silica gel flash chromatography system eluting with cyclohexane/ethyl acetate to give 4-[2-[(E)-2-(1,3benzothiazol-5-yl)vinyl]-3-chloro-6- fluorophenyl]-5-hydroxy-2,6-dimethylpyridazin-3-one as a white solid (302 mg, 73% yield).

The resulting product was dissolved in 3:2 methanol/ethyl acetate (25 ml). The solution was treated with activated carbon (100 mg), then stirred at room temperature. for 1 hour. The mixture was filtered through Celite®, then washed with additional MeOH/EtOAc 3:2 (10 ml). The filtrate was treated with SiliCycle SiliaMetS® thiol (SH) metal scavenging resin (300 mg), then stirred at RT for 16 hours. The mixture was filtered to remove the resin, then the filtrate was concentrated in vacuo to give an off-white solid ( 286 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=10.84 (br s, 1H), 9.41 (s, 1H), 8.14 (d, J=8.4 Hz, 1H), 8 .00 (d, J=1.5 Hz, 1H), 7.62 (dd, J=5.1, 8.7 Hz, 1H), 7.54 (dd, J=1.5, 8.4 Hz, 1H), 7.29 (t, J=8.7 Hz, 1H), 7.09 (d, J=16.5 Hz, 1H), 6.74 (d, J=16.5 Hz, 1H), 3.54 (s, 3H), 2.18 (s, 3H).

4.2. 4-[2-[2-(1,3-Benzothiazol-5-yl)ethyl]-3-chloro-6-fluorophenyl]-5-hydroxy-2,6-dimethylpyridazin-3 one (1.350).

To a solution of 4-[2-[(E)-2-(1,3-benzothiazol-5-yl)vinyl]-3-chloro-6-fluorophenyl]-5-hydroxy-2,6dimethylpyridazin-3-one (835 mg, 1.95 mmol) in tetrahydrofuran (30 ml) under nitrogen atmosphere was added H^diisopropylethylamine (2.70 ml, 16.0 mmol). The stirred reaction mixture was heated to 70°C and 2,4,6-triisopropylbenzenesulfonylhydrazide (5.17 g, 15.6 mmol) was added in portions over 4 hours, then the mixture was heated to reflux for 16 hours. additional ^^diisopropylethylamine (1.70 mL, 9.80 mmol), then 2,4,6triisopropylbenzenesulfonylhydrazide (3.24 g, 9.77 mmol) and the mixture was heated to reflux for an additional 6 hours.

The reaction mixture was allowed to cool to room temperature, then concentrated directly into silica. The crude material was partially purified by an automated silica gel flash chromatography system eluting with cyclohexane/ethyl acetate gradient. The resulting material was further purified by reverse phase mass directed HPLC to give 4-[3-chloro-6-fluoro-2-[2-[4(methylsulfanylmethyl)phenyl]ethyl]phenyl]-5-hydroxy-2,6- dimethylpyridazin-3-one (1.350) as a pale yellow solid (227 mg, 27% yield).

¹ H NMR (500 MHz^MBO^) δ ppm 10.84 (br. s, 1H), 9.35 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7, 71 (d, J=1.0 Hz, 1H), 7.55 (dd, J=5.2, 8.8 Hz, 1H), 7.23 (t, J=8.8 Hz, 1H), 7.16 (dd, J=1.0, 8.3 Hz, 1H), 3.62 (s, 3H), 2.93-2.70 (m, 4H), 2.26 (s, 3H) .

Example 5. Preparation of [3-chloro-2-[2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl]-6-fluorophenyl]-5hydroxy-2,6-dimethylpyridazin-3-one (1.361).

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5.1. [5-[3-Chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl]phenyl]-1,3-dimethyl6 -oxopyridazin-4-yl]-2-methylpropanoate.

Ir(COD)Cl ₂ (299 mg, 0.45 mmol) and 4diphenylphosphanylbutyl(diphenyl)phosphane (0380 mg, 0.89 mmol) were then charged into an oven-dried round bottom flask. The flask was evacuated and filled with nitrogen (x3), then THF (75 ml) was added and the reaction mixture was stirred at room temperature for 30 min. A solution of [5-(3-chloro-6-fluoro-2-vinylphenyl)-1,3-dimethyl6-oxo-pyridazin-4-yl]-2-methylpropanoate [prepared as described in Example 4] was added dropwise (6 .7 g, 17.8 mmol) in THF and the mixture was stirred for 10 min followed by the dropwise addition of 4,4,5,5-tetramethyl1,3,2-dioxaborolane (3.02 mL, 20.8 mmol). The reaction mixture was stirred at 60°C overnight.

After 24 hours, the reaction mixture was cooled to room temperature, then it was concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a cyclohexane/ethyl acetate gradient to give [5-[3-chloro-6fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)ethyl]phenyl]-1,3-dimethyl-6-oxo-pyridazin-4yl]-2-methylpropanoate (4.50 g, 51% yield) as a yellow solid.

