US007700655B2

(12) United States Patent (10) Patent No.: US 7,700,655 B2 Muto et al. (45) Date of Patent: Apr. 20, 2010

(54) ANTIALLERGICAGENTS 6,262,044 B1 7/2001 MOller et al. 6.410,586 B1 6/2002 Moller et al. (75) Inventors: Susumu Muto, Tokyo (JP); Akiko Itai, 6,414,013 B1 7/2002 Fancelli et al. Tokyo (JP) 6,566,394 B1 5/2003 Takeuchi et al. 6,653,309 B1 1 1/2003 Saunders et al. 6,734, 180 B1 5/2004 Nunokawa et al. (73) Assignee: Institute of Medicinal Molecular 6,787,652 B1 9, 2004 Dow et al. Design, Inc., Tokyo (JP) 2002fOOO2199 A1 1/2002 Jeppesen et al. (*) Notice: Subject to any disclaimer, the term of this 2002fOO19412 A1 2/2002 Andresen et al. patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 11/783,324 DE 1 O17 606 1Of 1957 (Continued) (22) Filed: Apr. 9, 2007 OTHER PUBLICATIONS (65) Prior Publication Data Sant, et al., “The Mast Cell in Interstitial Cystitis: Role of Pathophysilogy and Pathogensis', Urology 69 (Suppl 4A): 34-40, US 2007/O1851 1 O A1 Aug. 9, 2007 2007.* Cited ref Google search Mast cell and hysteromyoma, (2009).* Related U.S. Application Data Kim, et al., “The Journal of Clinical Investigation.” 2001, vol. 108, No. 3, p. 437-446. (62) Division of application No. 10/515,623, filed as appli Yuan, et al., “Science.” 2001, vol. 293, p. 1673-1677. cation No. PCT/JP03/07120 on Jun. 5, 2003, now Macielag, et al., “The Journal of Medicinal Chemistry.” 1998, vol. 41. abandoned. No. 16 p. 2939-2945. (30) Foreign Application Priority Data (Continued) Jun. 6, 2002 (JP) ...... 2002-165148 Primary Examiner Yong Chu (74) Attorney, Agent, or Firm—Greenblum & Bernstein, (51) Int. Cl. P.L.C. A6 IK3I/I65 (2006.01) (52) U.S. Cl...... 514/620:564/162:564/165 (57) ABSTRACT (58) Field of Classification Search ...... 514/299, 514/317,387, 365,372, 427,438, 617, 620; A medicament for the preventive and/ortherapeutic treatment 564/162, 165 of allergic diseases and/or endometriosis and/or hyster See application file for complete search history. omyoma which comprises as an active ingredienta Substance selected from the group consisting of a compound repre (56) References Cited sented by the following general formula (I) and a pharmaco U.S. PATENT DOCUMENTS logically acceptable salt thereof, and a hydrate thereof and a solvate thereof: 3,331,874 A 7, 1967 Stecker 3,332,996 A 7, 1967 Zerweck et al. (I) 3,906,023 A 9, 1975 Buchel et al. 4,358,443 A 11, 1982 Coburn et al. 4,560,549 A 12/1985 Ritchey 4,659,710 A 4, 1987 Sato et al. 4,661,630 A 4, 1987 Harigaya et al. 4,690,924 A 9, 1987 Sato et al. 4,725,590 A 2/1988 Ritchey 4,742,083 A 5/1988 Ritchey wherein X represents a connecting group whose number of 4,786,644 A 11, 1988 Glamkowski et al. atoms in the main chain is 2 to 5 (said connecting group may 4,939,133 A 7, 1990 Connor et al. be substituted). A represents hydrogenatom or acetyl group, 4,952.588 A 8, 1990 Glamkowski et al. E represents an aryl group which may be substituted or a 4,966,906 A 10, 1990 Glamkowski et al. hetero aryl group which may be substituted, ring Z represents 5,126,341 A 6, 1992 Suzuki et al. an arene which may have one or more Substitutents in addi 5,589,514 A 12/1996 Naik et al. tion to the group represented by formula —O-A wherein A 5,661,153 A 8, 1997 Isobe et al. has the same meaning as that defined above and the group 5,679,696 A * 10/1997 Fenton et al...... 514,354 5,776,977 A 7, 1998 Naik et al. represented by formula —X-E wherein each of X and E has 5,811,428 A 9, 1998 Suto et al. the same meaning as that defined above, or a heteroarene 5,852,028 A 12/1998 Suto et al. which may have one or more substitutents in addition to the 5,935,966 A 8, 1999 Suto et al. group represented by formula—O-A wherein A has the same 6,002.884 A 12/1999 Okumura et al. meaning as that defined above and the group represented by 6,117,859 A 9, 2000 Evans et al. formula—X-E wherein each of X and E has the same mean 6,159,988 A 12/2000 Naik et al. ing as that defined above. 6,166,028 A 12/2000 Bloom et al. 6,225,329 B1B 5, 2001 Richter et al. 16 Claims, 2 Drawing Sheets US 7,700,655 B2 Page 2

U.S. PATENT DOCUMENTS JP 2001-522834 11, 2001 JP 2002-506072 2, 2002 2002/0165398 A1 1 1/2002 Jeppesen et al. JP 2004-501.146 1, 2004 2003, OO69267 A1 4/2003 Moller et al. WO 93.241.15 12/1993 2003/0083386 A1 5, 2003 Yuan et al. WO 96.17832 6, 1996 2004/004.8891 A1 3, 2004 Kato et al. WO 98.20864 5, 1998 2004/0087650 A1 5/2004 Saunders et al. WO 98.32O17 7, 1998 2004.0122244 A1 6, 2004 Suzuki et al. WO 99.24404 5, 1999 2004/O157844 A1 8, 2004 Dow et al. WO 99.4O907 8, 1999 2004/0259877 A1 12, 2004 Muto et al. WO 99.46236 9, 1999 2006, OO 14811 A1 1/2006 Muto et al. WO 99.46244 9, 1999 2006, OO19958 A1 1/2006 Muto et al. WO 99.46267 9, 1999 2007/0042.997 A1 2/2007 Itai et al. WO 99.55663 11, 1999 2008/0090779 A1 4/2008 Muto et al. WO 99.65449 12/1999 2008/0249071 A1 10, 2008 Muto et al. WO OO?O3991 1, 2000 2008/0311074 A1 12, 2008 Muto et al. WO OO/O5234 5, 2000 2008.031895.6 A1 12, 2008 Muto et al. WO OO,354.42 6, 2000 FOREIGN PATENT DOCUMENTS W 88: 58. DE 996074 6, 1965 WO O1? 12588 2, 2001

EP O198456 10, 1986 WO O1,68648 9, 2001 EP O221211 5, 1987 WO O1/98290 12/2001 EP O221346 5, 1987 WO 02/16633 2, 2002 EP O317991 5, 1989 WO O2/O76918 3, 2002

EP O483881 5, 1992 WO 02/49632 6, 2002 EP O551849 7, 1993 WO O2/O67919 9, 2002 EP O931544 7, 1999 WO O2/O76926 10, 2002

EP 1018514 12/2000 WO O2/O51397 T 2003 EP 1088.819 4/2001 WO O3,103647 12/2003 EP 1113000 4/2001 WO O3,103648 12/2003 EP 1205478 5/2002 WO O3,103654 12, 2003 EP 1219596 T 2002 WO O3,103655 12/2003 EP 1344525 9, 2003 WO O3,103656 12/2003 EP 1352650 10, 2003 WO O3,103657 12/2003 EP 1510210 3, 2005 WO O3,103658 12/2003 EP 1512396 3, 2005 WO O3,103665 12/2003 EP 1514544 3, 2005 WO 2004/006906 1, 2004 EP 1535.609 6, 2005 WO 2005/OO7151 1, 2005

EP 15335610 6, 2005 EP 1555.018 7/2005 OTHER PUBLICATIONS FR 1481713 6, 1966 Waisser, et al., “Archiv der Pharmazie.” 1998, vol. 331, No. 1, p. 3-6. GB 996074 6, 1965 Inaba, et al., "Chemical and Pharmaceutical Bulletin.” 2000, vol. 48, GB 1079 177 8, 1967 p. 131-139. GB 1099865 T 1969 Yamamoto, et al., “Chemical and Pharmaceutical Bulletin, 1996, GB 2031410 4f1980 vol. 44, p. 734–745. JP 37 OOO225 1, 1962 Hunt, et al., “The Journal of the Chemical Society.” 1956, p. 3099 JP 52-110835 9/1977 3107. JP 62-30780 2, 1987 Zwaagstra, et al., “European The Journal of Medicinal Chemistry.” JP 62-081359 4f1987 1996, vol. 31, p. 861-874. JP 63-104912 5, 1988 Sharanin, et al., "Zhournal Organicheskoi Khimii: Russian The Jour JP 10-87491 9, 1989 nal of Organic Chemistry.” 1980, vol. 16, p. 2185-2188. JP 2-138260 5, 1990 South, et al., “The Journal of Heterocyclic Chemistry.” 1991, vol. 28, JP 4-2 17916 8, 1992 p. 1017-1024. JP 4-2 17981 8, 1992 Tajika, “Yakugaku Zasshi: The Journal of the Pharmaceutical Society JP 6-009476 1, 1994 of Japan.” 1961, vol. 81, p. 1456-1459, together with partial English JP 62-99329 10, 1994 language translation of the same. JP 8-175990 T 1996 Okamiya, "Nihon Kagaku Zasshi.” 1962, vol. 83, p. 209-211, JP 9-227561 2, 1997 together with partial English language translation of the same. JP 97.09315 3, 1997 Yura, et al., “Chemical and Pharmaceutical Bulletin, 1962, vol. 10, JP 9-1697.47 6, 1997 p. 376-382. JP 10-45.738 2, 1998 Diez-Barra, et al., “Tetrahedron.” 1997, vol. 53, No. 33, p. 11437 JP 11-21225 1, 1999 11448. JP 11-021243 1, 1999 Duric, et al., “The Journal of Medicinal Chemistry.” 2000, vol. 43. JP 11-217361 8, 1999 No. 16, p. 2975-2981. JP 1105.12399 10, 1999 English language Abstract of JP 2000-80041. JP 2000-80041 3, 2000 English language Abstract of JP 9-169747. JP 2000-1694.79 6, 2000 English language Abstract of JP 63-104912. JP 2001-114768 1, 2001 English language Abstract of JP 11-21243. US 7,700,655 B2 Page 3

Aisen, “Journal of Pain and Symptom Management.” 2002, vol. 23. Robert-Piessard, et al., “Pharmaceutical Science.” 1997, vol. 3, No. No. 4, p. S35-40. 5/6, p. 295-299. Baud, et al., “Trends in Cell Biology.” 2001, vol. 11, No. 9, p. Sato, et al., “The Journal of Biological Chemistry.” 2002, vol. 277. 372-377. No. 44, p. 42060-42065. Clark, et al., “Nucleic Acids Research.” 1986, vol. 14, No. 20, p. Scheinman, et al., “Science.” 1995, vol. 270, p. 283-286. 7897-7914. Sullivan, et al., “The Journal of Medicinal Chemistry.” 1998, vol. 41. Daidone, et al., “Farmaco,” 1989, vol. 44, No. 5, p. 465-473. No. 4, p. 413-419. DiDonato, et al., “Nature.” 1997, vol. 388, p. 548-554. Umezawa, “Surgery Frontier.” 2002, vol. 9, No. 2, p. 88-91, together Dou, et al., “Proceedings of The National Academy of Sciences of the with English language translation of the same. United States of America.” 2003, vol. 100, No. 2, p. 721-726. Upadhyay, et al., “Indian Journal of Heterocyclic Chemistry.” 1991, Dumas, et al., “Bioorganic and Medicinal Chemistry Letters.” 1999, vol. 1, No. 2, p.71-74. vol. 9, No. 17, p. 2531-2536. Verma, et al., “Genes and Development” 1995, vol. 9 No. 22, p. Eldar-Finkelman, “Trends of Molecular Medicine.” 2002, vol. 8, No. 2723-2735. 3, p. 126-132. Wajant, “Cellular Signaling.” 2001, vol. 13, No. 6, p. 389-400. Frame, et al., “The Biochemical Journal.” 2001, vol. 359, No. PTI, p. West, et al., “Analytical Biochemistry.” 1990, vol. 190, No. 2, p. 1-16. 254-258. Hill, et al., “Cell.” 1993, vol. 73, No. 2, p. 395-406. Won, et al., “Neuroscience.” 1999, vol. 94, No. 1, p. 83-91. Hoshi, et al., “Proceedings of the National Academy of Sciences of Woronicz, et al., “Science.” 1997, vol. 278, p. 866-869. the United States of America,” 1996, vol. 93, No. 7, p. 2719-2723. Xu, et al., “The Journal of Neuroscience.” 2001, vol. 21, No. 1, Hsi, et al., “The Journal of Organic Chemistry.” 1972, vol. 37, No. 22. RC118, 5 pages. p. 3427-3431. Yamamoto, et al., “The Journal of Clinical Investigation.” 2001, vol. Ishige, et al., “Yakugaku Zasshi.” 1999, vol. 119, No. 7, p. 510-518. 107, No. 2, p. 135-142. Kang, et al., “Neuroreport.” 2001, vol. 12, No. 7, p. 1449-1452. Yin, et al., “Cell.” 1998, vol. 93, No. 5, p. 875-884. Karin, et al., “Proceedings of The National Academy of Science of Yin, et al., “Nature.” 1998, vol. 396, p. 77-80. the United States of America,” 1998, vol. 95, No. 16, p. 9067-9069. Zandi, et al., “Cell.” 1997, vol. 91, No. 2, p. 243-252. Karttunen, et al., “Proceedings of the National Academy of Sciences English language Abstract of JP 10-45738. of United States of America,” 1991, vol. 88, No. 9, p. 3972-3976. English language Abstract of JP9-227561. Kaytor, et al., “Current Opinion of Neurobiology,” 2002, vol. 12, No. English language Abstract of JP 10-87491. 3, p. 275-278. English language Abstract of JP 11-2 17361. Klosa, “Journal fuer Praktische Chemie.” 1964, vol. 25, No. 1-2, p. English language Abstract of JP 8-175990. 48-55, together with English language Abstract(Chemical Abstract) English language Abstract of JP 4-2 17916. of the same, col. 4022, paragraph 6-col. 4023. English language Abstract of JP 62-30780. Konta, et al., “The Journal of Biological Chemistry,” 2001, vol. 276, English language Abstract of JP 2000-169479. No. 16, p. 12697-12701. English language Abstract of JP 52-110835. Kopp, et al., “Science.” 1994, vol. 265, p. 956-959. English Language abstract of JP 2002-506072. Ladva, et al., “Indian Journal of Chemistry, Section B, 1996, vol. English Language abstract of JP 62-81359. 35B, No. 10, p. 1062-1066. English Language abstract of JP 2-138260. Lee, et al., “Proceedings of the National Academy of Science of the U.S. Appl. No. 10/433,619, to Muto et al. United States of America,” 1998, vol. 95, No. 16, p. 9319-9324. U.S. Appl. No. 10/515,341, to Muto et al. Madan et al., “Molecular Pharmacology', 2000, vol. 58, No. 3., pp. U.S. Appl. No. 10/515,343, to Muto et al. 526-534. U.S. Appl. No. 10/515,342, to Muto et al. Mailliot, et al., “Annals of The New York Academy of Science.” 2000, U.S. Appl. No. 10/515,294, to Muto et al. vol. 920, p. 107-114. U.S. Appl. No. 10/516,622, to Muto et al. Manna, et al., “The Journal of Immunology.” 1999, vol. 162, No. 4, p. U.S. Appl. No. 10/516,292, to Muto et al. 2095-2102. U.S. Appl. No. 10/516,293, to Muto et al. Matsumoto, et al., “Bioorganic and Medicinal Chemistry Letters.” English Language Translation of JP 37-225, Jan. 23, 1962. 2000, vol. 10, No. 9, p. 865-869. English language Abstract of JP 11-21225. Mattson, et al., “The Journal of Clinical Investigation.” 2001, vol. Berking, et al., “American Journal of Pathology.” 2001, vol. 158, No. 107, No. 3, p. 247-254. 3, pp. 943–953. Mattson, et al., “Cell and Tissue Research.” 2000, vol. 301, No. 1, p. Singh, et al., “Histology and Histopathology,” 2000, vol. 15, pp. 173-187. 843-849. Millet, et al., “The Journal of Biological Chemistry,” 2000, vol. 275, Recio, et al., “Cancer Research.” 2002, vol. 62, No. 22, pp. 6724 No. 20, p. 15114-15121. 6730. Mori, et al., “Yakugaku Zasshi.” 1975, vol. 95, No. 12, p. 1477-1482, Caplus Abstract of JP 37000225, Jan. 23, 1962. together with an English language abstract of the same. Matsuzaki, et al., “Amer. J. Reproductive Immunol.” 1986, vol. 40, p. Nedospasov et al., “Cold Spring Harbor Symposia on Quantitative 291-294. Biology.” 1986, vol. 51, No. 1, p. 611-624. Uchiide, et al., “Nikkei Medical.” 2002, No. 415, p. 28, with English Noble, et al., “Neuron.” 2003, vol. 38, No. 4, p. 555-565. translation. Ohsugi, et al., “Yakugaku Zasshi.” 1976, vol. 96, No. 2, p. 165-169, Uchiide, et al., “Fertility and Sterility,” 2002, vol. 78, No. 4, p. together with an English language abstract of the same. T82-786. Okamoto, 18" Meeting of the Japanese Inflammatory Society, Sym Chegini, “Frontiers in Bioscience.” 2002, vol. 7, p. e91-115. posium “Mechanism of Antirheumatic Pharmaceutical Composition English language abstract of JP 37 000 225, 1962. and New Development.” Tokyo, 2000 Presentation Abstract p. 57. Extended European Search Report for EP07 015427, Jul. 29, 2009. with English translation. Database Crossfire Beilstein XP002536489 (Abstract), Database Palanki, et al., “Current Medicinal Chemistry,” 2002, vol. 9, No. 2, p. Accession Nos. 2818733 and 2819714, 1964. 219-227. Database Crossfire Beilstein XP002536490 (Abstract), Database Phlel, et al., “Nature.” 2003, vol. 423, No. 6938, p. 435-439. Accession No. 2698830, 1965. Piu, et al., “Molecular and Cellular Biology,” 2001, vol. 21, No. 9, p. Database Crossfire Beilstein XP002536491 (Abstract), Database 3012-3024. Accession No. 3372658, 1959. Régnier, et al., “Cell.” 1997, vol. 90, No. 2, p. 373-383. * cited by examiner U.S. Patent Apr. 20, 2010 Sheet 1 of 2 US 7,700,655 B2

-Ha Diluent -e-. Test comp.

3 O

Pre 3O 6 12O 240 360 40 14AO Time (min) U.S. Patent Apr. 20, 2010 Sheet 2 of 2 US 7,700,655 B2

-H inhibitor -O- Placebo

250 -- inhibitor -O- Placebo 200

150

OO

50

Pre POS US 7,700,655 B2 1. 2 ANTIALLERGICAGENTS plasia, which is a major step of infiltration and lesion of mast cells, is significantly inhibited by the administration of a CROSS-REFERENCE TO RELATED leukotriene antagonist having antiallergic action to an APPLICATIONS endometriosis model rat (Nikkei Medical, 2002, No. 415, p. The present application is a divisional application of U.S. 28; Fertility and Sterility, (USA), 2002, Vol. 78, No. 4, p. application Ser. No. 10/515,623 filed Jun. 20, 2005 now aban 782-786). doned, which is incorporated by reference herein in its Therefore, an antiallergic drug, which strongly inhibits entirety, and which is a National Stage Application of Inter activation of mast cells and can be used as a therapeutic agent national Application No. PCT/JP03/07120, filed Jun. 5, 2003, 10 for radical treatment of allergic diseases, is usable as an which claims priority under the Paris Convention from Japa effective therapeutic agent for endometriosis. nese Patent Application No. 2002-165148, filed Jun. 6, 2002. 45% of patients with endometriosis are suffered from hys FIELD OF INVENTION teromyoma, which Suggests a relation of hysteromyoma and 15 allergy in the same manner as endometriosis. Accordingly, it The present invention relates to pharmaceutical composi is highly probable that an antiallergic agent, which can be tions effective for preventive and/or therapeutic treatment of used as a therapeutic agent for radical treatment of allergic allergic diseases such as pollinosis, bronchial asthma, atopic diseases, is useful as a therapeutic agent for hysteromyoma. dermatitis, urticaria; endometriosis, and hysteromyoma. N-phenylsalicylamide derivatives are disclosed as a plant growth inhibitor in the specification of U.S. Pat. No. 4,358, 443. As medicaments, said derivatives are disclosed as anti BACKGROUND ART inflammatory agents in the specification of European Patent No. 0.221.211, Japanese Patent Unexamined Publication Allergic diseases are understood to be caused by produc 25 (KOKAI) No. (Sho) 62-99329, and the specification of U.S. tion of IgE by an antigen Stimulation invaded in a body, and Pat. No. 6,117,859. Furthermore, they are disclosed as NF-kB Successive release of various chemical mediators such as inhibitors in the pamphlets of International Publication inflammatory cytokine, histamine, leukotriene and the like by WO99/65499, International Publication WO02/49632, and a degranulation from an activated mast cell stimulated by a International Publication WO02/076918, and as inhibitors complex of the antigen and IgE, thereby constriction of air 30 against the production of cytokines in the pamphlet of Inter way, accentuation of vascular permeability, inflammation of national Publication WOO2/O51397. skin, bronchi and the like are induced. Accordingly, antialler gic agents are understood mainly as drugs inhibiting allergic reaction type I and Successively induced allergic inflamma DISCLOSURE OF THE INVENTION tion, particularly as drugs inhibiting the production and 35 release of the mediators from mast cells, or those as being An object of the present invention is to provide medica antagonists against the aforementioned actions. At present, ments that enable radical preventive and/or therapeutic treat steroids, antihistaminic drugs, Suppressants or inhibitors of ment of allergy by an inhibition of allergic reactions. To the release of mediators and the like have been used as anti achieve the aforementioned object, the inventors of the allergic agents. Although steroids are very effective drugs, 40 they have a problem of side effects. Antihistaminic drugs are present invention conducted various researches on the anti only for symptomatic therapies and fail to achieve radical allergic actions of Salicylamide derivatives which are gener therapy. Suppressants or inhibitors of the release of mediators ally believed to have low toxicity. As a result, they found that are considered to have a high effectiveness. However, some of N-substituted salicylamide derivatives, particularly N-aryl them lack immediate effectiveness or have central side 45 salicylamide derivatives, specifically N-phenylsalicylamide effects. Accordingly, the antiallergic drugs currently avail derivatives wherein aniline moiety is substituted in both of 2 able are not fully satisfactory as they are. and 5-positions or in both of 3- and 5-positions, and N-thia Patients with endometriosis are increasing in recent years, Zol-2-yl-salicylamide derivatives wherein thiazole ring is and currently, 10 to 14% of females are considered to be substituted in both of 4- and 5-positions have extremely supe suffered from the disease. Endometriosis has been focused as 50 rior activity in inhibitory action against the proliferation of a cause of sterility, as well as the disease lowers the quality of mast cells, inhibitory action against the degranulation from life of patients with severe pains during menstruation and mast cells by antigen and IgE stimulation, and inhibitory coitus. For a treatment of the disease, a therapy by using a action against the production of IgE from activated B cells, hormone drug has been currently applied as a pseudo meno and that radical preventive and/or therapeutic treatment of pausal therapy. However, the aforementioned therapy induces 55 allergic diseases can be achieved. The inventors also con strong side effects, and it also has a risk of causing osteoporo ducted researches on hydroxyaryl derivatives which are sis during along-term administration. Therefore, at present, a analogous compounds thereof. The present invention was drug or a method for treatment with safety and high efficacy achieved on the basis of these findings. is not available. The present invention thus provides: In recent years, it was found that mast cells exist apparently 60 with high density in the lesion of endometriosis (American (1) A medicament for preventive and/or therapeutic treatment Journal of Reproductive Immunology (New York: 1998), of allergic diseases and/or endometriosis and/or hyster (Denmark), Vol. 40, No. 4, p. 291-294), and that mast cells are omyoma which comprises as an active ingredient a Sub activated to lead degranulation (Nikkei Medical, 2002, No. stance selected from the group consisting of a compound 415, p. 28; Fertility and Sterility, (USA), 2002, Vol. 78, No. 4, 65 represented by the following general formula (I) and a p. 782-786). Furthermore, a relation between endometriosis pharmacologically acceptable salt thereof, and a hydrate and allergy is strongly suggested, because interstitial hyper thereof and a solvate thereof: US 7,700,655 B2 4

