US008772200B2

(12) United States Patent (10) Patent No.: US 8,772,200 B2 Shibayama et al. (45) Date of Patent: Jul. 8, 2014 (54) NITROGEN-CONTAINING HETEROCYCLIC E. SE 38. COMPOUND AND AGRICULTURAL JP 2005-531518 10/2005 FUNGCIDE JP 2006-507336 3, 2006 (75) Inventors: Kotaro Shibayama, Odawara (JP); Jun E. 39. s: 3. Inagaki, Odawara (JP); Yuto Saiki, JP 568-53s.500 T 2008 Odawara (JP); Akira Mitani, Odawara JP 2009-507024 2, 2009 (JP); Raito Kuwahara, Odawara (JP); JP 2009-091320 4/2009 Motoaki Sato, Odawara (JP); Satoshi W. 365, A1 1923 Nishimura, Odawara (JP); Mami WO O3,063861 8, 2003 Kuboki, Odawara (JP) WO 2005, O70917 8, 2005 (73) Assignee: Nippon Soda Co., Ltd., Tokyo (JP) WO 2006/0983.082007/011022 9,1, 20062007 WO 2007/088978 A1 8, 2007 (*) Notice: Subject to any disclaimer, the term of this WO 2007 11718O 10/2007 patent is extended or adjusted under 35 WO 2008/06827O 6, 2008 U.S.C. 154(b) by 66 days. WO 2008.101682 A2 8, 2008 WO 2009/021696 2, 2009 (21) Appl. No.: 13/519,209 WO 2010/026771 3, 2010 (22) PCT Filed: Dec. 28, 2010 OTHER PUBLICATIONS (86). PCT No.: PCT/UP2010/073683 Burgos, Angev Chem Int, vol. 45, pp. 4321-4326, 2005.* Altman, Org Lett, vol. 9 (4), pp. 643-646, 2007.* S371 (c)(1), Toffano, CA 153:555220, abstract only of Science of Synthesis, vol. (2), (4) Date: Jun. 26, 2012 date 2008, 42, pp. 347-389, 2009.* Burgos et al., “Significantly Improved Method for the Pd-Catalyzed (87) PCT Pub. No.: WO2011/081174 Coupling of Phenols with Aryl Halides: Understanding Ligand PCT Pub. Date: Jul. 7, 2011 Effects”. Angewandte Chemie International Edition, vol. 45, Issue 26, pp. 4321-4326, Jun. 26, 2006. (65) Prior Publication Data (Continued) US 2012/O2897O2A1 Nov. 15, 2012 (30) Foreign Application Priority Data Primary Examiner — D M Seaman (74) Attorney, Agent, or Firm — Kenyon & Kenyon, LLP Jan. 4, 2010 (JP) ...... 2010-OOO194 (51) Int. Cl. (57) ABSTRACT CO7D 25/60 (2006.01) Provided is an agricultural fungicide that contains at least one AOIN 43/42 (2006.01) selected from the group consisting of a novel nitrogen-con AOIN 43/40 (2006.01) taining heterocyclic compound represented by Formula (I), a CO7D 215/20 (2006.01) salt thereof, or an N-oxide compound thereof. In Formula (I), CO7D 215/18 (2006.01) R represents a group represented by CR'R'R' or a cyano (52) U.S. Cl. group. R' to Reach independently represents a hydrogen CPC ...... A0IN 43/42 (2013.01); A0IN 43/40 atom, an unsubstituted or Substituted Cls alkyl group, an (2013.01); C07D 215/60 (2013.01); C07D unsubstituted or substituted hydroxyl group, or the like. R4 or 215/20 (2013.01); C07D 215/18 (2013.01) R5 represents a halogeno group or the like. Y or Z represents USPC ...... 504/247; 546/153:546/159 a carbonatom or the like, and A or D represents a benzene ring (58) Field of Classification Search or the like. X represents an oxygenatom or a nitrogenatom or CPC. C07D 215/60; C07D 215/20; C07D 215/18; the like. A01N 43/42: A01N 43/40 Formula (I) USPC ...... 546/159, 153: 504/247 (R), See application file for complete search history. (56) References Cited U.S. PATENT DOCUMENTS

2006/0211739 A1 9, 2006 Perez-Medrano et al.

FOREIGN PATENT DOCUMENTS

JP 54-O14977 2, 1979 JP 62-103051 5, 1987 JP O7-285938 10, 1995 JP 10-067746 3, 1998 9 Claims, No Drawings US 8,772.200 B2 Page 2

