Patent Application
20240251795
The present invention relates to method of controlling diamide-resistant pests by use of certain pesticidally active, in particular insecticidally active, diamide compounds. Further, present invention also relates to certain pesticidally active, in particular insecticidally active, diamide compounds, to processes for their preparation, to compositions comprising those compounds, and to their use for controlling animal pests, including arthropods and in particular insects or representatives of the order Lepidoptera, in particular diamide resistant Lepidoptera insects.
Bicyclic diamide (or bisamide) derivatives with insecticidal action are known and described, for example, in WO 2005/085234.
Bisamide insecticidal derivatives have been used widely during more than a decade and some insect populations have developed a level of resistance that renders them not susceptible enough to be sufficiently controlled by compounds of the bisamide class available on the market. The consequence of this evolution is that a higher dose of protectant must be used and/or the protection of the crops might be insufficient.
Diamide insecticides target the ryanodine receptor in insects and lead to a depletion of the intracellular calcium reservoirs (Ebbinghaus-Kintscher et al. 2006; Sattelle, Cordova, and Cheek 2008; Cordova et al. 2006). Commercial diamides can be attributed to two classes, the phthalic diamides with its sole representative being flubendiamide and the anthranilic diamides comprising chlorantraniliprole, cyantraniliprole, cyclaniliprole, and tetraniliprole. Other examples of phthalic diamides and anthranilic diamides are cyhalodiamide. fluchlordiniliprole and tetrachlorantraniliprole. All diamides share the same mode of action and so are grouped in the IRAC MoA Group 28.
The diamides represent a fast-growing class of insecticides introduced to the market since the commercialization of neonicotinoids (Sparks and Nauen 2015; Richardson et al. 2020; Troczka et al. 2017) and are extremely valuable insect control agents not least because they had exhibited little or no cross-resistance to older insecticide classes, which suffer markedly from resistance problems. However, reports of insect resistance to the diamides class of insecticides are on the increase.
The increase in resistance of such insects to diamide insecticides thus poses a significant threat to the cultivation of a number of commercially important crops, fruits and vegetables, and there is thus a need to find alternative insecticides capable of controlling diamide resistant insects (i.e. to find insecticides that do not exhibit any cross-resistance with the diamide class).
Resistance may be defined as “a heritable change in the sensitivity of a pest population that is reflected in the repeated failure of a product to achieve the expected level of control when used according to the label recommendation for that pest species” (IRAC 2009).
Cross-resistance occurs when resistance to one insecticide confers resistance to another insecticide via the same biochemical mechanism. This can happen within insecticide chemical groups or between insecticide chemical groups. Cross-resistance may occur even if the resistant insect has never been exposed to one of the chemical classes of insecticide.
Two of the major mechanisms for diamide resistance include:
Target site resistance has been described in numerous Lepidopteran species incl. Plutella xylostella (Troczka et al. 2012; Steinbach et al. 2015; Guo et al. 2014), Tuta absoluta (Roditakis et al. 2017; Zimmer et al. 2019), Spodoptera frugiperda (Bolzan et al. 2019) Spodoptera exigua (Zuo et al. 2020, 2017) Chilo suppressalis (Yao et al. 2017; Yang et al. 2017). Similar to what has been described for target site resistance against other insecticides e.g. organochlorines affecting the GABA receptor (ffrench-Constant et al. 1998) parallel evolution can also be observed for diamide resistance with two mutations i.e. I4970M and G4946E (P. xylostella numbering) frequently described across species (Richardson et al. 2020). However, that does not exclude that mutations in different positions in the target-site may cause high levels of diamide resistance.
The cytochrome P450 monooxygenases are an important metabolic system involved in the detoxification of xenobiotics in phase I i.e. modification (Dermauw, Van Leeuwen, and Feyereisen 2020; Bard 2000). As such, P450 monooxygenases play an important role in insecticide resistance. P450 monooxygenases have such a phenomenal array of metabolizable substrates because of the presence of numerous P450s (˜26-261) arthropodal species, as well as the broad substrate specificity of some P450s (Dermauw, Van Leeuwen, and Feyereisen 2020). Studies of monooxygenase-mediated resistance have indicated that resistance can be due to increased gene expression of one P450 involved (quantitative changes) in detoxification of the insecticide and might also be due to a mutation in the gene itself altering the amino acid composition (qualitative changes) (Feyereisen, Dermauw, and Van Leeuwen 2015). As such, metabolic cross-resistance mechanisms affect not only insecticides from the given class (e.g. neonicotinoids) but also seemingly unrelated insecticides. For example, cross-resistance relationships between the neonicotinoids and pymetrozine in Bemisia tabaci have been reported (Gorman et al. 2010; Nauen et al. 2013).
Apart from cytochrome P450s other enzyme and transport protein families may lead to insecticide resistance e.g. oxidases, hydrolases, transferases and ABC-transporters (Dermauw and Van Leeuwen 2014; Feyereisen, Dermauw, and Van Leeuwen 2015; Bass et al. 2014). P450s as well as other oxidases, transferases and ABC-transporters have been implicated in diamide resistance (Li et al. 2017; Mallott et al. 2019; Li et al. 2018; Shan et al. 2021).
Therefore, it is highly desirable to find classes of compounds offering a better control of the resistant insects.
It has now been surprisingly found that certain bicyclic diamide derivatives are able to still control diamide-resistant insects.
The present invention accordingly relates, in a first aspect, to a method for combating and controlling diamide-resistant insects to
wherein the compound of formula I is
wherein
It has further now been found that certain novel bicyclic bisamide derivatives provide improved control over these insects. Accordingly, a second aspect of the present invention relates to a compound of formula I as defined in the first aspect.
Through the use of a compound of formula I according to each aspect of the present invention the damage caused on plants, especially on useful plants and ornamentals in agriculture, in horticulture and in forests, or on organs, such as fruits, flowers, foliage, stalks, tubers or roots, of such plants, and in some cases even plant organs which are formed at a later point in time, by a diamide-resistant insect is controlled, reduced.
Compounds I which have at least one basic centre can form, for example, acid addition salts, for example with strong inorganic acids such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrous acid, a phosphorus acid or a hydrohalic acid, with strong organic carboxylic acids, such as C1-C4alkanecarboxylic acids which are unsubstituted or substituted, for example by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid or phthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or such as benzoic acid, or with organic sulfonic acids, such as C1-C4alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. Compounds I which have at least one acidic group can form, for example, salts with bases, for example mineral salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower-alkylamine, for example ethyl-, diethyl-, triethyl- or dimethylpropylamine, or a mono-, di- or trihydroxy-lower-alkylamine, for example mono-, di- or triethanolamine. Where appropriate, the corresponding internal salts can furthermore be formed. Preferred within the scope of the invention are agrochemically advantageous salts, however, the invention also encompasses salts which have disadvantage for agrochemical use, for example salts which are toxic to bees or fish, and which are employed, for example, for the isolation or purification of free compounds I or agrochemically utilizable salts thereof. Owing to the close relationship between the compounds I in free form and in the form of their salts, for the purposes of the invention the free compounds I or their salts hereinabove and hereinbelow are respectively to be understood as including, where appropriate, the corresponding salts or the free compounds I. The same applies analogously to tautomers of compounds I and salts thereof. In general, the free form is preferred in each case.
N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book “Heterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.
The compounds of formula I according to the invention also include hydrates which may be formed during the salt formation.
The term “C1-Cnalkyl” as used herein refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the carbon atoms having 1 to n carbon atoms, for example, any one of the radicals methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, or 1-ethyl-2-methylpropyl.
The term “C1-Cnhaloalkyl” as used herein refers to a straight-chain or branched saturated alkyl radical attached via any of the carbon atoms having 1 to n carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by a halogen independently selected from fluorine, chlorine, bromine and iodine, i.e., for example, any one of chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl. According a term “C1-C2fluoroalkyl” would refer to a C1-C2alkyl radical which carries 1, 2, 3, 4, or 5 fluorine atoms, for example, any one of difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.
The term “C1-Cnalkoxy” as used herein refers to a straight-chain or branched saturated alkyl radical having 1 to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. The term “haloC1-Cnalkoxy” as used herein refers to a C1-Cnalkoxy radical where one or more hydrogen atoms on the alkyl radical is replaced by the same or different halo atom(s)—examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy.
The term “C3-Cncycloalkyl” as used herein refers to 3-n membered cycloalkyl groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
The term “C3-Cnhalocycloalkyl” as used herein refers to a C3-Cncycloalkyl moiety substituted with one or more halo atoms which may be the same or different.
The term “C1-Cnalkanediyl” as used herein refers to a saturated straight-chain or branched hydrocarbon radical connected via two single bonds from one or more of its carbon atom(s) to two other groups, for example, acting like a spacer between two groups. Examples are methylene (or —CH2—) and the ethylene (—CH2CH2—).
The term “C1-Cnhaloalkanediyl” as used herein refers to a C1-Cnalkanediyl moiety substituted with one or more halo atoms which may be the same or different.
The term “C1-Cnalkylsulfanyl” as used herein refers to a C1-Cnalkyl moiety linked through a sulfur atom.
Similarly, the term “C1-Cnhaloalkylthio” or “C1-Cnhaloalkylsulfanyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through a sulfur atom.
The term “C1-Cnalkylsulfinyl” as used herein refers to a C1-Cnalkyl moiety linked through the sulfur atom of the S(═O) group. Similarly, the term “C1-Cnhaloalkylsulfinyl” or “C1-Cnhaloalkylsulfinyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through the sulfur atom of the S(═O) group.
The term “C1-Cnalkylsulfonyl” as used herein refers to a C1-Cnalkyl moiety linked through the sulfur atom of the S(═O)2 group. Similarly, the term “C1-Cnhaloalkylsulfonyl” or “C1-Cnhaloalkylsulfonyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through the sulfur atom of the S(═O)2 group.
The term “C2-Cnalkenyl” as used herein refers to a straight or branched alkenyl chain having from two to n carbon atoms and one or two double bonds, for example, ethenyl, prop-1-enyl, but-2-enyl.
The term “C2-Cnalkynyl” as used herein refers to a straight or branched alkynyl chain having from two to n carbon atoms and one triple bond, for example, ethynyl, prop-2-ynyl, but-3-ynyl.
Halogen or “halo” is generally fluorine, chlorine, bromine or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl.
The term “6-membered heteroaromatic” refers to a 6 membered aromatic ring having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen. Examples are pyridyl (or pyridinyl), pyridazinyl, pyrimidinyl, and pyrazinyl.
Examples of “5- or 6-membered heteroaromatic” refers to a 5- or 6-membered aromatic ring having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen. Examples are pyridyl (or pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (e.g. 1,2,4-triazoyl), furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl.
Examples of “9- or 10-membered heteroaromatic” refers to a 9- or 10-membered aromatic ring made up of two rings, having 1 to 4 carbon atoms replaced independently by nitrogen, sulfur, or oxygen (the heteroatoms can be in one ring or distributed amongst the two). Examples are purinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, imidazo[1,2-a]pyridinyl, and imidazo[4,5-b]pyridinyl.
As used herein, the term “controlling” refers to reducing the number of pests (or insects), eliminating pests and/or preventing further pest damage such that damage to a plant or to a plant derived product is reduced. The insect encompasses all stages in the life cycle of the insect.
As used herein, the term “effective amount” refers to the amount of the compound, or a salt thereof, which, upon single or multiple applications provides the desired effect.
The staggered line as used herein, for example, in Ya1 to Ya17, represent the point of connection/attachment to the rest of the compound.
An effective amount is readily determined by the skilled person in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount a number of factors are considered including, but not limited to: the type of plant or derived product to be applied; the pest to be controlled & its lifecycle; the particular compound applied; the type of application; and other relevant circumstances.
In a preferred embodiment of each aspect of the present invention, compound of formula I is represented by formula I-I
where R1, R3, R4, G1, G2, G3, G4, and V are as defined in the first aspect.
In a further preferred embodiment of each aspect of the present invention, compound of formula I is represented by formula Id, Ie, If, Ig, Ih, Ii, or Ij
wherein R1, R4 and R5 are as defined in the first aspect.
Embodiments according to the present invention are provided as set out below.
In an embodiment of each aspect of the invention, A is
In an embodiment of each aspect of the invention, V is
In an embodiment of each aspect of the invention G1, G2, G3 and G4, which form together with the two carbon atoms to which G1 and G4 are attached, a carbocyclic or heterocyclic ring system, wherein
wherein in each embodiment (i.e. any one of A to I), the ring system is unsubstituted or substituted by one or two independent substituents R5; if substituted by R5, the substitution can be on carbon or heteroatom, preferably on a carbon atom.
In an embodiment of each aspect of the invention, R1 is
In an embodiment of each aspect of the invention, R3 is
In an embodiment of each aspect of the invention, R4 is
In an embodiment of each aspect of the invention, X2 is
In an embodiment of each aspect of the invention, Y is
In an embodiment of each aspect of the invention, R5 is independently selected from
In an embodiment of each aspect of the invention, R6 is
In an embodiment of each aspect of the invention, R7 is independently selected from
In an embodiment of each aspect of the invention, R8 is
The present invention, accordingly, makes available a compound of formula I having the substituents A, V, R1, R3, R4, G1, G2, G3 and G4 as defined above in all combinations/each permutation.
Accordingly, made available, for example, is a compound of formula I with A being the first aspect (i.e. A is oxygen or sulfur), V being embodiment B (i.e. CR8), wherein R8 is embodiment D (i.e. R8 is hydrogen, fluorine, chlorine, bromine, iodine, or methyl); G1, G2, G3 and G4 being the embodiment B (i.e. G1 is carbon, nitrogen, sulfur or oxygen, G2 is carbon or a direct bond, G3 is carbon, and G4 is carbon, nitrogen or oxygen, wherein the ring system is unsubstituted or substituted by one or two substituents R5); R5 is embodiment C (i.e. halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, C3-C4cycloalkyl, C3-C4cycloalkoxy, (C1-C3alkyl)NHC(O), (C1-C3alkyl)2NC(O)); R1 being embodiment D (i.e. methyl, Cl, or Br); R3 being an embodiment F (i.e. pyridyl ring, which is substituted with one or two substituents independently selected from chlorine, bromine, and iodine); R4 being embodiment C (i.e. halogen, C1-C3haloalkyl, C1-C3haloalkoxy, or X2—Y); wherein X2 is embodiment C (i.e X2 is methylene (or —CH2—)) and Y is embodiment D (i.e. Y is C1-C3alkoxy, C1-C3haloalkoxy, or any one of Ya to Yj, where R7 is of embodiment B (i.e. halogen, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl and phenyl substituted by chlorine, bromine, trifluoromethyl or difluoromethyl).
In an embodiment of each aspect of the invention, the insects are those resistant to insecticides of the IRAC class 28 (https://irac-online.org>moa-classification), which act on the ryanodine receptors of the insects—such insecticides are generally referred to as diamides or phthalimide insecticides.
In an embodiment, the compounds of formula I do not demonstrate cross-resistance to at least one compound selected from chlorantraniliprole, cyantraniliprole, cyclantraniliprole, fluchlordiniliprole, tetrachlorantraniliprole, tetraniliprole, flubendiamide and cyhalodiamide.
The insects have developed target site resistance and have, for example, at least one of the mutations i.e. I4970M and G4946E (P. xylostella numbering). A skilled person would however not exclude that mutations in different positions in the target-site may also cause high levels of diamide resistance.
The diamide-resistant insects are preferably from the order Lepidoptera.
Preferred species are Plutella xylostella (Troczka et al. 2012; Steinbach et al. 2015; Guo et al. 2014), Tuta absoluta (Roditakis et al. 2017; Zimmer et al. 2019), Spodoptera frugiperda (Bolzan et al. 2019) Spodoptera exigua (Zuo et al. 2020, 2017) Chilo suppressalis (Yao et al. 2017; Yang et al. 2017).
In an embodiment of the first aspect, the method for combating and controlling diamide-resistant insects is in a defined area/field of plants where the ratio of diamide-resistant insects to their corresponding susceptile strains is greater than 1:20 (based on number of insects), preferably greater than 1:10, especially greater than 1:5.
In an embodiment of the first aspect, a compound of formula I controls the diamide-resistant insect better compared to the secondary amide analog of the compound of formula I. The improvement in control can be more than 20, preferably 30, more preferably 40, and most preferably 50, percent. The improvement in the control is assessed at the same level, for example at 5 ppm.
In an embodiment of the first aspect, the method for combating and controlling diamide-resistant insects is by applying to a plant susceptible to attack by the insect an effective amount of a compound of formula I; or by treating the propagation material with an effective amount of a compound of formula I.
In an embodiment of each aspect of the invention, the compound of formula I-I has as V nitrogen or CR8; as G1 carbon, nitrogen, sulfur or oxygen, as G2 carbon or a direct bond, as G3 carbon or nitrogen, as G4 carbon, nitrogen or oxygen, wherein the ring system formed with the two carbon atoms to which G1 and G4 are attached is unsubstituted or substituted by one or two independent substituents R5; as R5 selected from halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, C3-C4cycloalkyl, C3-C4cycloalkoxy, (C1-C3alkyl)NHC(O), and (C1-C3alkyl)2NC(O); as R1 halogen, or C1-C3alkyl; as R3 3-chloro-2-pyridyl or 3,5-dichloro-2-pyridyl; as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl; and as R8 hydrogen, fluorine, or chlorine.
In an embodiment of each aspect of the invention, the compound of formula I-I has as V nitrogen or CH; as G1 carbon, nitrogen, sulfur or oxygen, as G2 carbon or a direct bond, as G3 carbon or nitrogen, as G4 carbon, nitrogen or oxygen, wherein the ring system formed with the two carbon atoms to which G1 and G4 are attached is unsubstituted or substituted by one or two independent substituents R5; as R5 selected from halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, C3-C4cycloalkyl, C3-C4cycloalkoxy, (C1-C3alkyl)NHC(O), and (C1-C3alkyl)2NC(O); as R1 halogen, or C1-C3alkyl; as R3 3-chloro-2-pyridyl or 3,5-dichloro-2-pyridyl; as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I-I has as V nitrogen or CH; as G1 carbon, nitrogen, sulfur or oxygen, as G2 carbon or a direct bond, as G3 carbon or nitrogen, as G4 carbon, nitrogen or oxygen, wherein the ring system formed with the two carbon atoms to which G1 and G4 are attached is unsubstituted or substituted by one or two independent substituents R5; as R5 selected from halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, and (C1-C3alkyl)2NC(O); as R1 halogen, or C1-C3alkyl; as R3 3-chloro-2-pyridyl or 3,5-dichloro-2-pyridyl; as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I-I has as V CH; as G1 carbon, or oxygen, as G2 carbon or a direct bond, as G3 carbon or nitrogen, as G4 carbon, or nitrogen, wherein the ring system formed with the two carbon atoms to which G1 and G4 are attached is unsubstituted or substituted by one or two independent substituents R5; as R5 selected from halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, and (C1-C3alkyl)2NC(O); as R1 halogen, or C1-C3alkyl; as R3 3-chloro-2-pyridyl or 3,5-dichloro-2-pyridyl; as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I-I has as V CH; as G1 carbon, or oxygen, as G2 carbon or a direct bond, as G3 carbon or nitrogen, as G4 carbon, or nitrogen, wherein the ring system formed with the two carbon atoms to which G1 and G4 are attached is unsubstituted or substituted by one or two independent substituents R5; as R5 selected from halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, and C1-C3haloalkyl; as R1 halogen, or C1-C3alkyl; as R3 3-chloro-2-pyridyl; as R4 halogen, C1-C3haloalkyl, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Id and has as R5 selected from hydrogen, halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, C3-C4cycloalkyl, C3-C4cycloalkoxy, (C1-C3alkyl)NHC(O), and (C1-C3alkyl)2NC(O); as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Id and has as R5 selected from hydrogen, halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, and C1-C3haloalkyl; as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Ie and has as R5 selected from hydrogen, halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, C3-C4cycloalkyl, C3-C4cycloalkoxy, (C1-C3alkyl)NHC(O), and (C1-C3alkyl)2NC(O); as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Ie and has as R5 selected from hydrogen, halogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, and C1-C3haloalkyl; as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula If and has as R5 selected from hydrogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3haloalkyl, C3-C4cycloalkyl, C3-C4cycloalkoxy, (C1-C3alkyl)NHC(O), and (C1-C3alkyl)2NC(O); as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula If and has as R5 selected from hydrogen, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, and C1-C3haloalkyl; as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Ig and has as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Ih and has as R5 selected from hydrogen, halogen, C1-C3alkyl, and C1-C3haloalkyl; as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Ii and has as R5 selected from hydrogen, and C1-C3alkyl; as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula Ij and has as R5 selected from hydrogen, halogen, C1-C3alkyl, and C1-C3haloalkyl; as R1 halogen, or C1-C3alkyl; and as R4 halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, or X2—Y, where X2 is CH2 or CF2, and Y is selected from Ya to Yj; R7 is chlorine, bromine, fluorine, difluoromethyl, trifluoromethyl, cyclopropyl or phenyl substituted by trifluoromethyl.
In a third aspect, the present invention makes available a composition comprising a compound of formula I as defined in the second aspect, one or more auxiliaries and diluent, and optionally one or more other active ingredient.
In a fourth aspect, the present invention makes available a method of combating and controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound as defined in the second aspect or a composition as defined in the third aspect.
In a fifth aspect, the present invention makes available a method for the protection of plant propagation material from the attack by insects, acarines, nematodes or molluscs, which comprises treating the propagation material or the site, where the propagation material is planted, with an effective amount of a compound of formula I as defined in the second aspect or a composition as defined in the third aspect.
In a sixth aspect, the present invention makes available a plant propagation material, such as a seed, comprising, or treated with or adhered thereto, a compound of formula I as defined in the second aspect or a composition as defined in the third aspect.
Compounds of formula I can be prepared by those skilled in the art following known methods. More specifically compounds of formulae I, and intermediates therefor can be prepared as described below in the schemes and examples. Certain stereogenic centers have been left unspecified for the clarity and are not intended to limit the teaching of the schemes in any way.
The process according to the invention for preparing compounds of the formula I or, where appropriate, a tautomer and/or salt thereof, is carried out analogously to known processes, for example those described in CN 103109816, CN 103130770, CN 105085477, and CN 103694219.
In the following section G1, G2, G3, G4, and substituents R1, R3, R4, R5, R6, R7, R8, V, X2, and Y are defined as in formula I in the first aspect & embodiments unless otherwise stated.