-continued (I) -C-O-, -C-N-N-, -C=N-N-, | O O H. H. H H H O S S. |

N y -- S N-- 10 H. O Sk H wherein X represents a connecting group whose number of O atoms in a main chain is 2 to 5 (said connecting group may be substituted), A represents hydrogen atom or acetyl group, wherein a bond at the left end binds to ring Z and a bond at the E represents an aryl group which may be substituted or a 15 right end binds to E: heteroaryl group which may be substituted, (3) the aforementioned medicament which comprises as an ring Z represents an arene which may have one or more active ingredient a Substance selected from the group con substitutents in addition to the group represented by for sisting of the compound and a pharmacologically accept mula —O-A wherein A has the same meaning as that able salt thereof, and a hydrate thereof and a solvate defined above and the group represented by formula—X-E thereof, wherein X is a group represented by the following wherein each of X and E has the same meaning as that formula (said group may be substituted): defined above, or a heteroarene which may have one or more Substitutents in addition to the group represented by formula —O-A wherein A has the same meaning as that -C-N- 25 defined above and the group represented by formula—X-E O H wherein each of X and E has the same meaning as that defined above. Examples of preferred medicaments provided by the wherein a bond at the left end binds to ring Z and a bond at the present invention include: 30 right end binds to E: (2) the aforementioned medicament which comprises as an (4) the aforementioned medicament which comprises as an active ingredient a Substance selected from the group con active ingredient a substance selected from the group con sisting of the compound and a pharmacologically accept sisting of the compound and a pharmacologically accept able salt thereof, and a hydrate thereof and a solvate able salt thereof, and a hydrate thereof and a solvate thereof, wherein X is a group selected from the following 35 thereof, wherein A is a hydrogen atom; connecting group a (said group may be substituted): (5) the aforementioned medicament which comprises as an active ingredient a Substance selected from the group con Connecting group C. The groups of the following formulas: sisting of the compound and a pharmacologically accept able salt thereof, and a hydrate thereof and a solvate 40 thereof, whereinring Zis a C to Coarene which may have one or more Substitutents in addition to the group repre -C-N-, -C-N-C- sented by formula—O-A wherein A has the same meaning | | | | as that defined in the general formula (I) and the group O H O H. H. represented by formula—X-E wherein each of X and E has | | 45 the same meaning as that defined in the general formula (I), -C-N-C-C-, -C-C-C-, or a 5 to 13-membered heteroarene which may have one or | | | | | more Substitutents in addition to the group represented by O H. H. H. O H. H. formula —O-A wherein A has the same meaning as that H H O defined in the general formula (I) and the group repre -C-C=C-, -C=C-, -S-N-, 50 sented by formula—X-E wherein each of X and E has the | | same meaning as that defined in the general formula (I); O H H O H O H (6) the aforementioned medicament which comprises as an active ingredient a Substance selected from the group con -N-C-, -N-S-, -C-N-, sisting of the compound and a pharmacologically accept | || | || 55 able salt thereof, and a hydrate thereof and a solvate H. O H. O H. H. thereof, whereinring Z is a ring selected from the following | ring group f: -C-N-N=C-, -C-N-C-C-N-, | | | | || | Ring Group B benzene ring, naphthalene ring, thiophene O H H O H. H. O. H. ring, pyridine ring, indole ring, quinoxaline ring, and carba -C=N-N-C-, -N-C-N-, 60 Zole ring | || | || | H H. O H. O. H. wherein said ring may have one or more Substitutents in H addition to the group represented by formula—O-A wherein -C-N-N-C-, -C-N-N-C-, A has the same meaning as that defined in the general formula 65 (I) and the group represented by formula—X-E wherein each O H H O O H. H. H. of X and E has the same meaning as that defined in the general formula (I); US 7,700,655 B2 5 6 (7) the aforementioned medicament which comprises as an The present invention further provides: active ingredient a Substance selected from the group con (1) a compound represented by the general formula (I-1) or a sisting of the compound and a pharmacologically accept salt thereof, or a hydrate thereof or a solvate thereof: able salt thereof, and a hydrate thereof and a solvate thereof, wherein ring Z is a benzene ring which may have (I-1) one or more Substitutents in addition to the group repre O sented by formula—O-A wherein A has the same meaning as that defined in the general formula (I) and the group ls El represented by formula—X-E wherein each of X and E has Zl 10 the same meaning as that defined in the general formula (I); H (8) the aforementioned medicament which comprises as an active ingredient a Substance selected from the group con sisting of the compound and a pharmacologically accept wherein Z' represents 2-hydroxyphenyl group which may be able salt thereof, and a hydrate thereof and a solvate Substituted in the 5-position or 2-acetoxyphenyl group which thereof, wherein ring Z is a benzene ring which is Substi 15 may be substituted in the 5-position, and E' represents a tuted with halogen atom(s) in addition to the group repre phenyl group which may be substituted. sented by formula—O-A wherein A has the same meaning Preferably, provided is: as that defined in the general formula (I) and the group (2) the compound or a salt thereof, or a hydrate thereof or a represented by formula—X-E wherein each of X and E has solvate thereof, wherein E' is 2,5-bis(trifluoromethyl)phe the same meaning as that defined in the general formula (I); nyl group or 3.5-bis(trifluoromethyl)phenyl group, except (9) the aforementioned medicament which comprises as an that the following compounds are excluded: active ingredient a Substance selected from the group con N-3,5-bis(trifluoromethyl)phenyl-2-hydroxybenzamide, sisting of the compound and a pharmacologically accept N-3,5-bis(trifluoromethyl)phenyl-5-chloro-2-hydroxyben Zamide, able salt thereof, and a hydrate thereof and a solvate 25 thereof, wherein ring Z is a naphthalene ring which may N-3,5-bis(trifluoromethyl)phenyl-5-bromo-2-hydroxyben have one or more Substitutents in addition to the group Zamide, represented by formula —O-A wherein A has the same N-3,5-bis(trifluoromethyl)phenyl-2-hydroxy-5-iodoben Zamide, and meaning as that defined in the general formula (I) and the N-3,5-bis(trifluoromethyl)phenyl-2-hydroxy-5-nitroben group represented by formula —X-E wherein each of X 30 Zamide. and E has the same meaning as that defined in the general More preferably, provided is: formula (I); (3) the compound or a salt thereof, or a hydrate thereof or a (10) the aforementioned medicament which comprises as an solvate thereof, wherein Z' is 2-hydroxyphenyl group active ingredient a Substance selected from the group con which is substituted with a halogenatom in the 5-position sisting of the compound and a pharmacologically accept 35 or 2-acetoxyphenyl group which is Substituted with a halo able salt thereof, and a hydrate thereof and a solvate gen atom in the 5-position. thereof, wherein E is a C to Co aryl group which may be Moreover, the present invention provides: substituted or a 5 to 13-membered heteroaryl group which (1) a compound represented by the general formula (I-2) or a may be substituted; salt thereof, or a hydrate thereof or a solvate thereof: (11) the aforementioned medicament which comprises as an 40 active ingredient a Substance selected from the group con sisting of the compound and a pharmacologically accept (I-2) able salt thereof, and a hydrate thereof and a solvate O thereof, wherein E is a phenyl group which may be substi tuted; 45 Z2 ls E2 (12) the aforementioned medicament which comprises as an active ingredient a Substance selected from the group con H sisting of the compound and a pharmacologically accept

able salt thereof, and a hydrate thereof and a solvate 50 wherein Z represents 2-hydroxyphenyl group which may be thereof, wherein E is 3,5-bis(trifluoromethyl)phenyl Substituted in the 5-position or 2-acetoxyphenyl group which group; may be substituted in the 5-position, (13) the aforementioned medicament which comprises as an E represents a 2.5-di-substituted phenyl group wherein one active ingredient a Substance selected from the group con of said substitutents is trifluoromethyl group or a 3,5-di sisting of the compound and a pharmacologically accept 55 Substituted phenyl group wherein one of said Substitutents able salt thereof, and a hydrate thereof and a solvate is trifluoromethyl group, provided that the following com thereof, wherein E is a 5-membered heteroaryl group pounds are excluded: which may be substituted. 5-chloro-N-5-chloro-3-(trifluoromethyl)phenyl-2-hy From another aspect, the present invention provides use of droxybenzamide, each of the aforementioned substances for manufacture of the 60 5-fluoro-2-hydroxy-N-(2-(2.2.2-trifluoroethoxy)-5-(trifluo medicament according to the aforementioned (1) to (13). romethyl)phenylbenzamide, The present invention further provides a method for pre 5-fluoro-2-hydroxy-N-(2-(6,6,6-trifluorohexyloxy)-5-(trif ventive and/or therapeutic treatment of allergic diseases and/ luoromethyl)phenyl-benzamide, or endometriosis and/or hysteromyoma in a mammal includ 5-chloro-N-2-(4-chlorophenoxy)-5-(trifluoromethyl)phe ing a human, which comprises the step of administering 65 nyl-2-hydroxybenzamide, preventively and/or therapeutically effective amount of the 5-chloro-2-hydroxy-N-(2-(4-methylphenoxy)-5-(trifluo aforementioned substances to a mammal including a human. romethyl)phenylbenzamide, US 7,700,655 B2 7 5-chloro-N-2-(4-chlorophenyl)sulfanyl-5-(trifluoromethyl) phenyl-2-hydroxybenzamide, 5-chloro-2-hydroxy-N-2-(1-naphthyloxy)-5-(trifluorom ethyl)phenylbenzamide, and 5-chloro-2-hydroxy-N-2-(2-naphthyloxy)-5-(trifluorom 5 ethyl)phenylbenzamide. Preferably, provided is: (2) the compound or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z is 2-hydroxyphenyl group wherein R“represents a hydrocarbon group which may be which is substituted with a halogen atom in the 5-position 10 substituted, or 2-acetoxyphenyl group which is Substituted with a halo R" represents a halogen atom, cyano group, an acyl group gen atom in the 5-position. which may be substituted, or a heterocyclic group which Moreover, the present invention provides: may be substituted. (1) a compound represented by the general formula (I-3) or a Preferably, provided is: salt thereof, or a hydrate thereof or a solvate thereof: 15 (2) the compound or a salt thereof, or a hydrate thereof or a solvate thereof, wherein Z is 2-hydroxyphenyl group which is substituted with a halogenatom in the 5-position (I-3) or 2-acetoxyphenyl group which is Substituted with a halo gen atom in the 5-position. BRIEF EXPLANATION OF THE DRAWINGS FIG. 1 shows inhibitory effect of the medicament of the present invention (compound No. 50) against immediate type 25 allergy. wherein Z represents 2-hydroxyphenyl group which may be FIG. 2 shows inhibitory effect of the medicament of the Substituted in the 5-position or 2-acetoxyphenyl group which present invention (compound No. 50) against dermatitis with may be substituted in the 5-position, E represents a group represented by the following formula: an atopic dermatitis model. 30 BEST MODE FOR CARRYING OUT THE INVENTION Reference to the disclosure of the pamphlet of Interna tional Publication WOO2/49632 is useful for better under 35 standing of the present invention. The entire disclosure of the aforementioned pamphlet of International Publication WO02/49632 is incorporated by reference in the disclosures of the present specification. The terms used in the present specification have the fol wherein one of R and R represents hydrogen atom and 40 lowing meanings. the other represents a hydrocarbon group which may be Sub As the halogen atom, any of fluorine atom, chlorine atom, stituted or hydroxyl group which may be substituted, and bromine atom, or iodine atom may be used unless otherwise R represents a C to C. hydrocarbon group which may be specifically referred to. Substituted. Examples of the hydrocarbon group include, for example, Preferably, provided is: 45 an aliphatic hydrocarbon group, an aryl group, an arylene (2) the compound or a salt thereof, or a hydrate thereof or a group, an aralkyl group, a bridged cyclic hydrocarbon group, solvate thereof, wherein Z is 2-hydroxyphenyl group a spiro cyclic hydrocarbon group, and a terpene hydrocarbon. which is substituted with a halogen atom in the 5-position Examples of the aliphatic hydrocarbon group include, for or 2-acetoxyphenyl group which is Substituted with a halo example, alkyl group, alkenyl group, alkynyl group, alkylene 50 group, alkenylene group, alkylidene group and the like which gen atom in the 5-position. are straight chain or branched chain monovalent or bivalent The present invention also provides: acyclic hydrocarbon groups; cycloalkyl group, cycloalkenyl (1) a compound represented by the general formula (I-4) or a group, cycloalkanedienyl group, cycloalkyl-alkyl group, salt thereof, or a hydrate thereof or a solvate thereof: cycloalkylene group, and cycloalkenylene group, which are 55 saturated or unsaturated monovalent or bivalent alicyclic hydrocarbon groups. (I-4) Examples of the alkyl group include, for example, methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 60 neopentyl, 1,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methyl pentyl, 3.3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethyl butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethyl wherein Z represents 2-hydroxyphenyl group which may be butyl, 2-ethylbutyl, 1-ethylbutyl, 1-ethyl-1-methylpropyl, Substituted in the 5-position or 2-acetoxyphenyl group which 65 n-heptyl, n-octyl, n-nonyl, n-decyl. n-undecyl, n-dodecyl. may be substituted in the 5-position, n-tridecyl, n-tetradecyl, and n-pentadecyl, which are C to E" represents a group represented by the following formula: Cs straight chain or branched chain alkyl groups. US 7,700,655 B2 10 Examples of the alkenyl group include, for example, vinyl, propylpropyl, 4-cyclopropylbutyl, 5-cyclopropylpentyl, prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1- 6-cyclopropylhexyl, cyclobutylmethyl, cyclopentylmethyl, y1, but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2- cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, 4-en-1-yl, 3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, cyclooctylmethyl, and 6-cyclooctylhexyl, which are C to hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, Cacycloalkyl-alkyl groups. hex-5-en-1-yl 4-methylpent-3-en-1-yl 4-methylpent-3-en Examples of the cycloalkylenegroup include, for example, 1-yl, hept-1-en-1-yl, hept-6-en-1-yl, oct-1-en-1-yl, oct-7-en cyclopropane-1,1-diyl, cyclopropane-1,2-diyl, cyclobutane 1-yl. non-1-en-1-yl, non-8-en-1-yl, dec-1-en-1-yl, dec-9-en 1,1-diyl, cyclobutane-1,2-diyl, cyclobutane-1,3-diyl, cyclo 1-yl, undec-1-en-1-yl, undec-10-en-1-yl, dodec-1-en-1-yl, 10 pentane-1,1-diyl, cyclopentane-1,2-diyl, cyclopentane-1,3- dodec-11-en-1-yl, tridec-1-en-1-yl, tridec-12-en-1-yl, tet diyl. cyclohexane-1,1-diyl. cyclohexane-1,2-diyl. radec-1-en-1-yl, tetradec-13-en-1-yl, pentadec-1-en-1-yl, cyclohexane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane and pentadec-14-en-1-yl, which are C to Cs straight chain 1,1-diyl, cycloheptane-1,2-diyl, cyclooctane-1,1-diyl, and or branched chain alkenyl groups. cyclooctane-1,2-diyl, which are C to Cs cycloalkylene Examples of the alkynyl group include, for example, ethy 15 groups. nyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn Examples of the cycloalkenylene group include, for 1-yl, 1-methylprop-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1- example, 2-cyclopropene-1,1-diyl 2-cyclobutene-1,1-diyl. yl, hex-1-yn-1-yl, hex-5-yn-1-yl, hept-1-yn-1-yl, hept-6-yn 2-cyclopentene-1,1-diyl 3-cyclopentene-1,1-diyl 2-cyclo 1-yl, oct-1-yn-1-yl, oct-7-yn-1-yl, non-1-yn-1-yl, non-8-yn hexene-1,1-diyl 2-cyclohexene-1,2-diyl 2-cyclohexene-1, 1-yl, dec-1-yn-1-yl, dec-9-yn-1-yl, undec-1-yn-1-yl, undec 4-diyl 3-cyclohexene-1,1-diyl, 1-cyclobutene-1,2-diyl. 10-yn-1-yl, dodec-1-yn-1-yl, dodec-1 1-yn-1-yl, tridec-1-yn 1-cyclopentene-1,2-diyl, and 1-cyclohexene-1,2-diyl, which 1-yl, tridec-12-yn-1-yl, tetradec-1-yn-1-yl, tetradec-13-yn-1- are C to Ce cycloalkenylene groups. yl, pentadec-1-yn-1-yl, and pentadec-14-yn-1-yl, which are Examples of the aryl group include a monocyclic or a fused C. to Cs straight chain or branched chain alkynyl groups. polycyclic aromatic hydrocarbon group, and include, for Examples of the alkylene group include, for example, 25 example, phenyl, 1-naphthyl 2-naphthyl, anthryl, phenan methylene, ethylene, ethane-1,1-diyl, propane-1,3-diyl, pro thryl, and acenaphthylenyl, which are C to Caryl groups. pane-1,2-diyl, propane-2.2-diyl, butane-1,4-diyl, pentane-1, The aforementioned aryl group may be fused with the 5-diyl, hexane-1,6-diyl, and 1,1,4,4-tetramethylbutane-1,4- aforementioned C to Cs cycloalkyl group, C to C cycloalk diyl group, which are C to Cs straight chain or branched enyl group, Cs to C cycloalkanedienyl group or the like, and chain alkylene groups. 30 examples include, for example, 4-indanyl, 5-indanyl, 1.2.3, Examples of the alkenylene group include, for example, 4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen ethene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl, but-2- 6-yl, 3-acenaphthenyl, 4-acenaphthenyl, inden-4-yl, inden-5- ene-1,4-diyl, 2-methylpropene-1,3-diyl, pent-2-ene-1,5-diyl. yl, inden-6-yl, inden-7-yl 4-phenalenyl, 5-phenalenyl, and hex-3-ene-1,6-diyl, which are C to C Straight chain or 6-phenalenyl, 7-phenalenyl, 8-phenalenyl, and 9-phenalenyl. branched chain alkylene groups. 35 Examples of the arylene group include, for example, 1.2- Examples of the alkylidene group include, for example, phenylene, 1,3-phenylene, 1,4-phenylene, naphthalene-1,2- methylidene, ethylidene, propylidene, isopropylidene, butyl diyl, naphthalene-1,3-diyl, naphthalene-1,4-diyl, naphtha idene, pentylidene, and hexylidene, which are C to C lene-1,5-diyl, naphthalene-1,6-diyl, naphthalene-1,7-diyl. straight chain or branched chain alkylidene groups. naphthalene-1,8-diyl, naphthalene-2,3-diyl, naphthalene-2, Examples of the cycloalkyl group include, for example, 40 4-diyl, naphthalene-2,5-diyl, naphthalene-2,6-diyl, naphtha cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep lene-2,7-diyl. naphthalene-2,8-diyl, and anthracene-1,4-diyl. tyl, and cyclooctyl, which are C to Cs cycloalkyl groups. which are C to Carylene groups. The aforementioned cycloalkyl group may be fused with Examples of the aralkyl group include the groups in which benzene ring, naphthalene ring and the like, and examples one hydrogen atom of the alkyl group is Substituted with an include, for example, 1-indanyl, 2-indanyl, 1.2.3,4-tetrahy 45 aryl group, and include, for example, benzyl, 1-naphthylm dronaphthalen-1-yl, and 1.2.3,4-tetrahydronaphthalen-2-yl. ethyl 2-naphthylmethyl, anthracenylmethyl, phenanthrenyl Examples of the cycloalkenyl group include, for example, methyl, acenaphthylenylmethyl, diphenylmethyl, 1-phen 2-cyclopropen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, ethyl 2-phenethyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl 3-phenylpropyl. 1-cyclobuten-1-yl, and 1-cyclopenten-1-yl, which are C to 50 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl, 4-phenylbutyl, C cycloalkenyl groups. 4-(1-naphthyl)butyl, 4-(2-naphthyl)butyl, 5-phenylpentyl, The aforementioned cycloalkenyl group may be fused with 5-(1-naphthyl)pentyl, 5-(2-naphthyl)pentyl, 6-phenylhexyl, benzene ring, naphthalene ring and the like, and examples 6-(1-naphthyl)hexyl, and 6-(2-naphthyl)hexyl, which are C, include, for example, 1-indanyl, 2-indanyl, 1.2.3,4-tetrahy to Caralkyl groups. dronaphthalen-1-yl, 1.2.3,4-tetrahydronaphthalen-2-yl, 1-in 55 Examples of the bridged cyclic hydrocarbon group denyl, and 2-indenyl. include, for example, bicyclo[2.1.0 pentyl, bicyclo[2.2.1 Examples of the cycloalkanedienyl group include, for heptyl, bicyclo2.2.1]octyl, and adamanty1. example, 2.4-cyclopentadien-1-yl, 2.4-cyclohexanedien-1- Examples of the spiro cyclic hydrocarbon group include, y1, and 2.5-cyclohexanedien-1-yl, which are Cs to Cecycloal for example, Spiro3.4 octyl, and spiro4.5 deca-1,6-dienyl. kanedienyl groups. 60 Examples of the terpene hydrocarbon include, for The aforementioned cycloalkanedienyl group may be example, geranyl. neryl, linallyl, phytyl, menthyl, and bornyl. fused with benzene ring, naphthalene ring and the like, and Examples of the halogenated alkyl group include the examples include, for example, 1-indenyl and 2-indenyl. groups in which one hydrogen atom of the alkyl group is Examples of the cycloalkyl-alkyl group include the groups Substituted with a halogen atom, and include, for example, in which one hydrogen atom of the alkyl group is Substituted 65 fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, with a cycloalkyl group, and include, for example, cyclopro dichloromethyl, trichloromethyl, bromomethyl, dibromom pylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 3-cyclo ethyl, tribromomethyl, iodomethyl, diiodomethyl, triiodom