1H NMR (500 MHz, chloroform) δ=7.35 (dd, J=5.2, 8.9 Hz, 1H), 6.90 (t, J=8.6 Hz, 1H), 3.81 ( s, 3H), 2.59 (t, J=8.5 Hz, 2H), 2.53 (spt, J=7.0 Hz, 1H), 2.24 (s, 3H), 1.32- 1.16 (m, 12H), 1.08-1.00 (m, 2H), 0.98 (d, J=7.0 Hz, 3H), 0.94 (d, J=7.0 Hz , 3H).

5.2. [3-Chloro-2-[2-(2,2-dimethyl-1,3-benzodioxol-5-yl)ethyl]-6-fluorophenyl]-5-hydroxy-2,6-dimethylpyridazin-3-one (1.361 ).

5-Bromo-2,2-dimethyl-1,3-benzodioxole (70 mg, 0.30 mmol) was loaded into a 2-5 ml microwave vial. [5-[3-Chloro-6-fluoro-2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)ethyl]phenyl]-1,3-dimethyl-6 -oxopyridazin-4-yl]-2-methylpropanoate (100 mg, 0.20 mmol) was added as a solution in 1,4-dioxane (2 ml) followed by chloro(2-dicyclohexylphosphino-2',6'diisopropoxy- 1,G-biphenyl)[2-(2'-amino-1,G-biphenyl)]palladium(P) (RuPhos Pd-G2) (26 mg, 0.03 mmol) as solution in 1,4-dioxane (2 ml). 2 M aqueous potassium carbonate (0.30 mL, 0.61 mmol) was added and the mixture was heated to 140°C for 80 min under microwave irradiation.

The reaction mixture was cooled to room temperature, then filtered through a pre-wetted cartridge with 0.5 g silica-bound TMT, washing with acetonite ryl (2x2 ml). The filtrate was concentrated to dryness, then purified by reverse phase mass HPLC to give [3-chloro-2-[2-(2,2-dimethyl-1,3-benzodioxol-5yl)ethyl]-6-fluorophenyl]-5 -hydroxy-2,6-dimethylpyridazin-3-one (1.361) as a white solid (15 mg, 17% yield).

¹ H NMR (500 MHz, chloroform) δ ppm 7.43 (dd, J=5.2, 8.7 Hz, 1H), 6.99 (t, J=8.7 Hz, 1H), 6.56 (d, J=7.7 Hz, 1H), 6.40-6.36 (m, 2H), 3.74 (s, 3H), 2.85-2.78 (m, 1H), 2, 77-2.61 (m, 3H), 2.30 (s, 3H), 1.65 (s, 3H), 1.64 (s, 3H).

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Connections 1.019, 1.021, 1.027, 1.028, 1.036, 2.034, 3.030, 3.034, 4.034, 1.339, 1.340, 1.341, 1.342, 1.344, 1.345, 1.346, 1.347, 1.348, 1.349, 1.351, 1.352, 1.353, 1.354, 1.355, 1.356 , 1.044, 1.053, 1.357, 1.358, 1.359, 1.360, 2.362, 2.363 and 4.342 were prepared using the general methods described above. In table Figure 5 below shows the structure of these compounds and NMR data characterizing them.

In table 5. examples of the preparation of compounds of formula (I) are given. The numbering system used to describe the X and Y positions is shown for clarity only.

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Table5

Examples of preparation of compounds of formula (I)