As depicted in Scheme 1, compounds of formula Ia can be made from compounds of formula Ib by treatment with a thiation reagent such as Lawesson's reagent or phosphorus pentasulfide. The thiation of amides is well known and many examples are found in the literature. The compounds of formula Ia may have to be separated from regioisomers in case the regioselectivity of the thiation is not sufficient. Compounds of formula Ib may be made by ring opening of oxazinones of formula II upon treatment with ammonia or an equivalent of ammonia, for example ammonium acetate or ammonium hydroxide. A variety of solvents can be used, for example an ether, like tetrahydrofuran or a polar aprotic solvent like acetonitrile or an alcohol like methanol or ethanol or an aqueous solution or a combination thereof. The reaction may be performed advantageously with an excess of ammonia or equivalent under elevated temperature or pressure, commonly between 20° C. and 80° C. Conversion of amino acids of formula III and pyrazole carboxylic acids of formula IV to compounds of formula II is in many cases reported in the literature, for example in WO 2003/024222, WO 2004/011447, WO 2005/85234, WO 2007/020050, WO 2007/043677, Biorg. Med. Chem. 2016, 24, 403-427, or can be performed according to methods known to a person skilled in the art. The transformation may preferably be performed in one step in which compounds of formula III and IV are combined in an inert solvent, in the presence of dehydrating reagent such as methanesulfonyl chloride (optionally in the presence of a base such as pyridine or triethylamine).
Alternatively, compounds of formula Ia may be made, for example, from reaction of amino thioamides of formula IIIa and carboxylic acid chlorides of formula IV′, in an inert solvent such as acetone (optionally in the presence of a base like triethylamine). Acid chlorides of formula IV′ may be derived from carboxylic acids of formula IV using reaction conditions known to a person skilled in the art, for example oxalyl chloride in an inert solvent like dichloromethane (optionally in the presence of a catalytic amount of dimethylformamide). Thioamides of formula IIIa may be made from amino amides of formula IIIb, for example, by treatment with a thioation reagent such as phosphorus pentoxide or Lawesson's reagent in an inert solvent such as tetrahydrofuran. Such reactions are well precedented in the literature, for example in US 2017/349576, Synthesis 2001, 2021, or Bioorg. Chem. 2019, 88, 102941. Amino amides of formula IIIb can be prepared from amino acids of formula III by methods known to the person skilled in the art, for example reported in U.S. Pat. No. 9,238,640, WO 2016/193812, and Org. Biomol. Chem. 2011, 9, 6089.
Many amino acids of formula III are described in the literature, for example in WO 2005/85234, WO 2007/020050, WO 2007/043677, WO 2008/130021, Heterocycl. Chem. 1977, 14, 1053-1057, Biorg. Med. Chem. 2016, 24, 403-427 and can be prepared as already described or in a similar way by a person skilled in the art. Amino acids of formula III may also be made by synthetic routes as outlined in Scheme 2 and Scheme 3.
The starting compounds of formula V and intermediates V, VI, as depicted in Scheme 2, are in many cases known in the literature or can be prepared according to methods known to a person skilled in the art.
Compounds of formula V can be converted to compounds of formula V, for example, by treatment with a halogenating reagent like N-halosuccinimide in an inert solvent such as dimethyl formamide at temperatures commonly between 0° C. and 90° C. Compounds of formula V can be reacted, for example, with an organoboron reagent such as CH3B(OH)2 in the presence of a palladium catalyst such as (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) dichloride and a base like cesium fluoride or sodium carbonate in an inert solvent at elevated temperatures commonly 30° C. to 120° C., to give compounds of formula VI. Hydrolysis of esters of formula V or VI to acids of formula III can be performed by methods obvious to those skilled in the art.
Alternatively, amino acids of formula III may be obtained from starting compounds of formula VII and intermediates VIII, IX, X, XI, as depicted in Scheme 3. Compounds of formula VII-XI are in many cases known in the literature or can be prepared according to methods known to a person skilled in the art.
Compounds of formula VII can be converted to compounds of formula III, for example, by a Sandmeyer synthesis of isatins IX (see for example Kaila et al. J. Med. Chem. 2007, 50, 21-39, and Zhao et al. Tetrahedron Lett. 2014, 55, 1040-1044) and subsequent oxidative C—C bond cleavage (see for example US 2006/84676, or WO 2016/91774). Alternatively, compounds of formula VII can be halogenated, for example, by treatment with a halogenating agent such as N-halosuccinimide in an inert solvent such as dimethyl formamide to provide compounds of formula X. Compounds of formula XI may be prepared from compounds of formula X by a carboalkoxylation reaction, for example, in the presence of a palladium catalyst such as palladium acetate (optionally in the presence of a ligand, for example 1,1′-bis(diphenylphosphino)ferrocene), carbon monoxide, an alcohol such as methanol, and a base like triethylamine in an inert solvent such as dimethylsulfoxide at elevated temperature and pressure, commonly 30-120° C. and 2-20 bar. Hydrolysis of esters of formula XI to acids of formula III can be performed by methods known to those skilled in the art.
Many pyrazole carboxylic acids of formula IV are described in the literature, for example in WO 2019/224678, WO 2020/212991, Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279, and can be prepared as already described or in a similar way by a person skilled in the art. Additionally, pyrazole carboxylic acids of formula IVb may be made by a synthetic route as outlined in Scheme 4.
Compounds of formula XIII can be obtained from reaction of intermediate XII, previously reported in WO 2019/224678, with an appropriate hydrazine, for example, in an organic solvent like acetic acid at elevated temperature, commonly between 30° C. and 180° C. Compounds of formula XIV can be prepared from compounds of formula XIII upon reaction with an appropriate nucleophile, for example 4-(trifluoromethyl)-1H-triazole, using a base like potassium carbonate in an organic solvent like acetonitrile at elevated temperature, commonly 30-120° C. Hydrolysis of esters of formula XIV to acids of formula IVb can be performed by methods known to those skilled in the art.
It must be recognized that some reagents and reaction conditions may not be compatible with certain functionalities that may be present in the molecules described. In such cases it may be necessary to employ standard protection/deprotection protocols comprehensively reported in the literature and known to the person skilled in the art. In some cases, it may be necessary to perform further synthetic transformation to complete the synthesis of the desired compounds herein. A person skilled in the art may also recognize that it may be possible to achieve the synthesis of the desired compounds by performing some of the steps in the given synthetic routes in a different order than described. A person skilled in the art may also recognize that it may be possible to perform standard functional group interconversions and substitution reactions on the compounds described herein to introduce or modify existing substituents.
Depending on the procedure or the reaction conditions, the reactants can be reacted in the presence of a base. Examples of suitable bases are alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal amides, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal acetates, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal dialkylamides or alkali metal or alkaline earth metal alkylsilylamides, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium acetate, sodium carbonate, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine, N-methylmorpholine, benzyltrimethylammonium hydroxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The reactants can be reacted with each other as such, i.e. without adding a solvent or diluent. In most cases, however, it is advantageous to add an inert solvent or diluent or a mixture of these. If the reaction is carried out in the presence of a base, bases which are employed in excess, such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline, may also act as solvents or diluents.
The reactions are advantageously carried out in a temperature range from approximately −80° C. to approximately +140° C., preferably from approximately −30° C. to approximately +100° C., in many cases in the range between ambient temperature and approximately +80° C.
Depending on the choice of the reaction conditions and starting materials which are suitable in each case, it is possible, for example, in one reaction step only to replace one substituent by another substituent according to the invention, or a plurality of substituents can be replaced by other substituents according to the invention in the same reaction step.
Salts of compounds of formula I can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula I are obtained by treatment with a suitable acid or a suitable ion exchanger reagent and salts with bases are obtained by treatment with a suitable base or with a suitable ion exchanger reagent.
Salts of compounds of formula I can be converted in the customary manner into the free compounds I, acid addition salts, for example, by treatment with a suitable basic compound or with a suitable ion exchanger reagent and salts with bases, for example, by treatment with a suitable acid or with a suitable ion exchanger reagent.
Salts of compounds of formula I can be converted in a manner known per se into other salts of compounds of formula I, acid addition salts, for example, into other acid addition salts, for example by treatment of a salt of inorganic acid such as hydrochloride with a suitable metal salt such as a sodium, barium or silver salt, of an acid, for example with silver acetate, in a suitable solvent in which an inorganic salt which forms, for example silver chloride, is insoluble and thus precipitates from the reaction mixture.
Depending on the procedure or the reaction conditions, the compounds of formula I, which have salt-forming properties can be obtained in free form or in the form of salts.
The compounds of formula I and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can be present in the form of one of the isomers which are possible or as a mixture of these, for example in the form of pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, diastereomer mixtures or racemate mixtures, depending on the number, absolute and relative configuration of asymmetric carbon atoms which occur in the molecule and/or depending on the configuration of non-aromatic double bonds which occur in the molecule, the invention relates to the pure isomers and also to all isomer mixtures which are possible and is to be understood in each case in this sense hereinabove and hereinbelow, even when stereochemical details are not mentioned specifically in each case.
Diastereomer mixtures or racemate mixtures of compounds of formula I, in free form or in salt form, which can be obtained depending on which starting materials and procedures have been chosen can be separated in a known manner into the pure diasteromers or racemates on the basis of the physicochemical differences of the components, for example by fractional crystallization, distillation and/or chromatography.
Enantiomer mixtures, such as racemates, which can be obtained in a similar manner can be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, by chromatography on chiral adsorbents, for example high-performance liquid chromatography (HPLC) on acetyl cellulose, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, where only one enantiomer is complexed, or by conversion into diastereomeric salts, for example by reacting a basic end-product racemate with an optically active acid, such as a carboxylic acid, for example camphor, tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separating the diastereomer mixture which can be obtained in this manner, for example by fractional crystallization based on their differing solubilities, to give the diastereomers, from which the desired enantiomer can be set free by the action of suitable agents, for example basic agents.
Pure diastereomers or enantiomers can be obtained according to the invention not only by separating suitable isomer mixtures, but also by generally known methods of diastereoselective or enantioselective synthesis, for example by carrying out the process according to the invention with starting materials of a suitable stereochemistry.
N-oxides can be prepared by reacting a compound of the formula I with a suitable oxidizing agent, for example the H2O2/urea adduct in the presence of an acid anhydride, e.g. trifluoroacetic anhydride. Such oxidations are known from the literature, for example from J. Med. Chem., 32 (12), 2561-73, 1989 or WO 2000/15615.
It is advantageous to isolate or synthesize in each case the biologically more effective isomer, for example enantiomer or diastereomer, or isomer mixture, for example enantiomer mixture or diastereomer mixture, if the individual components have a different biological activity.
The compounds of formula I and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can, if appropriate, also be obtained in the form of hydrates and/or include other solvents, for example those which may have been used for the crystallization of compounds which are present in solid form.
The compounds according to the following Tables A-1 to A-7 below can be prepared according to the methods described above. The examples which follow are intended to illustrate the invention and show preferred compounds of formulae Id to Ij. The tables below illustrate specific compounds of the invention.
Table A-1 provides 324 compounds of formula Id,
wherein R1, R4, and R5 are defined in a row X.1 to X.324 of table X.
Table A-2 provides 324 compounds of formula Ie,
wherein R1, R4, and R5 are defined in a row X.1 to X.324 of table X.
Table A-3 provides 243 compounds of formula If,
wherein R1, R4, and R5 are defined in a row X.1 to X.243 of table X.
Table A-4 provides 27 compounds of formula Ig,
wherein R1, R4, and R5 are defined in a row X.1 to X.27 of table X.
Table A-5 provides 135 compounds of formula Ih,
wherein R1, R4, and R5 are defined in a row X.1 to X.54, X.136 to X.152, and X.271 to X-324 of table X.
Table A-6 provides 54 compounds of formula Ii,
wherein R1, R4, and R5 are defined in a row X.1 to X.54 of table X.
Table A-7 provides 27 compounds of formula Ij,
wherein R1, R4, and R5 are defined in a row X.28 to X.54 of table X.
Also made available are certain intermediate compounds of the amine of formulae IId, IIe, IIf, IIg, IIh, IIi, IIj, IV and Vd, Ve, Vf, Vg, Vh, Vi, Vj.
wherein, in each formula, whenever present,
In a further aspect, present invention provides a compound of formulae IId, IIe, IIf, IIg, IIh, IIi, IIj, IV and Vd, Ve, Vf, Vg, Vh, Vi, Vj, wherein, in each formula, whenever present, R1, R4, and R5 are as defined in the embodiments herein, R3 is 3-chloro-2-pyridyl, and R99 is hydrogen, methyl or ethyl. In a preferred embodiment, R1 is methyl, bromine, or chlorine; R4 is chlorine, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, and 4-chlorophenyl)methoxymethyl; R5 is hydrogen or bromine; R3 is 3-chloro-2-pyridyl, and R99 is hydrogen, methyl or ethyl.
The compounds of formula I according to the invention are preventively and/or curatively valuable active ingredients in the field of pest control, even at low rates of application, which have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants. The active ingredients according to the invention act against all or individual developmental stages of normally sensitive, but also resistant, animal pests, such as insects or representatives of the order Acarina. The insecticidal or acaricidal activity of the active ingredients according to the invention can manifest itself directly, i. e. in destruction of the pests, which takes place either immediately or only after some time has elapsed, for example during ecdysis, or indirectly, for example in a reduced oviposition and/or hatching rate.
Examples of the above mentioned animal pests are:
In a further aspect, the invention may also relate to a method of controlling damage to plant and parts thereof by plant parasitic nematodes (Endoparasitic-, Semiendoparasitic- and Ectoparasitic nematodes), especially plant parasitic nematodes such as root knot nematodes, Meloidogyne hapla, Meloidogyne incognita, Meloidogyne javanica, Meloidogyne arenaria and other Meloidogyne species; cyst-forming nematodes, Globodera rostochiensis and other Globodera species; Heterodera avenae, Heterodera glycines, Heterodera schachtii, Heterodera trifolii, and other Heterodera species; Seed gall nematodes, Anguina species; Stem and foliar nematodes, Aphelenchoides species; Sting nematodes, Belonolaimus longicaudatus and other Belonolaimus species; Pine nematodes, Bursaphelenchus xylophilus and other Bursaphelenchus species; Ring nematodes, Criconema species, Criconemella species, Criconemoides species, Mesocriconema species; Stem and bulb nematodes, Ditylenchus destructor, Ditylenchus dipsaci and other Ditylenchus species; Awl nematodes, Dolichodorus species; Spiral nematodes, Heliocotylenchus multicinctus and other Helicotylenchus species; Sheath and sheathoid nematodes, Hemicycliophora species and Hemicriconemoides species; Hirshmanniella species; Lance nematodes, Hoploaimus species; false rootknot nematodes, Nacobbus species; Needle nematodes, Longidorus elongatus and other Longidorus species; Pin nematodes, Pratylenchus species; Lesion nematodes, Pratylenchus neglectus, Pratylenchus penetrans, Pratylenchus curvitatus, Pratylenchus goodeyi and other Pratylenchus species; Burrowing nematodes, Radopholus similis and other Radopholus species; Reniform nematodes, Rotylenchus robustus, Rotylenchus reniformis and other Rotylenchus species; Scutellonema species; Stubby root nematodes, Trichodorus primitivus and other Trichodorus species, Paratrichodorus species; Stunt nematodes, Tylenchorhynchus claytoni, Tylenchorhynchus dubius and other Tylenchorhynchus species; Citrus nematodes, Tylenchulus species; Dagger nematodes, Xiphinema species; and other plant parasitic nematode species, such as Subanguina spp., Hypsoperine spp., Macroposthonia spp., Melinius spp., Punctodera spp., and Quinisulcius spp.
The compounds of the invention may also have activity against the molluscs. Examples of which include, for example, Ampullariidae; Arion (A. ater, A. circumscriptus, A. hortensis, A. rufus); Bradybaenidae (Bradybaena fruticum); Cepaea (C. hortensis, C. Nemoralis); ochlodina; Deroceras (D. agrestis, D. empiricorum, D. laeve, D. reticulatum); Discus (D. rotundatus); Euomphalia; Galba (G. trunculata); Helicelia (H. itala, H. obvia); Helicidae Helicigona arbustorum); Helicodiscus; Helix (H. aperta); Limax (L. cinereoniger, L. flavus, L. marginatus, L. maximus, L. tenellus); Lymnaea; Milax (M. gagates, M. marginatus, M. sowerbyi); Opeas; Pomacea (P. canaticulata); Vallonia and Zanitoides.
The active ingredients according to the invention can be used for controlling, i. e. containing or destroying, pests of the abovementioned type which occur in particular on plants, especially on useful plants and ornamentals in agriculture, in horticulture and in forests, or on organs, such as fruits, flowers, foliage, stalks, tubers or roots, of such plants, and in some cases even plant organs which are formed at a later point in time remain protected against these pests.
Suitable target plant or crops are, in particular, cereals, such as wheat, barley, rye, oats, rice, maize or sorghum; beet, such as sugar or fodder beet; fruit, for example pomaceous fruit, stone fruit or soft fruit, such as apples, pears, plums, peaches, almonds, cherries or berries, for example strawberries, raspberries or blackberries; leguminous crops, such as beans, lentils, peas or soya; oil crops, such as oilseed rape, mustard, poppies, olives, sunflowers, coconut, castor, cocoa or ground nuts; cucurbits, such as pumpkins, cucumbers or melons; fibre plants, such as cotton, flax, hemp or jute; citrus fruit, such as oranges, lemons, grapefruit or tangerines; vegetables, such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes or bell peppers; Lauraceae, such as avocado, Cinnamonium or camphor; and also tobacco, nuts, coffee, eggplants, sugarcane, tea, pepper, grapevines, hops, the plantain family and latex plants.
The compositions and/or methods of the present invention may be also used on any ornamental and/or vegetable crops, including flowers, shrubs, broad-leaved trees and evergreens.
For example the invention may be used on any of the following ornamental species: Ageratum spp., Alonsoa spp., Anemone spp., Anisodontea capsenisis, Anthemis spp., Antirrhinum spp., Aster spp., Begonia spp. (e.g. B. elatior, B. semperflorens, B. tubéreux), Bougainvillea spp., Brachycome spp., Brassica spp. (ornamental), Calceolaria spp., Capsicum annuum, Catharanthus roseus, Canna spp., Centaurea spp., Chrysanthemum spp., Cineraria spp. (C. maritime), Coreopsis spp., Crassula coccinea, Cuphea ignea, Dahlia spp., Delphinium spp., Dicentra spectabilis, Dorotheantus spp., Eustoma grandiflorum, Forsythia spp., Fuchsia spp., Geranium gnaphalium, Gerbera spp., Gomphrena globosa, Heliotropium spp., Helianthus spp., Hibiscus spp., Hortensia spp., Hydrangea spp., Hypoestes phyllostachya, Impatiens spp. (I. Walleriana), Iresines spp., Kalanchoe spp., Lantana camara, Lavatera trimestris, Leonotis leonurus, Lilium spp., Mesembryanthemum spp., Mimulus spp., Monarda spp., Nemesia spp., Tagetes spp., Dianthus spp. (carnation), Canna spp., Oxalis spp., Bellis spp., Pelargonium spp. (P. peltatum, P. Zonale), Viola spp. (pansy), Petunia spp., Phlox spp., Plecthranthus spp., Poinsettia spp., Parthenocissus spp. (P. quinquefolia, P. tricuspidata), Primula spp., Ranunculus spp., Rhododendron spp., Rosa spp. (rose), Rudbeckia spp., Saintpaulia spp., Salvia spp., Scaevola aemola, Schizanthus wisetonensis, Sedum spp., Solanum spp., Surfinia spp., Tagetes spp., Nicotinia spp., Verbena spp., Zinnia spp. and other bedding plants.
For example the invention may be used on any of the following vegetable species: Allium spp. (A. sativum, A. cepa, A. oschaninii, A. Porrum, A. ascalonicum, A. fistulosum), Anthriscus cerefolium, Apium graveolus, Asparagus officinalis, Beta vulgarus, Brassica spp. (B. Oleracea, B. Pekinensis, B. rapa), Capsicum annuum, Cicer arietinum, Cichorium endivia, Cichorum spp. (C. intybus, C. endivia), Citrillus lanatus, Cucumis spp. (C. sativus, C. melo), Cucurbita spp. (C. pepo, C. maxima), Cyanara spp. (C. scolymus, C. cardunculus), Daucus carota, Foeniculum vulgare, Hypericum spp., Lactuca sativa, Lycopersicon spp. (L. esculentum, L. lycopersicum), Mentha spp., Ocimum basilicum, Petroselinum crispum, Phaseolus spp. (P. vulgaris, P. coccineus), Pisum sativum, Raphanus sativus, Rheum rhaponticum, Rosemarinus spp., Salvia spp., Scorzonera hispanica, Solanum melongena, Spinacea oleracea, Valerianella spp. (V. locusta, V. eriocarpa) and Vicia faba.
Preferred ornamental species include African violet, Begonia, Dahlia, Gerbera, Hydrangea, Verbena, Rosa, Kalanchoe, Poinsettia, Aster, Centaurea, Coreopsis, Delphinium, Monarda, Phlox, Rudbeckia, Sedum, Petunia, Viola, Impatiens, Geranium, Chrysanthemum, Ranunculus, Fuchsia, Salvia, Hortensia, rosemary, sage, St. Johnswort, mint, sweet pepper, tomato and cucumber.
The active ingredients according to the invention are especially suitable for controlling Aphis craccivora, Diabrotica balteata, Heliothis virescens, Myzus persicae, Plutella xylostella and Spodoptera littoralis in cotton, vegetable, maize, rice and soya crops. The active ingredients according to the invention are further especially suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatos) and Chilo supressalis (preferably in rice).
The compounds of formula I are particularly suitable for control of
The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins, for example insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as d-endotoxins, e.g. Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), e.g. Vip1, Vip2, Vip3 or Vip3A; or insecticidal proteins of bacteria colonising nematodes, for example Photorhabdus spp. or Xenorhabdus spp., such as Photorhabdus luminescens, Xenorhabdus nematophilus; toxins produced by animals, such as scorpion toxins, arachnid toxins, wasp toxins and other insect-specific neurotoxins; toxins produced by fungi, such as Streptomycetes toxins, plant lectins, such as pea lectins, barley lectins or snowdrop lectins; agglutinins; proteinase inhibitors, such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin, papain inhibitors; ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolism enzymes, such as 3hydroxysteroidoxidase, ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidases, ecdysone inhibitors, HMG-COA-reductase, ion channel blockers, such as blockers of sodium or calcium channels, juvenile hormone esterase, diuretic hormone receptors, stilbene synthase, bibenzyl synthase, chitinases and glucanases.
In the context of the present invention there are to be understood by d-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1, Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncated toxins and modified toxins. Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, WO 02/15701). Truncated toxins, for example a truncated Cry1Ab, are known. In the case of modified toxins, one or more amino acids of the naturally occurring toxin are replaced. In such amino acid replacements, preferably non-naturally present protease recognition sequences are inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G-recognition sequence is inserted into a Cry3A toxin (see WO 03/018810).
Examples of such toxins or transgenic plants capable of synthesising such toxins are disclosed, for example, in EP-A-0 374 753, WO 93/07278, WO 95/34656, EP-A-0 427 529, EP-A-451 878 and WO 03/052073.
The processes for the preparation of such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above. Cry1-type deoxyribonucleic acids and their preparation are known, for example, from WO 95/34656, EP-A-0 367 474, EP-A-0 401 979 and WO 90/13651.
The toxin contained in the transgenic plants imparts to the plants tolerance to harmful insects. Such insects can occur in any taxonomic group of insects, but are especially commonly found in the beetles (Coleoptera), two-winged insects (Diptera) and moths (Lepidoptera).