(56) References Cited Chan, David C.M., et al., “Design, Synthesis, and Antifolate Activity of New Analogues of Piritrexim and Other Diamonopyrimidine OTHER PUBLICATIONS Dihdryofolate Reductase Inhibitors with (D-Carboxyalkoxy or EP Communication including Supplementary European Search (D-Carboxy-1-alkynyl Substitution in the Side Chain”, Journal of Report from EP Applin. No. 10841029.1, May 8, 2013, 6 pages. Medicinal Chemistry, 2005, vol. 48, No. 13, pp. 4420-4431. International Search Report issued for PCT/JP2010/073683, dated Office Action issued in KRApplin. No. 10-2012-7016781, dated Oct. Mar. 1, 2011, 10 pages (with English translation). Yamamoto, Yasunori, et al., “Cyclic Triolborates: Air- and Water 29, 2013, 10 pages (with English translation). Stable Ate Complexes of Organoboronic Acids”. Angew. Chem. Int. Office Action issued in JP Applin. No. 2011-547711, dated Nov. 19, Ed., 2008, vol. 47, pp. 928-931. 2013, 10 pages (with English translation). Calaway, Paul K., et al., “Utilization of Aryloxy Ketones in the Nakashima et al., “Ring Contraction of 3-Hydroxyguinolines to Synthesis of Quinolines by the Pfitzinger Reaction”. Jun. 1939, vol. Oxindoles with Hydrogen Peroxide in Acetic Acid.” Chem. Pharm. 61, No. 6, pp. 1355-1358. Bull, Japan, 1969, 17(11), pp. 2293-2298. Royer, Rene, et al., "Sur la formation des aldehydes aromatiques par Bhimani, “Studies on Compounds of Therapeutic Interest.” pyrodecomposition des aryloxyacetophenones'. Helvetica Chimica Saurashtra University, doctorate thesis, India, 2004, 280 pages. Acta, 1959, vol. 42, No. 7, pp. 2364-2370. Notice of Allowance issued in the JP Application No. 2011-547711, Ruiz, Javier, et al., “Intramolecular cyclisation of functionalised dated Feb. 12, 2014, 8 pages. heteroaryllithiums. Synthesis of novel indolizinone-based com pounds”, Tetrahedron, 2006, vol. 62, No. 26, pp. 6182-6189. * cited by examiner US 8,772,200 B2 1. 2 NITROGEN-CONTAINING HETEROCYCLC That is, the present invention includes the following COMPOUND AND AGRICULTURAL aspects. FUNGCDE <1> A nitrogen-containing heterocyclic compound repre sented by Formula (I), a salt thereof, or an N-oxide com TECHNICAL FIELD pound thereof. The present invention relates to novel nitrogen-containing heterocyclic compounds and an agricultural fungicide which Formula (I) contains at least one selected from the group consisting of the nitrogen-containing heterocyclic compounds as an active 10 ingredient. Priority is claimed on Japanese Patent Application No. 2010-000194 filed Jan. 4, 2010, the content of which is incorporated herein by reference. 15 (R) BACKGROUND ART In agricultural crop cultivation, a variety of control agents are used to deal with crop diseases. However, there are very In Formula (I), R represents a group represented by few agents which fully satisfy the requirements for use as a CRRR, an unsubstituted or substituted Co aryl group, or control agent due to reasons such as an insufficient control a cyano group; effect, limited use due to the emergence of agent-resistant pathogens, phytotoxic or contaminating effects on plants, or R" to Reach independently represents a hydrogen atom, toxicity to humans, domestic animals, and fish, and an 25 an unsubstituted or Substituted Cls alkyl group, an unsubsti adverse effect on the environment. Therefore, the need for tuted or Substituted Cls alkenyl group, an unsubstituted or agents having fewer disadvantages of this kind and which are Substituted Cls alkynyl group, an unsubstituted or Substi safe to use is required. tuted Cls cycloalkyl group, an unsubstituted or substituted Related to the present invention, in the following Patent Cas cycloalkenyl group, an unsubstituted or Substituted Co Document 1 or 2, quinoline derivatives having similar chemi 30 aryl group, an unsubstituted or Substituted heterocyclic cal structures to the compounds according to the present group, an unsubstituted or substituted Cls acyl group, an invention, and agricultural fungicides containing the quino unsubstituted or Substituted (1-imino)Cs alkyl group, an line derivatives as active ingredients, are disclosed. unsubstituted or Substituted carboxyl group, an unsubstituted or Substituted carbamoyl group, an unsubstituted or Substi 35 DOCUMENTS OF RELATED ART tuted hydroxyl group, an unsubstituted or Substituted amino group, an unsubstituted or Substituted mercapto group, a Sub stituted Sulfonyl group, a halogeno group, a cyano group, or a Patent Documents nitro group; 40 excepting in which: R to Rare all hydrogenatoms; R to Patent Document 1 Pamphlet of WO2005/070917 Rare all unsubstituted Cisalkyl groups; any one of R' to R Patent Document 2 Pamphlet of WO2007/011022 is a hydrogen atom and the remaining two are both unsubsti tuted Cls alkyl groups; and, any one of R' to R is an unsub SUMMARY OF THE INVENTION stituted Cls alkyl group and the remaining two are both 45 hydrogen atoms; Problems to be Solved by the Invention R" and R may be joined to form an unsubstituted or sub stituted 5- to 8-membered ring, or to form O—, RRC=, or An object of the present invention is to provide a novel R. N.— nitrogen-containing heterocyclic compound, and a salt thereof or N-oxide compound thereof, and an agricultural 50 R" represents a hydrogen atom or an unsubstituted or Sub fungicide, which has reliable effects, is safe to use and con stituted Cls alkyl group; tains at least one selected from the group consisting of the R" represents a hydrogen atom or an unsubstituted or sub nitrogen-containing heterocyclic compound, the salt and stituted Cls alkyl group; N-oxide compound thereofas an active ingredient. 55 R" represents an unsubstituted or substituted hydroxyl group, or an unsubstituted or Substituted Cls alkyl group; Means to Solve the Problems Reach independently represents an unsubstituted or sub stituted Cls alkyl group, an unsubstituted or Substituted Cas The inventors have studied intensively in order to solve the alkenyl group, an unsubstituted or Substituted Cls alkynyl above problems. As a result, a nitrogen-containing heterocy 60 group, an unsubstituted or Substituted Css cycloalkyl group, clic compound represented by Formula (I), a salt thereof oran an unsubstituted or substituted Cas cycloalkenyl group, an N-oxide compound thereofwere obtained. It was also discov unsubstituted or Substituted Co aryl group, an unsubsti ered that the nitrogen-containing heterocyclic compound, the tuted or substituted heterocyclic group, an unsubstituted or salt thereof or the N-oxide compound thereofare useful as an Substituted Cls acyl group, an unsubstituted or Substituted active ingredient of an agricultural fungicide, which has reli 65 (1-imino)Cs alkyl group, an unsubstituted or Substituted able effects and is safe to use. The present invention was carboxyl group, an unsubstituted or Substituted carbamoyl completed with further studies based on these findings. group, an unsubstituted or Substituted hydroxyl group, an US 8,772,200 B2 3 4 unsubstituted or Substituted amino group, an unsubstituted or In Formula (III), each of R,R,R, m1 and X represents the Substituted mercapto group, a Substituted Sulfonyl group, a same meaning as those in Formula (II) described above in halogeno group, a cyano group, or a nitro group: m represents a number of R and is an integer of 0 to 6: <2>; and Reach independently represents an unsubstituted or sub n1 represents a number of R and is an integer of 0 to 4. stituted Cls alkyl group, an unsubstituted or substituted Cls <4> An agricultural fungicide comprising, as an active ingre alkenyl group, an unsubstituted or Substituted Cls alkynyl dient, at least one selected from the group consisting of the group, an unsubstituted or substituted Cls cycloalkyl group, nitrogen-containing heterocyclic compound, the salt an unsubstituted or Substituted Cas cycloalkenyl group, an unsubstituted or substituted Co aryl group, an unsubsti thereof, and the N-oxide compound thereof, of any one tuted or substituted heterocyclic group, an unsubstituted or 10 <1> to <3>. Substituted Cls acyl group, an unsubstituted or substituted <5> An intermediate product of the nitrogen-containing het (1-imino)Cs alkyl group, an unsubstituted or Substituted erocyclic compound represented by Formula (I), the salt carboxyl group, an unsubstituted or Substituted carbamoyl thereof, or the N-oxide compound thereof, described above group, an unsubstituted or Substituted hydroxyl group, an in <1 >, the intermediate product being selected from the unsubstituted or Substituted amino group, an unsubstituted or 15 group consisting of 8-fluoro-3-hydroxyquinoline, 7,8-dif Substituted mercapto group, a Substituted Sulfonyl group, a halogeno group, a cyno group, or a nitro group: luoro-3-hydroxyquinoline, 7,8-difluoro-3-iodoquinoline, in represents a number of R and is an integer of 0 to 5: 8-fluoro-3-hydroxy-2-methylduinoline, and 7,8-difluoro any one of R' to Rand any one of R may bejoined to form 3-hydroxy-2-methylduinoline. an unsubstituted or substituted 5- to 8-membered ring: A represents: a 5- to 7-membered hydrocarbon ring or a 5 Effect of the Invention to 7-membered heterocyclic ring when R is a group repre sented by CRRR, or a benzene ring when R is an unsub stituted or Substituted Co aryl group or a cyano group; The nitrogen-containing heterocyclic compound, the salt D represents a 5- to 7-membered hydrocarbon ring or a 5 25 thereof, and N-oxide compound thereof according to the to 7-membered heterocyclic ring: present invention are novel compounds useful as an active X represents an oxygen atom, a Sulfur atom, a Sulfenyl ingredient of an agricultural fungicide which has reliable group, a Sulfonyl group, an unsubstituted or Substituted car effects and is safe to use. bon atom, or an unsubstituted or Substituted nitrogen atom; Y represents a carbon atom or a nitrogen atom; and The agricultural fungicide according to the present inven Z represents a carbon atom or a nitrogen atom. 30 tion is an agent which has excellent control effects, does not <2> A nitrogen-containing heterocyclic compound repre cause phytotoxicity in plants, and has little toxicity to sented by Formula (II), a salt thereof, or an N-oxide com humans, domestic animals, and fish or on the environment. pound thereof. MODES FOR CARRYING OUT THE INVENTION 35 Formula (II) Hereinafter, the present invention will be categorized into 1) a nitrogen-containing heterocyclic compound represented by Formula (I), and a salt thereof or an N-oxide compound 40 thereof, and 2) an agricultural fungicide and will be described in detail. 1) Nitrogen-containing heterocyclic compound repre sented by Formula (I), and salt thereof, or N-oxide compound (R'). thereof. 45 The nitrogen-containing heterocyclic compound accord ing to the present invention is represented by Formula (I) In Formula (II), each of R. R. R. n, D., X, Y, and Z (hereinafter, sometimes referred to as “compound (I)'), is represents the same meaning as those in Formula (I) preferably represented by Formula (II) (hereinafter, some described above in <1 >; and times referred to as “compound (II)'), and is more preferably m1 represents a number of R and is an integer of 0 to 6. 50 represented by Formula (III) (hereinafter, sometimes referred <3> A nitrogen-containing heterocyclic compound repre to as “compound (III)). sented by Formula (III), a salt thereof, oran N-oxide com The nitrogen-containing heterocyclic compound, the salt pound thereof. thereof, or the N-oxide compound thereof according to the 55 present invention may be a hydrate, a Solvate, a crystal poly morphism, or the like. Also, an asymmetric carbon atom, Formula (III) stereoisomers based on a double bond or the like, or a mixture (R), thereof, may be present in the nitrogen-containing heterocy sas clic compound, the salt thereof; or the N-oxide compound 60 thereof according to the present invention. First of all, the meaning of “unsubstituted” and “substi tuted in Formulae (I), (II), and (III) will be explained. The term “unsubstituted in the present specification means that the specified group is solely formed of a group serving as a 65 mother nucleus. When only the name of the group Serving as the mother nucleus is mentioned without mention of “substi tuted, it means “unsubstituted unless otherwise stated. US 8,772,200 B2 5 6 On the other hand, the term "substituted” means that a 5-bromo-2-pentynyl group; a Chaloalkoxy group Such as a hydrogen atom of a group Serving as a mother nucleus has 2-chloro-n-propoxy group or a 2,3-dichlorobutoxy group; a been substituted with a substituent having the same structure C- haloalkenyloxy group Such as a 2-chloropropenyloxy as or a different structure to the mother nucleus. The “sub group or a 3-bromobutenyloxy group; a Co haloaryl group stituent is a different group which is bonded to the group Such as a 4-chlorophenyl group, a 4-fluorophenyl group, or a serving as a mother nucleus. The “substituent may be one or 2,4-dichlorophenyl group; a Cohaloaryloxy group Such as more. At least two substituents may be the same or different. a 4-fluorophenyloxy group, or a 4-chloro-1-naphthoxy Terms such as “C.” or the like indicate that the number of group; a C-7 haloacyl group Such as a chloroacetyl group, a carbon atoms in a group serving as a mother nucleus is 1 to 6 trifluoroacetyl group, a trichloroacetyl group, or a 4-chlo or the like. The number of carbon atoms does not include 10 robenzoyl group; carbon atoms in a Substituent. For example, a butyl group a cyano group; an isocyano group; a nitro group; an isocy having an epoxy group as a Substituent is categorized as a C anate group; a cyanate group: an azide group; an amino alkoxy C alkyl group. group; a C-alkylamino group Such as a methylamino group. The “substituent” is not particularly limited as long as it is a dimethylamino group, or a diethylamino group; a Co chemically acceptable and has the effects of the present 15 arylamino group such as an anilino group or a naphthylamino invention. group; a Czaralkylamino group such as a benzylamino Examples of the “substituent include: a halogen atom group or a phenylethylamino group; a C-7 acylamino group Such as a fluorine atom, a chlorine atom, a bromine atom, or Such as a formylamino group, an acetylamino group, a pro an iodine atom; a C- alkyl group Such as a methyl group, an panoylamino group, abutyrylamino group, an i-propylcarbo ethyl group, an n-propyl group, an i-propyl group, an n-butyl nylamino group, or a benzoylamino group; a C- alkoxycar group, an S-butyl group, an i-butyl group, a t-butyl group, an bonylamino group Such as a methoxycarbonylamino group, n-pentyl group, or an n-hexyl group; a C-cycloalkyl group an ethoxycarbonylamino group, an n-propoxycarbonylamino Such as a cyclopropyl group, a cyclobutyl group, a cyclopen group, or an i-propoxycarbonylamino group; a carbamoyl tyl group, or a cyclohexyl group; a C2-alkenyl group Such as group; a Substituted carbamoyl group Such as a dimethylcar a vinyl group, a 1-propenyl group, a 2-propenyl group, a 25 bamoyl group, a phenylcarbamoyl group, or an N-phenyl-N- 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a methylcarbamoyl group; an imino Ce alkyl group Such as an 1-methyl-2-propenyl group, a 2-methyl-2-propenyl group, a iminomethyl group, a (1-imino)ethyl group, or a (1-imino)- 1-pentenyl group, a 2-pentenyl group, a 3-pentenyl group, a n-propyl group; a hydroxyimino C alkyl group such as a 4-pentenyl group, a 1-methyl-2-butenyl group, a 2-methyl-2- hydroxyiminomethyl group, a (1-hydroxyimino)ethyl group, butenyl group, a 1-hexenyl group, a 2-hexenyl group, a 3-hex 30 or a (1-hydroxyimino)propyl group; a Calkoxyimino enyl group, a 4-hexenyl group, and a 5-hexenyl group; a C Calkyl group Such as a methoxyiminomethyl group or a cycloalkenyl group such as a 2-cyclopropenyl group, a 2-cy (1-methoxyimino)ethyl group: clopentenyl group, or a 3-cyclohexenyl group; a C- alkynyl a mercapto group; an isothiocyanate group; a thiocyanate group Such as an ethynyl group, a 1-propynyl group, 2-pro group; a C- alkylthio group Such as a methylthio group, an pynyl group, a 1-butynyl group, a 2-butynyl group, a 3-buty 35 ethylthiogroup, an n-propylthiogroup, an i-propylthio group, nyl group, a 1-methyl-2-propynyl group, a 2-methyl-3-buty an n-butylthio group, an i-butylthio group, an S-butylthio nyl group, a 1-pentynyl group, a 2-pentynyl group, a group, or a t-butylthio group; a Calkenylthio group such as 3-pentynyl group, a 4-pentynyl group, a 1-methyl-2-butynyl a vinylthio group or an allylthio group; a C- alkynylthio group, a 2-methyl-3-pentynyl group, a 1-hexynyl group, or a group Such as an ethynylthio group or a propargylthio group; 1,1-dimethyl-2-butynyl group; 40 a Carylthio group such as a phenylthio group or a naph a C- alkoxy group Such as a methoxy group, an ethoxy thylthio group; a heteroarylthio group Such as a thiazolylthio group, an n-propoxy group, an i-propoxy group, an n-butoxy group or a pyridylthiogroup; a Cz-aralkylthio group such as group, an S-butoxy group, an i-butoxy group, or a t-butoxy a benzylthiogroup or a phenethylthio group; a (Calkylthio) group; a C2-alkenyloxy group Such as a vinyloxy group, an carbonyl group Such as a (methylthio)carbonyl group, an allyloxy group, a propenyloxy group, or abutenyloxy group; 45 (ethylthio)carbonyl group, a (n-propylthio)carbonyl group, a a C- alkynyloxy group Such as an ethynyloxy group or a (i-propylthio)carbonyl group, a (n-butylthio)carbonyl group, propargyloxy group; a Co aryl group Such as a phenyl a (i-butylthio)carbonyl group, a (s-butylthio)carbonyl group, group or a naphthyl group; a Coacyloxy group Such as a or a (t-butylthio)carbonyl group; phenoxy group or a 1-naphthoxy group; a Czaralkyl group a C alkylsulfinyl group such as a methylsulfinyl group, Such as a benzyl group or a phenethyl group; a C- aralky 50 an ethylsulfinyl group, or a t-butylsulfinyl group; a C- alk loxy group Such as a benzyloxy group or a phenethyloxy enylsulfinyl group Such as an allylsulfinyl group; a C- alky group; a C-7 acyl group Such as a formyl group, an acetyl nylsulfinyl group Such as a propargylsulfinyl group; a Co group, a propionyl group, a benzoyl group, or a cyclohexyl arylsulfinyl group Such as a phenylsulfinyl group; a heteroar carbonyl group; a C-, acyloxy group such as a formyloxy ylsulfinyl group Such as a thiazolylsulfinyl group or a pyridyl group, an acetyloxy group, a propionyloxy group, a benzoy 55 Sulfinyl group; a C- aralkylsulfinyl group Such as a benzyl loxy group, or a cyclohexylcarbonyloxy group; a Calkoxy Sulfinyl group or a phenethylsulfinyl group; a carbonyl group Such as a methoxycarbonyl group, an ethoxy Calkylsulfonyl group Such as a methylsulfonyl group, an carbonyl group, an n-propoxycarbonyl group, an ethylsulfonyl group, or a t-butylsulfonyl group; a C- alk i-propoxycarbonyl group, an n-butoxycarbonyl