USE OF DISUBSTITUTED BENZENES TO CONTROL INSECTICIDE-RESISTANT PESTS

The invention is in the technical field of insect control and relates to the use of a disubstituted benzenes for controlling insecticide -resistant pests such as mosquitoes and cockroaches.

Todays main insecticides used for vector control (including mosquitoes) relate to four chemical classes: pyrethroids, organochlorines (including DDT), organophosphates and carbamates. The use of pyrethroids far exceeds that of the other three classes due to its rapid and durable effect and its low toxicity and costs. However, recently resistance against pyrethroids have been reported which causes major concerns for the World Health Organisation (WHO) and solutions how to tackle the emerging resistance are seen as to be of critical importance for the future vector control management (see e.g. http://www.who.int/mal.aria/world malaria report 2011/WMR2011 chapter4.pdf).

Two main mechanisms of insecticide resistance were identified: target site resistance and metabolic resistance. Target site resistance occurs when the site of action of an insecticide is modified in mosquito populations so that the insecticide no longer binds effectively and the insect is therefore unaffected, or less affected, by the insecticide. Target site resistant mutations can affect acetylcholinesterase, which is the molecular target of organophosphates and carbamates, voltage-gated sodium channels (for pyrethroids and DDT), which is known as knock-down resistance (kdr), or the GABA receptor (for Dieldrin), which is known as resistance to Dieldrin (Rdl). Metabolic resistance occurs when increased levels or modified activities of a detoxifying enzyme system (such as esterases, monooxygenases or glutathione S -transferases (GST)) prevent the insecticide from reaching its intended site of action. Both mechansims of resistances can be found in the same vector populations and sometimes within the same vector.

Pyrethroids are the only insecticides that have obtained WHO recommendation against Malaria vectors or both Indoor Residuals Sprays (IRS) and Long Lasting Insecticidal Mosquito Nets (LLINs), in the form of Alpha-Cypermethrin, Bifenthrin, Cyfluthrin, Permethrin, Deltamethrin, Lambda-Cyhalothrin and Etofenprox. It has been the chemical class of choice in agriculture and public health applications over the last several decades because of its relatively low toxicity to humans, rapid knock-down effect, relative longevity (duration of 3-6 months when used as IRS), and low cost. However, massive use of pyrethroids in agricultural applications and for vector control led to the development of resistance in major malaria and dengue vectors. Strong resistance has e.g. been reported for the pyrethroid Deltamethrin (and Permethrin) for the Anopheles gambiae Tiassale (from southern Cote dTvoire) strain (Constant V.A. Edi et al., Emerging Infectious Diseases; Vol. 18, No. 9, September 2012). Pyrethroid resistance was also reported for Permethrin, Deltamethrin and Lambda-Cyhalothrin for the Aedes aegypti Cayman Island strain (Angela F. Harris et al., Am. J. Trop. Med. Hyg., 83(2), 2010) and Alpha- Cypermethrin, Permethrin and Lambda-Cyhalothrin for certain Anopheles strains (Win Van Bortel, Malaria Journal, 2008, 7: 102). Pyrethroid resistance has also been detected in cockroaches.

Due to the emerging resistance in pests such as mosquitoes and/or cockroaches against certain insecticides and in particular against pyrethroids there is an ongoing need for alternative solutions and strategies for pest control management and in particular for vector control management. With the present invention it has now been surprisingly found that certain substituted benzenes, particularly 1,4- disubstituted benzenes, and their agriculturally acceptable salts are useful for pest control management and in particular vector control management noticeable also for the control of insecticide -resistant pests such as mosquitoes and/or cockroaches. These benzenes may be represented by the following formula I:

I

in which

A is selected from the group consisting of hydrogen; aryl; alkylheterocyclyl; alkenylaminopolycyclyl; alkenylaminoheterocyclyl; alkylaminopolycyclyl; carbonylaminopolycyclyl; where the aryl, heterocyclyl and polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; and Formula 111, where Formula III is

-(CH ₂ )„-U-R ²

III

wherein n is O or l;

U is selected from the group consisting of -CH ₂ -, -O-CH ₂ -, oxygen, sulfur, sulfonyl, alkyl, oxyalkyloxy, alkenylamino, carbonylamino and -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, sulfonylalkyl, carbonylamino, and carbonylalkyl;

R ² is selected from aryl; alkylpolycyclyl; heterocyclyl; polycyclyl; where the aryl, heterocyclyl and polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; 1-R ³ ; 1-R ⁴ ; and 2-R ⁴ , wherein: where J, L, and W are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, aminoalkoxy, nitrilyl, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aryl, aryloxy, and heterocyclyl, where the aryl and heterocyclyl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy;

where X, Y, and Z are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, azido, carboxyl, alkyl, alkynyl, haloalkyl, haloalkylthio, nitrilyl, alkenyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, phenyl, aryl, aryloxy, and heterocyclyl, where the phenyl, aryl, and heterocyclyl moieties may be optionally substituted with halogen, haloalkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyaminoalkyl, 2-(Formula 111), 3-(Formula III), 5- (Formula III), and 6-(Formula III), wherein Formula III, n, U, R ² , R ³ , R ⁴ , R ⁵ , J, L, W, X, Y, and Z are as defined above;

R is -T-(CH2)m-R ¹ , -N(R ⁶ )(R ⁷ ) or heterocyclyl, where the heterocyclyl moiety may be optionally substituted with halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, alkylaza, arylcarbonyl, benzyl, allyl, propargyl, alkylamino; where the aryl moiety may be optionally substituted with halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl,

T is selected from the group consisting of -CH ₂ -, carbonyl, oxygen, nitrogen, and sulfur; m is 0, 1, 2, 3, or 4;

R ¹ is selected from the group consisting of -N(R ⁸ )(R ⁹ ); alkyl; aryl; -C(0)N(R ¹² )(R ¹³ ); oxyalkyl; haloalkyl; heterocyclyl; cycloalkyl; -N(0)(R ¹⁴ )(R ¹⁵ ); -P(0)(R ¹⁴ )(R ¹⁵ ); -P(S)(R ¹⁴ )(R ¹⁵ ); alkylamino, where the cycloalkyl, aryl and heterocyclyl moieties may be optionally substituted with halogen, hydroxy, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl, alkylamino; where R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylthio, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CE N(R ¹⁶ )(R ¹⁷ ), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl. Agriculturally acceptable salts of the 1,4-disubstituted benzenes include, but are not limited to, for example, the salts of hydrochloric acid, sulfonic acid, ethanesulfonic acid, trifluoroacetic acid, methylbenzenesulfonic acid, phosphoric acid, gluconic, acid, and pamoic acid.

The compounds discussed herein are disclosed in WO 2002017712A2 which describes the use of the compounds primarly for the control Heliothis virescens, the American budworm which is a moth of the Noctuidae family. The larvae feed on various important crops such as tobacco, soy, cotton etc. WO 2002017712A2 does not disclose the use of the compounds to control mosquitoes, not to mention insecticide-resistant mosquitoes.

The term "insecticide-resistant pest" respectively insecticide-resistant mosquito" resp. "insecticide- resistant cockroach" means a pest respectively a mosquito resp. a cockroach that is resistant to at least one insecticide selected from the group of pyrethroids, organophosphates and carbamates. A preferred embodiment of the invention is the control of "insecticide-resistant mosquitos" and/or "insecticide- resistant cockroach". In a preferred definition the term "insecticide-resistant mosquito" resp. "insecticide-resistant cockroach" refers to a mosquito resp. a cockroach that is resistant to a least one insecticide selected from the group of pyrethroids, organophospates and carbamates (preferably pyrethroids).

Pyrethroids in this connection refer more preferably to at least one compound selected from the group of Acrinathrin, Allethrin (d-cis-trans, d-trans), Beta-Cyfluthrin, Bifenthrin, Bioallethrin, Bioallethrin-S- cyclopentyl-isomer, Bioethanomethrin, Biopermethrin, Bioresmethrin, Chlovaporthrin, cis- Cypermethrin, cis-Resmethrin, cis-Permethrin, Clocythrin, Cycloprothrin, Cyfluthrin, Cyhalothrin, Cypermethrin (alpha-, beta-, theta-, zeta-), Cyphenothrin, Deltamethrin, Empenthrin (lR-isomer), Esfenvalerate, Etofenprox, Fenpropathrin, Fenpyrithrin, Fenvalerate, Flubrocythrinate, Flucythrinate, Flufenprox, Flumethrin, Fluvalinate, Fubfenprox, gamma-Cyhalothrin, Imiprothrin, Kadethrin, Lambda- Cyhalothrin, Permethrin (cis-, trans-), Phenothrin (lR-trans isomer), Prallethrin, Protrifenbute, Pyresmethrin, Resmethrin, RU 15525, Silafluofen, tau-Fluvalinate, Terallethrin, Tetramethrin (-1R- isomer), Tralomethrin, ZXI 8901 and Pyrethrin (pyrethrum).

Organophosphate refers preferably to a compound selected from the group of Acephate, Azamethiphos, Azinphos (-methyl, -ethyl), Bromophos-ethyl, Bromfenvinfos (-methyl), Butathiofos, Cadusafos, Carbophenothion, Chlorethoxyfos, Chlorfenvinphos, Chlormephos, Chlorpyrifos(-methyl/-ethyl), Coumaphos, Cyanofenphos, Cyanophos, Chlorfenvinphos, Demeton-S-methyl, Demeton-S- methylsulphon, Dialifos, Diazinon, Dichlofenthion, Dichlorvos/DDVP, Dicrotophos, Dimethoate, Dimethylvinphos, Dioxabenzofos, Disulfoton, EPN, Ethion, Ethoprophos, Etrimfos, Famphur, Fenamiphos, Fenitrothion, Fensulfothion, Fenthion, Flupyrazofos, Fonofos, Formothion, Fosmethilan, Fosthiazate, Heptenophos, Iodofenphos, Iprobenfos, Isazofos, Isofenphos, Isopropyl O-Salicylate, Isoxathion, Malathion, Mecarbam, Methacrifos, Methamidophos, Methidathion, Mevinphos, Monocrotophos, Naled, Omethoate, Oxydemeton-methyl, Parathion (-methyl/-ethyl), Phenthoate, Phorate, Phosalone, Phosmet, Phosphamidon, Phosphocarb, Phoxim, Pirimiphos (-methyl/-ethyl), Profenofos, Propaphos, Propetamphos, Prothiofos, Prothoate, Pyraclofos, Pyridaphenthion, Pyridathion, Quinalphos, Sebufos, Sulfotep, Sulprofos, Tebupirimfos, Temephos, Terbufos, Tetrachlorvinphos, Thiometon, Triazophos, Triclorfon and Vamidothion. In a more preferred embodiment, the term organophosphate refers to a compound selected from the group of Acephate, Chlorpyrifos, Dimethoate, Diazinon, Malathion, Methamidophos, Monocrotophos, Parathion-methyl, Profenofos and Terbufos.

Carbamate refers to a compound selected from the group of Alanycarb, Aldicarb, Aldoxycarb, Allyxycarb, Aminocarb, Bendiocarb, Benfuracarb, Bufencarb, Butacarb, Butocarboxim, Butoxycarboxim, Carbaryl, Carbofuran, Carbosulfan, Cloethocarb, Dimetilan, Ethiofencarb, Fenobucarb, Fenothiocarb, Formetanate, Furathiocarb, Isoprocarb, Metam-sodium, Methiocarb, Methomyl, Metolcarb, Oxamyl, Pirimicarb, Promecarb, Propoxur, Thiodicarb, Thiofanox, Trimethacarb, XMC, Xylylcarb and Triazamate. In a more preferred embodiment, the term "carbamate" refers to a compound selected from the group of Aldicarb, Benfuracarb, Carbaryl, Carbofuran, Carbosulfan, Fenobucarb, Methiocarb, Methomyl, Oxamyl, Thiodicarb and Triazamate.

In a more preferred embodiment of the invention, a compound of the invention is used to control insecticide-resistant mosquitoes that are resistant against at least one pyrethroid insecticide. In this connection the pyrethroid resistance is against one pyrethroid as defined above. In a more preferred embodiment the term "pyrethroid" refers to a compound selected from the group of Alpha- Cypermethrin, Bifenthrin, Cyfluthrin, Cypermethrin, Deltamethrin, D-D Trans-Cyphenothrin Esfenvalerate, Etofenprox, Lambda-Cyhalothrin, Permethrin, Pyrethrins (Pyrethrum), Phenothrin and Zeta-Cypermethrin. In a preferred embodiment pyrethroid resistance exists in regard to at least one pyrethroid selected from the group of Cyfluthrin, Cypermethrin, Deltamethrin, Lambda-Cyhalothrin, Permethrin. In a more preferred embodiment pyrethroid resistance exists in regard to at least one pyrethroid selected from the group of Cyfluthrin, Cypermethrin, Permethrin; more preferably against at least Cypermethrin.

In another more preferred embodiment of the invention, a compound of the invention is used to control insecticide-resistant cockroaches that are resistant against at least one pyrethroid insecticide selected from the group of Alpha-Cypermethrin, Bifenthrin, Cyfluthrin, Cypermethrin, Deltamethrin, D-D Trans- Cyphenothrin Esfenvalerate, Etofenprox, Lambda-Cyhalothrin, Permethrin, Pyrethrins (Pyrethrum), Phenothrin and Zeta-Cypermethri; or a carbamate selected from the group of Propoxur; or an organophosphate selected from the group of Fenthion. In a preferred embodiment pyrethroid resistance exists in regard to at least one pyrethroid selected from the group of Cyfluthrin, Cypermethrin, Deltamethrin, Lambda-Cyhalothrin and Permethrin; more preferably against at least Deltamethrin. In another preferred embodiment of the invention a compound is used to control multi-resistant pests, preferably mosquitoes resp. cockroaches. Multi-resistant mosquitoes refer to mosquitoes resp. cockroaches where several different resistance mechanisms are present simultaneously such as target- site resistance and metabolic resistance. The different resistance mechanisms may combine to provide resistance to multiple classes of products (IRAC publication: "Prevention and Management of Insecticide Resistance in Vectors of Public Health Importance"; second edition; 2011).

