USOO9426995B2

(12) United States Patent (10) Patent No.: US 9.426,995 B2 Slomczynska et al. (45) Date of Patent: *Aug. 30, 2016

(54) COMPOSITIONS AND METHODS FOR 2002fOO13326 A1 1/2002 Tiebes et al. CONTROLLING NEMATODES 2003/004.5546 A1 3/2003 Cai et al. 2003/0162812 A1* 8, 2003 Harmsen et al...... 514,340 2004/O127521 A1* 7/2004 Cai et al...... 514,341 (71) Applicant: Monsanto Technology LLC, St. Louis, 2004/0204461 A1 10/2004 Karp et al. MO (US) 2004/024.8950 A1 12/2004 Ishizuka et al. 2005, 0004.005 A1 1/2005 Kasibhatla et al. (72) Inventors: Urszula Slomczynska, Ballwin, MO 2009/0012031 A1 1/2009 Chinnaiyan et al. (US); Matt W. Dimmic, Maryland 2009/0048311 A1 2/2009 Williams et al. Heights, MO (US); Al Wideman, St. Louis, MO (US); William P. FOREIGN PATENT DOCUMENTS Haakenson, Jr., St. Louis, MO (US) EP O410551 A1 1, 1991 EP 0339854 B1 5, 1993 (73) Assignee: Monsanto Technology LLC, St. Louis, EP 141977O A1 5, 2004 MO (US) WO 87O6429 A1 11, 1987 WO 9519353 A1 6, 1995 (*)c Notice:- r Subject to any disclaimer, the term of this WO OO35285985.7969 A1 12/19986, 2000 patent is extended or adjusted under 35 WO 0.035913 A1 6, 2000 U.S.C. 154(b) by 0 days. WO WO O1? 66534 * 9, 2001 ... CO7D 295/205 WO O2/O76983 A1 10, 2002 This patent is Subject to a terminal dis- WO 0210O826 A2 12/2002 claimer. WO O3,O18008 A1 3, 2003 WO 2004058253 A1 T 2004 (21) Appl. No.: 13/763,087 WO 2004.110351 A2 12/2004 WO 2006O97030 A1 9, 2006 1-1. WO 2006 114400 A1 11, 2006 (22) Filed: Feb. 8, 2013 WO 2007043400 4/2007 O O WO 2007075459 A2 7/2007 (65) Prior Publication Data WO 2007 149395 A2 12/2007 WO 2008049864 A1 5, 2008 US 2013/021757O A1 Aug. 22, 2013 WO 2009100438 A2 8, 2009 Related U.S. Application Dat e pplication Uata OTHER PUBLICATIONS (63) Continuation of application No. 12/904,724, filed on Oct. 14, 2010, now Pat. No. 8,410,023, which is a Lankau et al. European Journal of Medicinal Chemistry, 42 (2007) continuation of application No. 12/703,750, filed on pp. 873-879.* Feb. 10, 2010, now Pat. No. 8,017,555. Plaskon et al. Tetrahedron, 64 (2008), pp. 5933-5943.* (60) Provisional application No. 61/151,482, filed on Feb. Ito et al. in Cancer Science 94(1), 3-8 (2003): 10, 2009 CAS RN 1071700-58-7, Accessed via STN Registry database, entry s dated Nov. 9, 2008. Accessed May 28, 2015.* (51) Int. Cl. CAS RN 314753-33-8, Accessed via STN Registry database, entry CO7D 413/04 (2006.01) CAS RN 312921-18-9. Accessed via STN Registry database, entry CO7D 413/06 (2006.01) dated Jan. 5, 2001. Accessed Nov. 24, 2015.* (52) U.S. Cl CAS RN310451-46-8. Accessed via STN Registry database, entry CPC A0IN 43/82 (2013.01); C07D 413/04 dated Dec. 21, 2000. Accessed Nov. 24, 2015.* ------(2013.01); Co7D 41306 (2013.01) Bridge et al., Musa Pest Fact Sheet No. 2, Nov. 1997. (58) Field of Classification search Barker et al., “Plant and Soil Nematodes: Societal Impact and Focus None for the Future,” 1994, J Nematol, 26(2): 127-137. See application file for complete search history. (Continued) (56) References Cited U.S. PATENT DOCUMENTS Primary Examiner — Alicia L Otton (74) Attorney, Agent, or Firm — Senniger Powers LLP: 3,192,103 A 6, 1965 Sousa et al. Molly B. Edwards 3,211,742 A 10, 1965 Lenaers et al. 3,218,331 A 11/1965 Eloy et al. 3,227,725 A 1/1966 Eloy et al. 3.264,318 A 8, 1966 Harmsen et al. (57) ABSTRACT 3,770,754 A 11/1973 Parsons 4,791,124 A 12, 1988 Lutomski et al. Compositions and processes for controlling nematodes are 4,908.357 A 3, 1990 Lutomski described herein, e.g., nematodes that infest plants or ani 5,633,271 A 5, 1997 Amoo et al. 5,912,243 A 6/1999 Dowling et al. mals. The compounds include oxazoles, oxadiazoles and 5,985,904 A 11/1999 Jeschke et al. thiadiazoles. 6,048,714. A 4/2000 Hiromoto 6,310,049 B1 10/2001 Wada et al. 7,041,685 B2 5, 2006 Cai et al. 15 Claims, No Drawings US 9,426,995 B2 Page 2

(56) References Cited Atkins, J.M., et al., “ATwo-Stage Iterative Process for the Synthesis of Poly-oxazoles,” 2005, Org Litrs, 7/15:3351-3354. OTHER PUBLICATIONS Iino, M., et al., “Rational Design and Evaluation of New Lead Compound Structures for Selective B ARKI Inhibitors,” 2002, J Med Chem, 45:2150-2159. Becker, “Seeking New Controls for Costly Nematodes.” 1999, Wang, Y. et al., “Rapid and Efficient Synthesis of 1,2,4-Oxadiazoles Agricultural Research, pp. 22-24. Utilizing Polymer-Supported Reagents Under Microwave Heating.” Carpenter et al., “Township Limits on 1.3-D Will Impact Adjust 2005, Organic Letters 7:925-928. ment to Methyl Bromide Phase-out.” 2001, California Agriculture, Haugwitz et al., “Antiparasitic Agents. 6. Synthesis and 55(3):12-18. Anthelmintic Activities of Novel Isothiocyanatophenyl-1,2,4- Carter, “Costs Uncertain: Methyl Bromide Phase-out Becomes oxadiozoles, 1985, J Med Chem, 28:1234-1241. Reality,” 2001, California Agriculture, 55(3):2. 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Hackney et al., “Marigold, Castor Bean, and Chrysanthemum as Obukhov, A.E., "Localization of the pump-induced electron inter Controls of Meloidogyne Incognita and Pratylenchus Alieni,” 1975, action and of spin-orbital coupling or the near-lying singlet and J Nematol, 7(1):84-90. triplet excited States in the impurity generation of light in the series Iino Minom et al., “Rational Design and Evaluation of New Lead multiatomic molecules,” 2004, Proceedings of SPIE-The Interna Compound Structures for Selective.beta. ARK1 Inhibitors,” 2002, J tional Society for Optical Engineering, 5402:400-411. Med Chem, American Chemical Society, 45:2150-2159. Patsenker et al., “Acylation of 5-phenyl-2-(fur-2-yl)oxazole,” 1997. Jessen et al., “The Discovery and Mechanism of Action of Novel Chem Hetero Compounds, 33/11: 1277-1271, XP055.136874. Tumor-Selective and Apoptosis-Inducing 3,5-Diary-1, 2,4- Pulici et al., “Trifluoroacetic Anhydride-Mediated Soled-Phase Ver Oxadiazole Series Using a Chemical Genetics Approach.” 2005, sion of the Robinson-Gabriel Synthesis of Oxazoles,” 2005, J Molecular Cancer Therapeutics, American Association of Cancer Combinatorial Chem, 7/3:463-473, XP055.136879. Research, 4:761-771. Shang, Z., “Oxidative c-Cyclization of Aromatic Aldehyde Loughlin et al., “Investigations into the Parallel Synthesis of Novel N-acylhdrazones by bis(trifluoroacertoxy)iodobenzene,” 2006, Pyrrole-Oxazole Analogues of the Insecticide Pirate.” 2006, Syn Synthetic Communications, 36(20):2927-2937. thesis, No. 12, 1975-1980. Shkumat, A.P. et al. 2-(2-furyl)- and 2-(2-thienyl)-5aryloxazoles, Prieto et al., “Application of Linear Discriminant Analysis in the Ukrainskii Khimicheskii Zhurnal, 1987, 53/5:529-533, Virtual Screening of Antichagasic Drugs. Through Trypanothione XP-002728980, Caplus Record 1988:75262. 1 page. Reductase Inhibition.” 2006, Molecular Diversity, 10:361-375. Sung, H-H... et al., Novel Alternating Fluorene-based Conjugated Prichard, “Anthelmintic Restistance.” 1994, Veterinary Parasitol Polymers Containing Oxadiazole Pendants with Various Terminal ogy, 54:259-268. Groups, 2004, Macromolecules, 37/21:7945-7954. Radspieler et al., “Total Synthesis of Phorbazole C.” 2001, Tetra Zhang, Z. et al., “Studies on the Synthesis and Biological Activity hedron, 57:4867-4871. of 2-aryl-5-(5-methylisoxazole-3-yl)-1,3,4-oxadiazole derivatives Sangster et al., “Pharmacology of Anthelmintic Restistance.” 1999, and related property,’ 1992, Lanzhou Daxue Suebao, Ziran Parasitology Today, 15(4): 141-146. Kexueban, 28/2: 103-111 (English Abstract only). 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Yale et al., “3,5-Disubstituted-1,2,4-Oxadiazoles and 4,5-Dihydro Yan et al., “Organic reactions in ionic liquids. Oxidative dimerisa 3.5-Disubstituted 1.2.4-Oxadiazoles,” 1978, Journal of Heterocy tion of thioamides with phenyliodine(III) diacetate.” 2003, J Chem clic Chemistry, 15:1373-1378. Res, 10:618-619, CAPLUS, Doc No. 1400.357 270. Zhang et al., “Discovery and Structure-Activity Relationship of Weaver, G.W., “Product Class 8: 1,3,4-Oxadiazoles,’ 2004, Science 3-Aryl-5-Aryl-1 . . . .” 2005, J of Medic Chem, 48 (16):5215-5223. of Synthesis, 13:219-251. "1,2,4-Oxadiazole.5(3-chloro-2-thienyl)-3-phenoxy.” Jun. 8, 2008, Loughlin, W.A., et al., “Synthesis of a Novel Pyrrole Oxazole Database Accession No. 1026287-93-3, Database Registry, Chemi Analogue of the Insecticide Pirate.” 2004, Aust. J. Chem, 57:227 cal Abstracts Service, Columbus, OH, XP002696671, 1 page. 232. How to Identify and Manage Pine Wilt Disease and Treat Wood Loughlin, W.A., et al., “Studies Towards the Synthesis of Products Infested by the Pinewood Nematodes online retrieved Phorbazoles A-D: Formation of the Pyrrole Oxazole Skeleton.” from the Internet on Jun. 5, 2010. URL:http://na.fs.fed.us/spfo/ 1999, Aust. J. Chem., 52:231-234. pubs/howtos.?ht pinewilt?pinewilt.htm). Rudi, A., et al., “Phorbazoles A-D, Novel Chlorinated Phenylpyr Anon., Herbicidal Oxadiazole Derivatives, 1990, Research Disclo rolyloxazoles from the Marine Sponge Phorbas aff, clathrate.” 1994, sure, 317, 777-9. Tetrahedron Letters, 35/16:2589-2592, 4 pages. Supplemental European Search Report issued Nov. 19, 2012 in European Patent Application No. 10741639.8, 10 pages. * cited by examiner US 9,426,995 B2 1. 2 COMPOSITIONS AND METHODS FOR replacement for methyl bromide is not found. Similarly, CONTROLLING NEMATODES broad-spectrum nematicides Such as Telone (various formu lations of 1,3-dichloropropene) have significant restrictions CROSS REFERENCE TO RELATED on their use because of toxicological concerns (Carter APPLICATIONS (2001) California Agriculture, 55(3):12-18). Organophos phate and carbamate pesticides are another important class This application is a continuation of U.S. patent applica of nematicides undergoing regulatory review and several of tion Ser. No. 12/904,724, filed Oct. 14, 2010, which is a these compounds are currently being phase out (e.g., continuation of U.S. patent application Ser. No. 12/703,750, fenamiphos, terbufos, cadusafos). filed Feb. 10, 2010, now U.S. Pat. No. 8,017,555, issued 10 To date little success has been achieved in finding safe Sep. 13, 2011, and claims the benefit of U.S. Provisional effective replacements for the toxic but efficacious conven Patent Application Ser. No. 61/151,482, filed Feb. 10, 2009, tional nematicides. A recent example of the poor efficacy of the entire disclosures of which are herein incorporated by many newer potential replacements for organophosphates reference. and carbamates is the study of alternatives to fenamiphos for 15 management of plant parasitic nematodes in bermudagrass. BACKGROUND OF THE INVENTION In these trials, none of the experimental treatments reduced population densities of the plant parasitic nematodes, or Nematodes (derived from the Greek word for thread) are consistently promoted turf visual performance or turf root active, flexible, elongate, organisms that live on moist production (Crow (2005) Journal of Nematology, 37(4):477 Surfaces or in liquid environments, including films of water 482). Consequently there remains an urgent need to develop within soil and moist tissues within other organisms. While environmentally safe, efficacious methods of controlling only 20,000 species of nematode have been identified, it is plant parasitic nematodes estimated that 40,000 to 10 million actually exist. Many Some plant species are known to be highly resistant to species of nematodes have evolved to be very successful nematodes. The best documented of these include marigolds parasites of plants and animals and are responsible for 25 (Tagetes spp.), rattlebox (Crotalaria spectabilis), chrysan significant economic losses in agriculture and livestock and themums (Chrysanthemum spp.), castor bean (Ricinus com for morbidity and mortality in humans (Whitehead (1998) munis), margosa (Azardiracta indica), and many members Plant Nematode Control. CAB International, New York). of the family Asteraceae (family Compositae) (Hackney & Nematode parasites of plants can infest all parts of plants, Dickerson. (1975).J Nematol 7(1):84-90). In the case of the including roots, developing flower buds, leaves, and stems. 30 Asteraceae, the photodynamic compound alpha-terthienyl Plant parasites are classified on the basis of their feeding has been shown to account for the strong nematicidal habits into the broad categories migratory ectoparasites, activity of the roots. Castor beans are plowed under as a migratory endoparasites, and sedentary endoparasites. Sed green manure before a seed crop is set. However, a signifi entary endoparasites, which include the root knot nematodes cant drawback of the castor plant is that the seed contains (Meloidogyne) and cyst nematodes (Globodera and Het 35 toxic compounds (such as ricin) that can kill humans, pets, erodera) induce feeding sites and establish long-term infec and livestock and is also highly allergenic. In most cases tions within roots that are often very damaging to crops however, the active principle(s) for plant nematicidal activ (Whitehead, Supra). It is estimated that parasitic nematodes ity has not been discovered and it remains difficult to derive cost the horticulture and agriculture industries in excess of commercially Successful nematicidal products from these S78 billion worldwide a year, based on an estimated average 40 resistant plants or to transfer the resistance to crops of 12% annual loss spread across all major crops. For example, agronomical importance Such as Soybeans and cotton. it is estimated that nematodes cause Soybean losses of Genetic resistance to certain nematodes is available in approximately $3.2 billion annually worldwide (Barker et al. Some commercial cultivars (e.g., soybeans), but these are (1994) Plant and Soil Nematodes. Societal Impact and restricted in number and the availability of cultivars with Focus for the Future. The Committee on National Needs and 45 both desirable agronomic features and resistance is limited. Priorities in Nematology. Cooperative State Research Ser Furthermore, the production of nematode resistant commer vice, US Department of Agriculture and Society of Nema cial varieties by conventional plant breeding based on tologists). Several factors make the need for safe and effec genetic recombination through sexual crosses is a slow tive nematode controls urgent. Continuing population process and is often further hampered by a lack of appro growth, famines, and environmental degradation have 50 priate germplasm. heightened concern for the Sustainability of agriculture, and Chemical means of controlling plant parasitic nematodes new government regulations may prevent or severely restrict continue to be essential for many crops which lack adequate the use of many available agricultural anthelmintic agents. natural resistance or a source of transgenic resistance. In the There are a very small array of chemicals available to specialty markets, economic hardship resulting from nema effectively control nematodes (Becker (1999) Agricultural 55 tode infestation is particularly high in Strawberries, bananas, Research Magazine 47(3):22-24; U.S. Pat. No. 6,048,714). and other high value vegetables and fruits. In the high In general, chemical nematicides are highly toxic com acreage crop markets, nematode damage is greatest in Soy pounds known to cause Substantial environmental damage beans and cotton. There are however, dozens of additional and are increasingly restricted in the amounts and locations crops that suffer from significant nematode infestation in which they can be used. For example, the Soil fumigant 60 including potato, pepper, onion, citrus, coffee, Sugarcane, methyl bromide which has been used effectively to reduce greenhouse ornamentals and golf course turfgrasses. nematode infestations in a variety of specialty crops, is To be useful in modern agriculture nematicides must have regulated under the U.N. Montreal Protocol as an ozone high potency, a broad spectrum of activity against different depleting Substance and is undergoing phase out in the US strains of nematodes and should not be toxic to non-target and world wide (Carter (2001) California Agriculture, 65 organisms. 55(3):2). It is expected that strawberry and other commodity Nematode parasites of vertebrates (e.g., humans, live crop industries will be significantly impacted if a suitable stock and companion animals) include gut roundworms, US 9,426,995 B2 3 4 hookworms, pinworms, whipworms, and filarial worms. dence because rapid re-infection occurs after treatment. In They can be transmitted in a variety of ways, including by fact, over the last 50 years, while nematode infection rates water contamination, skin penetration, biting insects, or by have fallen in the United States, Europe, and Japan, the ingestion of contaminated food. overall number of infections worldwide has kept pace with In domesticated animals, nematode control or “de-worm 5 the growing world population. Large scale initiatives by ing is essential to the economic viability of livestock regional governments, the World Health Organization, foun producers and is a necessary part of Veterinary care of dations, and pharmaceutical companies are now underway companion animals. Parasitic nematodes cause mortality in attempting to control nematode infections with currently animals (e.g., heartworm in dogs and cats) and morbidity as available tools, including three programs for control of a result of the parasites inhibiting the ability of the infected 10 Onchocerciasis (river blindness) in Africa and the Americas animal to absorb nutrients. The parasite-induced nutrient using ivermectin and vector control; The Global Alliance to deficiency leads to disease and stunted growth in livestock Eliminate Lymphatic Filariasis using DEC, albendazole, and and companion animals. For instance, in cattle and dairy ivermectin; and the highly successful Guinea Worm Eradi herds, a single untreated infection with the brown stomach cation Program. Until safe and effective vaccines are dis worm can permanently restrict an animals ability to convert 15 covered to prevent parasitic nematode infections, anthel feed into muscle mass or milk. mintic drugs will continue to be used to control and treat Two factors contribute to the need for novel anthelmintics nematode parasitic infections in both humans and domestic and vaccines to control animal parasitic nematodes. First, animals. Some of the more prevalent species of parasitic nematodes of Certain insecticidal oxazoles (U.S. Pat. No. 4,791,124) livestock are building resistance to the anthelmintic drugs and thiazoles (U.S. Pat. No. 4,908.357) and nematicidal available currently, meaning that these products are losing pyrazoles (U.S. Pat. No. 6,310,049) have been disclosed in their efficacy. These developments are not Surprising the art. The present invention discloses other oxazoles, because few effective anthelmintic drugs are available and oxadiazoles and thiadiazoles with Surprisingly potent nem most have been used continuously. Some parasitic species aticidal activity showing activity comparable to commercial have developed resistance to most of the anthelmintics 25 standards. Commercial level nematicidal potency has not (Geents et al. (1997) Parasitology Today 13:149-151; Prich previously been demonstrated with oxazoles, oxadiazoles ard (1994) Veterinary Parasitology 54:259-268). The fact and thiadiazoles. Importantly, these compounds are broadly that many of the anthelmintic drugs have similar modes of active against nematodes yet safe to non-target organisms. action complicates matters, as the loss of sensitivity of the U.S. Pat. No. 4,791,124 disclosed certain oxazoles and parasite to one drug is often accompanied by side resis 30 thiazoles with nematicidal activity against Meloidogyne tance—that is, resistance to other drugs in the same class incognita (root knot nematode) at 10 parts per million. (Sangster & Gill (1999) Parasitology Today 15(4): 141-146). However, compounds were not titrated to lower doses and Secondly, there are some issues with toxicity for the major not shown to have potency comparable to commercial compounds currently available. standards. Infections by parasitic nematode worms also result in 35 U.S. Pat. No. 6,310,049 disclosed certain nematicidal Substantial human mortality and morbidity, especially in pyrazoles with activity against root knot nematode. Several tropical regions of Africa, Asia, and the Americas. The pyrazole compounds are shown having activity at 100 ppm World Health Organization estimates 2.9 billion people are in an in vitro assay with a small Subset of the compounds infected, and in some areas, 85% of the population carries having activity at 50 ppm in a soil based greenhouse. One worms. While mortality is rare in proportion to infections, 40 compound is disclosed as having greenhouse activity at 20 morbidity is Substantial and rivals diabetes and lung cancer ppm and a single compound as having greenhouse activity in worldwide disability adjusted life year (DALY) measure at 5 ppm. It is not clear if any of these compounds have mentS. potency comparable to commercial standards. Examples of human parasitic nematodes include hook Some oxadiazoles compounds having Substituted furan or worms, filarial worms, and pinworms. Hookworms (1.3 45 thiophene rings but not unsubstituted furan or thiophene billion infections) are the major cause of anemia in millions rings are disclosed as being apoptosis inducers and useful as of children, resulting in growth retardation and impaired chemotherapeutic against certain cancers (Zhang et al. 2005 cognitive development. Filarial worms invade the lymphat J Med Chem. 48(16):5215-23). Notwithstanding some ics, resulting in permanently Swollen and deformed limbs Superficial chemical similarities the nematicidal analogs of (elephantiasis), and the eyes, causing African river blind 50 this invention do not induce apoptosis in mammalian cells ness. The large gut roundworm Ascaris lumbricoides infects and have equal potency against wild type C. elegans nema more than one billion people worldwide and causes malnu todes and ced-3 or ced-4 C. elegans mutants deficient in trition and obstructive bowel disease. In developed coun apoptosis. These analogs are therefore structurally and func tries, pinworms are common and often transmitted through tionally distinct from the apoptosis inducing oxadiazoles children in daycare. 55 disclosed by Cai et al in U.S. Pat. No. 7,041,685. Even in asymptomatic parasitic infections, nematodes can still deprive the host of valuable nutrients and increase the SUMMARY OF THE INVENTION ability of other organisms to establish secondary infections. In some cases, infections can cause debilitating illnesses and Compositions and processes for controlling nematodes can result in anemia, diarrhea, dehydration, loss of appetite, 60 are described herein, e.g., nematodes that infest plants or the or death. situs of plants. Nematodes that parasitize animals can also be Despite some advances in drug availability and public controlled using the methods and compounds described health infrastructure and the near elimination of one tropical herein. nematode (the water-borne Guinea worm), most nematode Described herein are nematicidal compositions compris diseases have remained intractable problems. Treatment of 65 ing an effective amount of a compound or a mixture of hookworm diseases with anthelmintic drugs, for instance, compounds having any of the formula described herein, for has not provided adequate control in regions of high inci example the compounds shown below. US 9,426,995 B2 5 6 Described herein is a compound of Formula I or a salt A compound of Formula II or a salt thereof, thereof,