group, and a enylsulfonyl group Such as an allylsulfonyl group; a C t-butoxycarbonyl group; carboxyl group; 60 alkylsulfonyl group Such as a propargylsulfonyl group; a a hydroxyl group; an oxo group; a C- haloalkyl group Carylsulfonyl group such as a phenylsulfonyl group; a Such as a chloromethyl group, a chloroethyl group, a trifluo heteroarylsulfonyl group Such as a thiazolylsulfonyl group or romethyl group, a 1,2-dichloro-n-propyl group, a 1-fluoro-n- apyridylsulfonyl group; a Cz-aralkylsulfonyl group such as butyl group, or a perfluoro-n-pentyl group; a Chaloalkenyl a benzylsulfonyl group or a phenethylsulfonyl group; group Such as a 2-chloro-1-propenyl group or a 2-fluoro-1- 65 a 5-membered heteroaryl group Such as a pyrrolyl group, a butenyl group; a C- haloalkynyl group Such as a 4.4- furyl group, a thienyl group, an imidazolyl group, a pyrazolyl dichloro-1-butynyl group, a 4-fluoro-1-pentynyl group or a group, an oxazolyl group, an isoxazolyl group, a thiazolyl US 8,772,200 B2 7 8 group, an isothiazolyl group, a triazolyl group, an oxadiazolyl chlorooctyl group, a 2,4,6-trichlorohexyl group, a perfluoro group, a thiadiazolyl group, or a tetrazolyl group; a 6-mem decyl group, or a 2.2.4.4.6.6-hexachlorooctyl group, prefer bered heteroaryl group Such as a pyridyl group, pyrazinyl ably a Chaloalkyl group; group, pyrimidinyl group, a pyridazinyl group, or a triazinyl an arylalkyl group (aralkyl group) such as a benzyl group, group; a Saturated heterocyclic group Such as an aziridinyl a phenethyl group, a 3-phenylpropyl group, a 1-naphthylm group, an epoxy group, a pyrrolidinyl group, a tetrahydro ethyl group, or a 2-naphthylmethyl group, preferably a Co furanyl group, a piperidyl group, a piperazinyl group, or a aryl Co alkyl group; morpholinyl group; a tri Callylsilyl group such as a trim a heteroarylalkyl group Such as a 2-pyridylmethyl group, a ethylsilyl group, a triethylsilyl group, or a t-butyldimethylsi 3-pyridylmethyl group, 4-pyridylmethyl group, a 2-(2-py lyl group; a triphenylsilyl group; and the like. 10 ridyl)ethyl group, a 2-(3-pyridyl)ethyl group, a 2-(4-pyridyl) The “substituent may have a different “substituent’. ethyl group, a 3-(2-pyridyl)propyl group, a 3-(3-pyridyl)pro R pyl group, a 3-(4-pyridyl)propyl group, a 2-pyrazinylmethyl R represents a group represented by CR'R'R', an unsub group, a 3-pyrazinylmethyl group, a 2-(2-pyrazinyl)ethyl stituted or substituted Co aryl group, or a cyano group. group, a 2-(3-pyrazinyl)ethyl group, a 3-(2-pyrazinyl)propyl R" to Reach independently represents a hydrogen atom, 15 group, a 3-(3-pyrazinyl)propyl group, a 2-pyrimidylmethyl an unsubstituted or Substituted Cls alkyl group, an unsubsti group, a 4-pyrimidylmethyl group, a 2-(2-pyrimidyl)ethyl tuted or substituted Cls alkenyl group, an unsubstituted or group, a 2-(4-pyrimidyl)ethyl group, a 3-(2-pyrimidyl)propyl Substituted Cls alkynyl group, an unsubstituted or Substi group, a 3-(4-pyrimidyl)propyl group, a 2-furylmethyl group, tuted Cls cycloalkyl group, an unsubstituted or Substituted a 3-furylmethyl group, a 2-(2-furyl)ethyl group, a 2-(3-furyl) Cas cycloalkenyl group, an unsubstituted or substituted Co ethyl group, a 3-(2-furyl)propyl group, or a 3-(3-furyl)propyl aryl group, an unsubstituted or Substituted heterocyclic group, preferably a 5- to 6-membered heteroaryl C. alkyl group, an unsubstituted or Substituted Cls acyl group, an group; unsubstituted or substituted (1-imino) Cls alkyl group, an a hydroxyalkyl group Such as a hydroxymethyl group, a unsubstituted or Substituted carboxyl group, an unsubstituted 25 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydrox or Substituted carbamoyl group, an unsubstituted or Substi ypropyl group, a 3-hydroxypropyl group, a 1-hydroxy-1-me tuted hydroxyl group, an unsubstituted or Substituted amino thylethyl group, a 2-hydroxy-1,1-dimethylethyl group, a group, an unsubstituted or Substituted mercapto group, a Sub 2-hydroxy-1,1-dimethylpropyl group, or a 2-hydroxy-2-me stituted Sulfonyl group, a halogeno group, a cyano group, or a thylpropyl group, preferably a hydroxyl C. alkyl group; 30 an alkoxyalkyl group Such as a methoxymethyl group, an nitro group. ethoxymethyl group, a 2-methoxyethyl group, a 2-ethoxy However, there are no cases in which R' to R are all ethyl group, a methoxy-n-propyl group, an n-propoxymethyl hydrogenatoms. Also, there are no cases in which R' to Rare group, an i-propoxyethyl group, an S-butoxymethyl group, a all unsubstituted Cls alkyl groups. Also, when any one of R' t-butoxyethyl group, a 2.2-dimethoxyethyl group, or a 2.2- to R is a hydrogen atom, there are no cases in which the 35 dimethoxy-1,1-dimethylethyl group, preferably a C remaining two are both unsubstituted Cls alkyl groups. Also, alkoxy C. alkyl group; when any one of R' to R is an unsubstituted Cls alkyl group, an acyloxyalkyl group Such as a formyloxymethyl group, there are no cases in which the remaining two are both hydro an acetoxymethyl group, a 2-acetoxyethyl group, a propio gen atoms. nyloxymethyl group, or a propionyloxyethyl group, prefer A“Cs alkyl group' is a saturated hydrocarbon having 1 to 40 ably C, acyloxy C. alkyl group: 8 carbonatoms. The Cs alkyl group may be a straight chain a trialkylsilyloxyalkyl group Such as a trimethylsilyloxym or a branched chain. Examples of the Cs alkyl group include ethyl group or a t-butyldimethylsilyloxymethyl group, pref a methyl group, an ethyl group, an n-propyl group, an n-butyl erably a triCo alkylsilyloxy C. alkyl group; group, an n-pentyl group, an n-hexyl group, an n-heptyl an arylsulfonyloxyalkyl group Such as a tosyloxymethyl group, an n-octyl group, an i-propyl group, an i-butyl group. 45 group or a 2-tosyloxy-1,1-dimethylethyl group, preferably a an S-butyl group, a t-butyl group, an i-pentyl group, a neo Calkyl-substituted Co arylsulfonyloxy Calkyl group; pentyl group, a 2-methylbutyl group, a 2.2-dimethylpropyl a cyanoalkyl group Such as a cyanomethyl group, a 2-cya group, an i-hexyl group and the like. Among these, a C noethyl group, or a 1-cyano-1-methylethyl group, preferably alkyl group is preferable. a cyano Ce alkyl group: Examples of “substituted Cls alkyl group' include: 50 an acylalkyl group Such as a formylmethyl group, a a cycloalkylalkyl group Such as a cyclopropylmethyl 2-formylethyl group, a 3-formylpropyl group, a 1-formyl-1- group, a 2-cyclopropylethyl group, a cyclopentylmethyl methylethyl group, a 2-formyl-1,1-dimethylethyl group, an group, or a 2-cyclohexylethyl group, preferably a C-cy acetylmethyl group, a 2-acetylethyl group, a 3-acetylpropyl cloalkyl C alkyl group: group, 1-acetyl-1-methylethyl group, or a 2-acetyl-1,1-dim a cycloalkenylalkyl group Such as a cyclopentenylmethyl 55 ethylethyl group, preferably a C-acyl C. alkyl group; group, a 3-cyclopentenylmethyl group, a 3-cyclohexenylm a 2-hydroxyiminoalkyl group such as a 2-hydroxyimino ethyl group, or a 2-(3-cyclohexenyl)ethyl group, preferably a ethyl group, a 2-hydroxyimino-1-methylethyl group, a 2-hy Cao cycloalkenyl Co alkyl group: droxy-1,1-dimethylethyl group, or a 2-hydroxyiminopropyl a haloalkyl group Such as a fluoromethyl group, a chlorom group, preferably 2-hydroxyimino C2-alkyl group; ethyl group, a bromomethyl group, a difluoromethyl group, a 60 an acylalkyl group Such as an acetylmethyl group, a 2-acet dichloromethyl group, a dibromomethyl group, a trifluorom ylethyl group, a 3-acetylpropyl group, a 1-acetyl-1-methyl ethyl group, a trichloromethyl group, a tribromomethyl ethyl group, or a 2-acetyl-1,1-dimethylethyl group, prefer group, a 2.2.2-trifluoroethyl group, a 2.2.2-trichloroethyl ably a formyl C alkyl group: group, a pentafluoroethyl group, a 4-fluorobutyl group, a a carboxyalkyl group Such as a carboxymethyl group, a 4-chlorobutyl group, a 3.3,3-trifluoropropyl group, a 2.2.2- 65 2-carboxyethyl group, a 3-carboxypropyl group, a 1-car trifluoro-1-trifluoromethylethyl group, a perfluorohexyl boxy-1-methylethyl group, or a 2-carboxy-1,1-dimethylethyl group, a perchlorohexyl group, a perfluorooctyl group, a per group, preferably a carboxy C. alkyl group; US 8,772,200 B2 10 an alkoxycarbonylalkyl group Such as a methoxycarbon Cas cycloalkenyl group include a 1-cyclobutenyl group, a ylmethyl group, a 2-methoxycarbonylethyl group, a 3-meth 1-cyclopentenyl group, a 3-cyclopentenyl group, a 1-cyclo oxycarbonylpropyl group, a 1-methoxycarbonyl-1-methyl hexenyl group, a 3-cyclohexenyl group, a 3-cycloheptenyl ethyl group, or a 2-methoxycarbonyl-1,1-dimethylethyl group, a 4-cyclooctenyl group, and the like. group, preferably a C- alkoxycarbonyl C. alkyl group; Examples of a “substituted Cas cycloalkenyl group' an azidoalkyl group Such as an azidomethyl group, a 2-azi include an alkyl-substituted cycloalkenyl group Such as a doethyl group, or a 1-azido-1-methylethyl group, preferably 2-methyl-3-cyclohexenyl group or a 3,4-dimethyl-3-cyclo an azido Ce alkyl group; and the like. hexenyl group, preferably a Cal cycloalkenyl group in which A “Cs alkenyl group' is an unsaturated hydrocarbon 1 to 3 C alkyl group(s) is(are) Substituted, and the like. group including 2 to 8 carbon atoms having at least one 10 A "Coo aryl group' is a monocyclic or polycyclic aryl carbon-carbon double bond. The Cs alkenyl group may be a straight chain or a branched chain. Examples of the Cas group having 6 to 10 carbon atoms. In the polycyclic aryl alkenyl group include a vinyl group, a 1-propenyl group, an group, if at least one ring is an aromatic ring, the remaining isoprompenyl group, an allyl group, a 1-butenyl group, a ring(s) may be any of a saturated alicyclic ring, an unsaturated 2-butenyl group, a 3-butenyl group, a 1-pentenyl group, a 15 alicyclic ring, and an aromatic ring. Examples of the Co 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a aryl group include a phenyl group, a naphthyl group, an 1-hexenyl group, a 2-hexenyl group, a 3-hexenyl group, a aZulenyl group, an indenyl group, an indanyl group, a tetrali 4-hexenyl group, a 5-hexenyl group, a 1-heptenyl group, a nyl group, and the like. Among these, a phenyl group is 6-heptenyl group, a 1-octenyl group, a 7-octenyl group, a preferable. 1-methyl-allyl group, a 2-methyl-allyl group, a 1-methyl-2- Examples of a “substituted Co aryl group' include an butenyl group, a 2-methyl-2-butenyl group, and the like. alkyl-substituted aryl group Such as a 2-chlorophenyl group, Among these, a C- alkenyl group is preferable. a 3.5-dichlorophenyl group, a 4-fluorophenyl group, a 3.5- Examples of a “substituted Cls alkenyl group” include: a difluorophenyl group, a 4-trifluoromethylphenyl group, or a haloalkenyl group Such as a 3-chloro-2-propenyl group, 2-methoxy-1-naphthyl group, a halogeno-Substituted aryl 4-chloro-2-butenyl group, a 4.4-dichloro-3-butenyl group, 25 group, and analkoxy-Substituted aryl group, preferably a C 4,4-difluoro-3-butenyl group, a 3.3-dichloro-2-propenyl alkyl-substituted Co aryl group, a halogeno-Substituted group, a 2,3-dichloro-2-propenyl group, a 3.3-difluoro-2- Coo aryl group, and a C- alkoxy Substituted aryl group. propenyl group, or a 2.4.6-trichloro-2-hexenyl group, prefer A "heterocyclic group' includes 1 to 4 heteroatom(s) ably Chaloalkenyl group; selected from the group consisting of a nitrogen atom, an a hydroxyalkenyl group Such as a 3-hydroxy-1-propenyl 30 group, a 4-hydroxy-1-butenyl group, a 1-hydroxyallyl group, oxygen atom, and a Sulfur atom, as a constituent atom of a or a 1-hydroxy-2-methylallyl group, preferably a hydroxy ring. The heterocyclic group may be monocyclic or polycy Calkenyl group; and the like. clic. A "Cs alkynyl group' is an unsaturated hydrocarbon Examples of the heterocyclic group include a 5-membered group including 2 to 8 carbon atoms having at least one 35 heteroaryl group, a 6-membered heteroaryl group, a con carbon-carbon triple bond. The Cs alkynyl group may be a densed heteroaryl group, a saturated heterocyclic group, a straight chain or a branched chain. Examples of the Cas partially unsaturated heterocyclic group and the like. alkynyl group include an ethynyl group, a 1-propynyl group, Examples of the 5-membered heteroaryl group include: a a propargyl group, a 1-butynyl group, a 2-butynyl group, a pyrrolyl group Such as a pyrrol-1-yl group, a pyrrol-2-yl 3-butynyl group, a 1-pentynyl group, a 2-pentynyl group, a 40 group, or a pyrrol-3-yl group; a furyl group Such as a furan 3-pentynyl group, a 4-pentynyl group, a 1-hexynyl group, a 2-yl group or a furan-3-yl group; a thienyl group Such as a 1-methyl-2-propynyl group, a 2-methyl-3-butynyl group, a thiophen-2-yl group, or a thiophen-3-yl group; an imidazolyl 1-methyl-2-butynyl group, a 2-methyl-3-pentynyl group, a group Such as an imidazol-1-yl group, an imidazol-2-yl 1,1-dimethyl-2-butynyl group, and the like. Among these, a group, an imidazol-4-yl group, or an imidazol-5-yl group; a C. alkynyl group is preferable. 45 pyrazolyl group Such as a pyrazol-1-yl group, a pyrazol-3-yl Examples of a “substituted Cls alkynyl group' include a group, a pyrazol-4-yl group, or a pyrazol-5-yl group; an haloalkynyl group Such as a 3-chloro-1-propynyl group, a oxazolyl group Such as an oxazol-2-yl group, an oxazol-4-yl 3-chloro-1-butynyl group, a 3-bromo-1-butynyl group, a group, or an oxazol-5-yl group; an isoxazolyl group Such as 3-bromo-2-propynyl group, a 3-iodo-2-propynyl group, a an isoxazol-3-yl group, an isoxazol-4-yl group, or an isox 3-bromo-1-hexynyl group, a 4.4.6.6-tetrafluoro-1-dodecynyl 50 azol-5-yl group; a thiazolyl group Such as a thiazol-2-yl group, a 5.5-dichloro-2-methyl-3-pentynyl group, or a group, a thiazol-4-yl group, or a thiazol-5-yl group; an 4-chloro-1,1-dimethyl-2-butynyl group, preferably a C isothiazolyl group Such as an isothiazol-3-yl group, an haloalkynyl group, and the like. isothiazol-4-yl group, or a thiazol-5-yl group; a triazolyl A “Cs cycloalkyl group' is an alkyl group including 3 to group Such as a 1,2,3-triazol-1-yl group, a 1,2,3-triazol-4-yl 8 carbon atoms having a cyclic moiety. Examples of the Cs 55 group, a 1,2,3-triazol-5-yl group, a 1,2,4-triazol-1-yl group, a cycloalkyl group include a cyclopropyl group, a cyclobutyl 1,2,4-triazol-3-yl group, or a 1,2,4-triazol-5-yl group; an oxa group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl diazolyl group Such as a 1,2,4-oxadiazol-3-yl group, a 1,2,4- group, a cyclooctyl group, and the like. Among these, a C oxadiazol-5-yl group, or a 1,3,4-oxadiazol-2-yl group; a thia cycloalkyl group is preferable. diazolyl group Such as a 1,2,4-thiadiazol-3-yl group, 1,2,4- Examples of a “substituted Cls cycloalkyl group' include 60 thiadiazol-5-yl group, or a 1.3,4-thiadiazol-2-yl group; a an alkyl-substituted cycloalkyl group Such as a 2,3,3-trimeth tetrazolyl group Such as a tetrazol-1-yl group or a tetrazol-2- ylcyclobutyl group, a 4.4.6.6-tetramethylcyclohexyl group, yl group; and the like. or a 1,3-dibutylcyclohexyl group, preferably a C Examples of the 6-membered heteroaryl group include: a cycloalkyl group in which 1 to 3 C alkyl group(s) is(are) pyridyl group Such as a pyridin-2-yl group, a pyridin-3-yl substituted, and the like. 65 group, or a pyridin-4-yl group; a pyrazinyl group Such as a A“Cs cycloalkenyl group' is an alkenyl group including pyrazin-2-yl group or a pyrazin-3-yl group; a pyrimidinyl 4 to 8 carbon atoms having a cyclic moiety. Examples of the group Such as a pyrimidin-2-yl group, a pyrimidin-4-yl US 8,772,200 B2 11 12 group, or a pyrimidin-5-yl group; a pyridazinyl group Such a A“(1-imino)Cs alkyl group' is an iminomethyl group or pyridazin-3-yl group or a pyridazin-4-yl group; a triazinyl a group in which a C-, alkyl group is bonded to an iminom group; and the like. ethyl group. Examples of the (1-imino)C is alkyl group Examples of the condensed heteroaryl group include: include an iminomethyl group, a (1-imino)ethyl group, a indol-1-yl group, an indol-2-yl group, an indol-3-yl group, an 5 (1-imino)propyl group, a (1-imino)butyl group, a (1-imino) indol-4-yl group, an indol-5-yl group, an indol-6-yl group, an pentyl group, a (1-imino)hexyl group, a (1-imino)heptyl indol-7-yl group; a benzofuran-2-yl group, a benzofuran-3-yl group, and the like. Among these, a (1-imino) Calkyl group group, a benzofuran-4-yl group, a benzofuran-5-yl group, a is preferable. benzofuran-6-yl group, a benzofuran-7-yl group; a ben Examples of a “substituted (1-imino)Cs alkyl group' Zothiophen-2-yl group, a benzothiophen-3-yl group, a ben 10 Zothiophen-4-yl group, a benzothiophen-5-yl group, a ben include: a (1-hydroxyimino)alkyl group Such as a hydroxy Zothiophen-6-yl group, a benzothiophen-7-yl group; a iminomethyl group, a (1-hydroxyimino)ethyl group, a (1-hy benzoimidazol-1-yl group, a benzoimidazol-2-yl group, a droxyimino)propyl group, ora (1-hydroxyimino)butyl group, benzoimidazol-4-yl group, a benzoimidazol-5-yl group, a preferably a (1-hydroxyimino)C alkyl group; a (1-alkoxy benzoxazol-2-yl group, a benzoxazol-4-yl group, a benzox 15 imino)alkyl group Such as a methoxyiminomethyl group, a azol-5-yl group, a benzothiazol-2-yl group, a benzothiazol (1-ethoxyimino)methyl group, a (1-methoxyimino)ethyl 4-yl group, a benzothiazol-5-yl group; a quinolin-2-yl group, group, a (1-t-butoxyimino)ethyl group, or a (1-ethoxyimino) a quinolin-3-yl group, a quinolin-4-yl group, a quinolin-5-yl ethyl group, preferably a (1-(C. alkoxy)imino)C alkyl group, a quinolin-6-yl group, a quinolin-7-yl group, a quino group; and the like. lin-8-yl group; and the like. A “substituted carboxyl group' is a group in which a C Examples of the other heterocyclic group include: a alkyl group, a C- alkenyl group, a C- alkynyl group, a 3-membered saturated heterocyclic ring Such as an aziridin Coo aryl group, a Co-o aryl C- alkyl group, or a 5 to 1-yl group, an aziridin-2-yl group, or an oxiranyl group; a 6-membered heterocyclic group is bonded to a carbonyl 5-membered Saturated heterocyclic ring Such as a pyrrolidin group. 