Transgenic plants containing one or more genes that code for an insecticidal resistance and express one or more toxins are known and some of them are commercially available. Examples of such plants are: YieldGardÒ (maize variety that expresses a Cry1Ab toxin); YieldGard RootwormÒ (maize variety that expresses a Cry3Bb1 toxin); YieldGard PlusÒ (maize variety that expresses a Cry1Ab and a Cry3Bb1 toxin); StarlinkÒ (maize variety that expresses a Cry9C toxin); Herculex IÒ (maize variety that expresses a Cry1 Fa2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33BÒ (cotton variety that expresses a Cry1Ac toxin); Bollgard IÒ (cotton variety that expresses a Cry1Ac toxin); Bollgard II® (cotton variety that expresses a Cry1Ac and a Cry2Ab toxin); VipCotÒ (cotton variety that expresses a Vip3A and a Cry1Ab toxin); NewLeafÒ (potato variety that expresses a Cry3A toxin); NatureGardÒ, Agrisure® GT Advantage (GA21 glyphosate-tolerant trait), Agrisure® CB Advantage (Bt11 corn borer (CB) trait) and ProtectaÒ.
Further examples of such transgenic crops are:
1. Bt11 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Genetically modified Zea mays which has been rendered resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia nonagrioides) by transgenic expression of a truncated Cry1Ab toxin. Bt11 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
2. Bt176 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Genetically modified Zea mays which has been rendered resistant to attack by the European corn borer (Ostrinia nubilalis and Sesamia nonagrioides) by transgenic expression of a Cry1Ab toxin. Bt176 maize also transgenically expresses the enzyme PAT to achieve tolerance to the herbicide glufosinate ammonium.
3. MIR604 Maize from Syngenta Seeds SAS, Chemin de I'Hobit 27, F-31 790 St. Sauveur, France, registration number C/FR/96/05/10. Maize which has been rendered insect-resistant by transgenic expression of a modified Cry3A toxin. This toxin is Cry3AO55 modified by insertion of a cathepsin-G-protease recognition sequence. The preparation of such transgenic maize plants is described in WO 03/018810.
4. MON 863 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/DE/02/9. MON 863 expresses a Cry3Bb1 toxin and has resistance to certain Coleoptera insects.
5. IPC 531 Cotton from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B-1150 Brussels, Belgium, registration number C/ES/96/02.
6. 1507 Maize from Pioneer Overseas Corporation, Avenue Tedesco, 7 B-1160 Brussels, Belgium, registration number C/NL/00/10. Genetically modified maize for the expression of the protein Cry1F for achieving resistance to certain Lepidoptera insects and of the PAT protein for achieving tolerance to the herbicide glufosinate ammonium.
7. NK603×MON 810 Maize from Monsanto Europe S.A. 270-272 Avenue de Tervuren, B1150 Brussels, Belgium, registration number C/GB/02/M3/03. Consists of conventionally bred hybrid maize varieties by crossing the genetically modified varieties NK603 and MON 810. NK603×MON 810 Maize transgenically expresses the protein CP4 EPSPS, obtained from Agrobacterium sp. strain CP4, which imparts tolerance to the herbicide Roundup® (contains glyphosate), and also a Cry1Ab toxin obtained from Bacillus thuringiensis subsp. kurstaki which brings about tolerance to certain Lepidoptera, include the European corn borer.
Transgenic crops of insect-resistant plants are also described in BATS (Zentrum für Biosicherheit und Nachhaltigkeit, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) Report 2003, (http://bats.ch).
The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as, for example, the so-called “pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818 and EP-A-0 353 191. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
Crops may also be modified for enhanced resistance to fungal (for example Fusarium, Anthracnose, or Phytophthora), bacterial (for example Pseudomonas) or viral (for example potato leafroll virus, tomato spotted wilt virus, cucumber mosaic virus) pathogens.
Crops also include those that have enhanced resistance to nematodes, such as the soybean cyst nematode.
Crops that are tolerance to abiotic stress include those that have enhanced tolerance to drought, high salt, high temperature, chill, frost, or light radiation, for example through expression of NF-YB or other proteins known in the art.
Antipathogenic substances which can be expressed by such transgenic plants include, for example, ion channel blockers, such as blockers for sodium and calcium channels, for example the viral KP1, KP4 or KP6 toxins; stilbene synthases; bibenzyl synthases; chitinases; glucanases; the so-called “pathogenesis-related proteins” (PRPs; see e.g. EP-A-0 392 225); antipathogenic substances produced by microorganisms, for example peptide antibiotics or heterocyclic antibiotics (see e.g. WO 95/33818) or protein or polypeptide factors involved in plant pathogen defence (so-called “plant disease resistance genes”, as described in WO 03/000906).
Further areas of use of the compositions according to the invention are the protection of stored goods and store rooms and the protection of raw materials, such as wood, textiles, floor coverings or buildings, and also in the hygiene sector, especially the protection of humans, domestic animals and productive livestock against pests of the mentioned type.
The present invention provides a compound of the second aspect for use in therapy. The present invention provides a compound of the first aspect, for use in controlling parasites in or on an animal. The present invention further provides a compound of the first aspect, for use in controlling ectoparasites on an animal. The present invention further provides a compound of the first aspect, for use in preventing and/or treating diseases transmitted by ectoparasites.
The present invention provides the use of a compound of the second aspect, for the manufacture of a medicament for controlling parasites in or on an animal. The present invention further provides the use of a compound of the first aspect, for the manufacture of a medicament for controlling ectoparasites on an animal. The present invention further provides the use of a compound of the first aspect, for the manufacture of a medicament for preventing and/or treating diseases transmitted by ectoparasites.
The present invention provides the use of a compound of the first aspect, in controlling parasites in or on an animal. The present invention further provides the use of a compound of the second aspect, in controlling ectoparasites on an animal.
The term “controlling” when used in context of parasites in or on an animal refers to reducing the number of pests or parasites, eliminating pests or parasites and/or preventing further pest or parasite infestation.
The term “treating” when used used in context of parasites in or on an animal refers to restraining, slowing, stopping or reversing the progression or severity of an existing symptom or disease.
The term “preventing” when used used in context of parasites in or on an animal refers to the avoidance of a symptom or disease developing in the animal.
The term “animal” when used used in context of parasites in or on an animal may refer to a mammal and a non-mammal, such as a bird or fish. In the case of a mammal, it may be a human or non-human mammal. Non-human mammals include, but are not limited to, livestock animals and companion animals. Livestock animals include, but are not limited to, cattle, camellids, pigs, sheep, goats and horses. Companion animals include, but are not limited to, dogs, cats and rabbits.
A “parasite” is a pest which lives in or on the host animal and benefits by deriving nutrients at the host animal's expense. An “endoparasite” is a parasite which lives in the host animal. An “ectoparasite” is a parasite which lives on the host animal. Ectoparasites include, but are not limited to, acari, insects and crustaceans (e.g. sea lice). The Acari (or Acarina) sub-class comprises ticks and mites. Ticks include, but are not limited to, members of the following genera: Rhipicaphalus, for example, Rhipicaphalus (Boophilus) microplus and Rhipicephalus sanguineus; Amblyomrna; Dermacentor; Haemaphysalis; Hyalomma; Ixodes; Rhipicentor; Margaropus; Argas; Otobius; and Ornithodoros. Mites include, but are not limited to, members of the following genera: Chorioptes, for example Chorioptes bovis; Psoroptes, for example Psoroptes ovis; Cheyletiella; Dermanyssus; for example Dermanyssus gallinae; Ortnithonyssus; Demodex, for example Demodex canis; Sarcoptes, for example Sarcoptes scabiei; and Psorergates. Insects include, but are not limited to, members of the orders: Siphonaptera, Diptera, Phthiraptera, Lepidoptera, Coleoptera and Homoptera. Members of the Siphonaptera order include, but are not limited to, Ctenocephalides felis and Ctenocephatides canis. Members of the Diptera order include, but are not limited to, Musca spp.; bot fly, for example Gasterophilus intestinalis and Oestrus ovis; biting flies; horse flies, for example Haematopota spp. and Tabunus spp.; haematobia, for example Haematobia irritans; Stomoxys; Lucilia; midges; and mosquitoes. Members of the Phthiraptera class include, but are not limited to, blood sucking lice and chewing lice, for example Bovicola ovis and Bovicola bovis.
The term “effective amount” when used used in context of parasites in or on an animal refers to the amount or dose of the compound of the invention, or a salt thereof, which, upon single or multiple dose administration to the animal, provides the desired effect in or on the animal. The effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the parasite to be controlled and the degree of infestation; the specific disease or disorder involved; the degree of involvement or the severity of the disease or disorder; the response of the individual; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
The compounds of the invention may be administered to the animal by any route which has the desired effect including, but not limited to topically, orally, parenterally and subcutaneously. Topical administration is preferred. Formulations suitable for topical administration include, for example, solutions, emulsions and suspensions and may take the form of a pour-on, spot-on, spray-on, spray race or dip. In the alternative, the compounds of the invention may be administered by means of an ear tag or collar.
Salt forms of the compounds of the invention include both pharmaceutically acceptable salts and veterinary acceptable salts, which can be different to agrochemically acceptable salts.
Pharmaceutically and veterinary acceptable salts and common methodology for preparing them are well known in the art. See, for example, Gould, P. L., “Salt selection for basic drugs”, International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al. “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities”, Organic Process Research and Development, 4: 427-435 (2000); and Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 66: 1-19, (1977). One skilled in the art of synthesis will appreciate that the compounds of the invention are readily converted to and may be isolated as a salt, such as a hydrochloride salt, using techniques and conditions well known to one of ordinary skill in the art. In addition, one skilled in the art of synthesis will appreciate that the compounds of the invention are readily converted to and may be isolated as the corresponding free base from the corresponding salt.
The present invention also provides a method for controlling pests (such as mosquitoes and other disease vectors; see also http://www.who.int/malaria/vector_control/irs/en/). In one embodiment, the method for controlling pests comprises applying the compositions of the invention to the target pests, to their locus or to a surface or substrate by brushing, rolling, spraying, spreading or dipping. By way of example, an IRS (indoor residual spraying) application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention. In another embodiment, it is contemplated to apply such compositions to a substrate such as non-woven or a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.
In one embodiment, the method for controlling such pests comprises applying a pesticidally effective amount of the compositions of the invention to the target pests, to their locus, or to a surface or substrate so as to provide effective residual pesticidal activity on the surface or substrate. Such application may be made by brushing, rolling, spraying, spreading or dipping the pesticidal composition of the invention. By way of example, an IRS application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention so as to provide effective residual pesticidal activity on the surface. In another embodiment, it is contemplated to apply such compositions for residual control of pests on a substrate such as a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.
Substrates including non-woven, fabrics or netting to be treated may be made of natural fibres such as cotton, raffia, jute, flax, sisal, hessian, or wool, or synthetic fibres such as polyamide, polyester, polypropylene, polyacrylonitrile or the like. The polyesters are particularly suitable. The methods of textile treatment are known, e.g. WO 2008/151984, WO 2003/034823, U.S. Pat. No. 5,631,072, WO 2005/64072, WO2006/128870, EP 1724392, WO 2005/113886 or WO 2007/090739.
Further areas of use of the compositions according to the invention are the field of tree injection/trunk treatment for all ornamental trees as well all sort of fruit and nut trees.
In the field of tree injection/trunk treatment, the compounds according to the present invention are especially suitable against wood-boring insects from the order Lepidoptera as mentioned above and from the order Coleoptera, especially against woodborers listed in the following tables A and B:
Agrilus planipennis
Anoplura glabripennis
Xylosandrus crassiusculus
X. mutilatus
Tomicus piniperda
Agrilus anxius
Agrilus politus
Agrilus sayi
Agrilus vittaticollis
Chrysobothris femorata
Texania campestris
Goes pulverulentus
Goes tigrinus
Neoclytus acuminatus
Neoptychodes trilineatus
Oberea ocellata
Oberea tripunctata
Oncideres cingulata
Saperda calcarata
Strophiona nitens
Corthylus columbianus
Dendroctonus frontalis
Dryocoetes betulae
Monarthrum fasciatum
Phloeotribus liminaris
Pseudopityophthorus pruinosus
Paranthrene simulans
Sannina uroceriformis
Synanthedon exitiosa
Synanthedon pictipes
Synanthedon rubrofascia
Synanthedon scitula
Vitacea polistiformis
The present invention may be also used to control any insect pests that may be present in turfgrass, including for example beetles, caterpillars, fire ants, ground pearls, millipedes, sow bugs, mites, mole crickets, scales, mealybugs, ticks, spittlebugs, southern chinch bugs and white grubs. The present invention may be used to control insect pests at various stages of their life cycle, including eggs, larvae, nymphs and adults.
In particular, the present invention may be used to control insect pests that feed on the roots of turfgrass including white grubs (such as Cyclocephala spp. (e.g. masked chafer, C. lurida), Rhizotrogus spp. (e.g. European chafer, R. majalis), Cotinus spp. (e.g. Green June beetle, C. nitida), Popillia spp. (e.g. Japanese beetle, P. japonica), Phyllophaga spp. (e.g. May/June beetle), Ataenius spp. (e.g. Black turfgrass ataenius, A. spretulus), Maladera spp. (e.g. Asiatic garden beetle, M. castanea) and Tomarus spp.), ground pearls (Margarodes spp.), mole crickets (tawny, southern, and short-winged; Scapteriscus spp., Gryllotalpa africana) and leatherjackets (European crane fly, Tipula spp.).
The present invention may also be used to control insect pests of turfgrass that are thatch dwelling, including armyworms (such as fall armyworm Spodoptera frugiperda, and common armyworm Pseudaletia unipuncta), cutworms, billbugs (Sphenophorus spp., such as S. venatus verstitus and S. parvulus), and sod webworms (such as Crambus spp. and the tropical sod webworm, Herpetogramma phaeopteralis).
The present invention may also be used to control insect pests of turfgrass that live above the ground and feed on the turfgrass leaves, including chinch bugs (such as southern chinch bugs, Blissus insularis), Bermudagrass mite (Eriophyes cynodoniensis), rhodesgrass mealybug (Antonina graminis), two-lined spittlebug (Propsapia bicincta), leafhoppers, cutworms (Noctuidae family), and greenbugs.
The present invention may also be used to control other pests of turfgrass such as red imported fire ants (Solenopsis invicta) that create ant mounds in turf.
In the hygiene sector, the compositions according to the invention are active against ectoparasites such as hard ticks, soft ticks, mange mites, harvest mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.
Examples of such parasites are:
The compositions according to the invention may be also suitable for protecting against insect infestation in the case of materials such as wood, textiles, plastics, adhesives, glues, paints, paper and card, leather, floor coverings and buildings.
The compositions according to the invention can be used, for example, against the following pests: beetles such as Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium rufovillosum, Ptilinuspecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthesrugicollis, Xyleborus spec., Tryptodendron spec., Apate monachus, Bostrychus capucins, Heterobostrychus brunneus, Sinoxylon spec. and Dinoderus minutus, and also hymenopterans such as Sirex juvencus, Urocerus gigas, Urocerus gigas taignus and Urocerus augur, and termites such as Kalotermes flavicollis, Cryptotermes brevis, Heterotermes indicola, Reticulitermes flavipes, Reticulitermes santonensis, Reticulitermes lucifugus, Mastotermes darwiniensis, Zootermopsis nevadensis and Coptotermes formosanus, and bristletails such as Lepisma saccharina.
The compounds of formulae I, or salts thereof, are especially suitable for controlling one or more pests selected from order Lepidoptera, especially one or more of the species Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Cydia pomonella, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includens, and Tuta absoluta (preferably in vegetables and corn). In a preferred embodiment of each aspect, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined Tables A-1 to A-7 and P”) controls one or more of pests selected from the species Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Cydia pomonella, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includens, and Tuta absoluta (preferably in vegetables and corn).
The compounds of formulae I, or salts thereof, are especially suitable for controlling one or more of the insects having diamide resistance selected from: Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Cydia pomonella, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includens, and Tuta absoluta. In a preferred embodiment of each aspect, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined Tables A-1 to A-7 and P”) controls one or more of the insects having diamide resistance selected from: Spodoptera littoralis, Spodoptera frugiperda, Plutella xylostella, Cnaphalocrocis medinalis, Cydia pomonella, Chrysodeixis includes, Chilo suppressalis, Elasmopalpus lignosellus, Pseudoplusia includens, and Tuta absoluta.
The compounds of formulae I, or salts thereof, are especially suitable for controlling one or more of insects having diamide resistance selected from: Plutella xylostella, Chilo suppressalis, and Tuta absoluta.
In a preferred embodiment of each aspect, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined Tables A-1 to A-7 and P”) controls one or more of Plutella xylostella, Chilo suppressalis, and Tuta absoluta, such as Plutella xylostella+TX, Chilo suppressalis+TX, and Tuta absoluta+TX.
Compounds according to the invention may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability). In particular, it has been surprisingly found that certain compounds of formula I may show an advantageous safety profile with respect to non-target arthropods, in particular pollinators such as honey bees, solitary bees, and bumble bees. Most particularly, Apis mellifera.
The compounds according to the invention can be used as pesticidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances. The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent pellets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. 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 used directly or diluted prior to use.
The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
The formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions. The active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.
The active ingredients can also be contained in very fine microcapsules. Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95% by weight of the capsule weight. The active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution. The encapsulating membranes can comprise, for example, natural or 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 the person skilled in the art. Alternatively, very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
The formulation adjuvants that are suitable for the preparation of the compositions according to the invention are known per se. As liquid carriers there may be used: 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, N,N-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, glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, 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, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone and the like.
Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances.
A large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use. Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono and di-alkylphosphate esters; and also further substances described e.g. in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).
Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
The compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a 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 invention is generally from 0.01 to 10%, based on the mixture to be applied. For example, the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow. Preferred oil additives comprise alkyl esters of C8C22 fatty acids, especially the methyl derivatives of C12-C18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively). Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10th Edition, Southern Illinois University, 2010.
The inventive compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, of compounds of the present invention and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance. Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations.
The rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. As a general guideline compounds may be applied at a rate of from 1 to 2000 l/ha, especially from 10 to 1000 l/ha.
Preferred formulations can have the following compositions (weight %):
The following Examples further illustrate, but do not limit, the invention.
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.
The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
Formulation types include an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EO), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP), a soluble granule (SG) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.
“Mp” means melting point in ° C. Free radicals represent methyl groups. 1H NMR measurements were recorded on a Brucker 400 MHz spectrometer, chemical shifts are given in ppm relevant to a TMS standard. Spectra measured in deuterated solvents as indicated. Either one of the LC-MS methods below was used to characterize the compounds. The characteristic LC-MS values obtained for each compound were the retention time (recorded in minutes) and the measured molecular ion (M+H)+.
Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 L/h, Desolvation Gas Flow: 650 L/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min, Flow (mL/min) 0.85.
Spectra were recorded on a ACQUITY Mass Spectrometer from Waters Corporations (SQD or SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.0 kV, Cone: 30 V, Extractor: 3.00 V, Source Temperature: 150° C., Desolvation Temperature: 400° C., Cone Gas Flow: 60 L/h, Desolvation Gas Flow: 700 L/h, Mass range: 140 to 800 Da) and an ACQUITY UPLC from Waters Corporations with solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 400, Solvent Gradient: A=Water/Methanol 9:1+0.1% formic acid, B=Acetonitrile+0.1% formic acid, gradient: 0-100% B in 2.5 min; Flow (mL/min) 0.75.
GC-MS was conducted on a Thermo, MS: ISQ and GC: Trace GC 1310 with a column from Zebron phenomenex: Phase ZB-5 ms 15 m, diam: 0.25 mm, 0.25 μm, He flow 1.5 mL/min, temp injector: 250° C., temp detector: 220° C., method: hold 0.7 min at 60° C., 80° C./min until 320° C., hold 2 min at 320° C., total time 6 min. CI reagent gas: Methane, flow 1 mL/min, ionization mode CI, polarity positive, scan time 0.2 s, Scan mass range 50-650 amu.
Spectra were recorded on a Mass Spectrometer from Agilent (Single quad mass spectrometer) equipped with an Multimode-Electron Spray and APCI (Polarity: positive and negative ions), Capillary: 4.00 kV, Corona Current 4.0 μA, Charging Voltage, 2.00 kV, Nitrogen Gas Flow: 9.0 L/min, Nebulizer Pressure: 40 psig, Mass range: 100 to 1000 m/z), dry gas temperature 250° C., Vaporizer temperature 200° C. and Spectra were recorded on LC-MS from Agilent: quaternary pump, heated column compartment, variable wave length detector. Column: Eclipse XDB C18, 5.0 μm, 150×4.6 mm, column temp.: Ambient, Wavelength (nm): 220, Solvents: A=0.05% TFA in water, B=0.05% TFA in Acetonitrile. Gradient: time/% B: 0/5, 0.5/5, 3.5/90, 5/90, 5.1/5, 7/5; Flow rate: 1.0 mL/min.
Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.20 kV, Cone range: 30 V, Extractor: 3.00 V, Source Temperature: 150° C., Desolvation Temperature: 400° C., Cone Gas Flow: 50 L/h, Desolvation Gas Flow: 1000 L/h, Mass range: 100 to 1000 Da).
Under argon, to a solution of methanesulfonyl chloride (0.0459 mL, 0.580 mmol, 2.00 equiv.) in acetonitrile (0.5 mL) were added dropwise at 0° C. a solution of 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid (prepared as described in Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279) (0.0932 g, 0.290 mmol, 1.00 equiv.) in acetonitrile (1.0 mL) and pyridine (0.03 mL, 0.371 mmol, 1.28 equiv.). The reaction mixture was stirred at 0° C. for 30 min. Then, a suspension of 3-amino-4,7-dibromonaphthalene-2-carboxylic acid (prepared as described in J. Am. Chem. Soc. 2006, 128, 9219-9230) (0.100 g, 0.290 mmol, 1.00 equiv.) in acetonitrile (2.0 mL) was added to the previous solution at room temperature, followed by pyridine (0.04 mL, 0.495 mmol, 1.71 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was then purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired product 7,10-dibromo-2-[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one as a yellow solid.
LC-MS (method 1): retention time 1.32 min, m/z 629 [M+H]+.
To a solution of 7,10-dibromo-2-[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one (0.067 g, 0.110 mmol, 1.00 equiv.) in acetonitrile (0.53 mL) was added dropwise ammonia (2 M in ethanol, 0.11 mL, 0.21 mmol, 2.0 equiv.). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by flash chromatography (methanol in dichloromethane) to afford the desired product 2-(3-chloro-2-pyridyl)-N-(1,6-dibromo-3-carbamoyl-2-naphthyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide, as a beige solid.
LC-MS (method 1): retention time 1.06 min, m/z 648 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1H), 8.45-8.50 (m, 1H), 8.37-8.42 (m, 1H), 8.12-8.18 (m, 2H), 8.06-8.11 (m, 1H), 7.85-7.89 (m, 1H), 7.76-7.82 (m, 1H), 7.51-7.58 (m, 2H), 6.93-6.99 (m, 1H), 4.87-4.98 (m, 2H).