O Formula II X C Formula I 5 1 A (y- A (r C B-N wherein, 10 A is an optionally Substituted aryl or optionally Substi wherein, tuted arylalkyl, or optionally substituted heteroaryl (includ A is an optionally Substituted aryl or optionally Substi ing pyridyl, pyrazyl, oxazolyl or isoxazolyl) or optionally tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl) or option substituted heteroarylalkyl wherein said substituents are ally substituted aryloxo or optionally substituted arylthio, or selected from the group consisting of halo, C1-C6 haloalkyl, optionally Substituted heteroaryl (including pyridyl, pyrazyl. 15 C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkyl, C2-C6 alk oxazolyl or isoxazolyl) or optionally substituted heteroary enyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl (C2-C6) alkynyl, C1-C6 lalkyl (e.g., heteroarylClalkyl or heteroarylC2alkyl or hydroxyalkyl, amino, ureido, cyano, C1-C6 acylamino, heteroarylClalkyl or heteroarylC2alkyl) or optionally sub hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy and stituted heteroaryloxo- or optionally substituted heteroaryl carboxy, C(H)O; thio wherein said substituents are selected from the group B is C(H) or C(CH): consisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 C is a heteroaryl including thienyl, furanyl, oxazolyl or cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, isoxazolyl each of which can be optionally independently C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, substituted with one or more substituents selected from: C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, amino, fluorine, chlorine, CH and OCF; and ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 25 X is O or S. acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; A compound of Formula IIa or a salt thereof, B is C(H) or C(CH); and C is an optionally Substituted pyrrolyl (including pyrrolyl Formula IIa 1, pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrro 30 R lyloxo (including pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrrolythio (including pyrrolyl-2 or pyrrolyl-3) R2 X O E R or optionally substituted pyrrolylalkyl (e.g., pyrrolyl C1 alkyl or pyrrolyl C2 alkyl) (including pyrrolyl-1, pyrrolyl-2 X-Qu s or pyrrolyl-3) wherein said substituents are selected from the 35 R Rs N R8 group consisting of methyl, alkyl, cycyl, heterocycl. R9 hydroxyalkyl and halogen. R4 A compound of Formula Ia or a salt thereof, wherein, 40 R and Rs are independently selected from hydrogen, Formula Ia CH, F, Cl, Br, CF. OCF; R R6 R and R are independently selected from hydrogen, F. R Cl, Br, CFs: R2 X O s 7 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, 45 OCH CN, C(H)O; le R7, Rs and Ro are independently selected from hydrogen, B1)- R Rs N R8 F, C1, CH, OCF; R9 B is C(H) or C(CH): R4 E is O or S; and X is O or S. 50 A compound of Formula IIb or a salt thereof, wherein, R and Rs are independently selected from hydrogen, Formula IIb CH, F, Cl, Br, CF and OCF: R R and Ra are independently selected from hydrogen, F. 55 Cl, Br, and CF; R2 X R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, E-4 OCH, CN, and CO: R3 Rs N R. R. Rs and Ro are independently selected from hydro 60 gen, CH, alkyl, cykloalkyl, heterocyl, and halogen (C1, F); R4 B is C(H) or C(CH); and X is a bond, CH, O or S. wherein, In some cases X is a bond. R and Rs are independently selected from hydrogen, 65 CH, F, Cl, Br, CF. OCF; In some cases X is CH, O or S. R and R are independently selected from hydrogen, F. In some cases X is CH2. Cl, Br, CFs: US 9,426,995 B2 7 8 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, A compound of Formula IIIb or a salt thereof, OCH, CN, CO: R. Rs and Ro are independently selected from hydrogen, F, C1, CH, OCF: Formula IIIb B is C(H), C(CH); and E is O or S: R X is O or S. A compound of Formula III or a salt thereof, 10

Formula III

15 wherein, R and Rs are independently selected from hydrogen, wherein, CH, F, Cl, Br, CF. OCF; A is an optionally Substituted aryl or optionally Substi R and Ra are independently selected from hydrogen, F. tuted arylalkyl (e.g., arylCalkyl or arylCalkyl), or option Cl, Br, CFs: ally Substituted heteroaryl (including pyridyl, pyrazyl. oxazolyl or isoxazolyl) or optionally substituted heteroary R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, lalkyl (e.g., heteroarylCalkyl or heteroarylCalkyl) wherein OCH CN, CO: said Substituents are selected from the group consisting of R. Rs and Ro are independently selected from hydrogen, halo, C-C6 haloalkyl, Co-Co aryl, Ca-C7 cycloalkyl, C-C, F, C1, CH, OCF.; alkyl, C-C alkenyl, C-C alkynyl, C-C10 aryl(C-C) 25 alkyl, C6-Co aryl(C-C)alkenyl, Co-Co aryl(C-C) alky B is C(H), C(CH): nyl, C-C hydroxyalkyl, amino, ureido, cyano, C-C acy E is O or S; and lamino, hydroxy, thiol, C-C acyloxy, azido, C-C alkoxy X is CH, O or S. and carboxy, C(H)O; In some cases X is O or S. B is C(H) or C(CH): 30 C is a heteroaryl including thienyl, furanyl, oxazolyl or In some cases X is CH2. isoxazolyl each of which can be optionally independently A compound of Formula IV or a salt thereof, substituted with one or more substituents selected from: fluorine, chlorine, CH and OCF; and 35 X is CH, O or S. Formula IV In some cases X is CH. In some cases X is O or S. A (r C A compound of Formula Ma or a salt thereof, 40 wherein, Formula IIIa A is an optionally Substituted aryl or optionally Substi tuted arylalkyl (e.g., arylCalkyl or arylCalkyl) or option R ally substituted aryloxo or optionally substituted arylthio, or 45 optionally Substituted heteroaryl (including pyridyl, pyrazyl. oxazolyl or isoxazolyl) or optionally substituted heteroary lalkyl (e.g., heteroarylCalkyl or heteroarylCalkyl) or optionally Substituted heteroaryloxo-or optionally Substi 50 tuted hetero arylthio wherein said substituents are selected from the group consisting of halo, C-C haloalkyl, Co-Co aryl, Ca-C, cycloalkyl, C-C6 alkyl, C-C alkenyl, C-C, wherein, alkynyl, Co-Co aryl(C-C)alkyl, Co-Co aryl(C-C)alk R and Rs are independently selected from hydrogen, enyl, C-C aryl (C-C) alkynyl, C-C hydroxyalkyl, CH, F, Cl, Br, CF. OCF; 55 amino, ureido, cyano, C-C acylamino, hydroxy, thiol, R and Ra are independently selected from hydrogen, F. C-C acyloxy, azido, C-C alkoxy and carboxy, C(H)O; Cl, Br, CFs: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, B is C(H) or C(CH); and OCH, CN, C(H)O: C is an optionally Substituted pyrrolyl (including pyrrolyl 60 1, pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrro R7, Rs and Ro are independently selected from hydrogen, lyloxo (including pyrrolyl-2 or pyrrolyl-3) or optionally F, C1, CH, OCF: substituted pyrrolythio (including pyrrolyl-2 or pyrrolyl-3) B is C(H) or C(CH): or optionally substituted pyrrolylalkyl (e.g., pyrrolyl C E is O or S; and alkyl) (including pyrrolyl-1, pyrrolyl-2 or pyrrolyl-3) X is CH, O or S. 65 wherein said Substituents are selected from the group con In some cases X is O or S. sisting of methyl, alkyl, cycyl, heterocycl, hydroxyalkyl and In some cases X is CH2. halogen. US 9,426,995 B2 9 10 A compound of formula IVa or a salt thereof, wherein, R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF; Formula IV a R and R are independently selected from hydrogen, F. R Cl, Br, CF; R6 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH CN, C(H)O; R. Rs and R are independently selected from hydrogen, "?tyNN- M No le F, C1, CH, OCF; R3 Rs B R8 10 B is C(H) or C(CH): R4 R9 E is O or S; and X is O or S. A compound of Formula Vb or a salt thereof, wherein, R and Rs are independently selected from hydrogen, 15 CH, F, Cl, Br, CF and OCF: R and Ra are independently selected from hydrogen, F. Formula Vb Cl, Br, and CF; R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, and CO: 2O R. R. Rs and Ro are independently selected from hydro gen, CH, alkyl, cykloalkyl, heterocyl, and halogen; B is C(H) or C(CH); and X is a bond, CH, O or S. In some cases X is a bond. 25 In some cases X is CH2. In some cases X is O or S. wherein, A compound of Formula V or a salt thereof, R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF; R and R are independently selected from hydrogen, F. 30 Formula V Cl, Br, CF; R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, CO: ry R. Rs and Ro are independently selected from hydrogen, 35 F, C1, CH, OCF; wherein, B is C(H), C(CH): A is an optionally Substituted aryl or optionally Substi E is O or S; and tuted arylalkyl (e.g., arylCalkyl or arylCalkyl), or option X is O or S. ally Substituted heteroaryl (including pyridyl, pyrazyl. A compound of Formula VI or a salt thereof, oxazolyl or isoxazolyl) or optionally substituted heteroary- 40 lalkyl (e.g., heteroarylCalkyl or heteroarylCalkyl wherein said Substituents are selected from the group consisting of Formula VI halo, C-C haloalkyl, Co-Co aryl, Ca-C, cycloalkyl, C-C, alkyl, C-C alkenyl, C-C alkynyl, Co-Co aryl(C-C) alkyl, C-C aryl(C-C)alkenyl, C-C aryl (C-C) alky- 45 nyl, C-C hydroxyalkyl, amino, ureido, cyano, C-C acy lamino, hydroxy, thiol, C-C acyloxy, azido, C-C alkoxy wherein, and carboxy, C(H)O; A is an optionally Substituted aryl or optionally Substi B is C(H) or C(CH): C is a heteroaryl including thienyl, furanyl, oxazolyl or 50 tuted arylalkyl (e.g., arylCalkyl or arylCalkyl), or option isoxazolyl each of which can be optionally independently ally Substituted heteroaryl (including pyridyl, pyrazyl. substituted with one or more substituents selected from: oxazolyl or isoxazolyl) or optionally substituted heteroary fluorine, chlorine, CH and OCF; and lalkyl (e.g., heteroryl C alkyl) wherein said Substituents are X is O or S. selected from the group consisting of halo, C-C haloalkyl, C-C aryl, C-C, cycloalkyl, C-C alkyl, C-C alkenyl, A compound of Formula Va or a salt thereof, 55 C-C alkynyl, Co-Co aryl(C-C)alkyl, Co-Co aryl(C-C) alkenyl, Co-Co aryl(C-C) alkynyl, C-C hydroxyalkyl, Formula Va. amino, ureido, cyano, C-C acylamino, hydroxy, thiol, R C-C acyloxy, azido, C-C alkoxy and carboxy, C(H)O; B is C(H) or C(CH): R Y- E R7 60 C is a heteroaryl including thienyl, furanyl, oxazolyl or isoxazolyl each of which can be optionally independently Qu substituted with one or more substituents selected from: R3 Rs B R8 fluorine, chlorine, CH and OCF; and R4 R9 65 X is CH, O or S. In some cases X is O or S. In some cases X is CH2. US 9,426,995 B2 11 12 A compound of Formula VIa or a salt thereof, oxazolyl or isoxazolyl) or optionally substituted heteroary lalkyl (e.g., heteroarylCalkyl or heteroarylCalkyl) or optionally Substituted heteroaryloxo-or optionally Substi Formula VIa tuted hetero arylthio wherein said substituents are selected from the group consisting of halo, C-C haloalkyl, Co-Co R aryl, C-C cycloalkyl, C-C alkyl, C-C alkenyl, C-C, alkynyl, Co-Co aryl(C-C)alkyl, Co-Co aryl(C-C)alk enyl, C-C aryl (C-C) alkynyl, C-C hydroxyalkyl, amino, ureido, cyano, C-C acylamino, hydroxy, thiol, 10 C-C acyloxy, azido, C-C alkoxy and carboxy, C(H)O; and C is an optionally Substituted pyrrolyl (including pyrrolyl 1, pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrro wherein, lyloxo (including pyrrolyl-2 or pyrrolyl-3) or optionally R and Rs are independently selected from hydrogen, 15 substituted pyrrolythio (including pyrrolyl-2 or pyrrolyl-3) CH, F, Cl, Br, CF. OCF; or optionally substituted pyrrolylalkyl (e.g., pyrrolyl C1 R and Ra are independently selected from hydrogen, F. alkyl) (including pyrrolyl-1, pyrrolyl-2 or pyrrolyl-3) Cl, Br, CF; wherein said Substituents are selected from the group con R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, sisting of methyl, alkyl, cycyl, heterocycl, hydroxyalkyl and OCH, CN, C(H)O; halogen. R7, Rs and R are independently selected from hydrogen, A compound of formula VIIa or a salt thereof, F, C1, CH, OCF: B is C(H) or C(CH): E is O or S: 25 Formula VIIa X is O or S. R R6 A compound of Formula VIb or a salt thereof, R X R7 NY-N s Formula VIb 30 NNo. le R3 Rs Rs Ro R R4

