USOO9453000B2

(12) United States Patent (10) Patent No.: US 9.453,000 B2 Kimura et al. (45) Date of Patent: *Sep. 27, 2016

(54) POLYCYCLIC COMPOUND (56) References Cited (75) Inventors: Teiji Kimura, Tsukuba (JP); Noritaka U.S. PATENT DOCUMENTS Kitazawa, Tsukuba (JP); Toshihiko 3,470,167 A 9, 1969 Sarkar Kaneko, Tsukuba (JP); Nobuaki Sato, 3,989,816 A 1 1/1976 Rajadhyaksha Tsukuba (JP); Koki Kawano, Tsukuba 4,910,200 A 3, 1990 Curtze et al. (JP): Koichi Ito, Tsukuba (JP); 5,281,626 A 1/1994 Oinuma et al. M s Tak ishi Tsukub JP 5,563,162 A 10, 1996 Oku et al. amoru Takaishi Tsukuba (JP); 5,804,577 A 9, 1998 Hebeisen et al. Takeo Sasaki, Tsukuba (JP); Yu 5,985,856 A 11/1999 Stella et al. Yoshida, Tsukuba (JP); Toshiyuki 6,235,728 B1 5, 2001 Golik et al. Uemura, Tsukuba (JP); Takashi Doko, g R 1939. E. al. Its SE E. Shinmyo, 7,138.414 B2 11/2006 Schoenafingereatch et al. et al. sukuba (JP); Daiju Hasegawa, 7,300,936 B2 11/2007 Parker et al. Tsukuba (JP); Takehiko Miyagawa, 7,314,940 B2 1/2008 Graczyk et al. Hatfield (GB); Hiroaki Hagiwara, 7,618,960 B2 11/2009 Kimura et al. Tsukuba (JP) 7,667,041 B2 2/2010 Kimura et al. 7,687,640 B2 3/2010 Kimura et al. 7,713,993 B2 5/2010 Kimura et al. (73) Assignee: EISAI R&D MANAGEMENT CO., 7,737,141 B2 6/2010 Kimura et al. LTD., Tokyo (JP) 7,880,009 B2 2/2011 Kimura et al. 7,897,632 B2 3/2011 Kimura et al. (*) Notice: Subject to any disclaimer, the term of this 7,935,815 B2 5/2011 Kimura et al. patent is extended or adjusted under 35 SS R: 38H SA U.S.C. 154(b) by 1597 days. 8,048,878www. B2 11/2011 KimuraUa et aal. This patent is Subject to a terminal dis- 2001/0051642 A1 12/2001 Ahn et al. claimer. 2002/O128263 A1 9, 2002 Mutel et al. (Continued) (21) Appl. No.: 12/671,873 FOREIGN PATENT DOCUMENTS (22) PCT Filed: Aug. 28, 2008 CN 1668593. A 9, 2005 (86). PCT No.: PCT/UP2008/065.365 DE 3541716 A1 5, 1987 S 371 (c)(1), (Continued)Continued (2), (4) Date: Sep. 23, 2010 OTHER PUBLICATIONS (87) PCT Pub. No.: WO2009/028588 Communication pursuant to Article 94(3) EPC issued Jul. 30, 2013 in European Patent Application No. 05743758.4. PCT Pub. Date: Mar. 5, 2009 (Continued) (65) Prior Publication Data US 2011 FOOO9619 A1 Jan. 13, 2011 Primary Examiner — Susanna Moore (74) Attorney, Agent, or Firm — Birch, Stewart, Kolasch & (30) Foreign Application Priority Data Birch, LLP Aug. 31, 2007 (JP) ...... 2007-225045 (57) ABSTRACT E30 SEM. O.C. Disclosed is a compound represented by the formula (1) (51) Int. Cl. (I) CO7D 47L/04 (2006.01) A6 IK 3/437 (2006.01) G) ()-X-G) CO7D 487/04 (2006.01) CO7D 49.8/04 (2006.01) CO7D 403/0 (2006.01) or a pharmacologically acceptable salt thereof, which is A61 P 25/28 (2006.01) effective as a therapeutic or prophylactic agent for a disease CO7D 403/04 (2006.01) induced by AB, wherein Ari represents an imidazolyl group (52) U.S. Cl. which may be substituted with a C1-6 alkyl group, or the CPC ...... C07D 403/10 (2013.01); C07D 471/04 like; Ara represents a phenyl group which may be substituted (2013.01); C07D 487/04 (2013.01); C07D with a C1-6 alkoxy group, or the like: X represents a double 498/04 (2013.01) bond, or the like; and Het represents a triazolyl group or the (58) Field of Classification Search like which may be substituted with a C1-6 alkyl group or the CPC ...... A61K 31/437; C07D 471/04 like, or the like. USPC ...... 544/112: 514/299 See application file for complete search history. 4 Claims, No Drawings US 9,453,000 B2 Page 2

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Invitation to Respond to Written Opinion issued May 23, 2013, in Office Action issued Aug. 11, 2011, in Chilean Patent Application Singapore Patent Application No. 201105886-4. No. 2542-2008. US 9,453,000 B2 1. 2 POLYCYCLIC COMPOUND Non-Patent Document 2 Nitsch RM, and sixteen others, Antibodies against B-amyloid slow cognitive decline in TECHNICAL FIELD Alzheimer's disease, Neuron, 2003, May 22:38, p. 547 554. The present invention relates to a pharmaceutical, more 5 Non-Patent Document 3 Jarrett J. T. and two others. The particularly, to a multi-cyclic cinnamide derivative effective carboxy terminus of the Bamyloid protein is critical for for treatment of a neurodegenerative disease caused by the seeding of amyloid formation: Implications for the amyloid-fi (hereinafter referred to as AB) such as Alzheim pathogenesis of Alzheimers disease, Biochemistry, 1993, er's disease or Down's syndrome and a medicine, in par 32(18), p. 4693-4697. ticular, a medicine for prevention or treatment of a disease 10 Non-Patent Document 4 Glenner G G, and one other, caused by AB comprising the derivative as an active ingre Alzheimer's disease: initial report of the purification and dient. characterization of a novel cerebrovascular amyloid pro tein, Biochemical and Biophysical Research Communi BACKGROUND ART 15 cations, 1984, May 16, 120(3), p. 885-890. Non-Patent Document 5 Masters C L, and five others, Alzheimer's disease is a disease characterized by degen Amyloid plaque core protein in Alzheimer disease and eration and loss of neurons as well as formation of senile Down syndrome, Proceeding of the National Academy of plaques and neurofibrillary degeneration. Currently, Science USA, 1985, June, 82(12), p. 4245-4249. Alzheimer's disease is treated only with symptomatic treat Non-Patent Document 6 Gouras G. K., and eleven others, ment using a symptom improving agent typified by an Intraneuronal A?42 accumulation in human brain, Ameri acetylcholinesterase inhibitor, and a fundamental remedy to can Journal of Pathology, 2000, January, 156(1), p. 15-20. inhibit progression of the disease has not yet been devel Non-Patent Document 7 Scheuner D, and twenty others, oped. It is necessary to develop a method for controlling the Secreted amyloid 3-protein similar to that in the senile cause of the onset of pathology in order to create a funda 25 plaques of Alzheimer's disease is increased in vivo by the mental remedy for Alzheimer's disease. presenilin 1 and 2 and APP mutations linked to familial It is assumed that AB-proteins as metabolites of amyloid Alzheimer's disease, Nature Medicine, 1996, August, precursor proteins (hereinafter referred to as APP) are highly 2(8), p. 864-870. involved in degeneration and loss of neurons and onset of Non-Patent Document 8 Forman M. S., and four others, symptoms of dementia (see Non-Patent Documents 1 and 2. 30 Differential effects of the Swedish mutant amyloid pre for example). Main molecular species of AB-protein are cursor protein on B-amyloid accumulation and secretion Af340 consisting of 40 amino acids and AB42 with two in neurons and normeuronal cells. The Journal of Bio amino acids added at the C-terminal. The AB40 and AB42 logical Chemistry, 1997, Dec. 19, 272(51), p. 32247 are known to have high aggregability (see Non-Patent 32253. 35 Non-Patent Document 9. Shearman MS, and nine others, Document 3, for example) and to be main components of L-685, 458, an Aspartyl Protease Transition State Mimic, senile plaques (see Non-Patent Documents 3, 4 and 5, for Is a Potent Inhibitor of Amyloid f-Protein Precursor example). Further, it is known that the AB40 and AB42 are Y-Secretase Activity, Biochemistry, 2000, Aug. 1,39(30), increased by mutation in APP and presenilin genes which is p. 8698-8704. observed in familial Alzheimer's disease (see Non-Patent 40 Non-Patent Document 10 Shearman MS, and six others, Documents 6, 7 and 8, for example). Accordingly, a com Catalytic Site-Directed Y-Secretase Complex Inhibitors pound that reduces production of AB40 and AB42 is Do Not Discriminate Pharmacologically between Notch expected as a progression inhibitor or prophylactic agent for S3 and B-APP Clevages, Biochemistry, 2003, Jun., 24, Alzheimer's disease. 42(24), p. 7580-7586. A? is produced by cleaving APP by B-secretase and 45 Non-Patent Document 11 Lanz, T A, and three others, Subsequently by Y-secretase. For this reason, attempts have Studies of AB pharmacodynamics in the brain, cerebro been made to create Y-secretase and B-secretase inhibitors in spinal fluid, and plasma in young (plaque-free) Tg2576 order to reduce AB production. Many of these secretase mice using the Y-secretase inhibitor N2-(2S)-2-(3,5-dif inhibitors already known are, for example, peptides and luorophenyl)-2-hydroxyethanoyl)-N1-(7S)-5-methyl-6- peptide mimetics such as L-685,458 (see Non-Patent Docu 50 oxo-6,7-dihydro-5H-dibenzob.dlazepin-7-yl)-L-alanina ment 9, for example), LY-411.575 (see Non-Patent Docu mide (LY-411575). The Journal of Pharmacology and ments 10, 11 and 12, for example) and LY-450,139 (see Experimental Therapeutics, 2004, April, 309(1), p. 49-55. Non-Patent Documents 13, 14 and 15). Nonpeptidic com Non-Patent Document 12 Wong GT, and twelve others, pounds are, for example, MRK-560 (see Non-Patent Docu Chronic treatment with the Y-secretase inhibitor LY-411, ments 16 and 17) and compounds having a plurality of 55 575 inhibits B-amyloid peptide production and alters aromatic rings as disclosed in Patent Document 1. However, lymphopoiesis and intestinal cell differentiation, The the compound represented by the formula (VI) as disclosed Journal of Biological Chemistry, 2004, Mar. 26, 279(13), in page 17 of the specification differs from the compound of p. 12876-12882. the present invention in that the compound is limited to a Non-Patent Document 13 Gitter B D, and ten others, compound having a 2-aminothiazolyl group as a main 60 Stereoselective inhibition of amyloid beta peptide secre Structure. tion by LY450139, a novel functional gamma secretase Non-Patent Document 1 Klein W. L., and seven others, inhibitor, Neurology of Aging 2004, 25, sup2, p. 571. Alzheimer's disease-affected brain: Presence of oligo Non-Patent Document 14 Lanz, TA, and eighteen others, meric A? ligands (ADDLS) suggests a molecular basis for Concentration-dependent modulation of amyloid-f in reversible memory loss, Proceeding of the National Acad 65 Vivo and in vitro using the Y-secretase inhibitor, emy of Science USA, 2003, Sep. 2: 100(18), p. 10417 LY-450139. The Journal of Pharmacology and Experim 10422. antal Therapeutics, 2006, November, 319(2) p. 924-933. US 9,453,000 B2 3 4 Non-Patent Document 15 Siemers ER, and thirteen others, heterocyclic group condensed with a 6- to 14-membered Effects of a Y-secretase inhibitor in a randamized study of non-aromatic hydrocarbon ring group or (3) a 5-membered patients with Alzheimer disease, Neurology, 2006, 66, p. aromatic heterocyclic group condensed with a 5- to 6O2-6O4. 14-membered non-aromatic heterocyclic group, which may Non-Patent Document 16 Best J D, and nine others. In vivo be substituted with 1 to 3 substituents selected from the characterization of AB (40) changes in brain and cerebro following Substituent Group A1Substituent Group A1: (1) spinal fluid using the novel Y-secretase inhibitor N-cis a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, 4-(4-chlorophenyl)sulfonyl)-4-(2,5-difluorophenyl)cy (4) a cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl clohexyl)-1,1,1-trifluoromethanesulphonlamide (MK group which may be substituted with 1 to 3 substituents 560) in the rat, The Journal of Pharmacology and 10 selected from Substituent Group A2, (7) a C2-6 alkenyl Experimantal Therapeutics, 2006, May 317(2) p. 786 group which may be substituted with 1 to 3 substituents 790. selected from Substituent Group A2. (8) a C2-6 alkynyl Non-Patent Document 17 Best JD, and thirteen others The group which may be substituted with 1 to 3 substituents novel Y-secretase inhibitor N-cis-4-(4-chlorophenyl)sul selected from Substituent Group A2, (9) a C3-8 cycloalkoxy fonyl)-4-(2,5-difluorophenyl)cyclohexyl)-1,1,1-trifluo 15 group, (10) a C3-8 cycloalkylthio group, (11) a formyl romethanesulphonlamide (MK-560) reduces amylid group, (12) a C1-6 alkylcarbonyl group which may be plaque deposition without evidence notch-related pathol substituted with 1 to 3 substituents selected from Substituent ogy in the Tg2576 mouse. The Journal of Pharmacology Group A2, (13) a C1-6 alkylthio group which may be and Experimantal Therapeutics, 2007, February, 320(2) p. substituted with 1 to 3 substituents selected from Substituent 552-558. Group A2, (14) a C1-6 alkylsulfinyl group which may be substituted with 1 to 3 substituents selected from Substituent Patent Document 1 WO 2004/110350 Group A2, (15) a C1-6 alkylsulfonyl group which may be DISCLOSURE THE INVENTION substituted with 1 to 3 substituents selected from Substituent Group A2, (16) a hydroxyimino group, (17) a C1-6 alkoxy 25 imino group, (18) a C1-6 alkyl group which may be substi Problem to be Solved by the Invention tuted with 1 to 3 substituents selected from Substituent As described above, a compound that inhibits production Group A2, (19) a C1-6 alkoxy group which may be substi of AB40 and AB42 from APP has been expected as a tuted with 1 to 3 substituents selected from Substituent therapeutic or prophylactic agent for a disease caused by AB Group A2. (20) an amino group which may be substituted which is typified by Alzheimer's disease. However, a non 30 with 1 or 2 substituents selected from Substituent Group A2. peptidic compound having high efficacy which inhibits (21) a carbamoyl group which may be substituted with 1 or production of AB40 and AB42 has not yet been known. 2 substituents selected from Substituent Group A2, (22) a 6 Accordingly, there is a need for a novel low-molecular to 14-membered aromatic hydrocarbon ring group which weight compound that inhibits production of AB40 and may be substituted with 1 to 3 substituents selected from 35 Substituent Group A2. (23) a 5- to 14-membered aromatic Af342. heterocyclic group which may be substituted with 1 to 3 Means for Solving the Problem substituents selected from Substituent Group A2, (24) a 6- to 14-membered non-aromatic hydrocarbon ring group which As a result of extensive studies, the present inventors have may be substituted with 1 to 3 substituents selected from found a nonpeptidic multi-cyclic compound that inhibits 40 Substituent Group A2, (25) a 5- to 14-membered non production of AB40 and AB42 from APP and thus found a aromatic heterocyclic group which may be substituted with prophylactic or therapeutic agent for a disease caused by AB 1 to 3 substituents selected from Substituent Group A2, (26) which is typified by Alzheimer's disease. This finding has a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy group, led to the accomplishment of the present invention. (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 Specifically, the present invention relates to the following 45 cycloalkylsulfonyl group, (30)—X-A (wherein X represents 1) to 19): an imino group, —O— or —S— and A represents a 6- to 1) A compound represented by the formula (I): 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Substituent Formula 1 50 Group A2), (31) —CO-A (wherein A is as defined above), (32) —CH-A (wherein A is as defined above), (33) a (I) carboxyl group, (34) a C1-6 alkoxycarbonyl group and (35) an azido group; Substituent Group A2: (1) a hydrogen atom, (DG)-X-G) (2) a halogenatom, (3) a hydroxyl group, (4) a cyano group, 55 (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 or a pharmacologically acceptable salt thereof, alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 wherein Ari represents an imidazolyl group which may be cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a substituted with a C1-6 alkyl group, formyl group, (12) a C1-6 alkylcarbonyl group, (13) a C1-6 Ara represents a phenyl group or a pyridinyl group, which alkylthio group, (14) a C1-6 alkylsulfinyl group, (15) a C1-6 may be substituted with 1 to 3 substituents selected from the 60 alkylsulfonyl group, (16) a hydroxyimino group, (17) a C1-6 group consisting of (1) a hydrogenatom, (2) a halogen atom, alkoxyimino group, (18) a C1-6 alkyl group (wherein the (3) a hydroxyl group and (4) a C1-6 alkoxy group, C1-6 alkyl group may be substituted with 1 to 3 substituents X represents –CR'—CR - (wherein R' and R are the selected from the group consisting of a halogen atom, a same or different and each represent (1) a hydrogenatom, (2) hydroxyl group, a C1-6 alkoxy group, a phenyl group which a C1-6 alkyl group or (3) a halogen atom) and Het is 65 may be substituted with 1 to 3 halogen atoms and a pyridinyl monovalent or divalent and represents (1) a 5-membered group which may be substituted with 1 to 3 halogen atoms), aromatic heterocyclic group, (2) a 5-membered aromatic (19) a C1-6 alkoxy group (wherein the C1-6 alkoxy group US 9,453,000 B2 5 6 may be substituted with 1 to 3 substituents selected from the 7) The compound or pharmacologically acceptable salt group consisting of a halogen atom, a hydroxyl group, a thereof according to 1) above, wherein Het represents a C1-6 alkoxy group, a phenyl group which may be substi triazolyl group which may be substituted with 1 or 2 tuted with 1 to 3 halogen atoms and a pyridinyl group which substituents selected from Substituent Group A1; may be substituted with 1 to 3 halogenatoms), (20) an amino 8) The compound or pharmacologically acceptable salt group which may be substituted with 1 or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups, (21) a carbamoyl thereof according to 1) above, wherein Het represents a group which may be substituted with 1 or 2 C1-6 alkyl group which may be substituted with 1 to 3 substituents groups, (22) a 6- to 14-membered aromatic hydrocarbon selected from Substituent Group A1 and is represented by ring group, (23) a 5- to 14-membered aromatic heterocyclic the following formula: group, (24) a 6- to 14-membered non-aromatic hydrocarbon 10 ring group, (25) a 5- to 14-membered non-aromatic hetero cyclic group, (26) a C2-6 alkenyloxy group, (27) a C2-6 Formula 3 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfonyl group, (30) —X-A' (wherein N-N/N. X represents an imino group, —O— —S- or —SO - and 15 X A represents a 6- to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic - 2 K. group which may be substituted with 1 to 3 halogen atoms), (31) —CO-A' (wherein A' is as defined above) and (32) =CH-A' (wherein A' is as defined above): wherein R and R are the same or different and each 2) The compound or pharmacologically acceptable salt represent a substituent selected from Substituent Group A1, thereof according to 1) above, wherein the compound is or Rand Rare taken together with a carbon atom to which represented by the formula (I-1), (I-2) or (I-3): they are bonded to form —CH-A (wherein A represents a 6 to 14-membered aromatic hydrocarbon ring group or a 5- to 25 14-membered aromatic heterocyclic group which may be Formula 2) substituted with 1 to 3 substituents selected from Substituent (I-1) Group A2). X represents a methylene group which may be substituted with a substituent selected from Substituent MeO NN X -G). Group A1, or an oxygen atom and n represents an integer 30 of 0 to 2: % N. 21 9) The compound or pharmacologically acceptable salt thereof according to 1) above, wherein Het represents a group which may be substituted with 1 to 3 substituents Me 35 selected from Substituent Group A1 and is represented by (I-2) the following formula: MeO N X GE) s Formula 4 an N N 2 40 -N R5 6 y-y–é" X3 Me (I-3) \ /, 45 MeO N X -(e) wherein R and R are the same or different and each represent a substituent selected from Substituent Group A1, % N N 2 N X represents a methylene group which may be substituted with a substituent selected from Substituent Group A1, or an 50 oxygen atom and n, represents an integer of 0 to 2: Me 10) The compound or pharmacologically acceptable salt thereof according to 1) above, wherein Het represents a wherein X and Het are as defined above; group which may be substituted with 1 to 3 substituents 3) The compound or pharmacologically acceptable salt 55 selected from Substituent Group A1 and is represented by thereof according to 1) above, wherein the compound is the following formula: represented by the formula (I-1) or (I-3); 4) The compound or pharmacologically acceptable salt Formula 5 thereof according to 1) above, wherein the compound is )ne represented by the formula (I-1); 60 N-N 5) The compound or pharmacologically acceptable salt thereof according to 1) above, wherein X represents - C) —CR'—CR - (wherein R' and Rare the same or different % N and each represent a hydrogen atom or a fluorine atom; 6) The compound or pharmacologically acceptable salt 65 wherein in represents an integer of 0 to 3: thereof according to 1) above, wherein X represents 11) The compound or pharmacologically acceptable salt CH-CH ; thereof according to 6) above, wherein in represents 0 or 2: US 9,453,000 B2 7 8 12) The compound or pharmacologically acceptable salt halogen atom, (3) a C1-6 alkyl group (wherein the C1-6 thereof according to 1) above, wherein Het represents a alkyl group may be substituted with 1 to 3 substituents group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a selected from Substituent Group A1 and is represented by C1-6 alkoxy group) and (4) a C1-6 alkoxy group (wherein the following formula: the C1-6 alkoxy group may be substituted with a halogen atom); 16) The compound or pharmacologically acceptable salt Formula 6 thereof according to 1) above, wherein the compound is selected from the following group: 10 1) (-)-8-(3-fluorophenyl)-2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra hydro 1.2.4 triazolo 1.5-alpyridine, 2) (-)-8-(4-isopropylphenyl)-2-(E)-2-3-methoxy-4-(4- wherein in represents an integer of 0 to 3: methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra 13) The compound or pharmacologically acceptable salt 15 hydro 1.2.4 triazolo 1.5-alpyridine, thereof according to 1) above, wherein Het represents a 3) (-)-8-(4-fluoro-2-methoxymethylphenyl)-2-(E)-2-3- group which may be substituted with 1 to 3 substituents methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5, selected from Substituent Group A1 and is represented by 6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, the following formulas: 4) (-)-8-(2-fluorophenyl)-2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra hydro-1,2,4-triazolo 1.5-alpyridin-8-ol. Formula 7 5) (+)-8-(3,5-difluorophenyl)-2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra 25 hydro 1.2.4 triazolo 1.5-alpyridin-8-ol. 6) 8-(4-fluorophenyl)-2-(E)-2-3-methoxy-4-(4-methyl 1H-imidazol-1-yl)phenyl vinyl-6-methyl-5,6,7,8-tetra hydro-1,2,4-triazolo 1.5-alpyridine, R s R R*, 7) 8-(4-fluorophenyl)-2-(E)-2-3-methoxy-4-(4-methyl N-N 30 1H-imidazol-1-yl)phenyl vinyl-7-methyl-5,6,7,8-tetra N-N W hydro-1,2,4-triazolo 1.5-alpyridine, 8) (-)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) -k N O.N - 2 R4 phenyl vinyl-7-phenyl-6,7-dihydro-5H-pyrrolo 1.2-b 1.2.4 triazole, 35 9) (-)-2-(E)-2-6-methoxy-5-(4-methyl-1H-imidazol-1-yl) wherein R and Rare as defined above; pyridin-2-ylvinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8-tet 14) The compound or pharmacologically acceptable salt rahydro-1,2,4-triazolo-1,5-alpyridine, thereof according to 1) above, wherein Substituent Group 10) (-)-8-(3,4-difluorophenyl)-2-(E)-2-6-methoxy-5-(4- A1 is a group consisting of (1) a hydrogen atom, (2) a methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) 40 rahydro-1,2,4-triazolo 1.5-alpyridine, a C3-8 cycloalkyl group which may be substituted with 1 to 11) (-)-8-(4-fluorophenyl)-2-(E)-2-6-methoxy-5-(4- 3 substituents selected from Substituent Group A2. (6) a methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet C1-6 alkyl group which may be substituted with 1 to 3 rahydro-1,2,4-triazolo 1.5-alpyridine, substituents selected from Substituent Group A2, (7) a 6- to 12) (-)-8-(3-chloro-4-fluorophenyl)-2-(E)-2-6-methoxy 14-membered aromatic hydrocarbon ring group which may 45 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5.6.7. be substituted with 1 to 3 substituents selected from Sub 8-tetrahydro 1,2,4-triazolo 1.5-alpyridine, stituent Group A2, (8) a 5- to 14-membered aromatic het 13) (+)-8-(2,4,5-trifluorophenyl)-2-(E)-2-6-methoxy-5- erocyclic group which may be substituted with 1 to 3 (4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8- substituents selected from Substituent Group A2, (9) a 6- to tetrahydro 1.2.4 triazolo 1.5-alpyridine, 14-membered non-aromatic hydrocarbon ring group which 50 14) (+)-8-(2,5-difluorophenyl)-2-(E)-2-6-methoxy-5-(4- may be substituted with 1 to 3 substituents selected from methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet Substituent Group A2, (10) a 5- to 14-membered non rahydro 1.2.4 triazolo 1.5-alpyridine, aromatic heterocyclic group which may be substituted with 15) (-)-8-(2-bromo-4-fluorophenyl)-2-(E)-2-6-methoxy 1 to 3 substituents selected from Substituent Group A2, (11) 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5.6.7. —X-A (wherein X represents an imino group, —O— or 55 8-tetrahydro-1,2,4-triazolo 1.5-apyridine, —S - and A represents a 6- to 14-membered aromatic 16) (-)-8-(2-chloro-4-fluorophenyl)-2-(E)-2-6-methoxy hydrocarbon ring group or a 5- to 14-membered aromatic 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5.6.7. heterocyclic group, which may be substituted with 1 to 3 8-tetrahydro-1,2,4-triazolo 1.5-apyridine, substituents selected from Substituent Group A2), (12) 17) (+)-8-(3-fluorophenyl)-2-(E)-2-6-methoxy-5-(4- =CH-A (wherein A represents a 6- to 14-membered aro 60 methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet matic hydrocarbon ring group or a 5- to 14-membered rahydro 1.2.4 triazolo 1.5-alpyridine, aromatic heterocyclic group, which may be substituted with 18) (-)-8-(2-chlorophenyl)-2-(E)-2-6-methoxy-5-(4- 1 to 3 substituents selected from Substituent Group A2) and methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet (13) an azido group; rahydro-1,2,4-triazolo 1.5-alpyridine, 15) The compound or pharmacologically acceptable salt 65 19) (–)-2-(E)-2-6-methoxy-5-(4-methyl-1H-imidazol-1- thereof according to 1) above, wherein Substituent Group yl)pyridin-2-ylvinyl-8-(2-trifluoromethylphenyl)-5.6.7. A2 is a group consisting of (1) a hydrogen atom, (2) a 8-tetrahydro-1,2,4-triazolo 1.5-apyridine, US 9,453,000 B2 9 10 20) (+)-2-(E)-2-6-methoxy-5-(4-methyl-1H-imidazol-1- 17) A medicine comprising the compound or pharmacologi yl)pyridin-2-ylvinyl-8-(naphthalen-1-yl)-5,6,7,8-tetra cally acceptable salt thereof according to any of 1) to 16) hydro-1,2,4-triazolo 1.5-alpyridine, above as an active ingredient; 21) (–)-2-(E)-2-6-methoxy-5-(4-methyl-1H-imidazol-1- 18) The medicine according to 17) above for preventing or yl)pyridin-2-ylvinyl-8-phenyl-5,6,7,8-tetrahydro-1,2, 5 treating a disease caused by amyloid-f; and 4triazolo 1.5-alpyridine, 19) The medicine according to 18) above, wherein the 22) (-)-8-(4-chlorophenyl)-2-(E)-2-6-methoxy-5-(4- disease caused by amyloid-fi is Alzheimer's disease, demen methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-8-phenyl tia, Down's syndrome or amyloidosis. 5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, The compound of the general formula (I) or pharmaco 23) (+)-8-(4-fluorophenyl)-2-(E)-2-5-methoxy-6-(4- 10 logically acceptable salt thereof according to the present methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-5,6,7,8-tet invention and the prophylactic or therapeutic agent for a rahydro-1,2,4-triazolo 1.5-alpyridine, disease caused by AB according to the present invention are novel inventions that have not yet been described in any 24) (-)-8-(4-chlorophenyl)-2-(E)-2-5-methoxy-6-(4- documents. methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-phenyl 15 Meanings of symbols, terms and the like used in the 5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, present specification will be explained and the present 25) (+)-8-(3,4-difluorophenyl)-2-(E)-2-5-methoxy-6-(4- invention will be described in detail below. methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-5,6,7,8-tet In the present specification, a structural formula of a rahydro-1,2,4-triazolo 1.5-alpyridine, compound may represent a certain isomer for convenience. 26) (–)-2-(E)-2-5-methoxy-6-(4-methyl-1H-imidazol-1- However, the present invention includes all isomers and yl)pyridin-3-yl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8- isomer mixtures such as geometric isomers which can be tetrahydro-1,2,4-triazolo 1.5-alpyridine-8-carbonitrile, generated from the structure of a compound, optical isomers 27) (-)-8-(4-chlorophenyl)-2-(E)-2-6-methoxy-5-(4- based on asymmetric carbon, Stereoisomers and tautomers. methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6-di The present invention is not limited to the description of a hydro-8H-1.2.4 triazolo.5.1-c. 1,4oxazine, 25 chemical formula for convenience and may include any one 28) (-)-8-(2,3-difluorophenyl)-2-(E)-2-6-methoxy-5-(4- of the isomers or mixtures thereof. Accordingly, the com methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet pound of the present invention may have an asymmetric rahydro-1,2,4-triazolo 1.5-alpyridine, carbon atom in the molecule and exist as an optically active 29) (-)-8-(2-fluoro-3-methylphenyl)-2-(E)-2-6-methoxy compound or racemate, and the present invention includes 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5.6.7. 30 each of the optically active compound and the racemate without limitations. Although crystal polymorphs of the 8-tetrahydro-1,2,4-triazolo 1.5-apyridine, compound may be present, the compound is not limited 30) (-)-8-(2-trifluoromethoxyphenyl)-2-(E)-2-6- thereto as well and may be present as a single crystal form methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvii or a mixture of single crystal forms. The compound may be nyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, 35 an anhydride or hydrate. 31) (-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-(E)-2-6- The “disease caused by AB” refers to a wide variety of methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvii diseases Such as Alzheimer's disease (see, for example, nyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, Klein W. L., and seven others, Alzheimer's disease-affected 32) (-)-8-(2-difluoromethoxyphenyl)-2-(E)-2-6-methoxy brain: Presence of oligomeric AB ligands (ADDLS) suggests 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5.6.7. 40 a molecular basis for reversible memory loss, Proceeding 8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, National Academy of Science USA, 2003, Sep. 2, 100(18), 33) (-)-8-(2-bromophenyl)-2-(E)-2-6-methoxy-5-(4- p. 10417-10422: Nitsch RM, and sixteen others, Antibodies methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet against B-amyloid slow cognitive decline in Alzheimer's rahydro-1,2,4-triazolo 1.5-alpyridine and disease, Neuron, 2003, May 22, 38(4), p. 547-554: Jarrett J 34) (-)-8-(3-fluoro-2-methylphenyl)-2-(E)-2-5-methoxy 45 T, and two others. The carboxy terminus of the Bamyloid 6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(4- protein is critical for the seeding of amyloid formation: trifluoromethylphenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo Implications for the pathogenesis of Alzheimers’ disease, 1.5-alpyridine, Biochemistry, 1993, May 11, 32(18), p. 4693-4697: Glenner 35) (–)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1- G G, and one other, Alzheimer's disease; initial report of the yl)phenyl vinyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tet 50 purification and characterization of a novel cerebrovascular rahydro-1,2,4-triazolo 1.5-alpyridine, amyloid protein, Biochemical and biophysical research 36) (–)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1- communications, 1984, May 16, 120(3), p. 885-890; Mas yl)phenyl vinyl-7-(2-trifluoromethylphenyl)-6,7-di ters C L. and six others, Amyloid plaque core protein in hydro-5H-pyrro 1.2-b1,2,4-triazole, Alzheimer disease and Down syndrome, Proceeding 37) (-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-(E)-2-6- 55 National Academy of Science USA, 1985, June, 82(12), p. methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvii 4245-4249; Gouras G. 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W. and three others, Intracellular accumula Alzheimer's disease cases bearing the Thr113-114ins pre tion of amyloidogenic fragments of amyloid-fi precursor senilin-1 mutation, Brain, 2000, December, 123(Pt12), p. protein in neurons with Niemann-Pick type C defects is 2467-2474), mild cognitive impairment (see, for example, associated with endosomal abnormalities, American Journal Gattaz, W F, and four others, Platelet phospholipase A2 of Pathology, 2004, March, 164(3), p. 975-985), amyo activity in Alzheimer's disease and mild cognitive impair trophic lateral Sclerosis (see, for example, Sasaki S, and one ment, Journal of Neural Transmission, 2004, May, 111(5), p. other, Immunoreactivity of B-amyloid precursor protein in 591-601; Assini A, and fourteen others, Plasma levels of amyotrophic lateral Sclerosis, Acta Neuropathologica (Berl), 25 amyloid B-protein 42 are increased in women with mild 1999, May, 97(5), p. 463-468; Tamaoka A, and four others, cognitive impariment, Neurology, 2004, Sep. 14, 63(5), p. Increased amyloid B protein in the skin of patients with 828-831), arteriosclerosis (see, for example, De Meyer G. R. amyotrophic lateral sclerosis, Journal of neurology, 2000, and eight others, Platelet phagocytosis and processing of August, 247(8), p. 633-635: Hamilton R L. and one other, B-amyloid precursor protein as a mechanism of macrophage Alzheimer disease pathology in amyotrophic lateral Sclero 30 activation in atherosclerosis, Circulation Reserach, 2002, sis, Acta Neuropathologica, 2004, June, 107(6), p. 515-522; Jun. 14, 90(11), p. 1197–1204). Turner BJ, and six others, Brain B-amyloid accumulation in The “5-membered aromatic heterocyclic group”, “6- to transgenic mice expressing mutant Superoxide dismutase 1, 14-membered aromatic hydrocarbon ring group', '5- to Neurochemical Research, 2004, December, 29(12), p. 2281 14-membered aromatic heterocyclic group', '6- to 14-mem 2286), hydrocephalus (see, for example, Weller RO, Pathol 35 bered non-aromatic hydrocarbon ring group' and "5- to ogy of cerebrospinal fluid and interstitial fluid of the CNS: 14-membered non-aromatic heterocyclic group' in the com Significance for Alzheimer disease, prion disorders and pound represented by the formula (I) of the present inven multiple Sclerosis, Journal of Neuropathology and Experi tion which is effective for treatment or prevention of a mental Neurology, 1998, October, 57(10), p. 885-894; Sil disease caused by AB are defined as follows. verberg G D, and four others, Alzheimer's disease, normal 40 The “5-membered aromatic heterocyclic group' is a pressure hydrocephalus, and senescent changes in CSF 5-membered aromatic heterocyclic group containing one or circulatory physiology: a hypothesis, Lancet neurology, more hetero atoms selected from the group consisting of a 2003, August,208), p. 506-511; Weller RO, and three others, nitrogen atom, a Sulfur atom and an oxygen atom such as: Cerebral amyloid angiopathy: Accumulation of AB in inter Stitial fluid drainage pathways in Alzheimer's disease, 45 Annals of the New York academy of sciences, 2000, April, Formula 8 903, p. 110-117; Yow H Y, and one other. A role for cerebrovascular disease in determining the pattern off-amy loid deposition in Alzheimer's disease, Neurology and -(D -() s - applied neurobiology, 2002, 28, p. 149; Weller RO, and four 50 HN N NN HN1 others, Cerebrovasculardisease is a major factor in the failure of elimination of AB from the aging human brain, Annals of the New York academy of sciences, 2002, Novem -(HN1 " -(DN ber, 977, p. 162-168), paraparesis (see, for example, O'Riordan S, and seven others, Presenilin-1 mutation 55 The "6- to 14-membered aromatic hydrocarbon ring (E280G), spastic paraparesis, and cranial MRI white-matter group' refers to a monocyclic, bicyclic or tricyclic aromatic abnormalities, Neurology, 2002, Oct. 8, 59(7), p. 1108-1110: hydrocarbon ring group having 6 to 14 carbon atoms. Matsubara-Tsutsui M, and seven others, Molecular evidence Preferable examples of the group include 6- to 14-membered of presenilin 1 mutation in familial early onset dementia, monocyclic, bicyclic, or tricyclic aromatic hydrocarbon ring American journal of Medical Genetics, 2002, Apr. 8, 114(3), 60 groups such as a phenyl group, an indenyl group, a naphthyl p. 292-298; Smith MJ, and eleven others, Variable pheno group, an aZulenyl group, a heptalenyl group, a biphenyl type of Alzheimer's disease with spastic paraparesis, Annals group, a fluorenyl group, a phenalenyl group, a phenanthre of Neurology, 2001, 49(1), p. 125-129: Crook R, and sev nyl group and an anthracenyl group. enteen others. A variant of Alzheimer's disease with spastic The “5- to 14-membered aromatic heterocyclic group' pararesis and unusual plaques due to deletion of exon 9 of 65 refers to a monocyclic, bicyclic or tricyclic aromatic het presenilin 1, Nature Medicine, 1998, April; 4(4), p. 452 erocyclic group having 5 to 14 carbon atoms. Preferable 455), progressive Supranuclear palsy (see, for example, examples of the group include (1) nitrogen-containing aro US 9,453,000 B2 15 16 matic heterocyclic groups such as a pyrrolyl group, a pyridyl Substituent groups A1 and A2 refer to the following group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl groups. group, a pyrazolinyl group, an imidazolyl group, an indolyl Substituent Group A1 refers to (1) a hydrogen atom, (2) group, an isoindolyl group, an indolizinyl group, a purinyl a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) group, an indazolyl group, a quinolyl group, an isoquinolyl a nitro group, (6) a C3-8 cycloalkyl group which may be group, a quinolizinyl group, a phthalazinyl group, a naph substituted with 1 to 3 substituents selected from Substituent thyridinyl group, a quinoxalinyl group, a quinazolinyl Group A2, (7) a C2-6 alkenyl group which may be substi group, a cinnolinyl group, a pteridinyl group, an imidazo tuted with 1 to 3 substituents selected from Substituent triazinyl group, a pyrazinopyridazinyl group, an acridinyl Group A2. (8) a C2-6 alkynyl group which may be substi group, a phenanthridinyl group, a carbazolyl group, a per 10 tuted with 1 to 3 substituents selected from Substituent Group A2, (9) a C3-8 cycloalkoxy group, (10) a C3-8 imidinyl group, a phenanthrolinyl group and a phenacyl cycloalkylthio group, (11) a formyl group, (12) a C1-6 group, (2) Sulfur-containing aromatic heterocyclic groups alkylcarbonyl group which may be substituted with 1 to 3 Such as a thienyl group and a benzothienyl group, (3) substituents selected from Substituent Group A2, (13) a oxygen-containing aromatic heterocyclic groups such as a 15 C1-6 alkylthio group which may be substituted with 1 to 3 furyl group, a pyranyl group, a cyclopentapyranyl group, a substituents selected from Substituent Group A2, (14) a benzofuranyl group and an isobenzofuranyl group and (4) C1-6 alkylsulfinyl group which may be substituted with 1 to aromatic heterocyclic groups containing two or more hetero 3 substituents selected from Substituent Group A2, (15) a atoms selected from the group consisting of a nitrogen atom, C1-6 alkylsulfonyl group which may be substituted with 1 to a Sulfur atom and an oxygenatom Such as a thiazolyl group, 3 substituents selected from Substituent Group A2, (16) a an isothiazolyl group, a benzothiazolinyl group, a benzothi hydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a adiazolyl group, a phenothiazinyl group, an isoxazolyl C1-6 alkyl group which may be substituted with 1 to 3 group, a furazanyl group, a phenoxazinyl group, a pyra substituents selected from Substituent Group A2. (19) a Zoloxazolyl group, an imidazothiazolyl group, a thienofuryl C1-6 alkoxy group which may be substituted with 1 to 3 group, a furopyrrolyl group and a pyridooxazinyl group. 25 substituents selected from Substituent Group A2, (20) an The "6- to 14-membered non-aromatic hydrocarbon ring amino group which may be substituted with 1 or 2 substitu group' refers to a cyclic aliphatic hydrocarbon group having ents selected from Substituent Group A2, (21) a carbamoyl 6 to 14 carbon atoms. Examples of the group include cyclic group which may be substituted with 1 or 2 substituents aliphatic hydrocarbon groups having 6 to 14 carbon atoms selected from Substituent Group A2, (22) a 6- to 14-mem Such as a cyclopropyl group, a cyclobutyl group, a cyclo 30 bered aromatic hydrocarbon ring group which may be pentyl group, a cyclohexyl group, a cycloheptyl group, a substituted with 1 to 3 substituents selected from Substituent cyclooctyl group, a spiro 3.4 octanyl group, a decanyl Group A2, (23) a 5- to 14-membered aromatic heterocyclic group, an indanyl group, a 1-acenaphthenyl group, a cyclo group which may be substituted with 1 to 3 substituents pentacyclooctenyl group, a benzocyclooctenyl group, an selected from Substituent Group A2, (24) a 6- to 14-mem indenyl group, a tetrahydronaphthyl group, a 6.7.8.9-tetra 35 bered non-aromatic hydrocarbon ring group which may be hydro-5H-benzocycloheptenyl group and a 1,4-dihy substituted with 1 to 3 substituents selected from Substituent dronaphthalenyl group. Group A2, (25) a 5- to 14-membered non-aromatic hetero The “5- to 14-membered non-aromatic heterocyclic cyclic group which may be substituted with 1 to 3 substitu group 1) has 5 to 14 ring-forming atoms, 2) contains 1 to ents selected from Substituent Group A2, (26) a C2-6 5 hetero atoms Such as a nitrogen atom, —O— or —S - in 40 alkenyloxy group, (27) a C2-6 alkynyloxy group, (28) a the ring-forming atoms, and 3) may contain one or more C3-8 cycloalkylsulfinyl group, (29) a C3-8 cycloalkylsulfo carbonyl groups, double bonds or triple bonds in the ring, nyl group, (30) —X-A (wherein X represents an imino and refers not only to a 5- to 14-membered non-aromatic group, —O— or —S— and A represents a 6- to 14-mem monocyclic heterocyclic group but also to a saturated het bered aromatic hydrocarbon ring group or a 5- to 14-mem erocyclic group condensed with an aromatic hydrocarbon 45 bered aromatic heterocyclic group which may be substituted ring group or a saturated hydrocarbon ring group or Satu with 1 to 3 substituents selected from Substituent Group rated heterocyclic group condensed with an aromatic het A2), (31) —CO-A (wherein A is as defined above), (32) erocyclic group. Specific examples of the 5- to 14-mem —CH-A (wherein A is as defined above), (33) a carboxyl bered non-aromatic heterocyclic group include an azetidinyl group, (34) a C1-6 alkoxycarbonyl group or (35) an azido ring, a pyrrolidinyl ring, a piperidinyl ring, an azepanyl ring, 50 group. an azocanyl ring, a tetrahydrofuranyl ring, a tetrahydropy Substituent Group A2 refers to (1) a hydrogen atom, (2) ranyl ring, a morpholinyl ring, a thiomorpholinyl ring, a a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) piperazinyl ring, a thiazolidinyl ring, a dioxanyl ring, an a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 imidazolinyl ring, a thiazolinyl ring, a 1,2-benzopyranyl alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 ring, an isochromanyl ring, a chromanyl ring, an indolinyl 55 cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a ring, an isoindolinyl ring, an azaindanyl group, an azatetra formyl group, (12) a C1-6 alkylcarbonyl group, (13) a C1-6 hydronaphthyl group, an azachromanyl group, a tetrahyd alkylthio group, (14) a C1-6 alkylsulfinyl group, (15) a C1-6 robenzofuranyl group, a tetrahydrobenzothienyl group, a alkylsulfonyl group, (16) a hydroxyimino group, (17) a C1-6 2,3,4,5-tetrahydro-benzob thienyl group, a 3,4-dihydro alkoxyimino group, (18) a C1-6 alkyl group (wherein the 2H-benzob.1.4 dioxepinyl group, an indan-1-onyl group, 60 C1-6 alkyl group may be substituted with 1 to 3 substituents a 6,7-dihydro-5H-cyclopentapyrazinyl group, a 6,7-dihydro selected from the group consisting of a halogen atom, a 5H-1pyridinyl group, a 6,7-dihydro-5H-1pyridinyl hydroxyl group, a C1-6 alkoxy group, a phenyl group which group, a 5,6-dihydro-4H-cyclopentab thienyl group, a 4.5, may be substituted with 1 to 3 halogen atoms and a pyridinyl 6,7-tetrahydro-benzob thienyl group, a 3,4-dihydro-2H group which may be substituted with 1 to 3 halogen atoms), naphthale-1-onyl group, a 2,3-dihydro-isoindol-1-onyl 65 (19) a C1-6 alkoxy group (wherein the C1-6 alkoxy group group, a 3,4-dihydro-2H-isoquinolin-1-onyl group and a may be substituted with 1 to 3 substituents selected from the 3,4-dihydro-2H-benzo 1.4oxapinyl group. group consisting of a halogen atom, a hydroxyl group, a US 9,453,000 B2 17 18 C1-6 alkoxy group, a phenyl group which may be substi The “C1-6 alkylthio group' refers to an alkyl group tuted with 1 to 3 halogen atoms and a pyridinyl group which having 1 to 6 carbon atoms in which one hydrogen atom is may be substituted with 1 to 3 halogenatoms), (20) an amino replaced by a sulfur atom. Preferable examples of the group group which may be substituted with 1 or 2 C1-6 alkyl include a methylthio group, an ethylthio group, an n-pro groups or C1-6 alkylcarbonyl groups, (21) a carbamoyl 5 pylthio group, an i-propylthio group, an n-butylthio group, group which may be substituted with 1 or 2 C1-6 alkyl an i-butylthio group, a tert-butylthio group, an n-pentylthio groups, (22) a 6- to 14-membered aromatic hydrocarbon group, an i-pentylthio group, a neopentylthio group, an ring group, (23) a 5- to 14-membered aromatic heterocyclic n-hexylthio group and a 1-methylpropylthio group. group, (24) a 6- to 14-membered non-aromatic hydrocarbon The “C1-6 alkylcarbonyl group' refers to an alkyl group ring group, (25) a 5- to 14-membered non-aromatic hetero- 10 cyclic group, (26) a C2-6 alkynyloxy group, (27) a C2-6 having 1 to 6 carbon atoms in which one hydrogen atom is alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, replaced by a carbonyl group. Preferable examples of the (29) a C3-8 cycloalkylsulfonyl group, (30) —X-A' (wherein group include an acetyl group, a propionyl group and a X represents an imino group, —O— —S- or —SO - and butyryl group. A represents a 6- to 14-membered aromatic hydrocarbon 15 The “C1-6 alkylsulfinyl group’ refers to an alkyl group ring group or a 5- to 14-membered aromatic heterocyclic having 1 to 6 carbon atoms in which one hydrogen atom is group which may be substituted with 1 to 3 halogen atoms), substituted with a sulfinyl group. Preferable examples of the (31) —CO-A' (wherein A' is as defined above) or (32) group include a methylsulfinyl group, an ethylmethylsulfinyl =CH-A' (wherein A' is as defined above). group, an n-propylsulfinyl group, an i-propylsulfinyl group, The “halogen atom” refers to a fluorine atom, a chlorine 20 an n-butylsulfinyl group, an i-butylsulfinyl group, a tert atom, a bromine atom, an iodine atom or the like and is butylsulfinyl group, an n-pentylsulfinyl group, an i-pentyl preferably a fluorine atom, a chlorine atom or a bromine Sulfinyl group, a neopentylsulfinyl group, an n-hexylsulfinyl atOm. group and a 1-methylpropylsulfinyl group. The “C3-8 cycloalkyl group' refers to a cyclic alkyl group The “C1-6 alkylsulfonyl group' refers to an alkyl group having 3 to 8 carbon atoms. Preferable examples of the 25 having 1 to 6 carbon atoms in which one hydrogen atom is group include a cyclopropyl group, a cyclobutyl group, a replaced by a sulfonyl group. Preferable examples of the cyclopentyl group, a cyclohexyl group, a cycloheptyl group group include a methanesulfonyl group and an ethanesulfo and a cyclooctyl group. nyl group. The "C2-6 alkenyl group' refers to an alkenyl group The “C1-6 alkoxyimino group' refers to an imino group having 2 to 6 carbon atoms. Preferable examples of the 30 in which a hydrogen atom is replaced by a C1-6 alkoxy group include linear or branched alkenyl groups such as a group. Preferable examples of the group include a methoxy vinyl group, an allyl group, a 1-propenyl group, an isopro imino group and an ethoxyimino group. penyl group, a 1-buten-1-yl group, a 1-buten-2-yl group, a The “C1-6 alkyl group' refers to an alkyl group having 1 1-buten-3-yl group, a 2-buten-1-yl group and a 2-buten-2-yl to 6 carbon atoms. Preferable examples of the group include group. 35 linear or branched alkyl groups such as a methyl group, an The "C2-6 alkynyl group' refers to an alkynyl group ethyl group, an n-propyl group, an i-propyl group, an n-butyl having 2 to 6 carbon atoms. Preferable examples of the group, an i-butyl group, a tert-butyl group, an n-pentyl group include linear or branched alkynyl groups such as an group, an i-pentyl group, a neopentyl group, an n-hexyl ethynyl group, a 1-propynyl group, a 2-propynyl group, a group, a 1-methylpropyl group, an 1,2-dimethylpropyl butynyl group, a pentynyl group and a hexynyl group. 40 group, a 1-ethylpropyl group, a 1-methyl-2-ethylpropyl The “C3-8 cycloalkoxy group' refers to a cyclic alkyl group, a 1-ethyl-2-methylpropyl group, a 1.1.2-trimethyl group having 3 to 8 carbon atoms in which one hydrogen propyl group, a 1-methylbutyl group, a 2-methylbutyl group, atom is replaced by an oxygen atom. Preferable examples of a 1,1-dimethylbutyl group, a 2.2-dimethylbutyl group, a the group include a cyclopropoxy group, a cyclobutoxy 2-ethylbutyl group, a 1,3-dimethylbutyl group, a 2-methyl group, a cyclopentoxy group, a cyclohexoxy group, a cyclo- 45 pentyl group and a 3-methylpentyl group. heptyloxy group and a cyclooctyloxy group. The “C2-6 alkenyloxy group' refers to an alkenyl group The “C3-8 cycloalkylthio group' refers to a cyclic alkyl having 2 to 6 carbon atoms in which one hydrogen atom is group having 3 to 8 carbon atoms in which one hydrogen replaced by an oxygen atom. Preferable examples of the atom is replaced by a sulfur atom. Preferable examples of group include linear or branched alkenyloxy groups such as the group include a cyclopropylthio group, a cyclobutylthio 50 a vinyloxy group, an allyloxy group, a 1-propenyloxy group, group, a cyclopentylthio group, a cyclohexylthio group, a an isopropenyloxy group, a 1-buten-1-yloxy group, a cycloheptylthio group and a cyclooctylthio group. 1-buten-2-yloxy group, a 1-buten-3-yloxy group, a 2-buten The “C1-6 alkoxy group' refers to an alkyl group having 1-yloxy group and a 2-buten-2-yloxy group. 1 to 6 carbon atoms in which a hydrogen atom is replaced The "C2-6 alkynyloxy group' refers to an alkynyl group by an oxygen atom. Preferable examples of the group 55 having 2 to 6 carbon atoms in which one hydrogen atom is include a methoxy group, an ethoxy group, an n-propoxy replaced by an oxygen atom. Preferable examples of the group, an i-propoxy group, an n-butoxy group, an i-butoxy group include linear or branched alkynyloxy groups such as group, a sec-butoxy group, a tert-butoxy group, an n-pen an ethynyloxy group, a 1-propynyloxy group, a 2-propyny toxy group, an i-pentoxy group, a sec-pentoxy group, a loxy group, abutynyloxy group, a pentynyloxy group and a tert-pentoxy group, an n-hexoxy group, an i-hexoxy group, 60 hexynyloxy group. a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a The “C3-8 cycloalkylsulfonyl group' refers to a cyclic 1-methyl-2-ethylpropoxy group, a 1-ethyl-2-methylpropoxy alkyl group having 3 to 8 carbon atoms in which one group, a 1,1,2-trimethylpropoxy group, a 1.1.2-trimethyl hydrogen atom is replaced by a Sulfonyl group. Preferable propoxy group, a 1,1-dimethylbutoxy group, a 2,2-dimeth examples of the group include a cyclopropylsulfonyl group, ylbutoxy group, a 2-ethylbutoxy group, a 1,3-dimethylbu- 65 a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a toxy group, a 2-methylpentoxy group, a 3-methylpentoxy cyclohexylsulfonyl group, a cycloheptylsulfonyl group and group and a hexyloxy group. a cyclooctylsulfonyl group. US 9,453,000 B2 19 20 The “C3-8 cycloalkylsulfinyl group' refers to a cyclic or Rand Rare taken together with a carbon atom to which alkyl group having 3 to 8 carbon atoms in which one they are bonded to form —CH-A (wherein A represents a 6 hydrogen atom is replaced by a sulfinyl group. Preferable to 14-membered aromatic hydrocarbon ring group or a 5- to examples of the group include a cyclopropylsulfinyl group, 14-membered aromatic heterocyclic group which may be a cyclobutylsulfinyl group, a cyclopentylsulfinyl group, a substituted with 1 to 3 substituents selected from Substituent cyclohexylsulfinyl group, a cycloheptylsulfinyl group and a Group A2). cyclooctylsulfinyl group. Examples of the “Het represented by the following for The “C1-6 alkoxycarbonyl group' refers to a carbonyl mula': group in which a hydrogen atom is substituted with a C1-6 alkyl group. Preferable examples of the group include an 10 ethoxycarbonyl group. Formula 12 Examples of the pyridinyl group as Ar which may be N-N/N. Substituted with a hydroxyl group include a tautomer rep X resented by the following formula: 15 - 2 K. Formula 9 HO N H wherein R and Rare taken together with a carbon atom to n O N which they are bonded to form —CH-A, include:

2 N Formula 13 Examples of the “Het which is a group represented by the -/\" following formula': 25 - 2-/* N \ % \ Formula 10 A, H. H A. N-N/N. 30 X2 Examples of the “Het which is a group represented by the - 2 K. following formula': 35 Formula 14 wherein R and R are the same or different and each N R5 represent a substituent selected from Substituent Group A1, or Rand Rare taken together with a carbon atom to which they are bonded to form —CH-A (wherein A represents a 6 y-y ('X to 14-membered aromatic hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic group which may be 40 \ /, substituted with 1 to 3 substituents selected from Substituent Group A2). X represents a methylene group or an oxygen atom and n represents an integer of 0 to 2, include groups wherein R and R are the same or different and each represented by the formulas: 45 represent a substituent selected from Substituent Group A1, X represents a methylene group or an oxygen atom and n, represents an integer of 0 to 2, include: Formula 11 N-N N-N1 No W W 50 Formula 15 2 2 N R3 R', N R3 R', N-N N-y\ 55 1N R5R6, ry (R5 R6, R s R s -- -- O N-N N-N ) 60 N-N R. R6, N-N R5 R6 2 -k 2 O N N R3 R* , R3 R* , 65 wherein R and R are the same or different and each represent a substituent selected from Substituent Group A1, US 9,453,000 B2 21 22 wherein R and R are the same or different and each Sulfonates), amino acid salts (such as aspartates and gluta represent a substituent selected from Substituent Group A1. mates), quaternary amine salts, alkali metal salts (such as Examples of the “Het which is a group represented by the Sodium salts and potassium salts) and alkali earth metal salts following formula': (such as magnesium salts and calcium salts). Next, the compound of the formula (I) of the present invention will be described. Formula 16 In the compound of the formula (I) or pharmacologically acceptable salt thereof, Ar is preferably an imidazolyl group Substituted with a C1-6 alkyl group, and Ar is more pref 10 erably an imidazolyl group Substituted with a methyl group. In the compound of the formula (I) or pharmacologically acceptable salt thereof, Ar is preferably a pyridinyl group or wherein in represents an integer of 0 to 3, include: a phenyl group which may be substituted with a halogen atom, a hydroxyl group or a C1-6 alkoxy group, Ar is more 15 preferably a phenyl group or a pyridinyl group, Substituted Formula 17 with a C1-6 alkoxy group, Ar is particularly preferably a phenyl group or a pyridinyl group, Substituted with a methoxy group, and Ar is most preferably a pyridinyl group Substituted with a methoxy group. In the compound of the formula (I) or pharmacologically acceptable salt thereof, X is preferably —CR'=CR , wherein R' and R are the same or different and each representahydrogen atom or a fluorine atom, and X is most 25 preferably -CH=CH-. In the compound of the formula (I) or pharmacologically acceptable salt thereof, Ar and Armore preferably have the following structural formulas: Examples of the “Het which is a group represented by the following formula': 30 Formula 20 MeO N s Formula 18 n

35 %N 2

Me wherein in represents an integer of 0 to 3, include: MeO N s 40 Formula 19 %\ 4.