Connection no. R ¹ R ² G X Y w D Detailed NMR data 1.019 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 1,2,3,4- tetrahydroquinolin6-yl- ¹ H NMR (400 MHz, chloroform) δ ppm 1.91 (br d, 1=5.26 Hz, 3 Η) 2.30 (s, 3 Η) 2.50 - 2.84 (m, 5 Η) 3.19-3.30 (m, 2 Η) 3.46 (s, 1 Η) 3.73 (s, 3 Η) 6.35 (d, 1=8.56 Hz, 1 Η) 6.57 - 6.65 (m, 2 Η) 6.97 (t, 1=8.56 Hz, 1 Η) 7.41 (dd, J=8.80, 5.14 Hz, 1H) 1.021 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 1N-IDOL-5-IL- ¹ H NMR (400 MHz, chloroform) δ ppm 2.18 (s, 3 H) 2.70 - 2.96 (m, 4 H) 3.69 (s, 3 H) 6.44 (ddd, 1= 3.00, 2.02, 0.73 Hz, 1 H) 6.78 (dd, 1=8.31, 1.59 Hz, 1 H) 6.89 (t, 1=8.56 Hz, 1H ) 7.14-7.18 (m, 1H) 7.18-7.26 (m, 2H) 7.37 (dd, J=8.80, 5.14 Hz, 1H) 8.21 (brs , 1H) 1.027 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2 -(trifluoromethyl)4-quinolyl- ¹ H NMR (400 MHz, chloroform) δ ppm 2.28 (s, 3 H) 2.81-2.94 (m, 1 H) 3.01 (brd, 1=6.11 Hz, 1 H) 3 .35 (s, 2 H) 3.75 (s, 3 H) 7.04 (t, 1=8.56 Hz, 1 H) 7.42 - 7.49 (m, 2 H) 7.58 ( ddd, 1=8.31, 6.97, 1.10 Hz, 1 H) 7.79 (ddd, 1=8.41,6.94, 1.28 Hz, 1 H) 7.86 (d, 1=8.07 Hz, 1 H) 8.20 (d, 1=8.56 Hz, 1 H) 1.028 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2-ethyl-1,3benzoxazol-6-yl- ^1H NMR (400 MHz, methanol) δ = 7.49 (dd, 1 = 5.3, 8.8 Hz, 1H), 7.40 (d, 1 = 8.3 Hz, 1H), 7.26 (d, 1 = 1.2 Hz, 1H), 7.08 (t, 1 = 8.8 Hz, 1H), 7.02 (dd, 1 = 1.2, 8.3 Hz, 1H), 3 .73 (s, 3H), 2.96 (q, 1 = 7.6 Hz, 2H), 2.91-2.74 (m, 4H), 2.33 (s, 3H), 1.42( 1.1 = 7.6 Hz, 3H) 1.036 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 4-quinolyl- ¹ H NMR (400 MHz, chloroform) δ ppm 2.28 (s, 3 H) 2.88 - 3.02 (m, 2 H) 3.24 (ddd, 1=19.47, 10.48, 6 .24 Hz, 2 H) 3.74 (s, 3 H) 7.00 (t, 1=8.56 Hz, 1 H) 7.17 (d, 1=4.52 Hz, 1H) 7.38 -7.51 (m, 2 H) 7.64 - 7.79 (m, 2 H) 8.03 (d, 1=8.19 Hz, 1 H) 8.65 (d, 1=4.40 Hz, 1H) 2,034 -Me -Me -H 6-F 3-C1 (E)- CH=CH- 2 -methyl-6 -quinolyl- ¹ H NMR (400 MHz, solvent) δ ppm 1.11 (1.1=7.15 Hz, 6 Η) 2.23 (s, ZN) 2.63-2.71 (m, 1 Η) 2, 74 (s, 3 Η) 3.69 (s, ZN) 6.81 (d,

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1=16.38 Hz, 1 N) 7.04 (t, 1=8.68 Hz, 1 N) 7.15 (d, 1=16.51 Hz, 1 N) 7.27 (s, 1 N ) 7.45 (dd, 1=8.86, 5.07 Hz, 1 N) 7.63 (d, 1=1.71 Hz, 1 N) 7.757.81 (m, 1 N) 7.94 ( d, 1=8.80 Hz, 1 N) 8.01 (d, 1=8.31 Hz, 1 N) 3,030 -Me -Me -(C=O)iPr 6-F 3-C1 -CH ₂ CH ₂ - 2-methyl-1,2,3,4tetrahydroquinolin6-yl- ¹ H NMR (400 MHz, solvent) δ ppm 0.96 (dd, 1=7.03, 2.02 Hz, 6 Η) 1.25 (d, 1=6.24 Hz, 3 Η) 1.58 - 1.69 (m, 1 Η) 1.90 - 1.98 (m, 1 Η) 2.24 (s, 3 Η) 2.54 (dt, 1=13.94, 6.97 Hz, 1 Η) 2.63 - 2.84 (m, 6 Η) 3.39 (td, 1=6.51, 3.12 Hz, 1 Η) 3.83 (s, 3 Η) 6.52 (br d , 1=6.48 Hz, 1 Η) 6.72 - 6.79 (m, 2 Η) 6.96 (t, 1=8.62 Hz, 1 Η) 7.40 (dd, 1=8, 80, 5.14 Hz, 1H) 3,034 -Me -Me -(C=O)iPr 6-F 3-C1 -CH ₂ - CH ₂ - 2-methyl-6-quinolyl- ¹ H NMR (400 MHz, solvent) δ ppm 0.97 (dd, 1=6.97, 4.40 Hz, 6 Η) 2.24 (s, 3 Η) 2.47 2.57 (m, 1 Η) 2.73 (s, 3 Η) 2.79 - 3.09 (m, 4 Η) 3.84 (s, 3 Η) 7.00 (t, 1=8.62 Hz, 1 Η) 7 .25 (d, 1=8.31 Hz, 1 Η) 7.49 (d, 1=1.10 Hz, 3 Η) 7.90 (d, 1=8.44 Hz, 1 Η) 7.96 (d, 1=8.31 Hz, 1 Η) 4,034 -Me -Me -(C=O)iPr 6-F 3-C1 (E)- CH=CH- 2-methyl-6-quinolyl- ¹ Η NMR (400 MHz, solvent) δ ppm 2.24 (s, 3 Η) 2.66 (s, 3 Η) 3.66 (s, 3 Η) 6.72 (d, 1=16.38 Hz , 1H) 6.93 7.07 (m, 2 Η) 7.26 (s, 1 Η) 7.38 (dd, 1=8.93, 5.14 Hz, 1 Η) 7.55 (d, 1=1.71 Hz, 1 Η) 7.66 (dd, 1=8.80, 1.96 Hz, 1 Η) 7.84 (d, 1=8.80 Hz, 1 Η) 7.99 ( d, 1=8.44 Hz, 1 Η) 1.339 -Me -Me -H 6-F 3-C1 -CH ₂ - CH ₂ - 2-methyl-5-1,3benzothiazolyl- ¹ Η NMR (500 MHz, chloroform) δ ppm 7.64 (d, I = 8.1 Hz, 1H), 7.52 (brs, 1H), 7.19 (dd, I = 5,1,8, 6 Hz, 1H), 7.01 (br d, I =8.1 Hz, 1H), 6.92 (t, I = 8.6 Hz, 1H), 3.80 (s, 3H), 2, 90 - 2.74 (m, 4H), 2.69 (s, 3H), 2.32 (s, 3H) 1,340 -Me -Me -H 6-F 3-C1 -CH ₂ - 2,2-dimethyl-6-3H- ¹ H NMR (400 MHz,