wherein, 35 R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF and OCF: R and Ra are independently selected from hydrogen, F. Cl, Br, and CF; R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, wherein, 40 OCH CN, and CO: R and Rs are independently selected from hydrogen, R. R. Rs and Ro are independently selected from hydro CH, F, Cl, Br, CF. OCF; gen, CH3, alkyl, cykloalkyl, heterocyl, and halogen; and R and Ra are independently selected from hydrogen, F. X is a bond, CH, O or S. Cl, Br, CF; In some cases X is a bond. R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, 45 In some cases X is O or S. OCH, CN, CO: In some cases X is CH. R. Rs and Ro are independently selected from hydrogen, A compound of Formula VIII or a salt thereof, F, C1, CH, OCF: B is C(H), C(CH): 50 E is O or S; and Formula VIII X is CH, O or S. X N C In some cases X is CH2. ry In some cases X is O or S. N-O A compound of Formula VII or a salt thereof 55 wherein, A is an optionally Substituted aryl or optionally Substi Formula VII tuted arylalkyl, or optionally substituted heteroaryl (includ A N C ing pyridyl, pyrazyl, oxazolyl or isoxazolyl) or optionally NY 60 substituted heteroarylalkyl wherein said substituents are N-O selected from the group consisting of halo, C-C haloalkyl, Co-Co aryl, Ca-C7 cycloalkyl, C-C alkyl, C-C alkenyl, wherein, C-C alkynyl, C-C aryl (C-C)alkyl, C-C aryl (C2-C) A is an optionally Substituted aryl or optionally Substi alkenyl, Co-Co aryl(C-C) alkynyl, C-C hydroxyalkyl, tuted arylalkyl (e.g., arylCalkyl or arylCalkyl) or option 65 amino, ureido, cyano, C-C acylamino, hydroxy, thiol, ally substituted aryloxo or optionally substituted arylthio, or C-C acyloxy, azido, C-C alkoxy and carboxy, C(H)O; optionally Substituted heteroaryl (including pyridyl, pyrazyl. B is C(H) or C(CH): US 9,426,995 B2 13 14 C is a heteroaryl including thienyl, furanyl, oxazolyl or lalkyl (e.g., heteroarylCalkyl or heteroarylCalkyl) wherein isoxazolyl each of which can be optionally independently said Substituents are selected from the group consisting of substituted with one or more substituents selected from: halo, C-C haloalkyl, Co-Co aryl, Ca-C, cycloalkyl, C-C, fluorine, chlorine, CH and OCF; and alkyl, C-C alkenyl, C-C alkynyl, C-C10 aryl(C-C) X is O or S. alkyl, Co-Co aryl(C-C)alkenyl, Co-Co aryl (C-C) alky A compound of Formula VIIIa or salt thereof, nyl, C-C hydroxyalkyl, amino, ureido, cyano, C-C acy lamino, hydroxy, thiol, C-C acyloxy, azido, C-C alkoxy and carboxy, C(H)O; Formula VIIIa B is C(H) or C(CH): 10 R C is a heteroaryl including thienyl, furanyl, oxazolyl or isoxazolyl each of which can be optionally independently substituted with one or more substituents selected from: R2 Y- E R fluorine, chlorine, CH, and OCF; and Y Qu 15 X is CH, O or S. R3 Rs Rs In some cases X is O or S. R9 R4 In some cases X is CH. A compound of Formula IXa or a salt thereof, wherein, R and Rs are independently selected from hydrogen,

CH, F, Cl, Br, CF, OCF, Formula IXa R and Ra are independently selected from hydrogen, F. Cl, Br, CF: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, 25 OCH, CN, C(H)O; R7, Rs and Ro are independently selected from hydrogen, F, C1, CH, OCF, E is O or S; and X is O or S. 30 A compound of Formula VIIIb or a salt thereof, wherein, R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF; Formula VIIIb 35 R and R are independently selected from hydrogen, F. Cl, Br, CF; R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH CN, C(H)O; R7, Rs and Ro are independently selected from hydrogen, 40 F, C1, CH, OCF.; E is O or S; and X is CH, O or S. In some cases X is O or S. wherein, R and Rs are independently selected from hydrogen, 45 In some cases X is CH. CH, F, Cl, Br, CF, OCF: A compound of Formula IXb or a salt thereof R and Ra are independently selected from hydrogen, F. Cl, Br, CFs: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, Formula IXb OCH, CN, CO: 50 R. Rs and R are independently selected from hydrogen, R F, C1, CH, OCF: E is O or S; and X is O or S, A compound of Formula IX or a salt thereof, 55

Formula IX A N X y Y- No 60 wherein, N-O R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF; A is an optionally Substituted aryl or optionally Substi R and R are independently selected from hydrogen, F. tuted arylalkyl (e.g., arylCalkyl or arylCalkyl), or option 65 Cl, Br, CFs: ally Substituted heteroaryl (including pyridyl, pyrazyl. R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, oxazolyl or isoxazolyl) or optionally substituted heteroary OCH CN, CO: US 9,426,995 B2 15 16 R. Rs and Ro are independently selected from hydrogen, A compound of Formula XI or a salt thereof, F, C1, CH, OCF, E is O or S; and Formula XI X is CH, O or S. X N C In some cases X is O or S. A1 n y In some cases X is CH2. O-N A compound of Formula X or a salt thereof,

10 wherein, Formula X A is an optionally Substituted aryl or optionally Substi A N C tuted arylalkyl, or optionally substituted heteroaryl (includ n y ing pyridyl, pyrazyl, oxazolyl or isoxazolyl) or optionally O-N substituted heteroarylalkyl wherein said substituents are 15 selected from the group consisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkyl, C2-C6 alk A is an optionally Substituted aryl or optionally Substi enyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 tuted arylalkyl (e.g., arylCalkyl or arylC2alkyl) or option aryl(C2-C6)alkenyl, C6-C10 aryl (C2-C6) alkynyl, C1-C6 ally substituted aryloxo or optionally substituted arylthio, or hydroxyalkyl, amino, ureido, cyano, C1-C6 acylamino, optionally Substituted heteroaryl (including pyridyl, pyrazyl. hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy and oxazolyl or isoxazolyl) or optionally substituted heteroary carboxy, C(H)O; lalkyl (e.g., heteroarylCalkyl or heteroarylCalkyl) or C is heterocycl including thienyl, furanyl, oxazolyl or optionally Substituted heteroaryloxo-or optionally Substi isoxazolyl each of which can be optionally independently tuted hetero arylthio wherein said substituents are selected substituted with one or more substituents selected from: from the group consisting of halo, C-C haloalkyl, Co-Co 25 fluorine, chlorine, CH and OCF; and aryl, C-C cycloalkyl, C2-C alkyl, C-C alkenyl, C-C, X is O or S. alkynyl, Co-Co aryl(C-C)alkyl, Co-Co aryl(C-C6)alk A compound of formula XIa or a salt thereof, enyl, C6-C10 aryl(C-C) alkynyl, C-C hydroxyalkyl, amino, ureido, cyano, C-C acylamino, hydroxy, thiol, 30 Formula XIa C-C acyloxy, azido, C-C alkoxy and carboxy, C(H)O; R and R2 X N E R7 C is an optionally Substituted pyrrolyl (including pyrrolyl 1, pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrro N 35 lyloxo (including pyrrolyl-2 or pyrrolyl-3) or optionally R3 Rs 121NN R8 substituted pyrrolythio (including pyrrolyl-2 or pyrrolyl-3) R9 or optionally substituted pyrrolylalkyl (e.g., pyrrol C1 alkyl) R4 (including pyrrolyl-1, pyrrolyl-2 or pyrrolyl-3) wherein said Substituents are selected from the group consisting of methyl, alkyl, cycyl, heterocycl, hydroxyalkyl and halogen, 40 wherein, R and Rs are independently selected from hydrogen, A compound of formula Xa or a salt thereof, CH, F, Cl, Br, CF, OCF: R and R are independently selected from hydrogen, F. Formula Xa Cl, Br, CFs: R6 45 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, R OCH CN, C(H)O; R2 X N s 7 R. Rs and R are independently selected from hydrogen, F, C1, CH, OCF; N-OS X le E is O or S; and R Rs N R8 50 X is O or S. A compound having the Formula XIb or a salt thereof,

wherein, Formula XIb R and Rs are independently selected from hydrogen, 55 CH, F, Cl, Br, CF, and OCF. R and Ra are independently selected from hydrogen, F. Cl, Br, and CF; R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, 60 OCH, CN, and CO: R. R. Rs and R are independently selected from hydro gen, CH3, alkyl, cykloalkyl, heterocyl, and halogen; and X is a bond, CH, O or S. 65 wherein, In some cases X is O or S. R and Rs are independently selected from hydrogen, In some cases X is CH2. CH, F, Cl, Br, CF. OCF; US 9,426,995 B2 17 18 R and Ra are independently selected from hydrogen, F. A compound of Formula XIIb or a salt thereof, Cl, Br, CF; R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, CO: Formula XIIb R. Rs and R are independently selected from hydrogen, 5 F, C1, CH, OCF: R E is O or S; and X is O or S.

A compound of Formula XII or a salt thereof, 10

Formula XII wherein, 15 R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF; R and Ra are independently selected from hydrogen, F. wherein, Cl, Br, CFs: A is an optionally Substituted aryl or optionally Substi R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl), or option OCH CN, CO: ally Substituted heteroaryl (including pyridyl, pyrazyl. R. Rs and R are independently selected from hydrogen, oxazolyl or isoxazolyl) or optionally substituted heteroary F, C1, CH, OCF; lalkyl (e.g., heteroarylC1 alkyl or heteroarylC2alkyl) E is O or S; and wherein said Substituents are selected from the group con X is CH, O or S. sisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 25 In some cases X is O or S. cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, In some cases X is CH2. C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, A compound of Formula XIII or a salt thereof, C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, amino, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 30 Formula XIII acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; A N C C is a heteroaryl including thienyl, furanyl, oxazolyl or Ny isoxazolyl each of which can be optionally independently N-S substituted with one or more substituents selected from: fluorine, chlorine, CH and OCF; and 35 A is an optionally Substituted aryl or optionally Substi X is CH, O or S. tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl) or option ally substituted aryloxo or optionally substituted arylthio, or In some cases X is O or S. optionally Substituted heteroaryl (including pyridyl, pyrazyl. In some cases X is CH2. oxazolyl or isoxazolyl) or optionally substituted heteroary A compound of the Formula XIIa or salt thereof, lalkyl or optionally substituted heteroaryloxo- or optionally 40 substituted hetero arylthio wherein said substituents are selected from the group consisting of halo, C1-C6 haloalkyl, Formula XIIa C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkyl, C2-C6 alk enyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 R aryl(C2-C6)alkenyl, C6-C10 aryl (C2-C6) alkynyl, C1-C6 45 hydroxyalkyl, amino, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; and C is an optionally Substituted pyrrolyl (including pyrrolyl 1, pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrro lyloxo (including pyrrolyl-2 or pyrrolyl-3) or optionally 50 substituted pyrrolythio (including pyrrolyl-2 or pyrrolyl-3) or optionally Substituted pyrrolylalkyl (including pyrrolyl-1, wherein, pyrrolyl-2 or pyrrolyl-3) wherein said substituents are R and Rs are independently selected from hydrogen, selected from the group consisting of methyl, alkyl, cycyl. heterocycl, hydroxyalkyl and halogen. CH, F, Cl, Br, CF. OCF; 55 R and Ra are independently selected from hydrogen, F. A compound of formula XIIIa or a salt thereof, Cl, Br, CF: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, Formula XIIIa OCH, CN, C(H)O: R7, Rs and Ro are independently selected from hydrogen, 60 R R6 F, C1, CH, OCF: X N s R B is C(H) or C(CH): E is O or S; and N y- le Rs NS R Rs X is CH, O or S. 65 In some cases X is O or S. 9 In some cases X is CH2. US 9,426,995 B2 19 20 wherein, A compound of Formula XIVb or a salt thereof, R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF, and OCF. R and Ra are independently selected from hydrogen, F. Formula XIVb Cl, Br, and CF; 5 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, and CO: R. R. Rs and Ro are independently selected from hydro gen, CH3, alkyl, cykloalkyl, heterocyl, and halogen; and 10 X is a bond, CH, O or S. In some cases X is a bond. In some cases X is O or S. In some cases X is CH2. wherein, A compound of Formula XIV or a salt thereof, 15 R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF, OCF: Formula XIV R and R are independently selected from hydrogen, F. Cl, Br, CFs: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, rty OCH CN, CO: R. R., and Ro are independently selected from hydrogen, F, C1, CH, OCF; wherein, E is O or S; and A is an optionally Substituted aryl or optionally Substi- 25 X is O or S. tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl), or option A compound of Formula XV or a salt thereof, ally Substituted heteroaryl (including pyridyl, pyrazyl. oxazolyl or isoxazolyl) or optionally substituted heteroary lalkyl (e.g., heteroarylC1 alkyl or heteroarylC2alkyl) Formula XV wherein said Substituents are selected from the group con 30 sisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, amino, 35 wherein, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 A is an optionally Substituted aryl or optionally Substi acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl), or option C is heteroaryl including thienyl, furanyl, oxazolyl or ally Substituted heteroaryl (including pyridyl, pyrazyl. isoxazolyl each of which can be optionally independently oxazolyl or isoxazolyl) or optionally substituted heteroary substituted with one or more substituents selected from: 40 lalkyl (e.g., heteroarylC1 alkyl or heteroarylC2alkyl) fluorine, chlorine, CH and OCF; and wherein said Substituents are selected from the group con X is O or S. sisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 A compound of Formula XIVa or a salt thereof, cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C 1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, 45 C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, amino, Formula XIV a ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 R acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; R X N E R7 C is a heteroaryl including thienyl, furanyl, oxazolyl or isoxazolyl each of which can be optionally independently N N 50 substituted with one or more substituents selected from: RS Rs NS Rs fluorine, chlorine, CH and OCF; and Ro X is CH, O or S. R4 In some cases X is O or S. In some cases X is CH. 55 A compound of Formula XVa or a salt thereof, wherein, R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF. Formula Xva R and Ra are independently selected from hydrogen, F. R Cl, Br, CF: 60 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, C(H)O; R7, Rs and R are independently selected from hydrogen, F, C1, CH, OCF: 65 E is O or S; and X is O or S. US 9,426,995 B2 21 22 wherein, pyrrolyl-2 or pyrrolyl-3) wherein said substituents are R and Rs are independently selected from hydrogen, selected from the group consisting of methyl, alkyl, cycyl. CH, F, Cl, Br, CF. OCF; heterocycl, hydroxyalkyl and halogen. R and Ra are independently selected from hydrogen, F. A compound of formula XVIa or a salt thereof, Cl, Br, CF: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, C(H)O; Formula XVIa R7, Rs and R are independently selected from hydrogen, R6 R X R F, C1, CH, OCF: 10 2 2N s 7 E is O or S; and 2 N X is CH, O or S. SN N e In some cases X is O or S. R3 Rs Rs In some cases X is CH2. R9 A compound of Formula XVb or a salt thereof, 15 wherein, Formula XVb R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF and OCF: R R and R are independently selected from hydrogen, F. 20 C1, Br, and CF: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH CN, and CO: R. R. Rs and Ro are independently selected from hydro gen, CH, alkyl, cykloalkyl, heterocyl, and halogen; and 25 X is a bond, CH, O or S. In some cases X is a bond. In some cases X is O or S. wherein, In some cases X is CH2. R and Rs are independently selected from hydrogen, A compound of Formula XVII or a salt thereof, CH, F, Cl, Br, CF. OCF; R and Ra are independently selected from hydrogen, F. 30 Cl, Br, CF; Formula XVII R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, X N C OCH, CN, CO: R. Rs and Ro are independently selected from hydrogen, ray F, C1, CH, OCF: 35 S-N E is O or S; and wherein, X is CH, O or S. A is an optionally Substituted aryl or optionally Substi A compound of Formula XVI or a salt thereof, tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl), or option 40 ally Substituted heteroaryl (including pyridyl, pyrazyl. oxazolyl or isoxazolyl) or optionally substituted heteroary Formula XVI lalkyl (e.g., heteroarylC1 alkyl or heteroarylC2alkyl) wherein said Substituents are selected from the group con sisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 45 cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, amino, wherein, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 A is an optionally Substituted aryl or optionally Substi acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl) or option C is a heteroaryl including thienyl, furanyl, oxazolyl or ally substituted aryloxo or optionally substituted arylthio, or 50 isoxazolyl each of which can be optionally independently optionally Substituted heteroaryl (including pyridyl, pyrazyl. substituted with one or more substituents selected from: oxazolyl or isoxazolyl) or optionally substituted heteroary fluorine, chlorine, CH and OCF; and lalkyl (e.g., heteroarylClalkyl or heteroarylC2alkyl) or X is O or S. optionally Substituted heteroaryloxo-or optionally Substi A compound of formula XVIIa or a salt thereof, tuted hetero arylthio wherein said substituents are selected 55 from the group consisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 Formula XVIIa alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6) alkenyl, C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, R amino, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, 60 R X N E R C1-C6 acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; and N C is an optionally Substituted pyrrolyl (including pyrrolyl s/ \, 1, pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrro R3 Rs Rs lyloxo (including pyrrolyl-2 or pyrrolyl-3) or optionally substituted pyrrolythio (including pyrrolyl-2 or pyrrolyl-3) or optionally Substituted pyrrolylalkyl (including pyrrolyl-1, US 9,426,995 B2 23 24 wherein, A compound of formula XVIIIa or a salt thereof, R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF. R and Ra are independently selected from hydrogen, F. Formula XVIIIa Cl, Br, CF: 5 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, C(H)O; R7, Rs and R are independently selected from hydrogen, F, C1, CH, OCF: E is O or S; and 10 X is O or S; A compound of formula XVIIb or a salt thereof, wherein, 15 Formula XVIIb R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF, OCF; R6 R and Ra are independently selected from hydrogen, F. R2 Cl, Br, CFs: R / E R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, R3 X N 2 2O OCH CN, C(H)O; s Rs R. Rs and R are independently selected from hydrogen, S-N Ro F, C1, CH, OCF; R E is O or S; and Rs X is CH, O or S. 25 In some cases X is O or S. In some cases X is CH2. wherein, A compound of formula XVIIIb or a salt thereof, R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF; R and Ra are independently selected from hydrogen, F, 30 Formula XVIIIb Cl, Br, CFs: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, R OCH, CN, CO: R. Rs and Ro are independently selected from hydrogen, F, C1, CH, OCF: 35 E is O or S; and X is O or S. A compound of Formula XVIII or a salt thereof, 40 wherein, R and Rs are independently selected from hydrogen, N Formula XVIII CH, F, Cl, Br, CF, OCF: A X R and R are independently selected from hydrogen, F. n y No Cl, Br, CF; S-N 45 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, CO: R. Rs and Ro are independently selected from hydrogen, wherein, F, C1, CH, OCF.; A is an optionally Substituted aryl or optionally Substi E is O or S; and tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl), or option X is CH, O or S. ally Substituted heteroaryl (including pyridyl, pyrazyl. 50 In some cases X is O or S. oxazolyl or isoxazolyl) or optionally substituted heteroary In some cases X is CH. lalkyl (e.g., heteroarylC1 alkyl or heteroarylC2alkyl) A compound of Formula XIX or a salt thereof, wherein said Substituents are selected from the group con sisting of halo, C1-C6 haloalkyl, C6-C10 aryl, C4-C7 55 cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Formula XIX C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6)alkenyl, C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, amino, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; 60 C is heteroaryl including thienyl, furanyl, oxazolyl or wherein, isoxazolyl each of which can be optionally independently A is an optionally Substituted aryl or optionally Substi substituted with one or more substituents selected from: tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl) or option fluorine, chlorine, CH, and OCF; and ally substituted aryloxo or optionally substituted arylthio, or X is CH, O or S. 65 optionally Substituted heteroaryl (including pyridyl, pyrazyl. In some cases X is O or S. oxazolyl or isoxazolyl) or optionally substituted heteroary In some cases X is CH2. lalkyl or optionally substituted heteroaryloxo- or optionally US 9,426,995 B2 25 26 substituted hetero arylthio wherein said substituents are R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, selected from the group consisting of halo, C1-C6 haloalkyl, OCH, CN, C(H)O: C6-C10 aryl, C4-C7 cycloalkyl, C2-C6 alkyl, C2-C6 alk R. Rs and R are independently selected from hydrogen, enyl, C2-C6 alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 F, C1, CH, OCF; aryl(C2-C6)alkenyl, C6-C10 aryl (C2-C6) alkynyl, C1-C6 5 E is O or S: hydroxyalkyl, amino, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, C1-C6 acyloxy, azido, C1-C6 alkoxy and B is C(H) or C(CH); and carboxy, C(H)O; X is a bond, CH, O or S. B is C(H) or C(CH); and A compound of formula XIXc or a salt thereof, C is an optionally Substituted heteroaryl, including thie 10 nyl, furanyl, oxazolyl, isoxazolyl and pyrrolyl (-1, -2 or -3), or optionally Substituted heteroarylalkyl (e.g., Formula XIXc heteroarylClalkyl or heteroarylC2alkyl), including pyrroy lalkyl (e.g., pyrrol C1 alkyl), furanylalkyl, thienylalkyl, oxazolylalkyl or isoxazolyl alkyl, or optionally substituted 15 hetroaryloxo including pyrroyloxo, furanyloxo or thieny loxo, optionally substituted heteroarylthio including pyrro lylthio, furanylthio and thienylthio wherein said substituents are selected from the group consisting of methyl, alkyl, cycyl, heterocycl, hydroxyalkyl, halogen (F or CL), and OCF. A compound of formula XIXa or a salt thereof, wherein, R and Rs are independently selected from hydrogen, 25 CH, F, Cl, Br, CF. OCF; Formula XIXa R and Ra are independently selected from hydrogen, F. R R6 Cl, Br, CFs: R2 X N R7 s R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, 30 OCH CN, CO: B- y le R. Rs and Ro are independently selected from hydrogen, R R5 R8 F, C1, CH, OCF; Ro R4 B is C(H) or C(CH): E is O or S; and 35 wherein, X is a bond, CH, O or S. R and Rs are independently selected from hydrogen, A compound of formula XIXd or a salt thereof, CH, F, Cl, Br, CF and OCF: R and Ra are independently selected from hydrogen, F. Formula XIXd Cl, Br, and CF; 40 R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, and CO: R R. R. Rs and Ro are independently selected from hydro gen, CH, alkyl, cykloalkyl, heterocyl, and halogen; B is C(H) or C(CH); and 45 X is a bond, CH, O or S. In some cases X is a bond. In some cases X is O or S. In some cases X is CH2. A compound of formula XIXb or a salt thereof, 50 wherein, R and Rs are independently selected from hydrogen, Formula XIXb CH, F, Cl, Br, CF. OCF; R and R are independently selected from hydrogen, F. 55 Cl, Br, CF: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, OCH CN, C(H)O; R7, Rs and Ro are independently selected from hydrogen, F, C1, CH, OCF; 60 E is O or S: B is C(H) or C(CH); and wherein, X is a bond, CH, O or S. R and Rs are independently selected from hydrogen, In some cases X is a bond. CH, F, Cl, Br, CF. OCF; 65 R and Ra are independently selected from hydrogen, F. In some cases X is O or S. Cl, Br, CFs: In some cases X is CH2. US 9,426,995 B2 27 28 A compound of formula XIXe or a salt thereof, A compound of Formula XXa or a salt thereof,

