US007820693B2

(12) United States Patent (10) Patent No.: US 7820,693 B2 Hattori et al. (45) Date of Patent: Oct. 26, 2010

(54) 1-(2H)-ISOQUINOLONE DERIVATIVE Won-Jea Cho, et al. “Molecular Modeling of 3-Arylisoquinolines Antitumor Agents Active Against A-549. A Comparative Molecular (75) Inventors: Kazuo Hattori, Kamakura (JP); Satoshi Field Analysis Study.” Bioorganic & Medicinal Chemistry Letters Niizuma, Kamakura (JP); Miyako 10, 2002, p. 2953-2961. Masubuchi, Kamakura (JP); Kohei Alain Rose, et al. "Oxygen Heterocycles. Part XIII. From Koyama, Kamakura (JP): Osamu 3-Arylisocoumarins to 3-Arlisoquinones and 4Aryl-5H-2, Kondoh, Kamakura (JP); Toshiyuki 3-benzodiazepines.”J. Chem. Soc. (C), 1968, p. 2205-2208. Tsukaguchi, Kamakura (JP): Takehiro Graham S. Poindexter. "Convenient Preparation of 3-Substituted Okada, Kamakura (JP) 1(2H)-Isoquinolinones.” J. Org. Chem. 1982, 47, p. 3787-3788. Won-Jea Gho. “Synthesis and Antitumor Activity of (73) Assignee: Chugai Seiyaku Kabushiki Kaisha, 3-Arylisoquinoline Derivatives.” Arch. Pharm. Res. vol. 20, No. 3, Tokyo (JP) 1997, p. 264-268. Seung Hoon Cheon, et al. “Structure-Activity Relationship Studies (*) Notice: Subject to any disclaimer, the term of this of Isoquinolinone Type Anticancer Agent.” Arch. Pharm. Res. Vol. patent is extended or adjusted under 35 24, No. 4, 2001, p. 276-208. U.S.C. 154(b) by 548 days. Thanh Nguyen Le, et al. “A Facile synthesis of benzocphenanthiridine alkaloids: Oxynitidine and oxysanguinarine (21) Appl. No.: 11/816,910 using lithiated toluamide-benzonitrile cycloaddition.” Tetrahedron (22) PCT Filed: Feb. 22, 2006 Letters 45, 2004, p. 2763-2766. Thanh Nguyen Le, et al. “A versatile total synthesis of (86). PCT No.: PCT/UP2OO6/3O318O benzocphenanthridine alkaloids using lithiated toluamide benzonitrile cycloaddition.” J. Org. Chem., 2004, 69,2768-2772. S371 (c)(1), John P. Wolfe, et al. “Simple, Efficient Catalyst System for the Pal (2), (4) Date: Aug. 22, 2007 ladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates.” J. Org. Chem. 2000, 65, p. 1158-1174. (87) PCT Pub. No.: WO2006/090743 (Continued) PCT Pub. Date: Aug. 31, 2006 Primary Examiner Zinna N Davis (65) Prior Publication Data (74) Attorney, Agent, or Firm—Browdy and Neimark, PLLC US 2009/OO3O195A1 Jan. 29, 2009 (57) ABSTRACT (30) Foreign Application Priority Data

Feb. 22, 2005 (JP) ------2005-045926 The present invention provides a compound having high anti Aug. 17, 2005 (JP) ------2005-236919 tumor activity, which is useful for therapeutic and preventive agents effective for proliferative diseases such as cancer; a (51) Int. Cl. production method thereof an intermediate compound useful A6 IK 3/47 (2006.01) for Such production; and a pharmaceutical composition com CO7D 40 I/O (2006.01) prising such a compound. The present invention provides a (52) U.S. Cl...... 514/309: 546/141 compound represented by the formula (1): (58) Field of Classification Search ...... None See application file for complete search history. Formula 1 (56) References Cited U.S. PATENT DOCUMENTS NH 4,461,773. A 7/1984 Gregory 4.942,163 A 7, 1990 Behrens 2006/0205767 A1 9/2006 Wong et al. 2007,0185160 A1 8, 2007 Hattori et al.

FOREIGN PATENT DOCUMENTS (1) EP 050827 A1 5, 1982 WO 9851307 A1 11, 1998 WO 99.11624 A1 3, 1999 wherein X represents an aryl group or heteroaryl group which WO 2005018568 A2 3, 2005 may be substituted, Cy represents a 4- to 7-membered mono WO 2005075431 A1 8, 2005 cyclic heterocyclic ring or a 8- to 10-membered condensed WO 2005075432 A1 8, 2005 heterocyclic ring which may be substituted, and Z represents O, S, or NRa; or a prodrug thereof; or a pharmaceutically OTHER PUBLICATIONS acceptable salt thereof, and a pharmaceutical and a pharma ceutical composition which comprise the compound. Won-Jea Cho, et al. “Synthesis and Biological Evaluation of 3-Arylisoquinolines as Antitumor Agents.” Bioorganic & Medicinal Chemistry Letters 8, 1998, p. 41-46. 16 Claims, No Drawings US 7820,693 B2 Page 2

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Equivalent: 3-Isocyanatopopanoyl Chloride.” Org. Synth. Collective, 3379-3385. col. 6, 1988, p. 715-718. Noboru Yagi, et al. “Synthesis of N-Substituted-7-acylamino-3- Y. Watanabe, et al. Jikken Kagaku Koza, Fourth Series, vol. 20, 1992, phenylisocarboStyril and 6-Phenylbenzimidazor2. 1-a- p. 358-359. isoquinoline Derivatives and their Fluorescence Spectra.”Yuki Gosei Ulrike Peters, et al. “Platelet Activating Factor Synthetic Studies.” Kagaku Kyokaishi, 1969, 27, p. 51-58. Tetrahedron, 1987, 43, p. 3803-3816. Thanh Nguyen, etal. “Synthesis of Oxychelerythrine Using Lithiated Edward J. Glamkowski, et al. “7-(Aminoacyl) and 7-(Aminoalkyl) Toluamide-Benzonitrile Cycloaddition.” Chem. Pharm. Bull., 2005, Derivatives of 1, 2,6,7-Tetrahydoindolo 1.7-ab 1.5 benzo 53, p. 118-120. diazepines as Potential Antidepressant Agents.” Bioorg. Med. Chem. Thanh Nguyen, et al. “Total Synthesis of Oxyfagaronine, Phenolic 1980, 23, p. 1380-1386. Benzacphenanthridine and General Synthetic Way of 2,3,7,8- and N. Selvakumar, et al. “Influence of Ethylene-Oxy Spacer Group on 2,3,8.9-Tetrasubstituted Benzocphenanthridine Alkaloids.” Chem. the Activity of Linezolid: Synthesis of Potent Antibacterials Possess Pahrm. Bull., 2006, 54, p. 476-480. ing a Thiocarbonyl Group.” Bioorg. Med. Chem. Letters, 2003, 13, p. Tuanli Yao, etal. “Regio- and Stereoselective Synthesis of Isoindolin 1-ones via Electrophilic Cyclization.” J. Org, Chem., 2005, 70, p. 4167-4172. 1432-1437. John Boot, et al. “Discovery and strucure-activity relationships of Jonathan L. Hartwell."o-Chlorobromobenzene.” Org. Synth. Collec novel selective norepinephrine and dual serotonin/norepinephrine tive, vol. 3, 1955, p. 185-187. reuptake inhibitors.” Bioorg. Med. Chem. Letters, 2005, 15, p. 699 Peter J. Harrington, et al. “Palladium-Catalyzed Reactions in the TO3. Synthesis of 3- and 4-Substituted Indoles. Approaches to Ergot Alka Daniela Spera, et al. “Estradiol derivatives bearing Sulfur-containing loids.” J. Org. Chem., 1984, 49, p. 2657-2662. Substituents at the 11B or 7o positions: versatile reagents for the Jingjun Yin, et al. “Palladium-Catalyzed Intermolecular Coupling of preparation of estrogen conjugates.” Bioorg. Med. Chem. Let Aryl Halides and Amides.” Org. Letters, 2000, 2, p. 1101-1104. ters.2004, 12, p. 4393-4401. R. Greg Browning, et al. “Synhess of chra N-arylpyrroidinones via a Jikken Kagaku Koza, Fourth Series, vol. 22, 1992, p. 137-173. palladium-catayzed cross-couping reaction.” Tetrahedron Letters, Munetaka Kunishima, et al. “Formation of carboxamides by direct 2001, 42, p. 7155-7157. condensation of carboxylic acides and amines in alcohols using a new Dominique Delaunay, et al. “Reactivity of B-Amino Alcohols with alcohol- and water-soluble condensing agent: DMT-MM.” Tetrahe Carbon Disulfide. Study on the Synthesis of 2-Oxazolidinethiones dron, 2001, 57, p. 1551-1558. and 2-Thiazolidinethiones.” J. Org. Chem., 1995, 60, p. 6604-6607. Mojmir Suchy, et al. “Synthesis, Absolute Configuration, and H.J. Zhu, et al. “Chiral Ligunds Derived from Abrine 8. An Experi Enantiomeric Enrichment of a Cruciferous Oxindole Phytoalexin, mental and Theoretical Study of Free Ligand Conformational Pref. (S)-(-)-Spirobrassinin, and Its Oxazoline Analog.” J. Org. Chem. erences and the Addition of Diethylzine to Benzaldehyde.” J. Org. 2001, 66, p. 3940-3947. Chem., 2005, 70, p. 261-267. Toshiya Morie, et al. “Asymmetric Synthesis of the Enantiomers of Seung Hoon Cheon. et al. “Structure-Activity Relationship Studies 2-Aminomethyl-4-(4-Fluorobenzyl) Morpholine, and Intermediate of Isoquinolinone Type Anticancer Agent.” Arch. Pharm. Res. Vol. of Mosapride, a Gastroprokinetic Agent.” Heterocycles, 1994, 38, p. 24, No. 4, p. 276-280 (2001). 1033-1040. Fujioka et al. Tetrahedron Lett. vol. 46, pp. 2197-2199 (2005). US 7,820,693 B2 1. 2 1-(2H)-ISOQUINOLONE DERIVATIVE Non-Patent Document 6 Bioorg. Med. Chem. Vol. 10, pp. 2953-2961 (2002) This application is a 371 of PCT JP2006/303180 filed Feb. Non-Patent Document 7 Tetrahedron Lett., Vol. 45, pp. 22, 2006. 2763-2766 (2004) Non-Patent Document 8 J. Org. Chem. Vol. 69, pp. 2768 FIELD OF THE INVENTION 2772 (2004) The present invention relates to a novel 1-(2H)-isoqui DISCLOSURE OF THE INVENTION nolone derivative and a pharmaceutical comprising the same as an active ingredient. The present invention particularly 10 Problems to be Solved by the Invention relates to an antitumor agent useful as a therapeutic agent for diseases such as Solid cancer. It is an object of the present invention to provide a com pound, which has high antitumor activity and is useful as a DESCRIPTION OF THE RELATED ART therapeutic and preventive agent effective for proliferative 15 diseases Such as cancer, a production method thereof, an Regarding a method for synthesizing a 1-(2H)-isoqui intermediate compound useful for Such production, and a nolone derivative having a Substituent at position 3, several pharmaceutical composition comprising Such a compound. reports have already been made. For example, in 1968, Rose et al., have reported a method of allowing ammonia to act on Means for Solving the Problems a 3-aryl isocoumarin derivative, so as to synthesize a 1-(2H)- isoquinolone derivative (see to Non-Patent Document 1). In The present inventors have conducted intensive studies addition, in 1982, Poindexter has reported a method of syn directed towards providing a novel therapeutic and preventive thesizing a 1-(2H)-isoquinolone derivative by the reaction of agent, which is effective for proliferative diseases such as N.2-dimethylbenzamide with a nitrile derivative (see to Non cancer. As a result, the inventors have found that the com Patent Document 2). 25 pound of the present invention has excellent antitumor activ Moreover, the pharmacological activity of such an isoqui ity and is excellent in terms of solubility in water, and that it nolone derivative has also been reported. Researchers of has preferred properties as a pharmaceutical interms of safety Octamer have reported an isoquinolone derivative having or the like, thereby completing the present invention. anti-inflammatory action (see to Patent Document 1). Also, That is to say, in one aspect, the present invention provides researchers of Guilford have reported that 3-phenyl-1-(2H)- 30 isoquinolone has an inhibitory activity on poly(ADP-ribose) a compound represented by the following formula (1): polymerase, and that it can be used as a radiosensitizer (see to Patent Document 3). Moreover, with regard to an isoqui Formula 1 nolone derivative having anticancer action, in 1989, research ers of Du Pont have reported that a 3-(1-naphthyl)-1-(2H)- 35 isoquinolone derivative exhibits anticancer action (see to NH Patent Document 2). Furthermore, a patent application, which is pending simultaneously with the present applica tion, discloses a 1-(2H)-isoquinolone derivative exhibiting anticancer action (published after the priority date of the 40 present application; see to Patent Documents 4 and 5). There after, Won-Jea Cho et al. have reported a 3-aryl isoquinolone (1) derivative having anticancer action (see to Non-Patent Docu ments 3 to 8). However, among Such isoquinolone deriva wherein X represents an aryl group or heteroaryl group, tives, no compounds have been commercialized as anticancer 45 wherein the aryl group or heteroaryl group may be substituted agent to date. Thus, it has been desired that a compound with one or more substituents selected from Group A: having higher anticancer activity and also having preferred wherein Group A consists of a Cls alkyl group (wherein physical properties be developed. the alkyl group may be substituted with one or more substitu Patent Document 1 International Publication WO98/ ents selected from a halogenatom, an aryl group, a heteroaryl 51307 50 group, —OR'', and NR'R''), a C-, alkenyl group Patent Document 2 U.S. Pat. No. 4.942,163 (wherein the C-, alkenyl group may be substituted with one Patent Document 3 International Publication WO99/ or more Substituents selected from a halogen atom, a Cs 11624 alkyl group, an aryl C- alkyl group, an aryl group, and a Patent Document 4 International Publication WO2005/ heteroaryl group), a C-, alkynyl group (wherein the C-, O75431 55 alkynyl group may be substituted with one or more substitu Patent Document 5 International Publication WO2005/ ents selected from a halogen atom, a Cls alkyl group, an aryl O75432 C- alkyl group, an aryl group, and a heteroaryl group), a Non-Patent Document 1 J. Chem. Soc. (C), pp. 2205 halogen atom, a hydroxyl group, an aryl group, a heteroaryl 2208 (1968) group, a cyano group, an amino group (wherein the nitrogen Non-Patent Document 2.J. Org. Chem. Vol. 47, pp. 3787 60 atom of the amino group may be substituted with one or two 3788 (1982) Substituents selected from a Cls alkyl group, which may be Non-Patent Document 3 Arch. Pharm. Res., vol. 20, pp. substituted with —OR' or NR'R'', an aryl group, an aryl 264-268 (1997) C, alkyl group, and a heteroaryl group), -S(O), R'' Non-Patent Document 4 Bioorg. Med. Chem. Lett. Vol. (wherein n1 represents an integer from 0 to 2), a C- alkoxy 8, pp. 41-46 (1998) 65 group (wherein the alkoxy group may be substituted with one Non-Patent Document 5 Arch. Pharm. Res., vol. 24, pp. or more groups selected from an aryl group, a heteroaryl 276-280 (2001) group, —OR'', NR'R'', and a halogen atom), a 4- to US 7,820,693 B2 3 4 7-membered heterocyclyl group (wherein the heterocyclyl bonyl group, a C- alkoxycarbonyl group, an azido group, group may be substituted with one or more Substituents —OR', NRR, and -S(O)R (wherein n2 represents Selected from a Cls alkyl group, an aryl group, an aryl Co an integer from 0 to 2); alkyl group, and a heteroaryl group), an aryloxy group, a wherein R is selected from a hydrogen atom, PO heteroaryloxy group, and a C- alkylenedioxy group; (OR')OR', a Cisalkyl group (wherein the alkyl group may wherein each of R', R', R', and R'' is independently be substituted with one or more substituents selected from a selected from a hydrogen atom, a C- alkyl group (wherein halogen atom, a hydroxyl group, a C- alkoxy group, which the alkyl group may be substituted with one or more substitu may be substituted with a C- alkoxy group, an aryl group, ents selected from a hydroxyl group, a C- alkoxy group, an and —NRR), an aryl group, a heteroaryl group, a C aryl Coalkoxy group, an aryl group, and a heteroaryl group). 10 alkylcarbonyl group, a C-7 alkenylcarbonyl group, a Cas an aryl group, and a heteroaryl group; or R'' and R', together cycloalkylcarbonyl group (wherein the C alkylcarbonyl with nitrogen to which they bind, may form a 4- to 7-mem group, Calkenylcarbonyl group, and Css cycloalkylcarbo bered heterocyclic ring containing at least one nitrogenatom; nyl group may be substituted with one or more Substituents Z represents O, S, or NRa, wherein Ra represents a hydro selected from a hydroxyl group, —NR7R, an aryl group, gen atom, a Cls alkyl group, an aryl Co alkyl group, an aryl 15 which may be substituted with a hydroxyl group, a heteroaryl group, or a heteroaryl group; group, a mercapto group, a C- alkylthio group, a guanidyl Cy represents a 4- to 7-membered monocyclic heterocyclic group, a carboxy group, a C- alkoxycarbonyl group, a C ring or a 8- to 10-membered condensed heterocyclic ring, alkylcarbonyloxy group, an aryl C. alkoxy group, an ami wherein the carbon atom(s) of the heterocyclic ring may be nocarbonyl group, a C- alkylaminocarbonyl group, and a substituted with one or more substituents selected from di (C. alkyl)aminocarbonyl group (wherein the C- alky Group Q1, and when the heterocyclic ring contains —NH-, laminocarbonyl group and di(C. alkyl)aminocarbonyl the nitrogen atom may be substituted with a substituent group may be substituted with one or more Substituents selected from Group Q2; selected from an amino group, a C- alkylamino group, and wherein Group Q1 consists of a Cls alkyl group, which a di(C. alkyl)amino group), and —(OCHRCH), OR" may be substituted with one or more substituents selected 25 (whereinl represents an integer from 1 to 20), an arylcarbonyl from Group B, a C-7 alkenyl group, which may be substituted group, a heteroarylcarbonyl group, a 4- to 12-membered het with one or more substituents selected from Group B, a erocyclyl carbonyl group (wherein the arylcarbonyl group, hydroxyl group, a C- alkoxy group (wherein the alkoxy heteroarylcarbonyl group, and heterocyclyl carbonyl group group may be substituted with one or more Substituents may be substituted with one or more substituents selected selected from a halogenatom, a hydroxyl group, a Calkoxy 30 from a hydroxyl group, a carboxy group, a C- alkyl group, a group, an amino group, a C- alkylamino group, a di(C- C. alkoxycarbonyl group, a C- alkylcarbonyl group alkyl)amino group, an aryl group, and a heteroaryl group), a (wherein the Calkoxycarbonyl group and C alkylcarbo Calkylcarbonyl group, —CONR'R'', a carboxy group, a nyl group may be substituted with one or more Substituents Calkoxycarbonyl group, which may be substituted with an selected from a hydroxyl group, NR'R'', and a carboxy aryl group, an aryloxy group, a heteroaryloxy group, an 35 group), a C- alkoxycarbonyl group (wherein the C amino group, a C- alkylamino group, a di(C- alkyl)amino alkoxycarbonyl group may be substituted with one or more 4 group, a 4- to 7-membered heterocyclyl group (wherein the to 12-membered heterocyclyl groups), CONR'R'', -CO heterocyclyl group may be substituted with one or two sub (OCHRCH), OR' (wherein k represents an integer stituents selected from a Cls alkyl group, an aryl group, an from 1 to 20), and S(O), R (wherein n? represents an aryl Co alkyl group, and a heteroaryl group), an oxo group. 40 integer of 1 or 2); each of R*, R33, R34, R3s, R37, R38, R7, R72, R84, and R and a thioxo group; is independently selected from a hydrogenatom, a Cls alkyl wherein each of RandR’ is independently selected from group (wherein the alkyl group may be substituted with one or a hydrogenatom, a Cls alkyl group (wherein the alkyl group more Substituents selected from a halogen atom, a hydroxyl may be substituted with one or more substituents selected 45 group, a Calkoxy group, —(OCH2CH2)—OH (wherein m from a halogen atom, a hydroxyl group, a C- alkoxy group. represents an integer from 1 to 20), a C- alkoxycarbonyl an aryl group, an amino group, a C- alkylamino group, and group, an aryl group, an amino group, a C- alkylamino a di(C. alkyl)amino group), an aryl group, and a heteroaryl group, and a di(C. alkyl)amino group), -S(O).R. group; or (wherein na represents an integer of 1 or 2), a C- alkylcar R" and Rif, together with a nitrogen atom to which they 50 bonyl group (wherein the C alkylcarbonyl group may be bind, may form a 4- to 7-membered heterocyclyl group con substituted with one or more substituents selected from an taining at least one nitrogen atom (wherein the heterocyclyl amino group, a C- alkylamino group, a di(C. alkyl)amino group may be substituted with one or more Substituents group, an aminocarbonyl group, an aryl group, which may be selected from a hydroxyl group, a Cls alkyl group (wherein Substituted with a hydroxyl group, a heteroaryl group, a the alkyl group may be substituted with one or more substitu 55 hydroxyl group, a mercapto group, a C- alkylthio group, a ents selected from a hydroxyl group, a Cls alkoxy group, and guanidyl group, and a carboxy group), a Calkylaminocar an aryl group), an aryl group, and a heteroaryl group); bonyl group, a C- alkoxycarbonyl group, a 4- to 7-mem wherein Group Q2 consists of a Cls alkyl group (wherein bered heterocyclyl carbonyl group, an aryl group, and a het the alkyl group may be substituted with one or more substitu eroaryl group; or ents selected from a halogen atom, a hydroxyl group, a C 60 R° and R, R and R, R7 and R, and RandR, alkoxy group, an amino group, a C- alkylamino group, a together with a nitrogenatom to which they bind, may form a di (C. alkyl)amino group, an aryl group, and a heteroaryl 4- to 7-membered heterocyclyl group containing at least one group), a C- alkoxycarbonyl group, an aryl Coalkoxycar nitrogen atom (wherein the heterocyclyl group may be Sub bonyl group, an aryl group, and a heteroaryl group; stituted with one or more substituents selected from a wherein Group B consists of a halogenatom, an aryl group, 65 hydroxyl group, a Cls alkyl group (wherein the alkyl group a heteroaryl group, an oxo group, a C- alkylcarbonyl group. may be substituted with one or more substituents selected a C- alkylaminocarbonyl group, a di(C. alkyl)aminocar from a hydroxyl group, a Cls alkoxy group, and an aryl US 7,820,693 B2 5 6 group), a Cls alkoxy group (wherein the alkoxy group may be substituted with one or more substituents selected from a -continued hydroxyl group, a Cls alkoxy group, and an aryl group), an aryl group, and a heteroaryl group); each of R and R is independently selected from a hydrogen atom, a Cls alkyl group (wherein the alkyl group R may be substituted with one or more substituents selected R1 Z Z from a hydroxyl group, a C- alkoxy group, an aryl C. alkoxy group, an aryl group, and a heteroaryl group), a C2-s 10 alkenyl group, a Cal cycloalkyl group, an aryl group, and a ( N- and R- N heteroaryl group; each of R' and R' is independently selected from a hydrogen atom, an aryl C alkyl group, and a Cls alkyl wherein the carbonatom(s) of the heterocyclic ring may be 15 substituted with one or more substituents selected from group; Group Q1; and each of R and R is independently selected from a R" represents a hydrogenatom, a Cls alkyl group (wherein hydrogenatom, a C- alkyl group, which may be substituted the alkyl group may be substituted with one or more substitu with one or more hydroxyl groups, and an aryl C alkyl ents selected from a halogen atom, a hydroxyl group, a C group; alkoxy group, an amino group, a C- alkylamino group, a each occurrence of R'' and R7 is independently selected di (C. alkyl)amino group, an aryl group, and a heteroaryl from a hydrogen atom, a C- alkyl group, a C- alkyl group. group), a C- alkoxycarbonyl group, an aryl Coalkoxycar which is Substituted with a hydroxyl group, and —CH2 bonyl group, an aryl group, or a heteroaryl group. In another aspect of the present invention, Cy may be a (OCH2CH), OR' (whereini represents an integer from 1 25 heterocyclic ring selected from the following group: to 20): R" is selected from a hydrogen atom, an aryl C. alkyl group, and a C- alkyl group, which may be substituted with Formula 3 one or more hydroxyl groups; and R represents a C- alkyl group, or a prodrug thereof, or a 30 pharmaceutically acceptable salt thereof. In one aspect of the present invention, Cy is not particularly limited. It may be a heterocyclic ring selected from the fol lowing group, for example: 35