US 7,700,655 B2 13 14 7-chromanyl, 8-chromanyl, 1-isochromanyl, 3-isochroma loxy, n-tetradecyloxy, and n-pentadecyloxy, which are C to nyl, 4-isochromanyl, 5-isochromanyl, 6-isochromanyl, 7-iso Cs straight chain or branched chain alkoxy groups. chromanyl, 8-isochromanyl, 2-thiochromanyl, 3-thiochro Examples of the alkenyl-oxy group include, for example, manyl, 4-thiochromanyl, 5-thiochromanyl, 6-thiochromanyl. vinyloxy, (prop-1-en-1-yl)oxy, allyloxy, isopropenyloxy, 7-thiochromanyl, 8-thiochromanyl, 1-isothiochromanyl. (but-1-en-1-yl)oxy, (but-2-en-1-yl)oxy, (but-3-en-1-yl)oxy, 3-isothiochromanyl, 4-isothiochromanyl, 5-isothiochroma (2-methylprop-2-en-1-yl)oxy, (1-methylprop-2-en-1-yl)oxy, nyl, 6-isothiochromanyl, 7-isothiochromanyl, 8-isothiochro (pent-1-en-1-yl)oxy, (pent-2-en-1-yl)oxy, (pent-3-en-1-yl) manyl, 1-indolinyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, oxy, (pent-4-en-1-yl)oxy, (3-methylbut-2-en-1-yl)oxy, 5-indolinyl, 6-indolinyl, 7-indolinyl, 1-isoindolinyl, 2-isoin (3-methylbut-3-en-1-yl)oxy, (hex-1-en-1-yl)oxy, (hex-2-en dolinyl, 4-isoindolinyl, 5-isoindolinyl, 2-(4H-chromenyl), 10 1-yl)oxy, (hex-3-en-1-yl)oxy, (hex-4-en-1-yl)oxy, (hex-5-en 3-(4H-chromenyl), 4-(4H-chromenyl), 5-(4H-chromenyl), 1-yl)oxy, (4-methylpent-3-en-1-yl)oxy, (4-methylpent-3-en 6-(4H-chromenyl), 7-(4H-chromenyl), 8-(4H-chromenyl), 1-yl)oxy, (hept-1-en-1-yl)oxy, (hept-6-en-1-yl)oxy, (oct-1- 1-isochromenyl, 3-isochromenyl, 4-isochromenyl, 5-isoch en-1-yl)oxy, (oct-7-en-1-yl)oxy, (non-1-en-1-yl)oxy, (non-8- romenyl, 6-isochromenyl, 7-isochromenyl, 8-isochromenyl, en-1-yl)oxy, (dec-1-en-1-yl)oxy, (dec-9-en-1-yl)oxy, (undec 1-(1H-pyrrolidinyl), 2-(1H-pyrrolidinyl), 3-(1H-pyrrolidi 15 1-en-1-yl)oxy, (undec-10-en-1-yl)oxy, (dodec-1-en-1-yl) nyl), 5-(1H-pyrrolidinyl), 6-(1H-pyrrolidinyl), and 7-(1H oxy, (dodec-11-en-1-yl)oxy, (tridec-1-en-1-yl)oxy, (tridec pyrrolidinyl), which are 8 to 10-membered saturated or unsat 12-en-1-yl)oxy, (tetradec-1-en-1-yl)oxy, (tetradec-13-en-1- urated fused polycyclic non-aromatic heterocyclic groups. yl)oxy, (pentadec-1-en-1-yl)oxy, and (pentadec-14-en-1-yl) Among the aforementioned heterocyclic groups, a mono oxy, which are C to Cs straight chain or branched chain cyclic or a fused polycyclic hetero aryl groups which may alkenyl-oxy groups. have 1 to 3 kinds of hetero atoms selected from oxygenatom, Examples of the alkynyl-oxy group include, for example, Sulfur atom, nitrogen atom and the like, in addition to the ethynyloxy, (prop-1-yn-1-yl)oxy, (prop-2-yn-1-yl)oxy, (but nitrogen atom that has the bond, as ring-constituting atoms 1-yn-1-yl)oxy, (but-3-yn-1-yl)oxy, (1-methylprop-2-yn-1- (ring forming atoms), and a monocyclic or a fused polycyclic yl)oxy, (pent-1-yn-1-yl)oxy, (pent-4-yn-1-yl)oxy, (hex-1-yn non-aromatic heterocyclic groups which may have 1 to 3 25 1-yl)oxy, (hex-5-yn-1-yl)oxy, (hept-1-yn-1-yl)oxy, (hept-6- kinds of hetero atoms selected from oxygen atom, Sulfur yn-1-yl)oxy, (Oct-1-yn-1-yl)oxy, (oct-7-yn-1-yl)oxy, (non-1- atom, nitrogen atom and the like, in addition to the nitrogen yn-1-yl)oxy, (non-8-yn-1-yl)oxy, (dec-1-yn-1-yl)oxy, (dec atom that has the bond, as ring-constituting atoms (ring form 9-yn-1-yl)oxy, (undec-1-yn-1-yl)oxy, (undec-10-yn-1-yl) ing atoms) are referred to as “cyclic amino group.” Examples oxy, (dodec-1-yn-1-yl)oxy, (dodec-1 1-yn-1-yl)oxy, (tridec include, for example, 1-pyrrolidinyl, 1-imidazolidinyl, 30 1-yn-1-yl)oxy, (tridec-12-yn-1-yl)oxy, (tetradec-1-yn-1-yl) 1-pyrazolidinyl, 1-oxazolidinyl, 1-thiazolidinyl, piperidino, oxy, (tetradec-13-yn-1-yl)oxy, (pentadec-1-yn-1-yl)oxy, and morpholino. 1-piperazinyl, thiomorpholin-4-yl, 1-homopip (pentadec-14-yn-1-yl)oxy, which are C to Cs straight chain eridinyl, 1-homopiperazinyl, 2-pyrrolin-1-yl, 2-imidazolin or branched chain alkynyl-oxy groups. 1-yl 2-pyrazolin-1-yl, 1-indolinyl, 2-isoindolinyl, 1.2.3,4- Examples of the cycloalkyl-oxy group include, for tetrahydroquinolin-1-yl, 1.2.3,4-tetrahydroisoquinolin-2-yl, 35 example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclo 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, 1-indolyl, 1-indazolyl, hexyloxy, cycloheptyloxy, and cyclooctyloxy, which are C and 2-isoindolyl. to Cs cycloalkyl-oxy groups. The aforementioned cycloalkyl group, cycloalkenyl group, Examples of the cycloalkyl-alkyl-oxy group include, for cycloalkanedienyl group, aryl group, cycloalkylene group, example, cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cy cycloalkenylene group, arylene group, bridged cyclic hydro 40 clopropylethoxy, 3-cyclopropylpropoxy, 4-cyclopropylbu carbon group, spiro cyclic hydrocarbon group, and heterocy toxy, 5-cyclopropylpentyloxy, 6-cyclopropylhexyloxy, clic group are generically referred to as “cyclic group. Fur cyclobutylmethoxy, cyclopentylmethoxy, cyclobutyl thermore, among said cyclic groups, particularly, aryl group, methoxy, cyclopentylmethoxy, cyclohexylmethoxy, 2-cyclo arylene group, monocyclic heteroaryl group, and fused poly hexylethoxy, 3-cyclohexylpropoxy, 4-cyclohexylbutoxy, cyclic heteroaryl group are generically referred to as “aro 45 cycloheptylmethoxy, cyclooctylmethoxy, and 6-cyclooctyl matic ring group. hexyloxy, which are C to Cacycloalkyl-alkyl-oxy groups. Examples of the hydrocarbon-oxy group include the Examples of the aryl-oxy group include, for example, phe groups in which a hydrogen atom of the hydroxy group is noxy, 1-naphthyloxy, 2-naphthyloxy, anthryloxy, phenan Substituted with a hydrocarbon group, and examples of the thryloxy, and acenaphthylenyloxy, which are C to Caryl hydrocarbon include similar groups to the aforementioned 50 OXy groups. hydrocarbon groups. Examples of the hydrocarbon-oxy Examples of the aralkyl-oxy group include, for example, group include, for example, alkoxy group (alkyl-oxy group), benzyloxy, 1-naphthylmethoxy, 2-naphthylmethoxy, anthra alkenyl-oxy group, alkynyl-oxy group, cycloalkyl-oxy cenylmethoxy, phenanthrenylmethoxy, acenaphthylenyl group, cycloalkyl-alkyl-oxy group and the like, which are methoxy, diphenylmethoxy, 1-phenethyloxy, 2-phenethy aliphatic hydrocarbon-oxy groups: aryl-oxy group; aralkyl 55 loxy, 1-(1-naphthyl)ethoxy, 1-(2-naphthyl)ethoxy, 2-(1- oxy group; and alkylene-dioxy group. naphthyl)ethoxy. 2-(2-naphthyl)ethoxy, 3-phenylpropoxy, Examples of the alkoxy (alkyl-oxy group) include, for 3-(1-naphthyl)propoxy, 3-(2-naphthyl)propoxy, 4-phenylbu example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, toxy, 4-(1-naphthyl)butoxy, 4-(2-naphthyl)butoxy, 5-phenyl isobutoxy, Sec-butoxy, tert-butoxy, n-pentyloxy, isopenty pentyloxy, 5-(1-naphthyl)pentyloxy, 5-(2-naphthyl)penty loxy, 2-methylbutoxy, 1-methylbutoxy, neopentyloxy, 1.2- 60 loxy, 6-phenylhexyloxy, 6-(1-naphthyl)hexyloxy, and 6-(2- dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpen naphthyl)hexyloxy, which are C, to Caralkyl-oxy groups. tyloxy, 3-methylpentyloxy, 2-methylpentyloxy, Examples of the alkylenedioxy group include, for 1-methylpentyloxy, 3.3-dimethylbutoxy, 2,2-dimethylbu example, methylenedioxy, ethylenedioxy, 1-methylmethyl toxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimeth enedioxy, and 1,1-dimethylmethylenedioxy. ylbutoxy, 2,3-dimethylbutoxy, 2-ethylbutoxy, 1-ethylbutoxy, 65 Examples of the halogenated alkoxy group (halogenated 1-ethyl-1-methylpropoxy, n-heptyloxy, n-octyloxy, n-nony alkyl-oxy group) include the groups in which a hydrogen loxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, n-tridecy atom of the hydroxy group is substituted with a halogenated

US 7,700,655 B2 17 18 (bromomethyl)sulfanyl, (iodomethyl)sulfanyl, (difluorom ethyl)sulfanyl, (trifluoromethyl)sulfanyl, (trichloromethyl) -continued sulfanyl. (2.2.2-trifluoroethyl)sulfanyl, (pentafluoroethyl) C-N-Ral (c)-9A) sulfanyl, (3,3,3-trifluoropropyl)sulfanyl, (heptafluoropropyl) | Sulfanyl. (heptafluoroisopropyl)sulfanyl, (nonafluorobutyl) O H sulfanyl, and (perfluorohexyl)sulfanyl, which are C to C. C-N-Ral (c)-10A) straight chain or branched chain halogenated alkyl-sulfanyl groups substituted with 1 to 13 halogen atoms. O R