To a mixture of 6-amino-2,2-difluoro-7-methyl-1,3-benzodioxole-5-carboxylic acid (15.5 g, 67.1 mmol, 1.0 equiv.) and 2-(3-Chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid (19.6 g, 67.1 mmol, 1.0 equiv.) in MeCN (340 mL) and pyridine (25 mL) at 5° C. was added dropwise MsCl (18.6 mL, 235 mmol, 3.5 equiv.) and the resulting reaction mixture was then stirred at room temperature for 4 h. The reaction mixture was poured on water (700 mL), stirred for 30 minutes, and cooled to 10° C. before collecting the resulting solids by filtration. The filter cake was washed with water and dried under reduced pressure to afford the desired 6-[2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazol-3-yl]-2,2-difluoro-4-methyl-[1,3]dioxolo[4,5-g][3,1]benzoxazin-8-one.
LC-MS (method 1): retention time 1.21 min, m/z 487 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (dd, J=4.4, 1.5 Hz, 1H), 8.40 (dd, J=8.0, 1.5 Hz, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.83 (dd, J=8.0, 4.7 Hz, 1H), 1.69 (s, 3H).
To a solution of 6-[2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazol-3-yl]-2,2-difluoro-4-methyl-[1,3]dioxolo[4,5-g][3,1]benzoxazin-8-one (29.0 g, 59.6 mmol, 1.0 equiv.) in EtOAc (524 mL) was added ammonium acetate (13.8 g, 179 mmol, 3.0 equiv.) and the resulting mixture was heated to 60° C. overnight. The mixture was diluted with EtOAc and the organic phase was extracted with water and brine. The organic phase was concentrated on Isolute® under reduced pressure and the residue was purified by flash chromatography (ethyl acetate in cyclohexane). The resulting material was recrystallized from EtOAc and cyclohexane to afford the desired product N-(6-carbamoyl-2,2-difluoro-4-methyl-1,3-benzodioxol-5-yl)-2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxamide.
LC-MS (method 1): retention time 1.01 min, m/z 504 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 10.38 (s, 1H), 8.49 (dd, J=4.7, 1.5 Hz, 1H), 7.85-7.94 (m, 1H), 7.44 (dd, J=8.0, 4.7 Hz, 1H), 7.29 (s, 1H), 7.11 (s, 1H), 5.94 (br s, 1H), 5.68 (br s, 1H), 2.17 (s, 3H).
Under argon, to a solution of methanesulfonyl chloride (0.0293 mL, 0.370 mmol, 2.00 equiv.) in acetonitrile (0.4 mL) was added dropwise at 0° C. a solution of 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid (prepared as described in Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279) (0.0595 g, 0.185 mmol, 1.00 equiv.) in acetonitrile (0.5 mL) and pyridine (0.015 mL). The reaction mixture was stirred at 0° C. for 30 minutes, then allowed to reach room temperature and stirred for 2 hours. Then, a suspension of 6-amino-5-methyl-2-(trifluoromethyl)quinoline-7-carboxylic acid (prepared as described in WO2007020050) (0.0500 g, 0.185 mmol, 1.00 equiv.) in acetonitrile (0.95 mL) and pyridine (0.030 mL) was added at 0° C. to the previous solution. The reaction mixture was warmed to room temperature and stirred for 20 hours. Ammonia (2 M in ethanol, 0.927 mL, 1.85 mmol, 10.0 equiv.) was added at room temperature and it was stirred for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude material by flash chromatography (ethyl acetate in cyclohexane) afforded the desired product 6-[[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carbonyl]amino]-5-methyl-2-(trifluoromethyl)quinoline-7-carboxamide.
LC-MS (method 1): retention time 1.00 min, m/z 573 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 10.50 (s, 1H), 8.46 (dd, J=4.7, 1.8 Hz, 1H), 8.28 (d, J=8.7 Hz, 1H), 8.12 (s, 1H), 7.84 (dd, J=8.0, 1.8 Hz, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.34 (dd, J=8.0, 4.7 Hz, 1H), 6.73 (s, 1H), 6.45 (br s, 1H), 5.93 (br s, 1H), 4.71 (q, J=8.4 Hz, 2H), 2.42 (s, 3H).
The compound was prepared using 7,10-dibromo-2-[2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one under the conditions described for compound P.1 (example 1, step 2).
LC-MS (standard): retention time 1.07 min, m/z 618 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 8.55 (dd, J=4.72, 1.45 Hz, 1H), 8.40 (d, J=1.82 Hz, 1H), 8.20 (dd, J=8.17, 1.27 Hz, 1H), 8.12-8.16 (m, 2H), 7.82-7.93 (m, 3H), 7.65 (dd, J=8.17, 4.54 Hz, 1H), 7.56 (s, 1H).
The compound was prepared using 1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid and 6-amino-5-methyl-2-trifluoromethyl-quinoline-7-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 1.00 min, m/z 543 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 10.70 (s, 1H), 8.48 (dd, J=4.72, 1.45 Hz, 1H), 8.12-8.25 (m, 1H), 8.06 (s, 1H), 7.88 (dd, J=7.99, 1.45 Hz, 1H), 7.60 (d, J=8.72 Hz, 1H), 7.49 (s, 1H), 7.40 (dd, J=7.99, 4.72 Hz, 1H), 6.49 (br s, 1H), 5.96 (br s, 1H), 2.31-2.41 (m, 3H).
The compound was prepared using 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (prepared as described in Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279) and 6-amino-5-methyl-2-trifluoromethyl-quinoline-7-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 0.94 min, 553 m/z [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 10.56 (s, 1H), 8.47 (dd, J=4.72, 1.45 Hz, 1H), 8.35 (d, J=8.72 Hz, 1H), 8.19 (s, 1H), 7.86 (dd, J=8.17, 1.63 Hz, 1H), 7.70 (d, J=9.08 Hz, 1H), 7.37 (dd, J=7.99, 4.72 Hz, 1H), 7.19 (s, 1H), 6.42 (br s, 1H), 5.89 (br s, 1H), 2.45 (s, 3H).
The compound was prepared using 2-(3-chloropyridin-2-yl)-5-difluoromethyl-2H-pyrazole-3-carboxylic acid (described in WO 2014/128136 and WO 2007/93402) and 6-amino-5-methyl-2-trifluoromethyl-quinoline-7-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 0.94 min, m/z 525 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 10.65 (s, 1H), 8.49 (dd, J=4.72, 1.45 Hz, 1H), 8.31 (d, J=8.72 Hz, 1H), 8.15 (s, 1H), 7.87 (dd, J=8.17, 1.63 Hz, 1H), 7.67 (d, J=9.08 Hz, 1H), 7.37-7.44 (m, 2H), 6.68-6.98 (t, J=54.68 Hz, 1H), 6.44 (br s, 1H), 5.95 (br s, 1H), 2.44 (s, 3H).
The compound was prepared using 7,10-dibromo-2-[5-bromo-2-(3-chloro-2-pyridyl)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one under the conditions described for compound P.1 (example 1, step 2).
LC-MS (method 1): retention time 1.01 min. m/z 626 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1H), 8.48-8.52 (m, 1H), 8.36-8.43 (m, 1H), 8.09-8.20 (m, 3H), 7.85-7.91 (m, 1H), 7.77-7.84 (m, 1H), 7.56-7.61 (m, 1H), 7.51-7.55 (m, 1H), 7.48-7.49 (m, 1H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid and 3-amino-4-chloro-quinoline-2-carboxylic acid (prepared as described in Chem. Heterocycl. Compd. 1975, 11, 1340-1340) under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 1.01 min, m/z 525 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 11.21 (s, 1H), 8.48 (dd, J=4.72, 1.45 Hz, 1H), 8.21-8.29 (m, 1H), 8.11-8.19 (m, 1H), 8.00-8.09 (m, 1H), 7.84 (dd, J=8.17, 1.64 Hz, 1H), 7.68-7.79 (m, 2H), 7.34 (dd, J=7.99, 4.72 Hz, 1H), 6.68 (s, 1H), 5.90-6.06 (m, 1H), 4.72 (q, J=8.36 Hz, 2H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid and 3-amino-4-chloro-naphthalene-2-carboxylic acid (prepared as described in WO 2005/085234) under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 0.98 min, m/z 494 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1H), 8.54 (dd, J=4.72, 1.45 Hz, 1H), ), 8.18-8.25 (m, 2H), 8.16 (s, 1H), 8.10 (d, J=7.99 Hz, 1H), 7.91 (br s, 1H), 7.84 (s, 1H), 7.75-7.81 (m, 1H), 7.68-7.74 (m, 1H), 7.65 (dd, J=7.99, 4.72 Hz, 1H), 7.52 (s, 1H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid and 3-amino-4-chloro-naphthalene-2-carboxylic acid under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 0.98 min, m/z 524 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 8.48 (dd, J=4.72, 1.45 Hz, 1H), 8.22 (d, J=8.36 Hz, 1H), 8.16 (s, 1H), 8.07-8.13 (m, 2H), 7.85 (br s, 1H), 7.74-7.80 (m, 1H), 7.67-7.73 (m, 1H), 7.55 (dd, J=7.99, 4.72 Hz, 2H), 6.97 (s, 1H), 4.87-4.97 (m, 2H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(difluoromethyl)pyrazole-3-carboxylic acid and 3-amino-4,7-dibromo-naphthalene-2-carboxylic acid under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 0.99 min, m/z 598 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.49-8.54 (m, 1H), 8.37-8.42 (m, 1H), 8.12-8.18 (m, 3H), 7.85-7.92 (m, 1H), 7.79-7.84 (m, 1H), 7.57-7.67 (m, 2H), 7.51-7.55 (m, 1H), 7.25 (t, J=54.31 Hz, 1H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-methoxy-pyrazole-3-carboxylic acid (prepared as described in Mol. Divers. 2012, 16, 711-725) and 3-amino-4-chloro-naphthalene-2-carboxylic acid under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 0.86 min, m/z 456 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.46 (s, 1H), 8.47 (dd, J=4.54, 1.64 Hz, 1H), 8.22 (d, J=8.36 Hz, 1H), 8.15 (s, 1H), 8.08-8.11 (m, 1H), 8.06-8.08 (m, 1H), 7.82 (br s, 1H), 7.74-7.79 (m, 1H), 7.70 (br d, J=7.27 Hz, 1H), 7.49-7.55 (m, 2H), 6.84 (s, 1H), 3.90 (s, 3H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(difluoromethyl)pyrazole-3-carboxylic acid and 3-amino-4-chloro-naphthalene-2-carboxylic acid under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 0.90 min, m/z 476 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1H), 8.52 (dd, J=4.72, 1.45 Hz, 1H), 8.22 (d, J=8.36 Hz, 1H), 8.15-8.19 (m, 2H), 8.10 (d, J=7.99 Hz, 1H), 7.86 (br s, 1H), 7.78 (t, J=7.18 Hz, 1H), 7.68-7.73 (m, 1H), 7.65 (s, 1H), 7.62 (dd, J=7.99, 4.72 Hz, 1H), 7.52 (s, 1H), 7.25 (t, J=54.13 Hz, 1H).
6-bromo-2,2-difluoro-1,3-benzodioxol-5-amine (0.533 g, 2.01 mmol, 1.00 equiv.), triethylamine (0.296 mL, 2.11 mmol, 1.05 equiv.), palladium(II) acetate (92.1 mg, 0.402 mmol, 20 mol %), and 1,1′-bis(diphenylphosphino)ferrocene (0.345 g, 0.603 mmol, 30 mol %) were charged into a pressure reactor and suspended in methanol (4.02 mL) and dimethylsulfoxide (6.03 mL). The reactor was pressurized with carbon monoxide (20 bar) and heated at 80° C. for 20 hours. The reaction mixture was cooled to room temperature, filtered, and the collected filtrate was diluted with water and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the crude material by flash chromatography (ethyl acetate in cyclohexane) afforded the desired product methyl 6-amino-2,2-difluoro-1,3-benzodioxole-5-carboxylate.
LC-MS (method 1): retention time 0.99 min, m/z 232 [M+H]+.
To a solution of methyl 6-amino-2,2-difluoro-1,3-benzodioxole-5-carboxylate (2.53 g, 7.22 mmol, 1.00 equiv.) in N,N-dimethylformamide (14.4 mL) was added N-bromosuccinimide (1.97 g, 10.8 mmol, 1.50 equiv.), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used in the next step without further purification.
LC-MS (method 1): retention time 1.11 min, m/z 310 [M+H]+.
To a solution of 6-amino-7-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylate (0.400 g, 1.29 mmol, 1.00 equiv.) in methanol (2.58 mL) and tetrahydrofuran (2.58 mL) was added sodium hydroxide (1 N, 1.29 mL, 1.29 mmol, 1.0 equiv.), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water and acidified by the addition of a few drops of aqueous 1 M hydrochloric acid. The resulting aqueous solution was extracted with ethyl acetate, and the organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the desired compound, 6-amino-7-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid.
LC-MS (method 1): retention time 0.94 min, m/z 296 [M+H]+.
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid and 6-amino-7-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 0.99 min, m/z 598 [M+H]+.
1H NMR (400 MHz, CD3OD) δ ppm 8.45 (dd, J=4.90, 1.63 Hz, 1H), 8.04 (dd, J=7.99, 1.45 Hz, 1H), 7.49-7.54 (m, 1H), 7.47 (s, 1H), 6.76 (s, 1H), 4.79 (q, J=8.72 Hz, 2H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid and 6-amino-7-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 0.98 min, m/z 568 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 9.74 (s, 1H), 8.36-8.62 (m, 1H), 7.92 (br d, J=7.99 Hz, 1H), 7.40-7.54 (m, 1H), 7.35-7.39 (m, 1H), 7.23 (d, J=2.18 Hz, 1H), 5.90-6.22 (m, 1H), 5.74 (br s, 1H).
The compound was prepared using 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and 6-amino-7-bromo-2,2-difluoro-1,3-benzodioxole-5-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 0.94 min, m/z 578 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 9.54 (s, 1H), 8.46 (dd, J=4.72, 1.45 Hz, 1H), 7.88 (dd, J=7.99, 1.45 Hz, 1H), 7.40 (dd, J=7.99, 4.72 Hz, 1H), 7.22 (s, 1H), 7.10 (s, 1H), 5.90-6.29 (m, 1H), 5.47-5.90 (m, 1H).
The compound was prepared using 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid and 3-amino-4-chloro-quinoline-2-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 0.96 min, m/z 505 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 11.28 (s, 1H), 8.50 (dd, J=4.72, 1.45 Hz, 1H), 8.27 (dd, J=8.54, 0.91 Hz, 1H), 8.18 (br s, 1H), 8.07 (d, J=7.99 Hz, 1H), 7.87 (dd, J=7.99, 1.45 Hz, 1H), 7.76-7.82 (m, 1H), 7.71-7.76 (m, 1H), 7.38 (dd, J=7.99, 4.72 Hz, 1H), 7.18 (s, 1H), 5.83 (br s, 1H).
The compound was prepared using 9-chloro-2-[2-(3-chloropyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5,8-triazaanthracen-4-one (prepared as described in WO 2007/20050) under the conditions described for compound P.1 (example 1, step 2).
LC-MS (method 1): retention time 0.83 min, m/z 496 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s, 1H), 9.05-9.17 (m, 2H), 8.50-8.60 (m, 1H), 8.18-8.23 (m, 2H), 8.08-8.14 (m, 1H), 7.83-7.90 (m, 1H), 7.57-7.74 (m, 2H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(difluoromethoxy)pyrazole-3-carboxylic acid (prepared as described in Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279) and 3-amino-4-chloro-naphthalene-2-carboxylic acid under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 0.94 min, m/z 492 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H), 8.50 (dd, J=4.54, 1.64 Hz, 1H), 8.22 (d, J=8.36 Hz, 1H), 8.15 (s, 1H), 8.13 (dd, J=7.99, 1.45 Hz, 1H), 8.10 (d, J=7.99 Hz, 1H), 7.86 (br s, 1H), 7.74-7.81 (m, 1H), 7.68-7.73 (m, 1H), 7.58 (dd, J=7.99, 4.72 Hz, 1H), 7.52 (s, 1H), 7.44 (t, J=72.48 Hz, 1H), 7.16 (s, 1H).
To a suspension of methyl 2-(3-chloro-2-pyridyl)-5-oxo-1H-pyrazole-3-carboxylate (prepared as described in Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279) (1.00 g, 3.94 mmol, 1.00 equiv.) in acetonitrile (20 mL) at −5° C. was added potassium carbonate (1.12 g, 8.08 mmol, 2.05 equiv.), and the reaction mixture was stirred at 20° C. for 15 minutes. The reaction mixture was cooled to 5° C. and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (0.775 mL, 4.53 mmol, 1.15 equiv.) was added dropwise. The reaction mixture was allowed to warm to room temperature, and subsequently heated to reflux overnight. The reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (ethyl acetate in cyclohexane) afforded the desired product methyl 2-(3-chloro-2-pyridyl)-5-(2,2,3,3,3-pentafluoropropoxy)pyrazole-3-carboxylate.
LC-MS (method 1): retention time 1.08 min, m/z 386 [M+H]+.
A solution of methyl 2-(3-chloro-2-pyridyl)-5-(2,2,3,3,3-pentafluoropropoxy)pyrazole-3-carboxylate (1.65 g, 4.27 mmol, 1.00 equiv.) and lithium hydroxide monohydrate (1.08 g, 25.6 mmol, 6.00 equiv.) in 2-methyltetrahydrofurane (10.7 mL) and water (10.7 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting aqueous residue was acidified with aqueous 1N hydrochloric acid. The reaction mixture was diluted and extracted with ethyl acetate. The combined organic layers were washed with water, then with brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 2-(3-chloro-2-pyridyl)-5-(2,2,3,3,3-pentafluoropropoxy)pyrazole-3-carboxylic acid as a white powder.
LC-MS (method 1): retention time 0.93 min, m/z 372 [M+H]+.
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(2,2,3,3,3-pentafluoropropoxy)pyrazole-3-carboxylic acid and 3-amino-4-chloro-naphthalene-2-carboxylic acid under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 1.06 min, m/z 574 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 8.48 (dd, J=4.72, 1.45 Hz, 1H), 8.22 (d, J=8.36 Hz, 1H), 8.16 (s, 1H), 8.07-8.13 (m, 2H), 7.85 (br s, 1H), 7.74-7.80 (m, 1H), 7.67-7.73 (m, 1H), 7.54-7.59 (m, 1H), 7.53 (s, 1H), 6.97 (s, 1H), 5.02 (t, J=13.44 Hz, 2H).
To a solution of 4-chlorobenzyl alcohol (0.125 g, 0.875 mmol, 3.00 equiv.) in tetrahydrofuran (2.00 mL) at 0° C. was added sodium hydride (60 mass %, 0.035 g, 0.875 mmol, 3.00 equiv.), and the resulting reaction mixture was stirred at 0° C. for 30 minutes. Then, a solution of 1-(3-chloropyridin-2-yl)-3-(chloromethyl)-1H-pyrazole-5-carboxylic acid (prepared as described in US 2011/28729) (0.0794 g, 0.292 mmol, 1.00 equiv.) in tetrahydrofuran (2.0 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was allowed to warm to room temperature, heated to reflux for 2 hours, and stirred at room temperature overnight. The reaction mixture was quenched by dropwise addition of saturated aqueous ammonium chloride solution (3.0 mL). The aqueous layer was adjusted to pH 2-3 by dropwise addition of aqueous 2N hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with water, then with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography to give 5-[(4-chlorophenyl)methoxymethyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid as a yellow oil.
LC-MS (method 1): retention time 0.95, m/z=378 [M+H]+.
The compound was prepared using 5-[(4-chlorophenyl)methoxymethyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid and 3-amino-4-chloro-naphthalene-2-carboxylic acid under the conditions described for compound P.1 (example 1, step 1 and 2).
LC-MS (method 1): retention time 1.07 min, m/z 580 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 8.49 (dd, J=4.54, 1.64 Hz, 1H), 8.22 (d, J=8.72 Hz, 1H), 8.15 (s, 1H), 8.07-8.14 (m, 2H), 7.81 (br s, 1H), 7.74-7.80 (m, 1H), 7.67-7.72 (m, 1H), 7.56 (dd, J=7.99, 4.72 Hz, 1H), 7.52 (s, 1H), 7.45 (s, 4H), 7.41 (s, 1H), 4.65 (s, 2H), 4.63 (s, 2H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid and 3-amino-4-chloro-quinoline-2-carboxylic acid under the conditions described for compound P.3 (example 3).
LC-MS (method 1): retention time 1.01 min, 495 m/z [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 11.37 (s, 1H), 8.51 (dd, J=4.72, 1.45 Hz, 1H), 8.27 (dd, J=8.54, 0.91 Hz, 1H), 8.19 (br s, 1H), 8.07 (d, J=7.99 Hz, 1H), 7.89 (dd, J=8.17, 1.63 Hz, 1H), 7.79 (ddd, J=8.27, 6.81, 1.63 Hz, 1H), 7.70-7.75 (m, 1H), 7.40-7.44 (m, 1H), 7.40 (s, 1H), 5.77 (br s, 1H).
To a solution of 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid (prepared as described in WO 2007/043677) (6.0 g, 20 mmol, 1.0 equiv.) in N-methyl-2-pyrrolidone (100 mL) was added copper chloride (8.2 g, 80 mmol, 4.0 equiv.). The reaction mixture was purged with argon and heated at 160° C. for 20 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate. The organic layer was washed 5 times with water, once with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was taken up in hot ethanol and forced to precipitate by the addition of water at room temperature. The precipitate was collected by filtration and dried in vacuo at 45° C. overnight to give 3-amino-4,7-dichloronaphthalene-2-carboxylic acid.
LC-MS (method 1): retention time 1.02 min, m/z 256 [M+H]+.
The compound was prepared using 5-chloro-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid (prepared as described in Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279) and 7,10-dichloro-2-[5-chloro-2-(3-chloro-2-pyridyl)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one under the conditions described for compound P.1 (example 1, step 1).
LC-MS (method 1): retention time 1.25 min, m/z 477 [M+H]+.
To a solution of 7,10-dichloro-2-[5-chloro-2-(3-chloro-2-pyridyl)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one (0.152 g, 0.318 mmol, 1.00 equiv.) in ethyl acetate (6.36 mL) was added ammonium acetate (73.9 mg, 0.954 mmol, 3.00 equiv.) and the reaction mixture was heated at 60° C. for 2.5 hours to give N-(3-carbamoyl-1,6-dichloro-2-naphthyl)-5-chloro-2-(3-chloro-2-pyridyl)pyrazole-3-carboxamide.
LC-MS (method 1): retention time 0.99 min, m/z 494 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (m, 1H), 8.09-8.26 (m, 6H), 7.75 (br d, J=9.08 Hz, 1H), 7.53-7.62 (m, 2H), 7.36 (s, 1H).
