US 2016.03261 O2A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0326102 A1 Kobayashi et al. (43) Pub. Date: Nov. 10, 2016

(54) CYCLIC COMPOUNDS (52) U.S. Cl. CPC ...... C07C317/12 (2013.01); C07D 317/72 (71) Applicant: Takeda Pharmaceutical Company (2013.01); C07D 309/28 (2013.01); C07C Limited, Osaka (JP) 2102/08 (2013.01); C07C 2101/16 (2013.01) (72) Inventors: Toshitake Kobayashi, Kanagawa (JP); (57) ABSTRACT Morihisa SAITOH, Kanagawa (JP); Yasufumi WADA, Kanagawa (JP); The present invention provides compounds having a Toll Hiroshi NARA, Kanagawa (JP); like receptor 4 (TLR4) signaling inhibitory action useful as Nobuyuki NEGORO, Kanagawa (JP); preventive and therapeutic of inflammatory disease and/or central nervous system disease or diseases such as Taisuke KATOH, Kanagawa (JP); chemotherapy-induced peripheral neuropathy (CIPN), che Masashi YAMASAKI, Kanagawa (JP): motherapy-induced neuropathic pain (CINP), liver injury, Takahiro TANAKA, Kanagawa (JP); ischemia-reperfusion injury (IRI) and the like. Naomi KITAMOTO, Kanagawa (JP) The present invention relates to a compound represented by (73) Assignee: Takeda Pharmaceutical Company formula (I) and a salt thereof: Limited, Osaka (JP)

(21) Appl. No.: 15/148,210 (I) (22) Filed: May 6, 2016 (30) Foreign Application Priority Data May 8, 2015 (JP) ...... 2015-095817 Publication Classification (51) Int. Cl. C07C 317/12 (2006.01) C07D 309/28 (2006.01) (wherein, each symbol is explained in greater detail in the C07D 31 7/72 (2006.01) specification). US 2016/0326102 A1 Nov. 10, 2016

CYCLIC COMPOUNDS 0007. In Patent Document 2 the following compound

TECHNICAL FIELD (I) 0001. The present invention relates to novel cyclic com pounds having a Toll-like receptor 4 (TLR4) signal inhibi tory action useful as preventive and therapeutic drugs of C-R autoimmune disease and/or inflammatory disease or dis eases such as chemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), SO-Y-Ar liver injury, ischemia-reperfusion injury (IRI) and the like, and use thereof. 0008 (wherein, each symbol is described in the descrip tion in the said literature) is reported as a TLR4 signaling BACKGROUND OF THE INVENTION inhibitor. 0002 TLR4 was initially discovered as a receptor which 0009. In Patent Documents 3 and 4 the following com recognizes lipopolysaccharide of Gram negative bacteria pound and activates the natural immunity system. However, in recent years, it has been elucidated that not only does TLR4 activate Such natural immunity reactions for preventing (I) infections, but also recognizes various endogenous ligands produced in said various diseases and activates various cells playing central roles in the said diseases. Moreover, it has been reported that expression of TLR4 is accentuated in lesions of various diseases and that onset and progression of diseases in disease model animals are markedly suppressed in TLR4 knockout mouse and mutant mouse. Accordingly, it is suggested that TLR4 plays an important role in auto immune disease and/or inflammatory disease, and diseases 0010 (wherein, each symbol is described in the descrip such as cardiac disease, renal disease, liver disease, central tion in the said literature) is reported as TLR4 signaling nervous system disease, infectious disease, malignant tumor, inhibitor. sepsis, septic shock and the like. DOCUMENT LIST 0003. In addition to such diseases, the relationship to ischemia-reperfusion injury (ischemia reperfusion injury: Patent Document IRI) caused by reperfusion of blood flow to organs and tissues in ischemic condition upon organ transplantation and 0011 Patent Document 1 WO99/46242 the like, is also reported. High Mobility Group Box 1 0012 Patent Document 2 WO 2001/010826 (HMGB-1), which is one of TLR4 endogenous ligands, 0013 Patent Document 3 WO 2007/032362 increases in transplanted organ. Moreover, the transplanted organ derived from donor with genetically impaired TLR4 0014 Patent Document 4 JP 2008-260760 function shows resistance to IRI-associated dysfunction. From Such publicly known knowledge, it is suggested that Non-Patent Document TLR4 signal due to HMGB-1 plays an important role in IRI (0015 Non-Patent Document 1 Liver Transpl. 2008 (Non-Patent Document 1, Non-Patent Document 2). October, 14(10), 1517-25 0004 As a result, TLR4 signaling inhibitors (may also be (0016 Non-Patent Document 2 J. Hepatol. 2010 July called “TLR4 inhibitors') are anticipated to be preventive 53(1), 67-72 and therapeutic drugs of autoimmune disease and/or inflam matory disease or diseases such as cardiac disease, renal SUMMARY OF THE INVENTION disease, liver disease, central nervous system disease, infec tious disease, malignant tumor, sepsis, septic shock, etc. Problems to be Solved by the Invention 0005. In Patent Document 1 the following compound 0017. The object of the present invention is to provide a compound having excellent TLR4 signaling inhibitory action, which is useful as a in the treatment and (Iaa) prevention autoimmune disease and/or inflammatory dis ease, and diseases such as chemotherapy-induced peripheral neuropathy (CIPN), chemotherapy-induced neuropathic pain (CINP), liver injury, ischemia-reperfusion injury (IRI) and the like. Means of Solving the Problems 0006 (wherein, each symbol is described in the descrip 0018. These inventors made assiduous investigations in tion in the said literature) is reported as a TLR4 signaling order to achieve a solution to said problem, and as a result, inhibitor. it was discovered that the compounds represented by the US 2016/0326102 A1 Nov. 10, 2016 following formula (I) have excellent TLR4 signaling inhibi group(s) optionally substituted by 1 to 3 substituent(s) tory action. The present invention was completed on the selected from a hydroxy group and a C- alkoxy group; basis of this discovery. 0036 W is CH or O; and 0019. In other words, the present invention is as follows. I0037 R is a C- alkoxy group optionally substituted by 0020 (1) A compound represented by the following for 1 to 3 Co cycloalkyl group(s) optionally substituted by 1 mula (I) or a salt thereof (hereinafter, abbreviated to com to 3 C alkyl group(s). pound (I): 0038 (8) Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-2,3-di hydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1, 4-dioxaspiro4.5 dec-6-ene-7-carboxylate. (I) 0039 (9) Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro 2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxym ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate. 0040 (10) Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-2,3-di hydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1, 4-dioxaspiro4.5 dec-6-ene-7-carboxylate. 0041 (11) A medicament comprising the compound or salt according to the above-mentioned (1). 0042 (12) The medicament according to the above mentioned (11), which is a toll-like receptor 4 inhibitor. 0043 (13) The medicament according to the above 0021 (wherein, mentioned (11), which is an agent for the prophylaxis or 0022 Ring A is an optionally substituted 5 or 6 mem treatment of autoimmune disease and/or inflammatory dis bered ring; CaSC. 0023 Ring B is an optionally substituted ring: 0044 (14) The medicament according to the above 0024) R' and Rare independently a hydrogen atom or a mentioned (11), which is an agent for the prophylaxis or substituent, or R' and R may bond together to form an treatment of chemotherapy-induced peripheral neuropathy optionally Substituted ring; (CIPN), chemotherapy-induced neuropathic pain (CINP), (0.025 W is CH, NH or O; and liver injury and/or ischemia-reperfusion injury (IRI). 0026 R is a substituent). 0045 (15) The compound or salt according to the above 0027 (2) The compound or salt according to the above mentioned (1) for use in the prophylaxis or treatment of mentioned (1), wherein Ring A is cyclopentene or cyclo autoimmune disease and/or inflammatory disease. hexene. 0046 (16) The compound or salt according to the above 0028 (3) The compound or salt according to the above mentioned (1) for use in the prophylaxis or treatment of mentioned (1), wherein Ring B is a benzene ring optionally chemotherapy-induced peripheral neuropathy (CIPN), che substituted by 1 to 3 substituent(s) selected from a halogen motherapy-induced neuropathic pain (CINP), liver injury atom and a C alkyl group. and/or ischemia-reperfusion injury (IRI). 0029 (4) The compound or salt according to the above 0047 (17) A method of inhibiting toll-like receptor 4 in mentioned (1), wherein as to R' and R. (1) R' and R are a mammal, which comprises administering an effective both hydrogen atoms, or (2) one of R and R is a hydrogen amount of the compound or salt according to the above atom, and the other is a hydroxy group, or R' and R may mentioned (1) to the mammal. bond together to form a 3- to 8-membered monocyclic 0048 (18) A method for the prophylaxis or treatment of non-aromatic heterocycle optionally substituted by 1 to 3 autoimmune disease and/or inflammatory disease in a mam C. alkyl group(s) optionally substituted by 1 to 3 Substitu mal, which comprises administering an effective amount of ent(s) selected from a hydroxy group and a C- alkoxy the compound or salt according to the above-mentioned (1) group. to the mammal. 0030 (5) The compound or salt according to the above 0049 (19) A method for the prophylaxis or treatment of mentioned (1), wherein W is CH or O. chemotherapy-induced peripheral neuropathy (CIPN), che 0031 (6) The compound or salt according to the above motherapy-induced neuropathic pain (CINP), liver injury mentioned (1), wherein R is a Calkoxy group optionally and/or ischemia-reperfusion injury (IRI) in a mammal, Substituted by 1 to 3 Co cycloalkyl group(s) optionally which comprises administering an effective amount of the Substituted by 1 to 3 C alkyl group(s). compound or salt according to the above-mentioned (1) to 0032 (7) The compound or salt according to the above the mammal. mentioned (1), wherein 0050 (20) Use of the compound or salt according to the 0033 Ring A is cyclopentene or cyclohexene; above-mentioned (1) for the production of an agent for the 0034 Ring B is a benzene ring optionally substituted by prophylaxis or treatment of autoimmune disease and/or 1 to 3 Substituent(s) selected from a halogen atom and a C inflammatory disease. alkyl group; 0051 (21) Use of the compound or salt according to the 0035 as to R' and R. (1) R' and Rare both hydrogen above-mentioned (1) for the production of an agent for the atoms, or (2) one of R and R is a hydrogen atom, and the prophylaxis or treatment of chemotherapy-induced periph other is a hydroxy group, or R' and R may bond together to eral neuropathy (CIPN), chemotherapy-induced neuropathic form a 3- to 8-membered monocyclic non-aromatic hetero pain (CINP), liver injury and/or ischemia-reperfusion injury cycle, which is optionally substituted by 1 to 3 C alkyl (IRI). US 2016/0326102 A1 Nov. 10, 2016

Effect of the Invention 0063. In this specification, for example, as "C. aryl group', phenyl, 1-naphthyl 2-naphthyl, 1-anthryl, 2-anthryl, 0052. The compound of the present invention has TLR4 9-anthryl and the like may be proposed. signaling inhibitory action and is useful as a preventive and 0064. In this specification, for example, as “Caralkyl therapeutic drug of autoimmune disease and/or inflamma group', benzyl, phenethyl, naphthylmethyl, phenylpropyl tory disease or disease Such as chemotherapy-induced and the like may be proposed. peripheral neuropathy (CIPN), chemotherapy-induced neu 0065. In this specification, for example, as “C alkoxy ropathic pain (CINP), liver injury, ischemia-reperfusion group', methoxy, ethoxy, propoxy, isopropoxy, butoxy, injury (IRI), etc. isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like may be proposed. DETAILED DESCRIPTION OF THE 0066. In this specification, for example, as “optionally INVENTION halogenated C. alkoxy group', C. alkoxy group which 0053. The present invention will now be described in may have 1 to 7, preferably 1 to 5 halogen atoms and the like detail. may be proposed. Specific examples comprise methoxy, 0054 The definition of each substituent used in this difluoromethoxy, trifluoromethoxy, ethoxy. 2, 2, 2-trifluo specification will now be described in detail. Each substitu roethoxy, propoxy, isopropoxy, butoxy, 4.4.4-trifluorobu ent has the following definitions unless otherwise specifi toxy, isobutoxy, Sec-butoxy, pentyloxy and hexyloxy. cally stated to the contrary. 0067. In this specification, for example, as “Co 0055. In this specification, for example, as “halogen cycloalkyloxy group', cyclopropyloxy, cyclobutyloxy, atom', fluorine, chlorine, bromine, iodine and the like may cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cycloocty be proposed. loxy and the like may be proposed. 0056. In this specification, for example, as “C alkyl 0068. In this specification, for example, as “C alkylthio group', methyl, ethyl, propyl, isopropyl, butyl, isobutyl, group', methylthio, ethylthio, propylthio, isopropylthio. sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl butylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbu and the like may be proposed. tyl, 3.3-dimethylbutyl, 2-ethyl butyl and the like may be 0069. In this specification, for example, as “optionally proposed. halogenated C. alkylthio group', C. alkylthio group 0057. In this specification, for example, as “optionally which may have 1 to 7, preferably 1 to 5 halogenatoms and halogenated C. alkyl group', C. alkyl group which may the like may be proposed. Specific examples comprise have 1 to 7, preferably 1 to 5 halogen atoms and the like may methylthio, difluoromethylthio, trifluoromethylthio, ethyl be proposed. Specific examples comprise methyl, chlorom thio, propylthio, isopropylthio, butylthio. 4.4.4-trifluorobu ethyl, difluoromethyl, trichloromethyl, trifluoromethyl, tylthio, pentylthio and hexylthio. ethyl 2-bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl, 0070. In this specification, for example, as “C alkyl pentafluoroethyl, propyl. 2,2-difluoropropyl. 3, 3, 3-trifluo carbonyl group', acetyl, propanoyl, butanoyl, 2-methylpro ropropyl, isopropyl, butyl, 4, 4, 4-trifluorobutyl, isobutyl, panoyl, pentanoyl 3-methylbutanoyl, 2-methylbutanoyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5,5-tri 2,2-dimethylpropanoyl, hexanoyl, heptanoyl and the like fluoropentyl, hexyl, and 6, 6, 6-trifluoro hexyl. may be proposed. 0058. In this specification, for example, as “C alkenyl 0071. In this specification, for example, as “optionally group', ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-prope halogenated C. alkyl-carbonyl group', C. alkyl-carbonyl nyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, group which may have 1 to 7, preferably 1 to 5 halogen 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- atoms and the like may be proposed. Specific examples pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like may comprise acetyl, chloroacetyl, trifluoroacetyl, trichloro be proposed. acetyl, propanoyl, butanoyl, pentanoyl and hexanoyl. 0059. In this specification, for example, as “C alkynyl 0072. In this specification, for example, as “C alkoxy group', ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-bu carbonyl group', methoxycarbonyl, ethoxycarbonyl, tynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pen propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexy isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbo nyl, 4-methyl-2-pentynyl and the like may be proposed. nyl, pentyloxycarbonyl, hexyloxycarbonyl and the like may 0060. In this specification, for example, as “Co be proposed. cycloalkyl group', cyclopropyl, cyclobutyl, cyclopentyl, 0073. In this specification, for example, as "Caryl cyclohexyl, cycloheptyl, cyclooctyl, bicyclo2.2.1 heptyl, carbonyl group', benzoyl, 1-naphthoyl 2-naphthoyl and the bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, adamanty1 and the like may be proposed. like may be proposed. 0074. In this specification, for example, as “Caralkyl 0061. In this specification, for example, as “optionally carbonyl group’, phenylacetyl, phenyl propionyl and the halogenated Co cycloalkyl group’, Co cycloalkyl group like may be proposed. which may have 1 to 7, preferably 1 to 5 halogenatoms and 0075. In this specification, for example, as “5 to 14 the like may be proposed. Specific examples comprise membered aromatic heterocyclyl-carbonyl group', nicoti cyclopropyl. 2,2-difluorocyclopropyl. 2,3-difluorocyclopro noyl, isonicotinoyl, thenoyl, furoyl may be proposed. pyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, 0076. In this specification, for example, as “3 to 14 cycloheptyl and cyclooctyl. membered non-aromatic heterocyclyl-carbonyl group'. 0062. In this specification, for example, as “Co morpholinyl carbonyl, piperidinylcarbonyl, pyrrolidinylcar cycloalkenyl group, cyclopropenyl, cyclobutenyl, cyclo bonyl may be proposed. pentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and the 0077. In this specification, for example, as “mono- or like may be proposed. di-C alkyl-carbamoyl group', methylcarbamoyl, ethylcar US 2016/0326102 A1 Nov. 10, 2016 bamoyl, dimethylcarbamoyl, diethylcarbamoyl N-ethyl-N- 0100 (15) Caryl-carbamoyloxy group (for example, methylcarbamoyl may be proposed. phenylcarbamoyloxy, naphthylcarbamoyloxy), 0078. In this specification, for example, as "mono- or 0101 (16) 5 to 14 membered aromatic heterocyclyl di-Cz aralkyl-carbamoyl group, benzylcarbamoyl, phen carbonyloxy group (for example, nicotinoyloxy), ethylcarbamoyl may be proposed. 0102 (17)3 to 14 membered non-aromatic heterocyclyl 0079. In this specification, for example, as “C alkyl carbonyloxy group (for example, morpholinylcarbonyloxy, Sulfonyl group', methylsulfonyl, ethylsulfonyl, propylsul piperidinylcarbonyloxy), fonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, 0103 (18) Optionally halogenated C. alkylsulfonyloxy tert-butylsulfonyl and the like may be proposed. group (for example, methylsulfonyloxy, trifluoromethylsul 0080. In this specification, for example, as “optionally fonyloxy), halogenated C. alkylsulfonyl group', C alkylsulfonyl I0104 (19) C- arylsulfonyloxy group (for example, group which may have 1 to 7, preferably 1 to 5 halogen phenylsulfonyloxy, toluenesulfonyloxy) optionally Substi atoms and the like may be proposed. Specific examples tuted by C. alkyl group, comprise methylsulfonyl, difluoromethylsulfonyl, trifluo 0105 (20) Optionally halogenated C. alkylthio group, romethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropyl 0106 (21) 5 to 14 membered aromatic heterocyclic sulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentyl grOup, sulfonyl and hexylsulfonyl. 0107 (22) 3 to 14 membered non-aromatic heterocyclic I0081. In this specification, for example, as "Caryl grOup, Sulfonyl group’, phenylsulfonyl, 1-naphthylsulfonyl, (0.108 (23) Formyl group, 2-naphthylsulfonyl and the like may be proposed. 0109 (24) Carboxy group, 0082 In this specification, for example, as “substituent’, 0110 (25) Optionally halogenated C. alkyl-carbonyl halogen atom, cyano group, nitro group, optionally Substi grOup, tuted hydrocarbon group, optionally Substituted heterocyclic 0111 (26) Caryl-carbonyl group, group, acyl group, optionally Substituted amino group, 0112 (27) 5 to 14 membered aromatic heterocyclyl optionally Substituted carbamoyl group, optionally Substi carbonyl group, tuted thiocarbamoyl group, optionally Substituted Sulfamoyl 0113 (28) 3 to 14 membered non-aromatic heterocyclyl group, optionally substituted hydroxy group, optionally Sub carbonyl group, stituted sulfanyl (SH) group, optionally substituted silyl 0114 (29) C- alkoxy-carbonyl group, group and the like may be proposed. 0115 (30) C. aryloxy-carbonyl group (for example 0083. In this specification, for example as “hydrocarbon phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphth group' (including "hydrocarbon group' in “in optionally yloxycarbonyl), Substituted hydrocarbon group'), C alkyl group, C. 0116 (31) Czaralkyloxy-carbonyl group (for example alkenyl group, C2-alkynyl group, Cao cycloalkyl group. benzyloxycarbonyl, phenethyloxycarbonyl), Cao cycloalkenyl group, C-14 aryl group and C7-6 aralkyl 0117 (32) Carbamoyl group, group may be proposed. 0118 (33) Thiocarbamoyl group, 0084. In this specification, for example, as “optionally 0119 (34) Mono- or di-C alkyl-carbamoyl group, substituted hydrocarbon group', optionally substituted 0120 (35) Caryl-carbamoyl group (for example, phe hydrocarbon group selected from the following substituent nylcarbamoyl). group A may be proposed. I0121 (36) 5 to 14 membered aromatic heterocyclyl I0085. Substituent Group A carbamoyl group (for example, pyridylcarbamoyl, thienyl I0086 (1) Halogen atom, carbamoyl), I0087 (2) Nitro group, 0.122 (37) 3 to 14 membered non-aromatic heterocyclyl 0088 (3) Cyano group, carbamoyl group (for example, morpholinylcarbamoyl, pip I0089 (4) Oxo group, eridinylcarbamoyl), 0090 (5) Hydroxy group, (0123 (38) Optionally halogenated C. alkylsulfonyl 0091 (6) Optionally halogenated C. alkoxy group, grOup, 0092 (7) C. aryloxy group (for example, phenoxy, 0.124 (39) C-arylsulfonyl group, naphthoxy), 0.125 (40) 5 to 14 membered aromatic heterocyclylsul 0093 (8) C7 aralkyloxy group (for example, benzy fonyl group (for example, pyridyl Sulfonyl, thienyl Sulfo loxy), nyl), 0094 (9) 5 to 14 membered aromatic heterocyclyl-oxy 0126 (41) Optionally halogenated C. alkylsulfinyl group (for example, pyridyloxy), grOup, 0095 (10) 3 to 14 membered non-aromatic heterocyclyl 0127 (42) Carylsulfinyl group (for example phenyl oxy group (for example, morpholinyloxy, piperidinyloxy), sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl), 0096 (11) C alkyl-carbonyloxy group (for example, I0128 (43) 5 to 14 membered aromatic heterocyclyl acetoxy, propanoyloxy), Sulfinyl group (for example, pyridyl Sulfinyl, thienyl sulfi 0097 (12) C. aryl-carbonyloxy group (for example nyl), benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), I0129 (44) Amino group, 0098 (13)C alkoxy-carbonyloxy group (for example, 0.130 (45) Mono- or di-C alkylamino group (for methoxycarbonyloxy, ethoxycarbonyloxy, propoxy carbo example methylamino, ethylamino, propylamino, isopropy nyloxy, butoxycarbonyloxy), lamino, butylamino, dimethylamino, diethylamino, dipropy 0099 (14) Mono- or di-C alkyl-carbamoyloxy group lamino, dibutylamino, N-ethyl-N-methylamino), (for example, methylcarbamoyloxy, ethylcarbamoyloxy, I0131 (46) Mono- or di-C arylamino group (for dimethylcarbamoyloxy, diethylcarbamoyloxy), example, phenylamino), US 2016/0326102 A1 Nov. 10, 2016

0132 (47) 5 to 14 membered aromatic heterocyclyl purinyl, isoquinolyl, quinolyl, phthalidinyl, naphthyridinyl, amino group (for example, pyridylamino), quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, 3-car 0.133 (48) C7 aralkylamino group (for example, ben bolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazi Zylamino), nyl, phenoxazinyl, etc. may be proposed. 0134 (49) Formylamino group, 0152. In this specification, for example, as “non-aromatic I0135 (50) C alkyl-carbonylamino group (for example, heterocyclic group' (including “3 to 14 membered non acetylamino, propanoylamino, butanoylamino), aromatic heterocyclic group'), 3 to 14 membered (prefer 0136 (51) (C. alkyl) (C. alkyl-carbonyl)amino group ably 4 to 10 membered) non-aromatic heterocyclic group, (for example N-acetyl-N-methylamino), containing 1 to 4 heteroatoms selected from nitrogen atom, 0137 (52) Caryl-carbonylamino group (for example, Sulfur atom and oxygen atom in addition to the carbon atom phenyl carbonylamino, naphthyl carbonylamino), content as ring atoms, may be proposed. 0138 (53) C. alkoxy-carbonylamino group (for 0153. As ideal example of said “non-aromatic heterocy example methoxycarbonylamino, ethoxycarbonylamino, clic group', 3 to 8 membered monocyclic non-aromatic propoxycarbonylamino, butoxycarbonylamino, tert-butoxy heterocyclic group Such as aziridinyl, oxiranyl, thiranyl. carbonylamino), aZetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahy I0139 (54) C. aralkyloxy-carbonylamino group (for drofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazo example benzyloxycarbonylamino), lidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, 0140 (55) C. alkylsulfonylamino group (for example, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahy methylsulfonylamino, ethylsulfonylamino), drooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, 0141 (56) Carylsulfonylamino group (for example, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, phenylsulfonylamino, toluenesulfonylamino) optionally tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyra Substituted by C. alkyl group, nyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, 0142 (57) Optionally halogenated C alkyl group, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl. 0143 (58) Calkenyl group, aZocanyl, diazocanyl, etc.; 0144 (59) C- alkynyl group, 0154 9 to 14 membered condensed polycyclic (prefer (0145 (60) Co cycloalkyl group, ably bicyclic or tricyclic) non-aromatic heterocyclic group 0146 (61) Co cycloalkenyl group, and, such as dihydrobenzofuranyl, dihydrobenzoimidazolyl, 0147 (62) Caryl group. dihydrobenzooxazolyl, dihydrobenzothiazolyl, dihydroben 0148 For example, in “optionally substituted hydrocar Zoisothiazolyl, dihydronaphtho2, 3-bithienyl, tetrahy bon group”, said number of substituents is 1 to 5, preferably droisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indoli 1 to 3. When the number of substituents is 2 or more, each nyl, isoindolinyl, tetrahydrothieno 2, 3-cpyridinyl, substituent may be the same or different. tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahy 0149. In this specification, as "heterocyclic group' (in drophenanthridinyl, hexahydrophenothiazinyl, hexahydro cluding "heterocyclic group” in “optionally substituted het phenoxazinyl, tetrahydrophthalidinyl, tetrahydronaphthy erocyclic group'), for example (i) aromatic heterocyclic ridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, group, (ii) non-aromatic heterocyclic group and (iii) 7-10 tetrahydrocarbazolyl, tetrahydro-3-carbolinyl, tetrahy membered bridged heterocyclic group, each containing droacridinyl, tetrahydrophenazinyl, tetrahydrothioxanethe respectively 1 to 4 heteroatoms selected from oxygen, Sulfur nyl, octahydroisoquinolyl, etc. may be proposed. and nitrogen atoms in addition to the carbon atom content as 0.155. In this specification, as ideal example of “7 to 10 ring atoms, may be proposed. membered bridged heterocyclic group', quinuclidinyl and 0150. In this specification, as “aromatic heterocyclic 7-azabicyclo[2.2.1]heptanyl may be proposed. group' (including “5-14 membered aromatic heterocyclic 0156. In this specification, as “nitrogen-containing het group'. 5 to 14 membered (preferably 5 to 10 membered) erocyclic group', those groups among "heterocyclic groups” aromatic heterocyclic group containing 1 to 4 heteroatoms that contain at least one nitrogen atom as ring atom content selected from nitrogen atom, Sulfur atom and oxygen atom may be proposed. in addition to the carbon atom content as ring atoms, may be proposed. 0157. In this specification, for example, as “optionally 0151. As ideal examples of said “aromatic heterocyclic Substituted heterocyclic group', heterocyclic groups option group'. 5 to 6 membered monocyclic aromatic heterocyclic ally substituted by substituent(s) selected from said substitu groups such as thienyl, furyl, pyrrolyl, imidazolyl pyra ent group A may be proposed. Zolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl pyridyl, 0158. The number of substituents in “optionally substi pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1.3, tuted heterocyclic group' is for example 1 to 3. When the 4-oxadiazolyl, 1,2,4-thiadiazolyl, 1.3,4-thiadiazolyl, triaz number of substituents is 2 or more, each substituent may be olyl, tetrazolyl, triazinyl etc.; 8 to 14 membered condensed the same or different. polycyclic (preferably bicyclic or tricyclic) aromatic hetero 0159. In this specification, as “acyl group', for example, cyclic group Such as benzothiophenyl, benzofuranyl, benz formyl group, carboxy group, carbamoyl group, thiocarbam imidazolyl, benZOxazolyl, benzoisoxazolyl, benzothiazolyl, oyl group, Sulfino group, Sulfo group, Sulfamoyl group and benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thien phosphono group, each respectively optionally substituted opyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridi by "1 or 2 substituents selected from C alkyl group, C nyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, alkenyl group, Co cycloalkyl group, Co cycloalkenyl imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, group, C-14 aryl group, C7-16 aralkyl group, 5 to 14 mem pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidi bered aromatic heterocyclic group and 3 to 14 membered nyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho2, 3-b non-aromatic heterocyclic group, which may each further thienyl, phenoxathienyl, indolyl, isoindolyl, 1H-indazolyl, have 1 to 3 Substituent(s) selected from halogen atoms, US 2016/0326102 A1 Nov. 10, 2016 optionally halogenated C. alkoxy group, hydroxy group, group, which substituents may each respectively be substi nitro group, cyano group, amino group and carbamoyl tuted by 1-3 substituents selected from substituent group A” group, may be proposed. may be proposed. 0160 Moreover, as “acyl group', hydrocarbon-sulfonyl 0164. As ideal examples of an optionally substituted group, heterocyclyl-Sulfonyl group, hydrocarbon-sulfinyl amino group, an amino group, mono- or di-(optionally group, heterocyclyl-sulfinyl group may also be proposed. halogenated C. alkyl)amino group (for example, methyl 0161 Wherein, as hydrocarbon-sulfonyl group, a sulfo amino, trifluoromethylamino, dimethylamino, ethylamino, nyl group bonded with a hydrocarbon group; as heterocy diethylamino, propylamino, dibutylamino), mono- or clyl-Sulfonyl group, a Sulfonyl group bonded with a hetero di-C alkenylamino group (for example, diallylamino), cyclic group; as hydrocarbon-sulfinyl group, a Sulfinyl group mono- or di-Clio cycloalkylamino group (for example, bonded with a hydrocarbon group; as heterocyclyl-sulfinyl cyclopropylamino, cyclohexylamino), mono- or di-Ca group, a sulfinyl group bonded with a heterocyclic group are arylamino group (for example, phenylamino), mono- or respectively denoted. di-C, aralkylamino group (for example, benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 0162 Ideal examples of “acyl group' include formyl alkyl)-carbonylamino group (for example, acetylamino, pro group, carboxy group, C- alkyl-carbonyl group, C2-alk pionylamino), mono- or di-Caryl-carbonylamino group enyl-carbonyl group (for example, crotonoyl), Co (for example, benzoylamino), mono- or di-C. aralkyl cycloalkyl-carbonyl group (for example cyclobutanecarbo carbonylamino group (for example, benzylcarbonylamino), nyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclohep mono- or di-5 to 14 membered aromatic heterocyclyl tanecarbonyl), Cocycloalkenyl-carbonyl group (for carbonylamino group (for example, nicotinoylamino, isoni example 2-cyclohexenecarbonyl), C aryl-carbonyl cotinoylamino), mono- or di-3 to 14 membered non-aro group, Cz-e aralkyl-carbonyl group, 5 to 14 membered matic heterocyclyl-carbonylamino group (for example, aromatic heterocyclyl-carbonyl group, 3 to 14 membered piperidinyl carbonylamino), mono- or di-C alkoxy-carbo non-aromatic heterocyclyl-carbonyl group, Calkoxy-car nylamino group (for example tert-butoxycarbonylamino), 5 bonyl group, C. aryloxy-carbonyl group (for example, to 14 membered aromatic heterocyclyl-amino group (for phenyloxycarbonyl, naphthyloxycarbonyl), C. aralky example, pyridylamino), carbamoylamino group, (mono- or loxy-carbonyl group (for example, benzyloxycarbonyl, di-C alkyl-carbamoyl)amino group (for example, methyl phenethyloxycarbonyl), carbamoyl group, mono- or di-C carbamoylamino), (mono- or di-C. aralkyl-carbamoyl) alkyl-carbamoyl group, mono- or di-C alkenyl-carbamoyl amino group (for example, benzylcarbamoylamino), C. group (for example, diallylcarbamoyl), mono- or di-Co alkylsulfonylamino group (for example, methylsulfo cycloalkyl-carbamoyl group (for example, cyclopropylcar nylamino, ethylsulfonylamino), C arylsulfonylamino bamoyl), mono- or di-C aryl-carbamoyl group (for group (for example, phenylsulfonylamino), (C. alkyl) example, phenylcarbamoyl), mono- or di-C, aralkyl-car (C. alkyl-carbonyl)amino group (for example N-acetyl bamoyl group, 5 to 14 membered aromatic heterocyclyl N-methylamino), (C. alkyl) (C. aryl-carbonyl)amino carbamoyl group (for example, pyridylcarbamoyl), thiocar group (for example N-benzoyl-N-methylamino) may be bamoyl group, mono- or di-C alkyl-thiocarbamoyl group (for example methylthiocarbamoyl N-ethyl-N-methylthio proposed. carbamoyl), mono- or di-C alkenyl-thiocarbamoyl group 0.165. In this specification, as “optionally substituted car (for example, diallylthiocarbamoyl), mono- or di-Co bamoyl group', for example, a carbamoyl group optionally cycloalkyl-thiocarbamoyl group (for example, cyclopropy substituted by "1 or 2 substituent(s) selected from C alkyl lthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C- group, C2-alkenyl group, Calocycloalkyl group, C-14 aryl 14 aryl-thiocarbamoyl group (for example, phenylthiocar group. Czaralkyl group, Calkyl-carbonyl group, Ca bamoyl), mono- or di-C. aralkyl-thiocarbamoyl group aryl-carbonyl group, C. aralkyl-carbonyl group, 5 to 14 (for example, benzylthiocarbamoyl, phenethylthiocarbam membered aromatic heterocyclyl-carbonyl group, 3 to 14 oyl), 5 to 14 membered aromatic heterocyclyl-thiocarbam membered non-aromatic heterocyclyl-carbonyl group, C. oyl group (for example, pyridylthiocarbamoyl), Sulfino alkoxy-carbonyl group, 5 to 14 membered aromatic hetero group, Calkylsulfinyl group (for example, methylsulfinyl, cyclic group, carbamoyl group, mono- or di-C alkyl ethyl Sulfinyl), Sulfo group, Ce alkylsulfonyl group, Ca carbamoyl group and mono- or di-C7 aralkyl-carbamoyl aryl Sulfonyl group, phosphono group, mono- or di-C group, each of which Substituents may be optionally Sub alkyl phosphono group (for example, dimethylphosphone, stituted by 1 to 3 substituent(s) selected from substituent diethylphosphone, diisopropylphosphone and dibutyl group A” may be proposed. phosphono) may be proposed. 0166 As ideal examples of optionally substituted car 0163. In this specification, for example, as “optionally bamoyl group, carbamoyl group, mono- or di-C alkyl Substituted amino group', an amino group which may have carbamoyl group, mono- or di-C alkenyl-carbamoyl "1 or 2 substituents selected from C alkyl group, C group (for example, diallylcarbamoyl), mono- or di-Co alkenyl group, Cao cycloalkyl group, C-14 aryl group. cycloalkyl-carbamoyl group (for example, cyclopropylcar C7-6 aralkyl group, Co alkyl-carbonyl group, C-14 aryl bamoyl cyclohexylcarbamoyl), mono- or di-Caryl-car carbonyl group, Cz aralkyl-carbonyl group, 5 to 14 mem bamoyl group (for example, phenylcarbamoyl), mono- or bered aromatic heterocyclyl-carbonyl group, 3 to 14 mem di-C. aralkyl-carbamoyl group, mono- or di-C alkyl bered non-aromatic heterocyclyl-carbonyl group, C. carbonyl-carbamoyl group (for example, acetylcarbamoyl, alkoxy-carbonyl group, 5 to 14 membered aromatic hetero propionylcarbamoyl), mono- or di-C aryl-carbonyl-car cyclic groups, carbamoyl group, mono- or di-C alkyl bamoyl group (for example, benzoylcarbamoyl), and 5 to 14 carbamoyl group, mono- or di-Caralkyl-carbamoyl membered aromatic heterocyclyl-carbamoyl group (for group, Ce alkylsulfonyl group and C. aryl Sulfonyl example, pyridylcarbamoyl) may be proposed. US 2016/0326102 A1 Nov. 10, 2016