Examples of the heterocyclic-sulfanyl group include the 10 C-N-Ral (c)-11A) groups in which a hydrogen atom of the Sulfanyl group is | Substituted with a heterocyclic group, and examples of the S H heterocyclic ring include similar groups to the aforemen tioned heterocyclic groups. Examples of the heterocyclic C-N-Ral (c)-12A) Sulfanyl group include, for example, a monocyclic het 15 S R eroaryl-sulfanyl group, a fused polycyclic heteroaryl (c)-13A) Sulfanyl group, a monocyclic non-aromatic heterocyclic O Sulfanyl group, and a fused polycyclic non-aromatic -S-N-Ra, heterocyclic-Sulfanyl group. | Examples of the monocyclic heteroaryl-sulfanyl group O H include, for example, (imidazol-2-yl)sulfanyl. (1,2,4-triazol (c)-14A) 2-yl)sulfanyl. (pyridin-2-yl)sulfanyl. (pyridin-4-yl)sulfanyl. O and (pyrimidin-2-yl)sulfanyl. -S-N-Ra, Examples of the fused polycyclic heteroaryl-sulfanyl OIl R group include, for example, (benzimidazol-2-yl)sulfanyl. 25 (quinolin-2-yl)sulfanyl, and (quinolin-4-yl)sulfanyl. S-N-Ral (c)-15A) Examples of the monocyclic non-aromatic heterocyclic | Sulfanyl groups include, for example, (3-pyrrolidinyl)sulfa O H nyl, and (4-piperidinyl)sulfanyl. S-N-Ral (c)-16A) Examples of the fused polycyclic non-aromatic heterocy 30 | clic-sulfanyl group include, for example, (3-indolinyl)sulfa O Rb1 (c)-17A) nyl, and (4-chromanyl)sulfanyl. O Examples of the acyl group include, for example, formyl group, glyoxyloyl group, thioformyl group, carbamoyl -S-O-Ra, group, thiocarbamoyl group, Sulfamoyl group, Sulfinamoyl 35 group, carboxy group, Sulfo group, phosphono group, and O groups represented by the following formulas: S-O-Ral (c)-18A) O 40 O-Ral (c)-19A) C-Ral (CO-1A) s | - PEO O C-O-Ral (o)-2A) -R 45 (c)-20A) O O C-C-Ral (c)-3A) --e. || || O O O -4A 50 S-Ral (c)-21A) -C-C-O-Ra, (c)-4A) || || O O O C-S-Ral (c)-5A) 55 wherein R'' and R' may be the same or different and repre sent a hydrocarbon group or a heterocyclic group, or R'' and O R' combine to each other, together with the nitrogenatom to C-Ral (c)-6A) which they bind, to form a cyclic amino group. | S In the definition of the aforementioned acyl group, among 60 the groups represented by the formula (c)-1A), those groups C-O-Ral (a)-7A) in which R' is a hydrocarbon group are referred to as “hydro carbon-carbonyl group' whose examples include, for S example, acetyl, propionyl, butyryl, isobutyryl, Valeryl, isov C-S-Ral (c)-8A) aleryl, pivaloyl, lauroyl, myristoryl, palmitoyl, acryloyl, pro 65 pioloyl, methacryloyl, crotonoyl, isocrotonoyl, cyclohexyl S carbonyl, cyclohexylmethylcarbonyl, benzoyl, 1-naphthoyl, 2-naphthoyl, and phenylacetyl, and those groups in which US 7,700,655 B2 19 20 R" is a heterocyclic group are referred to as "heterocyclic groups in which R' is a heterocyclic group are referred to as ring-carbonyl group' whose examples include, for example, “N-heterocyclic ring-thiocarbamoyl group.” 2-thenoyl, 3-furoyl, nicotinoyl, and isonicotinoyl. Among the groups represented by the formula (c)-12A), Among the groups represented by the formula (c)-2A), those groups in which both R'' and R'' are hydrocarbon those groups in which R' is a hydrocarbon group are referred 5 groups are referred to as “N,N-di(hydrocarbon)-thiocarbam to as “hydrocarbon-oxy-carbonyl group” whose examples oyl group,” those groups in which both R'' and R'' are het include, for example, methoxycarbonyl, ethoxycarbonyl, erocyclic groups are referred to as “N,N-di(heterocyclic phenoxycarbonyl, and benzyloxycarbonyl, and those groups ring)-thiocarbamoyl group,” those groups in which R' is a in which R' is a heterocyclic group are referred to as “het hydrocarbon group and R' is a heterocyclic group are erocyclic ring-oxy-carbonyl group' whose examples include, 10 referred to as “N-hydrocarbon-N-heterocyclic ring-thiocar for example, 3-pyridyloxycarbonyl. bamoyl group,” and those groups in which R'' and R' com Among the groups represented by the formula (c)-3A), bine to each other, together with the nitrogen atom to which those groups in which R" is a hydrocarbon group are referred they bind, to form a cyclic amino group are referred to as to as “hydrocarbon-carbonyl-carbonyl group” whose “cyclic amino-thiocarbonyl group.” examples include, for example, pyruvoyl, and those groups in 15 Among the groups represented by the formula (c)-13A), which R' is a heterocyclic group are referred to as "hetero those groups in which R" is a hydrocarbon group are referred cyclic ring-carbonyl-carbonyl group.” to as “N-hydrocarbon-sulfamoyl group, and those groups in Among the groups represented by the formula (c)-4A), which R' is a heterocyclic group are referred to as “N-het those groups in which R' is a hydrocarbon group are referred erocyclic ring-Sulfamoyl group.” to as “hydrocarbon-oxy-carbonyl-carbonyl group' whose Among the groups represented by the formula (c)-14A). examples include, for example, methoxalyl and ethoxalyl those groups in which both R'' and R'' are hydrocarbon groups, and those groups in which R' is a heterocyclic group groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl are referred to as "heterocyclic ring-oxy-carbonyl-carbonyl group' whose examples include, for example, N,N-dimeth group.” ylsulfamoyl group, those groups in which both R'' and R' Among the groups represented by the formula (c)-5A), 25 are heterocyclic groups are referred to as “N,N-di(heterocy those groups in which R' is a hydrocarbon group are referred clic ring)-sulfamoyl group,” those groups in which R" is a to as “hydrocarbon-sulfanyl-carbonyl group, and those hydrocarbon group and R' is a heterocyclic group are groups in which R' is a heterocyclic group are referred to as referred to as “N-hydrocarbon-N-heterocyclic ring-sulfa "heterocyclic ring-sulfanyl-carbonyl group.” moyl group,” and those groups in which R'' and R' combine Among the groups represented by the formula (c)-6A). 30 to each other, together with the nitrogen atom to which they those groups in which R" is a hydrocarbon group are referred bind, to form a cyclic amino group are referred to as "cyclic to as “hydrocarbon-thiocarbonyl group, and those groups in amino-Sulfonyl group' whose examples include, for example which R' is a heterocyclic group are referred to as "hetero 1-pyrrolylsulfonyl. cyclic ring-thiocarbonyl group.” Among the groups represented by the formula (c)-15A). Among the groups represented by the formula (c)-7A), 35 those groups in which R" is a hydrocarbon group are referred those groups in which R" is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl group, and those to as “N-hydrocarbon-sulfinamoyl group, and those groups groups in which R' is a heterocyclic group are referred to as in which R' is a heterocyclic group are referred to as “N-het "heterocyclic ring-oxy-thiocarbonyl group.” erocyclic ring-Sulfinamoyl group.” Among the groups represented by the formula (c)-16A). Among the groups represented by the formula (co-8A), 40 those groups in which both R'' and R'' are hydrocarbon those groups in which R" is a hydrocarbon group are referred groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl to as “hydrocarbon-sulfanyl-thiocarbonyl group, and those group,” those groups in which both R'' and R'' are hetero groups in which R' is a heterocyclic group are referred to as cyclic groups are referred to as “N,N-di(heterocyclic ring)- "heterocyclic ring-sulfanyl-thiocarbonyl group.” Sulfinamoyl group,” those groups in which R' is a hydrocar Among the groups represented by the formula (c)-9A), 45 bon group and R' is a heterocyclic group are referred to as those groups in which R" is a hydrocarbon group are referred “N-hydrocarbon-N-heterocyclic ring-sulfinamoyl group.” to as referred to as “N-hydrocarbon-carbamoyl group” whose and those groups in which R'' and R' combine to each other, examples include, for example, N-methylcarbamoyl group, together with the nitrogenatom to which they bind, to form a and those groups in which R' is a heterocyclic group are cyclic amino group are referred to as "cyclic amino-Sulfinyl referred to as “N-heterocyclic ring-carbamoyl group.” 50 Among the groups represented by the formula (c)-10A), group.” those groups in which both R'' and R'' are hydrocarbon Among the groups represented by the formula (c)-17A). groups are referred to as “N,N-di(hydrocarbon)-carbamoyl those groups in which R' is a hydrocarbon group are referred group' whose examples include, for example, N,N-dimeth to as “hydrocarbon-oxy-Sulfonyl group, and those groups in ylcarbamoyl group, those groups in which both R'' and R' 55 which R' is a heterocyclic group are referred to as "hetero are heterocyclic groups are referred to as “N,N-di(heterocy cyclic ring-oxy-Sulfonyl group.” clic ring)-carbamoyl group,” those groups in which R' is a Among the groups represented by the formula (c)-18A), hydrocarbon group and R' is a heterocyclic group are those groups in which R' is a hydrocarbon group are referred referred to as “N-hydrocarbon-N-heterocyclic ring-substi to as “hydrocarbon-oxy-Sulfinyl group, and those groups in tuted carbamoyl group,” and those groups in which R'' and 60 which R' is a heterocyclic group are referred to as "hetero R' combine to each other, together with the nitrogenatom to cyclic ring-oxy-sulfinyl group.” which they bind, to form a cyclic amino group are referred to Among the groups represented by the formula (c)-19A), as “cyclic amino-carbonyl group” whose examples include, those groups in which both R'' and R'' are hydrocarbon for example, morpholino-carbonyl. groups are referred to as “O.O'-dichydrocarbon)-phosphono Among the groups represented by the formula (c)-11A), 65 group,” those groups in which both R'' and R'' are hetero those groups in which R' is a hydrocarbon group are referred cyclic groups are referred to as “O,O'-dicheterocyclic ring)- to as “N-hydrocarbon-thiocarbamoyl group, and those phosphono group,” and those groups in which R' is a hydro US 7,700,655 B2 21 22 carbon group and R' is a heterocyclic group are referred to as group, carbamoimidoyl group (amidino group), azido group, “O-hydrocarbon-O'-heterocyclic ring-phosphono group.” imino group, hydroxyamino group, hydroxyimino group, Among the groups represented by the formula (c)-20A). aminooxy group, diazo group, semicarbazino group, semi those groups in which R" is a hydrocarbon group are referred carbazono group, allophanyl group, hydantoyl group, phos to as “hydrocarbon-sulfonyl group' whose examples include, 5 phano group, phosphoroso group, phospho group, boryl for example, methanesulfonyl and benzenesulfonyl, and group, silyl group, Stannyl group, Selanyl group, oxido group those groups in which R' is a heterocyclic group are referred and the like. to as "heterocyclic ring-Sulfonyl group.” Among the groups represented by the formula (c)-21A), When two or more substitutents exist according to the those groups in which R" is a hydrocarbon group are referred 10 aforementioned definition of “which may be substituted.” to as “hydrocarbon-sulfinyl group' whose examples include, said two or more Substitutents may combine to each other, for example, methylsulfinyl and benzenesulfinyl, and those together with atom(s) to which they bind, to form a ring. For groups in which R' is a heterocyclic group are referred to as these cyclic groups, as ring-constituting atoms (ring forming "heterocyclic ring-sulfinyl group.” atoms), one to three kinds of one or more hetero atoms Examples of the hydrocarbon in the groups represented by 15 selected from oxygen atom, Sulfur atom, nitrogen atom and the aforementioned formulas (c)-1A) through (co-21A) the like may be included, and one or more Substitutents may include the similar groups to the aforementioned hydrocar exist on the ring. The ring may be monocyclic or fused poly bon group. Examples of the hydrocarbon-carbonyl group rep cyclic, and aromatic or non-aromatic. resented by the formula (c)-1A) include, for example, an The above substitutents according to the aforementioned alkyl-carbonyl group, an alkenyl-carbonyl group, an alkynyl definition of “which may be substituted may further be sub carbonyl group, a cycloalkyl-carbonyl group, a cycloalkenyl stituted with the aforementioned substitutents at the chemi carbonyl group, a cycloalkanedienyl-carbonyl group, a cally substitutable positions on the substitutent. Kind of sub cycloalkyl-alkyl-carbonyl group, which are aliphatic hydro stitutents, number of Substitutents, and positions of carbon-carbonyl groups; an aryl-carbonyl group; an aralkyl substitutents are not particularly limited, and when the sub carbonyl group; a bridged cyclic hydrocarbon-carbonyl 25 stitutents are substituted with two or more substitutents, they group; a spirocyclic hydrocarbon-carbonyl group; and a ter may be the same or different. Examples of the substitutent pene family hydrocarbon-carbonyl group. In the following, include, for example, a halogenated alkyl-carbonyl group groups represented by the formulas (c)-2A) through (c)-21A) whose examples include, for example, trifluoroacetyl, a halo are similar to those explained above. genated alkyl-sulfonyl group whose examples include, for Examples of the heterocyclic ring in the groups repre 30 example, trifluoromethanesulfonyl, an acyl-oxy group, an sented by the aforementioned formulas (c)-1A) through acyl-sulfanyl group, an N-hydrocarbon-amino group, an (c)-21A) include similar groups to the aforementioned het N,N-di(hydrocarbon)-amino group, an N-heterocyclic ring erocyclic group. Examples of the heterocyclic ring-carbonyl amino group, an N-hydrocarbon-N-heterocyclic ring-amino group represented by the formula (c)-1A) include, for group, an acyl-amino group, and a di(acyl)-amino group. example, a monocyclic heteroaryl-carbonyl group, a fused 35 Moreover, substitution on the aforementioned substitutents polycyclic heteroaryl-carbonyl group, a monocyclic non-aro may be repeated multiple orders. matic heterocyclic ring-carbonyl group, and a fused polycy Examples of the acyl-oxy group include the groups in clic non-aromatic heterocyclic ring-carbonyl group. In the which hydrogen atom of hydroxy group is Substituted with following, groups represented by the formulas (c)-2A) acyl group, and include, for example, formyloxy group, gly through (c)-21A) are similar to those explained above. 40 oxyloyloxy group, thioformyloxy group, carbamoloxy Examples of the cyclic amino in the groups represented by group, thiocarbamoyloxy group, Sulfamoyloxy group, Sulfi the aforementioned formulas (c)-10A) through (c)-16A) namoloxy group, carboxyoxy group, Sulphooxy group, include similar groups to the aforementioned cyclic amino phosphonooxy group, and groups represented by the follow group. ing formulas: In the present specification, when a certain functional 45 group is defined as “which may be substituted, the definition means that the functional group may sometimes have one or (c)-1B) more Substitutents at chemically Substitutable positions, -O-C-Ra, unless otherwise specifically mentioned. Kind of substi tutents, number of substitutents, and the position of substi 50 O tutents existing in the functional groups are not particularly (c)-2B) limited, and when two or more Substitutents exist, they may -O-C-O-Ra2, be the same or different. Examples of the substitutent existing O in the functional group include, for example, halogen atoms, (c)-3B) -O-C-C-Ra2, OXO group, thioxo group, nitro group, nitroso group, cyano 55 || || group, isocyano group, cyanato group, thiocyanato group. O O isocyanato group, isothiocyanato group, hydroxy group, Sul (c)-4B) fanyl group, carboxy group, Sulfanylcarbonyl group, oxalo -O-C-C-O-R, group, methooxalo group, thiocarboxy group, dithiocarboxy || || O O group, carbamoyl group, thiocarbamoyl group, Sulfo group, 60 (c)-5B) Sulfamoyl group, Sulfino group, Sulfinamoyl group, Sulfeno -O-C-S-Ra2, group, Sulfenamoyl group, phosphono group, hydroxyphos phonyl group, hydrocarbon group, heterocyclic group, hydro O (c)-6B) carbon-oxy group, heterocyclic ring-oxy group, hydrocar -O-C-Ra, bon-sulfanyl group, heterocyclic ring-sulfanyl group, acyl 65 group, amino group, hydrazino group, hydrazono group, dia S Zenyl group, ureido group, thioureido group, guanidino US 7,700,655 B2 23 24 "hydrocarbon-carbonyl-oxy group' whose examples -continued include, for example, acetoxy and benzoyloxy, and those groups in which R' is a heterocyclic group are referred to as O-C-O-Ra (a)-7B) "heterocyclic ring-carbonyl-oxy group. Among the groups represented by the formula (c)-2B), S those groups in which R' is a hydrocarbon group are referred O-C-S-Ra (c)-8B) to as “hydrocarbon-oxy-carbonyl-oxy group, and those groups in which R' is a heterocyclic group are referred to as S "heterocyclic ring-oxy-carbonyl-oxy group.” O-C-N-Ra2 (c)-9B) 10 Among the groups represented by the formula (c)-3B), | those groups in which R' is a hydrocarbon group are referred O H to as “hydrocarbon-carbonyl-carbonyl-oxy group, and those O-C-N-Ra2 (c)-10B) groups in which R' is a heterocyclic group are referred to as "heterocyclic ring-carbonyl-carbonyl-oxy group.” E is 15 Among the groups represented by the formula (c)-4B), those groups in which R' is a hydrocarbon group are referred O-C-N-R (c)-11B) to as “hydrocarbon-oxy-carbonyl-carbonyl-oxy group, and | those groups in which R' is a heterocyclic group are referred S H to as "heterocyclic ring-oxy-carbonyl-carbonyl-oxy group.” O-C-N-Ra2 (c)-12B) Among the groups represented by the formula (c)-5B), ls those groups in which R' is a hydrocarbon group are referred (c)-13B) to as “hydrocarbon-sulfanyl-carbonyl-oxy group, and those O groups where R' is a heterocyclic group are referred to as "heterocyclic ring-sulfanyl-carbonyl-oxy group.” -O-S-N-Ra2, | 25 Among the groups represented by the formula (c)-6B). O H those groups in which R' is a hydrocarbon group are referred (c)-14B) to as “hydrocarbon-thiocarbonyl-oxy group, and those O groups where R' is a heterocyclic group are referred to as -O-S-N-R4,a2 "heterocyclic ring-thiocarbonyl-oxy group.” 30 Among the groups represented by the formula (c)-7B). , is those groups in which R' is a hydrocarbon group are referred O-S-N-R (c)-15B) to as “hydrocarbon-oxy-thiocarbonyl-oxy group, and those | groups in which R' is a heterocyclic group are referred to as O H "heterocyclic ring-oxy-thiocarbonyl-oxy group.” 35 Among the groups represented by the formula (co-8B), O-S-N-R (c)-16B) those groups in which R' is a hydrocarbon group are referred , is to as “hydrocarbon-sulfanyl-thiocarbonyl-oxy group, and (c)-17B) those groups wherein R* is a heterocyclic group are referred O to as "heterocyclic ring-Sulfanyl-thiocarbonyl-oxy group.” 40 Among the groups represented by the formula (c)-9B), -O-S-O-R4,a2 those groups in which R' is a hydrocarbon group are referred | to as “N-hydrocarbon-carbamoyl-oxy group, and those O groups in which R' is a heterocyclic group are referred to as O-S-O-Ra2 (c)-18B) “N-heterocyclic ring-carbamoyl-oxy group.” 45 Among the groups represented by the formula (c)-10B), O those groups in which both R" and R'' are hydrocarbon O-Ra2 (c)-19B) groups are referred to as “N,N-di(hydrocarbon)-carbamoyl s oxy group,” those groups in which both R" and R'' are -O-PEO heterocyclic groups are referred to as “N,N-di(heterocyclic -Rs 50 ring)-carbamoyl-oxy group,” those groups in which R“ is a (c)-20B) hydrocarbon group and R is a heterocyclic group are O referred to as “N-hydrocarbon-N-heterocyclic ring-carbam oyl-oxy group,” and those groups in which R* and R' com -O-S-Ra2, bine to each other, together with the nitrogen atom to which O 55 they bind, to form a cyclicic amino group are referred to as “cyclicamino-carbonyl-oxy group.” O-S-Ra2 (c)-21B) Among the groups represented by the formula (c)-11B), those groups in which R' is a hydrocarbon group are referred O to as “N-hydrocarbon-thiocarbamoyl-oxy group, and those 60 groups in which R' is a heterocyclic group are referred to as wherein R* and R' may be the same or different and repre “N-heterocyclic ring-thiocarbamoyl-oxy group.” sent a hydrocarbon group or a heterocyclic group, or R* and Among the groups represented by the formula (c)-12B), R’ combine to each other, together with the nitrogenatom to those groups in which both R' and R'' are hydrocarbon which they bind, to form a cyclic amino group. groups are referred to as “N,N-di(hydrocarbon)-thiocarbam In the definition of the aforementioned acyl-oxy group, 65 oyl-oxy group,” those groups in which both R" and R'' are among the groups represented by the formula (c)-1B), those heterocyclic groups are referred to as “N,N-di(heterocyclic groups in which R' is a hydrocarbon group are referred to as ring)-thiocarbamoyl-oxy group,” those groups in which R' US 7,700,655 B2 25 26 is a hydrocarbon group and R is a heterocyclic group are which R' is a heterocyclic group are referred to as "hetero referred to as “N-hydrocarbon-N-heterocyclic ring-thiocar cyclic ring-Sulfinyl-oxy group.” bamoyl-oxy group,” and those groups in which R" and R' Examples of the hydrocarbon in the groups represented by combine to each other, together with the nitrogen atom to the aforementioned formulas (c)-1B) through (c)-21B) which they bind, to form a cyclic amino group are referred to include the similar groups to the aforementioned hydrocar as “cyclicamino-thiocarbonyl-oxy group.” bon group. Examples of the hydrocarbon-carbonyl-oxy Among the groups represented by the formula (c)-13B), group represented by the formula (c)-1B) include, for those groups in which R' is a hydrocarbon group are referred example, an alkyl-carbonyl-oxy group, an alkenyl-carbonyl to as “N-hydrocarbon-sulfamoyl-oxy group, and those oxy group, an alkynyl-carbonyl-oxy group, a cycloalkyl-car groups in which R' is a heterocyclic group are referred to as 10 “N-heterocyclic ring-Sulfamoyl-oxy group.” bonyl-oxy group, a cycloalkenyl-carbonyl-oxy group, a Among the groups represented by the formula (c)-14B), cycloalkanedienyl-carbonyl-oxy group, and a cycloalkyl those groups in which both R" and R'' are hydrocarbon alkyl-carbonyl-oxy group, which are aliphatic hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl carbonyl-oxy groups; an aryl-carbonyl-oxy group; an oxy group,” those groups in which both R* and R'' are 15 aralkyl-carbonyl-oxy group; a bridged cyclic hydrocarbon heterocyclic groups are referred to as “N,N-di(heterocyclic carbonyl-oxy group; a spirocyclic hydrocarbon-carbonyl ring)-sulfamoyl-oxy group,” those groups in which R" is a oxy group; and a terpene family hydrocarbon-carbonyl-oxy hydrocarbon group and R is a heterocyclic group are group. In the following, groups represented by the formulas referred to as “N-hydrocarbon-N-heterocyclic ring-sulfa (c)-2B) through (co-21B) are similar to those explained above. moyl-oxy group,” and those groups in which R" and R' Examples of the heterocyclic ring in the groups repre combine to each other, together with the nitrogen atom to sented by the aforementioned formulas (c)-1B) through which they bind, to form a cyclic amino group are referred to (c)-21B) include similar groups to the aforementioned het as “cyclic amino-Sulfonyl-oxy group. erocyclic group. Examples of the heterocyclic ring-carbonyl Among the groups represented by the formula (c)-15B), group represented by the formula (c)-1B) include, for those groups in which R' is a hydrocarbon group are referred 25 example, a monocyclic heteroaryl-carbonyl group, a fused to as “N-hydrocarbon-sulfinamoyl-oxy group, and those polycyclic heteroaryl-carbonyl group, a monocyclic non-aro groups where R' is a heterocyclic group are referred to as matic heterocyclic ring-carbonyl group, and a fused polycy “N-heterocyclic ring-Sulfinamoyl-oxy group.” clic non-aromatic heterocyclic ring-carbonyl group. In the Among the groups represented by the formula (c)-16B), following, groups represented by the formulas (c)-2B) those groups in which both R" and R'' are hydrocarbon 30 through (c)-21B) are similar to those groups explained above. groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl Examples of the cyclic amino in the groups represented by oxy group,” those groups in which both R' and R'' are the aforementioned formulas (c)-10B) through (c)-16B) heterocyclic groups are referred to as “N,N-di(heterocyclic include similar groups to the aforementioned cyclic amino ring)-sulfinamoyl-oxy group,” those groups in which R is a group. hydrocarbon group and R is a heterocyclic group are 35 The aforementioned acyl-oxy group, hydrocarbon-oxy referred to as “N-hydrocarbon-N-heterocyclic ring-sulfi group, and heterocyclic-oxy group are generically referred to namoyl-oxy group,” and those groups in which R" and R' as “substituted oxy group.” Moreover, these substituted oxy combine to each other, together with the nitrogen atom to group and hydroxy group are generically referred to as which they bind, to form a cyclic amino group are referred to “hydroxy group which may be substituted.” as “cyclic amino-Sulfinyl-oxy group.” 40 Among the groups represented by the formula (c)-17B). Examples of the acyl-sulfanyl group include the groups in those groups in which R' is a hydrocarbon group are referred which hydrogen atom of Sulfanyl group is substituted with to as “hydrocarbon-oxy-Sulfonyl-oxy group.” and those acyl group, and include, for example, formylsulfanyl group, groups in which R' is a heterocyclic group are referred to as glyoxyloylsulfanyl group, thioformylsulfanyl group, car "heterocyclic ring-oxy-Sulfonyl-oxy group.” 45 bamoyloxy group, thicarbamoyloxy group, Sulfamoyloxy Among the groups represented by the formula (c)-18B), group, Sulfinamoyloxy group, carboxyoxy group, Sulphooxy those groups in which R' is a hydrocarbon group are referred group, phosphonooxy group, and groups represented by the to as “hydrocarbon-oxy-Sulfinyl-oxy group, those groups in following formulas: which R' is a heterocyclic group are referred to as "hetero cyclic ring-oxy-Sulfinyl-oxy group.” 50 Among the groups represented by the formula (c)-19B), (c)-1C) those groups in which both R" and R'' are hydrocarbon -S-C-Rai, groups are referred to as “O,O'-dihydrocarbon)-phosphono O oxy group,” those groups in which both R' and R'' are (c)-2C) heterocyclic groups are referred to as “O,O'-dicheterocyclic 55 -S-C-O-Ra, ring)-phosphono-oxy group.” and those groups in which R' O is a hydrocarbon group and R is a heterocyclic group are (c)-3C) referred to as “O-hydrocarbon substituted-O'-heterocyclic -S-C-C-Ra, ring Substituted phophono-oxy group.” || || O O Among the groups represented by the formula (c)-20B), 60 (c)-4C) those groups in which R' is a hydrocarbon group are referred -S-C-C-O-Ra, to as “hydrocarbon-sulfonyl-oxy group, and those groups in || || which R' is a heterocyclic group referred to as "heterocyclic O O (c)-5C) ring-Sulfonyl-oxy group.” -S-C-S-Ra, Among the groups represented by the formula (c)-21B), 65 those groups in which R' is a hydrocarbon group are referred O to as “hydrocarbon-sulfinyl-oxy group, and those groups in US 7,700,655 B2 27 28 combine to each other, together with the nitrogen atom to -continued which they bind, to form a cyclic amino group which may be S-C-Ra (c)-6C) substituted. In the definition of the aforementioned acyl-sulfanyl S group, among the groups represented by the formula (c)-1C), -7C those groups in which R" is a hydrocarbon group are referred -S-C-O-Ra, (a)-7C) to as “hydrocarbon-carbonyl-Sulfanyl group, and those | S groups in which R" is a heterocyclic group are referred to as -8C "heterocyclic ring-carbonyl-Sulfanyl group.” -S-C-S-Ra, (c)-8C) 10 Among the groups represented by the formula (c)-2C). those groups in which R" is a hydrocarbon group are referred S to as “hydrocarbon-oxy-carbonyl-Sulfanyl group, and those -9C -S-C-N-Ra, (c)-9C) groups in which R" is a heterocyclic group are referred to as | "heterocyclic ring-oxy-carbonyl-Sulfanyl group.” O H 15 Among the groups represented by the formula (c)-3C). those groups in which R" is a hydrocarbon group are referred S-C-N-Ra (c)-10C) to as “hydrocarbon-carbonyl-carbonyl-Sulfanyl group.” and , is those groups in which R" is a heterocyclic group are referred to as "heterocyclic ring-carbonyl-carbonyl-Sulfanyl group.” S-C-N-Ra (c)-11C) Among the groups represented by the formula (c)-4C). | those groups in which R" is a hydrocarbon group are referred S H to as “hydrocarbon-oxy-carbonyl-carbonyl-sulfanyl group.” S-C-N-Ra (c)-12C) and those groups in which R" is a heterocyclic group are referred to as "heterocyclic ring-oxy-carbonyl-carbonyl-sul k 25 fanyl group.” (c)-13C) O Among the groups represented by the formula (c)-5C), -S-S-N-Ra, those groups in which R" is a hydrocarbon group are referred | to as “hydrocarbon-sulfanyl-carbonyl-Sulfanyl group, and O H those groups in which R" is a heterocyclic group are referred 30 (c)-14C) to as "heterocyclic ring-Sulfanyl-carbonyl-Sulfanyl group.” O | Among the groups represented by the formula (co-6C), -S-S-N-Ra, those groups in which R" is a hydrocarbon group are referred , is to as “hydrocarbon-thiocarbonyl-Sulfanyl group, and those 35 groups in which R" is a heterocyclic group are referred to as S-S-N-Ra (c)-15C) "heterocyclic ring-thiocarbonyl-sulfanyl group.” | Among the groups represented by the formula (c)-7C). O H those groups in which R" is a hydrocarbon group are referred to as “hydrocarbon-oxy-thiocarbonyl-Sulfanyl group, and S-S-N-Ra (c)-16C) those groups in which R" is a heterocyclic group are referred I k 40 to as "heterocyclic ring-oxy-thiocarbonyl-Sulfanyl group.” (c)-17C) Among the groups represented by the formula (co-8C). O those groups in which R" is a hydrocarbon group are referred -S-S-O-Ra, to as “hydrocarbon-sulfanyl-thiocarbonyl-sulfanyl group.” | 45 and those groups in which R" is a heterocyclic group are O referred to as "heterocyclic ring-sulfanyl-thiocarbonyl-sulfa S-S-O-Ra3 (c)-18C) nyl group.” Among the groups represented by the formula (c)-9C), O those groups in which R" is a hydrocarbon group are referred O-Ra3 (c)-19C) 50 to as “N-hydrocarbon-carbamoyl-sulfanyl group, and those s groups in which R" is a heterocyclic group are referred to as -S-PEO “N-heterocyclic ring-carbamoyl-sulfanyl group. Among the groups represented by the formula (c)-10C), -R those groups in which both R" and Rare a hydrocarbon (c)-20C) 55 groups are referred to as “N,N-di(hydrocarbon)-carbamoyl O sulfanyl group,” those groups in which both R" and Rare -S-S-Ra, heterocyclic groups are referred to as “N,N-di(heterocyclic ring)-carbamoyl-sulfanyl group, those groups in which R' O is a hydrocarbon group and R' is a heterocyclic group are S-S-Ra3 (c)-21C) 60 referred to as “N-hydrocarbon-N-heterocyclic ring-carbam oyl-sulfanyl group,” and those groups in which R" and R' O combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group are referred to as “cyclicamino-carbonyl-Sulfamoyl group.” wherein R* and R may be the same or different and repre 65 Among the groups represented by the formula (c)-11C), sent a hydrocarbon group which may be substituted or a those groups in which R" is a hydrocarbon group are referred heterocyclic group which may be substituted, or R and R' to as “N-hydrocarbon-thiocarbamoyl-sulfanyl group, and US 7,700,655 B2 29 30 those groups in which R" is a heterocyclic group are referred Among the groups represented by the formula (c)-20C), to as “N-heterocyclic ring-thiocarbamoyl-sulfanyl group.” those groups in which R" is a hydrocarbon group are referred Among the groups represented by the formula (c)-12C), to as “hydrocarbon-sulfonyl-Sulfanyl group, and those those groups in which both R" and R' are hydrocarbon groups in which R" is a heterocyclic group are referred to as groups are referred to as “N,N-di(hydrocarbon)-thiocarbam "heterocyclic ring-Sulfonyl-Sulfanyl group.” oyl-sulfanyl group,” those groups in which and R' and R' Among the groups represented by the formula (c)-21C), are heterocyclic groups are referred to as “N,N-di(heterocy those groups in which R" is a hydrocarbon group are referred clic ring)-thiocarbamoyl-sulfanyl group, those groups in to as “hydrocarbon-sulfinyl-sulfanyl group, and those which R" is a hydrocarbon group and R is a heterocyclic groups in which R" is a heterocyclic group are referred to as group are referred to as “N-hydrocarbon-N-heterocyclic ring 10 "heterocyclic ring-sulfinyl-sulfanyl group.” thiocarbamoyl-sulfanyl group, and those groups in which Examples of the hydrocarbon in the groups represented by RandR combine to each other, together with the nitrogen the aforementioned formulas (c)-1C) through (c)-21C) atom to which they bind, to form a cyclic amino group are include similar groups to the aforementioned hydrocarbon referred to as "cyclicamino-thiocarbonyl-sulfamoyl group.” group. Examples of the hydrocarbon-carbonyl-Sulfanyl Among the groups represented by the formula (c)-13C), 15 group represented by the formula (c)-1C) include, for those groups in which R" is a hydrocarbon group are referred example, an alkyl-carbonyl-Sulfanyl group, an alkenyl-carbo to as “N-hydrocarbon-sulfamoyl-sulfanyl group, and those nyl-Sulfanyl group, an alkynyl-carbonyl-sulfanyl group, a groups in which R" is a heterocyclic group are referred to as cycloalkyl-carbonyl-sulfanyl group, a cycloalkenyl-carbo “N-heterocyclic ring-sulfamoyl-sulfanyl group.” nyl-Sulfanyl group, a cycloalkanedienyl-carbonyl-Sulfanyl Among the groups represented by the formula (c)-14C), group, a cycloalkyl-alkyl-carbonyl-Sulfanyl group which are those groups in which both R" and R are hydrocarbon aliphatic hydrocarbon-carbonyl-Sulfanyl groups; an aryl-car groups are referred to as “N,N-di(hydrocarbon)-sulfamoyl bonyl-Sulfanyl group; an aralkyl-carbonyl-Sulfanyl group; a sulfanyl group,” those groups in which both R" and Rare bridged cyclic hydrocarbon-carbonyl-sulfanyl group; a spiro heterocyclic groups are referred to as “N,N-di(heterocyclic cyclic hydrocarbon-carbonyl-sulfanyl group; and a terpene ring)-sulfamoyl-sulfinyl group,” those groups in which R" is 25 family hydrocarbon-carbonyl-sulfanyl group. In the follow a hydrocarbon group and R is a heterocyclic group are ing, groups represented by the formulas (c)-2C) through referred to as “N-hydrocarbon-N-heterocyclic ring-sulfa (c)-21C) are similar to those explained above. moyl-sulfanyl group,” and those groups in which RandR Examples of the heterocyclic ring in the groups repre combine to each other, together with the nitrogen atom to sented by the aforementioned formulas (c)-1C) through which they bind, to form a cyclic amino group are referred to 30 (c)-21 C) include similar groups to the aforementioned het as “cyclicamino-Sulfonyl-Sulfanyl group.” erocyclic group. Examples of the heterocyclic ring-carbonyl Among the groups represented by the formula (c)-15C), sulfanyl group represented by the formula (c)-1C) include, for those groups in which R" is a hydrocarbon group are referred example, a monocyclic heteroaryl-carbonyl-Sulfanyl group, a to as “N-hydrocarbon-sulfinamoyl-sulfanyl group, and those fused polycyclic heteroaryl-carbonyl-sulfanyl group, a groups in which R" is a heterocyclic group are referred to as 35 monocyclic non-aromatic heterocyclic ring-carbonyl-Sulfa “N-heterocyclic ring-Sulfinamoyl-sulfanyl group. nyl group, and a fused polycyclic non-aromatic heterocyclic Among the groups represented by the formula (c)-16C), ring-carbonyl-Sulfanyl group. In the following, groups repre those groups in which both R" and R' are hydrocarbon sented by the formula (co-2C) through (co-21C) are similar to groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl those groups explained above. sulfanyl group,” those groups in which both R" and Rare 40 Examples of the cyclic amino in the groups represented by heterocyclic groups are referred to as “N,N-di(heterocyclic the aforementioned formulas (c)-10C) through (c)-16C) ring)-sulfinamoyl-sulfanyl group,” those groups in which R' include similar groups to the aforementioned cyclic amino is a hydrocarbon group and R is a heterocyclic group are group. referred to as “N-hydrocarbon-N-heterocyclic ring-sulfi The aforementioned acyl-sulfanyl group, hydrocarbon namoyl-sulfanyl group,” and those groups in which R" and 45 Sulfanyl group, and heterocyclic-sulfanyl group are generi R” combine to each other, together with the nitrogenatom to cally referred to as “substituted sulfanyl group.” Moreover, which they bind, to form a cyclic amino group are referred to these Substituted Sulfanyl group and Sulfanyl group are as “cyclicamino-sulfanyl-Sulfanyl group.” generically referred to as 'sulfanyl group which may be Sub Among the groups represented by the formula (c)-17C). Stituted. those groups in which R" is a hydrocarbon group are referred 50 Examples of the N-hydrocarbon-amino group include the to as “hydrocarbon-oxy-Sulfonyl-Sulfanyl group and those groups in which one hydrogen atom of amino group is Sub groups in which R" is a heterocyclic group are referred to as stituted with a hydrocarbon group, and include, for example, "heterocyclic ring-oxy-Sulfonyl-sulfanyl group.” an N-alkyl-amino group, an N-alkenyl-amino group, an Among the groups represented by the formula (c)-18C), N-alkynyl-amino group, an N-cycloalkyl-amino group, an those groups in which R" is a hydrocarbon group are referred 55 N-cycloalkyl-alkyl-amino group, an N-aryl-amino group, to as “hydrocarbon-oxy-sulfinyl-Sulfanyl group, and those and an N-aralkyl-amino group. groups in which R" is a heterocyclic group are referred to as Examples of the N-alkyl-amino group include, for "heterocyclic ring-oxy-Sulfinyl-Sulfanyl group.” example, methylamino, ethylamino, n-propylamino, isopro Among the groups represented by the formula (c)-19C), pylamino, n-butylamino, isobutylamino, Sec-butylamino, those groups in which both R" and R' are hydrocarbon 60 tert-butylamino, n-pentylamino, isopentylamino, (2-methyl groups are referred to as “O,O'-dihydrocarbon)-phosphono butyl)amino, (1-methylbutyl)amino, neopentylamino, (1.2- sulfanyl group,” those groups in which both R" and Rare dimethylpropyl)amino, (1-ethylpropyl)amino, n-hexy heterocyclic groups are referred to as “O,O'-dicheterocyclic lamino, (4-methylpentyl)amino, (3-methylpentyl)amino, ring)-phosphono-sulfanyl group, and those groups in which (2-methylpentyl)amino, (1-methylpentyl)amino, (3.3-dim R" is a hydrocarbon group andR is a heterocyclic group are 65 ethylbutyl)amino, (2,2-dimethylbutyl)amino, (1,1-dimethyl referred to as “O-hydrocarbon-O'-heterocyclic ring butyl)amino, (1,2-dimethylbutyl)amino, (1,3-dimethylbutyl) phosphono-Sulfanyl group.” amino, (2,3-dimethylbutyl)amino, (2-ethylbutyl)amino,