Formula 2) 40 In another aspect of the present invention, the carbon atom(s) of Cy are substituted with one or two groups selected from a hydroxyl group, and the groups —C(=O)—OR, O CRR ORS, CRRYCRR OR, C(O) Z Z Z NR54R55, and CR5 IR52 NR56R57; 45 R" represents a hydrogen atom or a C- alkyl group (wherein the alkyl group may be substituted with a hydroxyl On N1 -- -- group or a C- alkoxy group); > -/ su su each of R and R is independently selected from a 50 hydrogen atom, a C- alkyl group (wherein the alkyl group Z Z Z may be substituted with one or more substituents selected from a hydroxyl group and an amino group), and a C alkenyl group; -- -- 2 each of R and R is independently selected from a hydro 21 21 55 gen atom and a C- alkyl group: Z Z Z Z R represents a hydrogen atom, a C- alkyl group RI (wherein the alkyl group may be substituted with 1 to 3 -( N-( Substituents selected from an aryl group, a hydroxyl group, a C- alkoxy group, a C- alkoxy C- alkoxy group, and N- ) - U - U - 60 —NR'R''), a C- alkylcarbonyl group (wherein the alkylcar Z Z Z bonyl group may be substituted with 1 to 3 substituents selected from a hydroxyl group, a C- alkoxy group, an aryl RI l group, NR'R'', a carboxy group, —CONR'R'', and NN N1 - N -(OCHRCH), OR7 (wherein R7, R', and 1 are the 65 same as those defined above)), an arylcarbonyl group or a 4 to 7-membered heterocyclyl carbonyl group (wherein the arylcarbonyl group and heterocyclyl carbonyl group may be US 7,820,693 B2 7 8 substituted with one or more substituents selected from a group may be substituted with one or more Substituents carboxy group, a Calkoxycarbonyl group, and a C alky selected from a hydroxyl group, a C- alkylamino group, a lcarbonyl group (wherein the Calkoxycarbonyl group and di (C. alkyl)amino group, and a 4- to 7-membered hetero Calkylcarbonyl group may be substituted with one or more cyclyl group containing at least one nitrogen atom (wherein substituents selected from NR'R'', a carboxy group, and 5 the heterocyclyl group may be substituted with a hydroxyl a hydroxyl group)), or -CO(OCHRCH), OR7 group)). (wherein R. R', and kare the same as those defined above), each of R and R is independently selected from a In yet another aspect, the present invention provides the hydrogen atom and a C- alkyl group (wherein the alkyl compound represented by the formula (1), a prodrug thereof, group may be substituted with a hydroxyl group or an amino 10 and a pharmaceutically acceptable salt thereof. group); or R and R, together with a nitrogen atom to wherein the carbon atom(s) of Cy are substituted with the which they bind, may form a 4- to 7-membered heterocyclic group CRR OR; ring (wherein the heterocyclic ring may be substituted with 1 wherein each of RandR is independently selected from to 3 Substituents selected from a hydroxyl group and a a hydrogenatom, a C- alkyl group (wherein the alkyl group hydroxy C. alkyl group); 15 may be substituted with a hydroxyl group or an amino group), each of R and R7 is independently selected from a and a C2-alkenyl group: hydrogen atom, a C- alkyl group (wherein the alkyl group may be substituted with a hydroxyl group oranamino group), R is selected from a hydrogenatom, PO(OR')OR', a and a C- alkylsulfonyl group (wherein the alkylsulfonyl C. alkylcarbonyl group, a C-s cycloalkylcarbonyl group group may be substituted with a hydroxyl group or an amino (wherein the C- alkylcarbonyl group and Css cycloalkyl group); or R and R7, together with a nitrogen atom to carbonyl group may be substituted with one or more substitu which they bind, may form a 4- to 7-membered heterocyclic ents selected from a hydroxyl group, NR7R, an aryl ring (wherein the heterocyclic ring may be substituted with 1 group, a carboxy group, a C- alkoxycarbonyl group, a C to 3 Substituents selected from a hydroxyl group and a alkylaminocarbonyl group, and a di(C. alkyl)aminocarbo hydroxy C. alkyl group); 25 nyl group (wherein the C alkylaminocarbonyl group and each of R'' and R is independently selected from a di (C. alkyl)aminocarbonyl group may be substituted with hydrogen atom, a C- alkyl group, and a C- alkylcarbonyl one or more Substituents selected from an amino group, a C group (wherein the alkylcarbonyl group may be substituted alkylamino group, and a di(Calkyl)amino group)), an aryl with 1 to 3 substituents selected from a hydroxyl group, a C carbonyl group, and a 4- to 7-membered heterocyclyl carbo alkoxy group, an aryl group, an amino group, a C- alky 30 nyl group (wherein the arylcarbonyl group and heterocyclyl lamino group, a di(C. alkyl)amino group, and a carboxy carbonyl group may be substituted with one or more substitu group); or R'' and R, together with a nitrogen atom to ents selected from a carboxy group, a C alkoxycarbonyl which they bind, may form a 4- to 7-membered heterocyclic group, a C- alkylcarbonyl group (wherein the Calkoxy r1ng, carbonyl group and C alkylcarbonyl group may be substi each of R and R is independently selected from a hydro 35 tuted with one or more substituents selected from a hydroxyl gen atom and a C- alkyl group, and group, —NR'R'', a carboxy group, and a hydroxyl group)); each of R and R is independently selected from a each of R7 and R is independently selected from a hydrogen atom and a C- alkyl group (wherein the alkyl hydrogen atom, a Cls alkyl group (wherein the alkyl group group may be substituted with a hydroxyl group or an amino may be substituted with one or more substituents selected group); or R and R', or RandR, together with a nitrogen 40 from a halogen atom, a hydroxyl group, a C- alkoxy group. atom to which they bind, may form a 4- to 7-membered an aryl group, an amino group, a C- alkylamino group, and heterocyclic ring. a di(C. alkyl)amino group), -S(O)2R (wherein n2 rep In another aspect of the present invention, the Substi resents an integer of 1 or 2), a C- alkylcarbonyl group tuent(s) on the ring carbon atom(s) of Cy are selected from a (wherein the C alkylcarbonyl group may be substituted hydroxyl group, a Cls alkyl group (wherein the alkyl group 45 with one or more Substituents selected from an amino group, may be substituted with one or more substituents selected a C- alkylamino group, a di(Calkyl)amino group, and an from a hydroxyl group, a C- alkylamino group, a di(C. aryl group), a C- alkylaminocarbonyl group, a C- alkoxy alkyl)amino group, a 4- to 7-membered heterocyclyl group carbonyl group, an aryl group, and a heteroaryl group; or containing at least one nitrogen atom (wherein the heterocy clyl group may be substituted with a hydroxyl group, or a C 50 R7 and R, together with a nitrogen atom to which they alkyl group, which may be substituted with a hydroxyl bind, may form a 4- to 7-heterocyclyl group containing at group), a C- alkylcarbonyloxy group (wherein the C least one nitrogenatom (wherein the heterocyclyl group may be substituted with a hydroxyl group, a Cls alkyl group alkylcarbonyloxy group may be substituted with one or two (wherein the alkyl group may be substituted with a hydroxyl Substituents selected from a hydroxyl group and group, a Cls alkoxy group, or an aryl group), a Cls alkoxy —(OCH2CH), OR' (wherein R' and 1 are the same as 55 those defined above), OCO(OCHR7°CH), OR7 group (wherein the alkoxy group may be substituted with a (wherein R. R', and k are the same as those defined hydroxyl group, a Cisalkoxy group, oran aryl group), an aryl above)), and CONR'R'': group, or a heteroaryl group); wherein each of R'' and R is selected from a hydrogen R is selected from a hydrogen atom, a Cls alkyl group atom and a C- alkyl group; or R'' and R', together with 60 (wherein the alkyl group may be substituted with one or more nitrogen to which they bind, may form a 4- to 7-membered Substituents selected from a hydroxyl group, a C- alkoxy heterocyclic ring containing at least one nitrogen atom group, an aryl C- alkoxy group, an aryl group, and a het (wherein the heterocyclyl group may be substituted with a eroaryl group), a C2-s alkenyl group, a C-cycloalkyl group. hydroxyl group). an aryl group, and a heteroaryl group; and In still another aspect of the present invention, the substitu 65 each of R'' and R is independently selected from a ent(s) on the ring carbon atom(s) of Cy are selected from a hydrogen atom, an aryl Co alkyl group, and a Cls alkyl hydroxyl group and a Cls alkyl group (wherein the alkyl group. US 7,820,693 B2 10 In still another aspect of the present invention, the substitu preferred properties as a pharmaceutical in terms of water ent(s) on the ring carbon atom(s) of Cy are selected from a solubility and safety. In addition, the present invention pro hydroxyl group, a hydroxymethyl group, and a 1-hydroxy-1- vides a compound, which is useful as a therapeutic and pre methylethyl group. ventive agent effective for proliferative diseases such as can In still another aspect of the present invention, a substituent cer, a production method thereof, an intermediate compound on the ring nitrogenatom of Cy is selected from an Cs alkyl useful for Such production, and a pharmaceutical composi group (wherein the alkyl group may be substituted with a tion comprising Such a compound. hydroxyl group). In yet another aspect of the present invention, the Substitu Embodiments of the Invention ent(s) on the ring carbon atom(s) of Cy are —CH2— 10 OCOCH (OCHCH), OR7 (wherein R7 and 1 are the In the present invention, the term “aryl group' is used to same as those defined above), a propionyloxymethyl group, mean an aromatic hydrocarbon group containing 6 to 10 which is substituted with one or two hydroxyl groups, or carbon atoms, which includes phenyl, 1-naphthyl 2-naph -CH, OCO(OCHR7°CH), OR7 (wherein R7, R7, thyl, and others. and k are the same as those defined above). 15 In the present invention, the term "heteroaryl group' is In one aspect of the present invention, Z is preferably O. In used to mean a 5- to 10-membered aromatic heterocyclyl addition, the Substituent(s) on the ring carbon atom(s) of Cy group containing one or more heteroatoms selected from an are not particularly limited. For example, it may be selected oxygenatom, a nitrogenatom, and a Sulfur atom. Examples of from a hydroxyl group and a Cls alkyl group (wherein the Such a heteroaryl group may include furyl, thienyl, pyrrolyl, alkyl group may be substituted with one or more Substituents imidazolyl pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, selected from a hydroxyl group, a C- alkylcarbonylamino isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, group, and a 4- to 7-membered heterocyclyl group containing pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, at least one nitrogen atom (wherein the heterocyclyl group quinolinyl, isoquinolyl, and benzimidazolyl. may be substituted with a hydroxyl group), and in particular, In the present invention, the term “halogenatom' is used to it may be substituted with a hydroxyl group). 25 mean a fluorine atom, a chlorine atom, a bromine atom, an In one aspect of the present invention, X may be an aryl iodine atom, or the like. A preferred example of such a halo group, which may be substituted with one or more substitu gen atom is a fluorine atom. ents selected from Group A1; wherein Group A1 consists of a In the present invention, the term "Cs alkyl group' is used Cs alkyl group (wherein the alkyl group may be substituted to mean a linear or branched alkyl group containing 1 to 8 with one or more Substituents selected from a halogen atom 30 carbon atoms, or a cyclic or partially cyclic alkyl group con and NR'R''), a halogen atom, a hydroxyl group, an aryl taining 3 to 8 carbon atoms. Examples of Such a Cls alkyl group, an amino group (wherein the nitrogen atom of the group may include methyl, ethyl, n-propyl, i-propyl. n-butyl, amino group may be substituted with one or two Substituents s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbu selected from a Cls alkyl group and an aryl group), —SR'', tyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, a C- alkoxy group (wherein the alkoxy group may be sub 35 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbu stituted with one or more substituents selected from —OR'' tyl, 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclo and a halogen atom), and a 4- to 7-membered heterocyclyl hexyl, cycloheptyl, cyclooctyl, methylcyclopropyl, cyclopro group (wherein the heterocyclyl group may be substituted pylmethyl, and methylhexyl. A preferred example of such a with one or two Substituents selected from Cs alkyl groups); Cs alkyl group is a linear or branched Cls alkyl group, and wherein each of R'', R', R', and R'' is independently 40 selected from a hydrogenatom, a Cls alkyl group, and an aryl a more preferred example is a linear or branched C. alkyl group; or R'' and R', together with nitrogen to which they group. bind, may form a 4- to 7-membered heterocyclic ring con In the present invention, the term “C, alkenyl group” is taining at least one nitrogen atom. used to mean a linear or branched alkenyl group containing 2 In one aspect of the present invention, X may be an aryl 45 to 7 carbonatoms. Examples of such a C-, alkenyl group may group, which may be substituted with one or more substitu include ethenyl (vinyl), 1-propenyl, 2-propenyl(allyl), pro ents selected from a halogen atom, a C- alkyl group, a halo pen-2-yl, 3-butenyl(homoallyl), and 1.4-pentadien-3-yl. C. alkyl group, a C- alkoxy group, a halo Ce alkoxy In the present invention, the term “C, alkynyl group” is group, an aryl group, and a 4- to 7-membered heterocyclyl used to mean a linear or branched alkynyl group containing 2 group. More specifically, X is an aryl group, and the aryl 50 to 7 carbon atoms. Examples of Such a C-, alkynyl group group may be substituted with an ethyl group, a trifluorom may include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, ethyl group, a trifluoromethoxy group, an ethoxy group, a 2-butynyl, and 3-butynyl. propoxy group, a phenyl group, or a morpholinyl group. In the present invention, the term "C. alkoxy group' is In another aspect, the present invention provides a phar used to mean an alkyloxy group having a linear or branched maceutical composition, which comprises, as an active ingre 55 alkyl group containing 1 to 6 carbon atoms, and a cyclic or dient, the compound represented by the formula (1), a pro partially cyclic alkyl group containing 3 to 6 carbon atoms, as drug thereof, or a pharmaceutically acceptable salt thereof. alkyl portions thereof. Examples of Such a C- alkoxy group In a further aspect, the present invention provides a thera may include methoxy, ethoxy, n-propoxy, i-propoxy, n-bu peutic and preventive agent used formalignant tumor such as toxy, S-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbu Solid cancer, which comprises, as an active ingredient, the 60 toxy, 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, compound represented by the formula (1), a prodrug thereof, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methyl or a pharmaceutically acceptable salt thereof. pentoxy, 1-methylpentoxy, 3-ethylbutoxy, 2-ethylbutoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, EMBODIMENTS OF THE INVENTION and cyclopropylmethoxy. 65 In the present invention, the term “aryloxy group' is used The present invention provides a 1-(2H)-isoquinolone to mean an aryloxy group having, as an aryl portion thereof, derivative, which has excellent antitumor action and also has an aromatic hydrocarbon group containing 6 to 10 carbon US 7,820,693 B2 11 12 atoms, which has already been defined above. Examples of containing 3 to 6 carbonatoms. The two alkylportions may be Such an aryloxy group may include phenoxy, 1-naphthoxy, either identical to or different from each other. Examples of and 2-maphthoxy. Such a “di(C. alkyl)amino group' may include dimethy In the present invention, the term "heteroaryloxy group' is lamino, diethylamino, di-n-propylamino, di-i-propylamino, used to mean a heteroaryloxy group having, as a heteroaryl di-n-butylamino, methyl-n-butylamino, methyl-S-buty portion thereof, a 5- to 10-membered aromatic heterocyclyl lamino, methyl-i-butylamino, methyl-t-butylamino, ethyl-n- group containing a heteroatom selected from at least one butylamino, ethyl-S-butylamino, ethyl-i-butylamino, and oxygen atom, nitrogen atom, and Sulfur atom, which has ethyl-t-butylamino. already been defined above. Examples of such a heteroary In the present invention, the term "C. alkylcarbonyl loxy group may include furyloxy, thienyloxy, pyrrolyloxy, 10 group' is used to mean an alkylcarbonyl group having, as imidazolyloxy, pyrazolyloxy, oxazolyloxy, isoxazolyloxy, alkyl portions thereof, a linear or branched alkyl group con thiazolyloxy, isothiazolyloxy, oxadiazolyloxy, thiadiazoly taining 1 to 6 carbon atoms, and a cyclic or partially cyclic loxy, triazolyloxy, tetrazolyloxy, pyridinyloxy, pyrimidiny alkyl group containing 3 to 6 carbon atoms. loxy, pyrazinyloxy, pyridazinyloxy, indolyloxy, quinoliny In addition, in the present invention, the term "Calkoxy loxy, and isoquinolinyloxy. 15 carbonyl group (wherein the alkoxycarbonyl group may be In the present invention, the term "heteroarylcarbonyl substituted with one or more substituents selected from an group' is used to mean a heteroarylcarbonyl group having, as amino group, a guanidyl group, a carboxy group, a mercapto a heteroaryl portion thereof, a 5- to 10-membered aromatic group, an aminocarbonyl group, a methylthio group, a phenyl heterocyclyl group containing a heteroatom selected from at group, which may be substituted with a hydroxyl group, a least one oxygenatom, nitrogenatom, and Sulfur atom, which hydroxyl group, and an indolyl group) also includes an has already been defined above. Examples of such a het C.-amino acid-derived group (a group obtained by conversion eroarylcarbonyl group may include furylcarbonyl, thienyl of a carboxy group to a carbonyl group). Such as alanine, carbonyl, pyrrolylcarbonyl, imidazolylcarbonyl, pyrazolyl arginine, asparagine, aspartic acid, cysteine, glutamine, carbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, glutamic acid, glycine, histidine, isoleucine, leusine, lysine, thiazolylcarbonyl, isothiazolylcarbonyl, oxadiazolylcarbo 25 methionine, phenylalanine, serine, threonine, tryptophan, nyl, thiadiazolylcarbonyl, triazolylcarbonyl, tetrazolylcarbo tyrosine, or valine. nyl, pyridinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcar In the present invention, the term "C-7 alkenylcarbonyl bonyl, pyridazinylcarbonyl, indolylcarbonyl, group' is used to mean an alkenylcarbonyl group having, as quinolinylcarbonyl, and isoquinolinylcarbonyl. an alkenyl portion thereof, a linear or branched alkenyl group In the present invention, the term "haloC alkyl group” is 30 containing 2 to 7 carbon atoms. Examples of such a C-7 used to mean an alkyl group Substituted with one or more alkenylcarbonyl group may include ethenylcarbonyl(vinyl halogen atoms, which has, as alkyl portions thereof, a linear carbonyl), 1-propenylcarbonyl, 2-propenylcarbonyl(allylcar or branched alkyl group containing 1 to 6 carbon atoms, and bonyl), propen-2-ylcarbonyl, 3-butenylcarbonyl(homoallyl a cyclic or partially cyclic alkyl group containing 3 to 6 carbonyl), and 1.4-pentadien-3-ylcarbonyl. carbon atoms. Examples of such a haloC alkyl group may 35 In the present invention, the term "C. alkylcarbony include trifluoromethyl, trichloromethyl, chlorodifluorom lamino group' is used to mean an alkylcarbonylamino group ethyl, 2.2.2-trifluoroethyl, perfluoroethyl, 2.2.2-trichloroet having, as alkyl portions thereof, a linear or branched alkyl hyl, bromomethyl, dibromomethyl, tribromomethyl, iodom group containing 1 to 6 carbonatoms, and a cyclic or partially ethyl, difluoromethyl, and dichloromethyl. cyclic alkyl group containing 3 to 6 carbon atoms. In the present invention, the term "haloC alkoxy group' 40 In the present invention, the term "C. alkylcarbonyloxy is used to mean an alkoxy group Substituted with one or more group' is used to mean an alkylcarbonyloxy group having, as halogen atoms, which has, as alkyl portions thereof, a linear alkyl portions thereof, a linear or branched alkyl group con or branched alkyl group containing 1 to 6 carbon atoms, and taining 1 to 6 carbon atoms, and a cyclic or partially cyclic a cyclic or partially cyclic alkyl group containing 3 to 6 alkyl group containing 3 to 6 carbon atoms. carbonatoms. Examples of such a haloCalkoxy group may 45 In the present invention, the term "Ce alkoxycarbonyl include trifluoromethoxy, trichloromethoxy, chlorodifluo group' is used to mean an alkoxycarbonyl group having, as romethoxy, 2.2.2-trifluoroethoxy, perfluoroethoxy, 2.2.2- alkoxy portions thereof, a linear or branched alkoxy group trichloroethoxy, bromomethoxy, dibromomethoxy, tribro containing 1 to 6 carbonatoms, and a cyclic or partially cyclic momethoxy, iodomethoxy, difluoromethoxy, and alkoxy group containing 3 to 6 carbon atoms. dichloromethoxy. 50 In the present invention, the term "Ce alkylaminocarbo In the present invention, the term "Ce alkylamino group' nyl group' is used to mean an alkylaminocarbonyl group is used to mean an alkylamino group having, as alkyl portions having, as alkyl portions thereof, a linear or branched alkyl thereof, a linear or branched alkyl group containing 1 to 6 group containing 1 to 6 carbonatoms, and a cyclic or partially carbon atoms, and a cyclic or partially cyclic alkyl group cyclic alkyl group containing 3 to 6 carbon atoms. containing 3 to 6 carbon atoms. Examples of Such a C 55 In the present invention, the term "di(C. alkyl)aminocar alkylamino group may include methylamino, ethylamino, bonyl group' is used to mean a dialkylaminocarbonyl group n-propylamino, i-propylamino, n-butylamino, S-butylamino, having, as two alkyl portions thereof, a linear or branched i-butylamino, t-butylamino, n-pentylamino, 3-methylbuty alkyl group containing 1 to 6 carbon atoms, and a cyclic or lamino, 2-methylbutylamino. 1-methylbutylamino. 1-ethyl partially cyclic alkyl group containing 3 to 6 carbon atoms, propylamino, n-hexylamino, 4-methylpentylamino, 3-meth 60 which may be either identical to or different from each other. ylpentylamino, 2-methylpentylamino, In the present invention, the term "amino Calkoxycar 1-methylpentylamino, 3-ethylbutylamino, and 2-ethylbuty bonyl group' is used to mean an aminoalkoxycarbonyl group lamino. having, as alkoxy portions thereof, a linear or branched In the present invention, the term "di(C. alkyl)amino alkoxy group containing 1 to 6 carbon atoms, and a cyclic or group' is used to mean a dialkylamino group having, as two 65 partially cyclic alkoxy group containing 3 to 6 carbon atoms. alkyl portions, a linear or branched alkyl group containing 1 In the present invention, the term "hydroxy C. alkyl to 6 carbon atoms, and a cyclic or partially cyclic alkyl group group' is used to mean a hydroxyalkyl group having, as alkyl US 7,820,693 B2 13 14 portions thereof, a linear or branched alkyl group containing ring, or spiro ring skeleton. An aromatic heterocyclic ring is 1 to 6 carbon atoms, and a cyclic or partially cyclic alkyl also included therein. Specific examples may include isoben group containing 3 to 6 carbon atoms. Zofuranyl, chromenyl, indolizinyl, indolyl, isoindolyl, inda In the present invention, the term "Ce alkylthio group' is Zolyl, puryl, quinolizinyl, isoquinolinyl, quinolinyl, used to mean an alkylthio group having, as alkyl portions phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cin thereof, a linear or branched alkyl group containing 1 to 6 nolinyl, pteridinyl, isochromanyl, chromanyl, quinuclidinyl, carbon atoms, and a cyclic or partially cyclic alkyl group oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, diazacy containing 3 to 6 carbon atoms. Examples of Such a C cloheptyl, oxacyclooctyl, dioxacyclooctyl, azacyclooctyl, alkylthio group may include methylthio, ethylthio, n-propy diazacyclooctyl, azaoxacyclooctyl, thiacyclooctyl, dithiacy lthio, i-propylthio, n-butylthio, s-butylthio, i-butylthio, t-bu 10 clooctyl, thiaoxacyclooctyl, azathiacyclooctyl, oxacy tylthio, n-pentylthio. 3-methylbutylthio, 2-methylbutylthio. clononyl, dioxacyclononyl, trioxacyclononyl, azacy 1-methylbutylthio. 1-ethylpropylthio, n-hexylthio. 4-methyl clononyl, aZaoxacyclononyl, triazacyclononyl, pentylthio. 3-methylpentylthio, 2-methylpentylthio, 1-meth thiacyclononyl, dithiacyclononyl, azadithiacyclononyl, ylpentylthio. 3-ethylbutylthio, and 2-ethylbutylthio. oxacyclodecanyl, dioxacyclodecanyl, trioxacyclodecanyl. In the present invention, the term “aryl C. alkyl group' is 15 azacyclodecanyl, diazacyclodecanyl, azaoxacyclodecanyl. used to mean an aralkyl group, which has, as an aryl group azadioxacyclodecanyl, diazaoxacyclodecanyl, thiacyclode thereof, the defined aromatic hydrocarbon group containing 6 canyl, dithiacyclodecanyl, trithiacyclodecanyl, azathiacyclo to 10 carbon atoms, and as alkyl portions thereof, a linear or decanyl, diazathiacyclodecanyl, oxacycloundecanyl, diox branched alkyl group containing 1 to 6 carbon atoms, and a acycloundecanyl, trioxacycloundecanyl, azacycloundecanyl. cyclic or partially cyclic alkyl group containing 3 to 6 carbon diazacycloundecanyl, triazacycloundecanyl, thiacyclounde atoms. Examples of such an aryl C alkyl group may include canyl, dithiacycloundecanyl, trithiacycloundecanyl, azaox benzyl, 1-phenethyl, and 2-phenethyl. acycloundecanyl, azathiacycloundecanyl, azadioxacycloun In the present invention, the term “aryl C alkoxy group' decanyl, diazaoxacycloundecanyl, azathiacycloundecanyl. is used to mean an aralkyloxy group, which has, as an aryl diazathiacycloundecanyl, azadithiacycloundecanyl, oxacy group thereof, the defined aromatic hydrocarbon group con 25 clododecanyl, dioxacyclododecanyl, trioxacyclododecanyl. taining 6 to 10 carbon atoms, and as alkoxy portions thereof, tetraoxacyclododecanyl, azacyclododecanyl, diazacy a linear or branched alkoxy group containing 1 to 6 carbon clododecanyl, triazacyclododecanyl, tetraazacyclododeca atoms, and a cyclic or partially cyclic alkoxy group contain nyl, thiacyclododecanyl, dithiacyclododecanyl, trithiacy ing 3 to 6 carbonatoms. Examples of such an aryl Coalkoxy clododecanyl. tetrathiacyclododecanyl, group may include benzyloxy, 1-phenethyloxy, and 2-phen 30 aZaoxacyclododecanyl, azathiacyclododecanyl, diazaoxacy ethyloxy. clododecanyl, azadioxacyclododecanyl, azatrioxacy In the present invention, the term “a 4- to 7-membered clododecanyl, azadithiacyclododecanyl, diazadithiacy heterocyclic ring containing at least one nitrogen atom' is clododecanyl, azatrithiacyclododecanyl, as well as specific used to mean a saturated or unsaturated heterocyclic ring examples of “4- to 7-membered heterocyclyl group described containing 4 to 7 atoms in the ring thereof, which contains one 35 later. The position of the heterocyclyl group to be substituted or more nitrogen atoms and may also contain one or more is not particularly limited, as long as it is a Substitutable heteroatoms selected from an oxygen atom and a Sulfur position on a carbonatom or nitrogenatom. In addition, when atoms. Such a heterocyclic ring may have a monocyclic ring, the heterocyclyl group has —NH in the ring thereof, the condensed ring, or spiro ring skeleton. An aromatic hetero Substituent of the heterocyclic ring may be present on a car cyclic ring is also included therein. Specific examples may 40 bon atom or a nitrogen atom, unless otherwise specified. include aZetidine, pyrrolidine, piperidine, piperazine, pyr In the present invention, the term “4- to 7-membered het role, imidazole, imidazoline, imidazolidine, pyrazole, pyra erocyclic ring is used to mean a Saturated or unsaturated Zoline, oxazoline, oxazolidine, morpholine, thiomorpholine, heterocyclyl group containing 4 to 7 atoms in the ring thereof, and hexamethyleneimine. which may contain one or more heteroatoms selected from a In the present invention, the term “4- to 7-heterocyclyl 45 nitrogen atom, an oxygen atom, and a Sulfur atom. The het group containing at least one nitrogen atom' is used to mean erocyclic ring may have a monocyclic ring, condensed ring, a Saturated or unsaturated heterocyclyl group containing 4 to or spiro ring skeleton. An aromatic heterocyclic ring is also 7 atoms in the ring thereof, which contains one or more included therein. Specific examples may include azetidinyl, nitrogen atoms and may also contain one or more heteroat pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, imidazolyl, oms selected from an oxygenatom and a Sulfur atom. Such a 50 imidazolinyl, pyrazolyl pyrazolinyl, oxazolinyl, morpholi heterocyclyl group may have a monocyclic ring, condensed nyl, thiomorpholinyl, pyridinyl, pyrazinyl, pyrimidinyl, ring, or spiro ring skeleton. An aromatic heterocyclyl group is pyridazinyl, hexamethyleneimino, furyl, tetrahydrofuryl, also included therein. Specific examples may include aZetidi thienyl, tetrahydrothienyl, dioxolanyl, oxathiolanyl, and nyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrrolyl, imida dioxanyl. The position of the heterocyclyl group to be substi Zolyl, imidazolinyl, imidazolidinyl, pyrazolyl pyrazolinyl, 55 tuted is not particularly limited, as long as it is a Substitutable oxazolinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, position on a carbonatom or nitrogenatom. In addition, when pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolidinyl, the heterocyclyl group has —NH in the ring thereof, the hexamethyleneimino, and octahydroisoquinolyl. The posi Substituent of the heterocyclic ring may be present on a car tion of the heterocyclyl group to be substituted is not particu bon atom or a nitrogen atom, unless otherwise specified. larly limited, as long as it is a Substitutable position on a 60 Specific examples of Such a heterocyclic ring having a Sub carbon atom or nitrogen atom. stituent(s) may include methyldioxolanyl, dimethyldioxola In the present invention, the term “4- to 12-membered nyl, ethyldioxolanyl, diethyldioxolanyl, hydroxypiperidinyl, heterocyclyl group' is used to meana Saturated or unsaturated hydroxymethylpiperidinyl, hydroxyethylpiperidinyl, meth heterocyclyl group containing 4 to 12 atoms in the ring oxypiperidinyl, ethoxypiperidinyl, methylthiopiperidinyl, thereof, which may contain one or more heteroatoms selected 65 carboxytetrahydrofuryl, hydroxytetrahydrofuryl, dihydrox from a nitrogenatom, an oxygenatom, and a Sulfur atom. The ytetrahydrofuryl, trihydroxytetrahydrofuryl, hydroxytet heterocyclic ring may have a monocyclic ring, condensed rahydropyranyl, dihydroxytetrahydropyranyl, trihydroxytet US 7,820,693 B2 15 16 rahydropyranyl, tetrahydroxytetrahydropyranyl. phenyltetrahydrothienyl, methoxycarbonyldioxolanyl, and -continued Formula 5 methylcarbonylpiperazinyl. Z Z Z In the present invention, the term “4- to 7-membered monocyclic heterocyclic ring is used to mean a saturated or N1 N1 R!NN -l N1 unsaturated monocyclic heterocyclyl group containing 4 to 7 / / ) / atoms in the ring thereof, which contains one or more het O S eroatoms selected from a nitrogenatom, an oxygenatom, and O Z Z a Sulfur atom. An aromatic monocyclic heterocyclic ring is 10 also included therein. Further, when the heterocyclic ring has —NH in the ring thereof, the substituent of the heterocyclic RINN -l N1 O l N1 ring may be present on a carbon atom or a nitrogen atom, unless otherwise specified. When Cy in the formula (1) is a 4 to 7-membered monocyclic heterocyclic ring, examples of a 15 O O group consisting of Cy Substituted with the group Z may Z Z Z Z include the following groups: ------N1 Formula 4 ( --- su Null O Z Z