1-yl group, a pyrrolidin-2-yl group, a pyrrolidin-3-yl group, a 25 Examples of the “substituted carboxyl group' include: an tetrahydrofuran-2-yl group, a tetrahydrofuran-3-yl group, or alkoxycarbonyl group Such as a methoxycarbonyl group, an a 1.3dioxiran-2-yl group; a 6-membered saturated hetero ethoxycarbonyl group, an n-propoxycarbonyl group, an cyclic ring such as a piperidin-1-yl group, a piperidin-2-yl i-propoxycarbonyl group, an n-butoxycarbonyl group, an group, a piperidin-3-yl group, a piperidin-4-yl group, a pip i-butoxycarbonyl group, a t-butoxycarbonyl group, an n-pen erazin-1-yl group, a piperazin-2-yl group, a morpholin-2-yl 30 tyloxycarbonyl group, oran n-hexyloxycarbonyl group, pref group, a morpholin-3-yl group, or a morpholin-4-yl group; a erably a C- alkoxycarbonyl group; 1,3-benzodioxol-4-yl group, a 1,3-benzodioxol-5-yl group, a an alkenyloxycarbonyl group such as a vinyloxycarbonyl 1,4-benzodioxan-5-yl group, a 1,4-benzodioxan-6-yl group, group or anallyloxycarbonyl group, preferably a Calkeny a 3,4-dihydro-2H-1,5-benzodioxepin-6-yl group, a 3,4-dihy loxycarbonyl group; dro-2H-1,5-benzodioxepin-7-yl group, a 2,3-dihydrobenzo 35 an alkynyloxycarbonyl group Such as an ethynyloxycarbo furan-4-yl group, a 2,3-dihydrobenzofuran-5-yl group, a 2.3- nyl group or a propargyloxycarbonyl group, preferably a C dihydrobenzofuran-6-yl group, or a 2,3-dihydrobenzofuran alkynyloxycarbonyl group; 7-yl group; and the like. an aryloxycarbonyl group Such as a phenoxycarbonyl Examples of a “substituted heterocyclic group' include: a group or a naphthoxycarbonyl group, preferably a Coary 4-chloro-2-pyridinyl group, a 3-chloro-2-pyrazinyl group, a 40 loxycarbonyl group; 4-methyl-2-pyridinyl group, a 5-trifluoromethyl-2-pyrimidi an aralkyloxycarbonyl group Such as a benzyloxycarbonyl nyl group, a 3-methyl-2-quinolyl group, and the like. group, preferably a Caryl Calkoxycarbonyl group; and A "Cs acyl group' is a group in which a hydrogenatom, the like. a C-7 alkyl group, a C2-7 alkenyl group, a C-7 alkynyl group. A “substituted carbamoyl group' is a group in which a C a C-7 aryl group, or a 5- to 7-membered heterocyclic group is 45 alkyl group, a C2-alkenyl group, a C2-alkynyl group, a bonded to a carbonyl group. Coo aryl group, a Co-o aryl C- alkyl group, or a 5 to Examples of the Cs acyl group include: a formyl group; 6-membered heterocyclic group is bonded to a carbamoyl an alkylcarbonyl group Such as an acetyl group, a propionyl group. group, an n-propylcarbonyl group, an n-butylcarbonyl group, Examples of the “substituted carbamoyl group' include: a a pentanoyl group, a Valeryl group, an octanoyl group, an 50 monoalkylcarbamoyl group or a dialkylcarbamoyl group, i-propylcarbonyl group, an i-butylcarbonyl group, a pivaloyl Such as a methylcarbamoyl group, an ethylcarbamoyl group, group, oranisovaleryl group, preferably a C- alkylcarbonyl a dimethylcarbamoyl group, or a diethylcarbamoyl group, group; an alkenylcarbonyl group Such as an acryloyl group, or preferably a mono Ce alkylcarbamoyl group or a di C. a metacryloyl group, preferably a C- alkenylcarbonyl alkylcarbamoyl group; a monoarylcarbamoyl group Such as a group; an alkynylcarbonyl group Such as a propioloyl group, 55 phenylcarbamoyl group or a 4-methylphenylcarbamoyl preferably a C- alkynylcarbonyl group: an arylcarbonyl group, preferably a mono Co arylcarbamoyl group; and the group Such as a benzoyl group; a heterocyclic carbonyl group like. Such as a 2-pyridylcarbonyl group or a thienylcarbonyl group; Examples of a “substituted hydroxyl group' include: an and the like. alkoxy group Such as a methoxy group, an ethoxy group, an Examples of a 'substituted C acyl group' include: a 60 n-propoxy group, an n-butoxy group, an n-pentyloxy group, haloacyl group Such as a monofluoroacetyl group, a an n-hexyloxy group, a decyloxy group, a dodecyloxy group, monochloroacetyl group, a monobromoacetyl group, a dif a lauryloxy group, an i-propoxy group, an i-butoxy group, an luoroacetyl group, a dichloroacetyl group, a dibromoacetyl S-butoxy group, a t-butoxy group, a 1-ethylpropoxy group, an group, a trifluoroacetyl group, a trichloroacetyl group, a tri i-hexyloxy group, a 4-methylpentoxy group, a 3-methylpen bromoacetyl group, a 3,3,3-trifluoropropionyl group, a 3.3.3- 65 toxy group, a 2-methylpentoxy group, a 1-methylpentoxy trichloropropionyl group, or a 2.2.3,3,3-pentafluoropropio group, a 3.3-dimethylbutoxy group, a 2.2-dimethylbutoxy nyl group, preferably a C-7 haloacyl group; and the like. group, a 1,1-dimethylbutoxy group, a 1,2-dimethylbutoxy US 8,772,200 B2 13 14 group, a 1,3-dimethylbutoxy group, a 2,3-dimethylbutoxy lamino group, preferably a mono Cao arylamino group; a group, a 1-ethylbutoxy group, or a 2-ethylbutoxy group, pref diarylamino group Such as a di-1-naphthylamino group, pref erably a C- alkoxy group; erably a di Co arylamino group; an aralkylamino group a cycloalkylalkoxy group Such as a cyclopropylmethyloxy Such as a benzylamino group, preferably a Co aryl C. group or a 2-cyclopentylethyloxy group, preferably a Cs 5 alkylamino group; an acylamino group Such as an acety cycloalkyl Coalkoxy group; an aralkyloxy group Such as a lamino group, a trifluoroacetylamino group, or a benzoy benzyloxy group, preferably a Co aryl Coalkoxy group; a lamino group, preferably a C-acylamino group: an alkoxy haloalkoxy group Such as a chloromethoxy group, a dichlo carbonylamino group Such as a methoxycarbonylamino romethoxy group, a trichloromethoxy group, a trifluo group or a t-butoxycarbonylamino group, preferably a C romethoxy group, a 1-fluoroethoxy group, a 1,1-difluoroet 10 alkoxycarbonylamino group; and the like. hoxy group, a 2.2.2-trifluoroethoxy group, or a Examples of a “substituted mercapto group' include: an pentafluoroethoxy group, preferably a C- haloalkoxy alkylthio group Such as a methylthio group or an ethylthio group; an alkenyloxy group Such as a vinyloxy group, a group, preferably a C- alkylthio group; an arylthio group 1-propenyloxy group, an allyloxy group, a 1-butenyloxy Such as a phenylthio group or a 4-methylphenylthio group, group, a 2-butenyloxy group, a 3-butenyloxy group, a 1-pen 15 preferably a Co arylthiogroup; an acylthiogroup Such as an tenyloxy group, a 2-pentenyloxy group, a 3-pentenyloxy acetylthio group or a benzoylthio group, preferably a C group, a 4-pentenyloxy group, a 1-hexenyloxy group, a acylthio group; and the like. 2-hexenyloxy group, a 3-hexenyloxy group, a 4-hexenyloxy Examples of a “substituted sulfonyl group' include: an group, a 5-hexenyloxy group, a 1-methyl-2-propenyloxy alkylsulfonyl group Such as a methylsulfonyl group, an eth group, a 2-methyl-2-propenyloxy group, a 1-methyl-2-bute ylsulfonyl group, an n-propylsulfonyl group, an i-propylsul nyloxy group, or a 2-methyl-2-butenyloxy group, preferably fonyl group, an n-butylsulfonyl group, an i-butylsulfonyl a C2-alkenyloxy group: group, an S-butylsulfonyl group, a t-butylsulfonyl group, an an alkynyloxy group such as an ethynyloxy group, a pro n-pentylsulfonyl group, an i-pentylsulfonyl group, a neopen pynyloxy group, a propargyloxy group, a 1-butynyloxy tylsulfonyl group, a 1-ethylpropylsulfonyl group, an n-hexy group, a 2-butynyloxy group, a 3-butynyloxy group, a 1-pen 25 lsulfonyl group, or an i-hexylsulfonyl group, preferably a tynyloxy group, a 2-pentynyloxy group, a 3-pentynyloxy C. alkylsulfonyl group; a haloalkylsulfonyl group Such as a group, a 4-pentynyloxy group, a 1-hexynyloxy group, a trifluoromethylsulfonyl group, preferably a C- haloalkyl 1-methyl-2-propynyloxy group, a 2-methyl-3-butynyloxy Sulfonyl group; an arylsulfonyl group Such as a phenylsulfo group, a 1-methyl-2-butynyloxy group, a 2-methyl-3-penty nyl group or a 4-methylphenylsulfonyl group, preferably a nyloxy group, or a 1,1-dimethyl-2-butynyloxy group, prefer 30 Co arylsulfonyl group; a sulfo group; an alkoxysulfonyl ably a C- alkynyloxy group; a cycloalkyloxy group Such as group Such as a methoxysulfonyl group or an ethoxysulfonyl a cyclopropyloxy group, a cyclobutyloxy group, a cyclopen group, preferably a C- alkoxysulfonyl group; a sulfamoyl tyloxy group, a cyclohexyloxy group, a cycloheptyloxy group; a Sulfamoyl group Such as an N-methylsulfamoyl group, a cyclooctyloxy group, a 2-methylcyclopropyloxy group, an N-ethylsulfamoyl group, a N,N-dimethylsulfamoyl group, a 2-ethylcyclopropyloxy group, a 2.3,3-trimethylcy 35 group, oran N,N-diethylsulfamoyl group, preferably a mono clobutyloxy group, a 2-methylcyclopentyloxy group, a 2-eth C. alkylsulfamoyl group or a di C-alkylsulfamoyl group; ylcyclohexyloxy group, a 2-ethylcyclooctyloxy group, a 4.4. a monoarylsulfamoyl group Such as a phenylsulfamoyl group 6,6-tetramethylcyclohexyloxy group, or a 1.3- or a 4-methylsulfamoyl group, preferably a mono Cao aryl dibutylcyclohexyloxy group, preferably a C-cycloalkyloxy Sulfamoyl group; and the like. group; an aryloxy group Such as a phenyloxy group, a naph 40 Examples of a "halogeno group' include a fluorine atom, a thyloxy group, an azulenyloxy group, an indenyloxy group, chlorine atom, a bromine atom, an iodine atom, and the like. an indanyloxy group, or a tetralinyloxy group, preferably a As a preferred combination of a group represented by Co-lo aryloxy group: CRRR, the following combination may be included. an arylalkyloxy group (aralkyloxy group) Such as a benzy R" is an unsubstituted or substituted hydroxyl group; loxy group, a phenethyloxy group, or a 2-naphthylmethyloxy 45 R’ is a hydrogen atom or an unsubstituted or substituted group, preferably a Co-o aryl Co alkyloxy group; Cs alkyl group; and an acyloxy group Such as an acetyloxy group, a propiony R is a hydrogenatom, an unsubstituted or substituted Cls loxy group, an n-propylcarbonyloxy group, an i-propylcar alkyl group, an unsubstituted or Substituted Cls alkenyl bonyloxy group, an n-butylcarbonyloxy group, an i-butylcar group, an unsubstituted or substituted Cls alkynyl group, an bonyloxy group, a pentanoyloxy group, or a pivaloyloxy 50 unsubstituted or Substituted C-5 cycloalkyl group, an unsub group, preferably a C-7 acyloxy group; stituted or Substituted Co aryl group, an unsubstituted or an alkoxycarbonylalkyloxy group Such as a methoxycar Substituted heterocyclic group, an unsubstituted or Substi bonylmethyloxy group or a 1-methoxycarbonyl-1-methyl tuted Cls acyl group, an unsubstituted or Substituted ethyloxy group, preferably a Calkoxycarbonyl Calkoxy (1-imino)C is alkyl group, an unsubstituted or substituted group; 55 Cs alkoxycarbonyl group, an unsubstituted or Substituted a trialkylsilyloxy group such as a trimethylsilyloxy group hydroxyl group, or a cyano group. or a t-butyldimethylsilyloxy group, preferably a trialkylsily The following combination may also be included as a loxy group; preferred example. and the like. R" is an unsubstituted or substituted Cls alkyl group; Examples of a “substituted amino group' include: an alky 60 R is an unsubstituted or substituted Cls alkyl group; and lamino group Such as a methylamino group, an ethylamino R is a substituted Cls alkyl group, an unsubstituted or group, an n-propylamino group, an n-butylamino group, a Substituted Casalkenyl group, an unsubstituted or Substituted dimethylamino group, or a diethylamino group, preferably a Cs alkynyl group, an unsubstituted or substituted Cls mono C-alkylamino group or a diCo alkylamino group; a cycloalkyl group, an unsubstituted or substituted Co aryl mono Ce alkylideneamino group Such as a methylidene 65 group, an unsubstituted or Substituted heterocyclic group, an amino group, oran ethylideneamino group; a monoarylamino unsubstituted or Substituted Cls acyl group, an unsubstituted group Such as a phenylamino group or a 4-methylpheny or Substituted (1-imino)Cs alkyl group, an unsubstituted or US 8,772,200 B2 15 16 Substituted Cls alkoxycarbonyl group, an unsubstituted or Substituted mercapto group, a Substituted Sulfonyl, a halo Substituted carbamoyl group, an unsubstituted or Substituted geno group, a cyano group, or a nitro group. Sulfonyl group, or a cyano group. The groups represented by R may be the same as the R" and R may be joined to form an unsubstituted or sub examples given in the groups represented by R' to R. stituted 5- to 8-membered ring, or to form O—, RRC=, or In Formula (I) and (II), n represents the number of Rand RN . is an integer of 0 to 5. In Formula (III), n1 represents the Here, R represents a hydrogenatom oran unsubstituted or number of R and is an integer of 0 to 4. substituted Cls alkyl group. R” represents a hydrogen atom R preferably represents a C- alkyl group, a C or an unsubstituted or Substituted Cls alkyl group. R' repre haloalkyl group, a Co aryl C alkyl group, a Cs 10 cycloalkyl group, a Co-o-aryl group, a C-7 acyl group, a C sents an unsubstituted or Substituted hydroxyl group, or an alkoxycarbonyl group, a C- alkoxy group, an amino group. unsubstituted or substituted Cls alkyl group. a mono C allylamino group, di C-allylamino group, a The unsubstituted or substituted Cisalkyl group in R. R. C- alkoxycarbonylamino group, a C- alkylthio group, a and R may be the same as the “Cs alkyl group” given as the C. alkylsulfonyl group, a halogeno group, a cyano group or examples in R' to Rabove. 15 a nitro group. The substituted hydroxyl group in R' may be the same as Any one of R' to R and any one of R, by being joined, the “substituted hydroxyl group” given as the examples in R' may form an unsubstituted or substituted 5- to 8-membered to Rabove. r1ng. Examples of the unsubstituted or substituted 5- to 8-mem Examples of the 5- to 8-membered ring include: an aro bered ring, which may be formed from R' and R being matic hydrocarbon ring Such as a benzene ring; a Css joined, include: analiphatic hydrocarbon ring Such as a cyclo cycloalkene ring Such as a cyclopentene ring, a cyclopenta propane ring, a cyclobutane ring, a cyclopentane ring, a diene ring, a cyclohexene ring, a cycloheptene ring, or a cyclohexane ring, a cycloheptane ring, or a cyclooctane ring, cyclooctene ring; and the like. preferably a C-s cycloalkane ring; an unsaturated heterocy A, D. clic ring Such as an oxirane ring, a 1.3dioxirane ring, a 25 When R is a group represented by CR'R'R''. A represents dihydro-2H-pyran ring, a dihydro-2H-thiopyran ring, and a a 5- to 7-membered hydrocarbon ring or a 5- to 7-membered tetrahydropyridine ring, preferably an oxygen-containing 3 heterocyclic ring. to 5-membered unsaturated heterocyclic ring. Examples of the 5- to 7-membered hydrocarbon ring The unsubstituted or Substituted Co aryl group in R may include: an aromatic hydrocarbon ring Such as a benzene ring; be the same as the “Caryl group” given as the examples in 30 a CS-7 cycloalkene ring Such as a cyclopentene ring, a cyclo R" to Rabove. It is preferably a phenyl group. hexene ring, a cycloheptene ring; an aromatic 5- to 7-mem R bered heterocyclic ring such as a furan ring, a thiophene ring, Reach independently represents an unsubstituted or sub a pyrrole ring, an imidazole ring, a pyrazole ring, a thiazole stituted Cls alkyl group, an unsubstituted or Substituted Cs ring, an oxazole ring, an isoxazole ring, a pyridine ring, a alkenyl group, an unsubstituted or substituted Cls alkynyl 35 pyrazine ring, a pyrimidine ring, a pyridazine ring, anazepine group, an unsubstituted or Substituted Cls cycloalkyl group, ring, or a diazepine ring; an unsaturated 5- to 7-membered an unsubstituted or Substituted Cas cycloalkenyl group, an heterocyclic ring Such as a dihydro-2H-pyran ring, a dihydro unsubstituted or Substituted Co aryl group, an unsubsti 2H-thiopyran ring, or a tetrahydropyridine ring; and the like. tuted or substituted heterocyclic group, an unsubstituted or Among these, an aromatic hydrocarbon ring is preferable and Substituted Cls acyl group, an unsubstituted or substituted 40 a benzene ring is more preferable. (1-imino)Cs alkyl group, an unsubstituted or Substituted When R is an unsubstituted or Substituted Co aryl group carboxyl group, an unsubstituted or Substituted carbamoyl or a cyano group. A represents a benzene ring. group, an unsubstituted or Substituted hydroxyl group, an That is, it is preferable that the compound according to the unsubstituted or Substituted amino group, an unsubstituted or present invention be a compound (II) or (III). Substituted mercapto group, a Substituted Sulfonyl group, a 45 D represents a 5- to 7-membered hydrocarbon ring or a 5 halogeno group, a cyano group, or a nitro group. to 7-membered heterocyclic ring. Examples of the 5- to The groups represented by R may be the same as the 7-membered hydrocarbon ring and the 5- to 7-membered examples given in the groups represented by R' to R. heterocyclic ring include the same as the examples given In Formulae (I), (II) and (III), m and m1 represent the above as A, and among these, anaromatic hydrocarbon ring is number of R and are an integer of 0 to 6. 50 preferable and a benzene ring is more preferable. R" preferably represents a C- alkyl group, a C That is, it is more preferable that the compound according haloalkyl group, a C- alkenyl group, a Css cycloalkyl to the present invention be a compound (III). group, a hydroxyl group, a C- alkoxy group, or a halogen X,Y,Z) group. X represents an oxygen atom, a Sulfur atom, a Sulfenyl R 55 group, a Sulfonyl group, an unsubstituted or Substituted car Reach independently represents an unsubstituted or sub bon atom, or an unsubstituted or Substituted nitrogen atom. stituted Cls alkyl group, an unsubstituted or Substituted Cs Examples of a substituent of the carbon atom include an alkenyl group, an unsubstituted or Substituted Cls alkynyl OXO group, a C2-alkenylamino group, and a hydroxyl group. group, an unsubstituted or Substituted Cls cycloalkyl group, Y represents a carbonatom oranitrogenatom. Z represents an unsubstituted or Substituted Cas cycloalkenyl group, an 60 a carbonatom or a nitrogenatom. It is preferable that Y and Z unsubstituted or substituted Co aryl group, an unsubsti be both carbon atoms, and D be an aromatic ring which tuted or substituted heterocyclic group, an unsubstituted or includes both Y and Z. Substituted Cls acyl group, an unsubstituted or substituted A salt or an N-oxide compound according to the present (1-imino)Cs allyl group, an unsubstituted or Substituted car invention is not particularly limited as long as it is an agricul boxyl group, an unsubstituted or Substituted carbamoyl 65 turally acceptable salt or N-oxide compound. Examples of the group, an unsubstituted or Substituted hydroxyl group, an salt include: a salt of an inorganic acid Such as hydrochloric unsubstituted or Substituted amino group, an unsubstituted or acid or Sulfuric acid; a salt of an organic acid Such as acetic US 8,772,200 B2 17 18 acid or lactic acid; a salt of an alkali metal Such as lithium, The compound represented by Formula (I) may be pro Sodium, or potassium; a salt of an alkali earth metal Such as duced by reacting a compound represented by Formula (3) calcium or magnesium; a salt of a transition metal Such as iron and a compound represented by Formula (4) by conventional or copper; a salt of an organic base such as ammonia, triethy methods. lamine, tributylamine, pyridine, or hydrazine; and the like. (Production of the Compound According to the Present According to the present invention, 8-flouoro-3-hydrox Invention) ycuinoline, 7,8-diflouoro-3-hydroxyquinoline, 8-flouoro-3- The compound according to the present invention may be hydroxy-2-methylduinoline, or 7,8-diflouoro-3-hydroxy-2- produced in accordance with the following synthesis meth methylduinoline is a useful intermediate product. ods. 10 (Synthesis Method 3) (Synthesis Method 1) (R), (R), 15 M Z D A N ( y1) NR Z A N Q y1 NR 4 -- -e- (R) N 4 -- 1. (R) 2 X N O H N H1 (5) (6) (1) (2) (R), (R), D D Z 25 y1 NR Z NR