0167. In this specification, as “optionally substituted thio Substituent selected from C alkyl group, Ce alkenyl carbamoyl group', for example, a thiocarbamoyl group group, Co cycloalkyl group, C-14 aryl group, C7-16 aralkyl which may have "1 or 2 substituent(s) selected from C. group, C-alkyl-carbonyl group, C-aryl-carbonyl group. alkyl group, Ce alkenyl group, Cocycloalkyl group. C. aralkyl-carbonyl group, 5 to 14 membered aromatic C-1 aryl group, C7-6 aralkyl group, Co alkyl-carbonyl heterocyclyl-carbonyl group, 3 to 14 membered non-aro group. C. aryl-carbonyl group, C7 aralkyl-carbonyl matic heterocyclyl-carbonyl group, Ce alkoxy-carbonyl group, 5 to 14 membered aromatic heterocyclyl-carbonyl group, 5 to 14 membered aromatic heterocyclic group, group, 3 to 14 membered non-aromatic heterocyclyl-carbo carbamoyl group, mono- or di-C alkyl-carbamoyl group, nyl groups, Calkoxy-carbonyl group, 5 to 14 membered mono- or di-C7-caralkyl-carbamoyl group, Ce alkylsulfo aromatic heterocyclic group, carbamoyl group, mono- or di-C alkyl-carbamoyl group and mono- or di-C- nyl group and Caryl Sulfonyl group, wherein each of aralkyl-carbamoyl group', wherein each of such Substituents such substituent may respectively have 1 to 3 substituent(s) may respectively have 1 to 3 substituent(s) selected from selected from Substituent group A” may be proposed. Substituent group A” and may be proposed. 0172 Ideal examples of optionally substituted hydroxy 0168 Ideal examples of optionally substituted thiocar group comprise a hydroxy group, Co alkoxy group, C2 bamoyl group comprise a thiocarbamoyl group, mono- or alkenyloxy group (for example, allyloxy, 2-butenyloxy, di-C alkyl-thiocarbamoyl group (for example, methylth 2-pentenyloxy, 3-hexenyloxy), Cocycloalkyloxy group iocarbamoyl ethylthiocarbamoyl, dimethylthiocarbamoyl, (for example, cyclohexyloxy), C aryloxy group (for diethylthiocarbamoyl N-ethyl-N-methylthiocarbamoyl), example, phenoxy, naphthyloxy), Cz-e aralkyloxy group mono- or di-C alkenyl-thiocarbamoyl group (for example, (for example, benzyloxy, phenethyloxy), C alkyl-carbo diallylthiocarbamoyl), mono- or di-Cocycloalkyl-thiocar nyloxy group (for example, acetyloxy, propionyloxy, bamoyl group (for example, cyclopropylthiocarbamoyl, butyryloxy, isobutyryloxy, pivaloyloxy), Caryl-carbony cyclohexylthiocarbamoyl), mono- or di-C aryl-thiocar loxy group (for example, benzoyloxy), C, aralkyl-carbo bamoyl group (for example, phenylthiocarbamoyl), mono nyloxy group (for example, benzylcarbonyloxy), 5 to 14 or di-Caralkyl-thiocarbamoyl group (for example, ben membered aromatic heterocyclyl-carbonyloxy group (for Zylthiocarbamoyl phenethylthiocarbamoyl), mono- or example, nicotinoyloxy), 3 to 14 membered non-aromatic di-C alkyl-carbonyl-thiocarbamoyl group (for example, heterocyclyl-carbonyloxy group (for example, piperidinyl acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or carbonyloxy), C alkoxy-carbonyloxy group (for example di-Cola aryl-carbonyl-thiocarbamoyl group (for example, tert-butoxycarbonyloxy). 5 to 14 membered aromatic het benzoylthiocarbamoyl), and 5 to 14 membered aromatic erocyclyl-oxy group (for example, pyridyloxy), carbamoy heterocyclyl-thiocarbamoyl group (for example, pyridylth loxy group, Ce alkyl-carbamoyloxy group (for example, iocarbamoyl). methylcarbamoyloxy), C. aralkyl-carbamoyloxy group 0169. In this specification, as "optionally substituted sul (for example, benzylcarbamoyloxy), C alkylsulfonyloxy famoyl group', a Sulfamoyl group which may have 1 or 2 group (for example, methylsulfonyloxy, ethylsulfonyloxy) Substituent(s) selected from C alkyl group, Ce alkenyl and Carylsulfonyloxy group (for example, phenylsulfo group, C-10 cycloalkyl group, C-14 aryl group, C7-16 aralkyl nyloxy). group, C-alkyl-carbonyl group, C-aryl-carbonyl group. 0173. In this specification, as "optionally substituted sul Czaralkyl-carbonyl group, 5 to 14 membered aromatic fanyl group', for example, Sulfanyl group which may have heterocyclyl-carbonyl group, 3 to 14 membered non-aro “a substituent selected from C alkyl group, Calkenyl matic heterocyclyl-carbonyl group, C alkoxy-carbonyl group, C-10 cycloalkyl group, C-14 aryl group, C7-16 aralkyl group, 5 to 14 membered aromatic heterocyclic group, group, C- alkyl-carbonyl group, C-14 aryl-carbonyl group carbamoyl group, mono- or di-C alkyl-carbamoyl group and 5 to 14 membered aromatic heterocyclic group, wherein and mono- or di-Ca-aralkyl-carbamoyl group, wherein each of such substituents may respectively have 1 to 3 each of such substituents may respectively have 1 to 3 Substituents selected from Substituent group A” and haloge substituent(s) selected from substituent group A” may be nated Sulfanyl group may be proposed. proposed. 0170 Ideal examples of optionally substituted sulfamoyl 0.174 Ideal examples of optionally substituted sulfanyl group comprise a sulfamoyl group, mono- or di-C alkyl group comprise a sulfanyl (—SH) group, Calkylthio Sulfamoyl group (for example, methylsulfamoyl ethylsul group, Calkenylthio group (for example allylthio. 2-bute famoyl, dimethylsulfamoyl, diethylsulfamoyl N-ethyl-N- nylthio. 2-pentenylthio, 3-hexenylthio), Co cycloalkylthio methylsulfamoyl), mono- or di-C alkenyl-Sulfamoyl group (for example, cyclohexylthio), C arylthio group group (for example, diallylsulfamoyl), mono- or di-Co (for example, phenylthio, naphthylthio), C. aralkylthio cycloalkyl-sulfamoyl group (for example, cyclopropylsulfa group (for example, benzylthio, phenethylthio), C alkyl moyl, cyclohexylsulfamoyl), mono- or di-C aryl-sulfa carbonylthio group (for example, acetylthio, propionylthio. moyl group (for example, phenylsulfamoyl), mono- or butyrylthio, isobutyrylthio, pivaloylthio), C aryl-carbo di-C. aralkyl-sulfamoyl group (for example, benzylsulfa nylthio group (for example, benzoylthio), 5 to 14 membered moyl phenethylsulfamoyl), mono- or di-C alkyl-carbo aromatic heterocyclyl-thio group (for example, pyridylthio) nyl-Sulfamoyl group (for example, acetylsulfamoyl, propio and halogenated thio group (for example, pentafluorothio). nylsulfamoyl), mono- or di-C aryl-carbonyl-Sulfamoyl 0.175. In this specification, as “optionally substituted silyl group (for example, benzoylsulfamoyl) and 5 to 14 mem group', for example, a silyl group which may have "1 to 3 bered aromatic heterocyclyl-sulfamoyl group (for example, Substituent(s) selected from C alkyl group, Ce alkenyl pyridylsulfamoyl). group, C-10 cycloalkyl group, C-14 aryl group and C7-16 0171 In this specification, as “optionally substituted aralkyl group, which respectively may have 1 to 3 Substitu hydroxy group', an hydroxy group which may have “a ent(s) selected from Substituent group A” may be proposed. US 2016/0326102 A1 Nov. 10, 2016

0176). As ideal examples of optionally substituted silyl naphtho2, 3-bithiophene, phenoxathiin, indole, isoindole, group, a tri-C alkylsilyl group (for example trimethylsilyl 1H-indazole, purine, isoquinoline, quinoline, phthalazine, and tert-butyl (dimethyl)silyl) may be proposed. naphthyridine, quinoxaline, quinazoline, cinnoline, carba (0177. In this specification, as “C alkylene group', for Zole, B-carboline, phenanthridine, acridine, phenazine, phe example, —CH2—, —(CH) , —(CH2). , —(CH) , nothiazine, phenoxazine, etc. may be proposed. —(CH2)5 , —(CH) , —CH(CH)— —(CCH) , 0186. In this specification, as “non-aromatic hetero —CH(CHs)— —CH(CH,)— —CH(CH(CH))—, cycle', for example, 3 to 14 membered (preferably 4 to 10 —(CH(CH) , —CH2—CH(CH) , —CH(CH)— membered) non-aromatic heterocycles containing 1 to 4 CH , —CH2—CH2—C(CH) , —C(CH) CH heteroatom(s) selected from nitrogen atom, Sulfur atom and oxygen atom in addition to the carbon atom content as ring CH-CH-CH - may be proposed. atoms may be proposed. As ideal examples of said “non 0178. In this specification, as “C alkenylene group', aromatic heterocycle', 3 to 8 membered monocyclic non for example, —CH=CH , —CH2—CH=CH aromatic heterocycles Such as aziridine, oxirane, thirane, -CH=CH-CH , —C(CH) CH=CH-, aZetidine, oxetane, thietane, tetrahydrothiophene, tetrahy —CH=CH-C(CH) , —CH2—CH=CH-CH . drofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, —CH CH-CH=CH-, -CH=CH-CH, CH, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, CH-CH CH-CH , -CH=CH-CH CH thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetra CH , —CH2—CH2—CH2—CH=CH may be pro hydroisoxazole, piperidine, piperazine, tetrahydropyridine, posed. dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, 0179. In this specification, as “C alkynylene group', tetrahydropyridazine, dihydropyran, tetrahydropyran, tetra for example, C=C , CH-C=C , C=C hydrothiopyran, morpholine, thiomorpholine, azepanine, CH2—, (CCH) C=C , C=C-(CH) , diazepane, azepine, azocane, diazocane, Oxepane, etc., and, —CH2—C=C CH , —CH, CH, C=C, 0187 9 to 14 membered condensed polycyclic (prefer C=C CH-CH , C=C C=C , -C=C ably bi- or tri-cyclic) non-aromatic heterocycles such as CH2—CH2—CH2—, CH, CH, CH, C=C may dihydrobenzofuran, dihydrobenzoimidazole, dihydrobenzo be proposed. xazole, dihydrobenzothiazole, dihydrobenzoisothiazole, 0180. In this specification, as “hydrocarbon ring, for dihydronaphtho2, 3-bithiophene, tetrahydroisoquinoline, example, C. aromatic hydrocarbon ring, Co cycloal tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, kane and Co cycloalkene may be proposed. tetrahydrothieno 2, 3-cpyridine, tetrahydrobenzoazepine, 0181. In this specification, as "C. aromatic hydrocar tetrahydroquinoxaline, tetrahydrophenanthridine, hexahy bon ring, for example, benzene and naphthalene may be drophenothiazine, hexahydrophenoxazine, tetrahy proposed. drophthalazine, tetrahydronaphthyridine, tetrahydroqui 0182. In this specification, as "Co cycloalkane', for nazoline, tetrahydrocinnoline, tetrahydrocarbozole, example, cyclopropane, cyclobutane, cyclopentane, cyclo tetrahydro-P3-carboline, tetrahydroacridine, tetrahydro hexane, cycloheptane and cyclooctane may be proposed. phenazine, tetrahydrothioxanthene, octahydroisoquinoline, 0183 In this specification, as "Co cycloalkene', for etc. may be proposed. example, cyclopropene, cyclobutene, cyclopentene, cyclo 0188 In this specification, as “nitrogen-containing het hexene, cycloheptene and cyclooctene may be proposed. erocycle’, among "heterocycle', those containing at least 1 0184. In this specification, as "heterocycle', for example, nitrogen atom as ring atoms may be proposed. aromatic heterocycles and non-aromatic heterocycles 0189 In this specification, as represented in the following respectively containing 1 to 4 heteroatom(s) selected from nitrogen atom, Sulfur atom and oxygen atom in addition to formulae, when a non-aromatic bond Q condensed with an the carbon atom content as ring atoms may be proposed. aromatic ring Q' is present, the non-aromatic ring Q forms 0185. In this specification, as “aromatic heterocycle', for a ring in which the bond C'C' is a double bond. example 5 to 14 membered (preferably 5 to 10 membered) aromatic heterocycles containing 1 to 4 heteroatom(s) selected from nitrogen atom, Sulfur atom and oxygen atom in addition to the carbon atom content as ring atoms may be C3 2 CS-2 proposed. Ideal examples of said “aromatic heterocycle” O)O)Salt - OO- Q II, QN comprise 5 to 6 membered monocyclic aromatic hetero cycles Such as thiophene, furan, pyrrole, imidazole, pyra 0190. For example, when said condensed ring QQ' is an Zole, thiazole, isothiazole, oxazole, isoxazole, pyridine, indane ring, a depiction is used whereby the non-aromatic pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1.3,4- ring Q is cyclopentene ring, and the aromatic ring Q' is oxadiazole, 1,2,4-thiadiazole, 1.36.4-thiadiazole, triazole, benzene. tetrazole, triazine, etc.; and 8 to 14 membered condensed polycyclic (preferably bi- or tri-cyclic) aromatic hetero 0191 The definition of each symbol in formula (I) will cycles such as benzothiophene, benzofuran, benzimidazole, now be described in detail. benzoxazole, benzoisoxazole, benzothiazole, benzoisothiaz 0.192 Ring A is an optionally substituted 5 or 6 mem ole, benzotriazole, imidazopyridine, thienopyridine, furo bered ring. pyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyri (0193 As “5 or 6 membered ring of “optionally further dine, thiazolopyridine, imidazopyrazine, substituted 5 or 6 membered ring represented by Ring A, a imidazopyrimidine, thienopyrimidine, furopyrimidine, pyr benzene ring, Cse cycloalkene, 5 or 6 membered monocy rolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, clic aromatic heterocycle and 5 to 6 membered monocyclic thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, non-aromatic heterocycle may be proposed. US 2016/0326102 A1 Nov. 10, 2016

0194 As said Cse cycloalkene, a 5 or 6 membered membered (preferably 4-10 membered) non-aromatic het cycloalkene among said “Clio cycloalkene' may be pro erocycle, preferably a 3-8 membered monocyclic non-aro posed. matic heterocycle (for example, dioxolane). 0.195 As far as said 5 to 6 membered monocyclic aro 0211) R' and R are more preferably independently, a matic heterocycle is concerned, 5 to 6 membered monocycle hydrogen atom or a hydroxy group (preferably, both are of said “aromatic heterocycle' may be proposed. hydrogen atoms, or the one is a hydrogenatom and the other 0196. As far as said 5-6 membered monocyclic non is a hydroxy group) or R' and R may bond together to form aromatic heterocycle is concerned, 5 to 6 membered mono a 3 to 14 membered (preferably 4 to 10 membered) non cycle of said “non-aromatic heterocycle' may be proposed. aromatic heterocycle, preferably a 3 to 8 membered mono (0197) The “5 or 6 membered ring of “optionally further cyclic non-aromatic heterocycle (for example, dioxolane), substituted 5 or 6 membered ring represented by Ring A which is optionally substituted by 1 to 3 C alkyl group(s) may be further substituted by substituent selected from, for (for example, methyl), optionally substituted by 1 to 3 example, said Substituent group A, wherein the number of Substituent(s) selected from a hydroxy group and a C substituents is, for example, 1 to 3. When the number of alkoxy group (for example, methoxy). Substituents is 2 or more, each Substituent may be the same 0212. Still more preferably, (1) R' and Rare both hydro or different. gen atoms, or (2) one of R' and R is a hydrogen atom, and 0198 Ring A is preferably optionally further substituted the other is a hydroxy group, or R' and R may bond together Cs cycloalkene (for example, cyclopentene, cyclohexene). to form a 3 to 8 membered monocyclic non-aromatic het 0199 Ring A is more preferably Cs cycloalkene (for erocycle (for example, dioxolane), which is optionally Sub example cyclopentene, cyclohexene). stituted by 1 to 3 C alkyl group(s) (for example, methyl), 0200 Ring A is still more preferably cyclopentene or optionally substituted by 1 to 3 substituent(s) selected from cyclohexene. a hydroxy group and a C- alkoxy group (for example, 0201 Ring A is particularly preferably cyclopentene. methoxy). 0202 Ring B is an optionally substituted benzene ring. 0213 Particularly preferably, R and R may bond 0203 The “benzene ring of “optionally substituted ben together to form a 3 to 14 membered (preferably 4 to 10 Zene ring represented by Ring B, for example, may be membered) non-aromatic heterocycle (preferably 3 to 8 substituted by substituent or substituents selected from said membered monocyclic non-aromatic heterocycle (for substituent group A, wherein the number of substituents is example, dioxolane)), which is optionally substituted by 1 to for example 1 to 3. When the number of substituents is 2 or 3 C. alkyl group(s) (for example, methyl), optionally more, each substituent may be the same or different. substituted by 1 to 3 substituent(s) selected from a hydroxy 0204 Ring B is preferably a benzene ring optionally group and a C- alkoxy group (for example, methoxy). substituted by 1 to 3 substituent(s) selected from (1) a 0214 W is CH, NH or O. halogen atom (for example, fluorine atom, chlorine atom, 0215 W is preferably CH, or O. bromine atom), and, (2) a C- alkyl group (for example, 0216 W is more preferably CH. methyl). 0217 R is a substituent. 0205 Ring B is more preferably a benzene ring option (0218 R is preferably an optionally substituted hydroxy ally substituted by 1 to 3 halogen atom(s) (for example group. Substituent (Substituent group A) on the optionally fluorine atom, chlorine atom). substituted hydroxy group may also be substituted by sub (0206) R' and Rare independently a hydrogen atom or a stituent selected from substituent group A, wherein the substituent, or R' and R may bond together to form an number of substituents is, for example, 1 to 3. When the optionally Substituted ring. number of substituents is 2 or more, each substituent may be 0207 As the “ring of “optionally substituted ring the same or different. formed by R' and R bonding together, non-aromatic hydro (0219 R is more preferably an optionally substituted C. carbon ring (Cso cycloalkane, Cao cycloalkene) and non alkoxy group (for example, methoxy, ethoxy). aromatic heterocycle may be proposed. 0220 R is further more preferably a C- alkoxy group 0208. The “ring of “optionally substituted ring formed (for example, methoxy, ethoxy) optionally substituted by 1 by R' and R bonding together, for example, may be sub to 3 Co cycloalkyl group(s) (for example, cyclopropyl) stituted by substituent or substituents selected from said optionally Substituted by 1 to 3 C alkyl group(s) (for substituent group A, wherein the number of substituents is example, methyl). for example 1 to 3. When the number of substituents is 2 or 0221) R' is still more preferably a Calkoxy group (for more, each substituent may be the same or different. More example, ethoxy). over, said Substituent group A may also be substituted by 0222. The following compounds may be proposed as Substituent or Substituents selected from Substituent group A, wherein the number of substituents is for example 1 to 3. ideal compounds (I). When the number of substituents is 2 or more, each sub 0223 Compound a stituent may be the same or different. 0224 Compound (I), 0209. The “ring” of “optionally substituted ring formed 0225 wherein, by R' and R bonding together is preferably a 3 to 14 0226 Ring A is Cse cycloalkene (for example, cyclopen membered (preferably 4 to 10 membered) non-aromatic tene, cyclohexene) which may be further substituted, heterocycle, more preferably a 3 to 8 membered monocyclic 0227 Ring B is optionally substituted benzene ring, non-aromatic heterocycle (for example, dioxolane). (0228) R' and R are independently hydrogen atom or 0210) R' and Rare preferably independently a hydrogen optionally substituted hydroxy group, or R' and R may atom or an optionally substituted hydroxy group or R' and bond together to form an optionally substituted 3 to 14 R may bond together to form an optionally substituted 3-14 membered (preferably 4 to 10 membered) non-aromatic US 2016/0326102 A1 Nov. 10, 2016 heterocycle, preferably a 3 to 8 membered monocyclic Substituted by 1 to 3 C alkyl group(s) (for example, non-aromatic heterocycle (for example, dioxolane), methyl) optionally substituted by 1 to 3 substituent(s) 0229 W is CH or O, and, selected from a hydroxy group and a C- alkoxy group (for 0230 R is an optionally substituted C. alkoxy group example, methoxy), (for example, methoxy, ethoxy). (0256 W is CH, and, 0231 Compound B (0257 R is a C- alkoxy group (for example, ethoxy). 0232 Compound (I), 0258. The compounds of Example 1-21 may be proposed 0233 wherein, as specific examples of said compound (I). 0234 Ring A is Cse cycloalkene (for example cyclopen (0259 Among them, ethyl (2R,3R,8R)-8-(((1S)-7-chloro tene, cyclohexene), 2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxym 0235 Ring B is a benzene ring optionally substituted by ethyl)-1,4-dio xaspiro4.5 dec-6-ene-7-carboxylate (Ex 1 to 3 substituent(s) selected from ample 6), ethyl (2R.3R8R)-8-(((1S)-7-chloro-5-fluoro-2,3- 0236 (1) a halogen atom (for example, fluorine atom, dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)- chlorine atom, bromine atom), and, 1,4-dioxaspiro4.5dec-6-ene-7-carboxylate (Example 14), 0237 (2) a C- alkyl group (for example, methyl), and ethyl (2R,3R8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-in 0238) R' and Rare independently a hydrogen atom or a den-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1,4-dio xaspiro hydroxy group (preferably, both are hydrogen atom or the 4.5 dec-6-ene-7-carboxylate (Example 21) are preferable. one is a hydrogen atom and the other is a hydroxy group) or 0260. When compound (I) is a salt, as such salts, for R" and R may bond together to form a 3-14 membered example, metal salts, ammonium salts, salts with organic (preferably 4-10 members) non-aromatic heterocycle (pref bases, salts with inorganic acids, salts with organic acids, erably 3-8 membered monocyclic non-aromatic heterocycle salts with basic or acidic amino acids, etc., may be proposed. (for example, dioxolane)) optionally substituted by 1 to 3 Ideal examples of metal salts include alkali metal salts such C. alkyl group(s) (for example, methyl), optionally sub as sodium salts, potassium salts, etc., alkaline earth metal stituted by 1 to 3 substituent(s) selected from a hydroxy salts such as calcium salts, magnesium salts, barium salts, group and a C- alkoxy group (for example, methoxy), etc., aluminum salts, etc. Ideal examples of salts with 0239 W is CH or O, and, organic base include salts with, for example, trimethylam (0240 R is a C- alkoxy group (for example, methoxy, ine, triethylamine, pyridine, picoline, 2, 6-lutidine, etha ethoxy) optionally Substituted by 1 to 3 Cocycloalkyl nolamine, diethanolamine, triethanolamine, cyclohexylam group(s) (for example, cyclopropyl) optionally Substituted ine, dicyclohexylamine, N, N'-dibenzylethylenediamine, by 1 to 3 C alkyl group(s) (for example, methyl). etc. Ideal examples of salts with inorganic acids, include 0241 Compound C salts with, for example, hydrochloric acid, hydrobromic 0242 Compound (I), acid, nitric acid, Sulfuric acid, phosphoric acid, etc. Ideal 0243 wherein, examples of salts with organic acids, include salts with, for 0244 Ring A is cyclopentene or cyclohexene, example, formic acid, acetic acid, trifluoroacetic acid, 0245 Ring B is a benzene ring optionally substituted by phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic 1 to 3 substituent(s) selected from acid, citric acid, Succinic acid, malic acid, methanesulfonic 0246 (1) a halogen atom (for example, fluorine atom, acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. chlorine atom, bromine atom), and, 0261) Ideal examples of salts with basic amino acids, 0247 (2) a C- alkyl group (for example, methyl), include salts with, for example, arginine, lysine, ornithine, 0248. As to R' and R. (1) R' and Rare both hydrogen etc., and as ideal examples of salts with acidic amino acids, atoms, or (2) one of R and R is a hydrogen atom, and the salts with, for example, aspartic acid, glutamic acid, etc. may other is a hydroxy group, or R' and R may bond together to be proposed. form a 3 to 8 membered monocyclic non-aromatic hetero 0262 Among these, pharmacologically permitted salts cycle (for example, dioxolane), which is optionally Substi are preferred. For example, when the compound has acid tuted by 1 to 3 C alkyl group(s) (for example, methyl). functionality, inorganic salts such as alkali metal salts (for optionally substituted by 1 to 3 substituent(s) selected from example, Sodium salt, potassium salt, etc.), alkaline earth a hydroxy group and a C- alkoxy group (for example, metal salts (for example, calcium salt, magnesium salt, etc.), methoxy), etc. and ammonium salts may be proposed; and when the 0249 W is CH or O, and, compound has basic functionality, Salts with inorganic acids (0250 R is a C alkoxy group (for example, methoxy, Such as hydrochloric acid, hydrobromic acid, nitric acid, ethoxy) optionally Substituted by 1 to 3 Cocycloalkyl Sulfuric acid, phosphoric acid, etc., and salts with organic group(s) (for example, cyclopropyl) optionally Substituted acids such as acetic acid, phthalic acid, fumaric acid, oxalic by 1 to 3 C alkyl group(s) (for example, methyl). acid, tartaric acid, maleic acid, citric acid. Succinic acid, 0251 Compound D methanesulfonic acid, benzenesulfonic acid, p-toluenesulfo 0252 Compound (I), wherein, nic acid, etc. may be proposed. 0253 Ring A is Cse cycloalkene (for example, cyclopen 0263. Processes for Production tene, cyclohexene), 0264. Processes for the production of the compounds of 0254 Ring B is a benzene ring optionally substituted by the present invention will now be described. 1 to 3 halogen atom(s) (for example fluorine atom, chlorine 0265 Starting materials and reagents used in any of the atom), steps in the following processes for production and the 0255) R' and R may bond together to form a 3 to 14 obtained compounds may be in the form of a respective salt. membered (preferably 4 to 10 membered) non-aromatic As examples of such salts, the same kinds of salts as the said heterocycle (preferably 3 to 8 membered monocyclic non salts of the compounds of the present invention may be aromatic heterocycle (for example, dioxolane)), optionally proposed. US 2016/0326102 A1 Nov. 10, 2016