1. - - - N 25 O eSS/

30 wherein R' is the same as defined above, and each hetero cyclic ring may have a substituent as defined above. In the present invention, the term “8- to 10-membered condensed heterocyclic ring is used to mean a saturated or 35 unsaturated cyclic heterocyclyl group containing to 10 atoms in the ring thereof, which contains one or more heteroatoms selected from a nitrogen atom, an oxygen atom, and a Sulfur atom. An aromatic cyclic heterocyclic ring is also included therein. When Cy in the formula (1) is a 8- to 10-membered 40 condensed heterocyclic ring, examples of a group consisting of Cy substituted with the group Z= may include the follow ing groups:

Formula 6 Z Z

C.Z C.Z Z / \ N1 --- 55

O sN O

Z Z 60 S ul N1 RINN l N1 Z

65 US 7,820,693 B2 17 18 decanylcarbonyl, azadithiacycloundecanylcarbonyl, oxacy -continued clododecanylcarbonyl, dioxacyclododecanylcarbonyl, Z trioxacyclododecanylcarbonyl, tetraoxacyclododecanylcar bonyl, azacyclododecanylcarbonyl, diazacyclododecanyl RelNN N1 Z carbonyl, triazacyclododecanylcarbonyl, tetraazacyclodode canylcarbonyl, thiacyclododecanylcarbonyl, dithiacyclododecanylcarbonyl, trithiacyclododecanylcarbo nyl, tetrathiacyclododecanylcarbonyl, azaoxacyclododecan ylcarbonyl, azathiacyclododecanylcarbonyl, diazaoxacy 10 clododecanylcarbonyl, azadioxacyclododecanylcarbonyl, C or aZatrioxacyclododecanylcarbonyl, azadithiacyclododecanyl carbonyl, diazadithiacyclododecanylcarbonyl, and aza N1 trithiacyclododecanylcarbonyl. In addition, uronic acid residues (groups obtained by con 15 version of a carboxy group to a carbonyl group) derived from monosaccharides capable of adopting a cyclic structure. Such as alluronic acid, altruronic acid, glucuronic acid, mannu wherein R' is the same as defined above, and each hetero ronic acid, guluronic acid, iduronic acid, galacturonic acid, or cyclic ring may have a substituent as defined above. taluronic acid, are also included. In the present invention, the term “4- to 12-membered Moreover, a pyrrolidin-2-ylcarbonyl group derived from heterocyclyl carbonyl group' is used to mean a heterocyclyl proline that is an O-amino acid is also included. carbonyl group having a saturated or unsaturated heterocyclyl R32, R33, R34, R3s, R37, R3s, R7, R72, R84, and Rare the group containing 4 to 12 atoms in the ring thereof, which may same as those, which have already been defined above. Pref contain, as a 4- to 12-membered heterocyclic ring portion erably, each of R', R. R. and R is independently thereof, one or more heteroatoms selected from a nitrogen 25 selected from a hydrogen atom, a Cls alkyl group (wherein atom, an oxygen atom, and a Sulfur atom, as defined above. the alkyl group may be substituted with one or more substitu Specific examples may include aZetidinylcarbonyl, pyrrolidi ents selected from a halogen atom, a hydroxyl group, a C nylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, pyr alkoxy group, an aryl group, an amino group, a C alky rolylcarbonyl, imidazolylcarbonyl, imidazolinylcarbonyl, lamino group, and a di(Calkyl)amino group), S(O).R. pyrazolylcarbonyl, pyrazolinylcarbonyl, oxazolinylcarbo 30 (wherein n+ and Rare the same as those defined above), a nyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, pyridi C. alkylcarbonyl group (wherein the C alkylcarbonyl nylcarbonyl, pyrazinylcarbonyl, pyrimidinylcarbonyl, group may be substituted with one or more substituents pyridazinylcarbonyl, hexamethyleneiminocarbonyl, furyl selected from an amino group, a C- alkylamino group, a carbonyl, tetrahydrofurylcarbonyl, thienylcarbonyl, tetrahy di(C. alkyl)amino group, and an aryl group), a C- alky drothienylcarbonyl, dioxacyclopentylcarbonyl, isobenzo 35 laminocarbonyl group, a C- alkoxycarbonyl group, an aryl furanylcarbonyl, chromenylcarbonyl, indolizinylcarbonyl, group, and a heteroaryl group; or indolylcarbonyl, isoindolylcarbonyl, indazolylcarbonyl, preferably, Rand R, and R and R, together with a purylcarbonyl, quinolizinylcarbonyl, isoquinolinylcarbonyl, nitrogen atom to which they bind, may form a 4- to 7-mem quinolinylcarbonyl, phthalazinylcarbonyl, naphthyridinyl bered heterocyclyl group containing at least one nitrogen carbonyl, quinoxalinylcarbonyl, quinazolinylcarbonyl, cin 40 atom (wherein the heterocyclyl group may be substituted nolinylcarbonyl, pteridinylcarbonyl, isochromanylcarbonyl, with one or more substituents selected from a hydroxyl group, chromanylcarbonyl, quinuclidinylcarbonyl, oxacycloheptyl a Cls alkyl group (wherein the alkyl group may be substi carbonyl, dioxacycloheptylcarbonyl, thiacycloheptylcarbo tuted with one or more substituents selected from a hydroxyl nyl, diazacycloheptylcarbonyl, oxacyclooctylcarbonyl, diox group, a C-salkoxy group, and an aryl group), a C-8 alkoxy acyclooctylcarbonyl, azacyclooctylcarbonyl, 45 group (wherein the alkoxy group may be substituted with one diazacyclooctylcarbonyl, azaoxacyclooctylcarbonyl, thiacy or more Substituents selected from a hydroxyl group, a Cs clooctylcarbonyl, dithiacyclooctylcarbonyl, thiaoxacyclooc alkoxy group, and an aryl group), an aryl group, and a hetero tylcarbonyl, azathiacyclooctylcarbonyl, oxacyclononylcar aryl group). bonyl, dioxacyclononylcarbonyl, trioxacyclononylcarbonyl, Furthermore, preferably, each of R° and R is indepen azacyclononylcarbonyl, azaoxacyclononylcarbonyl, triaza 50 dently selected from a hydrogenatom, a Cls alkyl group, and cyclononylcarbonyl, thiacyclononylcarbonyl, dithiacy a C- alkylcarbonyl group, or R and R, together with a clononylcarbonyl, azadithiacyclononylcarbonyl, oxacyclo nitrogen atom to which they bind, may form a 4- to 7-mem decanylcarbonyl, dioxacyclodecanylcarbonyl, bered heterocyclyl group containing at least one nitrogen trioxacyclodecanylcarbonyl, azacyclodecanylcarbonyl, atom (wherein the heterocyclyl group may be substituted diazacyclodecanylcarbonyl, azaoxacyclodecanylcarbonyl, 55 with a hydroxyl group or a Cls alkyl group (wherein the alkyl azadioxacyclodecanylcarbonyl, diazaoxacyclodecanylcar group may be substituted with a substituent selected from a bonyl, thiacyclodecanylcarbonyl, dithiacyclodecanylcarbo hydroxyl group and a Cls alkoxy group)). nyl, trithiacyclodecanylcarbonyl, azathiacyclodecanylcarbo Still further, preferably, RandR, together with a nitro nyl, diazathiacyclodecanylcarbonyl, gen atom to which they bind, may form a 4- to 7-membered oxacycloundecanylcarbonyl, dioxacycloundecanylcarbonyl, 60 heterocyclyl group containing at least one nitrogen atom. trioxacycloundecanylcarbonyl, azacycloundecanylcarbonyl, Preferably, each of R7' and R7 is independently selected diazacycloundecanylcarbonyl, triazacycloundecanylcarbo from a hydrogen atom, a Cls alkyl group (wherein the Cs nyl, thiacycloundecanylcarbonyl, dithiacycloundecanylcar alkyl group is substituted with —(OCHCH), OH or 1 to bonyl, trithiacycloundecanylcarbonyl, azaoxacycloundecan 5 hydroxyl groups), and a C- alkoxycarbonyl group. ylcarbonyl, azathiacycloundecanylcarbonyl, 65 In the present invention, the term" S(O), R'' is used to azadioxacycloundecanylcarbonyl, diazaoxacycloundecanyl mean - SR", -SOR'', or - SOR". For example, such carbonyl, azathiacycloundecanylcarbonyl, diazathiacycloun —S(O), R'' includes —S(O), (C. alkyl group), S(O), US 7,820,693 B2 19 20 (aryl group), and —S(O) (heteroaryl group). Specific sented by the formula (1) of the present invention may include examples of “ S(O), R'' may include methylthio, eth those, which act as prodrugs by themselves. In order to impart ylthio, n-propylthio, isopropylthio, trifluoromethylthio, ben preferred properties as a pharmaceutical, the “prodrug of the Zylthio. 4-methylphenylthio, phenylthio, methylsulfinyl, eth present invention includes compounds obtained by further ylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, converting the compound to derivatives. trifluoromethylsulfinyl, benzylsulfinyl, 4-methylphenylsulfi Examples of the “prodrug of the present invention may nyl, phenylsulfinyl, methylsulfonyl, ethylsulfonyl, n-propyl include: sulfonyl, isopropylsulfonyl, trifluoromethylsulfonyl, benzyl Sulfonyl, 4-methylphenylsulfonyl, and phenylsulfonyl. 1) a compound wherein a hydroxyl group is protected by a In the present invention, the term "Ce alkylenedioxy 10 protecting group, when the compound of the formula (1) has group' is a divalent group '-O-(C. alkylene)-O- the hydroxyl group in the molecule thereof; which contains a linear or branched alkylene group contain 2) a compound wherein a —NH-group or amino group is ing 1 to 6 carbon atoms and binds to a carbon atom adjacent protected by a protecting group, when the compound of the thereto. Examples of such a C- alkylenedioxy group may formula (1) has the —NH group or amino group in the mol include methylenedioxy, ethylenedioxy, methylmethylene 15 ecule thereof, and dioxy, and dimethylmethylenedioxy. In the present invention, the term “oxo group' is used to 3) a compound wherein a carboxy group is converted to an mean “—O. For example, a methylene group substituted ester group or an amino group, which may be substituted, with an oxo group forms a carbonyl group " C(=O)— when the compound of the formula (1) has the carboxy group In the present invention, the term “thioxo group' is used to in the molecule thereof. mean “—S. For example, a methylene group substituted Examples of Such a protecting group for a hydroxyl group with an thioxo group forms a thiocarbonyl group in the prodrug of the present invention, such as R' or R. * C(—S) - may include - PO(OR')OR', a Calkylcarbonyl group, a In the present invention, when any given group is substi C-7 alkenylcarbonyl group, a Cs cycloalkylcarbonyl group tuted with one or more substituents, such substituents may be 25 (wherein the C- alkylcarbonyl group, C, alkenylcarbonyl either identical to or different from one another. The number group, and a Cs cycloalkylcarbonyl group may be substi of Such substituents ranges from 1 to the maximum number, tuted with one or more substituents selected from a hydroxyl which is substitutable on a chemical structure. The number of group, —NR7R, an aryl group, which may be substituted substituents is, for example, between 1 and 7, typically with a hydroxyl group, a heteroaryl group, a mercapto group, between 1 and 5, and particularly between 1 and 3. 30 a C- alkylthio group, a guanidyl group, a carboxy group, a n1 is preferably 0 or 2, and each of n3 and na is preferably Calkoxycarbonyl group, a C- alkylcarbonyloxy group, 2. an aryl C alkoxy group, an aminocarbonyl group, a C Preferred examples of R of S(O).R, which is a alkylaminocarbonyl group, and a di(C. alkyl)aminocarbo specific example of R° and R in NR'R'', may include nyl group (wherein the C- alkylaminocarbonyl group and a Cls alkyl group (wherein the Cs alkyl group may be 35 di (C. alkyl)aminocarbonyl group may be substituted with Substituted with one or more hydroxyl groups), a C-salkenyl one or more Substituents selected from an amino group, a C group, a C. cycloalkyl group, and an aryl group. alkylamino group, and a di(C. alkyl)amino group), and Preferably, each of R'' and R is independently selected -(OCHRCH), OR7 (wherein 1, R7, and R'' are the from a hydrogen atom and an aryl C. alkyl group. Among same as those defined above)), an arylcarbonyl group, a het others, it is preferable to select from among a hydrogenatom 40 eroarylcarbonyl group, a 4- to 12-membered heterocyclyl and a benzyl group. In addition, R'' and R are preferably carbonyl group (wherein the arylcarbonyl group, heteroaryl identical to each other. carbonyl group, and heterocyclyl carbonyl group may be The present invention includes a salt of the compound substituted with one or more substituents selected from a represented by the formula (1) and a pharmacologically hydroxyl group, a carboxy group, a C- alkoxycarbonyl acceptable salt of the prodrug of the compound. These salts 45 group, and a C- alkylcarbonyl group (wherein the C are produced by allowing the compound or the prodrug alkoxycarbonyl group and C alkylcarbonyl group may be thereof to come into contact with an acid or base, which can substituted with one or more substituents selected from a be used in production of a pharmaceutical. Examples of Such hydroxyl group, —NR'R'', and a carboxy group)), a C a salt may include: hydrochloride, hydrobromide, hydroio alkoxycarbonyl group (wherein the C- alkoxycarbonyl dide, Sulfate, Sulfonate, methanesulfonate, toluenesulfonate, 50 group may be substituted with a 4- to 12-membered hetero phosphate, phosphonate; carboxylates Such as formate, cyclyl carbonyl group), CONR'R'', and – CO acetate, oxalate, maleate, citrate, malate. Succinate, malonate, (OCHR7°CH), OR7 (wherein k, R', and R7 are the benzoate, salicylate, fluoroacetate or trifluoroacetate, or same as those defined above). alkali metal salts such as a sodium salt or a potassium salt; and Herein, each of R7, R. R., and R is independently alkali earth metal salts such as a magnesium salt or a calcium 55 selected from a hydrogen atom, a Cls alkyl group (wherein salt; and ammonium salts such as an ammonium salt, an the alkyl group may be substituted with one or more substitu alkylammonium salt, a dialkylammonium salt, a trialkylam ents selected from a halogen atom, a hydroxyl group, a C monium salt, or a tetraalkylammonium salt. alkoxy group, —(OCH2CH), OH (wherein m is the same The “prodrug of the present invention means a derivative as that defined above), a C- alkoxycarbonyl group, an aryl of the compound represented by the formula (1), which is 60 group, an amino group, a C- alkylamino group, and a di(C- converted to the compound represented by the formula (1) or alkyl)amino group), -S(O), R (wherein n4 represents an a pharmaceutically acceptable salt thereof, as a result of enzy integer of 1 or 2), a C- alkylcarbonyl group (wherein the matic or nonenzymatic decomposition under physiological Calkylcarbonyl group may be substituted with one or more conditions. When such a prodrug is administered to a patient, Substituents selected from an amino group, a C- alkylamino it may be inactive. However, such a prodrug is converted to 65 group, a di(C. alkyl)amino group, an aminocarbonyl group. the compound of the formula (1) and exists in the form of the an aryl group, which may be substituted with a hydroxyl compound of the formula (1) in vivo. The compound repre group, a heteroaryl group, a hydroxyl group, a mercapto US 7,820,693 B2 21 22 group, a C- alkylthio group, a guanidyl group, and a carboxy alkyl ester, a Calkoxy Calkyl ester, an aryloxy Calkyl group), a C- alkylaminocarbonyl group, a C- alkoxycar ester, an aryl Calkoxy Calkyl ester, a hydroxy Calkyl bonyl group, a 4- to 7-membered heterocyclyl carbonyl ester, an amino C alkyl ester, a C- alkylamino Ce alkyl group, an aryl group, and a heteroaryl group; or ester, and a di(C. alkyl)amino Ce alkyl ester. Preferred R7 and R, together with a nitrogen atom to which they ester groups include a methyl ester group, an ethyl ester bind, may form a 4- to 7-membered heterocyclyl group group, a 2-hydroxyethyl ester group, and a 2-(dimethy (wherein the heterocyclyl group may be substituted with a lamino)ethyl ester group. hydroxyl group, a Cls alkyl group (wherein the alkyl group The amide group is an amide group represented by may be substituted with a hydroxyl group, a Cls alkoxy - CONR'R'', for example. Each of R7' and R7° may be group, or an aryl group), a Cls alkoxy group (wherein the 10 independently selected from a hydrogen atom, a C- alkyl alkoxy group may be substituted with a hydroxyl group, a group, an aryl group, a heteroaryl group, an aryl C-6 alkyl Cs alkoxy group, or an aryl group), an aryl group, or a group, a heteroaryl Co alkyl group, a C- alkoxy Co alkyl heteroaryl group); group, an aryloxy C1-alkyl group, an aryl Coalkoxy C. R is selected from a hydrogen atom, a Cls alkyl group alkyl group, a hydroxyl C alkyl group, an amino C alkyl (wherein the alkyl group may be substituted with one or more 15 group, a C- alkylamino C- alkyl group, a di(C. alkyl) Substituents selected from a hydroxyl group, a C- alkoxy amino C alkyl group, a hydroxyl group, and an alkoxy group, an aryl C- alkoxy group, an aryl group, and a het group. Each of R'' and R' is preferably a hydrogen atom, a eroaryl group), a C2-s alkenyl group, a Cal cycloalkyl group. methyl group, an ethyl group, a 2-hydroxyethyl group, or a an aryl group, or a heteroaryl group. 2-(dimethylamino)ethyl group. A protecting group for a hydroxyl group is preferably Specific examples of (OCHRCH), OR7 (wherein 1, selected from a C- alkylcarbonyl group (wherein the C R’, and R'' are the same as those defined as above) may alkylcarbonyl group may be substituted with 1 to 3 substitu include —(OCH2CH), OH, - OCH2CH2—OCH, ents selected from a hydroxyl group, NR7R, a carboxy —(OCHCH), OCH, —(OCHCH), OCH, group, a C- alkylcarbonyloxy group, a C- alkylaminocar —(OCH2CH2). OCH, —(OCH2CH), OCH, bonyl group, which may be substituted with an amino group, 25 —(OCH2CH), OCH, —(OCH2CH), OH, and (OCHR7CH), OR7 (wherein 1, R7, R7 are the —(OCH2CH), OH, —(OCH2CH), OH, same as those defined above)), an arylcarbonyl group, which —(OCH2CH), OCH, —(OCH2CH), OCH, may be substituted with a carboxy group, a heteroarylcarbo —(OCHCH), OCH, —(OCHCH), OCH, nyl group, a C- alkoxycarbonyl group, which may be Sub —(OCH2CH)—OCH, —(OCH2CH2). OCH, stituted with a 4- to 12-heterocyclyl group, —CONR'R'' 30 —(OCHCH), OH, —(OCHCH.) OH, (wherein R'' and R'' are the same as those defined above), —(OCH2CH), OH, —(OCH2CH), OH, and CO(OCHRCH), OR7 (whereink, R', and R' —(OCH2CH)—OH, and —(OCH2CH), OH. In addi are the same as those defined above). tion, an acetyl group is particularly preferable as a C- alky Preferably, each of R7 and R is independently selected lcarbonyl group in a C- alkylcarbonyl group, which is Sub from a hydrogen atom, a Cls alkyl group (wherein the Cs 35 stituted with -(OCHR7CH), OR7. alkyl group may be substituted with an amino group), and an Specific examples of -CO(OCHRCH), OR7 C.-amino acid-derived group (a group obtained by conversion (wherein k, R', and R'' are the same as those defined of a carboxy group to a carbonyl group). above) may include —CO(OCH2CH), OH, -CO In addition, such a protected hydroxyl group may be esters (OCHCH), OH, -CO(OCH2CH), OH, -CO of naturally occurring type amino acids (namely, asparagine, 40 (OCHCH), OH, -CO(OCHCH), OH, -CO aspartic acid, alanine, arginine, isoleucine, glycine, (OCHCH), OH, —CO(OCHCH), OH, glutamine, glutamic acid, cysteine, serine, tyrosine, tryp COOCHCH, OCH(CHOH)CHOH, CO tophan, threonine, Valine, histidine, phenylalanine, proline, (OCHCH), OCH(CHOH)CH-OH, methionine, lysine, and leucine), esters of non-naturally —CO(OCH2CH), OH, -CO(OCH2CH) OCH, occurring type amino acids, dipeptide esters, tripeptide 45 - COOCH(CH (OCHCH), OH)CH (OCHCH)– esters, or tetrapeptide esters. OH, -COOCH(CHOCH(CH (OCHCH), OH)CH, Examples of a protecting group for an —NH-group or (OCHCH), OH)CH (OCHCH), OH, -COOCH amino group may include a C- alkylcarbonyl group, an (CHOCHCH-OH)CHOCHCH-OH, -COOCH(CH, arylcarbonyl group, a heteroarylcarbonyl group, a C (OCHCH), OH)CH, (OCHCH), OH, alkoxycarbonyl group, a C- alkylaminocarbonyl group, a 50 - COOCHCH, OCH – CO(OCHCH), OCH, di (C. alkyl)aminocarbonyl group, an aryl C. alkyl group, - CO(OCHCH), OCH – CO(OCHCH), OCH, a heteroaryl C. alkyl group, an (aryl C alkyl)aminocar - CO(OCHCH), OCH – CO(OCHCH), OCH, bonyl group, —P(=O)(OH), —CHOP(=O)(OH), a C - CO(OCHCH), OCH, -CO(OCH2CH) OCH, alkyl group, and a C- alkylsulfonyl group. In addition, such —CO(OCHCH), OCH, -CO(OCHCH), OCH, a protected—NH-group or amino group may be amides of 55 - CO(OCHCH), OCH, -CO(OCH2CH), -OH, naturally occurring type or non-naturally occurring type and —CO(OCHCH), OH. amino acids, dipeptide amides, tripeptide esters, and tet Each of k, l, i, m, and represents an integer from 1 to 20. rapeptide amides. Each of them is preferably an integer from 1 to 12 in view of Moreover, an amino group is protected by a protecting commercial availability of corresponding reagent. group, so that it may form a Saturated or unsaturated hetero 60 Preferably, each of R and R’ is independently selected cyclyl group, Such as a phthalic acid imide group, a Succinic from a hydrogen atom, a methyl group, and a vinyl group. In acid imide group, a glutaric acid imide group, or a 1-pyrrolyl addition, R and Rare preferably identical to each other. group. Moreover, particularly preferably, R and R° are simulta When a carboxy group is converted to an ester group or an neously a hydrogen atom and a methyl group. amide group, which may be substituted, examples of such an 65 R is preferably selected from a hydrogen atom, a C ester group may include a C- alkyl ester, an aryl ester, a alkylcarbonyl group (wherein the C- alkylcarbonyl group heteroaryl ester, an aryl C. alkyl ester, a heteroaryl C. may be substituted with 1 to 3 substituents selected from a US 7,820,693 B2 23 hydroxyl group, —(OCH2CH), OR' (wherein R' and 1 are the same as those defined above)), and —CO (OCHR7°CH), OR7 (wherein R7, R7, and k are the Formula 7 same as those defined above). Preferred examples of a C- alkylcarbonyl group in R. which may be substituted with a hydroxyl group, may include a 2.3-dihydroxypropionyl group, a 2.2-bis(hydroxymethyl) propionyl group, and a 3-hydroxy-2.2-bis(hydroxymethyl) propionyl group. Preferred examples of a propionyl group, which is substi 10 tuted with 1 or 2 hydroxyl groups, in a propionyloxy group Substituted with 1 or 2 hydroxyl groups, may include a 2.3- dihydroxypropionyl group and a 2.2-bis(hydroxymethyl)pro pionyl group. Specific examples of the present invention include the 15 compound represented by the following formula and com However, the present invention is not limited to such pounds shown in the following table: examples.