Formula XIXe Formula XXa R R6 R2 R7 R R X N s

le N-ON /X1 N Rs R3 Rs Ro R4

wherein, wherein, 15 R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF and OCF: R and Rs are independently selected from hydrogen, R and R are independently selected from hydrogen, F. CH, F, Cl, Br, CF, OCF: Cl, Br, and CF; R and Ra are independently selected from hydrogen, F. R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, Cl, Br, CFs: OCH CN, and CO: R. R. Rs and Ro are independently selected from hydro R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, gen, CH3, alkyl, cykloalkyl, heterocyl, and halogen; OCH, CN, CO: B is C(H) or C(CH); and R. Rs and Ro are independently selected from hydrogen, X is a bond, CH, O or S. F, C1, CH, OCF: In some cases X is a bond. 25 In some cases X is O or S. B is C(H) or C(CH); and In some cases X is CH. E is O or S: A compound of Formula XXb or a salt thereof, X is a bond, CH, O or S. A compound of Formula XX or a salt thereof, 30 Formula XXb R E R Formula XX R2 X N A N C 2 Yy- 35 OS / R8 O- B R3 Rs R9 R4 wherein, A is an optionally Substituted aryl or optionally Substi- 40 wherein, tuted arylalkyl (e.g., arylClalkyl or arylC2alkyl) or option R and Rs are independently selected from hydrogen, CH, F, Cl, Br, CF. OCF; ally substituted aryloxo or optionally substituted arylthio, or R and Ra are independently selected from hydrogen, F. optionally Substituted heteroaryl (including pyridyl, pyrazyl. Cl, Br, CFs: oxazolyl or isoxazolyl) or optionally substituted heteroary R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, lalkyl (e.g., heteroarylClalkyl or heteroarylC2alkyl) or 45 OCH CN, C(H)O; optionally Substituted heteroaryloxo-or optionally Substi R. Rs and R are independently selected from hydrogen, tuted hetero arylthio wherein said substituents are selected F, C1, CH, OCF; from the group consisting of halo, C1-C6 haloalkyl, C6-C10 E is O or S: aryl, C4-C7 cycloalkyl, C2-C6 alkyl, C2-C6 alkenyl, C2-C6 B is C(H) or C(CH); and alkynyl, C6-C10 aryl(C1-C6)alkyl, C6-C10 aryl(C2-C6) 50 X is a bond, CH, O or S. alkenyl, C6-C10 aryl(C2-C6) alkynyl, C1-C6 hydroxyalkyl, In some cases X is a bond. amino, ureido, cyano, C1-C6 acylamino, hydroxy, thiol, In some cases X is O or S. C1-C6 acyloxy, azido, C1-C6 alkoxy and carboxy, C(H)O; In some cases X is CH2. A compound of having Formula XXc or a salt thereof, B is C(H) or C(CH); and 55 C is an optionally Substituted heteroaryl, including thie nyl, furanyl, oxazolyl, isoxazolyl and pyrrolyl (-1, -2 or Formula XXc -3), or optionally Substituted heteroarylalkyl (e.g., heteroarylClalkyl or heteroarylC2alkyl), including pyrroy lalkyl (e.g., pyrrol C1 alkyl), furanylalkyl, thienylalkyl, 60 oxazolylalkyl or isoxazolyl alkyl, or optionally substituted hetroaryloxo including pyrroyloxo, furanyloxo or thieny loxo, optionally substituted heteroarylthio including pyrro lylthio, furanylthio and thienylthio wherein said substituents are selected from the group consisting of methyl, alkyl, 65 cycyl, heterocycl, hydroxyalkyl, halogen (F or Cl), and OCF. US 9,426,995 B2 29 30 wherein, In certain embodiments: the compound has Formula Ia R and Rs are independently selected from hydrogen, and X is a bond; the compound has Formula VIIIb and X and CH, F, Cl, Br, CF. OCF; E are both O; the compound has Formula XIXb and X is a R and Ra are independently selected from hydrogen, F. bond and E is O. Cl, Br, CF; Also described herein is a method for control of unwanted R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, nematodes, the method comprising administering to mam OCH, CN, CO: mals, birds, or their food, plants, seeds or soil a composition R. Rs and R are independently selected from hydrogen, comprising an effective amount of a compound of any of F, C1, CH, OCF: Formulas I, Ia, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, V, Va, Vb, B is C(H) or C(CH): 10 VI, VIa, VIb, VII, VIIa, VIII, VIIIa, VIIIb, IX, IXa, IXb, X, E is O or S; and Xa, XI, XIa, XIb, XII, XIIa, XIIb, XIII, XIIIa, XIV, XIVa, X is a bond, CH, O or S. XIVb. XV, XVa, XVb, XVI, XVIa, XVII, XVIIa, XVIIb, In some cases X is a bond. XVIII, XVIIIa, XVIIIb, XIX, XIXa, XIXb, XIXc, XIXd, In some cases X is O or S. 15 XIXe, XX, XXa, XXb, XXc, XXd and XXe. In some cases X is CH2. In some cases the method entails controlling plant para A compound of Formula XXd or a salt thereof, sitic nematodes and comprises administering to plant Subject to attack by Such nematodes, the seeds of Such plants or the soil in which Such plants are grown or are to be planted. Formula XXd Also described is a nematicidal composition comprising a compound of any of Formulas I, Ia, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIII, VIIIa, VIIIb, IX, IXa, IXb, X, Xa, XI, XIa, XIb, XII, XIIa, XIIb, XIII, XIIIa, XIV, XIVa, XIVb. XV, XVa, XVb. XVI, XVIa, 25 XVII, XVIIa, XVIIb, XVIII, XVIIIa, XVIIIb, XIX, XIXa, XIXb, XIXc, XIXd, XIXe, XX, XXa, XXb, XXc, XXd and XXe at a concentration sufficient to reduce the viability of a parasitic nematode. In some cases, the nematicidal composition further wherein, 30 includes an aqueous Surfactant. Examples of Surfactants that R and Rs are independently selected from hydrogen, can be used include, Span 20, Span 40, Span 80, Span 85, CH, F, Cl, Br, CF. OCF; Tween 20, Tween 40, Tween 80, Tween 85, Triton X 100, R and Ra are independently selected from hydrogen, F. Makon 10, Igepal CO 630, Brij 35, Brij97, Tergitol TMN 6, Cl, Br, CF: Dowfax 3B2, Physan and Toximul TA15. In some cases, the 35 nematicidal composition further includes a permeation R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, enhancer (e.g., cyclodextrin). In some cases, the nematicidal OCH, CN, C(H)O; composition further includes a co-solvent. Examples of R7, Rs and R are independently selected from hydrogen, co-solvents that can be used include ethyl lactate, methyl F, C1, CH, OCF: Soyatefethyl lactate co-solvent blends (e.g., Steposol), iso E is O or S: 40 propanol, acetone, 1,2-propanediol, n-alkylpyrrolidones B is C(H) or C(CH); and (e.g., the AgSolex series), a petroleum based-oil (e.g., aro X is a atom, CH, O or S. matic 200) or a mineral oil (e.g., paraffin oil)). In some cases, A compound of Formula XXe or a salt thereof, the nematicidal composition further includes another pesti cide (e.g., nematicide, insecticide or fungicide) Such as an 45 avermectin (e.g., ivermectin), milbemycin, imidacloprid, Formula XXe aldicarb, oxamyl, fenamiphos, fosthiazate, metam Sodium, etridiazole, penta-chloro-nitrobenzene (PCNB), flutolanil, R metalaxyl, mefonoxam, and fosetyl-al. Useful fungicides include, but are not limited to, silthiofam, fludioxonil, 50 myclobutanil, azoxystrobin, chlorothalonil, propiconazole, tebuconazole and pyraclostrobin. The composition may also comprise herbicides (e.g., trifloxysulfuron, glyphosate, halo Sulfuron) and other chemicals for disease control (e.g., chitosan). 55 Also described is a nematicidal composition comprising: wherein, oxazole, oxadiazole or thiadiazole analogs or mixtures of R and Rs are independently selected from hydrogen, analogs selected from the group consisting of the com CH, F, Cl, Br, CF. OCF; pounds 3-(4-chlorophenyl)-5-(furan-2-ylmethyl)-1,2,4-OX R and Ra are independently selected from hydrogen, F. adiazole, 3-(3-chlorophenyl)-5-(furan-2-ylmethyl)-1,2,4- Cl, Br, CFs: 60 oxadiazole, 3-(4-chlorophenoxy)-5-(furan-2-yl)-1,2,4- R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, oxadiazole, 3-(3-chlorophenoxy)-5-(furan-2-yl)-1,2,4- OCH, CN, CO: oxadiazole, 3-(4-chlorobenzyl)-5-(furan-2-yl)-1,2,4- R. Rs and R are independently selected from hydrogen, thiadiazole, 4-(2,4-dichlorophenyl)-2-(furan-2-yl)oxazole, F, C1, CH, OCF: 4-(2,4-dimethylphenyl)-2-(furan-2-yl)oxazole, 4-(4-chloro B is C(H) or C(CH): 65 phenyl)-2-(furan-2-yl)oxazole, 5-(4-chlorophenyl)-2-(thio E is O or S; and phen-2-ylthio)oxazole, 5-(4-chlorophenyl)-2-(1H-pyrrol-1- X is a bond, CH, O or S. yl)oxazole. US 9,426,995 B2 31 32 In various embodiments the composition further com XXc, XXd or XXe. The compound may be delivered by prises an aqueous Surfactant. Examples of Surfactants that several means including pre-planting, post-planting and as a can be used include, Span 20, Span 40, Span 80, Span 85, feed additive, drench, external application, pill or by injec Tween 20, Tween 40, Tween 80, Tween 85, Triton X 100, tion. Makon 10, Igepal CO 630, Brij 35, Brij97, Tergitol TMN 6, In still another aspect, methods of inhibiting a parasitic Dowfax 3B2, Physan and Toximul TA15. In some cases, the nematode (e.g., M. incognita, H. glycines, B. longicaudatus, nematicidal composition further includes a permeation H. Contortus, A. suum, B. malayi) are provided. Such meth enhancer (e.g., cyclodextrin). In some cases, the nematicidal ods can include contacting the nematode (at any stage of composition further includes a co-solvent. Examples of growth), with a compound, e.g., a compound having For co-solvents that can be used include ethyl lactate, methyl 10 Soyatefethyl lactate co-solvent blends (e.g., Steposol), iso mula I, Ia, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, V, Va, Vb, VI, propanol, acetone, 1,2-propanediol, n-alkylpyrrolidones VIa, VIb, VII, VIIa, VIII, VIIIa, VIIIb, IX, IXa, IXb, X, Xa, (e.g., the AgSolex series), a petroleum based-oil (e.g., aro XI, XIa, XIb, XII, XIIa, XIIb, XIII, XIIIa, XIV, XIVa, XIVb, matic 200) or a mineral oil (e.g., paraffin oil)). In some cases, XV, XVa, XVb, XVI, XVIa, XVII, XVIIa, XVIIb, XVIII, the nematicidal composition further includes another pesti 15 XVIIIa, XVIIIb, XIX, XIXa, XIXb, XIXc, XIXd, XIXe, cide (e.g., nematicide, insecticide or fungicide) Such as an XX, XXa, XXb, XXc, XXd or XXe is provided. avermectin (e.g., ivermectin), milbemycin, imidacloprid, In another aspect, methods of reducing the viability or aldicarb, oxamyl, fenamiphos, fosthiazate, metam Sodium, fecundity or slowing the growth or development or inhibit etridiazole, penta-chloro-nitrobenzene (PCNB), flutolanil, ing the infectivity of a nematode using a nematicidal com metalaxyl, mefonoxam, and fosetyl-al. Useful fungicides pound, e.g., a compound having Formula I, Ia, II, IIa, IIb, III, include, but are not limited to, silthiofam, fludioxonil, IIIa, IIIb, IV, IVa, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIII, myclobutanil, azoxystrobin, chlorothalonil, propiconazole, VIIIa, VIIIb, IX, IXa, IXb, X, Xa, XI, XIa, XIb, XII, XIIa, tebuconazole and pyraclostrobin. The composition may also XIIb, XIII, XIIIa, XIV, XIVa, XIVb. XV, XVa, XVb, XVI, comprise herbicides (e.g., trifloxysulfuron, glyphosate, halo XVIa, XVII, XVIIa, XVIIb, XVIII, XVIIIa, XVIIIb, XIX, Sulfuron) and other chemicals for disease control (e.g., 25 XIXa, XIXb, XIXc, XIXd, XIXe, XX, XXa, XXb, XXc, chitosan). XXd or XXe is provided. Such methods can include con Also described is a method for control of unwanted tacting the nematode with specific a compound, e.g., a parasitic nematode (e.g., nematodes other than C. elegans), compound having Formula I, Ia, II, IIa, IIb, III, IIIa, IIIb, IV. the method including administering to vertebrates, plants, IVa, V, Va, Vb, VI, VIa, VIb, VII, VIIa, VIII, VIIIa, VIIIb, seeds or soil a nematicidal composition including a com 30 IX, IXa, IXb, X, Xa, XI, XIa, XIb, XII, XIIa, XIIb, XIII, pound of any of the formulae described herein in any of the XIIIa, XIV, XIVa, XIVb. XV, XVa, XVb, XVI, XVIa, XVII, nematicidal compositions described herein. XVIIa, XVIIb, XVIII, XVIIIa, XVIIIb, XIX, XIXa, XIXb, In some instances, the nematode infects plants and the XIXc, XIXd, XIXe XX, XXa, XXb, XXc, XXd or XXe; (c) nematicidal composition is applied to the soil or to plants. In reducing the viability or fecundity of the nematode parasite. Some instances, the nematicidal composition is applied to 35 Also described is a method for reducing the viability, soil before planting. In some instances, the nematicidal growth, or fecundity of a nematode parasite, the method composition is applied to Soil after planting. In some comprising exposing the nematode to a compound having instances, the nematicidal composition is applied to Soil Formula I, Ia, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, V, Va, Vb, using a drip system. In some instances, the nematicidal VI, VIa, VIb, VII, VIIa, VIII, VIIIa, VIIIb, IX, IXa, IXb, X, composition is applied to Soil using a drench system. In 40 Xa, XI, XIa, XIb, XII, XIIa, XIIb, XIII, XIIIa, XIV, XIVa, Some instances, the nematicidal composition is applied to XIVb. XV, XVa, XVb, XVI, XVIa, XVII, XVIIa, XVIIb, plant roots or plant foliage (e.g., leaves, stems). In some XVIII, XVIIIa, XVIIIb, XIX, XIXa, XIXb, XIXc, XIXd, instances the nematicide composition is tilled into the Soil or XIXe, XX, XXa, XXb, XXc, XXd or XXe and a method of applied in furrow. In some instances, the nematicidal com protecting a plant from a nematode infection, the method position is applied to seeds. In some instances, the nematode 45 comprising applying to the plant, to the soil, or to seeds of parasite infects a vertebrate. In some instances, the nemati the plant an compound a compound having Formula I, Ia, II, cidal composition is administered to non-human vertebrate. IIa, IIb, III, IIIa, IIIb, IV, IVa, V, Va, Vb, VI, VIa, VIb, VII, In some instances, the nematicidal composition is adminis VIIa, VIII, VIIIa, VIIIb, IX, IXa, IXb, X, Xa, XI, XIa, XIb, tered to a human. In some instances, the nematicidal com XII, XIIa, XIIb, XIII, XIIIa, XIV, XIVa, XIVb. XV, XVa, position is formulated as a drench to be administered to a 50 XVb, XVI, XVIa, XVII, XVIIa, XVIIb, XVIII, XVIIIa, non-human animal. In some instances, the nematicidal com XVIIIb, XIX, XIXa, XIXb, XIXc, XIXd, XIXe, XX, XXa, position is formulated as an orally administered drug. In XXb, XXc, XXd or XXe. Some instances, the nematicidal composition is formulated Also described is a method for protecting a vertebrate as an injectable drug. In some instances, the nematicidal (e.g., a bird or a mammal) from a nematode infection, the composition is formulated for topical applications such as 55 method comprising administering to the vertebrate a com pour-ons, or for the use in tags or collars. pound having I, Ia, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, V. Va, Also described herein is a method of treating a disorder Vb, VI, VIa, VIb, VII, VIIa, VIII, VIIIa, VIIIb, IX, IXa, IXb, (e.g., an infection) caused by a parasitic nematode, (e.g., M. X, Xa, XI, XIa, XIb, XII, XIIa, XIIb, XIII, XIIIa, XIV, XIVa, incognita, H. glycines, B. longicaudatus, H. Contortus, A. XIVb. XV, XVa, XVb, XVI, XVIa, XVII, XVIIa, XVIIb, suum, B. malayi) in a subject, e.g., a host plant, animal, or 60 XVIII, XVIIIa, XVIIIb, XIX, XIXa, XIXb, XIXc, XIXd, person. The method includes administering to the Subject an XIXe, XX, XXa, XXb, XXc, XXd or XXe. The bird can be effective amount of a compound having formula I, Ia, II, IIa, a domesticated fowl (e.g., a chicken, turkey, duck, or goose). IIb, III, IIIa, IIIb, IV, IVa, V, Va, Vb, VI, VIa, VIb, VII, VIIa, The mammal can be a domesticated animal, e.g., a compan VIII, VIIIa, VIIIb, IX, IXa, IXb, X, Xa, XI, XIa, XIb, XII, ion animal (e.g., a cat, dog, horse or rabbit) or livestock (e.g., XIIa, XIIb, XIII, XIIIa, XIV, XIVa, XIVb. XV, XVa, XVb, 65 a cow, sheep, pig, goat, alpaca or llama) or can be a human. XVI, XVIa, XVII, XVIIa, XVIIb, XVIII, XVIIIa, XVIIIb, Described herein are methods for controlling nematodes XIX, XIXa, XIXb, XIXc, XIXd, XIXe, XX, XXa, XXb, parasites by administering a compound described herein. US 9,426,995 B2 33 34 The methods include administering to vertebrates, plants, -continued seeds or soil a nematicidal composition comprising: Formulas: a. an effective amount of a compound or a mixture of compounds having any of the formulae described XIXa herein, for example one of the following formulas: 5 R R6 R2 X N R N N/S Formulas: B NO le 10 R3 Rs R8 Ia R9