0266. When the compound obtained in any of the steps is 0279 Amides: N,N-dimethylformamide, N-methylpyr the free compound, said free compound can be converted to rolidone, etc., a target salt using by itself a well-known process. Con 0280 Halogenated hydrocarbons: , car versely, when the compound obtained in any of the steps is bon tetrachloride, etc., a salt, said salt can be converted to the free body or another 0281 Nitriles: acetonitrile, etc., type of intended salt by itself well-known process. 0282. Sulfoxides: dimethyl sulfoxide, etc., 0267. The compound obtained in any of the steps may be 0283 Aromatic organic bases types: pyridine, etc., used in the following reaction either still in the form of the 0284 Acid anhydrides: acetic anhydride, etc., reaction liquid, or after obtaining the crude product. Alter 0285 Organic acids: formic acid, acetic acid, trifluoro natively, the compound obtained in each of the steps can be acetic acid, etc., isolated and/or purified from the reaction mixture by a 0286 Inorganic acids: hydrochloric acid, sulfuric acid, separation means such as concentration, crystallization, etc recrystallization, distillation, Solvent extraction, fractionat ing, chromatography, etc. in accordance with conventional 0287 Esters: ethyl acetate, etc., procedures. 0288 Ketones: , methyl ethyl ketone, etc., 0268 If a raw material or reagent in any of the steps is a 0289 Water. marketed, commercial product, then such a product can be 0290 Said solvents may be used in a combination of two used. or more thereof in suitable proportions. 0269. In the reactions in any of the steps, the reaction 0291. When base is used in the reactions in any of the time can differ depending on the reagent and solvent used, steps, for example, a base shown below or a base described but unless otherwise specifically stated, said reaction time is in the Examples may be used. usually 1 min to 48 hours, preferably 10 mins to 8 hours. 0292 Inorganic bases: Sodium hydroxide, magnesium 0270. In the reactions in any of the steps, the reaction hydroxide, Sodium carbonate, calcium carbonate, sodium temperature can differ depending on the reagent and solvent bicarbonate, etc., used, but unless otherwise specifically stated, said reaction 0293 Organic bases: triethylamine, diethylamine, pyri temperature is usually -78° C. to 300° C., preferably -78° dine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4- to 150° C. diazabicyclo[2.2.2]octane, 1,8-diazabicyclo5.4.0-7-unde 0271 In the reactions in any of the steps, the pressure can cene, imidazole, piperidine, etc., differ depending on the reagent and solvent used, but unless 0294 Metal alkoxides: sodium ethoxide, potassium tert otherwise specifically stated, said pressure is usually 1 butoxide, etc., atmosphere to 20 atmospheres, preferably 1 atmosphere to 3 0295 Alkali metal hydrides: sodium hydride, etc., atmospheres. 0296 Metallic amides: sodium amide, lithium diisopro 0272. In the reactions in any of the steps, for example, a pylamide, lithium hexamethyl disilazide, etc., microwave synthesizing apparatus Such as an Initiator made 0297 Organolithiums: n-butyllithium, etc. by the Biotage Corporation may be used. The reaction 0298. When acid or acid catalyst is used in the reactions temperature can differ depending on the reagents and solvent in any of the steps, for example, an acid or acidic catalyst used, but unless otherwise specifically stated, the reaction shown below, or an acid or acidic catalyst described in the temperature is usually room temperature to 300° C., pref Examples, may be used. erably 50° to 250° C. The reaction time can differ depending 0299 Inorganic acids: hydrochloric acid, sulfuric acid, on the reagents and solvent used, but unless otherwise nitric acid, hydrobromic acid, phosphoric acid, etc., specifically stated, the reaction time is usually 1 min to 48 0300 Organic acids: acetic acid, trifluoroacetic acid, cit hours, preferably 1 minto 8 hours. ric acid, p-toluenesulfonic acid, 10-camphor Sulfonic acid, 0273. In the reactions in any of the steps, unless other etc. wise specifically stated to the contrary, 0.5 equivalents to 20 0301 Lewis acids: Boron trifluoride com equivalents, more preferably 0.8 equivalents to 5 equivalents plex, Zinc iodide, anhydrous aluminum chloride, anhydrous reagent are used with respect to the substrate. When the Zinc chloride lead, anhydrous iron chloride, etc. reagent is used as a catalyst, 0.001 equivalents to 1 equiva 0302) The reactions in any of the steps are not restricted lent, more preferably 0.01 equivalents to 0.2 equivalents unless otherwise specifically stated, and can be performed in reagent is used with respect to the substrate. When the accordance with processes that are in themselves well reagent serves as the reaction solvent, the reagent is used in known, for example, processes as described in the Fifth the amount of solvent. Series of Experimental Chemistry, Vol. 13 to 19. (The 0274. In the reactions in any of the steps, unless other Chemical Society of Japan); New Experimental Chemistry wise specifically stated to the contrary, Such reactions may Course, Vol. 14 to 15 (The Chemical Society of Japan): Fine be performed in the absence of solvent or with dissolution or Organic Chemistry, Revised Second Edition (L. F. Tietze, Suspension in a Suitable solvent. As specific examples, those Th. Eicher, Nankodo); Revised Organic Name Reactions, solvents described later in the Examples, or those given their mechanism and essence (Hideo Togo, Kodansha); below may be proposed: ORGANIC SYNTHESES Collective Volume I to VII (John 0275 Alcohols: , ethanol, tert-butyl , Wiley & Sons Inc); Modern Organic Synthesis in the 2-methoxyethanol, etc., Laboratory A Collection of Standard Experimental Proce 0276 Ethers: diethyl ether, diphenyl ether, tetrahydro dures (Jie Jack Li, OXFORD UNIVERSITY Publication): furan, 1.2-dimethoxyethane, etc., Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol. 14 0277 Aromatic hydrocarbons: chlorobenzene, , (Elsevier Japan Co. Ltd.); Strategic Applications of Named Xylene, etc., Reactions in Organic Synthesis (Translation Supervised by 0278 Saturated hydrocarbons: cyclohexane, hexane, etc., Tomioka Kiyoshi, Kagaku Dojin Publication), Comprehen US 2016/0326102 A1 Nov. 10, 2016

sive Organic Transformations (VCH Publishers Inc) 1989, peroxide, tert-butylhydroperoxide, etc., a perchlorate salt etc., or in accordance with processes as described in the Such as tetrabutylammonium perchlorate, etc., a chlorate salt Examples. Such as Sodium chlorate, etc., a chlorite Such as sodium 0303. In each step, protecting or deprotecting reactions chlorite, etc., a periodate Such as Sodium periodate, etc., a for the functional groups are performed in accordance with high atomic valency iodine reagent such as iodoSobenzene, processes which are in themselves well-known, for etc., a reagent containing manganese such as manganese examples, processes described in “Protective Groups in dioxide, potassium permanganate, etc., a lead compound Groups in Organic Synthesis, 4th Ed. (Theodora W. Such as lead tetraacetate, etc., a reagent containing chro Greene, Peter G. M. Wuts) published by Wiley-Interscience mium Such as pyridinium chlorochromate (PCC), pyri in 2007; or “Protecting Groups 3rd Ed.” (P. J. Kocienski) dinium dichromate (PDC), Jones reagent, etc., a halogen published by Thieme in 2004; or in accordance with pro compound such as N-bromo succinimide (NBS), etc., oxy cesses described in the Examples. gen, oZone, Sulfur trioxide/pyridine complex, osmium tet 0304. In the case of hydroxy groups of protected alcohols roxide, selenium dioxide, 2,3-dichloro-5,6-dicyano-1,4-ben and phenolic hydroxy groups, for example, ether groups Zoquinone (DDQ), etc. such as methoxymethyl ether, benzyl ether, tert-butyldim 0313 When a radical cyclization reaction is performed in ethylsilyl ether, tetrahydropyranyl ether, etc.: carboxylate any of the steps, the radical initiator which is used may ester groups such as acetic acid ester, etc.; Sulfonic acid ester comprise an azo compound such as azobisisobutyronitrile groups such as methanesulfonic ester, etc.; carboxylic acid (AIBN), etc.; a water-soluble radical initiator such as 4-4'- ester groups such as tert-butyl carbonate, etc., and the like, azobis-4-cyanopentanoic acid (ACPA), etc.; triethyl boron may be proposed. in the presence of air or of oxygen; benzoyl peroxide, etc. 0305. In the case of carbonyl groups of protected alde Moreover, as far as the radical reaction reagent used is hydes, for example, acetal groups such as dimethyl acetal, concerned, tributylstannane, tris trimethylsilyl silane, 1.1.2, etc., cyclic acetal groups such as 1,3-dioxane, etc., and the 2-tetraphenyldisilane, diphenylsilane, Samarium iodide, etc. like may be proposed. may be proposed. 0306 In the case of carbonyl groups of protected ketones, 0314. When a Wittig reaction is performed in any of the for example, ketal groups such as dimethyl ketal, etc., cyclic steps, an alkylidene phosphorane, etc. may be proposed as ketal groups such as 1,3-dioxane, etc., oxime group Such as the Wittig reagent used. An alkylidene phosphorane can be O-methyloxime, etc., hydrazone groups such as N,N-dim prepared by itself a well-known process, such as, for ethylhydrazone, etc., and the like, may be proposed. example, the reaction of a phosphonium salt with strong 0307. In the case of protected carboxyl groups, for base. example, ester groups such as methyl ester, etc., amide 0315. In any of the steps, when a Horner-Emmons reac groups, etc. Such as N,N-dimethyl amide, etc., and the like, tion is performed, the reagent used may comprise a phospho may be proposed. noacetic acid ester Such as methyl dimethylphosphonoac 0308. In the case of protected thiols, for example, ether etate, ethyl diethylphosphonoacetate, etc., a base Such as an groups such as benzylthio ether, etc., ester groups such as alkali metal hydride, an organolithium, etc. thioacetic acid ester, thiocarbonate, thiocarbamate, etc., and 0316. When a Friedel–Crafts reaction is performed in any the like may be proposed. of the steps, the reagent used may comprise a combination 0309. In the case of protected amino groups and aromatic of Lewis acid and acid chloride or a combination of Lewis heterocycles such as imidazole, pyrrole, indole, etc., car acid and alkylating agent (for example alkyl halide, alcohol, bamate groups such as benzyl carbamate, etc., amide groups olefin, etc.) may be proposed. Alternatively, an organic acid Such as acetamide, etc., alkylamine groups such as N-triph and/or inorganic acid can be used instead of the Lewis acid, enylmethylamine, etc., Sulfonamide groups such as methane and an acid anhydride Such as acetic anhydride, etc. can be Sulfonamide, etc., and the like, may be proposed. used instead of the acid chloride. 0310. The elimination of the protecting groups can be 0317. When an aromatic nucleophilic substitution reac carried out using itself well-known process, for example a tion is performed in any of the steps, as the reagent used a process using acid, base, UV light, hydrazine, phenylhydra nucleophilic reagent (for example, amine, imidazole, etc.) zine, sodium N-methyl dithiocarbamate, tetrabutylammo and base (for example, organic base, etc.) may be used. nium fluoride, palladium acetate, trialkylsilyl halide (for 0318. In any of the steps, when a nucleophilic addition example, trimethylsilyl iodide, trimethylsilyl ), or reaction using a carbanion, a nucleophilic 1,4-addition reac reducing method or the like. tion using a carbanion (Michael addition reaction) or a 0311. When a reducing reaction is performed in any of nucleophilic Substitution reaction using a carbanion, is per the steps, the reducing agent used may comprise, for formed, as the base used to generate the carbanion, an example, a metal hydride Such as lithium aluminum hydride, organolithium, metal alkoxide, inorganic base, organic base, Sodium acetoxy borohydride, Sodium cyanoborohydride, etc. may be proposed. disobutylaluminium hydride (DIBAL-H), sodium borohy 0319. When a Grignard reaction is performed in any of dride, acetoxy borohydride tetramethylammonium, etc., a the steps, the Grignard reagent may comprise an aryl mag borane Such as borane tetrahydrofuran complex, etc., Raney nesium halide Such as phenylmagnesium bromide, etc., an nickel, Raney cobalt, hydrogen, formic acid, etc. When a alkylmagnesium halide Such as methyl magnesium bromide, carbon-carbon double bond or triple bond is being reduced, etc. The Grignard reagent can be prepared by itself well a process using a catalyst Such as a palladium-carbon known process, for example, by reacting metal magnesium catalyst, Lindlar catalyst, etc. may be applied. with alkyl halide or aryl halide in tetrahydrofuran or ether as 0312. When an oxidation reaction is performed in any of solvent. the steps, the oxidizing agent used may comprise a peroxy 0320 In any of the steps, when a Knoevenagel conden acid such as m-chloroperbenzoic acid (MCPBA), hydrogen sation reaction is performed, the reagents used may com US 2016/0326102 A1 Nov. 10, 2016 prise an active methylene compound with two electrophilic pound Such as palladium (II) acetate, tetrakis(triphenylphos groups (for example, malonic acid, diethyl malonate, malo phine)palladium (O), dichlorobis(triphenylphosphine)palla nitrile, etc.) and base (for example organic base, metal dium (II), dichlorobis(triethylphosphine)palladium (II), tris alkoxide, inorganic base). (dibenzylideneacetone)dipalladium (0), 1,1'-bis 0321) When a Vilsmeier-Haack reaction is performed in (diphenylphosphino) ferrocene palladium (II) chloride, any of the steps, the reagent used may comprise a phospho palladium (II) acetate, etc.; a nickel compound Such as rus oxychloride and an amide derivative (for example N.N- tetrakis(triphenylphosphine)nickel (O), etc.; a rhodium com dimethylformamide, etc.). pound Such as tris(triphenylphosphine)rhodium (III) chlo 0322. In any of the steps, when an azide forming reaction ride, etc.; a cobalt compound; a copper compound Such as is performed with an alcohol, alkyl halide or sulfonate, as the copper oxide, copper (I) iodide, etc.; a platinum compound, azide forming agent which is used, diphenylphosphoryl etc. may be proposed. Moreover, base may be added to the azide (DPPA), trimethylsilyl azide, sodium azide, etc. may reaction, and as Such base, inorganic bases, etc. may be be proposed. For example, when an alcohol is subjected to proposed. azide formation, for example, a process using diphenylphos phoryl azide and 1, 8-diazabicyclo[5.4.0]undec-7-ene 0327. When a thiocarbonylation reaction is performed in (DBU) or a process using trimethylsilyl azide and Lewis any of the steps, as thiocarbonylation agent, typically phos acid, may be applied. phorous pentasulfide is used, but other than phosphorous 0323 When a reductive amination reaction is performed pentasulfide, a reagent having a 1.3.2.4-dithiadiphosphet in any of the steps, the reducing agent used may comprise ane-2,4-disulfide structure Such as 2, 4-bis(4-methoxyphe Sodium acetoxyborohydride, sodium cyanoborohydride, nyl-1, 3, 2,4-dithiadiphosphetane-2,4-disulfide (Lawesson hydrogen, formic acid, etc. When the Substrate is as amine reagent) may be used. compound, as the carbonyl compound used, in addition to 0328. When a Wohl-Ziegler reaction is performed in any paraformaldehyde, an aldehyde Such as acetaldehyde, etc., a of the steps, the halogenating agent, may comprise N-iodo ketone such as cyclohexanone, etc. may be proposed. When succinimide, N-bromosuccinimide (NBS), N-chlorosuccin the Substrate is a carbonyl compound, as the amine used, imide (NCS), bromine, chlorosulfuric acid, etc. Moreover, ammonia, a primary amine Such as methylamine, etc., or a the reaction can be accelerated by applying heat, light, secondary amine Such as dimethylamine, etc., or the like radical initiator such as benzoyl peroxide, azobisisobuty may be proposed. ronitrile, etc. to the reaction. 0324 When a Mitsunobu reaction is performed in any of 0329. When a hydroxy group halogenation is performed the steps, as the reagent used, aZodicarboxylic acid ester (for in any of the steps, the halogenating agent used comprises an example, diethyl azodicarboxylate (DEAD), diisopropyl acid halide compound of an inorganic acid with hydrohalic aZodicarboxylate (DIAD), etc.) and triphenylphosphine may acid; specific examples include in the case of chlorination, be used. hydrochloric acid, thionyl chloride, phosphorus oxychlo 0325 In any of the steps, when an esterification reaction, ride, etc.; and in the case of bromination, 48% hydrobromic amidation reaction or urea-forming reaction is performed, as acid, etc. Moreover, a process to obtain alkyl halide from the reagent which is used, a halogenated acyl compound alcohol based on the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide, etc. may be Such as acid chloride, acid bromide, etc., an activated used. Alternatively, a method via a two stage reaction may carboxylic acid compound Such as acid anhydride, active be applied, wherein an alcohol is first converted to sulfonic ester, Sulfate ester, etc. may be proposed. As carboxylic acid acid ester, and then the alkyl halide synthesized by reaction activating agent, a carbodiimide-based condensing agent with , lithium chloride or sodium iodide. such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide 0330. When an Arbuzov reaction is performed in any of hydrochloride (WSCD), etc.; a triazine-based condensing the steps, the reagent used may comprise an alkyl halide agent such as 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4- Such as ethyl bromoacetate, etc., a phosphite such as triethyl methyl morpholinium chloride-n-hydrate (DMT-MM); a phosphite or tri(isopropyl) phosphite, etc. carbonate ester-based condensing agent such as 1,1-carbo 0331 When a sulfonic acid ester forming reaction is nyldiimidazole (CDI), etc.; diphenylphosphorazidate performed in any of the steps, examples of Sulfonylating (DPPA); benzotriazol-1-yloxy-tris dimethylamino phospho agent used include methanesulfonyl chloride, p-toluenesul nium salt (BOP reagent); 2-chloro-1-methyl-pyridinium fonyl chloride, methanesulfonic acid anhydride, p-toluene iodide (Mukaiyama reagent); thionyl chloride, a halo formic sulfonic acid anhydride and the like. acid lower alkyl ester such as ethyl chloroformate, etc.; 0332. When a hydrolysis reaction is performed in any of O-(7-azabenzotriazol-1-yl)-N.N.N',N'-tetramethyl uronium the steps, an acid or base is used as the reagent. Moreover, hexafluorophosphate (HATU); sulfuric acid; or combina when acid hydrolysis of tert-butyl ester is performed, formic tions of these, etc. may be proposed. When a carbodiimide acid and/or triethylsilane, etc. can be added in order to trap based condensing agent is used, an additive such as 1-hy by-produced tert-butyl cations using reduction. droxy benzotriazole (HOBt), N-hydroxy succinimide 0333 When a dehydration reaction is performed in any of (HOSu), dimethylaminopyridine (DMAP), etc. may also be the steps, as the dehydrating agent used, Sulfuric acid, added to the reaction. diphosphorous pentoxide, phosphorus oxychloride, N.N- 0326. When a coupling the reaction is performed in any dicyclohexylcarbodiimide, alumina, polyphosphoric acid, of the steps, as the metal catalyst used, a palladium com etc. may be proposed. US 2016/0326102 A1 Nov. 10, 2016

0334 Compound (I) can be produced by the following 0337 Compound (3) can be synthesized by the following process from Compound (2). process from Compound (5).

LG O

Reducing reaction -e-

O RI (3) (5) N R3 OH 2 Substitution reaction Halogenation, or Sulfonyl R -e- W. esterification or SH esterification -e- (2)

(6) LG

O R1 N R3 R2 W. S Oxidation reaction He (3)

0338 (wherein, LG has the same said meaning) 0339 Compound (5) may be a commercial product, or can be produced by a well-known process or a process based CO on Such a process. (4) 0340 Compound (2) can be synthesized in accordance with itself well-known method; and for example, 0341 Compound (2a) can be produced by the following process from Compound (7). O R1 O N R3 Halogenation, or R2 sulfonyl esterification W. N R3 O Rio SO -> W. OH

A (7) O

N R3 Substitution reaction (I) Ho W. LG 0335 (wherein, LG is a leaving group, and the other symbols have the same said meanings) As leaving group (8) represented by LG, for example, a halogen atom (chlorine O O atom, bromine atom, iodine atom, etc.). Substituted Sulfo nyloxy group (C. alkylsulfonyloxy group Such as methane N R3 N R3 Sulfonyloxy, ethane sulfonyloxy, etc.; Caryl Sulfonyloxy W. Deprotection group Such as benzene Sulfonyloxy, p-toluene Sulfonyloxy, He etc.; C, aralkyl sulfonyloxy group, etc. Such as benzyl S SH Sulfonyloxy group, etc.), acyloxy group (acetoxy, benzoy 1N (2a) loxy, etc.) and the like may be proposed. O 0336 Compound (4) can be produced from Compound (2) by performing a Substitution reaction using Compound (3) in the presence of base. US 2016/0326102 A1 Nov. 10, 2016 15

0342 (wherein, each symbol has the same said meaning) -continued O 0343 Compound (9) can be produced from Compound O (8) by a Substitution reaction using thioacetic acid or a thioacetate salt, in the presence of base. As the salt of R3 thioacetic acid, the potassium salt, Sodium salt, etc. may be Deprotection proposed. 0344 Compound (7) can be synthesized in accordance with itself well-known method; and for example, 0345 Compound (7a) can be synthesized in accordance with a process which is well-known in the literature (Syn thetic Communications, 16(2), 149-156 (1986)).

Acetalization -e- (7a) O

PGO OPG CrsOH )-( , -Si-O O-Si 0346 Moreover, Compound (7), when Compound (7b), can be synthesized in accordance with a process well-known in the literature (WO2011/093512A1). R3 (18) / Acetal exchange

(7b)

(17) OPG OH O O 0347 Compound (2), when Compound (2b), can be pro R3 duced by the following process from Compound (12). O PGO Deprotection --- S

Carbonylation ls (19) OH

O Halogenation, or R3 sulfonyl esterification O or esterification HO -- SH OH (2b)

0348 (wherein, PG is a protecting group, and the other K O R3 Substitution symbols have the same said meanings) O reaction He 0349 Compound (13) can be produced from Compound LG (12) by carbonylation using a carbonylation reagent in the presence of base. As carbonylation reagent, diethyl carbon (14) ate, ethyl chloroformate, acetyl chloride, acetic anhydride, N,N-dimethylformamide may be proposed. US 2016/0326102 A1 Nov. 10, 2016

0350 Compound (15) can be produced by a substitution reaction of Compound (14) using thioacetic acid or a thio LG acetate salt, in the presence of base. As the salt of thioacetic acid, the potassium salt, Sodium salt, etc. may be proposed.

0351 Compound (19) can be produced from Compound HO (18) using an acetal-exchange reaction in the presence of HO O acid. O (3) 0352 Compound (18) can be synthesized by the follow R3 O Substitution reaction ing process from Compound (20). -e- SH

HO OH (2b) HO Deprotection Hos HO O HO OH O O R3 R-LG (20) (22) PGO OPG Trimethylsilylation S Alkylation -e- HO OH (21)

() ( , (4a) -O O- R RO RO O O (18) 3 O R

0353 (wherein, each symbol has the same said meaning) S 0354 Compound (12) and Compound (20) may be com mercial products, or can be produced by well-known pro cesses or processes based on Such processes. 0355 Compound (2), when Compound (2c), can be pro duced by the following process from Compound (16). (4b)

O 0358 (wherein, R is an optionally substituted alkyl O group, and the other symbols have the same said meanings) R3 0359 Compound (4a) can be produced from Compound Reducing reaction (2b) by a Substitution reaction using Compound (3) in the S -e- presence of base. 0360 Compound (4b) can be produced from Compound es (4a) by alkylation using Compound (22) in the presence of base. (16) O 0361. A marketed product may be used as Compound (22) or it can be prepared by a well-known process or a HO R3 process based on Such a process. 0362. When Compound (I) includes optical isomers, ste reoisomers, positional isomers or rotational isomers, these SH are also included within Compound (I), and also, these can be obtained as respectively isolated products by in them (2c) selves well-known synthesis techniques and separational techniques (for example, concentration, Solvent extraction, column chromatography, recrystallization, etc.). For 0356 (wherein, each symbol has the same said meaning). example, when optical isomers are present in Compound (I), 0357 Compound (4), when Compound (4b), can be pro the optical isomers resolved from said compound are also duced by the following process from Compound (2b). included within Compound (I). US 2016/0326102 A1 Nov. 10, 2016