TABLE 1.

Compound No. Example

CF Example 1-1

CF Example 1-2

CF Example 1-3

CF Example 1-4

CF Example 1-5

CF Example 1-6 US 7,820,693 B2 25 26

TABLE 1-continued Compound No. Y Example 7 CF H H H H O Example 1-7

N 1."

CF O Example 1-8

O

CF HO Example O 1-9

N l N 1.:

10 CF O Example 1-10

O N 1"

HO

11 CF O Example 1-11

O N 1" 3. 12 CF O Example 1-12

O N 1" C )–

13 CF O Example 1-13

O N 1."

HO US 7,820,693 B2 27 28

TABLE 1-continued Compound No. R1a R2a R3a R4a Risa Y Example

14 CF H. H. H. H O Example 1-14

O N 1."

HO-S

15 CF H. H. H. H O Example 1-15

N 1"

16 CF H H H H O Example 1-16

O N 1."

17 CF H. H. H. H O Example 1-17

O N 1"

18 CF H H H H O Example 1-18 N 1." N N

19 : H H H H O Example

N ul : 1-19 1 O N

O s HO

2O OMe H. H. H. H O Example 1-2O

O N 1."

HO-Š

21 Me H. H. H. H O Example 1-21

O N 1."

HO-S

22 OCF H. H. H. H Example 1-22

N 1:

HO sO US 7,820,693 B2 29 30

TABLE 1-continued Compound No. Example

23 H. H. H. H Example 1-23 : 1

24 Et Example 1-24 : HHOO NN 1. 25 OMe OMe sOsO Example 1-2S : 1 sO\ /lO N

26 Example 1-26 : 1. O l N

27 OCF, Example 1-27 : l 1 O N

28 Example 1-28 HHHOOO : ul 1. O N

HO

29 Example 1-29 : l 1 O N - 30 CF O Example s 1-3O US 7,820,693 B2 31 32

TABLE 1-continued

Compound No. R1a R2a R3a R4a Risa Y Example

31 CF H. H. H. H O Example 1-31

O N -"

NH2

32 CF H. H. H. H O Example 1-32

O N 1."

si NH

33 CF H H H H O Example 1-33

O N 1" KN

34 CF H H H H O Example 1-34 1" O N

( )OH

35 CF H H H H O Example 1-3S N -" N N US 7,820,693 B2 33 34

TABLE 1-continued

Compound No. R1a R2a R3a R4a Risa Y Example

36 CF H. H. H. H O Example 1-36

N N N 1."

HO-S

37 Et H. H. H. H O Example 1-37 1." ... /O N

38 CF H. H. H. H O Example 1-38

O N 1." \-on

39 CF, H H H H O Example 1-39 : 1.

40 : H H H H O Example

O l : 1-40 1N1 O N 1.

41 : H. H. H. H O Example ul 1-41 1N-1 1" US 7,820,693 B2 35 36

TABLE 1-continued

Compound No. R1a R2a R3a R4a R5a Y Example

42 : H H H H O Example 1-42 1N19 1" ON-ol O N HO

43 CF H H H CF, O Example 1-43

O N 1."

HO-S

44 CF H. H. H. H O Example 1-44

O N 1"

HO

45 CF, H H H H O O Example 1-45 1" U N

46 CF H H H H O Example 1-46

HO N 1"

47 : H. H. H. H O Example 1-47

O N 1."

HO-S

48 : H H H H O Example 1-48

O N 1."

HO-S

49 CF H. H. H. H O Example us 1-49 O N 1"

US 7,820,693 B2 41 42

TABLE 2-continued Compound No. Example Example OO.Y O fCF Example

CF

O Example 2-8 1" HO N

O Example 2-9

uCCF

Example 2-10

CF HO N

A11 Example 2-11

CF HO

A12 O Example 2-12

CF US 7,820,693 B2 43 44

TABLE 2-continued Compound No. Y X Example

A13 O Example 2-13 --- :

CF HN O

A14 O Example 2-14 --- : s CF

HN-RO

A15 Example 2-15

CF

HO -O O

A16 Example 2-16

s CF HO iv,

A17 Example , 2-17 uCCF

A18 Example 2-18

A19 Example 2-19

uCCF US 7,820,693 B2 45 46

TABLE 2-continued Compound No. Example Example 2-2O

() CF

A21 Example 2-21

A22 Example 2-22

S uCCF N S

A23 O Example 2-23 HO : O N1 :

S CF N-S

A24 Example 2-24 HQ O CF

A25 Example 2-2S

HO O N :

CF

A26 Example 2-26 HO 1.: y O N s CF N US 7,820,693 B2 47 48

TABLE 2-continued Compound No. Example

A27 Example 2-27

HO - S CF N

A28 Example 2-28

\ s CF

A29 Example 2-29

uCCF

A30 Example 2-30

s CF HO N-S

A31 Example 2-31

A32 Example 2-32

A33 Example 2-33

S-N- US 7,820,693 B2 49 50

TABLE 2-continued Compound No. Y Example

A34 O Example 2-34 O ul N1 : Q \ / ) S-N-s O

A3S O Example 2-3S O ul N1 : A / S-N- CF O

A36 O Example 2-36 O l N1 :

CF -N- O

A37 O Example 2-37 O l N1 : \\ -- y CF O

A38 O Example 2-38 O l N1 : HO \ / \ -- CF O

A39 O Example 2-39 O l N1 :

HO

A40 O Example 2-40 O ul N1 :

HO-Š US 7,820,693 B2 51 52

TABLE 2-continued Compound No. Y X Example

A41 O Example 2-41 1" O N :

S O HO -S n-1N

A42 O Example 2-42 1" O N :

HO- S O n1n1.

A43 O Example 2-43 1" O N :

S O HO S n1

A44 O Example 2-44 1" O N :

HO-S OH

OH

A45 O Example 2-45 1" O N : s OH HO

A46 O Example 2-46

O N 1" N

S) / -N N HO

A47 O Example 2-47 1" O N :

s S HO-S N

A48 O Example 2-48 1" O N :

s ORS HO-S AN US 7,820,693 B2 53 54

TABLE 2-continued Compound No. Example

A49 Example 2-49

CF

ASO Example 2-SO

CF

A51 Example 2-51

CF

A52 Example 2-52

CF

AS3 Example 2-53

CF

AS4 Example 2-54

CF

ASS Example 2-55

CF

A56 Example 2-56

CF US 7,820,693 B2 55 56

TABLE 2-continued Compound No. X Example

A57 O Example 2-57

N N 1"

HO CF

AS8 O Example 2-58 1." HO N :

CF

AS9 Example 2-59 N l, 1" CF

HO

A60 Example 2-60

HN

CF

A61 Example 2-61

A62 Example 2-62 N

uCCF

A63 Example 2-63

CF

A64 Example 2-64

CF US 7,820,693 B2 57 58

TABLE 2-continued

Compound No. Y X Example

A65 Example 2-6S

:

CF

A66 Example 2-66

:

CF

A67 Example 2-67

:

CF

A68 O Example 2-68 1." N :

A.\-/ CF

A69 O Example 2-69 1" O N : CF

HO

A70 O Example 2-70 1" O N :

HO-S

A71 O Example 1N 2-71

O N 1"

US 7,820,693 B2 65 66

TABLE 3-1-continued Compound No. Example Example 3-5

HCI

Example 3-6

Example 3-7

Example 3-8

Example 3-9

B10 Example 3-10 US 7,820,693 B2 67 68

TABLE 3-1-continued

Compound No. Y Example

B11 HCI O Example 3-11 l -" O O N

N s 1. O-S

B12 O Example 3-12

HCI O O l N 1." ~s

B13 O Example 3-13

HCI O O l N -"

IN- O s

B14 O Example 3-14

HCI O O ul N 1."

N-- O w –

B15 O Example 3-15

HCI O O l N 1." N-S H

B16 Example 3-16 US 7,820,693 B2 69 70

TABLE 3-1-continued Compound No. Y Example B17 O Example 3-17

Na O l N 1.: O \ / O s O

O

B18 O Example 3-18

Na O l N 1." O \ /

O S

O

O

B19 O Example 3-19 l : HCI O O N1 H \ / HN1\1 N O-Ss O

O Example 3-20

HCI O ul N 1" O

1. O

B21 HCI O Example 3-21

O l N 1" O

1. Nulls O

B22 O Example 3-22

HCI O ul N 1.: O

O

B23 Example 3-23

HCI O HN

US 7,820,693 B2 73 74 (B23); (R)-2-oxo-3-1-oxo-3-trifluoromethylphenyl-1,2-di hydroisoquinolin-7-yl)-oxazolidin-5-ylmethyl 2-amino 2-methylpropionate hydrochloride, Formula 10 (B24); (R)-2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- dihydroisoquinolin-7-yloxazolidin-5-ylmethyl 2-methyl 2-(methylamino)propionate hydrochloride, N (B25); (R)-2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- dihydroisoquinolin-7-yloxazolidin-5-ylmethyl 1-amino NH CF cyclopentanecarboxylate hydrochloride, and Y (B26): dibenzyl phosphoate (R)-2-oxo-3-1-oxo-3-(2-trif luoromethylphenyl)-1,2-dihydroisoquinolin-7-yl)-oxazo O lidin-5-ylmethyl ester. Furthermore, the present invention includes the compound represented by the following formula and compounds shown However, the present invention is not limited to such in the following table: examples.

TABLE 4-1 Compound No. Y Example

C1 O Example 4-1

Na O l N 1." O

O O

O

C2 O Example 4-2

Na O l N 1." O

O

O

O

C3 Na" O Example 4-3 l 1: O O O N

O O-S

C4 Na" O Example 4-4

O O O O l N 1.:

N O s

C5 Na" O Example 4-5

O l N1 : O

O US 7,820,693 B2 75 76

TABLE 4-1-continued

Compound No. Y Example

O Example 4-6 Na" O ---

O

O

O

Example 4-7

Example 4-8

TFA Example 4-9

C10 Example 4-10 US 7,820,693 B2

TABLE 4-1-continued

Compound No. Y Example

C11 O Example 4-11

N 1" Na O O

O O

C12 O Example 4-12

N 1" Na" O O

O O

C13 Na" O Example 4-13

N 1" O O O

O O

O

C14 Na" O Example 4-14

N 1" ---,O O )

C15 O Example 4-15 : O ) HO O

C16 Example 4-16 US 7,820,693 B2 79 80

TABLE 4-1-continued

Compound No. Example

C17 Example 4-17

HO O

HO O

OH

C18 Example 4-18

HCI

C19 Example 4-19

HCI

Example 4-20

HCI US 7,820,693 B2 81 82

TABLE 4-1-continued

Compound No. Y Example

C21 O Example 4-21 X- N1 : O

O H / /N-K Y.

HO /

C22 O Example 4-22 X- N1 : O "vu HO~~ H S OH

C23 O Example 4-23 X---: O ) ~~ H OH

C24 Example 4-24

C25 O Example 4-25 ls, )

C26 O Example 4-26

OH HO 1. ) H H US 7,820,693 B2 83 84

TABLE 4-1-continued

Compound No. Example

C27 Example 4-27

C28 Example 4-28

C29 Example 4-29

C30 Example 4-30

C31 Example 4-31 US 7,820,693 B2 85 86

TABLE 4-1-continued Compound No. Example

C32 Example 4-32

Example 4-33

C34 Example 4-34

C35 Example 4-35

C36 Example 4-36 US 7,820,693 B2 87 88

TABLE 4-1-continued

Compound No. Example

C37 Example 4-37

C38 Example 4-38

Example 4-39

C40 Example 4-40 US 7,820,693 B2 89 90

TABLE 4-1-continued

Compound No. Example

C41 Example 4-41

Example 4-42

Example 4-43

Example 4-44 US 7,820,693 B2 91 92

TABLE 4-1-continued

Compound No. Example

C45 Example 4-45

C46 Example 4-46

C47 Example 4-47

Example 4-48 US 7,820,693 B2 93 94

TABLE 4-1-continued Compound No. Example 7) Example 4-49 o–/ - OX-- / / O O ) ( , / . C50 HO O Example 4-50 : --YY-u O O/ N1 Example 4-51 HO N-N O

O : - C O X N1 O ) HO N-1 no-1N1 O O lsO

O Example 4-52 HONu O X- 1. -- O / CS4 OX-r Example 4-53 Hos--N-011 Out Example 4-54

US 7,820,693 B2 101 102

TABLE 5-1-continued

Compound No.

HCI

HN

HCI

HCI

HCI

HN

HCI

D10 US 7,820,693 B2 103 104

TABLE 5-1-continued

Compound No. Y

D11 O

O l N 1" O

X O S D.

D12 O

O O HO O ls s O

D13 O

/ / / ) X---

D15 O US 7,820,693 B2 105 106

TABLE 5-1-continued US 7,820,693 B2 107 108

TABLE 5-1-continued

Compound No.

C) |CUNG ~

C)(UD |No. Π~

C) (~~ C) US 7,820,693 B2 109 110

TABLE 5-1-continued

Compound No.

D25

D26

D27

D28 US 7,820,693 B2 111 112

TABLE 5-1-continued

US 7,820,693 B2 117 118 Representative Production Methods The compound represented by the formula (1) of the -continued present invention can be produced by the following method, N X for example. However, the method for producing the com He pound of the present invention is not limited thereto. The NH compounds of the present invention are all novel compounds, HN which have not been described in any publications. The com O pounds can be produced by known chemical techniques. As a IV O raw material compound used in production, a commercially 10 available compound can be used. Otherwise, such a com N X pound can also be produced by conventional methods, as Cy NH necessary. In the following reaction processes 1 to 8 and the NH Hoss relevant descriptions, X. Cy, and Ra have the same definitions I Palladium catalyst as those described in the formula (1). Moreover, codes used in 15 or copper catalyst the following reaction formulas have common means, which can be understood by persons skilled in the art in the present technical field. Furthermore, L represents C1 or Br, LG rep O S-* resents a leaving group Such as a halogen atom, a nitro group, NH a methanesulfonyloxy group, a trifluoromethanesulfonyloxy cy N group, or a p-toluenesulfonyloxy group; G represents a hydrogen atom or a C- alkyl group Such as a methyl group; O Rc represents a C- alkyl group; Rd represents an acyl group (1a) included in the definitions of R (for example, S(O).R. 25 a C- alkylcarbonyl group, which may be substituted wherein L represents C1 or Br; G represents a hydrogen (wherein when a Substituent is an amino group or a C atom or a methyl group; and X and Cy are the same as those alkylamino group, the group is protected by a protecting defined above. group), etc.); J represents an azido group, —OR, or 30 A 2-methylbenzamide derivative II can be easily prepared —NRR: Rf and Rg have the same definitions as those of by applying a conventional amidation method to a known the aforementioned R'' and R'; Rh represents a Cls alkyl 2-methylbenzoic acid derivative I. A compound represented group or a C-, alkenyl group; Y represents O or S; and PG by the formula (III) can be produced from the obtained com represents a protecting group (for example, acetyl, t-butoxy pound represented by the formula II according to known carbonyl, benzyloxycarbonyl, t-butyldimethylsilyl, etc.) or a 35 methods (U.S. Pat. No. 4.942,163; Arch. Pharm. Res., vol. 20, hydrogen atom; wherein R', R’, R, R', and Rare the pp. 264-268 (1997); Bioorg. Med. Chem. Lett. Vol. 8, pp. same as those defined above. 41-46 (1998); Arch. Pharm. Res., vol. 24, pp. 276-280 (2001): Bioorg. Med. Chem. vol. 10, pp. 2953-2961 (2002)). Thus, 1. General Synthesis Method of Compound (1a) Repre the compound represented by the formula (III) can be sented by the Formula (1) 40 obtained by subjecting the compound represented by the for Reaction Process 1 mula II to lithiation with a suitable base (for example, LDA, t-BuLi, s-BuLi, or BuLi) in a suitable solvent (for example, THF or EtO) at a suitable temperature (for example, between Formula 12 45 -78°C. and the boiling point of the solvent), and then allow CH ing the resulting intermediate to react with a commercially available reagent, or with an aromatic or hetero aromatic nitrile derivative, which has been prepared by a known I -O- Amidation method, at a suitable temperature (for example, between -78° 50 C. and the boiling point of the solvent) O A compound represented by the formula (IV) can be pro I duced from the compound represented by the formula (III) CH G according to known methods (Aromatic amination reaction: X Wolfe, J. P. J. Org. Chem., vol. 65, pp. 1158-1174 (2000), Hess N 55 Harris, M. C., Org. Lett., vol. 4, pp. 2885-2888 (2002), I YCH, Huang, X. Org. Lett. Vol. 3, pp. 3417-3419 (2001)). Thus, the compound represented by the formula IV can be produced O by allowing the compound represented by the formula (III) to II react in a suitable solvent (toluene, THF, 1,4-dioxane, xylene, X 60 dimethoxyethane, etc.) in the presence of a suitable palladium N Palladium catalyst aromatic amination catalyst (for example, Pd(OAc), Pd, dba PdClP(o-tol), He NH Pd(OCCF), etc.), a Suitable ligand (for example, P(o-tol), L BINAP, DPPF, P(t-Bu), 2-dicyclohexylphosphino-2'-(N.N- dimethylamino)biphenyl, 2-(di-t-butylphosphino)biphenyl, O 65 2-(dicyclohexylphosphino)biphenyl, etc.), and LiHMDS, at a III suitable temperature (between a room temperature and the boiling point of the solvent). US 7,820,693 B2 119 120 A compound represented by the formula (V) can be pro ence of a Suitable solvent (1,4-dioxane, tetrahydrofuran, duced from the compound represented by the formula (IV) diethyl ether, toluene, etc.), a Suitable copper catalyst (metal according to known methods (Sandmeyer's reaction: J. L. copper (powders), copper(I) chloride, copper(I) oxide, cop Hartwell, Org. Synth., III, p. 185 (1955); P.J. Harrington, and per(II) oxide, copper(II) chloride, copper(II) sulfate, copper L. S. Hegedus, J. Org. Chem. Vol. 49, p. 2657 (1984)). A compound represented by the formula (1a) can be pro (II) acetate, copper(II) acetoacetate, copper(I) iodide, copper duced from the compound represented by the formula (V) (I) trifluoromethanesulfonate, etc.), a suitable ligand (1.2- according to known methods (Palladium catalyst aromatic cyclohexanediamine, N,N'-dimethylethylenediamine, N,N'- amidation: Org. Lett., Vol. 2, pp. 1101-1104 (2000); Tetrahe dimethyl-1,2-cyclohexanediamine, 1,10-phenanthroline, dron Lett., vol. 42, pp. 7155-7157 (2001)). Thus, the com 10 etc.), and a suitable base (potassium phosphate, potassium pound represented by the formula (1a) can be produced by carbonate, cesium carbonate, sodium t-butoxide, potassium allowing the compound represented by the formula (V) to hexamethyldisilaZane, Sodium hexamethyldisilaZane, phosp react with a commercially available reagent or a cyclic amide haZene, etc.), at a Suitable temperature (between a room tem prepared by a known method, a Suitable solvent (toluene, perature and the boiling point of the solvent. THF, 1,4-dioxane, Xylene, dimethoxyethane, etc.), a Suitable 15 2. General Synthesis Method of Compound (1b) Repre palladium catalyst (for example, Pd(OAc), Pd, dba, PdCl sented by the Formula (1) P(O-tol), Pd(OCCF), etc.), a suitable ligand (for example, P(o-tol), BINAP, DPPF, P(t-Bu), 2-dicyclohexy Reaction Process 2

Formula 13 N X

NH NH HN O IV VI

X Palladium N catalyst aromatic NH amination L

III Y S-*

NH Cy O (1b) lphosphino-2'-(N,N-dimethylamino)biphenyl, 2-(di-t-bu wherein A represents —O—C(=O)—(wherein PG binds tylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, to an oxygen atom, and B binds to a carbonyl group), O, or 2,6'-dimethoxy-2-(dicyclohexylphosphino)biphenyl, 2',4', 50 N Rb'; Rb" represents a substituents selected from Group 6'-triisopropyl-2-(dicyclohexylphosphino)biphenyl, 4.5-bis Q2, which has already been defined above; B represents a diphenylphosphanyl-9,9-dimethyl-9H-xanthene, 4,5-bis(bis linking group having, as a main chain, 1 to 5 atoms selected (3,5-bistrifluoromethylphenyl)phosphanyl-9,9-dimethyl from an oxygen atom, a Sulfur atom, a nitrogen atom, and a 9H-xanthene, 1,3-diallyldihydroimidazolium salt, etc.), and a carbonatom (wherein the main chain terminal atom of B that suitable base (t-BuONa, CsCO, KPO, etc.), at a suitable 55 binds to —NH of the compound represented by the formula temperature (between a room temperature and the boiling (IV) is a carbonatom), wherein the linking group may contain point of the solvent). a double bond, and wherein the carbon atom(s) of the linking Moreover, the compound represented by the formula (1a) group may be substituted with one or more Substituents can also be produced from the compound represented by the selected from the defined Group Q1, and the nitrogen atom formula (V) according to known methods (Copper catalyst 60 thereof may be substituted with one or more substituents aromatic amidation reaction: Buchwald, S. L., J. Am. Chem. selected from the defined Group Q2; PG represents a protect Soc., vol. 123, pp. 7727-7729 (2001), Buchwald, S. L., J. Am. ing group (for example, acetyl, t-butoxycarbonyl, benzyloxy Chem. Soc., vol. 124, pp. 7421-7428 (2002)). Thus, the com carbonyl, t-butyldimethylsilyl, etc.) or a hydrogenatom; and pound represented by the formula (1a) can be produced by Cy, Y. X, and L are the same as those defined above). allowing the compound represented by the formula (V) to 65 A compound represented by the formula (VI) can be react with a commercially available reagent or a suitable obtained by subjecting the compound represented by the for amide compound prepared by a known method in the pres mula (IV) used in reaction process 1 to a known method (for US 7,820,693 B2 121 122 example, an N-alkylation reaction with an alkylhalide, which 4. General Synthesis Method of Compound (1 d) Repre can be purchased as a reagent, or is prepared by a known sented by the Formula (1) method; a reductive alkylation reaction with aldehyde or ketone, which can be purchased as a reagent, or is prepared by Reaction Process 4 a known method; a reaction with a commercially available reagent Such as glycidol or with epoxide prepared by a known Formula 15 method; the methods disclosed in EP50827 and U.S. Pat. No. Rc 4,461,773, etc.). O1 Moreover, the compound represented by the formula (VI) 10 Rc can also be produced from the compound represented by the N o1 O --- formula (III) used in reaction process 1 according to known NH methods (Aromatic amination: Org. Lett. Vol. 2, pp. 1101 N 1104 (2000); Tetrahedron Lett., vol. 42, pp. 7155-7157 Cy O (2001)). A compound represented by the formula (1b) can be 15 produced by deprotecting the compound represented by the VII formula (VI) according to a known method, as necessary, and N No then subjecting the resulting compound to known methods O (when A is O or N Rb", a carbonylation reaction or thiocar NH Her bonylation reaction using phosgene, CS, etc.; Journal of N Organic Chemistry, vol. 60(20), pp. 6604-6607 (1995), Jour Cy O nal of Organic Chemistry, vol. 66(11), pp. 3940-3947 (2001): a cyclization reaction using a halogenated acetyl halide: Het 25 VIII erocycles, vol. 38(5), pp. 1033-1040 (1994); when A is X CO(=O), a condensation reaction using DCC, WSCI N (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydro O chloride) or a BOP reagent). NH N 3. General Synthesis Method of Compound (1c) Repre 30 sented by the Formula (1) Cy O Reaction Process 3 (1d)