Me -(X2N,-- O, ---O O s MeO N

N-N- N N-N -{ N %N 2 50 - N2. N O, al H Me O . and most preferably have the following structural formulas: In the present invention, the “pharmacologically accept 55 able salt' is not particularly limited insofar as it is a pharmacologically acceptable salt formed with the com pound of the general formula (I) which is a prophylactic or Formula 21 therapeutic agent for a disease caused by AB. Preferable MeO N s MeO e n e N specific examples of the salt include hydrohalides (such as 60 hydrofluorides, hydrochlorides, hydrobromides and hydroiodides), inorganic acid salts (such as Sulfates, nitrates, % N. 21 %N 2 N perchlorates, phosphates, carbonates and bicarbonates), organic carboxylates (such as acetates, oxalates, maleates, tartrates, fumarates and citrates), organic Sulfonates (such as 65 Me Me methanesulfonates, trifluoromethanesulfonates, ethanesul fonates, benzenesulfonates, toluenesulfonates and camphor US 9,453,000 B2 23 24 In the compound of the formula (I) or pharmacologically acceptable salt thereof, Het is preferably a triazolyl group Formula 25 which may be substituted with 1 or 2 substituents selected )nd from Substituent Group A1, Het is preferably a group which may be substituted with 49-y 1 to 3 substituents selected from Substituent Group A1 and is represented by the following formula: wherein in represents an integer of 0 to 3. 10 Het is more preferably a group which may be substituted with 1 to 3 substituents selected from Substituent Group A1 Formula 22 and is represented by the following formula:

N-N 15 Formula 26 -k N2 K R4 N-N

- N2 K R4 wherein R and R are the same or different and each represent a substituent selected from Substituent Group A1, or Rand Rare taken together with a carbon atom to which wherein R and R are the same or different and each they are bonded to form —CH-A (wherein A represents a 6 represent a substituent selected from Substituent Group A1, to 14-membered aromatic hydrocarbon ring group or a 5- to or Rand Rare taken together with a carbon atom to which 14-membered aromatic heterocyclic group which may be 25 they are bonded to form —CH-A (wherein A represents a 6 substituted with 1 to 3 substituents selected from Substituent to 14-membered aromatic hydrocarbon ring group or a 5- to Group A2). X represents an oxygen atom or a methylene 14-membered aromatic heterocyclic group which may be group which may be substituted with a substituent selected substituted with 1 to 3 substituents selected from Substituent from Substituent Group A1 and n represents an integer of Group A2). X represents a methylene group which may be 0 to 2, 30 substituted with a substituent selected from Substituent Group A1, or an oxygen atom and n represents an integer Het is preferably a group which may be substituted with of 0 to 2, and 1 to 3 substituents selected from Substituent Group A1 and Het is more preferably a group which may be substituted is represented by the following formula: with 1 to 3 substituents selected from Substituent Group A1 35 and is represented by the following formula:

Formula 23 Formula 27 N R65 N y ( R 40 ul- N X3

45 wherein in represents an integer of 0 to 3, and wherein R and R are the same or different and each Het is most preferably a group which may be substituted represent a substituent selected from Substituent Group A1, with 1 to 3 substituents selected from Substituent Group A1 X represents a methylene group which may be substituted and is represented by the following formula: with a substituent selected from Substituent Group A1, or an 50 oxygen atom and n, represents an integer of 0 to 2. Formula 28 Het is preferably a group which may be substituted with 1 to 3 substituents selected from Substituent Group A1 and N-N s^\ is represented by the following formula: () f O 55 2 2 N R3 R*, N R3 R*, Formula 24 -() N-N 60 -k N2- NH - N2 4 R wherein in represents an integer of 0 to 3, or Substituent Group A1 is preferably a group consisting of Het is preferably a group which may be substituted with 65 (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl 1 to 3 substituents selected from Substituent Group A1 and group, (4) a cyano group, (5) a nitro group, (6) a C3-8 is represented by the following formula: cycloalkyl group which may be substituted with 1 to 3 US 9,453,000 B2 25 26 substituents selected from Substituent Group A2. (7) a C2-6 14-membered aromatic heterocyclic group which may be alkenyl group which may be substituted with 1 to 3 sub substituted with 1 to 3 substituents selected from Substituent stituents selected from Substituent Group A2. (8) a C2-6 Group A2) and (13) an azidoaZido group. alkynyl group which may be substituted with 1 to 3 sub When Substituent Group A1 is a 6- to 14-membered stituents selected from Substituent Group A2, (9) a C3-8 aromatic hydrocarbon ring group or a 5- to 14-membered cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a aromatic heterocyclic group, Substituent Group A2 is pref formyl group, (12) a C1-6 alkylcarbonyl group which may erably a group consisting of (1) a hydrogen atom, (2) a be substituted with 1 to 3 substituents selected from Sub halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) stituent Group A2, (13) a C1-6 alkylthio group which may a nitro group, (6) a C3-8 cycloalkyl group, (7) a C2-6 be substituted with 1 to 3 substituents selected from Sub 10 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8 stituent Group A2, (14) a C1-6 alkylsulfinyl group which cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a may be substituted with 1 to 3 substituents selected from formyl group, (12) a C1-6 alkylcarbonyl group, (13) a C1-6 Substituent Group A2, (15) a C1-6 alkylsulfonyl group alkylthio group, (14) a C1-6 alkylsulfinyl group, (15) a C1-6 which may be substituted with 1 to 3 substituents selected alkylsulfonyl group, (16) a hydroxyimino group, (17) a C1-6 from Substituent Group A2, (16) a hydroxyimino group, 15 alkoxyimino group, (18) a C1-6 alkyl group (wherein the (17) a C1-6 alkoxyimino group, (18) a C1-6 alkyl group C1-6 alkyl group may be substituted with 1 to 3 substituents which may be substituted with 1 to 3 substituents selected selected from the group consisting of a halogen atom, a from Substituent Group A2, (19) a C1-6 alkoxy group which hydroxyl group, a C1-6 alkoxy group, a phenyl group which may be substituted with 1 to 3 substituents selected from may be substituted with 1 to 3 halogen atoms and a pyridinyl Substituent Group A2. (20) an amino group which may be group which may be substituted with 1 to 3 halogen atoms), substituted with 1 or 2 substituents selected from Substituent (19) a C1-6 alkoxy group (wherein the C1-6 alkoxy group Group A2. (21) a carbamoyl group which may be substituted may be substituted with 1 to 3 substituents selected from the with 1 or 2 substituents selected from Substituent Group A2. group consisting of a halogen atom, a hydroxyl group, a (22) a 6- to 14-membered aromatic hydrocarbon ring group C1-6 alkoxy group, a phenyl group which may be substi which may be substituted with 1 to 3 substituents selected 25 tuted with 1 to 3 halogen atoms and a pyridinyl group which from Substituent Group A2, (23) a 5- to 14-membered may be substituted with 1 to 3 halogenatoms), (20) an amino aromatic heterocyclic group which may be substituted with group which may be substituted with 1 or 2 C1-6 alkyl 1 to 3 substituents selected from Substituent Group A2, (24) groups or C1-6 alkylcarbonyl groups, (21) a carbamoyl a 6- to 14-membered non-aromatic hydrocarbon ring group group which may be substituted with 1 or 2 C1-6 alkyl which may be substituted with 1 to 3 substituents selected 30 groups, (22) a 6- to 14-membered aromatic hydrocarbon from Substituent Group A2, (25) a 5- to 14-membered ring group, (23) a 5- to 14-membered aromatic heterocyclic non-aromatic heterocyclic group which may be substituted group, (24) a 6- to 14-membered non-aromatic hydrocarbon with 1 to 3 substituents selected from Substituent Group A2. ring group, (25) a 5- to 14-membered non-aromatic hetero (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy cyclic group, (26) a C2-6 alkenyloxy group, (27) a C2-6 group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8 35 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, cycloalkylsulfonyl group, (30)—X-A (wherein X represents (29) a C3-8 cycloalkylsulfonyl group, (30) —X-A' (wherein an imino group, —O— or —S - and A represents a 6- to X represents an imino group, —O— —S— or —SO - and 14-membered aromatic hydrocarbon ring group or a 5- to A represents a 6- to 14-membered aromatic hydrocarbon 14-membered aromatic heterocyclic group which may be ring group or a 5- to 14-membered aromatic heterocyclic substituted with 1 to 3 substituents selected from Substituent 40 group which may be substituted with 1 to 3 halogen atoms), Group A2), (31) —CO-A (wherein A is as defined above), (31) —CO-A' (wherein A' is as defined above) and (32) (32) —CH-A (wherein A is as defined above), (33) a —CH-A' (wherein A' is as defined above): carboxyl group, (34) a C1-6 alkoxycarbonyl group and (35) more preferably a group consisting of (1) a hydrogen an azidoazido group. atom, (2) a halogen atom, (3) a nitro group, (4) a C1-6 Substituent Group A1 is more preferably a group consist 45 alkylcarbonyl group, (5) a C1-6 alkylthio group, (6) a C1-6 ing of (1) a hydrogen atom, (2) a halogen atom, (3) a alkyl sulfonyl group, (7) a C1-6 alkyl group (wherein the hydroxyl group, (4) a cyano group, (5) a C3-8 cycloalkyl C1-6 alkyl group may be substituted with 1 to 3 substituents group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a selected from Substituent Group A2. (6) a C1-6 alkyl group hydroxyl group, a C1-6 alkoxy group, a phenyl group which which may be substituted with 1 to 3 substituents selected 50 may be substituted with 1 to 3 halogen atoms and a pyridinyl from Substituent Group A2. (7) a 6- to 14-membered aro group which may be substituted with 1 to 3 halogen atoms), matic hydrocarbon ring group which may be substituted (8) a C1-6 alkoxy group (wherein the C1-6 alkoxy group with 1 to 3 substituents selected from Substituent Group A2. may be substituted with 1 to 3 substituents selected from the (8) a 5- to 14-membered aromatic heterocyclic group which group consisting of a halogen atom, a hydroxyl group, a may be substituted with 1 to 3 substituents selected from 55 C1-6 alkoxy group, a phenyl group which may be substi Substituent Group A2, (9) a 6- to 14-membered non-aro tuted with 1 to 3 halogen atoms and a pyridinyl group which matic hydrocarbon ring group which may be substituted may be substituted with 1 to 3 halogen atoms), (9) an amino with 1 to 3 substituents selected from Substituent Group A2. group which may be substituted with 1 or 2 C1-6 alkyl (10) a 5- to 14-membered non-aromatic heterocyclic group groups or C1-6 alkylcarbonyl groups and (10) a 5- to which may be substituted with 1 to 3 substituents selected 60 14-membered aromatic heterocyclic group; and from Substituent Group A2, (11) —X-A (wherein X repre most preferably a group consisting of (1) a hydrogen sents an imino group, —O— or —S - and A represents a 6 atom, (2) a halogen atom, (3) a C1-6 alkyl group (wherein to 14-membered aromatic hydrocarbon ring group or a 5- to the C1-6 alkyl group may be substituted with 1 to 3 14-membered aromatic heterocyclic group which may be Substituents selected from the group consisting of a halogen substituted with 1 to 3 substituents selected from Substituent 65 atom and a C1-6 alkoxy group) and (4) a C1-6 alkoxy group Group A2), (12) —CH-A (wherein A represents a 6- to (wherein the C1-6 alkoxy group may be substituted with a 14-membered aromatic hydrocarbon ring group or a 5- to halogen atom).

US 9,453,000 B2 29 30 25) (+)-8-(3,4-difluorophenyl)-2-(E)-2-5-methoxy-6-(4- 39) (S)-2-(E)-2-6-methoxy-5-(4-methyl-1H-imidazol-1- methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-5,6,7,8-tet yl)pyridine-1-ylvinyl-7-(2-trifluoromethylphenyl)-6,7- rahydro-1,2,4-triazolo 1.5-alpyridine, dihydro-5H-pyrro 1,2-b1,2,4-triazole, and 40) (S)-7-(5-fluoro-2-trifluoromethyphanyl)-2-(E)-2-6- 26) (–)-2-(E)-2-5-methoxy-6-(4-methyl-1H-imidazol-1- methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-ylvii yl)pyridin-3-yl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8- 5 nyl-6,7-dihydro-5H-pyrro 1.2-b1.2.4 triazole. tetrahydro-1,2,4-triazolo 1.5-alpyridine-8-carbonitrile, Methods for preparing the compound of the general 27) (-)-8-(4-chlorophenyl)-2-(E)-2-6-methoxy-5-(4- formula (I) of the present invention will be described below. methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6-di The compound represented by the general formula (I): hydro-8H-1.2.4 triazolo.5.1-c. 1,4oxazine, 28) (-)-8-(2,3-difluorophenyl)-2-(E)-2-6-methoxy-5-(4- 10 methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet rahydro-1,2,4-triazolo 1.5-alpyridine, Formula 29 29) (-)-8-(2-fluoro-3-methylphenyl)-2-(E)-2-6-methoxy 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5.6.7. (I) 8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, 15 30) (-)-8-(2-trifluoromethoxyphenyl)-2-(E)-2-6- methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvii O-O-x-GE) nyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, 31) (-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-(E)-2-6- methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvii 2O nyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, wherein Art, Ar., X and Het are as defined above, is 32) (-)-8-(2-difluoromethoxyphenyl)-2-(E)-2-6-methoxy synthesized according to a method such as the following 5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5.6.7. General Preparation Method 1 to General Preparation 8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, Method 8, for example. It is obvious that, in order to prepare 33) (-)-8-(2-bromophenyl)-2-(E)-2-6-methoxy-5-(4- 25 the compound of the present invention conveniently, the methyl-1H-imidazol-1-yl)pyridin-2-ylvinyl-5,6,7,8-tet method comprises a protection reaction step and a depro rahydro-1,2,4-triazolo 1.5-alpyridine and tection reaction step appropriately, using a protecting group 34) (-)-8-(3-fluoro-2-methylphenyl)-2-(E)-2-5-methoxy known to a person skilled in the art which is suitably 6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(4- selected for each step (see T. Greene et al., “Protective trifluoromethylphenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo 30 Groups in Organic Synthesis”, John Wiley & Sons, Inc., 1.5-alpyridine, 35) (–)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1- New York, 1981). It is also obvious that, in order to prepare yl)phenyl vinyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tet the compound of the present invention conveniently, all rahydro-1,2,4-triazolo 1.5-alpyridine, isomers and isomer mixtures such as geometric isomers 36) (–)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1- 35 which can be generated from the structure of the compound, yl)phenyl vinyl-7-(2-trifluoromethylphenyl)-6,7-di optical isomers based on asymmetric carbon, Stereoisomers, hydro-5H-pyrro 1.2-b1,2,4-triazole, and tautomers can be prepared as a single compound by a 37) (-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-(E)-2-6- technique known to a person skilled in the art which is methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-ylvii Suitable for each step such as fractional crystallization or nyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridine, 40 column chromatography. 38) (5R,8S)-2-(E)-2-6-methoxy-5-(4-methyl-1H-imida General Preparation Method 1 Zol-1-yl)pyridin-2-ylvinyl-5-methyl-8-(2-trifluorom Typically used General Preparation Method 1 for the ethylphenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-a compound of the general formula (I) of the present invention pyridine, will be described below.

Formula 30 Osy, R10 O O O y - Yo () X-CO2H - - () X - X-O. Step 1-1 G Yui R11 N 1-6 R10 (1) (3) (I-9) ser 1-4) Step 1-3 /s is r(2b)

(I-6) or US 9,453,000 B2

-continued pie -a- R10 2 2 R10 R10 SY Stepp 1-9 SY, +NHR RSSY, SY, X-( X5 X-( (22) XI-Q) X-( N e 11(M.ind O tell -e-Step 1-5 N a 1. N a 1. G G \, Step Y. I ity (b))Xs

In the formula, the following partial structure (formula X represents a carbon atom or an oxygen atom, nd, ne, ni III-3, III-4, III-6, III-7 or III-8): and nj each represent an integer of 1 to 2; and inl represents an integer of 0 to 2. 15 The above General Preparation Method 1 includes a Formula 31 method of condensing a carboxylic acid compound (1) with a compound (2a) in Step 1-1 to convert the carboxylic acid (III-3) compound (1) into an ester compound (3) and reacting the ester compound (3) with ammonia, an ammonium salt or formamide in Step 1-2 to prepare a compound of the general formula (I-9); a method of reacting the compound of the (III-4) general formula (I-9) with a compound (2b) in Step 1-3 to prepare a compound of the general formula (I-4); a method 25 of reacting the ester compound (3) with ammonia, an ammonium salt or formamide in Step 1-4 to convert the ester compound (3) into an oxazole compound (21) and then reacting the oxazole compound (21) with an amine com (III-6) pound (22) in Step 1-5 to prepare a compound of the general 30 formula (I-4); a method of preparing a compound of the general formula (I-6) or a compound of the general formula (I-7) from the compound of the general formula (I-9) in Step 1-6; a method of preparing a compound of the general formula (I-6) or a compound of the general formula (I-7) 35 from the oxazole compound (21) in Step 1-7; a method of preparing a compound of the general formula (I-8) from the ester compound (3) and ammonia, an ammonium salt or (III-7) formamide in Step 1-8; and a method of preparing a com pound of the general formula (I-8) from the oxazole com 40 pound (21) in Step 1-9. Preparation of Compound of General Formula (I-6) or Compound of General Formula (I-7) The compound of the general formula (I-6) or the com (III-8) pound of the general formula (I-7) can be prepared from a 45 compound of the general formula (I-9) by intramolecular cyclization reaction according to Step 1-6. Specifically, Step 1-6 as an intramolecular cyclization reaction may employ a known method described in many documents such as N-alkylation reaction (see The Journal of Organic Chemis 50 try, 1977, vol. 42, p. 3925, for example). The compound can is a partial structure corresponding to the above-described also be prepared from an oxazole compound (21) by intra Het, molecular cyclization reaction according to Step 1-7. Spe wherein Art, Ar and X are as defined above; Xs, X, Yo cifically, Step 1-7 may employ a method of forming a and Y are the same or different and each represent a carbon triazole or imidazole ring and cyclizing the second ring at 55 the same time in the presence or absence of a nitrogen atom atom, a nitrogenatom or a sulfur atom; R', R'' and R'' are source (see The Chemistry of Heterocyclic Compounds. the same or different and represent groups selected from the Imidazole and Derivatives, Part I, p. 33, Inters. Publish. above Substituent Group A1 which may optionally form a 1953, for example). ring; L represents a halogen atom such as a chlorine atom, Step 1-6 is preferably, for example, a method of stirring a bromine atom or an iodine atom, a Sulfonate group Such as 60 a compound of the general formula (I-9), wherein X is a methanesulfonate group, a p-toluenesulfonate group or a —CR'=CR'— and R' represents a C1-6 alkyl group trifluoromethanesulfonate group, or a hydroxyl group: La Substituted with a halogen atom or a C1-6 alkoxy group represents a halogen atom such as a chlorine atom, a substituted with a halogen atom, or R' represents a C1-6 bromine atom or an iodine atom, a Sulfonate group Such as alkyl group (wherein the C1-6 alkyl group is substituted a methanesulfonate group, a p-toluenesulfonate group or a 65 with a halogen atom, a C1-6 alkoxy group Substituted with trifluoromethanesulfonate group, a boronic acid group or a a halogen atom or a C1-6 alkylamino group Substituted with boronate group Such as a boronic acid pinacol ester group; a halogen atom), in a solvent in the presence of 1.0 to 10.0 US 9,453,000 B2 33 34 equivalents of a base with respect to the compound of the nitrogen source, for example. The compound can also be general formula (I-9). The base used varies according to the prepared from an oxazole compound (21) according to Step starting material and is not particularly limited. Preferable 1-9 using ammonia, an ammonium salt or formamide as a examples of the base include alkali metal hydrides (such as nitrogen source, for example. Specifically, Step 1-8 or Step sodium hydride and lithium hydride), alkali metal salts (such 1-9 varies according to the starting material and is not as potassium carbonate, sodium carbonate and cesium car particularly limited insofar as the conditions are similar to bonate), metal alkoxides (such as sodium methoxide and those in this reaction. A known method described in many tert-butyl potassium) and organometallic salts (such as documents may be used for the reaction (see The Chemistry lithium diisopropyl amide and lithium hexamethyldisila of Heterocyclic Compounds. Imidazole and Derivatives, Zane). The solvent used varies according to the starting 10 Part I, p. 33, Inters. Publish. 1953, for example). The material, and is not particularly limited insofar as the solvent reaction is preferably a method of stirring an ester com does not inhibit the reaction and allows the starting material pound (3) or an oxazole compound (21) and 1.0 to 100.0 to be dissolved therein to a certain extent. Preferable equivalents of ammonia or an ammonium salt such as examples of the solvent include ether solvents such as ammonium acetate with respect to the ester compound (3) or tetrahydrofuran, 1.4-dioxane and diethyl ether, halogenated 15 the oxazole compound (21) in a solvent, for example. The Solvents such as methylene chloride, 1,2-dichloroethane and solvent used is not particularly limited insofar as the solvent chloroform; polar solvents such as N,N-dimethylformamide does not inhibit the reaction and allows the starting material and N-methylpyrrolidone; nonpolar solvents such as toluene to be dissolved therein to a certain extent. Preferable and benzene; and a mixture thereof. The reaction tempera examples of the solvent include nonpolar solvents such as ture must be a temperature that can complete the reaction toluene and benzene, alcohol solvents such as methanol and without promoting formation of an undesirable by-product, ethanol; organic acids such as acetic acid; water, and a and is preferably -78° C. to 200° C., for example. Under mixture thereof. Formamide may optionally be used as a preferable reaction conditions, the reaction is completed in nitrogen atom source and a solvent. The reaction tempera 1 to 24 hours, and the progress of the reaction can be ture must be a temperature that can complete the reaction monitored by a known chromatography technique. An unde 25 without promoting formation of an undesirable by-product, sirable by-product can be removed by a technique known to and is preferably room temperature to 250° C., for example. a person skilled in the art Such as a conventional chroma The yield may be improved when the reaction is performed tography technique, extraction or/and crystallization. using a tight container. Under preferable reaction conditions, Step 1-7 is preferably, for example, a method of stirring the reaction is completed in 1 to 24 hours, and the progress an oxazole compound (21), wherein X is —CR'=CR'— 30 of the reaction can be monitored by a known chromatogra and R' represents a C1-6 alkyl group substituted with a phy technique. An undesirable by-product can be removed halogen atom or a C1-6 alkoxy group substituted with a by a technique known to a person skilled in the art such as halogen atom, or R' represents a C1-6 alkyl group (wherein a conventional chromatography technique, extraction or/and the C1-6 alkyl group is Substituted with a halogen atom, a crystallization. C1-6 alkoxy group Substituted with a halogen atom or a 35 Preparation of Compound of General Formula (I-4) C1-6 alkylamino group Substituted with a halogen atom), in The compound of the general formula (I-4) can be pre a solvent in the presence of 1.0 to 100 equivalents of pared by reacting a compound of the general formula (I-9) ammonia or an ammonium salt such as ammonium acetate with a compound of the general formula (2b) according to with respect to the oxazole compound (21). Step 1-7 may Step 1-3. Specifically, Step 1-3 may employ a known also be a method of stirring an oxazole compound (21), 40 method described in many documents such as N-alkylation wherein X is –CR'—CR'— and R' represents a C1-6 reaction (see The Journal of Organic Chemistry, 1977, vol. alkyl group Substituted with an amino group or a C1-6 42, p. 3925, for example) or N-arylation reaction (see The alkoxy group Substituted with an amino group, or R' Journal of Organic Chemistry, 2001, vol. 66, p. 7892; represents a C1-6 alkyl group (wherein the C1-6 alkyl group Journal of Medicinal Chemistry, 1981, Vol. 24, p. 1139; or is substituted with an amino group, a C1-6 alkoxy group 45 Journal of Medicinal Chemistry, 1991, vol.39, p. 2671, for Substituted with an amino group or a C1-6 alkylamino group example). Substituted with an amino group), in a solvent. The solvent N-alkylation reaction is preferably, for example, a method used is not particularly limited insofar as the solvent does of stirring a compound of the general formula (I-9) and 1.0 not inhibit the reaction and allows the starting material to be to 10.0 equivalents of a compound (2b), wherein L. repre dissolved therein to a certain extent. Preferable examples of 50 sents a halogen atom such as a chlorine atom, a bromine the solvent include nonpolar solvents such as toluene and atom or an iodine atom or a Sulfonate group Such as a benzene: alcohol solvents such as methanol and ethanol: methanesulfonate group, a p-toluenesulfonate group or a organic acids such as acetic acid; water, and a mixture trifluoromethanesulfonate group, with respect to the com thereof. The reaction temperature must be a temperature that pound of the general formula (I-9) in a solvent in the can complete the reaction without promoting formation of 55 presence of 1.0 to 10.0 equivalents of a base with respect to an undesirable by-product, and is preferably room tempera the compound of the general formula (I-9). The base used ture to 250° C., for example. Under preferable reaction varies according to the starting material and is not particu conditions, the reaction is completed in 1 to 24 hours, and larly limited. Preferable examples of the base include alkali the progress of the reaction can be monitored by a known metal hydrides (such as sodium hydride and lithium chromatography technique. An undesirable by-product can 60 hydride), alkali metal salts (such as potassium carbonate, be removed by a technique known to a person skilled in the Sodium carbonate and cesium carbonate) and metal alkox art such as a conventional chromatography technique, ides (such as Sodium methoxide and potassium tert-butox extraction or/and crystallization. ide). The solvent used varies according to the starting Preparation of Compound of General Formula (I-8) material, and is not particularly limited insofar as the solvent The compound of the general formula (I-8) can be pre 65 does not inhibit the reaction and allows the starting material pared from an ester compound (3) according to Step 1-8 to be dissolved therein to a certain extent. Preferable using ammonia, an ammonium salt or formamide as a examples of the solvent include ether solvents such as US 9,453,000 B2 35 36 tetrahydrofuran, 1.4-dioxane and diethyl ether, halogenated the general formula (I-9). The base used varies according to Solvents such as methylene chloride, 1,2-dichloroethane and the starting material, the solvent used and the like, and is not chloroform; polar solvents such as N,N-dimethylformamide particularly limited insofar as the base does not inhibit the and N-methylpyrrolidone; nonpolar solvents such as toluene reaction. Preferable examples of the base include organic and benzene; and a mixture thereof. The reaction tempera 5 bases such as triethylamine, pyridine and tetramethylethyl ture must be a temperature that can complete the reaction enediamine; alkali metal salts such as potassium carbonate, without promoting formation of an undesirable by-product, Sodium carbonate, potassium acetate, Sodium acetate and and is preferably 0° C. to 200° C., for example. Under cesium carbonate; and metal alkoxides such as sodium preferable reaction conditions, the reaction is completed in methoxide and potassium tert-butoxide. The copper reagent 1 to 24 hours, and the progress of the reaction can be 10 monitored by a known chromatography technique. An unde used varies according to the starting material and is not sirable by-product can be removed by a technique known to particularly limited. Preferable examples of the copper a person skilled in the art Such as a conventional chroma reagent include copper acetate and di-B-hydroxo-bis(N.N. tography technique, extraction or/and crystallization. N',N'-tetramethylethylenediamine)copper(II) chloride. The N-arylation reaction may be i) Ullmann reaction, ii) a 15 Solvent used varies according to the starting material, the coupling reaction of an arylboronic acid derivative using a reagent and the like, and is not particularly limited insofar as copper compound or iii) nucleophilic Substitution reaction. the solvent does not inhibit the reaction and allows the In the case of i) Ullmann reaction, there are no specific starting material to be dissolved therein to a certain extent. limitations to the reaction conditions. Ullmann reaction is Preferable examples of the solvent include ether solvents preferably, for example, a method of stirring a compound of Such as tetrahydrofuran, 1.4-dioxane and diethyl ether; halo the general formula (I-9) and 1.0 to 10.0 equivalents of a genated solvents such as methylene chloride, 1,2-dichlo compound (2b), wherein L2 represents a halogen atom Such roethane and chloroform; polar solvents such as ethyl as a chlorine atom, a bromine atom or an iodine atom, with acetate, N,N-dimethylformamide and N-methylpyrrolidone: respect to the compound of the general formula (I-9) in a nonpolar solvents such as toluene, benzene and dichloroben solvent in the presence of 0.01 to 1.0 equivalent of a copper 25 Zene; and a mixture thereof. The reaction temperature must reagent Such as copper, copper bromide or copper iodide be a temperature that can complete the reaction without with respect to the compound of the general formula (I-9) promoting formation of an undesirable by-product, and is with 1.0 to 10.0 equivalents of a base added with respect to preferably room temperature to 200° C., for example. Good the compound of the general formula (I-9). The base used results such as reduction in the reaction time and improve varies according to the starting material and is not particu 30 larly limited. Preferable examples of the base include alkali ment of the yield can be achieved when the reaction is metal salts (such as potassium carbonate, sodium carbonate, performed in an oxygen atmosphere or air stream. Under potassium acetate, Sodium acetate and cesium carbonate) preferable reaction conditions, the reaction is completed in and metal alkoxides (such as sodium methoxide and potas 1 to 24 hours, and the progress of the reaction can be sium tert-butoxide). The solvent used varies according to the 35 monitored by a known chromatography technique. An unde starting material, the reagent and the like, and is not par sirable by-product can be removed by a technique known to ticularly limited insofar as the solvent does not inhibit the a person skilled in the art such as a conventional chroma reaction and allows the starting material to be dissolved tography technique, extraction or/and crystallization. therein to a certain extent. Preferable examples of the In iii) nucleophilic Substitution reaction, a compound of Solvent include ether solvents such as tetrahydrofuran, 1.4- 40 the general formula (I-9) and 2.0 to 5.0 equivalents of a dioxane and diethyl ether, halogenated Solvents such as compound (2b), wherein L2 represents a halogen atom Such methylene chloride, 1,2-dichloroethane and chloroform: as a chlorine atom, a bromine atom or an iodine atom or a alcohol solvents such as amyl alcohol and isopropyl alcohol; Sulfonate group Such as a methanesulfonate group, a p-tolu polar solvents such as N,N-dimethylformamide and N-meth enesulfonate group or a trifluoromethanesulfonate group, ylpyrrolidone; nonpolar solvents such as toluene, benzene 45 with respect to the compound of the general formula (I-9) and dichlorobenzene; and a mixture thereof. The reaction are preferably stirred in a solvent in the presence or absence temperature must be a temperature that can complete the of 1.0 to 5.0 equivalents of a base with respect to the reaction without promoting formation of an undesirable compound of the general formula (I-9), for example. The by-product, and is preferably room temperature to 200° C. base used varies according to the starting material and is not for example. Under preferable reaction conditions, the reac 50 particularly limited. Preferable examples of the base include tion is completed in 1 to 24 hours, and the progress of the Sodium hydride, Sodium hydroxide, potassium hydroxide, reaction can be monitored by a known chromatography potassium carbonate, Sodium carbonate, cesium carbonate, technique. An undesirable by-product can be removed by a barium carbonate, pyridine, lutidine and triethylamine. The technique known to a person skilled in the art such as a Solvent used varies according to the starting material, and is conventional chromatography technique, extraction or/and 55 not particularly limited insofar as the solvent does not inhibit crystallization. the reaction and allows the starting material to be dissolved The ii) coupling reaction of an arylboronic acid derivative therein to a certain extent. Preferable examples of the using a copper compound is preferably, for example, a solvent include acetonitrile, tetrahydrofuran, dimethyl sul method of stirring a compound of the general formula (I-9) foxide, N,N-dimethylformamide and N-methylpyrrolidine. and 1.0 to 10.0 equivalents of a compound (2b), wherein L. 60 The base may optionally be used as a solvent. The reaction represents a boronic acid group or a boronate group Such as temperature must be a temperature that can complete the a boronic acid pinacol ester group, with respect to the reaction without promoting formation of an undesirable compound of the general formula (I-9) in a solvent in the by-product, and is preferably room temperature to 150° C. presence of 0.01 to 1.0 equivalent of a copper reagent Such for example. Under preferable reaction conditions, the reac as copper, copper bromide or copper iodide with respect to 65 tion is completed in 1 to 24 hours, and the progress of the the compound of the general formula (I-9) with 1.0 to 10.0 reaction can be monitored by a known chromatography equivalents of a base added with respect to the compound of technique. An undesirable by-product can be removed by a US 9,453,000 B2 37 38 technique known to a person skilled in the art such as a Preparation of Ester Compound (3) conventional chromatography technique or/and crystalliza The ester compound (3) is prepared by condensation tion. reaction of a carboxylic acid compound (1) with a com The compound of the general formula (I-4) can be pre pound (2a) according to Step 1-1. Specifically, Step 1-1 pared by reacting an oxazole compound (21) with an amine varies according to the starting material and is not particu compound (22) according to Step 1-5. Specifically, Step 1-5 larly limited insofar as the conditions are similar to those in varies according to the starting material and is not particu this reaction. A known method described in many docu larly limited insofar as the conditions are similar to those in ments may be used for the reaction. Preferable examples of this reaction. A known method described in many docu the reaction include i) nucleophilic substitution reaction of a ments may be used for the reaction (see Heterocyclic Com 10 carboxylic acid compound (1) with a compound (2a). pounds, vol. 5, Wiley, New York, N.Y. 1950, p. 214, for wherein L. represents a halogen atom such as a chlorine example). Preferably, an oxazole compound (21) and 1.0 to atom, a bromine atom or an iodine atom or a Sulfonate group 100.0 equivalents of an amine compound (22) with respect Such as a methanesulfonate group, a p-toluenesulfonate to the oxazole compound (21) are stirred in a solvent, for group or a trifluoromethanesulfonate group (see Shin Jikken example. The solvent used is not particularly limited insofar 15 Kagaku Koza (New Courses in Experimental Chemistry), as the solvent does not inhibit the reaction and allows the vol. 22, Yuki Gosei (Organic Synthesis) IV, edited by The starting material to be dissolved therein to a certain extent. Chemical Society of Japan, Maruzen Co., Ltd., November Preferable examples of the solvent include ether solvents 1992, p. 49-50, for example) and ii) dehydration condensa Such as tetrahydrofuran, 1.4-dioxane and diethyl ether; halo tion reaction of a carboxylic acid compound (1) with a genated solvents such as methylene chloride, 1,2-dichlo compound (2a) (see Shin Jikken Kagaku Koza (New roethane and chloroform; alcohol solvents such as amyl Courses in Experimental Chemistry), vol. 22, Yuki Gosei alcohol and isopropyl alcohol; polar solvents such as N.N- (Organic Synthesis) IV, edited by The Chemical Society of dimethylformamide and N-methylpyrrolidone; nonpolar Japan, Maruzen Co., Ltd., November 1992, p. 43-47, for Solvents such as toluene, benzene and dichlorobenzene: example). organic acids such as acetic acid; water, and a mixture i) Nucleophilic substitution reaction is preferably, for thereof. The amine compound (22) to be reacted may be 25 example, a method of stirring a carboxylic acid compound used as a solvent. The reaction temperature must be a (1) and 1.0 to 10.0 equivalents of a compound (2a) with temperature that can complete the reaction without promot respect to the carboxylic acid compound (1) in a solvent in ing formation of an undesirable by-product, and is prefer the presence of 1.0 to 10.0 equivalents of a base with respect ably room temperature to 200° C., for example. Under to the carboxylic acid compound (1). The base used varies preferable reaction conditions, the reaction is completed in 30 according to the starting material and is not particularly 1 to 24 hours, and the progress of the reaction can be limited. Preferable examples of the base include alkali metal monitored by a known chromatography technique. An unde hydroxides such as sodium hydroxide and lithium hydrox sirable by-product can be removed by a technique known to ide; alkali metal carbonates Such as sodium carbonate; alkali a person skilled in the art Such as a conventional chroma metal salts of alcohols such as Sodium methoxide and tography technique, extraction or/and crystallization. potassium tert-butoxide; organic bases such as triethylam Preparation of Compound of General Formula (I-9) 35 ine, pyridine and diazabicyclononene; organic metals such The compound of the general formula (I-1) can be pre as butyl lithium and lithium diisobutylamide; alkali metal pared from an ester compound (3) according to Step 1-2 hydrides such as sodium hydride; and alkali metal ammo using ammonia, an ammonium salt or formamide as a nium salts such as Sodium amide. The solvent used varies nitrogen atom source, for example. Specifically, Step 1-2 according to the starting material and the base used, and is varies according to the starting material and is not particu 40 not particularly limited insofar as the solvent does not inhibit larly limited insofar as the conditions are similar to those in the reaction and allows the starting material to be dissolved this reaction. A known method described in many docu therein to a certain extent. Preferable examples of the ments may be used for the reaction (see The Chemistry of Solvent include polar solvents such as nitromethane, acetoni Heterocyclic Compounds. Imidazole and Derivatives, Part I, trile, 1-methyl-2-pyrrolidone, N,N-dimethylformamide and p. 33. Inters. Publish. 1953, for example). The reaction is 45 dimethyl sulfoxide; ether solvents such as tetrahydrofuran, preferably a method of stirring an ester compound (3) and 1,4-dioxane and 1,2-dimethoxyethane; nonpolar solvents 1.0 to 100.0 equivalents of ammonia or an ammonium salt Such as benzene, toluene and Xylene; alcohol solvents such Such as ammonium acetate with respect to the ester com as ethanol and methanol; halogenated Solvents such as pound (3) in a solvent, for example. The solvent used is not chloroform and methylene chloride; water; and a mixed particularly limited insofar as the solvent does not inhibit the 50 solvent thereof. The reaction temperature must be a tem reaction and allows the starting material to be dissolved perature that can complete the reaction without promoting therein to a certain extent. Preferable examples of the formation of an undesirable by-product, and is preferably Solvent include nonpolar solvents such as toluene and ben -78 to 150° C., for example. Under preferable reaction Zene; alcohol Solvents such as methanol and ethanol; organic conditions, the reaction is completed in 1 to 24 hours, and acids such as acetic acid; water; and a mixture thereof. the progress of the reaction can be monitored by a known Formamide may optionally be used as a nitrogen atom 55 chromatography technique. An undesirable by-product can Source and a solvent. The reaction temperature must be a be removed by a technique known to a person skilled in the temperature that can complete the reaction without promot art such as a conventional chromatography technique, ing formation of an undesirable by-product, and is prefer extraction or/and crystallization. ably room temperature to 250° C., for example. The yield ii) Dehydration condensation reaction is preferably, for may be improved when the reaction is performed using a 60 example, a method of stirring a carboxylic acid compound tight container. Under preferable reaction conditions, the (1) and 1.0 to 10.0 equivalents of a compound (2a) with reaction is completed in 1 to 24 hours, and the progress of respect to the carboxylic acid compound (1) in a solvent in the reaction can be monitored by a known chromatography the presence of 0.1 to 10.0 equivalents of a condensing agent technique. An undesirable by-product can be removed by a with respect to the carboxylic acid compound (1). The technique known to a person skilled in the art such as a 65 condensing agent used varies according to the starting conventional chromatography technique, extraction or/and material and is not particularly limited. Preferable examples crystallization. of the condensing agent include inorganic acids such as US 9,453,000 B2 39 40 hydrochloric acid and Sulfuric acid; organic acids such as Solvents such as methanol and ethanol; organic acids such as p-toluenesulfonic acid and methanesulfonic acid; and 1.3- acetic acid; water, and a mixture thereof. Formamide may dicyclohexylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopro optionally be used as a nitrogen atom source and a solvent. pyl)carbodiimide, benzotriazol-1-yloxytris(dimethylamino) The reaction temperature must be a temperature that can phosphonium hexafluorophosphate, diethyl complete the reaction without promoting formation of an cyanophosphonate, bis(2-oxo-3-oxazolidinyl)phosphonic undesirable by-product, and is preferably room temperature chloride and diphenylphosphoryl azide. Preferably, 1.0 to to 250° C., for example. The yield may be improved when 5.0 equivalents of N-hydroxysuccinimide, N-hydroxyben the reaction is performed using a tight container. Under Zotriazole or dimethylaminopyridine may be added in order preferable reaction conditions, the reaction is completed in to make the reaction efficiently proceed, for example. The 10 1 to 24 hours, and the progress of the reaction can be Solvent used varies according to the starting material and the monitored by a known chromatography technique. An unde condensing agent used, and is not particularly limited inso sirable by-product can be removed by a technique known to far as the solvent does not inhibit the reaction and allows the a person skilled in the art such as a conventional chroma starting material to be dissolved therein to a certain extent. tography technique, extraction or/and crystallization. Preferable examples of the solvent include halogenated 15 Preparation of Compound (2b) Solvents such as chloroform, methylene chloride and 1.2- The compound (2b) is commercially available or can be dichloroethane; polar solvents such as tetrahydrofuran and N,N-dimethylformamide; and a mixed solvent thereof. The prepared by a method known to a person skilled in the art reaction temperature must be a temperature that can com (see Shin Jikken Kagaku Koza (New Courses in Experi plete the reaction without promoting formation of an unde mental Chemistry), vol. 19, Yuki Gosei (Organic Synthesis) sirable by-product, and is preferably ice-cold temperature to I, edited by The Chemical Society of Japan, Maruzen Co., 150° C., for example. Under preferable reaction conditions, Ltd., September 1992, p. 363-482; and Shin Jikken Kagaku the reaction is completed in 1 to 24 hours, and the progress Koza (New Courses in Experimental Chemistry), vol. 24. of the reaction can be monitored by a known chromatogra Yuki Gosei (Organic Synthesis) VII, edited by The Chemi phy technique. An undesirable by-product can be removed cal Society of Japan, Maruzen Co., Ltd., June 1992, p. by a technique known to a person skilled in the art such as 25 61-90, for example). a conventional chromatography technique or/and crystalli Preparation of Compound (22) Zation. The compound (22) is commercially available or can be Preparation of Oxazole Compound (21) prepared by a method known to a person skilled in the art The oxazole compound (21) can be prepared by reacting (see Shin Jikken Kagaku Koza (New Courses in Experi an ester compound (3) with ammonia, an ammonium salt or 30 mental Chemistry), vol. 20, Yuki Gosei (Organic Synthesis) formamide as a nitrogen atom source according to Step 1-4. II, edited by The Chemical Society of Japan, Maruzen Co., for example. Specifically, Step 1-4 varies according to the Ltd., July 1992, p. 279-372, for example). starting material and is not particularly limited insofar as the Preparation of Compound (2a) conditions are similar to those in this reaction. A known The compound (2a) is commercially available or can be method described in many documents may be used for the 35 prepared by a method known to a person skilled in the art reaction (see Synthesis, 1998, vol. 9, p. 1298, for example). (see Shin Jikken Kagaku Koza (New Courses in Experi Preferably, an ester compound (3) and 1.0 to 100.0 equiva mental Chemistry), vol. 19, Yuki Gosei (Organic Synthesis) lents of ammonia or an ammonium salt such as ammonium I, edited by The Chemical Society of Japan, Maruzen Co., acetate with respect to the ester compound (3) are stirred in Ltd., September 1992, p. 363-482; and Shin Jikken Kagaku a solvent, for example. The Solvent used is not particularly 40 Koza (New Courses in Experimental Chemistry), vol. 20. limited insofar as the solvent does not inhibit the reaction Yuki Gosei (Organic Synthesis) II, edited by The Chemical and allows the starting material to be dissolved therein to a Society of Japan, Maruzen Co., Ltd., July 1992, p. 1-110, for certain extent. Preferable examples of the solvent include example). nonpolar solvents such as toluene and benzene, alcohol Preparation of Carboxylic Acid Compound (1)

Formula 32 O O W Step 2-1 Step 2-4 L3 -- - W-H (9) GO-K

(10) (4) (5) (6) Step 2-5 O O Step 2-10 -- y ( HN L Step 2-7 R13 OV 2 Aeolicoi (11) (13) ii) L5 O Step 2-6 ) ( O

Step 2-8 R 14 R15 ls He ON L4. Step 2-8 iii) AcONH,(14) AcOH G) (D-x. OV Step 2-3) G GD X-CO2H (12) US 9,453,000 B2 41 42 -continued Step 2-11 R26 G)"Step 2-9 GD (D-1, S O -- R13 OV (15) (16) (17) (18a)