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CH ₂ - benzofuranyl- methanol) δ ppm 7.50 (dd, 1=5,1,8,8 Hz,1H), 7.08 (t, 1=8.8 Hz,1H), 6.97(d, 1=7, 5 Hz,1H), 6.44(dd, 1=1.2, 7.5 Hz,1H), 6.29 (d, J=l,2 Hz, 1H), 3.73 (s, 3H) , 2.93 (s, 2H), 2.79 2.50 (m, 4H), 2.33 (s, 3H), 1.41 (s, 6H) 1.341 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2-methyl-6-1,3benzoxazolyl- ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (br.s, 1H), 7.54 (dd,J=5.2, 8.9 Hz, 1H), 7.50 (d, 1=8.1 Hz, 1H), 7.24 (d, 1=1.4 Hz, 1H), 7.22 (t, 1=8.9 Hz, 1H), 6.96 (dd, 1= 1.4, 8.1 Hz, 1H), 3.61 (s, 3H), 2.87 - 2.66 (m, 4H), 2.57 (s, 3H), 2.25 (s, 3H ) 1,342 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2,2-difluoro-5-1,3benzodioxolyl- ^1H NMR (400 MHz, chloroform) δ ppm 7.38 (dd, 1=8.8, 5.1 Hz, 1H), 6.94 (t, 1=8.8 Hz, 1H), 6.87 (d, 1=8.1 Hz, 1H), 6.70-6.63 (m, 2H), 3.68 (s, 3H), 2.76 - 2.65 (m, 4H), 2, 26 (s, 3H) 1,344 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 1-methyl-3indazolyl- ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.86 (s, 1H), 7.59 - 7.53 (m, 2H), 7.34 (t, 1=7.2 Hz, 1H) , 7.27 - 7.21 (m, 2H), 7.02 (t, 1=7.2 Hz, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 2, 99 - 2.92 (m, 2H), 2.87 2.83 (m, 2H), 2.23 (s. 3H) 1.345 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 1 -methyl-5 pyrrolo[2,3b]pyridinyl- ¹ H NMR (400 MHz, methanol) δ ppm 8.12 (d, 1=1.7 Hz, 1H), 7.95 (d, 1=1.7 Hz, 1H), 7.52 (d, 1 =3.5 Hz, 1H), 7.46 (dd, 1=5,1,8,8 Hz, 1H), 7.10 (t, 1=8.8 Hz, 1H), 6.64 (d , 1=3.5 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 3.11 2.99 (m, 2H), 2.98 - 2.82 (m , 2H), 2.30 (s, 3H) 1,346 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 5-benzofuranyl- ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.82 (s, 1H), 7.93 (d, 1=1.8 Hz, 1H), 7.57-7.53 (m, 1H) , 7.45 (d, 1=8.4 Hz, 1H), 7.28 (br. s, 1H), 7.21 (t, 1=8.5 Hz, 1H), 6.92 (d, 1=8.4 Hz, 1H), 6.87 (br. s, 1H), 3.61 (s, 3H), 2.76-2.67 (m, 4H),