35 Formula 14 wherein Rc, Cy, and X are the same as those defined X S N above. A compound represented by the formula (1d) can be pro NH He duced by deprotecting the compound represented by the for Cy N 40 mula (VII), which can be produced by reaction process 2, by O known methods (for example, a reaction under acidic condi (1b) tions such as TFA, etc.), and then Subjecting the obtained compound represented by the formula (VIII) to a known 45 method (for example, a condensation reaction with a diamine derivative, which can be purchased as a reagent or prepared X NRa N by a known method: Tetrahedron Letters, vol. 46, pp. 2197 2199 (2005), Bioorganic & Medicinal Chemistry Letters, vol. NH 8, pp. 361-364 (1998), Journal of Medicinal Chemistry, vol. Cy N 50 29, pp. 1065-1080 (1986), Bioorganic & Medicinal Chemis O try Letters, vol. 13, pp. 1989-1992 (2003)). (1c) 5. General Synthesis Method of Compound (1e) Repre sented by the Formula (1) 55 Reaction Process 5 wherein Ra, Cy, and X are the same as those defined above. Formula 16 A compound represented by the formula (1c) can be pro duced by Subjecting the compound represented by the for 60 mula (1b'), which can be produced by reaction process 2, to a NH known method (for example, a reaction of ammonia, or alky lamine or alkoxyamine which is commercially available or can be prepared by a known method, with a condensing agent 65 HO-(CH), O such as WSC or DCC: Bioorganic & Medicinal Chemistry IX Letters, vol. 12, pp. 2931-2934 (2002)). US 7,820,693 B2 123 124

-continued -continued X O S-* O N

NH 5 NH -- Cy N Cy N Rd-O-(CH2) O LG-(CH) O (1e) X 10 X wherein Rd, Cy, and X are the same as those defined O N above, and n represents an integer between 0 and 8. With regard to the synthesis of an ester derivative, a com NH -- pound represented by the formula (1e) can be produced by Cy N Subjecting the compound represented by the formula (IX), which can be produced by reaction process 1 or 2, to a known 15 J-(CH), O method (for example, a condensation reaction of a DCC, (1f) WSCI reagent, or the like, with DMAP, or an acylation reac X tion using an acid anhydride oran acid halide: Jikken Kagaku O N Koza, 4" edition, (Maruzen), Vol. 22, pp. 43-82), using car boxylic acid, an acid anhydride, amino acid, or the like, which NH He is commercially available or can be synthesized by a known Cy N method. N-(CH) O With regard to the synthesis of a carbonate derivative, a compound represented by the formula (1e) can be produced X by activating alcohol, which is commercially available or can 25 O N be synthesized by a known method, according to a known method (a reaction using phosgene or the like: Organic Syn NH He thesis Collective Volume 6, p. 715, (1988), a reaction using Cy N 4-nitrophenyl chloroformate; WO2005-018568), and then condensing the resultant compound with the compound rep HN-(CH), O resented by the formula (IX). As an alternative synthesis 30 method, such a compound represented by the formula (1e) X can be produced by activating the compound represented by O N the formula (IX) according to a known method (a reaction using phosgene or the like: Organic Synthesis Collective NH Volume 6, p. 715, (1988), a reaction using 4-nitrophenyl 35 Cy N chloroformate; WO2005-018568), and then condensing the resultant compound with alcohol, which is commercially Rd-HN-(CH), O available or can be synthesized by a known method. (11) With regard to the synthesis of a carbamate derivative, a compound represented by the formula (1e) can be produced by activating the compound represented by the formula (IX) 40 wherein LG, J, Rd, Cy, and Xare the same as those defined according to a known method (a reaction using phosgene or above, and n represents an integer between 0 and 8. the like: Organic Synthesis Collective Volume 6, p. 715, A compound represented by the formula (1f) can be pro (1988), a reaction using 4-nitrophenyl chloroformate; duced by converting a hydroxyl group of the compound rep WO2005-018568), and then condensing the resultant com 45 resented by the formula (IX), which can be produced by pound with amine, which is commercially available or can be reaction process 1 or 2, to a leaving group according to the synthesized by a known method. Further, as an alternative known method, and then Subjecting the obtained compound synthesis method, Such a derivative can be produced by Sub jecting the compound represented by the formula (IX) to a to a known method (for example, a reaction with oxygen known method (Jikken Kagaku Koza, Vol. 20, p. 358 (4" nucleophilic species (for example, sodium alkoxide, etc.): edition)), using isocyanate, which is commercially available 50 Tetrahedron, vol.43, pp. 3803-3816 (1987), nitrogen nucleo or can be synthesized by a known method. philic species (for example, morpholine, piperidine, pyrroli 6. General Synthesis Method of Compound (1f. 1g, 1k, 11) dine, etc.): J. Med. Chem. vol. 23, pp. 1380-1386 (1980), Represented by the Formula (1) Bioorg. Med. Chem. Lett. vol. 13, pp. 4169-4172 (2003), or sulfur nucleophilic species (for example, NaSMe etc.): Reaction Process 6 55 Bioorganic Med. Chem. Lett. vol. 15, pp. 699-703 (2005), Bioorganic Med. Chem. Vol. 12, pp. 4393-4401 (2004)). A compound represented by the formula (1k) can be synthe Formula 17 sized by allowing the compound represented by the formula 60 (X) to react with sodium azide acting as nucleophilic species according to the known method, and then reducing the NH obtained compound. A compound represented by the formula (11) can be produced by Subjecting the obtained compound represented by the formula (1k) to an acylation reaction (for HO-(CH), O 65 example, a condensation reaction of carboxylic acid or the IX like with a DCC, WSCI reagent, or the like, an acylation reaction using an acid anhydride or an acid halide: Jikken US 7,820,693 B2 125 126 Kagaku Koza, 4" edition (Maruzen), vol. 22, pp. 137-173, A compound represented by the formula (1n) can be pro Tetrahedron, vol. 57, pp. 1551-1558 (2001)). duced by Subjecting the compound represented by the for 7. General Synthesis Method of Compound (1m) Repre mula (XI), which can be produced by reaction process 1 or sented by the Formula (1) reaction process 2, to a known method (for example, a reac Reaction Process 7 tion with an organic metal reagent Such as MeMgBr: J. Org. Chem. vol. 70, pp. 261-267 (2005)). Some of starting material compounds for the compound of Formula 18 the present invention are novel compounds. Such novel com X pounds can be easily synthesized in the same manner as for O N 10 known raw material compounds, or by applying methods known to persons skilled in the art. Examples of a method for producing the compound repre O cCyy N NH --> sented by the formula (1) of the present invention have been given above. Isolation and purification of the compounds of R-0-I-chi: O 15 XI interest shown in the aforementioned reaction processes can X be carried out by applying common chemical operations such O N as extraction, concentration, distillation, crystallization, fil tration, recrystallization, or various types of chromatography. The compound of the present invention and a pharmaceu O cCvy N NH -ss tically acceptable salt thereof include all stereoisomers of the Ho-1-cis O compound represented by the formula (1) (for example, an XII enantiomer and a diastereomer (including cis- and trans-geo X metric isomers)), racemate of the aforementioned isomers, O N and other mixtures. 25 NH In addition, the compound of the present invention and a O Cy N pharmaceutically acceptable salt thereof can be present in several tautomeric forms, such as enol and imine forms, keto Re-I-chi: O and enamine forms, and mixtures thereof. Such tautomeric (1m) isomers are present in a solution in the form of a mixture of 30 tautomeric sets. In a solid form, either one tautomeric isomer is generally dominant. There are cases where only either one wherein Rc, Rf, Rg, Cy, and X are the same as those tautomeric isomer is described, but the present invention defined above, and n represents an integer between 0 and 6. includes all tautomeric isomers of the compound of the A compound represented by the formula (1 m) can be pro present invention. duced by hydrolyzing according to the known method the 35 compound represented by the formula (XI), which can be When the compound of the present invention is obtained in produced by reaction process 1 or reaction process 2, and then the free form, it can be converted into a salt, which the com Subjecting the resulting compound to the same acylation reac pound may form, a hydrate thereof, or a solvate thereof, tion as performed in reaction process 6, using amine, which is according to a common method. commercially available or can be synthesized by a known 40 In addition, when the compound of the present invention is method. obtained in the form of such a salt, hydrate, or solvate of the 8. General Synthesis Method of Compound (1n) Repre compound, they can be converted to a free form of the com sented by the Formula (1) pound according to a common method. Reaction Process 8 The compound of the present invention or a pharmaceuti 45 cally acceptable salt thereof has excellent antitumor action. It is excellent interms of stability in vivo and solubility in water, and is useful as a preventive ortherapeutic agent (particularly Formula 19 as a therapeutic agent) used for proliferative diseases such as X O N cancer. Excellent water solubility results in excellent absorb 50 ing properties of the compound, a prodrug thereof, and a salt NH thereof, in vivo. Further, an increase in beneficial effect can be O Cy N anticipated. Moreover, the compound of the present invention or a pharmaceutically acceptable salt is useful as a preventive R-ol-ch: O ortherapeutic agent (particularly as a therapeutic agent) used XI 55 for various types of cancers such as breast cancer, colon X cancer, ovarian cancer, lung cancer, pancreatic cancer, liver O N cancer, uterine cancer, brain tumor, prostatic cancer, blood NH cancer (acute leukemia, malignant lymphoma, etc.), bladder Rh Cy N cancer, esophageal cancer, skin cancer, testicular cancer, thy 60 roid cancer, and stomach cancer, and in particular, Solid can cers such as breast cancer, colon cancer, ovarian cancer, lung R-)-ch: O cancer, pancreatic cancer, liver cancer, uterine cancer, brain HO tumor, prostatic cancer, and stomach cancer. Furthermore, (1n) since the compound of the present invention is characterized 65 in that it causes few effects (enzyme inhibition, etc.) on drug wherein Rc, Rh, Cy, and X are the same as those defined metabolizing enzymes such as CYP3A4, it has preferred above, and n represents an integer between 0 and 6. effects as a pharmaceutical in terms of safety. US 7,820,693 B2 127 128 The aforementioned methods include a step of administer day. It is desired that Such an amount of pharmaceutical ing to patients, who need Such treatment or who suffer from composition be administered depending on symptoms. the aforementioned diseases or symptoms, a pharmaceutical composition comprising the compound disclosed in the EXAMPLES present invention or a pharmaceutically acceptable salt thereof, at a pharmaceutically effective dosage. The present invention will be more specifically described When the pharmaceutical composition of the present in the following examples. However, these examples are not invention is used as a therapeutic or preventive agent for intended to limit the scope of the present invention. It is to be proliferative diseases Such as cancer, examples of an admin noted that NMR analysis was carried out using JNM-EX270 istration method may include oral, intrarectal, parenteral (in 10 (270 MHz), JNMGSX400 (400 MHz) or JNM-A500 (500 travenous, intramuscular, or Subcutaneous), intracisternal, MHz), which are manufactured by JEOL, or NMR (300 intravaginal, intraperitoneal, intravesical, and local (admin MHz) manufactured by Bruker. NMR data was indicated with istration of drop, powders, ointment, or cream) administra ppm (parts per million). The deuterium lock signal from a tions, and inhalation (intraoral or nasal spray). Examples of sample solvent was referred. Mass spectrum data was Such an administration form may include a tablet, a capsule, 15 obtained using JMS-DX303 or JMS-SX/SX102A manufac a granule, a powder, a pill, an aqueous or nonaqueous oral tured by JEOL, or Quttromicro manufactured by Micromass. Solution, a Suspension, and a parenteral Solution, which is In addition, mass spectrum data including high performance filled in a container suitable for dividing the solution into liquid chromatography was obtained, using a micromass individual dosages. In addition, such an administration form (ZMD manufactured by Micromass) equipped with a 996 can also be adapted to various administration methods includ 600E gradient high performance liquid chromatography ing controlled released preparations such as those used in manufactured by Waters, or using a micromass (ZO manu Subcutaneous transplantation. factured by Micromass) equipped with a 2525 gradient high The aforementioned pharmaceutical can be produced performance liquid chromatography manufactured by according to known methods using additives such as an Waters. Any of the following conditions were applied for such excipient, a lubricant (coating agent), a binder, a disintegra 25 high performance liquid chromatography. tor, a stabilizer, a flavoring agent, or a diluent. High Performance Liquid Chromatography Condition 1 Examples of an excipient may include starches such as starch, potato starch, or corn starch, lactose, crystalline cel Column: Combi ODS (ODS, 5 um, 4.6 mm I.D.x50 mm, lulose, and calcium hydrogen phosphate. manufactured by Wako Pure Chemical Industries, Ltd.), Examples of a coating agent may include ethyl cellulose, 30 COSMOSIL (ODS, 5 um, 4.6 mm I.D.x50 mm, manufac hydroxypropylcellulose, hydroxypropylmethylcellulose, tured by Nacalai Tesque, Inc.), Inertsil C18 (ODS, 5um, 4.6 shellac, talc, carnauba wax, and paraffin. mm I.D.x50 mm, manufactured by GL Sciences, Inc), or Examples of a binder may include polyvinylpyrrolidone, SunFire C18 (ODS, 5um, 4.6 mm I.D.x50mm, manufactured macrogol, and the same compounds as those described in the by Waters) excipient. 35 Mobile phase: Water (A) that contains 0.05% trifluoroacetic Examples of a disintegrator may include the same com acid and acetonitrile (B) that contains 0.05% trifluoroacetic pounds as those described in the excipient, and chemically acid modified Starches and celluloses, such as croScarmellose Sodium, carboxymethyl starch sodium, or crosslinked poly Elution method: A Stepwise solvent gradient elution compris vinylpyrrolidone. 40 ing eluting from 10% B to 95% B (3.5 minutes), eluting from Examples of a stabilizer may include: p-hydroxybenzoic 95% B to 10% B (1 minute), and then retaining at 10% B (0.5 esters such as methylparabenor propylparaben; alcohols such minutes) as chlorobutanol, benzyl alcohol, or phenylethyl alcohol: Flow rate: 4.0 ml/minute benzalkonium chloride; phenols such as phenol or cresol; High Performance Liquid Chromatography Condition 2 thimerosal; dehydroacetic acid; and Sorbic acid. 45 Examples of a flavoring agent may include commonly used Column: Combi ODS (ODS, 5 um, 4.6 mm I.D.x50 mm, Sweeteners, acidulants, and aromatics. manufactured by Wako Pure Chemical Industries, Ltd.), Examples of a solvent used in production of a liquid agent COSMOSIL (ODS, 5 um, 4.6 mm I.D.x50 mm, manufac may include ethanol, phenol, chlorocresol, purified water, tured by Nacalai Tesque, Inc.), Inertsil C18 (ODS, 5um, 4.6 and distilled water. 50 mm I.D.x50 mm, manufactured by GL Sciences, Inc), or Examples of a Surfactant or emulsifier may include SunFire C18 (ODS, 5um, 4.6 mm I.D.x50mm, manufactured polysorbate 80, polyoxyl 40 Stearate, and lauromacrogol. by Waters) When the pharmaceutical composition of the present Mobile phase: Water (A) that contains 0.05% trifluoroacetic invention is used as a therapeutic or preventive agent for acid and acetonitrile (B) that contains 0.05% trifluoroacetic proliferative diseases, the amount used of the compound of 55 acid the present invention or a pharmaceutically acceptable salt thereof is different depending on symptom, age, body weight, Elution method: A Stepwise solvent gradient elution compris relative physical conditions, the use of other agents, an ing eluting from 30% B to 35% B (0.2 minutes), eluting from administration method, etc. For example, for a patient (a 35% B to 98% B (3.3 minutes), eluting from 98% B to 30% B hematherm, and particularly a human), in the case of admin 60 (1 minute), and then retaining at 30% B (0.5 minutes) istering an active ingredient (the compound represented by Flow rate: 4.0 ml/minute the formula (1) of the present invention) as an oral agent, an effective amount is generally preferably 0.01 and 5,000 mg. High Performance Liquid Chromatography Condition 3 and more preferably between 0.1 and 500 mg per kg of body Column: Combi ODS (ODS, 5 um, 4.6 mm I.D.x50 mm, weight per day. In the case of a parenteral agent, such an 65 manufactured by Wako Pure Chemical Industries, Ltd.), or effective amount is preferably 0.01 and 5,000 mg, and more SunFire C18 (ODS, 5um, 4.6 mm I.D.x50mm, manufactured preferably between 0.1 and 500 mg per kg of body weight per by Waters) US 7,820,693 B2 129 130 Mobile phase: Water (A) that contains 0.05% trifluoroacetic Step B acid and acetonitrile (B) that contains 0.05% trifluoroacetic acid 7-Chloro-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one Elution method: A Stepwise solvent gradient elution compris ing eluting from 10% B to 95% B (2 minutes), retaining at 95% B (1.5 minutes), eluting from 95% B to 10% B, and retaining at 10% B (0.5 minutes) Formula 21 Flow rate: 4.0 ml/minute An organic synthetic reaction was carried out using a com 10 mercially available reagent, which has not been further puri fied before use. The term “room temperature' is used herein to mean a temperature ranging from 20° C. to 25°C. All antiposic reactions were carried out in a nitrogen atmosphere. 15 Concentration under reduced pressure or solvent distillation was carried out using a rotary evaporator, unless otherwise specified. A 1.8 M lithium diisopropylamide THF solution (45.3 ml, For preparation of compounds, a functional group is pro 81.6 mmol) was diluted with THF (68 ml). Thereafter, a tected by a protecting group as necessary, a protector of a solution obtained by dissolving the 5-chloro-2.N-dimethyl target molecule is prepared, and the protecting group is then benzamide (5.0g, 27.2 mmol) prepared in step A in THF (28 removed. Operations to select such a protecting group and to ml) was added dropwise to the diluted solution at -78° C. remove it were carried out according to the method described Thereafter, a solution obtained by dissolving 2-trifluorometh in Greene and Wuts, “Protective Group in Organic Synthe ylbenzonitrile (4.65g, 27.2 mmol) in THF (28 ml) was further 25 added thereto, and the obtained mixture was then stirred at sis.” 2" edition, John Wiley & Sons, 1991, for example. -78°C. for 2.5 hours. The temperature of the reaction solu tion was increased to a room temperature, and a saturated Example 1-1 ammonium chloride aqueous solution was added thereto, fol lowed by extraction with ethyl acetate. The extract was 7-(2-Oxoazetidin-1-yl)-3-(2-trifluoromethylphenyl)- 30 washed with a saturated Saline Solution, and was then dried 2H-isoquinolin-1-one over anhydrous sodium sulfate. Thereafter, a solid generated as a result of Vacuum concentration was filtrated, so as to Step A obtain 7-chloro-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one (6.87 g; yield: 78%) in the form of a colorless solid. 5-Chloro-2,N-dimethylbenzamide 35 'H-NMR (270 MHz, CDC1) & (ppm): 6.49 (1H, s), 7.33 7.72 (5H, m), 7.81-7.84 (1H, d, J=7.26 Hz), 8.32-8.33 (1H, d, J=1.65 Hz), 9.18 (1H, brs) ESI (LC-MS positive mode) m/z 324 (M+H). Formula 20 40 Step C 7-Amino-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one

45

Thionyl chloride (42.8 ml, 586 mmol) was added to Formula 22 5-chloro-2-methylbenzoic acid (25.0 g, 147 mmol). The mix ture was stirred under heating to reflux for 1.5 hours. There after, excessive thionyl chloride was distilled away under 50 reduced pressure. The residue was dissolved in methylene chloride (140 ml), and a 40% methylamine aqueous solution (34.2 ml, 440 mmol) was then added dropwise thereto under cooling on ice. Thereafter, the obtained mixture was stirred at 0°C. for 1 day. Thereafter, the reaction solution was extracted 55 with ethyl acetate, and the extract was then washed with a A 1 M lithium bis(trimethylsilyl)amide THF solution (21 saturated saline solution. The resultant was then dried over mL, 21 mmol) was added to a mixture of the 7-chloro-3-(2- anhydrous sodium Sulfate, and the solvent was distilled away trifluoromethylphenyl)-2H-isoquinolin-1-one (2.50 g, 7.72 under reduced pressure. The obtained residue was purified by 60 mmol) prepared in step B, 2-(dicyclohexylphosphino)biphe silica gel column chromatography (ethyl acetate:hexane-1:3 nyl (64.9 mg, 0.185 mmol), and tris(dibenzylideneacetone) to 3:2), so as to obtain 5-chloro-2,N-dimethylbenzamide dipalladium (70.7 mg, 0.0772 mmol), and the obtained mix (24.2 g; yield: 90%) in the form of a colorless solid. ture was stirred under heating to reflux for 1 day. Thereafter, 'H-NMR (270 MHz, CDC1) & (ppm): 2.40 (3H, s), 2.99 the reaction Solution was cooled to a room temperature, and 1 (3H, d, J=4.6Hz), 5.77 (1H, brs), 7.15 (1H, d, J=8.3 Hz), 7.27 65 N hydrochloric acid (63 ml) was then added thereto, followed (1H, dd, J=2.3, 8.3 Hz), 7.33 (1H, d, J=2.3 Hz) by stirring for 5 minutes. Thereafter, the reaction solution was ESI (LC-MS positive mode) m/z 184 (M+H). neutralized with a 5N sodium hydroxide aqueous solution (8 US 7,820,693 B2 131 132 ml), and then extracted with methylene chloride. The extract The 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin was washed with a saturated Saline solution, and was then 1-one (10.0 mg, 0.024 mmol) prepared in step D, copper dried over anhydrous sodium sulfate, followed by concentra iodide (I) (0.48 mg, 0.0025 mmol), 2-azetidinone (2.13 mg, tion. The obtained residue was purified by silica gel column 0.03 mmol), and potassium phosphate (11.1 mg, 0.0525 chromatography (ethyl acetate hexane 3:1 to 6:1), so as to mmol) were suspended in 1,4-dioxane (0.25 ml). Thereafter, obtain 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquino N,N'-dimethylethylenediamine (2.6 ul) was added to the sus lin-1-one (2.14 g; yield: 91%) in the form of a brown solid. pension, and the obtained mixture was stirred under heating 'H-NMR (270 MHz, CDC1) & (ppm): 4.00 (2H, brs), 6.43 to reflux overnight. Thereafter, the reaction solution was (1H, s), 7.07 (1H, dd, J=2.5, 8.3 Hz), 7.40 (1H, d, J=8.3 Hz), cooled to a room temperature, and a saturated ammonium 7.50-7.69 (4H, m), 7.76-7.83 (1H, m), 8.63 (1H, brs) 10 chloride aqueous solution was then added thereto, followed ESI (LC-MS positive mode) m/z 305 (M+H). by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled Step D away under reduced pressure. The obtained residue was puri 7-Iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin fied by silica gel column chromatography (ethyl acetate hex 15 ane=3:1 to 6:1), so as to obtain 7-(2-oxoazetidin-1-yl)-3-(2- 1-one trifluoromethylphenyl)-2H-isoquinolin-1-one (3.8 mg; yield: 44%) in the form of a colorless solid. Formula 23 'H-NMR (270 MHz, CDC1) & (ppm): 3.20 (2H, t, J=4.6 Hz), 3.77 (2H, t, J=4.6 Hz), 6.51 (1H, s), 7.50-7.71 (4H, m), 7.80-7.87 (2H, m), 8.27 (1H, dd, J=2.3, 8.6 Hz), 8.65 (1H, brs) ESI (LC-MS positive mode) m/z. 359 (M+H). The following compounds (Examples 1-2 to 1-12) were synthesized by a reaction similar to step E of Example 1-1, 25 using the 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one obtained in step D of Example 1-1 as a raw material. A 1 N sulfuric acid aqueous solution (30 ml) and sodium Example 1-2 nitrite (862.5 mg, 12.5 mmol) were added at 0°C. to an acetic acid solution (15 ml) that contained the 7-amino-3-(2-trifluo 7-(2-Oxopiperidin-1-yl)-3-(2-trifluoromethylphe romethylphenyl)-2H-isoquinolin-1-one (1.52 g, 5.0 mmol) 30 nyl)-2H-isoquinolin-1-one obtained in step C, and the obtained mixture was stirred for 30 minutes. Thereafter, sodium iodide (2.62 g, 17.5 mmol) and copper iodide (I) (952.3 mg, 5.0 mmol) were added to the reaction solution, and the obtained mixture was stirred at 80° Formula 25 C. for 1 hour. The reaction solution was cooled, and a satu 35 rated Sodium bicarbonate aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated Saline solution, and was then O N dried over anhydrous sodium sulfate, followed by concentra tion. The obtained residue was purified by silica gel column N chromatography (ethyl acetate:hexane=1:4 to 1:2). The 40 N F resultant was washed with a sodium thiosulfate aqueous solu tion, so as to obtain 7-iodo-3-(2-trifluoromethylphenyl)-2H O isoquinolin-1-one (1.87 g; yield: 90%) in the form of a pale yellow solid. 'H-NMR (270 MHz, CDC1) & (ppm): 6.47 (1H, s), 7.31 45 'H-NMR (270 MHz, CDC1) & (ppm): 1.95-2.00 (4H, m), (1H, d, J=8.6 Hz), 7.55 (1H, dd, J=1.7, 7.3 Hz), 7.59-7.73 2.61 (2H, t, J=5.9 Hz), 3.78 (2H, t, J=6.1 Hz), 6.52 (1H, s), (2H, m), 7.83 (1H, dd, J–2.0, 6.9 Hz), 7.96 (1H, dd, J=1.8, 8.4 7.52-7.69 (4H, m), 7.73 (1H, dd, J=2.3, 8.6 Hz), 7.83 (1H, dd, Hz), 8.72 (1H, d, J=1.6 Hz), 9.06 (1H, brs) J=1.7, 7.6 Hz), 8.24 (1H, d, J=2.3 Hz), 8.44 (1H, brs) ESI (LC-MS positive mode) m/z 416 (M+H). ESI (LC-MS positive mode) m/z 387 (M+H). 50 Step E Example 1-3 7-(2-Oxoazetidin-1-yl)-3-(2-trifluoromethylphenyl)- 7-(2-Oxo-2H-pyridin-1-yl)-3-(2-trifluoromethylphe 2H-isoquinolin-1-one nyl)-2H-isoquinolin-1-one 55