OV

In the formula, Ari, Ars, R' and X are as defined above; does not inhibit the reaction and allows the starting material V represents a protecting group for a carboxylic group Such to be dissolved therein to a certain extent. Preferable as a methyl group, an ethyl group, a benzyl group, an allyl examples of the solvent include alcohol solvents such as group, a triphenylmethyl group, a tert-butyl group or a methanol, ethanol and ethylene glycol, ether solvents such tert-butyldimethylsilyl group; L and Le each represent a as tetrahydrofuran; halogenated solvents such as dichlo hydrogen atom, a halogen atom Such as a fluorine atom, a romethane and chloroform; water, and a mixed solvent chlorine atom, a bromine atom or an iodine atom, a Sulfonate 25 thereof. In the case of acid hydrolysis, an organic acid Such group Such as a trifluoromethanesulfonate group, a trialky as acetic acid or formic acid may be used as a solvent. The ltin group or a leaving group Such as a boronic acid or reaction temperature must be a temperature that can com boronate group: La represents a formyl group, an alkanoyl plete the reaction without promoting formation of an unde group such as an acetyl group, an alkoxycarbonyl group sirable by-product, and is preferably room temperature to Such as a methyl ester group, a halogen atom such as a 30 100° C., for example. Under preferable reaction conditions, fluorine atom, a chlorine atom, a bromine atom or an iodine the reaction is completed in 1 to 24 hours, and the progress atom, a sulfonate group such as a trifluoromethanesulfonate of the reaction can be monitored by a known chromatogra group, a trialkyltin group or a boronic acid or boronate phy technique. An undesirable by-product can be removed group; Ls represents a halogen atom Such as a fluorine atom, by a technique known to a person skilled in the art Such as a chlorine atom, a bromine atom or an iodine atom or a 35 a conventional chromatography technique or/and crystalli Sulfonate group Such as a trifluoromethanesulfonate group; Zation. W represents a phosphate group Such as a diethylphosphonyl Preparation of Ester Compound (8) group, a diphenylphosphonyl group or a bis(2.2.2-trifluoro The ester compound (8) can be prepared as shown by the ethyl)phosphonyl group, a phosphonium salt such as triph above reaction formula, but the preparation is not limited enylphosphonium bromide or a silyl group Such as a trim 40 thereto. Specifically, the ester compound (8) can be prepared ethylsilyl group; R is as defined for the R'; R' is as by reacting a compound (4) with a compound (5) in Step 2-1 defined for the R; and R'' and R' each represent a C1-6 to obtain a carbonyl compound (6) and then condensing the alkyl group. carbonyl compound (6) by condensation reaction Such as The carboxylic acid compound (1) is prepared by hydro Horner-Emmons reaction, Wittig reaction or Peterson reac lysis of an ester compound (8) according to Step 2-3. 45 tion in Step 2-2, for example. Alternatively, the ester com Specifically, Step 2-3 varies according to the starting mate pound (8) can be prepared by Subjecting a carbonyl com rial and is not particularly limited insofar as the conditions pound (6) as a starting material to Step 2-4 to prepare a are similar to those in this reaction. A known method compound (10) and condensing the compound (10) with a described in many documents may be used for the reaction compound (11) by condensation reaction Such as Horner (see Shin Jikken Kagaku Koza (New Courses in Experi 50 Emmons reaction, Wittig reaction or Peterson reaction in mental Chemistry), Vol. 22, Yuki Gosei (Organic Synthesis) Step 2-5. Alternatively, the ester compound (8) can be IV, edited by The Chemical Society of Japan, Maruzen prepared by forming Art in a compound (17) from an amino Co., Ltd., November 1992, p. 6-11, for example). Preferably, compound (13) as a starting material through three-stage an ester compound (8) is stirred in a solvent in the presence reaction in Step 2-7 and then performing coupling reaction of 1.0 to 100.0 equivalents of a base or acid with respect to 55 of the compound (17) with a compound (18a) or compound the ester compound (8), for example. The base used varies (18b) according to Step 2-11. The ester compound (8) can according to the starting material and is not particularly also be prepared by converting a compound (15) as a starting limited. Preferable examples of the base include sodium material into a compound (17) according to Step 2-9 and hydride, Sodium hydroxide, potassium hydroxide, potassium then subjecting the compound (17) to Step 2-11. carbonate, sodium carbonate, cesium carbonate and barium 60 Conversion of Carbonyl Compound (6) into Ester Com carbonate. The acid used varies according to the starting pound (8) and Conversion of Compound (10) into Ester material and is not particularly limited. Preferable examples Compound (8) of the acid include inorganic acids such as hydrochloric acid A carbonyl compound (6) can be converted into the ester and Sulfuric acid; organic acids such as trifluoroacetic acid compound (8) and a compound (10) can be converted into and p-toluenesulfonic acid; and Lewis acids such as boron 65 the ester compound (8) by a method known to a person trichloride. The solvent used varies according to the starting skilled in the art. For example, the ester compound (8) can material, and is not particularly limited insofar as the solvent be prepared from a carbonyl compound (6) and a compound US 9,453,000 B2 43 44 (7) according to Step 2-2. Alternatively, the ester compound method of adding a base in the presence of a compound (7) (8) can be prepared from a compound (10) and a compound or compound (10) and a carbonyl compound (6) or a (11) according to Step 2-5. Specifically, coupling reaction in compound (11). This reaction is preferably performed in the Step 2-2 or Step 2-5 varies according to the starting material presence of a solvent from the viewpoint of handleability and is not particularly limited insofar as the conditions are and stirring efficiency. The solvent used varies according to similar to those in this reaction. A method known to a person the starting material and the base used, and is not particu skilled in the art may be used for the reaction. Preferable larly limited insofar as the solvent does not inhibit the examples of the method include Wittig reaction, Horner reaction and allows the starting material to be dissolved Emmons reaction and Peterson reaction (see Shin Jikken therein to a certain extent. Preferable examples of the Kagaku Koza (Courses in Experimental Chemistry), vol. 19, 10 Solvent include polar solvents such as 1-methyl-2-pyrroli Yuki Gosei (Organic Synthesis) II, edited by The Chemical done, N,N-dimethylformamide and dimethyl sulfoxide: Society of Japan, Maruzen Co., Ltd., June 1992, p. 57-85, ether solvents such as tetrahydrofuran, 1.4-dioxane and for example). 1.2-dimethoxyethane; nonpolar solvents such as benzene, In Wittig reaction, a compound (7) or compound (10), toluene and Xylene; alcohol solvents such as ethanol and wherein W represents a phosphonium salt, and 0.5 to 2.0 15 methanol; water; and a mixed solvent thereof. The base used equivalents of a carbonyl compound (6) or a compound (11) varies according to the starting material and the solvent. with respect to the compound (7) or compound (10) are Preferable examples of the base include alkali metal hydrox preferably stirred in a solvent in the presence of 1.0 to 5.0 ides such as sodium hydroxide and lithium hydroxide: alkali equivalents of a base with respect to the compound (7) or metal carbonates such as sodium carbonate; alkali metal compound (10), for example. This reaction may be a method salts of alcohols such as Sodium methoxide and potassium of first treating a compound (7) or compound (10) and a base tert-butoxide, organic bases such as triethylamine, pyridine to form a phosphorus ylide and then adding a carbonyl and diazabicyclononene; organic metals such as butyl compound (6) or a compound (11) to the ylide; or a method lithium and lithium diisobutylamide: alkali metal hydrides of adding a base in the presence of a compound (7) or Such as sodium hydride; and alkali metal ammonium salts compound (10) and a carbonyl compound (6) or a compound 25 Such as sodium amide. The reaction temperature must be a (11). This reaction is preferably performed in the presence of temperature that can complete the reaction without promot a solvent from the viewpoint of handleability and stirring ing formation of an undesirable by-product, and is prefer efficiency. The solvent used varies according to the starting ably -78 to 150° C., for example. Under preferable reaction material and the base used, and is not particularly limited conditions, the reaction is completed in 1 to 24 hours, and insofar as the solvent does not inhibit the reaction and allows 30 the progress of the reaction can be monitored by a known the starting material to be dissolved therein to a certain chromatography technique. An undesirable by-product can extent. Preferable examples of the solvent include polar be removed by a technique known to a person skilled in the Solvents such as nitromethane, acetonitrile, 1-methyl-2-pyr art such as a conventional chromatography technique, rolidone, N,N-dimethylformamide and dimethyl sulfoxide: extraction or/and crystallization. ether solvents such as tetrahydrofuran, 1.4-dioxane and 35 In Peterson reaction, a compound (7) or compound (10), 1.2-dimethoxyethane; nonpolar solvents such as benzene, wherein W represents a silyl group, and 0.5 to 2.0 equiva toluene and Xylene; alcohol solvents such as ethanol and lents of a carbonyl compound (6) or a compound (11) with methanol; halogenated solvents such as chloroform and respect to the compound (7) or compound (10) are prefer methylene chloride; water; and a mixed solvent thereof. The ably stirred in a solvent in the presence of 1.0 to 5.0 base used varies according to the starting material and the 40 equivalents of a base with respect to the compound (7) or solvent. Preferable examples of the base include alkali metal compound (10), for example. This reaction may be a method hydroxides such as sodium hydroxide and lithium hydrox of first treating a compound (7) or compound (10) and a base ide; alkali metal carbonates such as sodium carbonate; alkali to form a carbanion and then adding a carbonyl compound metal salts of alcohols such as Sodium methoxide and (6) or a compound (11) to the carbanion; or a method of potassium tert-butoxide; organic bases such as triethylam 45 adding a base in the presence of a compound (7) or com ine, pyridine and diazabicyclononene; organic metals such pound (10) and a carbonyl compound (6) or a compound as butyl lithium and lithium diisobutylamide; and alkali (11). This reaction is preferably performed in the presence of metal hydrides such as sodium hydride. The reaction tem a solvent from the viewpoint of handleability and stirring perature must be a temperature that can complete the reac efficiency. The solvent used varies according to the starting tion without promoting formation of an undesirable by 50 material and the base used, and is not particularly limited product, and is preferably -78 to 150° C., for example. insofar as the solvent does not inhibit the reaction and allows Under preferable reaction conditions, the reaction is com the starting material to be dissolved therein to a certain pleted in 1 to 24 hours, and the progress of the reaction can extent. Preferable examples of the solvent include polar be monitored by a known chromatography technique. An solvents such as 1-methyl-2-pyrrolidone, N,N-dimethylfor undesirable by-product can be removed by a technique 55 mamide and dimethyl sulfoxide; ether solvents such as known to a person skilled in the art Such as a conventional tetrahydrofuran, 1.4-dioxane and 1,2-dimethoxyethane; chromatography technique, extraction or/and crystallization. nonpolar solvents such as benzene, toluene and Xylene; In Horner-Emmons reaction, a compound (7) or com alcohol Solvents such as ethanol and methanol; water, and a pound (10), wherein Wrepresents a phosphite group, and 0.5 mixed solvent thereof. The base used varies according to the to 2.0 equivalents of a carbonyl compound (6) or a com 60 starting material and the solvent. Preferable examples of the pound (11) with respect to the compound (7) or compound base include alkali metal hydroxides such as Sodium hydrox (10) are preferably stirred in a solvent in the presence of 1.0 ide and lithium hydroxide; alkali metal carbonates Such as to 5.0 equivalents of a base with respect to the compound (7) Sodium carbonate; alkali metal salts of alcohols such as or compound (10), for example. This reaction may be a Sodium methoxide and potassium tert-butoxide; organic method of first treating a compound (7) or compound (10) 65 bases such as triethylamine, pyridine and diazabicyclonon and a base to form a carbanion and then adding a carbonyl ene; organic metals such as butyl lithium and lithium compound (6) or a compound (11) to the carbanion; or a disobutylamide; alkali metal hydrides such as sodium US 9,453,000 B2 45 46 hydride; and alkali metal ammonium salts such as sodium is completed in 1 to 24 hours, and the progress of the amide. The reaction temperature must be a temperature that reaction can be monitored by a known chromatography can complete the reaction without promoting formation of technique. an undesirable by-product, and is preferably -78 to 150° C. In Suzuki-Miyaura reaction, a halogen compound or for example. Under preferable reaction conditions, the reac trifluoromethanesulfonate compound (17), wherein La rep tion is completed in 1 to 24 hours, and the progress of the resents a chlorine atom, a bromine atom, an iodine atom or reaction can be monitored by a known chromatography a Sulfonate group Such as a trifluoromethanesulfonate group, technique. An undesirable by-product can be removed by a is preferably coupled with 1.0 to 5.0 equivalents of a boronic technique known to a person skilled in the art such as a acid compound or boronate compound (18a; wherein L is a conventional chromatography technique, extraction or/and 10 boronic acid or boronate group) with respect to the com crystallization. pound (17) in the presence of 0.01 to 0.5 equivalent of a Conversion of Compound (17) into Ester Compound (8) transition metal catalyst with respect to the compound (17), A compound (17) can be converted into the ester com for example. This reaction is preferably performed in the pound (8) by a method known to a person skilled in the art. presence of a solvent from the viewpoint of handleability The ester compound (8) can be prepared from a compound 15 and stirring efficiency. The solvent used varies according to (17) together with a compound (18a) or compound (18b) the starting material and the transition metal catalyst used, according to Step 2-11, for example. Specifically, the cou and is not particularly limited insofar as the solvent does not pling reaction in Step 2-11 varies according to the starting inhibit the reaction and allows the starting material to be material and is not particularly limited insofar as the con dissolved therein to a certain extent. Preferable examples of ditions are similar to those in this reaction. A method known the solvent include acetonitrile, tetrahydrofuran, 1.4-diox to a person skilled in the art may be used for the reaction. ane, 1,2-dimethoxyethane, benzene, toluene, Xylene, Preferable examples of the method include Mizoroki-Heck 1-methyl-2-pyrrolidone, N,N-dimethylformamide, water reaction (see R. F. Heck, “Org. Reactions.”. 1982, vol. 27, p. and a mixed solvent thereof. The reaction temperature must 345, for example), Suzuki-Miyaura reaction (see A. Suzuki, be a temperature that can complete the coupling reaction, “Chem. Rev., 1995, vol. 95, p. 2457, for example), Sono 25 and is preferably room temperature to 200°C. This reaction gashira reaction (see K. Sonogashira, "Comprehensive is performed preferably in an inert gas atmosphere, and more Organic Synthesis', 1991, vol. 3, p. 521) and Stille coupling preferably in a nitrogen or argon atmosphere. Under pref reaction (see J. K. Stille, “Angew. Chem. Int. Ed. Engl.”. erable reaction conditions, the reaction is completed in 1 to 1986, vol. 25, p. 508, for example). 24 hours, and the progress of the reaction can be monitored In Mizoroki-Heck reaction, a halogen compound or tri 30 by a known chromatography technique. The transition metal flate compound (17), wherein La represents a chlorine atom, catalyst is preferably a known palladium complex, and more a bromine atom, an iodine atom or a sulfonate group such as preferably a known palladium complex such as palladium a trifluoromethanesulfonate group, is preferably coupled (II) acetate, dichlorobis(triphenylphosphine)palladium (II), with 1.0 to 5.0 equivalents of an alkene compound (18a; tetrakis(triphenylphosphine)palladium (O), or tris(diben wherein L is a hydrogen atom) with respect to the com 35 Zylideneacetone)dipalladium (0). A phosphorus ligand (pref pound (17) in the presence of 0.01 to 0.2 equivalent of a erably triphenylphosphine, tri-o-tolylphosphine, tricyclo transition metal catalyst with respect to the compound (17), hexylphosphine, or tri-tert-butylphosphine, for example) for example. This reaction is preferably performed in the may be appropriately added in order to make the reaction presence of a solvent from the viewpoint of handleability efficiently proceed. A quaternary ammonium salt, preferably and stirring efficiency. The Solvent used varies according to 40 tetrabutylammonium chloride or tetrabutylammonium bro the starting material and the transition metal catalyst used, mide, for example, may also be appropriately added in order and is not particularly limited insofar as the solvent does not to make the reaction efficiently proceed. In this reaction, a inhibit the reaction and allows the starting material to be preferable result may be achieved in the presence of a base. dissolved therein to a certain extent. Preferable examples of The base used at this time varies according to the starting the solvent include acetonitrile, tetrahydrofuran, 1.4-diox 45 material, the solvent used and the like, and is not particularly ane, 1,2-dimethoxyethane, benzene, toluene, Xylene, limited. Preferable examples of the base include sodium 1-methyl-2-pyrrolidone and N,N-dimethylformamide. The hydroxide, barium hydroxide, potassium fluoride, cesium reaction temperature must be a temperature that can com fluoride, Sodium carbonate, potassium carbonate, cesium plete the coupling reaction, and is preferably room tempera carbonate and potassium phosphate. Under preferable reac ture to 150° C. This reaction is performed preferably in an 50 tion conditions, the reaction is completed in 1 to 24 hours, inert gas atmosphere, and more preferably in a nitrogen or and the progress of the reaction can be monitored by a argon atmosphere. The transition metal catalyst is preferably known chromatography technique. In this reaction, the a palladium complex, for example, and more preferably a desired ester compound (8) can be efficiently obtained even known palladium complex Such as palladium (II) acetate, when the compound (18a) is a halide or a trifluoromethane dichlorobis(triphenylphosphine)palladium (II), tetrakis(tri 55 Sulfonate compound, wherein Le is a chlorine atom, a phenylphosphine)palladium (O) or tris(dibenzylideneac bromine atom, an iodine atom or a trifluoromethanesul etone)dipalladium (O). It is also preferable to appropriately fonate group, for example, and the compound (17) is a add a phosphorus ligand (preferably triphenylphosphine, boronic acid compound or boronate compound, wherein La tri-o-tolylphosphine, tri-tert-butylphosphine or 2-(di-tert is a boronic acid or boronate group, for example. butylphosphino)biphenyl, for example) in order to make the 60 The reaction conditions in Sonogashira reaction vary reaction efficiently proceed. A preferable result may be according to the starting material, the Solvent and the achieved in the presence of a base. The base used is not transition metal catalyst, and are not particularly limited particularly limited insofar as the base is used in a coupling insofar as the conditions are similar to those in this reaction. reaction similar to this reaction. Preferable examples of the A method known to a person skilled in the art may be used base include triethylamine, N,N-diisopropylethylamine, 65 for the reaction. Preferably, a compound (17), wherein La N,N-dicyclohexylmethylamine and tetrabutylammonium represents a chlorine atom, a bromine atom, an iodine atom chloride. Under preferable reaction conditions, the reaction or a Sulfonate group Such as a trifluoromethanesulfonate US 9,453,000 B2 47 48 group, and 1.0 to 5.0 equivalents of an alkyne compound for example. Specifically, Step 2-1 varies according to the (18b) with respect to the compound (17) are stirred in a starting material and is not particularly limited insofar as the solvent, for example. Preferable examples of the solvent conditions are similar to those in this reaction. A method used include acetonitrile, tetrahydrofuran, 1.4-dioxane, 1.2- known to a person skilled in the art may be used for the dimethoxyethane, benzene, toluene, Xylene, 1-methyl-2-pyr reaction. For example, a compound (4) and 1.0 to 5.0 rolidone, N,N-dimethylformamide and dimethyl sulfoxide. equivalents of a compound (5) with respect to the compound More preferable examples of the solvent include tetrahy (4) are stirred in a solvent in the presence or absence of 1.0 drofuran, 1.4-dioxane, 1-methyl-2-pyrrolidone and N,N-di to 5.0 equivalents of a base with respect to the compound (4) methylformamide. The reaction temperature must be a tem (see D. D. Davey et al., “J. Med. Chem.”, 1991, vol.39, p. perature that can complete the coupling reaction, and is 10 preferably room temperature to 150° C. This reaction is 2671-2677). Preferable examples of the base used include performed preferably in an inert gas atmosphere, and more Sodium hydride, Sodium hydroxide, potassium hydroxide, preferably in a nitrogen or argon atmosphere. Under pref potassium carbonate, Sodium carbonate, cesium carbonate, erable reaction conditions, the reaction is completed in 1 to barium carbonate, pyridine, lutidine and triethylamine. The 24 hours, and the progress of the reaction can be monitored 15 Solvent used varies according to the starting material, and is by a known chromatography technique. The transition metal not particularly limited insofar as the solvent does not inhibit catalyst is preferably 0.01 to 0.5 equivalent with respect to the reaction and allows the starting material to be dissolved the compound (17) of a known palladium complex, and therein to a certain extent. Preferable examples of the more preferably a known palladium complex Such as pal solvent include acetonitrile, tetrahydrofuran, dimethyl sul ladium (II) acetate, dichlorobis(triphenylphosphine)palla foxide, N,N-dimethylformamide and N-methylpyrrolidine. dium (II), tetrakis(triphenylphosphine)palladium (O) or tris The base may optionally be used as a solvent. The reaction (dibenzylideneacetone)dipalladium (O). A phosphorus temperature must be a temperature that can complete the ligand (preferably triphenylphosphine, tri-o-tolylphosphine reaction without promoting formation of an undesirable or tri-tert-butylphosphine, for example) may be appropri by-product, and is preferably room temperature to 150° C. ately added, for example, in order to make the reaction 25 for example. Under preferable reaction conditions, the reac efficiently proceed. In the reaction, a metal halide or a tion is completed in 1 to 24 hours, and the progress of the quaternary ammonium salt, preferably copper (I) iodide, reaction can be monitored by a known chromatography lithium chloride, tetrabutylammonium fluoride or silver (I) technique. An undesirable by-product can be removed by a oxide, for example, may be added. A preferable result may technique known to a person skilled in the art Such as a beachieved in the presence of a base. The base used here is 30 conventional chromatography technique or/and crystalliza not particularly limited insofar as the base is used in a coupling reaction similar to this reaction. Preferable tion. examples of the base include basic solvents such as dieth The carbonyl compound (6) can also be prepared from a ylamine, triethylamine, N,N-diisopropylethylamine, piperi compound (17) as a starting material according to Step 2-10, dine and pyridine. 35 for example. Specifically, Step 2-10 varies according to the In Stille coupling reaction, a trialkyltin compound (17), starting material and is not particularly limited insofar as the wherein La represents an alkyltin group, and 1.0 to 5.0 conditions are similar to those in this reaction. A method equivalents of a halide or a trifluoromethanesulfonate com known to a person skilled in the art may be used for the pound (18a), wherein Le represents a chlorine atom, a reaction. For example, it is possible to use a two-stage bromine atom, an iodine atom or a trifluoromethanesul 40 method of converting a compound (17), wherein La repre fonate group, with respect to the compound (17) are pref sents a chlorine atom, a bromine atom, an iodine atom or a erably stirred in a solvent in the presence of 0.01 to 0.2 Sulfonate group Such as a trifluoromethanesulfonate group, equivalent of a transition metal catalyst with respect to the into a vinyl compound by Stille coupling reaction using 1.0 compound (17), for example. It is preferable to appropriately to 5.0 equivalents of a vinyltin compound with respect to the use 0.1 to 5.0 equivalents of copper (I) halide or/and lithium 45 compound (17) and then oxidizing the carboxylic acid by chloride in order to make the reaction efficiently proceed. ozone oxidation reaction (see S.S. Chandran et al., “Bioorg. Preferable examples of the solvent used in this reaction Med. Chem. Lett.”, 2001, vol. 11, p. 1493-1496, for include toluene, xylene, N,N-dimethylformamide, N,N-di example). It is also possible to use carbon monoxide inser methylacetamide, 1-methyl-2-pyrrolidone and dimethyl Sul tion reaction using a transition metal catalyst (see T. Okano foxide. The reaction temperature must be a temperature that 50 et al., “Bull. Chem. Soc. Jpn.”, 1994, vol. 67, p. 2329-2332, can complete the coupling reaction, and is preferably room for example). temperature to 150° C. The preferable transition metal Preparation of Compound (4) catalyst is a palladium complex, preferably a known palla The compound (4) is commercially available or can be dium complex Such as palladium (II) acetate, dichlorobis obtained by a technique known to a person skilled in the art. (triphenylphosphine)palladium (II), tetrakis(triphenylphos 55 If not commercially available, the preferable compound (4), phine)palladium (O) or tris(dibenzylideneacetone) wherein L. represents a fluorine atom, a chlorine atom or a dipalladium (O), for example, and more preferably tetrakis bromine atom, can be obtained by oxidizing a corresponding (triphenylphosphine)palladium (O) O tris alcohol compound by an oxidation reaction known to a (dibenzylideneacetone)dipalladium (O), for example. This person skilled in the art; or the carbonyl compound can be reaction is performed preferably in an inert gas atmosphere, 60 obtained by reducing a corresponding ester compound by a and more preferably in a nitrogen or argon atmosphere. known reduction reaction. Under preferable reaction conditions, the reaction is com Preparation of Compound (5) pleted in 1 to 24 hours, and the progress of the reaction can The compound (5) used in this step is commercially be monitored by a known chromatography technique. available or can be obtained by a technique known to a Preparation of Carbonyl Compound (6) 65 person skilled in the art. (see M. Komoto et al., “Agr. Biol. The carbonyl compound (6) can be prepared from a Chem.”, 1968, vol. 32, p. 983-987; or J. M. Kokosa et al., “J. compound (4) as a starting material according to Step 2-1, Org. Chem.”, 1983, vol. 48, p. 3605-3607, for example). US 9,453,000 B2 49 50 desired phosphonate compound (7) can be efficiently W O obtained by modification of R by a technique known to a L5 person skilled in the art. M + The alkyl halide compound (19a), phosphonate com R13 OV Step 3-1 pound (19b), phosphonic acid halide compound (19C), phos (19a) (20a) N phonate compound (20a), halogenated formate compound W O W O (20b) and ester compound (20c) used in this step are commercially available or can be obtained by a technique ) -- L5 ( ) ( known to a person skilled in the art. R13 OV Step 3-2 R13 OV 10 Preparation of Compound (10) (19b) (20b) (7) The compound (10) can be prepared from a compound (6) and a compound (9) according to Step 2-4. Specifically, Step O 2-4 varies according to the starting material and is not W -- 7-( / 3-3) particularly limited insofar as the conditions are similar to L5 R13 OV 15 those in this reaction. A method known to a person skilled in the art may be used for the reaction (see Journal of the (19c) (20c) American Chemistry, 1961, vol. 83, p. 173, for example). Preferably, a compound (6) and 1.0 to 10.0 equivalents of a In the formula R. W. Ls and V are as defined above. compound (9) with respect to the compound (6) are stirred The above reaction formula shows an example of a in a solvent in the presence of 1.0 to 10.0 equivalents of a method for preparing the phosphonate compound (7). Spe base with respect to the compound (6), for example. The cifically, the phosphonate compound (7) is commercially base used varies according to the starting material and is not available or can be obtained by a method shown in the above particularly limited. Preferable examples of the base include Step 3-1 to Step 3-3 and known to a person skilled in the art organic bases such as 1,8-diazabicyclo5.4.0-7-undecene 25 and diisopropylamine; and alkali metal salts such as potas (see C. Patois et al., “Synth. Commun., 1991, vol. 22, p. sium carbonate and Sodium carbonate. The solvent used 2391; or J. A. Jackson et al., “J. Org. Chem.”, 1989, vol. 20, varies according to the starting material, and is not particu p. 5556, for example). Step 3-1 is a step of obtaining the larly limited insofar as the solvent does not inhibit the desired phosphonate compound (7) by stirring a phospho reaction and allows the starting material to be dissolved nate compound (20a) and 1.0 to 2.0 equivalents of an alkyl 30 therein to a certain extent. Preferable examples of the halide compound (19a) with respect to the phosphonate solvent include hexane, toluene, diethyl ether, tetrahydro compound (20a) in a solvent in the presence of 1.0 to 1.5 furan, N,N-dimethylformamide, hexamethylphosphoric tri equivalents of a base with respect to the phosphonate amide and a mixed solvent thereof. The reaction temperature compound (20a) to introduce R, for example. Step 3-2 is must be a temperature that can complete the reaction without a step of obtaining the desired phosphonate compound (7) 35 promoting formation of an undesirable by-product, and is by stirring a phosphonate compound (19b) and 1.0 to 2.0 preferably -78° C. to 100° C. Under preferable reaction equivalents of a halogenated formate compound (20b) with conditions, the reaction is completed in 1 to 24 hours, and respect to the phosphonate compound (19b) in a solvent in the progress of the reaction can be monitored by a known the presence of 1.0 to 1.5 equivalents of a base with respect chromatography technique. An undesirable by-product can to the phosphonate compound (19b). Step 3-3 is a step of 40 be removed by a technique known to a person skilled in the obtaining the desired phosphonate compound (7) by Stirring art such as a conventional chromatography technique or/and a phosphonic acid halide compound (19c) and 1.0 to 2.0 crystallization. equivalents of an ester compound (20c) with respect to the Preparation of Compound (9) phosphonic acid halide compound (19C) in a solvent in the The compound (9) used in this step is commercially presence of 1.0 to 1.5 equivalents of a base with respect to 45 available or can be obtained by a technique known to a person skilled in the art. the phosphonic acid halide compound (19c). The base used Preparation of Compound (11) varies according to the starting material and is not particu The compound (11) used in this step is commercially larly limited. Preferable examples of the base include available or can be obtained by a technique known to a sodium hydride, n-butyl lithium, lithium diisopropylamide, 50 person skilled in the art. lithium bis(trimethylsilyl)amide and sodium bis(trimethyl Preparation of Amine Compound (13) silyl)amide. The solvent used varies according to the starting The amine compound (13) is commercially available or material, and is not particularly limited insofar as the solvent can be obtained by a technique known to a person skilled in does not inhibit the reaction and allows the starting material the art. Preferably, the compound can be prepared from a to be dissolved therein to a certain extent. Preferable 55 nitro compound (12) as a starting material according to Step examples of the solvent include hexane, toluene, diethyl 2-6. Specifically, reduction reaction in Step 2-6 varies ether, tetrahydrofuran, N,N-dimethylformamide, hexameth according to the starting material and is not particularly ylphosphoric triamide and a mixed solvent thereof. The limited insofar as the conditions are similar to those in this reaction temperature must be a temperature that can com reaction. A method known to a person skilled in the art may plete the reaction without promoting formation of an unde 60 be used for the reaction (see Shin Jikken Kagaku Koza (New sirable by-product, and is preferably -78° C. to 100° C. Courses in Experimental Chemistry), vol. 14, Yuki Kagob Under preferable reaction conditions, the reaction is com utsu No Gosei To Hannou (Synthesis and Reaction of pleted in 1 to 24 hours, and the progress of the reaction can Organic Compounds) III, edited by The Chemical Society be monitored by a known chromatography technique. An of Japan, Maruzen Co., Ltd., February 1978, p. 1333-1341, undesirable by-product can be removed by a technique 65 for example). The reaction is preferably a catalytic reduction known to a person skilled in the art Such as a conventional method using a metal catalyst or a reduction method using chromatography technique or/and crystallization. The a metal, for example. The catalytic reduction method is US 9,453,000 B2 51 52 preferably performed in a hydrogen atmosphere at normal tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl, pressure to 100 atm. Preferable examples of the metal 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1.2-bis(diphe catalyst used in this reaction include platinum, platinum nylphosphino)ethane or 1, 1'-bis(diphenylphosphino) ferro oxide, platinum black, Raney nickel and palladium-carbon. cene may be appropriately added in order to make the The solvent used in the present reaction varies according to reaction efficiently proceed, for example. A preferable result the starting material, and is not particularly limited insofar as the solvent does not inhibit the reaction and allows the may be achieved in the presence of a base. The base used is starting material to be dissolved therein to a certain extent. not particularly limited insofar as the base is used in a Preferable examples of the solvent include methanol, etha 10 coupling reaction similar to this reaction. Preferable nol, diethyl ether, tetrahydrofuran, methylene chloride, chlo examples of the base include sodium hydroxide, barium roform and ethyl acetate. An acidic Substance Such as acetic hydroxide, potassium fluoride, cesium fluoride, Sodium car acid or hydrochloric acid may be appropriately added in bonate, potassium carbonate, cesium carbonate, potassium order to make the reaction efficiently proceed. The reduction 15 phosphate and sodium tert-butoxide. The solvent used varies method using a metal preferably employs Zinc, iron or tin, according to the starting material and the transition metal for example, and is preferably performed under acidic catalyst used, and is not particularly limited insofar as the conditions using hydrochloric acid, acetic acid or ammo solvent does not inhibit the reaction and allows the starting nium chloride, for example. The solvent used in the present material to be dissolved therein to a certain extent. Prefer reaction varies according to the starting material, and is not particularly limited insofar as the solvent does not inhibit the able examples of the solvent include acetonitrile, tetrahy reaction and allows the starting material to be dissolved drofuran, 1.4-dioxane, 1,2-dimethoxyethane, benzene, tolu therein to a certain extent. Preferable examples of the ene, Xylene, 1-methyl-2-pyrrolidone and N,N- Solvent include methanol, ethanol and 2-propanol. The reac 25 dimethylformamide. The reaction temperature must be a tion temperature must be a temperature that can complete temperature that can complete the coupling reaction, and is the reaction without promoting formation of an undesirable preferably room temperature to 100° C., for example. This by-product, and is preferably room temperature to 100° C. reaction is performed preferably in an inert gas atmosphere, Under preferable reaction conditions, the reaction is com and more preferably in a nitrogen or argon atmosphere. A pleted in 1 to 24 hours, and the progress of the reaction can 30 method known to a person skilled in the art may be used for be monitored by a known chromatography technique. An the treatment after the second stage (see T. W. Green, undesirable by-product can be removed by a technique “Protective Groups in Organic Synthesis”, John Wiley & known to a person skilled in the art Such as a conventional Sons, Inc., 1981). An undesirable by-product can be chromatography technique or/and crystallization. 35 The preferable amine compound (13) can also be prepared removed by a technique known to a person skilled in the art from a compound (15) as a starting material which is Such as a conventional chromatography technique or/and commercially available or can be obtained by a technique crystallization. known to a person skilled in the art, according to coupling In the preferable amine compound (13), La can be modi 40 fied by a method known to a person skilled in the art, and a reaction in Step 2-8. Specifically, the coupling reaction in hydrogen atom in La can be preferably converted into a Step 2-8 varies according to the starting material and is not halogen substituent (see Shin Jikken Kagaku Koza (New particularly limited insofar as the conditions are similar to Courses in Experimental Chemistry), vol. 14, Yuki Kagob those in this reaction. A method known to a person skilled utsu No Gosei To Hannou (Synthesis and Reaction of in the art may be used for the reaction. Preferably, for 45 Organic Compounds) II, edited by The Chemical Society of Japan, Maruzen Co., Ltd., November 1977, p. 354-360, for example, it is possible to use a two-stage method of per example). forming coupling reaction of benzophenone imine using a Preparation of Nitro Compound (12) transition metal catalyst and then performing a known The nitro compound (12) is commercially available or can benzophenone removal reaction treatment (see S. L. Buch 50 be obtained by a technique known to a person skilled in the art. If not commercially available, the preferable compound wald et al., “Tetrahedron Lett.”, 1997, vol. 38, p. 6367-6370; (12), wherein La represents a fluorine atom, a chlorine atom, or J. F. Hartwig et al., “J. Am. Chem. Soc., 1998, vol. 120, a bromine atom or an iodine atom, can be efficiently p. 827-828, for example). In the coupling reaction of ben obtained from a corresponding precursor by a nitration Zophenone imine, a compound (15) and 1.0 to 10.0 equiva 55 reaction known to a person skilled in the art (see Shin Jikken lents of benzophenone imine with respect to the compound Kagaku Koza (New Courses in Experimental Chemistry), vol. 14, Yuki Kagobutsu No Gosei To Hannou (Synthesis (15) are stirred in a solvent in the presence of 0.01 to 0.2 and Reaction of Organic Compounds) III, edited by The equivalent of a catalyst with respect to the compound (15). Chemical Society of Japan, Maruzen Co., Ltd., February Preferable examples of the catalyst that can be used include 60 1978, p. 1261-1300, for example). known palladium complexes such as palladium (II) acetate, Preparation of Compound (17) dichlorobis(triphenylphosphine)palladium (II), tetrakis(tri The compound (17) can be obtained by a technique phenylphosphine)palladium (0) and tris(dilbenzylideneac known to a person skilled in the art. Preferably, the com pound (17) can be prepared i) from a compound (15) as a etone)dipalladium (0); and known nickel catalysts Such as 65 starting material according to Step 2-9 or ii) from an amine (1,5-cyclooctadiene)nickel (O). Preferably, a phosphorus compound (13) as a starting material according to Step 2-7. ligand Such as triphenylphosphine, tri-o-tolylphosphine, tri for example. US 9,453,000 B2 53 54 In the case of i), Step 2-9 is performed by the same a person skilled in the art such as a conventional chroma method as in the above Step 2-1. tography technique or/and crystallization. In the case of ii), an amine compound (13) can be The compound (14) used in the second stage of this step efficiently converted into the compound (17) in Step 2-7 by is commercially available or can be obtained by a technique treating the amine compound (13) with a mixed solvent of 5 known to a person skilled in the art. If not commercially acetic anhydride and formic acid in a first stage, condensing available, the preferable compound (14) can be prepared the compound with a compound (14) under basic conditions from a corresponding carbonyl compound by a halogenation in a second stage, and heating the condensate with ammo reaction known to a person skilled in the art (see Shin Jikken nium acetate and acetic acid in a third stage, for example. In Kagaku Koza (New Courses in Experimental Chemistry), the first stage, a compound (13) is stirred in a mixed solvent 10 vol. 19, Yuki Gosei (Organic Synthesis) II, edited by The of 2.0 to 10.0 equivalents of acetic anhydride with respect to Chemical Society of Japan, Maruzen Co., Ltd., June 1992, the compound (13) and 10.0 to 20.0 equivalents of formic p. 363-482, for example). acid with respect to the compound (13) at ice-cold tempera La in the compound (17) can be modified by a technique ture to 50° C. In the second stage, 1.0 to 5.0 equivalents of known to a person skilled in the art, and can be preferably a base is preferably used with respect to the compound (13). 15 converted into, for example, an iodine group (see S. L. Examples of the base include sodium hydride, sodium Buchwald et al., “J. Am. Chem. Soc., 2002, vol. 124, p. hydroxide, potassium hydroxide, lithium hydroxide, n-butyl 14844-14845, for example), a lower alkyltin group (see J. lithium, lithium diisopropylamide, lithium bis(trimethylsi Marti et al., “Synth. Commun., 2000, vol. 30, p. 3023 lyl)amide and sodium bis(trimethylsilyl)amide. The solvent 3030, for example) or a boron group (see N. Miyaura et al., used in the present reaction varies according to the starting “J. Org. Chem.”, 1995, vol. 60, p. 7508-7510, for example). material, and is not particularly limited insofar as the solvent The compounds (18a) and (18b) are commercially available does not inhibit the reaction and allows the starting material or can be obtained by a technique known to a person skilled to be dissolved therein to a certain extent. Preferable in the art. examples of the solvent include diethyl ether, tetrahydro The compound of the general formula (I-9), general furan, dimethyl sulfoxide and N,N-dimethylformamide. 25 formula (I-4) or general formula (I-6), wherein two of R". Preferably, potassium iodide or sodium iodide may be R'' and R' form a ring, can be prepared from the compound added, for example, in order to make the reaction efficiently (2a) as a starting material, wherein R'' and R' form a ring, proceed. The reaction temperature must be a temperature by the same method as above. When the method as above is that can complete the reaction without promoting formation performed using the compound (2a) as a starting material, of an undesirable by-product, and is preferably room tem 30 wherein R' or R' represents an alkyl group substituted perature to 100° C., for example. In the third stage, the with a halogenatom such as a chlorine atom, a bromine atom condensate is preferably treated in a mixture of 5.0 to 10.0 or an iodine atom, the compound of the general formula equivalents of ammonium acetate with respect to the com (I-9), general formula (I-4) or general formula (I-6), wherein pound (13) and 10.0 to 20.0 equivalents of acetic acid with two of R". R'' and R' form a ring, can be prepared in Step respect to the compound (13) at 50 to 100° C. Under 35 1-2, Step 1-5, Step 1-6 or Step 1-7. preferable reaction conditions, the reaction is completed in General Preparation Method 2 1 to 24 hours, and the progress of the reaction can be Typically used General Preparation Method 2 for the monitored by a known chromatography technique. An unde compound of the general formula (I) of the present invention sirable by-product can be removed by a technique known to will be described below.

Formula 34

R10 SY, O X-( l o (3) N-I X d Os. R' () R" () sy, (I-9) (I-6) HN1 Y1 R Os-R" (23a) Yio Step 4-11 HN1 Y11 R11 (23a) X-Y13 X Step 4-1 Step 4-12 () " HN1 Y11... R11 () US 9,453,000 B2

-continued 1) P 2) Deprotection Step 4-3 Y11. O Os.SS - R' HN1 R 11 3) R10 2 R10 Yio R12 HO1 10 NR 10 X -(5. +NHR2 R SY, -Y1 R11 2 (23d) (23e) N a-Y --(22) N 4-Y R12 ) Deprotectior Step 4-9) R11 Step 4-4 R11 3) O Step(23b) 4-5 HO1 "R"10. (25) (I-4) (23e) Step 4-10

Step 4-7

In the formula, the following partial structure (formula wherein Ar, Ar., X, X, Xs, X, Y, Y, R', R', R', III-3, III-4, III-6, III-7 or III-8): ind, ne, ni, nj and inl are as defined above; Y represents a 30 carboxyl group, an ester group, a thioester group, a dithio ester group, a nitrile group, a thioimino ether group or an Formula 35 iminoether group; Ya represents an oxygenatom, a nitrogen atom or a sulfur atom; and P represents a protecting group (III-3) for an amino group such as a methyl carbamate group, a 35 benzyl carbamate group, a tert-butyl carbamate group, an allyl group, an acetyl group or a formyl group. The above General Preparation Method 2 includes a method of reacting a compound (1a) with an amine com (III-4) pound (23a) or amine compound (23b) according to Step 4-1 40 or Step 4-5 to convert the compound (1a) into a compound (24) or compound (26), or converting a compound (1a) into a compound (24) or compound (26) according to Step 4-9 or Step 4-10 which is a three-stage reaction including depro (III-6) tection, and further reacting the resulting compound (24) or 45 compound (26) with ammonia, an ammonium salt or for mamide in Step 4-2 or Step 4-6 to prepare a compound of the general formula (I-9), the general formula (I-4), the general formula (I-6), the general formula (I-7) or the general formula (I-8); a method of once converting a compound (24) 50 or compound (26) into an oxazole compound (25) or a compound (27) by dehydration reaction in Step 4-3 or Step 4-7, and then reacting the oxazole compound (25) or the (III-7) compound (27) with ammonia, an ammonium salt, forma mide or an amine compound (22) in Step 4-4. Step 4-8 or 55 Step 4-12 to prepare a compound of the general formula (I-9), the general formula (I-4), the general formula (I-6), the general formula (I-7) or the general formula (I-8); and a method of reacting a compound (1a) with an amine com (III-8) pound (23a) according to Step 4-11 to prepare a compound 60 of the general formula (I-9), the general formula (I-6), the general formula (I-7) or the general formula (I-8). Preparation of Compound of General Formula (I-4) The compound of the general formula (I-4) can be pre pared by i) reacting a compound (26) in the presence of an 65 acid or base and optionally in the presence of ammonia, an is a partial structure corresponding to the above-described ammonium salt, formamide or the like according to Step Het, 4-6. The compound can also be prepared by ii) reacting a US 9,453,000 B2 57 58 compound (25) or compound (27) with an amine compound The method ii), specifically, Step 4-4 or Step 4-8 varies (22), ammonia, an ammonium salt, formamide or the like according to the starting material and is not particularly according to Step 4-4 or Step 4-8. limited insofar as the conditions are similar to those in this The method i), specifically, Step 4-6 varies according to reaction. A known method described in many documents the starting material and is not particularly limited insofar as 5 may be used for the reaction (see Heterocyclic Compounds, the conditions are similar to those in this reaction. A known vol. 5, Wiley, New York, N.Y. 1950, p. 214; and The Journal method described in many documents may be used for the of Organic Chemistry, 1962, Vol. 27, p. 3240, for example). reaction (see Heterocyclic Compounds, Vol. 5, Wiley, New For example, an oxazole compound (25) or a compound (27) York, N.Y. 1957, p. 503; and Journal of Heterocyclic Chem and 1.0 to 100.0 equivalents of an amine compound (22), istry, 1982, vol. 19, p. 193, for example). Preferably, a 10 ammonia, an ammonium salt Such as ammonium acetate or compound (26), wherein Y represents an oxygen atom or ammonium carbonate or formamide with respect to the a sulfur atom, is stirred in a solvent in the presence of 1.0 to compound (25) or compound (27) are stirred in a solvent. 100.0 equivalents of ammonia, an ammonium salt such as The solvent used is not particularly limited insofar as the ammonium acetate or ammonium carbonate or formamide solvent does not inhibit the reaction and allows the starting with respect to the compound (26), for example. The solvent 15 material to be dissolved therein to a certain extent. Prefer used is not particularly limited insofar as the solvent does able examples of the solvent include ether solvents such as not inhibit the reaction and allows the starting material to be tetrahydrofuran, 1.4-dioxane and diethyl ether, halogenated dissolved therein to a certain extent. Preferable examples of Solvents such as methylene chloride, 1,2-dichloroethane and the solvent include ether solvents such as tetrahydrofuran, chloroform; alcohol solvents such as amyl alcohol and 1,4-dioxane and diethyl ether, halogenated Solvents such as isopropyl alcohol; polar solvents such as N,N-dimethylfor methylene chloride, 1,2-dichloroethane and chloroform: mamide and N-methylpyrrolidone; nonpolar solvents such alcohol solvents such as amyl alcohol and isopropyl alcohol; as toluene, benzene and dichlorobenzene: organic acids Such polar solvents such as N,N-dimethylformamide and N-meth as acetic acid; water, and a mixture thereof. The amine ylpyrrolidone; nonpolar solvents such as toluene, benzene Source to be reacted may be used as a solvent. The reaction and dichlorobenzene, organic acids such as acetic acid; 25 temperature must be a temperature that can complete the water, and a mixture thereof. Formamide may be used as a reaction without promoting formation of an undesirable Solvent. The reaction temperature must be a temperature that by-product, and is preferably room temperature to 200°C., can complete the reaction without promoting formation of for example. Under preferable reaction conditions, the reac an undesirable by-product, and is preferably room tempera tion is completed in 1 to 24 hours, and the progress of the ture to 200° C., for example. Under preferable reaction 30 reaction can be monitored by a known chromatography conditions, the reaction is completed in 1 to 24 hours, and technique. An undesirable by-product can be removed by a the progress of the reaction can be monitored by a known technique known to a person skilled in the art such as a chromatography technique. An undesirable by-product can conventional chromatography technique, extraction or/and be removed by a technique known to a person skilled in the crystallization. The amine compound (22) used in this step art such as a conventional chromatography technique, 35 is commercially available or can be obtained by a technique extraction or/and crystallization. known to a person skilled in the art. Alternatively, a compound (26), wherein Y represents a Preparation of Compound of General Formula (I-9), Gen nitrogen atom, is stirred in a solvent in the presence or eral Formula (I-6), General Formula (I-7) and General absence of 0.1 to 10 equivalents of an acid, base or organic Formula (I-8) salt with respect to the compound (26). Preferable examples 40 The compound of the general formula (I-9), the general of the acid, base or organic salt used include inorganic acids formula (I-6), the general formula (I-7) or the general Such as hydrochloric acid and Sulfuric acid; organic acids, formula (I-8) can be prepared by i) reacting a compound (24) Such as p-toluenesulfonic acid and methanesulfonic acid; or compound (25) in the presence of ammonia, an ammo organic bases such as pyridine and dimethylamino pyridine; nium salt, formamide or the like according to Step 4-2 or and organic salts such as pyridinium p-toluenesulfonate and 45 Step 4-12. The compound can also be prepared by ii) tetrabutylammonium hydroxide. The solvent used is not reacting a compound (1a) with an amine compound (23a) particularly limited insofar as the solvent does not inhibit the according to Step 4-11. reaction and allows the starting material to be dissolved The method i), specifically, Step 4-2 or Step 4-12 is the therein to a certain extent. Preferable examples of the same method as in Step 4-6. solvent that can be used include ether solvents such as 50 The methodii), specifically, Step 4-11 varies according to tetrahydrofuran, 1.4-dioxane and diethyl ether, halogenated the starting material and is not particularly limited insofar as Solvents such as methylene chloride, 1,2-dichloroethane and the conditions are similar to those in this reaction. A known chloroform; alcohol Solvents such as methanol, ethanol, method described in many documents may be used for the amyl alcohol and isopropyl alcohol; polar solvents such as reaction (see Journal of the Chemical Society, 1962, p. 5149: N,N-dimethylformamide and N-methylpyrrolidone; nonpo 55 and Journal of Medicinal Chemistry, 1983, Vol. 26, p. 1187, lar solvents such as toluene, benzene and dichlorobenzene: for example). For example, a compound (1a), wherein Y' water, and a mixture thereof. The above acid, base or organic represents a nitrile group, a thioimino ether group or an salt may be used as a solvent. The reaction temperature must imino ether group, and 1.0 to 5.0 equivalents of an amine be a temperature that can complete the reaction without compound (23a) with respect to the compound (1a) are promoting formation of an undesirable by-product, and is 60 stirred in a solvent. The solvent used is not particularly preferably room temperature to 200°C., for example. Under limited insofar as the solvent does not inhibit the reaction preferable reaction conditions, the reaction is completed in and allows the starting material to be dissolved therein to a 1 to 24 hours, and the progress of the reaction can be certain extent. Preferable examples of the solvent include monitored by a known chromatography technique. An unde ether solvents such as tetrahydrofuran, 1.4-dioxane and sirable by-product can be removed by a technique known to 65 diethyl ether, halogenated solvents such as methylene chlo a person skilled in the art Such as a conventional chroma ride, 1,2-dichloroethane and chloroform; alcohol solvents tography technique, extraction or/and crystallization. Such as methanol, ethanol, butanol, amyl alcohol and iso US 9,453,000 B2 59 60 propyl alcohol; polar solvents such as N,N-dimethylforma group, and 1.0 to 100.0 equivalents of an amine compound mide and N-methylpyrrolidone; nonpolar solvents such as (23a) or amine compound (23b) with respect to the com toluene, benzene and dichlorobenzene: organic acids such as pound (1a) are stirred in a solvent. The solvent used is not acetic acid; water; and a mixture thereof. The yield may be particularly limited insofar as the solvent does not inhibit the improved when performing reaction in the presence of 1.0 to reaction and allows the starting material to be dissolved 10.0 equivalents of an organic amine Such as triethylamine, therein to a certain extent. Preferable examples of the diisopropylamine or pyridine or an alkali metal salt Such as Solvent include ether solvents such as tetrahydrofuran, 1.4- potassium carbonate or Sodium carbonate with respect to the dioxane and diethyl ether, halogenated Solvents such as compound (1a). The reaction temperature must be a tem methylene chloride, 1,2-dichloroethane and chloroform: perature that can complete the reaction without promoting 10 alcohol solvents such as methanol, ethanol and isopropyl formation of an undesirable by-product, and is preferably alcohol; polar solvents such as N,N-dimethylformamide and room temperature to 200° C., for example. Under preferable N-methylpyrrolidone; nonpolar solvents such as toluene, reaction conditions, the reaction is completed in 1 to 72 benzene and dichlorobenzene, organic acids such as acetic hours, and the progress of the reaction can be monitored by acid; organic bases such as pyridine; water; and a mixture a known chromatography technique. An undesirable by 15 thereof. The amine compound (23a) or amine compound product can be removed by a technique known to a person (24b) may be used as a solvent. The yield may be improved skilled in the art Such as a conventional chromatography when using 0.1 to 1.0 equivalent of an inorganic acid such technique, extraction or/and crystallization. as hydrochloric acid, a Lewis acid such as trifluoroborate or Preparation of Compound (24) and Compound (26) an organic acid Such as p-toluenesulfonic acid with respect The compound (24) or compound (26) can be prepared by to the compound (1a) or when using 1.0 to 10.0 equivalents reacting a compound (1a) with an amine compound (23a) or of an organic base Such as triethylamine, pyridine or diiso amine compound (23b) according to Step 4-1 or Step 4-5. propylethylamine with respect to the compound (1a). The Specifically, Step 4-1 or Step 4-5 varies according to the reaction temperature must be a temperature that can com starting material and is not particularly limited insofar as the plete the reaction without promoting formation of an unde conditions are similar to those in this reaction. A known 25 sirable by-product, and is preferably 0 to 200° C., for method described in many documents may be used for the example. Under preferable reaction conditions, the reaction reaction (see Shin Jikken Kagaku Koza (New Courses in is completed in 1 to 24 hours, and the progress of the Experimental Chemistry), vol. 22, Yuki Gosei (Organic reaction can be monitored by a known chromatography Synthesis) IV, edited by The Chemical Society of Japan, technique. An undesirable by-product can be removed by a Maruzen Co., Ltd., November 1992, p. 137-163; and 30 technique known to a person skilled in the art Such as a Organic Synthesis, 1941, I, p. 5, for example). For example, conventional chromatography technique, extraction or/and a compound (1a), wherein Y represents a carboxyl group, crystallization. and 1.0 to 10.0 equivalents of a compound (23a) or com The compound (24) or compound (26) can also be pre pound (23b) with respect to the compound (1a) are stirred in pared from a compound (1a) according to Step 4-9 or Step a solvent in the presence of 0.1 to 10.0 equivalents of a condensing agent with respect to the compound (1a). The 35 4-10. Specifically, Step 4-9 or Step 4-10 consists of a condensing agent used varies according to the starting three-stage reaction including a deprotection step. In a first material and is not particularly limited. Preferable examples stage, a compound (1a) is condensed with a compound (23c) of the condensing agent include inorganic acids such as or compound (23d) by dehydration. In a second stage, the hydrochloric acid and Sulfuric acid; organic acids such as protecting group is deprotected. In a third stage, the con p-toluenesulfonic acid and methanesulfonic acid, 1,3-dicy 40 densate is condensed with a compound (23e). clohexylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl) The first-stage condensation reaction may be performed carbodiimide, benzotriazol-1-yloxytris(dimethylamino) by the same method as in Step 4-1. The second-stage phosphonium hexafluorophosphate, diethyl deprotection reaction varies according to the starting mate cyanophosphonate and bis(2-oxo-3-oxazolidinyl)phospho rial and is not particularly limited insofar as the conditions nic chloride. Preferably, 1.0 to 5.0 equivalents of N-hy 45 are similar to those in this reaction. A known method droxysuccinimide, N-hydroxybenzotriazole or dimethylam described in many documents may be used for the reaction inopyridine may be added with respect to the compound (1a) (see T. W. Green, “Protective Groups in Organic Synthesis', in order to make the reaction efficiently proceed, for John Wiley & Sons, Inc., 1999, p. 615-626). Preferably, the example. The solvent used varies according to the starting condensation compound in the first stage, wherein P rep material and the condensing agent used, and is not particu 50 resents a tert-butyl carbamate group, is stirred in a solvent in larly limited insofar as the solvent does not inhibit the the presence of 1.0 to 100.0 equivalents of an acid with reaction and allows the starting material to be dissolved respect to the compound, for example. Examples of the acid therein to a certain extent. Preferable examples of the used include inorganic acids such as hydrochloric acid and Solvent include halogenated Solvents such as chloroform, methylene chloride and 1,2-dichloroethane; and polar sol Sulfuric acid; and organic acids Such as trifluoroacetic acid vents such as tetrahydrofuran and N,N-dimethylformamide. 55 and methanesulfonic acid. The solvent used is not particu The reaction temperature must be a temperature that can larly limited insofar as the solvent does not inhibit the complete the reaction without promoting formation of an reaction and allows the starting material to be dissolved undesirable by-product, and is preferably ice-cold tempera therein to a certain extent. Preferable examples of the ture to 150° C., for example. Under preferable reaction Solvent include ethyl acetate, methanol, ethanol, 1,4-diox conditions, the reaction is completed in 1 to 24 hours, and 60 ane, methylene chloride, chloroform, methanol, isopropyl the progress of the reaction can be monitored by a known alcohol, N,N-dimethylformamide and N-methylpyrrolidone. chromatography technique. An undesirable by-product can The reaction temperature must be a temperature that can be removed by a technique known to a person skilled in the complete the reaction without promoting formation of an art Such as a conventional chromatography technique or/and undesirable by-product, and is preferably 0 to 100° C., for crystallization. 65 example. Under preferable reaction conditions, the reaction Alternatively, a compound (1a), wherein Y represents a is completed in 1 to 24 hours, and the progress of the cyano group, an imino ether group or a thioimino ether reaction can be monitored by a known chromatography US 9,453,000 B2 61 62 technique. An undesirable by-product can be removed by a chloroform; polar solvents such as N,N-dimethylformamide technique known to a person skilled in the art such as a and N-methylpyrrolidone; nonpolar solvents such as tolu conventional chromatography technique, extraction or/and ene, benzene and dichlorobenzene; and a mixture thereof. crystallization. The dehydration reagent may be used as a solvent. The The third-stage condensation reaction may be performed reaction temperature must be a temperature that can com by the same method as in Step 4-1. plete the reaction without promoting formation of an unde Preparation of Compound (1a) sirable by-product, and is preferably 0 to 200° C., for The compound (1a) can be prepared from a compound (4) example. Under preferable reaction conditions, the reaction or compound (17) by the same method as in the above Step is completed in 1 to 24 hours, and the progress of the 2-1 or Step 2-10. reaction can be monitored by a known chromatography Preparation of Compound (25) and Compound (27) technique. An undesirable by-product can be removed by a The compound (25) or compound (27) can be prepared technique known to a person skilled in the art Such as a from the compound (24) or compound (26) by dehydration conventional chromatography technique, extraction or/and reaction according to Step 4-3 or Step 4-7. Specifically, Step crystallization. 4-3 or Step 4-7 varies according to the starting material and Preparation of Compound (23a), Compound (23b), Com is not particularly limited insofar as the conditions are pound (23c), Compound (23d) and Compound (23e) similar to those in this reaction. A known method described The compound (23a), compound (23b), compound (23c), in many documents may be used for the reaction (see The compound (23d) and compound (23e) are commercially Chemistry of Heterocyclic Compounds, 45; Wiley, New available or can be obtained by a technique known to a York, 1986, p. 1, for example). For example, the compound 20 person skilled in the art. (24) or compound (26) is stirred in a solvent in the presence General Preparation Method 3 of 1.0 to 100.0 equivalents of a dehydration reagent with Typically used General Preparation Method 3 for the respect to the compound (24) or compound (26). The compound of the general formula (I) of the present invention dehydration reagent used varies according to the starting will be described below.