US 7,700,655 B2 33 34 which R" is a heterocyclic group are referred to as "hetero -continued cyclic ring-carbonyl-amino group.” -8D -N-C-S-Ra', (c)-8D) Among the groups represented by the formula (c)-2D). | || those groups in which R' is a hydrocarbon group are referred H S to as “hydrocarbon-oxy-carbonyl-amino group, and those -9D groups in which R" is a heterocyclic group are referred to as -N-C-N-Ra', (c)-9D) "heterocyclic ring-oxy-carbonyl-amino group.” | | | Among the groups represented by the formula (c)-3D), H. O. H. those groups in which R' is a hydrocarbon group are referred N-C-N-Ra (c)-10D) 10 to as “hydrocarbon-carbonyl-carbonyl-amino group, and s those groups in which R" is a heterocyclic group are referred h I Rb4 to as "heterocyclic ring-carbonyl-carbonyl-amino group.” N-C-N-R (c)-11D) Among the groups represented by the formula (c)-4D), | || | those groups in which R' is a hydrocarbon group are referred H S H 15 to as “hydrocarbon-oxy-carbonyl-carbonyl-amino group.” N-C-N-R (c)-12D) and those groups in which R' is a heterocyclic group are | || | referred to as "heterocyclic ring-oxy-carbonyl-carbonyl H S Rb4 amino group.” (c)-13D) Among the groups represented by the formula (c)-5D). O those groups in which R' is a hydrocarbon group are referred -N-S-N-Ra', to as “hydrocarbon-sulfanyl-carbonyl-amino group, and | || | those groups in which R" is a heterocyclic group are referred H. O. H. to as "heterocyclic ring-Sulfanyl-carbonyl-amino group.” (c)-14D) O Among the groups represented by the formula (c)-6D). 25 those groups in which R' is a hydrocarbon group are referred to as “hydrocarbon-thiocarbonyl-amino group, and those ----e. groups in which R" is a heterocyclic group are referred to as H. O. Rb "heterocyclic ring-thiocarbonyl-amino group.” N-S-N-Ra (c)-15D) Among the groups represented by the formula (a)-7D). | || | 30 those groups in which R' is a hydrocarbon group are referred H. O. H. to as “hydrocarbon-oxy-thiocarbonyl-amino group, and those groups in which R" is a heterocyclic group are referred N-S-N-R (c)-16D) to as "heterocyclic ring-oxy-thiocarbonyl-amino group.” | || | H. O. Rb Among the groups represented by the formula (co-8D), (c)-17D) 35 those groups in which R' is a hydrocarbon group are referred O to as “hydrocarbon-sulfanyl-thiocarbonyl-amino group, and | -N-S-O-Ra', those groups in which R" is a heterocyclic group are referred | || to as "heterocyclic ring-Sulfanyl-thiocarbonyl-amino group.” H. O Among the groups represented by the formula (c)-9D). 40 those groups in which R' is a hydrocarbon group are referred N-S-O-Ra (c)-18D) to as “N-hydrocarbon-carbamoyl group.” and those groups in | || which R" is a heterocyclic group are referred to as “N-het H. O erocyclic ring-carbamoyl-amino group.” O-Ra (c)-19D) s Among the groups represented by the formula (co-10D). 45 those groups in which both R* and R are hydrocarbon groups are referred to as “N,N-di(hydrocarbon)-carbamoyl ---oH O-Rb amino group,” those groups in which both R* and R are (c)-20D) heterocyclic groups are referred to as “N,N-di(heterocyclic O ring)-carbamoyl-amino group,” those groups in which R is -N-S-Ra', 50 a hydrocarbon group and R' is a heterocyclic group are | || referred to as “N-hydrocarbon-N-heterocyclic ring-carbam H. O oyl-amino group,” and those groups in which R* and R' N-S-Ra (c)-21D) combine to each other, together with the nitrogen atom to | || which they bind, to form a cyclic amino group are referred to H. O 55 as “cyclic amino-carbonyl-amino group.” Among the groups represented by the formula (c)-11D). those groups in which R' is a hydrocarbon group are referred wherein R* and R may be the same or different and repre to as “N-hydrocarbon-thiocarbamoyl-amino group, and sent a hydrocarbon group which may be substituted or a those groups in which R" is a heterocyclic ring group are heterocyclic group which may be substituted, or R'' and R' 60 referred to as “N-heterocyclic-thiocarbamoyl-amino group.” combine to each other, together with the nitrogen atom to Among the groups represented by the formula (c)-12D). which they bind, to form a cyclic amino group which may be those groups in which both R'' and R'' are hydrocarbon substituted. groups are referred to as “N,N-di(hydrocarbon)-thiocarbam In the definition of the aforementioned acyl-amino group, oyl-amino group,” those groups in which both RandR'' are among the groups represented by the formula (c)-1D), those 65 heterocyclic groups are referred to as “N,N-di(heterocyclic groups in which R" is a hydrocarbon group are referred to as ring)-thiocarbamoyl-amino group, those groups in which "hydrocarbon-carbonyl-amino group, and those groups in R" is a hydrocarbon group andR is a heterocyclic group are US 7,700,655 B2 35 36 referred to as “N-hydrocarbon-N-heterocyclic ring-thiocar in which R" is a heterocyclic group are referred to as "het bamoyl-amino group,” and those groups in which RandR erocyclic ring-Sulfinyl-amino group.” combine to each other, together with the nitrogen atom to Examples of the hydrocarbon in the groups represented by which they bind, to form a cyclic amino group are referred to the aforementioned formulas (c)-1D) through (co-21D) as “cyclic amino-thiocarbonyl-amino group. include the similar groups to the aforementioned hydrocar Among the groups represented by the formula (c)-13D), bon group. Examples of the hydrocarbon-carbonyl-amino those groups in which R' is a hydrocarbon group are referred groups represented by the formula (c)-1D) include, for to as “N-hydrocarbon-sulfamoyl-amino group, and those example, an alkyl-carbonyl-amino group, an alkenyl-carbo groups in which R" is a heterocyclic group are referred to as nyl-amino group, an alkynyl-carbonyl-amino group, a “N-heterocyclic ring-Sulfamoyl-amino group.” 10 cycloalkyl-carbonyl-amino group, a cycloalkenyl-carbonyl Among the groups represented by the formula (c)-14D), those groups in which both R" and R are hydrocarbon amino group, a cycloalkanedienyl-carbonyl-amino group, a groups are referred to as “di(hydrocarbon)-sulfamoyl-amino cycloalkyl-alkyl-carbonyl-amino group which are aliphatic group,” those groups in which both R'' and R'' are hetero hydrocarbon-carbonyl-amino groups; an aryl-carbonyl cyclic groups are referred to as “N,N-di(heterocyclic ring)- 15 amino group; an aralkyl-carbonyl-amino group; a bridged sulfamoyl-amino group,” those groups in which R is a cyclic hydrocarbon-carbonyl-amino group; a spiro cyclic hydrocarbon group and R is a heterocyclic group are hydrocarbon-carbonyl-amino group; and a terpene family referred to as “N-hydrocarbon-N-heterocyclic ring-sulfa hydrocarbon-carbonyl-amino group. In the following, groups moyl-amino group,” and those groups in which R* and R' represented by the formulas (co-2D) through (c)-21D) are combine to each other, together with the nitrogen atom to similar to those explained above. which they bind, to form a cyclic amino group are referred to Examples of the heterocyclic ring in the groups repre as “cyclic amino-Sulfonyl-amino group.” sented by the aforementioned formulas (c)-1D) through Among the groups represented by the formula (c)-15D), (c)-21D) include similar groups to the aforementioned het those groups in which R' is a hydrocarbon group are referred erocyclic group. Examples of the heterocyclic ring-carbonyl to as “N-hydrocarbon-sulfinamoyl-amino group, and those 25 amino group represented by the formula (c)-1D) include, for groups in which R" is a heterocyclic group are referred to as example, a monocyclic heteroaryl-carbonyl-amino group, a “N-heterocyclic ring-Sulfinamoyl-amino group.” fused polycyclic heteroaryl-carbonyl-amino group, a mono Among the groups represented by the formula (c)-16D), cyclic non-aromatic heterocyclic-carbonyl-amino group, and those groups in which both R" and R'' are hydrocarbon a fused polycyclic non-aromatic heterocyclic-carbonyl groups are referred to as “N,N-di(hydrocarbon)-sulfinamoyl 30 amino group,” those groups in which both R* and R'' are amino group. In the following, groups represented by the heterocyclic groups are referred to as “N,N-di(heterocyclic formulas (c)-2D) through (c)-21D) are similar to those groups ring)-sulfinamoyl-amino group.” groups in which R" is a explained above. hydrocarbon group and R is a heterocyclic group are Examples of the cyclic amino in the groups represented by referred to as “N-hydrocarbon-N-heterocyclic ring-sulfi 35 the aforementioned formulas (co-10D) through (c)-16D) namoyl-amino group,” and those groups in which RandR include similar groups to the aforementioned cyclic amino combine to each other, together with the nitrogen atom to group. which they bind, to form a cyclic amino group are referred to Examples of the di(acyl)-amino group include the groups as “cyclic amino-Sulfinyl-amino group.” in which two hydrogenatoms of amino group are Substituted Among the groups represented by the formula (c)-17D), 40 with acyl groups in the definitions of the aforementioned those groups in which R' is a hydrocarbon group are referred substitutents according to “which may be substituted.” to as “hydrocarbon-oxy-Sulfonyl-amino group, and those Examples include, for example, di(formyl)-amino group, groups in which R" is a heterocyclic group are referred to as di(glyoxyloyl)-amino group, di(thioformyl)-amino group, "heterocyclic ring-oxy-Sulfoyl-amino group.” di(carbamoyl)-amino group, di(thiocarbamoyl)-amino Among the groups represented by the formula (c)-18D), 45 group, di(sulfamoyl)-amino group, di(sulfinamoyl)-amino those groups in which R' is a hydrocarbon group are referred group, di(carboxy)-amino group, di(Sulfo)-amino group, to as “hydrocarbon-oxy-Sulfinyl-amino group, and those di(phosphono)-amino group, and groups represented by the groups in which R" is a heterocyclic group are referred to as following formulas: "heterocyclic ring-oxy-Sulfinyl-amino group.” Among the groups represented by the formula (c)-19D), 50 those groups in which both R" and R'' are hydrocarbon (c)-1E) groups are referred to as “O,O'-dihydrocarbon)-phosphono -N-HC-Ra V, amino group,” those groups in which both R* and R'' are heterocyclic groups are referred to as “O,O'-dicheterocyclic | 2 ring)-phosphono-amino group, and those groups in which 55 (c)-2E) R“is a hydrocarbon group andR is a heterocyclic group are -N-F-C-O-Ras Y, referred to as “O-hydrocarbon-O'-heterocyclic ring I phosphono-amino group.” 2 Among the groups represented by the formula (c)-20D), (c)-3E) those groups in which R' is a hydrocarbon group are referred 60 -N-H-C-C-Ras to as “hydrocarbon-sulfonyl-amino group, and those groups )2 in which R" is a heterocyclic group are referred to as “het (c)-4E) erocyclic ring-Sulfonyl-amino group.” -N-A-C-C-O-Ras Y, Among the groups represented by the formula (c)-21D), 65 those groups in which R' is a hydrocarbon group are referred i-r)2 to as “hydrocarbon-sulfinyl-amino group, and those groups US 7,700,655 B2 37 38

-continued -continued (c)-5E) (c)-20E) O -N i-r) -N-HS-Ras , 2 O 2 (c)-21E) -N-HS-Ras 10 O 2

wherein R* and R may be the same or different and repre 15 sent hydrogen atom, a hydrocarbon group which may be Substituted or a heterocyclic group which may be substituted, or R and R' combine to each other, together with the nitrogen atom to which they bind, to form a cyclic amino group which may be substituted. In the definition of aforementioned di(acyl)-amino group, among the groups represented by the formula (c)-1E), those (c)-10E) groups in which R" is a hydrocarbon group are referred to as “bis(hydrocarbon-carbonyl)-amino group, and those groups in which R" is a heterocyclic group are referred to as “bis 25 (heterocyclic ring-carbonyl)-amino group.” (c)-11E) Among the groups represented by the formula (c)-2E). those groups in which R" is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-carbonyl)-amino group, and those groups in which R" is a heterocyclic group are referred (c)-12E) 30 to as “bis(heterocyclic ring-oxy-carbonyl)-amino group.” Among the groups represented by the formula (c)-3E), those groups in which R" is a hydrocarbon group are referred to as “bis(hydrocarbon-carbonyl-carbonyl)-amino group.” (c)-13E) and those groups in which R" is a heterocyclic group are 35 referred to as “bis(heterocyclic ring-carbonyl-carbonyl)- amino group.” Among the groups represented by the formula (c)-4E), those groups in which R" is a hydrocarbon group are referred (c)-14E) to as "bis(hydrocarbon-oxy-carbonyl-carbonyl)-amino 40 group,” and those groups in which R" is a heterocyclic group are referred to as “bis(heterocyclic ring-oxy-carbonyl-carbo nyl)-amino group.” Among the groups represented by the formula (c)-5E), those groups in which R" is a hydrocarbon group are referred (c)-15E) 45 to as “bis(hydrocarbon-sulfanyl-carbonyl)-amino group.” and those groups in which R" is a heterocyclic group are referred to as “bis(heterocyclic ring-sulfanyl-carbonyl)- amino group.” (c)-16E) Among the groups represented by the formula (c)-6E), 50 those groups in which R" is a hydrocarbon group are referred to as “bis(hydrocarbon-thiocarbonyl)-amino group, and those groups in which R" is a heterocyclic group are referred (c)-17E) to as “bis(heterocyclic ring-thiocarbonyl)-amino group.” Among the groups represented by the formula (c)-7E), 55 those groups in which R" is a hydrocarbon group are referred to as “bis(hydrocarbon-oxy-thiocarbonyl)-amino group, and those groups in which R" is a heterocyclic group are referred (c)-18E) to as “bis(heterocyclic ring-oxy-thiocarbonyl)-amino group.” Among the groups represented by the formula (c)-8E). 60 those groups in which R" is a hydrocarbon group are referred to as “bis(hydrocarbon-sulfanyl-thiocarbonyl)-amino (c)-19E) group,” and those groups in which R" is a heterocyclic group are referred to as “bis(heterocyclic ring-sulfanyl-thiocarbo nyl)-amino group.” 65 Among the groups represented by the formula (c)-9E). those groups in which R" is a hydrocarbon group are referred to as “bis(N-hydrocarbon-carbamoyl)-amino group, and US 7,700,655 B2 39 40 those groups in which R" is a heterocyclic group are referred Among the groups represented by the formula (c)-17E), to as “bis(N-heterocyclic ring-carbamoyl)-amino group.” those groups in which R" is a hydrocarbon group are referred Among the groups represented by the formula (c)-10E), to as "bis(hydrocarbon-oxy-Sulfonyl)-amino group, and those groups in which both R" and R are hydrocarbon those groups in which R" is a heterocyclic group are referred groups are referred to as “bis N,N-di(hydrocarbon)-carbam to as “bis(heterocyclic ring-oxy-Sulfonyl)-amino group.” oyl-amino group,” those groups in which both R" and R' Among the groups represented by the formula (c)-18E). are heterocyclic groups are referred to as “bisN,N-di(hetero those groups in which R" is a hydrocarbon group are referred cyclic ring)-carbamoyl-amino group.” groups in which R' to as “bis(hydrocarbon-oxy-sulfinyl)-amino group, and is a hydrocarbon group and R is a heterocyclic group are those groups in which R" is a heterocyclic group are referred referred to as “bis(N-hydrocarbon-N-heterocyclic ring-car 10 to as “bis(heterocyclic ring-oxy-Sulfinyl)-amino group.” bamoyl)-amino group,” and those groups in which R" and Among the groups represented by the formula (c)-19E). R” combine to each other, together with the nitrogenatom to those groups in which both R" and R are hydrocarbon which they bind, to form a cyclic amino groups are referred to groups are referred to as “bisO.O'-dichydrocarbon)- as “bis(cyclic amino-carbonyl)amino group.” phosphono-amino group,” those groups in which both R' Among the groups represented by the formula (c)-11E), 15 and Rare heterocyclic groups are referred to as “bis(O,O'- those groups in which R" is a hydrocarbon group are referred di(heterocyclic ring)-phosphono-amino group, and those to as “bis(N-hydrocarbon-thiocarbamoyl)-amino group, and groups in which R" is a hydrocarbon group and R is a those groups in which R" is a heterocyclic group are referred heterocyclic group are referred to as “bis(O-hydrocarbon-O'- to as “bis(N-heterocyclic ring-thiocarbamoyl)-amino group.” heterocyclic ring-phosphono)-amino group. Among the groups represented by the formula (c)-12E), Among the groups represented by the formula (c)-20E). those groups in which both R" and R are hydrocarbon those groups in which R" is a hydrocarbon group are referred groups are referred to as “bisN,N-di(hydrocarbon)-thiocar to as “bis(hydrocarbon-sulfonyl)-amino group, and those bamoyl-amino group,” those groups in which both R" and groups in which R" is a heterocyclic group are referred to as R" are heterocyclic groups are referred to as “bisN,N-di “bis(heterocyclic ring-Sulfonyl)-amino group.” (heterocyclic ring)-thiocarbamoyl-amino group, those 25 Among the groups represented by the formula (c)-21E), groups in which R" is a hydrocarbon group and R is a those groups in which R" is a hydrocarbon group are referred heterocyclic group are referred to as “bis(N-hydrocarbon-N- to as “bis(hydrocarbon-sulfinyl)-amino group, and those heterocyclic ring-thiocarbamoyl)-amino group, and those groups in which R" is a heterocyclic group are referred to as groups in which RandR' combine to each other, together “bis(heterocyclic ring-sulfinyl)-amino group.” with the nitrogen atom to which they bind, to form a cyclic 30 Examples of the hydrocarbon in the groups represented by amino group are referred to as “bis(cyclic amino-thiocarbo the aforementioned formulas (c)-1E) through (c)-21E) nyl)-amino group.” include the similar groups to the aforementioned hydrocar bon group. Examples of the bis(hydrocarbon-carbonyl)- Among the groups represented by the formula (c)-13E), amino groups represented by the formula (c)-1E) include, for those groups in which R" is a hydrocarbon group are referred 35 example, a bis(alkyl-carbonyl)-amino group, a bis(alkenyl to as "bis(N-hydrocarbon-sulfamoyl)-amino group, and carbonyl)-amino group, a bis(alkynyl-carbonyl)-amino those groups in which R" is a heterocyclic group are referred group, a bis(cycloalkyl-carbonyl)-amino group, a bis(cy to as “bis(N-heterocyclic ring-Sulfamoyl)-amino group.” cloalkenyl-carbonyl)-amino group, a bis(cycloalkanedienyl Among the groups represented by the formula (c)-14E), carbonyl)-amino group, a bis(cycloalkyl-alkyl-carbonyl)- those groups in which both R" and R are hydrocarbon 40 amino group which are bis(aliphatic hydrocarbon-carbonyl)- groups are referred to as “bisN,N-di(hydrocarbon)-sulfa amino groups; a bis(aryl-carbonyl)-amino group; a bis moyl-amino group,” those groups in which both R" and R' (aralkyl-carbonyl)-amino group; a bis(bridged cyclic are heterocyclic groups are referred to as “bisN,N-di(hetero hydrocarbon-carbonyl)-amino group; a bis(spiro cyclic cyclic ring)-Sulfamoyl-amino group, those groups in which hydrocarbon-carbonyl)-amino group; and a bis(terpene fam R" is a hydrocarbon group andR is a heterocyclic group are 45 ily hydrocarbon-carbonyl)-amino group. In the following, referred to as “bis(N-hydrocarbon-N-heterocyclic ring-sulfa groups represented by the formulas (c)-2E) through (c)-21E) moyl)-amino group,” and those groups in which R" and R' are similar to those explained above. combine to each other, together with the nitrogen atom to Examples of the heterocyclic ring in the groups repre which they bind, to form a cyclic amino group are referred to sented by the aforementioned formulas (c)-1E) through as “bis(cyclic amino-Sulfonyl)amino group.” 50 (c)-21E) include similar groups to the aforementioned hetero Among the groups represented by the formula (c)-15E), cyclic group. Examples of the bis(heterocyclic ring-carbo those groups in which R" is a hydrocarbon group are referred nyl)-amino group represented by the formula (c)-1E) include, to as "bis(N-hydrocarbon-sulfinamoyl)-amino group, and for example, a bis(monocyclic heteroaryl-carbonyl)-amino those groups in which R" is a heterocyclic group are referred group, a bis(fused polycyclic heteroaryl-carbonyl)-amino to as “bis(N-heterocyclic ring-Sulfinamoyl)-amino group.” 55 group, a bis(monocyclic non-aromatic heterocyclic-carbo Among the groups represented by the formula (c)-16E), nyl)-amino group, and a bis(fused polycyclic non-aromatic those groups in which R" and Rare hydrocarbon groups heterocyclic-carbonyl)-amino group. In the following, are referred to as “bis N,N-di(hydrocarbon)-sulfinamoyl groups represented by the formulas (c)-2E) through (c)-21E) amino group,” those groups in which Rand Rare hetero are similar to those groups explained above. cyclic groups are referred to as “bis N,N-di(heterocyclic 60 Examples of the cyclic amino in the groups represented by ring)-sulfinamoyl-amino group,” those groups in which R' the aforementioned formulas (co-1 OE) through (c)-16E) is a hydrocarbon group and R is a heterocyclic group are include similar groups to the aforementioned cyclic amino referred to as “bis(N-hydrocarbon-N-heterocyclic ring-sulfi group. namoyl)-amino group,” and those groups in which R" and The aforementioned acyl-amino group and di(acyl)-amino R” combine to each other, together with the nitrogenatom to 65 group are generically referred to as 'acyl Substituted amino which they bind, to form a cyclic amino group are referred to group.” Furthermore, the aforementioned N-hydrocarbon as “bis(cyclic amino-Sulfinyl)amino group.” amino group, N,N-di(hydrocarbon)-amino group, N-hetero US 7,700,655 B2 41 42 cyclic-amino group, N-hydrocarbon-N-heterocyclic-amino group, cyclic amino group, acyl-amino group, and di(acyl)- -continued amino group are generically referred to as “substituted amino group.” In the following, compounds represented by the aforemen -C-N-C-C-, -C-C-C-, tioned general formula (I) are explained in details. | | | | | "Connecting group whose number of atoms of main chain O H. H. H. O H. H. is 2 to 5’ in the definition of X means connecting groups wherein 2 to 5 atoms in a main chain link together between 10 H H O rings Z and E. The aforementioned “number of atoms of the -C-C=C-, -C=C-, -S-N-, main chain' is counted so as to minimize the number of | | connecting atoms existing between the rings Zand E. regard O H H O H less of the presence or absence of hetero atom(s). For O H example, the number of atoms of 1.2-cyclopentylene is 15 counted as 2, the number of atoms of 1.3-cyclopentylene is -N-C-, -N-S-, -C-N-, counted as 3, the number of atoms of 1,4-phenylene is | || | || counted as 4, and the number of atoms of 2,6-pyridine-diyl is H. O H. O H. H. counted as 3. | The aforementioned “connecting group whose number of -C-N-N=C-, -C-N-C-C-N-, atoms of main chain is 2 to 5’ is formed by one functional | | | | || | group selected from the following group of divalent group O H H O H. H. O. H -1, or formed by combining 2 to 4 functional groups of 1 to -C=N-N-C-, -N-C-N-, 4 kinds selected from the following divalent group C-2. || 25 H H. O H. O. H. Divalent group C-1 the following formulas: -C-N-N-C-, -C-N-N-C- | | | || | | | | --- - CEC O H H O O H. H. H. 30 H H -C-O-, -C-N-N-, -C=N-N-, - CEN- -NEN- -N= o | O O H. H. H H H O H O 35 S N Divalent group C-2 the following formulas: X--N 1.-- O H. O N H O -O- -S- -S- -S- 40 O O wherein a bond at the left end binds to ring Z and a bond at the right end binds to E. -C-| -C- - C- -C- 45 The group represented by the following formula is most H O S N-H preferred: --- -CEC- --- H. H. H -C-N-