0363 Optical isomers can be produced using in them 0374. As said “method of crystallization from solution', selves well-known processes. More specifically, optical iso a method is generally applied wherein using a factor relating mers may be obtained by using an optically active interme to the solubility of the compound (solvent composition, pH, diate or by resolving the final racemate product in temperature, ionic strength, redox state, etc.) or the quantity accordance with conventional procedures. of solvent, a transition from an unsaturated State to a 0364. As optical resolution method, itself well-known Super-saturated State is achieved; specific examples include, process, for example a fractional crystallization method, for example, a concentration method, slow-cooling method, chiral column method, diastereomer method, etc. is used. reaction method (diffusion method, electrolysis method), 0365. 1) Fractional Crystallization Method hydrothermal cultivation method, fusing method, etc. As the 0366. A method wherein a salt is formed between the Solvent which is used, for example, an aromatic hydrocarbon racemate and an optically active compound (for example, (for example, benzene, toluene, Xylene, etc.), halogenated (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)- hydrocarbon (for example, dichloromethane, , tartaric acid, (+)-1-phenethyl amine, (-)-1-phenethylamine, etc.), Saturated hydrocarbon (for example, hexane, heptane, cinchonine, (-)-cinchonidine, brucine, etc.), and this then cyclohexane, etc.), ether (for example, diethyl ether, diiso separated by a fractional crystallization method, and then in propyl ether, tetrahydrofuran, dioxane, etc.), nitrile (for accordance with requirements, the free optical isomer is example, acetonitrile, etc.), ketone (for example, acetone, obtained via a neutralization step. etc.), Sulfoxide (for example, dimethyl Sulfoxide, etc.), acid 0367 2) Chiral Column Method amide (for example N,N-dimethylformamide, etc.), ester 0368. A method wherein the racemate or a salt thereof is (for example ethyl acetate, etc.), alcohol (for example separated using a column for optical isomer separation (a methanol, ethanol, 2-propanol, etc.), water, etc. may be chiral column). For example, in the case of liquid chroma proposed. These solvents may be used singly or a mixture of tography, the mixture of optical isomers is added to two or more thereof in a suitable proportion (for example 1:1 ENANTIO-OVM (made by Tosoh Corp.) or one of the to 1:100 (volume ratio)) may be used. Seed crystals can be CHIRAL series (made by Daicel Chemical Industries Ltd.), used in accordance with requirements. and development performed with a solution comprising one 0375. As said “method of crystallization from vapor, for of, or a mixture of water, various buffers (for example example, a vaporization method (sealed tube method, gas phosphate-buffer solution, etc.) and organic solvent (for flow method), gas phase reaction method, chemical transport example, ethanol, methanol, 2-propanol, acetonitrile, trif method and the like methods may be proposed. luoroacetic acid, diethylamine, etc.), and the optical isomers 0376. As said “method of crystallization from melt”, for thereby separated. Moreover, for example, in the case of gas example, a normal freezing method (pull-up method, tem chromatography, a chiral column such as CP-Chirasil-DeX perature gradient method, Bridgman method), Zone melting CB (made by GL Sciences Inc.), etc. may be used to cause method (Zone leveling method, float Zone method), special separation. growth method (VLS method, liquid phase epitaxy method), 0369. 3) Diastereomer Method etc. may be proposed. 0370. A method wherein the racemic mixture is formed 0377 As ideal example of crystallization method, a into a mixture of diastereomers by a chemical reaction with method wherein compound (I) is dissolved in a suitable an optically active reagent, and then this mixture formed into Solvent (alcohol, etc., such as methanol, ethanol, etc.) at a the single Substances via conventional separational means temperature of 20 to 120° C., and then the obtained solution (for example, fractional crystallization, chromatography is cooled to a temperature below the temperature when it method, etc.), etc., and then the optical isomers obtained by dissolved (for example 0 to 50° C., preferably 0 to 20° C.), cleaving the optically active reagent position by a chemical etc., may be proposed. treatment such as hydrolysis reaction, etc. For example, 0378. The crystals of the present invention obtained in when compound (I) contains an hydroxy or a primary or this way can, for example, be isolated by filtration, etc. secondary amino within the molecule, the diastereomer of 0379 A crystallographic analysis method based on pow the ester or amide compound is respectively obtained by der X-ray diffraction is generally used as a method of Subjection of said compound to a condensation reaction with analyzing the obtained crystals. Moreover, as a method of an optically active organic acid (for example, MTPA determining the crystal orientation, a mechanical method or C.-methoxy-O-(trifluoromethyl)phenyl acetic acid, (-)- optical method or the like may be proposed. methoxy acetic acid, etc.). On the other hand, when com 0380. The crystals of compound (I) obtained by said pound (I) contains a carboxy group, the diastereomer of the methods of production have high purity and high quality, ester or amide is respectively obtained by subjection of said have low hygroscopicity, and, their quality does not dete compound to a condensation reaction with an optically riorate even if stored for a long time under ambient condi active amine or alcohol reagent. The separated diastereomer tions, and they have extremely excellent safety. Moreover, may then be converted into the optical isomer of original the biological properties (for example pharmacokinetics compound by subjection to hydrolysis with acid or hydro (absorptivity, distribution, metabolism, excretion), drug effi lysis with hydrolysis. cacy expression, etc.) are excellent; properties which are 0371 Compound (I) may be crystalline. extremely useful in a drug. 0372 Crystals of compound (I) can be produced by 0381 Prodrugs of compound (I) are compounds which causing crystallization by Subjecting compound (I) to itself are converted to compound (I) by reactions due to gastric well-known crystallization process. acid or enzymes or the like under physiological conditions; 0373) Wherein as crystallization method, for example a namely compounds transformed into compound (I) due to method of crystallization from solution, a method of crys enzymatic oxidation, reduction, hydrolysis, etc., occurring, tallization from vapor, a method of crystallization method and compounds transformed into compound (I) due to from a melt, etc., may be proposed. hydrolysis caused by gastric acid, etc., occurring. Examples US 2016/0326102 A1 Nov. 10, 2016 of prodrugs of compound (I) include compounds wherein an reaction syndrome (CARS), burn injury, trauma, postopera amino group of compound (I) has been acylated, alkylated tive complication, cardiac failure, shock, hypotension, rheu or phosphorylated for example, compounds wherein an matoid arthritis, osteoarthritis, gastritis, ulcerative colitis, amino group of compound (I) has been eicosanoylated, peptic ulcer, stress-induced peptic ulcer, Crohn's disease, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3- autoimmune disease, graft rejection after organ transplanta dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, tion, ischemia-reperfusion injury (IRI), liver injury (acute pyrrolidyl methylated, pivaloyloxymethylated or tert-buty liver injury (ALI), ACLF), acute coronary microvascular lated; compounds wherein a hydroxy group of compound (I) has been acylated, alkylated, phosphorylated or borylated embolism, shock-induced vascular embolism (disseminated for example, compounds wherein a hydroxy group has been intravascular coagulation (DIC) or the like), ischemic acetylated, palmitoylated, propanoylated, pivaloylated, suc encephalopathy, arteriosclerosis, pernicious anemia, Fan cinylated, fumarylated, alanylated, dimethylaminomethyl coni anemia, sickle cell anemia, pancreatitis, nephrotic Syn carbonylated, etc.; and compounds wherein a carboxyl drome, acute and chronic nephropathy, nephritis, renal fail group of compound (I) has been formed into an ester or ure, insulin dependent diabetes mellitus, non-insulin amide for example, compounds wherein a carboxyl group dependent diabetes mellitus, hepatic porphyria, alcohol poi of compound (I) has been formed into an ethyl ester group, soning, Parkinson's disease, chronic leukemia, acute leuke phenyl ester group, carboxymethyl ester group, dimethyl mia, tumor, myeloma, infant and adult respiratory distress aminomethyl ester group, pivaloyloxymethyl ester group, syndrome, chronic obstructive pulmonary disease, demen ethoxycarbonyloxyethyl ester group, phthalidyl ester group, tia, Alzheimer's disease, multiple Sclerosis, optic nerve (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester group, myelitis, Vitamin E deficiency, ageing, Sunburn, muscular cyclohexyloxycarbonylethyl ester group, or methylamide dystrophy, myocarditis, cardiomyopathy, myocardial infarc group, and the like. These compounds can be produced tion, myocardial infarction sequellae, osteoporosis, pneumo from compound (I) by well-known processes. nia, hepatitis, psoriasis, pain, cataract, influenza infection, malaria, human immunodeficiency virus (HIV) infection, 0382 Moreover, the prodrugs of compound (I) may be radiation damage, burn, hypercalcemia, ankylosing spondy those that transform into compound (I) under physiological litis, osteopenia, Paget’s disease, osteomalacia, bone frac conditions in the same way as described in “Development of ture, acute bacterial meningitis, Helicobacter pylori infec Pharmaceuticals” (Hirokawa Publishing, 1990) vol. 7, tion, invasive Staphylococcus infection, tuberculosis, Molecular Design 163-198 systemic fungal infection, herpes simplex viral infection, 0383. In this specification, the compounds (I) and the varicella-zoster viral infection, human papilloma virus prodrugs of compounds (I) may be collectively termed “the infection, acute viral encephalitis, encephalitis, meningitis, compounds of the present invention’. hypoinmunity accompanying infection, bronchial asthma, 0384 Compound (I) may be any of hydrate, non-hydrate, atopic dermatitis, allergic rhinitis, reflux esophagitis, fever, Solvate and non-Solvate. hypercholesterolemia, hyperglyceridemia, hyperlipidemia, 0385 Compounds which are isotopically labeled (for diabetic complications, diabetic nephropathy, diabetic neu example, with H, C, S., I, etc.) are also included in ropathy, diabetic retinopathy, gout, gastric atony, hemor compound (I). rhoids, systemic lupus erythematosus, spinal cord injury, 0386 Moreover, compounds substituted with heavy insomnia, Schizophrenia, epilepsy, cirrhosis, hepatic insuf hydrogen in which H has been replaced by H (D) are also ficiency, unstable angina, cardiac valvular disease, throm included within compound (I). bocytopenia or hypotension due to dialysis, acute ischemic 0387 Tautomers are also included within compound (1). cerebral apoplexy, acute cerebral thrombosis, cancer metas 0388 Compound (I) may be present as a pharmacologi tasis, urinary bladder cancer, breast cancer, uterine cervical cally acceptable co-crystal or co-crystalline salt. cancer, colorectal cancer, gastric cancer, ovarian cancer, 0389. Wherein, co-crystal and co-crystalline salt denotes prostate cancer, Small cell lung cancer, non-Small cell lung a crystalline Substance constructed from at least two unique cancer, malignant melanoma, Hodgkin’s disease, non-Hodg Solids at room temperature having various different physical kin's lymphoma, side effects due to anticancer agent and characteristics (for example, structure, melting point, heat of immunosuppressant drug administration, chronic obstruc fusion, hygroscopicity, Solubility and stability, etc.). Co tive pulmonary disease, cystic fibrosis, pulmonary fibrosis, crystals and co-crystalline salts can be produced in accor autoimmune hemolytic anemia, meningitis, inflammatory dance with well-known crystallization methods. pulmonary disease (for example, silicosis, pulmonary Sar 0390 Compound (I) may be used as PET tracer. coidosis, tuberculosis), endometriosis, cachexia (for 0391 The compounds of the present invention have example, cachexia due to infection, cancerous cachexia, excellent TLR4 signaling inhibitory action, and so said cachexia due to acquired immunodeficiency syndrome), compounds are useful as safe drugs based on the said action. cancer pain, Addison's disease, acute pain due to inflam 0392 Accordingly, the TLR4 signaling inhibiting sub mation, pain due to chronic inflammation, post-operative stances in the present invention can be used with respect to pain (incision wound pain, deep pain, visceral pain, chronic mammalian organisms (for example, mouse, rat, hamster, post-operative pain, or the like), myalgia (myalgia accom rabbit, cat, dog, cow, sheep, monkey, human, or the like) as panying chronic pain, stiff neck, or the like), arthralgia, preventive and/or therapeutic agents of for example, auto toothache, temporomandibular arthralgia, headache (mi immune disease and/or inflammatory disease, and diseases graine headache, tension headache, headache accompanying Such as infectious disease, cardiac disease, central nervous pyrexia, headache accompanying hypertension), visceral system disease, hypoinmunity and the like; for example, pain (cardialgia, anginal pain, abdominal pain, kidney pain, sepsis including serious sepsis, septic shock, septicemia, urinary tract pain, bladder pain), pain of the obstetric and endotoxic shock, exotoxic shock, systemic inflammatory gynecological area (intermenstrual pain, dysmenorrheal and response syndrome (SIRS), compensatory antiinflammatory labour pain), neurogenic pain (spinal disc herniation, nerve US 2016/0326102 A1 Nov. 10, 2016 root pain, post-herpes Zoster neuralgia, trigeminal neuralgia, example, Subcutaneous injection agent, intravenous injec lumbago, or the like), chemotherapys ((taxane anticancer tion agent, intramuscular injection agent, intraperitoneal drugs (for example, paclitaxel (taxol), docetaxel), vinca injection agent), drip infusion agent, percutaneous absorp alkaloid anticancer drugs (for example, Vincristine, vinblas tion preparation, cream agent, ointment, lotion, patch, Sup tine), platinum preparations (for example, cisplatin, carbo pository (for example, anal Suppository, vaginal Supposi platin, oxaliplatin), molecular target drug (for example, tory), pellet, transnasal agent, transpulmonary agent bortezomib) or the like))-induced peripheral neuropathy (inhalant), instillation, or the like. (CIPN) and associated neurological symptoms (chemo 0395. The content of the compound of the present inven therapy-induced neuropathic pain (CINP) (dysesthesia such tion in the drug of the present invention is about 0.01 wt.% as numbness and/or pain (for example, muscle pain, nerve to about 100 wt.% of the total drug. Said dose differs pain))), reflex sympathetic atrophy, complex local pain depending on the administration Subject, administration syndrome, pituitary gland abscess, thyroiditis, peritonitis, route, disease, or the like, however, for example, with erythema nodosum), allergic conjunctivitis, pollinosis, metal respect to a patient with chemotherapy-induced peripheral allergy, exudative otitis media, Meniere's disease, contact neuropathy (CIPN), chemotherapy-induced neuropathic dermatitis, anaphylaxis, urticaria, myasthenia gravis, pain (CINP), liver injury and/or ischemia-reperfusion injury Sjogren's syndrome, Basedow's disease, leukocyte abnor (IRI) (about 60 kg in weight), as orally administered agent, mality, renal tubulointerstitial disorder (including fibrillary about 0.01 mg/kg body weight to about 500 mg/kg body pathology), acute coronary artery syndrome, atherosclerotic weight, preferably about 0.1 mg/kg body weight to about 50 aortic aneurysm, cardiac anaphylaxis, deep vein thrombosis, mg/kg body weight, more preferably about 1 mg/kg body ophthalmologic diseases (for example, pterygium, spring weight to about 30 mg/kg body weight as effective ingre catarrh, dry eye, or the like), food allergy, NUD (Non Ulcer dient (compound (I)) per day, may be administered once a Dyspepsia), gastric MALT lymphoma, ulcer due to non day or divided into several times. steroid anti-inflammatory drug, gastric hyperacidity, gastric 0396. As the pharmacologically acceptable carrier which hyperacidity and ulcer due to postoperative stress, obesity, may be used in the production of the drug of the present edema, granuloma, atopic myelitis, neurofibroma, nasal invention, various conventionally used organic or inorganic mucosal hypersensitivity, osteoarthritis, Scleroderma, or the carrier Substances may be proposed, and for example, like. Moreover, the TLR4 signaling inhibiting substance of excipients, lubricants, binding agents and disintegrating the present invention can also be used for increasing effi agents in Solid preparations; and, solvents, solubilizers, ciency of in vitro fertilization. Suspending agents, isotonizing agents, buffer agents and 0393 Wherein, the “prevention' of said disease means, analgesics and the like in liquid preparations may be pro for example, the administration of a drug containing the posed. Furthermore, additives such as conventional preser compound of the present invention to a patient who has not Vatives, anti-oxidant, colorant, Sweetener, adsorbent, wet yet developed the said disease but is thought to be of high ting agent, or the like can be suitably used in a Suitable risk of onset due to Some factor related to the said disease, quantity in accordance with requirements. or to a patient who has developed the disease but without 0397. The dose when the pharmaceutical composition of Subjective symptoms, or the administration of a drug con the present invention is a slow release preparation varies in taining the compound of the present invention to a patient various ways depending on the kind and content of com who, following treatment of the said disease, is concerned pound (I), agent form, duration of drug release, administra about recurrence of said disease. tion Subject animal (mammalian organism Such as mouse, 0394. A drug containing the compound of the present rat, hamster, guinea pig, rabbit, cat, dog, cow, horse, pig, invention can be used as a compound of the present inven sheep, monkey, human or the like) and object of adminis tion alone or as pharmaceutical composition of a mixture of tration, however, for example, when applied by a parenteral a compound of the present invention and pharmacologically administration route, the administration preparation may be acceptable carrier, in accordance with well-known processes designed so that about 0.1 to about 100 mg of compound (I) for the production of drug preparations (for examples, is released in a week. processes in accordance with Pharmacopeia of Japan). Phar 0398. Examples of excipient include lactose, sucrose, maceutical compositions containing the compound of the D-mannitol, Starch, corn starch, crystalline cellulose, light present invention can be safely administered orally or par anhydrous silicic acid, etc. enterally (example, intravenously, intramuscularly, Subcuta 0399. Examples of lubricant include magnesium stearate, neously, by intraorgan administration, intranasally, intracu calcium Stearate, talc, colloidal silica, etc. taneously, by eye drops, intracerebrally, endorectally, 04.00 Examples of binding agent include crystalline cel intravaginally, intraperitoneally, by intratumor administra lulose. Sucrose, D-mannitol, dextrin, hydroxypropylcellu tion, by tumor proximal administration, by administration at lose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, the focus of the disease, or the like); for example as a tablet starch, Sucrose, gelatin, methyl cellulose, carboxymethyl (including Sugar coated tablet, film coated tablet, Sublingual cellulose sodium, etc. tablet, oral cavity disintegration tablet, buccal tablet), pill, 04.01 Examples of disintegrating agent include starch, powder, granules, encapsulated formulation (including soft carboxymethylcellulose, carboxymethylcellulose calcium, capsule agent and microcapsule agent), troche agent, Syrup. carboxymethyl starch sodium, L-hydroxypropylcellulose, liquid agent (including organ preservation Solution and etc. organ perfusion solution), emulsion, Suspending agent, con 0402. Examples of solvent include water used for injec trolled release preparation (for example, rapid release prepa tion, alcohol, propylene glycol, macrogol, Sesame oil, corn ration, slow release preparation, controlled-release micro oil, olive oil, etc. capsule agent), aerosol, film agent (for example, oral cavity 0403. Examples of solubilizer include polyethylenegly disintegration film, oral mucosal patch), injectable (for col, propylene glycol, D-mannitol, benzylbenzoate, ethanol, US 2016/0326102 A1 Nov. 10, 2016 20 tris aminomethane, , triethanolamine, sodium 0412 (1) Antibacterial agents carbonate, sodium citrate, etc. 0413 (i) Sulfa drugs 04.04 Examples of Suspending agent include Surfactants 0414 Sulfamethizole, sulfisoxazole, sulfamonomethox Such as Stearyl triethanolamine, Sodium lauryl Sulfate, lau ine, Sulfamethizole, Salazosulfapyridine, silver Sulfadiazine, rylamino propionic acid, lecithin, benzalkonium chloride, etc. benzethonium chloride, glyceryl monostearate, etc., hydro 0415 (ii) Quinoline antibacterial agents philic macromolecules Such as polyvinyl alcohol, polyvi 0416 Nalidixic acid, pipemidic acid trihydrate, enoxacin, nylpyrrolidone, carboxymethylcellulose sodium, methyl norfloxacin, ofloxacin, toSufloxacin tosilate, ciprofloxacin cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydrochloride, lomefloxacin hydrochloride, sparfloxacin, hydroxypropylcellulose, etc., and the like. fleroxacin, etc. 04.05 Examples of isotonizing agent include glucose, 0417 (iii) Antitubercular agent D-Sorbitol, Sodium chloride, glycerol, D-mannitol, etc. 0418 Isoniazid, ethambutol (ethambutol hydrochloride), 04.06 Examples of buffer agent include buffers such as p-aminosalicylate (calcium p-aminosalicylate), pyraZina phosphates, acetates, carbonates, citrates, etc. mide, ethionamide, protionamide, rifampicin, Streptomycin 04.07 Examples of analgesic include benzyl alcohol, etc. Sulphate, kanamycin Sulfate, cycloserine, etc. 04.08 Examples of preservative include parahydroxyben 0419 (iv) Acid fast bacterium drugs Zoic acid esters, , benzyl alcohol, phenylethyl 0420 Diaminodiphenylsulfone, rifampicillin, etc. alcohol, dehydroacetic acid, Sorbic acid, etc. 0421 (v) Antiviral agents 04.09 Examples of anti-oxidant include sulfite, ascorbic 0422 Idoxuridine, acyclovir, Vidarabine, ganciclovir, etc. acid, C.-tocopherol, etc. 0423 (vi) Anti HIV drugs 0410. During the prevention and/or treatment of various 0424 Zidovudine, didanosine, Zalcitabine, indinavir sul diseases, the compounds of the present invention can be fate ethanolate, ritonavir, etc. used together with other agents. Hereinafter, drugs which are 0425 (vii) Anti-spirochetal drugs used when the compounds of the present invention are used 0426 (viii) Antibiotics concomitantly with other drugs will be referred to as “com 0427 Tetracycline hydrochloride, amplicillin, piperacil bined used agents of the present invention'. lin, gentamicin, dibekacin, kanendomycin, lividomycin, 0411. The TLR4 signaling inhibiting substance can be tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, co-used concomittantly with other drugs. Examples of Such oxytetracycline, rollitetracycline, doxycycline, amplicillin, co-used drugs include antibacterial agents, antifungal piperacillin, ticarcillin, cephalothin, cephapirin, cephalori agents, nonsteroidal antiinflammatory drugs, steroid drugs, dine, cefaclor, cephalexin, cefroxadine, cefadroxil, cefaman anticoagulants, antiplatelet drugs, thrombolytic drugs, dole, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime immunomodulators, antiprotozoal drugs, antitussive-expec axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, torant drugs, sedatives, anesthetic drugs, narcotic antago cefsulodin, cefimenoxime, cefpodoxime proxetil, cefpirome, nists, antiulcer drugs, drugs for treating hyperlipidemia, cefoZopran, cefepime, cefsulodin, cefimenoXime, cefineta drugs for treating arteriosclerosis, HDL elevating drugs, Zole, cefiminox, cefoxitin, cefbuperaZone, latamoxef, flo unstable plaque stabilization drugs, myocardial protective moxef, cefazolin, cefotaxime, cefoperaZone, ceftizoxime, agents, drugs for treating hypothyroidism, drugs for treating moxalactam, thienamycin, Sulfazecin, aztreonam or salts nephrotic syndrome, drugs for treating chronic renal failure, thereof, griseofulvin, Lankacidin species (J. Antibiotics, 38. diuretics, antihypertensive drugs, drugs for treating cardiac 877-885 (1985) and the like. failure, muscle relaxants, antiepileptic drugs, cardiotonics, 0428 (2) Antifungal Drugs vasodilators, vasoconstrictors, drugs for treating arrhythmia, 0429 (i) polyene antibiotics (for example, amphotericin drugs for treating diabetic mellitus, vasopressor, tranquil B, nystatin, trichomycin) izer, antipsychotic, drugs for treating Alzheimer's disease, 0430 (ii) griseofulvin, pyrrolnitrin, etc. antiparkinsonian agents, drugs for treating amyotrophic lat 0431 (iii) cytosine metabolism antagonists (for example, eral Sclerosis, nerve nutritional factors, antidepressants, flucytosine) drugs for treating schizophrenia, anticancer drugs, Vitamin 0432 (iv) Imidazole derivatives (for example, econazole, drugs, Vitamin derivatives, drugs for treating arthritis, anti clotrimazole, miconazole nitrate, bifonazole, croconazole) rheumatics, antiallergic drugs, antiasthmatic drugs, drugs for 0433 (v) triazole derivatives (for example, fluconazole, treating atopic dermatitis, drugs for treating allergic rhinitis, itraconazole, azole compounds (2-((1R,2R)-2-(2, 4-difluo drugs for treating pollakiuria/involuntary micturition, pro rophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl) teolytic drugs, protease inhibitors, anti SIDS drugs, antisep propyl)-4-(4-(2,2,3,3-tetrafluoropropoxy)phenyl)-3(2H, sis drugs, anti septic shock drugs, endotoxin antagonists or 4H)-1,2,4-triazolone) antibodies, signal transduction inhibitors, inflammatory 0434 (vi) thiocarbamic acid derivatives (for example, mediator action inhibitors, inflammatory mediator action tolnaftate) inhibiting antibodies, inflammatory mediator production 0435 (vii) Echinocandin derivatives (for example caspo inhibitors, antiinflammatory mediator action depressant, fungin, micafungin, anidulafungin). antiinflammatory mediator action inhibiting antibody, anti 0436 (3) Nonsteroidal Antiinflammatory Drugs inflammatory mediator production inhibitor, a1 adrenergic 0437 Acetaminophen, phenacetin, ethenZamide, Sulpy agents, antiemetics, agents for preventing elevated methe rine, antipyrine, Migrenin, aspirin, , flufe moglobin, etc. Among these, anticancer drugs, antibacterial namic acid, diclofenac sodium, loxoprofen Sodium, phe agents, antifungal agents, nonsteroidal antiinflammatory nylbutaZone, indomethacin, ibuprofen, ketoprofen, drugs, steroid drugs, anticoagulants, antiemetics, agents for naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, preventing elevated methemoglobin, etc. are preferred. The floctafenine, epirizole, tiaramide hydrochloride, Zaltoprofen, following comprise specific examples. gabexate mesilate, camo.stat mesilate, ulinastatin, colchi US 2016/0326102 A1 Nov. 10, 2016 cine, probenecid, Sulfinpyrazone, benzbromarone, allopuri 0460 (13) Narcotic Antagonists nol, Sodium aurothiomalate, Sodium hyaluronate, sodium 0461) Levallorphan, nalorphine, naloxone and salts salicylate, morphine hydrochloride, Salicylic acid, atropine, thereof, etc. Scopolamine, morphine, pethidine, , ketoprofen, 0462 (14) Antiulcer Drugs naproxen, oxymorphone, meloxicam, celecoxib, rofecoxib 0463 Metoclopromide, histidine hydrochloride, lanso and salts thereof, etc. prazole, metoclopramide, pirenzepine, cimetidine, raniti 0438 (4) Steroid Drugs dine, famotidine, urogastrin, oxethazaine, proglumide, 0439 Dexamethasone, hexestrol, methimazole, betame omeprazole. Sucralfate, Sulpiride, cetraxate, gefarnate, aldi thasone, triamcinolone, triamcinolone acetonide, fluocinon oxa, teprenone, prostaglandin, etc. ide, fluocinolone acetonide, prednisolone, methylpredniso 0464 (15) Drugs for Treating Hyperlipidemia lone, cortisone acetate, hydrocortisone, fluorometholone, 0465 HMG-Co Reductase inhibitors (for example, fluv beclomethasone propionate, estriol, etc. astatin, cerivastatin, atorvastatin, etc.), fibrate system agents 0440 (5) Anticoagulants (for example, simfibrate, aluminum clofibrate, clinofibrate, 0441 Heparin sodium, sodium citrate, activated protein fenofibrate, etc.), bile acid adsorbents (for example, C, tissue factor pathway inhibitors, antithrombin III, cholestyramine, etc.), nicotinic acid preparation (for dalteparin Sodium, warfarin potassium, argatroban, gabex example, nicomol, niceritrol, tocopherol nicotinate, etc.), ate, Sodium citrate, etc. probucol and derivatives thereof, polyunsaturated fatty acid 0442 (6) Antiplatelet Drugs derivative (for example, ethyl icosapentate, polyene phos 0443 OZagrel sodium, ethyl icosapentate, beraprost phatidylcholine, melinamide, etc.), plant sterols (for Sodium, alprostadil, ticlopidine hydrochloride, pentoxifyl example, yoryZanol, Soy Sterol, etc.), elastase, dextran Sul line, dipyridamole, etc. fate sodium, squalene synthase inhibitors, squalene epoxi 0444 (7) Thrombolytic Drugs dase inhibitors, CETP inhibitors, 2-chloro-3-(4-(2-methyl 0445 Tisokinase, urokinase, Streptokinase, etc. 2-phenyl propoxy) phenyl) propionic acid ethyl ester 0446 (8) Immunomodulators (Chem, Pharm. Bull), 38, 2792-2796 (1990), LDL receptor 0447 Cyclosporine, tacrolimus, gusperimus, azathio enhancer, cholesterol absorption inhibitors (EZetimibe, etc.), prine, antilymphocyte serum, dried Sulfonated immuno MTP inhibitors, ileal bile acid transporter inhibitors, SCAP globulin, erythropoietin, colony stimulating factor, interleu ligand, FXR ligands, etc. kin, interferon, etc. 0466 (16) Drugs for Treating Arteriosclerosis 0448 (9) Antiprotozoal Drugs 0467 MMP inhibitors, chymase inhibitors, ACAT inhibi 0449 Metronidazole, tinidazole, diethylcarbamazine cit tors (Avasimibe, Eflucimibe, etc.), apoAI Milano and ana rate, quinine hydrochloride, quinine Sulfate, etc. logue thereof, Scavenger receptor inhibitors, 15-lipoxy 0450 (10) Antitussive-Expectorant Drugs genase inhibitors, phospholipase A2 inhibitors, ABCA1 0451 Ephedrine hydrochloride, noscapine hydrochlo activator, LXR ligand, sphingomyelinase inhibitors, ride, codeine phosphate, dihydrocodeine phosphate, isopro paraoxonase activator, estrogen receptor agonists, etc. terenol hydrochloride, ephedrine hydrochloride, methyl 0468 (17) HDL-Elevating Drugs ephedrine hydrochloride, noscapine hydrochloride, 0469 Squalene synthase inhibitors, CETP inhibitors, alloclamide, chlorphedianol, picoperidamine, cloperastine, LPL activators, etc. protokylol, isoproterenol, salbutamol, terbutalin, oxymete 0470 (18) Unstable Plaque Stabilizing Drugs banol, morphine hydrochloride, dextropethorphan hydro 0471) MMP inhibitors, chymase inhibitors, ACAT inhibi bromide, oxycodone hydrochloride, phosphoric acid dimor tors, lipid rich plaque retraction agents, etc. phan, tipepidine hibenzate, pentoxyverine citrate, clofedanol 0472 (19) Myocardial Protective Agents hydrochloride, benzonatate, guaifenesin, bromhexine hydro 0473 Oral agents for cardiac ATP-K, endothelin antago chloride, ambroXol hydrochloride, acetylcysteine, cysteine nists, urotensin antagonists, etc. ethyl ester hydrochloride, carbocisteine, etc. 0474 (20) Drugs for Treating Hypothyroidism 0452 (11) Sedatives 0475. Desicated thyroid (Chireoido), sodium levothyrox 0453 Chlorpromazine hydrochloride, atropine sulfate, ine (Thyradin-S), liothyronine sodium (thyronine, thyrom , , , , thiopen ine) and the like. tal sodium, Sodium, , , flu 0476 (21) Drugs for Treating Nephrotic Syndrome razepam, , , , bromval 0477 Prednisolone (predonine), prednisolone sodium erylurea, hydrate, sodium, etc. Succinate (predonine), methylprednisolone sodium Succi 0454 (12) Anesthetic Drugs nate (Solu-Medrol), betamethasone (Rinderon), and the like. 0455 (12-1) Local Anesthetics 0478 (22) Agents for Treating Chronic Renal Failure 0456 Cocaine hydrochloride, procaine hydrochloride, 0479. Diuretics (for example, furosemide (Lasix), lidocaine, dibucaine hydrochloride, tetracaine hydrochlo bumetanide (Lunetoron), azosemide (Diart)). Antihyperten ride, mepivacaine hydrochloride, bupivacaine hydrochlo sive agents (for example, ACE inhibitors, enalapril maleate ride, Oxybuprocaine hydrochloride, ethylaminobenzoic acid, (Renivace), calcium antagonists (manidipine), a receptor oxethazaine and the like. blockers, AII antagonists (Candesartan)) and the like. 0457 (12-2) General Anesthetics 0480 (23) Diuretics 0458 (i) Inhalation anesthetics (for example, ether, 0481. Thiazide derivative diuretics (benzylhydrochloro , , influran, ) thiazide, cyclopenthiazide, ethiazide, hydrochlorothiazide, 0459 (ii) Intravenous anesthetics (for example, ketamine hydroflumethiazide, methylclothiazide, penfluthiazide, hydrochloride, droperidol, thiopental sodium, thiamylal polythiazide, trichlormethiazide, etc.), loop diuretics (chlo sodium, pentobarbital) and the like. rthalidone, clofenamide, indapamide, mefruside, meticrane, US 2016/0326102 A1 Nov. 10, 2016 22