Formula 36 L4 N R10 () (3. H-X-XR&NY1 (17) N 4-Y 's NJ-R" (28) PrSY16 Step 5-1 H-X { N2Y Step 5-2 R11 (29)

Pr NU-R"NY1 (Step 5-3 X RO L-R (s N -Y11 NR11 (2b)

(I-5) 2 R10 R10 pie R SY1 O N.N. 1 O SSYi,

(I-8)

55 material and is not particularly limited. Preferable examples In the formula, the following partial structure (formula of the dehydration reagent include phosphorus oxychloride, III-4, III-5, III-7 or III-8): thionyl chloride, phosgene, triphosgene, carbonyldiimida Zole, hydrochloric acid, Sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, triphenylphosphine-carbon tet 60 rachloride and triphenylphosphine-carbon tetrabromide. The Formula 37 solvent used is not particularly limited insofar as the solvent (III-4) does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Preferable examples of the solvent include ether solvents such as 65 tetrahydrofuran, 1.4-dioxane and diethyl ether, halogenated Solvents such as methylene chloride, 1,2-dichloroethane and US 9,453,000 B2 63 64 -continued complex, for example, and more preferably a known palla dium complex Such as palladium (II) acetate, dichlorobis R10 (III-5) (triphenylphosphine)palladium (II), tetrakis(triphenylphos Pr NN y1 phine)palladium (O) or tris(dibenzylideneacetone) dipalladium (0). A phosphorus ligand Such as als, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphos phine or 2-(di-tert-butylphosphino)biphenyl may be prefer R10 or (III-7) ably added, for example, in order to make the reaction efficiently proceed. A preferable result may be achieved in 10 the presence of a base. The base used is not particularly —(Of2. limited insofar as the base is used in a coupling reaction similar to this reaction. Preferable examples of the base include triethylamine, N,N-diisopropylethylamine, N,N-di (III-8) cyclohexylmethylamine and tetrabutylammonium chloride. 15 The solvent used varies according to the starting material and the transition metal catalyst used, and is not particularly limited insofar as the solvent does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Preferable examples of the solvent include is a partial structure corresponding to the above-described acetonitrile, tetrahydrofuran, 1.4-dioxane, 1,2-dimethoxy Het, ethane, benzene, toluene, Xylene, 1-methyl-2-pyrrolidone wherein Ari, Ars, X, Xs, X, Yo Yi, R', R', R', L2, La and N,N-dimethylformamide. The reaction temperature ind, ne, ni and nj are as defined above; and Pr represents a must be a temperature that can complete the coupling protecting group for a heterocycle nitrogen atom Such as a reaction, and is preferably room temperature to 150° C., for 25 example. This reaction is performed preferably in an inert trityl group, a methoxymethyl group, a benzyl group or a gas atmosphere, and more preferably in a nitrogen or argon methanesulfonic acid group. atmosphere, for example. Under preferable reaction condi The above General Preparation Method 3 includes a tions, the reaction is completed in 1 to 24 hours, and the method of reacting a compound (17) with a heterocyclic progress of the reaction can be monitored by a known compound (28) in Step 5-1 to prepare a compound of the 30 chromatography technique. An undesirable by-product can general formula (I-4), the general formula (I-7) or the be removed by a technique known to a person skilled in the general formula (I-8); and a method of reacting a compound art such as a conventional chromatography technique, (17) with a heterocyclic compound (29) having a protecting extraction or/and crystallization. group in Step 5-2 to once convert the compound (17) into a In Sonogashira reaction, a compound (17), wherein La compound of the general formula (I-5) having a protecting 35 represents a chlorine atom, a bromine atom, an iodine atom group and then deprotecting the protecting group of the or a Sulfonate group Such as a trifluoromethanesulfonate compound of the general formula (I-5) and Subsequently group, and 1.0 to 5.0 equivalents of a compound (28) or reacting the compound with a compound (2b) in Step 5-3 to compound (29), wherein X represents an alkynyl group, prepare a compound of the general formula (I-4), the general with respect to the compound (17) are stirred in a solvent in formula (I-7) or the general formula (I-8). 40 the presence of 0.01 to 0.5 equivalent of a transition metal Preparation of Compounds of General Formula (I-4) and catalyst with respect to the compound (17), for example. The (I-5) transition metal catalyst used is preferably a known palla The compound of the general formula (I-4) or (I-5) can be dium complex, for example, and more preferably a known prepared by i) reacting a compound (17) with a compound palladium complex Such as palladium (II) acetate, dichlo (28) or compound (29) according to Step 5-1 or Step 5-2. 45 robis(triphenylphosphine)palladium (II), tetrakis(triphenyl The compound of the general formula (I-4) can also be phosphine)palladium (O) or tris(dibenzylideneacetone)dipal prepared by ii) deprotecting the protecting group of the ladium (0). A phosphorus ligand Such as triphenylphosphine, compound of the general formula (I-5) and then reacting the tri-o-tolylphosphine or tri-tert-butylphosphine may be pref compound with a compound (2b) according to Step 5-3. erably added, for example, in order to make the reaction The method i), specifically, Step 5-1 or Step 5-2 varies 50 efficiently proceed. In the reaction, a good result may be according to the starting material and is not particularly achieved when adding a metal halide or a quaternary ammo limited insofar as the conditions are similar to those in this nium salt, preferably copper (I) iodide, lithium chloride, reaction. A known method described in many documents tetrabutylammonium fluoride or silver (I) oxide, for such as Mizoroki-Heck reaction (see R. F. Heck, “Org. example. A preferable result may be achieved in the pres Reactions.”. 1982, vol. 27, p. 345, for example) or Sono 55 ence of a base. The base used here is not particularly limited gashira reaction (see K. Sonogashira, "Comprehensive insofar as the base is used in a coupling reaction similar to Organic Synthesis', 1991, vol. 3, p. 521, for example) may this reaction. Preferable examples of the base include dieth be used for the reaction. ylamine, triethylamine, N,N-diisopropylethylamine, piperi In Mizoroki-Heck reaction, a compound (17), wherein La dine and pyridine. Preferable examples of the solvent used represents a chlorine atom, a bromine atom, an iodine atom 60 include acetonitrile, tetrahydrofuran, 1.4-dioxane, 1,2-dime or a Sulfonate group Such as a trifluoromethansulfonate, thoxyethane, benzene, toluene, Xylene, 1-methyl-2-pyrroli group, and 1.0 to 5.0 equivalents of a compound (28) or done, N,N-dimethylformamide and dimethyl sulfoxide. compound (29), wherein X represents an alkenyl group, More preferable examples of the solvent include tetrahy with respect to the compound (17) are stirred in a solvent in drofuran, 1.4-dioxane, 1-methyl-2-pyrrolidone and N,N-di the presence of 0.01 to 0.5 equivalent of a transition metal 65 methylformamide. The reaction temperature must be a tem catalyst with respect to the compound (17), for example. The perature that can complete the coupling reaction, and is transition metal catalyst used is preferably a palladium preferably room temperature to 150° C., for example. This US 9,453,000 B2 65 66 reaction is performed preferably in an inert gas atmosphere, In the formula, X, Yo Yi, Y. R', R'' and R'' are as and more preferably in a nitrogen or argon atmosphere, for defined above; L., represents a hydrogen atom, a halogen example. Under preferable reaction conditions, the reaction atom such as a chlorine atom, a bromine atom or an iodine is completed in 1 to 24 hours, and the progress of the atom, a sulfonate group such as a trifluoromethanesulfonate reaction can be monitored by a known chromatography 5 group, a trialkyltin group or a leaving group such as a technique. An undesirable by-product can be removed by a boronic acid or boronate group; and Ys represents an technique known to a person skilled in the art such as a oxygen atom, or a nitrogen atom which may be substituted conventional chromatography technique, extraction or/and with a substituent selected from the above Substituent Group crystallization. A1. The method ii), specifically, Step 5-3 consists of first 10 The compound (28) can be prepared by i) condensing a stage deprotection reaction and second-stage reaction with a compound (31) with an alkene or alkyne compound accord compound (2b). The first-stage deprotection reaction varies ing to Step 6-1. The compound (28) can also be prepared by according to the starting material and is not particularly ii) cyclizing a compound (32) according to Step 6-2. limited insofar as the conditions are similar to those in this The method i), specifically, Step 6-1 varies according to reaction. A known method described in many documents 15 the starting material and is not particularly limited insofar as may be used for the reaction (see T. W. Green, “Protective the conditions are similar to those in this reaction. A known Groups in Organic Synthesis”, John Wiley & Sons, Inc., method described in many documents such as Mizoroki 1999, p. 615-626). Preferably, the compound of the general Heck reaction (see R. F. Heck, “Org. Reactions.”. 1982, vol. formula (I-5) is stirred in a solvent in the presence of 1.0 to 27, p. 345, for example), Suzuki-Miyaura reaction (see A. 100.0 equivalents of an acid or base with respect to the Suzuki, "Chem. Rev., 1995, vol. 95, p. 2457, for example), compound of the general formula (I-5), for example. Pref. Sonogashira reaction (see K. Sonogashira, "Comprehensive erable Examples of the acid used include inorganic acids Organic Synthesis”, 1991, vol. 3, p. 521) or Stille coupling Such as hydrochloric acid and sulfuric acid; and organic reaction (see J. K. Stille, "Angew. Chem. Int. Ed. Engl.”, acids such as trifluoroacetic acid, methanesulfonic acid and 1986, vol. 25, p. 508, for example) may be used for the p-toluenesulfonic acid. Preferable examples of the base used 25 reaction. include alkali metal hydroxides such as sodium hydroxide In Mizoroki-Heck reaction, a compound (31), wherein L, and potassium hydroxide; alkali metal carbonates such as represents a chlorine atom, a bromine atom, an iodine atom potassium carbonate and sodium carbonate; and organic or a sulfonate group such as a trifluoromethanesulfonate amines such as ammonia and methylamine. The solvent used group, and 1.0 to 5.0 equivalents of an alkene compound, is not particularly limited insofar as the solvent does not 30 wherein the alkene compound refers to a compound having inhibit the reaction and allows the starting material to be a double bond in the molecule, with respect to the compound dissolved therein to a certain extent. Preferable examples of (31) are stirred in a solvent in the presence of 0.01 to 0.2 the solvent include acetonitrile, tetrahydrofuran, 1,4-diox equivalent of a transition metal catalyst with respect to the ane, 1,2-dimethoxyethane, ethyl acetate, methanol, ethanol, compound (31), for example. The transition metal catalyst benzene, toluene, xylene, chloroform, methylene chloride, 35 used is preferably a palladium complex, for example, and water and a mixed solvent thereof. The acid or base may be more preferably a known palladium complex such as pal used as a solvent. The reaction temperature must be a ladium (II) acetate, dichlorobis(triphenylphosphine)palla temperature that can complete the deprotection reaction, and dium (II), tetrakis(triphenylphosphine)palladium (0) or tris is preferably room temperature to 150° C., for example. (dibenzylideneacetone)dipalladium (0). A phosphorus Under preferable reaction conditions, the reaction is com 40 ligand such as triphenylphosphine, tri-o-tolylphosphine, tri pleted in 1 to 24 hours, and the progress of the reaction can tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl be monitored by a known chromatography technique. An may be preferably added, for example, in order to make the undesirable by-product can be removed by a technique reaction efficiently proceed. A preferable result may be known to a person skilled in the art such as a conventional achieved in the presence of a base. The base used is not chromatography technique, extraction or/and crystallization. 45 particularly limited insofar as the base is used in a coupling The second stage reaction of the compound (I-5) with the reaction similar to this reaction. Preferable examples of the compound (2b) may be performed by the same method as in base include triethylamine, N,N-diisopropylethylamine, Step 1-3. N,N-dicyclohexylmethylamine and tetrabutylammonium Preparation of Compound (28) chloride. The solvent used varies according to the starting 50 material and the transition metal catalyst used, and is not particularly limited insofar as the solvent does not inhibit the reaction and allows the starting material to be dissolved Formula 38 therein to a certain extent. Preferable examples of the R12 N R10 Solvent include acetonitrile, tetrahydrofuran, 1.4-dioxane, W NY1 55 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl 2-pyrrolidone and N,N-dimethylformamide. The reaction L-Q - YIII Step 6-1 N R11 temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to (31) R N R10 150° C., for example. This reaction is performed preferably 14 o Nas Y16 60 in an inert gas atmosphere, and more preferably in a nitrogen H-X \,-R"Yi, H-X-XS) Y or argon atmosphere, for example. Under preferable reaction / N111 conditions, the reaction is completed in 1 to 24 hours, and Ys-Y R11 the progress of the reaction can be monitored by a known chromatography technique. An undesirable by-product can (28) 65 be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and crystallization. US 9,453,000 B2 67 68 In Suzuki-Miyaura reaction, a compound (31), wherein L, example, in order to make the reaction efficiently proceed. In represents a chlorine atom, a bromine atom, an iodine atom the reaction, a good result may be achieved when adding a or a sulfonate group such as a trifluoromethanesulfonate metal halide or a quaternary ammonium salt, preferably group, and 1.0 to 5.0 equivalents of an alkene or alkyne copper (I) iodide, lithium chloride, tetrabutylammonium boronic acid or boronate compound, wherein the boronic 5 fluoride or silver (I) oxide, for example. A preferable result acid or boronate compound refers to a boronic acid or may be achieved in the presence of a base. The base used boronate compound directly bonded to a double bond or here is not particularly limited insofar as the base is used in triple bond, with respect to the compound (31) are stirred in a coupling reaction similar to this reaction. Preferable a solvent in the presence of 0.01 to 0.5 equivalent of a examples of the base include diethylamine, triethylamine, transition metal catalyst with respect to the compound (31), 10 N,N-diisopropylethylamine, piperidine and pyridine. Pref for example. The transition metal catalyst used is preferably erable examples of the solvent used include acetonitrile, a known palladium complex, and more preferably a known tetrahydrofuran, 1.4-dioxane, 1,2-dimethoxyethane, ben palladium complex such as palladium (II) acetate, dichlo Zene, toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimeth robis(triphenylphosphine)palladium (II), tetrakis(triphenyl ylformamide and dimethyl sulfoxide. More preferable phosphine)palladium(0) or tris(dibenzylideneacetone)dipal 15 examples of the solvent include tetrahydrofuran, 1.4-diox ladium (0). A phosphorus ligand such as triphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine or tri-tert-bu ane, 1-methyl-2-pyrrolidone and N,N-dimethylformamide. tylphosphine may be preferably added, for example, in order The reaction temperature must be a temperature that can to make the reaction efficiently proceed. A quaternary complete the coupling reaction, and is preferably room ammonium salt, preferably tetrabutylammonium chloride or temperature to 150° C., for example. This reaction is per tetrabutylammonium bromide, for example, may also be formed preferably in an inert gas atmosphere, and more added in order to make the reaction efficiently proceed. In preferably in a nitrogen or argon atmosphere, for example. this reaction, a preferable result may be achieved in the Under preferable reaction conditions, the reaction is com presence of a base. The base used at this time varies pleted in 1 to 24 hours, and the progress of the reaction can according to the starting material, the solvent used and the be monitored by a known chromatography technique. An like, and is not particularly limited. Preferable examples of 25 undesirable by-product can be removed by a technique the base include sodium hydroxide, barium hydroxide, known to a person skilled in the art such as a conventional potassium fluoride, cesium fluoride, sodium carbonate, chromatography technique, extraction or/and crystallization. potassium carbonate, cesium carbonate and potassium phos In Stille coupling reaction, a compound (31), wherein L, phate. The solvent used varies according to the starting represents a chlorine atom, a bromine atom, an iodine atom material and the transition metal catalyst used, and is not 30 or a trifluoromethanesulfonate group, and 1.0 equivalent or particularly limited insofar as the solvent does not inhibit the more of a trialkyltin compound, wherein the trialkyltin reaction and allows the starting material to be dissolved compound refers to an alkyltin compound directly bonded to therein to a certain extent. Preferable examples of the a double bond or triple bond, with respect to the compound Solvent include acetonitrile, tetrahydrofuran, 1.4-dioxane, (31) are stirred in a solvent in the presence of 0.01 to 0.2 1.2-dimethoxyethane, benzene, toluene, xylene, 1-methyl equivalent of a transition metal catalyst with respect to the 2-pyrrolidone, N.N-dimethylformamide, water and a mixed 35 compound (31), for example. The transition metal catalyst solvent thereof. The reaction temperature must be a tem used is preferably a palladium complex, for example, and perature that can complete the coupling reaction, and is more preferably a known palladium complex such as pal preferably room temperature to 200° C., for example. This ladium (II) acetate, dichlorobis(triphenylphosphine)palla reaction is performed preferably in an inert gas atmosphere, dium (II), tetrakis(triphenylphosphine)palladium (0) or tris and more preferably in a nitrogen or argon atmosphere, for 40 (dibenzylideneacetone)dipalladium (0). In order to make the example. Under preferable reaction conditions, the reaction reaction efficiently proceed, 0.1 to 5.0 equivalents of copper is completed in 1 to 24 hours, and the progress of the (I) halide or/and lithium chloride may be added. Preferable reaction can be monitored by a known chromatography examples of the solvent used include toluene, xylene, N.N- technique. An undesirable by-product can be removed by a dimethylformamide, N,N-dimethylacetamide, 1-methyl-2- technique known to a person skilled in the art such as a 45 pyrrolidone and dimethyl sulfoxide. The reaction tempera conventional chromatography technique, extraction or/and ture must be a temperature that can complete the coupling crystallization. The desired compound (28) can also be reaction, and is preferably room temperature to 150° C., for obtained from a combination of the boronic acid compound example. This reaction is performed preferably in an inert orboronate compound (31), wherein L, represents a boronic gas atmosphere, and more preferably in a nitrogen or argon acid group or a boronate group, with a halogenated alkene 50 atmosphere, for example. Under preferable reaction condi compound or an enol trifluoromethanesulfonate compound tions, the reaction is completed in 1 to 24 hours, and the by the same method as above. progress of the reaction can be monitored by a known In Sonogashira reaction, a compound (31), wherein L, chromatography technique. An undesirable by-product can represents a chlorine atom, a bromine atom, an iodine atom be removed by a technique known to a person skilled in the or a sulfonate group such as a trifluoromethanesulfonate art such as a conventional chromatography technique, group, and 1.0 to 5.0 equivalents of an alkyne compound, 55 extraction or/and crystallization. The desired compound (28) wherein the alkyne compound refers to a compound having can also be obtained from a combination of the tin com HC=C- in the molecule, with respect to the compound pound (31), wherein L7 represents a trialkyltin group, with (31) are stirred in a solvent in the presence of 0.01 to 0.5 a halogenated alkene compound or enol trifluoromethane equivalent of a transition metal catalyst with respect to the sulfonate compound by the same method as above. The compound (31), for example. The transition metal catalyst 60 halogenated alkene compound refers to a compound of used is preferably a known palladium complex, for example, which the hydrogen atom bonded to the double bond in the and more preferably a known palladium complex such as molecule is replaced by a halogen atom. The enol trifluo palladium (II) acetate, dichlorobis(triphenylphosphine)pal romethanesulfonate compound refers to a compound of ladium (II), tetrakis(triphenylphosphine)palladium (0) or which the hydrogen atom of the enol ester group in the tris(dibenzylideneacetone)dipalladium (0). A phosphorus 65 molecule is replaced by a trifluoromethanesulfonyl group. ligand Such as triphenylphosphine, tri-o-tolylphosphine or The method ii), specifically, Step 6-2 may be performed tri-tert-butylphosphine may be preferably added, for by the same method as in Step 4-2 or Step 4-6. US 9,453,000 B2 69 70 Preparation of Compound (31) In the formula, the following partial structure (formula The compound (31) is commercially available or prepared III-4, III-5, III-7 or III-8): by a method known to a person skilled in the art. If not commercially available, the compound (31), wherein L7 is a Formula 40 boronic acid group or a boronate group, can be prepared by 5 a method known to a person skilled in the art, for example, R10 (III-4) although the method varies according to the starting material R SY (see Shin Jikken Kagaku Koza (New Courses in Experi- - R mental Chemistry), Vol. 22, Yuki Gosei (Organic Synthesis) N4Y11 VI, edited by The Chemical Society of Japan, Maruzen 10 R!, Co., Ltd., September 1992, p. 61-90, for example). The O (III-5) compound (31), wherein L7 is a trialkyltin group, can be NSN -R prepared by a method known to a person skilled in the art, - RO O although the method varies according to the starting material N4Y11. (see Shin Jikken Kagaku Koza (New Courses in Experi- 15 R11, mental Chemistry), Vol. 22, Yuki Gosei (Organic Synthesis) O (III-7) VI, edited by The Chemical Society of Japan, Maruzen sy, O Co., Ltd., September 1992, p. 179-201, for example). Preparation of Compound (32) N2Y The compound (32) is commercially available or prepared 20 y )ni by a method known to a person skilled in the art. If not (bs pil commercially available, the compound (32) can be prepared if X by the same method as in Step 1-1 or Step 4-1, for example. (III-8) Preparation of Compound (29) SY \ The compound (29) is commercially available or can be 25 —( Xs prepared by the same method as in the case of the compound N-4s is M. d (28) if not commercially available. pi The compound of the general formula (I-7) or the general is a partial structure corresponding to the above-described formula (I-8) can be prepared from the compound (28) or Het, compound (29), wherein two of R', R'' and R' form a 30 wherein Arl, Ar., X, Xs, X, Yo Yi, R', R'R''. L., Pr, ring, as a starting material by the same method as above. ind, ne, ni and nj are as defined above; and L, and L, each |General Preparation Method 4) represent a halogen atom such as hydrogen, chlorine, bro Typically used General Preparation Method 4 for the mine or iodine, a Sulfonate group Such as a trifluorometh compound of the general formula (I) of the present invention anesulfonate group or a trialkyltin group or a leaving group will be described below. Such as a boron acid or boronate group.

Formula 39 L' s x1"

(33) O Pr cNY1 R L N2Y Step 7-2 R11 (34b)

Prs NS , 1 R10 Step 5-3 X-(RO L-R G Q N2Yi NRI 2 (2b) (I-5) R12 R10 R 10 pie SY1 O NY1 O Syk X-Q X-(O X-O Xs G N-is () (b)).y) () N-4 I-9. (I-4) (I-8) US 9,453,000 B2 71 72 The above General Preparation Method 4 includes a be removed by a technique known to a person skilled in the method of condensing a compound (33) with a heterocyclic art such as a conventional chromatography technique, compound (34a) in Step 7-1 to prepare a compound of the extraction or/and crystallization. general formula (I-4), the general formula (I-7) or the In Suzuki-Miyaura reaction, a compound (33), wherein general formula (I-8); and a method of condensing a com L' represents a boronic acid or boronate group, and 0.5 to pound (33) with a heterocyclic compound (34b) having a 5.0 equivalents of a compound (34a) or compound (34b). protecting group in Step 7-2 to convert the compound (33) wherein L, represents a chlorine atom, a bromine atom, an into a compound of the general formula (I-5) having a iodine atom or a Sulfonate group Such as a trifluorometh protecting group and then deprotecting the protecting group anesulfonate group, with respect to the compound (33) are of the compound of the general formula (I-5) and subse 10 stirred in a solvent in the presence of 0.01 to 1.0 equivalent quently reacting the compound with a compound (2b) in of a transition metal catalyst with respect to the compound Step 5-3 to prepare a compound of the general formula (I-4), (33), for example. The transition metal catalyst used is the general formula (I-7) or the general formula (I-8). preferably a known palladium complex, for example, and Preparation of Compound of General Formula (I-4) and more preferably a known palladium complex Such as pal Compound of General Formula (I-5) 15 ladium (II) acetate, dichlorobis(triphenylphosphine)palla The compound of the general formula (I-4) or the com dium (II), tetrakis(triphenylphosphine)palladium (O) or tris pound of the general formula (I-5) can be prepared by (dibenzylideneacetone)dipalladium (O). A phosphorus reacting a compound (33) with a compound (34a) or com ligand Such as triphenylphosphine, tri-o-tolylphosphine, tri pound (34b) according to Step 7-1 or Step 7-2. Specifically, cyclohexylphosphine or tri-tert-butylphosphine may be pref Step 7-1 or Step 7-2 varies according to the starting material erably added, for example, in order to make the reaction and is not particularly limited insofar as the conditions are efficiently proceed. A good result may be achieved when similar to those in this reaction. A known method described appropriately adding a quaternary ammonium salt, prefer in many documents may be used for the reaction. Preferable ably tetrabutylammonium chloride or tetrabutylammonium examples of the method include Mizoroki-Heck reaction bromide, for example. In this reaction, a preferable result (see R. F. Heck, “Org. Reactions.”, 1982, vol. 27, p. 345, for may be achieved in the presence of a base. The base used at example), Suzuki-Miyaura reaction (see A. Suzuki, “Chem. 25 this time varies according to the starting material, the solvent Rev., 1995, vol. 95, p. 2457, for example), Sonogashira used and the like, and is not particularly limited. Preferable reaction (see K. Sonogashira, “Comprehensive Organic examples of the base include sodium hydroxide, barium Synthesis”, 1991, vol. 3, p. 521) and Stille coupling reaction hydroxide, potassium fluoride, cesium fluoride, Sodium car (see J. K. Stille, “Angew. Chem. Int. Ed. Engl., 1986, vol. bonate, potassium carbonate, cesium carbonate and potas 25, p. 508, for example). 30 sium phosphate. The Solvent used varies according to the In Mizoroki-Heck reaction, a compound (33), wherein L, starting material and the transition metal catalyst used, and represents a hydrogen atom and X represents an alkenyl is not particularly limited insofar as the solvent does not group, and 0.5 to 5.0 equivalents of a compound (34a) or inhibit the reaction and allows the starting material to be compound (34b), wherein L, represents a chlorine atom, a dissolved therein to a certain extent. Preferable examples of bromine atom, an iodine atom or a sulfonate group Such as the solvent include acetonitrile, tetrahydrofuran, 1.4-diox a trifluoromethanesulfonate group, with respect to the com 35 ane, 1,2-dimethoxyethane, benzene, toluene, Xylene, pound (33) are stirred in a solvent in the presence of 0.01 to 1-methyl-2-pyrrolidone, N,N-dimethylformamide, water 1.0 equivalent of a transition metal catalyst with respect to and a mixed solvent thereof. The reaction temperature must the compound (33), for example. The transition metal cata be a temperature that can complete the coupling reaction, lyst used is preferably a palladium complex, for example, and is preferably room temperature to 200°C., for example. and more preferably a known palladium complex Such as 40 This reaction is performed preferably in an inert gas atmo palladium (II) acetate, dichlorobis(triphenylphosphine)pal sphere, and more preferably in a nitrogen or argon atmo ladium (II), tetrakis(triphenylphosphine)palladium (O) or sphere, for example. Under preferable reaction conditions, tris(dibenzylideneacetone)dipalladium (O). A phosphorus the reaction is completed in 1 to 24 hours, and the progress ligand Such as triphenylphosphine, tri-o-tolylphosphine, tri of the reaction can be monitored by a known chromatogra tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl 45 phy technique. An undesirable by-product can be removed may be preferably added, for example, in order to make the by a technique known to a person skilled in the art Such as reaction efficiently proceed. A preferable result may be a conventional chromatography technique, extraction or/and achieved in the presence of a base. The base used is not crystallization. The desired compound of the general for particularly limited insofar as the base is used in a coupling mula (I-4) or general formula (I-5) can also be obtained from reaction similar to this reaction. Preferable examples of the 50 a combination of the compound (33), wherein L, represents base include triethylamine, N,N-diisopropylethylamine, a chlorine atom, a bromine atom, an iodine atom or a N,N-dicyclohexylmethylamine and tetrabutylammonium Sulfonate group Such as a trifluoromethanesulfonate group, chloride. The solvent used varies according to the starting with the compound (34a) or compound (34b), wherein L, material and the transition metal catalyst used, and is not represents a boronic acid or boronate group, by the same particularly limited insofar as the solvent does not inhibit the method as above. reaction and allows the starting material to be dissolved 55 In Sonogashira reaction, an alkyne compound (33), therein to a certain extent. Preferable examples of the wherein L, represents a hydrogen atom, and X represents Solvent include acetonitrile, tetrahydrofuran, 1.4-dioxane, an alkynyl group, and 0.5 to 5 equivalents of a compound 1.2-dimethoxyethane, benzene, toluene, Xylene, 1-methyl (34a) or compound (34b), wherein L, represents a chlorine 2-pyrrolidone and N,N-dimethylformamide. The reaction atom, a bromine atom, an iodine atom or a sulfonate group temperature must be a temperature that can complete the 60 Such as a trifluoromethanesulfonate group, with respect to coupling reaction, and is preferably room temperature to the compound (33) are stirred in a solvent in the presence of 150° C., for example. This reaction is performed preferably 0.01 to 1.0 equivalent of a transition metal with respect to in an inert gas atmosphere, and more preferably in a nitrogen the compound (33), for example. The transition metal cata or argon atmosphere, for example. Under preferable reaction lyst used is preferably a known palladium complex, for conditions, the reaction is completed in 1 to 24 hours, and 65 example, and more preferably a known palladium complex the progress of the reaction can be monitored by a known Such as palladium (II) acetate, dichlorobis(triphenylphos chromatography technique. An undesirable by-product can phine)palladium (II), tetrakis(triphenylphosphine)palladium US 9,453,000 B2 73 74 (O) or tris(dibenzylideneacetone)dipalladium (O). A phos tris(dibenzylideneacetone)dipalladium (O), for example, and phorus ligand Such as triphenylphosphine, tri-o-tolylphos more preferably tetrakis(triphenylphosphine)palladium (O) phine or tri-tert-butylphosphine may be preferably added, or tris(dibenzylideneacetone)dipalladium (O), for example. for example, in order to make the reaction efficiently pro In order to make the reaction efficiently proceed, 0.1 to 5.0 ceed. In the reaction, a good result may be achieved when equivalents of copper (I) halide or/and lithium chloride may adding a metal halide or a quaternary ammonium salt Such be appropriately used. Preferable examples of the solvent as preferably copper (I) iodide, lithium chloride, tetrabuty used include toluene, xylene, N,N-dimethylformamide, lammonium fluoride or silver (I) oxide, for example. A N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl preferable result may be achieved in the presence of a base. sulfoxide and a mixture thereof. The reaction temperature The base used here is not particularly limited insofar as the 10 must be a temperature that can complete the coupling base is used in a coupling reaction similar to this reaction. reaction, and is preferably room temperature to 150° C., for Preferable examples of the base include diethylamine, tri example. This reaction is performed preferably in an inert ethylamine, N,N-diisopropylethylamine, piperidine and gas atmosphere, and more preferably in a nitrogen or argon pyridine. Preferable examples of the solvent used include atmosphere, for example. Under preferable reaction condi acetonitrile, tetrahydrofuran, 1.4-dioxane, 1,2-dimethoxy 15 tions, the reaction is completed in 1 to 24 hours, and the ethane, benzene, toluene, Xylene, 1-methyl-2-pyrrolidone, progress of the reaction can be monitored by a known N,N-dimethylformamide, dimethyl sulfoxide and a mixture chromatography technique. An undesirable by-product can thereof. More preferable examples of the solvent include tetrahydrofuran, 1.4-dioxane, 1-methyl-2-pyrrolidone and be removed by a technique known to a person skilled in the N,N-dimethylformamide. The reaction temperature must be art such as a conventional chromatography technique, a temperature that can complete the coupling reaction, and extraction or/and crystallization. The desired compound of is preferably room temperature to 150°C., for example. This the general formula (I-4) or general formula (I-5) can also be reaction is performed preferably in an inert gas atmosphere, obtained from a combination of the compound (33), wherein and more preferably in a nitrogen or argon atmosphere, for L' represents a trialkyltin group, with the compound (34a) example. Under preferable reaction conditions, the reaction or compound (35b), wherein L7 represents a chlorine atom, is completed in 1 to 24 hours, and the progress of the 25 a bromine atom, an iodine atom or a trifluoromethanesul reaction can be monitored by a known chromatography fonate group, by the same method as above. technique. An undesirable by-product can be removed by a Preparation of Compound (34a) and Compound (34b) technique known to a person skilled in the art such as a The compound (34a) or compound (34b) can be prepared conventional chromatography technique, extraction or/and by the same method as in the case of the compound (31). crystallization. 30 Preparation of Compound (33) In Stille coupling reaction, a compound (33), wherein L, The compound (33) can be prepared from a compound represents a chlorine atom, a bromine atom, an iodine atom (13) or compound (15) by the same method as in Step 2-7 or a trifluoromethanesulfonate group, and 0.5 to 5 equiva or Step 2-9. lents of a compound (34a) or compound (34b), wherein L, The compound of the general formula (I-7) or the general represents an alkyltin group, with respect to the compound 35 formula (I-8) can be prepared from the compound (34a) or (33) are stirred in a solvent in the presence of 0.01 to 1.0 compound (34b), wherein two of R', R'' and R' form a equivalent of a transition metal catalyst with respect to the ring, as a starting material by the same method as above. compound (33), for example. The transition metal catalyst General Preparation Method 5 used is preferably a known palladium complex Such as Typically used General Preparation Method 5 for the palladium (II) acetate, dichlorobis(triphenylphosphine)pal compound of the general formula (I) of the present invention ladium (II), tetrakis(triphenylphosphine)palladium (O) or will be described below.

Formula 41

(35) O N R11 O O PrSNY1N R Step 8-1 (36a)36a R2 N2Y Step 8-2 R11 (36b)

R10 Pr N NY1 StepStep 5-3 X L-R12 G. GS2, NR11 (2b) US 9,453,000 B2 75 -continued R12 N NY1 O (s X-Q Y X-O GC N1 NR11 (b). (I-4) (I-7) (I-8)

In the formula, the following partial structure (formula particularly limited insofar as the conditions are similar to III-4, III-5, III-7 or III-8): those in this reaction. A known method described in many documents such as Wittig reaction, Horner-Emmons reac 15 tion or Peterson reaction (see Shin Jikken Kagaku Koza Formula 42 (new Courses in Experimental Chemistry), vol. 19, Yuki (III-4) Gosei (Organic Synthesis) II, edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p. 57-85, for example) may be used. In Wittig reaction, a compound (35), wherein Ls repre sents a phosphonium salt, and 0.5 to 2.0 equivalents of a (III-5) carbonyl compound (36a) or a compound (36b) with respect to the compound (35) are stirred in a solvent in the presence 25 of 1.0 to 5.0 equivalents of a base with respect to the compound (35), for example. This reaction may be a method of first reacting a compound (35) with a base to form a (III-7) phosphorus ylide and then adding a carbonyl compound (36a) or a compound (36b) to the ylide; or a method of 30 adding a base in the presence of a compound (35) and a carbonyl compound (36a) or a compound (36b). The base used varies according to the starting material and the solvent and is not particularly limited. Preferable examples of the base include alkali metal hydroxides such as Sodium hydrox (III-8) 35 ide and lithium hydroxide; alkali metal carbonates Such as Sodium carbonate; alkali metal salts of alcohols such as Sodium methoxide and potassium tert-butoxide; organic bases such as triethylamine, pyridine and diazabicyclonon ene; organic metals such as butyl lithium and lithium 40 disobutylamide; and alkali metal hydrides such as sodium is a partial structure corresponding to the above-described hydride. The solvent used varies according to the starting Het, material and the base used, and is not particularly limited wherein Ari, Ars, X, Xs, X, Yo Yi, R, R2, R', R', insofar as the solvent does not inhibit the reaction and allows R". L., Pr, nd, ne, ni and nj are as defined above; and the starting material to be dissolved therein to a certain Ls represents a phosphite group Such as a diethylphosphonyl 45 extent. Preferable examples of the solvent used include polar group, a phosphonium salt such as triphenylphosphonium Solvents such as nitromethane, acetonitrile, 1-methyl-2-pyr bromide or a silyl group Such as a trimethylsilyl group. rolidone, N,N-dimethylformamide and dimethyl sulfoxide: The above General Preparation Method 5 is an example of ether solvents such as tetrahydrofuran, 1.4-dioxane and a method of condensing a compound (35) with a heterocy 1.2-dimethoxyethane; nonpolar solvents such as benzene, clic compound (36a) in Step 8-1 to prepare a compound of 50 toluene and Xylene; alcohol solvents such as ethanol and the general formula (I-4), the general formula (I-7) or the methanol; halogenated solvents such as chloroform and general formula (I-8); or a method of reacting a compound methylene chloride; water; and a mixed solvent thereof. The (35) with a heterocyclic compound (36b) having a protecting reaction temperature must be a temperature that can com group in Step 8-2 to once convert the compound (35) into a plete the reaction without promoting formation of an unde compound of the general formula (I-5) having a protecting 55 sirable by-product, and is preferably -78 to 150° C., for group and then deprotecting the protecting group of the example. Under preferable reaction conditions, the reaction compound of the general formula (I-5) and Subsequently is completed in 1 to 24 hours, and the progress of the reacting the compound with a compound (2b) in Step 5-3 to reaction can be monitored by a known chromatography prepare a compound of the general formula (I-4), the general technique. An undesirable by-product can be removed by a formula (I-7) or the general formula (I-8). 60 technique known to a person skilled in the art Such as a Preparation of Compound of General Formula (I-4) and conventional chromatography technique, extraction or/and Compound of General Formula (I-5) crystallization. The compound of the general formula (I-4) or the com In Horner-Emmons reaction, a compound (35), wherein pound of the general formula (I-5) can be prepared by Ls represents a phosphite group, is reacted with 0.5 to 2.0 reacting a compound (35) with a compound (36a) or (36b) 65 equivalents of a carbonyl compound (36a) or a compound according to Step 8-1 or Step 8-2. Specifically, Step 8-1 or (36b) with respect to the compound (35) in a solvent in the Step 8-2 varies according to the starting material and is not presence of 1.0 to 5.0 equivalents of a base with respect to US 9,453,000 B2 77 78 the compound (35), for example. This reaction may be a temperature must be a temperature that can complete the method of first treating a compound (35) and a base to form reaction without promoting formation of an undesirable a carbanion and then adding a carbonyl compound (36a) or by-product, and is preferably -78 to 150° C., for example. a compound (36b) to the carbanion; or a method of adding Under preferable reaction conditions, the reaction is com a base in the presence of a compound (35) and a carbonyl pleted in 1 to 24 hours, and the progress of the reaction can compound (36a) or a compound (36b). The base used varies be monitored by a known chromatography technique. An according to the starting material and the solvent and is not undesirable by-product can be removed by a technique particularly limited. Preferable examples of the base include known to a person skilled in the art Such as a conventional alkali metal hydroxides Such as sodium hydroxide and chromatography technique, extraction or/and crystallization. lithium hydroxide; alkali metal carbonates such as sodium 10 carbonate; alkali metal salts of alcohols such as sodium Preparation of Compound (36a) and Compound (36b) methoxide and potassium tert-butoxide; organic bases Such The compound (36a) and the compound (36b) are com as triethylamine, pyridine and diazabicyclononene; organic mercially available or can be prepared by a technique known metals such as butyl lithium and lithium diisobutylamide: to a person skilled in the art. If not commercially available, alkali metal hydrides such as sodium hydride; and alkali 15 the compounds can be prepared by acylation of a compound metal ammonium salts such as Sodium amide. The solvent (31), for example (see Shin Jikken Kagaku Koza (New used varies according to the starting material and the base Courses in Experimental Chemistry), vol. 21, Yuki Gosei used, and is not particularly limited insofar as the solvent (Organic Synthesis) III, edited by The Chemical Society of does not inhibit the reaction and allows the starting material to be dissolved therein to a certain extent. Preferable Japan, Maruzen Co., Ltd., February 1991, p. 184-194, for examples of the solvent include polar solvents such as example). 1-methyl-2-pyrrolidone, N,N-dimethylformamide and dim Preparation of Compound (35) ethyl sulfoxide; ether solvents such as tetrahydrofuran, 1.4- The compound (35) can be prepared from a compound (6) dioxane and 1,2-dimethoxyethane; nonpolar solvents such or compound (17) as a starting material by a known method as benzene, toluene and Xylene, alcohol Solvents such as 25 described in many documents. Preferably, for example, i) the ethanol and methanol; water, and a mixed solvent thereof. compound (35) as a Wittig reagent, wherein Ls represents a The reaction temperature must be a temperature that can phosphonium salt, can be prepared by halogenating a cor complete the reaction without promoting formation of an responding alcohol compound by a method known to a undesirable by-product, and is preferably -78 to 150° C., for person skilled in the art (see Shin Jikken Kagaku Koza (New example. Under preferable reaction conditions, the reaction 30 is completed in 1 to 24 hours, and the progress of the Courses in Experimental Chemistry), vol. 19, Yuki Gosei reaction can be monitored by a known chromatography (Organic Synthesis) II, edited by The Chemical Society of technique. An undesirable by-product can be removed by a Japan, Maruzen Co., Ltd., June 1992, p. 430-438, for technique known to a person skilled in the art such as a example), and then reacting the compound with an organo conventional chromatography technique, extraction or/and 35 phosphorus compound Such as triphenylphosphine (see crystallization. Organic Reaction, 1965, vol. 14, p. 270, for example). ii) In Peterson reaction, a compound (35), wherein Ls rep The compound (35) as a Horner-Emmons reagent, wherein resents a silyl group, is reacted with 0.5 to 2.0 equivalents Ls represents a phosphite, can be prepared by halogenating of a carbonyl compound (36a) or a compound (36b) with a corresponding alcohol compound by a method known to a respect to the compound (35) in a solvent in the presence of 40 person skilled in the art (see Shin Jikken Kagaku Koza (New 1.0 to 5.0 equivalents of a base with respect to the compound Courses in Experimental Chemistry), vol. 19, Yuki Gosei (35), for example. This reaction may be a method of first (Organic Synthesis) II, edited by The Chemical Society of treating a compound (35) and a base to form a carbanion and Japan, Maruzen Co., Ltd., June 1992, p. 430-438, for then adding a carbonyl compound (36a) or a compound example), and then reacting the compound with an alkyl (36b) to the carbanion; or a method of adding a base in the 45 phosphinite by Arbuzov reaction (see Chemical Review, presence of a compound (35) and a carbonyl compound 1981, Vol. 81, p. 415, for example) or with a metal phos (36a) or a compound (36b). The base used varies according phonite by Becker reaction (see Journal of the American to the starting material and the solvent and is not particularly Chemical Society, 1945, vol. 67, p. 1180, for example). limited. Preferable examples of the base include alkali metal Alternatively, the Horner-Emmons reagent can be prepared hydroxides such as sodium hydroxide and lithium hydrox 50 from a corresponding carbonyl compound and a chlorophos ide; alkali metal carbonates such as sodium carbonate; alkali phate in the presence of a base (see The Journal of Organic metal salts of alcohols such as Sodium methoxide and Chemistry, 1989, vol. 54, p. 4750, for example). iii) The potassium tert-butoxide; organic bases such as triethylam compound (35) as a Peterson reagent, wherein Lo represents ine, pyridine and diazabicyclononene; organic metals such a silyl group, can be prepared from a corresponding halogen as butyl lithium and lithium diisobutylamide: alkali metal 55 compound and a trialkylsilyl chloride in the presence of a hydrides such as sodium hydride; and alkali metal ammo base (see Journal of Organometallic Chemistry, 1983, vol. nium salts such as Sodium amide. The solvent used varies 248, p. 51, for example). according to the starting material and the base used, and is The compound of the general formula (I-7) or the com not particularly limited insofar as the solvent does not inhibit pound of the general formula (I-8) can be prepared from the the reaction and allows the starting material to be dissolved 60 compound (36a) or compound (36b), wherein two of R', therein to a certain extent. Preferable examples of the Solvent include polar solvents such as 1-methyl-2-pyrroli R'' and R' form a ring, as a starting material by the same done, N,N-dimethylformamide and dimethyl sulfoxide: method as above. ether solvents such as tetrahydrofuran, 1.4-dioxane and General Preparation Method 6 1.2-dimethoxyethane; nonpolar solvents such as benzene, 65 Typically used General Preparation Method 6 for the toluene and Xylene; alcohol solvents such as ethanol and compound of the general formula (I) of the present invention methanol; water; and a mixed solvent thereof. The reaction will be described below. US 9,453,000 B2 79 80

Formula 43

O

(I-8)