R4 O-N- le R R R IV a 3 5 R 8 R R6 2O R4 9 R2 X O R7 X-N N wherein, R Rs NN le Rs R and Rs are independently selected from hydrogen, Ro 25 CH, F, Cl, Br, CF and OCF; R4 R and R are independently selected from hydrogen, F. Formulas: Cl, Br, and CF: VIIa R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, R R6 30 OCH CN, and CO: R2 X N R R. R. Rs and Ro are independently selected from hydro N s gen, CH, alkyl, cykloalkyl, heterocyl, and halogen; N NN le B is C(H) or C(CH); and R3 Rs R8 35 X is a bond, CH, O or S. R4 R9

Xa R R Formulas: 6 R X N R 40 IIa

O-3 le R2 X O E R7 R Rs Rs R4 R 9 45 E/ N R 3 R 5 R8 Formulas: Ro R4 XIIIa R IIb R6 R 50 R X Ny s R R NN's le R3 Rs Rs Rs. R4 R9 55 R4 Formulas:

R XVIa Wa R R6 60 R2 X N- N s R7 R X O E R X-N SN / le NS / N R Rs Rs R3 Rs Rs Ro 65 R9 US 9,426,995 B2 35 -continued -continued Vb Formulas:

VIIa 5 R Rs R2 X N E R Ns/ N R3 Rs N R8 10 Formulas: R9 R4 VIIIa VIIb R R6 R7 15 R3 X N / Rs R4 S-N R9 2O Rs

VIIIb. wherein, R and Rs are independently selected from hydrogen, 25 CH, F, Cl, Br, CF. OCF; R and R are independently selected from hydrogen, F. Cl, Br, CF;

Formulas: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, 30 OCH CN, CO: XIa R. R. Rs and R are independently selected from hydro gen, F, C1, CH, OCF: R B is C(H), C(CH): 35 E is O or S; and R8 X is O or S.

XIb Formulas: 40 IIIa R2 R R7 Rs R3 E O X \ 45 \ y N R8 R B-N Formulas: Rs Ro IIIb. XIVa. 50 R2 R R6 R3 E O X W \ y- 21 Rs 55 R4 B-N Rs R9 Formulas:

XIVb WIa R2 60 R R7 R3 E O X \ \ y N Rs 65 R N - B Rs

US 9,426,995 B2 40 -continued Solvent. Examples of co-solvents that can be used include XXc ethyl lactate, methyl soyate/ethyl lactate co-solvent blends R2 R6 (e.g., Steposol), isopropanol, acetone, 1,2-propanediol. R E n-alkylpyrrolidones (e.g., the AgSolex series), a petroleum R3 W based-oil (e.g., aromatic 200) or a mineral oil (e.g., paraffin X N oil)). In some cases, the nematicidal composition further n f 2 R8 includes another pesticide (e.g., nematicide, insecticide or R4 O- B Ro fungicide) such as an avermectin (e.g., ivermectin), milbe Rs mycin, imidacloprid, aldicarb, oxamyl, fenamiphos, fosthi Formulas: 10 azate, metam Sodium, etridiazole, penta-chloro-nitroben XIX Zene (PCNB), flutolanil, metalaxyl, mefonoxam, and R fosetyl-al. Useful fungicides include, but are not limited to, R R silthiofam, fludioxonil, myclobutanil, azoxystrobin, chloro thalonil, propiconazole, tebuconazole and pyraclostrobin. R3 N E 15 The composition may also comprise herbicides (e.g., tri XN/ \ floxysulfuron, glyphosate, halosulfuron) and other chemi \ y- N Rs cals for disease control (e.g., chitosan). R B- O Also featured is a method for control of unwanted nema todes comprising administering to vertebrates, plants, seeds XIXe or soil a nematicidal composition comprising an effective R amount of: (a) a compound selected from the group con R R6 sisting of 3-(4-chlorophenyl)-5-(furan-2-ylmethyl)-1,2,4- R3 E oxadiazole, 3-(3-chlorophenyl)-5-(furan-2-ylmethyl)-1,2,4- N X W oxadiazole, 3-(4-chlorophenoxy)-5-(furan-2-yl)-1,2,4- \ Y- 4N 25 oxadiazole, 3-(3-chlorophenoxy)-5-(furan-2-yl)-1,2,4- R B- O oxadiazole, 3-(4-chlorobenzyl)-5-(furan-2-yl)-1,2,4- thiadiazole, 4-(2,4-dichlorophenyl)-2-(furan-2-yl)oxazole, Formulas: 4-(2,4-dimethylphenyl)-2-(furan-2-yl)oxazole, 4-(4-chloro phenyl)-2-(furan-2-yl)oxazole, 5-(4-chlorophenyl)-2-(thio

XXd 30 phen-2-ylthio)oxazole, 5-(4-chlorophenyl)-2-(1H-pyrrol-1- yl)oxazole. Also featured is a method for control of unwanted nema todes comprising administering to vertebrates a nematicidal composition comprising an effective amount of: (a) a com 35 pound selected from the group consisting of 3-(4-chloro phenyl)-5-(furan-2-ylmethyl)-1,2,4-oxadiazole, 3-(3-chlo rophenyl)-5-(furan-2-ylmethyl)-1,2,4-oxadiazole, 3-(4- XXe chlorophenoxy)-5-(furan-2-yl)-1,2,4-oxadiazole, 3-(3- chlorophenoxy)-5-(furan-2-yl)-1,2,4-oxadiazole, 3-(4- 40 chlorobenzyl)-5-(furan-2-yl)-1,2,4-thiadiazole, 4-(2,4- dichlorophenyl)-2-(furan-2-yl)oxazole, 4-(2,4- dimethylphenyl)-2-(furan-2-yl)oxazole, 4-(4-chlorophenyl)- 2-(furan-2-yl)oxazole, 5-(4-chlorophenyl)-2-(thiophen-2- ylthio)oxazole, 5-(4-chlorophenyl)-2-(1H-pyrrol-1-yl) 45 oxazole. In certain embodiments of the method the composition further comprises an aqueous Surfactant. Examples of Sur wherein, factants that can be used include, Span 20, Span 40, Span 80, R and Rs are independently selected from hydrogen, Span 85, Tween 20, Tween 40, Tween 80, Tween 85, Triton CH, F, Cl, Br, CF, OCF: 50 X 100, Makon 10, Igepal CO 630, Brij 35, Brij97, Tergitol R and Ra are independently selected from hydrogen, F. TMN 6, Dowfax 3B2, Physan and Toximul TA15. In some Cl, Br, CF; cases, the nematicidal composition further includes a per R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, meation enhancer (e.g., cyclodextrin). In some cases, the OCH, CN, CO: nematicidal composition further includes a co-solvent. R. R. Rs and R are independently selected from hydro 55 Examples of co-solvents that can be used include ethyl gen, F, Cl, CH, OCF; lactate, methyl Soyate/ethyl lactate co-solvent blends (e.g., B is C(H) or C(CH): Steposol), isopropanol, acetone, 1,2-propanediol, n-alky E is O or S: lpyrrolidones (e.g., the AgSolex series), a petroleum based X is a bond, CH, O or S. oil (e.g., aromatic 200) or a mineral oil (e.g., paraffin oil)). The compositions can also include an aqueous Surfactant. 60 In some cases, the nematicidal composition further includes Examples of surfactants that can be used include, Span 20, another pesticide (e.g., nematicide, insecticide or fungicide) Span 40, Span 80, Span 85, Tween 20, Tween 40, Tween 80, Such as an avermectin (e.g., ivermectin), milbemycin, imi Tween 85, Triton X 100, Makon 10, Igepal CO 630, Brij 35, dacloprid, aldicarb, oxamyl, fenamiphos, fosthiazate, metam Brij97, Tergitol TMN 6, Dowfax 3B2, Physan and Toximul sodium, etridiazole, penta-chloro-nitrobenzene (PCNB), flu TA 15. In some cases, the nematicidal composition further 65 tolanil, metalaxyl, mefonoxam, and fosetyl-al. Useful fun includes a permeation enhancer (e.g., cyclodextrin). In some gicides include, but are not limited to, silthiofam, fludioXo cases, the nematicidal composition further includes a co nil. myclobutanil, azoxystrobin, chlorothalonil, US 9,426,995 B2 41 propiconazole, tebuconazole and pyraclostrobin. The com -continued position may also comprise herbicides (e.g., trifloxysulfu Formulas: ron, glyphosate, halosulfuron) and other chemicals for dis VIIa ease control (e.g., chitosan); the nematode infects plants and the nematicidal composition is applied to the Soil or to 5 R R6 plants; the nematicidal composition is applied to Soil before planting; the nematicidal composition is applied to Soil after R X N s R planting; the nematicidal composition is applied to Soil using y NNo. le a drip system; the nematicidal composition is applied to Soil 10 R3 Rs R8 using a drench system; the nematicidal composition is R9 applied to plant roots; the pesticidal composition is applied R4 to seeds; the nematicidal composition is applied to the Xa foliage of plants; the nematode infects a vertebrate; the 6 nematicidal composition is administered to a bird or non 15 R X 2N. s R7 human mammal; the nematicidal composition is adminis N- M N tered to a human; the nematicidal composition is formulated le as a drench to be administered to a non-human animal; the R3 Rs Rs nematicidal composition is formulated as an orally admin R9 istered drug; and the nematicidal composition is formulated 2O R4 as an injectable drug. Formulas: The methods described hereon are particularly valuable XIIIa for the control nematodes attacking the roots of desired crop plants, ornamental plants, and turfgrasses. The desired crop plants can be, for example, soybeans, cotton, corn, tobacco, 25 R2 X N s R wheat, Strawberries, tomatoes, banana, Sugar cane, Sugar y beet, potatoes, or citrus. NN's le R3 Rs R8 Also described is a nematicidal feed for a non-human R9 vertebrate including: 30 R4 a. a feed; and XVIa b. a nematicidal composition, including a nematicidal R X N s R composition described herein. e. In some instances, the feed is selected from the group 35 N- -N SN, le consisting of Soy, wheat, corn, Sorghum, millet, alfalfa, R3 Rs R8 clover, and rye. R9 Also described are feeds that have been supplemented to R4 include one or more of the compounds described herein. Formulas: 40 XIX A nematicidal feed for a non-human vertebrate can com 8. prise: (a) an animal feed; and (b) an effective amount of a nematicidal compound or mixtures of compounds having any of the formulae described herein, for example having R X N s R one of the formula below: 45 y BNo. le R3 Rs R8 R9 Formulas: R4 XXa Ia 50 R R6 R R6 R2 X N s R R2 X R e O s N- M N N le B- X- le 55 R3 Rs R8 R3 Rs Rs R9 R9 R4 R4 IV a R wherein, R6 60 R and Rs are independently selected from hydrogen, R X R7 CH, F, Cl, Br, CF, and OCF. R and R are independently selected from hydrogen, F. N- X-N s NN A le Cl, Br, and CF; R3 Rs B Rs R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, Ro 65 OCH, CN, and CO: R4 R. R. Rs and R are independently selected from hydro gen, CH, alkyl, cykloalkyl, heterocyl, and halogen; US 9,426,995 B2 43 B is C(H) or C(CH); and -continued X is a bond, CH, O or S. Formulas: XIa R 5 Formulas: R N-e E R7 IIa R3 Rs 12N Qu R8 10 R9 R4 XIb R R6

15 R3 X N / IIb Y f 2 Rs R O-N R9 Rs 20 Formulas: XIVa. R

Formulas: 25 R2 Y-N E R7 NN N Wa R R. S Rs Ro R4

30 XIVb R R R3 X

Vb 35 R Rs Formulas: VIIa 40 R R2 X N N E R 45 R3 Rs ! / N. Rs Formulas: R4 Ro VIIIa VIIb R R6 R E 50 R3 X N /

R4 S-N Ro Rs 55

wherein, VIIIb. R and Rs are independently selected from hydrogen, go CH, F, Cl, Br, CF, OCF; R and Ra are independently selected from hydrogen, F. Cl, Br, CFs: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, 65 OCH CN, CO: R. R. Rs and Ro are independently selected from hydro gen, F, C1, CH, OCF;

US 9,426,995 B2 47 B is C(H), C(CH): -continued E is O or S; and Formulas: XXd X is CH, O or S. R R R R3 E Formulas: N X \ 2 XIXb f N Rs R O-B R R 10