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2.25 (s, ZN) 1,347 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 6-benzothiophenyl- ^1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.87 (d, 1=8.24 Hz, 1H), 7.72 (d, 1=5.4 Hz ,1H), 7.58 -7.54 (m, 1H), 7.52 (s, 1H), 7.37 (d, 1=5.4 Hz, 1H), 7.22 (t, 1= 8.8 Hz, 1H), 7.00 (d, 1=8.24 Hz, 1H), 3.61 (s, 3H), 2.79 - 2.69 (m, 4H), 2.25 ( s.3H) 1,348 -Me -Me -H 6-F 3-C1 -CH ₂ - CH ₂ - 5-benzothiophenyl- ^1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 7.86 (m, 1H), 7.72 (m, 1H), 7.58-7.52 (m, 2H), 7.37 (m, 1H), 7.22 (m, 1H), 7.01-6.98 (m, 1H), 3.61 (s, 3H), 2.79 - 2.71 (m,4H), 2.25 (s, 3H) 1,349 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 6-1,3- benzothiazolyl- 'NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 9.30 (s, 1H), 7.95 (d, 1=8.3 Hz, 1H), 7.81 ( s, 1H), 7.57 - 7.53 (m, 1H), 7.24-7.16 (m, 2H), 3.59 (s, 3H), 2.82-2.73 (m, 4H), 2.24 (s. 3H) 1.351 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 3-methyl-6-1,2benzoxazolyl- % NMR (400 MHz, DMSO-d6) δ ppm 10.81 (s, 1H), 7.70 (d, 1=8.04 Hz, 1H), 7.54 (m, 1H), 7.29 ( s, 1H), 7.21 (t, J=8.7 Hz, 1H), 7.01 (d, 1=8.04 Hz, 1H), 3.60 (s, 3H), 2.86 - 2.73 (m, 4H), 2.50 (s, 3H), 2.24 (s. 3H) 1.352 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 5-2-oxo-3N-1,3benzoxazolyl- ¹ H NMR (400 MHz, methanol) δ ppm 7.49 (dd, 1=5,1,8,8 Hz, 1H), 7.09 (t, 1=8.8 Hz, 1H), 7.04 (d, 1=8.2 Hz, 1H), 6.74 (dd, 1=1.5, 8.2 Hz, 1H), 6.71 (d, 1=1.5 Hz, 1H), 3 .72 (s, 3H), 2.88 - 2.65 (m, 4H), 2.32 (s, 3H) 1.353 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 6-1- methylindazolyl- ^1H NMR (400 MHz, methanol) δ ppm 7.90 (d, 1=1.0 Hz, 1H), 7.58 (dd, 1=0.6, 8.3 Hz, 1H), 7.51 (dd, J=5,l, 8.8 Hz, 1H), 7.10 (br. s, 1H), 7.11(1, 1=8.8 Hz, 1H), 6.81 (dd, 1=1.0, 8.3 Hz, 1H), 3.98 (s, 3H), 3.68 (s, 3H), 2.99 - 2.77 (m, 4H), 2.27 (s , 3H)

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1.354 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 5-1- methylindazolyl- ^1H NMR (400MHz, methanol) 7.86 (s, 1H), 7.49 (dd, J=5.l, 8.8 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.35 (s, 1H), 7.09 (t, J=8.8 Hz, 1H), 7.07 (d, J=8.6 Hz, 1H), 4.00 (s, ZN), 3.70 (s, ZN), 2.922.74 (w, 4N), 2.30 (s, ZN) 1.355 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 6-1 -methylindolyl- ^1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, W), 7.58 - 7.55 (m, 1H), 7.40 (d,lH), 7.23 7.20 (m, 2H), 6.93 (s, 1H), 6.66 (d, 1H), 6.33 (d, 1H), 3.71 (s, 3H), 3.62 (s, 3H) , 2.76 - 2.68 (m, 4H), 2.26 (s, 3H) 1.356 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 5-1 -methylindolyl- ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, W), 7.57 - 7.54 (m, 1H), 7.33 -7.29 (m, lH), 7, 26 (d,lH), 7.21 (t, 1H), 7.15 (s, 1H), 6.76 (d, 1H), 6.31 (d, 1H), 3.73 (s, 3H ), 3.61 (s, 3H), 2.72-2.64 (m, 4H), 2.27 (s, 3H) 1,044 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 1-naphthyl- ¹ H NMR (400 MHz, DMSO-d6) δ ppm 10.96 (s, W), 7.91 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz , 1H), 7.63 - 7.59 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7 .44-7.36 (m, 2H), 7.287.23 (m, 2H), 3.64 (s, 3H), 3.12-3.03 (m, 2H), 2.80 - 2.72 (m, 2H), 2.28 (s. 3H) 1.053 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2-naphthyl- ^1H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, W), 7.86 - 7.78 (m, 3H), 7.58-7.55 (m, 1H), 7, 51 -7.42 (m, 3H), 7.23 (t, J=8.7 Hz, 1H), 7.167.14 (1H), 3.61 (s, 3H), 2.88 - 2.72 (m, 4H), 2.25 (s, 3H) 1.357 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 5-2-oxoindolinyl- ¹ HNMR (400 MHz, DMSO-d6) 10.82 (br. s, 1H), 10.28 (s, 1H), 7.55 (dd, J=5.3, 8.7 Hz, 1H), 7.21 (t, 1=8.7Hz, 1H), 6.85 (br.s, 1H), 6.79 (br.d, J=7.8 Hz, 1H), 6.68 (d, 1=7.8Hz. 1H), 3.61 (s, 3H), 3.40 (s, 2H), 2.73 2.52 (m, 4H), 2.26 (s, 3H)