In the formula, the following partial structure (formula compound (38a) in Step 9-1 to prepare a compound of the III-4, III-5, III-7 or III-8): general formula (I-4), the general formula (I-7) or the 35 general formula (I-8); or a method of condensing a com pound (6) with a heterocyclic compound (36b) having a Formula 44 protecting group in Step 8-2 to once convert the compound (6) into a compound of the general formula (I-5) having a (III-4) protecting group and then deprotecting the protecting group 40 of the compound of the general formula (I-5) and subse quently reacting the compound with a compound (2b) in Step 5-3 to prepare a compound of the general formula (I-4), (III-5) the general formula (I-7) or the general formula (I-8). 45 Preparation of Compound of General Formula (I-4) and Compound of General Formula (I-5) The compound of the general formula (I-4) or general formula (I-5) can be prepared by reacting a compound (6) (III-7) with a compound (38a) or compound (36b) according to 50 Step 9-1 or Step 9-2. Specifically, Step 9-1 or Step 9-2 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction. A known method described in many documents such as Wittig reaction, Horner-Emmons reaction or Peter 55 son reaction may be used for the reaction (see Jikken (III-8) Kagaku Koza (Courses in Experimental Chemistry), vol. 19, Yuki Gosei (Organic Synthesis) II, edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p. 57-85, for example). 60 In Wittig reaction, a carbonyl compound (6) and 0.5 to 2.0 equivalents of a compound (38a) or compound (38b). is a partial structure corresponding to the above-described wherein Ls represents a phosphonium salt, with respect to Het, the carbonyl compound (6) are stirred in a solvent in the wherein Ar, Ar2. X, Xs. X6. Yo: Y11. R. R2, Rio, Ril, presence of 1.0 to 5.0 equivalents of a base with respect to R". L2, Ls, Pr, nd, ne, ni and nj are as defined above. 65 the carbonyl compound (6), for example. This reaction may The above General Preparation Method 6 is an example of be a method of first reacting a compound (38a) or compound a method of condensing a compound (6) with a heterocyclic (38b) with a base to form a phosphorus ylide and then US 9,453,000 B2 81 82 adding a carbonyl compound (6) to the ylide; or a method of ing formation of an undesirable by-product, and is prefer adding a base in the presence of a carbonyl compound (6) ably -78 to 150° C., for example. Under preferable reaction and a compound (38a) or compound (38b). The base used conditions, the reaction is completed in 1 to 24 hours, and varies according to the starting material and the solvent and the progress of the reaction can be monitored by a known is not particularly limited. Preferable examples of the base chromatography technique. An undesirable by-product can include alkali metal hydroxides such as Sodium hydroxide be removed by a technique known to a person skilled in the and lithium hydroxide; alkali metal carbonates such as art such as a conventional chromatography technique, Sodium carbonate; alkali metal salts of alcohols such as extraction or/and crystallization. Sodium methoxide and potassium tert-butoxide; organic In Peterson reaction, a carbonyl compound (6) and 0.5 to bases such as triethylamine, pyridine and diazabicyclonon 10 2.0 equivalents of a compound (38a) or compound (38b). ene; organic metals such as butyl lithium and lithium wherein Ls represents a silyl group, with respect to the disobutylamide; and alkali metal hydrides such as sodium carbonyl compound (6) are stirred in a solvent in the hydride. The solvent used varies according to the starting presence of 1.0 to 5.0 equivalents of a base with respect to material and the base used, and is not particularly limited the carbonyl compound (6), for example. This reaction may insofar as the solvent does not inhibit the reaction and allows 15 be a method of first treating a compound (38a) or compound the starting material to be dissolved therein to a certain (38b) and a base to form a carbanion and then adding a extent. Preferable examples of the solvent used include polar carbonyl compound (6) to the carbanion; or a method of Solvents such as nitromethane, acetonitrile, 1-methyl-2-pyr adding a base in the presence of a carbonyl compound (6) rolidone, N,N-dimethylformamide and dimethyl sulfoxide: and a compound (38a) or compound (38b). The base used ether solvents such as tetrahydrofuran, 1.4-dioxane and varies according to the starting material and the solvent and 1.2-dimethoxyethane; nonpolar solvents such as benzene, is not particularly limited. Preferable examples of the base toluene and Xylene; alcohol solvents such as ethanol and include alkali metal hydroxides such as Sodium hydroxide methanol; halogenated solvents such as chloroform and and lithium hydroxide; alkali metal carbonates such as methylene chloride; water; and a mixed solvent thereof. The Sodium carbonate; alkali metal salts of alcohols such as reaction temperature must be a temperature that can com 25 Sodium methoxide and potassium tert-butoxide; organic plete the reaction without promoting formation of an unde bases such as triethylamine, pyridine and diazabicyclonon sirable by-product, and is preferably -78 to 150° C., for ene; organic metals such as butyl lithium and lithium example. Under preferable reaction conditions, the reaction disobutylamide; alkali metal hydrides such as sodium is completed in 1 to 24 hours, and the progress of the hydride; and alkali metal ammonium salts such as Sodium reaction can be monitored by a known chromatography 30 amide. The solvent used varies according to the starting technique. An undesirable by-product can be removed by a material and the base used, and is not particularly limited technique known to a person skilled in the art such as a insofar as the solvent does not inhibit the reaction and allows conventional chromatography technique, extraction or/and the starting material to be dissolved therein to a certain crystallization. extent. Preferable examples of the solvent include polar In Horner-Emmons reaction, a carbonyl compound (6) 35 solvents such as 1-methyl-2-pyrrolidone, N,N-dimethylfor and 0.5 to 2.0 equivalents of a compound (38a) or compound mamide and dimethyl sulfoxide; ether solvents such as (38b), wherein Ls represents a phosphite group, with respect tetrahydrofuran, 1.4-dioxane and 1,2-dimethoxyethane; to the carbonyl compound (6) are stirred in a solvent in the nonpolar solvents such as benzene, toluene and Xylene; presence of 1.0 to 5.0 equivalents of a base with respect to alcohol Solvents such as ethanol and methanol; water, and a the carbonyl compound (6), for example. This reaction may 40 mixed solvent thereof. The reaction temperature must be a be a method of first treating a compound (38a) or compound temperature that can complete the reaction without promot (38b) and a base to form a carbanion and then adding a ing formation of an undesirable by-product, and is prefer carbonyl compound (6) to the carbanion; or a method of ably -78 to 150° C., for example. Under preferable reaction adding a base in the presence of a carbonyl compound (6) conditions, the reaction is completed in 1 to 24 hours, and and a compound (38a) or compound (38b). The base used 45 the progress of the reaction can be monitored by a known varies according to the starting material and the solvent and chromatography technique. An undesirable by-product can is not particularly limited. Preferable examples of the base be removed by a technique known to a person skilled in the include alkali metal hydroxides such as Sodium hydroxide art such as a conventional chromatography technique, and lithium hydroxide; alkali metal carbonates such as extraction or/and crystallization. Sodium carbonate; alkali metal salts of alcohols such as 50 Preparation of Compound (38a) and Compound (38b) Sodium methoxide and potassium tert-butoxide; organic The compound (38a) and the compound (38b) are com bases such as triethylamine, pyridine and diazabicyclonon mercially available or prepared by a technique known to a ene; organic metals such as butyl lithium and lithium person skilled in the art. If not commercially available, for disobutylamide; alkali metal hydrides such as sodium example, i) the compound (38a) or compound (38b) as a hydride; and alkali metal ammonium salts such as sodium 55 Wittig reagent, wherein Ls represents a phosphonium salt, amide. The solvent used varies according to the starting can be prepared by halogenating a corresponding alcohol material and the base used, and is not particularly limited compound by a method known to a person skilled in the art insofar as the solvent does not inhibit the reaction and allows (see Shin Jikken Kagaku Koza (New Courses in Experi the starting material to be dissolved therein to a certain mental Chemistry), vol. 19, Yuki Gosei (Organic Synthesis) extent. Preferable examples of the solvent include polar 60 I, edited by The Chemical Society of Japan, Maruzen Co., solvents such as 1-methyl-2-pyrrolidone, N,N-dimethylfor Ltd., June 1992, p. 430-438, for example), and then reacting mamide and dimethyl sulfoxide; ether solvents such as the compound with an organophosphorus compound Such as tetrahydrofuran, 1.4-dioxane and 1,2-dimethoxyethane; triphenylphosphine (see Organic Reaction, 1965, vol. 14, p. nonpolar solvents such as benzene, toluene and Xylene; 270, for example). ii) The compound (38a) or compound alcohol solvents such as ethanol and methanol; water, and a 65 (38b) as a Horner-Emmons reagent, wherein Ls represents a mixed solvent thereof. The reaction temperature must be a phosphite, can be prepared by halogenating a corresponding temperature that can complete the reaction without promot alcohol compound by a method known to a person skilled in US 9,453,000 B2 83 84 the art (see Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol. 19, Yuki Gosei (Organic Formula 46 Synthesis) II, edited by The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p. 430-438, for example), and (III-4) then reacting the compound with an alkyl phosphinite by Arbuzov reaction (see Chemical Review, 1981, vol. 81, p. 415, for example) or with a metal phosphonite by Becker reaction (see Journal of the American Chemical Society, 1945, vol. 67, p. 1180, for example). Alternatively, the (III-7) compound can be prepared from a corresponding carbonyl 10 compound and a chlorophosphate in the presence of a base (see Journal of Organic Chemistry, 1989, vol. 54, p. 4750, for example). iii) The compound (38a) or compound (38b) as a Peterson reagent, wherein Lo represents a silyl group, 15 can be prepared from a corresponding halogen compound (III-8) and a trialkylsilyl chloride (see Journal of Organometallic Chemistry, 1983, vol. 248, p. 51, for example). The compound of the general formula (I-7) or the com pound of the general formula (I-8) can be prepared from the compound (38a) or compound (38b), wherein two of R', R'' and R' form a ring, as a starting material by the same is a partial structure corresponding to the above-described method as above. Het, General Preparation Method 7 wherein Ari, Ar., X, Xs, X, Yo Yi, R', R', R', L7, Typically used General Preparation Method 7 for the 25 L', nd, ne, ni and nj are as defined above; and R' is as compound of the general formula (I) of the present invention defined for R''. will be described below. The above General Preparation Method 7 is an example of a method of condensing a compound (39) with a compound 30 (40) in Step 10 to prepare a compound of the general Formula 45 formula (I-4), the general formula (I-7) or the general R 2 }sy," O O formula (I-8). X-( StepStep 10 Preparation of Compound of General Formula (I-4) N4Yil L-R The compound of the general formula (I-4) can be pre L7' 35 pared by reacting a compound (39) with a compound (40) (40) according to Step 10. Specifically, Step 10 varies according to the starting material and is not particularly limited insofar as the conditions are similar to those in this reaction. A (39) known method described in many documents such as Mizo R12 N R10 NY1 40 roki-Heck reaction (see R. F. Heck, “Org. Reactions., 1982, O vol. 27, p. 345, for example), Suzuki-Miyaura reaction (see A. Suzuki, “Chem. Rev., 1995, vol. 95, p. 2457, for example), Sonogashira reaction (see K. Sonogashira, "Com prehensive Organic Synthesis”, 1991, vol. 3, p. 521) or Stille 45 coupling reaction (see J. K. Stille, “Angew. Chem. Int. Ed. Engl., 1986, vol. 25, p. 508, for example) may be used for the reaction. In Mizoroki-Heck reaction, a compound (39), wherein L, represents a chlorine atom, a bromine atom, an iodine atom O 50 or a Sulfonate group Such as a trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of an alkene compound (40), wherein L, represents a hydrogen atom and R' represents a C1-6 alkenyl group which may be substituted with 1 to 3 substituents selected from the above Substituent (I-7) 55 Group A1, with respect to the compound (39) are stirred in a solvent in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound (39), for example. The transition metal catalyst used is preferably a palladium complex, for example, and more preferably a 60 known palladium complex Such as palladium (II) acetate, dichlorobis(triphenylphosphine)palladium (II), tetrakis(tri phenylphosphine)palladium (O) or tris(dibenzylideneac etone)dipalladium (0). A phosphorus ligand Such as triph (I-8) enylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine 65 or 2-(di-tert-butylphosphino)biphenyl may be preferably In the formula, the following partial structure (formula added, for example, in order to make the reaction efficiently III-4, III-7 or III-8): proceed. A preferable result may be obtained in the presence US 9,453,000 B2 85 86 of a base, and the base used is not particularly limited insofar phy technique. An undesirable by-product can be removed as the base is used in a coupling reaction the same as this by a technique known to a person skilled in the art Such as reaction. Preferable examples of the base include triethyl a conventional chromatography technique, extraction or/and amine, N,N-diisopropylethylamine, N,N-dicyclohexylmeth crystallization. The desired compound of the general for ylamine and tetrabutylammonium chloride. The solvent mula (I-4) can also be obtained from a combination of the used varies according to the starting material and the tran compound (39), wherein L' represents a boronic acid group sition metal catalyst used, and is not particularly limited or a boronate group, with the compound (40), wherein L, insofar as the solvent does not inhibit the reaction and allows represents a chlorine atom, a bromine atom, an iodine atom the starting material to be dissolved therein to a certain or a Sulfonate group Such as a trifluoromethanesulfonate extent. Preferable examples of the solvent include acetoni 10 group, by the same method as above. trile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, In Sonogashira reaction, a compound (39), wherein L, benzene, toluene, xylene, 1-methyl-2-pyrrolidone and N,N- represents a chlorine atom, a bromine atom, an iodine atom dimethylformamide. The reaction temperature must be a or a Sulfonate group Such as a trifluoromethanesulfonate temperature that can complete the coupling reaction, and is group, and 1.0 to 10 equivalents of an alkyne compound preferably room temperature to 150° C., for example. This 15 (40), wherein L, represents a hydrogen atom and R' reaction is performed preferably in an inert gas atmosphere, represents a C1-6 alkynyl group which may be substituted and more preferably in a nitrogen or argon atmosphere, for with 1 to 3 substituents selected from the above Substituent example. Under preferable reaction conditions, the reaction Group A1, with respect to the compound (39) are stirred in is completed in 1 to 24 hours, and the progress of the a solvent in the presence of 0.01 to 0.5 equivalent of a reaction can be monitored by a known chromatography transition metal catalyst with respect to the compound (39), technique. An undesirable by-product can be removed by a for example. The transition metal catalyst used is preferably technique known to a person skilled in the art such as a a known palladium complex, for example, and more pref conventional chromatography technique, extraction or/and erably a known palladium complex Such as palladium (II) crystallization. acetate, dichlorobis(triphenylphosphine)palladium (II), tet In Suzuki-Miyaura reaction, a compound (39), wherein 25 rakis(triphenylphosphine)palladium (O) or tris(dibenzylide L' represents a chlorine atom, a bromine atom, an iodine neacetone)dipalladium (0). A phosphorus ligand Such as atom or a sulfonate group Such as a trifluoromethanesul triphenylphosphine, tri-o-tolylphosphine or tri-tert-butyl fonate group, and 1.0 to 10.0 equivalents of a compound phosphine may be preferably added, for example, in order to (40), wherein L, represents a boronic acid group or a make the reaction efficiently proceed. In the reaction, a good boronate group, with respect to the compound (39) are 30 result may be achieved when adding a metal halide or a stirred in a solvent in the presence of 0.01 to 0.5 equivalent quaternary ammonium salt, preferably copper (I) iodide, of a transition metal catalyst with respect to the compound lithium chloride, tetrabutylammonium fluoride or silver (I) (39), for example. The transition metal catalyst used is oxide, for example. A preferable result may be obtained in preferably a known palladium complex, and more preferably the presence of a base, and the base used here is not a known palladium complex such as palladium (II) acetate, 35 particularly limited insofar as the base is used in a coupling dichlorobis(triphenylphosphine)palladium (II), tetrakis(tri reaction the same as this reaction. Preferable examples of the phenylphosphine)palladium (O) or tris(dibenzylideneac base include diethylamine, triethylamine, N,N-diisopropyl etone)dipalladium (0). A phosphorus ligand Such as triph ethylamine, piperidine and pyridine. Preferable examples of enylphosphine, tri-o-tolylphosphine, the solvent used include acetonitrile, tetrahydrofuran, 1.4- tricyclohexylphosphine or tri-tert-butylphosphine may be 40 dioxane, 1,2-dimethoxyethane, benzene, toluene, Xylene, preferably added, for example, in order to make the reaction 1-methyl-2-pyrrolidone, N,N-dimethylformamide and dim efficiently proceed. Aquaternary ammonium salt, preferably ethyl sulfoxide. More preferable examples of the solvent tetrabutylammonium chloride or tetrabutylammonium bro include tetrahydrofuran, 1.4-dioxane, 1-methyl-2-pyrroli mide, for example, may also be added in order to make the done and N,N-dimethylformamide. The reaction tempera reaction efficiently proceed. In this reaction, a preferable 45 ture must be a temperature that can complete the coupling result may be achieved in the presence of a base. The base reaction, and is preferably room temperature to 150° C., for used at this time varies according to the starting material, the example. This reaction is performed preferably in an inert Solvent used and the like, and is not particularly limited. gas atmosphere, and more preferably in a nitrogen or argon Preferable examples of the base include sodium hydroxide, atmosphere, for example. Under preferable reaction condi barium hydroxide, potassium fluoride, cesium fluoride, 50 tions, the reaction is completed in 1 to 24 hours, and the Sodium carbonate, potassium carbonate, cesium carbonate progress of the reaction can be monitored by a known and potassium phosphate. The solvent used varies according chromatography technique. An undesirable by-product can to the starting material and the transition metal catalyst used, be removed by a technique known to a person skilled in the and is not particularly limited insofar as the solvent does not art such as a conventional chromatography technique, inhibit the reaction and allows the starting material to be 55 extraction or/and crystallization. dissolved therein to a certain extent. Preferable examples of In Stille coupling reaction, a compound (39), wherein L, the solvent include acetonitrile, tetrahydrofuran, 1.4-diox represents a chlorine atom, a bromine atom, an iodine atom ane, 1,2-dimethoxyethane, benzene, toluene, Xylene, or a trifluoromethanesulfonate group, and 1.0 equivalent or 1-methyl-2-pyrrolidone, N,N-dimethylformamide, water more of a compound (40), wherein L, represents a trialkyltin and a mixed solvent thereof. The reaction temperature must 60 group, with respect to the compound (39) are stirred in a be a temperature that can complete the coupling reaction, solvent in the presence of 0.01 to 0.2 equivalent of a and is preferably room temperature to 200°C., for example. transition metal catalyst with respect to the compound (39), This reaction is performed preferably in an inert gas atmo for example. The transition metal catalyst used is preferably sphere, and more preferably in a nitrogen or argon atmo a palladium complex, for example, and more preferably a sphere, for example. Under preferable reaction conditions, 65 known palladium complex Such as palladium (II) acetate, the reaction is completed in 1 to 24 hours, and the progress dichlorobis(triphenylphosphine)palladium (II), tetrakis(tri of the reaction can be monitored by a known chromatogra phenylphosphine)palladium (O) or tris(dibenzylideneac US 9,453,000 B2 87 88 etone)dipalladium (O). In order to make the reaction effi -continued ciently proceed, 0.1 to 5.0 equivalents of copper (I) halide or/and lithium chloride may be added. Preferable examples of the solvent used include toluene, xylene, N,N-dimethyl formamide, N,N-dimethylacetamide, 1-methyl-2-pyrroli done and dimethyl sulfoxide. The reaction temperature must be a temperature that can complete the coupling reaction, and is preferably room temperature to 150°C., for example. This reaction is performed preferably in an inert gas atmo sphere, and more preferably in a nitrogen or argon atmo (I-8) sphere, for example. Under preferable reaction conditions, 10 the reaction is completed in 1 to 24 hours, and the progress In the formula, the following partial structure (formula of the reaction can be monitored by a known chromatogra III-4, III-7 or III-8): phy technique. An undesirable by-product can be removed by a technique known to a person skilled in the art such as a conventional chromatography technique, extraction or/and 15 crystallization. The desired compound of the general for Formula 48 mula (I-4) can also be obtained from a combination of the (III-4) compound (39), wherein L' represents a trialkyltin group, with the compound (40), wherein L, represents a chlorine atom, a bromine atom, an iodine atom or a trifluorometh anesulfonate group, by the same method as above. The compound (40) is commercially available or can be prepared by a method known to a person skilled in the art. (III-7) Preparation of Compound (39) The compound (39) can be prepared by a method in the 25 above General Preparation Methods 1 to 6. The compound of the general formula (I-7) or the general formula (I-8) can be prepared by the same method as above using, as a starting material, the compound (39), wherein R" and Reach represent an alkyl group substituted with (III-8) an alkenyl group or an alkynyl group or an alkenyl group, an 30 alkynyl group or an alkyl group Substituted with a halogen atom and L' represents a chlorine atom, a bromine atom, an iodine atom, a Sulfonate group such as a trifluoromethane Sulfonate group, or a trialkyltin group, without use of the compound (40). 35 General Preparation Method 8 is a partial structure corresponding to the above-described Typically used General Preparation Method 8 for the Het, compound of the general formula (I) of the present invention wherein Ari, Ars, X, Xs, X, Yo Yi, R', R', R', Ls, nd, will be described below. ne, ni and nj are as defined above. 40 The above General Preparation Method 8 is an example of a method of condensing a compound (41) with a compound (42) in Step 12 to prepare a compound of the general Formula 47 formula (I-4), the general formula (I-7) or the general formula (I-8). 45 Preparation of Compound of General Formula (I-4) The compound of the general formula (I-4) can be pre pared by condensing a compound (41) with a compound (42) according to Step 12. Specifically, Step 12 varies according to the starting material and is not particularly 50 limited insofar as the conditions are similar to those in this reaction. For example, a known method described in many O documents such as coupling reaction using a copper com pound of an arylboronic acid derivative (see The Journal of Organic Chemistry, 2001, vol. 66, p. 7892, for example), 55 Ullmann reaction (see Journal of Medicinal Chemistry, 1981, Vol. 24, p. 1139, for example) or nucleophilic substi tution reaction (see Journal of Medicinal Chemistry, 1991, vol. 39, p. 2671-2677, for example) may be used for the reaction. 60 The coupling reaction of an arylboronic acid derivative O using a copper compound is, for example, a method of stirring a compound (41), wherein L. represents a boronic acid group or a boronate group, and 1.0 to 10.0 equivalents of a compound (42) with respect to the compound (41) in a 65 solvent in the presence of 0.01 to 1.0 equivalent of a copper (I-7) reagent Such as copper, copper bromide or copper iodide with respect to the compound (41) by addition of 1.0 to 10.0 US 9,453,000 B2 89 90 equivalents of a base with respect to the compound (41). The 1 to 24 hours, and the progress of the reaction can be base used varies according to the starting material, the monitored by a known chromatography technique. An unde Solvent used and the like, and is not particularly limited sirable by-product can be removed by a technique known to insofar as the base does not inhibit the reaction. Preferable a person skilled in the art such as a conventional chroma examples of the base include organic bases Such as trieth tography technique, extraction or/and crystallization. ylamine, pyridine and tetramethylethylenediamine; alkali In nucleophilic Substitution reaction, a compound (41), metal salts such as potassium carbonate, sodium carbonate, wherein L. represents a halogen atom Such as a chlorine potassium acetate, Sodium acetate and cesium carbonate; atom, a bromine atom or an iodine atom or a Sulfonate group and metal alkoxides such as Sodium methoxide and potas Such as a methanesulfonate group, a p-toluenesulfonate sium tert-butoxide. The copper reagent used varies accord 10 ing to the starting material and is not particularly limited. group or a trifluoromethanesulfonate group, and 2.0 to 5.0 Preferable examples of the copper reagent include copper equivalents of a compound (42) with respect to the com acetate and di-L-hydroxo-bis(N.N.N',N'-tetramethylethyl pound (41) are stirred in a solvent in the presence or absence enediamine)copper (II) chloride. The solvent used varies of 1.0 to 5.0 equivalents of a base with respect to the according to the starting material, the reagent and the like, 15 compound (41), for example. The base used varies accord and is not particularly limited insofar as the solvent does not ing to the starting material and is not particularly limited. inhibit the reaction and allows the starting material to be Preferable examples of the base include sodium hydride, dissolved therein to a certain extent. Preferable examples of Sodium hydroxide, potassium hydroxide, potassium carbon the solvent include ether solvents such as tetrahydrofuran, ate, Sodium carbonate, cesium carbonate, barium carbonate, 1,4-dioxane and diethyl ether, halogenated Solvents such as pyridine, lutidine and triethylamine. The solvent used varies methylene chloride, 1,2-dichloroethane and chloroform: according to the starting material, and is not particularly polar solvents such as ethyl acetate, N,N-dimethylforma limited insofar as the solvent does not inhibit the reaction mide and N-methylpyrrolidone; nonpolar solvents such as and allows the starting material to be dissolved therein to a toluene, benzene and dichlorobenzene, and a mixture certain extent. Preferable examples of the solvent include thereof. The reaction temperature must be a temperature that 25 acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N,N-dim can complete the reaction without promoting formation of ethylformamide and N-methylpyrrolidine. The base may an undesirable by-product, and is preferably room tempera optionally be used as a solvent. The reaction temperature ture to 200° C., for example. Good results such as reduction must be a temperature that can complete the reaction without in the reaction time and improvement of the yield may be promoting formation of an undesirable by-product, and is achieved when the reaction is performed in an oxygen 30 preferably room temperature to 150° C., for example. Under atmosphere or air stream. Under preferable reaction condi preferable reaction conditions, the reaction is completed in tions, the reaction is completed in 1 to 24 hours, and the 1 to 24 hours, and the progress of the reaction can be progress of the reaction can be monitored by a known monitored by a known chromatography technique. An unde chromatography technique. An undesirable by-product can sirable by-product can be removed by a technique known to be removed by a technique known to a person skilled in the 35 a person skilled in the art such as a conventional chroma art such as a conventional chromatography technique, tography technique or/and crystallization. extraction or/and crystallization. Preparation of Compound (41) In Ullmann reaction, a compound (41), wherein La rep The compound (41) is prepared by the same method as in resents a halogen atom Such as a chlorine atom, a bromine the above General Preparation Methods 1 to 7. atom or an iodine atom, and 1.0 to 10.0 equivalents of a 40 Preparation of Compound (42) compound (42) with respect to the compound (41) are stirred The compound (42) is commercially available or prepared in a solvent in the presence of 0.01 to 1.0 equivalent of a by a method known to a person skilled in the art. copper reagent such as copper, copper bromide or copper The compound of the general formula (I-7) or the general iodide with respect to the compound (41) by addition of 1.0 formula (I-8) can be prepared from the compound (41), to 10.0 equivalents of a base with respect to the compound 45 wherein two of R', R'' and R' form a ring, as a starting (41), for example. The base used varies according to the material by the same method as above. starting material and is not particularly limited. Preferable General Preparation Methods 1 to 8 for the compound of examples of the base include alkali metal salts such as the present invention described above in detail are methods potassium carbonate, sodium carbonate, potassium acetate, for preparing a compound represented by the general for Sodium acetate and cesium carbonate; and metal alkoxides 50 mula (I-9), the general formula (I-4), the general formula Such as sodium methoxide and potassium tert-butoxide. The (I-5), the general formula (I-6), the general formula (I-7) or Solvent used varies according to the starting material, the the general formula (I-8), wherein Het falls within a part of reagent and the like, and is not particularly limited insofar as the definition of Het in the general formula (I). However, the the solvent does not inhibit the reaction and allows the compound of the general formula (I), wherein Het falls starting material to be dissolved therein to a certain extent. 55 within another part of the definition of Het, can be prepared Preferable examples of the solvent that can be used include almost in the same manner as in the above General Prepa ether solvents such as tetrahydrofuran, 1.4-dioxane and ration Methods 1 to 8, or can be prepared by another method diethyl ether, halogenated solvents such as methylene chlo itself known to a person skilled in the art. The examples ride, 1,2-dichloroethane and chloroform; alcohol solvents described later will provide reference to these Preparation Such as amyl alcohol and isopropyl alcohol; polar solvents 60 Methods, and the compound of the general formula (I) can such as N,N-dimethylformamide and N-methylpyrrolidone: be easily prepared by a method itself known to a person nonpolar solvents such as toluene, benzene and dichloroben skilled in the art based on these examples. Zene; and a mixture thereof. The reaction temperature must The compound of the general formula (I) or pharmaco be a temperature that can complete the reaction without logically acceptable salt thereof according to the present promoting formation of an undesirable by-product, and is 65 invention is effective for prevention or treatment of a disease preferably room temperature to 200°C., for example. Under caused by AB and is excellent in terms of pharmacokinetics, preferable reaction conditions, the reaction is completed in toxicity, stability, absorption and the like. US 9,453,000 B2 91 92 A prophylactic or therapeutic agent for a disease caused used for a pharmaceutical, a quasi drug, a cosmetic or the by AB comprising the compound of the formula (I) or like may be used. Examples of the base material include pharmacologically acceptable salt thereof according to the materials such as animal and vegetable oils, mineral oils, present invention as an active ingredient can be prepared by ester oils, waxes, higher alcohols, fatty acids, silicone oils, a conventional method. Preferable examples of the dosage Surfactants, phospholipids, alcohols, polyhydric alcohols, form include tablets, powders, fine granules, granules, water-soluble polymers, clay minerals and purified water. A coated tablets, capsules, syrups, troches, inhalants, Supposi pH adjuster, an antioxidant, a chelator, a preservative and tories, injections, ointments, ophthalmic Solutions, ophthal fungicide, a colorant, a flavor or the like may be added mic ointments, nasal drops, ear drops, cataplasms and where necessary. Further, an ingredient having a differen lotions. The prophylactic or therapeutic agent can be pre 10 tiation inducing effect such as a blood flow enhancer, a pared by using ingredients typically used such as an excipi bactericide, an antiphlogistic, a cell activator, Vitamin, ent, a binder, a lubricant, a colorant and a corrective, and amino acid, a humectant or a keratolytic agent may be ingredients used where necessary Such as a stabilizer, an blended where necessary. emulsifier, an absorbefacient, a Surfactant, a pH adjuster, a The dose of the therapeutic or prophylactic agent of the preservative and an antioxidant, and can be prepared by 15 present invention varies according to the degree of symp blending ingredients generally used as materials for a phar toms, age, sex, body weight, mode of administration, type of maceutical preparation. Examples of Such ingredients salt and specific type of disease, for example. Typically, the include animal and vegetable oils such as soybean oil, beef compound of the formula (I) or pharmacologically accept tallow and synthetic glyceride; hydrocarbons such as liquid able salt thereof is orally administered to an adult at about paraffin, squalane and Solid paraffin; ester oils such as 30 ug to 10g, preferably 100 ug to 5 g, and more preferably octyldodecyl myristate and isopropyl myristate; higher alco 100 g to 100 mg per day, or is administered to an adult by hols such as cetostearyl alcohol and behenyl alcohol; a injection at about 30 ug to 1 g, preferably 100 lug to 500 mg. silicone resin; Silicone oil; Surfactants such as polyoxyeth and more preferably 100 ug to 30 mg per day, in a single ylene fatty acid ester, Sorbitan fatty acid ester, glycerin fatty dose or several divided doses, respectively. acid ester, polyoxyethylene Sorbitan fatty acid ester, poly 25 For prevention or treatment of a disease caused by AB oxyethylene hydrogenated castor oil and a polyoxyethylene Such as Alzheimer's disease, senile dementia, Down's dis polyoxypropylene block copolymer; water-soluble polymers ease and amyloidosis, the compound represented by the Such as hydroxyethylcellulose, polyacrytic acid, a car formula (I) or a pharmacologically acceptable salt thereof boxyvinyl polymer, polyethylene glycol, polyvinylpyrroli according to the present invention may be used in combi done and methylcellulose; lower alcohols such as ethanol 30 nation with for compounds having mechanisms as described and isopropanol; polyhydric alcohols such as glycerin, pro below. pylene glycol, dipropylene glycol and sorbitol; sugars such For example, such compounds include cholinesterase as glucose and Sucrose; inorganic powders such as silicic inhibitors (e.g., donepezil, huperzine A, tacrine, rivastig anhydride, magnesium aluminum silicate and aluminum mine, galantamine); AMPA receptor antagonists (e.g., 1.2- silicate; and purified water. Examples of the excipient used 35 dihydropyridine compounds such as 3-(2-cyanophenyl)-5- include lactose, corn starch, Saccharose, glucose, mannitol, (2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one); NMDA sorbitol, crystalline cellulose and silicon dioxide. Examples receptor antagonists (e.g., memantine); acetylcholine releas of the binder used include polyvinyl alcohol, polyvinyl ing stimulants (e.g., pramiracetam; aniracetam); calcium ether, methylcellulose, ethylcellulose, gum arabic, traga channel agonists (e.g., nefiracetam); free radical scavengers canth, gelatin, shellac, hydroxypropylmethylcellulose, 40 (e.g., EGb 761); platelet activating factor antagonists (e.g., hydroxypropylcellulose, polyvinylpyrrolidone, a polypro EGb 761); platelet aggregation antagonists (e.g., EGb 761, pylene glycol-polyoxyethylene block copolymer and meglu triflusal); insulin sensitizers (e.g., rosiglitaZone); peroxi mine. Examples of the disintegrator used include starch, Some proliferator-activated receptor agonists (e.g., rosigli agar, gelatin powder, crystalline cellulose, calcium carbon taZone); peroxisome proliferator-activated receptor gamma ate, Sodium bicarbonate, calcium citrate, dextrin, pectin and 45 agonists (e.g., rosiglitaZone); monoamine oxidase B inhibi carboxymethylcellulose calcium. Examples of the lubricant tors (e.g., rasagiline, selegiline, procaine); carnitine acetyl used include magnesium Stearate, talc, polyethylene glycol, transferase stimulants (e.g., levacecarnine); NSAIDs (e.g., silica and hydrogenated vegetable oil. Examples of the triflusal, cyclooxygenase-2 inhibitors, such as celecoxib); colorant used include those permitted to be added to phar nerve growth factor agonists (e.g., xaliproden, FPF 1070): maceuticals. Examples of the corrective used include cocoa 50 beta-amyloid inhibitors (e.g., tarenflurbil, tramiprosate, leu powder, menthol, empasm, mentha oil, borneol and cinna prorelin-D); immunomodulators (e.g., tarenflurbil, immune mon powder. globulin, icosapentethyl ester); NF-kappa B inhibitors (e.g., For example, an oral preparation is prepared by adding an tarenflurbil); thyrotropin releasing hormone agonists (e.g., active ingredient compound or a salt thereof or a hydrate of taltirelin); dopamine D2 receptor antagonists (e.g., risperi the compound or salt, an excipient, and, where necessary, a 55 done); serotonin 2 receptor antagonists (e.g., risperidone); binder, a disintegrant, a lubricant, a colorant and a correc muscarinic M1 receptor agonists (e.g., cevimeline); alpha 1 tive, for example, and then forming the mixture into powder, adrenoceptor agonists (e.g., modafinil); serotonin 3 receptor fine granules, granules, tablets, coated tablets or capsules, antagonists (e.g., alosetron); dopamine D2 receptor agonists for example, by a conventional method. It is obvious that (e.g., aripiprazole); dopamine D2 receptor antagonists (e.g., tablets or granules may be appropriately coated, for 60 aripiprazole); serotonin 1A receptor agonists (e.g., aripipra example, Sugar coated, where necessary. A syrup or an Zole); serotonin 2A receptor antagonists (e.g., aripiprazole); injection preparation is prepared by adding a pH adjuster, a glucocorticoidantagonists (e.g., mifepristone); progesterone solubilizer and an isotonizing agent, for example, and a antagonists (e.g., mifepristone); HMG-CoA reductase solubilizing agent, a stabilizer and the like where necessary inhibitors (e.g., atorvastatin, simvastatin); adenosine uptake by a conventional method. An external preparation may be 65 inhibitors (e.g., propentofylline); phosphodiesterase inhibi prepared by any conventional method without specific limi tors (e.g., propentofylline); acetylcholine receptor agonists tations. As a base material, any of various materials usually (e.g., choline alfoscerate); membrane permeability enhanc US 9,453,000 B2 93 94 ers (e.g., choline alfoscerate); cannabinoid 1 receptor prolyl-L-glutamine), DAS 431, DEBIO 9902, DAR 100, antagonists (e.g., rimonabant); cannabinoid receptor ago mitocquinone, IPL 455903 (i.e., 5(S)-3-(Cyclopentyloxy)-4- nists (e.g., dronabinol); angiogenesis inhibitors (e.g., pacli methoxyphenyl-3(S)-(3-methylbenzyl)piperidin-2-one), taxel); immunosuppressants (e.g., paclitaxel); tubulin E2CDS, PYM 50028, PBT 2, lecozotan, SB 742457, CX antagonists (e.g., paclitaxel); thromboxane A2 synthase 717, AVE 1625 (i.e., 1-(bis(4-chlorophenyl)methyl)-3-((3.5- inhibitors (e.g., triflusal); antioxidants (e.g., idebenone); difluorophenyl)(methylsulfonyl)methylene)azetidine), LY alpha adrenoreceptor antagonists (e.g., nicergoline); estro 450139 (i.e., N2-2(s)-Hydroxy-3-methylbutyryl-N1-3- gen agonists (e.g., conjugated estrogens, triloStane); 3-beta methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1 (S)- hydroxysteroid dehydrogenase inhibitors (e.g., triloStane); yl)-L-alaninamide). EM 1421 (i.e., 4,4'-(2R.3S)-2,3-Dim signal transduction pathway inhibitors (e.g., triloStane); 10 ethylbutane-1,4-diyl bis(1,2-dimethoxybenzene), SRN 001, melatonin receptor agonists (e.g., ramelteon); immunos TTP 488, PRX 03140, dimebolin, glycine-proline-gluta timulants (e.g., immune globulin, icosapentethyl ester, pro mate, C105, AL 208, MEM 3454, AC 1202, L 830982, LY caine); HIV entry inhibitors (e.g., procaine); sodium channel 451395 (i.e., (R) N-2-4-(methylsulfonamidomethyl)bi antagonists (e.g., procaine); microtubule inhibitor (e.g., phenyl-4-ylpropylpropane-2-sulfonamide), MK 0249, LY CPH 82); glycine NMDA agonists (e.g., cycloserine); 15 2062430, diethylnorspermine, neboglamine, S 18986, SA adenosine A1 receptor antagonists (e.g., KW 3902); ATPase 4503 (CAS Number 165377-44-6), GRI 1, S 17092 (i.e., stimulants (e.g., triacetyluridine); mitochondrial function (2S,3aS,7aS)-1 (R,R)-2-Phenylcyclopropylcarbonyl-2- enhancers (e.g., triacetyluridine); growth hormone releasing (thiazolidin-3-yl)carbonyloctahydro-1H-indole), SL factor agonists (e.g., tesamorelin); butylcholine esterase 251188, EUK 189, R 1450, 6,6-dimethyl-3-(2-hydroxy inhibitor (e.g., bisnorcymserine); alpha adrenergic receptor ethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4 antagonists (e.g., nicergoline); NO synthase type II inhibi (5H)-one, CERE 110, dexefaroxan, CAD 106, HF 0220, HF tors (e.g., arundic acid); chelating agents (e.g., PBT 2); 0420, EHT 0202, VP 025, MEM 1414, BGC 201259 (i.e., amyloid fibrillogenesis inhibitors (e.g., TTP488, PF N,N-Dimethylcarbamic acid, 4-1 (S)-(methylamino)-3-(4- 4494700); serotonin 4 receptor agonists (e.g., PRX 03140); nitrophenoxy)propylphenyl ester), EN 100, ABT 834, ABT serotonin 6 receptor antagonists (e.g., SB 742457); benzo 25 239 (i.e., 4-2-2-(2R)-2-Methylpyrrolidinylethyl-benzo diazepine receptor inverse agonists (e.g., radequinil); Ca furan-5-yl)benzonitrile), SGS 518, R 1500, C9138, SSR channel antagonists (e.g., Safinamide); nicotinic receptor 180711, alfatradiol, R 1577, T 817MA (i.e., 1-3-2-(1- agonists (e.g., ispronicline); and ACE inhibitor (e.g., CTS Benzothien-5-yl)ethoxypropylazetidin-3-olmaleate), CNP 21166). 1061 (i.e., 4-Methyl-5-(2-nitrooxyethyl)thiazole), KTX Further, the above compounds include, for example, 30 01.01 (i.e., sodium beta-hydroxybutyrate), GSK 189254 (i.e., huperzine A, tacrine, rivastigmine, galantamine, pramirac 6-3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzodiazepin-7- etam, aniracetam, nefiracetam, EGb 761, rosiglitazone, rasa yloxy-N-methylnicotinamide), AZD 1080, ACC 001, PRX giline, levacecarnine, celecoxib, 3-(2-cyanophenyl)-5-(2- 07034, midazolam, R-phenserine, AZD 103 (CAS Number pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, talampanel, 488-59-5), SN. 522, NGX 267 (CAS Number 503431-81-0), becampanel, memantine, Xaliproden, tarenflurbil, tramipro 35 N-PEP-12, RN 1219, FGLL, AVE 8112, EVT 101, NP sate, leuprorelin-D, taltirelin, risperidone, cevimeline, 031112, MK 0752, MK 0952, LX 6171, PAZ 417, AV 965, modafinil, alosetron, aripiprazole, mifepristone, atorvasta PF 3084014, SYN 114, GSI 953, SAM 315, SAM 531, tin, propentofylline, choline alfoscerate, FPF 1070 (CAS D-serine, leteprinim potassium, BR 16A (CAS Number Number 143637-01-8), rimonabant, dronabinol, docosa 149175-77-9), RPR 107393 (CAS Number 190841-57-7), hexaenoic acid, paclitaxel, triflusal, idebenone, nicergoline, 40 NXD 2858, REN 1654, CDD 0102, NC 1900 (CAS Number conjugated estrogens, triloStane, simvastatin, selegiline, 132925-74-7), ciclosporin, NCX 2216 (i.e., (E)-4-(Ni ramelteon, immune globulin, icosapentethyl ester, procaine, trooxy)butyl 3-4-2-(2-fluorobiphenyl-4-yl)propanoyloxy CPH 82, cycloserine, KW 3902 (CAS Number 136199-02 3-methoxyphenylacrylate), NXD 3109, NXD 1191, ZSET 5), triacetyluridine, estrogen dementia therapeutics (e.g., 845 (i.e., 3.3-diphenylimidazo[1,2-alpyridin-2-(3H)-one), MIGENIX, Vancouver, Canada), tesamorelin, bisnorcym 45 ET 002, NT 13, RO 638695 (i.e., 1,6-(1,6-dioxohexyl) serine, nicergoline, arundic acid, PBT 2, TTP488, PF dipyrrolidine-(2R)-carboxylic acid), bisnorcymserine, BA 4494700, PRX 03140, SB 742457, radequinil, safinamide, 1016, XD 4241, EUK 207 (i.e., (SP-5-13)-(acetato-KO)13, ispronicline, CTS 21166, Bapineuzumab, NP 031112, (2S, 16, 19.22-tetraoxa-3,6-diazatricyclo[21.3.18.12 octacosa-1 3aS,7aS)-1 (R,R)-2-Phenylcyclopropylcarbonyl-2-(thi (27).2.6.8,10,12(28).23.25-octaene-27.28-diolato(2-)-KN3, azolidin-3-yl)carbonyloctahydro-1H-indole, citalopram, 50 KN6, KO27, KO28)manganese), LG 617 inhibitors, ZSET venlafaxine, levprorelin, prasterone, peptide T (CAS Num 1446, PAN 811, F 14413 (i.e., 2-5-fluoro-2(S)-methoxy-2, ber 53-43-0), besipiridine, lexipafant, stacofylline, SGS 742 3-dihydro-1,4-benzodioxin-2-yl-4,5-dihydro-1H-imida (CAS Number 123690-78-8), T 588 (CAS Number 142935 zole), FP7832 (i.e., N-2-(5-methoxy-1-nitroso-1H-indol-3- 03-3), nerispiridine, dexanabinol, sabcomeline, GTS 21 yl)ethyl)acetamide), ARA 014418 (i.e., N-(4- (CAS Number 156223-05-1), CX 516 (CAS Number 55 methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea), AZD 154235-83-3), ABT 089 (CAS Number 161417-03-4), anap 3102, KP 544 (i.e., 2-amino-5-(4-chlorophenylethynyl)-4- sos, tesofensine, SIB 1553A (i.e., 4-2-(1-methyl-yl-2-pyr (4-trans-hydroxycyclohexylamino)pyrimidine), DP 155, rolidinyl)ethylthiaphenol), ladostigil, radequinil, GPI 5-chloro-N-3-2-(dimethylamino)ethyl)-1H-indol-5-yl) 1485, ispronicline, arundic acid, MEM 1003 (i.e., 3-Isopro naphthalene-2-sulfonamide, TAK 070, huperzine, N-2-(3. pyl 5-(2-methoxyethyl) 4-(2-chloro-3-cyanophenyl)-2,6-di 60 5-dimethyladamant-1-yl)ethyl)acetamidine hydrochloride, methylpyridine-3,5-dicarboxylate), V 3381 (i.e., 2-(2,3-Di 6-4-(dimethylamino)methyl-5-ethyl-2-methoxyphenyl hydro-1H-inden-3-ylamino)acetamide hydrochloride), pyridin-2-amine, 4,6-diphenyl-3-(4-(pyrimidin-2-yl)piper farampator, paliroden, prasterone-paladin, urocortin, DPb99 azin-1-yl)pyridazine, N-(1S,2R)-3-(3,5-difluorophenyl)-1- (i.e., 2,2'-(Ethylenedioxy)bis(2,1-phenylene)bis N-2-2- hydroxy-1-(5S,6R)-5-methyl-6-(neopentyloxy)morpholin (octyloxy)ethoxy-2-oxoethyliminobis(acetic acid)), caps 65 3-yl)propan-2-yl)acetamide hydrochloride, N-(1R,2S)-3- erod, DU 125530, bapineuZumab, AL 108 (i.e., L-Asparagi (3,5-difluorophenyl)-1-hydroxy-1-(2R,4R)-4- nyl-L-alanyl-L-prolyl-L-Valyl-L-seryl-L-isoleucyl-L- phenoxypyrrolidin-2-yl)propan-2-yl)-3-((R)-2- US 9,453,000 B2 95 96 (methoxymethyl)pyrrolidine-1-carbonyl-5- acetohydrazide), CGP 50068 (CAS Number 158647-49-5), methylbenzamide, R 1589, midafotel, phenserine, cerebrocrast, desferri-nordanoxamine, isolichenan, MHP coluracetam, physostigmine, cipralisant, nitroflurbiprofen, 133 (i.e., 3-(N,N-dimethylcarbamoyloxy)-1-methyl-2-(4- PPI 1019 (i.e., (3C.5 B.7C, 12C.)-trihydroxycholan-24-oyl-L- phenyl-semicarbazonomethyl)pyridinium chloride), FR leucyl-L-Valyl-L-phenylalanyl-L-phenylalanyl-L-alanine), 152558 (CAS Number 151098-08-7), GVS 111 (CAS Num dapsone, MDL 100453 (CAS Number 129938-34-7), NS ber 157115-85-0), P 11149 (CAS Number 164724-79-2), 377, midaxifylline, propofol phosphate, metrifonate, cero PDC 008004, KST 2818 (CAS Number 158623-26-8), KST napril, tenilsetam, Sufoxazine, Seglitide, ebiratide, nebrac 5410 (CAS Number 158623-27-9), RU 52583 (CAS Num etam, millacemide, iododoxorubicin, SM 10888 (CAS Num ber 123829-33-4), PD 151832 (CAS Number 149929-39-5), ber 129297-21-8), U 80816 (CAS Number 138554-11-7), 10 UCL 1199 (i.e., 4-2-(5-Nitropyridin-2-ylsulfanyl)ethyl YM 954 (CAS Number 132041-85-1), SUT 8701 (CAS 1H-imidazole), isovanihuperzine A, SIB 1765F (CAS Num Number 123577-73-1), apovincamine, FR 121196 (CAS ber 179120-52-6), JWS USC 751X (i.e., 3-2-(5-dimeth Number 133920-65-7), LY 274614 (CAS Number 136109 ylaminomethyl)-2-furanylmethylthioethylamino-4- 04-1), CL 275838 (CAS Number 115931-65-2), igmesine, K nitropyridazine), GR 175737 (i.e., 3-(4-Chlorobenzyl)-5-2- 7259 (CAS Number 133667-88-6), vinconate, itasetron, CL 15 (1H-imidazol-4-yl)ethyl-1,2,4-oxadiazole), KS 505A (CAS 287663 (CAS Number 125109-98-0), WAY 100289 (CAS Number 131774-53-3), ZTTA 1 (i.e., N-benzyloxycarbonyl Number 136013-69-9). SR 46559A (CAS Number 137733 thioprolyl-thioprolynal-dimethylaceta 1), AGN 190837 33-6), GYKI46903 (CAS Number 142999-59-5), L 670548 (CAS Number 136527-40-7), P 10358 (188240-59-7), WAY (CAS Number 121564-89-4), Y 29794 (CAS Number 131256 (CAS Number 174001-71-9), DBO 83 (i.e., 3-(6- 1291.84-48-1), AF 125 (CAS Number 7631-86-9), KFM 19 chloropyridazin-3-yl)-diazabicyclo[3.2.1]octane dihydro (CAS Number 133058-72-7), ST 796 (i.e., (S)-3-3-(trifluo chloride monohydrate), FUB 181 (CAS Number 152029 romethyl)benzoyl)aminohexahydroazepin-2-one), RU 80-6), RJR 2557, WSU 2088, LVV-haemorphin-7, M 40 33965 (CAS Number 122321-05-5), SDZ 210086 (i.e., (i.e., galanin1-12-Pro3-(Ala-Leu)-Ala-NH), SIB 1757, (-)-1'.2(S)-Dimethylspiro 1,3-dioxolan-4,4'-piperidine), L SKF 74652 (i.e., 5-chloro-2-(4-methoxy phenyl)-3-benzo 689660 (CAS Number 144860-79-7), L 689560 (CAS Num 25 furanyl-4-3-(diethylamino)-propoxyphenylmethanone), ber 139051-78-8), ST 618 (i.e., 1-(6,7-Dimethoxy-1,2,3,4- CGP 71982, SCH 57790 (i.e., 4-cyclohexyl-alpha-4-4- tetrahydro-2-naphthyl)-4-hydroxy pyrrolidin-2-one), U methoxyphenylsulfinylphenyl-1-piperazineacetonitrile), 74500A (CAS Number 110101-65-0), GEA857 (CAS Num Putrescine-D-YiAbetall, DU 14 (i.e. p-O-(sulfamoyl)-N- ber 120493-42-7), BIBN 99 (CAS Number 145301-48-0), tetradecanoyl tyramine), CLZ 4, SL 340026, PPRT 424, DX 9366, ONO 1603 (CAS Number 114668-76-7), MDL 30 ciproxifan, UR 1827 (i.e., 2-(1-benzylpiperidin-4-yl)-1-4- 102234 (CAS Number 137766-81-5), P9939 (CAS Number (5-methylpyrimidin-4-ylamino)phenyl-1-ethanone), cap 157971-37-4), PD 140532 (CAS Number 157971-39-6), roctamine, TGS 20 (i.e., L-pyroglutamil-D-alanine amide), azetirelin, MR 16728 (CAS Number 147614-21-9), dabelo PG 9 (i.e., alpha-tropanyl 2-(4-bromo)phenylpropionate), tine, MDL 102503 (i.e., 8-1 (R)-methyl-2-phenylethyl-1,3- TEI 3356 (i.e., (16S)-15-Deoxy-16-hydroxy-16-methyl-9- dipropyl-7H-xanthine), PD 141606 (i.e., (+)-(Z)-3-(3-Phe 35 (O)-methano-DELTA6(9alpha)-prostaglandin I1), LY nyl-2-propynyloxyimino)-1-azabicyclo2.2.1]heptane), 392098 (i.e., Thiophene, 3-(2-methylethyl-2)sulphonylam SNK 882 (CAS Number 152221-12-0), L 696986 (CAS inopropyl-2phenyl-4-yl-), PG 1000, DM 232, NEPP 11 Number 141553-45-9), tazomeline, LY235959 (CAS Num (i.e., 12-iso-15-Deoxy-18-(4-methyl)phenyl-13, 14-dihydro ber 137433-06-8), 2-(2-thiooxopyrrolidin-1-yl)acetamide, delta7-prostaglandin A1 methyl ester), VA 100 (i.e., (2,3- AK 30 NGF, ABT 418 (CAS Number 147402-53-7), itame 40 Dihydro-2-(4-fluorobenzoyl)aminoethyl-1-methyl-5- line, HUP 13, sibopirdine, KST 5452 (CAS Number phenyl-1H-1,4-benzodiazepine), VA 101 (i.e., (2,3-dihydro 157998-88-4), TJ 54, U 92798 (i.e., 7-4-Bis(4-fluorophe 2-(2-thienylcarbonyl)aminoethyl-1-methyl-5-phenyl nyl)methylperhydro-1,4-diazepin-1-ylmethyl-4-isopropyl 1H-1,4-benzodiazepine), NC 111585 (i.e., (3S)-1,3-Bis-3- 2-methoxy-2,4,6-cycloheptatrien-1-one), U 92032 (CAS (3-azabicylo2.2.2]octanyl)-1,2,5-thiadiazol-4-yloxy)-1- Number 142223-92-5), 3-(sulfamoyloxy)estra-1,3,5(10)- 45 propyn-1-ylbenzene, 2L-(+)-tartate), IN 201, imoproxifan, trien-17-one, P 11012 (CAS Number 164723-36-8), A82695 kanokodiol, picroside I, picroside II, DM 235 (i.e., 1-(4- (CAS Number 147388-86-1), FR 76659 (CAS Number Benzoylpiperazin-1-yl)propan-1-one), monoclonal antibody 116904-25-7), apaxifylline, CX 417, 7 MEOTA (CAS Num 1OD5, JLK2, JLK 6, JLK 7, DAPT (i.e., N-N-(3,5- ber 5778-80-3), BU 4514N (CAS Number 151013-39-7), difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl pregnenolone, mexidol, ST 857 (CAS Number 154755-63 50 ester), huperine X, SGS 111 (i.e., (S)-ethyl 2-1-(2-pheny 2), RU 49041 (CAS Number 123828-80-8), RU 35929 lacetyl)pyrrolidine-2-carboxamidoacetate), NP 7557, C (CAS Number 111711-47-8), P 878.184, P 128 (CAS Num 9136, C 7617, R 1485, rofecoxib, velnacrine, montirelin, ber 157716-52-4), eurystatin A, eurystatin B, LK 12, NBI lazabemide, ORG 2766 (CAS Number 50913-82-1), sabe 108, NBI 107, NBI 117, L 705106, bacoside A+B, clause luzole, adafenoxate, CAS Number 9061-61-4, ipidacrine, namide, SM 21 (CAS Number 155156-22-2), alaptide, RS 55 bemesetron, idazoxan, linopirdine, selfotel, Suritozole, 17017 (i.e., 1-(4-Amino-5-chloro-2-methoxyphenyl)-5-(1- milameline, Xanomeline, TJ 960, fasoracetam, eptastigmine, piperidinyl)-1-pentanone hydrochloride), AF 150(S) (i.e., ensaculin, Zanapezil, posatirelin, Zacopride, RS 86 (CAS (S)-1-Methyl-piperidine-4-spiro-(2-methylthiazoline)), Number 3576-73-6), ORG 5667 (CAS Number 37552-33 RO 153505 (CAS Number 78771-13-8), PV 113 (i.e., 1.2, 3), RX 77368 (CAS Number 76820-40-1), BMS 181168 3,4-Tetrahydropyrrolo-1,2-a-pyrazine), arisugacin, A 60 (CAS Number 123259-91-6), BY 1949 (CAS Number 98.284 (i.e., 20R)-(3-Methylisoxazol-5-yl)guinuclidine), AP 90158-59-1), AWD 5239 (CAS Number 109002-93-9), YM 5 (CAS Number 136941-85-0), BD 1054, SDZ NDD 094 796 (171252-79-2), aloracetam, CI-933 (CAS Number (i.e., bis-(2-(2-methylimidazol-1-yl)methyl)-pyridine-tris 91829-95-7), ST 793 (CAS Number 99306-37-3), cebarac (hydrogen-fumarate), AZ36041 (CAS Number 173324-76 etam, Zifrosilone, talsaclidine, alvameline, JTP 2942 O), quilostigmine, A 84543 (i.e., 3-1-Methylpyrrolidin-2- 65 (148152-77-6), OPC 14117 (CAS Number 103233-65-4), (S)-ylmethoxypyridine fumarate), BTG 4247 (i.e., (2-2- elziverine, AP 521 (i.e., N-(1,3-Benzodioxol-5-ylmethyl)-1, Chloroethoxy-4-(dimethylamino)phenylphosphoryl 2,3,4-tetrahydro 1 benzothieno2.3-cpyridine-3 (R)-car

US 9,453,000 B2 99 100 methoxybiphenyl-3-yl)ethyl-3,6-dimethyl-5,6- Reference Examples 1 and 2 dihydropyrimidin-4(3H)-one, AZD 1080, ARA 014418, XD 4241, Z321 (CAS No. 130849-58-0), ONO 1603 (CAS No. Synthesis of (+)-2-(E)-2-5-methoxy-6-(4-methyl 114668-76-7), JTP 3399, Eurystatin A (CAS No. 137563 1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif 63-4), Eurystatin B (CAS No. 137563-64-5), P 128 (CAS 5 luorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-a No. 157716-52-4), Y 29794(CAS No. 1291.84-48-1), ZTTA pyridine and (-)-2-(E)-2-5-methoxy-6-(4-methyl 1, JTP 4819 (CAS No. 162203-65-8), Monoclonal antibody 1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5- 266, dulloxetine, escitalopram oxalate, fluoxetine, fluvoxam trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, ine maleate, paroxetine, Sertraline, dapoxetine, desvenlafax 5-alpyridine ine, Sibutramine, nefazodone, milnacipran, desipramine, 10 dulloxetine, and bici fadine.

BEST MODE FOR CARRYING OUT THE Formula 49 INVENTION 15

The present invention will now be described in detail with MeO reference to examples; however, the examples are provided 21 only for illustration purposes. The prophylactic or therapeu tic agent for a disease caused by AB according to the present N invention is not limited to the following specific examples in any cases. A person skilled in the art can fully implement the present invention by making various modifications to not only the following reference examples and examples but 25 also the claims of the present specification, and Such modi fications are within the scope of the claims of the present specification. MeO 21 N When the compound in the Examples include stereoiso mers, and the absolute configuration has not been deter 30 F mined, there are the cases that the name of the compounds with optical rotating power and its chemical structural formula are not described correspondingly in the following )- F F Examples. 35 The following abbreviations are used in the following examples. Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pen DMF: N,N-Dimethylformamide tanoic acid N'-(E)-3-5-methoxy-6-(4-methyl-1H THF: Tetrahydrofuran imidazol-1-yl)pyridin-3-yl)acryloylhydrazide 40 EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide IPEA (0.14 mL) and BOPC1 (100 mg) were added to a hydrochloride solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid HOBT: 1-Hydroxybenzotriazole hydrazide hydrochloride (83 mg) and (E)-3-5-methoxy-6- IPEA: Diisopropylethylamine (4-methyl-1H-imidazol-1-yl)pyridin-3-yl)acrylic acid (CAS 45 No. 870837-77-7, 68 mg) in methylene chloride (5 mL), and IPA: 2-Propanol the reaction solution was stirred at room temperature for 18 DMAP: 4-(Dimethylamino)pyridine hours. Ethyl acetate and saturated sodium bicarbonate water TEA: Triethylamine were added to the reaction Solution, and the organic layer CDI: Carbonyldiimidazole was separated. The resulting organic layer was dried over 50 anhydrous magnesium sulfate and concentrated under TBAF: Tetrabutylammonium fluoride reduced pressure to obtain 112 mg of the title compound. DBU: 1.8-Diazabicyclo[5.4.0]undec-7-enet: Tertiary The property value of the compound is as follows. BOPCl: Bis(2-oxo-3-oxazolidinyl)phosphonic chloride ESI-MS; m/z 522 M"+H. DIBAL-H: Diisobutylaluminum hydride 55 Synthesis of 5-(E)-2-5-4-chloro-1-(3,4,5-trifluo DAST: Diethylaminosulfur trifluoride rophenyl)butyl-1,3,4-oxadiazol-2-yl) vinyl-3- BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine Chromatography was performed using BW-300 manufac A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic tured by Fuji Silysia Chemical Ltd. as a carrier unless 60 acid N'-(E)-3-5-methoxy-6-(4-methyl-1H-imidazol-1-yl) otherwise specified. pyridin-3-yllacryloylhydrazide (112 mg) in phosphorus LC-MS: High performance liquid chromatography for oxychloride (2 mL) was stirred at 120° C. for 3.5 hours. The preparative isolation of a target compound using mass reaction solution was left to cool to room temperature and spectroscopy. As an elution solvent, a 10% to 99% linear then concentrated under reduced pressure to obtain 108 mg gradient system of water containing 0.1% trifluoroacetic 65 of the title compound. The property value of the compound acid and acetonitrile containing 0.1% trifluoroacetic acid is as follows. was used. US 9,453,000 B2 101 102 Synthesis of (+)-2-(E)-2-5-methoxy-6-(4-methyl 1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif -continued luorophenyl)-5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-a

pyridine and (-)-2-(E)-2-5-methoxy-6-(4-methyl 1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5- trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, 5-alpyridine A solution of 5-(E)-2-5-4-chloro-1-(3,4,5-trifluoro phenyl)butyl-1,3,4-oxadiazol-2-yl) vinyl-3-methoxy-2- (4-methyl-1H-imidazol-1-yl)pyridine (495 mg) in acetic 10 acid (2 mL) was stirred at 150° C. for 25 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and Saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous mag 15 nesium Sulfate and then concentrated under reduced pres Sure. The residue was purified by silica gel column chro matography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain a race mate of the title compound. The resulting racemate was separated by CHIRALPAKTM IA manufactured by Daicel Sodium hydride (containing 40% of mineral oil, 4 mg) Chemical Industries, Ltd. (2 cmx25 cm; mobile phase: was added to a solution of 2-(E)-2-5-methoxy-6-(4- ethanol) to obtain the title optically active compound with a methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif retention time of 20 minutes and positive optical rotation (11 luorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri mg, >99% ee) and the title optically active compound with 25 dine synthesized by the method in Reference Examples 1 a retention time of 25 minutes and negative optical rotation (12 mg, >99% ee). and 2 (21 mg) in DMF (2 mL), and the reaction solution was The property values of (+)-2-(E)-2-5-methoxy-6-(4- stirred at room temperature for 30 minutes while bubbling methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif with oxygen gas. Ethyl acetate and Saturated aqueous luorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri ammonium chloride were added to the reaction solution, and dine are as follows. 30 'H-NMR (CDC1) & (ppm): 1.97-2.06 (m, 1H), 2.07-2.25 the organic layer was separated. The resulting organic layer (m. 2H), 2.29 (s, 3H), 2.34-2.42 (m, 1H), 3.97 (s, 3H), was dried over anhydrous magnesium sulfate and then 4.23-4.30 (m, 3H), 6.81 (dd, J=8.0, 6.4 Hz, 2H), 7.08 (d. concentrated under reduced pressure. The resulting racemic J=16.0 Hz, 1H), 7.46 (d. J=2.0 Hz, 1H), 7.49 (d. J=16.0 Hz, crude product of the title compound was separated by 1H), 7.52 (brs, 1H), 8.14 (d. J–2.0 Hz, 1H), 8.34 (brs, 1H). 35 The property values of (-)-2-(E)-2-5-methoxy-6-(4- CHIRALPAKTM AD-H manufactured by Daicel Chemical methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif Industries, Ltd. (2 cmx25 cm; mobile phase: hexane:etha luorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri nol=1:1) to obtain the title optically active compound with dine are as follows. a retention time of 7 minutes and negative optical rotation 'H-NMR (CDC1) & (ppm): 1.97-2.06 (m, 1H), 2.07-2.25 40 (3.7 mg, D-99% ee) and the title optically active compound (m. 2H), 2.29 (s, 3H), 2.34-2.42 (m, 1H), 3.97 (s, 3H), with a retention time of 10 minutes and positive optical 4.23-4.30 (m, 3H), 6.81 (dd, J=8.0, 6.4 Hz, 2H), 7.08 (d. rotation (3.2 mg, D-99% ee). J=16.0 Hz, 1H), 7.46 (d. J=2.0 Hz, 1H), 7.49 (d. J=16.0 Hz, 1H), 7.52 (brs, 1H), 8.14 (d. J–2.0 Hz, 1H), 8.34 (brs, 1H). The property values of (-)-2-(E)-2-5-methoxy-6-(4- 45 methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif Reference Examples 3 and 4 luorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri Synthesis of (-)-2-(E)-2-5-methoxy-6-(4-methyl din-8-ol are as follows. 1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif ESI-MS; m/z. 483 M+H. 'H-NMR (CDC1) & (ppm): luorophenyl)-5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-a 50 2.01-2.16 (m, 2H), 2.28 (s, 3H), 2.30-2.39 (m. 1H), 2.40 pyridin-8-ol and (+)-2-(E)-2-5-methoxy-6-(4- 2.53 (m. 1H), 3.91 (s.3H), 4.19-4.28 (m. 1H), 4.29-4.36 (m, methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4, 1H), 7.00-7.05 (m, 3H), 7.33 (d. J=1.6 Hz, 1H), 7.41 (d. 5-trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin-8-ol J=16.8 Hz, 1H), 7.46 (brs, 1H), 8.02 (d. J=1.6 Hz, 1H), 8.28 55 (brs, 1H). Formula 50 The property values of (+)-2-(E)-2-5-methoxy-6-(4- methyl-1H-imidazol-1-yl)pyridin-3-yl vinyl-8-(3,4,5-trif luorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri din-8-ol are as follows. 60 ESI-MS; m/z. 483 M+H. 'H-NMR (CDC1) & (ppm): 2.01-2.16 (m, 2H), 2.28 (s, 3H), 2.30-2.39 (m. 1H), 2.40 2.53 (m. 1H), 3.91 (s.3H), 4.19-4.28 (m. 1H), 4.29-4.36 (m,

65 1H), 7.00-7.05 (m, 3H), 7.33 (d. J=1.6 Hz, 1H), 7.41 (d. J=16.8 Hz, 1H), 7.46 (brs, 1H), 8.02 (d. J=1.6 Hz, 1H), 8.28 (brs, 1H). US 9,453,000 B2 103 104 Examples 1 and 2 added to the residue, and the precipitated powder was collected by filtration. The resulting powder was crystallized Synthesis of (+)-8-(3-fluorophenyl)-2-(E)-2-3- from ethanol and diethyl ether to obtain 9.22 g of the title methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii compound. The property values of the compound are as nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine 5 follows. and (-)-8-(3-fluorophenyl)-2-(E)-2-3-methoxy-4- ESI-MS; m/z 286 M-H-2HCl). H-NMR (DMSO-D) 8 (4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- (ppm): 1.46 (t, J=6.8 Hz, 3H), 2.35 (s.3H), 3.93 (s.3H), 4.54 tetrahydro 1,2,4-triazolo 1.5-alpyridine (q, J=6.8 Hz, 2H), 7.18 (d. J=16.0 Hz, 1H), 7.50 (dd, J=8.0, 12 Hz, 1H), 7.68-7.77 (m, 3H), 8.01 (d. J=16.0 Hz, 1H), Formula 51 10 9.35 (s, 1H). N-N Synthesis of 5-chloro-2-(3-fluorophenyl)pentanoic acid 15 A solution of 3-fluorophenylacetic acid (500mg) in THF (15 mL) was stirred at -78° C. for 5 minutes. A 2.66 M %\ cr' solution of n-butyl lithium in hexane (2.44 mL) was added, and the reaction solution was stirred at -78° C. for three hours. Thereafter, the reaction solution was stirred at 0° C.

for one hour, 1-bromo-3-chloropropane was added, and the reaction solution was stirred at room temperature for 17 N-N hours. Thereafter, ethyl acetate and 1 Naqueous hydrochlo ric acid were added to the reaction Solution, and the organic layer was separated. The resulting organic layer was dried 25 over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 734 mg of the title compound. cr' / % The property values of the compound are as follows. H-NMR (CDC1) & (ppm): 1.64-1.85 (m, 2H), 1.90-2.02 1- F ) (m. 1H), 2.14-2.32 (m, 1H), 3.46-3.61 (m, 3H), 6.93-7.11 30 (m, 3H), 723-7.37 (m, 1H). Synthesis of tert-butyl N'-(5-chloro-2-(3-fluorophe Synthesis of (E)-3-3-methoxy-4-(4-methyl-1H nyl)pentanoylhydrazinecarboxylate imidazol-1-yl)phenylacrylonitrile 35 IPEA (1.9 mL), HOBt (85.9 mg) and EDC (1.22 g) were A lithium hydroxide monohydrate powder (2.23 g) was added to a solution of 5-chloro-2-(3-fluorophenyl)pentanoic added to a Suspension of 3-methoxy-4-(4-methyl-1H-imida acid (734 mg) and tert-butyl carbazate (504 mg) in DMF (10 Zol-1-yl)benzaldehyde (CAS No. 870837-18-6, 10 g) and mL), and the reaction solution was stirred at room tempera diethyl cyanomethylphosphonate (8.2 g) in THF (50 ml) ture for seven hours. Ethyl acetate and water were added to under ice-cooling, and the reaction solution was stirred at the 40 the reaction solution, and the organic layer was separated. same temperature for one hour. Ethyl acetate (200 mL) and The resulting organic layer was dried over anhydrous mag water were added to the reaction solution, and the organic nesium Sulfate and then concentrated under reduced pres layer was separated. The organic layer was washed with Sure. The residue was purified by silica gel column chro brine, dried over anhydrous magnesium sulfate and then matography (elution solvent: heptane-ethyl acetate system) filtered through a silica gel pad (carrier: ChromatorexTM 45 to obtain 711 mg of the title compound. The property values NH). The filtrate was concentrated under reduced pressure. of the compound are as follows. The resulting residue was crystallized from ethyl acetate and 'H-NMR (CDC1) & (ppm): 1.43 (s, 9H), 1.56-2.06 (m, hexane, and the crystals were collected by filtration. The 3H), 2.12-2.32 (m. 1H), 3.36-3.58 (m, 3H), 6.55 (brs, 1H), resulting crystals were dried under reduced pressure to 6.90-7.16 (m, 3H), 7.20-7.34 (m, 1H), 7.67 (brs, 1H). obtain 7.49 g of the title compound. The property values of 50 the compound are as follows. Synthesis of (+)-8-(3-fluorophenyl)-2-(E)-2-3- 'H-NMR (CDC1) & (ppm): 2.30 (s, 3H), 3.91 (s, 3H), methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii 5.90 (d. J=16.8 Hz, 1H), 6.93 (d. J=0.8 Hz, 1H), 7.06 (d. nyl-5,6,7,8-tetrahydro1,2,4-triazolo 1.5-alpyridine J=1.6 Hz, 1H), 7.13 (dd, J=8.0, 1.6 Hz, 1H), 7.29 (d. J=8.0 and (-)-8-(3-fluorophenyl)-2-(E)-2-3-methoxy-4- HZ, 1H), 7.39 (d. J=16.8 Hz, 1H), 7.74 (d. J=0.8 Hz, 1H). 55 (4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- tetrahydro 1.2.4 triazolo 1.5-alpyridine Synthesis of ethyl (E)-3-3-methoxy-4-(4-methyl 1H-imidazol-1-yl)phenylacrylimidate dihydrochlo A solution of 4N hydrochloric acid in ethyl acetate (12.1 ride mL) was added to tert-butyl N'-(5-chloro-2-(3-fluorophenyl) 60 pentanoylhydrazinecarboxylate (711 mg), and the reaction A suspension of (E)-3-3-methoxy-4-(4-methyl-1H-imi solution was stirred at room temperature for two hours. The dazol-1-yl)phenylacrylonitrile (7.45 g) in ethanol (75 mL) reaction Solution was concentrated under reduced pressure was bubbled with hydrogen chloride gas under ice-cooling to obtain a crude product of 5-chloro-2-(3-fluorophenyl) for 10 minutes and at room temperature for 15 minutes, and pentanoic acid hydrazide hydrochloride. A solution of ethyl then the reaction solution was stirred at room temperature 65 (E)-3-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl overnight. The reaction solution was concentrated under acrylimidate dihydrochloride (576 mg) and triethylamine reduced pressure. Then, ethanol and diethyl ether were (1.24 mL) in ethanol (10 mL) was added to a solution of the US 9,453,000 B2 105 106 resulting crude product of 5-chloro-2-(3-fluorophenyl)pen -continued tanoic acid hydrazide hydrochloride and triethylamine (1 mL) in ethanol (10 mL), and the reaction solution was stirred N-N at 80°C. in a nitrogen atmosphere for 23 hours. The reaction Solution was cooled to room temperature and then the MeO N I / solvent was evaporated under reduced pressure. Ethyl acetate and Saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous mag % N. nesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatog raphy (carrier: Chromatorex NH; elution solvent: heptane: ethyl acetate=1:1->ethyl acetate->ethyl acetate:metha nol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=9:1) to obtain 306 mg of a racemate of the 15 title compound. The resulting racemate (152 mg) was sepa 119 mg of a racemate of the title compound was obtained rated by CHIRALPAKTM IA manufactured by Daicel from 4-cyanophenylacetic acid (1 g) by the same method as Chemical Industries, Ltd. (2 cmx25 cm; mobile phase: in Examples 1 and 2. The racemate (60 mg) was separated hexane:ethanol=1:1) to obtain a (+)-isomer of the title by CHIRALPAKTM IB manufactured by Daicel Chemical optically active compound with a retention time of 14 Industries, Ltd. (2 cmx25 cm; mobile phase: ethanol) to minutes (60 mg; >99% ee) and a (-)-isomer of the title obtain a (-)-isomer of the title optically active compound optically active compound with a retention time of 15.5 with a retention time of 18.5 minutes (22.3 mg: 98% ee) and minutes (61 mg: 92% ee). a (+)-isomer of the title optically active compound with a The property values of (+)-8-(3-fluorophenyl)-2-(E)-2- retention time of 33 minutes (23 mg: 98% ee). (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl 25 The property values of (-)-1-4-2-(E)-2-3-methoxy 5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-alpyridine are as fol 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra lows. hydro 1.2.4 triazolo 1.5-alpyridin-8-yl)phenylpentan-1- ESI-MS; m/z 430 M*-i-H. 'H-NMR (CDC1) & (ppm): one are as follows. 2.01-2.46 (m, 7H), 3.85 (s, 3H), 4.21-4.38 (m, 3H), 6.81 ESI-MS; m/z 496 M--H. 'H-NMR (CDC1) & (ppm): 7.02 (m, 4H), 7.06 (d. J=16.0 Hz, 1H), 7.10-7.24 (m, 3H), 0.95 (t, J=7.2 Hz, 3H), 1.34-1.46 (m, 2H), 1.66-1.76 (m, 7.26-7.34 (m, 1H), 7.51 (d. J=16.0 Hz, 1H), 7.69 (brs, 1H). 30 2H), 2.00-2.48 (m, 7H), 2.94 (t, J=7.6 Hz, 2H), 3.85 (s.3H), The property values of (-)-8-(3-fluorophenyl)-2-(E)-2- 4.24-4.35 (m, 2H), 4.36-4.43 (m, 1H), 6.91 (brs, 1H), 7.06 (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl (d. J=16.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.18-7.30 (m, 3H), 5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-alpyridine are as fol 7.50 (d. J=16.4 Hz, 1H), 7.73 (brs, 1H), 7.87-7.97 (m, 2H). lows. The property values of (+)-1-4-2-(E)-2-3-methoxy ESI-MS; m/z 430 M*-i-H. 'H-NMR (CDC1) & (ppm): 35 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra 2.01-2.46 (m, 7H), 3.85 (s, 3H), 4.21-4.38 (m, 3H), 6.81 hydro 1,2,4-triazolo 1.5-alpyridin-8-yl)phenylpentan-1- 7.02 (m, 4H), 7.06 (d. J=16.0 Hz, 1H), 7.10-7.24 (m, 3H), one are as follows. 7.26-7.34 (m, 1H), 7.51 (d. J=16.0 Hz, 1H), 7.69 (brs, 1H). ESI-MS; m/z 496 M--H. 'H-NMR (CDC1) & (ppm): Examples 3 and 4 0.95 (t, J=7.2 Hz, 3H), 1.34-1.46 (m, 2H), 1.66-1.76 (m, 40 2H), 2.00-2.48 (m, 7H), 2.94 (t, J=7.6 Hz, 2H), 3.85 (s.3H), Synthesis of (-)-1-4-2-(E)-2-3-methoxy-4-(4- 4.24-4.35 (m, 2H), 4.36-4.43 (m, 1H), 6.91 (brs, 1H), 7.06 methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- (d. J=16.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.18-7.30 (m, 3H), tetrahydro 1.2.4 triazolo 1.5-alpyridin-8- 7.50 (d. J=16.4 Hz, 1H), 7.73 (brs, 1H), 7.87-7.97 (m, 2H). yl)phenylpentan-1-one and (+)-1-(4-2-(E)-2-3- Examples 5 and 6 methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl 45 vinyl-5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-a) Synthesis of (-)-8-(4-isopropylphenyl)-2-(E)-2-3- pyridin-8-yl)phenylpentan-1-one methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii nyl-5,6,7,8-tetrahydro1,2,4-triazolo 1.5-alpyridine and (+)-8-(4-isopropylphenyl)-2-(E)-2-3-methoxy 50 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5.6.7. Formula 52 8-tetrahydro 1.2.4 triazolo 1.5-alpyridine