X A || N OH A || N (R), (R), 2 2 N N

(In the formulae, R. R. R. A. D., X, Y, Z. m. and n represent (In the formulae, R. R. R. A. D., X, Y, Z. mand n represent the same meaning as those described above. Q represents a 35 the same meaning as those described above. M represents halogen atom.) lithium or magnesium.) The compound represented by Formula (I) may be pro A compound represented by Formula (5) is obtained by duced by reacting a compound represented by Formula (1) lithiation or magnesium complexation using an alkyllithium and a compound represented by Formula (2) by conventional reagent or a Grignard reagent or a manufactured complex methods. 40 prepared from an allyllithium reagent or a Grignard reagent, According to the present invention, 7,8-diflouoro-3-iodo and then a compound represented by Formula (6) is added quinoline is a useful intermediate product. thereto, resulting in the production of a compound repre (Synthesis Method 2) sented by Formula (7). Examples of the alkyllithium reagent used in the lithiation 45 include methyllithium, n-butyllithium, s-butyllithium, t-bu (R) tyllithium, and the like. | Examples of the Grignard reagent used in the magnesium N X (D ) complexation include methylmagnesium chloride, ethylmag A || Y1 SR - 50 nesium chloride, n-butylmagnesium chloride, i-propylmag nesium chloride, and the like. Also, for example, a manufac e-GON -- Q tured complex prepared from n-butylmagnesium chloride (3) (4) and n-butyllithium may be used. (R), A solvent used in the lithiation or magnesium complex ation is not particularly limited as long as it forms an anhy D drous reaction system without dissolving the compound to Z react therewith or exhibit any particular interaction therewith. NR Suitable examples thereof include: an alkane-based solvent X such as pentane, hexane, heptane, ISOPAR (registered trade A || N 60 mark) E, or ISOPAR (registered trademark) G; an aromatic (R) based solvent such as benzene, toluene, or ortho-Xylene; an 2 ether-based solvent such as diethyl ether or tetrahydrofuran: N and a mixture thereof. Among these, an ether-based solvent such as diethyl ether or tetrahydrofuran is preferable. The 65 reaction may be performed in a nitrogen atmosphere and an (In the formulae, R. R. R. A. D. Q. X, Y, Z. m and n anhydrous system, and prepared at a temperature of -10°C. represent the same meaning as those described above.) to -78° C. US 8,772,200 B2 19 20 (Synthesis Method 4) -continued (R), (R), D Z RI' D y1 Z 1 SC. X OH y1 NR N Oxidizing agent 4 A Her (R) 2 4 N1s OH 10 (R) N R2 2 (11) N (7) (In the formulae, R. R. A. D., X, Y, Z. m and n represent 15 the same meaning as those described above. R'' and R. among the above R' to R, represent an unsubstituted or Substituted alkyl group, an unsubstituted or Substituted alk enyl group, an unsubstituted or Substituted alkynyl group, an (R), unsubstituted or Substituted aryl group, oran unsubstituted or Substituted heterocyclic ring. Hal represents a halogenatom.) D A compound represented by Formula (10) may be pro Z duced by reacting an equivalent of a Grignard reagent with a 1n compound represented by Formula (9). Also, a compound represented by Formula (11) may be produced by reacting at N least two equivalents of a Grignard reagent with the com 25 (R')-(iii. A O pound represented by Formula (9). 2 N (Synthesis Method 6) (8) (R), 30 (In the formulae, R. R. R. A. D.Y. Z. mandin represent the D same meaning as those described above.) y1 Z G A compound represented by Formula (8) is produced by r R2MgHal oxidation by reacting an oxidizing agent with a compound X O e 35 R4 A N represented by Formula (7). The above oxidation reaction (R) may be performed without particular limitation as long as the 2 reaction oxidizes a secondary hydroxyl group. For example, N an oxidation method such as a Jones oxidation, an oZone (12) oxidation, or a Swern oxidation, or using an oxidizing 40 (R), reagent, Such as manganese dioxide, or a Dess-Martin D reagent, may be adopted. Z R2 (Synthesis Method 5) y1 R2 X OH 45 A N (R), (R) 2 D N Y Z RI' Y (13) r R2MgHal 50 (R), X O e R4 A N D (R) Z R2 2 y1 N R2 (9) 55 N X OH (R), (R')-(AH 2 D N R2 Z RI' (14) y1 60 R2 N X OH (In the formulae, R. R. R. A. D., X, Y, Z. m., n and Hal (R') iii. - A - represent the same meaning as those described above. G 2 represents a leaving group. Such as an alkoxy group, or a N 65 halogen atom.) A compound represented by Formula (13) may be pro duced by reacting one equivalent of a Grignard reagent with US 8,772,200 B2 21 22 a compound represented by Formula (12). Also, a compound -continued represented by Formula (14) may be produced by reacting at (R), least two equivalents of a Grignard reagent with the com D pound represented by Formula (12). Z (Synthesis Method 7) NR 1s X --Chlorinating agent (R), (R), 2 D 10 Nt Z 1N O Hydrolysis X (19) A N (R)4 15 2 N (15) (R), D Z (R), NR X -e- D N Z NH y1 2 25 (R')iii. - A - Alkylation 2 N Hal X O A N (20) (R), 2 N 30 (16) (R), Kl D Z \ K2 35 (R), D Z X O A N NR (R), X 2 40 (R) /A1S (17) 2 N R4 (21) (In the formulae, R. R. A. D., X, Y, Z. m, and n represent 45 the same meaning as those described above. J represents an alkoxycarbonyl group or a cyano group. K' and K represent (In the formulae, R. R. R. A. D., X, Y, Z. m., n and Hal an alkyl group.) represent the same meaning as those described above. R' A compound represented by Formula (16) may be pro represents an unsubstituted or Substituted alkoxy group, an duced by hydrolysis using conventional methods. Also, a 50 unsubstituted or Substituted alkyl group, an unsubstituted or compound represented by Formula (17) may be produced by Substituted alkenyl group, an unsubstituted or Substituted reacting an alkylating agent in the presence of a base. alkynyl group, an unsubstituted or Substituted aryl group, or an unsubstituted or Substituted heterocyclic ring, an unsub (Synthesis Method 8) stituted or Substituted amino group, or an unsubstituted or 55 Substituted thioalkyl group.) (R), An N-oxide compound represented by Formula (19) may be produced by oxidizing a compound represented by For D mula (18) using conventional methods such as the use of an y1 Z NR oxidizing agent. A compound represented by Formula (20) Oxidizing agent 60 may be produced by reacting a conventional halogenating N X agent Such as phosphorus oxychloride with the compound (R)4 A represented by Formula (19). And then, the compound repre 2 sented by Formula (20) is subjected to a nucleophilic substi N H 65 tution reaction or a coupling reaction using an organic metal catalyst to synthesize a compound represented by Formula (21). US 8,772,200 B2 23 24 (Synthesis Method 9) For example, it may be used to prevent: Sugar beet: Leaf spot (Cercospora beticola), Black root rot (Aphanomyces cochloides), Root rot (Thanatephorus cucumeris), Leaf rot (Thanatephorus cucumeris); pi peanut: Brown leaf spot (Mycosphaerella arachidis), B Black rust (Mycosphaerella berkeleyi); (R) (1st-nor (R), cucumber: Powdery mildew (Sphaerotheca filliginea), 2 Downy mildew (Pseudoperonospora cubensis), Gummy N D stem blight (Mycosphaerella melonis), Wilt (Fusarium (22) -- y1'N, He 10 Oxysporum), Sclerotinia rot (Sclerotinia Sclerotiorum), Gray OR mold (Botrytis cinerea), Anthracnose (Colletotrichum -- OR orbiculare), Scab (Cladosporium cucumerinum), Target leaf M k -* spot (Corynespora cassicola), Damping-off (Pythium A || N OR (24) (R) debaryanam, Rhizoctonia Solani Kuhn), Bacterial spot 2 15 (Pseudomonas Syringae pv. Lecrymans); N tomato: Gray mold (Botrytis cinerea), Leaf mold (Cla (23) dosporium fulvum), Phytophthora root rot (Phytophthora (R), infestans); eggplant: Gray mold (Botrytis cinerea), Black rot D (Corynespora melongenae), Powdery mildew (Erysiphe Z cichoracearum), Sooty mold (Mycovellosiella nattrassii); NR strawberry: Gray mold (Botrytis cinerea), Powdery mil X dew (Sohaerotheca humuli), Anthracnose (Colletotrichum A || N acutatum, Colletotrichum fragariae), Phytophthora root rot (R), 25 (Phytophthora cactorum); 2 onion: Gray mold neck rot (Botrytis allii), Gray mold (Bot N rytis cinerea), Leafblight (Botrytis squamosa), Downy mil dew (Peronospora destructor); cabbage: Clubroot (Plasmodiophora brassicae), Soft rot (In the formulae, R,R,R, A, D, X,Y,Z. m, and n represent 30 (Erwinia carotovora), Downy mildew (Peronospora para the same meaning as those described above. R' represents a sitica); Cs alkyl group. Mrepresents an alkali metal Such as lithium, kidney bean: Sclerotinia rot (Sclerotinia sclerotiorum), Sodium, or potassium. L. represents a halogen atom. Gray mold (Botrytis cinerea); The compound represented by Formula (I) may be pre apple: Powdery mildew (Podosphaera leucotricha), Scab 35 (Venturia inaequalis), Monilia disease (Monilinia mali), pared by a Suzuki coupling reaction of a boronic acid deriva Brooks fruit spot (Mycosphaerella pomi), Brown canker tive represented by Formula (22) or Formula (23) and a halide (Valsa mali). Alternaria blotch (Alternaria mali), Cedar apple derivative represented by Formula (24). rust (Gymnosporangium yamadae), White rot (Botry The N-oxide compound may be prepared by a conventional Osphaeria berengeriana), Anthracnose (Glomerella Cingu oxidation reaction. For example, in solvents or in the absence 40 lata, Collectotrichum acutatum), Marssonia blotch (Diplo of solvents, it may be prepared by causing contact between carpon mali), Fly speck (Zygophiala jamaicensis). Sooty the compound represented by Formula (I) and peroxide Such blotch (Gloeodes ponigena); as hydrogen peroxide. persimmon: Powdery mildew (Phyllactinia kakicola), In any reaction, after the reaction is completed, the result Anthracnose (Gloeosporium kaki), Angular leaf spot (Cer ant is subjected to a normal post reaction operation in an 45 cospora kaki); organic synthetic chemistry, followed by Subjecting to a con peach: Brown rot (Monilinia fructicola), Scab (Cladospo ventional separation and purification, if needed, to efficiently rium carpophilum), Phomopsis bacterial rot (Phomopsis sp.); isolate a desired product. cherry: Brown rot (Monilinia fructicola); The structure of the desired product may be identified and grape: Gray mold (Botrytis cinerea), Powdery mildew confirmed using 'H-NMR spectrum, IR spectrum, or mass 50 (Uncinula necator), Ripe rot (Glomerella Cingulata, Colle spectrum measurements, or by elemental analysis or the like. torichum acutatum), Downy mildew (Plasmopara viticola), 2) Agricultural Fungicide Bird's eye rot (Elsinoe ampelina), Leaf spot (Pseudocer An agricultural fungicide according to the present inven cospora vitis), Black rot (Guignardia bidwelli); tion contains, as an active ingredient thereof, at least one pear: Scab (Venturia nashicola), Cedar apple rust (Gym 55 nosporangium asiaticum), Leaf spot (Alternaria kikuchiana), selected from the group consisting of the nitrogen-containing Black rot (Botryosphaeria berenengeriana), Powdery mil heterocyclic compound, the salt thereof, and the N-oxide dew (Phyllactinia mali); compound thereof. tea: Collar rot (Pestalotia theae), Anthracnose (Colletotri The fungicide according to the present invention has an chum theae-simensis); excellent fungicidal capacity over a wide variety of filamen 60 citrus: Scab (Elsinoe fawcetti), Blue mold (Penicillium tous fungi, such as bacteria which belong to Oomycetes, italicum), Green mold (Penicillium digitatum), Gray mold Ascomycetes, Deuteromycetes, or Basidiomycetes. (Botrytis cinerea), Melanose (Diaporthe citri), Bacterial can The fungicide according to the present invention may be ker (Xanthomonas campestris pv. Citri): used to prevent various diseases that occur in the cultivation wheat: Powdery mildew (Erysiphe graminis f.sp. tritici), of agricultural crops including flowers, turf, and grass 65 Petch (Gibberella zeae), Leaf rust (Puccinia recondita), through seed treatment, foliar spraying, soil application or Brown snow mold (Pythium iwayamai), Red Snow mold Submerged application. (Monographella nivalis), Black eye spot (Pseudocer US 8,772,200 B2 25 26 cosporella herpotrichoides), Leaf blight (Septoria tritici), higher fatty acid ester, polyoxyethylene-added Sorbitan Glume blotch (Leptosphaeria nodorum), Tiphula Snow higher fatty acid ester, polyoxyethylene-added tristyrylphe blight (Tiphula incarnata), Sclerotinia Snow blight (Myrio nylether; a sulfuric ester salt of polyoxyethylene-added alky sclerotinia borealis), Take-all (Gaeumanomyces graminis); lphenylether, an alkylbenzene sulfonate, a sulfuric ester salt barley: Leaf stripe (Pyrenophoragraminea), Rhynchospo of higher alcohol, an alkylnaphthalene Sulfonate, a polycar rium scald (Rhynchosporium secalis), Loose Smut (Ustilago boxylate, a lignin Sulfonate, a formaldehyde condensate of tritici, U.nuda); alkylnaphthalene Sulfonate, an isobutylene-anhydrous rice: Neck rot (Pyricularia oryzae). Sheath blight (Rhizoc maleic acid copolymer, and the like. tonia Solani), Bakanae disease (Gibberallafiujikuroi), Heli The thus obtained water-dispersible powder, the emulsion, minthosporium blight (Cochliobolus niyabeanus), Damping 10 a flowable agent, the water-soluble powder, or the water off (Pythium graminicolum), Bacterial blight (Xanthomonas dispersible granules is diluted with water to a predetermined Oryzae), Bacterial damping-off (Burkholderia plantarii), concentration and used as a solution, a suspension, or an Brown stripe (Acidovorax avenae), Bacterial grain rot emulsion to be sprayed onto plants. Also, the powder and the (Burkholderia glunae); granules are used sprayed onto plants as they are. tobacco: Sclerotinia rot (Sclerotinia sclerotiorum), Pow 15 The amount of the fungicide according to the present dery mildew (Erysiphe cichoracearum); invention is, normally, with respect to the total amount of the tulip: Gray mold (Botrytis cinerea); formulation, preferably 0.01 to 90% by weight, and more bent grass: Sclerotinia Snow blight (Sclerotinia borealis), preferably 0.05 to 85% by weight. Brown blight (Pythium asphanidermatum); The application rate of the fungicide according to the orchard grass: Powdery mildew (Erysiphe graminis); present invention, although it differs depending on weather soybean: Purple blotch (Cercospora kikuchii), Downy mil conditions, formulation form, time of application, method of dew (Peronospora Manshurica), Stem rot (Phytophthora application, area of application, control target disease, or Sojae); target crop, is, normally as an amount of active ingredient potatotomato: Phytophthora root rot (phytophthora compound per 1 hectare, 1 to 1,000 g, and preferably 10 to infestans); 25 100 g. or the like. When the water-dispersible powder, the emulsion, the sus Also, the fungicide according to the present invention pension, the water-soluble powder, or the water-dispersible exhibits an excellent fungicidal effect on resistant bacteria as granules is diluted with water, the applied concentration is 1 well. Examples of the resistant bacteria include: gray mold to 1,000 ppm, and preferably 10 to 250 ppm. germs (Botrytis cinerea), Sugar beet brown spot germs (Cer 30 The fungicide according to the present invention may be cospora beticola), apple scab germs (Venturia inaequalis), mixed with other fungicides or insecticides/acaricides, or pear scab germs (Venturia nashicola), resistant to a benzimi Synergists. dazole-based fungicide Such as thiophanate-methyl, Representative examples of other fungicides, insecticides, benomyl, or carbendazim; Gray mold germs (Botrytis acaricides, and plant growth regulators that may be mixed and cinerea) resistant to a dicarboximide-based fungicide (Such 35 used with the fungicide according to the present invention are as VincloZolin, procymidone, or iprodione), and the like. shown below. Examples of diseases in which application of the fungicide Fungicide: according to the present invention is more preferable include benzoimidazole series such as benomyl, carbendazim, Scab of apple, Gray mold of cucumber, Powdery mildew of fuberidazole, thiabendazole, or thiophanate-methyl; wheat, Late blight of tomato, Leaf rust of wheat, Neck rot of 40 dicarboximide series such as chloZolinate, iprodione, pro rice, Wilt disease of cucumber, and the like. cymidone, or VincloZoline; Also, the fungicide according to the present invention is an DMI-fungicide such as imazalil, Oxpoconazole, perfra agent with low phytotoxicity, low toxicity to fish or warm Zoate, prochloraZ, triflumizole, triforine, pyrifenox, fenari blooded animals, and high safety. mol, nuarimol, azaconazole, bitertanol, bromuconazole, The fungicide according to the present invention may be 45 cyproconazole, difenoconazole, diniconazole, epoxycona used in an agrochemically acceptable form, that is, in a form Zole, fenbuconazole, fluguinconazole, fulsilaZole, flutriafol. of an agrochemical formulation, Such as a water-dispersible hexaconazole, imibenconazole, ipconazole, metconazole, powder, granules, a powder, an emulsion, a water-soluble myclobutanil, penconazole, propiconazole, prothioconazole, powder, a Suspension, or water-dispersible granules. simeconazole, tebuconazole, tetraconzole, triadimefon, tri Examples of an additive and a carrier used in the formula 50 adimenol, triticonazole, etaconazole, furconazole-cis, tion of a solid include: vegetable powder Such as Soybean ipconazole, or imibenconazole; flour or wheat flour; mineral fine powder such as diatomite, phenylamide series such as benalaxyl, furalaxyl, metal apatite, plaster, talc, bentonite, pyrophylite, or clay; an axyl, metalaxyl-M, oxadixyl, or ofurace; organic or inorganic compound Such as Sodium benzoate, amine series such as aldimorph, dodemorph, fempropi urea, or Sulfate of Soda; and the like. 55 morph, tridemorph, fenpropidine, piperalin, or spiroxamine; Examples of a solvent used in the formulation of a liquid phosphorothiolate series such as EDDP, iprobenfos, pyra include: an aromatic hydrocarbon Such as kerosene, Xylene, Zophos: or a petroleum-based aromatic hydrocarbon; cyclohexane, dithiolane series such as isoprothiolane; cyclohexanone, dimethyl formamide, dimethyl Sulfoxide, an carboxamide series such as benodanil, boScalid, carboxin, alcohol, acetone, trichloroethylene, methylisobutylketone, 60 fenfuran, flutolanil, furametpyr, mepronil, oxycarboxin, mineral oil, vegetable oil, water, and the like. penthiopyrad, or thifluZamide; Also, in the formulations, in order to attain a uniform and hydroxy-(2-amino)pyrimidine Such as bupurimate, dime stable form, a surfactant may be added as necessary. thirimol, or ethirimol; The surfactant which may be added is not particularly AP fungicide (anilinopyrimidine) Such as cyprodinil, limited. Examples of the Surfactant include: a non-ionic Sur 65 mepanipyrim, or pyrimethanil; factant such as polyoxyethylene-added alkylphenylether, N-phenylcarbamate such as diethofencarb; QoI-fungicide polyoxyethylene-added alkylether, polyoxyethylene-added (Qo inhibitor) Such as azoxystrobin, picoxystrobin, pyraclos US 8,772,200 B2 27 28 trobin, kresoxim-methyl, trifloxystrobin, dimoxystrobin, Other insecticides of benzoyl urea series: metominostrobin, orysastrobin, famoxadone, fluoxastrobin, microbial agrochemicals such as diflubenZuron, chlorflua fenamidone, metominofen, pyribencarb; Zuron, hexaflumuron, triflumuron, tetrabenZuron, flufenoXu PP fungicide (phenylpyrrole) such as fenpiconyl, fludiox ron, flucycloXuron, buprofezin, pyriproxyfen, methoprene, onil; benZoepin, diafenthiuron, acetamiprid, imidacloprid, niten quinoline series Such as quinoxyfen; pyram, fipronil, cartap, thiocyclam, benSultap, nicotine Sul AH fungicide (aromatic hydrocarbon) Such as biphenyl, fate, rotenone, metaldehyde, machine oil, BT, insect patho chloroneb, dicloran, quintoZene, tecnaZene, or tolktfos-me genic viruses, or the like. thyl: Nematocides: MBI-R such as phthalide, pyroquilon, or tricyclazole; 10 MBI-D such as carpropamid, diclocymet, or fenoxanil; Fenamiphos, fosthiazate or the like. SBI agent such as fenhexamid, pyributicarb, or terbinafin; Acaricides: phenylurea Such as pencycuron; chlorobenzilate, phenisobromolate, dicofol, amitraz, Qil-fungicide (Qi inhibitor) Such as cyaZofamid; BPPS, benzomate, hexythiazox, fenbutatin oxide, polynac benzamide such as Zoxamide; 15 tins, chinomethionat, CPCBS, tetradifon, avermectin, milbe enopyranuron Such as blasticidin, mildiomycin; mectin, clofentezine, cyhexatin, pyridaben, fenpyroximate, hexopyranosyl Such as kasugamycin; tebufenpyrad, pyrimidifen, phenothiocarb, dienochloror the glucopyranocyl Such as Streptomycin, validamycin; like. cyanoacetamide Such as cymoxanil; Plant growth regulator: carbamate Such as propamocarb, prothiocarb, or polycar abscisic acid, indolebutyric acid, uniconazole, ethylchloZ bamate; ate, ethephon, cloxyfonac, chlormeduat, chlorella extract, uncoupling agent such as binapacryl, dinocap, ferimZone, calcium peroxide, cyanamide, dichlorprop, gibberellin, or fluazinam, daminozide, decyl alcohol, trinexapac-ethyl, mepiduat chlo organotin compound Such as triphenyltin acetate, triph ride, paclobutraZol, paraffin, wax, piperonyl butoxide, enyltin chloride, or triphenyltin hydroxide: 25 pyraflufen-ethyl, flurprimidol, prohydrojasmon, prohexadi organophosphate Such as phosphoric acid, tolclofoS-me one-calcium, benzylaminopurine, pendimethalin, forchlor thyl, or fosetyl: fenuron, maleic hydrazide potassium, 1-naphthylacetamide, phthalamic acid Such as techlofthalam: 4-CPA, MCPB, corrin, oxyquinoline sulfate, ethychlozate, benzotriazine Such as triazoxide; butralin, 1-methylcyclopropene, aviglycine hydrochloride. benzenesulfonamide such as flusulfamide: 30 pyridaZinone Such as diclomezin, CAA fungicide (carboxylic acid amid) such as dimetho EXAMPLES morph, flumorph, benthiavalicarb, iprovalicarb, or mandipro pamid; Hereinafter, the present invention is described in more tetracycline Such as oxytetracycline; 35 detail with reference to examples, however, the present inven thiocarbamate Such as methasulfocarb; or tion is not in the least limited by the following examples. other compounds such as etridiazole, polyoxin, oxolinic acid, hydroxyisoxazol, octhinoline, silthiofam, diflumetorim, Example 1 acilbenzolar-S-methyl, probenazole, tiadinil, ethaboxam, cyflufenamid, produinazid, metrafenone, fluopicolide, cop 40 Synthesis of per (II) hydroxide, organocopper, Sulfur, ferbam, manzeb, 1-2-(duinolin-3-yloxy)-phenyl-ethanone maneb, metiram, propineb, thiuram, Zineb, Ziram, captan, captafol, folpet, chlorothalonil, dichlofluanid, tolylfluanid, dodine, guazatline, iminoctadine, anilazine, dithianon, chlo ropicrin, dazomet, metam-Sodium, chinomethionat, cypro 45 furam, silthiofam, ago-bacterium, or fluoroimide. Insecticidesacaricides: OH Organophosphorous and carbamate series insecticides: -- fenthion, fenitrothion, diazinon, chlorpyrifos, ESP. vami CC2 C -e- dothion, phenthoate, dimethoate, formothion, malathon, 50 N Br O trichlorhon, thiometon, phosmet, dichlorvos, acephate, EPBP, methyl parathion, oxydemeton-methyl, ethion, salithion, cyanophos, isoxathion, pyridaphenthion, phosa lone, methidathion, Sulprofos, chlorfenVinphos, tetrachlorV inphos, dimethylvinhos, propaphos, isofenphos, ethylthi 55 ometon, profenofos, pyraclofos, monocrotophos, AZinphos N methyl, aldicarb, methomyl, thiodicarb, carbofuran, carbosulfan, benfuracarb, furathiocarb, propoxur, BPMC, 2 MTMC, MIPC, carbaryl, pirimicarb, ethiofencarb, fenoxy carb, EDDP or the like. 60 Pyrethroid series insecticides: 0.73 g of 3-quinolinol, 1.8g of cesium carbonate, 0.18 g of permethrin, cypermethrin, Deltamethrine, fenvalerate, dipivaloylmethane, 2.0 g of 2-bromoacetophenone, and 0.50 fenpropathrin, pyrethrin, allethrin, tetramethrine, resmethrin, g of copper (I) chloride were dissolved in 10 ml of N-meth dimethrin, propathrin, phenothrin, prothrin, fluvalinate, ylpyrrolidone, and the mixture was stirred for 3 hours at 130° cyfluthrin, cyhalothrin, flucythrinate, ethofenproX, cycropro 65 C. The resultant was purified by silica gel column chroma thrin, tralomethrin, silafluofen, brofenprox, acrinathrin or the tography, and 0.82 g of 1-2-(duinolin-3-yloxy)-phenyl like. ethanone (Compound Number 1) was obtained. US 8,772,200 B2 29 30 Compounds represented by Compound Numbers 2 to 13 A compound represented by Compound Number 21 was were synthesized in the same manner as that of Example 1. synthesized in the same manner as that of Example 3. Example 2 Example 4 Synthesis of 3-(2-t-butyl-phenoxy)-quinoline Synthesis of 2-bromo-N,N-dimethyl-6-(quinolin-3- yloxy)-benzamide