XXe R3 X N

R2 y N N Rs R6 R B-O R9 R3 E 15 N X W Rs 2 XIXc f 2 Rs R2 O-B R R3 X wherein, R and Rs are independently selected from hydrogen, R B- O Ro Rs CH, F, Cl, Br, CF, OCF: 25 R and R are independently selected from hydrogen, F. Formulas: Cl, Br, CFs: R is selected from hydrogen, CH, CF, F, Cl, Br, OCF, R OCH CN, CO: E R R. R. Rs and Ro are independently selected from hydro R2 X N 30 gen, F, C1, CH, OCF; e N B is C(H) or C(CH): (S/ Rs E is O or S: R3 Rs R9 X is a bond, CH, O or S. R4 The feed can be selected from the group consisting of: 35 Soy, wheat, corn, Sorghum, millet, alfalfa, clover, and rye. As used herein, an agent with “anthelmintic or anthel R2 R6 minthic or antihelminthic activity” is an agent, which when R W E tested, has measurable nematode-killing activity or results in R3 X N reduced fertility or sterility in the nematodes such that fewer 40 viable or no offspring result, or compromises the ability of ne-Ys, the nematode to infect or reproduce in its host, or interferes R4 O- B Ro with the growth or development of a nematode. The agent Rs may also display nematode repellant properties. In the assay, the agent is combined with nematodes, e.g., in a well of 45 microtiter dish, in liquid or solid media or in the soil containing the agent. Staged nematodes are placed on the Formulas: media. The time of survival, viability of offspring, and/or the XIX movement of the nematodes are measured. An agent with R “anthelmintic or anthelminthic or antihelmthic activity” can, R R 50 for example, reduce the survival time of adult nematodes R3 E relative to unexposed similarly staged adults, e.g., by about N X \ 20%, 40%, 60%, 80%, or more. In the alternative, an agent \ NY- N Rs with “anthelmintic or anthelminthic or antihelminthic activ R4 B- O ity may also cause the nematodes to cease replicating, 55 regenerating, and/or producing viable progeny, e.g., by about 20%, 40%, 60%, 80%, or more. The effect may be apparent immediately or in Successive generations. XIXe The term “halo' or “halogen refers to any radical of R2 fluorine, chlorine, bromine or iodine. R R6 60 The term “alkyl as employed herein by itself or as part of another group refers to both Straight and branched chain R3 E N X W radicals of up to ten carbons. Typical Co alkyl groups N include methyl, ethyl, propyl, isopropyl, butyl, Sec-butyl, (S1 Nes, tert-butyl, 3-pentyl, hexyl and octyl groups, which may be R B- O 65 optionally substituted. Rs The term “alkenyl' as employed herein by itself or as part of another group means a straight or branched chain radical US 9,426,995 B2 49 50 of 2-10 carbon atoms, unless the chain length is limited Common acyloxy groups are any C acyl (alkanoyl) thereto, including at least one double bond between two of attached to an oxy (—O—) group, e.g., formyloxy, acetoxy, the carbon atoms in the chain. Typical alkenyl groups propionoyloxy, butanoyloxy, pentanoyloxy and hexanoy include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-prope loxy. nyl, 1-butenyl and 2-butenyl. The term heterocycle is used herein to mean a saturated or The term “alkynyl is used herein to mean a straight or partially saturated 3-7 membered monocyclic, or 7-10 mem branched chain radical of 2-10 carbon atoms, unless the bered bicyclic ring system, which consists of carbon atoms chain length is limited thereto, wherein there is at least one and from one to four heteroatoms independently selected triple bond between two of the carbon atoms in the chain. from the group consisting of O, N, and S, wherein the 10 nitrogen and Sulfur heteroatoms can be optionally oxidized, Typical alkynyl groups include ethynyl, 1-propynyl, the nitrogen can be optionally quaternized, and including 1-methyl-2-propynyl, 2-propynyl, 1-butynyl and 2-butynyl. any bicyclic group in which any of the above-defined Alkoxy groups contain oxygen Substituted by one of the heterocyclic rings is fused to a benzene ring, and wherein the Co alkyl groups mentioned above, which may be option heterocyclic ring can be substituted on carbon or on a ally substituted. 15 nitrogen atom if the resulting compound is stable. Alkylthio groups contain sulfur substituted by one of the Common saturated or partially Saturated heterocyclic Co alkyl groups mentioned above, which may be option groups include tetrahydrofuranyl, pyranyl, piperidinyl, pip ally substituted. Also included are the sulfoxides and sul erazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indoli fones of Such alkylthio groups. nyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl. Amino groups include —NH, -NHRs and —NRR, chromanyl, pyrazolidinyl pyrazolinyl, tetronoyl and wherein Rs and R are Coalkyl or cycloalkyl groups, or tetramoyl groups. Rs and R are combined with the N to form a ring The term "heteroaryl' as employed herein refers to groups structure, Such as a piperidine, or Rs and R are combined having 5 to 14 ring atoms; 6, 10 or 14 at electrons shared in with the N and other group to form a ring, such as a a cyclic array; and containing carbon atoms and 1, 2 or 3 piperazine. The alkyl group may be optionally Substituted. 25 oxygen, nitrogen or Sulfur heteroactoms. The term “aryl as employed herein by itself or as part of Example heteroaryl groups include thienyl (thiophenyl), another group refers to monocyclic, bicyclic or tricyclic benzob thienyl, naphtho2,3-bithienyl, thianthrenyl, furyl aromatic groups containing from 6 to 14 carbons in the ring. (furanyl), pyranyl, isobenzofuranyl, chromenyl, Xanthenyl, Common aryl groups include Caryl, preferably Co phenoxanthiinyl, pyrrolyl, including without limitation aryl. Typical Cea aryl groups include phenyl, naphthyl, 30 2H-pyrrolyl, imidazolyl, pyrazolyl pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, biphenylenyl and fluorenyl groups. isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-qui Cycloalkyl groups are Cs cycloalkyl. Typical cycloalkyl nolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclo 35 quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, B-carboli hexyl and cycloheptyl. nyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthroli The term “arylalkyl is used herein to mean any of the nyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, above-mentioned Co alkyl groups substituted by any of furazanyl, phenoxazinyl, 1,4-dihydroquinoxaline-2,3-dione, the above-mentioned Caryl groups. Preferably the ary 7-aminoisocoumarin, pyrido 1.2-Opyrimidin-4-one, pyra lalkyl group is benzyl, phenethyl or naphthylmethyl. Pre 40 Zolo 1.5-Opyrimidinyl, including without limitation pyra ferred arylalkyl groups are arylCalkyl and arylCalkyl. Zolo 1.5-Opyrimidin-3-yl, 1,2-benzoisoxazol-3-yl, benz The term “arylalkenyl' is used herein to mean any of the imidazolyl, 2-oxindolyl and 2-oxobenzimidazolyl. Where above-mentioned Coalkenyl groups substituted by any of the heteroaryl group contains a nitrogen atom in a ring. Such the above-mentioned Caryl groups. nitrogen atom may be in the form of an N-oxide, e.g., a The term “arylalkynyl is used herein to mean any of the 45 pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-ox above-mentioned Co alkynyl groups substituted by any of ide. the above-mentioned Caryl groups. The term "heteroaryloxy” is used herein to mean oxygen The term “aryloxy' is used herein to mean oxygen substituted by one of the above-mentioned heteroaryl Substituted by one of the above-mentioned Caryl groups, groups, which may be optionally substituted. Useful het which may be optionally substituted. Common aryloxy 50 eroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrro groups include phenoxy and 4-methylphenoxy. lyloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy. The term “arylalkoxy” is used herein to mean any of the The term "heteroarylalkoxy” is used herein to mean any above mentioned Coalkoxy groups Substituted by any of of the above-mentioned Coalkoxy groups substituted by the above-mentioned aryl groups, which may be optionally any of the above-mentioned heteroaryl groups, which may Substituted. Example arylalkoxy groups include benzyloxy 55 be optionally substituted. and phenethyloxy. A preferred pyrrolalkyl is pyrrol C alkyl. Example haloalkyl groups include Co alkyl groups Preferred furanlalkyl, thienylalkyl, oxazolyalkyl and isox substituted by one or more fluorine, chlorine, bromine or azolylalkyl groups are furanlCalkyl, thienylCalkyl, iodine atoms, e.g., fluoromethyl, difluoromethyl, trifluorom oxazolyC alkyl and isoxazolylcalkyl respectively. ethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, 60 A permeation enhancer is generally an agent that facili chlorofluoromethyl and trichloromethyl groups. tates the active compounds of the invention. Acylamino (acylamido) groups include any C acyl A co-solvent (i.e., a latent solvent or indirect solvent) is an (alkanoyl) attached to an amino nitrogen, e.g., acetamido, agent that becomes an effective solvent in the presence of an chloroacetamido, propionamido, butanoylamido, pentanoy active solvent and can improve the properties of the primary lamido and hexanoylamido, as well as aryl-substituted C 65 (active) solvent. acylamino groups, e.g., benzoylamido, and pentafluoroben The composition can be produced in concentrated form Zoylamido. that includes little or no water. The composition can be US 9,426,995 B2 51 52 diluted with water or some other solvent prior to use to treat conenoides, Hemicycliophora, Paratylenchus, Tilenchulus, plants, seeds, soil or vertebrates. Aphelenchoides, Bursaphelenchus, Rhadinaphelenchus, The details of one or more embodiments of the invention Longidorus, Xiphinema, Trichodorus, and Paratrichodorus, are set forth in the accompanying drawings and the descrip Dirofiliaria, Onchocerca, Brugia, Acanthocheilonema, Ael tion below. Other features, objects, and advantages of the urostrongylus, Anchlostoma, Angiostrongylus, Ascaris, invention will be apparent from the description and draw Bunostomum, Capillaria, Chabertia, Cooperia, Crenosoma, ings, and from the claims. Dictyocaulus, Dioctophyme, Dipetalonema, Dracunculus, Enterobius, Filaroides, Haemonchus, Lagochilascaris, Loa, DETAILED DESCRIPTION Manseonella, Muellerius, Necator, Nematodirus, Oesoph 10 agostomum, Ostertagia, Parafilaria, Parascaris, Physallop Described herein are certain compounds, some of which tera, Protostrongylus, Setaria, Spirocerca, Stephanogilaria, are oxazole, oxadiazole and thiadiazole analogs with potent Strongyloides, Strongylus, Thelazia, Toxascaris, Toxocara, broad spectrum nematicidal activity. Trichinella, Tricho strongylus, Trichuris, Uncinaria, and The nematicidal compounds may be supplied to plants Wuchereria. Particularly preferred are nematodes including exogenously, through sprays for example. These compounds 15 Dirofilaria, Onchocerca, Brugia, Acanthocheilonema, Dipe may also be applied as a seed coat. The compounds can be talonema, Loa, Mansonella, Parafilaria, Setaria, Stephano applied to plants or the environment of plants needing filaria, and Wucheria, Pratylenchus, Heterodera, Meloid nematode control, or to animals or the food of animals ogyne, Paratylenchus. Species that are particularly preferred needing nematode parasite control. The compositions may a. Ancylostoma caninum, Haemonchus contortus, be applied by, for example drench or drip techniques. With Trichinella spiralis, Trichurs muris, Dirofilaria immitis, drip applications compounds can be applied directly to the Dirofilaria tenuis, Dirofilaria repens, Dirofilari ursi, Ascaris base of the plants or the soil immediately adjacent to the suum, Toxocara Canis, Toxocara Cati, Strongyloides ratti, plants. The composition may be applied through existing Parastrongyloides trichosuri, Heterodera glycines, Glo drip irrigation systems. This procedure is particularly appli bodera pallida, Meloidogyne javanica, Meloidogyne incog cable for cotton, Strawberries, tomatoes, potatoes, veg 25 nita, and Meloidogyne arenaria, Radopholus similis, Lon etables and ornamental plants. Alternatively, a drench appli gidorus elongatus, Meloidogyne hapla, and Pratylenchus cation can be used where a sufficient quantity of nematicidal penetrans. composition is applied Such that it drains to the root area of The following examples are, therefore, to be construed as the plants. The drench technique can be used for a variety of merely illustrative, and not limitative of the remainder of the crops and turf grasses. The drench technique can also be 30 disclosure in any way whatsoever. All of the publications used for animals. Preferably, the nematicidal compositions cited herein are hereby incorporated by reference in their would be administered orally to promote activity against entirety. internal parasitic nematodes. Nematicidal compositions may also be administered in Some cases by injection of the host EXAMPLES animal or by topical applications. 35 The concentration of the nematicidal composition should Example 1 be sufficient to control the parasite without causing signifi cant phytotoxicity to the desired plant or undue toxicity to M. incognita testing of several nematicidal compounds in the animal host. The compounds disclosed in this invention a miniaturized greenhouse assay. have a good therapeutic window. 40 Overview: We have surprisingly found that certain oxazole, oxadi The test compound is dissolved in an acetone solution and azole and thiadiazole analogs (e.g., 3-(4-chlorophenyl)-5- added to water. A sprouted cucumber seedling is placed into (furan-2-ylmethyl)-1,2,4-oxadiazole, 3-(3-chlorophenyl)-5- a vial with dry sand and the water-chemical solution is added (furan-2-ylmethyl)-1,2,4-oxadiazole, 3-(4-chlorophenoxy)- immediately. Twenty four hours later Meloidogyne incog 5-(furan-2-yl)-1,2,4-oxadiazole, 3-(3-chlorophenoxy)-5- 45 nita eggs are added to the vials and 10 to 12 days later the (furan-2-yl)-1,2,4-oxadiazole, 3-(4-chlorobenzyl)-5-(furan roots are evaluated for nematode galling. 2-yl)-1,2,4-thiadiazole, 4-(2,4-dichlorophenyl)-2-(furan-2- Procedure: yl)oxazole, 4-(2,4-dimethylphenyl)-2-(furan-2-yl)oxazole, Cucumber seeds are sprouted for 3 days in moist paper 4-(4-chlorophenyl)-2-(furan-2-yl)oxazole, 5-(4-chlorophe towels. Acceptable sprouts should be 3 to 4 cm long with nyl)-2-(thiophen-2-ylthio)oxazole, 5-(4-chlorophenyl)-2- 50 several lateral roots just emerging. Stock Solutions of chem (1H-pyrrol-1-yl)oxazole) have nematicidal potencies com istry are prepared in a mixture of acetone and Triton X100 parable with organophosphate and carbamate standards yet (412 mg in 500 mL) to a final concentration of 5 mg/mL. display excellent selectivity for nematodes over plants and The chemical stock solution is then added to 10 mL deion animals. Thus, these analogs will provide useful compounds ized water plus 0.015% Triton X 100 and mixed thoroughly. for nematode parasite control. 55 This is enough to test each condition in triplicate. Ten mL The nematicidal agents described herein can be applied in dry sand is added to each vial. At this time the solubility of conjunction with another pesticidal agents. The second the chemistry is visually determined and recorded as either agent may, for example, be applied simultaneously or ppt (large precipitates) or cloudy (fine precipitates). Seed sequentially. Such pesticidal agents can include for example, lings are planted by tilting the vial and laying the seedling avermectins for animal applications. 60 in the correct orientation so that the cotyledons are just The aforementioned nematicidal compositions can be above the sand and then tilting back to cover the radicles used to treat diseases or infestations caused by nematodes of with sand. 3.3 ml water?chemical mix is added to each vial the following non-limiting, exemplary genera: Anguina, and the vials placed in racks under fluorescent light banks. Dity lenchus, Tilenchorhynchus, Pratylenchus, Radopholus, The vials are inoculated two days after planting by adding Hirschmanniella, Nacobbus, Hoplolaimus, Scutellonema, 65 500 vermiform M. incognita eggs to each vial in 50 uL of Rotylenchus, Helicotylenchus, Rotylenchulus, Belonolai deionized or spring water. The vials are then kept under the mus, Heterodera, other cyst nematodes, Meloidogyne, Cri fluorescent lamps at ambient room temperature and watered US 9,426,995 B2 53 54 as needed with 1 mL deionized water, usually twice during TABLE 1 A-continued duration of test. Harvest of the cucumber plants is done 10 Potent nematicidal oxadiazole, thiadiazole and to 12 days after inoculation by washing sand off the roots. oxazole 2-thiophene and 2-furan analogs A root gall rating and visual phytotoxicity rating is assigned showing examples of substitutions compatible with high activi using the following scales: Gall rating scale (Gall: % root 5 mass galled): 0–0-5%; 1=6-20%; 2=21-50%; and 3–51 8 ppm 100%. The average of the triplicate gall rating is then Name Analog gall ratings calculated: green=0.00-0.33 (no galls); yellow=0.67-1.33 7 O 1.33 (mild galling); orange=1.67-2.33 (moderate galling); N \ red=2.67-3.00 (severe galling). Visual phytotoxicity scale is 10 N1,N. also assigned (Vis, tox; visual reduction in root mass com pared to the control): rs1-mild stunting: rs2=moderate stunt \ { ing: rs3-severe stunting. 8 O O.676 TABLE 1A 15 C \ NN1S Potent nematicidal oxadiazole, thiadiazole and oxazole 2-thiophene and 2-furan analogs showing examples of Substitutions compatible with high activity \ { d 8 ppm 9 s 1.33 Name Analog gall ratings S le 1 NS 1.37 C O O le y C 25 N \ { \ N Oxamyl 1.33, 1.33°, N - O (1 ppm) 1.33°, 1.33d Data with the same letters are taken from the same test. 2 s 1.3a 30 O A variety of single or double substitutions on the six le membered aromatic ring of the phenyl-2-furan and phenyl N 2-thiophene oxadiazoles and oxazoles are compatible with \ N high nematicidal activity. Examples of preferred single 35 Substitutions include but are not limited to halogens, CH, C N CF. OCF, and OCH especially in the para position (4-po 3 O Of sition) of the phenyl ring. The phenyl ring can also be multiply Substituted in a way compatible with high nemati N \ cidal efficacy. Ring numbering system is shown below. sk N1N 40 N-O

C 45 4 O Of N \ C sk\ N1,N. N-O 50 TABLE 1B 5 O 0.67 A potent nematicidal oxazole pyrole analogs N \ showing example showing high nematicidal activi 55 1 ppm gall Y-N Name Analog ratings* N-S 10 o 1.33 C C 60 y- 2 6 O 0.33 \ { Oxamyl 1.33e Fenamiphos O