SotolaZone, tripamide, quinethaZone, metolaZone, furo (0503 (30) Vasoconstrictors semide, etc.), potassium sparing diuretics (spironolactone, 0504 Dopamine, dobutamine denopamine, etc. triamterene, etc.). 0505 (31) Drugs for treating arrhythmia 0482 (24) Antihypertensive Drugs 0506 (i) Sodium channel blockers (for example, quini 0483 (i) Sympatholytic Agents dine, procainamide, disopyramide, ajmaline, cibenzoline, 0484 C.2 agonist (for example, clonidine, guanabenz, lidocaine, diphenylhydantoin, mexiletine, propafenone, fle guanfacine, methyldopa, etc.), gangliolytic (for example, cainide, pilsicainide, , etc.) hexamethonium, trimethaphan, etc.), presynaptic blockers 0507 (ii) (blockers (for example, propranolol, alprenolol, (for example, alseroxylon, dimethylamino reserpinate, res bufetolol, oxprenolol, atenolol, acebutolol, metoprolol, biso cinnamine, reserpine, Syrosingopine, etc.), neuron blockers prolol, pindolol, carteolol, arotinolol, etc.) (for example, betanidine, guanethidine, etc.), C.1 blockers 0508 (iii) Potassium channel blockers (for example, (for example, bunaZosin, doxazosin, prazosin, teraZosin, amiodarone, etc.) urapidil, etc.), B blockers (for example, propranolol, nadolol. 0509 (iv) Calcium channel blockers (for example, Vera timolol, nipradillol, bunitrolol, indenolol, penbutolol, car pamil, diltiazem, etc.), and the like. teolol, carvedilol, pindolol, acebutolol, atenolol, bisoprolol. 0510 (32) Vasopressors metoprolol, labetalol, amoSulalol, arotinolol, etc.) and the 0511 Dopamine, dobutamine, denopamine, digitoxin, like. digoxin, methyldigoxin, lanatoside C, G-strophanthin, etc. 0512 (33) Drugs for Treating Diabetic Mellitus 0485 (ii) Vasodilators 0513 Sulfonylurea agents (for example, tolbutamide, 0486 Calcium channel antagonists (for example, mani chlorpropamide, glyclopyramide, acetohexamide, tolaZ dipine, , nilvadipine, nisoldipine, nitrendipine, amide, glibenclamide, glybuzole, etc.), biguanide agents (for benidipine, amlodipine, aranidipine, etc.), phthalazines (for example, metformin hydrochloride, bulformin hydrochlo example, budralazine, cadralazine, ecarazine, hydralazine, ride, etc.), C-glucosidase inhibitors (for example, Voglibose, todralazine, etc.) and the like. acarbose, etc.), insulin sensitizers (for example, pioglita 0487 (iii) ACE Inhibitors Zone, roZiglitaZone, troglitaZone, etc.), insulin, glucagon, 0488 Alacepril, captopril, cilazapril, delapril, enalapril, agents for treating diabetis complications (for example, lisinopril, temocapril, trandolapril, quinapril, imidapril, epalrestat, etc.), DPP4 inhibitors (for example, sitagliptin, benazepril, perindopril, etc. Vildagliptin, Alogliptin, linagliptin, etc.) and the like. 0489 (iv) AII Antagonists 0514 (34) Tranquilizers 0490 Losartan, Candesartan, Valsartan, Telmisartan, 0515 , , , chlordiazepox Irbesartan, forasartan, etc. ide, , , , , bro 0491 (v) Diuretics mazepam, , , hydroxy Zine, etc. 0492 (for example, said diuretics, etc.). 0516 (35) Antipsychotics 0493 (25) Drugs for Treating Cardiac Failure 0517 Chlorpromazine hydrochloride, prochlorperazine, 0494 Cardiotonics (for example, digitoxin, digoxin, trifluoperazine, thioridazine hydrochloride, perphenazine methyldigoxin, lanatoside C, proscillaridin, etc.), a, 3 ago maleate, fluiphenazine enanthate, prochlorperazine maleate, nists (for example, epinephrine, norepinephrine, isoprotere levomepromazine maleate, promethazine hydrochloride, nol, dopamine, docarpamine, dobutamine, denopamine, haloperidol, bromperidol, spiperone, reserpine, clo etc.), phosphodiesterase inhibitors (for example, amrinone, capramine hydrochloride, Sulpiride, Zotepine, etc. milrinone, olprinone hydrochloride, etc.) calcium channel 0518 (36) Drug for Treating Alzheimer's Diseases sensitizers (for example, pimobendan, etc.), nitrovasodila 0519 (i) Cholinesterase inhibitors such as donepezil, tors (for example, nitroglycerin, isosorbide dinitrate, etc.), rivastigmine, galantamine, etc. ACE inhibitors (for example, said ACE inhibitor, etc.), 0520 (ii) Cerebral function activators, etc. such as ide diuretics (for example, said diuretic, etc.), carperitide, ubi benone, memantine, Vinpocetine, etc. decarenone, Vesnarinone, aminophylline, etc. 0521 (37) Antiparkinsonian Agents 0522 L-DOPA, deprenyl, carbidopa-i-levodopa, per 0495 (26) Muscle Relaxants golide, ropinirole, cabergoline, pramipexole, entacapone, 0496 Pridinol, tubocurarine, pancuronium, tolperisone lazabemide, etc. hydrochloride, chlorphenesin carbamate, , chlorme 0523 (38) Drugs for Treating Amyotrophic Lateral Scle Zanone, mephenesin, chlorZoxazone, eperisone, tizanidine, rosis etc. 0524 Riluzole, mecasermin, gabapentin, etc. 0497 (27) Antiepileptic Drugs 0525 (39) Antidepressants 0498 Phenytoin, ethosuximide, acetazolamide, chlordi 0526 Imipramine, clomipramine, noxiptiline, phenel azepoxide, trimethadione, , phenobarbital, zine, amitriptyline hydrochloride, nortriptyline hydrochlo , Sultiame, sodium valproate, , diaz ride, amoxapine, mianserin hydrochloride, maprotiline epam, nitrazepam, etc. hydrochloride, Sulpiride, fluvoxamine maleate, traZodone 0499 (28) Cardiotonics hydrochloride, etc. 0500 aminophylline, etillefrine, dopamine, dobutamine, 0527 (40) Drugs for Treating Schizophrenia denopamine, aminophylline, amrinone, pimobendane, ubi 0528 Olanzapine, risperidone, quetiapine, iloperidone, decarenone, digitoxin, digoxin, methyldigoxin, lanatoside etc C, G-strophanthin, etc. 0529 (41) Anticancer Drugs 0501 (29) Vasodilators 0530 6-O-(N-chloroacetylcarbamoyl)fumagillol, bleo 0502. Oxyfedrine, diltiazem, tolazoline, hexobendine, mycin, methotrexate, actinomycin D. mitomycin C, dauno bamethan, clonidine, methyldopa, guanabenz, etc. rubicin, adriamycin, neocarzinostatin, cytosine arabinoside, US 2016/0326102 A1 Nov. 10, 2016 fluorouracil, tetrahydrofuryl-5-fluorouracil, Picibanil, lenti peptide compounds such as JTE-607, eritoran, S-5920, nan, levamisole, bestatin, azimexon, glycyrrhizin, doxoru FR-167653, ONO-1714, ONO-5046(sivelestat), bicin hydrochloride, aclarubicin hydrochloride, bleomycin GW-273629, RWJ-67657, GR-270773, NOX-100, hydrochloride, peplomycin Sulphate, Vincristine Sulfate, Vin GR-270773, NOX-100, INO-1001, etc. and the like. blastine Sulfate, irinotecan hydrochloride, cyclophosph 0553 (50) Drugs for Improving Prognosis after Coronary amide, melphalan, buSulfan, thiotepa, procarbazine hydro Artery Bypass Surgery chloride, cisplatin, azathioprine, mercaptopurine, tegafur, 0554 Eritoran, etc. carmofur, cytarabine, methyl , testosterone pro pionate, testosterone enanthate, mepitioStane, fosfestrol, 0555 (51) Antiemetics chlormadinone acetate, leuprorelin acetate, buserelin 0556 Phenothiazine derivatives, 5-HT3 receptor antago acetate, paclitaxel, docetaxel, oxaliplatin, Vincristine, Vin nists, etc. blastine, cisplatin, carboplatin, bortezomib, etc. 0557 (52) Agents for Preventing Elevated Methemoglo 0531 (42) Vitamin Drugs bin 0532 (i) Vitamin A types: Vitamin A, Vitamin A and 0558 Methylene blue, ascorbic acid, etc. retinol palmitate 0559 (53) Anticytokine agents 0533 (ii) Vitamin D types: Vitamin D, D, D, D, and 0560 (I) Protein Preparations Ds 0534 (iii) Vitamin E types: C-tocopherol, B-tocopherol, 0561 (i) TNF inhibitors Y-tocopherol, 8-tocopherol, nicotinic acid dl-C-tocopherols 0562 Etanercept, Infliximab, adalimubab, certolizumab 0535 (iv) Vitamin K types: Vitamin K. K. K. and K pegol, golimumab, PASSTNF-C. soluble TNF-C. receptor, 0536 (v) Folic acid (Vitamin M) TNF-C. binding protein, anti TNF-C. antibody, etc. 0537 (vi) Vitamin B types: Vitamin B, Vitamin B, 0563 (ii) Interleukin-1 inhibitors Vitamin B, Vitamin Bs, Vitamin B and Vitamin B 0564 Anakinra (interleukin-1 receptor antagonists), 0538 (vii) Biotin (Vitamin H), etc. soluble interleukin-1 receptor, etc. 0539 (43) Vitamin Derivatives 0565 (iii) Interleukin-6 inhibitors 0540 Various vitamin derivatives such as, for example, 0566 Tocilizumab (anti interleukin-6 receptor antibody), ascorbic acid, Vitamin D derivatives Such as 5, 6-trans anti interleukin-6 antibody, etc. cholecalciferol. 2, 5-hydroxycholecalciferol and 1-O-hy 0567 (iv) Interleukin-10 drugs droxycholecalciferol, etc., Vitamin D derivatives such as 5, 6-trans-ergocalciferol, etc., etc. 0568 Interleukin-10, etc. 0541 (44) Antiallergic Drugs 0569 (v) Interleukin-12/23 inhibitors 0542 Diphenhydramine, chlorpheniramine, 0570 Ustekinumab, briakinumab (anti interleukin-12/23 tripelennamine, clemizole, diphenylpyraline, methoxyphe antibody), etc. namine, disodium cromoglycate, tranilast, repirinast, aml (0571 (vi) interleukin-17 inhibitors exanox, ibudilast, ketotifen, terfenadine, meduitazine, 0572. Secukinumab, ixekizumab, brodalumab, etc. aZelastine, epinastine, OZagrel hydrochloride, Pranlukast (0573 (II) Non-Protein Preparations hydrate, seratrodast, etc. 0574 (i) MAPK inhibitors 0543 (45) Antiasthmatic Drugs 0544 Isoprenaline hydrochloride, salbutamol sulphate, 0575 BMS-582949, etc. procaterol hydrochloride, terbutaline sulfate, trimetoquinol (0576 (ii) Gene control drugs hydrochloride, tulobuterol hydrochloride, orciprenaline sul 0577. Inhibitors of molecules related to signal transduc fate, fenoterol hydrobromide, ephedrine hydrochloride, ipra tions such as NF-K, NF-kB, IKK-1, IKK-2, AP-1, etc. tropium bromide, oxitropium bromide, flutropium bromide, (0578 (iii) Cytokine production inhibitors theophylline, aminophylline, disodium cromoglycate, tranil 0579. Iguratimod, tetomilast, etc. ast, repirinast, ibudilast, ketotifen, terfenadine, meduitazine, 0580 (iv) TNF-C. converting enzyme inhibitors aZelastine, epinastine, OZagrel hydrochloride, Pranlukast 0581 (v) Interleukin-1 B converting enzyme inhibitors hydrate, seratrodast, dexamethasone, prednisolone, hydro 0582 VX-765, etc. cortisone, beclomethasone proprionate, etc. 0545 (46) Drugs for Treating Atopic Dermatitis 0583 (vi) Interleukin-6 antagonists 0546 Disodium cromoglycate, etc. 0584 HMPL-004, etc. 0547 (47) Drugs for Treating Allergic Rhinitis 0585 (vii) Interleukin-8 inhibitors 0548 Disodium cromoglycate, chlorpheniramine 0586 IL-8 antagonists, CXCR1 & CXCR2 antagonists, maleate, alimemazine tartrate, clemastine fumarate, cefalexin, etc. homochlorcyclizine hydrochloride, terfenadine, meduita 0587 (viii) chemokine antagonists Zine, etc. 0588 CCR9 antagonists (CCX-282, CCX-O25), MCP-1 0549 (48) Drugs for Treating Pollakiuria/Involuntary antagonists, etc. Micturition 0589 (ix) Interleukin-2 receptor antagonists 0550 Flavoxate hydrochloride, etc. 0590 Denileukin, diftitox, etc. 0551 (49) Antisepsis Drugs 0552. Peptide compounds such rBPI-21 (bactericidal per 0591 (x) Therapeutic vaccines meability increasing protein), BI-51017 (antithrombin III), 0592 TNF-C. vaccine, etc. SC-59735(rTFPI), r-PAF acetylhydrolase, LY-203638 (r-ac 0593 (xi) Gene therapy drugs tivated protein C), anti TNF-C. antibody, anti CD14 antibody, 0594 Gene therapy drugs having the object of elevating CytoPab, alkaline phosphatase (LPS inactivator), etc., non expression of genes having antiinflammatory effect such as US 2016/0326102 A1 Nov. 10, 2016 24 interleukin-4, interleukin-10, soluble interleukin-1 receptor, 0606. The content of co-used drug in the combined use soluble TNF-C. receptor, etc. agent of the present invention, differs depending on the form 0595 (xii) Antisense compounds of the preparation, however, said content is usually about 0596 ISIS-104838, etc. 0.01 to 100 wt.%, preferably about 0.1 to 50 wt.%, and 0597 (54) Integrin Inhibitors more preferably about 0.5 to 20 wt.% with respect to the 0598 Natalizumab, vedolizumab, AJM300, TRK-170, whole pharmaceutical preparation. E-6007, etc. 0607. The content of additive such as carrier, etc. in the 0599 Antidepressant drugs (for example, amitriptyline, combined use agent of the present invention, differs depend imipramine, clomipramine, desipramine, doxepin, nortrip ing on the form of the preparation, however said content is tyline, dulloxetine, milnacipran, , paroxetine, Ser usually about 1 to 99.99 wt.%, preferably about 10 to 90 wt. traline, citalopram, etc.) Anticonvulsants drugs (for % with respect to the whole pharmaceutical preparation. example, carbamazepine, pregabalin, gabapentin, lam 0608 Moreover, the compound of the present invention otrigine, phenytoin, valproic acid, etc.) and co-used drug may be contained in similar contents when 0600 Narcotics (for example, morphine, oxycodone, fen each are respectively formulated pharmaceutically sepa tanyl, methadone, codeine, tramadol, etc.). rately. 0601 (55) Others 0609. The dose differs depending on the type of the 0602 Hydroxycam, diacerein, megestrol acetate, nicer compound of the present invention, the administration route, goline, prostaglandins, etc. the symptoms and the age of patient, etc., and, for example, 0603 During combined use, the times of administration when compound (I) is orally administered to a patient (about of the compound of the present invention and the co-used 60 kg in weight) with chemotherapy-induced peripheral drug are not restricted, and compounds of the present neuropathy (CIPN), chemotherapy-induced neuropathic invention and co-used drug may be administered at the same pain (CINP), liver injury and/or ischemia-reperfusion injury or different times with respect to an administration subject. (IRI), about 0.1 mg/kg body weight to about 30 mg/kg body If the dose of the co-used drug is in accordance with the dose weight, preferably about 1 mg/kg to 20 mg/kg in weight used clinically, then the co-used dose can be suitably body weight are administered per day, either in one admin selected depending on the administration Subject, adminis istrative dose or divided several times. tration route, disease and combination. The form of the administration of the combination is not restricted in par 0610 The dose when the drug of the present invention is ticular, and the compound of the present invention and a slow release preparation varies depending on the kind and co-used drug may be combined during administration. As the content of compound (I), the agent form, the duration of Such form of administration, for example, (1) administration the drug release, the administered subject animal (for of single pharmaceutical preparation obtained by formulat example, mammalian organism Such as mouse, rat, hamster, ing the compound of the present invention and a co-used guinea pig, rabbit, cat, dog, cow, horse, pig, sheep, monkey, drug at the same time, (2) administration at the same time human, etc.) and the purpose of the administration, but for and by the same administration route of two kinds of example when applied by parenteral administration, about pharmaceutical preparations in which the compound of the 0.1 to 100 mg of compound (1) should be released from the present invention and the co-used drug are separately for administered pharmaceutical preparation over a week. mulated, (3) administration at different times but by the 0611. The co-used drug can be established in an amount same administration route of two kinds of pharmaceutical within a range with which adverse reactions are not a preparations in which the compound of the present invention problem. The daily dose of the co-used drug varies depend and the co-used drug are separately formulated, (4) admin ing on the severity of the symptoms, the age, gender, body istration at the same time but by different administration weight and sensitivity of the administration Subject, the routes of two kinds of pharmaceutical preparations in which duration of administration, the interval, the properties, com the compound of the present invention and the co-used drug pound and kind of drug preparation and the type of active are separately formulated, and (5) administration at different ingredient; and is not limited in particular, however, usually times and by different administration routes of two kinds of the dose of drug by oral administration is about 0.001 to pharmaceutical preparations in which the compound of the 2000 mg, preferably about 0.01 to 500 mg, more preferably present invention and the co-used drug are separately for about 0.1 to 100 mg per 1 kg body weight of mammalian mulated, (for example, administration of co-used drug after organism; divided by 1 to 4 times per day. having administered the compound of the present invention 0612. When a co-used drug of the present invention is or administration in the reverse order to this), may be administered, the compound of the present invention and proposed. co-used drug may be administered over the same time 0604. The compounding ratio of the compound of the periods, or may be administered over different time periods. present invention and co-used drug in the combined use When administered over different periods, the time differ agent of the present invention can be Suitably selected ence varies depending on the administered active ingredient, depending on the administration Subject, the administration formulation and administration method, however, for route, the disease, etc. example, when the co-used drug is administered first, a 0605 For example, the content of the compound of the method may be adopted wherein the compound of the present invention in the combined use agent of the present present invention is administered within 1 minute to 3 days, invention, differs depending on the form of the preparation, preferably within 10 minutes to 1 day, more preferably still however, said content is usually about 0.01 to 100 wt.%. 15 minutes to 1 hour, after administration of the co-used preferably about 0.1 to 50 wt.%, and more preferably about drug. When the compound of the present invention is 0.5 to 20 wt.% with respect to the whole pharmaceutical administered first, a method may be adopted wherein the preparation. co-used drug is administered within 1 minute to 1 day, US 2016/0326102 A1 Nov. 10, 2016 preferably 10 minutes to 6 hours, more preferably 15 min Example 1 utes to 1 hour, after the administration of the compound of the present invention. Ethyl 6-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfo nyl)cyclohex-1-ene-1-carboxylate (a mixture of 4 EXAMPLES stereoisomers) 0613. The present invention will now be described in (0643 Step A detail by reference to the following Examples, Test 0644 Sodium borohydride (1.7 g) was added with ice Examples and Preparation Examples, but the invention is in cooling to an ethanol Solution (60 mL) of 4-chloroindan-1- no way limited by these, and moreover changes may be one (5.0 g) and the mixture was stirred at room temperature made thereto within a range that do not deviate from the for one hour. About half of the solvent was eliminated by Scope of the present invention. distillation under reduced pressure, and water was added to 0614. In the following Examples, “room temperature' the residue and extraction performed with ethyl acetate. The usually denotes about 10° C. to about 35° C. The ratios liquid extract was washed with Saturated aqueous sodium shown for mixed solvents denote the ratios by volume, chloride solution and was dried with sodium sulfate, and the unless otherwise stated in particular. '% denotes wt.% unless solvent was eliminated by distillation under reduced pres otherwise stated in particular. Sure, and 4-chloroindan-1-ol (5.0 g) was obtained as a white 0615. In HPLC (high performance liquid chromatogra solid. phy), a description of C18, denotes that octadecyl-bonded (0645 H NMR (300 MHz, CDC1) & 1.77 (1H, d, J=7.2 silica gel was used. The ratios for the eluting solvents denote Hz), 1.91-2.03 (1H, m), 2.47-2.59 (1H, m), 2.79-2.90 (1H, the ratios by volume unless otherwise stated in particular. m), 3.05-3.16 (1H, m), 5.25-5.32 (1H, m), 7.17-7.33 (3H, 0616) The following abbreviations are used in the fol m). lowing Examples. (0646 Step B 0617 mp: Melting point 0647 Phosphorous tribromide (2.8 mL) was added at 0° 0618 MS: Mass spectrum C. to a diethyl ether solution (70 mL) of 4-chloroindan-1-ol 0619. M+H" (M-H): Molecular ion peaks (5.0 g) and the mixture was stirred at the same temperature 0620 M: Molar concentration for four hours. The reaction mixture was diluted with 0621 N: Normal saturated aqueous sodium bicarbonate solution and 0622 CDC1: Deuterated chloroform extracted with ethyl acetate. The liquid extract was washed 0623 DMSO-d: Deuterated dimethyl sulfoxide with saturated aqueous sodium chloride solution and was 0624 'H NMR: Proton nuclear magnetic resonance dried with magnesium sulfate, and the solvent was elimi 0625 LC/MS: Liquid chromatograph mass spectrometer nated by distillation under reduced pressure, and 1-bromo 0626. ESI: Electrospray Ionization 4-chloroindane (6.83 g) was obtained as a colorless oily 0627 APCI: Atmospheric Pressure Chemical Ionization Substance. 0628 SFC: Supercritical fluid chromatography (0648 H NMR (300 MHz, CDC1,) & 2.47-2.72 (2H, m), 0629. THF: Tetrahydrofuran 2.92-3.05 (1H, m), 3.11-3.26 (1H, m), 5.57 (1H, dd, J=6.2, 0630 DME: 1,2-dimethoxyethane 2.5 Hz), 7.15-7.26 (2H, m), 7.31 (1H, d, J=7.6 Hz). 0631 IPE: Diisopropyl ether (0649 Step C 0632. DMF: N,N-dimethylformamide 0650 Potassium carbonate (7.74 g) was added at room 0633 DMA: N,N-dimethylacetamide temperature to a mixture of glutaraldehyde (5.6 M aqueous 0634) NMP: N-methyl-2-pyrrollidone solution, 150 mL) and ethyl (diethoxyphosphoryl)acetate 0635. DMSO: Dimethyl sulfoxide (115 mL), and the mixture was stirred at the same tempera 0636 CPBA: m-Chloroperbenzoic acid ture for one hour. An aqueous solution (300 mL) of potas 0637 TMSOTf: Trimethylsilyl triflate sium carbonate (116 g) was added to the reaction mixture, 0638 DBU: 1,8-diazabicyclo[5.4.0-7-undecene. and it was stirred overnight at the same temperature. Sodium 0639 H NMR was measured with a Fourier transform chloride (100 g) was added to the reaction mixture and NMR. ACD/SpecManager (brand name) etc., was used for extraction was performed with ethyl acetate. The liquid the analysis. No description is provided for the extremely extract was concentrated, and the residue was purified by slight peaks of the protons of, for example, hydroxy groups silica gel column chromatography (ethyl acetate/hexane) and amino groups, etc. and ethyl 6-hydroxycyclohex-1-ene-1-carboxylate (54.6 g) 0640 The MS was measured using an LC/MS. The was obtained as a colorless oily Substance. ionization method used was an ESI method or APCI method. 0651 H NMR (300 MHz, CDC1) & 129-134 (3H, m), The data described is the actual values (found). Usually the 1.54-1.62 (1H, m), 1.71-1.85 (3H, m), 2.10-2.30 (2H, m), molecular ion peaks are seen, but when a compound has a 3.13 (1H, d, J=2.6 Hz), 4.24 (2H, q, J=6.9 Hz), 4.54 (1H, t-butoxycarbonyl group, a peak after elimination of a tert brs), 7.10 (1H, t, J=4.0 Hz). butoxycarbonyl group or tert-butyl group may be observed 0652 Step D as a fragment ion. Moreover, in the case of a compound 0653 N.N-dimethyl-4-aminopyridine (3.88 g) and acetic having a hydroxy group, a peak after the elimination of H2O anhydride (90 mL) were successively added at room tem may be observed. In the case of a salt, usually a fragmention perature to a pyridine solution (350 mL) of ethyl 6-hydroxy peak or the molecular ion peak of the compound is observed. cyclohex-1-ene-1-carboxylate (54.0 g), and the mixture was 0641. In the optical rotation ((a),), the unit of the sample stirred at the same temperature for one hour. The reaction concentration (c) is g/100 mL. mixture was diluted with Saturated aqueous sodium bicar 0642 For the elemental analysis values (Anal), theoreti bonate solution and extraction was performed with ethyl cal values (Calcd) and the actual values (Found) are pro acetate. The liquid extract was washed with Saturated aque vided. ous sodium bicarbonate solution and Saturated aqueous US 2016/0326102 A1 Nov. 10, 2016 26