10 Br

2 NH2 N OH 15 O O N

2 N N Br

2 N N N

O O 0.60 g of 2-t-butylphenol, 1.3 g of cesium carbonate, 0.07 25 N g of dipivaloylmethane, 0.42 g of 3-bromoquinoline, and 0.20 g of copper (I) chloride were dissolved in 4 ml of N-meth 2 ylpyrrolidone, and the mixture was stirred for one day at 130° N C. The resultant was purified by silica gel column chroma tography, and 0.04 g of 3-(2-t-butyl-phenoxy)-quinoline 30 After 0.34g of 2-bromo-6-(quinolin-3-yloxy)-benzamide (Compound Number 14) was obtained. was dissolved in 2 ml of N-methylpyrrolidone, 47 mg of Compounds represented by Compound Numbers 15 to 19 sodium hydride was added thereto at room temperature. After were synthesized in the same manner as that of Example 2. 0.21 g of methyl iodide was added to the reaction solution, the mixture was heated to 100° C. and stirred for 4 hours. After Example 3 35 the liquid was separated with ethyl acetate, the solvent was evaporated and the resultant was purified by silica gel column Synthesis of chromatography to obtain 0.11 g of 2-bromo-N,N-dimethyl 2-chloro-6-(quinolin-3-yloxy)-benzamide 6-(quinolin-3-yloxy)-benzamide (Compound Number 22). 40 Example 5 C Synthesis of 1-2-(duinolin-3-yloxy)-phenyl-ethanone oxime Š 45 O -e- N

2 N 50 C N NH2 2 55 N N O O

2 N 60 1.18 g of 2-chloro-6-(quinolin-3-yloxy)-benzonitrile was N O N YOH dissolved in 5 ml of 80% sulfuric acid and the mixture was stirred for 3 hours at 100° C. After being neutralized with an 2 aqueous solution of Sodium hydroxide, the liquid was sepa N rated with ethyl acetate, the organic layer was concentrated 65 and 1.03 g of 2-chloro-6-(quinolin-3-yloxy)-benzamide 0.46 g of 1-2-(duinolin-3-yloxy)-phenyl-ethanone and (Compound Number 20) was obtained. 0.15g of hydroxylamine hydrochloride were dissolved in 3 US 8,772,200 B2 31 32 ml of pyridine and then the mixture was stirred for 24 hours at -continued room temperature. After the reaction mixture was treated with dilute hydrochloric acid and separated with ethyl acetate, the F organic layer was concentrated to obtain 0.54 g of 1-2- F (quinolin-3-yloxy)-phenyl-ethanone oxime (Compound 5 F Number 23). O O Compounds represented by Compound Numbers 24 to 26 N Y were synthesized in the same manner as that of Example 5. 2 1 10 N Example 6 After 0.26 g of 1-2-(duinolin-3-yloxy)-phenyl-ethanone Synthesis of and 0.16 g of (trifluoromethyl)trimethylsilane were dissolved 3-2-(1,1-dimethoxy-ethyl)-phenoxy-quinoline 15 in 3 ml of tetrahydrofuran, 2 drops of tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution) was added under ice-cooling and then stirred for 4 hours. After the reaction mixture was concentrated and purified by silica gel column chromatography to obtain 0.34 g of 3-2-(2.2.2-trifluoro-1- methyl-1-trimethylsilanyloxy-ethyl)-phenoxy-quinoline (Compound Number 28).

Example 8 s- O - 25 2 Synthesis of 1,1,1-trifluoro-2-[2-(duinolin-3-yloxy)- N phenyl-propan-2-ol

30

F N d) O\ O F F 2 35 N O O N Y After 0.13 g of 1-2-(duinolin-3-yloxy)-phenyl-ethanone 2 1 N and 0.06 g of trimethyl orthoformate were dissolved in 1.5 ml 40 of methanol, 0.02 g of tetrabutylammonium tribromide was added and the mixture was stirred for 4 days at room tem perature. The reaction mixture was concentrated and then purified by silica gel column chromatography to obtain 0.08 g of 3-2-(1,1-dimethoxy-ethyl)-phenoxy-quinoline (Com 45 pound Number 27). Example 7 50 Synthesis of 3-2-(2.2.2-trifluoro-1-methyl-1-trim F ethylsilanyloxy-ethyl)-phenoxy-quinoline F F 55 N O O

2 N

60 After 0.17 g of 3-2-(2.2.2-trifluoro-1-methyl-1-trimethyl N silanyloxy-ethyl)-phenoxy-quinoline was dissolved in 1.5 2 ml of tetrahydrofuran, 1 ml of tetrabutylammonium fluoride 65 (1.0 M tetrahydrofuran solution) was added and the mixture was stirred for 16 hours. The reaction mixture was concen trated and then purified by silica gel column chromatography US 8,772,200 B2 33 34 to obtain 0.11 g of 1,1,1-trifluoro-2-2-(duinolin-3-yloxy)- -continued phenyl-propan-2-ol (Compound Number 29). F Example 9

Synthesis of 2-2-fluoro-6-(8-fluoro-quinolin-3- OH yloxy)-phenyl-3,3-dimethyl-butan-2-ol N O -- 2 10 N F F F

15 O O He N O OH N 2 N 2 N F F F After 0.3 g of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-ben 25 Zoic acid ethyl ester was dissolved in 4.5 ml of tetrahydrofu O OH ran, the solution was cooled to -78° C., and 0.77 ml of N methylmagnesium chloride (3.0 M diethyl ether solution) was added dropwise. After the reaction temperature was 2 increased to room temperature, the reaction solution was N 30 treated with dilute hydrochloric acid and the liquid was sepa rated with ethyl acetate. The organic layer was concentrated F and then purified by silica gel column chromatography to obtain 0.12 g of 2-2-fluoro-6-(8-fluoroquinolin-3-yloxy) After 0.15g of 1-2-fluoro-6-(8-fluoro-quinolin-3-yloxy)- phenylpropan-2-ol (Compound Number 36) and 0.05 g of phenyl-ethanone was dissolved in 1.5 ml of tetrahydrofuran, 35 2-2-fluoro-6-(8-fluoro-2-methylduinolin-3-yloxy)phenyl and then the solution was cooled to -78°C., 0.3 ml of t-bu propan-2-ol (Compound Number 37). tylmagnesium chloride (2.0 M diethyl ether solution) was Compounds represented by Compound Numbers 38 to 49 added dropwise. After the reaction temperature was increased were synthesized in the same manner as that of Example 10. to room temperature, the reaction solution was treated with Example 11 dilute hydrochloric acid, and then the liquid was separated 40 with ethyl acetate. The organic layer was concentrated and then purified by silica gel column chromatography to obtain Synthesis of 7-(quinolin-3-ylamino)-indan-1-one 0.04 g of 2-2-fluoro-6-(8-fluoro-quinolin-3-yloxy)-phenyl 3.3-dimethylbutan-2-ol (Compound Number 30). Compounds represented by Compound Numbers 31 to 35 45 were synthesized in the same manner as that of Example 9. N Br -- He Example 10 2 N O Synthesis of 2-2-fluoro-6-(8-fluoroquinolin-3- 50 NH2 yloxy)phenylpropan-2-ol and 2-2-fluoro-6-(8- fluoro-2-methylduinolin-3-yloxy)phenylpropan-2-ol

55 N

2 N 60 0.43 g of 3-bromoquinoline, 0.29 g of 7-aminoindan-1- N one, 0.08g of copper(I) iodide, 0.41 g of potassium carbon ate, and 4 ml of N-methylpyrrolidone were mixed, and then 2 the mixture was stirred for 2 hours at 200° C. The resultant 65 mixture was purified by silica gel column chromatography to obtain 0.15g of 7-(quinolin-3-ylamino)-indan-1-one (Com pound Number 50). US 8,772,200 B2 35 36 A compound represented by Compound Number 51 was After 3 ml of tetrahydrofuran was cooled to -10°C., 0.91 synthesized in the same manner as that of Example 11. ml of n-butyllithium (2.6M hexane solution) and 1.35 ml of n-butylmagnesium chloride (0.91 M tetrahydrofuran solu Example 12 tion) were added. After 30 minutes of stirring, 0.98 g of 8-fluoro-3-iodoquinoline was added and the mixture was Synthesis of 3-(t-butyl-benzyl)-8-fluoroquinoline stirred for 15 minutes. 0.49 g of 2-t-butylbenzaldehyde was added to the reaction solution and the mixture was stirred for 3 hours. After dilute hydrochloric acid was added to the reaction mixture, the liquid was separated with ethyl acetate. 10 After the organic layer was concentrated and purified by silica K gel column chromatography, 0.55g of (2-t-butyl-phenyl)-(8- fluoro-quinolin-3-yl)-methanol (Compound Number 54) was No obtained. 2 Compounds represented by Compound Numbers 55 to 56 N 15 were synthesized in the same manner as that of Example 13. coF Example 14 Synthesis of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3- yl)-methanone

--

Br 2 25 CCN F

After 0.69 g of triol salt derived from 8-fluoroquinoline-3- OH boric acid and 1,1,1-tris(hydroxymethyl)ethane by a method 30 reported in the literature (Angew. Chem. Int. Ed., 2008, 47. 928-931) and 0.45 g of 1-bromomethyl-2-t-butylbenzene were dissolved in 10 ml of toluene, 0.46 g of tetrakis triph enylphosphine palladium was added and the mixture was 35 stirred for 3 hours. After the solvent of the reaction mixture was evaporated, the resultant was purified by silica gel col umn chromatography to obtain 0.14 g of 3-(t-butyl-benzyl)- 8-fluoroquinoline (Compound Number 52). A compound represented by Compound Number 53 was 40 synthesized in the same manner as that of Example 12. Example 13

Synthesis of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3- 45 yl)-methanol After 0.32 g of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3- yl)-methanol was dissolved in 3 ml of dichloromethane, 0.51 g of Dess-Martin reagent was added and the mixture was stirred for 1 hour at room temperature. After water was added and then the liquid was separated with ethyl acetate, the N organic layer was concentrated and purified by silica gel column chromatography to obtain 0.21 g of (2-t-butyl-phe 2 nyl)-(8-fluoro-quinolin-3-yl)-methanone (Compound Num ber 57). Compounds represented by Compound Numbers 58 to 59 were synthesized in the same manner as that of Example 14. Example 15

60 Synthesis of 2-chloro-3-(1,1-dimethylindan-7-yloxy) OH quinoline 0.2 g of 3-(1,1-dimethylindan-7-yloxy) quinolone was dis solved in 5 mL of chloroform, and 0.2 g of m-CPBA (70%) 65 was added and stirred overnight at room temperature. After the reaction mixture was diluted with chloroform and washed with Saturated Sodium bicarbonate water, magnesium Sulfate US 8,772,200 B2 37 38 was added to dry the resultant. The solvent was evaporated stirred for 24 hours at 130° C. The reaction solution was under reduced pressure to obtain 0.2 g of 3-(1,1-dimethylin purified by silica gel column chromatography, and 0.55g of dan-7-yloxy) quinoline-N-oxide. 8-fluoro-3-(3-fluoro-2-iodophenoxy)- quinoline WaS The resultant was dissolved in phosphorus oxychloride and obtained. heated under reflux for 4 hours. Phosphorus oxychloride was 5 evaporated under reduced pressure and the residue was dis Step 2) Synthesis of difluoro-2-fluoro-6-(8-fluoro Solved in ethyl acetate and was washed with Saturated sodium quinolin-3-yloxy)-ethyl acetate bicarbonate water. The organic layer was dried with magne sium sulfate and evaporated under reduced pressure. The crude product obtained was purified by silica gel column 10 chromatography, and 0.13 g of 2-chloro-3-(1,1-dimethylin F dan-7-yloxy) quinoline (Compound Number 60) was obtained. A compound represented by Compound Number 61 was 15 I synthesized in the same manner as that of Example 15. O -e- Example 16 N 2 Synthesis of 3-(2-cyanophenoxy)guinoline N After 0.27 g of 3-hydroxyquinoline was dissolved in F N-methyl-2-pyrrolidone, 0.087 g of sodium hydride (60% oil dispersion) was added under ice-cooling, and the mixture was stirred for 30 minutes. At the same temperature, 0.27 g of 25 2-fluorobenzonitrile was added and then the mixture was stirred for 6 hours at room temperature. After the reaction F mixture was poured into ice water, extracted with ethyl O acetate, and washed with Saturated Saline solution, the result ant was dried with magnesium sulfate. After the solvent was 30 1N evaporated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain 0.37 d) F F g of 3-(2-cyanophenoxy)guinoline (Compound Number 62). N Compounds represented by Compound Numbers 63 to 66 2 were synthesized in the same manner as that of Example 16. 35 N Example 17 Synthesis of difluoro-2-fluoro-6-(8-fluoroquinolin After 0.4 g of 8-fluoro-3-(3-fluoro-2-iodophenoxy)- 3-yloxy)-ethyl acetate 40 quinoline was dissolved in 4 ml of dimethylsulfoxide, 0.25g Step 1) Synthesis of of copper (powder) and 0.41 g of bromodifluoroethyl acetate 8-fluoro-3-(3-fluoro-2-iodophenoxy)-quinoline were added thereto, and then the mixture was stirred for 24 hours at 40°C. The reaction solution was purified by silica gel column chromatography, and 0.27g of difluoro-2-fluoro-6- 45 (8-fluoroquinolin-3-yloxy)-ethyl acetate (Compound Num F ber 292) was obtained. N OH -- Ho Example 18 2 I 50 N F Synthesis of 1,1-difluoro-1-(2-fluoro-6-(8-fluoro F quinolin-3-yloxy)-phenyl-2-methyl-propan-2-ol

55

N

2 60 N

2 16 ml of N-methylpyrrolidone was added to 1.06 g of 65 8-fluoro-3-hydroxyquinoline, 1.94 g of 2,6-difluoroiodoben Zene, and 1.7 g of potassium carbonate, and the mixture was US 8,772,200 B2 39 40 -continued 1-2-(7,8-difluoroquinolin-3-yloxy)-6-fluoro-phenyl-etha none (Compound Number 391). Example 20 OH Synthesis of 2-2-(7,8-difluoroquinolin-3-yloxy)-6- fluoro-phenyl-propan-2-ol N

2 10 F

0.18 g of difluoro-2-fluoro-6-(8-fluoroquinolin-3-yloxy)- -e- ethyl acetate was dissolved in 3 ml of tetrahydrofuran and 0.4 15 O O ml of methylmagnesium chloride (3.0 M tetrahydrofuran N solution) was added dropwise at 0°C. After the mixture was 2 stirred for 2 hours at 0° C., dilute hydrochloric acid was F N added, and the liquid was separated with ethyl acetate. The organic layer was concentrated and purified by silica gel F column chromatography to obtain 0.10 g of 1,1-difluoro-1- 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl-2-methyl propan-2-ol (Compound Number 293). Example 19 25 Synthesis of 1-2-(7,8-difluoroquinolin-3-yloxy)-6- fluoro-phenylethanone

30

OH F F N -- He 2 F N 35 O OH F F O N

2 40 F N

F After 0.64 g of 1-2-(7,8-difluoroquinolin-3-yloxy)-6- 45 fluoro-phenyl-ethanone was dissolved in 10 ml of tetrahy drofuran, the resultant was cooled to 0° C. and 1.5 ml of methylmagnesium chloride (3.0 Mtetrahydrofuran solution) F was added dropwise. Dilute hydrochloric acid was added to the reaction Solution, and the liquid was separated with ethyl 50 acetate. The organic layer was concentrated and purified by silica gel column chromatography to obtain 0.49 g of 2-2- (7,8-difluoroquinolin-3-yloxy)-6-fluoro-phenyl-propan-2- O O ol (Compound Number 124). N Example 21 2 55 F N Synthesis of 3-2-(7,8-difluoroquinolin-3-yloxy)-6- F fluoro-phenyl-3-methyl-butan-2-one

After 0.91 g of 7,8-difluoro-3-hydroxyquinoline and 0.94g 60 of 2,6-difluoroacetophenone were dissolved in 10 ml of dim I F N O ethylformamide, 0.9 g of potassium carbonate was added. -- He The reaction solution was heated to 100° C. and the mixture 2 was stirred for 4.5 hours. Dilute hydrochloric acid was added F N to the reaction solution and the solution was separated by 65 ethyl acetate. The organic layer was concentrated and purified F OH by silica gel column chromatography to obtain 0.64 g of US 8,772,200 B2 41 42 -continued obtain 3.0 g of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-ben F Zaldehyde (Compound Number 341). O Example 23

N O Synthesis of 1-2-fluoro-6-(8-fluoroquinolin-3- yloxy)-phenyl-propane-1,2-dione 2 F N 10 Step 1) Synthesis of 2-fluoro-6-(8-fluoroquinolin-3- F yloxy)-phenyl-trimethylsilyloxy-acetonitrile 3 ml of N-methylpyrrolidone was added to 0.78 g of 7.8- difluoro-3-iodoquinoline, 0.26 g of 3-(2-fluoro-6-hydrox 15 yphenyl)-3-methyl-butan-2-one, 1.05 g of cesium carbonate, F 53 mg of dipivaloylmethane, and 0.27g of copper (I) chlo ride. After 48 hours of stirring at 130°C., the reaction solution was filtered with CELITE and the liquid was separated with CHO ethyl acetate. The organic layer was concentrated and purified O by silica gel column chromatography to obtain 0.05 g of N 3-2-(7,8-difluoroquinolin-3-yloxy)-6-fluoro-phenyl-3-me 2 thyl-butan-2-one (Compound Number 267). N