The term "insecticide-resistance" is the term used to describe the situation in which the pests are no longer killed by the standard dose of insecticide (they are no longer susceptible to the insecticide) or manage to avoid coming into contact with the insecticide). See 1.2.; p.27; "Global Plan for Insecticide Resistance Management", WHO 2012). As an example, WHO recommended standard dose of insecticide for indoor residual treatment against mosquito vectors are: Alpha-Cypermethrin 20-30 mg/m ² , Bifenthrin 25-50 mg/m ² , Cyfluthrin 20-50 mg/m ² , Deltamethrin 20-25 mg/m ² , Etofenprox 100-300 mg/m ² , Lambda-Cyhalothrin 20-30 mg/m ² WHO recommended standard dose of insecticide products treatment of nets for malaria vector control are: Alpha-Cypermethrin 20-40 mg/m ² , Cyfluthrin 50 mg/m ² , Deltamethrin 15-25 mg/m ² , Etofenprox 200 mg/m ² , Lambda-Cyhalothrin 10-15 mg/m ² , Permethrin 200-500 mg/m ² (http://www.wIx).int/whopes/Insecticides ITN Malaria ok3.pdf). WHO recommended standard dose for space spraying against mosquitoes are described in the publication: ILU£L _~ .^^^^ WHO recommended insecticide doses for bed bug control are e.g. for Deltamethrin 0.3 - 0.5 g/1 or g/kg; Cyfluthrin 0.4 g/1 or g/kg; Cypermethrin 0.5-2.0 g/1 or g/kg; Permethrin 1.25 g/1 or g/kg etc. (see Pesticides and their Application, WHO 2006 ; WHO/CDS/NTD/WHOPES/GCDPP/2006.1).

The term "control" insecticide-resistant mosquitoes resp. cockroaches refers to the possibility to be able to kill and/or repel mosquitoes resp. cockroaches that are insecticide-resistant (in the case of mosquitoes in order to avoid the biting of humans and transmission of the vectors to humans). In a preferred embodiment of the invention the insecticide-resistant mosquitoes are selected from the genus Anopheles, Culex and Aedes. Examples include Aedes aegypti, Aedes albopictus, Aedes japonicas, Aedes sticticus, Aedes vexans, Coquillettidia perturbans, Culex molestus, Culex pallens, Culex pipiens, Culex quinquefasciatus, Culex restuans, Culex tarsalis, Anopheles albimanus, Anopheles albitarsis, Anopheles annularis, Anopheles aquasalis, Anopheles arabiensis, Anopheles aconitus, Anopheles atroparvus, Anopheles balabacensis, Anopheles coluzzii, Anopheles culicifacies, Anopheles darlingi, Anopheles dirus, Anopheles farauti, Anopheles flavirostris, Anopheles fluviatilis, Anopheles freeborni, Anopheles funestus, Anopheles gambiae s.l. , Anopheles koliensis, Anopheles labranchiae, Anopheles lesteri, Anopheles leucosphyrus, Anopheles maculatus, Anopheles marajoara, Anopheles melas, Anopheles merus, Anopheles messeae, Anopheles minimus, Anopheles moucheti, Anopheles nili, Anopheles nuneztovari, Anopheles plumbeus, Anopheles pseudopunctipennis, Anopheles punctipennis, Anopheles punctulatus, Anopheles quadrimaculatus, Anopheles sacharovi, Anopheles sergentii, Anopheles sinensis, Anopheles stephensi, Anopheles subpictus, Anopheles sundaicus, Anopheles superpictus, and Mansonia titillans, Ochlerotatus stimulans, Ochlerotatus japonicas. In a more preferred embodiment of the invention the insecticide-resistant mosquitoes are selected from the group of Anopheles gambiae, Anopheles funestus, Aedes aegypti and Culex spp. In another more preferred embodiment of the invention an active ingredient is used against insecticide -resistant mosquitoes that are selected from the group of Anopheles gambiae RSPH, Anopheles gambiae VK7, Anopheles gambiae strain Tiassale, Anopheles funestus FUMOZ-R and Culex quinquefasciatus strain POO.

Anopheles gambiae, strain RSPH is a multi-resistant mosquito (target-site and metabolic-resistance) that is described in the reagent catalog of the Malaria Research and Reference Reagent Resource Center (www.MR4.org; MR4-number: MRA-334).

Anopheles gambiae, strain Tiassale is a multi-resistant mosquito (target and metabolic-resistant strain) which shows cross-resistance between carbamates, organophosphates and pyrethroids and is described in Constant V.A. Edi et al., Emerging Infectious Diseases; Vol. 18, No. 9, September 2012 & Ludovic P Ahoua Alou et al., Malaria Journal 9: 167, 2010).

Anopheles gambiae, strain VK7 is a target-resistant mosquito and is described in Dabire Roch Kounbobr et al., Malaria Journal, 7: 188, 2008. Anopheles funestus, strain FUMOZ-R is a metabolic-resistant strain and is described in Hunt et al., Med Vet Entomol. 2005 Sep; 19(3):271-5). In this article it has been reported that Anopheles funestus - as one of the major malaria vector mosquitoes in Africa - showed resistance to pyrethroids and carbamate insecticides in South Africa.

Culex quinquefasciatus (metabolic-resistant to DDT strain P00); received from Texchem, Penang, Malaysia.

In a preferred embodiment of the invention the insecticide-resistant cockroaches are selected from the genus Blattodea e.g. Blatta orientalis, Blattella asahinai, Blattella germanica, Leucophaea maderae, Loboptera decipiens, Neostylopyga rhombifolia, Panchlora spp., Parcoblatta spp., Periplaneta spp., z. B. Periplaneta americana, Periplaneta australasiae, Pycnoscelus surinamensis, Supella longipalpa. In a more preferred embodiment of the invention the insecticide-resistant cockroaches are selected from Blattella germanica, more preferably the strain Ukraine. In another preferred embodiment of the invention, a compound of the formula (I) is used in vector control. For the purpose of the present invention, a vector is a pest - such as an arthropod, in particular an insect or arachnid, capable of transmitting pathogens such as, for example, viruses, worms, single- cell organisms and bacteria from a reservoir (animal, human, etc.) to a host. The pathogens can be transmitted either mechanically (for example trachoma by non-stinging flies) to a host, or by injection (for example malaria parasites by mosquitoes) into a host.

Examples of vectors and the diseases or pathogens they transmit are:

1) Mosquitoes

- Anopheles: malaria, filariasis;

- Culex: Japanese encephalitis, other viral diseases, filariasis, transmission of other worms; - Aedes: yellow fever, dengue fever, chikungunya, other viral diseases (e.g. Zika virus), and filariasis;

- Simuliidae: transmission of worms, in particular Onchocerca volvulus;

- Psychodidae: transmission of leishmaniasis

2) Lice: skin infections, epidemic typhus;

3) Fleas: plague, endemic typhus, cestodes; 4) Flies: sleeping sickness (trypanosomiasis); cholera, other bacterial diseases;

5) Mites: acariosis, epidemic typhus, rickettsialpox, tularaemia, Saint Louis encephalitis, tick-borne encephalitis (TBE), Crimean-Congo haemorrhagic fever, borreliosis;

6) Ticks: borellioses such as Borrelia burgdorferi sensu lato., Borrelia duttoni, tick-borne encephalitis, Q fever (Coxiella burnetii), babesioses (Babesia canis canis), ehrlichiosis. Examples of vectors in the sense of the present invention are insects and arachnids such as mosquitoes, in particular of the genera Aedes, Anopheles, for example A. gambiae, A. arabiensis, A. funestus, A. dirus (malaria) and Culex, psychodids such as Phlebotomus, Lutzomyia, lice, fleas, flies, mites and ticks capable of transmitting pathogens to animals and/or humans. In a preferred embodiment of the invention, vector control refers to Malaria and Dengue vector control and vectors in connection with the present invention are preferably insecticide-resistant mosquitoes.

A skilled person in the art is fully aware that application rates for a compound of the invention to control insecticide-resistant pests such as mosquitoes resp. cockroaches depend on various factors such as the formulation type, application form, the object/surface to be treated etc.

However, as a general guidance the application rate for an active ingredient of the invention to control insecticide-resistant mosquitoes is preferably at least 0.8 - 20 mg/m ² , more preferably at least 4 - 20 mg/m ² .

As general guidance for the application rate for an active ingredient of the invention to control insecticide-resistant cockroaches is preferably at least 100-200 mg/m ² , more preferably 200 mg/m ² .

In another preferred embodiment of the invention, it has been found that a compound of the invention can also be used for vector control solutions. Vector control solutions are means to control a vector, such as a mosquito and in particular relate to an indoor residual spray, an insecticide treated net, a longer lasting insecticide net, space spray, spatial repellent and/or a household insecticidal product to control insecticide-resistant mosquitoes.

Indoor residual sprays (IRS) according to the invention refer to formulations that are applied on walls and roofs of houses and domestic animal shelters in order to kill adult vector mosquitoes that land and rest on these surfaces. The primary effect of such sprays is towards curtailing malaria (and dengue) transmission by reducing the life span of vector mosquitoes so that they can no longer transmit the disease from one person to another and reducing the density of the vector mosquitoes.

Insecticide treated net (ITN) are mosquito nets or bednets impregnated with insecticides that are useful for vector control. However, only pyrethroid insecticides are approved for use on ITNs. There are several types of nets available. Nets may vary by size, material and/or treatment. Most nets are made of polyester but nets are also available in cotton, polyethylene, or polypropylene. Previously, nets had to be retreated every 6-12 months, more frequently if the nets were washed. Nets were retreated by simply dipping them in a mixture of water and insecticide and allowing them to dry in a shady place. WHO recommends various formulations for retreatment (see http://www.who.int/whopes/Insecticides ITN Malaria ok3.pdf). The need for frequent retreatment was a major barrier to widespread use of ITNs in endemic countries. The additional cost of the insecticide and the lack of understanding of its importance resulted in very low retreatment rates in most African countries. More recently, several companies have developed long-lasting insecticide-treated nets (LLINs) that maintain effective levels of insecticide for at least 3 years. Longer lasting insecticide net (LLINs) are nets that are treated at factory level by a process that binds or incorporates insecticides into the fibres. WHO recommended LLINs are made from polyester, polyethylene, polypropylene and compounds such as deltamethrin, alpha-cypermethrin, permethrin and PBO to increase efficacy (>ittp://\v\v\v.vvhc).iiit/whopes/I .out; lasting insecticidal nets Jul 2012.pdf). In another embodiment of the invention ITN and LLINs made from polypropylene wherein an active ingredient is embedded are preferred. In particular such LLINs are described in WO2009/121580A2, WO2011/128380A1, WO2011/141260A1.

Space sprays are liquid insecticidal formulations that can be dispersed into the air in the form of hundreds of millions of tiny droplets less than 50μιη in diameter. They are only effective while the droplets remain airborne. Space sprays are applied mainly as thermal fogs or cold fogs.

Spatial repellents, or area repellents (also known as deterrents ) are defined as chemicals that work in the vapor phase to prevent human-vector contact by disrupting normal behavioral patterns within a designated area or "safe zone" (e.g. a space occupied by potential human hosts) thus making the space unsuitable for the insect. The compound(s) of the present invention may also be comprised in household insecticidal products such as e.g. "heated" air fresheners in which insecticidal compositions are released upon heating (electrically or by burning), smoke coils, vaporizers, aerosols, pressure-free spray products, for example pump and atomizer sprays, automatic fogging systems, foggers, foams, gels, evaporator products with evaporator tablets made of cellulose or plastic, liquid evaporators, gel and membrane evaporators, propeller-driven evaporators, energy-free or passive evaporation systems, moth papers, moth bags and moth gels, as granules or dusts, in baits for spreading or in bait stations.

According to another preferred embodiment of the invention, a compound of the invention is used together with a base material. In a prefered embodiment of the invention it has been found that a compound of the invention can be used with a suitable base material selected from the group of a polymers such thermoplastics or thermosets; plant-based materials; coating/impregnation solutions and/or mixtures thereof to control insecticide-resistant pests.

Another embodiment of the invention refers to a method to control insecticide-resistant mosquitoes resp. cockroaches by using a compound as discussed herein.

According to the present invention, the term "knock-down" describes the state of an animal on its back or side, which is still capable of uncoordinated movement including short periods of flying.

Some preferred compounds of the invention used in the context of the present invention are those in which: A is selected from the group consisting of hydrogen; alkylaminopolycyclyl; carbonylaminopolycyclyl; where the polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; and Formula III, where Formula III is

-(CH ₂ ) _n -U- ²

III

wherein n is 0 or 1;

U is selected from the group consisting of -CH ₂ -, oxygen, and -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, sulfonylalkyl, carbonylamino, and carbonylalkyl; R ² is selected from aryl, alkylpolycyclyl; heterocyclyl; polycyclyl; where the aryl, heterocyclyl and polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; and 1-R ³ , wherein R ³ is: where J, L, and W are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, carboxyl,alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, nitrilyl, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aryl, and aryloxy, where the aryl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyaminoalkyl;

R is -T-(CH2)m-R ¹ , where T is selected from the group consisting of -CH2-, oxygen, nitrogen, and sulfur; m is 1, 2, 3, or 4; R ¹ is -N(R ⁸ )(R ⁹ ), where R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CH ₂ ) _p -N(R ¹⁶ )(R ¹⁷ ), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; and the corresponding agriculturally acceptable salts thereof.

Some particularly preferred compounds are those in which: A is hydrogen or Formula 111, where Formula III is -(CH ₂ ) _n -U-R ²

III

wherein n is 0 or 1; U is selected from the group consisting of -CH ₂ -, oxygen, and -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, sulfonylalkyl, carbonylamino, and carbonylalkyl; R ² is selected from heterocyclyl; polycyclyl; where the heterocyclyl and polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; and 1-R ³ , wherein R ³ is:

where J, L, and W are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, nitrilyl, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aryl, and aryloxy, where the aryl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyaminoalkyl; T is oxygen or nitrogen, m is 2, 3, or 4; R ¹ is -N(R ⁸ )(R ⁹ ), where R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CH2) _P -N(R ¹⁶ )(R ¹⁷ ), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl. Some more particularly preferred compounds are those in which A is Formula III, where Formula III is

Ill

wherein n is 1 ; U is oxygen or -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, sulfonylalkyl, carbonylamino, and carbonylalkyl; R ² is 1-R ³ , wherein R ³ is:

R ³

where J, L, and W are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, carboxyl,alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, nitrilyl, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aryl, and aryloxy, where the aryl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyaminoalkyl; T is oxygen or nitrogen; m is 2; R ¹ is -N(R ⁸ )(R ⁹ ), where R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CH ₂ ) _P -N(R ¹⁶ )(R ¹⁷ ), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl;

Some yet even more particularly preferred compounds are those in which:

U is oxygen or -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, sulfonylalkyl, carbonylamino, and carbonylal R ² is 1-R ³ , wherein R ³ is

S?

where J, L, and W are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, nitrilyl, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aryl, and aryloxy, where the aryl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are independently selected from hydrogen, halogen, and alkoxy; T is oxygen; R ¹ is -N(R ⁸ )(R ⁹ ); where R ⁸ and R ⁹ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CH2) _P -N(R ¹⁶ )(R ¹⁷ ), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl;

Some still yet even more particularly preferred compounds are those in which: U is oxygen or -NR ⁵ , where R ⁵ is hydrogen; R ² is 1-R ³ , wherein R ³ is:

R ³

where J, L, and W are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkenyl, alkoxy, haloalkoxy, nitrilyl, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aryl, and aryloxy, where the aryl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are hydrogen; R ¹ is -N(R ⁸ )(R ⁹ ); where R ⁸ and R ⁹ are alkyl.