55 MeO Formula 53

60 MeO

65

US 9,453,000 B2 109 110 room temperature for one hour. Brine and ethyl acetate were ESI-MS; m/z 418 M"+H. 'H-NMR (CDC1) & (ppm): added to the reaction Solution and the organic layer was 2.03-2.48 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H), 4.63 (t, separated. The resulting organic layer was dried over anhy J=6.0 Hz, 1H), 6.88-6.98 (m, 3H), 7.07 (d. J=16.8 Hz, 1H), drous magnesium sulfate and then concentrated under 7.12-7.24 (m, 4H), 7.54 (d. J=16.8 Hz, 1H), 7.69 (d. J–1.2 reduced pressure. The resulting residue was purified by HZ, 1H). silica gel column chromatography (carrier: Chromatorex The property values of (+)-2-(E)-2-3-methoxy-4-(4- NH; elution solvent: ethyl acetate->ethyl acetate:metha methyl-1H-imidazol-1-yl)phenyl vinyl-8-thiophen-2-yl-5, nol=9:1) to obtain 0.44 mg of the title compound. 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are as fol The property values of 8-(4-methanesulfonylphenyl)-2- lows. {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl 10 ESI-MS; m/z 418 M"+H. 'H-NMR (CDC1) & (ppm): vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are 2.03-2.48 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H), 4.63 (t, as follows. J=6.0 Hz, 1H), 6.88-6.98 (m, 3H), 7.07 (d. J=16.8 Hz, 1H), ESI-MS; m/z 490 M*-i-H. 'H-NMR (CDC1) & (ppm): 7.12-7.24 (m, 4H), 7.54 (d. J=16.8 Hz, 1H), 7.69 (d. J–1.2 1.96-2.48 (m, 7H), 3.05 (s, 3H), 3.85 (s, 3H), 4.31 (t, J=5.6 HZ, 1H). Hz, 2H), 4.42 (t, J=7.2 Hz, 1H), 6.91 (brs, 1H), 7.05 (d. 15 J=16.4 Hz, 1H), 7.10-7.30 (m, 3H), 7.38 (d. J=8.4 Hz, 2H), Example 12 7.49 (d. J=16.4 Hz, 1H) 7.69 (d. J=0.8 Hz, 1H), 7.92 (d. Synthesis of 2-(E)-2-3-methoxy-4-(4-methyl-1H J=8.4 Hz, 2H). imidazol-1-yl)phenyl vinyl-8-1-phenylmethyl-(E)- Examples 10 and 11 lidene-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri dine Synthesis of (-)-2-(E)-2-3-methoxy-4-(4-methyl 1H-imidazol-1-yl)phenyl vinyl-8-thiophen-2-yl-5, 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine and 25 (+)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol Formula 57 1-yl)phenyl vinyl-8-thiophen-2-yl-5,6,7,8-tetra hydro 1.2.4 triazolo 1.5-alpyridine N-N

30 MeO Formula 56

35 MeO

Synthesis of tert-butyl 40 5-chloro-2-1-phenylmethyl-(E)-lidenepentanoate Ethanol (30 mL), benzaldehyde (3 mL) and lithium hydroxide monohydrate (3.71 g) were added to a solution of a solution of tert-butyl 5-chloro-2-(diethoxyphosphoryl) 45 pentanoate (CAS No. 870843-25-7) (10.7 g) in THF (90 mL), and the reaction solution was stirred at room tempera ture for 19.5 hours. Thereafter, ethyl acetate and saturated sodium bicarbonate water were added to the reaction solu tion, and the organic layer was separated. The resulting 50 organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 258.6 mg of a racemate of the title compound was 6.57 g of the title compound. The property values of the obtained from thiophen-2-ylacetic acid (500 mg) by the 55 compound are as follows. same method as in Examples 1 and 2. The racemate (106 H-NMR (CDC1) & (ppm): 1.55 (S. 9H), 1.96-2.14 (m, mg) was separated by CHIRALCELTMOJ-H manufactured 2H), 2.59-2.68 (m, 2H), 3.56 (t, J=6.8 Hz, 2H), 7.23-7.41 by Daicel Chemical Industries, Ltd. (2 cmx25 cm; mobile (m, 5H), 7.62 (brs, 1H). phase: ethanol) to obtain a (-)-isomer of the title optically active compound with a retention time of 11 minutes (51.5 60 Synthesis of mg; >99% ee) and a (+)-isomer of the title optically active 5-chloro-2-1-phenylmethyl-(E)-lidenepentanoic compound with a retention time of 19 minutes (52.1 mg: acid 98% ee). The property values of (-)-2-(E)-2-3-methoxy-4-(4- Anisole (1.16 mL) was added to tert-butyl 5-chloro-2-1- methyl-1H-imidazol-1-yl)phenyl vinyl-8-thiophen-2-yl-5, 65 phenylmethyl-(E)-lidenepentanoate (1 g). Trifluoroacetic 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are as fol acid (5 mL) was further added under ice-cooling, and the lows. reaction Solution was stirred in a nitrogen atmosphere under US 9,453,000 B2 111 112 ice-cooling for four hours. Thereafter, the reaction solution HZ, 1H), 7.16-7.46 (m, 8H), 7.62 (d. J=16.0 Hz, 1H), 7.70 was concentrated under reduced pressure and the resulting (d. J=1.2 Hz, 1H), 7.79 (brs, 1H). residue was dissolved in ethyl acetate at 80°C. The solution was left to stand at room temperature and the precipitated Examples 13 and 14 crystals were collected by filtration. The crystals collected 5 by filtration was washed with ethyl acetate: heptane=1:1 to obtain 188.6 mg of the title compound. The property values Synthesis of (-)-2-(E)-2-3-methoxy-4-(4-methyl of the compound are as follows. 1H-imidazol-1-yl)phenyl vinyl-8-thiophen-3-yl-5, H-NMR (CDC1) & (ppm): 2.02-2.22 (m. 2H), 2.67-2.77 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine and (m. 2H), 3.60 (t, J–6.4 Hz, 2H), 7.32-7.47 (m, 5H), 7.86 (brs, 10 (+)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol 1H). 1-yl)phenyl vinyl-8-thiophen-3-yl-5,6,7,8-tetra hydro 1.2.4 triazolo 1.5-alpyridine Synthesis of 2-(E)-2-3-methoxy-4-(4-methyl-1H imidazol-1-yl)phenyl vinyl-8-1-phenylmethyl-(E)- lidene-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri 15 dine Formula 58

IPEA (4 mL), HOBt (1.81 g) and EDC (2.56 g) were added to a solution of 5-chloro-2-1-phenylmethyl-(E)- lidenepentanoic acid (1.5 g) and tert-butyl carbazate (1.06 MeO N g) in DMF (20 mL), and the reaction solution was stirred at room temperature for 2.5 hours. Ethyl acetate and water were added to the reaction solution and the organic layer was % N. separated. The resulting organic layer was dried over anhy 25 drous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain an (E)/(Z) mixture of tert-butyl N-N N'-(5-chloro-2-1-phenylmethylidene 30 pentanoylhydrazinecarboxylate (1.97g). A solution of 4N MeO S. l hydrochloric acid in ethyl acetate (12.1 mL) was added to the resulting (E)/(Z) mixture of tert-butyl N'-(5-chloro-2- 1-phenylmethylidenelpentanoylhydrazinecarboxylate % N. N (0.726 g), and the reaction solution was stirred at room 35 temperature for seven hours. The reaction solution was concentrated under reduced pressure. A solution of ethyl (E)-3-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl acrylimidate dihydrochloride (0.576 g) and triethylamine 40 244.7 mg of a racemate of the title compound was (1.24 mL) in ethanol (10 mL) was added to a solution of the obtained from thiophen-3-ylacetic acid (500 mg) by the resulting residue and triethylamine (1 mL) in ethanol (10 same method as in Examples 1 and 2. The racemate (103 mL). The reaction solution was stirred at 80°C. in a nitrogen mg) was separated by CHIRALCELTMOJ-H manufactured atmosphere for 16 hours. The reaction solution was cooled by Daicel Chemical Industries, Ltd. (2 cmx25 cm; mobile to room temperature and then the solvent was evaporated 45 phase: ethanol) to obtain a (-)-isomer of the title optically under reduced pressure. Ethyl acetate and Saturated sodium active compound with a retention time of 11 minutes (47.1 bicarbonate water were added to the resulting residue, and mg; >99% ee) and a (+)-isomer of the title optically active the organic layer was separated. The resulting organic layer compound with a retention time of 19.5 minutes (45.9 mg). was dried over anhydrous magnesium sulfate and then The property values of (-)-2-(E)-2-3-methoxy-4-(4- concentrated under reduced pressure. The residue was puri 50 methyl-1H-imidazol-1-yl)phenyl vinyl-8-thiophen-3-yl-5, fied by silica gel column chromatography (carrier: Chroma 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are as fol torex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl lows. acetate->ethyl acetate:methanol=9:1) and further purified by ESI-MS; m/z 418 M+H. 'H-NMR (CDC1) & (ppm): silica gel column chromatography (elution solvent: ethyl 2.00-2.42 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H), 4.45 (t, acetate->ethyl acetate:methanol=9:1). Then, the purified 55 J=5.2 Hz, 1H), 6.91 (brs, 1H), 6.98-7.24 (m, 6H), 7.31 (dd. product was separated by CHIRALPAKTMIA manufactured J=3.2, 5.2 Hz, 1H), 7.54 (d. J=16.0 Hz, 1H), 7.69 (d. J=1.2 by Daicel Chemical Industries, Ltd. (2 cmx25 cm; mobile HZ, 1H). phase: ethanol) to obtain the title compound with a retention The property values of (+)-2-(E)-2-3-methoxy-4-(4- time of 33 minutes (12.3 mg). methyl-1H-imidazol-1-yl)phenyl vinyl-8-thiophen-3-yl-5, The property values of 2-(E)-2-3-methoxy-4-(4-methyl 60 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are as fol 1H-imidazol-1-yl)phenyl vinyl-8-1-phenylmethyl-(E)- lows. lidene-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are ESI-MS; m/z 418 M+H. 'H-NMR (CDC1) & (ppm): as follows. 2.00-2.42 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H), 4.45 (t, ESI-MS; m/z 424 M*-i-H. 'H-NMR (CDC1) & (ppm): 65 J=5.2 Hz, 1H), 6.91 (brs, 1H), 6.98-7.24 (m, 6H), 7.31 (dd. 2.11-2.21 (m, 2H), 2.30 (s, 3H), 2.93-3.01 (m, 2H), 3.89 (s. J=3.2, 5.2 Hz, 1H), 7.54 (d. J=16.0 Hz, 1H), 7.69 (d. J=1.2 3H), 4.29 (t, J=6.0 Hz, 2H), 6.92 (brs, 1H), 7.10 (d. J=16.0 HZ, 1H). US 9,453,000 B2 113 114 Examples 15 and 16 carbamate (727 mg), and the reaction Solution was stirred at Synthesis of (+)-8-benzyl-2-(E)-2-3-methoxy-4- room temperature for three hours. The reaction solution was (4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- concentrated under reduced pressure. IPEA (2.45 mL), tetrahydro 1.2.4 triazolo 1.5-alpyridine and (-)-8- 5 HOBT (646 mg) and EDC (916 mg) were added to a benzyl-2-(E)-2-3-methoxy-4-(4-methyl-1H solution of the resulting residue and (E)-3-3-methoxy-4-(4- imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2, methyl-1H-imidazol-1-yl)phenylacrylic acid (CAS No. 4triazolo 1.5-alpyridine 970839-41-1, 617 mg) in DMF (15 mL), and the reaction 10 solution was stirred at room temperature for 25 hours. Ethyl acetate and water were added to the reaction solution and the Formula 59 organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concen N-N 15 trated under reduced pressure. A solution of the resulting residue in phosphorus oxychloride (20 mL) was heated MeO N I / under reflux for 1.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Acetic acid (12 mL) and ammonium acetate (7.34 g) were added to the resulting residue, and the reaction solution was stirred at 150° C. for 2.5 hours. The )- reaction solution was left to cool to room temperature and 25 then concentrated under reduced pressure. Ethyl acetate and MeO I 2 saturated sodium bicarbonate water were added to the result ing residue, and the organic layer was separated. The result e cr's e ing organic layer was dried over anhydrous magnesium 30 sulfate and then concentrated under reduced pressure. The %N c residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) 35 and further purified by silica gel column chromatography Synthesis of tert-butyl (elution solvent: ethyl acetate->ethyl acetate:methanol=9:1) (3-benzyl-2-oxopiperidin-1-yl)carbamate to obtain 10.3 mg of a racemate of the title compound. The 10% palladium-carbon powder (50.36% aqueous, 1.92 g) resulting racemate (10.3 mg) was separated by CHIRAL was added to a solution of the (E)/(Z) mixture of tert-butyl 40 CELTMOD-H manufactured by Daicel Chemical Industries, N'-5-chloro-2-(1-phenylmethylidene)pentanoylhydrazin Ltd. (2 cmx25 cm; mobile phase: hexane:ethanol=1:1) to ecarboxylate obtained in the process of Example 12 in obtain a (+)-isomer of the title optically active compound ethanol (20 mL), and the reaction Solution was stirred in a hydrogen atmosphere at room temperature for 10 days. with a retention time of 8 minutes (2.83 mg, >99% ee) and Thereafter, the reaction solution was filtered through celite 45 a (-)-isomer of the title optically active compound with a and the solvent was evaporated under reduced pressure. retention time of 13.5 minutes (3.27 mg, >99% ee). DBU (0.598 mL) was added to a solution of the resulting The property values of (+)-8-benzyl-2-(E)-2-3- residue in THF (50 mL) and the mixture was heated under methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5.6, reflux for 44 hours. Thereafter, the solvent was evaporated 7,8-tetrahydro 1.2.4 triazolo 1.5-apyridine are as follows. under reduced pressure. The resulting residue was purified 50 by silica gel column chromatography (elution solvent: hep ESI-MS; m/z 426 M"+H. 'H-NMR (CDC1) & (ppm): tane-ethyl acetate system) to obtain 727 mg of the title 1.50-1.76 (m, 1H), 1.86-2.02 (m, 2H), 2.06-2.18 (m. 1H), compound. The property values of the compound are as 2.30 (s, 3H), 2.76 (dd, J=10.4, 13.2 Hz, 1H), 3.16-3.28 (m, follows. 1H), 3.65 (dd, J=3.6, 13.2 Hz, 1H), 3.89 (s.3H), 4.03-4.13 H-NMR (CDC1) & (ppm): 1.36-1.60 (m. 10H), 1.70 55 (m. 1H), 4.14-4.24 (m, 1H), 6.92 (brs, 1H), 7.09 (d. J=16.4 1.98 (m, 3H), 2.60-2.78 (m, 2H), 3.36-3.48 (m. 1H), 3.50 HZ, 1H), 7.16-7.35 (m, 8H), 7.58 (d. J=16.4 Hz, 1H), 7.71 (d. J=1.2 Hz, 1H). 3.66 (m, 2H), 6.69 (brs, 1H), 7.11-7.32 (m, 5H). The property values of (-)-8-benzyl-2-(E)-2-3- Synthesis of (+)-8-benzyl-2-(E)-2-3-methoxy-4- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5.6, (4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- 60 7,8-tetrahydro 1.2.4 triazolo 1.5-apyridine are as follows. tetrahydro 1.2.4 triazolo 1.5-alpyridine and (-)-8- ESI-MS; m/z 426 M+H. 'H-NMR (CDC1) & (ppm): benzyl-2-(E)-2-3-methoxy-4-(4-methyl-1H 1.50-1.76 (m, 1H), 1.86-2.02 (m, 2H), 2.06-2.18 (m. 1H), imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2, 2.30 (s, 3H), 2.76 (dd, J=10.4, 13.2 Hz, 1H), 3.16-3.28 (m, 4triazolo 1.5-alpyridine 1H), 3.65 (dd, J=3.6, 13.2 Hz, 1H), 3.89 (s.3H), 4.03-4.13 65 (m. 1H), 4.14-4.24 (m, 1H), 6.92 (brs, 1H), 7.09 (d. J=16.4 A solution of 4N hydrochloric acid in ethyl acetate (13 HZ, 1H), 7.16-7.35 (m, 8H), 7.58 (d. J=16.4 Hz, 1H), 7.71 mL) was added to tert-butyl (3-benzyl-2-oxopiperidin-1-yl) (d. J=1.2 Hz, 1H).

US 9,453,000 B2 117 118 -continued anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by N-N silica gel column chromatography (carrier: Chromatorex I 2 NH; elution solvent: ethyl acetate-methanol system) to S N obtain 1.484 g of the title compound. The property values of the compound are as follows. 'H-NMR (CDC1) & (ppm): 1.90-2.08 (m, 3H), 2.20-2.26 (m. 1H), 2.30 (s.3H), 3.60-3.66 (m. 1H), 3.74-3.83 (m, 2H), Br 10 3.78 (s, 3H), 6.44 (d. J=15.6 Hz, 1H), 6.84-6.91 (m, 3H), 7.11 (d. J–8 Hz, 1H), 7.21 (d. J=8.4 Hz, 2H), 7.40-7.46 (m, 3H), 7.72 (d. J=1.6 Hz, 1H), 10.22 (s, 1H).

15 Synthesis of (-)-8-(4-bromophenyl)-2-(E)-2-3- Synthesis of methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii 1-amino-3-(2-bromophenyl)piperidin-2-one nyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyri dine and (+)-8-(4-bromophenyl)-2-(E)-2-3- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl A solution of ethyl 4-bromophenylacetate (2.0 g) in DMF vinyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-all (5 mL) was added to a suspension of Sodium hydride pyridine (containing 40% of mineral oil, 362 mg) in DMF (20 mL) under ice-cooling. The reaction solution was stirred for 10 minutes, further stirred at room temperature for 30 minutes A solution of (E)-N-3-(4-bromophenyl)-2-oxopiperidin and then ice-cooled again. A solution of 1-chloro-3-iodo 25 1-yl)-3-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl propane (1.85g) in DMF (5 mL) was added to the reaction acrylamide (1.434 g) in phosphorus oxychloride (6 mL) was mixture, and the reaction solution was stirred at room heated under reflux for one hour. The reaction mixture was temperature overnight. Water and ethyl acetate were added left to cool to room temperature and then concentrated under to the reaction mixture and the organic layer was separated. 30 reduced pressure. Acetic acid (7 mL) and ammonium acetate The resulting organic layer was washed with Saturated (4.8 g) were added to the residue, and the reaction solution aqueous sodium chloride, dried over anhydrous magnesium was stirred at 150° C. for one hour. The reaction mixture was Sulfate and then concentrated under reduced pressure. left to cool to room temperature and then concentrated under Hydrazine monohydrate (8 mL) was added to a solution of reduced pressure. Saturated sodium bicarbonate water and the resulting residue in ethanol (20 mL), and the reaction 35 ethyl acetate and were added to the residue, and the organic Solution was stirred at room temperature for one day. The layer was separated. The resulting organic layer was washed reaction mixture was concentrated under reduced pressure. with Saturated aqueous sodium chloride, dried over anhy Saturated sodium bicarbonate water and ethyl acetate and drous magnesium Sulfate and then concentrated under were added to the residue, and the organic layer was 40 reduced pressure. The resulting residue was purified by separated. The resulting organic layer was washed with silica gel column chromatography (carrier: Chromatorex saturated aqueous Sodium chloride, dried over anhydrous NH; elution solvent: heptane-ethyl acetate system) to obtain magnesium sulfate and then concentrated under reduced 770 mg of a racemate of the title compound. The resulting pressure. The residue was purified by silica gel column racemate (73 mg) was separated by CHIRALPAKTM IB chromatography (carrier: Chromatorex NH; elution solvent: 45 heptane-ethyl acetate system) to obtain 898 mg of the title manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 compound. The property values of the compound are as cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain follows. the title optically active compound with a retention time of H-NMR (CDC1) & (ppm): 1.80-2.00 (m, 3H), 2.08-2.15 17 minutes and negative optical rotation (21 mg) and the title (m. 1H), 2.14-3.67 (m, 3H), 4.62 (s. 2H), 7.06 (d. J=8.4 Hz, 50 optically active compound with a retention time of 20 2H), 7.42 (d. J=8.4 Hz, 2H). minutes and positive optical rotation (23 mg). The property values of the title optically active compound Synthesis of (E)-N-3-(4-bromophenyl)-2-oxopiperi with a retention time of 17 minutes are as follows. din-1-yl)-3-3-methoxy-4-(4-methyl-1H-imidazol-1- 55 H-NMR (CDC1) & (ppm): 1.98-2.26 (m, 3H), 2.30 (s, yl)phenylacrylamide 3H), 2.32-2.39 (m. 1H), 3.86 (s, 3H), 4.27-4.32 (m, 3H), 6.92 (s, 1H), 7.03-7.09 (m, 3H), 7.14-7.16 (m, 2H), 7.22 (d. J=7.6 Hz, 1H), 7.47 (d. J=8.4 Hz, 2H), 7.51 (d. J=16 Hz, BOPC1 (1.18 g) was added to a suspension of (E)-3-3- 1H), 7.72 (s, 1H). methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylacrylic acid 60 The property values of the title optically active compound (800 mg), 1-amino-3-(4-bromophenyl)piperidin-2-one (898 with a retention time of 20 minutes are as follows. mg) and TEA (0.9 mL) in DMF (20 mL), and the reaction 'H-NMR (CDC1) & (ppm): 1.98-2.26 (m, 3H), 2.30 (s, solution was stirred at room temperature overnight. Water 3H), 2.32-2.39 (m. 1H), 3.86 (s, 3H), 4.27-4.32 (m, 3H), and ethyl acetate were added to the reaction mixture and the 65 6.92 (s, 1H), 7.03-7.09 (m, 3H), 7.14-7.16 (m, 2H), 7.22 (d. organic layer was separated. The resulting organic layer was J=7.6 Hz, 1H), 7.47 (d. J=8.4 Hz, 2H), 7.51 (d. J=16 Hz, washed with Saturated aqueous sodium chloride, dried over 1H), 7.72 (s, 1H). US 9,453,000 B2 119 120 Examples 22 and 23 1.2.4 triazolo 1.5-alpyridine (150 mg) in dioxane (7 mL) and water (0.7 mL). The reaction solution was stirred in a Synthesis of (-)-2-(E)-2-3-methoxy-4-(4-methyl nitrogen atmosphere at 100° C. overnight. The reaction 1H-imidazol-1-yl)phenyl vinyl-8-(2-methoxymeth mixture was left to cool to room temperature. Then, water ylphenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-a 5 and ethyl acetate were added to the reaction mixture and the pyridine and (+)-2-(E)-2-3-methoxy-4-(4-methyl organic layer was separated. The resulting organic layer was 1H-imidazol-1-yl)phenyl vinyl-8-(2- washed with Saturated aqueous Sodium chloride, dried over methoxymethylphenyl)-5,6,7,8-tetrahydro-1,2,4 anhydrous magnesium sulfate and then concentrated under triazolo 1.5-alpyridine reduced pressure. The resulting residue was purified by 10 silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) and further separated by CHIRALPAKTM AD-H manufactured Formula 63 by Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile 15 phase: ethanol, flow rate: 10 mL/min) to obtain the title optically active compound with a retention time of 16 minutes and negative optical rotation (6.2 mg) and the title S. optically active compound with a retention time of 18 minutes and positive optical rotation (8 mg). The property values of the title optically active compound /S N with a retention time of 16 minutes are as follows. le H-NMR (CDC1) & (ppm): 1.98-2.15 (m, 2H), 2.20-2.29 (m. 1H), 2.30 (s, 3H), 2.36-2.43 (m. 1H), 3.41 (s, 3H), 3.85 25 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.46 (dd, J=11.6 Hz, 1.6 Hz, 1H), 4.61 (t, J–6.4 Hz, 1H), 4.71 (dd, J=11.6 Hz, 1.6 Hz, 1H), 6.85-6.88 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06 (dd. J=16 Hz, 1.6 Hz, 1H), 7.11-7.15 (m, 2H), 7.21 (dd, J=8 Hz, O S ^ V 1.6 Hz, 1H), 7.24-7.29 (m, 1H), 7.37-7.40 (m, 1H), 7.48 (dd. J=16 Hz, 1.6 Hz, 1H), 7.69 (t, J=1.6 Hz, 1H). N 7 N The property values of the title optically active compound with a retention time of 18 minutes are as follows. le 'H-NMR (CDC1) & (ppm): 1.98-2.15 (m, 2H), 2.20-2.29 35 (m. 1H), 2.30 (s, 3H), 2.36-2.43 (m. 1H), 3.41 (s, 3H), 3.85 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.46 (dd, J=11.6 Hz, 1.6 Hz, 1H), 4.61 (t, J–6.4 Hz, 1H), 4.71 (dd, J=11.6 Hz, 1.6 Hz, Synthesis of 8-(2-bromophenyl)-2-(E)-2-3- 1H), 6.85-6.88 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06 (dd. methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii J=16 Hz, 1.6 Hz, 1H), 7.11-7.15 (m, 2H), 7.21 (dd, J=8 Hz, nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine 40 1.6 Hz, 1H), 7.24-7.29 (m, 1H), 7.37-7.40 (m, 1H), 7.48 (dd. J=16 Hz, 1.6 Hz, 1H), 7.69 (t, J=1.6 Hz, 1H). 663 mg of the title compound was obtained from (E)-N- 3-(2-bromophenyl)-2-oxopiperidin-1-yl)-3-3-methoxy-4- (4-methyl-1H-imidazol-1-yl)phenylacrylamide (1.130 g) Examples 24 and 25 using ethyl 2-bromophenylacetate as a starting material by 45 the same method as in Examples 20 and 21. The property Synthesis of (-) and (+)-8-(4-fluoro-2-methoxym values of the compound are as follows. ethylphenyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H H-NMR (CDC1) & (ppm): 2.03-2.20 (m, 3H), 2.30 (s, imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro-1,2, 3H), 2.35-2.42 (m. 1H), 3.86 (s, 3H), 4.25-4.35 (m, 2H), 4triazolo 1.5-alpyridine 4.76 (t, J=6.4 Hz, 1H), 6.86 (bird, J=7.6 Hz, 1H), 6.92 (s, 50 1H), 7.08 (d. J=16.4, 0.8 Hz, 1H), 7.13-7.17 (m, 3H), 7.21 (d. J=7.6 Hz, 1H), 7.26-7.27 (m, 2H), 7.51 (dd, J=7.6, 0.8 HZ, 1H), 7.69 (d. J=0.8 Hz, 1H). Formula 64 Synthesis of (-)-2-(E)-2-3-methoxy-4-(4-methyl 55 1H-imidazol-1-yl)phenyl vinyl-8-(2-methoxymeth ylphenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-a pyridine and (+)-2-(E)-2-3-methoxy-4-(4-methyl 1H-imidazol-1-yl)phenyl vinyl-8-(2- methoxymethylphenyl)-5,6,7,8-tetrahydro-1,2,4 60 triazolo 1.5-alpyridine Potassium methoxymethyl trifluoroborate (CAS No. 910251-11-5, 372 mg), palladium acetate (7 mg), BINAP (19 mg) and cesium carbonate (1.2 g) were added to a mixed 65 solution of 8-(2-bromophenyl)-2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro US 9,453,000 B2 121 122 -continued 7.04 (d. J=16 Hz, 1H), 7.11-7.14 (m, 3H), 7.20 (d. J=8.0 Hz, 1H), 7.47 (d. J=16 Hz, 1H), 7.69 (d. J=1.2 Hz, 1H). N-N 2 O Examples 26 and 27 N1S \ Synthesis of (-)-2-2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- tetrahydro-1,2,4-triazolo 1.5-alpyridin-8- /S N yl)benzonitrile and (+)-2-2-(E)-2-3-methoxy-4- le F 10 (4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- tetrahydro-1,2,4-triazolo 1.5-alpyridin-8- yl)benzonitrile Synthesis of 8-(2-bromo-4-fluorophenyl)-2-(E)-2- 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl 15 Formula 65

vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri dine 559 mg of the title compound was obtained from (E)-N- 3-(2-bromo-4-fluorophenyl)-2-oxopiperidin-1-yl)-3-3- N methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylacrylamide (953 mg) using methyl 2-bromo-4-fluorophenylacetate as a starting material by the same method as in Examples 20 and 21. The property values of the compound are as follows. 25 A. H-NMR (CDC1) & (ppm): 1.98-2.20 (m, 3H), 2.30 (s, e 3H), 2.35-2.42 (m. 1H), 3.86 (s, 3H), 4.28-4.31 (m, 2H), 4.71 (t, J=6.4 Hz, 1H), 6.87 (dd, J=8.4 Hz, 5.6 Hz, 1H), 6.92 (t, J=1.2 Hz, 1H), 6.96-7.01 (m, 1H), 7.07 (d. J=16.4 Hz, 1H), 7.14-7.16 (m, 2H), 7.22 (d. J=8.0 Hz, 1H), 7.36 (dd. 30 2 A. J=8.0, 2.8 Hz, 1H), 7.51 (d. J=16.4 Hz, 1H), 7.70 (d. J=1.2 S N HZ, 1H). Synthesis of (-) and (+)-8-(4-fluoro-2-methoxym N ethylphenyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H 35 ^ imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro-1,2, le 4triazolo 1.5-alpyridine

The title optically active compound with a retention time 40 A suspension of 8-(2-bromophenyl)-2-(E)-2-3- of 15 minutes in CHIRALPAKTM IB manufactured by methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5.6, Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile 7,8-tetrahydro 1.2.4 triazolo 1.5-apyridine (45 mg), Zinc phase: hexane:ethanol=1:1, flow rate: 20 mL/min) and posi cyanide (22 mg) and tetrakistriphenylphosphine palladium tive optical rotation (1.1 mg) and the title optically active (11 mg) in DMF (2 mL) was subjected to microwave compound with a retention time of 25 minutes in the 45 reaction in a nitrogen atmosphere at 160° C. for two hours. CHIRALPAKTM IB and negative optical rotation (0.4 mg) The reaction mixture was left to cool to room temperature. were obtained from 8-(2-bromo-4-fluorophenyl)-2-(E)-2- Then, aqueous ammonia and ethyl acetate were added to the (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl reaction mixture and the organic layer was separated. The 5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-alpyridine (40 mg) by resulting organic layer was washed with Saturated aqueous the same method as in Examples 22 and 23. 50 Sodium chloride, dried over anhydrous magnesium sulfate The property values of the title optically active compound and then concentrated under reduced pressure. The resulting with a retention time of 15 minutes are as follows. residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl 'H-NMR (CDC1) & (ppm): 1.93-2.02 (m. 1H), 2.04-2.14 acetate system) to obtain 34 mg of a racemate of the title (m. 1H), 2.18-2.28 (m, 1H), 2.29 (s.3H), 2.32-2.40 (m. 1H), 55 compound. The resulting racemate (28 mg) was separated by 3.42 (s.3H), 3.84 (s.3H), 4.30 (t, J-6 Hz, 2H), 4.44 (d. J=12 CHIRALPAKTM IB manufactured by Daicel Chemical HZ, 1H), 4.50 (t, J=6 Hz, 1H), 4.65 (d. J=12 Hz, 1H), 6.84 Industries, Ltd. (2 cmx25 cm, mobile phase: ethanol, flow (dd, J=8.4 Hz, 5.2 Hz, 1H), 6.90 (s, 1H), 6.92-6.97 (m. 1H), rate: 10 mL/min) to obtain the title optically active com 7.04 (d. J=16 Hz, 1H), 7.11-7.14 (m, 3H), 7.20 (d. J=8.0 Hz, pound with a retention time of 17 minutes and negative 1H), 7.47 (d. J=16 Hz, 1H), 7.69 (d. J=1.2 Hz, 1H). 60 optical rotation (11.9 mg) and the title optically active The property values of the title optically active compound compound with a retention time of 19 minutes and positive with a retention time of 25 minutes are as follows. optical rotation (13 mg). 'H-NMR (CDC1) & (ppm): 1.93-2.02 (m. 1H), 2.04-2.14 The property values of the title optically active compound (m. 1H), 2.18-2.28 (m, 1H), 2.29 (s.3H), 2.32-2.40 (m. 1H), with a retention time of 17 minutes are as follows. 3.42 (s.3H), 3.84 (s.3H), 4.30 (t, J-6 Hz, 2H), 4.44 (d. J=12 65 H-NMR (CDC1) & (ppm): 2.05-2.27 (m, 3H), 2.31 (s, HZ, 1H), 4.50 (t, J=6 Hz, 1H), 4.65 (d. J=12 Hz, 1H), 6.84 3H), 2.47-2.53 (m. 1H), 3.86 (s, 3H), 4.30-4.37 (m, 2H), (dd, J=8.4 Hz, 5.2 Hz, 1H), 6.90 (s, 1H), 6.92-6.97 (m. 1H), 4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, 1H), 7.06 (d. J=16 Hz, US 9,453,000 B2 123 124 1H), 7.13-7.17 (m, 3H), 7.22 (d. J=8 Hz, 1H), 7.26-7.31 (m, The property values of the title optically active compound 2H), 7.42 (dd, J=8 Hz, 2.8 Hz, 1H), 7.48 (d. J=16 Hz, 1H), with a retention time of 23 minutes are as follows. 7.73 (s, 1H). 'H-NMR (CDC1) & (ppm): 2.00-2.09 (m. 1H), 2.16-2.27 The property values of the title optically active compound (m. 2H), 2.30 (s, 3H), 2.46-2.53 (m, 1H), 3.86 (s, 3H), with a retention time of 19 minutes are as follows. 5 4.27-4.39 (m, 2H), 4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, H-NMR (CDC1) & (ppm): 2.05-2.27 (m, 3H), 2.31 (s, 1H), 7.06 (d. J=16 Hz, 1H), 7.13-7.16 (m, 3H), 7.22 (d. 3H), 2.47-2.53 (m. 1H), 3.86 (s, 3H), 4.30-4.37 (m, 2H), J=7.6 Hz, 1H), 7.30 (dd, J=8 Hz, 2.8 Hz, 1H), 7.42 (dd, J=8 4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, 1H), 7.06 (d. J=16 Hz, Hz, 2.8 Hz, 1H), 7.48 (d. J=16 Hz, 1H), 7.73 (s, 1H). 1H), 7.13-7.17 (m, 3H), 7.22 (d. J=8 Hz, 1H), 7.26-7.31 (m, 2H), 7.42 (dd, J=8 Hz, 2.8 Hz, 1H), 7.48 (d. J=16 Hz, 1H), 10 Examples 30 and 31 7.73 (s, 1H). Synthesis of (-)-8-(4-fluoro-2-pyridin-3-yl-phenyl)- 2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1- Examples 28 and 29 yl)-phenyl-vinyl-5,6,7,8-tetrahydro-1,2,4-triazolo Synthesis of 5-fluoro-2-(-)-2-(E)-2-3-methoxy 15 1.5-alpyridine and (+)-8-(4-fluoro-2-pyridin-3-yl 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5.6.7. phenyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H 8-tetrahydro-1,2,4-triazolo 1.5-alpyridin-8- imidazol-1-yl)-phenyl-vinyl-5,6,7,8-tetrahydro-1, yl)benzonitrile and 5-fluoro-2-(+)-2-(E)-2-3- 2.4 triazolo 1.5-apyridine methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-all pyridin-8-yl)benzonitrile Formula 67

25 -N Formula 66 I o O N /

S 30 7NN

35

N-N N

40 l N-l.N / / le F 45 Pyridine-3-borane acid (18.1 mg), tetrakis(triphenylphos phine)palladium (5.7 mg) and a 2 M Sodium carbonate The title optically active compound with a retention time solution (197 ul) in toluene (1.2 ml)/ethanol (0.3 ml) were of 17 minutes in CHIRALPAKTM IB manufactured by 50 added to 8-(2-bromo-4-fluorophenyl)-2-(E)-2-3-methoxy Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile phase: hexane:ethanol=9:1, flow rate: 20 mL/min) and nega 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra tive optical rotation (9.5 mg) and the title optically active hydro 1.2.4 triazolo 1.5-alpyridine (50 mg) as a starting compound with a retention time of 23 minutes in the material, and the reaction solution was stirred at 100° C. for CHIRALPAKTM IB and positive optical rotation (9.4 mg) 55 two hours. Thereafter, tetrakis(triphenylphosphine)palla were obtained from 8-(2-bromo-4-fluorophenyl)-2-(E)-2- dium (17.0 mg) was added and the reaction solution was (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl stirred for 16 hours. The reaction solution was diluted with 5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-alpyridine (40 mg) by ethyl acetate and the organic layer was washed with brine. the same method as in Examples 26 and 27. The resulting organic layer was dried over anhydrous mag The property values of the title optically active compound 60 with a retention time of 17 minutes are as follows. nesium Sulfate and then concentrated under reduced pres H-NMR (CDC1) & (ppm): 2.00-2.09 (m. 1H), 2.16-2.27 Sure. The residue was purified by silica gel column chro (m. 2H), 2.30 (s, 3H), 2.46-2.53 (m, 1H), 3.86 (s, 3H), matography (elution solvent: heptane-ethyl acetate system) 4.27-4.39 (m, 2H), 4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, to obtain 15.4 mg of a racemate of the title compound. The 1H), 7.06 (d. J=16 Hz, 1H), 7.13-7.16 (m, 3H), 7.22 (d. 65 resulting racemate (15.4 mg) was separated by CHIRAL J=7.6 Hz, 1H), 7.30 (dd, J=8 Hz, 2.8 Hz, 1H), 7.42 (dd, J=8 PAKTM IB manufactured by Daicel Chemical Industries, Hz, 2.8 Hz, 1H), 7.48 (d. J=16 Hz, 1H), 7.73 (s, 1H). Ltd. (2 cmxcm, mobile phase: hexane:ethanol-3:7, flow US 9,453,000 B2 125 126 rate: 20 mL/min) to obtain the title optically active com (2-nitrophenyl)-2-oxopiperidin-1-yl)acrylamide (1.279 g) pound with a retention time of 31 minutes and negative using methyl 2-nitrophenylacetate as a starting material by optical rotation (5.0 mg) and the title optically active com the same method as in Examples 20 and 21. The property pound with a retention time of 41 minutes and positive values of the compound are as follows. optical rotation (4.7 mg). H-NMR (CDC1) & (ppm): 2.13-2.32 (m, 3H), 2.29 (s. The property values of the title optically active compound 3H), 2.55-2.61 (m. 1H), 3.85 (s, 3H), 4.31-4.35 (m, 2H), with a retention time of 31 minutes are as follows. 4.92-4.95 (m. 1H), 6.91-6.92 (m, 1H), 7.04 (d. J=16.4 Hz, 'H-NMR (CDC1) & (ppm): 1.80-2.20 (m, 4H), 2.30 (s, 1H), 7.12-7.14 (m, 3H), 7.21 (d. J=7.6 Hz, 1H), 7.43-7.49 3H), 3.86 (s.3H), 405-4.30 (m, 3H), 6.90 (s, 1H), 7.00-7.05 10 (m. 2H), 7.56-7.60 (m. 1H), 7.69 (d. J=1.6 Hz, 1H), 8.03 (dd. (m. 1H), 7.05 (d. J=16.0 Hz, 1H), 7.10-7.20 (m, 2H), 7.25-7.45 (m, 3H), 7.50 (d. J=16.0 Hz, 1H), 7.70 (d. J=8.4 J=8.0, 1.6 Hz, 1H). HZ, 1H), 7.71 (s, 1H), 7.80 (d. J=8.4 Hz, 1H), 8.70 (d. J=4.8 HZ, 1H), 8.80 (brd-s, 1H). The property values of the title optically active compound 15 Synthesis of 2-((-)-2-(E)-2-3-methoxy-4-(4- with a retention time of 41 minutes are as follows. methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- 'H-NMR (CDC1) & (ppm): 1.80-2.20 (m, 4H), 2.30 (s, tetrahydro-1,2,4-triazolo 1.5-alpyridin-8-yl)phe 3H), 3.86 (s.3H), 405-4.30 (m, 3H), 6.90 (s, 1H), 7.00-7.05 nylamine and 2-((+)-2-(E)-2-3-methoxy-4-(4- (m. 1H), 7.05 (d. J=16.0 Hz, 1H), 7.10-7.20 (m, 2H), methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- 7.25-7.45 (m, 3H), 7.50 (d. J=16.0 Hz, 1H), 7.70 (d. J=8.4 HZ, 1H), 7.71 (s, 1H), 7.80 (d. J=8.4 Hz, 1H), 8.70 (d. J=4.8 tetrahydro-1,2,4-triazolo 1.5-alpyridin-8-yl) HZ, 1H), 8.80 (brd-s, 1H). phenylamine Examples 32 and 33 25 A mixed solution of 2-(E)-2-3-methoxy-4-(4-methyl Synthesis of 2-((-)-2-(E)-2-3-methoxy-4-(4- 1H-imidazol-1-yl)phenyl vinyl-8-(2-nitrophenyl)-5,6,7,8- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- tetrahydro 1.2.4 triazolo 1.5-alpyridine (178 mg) and tetrahydro-1,2,4-triazolo 1.5-alpyridin-8-yl)phe sodium dithionite (340mg) in ethanol (10 mL) and water (2 nylamine and 2-((+)-2-(E)-2-3-methoxy-4-(4- 30 methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- mL) was stirred at room temperature for one hour. Water and tetrahydro-1,2,4-triazolo 1.5-alpyridin-8-yl) ethyl acetate were added to the reaction mixture and the phenylamine organic layer was separated. The resulting organic layer was washed with Saturated aqueous Sodium chloride, dried over 35 anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by Formula 68 silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain N- N 40 70 mg of a racemate of the title compound. The resulting | NH2 racemate (30 mg) was separated by CHIRALPAKTM ADH O N manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title optically active compound with a retention time of 45 17 minutes and negative optical rotation (12.7 mg) and the le title optically active compound with a retention time of 28 minutes and positive optical rotation (13.2 mg). The property values of the title optically active compound 50 with a retention time of 17 minutes are as follows. O S / NH2 'H-NMR (CDC1) & (ppm): 2.10-2.18 (m. 1H), 2.24-2.34 (m,3H), 2.30 (s, 3H), 3.87 (s.3H), 4.03 (brs, 2H), 4.26-2.30 (m. 2H), 4.36 (t, J=5.6 Hz, 1H), 6.77-6.81 (m, 2H), 6.88 (dd. /S N 55 J=7.6 Hz, 1.2 Hz, 1H), 6.92 (t, J=1.6 Hz, 1H), 7.05 (d. J=16 le HZ, 1H), 7.10-7.15 (m, 3H), 7.22 (d. J=7.6 Hz, 1H), 7.50 (d. J=16 Hz, 1H), 7.70 (d. J=1.2 Hz, 1H). The property values of the title optically active compound 60 with a retention time of 28 minutes are as follows. Synthesis of 2-(E)-2-3-methoxy-4-(4-methyl-1H H-NMR (CDC1) & (ppm): 2.10-2.18 (m. 1H), 2.24-2.34 imidazol-1-yl)phenyl vinyl-8-(2-nitrophenyl)-5.6.7. (m,3H), 2.30 (s, 3H), 3.87 (s.3H), 4.03 (brs, 2H), 4.26-2.30 8-tetrahydro 1.2.4 triazolo 1.5-alpyridine (m. 2H), 4.36 (t, J=5.6 Hz, 1H), 6.77-6.81 (m, 2H), 6.88 (dd. 65 J=7.6 Hz, 1.2 Hz, 1H), 6.92 (t, J=1.6 Hz, 1H), 7.05 (d. J=16 The title compound (920 mg) was obtained from (E)-3- HZ, 1H), 7.10-7.15 (m, 3H), 7.22 (d. J=7.6 Hz, 1H), 7.50 (d. 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-N-3- J=16 Hz, 1H), 7.70 (d. J=1.2 Hz, 1H). US 9,453,000 B2 127 128 Examples 34 and 35 Examples 36 and 37 Synthesis of N-(2-((-)-2-(E)-2-3-methoxy-4-(4- Synthesis of (-)-8-(3,4-dimethoxyphenyl)-2-(E)-2- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl tetrahydro-1,2,4-triazolo 1.5-alpyridin-8-ylphenyl 5 vinyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyri acetamide and N-2-((+)-2-(E)-2-3-methoxy-4-(4- dine and (+)-8-(3,4-dimethoxyphenyl)-2-(E)-2-3- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl tetrahydro-1,2,4-triazolo 1.5-alpyridin-8-ylphenyl vinyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-all acetamide pyridine 10

Formula 69 Formula 70

15 N-N N-N O I l N I N 5-(O S. / ^ N le le - O O

25

N-N| Z HN -( O Z O S N O N N

^ N N 7 N le e - O O

35 Acetic anhydride (0.045 mL) was added to a solution of 559 mg of the title compound was obtained from (E)-N- 2-((-)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) 3-(3,4-dimethoxyphenyl)-2-oxopiperidin-1-yl)-3-3- phenyl vinyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyri methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylacrylamide din-8-yl)phenylamine (41 mg) in pyridine (2 mL), and the 40 (401 mg) using ethyl 3,4-dimethoxyphenylacetate as a start reaction solution was stirred at 50° C. overnight. The reac ing material by the same method as in Examples 20 and 21. tion mixture was left to cool to room temperature and then The resulting racemate (77 mg) was separated by CHIRAL concentrated under reduced pressure. The resulting residue PAKTM IA manufactured by Daicel Chemical Industries, was purified by CHIRALPAKTM IB manufactured by Daicel Ltd. (2 cmx25 cm, mobile phase: ethanol, flow rate: 10 45 mL/min) to obtain the title optically active compound with Chemical Industries, Ltd. (2 cmx25 cm, mobile phase: a retention time of 24 minutes and negative optical rotation ethanol, flow rate: 10 mL/min) to obtain the title optically (17.8 mg) and the title optically active compound with a active compound with a retention time of 11 minutes and retention time of 31 minutes and positive optical rotation negative optical rotation (14.9 mg) and the title optically (19.0 mg). active compound with a retention time of 14 minutes and 50 The property values of the title optically active compound positive optical rotation (15.1 mg). with a retention time of 24 minutes are as follows. The property values of the title optically active compound 'H-NMR (CDC1) & (ppm): 2.20-2.14 (m, 2H), 2.18-2.27 with a retention time of 11 minutes are as follows. (m. 1H), 2.30 (s, 3H), 2.31-2.38 (m. 1H), 3.86 (s, 6H), 3.87 'H-NMR (CDC1) & (ppm): 220-2.28 (m. 1H), 2.23 (s, (s, 3H), 4.23-4.36 (m, 3H), 6.64 (dd, J=8.4 Hz, 1.6 Hz, 1H), 3H), 2.30 (s.3H), 2.32-2.48 (m, 3H), 3.89 (s.3H), 4.24-4.32 55 6.71 (d. J=1.6 Hz, 1H), 6.83 (d. J=8.4 Hz, 1H), 6.91 (q, J=1.2 (m. 2H), 4.37 (t, J=6 Hz, 1H), 6.93 (t, J–1.2 Hz, 1H), 7.01 HZ, 1H), 7.08 (dd, J=16.4 Hz, 0.8 Hz, 1H), 7.13-7.16 (m, (d. J=16 Hz, 1H), 7.14-7.16 (m, 2H), 7.19-7.25 (m, 2H), 2H), 7.22 (d. J=8.4 Hz, 1H), 7.53 (d. J=16.4 Hz, 1H), 7.70 7.29-7.39 (m, 2H), 7.45 (d. J=16 Hz, 1H), 7.72-7.75 (m, 2H), (s, 1H). 9.87 (s, 1H). The property values of the title optically active compound The property values of the title optically active compound 60 with a retention time of 31 minutes are as follows. with a retention time of 14 minutes are as follows. 'H-NMR (CDC1) & (ppm): 2.20-2.14 (m, 2H), 2.18-2.27 H-NMR (CDC1) & (ppm): 2.20-2.28 (m. 1H), 2.23 (s, (m. 1H), 2.30 (s, 3H), 2.31-2.38 (m. 1H), 3.86 (s, 6H), 3.87 3H), 2.30 (s.3H), 2.32-2.48 (m, 3H), 3.89 (s.3H), 4.24-4.32 (s, 3H), 4.23-4.36 (m, 3H), 6.64 (dd, J=8.4 Hz, 1.6 Hz, 1H), (m. 2H), 4.37 (t, J=6 Hz, 1H), 6.93 (t, J–1.2 Hz, 1H), 7.01 6.71 (d. J=1.6 Hz, 1H), 6.83 (d. J=8.4 Hz, 1H), 6.91 (q, J=1.2 (d. J=16 Hz, 1H), 7.14-7.16 (m, 2H), 7.19-7.25 (m, 2H), 65 HZ, 1H), 7.08 (dd, J=16.4 Hz, 0.8 Hz, 1H), 7.13-7.16 (m, 7.29-7.39 (m, 2H), 7.45 (d. J=16 Hz, 1H), 7.72-7.75 (m, 2H), 2H), 7.22 (d. J=8.4 Hz, 1H), 7.53 (d. J=16.4 Hz, 1H), 7.70 9.87 (s, 1H). (s, 1H). US 9,453,000 B2 129 130 Examples 38 and 39 Examples 40 and 41 Synthesis of (-)-2-(E)-2-3-methoxy-4-(4-methyl Synthesis of (-)-8-(5-chlorothiophen-2-yl)-2-(E)-2- 1H-imidazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5, 5 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine and vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri (+)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol dine and (+)-8-(5-chlorothiophen-2-yl)-2-(E)-2-3- 1-yl)phenyl vinyl-8-(pyridin-2-yl)-5,6,7,8-tetra methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl hydro 1.2.4 triazolo 1.5-alpyridine vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-all 10 pyridine

Formula 71 Formula 72

15

MeO I % MeO

N 2O % N. o

25

MeOe S NZ W \ 30 N %N o

A 35

208.5 mg of a racemate of the title compound was obtained from methyl 2-pyridylacetate (6.76 g) by the same Synthesis of ethyl (5-chlorothiophen-2-yl)acetate method as in Examples 20 and 21. The racemate (100 mg) 40 was separated by CHIRALCELTM OD-H manufactured by Methyl methylsulfinylmethyl sulfide (5.53 g) and potas Daicel Chemical Industries, Ltd. (2 cmx25 cm; mobile sium hydroxide (2 g) were added to a solution of 5-chloro phase: ethanol) to obtain a (-)-isomer of the title optically 2-thiophenecarboxyaldehyde (6.21 g) in methanol (70 mL), active compound with a retention time of 17 minutes (43.6 and the reaction solution was stirred with heating under mg, 79% ee) and a (+)-isomer of the title optically active 45 reflux for 21 hours. After leaving to cool to room tempera compound with a retention time of 24 minutes (47.7 mg: ture, the solvent was evaporated under reduced pressure. 87% ee). Methylene chloride was added to the residue, the insoluble The property values of (-)-2-(E)-2-3-methoxy-4-(4- matter was removed by filtration, and the solvent was methyl-1H-imidazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5, evaporated under reduced pressure. Then, the residue was 50 purified by silica gel column chromatography (elution sol 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are as fol vent: heptane-ethyl acetate system) to obtain 5.61 g of a lows. (E)/(Z) mixture of 2-chloro-5-(2-methanesulfinyl-2-methyl ESI-MS; m/z 413 M*-i-H. 'H-NMR (CDC1) & (ppm): Sulfanylvinyl)thiophene. A Saturated solution of hydrogen 2.04-2.17 (m. 1H), 2.19-2.46 (m, 6H), 3.85 (s, 3H), 4.20 chloride in ethanol (10 mL) was added to a solution of the 4.37 (m, 2H), 4.48 (t, J=6.4 Hz, 1H), 6.90 (t, J=1.2 Hz, 1H), 55 resulting (E)/(Z) mixture of 2-chloro-5-(2-methanesulfinyl 7.06 (d. J=16.4 Hz, 1H), 7.10-7.24 (m, 5H), 7.49 (d. J=16.4 2-methylsulfanylvinyl)thiophene (5.61 g) in ethanol (80 HZ, 1H), 7.62-7.72 (m, 2H), 8.57 (dd, J=2.4, 5.6 Hz, 1H). mL), and the reaction solution was stirred with heating under The property values of (+)-2-(E)-2-3-methoxy-4-(4- reflux for 23 hours. After leaving to cool to room tempera methyl-1H-imidazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5, ture, the solvent was evaporated under reduced pressure. 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are as fol 60 The residue was purified by silica gel column chromatog lows. raphy (elution solvent: heptane-ethyl acetate system) to ESI-MS; m/z 413 M*-i-H. 'H-NMR (CDC1) & (ppm): obtain 3.31 g of the title compound. The property values of 2.04-2.17 (m. 1H), 2.19-2.46 (m, 6H), 3.85 (s, 3H), 4.20 the compound are as follows. 4.37 (m, 2H), 4.48 (t, J=6.4 Hz, 1H), 6.90 (t, J=1.2 Hz, 1H), 65 ESI-MS; m/z 205 M*-i-H. 'H-NMR (CDC1,) & (ppm): 7.06 (d. J=16.4 Hz, 1H), 7.10-7.24 (m, 5H), 7.49 (d. J=16.4 1.28 (t, J=7.2 Hz, 3H), 3.72 (d. J=0.8 Hz, 2H), 4.18 (q, J=7.2 HZ, 1H), 7.62-7.72 (m, 2H), 8.57 (dd, J=2.4, 5.6 Hz, 1H). Hz, 2H), 6.67-6.71 (m, 1H), 6.75 (d. J=3.6 Hz, 1H). US 9,453,000 B2 131 132 Synthesis of (-)-8-(5-chlorothiophen-2-yl)-2-(E)-2- ESI-MS; m/z 452 M+H. 'H-NMR (CDC1) & (ppm): 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri 2.03-2.22 (m, 2H), 2.23-2.36 (m, 4H), 2.37-2.47 (m, 1H), dine and (+)-8-(5-chlorothiophen-2-yl)-2-(E)-2-3- 3.86 (s, 3H), 4.29 (t, J=5.6 Hz, 2H), 4.74 (t, J=7.6 Hz, 1H), methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl 6.92 (brs, 1H), 6.94 (d. J=5.6 Hz, 1H), 7.07 (d. J=16.4 Hz, vinyl-5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-a) 5 1H), 7.12-7.24 (m, 4H), 7.53 (d. J=16.4 Hz, 1H), 7.71 (brs, pyridine 1H). 5.2 mg of a racemate of the title compound was obtained The property values of (+)-8-(5-chlorothiophen-2-yl)-2- from ethyl (5-chlorothiophen-2-yl)acetate (3.31 g) by the {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl same method as in Examples 20 and 21. The racemate (5.2 10 vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are mg) was separated by CHIRALPAKTMIA manufactured by as follows. Daicel Chemical Industries, Ltd. (2 cmx25 cm; mobile phase: hexane:ethanol=1:1) to obtain a (-)-isomer of the title ESI-MS; m/z 452 M*-i-H. 'H-NMR (CDC1,) & (ppm): optically active compound with a retention time of 11.5 2.03-2.22 (m, 2H), 2.23-2.36 (m, 4H), 2.37-2.47 (m, 1H), minutes (1.08 mg; >99% ee) and a (+)-isomer of the title 15 3.86 (s, 3H), 4.29 (t, J=5.6 Hz, 2H), 4.74 (t, J=7.6 Hz, 1H), optically active compound with a retention time of 24 6.92 (brs, 1H), 6.94 (d. J=5.6 Hz, 1H), 7.07 (d. J=16.4 Hz, minutes (0.74 mg. D99% ee). 1H), 7.12-7.24 (m, 4H), 7.53 (d. J=16.4 Hz, 1H), 7.71 (brs, The property values of (-)-8-(5-chlorothiophen-2-yl)-2- {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl 1H). vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine are The following compounds were obtained by the same as follows. method as in Examples 20 and 21 (Table 1). TABLE 1.