-- -NEN- --- 50 O H H O

When 2 or more divalent groups combine, each group may be wherein the bond at the left end binds to ring Z and the bond the same or different. 55 at the right end binds to E. The aforementioned “connecting group wherein the num Examples of the Substitutent, according to “connecting ber of atoms of the main chain is 2 to 5’ is preferably a group group which may be substituted in the definition of “a con selected from the following “connecting group C. necting group whose number of atoms of the main chain is 2 to 5, include similar groups to the substitutents in the defi Connecting group C, the following formulas: 60 nition of the aforementioned “which may be substituted. A C to C alkyl group is preferred, and a methyl group is more preferred. The substitutent may combine with a substitutent of the ring E or Z, together with atoms to which they bind, to -C-N-, -C-N- 65 form a cyclic group which may be substituted. Examples O H O H include the compounds represented by the general formula (I) being those represented by the following formulas: US 7,700,655 B2 43 44 the same meaning as that defined above' is more preferred. CF Preferred examples of said substitutents include groups selected from the following Substituent Group Y-1Z. Halogen OH O atom and tert-butyl group (1,1-dimethyl)ethyl group are 5 more preferred, and halogen atom is most preferred. Substituent Group Y-1Z halogen atom, nitro group, cyano N group, hydroxy group, methoxy group, methyl group, isopro pyl group, tert-butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethen-1-yl group, 2,2-dicyanoethen-1-yl group, 10 2-cyano-2-(methoxycarbonyl)ethen-1-yl group, 2-carboxy Br 2-cyanoethen-1-yl group, ethynyl group, phenylethynyl O group, (trimethylsilyl)ethynyl group, trifluoromethyl group, N O pentafluoroethyl group, phenyl group, 4-(trifluoromethyl) phenyl group, 4-fluorophenyl group, 2,4-difluorophenyl 15 group, 2-phenethyl group, 1-hydroxyethyl group, 1-(meth OH O oxyimino)ethyl group, 1-(benzyloxy)iminoethyl group, 2-thienyl group thiophen-2-yl group, 3-thienyl group thiophen-3-yl group. 1-pyrrolyl group pyrrol-1-yl group. N 2-methylthiazol-4-yl group, imidazol-2-alpyridin-2-yl group, 2-pyridyl group pyridin-2-yl group, acetyl group, H 2O isobutyryl group, piperidinocarbonyl group, 4-benzylpiperi dinocarbonyl group, (pyrrol-1-yl)sulfonyl group, carboxy Br group, methoxycarbonyl group, N-3,5-bis(trifluoromethyl) phenylcarbamoyl group, N,N-dimethylcarbamoyl group, In the aforementioned general formula (I), examples of A sulfamoyl group, N-3,5-bis(trifluoromethyl)phenylsulfa include hydrogenatom or acetyl group, and hydrogenatom is 25 moyl group, N,N-dimethylsulfamoyl group, amino group, preferred. N,N-dimethylamino group, acetylamino group, benzoy Examples of the “arene' in “an arene which may have one lamino group, methanesulfonylamino group, benzenesulfo or more Substitutents in addition to the group represented by nylamino group, 3-phenylureido group, (3-phenyl)thioureido formula —O-A wherein A has the same meaning as that group, (4-nitrophenyl)diazenyl group, and {4-(pyridin-2-yl) defined above and the group represented by formula —X-E 30 sulfamoylphenyldiazenyl group wherein each of X and E has the same meaning as that defined When “an arene which may have one or more substitutents above in the definition of ring Z include a monocyclic or in addition to the group represented by formula —O-A fused heterocyclic aromatic hydrocarbon, and include, for example, benzene ring, naphthalene ring, anthracene ring, wherein A has the same meaning as that defined above and the phenanthrene ring, and acenaphylene ring. C to Co arenes 35 group represented by formula—X-E wherein each of X and Such as benzene ring, naphthalene ring and the like are pre E has the same meaning as that defined above' in the afore ferred, benzene ring and naphthalene ring are more preferred, mentioned definition of ring Z is “a benzene ring which may and benzene ring is most preferred. have one or more Substitutents in addition to the group rep Examples of the substitutent in the definition of “an arene resented by formula—O-A wherein A has the same meaning which may have one or more substitutents in addition to the 40 as that defined above and the group represented by formula group represented by formula—O-A wherein A has the same —X-E wherein each of X and E has the same meaning as that meaning as that defined above and the group represented by defined above. it is most preferable that one substitutent formula—X-E wherein each of X and E has the same mean exists and locates on the position of R when the following ing as that defined above' in the aforementioned definition of partial formula (IZ-1) in the general formula containing ringZ ring Zinclude similar groups to the substitutent explained for 4s the definition “which may be substituted.” The position of (IZ-1) Substitutents existing on the arene is not particularly limited, No and when two or more substitutents exist, they may be the same or different. N When “an arene which may have one or more substitutents 50 in addition to the group represented by formula —O-A wherein Ahas the same meaning as that defined above and the group represented by formula—X-E wherein each of X and is represented by the following formula (IZ-2). E has the same meaning as that defined above' in the afore mentioned definition of ring Z is “a benzene ring which may have one or more Substitutents in addition to the group rep 55 (IZ-2) resented by formula—O-A wherein A has the same meaning No as that defined above and the group represented by formula —X-E wherein each of X and E has the same meaning as that defined above.” “a benzene ring which has one to three sub stitutents in addition to the group represented by formula 60 —O-A wherein A has the same meaning as that defined above and the group represented by formula—X-E wherein each of X and E has the same meaning as that defined above' is preferred, and “a benzene ring which has one substitutent in addition to the group represented by formula—O-A wherein 65 A has the same meaning as that defined above and the group At this time, said substitutents can be defined as R. Preferred represented by formula —X-E wherein each of X and E has examples of R include a group selected from the following US 7,700,655 B2 45 46 Substituent Group Y-2Z. Halogen atom and tert-butyl group acridine ring, phenoxazine ring, phenothiazine ring, phena are more preferred, and halogen atom is most preferred. Zine ring, phenanthridine ring, phenanthroline ring, thian Substituent Group Y-2Z halogen atom, nitro group, cyano threne ring, indolizine ring, and phenoxathiine ring, which group, methoxy group, methyl group, isopropyl group, tert are 5 to 14-membered monocyclic or fused polycyclic aro butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethen matic heterocyclic rings. 5 to 13-membered monocyclic or 1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2-(meth fused polycyclic aromatic heterocyclic rings are preferred, oxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1- and thiophene ring, pyridine ring, indole ring, quinoxaline yl group, ethynyl group, phenylethynyl group, ring, and carbazole ring are more preferred. (trimethylsilyl)ethynyl group, trifluoromethyl group, pen Examples of the substitutent in the definition of “a hetero tafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl 10 arene which may have one or more Substitutents in addition to group, 4-fluorophenyl group, 2,4-difluorophenyl group, the group represented by formula —O-A wherein A has the 2-phenethyl group, 1-hydroxyethyl group, 1-(methoxy same meaning as that defined above and the group repre imino)ethyl group, 1-(benzyloxy)iminoethyl group, 2-thie sented by formula —X-E wherein each of X and E has the nyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthi same meaning as that defined above' in the aforementioned azol-4-yl group, imidazol-2-alpyridin-2-yl group, 2-pyridyl 15 definition of ring Zinclude similar groups to the Substitutent group, acetyl group, isobutyryl group, piperidinocarbonyl explained for the aforementioned definition “which may be group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sul substituted.” The position of substitutents existing on the fonyl group, carboxy group, methoxycarbonyl group, N-3, hetero arene is not particularly limited, and when two or more 5-bis(trifluoromethyl)phenylcarbamoyl group, N,N-dimeth substitutents exist, they may be the same or different. ylcarbamoyl group, Sulfamoyl group, N-3,5-bis Halogenatoms are preferred as the substitutent in the defi (trifluoromethyl)phenylsulfamoyl grOup, N,N- nition of “a hetero arene which may have one or more sub dimethylsulfamoyl group, amino group, N,N-dimethylamino stitutents in addition to the group represented by formula group, acetylamino group, benzoylamino group, methane —O-A wherein A has the same meaning as that defined above Sulfonylamino group, benzenesulfonylamino group, 3-phe and the group represented by formula—X-E wherein each of nylureido group, (3-phenyl)thioureido group, (4-nitrophenyl) 25 X and E has the same meaning as that defined above' in the diazenyl group, and {4-(pyridin-2-yl)sulfamoyl aforementioned definition of ring Z. phenyldiazenyl group Examples of the aryl group of “an aryl group which may be substituted in the definition of E include similar groups to the When “an arene which may have one or more substitutents aryl group in the definition of the aforementioned “hydrocar in addition to the group represented by formula —O-A 30 bon group, and C to Co aryl groups such as phenyl group, wherein Ahas the same meaning as that defined above and the 1-naphthyl group, 2-naphthyl group and the like are pre group represented by formula —X-E wherein each of X and ferred, and phenyl group is most preferred. E has the same meaning as that defined above' in the afore Examples of the substitutent in the definition of “an aryl mentioned definition of ring Z is “a naphthalene ring which group which may be substituted in the definition of E include may have one or more Substitutents in addition to the group 35 similar groups to the substitutent explained for the definition represented by formula—O-A wherein Ahas the same mean “which may be substituted.” The position of substitutents ing as that defined above and the group represented by for existing on the aryl group is not particularly limited, and mula —X-E wherein each of X and E has the same meaning when two or more substitutents exist, they may be the same or as that defined above.” naphthalene ring is preferred. different. Examples of the "hetero arene' in “a hetero arene which 40 When “an aryl group which may be substituted in the may have one or more Substitutents in addition to the group aforementioned definition of E is “a phenyl group which may represented by formula—O-A wherein Ahas the same mean be substituted,” “a mono-substituted phenyl group,” “a di ing as that defined above and the group represented by for Substituted phenyl group, and “a phenyl group which has mula —X-E wherein each of X and E has the same meaning three or more substitutents' are preferred, and “a di-substi as that defined above' in the aforementioned definition of ring 45 tuted phenyl group' is more preferred. Z include a monocyclic or a fused polycyclic aromatic het When “an aryl group which may be substituted in the erocyclic rings containing at least one of 1 to 3 kinds of aforementioned definition of E is “a di-substituted phenyl heteroatoms selected from oxygen atom, Sulfur atom and group. preferred examples of the group include groups rep nitrogen atom and the like as ring-constituting atoms (ring resented by the following Substituent Group 6-1e. forming atoms), and include, for example, furan ring, 50 thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, Substituent Group 6-1e 3,5-bis(trifluoromethyl)phenyl thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, group, 3,4-propylenedioxyphenyl group, 3,5-dichlorophenyl 1.2.3-oxadiazole ring, 1,2,3-thiadiazole ring, 1,2,3-triazole group, 2,4-dihydroxyphenyl group, 2,5-dimethoxyphenyl ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine group, 2-chloro-5-(trifluoromethyl)phenyl group, 3.5-bis(1, ring, 1,2,3-triazine ring, 1,2,4-triazine ring, 1 H-azepine ring, 55 1-dimethyl)ethylphenyl group, 2,5-bis(trifluoromethyl)phe 1,4-oxepine ring, 1.4-thiazepine ring, benzofuran ring, nyl group, 4-chloro-2-(trifluoromethyl)phenyl group, isobenzofuran ring, benzobthiophene ring, benzoc 2-fluoro-3-(trifluoromethyl)phenyl group, 4-fluoro-3-(trif thiophene ring, indole ring, 2H-isoindole ring, 1H-indazole luoromethyl)phenyl group, 4-chloro-3-(trifluoromethyl)phe ring, 2H-indazole ring, benzoxazole ring, 1.2-benzisoxazole nyl group, 3-fluoro-5-(trifluoromethyl)phenyl group, ring, 2.1-benzisoxazole ring, benzothiazole ring, 1,2-ben 60 3-bromo-5-(trifluoromethyl)phenyl group, 2-fluoro-5-(trif Zisothiazole ring, 2.1-benzisothiazole ring, 1.2.3-benzoxa luoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phe diazol ring, 2.1,3-benzoxadiazol ring, 1,2,3-benzothiadiazole nyl group, 2-nitro-5-(trifluoromethyl)phenyl group, 4-cyano ring, 2,1,3-benzothiadiazole ring, 1 H-benzotriazole ring, 3-(trifluoromethyl)phenyl grOup, 2-methyl-3- 2H-benzotriazole ring, quinoline ring, isoquinoline ring, cin (trifluoromethyl)phenyl group, 4-methyl-3-(trifluoromethyl) noline ring, quinazoline ring, quinoxaline ring, phthalazine 65 phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, ring, naphthyridine ring, 1H-1,5-benzodiazepine ring, carba 4-methoxy-3-(trifluoromethyl)phenyl group, 3-methoxy-5- Zole ring, C-carboline ring, B-carboline ring, Y-carboline ring, (trifluoromethyl)phenyl group, 2-methoxy-5-(trifluorom US 7,700,655 B2 47 48 ethyl)phenyl group, 2-methylsulfanyl-5-(trifluoromethyl) romethoxy)phenyl group, 3,4-dihexyloxyphenyl group, 2,4- phenyl group, 2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl bis(trifluoromethyl)phenyl group, 4-cyano-2-(trifluo group, 2-morpholino-5-(trifluoromethyl)phenyl group, romethoxy)phenyl grOup, 2-(4-cyanophenoxy)-5- 2-chloro-4-(trifluoromethyl)phenyl group, 2,5-dichlorophe (trifluoromethyl)phenyl group, and 2-(4-methoxyphenoxy)- nyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl 5-(trifluoromethyl)phenyl group group, 3,5-dinitrophenyl group, 2,5-bis(1,1-dimethyl)ethyl When “an aryl group which may be substituted in the phenyl group, 5-(1,1-dimethyl)ethyl-2-methoxyphenyl aforementioned definition of E is “a di-substituted phenyl group, 3,5-dimethylphenyl group, 4-methoxybiphenyl-3-yl group.” “a 2,5-di-substituted phenyl group, and “a 3,5-di group, 3,5-dimethoxyphenyl group, 3.5-bis(methoxycarbo substituted phenyl group' are preferred. nyl)phenyl group, 2-bromo-5-(trifluoromethyl)phenyl group, 10 When “an aryl group which may be substituted in the 3-methoxycarbonyl-5-(trifluoromethyl)phenyl group, 3-car aforementioned definition of E is “a 2,5-di-substituted phenyl boxy-5-(trifluoromethyl)phenyl group, 2-(2-naphthyloxy)-5- group. preferred examples of the group include groups rep (trifluoromethyl)phenyl group, 2-(2,4-dichlorophenoxy)-5- resented by the following Substituent Group 6-2e. (trifluoromethyl)phenyl group, 2-4-(trifluoromethyl) Substituent Group 6-2e 2,5-dimethoxyphenyl group, piperidin-1-yl-5-(trifluoromethyl)phenyl group, 2-(2.2.2- 15 2-chloro-5-(trifluoromethyl)phenyl group, 2,5-bis(trifluo trifluoroethoxy)-5-(trifluoromethyl)phenyl group, 2-(2- romethyl)phenyl group, 2-fluoro-5-(trifluoromethyl)phenyl methoxyphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4- group, 2-nitro-5-(trifluoromethyl)phenyl group, 2-methyl-5- chloro-3,5-dimethylphenoxy)-5-(trifluoromethyl)phenyl (trifluoromethyl)phenyl group, 2-methoxy-5-(trifluorom group, 2-piperidino-5-(trifluoromethyl)phenyl group, 2-(4- ethyl)phenyl group, 2-methylsulfanyl-5-(trifluoromethyl) methylphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4- phenyl group, 2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl chlorophenoxy)-5-(trifluoromethyl)phenyl group, 3,5-dicar group, 2-morpholino-5-(trifluoromethyl)phenyl group, 2.5- boxyphenyl group, 5-isopropyl-2-methylphenyl group, 2.5- dichlorophenyl group, 2,5-bis(1,1-dimethyl)ethylphenyl diethoxyphenyl group, 2,5-dimethylphenyl group, 5-chloro group, 5-(1,1-dimethyl)ethyl-2-methoxyphenyl group, 2-cyano group, 5-diethylsulfamoyl-2-methoxyphenyl group, 4-methoxybiphenyl-3-yl group, 2-bromo-5-(trifluorom 2-chloro-5-nitrophenyl group, 2-methoxy-5-(phenylcarbam 25 ethyl)phenyl group, 2-(2-naphthyloxy)-5-(trifluoromethyl) oyl)phenyl group, 5-acetylamino-2-methoxyphenyl group, phenyl group, 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl) 5-methoxy-2-methylphenyl group, 2,5-dibutoxyphenyl phenyl group, 2-4-(trifluoromethyl)piperidin-1-yl-5- group, 2,5-diisopentyloxy group, 5-carbamoyl-2-methox (trifluoromethyl)phenyl group, 2-(2.2.2-trifluoroethoxy)-5- yphenyl group, 5-(1,1-dimethyl)propyl)-2-phenoxyphenyl (trifluoromethyl)phenyl group, 2-(2-methoxyphenoxy)-5- group, 2-hexyloxy-5-methanesulfonyl group, 5-(2,2-dimeth 30 (trifluoromethyl)phenyl grOup, 2-(4-chloro-3,5- ylpropionyl)-2-methylphenyl group, 5-methoxy-2-(1-pyrro dimethylphenoxy)-5-(trifluoromethyl)phenyl group, lyl)phenyl group, 5-chloro-2-(p-toluenesulfonyl)phenyl 2-piperidino-5-(trifluoromethyl)phenyl group, 2-(4-meth grOup, 2-chloro-5-(p-toluenesulfonyl)phenyl grOup, ylphenoxy)-5-(trifluoromethyl)phenyl group, 2-(4-chlo 2-fluoro-5-methanesulfonyl group, 2-methoxy-5-phenoxy rophenoxy)-5-(trifluoromethyl)phenyl group, 5-isopropyl-2- group, 4-methylbiphenyl-3-yl group, 2-methoxy-5-(1-me 35 methylphenyl group, 2,5-diethoxyphenyl group, 2.5- thyl-1-phenylethyl)phenyl group, 5-morpholino-2-nitrophe dimethylphenyl grOup, 5-chloro-2-cyano grOup, nyl group, 5-fluoro-2-(1-imidazolyl)phenyl group, 2-butyl-5- 5-diethylsulfamoyl-2-methoxyphenyl group, 2-chloro-5-ni nitrophenyl grOup, 5-(1,1-dimethyl)propyl-2- trophenyl group, 2-methoxy-5-(phenylcarbamoyl)phenyl hydroxyphenyl group, 2-methoxy-5-methylphenyl group, group, 5-acetylamino-2-methoxyphenyl group, 5-methoxy 2,5-difluorophenyl group, 4-isopropyl-2-(trifluoromethyl) 40 2-methylphenyl group, 2,5-dibutoxyphenyl group, 2,5-diiso phenyl group, 2-nitro-4-(trifluoromethyl)phenyl group, pentyloxy group, 5-carbamoyl-2-methoxyphenyl group, 4-bromo-3-(trifluoromethyl)phenyl group, 4-bromo-2-(trif 5-(1,1-dimethyl)propyl)-2-phenoxyphenyl group, 2-hexy luoromethyl)phenyl group, 2-bromo-4-(trifluoromethyl)phe loxy-5-methanesulfonyl group, 5-(2,2-dimethylpropionyl)- nyl group, 4-fluoro-2-(trifluoromethyl)phenyl group, 4-iso 2-methylphenyl group, 5-methoxy-2-(1-pyrrolyl)phenyl propoxy-2-(trifluoromethyl)phenyl group, 4-cyano-2- 45 grOup, 5-chloro-2-(p-toluenesulfonyl)phenyl grOup, (trifluoromethyl)phenyl group, 2,6-diisopropylphenyl group, 2-chloro-5-(p-toluenesulfonyl)phenyl group, 2-fluoro-5- 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 2,4- methanesulfonyl group, 2-methoxy-5-phenoxy group, dichlorophenyl group, 2,3-dimethylphenyl group, indan-5-yl 2-methoxy-5-(1-methyl-1-phenylethyl)phenyl group, 5-mor group, 2,4-dimethylphenyl group, 2,6-dichlorophenyl group, pholino-2-nitrophenyl group, 5-fluoro-2-(1-imidazolyl)phe 4-bromo-2-(trifluoromethoxy)phenyl group, 3,4-ethylene 50 nyl group, 2-butyl-5-nitrophenyl group, 5-(1,1-dimethyl) dioxyphenyl group, 3-chloro-4-cyanophenyl group, propyl-2-hydroxyphenyl group, 2-methoxy-5-methylphenyl 3-chloro-4-(trifluoromethoxy)phenyl group, 2-chloro-4-cy group, 2,5-difluorophenyl group, 2-benzoyl-5-methylphenyl anophenyl group, 2,3-dichlorophenyl group, 4-isopropyl-3- grOup, 2-(4-cyanophenoxy)-5-(trifluoromethyl)phenyl methylphenyl group, 4-(1,1-dimethyl)propyl-2-hydrox group, and 2-(4-methoxyphenoxy)-5-(trifluoromethyl)phe yphenyl group, 3-chloro-2-cyanophenyl group, 2-cyano-4- 55 methylphenyl group, 2,2-difluoro-1,3-benzodioxol-4-yl nyl group group, 2,2,3,3-tetrafluoro-1,4-benzodioxen-5-yl group, When “an aryl group which may be substituted in the 3-chloro-4-(trifluoromethylsulfanyl)phenyl group, 2-nitro-4- aforementioned definition of E is “a 2,5-di-substituted phenyl (trifluoromethoxy)phenyl group, 2,2-difluoro-1,3-benzo group.” “a 2,5-di-substituted phenyl group wherein at least dioxol-5-yl group, 2-methyl-4-(trifluoromethoxy)phenyl 60 one of said substitutents is trifluoromethyl group' is more group, 4-bromo-2-fluorophenyl group, 2,4-bis(methane preferred, a group selected from the following Substituent Sulfonyl)phenyl group, 2.2.3,3-tetrafluoro-1,4-benzodioxen Group 6-3e is further preferred, and 2.5-bis(trifluoromethyl) 6-yl group, 2-benzoyl-4-chlorophenyl group, 2-bromo-4- phenyl group is most preferred. fluorophenyl group, 3,4-dimethoxyphenyl group, 3,4- Substituent Group 6-3e 2-chloro-5-(trifluoromethyl)phenyl difluorophenyl group, 3-chloro-4-methoxyphenyl group, 65 group, 2,5-bis(trifluoromethyl)phenyl group, 2-fluoro-5-(tri 2-chloro-4-nitrophenyl group, 2,4-difluorophenyl group, fluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl)phe 2-benzoyl-5-methylphenyl group, 2-bromo-4-(trifluo nyl group, 2-methyl-5-(trifluoromethyl)phenyl group, US 7,700,655 B2 49 50 2-methoxy-5-(trifluoromethyl)phenyl group, 2-methylsulfa nylphenyl group, 4-(1-methylpropyl)phenyl group, 3-ben nyl-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidinyl)-5- Zoylphenyl group, 3-methoxyphenyl group, 4-(acetylamino) (trifluoromethyl)phenyl group, 2-morpholino-5-(trifluorom phenyl group, 4-sulfamoylphenyl group, 4-difluoromethoxy) ethyl)phenyl group, 2-bromo-5-(trifluoromethyl)phenyl phenyl grOup, 3-methylsulfanylphenyl grOup, group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group, 4-methanesulfonylphenyl group, 3-(butylsulfamoyl)phenyl 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group, group, 3-benzyloxyphenyl group, 4-(p-toluenesulfony 2-4-(trifluoromethyl)piperidin-1-yl)-5-(trifluoromethyl) lamino)phenyl group, 4-morpholinophenyl group, 3-(1,1- phenyl group, 2-(2.2.2-trifluoroethoxy)-5-(trifluoromethyl) dimethyl)ethylphenyl group, 3-(5-methylfuran-2-yl)phenyl phenyl group, 2-(2-methoxyphenoxy)-5-(trifluoromethyl) group, 3-sulfamoylphenyl group, 3-(trifluoromethanesulfo phenyl grOup, 2-(4-chloro-3,5-dimethylphenoxy)-5- 10 nyl)phenyl group, 3-hexyloxyphenyl group, 4-acetylphenyl (trifluoromethyl)phenyl grOup, 2-piperidino-5- group, biphenyl-2-yl group, biphenyl-4-yl group, 3-5-phe (trifluoromethyl)phenyl group, 2-(4-methylphenoxy)-5- nyl-3-(trifluoromethyl)pyrazol-1-yl)phenyl group, 3-5-(1, (trifluoromethyl)phenyl group, 2-(4-chlorophenoxy)-5- 1-dimethyl)ethyl-3-(trifluoromethyl)pyrazol-1-yl)phenyl (trifluoromethyl)phenyl group, 2-(4-cyanophenoxy)-5- grOup, 4-3,5-bis(trifluoromethyl)pyrazol-1-yl)phenyl (trifluoromethyl)phenyl group, and 2-(4-methoxyphenoxy)- 15 grOup, 3-3,5-bis(trifluoromethyl)pyrazol-1-yl)phenyl 5-(trifluoromethyl)phenyl group group, and 4-5-phenyl-3-(trifluoromethyl)pyrazol-1-yl When “an aryl group which may be substituted in the phenyl group aforementioned definition of E is “a 3,5-di-substituted phenyl When “an aryl group which may be substituted in the group. preferred examples of the group include groups rep aforementioned definition of E is “a phenyl group which has resented by the following Substituent Group 6-4e. three or more substitutents.” preferred examples of the group Substituent Group 6-4e 3,5-bis(trifluoromethyl)phenyl include groups represented by the following Substituent group, 3,5-dichlorophenyl group, 3.5-bis(1,1-dimethyl) Group 6-7e. ethylphenyl group, 3-fluoro-5-(trifluoromethyl)phenyl Substituent Group 6-7e 3,5-bis(trifluoromethyl)-2-bro group, 3-bromo-5-(trifluoromethyl)phenyl group, 3-meth mophenyl group, 3,4,5-trichlorophenyl group, 3,5-dichloro oxy-5-(trifluoromethyl)phenyl group, 3,5-difluorophenyl 25 4-hydroxyphenyl group, pentafluorophenyl group, 3.5.5.8.8- group, 3,5-dinitrophenyl group, 3,5-dimethylphenyl group, pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl group, 3.5- 3,5-dimethoxyphenyl group, 3,5-bis(methoxycarbonyl)phe bis(trifluoromethyl)-2-methylphenyl group, 2,6-dichloro-4- nyl group, 3-methoxycarbonyl-5-(trifluoromethyl)phenyl (trifluoromethyl)phenyl grOup, 2,4-dimethoxy-5- group, 3-carboxy-5-(trifluoromethyl)phenyl group, and 3.5- (trifluoromethyl)phenyl grOup, 2,4-difluoro-5- dicarboxyphenyl group 30 (trifluoromethyl)phenyl grOup, 4-chloro-2-(4- When “an aryl group which may be substituted in the chlorobenzenesulfonyl)-5-(trifluoromethyl)phenyl group, aforementioned definition of E is “a 3,5-di-substituted phenyl 5-chloro-2-nitro-4-(trifluoromethyl)phenyl group, 2,3-dif group.” “a 3,5-di-substituted phenyl group wherein at least luoro-4-(trifluoromethyl)phenyl group, 2,3,5,6-tetrafluoro one of said substitutents is trifluoromethyl group' is more 35 4-(trifluoromethyl)phenyl group, 2,4,6-trimethylphenyl preferred, a group selected from the following Substituent group, 2-cyano-4,5-dimethoxyphenyl group, 2,4-dichloro-5- Group 6-5e is further preferred, and 3.5-bis(trifluoromethyl) isopropoxyphenyl group, 2,3,5-trifluorophenyl group, 2,4,5- phenyl group is most preferred. trichlorophenyl group, and 5-ethoxy-4-fluoro-2-nitrophenyl Substituent Group 6-5e 3,5-bis(trifluoromethyl)phenyl group 40 When “an aryl group which may be substituted in the group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo aforementioned definition of E is “a naphthyl group which 5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluorom may be substituted, preferred examples of the group include ethyl)phenyl group, 3-methoxycarbonyl-5-(trifluoromethyl) 1-naphthyl group, 4-methoxynaphthalen-2-yl group, and phenyl group, and 3-carboxy-5-(trifluoromethyl)phenyl 4-hydroxy-3-methylnaphthalen-1-yl group. group 45 Examples of the "heteroaryl group' in “a heteroaryl group When “an aryl group which may be substituted in the which may be substituted in the definition of E include aforementioned definition of E is “a mono-substituted phenyl similar groups to the "monocyclic heteroaryl group' and group. preferred examples of the group include groups rep “fused polycyclic heteroaryl group' in the definition of the resented by the following Substituent Group 6-6e. aforementioned "heterocyclic group.” A 5 to 13-membered Substituent Group 6-6e 4-methoxyphenyl group, 4-chlo 50 heteroaryl group is preferred, and preferred examples of the rophenyl group, 2-methoxyphenyl group, 2-(trifluoromethyl) group include thienyl group, pyrazolyl group, oxazolyl phenyl group, 3-(trifluoromethyl)phenyl group, 4-(trifluo group, 1,3,4-thiadiazolyl group, pyridyl group, pyrimidinyl romethyl)phenyl group, 3-chlorophenyl group, biphenyl-3-yl group, indolyl group, quinolyl group, carbazolyl group, thia group, 3-acetylphenyl group, 3-(acetylamino)phenyl group, Zolyl group, and pyrazinyl group. 