C 65 The phenyl-N-pyrole analog has nematicidal potency equivalent to the commercial carbamate nematicide oxamyl US 9,426,995 B2 55 56 and similar to the nematicide fenamiphos. Oxamyl and TABLE 2A fenamiphos are highly toxic compounds classified as toxic ity Class I chemicals by the US Environmental Protection RKN greenhouse soil assay on cucumber plants Agency. 0 day Example 2 1 kg/ Name Analog harate General Greenhouse Testing Protocols 10 3 O 89% N \ Soybean Planting and Growth: Soybeans seeds are planted in 100% sand in two inch 0-y-n square plastic pots. Chemical treatment is done when the N-O Soybeans show the first trifoliate beginning to emerge about 15 10 to 12 days after planting. At least four hours after C chemical application the nematode soybean cyst nematode (SCN) eggs are applied and 28 days after the egg inoculation 10 the test is harvested. C O NC) 100% Cucumber Planting and Growth O-cy 2 Cucumber seeds are planted in a sandy soil mixture in two N inch square plastic pots. When the cotyledons are fully opened and just as the first leaf begins to emerge, usually 7 25 4 O \ 83% days after planting, chemistry for the 7-day treatment is N applied. One week later the chemistry for the 0 day treat O N S ment is applied. Separate plants are used for each applica tion. The plants are generally in the 1-2 leaf stage now. At least four hours after the chemistry application the pots are inoculated with root knot nematode (RKN) eggs. Plants are 30 rated for galling 14 days after the egg inoculation. Fenamiphos 100% Chemical Formulation and Application One milligram of chemistry per four pots is equal to one Data shows percent control (i.e., galling reduction) relative to the control blank treatment, kilogram per hectare of chemical. A standard test uses four 35 replications. For rates above 2 kg/ha, the desired amount of Data with the same letters are taken from the same test. chemical is weighed into a 30 ml vial (example: 8 kg/ha rate-8 mg chemical in 30 ml vial). The chemical is dissolved TABLE 2B in 2 ml of appropriate solvent, generally acetone. For rates below 2 kg/ha, 2 milligrams of chemistry is weighed into the 40 SCN greenhouse soil assav on sowbean plants vial and dissolved in 2 ml of the solvent. The appropriate 0 day amount of chemical concentrate is then pipetted into a 0.25 kg/ separate 30 ml vial and solvent is added to bring the volume Name Analog harate to 2 ml (example 0.5 kg/ha=0.5 ml of concentrate--1.5 ml solvent). Each dissolved concentrate is then brought to a 45 3 O 79%, total of 20 milliliters using 0.05% Triton X 100 surfactant N \ 790, Solution. 0-y-n Chemical and Nematode Application N-O Pots to be treated are moist but not saturated. To each of 50 four pots, five milliliters of the appropriate chemical solu tion is pipetted to the media Surface making Sure to avoid C contact with the base of the plant. Immediately following 4 O 67%, chemical application, using a mist nozzle, the pot surface is N \ 789, wetted sufficiently to saturate the pot watering in the chem 55 O N1S istry. The chemical application is done in the morning. C \ Nematode eggs, either SCN or RKN, are added to dis N-O tilled water to create a concentration of 1000 vermiform eggs per liter of water. At least four hours after chemical treatment the eggs are applied to the treated pots plus 60 Oxamyl 67.9% non-treated check plants. A small hole about 1 cm deep is Fenamiphos 90% punched into the pot surface. One milliliter of the nematode *Data shows percent control (i.e., cyst reduction) relative to the control blank treatment, egg slurry is pipetted into the hole. Immediately afterwards Data with the same letters are taken from the same test. the hole is gently covered. Watering of the test plants is then restricted to only water as needed to prevent wilt for a period 65 Certain oxazoles, oxadiazoles and thiadiazoles are highly of 24 hours. After the 24 hour restricted watering, normal efficacious nematicides in bioactive soil with potencies Sub-irrigation watering is done for the duration of the test. comparable to fenamiphos and oxamyl. US 9,426,995 B2 57 58 Example 3 Eurofins/Product Safety Laboratories (Dayton, N.J.). CD-1/ Swiss derived albino mice were obtained and group housed Belonalaimus longicaudatus (Sting Nematode) in Suspended solid bottom caging. The mice were fed rodent Testing Protocols chow and filtered tap water was supplied ad libitum. Fol lowing acclimation to the laboratory setting, a group of Populations of sting (Belonolaimus longicaudatus) nema animals was fasted overnight by removing food from the todes are maintained on St. Augustine turfgrass on Soil in cages. After the fasting period, three female mice were 15-cm pots. At test initiation the turf is removed from the selected based on vitality and initial body weights. The pots and the soil containing nematode eggs, juveniles, and individual compound doses were calculated from these body adults is Subdivided into pots each containing a volume of weights. 125 cm. The compounds to be tested are dissolved in 3 ml 10 of acetone using 3, 6, or 15 mg to achieve equivalent Surface The test Substance was prepared as a 1% (50 mg/kg) or area application rates of 2, 4, or 10 kg/ha, respectively. The 5% (500 mg/kg) weight to weight (w/w) mixture in a 0.5% 3 ml acetone stock solution is added to 30 ml of water, and w/w solution of carboxymethylcellulose (CMC) in distilled 5 ml of that solution is used to drench each of 6 replicate test water. A tissue homogenizer was used to create a homoge pots prepared as described above. The treated pots contain neous mixture. A dose of 50 or 500 mg/kg was administered ing nematodes are incubated in the laboratory at ambient 15 to three healthy mice per dose level by oral intubation using temperature of approximately 25°C. After 3 days the soil a ball-tipped gavage needle attached to a syringe. After from each pot is washed onto a modified Baermann appa administration, the animals were returned to their cages, and ratus comprised of a screen Supporting a layer of filter paper feed was replaced immediately after dosing. on which the soil sample is placed and set in a dish of water. The animals were observed for mortality, signs of gross The samples are then incubated at 25° C. for 24 hours to toxicity and behavioral changes during the first several hours allow the live nematodes to migrate through the paper and post dosing and at least once daily for up to 14 days. Body screen and into a water reservoir to be collected for counting weights were recorded prior to initiation and on Days 7 and with a light microscope. Nematodes that have been killed or 14 or a soon as possible after death. immobilized by the test compounds are not able to migrate into the reservoir. 25 Example 6 Example 4 Advanced Greenhouse Testing Protocols C. elegans Testing Protocols Pre-Plant Incorporated Test (PPI) Various compounds were tested for nematicidal activity 30 The PPI test examines the effect of pre-incorporation of against C. elegans using contact assays in wells. The assays compounds in Soil and longer aging to simulate in furrow were performed as described below. The test compounds methods of nematicide application in the field. The PPI test were solubilized in DMSO at 10 mg/ml to create 100x stock exposes compounds to a higher Volume of soil and drying Solutions. A dilution series was created by diluting the Stock which can result in more severe soil binding. Compounds solution with DMSO. For each well assay 4 ul of the 35 are also aged for longer periods which can lead to more appropriate dilution is added to a well of a test plate. extensive biotic and abiotic degradation further limiting A 400 ul aliquot of bacterial stock (in M9 buffer with activity. ampicillin and nystatin) are added to each well of the test The chemically treated soil (sandy soil mix) for all plate. Worms are added and the test plate placed on a rotary treatment days (e.g., 7 days, 14 days, 21 days) treatments is shaker and held at 20° C. Worms are examined and scored potted into their appropriate pots. On the same day the 7 day at 4 hrs, 24 hrs, 48 hrs and 72 hours. 40 treatment pots are seeded. One week later eggs are applied L1 worms and L4 worms were used in the assay. L1 and 14 days after egg application the test is harvested. The worms are prepared by plating eggs on a plate without a 14 day treatments are planted 7 days after the first planting. bacterial feeding layer. The eggs hatch and arrest at the L1 The 14 day planting and 7 day inoculation happen on the stage. This L1 stage population is then used to create a stock for the experiments. To create an L4 stage stock a small same day. One week later the 14 day treatments are inocu number of worms are taken from an overgrown and starved 45 lated with eggs. These are harvested 14 days after the plate of worms and seeded on a plate with a bacterial feeder inoculation. The 21 day treatments are planted 14 days after layer. A 25ul aliquot of worms is added to each well in the the first planting. The 14 day inoculation and 21 day planting assay. are done on the same day. One week later the 21 day plants To demonstrate that these compounds do not affect nema are inoculated with eggs. The 7 day treatment is harvested todes by induction of apoptosis, Caenorhabditis elegans 50 the same day as the 21 day inoculation. Fourteen days after mutants defective in the apoptotic pathway, ced-3(n717) and inoculation the 21 day plants are harvested. ced-4(N1162) mutants (Ellis H M, Horvitz H R. Genetic control of programmed cell death in the nematode C. elegans. 1986 Cell 44:817-829), were evaluated for suscep Treatment Planting Inoculation Harvest tibility to 10 g/ml DC5823 on NGM agar plates. No 55 7 day day O day 7 day 21 observable phenotypic difference in susceptibility between 14 day day 7 day 14 day 28 the wild-type C. elegans strain (N2 Bristol) and the ced-3 21 day day 14 day 21 day 35 and ced-4 mutants were observed, including time to mor tality. These data indicate that the claimed structures do not For each compound a stock is prepared using 4 mg affect apoptosis in either mammalian cells or nematodes. 60 material in 4 ml of acetone. The soil is mixed by placing 80 ml of field soil and 320 ml of sand in a plastic bag and Example 5 mixing well. The formulation for treatment is done by adding 2.13 ml (8 kg/ha rate), 1.06 ml (4 kg/ha rate) or 0.53 Mouse Acute Toxicity Testing ml (2 kg/ha rate) to a vial and raising it with 10 ml in 0.05% 65 X100. Soil is then treated by adding the entire 10 ml to the Acute oral toxicity testing was performed in mice in 400 ml of mix in the bag. The treated soil is immediately accordance with test method P203.UDP, as administered by mixed well in the sealed bag to distribute the compound US 9,426,995 B2 59 60 evenly. Approximately 95 ml is used to fill each 2-inch -continued square pot up to the top with some soil compression and flattening. For each compound and for the control treatments Y\ ?yn, 4 pots are filled. All pots are watered until moist but with no R - O N 21 run-out through the bottom. The PPI test simulates 8, 4 and 2 kg/ha rates incorporated 15 cm deep in the field and is equivalent to the 2, 1 and 0.5 kg/ha drench application rates in the standard 2-inch pot cucumber greenhouse assay. 10 The alpha aminoketone 1 is reacted with carbon disulfide Example 9 in the presence of sodium carbonate in ethanol to yield the Seed Treatment Test of Root Knot Nematode on corresponding oxazole-2-thiol 2 in good yield with an Cucumber Plants and Soybean Cyst Nematode on acceptable purity for the next step. The thiol conversion of Soybean Plants 15 the compound 2 to chlorine is accomplished with phospho rouschloride (POCl3) in presence of triethylamine at higher For a given concentration the chemical is dissolved in 500 temperature. Then, the compound 3 is reacted with the ul of acetone and one gram of cucumber seed (RKN test) or appropriate derivative of pyrrole (after treatment with soybean seed (SCN test) is added (e.g., 20 mg active sodium hydride) at higher temperature to yield the desired ingredient in 500 ul acetone plus 1 gram of seed). The seed 2-pyrrol-5-substituted oxazole analog 5. Solutions are agitated until all seeds were thoroughly cov ered with the chemical solution. The acetone is then allowed Specifically, the compounds of this invention with For mulae IIIa can be prepared as illustrated by the exemplary to evaporate by air drying the seeds. The seeds are planted reaction in Scheme 2. in 2-inch pots containing Sandy soil and then the pots are 25 inoculated with 1000 Meloidogyne incognita (RKN) or 1000 Heterodera glycines (SCN) eggs per pot three days after planting. Plants are rated for galling 14 days after egg Scheme 2: Synthetic scheme to compounds of the Formula IIIa inoculation for RKN or 28 days after egg inoculation for SCN. 30

Example 10 A O R- Z 2 Description of Synthesis of the Compounds of the Formulas I to XX 35 NHHCI The compounds of this invention of the Formulas I to XX 1 may be prepared using methods known to those skilled in the s art. Specifically, the compounds of this invention with A O O POC Formula Ia can be prepared as illustrated by the exemplary 40 R- Z R2 - reaction in Scheme 1. N H Scheme 1: Synthetic scheme to compounds of the Formula Ia 3 45 s R2 NS A O A O NaCO3. CS R- Z -e-2 3. 2 N NHHCI 50 1

R- \ O SH POCl3 55 N 2 HN1VR2X The appropriate alpha amine ketone 1 is reacted with acyl 60 chloride 2 in presence of base to yield the acylaminoketone Z S. 3. A cyclization of the linear precursor 3 to corresponding

R- \ O --e-4 oxazol compound 4 is accomplished with phosphorousoxy S. NaH chloride in good yields. 65 Specifically, the compounds of this invention with For mula VIIIa can be prepared as illustrated by the exemplary reaction in Scheme 3. US 9,426,995 B2 61 -continued Scheme 3: Synthetic scheme to compounds of the Formula VIIIa O NH R o R AR R2 YC OH Br EN InC -OH C -e- \ / TEA, CC1, N Dioxane, DIEA -5-10° \ / H O-50 C. 1 2 RN/F YC NH2OHHCI NH -e- DIEA, MeOH, rt 10 R SC o -O N R2 Dioxane \ / 120° C., 15h O

R2 = (,

25 Specifically, the compounds of this invention with For mulae XIIIa can be prepared as illustrated by the exemplary reaction in Scheme 5. The appropriate benzimidamine is reacted with trichloromethyl hypochlorothioite to yield the 30 corresponding 5-chloro-3-substitutted-1,2,4-thiadiazole 2. The chlorine displacement of intermediate 2 with the appro S. f.R O, RY is priate derivative of pyrrole was accomplished in DMSO to afford the desired 5-pyrrolyl thiadiazole anolog 4 * (ii ( ; (; , ; 35 Scheme 5: Synthetic scheme to compounds of the Formulae XIIIa First, cyanogen bromide in tetrachloromethane is reacted v. C. with the appropriate phenol analog 1 in the presence of N C >< triethylamine to give the corresponding cyanate 2 which in 40 R-H Ns C the next step is converted to the corresponding amidoxime 2 NH 6 3 by reacting with hydroxylamine in methanol in the pres ence of DIEA. Then, the amidoxime 3 is reacted with the NH2 appropriate analog of acyl chloride to give a linear precursor 45 1 4 which after cyclization yields the desired 3,5-disubsti s tuted-1,2,4-oxadiazole 5 in?), Specifically, the compounds of this invention with For N Ms mulae IXa can be prepared as illustrated by the exemplary R- 3 reaction in Scheme 4. The benzonitrile 1 is conerted to the 50 2 N Hos corresponding hydroxyimidate 2 when reacted with hydrox ylamine hydrochloride in methanol in the presence of DIEA NN'sX-c. in methanol at room temperature overnight. Then the ben 2 Zohydroxyimidate 2 is acylated with an appropriate furan or 55 NS s thiophene acetyl chloride in the presence of DIEA to give a A N /N linear precursor 3 which after cyclization yields the desired R / KYM 3,5-disubstituted 1,2,4-oxadiazole 4. N-S 4 60 Scheme 4: Synthetic scheme to compounds of the Formulae DXa Specifically, the compounds of this invention with For NH2OHHCI mula XVa can be prepared as illustrated by the exemplary DIEA, MeOH, rt reaction in Scheme 6. The synthesis starts with the reaction 65 of an appropriate benzamide substrate 1 with chlorocarbo 1 nylsulfenyl chloride to yield the oxathiazolone compound 2. In the next step the oxathiazoline intermediate 2 is reacted US 9,426,995 B2 63 64 with the appropriate 2-(furanyl) or (thiophenylacetonitrile in Formula Ia Example : 5-(4-chlorophenyl)-2-(1H toluene under microwave conditions to give the desired pyrrol-1-yl)oxazole 3,5-disubstituted-1,2,4-thiadiazole product 4. The starting 2-amino-1-(4-chlorophenyl)ethanone hydro chloride was prepared according to the following procedure. Scheme 6: Synthetic scheme to compounds of the Formulae XVa. The 1-(4-chlorophenyl)ethanone (1.0 eq.) was dissolved in glacial acetic acid (1 mL per mmol). To this was added a slurry of pyridinium bromide perbromide (1.03 eq.) in acetic R--1N acid (1 mL per mmol). The heterogeneous mixture was 21 NH CICOSC 10 stirred for 4 h at ambient temperature. After about 30 min. toluene the mixture turned homogeneous. After pouring into ice NH2 water a yellow precipitate was filtered off and washed with water (2x1 mL per mmol of starting ketone). Drying of the 1 precipitate afforded 2-bromo-1-(4-chlorophenyl)ethanone in R N / R. 15 ca. 90% yield. I A mixture of 2-bromo-1-(4-chlorophenyl)ethanone (1.0 2 2N 3 eq.) and NaNCCHO) (1.1 eq.) in acetonitrile (1.5 mL per S mmol) was heated to reflux for 4 h at 105° C. ext, tempera ture. The formed sodium bromide was removed by filtration and the filtrate concentrated in vacuo. The residue was skO dissolved in ethanol (2.5 mL per mmol) and conc. aq. hydrochloric acid (0.9 mL per mmol) added at ambient 2 temperature. After stirring for 72 hat room temperature the 1N solids were filtered off and washed with ethanol (lx 0.5 mL R 25 per mmol). Drying of the solids afforded 2-amino-1-(4- 2 N R2 chlorophenyl)ethanone hydrochloride in ca. 50% yield that was used in the next step without purification. 2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 | > / g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 30 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g. 4.08 immol) in water (4 mL) at ambient temperature. After heating to 80° C. ext, temp. for 18 h the cold mixture was filtered. re-r', '('. S S The filtrate was diluted with acetic acid (40 mL) and stirred 35 for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole Specifically, the compounds of this invention with For 2-thiol which was of ca. 61% purity (HPLC-MS) and used mula XIXb can be prepared as illustrated by the exemplary as is in the next step. The crude oxazole-2-thiol compound reaction in Scheme 7. (1.42 g, max. 3.88 mmol) was suspended in phosphorous 40 oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext, temperature for 4 h. The reaction Scheme 7: Synthetic scheme to compounds of the Formula XIXb mixture was poured into water (50 mL) and extracted with O ethyl acetate (3x40 mL). The combined organic layers were 45 washed with aq. sat. bicarbonate (100 mL) and water (50 HN l R mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO, 5-40% ethyl acetate in hep DIEA, NMP, 130° C. tanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 y-n-" 50 mg, 0.49 mmol, 13%, purity 96% HPLC-MS). In the next step, pyrrole (2 mL) was treated with sodium