In another aspect, the present invention is directed to the use of certain 1,4-disubstituted benzenes and agriculturally acceptable salts thereof falling within the scope of formula I above to control insecticide- resistant pests. These compounds include, for example, the following 1,4-disubstituted benzenes: in which:

A is Formula 111, where Formula III is

-(CH,)„-U-R ^:

III

wherein

n is 1; U is oxygen; R ² is 1-R ³ ; wherein: R ³ is

R*

where J is 2-chloro or 2-fluoro, L is 3-chloro or 5-fluoro, and W is hydrogen or 4-chloro.

B and D are hydrogen; R is -T-(CH2) _m - ¹ , where T is oxygen; m is 2; R ¹ is -N(R ⁸ )(R ⁹ ), where R ⁸ and R ⁹ are ethyl. Additional preferred compounds are those in which A is selected from the group consisting of hydrogen; alkylaminopolycyclyl; and carbonylaminopolycyclyl; where the polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; and Formula III, where Formula 111 is

-(CH ₂ )„-U-R ²

III

wherein n is 0 or 1; U is selected from the group consisting of -CH ₂ -, oxygen, alkyl, oxyalkyloxy, alkenylamino, carbonylamino and -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, sulfonylalkyl, carbonylamino, and carbonylalkyl; R ² is selected from aryl; alkylpolycyclyl; heterocyclyl; polycyclyl; where the aryl, heterocyclyl and polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; and 1-R ⁴ , wherein R ⁴ is

R ⁴

where X, Y, and Z are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, azido, carboxyl, alkyl, alkynyl, haloalkyl, haloalkylthio, nitrilyl, alkenyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, phenyl, aryl, and aryloxy, where the phenyl and aryl moieties may be optionally substituted with halogen, haloalkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkoxyaminoalkyl; R is -T -(CH2)m-R ¹ or heterocyclyl; where the heterocyclyl moiety may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl, benzyl, allyl, propargyl; T is selected from the group consisting of -CH ₂ -, oxygen, nitrogen, and sulfur; m is 1, 2, 3, or 4; R ¹ is selected from the group consisting of -N(R ⁸ )(R ⁹ ); alkyl; aryl; -C(0)N(R ¹² )(R ¹³ ); oxyalkyl; haloalkyl; heterocyclyl; cycloalkyl; and N(0)(R ¹⁴ )(R ¹⁵ ), where the aryl and heterocyclyl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl; where R ⁸ , R ⁹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl , aminoalkyl, carbonylamino, and -(CH ₂ ) _P - N(Ri6)(Rn), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; and the corresponding agriculturally acceptable salts thereof.

Additional particularly preferred compounds are those in which:

A is hydrogen or Formula 111, where Formula 111 is

-(CH ₂ )„-U- ²

III

wherein n is 0 or 1 ; U is selected from the group consisting of -CH2-, oxygen, and -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, sulfonylalkyl, carbonylamino, and carbonylalkyl; R ² is selected from alkylpolycyclyl; heterocyclyl; polycyclyl; where the heterocyclyl and polycyclyl moieties are optionally substituted with one or more of the following: halogen, cyano, nitro, amino, carboxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, or aryl; and 1-R ⁴ wherein R ⁴ is

R ⁴

where X, Y, and Z are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, azido, carboxyl, alkyl, alkynyl, haloalkyl, haloalkylthio, nitrilyl, alkenyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, phenyl, aryl, and aryloxy, where the phenyl and aryl moieties may be optionally substituted with halogen, haloalkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkoxyaminoalkyl;

R is -T-(CH2)m-R ¹ or heterocyclyl; where the heterocyclyl moiety may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl, benzyl, allyl, propargyl; T is selected from the group consisting of oxygen, nitrogen, and sulfur; m is 1, 2, 3, or 4; R ¹ is selected from the group consisting of -N(R ⁸ )(R ⁹ ); alkyl; aryl; -C(0)N(R ¹² )(R ¹³ ); oxyalkyl; haloalkyl; heterocyclyl; cycloalkyl; and -N(0)(R ¹⁴ )(R ¹⁵ ), where the aryl and heterocyclyl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl; where R ⁸ , R ⁹ , R ¹⁰ , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CH2) _P - N(R ¹⁶ )(R ¹⁷ ), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; and the corresponding agriculturally acceptable salts thereof.

Additional more particularly preferred compounds are those in which

A is Formula 111, where Formula III is

-(CH ₂ )„-U-R ²

HI

wherein n is 1 ; U is oxygen or -NR ⁵ , where R ⁵ is selected from the group consisting of hydrogen, hydroxy, alkyl, sulfonylalkyl, carbonylamino, and carbonylalkyl; R ² is 1-R ⁴ wherein R ⁴ is

R*

where X, Y, and Z are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, azido, carboxyl, alkyl, alkynyl, haloalkyl, haloalkylthio, nitrilyl, alkenyl, alkoxy, Iialoalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, phenyl, aryl, and aryloxy, where the phenyl and aryl moieties may be optionally substituted with halogen, haloalkyl, haloalkyl, alkoxy, or haloalkoxy; B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkoxyaminoalkyl;

R is -T-(CH2)m-R ¹ or heterocyclyl; where the heterocyclyl moiety may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl, benzyl, allyl, propargyl; T is oxygen or nitrogen; m is 1, 2, 3, or 4; R ¹ is selected from the group consisting of - N(R ⁸ )(R ⁹ ); alkyl; aryl; -C(0)N(R ¹² )(R ¹³ ); oxyalkyl; haloalkyl; heterocyclyl; cycloalkyl; and - N(0)(R ¹⁴ )(R ¹⁵ ), where the aryl and heterocyclyl moieties may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl; where R ⁸ , R ⁹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CH2) _P -N(Ri6)(Rn), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, andaminoalkyl; and the corresponding agriculturally acceptable salts thereof.

Additional yet even more particularly preferred compounds are those in which:

A is Formula III, where Formula III is -(CH ₂ ) _n -U-R ²

in

wherein

U is oxygen or -NR ⁵ , where R ⁵ is hydrogen; R ² is 1-R ⁴ wherein R ⁴ is

where X, Y, and Z are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, azido, carboxyl, alkyl, alkynyl, haloalkyl, haloalkylthio, nitrilyl, alkenyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, phenyl, aryl, and aryloxy, where the phenyl and aryl moieties may be optionally substituted with halogen, haloalkyl, haloalkyl, alkoxy, or haloalkoxy; B and D are independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, and alkoxyaminoalkyl;

R is -T-(CH2)m-R ¹ or heterocyclyl; where the heterocyclyl moiety may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl, benzyl, allyl, propargyl; T is oxygen or nitrogen; m is 2; R ¹ is -N(R ⁸ )(R ⁹ ) or -N(0)(R ¹⁴ )(R ¹⁵ ), where R ⁸ , R ⁹ , R ¹⁴ , and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, carbonylamino, and -(CH2) _P -N(R ¹⁶ )(R ¹⁷ ), where p is 1 or 2; R ¹⁶ and R ¹⁷ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkoxyalkyl, and aminoalkyl; and the corresponding agriculturally acceptable salts thereof.

Additional still yet even more particularly preferred compounds are those in which:

A is Formula 111, where Formula III is

-(CH ₂ ) _n -U-R ²

in

wherein

U is 0 or -NR ⁵ , where R ⁵ is hydrogen;

R ² is selected from 1-R ⁴ wherein R ⁴ is

*

where X, Y, and Z are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, amino, azido, carboxyl, alkyl, alkynyl, haloalkyl, haloalkylthio, nitrilyl, alkenyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, phenyl, aryl, and aryloxy, where the phenyl and aryl moieties may be optionally substituted with halogen, haloalkyl, haloalkyl, alkoxy, or haloalkoxy;

B and D are hydrogen; the heterocyclyl is a piperazinyl moiety, where the piperazinyl moiety may be optionally substituted with halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxycarbonyl, aryl, arylcarbonyl, benzyl, allyl, propargyl; T is oxygen; R ¹ is -N(R ⁸ )(R ⁹ ) or -N(0)(R ¹⁴ )(R ¹⁵ ), where R ⁸ , R ⁹ , R ¹⁴ , and R ¹⁵ are independently selected from the group consisting of hydrogen, alkyl, alkoxy, acetyl, alkoxycarbonyl, alkoxyalkyl, aminoalkyl, and carbonylamino; and the corresponding agriculturally acceptable salts thereof.

Further preferred compounds are those in which

A is Formula III, where Formula III is

in

wherein

U is 0; R ² is selected from 1-R ⁴ wherein R ⁴ is

where X, Y, and Z are independently selected from the groupconsisting of hydrogen, halogen, cyano, nitro, amino, azido, carboxyl, alkyl, alkynyl, haloalkyl, haloalkylthio, nitrilyl, alkenyl, alkoxy, haloalkoxy, carbonyl, alkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, phenyl, aryl, and aryloxy, where the phenyl and aryl moieties may be optionally substituted with halogen, haloalkyl, haloalkyl, alkoxy, or haloalkoxy; R ¹ is -N(R ⁸ )(R ⁹ ) or -N(0)(R ¹⁴ )(R ¹⁵ ), where R ⁸ , R ⁹ , R ¹⁴ and R ¹⁵ are alkyl; and the corresponding agriculturally acceptable salts thereof.

In addition to the use of those compounds set forth above, the present invention is also directed to the use of certain 1,4-disubstituted benzenes and agriculturally acceptable salts thereof falling within the scope of formula I beneath to control insecticide-resistant pests.

These compounds include, for example, the following 4-disubstituted benzenes:

in which:

A is Formula III, where Formula III is

in

wherein n is 1; U is oxygen; R ² is 1-R ⁴ ; wherein: R ⁴ is

E ⁴

where X is 4-chloro or 5-chloro, Y is 6-chloro or 6-bromo, and Z is hydrogen; B and D are hydrogen; R is -T-(CH2)m-Ri or a piperazinyl moiety; where the piperazinyl moiety is substituted with 4-ethyl; T is oxygen; m is 2; R ¹ is -N(R ⁸ )(R ⁹ ) or -N(0)(R ¹⁴ )(R ¹⁵ ), where R ⁸ , R ⁹ , R ¹⁴ and R ¹⁵ are ethyl; and the agriculturally acceptable salts thereof, preferably the hydrochloride salts.

In another aspect, the present invention is directed to a the use of a composition containing an insecticidally effective amount of a compound of Formula I, including, without limitation, those compounds disclosed above as being preferred, particularly preferred, and per se novel, in admixture with at least one agriculturally acceptable extender or adjuvant, wherein A, B, D, and R are as defined above to control insecticide-resistant pests.

For the purposes of this invention, as regards to the above substituents, the terms "alkyF'and "alkoxy", alone or as part of a larger moiety, include chains of 1 to 14 carbon atoms, preferably straight or branched alkyls of 1 to 6 carbon atoms; while "halogen" or "halo", alone or as part of a larger moiety, includes chlorine, bromine, fluorine, and iodine atoms. The terms "alkenyl" or "alkynyl", used alone or as part of a larger moiety, includes straight or branched chains of at least two carbon atoms containing at least one carbon-carbon double or triple bond, preferably up to 12 carbon atoms, more preferably, up to ten carbon atoms, most preferably up to seven carbon atoms. The term "cycloalkyl" includes rings of three to twelve carbon atoms, preferably rings of three to six carbon atoms. The terms "haloalkyl" and "haloalkoxy", alone or as part of a larger moiety, include straight or branched chain alkyls of 1 to 14 carbon atoms, preferably lower straight or branched chain alkyls of 1 to 6 carbon atoms, wherein one or more hydrogen atoms have been replaced with halogen atoms, as, for example, trifluoromethyl or 2,2,2- trifluoroethoxy, respectively. "Aryl" refers to an aromatic ring structure, including fused rings, having 5 to 10 carbon atoms. "Heterocyclyl" refers to an aromatic ring structure, including fused rings, having at least one nitrogen, sulfur or oxygen atom. "Amino" refers to compounds of nitrogen that may be considered derived from ammonia and includes primary, secondary and tertiary amines wherein one or more of the hydrogen atoms is replaced with alkyl groups. "THF" refers to tetrahydrofuran, "DMF" refers to Ν,Ν-dimethylformamide, "DPAD" refers to l,l'-(azodicarbonyl)dipiperidine, and "A.T." refers to ambient temperature.

For the use according to the present invention, the active compounds are formulated into insecticidal compositions by admixture in insecticidally effective amount with adjuvants and carriers normally employed in the art for facilitating the dispersion of active ingredients for the particular utility desired, recognizing the fact that the formulation and mode of application of a toxicant may affect the activity of the material in a given application. Thus, for the use according to the present invention the present insecticidal compounds may be formulated as granules of relatively large particle size, as water-soluble or water-dispersible granules, as powdery dusts, as wettable powders, as emulsifiable concentrates, as solutions, or as any of several other known types of formulations, depending on the desired mode of application. These insecticidal compositions may be applied either as water-diluted sprays, or dusts, or granules to the areas in which insect control is desired. These formulations may contain as little as 0.1 %, 0.2% or 0.5% to as much as 95% or more by weight of active ingredient. Dusts are free flowing admixtures of the active ingredients with finely divided solids such as talc, natural clays, kieselguhr, flours such as walnut shell and cottonseed flours, and other organic and inorganic solids which act as dispersants and carriers for the toxicant; these finely divided solids have an average particle size of less than about 50 microns. A typical dust formulation useful herein is one containing 1.0 part or less of the insecticidal compound and 99.0 parts of talc.

Wettable powders are in the form of finely divided particles which disperse readily in water or other dispersant. The wettable powder is ultimately applied to the locus where insect control is desired either as a dry dust or as an emulsion in water or other liquid. Typical carriers for wettable powders include Fuller's earth, kaolin clays, silicas, and other highly absorbent, readily wet, inorganic diluents.