N-N MeO N I Z E2 N El

N 7NN le

E1 E2 DATA: MS miz Note

N H M + H: 463 Optically active compound n (ESI) (separation conditions OD-H: retention time 36 2 min, optical rotation (-))

43 7, N H M + H: 463 Optically active compound n (ESI) (separation conditions OD-H: retention time 46 2 min, optical rotation (+))

H M + H: 480 Optically active compound (ESI) (separation conditions AD-H: retention time 33 min, optical rotation (+)) CF

45 4, H M + H: 480 Optically active compound * (ESI) (separation conditions AD-H: retention time 47 min, optical rotation (-)) CF

46 / H M + H: 430 Optically active compound : N (ESI) (separation conditions 80% M ethanol-hexane: IB: retention time 15 min, optical rotation (+)) US 9,453,000 B2 133 134 TABLE 1-continued

N-N I MeO N N

le

Example E1 E2 DATA: MS miz Note

47 H M + H:430 Optically active compound : N/ (ESI) (separation conditions 80% ethanol-hexane: IB: retention time 27 min, n:M optical rotation (-))

48 H M - H: 448 (ESI) F

F

49 H M + H: 448 (ESI)

DC F

50 H M + H: 464 (ESI)

C F

51 : H M + H: 466 (ESI)

DC F

52 F H M - H: 466 (ESI) US 9,453,000 B2 135 136 Examples 53 and 54 The property values of (-)-2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5, Synthesis of (+)-2-(E)-2-3-methoxy-4-(4-methyl 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin-8-ol are as fol 1H-imidazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5, lows. 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin-8-ol 5 ESI-MS; m/z 429 M*-i-H. 'H-NMR (CDC1,) & (ppm): and (-)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imi 2.11-2.37 (m, 6H), 2.50-2.64 (m, 1H), 3.81 (s, 3H), 4.22 dazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5,6,7,8- 4.32 (m, 1H), 4.35-4.44 (m, 1H), 6.88 (brs, 1H), 6.96-7.10 tetrahydro 1,2,4-triazolo 1.5-alpyridin-8-ol (m,3H), 7.16 (d. J=8.0 Hz, 1H), 7.24-7.38 (m, 2H), 7.43 (d. J=16.4 Hz, 1H), 7.66 (d. J=1.2 Hz, 1H), 7.74 (dt, J=1.2, 8.0 10 HZ, 1H), 8.54-8.62 (m. 1H). Formula 73 Examples 55 and 56 Synthesis of (-)-8-(4-isopropylphenyl)-2-(E)-2-3- 15 methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin MeO S 8-ol and (+)-8-(4-isopropylphenyl)-2-(E)-2-3- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl % N. vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-all pyridin-8-ol

25 Formula 74

MeO S.

OH MeO %\ 30

Sodium hydride (containing 40% of mineral oil, 21 mg) 35 was added to a solution of 2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5, 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine synthesized by the method in Example 38 and 39 (108 mg) in DMF (1.2 mL), and the reaction Solution was stirred at room tempera 40 ture for three hours under oxygen bubbling. Sodium thio Sulfate pentahydride was added to the reaction Solution, and the reaction Solution was stirred at room temperature for several minutes. Ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution and the 45 organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated A racemate of title compound (67.1 mg) was obtained under reduced pressure to obtain the racemic title com pound. from 8-(4-isopropylphenyl)-2-(E)-2-3-methoxy-4-(4- 50 methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro The racemate of the title compound was separated by 1.2.4 triazolo 1.5-alpyridine synthesized in Examples 5 CHIRALPAKTM IA manufactured by Daicel Chemical and 6 (117.4 mg) by the same method as in Examples 53 and Industries, Ltd. (2 cmx25 cm; mobile phase: ethanol) to 54. The racemate of the title compound was separated by obtain a (+)-isomer of the title optically active compound CHIRALPAKTM AD-H manufactured by Daicel Chemical with a retention time of 11 minutes (49.3 mg, >99% ee) and 55 Industries, Ltd. (2 cmx25 cm; mobile phase: hexane:etha a (-)-isomer of the title optically active compound with a nol=1:1) to obtain a (-)-isomer of the title optically active retention time of 13 minutes (44.6 mg, 94% ee). compound with a retention time of 13.5 minutes (20.7 mg: The property values of (+)-2-(E)-2-3-methoxy-4-(4- >99% ee) and a (+)-isomer of the title optically active methyl-1H-imidazol-1-yl)phenyl vinyl-8-(pyridin-2-yl)-5, compound with a retention time of 16.5 minutes (20.1 mg: 6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin-8-ol are as fol 60 98% ee). lows. The property values of (-)-8-(4-isopropylphenyl)-2-(E)- ESI-MS; m/z 429 M*-i-H. 'H-NMR (CDC1) & (ppm): 2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii 2.11-2.37 (m, 6H), 2.50-2.64 (m, 1H), 3.81 (s, 3H), 4.22 nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin-8-ol are 4.32 (m, 1H), 4.35-4.44 (m, 1H), 6.88 (brs, 1H), 6.96-7.10 as follows. (m,3H), 7.16 (d. J=8.0 Hz, 1H), 7.24-7.38 (m, 2H), 7.43 (d. 65 ESI-MS; m/z 470 M+H. 'H-NMR (CDC1) & (ppm): J=16.4 Hz, 1H), 7.66 (d. J=1.2 Hz, 1H), 7.74 (dt, J=1.2, 8.0 1.23 (d. J=6.8 Hz, 6H), 1.92-2.05 (m, 1H), 2.21-2.40 (m, HZ, 1H), 8.54-8.62 (m. 1H). 6H), 2.84-2.96 (m, 1H), 3.82 (s.3H), 4.25 (t, J=5.6 Hz, 2H),

US 9,453,000 B2 139 140 Synthesis of 8-(2-fluorophenyl)-2-(E)-2-3- Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii phase: ethanol, flow rate: 10 mL/min) and positive optical nyl-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyri rotation (20.6 mg) and the title optically active compound dine with a retention time of 14 minutes in the CHIRALPAKTM 468 mg of the title compound was obtained from (E)-N- IA and negative optical rotation (17.2 mg) were obtained 3-(2-fluorophenyl)-2-oxopiperidin-1-yl)-3-3-methoxy-4- from 8-(2-fluorophenyl)-2-(E)-2-3-methoxy-4-(4-methyl (4-methyl-1H-imidazol-1-yl)phenylacrylamide (761 mg) 1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro-1,2,4 using methyl 2-fluorophenylacetate as a starting material by triazolo 1.5-alpyridine (50 mg) by the same method as in Examples 53 and 54. the same method as in Examples 20 and 21. The property 10 values of the compound are as follows. The property values of the title optically active compound H-NMR (CDC1) & (ppm): 2.03-2.24 (m, 3H), 2.29 (s. with a retention time of 12 minutes are as follows. 3H), 2.33-2.39 (m. 1H), 3.85 (s, 3H), 4.27-4.30 (m, 2H), H-NMR (CDC1) & (ppm): 2.04-2.11 (m. 1H), 2.22-2.36 4.58-4.61 (m. 1H), 6.91-6.92 (m, 1H), 6.93-6.98 (m, 1H), (m. 2H), 2.30 (s, 3H), 3.76 (s, 3H), 4.13-4.20 (m, 1H), 7.05-7.15 (m, 5H), 7.21 (d. J=7.6 Hz, 1H), 7.24-7.30 (m, 15 4.29-4.35 (m. 1H), 6.85-6.99 (m, 4H), 7.09 (d. J=8 Hz, 2H), 1H), 7.51 (d. J=16.4 Hz, 1H), 7.69 (d. J=1.2 Hz, 1H). 7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H), 7.34 (d. J=18.8 Hz, 1H), 7.65 (d. J=0.8 Hz, 1H), 7.83-7.88 (m, 1H). Synthesis of (-)-2-(E)-2-3-methoxy-4-(4-methyl The property values of the title optically active compound 1H-imidazol-1-yl)phenyl vinyl-8-phenyl-5,6,7,8- with a retention time of 14 minutes are as follows. tetrahydro-1,2,4-triazolo 1.5-alpyridin-8-ol and 'H-NMR (CDC1) & (ppm): 2.04-2.11 (m. 1H), 2.22-2.36 (+)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol (m. 2H), 2.30 (s, 3H), 3.76 (s, 3H), 4.13-4.20 (m, 1H), 1-yl)phenyl vinyl-8-phenyl-5,6,7,8-tetrahydro-1,2, 4.29-4.35 (m. 1H), 6.85-6.99 (m, 4H), 7.09 (d. J=8 Hz, 2H), 4triazolo 1.5-alpyridin-8-ol 7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H), 7.34 (d. J=18.8 Hz, 1H), 7.65 (d. J=0.8 Hz, 1H), 7.83-7.88 (m, 1H). The title optically active compound with a retention time The following compounds were obtained by the same of 12 minutes in CHIRALPAKTM IA manufactured by method as in Examples 53 and 54 (Table 2). TABLE 2

N-N MeO S. I Z E2 N El

N /NN le

E1 E2 DATA: MS miz Note

: OH M + H: 496 Optically active compound (ESI) (separation conditions IA: retention time 21 min, optical rotation (-)) CF

62 o, OH M - H: 496 Optically active compound (ESI) (separation conditions IA: retention time 29 min, optical rotation (+)) CF

N OH M + H: 479 Optically active compound n (ESI) (separation conditions AD-H: retention time 15 min, 2 optical rotation (-))

A, OH M + H: 479 Optically active compound (ESI) (separation conditions AD-H: retention time 21 min, optical rotation (+)) US 9,453,000 B2 141 142 Examples 65 and 66 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction Solution, and the organic layer Synthesis of (+)-8-(3-fluorophenyl)-2-(E)-2-3- was separated. The resulting organic layer was dried over methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii anhydrous magnesium sulfate and concentrated under nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri reduced pressure to obtain 227 mg of the title compound. dine-8-carbonitrile and (-)-8-(3-fluorophenyl)-2- The property value of the compound is as follows. {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) ESI-MS; m/z 458 M"+H. phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5- apyridine-8-carbonitrile Synthesis of 8-(3-fluorophenyl)-2-(E)-2-3- 10 methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri dine-8-carbaldehyde oxime Formula 77 Sodium acetate (58.7 mg) and hydroxylammonium chlo 15 ride (49.8 mg) were added to a solution of 8-(3-fluorophe nyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-all MeO N pyridine-8-carbaldehyde (164 mg) in ethanol (10 mL), and the reaction solution was stirred at room temperature for five %N hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution and the organic layer was separated. The resulting organic layer was dried over anhy drous magnesium Sulfate and then concentrated under 25 reduced pressure to obtain 169 mg of the title compound. The property value of the compound is as follows. ESI-MS; m/z 473 M"+H. MeO S Synthesis of (+)-8-(3-fluorophenyl)-2-(E)-2-3- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii %\ nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri dine-8-carbonitrile and (-)-8-(3-fluorophenyl)-2- {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5- 35 apyridine-8-carbonitrile Synthesis of (8-(3-fluorophenyl)-2-(E)-2-3- 1,1'-Carbonylbis-1H-imidazole (290 mg) was added to a methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii solution of 8-(3-fluorophenyl)-2-(E)-2-3-methoxy-4-(4- nyl-5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-alpyridin methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 8-yl)methanol 40 1.2.4 triazolo 1.5-alpyridine-8-carbaldehyde oxime (169 mg) in THF (15 mL), and the mixture was heated under Paraformaldehyde (186 mg) and sodium hydride (con reflux for 2.5 hours. The reaction solution was cooled to taining 40% of mineral oil, 28.7 mg) were added to a room temperature. Then, ethyl acetate and brine were added solution of 8-(3-fluorophenyl)-2-(E)-2-3-methoxy-4-(4- to the reaction solution and the organic layer was separated. methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 45 The resulting organic layer was dried over anhydrous mag 1.2.4 triazolo 1.5-alpyridine synthesized by the method in nesium sulfate and concentrated under reduced pressure. Examples 1 and 2 (154 mg) in DMF (3 mL), and the reaction The residue was purified by silica gel column chromatog solution was stirred at room temperature for 30 minutes. raphy (carrier: Chromatorex NH; elution solvent: heptane: Thereafter, ethyl acetate and saturated sodium bicarbonate ethyl acetate=1:1->ethyl acetate->ethyl acetate:metha water were added to the reaction solution, and the organic 50 nol=9:1) to obtain 84.6 mg of a racemate of the title layer was separated. The resulting organic layer was dried compound. The resulting racemate (84.6 mg) was separated over anhydrous magnesium Sulfate and concentrated under by CHIRALPAKTM IA manufactured by Daicel Chemical reduced pressure to obtain 204 mg of the title compound. Industries, Ltd. (2 cmx25 cm; mobile phase: hexane:etha The property value of the compound is as follows. nol=1:1) to obtain a (+)-isomer of the title optically active ESI-MS; m/z 460 M+H. 55 compound with a retention time of 14 minutes (26.5 mg: >99% ee) and a (-)-isomer of the title optically active Synthesis of 8-(3-fluorophenyl)-2-(E)-2-3- compound with a retention time of 17 minutes (25.1 mg: methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii 98% ee). nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri The property values of (+)-8-(3-fluorophenyl)-2-(E)-2- dine-8-carbaldehyde 60 (3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl 5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-apyridine-8-carboni Dess-Martin periodinane (304 mg) was added to a solu trile are as follows. tion of (8-(3-fluorophenyl)-2-(E)-2-3-methoxy-4-(4- ESI-MS; m/z 455 M*-i-H. 'H-NMR (CDC1,) & (ppm): methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 2.12-2.25 (m. 1H), 2.26-2.51 (m, 5H), 2.67-2.77 (m, 1H), 1.2.4 triazolo 1.5-alpyridin-8-yl)methanol (165 mg) in 65 3.87 (s, 3H), 4.26-4.42 (m, 2H), 6.92 (t, J=1.2 Hz, 1H), methylene chloride (10 mL), and the reaction solution was 6.99-7.27 (m, 7H), 7.37-7.44 (m, 1H), 7.58 (d. J=16.0 Hz, stirred in a nitrogen atmosphere at room temperature for four 1H), 7.71 (d. J=1.6 Hz, 1H).

US 9,453,000 B2 145 146 The property values of tert-butyl N'-(5-chloro-2-(3,4,5- 3.72 (m, 1H), 3.78-3.82 (m, 2H), 3.84 (s, 3H), 6.41 (d. trifluorophenyl)pentanoylhydrazinecarboxylate are as fol J=16.0 Hz, 1H), 6.88 (brd, J=8.0 Hz, 1H), 6.90 (brs, 1H), lows. 6.93 (s, 1H), 7.00 (dd, J=6.8, 3.6 Hz, 2H), 7.14 (d. J=8.0 Hz, ESI-MS; m/z 403 M"+Na. 'H-NMR (CDC1) & (ppm): 1H), 7.44 (d. J=16.0 Hz, 1H), 7.74 (d. J=1.2 Hz, 1H), 9.87 1.45 (s, 9H), 1.64-2.00 (m, 3H), 2.15-2.26 (m, 1H), 3.30 (t, (brs, 1H). J–7.2 Hz, 1H), 3.47-3.60 (m, 2H), 6.99 (dd, J–8.4, 6.4 Hz, 2H). Synthesis of 2-(E)-2-3-methoxy-4-(4-methyl-1H The property value of tert-butyl N'-(5-(benzotriazol-1- imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluorophe yloxy)-2-(3,4,5-trifluorophenyl)pentanoylhydrazinecar nyl)-5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-alpyridine boxylate is as follows. 10 ESI-MS; m/z 480 M+H. A solution of (E)-3-3-methoxy-4-(4-methyl-1H-imida Zol-1-yl)phenyl-N-(2-oxo-3-(3,4,5-trifluorophenyl)piperi Synthesis of tert-butyl 2-oxo-3-(3,4,5-trifluorophe din-1-yl)acrylamide (95 mg) in phosphorus oxychloride (2 nyl)piperidin-1-yl)carbamate mL) was stirred at 120° C. for one hour. The reaction 15 Solution was left to cool to room temperature and then Sodium iodide (131 mg) and sodium hydride (containing concentrated under reduced pressure. Ammonium acetate 40% of mineral oil, 70 mg) were added to a solution of (302 mg) was added to a solution of the residue in acetic acid tert-butyl N'-(5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluoro (1 mL), and the reaction solution was stirred at 150° C. for phenyl)pentanoylhydrazinecarboxylate (420 mg) in DMF three hours. The reaction solution was left to cool to room (3 mL), and the reaction solution was stirred at 100° C. for temperature. Then, ethyl acetate and Saturated Sodium bicar 19 hours. The reaction solution was left to cool to room bonate water were added to the reaction solution, and the temperature. Ethyl acetate and Saturated sodium bicarbonate organic layer was separated. The resulting organic layer was water were added to the reaction solution, and the organic dried over anhydrous magnesium sulfate and then concen layer was separated. The resulting organic layer was dried trated under reduced pressure. The residue was purified by over anhydrous magnesium sulfate and then concentrated 25 silica gel column chromatography (carrier: Chromatorex under reduced pressure. The residue was purified by silica NH; elution solvent: heptane:ethyl acetate=1:1->ethyl gel column chromatography (elution solvent: heptane acetate) to obtain 50 mg of a racemate of the title compound. ->ethyl acetate) to obtain 134 mg of the title compound. The The property values of the compound are as follows. property values of the compound are as follows. ESI-MS; m/z. 466 M"+H. 'H-NMR (CDC1) & (ppm): H-NMR (CDOD) 8 (ppm): 1.50 (s, 9H), 1.90-2.05 (m, 30 1.97-2.25 (m, 3H), 2.30 (s, 3H), 2.32-2.42 (m. 1H), 3.86 (s, 3H), 2.15-2.23 (m. 1H), 3.61-3.80 (m, 3H), 6.70 (brs, 1H), 3H), 4.24-4.30 (m, 3H), 6.82 (dd, J=8.0, 6.0 Hz, 2H), 6.91 6.90 (t, J=8.0, 6.8 Hz, 2H). (brs, 1H), 7.05 (d. J=16.8 Hz, 1H), 7.14 (dd, J–8.4, 1.6 Hz, 1H), 7.16 (s, 1H), 7.21 (d. J=8.4 Hz, 1H), 7.50 (d. J=16.8 Hz, Synthesis of 1H), 7.69 (d. J=1.2 Hz, 1H). 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one 35 hydrochloride Synthesis of (-)-2-(E)-2-3-methoxy-4-(4-methyl 1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluoro A solution of 4 N hydrochloric acid in ethyl acetate (1 phenyl)-5,6,7,8-tetrahydro 1,2,4-triazolo 1.5-alpyri mL) was added to a solution of tert-butyl 2-oxo-3-(3,4,5- din-8-yl)methanol and (+)-2-(E)-2-3-methoxy-4- trifluorophenyl)piperidin-1-yl)carbamate (134 mg) in chlo 40 (4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- roform (1 mL), and the reaction solution was stirred at room trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, temperature for three hours. The reaction solution was 5-alpyridin-8-yl)methanol concentrated under reduced pressure to obtain 109 mg of the title compound. The property value of the compound is as Sodium hydride (40% oil suspension, 31 mg) was added follows. 45 to a solution of 2-(E)-2-3-methoxy-4-(4-methyl-1H-imi ESI-MS; m/z 245 M+H. dazol-1-yl)phenyl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8- tetrahydro 1.2.4 triazolo 1.5-alpyridine (180 mg) and para Synthesis of (E)-3-3-methoxy-4-(4-methyl-1H formaldehyde (200 mg) in DMF (3 mL), and the reaction imidazol-1-yl)phenyl-N-(2-oxo-3-(3,4,5-trifluoro solution was stirred at room temperature for 30 minutes. phenyl)piperidin-1-yl)acrylamide 50 Ethyl acetate and saturated sodium bicarbonate water were added to the reaction Solution, and the organic layer was IPEA (0.41 mL), HOBT (105 mg) and EDC (149 mg) separated. The resulting organic layer was dried over anhy were added to a solution of 1-amino-3-(3,4,5-trifluorophe drous magnesium Sulfate and then concentrated under nyl)piperidin-2-one hydrochloride (109 mg) and (E)-3-3- reduced pressure to obtain 194 mg of a racemic crude methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylacrylic acid 55 product. The resulting racemate (40 mg) was separated by (100 mg) in DMF (2 mL), and the reaction solution was CHIRALPAKTM IB manufactured by Daicel Chemical stirred at room temperature for three hours. Ethyl acetate and Industries, Ltd. (2 cmx25 cm, mobile phase: hexane:etha saturated sodium bicarbonate water were added to the reac nol=7:3) to obtain the title optically active compound with tion solution, and the organic layer was separated. The a retention time of 9 minutes and negative optical rotation resulting organic layer was dried over anhydrous magne 60 (10 mg) and the title optically active compound with a sium sulfate and then concentrated under reduced pressure. retention time of 11 minutes and positive optical rotation (10 The residue was purified by silica gel column chromatog mg). raphy (elution solvent: ethyl acetate->ethyl acetate:metha The property values of the title optically active compound nol=5:1) to obtain 95 mg of the title compound. The with a retention time of 9 minutes are as follows. property values of the compound are as follows. 65 H-NMR (CDC1) & (ppm): 1.84-1.97 (m. 1H), 2.05-2.16 ESI-MS; m/z 485 M*-i-H. 'H-NMR (CDOD) 8 (ppm): (m. 2H), 2.21-2.29 (m, 1H), 2.30 (s.3H), 3.89 (s.3H), 3.89 1.94-2.10 (m, 3H), 2.22-2.30 (m. 1H), 2.31 (s, 3H), 3.64 (d. J=11.6 Hz, 1H), 4.08 (d. J=11.6 Hz, 1H), 4.10 (td, J=13.2, US 9,453,000 B2 147 148 6.0 Hz, 1H), 4.30 (dd, J–13.2, 6.0 Hz, 1H), 6.80 (dd, J=8.8, and then concentrated under reduced pressure. CDI (180 6.4 Hz, 2H), 6.92 (brs, 1H), 7.07 (d. J=16.4 Hz, 1H), 7.16 mg) was added to a solution of the residue in THF (13 mL), (brs, 1H), 7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.24 (d. J=8.0 Hz, and the reaction solution was heated under reflux for one 1H), 7.57 (d. J=16.4 Hz, 1H), 7.72 (brs, 1H). hour. The reaction solution was left to cool to room tem The property values of the title optically active compound 5 perature. Then, ethyl acetate and brine were added to the with a retention time of 11 minutes are as follows. reaction solution, and the organic layer was separated. The H-NMR (CDC1) & (ppm): 1.84-1.97 (m. 1H), 2.05-2.16 resulting organic layer was dried over anhydrous magne (m. 2H), 2.21-2.29 (m, 1H), 2.30 (s, 3H), 3.89 (s.3H), 3.89 sium Sulfate and then concentrated under reduced pressure. (d. J=11.6 Hz, 1H), 4.08 (d. J=11.6 Hz, 1H), 4.10 (td, J=13.2, The resulting racemic crude product was separated by 6.0 Hz, 1H), 4.30 (dd, J–13.2, 6.0 Hz, 1H), 6.80 (dd, J=8.8, 10 CHIRALPAKTM IA manufactured by Daicel Chemical 6.4 Hz, 2H), 6.92 (brs, 1H), 7.07 (d. J=16.4 Hz, 1H), 7.16 Industries, Ltd. (2 cmx25 cm, mobile phase: hexane:etha (brs, 1H), 7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.24 (d. J=8.0 Hz, nol=1:1) to obtain the title optically active compound with 1H), 7.57 (d. J=16.4 Hz, 1H), 7.72 (brs, 1H). a retention time of 11 minutes and negative optical rotation 15 (38 mg) and the title optically active compound with a Examples 71 and 72 retention time of 15 minutes and positive optical rotation (40 mg). Synthesis of (+)-2-(E)-2-3-methoxy-4-(4-methyl The property values of the title optically active compound 1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluoro with a retention time of 11 minutes are as follows. phenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri 'H-NMR (CDC1) & (ppm): 2.20-2.29 (m. 1H), 2.30 (s, dine-8-carbonitrile and (-)-2-(E)-2-3-methoxy-4- 3H), 2.35-2.50 (m, 2H), 2.68-2.75 (m. 1H), 3.87 (s, 3H), (4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- 4.26-4.34 (m, 1H), 4.36-4.44 (m, 1H), 6.92 (brs, 1H), 7.04 trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, (d. J=16.8 Hz, 1H), 7.05 (dd, J–7.6, 6.4 Hz, 2H), 7.16 (brs, 5-alpyridine-8-carbonitrile 1H), 7.17 (brd, J=7.2 Hz, 1H), 7.24 (d. J=7.2 Hz, 1H), 7.56 (d. J=16.8 Hz, 1H), 7.70 (brs, 1H). 25 The property values of the title optically active compound with a retention time of 15 minutes corresponded to the Formula 80 property values of the title optically active compound with a retention time of 11 minutes. 30 Examples 73 and 74 CN Synthesis of (+)-8-(4-chlorophenyl)-2-(E)-2-3- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri 35 dine-8-carbonitrile and (-)-8-(4-chlorophenyl)-2- {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5- apyridine-8-carbonitrile 40

MeO Formula 81

45

MeO N

Dess-Martin periodinane (190 mg) was added to a solu 50 %N tion of the crude product of {2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluoro phenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin-8- yl)methanol obtained in Examples 69 and 70 (111 mg) in methylene chloride (8 mL), and the reaction solution was 55 stirred at room temperature for 10 hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reac MeO N tion solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magne sium sulfate and then concentrated under reduced pressure. 60 % N. Sodium acetate (35 mg) and hydroxyamine hydrochloride (30 mg) were added to a solution of the residue in ethanol (7 mL), and the reaction solution was stirred at room temperature for four hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solu 65 A racemate of the title compound obtained from 8-(4- tion, and the organic layer was separated. The resulting chlorophenyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imida organic layer was dried over anhydrous magnesium Sulfate Zol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro1,2,4-triazolo1, US 9,453,000 B2 149 150 5-alpyridine (197 mg) by the same method as in Examples compound with a retention time of 13 minutes and positive 65 and 66 was separated by CHIRALPAKTM IA manufac optical rotation (24 mg) and the title optically active com tured by Daicel Chemical Industries, Ltd. (2 cmx25 cm, pound with a retention time of 16 minutes and negative mobile phase: ethanol) to obtain the title optically active optical rotation (24 mg). compound with a retention time of 16 minutes and positive The property values of the title optically active compound optical rotation (40 mg) and the title optically active com with a retention time of 13 minutes are as follows. pound with a retention time of 18 minutes and negative optical rotation (47 mg). H-NMR (CDC1) & (ppm): 2.16-2.27 (m. 1H), 2.30 (s, The property values of the title optically active compound 3H), 2.36-2.47 (m, 2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H), with a retention time of 16 minutes are as follows. 10 4.27-4.43 (m, 2H), 6.92 (brs, 1H), 7.05 (d. J=16.4 Hz, 1H), 'H-NMR (CDC1) & (ppm): 2.13-2.25 (m. 1H), 2.30 (s, 7.10-7.14 (m, 1H), 7.15-7.27 (m, 5H), 7.57 (d. J=16.4 Hz, 3H), 2.32-2.47 (m, 2H), 2.66-2.75 (m, 1H), 3.87 (s, 3H), 1H), 7.70 (brs, 1H). 428-4.42 (m, 2H), 6.93 (brs, 1H), 7.06 (d. J=16.0 Hz, 1H), The property values of the title optically active compound with a retention time of 16 minutes are as follows. 7.17 (d. J=1.6 Hz, 1H), 7.18 (dd, J–8.4, 1.6 Hz, 1H), 7.24 (d. 15 J=8.4 Hz, 1H), 7.28 (d. J=8.8 Hz, 2H), 7.41 (d. J–8.8 Hz, 'H-NMR (CDC1) & (ppm): 2.16-2.27 (m. 1H), 2.30 (s, 2H), 7.57 (d. J=16.0 Hz, 1H), 7.71 (d. J=1.2 Hz, 1H). The property values of the title optically active compound 3H), 2.36-2.47 (m, 2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H), with a retention time of 18 minutes are as follows. 4.27-4.43 (m, 2H), 6.92 (brs, 1H), 7.05 (d. J=16.4 Hz, 1H), 'H-NMR (CDC1) & (ppm): 2.13-2.25 (m. 1H), 2.30 (s, 7.10-7.14 (m, 1H), 7.15-7.27 (m, 5H), 7.57 (d. J=16.4 Hz, 3H), 2.32-2.47 (m, 2H), 2.66-2.75 (m, 1H), 3.87 (s, 3H), 1H), 7.70 (brs, 1H). 428-4.42 (m, 2H), 6.93 (brs, 1H), 7.06 (d. J=16.0 Hz, 1H), 7.17 (d. J=1.6 Hz, 1H), 7.18 (dd, J–8.4, 1.6 Hz, 1H), 7.24 (d. J=8.4 Hz, 1H), 7.28 (d. J=8.8 Hz, 2H), 7.41 (d. J–8.8 Hz, Examples 77, 78, 79 and 80 2H), 7.57 (d. J=16.0 Hz, 1H), 7.71 (d. J=1.2 Hz, 1H). 25 Examples 75 and 76 Synthesis of (-)-8-(3,5-difluorophenyl)-2-(E)-2-3- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii Synthesis of (+)-8-(3,4-difluorophenyl)-2-(E)-2-3- nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii dine-8-carbonitrile, (+)-8-(3,5-difluorophenyl)-2- nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) dine-8-carbonitrile and (-)-8-(3,4-difluorophenyl)- phenyl vinyl-5,6,7,8-tetrahydro.1.2.4 triazolo 1.5- 2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) apyridine-8-carbonitrile, (-)-8-(3,5-difluorophe phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5- nyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol apyridine-8-carbonitrile 35 1-yl)phenyl vinyl-5,6,7,8-tetrahydro1.2.4 triazolo 1.5-alpyridin-8-ol and (+)-8-(3,5-difluorophenyl)- 2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5- Formula 82 apyridin-8-ol

40

CN MeO Formula 83

45

MeO

50

MeO

55

MeO 60 A racemate of the title compound obtained from 8-(3,4- dichlorophenyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imi dazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine (132 mg) by the same method as in Examples 65 and 66 was separated by CHIRALPAKTM IA 65 manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile phase: ethanol) to obtain the title optically active US 9,453,000 B2 151 152 -continued manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile phase: 50% ethanol-hexane, flow rate: 10 N-N mL/min) to obtain the title optically active compound with a retention time of 20 minutes and positive optical rotation MeO S. I 5 ((+)-8-(3,5-difluorophenyl)-2-(E)-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro F 1.2.4 triazolo 1.5-alpyridin-8-ol. 11.3 mg) and the title N optically active compound with a retention time of 22 ^ minutes and negative optical rotation ((-)-8-(3,5-difluoro e F 10 phenyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-

yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-al pyridin-8-ol. 11.6 mg). The property values of the title optically active compound with a retention time of 22 15 minutes and negative optical rotation are as follows. MeO S. 'H-NMR (CDC1) & (ppm): 1.98-2.20 (m, 2H), 2.28 (s, 3H), 2.26-2.40 (m. 1H), 2.40-2.56 (m, 1H), 3.77 (s, 3H), N 4.18-4.36 (m, 2H), 6.70-6.78 (m, 1H), 6.80-6.90 (m, 2H), ^ 6.90-7.05 (m, 4H), 7.11 (d. J=8.0 Hz, 1H), 7.40 (d. J=16 Hz, le 1H), 7.73 (s, 1H).

The property values of the title optically active compound 8-(3.5-Difluorophenyl)-2-(E)-2-3-methoxy-4-(4- with a retention time of 20 minutes and positive optical methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 25 rotation corresponded to the values of the (-)-isomer. 1.2.4 triazolo 1.5-alpyridine-8-carbonitrile (80 mg) was The following compounds were obtained by the same obtained from 8-(3,5-difluorophenyl)-2-(E)-2-3-methoxy method as in Examples 65 and 66 (Table 3). 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetra hydro 1.2.4 triazolo 1.5-alpyridine (160 mg) by the same TABLE 3 method as in Examples 65 and 66. At the same time, 30 8-(3,5-difluorophenyl)-2-(E)-2-3-methoxy-4-(4-methyl 1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridin-8-ol generated in the reaction step in MeO N I / E E. the middle (80 mg) was isolated. 35 The resulting 8-(3,5-difluorophenyl)-2-(E)-2-3- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-5.6, 7,8-tetrahydro 1.2.4 triazolo 1.5-apyridine-8-carbonitrile (80 mg) was optically resolved by CHIRALPAKTM ADH manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 40 cm, mobile phase: 80% ethanol-hexane, flow rate: 10 mL/min) to obtain the title optically active compound with a retention time of 15 minutes and positive optical rotation E2 DATA: MS miz ((+)-8-(3,5-difluorophenyl)-2-(E)-2-3-methoxy-4-(4- CN M' + H: 505 Optically active methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 45 (ESI) 1.2.4 triazolo 1.5-alpyridine-8-carbonitrile, 29.6 mg) and the title optically active compound with a retention time of 18 minutes and negative optical rotation ((-)-8-(3,5-difluo rophenyl)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imidazol 1-yl)phenyl vinyl-5,6,7,8-tetrahydro1.2.4 triazolo 1.5-a 50 pyridine-8-carbonitrile, 35.1 mg). The property values of the title optically active compound 82 CN M + H: 505 Optically active with a retention time of 18 minutes and negative optical (ESI) rotation are as follows. H-NMR (CDC1) & (ppm): 2.16-2.32 (m. 1H), 2.30 (s, 55 3H), 2.34-2.50 (m, 2H), 2.66-2.78 (m, 1H), 3.88 (s, 3H), 4.26-4.44 (m, 2H), 6.84-6.96 (m, 4H), 7.06 (d. J–16 Hz, 1H), 7.16-7.22 (m, 2H), 7.24 (d. J=8.4 Hz, 1H), 7.59 (d. J=16 Hz, 1H), 7.71 (d. J=0.80 Hz, 1H). 83 CN M' + H:455 Optically active (ESI) ESI-MS; m/z 473 M+H. 60 The property values of the title optically active compound with a retention time of 15 minutes and positive optical rotation corresponded to the values of the (-)-isomer. 5 min, 8-(3.5-Difluorophenyl)-2-(E)-2-3-methoxy-4-(4- optical methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 65 rotation (+)) 1.2.4 triazolo 1.5-alpyridin-8-ol obtained in the same man ner (80 mg) was optically resolved by CHIRALPAKTMADH US 9,453,000 B2 153 154 TABLE 3-continued TABLE 3-continued

N-N I E. MeO N-N/ El

10 / le e

E1 E2 DATA: MS miz Note Example E1 E2 DATA: MS miz Note 15 F CN M+H:455 Optically active 90 CN M - H: 489 Optically active (ESI) compound (ESI) compound : (separation (separation conditions conditions AD-H: ethanol: AD-H: ethanol: retention retention time 18 min, time 37 min, optical optical rotation (-)) rotation (+)) 85 F CN M - H: 473 Optically active (ESI) compound *.. (separation 25 Examples 91 and 92 '7. conditions LA: 80% Synthesis of (-)-2-(Z)-1-fluoro-2-3-methoxy-4-(4- ethanol-hexane: F retention methyl-1H-imidazol-1-yl)phenyl vinyl-8-(2,4,6- time 15 min, trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, optical 30 5-alpyridine and (+)-2-(Z)-1-fluoro-2-3-methoxy rotation (+)) 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(2,4, 86 F CN M - H: 473 Optically active 6-trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo (ESI) compound 1.5-alpyridine (separation conditions 35 LA: 80% ethanol-hexane: F retention Formula 84 time 20 min, optical rotation (-)) 40 N-N 87 F CN M - H: 491 Optically active (ESI) compound I *. (separation ' conditions LA: 70% F ethanol-hexane: 45 N an orF / F retention time 28 min, F optical rotation (+)) 88 F CN M - H: 491 Optically active 50 (ESI) compound : (separation MeO I 7 F conditions S. N 2. LA: 70% ethanol-hexane: F F retention time 55 N 4\ F 33 min, F optical F rotation (-)) 89 *. CN M+H: 489 Optically active '. (ESI) compound (separation 60 conditions Synthesis of (Z)-2-fluoro-3-3-methoxy-4-(4- F AD-H: ethanol: methyl-1H-imidazol-1-yl)phenyl-N-(2-oxo-3-(2,4, retention 6-trifluorophenyl)piperidin-1-yl)acrylamide C time 17 min, optical 65 BOPC1 (221 mg) was added to a suspension of (Z)-2- rotation (-)) fluoro-3-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phe nylacrylic acid (CAS No. 87.0838-71-4, 240 mg), 1-amino US 9,453,000 B2 155 156 3-(2,4,6-trifluorophenyl)piperidin-2-one (106 g) and IPEA Examples 93 and 94 (0.45 mL) in DMF (5 mL), and the reaction solution was stirred at room temperature for 16 hours. Saturated sodium Synthesis of (+)-2-(Z)-1-fluoro-2-3-methoxy-4-(4- bicarbonate water and ethyl acetate were added to the methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- reaction mixture and the organic layer was separated. The trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, resulting organic layer was dried over anhydrous magne 5-alpyridin-8-ol and (-)-2-(Z)-1-fluoro-2-3- sium sulfate and then concentrated under reduced pressure. methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl The resulting residue was purified by silica gel column vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro chromatography (carrier: Chromatorex NH; elution solvent: 1.2.4 triazolo 1.5-alpyridin-8-ol ethyl acetate) to obtain 110 mg of the title compound. The 10 property value of the compound is as follows. ESI-MS; m/z 503 M+H. Formula 85) Synthesis of (-)-2-(Z)-1-fluoro-2-3-methoxy-4-(4- methyl-1H-imidazol-1-yl)phenyl vinyl-8-(2,4,6- 15 trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, 5-alpyridine and (+)-2-(Z)-1-fluoro-2-3-methoxy 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(2,4, MeO 6-trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine A solution of (Z)-2-fluoro-3-3-methoxy-4-(4-methyl

1H-imidazol-1-yl)phenyl-N-(2-oxo-3-(2,4,6-trifluorophe nyl)piperidin-1-yl)acrylamide (110 mg) in phosphorus oxy 25 chloride (2 mL) was heated under reflux for three hours. The reaction mixture was left to cool to room temperature and then concentrated under reduced pressure. Acetic acid (3 MeO mL) and ammonium acetate (506 mg) were added to the residue, and the reaction solution was stirred at 150° C. for 30 two hours. The reaction mixture was left to cool to room temperature and then concentrated under reduced pressure. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue, and the organic layer was separated. The resulting organic layer was washed with 35 saturated aqueous Sodium chloride, dried over anhydrous Synthesis of magnesium sulfate and then concentrated under reduced 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid pressure. The resulting residue was purified by silica gel hydrazide hydrochloride column chromatography (carrier: Chromatorex NH; elution 40 solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl A solution of 4 N hydrochloric acid in ethyl acetate (2 acetate:methanol=9:1) to obtain 42 mg of a racemate of the mL) was added to a solution of tert-butyl N'-(5-chloro-2-(3. title compound. The resulting racemate (22 mg) was sepa 4,5-trifluorophenyl)pentanoylhydrazinecarboxylate (300 rated by CHIRALPAKTM AD-H manufactured by Daicel mg) in ethyl acetate (2 mL), and the reaction solution was Chemical Industries, Ltd. (2 cmx25 cm, mobile phase: 45 stirred at room temperature for one hour. The reaction hexane:ethanol=1:1) to obtain the title optically active com Solution was concentrated under reduced pressure to obtain pound with a retention time of 10 minutes and negative 250 mg of the title compound. The property value of the optical rotation (3.8 mg) and the title optically active com compound is as follows. pound with a retention time of 13 minutes and positive ESI-MS; m/z 281 M+H. optical rotation (4.4 mg). 50 The property values of the title optically active compound Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pen with a retention time of 10 minutes are as follows. tanoic acid N' {(Z)-2-fluoro-3-3-methoxy-4-(4- 'H-NMR (CDC1) & (ppm): 2.03-2.24 (m, 3H), 2.29 (s. methyl-1H-imidazol-1-yl)phenylacryloylhydrazide 3H), 2.30-2.39 (m. 1H), 3.85 (s, 3H), 4.21-4.30 (m. 1H), 55 IPEA (0.14 mL) and BOPC1 (100 mg) were added to a 4.37-4.45 (m. 1H), 4.52-4.59 (m. 1H), 6.65 (d. J=38.8 Hz, solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid 1H), 6.70 (t, J=8.8 Hz, 2H), 6.92 (brs, 1H), 7.21 (d. J=8.0 hydrazide hydrochloride (83 mg) and (Z)-2-fluoro-3-3- HZ, 1H), 7.24 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (brs, 1H), 7.72 methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylacrylic acid (d. J=1.2 Hz, 1H). (CAS No. 870838-71-4, 72 mg) in methylene chloride (5 The property values of the title optically active compound 60 mL), and the reaction solution was stirred at room tempera with a retention time of 13 minutes are as follows. ture for 13 hours. Ethyl acetate and saturated sodium bicar 'H-NMR (CDC1) & (ppm): 2.03-2.24 (m, 3H), 2.29 (s. bonate water were added to the reaction solution, and the 3H), 2.30-2.39 (m. 1H), 3.85 (s, 3H), 4.21-4.30 (m. 1H), organic layer was separated. The resulting organic layer was 4.37-4.45 (m. 1H), 4.52-4.59 (m. 1H), 6.65 (d. J=38.8 Hz, dried over anhydrous magnesium sulfate and then concen 1H), 6.70 (t, J=8.8 Hz, 2H), 6.92 (brs, 1H), 7.21 (d. J=8.0 65 trated under reduced pressure. The residue was purified by HZ, 1H), 7.24 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (brs, 1H), 7.72 silica gel column chromatography (elution solvent: heptane: (d. J=1.2 Hz, 1H). ethyl acetate=1:1->ethyl acetate->ethyl acetate:metha US 9,453,000 B2 157 158 nol=9:1) to obtain 84 mg of the title compound. The rotation (22 mg) and the title optically active compound with property value of the compound is as follows. a retention time of 11 minutes and negative optical rotation ESI-MS; m/z 539 M+H. (23 mg). The property values of (+)-2-(Z)-1-fluoro-2-3- Synthesis of 2-4-chloro-1-(3,4,5-trifluorophenyl) methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8- butyl-5-(Z)-1-fluoro-2-3-methoxy-4-(4-methyl (3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro 1,2,4-triazolol, 1H-imidazol-1-yl)phenyl vinyl-1,3,4-oxadiazole 5-alpyridin-8-ol are as follows. 'H-NMR (CDC1) & (ppm): 2.03-2.16 (m, 2H), 2.28 (s, A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic 3H), 2.31-2.39 (m. 1H), 2.46-2.58 (m, 1H), 3.77 (s, 3H), acid N' {(Z)-2-fluoro-3-3-methoxy-4-(4-methyl-1H-imi 10 4.23-4.31 (m. 1H), 4.36-4.43 (m, 1H), 6.60 (d. J=37.6 Hz, dazol-1-yl)phenylacryloylhydrazide (84 mg) in phospho 1H), 6.89 (brs, 1H), 6.98 (dd, J–8.4, 1.6 Hz, 1H), 7.06 (dd. rus oxychloride (1 mL) was stirred at 120° C. for 7.5 hours. J–8.4, 6.4 Hz, 2H), 7.13 (d. J–8.4 Hz, 1H), 7.16 (brs, 1H), The reaction solution was left to cool to room temperature 7.72 (d. J=1.2 Hz, 1H). and then concentrated under reduced pressure to obtain 81 The property values of (-)-2-(Z)-1-fluoro-2-3- mg of the title compound. The property value of the com 15 methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8- pound is as follows. (3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro 1,2,4-triazolol, ESI-MS; m/z 521 M+H. 5-alpyridin-8-ol are as follows. Synthesis of 2-(Z)-1-fluoro-2-3-methoxy-4-(4- H-NMR (CDC1) & (ppm): 2.03-2.16 (m, 2H), 2.28 (s, methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- 3H), 2.31-2.39 (m. 1H), 2.46-2.58 (m, 1H), 3.77 (s, 3H), trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, 4.23-4.31 (m. 1H), 4.36-4.43 (m, 1H), 6.60 (d. J=37.6 Hz, 5-alpyridine 1H), 6.89 (brs, 1H), 6.98 (dd, J–8.4, 1.6 Hz, 1H), 7.06 (dd. J–8.4, 6.4 Hz, 2H), 7.13 (d. J–8.4 Hz, 1H), 7.16 (brs, 1H), A solution of 2-4-chloro-1-(3,4,5-trifluorophenyl)butyl 7.72 (d. J=1.2 Hz, 1H). 5-(Z)-1-fluoro-2-3-methoxy-4-(4-methyl-1H-imidazol-1- 25 yl)phenyl vinyl-1,3,4-oxadiazole (81 mg) and ammonium Examples 95 and 96 acetate (358 mg) in acetic acid (2 mL) was stirred at 150° C. for three hours. The reaction solution was left to cool to Synthesis of (+)-2-(E)-2-[2-fluoro-5-methoxy-4-(4- room temperature. Then, ethyl acetate and Saturated sodium methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- bicarbonate water were added to the reaction solution, and 30 trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, the organic layer was separated. The resulting organic layer 5-alpyridin-8-ol and (-)-2-(E)-2-[2-fluoro-5- was dried over anhydrous magnesium sulfate and then methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl concentrated under reduced pressure. The residue was puri vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro fied by silica gel column chromatography (carrier: Chroma 1.2.4 triazolo 1.5-alpyridin-8-ol torex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl 35 acetate) to obtain 98 mg of the title compound. The property values of the compound are as follows. 'H-NMR (CDC1) & (ppm): 1.99-208 (m. 1H), 2.09-2.28 Formula 86) (m. 2H), 2.31 (s, 3H), 2.35-2.44 (m. 1H), 3.87 (s, 3H), 4.28 (t, J–7.2 Hz, 1H), 4.34 (t, J=5.2 Hz, 2H), 6.74 (d. J=38.4 Hz, 40 1H), 6.82 (dd, J–8.0, 6.4 Hz, 2H), 6.94 (brs, 1H), 7.25 (d. J=8.4 Hz, 1H), 7.28 (dd, J–8.4, 1.6 Hz, 1H), 7.36 (brs, 1H), MeO 7.73 (d. J=0.8 Hz, 1H).