Example 22 25 F F Synthesis of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-benzaldehyde 2

30 O O OH F N > s1 N -- Hip 2 N 2 N CHO 35 F F F After 3.2 g of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-ben Zaldehyde was dissolved in 70 ml ofdichloromethane and the 40 resultant was cooled to 0°C., 1.3 g of titanium tetraisopro poxide was added. After the reaction solution was warmed to room temperature, 4.5g of trimethylsilyl cyanide was added thereto, and the mixture was stirred for 2 hours. Dilute hydro chloric acid was added to the reaction Solution and the solu 45 tion was extracted with dichloromethane. The organic layer was concentrated and purified by silica gel column chroma tography to obtain 3.1 g of 2-fluoro-6-(8-fluoroquinolin-3- yloxy)-phenyl-trimethylsilyloxy-acetonitrile (approxi F mately 90% purity). 50 Step 2) Synthesis of 1-2-fluoro-6-(8-fluoroquinolin 3-yloxy)-phenyl-1-hydroxy-propan-2-one O O N 55 2 F N F 2 60 After 30 ml of acetonitrile was added to 3.0 g of 8-fluoro O O 3-hydroxyquinoline, 3.1 g of potassium carbonate and 3.5g N d s1 of 2,6-difluoroacetophenone were added. After the reaction 2 solution was heated under reflux for 3 hours, the reaction N solution was filtered with CELITE. After the filtrate was 65 extracted with ethyl acetate, the organic layer was concen trated and purified by silica gel column chromatography to US 8,772,200 B2 43 44 -continued tography to obtain 0.08g of 1-2-fluoro-6-(8-fluoroquinolin F 3-yloxy)-phenyl-propane-1,2-dione (Compound Number O 396). Example 24

O OH Synthesis of 1-2-fluoro-6-(8-fluoroquinolin-3- N yloxy)-phenyl-2-hydroxy-2-methyl-propan-1-one 2 10 Step 1) Synthesis of 1-2-fluoro-6-(8-fluoroquinolin N 3-yloxy)-phenyl-2-hydroxy-2-methyl-propane-1,2- F diol

15 3.3 g of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl F trimethylsilyloxy-acetonitrile (approximately 90% purity) was dissolved in 50 ml of diethyl ether and 5.7 ml of meth 2 ylmagnesium bromide (3.0 M diethyl ether solution) was -e- added dropwise at room temperature. After the mixture was O n1 stirred for 1 hour at room temperature, the resultant was 1. heated under reflux for 3 hours, and then treated with dilute 2 hydrochloric acid. The resultant was subjected to extraction N with ethyl acetate, and then the organic layer was concen 25 trated to obtain 3.9 g of crude product. 20 ml of 2N hydro F chloric acid and 10 ml of tetrahydrofuran were added to 1.9 g, of the crude product and the mixture was stirred for 4 hours at room temperature. The reaction solution was extracted with ethyl acetate and then purified by Silica gel column chroma 30 tography to obtain 0.4 g of 1-2-fluoro-6-(8-fluoroquinolin 3-yloxy)-phenyl-1-hydroxy-propan-2-one.

Step 3) Synthesis of 1-2-fluoro-6-(8-fluoroquinolin 3-yloxy)-phenyl-propane-1,2-dione 35

40 F O

OH Hip O OH O OH N 45 N

2 2 N N F 50 F F O 3.3 g of 2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl trimethylsilyloxy-acetonitrile was dissolved in 50 ml of diethyl ether and 5.7 ml of methylmagnesium bromide (3.0M O O 55 diethyl ether solution) was added dropwise at room tempera N ture. After the mixture was stirred for 1 hour at room tem perature, the resultant was heated under reflux for 3 hours, 2 and then treated with dilute hydrochloric acid. The resultant N was subjected to extraction with ethyl acetate and then the F 60 organic layer was concentrated to obtain 3.9 g of crude prod uct. 1.9 g of the crude product was dissolved in 20 ml of tetrahydrofuran and 3.2 ml of methylmagnesium bromide After 0.14 g of 1-2-fluoro-6-(8-fluoroquinolin-3-yloxy)- (3.0 M diethyl ether solution) was added dropwise at 0°C. phenyl)-1-hydroxy-propan-2-one was dissolved in 10 ml of After 3 hours of stirring at 0°C. 20 ml of 2N hydrochloric dichloromethane, 0.91 g of Dess-Martin reagent was added 65 acid was added and the mixture was stirred for one day at thereto at 0°C. After 3 hours of stirring, the reaction solution room temperature. The reaction solution was extracted with was concentrated and purified by silica gel column chroma ethyl acetate and purified by silica gel column chromatogra US 8,772,200 B2 45 phy to obtain 0.25 g of 1-2-fluoro-6-(8-fluoroquinolin-3- -continued yloxy)-phenyl-2-methyl-propane-1,2-diol as a crude prod F uct. Me Step 2) Synthesis of 1-2-fluoro-6-(8-fluoroquinolin MeMgCl 3-yloxy)-phenyl-2-hydroxy-2-methyl-propan-1-one O O He N

2 10 F N Me F F F OH OH O OH 15 N d) Me Me 2 N N 2 F 2O F N Me

F

25 26.3 g of 7,8-difluoro-3-hydroxy-2-methylduinoline was dissolved in 200 mL of dimethylformamide. 27.2 g of 2.6- difluoroacetophenone and 24.0 g of potassium carbonate F were added to the solution and the mixture was stirred for 4 hours at 100° C. After the thus obtained reaction solution was 30 poured into ice water, and neutralized with dilute hydrochlo OH ric acid, the liquid was separated with ethyl acetate. The O O organic layer was concentrated and purified by silica gel N column chromatography to obtain 17.0 g of 1-2-fluoro-6-(7. 8-difluoro-2-methylduinolin-3-yloxy)-phenyl-ethanone. 2 35 N After 11.0 g of 1-2-fluoro-6-(7,8-difluoro-2-meth ylquinolin-3-yloxy)-phenyl-ethanone obtained was dis F solved in 80 ml of tetrahydrofuran and cooled to 0°C., 16.6 ml of methylmagnesium chloride (3.0 M tetrahydrofuran 0.15 g of 1-2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phe- 40 solution) was added dropwise. After the resultant was nyl-2-methyl-propane-1,2-diol was dissolved in 10 ml of warmed to room temperature and stirred for 2 hours, the dichloromethane, and 0.20 g of Dess-Martin reagent was reaction solution was treated with dilute hydrochloric acid added thereto at 0°C. After 2 hours of stirring, the reaction and the liquid was separated with ethyl acetate. The organic Solution was concentrated and purified by silica gel column layer was concentrated and purified by silica gel column chromatography to obtain 0.03 g of 1-2-fluoro-6-(8-fluoro 45 chromatography to obtain 10.0 g of 2-2-fluoro-6-(7,8-dif quinolin-3-yloxy)-phenyl-2-hydroxy-2-methyl-propan-1- luoro-2-methylduinolin-3-yloxy)phenylpropan-2-ol (Com one (Compound Number 398). pound Number 125) was obtained.

Example 25 50 Example 26

Synthesis of 2-2-fluoro-6-(7,8-difluoro-2-meth Synthesis of 2-2-fluoro-6-(7,8-difluoroquinolin-3- ylquinolin-3-yloxy)phenylpropan-2-ol yloxy)phenylpropan-2-ol

55

F O

Me 60

OH N F K2CO3 2 Hs F N Me 65 US 8,772,200 B2

-continued -continued F O

N -e- Me F N 1-a not cH2SO4 H MeMgCl O O He F N O

2 F N 10 O F F N F F OH 15 After 15.7g of 2,3-difluoroaniline was added to 825 mL of d) Me Me water, and then 24.2 g of trichloroacetaldehyde 1-hydrate, N 30.8g of hydroxylamine hydrochloride, 138.6 g of anhydrous sodium sulfate were added thereto, the mixture was stirred for 2 F N 10 hours at 50° C. After the resultant was cooled to room temperature, 44 mL of 2N hydrochloric acid was added, and F then stirred for 30 minutes, followed by collecting the crystal by filtration. After the thus obtained crystals were dried, and 0.5g of 7,8-difluoro-3-hydroxyquinoline was dissolved in then added to concentrated sulfuric acid heated to 70° C., the 10 mL of dimethylformamide. 0.52 g of 2,6-difluoroac 25 mixture was stirred for 1 hour at 80 to 90° C. The reaction etophenone and 0.46 g of potassium carbonate were added to Solution was poured into ice, followed by Subjecting to the solution, and the mixture was stirred for 2.5 hours at 100° extraction with ethyl acetate, and then washing with Saturated C. The thus obtained reaction solution was poured into ice saline Solution. After the organic layer was dried with mag water and then neutralized with dilute hydrochloric acid, the nesium sulfate, the solvent was evaporated under reduced liquid was separated with ethyl acetate. The organic layer was 30 pressure to obtain 26 g of a crude product of 6,7-difluorois concentrated and purified by silica gel column chromatogra atin. phy to obtain 0.38 g of 1-2-fluoro-6-(7,8-difluoroquinolin Step 2) Synthesis of 3-yloxy)-phenyl-ethanone (Compound Number 391). 7,8-difluoro-3-hydroxy-2-methylduinoline After 0.38 g of 1-2-fluoro-6-(7,8-difluoroquinolin-3- 35 yloxy)-phenyl-ethanone obtained was dissolved in 5 ml of tetrahydrofuran and cooled to 0°C., 1.4 ml of methylmagne sium bromide (3.0 M diethyl ether solution) was added drop O wise. After the resultant was warmed to room temperature O 40 Br and stirred for 2 hours, the reaction solution was treated with Me dilute hydrochloric acid and the liquid was separated with O KOH ethyl acetate. The organic layer was concentrated and purified H2O by silica gel column chromatography to obtain 0.33 g of 2-2-fluoro-6-(7,8-difluoroquinolin-3-yloxy)phenylpro F N 45 F pan-2-ol (Compound Number 124). COOH Hereinafter, the intermediate product according to the PhNO present invention is described in more detail with reference to OH 180° C. n 6 hrs examples, however, the intermediate product according to the -> present invention is not in the least limited by the following 50 2 examples. F N Me Example 27 F N OH Synthesis of 55 2 7,8-difluoro-3-hydroxy-2-methylduinoline F N Me Step 1) Synthesis of 6,7-difluoroisatin F

60 After 41 g of the crude product of 6,7-difluoroisatin was added to 200 mL of water, 75.3 g of potassium hydroxide (6 C OH NHOHHCI equivalents) was added thereto under ice-cooling and the Na2SO4/HO mixture was stirred for 30 minutes. 42 g of bromoacetophe F NH2 + Cl -)-( --- none (1.4 equivalents) was added dropwise to the Suspension C OH 65 while maintaining the internal temperature of the reaction solution at 20 to 25°C., and the mixture was further stirred overnight at room temperature. After the resultant was neu US 8,772,200 B2 49 50 tralized with concentrated hydrochloric acid, the precipitated (normal hexane:ethyl acetate) to obtain 185.5g of 7,8-difluo crystals were collected by filtration and washed with a small roquinoline (91%) as a hazel solid. amount of water. The thus obtained crystals were sufficiently dried, and then added little by little to 100 mL of nitrobenzene Step 2) Synthesis of 7,8-difluoro-3-iodoquinoline heated to 130 to 140°C., and the mixture was stirred further 5 for 1 hour at 150° C. After the reaction solution was cooled to room temperature, the precipitated crystals were washed with chloroform to obtain 26.3 g of 7,8-difluoro-3-hydroxy-2- methylduinoline. N 10 H NMR (300 MHz, DMSO-d6) & 2.57 (s.3H), 7.4 to 7.7 2 (m,3H), 10.60 (bs, 1H). The following compound was produced using the same method. 15 8-fluoro-3-hydroxy-2-methylduinoline In a 3 L eggplant-shaped flask containing a stir bar, 7.8- difluoroquinoline (185.5 g, 1.12 mol), N-iodosuccinimide H NMR (300 MHz, DMSO-d6) & 2.56 (s.3H), 7.2 to 7.6 (505.4g, 2.25 mol), and acetic acid (927 mL) were introduced (m, 4H), 10.53 (bs, and the mixture was stirred for 30 hours at 90° C. After cooling, the precipitated crystals was filtered and dried. On Example 28 the other hand, the filtrate was concentrated under reduced pressure, the residual acetic acid was neutralized with sodium hydrogen carbonate, and the resultant was Subjected to Synthesis of 7,8-difluoro-3-hydroxyquinoline 25 extraction with ethyl acetate. In addition, after the filtrate was dried with magnesium Sulfate, filtered and concentrated, the thus obtained crude product was purified by silica gel column Step 1) Synthesis of 7,8-difluoroquinoline chromatography (normal hexane:ethyl acetate) to obtain 227.2 g (70%) of 7,8-difluoro-3-iodoquinoline was obtained 30 as a hazel solid combined with the previously obtained crys tals. H-NMR (300 MHz, CDC1) & 7.39 to 7.51 (m, 2H), 8.55 -- rol -- (m. 1H), 9.08 (d. 1H, J=2.1 Hz). F NH2 OH 35 F 2 Step 3) Synthesis of 7,8-difluoro-3-hydroxyquinoline 1 N 40 2 N N F N 2 2

45 In a 3 L eggplant-shaped flask containing a stir bar, 80% sulfuric acid (607.7 g. 49.57 mol) was introduced and cooled to 0°C., and then 2,3-difluoroaniline (160.0 g, 1.24 mol) was In a 3 L eggplant-shaped flask containing a stir bar, 7.8- slowly added. After the addition, the mixture was stirred for 1 50 difluoro-3-iodoquinoline (227.2 g, 0.78 mol), dimethylsul hour at room temperature, Sodium iodide (1.85g, 12.3 mmol) foxide (600 mL), and water (600 mL) were introduced and was further added thereto, and then the mixture was heated in sodium hydroxide (131.5g, 2.34 mol), CuI (14.8 g., 0.078 an oil bath until the temperature thereof reached 150° C. mol), and 1,10-phenanthroline (28.1 g, 0.156 mol) were (temperature of the bath). When it reached this temperature, added. The mixture was further heated to 100° C. in an oil glycerin (125.5 g, 1.36 mol) was added dropwise over a 55 bath and was stirred for 24 hours. After cooling, the organic period of one hour, and the mixture was stirred for 1 hour at layer was removed by adding ethyl acetate and water. The 150° C. The temperature of the bath was further elevated to thus obtained aqueous layer was neutralized with concen 180°C., and the water was evaporated over a period of 2 hours trated hydrochloric acid, and then the precipitated crystals using a distillation apparatus. After confirming that the start were filtered and dried. On the other hand, after the filtrate ing material had disappeared, the mixture was neutralized 60 was extracted with ethyl acetate, dried with magnesium Sul using 10N aqueous Sodium hydroxide while cooling with an fate, filtered and concentrated, the crude product obtained ice-water bath (the inner temperature is 60 to 70° C.). After was purified by Silica gel column chromatography (normal the neutralization, before the inner temperature returned to hexane:ethyl acetate) to obtain 133.7 g (95%) of 7,8-difluoro room temperature, the resultant was subjected to extraction 3-hydroxyquinoline as a hazel solid combined with the pre with ethyl acetate, and the extract was dried with magnesium 65 viously obtained crystals. sulfate, filtered, and concentrated. The thus obtained crude H-NMR (300 MHz, CDOD) & 7.39 to 7.60 (m, 3H), 8.59 product was purified by silica gel column chromatography (d. 1H, J=2.4 Hz).

US 8,772,200 B2

TABLE 41-continued Compound No H-NMR b-16 1.06 (s.9H), 1.75 (d. 3H), 4.93 (s, 1H), 6.54 (d. 1H), 6.84 (dd. 1H), 7.07-7.12 (m, 1H), 7.13 (d. 1H), 7.61 (d. 1H), 7.75 (d. 1H), 8.45 (d. 1H). b-19 1.50 (s.3H), 1.67 (s, 3H), 1.81-197 (m, 4H), 2.80 (m, 2H), 2.97 (m, 2H), 5.90 (s, 1H), 7.19-7.37 (m, 3H), 7.72 (m, 1H), 8.55 (d. 1H). b-20 1.52 (s.3H), 1.58 (s, 3H), 5.88 (s, 1H), 7.23-7.42 (m, 4H), 7.62 (d. 1H), 8.38 (d. 1H), 8.83 (d. 1H). b-21 2.59 (s.3H), 2.80 (t, 2H), 4.07 (t, 2H), 4.73 (s. 2H), 6.65 (d. 1H), 6.91 (t, 1H), 6.97 (d. 1H), 7.28 7.35 (m, 1H), 8.24 (d. 1H). b-22 1.73 (d. 6H), 2.02 (s, 1H), 3.02 (t, 2H), 4.07 (t, 2H), 4.73 (s. 2H), 6.57 (d. 1H), 6.82-6.89 (m, 1H), 6.98 (d. 1H), 7.10-7.15 (m, 1H), 8.25 (d. 1H). b-23 2.63 (s.3H), 6.60 (d. 1H), 6.77 (d. 2H), 6.89 (t, 1H), 7.25-7.32 (m, 1H), 7.62 (d. 1H), 7.76 (d. 1H), 8.16 (d. 1H).