Wettable powders normally are prepared to contain about 5-80% of active ingredient, depending on the absorbency of the carrier, and usually also contain a small amount of a wetting, dispersing, or emulsifying agent to facilitate dispersion.

For example, a useful wettable powder formulation contains 80.8 parts of the insecticidal compound, 17.9 parts of Palmetto clay, and 1.0 part of sodium lignosulfonate and 0.3 part of sulfonated aliphatic polyester as wetting agents. By way of illustration, compound 223 was formulated as a 25% wettable powder (25%WP) as follows:

COMPONENT AMOUNT < t/wt%)

Compound 223 ( 1% pure) 27.5%

Diluent 5.0%

Wetting Agent 1.0%

Dispersing Agent 16.0%

UV Stabilizer 0.5%

Carrier Diluent 50.0%

Other useful formulations for insecticidal applications are emulsifiable concentrates (ECs) which are homogeneous liquid compositions dispersible in water or other dispersant, and may consist entirely of the insecticidal compound and a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone, or other non-volatile organic solvent. For insecticidal application these concentrates are dispersed in water or other liquid carrier, and normally applied as a spray to the area to be treated. The percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises 0.5 to 95% of active ingredient by weight of the insecticidal composition.

Flowable formulations are similar to ECs except that the active ingredient is suspended in a liquid carrier, generally water. Flowables, like ECs, may include a small amount of a surfactant, and contain active ingredient in the range of 0.5 to 95%, frequently from 10 to 50%, by weight of the composition. For application, flowables may be diluted in water or other liquid vehicle, and are normally applied as a spray to the area to be treated.

Typical wetting, dispersing, or emulsifying agents used in agricultural formulations include, but are not limited to, the alkyl and alkylaryl sulfonates and sulfates and their sodium salts; alkylaryl polyether alcohols; sulfated higher alcohols; polyethylene oxides; sulfonated animal and vegetable oils; sulfonated petroleum oils; fatty acid esters of poly hydric alcohols and the ethylene oxide addition products of such esters; and the addition product of long-chain mercaptans and ethylene oxide. Many other types of useful surface-active agents are available in commerce. The surface-active agents, when used, normally comprise from 1 to 15% by weight of the composition.

Other useful formulations include suspensions of the active ingredient in a relatively non-volatile solvent such as water, com oil, kerosene, propylene glycol, or other suitable solvents. Still other useful formulations for insecticidal applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene, or other organic solvents. Granular formulations, wherein the toxicant is carried on relatively coarse particles, are of particular utility for aerial distribution. Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low boiling dispersant solvent carrier, such as carbon dioxide, propane, or butane, may also be used. Water-soluble or water-dispersible granules are also useful formulations for insecticidal application of the present compounds. Such granular formulations are free-flowing, non-dusty, and readily water-soluble or water-miscible. In use, the granular formulations, emulsifiable concentrates, flowable concentrates, solutions, etc., may be diluted with water to give a concentration of active ingredient in the range of say 0.1% or 0.2% to 1.5% or 2%.

The compounds of the present invention were prepared by methods generally known to those skilled in the art. Many of the compounds of the present invention in which R ¹ is naphthyl were prepared in the manner shown in Schema 1. In Schema 1, a 4-hydroxy -benzaldehyde (SMI) was reacted with the appropriately substituted alkyl chloride hydrochloride salt (SM2) in a solvent, for example, DMF or THF, at 0°C to ambient temperature in the presence of a base, for example, potassium carbonate, to yield the appropriately substituted alkoxy benzaldehyde (BB). The appropriately substituted benzaldehyde (BB) was then reduced in a solvent, for example methanol, with a reducing agent, for example, lithium aluminum hydride, sodium borohydride, or triacetoxyborohydride, to yield the appropriately substituted phenyl alkoxy alcohol (CC). The appropriately substituted phenyl alkoxy alcohol (CC) can also be prepared by reacting the appropriately substituted alkyl chloride hydrochloride salt (SM2) with either the appropriately substituted acid (SM3) or phenyl alcohol (SM4) in a solvent in the presence of a reducing agent as set forth above. The appropriately substituted phenyl alkoxy alcohol (CC) can then be reacted with either p-toluene sulfonyl chloride (SM5) and a base, for example triethylamine, in a solvent to form the appropriately substituted phenyl alkylthio- or alkoxysulfonyl toluene (DD) or sulfonyl chloride in a solvent to form the appropriately substituted phenylalkylthio or phenylalkoxy chloride hydrochloride (EE). If necessary, the naphthyl ring can be prepared at this time. In general, the naphthyl ring was prepared via the formation of the appropriate naphthol. The preparation of the naphthol begins by reacting: 1) the appropriately substituted benzaldehyde (SM6) with either sodium hydride and 3-(triphenylphosphino )propanoate hydrochloride in THF and N-N- dimethylsulfoxide(DMF) or with succinic acid, disodium salt and acetic anhydride to form the appropriately substituted phenylbutenoic acid (FF); 2) the appropriately substituted phenyl iodide (SM7) with but-3-ynol, a base, for example, triethylamine, copper iodide and a palladium phosphine complex to yield the appropriately substituted phenylbutynol (GG); 3) the appropriately substituted phenylcarbonylpropanoic acid (SM8) with zinc and mercury (II) chloride in water to form the appropriately substituted phenylbutanoic acid (HH), which can also be preprepared by hydrogenating the appropriately substituted phenylbutenoic acid (FF) or phenylbutynol (GG) in alcohol with palladium on carbon followed by treatment with chromium oxide and sulfuric acid; 4) the appropriately substituted 2-(diethylaminocarbonyl)benzene (SM9) with n-butyllithium followed by prop-2-enylbromide and a dimethylthio-copper chloride complex to yield the appropriately substituted 2-(diefhylaminocarbonyl)-3- prop-2-enylbenzene (JJ); or 5) the appropriately substituted benzene (SMIO) with oxolan-2-one and aluminium chloride at elevated temperature to form the appropriately substituted trihydronaphthalen-1- one (KK). The trihydronaphthalen-l-one (KK) can also be prepared by reacting the appropriately substituted phenylbutanoic acid (HH) with an acid, for example polyphosphoric acid, or reacting the appropriately substituted 2-(diethylaminocarbonyl)-3-prop-2-enylbenzene (JJ) with methyllithium. The appropriately substituted trihydronaphthalen-l-one (KK) is then reacted with bromine in a solvent, for example methylene chloride, to form the appropriately substituted 2-bromo-trihydronaphthalen-l-one (LL). The appropriately substituted 2-bromo-trihydronaphthalen-l-one (LL) is then reduced with a reducing agent and Hthiumbromide in a solvent, for example, DMF, in the manner described above to form the appropriately substituted naphthol (MM), which is commercially available when (MM) is 4- chloronaphthol. The appropriately substiuted naphthol (MM) was then reacted with either the appropriately substituted benzaldehyde (BB), alcohol (CC), toluene (DD), or hydrochloride (EE) to form the targeted 1-substitutedalkylthio or alkoxy-4-((substituted naphth-l-yl)oxyalkyl)benzene (1), for example, (2-(4-(((4-chloronaphthyl)methoxy )methyl)phenoxy)ethyl)diethylamine. Additional substituents can be added to the naphthol ring by reacting a 6-aminonaphth-l-ol (SM11) with toluene sulfonyl chloride in the manner disclosed above to yield the 6-amino-l- (methylphenylsulfonyloxy)naphthalene (NN). The 6-amino-l-(methylphenylsulfonyloxy)naphthalene (NN) was then reacted with t-butyl nitrite in a solvent, for example at 0 °C followed by a copper (II) halide, for example, copper (II) chloride, to yield the appropriate 6-halo-l- (methylphenylsulfonyloxy)naphthalene (PP). The 6-amino-l-(methylphenylsulfonyloxy)naphthalene (NN) was also reacted with an excess of a copper (II) halide, for example, copper (II) chloride, in a solvent followed by t-butyl nitrite in the manner disclosed above to form the appropriate 5,6-dihalo-l- (methylphenylsulfonyloxy)naphthalene (QQ). The appropriately substituted naphthalene (QQ) or (PP) can then reacted with a base, for example, potassium hydroxide, and an alcohol, for example, ethanol, in a mixture of a solvent, for example, THF, and water to yield the appropriately substituted naphthol (RR), for example 5,6-dichloronaphthol. When the naphthol was a 5,6-dihalonaphthol (RR) it was reacted with either the appropriately substituted benzaldehyde (BB), alcohol (CC), toluene (DD), or hydrochloride (EE) and a borane-pyridine complex under acidic conditions, or a base, for example, sodium hydride or triethylamine, in a solvent, for example DMF, or a phosphine complex, for example n-butylphosphine, and DP AD in a solvent, for example, THF, to form the targeted 1 -substituted alkylthio or alkoxy-4-( (5 ,6-substituted naphth-l-yl)oxyalkyl)benzene (la), for example, (2-(4-((5,6-dichloronaphthyloxy )methyl)phenoxy )ethyl)diethylamine. A halo substituent, for example chloro, can be added to the 4- postion of naphthol ring at this time by reacting the appropriately substituted naphthol (MM) or (RR) with a sulfuryl halide, for example, sulfuryl chloride, in a solvent to yieldthe appropriately substituted 4- halonaphthol (SS). The appropriately substituted 4-halonaphthol (SS) can be reacted either the appropriately substituted benzaldehyde (BB), alcohol (CC), toluene (DD), or hydrochloride (EE) in the manner described above to form the targeted 1-substitutedalkylthio or alkoxy-4-((5,6-substituted naphth- l-yl)oxyalkyl)benzene (lb), for example, (2-(4-((4,6-dichloronaphthyloxy )methyl)phenoxy )ethyl)diethylamine.

As depicted in Schema 2, compounds of the present invention wherein U is nitrogen and n is 1 were prepared by reacting the appropriately substituted benzaldehyde (BB) with the appropriately substituted 1-aminonaphthalene (SM12), for example, l-amino-4-chloronaphthalene, under acidic conditions to form the appropriately substituted l-aza-l-naphthyl-2-phenylethene (TT), which was then reduced with a reducing agent in the manner disclosed above to yield the targeted targeted 1 -substituted -4- ((substituted naphth-l-yl)aminoalkyl)benzene (IV), for example, (2-(4-(((4-chloronaphthyl)amino )methyl)phenoxy)ethyl) diethylamine.

As depicted in Schema 3, compounds of the present invention wherein U is -CH ₂ - and n is 1 were prepared by reacting the appropriately substituted 1-aminonaphthalene (SMI 2) with the appropriately substituted 4-methylthio-, 4-methoxy-, or 4-methylamino-l-vinylbenzene (SMI 3) with t-butylnitrite, in a solvent, for example, acetonitrile, in the presence of palladium acetate to form the appropriately substituted 2-(4-methylthio-, 4-methoxy-, or 4-methylaminophenyl)vinylnaphthalene (UU). The vinylnaphthalene was then hydrogenated in a solvent, for example, ethanol, with a palladium on carbon to form the appropriately substituted 2-(4-methylthio-, 4-methoxy-, or 4- methylaminophenyl)ethylnaphthalene (WW). The ethylnaphthalene (WW) was then reacted in solvent, for example methylene chloride, with boron tribromide to form the appropriately substituted 2-( 4-thio-, 4-hydroxy-, or 4-aminophenyl)ethylnaphthalene (XX). The ethylnaphthalene (XX) was in turn reacted with the appropriately substituted alkyl chloride hydrochloride salt (SM2) and an excess of a base, for example, potassium carbonate, in solvent, for example, DMF, to form the targeted 1-substituted -4- ((substituted naphth-l-yl)ethyl)benzene (V), for example, (2-(4-(((4- chloronaphthyl)amino)methyl)phenoxy)ethyl) diethylamine.

Schema 4 depicts another route in which the compounds of the present invention may be prepared. In Schema 4, the appropriately substituted benzaldehyde (SM3) is reacted with a haloalkylbromide, for example, l-bromo-2-chloromoethane, to yield the appropriately substituted 4-haloalkoxybenzaldehdye (YY), which in turn is reduced with a reducing agent in an alcohol, for example methanol, in the manner described above to form the appropriately substituted 4-haloalkoxyphenylmethan-l-ol (ZZ). The phenylmethan-l-ol (ZZ) was then reacted at 0°C to ambient temperature with the appropriately substituted naphthol or phenol (SM14), a phosphine complex , and DP AD in a solvent in the manner described above to yield the corresponding halo- 1 -(4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)phenoxy)alkane (AAA), for example, 2-chloro-l-(4-((4- chloronaphthyloxy)methyl)phenoxy)ethane. The alkane (AAA) was then reacted with the appropriate substituent, for example, cis-2,6-dimethylpiperidine, and a base in acetonitrile to form the corresponding, l-( subtituted alkoxy )-4-((4-substituted naphthyl or phenyl)oxy)methyl)benzene (VI), for example l-(2-(2,6-dimethylpiperidyl)ethoxy)-4-(( 4-chloronaphthyloxy)methyl)benzene. At this point, the benzene (VI) can optionally be reacted with 3-chloroperoxybenzoic acid in chloroform at 0°C to form the corresponding 2-( 4-substituted naphthyl or phenyl)oxy)methyl)phenoxy)alkyl)alkanone (VII), for example, amino(2-(4-((5,6 dichloronaphthyloxy)methyl)phenoxy )ethyl)diethyl-l-one

Schema 5 illustrates yet another route for preparing the compounds of the present invention wherein R ¹ is a disubstituted amino. In schema 5, the appropriately substituted (4-hydroxyphenyl)methan-l-ol (SM4) was reacted with a bromomethylisocyanate and a reducing agent, for example potassium carbonate, in a solvent, for example, DMF, in the manner disclosed above to form the corresponding (4- (cyanomethoxy)phenyl)methan-l-ol (BBB). The methan-l-ol (BBB) was then reacted with sulfinyl chloride in a solvent, for example, chloroform, at 0°C to form the corresponding 4-(cyanomethoxy)-l- (chloromethyl)benzene (CCC), which was in turn reacted with the appropriately substituted naphthol or phenol (SM14) and a reducing agent, for example, potassium carbonate, in a solvent, for example DMF, in the manner described above to yield the corresponding l-((( 4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(cyanomethoxy)benzene (DDD). The 4-(cyanomethoxy)benzene (DDD) was reacted with borane in a solvent, for example, THF, at 0°C to form the appropriately substituted l-(((4- substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(aminomethoxy)benzene (EEE). The 4- (aminomethoxy)benzene (EEE) was in turn reacted with the appropriate oxoalkyl chloride, for example, acetyl chloride, in a solvent, for example, pyridine or THF, at 0°C to yield the corresponding l-(((4- substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-(oxoalkylaminomethoxy)benzene (FFF). The 4-(oxoalkylaminomethoxy)benzene (FFF) was then reacted with borane in a solvent in the manner described above to yield the targeted 1 -(((4-substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4- (alkylaminomethoxy)benzene (VIII). At this point, additional moieties can be optionally added to the amino group by reacting the 4-(alkylaminomethoxy)benzene (VIII) with the appropriate substituted alkyl, alkoxy, or alkoxyalkyl halide and a base, for example, triethylamine, to yield the target l-(((4- substituted naphthyl- or 4-substituted phenyl)oxy)methyl)-4-((disubstituted amino)methoxy)benzene (IX). Schema 1

Solvent

0 or S

B Solvent

Hydrochloride

El Schema 1 (continued)

Schenia 1 (continued)

Berane-p Mee/Add

mm

Sclieraa 1 (contkaei)

Borane-pyridine Acid

where Z is halo

Schema 2

Schema 4

unsubstituted naphthyl or phenyl

^' ¥11

Sehenm 5

VIII

The present invention is now described in more detail by reference to the following examples, but it should be understood that the invention is not construed as being limited thereto. EXAMPLES: EXAMPLE 1

This example illustrates one protocol for the preparation of (2-(4-((5,6- dichloronaphthyloxy)methyl)phenoxy)ethyl)diethylamine (Compound 223) . Step A (6-aminonapthyl)( ( 4-methylphenyl)sulfonyl)oxy

A stirred solution of 5.0 grams (0.031 mole) of 6-amino-l-naphthol(available from TCI America, Portland, OR) and 6.1 grams (0.032 mole) of p-toluenesulfonyl chloride (available from Aldrich Chemical Company, Milwaukee, WI) in 225 mL of methylene chloride (available from J. T. Baker Inc., Phillipsburg, NJ) was cooled in an ice bath, and 5.3 grams (0.038 mole) of triethylamine was added dropwise. The reaction mixture was then allowed to warm to ambient temperature where it stirred for about 18 hours. After this time, the reaction mixture was washed with three 75 mL portions of water, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 9.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.