Synthesis of (+)-2-(Z)-1-fluoro-2-3-methoxy-4-(4- 45 methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, 5-alpyridin-8-ol and (-)-2-(Z)-1-fluoro-2-3- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro 50 1.2.4 triazolo 1.5-alpyridin-8-ol Sodium hydride (containing 40% of mineral oil, 16.2 mg) was added to a solution of 2-(Z)-1-fluoro-2-3-methoxy 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trif 55 luorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyri dine (98 mg) in DMF (2 mL), and the reaction solution was stirred at room temperature for 40 minutes. Ethyl acetate and a saturated sodium thiosulfate solution were added to the reaction Solution, and the organic layer was separated. The 60 resulting organic layer was washed with Saturated sodium Synthesis of (E)-3-2-fluoro-5-methoxy-4-(4- bicarbonate water, dried over anhydrous magnesium Sulfate methyl-1H-imidazol-1-yl)phenylacrylic acid and then concentrated under reduced pressure. The residue was separated by CHIRALCELTM OD-H manufactured by Lithium hydroxide monohydrate (240 mg) was added to Daicel Chemical Industries, Ltd. (2 cmx25 cm; mobile 65 a mixed solution of 2-fluoro-5-methoxy-4-(4-methyl-1H phase: ethanol) to obtain the title optically active compound imidazol-1-yl)benzaldehyde (CAS No. 870851-52-8, 1.03 with a retention time of 9 minutes and positive optical g) and triethyl phosphonoacetate (1.09 g) in THF (4 mL)- US 9,453,000 B2 159 160 ethanol (1 mL), and the reaction solution was stirred at room solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl temperature for five hours. A 2 N sodium hydroxide solution acetate:methanol=4:1) to obtain a racemate of the title (4 mL) was added to the reaction solution, and the reaction compound. Sodium hydride (40% oil Suspension, 22.2 mg) solution was stirred for 17 hours. 2 Naqueous hydrochloric was added to a solution of the resulting racemate (134 mg) acid (4 mL) was added to the reaction solution, and the in DMF (2 mL), and the reaction solution was stirred at room reaction solution was stirred at room temperature for 30 temperature for one hour. Ethyl acetate and a saturated minutes. The precipitated solid was collected by filtration sodium thiosulfate solution were added to the reaction and washed with water and ether. The resulting solid was Solution, and the organic layer was separated. The resulting air-dried to obtain 1.03 g of the title compound. The property organic layer was washed with Saturated Sodium bicarbonate value of the compound is as follows. 10 water, dried over anhydrous magnesium sulfate and then ESI-MS; m/z 277 M+H. concentrated under reduced pressure. The residue was sepa Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pen rated by CHIRALPAKTM IA manufactured by Daicel tanoic acid N'-(E)-3-2-fluoro-5-methoxy-4-(4- Chemical Industries, Ltd. (2 cmx25 cm; mobile phase: 15 hexane:ethanol=1:1) to obtain the title optically active com methyl-1H-imidazol-1-yl)phenylacryloylhydrazide pound with a retention time of 7 minutes (26 mg) and the IPEA (0.31 mL) and BOPC1 (119 mg) were added to a title optically active compound with a retention time of 8 solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid minutes (24 mg). hydrazide hydrochloride (114 mg) and (E)-3-2-fluoro-5- The property values of the title optically active compound methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylacrylic acid with a retention time of 7 minutes are as follows. (99 mg) in methylene chloride (5 mL), and the reaction ESI-MS; m/z 500 M+H. 'H-NMR (CDC1) & (ppm): solution was stirred at room temperature for one hour. Ethyl 2.01-2.14 (m, 2H), 2.26 (s, 3H), 2.28-2.36 (m. 1H), 2.45 acetate and a saturated ammonium chloride solution were 2.57 (m. 1H), 3.74 (s.3H), 4.17-4.25 (m. 1H), 4.28-4.37 (m, added to the reaction Solution, and the organic layer was 1H), 6.83 (brs, 1H), 6.88 (d. J=10.4 Hz, 1H), 6.89 (d. J=6.4 separated. The resulting organic layer was dried over anhy 25 HZ, 1H), 7.05 (d. J=16.4 Hz, 1H), 7.06 (dd, J=8.8, 6.4 Hz, drous magnesium sulfate and concentrated under reduced 2H), 7.42 (d. J=16.4 Hz, 1H), 7.67 (d. J=1.6 Hz, 1H). pressure to obtain 200 mg of the title compound. The The property values of the title optically active compound property value of the compound is as follows. with a retention time of 8 minutes are as follows. ESI-MS; m/z 539 M+H. ESI-MS; m/z 500 'H-NMR (CDC1) & (ppm): 2.01-2.14 30 (m. 2H), 2.26 (s.3H), 2.28-2.36 (m. 1H), 2.45-2.57 (m. 1H), Synthesis of 2-4-chloro-1-(3,4,5-trifluorophenyl) 3.74 (s, 3H), 4.17-4.25 (m. 1H), 4.28-4.37 (m, 1H), 6.83 butyl-5-(E)-2-[2-fluoro-5-methoxy-4-(4-methyl (brs, 1H), 6.88 (d. J=10.4 Hz, 1H), 6.89 (d. J=6.4 Hz, 1H), 1H-imidazol-1-yl)phenyl vinyl-1,3,4-oxadiazole 7.05 (d. J=16.4 Hz, 1H), 7.06 (dd, J=8.8, 6.4 Hz, 2H), 7.42 (d. J=16.4 Hz, 1H), 7.67 (d. J=1.6 Hz, 1H). A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic 35 acid N'-(E)-3-2-fluoro-5-methoxy-4-(4-methyl-1H-imida Examples 97,98, 99 and 100 Zol-1-yl)phenylacryloylhydrazide (200 mg) in phosphorus Synthesis of (6R,8R)-8-(4-fluorophenyl)-2-(E)-2- oxychloride (2 mL) was stirred at 120° C. for 5.5 hours. The 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl reaction solution was left to cool to room temperature and vinyl-6-methyl-5,6,7,8-tetrahydro-1,2,4-triazolo.1, then concentrated under reduced pressure. Ethyl acetate and 40 5-alpyridine, (6R,8S)-8-(4-fluorophenyl)-2-(E)-2- saturated sodium bicarbonate water were added to the resi 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl due, and the organic layer was separated. The resulting vinyl-6-methyl-5,6,7,8-tetrahydro-1,2,4-triazolo.1, organic layer was dried over anhydrous magnesium Sulfate 5-alpyridine, (6S,8R)-8-(4-fluorophenyl)-2-(E)-2- and concentrated under reduced pressure to obtain 180 mg 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl of the title compound. The property value of the compound 45 vinyl-6-methyl-5,6,7,8-tetrahydro-1,2,4-triazolo.1, is as follows. 5-alpyridine and (6S,8S)-8-(4-fluorophenyl)-2-(E)- ESI-MS; m/z 521 M+H. 2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl Synthesis of (+)-2-(E)-2-[2-fluoro-5-methoxy-4-(4- vinyl-6-methyl-5,6,7,8-tetrahydro-1,2,4-triazolo.1, methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- 50 5-alpyridine trifluorophenyl)-5,6,7,8-tetrahydro 1.2.4 triazolol, 5-alpyridin-8-ol and (-)-2-(E)-2-[2-fluoro-5- methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro Formula 87 1.2.4 triazolo 1.5-alpyridin-8-ol 55 A solution of 2-4-chloro-1-(3,4,5-trifluorophenyl)butyl 5-(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1- yl)phenyl vinyl-1,3,4-oxadiazole (180 mg) and ammo nium acetate (533 mg) in acetic acid (2 mL) was stirred at 60 150° C. for 24 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and Saturated sodium bicarbonate water were added to the reaction solu tion, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium Sulfate 65 and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution US 9,453,000 B2 161 162 -continued s H-NMR (CDC1) & (ppm): 1.12 (d. J=6.8 Hz, 3H), 2.08-2.11 (m, 2H), 2.30 (s.3H), 2.31-2.37 (m. 1H), 3.76 (dd. J=12.8 Hz, 9.6 Hz, 1H), 3.87 (s, 3H), 4.37 (dd, J=12.8 Hz, 5.2 Hz, 1H), 4.49 (t, J–4.4 Hz, 1H), 6.92 (t, J=0.8 Hz, 1H), 7.00-7.03 (m, 4H), 7.08 (d. J=16.4 Hz, 1H), 7.14-7.17 (m, 2H), 7.23 (d. J=8.0 Hz, 1H), 7.54 (d. J=16.4 Hz, 1H), 7.70 O N / (d. J=1.6 Hz, 1H). The property values of the title optically active compound with a retention time of 15 minutes are as follows. /S N 10 H-NMR (CDC1) & (ppm): 1.20 (d. J=6.4 Hz, 3H), le F 1.66-1.76 (m, 1H), 2.29 (s.3H), 2.30-2.42 (m, 2H), 3.76 3.83 (m. 1H), 3.85 (s.3H), 4.19 (dd, J=11.6 Hz, 5.6 Hz, 1H),

4.36 (dd, J=11.6 Hz, 5.6 Hz, 1H), 6.91 (t, J=1.2 Hz, 1H), 7.02-7.07 (m, 3H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 3H), 15 7.48 (d. J=16.0 Hz, 1H), 7.69 (d. J=1.6 Hz, 1H). The property values of the title optically active compound with a retention time of 30 minutes are as follows. O S H-NMR (CDC1) & (ppm): 1.20 (d. J=6.4 Hz, 3H), 1.66-1.76 (m, 1H), 2.29 (s.3H), 2.30-2.42 (m, 2H), 3.76 3.83 (m. 1H), 3.85 (s.3H), 4.19 (dd, J=11.6 Hz, 5.6 Hz, 1H), 4.36 (dd, J=11.6 Hz, 5.6 Hz, 1H), 6.91 (t, J=1.2 Hz, 1H), /S N 7.02-7.07 (m, 3H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 3H), y- F 7.48 (d. J=16.0 Hz, 1H), 7.69 (d. J=1.6 Hz, 1H). 25 Examples 101 and 102 Synthesis of (7S,8S)-8-(4-fluorophenyl)-2-(E)-2- 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-7-methyl-5,6,7,8-tetrahydro-1,2,4-triazolo.1, 30 5-alpyridine and (7R,8R)-8-(4-fluorophenyl)-2- O S / {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) phenyl vinyl-7-methyl-5,6,7,8-tetrahydro-1,2,4 triazolo 1.5-alpyridine N W N

le F 35

Formula 88)

388 mg of a diastereomer mixture of the title compound was obtained from (E)-N-3-(4-fluorophenyl)-5-methyl-2- 40 oxopiperidin-1-yl)-3-3-methoxy-4-(4-methyl-1H-imida Zol-1-yl)phenylacrylamide (662 mg) using methyl 4-fluo MeO rophenylacetate and 1-bromo-3-chloro-2-methylpropane as starting materials by the same method as in Examples 20 and 21. The resulting diastereomer mixture (388 mg) was sepa 45 rated by CHIRALPAKTM OD-H manufactured by Daicel Chemical Industries, Ltd. (2 cmx25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title optically active compound with a retention time of 10 minutes and negative optical rotation (67 mg), the title optically active 50 compound with a retention time of 13 minutes and positive optical rotation (69 mg), the title optically active compound MeO with a retention time of 15 minutes and negative optical rotation (93 mg) and the title optically active compound with a retention time of 30 minutes and positive optical rotation 55 (92 mg). The property values of the title optically active compound with a retention time of 10 minutes are as follows. 'H-NMR (CDC1) & (ppm): 1.12 (d. J=6.8 Hz, 3H), 2.08-2.11 (m, 2H), 2.30 (s.3H), 2.31-2.37 (m. 1H), 3.76 (dd. 60 J=12.8 Hz, 9.6 Hz, 1H), 3.87 (s, 3H), 4.37 (dd, J=12.8 Hz, Synthesis of 5.2 Hz, 1H), 4.49 (t, J–4.4 Hz, 1H), 6.92 (t, J=0.8 Hz, 1H), 3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl 7.00-7.03 (m, 4H), 7.08 (d. J=16.4 Hz, 1H), 7.14-7.17 (m, toluene-4-Sulfonate 2H), 7.23 (d. J=8.0 Hz, 1H), 7.54 (d. J=16.4 Hz, 1H), 7.70 (d. J=1.6 Hz, 1H). 65 Triethylamine (4.64 mL), p-toluenesulfonyl chloride The property values of the title optically active compound (4.66 g) and DMAP (271 mg) were added to a solution of with a retention time of 13 minutes are as follows. 4-(tert-butyldiphenylsilanyloxy)butan-2-ol (7.3 g; CAS US 9,453,000 B2 163 164 #114079-44-6) in 1,2-dichloroethane (80 mL) at 0°C., and saturated ammonium chloride solution were added to the the reaction solution was stirred at 60° C. for three hours. reaction solution, and the organic layer was separated. The The reaction solution was left to cool to room temperature resulting organic layer was washed with brine, dried over and then concentrated under reduced pressure. Ethyl acetate anhydrous magnesium sulfate and then concentrated under and brine were added to the residue, and the organic layer 5 reduced pressure. The residue was purified by silica gel was separated. The resulting organic layer was dried over column chromatography (elution solvent: heptane-ethyl anhydrous Sodium sulfate and then concentrated under acetate system) to obtain 525 mg of the title compound. The reduced pressure. The residue was purified by silica gel property value of the compound is as follows. column chromatography (elution solvent: heptane-ethyl ESI-MS; m/z. 363 M"+Na. acetate system) to obtain 6.4 g of the title compound. The 10 property value of the compound is as follows. Synthesis of 5-(N-tert-butoxycarbonylhydrazino)-4- ESI-MS; m/z 505 M+Na. (4-fluorophenyl)-3-methyl-5-oxo-1-pentyl toluene-4- sulfonate Synthesis of 5-(tert-butyldiphenylsilanyloxy-2-(4- fluorophenyl)-3-methylpentanoic acid 15 p-Toluenesulfonyl chloride (321 mg) was added to a solution of tert-butyl N'-[2-(4-fluorophenyl)-5-hydroxy-3- n-Butyl lithium (4.89 mL; 2.66 M solution in hexane) was methylpentanoylhydrazinecarboxylate (520 mg) in pyri added dropwise to a solution of 4-fluorophenylacetic acid (1 dine (6 mL). The reaction solution was stirred at room g) in THF (30 mL) at -78°C., and the reaction solution was temperature for 12 hours and then concentrated under stirred for 20 minutes. The reaction solution was heated to reduced pressure. Ethyl acetate and brine were added to the 0° C. and stirred for 30 minutes. Then, a solution of residue, and the organic layer was separated. The resulting 3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl toluene-4- organic layer was dried over anhydrous magnesium sulfate sulfonate (3.2 g) in THF (10 mL) was added dropwise to the and concentrated under reduced pressure. The residue was reaction solution. The reaction solution was heated to room purified by silica gel column chromatography (elution sol temperature and stirred at the same temperature for 12 hours. 25 vent: heptane-ethyl acetate system) to obtain 335 mg of the Then, 1 N hydrochloric acid and ethyl acetate were added to title compound. The property value of the compound is as the reaction solution, and the organic layer was separated. follows. The resulting organic layer was washed with brine, dried ESI-MS; m/z 517 M"+Na. over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica 30 Synthesis of tert-butyl N'-(5-chloro-2-(4-fluorophe gel column chromatography (elution solvent: heptane-ethyl nyl)-5-hydroxy-3-methylpentanoylhydrazinecar acetate system) to obtain 986 mg of the title compound. The boxylate property values of the compound are as follows. 'H-NMR (CDC1) & (ppm): 0.64 (d. J=6.8 Hz, 3H), 1.04 Lithium chloride (283 mg) was added to a solution of (s, 9H), 1.31-1.43 (m. 1H), 1.79-1.86 (m. 1H), 2.29-245 (m, 35 5-(N-tert-butoxycarbonylhydrazino)-4-(4-fluorophenyl)-3- 1H), 3.31 (d. J=10.0 Hz, 1H), 3.67-3.78 (m, 2H), 6.98 (t, methyl-5-oxo-1-pentyl toluene-4-sulfonate (330 mg) in J=8.8 Hz, 2H), 7.21-7.28 (m, 3H), 7.32-7.42 (m, 5H), 7.65 DMF (5 mL). The reaction solution was stirred at 80° C. for (d. J=7.6 Hz, 4H). three hours and then left to cool to room temperature. Water and ethyl acetate were added to the reaction solution, and the Synthesis of tert-butyl N'-(5-(tert-butyldiphenylsila 40 organic layer was separated. The resulting organic layer was nyloxy)-2-(4-fluorophenyl)-3-methylpentanoylhy washed with brine, and then dried over anhydrous magne drazinecarboxylate sium Sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography BOPC1 (860 mg) and IPEA (0.552 mL) were added to a (elution solvent: heptane-ethyl acetate system) to obtain 170 solution of 5-(tert-butyldiphenylsilanyloxy-2-(4-fluorophe 45 mg of the title compound. The property value of the com nyl)-3-methylpentanoic acid (980 mg) and tert-butyl carba pound is as follows. Zate (558 mg) in methylene chloride (15 mL) at 0°C. The ESI-MS; m/z 381 M+Na. reaction solution was stirred at room temperature for 15 hours. Then, ethyl acetate and a Saturated ammonium chlo Synthesis of (7S,8S)-8-(4-fluorophenyl)-2-(E)-2- ride solution were added to the reaction solution, and the 50 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl organic layer was separated. The resulting organic layer was vinyl-7-methyl-5,6,7,8-tetrahydro-1,2,4-triazolo.1, washed with brine, dried over anhydrous magnesium Sulfate 5-alpyridine and (7R,8R)-8-(4-fluorophenyl)-2- and then concentrated under reduced pressure. The residue {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) was purified by silica gel column chromatography (elution phenyl vinyl-7-methyl-5,6,7,8-tetrahydro-1,2,4 solvent: heptane-ethyl acetate system) to obtain 1.04 g of the 55 triazolo 1.5-alpyridine title compound. The property value of the compound is as follows. A solution of 4 N hydrochloric acid in ethyl acetate (3 ESI-MS; m/z 601 M+Na. mL) was added to tert-butyl NT-5-chloro-2-(4-fluorophe nyl)-5-hydroxy-3-methylpentanoylhydrazinecarboxylate Synthesis of tert-butyl N'-[2-(4-fluorophenyl)-5- 60 (170 mg). The reaction solution was stirred at room tem hydroxy-3-methylpentanoylhydrazinecarboxylate perature for two hours and then concentrated under reduced pressure. Subsequently, triethylamine (0.292 mL) was added TBAF (2.7 mL; 1 M solution in THF) was added to a to a solution of the residue in ethanol (3 mL). A mixed solution of tert-butyl N'-(5-(tert-butyldiphenylsilanyloxy)-2- solution of ethyl (E)-3-3-methoxy-4-(4-methyl-1H-imida (4-fluorophenyl)-3-methylpentanoylhydrazinecarboxylate 65 Zol-1-yl)phenylacrylimidate dihydrochloride (150 mg) and (1.04 g) in THF (20 mL). The reaction solution was stirred triethylamine (0.292 mL) in ethanol (3 mL) was added at room temperature for 1 hours. Then, ethyl acetate and a dropwise to the Solution, and the reaction Solution was US 9,453,000 B2 165 166 stirred at 80° C. for 12 hours. The reaction solution was left Synthesis of benzyl (3,4,5-trifluorophenyl)acetate to cool to room temperature and then concentrated under reduced pressure. Saturated sodium bicarbonate water and Triethylamine (0.808 mL) and benzyl chloroformate ethyl acetate were added to the resulting residue, and the (0.752 mL) were sequentially added dropwise to a solution organic layer was separated. The resulting organic layer was of 3,4,5-trifluorophenylacetic acid (1 g) in methylene chlo washed with brine, dried over anhydrous magnesium Sulfate ride (15 mL) at 0°C., and the reaction solution was stirred and then concentrated under reduced pressure. The residue at 0°C. for five minutes. DMAP (64.4 mg) was added to the was purified by silica gel column chromatography (elution reaction solution which was then stirred at 0° C. for 30 Solvent: ethyl acetate-methanol system) to obtain a racemate minutes. Ethyl acetate and Saturated Sodium bicarbonate of the title compound. The resulting racemate was separated 10 water were added to the reaction solution, and the organic by CHIRALPAKTM IB manufactured by Daicel Chemical layer was separated. The resulting organic layer was washed Industries, Ltd. (2 cmx25 cm; mobile phase: hexane:etha with brine, dried over anhydrous magnesium sulfate and nol=1:1) to obtain the title optically active compound with then concentrated under reduced pressure. The residue was a retention time of 25 minutes (20.7 mg, D-99% ee) and the 15 purified by silica gel column chromatography (elution sol title optically active compound with a retention time of 36 vent: heptane-ethyl acetate system) to obtain 1.43 g of the minutes (22.4 mg. D99% ee). title compound. The property values of the compound are as The property values of the title compound with a retention follows. time of 25 minutes are as follows. ESI-MS; m/z 444 (M"--H. 'H-NMR (CDC1) & (ppm): H-NMR (CDC1) & (ppm): 3.59 (s. 2H), 5.14 (s. 2H), 1.06 (d. J=6.4 Hz, 3H), 1.88-2.00 (m, 1H), 2.11-2.25 (m, 6.90 (dd, J=8.0, 6.4 Hz, 2H), 7.29-7.38 (m, 5H), 3.83 (s.3H), 2H), 2.29 (s. 3H), 3.72 (d. J=9.2 Hz, 1H), 3.84 (s, 3H), 3.89 (s.3H), 6.44 (s, 1H), 6.95 (brs, 1H), 7.04 (d. J=1.6 Hz, 4.26-4.37 (m, 2H), 6.90 (s, 1H), 7.00-7.12 (m, 7H), 7.19 (d. 1H), 7.07 (dd, J=8.0, 1.6 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), J=8.0 Hz, 1H), 7.45 (d. J=16.4 Hz, 1H), 7.69 (s, 1H). 7.28 (d. J=8.0 Hz, 1H), 7.78 (d. J=1.2 Hz, 1H), 7.83 (s, 1H), The property values of the title compound with a retention 8.09 (dd, J=8.8, 5.2 Hz, 2H). time of 36 minutes are as follows. 25 ESI-MS; m/z 444 (M"--H. 'H-NMR (CDC1) & (ppm): Synthesis of benzyl (2S,3R)-5-(tert-butyldiphe 1.06 (d. J=6.4 Hz, 3H), 1.88-2.00 (m, 1H), 2.11-2.25 (m, nylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl) 2H), 2.29 (s. 3H), 3.72 (d. J=9.2 Hz, 1H), 3.84 (s, 3H), pentanoate and benzyl (2S,3S)-5-[(tert-butyldiphe 4.26-4.37 (m, 2H), 6.90 (s, 1H), 7.00-7.12 (m, 7H), 7.19 (d. nylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl) J=8.0 Hz, 1H), 7.45 (d. J=16.4 Hz, 1H), 7.69 (s, 1H). 30 pentanoate Examples 103 and 104 n-Butyl lithium (1.82 mL: 2.66 M solution in hexane) was added dropwise to a solution of diisopropylamine (0.735 Synthesis of (7S,8S)-2-(E)-2-3-methoxy-4-(4- mL) in THF (6 mL) at 0°C. The reaction solution was stirred methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- 35 at 0°C. for 20 minutes and then cooled to -78° C. Benzyl trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo.1, (3,4,5-trifluorophenyl)acetate (1.13 g) in THF (18 mL) was 5-alpyridin-7-ol and (7R,8R)-2-(E)-2-3-methoxy added dropwise to the reaction Solution, and the reaction 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4, solution was stirred at -78° C. for 15 minutes. Thereafter, 5-trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo 3-(tert-butyldiphenylsiloxy)propanol (CAS No. 112897-03 1.5-alpyridin-7-ol 40 7, 1.26 g) in THF (6 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at -78°C. for 30 minutes. A saturated ammonium chloride Solution was added to the reaction solution, and the reaction solution was Formula 89 returned to room temperature. Ethyl acetate was added and 45 the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium ... OH sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography MeO (elution solvent: heptane-ethyl acetate system) to obtain 840 50 mg of benzyl (2S,3R)-5-[(tert-butyldiphenylsilanyloxy)-3- hydroxy-2-(3,4,5-trifluorophenyl)pentanoate and 765 mg of benzyl (2S,3S)-5-[(tert-butyldiphenylsilanyloxy)-3-hy droxy-2-(3,4,5-trifluorophenyl)pentanoate. The property values of benzyl (2S,3R)-5-(tert-butyldi 55 phenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pen tanoate are as follows. ESI-MS; m/z 615 M*-i-Na. 'H-NMR (CDC1) & (ppm): 1.03 (s, 9H), 1.57-1.62 (m, 2H), 3.49 (d. J=2.4 Hz, 1H), 3.57 MeO (d. J=6.8 Hz, 1H), 3.77-3.85 (m, 2H), 4.46 (m. 1H), 5.07 (d. 60 J=12.4 Hz, 1H), 5.14 (d. J=12.4 Hz, 1H), 7.02 (dd, J=8.8, 6.4 Hz, 2H), 7.20-7.45 (m, 11H), 7.62 (d. J=8.0 Hz, 4H). The property values of benzyl (2S,3S*)-5-(tert-butyldi phenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophenyl)pen tanoate are as follows. 65 ESI-MS; m/z 615 M*-i-Na. 'H-NMR (CDC1) & (ppm): 1.03 (s, 9H), 1.45-1.51 (m, 2H), 3.54 (d. J=4.0 Hz, 1H), 3.57 (d. J=9.2 Hz, 1H), 3.73-3.81 (m, 2H), 4.38 (m. 1H), 5.13 (d. US 9,453,000 B2 167 168 J=12.4 Hz, 1H), 5.19 (d. J=12.4 Hz, 1H), 6.91 (dd, J=8.8, 6.4 was purified by silica gel column chromatography (elution Hz, 2H), 7.24-7.44 (m. 11H), 7.57-7.62 (m, 4H). solvent: heptane-ethyl acetate system) to obtain 383 mg of the title compound. The property value of the compound is Synthesis of benzyl (2S,3R)-5-(tert-butyldiphe as follows. nylsilanyloxy)-3-methoxymethoxy-2-(3,4,5-trifluo ESI-MS; m/z. 445 M*-i-Na. rophenyl)pentanoate Synthesis of tert-butyl N'-(2S,3R)-5-chloro-3- IPEA (0.742 mL) and chloromethyl methyl ether (0.324 methoxymethoxy-2-(3,4,5-trifluorophenyl)pen mL) were added to a solution of benzyl (2S,3R)-5-(tert tanoylhydrazinecarboxylate butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophe 10 nyl)pentanoate (840 mg) in 1,2-dichloroethane (20 mL) at 0° Triethylamine (0.209 mL) and methanesulfonyl chloride C. The reaction solution was stirred at 60° C. for 4 hours and (58 uL) were added to a solution of tert-butyl N'-(2S,3R)- then left to cool to room temperature and concentrated under 5-hydroxy-3-methoxymethoxy-2-(3,4,5-trifluorophenyl) reduced pressure. Ethyl acetate and a saturated ammonium pentanoylhydrazinecarboxylate (264 mg) in methylene chloride Solution were added to the residue, and the organic 15 chloride (10 mL) at 0°C. The reaction solution was stirred layer was separated. The resulting organic layer was washed at 0° C. for 30 minutes. Then, ethyl acetate and saturated with brine, dried over anhydrous magnesium sulfate and sodium bicarbonate water were added to the reaction solu then concentrated under reduced pressure. The residue was tion, and the organic layer was separated. The resulting purified by silica gel column chromatography (elution sol organic layer was washed with brine, dried over anhydrous vent: heptane-ethyl acetate system) to obtain 875 mg of the magnesium sulfate and then concentrated under reduced title compound. The property values of the compound are as pressure. Subsequently, lithium chloride (265 mg) was follows. added to a solution of the residue in DMF (5 mL), and the H-NMR (CDC1) & (ppm): 1.03 (s, 9H), 1.55-1.64 (m, reaction solution was stirred at 80° C. for three hours. The 1H), 1.70-1.82 (m, 1H), 3.11 (s, 3H), 3.60-3.73 (m, 2H), reaction Solution was left to cool to room temperature. Then, 3.74 (d. J=6.0 Hz, 1H), 4.38-4.41 (m. 1H), 4.39 (d. J=6.4 Hz, 25 water and ethyl acetate were added to the reaction solution, 1H), 4.51 (d. J=6.4 Hz, 1H), 5.12 (s. 2H), 6.95 (dd, J=8.8, and the organic layer was separated. The resulting organic 6.8 Hz, 2H), 7.25-7.43 (m, 11H), 7.61 (d. J=8.0 Hz, 4H). layer was washed with brine, dried over anhydrous magne sium Sulfate and then concentrated under reduced pressure. Synthesis of tert-butyl N'-(2S,3R)-5-(tert-butyl The residue was purified by silica gel column chromatog diphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5- 30 raphy (elution solvent: heptane-ethyl acetate system) to trifluorophenyl)pentanoylhydrazinecarboxylate obtain 87.5 mg of the title compound. The property value of the compound is as follows. Palladium-carbon (258 mg; 10 wt %) was added to a ESI-MS; m/z 463 M*-i-Na. solution of benzyl (2S,3R)-5-[(tert-butyldiphenylsilany loxy)-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentano 35 Synthesis of (7S,8S)-2-(E)-2-3-methoxy-4-(4- ate (770 mg) in methanol (10 mL). The reaction solution was methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- stirred in a hydrogen atmosphere for two hours and then trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolol, filtered through celite, and the filtrate was concentrated 5-alpyridin-7-ol and (7R,8R)-2-(E)-2-3-methoxy under reduced pressure. Subsequently, BOPC1 (493 mg) and 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4, IPEA (0.316 mL) were added to a solution of the residue of 40 5-trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo tert-butyl carbazate (320 mg) in methylene chloride (20 mL) 1.5-alpyridin-7-ol at 0°C. The reaction solution was stirred at room tempera ture for 15 hours. Then, ethyl acetate and a saturated A solution of 4 N hydrochloric acid in ethyl acetate (2 ammonium chloride solution were added to the reaction mL) was added to tert-butyl N'-(2S,3R)-5-chloro-3- Solution, and the organic layer was separated. The resulting 45 methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoylhy organic layer was washed with brine, dried over anhydrous drazinecarboxylate (100 mg). The reaction solution was magnesium sulfate and then concentrated under reduced stirred at room temperature for two hours and then concen pressure. The residue was purified by silica gel column trated under reduced pressure. Subsequently, triethylamine chromatography (elution solvent: heptane-ethyl acetate sys (0.156 mL) was added to a solution of the residue in ethanol tem) to obtain 603 mg of the title compound. The property 50 (2.5 mL). A mixed solution of ethyl (E)-3-3-methoxy-4-(4- value of the compound is as follows. methyl-1H-imidazol-1-yl)phenylacrylimidate dihydrochlo ESI-MS; m/z 683 M+Na. ride (80 mg) and triethylamine (0.156 mL) in ethanol (2.5 mL) was added dropwise to the Solution, and the reaction Synthesis of tert-butyl N'-(2S,3R)-5-hydroxy-3- solution was stirred at 80° C. for 12 hours. The reaction methoxymethoxy-2-(3,4,5-trifluorophenyl)pen 55 Solution was left to cool to room temperature and then tanoylhydrazinecarboxylate concentrated under reduced pressure. Saturated sodium bicarbonate water and ethyl acetate were added to the TBAF (1.36 mL; 1 M solution in THF) was added to a resulting residue, and the organic layer was separated. The solution of tert-butyl N'-(2S,3R)-5-(tert-butyldiphenylsi resulting organic layer was washed with brine, dried over lanyloxy)-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pen 60 anhydrous magnesium sulfate and then concentrated under tanoylhydrazinecarboxylate (600mg) in THF (10 mL). The reduced pressure. The residue was purified by silica gel reaction Solution was stirred at room temperature for one column chromatography (elution solvent: heptane-ethyl hour. Then, ethyl acetate and a saturated ammonium chlo acetate system) to obtain a racemate of the title compound. ride solution were added to the reaction solution, and the The resulting racemate was separated by CHIRALCELTM organic layer was separated. The resulting organic layer was 65 OD-H manufactured by Daicel Chemical Industries, Ltd. (2 washed with brine, dried over anhydrous magnesium Sulfate cmx25 cm; mobile phase: hexane:ethanol=8:2) to obtain the and then concentrated under reduced pressure. The residue title optically active compound with a retention time of 11

US 9,453,000 B2 171 172 -continued tem) to obtain 1.77 g of the title compound. The property OH value of the compound is as follows. ESI-MS; m/z 345 M+H. N-N Synthesis of tert-butyl N-4,5-dihydroxy-2-(3,4,5- trifluorophenyl)pentanoylhydrazinecarboxylate MeOe N I NZ Osmium tetroxide (2.61 mL.: 2.5 wt %) was added to a F solution of tert-butyl N'-[2-(3,4,5-trifluorophenyl)penten-4- / 10 oylhydrazinecarboxylate (1.77 g) and N-methylmorpholine le F F N-oxide (1.81 g) in acetone (40 mL) and water (40 mL). The reaction solution was stirred at room temperature for 4 hours. Then, ethyl acetate and a saturated Sodium thiosulfate Solution were added to the reaction Solution, and the organic 15 layer was separated. The resulting organic layer was washed with 1 N hydrochloric acid and brine, dried over anhydrous Sodium sulfate and then concentrated under reduced pres MeO Sure. The residue was purified by silica gel column chro matography (elution solvent: ethyl acetate-methanol system) to obtain 1.09 g of the title compound. The property value of the compound is as follows. ESI-MS; m/z 401 M+Na. Synthesis of 5-(N-tert-butoxycarbonylhydrazino)-2- 25 hydroxy-5-oxo-4-(3,4,5-trifluorophenyl)pentyl tolu ene-4-Sulfonate Synthesis of 2-(3,4,5-trifluorophenyl)-4-pentenoic p-Toluenesulfonyl chloride (605 mg) was added to a acid solution of tert-butyl N-4,5-dihydroxy-2-(3,4,5-trifluoro 30 phenyl)pentanoylhydrazinecarboxylate (1.09 g) in pyridine n-Butyl lithium (7.89 mL; 2.66 M solution in hexane) was (11 mL) at room temperature. The reaction Solution was added to a solution of 3,4,5-trifluorophenylacetic acid (2 g) stirred at room temperature for 12 hours and then concen in THF (50 mL) at -78°C. The reaction solution was stirred trated under reduced pressure. Ethyl acetate was added to the at -78° C. for 20 minutes. Then, the reaction solution was residue, and the organic layer was washed with brine, dried 35 over anhydrous Sodium sulfate and then concentrated under heated to 0° C. and further stirred for 30 minutes. Allyl reduced pressure. The residue was purified by silica gel bromide (0.999 mL) was added dropwise to the reaction column chromatography (elution solvent: heptane-ethyl Solution, and the reaction solution was stirred at room acetate system) to obtain 1.03 g of the title compound. The temperature for three hours. A 1 N sodium hydroxide property value of the compound is as follows. solution and diethyl ether were added to the reaction solu 40 tion, and the aqueous layer was separated. 5 N hydrochloric ESI-MS; m/z 555 M"+H. acid and ethyl acetate were added to the resulting aqueous Synthesis of tert-butyl N'-(5-chloro-4-hydroxy-2-(3, layer, and the organic layer was separated. The resulting 4,5-trifluorophenyl)pentanoylhydrazinecarboxylate organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced 45 Lithium chloride (818 mg) was added to a solution of pressure. The residue was purified by silica gel column 5-(N-tert-butoxycarbonylhydrazino)-2-hydroxy-5-oxo-4- chromatography (elution solvent: heptane-ethyl acetate sys (3,4,5-trifluorophenyl)pentyl toluene-4-sulfonate (1.03 g) in tem) to obtain 1.45 g of the title compound. The property DMF (8 mL). The reaction solution was stirred at 80° C. for values of the compound are as follows. three hours and then left to cool to room temperature. Water 'H-NMR (CDC1) & (ppm): 2.44-2.52 (m. 1H), 2.72-2.81 50 and ethyl acetate were added to the reaction solution, and the (m. 1H), 3.58 (t, J=7.6 Hz, 1H), 5.03-5.10 (m, 2H), 5.60 organic layer was separated. The resulting organic layer was 5.71 (m, 1H), 6.90 (dd, J–8.4, 6.4 Hz, 2H). washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue Synthesis of tert-butyl N'-[2-(3,4,5-trifluorophenyl) was purified by silica gel column chromatography (elution penten-4-oylhydrazinecarboxylate 55 solvent: heptane-ethyl acetate system) to obtain 734 mg of the title compound. The property value of the compound is BOPC1 (2.57 g) and IPEA (1.65 mL) were added to a as follows. solution of 2-(3,4,5-trifluorophenyl)-4-pentenoic acid (1.45 ESI-MS; m/z 419 M"+Na. g) and tert-butyl carbazate (1.94 g) in methylene chloride (30 mL) at 0°C. The reaction solution was stirred at room 60 Synthesis of tert-butyl N'-[4-(tert-butyldiphenylsila temperature for 15 hours. Then, ethyl acetate and a saturated nyloxy)-5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl ammonium chloride solution were added to the reaction hydrazinecarboxylate Solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous tert-Butyldiphenylchlorosilane (0.889 mL), imidazole magnesium sulfate and then concentrated under reduced 65 (233 mg) and DMAP (41.9 mg) were added to a solution of pressure. The residue was purified by silica gel column tert-butyl N'-(5-chloro-4-hydroxy-2-(3,4,5-trifluorophenyl) chromatography (elution solvent: heptane-ethyl acetate sys pentanoylhydrazinecarboxylate (680 mg) in DMF (5 mL). US 9,453,000 B2 173 174 The reaction solution was stirred at 60° C. for two hours and added to the reaction Solution, and the organic layer was then left to cool to room temperature. A Saturated ammo separated. The resulting organic layer was washed with nium chloride solution and ethyl acetate were added to the brine, dried over anhydrous magnesium sulfate and then reaction Solution, and the organic layer was separated. The concentrated under reduced pressure. The residue was puri resulting organic layer was washed with brine, dried over 5 fied by silica gel column chromatography (elution solvent: anhydrous magnesium Sulfate and then concentrated under ethyl acetate-methanol system) to obtain a diastereomer reduced pressure. The residue was purified by silica gel mixture of the title compound. The resulting mixture was column chromatography (elution solvent: heptane-ethyl separated by CHIRALPAKTM IA manufactured by Daicel acetate system) to obtain 831 mg of the title compound. The Chemical Industries, Ltd. (2 cmx25 cm; mobile phase: property value of the compound is as follows. 10 ethanol) to obtain (6R,8S)-2-(E)-2-3-methoxy-4-(4- ESI-MS; m/z 657 M+Na. methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluoro Synthesis of 6-(tert-butyldiphenylsilanyloxy)-2- phenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridin-6- {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl) ol and (6S,8R)-2-(E)-2-3-methoxy-4-(4-methyl-1H phenyl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetra- 15 imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluorophenyl)-5.6, hydro-1,2,4-triazolo 1.5-alpyridine 7,8-tetrahydro-1,2,4-triazolo 1.5-alpyridin-6-ol as an optically active compound with a retention time of 5.8 TFA (5 mL) was added dropwise to a solution of tert-butyl minutes (40.6 mg) and an optically active compound with a N'-[4-(tert-butyldiphenylsilanyloxy)-5-chloro-2-(3,4,5-trif. retention time of 7.1 minutes (39.0 mg), respectively. luorophenyl)pentanoylhydrazinecarboxylate (830 mg) in 20 The property values of the compound with a retention methylene chloride (10 mL) at 0°C. The reaction solution time of 5.8 minutes are as follows. was stirred at room temperature for two hours. Then, Satu ESI-MS; m/z 482 M*-i-H. 'H-NMR (CDOD) 8 (ppm): rated sodium bicarbonate water and chloroform were added, 1.90-2.20 (m. 1H), 2.24 (s, 3H), 2.40-2.49 (m. 1H), 3.91 (s, and the organic layer was separated. The aqueous layer was 3H), 4.25 (d. J=13.2 Hz, 1H), 4.41-4.53 (m, 3H), 7.06 (d. extracted with chloroform twice. The resulting organic lay- 25 J=1.6 Hz, 1H), 7.08 (d. J=16.0 Hz, 1H), 7.14 (dd, J=8.8, 6.0 ers were combined, washed with brine, dried over anhydrous HZ, 1H), 7.23 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d. J=8.0 Hz, magnesium sulfate and then concentrated under reduced 1H), 7.35 (d. J=1.6 Hz, 1H), 7.48 (d. J=16.0 Hz, 1H), 7.79 pressure. Subsequently, triethylamine (1.28 mL) was added (s, 1H). to a solution of the residue in ethanol (10 mL). A mixed The property values of the compound with a retention solution of ethyl (E)-3-3-methoxy-4-(4-methyl-1H-imida- 30 time of 7.1 minutes are as follows. Zol-1-yl)phenylacrylimidate dihydrochloride (400 mg) in ethanol (10 mL) and triethylamine (1.28 mL) was added ESI-MS; m/z 482 M"+H. 'H-NMR (CDOD) 8 (ppm): dropwise to the solution, and the reaction Solution was 1.90-2.20 (m. 1H), 2.24 (s, 3H), 2.40-2.49 (m. 1H), 3.91 (s, stirred at 80° C. for 12 hours. The reaction solution was left 3H), 4.25 (d. J=13.2 Hz, 1H), 4.41-4.53 (m, 3H), 7.06 (d. to cool to room temperature and then concentrated under 35 J=1.6 Hz, 1H), 7.08 (d. J=16.0 Hz, 1H), 7.14 (dd, J=8.8, 6.0 reduced pressure. Saturated sodium bicarbonate water and HZ, 1H), 7.23 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d. J=8.0 Hz, ethyl acetate were added to the resulting residue, and the 1H), 7.35 (d. J=1.6 Hz, 1H), 7.48 (d. J=16.0 Hz, 1H), 7.79 organic layer was separated. The resulting organic layer was (s, 1H). washed with brine, dried over anhydrous magnesium Sulfate The remaining diastereomers were separated by CHI and then concentrated under reduced pressure. The residue 40 RALPAKTM AD-H manufactured by Daicel Chemical was purified by silica gel column chromatography (elution Industries, Ltd. (2 cmx25 cm; mobile phase: ethanol) to solvent: heptane-ethyl acetate system) to obtain 510 mg of obtain (6S,8S)-2-(E)-2-3-methoxy-4-(4-methyl-1H-imi the title compound. The property value of the compound is dazol-1-yl)phenyl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8- as follows. tetrahydro-1,2,4-triazolo 1.5-alpyridin-6-ol and (6R8R)-2- ESI-MS; m/z 720 M+H. 45 {(E)-2-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4 Synthesis of (6R,8S)-2-(E)-2-3-methoxy-4-(4- triazolo 1.5-alpyridin-6-ol as an optically active compound methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- with a retention time of 6.2 minutes (10.2 mg) and an trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo.1, optically active compound with a retention time of 8.2 5-alpyridin-6-ol, (6S,8R)-2-(E)-2-3-methoxy-4-(4- 50 methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- minutes (7.4 mg), respectively. trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo.1, The property values of the compound with a retention 5-alpyridin-6-ol, (6S,8S)-2-(E)-2-3-methoxy-4-(4- time of 6.2 minutes are as follows. methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4,5- ESI-MS; m/z 482 IM+H. 'H-NMR (CDOD) 8 (ppm): trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo.1, 55 2.06-2.15 (m, 1H), 2.23 (s.3H), 2.49-2.55 (m, 1H), 3.90 (s, 5-alpyridin-6-ol and (6R,8R)-2-(E)-2-3-methoxy 3H), 4.06 (dd, J=12.0, 8.0 Hz, 1H), 4.35-4.48 (m, 3H), 4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8-(3,4, 7.03-7.12 (m, 2H), 7.15 (dd, J=8.8, 6.4 Hz, 2H), 7.22 (dd. 5-trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo J=8.0, 1.6 Hz, 1H), 7.32 (d. J=8.0 Hz, 1H), 7.33 (d. J=1.6 1.5-alpyridin-6-ol HZ, 1H), 7.46 (d. J=16.4 Hz, 1H), 7.79 (s, 1H). 60 The property values of the compound with a retention TBAF (1.06 mL; 1 M solution in THF) was added to a time of 8.2 minutes are as follows. solution of 6-(tert-butyldiphenylsilanyloxy)-2-(E)-2-3- ESI-MS; m/z 482 M*-i-H. 'H-NMR (CDOD) 8 (ppm): methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl vinyl-8- 2.06-2.15 (m, 1H), 2.23 (s.3H), 2.49-2.55 (m, 1H), 3.90 (s, (3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-1,2,4-triazolo1, 3H), 4.06 (dd, J=12.0, 8.0 Hz, 1H), 4.35-4.48 (m, 3H), 5-alpyridine (510 mg) in THF (10 mL), and the reaction 65 7.03-7.12 (m, 2H), 7.15 (dd, J=8.8, 6.4 Hz, 2H), 7.22 (dd. Solution was stirred at room temperature for one hour. J=8.0, 1.6 Hz, 1H), 7.32 (d. J=8.0 Hz, 1H), 7.33 (d. J=1.6 Saturated sodium bicarbonate water and ethyl acetate were HZ, 1H), 7.46 (d. J=16.4 Hz, 1H), 7.79 (s, 1H). US 9,453,000 B2 175 176 Examples 111 and 112 acetate system) to obtain 210 mg of the title compound. The property value of the compound is as follows. Synthesis of (-) and (+)-8-cyclopropyl-2-(E)-2-3- ESI-MS; m/z. 313 M+Na. 'H-NMR (CDC1) & (ppm): methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii 0.20-0.31 (m, 2H), 0.57-0.70 (m, 2H), 0.90-1.00 (m, 1H), nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine 5 1.43-1.55 (m, 1H), 1.48 (s, 9H), 1.81-1.97 (m, 4H), 3.49 3.60 (m, 2H), 6.48 (brs, 1H), 7.38 (brs, 1H). Synthesis of 5-chloro-2-cyclopropyl-Valeric acid Formula 92 hydrazide

10 Trifluoroacetic acid (0.5 ml) was added to a solution of tert-butyl N'-(5-chloro-2-cyclopropyl-pentanoyl)-hydrazin ecarboxylate (208 mg) in methylene chloride (1 ml) under ice-cooling, and then the reaction solution was stirred at 15 room temperature for two hours. A saturated Sodium bicar bonate solution and ethyl acetate were added to the reaction Solution, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine. The combined aqueous lay ers were reextracted with ethyl acetate (twice). The com bined organic layers were dried over anhydrous magnesium Sulfate and then concentrated under reduced pressure to obtain 127 mg of the title compound. The property values of 25 the compound are as follows. ESI-MS; m/z 191 M*-i-H. 'H-NMR (CDC1,) & (ppm): 0.16-0.24 (m, 2H), 0.52-0.68 (m, 2H), 0.86-0.95 (m, 1H), 1.31-1.37 (m, 1H), 1.78–2.00 (m, 4H), 3.48-3.60 (m, 2H), 3.96 (brs, 2H), 6.88 (brs, 1H). 30 Synthesis of (-) and (+)-8-cyclopropyl-2-(E)-2-3- Synthesis of tert-butyl N'-(5-chloro-2-cyclopropyl methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii pentanoyl)-hydrazinecarboxylate nyl-5,6,7,8-tetrahydro1,2,4-triazolo 1.5-alpyridine 35 A solution of 5-chloro-2-cyclopropyl-Valeric acid hydraz n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was ide (125 mg) in ethanol (1.5 mL) was added to a solution of added dropwise to a solution of diisopropylamine (1.5 ml) in ethyl (E)-3-3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phe THF (15 ml) at -30°C., and the reaction solution was stirred at the same temperature for 15 minutes. The reaction solu nylacrylimidate dihydrochloride (259 mg) and TEA (0.46 tion was cooled to -78°C. Then, a solution of cyclopropy 40 ml) in ethanol (3 ml), and the reaction solution was stirred lacetic acid (CAS No. 5239-82-7, 500 mg) in THF (3 ml) at 70° C. for 22 hours. The reaction solution was left to cool was added dropwise and the reaction solution was further to room temperature. Then, ethyl acetate and water were stirred at room temperature for three hours. The reaction added to the reaction Solution, and the organic layer was solution was cooled to 0° C., and then 1-bromo-3-chloro separated. The organic layer was washed with brine, dried propane (CAS No. 109-70-6, 0.55 ml) was added dropwise. 45 over anhydrous magnesium Sulfate and then concentrated The reaction solution was stirred at the same temperature for under reduced pressure. The resulting residue was purified 10 minutes and at room temperature for further one hour. Ice by silica gel column chromatography (carrier: Chroma water and diethyl ether were added to the reaction solution, torexTM NH; elution solvent: heptane-ethyl acetate system) and the aqueous layer was separated. Then, 5N hydrochloric and again purified by silica gel column chromatography acid (3 ml) and ethyl acetate were added to the aqueous 50 (elution solvent: ethyl acetate-methanol system) to obtain 43 layer, and the organic layer was separated. The resulting mg of racemic 8-cyclopropyl-2-(E)-2-3-methoxy-4-(4- ethyl acetate layer was washed with brine, dried over methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro anhydrous magnesium Sulfate and then concentrated under 1.2.4 triazolo 1.5-alpyridine. Then, the racemate was sepa reduced pressure to obtain crude 5-chloro-2-cyclopropyl rated by CHIRALPAKTM IB manufactured by Daicel Valeric acid (550 mg). 55 Chemical Industries, Ltd. (2 cmx25 cm; mobile phase: 20% IPEA (1.6 ml) and BOPC1 (1.2 g) were added to a solution ethanol-hexane) to obtain the title optically active compound of the crude 5-chloro-2-cyclopropyl-valeric acid (550 mg) with a retention time of 28 minutes and negative optical and tert-butyl carbazate (CAS No. 870-46-2, 555 mg) in rotation (16.4 mg: 100% ee) and the title optically active methylene chloride (5 ml), and the reaction solution was compound with a retention time of 49 minutes and positive stirred at room temperature for three hours. Ethyl acetate and 60 optical rotation (16.3 mg: 99% ee). water were added to the reaction solution, and the organic The property values of the title optically active compound layer was separated. The organic layer was sequentially with a retention time of 28 minutes are as follows. washed with 1 N hydrochloric acid, water, a saturated ESI-MS; m/z. 376 M*-i-H. 'H-NMR (CDC1,) & (ppm): sodium bicarbonate solution and brine, dried over anhydrous 0.31-0.39 (m. 1H), 0.52-0.65 (m, 2H), 0.73-0.81 (m, 1H), magnesium sulfate and then concentrated under reduced 65 0.99-1.09 (m. 1H), 1.83-1.93 (m, 1H), 1.97-2.17 (m, 2H), pressure. The resulting residue was purified by silica gel 2.21-2.32 (m, 1H), 2.30 (s.3H), 2.33-2.40 (m, 1H), 3.88 (s, column chromatography (elution solvent: heptane-ethyl 3H), 4.16 (t, J=6.0 Hz, 2H), 6.91 (d. J=0.8 Hz, 1H), 7.08 (d. US 9,453,000 B2 177 178 J=16.4 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d. J–1.6 ether system) to obtain 1.00 g of the title compound. The HZ, 1H), 7.22 (d. J=8.0 Hz, 1H), 7.54 (d. J=16.4 Hz, 1H), property value of the compound is as follows. 7.69 (d. J=0.8 Hz, 1H). ESI-MS; m/z 233 M+H. The property values of the title optically active compound with a retention time of 49 minutes are as follows. 5 Synthesis of tert-butyl N'-(5-chloro-2-cyclohexyl ESI-MS; m/z. 376 M*-i-H. 'H-NMR (CDC1) & (ppm): pentanoyl)-hydrazinecarboxylate 0.31-0.39 (m. 1H), 0.52-0.65 (m, 2H), 0.73-0.81 (m, 1H), 0.99-1.09 (m. 1H), 1.83-1.93 (m, 1H), 1.97-2.17 (m, 2H), A 5 N sodium hydroxide solution (2.5 ml) was added to 2.21-2.32 (m, 1H), 2.30 (s.3H), 2.33-2.40 (m, 1H), 3.88 (s, a solution of methyl 5-chloro-2-cyclohexyl-valerate (1.00 g) 3H), 4.16 (t, J=6.0 Hz, 2H), 6.91 (d. J=0.8 Hz, 1H), 7.08 (d. 10 in THF (3 ml)-methanol (6 ml). The reaction solution was J=16.4 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d. J–1.6 stirred at room temperature for six hours and at 60° C. for HZ, 1H), 7.22 (d. J=8.0 Hz, 1H), 7.54 (d. J=16.4 Hz, 1H), further two hours. After allowing the reaction solution to cool, water and diethyl ether were added to the reaction 7.69 (d. J=0.8 Hz, 1H). Solution, and the aqueous layer was separated. 5 N hydro Examples 113 and 114 15 chloric acid (2.6 ml) and ethyl acetate were added to the aqueous layer, and the organic layer was separated. The Synthesis of (+) and (-)-8-cyclohexyl-2-(E)-2-3- ethyl acetate extraction layer was washed with brine, dried methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii over anhydrous magnesium Sulfate and then concentrated under reduced pressure. The resulting residue was purified nyl-5,6,7,8-tetrahydro 1.2.4 triazolo 1.5-alpyridine 2O by Silica gel column chromatography (heptane-ethyl acetate system) to obtain 5-chloro-2-cyclohexyl-Valeric acid (287 mg). IPEA (0.68 ml) and BOPC1 (496 mg) were added to a Formula 93 solution of 5-chloro-2-cyclohexyl-Valeric acid (285 mg) and 25 tert-butyl carbazate (215 mg) in methylene chloride (2.5 ml), N-N and the reaction solution was stirred at room temperature for 5.5 hours. Ethyl acetate and water were added to the reaction Solution, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, 30 water, a saturated Sodium bicarbonate Solution and brine, % N. cr'. dried over anhydrous magnesium sulfate and then concen trated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution sol

vent: heptane-ethyl acetate system) to obtain 156 mg of the 35 title compound. The property values of the compound are as N-N follows. ESI-MS; m/z. 355 M+Na. 'H-NMR (CDC1) & (ppm): Y.Y. 0.90-132 (m, 6H), 1.47 (s, 9H), 1.50-1.94 (m, 10H), 3.46 3.61 (m, 2H), 6.46 (brs, 1H), 7.14 (brs, 1H). 40 % N. cr'? () Synthesis of 5-chloro-2-cyclohexyl-valeric acid hydrazide hydrochloride )- tert-Butyl N'-(5-chloro-2-cyclohexyl-pentanoyl)-hydra 45 Zinecarboxylate (155 mg) was dissolved in a solution of 4N hydrogen chloride in dioxane (2 ml), and the reaction Synthesis of methyl 5-chloro-2-cyclohexyl-valerate solution was stirred at room temperature for one hour. The reaction Solution was concentrated under reduced pressure n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was to obtain 144 mg of the title compound. The property value added dropwise to a solution of diisopropylamine (1.55 ml) 50 of the compound is as follows. in THF (15 ml) under ice-cooling, and the reaction solution ESI-MS; m/z 233 M"+H HCl). was stirred at the same temperature for 10 minutes. The reaction solution was cooled to -78°C. Then, a solution of Synthesis of (+) and (-)-8-cyclohexyl-2-(E)-2-3- methyl cyclohexylacetate (CAS No. 14352-61-5, 500 mg) in methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylvii THF (3 ml) was added dropwise and the reaction solution 55 nyl-5,6,7,8-tetrahydro1,2,4-triazolo 1.5-alpyridine was stirred at the same temperature for 30 minutes. Then, 1-chloro-3-iodopropane (CAS No. 6940-76-7, 1.1 ml) was A solution of 5-chloro-2-cyclohexyl-Valeric acid hydraz added dropwise to the reaction solution. The reaction solu ide hydrochloride (144 mg) and TEA (0.32 ml) in ethanol (1 tion was stirred at the same temperature for 20 minutes and ml) was added to a solution of ethyl (E)-3-3-methoxy-4- then gradually heated to room temperature. Water and ethyl 60 (4-methyl-1H-imidazol-1-yl)phenylacrylimidate dihydro acetate were added to the reaction solution, and the organic chloride obtained in Example 1 (167 mg) and TEA (0.32 ml) layer was separated. The organic layer was sequentially in ethanol (1.6 ml), and the reaction Solution was stirred at washed with 1 N hydrochloric acid, water, a saturated 70° C. for two days. The reaction solution was left to cool sodium bicarbonate solution and brine, dried over anhydrous to room temperature. Then, ethyl acetate and water were magnesium sulfate and then concentrated under reduced 65 added to the reaction Solution, and the organic layer was pressure. The resulting residue was purified by silica gel separated. The organic layer was washed with brine, dried column chromatography (elution solvent: hexane-diethyl over anhydrous magnesium Sulfate and then concentrated US 9,453,000 B2 179 180 under reduced pressure. The resulting residue was purified purified by Silica gel column chromatography (carrier: Chro by silica gel column chromatography (carrier: Chroma matorexTMNH; elution solvent: ethyl acetate) to obtain 2.03 torexTM NH; elution solvent: heptane-ethyl acetate system) g of a carbazide compound. and again purified by silica gel column chromatography Potassium tert-butoxide (850 mg) was added to a solution (elution solvent: ethyl acetate-methanol system) to obtain 27 of the carbazide compound (2.03 g) in THF (30 ml) under mg of racemic 8-cyclohexyl-2-(E)-2-3-methoxy-4-(4- ice-cooling. The reaction solution was stirred at the same methyl-1H-imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro temperature for 30 minutes and at room temperature for 1.2.4 triazolo 1.5-alpyridine. Then, the racemate was sepa further 1.5 hours. Ethyl acetate and water were added to the rated by CHIRALPAKTM IB manufactured by Daicel reaction solution, and the organic layer was separated. The Chemical Industries, Ltd. (2 cmx25 cm; mobile phase: 20% 10 organic layer was sequentially washed with water and brine, ethanol-hexane) to obtain the title optically active compound dried over anhydrous magnesium sulfate and then concen with a retention time of 16 minutes and positive optical trated under reduced pressure. The resulting residue was rotation (11.0 mg: 100% ee) and the title optically active purified by silica gel column chromatography (elution sol compound with a retention time of 39 minutes and negative vent: heptane-ethyl acetate system) to obtain 907 mg of the optical rotation (10.2 mg: 100% ee). 15 title compound. The property values of the compound are as The property values of the title optically active compound follows. with a retention time of 16 minutes are as follows. ESI-MS; m/z 237 (MNal. 'H-NMR (CDC1) & (ppm): ESI-MS; m/z 418 M"+H. 'H-NMR (CDC1) & (ppm): 1.48 (s, 9H), 1.78-1.96 (m, 4H), 2.47 (t, J=6.4 Hz, 2H), 3.58 1.07-1.54 (m, 7H), 1.66-1.85 (m, 4H), 1.90-2.06 (m, 2H), (t, J=6.0 Hz, 2H), 6.66 (brs, 1H). 2.13-2.25 (m, 2H), 2.30 (s.3H), 2.84-2.92 (m, 1H), 3.88 (s, 3H), 4.01-4.11 (m. 1H), 4.16-4.24 (m. 1H), 6.91 (s, 1H), Synthesis of 1-aminopiperidin-2-one hydrochloride 7.06 (d. J=16.4 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d. J=1.6 Hz, 1H), 7.22 (d. J=8.0 Hz, 1H), 7.52 (d. J=16.4 tert-Butyl (2-oxopiperidin-1-yl)carbamate (129 mg) was HZ, 1H), 7.69 (s, 1H). dissolved in a solution of 4N hydrogen chloride in dioxane The property values of the title optically active compound 25 (2 ml), and the reaction solution was stirred at room tem with a retention time of 39 minutes are as follows. perature for one hour. The reaction solution was concen ESI-MS; m/z 418 M"+H. 'H-NMR (CDC1) & (ppm): trated under reduced pressure to obtain 92 mg of the title 1.07-1.54 (m, 7H), 1.66-1.85 (m, 4H), 1.90-2.06 (m, 2H), compound. The property values of the compound are as 2.13-2.25 (m, 2H), 2.30 (s.3H), 2.84-2.92 (m, 1H), 3.88 (s, follows. 3H), 4.01-4.11 (m. 1H), 4.16-4.24 (m. 1H), 6.91 (s, 1H), 30 H-NMR (DMSO-D) 8 (ppm): 1.69-1.77 (m, 2H), 1.82 7.06 (d. J=16.4 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 1.90 (m, 2H), 2.41 (t, J=6.4 Hz, 2H), 3.54 (t, J=6.0 Hz, 2H). (d. J=1.6 Hz, 1H), 7.22 (d. J=8.0 Hz, 1H), 7.52 (d. J=16.4 HZ, 1H), 7.69 (s, 1H). Synthesis of (E)-3-3-methoxy-4-(4-methyl-1H imidazol-1-yl)phenyl-N-(2-oxopiperidin-1-yl)acryl Example 115 35 amide Synthesis of 2-(E)-2-3-methoxy-4-(4-methyl-1H IPEA (0.26 ml), HOBT (121 mg) and EDC (172 mg) were imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2, sequentially added to a Suspension of 1-aminopiperidin-2- 4triazolo 1.5-alpyridine one hydrochloride (92 mg) and (E)-3-3-methoxy-4-(4- 40 methyl-1H-imidazol-1-yl)phenylacrylic acid (CAS No. 870839-41-1, 150 mg) in DMF (4 ml), and the reaction Solution was stirred at room temperature overnight. Ethyl Formula 94) acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was 45 sequentially washed with a saturated sodium bicarbonate Solution and brine. The combined aqueous layers were l reextracted with ethyl acetate (twice). The combined organic % layers were dried over anhydrous magnesium Sulfate and concentrated under reduced pressure. The resulting residue 50 was triturated with ethyl acetate to obtain 97 mg of the title compound. The property values of the compound are as follows. ESI-MS; m/z. 355 M+H. 'H-NMR (CDC1) & (ppm): 1.87-2.04 (m, 4H), 2.30 (s.3H), 2.56 (t, J=6.4 Hz, 2H), 3.70 55 (t, J=6.0 Hz, 2H), 3.86 (s.3H), 6.47 (d. J=16.0 Hz, 1H), 6.92 Synthesis of tert-butyl (s, 1H), 7.00 (s, 1H), 7.04 (d. J=8.0 Hz, 1H), 7.20 (d. J=8.0 (2-oxopiperidin-1-yl)carbamate HZ, 1H), 7.52 (d. J=16.0 Hz, 1H), 7.72 (s, 1H), 9.03 (brs, 1H). A 4 N sodium hydroxide solution (4 ml) and 5-bromo valeryl chloride (CAS No. 4509-90-4, 1.06 ml) were added 60 Synthesis of 2-(E)-2-3-methoxy-4-(4-methyl-1H to a solution of tert-butyl carbazate (CAS No. 870-46-2, 1 g) imidazol-1-yl)phenyl vinyl-5,6,7,8-tetrahydro 1.2, in methylene chloride (10 ml) under ice-cooling. The reac 4triazolo 1.5-alpyridine tion solution was stirred at the same temperature for 40 minutes, and then the organic layer was separated. The A suspension of (E)-3-3-methoxy-4-(4-methyl-1H-imi organic layer was sequentially washed with water and brine, 65 dazol-1-yl)phenyl-N-(2-oxopiperidin-1-yl)acrylamide (96 dried over anhydrous magnesium sulfate and then concen mg) in phosphorus oxychloride (1 ml) was stirred at 150° C. trated under reduced pressure. The resulting residue was for 1.5 hours. Phosphorus oxychloride was evaporated from