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1.358 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2-methyl-1,3- DIOXOIZOINDOLIN5-yl- ^1H NMR (500 MHz, chloroform) δ ppm 7.68 (d, J = 7.6 Hz, 1H), 7.52 (br s, 1H), 7.45 (dd, J = 5.2, 8 .7 Hz, 1H), 7.39 7.34 (m, 1H), 7.05 (t, J = 8.7 Hz, 1H), 3.78 (s, 3H), 3.15 (s, 3H), 3.04 - 2.85 (m, 3H), 2.82-2.71 (m, 1H), 2.32 (s, 3H) 1.359 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2-1,3- benzoxazolyl- 'NMR (400 MHz, d6DMSO), δ ppm 10.81 (s,lH), 7.65 -7.57 (m, 3H), 7.36 - 7.30 (m, 2H), 7.28 - 7.23 (t,lH), 3.53 (s, 3H), 3.09 - 2.99 (m, 4H), 2.19 (s, 3H) 1,360 -Me -Me -H 6-F 3-C1 -CH ₂ CH ₂ - 2-1,3-benzothiazolyl ^1H NMR (400 MHz, DMSO-D6) δ ppm 10.85 (br. s,lH), 8.04-8.02 (d, 1H), 7.91-7.89 (d, 1H), 7.61 -7.58(dd, 1H), 7.49 -7.46(1, 1H), 7.41-7.37 (t, 1H), 7.28 - 7.23 (t, 1H ), 3.57 (s, 3H), 3.26 - 3.13 (m, 2H), 3.07 - 2.92 (m, 2H), 2.21 (s, 3H) 2,362 -Me -Me -H 6-F 3-C1 (E)- CH=CH- 6-2,2-dimethyl-3Nbenzofuranyl- *H NMR (400 MHz, methanol) 7.52 (dd, 1=5.1, 8.8 Hz, 1H), 7.12(1, 1=8.8 Hz, 1H), 7.05 (d, 1=7.6 Hz, 1H), 6.91 (d, 1=16.4 Hz, 1H), 6.70 (dd, 1=1,3,7.6 Hz, 1H), 6.62 ( s, 1H), 6.47 (d, 1=16.4 Hz, 1H), 3.66 (s, 3H), 2.97 (s, 2H), 2.26 (s, 3H), 1, 42 (s, 6H) 2,363 -Me -Me -H 6-F 3-C1 (E)- CH=CH- 6-imidazo[1,2a]pyrazinyl- ¹ H NMR (400 MHz, DMSO-d6) 10.83 (br. S, 1H), 9.06 (s, 1H), 8.55 (d, 1=1.1 Hz, 1H), 8.07 ( s, 1H), 7.79 (d, 1=1.1 Hz, 1H), 7.63 (dd, 1=5.3, 8.8 Hz, 1H), 7.48 (d, 1=15 ,9 Hz, 1H), 7.28 (1.1=8.8 Hz, 1H), 6.65 (d, 1=15.9 Hz, 1H), 3.56 (s, 3H), 2, 20 (s, 3H) 4,342 -Me -Me (C=O)iPr 6-F 3-C1 (E)CH=CH- 2,2-difluoro-5-1,3benzodioxolyl- ^1H NMR (400 MHz, chloroform) δ = 7.43 (dd, 1 = 5.1, 8.9 Hz, 1H), 7.12 (d, 1 = 1.6 Hz, 1H), 7.05 6.95 (m, 3H), 6.91 (d, 1 = 16.5 Hz, 1H), 6.60 (d, 1 = 16.5 Hz, 1H), 3.71 (s, 3H), 2.64 (spt, 1 = 7.0 Hz, 1H), 2.23 (s, 3H), 1.10 (d, 1 = 7.0 Hz, 3H), 1.07 (d, 1 = 7.0 Hz, 3H)

Biological examples.

B1 Post-emergence efficiency - test 1.

Seeds of a number of tested species were sown in standard soil in pots: Solarium nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). After cultivation for 8 days (post-emergence) under controlled greenhouse conditions (at 24/16°C, day/night; 14-hour photoperiod; 65% humidity), the plants were sprayed with an aqueous spray solution obtained from

- 59 047300 composition based on the technical active ingredient in an acetone/water solution (50:50) containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). The compounds were applied at a rate of 250 g/ha. The test plants were then grown in a greenhouse under controlled greenhouse conditions (24/16°C, day/night; 14-hour photoperiod; 65% humidity) and watered twice daily. After 13 days, the test assessed the damage, expressed as a percentage, that had been caused to the plant. Biological activity values were determined on a five-point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A missing value in the table indicates that the compound was not tested against that species.

Table 6

Control of certain weed species using compounds of formula (I) after post-emergence application

Compound AMARE SOLNI SETFA LOLPE ECHCG IPOHE 1.019 4 5 5 5 3 5 1.027 2 4 4 4 5 1.028 5 5 5 5 5 5 1.036 5 5 5 5 5 5 2,034 1 5 2 2 3 3,030 5 5 5 5 5 5 3,034 4 5 5 5 4 4 4,034 1 5 2 1 3 1.357 5 5 5 5 4 5 4,342 0 4 1 2 1 3

B2 Post-emergence efficiency - test 2.

Seeds of a number of tested species were sown in standard soil in pots: Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH). After cultivation for 8 days (post-emergence) under controlled greenhouse conditions (at 24/16°C, day/night; 14-hour photoperiod; 65% humidity), the plants were sprayed with an aqueous spray solution prepared from a formulation based on technical active ingredient in an acetone/water solution (50:50) containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN 9005-64-5). The compounds were applied at a rate of 250 g/ha. Test plants were then grown in a greenhouse under controlled greenhouse conditions (24/16°C, day/night; 14-hour photoperiod; 65% humidity) and watered twice daily. After 13 days, the test assessed the damage, expressed as a percentage, that had been caused to the plant. Biological activity values were determined on a five-point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A missing value in the table indicates that the compound was not tested against that species.