The compound was prepared using 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid and 3-amino-4,7-dichloro-naphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 0.99 min, m/z 538 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (br s, 1H), 8.51 (dd, J=4.54, 1.63 Hz, 1H), 8.25 (d, J=2.18 Hz, 1H), 8.23 (d, J=9.08 Hz, 1H), 8.15 (dd, J=7.99, 1.45 Hz, 1H), 8.13 (s, 1H), 7.88 (s, 1H), 7.78 (dd, J=9.08, 2.18 Hz, 1H), 7.60 (dd, J=7.99, 4.72 Hz, 1H), 7.57 (s, 1H), 7.49 (s, 1H).
The compound was prepared using 5-chloro-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid and 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 1.00 min, m/z 538 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.02 (br s, 1H), 8.50 (dd, J=4.72, 1.45 Hz, 1H), 8.38 (d, J=2.18 Hz, 1H), 8.10-8.17 (m, 4H), 7.86 (dd, J=9.08, 2.18 Hz, 1H), 7.59 (dd, J=7.99, 4.72 Hz, 1H), 7.55 (s, 1H), 7.36 (s, 1H).
The compound was prepared using 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid and 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 1.01 min, m/z 582 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (br s, 1H), 8.48 (dd, J=4.72, 1.45 Hz, 1H), 8.32 (d, J=1.82 Hz, 1H), 8.22 (s, 1H), 8.04-8.12 (m, 2H), 7.79 (dd, J=9.08, 1.82 Hz, 1H), 7.55 (dd, J=7.99, 4.72 Hz, 1H), 7.50 (s, 1H), 7.23 (s, 1H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid and 3-amino-7-bromo-4-chloro-naphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 1.05 min, m/z 572 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.54 (dd, J=4.72, 1.45 Hz, 1H), 8.41 (d, J=1.82 Hz, 1H), 8.14-8.23 (m, 2H), 8.13 (s, 1H), 7.86-7.94 (m, 2H), 7.84 (s, 1H), 7.65 (dd, J=7.99, 4.72 Hz, 1H), 7.57 (br s, 1H).
Under argon, to a solution of 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid (0.33 g, 1.1 mmol, 1.00 equiv.) in dioxane (13.0 mL) was added trimethylboroxine (0.200 g, 1.50 mmol, 1.4 equiv.), cesium carbonate (1.10 g, 3.30 mmol, 3.0 equiv.), tris(dibenzylideneacetone)dipalladium(0) (0.10 g, 0.11 mmol, 10 mol %) and PEPPSI-IPr (0.13 g, 0.18 mmol, 17 mol %). The reaction mixture was stirred at 100° C. overnight, cooled to room temperature, and diluted with ethyl acetate and water. The resulting slurry was filtered over a plug of celite. The layers of the filtrate were separated, and the organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was used without further purification in the next step.
LC-MS (method 1): retention time 1.00 min, m/z 236 [M+H]+.
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid and 3-amino-4-chloro-7-methylnaphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 1.02 min, m/z 508 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1H), 8.54 (d, J=4.7 Hz, 1H), 8.18-8.21 (m, 1H), 8.11 (d, J=8.9 Hz, 1H), 8.03 (s, 1H), 7.84-7.88 (m, 2H), 7.83 (s, 1H), 7.65 (dd, J=8.0, 4.7 Hz, 1H), 7.58-7.63 (m, 1H), 7.50 (s, 1H), 2.52 (br s, 3H).
The compound was prepared using 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid and 3-amino-4,7-dichloro-naphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 1.04 min, m/z 528 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1H), 8.54 (br d, J=3.63 Hz, 1H), 8.18-8.28 (m, 3H), 8.13 (s, 1H), 7.92 (br s, 1H), 7.84 (s, 1H), 7.79 (br d, J=9.08 Hz, 1H), 7.63-7.68 (m, 1H), 7.57 (br s, 1H).
The compound was prepared using 5-chloro-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid and 3-amino-4,7-dibromonaphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 1.01 min, m/z 582 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.50 (m, 2H), 8.30-8.36 (m, 1H), 8.20-8.25 (m, 1H), 8.05-8.13 (m, 2H), 7.80 (dd, J=9.08, 1.82 Hz, 1H), 7.56 (dd, J=7.99, 4.72 Hz, 1H), 7.49 (br s, 1H), 7.23 (s, 1H).
Under argon, palladium(II) acetate (32.5 mg, 0.14 mmol, 10 mol %) and 1,3-DPPP (120 mg, 0.29 mmol, 20 mol %) were suspended in dioxane (22.0 mL) and stirred for 10 minutes at room temperature. Then methylboronic acid (0.13 g, 1.50 mmol, 1.5 equiv.), potassium phosphate (1.10 g, 5.07 mmol, 3.5 equiv.), and 3-amino-4,7-dibromonaphthalene-2-carboxylic acid (0.50 g, 1.45 mmol, 1.00 equiv.) were added, and the resulting reaction mixture was stirred at 110° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and water. The organic phase was separated extracted with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (ethyl acetate in cyclohexane) afforded the desired product 3-amino-4,7-dimethylnaphthalene-2-carboxylic acid.
LC-MS (method 1): retention time 0.86 min, m/z 216 [M+H]+.
N-(3-carbamoyl-1,6-dimethyl-2-naphthyl)-2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxamide was prepared using 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid and 3-amino-4,7-dimethylnaphthalene-2-carboxylic acid under the conditions described for compound P.24 (example 24, step 2 and 3).
LC-MS (method 1): retention time 1.02 min. m/z 488 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 10.34 (s, 1H), 8.50 (dd, J=4.7, 1.5 Hz, 1H), 7.86-7.92 (m, 2H), 7.83 (s, 1H), 7.58 (s, 1H), 7.38-7.45 (m, 2H), 7.32 (s, 1H), 6.23 (br s, 1H), 5.66 (br s, 1H), 2.51 (s, 3H), 2.48 (s, 3H).
Under argon, 5-Bromo-6-quinolinamine (2.9 g, 13 mmol, 1.0 equiv.), trimethylboroxine (50% solution in THF; 2.1 g, 17 mmol, 1.3 equiv.), Cs2CO3 (8.6 g, 26 mmol, 2.0 equiv.), and Pd(dppf)Cl2 (0.50 g, 0.65 mmol, 5 mol %) are suspended in dioxane (40 mL) and the resulting reaction mixture is heated to 90° C. overnight. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired product 5-methylquinolin-6-amine.
LC-MS (method 1): retention time 0.19 min, m/z 159 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 8.68 (dd, J=4.2, 1.6 Hz, 1H), 8.18-8.24 (m, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.34 (dd, J=8.5, 4.2 Hz, 1H), 7.19 (d, J=9.1 Hz, 1H), 3.91 (br s, 2H), 2.41 (s, 3H).
To a suspension of 5-methylquinolin-6-amine (1.8 g, 11 mmol, 1.0 equiv.) in acetic acid (16 mL) at room temperature was added in portions N-bromosuccinimide (2.2 g, 12 mmol. 1.1 equiv.), and the resulting reaction mixture was stirred at room temperature for 15 h. The reaction mixture was diluted with EtOAc and water. The organic phase was separated, extracted with brine, and concentrated in vacuo. Purification of the resulting residue by flash chromatography (ethyl acetate in cyclohexane) afforded the desired product 7-bromo-5-methylquinolin-6-amine.
LC-MS (method 1): retention time 0.38 min, m/z 237 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 8.68 (dd, J=4.2, 1.6 Hz, 1H), 8.22 (s, 1H), 8.17-8.21 (m, 1H), 7.36 (dd, J=8.7, 4.4 Hz, 1H), 4.40 (br s, 2H), 2.48 (s, 3H).
In a pressure reactor, 7-bromo-5-methylquinolin-6-amine (0.40 g, 1.7 mmol, 1.0 equiv.), Et3N (0.25 mL, 1.8 mmol, 1.1 equiv.), palladium(II) acetate (39 mg, 0.17 mmol, 10 mol %) and dppf (0.15 g, 0.25 mmol, 15 mol %) were suspended in DMSO (13 mL) and MeOH (8.6 mL). The reaction mixture was put under 20 bars of carbon monoxide pressure and heated to 80° C. for 20 h. The reaction mixture was concentrated in vacuo, the residue was diluted with EtOAc and water, and the resulting slurry was filtered over a pad of celite. The organic phase of the filtrate was separated, extracted with water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the resulting residue by flash chromatography (ethyl acetate in cyclohexane) afforded the desired product methyl 6-amino-5-methylquinoline-7-carboxylate.
LC-MS (method 1): retention time 0.51 min, m/z 217 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 8.67-8.71 (m, 2H), 8.14-8.21 (m, 1H), 7.36 (dd, J=8.7, 4.0 Hz, 1H), 5.83 (br s, 2H), 3.98 (s, 3H), 2.41 (s, 3H).
To a solution of methyl 6-amino-5-methylquinoline-7-carboxylate (0.14 g, 0.65 mmol, 1.0 equiv.) in THF (1.3 mL), water (1.3 mL), and MeOH (1.3 mL) was added LiOH (82 mg, 1.9 mmol, 3.0 equiv.), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the aqueous residue was adjusted to pH 5-6 using aqueous 4M HCl solution. The resulting precipitate was collected by filtration to afford the desired compound 6-amino-5-methylquinoline-7-carboxylic acid.
LC-MS (method 1): retention time 0.22 min, m/z 203 [M+H]+.
1H NMR 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (br d, J=4.4 Hz, 1H), 8.73 (br d, J=8.4 Hz, 1H), 8.61 (s, 1H), 7.73 (br dd, J=8.7, 4.7 Hz, 1H), 2.41 (s, 3H).
To a solution of 6-amino-5-methylquinoline-7-carboxylic acid (0.12 g, 0.58 mmol, 1.0 equiv.), and 5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid (0.18 g, 0.58 mmol, 1.0 equiv.) in acetonitrile (5.8 mL) and pyridine (0.21 mL, 2.6 mmol, 4.5 equiv.) was added dropwise at 0° C. a solution of MsCl (0.16 mL, 2.0 mmol, 3.5 equiv.) in acetonitrile (0.5 mL), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (5 mL), and the resulting precipitate was collected by filtration to give the desired compound 2-[5-bromo-2-(3-chloro-2-pyridyl)pyrazol-3-yl]-10-methylpyrido[2,3-g][3,1]benzoxazin-4-one.
LC-MS (method 1): retention time 1.06 min, m/z 468 [M+H]+.
To a solution of 2-[5-bromo-2-(3-chloro-2-pyridyl)pyrazol-3-yl]-10-methylpyrido[2,3-g][3,1]benzoxazin-4-one (19 mg, 0.41 mmol, 1.0 equiv.) in ethyl acetate (4.1 mL) was added ammonium acetate (94 mg, 1.2 mmol, 3.0 equiv.), and the resulting reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with cyclohexane (4 mL), and the resulting precipitate was collected by filtration to give the desired compound 6-[[5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carbonyl]amino]-5-methylquinoline-7-carboxamide.
LC-MS (method 1): retention time 0.78 min, m/z 485 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (br s, 1H), 8.96 (br d, J=3.3 Hz, 1H), 8.45-8.60 (m, 2H), 8.16 (br d, J=7.6 Hz, 1H), 8.06 (s, 1H), 8.03 (br s, 1H), 7.58-7.67 (m, 2H), 7.56 (br s, 1H), 7.44 (s, 1H), 2.47 (s, 3H).
To a suspension of methyl 5-nitro-1H-indazole-6-carboxylate (7.6 g, 32 mmol, 1.0 equiv.) in EtOAc (350 mL) and 2-MeTHF (50 mL) at room temperature was added trimethyloxonium tetrafluoroborate (8.9 g, 54 mmol, 1.2 equiv.), and the resulting reaction mixture was stirred at room temperature overnight. The resulting suspension is filtered, and the filter cake was rinsed with EtOAc. The combined organic filtrates were extracted with saturated aqueous NaHCO3 solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with diisopropyl ether to give the desired compound 2-methyl-5-nitro-indazole-6-carboxylate.
LC-MS (method 1): retention time 0.76 min, m/z 236 [M+H]+.
1H NMR (400 MHz, CDCl3) δ ppm 8.42 (s, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 4.33 (s, 3H), 3.95 (s, 3H).
In a pressure reactor under hydrogen pressure (8 bar), a solution of 2-methyl-5-nitro-indazole-6-carboxylate (2.0 g, 8.5 mmol, 1.0 equiv.) and Pd/C (10%; 90 mg, 85 μmol, 10 mol %) in MeOH (26 mL) was heated to 35° C. for 2 h. The reaction mixture was filtered over a pad of celite and the filter cake was rinsed with MeOH. The combined filtrate was concentrated under reduced pressure, and the resulting solid residue was triturated with pentane/diisopropyl ether (5:1) to give the desired compound methyl 5-amino-2-methyl-indazole-6-carboxylate.
LC-MS (method 1): retention time 0.32 min, m/z 206 [M+H]+.
1H NMR (400 MHz, acetone-d6) δ ppm 8.29 (s, 1H), 7.85 (s, 1H), 6.83 (s, 1H), 5.66 (br s, 2H), 4.15 (s, 3H), 3.89 (s, 3H).
To a solution of methyl 5-amino-2-methyl-indazole-6-carboxylate (0.85 g, 4.1 mmol, 1.0 equiv.) in AcOH (15 mL) was added in portions N-bromosuccinimide (0.74 g, 4.1 mmol, 1.0 equiv.), and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure and the resulting residue was diluted with EtOAc and saturated aqueous solution of NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (EtOAc/cyclohexane) afforded the desired product methyl 5-amino-4-bromo-2-methyl-indazole-6-carboxylate.
LC-MS (method 1): retention time 0.86 min, m/z 284 [M+H]+.
1H NMR (400 MHz, acetone-d6) δ ppm 8.35 (d, J=0.7 Hz, 1H), 7.92 (s, 1H), 6.00 (br s, 2H), 4.21 (s, 3H), 3.93 (s, 3H).
Under argon, to a mixture of methyl 5-amino-4-bromo-2-methyl-indazole-6-carboxylate (0.48 g, 1.7 mmol, 1.0 equiv.), trimethylboroxine (0.28 g, 2.2 mmol, 1.3 equiv.), Cs2CO3 (1.1 g, 3.4 mmol, 2.0 equiv.) in 2-MeTHF (20 mL) and water (3 mL) was added Pd(dppf)Cl2 (65 mg, 84 μmol, 5 mol %) and the resulting reaction mixture was heated at 95° C. overnight. The reaction mixture was diluted with EtOAc and the organic phase was extracted with saturated aqueous solution of NaHCO3 and water, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid residue was triturated with diisopropyl ether to afford the desired compound methyl 5-amino-2,4-dimethyl-indazole-6-carboxylate.
LC-MS (method 1): retention time 0.58 min, m/z 220 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (s, 1H), 8.09 (s, 1H), 5.62 (s, 2H), 4.13 (s, 3H), 3.85 (s, 3H), 2.23 (s, 3H).
To a solution of methyl 5-amino-2,4-dimethyl-indazole-6-carboxylate (0.38 g, 1.7 mmol, 1.0 equiv.) in THF (2.8 mL), MeOH (2.8 mL), and water (2.8 mL) was added LiOH (0.22 g, 5.2 mmol, 3.0 equiv.), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the aqueous residue was filtered over a pad of celite. The aqueous filtrate was extracted with diethyl ether and 2-MeTHF, acidified to pH 5.2 with aqueous 1M HCl solution, and saturated with solid NaCl. The resulting aqueous mixture was diluted with 2-MeTHF, and the organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give the desired compound 5-amino-2,4-dimethyl-indazole-6-carboxylic acid.
LC-MS (method 1): retention time 0.18 min, m/z 206 [M+H]+.
To a mixture of 5-amino-2,4-dimethyl-indazole-6-carboxylic acid (0.28 g, 1.4 mmol, 1.0 equiv.), 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carboxylic acid (0.40 g, 1.4 mmol, 1.0 equiv.), and pyridine (0.44 mL, 5.5 mmol, 4.0 equiv.) in MeCN (15 mL) at 0° C. was added dropwise MsCl (2.6 mL, 3.4 mmol, 2.5 equiv.) and the resulting reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with 2-MeTHF/EtOAc (1:1) and water. The organic phase was separated, extracted with saturated aqueous NaHCO3 solution and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (EtOAc/cyclohexane) afforded the desired product 6-[2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazol-3-yl]-2,4-dimethyl-pyrazolo[3,4-g][3,1]benzoxazin-8-one.
LC-MS (method 1): retention time 1.09 min, m/z 461 [M+H]+.
To a solution of 6-[2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazol-3-yl]-2,4-dimethyl-pyrazolo[3,4-g][3,1]benzoxazin-8-one (75 mg, 0.16 mmol, 1.0 equiv.) in 2-MeTHF (8 mL) and EtOAc (8 mL) was added ammonium acetate (50 mg, 0.65 mmol, 4.0 equiv.) and the resulting reaction mixture was heated to 60° C. for 4 h. The reaction mixture was diluted with 2-MeTHF/EtOAc (1:1) and water, and the organic phase was separated, extracted with water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid residue was triturated with diisopropyl ether and diisopropyl ether/diethyl ether (3:1) to afford the desired compound 5-[[2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl]amino]-2,4-dimethylindazole-6-carboxamide.
LC-MS (method 1): retention time 0.86 min, m/z 478 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (br s, 1H), 8.53 (d, J=4.7 Hz, 1H), 8.23-8.31 (m, 1H), 8.08-8.14 (m, 1H), 7.85 (br d, J=2.5 Hz, 1H), 7.49-7.69 (m, 3H), 6.91 (br s, 1H), 4.23 (s, 3H), 2.32 (d, J=2.2 Hz, 3H).
The compound was prepared using 5-amino-2,4-dimethylindazole-6-carboxylic acid (for preparation see example P.34) and 5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid, under the conditions described for compound P.34 (example 34, step 6 and 7).
LC-MS (method 1): retention time 0.79 min, m/z 488 [M+H]+.
1H NMR (400 MHz, acetone-d6) δ ppm 10.31 (s, 1H), 8.49 (dd, J=4.7, 1.5 Hz, 1H), 8.27 (s, 1H), 8.06 (dd, J=8.0, 1.5 Hz, 1H), 7.85 (s, 1H), 7.50-7.60 (m, 2H), 7.26 (s, 1H), 6.92 (br s, 1H), 4.22 (s, 3H), 2.32 (s, 3H).
To a solution of methyl 5-amino-2-methyl-indazole-6-carboxylate (2.6 g, 12.8 mmol, 1.0 equiv.), as described in example 34, in AcOH (50 mL) was added in portions N-chlorosuccinimide (1.7 g, 12.8 mmol, 1.0 equiv.), and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure and the resulting residue was diluted with EtOAc and saturated aqueous solution of NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (EtOAc/cyclohexane) afforded the desired product methyl 5-amino-4-chloro-2-methyl-indazole-6-carboxylate.
LC-MS (method 1): retention time 0.85 min, m/z 240 [M+H]+.
1H NMR (400 MHz, acetone-d6) δ ppm 8.31 (d, J=0.7 Hz, 1H), 7.99 (s, 1H), 5.96 (br s, 2H), 4.22 (s, 3H), 3.93 (s, 3H).
To a solution of methyl 5-amino-4-chloro-2-methyl-indazole-6-carboxylate (1.6 g, 6.7 mmol, 1.0 equiv.) in THF (13 mL), MeOH (13 mL), and water (13 mL) was added LiOH (0.84 g, 20 mmol, 3.0 equiv.), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the aqueous residue was filtered over a pad of celite. The aqueous filtrate was extracted with diethyl ether and 2-MeTHF, acidified to pH 5 with aqueous 1M HCl solution. The resulting precipitate was filtered off, the filter cake was washed with water, and the collected solids were dried and triturated with diisopropyl ether to give the desired compound 5-amino-4-chloro-2-methyl-indazole-6-carboxylic acid.
LC-MS (method 1): retention time 0.67 min. m/z 226 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1H), 8.12 (s, 1H), 4.15 (s, 3H).
LC-MS (method 1): retention time 0.86 min, m/z 498 [M+H]+.
1H NMR (400 MHz, acetone-d6) δ ppm 10.02 (s, 1H), 8.05-8.12 (m, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.34 (br d, J=9.4 Hz, 3H), 7.20 (dd, J=8.0, 4.7 Hz, 1H), 6.95 (br s, 1H), 3.76 (s, 3H).
Ethyl 5-bromo-4-methoxy-2-oxo-pent-3-enoate (9.3 g, 37 mmol, 1.0 equiv.), as described in WO 2019/224678, and (3-chloro-2-pyridyl)hydrazine (5.3 g, 37 mmol, 1.0 equiv.) were dissolved in glacial AcOH (93 mL), and the resulting reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0° C., before concentrated H2SO4 (4.0 mL) was added carefully, and stirring was continued at room temperature for 30 min. The reaction mixture was diluted with EtOAc and water, the organic phase was separated and extracted with water, saturated solution of NaHCO3, and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of the resulting residue by flash chromatography (EtOAc/cyclohexane) afforded the desired product ethyl 5-(bromomethyl)-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylate.
LC-MS (method 1): retention time 0.97 min, m/z 344 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (dd, J=4.7, 1.5 Hz, 1H), 8.26 (dd, J=8.0, 1.5 Hz, 1H), 7.69 (dd, J=8.4, 4.7 Hz, 1H), 7.21 (s, 1H), 4.72 (s, 2H), 4.15 (q, J=7.3 Hz, 2H), 1.09 (t, J=7.1 Hz, 3H).
To a solution of ethyl 5-(bromomethyl)-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylate (2.0 g, 5.8 mmol, 1.0 equiv.) and 4-chloro-2H-indazole (1.1 g, 7.0 mmol, 1.2 equiv.) in NMP (12 mL) was added potassium carbonate (1.6 g, 12 mmol, 2.0 equiv.) and potassium iodide (0.19 g, 1.2 mmol, 20 mol %), and the resulting suspension was stirred at room temperature for 16 h. The reaction mixture was diluted with water and EtOAc. The organic phase was separated, extracted with aqueous 1M HCl and brine, dried over MgSO4, filtered and concentrated. Purification of the resulting residue by flash chromatography (EtOAc/cyclohexane) afforded the two desired products.
LC-MS (method 1): retention time 1.07 min, m/z 416 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (dd, J=4.7, 1.5 Hz, 1H), 8.23 (dd, J=8.4, 1.5 Hz, 1H), 8.19 (d, J=0.7 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.67 (dd, J=8.0, 4.7 Hz, 1H), 7.41 (dd, J=8.4, 7.6 Hz, 1H), 7.25 (d, J=7.3 Hz, 1H), 6.91 (s, 1H), 5.80 (s, 2H), 4.10 (q, J=6.9 Hz, 2H), 1.05 (t, J=7.1 Hz, 3H).
LC-MS (method 1): retention time 1.03 min, m/z 416 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.55 (dd, J=4.7, 1.5 Hz, 1H), 8.25 (dd, J=8.0, 1.5 Hz, 1H), 7.69 (dd, J=8.2, 4.5 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.25 (dd, J=8.4, 7.3 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.12 (s, 1H), 5.80 (s, 2H), 4.12 (q, J=6.9 Hz, 2H), 1.07 (t, J=7.1 Hz, 3H).