Step B (5,6-dichloronapthyl)((4-methylphenyl)sulfonyl)oxy Under a nitrogen atmosphere, 2.0 grams (0.0064 mole) of (6-aminonapthyl)(( 4- methylphenyl)sulfonyl)oxy was taken up in 6 mL of acetonitrile (available from EM Sciences, Gibbstown, NJ). The mixture was stirred at ambient temperature for ten minutes and then 5.1 grams (0.038 mole) of copper (II) chloride was added. The resulting mixture was stirred at ambient temperature for ten minutes. At the conclusion of this period, the mixture was cooled in an ice bathand 0.85 mL (0.0064 mole) of t-butyl nitrite was added dropwise during a ten minute period. Upon completion of addition, the reaction mixture was stirred at 7-8°C for 1.25 hours. At the conclusion of this period, the reaction mixture was poured into an ice-cold aqueous 10% hydrochloric acid solution and extracted with ethyl acetate. The extract was washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 2.0 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 1.0 grams of title compound; mp 104-109 °C. The NMR spectrum was consistent with the proposed structure.

Step C 5,6-dichloronaphthol

To a mixture of 0.85 gram (0.0023 mole) of (5,6-dichloronapthyl)((4-methylphenyl)sulfonyl)oxy in 40 mL of ethanol (available from J. T. Baker Inc.) was added 5 mL of tetrahydrofuran (THF, available from Aldrich Chemical Company). The resulting mixture was stirred to effect dissolution and then a solution of 1.3 grams (0.023 mole) of potassium hydroxide (available from VWR Scientific Products, Bridgeport, NJ) in 40 mL of water was added. Upon completion of addition, the reaction mixture was under reflux for one hour. After this time, most of the solvent was removed under reduced pressure to yield a residue. The residue was extracted with one 20 mL portion of diethyl ether. Theextract was acidified to a pH of 5-6 with ice-cold aqueous 5% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract was washed with an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.33 gram of title compound. The NMR spectrum was consistent with the proposed structure.

Step D (4-(2-diethylamino )ethoxy)phenyl)methan-l-ol

A solution of 37.2 grams (0.22 mole) of2-(diethylamino)ethyl chloride hydrochloride (available from Aldrich Chemical Company), 26.8 grams (0.22 mole) of 4-hydroxybenzyl alcohol (available from Aldrich Chemical Company) and 89 grams (0.65 moles) of potassium carbonate (available from VWR Scientific Products) in 1200 mL of Ν,Ν-dimethylformamide (DMF, available from EM Sciences) was stirred at ambient temperature for about 18 hours. After this time, the solvent was remove under reduced pressure, yielding a residue. The residue was taken up in water and then extracted with ethyl acetate. The extract was washed with one portion of an aqueous 10% sodium hydroxide solution followed by one portion of water and then one portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 2.3 8 grams of title compound. The NMR spectrum was consistent with the proposed structure.

Step E Compound 223 A stirred solution of 0.33 gram gram (0.00 16 mole) of 5,6-dichloronapthol and 0.35 gram (0.0016 mole) of(4-(2-diethylamino)ethoxy)phenyl)methan-l-ol in 15 mL of THF was cooled in an ice bath, and 0.24 mL (0.0017 mole) of tributylphosphine (available from Aldrich Chemical Company) followed by 0.42 gram (0.0017 mole) of l-l'-(azadicarbomyl)dipiperidine (available from Aldrich Chemical Company) were added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 72 hours. After this time, the reaction mixture was diluted with ethyl acetate, and an aqueous solution saturated with sodium chloride was added. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding about 0.45 gram of crude product. The crude product was purified by column chromatography on silica gel, yielding 0.13 gram of Compound 223. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 2

This example illustrates one protocol for the preparation of the hydrochloride salt of (2-(4-((5,6- dichloronaphthyloxy)methyl)phenoxy)ethyl)diethylamine (Compound 224) . Compound 225 (prepared in the manner of Example 1), 0.07 gram (0.00017 mole), was taken up in 1 mL of methylene chloride (available from EM Sciences) and 1 mL of one molar hydrochloric acid in diethyl ether (available from Aldrich Chemical Company) was added. The solvent was removed under reduced pressure to yield a solid. The solid was taken up in heptane. The resulting precipitate was collected by vacuum filtration, yielding 0.07 gram of Compound 226; mp 204-206°C. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 3

This example illustrates one protocol for the preparation of (2-(4-((6-quinolylamino )methyl)phenoxy)ethyl)diethylamine (Compound 15). Step A 4-(2-(diethylamino )ethoxy )benzaldehyde

A solution of 5.0 grams (0.041 mole) of 4-hydroxybenzaldehdye (available from Aldrich Chemical Company), 8.5 grams (0.049 mole) of2-diethylaminoethyl chloride hydrochloride (available from Aldrich Chemical Company), and 13.5 grams (0.098 mole) of potassium carbonate (available from J. T. Baker Inc.) in lOOmL of DMF was stirred at ambient temperature for 72 hours. At the conclusion of this period, the reaction mixture was poured into 100 mL of water and extracted with three 50 mL portions of diethyl ether. The combined extracts were washed with one 25 mL portion of water, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 5.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.

Step B Compound 15 To a stirred solution of 1.0 gram (0.0045 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde and 0.65 gram (0.0045 mole) of 6-aminoquinoline (available from Aldrich Chemical Company) in 25 mL of 1,2- dichloroethane (DCE, available from Aldrich Chemical Company)was added 0.3mL (0.0045 mole) of glacial acetic acid (available from J. T. Baker Inc.) followed by 1.4 grams (0.0068 mole) of sodium triacetoxyborohydride (available from Aldrich Chemical Company). Upon completion of addition, the reaction mixture was stirred at ambient temperature for three hours. At the conclusion of this period, 50 mL of 10% aqueous sodium hydroxide was added dropwise. The resulting solution was extracted with three 25 mL portions of diethyl ether. The extracts were combined, washed with one 25 mL portion of an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.25 grams of a dark brown paste. The dark brown paste was purified by column chromatography on silica gel, yielding 0.13 gram of Compound 15. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 4 This example illustrates one protocol for the preparation of (2-(4-(((4-chloronaphthyl)amino )mefhyl)-2- methoxyphenoxy)ethyl)diethylamine (Compound 263).

Step A 4-(2-(diethylamino )ethoxy)-2-methoxybenzaldehyde

This compound was prepared in the manner of Step A, Example 3, using 2.5 grams (0.016 mole) of 4- hydroxy-2-methoxybenzaldehdye (available from Lancaster Synthesis Inc., Windham, NH), 3.4 grams (0.02 mole) of 2-diethylaminoethyl chloride hydrochloride, and 5.5 grams (0.04 mole) of potassium carbonate in 75 mL of DMF. The yield of the title compound was 2.6 grams. The NMR spectrum was consistent with the proposed structure.

Step B Compound 263 This compound was prepared in the manner of Step B, Example 3, using 1.0 gram (0.004 mole) of 4-(2- (diethylamino)ethoxy)-2-methoxybenzaldehyde, 0.71 gram (0.004 mole) of l-amino-4- chloronaphthalene (available from Aldrich Chemical Company), 0.25 mL (0.004 mole) of glacial acetic acid, 1.3 grams (0.006 mole) of sodium triacetoxyborohydride and 50 mL of 1,2-dichloroethane (DCE). The yield of Compound 263 was 0.52 gram. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 5

This example illustrates one protocol for the preparation of (2-(4-(((4 chloronaphthyl)methoxy)methyl)phenoxy)ethyl)diethylamine (Compound 8) .

Step A (4-(2-diethylamino )ethoxy)phenyl)methan-l-ol A solution of 4.0 grams (0.08 mole) of 4-(2-(diethylamino )ethoxy )benzaldehyde (prepared in the manner of Step A, Example 3) and 2.7 grams (0.08 mole) of sodium borohydride (available from Aldrich Chemical Company) in 40 mL of methanol (available from J. T. Baker Inc,) was stirred at ambient temperature for about 18 hours. After this time, the reaction mixture was quenched with water and extracted with several portions of methylene chloride. The organic extracts were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 4.1 grams of title compound.

Step B 4-chloronaphthalenecarbaldehye

To a stirred solution of 6.7 grams (0.026 mole) of a 1.0 M solution of tin(iv)chloride in dichloromethane (available from Aldrich Chemical Company) in 10 mL of methylene chloride was added 3.0 grams (0.026 mole) of 3,3-dichloromethyl methyl ether (available from Aldrich Chemical Company). The resulting solution was stirred for one hour at ambient temperature. After this time, a solution of 2.8 mL (0.021 mole) of 4-chloronaphthalene was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. At the conclusion of this period, the reaction mixture was quenched with water, washed with water followed by an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding about 2.1 grams of title compound.

Step C (4-chloronaphthyl)methan-l-ol

This compound was prepared in the manner of Step C, Example 1, using 2.1 grams (0.011 mole) of 4- chloronaphthalenecarbaldehye, 70 mL of methanol, 20 mL of THF, and 2 grams (0.054 mole) of sodium borohydride. This preparation differs in that sodium borohydride was used rather than a solution of potassium hydroxide in water. The yield of the title compound was 1.9 grams.

Step D Compound 8

This compound was prepared in the manner of Step E, Example 1, using 0.5 gram (0.0026 mole) of (4- chloronaphthyl)methan-l-ol, 0.6 gram of(4-(2-diethylamino)ethoxy)phenyl)methan-l-ol, 70 mL of THF, 0.79 mL (0.0031 mole)of tributylphosphine, and 0.73 gram (0.0029 mole) of 1- l'(azadicarbomyl)dipiperidine. The yield of Compound 8 was 0.3 gram.

EXAMPLE 6

This example illustrates one protocol for the preparation of l-(2-(2,6-dimethylpiperidyl)ethoxy)-4-(( 4- chloronaphthyloxy)methyl)benzene (Compound 106).

Step A Mixture of 4-(2-bromoethoxy)benzaldehyde and 4-(2-chloroethoxy)benzaldehyde Sodium hydride (60% dispersion in mineral oil, available from Aldrich Chemical Company),4.4 grams (0.11 mole), was washed with three portion of hexane (available from J. T. Baker Inc.) and 200 mL of DMF was added. The resulting mixture was cooled to 0°C and 50 mL (0.6 mole) of l-bromo-2- chloromoethane (available from Aldrich Chemical Company) followed by 12.2 grams (0.1 mole) 4- hydroxybenzaldehyde were added. Upon completion of addition, the reaction mixture was heated to 40 °C where it stirred for about 72 hours. After this time, the reaction mixture was extracted with several portions of ethyl acetate. The organic extracts were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 7.4 grams of title mixture. The NMR spectrum was consistent with the proposed structure. This compound was prepared several times in the manner described above.

Mixture of (4-(2-bromoethoxy)phenyl)methan-l-ol and (4-(2-chloroethoxy )phenyl)methan- 1 -ol This compound was prepared in the manner of Step C, Example 1, using8.7 grams (0.047 mole) of the mixture of 4-(2-bromoethoxy)benzaldehyde and (4-(2-chloroethoxy)phenyl)methan-l-ol, 400 mL of methanol, and 3.5 grams (0.094 mole) of sodium borohydride. This preparation differs in that no THF was used and sodium borohydride was used rather than a solution of potassium carbonate in water. The yield of the title mixture was 8.4 grams. The NMR spectrum was consistent with the proposed structure.