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Table 7

Control of certain weed species using compounds of formula (I) after post-emergence application

Compound AMARE ZEAMX SETFA ABUTH ECHCG IPOHE 1.339 4 0 4 3 5 4 1,340 5 5 5 5 5 4 1.341 5 4 4 5 5 5 1,342 5 4 4 5 5 5 1.318 4 2 5 4 4 4 1,344 3 1 4 2 3 1.345 4 2 4 4 3 4 1,346 2 2 0 4 4 3 1,347 4 4 4 4 4 4 1,348 4 4 4 3 4 4 1,349 4 2 4 4 4 4 1,350 4 3 4 5 4 3 1.351 5 5 4 5 4 5 1.352 4 3 4 4 4 3 1.353 4 3 4 4 4 3 1.354 4 4 4 4 5 4 1.355 4 1 2 3 1 4 1.356 5 2 5 4 4 4 1,044 3 1 0 3 0 4 1.053 4 4 4 3 3 4 1.357 2 5 4 4 4 1.359 3 1 3 4 3 2 1,361 3 4 5 5 4 5 2,363 1 0 0 0 0 2

B3 Pre-emergence efficiency - test 1.

Seeds of a number of tested species were sown in standard soil in pots: Solarium nigrum (SOLNI), Amaranthus retoflexus (AMARE), Setaria faberi (SETfA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Lolium perenne (LOLPE). After cultivation for one day (pre-emergence) under controlled greenhouse conditions (24/16°C, day/night; 14-hour photoperiod; 65% humidity), the plants were sprayed with an aqueous spray solution prepared from a formulation based on technical active ingredient in an acetone/water solution (50:50) containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN CAS 9005-64-5). The compounds were applied at a rate of 250 g/ha. The test plants were then grown in a greenhouse under controlled conditions (24/16°C, day/night; 14-hour photoperiod; 65% humidity) and watered twice daily. After 13 days, the test assessed the damage, expressed as a percentage, that had been caused to the plant. Biological activity values were determined on a five-point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A missing value in the table indicates that the compound was not tested against that species.

Table 8

Control of certain weed species using compounds of formula (I) after pre-emergence application

Compound 1.019 AMARE 5 SOLNI 5 SETFA 4 LOLPE 3 ECHCG 1 IPOHE 1 1.027 1 4 1 3 3 3 1.028 5 5 5 5 1 5 1.036 5 5 5 5 5 5 2,034 1 2 1 1 1 0 3,030 5 5 5 5 5 5 3,034 5 5 5 5 5 2 4,034 0 1 0 0 0 0 4,342 1 3 0 0 0 1

B4 Pre-emergence efficiency - test 2.

- 61 047300

Seeds of a number of tested species were sown in standard soil in pots: Amaranthus retoflexus (AMARE), Setaria faberi (SETFA), Echinochloa crus-galli (ECHCG), Ipomoea hederacea (IPOHE), Zea Mays (ZEAMX), Abutilon theophrasti (ABUTH). After cultivation for one day (pre-emergence) under controlled greenhouse conditions (24/16°C, day/night; 14-hour photoperiod; 65% humidity), the plants were sprayed with an aqueous spray solution prepared from a formulation based on technical active ingredient in an acetone/water solution (50:50) containing 0.5% Tween 20 (polyoxyethylene sorbitan monolaurate, CAS RN CAS 9005-64-5). The compounds were applied at a rate of 250 g/ha. The test plants were then grown in a greenhouse under controlled conditions (24/16°C, day/night; 14-hour photoperiod; 65% humidity) and watered twice daily. After 13 days, the test assessed the damage, expressed as a percentage, that had been caused to the plant. Biological activity values were determined on a five-point scale (5=80-100%; 4=60-79%; 3=40-59%; 2=20-39%; 1=0-19%). A missing value in the table indicates that the compound was not tested against that species.

Table 9 Control of selected weed species by compounds of formula (I) after pre-emergence application

Compound AMARE ZEAMX SETFA ABUTH ECHCG IPOHE 1.339 5 1 5 4 5 2 1,340 5 3 5 5 5 5 1.341 5 4 5 5 5 5 1,342 5 1 5 4 5 1.318 5 2 5 3 5 4 1,344 3 0 2 4 2 3 1.345 5 1 5 4 2 5 1,346 3 1 0 4 0 3 1,347 5 3 3 5 2 5 1,348 5 1 3 3 4 5 1,349 5 4 5 4 5 5 1,350 5 4 5 5 5 5 1.351 5 5 5 5 5 5 1.352 5 4 5 4 3 3 1.353 5 4 5 4 5 5 1.354 4 4 5 4 5 5 1.355 3 1 1 0 0 2 1.356 3 0 1 1 1 2 1,044 2 1 0 3 0 3 1.053 4 1 2 2 2 1 1.357 4 1 4 4 4 3 1.359 5 3 5 5 5 4 1,361 4 1 5 5 3 4 2,363 5 2 4 5 5 5 1.339 1 0 1 0 1 0