3-carbamoylphenyl group, 3-methylcarbomoylphenyl group, 55 A 5-membered heteroaryl group is more preferred as the 4-methylphenyl group, 3-(trifluoromethoxy)phenyl group, "heteroaryl group' in “a heteroaryl group which may be 2-benzylphenyl group, 4-(trifluoromethoxy)phenyl group, substituted in the definition of E. Thienyl group, pyrazolyl 4-(1,1-dimethyl)ethylphenyl group, 3-isopropoxyphenyl group, oxazolyl group, 1,3,4-thiadiazolyl group, and thiaz group, 4-isopropoxyphenyl group, 4-hexylphenyl group, olyl group are further preferred, and thiazolyl group is most 3-methylphenyl group, 4-cyclohexylphenyl group, 4-ben 60 preferred. Zylphenyl group, 2-chlorophenyl group, 2-methylphenyl Examples of the substitutent in the definition of “a het group, 4-butylphenyl group, 4-benzyloxyphenyl group, eroaryl group which may be substituted in the aforemen 3-benzylphenyl group, 4-hexyloxyphenyl group, 3-isopropy tioned definition of E include similar groups to the substi lphenyl group, 4-cyanophenyl group, 3-cyanophenyl group, tutent explained for the definition “which may be 4-(ethoxycarbonylmethyl)phenyl group, 3-(trifluoromethyl 65 substituted.” The position of substitutents existing on the Sulfanyl)phenyl group, 4-(trifluoromethylsulfanyl)phenyl heteroaryl group is not particularly limited, and when two or group, 4-(trifluoromethanesulfonyl)phenyl group, 3-ethy more substitutents exist, they may be the same or different. US 7,700,655 B2 51 52 When “a heteroaryl group which may be substituted in the selected from the following Substituent Group Y'-1Z. Ahalo aforementioned definition of E is “a thiazolyl group which gen atom and tert-butyl group are more preferred, and a may be substituted,” “a thiazol-2-yl group which may be halogen atom is most preferred. substituted.” “A mono-substituted thiazol-2-yl group' and “a Substituent Group Y-1Zahalogenatom, nitro group, cyano di-substituted thiazol-2-yl group' are more preferred, and “a group, methoxy group, methyl group, isopropyl group, tert di-substituted thiazol-2-yl group' is further preferred. butyl group, 1,1,3,3-tetramethylbutyl group, 2-phenylethen When “a heteroaryl group which may be substituted in the 1-yl group, 2,2-dicyanoethen-1-yl group, 2-cyano-2-(meth aforementioned definition of E is “a di-substituted thiazol-2- oxycarbonyl)ethen-1-yl group, 2-carboxy-2-cyanoethen-1- yl group, a group selected from the following Substituent yl group, ethynyl group, phenylethynyl group, Group 8-8e is preferred, and 4-(1,1-dimethyl)ethyl-5-[(2,2- 10 (trimethylsilyl)ethynyl group, trifluoromethyl group, pen dimethyl)propionylthiazol-2-yl group is most preferred. tafluoroethyl group, phenyl group, 4-(trifluoromethyl)phenyl Substituent Group 8-8e 5-bromo-4-(1,1-dimethyl)ethyl group, 4-fluorophenyl group, 2,4-difluorophenyl group, thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl 2-phenethyl group, 1-hydroxyethyl group, 1-(methoxy group, 5-cyano-4-(1,1-dimethyl)ethylthiazol-2-yl group, imino)ethyl group, 1-(benzyloxy)iminoethyl group, 2-thie 5-methylthiazol-2-yl group, 4.5-dimethylthiazol-2-yl group, 15 nyl group, 3-thienyl group, 1-pyrrolyl group, 2-methylthi 5-methyl-4-phenylthiazol-2-yl group, 5-(4-fluorophenyl)-4- azol-4-yl group, imidazol-2-alpyridin-2-yl group, 2-pyridyl methylthiazol-2-yl group, 4-methyl-5-3-(trifluoromethyl) group, acetyl group, isobutyryl group, piperidinocarbonyl phenylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-eth group, 4-benzylpiperidinocarbonyl group, (pyrrol-1-yl)sul ylthiazol-2-yl group, 4-ethyl-5-phenylthiazol-2-yl group, fonyl group, carboxy group, methoxycarbonyl group, N-3, 4-isopropyl-5-phenylthiazol-2-yl group, 4-butyl-5-phe 5-bis(trifluoromethyl)phenylcarbamoyl group, N,N-dimeth nylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-(2,2-dim ylcarbamoyl group, Sulfamoyl group, N-3,5-bis ethyl)propionylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl (trifluoromethyl)phenylsulfamoyl grOup, N,N- 5-(ethoxycarbonyl)thiazol-2-yl group, 4-(1,1-dimethyl) dimethylsulfamoyl group, amino group, N,N-dimethylamino ethyl-5-piperidinothiazol-2-yl group, 4-(1,1-dimethyl) group, acetylamino group, benzoylamino group, methane ethyl-5-morpholinothiazol-2-yl group, 4-(1,1-dimethyl) Sulfonylamino group, benzenesulfonylamino group, 3-phe ethyl-5-(4-methylpiperazin-1-yl)thiazol-2-yl group, 4-(1, 25 nylureido group, (3-phenyl)thioureido group, (4-nitrophenyl) 1-dimethyl)ethyl-5-(4-phenylpiperazin-1-yl)thiazol-2-yl diazenyl group, and (4-(pyridin-2-yl)sulfamoylphenyl) group, 5-carboxymethyl-4-phenylthiazol-2-yl group, 4.5- diazenyl group diphenylthiazol-2-yl group, 4-benzyl-5-phenylthiazol-2-yl “2-Acetoxyphenyl group which is substituted in the 5-po group, 5-phenyl-4-(trifluoromethyl)thiazol-2-yl group, sition' is preferred as the “2-acetoxyphenyl group which may 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4-phenylthi 30 be substituted in the 5-position” in the definition of Z'. azol-2-yl group, 5-ethoxycarbonyl-4-phenylthiazol-2-yl A halogen atom is preferred as the substitutent in the defi group, 5-ethoxycarbonyl-4-(pentafluorophenyl)thiazol-2-yl nition of “2-acetoxyphenyl group which may be substituted group, 5-methylcarbamoyl-4-phenylthiazol-2-yl group, in the 5-position' and “2-acetoxyphenyl group which is sub 5-ethylcarbamoyl-4-phenylthiazol-2-yl group, 5-isopropyl stituted in the 5-position” in the definition of Z'. carbamoyl-4-phenylthiazol-2-yl group, 5-(2-phenylethyl) 35 The definition “which may be substituted in the definition carbamoyl-4-phenylthiazol-2-yl group, 5-ethoxycarbonyl-4- of “a phenyl group which may be substituted in the definition (trifluoromethyl)thiazol-2-yl group, 5-carboxy-4-(1,1- of E' has the same meaning as “which may be substituted.” dimethyl)ethylthiazol-2-yl group, 5-(ethoxycarbonyl) Examples of the substitutent in the definition of “a phenyl methyl-4-phenylthiazol-2-yl grOup, 5-carboxy-4- group which may be substituted” in the definition of E' phenylthiazol-2-yl group, and 5-propylcarbamoyl-4- 40 include similar groups to the Substitutents explained for the phenylthiazol-2-yl group. definition “which may be substituted.” A position of a substi When “a heteroaryl group which may be substituted in the tutent existing on the phenyl group is not particularly limited, aforementioned definition of E is “a mono-substituted thia and when two or more substitutents exist, they may be the Zol-2-yl group preferred examples of the group include same or different. groups represented by the following Substituent Group 6-9e. 45 Preferred examples of “a phenyl group which may be sub Substituent Group 8-9e 4-(1,1-dimethyl)ethylthiazol-2-yl stituted” in the definition of E' include 3.5-bis(trifluorom group, 4-phenylthiazol-2-yl group, 4-3,5-bis(trifluorom ethyl)phenyl group, 2,5-bis(trifluoromethyl)phenyl group, a ethyl)phenylthiazol-2-yl group, 4-(2,4-dichlorophenyl)thia phenyl group which has three or more substitutents whereinat Zol-2-yl group, 4-(3,4-dichlorophenyl)thiazol-2-yl group, least one of said Substitutents is trifluoromethyl group, and a 4-4-(trifluoromethyl)phenylthiazol-2-yl group, 4-(2,5-dif di-Substituted phenyl group wherein at least one of said Sub luorophenyl)thiazol-2-yl group, 4-(4-methoxyphenyl)thia 50 stitutents is trifluoromethyl group, (provided that a 2,5-di Zol-2-yl group, 4-3-(trifluoromethyl)phenylthiazol-2-yl substituted phenyl group and a 3,5-di-substituted phenyl group, and 4-(pentafluorophenyl)thiazol-2-yl group group are excluded as said di-substituted phenyl group.) 3.5- The compounds represented by the aforementioned gen Bis(trifluoromethyl)phenyl group and 2.5-bis(trifluorom eral formula (I-1) are explained in details. ethyl)phenyl group are more preferred. Examples of the substitutent in the definition of “2-hydrox 55 When “a phenyl group which may be substituted in the yphenyl group which may be substituted in the 5-position definition of E is “a phenyl group which has three or more and “2-acetoxyphenyl group which may be substituted in the substitutents wherein at least one of said substitutents is trif 5-position” in the definition of Z' include similar groups to luoromethyl group, preferred examples of the group include the substitutent explained for the definition “which may be groups represented by the following Substituent Group o'-le. substituted.” 60 “2-Hydroxyphenyl group which is substituted in the 5-po Substituent Group o'-1e 3.5-bis(trifluoromethyl)-2-bro sition' is preferred as the “2-hydroxyphenyl group which mophenyl group, 3,5-bis(trifluoromethyl)-2-methylphenyl may be substituted in the 5-position” in the definition of Z'. group, 2,6-dichloro-4-(trifluoromethyl)phenyl group, 2,4- Preferred examples of the substitutent in the definition of dimethoxy-5-(trifluoromethyl)phenyl group, 2,4-difluoro-5- “2-hydroxyphenyl group which may be substituted in the 65 (trifluoromethyl)phenyl group, 4-chloro-2-(4-chlorobenze 5-position” and “2-hydroxyphenyl group which is substituted nesulfonyl)-5-(trifluoromethyl)phenyl group, 5-chloro-2- in the 5-position” in the definition of Z' include a group nitro-4-(trifluoromethyl)phenyl group, 2,3-difluoro-4- US 7,700,655 B2 53 54 (trifluoromethyl)phenyl group, and 2,3,5,6-tetrafluoro-4- 2-4-(trifluoromethyl)piperidin-1-yl)-5-(trifluoromethyl) (trifluoromethyl)phenyl group phenyl group, 2-(2.2.2-trifluoroethoxy)-5-(trifluoromethyl) When “a phenyl group which may be substituted in the phenyl group, 2-(2-methoxyphenoxy)-5-(trifluoromethyl) definition of E is “a di-substituted phenyl group wherein at phenyl grOup, 2-(4-chloro-3,5-dimethylphenoxy)-5- least one of said Substitutents is trifluoromethyl group, (pro (trifluoromethyl)phenyl grOup, 2-piperidino-5- vided that a 2,5-di-substituted phenyl group and a 3,5-di (trifluoromethyl)phenyl group, 2-(4-methylphenoxy)-5- Substituted phenyl group are excluded from said di-substi (trifluoromethyl)phenyl group, 2-(4-chlorophenoxy)-5- tuted phenyl group) preferred examples of the group include (trifluoromethyl)phenyl group, 2-(4-cyanophenoxy)-5- groups represented by the following Substituent Group 6'-2e. (trifluoromethyl)phenyl group, and 2-(4-methoxyphenoxy)- 5-(trifluoromethyl)phenyl group Substituent Group 8'-2e 4-chloro-2-(trifluoromethyl)phe 10 nyl group, 2-fluoro-3-(trifluoromethyl)phenyl group, A group selected from the following Substituent Group 4-fluoro-3-(trifluoromethyl)phenyl group, 4-chloro-3-(trif 8-2e is preferred as “a 3,5-di-substituted phenyl group luoromethyl)phenyl group, 4-nitro-3-(trifluoromethyl)phe wherein one of said substitutents is trifluoromethyl group' in nyl group, 4-cyano-3-(trifluoromethyl)phenyl group, 2-me the definition of E. thyl-3-(trifluoromethyl)phenyl grOup, 4-methyl-3- 15 Substituent Group 8-2e 3,5-bis(trifluoromethyl)phenyl (trifluoromethyl)phenyl grOup, 4-methoxy-3- group, 3-fluoro-5-(trifluoromethyl)phenyl group, 3-bromo (trifluoromethyl)phenyl group, 2-chloro-4-(trifluoromethyl) 5-(trifluoromethyl)phenyl group, 3-methoxy-5-(trifluorom phenyl group, 4-isopropyl-2-(trifluoromethyl)phenyl group, ethyl)phenyl group, 3-methoxycarbonyl-5-(trifluoromethyl) 2-nitro-4-(trifluoromethyl)phenyl group, 4-bromo-3-(trifluo phenyl group, and 3-carboxy-5-(trifluoromethyl)phenyl romethyl)phenyl group, 4-bromo-2-(trifluoromethyl)phenyl group group, 2-bromo-4-(trifluoromethyl)phenyl group, 4-fluoro Compounds represented by the aforementioned general 2-(trifluoromethyl)phenyl group, 4-isopropoxy-2-(trifluo formula (I-3) are explained in details. romethyl)phenyl group, 4-cyano-2-(trifluoromethyl)phenyl Examples of the substitutent in the definition of “2-hydrox group, and 2.4-bis(trifluoromethyl)phenyl group yphenyl group which may be substituted in the 5-position Compounds represented by the aforementioned general and “2-acetoxyphenyl group which may be substituted in the formula (I-2) are explained in details. 25 5-position” in the definition of Z include similar groups to Examples of the substitutent in the definition of “2-hydrox the substitutent explained for the definition “which may be yphenyl group which may be substituted in the 5-position substituted.” and “2-acetoxyphenyl group which may be substituted in the “2-Hydroxyphenyl group which is substituted in the 5-po 5-position” in the definition of Z include similar groups to sition' is preferred as the “2-hydroxyphenyl group which the substitutent explained for the definition “which may be 30 may be substituted in the 5-position” in the definition of Z. substituted.” A halogen atom, nitro group, methyl group and methoxy “2-Hydroxyphenyl group which is substituted in the 5-po group are preferred as the substitutent in the definition of sition' is preferred as the “2-hydroxyphenyl group which “2-hydroxyphenyl group which may be substituted in the may be substituted in the 5-position” in the definition of Z. 5-position” and “2-hydroxyphenyl group which is substituted A halogen atom, nitro group, methyl group, and methoxy 35 in the 5-position” in the definition of Z, and a halogen atom group are preferred as the substitutent in the definition of is most preferred. “2-hydroxyphenyl group which may be substituted in the “2-Acetoxyphenyl group which is substituted in the 5-po 5-position” and “2-hydroxyphenyl group which is substituted sition' is preferred as the “2-acetoxyphenyl group which may in the 5-position” in the definition of Z, and a halogen atom be substituted in the 5-position” in the definition of Z. is most preferred. A halogen atom is preferred as the substitutent in the defi “2-Acetoxyphenyl group which is substituted in the 5-po 40 nition of “2-acetoxyphenyl group which may be substituted sition' is preferred as the “2-acetoxyphenyl group which may in the 5-position' and “2-acetoxyphenyl group which is sub be substituted in the 5-position” in the definition of Z. stituted in the 5-position” in the definition of Z. Ahalogen atom is preferred as the substitutent in the defi Examples of the substitutent in the definition of “a hydro nition of “2-acetoxyphenyl group which may be substituted carbon group which may be substituted in the definition of in the 5-position' and “2-acetoxyphenyl group which is sub 45 RandR and “a C to Ca hydrocarbon group which may stituted in the 5-position” in the definition of Z. be substituted” in the definition of R include similar groups Examples of the substitutent in the definition of “a 2,5-di to the substitutent explained for the definition “which may be Substituted phenyl group wherein one of said Substitutents is substituted.” trifluoromethyl group' and “a 3,5-di-substituted phenyl Examples of the “hydrocarbon group' in the definition of group wherein one of said substitutents is trifluoromethyl 50 “a hydrocarbon group which may be substituted in the defi group” in the definition of E include similar groups to the nition of R. and R and "a C. to Ca hydrocarbon group substitutent explained for the definition “which may be sub which may be substituted” in the definition of R include Stituted. similar groups to the “hydrocarbon group' in the aforemen A group selected from the following Substituent Group tioned definition. 6°-1e is preferred as “a 2,5-di-substituted phenyl group 55 Examples of the “hydroxy group which may be substi wherein one of said substitutents is trifluoromethyl group' in tuted” in the definition of R° and R include similar the definition of E. groups to the “hydroxy group which may be substituted” Substituent Group 8-1e 2-chloro-5-(trifluoromethyl)phe explained for the definition “which may be substituted.” nyl group, 2.5-bis(trifluoromethyl)phenyl group, 2-fluoro-5- As E, 3.5-bis(1,1-dimethyl)ethylphenyl group, 2,5-bis (trifluoromethyl)phenyl group, 2-nitro-5-(trifluoromethyl) 60 (1,1-dimethyl)ethylphenyl group, 5-(1,1-dimethyl)ethyl phenyl group, 2-methyl-5-(trifluoromethyl)phenyl group, 2-methoxyphenyl group, 4-methoxybiphenyl-3-yl group, 2-methoxy-5-(trifluoromethyl)phenyl group, 2-methylsulfa 5-(1,1-dimethyl)propyl)-2-phenoxyphenyl group, 4-meth nyl-5-(trifluoromethyl)phenyl group, 2-(1-pyrrolidinyl)-5- ylbiphenyl-3-yl group and 5-(1,1-dimethyl)propyl)-2-hy (trifluoromethyl)phenyl group, 2-morpholino-5-(trifluorom droxyphenyl group are preferred, and 3,5-bis(1,1-dimethyl) ethyl)phenyl group, 2-bromo-5-(trifluoromethyl)phenyl 65 ethylphenyl group is more preferred. group, 2-(2-naphthyloxy)-5-(trifluoromethyl)phenyl group, Compounds represented by the aforementioned general 2-(2,4-dichlorophenoxy)-5-(trifluoromethyl)phenyl group, formula (I-4) are explained in details. US 7,700,655 B2 55 56 Examples of the substitutent in the definition of “2-hydrox Among the compound represented by the general formulas yphenyl group which may be substituted in the 5-position (I), (I-1), (I-2), (I-3) and (I-4), preferred compounds are those and “2-acetoxyphenyl group which may be substituted in the other than “substituted benzoic acid derivatives represented 5-position” in the definition of Z' include similar groups to by the following general formula (X-1) and/or compounds the substitutent explained for the definition “which may be represented by the following Compound Group (p-1. substituted.” “2-Hydroxyphenyl group which is substituted in the 5-po sition' is preferred as the “2-hydroxyphenyl group which (X-1) may be substituted in the 5-position” in the definition of Z. Ahalogenatom, phenyl group, 4-fluorophenyl group, 2,4- 10 difluorophenyl group, 4-(trifluoromethyl)phenyl group, 1-pyrrolyl group and 2-thienyl group are preferred as the substitutent in the definition of “2-hydroxyphenyl group which may be substituted in the 5-position' and “2-hydrox wherein R' represents the following general formula yphenyl group which is substituted in the 5-position” in the 15 (X-2): definition of Z', and a halogen atom is most preferred. “2-Acetoxyphenyl group which is substituted in the 5-po (X-2) sition' is preferred as the “2-acetoxyphenyl group which may O be substituted in the 5-position” in the definition of Z'. Ahalogen atom is preferred as the substitutent in the defi R1003 R1005 nition of “2-acetoxyphenyl group which may be substituted in the 5-position' and “2-acetoxyphenyl group which is sub stituted in the 5-position” in the definition of Z'. R1004 CH Examples of the substitutent in the definition of “a hydro O carbon group which may be substituted in the definition of 25 R“, and “an acyl group which may be substituted” and “a heterocyclic group which may be substituted in the defini or the following general formula (X-3): tion of R' include similar groups to the substitutent explained for the definition “which may be substituted.” (X-3) Examples of the “hydrocarbon group” in the definition of 30 OR 1009 “a hydrocarbon group which may be substituted in the defi R1003 R1005 nition of R“ include similar groups to the “hydrocarbon group' in the aforementioned definition. Examples of the “acyl group” in the definition of “an acyl R1004 CH group which may be substituted” in the definition of R' 35 include similar groups to the “acyl group' in the aforemen OR 1010 tioned definition. Examples of the "heterocyclic group” in the definition of “a wherein each of R', R'' and R' independently repre heterocyclic group which may be substituted in the defini sents hydrogen atom, an alkyl group having from 1 to 6 tion of R“ include similar groups to the "heterocyclic 40 carbons or an alkoxy group having from 1 to 6 carbons, each group' in the aforementioned definition. of R'' and R' independently represents hydrogenatom, A group selected from the following Substituent Group 6-1e is preferred as E', and 4-(1,1-dimethyl)ethyl)-5-[(2,2- an alkyl group having from 1 to 6 carbons, or an acyl group dimethyl)propionylthiazol-2-yl group is most preferred. having from 2 to 11 carbons; 45 R' represents hydrogen atom, a lower alkyl group having Substituent Group 6-1e 5-bromo-4-(1,1-dimethyl)ethyl thiazol-2-yl group, 5-bromo-4-(trifluoromethyl)thiazol-2-yl from 1 to 6 carbons, which may be substituted, an aryl group, 5-cyano-4-(1,1-dimethyl)ethylthiazol-2-yl group, group having from 6 to 12 carbons, which may be substi 5-methylthiazol-2-yl group, 4-(1,1-dimethyl)ethyl-5-[(2,2- tuted, a heteroaryl group having from 4 to 11 carbons, dimethyl)propionylthiazol-2-yl group, 4-(1,1-dimethyl) 50 which may be substituted, an aralkyl group having from 7 ethyl-5-(ethoxycarbonyl)thiazol-2-yl group, 4-(1,1-dim to 14 carbons, which may be substituted, a heteroarylalkyl ethyl)ethyl-5-piperidinothiazol-2-yl grOup, 4-(1,1- group having from 5 to 13 carbons, which may be substi dimethyl)ethyl-5-morpholinothiazol-2-yl group, 4-(1,1- tuted, or an acyl group having from 2 to 11 carbons; dimethyl)ethyl-5-(4-methylpiperazin-1-yl)thiazol-2-yl X' represents carboxy group which may be esterified or group, 4-(1,1-dimethyl)ethyl-5-(4-phenylpiperazin-1-yl) 55 thiazol-2-yl group, 5-carboxymethyl-4-phenylthiazol-2-yl amidated. group, 5-acetyl-4-phenylthiazol-2-yl group, 5-benzoyl-4- Compound Group (p-1 phenylthiazol-2-yl group, 5-ethoxycarbonyl-4-phenylthi azol-2-yl group, 5-ethoxycarbonyl-4-(pentafluorophenyl) thiazol-2-yl group, 5-methylcarbamoyl-4-phenylthiazol-2-yl 60 group, 5-ethylcarbamoyl-4-phenylthiazol-2-yl group, 5-iso propylcarbamoyl-4-phenylthiazol-2-yl group, 5-(2-phenyl OH ethyl)carbamoyl-4-phenylthiazol-2 yl group, 5-ethoxycarbo nyl-4-(trifluoromethyl)thiazol-2-yl group, 5-carboxy-4-(1, N C F. 1-dimethyl)ethylthiazol-2-yl grOup, 5-carboxy-4- 65 phenylthiazol-2-yl group, and 5-propylcarbamoyl-4- phenylthiazol-2-yl group. US 7,700,655 B2 57 58 -continued mineral acid salts such as hydrochloride, oxalate, hydrosul C fate, nitrate, phosphate, or organic acid salts such as methane Sulfonate, benzene Sulfonate, para-toluene Sulfonate, acetate, OH O O N propionate, tartrate, fumarate, maleate, malate, oxalate. Suc 5 cinate, citrate, benzoate, mandelate, cinnamate, lactate. Salts C Nn 2 may sometimes beformed with amino acids such as glycine. N CF3, AS active ingredients of the medicament of the present inven H tion, pharmacologically acceptable salts may also be suitably used. The compounds or salts thereof represented by the afore C mentioned general formulas (I), (I-1), (I-2), (I-3) and (I-4) C may exist as hydrates or Solvates. As active ingredients of the medicament of the present invention, any of the aforemen OH O O N tioned Substances may be used. Furthermore, the compounds represented by the aforementioned general formulas (I), (I-1), OHCHN Na2 (I-2), (I-3) and (I-4) may sometimes have one or more asym N CF, metric carbons, and may exist as steric isomers such as opti H cally active Substance and diastereomer. As active ingredients of the medicament of the present invention, pure forms of Stereoisomers, arbitrary mixture of enantiomers or diastere O 20 omers, and racemates may be used. ON Furthermore, when the compounds represented by the gen N eral formulas (I), (I-1). (I-2), (I-3) and (I-4) has, for example, H 2-hydroxypyridine form, the compounds may exist as 2-py ridone form which is a tautomer. As active ingredients of the OH 25 medicament of the present invention, pure forms of tautomers or a mixture thereof may be used. When the compounds Each compound defined by the aforementioned general represented by the general formulas (I), (1-1), (I-2), (I-3) and formulas (I-1), (I-2), (I-3), and (I-4), or a pharmacologically (1-4) have olefinic double bonds, the configuration may be in acceptable salt thereof, or a hydrate thereof or a solvate either E or Z. and as active ingredients of the medicament of thereof is novel. Uses of the compound according to the 30 the R invention, s 1. ther of the aforementioned chemical Substance invention are not particu- configurauons or a m1XLure ereo may e use larly limited. Examples of the compounds included in the general for The compounds represented by the aforementioned gen- mulas (I) (I-1), (I-2), (I-3) and (I-4) as active ingredients of eral formulas (I), (I-1), (I-2), (I-3) and (I-4) may form salts. titles of th E. ent yer E. shown by Examples of pharmacologically acceptable salts include, 35 YY the active ingredients of the medicaments of the when acidic groups exist, metal salts such as lithium salt, present invention are not limited to the compound set out Sodium salt, potassium salt, magnesium salt, calcium salts, or below. ammonium salts such as ammonium salt, methylammonium The abbreviations used in the following tables have the salt, dimethylammonium salt, trimethylammonium salt, following meanings. dicyclohexylammonium salt, and when basic groups exist, Me: methyl group, Et: ethyl group.