Step C 2-chloro-l-(4-((4-chloronaphthyloxy)methyl)phenoxy)ethane

A stirred solution of 8.4 grams (0.045 mole) of the mixture of(4-(2-bromoethoxy)phenyl)methan-l-ol and (4-(2-chloroethoxy)phenyl)meth.an-l-ol, 8.1 grams (0.045 mole) of 4-chloronaphthol, and 13.7 mL (0.054 mole) of tributylphosphine in 500 mL of THF was cooled in an ice bath and 12.6 grams (0 .049 mole) of l-l'-( azodicarbomyl)dipiperidine was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for 24 hours. After this time, the solvent was reduced under reduce pressure, yielding a solid. The solid was purified by column chromatography on silica gel, yielding 15 grams of crude product. The crude product was further purified by column chromatography on silca gel, yielding 6.7 grams of title compound. Step D Compound 106

A stirred mixture of 0.4 grams (0.001 mole) of 2-chloro-l-(4-((4- chloronaphthyloxy)methyl)phenoxy)ethane and 5 mL (0.037 mole) of cis-2,6-dimethylpiperidine was heated to just below reflux for about 72 hours. After this time, the reaction mixture was analyzed by thin layer chromatography (TLC), which indicated the reaction was incomplete. The reaction mixture was concentrated under reduced pressure and subject to column chromatography on silica gel, yielding 0.2 gram of compound 106. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 7

This example illustrates one protocol for the preparation of amino(2-(4-((5,6- dichloronaphthyloxy)methyl)phenoxy)ethyl)diethyl- 1 -one (Compound 183). (2-(4-((5,6-Dichloronaphthyloxy )methyl)phenoxy )ethyl)diethylamine (prepared in the manner of Example 1), 0.1 gram (0.0003 mole), was taken up in 10 mL of chloroform (available from EM Sciences). The resulting solution was cooled to 0 °C in an ice bath and 0.09 gram (0.0004 mole) of 3- chloroperoxybenzoic acid (available from Aldrich Chemical Company) was added. Upon completion of addition, the resulting mixture was stirred for ten minutes and then the ice bath was removed. The reaction mixture was allowed to warm to ambient temperature where it stirred for 35 minutes. At the conclusion of this period, the reaction mixture was poured into a solution of 25 mL of chloroform and 10 mL of aqueous 5% sodium hydroxide. The organic layer was separated, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.15 gram of compound 183; mp 81-87°C. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 8

This example illustrates one protocol for the preparation of (2-(4-((4,6- dichloronaphthyloxy)methyl)phenoxy)ethyl)diethylamine (Compound 216).

Step A 4,6-dichloronaphthol

This compound was prepared in the manner of Step B, Example 1, using 5.0 grams (0.029 mole) of 6- aminonaphthol, 200 mL of acetonitrile, 4 grams (0.03 mole) of copper (II) chloride, and 3.3 grams (0.032 mole) of t-butyl nitrite. The yield of the title compound was 1.4 grams. Step B Compound 216

This compound was prepared in the manner of Step E, Example 1, using 0.4 gram (0.0022 mole) of 4,6- dichloronaphthol, 0.49 gram (0.0022 mole) of (4-(2-diethylamino)ethoxy)phenyl)methan-l-ol, 80 mL of THF, 0.5 gram (0.0025 mole) of tributylphosphine, and 0.55 gram (0.0022 mole) of 1- l'(azodicarbomyl)dipiperidine. The yield of Compound 216 was 0.3 gram. EXAMPLE 9

This example illustrates one protocol for the preparation of (2-(4-(((4-10 chloronaphthyl) amino )methyl)phenoxy)ethyl)diethylamine (Compound 84).

A stirred solution of 0.2 gram (0.0001 mole) of 4-(2-(diethylamino)ethoxy)benzaldehyde (prepared in the manner of Step A, Example 3), 0.22 gram (0.0001 mole) of l-amino-4-chloronaphthalene (available from Aldrich Chemical Company), and one drop of p-toluenesulfonic acid monohydrate (available from Aldrich Chemical Company) in 5 mL of toluene was heated at reflux for ten hours. At the conclusion of this period, the reaction mixture was concentrated under reduced pressure, yielding a residue. The residue was taken up in 5 mL of methanol and about 0.2 grams (0.004 mole) of sodium borohydride was added. The resulting mixture was stirred at ambient temperature for about 18 hours. After this time, the mixture was quenched with water and extracted with several portions of diethyl ether. The extracts were combined, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.8 gram of Compound 84. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 10

This example illustrates one protocol for the preparation of (2-(4-(((4-chloronaphthyl)amino )methyl)phenylthio )ethyl)diethylamine (Compound 71). Step A (4-(2-diethylamino)ethylthio)phenyl)methan- 1 -ol

Under a nitrogen atmosphere, 0.6 gram (0.0 17 mole) of lithium aluminum hydride (available from Aldrich Chemical Company) was taken up in 20 mL of THF. The resulting mixture was stirred to effect dissolution and a solution of one gram (0.007 mole) of2-mercaptobenzoic acid (available from Aldrich Chemical Company) 10 mL of THF was added. The resulting was stirred for 70 minutes. At the conclusion of this period, the solution was cooled in an ice bath and 10 mL of ethyl acetate was carefully added during a 30 minute period. Upon completion of addition, 5 mL of water followed by 1.3 grams (0.008 mole) of 2-(diethylamino)ethyl chloride hydrochloride was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. After this time, about 10 mL of aqueous 10% sodium hydroxide followed by an addition 10 mL of ethyl acetate was added. The resulting mixture was filtered. The organic layer of the filtrate was separated from the aqueous layer, washed with an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered, yielding 3.32 grams of a yellow liquid. The yellow liquid was purified by column chromatography on silica gel, yielding 0.5 gram of title compound. The NMR spectrum was consistent with the proposed structure.

Step B 4-(2-(diethylamino)ethylthio )benzaldehyde

Under a nitrogen atmosphere, a stirred solution of 0.2 mL (0.003 mole) of dimethyl sulfoxide (DMSO, available from Aldrich Chemical Company) in 10 mL of methylene chloride of was cooled to -60°C and 0.2 mL (0.002 mole) of oxalyl chloride (available from Aldrich Chemical Company) was added. The resulting solution was stirred at -60°C for 15 minutes. At the conclusion of this period, a solution of 0.5 gram (0.002 mole) of (4-(2-diethylamino)ethylthio )phenyl)methan-l-ol in about 20 mL of methylene chloride was added. The mixture was stirred at -60°C to -40°C of 30 minutes and 1.5 mL (0.011 mole) of triethylamine was added. Upon completion of addition, the reaction mixture was stirred at -40°C for 1.5 hours. At the conclusion of this period, the reaction mixture was filtered through a silica gel plug. The filter cake was washed with one 150 mL portion of ethyl acetate. The filtrate was concentrated under reduced pressure, yielding 0.2 gram of title compound. The NMR spectrum was consistent with the proposed structure.

Step C Mixture of (2-( 4-(2-aza-2-( 4-chloronaphthyl)vinyl)phenylthio

)ethyl)diethylamine and Compound 71 A solution of 0.2 (0.001 mole) of 4-(2-15 (diethylamino)ethylthio)benzaldehyde, 0.2 gram 6-amino-4- chloronaphthalene, 0.4 gram (0.002 mole) of sodium triacetoxyborohydride and 10 drops of glacial acetic acid in 10 mL of DCE was stirred at ambient temperature for about 18 hours. At the conclusion of this period, 50 mL of 10% aqueous sodium hydroxide followed by 75 mL of ethyl acetate was added. The organic layer was separated from the aqueous layer and filtered through phase separated filter paper, yielding 0.4 gram of crude product. This crude product was combined with 0.1 gram of crude product prepared in a similar experiment to yield a total of 0.5 gram of crude product. The 0.5 gram of crude product was purified by column chromatography on silica gel, yielding 0.1 gram of mixture of (2-(4-(2- aza-2-( 4-chloronaphthyl)vinyl)phenylthio)ethyl)diethylamine and Compound 71. The NMR spectrum was consistent with the proposed structure.

Step D Compound 71

A stirred solution of 0.1 gram (0.0008 mole) of borane-dimethylamine complex (available from Aldrich Chemical Company) and 0.1 gram (0.0003 mole) of the mixture of (2-(4-(2-aza-2-(4- chloronaphthyl)vinyl)phenylthio)ethyl)diethylamine and Compound 71 in 2 mL of glacial acetic acid was heated at 60°C for three hours. After this time, the reaction mixture was allowed to cool to ambient temperature and 5 ml of ethyl acetate was added. The resulting mixture was washed with an aqueous 10% sodium hydroxide solution. The organic layer was separated from the aqueous layer and filtered through phase separation filter paper, yielding 0.1 gram of an oil. The oil was purified by column chromatography on silica gel, yielding 0.1 gram of product. The 0.1 gram of product was combined with 0.1 gram of product from a previous experiment to yield 0.2 gram of Compound 71. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 11

This example illustrates one protocol for the preparation of diethyl(2-( 4-((2,3,4- trichlorophenoxy)methyl)phenoxy)ethyl)amine (Compound 308) . Step A (2-( 4-chloromethyl)phenoxy )ethyl)diethylamine hydrochloride

Under a nitrogen atmosphere, 2 mL (0.027 mole) of thionyl chloride (available from J. T. Baker Inc.) was added dropwise to a stirred solution of 5.8 grams (0.026 mole) of 4-(2- (diethylamino)ethoxy)benzaldehyde (prepared in the manner of Step A, Example 3) in 150 mL of methylene chloride. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 2.5 hours. After this time, the reaction mixture was heated to 50°C and the solvent was removed under reduced pressure, yielding 7.2 grams of title compound. The NMR spectrum was consistent with the proposed structure.

Step B Compound 308

A stirred solution of 0.3 gram (0.001 mole) of(2-(4-chloromethyl)phenoxy)ethyl)diethylamine hydrochloride, 0.2 gram (0.0009 mole) of 2,3,4-trichlorophenol (available from Aldrich Chemical Company), 0.9 gram (0.003 mole) of cesium carbonate (available from Aldrich Chemical Company) and a catalytic amount of sodium iodide (available from Aldrich Chemical Company) in 10 mL of acetone (available from J. T. Baker Inc.) was heated to 60 C for about 18 hours. After this time, the solvent was removed under reduced pressure and about 1 0 mL of methylene chloride was added. The resulting solution was filtered, and the filtrate was filtered through a silica gel pad, yielding 0.2 gram of Compound 308. The NMR spectrum was consistent with the proposed structure. EXAMPLE 12

This example illustrates one protocol for the preparation of diethyl(2-( 4-((2,5- difluorophenoxy)methyl)phenoxy)ethyl)amine (Compound 346).

This compound was prepared in the manner of Step B, Example 11, using 0.3 gram (0.001 mole) of(2- (4-chloromethyl)phenoxy)ethyl)diethylamine hydrochloride, 0.1 gram (0.0009 mole) of 2,5- difluorophenol (available from Aldrich Chemical Company), 0.9 gram (0.003 mole) of cesium carbonate and a catalytic amount of sodium iodide in 10 mL of acetone. The yield of Compound 346 was 0.2 gram. The NMR spectrum was consistent with the proposed structure.

EXAMPLE 13

This example illustrates one protocol for the preparation of l,2-dichloro-5-{ [ 4-( 4- ethylpiperazinyl)phenyl]methoxy} naphthalene (Compound 355).

Step A 4-piperazinylbenzonitrile

Under a nitrogen atmosphere, a stirred miture of 10.0 grams (0.055 mole) of 4-bromobenzonitrile (available from Aldritch Chemical Company) and 23.7 grams (0.28 mole) of piperazine (available from Aldritch Chemical Company was heated at 120°C for about 45 hours. After this time, the reaction mixture was taken up in 150 ml of aqueous 10% sodium hydroxide. The resulting solution was extracted with three 50 mL portions of methylene chloride. The combined extracts were washed with one 50 mL portion of an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 8.6 grams of a green paste. The green paste was purified by column chromatography on silica gel, yielding 3.8 grams of a paste. The paste was taken up in 50 mL of diethyl ether. The resulting solution was warmed on a rotovap and decanted away from the insoluble paste. The decantate was concentrated, yielding 3.2 grams of the title comound. The NMR spectrum was consistent with the proposed structure.

Step B 4-(4-ethyl)piperazinylbenzonitrile

Under a nitrogen atmosphere, a stirred solution of 3.16 grams (0.017 mole) of 4-piperazinylbenzonitrile, 2.0 mL (0.025 mole) of iodoethane (available from Aldritch Chemical Company), and 7.1 mL (0.051 mole) of triethylamine in 50 mL of THF was heated at reflux for about three hours. At the conclusion of this period, the reaction mixture was allowed to cool to ambient temperature and lOOmL of water was added. The resulting solution was extracted with two 50 mL portions of diethyl ether. The combined extracts were washed with 100 mL portion of water, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 3.2 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 2.9 grams of tilte compound. The NMR spectrum was consistent with the proposed structure.

Step C 4-(4-ethylpiperazinyl)benzaldehyde

Under a nitrogen atmosphere, a stirred solution of 2.8 grams (0.013 mole) of 4-(4- ethyl)piperazinylbenzonitrile in 35 mL of anhydrous toluene (available from Aldrich Chemical Company) was cooled to -70°C and 12 mL (0.02 mole) of diisobutylaluminum hydride (1.5M in toluene, available from Aldritch Chemical Company) was added dropwise at a rate to maintain the temperature below -60°C during about a 15 minute period. Upon completion of addition, the reaction mixture was stirred at -60°C for two hours. At the conclusion of this period, 10 mL of methanol was added dropwise followed by 10 mL of water. The resulting solution was allowed to warm to ambient temperature. Once at the prescribed temperature, 10 mL of methylene chloride was added. The resulting mixture was filtered and the filtrate was transferred to a separatory funnel. The organic layer was separated from the aqueous layer, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 1.6 grams of an orange paste. The orange pasted was was filtered through a silica gel plug. The filter cake was washed with one 75 mL portion of methylene chloride followed by one 50 mL portion of a 5% methanol/95% methylene chloride solution. The filtrate was concentrated under reduced pressure, yielding 0.5 gram of title compound. The NMR spectrum was consistent with the proposed structure.

Step D [4-(4-ethylpiperazinyl)phenyl]methan-l-ol

This compound was prepared in the manner of Step A, Example 5, using 0.4 gram (0.019 mole) of [4-(4- ethylpiperazinyl)benzaldehyde and 0.4 gram (0.01 mole) of sodium borohydride in 40 mL of absolute ethanol (available from J.T. Baker Inc.) The yield of the title compound was 0.3 gram. The NMR Spectrum was consistend with the proposed structure.