Claims (12)

1. Compound of formula (I) - 62 047300 or its salt or N-oxide, where R ¹ is selected from the group consisting of methyl, ethyl, n-propyl, cyclopropyl, propargyl and C ₁ haloalkyl; R ² is selected from the group consisting of hydrogen, halogen, C ₁ -C ₆ alkyl, C-C-C-alkyl, C-C/alkoxy. C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl and C ₂ -C ₆ haloalkynyl; G is hydrogen or C(O)R ³ where R ³ is isopropyl, tert-butyl, methyl, ethyl, propargyl, methoxy, ethoxy or tert-butoxy; X represents hydrogen, halogen or C1haloalkyl; Y is hydrogen, C ₁ -C ₃ alkyl, cyclopropyl, C 1 -C ₃ haloalkyl or halogen; D is either a substituted or unsubstituted naphthalene ring system, or a substituted or unsubstituted 8-10 membered bicyclic saturated, partially saturated or unsaturated heterocyclic ring system containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, and wherein, if D is substituted, then it is substituted at least one carbon atom in the ring with R ⁸ and/or at least one nitrogen atom in the ring with R ⁹ ; each R ⁸ independently represents oxo, hydroxyl, halogen, cyano, C1- _C6 alkyl, C1- _C6 haloalkyl, C1- _C6 haloalkoxy, _C1 - _C3 haloalkoxy- _C1 - _C3 alkyl-, C1- _C6 alkoxy, C1- _C3 alkoxyC1- _C3 alkyl, _C1 - _C3 alkoxy- _C1 - _C3 alkoxy- _C1 - _C3 alkyl-, _C3 - _C6 cycloalkyl, _C2 - _C6 alkenyl, C ₂ -C ₆ haloalkenyl, C ₂ -C ₆ alkynyl, C1-C ₆ hydroxyalkyl-, C1-C ₆ alkylcarbonyl-, C1-C ₆ alkyl-8(O) _t -, amino, C1-C ₆ alkylamino, C1 -C ₆ dialkylamino, -C(C1-C ₃ alkyl)=K-O-C1-C ₃ alkyl or C2-C6haloalkynyl; t is an integer equal to 0, 1 or 2; each R ⁹ independently represents C1- _C4 alkyl, _C1 - _C4 alogenalkyl, hydroxyl, C1- _C4 alkoxy or _C1 - _C4 alkylthio; W represents where a is the point of attachment to the phenylpyridazinone/phenylpyridazinedione moiety, b is the point of attachment to ring D, R ¹⁰ , R ¹¹ , R ¹² and R ¹³ are each hydrogen; and R ¹⁴ and R ¹⁵ are each hydrogen. 2. The compound according to claim 1, where X is in the ortho position relative to the pyridazinone/pyridazinedione moiety. 3. The connection according to any of the previous paragraphs, where Y is in the ortho position relative to the fragment -W-D. 4. A compound according to any of the preceding claims, wherein D is substituted or unsubstituted naphthalene, indolizine, indole, isoindole, indoline, isoindoline, 3-H-indole, benzofuran, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, benzoxazole, benzodioxole, purine, 4H-quinolysine, quinoline, isoquinoline, tetrahydroquinoline, cinnoline, phthalazine, quinoxaline, 1-8naphthyridine, pteridine, 1H-pyrrolo[2,3-b]pyridine, imidazo[1,2-a]pyrazine or 1Hbenzotriazole ring system, and wherein, if D is substituted, then it is substituted at least one ring carbon atom with R ⁸ and/or at least one ring nitrogen atom with R ⁹ . 5. A compound according to any of the preceding claims, wherein D is a substituted or unsubstituted naphthalene, indolizine, indole, isoindole, 3-H-indole, benzofuran, benzothiophene, 1H-indazole, benzimidazole, benzthiazole, benzoxazole, purine, 4H-quinolysine, quinoline, isoquinoline, tetrahydroquinoline, cinnoline, phthalazine, quinoxaline, 1-8-naphthyridine or pteridine ring system, and wherein, if D is substituted, then it is substituted at least one carbon atom in the ring with R ⁸ and/or at least one nitrogen atom in the ring using R ⁹ . 6. Connection according to any of the previous paragraphs, where W represents W1. 7. A compound according to any one of claims 1 to 5, where W is W2. 8. A herbicidal composition comprising a herbicidal compound according to any one of claims 1 to 7 and an agriculturally acceptable adjuvant. 9. Herbicidal composition according to claim 8, additionally containing at least one additional - 63 047300 body pesticide. 10. The herbicidal composition according to claim 9, wherein the additional pesticide is a herbicide or a herbicide antidote. 11. A method for controlling the growth of unwanted plants, comprising the use of a compound of formula (I) according to any one of claims 1 to 7 or a herbicidal composition according to any of claims 8 to 10 in relation to unwanted plants or the place where they grow. 12. Use of a compound of formula (I) according to any one of claims 1 to 7 as a herbicide.