Sodium chloride solution and was dried with magnesium 0663 Step H sulfate, and the solvent was eliminated by distillation under 0664 mCPBA (4.14g, 72%) was added with ice cooling reduced pressure. The residue was purified by silica gel to a mixture of ethyl 6-((4-chloro-2,3-dihydro-1H-inden-1- column chromatography (ethyl acetate/hexane) and ethyl yl)sulfanyl)cyclohex-1-ene-1-carboxylate (a mixture of 4 6-acetoxycyclohex-1-ene-1-carboxylate (42.0 g) was Stereoisomers) (338 mg) and acetonitrile (4 mL), and the obtained as a colorless oily Substance. mixture was stirred at room temperature for one hour. The 0654 MS: M+H 213.2. reaction mixture was diluted with Saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The 0655 Step E liquid extract was washed with aqueous Sodium chloride 0656 Triethylamine (30.3 mL) and potassium thioacetate Solution and was dried with magnesium sulfate, and the (27.1 g) were successively added at room temperature to an solvent was eliminated by distillation under reduced pres ethanol solution (320 mL) of ethyl 6-acetoxycyclohex-1- Sure. The residue was purified by silica gel column chro ene-1-carboxylate (42.0 g), and the mixture stirred overnight matography (ethyl acetate/hexane) and ethyl 6-((4-chloro at the same temperature. The reaction mixture was concen 2,3-dihydro-1H-inden-1-yl)sulfonyl)cyclohex-1-ene-1- trated under reduced pressure, and water was added to the carboxylate (a mixture of 4 stereoisomers) (342 mg) was residue and extraction was performed with ethyl acetate. The obtained as a colorless oily Substance. liquid extract was washed with Saturated aqueous sodium 0665 H NMR (300 MHz, CDC1) & 1.30-140 (3H, m), chloride solution and was dried with sodium sulfate, and the 1.53-1.79 (2H, m), 1.94-2.15 (1H, m), 2.17-2.32 (1H, m), solvent was eliminated by distillation under reduced pres 2.35-2.52 (2.5H, m), 2.58-2.75 (1H, m), 2.86-3.09 (1.5H, Sure. The residue was purified by silica gel column chro m), 3.21-3.36 (1H, m), 4.22-4.31 (2H, m), 4.36-4.41 (0.5H, matography (ethyl acetate/hexane) and ethyl 6-(acetylsulfa m), 4.59–4.64 (0.5H, m), 4.86-4.92 (1H, m), 7.15-7.24 (1H, nyl)cyclohex-1-ene-1-carboxylate (37.1 g) was obtained as m), 7.28-7.32 (1H, m), 7.38-7.45 (1H, m), 7.48 (0.5H, d, a colorless oily substance. MS: M+H 229.2. J=7.6 Hz), 7.62 (0.5H, d, J=7.6 Hz). 0657 Step F Example 2 0658) 4N hydrochloric acid (ethyl acetate solution, 203 mL) was added at room temperature to an ethanol Solution Ethyl (2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1- (200 mL) of ethyl 6-(acetylsulfanyl)cyclohex-1-ene-1-car yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro boxylate (37.0 g) and the mixture was stirred overnight at 4.5 dec-6-ene-7-carboxylate (a mixture of 4 diaste 50° C. The reaction mixture was concentrated under reduced reomers) pressure, and Saturated aqueous sodium bicarbonate Solution 0666 Step A was added to the residue and extraction was performed with 0667 Sodium borohydride (52.5 g) was added with ice ethyl acetate. The liquid extract was washed with water and cooling to a methanol solution (1000 mL) of dimethyl saturated aqueous Sodium chloride Solution and was dried (4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate (87 with sodium sulfate, and the solvent was eliminated by mL) and the mixture was stirred at the same temperature for distillation under reduced pressure. The residue was purified one hour and at room temperature overnight. The reaction by Silica gel column chromatography (ethyl acetate/hexane) mixture was concentrated under reduced pressure, and then and ethyl 6-sulfanylcyclohex-1-ene-1-carboxylate (21.0 g) diluted with Saturated aqueous Sodium chloride Solution and was obtained as a colorless oily Substance. stirred at room temperature for one hour, and then extracted 0659 'H NMR (300 MHz, CDC1) & 1.31 (3H, t, J=7.0 eight times with ethyl acetate. The liquid extracts were Hz), 1.66-1.75 (1H, m), 1.85-1.97 (3H, m), 2.11 (1H, d, combined and dried with sodium sulfate, and the solvent was J=6.8 Hz), 2.14-2.38 (2H, m), 4.01-4.08 (1H, m), 4.18-4.28 eliminated by distillation under reduced pressure (4R,5R)- (2H, m), 6.92-6.96 (1H, m). 2,2-dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (64.8 g) 0660 Step G was obtained as a straw-colored oily Substance. 0668 –(300 MHz, DMSO-d) & 1.30 (6H, s), 3.40-3.58 0661 DBU (0.18 mL) was added with ice cooling to a (4H, m), 3.67-3.82 (2H, m), 4.81 (2H, t, J=5.7 Hz). mixture of ethyl 6-sulfanylcyclohex-1-ene-1-carboxylate 0669 Step B (200 mg), 1-bromo-4-chloroindane (249 mg) and DMF (4 0670 Amberlyst 15 hydrogen form (4.8 g., purchased mL), and the mixture was stirred at the same temperature for from SIGMA-ALDRICH) was added at room temperature to 20 minutes. The reaction mixture was diluted with water and a mixture of ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl) extracted with ethyl acetate. The liquid extract was washed dimethanol (86 g), methanol (121 mL) and water (1205 mL), with water and Saturated aqueous sodium chloride Solution and the mixture was stirred overnight at 60° C. The solids and was dried with magnesium sulfate, and the solvent was were eliminated by filtration, and the filtrate was concen eliminated by distillation under reduced pressure. The resi trated under reduced pressure. Ethanol was added to the due was purified by silica gel column chromatography (ethyl residue, and the mixture was concentrated to dryness. The acetate/hexane) and ethyl 6-((4-chloro-2,3-dihydro-1H-in obtained solids were brayed with mortar, and washed with den-1-yl)sulfanyl)cyclohex-1-ene-1-carboxylate (a mixture liquid mixture of hexane/IPE=1/1, and (2R,3R)--1,2, of 4 stereoisomers) (338 mg) was obtained as a colorless oily 3,4-tetraol (51.7 g) was obtained. Substance. 0671 'H NMR (300 MHz, DMSO-d) & 2.48-2.53 (2H, 0662 H NMR (300 MHz, CDC1) & 1.28-1.34 (3H, m), m), 3.28-3.43 (4H, m), 4.22 (2H, d. J=5.7 Hz), 4.35-4.48 1.68-1.85 (2H, m), 1.88-2.04 (2H, m), 2.13-2.30 (2H, m), (2H, m). 2.30-2.45 (1H, m), 2.51-2.67 (1H, m), 2.87-2.98 (1H, m), 0672 Step C 3.08-3.20 (1H, m), 3.97 (1H, d, J=14.4 Hz), 4.17-4.27 (2H, 0673 Benzoyl chloride (103 mL) was added at room m), 4.50-4.60 (1H, m), 6.94-6.99 (1H, m), 7.09-7.21 (2H, temperature to NMP solution (1000 mL) of (2R,3R)-butane m), 7.23-7.33 (11H, m). 1,2,3,4-tetraol (51.7 g) and the mixture was stirred at 50° C. US 2016/0326102 A1 Nov. 10, 2016 27 for two hours. Water (1500 mL) was added to the reaction 0683 Step G mixture and the solids formed were recovered by filtration 0684 Potassium thioacetate (91 g) was added at room and washed with water. The obtained solids were dissolved temperature to a DMSO (500 mL) solution of ethyl 8-(((tri in ethyl acetate and washed with water and Saturated aque fluoromethyl)sulfonyl)oxy)-1,4-dioxaspiro4.5 dec-7-ene ous Sodium chloride solution and dried with magnesium 7-carboxylate (144 g) and the mixture was stirred at the sulfate. The solvent was eliminated by distillation under same temperature for six hours. The reaction mixture was reduced pressure, and the obtained solids were recrystallized diluted with water and extracted with ethyl acetate. The from ethyl acetate/hexane, and (2R,3R)-2,3-dihydroxybu liquid extract was washed with water and Saturated aqueous tane-1,4-diyl dibenzoate (77.3 g) was obtained. Sodium chloride solution and was dried with magnesium sulfate, and the solvent was eliminated by distillation under 0674) MS, found: 353.0. reduced pressure. The residue was purified by silica gel 0675 Step D column chromatography (ethyl acetate/hexane) and ethyl 0676 Chlorotrimethylsilane (62.8 mL) was added with 8-(acetylsulfanyl)-1,4-dioxaspiro4.5 dec-7-ene-7-carboxy ice cooling to a mixture of (2R,3R)-2,3-dihydroxybutane-1, late (71.8 g) was obtained as a straw-colored oily Substance. 4-diyl dibenzoate (77.3 g), N,N-dimethyl-4-aminopyridine 0685 MS, found: 309.0. (2.86 g), triethylamine (71.8 mL) and DMF (780 mL), and 0686 Step H the mixture was stirred at the same temperature for one hour. 0687 4N hydrochloric acid (ethyl acetate solution, 345 The reaction mixture was diluted with Saturated aqueous mL) was added with ice cooling to a THF (500 mL) solution sodium bicarbonate solution and extracted with ethyl of ethyl 8-(acetylsulfanyl)-1,4-dioxaspiro4.5 dec-7-ene-7- acetate. The liquid extract was washed with water and carboxylate (79.1 g) and the mixture was stirred at room saturated aqueous Sodium chloride Solution and was dried temperature for six hours, and then further 4N hydrochloric with magnesium sulfate, and the solvent was eliminated by acid (ethyl acetate solution, 1036 mL) was added, and the distillation under reduced pressure. The obtained solids were mixture was stirred overnight at room temperature. The washed with hexane, and (2R,3R)-2,3-bis(trimethylsilyl) reaction mixture was concentrated down under reduced oxy)butane-1,4-diyl dibenzoate (105 g) was obtained. pressure to a volume of about 500 mL, and then diluted with 0677. MS, found: 475.2. water, and extraction was performed with ethyl acetate. The 0678 Step EE liquid extract was washed with water, Saturated aqueous 0679. A THF solution (300 mL) of 1,4-dioxaspiro4.5 Sodium bicarbonate solution and Saturated aqueous sodium decan-8-one (100 g) was added while heating under reflux to chloride Solution and was dried with magnesium sulfate, and a mixture of diethyl carbonate (189 g), potassium t-butoxide the solvent was eliminated by distillation under reduced (216 g) and THF (900 mL), and the mixture was stirred at pressure. The residue was purified by silica gel column the same temperature for five hours. The solids recovered by chromatography (ethyl acetate/hexane) and ethyl 6-(acetyl filtration were washed with ethyl acetate and dissolved in sulfanyl)-3-oxocyclohex-1-ene-1-carboxylate (59.1 g) was water (100 mL), and then added to a liquid mixture of water obtained as a straw-colored oily Substance. (50 mL) and acetic acid (50 mL) while ice cooling, and then 0688 MS=(M-H)241.0. extracted three times with ethyl acetate. The liquid extracts 0689 Step I were combined and washed with water (twice), saturated 0690 Pyridinium p-toluenesulfonate (20.2 g) was added aqueous sodium bicarbonate Solution and Saturated aqueous with ice cooling to a mixture of ethyl 6-(acetylsulfanyl)-3- Sodium chloride solution and dried with magnesium Sulfate oxocyclohex-1-ene-1-carboxylate (18.5 g), trimethoxymeth and filtered using silica gel. The filtrate was concentrated ane (40.5 g) and methanol (382 mL), and the mixture was under reduced pressure, and ethyl 8-hydroxy-1,4-dioxaspiro stirred at room temperature for six hours. The reaction 4.5 dec-7-ene-7-carboxylate (101 g) was obtained as an mixture was diluted with Saturated aqueous sodium bicar oily Substance. bonate Solution, and the organic solvent was eliminated by distillation under reduced pressure. The residue was 0680 "H NMR (300 MHz, DMSO-d) & 1.13-1.21 (3H, extracted twice with ethyl acetate, and the extracts were m), 1.76 (2H, t, J=6.6 Hz), 2.33-2.42 (4H, m), 3.86-3.99 combined and washed with water and Saturated aqueous (6H, m), 12.14 (1H, s). sodium chloride solution and was dried with sodium sulfate, 0681 Step F and the solvent was eliminated by distillation under reduced 0682 Trifluoromethanesulfonic anhydride (124 mL) was pressure. A procedure wherein toluene was added to the added at -78° C. to a mixture of ethyl 8-hydroxy-1,4- residue and then eliminated by distillation under vacuum, dioxaspiro4.5 dec-7-ene-7-carboxylate (115 g), N-ethyl-N- was repeated several times, and ethyl 6-(acetylsulfanyl)-3, (1-methylethyl) propan-2-amine (106 mL) and toluene 3-dimethoxycyclohex-1-ene-1-carboxylate (22.6 g) was (1008 mL), and the mixture was stirred at the same tem thereby obtained. perature for one hour. The reaction mixture was diluted with (0691 H NMR (300 MHz, CDC1) & 1.27 (3H, t, J–70 saturated aqueous Sodium bicarbonate Solution and was Hz), 1.70- 1.83 (1H, m), 1.84-1.96 (1H, m), 1.98-2.08 (1H, stirred at room temperature for 30 minutes, and thereafter, m), 2.12-2.28 (1H, m), 2.32 (3H, s), 3.25 (3H, s), 3.30 (3H, about half of the organic solvent was eliminated by distil s), 4.15-4.26 (2H, m), 4.63-4.70 (1H, m), 6.81-703 (1H, m). lation under reduced pressure, and the obtained mixture was 0692 Step J extracted twice with ethyl acetate. The liquid extracts were (0693 TMSOTf (755 uL) was added with ice cooling to a combined and washed with water and Saturated aqueous mixture of ethyl 6-(acetylsulfanyl)-3,3-dimethoxycyclohex Sodium chloride Solution and dried with magnesium sulfate, 1-ene-1-carboxylate (24 g), (2R,3R)-2,3-bis(trimethylsilyl) and the solvent was eliminated by distillation under reduced oxy)butane-1,4-diyl dibenzoate (39.5 g) and acetonitrile pressure, and ethyl 8-(((trifluoromethyl)sulfonyl)oxy)-1,4- (550 mL), and the mixture was stirred at the same tempera dioxaspiro4.5 dec-7-ene-7-carboxylate (181 g) was ture for one hour. The reaction mixture was concentrated obtained. MS: M+H 361.0. under reduced pressure, and the residue was purified by US 2016/0326102 A1 Nov. 10, 2016 28 silica gel column chromatography (ethyl acetate/hexane). concentrated under reduced pressure. The obtained solids The obtained solids were washed with hexane and ethyl were washed with hexane, and (2S,3S)-butane-1,2,3,4-tet (2R,3R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1, raol (22.1 g) was obtained. 4-dioxaspiro4.5dec-6-ene-7-carboxylate (a mixture of 2 (0703 H NMR (300 MHz, DMSO-d) & 3.32-3.48 (6H, diastereomers) (41.5 g) was obtained. m), 4.21 (2H, d. J=5.3 Hz), 4.37-4.44 (2H, m). 0694 MS, found: 577.1. 0704 Step B 0695) Step K (0705 Benzoyl chloride (39.8 mL) was added at room 0696 Potassium carbonate (86 mg) was added with ice temperature to an NMP solution (200 mL) of (2S,3S)- cooling to a mixture of ethyl (2R,3R)-8-(acetylsulfanyl)-2, butane-1,2,3,4-tetraol (19.0 g) and the mixture was stirred at 3-bis((benzoyloxy)methyl)-1,4-dioxaspiro4.5 dec-6-ene-7- 50° C. for two hours. The reaction mixture was cooled to carboxylat e (a mixture of 2 diastereomers) (115 mg), room temperature, and thereafter, water (800 mL) was 1-bromo-4-chloroindane (48 mg) and methanol (4 mL), and added, and the mixture was stirred at room temperature for the mixture was stirred at room temperature for three hours. two hours. The solids were recovered by filtration and The reaction mixture was diluted with 1N hydrochloric acid dissolved in ethyl acetate and dried with sodium sulfate. The and extraction was performed with ethyl acetate/THF liquid solvent was eliminated by distillation under reduced pres mixture. The liquid extract was washed with saturated sure, and the obtained solids were washed with ethyl acetate/ aqueous Sodium chloride solution and was dried with mag hexane liquid mixture, and (2S,3S)-2,3-dihydroxybutane-1, nesium sulfate, and the solvent was eliminated by distilla 4-diyl dibenzoate (31.6 g) was obtained. tion under reduced pressure. The residue was purified by 0706, MS, found: 353.1. silica gel column chromatography (ethyl acetate/hexane) (0707 Step C and ethyl (2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl) (0708 Chlorotrimethylsilane (16.3 mL) was added with sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec ice cooling to a mixture of (2S,3S)-2,3-dihydroxybutane-1, 6-ene-7-carboxylate (a mixture of 4 diastereomers) (62.0 4-diyl dibenzoate (20.0 g), N,N-dimethyl-4-aminopyridine mg) was obtained as a colorless oily Substance. (0.74 g), triethylamine (18.6 mL) and DMF (300 mL), and 0697 MS, found: 477.4. the mixture was stirred at the same temperature for two 0698 Step L hours. The reaction mixture was diluted with saturated (0699 mCPBA (66.7 mg, 74%) was added with ice cool aqueous sodium bicarbonate Solution and extracted with ing to an acetonitrile solution (2 mL) of ethyl (2R,3R)-8- ethyl acetate. The liquid extract was washed with water and ((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hy saturated aqueous sodium chloride solution and was dried droxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate with magnesium sulfate, and the solvent was eliminated by (a mixture of 4 diastereomers) (62.0 mg) and the mixture distillation under reduced pressure, and (2S,3S)-2,3-bis was stirred at room temperature for two hours. The reaction ((trimethylsilyl)oxy)butane-1,4-diyl dibenzoate (22.5 g) was mixture was diluted with water and extracted with ethyl obtained as a white solid. acetate. The liquid extract was washed with Saturated aque 0709 H NMR (300 MHz, CDC1) & 0.15-0.19 (18H, m), ous sodium chloride solution and was dried with magnesium 4.09-4.16 (2H, m), 4.34-4.43 (2H, m), 4.47-4.57 (2H, m), sulfate, and the solvent was eliminated by distillation under 742-7.51 (4H, m), 7.51-7.60 (2H, m), 8.03-8.08 (4H, m). reduced pressure. The residue was purified by silica gel 07.10 Step D column chromatography (ethyl acetate/hexane) and ethyl 0711 TMSOTf (176 uL) was added with ice cooling to a (2R,3R)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)- mixture of ethyl 6-(acetylsulfanyl)-3,3-dimethoxycyclohex 2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7- 1-ene-1-carboxylate (5.61 g), (2S,3S)-2,3-bis(trimethylsi carboxylate (a mixture of 4 diastereomers) (57 mg) was lyl)oxy)butane-1,4-diyl dibenzoate (12.0 g) and acetonitrile obtained. (100 mL), and the mixture was stirred at the same tempera (0700 "H NMR (400 MHz, CDC1) & 1.30-141 (3H, m), ture for one hour. The reaction mixture was concentrated 1.83-1.95 (1H, m), 2.07-2.15 (1H, m), 2.27-2.51 (3.5H, m), under reduced pressure, and the residue was purified by 2.59-2.71 (1H, m), 2.84-2.93 (0.5H, m), 2.96-3.11 (1H, m), silica gel column chromatography (ethyl acetate/hexane). 3.20-3.33 (1H, m), 3.68-3.77 (2H, m), 3.78-3.91 (2H, m), The obtained solids were recrystallized from ethyl acetate/ 3.98-4.04 (0.5H, m), 4.07-4.36 (5H, m), 4.55-4.60 (0.5H, hexane and ethyl (2S,3S)-8-(acetylsulfanyl)-2,3-bis((ben m), 4.84-4.93 (1H, m), 6.92-6.97 (0.5H, m), 6.99-704 Zoyloxy)methyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxy (0.5H, m), 7.16-7.23 (1H, m), 7.29-7.34 (1H, m), 7.45-7.50 late (a mixture of 2 diastereomers) (10.1 g) was obtained. (0.5H, m), 7.52-7.59 (0.5H, m). 0712. MS, found: 577.1. Example 3 0713 Step E 0714 Potassium carbonate (202 mg) was added with ice Ethyl (2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1- cooling to a mixture of ethyl (2S,3S)-8-(acetylsulfanyl)-2, yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro 3-bis((benzoyloxy)methyl)-1,4-dioxaspiro4.5 dec-6-ene-7- 4.5 dec-6-ene-7-carboxylate (a mixture of 4 diaste carboxylate (a mixture of 2 diastereomers) (270 mg), 1-bromo-4-chloroindane (113 mg) and methanol (8 mL), reomers) and the mixture was stirred at room temperature for three 0701 Step A hours. The reaction mixture was diluted with 1N hydrochlo 0702 Amberlyst 15 hydrogen form (1.0 g, purchased ric acid and extraction was performed with an ethyl acetate/ from SIGMA-ALDRICH) was added at room temperature to THF liquid mixture. The liquid extract was washed with the mixture of ((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5- saturated aqueous Sodium chloride solution and was dried diyl)dimethanol (30.0 g), methanol (28 mL) and water (280 with magnesium sulfate, and the solvent was eliminated by mL), and the mixture was stirred overnight at 60° C. The distillation under reduced pressure. The residue was purified solids were eliminated by filtration, and the filtrate was by Silica gel column chromatography (ethyl acetate/hexane) US 2016/0326102 A1 Nov. 10, 2016 29 and ethyl (2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl) with ethyl acetate. The liquid extract was washed with sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec saturated aqueous Sodium chloride solution and was dried 6-ene-7-carboxylate (a mixture of 4 diastereomers) (177 mg) with magnesium sulfate, and the solvent was eliminated by was obtained as a colorless oily Substance. distillation under reduced pressure, and 1-bromo-7-chlor 0715 MS, found: 477.3. oindane (11.8 g) was obtained as a straw-colored oily 0716 Step F Substance. 0717 mCPBA (205 mg, 72%) was added with ice cool 0724 'H NMR (300 MHz, CDC1,) & 2.51-2.58 (2H, m), ing to an acetonitrile solution (4 mL) of ethyl (2S,3S)-8- 2.87-2.96 (1H, m), 3.22-3.37 (1H, m), 5.56-5.62 (1H, m), ((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hy 7.14-7.22 (3H, m). droxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate 0725 Step C (a mixture of 4 diastereomers) (177 mg) and the mixture was 0726 Sodium borohydride (0.24 g) was added with ice stirred at 50° C. for three hours. The reaction mixture was cooling to a mixture of ethyl 6-(acetylsulfanyl)-3-oxocyclo diluted with water, and extracted with ethyl acetate. The hex-1-ene-1-carboxylate (1.56 g), cerium chloride (III) (2.88 liquid extract was washed with Saturated aqueous sodium g), ethanol (35 mL), and the mixture was stirred at the same chloride Solution and was dried with magnesium sulfate, and temperature for three hours. The reaction mixture was the solvent was eliminated by distillation under reduced diluted with water, and extracted with ethyl acetate. The pressure. The residue was purified by silica gel column liquid extract was washed with Saturated aqueous sodium chromatography (ethyl acetate/hexane) and then separated chloride Solution and was dried with magnesium sulfate, and and recovered twice using HPLC (C18, mobile phase: the solvent was eliminated by distillation under reduced waterfacetonitrile (0.1% TFA containing system)) and ethyl pressure. The residue was purified by silica gel column (2S,3S)-8-((4-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)- chromatography (ethyl acetate/hexane) and ethyl 3-hy 2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7- droxy-6-sulfanylcyclohex-1-ene-1-carboxylate (single rela carboxylate (a mixture of 4 diastereomers) (26.0 mg) was obtained. tive configuration) (361 mg) was obtained as a colorless oily 0718 H NMR (300 MHz, CDC1,) & 1.32-1.38 (3H, m), Substance. 1.91-2.07 (2H, m), 2.39-2.61 (3H, m), 2.82-3.04 (2H, m), 0727 H NMR (300 MHz, CDC1) & 1.32 (3H, t, J–70 3.22-3.32 (1H, m), 3.67-3.75 (2H, m), 3.81-3.90 (2H, m), Hz), 1.75 (1H, brs), 1.84-1.93 (1H, m), 1.99-2.12 (3H, m), 4.01-4.35 (6H, m), 4.54-4.92 (2H, m), 6.91-703 (1H, m), 2.19 (1H, d, J–7.2 Hz), 3.95-4.02 (1H, m), 4.25 (2H, q, J–7.2 7.17-7.23 (1H, m), 7.29-7.33 (1H, m), 7.47-7.58 (1H, m). Hz), 4.34-4.41 (1H, m), 6.76-6.79 (1H, m). 0728 Step D Example 4 0729 Potassium carbonate (247 mg) was added with ice cooling to a mixture of ethyl 3-hydroxy-6-sulfanylcyclohex Ethyl 6-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfo 1-ene-1-carboxylate (single relative configuration) (361 nyl)-3-hydroxycyclohex-1-ene-1-carboxylate (race mg), 1-bromo-7-chloroindane (413 mg) and methanol (6 mate, low polarity) mL), and the mixture was stirred at the same temperature for two hours. The reaction mixture was diluted with 1N hydro Example 5 chloric acid and extracted with ethyl acetate. The liquid extract was washed with Saturated aqueous sodium chloride Ethyl 6-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfo Solution and was dried with magnesium sulfate, and the nyl)-3-hydroxycyclohex-1-ene-1-carboxylate (race solvent was eliminated by distillation under reduced pres mate, high polarity) Sure. The residue was purified by silica gel column chro 0719. Step A matography (ethyl acetate/hexane) and ethyl 6-((7-chloro 0720 Sodium borohydride (3.41 g) was added with ice 2,3-dihydro-1H-inden-1-yl)sulfanyl)-3-hydroxycyclohex-1- cooling to an ethanol solution (200 mL) of 7-chloroindan ene-1-carboxylate (a mixture of 4 stereoisomers) (245 mg) 1-one (10.0 g) and the mixture was stirred overnight at room obtained as a colorless oily Substance. temperature. About half of the solvent was eliminated by (0730 MS, found: 375.1. distillation under reduced pressure, and water was added to (0731 Step E the residue and extraction was performed with ethyl acetate. (0732 mCPBA (646 mg, 72%) was added with ice cool The liquid extract was washed with Saturated aqueous ing to an acetonitrile solution (8 mL) of ethyl 6-((7-chloro sodium chloride solution and was dried with sodium sulfate, 2,3-dihydro-1H-inden-1-yl)sulfanyl)-3-hydroxycyclohex-1- and the solvent was eliminated by distillation under reduced ene-1-carboxylate (a mixture of 4 stereoisomers) (432 mg) pressure. The residue was purified by silica gel column and the mixture was stirred at room temperature for five chromatography (ethyl acetate/hexane) and 7-chloroindan hours. The reaction mixture was diluted with saturated 1-ol (8.82 g) was obtained as a straw-colored oily Substance. aqueous sodium bicarbonate Solution and extracted with 0721 'H NMR (400 MHz, CDC1,) & 2.06-2.16 (1H, m), ethyl acetate. The liquid extract was washed with saturated 2.30 (1H, d, J–2.9 Hz), 2.37-2.47 (1H, m), 2.82–2.91 (1H, aqueous Sodium chloride solution and was dried with mag m), 3.15-3.24 (1H, m), 5.40-5.45 (1H, m), 7.14-7.23 (3H, nesium sulfate, and the solvent was eliminated by distilla m). tion under reduced pressure. The residue was purified by 0722 Step B silica gel column chromatography (ethyl acetate/hexane) 0723 Diethyl ether solution (10 mL) of phosphorous and a fraction of a low polarity compound and a fraction of tribromide (5.43 mL) was added at 0°C. to a diethyl ether a high polarity compound were recovered, and these were solution (200 mL) of 7-chloroindan-1-ol (8.82 g) and the respectively concentrated, and ethyl 6-((7-chloro-2,3-di mixture was stirred at the same temperature for two hours. hydro-1H-inden-1-yl)sulfonyl)-3-hydroxycyclohex-1-ene The reaction mixture was diluted with water and extracted 1-carboxylate (racemate) was obtained. US 2016/0326102 A1 Nov. 10, 2016 30

0733 Low polarity compound (yield 37 mg) 'H NMR separated and recovered by HPLC (column=CHIRALPAK (300 MHz, CDC1) & 1.36 (3H, t, J–7.2 Hz), 1.83-2.14 (4H, IC, 50 mmIDX500 mmL, mobile phase: 2-propanol), and the m), 2.32-2.51 (2H, m), 2.82-2.99 (2H, m), 3.36-3.48 (1H, fraction from the second peak was recovered and concen m), 4.27-4.35 (3H, m), 4.85-4.90 (1H, m), 5.06 (1H, d. J–7.9 trated, and ethyl (2R,3R8R)-8-(((1S)-7-chloro-2,3-dihydro Hz), 7.19-7.25 (4H, m). 1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dio (0734. High polarity compound (yield 57 mg) 'H NMR xaspiro4.5 dec-6-ene-7-carboxylate (18 mg) was thereby (300 MHz, CDC1) & 1.24 (3H, t, J–7.0 Hz), 1.87-2.16 (4H, obtained. m), 2.47-2.64 (2H, m), 2.70-2.80 (1H, m), 2.86-2.95 (1H, 0743 H NMR (300 MHz, CDC1) & 1.22 (3H, t, J–70 m), 3.45-3.59 (1H, m), 4.16-4.26 (2H, m), 4.30-4.39 (1H, Hz), 1.90-1.99 (2H, m), 2.14-2.32 (2H, m), 2.42-2.64 (3H, m), 4.52-4.57 (1H, m), 5.10 (1H, d, J=7.9 Hz), 7.19-7.25 m), 2.71-2.80 (1H, m), 2.84-2.95 (1H, m), 3.43-3.57 (1H, (4H, m). m), 3.67-3.77 (2H, m), 3.80-3.93 (2H, m), 4.07-4.26 (4H, m), 4.57 (1H, d, J=4.2 Hz), 5.10 (1H, d, J=7.9 Hz), 6.97-7.00 Example 6 (1H, m), 7.17-7.25 (3H, m). 0744. The Compound of Example 6 can be synthesized Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro using a method of synthesis as per following Step D to Step 1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1, I. 4-dioxaspiro4.5 dec-6-ene-7-carboxylate 0745) Step D 0735 Step A 0746 Borane dimethyl sulfide complex (12.1 mL) was 0736 Potassium carbonate (5.70 g) was added with ice added with ice cooling under a nitrogen atmosphere to a cooling to a mixture of ethyl (2R,3R)-8-(acetylsulfanyl)-2, THF solution (200 mL) of 1M 3-bis((benzoyloxy)methyl)-1,4-dioxaspiro4.5 dec-6-ene-7- 0747 (3aR)-1-methyl-3,3-diphenyltetrahydro-3H-pyr carboxylat e (a mixture of 2 diastereomers) (7.63 g). rolo 1.2-c.1.3.2 oxazaborole (toluene solution, 48.0 mL) 1-bromo-7-chloroindane (3.19 g) and methanol (100 mL), and the mixture was stirred at the same temperature for 30 and the mixture was stirred at room temperature for one minutes. A THF solution (130 mL) of 7-chloroindan-1-one hour. The reaction mixture was diluted with 1N hydrochloric (20.0 g) was added with ice cooling to the reaction mixture, acid, and extraction was performed with an ethyl acetate/ and the mixture was stirred at the same temperature for one THF liquid mixture. The liquid extract was washed with hour. Methanol (48.6 mL) was added to the reaction mixture, saturated aqueous Sodium chloride Solution and was dried and concentration was performed under reduced pressure. with magnesium sulfate, and the solvent was eliminated by The residue was diluted with 1N hydrochloric acid and distillation under reduced pressure. The residue was purified extraction was performed with a liquid mixture of ethyl by Silica gel column chromatography (ethyl acetate/hexane) acetate/THF. The aqueous phase was extracted with ethyl and ethyl (2R,3R)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl) acetate, and the extracts were combined and washed with sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec saturated aqueous sodium chloride Solution and dried with 6-ene-7-carboxylate (a mixture of 4 diastereomers) (3.86 g) sodium sulfate, and the solvent was eliminated by distilla was obtained as a colorless solid. tion under reduced pressure. The residue was filtered 0737. MS, found: 477.1. through silica gel, and elution performed with ethyl acetate. 0738 Step B The solvent was eliminated by distillation under reduced (0739 mCPBA (4.68 g., 72%) was added with ice cooling pressure, and the residue was purified by silica gel column to a mixture of ethyl (2R,3R)-8-((7-chloro-2,3-dihydro-1H chromatography (ethyl acetate/hexane). The obtained solids inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxas were recrystallized from toluene/hexane, and washed with a piro4.5 dec-6-ene-7-carboxylate (a mixture of 4 diaste mixed solvent of cool toluene/hexane, and (1S)-7-chloroin reomers) (3.86 g), acetonitrile (60 mL) and DMF (30 mL) dan-1-ol (11.1 g) was obtained. Optical purity 99.8% ee and the mixture was stirred at room temperature for four (analytic conditions: CHIRALCEL OD, 4.6 mmIDx250 hours. The reaction mixture was diluted with saturated mmL, mobile phase: hexane/2-propanol=90/10, flow rate: aqueous sodium bicarbonate Solution and extracted with 1.0 mL/min, column temperature: 30° C.) ethyl acetate. The liquid extract was washed with water and 0748 H NMR (300 MHz, CDC1) & 2.11 (1H, dddd, saturated aqueous Sodium chloride Solution and was dried J=13.9, 8.6, 4.2, 3.2 Hz), 2.27 (1H, d, J=3.8 Hz), 2.42 (1H, with magnesium sulfate, and the solvent was eliminated by ddt, J=14.1, 8.7, 6.9 Hz), 2.87 (1H, ddd, J=16.3, 9.0, 4.2 Hz), distillation under reduced pressure. The residue was purified 3.20 (1H, dt, J=16.1, 7.8 Hz), 5.43 (1H, dt, J=6.8, 3.4 Hz), by Silica gel column chromatography (ethyl acetate/hexane) 7.11-7.24 (3H, m). and ethyl (2R,3R)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl) 0749. The compound of Step D can also be synthesized sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec according to the synthesis method shown in Step D'. 6-ene-7-carboxylate (a mixture of 4 diastereomers) (3.23 g) (0750 (Step D') was obtained as a colorless oily Substance. 0751. To a suspension of 7-chloroindan-1-one (25.0 g), 0740 MS, found: 504.1. potassium formate (25.2 g), 2-propanol (1.242 mL) and 0741 Step C water (186 mL) was added chloro(((1S,2S)-(+)-2-amino-1, 0742 Ethyl (2R,3R)-8-((7-chloro-2,3-dihydro-1H-inden 2-diphenylethyl)(4-toluenesulfonyl)amide)(p-cymene)ru 1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 thenium(II) (0.955 g) at room temperature, and the mixture dec-6-ene-7-carboxylate (a mixture of 4 diastereomers) (100 was stirred overnight at 50° C. under argon atmosphere. The mg) was separated and recovered using HPLC obtained mixture was extracted with ethyl acetate, and the (column=CHIRALPAK IC, 50 mmIDx500 mmL, mobile extract was washed with saturated brine, and dried over phase: hexane/ethyl acetate=20/80), and the fractions from magnesium Sulfate, and the solvent was evaporated under the first peak and the second peak were recovered, com reduced pressure. The residue was purified by silica gel bined, and concentrated (50 mg). 30 mg of the residue was column chromatography (ethyl acetate/hexane). To the US 2016/0326102 A1 Nov. 10, 2016