To a solution of ethyl 5-[(4-chloroindazol-1-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylate (0.81 g, 1.9 mmol, 1.0 equiv.) in EtOH (7.7 mL) at room temperature was added aqueous 2M NaOH solution (1.9 mL, 3.9 mmol, 2.0 equiv.), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and water, and the aqueous layer was separated and acidified to pH 2 by addition of aqueous 1M HCl solution. The resulting aqueous mixture was extracted with EtOAc, and the organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give the desired compound 5-[(4-chloroindazol-1-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid.
LC-MS (method 1): retention time 0.88 min, m/z 388 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 13.54 (br s, 1H), 8.51 (dd, J=4.7, 1.5 Hz, 1H), 8.16-8.22 (m, 2H), 7.76 (d, J=8.7 Hz, 1H), 7.64 (dd, J=8.0, 4.7 Hz, 1H), 7.41 (dd, J=8.4, 7.6 Hz, 1H), 7.24 (d, J=7.3 Hz, 1H), 6.82 (s, 1H), 5.78 (s, 2H).
To a solution of 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid (0.31 g, 1.0 mmol, 1.0 equiv.), as described in WO 2007/043677, and 5-[(4-chloroindazol-1-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid (0.40 g, 1.0 mmol, 1.0 equiv.) in pyridine (0.33 mL, 4.2 mmol, 4.0 equiv.) and MeCN (6.1 mL) at 0° C. was added dropwise MsCl (0.20 mL, 2.6 mmol, 2.5 equiv.), and the resulting reaction mixture was stirred at 0° C. for 30 minutes. Cooling was removed and the reaction mixture was stirred at room temperature for 3 h. Then, additional 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid (0.31 g, 1.0 mmol, 1.0 equiv.) and MsCl (0.20 mL, 2.6 mmol, 2.5 equiv.) were added to the reaction, and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the resulting solid was collected by filtration and triturated with diethyl ether to give the desired compound 7-bromo-10-chloro-2-[5-[(4-chloroindazol-1-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one.
To a solution of 7-bromo-10-chloro-2-[5-[(4-chloroindazol-1-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one (0.88 g, 1.1 mmol, 1.0 equiv.) in ethyl acetate (5.4 mL) at room temperature was added (NH4)2CO3 (1.0 g, 11 mmol, 10 equiv.), and the resulting reaction mixture was heated to 77° C. for 1.5 h. The reaction mixture was diluted with water, and the resulting solid was collected by filtration and washed with EtOAc. Purification of the resulting solid residue by flash chromatography (EtOAc/cyclohexane) afforded the desired product N-(6-bromo-3-carbamoyl-1-chloro-2-naphthyl)-5-[(4-chloroindazol-1-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxamide.
LC-MS (method 1): retention time 1.12 min, m/z 668 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1H), 8.46 (dd, J=4.7, 1.5 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.24 (d, J=0.7 Hz, 1H), 8.08-8.13 (m, 2H), 8.06 (s, 1H), 7.85 (dd, J=9.1, 2.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.55 (dd, J=8.0, 4.7 Hz, 1H), 7.48 (s, 1H), 7.42-7.47 (m, 1H), 7.27 (d, J=7.3 Hz, 1H), 7.13 (s, 1H), 5.84 (s, 2H).
The compound was prepared from ethyl 5-[(4-chloroindazol-2-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylate, as described in example 37 (step 2), under the conditions given in example 37 (step 3).
LC-MS (method 1): retention time 0.84 min, m/z 388 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 13.59 (br s, 1H), 8.65 (s, 1H), 8.53 (dd, J=4.7, 1.8 Hz, 1H), 8.22 (dd, J=8.0, 1.5 Hz, 1H), 7.65 (dd, J=8.0, 4.7 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.25 (dd, J=8.4, 7.3 Hz, 1H), 7.15 (d, J=7.3 Hz, 1H), 7.04 (s, 1H), 5.78 (s, 2H).
The compound was prepared from 5-[(4-chloroindazol-2-yl)methyl]-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid and 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid under the conditions given in example 37 (step 4 and 5).
LC-MS (method 1): retention time 1.09 min, m/z 688 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 8.73 (s, 1H), 8.47 (dd, J=4.7, 1.5 Hz, 1H), 8.38 (d, J=2.2 Hz, 1H), 8.09-8.14 (m, 2H), 8.07 (s, 1H), 7.86 (dd, J=9.1, 1.8 Hz, 1H), 7.78 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.56 (dd, J=8.2, 4.5 Hz, 1H), 7.49 (s, 1H), 7.25-7.31 (m, 2H), 7.17 (d, J=7.3 Hz, 1H), 5.85 (s, 2H).
To a solution of 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid (0.43 g, 1.4 mmol, 1.0 equiv.), as described in WO 2007/043677, and 2-(3-chloro-2-pyridyl)-5-[[5-(trifluoromethyl)tetrazol-2-yl]methyl]pyrazole-3-carboxylic acid (0.54 g, 1.4 mmol, 1.0 equiv.), as described in WO 2011/157664, in pyridine (0.46 mL, 5.7 mmol, 4.0 equiv.) and MeCN (29 mL) at 0° C. was added dropwise MsCl (0.28 mL, 3.6 mmol, 2.5 equiv.), and the resulting reaction mixture was stirred at 0° C. for 30 minutes. Cooling was removed, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. The resulting solid was collected by filtration and washed with diethyl ether to give the desired compound 7-bromo-10-chloro-2-[2-(3-chloro-2-pyridyl)-5-[[5-(trifluoromethyl)tetrazol-2-yl]methyl]pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one.
LC-MS (method 1): retention time 1.30 min, m/z 637 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1H), 8.64 (d, J=1.8 Hz, 1H), 8.62 (dd, J=4.7, 1.5 Hz, 1H), 8.34 (dd, J=8.2, 1.6 Hz, 1H), 8.12 (d, J=9.1 Hz, 1H), 7.95-7.99 (m, 1H), 7.76 (dd, J=8.0, 4.7 Hz, 1H), 7.51 (s, 1H), 6.35 (s, 2H)
To a solution of 7-bromo-10-chloro-2-[2-(3-chloro-2-pyridyl)-5-[[5-(trifluoromethyl)tetrazol-2-yl]methyl]pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one (0.44 g, 0.69 mmol, 1.0 equiv.) in ethyl acetate (6.9 mL) at room temperature was added (NH4)2CO3 (0.66 g, 6.9 mmol, 10 equiv.), and the resulting reaction mixture was heated to 77° C. for 1 h. The reaction mixture was diluted with water and EtOAc. The organic phase was separated, dried over MgSO4, filtered and concentrated to give the desired product N-(6-bromo-3-carbamoyl-1-chloro-2-naphthyl)-2-(3-chloro-2-pyridyl)-5-[[5-(trifluoromethyl)tetrazol-2-yl]methyl]pyrazole-3-carboxamide.
LC-MS (method 1): retention time 1.07 min, m/z 654 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1H), 8.46-8.51 (m, 1H), 8.40 (s, 1H), 8.11-8.17 (m, 2H), 8.10 (s, 1H), 7.86-7.92 (m, 1H), 7.84 (br s, 1H), 7.55-7.60 (m, 1H), 7.53 (br s, 1H), 7.47 (s, 1H), 6.34 (s, 2H).
Under argon, a solution of 3-amino-7-bromo-4-chloronaphthalene-2-carboxylic acid (0.20 g, 0.67 mmol, 1.0 equiv.), as described in WO 2007/043677, and CuCN (0.12 g, 1.3 mmol, 2.0 equiv.) in NMP (2.7 mL) was heated to 200° C. for 4 h and stirred at room temperature overnight. The reaction mixture was diluted with ice water, saturated NH4Cl solution and EtOAc. The resulting suspension was filtered over a pad of celite, and the organic phase of the filtrate was separated, dried over MgSO4, filtered, and concentrated to give the desired compound 3-amino-4-chloro-7-cyano-naphthalene-2-carboxylic acid.
LC-MS (method 1): retention time 0.91 min, m/z 247 [M+H]+.
To a solution of 3-amino-4-chloro-7-cyano-naphthalene-2-carboxylic acid (0.16 g, 0.66 mmol, 1.0 equiv.) and 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid (0.21 g, 0.66 mmol, 1.0 equiv.), as described in Bioorg. Med. Chem. Lett. 2007, 17, 6274-6279, in pyridine (0.21 mL, 2.7 mmol, 4.0 equiv.) and MeCN (2.46 mL) at 0° C. was added dropwise MsCl (0.13 mL, 1.6 mmol, 2.5 equiv.), and the resulting reaction mixture was stirred at 0° C. for 30 minutes. The ice-bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. The resulting solid was collected by filtration and washed with diethyl ether to give the desired compound 10-chloro-2-[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]-4-oxo-benzo[g][3,1]benzoxazine-7-carbonitrile.
LC-MS (method 1): retention time 1.20 min, m/z 532 [M+H]+.
To a solution of 10-chloro-2-[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]-4-oxo-benzo[g][3,1]benzoxazine-7-carbonitrile (36 mg, 68 μmol, 1.0 equiv.) in EtOAc (0.33 mL) at room temperature was added (NH4)2CO3 (65 mg, 0.68 mmol, 10 equiv.), and the resulting reaction mixture was heated to 77° C. for 1 h. The reaction mixture was diluted with water and EtOAc. The organic phase was separated, dried over MgSO4, filtered, and concentrated to give the desired product N-(3-carbamoyl-1-chloro-6-cyano-2-naphthyl)-2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxamide.
LC-MS (method 1): retention time 0.98 min, m/z 549 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (br s, 1H), 8.74 (br s, 1H), 8.47 (dd, J=4.5, 1.3 Hz, 1H), 8.30-8.39 (m, 1H), 8.28 (br s, 1H), 8.09 (br d, J=8.0 Hz, 1H), 7.82-8.05 (m, 2H), 7.60 (br s, 1H), 7.53 (dd, J=8.0, 4.7 Hz, 1H), 6.81-7.03 (m, 1H), 4.92 (q, J=8.7 Hz, 2H).
To a solution of ethyl 5-(bromomethyl)-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylate (1.0 g, 2.9 mmol, 1.0 equiv.), as described in example 37 (step 1), and 5-[4-(trifluoromethyl)phenyl]-2H-tetrazole (0.80 g, 3.6 mmol, 1.2 equiv.) in NMP (6 mL) was added potassium carbonate (0.83 g, 6.0 mmol, 2.0 equiv.) and potassium iodide (0.10 g, 0.60 mmol, 20 mol %), and the resulting suspension was stirred at room temperature for 20 h. The reaction mixture was diluted with water and EtOAc. The organic layers was separated, extracted with aqueous 1M HCl and brine, dried over MgSO4, filtered and concentrated. Purification of the resulting residue by flash chromatography (EtOAc/cyclohexane) afforded the desired product ethyl 2-(3-chloro-2-pyridyl)-5-[[5-[4-(trifluoromethyl)phenyl]tetrazol-2-yl]methyl]pyrazole-3-carboxylate.
LC-MS (method 1): retention time 1.16 min, m/z 478 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (dd, J=4.7, 1.8 Hz, 1H), 8.21-8.29 (m, 3H), 7.93 (d, J=8.0 Hz, 2H), 7.69 (dd, J=8.0, 4.7 Hz, 1H), 7.25 (s, 1H), 6.19 (s, 2H), 4.14 (q, J=7.0 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H).
To a solution of ethyl 2-(3-chloro-2-pyridyl)-5-[[5-[4-(trifluoromethyl)phenyl]tetrazol-2-yl]methyl]pyrazole-3-carboxylate (1.2 g, 2.1 mmol, 1.0 equiv.) in EtOH (8.4 mL) at room temperature was added aqueous 2M NaOH solution (2.1 mL, 4.2 mmol, 2.0 equiv.), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc and water, and the aqueous layer was separated and acidified to pH 2 by addition of aqueous 1M HCl solution. The resulting aqueous mixture was extracted with EtOAc, and the organic phase was dried over MgSO4, filtered and concentrated. Purification of the resulting residue by flash chromatography (EtOAc/cyclohexane) afforded the desired product 2-(3-chloro-2-pyridyl)-5-[[5-[4-(trifluoromethyl)phenyl]tetrazol-2-yl]methyl]pyrazole-3-carboxylic acid.
LC-MS (method 1): retention time 0.96 min, m/z 450 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 13.69 (br s, 1H), 8.53 (dd, J=4.7, 1.5 Hz, 1H), 8.29 (d, J=8.0 Hz, 2H), 8.22 (dd, J=8.0, 1.5 Hz, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.66 (dd, J=8.0, 4.7 Hz, 1H), 7.16 (s, 1H), 6.17 (s, 2H)
The compound was prepared from 2-(3-chloro-2-pyridyl)-5-[[5-[4-(trifluoromethyl)phenyl]tetrazol-2-yl]methyl]pyrazole-3-carboxylic acid and 3-amino-7-bromo-4-chloro-naphthalene-2-carboxylic acid under the conditions described in example 39, step 1.
LC-MS (method 1): retention time 1.38 min.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1H), 8.64 (d, J=2.2 Hz, 1H), 8.61 (dd, J=4.7, 1.8 Hz, 1H), 8.33 (dd, J=8.2, 1.6 Hz, 1H), 8.30 (d, J=8.0 Hz, 2H), 8.13 (d, J=9.4 Hz, 1H), 7.92-7.99 (m, 3H), 7.75 (dd, J=8.0, 4.7 Hz, 1H), 7.47 (s, 1H), 6.27 (s, 2H).
To a solution of 7-bromo-10-chloro-2-[2-(3-chloro-2-pyridyl)-5-[[5-[4-(trifluoromethyl)phenyl]tetrazol-2-yl]methyl]pyrazol-3-yl]benzo[g][3,1]benzoxazin-4-one (0.86 g, 1.2 mmol, 1.0 equiv.) in ethyl acetate (6.0 mL) at room temperature was added (NH4)2CO3 (1.2 g, 12 mmol, 10 equiv.), and the resulting reaction mixture was heated to 77° C. for 1.5 h. The reaction mixture was diluted with water and EtOAc. The organic phase was separated, dried over MgSO4, filtered and concentrated. Purifications of the resulting residue by flash chromatography (EtOAc/cyclohexane) and reverse phase chromatography afforded the desired product N-(6-bromo-3-carbamoyl-1-chloro-2-naphthyl)-2-(3-chloro-2-pyridyl)-5-[[5-[4-(trifluoromethyl)phenyl]tetrazol-2-yl]methyl]pyrazole-3-carboxamide.
LC-MS (method 1): retention time 1.17 min, m/z 730 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 8.48 (dd, J=4.7, 1.5 Hz, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.33 (d, J=8.4 Hz, 2H), 8.07-8.15 (m, 3H), 7.96 (d, J=8.4 Hz, 2H), 7.82-7.89 (m, 2H), 7.57 (dd, J=8.4, 4.7 Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 6.25 (s, 2H).
To a solution of 7-methyl-1,3-benzothiazol-6-amine (1.0 g, 6.1 mmol, 1.0 equiv.) in acetic acid (30 mL) at 10° C. was added dropwise a solution of bromine (0.31 mL, 6.1 mmol, 1.0 equiv.) in acetic acid (20 mL), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were extracted with saturated aqueous sodium bicarbonate solution, water, and brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford the desired product 5-bromo-7-methyl-1,3-benzothiazol-6-amine.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.02 (s, 1H), 8.02 (s, 1H), 5.30 (s, 2H), 2.38 (s, 3H).
In a pressure reactor under CO pressure (6.9 bar), a mixture of 7-bromo-2-methyl-1,3-benzoxazol-6-amine (0.80 g, 3.3 mmol, 1.0 equiv.), triethylamine (1.4 mL, 9.9 mmol, 3.0 equiv.) and Pd(dppf)Cl2 DCM complex (0.27 g, 0.33 mmol, 10 mol %) in methanol (30 mL) was stirred at 100° C. for 12 h. Reaction mixture was filtered over a plug of celite and the filtrate was evaporated was concentrated under reduced pressure. The resulting crude residue was purified by flash chromatography to afford the desired product methyl 6-amino-7-methyl-1,3-benzothiazole-5-carboxylate.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (s, 1H), 8.32 (s, 1H), 6.63 (s, 2H), 3.88 (s, 3H), 2.38 (s, 3H).
MS (method 5): m/z 223 [M+H]+.
To a solution of methyl 6-amino-7-methyl-1,3-benzothiazole-5-carboxylate (0.70 g, 3.2 mmol, 1.0 equiv.) in methanol (10 mL) and THF (5.0 mL) at 0° C. was added dropwise a solution of LiOH hydrate (0.66 g, 16 mmol, 5.0 equiv.) in water (3.0 mL). The resulting reaction mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated under reduced pressure and the aqueous residue was acidified to pH 2-3 at 0° C. using 2N aqueous HCl. The aqueous phase was extracted with DCM/MeOH (v:v; 9:1). The combined organic phases were extracted with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 6-amino-7-methyl-1,3-benzothiazole-5-carboxylic acid.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (s, 1H), 8.32 (s, 1H), 2.32 (s, 3H).
MS (method 5): m/z 209 [M+H]+.
To a mixture of 6-amino-7-methyl-1,3-benzothiazole-5-carboxylic acid (0.20 g, 0.96 mmol, 1.0 equiv.), 5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid (0.35 g, 1.2 mmol, 1.2 equiv.), pyridine (78 μL, 0.96 mmol, 1.0 equiv.) in acetonitrile (10 mL) at 0° C. was added methanesulfonyl chloride (74 μL, 0.96 mmol, 1.0 equiv.), and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc. The combined organic phases were extracted with brine, dried over Na2SO4 and concentrated under reduced pressure to afford crude 6-[5-bromo-2-(3-chloro-2-pyridyl)pyrazol-3-yl]-4-methyl-thiazolo[4,5-g][3,1]benzoxazin-8-one.
MS (method 5): m/z 474 [M+H]+.
To a mixture of 6-[5-bromo-2-(3-chloro-2-pyridyl)pyrazol-3-yl]-4-methyl-thiazolo[4,5-g][3,1]benzoxazin-8-one (0.20 g, 0.42 mmol, 1.0 equiv.) in acetonitrile (20 mL) at room temperature was added 2M solution of ammonia in ethanol (10 mL, 20 mmol, 48 equiv.) and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash reverse-phase column chromatography (water/acetonitrile). to afford the desired product 6-[[5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carbonyl]amino]-7-methyl-1,3-benzothiazole-5-carboxamide.
MS (method 5): m/z 491 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 9.46 (s, 1H), 8.51 (dd, J=1.2 Hz, 4.4 Hz, 1H), 8.18-8.14 (m, 2H), 7.96 (s, 1H), 7.61 (dd, J=4.8 Hz, 8.0 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 2.37 (s, 3H).
To a mixture of 6-amino-2,7-dimethyl-1,3-benzothiazole-5-carboxylic acid (0.15 g, 0.68 mmol, 1.0 equiv.) which may be prepared as described in example 42 (step 1-3), 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid (0.22 g, 0.68 mmol, 1.0 equiv.) in acetonitrile (10 mL) and pyridine (0.16 g, 2.0 mmol, 3.0 equiv.) at 0° C. was added methanesulfonyl chloride (0.31 g, 2.7 mmol, 4.0 equiv.) and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were extracted with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the desired compound 6-[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]-2,4-dimethyl-thiazolo[4,5-g][3,1]benzoxazin-8-one.
MS (method 5): m/z 508 [M+H]+.
To a mixture of 6-[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazol-3-yl]-2,4-dimethyl-thiazolo[4,5-g][3,1]benzoxazin-8-one (0.15 g, 0.21 mmol, 1.0 equiv.) in acetonitrile (10 mL) at 0° C. was added 2M NH3 in ethanol (1.0 mL, 2.1 mmol, 10 equiv.) and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were extracted with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (hexane/EtOAc) to afford the desired compound 6-[[2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carbonyl]amino]-2,7-dimethyl-1,3-benzothiazole-5-carboxamide.
MS (method 5): m/z 525 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.47 (s, 1H), 8.48 (dd, J=1.6 Hz, 4.8 Hz, 1H), 8.13 (dd, J=1.6 Hz, 8.0 Hz, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.56 (dd, J=4.8 Hz, 8.0 Hz, 2H), 6.88 (s, 1H), 4.95 (q, J=8.4 Hz, 2H), 2.82 (s, 3H), 2.31 (s, 3H).
The compound can be prepared from 6-amino-7-methyl-1,3-benzothiazole-5-carboxylic acid (described in example 42) and 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid using the procedure described in example 43 (step 1+2).
MS (method 5): m/z 511 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 9.46 (s, 1H), 8.48 (dd, J=1.2 Hz, 4.4 Hz, 1H), 8.14 (s, 1H), 8.13 (dd, J=1.6 Hz, 8.0 Hz 1H), 7.96 (s, 1H), 7.58-7.54 (m, 2H), 6.90 (s, 1H), 4.96 (q, J=8.8 Hz, 2H), 2.38 (s, 3H).
The compound can be prepared from 6-amino-2,7-dimethyl-1,3-benzothiazole-5-carboxylic acid and 5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid using the procedure described in example 43 (step 1+2).
MS (method 5): m/z 505 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (s, 1H), 8.51 (dd, J=1.6 Hz, 4.8 Hz, 1H), 8.17 (dd, J=1.6 Hz, 8.4 Hz, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.61 (dd, J=4.8 Hz, 8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 2.82 (s, 3H), 2.31 (s, 3H).
The compound can be prepared from 6-amino-2,7-dimethyl-1,3-benzoxazole-5-carboxylic acid which may be prepared as described in example 42 (step 1-3) and 5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid using the procedure described in example 43 (step 1+2).
MS (method 5): m/z 489 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.50 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.16 (dd, J=8.0 Hz, 1.2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.62-7.58 (m, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 2.63 (s, 3H), 2.25 (s, 3H).
The compound can be prepared from 6-amino-2,7-dimethyl-1,3-benzoxazole-5-carboxylic acid and 2-(3-chloro-2-pyridyl)-5-(2,2,2-trifluoroethoxy)pyrazole-3-carboxylic acid using the procedure described in example 43 (step 1+2).
MS (method 5): m/z 509 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (s, 1H), 8.47 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.12 (dd, J=8.4 Hz, 1.2 Hz, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.57-7.53 (m, 2H), 6.88 (s, 1H), 4.92 (q, J=8.8 Hz, 2H), 2.63 (s, 3H), 2.25 (s, 3H).
To a solution of 2-chloroquinolin-6-amine (4.5 g, 25 mmol, 1.0 equiv.) in AcOH (151 mL) at room temperature was added dropwise bromine (1.3 mL, 25 mmol, 1.0 equiv.) and the resulting reaction mixture was stirred at room temperature for 30 minutes. The formed solid was collected by filtration and triturated with water. The residue was basified to pH 9-10 using aqueous 2M NaOH solution and the desired product was collected by filtration.
LC-MS (method 1): retention time 0.97 min, m/z 257 [M+H]+.