A No N X NE

Compound A X E Number No S Z

1 OH O CF - 1n

Br US 7,700,655 B2 59 60 -continued OH --- O

Br

OH

Br

OH

MeO OH

OH

C

OH

MeO OH --> uCO

C US 7,700,655 B2 62 -continued

10 O O VW C -N1 O C

11 1. N

12 H C

C

13 N 1. \,1.

14 H

C

15 N1

oOH

16 O CF

u). CF

17 CF3 l, 5 US 7,700,655 B2 64 -continued

A No O

N N Y E Z H

Compound A n E Number (rO 18 OH C

C

19 OH C C a C OH OMe

C OMe 21 C OH CF 22 C OH 23 OH SOF

coN S. N Cl

C US 7,700,655 B2 65 66 -continued

24 OH CF3

/

CF

25 OH CF /

C

26 OH Me Me Me /

Me C Me Me

27 OH CF3

Y CF

28 OH CF

Y CF

29

30 US 7,700,655 B2 67 -continued 31 COH

32 OH

CC

33 OH OMe

CC 34 ul COOMe

cC 35 OH OS ) CC 36 OH up C)

CBr

37 OH

CBr

US 7,700,655 B2 89 90 -continued

100 OH CF

CC u CF

101 OH CF

CBr u CF

102 OH CF

CMe u CF 103 ul CF

u CF CC

104 OH

CC

105 OH F. C

CC 106 OH u)CF CBr

US 7,700,655 B2 93 -continued 115 OH CrCF CC

116 OH CF

CC u NO 117 OH CCF3 CBr

118 OH CF MDC CC 119 OH CCF CC

120 OH CF

CC u Me

121 OH CF C OMe CC US 7,700,655 B2 95 96 -continued 122 OH CF

O OMe CBr 123 OH CF

CBr OOMe 124 OH CF

CC u OMe 125 OH CF

CC u SMe 126 OH CF

CBr

127 OH CF

CBr C D 128 OH O CF

C8 US 7,700,655 B2 97 98 -continued 129 OH C DO CF

CC 130 ul CF

u C CC 131 OH CF

CNO OC

132 OH CF

CMe u C

133 OH CF

COMe u C 134 OH CCF3 CMe 135 OH CCF CMe US 7,700,655 B2 99 100 -continued 136 OH CF

CMe OMe 137 OH CF O OMe CMe 138 OH CF

CMe OOMe 139 OH

140 OH

141 OH C

CBr 142 OH C

CC OC 143 OH C C C CBr US 7,700,655 B2 101 102 -continued 144 OH C. CBr 145 OH C

C C 146 OH

C C 147 OH

C C 148 OH

C C 149 OH

C C 150 OH C

Br

O C cBr 151 OH C

C C O C US 7,700,655 B2 103 104 -continued

152 OH

uo. C CNO

153 OH C

O C CMe

154 OH C

O C COMe

155 OH C

C

o C CBr

156 OH C

CBr 157 OH c

CC DC 158 OH NO 2

NO CBr US 7,700,655 B2 105 106 -continued

159 OH Me Me Me

CC

160 OH

CC

161 OH

CBr

162 OH Me

CC

163 OH Me

CBr

164 OH Me Me

Me CC US 7,700,655 B2 107 108 -continued

16S OH

CC

166 OH

CC

167 OH

CBr OMe 168 OH OMe

W OMe CBr 169 OH

Me

OYY a Y. W.

CC 170 OH COMe

Y COMe CBr 171 OH H

C C US 7,700,655 B2 109 110 -continued

172 C

173 OH Me Me Me

Me

Me Me Me

174 Me Me Me

O

Me C

175 OH Me Me Me

CNO

176 OH Me Me Me

Me Me

177 OH Me Me Me

Me OMe US 7,700,655 B2 111 112 -continued

178 O Me us Me Me O

OMe C

179 OH Me Me Me

Me

18O OH N

Br

181 OH Me

-( Br Br 182 OH -( C.

CBr

183 OH Me

CN

Br

184 OH Me

CN

Br US 7,700,655 B2 113 114 -continued 18S OH -Cl

CBr 186 OH

CBr 187 OH

CBr 188 OH -(N C S Me 189 OH N Me —{ S C F 190 OH N Me

CBr 191 OH Me Me (N Me S Et CBr 192 OH N Et

CBr US 7,700,655 B2 115 116 -continued

193 OH

Br

194 OH

Br

195 OH Me N

—{ MeO S CC Me Me Me

196 OH Me Me N

—{ MeO S CBr Me Me Me

197 OH Me Me N —{ Me S COEt CBr 198 OH Me

CBr

199 OH

CBr US 7,700,655 B2 117 118 -continued 200 OH Me Me -c I Br

Me

OH

Br

OH

CBr OH

CBr 204 OH

CBr

205 OH

CBr OH

CBr US 7,700,655 B2 119 120 -continued

OH

CBr

208 OH

CBr

209 OH

CBr 210 OH

CC 211 OH

CBr

212 OH

CBr

213 OH

CBr US 7,700,655 B2 121 122 -continued

214 OH

Br S N

215 OH

S Br O

216 OH N

Br

217 O –K

Me Me C

218 OH

-( C O Et

219 OH .O -( C O Et

US 7,700,655 B2

-continued A No

N-X N E

Compound OH X E Number

C 301 OH 1)N1 O

C

3O2 OH CF3

O

us N N CF3 H C O 303 OH usO CF H 1 N O CF C

304 OH O CF

N 1 N1 H

CF C

305 OH Me CF

O Me

us N N CF H 3 C O

306 OH H CF

u), CF CC US 7,700,655 B2 127 128 -continued 307 OH ---O u),CF3 C u),CF

309 OH O CF3 YN 1. 1. CF CC 310 OH 1)N1 CF

CF CC

311 OH

CC

312 OH 1n 1 CF3

u CF CC 313 OH 11 CF es. u), CC US 7,700,655 B2 129 130 -continued 314 OH O CF3 ulN1 H O u), CC 315 OH O CF3

u), CF CC 316 OH

u), CF CC 317 OH CF3

u), CF CC 3.18 OH

u), CF CC 319 OH CF3

u), CF CC 320 OH

u). CF

321 OH

u), CF CC US 7,700,655 B2 131 132 -continued

A No O

S. 1. E Z NH

Compound A Number (r 322 OH CF

C OH uo. CF 323 OH CF

u O CF 324 OH CF

HO O O CF 325 OH CF

HO C O CF 326 OH CF C

uo. CF cC 327 OH CF HO

r uo. CF 328 OH CF

r O CF

US 7,700,655 B2 141 142 -continued 357 OH CF3

CC O Me

C

Me 358 COH CF C O

359 OH CF3

CC

O Me 360 OH CF3

CC

Ol C 361 OH COH

Y COH CBr 362 OH Me Me

CC Me US 7,700,655 B2 143 144 -continued

363 OH OEt

CC OOEt

364 OH Me

CC

365 OH

CC OCN

366 OH SONEt

CC OOMe

367 OH NO

CC OC

368 OH O l

CC OMe

369 OH OMe

CC OOMe US 7,700,655 B2 145 146 -continued

370 OH O

C

OMe

371 OH OMe

C Me

372 OH O 1N1a Me

C 'N-1\- Me

373 OH Me C S e N-> Me Me

374 OH CONH2

C OMe

375 OH Me Me Me

CC US 7,700,655 B2 147 148 -continued

376 OH SOMe

CC

377 OH Me Me O Me

CC

Me

378 OH OMe

CC

379 OH

CC

380 OH

CC

381 OH SOMe

CC

US 7,700,655 B2 161 162 -continued

424 OH Me

CC Me Me

425 OH Me

CC 426 OH s Me CC

427 OH Me

Me

CC

428 OH Me

Me CC 429 OH -O.

CC

430 OH

CC US 7,700,655 B2 163 164 -continued 431 OH OCF

CC 432 OH Cl

C CC 433 OH Me Me

Me

CC 434 OH

Y Me C Me 435 COH CO 436 OH Me

Me CC 437 OH Me -> Me

CC 438 OH C

C CC US 7,700,655 B2 165 166 -continued

439 OH N Me O Me

CC

440 OH Br

OCF CC

441 OH r Me

CC

442 OH

a Me

CC

443 OH

CC

444 OH

CC

445 OH OMe

OMe

CC oCN

US 7,700,655 B2 173 174 -continued

468 OH

C U

469 OH Br

CC

470 OH SOMe

SOMe CC

471 OH Me Me O O O OH N H FC CF CC C

472 OH O F F

F O F

C

473 OH C

O C

474 OH F

Br CC

US 7,700,655 B2 181 182 -continued

498 OH OH CF CF

CC

499 OH

e SMe

CC 500 OH SOMe

CC

OH Me

CC

502 OH

CC

503 OH

CC

SO4 OH

CC

US 7,700,655 B2 187 188 -continued 521 OH O'sO

522 OH

CF

523 OH

CF

524 OH

525 OH CF

Y CF

OES-NH

CF

526 OH CF3

CF C