obtained oil was added hexane (20 mL), and the mixture was 0761 Step H solidified in a freezer. Hexane (200 mL) was added thereto, 0762. A THF solution (19 mL) of DBU (2.28 g) was and the mixture was stirred at room temperature for 1 hr. The added with ice cooling to a mixture of ethyl (2R,3R8R)-2, resulting solid was collected by filtration, and washed with 3-bis(hydroxymethyl)-8-sulfaanyl-1,4-dioxaspiro4.5 dec hexane. The obtained solid was recrystallized from toluene, 6-ene-7-carboxylate (3.50 g), (1R)-1-bromo-7-chloroindane and (1S)-7-chloroindan-1-ol (5.19 g) was obtained as a (3.99 g) and THF (38 mL), and the mixture was stirred at the white solid. Optical purity 99.5% ee (analysis condition; same temperature for one hour. The reaction mixture was column: CHIRALCEL ODH, 4.6 mmIDx250 mmL, mobile diluted with water and extracted with ethyl acetate. The phase: hexane/2-propanol=90/10, flow rate: 1.0 mL/min, liquid extract was washed with Saturated aqueous sodium column temperature: 30° C.). The mother liquor and wash chloride solution and was dried with sodium sulfate, and the ing were combined, and concentrated to dryness, and the solvent was eliminated by distillation under reduced pres obtained solid was recrystallized from hexane, and addi Sure. The residue was purified by silica gel column chro tional (1S)-7-chloroindan-1-ol (13.2 g) was obtained as a matography (ethyl acetate/hexane). The obtained oil was white solid. Optical purity 99.5% ee (analysis condition; kept in a freezer for 3 days, and crystallized from acetonitrile column: CHIRALCEL ODH, 4.6 mmIDx250 mmL, mobile using the solid partially formed, and the solids recovered by phase: hexane/2-propanol=90/10, flow rate: 1.0 mL/min, filtration were recrystallized from acetonitrile/hexane, and column temperature: 30° C.). ethyl (2R,3R8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-inden 0752 Step E 1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dio xaspiro4.5 dec-6-ene-7-carboxylate (2.60 g) was obtained as a white (0753 Phosphorous tribromide (2.80 mL) was added at solid. 10° C. to a diethyl ether solution (150 mL) of (1S)-7- 0763 H NMR (400 MHz, CDC1) & 1.30 (3H, t, J=7.2 chloroindan-1-ol (5.0 g) and the mixture was stirred at the Hz), 1.82-1.96 (3H, m), 2.02-2.40 (4H, m), 2.45-2.58 (1H, same temperature for two hours. The reaction mixture was m), 2.89 (1H, dd, J=16.3, 8.2 Hz), 3.23-3.36 (1H, m), diluted with Saturated aqueous sodium bicarbonate Solution 3.64-3.76 (2H, m), 3.79-3.95 (3H, m), 405-4.33 (4H, m), and extracted with ethyl acetate. The liquid extract was 4.68 (1H, d, J=6.8 Hz), 6.54 (1H, s), 7.08-7.17 (3H, m). washed with Saturated aqueous Sodium chloride Solution and 0764) Step I was dried with magnesium Sulfate, and the solvent was 0765 mCPBA (3.10 g, 70%) was added with ice cooling eliminated by distillation under reduced pressure, and (1R)- to a mixture of ethyl (2R,3R8R)-8-(((1S)-7-chloro-2,3- 1-bromo-7-chloroindane (6.13 g) was obtained as a colorless dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1, oily substance. 4-dio Xaspiro4.5 dec-6-ene-7-carboxylate (2.60 g), acetoni 0754 H NMR (300 MHz, CDC1) & 2.52-2.59 (2H, m), trile (20 mL) and DMF (20 mL), and the mixture was stirred 2.87-2.97 (1H, m), 3.22-3.37 (1H, m), 5.57-5.62 (1H, m), overnight at room temperature. The reaction mixture was 7.15-7.23 (3H, m). diluted with water and extracted with ethyl acetate. The (0755 Step F liquid extract was washed with water, Saturated aqueous 0756 Potassium carbonate (11.9 g) was added with ice Sodium bicarbonate solution and Saturated aqueous sodium cooling to a methanol solution (281 mL) of ethyl (2R,3R)- chloride solution and was dried with sodium sulfate, and the 8-(acetylsulfanyl)-2,3-bis((benzoyloxy)methyl)-1,4-dioxas solvent was eliminated by distillation under reduced pres piro4.5 dec-6-ene-7-carboxylate (a mixture of 2 diaste Sure. The residue was purified by silica gel column chro reomer) (15.6 g) and the mixture was stirred at the same matography (ethyl acetate/hexane) and the residue was temperature for one hour. 1N hydrochloric acid (215 mL) crystallized from ethyl acetate/hexane. The solids recovered was added to the reaction mixture and extraction was by filtration were recrystallized from ethyl acetate?heptane, performed with ethyl acetate. The liquid extract was washed and ethyl (2R,3R8R)-8-(((1S)-7-chloro-2,3-dihydro-1H-in with Saturated aqueous Sodium chloride solution and was den-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dio xaspiro dried with sodium sulfate, and the solvent was eliminated by 4.5 dec-6-ene-7-carboxylate (1.69 g) was obtained as a distillation under reduced pressure. The residue was purified white solid. by Silica gel column chromatography (ethyl acetate/hexane) Example 7 and ethyl (2R,3R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4- dioxaspiro4.5 dec-6-ene-7-carboxylate (a mixture of 2 Ethyl (2S,3S,8R)-8-(((1S)-7-chloro-2,3-dihydro-1H diastereomers) (6.39 g) was obtained as a straw-colored oily inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dio Substance. xaspiro4.5 dec-6-ene-7-carboxylate (0757. H NMR (300 MHz, CDC1) & 1.32 (3H, t, J–7.2 0766 Step A Hz), 1.81-2.03 (3H, m), 2.07-2.36 (4H, m), 3.66-432 (9H, 0767 Potassium carbonate (3.74 g) was added with ice m), 6.47-6.63 (1H, m). cooling to a mixture of ethyl (2S,3S)-8-(acetylsulfanyl)-2, 3-bis((benzoyloxy)methyl)-1,4-dioxaspiro4.5 dec-6-ene-7- 0758 Step G carboxylate (a mixture of 2 diastereomers) (5.0 g), 1-bromo (0759 Ethyl (2R,3R)-2,3-bis(hydroxymethyl)-8-sulfanyl 7-chloroindane (2.09 g) and methanol (80 mL), and the 1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (a mixture of 2 mixture was stirred at room temperature for one hour. The diastereomers) (7.50 g) was crystallized from toluene (5 mL) reaction mixture was diluted with 1N hydrochloric acid, and and pulverized in a mixed solvent of toluene? IPE 10/1. The extraction was performed with ethyl acetate/THF liquid solids were recovered by filtration, and ethyl (2R,3R8R)- mixture. The liquid extract was washed with saturated 2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro4.5 dec aqueous Sodium chloride solution and was dried with mag 6-ene-7-carboxylate (1.82 g) was obtained as a white solid. nesium sulfate, and the solvent was eliminated by distilla 0760 "H NMR (300 MHz, CDC1) & 1.32 (3H, t, J=7.2 tion under reduced pressure. The residue was purified by Hz), 1.83-2.32 (7H, m), 3.65-4.34 (9H, m), 6.58 (1H, s). silica gel column chromatography (ethyl acetate/hexane) US 2016/0326102 A1 Nov. 10, 2016 32 and ethyl (2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl) distillation under reduced pressure, and (2S,3S)-8-((7- sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hy 6-ene-7-carboxylate (a mixture of 4 diastereomers) (2.16 g) droxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylic was obtained as a colorless solid. acid (a mixture of 4 diastereomers) (2.45 g) was obtained as 0768 MS, found: 477.1. a pale yellow solid. 0769 Step B 0777. MS, found: 449.1. (0770 mCPBA (2.84 g., 72%) was added at room tem 0778 Step B perature to a mixture of ethyl (2S,3S)-8-((7-chloro-2,3- (0779 Diethyl diazene-1,2-dicarboxylate (40% toluene dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1, Solution, 632 mg) was added with ice cooling to a mixture 4-dioxaspiro4.5dec-6-ene-7-carboxylate (2.16 g). of (2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfa acetonitrile (30 mL) and DMF (30 mL), and the mixture was nyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 dec-6-ene stirred at room temperature for five hours. The reaction 7-carboxylic acid (a mixture of 4 diastereomers) (310 mg), mixture was diluted with Saturated aqueous Sodium bicar (1-methylcyclopropyl)methanol (96 L), triphenylphosphine bonate solution and extracted with ethyl acetate. The liquid (381 mg) and THF (6 mL), and the mixture was stirred extract was washed with Saturated aqueous Sodium chloride overnight while warming to room temperature. The reaction Solution and was dried with magnesium sulfate, and the mixture was diluted with water, and extracted with ethyl solvent was eliminated by distillation under reduced pres acetate. The liquid extract was washed with Saturated aque Sure. The residue was purified by silica gel column chro ous sodium chloride solution and was dried with magnesium matography (ethyl acetate/hexane) and ethyl (2S,3S)-8-((7- sulfate, and the solvent was eliminated by distillation under chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis reduced pressure. The residue was purified by silica gel (hydroxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7- column chromatography (ethyl acetate/hexane) and carboxylate (a mixture of 4 diastereomers) (1.60 g) was (1-methylcyclopropyl)methyl (2S,3S)-8-((7-chloro-2,3-di obtained as a colorless Solid. hydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1, 0771 MS, found: 509.1. 4-dioxaspiro4.5dec-6-ene-7-carboxylate (a mixture of 4 0772 Step C diastereomers) (206 mg) was obtained as a colorless solid. (0773 Ethyl (2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden 0780 MS, found: 518.2. 1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 0781 Step C dec-6-ene-7-carboxylate (a mixture of 4 diastereomers) (800 0782 mCPBA (219 mg, 72%) was added with ice cool mg) was separated and recovered by HPCL ing to a mixture of (1-methylcyclopropyl)methyl (2S,3S)- (column=CHIRALPAK IC, 50 mmIDx500 mmL, mobile 8-((7-chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis phase: hexane/ethyl acetate-40/60), and the fractionated (hydroxymethyl)-1,4-dioxaspiro4.5dec-6-ene-7- fraction from the fourth peak was recovered and concen carboxylate (a mixture of 4 diastereomers) (206 mg), trated, and ethyl (2S,3S,8R)-8-(((1S)-7-chloro-2,3-dihydro acetonitrile (1.5 mL) and DMF (3 mL), and the mixture was 1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dio stirred at room temperature for four hours. The reaction xaspiro4.5 dec-6-ene-7-carboxylate (196 mg) was mixture was diluted with Saturated aqueous sodium bicar obtained. bonate solution and extracted with ethyl acetate. The liquid 0774 H NMR (300 MHz, CDC1) & 121 (3H, t, J–7.0 extract was washed with water and Saturated aqueous Hz), 1.86-2.05 (3H, m), 2.15-2.28 (1H, m), 2.41-2.62 (3H, Sodium chloride solution and was dried with magnesium m), 2.71-2.81 (1H, m), 2.85-2.95 (1H, m), 3.44-3.57 (1H, sulfate, and the solvent was eliminated by distillation under m), 3.67-3.77 (2H, m), 3.81-3.91 (2H, m), 3.99-4.06 (1H, reduced pressure. The residue was purified by silica gel m), 4.10-4.26 (3H, m), 4.57 (1H, d, J=4.9 Hz), 5.08 (1H, d, column chromatography (ethyl acetate/hexane) and J=8.3 Hz), 6.90-6.93 (1H, m), 7.17-7.25 (3H, m). (1-methylcyclopropyl)methyl (2S,3S)-8-((7-chloro-2,3-di hydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1, Example 8 4-dioxaspiro4.5dec-6-ene-7-carboxylate (a mixture of 4 diastereomers) (75 mg) was obtained. (1-methylcyclopropyl)methyl (2S,3S)-8-((7-chloro 0783 H NMR (300 MHz, CDC1) & 0.33-0.57 (4H, m), 2,3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hy 1.08-1.22 (3H, m), 1.77-2.08 (4H, m), 2.14-2.30 (1.5H, m), droxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-car 2.35-2.53 (2H, m), 2.57-2.64 (0.5H, m), 2.71-2.99 (2H, m), boxylate (a mixture of 4 diastereomers) 3.38-3.55 (1H, m), 3.66-3.76 (2H, m), 3.80-3.91 (2H, m), 0775 Step A 4.00-4.11 (2H, m), 4.15-4.25 (1H, m), 4.53-4.57 (0.5H, m), 0776 0.75M barium hydroxide octahydrate aqueous 4.91-4.99 (0.5H, m), 5.03-5.13 (1H, m), 6.91-7.04 (1H, m), solution (23.7 mL) was added to an acetonitrile solution (60 7.16-7.25 (3H, m). mL) of ethyl (2S,3S)-8-((7-chloro-2,3-dihydro-1H-inden-1- yl)sulfanyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 Example 14 dec-6-ene-7-carboxylate (a mixture of 4 diastereomers) (2.7 Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3- g) and the mixture was stirred at 60° C. for two hours. The dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxym reaction mixture was diluted with 1N hydrochloric acid and ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate extracted with ethyl acetate. The organic phase was extracted with 1N aqueous sodium hydroxide solution and 0784 Step A was washed with ethyl acetate. The aqueous phase was made 0785 Borane dimethyl sulfide complex (15.0 mL) was acidic (pH-3 to 4) with 2N hydrochloric acid and extracted added with ice cooling under a nitrogen atmosphere to a with ethyl acetate. The liquid extract was washed with THF solution (100 mL) of (3aR)-1-methyl-3,3-diphenyltet saturated aqueous Sodium chloride Solution and was dried rahydro-3H-pyrrolo 1.2-c.1.3.2 oxazaborole (3.0 g) and with magnesium sulfate, and the solvent was eliminated by the mixture was stirred at the same temperature for one hour. US 2016/0326102 A1 Nov. 10, 2016

A THF solution (20 mL) of 7-chloro-5-fluoroindan-1-one 0795 H NMR (300 MHz, CDC1) & 1.27 (3H, t, J=7.2 (5.0 g) was added at -78°C. to the reaction mixture, and the Hz), 1.88-2.00 (2H, m), 2.13-2.27 (2H, m), 2.37-2.66 (3H, mixture was stirred overnight while warming to room tem m), 2.68-2.77 (1H, m), 2.83-2.94 (1H, m), 3.43-3.57 (1H, perature. The reaction mixture was diluted with ice cooling m), 3.67-3.76 (2H, m), 3.80-3.93 (2H, m), 4.07-4.30 (4H, with methanol, and the reaction mixture was concentrated m), 4.51-4.55 (1H, m), 5.09 (1H, d, J=7.9 Hz), 6.89-7.01 under reduced pressure. The residue was purified by silica (3H, m). gel column chromatography (ethyl acetate/hexane) and (1S)-7-chloro-5-fluoroindan-1-ol (4.87 g) was obtained as a Example 15 straw-colored solid. 0786 'H NMR (300 MHz, CDC1) & 2.08-2.21 (2H, m), Ethyl (2S,3S,8R)-8-(((1S)-7-chloro-5-fluoro-2,3- 2.37-2.50 (1H, m), 2.80-2.91 (1H, m), 3.13–3.26 (1H, m), dihydro-1H-inden-1-yl)sulfonyl-2,3-bis(hydroxy 5.35-5.41 (1H, m), 6.84-6.97 (2H, m). ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate 0787 Step B 0796 Step A 0788 Phosphorous tribromide (505 uL) was added at 0797 Ethyl (2S,3S)-8-(acetylsulfanyl)-2,3-bis((benzoy -78°C. to a diethyl ether solution (20 mL) of (1S)-7-chloro loxy)methyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate 5-fluoroindan-1-ol (1.0 g) and the mixture was stirred for (a mixture of 2 diastereomers) (3.0 g) was separated and two hours while warming to 0°C. The reaction mixture was recovered using HPLC (column=CHIRALPAK IA, 50 diluted with Saturated aqueous sodium bicarbonate Solution mmIDX500 mmL, mobile phase: hexane/ethanol=50/50) and extracted with ethyl acetate. The liquid extract was and the first peak fraction was concentrated, and ethyl washed with Saturated aqueous Sodium chloride Solution and (2S,3S,8R)-8-(acetylsulfanyl)-2,3-bis((benzoyloxy) was dried with magnesium Sulfate, and the solvent was methyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxy late (1.36 eliminated by distillation under reduced pressure, and (1R)- g) was obtained as a white Solid. 1-bromo-7-chloro-5-fluoroindan (1.33 g) was obtained as a 0798 MS, found: 577.2. Straw-colored oily Substance. 0799 Step B 0789 H NMR (300 MHz, CDC1) & 2.54-2.62 (2H, m), 0800 Potassium carbonate (632 mg) was added with ice 2.86-2.95 (1H, m), 3.22-3.36 (1H, m), 5.51-5.57 (1H, m), cooling to a mixture of ethyl (2S,3S,8R)-8-(acetylsulfanyl)- 6.85-6.99 (2H, m). 2,3-bis((benzoyloxy)methyl)-1,4-dioxaspiro4.5 dec-6-ene 0790 Step C 7-carboxylate (846 mg), methanol (8 mL) and THF (8 mL), 0791) DBU (0.16 mL) was added with ice cooling to a and the mixture was stirred at the same temperature for one mixture of ethyl (2R,3R8R)-2,3-bis(hydroxymethyl)-8-sul hour. Chlorotrimethylsilane (1.35 mL) was added to the fanyl-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (286 mg), reaction mixture, and the mixture was diluted with saturated (1R)-1-bromo-7-chloro-5-fluoroindan (305 mg) and THF (6 aqueous sodium chloride Solution and extracted with ethyl mL), and the mixture was stirred at room temperature for acetate. The liquid extract was dried with sodium sulfate, one hour. The reaction mixture was diluted with water and and the solvent was eliminated by distillation under reduced extracted with ethyl acetate. The liquid extract was washed pressure. The residue was purified by silica gel column with Saturated aqueous Sodium chloride solution and was chromatography (ethyl acetate/hexane) and ethyl (2S,3S, dried with magnesium sulfate, and the solvent was elimi 8R)-2,3-bis(hydroxymethyl)-8-sulfanyl-1,4-dioxaspiro4.5 nated by distillation under reduced pressure. The residue dec-6-ene-7-carboxylate (368 mg) was obtained as a color was purified by Silica gel column chromatography (ethyl less oily Substance. acetate/hexane) and ethyl (2R,3R8R)-8-(((1S)-7-chloro-5- 0801 MS-(M-H)-303.0. fluoro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hy 0802 Step C droxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate 0803 DBU (94 uL) was added with ice cooling to a (450 mg) was obtained as a colorless oily Substance. mixture of ethyl (2S,3S,8R)-2,3-bis(hydroxymethyl)-8-sul 0792. MS, found: 495.1. fanyl-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (173 mg), 0793 Step D (1R)-1-bromo-7-chloro-5-fluoroindan (184 mg) and THF (2 0794. mCPBA (506 mg, 72%) was added with ice cool mL), and the mixture was stirred at room temperature for 30 ing to a mixture of ethyl (2R,3R8R)-8-(((1S)-7-chloro-5- minutes. The reaction mixture was diluted with water, and fluoro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hy extracted with ethyl acetate. The liquid extract was washed droxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate with Saturated aqueous Sodium chloride solution and was (454 mg), acetonitrile (4 mL) and DMF (4 mL), and the dried with sodium sulfate, and the solvent was eliminated by mixture was stirred at room temperature for six hours. The distillation under reduced pressure. The residue was purified reaction mixture was diluted with Saturated aqueous sodium by Silica gel column chromatography (ethyl acetate/hexane) bicarbonate solution and extracted with ethyl acetate. The and ethyl (2S,3S,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-di liquid extract was washed with water and Saturated aqueous hydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hydroxymethyl)-1, Sodium chloride solution and was dried with magnesium 4-dioxaspiro4.5dec-6-ene-7-carboxylate (145 mg) was sulfate, and the solvent was eliminated by distillation under obtained as a colorless oily Substance. reduced pressure. The residue was purified by silica gel 0804 MS, found: 495.1. column chromatography (ethyl acetate/hexane) and then 0805 Step D crystallized from ethyl acetate/hexane. The solids recovered (0806. mCPBA (227 mg, 70%) was added with ice cool by filtration were recrystallized twice from ethyl acetate/ ing to a mixture of ethyl (2S,3S,8R)-8-(((1S)-7-chloro-5- hexane, and ethyl (2R,3R8R)-8-(((1S)-7-chloro-5-fluoro-2, fluoro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hy 3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxym droxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (64 mg) (145 mg), acetonitrile (1 mL) and DMF (0.5 mL), and the was obtained. mixture was stirred at room temperature for one hour. The US 2016/0326102 A1 Nov. 10, 2016 34 reaction mixture was diluted with Saturated aqueous sodium eliminated by distillation under reduced pressure. The resi thiosulfate solution and extracted with ethyl acetate. The due was purified by silica gel column chromatography (ethyl liquid extract was washed with Saturated aqueous sodium acetate/hexane) and 8-chloro-N-methoxy-3,4-dihydronaph chloride solution and was dried with sodium sulfate, and the thalen-1 (2H)-imine (1.78 g) was obtained as a colorless oily solvent was eliminated by distillation under reduced pres Substance. Sure. The residue was purified by silica gel column chro 0813 MS: M+H" 210.1. matography (ethyl acetate/hexane) and then was separated 0814 Step C and recovered using HPLC (column=CHIRALPAKIA, 50 0815. A mixture of 8-chloro-N-methoxy-3,4-dihydro mmIDX500 mmL, mobile phase: hexane/ethanol=20/80) naphthalen-1 (2H)-imine (1.78 g), 6N hydrochloric acid (30 and the obtained fraction was concentrated. The residue was mL) and DME (20 mL) was heated under reflux for three purified by silica gel column chromatography (ethyl acetate/ hours. The reaction mixture was extracted with ethyl acetate. hexane) and ethyl (2S,3S,8R)-8-(((1S)-7-chloro-5-fluoro-2, The liquid extract was washed with water and saturated 3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxym aqueous Sodium chloride solution and was dried with mag ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (31 mg) nesium sulfate, and the solvent was eliminated by distilla was obtained. tion under reduced pressure. The residue was purified by 0807 H NMR (300 MHz, CDC1) & 1.27 (3H, t, J–7.2 silica gel column chromatography (ethyl acetate/hexane) Hz), 1.87-1.96 (1H, m), 2.12-2.29 (1H, m), 2.33-2.47 (1H, and 8-chloro-3,4-dihydronaphthalen-1 (2H)-one (1.34 g) m), 2.49-2.66 (2H, m), 2.68-2.80 (1H, m), 2.89 (1H, dd, was obtained as a colorless oily Substance. J=16.2, 8.7 Hz), 3.42-3.60 (1H, m), 3.67-3.78 (2H, m), 0816) "H NMR (300 MHz, DMSO-d) & 1.94-2.07 (2H, 3.81-3.91 (2H, m), 3.98-4.08 (1H, m), 4.14-4.34 (3H, m), m), 2.62 (2H, t, J=6.6 Hz), 2.96 (2H, t, J=6.2 Hz), 7.29-7.41 4.52 (1H, d, J=4.9 Hz), 5.08 (1H, d, J=7.9 Hz), 6.88-6.94 (2H, m), 743-7.51 (1H, m). (2H, m), 6.98 (1H, dd, J–8.7, 1.9 Hz). 0817 Step D 0818 Sodium borohydride (0.63 g) was added with ice Example 16 cooling to an ethanol solution (50 mL) of 8-chloro-3,4- dihydro-naphthalen-1 (2H)-one (2.0 g) and the mixture was Ethyl (2R.3R8R)-8-((8-chloro-1,2,3,4-tetrahy stirred overnight at room temperature. About half of the dronaphthalen-1-ylsulfonyl)-2,3-bis(hydroximethyl)- solvent was eliminated by distillation under reduced pres 1,4-dioxaspiro4.5dec-6-ene-7-carboxylate (single Sure, and water was added to the residue, and extraction was diastereomer, the first peak) performed with ethyl acetate. The liquid extract was washed with Saturated aqueous Sodium chloride solution and was Example 17 dried with sodium sulfate, and the solvent was eliminated by distillation under reduced pressure. The residue was purified Ethyl (2R.3R8R)-8-((8-chloro-1,2,3,4-tetrahy by Silica gel column chromatography (ethyl acetate/hexane) dronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxym and 8-chloro-1,2,3,4-tetrahydronaphthalen-1-ol (2.03 g) was ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate obtained as a colorless Solid. (single diastereomer, the second peak) 0819 H NMR (300 MHz, CDC1,) & 1.73-1.84 (2H, m), (0808 Step A 1.91-2.03 (1H, m), 2.15-2.24 (1H, m), 2.36 (1H, dd, J=3.8, 0809. A mixture of 3,4-dihydronaphthalen-1 (2H)-one 1.1 Hz), 2.64-2.77 (1H, m), 2.81-2.91 (1H, m), 5.06-5.11 (5.90 g), O-methylhydroxylamine hydrochloride (5.06 g), (1H, m), 7.02-7.07 (1H, m), 7.14 (1H, t, J=7.7 Hz), 7.21-7. pyridine (4 mL) and ethanol (80 mL) was heated under 25 (1H, m). reflux for two hours and 30 minutes. The reaction mixture 0820 Step E was concentrated under reduced pressure, and the residue 0821 8-chloro-1,2,3,4-tetrahydronaphthalen-1-ol (2.03 was diluted with 1N hydrochloric acid, and extracted with g) was added at 0°C. to a diethyl ether solution (50 mL) of ethyl acetate. The liquid extract was washed with water and phosphorous tribromide (1.05 mL) and the mixture was saturated aqueous Sodium chloride Solution and was dried stirred at the same temperature for two hours. The reaction with magnesium sulfate, and the solvent was eliminated by mixture was diluted with water, and extracted with ethyl distillation under reduced pressure. The residue was purified acetate. The liquid extract was washed with Saturated aque by Silica gel column chromatography (ethyl acetate/hexane) ous sodium chloride solution and was dried with magnesium and N-methoxy-3,4-dihydronaphthalen-1 (2H)-imine (6.96 sulfate, and the solvent was eliminated by distillation under g) was obtained as a colorless oily Substance. reduced pressure, and 1-bromo-8-chloro-1,2,3,4-tetrahy 08.10 "H NMR (300 MHz, DMSO-d) & 1.68-1.81 (2H, dronaphthalene (2.54 g) was obtained as a straw-colored m), 2.63-2.73 (4H, m), 3.90 (3H, s), 7.14-7.23 (2H, m), oily Substance. 7.24-7.32 (1H, m), 7.77-7.88 (1H, m). 0822. MS=(M-H)-244.8. 0811 Step B 0823. Step F 0812 Palladium (II) acetate (106 mg) was added at room 0824 DBU (0.125 mL) was added with ice cooling to a temperature to a mixture of N-methoxy-3,4-dihydronaph mixture of ethyl (2R.3R8R)-2,3-bis(hydroxymethyl)-8-sul thalen-1 (2H)-imine (1.65 g), N-chlorosuccinimide (1.32 g) fanyl-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (230 mg), and acetic acid (60 mL), and the mixture was stirred at 90° 1-bromo-8-chloro-1,2,3,4-tetrahydronaphthalene (186 mg) C. for 30 minutes. The reaction mixture was concentrated and THF (6 mL), and the mixture was stirred at the same under reduced pressure, and the residue was diluted with 2N temperature for one hour. The reaction mixture was diluted aqueous Sodium hydroxide solution and extraction was with water and extracted with ethyl acetate. The liquid performed with ethyl acetate. The liquid extract was washed extract was washed with Saturated aqueous sodium chloride with water and Saturated aqueous sodium chloride Solution Solution and was dried with magnesium sulfate, and the and was dried with magnesium sulfate, and the solvent was solvent was eliminated by distillation under reduced pres US 2016/0326102 A1 Nov. 10, 2016