Under argon, 5-bromo-2-chloroquinolin-6-amine (6.5 g, 25 mmol, 1.0 equiv.), trimethylboroxine (4.8 g, 38 mml, 1.5 equiv.), Cs2CO3 (16.6 g, 51 mmol, 2.0 equiv.), and Pd(dppf)Cl2 (0.97 g, 1.3 mmol, 5 mol %) are suspended in dioxane (78 mL) and the resulting reaction mixture is heated to 80° C. for 12 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired product 2-chloro-5-methyl-quinolin-6-amine.
LC-MS (method 1): retention time 0.80 min, m/z 193 [M+H]+.
To a solution of 2-chloro-5-methyl-quinolin-6-amine (1.6 g, 8.5 mmol, 1.0 equiv.) in acetic acid (85 mL) at room temperature was added dropwise bromine (0.52 mL, 10 mmol, 1.2 equiv.) and the resulting reaction mixture was stirred at room temperature overnight. The formed solid was collected by filtration and triturated with water. The residue was basified to pH 9-10 using aqueous 2M NaOH solution and the desired product was collected by filtration.
LC-MS (method 1): retention time 0.99 min, m/z 271 [M+H]+.
In a sealed pressure tube, a solution of 7-bromo-2-chloro-5-methylquinolin-6-amine (90 mg, 0.33 mmol, 1.0 equiv.) and NaOMe (5.4M in MeOH; 0.31 mL, 1.7 mmol, 5 equiv.) in MeOH (1.7 mL) was heated to 120° C. for 48 h. The reaction mixture was poured onto cold water and the formed solid was collected by filtration to give the desired product.
LC-MS (method 1): retention time 1.01 min, m/z 267 [M+H]+.
In a pressure reactor, 7-bromo-2-methoxy-5-methylquinolin-6-amine (53 mg, 0.20 mmol, 1.0 equiv.), Et3N (30 μL, 0.21 mmol, 1.1 equiv.), Pd(dppf)Cl2 (15 mg, 20 μmol, 10 mol %) were suspended in DMSO (7.4 mL) and MeOH (5.1). The reaction mixture was put under 5 bars of carbon monoxide and heated to 120° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue was diluted with EtOAc and water, and the resulting slurry was filtered over a pad of celite. The organic phase of the filtrate was separated, extracted with water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the resulting residue by flash chromatography (ethyl acetate in cyclohexane) afforded the desired product methyl 6-amino-2-methoxy-5-methylquinoline-7-carboxylate.
LC-MS (method 1): retention time 0.99 min, m/z 247 [M+H]+.
To a solution of methyl 6-amino-2-methoxy-5-methylquinoline-7-carboxylate (49 mg, 0.20 mmol, 1.0 equiv.) in THF (0.80 mL), water (0.80 mL), and MeOH (0.80 mL) was added LiOH (25 mg, 0.60 mmol, 3.0 equiv.), and the resulting reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure, and the aqueous residue was adjusted to pH 5-6 using aqueous 1M HCl solution. The aqueous mixture was extracted with EtOAc, and the combined organic phases were extracted with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography to give the desired 6-amino-2-methoxy-5-methylquinoline-7-carboxylic acid.
LC-MS (method 1): retention time 0.74 min, m/z 233 [M+H]+.
To a solution of 6-amino-2-methoxy-5-methylquinoline-7-carboxylic acid (22 mg, 95 μmol, 1.0 equiv.), and 5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carboxylic acid (30 mg, 95 μmol, 1.0 equiv.) in acetonitrile (2.4 mL) and pyridine (39 μL, 0.47 mmol, 5.0 equiv.) was added dropwise at 0° C. a MsCl (22 μL, 0.28 mmol, 3 equiv.), and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration to give the desired compound 2-[5-bromo-2-(3-chloro-2-pyridyl)pyrazol-3-yl]-7-methoxy-10-methylpyrido[2,3-g][3,1]benzoxazin-4-one.
LC-MS (method 1): retention time 1.25 min, m/z 498 [M+H]+.
To a solution of 2-[5-bromo-2-(3-chloro-2-pyridyl)pyrazol-3-yl]-7-methoxy-10-methylpyrido[2,3-g][3,1]benzoxazin-4-one (30 mg, 58 μmol, 1.0 equiv.) in ethyl acetate (1.9 mL) was added ammonium acetate (51 mg, 0.66 mmol, 7.0 equiv.), and the resulting reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was diluted with water, and the resulting precipitate was collected by filtration and washed with water to give the desired compound 6-[[5-bromo-2-(3-chloro-2-pyridyl)pyrazole-3-carbonyl]amino]-2-methoxy-5-methylquinoline-7-carboxamide.
LC-MS (method 1): retention time 0.92 min, m/z 515 [M+H]+.
1H NMR (600 MHz, DMSO-d6) δ ppm 10.44 (s, 1H), 8.50 (dd, J=4.7, 1.6 Hz, 1H), 8.41 (d, J=9.3 Hz, 1H), 8.16 (dd, J=8.0, 1.5 Hz, 1H), 7.96 (br s, 1H), 7.82 (s, 1H), 7.60 (dd, J=8.0, 4.7 Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1H), 7.11 (d, J=9.1 Hz, 1H), 4.00 (s, 3H), 2.41 (s, 3H).
Further examples of compounds of the formula I are shown in Table P.
1H NMR (400 MHz, DMSO-d6) δ ppm 10.56 (s, 1 H), 8.45-8.50 (mm, 1 H), 8.45-8.50 (m, 1 H), 8.37-8.42 (m, 1 H), 8.12-8.18 (m, 2 H), 8.06-8.11 (m, 1 H), 7.85-7.89 (m, 1 H), 7.76-7.82 (m, 1 H), 7.51-7.58 (m, 2 H), 6.93-6.99 (m, 1 H), 4.87-4.98 (m, 2 H).
1H NMR (400 MHz, CDCl3) δ ppm 10.38 (s, 1H), 8.49 (dd, J = 4.7, 1.5 Hz, 1H), 7.85-7.94 (m, 1H), 7.44 (dd, J = 8.0, 4.7 Hz, 1H), 7.29 (s, 1H), 7.11 (s, 1H), 5.94 (br s, 1H), 5.68 (br s, 1H), 2.17 (s, 3H).
1H NMR (400 MHz, CDCl3) δ ppm 10.50 (s, 1 H), 8.46 (dd, J = 4.7, 1.8 Hz, 1 H), 8.28 (d, J = 8.7 Hz, 1 H), 8.12 (s, 1 H), 7.84 (dd, J = 8.0, 1.8 Hz, 1 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.34 (dd, J = 8.0, 4.7 Hz, 1 H), 6.73 (s, 1 H), 6.45 (br s, 1 H), 5.93 (br s, 1 H), 4.71 (q, J = 8.4 Hz, 2 H), 2.42 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 8.55 (dd, J = 4.72, 1.45 Hz 1 H), 8.40 (d, J = 1.82 Hz, 1 H), 8.20 (dd, J = 8.17, 1.27 Hz, 1 H), 8.12-8.16 (m, 2 H), 7.82-7.93 (m, 3 H), 7.65 (dd, J = 8.17, 4.54 Hz, 1 H), 7.56 (s, 1 H).
1H NMR (400 MHz, CDCl3) δ ppm 10.70 (s, 1 H), 8.48 (dd, J = 4.72, 1.45 Hz, 1 H), 8.12-8.25 (m, 1 H), 8.06 (s, 1 H), 7.88 (dd, J = 7.99, 1.45 Hz, 1 H), 7.60 (d, J = 8.72 Hz, 1 (dd, J = 7.99, 4.72 Hz, 1 H), 6.49 (br s, 1 H), 5.96 (br s, 1 H), 2.31-2.41 (m, 3 H).
1H NMR (400 MHz, CDCl3) δ ppm 10.56 (s, 1 H), 8.47 (dd, J = 4.72, 1.45 Hz, 1 H), 8.35 (d, J = 8.72 Hz, 1 H), 8.19 (s, 1 H), 7.86 (dd, J = 8.17, 1.63 Hz, 1 H), 7.70 (d, J = 9.08 Hz, 1 H), 7.37 (dd, J = 7.99, 4.72 Hz, 1 H), 7.19 (s, 1 H), 6.42 (br s, 1 H), 5.89 (br s, 1 H), 2.45 (s, 3 H).
1H NMR (400 MHz, CDCl3) δ ppm 10.65 (s, 1 H), 8.49 (dd, J = 4.72, 1.45 Hz, 1 H), 8.31 (d, J = 8.72 Hz, 1 H), 8.15 (s, 1 H), 7.87 (dd, J = 8.17, 1.63 Hz, 1 H), 7.67 (d, J = 9.08 Hz, 1 H), 7.37-7.44 (m, 2 H), 6.68-6.98 (t, J = 54.68 Hz, 1 H), 6.44 (br s, 1 H), 5.95 (br s, 1 H), 2.44 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.66 (s, 1 H), 8.48-8.52 (m, 1 H), 8.36-8.43 (m, 1 H), 8.09-8.20 (m, 3 H), 7.85-7.91 (m, 1 H), 7.77-7.84 (m, 1 H), 7.56-7.61 (m, 1 H), 7.51-7.55 (m, 1 H), 7.48-7.49 (m, 1 H).
1H NMR (400 MHz, CDCl3) δ ppm 11.21 (s, 1 H), 8.48 (dd, J = 4.72, 1.45 Hz, 1 H), 8.21-8.29 (m, 1 H), 8.11-8.09 (m, 1 H), 8.00-8.09 (m, 1 H), 7.84 (dd, J = 8.17, 1.64 Hz, 1 H), 7.68-7.79 (m, 2 H), 7.34 (dd, J = 7.99, 4.72 Hz, 1 H), 6.68 (s, 1 H), 5.90-6.06 (m, 1 H), 4.72 (q, J = 8.36 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.78 (s, 1 H), 8.54 (dd, J = 4.72, 1.45 Hz, 1 H), 8.18- 8.25 (m, 2 H), 8.16 (s, 1 H), 8.10 (d, J = 7.99 Hz, 1 H), 7.91 (br s, 1 H), 7.84 (s, 1 H), 7.75-7.81 (m, 1 H), 7.68-7.74 (m, 1 H), 7.65 (dd, J = 7.99, 4.72 Hz, 1 H), 7.52 (s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1 H), 8.48 (dd, J = 4.72, 1.45 Hz, 1 H), 8.22 (d, J = 8.36 Hz, 1 H), 8.16 (s, 1 H), 8.07-8.13 (m, 2 H), 7.85 (br s, 1 H), 7.74- 7.80 (m, 1 H), 7.67- 7.73 (m, 1 H), 7.55 (dd, J = 7.99, 4.72 Hz, 2 H), 6.97 (s, 1 H), 4.87-4.97 (m, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1 H), 8.49-8.54 (m, 1 H), 8.37-8.42 (m, 1 H), 8.12-8.18 (m, 3 H), 7.85-7.92 (m, 1 H), 7.79-7.84 (m, 1 H), 7.57-7.67 (m, 2 H), 7.51-7.55 (m, 1 H), 7.25 (t, J = 54.31 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.46 (s, 1 H), 8.47 (dd, J = 4.54, 1.64 Hz, 1 H), 8.22 (d, J = 8.36 Hz, 1 H), 8.15 (s, 1 H), 8.08-8.11 (m, 1 H), 8.06-8.08 (m, 1 H), 7.82 (br s, 1 H), 7.74- 7.79 (m, 1 H), 7.70 (br d, J = 7.27 Hz, 1 H), 7.49- 7.55 (m, 2 H), 6.84 (s, 1 H), 3.90 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1 H), 8.52 (dd, J = 4.72, 1.45 Hz, 1 H), 8.22 (d, J = 8.36 Hz, 1 H), 8.15- 8.19 (m, 2 H), 8.10 (d, J = 7.99 Hz, 1 H), 7.86 (br s, 1 H), 7.78 (t, J = 7.18 Hz, 1 H), 7.68-7.73 (m, 1 H), 7.65 (s, 1 H), 7.62 (dd, J = 7.99, 4.72 Hz, 1 H), 7.52 (s, 1 H), 7.25 (t, J = 54.13 Hz, 1 H).
1H NMR (400 MHz, CD3OD) δ ppm 8.45 (dd, J = 4.90, 1.63 Hz, 1 H), 8.04 (dd, J = 7.99, 1.45 Hz, 1 H), 7.49-7.54 (m, 1 H), 7.47 (s, 1 H), 6.76 (s, 1 H), 4.79 (q, J = 8.72 Hz, 2 H).
1H NMR (400 MHz, CDCl3) δ ppm 9.74 (s, 1 H), 8.36-8.62 (m, 1 H), 7.92 (br d, J = 7.99 Hz, 1 H), 7.40-7.54 (m, 1 H), 7.35-7.39 (m, 1 H), 7.23 (d, J = 2.18 Hz, 1 H), 5.90-6.22 (m, 1 H), 5.74 (br s, 1 H).
1H NMR (400 MHz, CDCl3) δ ppm 9.54 (s, 1 H), 8.46 (dd, J = 4.72, 1.45 Hz, 1 H), 7.88 (dd, J = 7.99, 1.45 Hz, 1 H), 7.40 (dd, J = 7.99, 4.72 Hz, 1 H), 7.22 (s, 1 H), 7.10 (s, 1 H), 5.90-6.29 (m, 1 H), 5.47-5.90 (m 1 H).
1H NMR (400 MHz, CDCl3) δ ppm 11.28 (s, 1 H), 8.50 (dd, J = 4.72, 1.45 Hz, 1 H), 8.27 (dd, J = 8.54, 0.91 Hz, 1 H), 8.18 (br s, 1 H), 8.07 (d, J = 7.99 Hz, 1 H), 7.87 (dd, J = 7.99, 1.45 Hz, 1 H), 7.76-7.82 (m, 1 H), 7.71-7.76 (m, 1 H), 7.38 (dd, J = 7.99, 4.72 Hz, 1 H), 7.18 (s, 1 H), 5.83 (br s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s, 1 H), 9.05-9.17 (m, 2 H), 8.50-8.60 (m, 1 H), 8.18-8.23 (m, 2 H), 8.08-8.14 (m, 1 H), 7.83-7.90 (m, 1 H), 7.57-7.74 (m, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1 H), 8.50 (dd, J = 4.54, 1.64 Hz, 1 H), 8.22 (d, J = 8.36 Hz, 1 H), 8.15 (s, 1 H), 8.13 (dd, J = 7.99, 1.45 Hz, 1 H), 8.10 (d, J = 7.99 Hz, 1 H), 7.86 (br s, 1 H), 7.74-7.81 (m, 1 H), 7.68-7.73 (m, 1 H), 7.58 (dd, J = 7.99, 4.72 Hz, 1 H), 7.52 (s, 1 H), 7.44 (t, J = 72.48 Hz, 1 H), 7.16 (s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1 H), 8.48 (dd, J = 4.72, 1.45 Hz, 1 H), 8.22 (d, J = 8.36 Hz, 1 H), 8.16 (s, 1 H), 8.07-8.13 (m, 2 H), 7.85 (br s, 1 H), 7.74- 7.80 (m, 1 H), 7.67- 7.73 (m, 1 H), 7.54- 7.59 (m, 1 H), 7.53 (s, 1 H), 6.97 (s, 1 H), 5.02 (t, J = 13.44 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1 H), 8.49 (dd, J = 4.54, 1.64 Hz, 1 H), 8.22 (d, J = 8.72 Hz, 1 H), 8.15 (s, 1 H), 8.07-8.14 (m, 2 H), 7.81 (br s, 1 H), 7.74- 7.80 (m, 1 H), 7.67- 7.72 (m, 1 H), 7.56 (dd, J = 7.99, 4.72 Hz, 1 H), 7.52 (s, 1 H), 7.45 (s, 4 H), 7.41 (s, 1 H), 4.65 (s, 2 H), 4.63 (s, 2 H).
1H NMR (400 MHz, CDCl3) δ ppm 11.37 (s, 1 H), 8.51 (dd, J = 4.72, 1.45 Hz, 1 H), 8.27 (dd, J = 8.54, 0.91 Hz, 1 H), 8.19 (br s, 1 H), 8.07 (d, J = 7.99 Hz, 1 H), 7.89 (dd, J = 8.17, 1.63 Hz, 1 H), 7.79 (ddd, J = 8.27, 6.81, 1.63 Hz, 1 H), 7.70- 7.75 (m, 1 H), 7.40- 7.44 (m, 1 H), 7.40 (s, 1 H), 5.77 (br s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (m, 1H), 8.09-8.26 (m, 6 H), 7.75 (br d, J = 9.08 Hz, 1 H), 7.53-7.62 (m, 2 H), 7.36 (s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (br s, 1 H), 8.51 (dd, J = 4.54, 1.63 Hz, 1 H), 8.25 (d, J = 2.8 Hz, 1 H), 8.23 (d, J = 9.08 Hz, 1 H), 8.15 (dd, J = 7.99, 1.45 Hz, 1 H), 8.13 (s, 1 H), 7.88 (s, 1 H), 7.78 (dd, J = 9.08, 2.18 Hz, 1 H), 7.60 (dd, J = 7.99, 4.72 Hz, 1 H), 7.57 (s, 1 H), 7.49 (s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.02 (br s, 1 H), 8.50 (dd, J = 4.72, 1.45 Hz, 1 H), 8.38 (d, J = 2.8 Hz, 1 H), 8.10-8.17 (m, 4 H), 7.86 (dd, J = 9.08, 2.18 Hz, 1 H), 7.59 (dd, J = 7.99, 4.72 Hz, 1 H), 7.55 (s, 1 H), 7.36 (s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (br s, 1 H), 8.48 (dd, J = 4.72, 1.45 Hz, 1 H), 8.32 (d, J = 1.82 Hz, 1 H), 8.22 (s, 1 H), 8.04-8.12 (m, 2 H), 7.79 (dd, J = 9.08, 1.82 Hz, 1 H), 7.55 (dd, J = 7.99, 4.72 Hz, 1 H), 7.50 (s, 1 H), 7.23 (s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H), 8.54 (dd, J = 4.72, 1.45 Hz, 1 H), 8.41 (d, J = 1.82 Hz, 1 H), 8.14- 8.23 (m, 2 H), 8.13 (s, 1 H), 7.66-7.94 (m, 2 H), 7.84 (s, 1 H), 7.65 (dd, J = 7.99, 4.72 Hz, 1 H), 7.57 (br s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.71 (s, 1 H), 8.54 (d, J = 4.7 Hz, 1 H), 8.18-8.21 (m, 1 H), 8.11 (d, J = 8.9 Hz, 1 H), 8.03 (s, 1 H), 7.84- 7.88 (m, 2 H), 7.83 (s, 1 H), 7.65 (dd, J = 8.0, 4.7 Hz, 1 H), 7.58-7.63 (m, 1 H), 7.50 (s, 1 H), 2.52 (br s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.80 (s, 1 H), 8.54 (br d, J = 3.63 Hz, 1 H), 8.18- 8.28 (m, 3 H), 8.13 (s, 1 H), 7.92 (br s, 1 H), 7.84 (s, 1 H), 7.79 (br d, J = 9.08 Hz, 1 H), 7.63- 7.68 (m, 1 H), 7.57 (br s, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.45- 8.50 (m, 2 H), 8.30- 8.36 (m, 1 H), 8.20- 8.25 (m, 1 H), 8.05- 8.13 (m, 2 H), 7.80 (dd, J = 9.08, 1.82 Hz, 1 H), 7.56 (dd, J = 7.99, 4.72 Hz, 1 H), 7.49 (br s, 1 H), 7.23 (s, 1 H).
1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1 H), 8.50 (dd, J = 4.7, 1.5 Hz, 1 H), 7.86-7.92 (m, 2 H), 7.83 (s, 1 H), 7.58 (s, 1 H), 7.38-7.45 (m, 2 H), 7.32 (s, 1 H), 6.23 (br s, 1 H), 5.66 (br s, 1 H), 2.51 (s, 3 H), 2.48 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.55 (br s, 1 H), 8.96 (br d, J = 3.3 Hz, 1 H), 8.45- 8.60 (m, 2 H), 8.16 (br d, J = 7.6 Hz, 1 H), 8.06 (s, 1 H), 8.03 (br s, 1 H), 7.58- 7.67 (m, 2 H), 7.56 (br s, 1 H), 7.44 (s, 1 H), 2.47 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.39 (br s, 1 H), 8.53 (d, J = 4.7 Hz, 1 H), 8.23-8.31 (m, 1 H), 8.08-8.14 (m, 1 H), 7.85 (br d, J = 2.5 Hz, 1 H), 7.49-7.69 (m, 3 H), 6.91 (br s, 1 H), 4.23 (s, 3 H), 2.32 (d, J = 2.2 Hz, 3 H).
1H NMR (400 MHz, acetone-d6) δ ppm 10.31 (s, 1 H), 8.49 (dd, J = 4.7, 1.5 Hz, 1 H), 8.27 (s, 1 H), 8.06 (dd, J = 8.0, 1.5 Hz, 1 H), 7.85 (s, 1 H), 7.50-7.60 (m, 2 H), 7.26 (s, 1 H), 6.92 (br s, 1 H), 4.22 (s, 3 H), 2.32 (s, 3 H).