Formula 26 Formula 24

60

65

US 7,820,693 B2 137 138 Example 1-13 was distilled away under reduced pressure. The obtained residue was dissolved in methanol (15 ml), and the obtained 7-((S)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- solution was stirred under heating to reflux for 10 minutes. (2-trifluoromethylphenyl)-2H-isoquinolin-1-one Thereafter, the reaction solution was concentrated, and a satu rated ammonium chloride aqueous Solution was then added to Step A the residue, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was 7-((S)-2,3-Dihydroxypropylamino)-3-(2-trifluorom then concentrated. The obtained residue was purified by silica ethylphenyl)-2H-isoquinolin-1-one gel column chromatography (methylene chloride:metha 10 nol=40:1 to 20:1), so as to obtain 7-((S)-5-hydroxymethyl-2- oXooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-iso quinolin-1-one (233.8 mg; yield: 78%). Formula 36 'H-NMR (270 MHz, DMSO-d) & (ppm): 3.55-3.79 (2H, m) 3.90-4.00 (1H, m), 4.22 (1H, t, J=8.9 Hz), 4.70-4.83 (1H, 15 m), 5.25 (1H, t, J=5.6 Hz), 6.49 (1H, s), 7.60-7.90 (5H, m), 8.09 (1H, dd, J=2.3, 8.6 Hz), 8.25 (1H, d, J=2.3 Hz), 11.62 (1H, brs) ESI (LC-MS positive mode) m/z 405 (M+H). Example 1-14 H 7-((R)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- (2-trifluoromethylphenyl)-2H-isoquinolin-1-one (R)-Glycidol (78.3 ul. 1.18 mmol) was added to an ethanol solution (4 ml) that contained the 7-amino-3-(2-trifluorom Step A ethylphenyl)-2H-isoquinolin-1-one obtained in step C of 25 Example 1-1, and the obtained mixture was stirred under 7-((R)-2,3-Dihydroxypropylamino)-3-(2-trifluorom heating to reflux for 3 days. Thereafter, the reaction solution ethylphenyl)-2H-isoquinolin-1-one was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography Formula 38 (methylene chloride:methanol=20:1), so as to obtain 7-((S)- 2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)- 2H-isoquinolin-1-one (281.9 mg; yield: 63%) in the form of a pale yellow amorphous Substance. 'H-NMR (270 MHz, DMSO-d) & (ppm): 2.95-3.05 (1H, m), 3.23-3.46 (3H, m), 3.64-3.73 (1H, m), 4.66 (1H, t, J=5.3 35 Hz), 4.84 (1H, d, J=5.0 Hz), 6.03 (1H, t, J=5.4 Hz), 6.29 (1H, s), 7.13 (1H, dd, J-2.0, 8.8 Hz), 7.24 (1H, d, J-2.0 Hz), 7.40 (1H, d, J=8.8 Hz), 7.58 (1H, d, J=7.5 Hz), 7.66 (1H, t, J–7.5 Hz), 7.75 (1H, t, J=7.5 Hz), 7.84 (1H, d, J–7.5 Hz), 11.24 (1H, The captioned compound was prepared by a reaction simi brs) 40 lar to step A of Example 1-13. ESI (LC-MS positive mode) m/z. 379 (M+H). 'H-NMR (270 MHz, DMSO-d) & (ppm): 2.95-3.05 (1H, Step B m), 3.20-3.46 (3H, m), 3.64-3.73 (1H, m), 4.60-4.70 (1H, m), 4.85 (1H, d, J–4.6 Hz), 6.00-6.08 (1H, m), 6.29 (1H, s), 7.13 7-((S)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- (1H, dd, J=2.0, 8.3 Hz), 7.24 (1H, s), 7.40 (1H, d, J=8.3 Hz), (2-trifluoromethylphenyl)-2H-isoquinolin-1-one 45 7.58 (1H, d, J=7.3 Hz), 7.66 (1H, t, J=7.3 Hz), 7.75 (1H, t, J=7.3 Hz), 7.84 (1H, d, J–7.3 Hz), 11.24 (1H, brs) ESI (LC-MS positive mode) m/z. 379 (M+H). Step B

Formula 37 50 7-((R)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- (2-trifluoromethylphenyl)-2H-isoquinolin-1-one

55 Formula 39

HO 60 The 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluorom ethylphenyl)-2H-isoquinolin-1-one (281.9 mg 0.745 mmol) obtained in step A was suspended in diethyl carbonate (2.93 ml), and thereafter, a 28% sodium methoxide-methanol solu 65 tion (117 ul) was added thereto. The obtained mixture was stirred at 105° C. for 13 hours. Thereafter, diethyl carbonate US 7,820,693 B2 139 140 The captioned compound was prepared by a reaction simi H-NMR (270 MHz, CDC1) & (ppm): 2.20-2.41 (2H, m), lar to step B of Example 1-13. 2.52-2.64 (1H, m), 2.73-2.86 (1H, m), 3.70-3.90 (2H, m), 'H-NMR (270 MHz, DMSO-d) & (ppm): 3.55-3.79 (2H, 4.49-4.53 (1H, m), 6.53 (1H, s), 7.53-7.70 (4H, m), 7.80-7.83 m) 3.90-4.00 (1H, m), 4.21 (1H, t, J=8.7 Hz), 4.70-4.83 (1H, (1H, m), 8.21 (1H, s), 8.25 (1H, d, J=2.31 Hz), 8.72 (1H, brs) m), 5.25 (1H, t, J=5.4 Hz), 6.49 (1H, s), 7.60-7.90 (5H, m), 5 EI-MS m/z 402 (M+). 8.09 (1H, dd, J=2.3, 8.9 Hz), 8.25 (1H, d, J=2.3 Hz), 11.62 (1H, brs) Example 1-17 ESI (LC-MS positive mode) m/z 405 (M+H). 7-(2-OXooxazolidin-3-yl)-3-(2-trifluoromethylphe Example 1-15 10 nyl)-2H-isoquinolin-1-one 7-(2-Oxopyrrolidin-1-yl)-3-(2-trifluoromethylphe nyl)-2H-isoquinolin-1-one Formula 42 15

Formula 40

N O O N N F O

The 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin 25 'H-NMR (270 MHz, CDC1,) & (ppm): 4.21 (2H, t, J=8.0 1-one (20.8 mg 0.05 mmol) prepared in step D of Example Hz), 4.57 (2H, t, J=8.0 Hz), 6.54 (1H, s), 7.55-7.75 (4H, m), 1-1, tris(dibenzylideneacetone)dipalladium (2.2 mg, 0.0025 7.83 (1H, d, J=7.3 Hz), 7.90-8.00 (1H, m), 8.60 (1H, dd, mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene J=2.5, 8.7 Hz), 8.73 (1H, brs) (4.2 mg, 0.0075 mmol), cesium carbonate (22.8 mg, 0.07 ESI (LC-MS positive mode) m/z. 375 (M+H). mmol), and 2-pyrrolidone (4.6 ul) were suspended in 1,4- 30 dixane (0.5 ml), and the Suspension was then stirred under Example 1-18 heating to reflux overnight. Thereafter, the reaction solution was cooled to a room temperature, and a saturated ammonium 7-(3-Methyl-2-oxo-2,3-dihydroimidazol-1-yl)-3-(2- chloride aqueous solution was then added thereto, followed trifluoromethylphenyl)-2H-isoquinolin-1-one by extraction with ethyl acetate. The extract was dried over 35 anhydrous sodium sulfate, and the solvent was then distilled Step A away under reduced pressure. The obtained residue was puri fied by silica gel column chromatography (ethyl acetate hex 1-(2,2-Dimethoxyethyl)-1-methyl-3-1-oxo-3-(2- ane=2:1 to 5:1), so as to obtain 7-(2-oxopyrrolidin-1-yl)-3- trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl) (2-trifluoromethylphenyl)-2H-isoquinolin-1-one (15.3 mg: yield: 82%) in the form of a colorless solid. 40 la H-NMR (270 MHz, CDC1) & (ppm): 2.23 (2H, quintet, J=7.5 Hz), 2.68 (2H, t, J–7.5 Hz), 4.01 (2H, t, J–7.5 Hz), 6.52 (1H, s), 7.53-7.71 (4H, m), 7.82 (1H, d, J–7.3 Hz), 8.05 (1H, Formula 43

d, J=2.3 Hz), 8.65 (1H, dd, J=2.3, 8.6 Hz), 8.76 (1H, brs) 45 ESI (LC-MS positive mode) m/z. 373 (M+H). The following compounds (Examples 1-16 and 1-17) were synthesized by a reaction similar to that of Example 1-15.

Example 1-16 50 7-((R)-2-Hydroxymethyl-5-oxopyrrolidin-1-yl)-3-(2- trifluoromethylphenyl)-2H-isoquinolin-1-one

55 The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one (30.4 mg. 0.1 mmol) obtained in step C of Example

Formula 41 1-1 was dissolved in a mixed solvent (0.5 ml) of methylene chloride and DMF (1:1). Thereafter, pyridine (16.2 ul, 0.2 mmol) and 4-nitrophenyl chloroformate (24.2 mg, 0.12 60 mmol) were added thereto under cooling on ice. The obtained mixture was then stirred at a room temperature for 2 hours. Thereafter, 2.2-dimethoxy-N-methylethylamine (15.4 ul, 0.12 mmol) was added to the reaction solution, and the obtained mixture was then stirred at a room temperature 65 overnight. Thereafter, water was added to the reaction solu tion, followed by extraction with ethyl acetate. The extract was washed with a saturated Saline solution, and then dried US 7,820,693 B2 141 142 over anhydrous sodium sulfate, followed by concentration. Using 5-chloro-2-methylbenzoic acid as a staring material, The obtained residue was purified by silica gel column chro the captioned compound was synthesized by a method similar matography (ethyl acetate:hexane 5:1), so as to obtain 1-(2, to step A of Example 1-1. 2-dimethoxyethyl)-1-methyl-3-1-oxo-3-(2-trifluorometh 'H-NMR (270 MHz, CDC1) & (ppm): 2.25 (3H, s), 2.85 ylphenyl)-1,2-dihydroisoquinolin-7-ylurea (17.5 mg; yield: 5 39%) in the form of a colorless amorphous substance. (3H, s), 3.12 (3H, s), 7.15 (1H, d, J–8.4 Hz)7.16 (1H, d. J–2.3 'H-NMR (270 MHz, DMSO-d) & (ppm): 3.08 (3H, s), Hz), 7.24 (1H, dd, J=2.3, 8.4 Hz) 3.45-3.54 (8H, m), 4.55 (1H, t, J=5.1 Hz), 6.48 (1H, s), ESI (LC-MS positive mode) m/z 198 (M+H). 7.50-7.70 (4H, m), 7.78-7.83 (1H, m), 7.98-8.02 (1H, m), Step B 8.11 (1H, brs), 8.22 (1H, dd, J–2.3, 8.6 Hz), 8.71 (1H, brs) 10 ESI (LC-MS positive mode) m/z 450 (M+H). 7-Chloro-3-(2-morpholin-4-ylphenyl)-2H-isoquino Step B lin-1-one 7-(3-Methyl-2-oxo-2,3-dihydroimidazol-1-yl)-3-(2- trifluoromethylphenyl)-2H-isoquinolin-1-one 15

Formula 46

Formula 44

25 A 1.8 M lithium diisopropylamide THF solution (5.39 ml, 9.69 mmol) was diluted with THF (10 ml). To the diluted The 1-(2,2-dimethoxyethyl)-1-methyl-3-1-oxo-3-(2-trif solution, a solution obtained by dissolving the 5-chloro-2.N. luoromethylphenyl)-1,2-dihydroisoquinolin-7-ylurea (17.5 30 N-trimethylbenzamide (383 mg, 1.94 mmol) prepared in step mg, 0.0389 mmol) obtained in step A was dissolved informic A in THF (5 ml) was added dropwise at -78°C. A solution acid (0.2 ml). The obtained solution was stirred at a room obtained by dissolving 2-(4-morpholino)benzonitrile (438 temperature overnight. Thereafter, formic acid was distilled mg, 2.33 mmol) in THF (5 ml) was further added to the away under reduced pressure, and the obtained residue was mixture. The obtained mixture was stirred at -78°C. for 30 then dissolved in methylene chloride. The obtained solution 35 minutes. Thereafter, a saturated ammonium chloride aqueous was washed with a saturated Sodium bicarbonate aqueous solution was added to the reaction solution, followed by Solution, and was then dried over anhydrous sodium Sulfate, extraction with ethyl acetate. The extract was washed with a followed by concentration. The obtained residue was purified saturated Saline solution, and was then dried over anhydrous by silica gel column chromatography (ethyl acetate:hex sodium sulfate, followed by concentration under reduced ane=4:1 to 1:0), so as to obtain 7-(3-methyl-2-oxo-2,3-dihy 40 pressure. The obtained yellow oil product was crystallized droimidazol-1-yl)-3-(2-trifluoromethylphenyl)-2H-iso from hexane/ethyl acetate (3:1), so as to obtain 7-chloro-3- quinolin-1-one (10.9 mg; yield: 73%) in the form of a (2-morpholin-4-ylphenyl)-2H-isoquinolin-1-one (575 mg: colorless solid. yield: 87%) in the form of a colorless crystal. 'H-NMR (270MHz, DMSO-d)8(ppm): 3.23 (3H, s) 6.52 H-NMR (400 MHz, CDC1) & (ppm): 2.97-3.00 (4H, m), (1H, s), 6.80 (1H, d. J=3.3 Hz), 7.20 (1H, d, J=3.3 Hz), 45 7.6.1-7.84 (4H, m), 7.85-7.93 (1H, m), 8.09 (1H, dd, J=2.6, 3.87-3.90 (4H, m), 6.71 (1H, s), 7.19 (2H, m), 7.43 (1H, dt, 8.6 Hz), 8.56 (1H, d, J=2.3 Hz), 11.66 (1H, brs) J=1.2, 7.6 Hz), 7.53 (1H, d, J=8.4 Hz), 7.59-7.62 (2H, m), ESI (LC-MS positive mode) m/z 386 (M+H). 8.39 (1H, s), 11.10 (1H, brs) ESI (LC-MS positive mode) m/z 341 (M+H). Example 1-19 50 Step C 7-((R)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- 7-Amino-3-(2-morpholin-4-ylphenyl)-2H-isoquino (2-morpholin-4-ylphenyl)-2H-isoquinolin-1-one lin-1-one Step A 55 5-Chloro-2.N.N-trimethylbenzamide

Formula 47

Formula 45 60

65

US 7,820,693 B2 151 152 The 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2-di Example 1-32 hydroisoquinolin-7-yloxazolidin-5-ylmethyl methane sulfonate (169.1 mg, 0.351 mmol) obtained in step C was N-2-Oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- dissolved in N,N-dimethylformamide (1.3 ml). Thereafter, dihydroisoquinolin-7-yloxazolidin-5- sodium azide (96.2 mg, 1.33 mmol) was added to the obtained ylmethyl)acetamide solution, and the mixture was then stirred at 65° C. for 4 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated Saline Solution, and was then dried Formula 67 over anhydrous sodium sulfate, followed by concentration 10 under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane 2:1 to 3:1), so as to obtain 7-(5-azidomethyl-2-oxooxazolidin-3- yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (139.6 mg; yield: 93%) in the form of a colorless solid. 15 H-NMR (270 MHz, CDC1) & (ppm): 3.64 (1H, dd, J–4.5, 13.3 Hz), 3.76 (1H, dd, J=4.4, 13.3 Hz), 4.03 (1H, dd, J=6.3, 9.2 Hz), 4.25 (1H, t, J=9.1 Hz), 482-4.93 (1H, m), 6.53 (1H, s), 7.52-7.72 (4H, m), 7.83 (1H, dd, J=1.5, 7.4 Hz), 7.94 (1H, d, J–2.6 Hz), 8.59 (1H, dd, J=2.6, 8.9 Hz), 8.64 (1H, brs) ESI (LC-MS positive mode) m/z 430 (M+H). Example 1-31 The 7-(5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trif luoromethylphenyl)-2H-isoquinolin-1-one (15.3 mg 0.038 7-(5-Aminomethyl-2-oxooxazolidin-3-yl)-3-(2-trif 25 mmol) obtained in Example 1-31 was dissolved in pyridine luoromethylphenyl)-2H-isoquinolin-1-one (380 ul). Thereafter, acetylchloride (3.2 ul) was added to the obtained solution, and the obtained mixture was stirred at a room temperature for 2 hours. Thereafter, 1 N hydrochloric acid was added to the reaction Solution under cooling on ice, Formula 66 30 followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methyl ene chloride:methanol=20:1), so as to obtain N-(2-oxo-3-1- 35 oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7- yloxazolidin-5-ylmethyl)acetamide (12.1 mg; yield: 71%) in the form of a colorless amorphous Substance. 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.85 (3H, s), 3.43-3.52 (2H, m), 3.89 (1H, dd, J=6.5, 9.1 Hz), 4.24 (1H, t, HN 40 J=9.0Hz), 4.71-4.82(1H, m), 6.49 (1H, s), 7.60-7.90 (5H, m), 8.08 (1H, dd, J–2.5, 8.7 Hz), 8.20(1H, d, J=2.5Hz), 8.23-8.32 The 7-(5-azidomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluo (1H, m), 11.62 (1H, brs) romethylphenyl)-2H-isoquinolin-1-one (50.0 mg, 0.116 ESI (LC-MS positive mode) m/z. 446 (M+H). mmol) obtained in Example 1-30 was dissolved in tetrahy 45 drofuran (387 ul). Thereafter, triphenylphosphine (33.6 mg, Example 1-33 0.128 mmol) and water (20.9 ul) were added to the obtained solution, and the obtained mixture was then stirred at 40°C. 7-(5-Morpholin-4-ylmethyl-2-oxooxazolidin-3-yl)-3- for 14 hours. Thereafter, 1 N hydrochloric acid (0.5 ml) was (2-trifluoromethylphenyl)-2H-isoquinolin-1-one added to the reaction solution, followed by washing with 50 ethyl acetate. A 1 N sodium hydroxide aqueous solution (1.0 ml) was added to the residual water layer, followed by extrac tion with ethyl acetate. The extract was washed with a satu Formula 68 rated Saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced 55 pressure. The obtained residue was purified by column chro matography using Bond Elut (registered trademark) NH2 (Varian; 1g), so as to obtain 7-(5-aminomethyl-2-oxooxazo lidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1- one (45.8 mg; yield: 98%) in the form of a colorless foaming 60 Substance. 'H-NMR (270 MHz, CDC1) & (ppm): 1.59 (3H, brs), 3.01 (1H, dd, J=5.6, 13.7 Hz), 3.16 (1H, dd, J–4.0, 13.7 Hz), 4.04 (1H, dd, J–6.8, 8.9 Hz), 4.19 (1H, t, J=8.9Hz), 4.69-4.80 (1H, m), 6.49 (1H, s), 7.52-7.72 (4H, m), 7.77-7.82 (1H, m), 7.90 65 7.92 (1H, m), 8.56 (1H, dd, J=2.5, 8.9 Hz) ESI (LC-MS positive mode) m/z 404 (M+H). US 7,820,693 B2 153 154 The 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2-di Example 1-35 hydroisoquinolin-7-yloxazolidin-5-ylmethyl 7-((R)-4-Benzyloxymethyl-3-methyl-2-oxoimidazo methanesulfonate (20.0 mg, 0.04.15 mmol) obtained in step C lidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino of Example 1-30 was dissolved in acetonitrile (0.1 ml). lin-1-one Thereafter, morpholine (3.6 ul) was added to the obtained Solution, and the obtained mixture was stirred under heating Step A to reflux for 22 hours. Thereafter, the reaction solution was cooled to a room temperature, and it was then concentrated 7-((R)-3-Benzyloxy-2-methylaminopropylamino)-3- 10 (2-trifluoromethylphenyl)-2H-isoquinolin-1-one under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol=40:1), so as to obtain 7-(5-morpholin-4-ylmethyl 2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-iso Formula 70 15 Chiral quinolin-1-one (9.7 mg; yield: 49%) in the form of a colorless amorphous Substance. 'H-NMR (270 MHz, CDOD) 8 (ppm): 2.55-2.70 (4H, m), 2.80 (2H, d, J=5.6 Hz), 3.70 (4H, t, J=4.6 Hz), 3.99 (1H, dd, J=7.0, 8.9 Hz), 4.30 (1H, t, J=8.9Hz), 4.89-5.01 (1H, m), 6.61 (1H, s), 7.59-7.79 (4H, m), 7.83-7.89 (1H, m), 8.24 (1H, d, J=2.5 Hz), 8.29 (1H, dd, J–2.5, 8.7 Hz) ESI (LC-MS positive mode) m/z 474 (M+H). 25 Example 1-34 7-5-(4-Hydroxypiperidin-1-ylmethyl)-2-oxooxazoli din-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one 30 BOP Reagent (1.2 g, 2.8 mmol), N,N-diisopropylethy lamine (0.5 ml, 3 mmol), and N.O-dimethylhydroxyamine hydrochloride (273 mg, 2.8 mmol) were added to a dichlo romethane solution that contained Fmoc-MeSer(BZl)-OH (1 35 g, 2.3 mmol). The obtained mixture was stirred at a room temperature for 1 day. Thereafter, the reaction solution was Formula 69 successively washed with 1 Nhydrochloric acid, with a satu rated sodium bicarbonate aqueous solution, and with a satu rated saline solution. Thereafter, the resultant was dried over 40 anhydrous sodium Sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane-1: 2). 238 mg out of the obtained oil product (850 mg) was dissolved in THF (2 ml), and the obtained solution was added 45 dropwise at -78°C. to a THF solution (8 ml) that contained lithium aluminum hydride (10 mg, 0.25 mmol). The obtained mixture was stirred at -78° C. for 1.5 hours. Thereafter, lithium aluminum hydride (10 mg, 0.25 mmol) was further HO added thereto, and the obtained mixture was stirred at -78°C. 50 for 30 minutes. Thereafter, a saturated ammonium chloride aqueous Solution was added to the reaction solution at -78° C., and the temperature of the obtained mixture was then increased to a room temperature. The mixture was filtered Using the 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1, through celite, and the filtrate was then extracted with dichlo 55 romethane. The extract was washed with a saturated saline 2-dihydroisoquinolin-7-ylloxazolidin-5-ylmethyl methane Solution, and was dried over anhydrous Sodium Sulfate, fol sulfonate obtained in step C of Example 1-30 as a raw mate lowed by concentration under reduced pressure. The gener rial, the captioned compound was synthesized by a method ated oil product was dissolved in 5 ml of methanol without similar to that of Example 1-33. being purified. Thereafter, 7-amino-3-(2-trifluoromethylphe 'H-NMR (270 MHz, CDOD) 8 (ppm): 1.50-1.65 (2H, m), 60 nyl)-2H-isoquinolin-1-one (100 mg, 0.33 mmol) and 1 ml of acetic acid were added thereto. Thereafter, sodium 1.81-1.92 (2H, m), 2.30-2.45 (2H, m), 2.78-2.82 (2H, m), cyanoborohydride (135 mg, 2.1 mmol) was added to the 2.87-3.00 (2H, m), 3.57-3.67 (1H, m), 3.95 (1H, dd, J=7.2, mixture under cooling on ice, and the temperature of the 8.9 Hz), 4.30 (1H, t, J=8.9 Hz), 4.85-5.00 (1H, m), 6.61 (1H, obtained mixture was increased to a room temperature, fol s), 7.60-7.80 (4H, m), 7.85-7.90 (1H, m), 8.24 (1H, d, J–2.4 65 lowed by stirring for 3 hours. Thereafter, a saturated sodium Hz), 8.29 (1H, dd, J=2.4, 8.7 Hz) bicarbonate aqueous Solution was added to the reaction solu ESI (LC-MS positive mode) m/z 488 (M+H). tion, and the mixture was then extracted with dichlo US 7,820,693 B2 155 156 romethane. The extract was dried over anhydrous sodium dazolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino Sulfate, and was then concentrated. The obtained residue was lin-1-one (16 mg; yield: 77%) in the form of a white foaming purified by silica gel column chromatography (ethyl acetate Substance. hexane-1:2 to 2:1). So as to obtain a yellow foaming Sub 'H-NMR (270 MHz, CDC1) & (ppm): 2.95 (3H, s), 3.58 stance. This yellow foaming Substance was dissolved in 5 3.68 (2H, m), 3.70-3.77 (1H, m), 3.81-3.90 (1H, m), 4.01 dichloromethane (5 ml), and piperidine (1 ml) was then added 4.08 (1H, m), 4.59 (2H, s), 6.50 (1H, s), 7.31-7.40 (5H, m), to the solution. The obtained mixture was stirred at a room 7.54-7.69 (4H, m), 7.77-7.83 (2H, m), 8.50 (1H, brs), 8.80 temperature. Four hours later, the reaction Solution was con (1H, dd, J=2.31, 8.90 Hz) centrated, and 1 N hydrochloric acid (2 ml) and methanol (2 ESI (LC-MS positive mode) m/z. 508 (M+H). ml) were then added thereto, followed by stirring at 40°C. Six 10 Example 1-36 hours later, the reaction solution was neutralized with a 1 N Sodium hydroxide aqueous Solution under cooling on ice. A 7-((R)-4-Hydroxymethyl-3-methyl-2-oxoimidazoli saturated Sodium bicarbonate aqueous solution was added to din-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino the resultant, and the mixture was then extracted with dichlo lin-1-one romethane. The extract was dried over anhydrous sodium 15 Sulfate, and was then concentrated. The obtained residue was purified by amino TLC used for preparative separation (Fuji Formula 72 Silysia Chemical Ltd., PLC05; dichloromethane:metha Chiral nol=20:1), so as to obtain 7-((R)-3-benzyloxy-2-methylami nopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one (48 mg; yield: 31%) in the form of a yellow foaming Substance. 'H-NMR (270 MHz, CDC1) & (ppm): 2.43 (3H, s), 2.99 3.04 (1H, m), 3.18-3.27 (1H, m), 3.34-3.42 (1H, m), 3.54 3.66 (2H, m), 4.55 (2H, s), 4.73 (1H, brt), 6.42 (1H, s), 7.01 25 (1H, dd, J=2.31, 8.24 Hz), 7.31-7.39 (6H, m), 7.48 (1H, d, J=2.47 Hz), 7.52-7.67 (3H, m), 7.80 (1H, d, J=6.76 Hz) ESI (LC-MS positive mode) m/z 482 (M+H). Ss Step B HO 30 The 7-((R)-4-benzyloxymethyl-3-methyl-2-oxoimidazo 7-((R)-4-Benzyloxymethyl-3-methyl-2-oxoimidazo lidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1- lidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino one (13 mg 0.025 mmol) prepared in Example 1-35 was lin-1-one dissolved in methanol (5 ml). Thereafter, 10% Pd C (3 mg) was added to the obtained solution, and the obtained mixture 35 was then stirred in a hydrogen atmosphere for 3 hours. The reaction solution was filtered through celite, and the filtrate Formula 71 was then concentrated. The obtained residue was purified by Chiral silica gel TLC used for preparative separation (dichlo romethane:methanol=20:1), so as to obtain 7-((R)-4-hy 40 droxymethyl-3-methyl-2-oxoimidazolidin-1-yl)-3-(2-trif luoromethylphenyl)-2H-isoquinolin-1-one (10.9 mg, quantitative) in the form of a white solid. 'H-NMR (270 MHz, CDC1) & (ppm): 2.97 (3H, s), 3.49 (1H, brs), 3.74-3.81 (2H, m), 3.88-3.93 (2H, m), 4.01-4.08 45 (1H, m), 6.50 (1H, s), 7.52-7.70 (4H, m), 7.80-7.82 (2H, m), 8.44 (1H, brs), 8.76 (1H, dd, J=2.47, 8.90 Hz) ESI (LC-MS positive mode) m/z 418 (M+H). Example 1-37 50 3-(2-Ethylphenyl)-7-((S)-5-hydroxymethyl-2-oxoox aZolidin-3-yl)-2H-isoquinolin-1-one