Step E Compound 355

This compound was prepared in the manner of Step E, Example 1, using 0.23 gram (0.0011 mole) of 5,6-dichloronapthol, 0.25 gram (0.0011 mole) of [4-(4-ethylpiperazinyl)phenyl]methan-l-ol, 0.36 mL (0.0014 mole) of tributylphosphine, and 0.35 gram (0.0014 mole) of l-l'(azadicarbomyl)dipiperidine in 15 mL of THF. The yield of compound 355 was 0.04 gram. The NMR spectrum was consistent with the proposed structure. EX AMPLE 14

This example illustrates one protocol for the preparation of 5-{ [4-(8-aza-l ,4-dioxaspiro[ 4.5]dec-8- yl)phenyl]methoxy} -1 ,2-dichloronaphthalene (Compound 362)

Step A 5-[( 4-bromophenyl)methoxy ]-l ,2-dichloronaphthalene A stirred mixture of 4.0 grams (0.019 mole) of 5,6-dichloronapthol in 60 mL of THF was cooled in an ice bath and 1.1 grams (0.023 mole) of Sodium hydride (60% dispersion in mineral oil) was added during a ten minute period. Upon completion of addition, the mixture was stirred for twenty minutes. After this time, a solution of 5.8 grams (0.023 mole) of 4-bromobenzyl bromide (available from Aldrich Chemical Company) in 40 mL of THF was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for seven days. After this time, the reaction mixture was taken up in 100 ml of water. The resulting solution was extracted with two 200 mL portions of diethyl ether. The combined extracts were washed with one 7 5 mL portion of a 10% aqueous lithium chloride solution, dried with sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding the crude product. The crude product was triturated with a mixture of diethyl ether and petroleum ether. The resulting solid was collected by filtration, yielding 5.3 grams of the title comound. The NMR spectrum was consistent with the proposed structure.

Step B Compound 362

To a 100 mL roundbottom flask was added 0.02 gram (0.00002 mole) of tris(dibenzylideneacetone )dipalladium (available from Strem Chemical, Newburyport, MA), 0.04 gram (0.00006 mole) of racemic 2,2'bis(diphenylphosphino)-l,l'-binaphthyl (available from Strem Chemical), and 35mL of toluene. The resulting mixture was evacuated and then backfilled with nitrogen. This evacuation and backfill procedure was repeated two more times. The resulting mixture was strirred at ambient temperature for 30 minutes. After this time, 0.75 gram (0.002 mole) of S-[(4-bromophenyl)methoxy]-l,2- dichloronaphthalene, 0.52 gram (0.004 mole) of 4-piperidone ethylene ketal (available from Lancaster Synthesis Inc.), and 0.38 gram (0.004 mole) of sodium t-butoxide (available from Aldrich Chemical Company) were added to the 100 mL round bottom flask. Upon completion of addition, the above set forth evacuation and backfill procedure was repeated three times. The reaction mixture was heated to 80-85°C were it stirred for 4 to 4.5 hours. After this time, the heating was discontinued and the reaction mixture was stirred for about 18 hours. After this time, the reaction mixture was filtered through a celite pad and rinsed with toluene. The filtrate was concentrated under reduced pressure yielding the crude product. The crude product was purified by column chromatography on neutral alumina (deactivated with 6% water), yielding 0.7 gram of title compound. The NMR spectrum was consistent with the proposed structure. It is well known to one of ordinary skill in the art that the compounds of formula I of the present invention can contain optically-active and racemic forms. It is also well known in the art that the compounds of formula I may contain stereoisomeric forms and/or exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic orstereoisomeric form, or mixtures thereof. It should be noted that it is well known in the art how to prepare optically-active forms, for example by resolution of a racemic mixture or by synthesis from optically- active starting materials. Representative compounds prepared by the methods exemplified above are listed in Table 1. Characterizing properties are given in Table 2.

BIOLOGICAL DATA Solvent: Acetone + 2000ppm Rapeseedoil-methylester (RME)

To produce a suitable preparation compounds 21, 178 and 223 of the invention were independently dissolved in acetone containing 2000ppm RME. The active compound solution was pipetted onto a glazed tile and, after drying, adult mosquitoes of the species:

- Anopheles gambiae (target-site-resistant and metabolic-resistant strain: RSPH), - Anopheles gambiae, (target-site-resistant strain Tiassale)

- Anopheles gambiae (target-site-resistant strain: VK7),

- Anopheles funestus (metabolic-resistant strain FUMOZ-R) and

-Culex quinquefasciatus (metabolic-resistant to DDT; strain POO), and adult cockroaches of the species:

- Blattella germanica (susceptible strain)

- Blattella germanica (metabolic resistant strain: Ukraine; resistant to Deltamethrin, Propoxur, Bendiocarb, Fenthion and DTT; the Ukraine strain is based on the place where specimens of these cockroaches were collected in 2012. The detailed collection area was Odessa at the Black Sea in the Ukraine. The strain was introduced into the insect rearing of the applicant. Extensive susceptibility assays of specimens of the Ukraine strain revealed different results in comparison to fully susceptible strains.) were placed onto the treated tile (each strain was tested on separate tiles). The exposition time for mosquitoes was 30 minutes and for cockroaches 60 minutes. 24 hours after contact to the treated surface, the knock-down proportion of the test animals in % was determined. Here, 100% (effect) means that all mosquitoes resp. cockroaches have been knocked-down; 0% (effect) means that none of the mosquitoes resp. cockroaches have been knocked-down.

Example 21 Example 178

Table 3: Efficiency of compounds 21, 178 and 223 against Anopheles gambiae RSPH

Table 4: Efficiency of compounds 21, 178 and 223 against Anopheles gambiae strain Tiassale

Anopheles gambiae

Tiassale

Example Compound concentration [mg/m ² ] Knock-Down after 24 hours

[%]

compound no. 21 20 13 compound no. 21 2 0 compound no. 178 20 100 compound no. 178 2 0 compound no. 223 20 25 compound no. 223 2 0

Table 5: Efficiency of compounds 21, 178 and 223 against Anopheles gambiae VK7

Anopheles gambiae VK7

Example Compound concentration [mg/m ² ] Knock-Down after 24 hours

[%]

compound no. 21 20 20

compound no. 21 4 20

compound no. 178 20 100

compound no. 178 4 60

compound no. 223 20 0

compound no. 223 4 10

Table 6: Efficiency of compounds 21, 178 and 223 against Anopheles gambiae FUMOZ-R

Anopheles FUMOZ-R

Example Compound concentration [mg/m ² ] Knock-Down after 24 hours

[%]

compound no. 21 20 0

compound no. 21 4 0

compound no. 178 20 100

compound no. 178 4 25

compound no. 223 20 0

compound no. 223 4 0

Table 7: Efficiency of compounds 21, 178 and 223 against Culex quinquefasciatus P00

Culex quinquefasciatus P00

Example Compound Knock-Down after 24 concentration hours [ ]

[mg/m ² ] compound no. 21 20 11

compound no. 21 4 22

compound no. 178 20 89

compound no. 178 4 78

compound no. 223 20 44

compound no. 223 4 33

Table 8: Efficiency of compounds 21, 178 and 223 against Blattella germanica (susceptible strain)

Blattella germanica

(susceptible strain)

Compound concentration Knock-Down after 24 hours

Example [mg/ni ² ] [%] compound no. 21 200 10 compound no. 178 200 90 compound no. 223 200 100

Table 9: Efficiency of compounds 21, 178 and 223 against Blattella germanica strain Ukraine

Blattella germanica Ukraine

Compound concentration Knock-Down after 24 hours

Example [mg/ni ² ] [%] compound no. 21 200 10 compound no. 178 200 80 compound no. 223 200 100 Table 1

lusectidckl Optionally Siibsttttitod Benzenes

Foimul !

Li and D are i 1; R k ¥11: T in O: ;n is 2: R ¹ is N¾C¾¾_

(■mrnd No. A

3

and D are Η ^» R is HI; T is D, m is 2; l< ^: ib N(C¾H

Cmmilkk ^{" "} 4

Table 1 (coninued)

Λ i UILii .....I i > ^; I ^; Rj \h \_ ^: * : >-n κ ^ϋ_1·. ^iKyiki Table 1 (eoiitiniied)

Table I (caetiiflied)

Λ is ΗΠ; 0 and D arejlL is HI^T^OL ^" CJfe nisi

Qn

Formula I

CtnpAMo, I

Table 1 (continued)

Immshl

A is Fil l ; 8 mi P are H; R is HI; T is O; n is 0; R? Is Ϊ-1 ; Y and Z are H

43 o CA 4- r

44 0 4-C1

47 2 N(C ₃ I¾ -OC,H ₄ 0- 4-CI

49 2 Μ(¾Ι¾ -NHCA- 4-Cl 50 2 N(C ₃ I¾ ₂ oc¾ 4-Cl 51 o 4-Cl 52 N(C ₂ HA C¾ 4-Cl 53 S0 ₂ 4-Cl S4 CO 4-Cl 55 M{C¾) ₂ CF* 4-Cl 56 -CH{OH} 4-Cl 5? M{CA) ₂ -c¾s- 4-CI 58 N(C ₃ H _S ) ₂ a¾so 4-Cl 59 Ν{€¾1¾ CH _a S<¾ 4-Cl m -GC¾ -CH _j NH* 4-Cl

Eflnnala l

Table 1 (cOTifintied)

71 2 S N -N(CA)a _. 4-Cl H H

77 2 0 M 4-Br H 11

78 2 o N 4-Br H H

79 2 o N - <boiiroiiyi)2 4-Br H H

82 2 0 N 4-CI H Ή

83 2 0 N -N(C¾) ₂ H H

84 2 0 N 4-CI H H

85 2 o N 4-Cl H H

Chloride Salt

«6 2 0 N ^■ N( ⁽ ¾ 8-Cl H H

87 2 0 N -N(!s»propyJ)2 4-Cl II H gg 2 0 N -N(C ₄ I¾ 4-Cl H H

89 2 0 N 4-Cl H II Table 1 (fit &m )

94 3 0 N -Ν(<3¾¾ 4-Cl H H

95 3 0 N 4-Cl H H

96 3 0 N 4-Cl H H

-O

105 o o 4-Cl H II Table 1 (coataued)

Eoinmlaj

109 2 O o -oo 4-Cl H H

1 14 2 0 o 4-Cl If H

115 2 0 0 -oo 4-CJ H H Table 1 (catitinued)

A is Fill; B and. D are II; R is F!I; n is 1 ; R ² is i-E ¹ ;

119 2 0 o 4-Cl H II

121 - 2 o 0 4-Cl H H

126 2 o o 4-Cl II H

IZJ 2 0 0 -o-o 4-Cl H H

128 2 0 o 4-Cl H H

129 2 o o CO" ^' 4-Cl H H

130 2 0 0 4-Cl H H

Table 1 (continued)

A is Fill; B and D we H; R is Fit n Is 1 ; ^J is l-R;

C mndWtt. m 1 u 1 Y Z

138 2 O O 4M 1 H H

⁽ TO

139 2 0 0 ^{3 H H}

140 2 O O 4-CI H H

141 2 O 0 4-0

-0 H H

142 2 o o i-CI 6-Cl H

-o

143 2 o 0 4-a H H Τ¾Μβ 1 (contiBiietl)

154 2 0 0 _cf 4-Cl H H

155 2 o o - 4-Cl H H

-ocf Tabte 1 (continued)

FopanJa l

Cm ^■ Z

162 2 0 0 4-Cl H H

-OO

164 2 o o 4-Cl H H

168 2 0 0 4-Cl H H

00 Ta e 1 {continued)

177 2 0 0 -OCA 4-Cl H H

178 2 o o 4-a H e

179 2 0 ^■ *CCA¾(oc¾ 4-a H H

ISO 2 o o -MHC ₆ ¾ 4-a H II

181 2 0 o 4-a

-€ 6-Cl H

182 2 0 0 4-a 6-Cl H

Hydrochloride Salt

184 2 0 0 -NHCCjH,) 4-a H H

185 2 o 0 4-Cl H H

Hyireefiiari fe Salt Table 1 (continued)

Formula!

A Is FBI; B an4 1) are H; R " i ^* s· FI1; n is 1; R ² is l-R ⁴ ;

Cinpnid Wo. m I H X 2

186 2 0 0 -N(C ₂ H _S ) ₂ 2-CI H H

117 2 0 0 3-Cl H H

118 2 0 0 4-Cl H H

189 2 0 0 4-CI H H

Chloride Salt

190 2 0 0 -H(C ₂ H _s )CCia _j 4~ci H H

Wide Silt

191 2 0 o -NCCHjCNCC _j Hp) 4-Cl H H

192 2 0 0 -N(C ₂ H ₅ XCH ₃ ) 4-CI H H

193 2 0 0 -N(¾HsKCH3) 4-Cl H H

Hy ΑΜΜ« « Salt

197 2 0 0 4ί€Η,σ;0€1¾ 4-Ci H H

198 2 o o 4-Ct H H

205 2 0 0 -N CH ₃ )Ci ₇ H _3j 4-Ct H H

2m 2 0 0 -N(C ₂ I¾ 5-Cl H II

207 2 o 0 6-Cl H H

208 2 o 0 7-Cl H H

2©9 2 0 0 8-Cl H H

210 2 o o -N(C ₃ H ₅ ¾ 2-Cl 4-Cl H

211 2 o o 2-Cl 5-a H

212 2 o o 2-Cl 6-CI H

213 2 o 0 2-Cl S€l H

214 2 o 0 4-Cl 5-Cl 6-Cl

215 2 o o ^■ M 4-Cl 5-Cl H

2W 2 0 o 4-CI &C1 H

217 2 0 o 4-Cl 6-Cl H

Chloride Sait

218 2 o 0 4-Cl 6-Cl H

Sulfonic Silt

219 2 0 0 •N(C» 4-Cl 6-Cl H

Trifiuoroaceiic Salt

220 2 0 0 -N(CA) ₂ 4-Cl 6-Cl H

MdhylbooHicuilfcnic

221 2 o o 4-CI 7-Cl H T& -e 1 {continued)

EoimB].a.l

A Is Fill; B and D are I¾ R is HI; n is i; R ² is 1-R«j

Cppnd No. ffi I M x Ϊ 2

222 ^" 2 0 0 4-Cl 8-Cl H

223 2 0 0 5-Cl 6-Cl H

224 2 0 0 5-CI 6-Cl H

Chloride salt

225 2 0 0 •N(C¾ 5-CI 6-Cl H

Phosphoric salt

226 2 0 0 -fflffll 5-C! 6-Cl H

227 2 0 0 6-Cl 8-C1 H

228 2 0 0 -N(CA) ₂ 4-Br il H

229 2 0 0 6-Br H e

230 2 0 0 S-Br H H

231 2 0 0 4-F H H

232 2 0 0 4-CF ₃ H H

233 2 0 0 "Ν·(€¾Ι¾ H H

234 2 0 0 N<C¾) _a «¾ H H

235 2 0 0 -N<C£¾ 4-OCB5 H H

236 2 0 0 4-OCH ₃ H H

Chloride Salt

243 2 0 0 ■» H

-o-^^-c, H

244 2 0 0 - CCJH^ 5-Cl H

245 2 0 0 5-Cl Wftr H

246 .2 0 0 ^■ N{C ₂ H _J ) _J 5-Cl 6-1 H

Tab!e t (continued)