Sure. The residue was purified by silica gel column chro 0833 Step B matography (ethyl acetate/hexane) and ethyl (2R,3R8R)-8- 0834 mCPBA (494 mg, 70%) was added with ice cool ((8-chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfanyl)-2,3- ing to a mixture of ethyl (6R)-6-(((1S)-7-chloro-2,3-di bis(hydroxymethyl)-1,4-di oxaspiro4.5 dec-6-ene-7- hydro-1H-inden-1-yl)sulfanyl)cyclohex-1-ene-1-carboxy carboxylate (a mixture of 2 diastereomers) (269 mg) was late (270 mg) and acetonitrile (3 mL), and the mixture was obtained as a colorless Solid. stirred at room temperature for one hour. The reaction mixture was diluted with Saturated aqueous Sodium thiosul 0825 MS, found: 491.2. fate solution and extracted with ethyl acetate. The liquid 0826 Step G extract was washed with Saturated aqueous sodium bicar 0827. mCPBA (302 mg, 72%) was added with ice cool bonate solution (twice) and saturated aqueous Sodium chlo ing to a mixture of ethyl (2R,3R8R)-8-((8-chloro-1,2,3,4- ride Solution and then was dried with magnesium sulfate, tetrahydronaphthalen-1-yl)sulfanyl)-2,3-bis(hydroxym and the solvent was eliminated by distillation under reduced ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (a pressure. The residue was purified by silica gel column mixture of 2 diastereomers) (269 mg), acetonitrile (3 mL) chromatography (ethyl acetate/hexane) and then recrystal and DMF (3 mL), and the mixture was stirred overnight at lized from ethyl acetate/IPE. The obtained solids were room temperature. The reaction mixture was diluted with separated and recovered using SFC (column-CHIRALPAK saturated aqueous sodium bicarbonate solution and AD-H, 20 mmIDx250 mmL, mobile phase: carbon dioxide/ extracted with ethyl acetate. The liquid extract was washed 2-propanol=90/10) and the obtained fraction was concen with Saturated aqueous Sodium chloride solution and was trated under reduced pressure, and ethyl (6R)-6-(((1S)-7- dried with magnesium sulfate, and the solvent was elimi chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)cyclohex-1- nated by distillation under reduced pressure. The residue ene-1-carboxylate (176 mg) was obtained as a pale-brown was purified by Silica gel column chromatography (ethyl solid. acetate/hexane) and then separated and recovered using 0835 H NMR (300 MHz, CDC1) & 1.25 (3H, t, J–7.2 HPLC (column=CHIRALPAK AD, 50 mmIDX500 mmL, Hz), 1.64-1.84 (2H, m), 1.96-2.34 (2H, m), 2.39-2.67 (3H, mobile phase: hexane/2-propanol=75/25). The fractions m), 2.76 (1H, dd, J=14.2, 7.4 Hz), 2.89 (1H, dd, J=16.1, 8.9 from the first peak and the second peak were each concen HZ), 3.43-3.61 (1H, m), 4.09-4.30 (2H, m), 4.59 (1H, d, trated, and ethyl (2R,3R8R)-8-((8-chloro-1,2,3,4-tetrahy J=5.7 Hz), 5.11 (1H, d, J=7.9 Hz), 7.14-7.25 (3H, m), 7.39 dronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4- (1H, t, J=4.0 Hz). di oxaspiro4.5 dec-6-ene-7-carboxylate (as single diastereomers) was obtained. Example 19 0828 The first peak (yield 98.5 mg) 'H NMR (300 MHz, CDC1,) & 1.18 (3H, t, J–7.0 Hz), 1.57-1.67 (1H, m), 1.87 Ethyl (2S,3S,8R)-8-(((1S)-8-chloro-1,2,3,4-tetrahy 1.99 (2H, m), 2.11-2.34 (4H, m), 2.49-2.74 (4H, m), 3.05 dronaphthalen-1-yl)sulfonyl)-2,3-bis(hydroxym 3.16 (1H, m), 3.66-3.75 (2H, m), 3.80-3.92 (2H, m), 4.06 ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate 4.21 (4H, m), 4.56 (1H, d, J=4.2 Hz), 5.20 (1H, dd, J=7.6, 2.6 Hz), 6.96-6.98 (1H, m), 707-7.12 (1H, m), 7.20 (1H, t, 0836 Step A J=7.7 Hz), 7.26-7.29 (1H, m). 0837 Under a nitrogen atmosphere, borane dimethyl sulfide complex (2.91 mL) was added at -78°C. to a mixture 0829. The second peak (yield 45.5 mg) "H NMR (300 of (3aR)-1-methyl-3,3-diphenyl tetrahydro-3H-pyrrolo 1.2- MHz, CDC1) & 1.37 (3H, t, J–7.2 Hz), 1.65-1.74 (1H, m), c.1.3.2 oxazaborole (0.61 g), 8-chloro-3,4-dihydronaph 1.84-2.10 (5H, m), 2.23-2.37 (2H, m), 2.63-2.75 (2H, m), thalen-1 (2H)-one (1.0 g), and THE (30 mL), and it was 3.01-3.14 (1H, m), 3.66-3.75 (2H, m), 3.79-3.93 (2H, m), stirred overnight while warming to room temperature. 4.00-4.23 (3H, m), 4.27-4.36 (2H, m), 4.87 (1H, d, J–4.9 Methanol was added with ice cooling to the reaction mix Hz), 5.27 (1H, dd, J=6.4, 1.9 Hz), 6.93-6.97 (1H, m), 7.11 ture, and the mixture concentrated down and the residue was (1H, d. J–7.6 Hz), 7.18-7.24 (1H, m), 7.27-7.31 (1H, m). purified by silica gel column chromatography (ethyl acetate/ hexane). The obtained solids were recrystallized from tolu Example 18 ene/hexane, and (1S)-8-chloro-1,2,3,4-tetrahydronaphtha len-1-ol (0.69 g) was obtained as a colorless solid. Ethyl (6R)-6-(((1S)-7-chloro-2,3-dihydro-1H-inden 0838 H NMR (300 MHz, CDC1) & 1.73-1.84 (2H, m), 1-yl)sulfonyl)cyclohex-1-ene-1-carboxylate 1.91-2.04 (1H, m), 2.15-2.24 (1H, m), 2.36 (1H, dd, J=3.8, 1.1 Hz), 2.64-2.77 (1H, m), 2.81-2.91 (1H, m), 5.06-5.11 0830 Step A (1H, m), 7.03-7.07 (1H, m), 7.14 (1H, t, J=7.6 Hz), 7.21-7. 0831 DBU (0.37 mL) was added with ice cooling to a 25 (1H, m). mixture of ethyl 6-sulfanylcyclohex-1-ene-1-carboxylate 0839 Step B (0.42 g), (1R)-1-bromo-7-chloro-5-fluoroindan (0.63 g) and 0840 Phosphorous tribromide (118 LL) was added at THF (5 mL), and the mixture was stirred at the same -10°C. to a diethyl ether solution (4 mL) of (1S)-8-chloro temperature for one hour. The reaction mixture was diluted 1,2,3,4-tetrahydronaphthalen-1-ol (230 mg) and the mixture with water and extracted with ethyl acetate. The liquid was stirred at the same temperature for 30 minutes. The extract was washed with Saturated aqueous Sodium chloride reaction mixture was diluted with Saturated aqueous sodium solution and was dried with sodium sulfate, and the solvent bicarbonate solution and extracted with ethyl acetate. The was eliminated by distillation under reduced pressure. The liquid extract was washed with Saturated aqueous sodium residue was purified by silica gel column chromatography chloride solution and was dried with sodium sulfate, and the (ethyl acetate/hexane) and then was separated and recovered solvent was eliminated by distillation under reduced pres using HPLC (C18, mobile phase: waterfacetonitrile (system sure, and (1R)-1-bromo-8-chloro-1,2,3,4-tetrahydronaph containing 0.1% TFA) and the first peak fraction was con thalene (196 mg) was obtained as a brown oily substance. centrated, and ethyl (6R)-6-(((1S)-7-chloro-2,3-dihydro-1H 0841 'H NMR (300 MHz, CDC1,) & 1.88-2.02 (1H, m), inden-1-yl)sulfanyl)cyclohex-1-ene-1-carboxylate (270 mg) 2.03-2.13 (1H, m), 2.23-2.41 (1H, m), 2.41-2.53 (1H, m), was obtained as a colorless oily Substance. 2.79-3.07 (2H, m), 5.68 (1H, brs), 7.01 (1H, d, J=7.6 Hz), 0832. MS, found: 359.0. 7.10-7.18 (1H, m), 7.19-7.25 (1H, m). US 2016/0326102 A1 Nov. 10, 2016 36

0842) Step C and the solvent was eliminated by distillation under reduced 0843. DBU (0.15 mL) was added with ice cooling to a pressure. The residue was purified by silica gel column mixture of ethyl (2S,3S,8R)-2,3-bis(hydroxymethyl)-8-sul chromatography (ethyl acetate/hexane) and ethyl 3-hy fanyl-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (368 mg), droxy-3,6-dihydro-2H-pyran-4-carboxylate (25.8 g) was (1R)-1-bromo-8-chloro-1,2,3,4-tetrahydronaphthalene (196 obtained as a straw-colored oily Substance. mg) and THF (3 mL), and the mixture was stirred at the 0850 "H NMR (300 MHz, CDC1) & 1.33 (3H, t, J=7.2 same temperature for one hour. The reaction mixture was Hz), 2.79 (1H, d, J=4.9 Hz), 3.72 (1H, dd, J=11.9, 3.2 Hz), diluted with water and extracted with ethyl acetate. The 3.95 (1H, dd, J=11.7, 3.0 Hz), 4.18-443 (5H, m), 7.04-7.08 liquid extract was dried with sodium sulfate, and the solvent (1H, m). was eliminated by distillation under reduced pressure. The 0851 Step B residue was purified by silica gel column chromatography 0852 Triethylamine (31.2 mL) was added with ice cool (ethyl acetate/hexane) and ethyl (2S,3S,8R)-8-(((1S)-8- ing to a THF (300 mL) solution of ethyl 3-hydroxy-3,6- chloro-1,2,3,4-tetrahydronaphthalen-1-yl)sulfanyl)-2,3-bis dihydro-2H-pyran-4-carboxylate (25.8 g) and the mixture (hydroxymethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxy was stirred at the same temperature for ten minutes. Meth late (279 mg) was obtained as a colorless oily Substance. anesulfonyl chloride (14.5 mL) was added to the reaction 0844 MS, found: 491.2. mixture and the mixture was stirred at the same temperature 0845 Step D for 30 minutes. The reaction mixture was diluted with ice 0846 mCPBA (367 mg, 70%) was added with ice cool cooled 1N hydrochloric acid and extracted with ethyl ing to a mixture of ethyl (2S,3S,8R)-8-(((1S)-8-chloro-1,2, acetate. The liquid extract was washed with Saturated aque 3,4-tetrahydronaphthalen-1-yl)sulfanyl)-2,3-bis(hydroxym ous Sodium chloride solution and was dried with sodium ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (279 mg) sulfate, and the solvent was eliminated by distillation under and acetonitrile (5 mL), and the mixture was stirred at room reduced pressure. To a mixture of the residue and toluene temperature for three hours. The reaction mixture was (400 mL), were successively added thioacetic acid (12.6 diluted with Saturated aqueous sodium thiosulfate Solution mL) and triethylamine (26.7 mL) under ice cooling and the and extracted with ethyl acetate. The liquid extract was mixture was stirred at the same temperature for 30 minutes. washed with Saturated aqueous Sodium chloride solution, The reaction mixture was diluted with 1N hydrochloric acid dried with magnesium sulfate, and the solvent was elimi and extracted with ethyl acetate. The liquid extract was nated by distillation under reduced pressure. The residue washed with Saturated aqueous sodium chloride Solution and was purified by Silica gel column chromatography (ethyl was dried with magnesium Sulfate, and the solvent was acetate/hexane) and then separated and recovered using SFC eliminated by distillation under reduced pressure. The resi (column=CHIRALCEL OJ-H, 20 mmIDx250 mmL, mobile due was purified by silica gel column chromatography (ethyl phase: carbon dioxide/methanol=86/14) and the obtained acetate/hexane) and ethyl 3-(acetylsulfanyl)-3,6-dihydro fraction was concentrated under reduced pressure. The resi 2H-pyran-4-carboxylate (24.7 g) was obtained as a straw due was crystallized from ethyl acetate?heptane, and ethyl colored oily Substance. (2S,3S,8R)-8-(((1S)-8-chloro-1,2,3,4-tetrahydronaphthalen 0853 'H NMR (300 MHz, CDC1) & 1.28 (3H, t, J–70 1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1,4-dioxaspiro4.5 Hz), 2.34 (3H, s), 3.85 (1H, dd, J=11.9, 2.5 Hz), 4.00 (1H, dec-6-ene-7-carboxylate (47 mg) was obtained. dd, J=12.1, 1.1 Hz), 4.17-4.31 (3H, m), 4.37-4.46 (1H, m), 0847 'H NMR (300 MHz, CDC1) & 1.18 (3H, t, J=7.2 4.52 (1H, brs), 7.05-7.09 (1H, m). Hz), 1.57-1.70 (1H, m), 1.84-197 (2H, m), 2.00-2.09 (1H, 0854 Step C m), 2.09-2.39 (3H, m), 2.46-2.55 (1H, m), 2.56-2.74 (3H, 0855 4N hydrochloric acid (ethyl acetate solution, 70 m), 3.02-3.18 (1H, m), 3.64-3.77 (2H, m), 3.80-3.93 (2H, mL) was added at room temperature to an ethanol Solution m), 3.97-4.24 (4H, m), 4.55 (1H, d, J=5.3 Hz), 5.19 (1H, dd, (70 mL) of ethyl 3-(acetylsulfanyl)-3,6-dihydro-2H-pyran J=7.6, 2.3 Hz), 6.86-6.92 (1H, m), 7.06-7.13 (1H, m), 4-carboxylate (24.7 g) and the mixture was stirred at 45° C. 7.16-7.24 (1H, m), 7.28 (1H, s). for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Silica gel Example 20 column chromatography (ethyl acetate/hexane) and ethyl 3-sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (19.5 g) Ethyl 3-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl) was obtained as a straw-colored oily Substance. sulfonyl)-3,6-dihydro-2H-pyran-4-carboxylate (a 0856 H NMR (300 MHz, CDC1) & 1.32 (3H, t, J–7.2 single diastereomer) Hz), 2.23 (1H, d, J=9.1 Hz), 3.67-3.75 (1H, m), 3.85-3.93 (1H, m), 4.01 (1H, dd, J=11.7, 1.9 Hz), 4.22-4.32 (3H, m), 0848 Step A 4.37-4.47 (1H, m), 6.82-6.86 (1H, m). 0849 While keeping the internal temperature at 20°C. or 0857 Step D less using ice cooling, (3R,4S)-tetrahydrofuran-3,4-diol 0858 DBU (0.34 mL) was added with ice cooling to a (45.0 g) was added dropwise to an aqueous Solution (220 mixture of ethyl 3-sulfanyl-3,6-dihydro-2H-pyran-4-car mL) of sodium periodate (97.0 g), and the mixture was then boxylate (0.43 g), (1R)-1-bromo-7-chloroindane (0.63 g) stirred overnight at room temperature. Sodium bicarbonate and THF (5 mL), and the mixture was stirred at the same (7.26 g) and ethyl(diethoxyphosphoryl)acetate (60.6 mL) temperature for one hour. The reaction mixture was diluted were added at room temperature to the reaction mixture, and with water and extracted with ethyl acetate. The liquid the mixture was stirred at the same temperature for three extract was washed with Saturated aqueous sodium chloride hours. Sodium bicarbonate (84.0 g) was added to the reac solution and was dried with sodium sulfate, and the solvent tion mixture, and the mixture was stirred overnight at an was eliminated by distillation under reduced pressure. The internal temperature of 50° C. The reaction mixture was residue was purified by silica gel column chromatography cooled to room temperature, and then the solids were (ethyl acetate/hexane) and ethyl 3-(((1S)-7-chloro-2,3-di eliminated by filtration. The solids were washed with THF, hydro-1H-inden-1-yl)sulfanyl)-3,6-dihydro-2H-pyran-4- and the washings were combined with the filtrate. Sodium carboxylate (a mixture of 2 diastereomers) (0.32 g) was chloride was added to the mixture and extraction performed obtained as a colorless oily substance. 1H NMR (300 MHz, with ethyl acetate. The aqueous phase was extracted twice CDC1) & 1.23-1.40 (3H, m), 2.23-2.60 (2H, m), 2.77-2.96 further with an ethyl acetate/THF liquid mixture, and the (1H, m), 3.20-3.42 (1H, m), 3.70 (0.6H, brs), 3.75-3.92 extracts were combined and dried with magnesium sulfate, (1.4H, m), 4.05 (0.6H, dd, J=11.7, 1.5 Hz), 4.16-4.33 (3.4H, US 2016/0326102 A1 Nov. 10, 2016 37 m), 4.34-4.47 (1H, m), 4.53 (0.4H, d, J=6.4 Hz), 4.79 (0.6H, droxymethyl)-1,4-dio xaspiro4.5 dec-6-ene-7-carboxylate d, J=6.8 Hz), 6.85-6.92 (0.6H, m), 6.94-6.99 (0.4H, m), (5.72 g), iodomethane (7.14 g) and DMF (50 mL), and the 7.06-7.21 (3H, m). mixture was stirred at the same temperature for one hour. 0859 Step E The reaction mixture was diluted with water and extracted 0860 mCPBA (0.58 g., 70%) was added with ice cooling with ethyl acetate. The liquid extract was washed with water to a mixture of ethyl 3-(((1S)-7-chloro-2,3-dihydro-1H and saturated aqueous sodium chloride Solution and was inden-1-yl)sulfanyl)-3,6-dihydro-2H-pyran-4-carboxylate washed with magnesium sulfate, and the solvent was elimi (a mixture of 2 diastereomers) (0.32 g) and acetonitrile (3 nated by distillation under reduced pressure. The residue mL), and the mixture was stirred at room temperature for was purified by Silica gel column chromatography (ethyl acetate/hexane) and ethyl (2R.3R8R)-8-(((1S)-7-chloro-2, one hour. The reaction mixture was diluted with saturated 3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(methoxym aqueous sodium thiosulfate solution and extracted with ethyl ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (5.91 g) acetate. The liquid extract was washed with Saturated aque was obtained as a straw-colored oily Substance. ous sodium bicarbonate Solution (twice) and Saturated aque ous Sodium chloride solution and was dried with sodium 0864 MS, found: 532.2. sulfate, and the solvent was eliminated by distillation under 0865 Step B reduced pressure. The residue was purified by silica gel 0866 mCPBA (7.15g, 65%) was added with ice cooling to a mixture of ethyl (2R,3R8R)-8-(((1S)-7-chloro-2,3- column chromatography (ethyl acetate/hexane) and the high dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(methoxymethyl)- polarity fraction was concentrated under reduced pressure. 1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (5.91 g), DMF Of the obtained residue, 100 mg was separated and recov (50 mL) and acetonitrile (50 mL), and the mixture stirred ered using SFC (column=CHIRALPAK AD-H, 20 mmIDx overnight at room temperature. The reaction mixture was 250 mmL, mobile phase: carbon dioxide/methanol=77/23) diluted with Saturated aqueous sodium bicarbonate Solution and the first peak fraction was concentrated down under and extracted with ethyl acetate. The liquid extract was reduced pressure. The residue was purified by silica gel washed with water and saturated aqueous sodium chloride column chromatography (ethyl acetate/hexane) and ethyl Solution and was dried with magnesium sulfate, and the 3-(((1S)-7-chloro-2,3-dihydro-1H-inden-1-yl)sulfonyl)-3,6- solvent was eliminated by distillation under reduced pres dihydro-2H-pyran-4-carboxylate (a single diastereomer) (36 Sure. The residue was purified by silica gel column chro mg) was obtained. matography (ethyl acetate/hexane) and was crystallized from ethanol/hexane, and the solids were recovered by 0861 H NMR (300 MHz, CDC1) & 1.31 (3H, t, J=7.2 filtration. The obtained solids were recrystallized from ethyl Hz), 2.35-2.52 (1H, m), 2.67 (1H, dd, J=14.2, 7.4 Hz), 2.87 acetate?heptane, and ethyl (2R,3R,8R)-8-(((1S)-7-chloro-2, (1H, dd, J=15.9, 8.7 Hz), 3.40-3.57 (1H, m), 3.79 (1H, dd, 3-dihydro-1H-inden-1-yl)sulfonyl)-2,3-bis(methoxym J=12.7, 3.2 Hz), 4.23-4.41 (4H, m), 4.52-4.63 (1H, m), ethyl)-1,4-dioxaspiro4.5 dec-6-ene-7-carboxylate (3.47 g) 4.80-4.88 (1H, m), 5.24 (1H, d, J=7.6 Hz), 7.15-7.25 (4H, was obtained as a white solid. 1H NMR (300 MHz, CDC1) m). & 1.19 (3H, t, J–7.2 Hz), 1.85-2.01 (1H, m), 2.15-2.35 (1H, Example 21 m), 2.39-2.62 (3H, m), 2.76 (1H, dd, J–14.4, 7.6 Hz), 2.88 (1H, dd, J=16.2, 8.7 Hz), 3.40 (3H, s), 3.42 (3H, s), Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-2,3-dihydro 3.44-3.66 (5H, m), 3.98-4.07 (1H, m), 408-4.27 (3H, m), 1H-inden-1-yl)sulfonyl)-2,3-bis(methoxymethyl)-1, 4.49-4.58 (1H, m), 5.07 (1H, d, J=8.3 Hz), 7.05 (1H, s), 4-dioxaspiro4.5 dec-6-ene-7-carboxylate 7.13-7.25 (3H, m). 0867. According to the methods shown in the Examples 0862 Step A or methods analogous thereto, the compounds of Examples 0863 Sodium hydride (1.26 g. 60% oil) was added with 9-13 in following tables were produced. The compounds of ice cooling to a mixture of ethyl (2R,3R8R)-8-(((1S)-7- Examples are shown in the following Table. MS in the table chloro-2,3-dihydro-1H-inden-1-yl)sulfanyl)-2,3-bis(hy means actual value. TABLE 1.

Example number IUPAC Name Structure MS

1 Ethyl 6-(4-chloro-2,3-dihydro O 368.9 cyclohex-1-ene-1-carboxylate 1N O M SEO

C

US 2016/0326102 A1 Nov. 10, 2016 43

0868. The NMR of the compound of Example 13 is TABLE 2-continued shown below. 0869 H NMR (300 MHz, CDC1) & 1.28-137 (3H, m), Compound NO production inhibitory effect at 100 nM 2.07-2.30 (2H, m), 2.33-2.43 (3H, m), 2.46-2.67 (4H, m), No. (% inhibition) 2.76-2.92 (2H, m), 3.33-3.47 (1H, m), 3.61-3.86 (4H, m), 19 107 398-4.11 (1H, m), 4.15-4.37 (4H, m), 4.64-4.77 (1H, m), 2O 104 4.78-4.90 (0.25H, m), 5.03-5.09 (0.5H, m), 5.30 (0.25H, d, 21 112 J=7.9 Hz), 7.00-7.25 (4H, m). Test Example 1 Test Example 2 Inhibitory Effect with Respect to NO Production Effect with Respect to Blood TNF-C. Concentration 0870. The inhibitory effect on TLR4 was determined Elevation by LPS Stimulation using the inhibition rate due to the test compound with respect to NO production as a result of addition of lipopo 0871 Various kinds of cytokines are produced in vivo lysaccharide (LPS) using murine macrophage cell line accompanying inflammatory response and abnormal immu RAW264.7. The cells were adjusted to 2x10 cells/mL using nity or the like. Therefore, the action of test compound with RPM1-1640 culture medium (phenol red free) supplemented respect to blood TNFC. concentration rise was investigated with 10% inactivated bovine fetal serum, and were plated on using laboratory animals. 384 well plate so as to contain 6x10" cells/30 uL per well. 0872. Female BALB/c mice (6 weeks old) were pur Thereafter the cells were cultured at 37° C. overnight under chased, and, after preliminary rearing for about 1 week, the 5% CO/95% air. The test compound dissolved in DMSO mice were divided into groups of four animals. The test was diluted 200 times using RPM1-1640 culture medium compound was dissolved in 10% captisol aqueous solution and adjusted so as to form a compound concentration of 500 and was intravenously administered to the test group at a nM. The prepared test compound 10 uL (final concentration dose of 3 mg/kg. Solvent was administered to control group 100 nM) was added to the cells, and LPS (Sigma) and mouse in the same way. LPS (5 mg/kg) was administered intrap interferon Y (Wako Pure Chemicals) were added in amounts eritoneally to the test group and the control group one hour of 10 uL so as to form final concentrations of 1.25 ng/mL after the administration of the test compound or solvent, and and 0.2 ng/mL respectively. The cells were further cultured blood was sampled one hour later. The serum was separated overnight, and then the nitrite ion (stable NO metabolite) from the obtained blood, and the TNFC. concentration in the concentration in the culture Supernatant was measured as an serum was measured using an assay kit made by R&D index of NO production. The nitrite ion concentration was Systems Inc. The inhibition rates of the test group with assayed by adding 10 uL of 20 g/mL 2,3-diamino naph respect to the control group are shown in Table 3. thalene (DAN) dissolved in 0.2N HCl to 20 L culture Supernatant, incubating at room temperature for ten minutes, TABLE 3 and then adding 10 uL of 0.5N NaOH, and measuring the Blood TNFC. fluorescent value at 460 nm (excitation wavelength 355 nm) Compound inhibition rate using an EnVision plate reader (Perkin Elmer). The NO No. (% inhibition) production inhibition rate (%) was calculated using the value without the addition of stimulating agent as control of 100% 6 93.1 inhibition, and the value without the addition of the com pound as control of 0% inhibition. The results thereof are shown in Table 2. Test Example 3 TABLE 2 Action on Liver Injury by Galactosamine/LPS Compound NO production inhibitory effect at 100 nM Stimulation No. (% inhibition) 1 96 0873. The action on liver injury by Galactosamine/LPS 2 99 stimulation was evaluated by elevation of blood alanine 3 10 transaminase (ALT) amount as an index. Galactosamine 4 10 (700 mg/kg) and LPS (5 g/kg) were administered intraperi 5 OO 6 O3 toneally to BALB/c mice (female, 7 weeks old, Japan 7 05 Charles River). After 8 hr, the blood was collected in the 8 99 presence of heparin. The obtained blood was centrifuged (4° 9 10 C., 10000xrpm, 10 min), and the blood plasma was col 10 OO 11 10 lected, and the ALT amount in the blood plasma was 12 OO measured by 7180 type Hitachi automated analytical appa 13 OO ratus (Hitachi High-Technologies Corporation). Compound 14 O7 6 was dissolved in 10% captisol solution (0.3, 1, 3 mg/kg), 15 O6 16 O8 and the solution was administered intravenously to the mice 17 86 in the tail vein 1 hr before Galactosamine/LPS administra 18 O4 tion. The meantstandard errors of the ALT amount in the blood plasma of each group were shown in Table 4. US 2016/0326102 A1 Nov. 10, 2016 44

TABLE 4 to mice (C57BL/6N, male, 8 weeks old) at 0.3 mg/kg. The test compound was dissolved in 10% captisol or 10% Galactosamine LPS stimulation captisol containing 0.1% N-methyl-2-pyrrolidone. The com pound was administered intravenously (0.1-10 mg/kg body Non-stimulation Compound No. 6 (mg/kg weight) to the mice immediately before intraperitoneal Vehicle Vehicle O.3 1 3 administration of various anticancer drugs. The pain thresh old was measured 1 week after oxaliplatin administration. ALT 83 1021 570 361 104 The pain threshold was evaluated as a weighted value (IU/L) 4 185iifiti 94 60** 10* * * (gram) showing pseudo-escape reaction, when the footpad Sample number = 5 (non-stimulation group) or 10 (Galactosamine LPS stimulation group), of the right hind limb was pressed using balance type ###P<0.001 vs. Non-stimulation. Vehicle group (Aspin-Welch t test), **P < 0.005, pressurizing device (Ugo Basile). The results are shown in ***P < 0.0005 vs. Galactosamine LPS stimulation-Vehicle group (One-tailed Shirley Table 6. The values in the table show the meantstandard Williams test) errors of the weighted values. 0874. As shown in Table 4, Compound 6 (0.3, 1, 3 mg/kg) dose-dependently and significantly inhibited the TABLE 6 increase in the ALT amount in the blood plasma due to Normal 3220 22.0 Galactosamine/LPS stimulation. As is clear from the results, Vehicle 83.3 23.0 it is Suggested that Compound 6 has effect on the prophy Compound No. 6 1 mg/kg 1900 - 46.1 3 mg/kg 153.3 46.1 laxis or treatment of liver injury. 10 mg/kg 310.0 + 45.6" Normal 273.3 11.2 Test Example 4 Vehicle 116.7 20.3 Compound No. 14 0.1 mg/kg 2O8.0 33.8 0.3 mg/kg 215.0 - 21.6 Inhibitory Effect on TNFC. Production from 1 mg/kg 310.0 + 33.8" HMGB-1 Stimulated-Human Kupffer Cell Normal 323.3 32.0 Vehicle 121.7 16.0 0875 TLR4 signal inhibitory activity in human Kupffer Compound No. 21 0.1 mg/kg 16O.O 29.7 cell was evaluated as an inhibition rate of the test compound 0.3 mg/kg 26SO 58.5 for TNFC. produced by addition of HMGB-1 (SHINO 1 mg/kg 285.0 + 19.3" TEST), using human primary Kupffer cells (Cati HUKCCS, Shirley-Williams"; LotiHK8226) purchase from GIBCO. Cell suspension pre P<0.01 ws wehicle pared in RPMI 1640-Gluta MAXTM medium supplemented with 10% inactivated bovine fetal serum was plated in 96-well I-type collagen-coated plate so as to contain 3.1x10' Pharmaceutical Preparation Example 1 cells/100 uL/well. Then, the cells were cultured for 6 hr at 37° C. under 5% CO/95% air to be adhered to the bottom Production of Capsule of the plate. The non-adhered cells were rinsed off with PBS, and the test compound dissolved in DMSO was added to the 0877 adhered cells (final concentration: 1, 10, 100 nM), and the mixture was cultured for 1 hr. Then, HMGB-1 was added 1) Compound of Example 1 30 mg thereto (final concentration: 10 ug/mL), and the mixture was 2) Finely powdered cellulose 10 mg incubated for additional 24 hr. TNFC. production amount 3) Lactose 19 mg contained in the culture Supernatant was quantified by 4) Magnesium Stearate 1 mg ELISA method (R&D systems). TNFC. production inhibition Total 60 mg rate (%) was calculated using the value under the HMGB 1-free condition as control of 100% inhibition and the value 1), 2), 3) and 4) are mixed, and packed into a gelatin capsule, under the compound-free condition as control of 0% inhi bition. The results are shown in Table 5. Pharmaceutical Preparation Example 2 TABLE 5 Production of Tablets Compound TNFC production Compound concentration inhibition rate 0878 No. (nM) (% inhibition) 6 1 45 1) Compound of Example 1 30 g 10 82 2) Lactose 50 g 100 85 3) Corn starch 15 g 4) Carboxymethylcellulose calcium 44 g 5) Magnesium Stearate 1 g Test Example 5 1000 tablets, total 140 g Evaluation of Analgesic Action on Oxaliplatin Induced-Neuropathic Pain Model Mouse 0879 The total quantities of 1), 2) and 3) and 30 g of 4) are kneaded with water, the kneaded mixture is then sub 0876 Oxaliplatin was diluted with saline by the prede jected to vacuum drying and granulation. To said granular termined concentration, and administered intraperitoneally powder is admixed 14 g of 4) and 1 g of 5) and the mixture US 2016/0326102 A1 Nov. 10, 2016

Subjected to tableting using a tableting machine. In this way, 10. (canceled) 1000 tablets containing 30 mg of compound of Example 1 11. A medicament comprising the compound according to per tablet are obtained. claim 9. 12.-16. (canceled) INDUSTRIAL APPLICABILITY 17. A method of inhibiting toll-like receptor 4 in a mammal, which comprises administering an effective 0880. The compounds of the present invention have amount of the compound according to claim 9 to the TLR4 signaling inhibitory action and are useful as agents for mammal. the prevention and treatment of autoimmune diseases and/or 18. A method for the prophylaxis or treatment of autoim inflammatory diseases, or diseases such as chemotherapy mune disease and/or inflammatory disease in a mammal, induced peripheral neuropathy (CIPN), chemotherapy-in which comprises administering an effective amount of the duced neuropathic pain (CINP), liver injury, ischemia-rep compound according to claim 9 to the mammal. erfusion injury (IRI) and the like. 19. A method for the prophylaxis or treatment of chemo 0881. This application is based on patent application No. therapy-induced peripheral neuropathy (CIPN), chemo 2015-095817 filed on May 8, 2015 in Japan, the contents of therapy-induced neuropathic pain (CINP), liver injury and/ which are incorporated in full herein. or ischemia-reperfusion injury (IRI) in a mammal, which 1.-8. (canceled) comprises administering an effective amount of the com 9. Ethyl (2R,3R,8R)-8-(((1S)-7-chloro-5-fluoro-2,3-di pound according to claim 9 to the mammal. hydro-1H-inden-1-yl)sulfonyl)-2,3-bis(hydroxymethyl)-1, 20.-21. (canceled) 4-dioxaspiro4.5dec-6-ene-7-carboxylate.