Bis(trichloromethyl)carbonate (4.5 mg 0.015 mmol) was Formula 73 dissolved in dichloromethane (4 ml). Thereafter, to the thus 55 obtained solution, a solution obtained by dissolving the 7-((R)-3-benzyloxy-2-methylaminopropylamino)-3-(2-trif. luoromethylphenyl)-2H-isoquinolin-1-one (20 mg, 0.04 mmol) prepared in Step A and N,N-diisopropylethylamine (16 ul, 0.09 mmol) in dichloromethane (1 ml) was added 60 dropwise under cooling on ice. After completion of the addi NH tion, the obtained mixture was stirred for 1 hour. Thereafter, y C water was added to the reaction Solution, and the mixture was then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel TLC used for 65 HO preparative separation (dichloromethane:methanol=20:1), so as to obtain 7-((R)-4-benzyloxymethyl-3-methyl-2-oxoimi US 7,820,693 B2 157 158 The captioned compound was synthesized by a method a starting material, the captioned compound was synthesized similar to that of Example 1-19. by a reaction similar to step B of Example 1-13. 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.10 (3H, t, J=7.5 Hz), 2.65 (2H, q, J=7.5 Hz), 3.57-3.75 (2H, m), 3.96 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.80-2.05 (2H, (1H, dd, J-9.0, 6.5 Hz), 4.21 (1H, t, J=9.0Hz), 4.70-4.80 (1H, m), 3.54-3.63 (2H, m), 3.92 (1H, dd, J=7.4, 8.7 Hz), 4.29 (1H, m), 5.25 (1H, t, J=6.0 Hz), 6.48 (1H, s), 7.27-7.45 (4H, m), t, J–8.7 Hz), 4.70 (1H, t, J=5.0 Hz), 4.85 (1H, quintet, J=7.1 7.72(1H, d, J=8.5 Hz), 8.08 (1H, d, J=8.5 Hz), 8.24 (1H, brs), Hz), 6.50 (1H, s), 7.60-7.90 (5H, m), 8.08 (1H, dd, J=2.5, 8.7 11.47 (1H, brs) Hz), 8.23 (1H, d, J–2.5 Hz), 11.62 (1H, brs) ESI (LC-MS positive mode) m/z. 365 (M+H). ESI (LC-MS positive mode) m/z. 419 (M+H). 10 Example 1-38 Example 1-39 7-(S)-5-(2-Hydroxyethyl)-2-oxooxazolidin-3-yl)-3- (2-trifluoromethylphenyl)-2H-isoquinolin-1-one 7-(S)-5-((R)-1,2-Dihydroxyethyl)-2-oxooxazolin-3- 15 yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1- Step A O 7-((S)-2,4-Dihydroxybutylamino)-3-(2-trifluorom ethylphenyl)-2H-isoquinolin-1-one Step A 3-(2-Trifluoromethylphenyl)-7-((2S,3R)-2,3,4-trihy droxybutylamino)-2H-isoquinolin-1-one Formula 74

25

Formula 76

30

Using (S)-3,4-epoxy-1-butanol prepared in accordance with a known method described in publications (for example, Journal of Organic Chemistry, 1992, vol. 57, pp. 4352-4361), 35 the captioned compound was prepared by a reaction similar to step A of Example 1-13. 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.50-1.60 (1H, m), 1.66-1.74 (1H, m), 3.00-3.18 (2H, m), 3.50-3.59 (2H, m), The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquino 3.75-3.85 (1H, m), 4.40 (1H, t, J=5.1 Hz), 4.72 (1H, d, J=5.3 40 Hz), 6.06 (1H, t, J=5.5 Hz), 6.29 (1H, s), 7.11 (1H, dd, J=2.6, lin-1-one (2.04 g. 0.986 mmol) obtained in step C of Example 8.7 Hz), 7.24 (1H, d, J=2.3 Hz), 7.40 (1H, d, J=8.6 Hz), 7.58 1-1 and D-(-)-erythrose (807mg, 6.72 mmol) were dissolved (1H, d, J=7.1 Hz), 7.63-7.77 (2H, m), 7.84 (1H, d, J=8.2 Hz), in methanol (40 ml). Thereafter, acetic acid (2.31 ml, 40.3 11.24 (1H, brs) 45 mmol) and a 1 M sodium cyanoborohydride THF solution ESI (LC-MS positive mode) m/z 393 (M+H). (20.2 ml, 20.2 mmol) were added at 0°C. to the obtained Step B Solution, and the obtained mixture was then stirred at a room 7-(S)-5-(2-Hydroxyethyl)-2-oxooxazolidin-3-yl)-3- temperature for 4 hours. Thereafter, the reaction mixture was (2-trifluoromethylphenyl)-2H-isoquinolin-1-one concentrated under reduced pressure, and water was then 50 added to the concentrate, followed by extraction with meth ylene chloride. The extract was washed with a saturated saline Formula 75 solution, and was then dried over sodium sulfate, followed by concentration under reduced pressure. The obtained residue 55 was purified by silica gel chromatography (methylene chlo ride:methanol=15:1 to 10:1), so as to obtain 3-(2-trifluorom ethylphenyl)-7-((2S,3R)-2,3,4-trihydroxybutylamino)-2H isoquinolin-1-one (1.15g, 42%). 60 'H-NMR (300 MHz, DMSO-d) & (ppm): 3.30-3.08 (1H, m), 3.43-3.45 (3H, m), 3.62 (2H, d, J=5.67 Hz), 4.41 (1H, s), 4.69 (1H, s), 4.79 (1H, s), 5.88 (1H, t, J=5.73 Hz), 6.29 (1H, s), 7.14 (1H, dd, J=2.26, 8.85 Hz), 7.26 (1H, d, J=2.25 Hz), 65 7.40 (1H, d, J=8.34 Hz), 7.58 (1H, d, J=7.71 Hz), 7.63-7.76 Using the 7-((S)-2,4-dihydroxybutylamino)-3-(2-trifluo (2H, m), 7.84 (1H, d. J=8.11 Hz), 11.20 (1H, s) romethylphenyl)-2H-isoquinolin-1-one obtained in step A as ESI (positive mode) m/z 409 (M+H). US 7,820,693 B2 159 160 Step B romethane), so as to obtain 2-2-(2-benzyloxyethoxy)ethoxy benzonitrile (529 mg, 71%) in the form of a colorless oil 7-(S)-5-((R)-1,2-Dihydroxyethyl)-2-oxooxazolin-3- product. yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1- 'H-NMR (400 MHz, CDC1) & (ppm): 3.65-3.67 (2H, m), O 3.79-3.81 (2H, m), 3.93 (2H, t, J=5.0 Hz), 4.24 (2H, t, J=5.0 Hz), 4.57 (2H, s), 6.88 (1H, d, J=7.5 Hz), 6.99 (1H, t, J–7.5 Hz), 7.26-7.35 (5H, m), 7.49 (1H, t, J=7.5 Hz), 7.54 (1H, d, J=7.5 Hz) Formula 77 ESI (LC-MS positive mode) m/z 298 (M+H). 10 Step B 3-2-[2-(2-Benzyloxyethoxy)ethoxyphenyl-7-((R)- 5-hydroxymethyl-2-oxooxazolidin-3-yl)-2H-iso quinolin-1-one 15

Formula. 79 HO

OH Using the 3-(2-trifluoromethylphenyl)-7-((2S,3R)-2,3,4- X- co-oNH OQ-1-0 trihydroxybutylamino)-2H-isoquinolin-1-one obtained in step A as a raw material, the captioned compound was Syn 25 \u O thesized by a method similar to step B of Example 1-13. HO 'H-NMR (300 MHz, DMSO-d) & (ppm): 3.79-3.91 (1H, m), 4.17 (2H, d, J=9.15 Hz), 4.75-4.81 (2H, m), 5.39 (1H, s), Using the 2-2-(2-benzyloxyethoxy)ethoxybenzonitrile 6.48 (1H, s), 7.64 (1H, d, J=7.62 Hz), 7.68-7.80 (3H, m), 7.87 prepared in step A as a raw material, the captioned compound (1H, d, J=7.31 Hz), 8.10 (1H, dd, J=2.40, 8.76 Hz), 8.26 (1H, 30 was synthesized by a method similar to that of Example 1-19. d, J–2.61 Hz), 11.59 (1H, s) 'H-NMR (270 MHz, DMSO-d) 8: 3.40-3.85 (8H, m), ESI (positive mode) m/z 435 (M+H). (1H, m), 4.21-4.30 (3H, m), 4.64-4.83 (1H, m), 6.73 (1H, s), 7.0–7.30 (7H, m), 7.32-7.50 (2H, m), 7.69 (1H, d, J=8.6 Hz), Example 1-40 8.05 (1H, dd, J=2.4, 8.9 Hz), 8.21 (1H, d, J=2.4 Hz) 35 3-2-[2-(2-Benzyloxyethoxy)ethoxyphenyl-7-((R)- ESI (LC-MS positive mode) m/z 531 (M+H). 5-hydroxymethyl-2-oxooxazolidin-3-yl)-2H-iso Example 1-41 quinolin-1-one 3-2-[2-(2-Hydroxyethoxy)ethoxyphenyl-7-((R)-5- Step A 40 hydroxymethyl-2-oxooxazolidin-3-yl)-2H-isoquino lin-1-one 2-2-(2-Benzyloxyethoxy)ethoxybenzonitrile

45 Formula 80

Formula 78

22 50 N-1-1- 2-Hydroxybenzonitrile (300 mg, 2.52 mmol), di(ethylene glycol) benzyl ether (593 mg, 3.02 mmol), and 1,1'-azobis(N, N-dimethylformamide) (867mg, 5.04 mmol) were dissolved Using the 3-2-[2-(2-benzyloxyethoxy)ethoxyphenyl in toluene (15 ml). Thereafter, tri-n-butylphosphine (1.26 ml, 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-2H-iso 5.04 mmol) was added at 20°C. to the obtained solution, and quinolin-1-one obtained in Example 1-40 as a raw material, the obtained mixture was stirred at the same above tempera 60 the captioned compound was synthesized by a method similar ture for 2 hours. The generated precipitate was filtrated, and to that of Example 1-36. the filtrate was then diluted with ethyl acetate (20 ml). The 'H-NMR (270 MHz, DMSO-d) 8: 3.40-3.85 (8H, m), ethyl acetate solution was washed with water twice, and then 3.87-4.0 (1H, m), 4.12-4.35 (3H, m), 4.64-4.83 (1H, m), 6.78 with a saturated saline solution once. The resultant was dried (1H, s), 7.0–7.26 (2H, m), 7.31-7.64 (2H, m), 7.73 (1H, d, over anhydrous sodium sulfate, and was then concentrated 65 J=8.9 Hz), 8.07 (1H, dd, J=2.5, 8.9 Hz), 8.22 (1H, d, J–2.5 under reduced pressure. The obtained pale brown oil product Hz) was purified by silica gel column chromatography (dichlo ESI (LC-MS positive mode) m/z. 441 (M+H).

US 7,820,693 B2 163 164 added to the obtained solution, and the obtained mixture was 'H-NMR (270 MHz, CDC1) & (ppm): 1.31 (3H, t, J=7.1 then stirred at a room temperature for 1 hour. Thereafter, a Hz), 1.53 (9H, s), 2.16-2.46 (2H, m), 3.53 (1H, dd, J=7.4, 9.1 saturated Sodium bicarbonate Solution was added to the reac HZ), 3.66-3.75 (1H, m), 3.84-3.93 (1H, m), 4.24 (2H, dd, tion mixture, and the obtained mixture was then extracted J=7.1, 14.3 Hz) with ethyl acetate. The extract was washed with a saturated 5 ESI (LC-MS positive mode) m/z 258 (M+H). saline Solution, and was then dried over magnesium Sulfate, Step B followed by concentration under reduced pressure. The obtained residue was purified by silica gel chromatography Ethyl 2-oxo-1-1-oxo-3-(2-trifluoromethylphenyl)-1, (methylene chloride:methanol=15:1), so as to obtain 7-5-(2- 2-dihydroisoquinolin-7-ylpyrrolidine-3-carboxylate hydroxy-1-hydroxymethylethyl)-2-oxooxazolidin-3-yl)-3- 10 (2-trifluoromethylphenyl)-2H-isoquinolin-1-one (20 mg. 73%). 'H-NMR (300 MHz, CDOD) 8 (ppm): 2.15 (1H, m), Formula 86) 3.78-3.93 (4H, m), 4.24-4.38 (2H, m), 4.94 (1H, q, J–8.1 Hz),

6.63 (1H, m), 7.63-7.81 (4H, m), 7.89 (1H, d, J=7.6 Hz), 15 8.27-8.31 (2H, m). N Example 1-45 O N Ethyl 2-oxo-1-1-oxo-3-(2-trifluoromethylphenyl)-1, N F 2-dihydroisoquinolin-7-ylpyrrolidine-3-carboxylate F ) ) O Step A /-o 1-tert-Butyl 2-oxopyrrolidine-1,3-dicarboxylate 3-ethyl ester 25 The 2-oxopyrrolidin-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (100 mg, 0.389 mmol) prepared in step A was suspended in dichloromethane (5 ml), and trifluoroacetic acid (0.5 mg, 6.490 mmol) was then added dropwise to the Formula 85 Suspension under cooling on ice. The temperature of the 30 mixture was increased to a room temperature, and the mixture was then stirred for 1 hour. Thereafter, the reaction solution was concentrated, so as to obtain a crude product of 2-oxopy -----k rrolidin-3-carboxylic acid ethyl. Using this crude product and the 7-iodo-3-(2-trifluorom 35 ethylphenyl)-2H-isoquinolin-1-one (161 mg, 0.389 mmol) A mixture of 2-pyrrolidone (1.0 ml, 10.5 mmol), di-tert obtained in step D of Example 1-1 as raw materials, 2-oxo butyl dicarbonate (4.6 g. 21.0 mmol), and 4-(dimethylamino) 1-1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquino pyridine (5.1 g, 42.0 mmol) was dissolved in acetonitrile (50 lin-7-ylpyrrolidin-3-carboxylic acid ethyl was synthesized ml), and the obtained solution was stirred at a room tempera by a reaction similar to step E of Example 1-1. ture for 2 hours. The reaction solution was poured into a 40 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.24 (3H, t, saturated ammonium chloride aqueous solution, and the J=7.1 Hz), 2.32-2.47 (2H, m), 3.81 (1H, t, J=8.7 Hz), 3.96– obtained solution was then extracted with ethyl acetate. The 4.04 (2H, m), 4.18 (2H, ddd, J=14.1, 7.1, 1.3 Hz), 6.50 (1H, s), extract was washed with a saturated ammonium chloride 7.63-7.81 (4H, m), 7.88 (1H, d, J=8.7 Hz), 8.10 (1H, dd, aqueous solution and with a saturated Saline solution. The J=8.7, 2.3 Hz), 8.37 (1H, d, J=2.3 Hz) 11.64 (1H, brs) resultant was dried over anhydrous sodium sulfate, and was 45 ESI (LC-MS positive mode) m/z. 445 (M+H). then concentrated, so as to obtain a crude product of 2-ox opyrrolidin-1-carboxylic acid tert-butyl (1.7 g, 75%) in the Example 1-46 form of a reddish brown substance. ATHF solution (10 ml) that contained the crude product of 7-(3-Hydroxymethyl-2-oxopyrrolidin-1-yl)-3-(2- 2-oxopyrrolidin-1-carboxylic acid tert-butyl (500 mg, 2.70 50 trifluoromethylphenyl)-2H-isoquinolin-1-one mmol) was added dropwise at -78° C. to a 1 M lithium hexamethyldisilazane THF solution (5.4 ml, 5.4 mmol), and the obtained mixture was stirred for 50 minutes. A solution obtained by dissolving ethyl chloroformate (0.27 ml, 2.84 Formula 87 mmol) in THF (5 ml) was further added dropwise to the 55 reaction solution at -78°C. The temperature of the mixture was increased to a room temperature, and the mixture was then stirred for 4 hours. Thereafter, the reaction solution was N poured into a saturated ammonium chloride aqueous solu O tion, followed by extraction with ethyl acetate. The extract 60 N was washed with a saturated Saline solution, and was then N dried over anhydrous sodium sulfate, followed by concentra HO O tion. The obtained residue was purified by silica gel chroma tography (hexane:ethyl acetate 5:1 to 2:1). So as to obtain 2-oxopyrrolidin-1,3-dicarboxylic acid 1-tert-butyl ester 65 The 2-oxo-1-1-oxo-3-(2-trifluoromethylphenyl)-1,2-di 3-ethyl ester (46.8 mg, 67%) in the form of a liver brown oil hydroisoquinolin-7-ylpyrrolidin-3-carboxylic acid ethyl (11 Substance. mg, 0.025 mmol) prepared in step B of Example 1-45, sodium US 7,820,693 B2 165 166 borohydride (9.5 mg, 0.25 mmol), and calcium chloride (27.7 The captioned compound was synthesized by a method mg, 0.25 mmol) were dissolved in methanol (5 ml), and the similar to that of Example 1-19. obtained solution was then stirred at a room temperature for 'H-NMR (270 MHz, CDOD) 8: 1.71 (2H, d, J-49 Hz), 16 hours. Thereafter, the reaction solution was concentrated, 3.59-3.86 (2H, m), 3.91-4.03 (1H, m), 4.11-4.25 (1H, m), and it was then purified using ODS cartridge 5 g (Mega Bond 5 4.63-4.82 (1H, m), 6.1-6.35 (3H, m), 6.50 (1H, s), 7.16-7.39 Elut (registered trademark) C18, manufactured by Varian; (3H, m), 7.49-7.68 (2H, m), 8.11-8.26 (2H, m), 8.44 (1H, brs) water methanol=1:0 to 0:1). The resultant was then prepara ESI (LC-MS positive mode) m/z. 377 (M+H). tively separated by preparative HPLC (column: Combi ODS (cp. 28.0 mmx50 mm) manufactured by Wako; developing Example 1-49 solvent: 0.05% trifluoroacetic acid-containing water: 0.05% 10 7-(2-Oxo-1.3oxazinan-3-yl)-3-(2-trifluorometh trifluoroacetic acid-containing acetonitrile=90:10 to 5:95), so as to obtain 7-(3-hydroxymethyl-2-oxopyrrolidin-1-yl)-3-(2- ylphenyl)-2H-isoquinolin-1-one trifluoromethylphenyl)-2H-isoquinolin-1-one (5 mg, 50%) in the form of a white amorphous Substance. Step A 'H-NMR (270 MHz, DMSO-d) & (ppm): 2.08-2.26 (2H, 15 7-3-(tert-Butyldimethylsilyloxy)propylamino-3-(2- m), 2.71-2.79 (1H, m), 3.65 (1H, dd, J–3.6, 10.6 Hz), 3.76 trifluoromethylphenyl)-2H-isoquinolin-1-one (1H, dd, J=5.2, 10.6 Hz), 3.87-3.92 (2H, m), 4.85 (1H, brs), 6.48 (1H, s), 7.63-7.81 (4H, m), 7.87 (1H, d, J=6.7 Hz), 8.17 (1H, dd, J=2.5, 8.7 Hz), 8.36 (1H, d, J=2.5 Hz), 11.56 (1H, brs) Formula 90 ESI (LC-MS positive mode) m/z 403 (M+H). Example 1-47 7-((R)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- (2-isobutylphenyl)-2H-isoquinolin-1-one 25

Formula 88)

30 The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one (300 mg. 0.986 mmol) obtained in step C of N Example 1-1 was dissolved in methanol (10 ml). Thereafter, 3-(tert-butyldimethylsilyl)oxyl-1-propanol (186 mg, 0.986 NH mmol), acetic acid (0.339 ml), and a 1 M sodium cyanoboro y C hydride THF solution (2.96 ml, 2.96 mmol) were added at 0° 35 C. to the obtained solution, and the obtained mixture was O stirred at a room temperature for 1 hour. Thereafter, a satu s rated sodium bicarbonate solution was added to the reaction HO mixture, and the obtained mixture was then extracted with methylene chloride. The extract was dried over magnesium The captioned compound was synthesized by a method 40 Sulfate, and was then concentrated under reduced pressure. similar to that of Example 1-19. The obtained residue was purified by silica gel chromatogra 'H-NMR (270 MHz, CDOD) 8: 0.68 (6H, d, J=6.6 Hz), phy (ethyl acetate:hexane=1:3), so as to obtain 7-3-(tert 1.68 (1H, sext, J–6.6 Hz), 2.50 (2H, d. J=6.6 Hz), 3.40-3.85 butyldimethylsilyloxy)propylamino-3-(2-trifluorometh (8H, m), 3.59-3.87 (1H, m), 3.92-4.05 (1H, m), 4.10-4.26 ylphenyl)-2H-isoquinolin-1-one (376 mg, 80%). (1H, m), 4.63-4.82 (1H, m), 6.50 (1H, s), 7.10-7.39 (4H, m), 45 'H-NMR (300 MHz, CDC1) & (ppm): 0.09 (6H, s), 0.94 7.63 (1H, d, J=8.6 Hz), 8.09-8.22 (1H, m) (9H, s), 1.85-1.95 (2H, m), 3.37 (2H, t, J=6.5 Hz), 3.81 (2H, ESI (LC-MS positive mode) m/z 393 (M+H). t, J=5.3 Hz), 6.43 (1H, s), 6.98 (1H, dd, J=2.3, 8.4 Hz), 7.38 Example 1-48 (1H, d, J=8.8 Hz), 7.45 (1H, d, J=2.7 Hz), 7.51-7.66 (3H, m), 7.79 (1H, d, J=7.5 Hz), 8.79 (1H, brs) 3-(2-Allylphenyl)-7-((R)-5-hydroxymethyl-2-oxoox 50 ESI (positive mode) m/z. 477 (M+H). aZolidin-3-yl)-2H-isoquinolin-1-one Step B 7-(3-Hydroxypropylamino)-3-(2-trifluoromethylphe nyl)-2H-isoquinolin-1-one

55 Formula 89 Formula 91

60

65 US 7,820,693 B2 167 168 The 7-3-(tert-butyldimethylsilyloxy)propylamino-3-(2- hydroxide (2 mg) was dissolved in methanol. The obtained trifluoromethylphenyl)-2H-isoquinolin-1-one (435 mg. mixture was stirred in a hydrogen atmosphere for 1 hour. 0.913 mmol) obtained in step A was dissolved in THF (9 ml). Thereafter, the reaction solution was filtered through celite, Thereafter, a 1 Mtetrabutylammonium fluoride THF solution and the concentrated residue was then preparatively separated (1.1 ml, 1.1 mmol) was added to the obtained solution at a by preparative HPLC (column: Combi ODS (cp. 28.0 mmx50 room temperature. The obtained mixture was stirred for 5 mm), manufactured by Wako; developing solvent: 0.05% hours. Thereafter, methylene chloride was added to the reac trifluoroacetic acid-containing water: 0.05% trifluoroacetic tion Solution. An organic layer thereof was washed with a acid-containing acetonitrile=90:10 to 5:95), so as to obtain saturated Saline solution, and was then dried over magnesium 7-(4-hydroxy-2-oxo-2,5-dihydropyrrol-1-yl)-3-(2-trifluo sulfate, followed by concentration under reduced pressure. 10 romethylphenyl)-2H-isoquinolin-1-one (1 mg, 15%) in the The obtained residue was purified by silica gel chromatogra form of a colorless oil substance. phy (methylene chloride:methanol-30:1), so as to obtain 'H-NMR (270 MHz, DMSO-d) & (ppm): 4.48 (2H, s), 7-(3-hydroxypropylamino)-3-(2-trifluoromethylphenyl)- 5.02 (1H, s), 6.41 (1H, s), 7.61-7.75 (4H, m), 7.84 (1H, d, 2H-isoquinolin-1-one (337 mg, 95%). J=7.6 Hz), 8.15 (1H, d, J=8.7 Hz), 8.35 (1H, s), 11.49 (1H, 'H-NMR (300 MHz, CDC1) & (ppm): 1.90-199 (2H, m), 15 brs), 11.99 (1H, brs) (2H, t, J=6.9 Hz), 3.84 (2H, t, J=5.7 Hz), 6.43 (1H, s), (1H, dd, ESI (LC-MS positive mode) m/z 387 (M+H). J=2.3, 8.0 Hz), 7.38 (1H, d, J=8.8 Hz), 7.51-7.66 (4H, m), 7.78 (1H, d, J=7.6 Hz), 8.65 (1H, brs) Example 1-51 ESI (positive mode) m/z. 363 (M+H). Step C 1-1-Oxo-3-(2-trifluoromethylphenyl)-1,2-dihy droisoquinolin-7-ylpyrrolidine-2,5-dione 7-(2-Oxo-1.3oxazinan-3-yl)-3-(2-trifluorometh ylphenyl)-2H-isoquinolin-1-one