1H NMR (400 MHz, acetone-d6) δ ppm 10.02 (s, 1 H), 8.05-8.12 (m, 2 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.34 (br d, J = 9.4 Hz, 3 H), 7.20 (dd, J = 8.0, 4.7 Hz, 1 H), 6.95 (br s, 1 H), 3.76 (s, 3 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 10.48 (s, 1 H), 8.46 (dd, J = 4.7, 1.5 Hz, 1 H), 8.37 (d, J = 1.8 Hz, 1 H), 8.24 (d, J = 0.7 Hz, 1 H), 8.08- 8.13 (m, 2 H), 8.06 (s, 1 H), 7.85 (dd, J = 9.1, 2.2 Hz, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.76 (s, 1 H), 7.55 (dd, J = 8.0, 4.7 Hz, 1 H), 7.48 (s, 1 H), 7.42- 7.47 (m, 1 H), 7.27 (d, J = 7.3 Hz, 1 H), 7.13 (s, 1 H), 5.84 (s, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1 H), 8.73 (s, 1 H), 8.47 (dd, J = 4.7, 1.5 Hz, 1 H), 8.38 (d, J = 2.2 Hz, 1 H), 8.09-8.14 (m, 2 H), 8.07 (s, 1 H), 7.86 (dd, J = 9.1, 1.8 Hz, 1 H), 7.78 (s, 1 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.56 (dd, J = 8.2 4.5 Hz, 1 H), 7.49 (s, 1 H), 7.25-7.31 (m, 2 H), 7.17 (d, J = 7.3 Hz, 1 H), 5.85 (s, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (s, 1 H), 8.46-8.51 (m, 1 H), 8.40 (s, 1 H), 8.11- 8.17 (m, 2 H), 8.10 (s, 1 H), 7.86-7.92 (m, 1 H), 7.84 (br s, 1 H), 7.55- 7.60 (m, 1 H), 7.53 (br s, 1 H), 7.47 (s, 1 H), 6.34 (s, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (br s, 1 H), 8.74 (br s, 1 H), 8.47 (dd, J = 4.5, 1.3 Hz, 1 H), 8.30-8.39 (m, 1 H), 8.28 (br s, 1 H), 8.09 (br d, J = 8.0 Hz, 1 H), 7.82-8.05 (m, 2 H), 7.60 (br s, 1 H), 7.53 (dd, J = 8.0, 4.7 Hz, 1 H), 6.81-7.03 (m, 1 H), 4.92 (q, J = 8.7 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1 H), 8.48 (dd, J = 4.7, 1.5 Hz, 1 H), 8.38 (d, J = 1.8 Hz, 1 H), 8.33 (d, J = 8.4 Hz, 2 H), 8.07- 8.15 (m, 3 H), 7.96 (d, J = 8.4 Hz, 2 H), 7.82- 7.89 (m, 2 H), 7.57 (dd, J = 8.4, 4.7 Hz, 1 H), 7.51 (s, 1 H), 7.42 (s, 1 H), 6.25 (s, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.57 (s, 1H), 9.46 (s, 1H), 8.51 (dd, J = 1.2 Hz, 4.4 Hz, 1H), 8.18-8.14 (m, 2H), 7.96 (s, 1H), 7.61 (dd, J = 4.8 Hz, 8.0 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 2.37 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.47 (s, 1H), 8.48 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.13 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 7.56 (dd, J = 4.8 Hz, 8.0 Hz, 2H), 6.88 (s, 1H), 4.95 (q, J = 8.4 Hz, 2H), 2.82 (s, 3H), 2.31 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (s, 1H), 9.46 (s, 1H), 8.48 (dd, J = 1.2 Hz, 4.4 Hz, 1H), 8.14 (s, 1H), 8.13 (dd, J = 1.6 Hz, 8.0 Hz 1H), 7.96 (s, 1H), 7.58- 7.54 (m, 2H), 6.90 (s, 1H), 4.96 (q, J = 8.8 Hz, 2H), 2.38 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.50 (s, 1H), 8.51 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.17 (dd, J = 1.6 Hz, 8.4 Hz, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 7.61 (dd, J = 4.8 Hz, 8.0 Hz, 1H), 7.50 (s, 1H), 7.41 (s, 1H), 2.82 (s, 3H), 2.31 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.50 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.16 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.80 (s, 1H), 7.69 (s, 1H), 7.62-7.58 (m, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 2.63 (s, 3H), 2.25 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.52 (s, 1H), 8.47 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.12 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 7.84 (s, 1H), 7.69 (s, 1H), 7.57-7.53 (m, 2H), 6.88 (s, 1H), 4.92 (q, J = 8.8 Hz, 2H), 2.63 (s, 3H), 2.25 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 10.44 (s, 1H), 8.50 (dd, J = 4.7, 1.6 Hz, 1H), 8.41 (d, J = 9.3 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.96 (br s, 1H), 7.82 (s, 1H), 7.60 (dd, J = 8.0, 4.7 Hz, 1H), 7.51 (s, 1H), 7.42 (s, 1 H), 7.11 (d, J = 9.1 Hz, 1H), 4.00 (s, 3H), 2.41 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1 H), 8.65 (d, J = 1.82 Hz, 1 H), 8.58- 8.62 (m, 1 H), 8.30- 8.35 (m, 1 H), 8.12- 8.17 (m, 1 H), 7.97- 8.01 (m, 1 H), 7.68- 7.74 (m, 1 H), 7.07 (s, 1 H), 4.84-5.06 (m, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (dd, J = 4.4, 1.5 Hz, 1 H), 8.40 (dd, J = 8.0, 1.5 Hz, 1 H), 7.96 (s, 1 H), 7.92 (s, 1 H), 7.83 (dd, J = 8.0, 4.7 Hz, 1 H), 1.69 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1 H), 8.62 (dd, J = 4.7, 1.5 Hz, 1 H), 8.30-8.35 (m, 2 H), 8.22 (dd, J = 8.7, 0.7 Hz, 1 H), 7.89 (ddd, J = 8.5, 7.1, 1.1 Hz, 1 H), 7.71-7.79 (m, 2 H), 7.07 (s, 1 H), 5.00 (q, J = 8.7 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.91 (s, 1 H), 8.62-8.68 (m, 2 H), 8.39 (dd, J = 8.17, 1.63 Hz, 1 H), 8.15 (d, J = 9.45 Hz, 1 H), 7.99 (dd, J = 9.26, 2.00 Hz, 1 H), 7.78 (dd, J = 8.36, 4.72 Hz, 1 H), 7.61 (s, 1 H), 7.26 (t, J = 54.13 Hz, 1 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.88 (s, 1 H), 8.60 (dd, J = 4.72, 1.45 Hz, 1 H), 8.28-8.35 (m, 2 H), 8.22 (d, J = 8.72 Hz, 1 H), 7.85-7.91 (m, 1 H), 7.76 (dd, J = 8.17, 0.91 Hz, 1 H), 7.72 (dd, J = 7.99, 4.72 Hz, 1 H), 6.85 (s, 1 H), 3.94 (s, 3 H).
1H NMR (400 MHz, CDCl3) δ ppm 7.56 (s, 1 H), 6.48 (br s, 2 H), 3.89 (s, 3 H).
1H NMR (400 MHz, CD3OD) δ ppm 7.67 (s, 1 H).
5
1H NMR (400 MHz, CDCl3) δ ppm 8.52 (dd, J = 4.72, 1.45 Hz, 1 H), 7.92 (dd, J = 8.17, 1.63 Hz, 1 H), 7.43 (dd, J = 8.36, 4.72 Hz, 1 H), 6.53 (s, 1 H), 4.74 (tq, J = 12.72, 1.09 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.51 (dd, J = 4.72, 1.45 Hz, 1 H), 8.17 (dd, J = 7.99, 1.45 Hz, 1 H), 7.61 (dd, J = 7.99, 4.72 Hz, 1 H), 6.59 (br s, 1 H), 4.96 (br t, J = 13.26 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (dd, J = 4.72, 1.45 Hz, 1 H), 8.21 (dd, J = 8.17, 1.27 Hz, 1 H), 7.65 (dd, J = 7.99, 4.72 Hz, 1 H), 7.37-7.44 (m, 4 H), 7.03 (s, 1 H), 4.58 (s, 2 H), 4.56 (s, 2 H).
1H NMR (400 MHz, TFA-d) δ ppm 9.01 (br d, J = 5.45 Hz, 1 H), 8.80 (s, 1 H), 8.71- 8.77 (m, 1 H), 8.16- 8.26 (m, 3 H), 7.87 (dd, J = 9.26, 2.00 Hz, 1 H), 7.40 (s, 1 H).
1H NMR (400 MHz, acetone-d6) δ ppm 8.35 (d, J = 0.7 Hz, 1 H), 7.92 (s, 1 H), 6.00 (br s, 2 H), 4.21 (s, 3 H), 3.93 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.12 (s, 1 H), 8.09 (s, 1 H), 5.62 (s, 2 H), 4.13 (s, 3 H), 3.85 (s, 3 H), 2.23 (s, 3 H).
1H NMR (400 MHz, CDCl3) δ 8.58 (dd, J = 4.7, 1.5 Hz, 1 H), 8.55 (s, 1 H), 8.01 (s, 1 H), 7.97 (dd, J = 8.2, 1.6 Hz, 1 H), 7.49 (dd, J = 8.0, 4.7 Hz, 1 H), 7.22 (s, 1 H), 4.20 (s, 3 H), 2.01 (s, 3 H)
1H NMR (400 MHz, acetone-d6) δ ppm 8.31 (d, J = 0.7 Hz, 1 H), 7.99 (s, 1 H), 5.96 (br s, 2 H), 4.22 (s, 3 H), 3.93 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (s, 1 H), 8.12 (s, 1 H), 4.15 (s, 3 H).
1H NMR (400 MHz, CDCl3) δ ppm 8.65 (d, J = 0.7 Hz, 1 H), 8.59 (dd, J = 4.7, 1.5 Hz, 1 H), 8.10 (s, 1 H), 8.01 (dd, J = 8.0, 1.5 Hz, 1 H), 7.53 (dd, J = 8.0, 4.7 Hz, 1 H), 7.51 (s, 1 H), 4.32 (s, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (dd, J = 4.7, 1.5 Hz, 1 H), 8.26 (dd, J = 8.0, 1.5 Hz, 1 H), 7.69 (dd, J = 8.4, 4.7 Hz, 1 H), 7.21 (s, 1 H), 4.72 (s, 2 H), 4.15 (q, J = 7.3 Hz, 2 H), 1.09 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (dd, J = 4.7, 1.5 Hz, 1 H), 8.23 (dd, J = 8.5, 1.5 Hz, 1 H), 8.19 (d, J = 0.7 Hz, 1 H), 7.77 (d, J = 8.7 Hz, 1 H), 7.67 (dd, J = 8.0, 4.7 Hz, 1 H), 7.41 (dd, J = 8.4, 7.6 Hz, 1 H), 7.25 (d, J = 7.3 Hz, 1 H), 6.91 (s, 1 H), 5.80 (s, 2 H), 4.10 (q, J = 6.9 Hz, 2 H), 1.05 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1 H), 8.55 (dd, J = 4.7, 1.5 Hz, 1 H), 8.25 (dd, J = 8.0, 1.5 Hz, 1 H), 7.69 (dd, J = 8.2, 4.5 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.25 (dd, J = 8.5, 7.3 Hz, 1 H), 7.15 (d, J = 7.3 Hz, 1 H), 7.12 (s, 1 H), 5.80 (s, 2 H), 4.12 (q, J = 6.9 Hz, 2 H), 1.07 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 13.54 (br s, 1 H), 8.51 (dd, J = 4.7, 1.5 Hz, 1 H), 8.16-8.22 (m, 2 H), 7.76 (d, J = 8.7 Hz, 1 H), 7.64 (dd, J = 8.0, 4.7 Hz, 1 H), 7.41 (dd, J = 8.4, 7.6 Hz, 1 H), 7.24 (d, J = 7.3 Hz, 1 H), 6.82 (s, 1 H), 5.78 (s, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 13.59 (br s, 1 H), 8.65 (s, 1 H), 8.53 (dd, J = 4.7, 1.8 Hz, 1 H), 8.22 (dd, J = 8.0, 1.5 Hz, 1 H), 7.65 (dd, J = 8.0, 4.7 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 1 H), 7.25 (dd, J = 8.4, 7.3 Hz, 1 H), 7.15 (d, J = 7.3 Hz, 1 H), 7.04 (s, 1 H), 5.78 (s, 2 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H), 8.64 (d, J = 1.8 Hz, 1 H), 8.62 (dd, J = 4.7, 1.5 Hz, 1 H), 8.34 (dd, J = 8.2, 1.6 Hz, 1 H), 8.12 (d, J = 9.1 Hz, 1 H), 7.95- 7.99 (m, 1 H), 7.76 (dd, J = 8.0, 4.7 Hz, 1 H), 7.51 (s, 1 H), 6.35 (s, 2 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 8.55 (dd, J = 4.7, 1.8 Hz, 1 H), 8.21-8.29 (m, 3 H), 7.93 (d, J = 8.0 Hz, 2 H), 7.69 (dd, J = 8.0, 4.7 Hz, 1 H), 7.25 (s, 1 H), 6.19 (s, 2 H), 4.14 (q, J = 7.0 Hz, 2 H), 1.08 (t, J = 7.1 Hz, 3 H).
1H NMR (400 MHz, DMSO-d6) δ ppm 13.69 (br s, 1 H), 8.53 (dd, J = 5.7, 1.5 Hz, 1 H), 8.29 (d, J = 8.0 Hz, 2 H), 8.22 (dd, J = 8.0, 1.5 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.66 (dd, J = 8.0, 4.7 Hz, 1 H), 7.16 (s, 1 H), 6.17 (s, 2 H)
1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H), 8.64 (d, J = 2.2 Hz, 1 H), 8.61 (dd, J = 4.7, 1.8 Hz, 1 H), 8.33 (dd, J = 8.33, 1.6 Hz, 1 H), 8.30 (d, J = 8.0 Hz, 2 H), 8.13 (d, J = 9.4 Hz, 1 H), 7.92-7.99 (m, 3 H),
1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (s, 1H), 8.32 (s, 1H), 6.63 (s, 2H), 3.88 (s, 3H), 2.38 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ ppm 9.01 (s, 1H), 8.32 (s, 1H), 2.32 (s, 3H).
The activity of the compositions according to the invention can be broadened considerably, and adapted to prevailing circumstances, by adding other insecticidally, acaricidally and/or fungicidally active ingredients. The mixtures of the compounds of formula I with other insecticidally, acaricidally and/or fungicidally active ingredients may also have further surprising advantages which can also be described, in a wider sense, as synergistic activity. For example, better tolerance by plants, reduced phytotoxicity, insects can be controlled in their different development stages or better behaviour during their production, for example during grinding or mixing, during their storage or during their use.
Suitable additions to active ingredients here are, for example, representatives of the following classes of active ingredients: organophosphorus compounds, nitrophenol derivatives, thioureas, juvenile hormones, formamidines, benzophenone derivatives, ureas, pyrrole derivatives, carbamates, pyrethroids, chlorinated hydrocarbons, acylureas, pyridylmethyleneamino derivatives, macrolides, neonicotinoids and Bacillus thuringiensis preparations.
The following mixtures of a compound of formula I with an active substances are preferred (the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-7 and P”):
The references in brackets behind the active ingredients, e.g. [3878-19-1] refer to the Chemical Abstracts Registry number. The above described mixing partners are known. Where the active ingredients are included in “The Pesticide Manual” [The Pesticide Manual—A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; The British Crop Protection Council], they are described therein under the entry number given in round brackets hereinabove for the particular compound; for example, the compound “abamectin” is described under entry number (1). Where “[CCN]” is added hereinabove to the particular compound, the compound in question is included in the “Compendium of Pesticide Common Names”, which is accessible on the internet [A. Wood; Compendium of Pesticide Common Names, Copyright® 1995-2004]; for example, the compound “acetoprole” is described under the internet address http://www.alanwood.net/pesticides/acetoprole.html.
Most of the active ingredients described above are referred to hereinabove by a so-called “common name”, the relevant “ISO common name” or another “common name” being used in individual cases. If the designation is not a “common name”, the nature of the designation used instead is given in round brackets for the particular compound; in that case, the IUPAC name, the IUPAC/Chemical Abstracts name, a “chemical name”, a “traditional name”, a “compound name” or a “develoment code” is used or, if neither one of those designations nor a “common name” is used, an “alternative name” is employed. “CAS Reg. No” means the Chemical Abstracts Registry Number.
The active ingredient mixture of the compounds of formula I selected from the compounds defined in the Tables P with active ingredients described above comprises a compound selected from one compound defined in the Table P and an active ingredient as described above preferably in a mixing ratio of from 100:1 to 1:6000, especially from 50:1 to 1:50, more especially in a ratio of from 20:1 to 1:20, even more especially from 10:1 to 1:10, very especially from 5:1 to 1:5, special preference being given to a ratio of from 2:1 to 1:2, and a ratio of from 4:1 to 2:1 being likewise preferred, above all in a ratio of 1:1, or 5:1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1:5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:3, or 2:3, or 1:2, or 1:600, or 1:300, or 1:150, or 1:35, or 2:35, or 4:35, or 1:75, or 2:75, or 4:75, or 1:6000, or 1:3000, or 1:1500, or 1:350, or 2:350, or 4:350, or 1:750, or 2:750, or 4:750. Those mixing ratios are by weight.
The compounds and mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a compound or mixture respectively as described above to the pests or their environment, with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
The mixtures comprising a compound of formula I selected from the compounds defined in the Tables A-1 to A-7 & P and one or more active ingredients as described above can be applied, for example, in a single “ready-mix” form, in a combined spray mixture composed from separate formulations of the single active ingredient components, such as a “tank-mix”, and in a combined use of the single active ingredients when applied in a sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days. The order of applying the compounds of formula I and the active ingredients as described above is not essential for working the present invention.
The compositions according to the invention can also comprise further solid or liquid auxiliaries, such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides, plant activators, molluscicides or herbicides.
The compositions according to the invention are prepared in a manner known per se, in the absence of auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries). These processes for the preparation of the compositions and the use of the compounds I for the preparation of these compositions are also a subject of the invention.
The application methods for the compositions, that is the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, dressing, scattering or pouring—which are to be selected to suit the intended aims of the prevailing circumstances—and the use of the compositions for controlling pests of the abovementioned type are other subjects of the invention. Typical rates of concentration are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient. The rate of application per hectare is generally 1 to 2000 g of active ingredient per hectare, in particular 10 to 1000 g/ha, preferably 10 to 600 g/ha.
A preferred method of application in the field of crop protection is application to the foliage of the plants (foliar application), it being possible to select frequency and rate of application to match the danger of infestation with the pest in question. Alternatively, the active ingredient can reach the plants via the root system (systemic action), by drenching the locus of the plants with a liquid composition or by incorporating the active ingredient in solid form into the locus of the plants, for example into the soil, for example in the form of granules (soil application). In the case of paddy rice crops, such granules can be metered into the flooded paddy-field.
The compounds of formula I of the invention and compositions thereof are also be suitable for the protection of plant propagation material, for example seeds, such as fruit, tubers or kernels, or nursery plants, against pests of the abovementioned type. The propagation material can be treated with the compound prior to planting, for example seed can be treated prior to sowing. Alternatively, the compound can be applied to seed kernels (coating), either by soaking the kernels in a liquid composition or by applying a layer of a solid composition. It is also possible to apply the compositions when the propagation material is planted to the site of application, for example into the seed furrow during drilling. These treatment methods for plant propagation material and the plant propagation material thus treated are further subjects of the invention. Typical treatment rates would depend on the plant and pest/fungi to be controlled and are generally between 1 to 200 grams per 100 kg of seeds, preferably between 5 to 150 grams per 100 kg of seeds, such as between 10 to 100 grams per 100 kg of seeds.
The term seed embraces seeds and plant propagules of all kinds including but not limited to true seeds, seed pieces, suckers, corns, bulbs, fruit, tubers, grains, rhizomes, cuttings, cut shoots and the like and means in a preferred embodiment true seeds.
The present invention also comprises seeds coated or treated with or containing a compound of formula I. The term “coated or treated with and/or containing” generally signifies that the active ingredient is for the most part on the surface of the seed at the time of application, although a greater or lesser part of the ingredient may penetrate into the seed material, depending on the method of application. When the said seed product is (re)planted, it may absorb the active ingredient. In an embodiment, the present invention makes available a plant propagation material adhered thereto with a compound of formula I. Further, it is hereby made available, a composition comprising a plant propagation material treated with a compound of formula I.
Seed treatment comprises all suitable seed treatment techniques known in the art, such as seed dressing, seed coating, seed dusting, seed soaking and seed pelleting. The seed treatment application of the compound formula I can be carried out by any known methods, such as spraying or by dusting the seeds before sowing or during the sowing/planting of the seeds.
The compounds of the invention can be distinguished from other similar compounds by virtue of greater efficacy at low application rates and/or different pest control, which can be verified by the person skilled in the art using the experimental procedures, using lower concentrations if necessary, for example 10 ppm, 5 ppm, 2 ppm, 1 ppm or 0.2 ppm; or lower application rates, such as 300, 200 or 100, mg of Al per m2. The greater efficacy can be observed by an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability).
In each aspect and embodiment of the invention, “consisting essentially” and inflections thereof are a preferred embodiment of “comprising” and its inflections, and “consisting of” and inflections thereof are a preferred embodiment of “consisting essentially of” and its inflections.
The disclosure in the present application makes available each and every combination of embodiments disclosed herein.
It should be noted that the disclosure herein in respect of a compound of formula I applies equally in respect of a compound of each of formulae I-I, Id, Ie, If, Ig, Ih, Ii, and Tables A-1 to A-7, and P.
The compounds of the invention can be distinguished from other similar compounds by virtue of greater efficacy at low application rates and/or different pest control, which can be verified by the person skilled in the art using the experimental procedures, using lower concentrations if necessary, for example 10 ppm, 5 ppm, 2 ppm, 1 ppm or 0.2 ppm; or lower application rates, such as 300, 200 or 100, mg of Al per m2. The greater efficacy can be observed by an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability).
The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 24 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm, or 0.2 ppm.
Resistant Plutella xylostella R1 (Diamond Back Moth) Larvicide L3, Feeding/Contact
Chinese cabbage plants were sprayed with diluted test solutions in an application chamber. Cut off leaves were placed into petri dishes with wetted filter paper and infested 1 day after application with 10 L3 multi-resistant Plutella xylostella larvae having the G4946E resistance mutation. Samples were assessed 4 days after infestation for mortality and growth regulation. CTPR was used as standard and a resistance factor of 146 was obtained for this strain.
Plutella xylostella resistant strain R1 originally collected from Taiwan in 2012 that carries the RyR mutation G4946E conferring resistance to diamides. The strain is reared on cabbage plants (Brassica aleracea) and selected approximately every two weeks with chlorantraniliprole.
The following compounds, according to the present invention, gave at least 80% control of the resistant strain of Plutella xylostella R1 at 50 ppm or below: P.1, P.3, P.4, P.5, P.6, P.7, P.8, P.9, P.25, P.26, P.27, P.28, P.30, P.34, P.36, P.41, P.46.
Table below lists the compounds providing at least 80% control of the resistant strain of Plutella xylostella R1 at 50 ppm or below
Resistant Plutella xylostella R4 (Diamond back moth) larvicide L1, feeding/contact 24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions by pipetting. After drying, around 30 Plutella eggs were pipetted through a plastic stencil onto a gel blotting paper and the plate was closed with it. The samples were assessed for mortality in comparison to untreated samples 8 days after infestation.
CTPR was used as standard and a resistance factor of 242 was obtained for this strain
Plutella xylostella resistant strain R4 originated in the lab in 2021 from crossing the R1 strain with a lab-reared susceptible P. xylostella strain (SUS). R4 can be reared and tested on artificial diet and also carries the RyR mutation G4946E conferring resistance to diamides. The strain is selected approximately every two weeks with chlorantraniliprole.
The following compounds, according to the present invention, gave at least 80% control of the resistant strain of Plutella xylostella R4 at 50 ppm or below:
Table below lists the compounds providing at least 80% control of the resistant strain of Plutella xylostella R4 at 50 ppm or below
Human embryonic kidney cells expressing the Plutella xylostella (Diamond back moth) ryanodine receptor, containing the G4946E resistance mutation, are loaded with Fluo-8 No Wash (NW) calcium-sensitive dye which responds by fluorescence to a change in intracellular calcium (e.g. stimulated by activation of ryanodine receptor). Test compounds are added in 10 rates to a 384-well plate containing dye-loaded cells and the fluorescent signal is measured using the Hamamatsu FDSS (Functional Drug Screening system). Dose-response curves are plotted to estimate the EC50. EC50 are normalized against an in-assay reference standard (cyantraniliprole) to address inter-assay variability. The ratio for a given compound is then obtained by the following formula:
The following compounds, according to the present invention, obtained a ratio REC50≤1:
| Number | Date | Country | Kind |
|---|---|---|---|
| 21192177.0 | Aug 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/072830 | 8/16/2022 | WO |