Fjg iiJai

A is Fill; B and D are H; ft is f 1¾ n is 1; R ¹ is 1-R ⁴ ;

257 2 O s -NCC ₂ H ₃ } ₂ 5-Cl 6-Cl H

25S 2 0= SO, -N(C ₂ H _S ) ₂ 5-Cl 6-a H

259 3 o o 4-Cl H H

260 4 o 0 4- H H

Please note that Compound No.261 is a mixture of Compound 212 aid (2-<4-

A is Fffl; R is Fl; T is Q; m is 2; R ¹ is -W(C¾) ₂ ;. R* is 1-R"; X is 4-Cl; Y and Z are H

CfflEgdNo, 1 B a u

267 2-Cl H 1 N

268 3-Cl H 1 N

269 2-Cl 3-Cl 1 N

270 2-Cl 6-CI 1 N

N

AatidDareB;RtsFII; T is O m is 2; R ¹ is M(Cfi ₅ _

273 5-Fffl 1 N 1-R ³ 4-Cl H H

274 6-ΠΠ 1 N 1-R ³ 4-Cl H H

Formula 1

A is Fill; B and DareHjl is HI; T is O; m is 2; ii is 1; II is O TaMs 1 (continued)

CmuBd o. ^■ ST ^■■ «:

275 -o-

EorpBlal

Λ is FIII; B and P ars H; R is HI; m is 2; T is 0; R ¹ is -NCC^; ills 1; K ² is t-R ³ ;

_!iEiAM _ J L

284 N 4-C1 H HE

285 N 2-a 3-CI H

286 N 2-a 3-Cl 4-CI

287 N 2-a 4-a H

211 2-a 4-a 5-Cl

289 N 3d 4-a H

290 N 3-Cl 5-CI H

291 N H H

292 N 2-CA -CI H

293 N 4-Cl H

294 N 2-P ^" 3-F H

295 N 2-F 3-F 4-F

296 N 2-P 4-F H

305 O 2-a H H

30* 0 4-a H H

307 0 2-a 3-a BE

308 0 2-a 3-a 4-a

309 0 2-CI 4-a If TaMe 1 (continued)

A is PHI; B and D are H; R is F¾ m Is 2; T is O; R ¹ is -N(C ₂ ¾) _¾ ; ti ls 1; R ² is rf;

u I L w

310 0 2-Cl 4-Cl 5-Cl

311 0 2-Cl 5-Cl H

312 O 2-Cl 6-CI H

313 0 3-Cl 4-Cl H

314 0 3-Cl 5-Cl H

315 0 2-Cl 4-Br H

316 0 2-Cl 6-Br H

31? 0 2-Cl 5-CH ₃ e

318 0 2-C(C¾) ₃ H H

319 0 3-C(CH ₃ ¾ H H

320 0 4-C(CH ₃ ) ₃ H H

321 0 2-isopropyl H H

342 0 2-Br 6-Br H

343 0 2-Br 4-CH, H

344 o 2-Br 4-CH, 6-Br

345 0 2-F 3-F H

346 0 2-F 5-F H Tsble 1 (continiei)

Λ isH!l; Bund D arc H; R is FH; m is 2; T is 0; R ¹ is -NCCftfe n is 1; R ² is rf;

JBiMa U J ^{" *} L W

347 0 2-F 6-F H

348 0 3-F 5-F H

349 O 4-F 6-F H

350 0 3-F 4-F 6-F

Formula I

A is Fill; 1 mi P are H; n is IjUisOjR* Is 1-R*

Cmpnd £ 2 Ϊ I

355 5-Cl 6-Cl H

356 -oM- 5-Cl 6-a H

357 5-a 6-Br H

358 5-Cl 6-a H

359 -oo 5-Cl 6-Cl H

360 -«5 - 5 6

CB, -a -a H

Table 1 (continued)

fined i ^' ϊ z

366 5-Cl 6-a H

-O

367 5-a 6-a H

379 2 4-a H CharacteiMng Data

Croud No Emg cj feimnla elthuz Point^hvaical State

1 C _B H _2? GI1¾0 OIL

7 SOLID

8 C ₂₄ ¾C1N0 ₂ SOLID

9 CjjHaNA SOLID

10 SOLID

1 1 C _¾ ¾C!NA OIL

12 C _2J H _3J FNA OIL

13 OIL

14 LIQUID

15 CANjO LIQUID

16 SOLID

17 C»H _M C1 A OIL

18 C„H _M C1N ₃ 0 LIQUID'

19 C^CIN 93-95 *C

20 Cs ^' HjiClN _j O OIL

21 SOLID

22 C _A ¾N OIL

23 OIL

24 C _IJ H _J F _S NO _J S

39 OIL

40 OIL

41 CjjHjiCIN FOAM

43 C _|¾ H _|7 BrO OIL

44 C„H _LS C ^. NA 220 *0

45 C _2! ¾ ₁ C10 ₃ 106-107 ^e C

46 OIL

47 C ₁₄ H _a ClN0 ₃ OIL

63 C ₂₃ H ₂₅ C1N _S 0 ₂ 123-125 °C Table 2 (continued)

Earoiiical Foimuli

CnH _u C > 92-93 °C

C _ls H„ClFNO SOLID

C _J OH _JT CSNA 122424 *C

C^ _S OINAC! SOLID

¾H„C1N ₄ 0 ₂ 159-161 °C

C _a H„CiNA 104-106 °C

C _A H _L? C A SOLID

C _B ¾C1N ₂ S OIL

C _I HaB£ O OIL

OIL

C _JT H _¾ N,0 LIQUID

OIL

C _B H„NA SOLID

C _2t ¾BfN,0 LIQUID

C _a H ₂₇ BrN ₂ 0 SOLID

C _{2J 3t} BrNjO SOLID

¾¾ ₅ ΒΓΜΑ SOLID

CJ¾ ₅ Bi*f ₂ 0 SOLID c _a ¾ciw ₂ o 184-187 °C

CaHaCINjO LIQUID

OIL

CjgHnCINjO.ClH

C _B i„ClN ₂ 0 PASTE

C _B H _3i CiK ₂ 0 SOLID c ₂ M ₃₅ cm _z o LIQUID

SOLID

CaH _¾ CIN ₂ 0 SOLID

CACMA 102-104 °C

OIL

Cj ₄ ¾CiN ₂ 0 SOLID

C ₂ ,H _J5 C1N ₂ 0 SOLID

LIQUID

LIQUID

LIQUID

LIQUID

SOLID

SOLID

89-90 °C

OIL

C^GI O, OIL

OIL

60-65 °C

C _¾ ¾C1N0 ₂ OIL Table 2 (continued)

CnipdNo.

107 OIL

108 C _2T B _¾ C1N0 ₄ 85-17 °C

109 C _s ¾C!N0 ₂ 89-91 °C

1 10 112-115 «C in C,,H ₉ ClNO, 88-91 °C

1 12 SOLID

113 C _2S ¾C!NA OIL

114 OIL

115 QSHBCI A OIL

116 CaftsClN j OIL

117 C^CINA 71-73 °C in CaHwClNOjS OIL

119 OIL

120 C _a ¾Ci ¾ OIL

121 LIQUID

122 C^CWO, 88-90 °C

123 OIL

124 OIL

125 C _¾ ¾ ₀ C!NO ₂ OIL

126 SEMI SOLID

127 CJHjsClNA 91-92 °C

121 SYRUP

129 <¾Η»,αΝΑ SYRUP

130 C _B H _S CI1¾N0 ₃ SYRUP

131 5i-59 ^e C

132 OIL

133 C»¾CI ₂ O _J OIL

134 C _a H _a CiN0 96-98 ^Q C

135 OIL

136 cXciNOj 95-96 ⁵ C

137 CMH _B CI _J O, 87-1.8 °C

138 C»H _>7 C1N,0, OIL

139 C _n ¾Cl O, OIL

140 CHfcClNOj OIL

141 C _H H _M CiNOj 75-77 °C

142 « 152454 °C

143 C„H ₃₂ C1N0 ₂ OIL

144 C _s H _a ClN0 ₂ S S3-S6 °C

145 CaHjjClNOj OIL

146 on:

147 C _x ¾ ₀ CWO ₂ OIL

14S C _M H _a C!N0 ₂ OIL

149 C»¾C!NA 131435 °C Tab!e 2 (oontiimed)

CmpdNo Empirical Formula MeltiB f ointfjPteical State

150 CuHaClNOi OIL

151 cyt^ci A OIL

152 Cj _f H»CiNjO, 133-136 °C

153 CaHuCIN OIL

154 C _¾ H _J4 ClNO, 90-91 °C

155 C _K ft _g ClF ₃ NA 80-82 °C

156 C _2G ¾QFNA 120-121 °C

157 CARINA OIL

158 C _M I½C1 ₂ N ₂ 0 ₂ OIL

159 C^H _M CJ 0 ₄ OIL

160 C^CINA OIL

161 C _K ¾C1N0 ₃ 123425 ^E C

162 Ο _ί ,Κ,,ΟΙΝ OIL

163 c„H _r aN OIL

169 CnHjiClN OIL

170 C _¾ H _¾ CINO _z OIL

181 OIL

1S3 ¾¾<¾ΝΟ, 81-87 °C

184 CjiHuCINO, LIQUID

185 C _¾ H _B €fM¾..C! 201-203 °C

186 C _2J ¾C1N0 ₂ LIQUID

187 C _2J ¾C1N0 ₂ OIL

188 C _2J ¾CINQ, OIL

189 C _B ¾C!N0 ₂ .CiH SOLID

190 C _j3 H ₂₇ ClN0 ₂ .l LIQUID

191 LIQUID

192 C ₁₂ H _M C1N0 ₂ SOLID

1» SOLID

194 C ₃ ¾CIN0 ₂ 84-15 °C

195 C _¾ H _¾ ClNO _s SYRUP

196 C ₃₅ H _¾ C3N0 ₂ OIL

197 C _H H _M CINO* OIL

198 C ₂ S¾C1N0 ₃ , SEMI-SOLID

199 138-145 ^Q C

200 C^H _jj ClNA OIL

201 C ₂₅ H ₃₀ C1NO _∑ OIL

202 C ₂₇ H _M C1N0, OIL

203 OIL Table 2 {eontinuM)

Cfflgd p Empirical Formula

204 C ₃₁ H _4S C1M0 ₂ OIL

205 C _iS ¾ClN0 ₂ 63-64 °C

206 LIQUID

207 C _B H _K C1N0 ₂ LIQUID

208 OIL

2» C _M ¾CI O _a LIQUID

IL

Table 2 (continued)

Cmoi No EmpMeal Fomula

269 SOLID

270 C ₂₃ H _e Cl ₃ N ₂ 0 SOLID

271 SOLID'

272 SOLID-

273 C _I9 H _J5 C1N,0 LIQUID

274 CaH-jCl aO LIQUID

279 OIL

280 C^^NA OIL

2S1 OIL

282 OIL

283 C _I9 H _JJ C1N ₂ 0 OIL

2S4 OIL

285 OIL

286 C _H H _B CI _{J J} O OIL

287 OIL

28S C _lf ¾cy¾0 OIL

289 C _R A ₄ Cl ₂ N ₂ 0 OIL

290 C^ _M CI _J N _J O OIL

291 LIQUID

292 C _M II,C1N ₂ 0 LIQUID

293 LIQUID

294 OIL

295 OIL

296 OIL

297 OIL

298 C _¾ H _A N ₂ 0 OIL

299 OIL

300 C,,¾N OIL

301 € _a l¾¾0 ₃ OIL

302 CjjHjj OIL

303 LIQUID

304 ^■ SOLID

305 c _lf ¾cwo ₂ SOLID Table 2 (continued)

Cmpd No

306 C _B ¾CIN0 ₂ SOLID

107 LIQUID

308 CuHaCyio, SOLID

309 C| ₉ H _S C1 ₂ N0 ₂ LIQUID

310 t _jp H _jj Ol _j I fO _j LIQUID

31 1 CKHBO _S NO, UQUID

312 LIQUID

313 SOLID

314 SEMI-SOLID

315 C,^¾sBiCI 0 ₂ SOLID

316 CnHjjBtCl Oi LIQUID

317 LIQUID

31S C\.H _{( (} N0 ₂ LIQUID

319 C _B ¾N0 ₂ SOLID

320 C _s ¾N0 ₂ LIQUID

321 C _B H _S1 N0 ₂ LIQUID

322 SOLID

323 W O, SOLID

324 SOLID

325 CJOHMNA LIQUID

326 LIQUID

327 CiiH _2i N ₂ Oj SOLID

321 SOLID

329 C _i5 ¾N0 ₃ LIQUID

330 LIQUID

331 € _s J¾M0 ₄ SOLID

332 C, _e ¾C!N0 ₂ LIQUID

333 C _2e ¾ClN0 ₂ SOLID'

334 C«¾CINA UQUID

335 LIQUID

336 LIQUID

337 ^" LIQUID

331 ¾¾,Ν0 ₂ SOLID

339 SOLID

3 § LIQUID

341 C _lt H _jj B¾»0 ₂ SOLID

342 LIQUID

343 € _¾ H _¾ BrN{¾ LIQUID

344 SOLID

345 C ₁₉ ¾F ₂ N0 ₂ SOLID

346 CuHaFjNO, LIQUID

34? C _lg H _¾ F ₂ N0 ₂ LIQUID

341 UQUID Ta e 2 (continued)

QirodMo 2¾Ba§§li@i¾ii3

349 LIQUID

350 LIQUID

351 LIQUID

352 LIQUID

353 SOLID

354 C½H ₁₄ C1,N ₂ 0 SOLID

355 Ca¾C¾ _s O SOLID

356 SOOD

35? C _s ¾BrCiN ₂ 0 150-151 °C

358 €¾i¾0LN ₂ O 142-145 °C

359 CACi^o 131-133 ^B C

3« yHaCljNjO 135-137 °C

361 SOL©

3·63 SOLID

36 <¼_¾«<¾Ν ₂ 0 SOLID

365 c _sl H _2s e¾N ₂ o SOLID-

366 € ₂₁ ¾£¾Ν ₂ 0 SOLID

267 CaHaCljNaO SOLID

361 C _¾ ¾CiJ¾Q SOLID

369 SOLID

370 CaHjjCljFNjO SOLID

371 CpiHjjCljNjO SOLID

372 OIL

373 OIL

374 C _i3 H _w CIN0 ₂ SEMI-SOLID

375 C _M H _M ONO _J OIL

376 C _a< H _s Cl _J N0 ₂ OIL

377 OIL

378 SOLID m

C^H _w CIN0 ₂ SOLID