15 (Formulation) Examples of the fungicide according to the present inven- Formulation example 5 Suspension tion are shown below, however, adding agents and the addi- The compound according to the present invention 10 parts tion ratio are not limited to these examples and it is possible 20 Polyoxyethylene alkyallylether 4 parts to vary them extensively. Also, parts informulation examples GlycerineSodium polycarboxylate 102 parts represent parts by weight. Xanthane gum 0.2 parts Water 73.8 parts Formulation example 1 Water-dispersible powder * The above were mixed and wet pulverized until the particle The compound according to the present invention 40 parts diameter becomes equalO to or less than 3 micron to obtain a Clay 48 parts suspension with 10% active ingredient. Sodium dioctylsulfo Succinate 4 parts Sodium lignin Sulfonate 8 parts 30 Formulation example 6 Water-dispersible granule The compound according to the present invention 40 parts Clay 36 parts The above were uniformly mixed and finely pulverized tO Potassium chloride 10 parts obtain water-dispersible powder with 40% active ingredient. Sodium alkylbenzene sulfonate 1 part 35 Sodium lignin Sulfonate 8 parts Formaldehyde condensation product of sodium 5 parts Formulation example 2 Emulsion alkylbenzene Sulfonate The compound according to the present invention 10 parts si,S) 200 9. p 53 N The above were mixed and finely pulverized, followed by Cyclohexanone 26 parts 40 adding a suitable amount of water and kneading therewith to Potassium dodecylbenzene Sulfonate 1 part be in clay shape. The clay shaped material was granulated and Polyoxyethylene alkylallylether 10 parts dried to obtain water-dispersible granule with 40% active ingredient. The above were mixed and dissolved to obtain an emulsion with 10%O active ingredient. 45 Biological Test Example 1 Control Test of Apple Scab Formulation lati examplele3 3 PowdPowder To apple seedlings grown in clay pots (Varieties “Rails The compound according to the present invention 10 parts 50 Janet', 3 to 4 leaf base), the emulsion of the compound Clay 90 parts according to the present invention with active ingredient of concentration of 100 ppm was sprayed. After being air dried The above were uniformly mixed and finely pulverized to at room temperature,p *. a conidium of applepp scabbacteria (Ven( obtain powder with 10% active ingredient turia inaqualis) was inoculated, and was held for 2 weeks in p gr 55 a room at 20° C. under a high humidity, with light and dark ness being repeated every 12 hours. Controlling effect was Formulation example 4 Granule determined by comparing the state of the appearance of lesion on the leaves with that of untreated. The compound according to the present invention 5 parts TO compounds represented by Compound Numbers 3, 6, 7, SR it E. 60 8, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 24, 25, 26, 28, Sodium(Oile dioctylsulfo Succinate 1 ppart S 29, 30, 31,33, 34,35,36, 37,38, 40, 41, 43,44, 45,46, 48,49, Potassium phosphate 1 part 52, 53, 54, 57, 59, 60, 61, 62,63, 64, 65 and 66, control test of an apple scab was carried out. As a result, all of the com pounds showed at least 75% protective value. The above were well pulverized, mixed, and well kneaded 65 Also, the same test was carried out to compounds repre with an addition of water, followed by granulating and drying sented by Compound Numbers 67, 68, 70, 73,74, 75, 76, 77, to obtain granule with 5% active ingredient. 78, 79,80, 82, 83, 84, 85,86, 87, 88, 89,90,91, 92,93, 94, 95, US 8,772,200 B2 93 94 96, 97,98, 100, 101, 102, 103, 104, 105,106, 107, 108, 109, 348, 353,355, 359, 360, 361, 363,364, 365, 371, 375,376, 110, 111, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 377, 378,379,380,381,382,386, 391,392,393, 395,397, 123, 124, 125, 126, 127, 128, 131, 132, 133, 134, 135, 136, 398, 399, 402, 403, 405, 406, 412, 414, 416, 417, 418, 423, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147,148, 424, 425, 426, 427, 428, 429, 431, 432, 433, 434, 435, 436, 149, 150, 151, 152, 156, 157, 158, 159, 160, 161, 162, 163, 437, 439, 440, 441,442, 444, a-2, a-5, a-6, a-7, a-8, a-10, b-1, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, b-2, b-3, b-7, b-8, b-12, b-16, c-3, and c-4. As a result, all of 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186,187, the compounds showed at least 75% protective value. 188, 190, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207,208, 209, 210, 211, 215, 217, 218, 219, 220, 221, 222, 223, 224, 225, 227, 228, 229, 230, 10 Biological Test Example 3 231, 232, 233,234, 235, 236, 237,238, 239, 240, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252,253, 254, 255, Submerged Application Test of Rice Neck Rot 256, 257, 258, 259, 260, 261, 262, 263,264, 265, 266, 267, 268, 269,270, 271, 272,273, 274, 276, 277,278, 279, 280, Rice seedlings were grown in pots where commercially 281, 283, 284, 285, 288, 289,290, 291, 292, 293, 294, 295, 15 available hilling is in a Submerged condition (Varieties 296,297, 298, 299, 300, 306, 308,309, 310, 311, 314, 315, “koshihikari', 1 leafbase), and the emulsion of the compound 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 327, 328, according to the present invention with active ingredient of 329, 330, 331, 332, 333,334, 335, 344, 347, 348, 349, 350, concentration of 400 ppm was drip treated to the surface of 353,354, 355, 356, 357, 358, 359, 360, 361, 362,363,364, the water. After 2 days, a conidium suspension of rice neck rot 365, 366, 367, 368, 369, 370,371, 372, 373, 374,375, 376, bacteria (Magnaporthe grisea) was spray inoculated, was 377, 378,379,380,381, 382,383,384, 385, 386, 387,388, held for 2 days in a darkroom at 25°C. under a high humidity, 389, 390, 391,392,393, 394,395,396, 397, 398, 399, 400, and then was held for 8 days in a room at 25°C., with light and 402, 403, 404, 406, 407, 408,409, 410, 411, 412, 413, 414, darkness being repeated in every 12 hours. Controlling effect 416, 417, 418, 419, 423, 424, 425, 426, 427, 428, 429, 430, was decided by the following grades after comparing the State 431, 432, 433, 434, 435, 437, 439, 440, 441, 442, 443, 445, 25 a-2, a-3, a-4, a-5, a-6, a-7, a-8, a-9, a-10, b-1, b-2, b-3, b-4, of the appearance of lesion on the leaves with that of b-5, b-6, b-7, b-8, b-9, b-10, b-11, b-12, b-13, b-14, b-15, untreated. b-16, b-17, b-20, b-22, b-23, b-24, c-2, c-3, c-4, c-5, d-5, and A (at least 60% protective value) d-6. As a result, all of the compounds showed at least 75% B (at least 40% but less than 60% protective value) protective value. 30 As a result of the present test, the controlling effect of the Biological Test Example 2 following compounds was evaluated as A. Compound Number: 5, 20, 21, 23, 25, 28, 32, 33, 34, 36, Control Test of Cucumber Gray Mold 37, 38, 43, 44, 48, 58, 66, 70, 71, 73,78, 84, 85, 88, 89,90, 35 106, 107, 227, 228, 234, 236, 260, 262,348, 353,356, 358, To cucumber seedlings grown in clay pots (Varieties 375, 376, 401, 402, a-6 “Cucumis sativus L., cotyledon base), the emulsion of the Also, the controlling effect of the following compounds compound according to the present invention with active was evaluated as B. ingredient of concentration of 100 ppm was sprayed. After Compound Number: 1, 3, 7,7. 12,1 13, 22, 46, 54, 55, 75, 95, being airdried at room temperature, a conidium suspension of 40 cucumber gray moldbacteria (Botrytis cinerea) was dropwise 98, 139, 151, 261, 359, 360, b 1 inoculated, and was held for 4 days in a dark room at 20°C. under a high humidity. Controlling effect was determined by Biological Test Example 4 comparing the state of the appearance of lesion on the leaves with that of untreated. 45 To compounds represented by Compound Numbers 10, 11, Submerged Application Test of Rice Neck Rot 12, 15, 18, 19, 22, 26, 29, 30, 31, 33, 34, 35,36, 37,38, 42,43, 44, 48, 49, 54, 57, and 59, control test of a cucumber gray Rice seedlings were grown in pots where commercially mold was carried out. As a result, all of the compounds available hilling is in a Submerged condition (Varieties showed at least 75% protective value. 50 “koshihikari', 1 leafbase), and the emulsion of the compound Also, the same test was carried out to compounds repre according to the present invention with active ingredient of sented by Compound Numbers 67, 73, 75, 76, 77, 80, 81, 82, concentration of 400 ppm was drip treated to the surface of 83, 86, 88, 89,90,92,93, 9495,96, 97,98,99, 100, 101, 102, the water. After 14 days, a conidium suspension of rice neck 104, 106, 107, 108, 109, 110, 111, 113, 114, 115, 116, 117, rot bacteria (Magnaporthe grisea) was spray inoculated, was 118, 119, 122, 123, 124, 125, 126, 127, 128, 133, 134, 138, 55 held for 2 days in a darkroom at 25°C. under a high humidity, 139, 140, 141, 142, 143, 144, 145, 146, 147,148, 149, 150, and then was held for 8 days in a room at 25°C., with light and 151, 152, 153, 156, 157, 158, 159, 160, 162, 163, 164, 166, darkness being repeated in every 12 hours. Controlling effect 167, 168, 169, 170, 171, 172,173, 174, 175, 176, 177, 178, was decided by the following grades after comparing the State 179, 180, 181, 183, 184, 185, 186, 187, 188, 192, 197, 198, of the appearance of lesion on the leaves with that of 199, 200, 201, 202, 203, 205, 208, 209, 210, 219, 220, 221, 60 untreated. 222, 223, 225, 227, 228, 229, 230, 231, 232, 233,234, 235, A (at least 60% protective value) 236, 237,238,239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252,253,254, 255, 256, 257, 258, 259, B (at least 40% but less than 60% protective value) 260, 261, 262, 263,264, 265,266, 267, 268,269, 270, 271, As a result of the present test, the controlling effect of the 272, 274, 275,278, 281, 284, 285,291, 292, 293,295, 296, 65 following compounds was evaluated as A. 297, 298, 299, 308, 309, 310,311, 314, 315, 316, 317, 318, Compound Number: 21, 36, 37,38, 43,44, 48, 84, 88,89, 319, 323,324, 325, 326, 327, 328,332, 333,338, 340, 344, 95, 106, 109, 125, 262, 266, 267,292, 350, 375, a-6 US 8,772,200 B2 95 96 Also, the controlling effect of the following compound was Substituted carbamoyl group, an unsubstituted or Substi evaluated as B. tuted hydroxyl group, an unsubstituted or Substituted Compound Number: 236 amino group, a halogeno group, a cyano group, or a nitro group; Biological Test Example 5 excepting in which: R', Rand Rare all hydrogenatoms: R", RandR are all unsubstituted Cisalkyl groups; any Seed Treatment Test of Cucumber Wilt one of R', RandR is a hydrogenatom and the remain ing two are both unsubstituted Cls alkyl groups; and, Cucumber seeds (Varieties “Cucumissativus L.) contami any one of R', RandR is an unsubstituted Cls alkyl nated by cucumber wilt bacteria (Fusarium oxysporum) were 10 group and the remaining two are both hydrogen atoms; treated with the emulsion of the compound according to the R" and R may be joined to form O—; present invention to obtain the seeds containing 1 g/kg active Reach independently represents an unsubstituted or sub ingredient. The seeds were sowed and after 3 weeks, control stituted Cls alkyl group, an unsubstituted Cls alkenyl ling effect was determined by comparing the degree of dis group, an unsubstituted Cls alkynyl group, an unsubsti ease occurrence with that of untreated. 15 tuted Cls cycloalkyl group, an Substituted or Substituted As a result, the following compounds showed an excellent hydroxyl group, a halogeno group, a cyano group, or a protective value of at least 75%. nitro group: Compound Number: 18, 36, 37, 43, 44, 48,77, 81, 83, 88, m1 represents a number of R and is an integer of 0 to 6; 92,94, 100, 103,109, 126, 225, 227, 228, 234, 235,241, 242, Reach independently represents an unsubstituted or sub 243, 244, 252,258, 266, 268, 298,395, 397, 425, 435, a-6, stituted Cls alkyl group, an unsubstituted Cls alkenyl a-7, a-8, b-8, b-12, c-4 group, an unsubstituted Cls alkynyl group, an unsubsti tuted Cls cycloalkyl group, an unsubstituted or Substi Biological Test Example 6 tuted hydroxyl group, a halogeno group, a cyano group, or a nitro group; Seed Treatment Test of Cucumber Wilt 25 in represents a number of Rand is an integer of 0 to 5; D represents a 5- to 7-membered hydrocarbon ring or a 5 Cucumber seeds (Varieties “Cucumis sativus L.) were to 7-membered heterocyclic ring: treated with the emulsion of the compound according to the X represents an oxygen atom; present invention to obtain the seeds containing 1 g/kg active Y represents a carbon atom; and ingredient. The seeds were sowed in Soil contaminated by 30 Z represents a carbon atom; and cucumber wilt bacteria (Fusarium oxysporum) and, after 3 wherein the Substituted Cls alkyl group is a C weeks, controlling effect was determined by comparing the cycloalkyl C alkyl group, a C cycloalkenyl C. degree of disease occurrence with that of untreated. alkyl group, a Chaloalkvl group, a Co aryl C. As a result, the following compounds showed an excellent alkyl group, 5- to 6-membered heteroaryl C. alkyl protective value of at least 75%. 35 group, a hydroxyl C alkyl group, a C alkoxy C. Compound Number: 17, 18, 31, 33, 34, 35,36, 37, 43, 86, alkyl group, a C-7 acyloxy C- alkyl group, a triCo 88, 96, 97, 100, 109, 227, 232,239, 242, 243, 244, 262, 265, alkylsilyloxy C. alkyl group, a C- alkyl-substituted 268, 295, 296, 375, 428, a-7, b-1. Coo arylsulfonyloxy Co alkyl group, a cyano Co The invention claimed is: alkyl group, a C-acyl Coalkyl group, a 2-hydroxy 1. A nitrogen-containing heterocyclic compound repre 40 imino Ce alkyl group, a formyl C alkyl group, a sented by Formula (II): carboxy Co alkyl group, a C- alkoxycarbonyl Co alkyl group, or an azido Calkyl group, the Substituted carboxyl group is a C- alkoxycarbonyl (II) group, a C2-alkenyloxycarbonyl group, a C2-alkyny 45 loxycarbonyl group, a Caryloxycarbonyl group, or a Coo aryl Coalkoxycarbonyl group, the substituted carbamoyl group is a mono C alkylcar bamoyl group, a di Ce alkylcarbamoyl group, or a mono Cao arylcarbamoyl group, 50 the Substituted hydroxyl group is a C- alkoxy group, a C-8 cycloalkyl C- alkoxy group, a Co-o aryl Co alkoxy group, a C- haloalkoxy group, a C2-alkeny loxy group, a C2-alkynyloxy group, a C. cycloalky loxy group, a Colo aryloxy group, a Co-o aryl C-6 55 alkyloxy group, a C-7 acyloxy group, a C- alkoxycar or a salt thereof, or an N-oxide compound thereof, bonyl C alkoxy group, or a tri C. alkylsilyloxy wherein, in Formula (II), R represents a group represented group, and by CRRR: the Substituted amino group is a mono Ce alkylamino R", R and R, each independently represents a hydrogen group, a diCo alkylamino group, a mono Coalkylide atom, an unsubstituted or Substituted Cls alkyl group, 60 neamino group, a mono Cao arylamino group, a di an unsubstituted Cls alkenyl group, an unsubstituted Co arylamino group, a Co aryl C alkylamino Cs alkynyl group, an unsubstituted Cls cycloalkyl group, a C-acylamino group, or a C- alkoxycarbo group, an unsubstituted Cas cycloalkenyl group, an nylamino group. unsubstituted Co aryl group, an unsubstituted hetero 2. A nitrogen-containing heterocyclic compound, a salt cyclic group, an unsubstituted C1s acyl group, an 65 thereof, or an N-oxide compound, according to claim 1, unsubstituted (1-imino)Cs alkyl group, an unsubsti wherein the nitrogen-containing heterocyclic compound is tuted or Substituted carboxyl group, an unsubstituted or represented by Formula (III): US 8,772,200 B2 97 98 5. A nitrogen-containing heterocyclic compound, a salt (III) thereof, or an N-oxide compound, according to claim 1, (R), wherein R represents a C- alkyl group, a C- haloalkyl “as aS group, a C- alkenyl group, a Css cycloalkyl group, a hydroxyl group, a C- alkoxy group, or a halogeno group. 2 R 6. A nitrogen-containing heterocyclic compound, a salt thereof, or an N-oxide compound according to claim 1, X wherein R represents a C- alkyl group, a C- haloalkyl 21 N group, a Coo aryl C- alkyl group, a Css cycloalkyl group. (R), 10 a C- alkoxy group, a halogeno group, a cyano group or a N-S4 nitro group. 7. A nitrogen-containing heterocyclic compound, a salt wherein each of R. R. R. m1 and X represents the same thereof, or an N-oxide compound, according to claim 6. meaning as those in Formula (II); and wherein the nitrogen-containing heterocyclic compound is n1 represents a number of Rand is an integer of 0 to 4. 15 2-2-fluoro-6-(8-fluoroquinolin-3-yloxy)-phenyl-3,3-dim 3. An agricultural fungicide comprising, as an active ingre ethyl-butan-2-ol. 2-2-fluoro-6-(8-fluoroquinolin-3-yloxy)- dient, at least one selected from the group consisting of the nitrogen-containing heterocyclic compound, the salt thereof, phenyl-propan-2-ol. 2-2-fluoro-6-(8-fluoro-2-meth and the N-oxide compound thereof, of claim 1. ylquinolin-3-yloxy)-phenyl-propan-2-ol, or 2-2-fluoro-6- 4. A nitrogen-containing heterocyclic compound, a salt (7,8-difluoro-2-methylduinolin-3-yloxy)-phenyl-propan-2- thereof, or an N-oxide compound, according to claim 1, ol. wherein R' represents the unsubstituted or substituted 8. An agricultural fungicide for seed treatment comprising, hydroxyl group, R represents the hydrogen atom or the as an active ingredient, at least one selected from the group unsubstituted or substituted Cls alkyl group, and R repre consisting of the nitrogen-containing heterocyclic com sents the hydrogenatom, the unsubstituted or Substituted Cs 25 pound, the salt thereof, and the N-oxide compound thereof, of alkyl group, the unsubstituted C-salkenyl group, the unsub claim 1. stituted Cls alkynyl group, the unsubstituted Css cycloalkyl 9. A method for treating a seed using an agricultural fun group, the unsubstituted Co aryl group, the unsubstituted gicide comprising, as an active ingredient, at least one hererocyclic group, the unsubstituted Cls acyl group, the selected from the group consisting of the nitrogen-containing unsubstituted (1-imino)Cs alkyl group, the Calkoxycar 30 heterocyclic compound, the salt thereof, and the N-oxide bonyl group, the unsubstituted or Substituted hydroxyl group, compound thereof, of claim 1. or, the cyano group. k k k k k