25 Formula 94) Formula 92 N O 30 N N F F O O

35 Using the 7-iodo-3-(2-trifluoromethylphenyl)-2H-iso quinolin-1-one (30 mg, 0.072 mmol) obtained in step D of Using the 7-(3-hydroxypropylamino)-3-(2-trifluorometh Example 1-1 as a raw material, the captioned compound was ylphenyl)-2H-isoquinolin-1-one obtained in step B as a raw synthesized by a reaction similar to step E of Example 1-1. material, the captioned compound was synthesized by a 'H-NMR (270 MHz, CDC1) & (ppm): 2.97 (4H, s), 6.65 method similar to step B of Example 1-13. 40 (1H, s), 7.26-7.84 (7H, m), 8.37 (1H, brs) 'H-NMR (300 MHz, CDC1) & (ppm): 2.22-2.31 (2H, m), ESI (LC-MS positive mode) m/z 387 (M+H). (2H, t, J=6.1 Hz), 4.47 (2H, t, J=5.3 Hz), 6.52(1H, s), (4H, m), 7.80-7.84 (2H, m), 8.22 (1H, brs), 9.09 (1H, brs) Example 2-1 ESI (positive mode) m/z 389 (M+H). 45 Ethyl 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1, Example 1-50 2-dihydroisoquinolin-7-ylloxazolidine-5-carboxylate 7-(4-Hydroxy-2-oxo-2,5-dihydropyrrol-1-yl)-3-(2- trifluoromethylphenyl)-2H-isoquinolin-1-one Step A 50 Ethyl 2-hydroxy-3-1-oxo-3-(2-trifluoromethylphe nyl)-1,2-dihydroisoquinolin-7-ylaminopropanoate

Formula 93

55 Formula 95

60 O O N HO ~~~ N OH A mixture of the 7-(4-benzyloxy-2-oxo-2,5-dihydropyr 65 rol-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one The 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquino (8 mg, 0.017 mmol) prepared in Example 1-8 and palladium lin-1-one (820 mg, 2.69 mmol) obtained in step C of Example US 7,820,693 B2 169 170 1-1 was dissolved in ethanol (5.4 ml). Thereafter, methyl Example 2-2 glycidate (313 mg, 2.69 mmol) was added to the obtained Solution, and the obtained mixture was stirred under heating Methyl 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)- to reflux for 4 days. Thereafter, the reaction solution was 1,2-dihydroisoquinolin-7-yloxazolidine-5-carboxy concentrated, and the concentrate was then subjected to silica late gel column chromatography (ethyl acetate:hexane-1:2 to 3:1), so as to obtain 2-hydroxy-3-1-oxo-3-(2-trifluorometh

ylphenyl)-1,2-dihydroisoquinolin-7-ylaminoethyl pro Formula 97 panoate (795.5 mg, 70%) in the form of a yellow foaming 10 Substance. 'H-NMR (270 MHz, CDC1,) 8 (ppm): 1.31 (3H, t, J=7.1 HZ), 3.28-3.33 (1H, m), 3.50-3.73 (2H, m), 408-4.31 (2H, m), 4.40-4.50 (2H, m), 6.44 (1H, s), 7.07 (1H, dd, J–2.6, 8.5 Hz), 7.40 (1H, d, J=8.5 Hz), 7.50-7.70 (4H, m), 7.78-7.83 15 (1H, m), 8.51 (1H, brs) ESI (LC-MS positive mode) m/z 421 (M+H). Step B Ethyl 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1, 2-dihydroisoquinolin-7-ylloxazolidine-5-carboxylate Using methylglycidate, the captioned compound was syn thesized by a method similar to that of Example 2-1. 'H-NMR (270 MHz, DMSO-d) & (ppm): 3.90 (3H, s), 25 4.30 (1H, dd, J=5.3,9.6 Hz), 4.44 (1H, t, J=9.6Hz), 5.15 (1H, dd, J=5.3, 9.6 Hz), 6.52 (1H, s), 7.53-7.73 (4H, m), 7.81 (1H, dd, J=1.0, 7.3 Hz), 7.91 (1H, d, J=2.5 Hz), 8.49 (1H, dd, Formula 96 J=2.5, 8.7 Hz), 9.28 (1H, brs) ESI (LC-MS positive mode) m/z. 433 (M+H). 30 Example 2-3 7-5-(1-Hydroxy-1-methylethyl)-2-oxooxazolidin-3- yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1- 35 O

Formula 98 40

The 2-hydroxy-3-1-oxo-3-(2-trifluoromethylphenyl)-1, 2-dihydroisoquinolin-7-ylaminopropanoic acid methyl (203 45 mg, 0.5 mmol) obtained in step A was dissolved in THF (2.5 ml). Thereafter, carbonyldimidazole (81 mg 0.5 mmol) was added to the obtained solution, and the obtained mixture was HO stirred at a room temperature for 5.5 hours. Thereafter, water 50 was added to the reaction solution, followed by extraction ATHF solution that contained methylmagnesium chloride with ethyl acetate. The extract was washed with a saturated (0.6 M, 290 ul) was added to a THF solution (0.5 ml) that saline solution, and was then dried over anhydrous sodium contained the 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)- sulfate. Thereafter, the solvent was distilled away under 55 1,2-dihydroisoquinolin-7-yloxazolidin-5-carboxylic acid reduced pressure. The obtained residue was purified by silica methyl (15.5 mg, 0.0358 mmol) obtained in Example 2-1 gel column chromatography (ethyl acetate:hexane 3:1 to under cooling on ice. The obtained mixture was stirred for 1 hour. Thereafter, a saturated ammonium chloride aqueous 6:1), so as to obtain 2-oxo-3-1-oxo-3-(2-trifluoromethylphe Solution was added to the reaction solution, and the mixture nyl)-1,2-dihydroisoquinolin-7-yloxazolidin-5-carboxylic 60 was then extracted with ethyl acetate. The extract was dried acid methyl mg, 70%) in the form of a colorless oil substance. over anhydrous Sodium sulfate, and was then concentrated under reduced pressure. The obtained residue was purified by 'H-NMR (270 MHz, CDC1) & (ppm): 1.37 (3H, t, J=7.2 silica gel column chromatography (acetone:hexane-1:1), so Hz), 4.26-4.49 (4H, m), 5.12 (1H, dd, J=5.5, 9.6 Hz), 6.53 as to obtain 7-5-(1-hydroxy-1-methylethyl)-2-oxooxazoli (1H, s), 7.54-7.72 (4H, m), 7.81-7.85 (1H, m), 7.94 (1H, d, 65 din-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one J=2.4 Hz), 8.52 (1H, brs), 8.57 (1H, dd, J=2.4, 8.9 Hz) (12.6 mg, 81%) in the form of a colorless amorphous sub ESI (LC-MS positive mode) m/z 447 (M+H). Stance. US 7,820,693 B2 171 172 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.30 (3H, s), The 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2-di 1.42 (3H, s), 2.76 (1H, s), 4.07 (1H, t, J=9.1 Hz), 4.25 (1H, dd, hydroisoquinolin-7-yloxazolidin-5-carboxylic acid (12.5 J=7.3, 9.1 Hz), 4.50 (1H, dd, J–7.3, 9.1 Hz), 6.51 (1H, s), mg, 0.03 mmol) obtained in Example 2-4 and a 25% ammonia aqueous solution (3.06 ul, 0.045 mmol) were dissolved in 7.50-7.70 (4H, m), 7.78-7.83 (1H, m), 7.92(1H, d, J=2.5 Hz), isopropanol (0.3 ml). Thereafter, 4-(4,6-dimethoxy-1,3,5-tri 8.51 (1H, dd, J=2.6, 8.8 Hz), 9.03 (1H, brs) azin-2-yl)-4-methylmorpholinium chloride (13.3 mg, 0.045 ESI (LC-MS positive mode) m/z 447 (M+H). mmol) was added to the solution, and the obtained mixture Example 2-4 was then stirred at a room temperature for 3.5 hours. There after, water was added to the reaction Solution, and the mix 2-Oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- ture was then extracted with ethyl acetate. The extract was 10 dried over anhydrous sodium sulfate, and the solvent was then dihydroisoquinolin-7-yloxazolidine-5-carboxylic distilled away under reduced pressure. The obtained residue acid was purified by silica gel column chromatography (methyl ene chloride:methanol-30:1), so as to obtain 2-oxo-3-1-oxo Formula 99 3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl) 15 oxazolidin-5-carboxylic amide (9.8 mg, 78%) in the form of a colorless amorphous Substance. H-NMR (270 MHz, DMSO-d) & (ppm): 4.12 (1H, dd, J=5.9, 8.9 Hz), 4.43 (1H, t, J=9.3 Hz), 5.09 (1H, dd, J=5.8, 9.6 Hz), 6.50 (1H, s), 7.63-7.92 (7H, m), 8.02(1H, dd, J=2.7, 8.6 Hz), 8.32 (1H, d, J-2.4 Hz), 11.64 (1H, brs) ESI (LC-MS positive mode) m/z 418 (M+H). The following compounds (Examples 2-6 to 2-10) were synthesized by a method similar to that of Example 2-5. HO Example 2-6 O 25 The 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2-di 2-Oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- hydroisoquinolin-7-yloxazolidin-5-carboxylic acid methyl dihydroisoquinolin-7-yloxazolidine-5-carboxylic (24.3 mg, 0.0562 mmol) obtained in Example 2-1 was sus acid methylamide pended in methanol (2 ml). Thereafter, lithium hydroxide 30 Formula 101 monohydrate (11.8 mg, 0.281 mmol) was added to the sus pension, and the obtained mixture was then stirred at a room temperature for 30 minutes. Thereafter, 1 Nhydrochloric acid (300 ul) was added thereto, and the reaction solution was then concentrated under reduced pressure. Ethyl acetate was added to the obtained residue. The mixture was washed with water, and was then dried over anhydrous sodium sulfate, so 35 as to obtain 2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1, 2-dihydroisoquinolin-7-ylloxazolidin-5-carboxylic acid (23.2 mg, 99%) in the form of a colorless amorphous sub Stance. 'H-NMR (270 MHz, DMSO-d) & (ppm): 4.23 (1H, dd, 40 J=5.5, 9.0 Hz), 4.49 (1H, t, J=9.6Hz), 5.23 (1H, dd, J=5.4,9.7 Hz), 6.50 (1H, s), 7.62-7.88 (6H, m), 8.01 (1H, dd, J=2.4, 8.6 Hz), 8.30 (1H, d, J=2.4 Hz), 11.64 (1H, brs) H-NMR (270 MHz, DMSO-d) & (ppm): 2.68 (3H, d, ESI (LC-MS positive mode) m/z. 419 (M+H). J-49 Hz), 4.14 (1H, dd, J=5.9, 8.9 Hz), 4.43 (1H, t, J–9.2 45 Hz), 5.12(1H, dd, J=5.8, 9.6 Hz), 6.50 (1H,s), 7.63-7.89 (5H, Example 2-5 m), 8.00 (1H, dd, J–2.4, 8.6 Hz), 8.33 (1H, d, J=2.4 Hz), 8.41-8.45 (1H, m), 11.64 (1H, brs) 2-Oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- ESI (LC-MS positive mode) m/z. 432 (M+H). dihydroisoquinolin-7-yloxazolidine-5-carboxylic Example 2-7 acid amide 50 2-Oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- dihydroisoquinolin-7-yloxazolidine-5-carboxylic acid dimethylamide Formula 100

Formula 102

55

60

HN 65

US 7,820,693 B2 175 176 Step B Using (R)-methylglycidate, the captioned compound was 7-(S)-5-(1-Hydroxy-1-methylethyl)-2-oxooxazoli synthesized by a method similar to that of Example 2-1. din-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino ESI (LC-MS positive mode) m/z. 433 (M+H). lin-1-one Step B

Formula 107 7-(R)-5-(1-Hydroxy-1-methylethyl)-2-oxooxazoli din-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one 10

Formula 109

15

HO The (S)-2-oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- dihydroisoquinolin-7-yloxazolidin-5-carboxylic acid methyl (400 mg, 0.925 mmol) obtained in step A was dis solved in THF (4.6 ml). A 3M methylmagnesium bromide THF solution (1.08 ml, 3.24 mmol) was added to the solution at -78°C., and the mixture was then stirred at 0°C. for 30 minutes. Thereafter, a Saturated ammonium chloride aqueous 25 Solution was added to the reaction Solution, and the mixture The captioned compound was synthesized by a method was then extracted with ethyl acetate. The extract was washed similar to step B of Example 2-11. with a saturated Saline Solution, and was then dried over 'H-NMR (270 MHz, CDC1,) & (ppm): 1.29 (3H, s), 1.41 anhydrous sodium sulfate. Thereafter, the solvent was dis (3H, s), 3.61 (1H, brs), 4.03 (1H, t, J=9.1 Hz), 4.26 (1H, t, tilled away under reduced pressure. The obtained residue was 30 purified by silica gel column chromatography (ethyl acetate: J=8.9 Hz), 4.49 (1H, t, J=8.4 Hz), 6.48 (1H, s), 7.43 (1H, d, hexane 4:1), so as to obtain 7-(S)-5-(1-hydroxy-1-methyl J=8.9 Hz), 7.54-7.68 (3H, m), 7.76 (1H, d, J=7.7 Hz), 7.83 ethyl)-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)- (1H, d, J=2.0), 8.40 (1H, dd, J=2.0, 8.8 Hz), 9.52 (1H, brs) 2H-isoquinolin-1-one (205.1 mg, 51%) in the form of a ESI (LC-MS positive mode) m/z. 433 (M+H). colorless foaming Substance. 'H-NMR (270 MHz, CDC1) & (ppm): 1.30 (3H, s), 1.43 35 Example 2-13 (3H, s), 4.09 (1H, t, J=9.1 Hz), 4.23 (1H, dd, J=7.4, 8.9 Hz), 4.50 (1H, dd, J=74, 9.0 Hz), 6.52(1H, s), 7.54-7.72 (5H, m), (S)-2-Oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- 7.80-7.85 (1H, m), 7.94 (1H, d, J=2.5 Hz), 8.57 (1H, dd, dihydroisoquinolin-7-yloxazolidine-5-carboxylic J=2.6, 8.8 Hz), 8.59 (1H, brs) acid amide ESI (LC-MS positive mode) m/z. 433 (M+H). 40 Example 2-12 Step A 7-(R)-5-(1-Hydroxy-1-methylethyl)-2-oxooxazoli (S)-2-Oxo-3-1-oxo-3-(2-trifluoromethylphenyl)-1,2- din-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino 45 dihydroisoquinolin-7-yloxazolidine-5-carboxylic lin-1-one acid Step A

Methyl(R)-2-oxo-3-1-oxo-3-(2-trifluoromethylphe Formula 110 nyl)-1,2-dihydroisoquinolin-7-ylloxazolidine-5-car 50 boxylate

Formula 108

55

HO 60

Using the (S)-2-oxo-3-1-oxo-3-(2-trifluoromethylphe nyl)-1,2-dihydroisoquinolin-7yloxazolidin-5-carboxylic 65 acid methyl obtained in step A of Example 2-11 as a raw material, the captioned compound was prepared by a method similar to that of Example 2-4.

US 7,820,693 B2 179 180 Using the (S)-2-oxo-3-1-oxo-3-(2-trifluoromethylphe Sodium hydride (7.5 mg 0.18 mmol) was added to a DMF nyl)-1,2-dihydroisoquinolin-7-yloxazolidin-5-carboxylic solution (0.5 ml) that contained 2-methoxymethanol (14.2 acid obtained in step A of Example 2-13 as a raw material, the captioned compound was synthesized by a method similar to mg, 0.18 mmol) under cooling on ice, and the obtained mix that of Example 2-5. ture was then stirred at 0°C. for 30 minutes. The methane 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.30-1.60 (2H, sulfonic acid (R)-2-oxo-3-1-oxo-3-(2-trifluoromethylphe m), 1.70- 1.90 (2H, m), 3.00-3.40 (2H, m), 3.70-4.00 (3H, m), nyl)-1,2-dihydroisoquinolin-7-yloxazolidin-5-ylmethyl 4.25-4.34 (1H, m), 4.35-4.45 (1H, m), 4.78 (1H, d. J–4.0 Hz), (30.0 mg, 0.06 mmol) obtained in step A of Example 2-22 was 5.62-5.75 (1H, m), 6.50 (1H, s), 7.60-7.83 (4H, m), 7.84-7.91 added to this reaction Solution under cooling on ice, and the (1H, m), 8.00-8.10 (1H, m), 8.27 (1H, dd, J=2.3, 6.1 Hz), 10 11.63 (1H, brs) obtained mixture was then stirred at 0° C. for 30 minutes. ESI (LC-MS positive mode) m/z 502 (M+H). Thereafter, water was added to the reaction solution, and the mixture was then extracted with methylene chloride. The Example 2-16 extract was washed with water and a Saturated Saline solution, 7-(R)-5-(4-Hydroxypiperidine-1-carbonyl)-2- 15 and was then dried over anhydrous magnesium sulfate. oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)- Thereafter, the solvent distilled away under reduced pressure. 2H-isoquinolin-1-one The obtained residue was purified by silica gel column chro matography (methylene chloride:methanol 40:1), so as to Formula 115 obtain 7-(R)-5-(2-methoxyethoxymethyl)-2-oxooxazoli din-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (3.1 mg, 11%) in the form of a colorless solid. 'H-NMR (300 MHz, DMSO-d) & (ppm): 3.23 (3H, s) 25 3.45-3.55 (2H, m), 3.60-3.80 (4H, m), 3.90-4.00 (1H, m), 4.20-4.30 (1H, m), 4.80-5.00 (1H, m), 6.48 (1H, s), 7.60-7.90 (5H, m), 8.07 (1H, d, J=8.5 Hz), 8.23 (1H, s), 11.59 (1H, brs) ESI (LC-MS positive mode) m/z 463 (M+H). 30 The following compounds (Examples 2-18 to 2-20) were synthesized by a reaction similar to that of Example 2-17. HO Example 2-18 Using the (R)-2-oxo-3-1-oxo-3-(2-trifluoromethylphe nyl)-1,2-dihydroisoquinolin-7-yloxazolidin-5-carboxylic 35 acid obtained in step A of Example 2-14 as a raw material, the 7-((R)-5-Methoxymethyl-2-oxooxazolidin-3-yl)-3- captioned compound was synthesized by a method similar to (2-trifluoromethylphenyl)-2H-isoquinolin-1-one that of Example 2-5. 'H-NMR (270 MHz, DMSO-d) & (ppm): 1.33-147 (2H, m), 1.75-1.87 (2H, m), 3.73-3.76 (1H, m), 4.11 (4H, dd, J=0.8, 5.3 Hz), 4.14-4.44 (2H, m), 4.83 (1H, d, J–3.8 Hz), 40 5.69 (1H, dd, J=5.3, 8.6 Hz), 6.50 (1H, s), 7.63-7.81 (4H, m), 7.87 (1H, d, J=7.6 Hz), 8.07 (1H, d, 8.7 Hz), 8.27 (1H, d, 4.0 Formula 117

Hz), 11.65 (1H, brs) ESI (LC-MS positive mode) m/z 502 (M+H). 45 Example 2-17 7-(R)-5-(2-Methoxyethoxymethyl)-2-oxooxazoli din-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquino lin-1-one 50

Formula 116

55

60 'H-NMR (300 MHz, CDC1) & (ppm): 3.45 (3H, s), 3.68 3.74 (2H, m), 4.10 (1H, t, J=6.0 Hz), 4.20 (1H, t, J=8.9 Hz), 4.75-4.90 (1H, m), 6.52 (1H, s), 7.5307.70 (4H, m), 7.82(1H, d, J–7.5 Hz), 7.94 (1H, d. J–2.4Hz), 8.60 (1H, brs), 8.62(1H, 65 dd, J=2.4, 8.8 Hz) ESI (LC-MS positive mode) m/z. 419 (M+H).

US 7,820,693 B2 193 194 Chlorosulfonylacetyl chloride (900 mg, 5.08 mmol) was Example 2-39 dissolved in diethyl ether (5 ml). Thereafter, methanol (206 ul, 5.08 mmol) was added to the solution at 0°C., and the 7-((R)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- obtained mixture was then stirred at 0°C. for 3 hours. There (2-propylphenyl)-2H-isoquinolin-1-one after, the temperature of the reaction solution was returned to 5 a room temperature, and the solvent was then distilled away under reduced pressure, so as to obtain methyl chlorosulfonyl acetate (850 mg.97%) in the form of a colorless oil substance. 'H-NMR (Bruker, 300 MHz, CDC1,) 8:3.91 (s.3H), 4.61 Formula 143 (s. 2H). 10 Step B 2-Hydroxyethanesulfonic acid (R)-2-oxo-3-1-oxo 3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin X NH 7-yloxazolidin-5-ylmethylamide 15 / M O S. HO S Formula 142

10 wt % Palladium carbon (10 mg) was added to a metha nol solution (5 ml) that contained the 3-(2-allylphenyl)-7- ((R)-5-hydroxymethyl-2- -oxazolidin-3-yl)-2H-isoquinolin 1-one (25 mg 0.03 mmol) obtained in Example 1-48. The 25 obtained mixture was stirred in a hydrogen atmosphere at a room temperature for 2 hours. Thereafter, the reaction mix O ture was filtrated, and the filtrate was then concentrated under | s reduced pressure, so as to obtain 7-((R)-5-hydroxymethyl-2- to \ -N- S | H oXooxazolidin-3-yl)-3-(2-propylphenyl)-2H-isoquinolin-1- O 30 one (8.1 mg, 58%) in the form of white powders. 'H-NMR (270 MHz, CDOD) 8: 0.83 (3H, t, J–7.6 Hz), The 7-((S)-5-aminomethyl-2-oxooxazolidin-3-yl)-3-(2- 1.55 (2H, sext, J=7.6 Hz), 2.66 (2H, t, J=7.6 Hz), 3.69-3.94 trifluoromethylphenyl)-2H-isoquinolin-1-one (20 mg 0.05 (2H, m), 4.03-4.12 (1H, m), 4.21-4.32 (1H, m), 4.92-4.71 mmol) prepared in step B of Example 2-31 was dissolved in 35 (1H, m), 6.58 (1H, s), 7.26-7.43 (4H, m), 7.71 (1H, d, J=8.6 methylene chloride (0.2 ml). Thereafter, the methyl chloro sulfonyl acetate (10.5 ul, 0.05 mmol) obtained in step A was Hz), 8.20-8.31 (2H, m) added to the solution under cooling on ice, and the obtained ESI (LC-MS positive mode) m/z. 379 (M+H). mixture was stirred at 0°C. for 30 minutes. Thereafter, water The following compounds (Examples 2-40 to 2-43) were was added to the reaction solution, and the mixture was then synthesized by a reaction similar to that of Example 1-19. extracted with methylene chloride. The extract was washed 40 with water and a saline Solution, and was then dried over Example 2-40 anhydrous magnesium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methyl 7-((R)-5-Hydroxymethyl-2-oxooxazolidin-3-yl)-3- ene chloride:methanol=20:1), so as to obtain a colorless solid 45 2-(2-methylallyl)phenyl-2H-isoquinolin-1-one (10 mg). This colorless solid (10 mg, 0.02 mmol) was dissolved in THF (0.2 ml). Thereafter, lithium tetrahydroborate (2 mg, 0.10 mmol) was added to the solution, and the obtained mix Formula 144) ture was stirred at a room temperature for 30 minutes. There 50 after, water was added to the reaction solution, and the mix ture was then extracted with methylene chloride. The extract was washed with water and a saturated Saline Solution, and N was then dried over anhydrous magnesium Sulfate. Thereaf NH ter, the solvent was distilled away. The obtained residue was 55 y C purified by silica gel column chromatography (methylene chloride:methanol=10:1), so as to obtain 2-hydroxyethane O sulfonic acid (R)-2-oxo-3-1-oxo-3-(2-trifluoromethylphe X nyl)-1,2-dihydroisoquinolin-7-yloxazolidin-5- HO S ylmethylamide (2.6 mg, 10%) in the form of a colorless 60 solid. 'H-NMR (300 MHz, DMSO-d) & (ppm): 3.06 (2H, t, H-NMR (270 MHz, CDC1) 8: 1.79 (3H, s), 3.35 (3H, s), J=6.4 Hz), 3.23-3.35 (2H, m), 3.71 (2H, t, J=6.3 Hz), 3.98 3.76-3.87 (1H, m), 4.00-4.09 (1H, m), 4.11-4.26 (2H, m), 4.03 (1H, m), 4.21 (1H, m), 4.72-4.78 (1H, m), 6.46 (1H, s), 4.49 (1H, s), 4.74-4.86 (1H, m), 4.96 (1H, s), 6.49 (1H, s), 7.60-7.87 (5H, m), 8.06 (1H, dd, J=2.0, 8.9 Hz), 8.20 (1H, d, 65 7.24-7.56 (5H, m), 7.90 (1H, d, J=2.5 Hz), 8.46 (1H, dd, J=1.8 Hz) J=8.9, 2.5 Hz), 8.89 (1H, s) ESI (LC-MS positive mode) m/z 512 (M+H). ESI (LC-MS positive mode) m/z 391 (M+H).