hydride (10 mg, 0.22 mmol. 55% wetted with mineral oil), then 75-(4-chlorophenyl)-2-(1H-pyrrol-1-yl)oxazole (45 mg, 0.21 mml) was added. The mixture was heated to 60° C. 55 ext, temperature for 1 h, 85°C. for 6 hand 100° C. for 6 h. More sodium hydride (10 mg, 0.22 mmol. 55% wetted with mineral oil) was added and the reaction mixture heated to 120° C. external temperature for 6 h. Analysis (HPLC-MS) showed the starting material to be consumed. The mixture 60 was evaporated to dryness in vacuo and partitioned between aq. Sat. ammonium chloride and ethyl acetate. Extraction of the water layer with ethyl acetate (3x50 mL) and evapora tion of the combined organic layers in vacuo gave crude The appropriate alpha-bromoacetophenone 1 is reacted product (80 mg), which was purified by column chromatog with the corresponding amide analog 2 in N-methylpyrroli 65 raphy (SiO2, 0-20% ethyl acetate in heptanes) to afford pure done (NMP) in presence of DIEA at higher temperature to 5-(4-chlorophenyl)-2-(1H-pyrrol-1-yl)oxazole (18 mg, 72.4 give the desired 2-4-disubstituted oxazol product 3. mol, yield 35%, purity 98.6% (HPLC-MS). LC-MS M-H US 9,426,995 B2 65 66 245 (C13H9ClN2O+H, requires 245.04). "H-NMR spectra (115-120° C.) overnight. The mixture was cooled down and is in accordance with the chemical structure. Solvent was removed in vacuo. The resulting residue was purified by HPLC purification to provide desired 3-(4- Formula IIIa Example: Chloro-phenoxy)-5-furan-2-yl-1,2,4-oxadiazole in a yield 5-(4-chlorophenyl)-2-(thiophen-2-ylmethyl)oxazole of 50% and purity of 99.9%. LC-MS M+H 263.3 (C12H7C1 N2O3+H, requires 263.65). "H NMR (DMSO A mixture of amine.HCl 1 (1.0g, 4.85 mmol), 2-thiophen d) & 8.17 (d. 1H, J=1.75), 7.63 (d. 1H, J=3.5), 7.55 (d. 2H, 2yl-acetyl chloride (0.80 g, 5.0 mmol) and NaHCOs (3.0 g, J=8.8), 7.46 (d. 2H, J=8.8), 6.87 (n, 1H). 36 mmol) in EtOAc (20 mL) and water (20 mL) was vigorously stirred for 16 h. After dilution with water (50 mL) 10 Formula IXa Example: 3-(4-Chloro-phenyl)-5- the layers were separated. The water layer was again furan-2-ylmethyl-1,2,4-oxadiazole extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated to an orange To the solution of 4-chlorobenzonitrile (5 mmol. 1 eq) in solid, 1.0 g. After trituration with MTBE, acylamide 3 was EtOH (6 mL) was added 50% aqueous solution of hydrox obtained as yellow solid, 0.9 g (yield 64%) 15 ylamine (7.5 mmol. 1.5 eq). Reaction mixture was heated at A mixture of acylamide 3 (0.76 g. 2.6 mmol) and POCl. 110° C. overnight (LCMS indicated reaction was com (4.5g, 29 mmol) was heated to reflux for 2 h. After cooling pleted). After cooling to room temperature, the reaction was to r,t the mixture was concentrated in vacuo. The residue was poured into 2M hydrochloric acid (100 mL) and extracted taken in CH2Cl and washed with saturated aqueous with EtOAc (2x100 mL). The combined aqueous layers NaHCO, dried and concentrated to a brown oil, 600 mg. were adjusted to pH 8 with 2M sodium hydroxide. Product Column chromatography on SiO, (elution with Heptane/ was extracted with EtOAc (2x100 mL). Organic extract was EtOAc 2/1) gave pure 5-(4-chlorophenyl)-2-(thiophen-2- washed with brine (2x80 mL), dried over anhydrous NaSO ylmethyl)oxazole as an oil that solidified on standing, 300 and concentrated in vacuo to give pure target amidoxime as mg, yield 42%. HPLC purity 99.6% (254 nm); LC-MS a white solid. M+H 276 (M+1) (C14H10CINOS+H, requires 276.02). 25 To the mixture of 2-furylacetic acid (0.5 mmol. 1 eq), H-NMR spectra is in accordance with the chemical struc DIEA (1 mmol. 2 eq) and 1,1'-carbonyldiimidazole (0.6 ture mmol. 1.2 eq) in dioxane was added 4-chloro-N-hydroxy benzimidamide (0.5 mmol. 1 eq) at room temperature. After 30 min Formula VIIIa Example: 3-(4-Chloro-phenoxy)-5- 30 stirring at room temperature the mixture was heated at furan-2-yl-1,2,4-oxadiazole 115-120° C. overnight. The mixture was cooled down and solvent was removed in vacuo. The residue was dissolved in DMSO (1-0.5 mL) and purified by HPLC purification to The Solution of cyanogen bromide (222 mg, 2.1 mmol. give target 3-(4-Chloro-phenyl)-5-furan-2-ylmethyl-1,2,4 1.05 eq) in tetrachloromethane (1.5 mL) was cooled down to 35 oxadiazole as a white solid in a yield of 62% and HPLC -5 oC. A solution of 4-chlorophenol (256 mg, 2 mmol. 1 eq) purity of 99.7%. LC-MS M+H 261.4 (C13H9ClN2O2+H, in of tetrachloromethane (1.5 mL) was added in one portion requires 261.68). H NMR (DMSO-d) & 8.01 (d. 2H, to the mixture. The resulting mixture was stirred vigorously J=8.5), 7.64 (d. 2H, J=8.5), 7.62 (s, 1H), 6.46 (s. 2H), 4.58 while TEA (0.28 mL, 2 mmol. 1 eq) was added dropwise. (s. 2H). After an additional 15 min stirring reaction was completed 40 (monitored by LCMS). Reaction mixture was diluted with water and product was extracted with CHCl (2x50 mL). Formulae XIIIa Example: 3-(4-chlorophenyl)-5- Organic phases were combined, washed with brine (2x50 (1H-pyrrol-1-yl)-1,2,4-thiadiazole mL), dried over anh. NSO and evaporated in vacuo to provide desired cyanate (200 mg, 65%), which was used in 45 the next step of synthesis without further purification. To a suspension of 4-chlorobenzimidamide (0.5g, 2.62 To the solution of 1-chloro-4-cyanatobenzene (200 mg. mmol) in DCM (10 mL) was added trichloromethyl 1.3 mmol, 1 eq) in MeOH (2 mL) was added NH2OH hypochlorothioite (0.30 mL, 0.54 g, 2.74 mmol). The mix hydrochloride (160 mg, 2.3 mmol. 1.8 eq) followed by ture was cooled to 0° C. ext, temperature, aq. 6N NaOH (3 DIEA (0.45 mL, 2.6 mmol. 2 eq) at 5° C. After 15 min 50 mL) added and the solution stirred for 30 min. After dilution stirring at room temperature reaction was completed (by with water (25 mL) and extraction of the water layer with LCMS). Reaction mixture was diluted with 2M HCl (30 mL) DCM (2x50 mL) the combined organic layers were dried and extracted with EtOAc (2x30 mL). The combined aque with sodium sulfate and concentrated in vacuo to afford ous layers were adjusted to pH 8 with 2M sodium hydroxide crude 5-chloro-3-(4-chlorophenyl)-1,2,4-thiadiazole (630 and product was extracted with EtOAc (2x40 mL) and 55 mg). The purification by column chromatography (SiO, washed with brine (2x40 mL). Organic layer was dried over 0-10% ethyl acetate in heptanes) gave 319 mg (1.38 mmol) anhydrous NaSO4, and concentrated in vacuo to give target of the pure product in a yield of 53%. 4-chlorophenyl hydroxycarbamimidate in a yield of 70%. The 5-chloro-1,2,4-thiadiazole compound (102 mg, 0.445 Compound was used in the next step of synthesis without mmol) was dissolved in DMSO (2 mL) and pyrrol (300 mg. further purification. 60 2.22 mmol) added at room temperature. The mixture was To the mixture of 4-chlorophenyl hydroxycarbamimidate heated for 18 h to 55° C. ext, temperature, however no (0.5 mmol. 1 eq) and DIEA (1.25 mmol. 2.5 eq) in dioxane conversion was found (sample tested by 'H-NMR). Sodium was added dropwise furan-2-carbonyl chloride (0.53 mmol. hydride (55% wetted with mineral oil, 20 mg, 0.467 mmol) 1.05 eq) at 0-5° C. The mixture was allowed to warm to was added and the mixture heated to 80° C. ext, temperature room temperature and then stirred for 0.5-1 h or until 65 for 5 h. As the conversion was not complete (sample tested complete as determined by LC-MS analysis of the reaction by 'H-NMR) the mixture was heated to 100° C. ext. mixture. The cyclodehydration reaction was run at reflux temperature for 6 h. The reaction mixture was poured into US 9,426,995 B2 67 68 water (10 mL) and crude product isolated by filtration. The Co-Co aryl(C-C) alkynyl, C-C hydroxyalkyl, purification by column chromatograpy (SiO, 0-10% ethyl amino, ureido, cyano, C-C acylamino, hydroxy, thiol, acetate inheptanes) afforded 3-(4-chlorophenyl)-5-(1H-pyr C-C acyloxy, azido, OCH, OCF, and C(H)O; rol-1-yl)-1,2,4-thiadiazole (52 mg, 0.199 mmol. 45%), and which was 98% pure (HPLC 254 nm). 'H-NMR spectra is 5 C is pyrrolyl pyrrolyloxo, pyrrolythio, or pyrrolylalkyl, in accordance with the chemical structure. each of which may be optionally independently sub stituted with one or more substituents selected from the Formula XVa Example: 3-(4-chlorophenyl)-5-(thio group consisting of CH, C-Co alkyl, cycloalkyl, phen-2-ylmethyl)-1,2,4-thiadiazole heterocycle, hydroxyalkyl, and halogen. 10 2. The coated seed of claim 1 comprising a compound of A mechanically stirred mixture of 4-chlorobenzamide formula VIIa or a salt thereof, (20.23 g, 130 mmol), toluene (150 mL), and chlorocarbo nylsulfenylchloride (19 g, 145 mmol) was heated to reflux for 3 h. After cooling to r.t. the mixture was concentrated in Formula VIIa vacuo to give a yellow solid foam, 27.65 g (100%). H-NMR 15 R R6 showed that this was almost pure oxathiazolone compound R that was used as is in the next step. R2 X N s A mixture of oxathiazolone 2 (0.25 g, 1.17 mmol) and 2-thiopheneacetonitrile (3.5g, 27 mmol) was heated in the Ny- N le microwave at 190° C. for 20 min. Excess furonitrile and NN Rs volatile byproducts were removed in vacuo (170° C., 2 R Rs O R9 mbar). The residual brown oil (300 mg) was purified by R4 column chromatography in SiO, (Heptane-EtOAc 3-1) to give 30 mg of impure product. Further purification by preparative HPLC gave 3-(4-chlorophenyl)-5-(thiophen-2- 25 wherein, ylmethyl)-1,2,4-thiadiazole, as brown solid, 7 mg (yield 2%) R and Rs are independently selected from the group and HPLC purity of 95% (254 nm). HPLC-MS (M+1)=293 consisting of hydrogen, CH, F, Cl, Br, CF and OCF; (C13H9ClN2S2+H, requires 293). 1H-NMR spectra is in R and Ra are independently selected from the group accordance with the chemical structure. consisting of hydrogen, F, Cl, Br, and CF; 30 R is selected from the group consisting of hydrogen, Formula XIXb Example: CH, CF, F, Cl, Br, OCF, OCH, CN, and C(H)O; 4-(2,4-Dichloro-phenyl)-2-furan-2-yl-oxazole R. R7. R. and Rs are independently selected from the group consisting of hydrogen, CH, C-Coalkyl, To the solution of furan-2-carboxamide (56 mg, 0.5 cycloalkyl, heterocycle, and halogen; and mmol. 1 eq) and DIEA (0.13 mL, 0.75mmo, 1.5 eq) in NMP 35 X is a bond, CH, O, or S. (1 mL) was added 2-bromo-1-(2,4-dichlorophenyl)ethanone 3. The coated seed of claim 1 wherein the coating is (0.6 mmol. 1.2 eq). Reaction mixture was heated at 130° C. applied to the seed as a composition comprising the com for 15 h. The mixture was cooled down, diluted with 1 M pound in an aqueous carrier. HCl (30 mL) and extracted with EtOAc (40 mL). The 4. The coated seed of claim 3 wherein the composition organic layer was washed with 1 M HCl (30 mL), 5% 40 comprises a surfactant. solution of NaHCO, (30 mL), brine (2x40 mL), dried over 5. The coated seed of claim 3 wherein the composition anhydrous Na2SO4, and concentrated in vacuo. The result comprises a co-solvent. ing residue was purified by HPLC purification to provide 6. The seed of claim 3 wherein the coating further desired 4-(2,4-Dichloro-phenyl)-2-furan-2-yl-oxazole in a comprises a pesticide. yield of 55% and HPLC 99.9% purity. LC-MSM-H-280.4 45 7. The composition coated seed of claim 6 wherein the (C13H7O12NO2+H, requires 281.11). "H NMR (DMSO-d) pesticide is selected from the group consisting of avermec 88.84 (s, 1H), 8.13 (d. 1H, J=8.5), 8.01 (s, 1 H), 7.78 (s, 1H), tin, ivermectin, milbemycin, imidacloprid, aldicarb, oxamyl. 7.58 (d. 1H, J=8.5), 7.29 (d. 1H, J=3.5), 6.77 (m, 1H). fenamiphos, fosthiazate, metam Sodium, etridiazole, penta chloro-nitrobenzene (PCNB), flutolanil, metalaxyl, What is claimed is: mefenoxam, fosetyl-al, silthiofam, fludioxonil, myclobuta 1. A coated seed wherein the coating comprises a com 50 nil, azoxystrobin, chlorothalonil, propiconazole, tebucon pound of Formula VII or a salt thereof, azole, pyraclostrobin, trifloxysulfuron, glyphosate and halo sulfuron. 8. A coated seed wherein the coating comprises a com Formula VII pound of Formula XII or a salt thereof, A y NY C 55 N-O Formula XII

wherein, 60 A is aryl, arylalkyl, aryloxo, arylthio, heteroaryl, het eroarylalkyl, heteroaryloxo, or heteroarylthio, each of which may be optionally independently substituted wherein, with one or more Substituents selected from the group A is arylor arylalkyl, each of which may be optionally consisting of halo, C-C haloalkyl, Co-Co aryl, C-C, 65 independently substituted with one or more substitu cycloalkyl, C-C alkyl, C-C alkenyl, C-C alkynyl, ents selected from the group consisting of halo, C-C, Co-Co aryl(C-C)alkyl, Co-Co aryl(C-C)alkenyl, haloalkyl, Co-Co aryl, C-C, cycloalkyl, C-C alkyl, US 9,426,995 B2 69 70 C-C alkenyl, C-C alkynyl, Co-Co aryl(C-C)alkyl, C-C aryl (C-C)alkenyl, C-C aryl (C-C) alky Formula XIIb nyl, C-C hydroxyalkyl, amino, ureido, cyano, C-C, acylamino, hydroxy, thiol, C-C acyloxy, azido, C-C, R2 alkoxy and carboxy, and C(H)O; and R R6 C is selected from the group consisting of thienyl, furanyl, N X W oxazolyl, and isoxazolyl, each of which can be option 2 ally independently substituted with one or more sub f 2NR, stituents selected from the group consisting of fluorine, R O-N chlorine, CH, and OCF; and 10 Rs Ro X is CH, O,or S. 9. The coated seed of claim 8 comprising a compound of wherein, Formula XIIa or a salt thereof, R and Rs are independently selected from the group consisting of hydrogen, CH, F, Cl, Br, CF, and OCF; 15 R and Ra are independently selected from the group Formula XIIa consisting of hydrogen, F, Cl, Br, and CF; R is selected from the group consisting of hydrogen, CH, CF, F, Cl, Br, OCF, OCH, CN, and C(H)O; R. R. and Rs are independently selected from the group consisting of hydrogen, F, Cl, CH, and OCF, E is O, or S; and X is CH, O, or S. 11. The coated seed of claim 8 wherein the coating is applied to the seed as a composition comprising the com 25 pound in an aqueous carrier. 12. The coated seed of claim 11 wherein the composition wherein, comprises a surfactant. R and Rs are independently selected from the group 13. The coated seed of claim 11 wherein the composition consisting of hydrogen, CH, F, Cl, Br, CF, and OCF; comprises a co-solvent. 30 14. The coated seed of claim 11 wherein the coating R and Ra are independently selected from the group further comprises a pesticide. consisting of hydrogen, F, Cl, Br, and CF; 15. The coated seed of claim 14 wherein the pesticide is R is selected from the group consisting of hydrogen, selected from the group consisting of avermectin, ivermec CH, CF, F, Cl, Br, OCF, OCH, CN, and C(H)O; tin, milbemycin, imidacloprid, aldicarb, oxamyl, fenami R7, R, and Rs are independently selected from the group 35 phos, fosthiazate, metam Sodium, etridiazole, penta-chloro consisting of hydrogen, F, Cl, CH, and OCF, nitrobenzene (PCNB), flutolanil, metalaxyl, mefenoxam, E is O, or S; and fosetyl-al, silthiofam, fludioxonil, myclobutanil, aZOX X is CH, O, or S. yStrobin, chlorothalonil, propiconazole, tebuconazole, pyra 10. The coated seed of claim 8 comprising a compound of clostrobin, trifloxysulfuron, glyphosate and halosulfuron. Formula XIIb or a salt thereof, k k k k k UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 9,426,995 B2 Page 1 of 1 APPLICATION NO. 13/763087 DATED : August 30, 2016 INVENTOR(S) : Urszula Slomczynska et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

In the Claims: Column 68, Claim 2, Line 32: "R6, R7, R and Roare independently selected from should read --Rs, R7, Rs and Roare independently selected from Column 68, Claim 2, Line 33: “group consisting of hydrogen, CH5, C-Coalkyl, cycloalkyl should read --group consisting of hydrogen, CH3, Co-Cio alkyl, cycloalkyl Column 68, Claim 8, Line 64: “A is arylor arylalkyl, each of which may be optionally should read --A is aryl or arylalkyl, each of which may be optionally Column 69, Claim 8, Line 11: “X is CH, O,or S' should read --X is CH, O, or S-- Column 69, Claim 9, Line 35: “R7, R and Ro are independently selected from the group should read --R7. Rs and Ro are independently selected from the group Column 69, Claim 9, Line 37: “E is O, or S. and should read --E is O or S; and-- Column 70, Claim 10, Line 19: “R, R and Ro are independently selected from the group should read --Rs, Rs and Ro are independently selected from the group Column 70, Claim 10, Line 21: “E is O, or S; and should read --E is O or S; and--

Signed and Sealed this Twenty-fifth Day of October, 2016 74-4-04- 2% 4 Michelle K. Lee Director of the United States Patent and Trademark Office