Novel fused cyclic compound and use thereof

DESCRIPTION

0002NOVEL FUSED CYCLIC COMPOUND AND USE THEREOF Technical Field [0001]

0003The present invention relates to a novel fused ring compound having a GPR40 receptor activation action. [0002] Background of the Invention

0004As a GPR40 receptor agonist useful a drug for the prophylaxis or treatment of diabetes and the like, the following compounds have been reported.

0005(1) WO2009/058237 describes the following compound as a GPR40 receptor agonist. [0003]

0006<img file="WO2010143733A1_D0001.tif" />

0007[0004]

0008(2) WO2009/054423 describes the following compound as a GPR40 receptor agonist.

0009[0005]

0010<img file="WO2010143733A1_D0002.tif" />

0011[0006] wherein L¹ and L³ are the same or different and each is CH or N, L² is O or NH, R¹ is -H or Ci_₆ alkyl, R² is a group of the formula (II) or the formula (III), [0007] <img file="WO2010143733A1_D0003.tif" />

0012[0008]

0013L⁴ is CH or N, A and B are the same or different and each is - O- (Ci-₆ alkyl substituted by one or more groups selected from group G¹) , amino optionally substituted by one or more groups selected from group G², -H or -R³ (wherein at least one of A and B is a group other than -H and -R³) , R³ are the same or different and each is Ci_₆ alkyl optionally substituted by one or more groups selected from the group consisting of -OH and halogen, halogen or -0- (Cχ-₆ alkyl), R⁴ is Cχ-₆ alkyl substituted by one or more groups selected from group G¹, n is 1 or 2, group G¹ is a group consisting of -NHCO₂R², -NH₂, -NHCOR², - NHCO- (cycloalkyl) , -NHCO- (aryl) , -NHSO₂R², 1, 3-dioxolan-4-yl optionally substituted by 1 to 5 Ci_₆ alkyl, -OH, -OCOR², -OR², -CO₂R², -CO₂H, -CONHR² and -CON (R²) ₂, group G² is a group consisting of -CO₂R² and -R², R² are the same or different and each is Ci-₆ alkyl optionally substituted by one or more groups selected from the group consisting of -OH and -OCO- (Ci_₆ alkyl). (3) WO2009/054390 describes the following compound as a GPR40 receptor agonist. [0009]

0014<img file="WO2010143733A1_D0004.tif" />

0015[0010] wherein R¹ is [0011] <img file="WO2010143733A1_D0005.tif" />

0016[ 0012 ]

0017R² is -H or -lower alkyl, R³ is the same or different and each is lower alkyl optionally substituted by (optionally protected OH) or -halogen, n is 1 or 2, R⁴ is lower alkyl substituted by (optionally protected OH) , L¹ is CH or N, L² is -O- or -NH-, L³ is CH or N, L⁴ is CH or N.

0018(4) WO2008/066097 describes the following compound as the GPR40 receptor agonist. [0013]

0019<img file="WO2010143733A1_D0006.tif" />

0020[ 0014 ] wherein R¹: -H, lower alkyl, halogeno lower alkyl, cycloalkyl, aryl, heterocyclic group, lower alkylene-R^A, -C(O)R^B, -CO₂R² or -S(O)_PR^B; lower alkylene, aryl or heterocyclic group for R¹ is optionally substituted; R^A: cycloalkyl, aryl, heterocyclic group, -S(O)pR°, -S(0)_p-aryl, -S (0) _p-heterocyclic group, -C(O)R⁰, -C(O) -aryl, -C (0) -heterocyclic group, -CO₂R⁰, -OR⁰, -0-aryl, -0- heterocyclic group, -N(R⁰J₂, -N (R⁰) -aryl, -N (R⁰) -heterocyclic group, -C(OR⁰) (aryl) ₂, -C (O)N (R⁰) -cycloalkyl or -C (O)N (R⁰) -aryl; aryl or heterocyclic group for R^A is optionally substituted; R^B: lower alkyl, halogeno lower alkyl, cycloalkyl, aryl, heterocyclic group, lower alkylene-cycloalkyl, lower alkylene- aryl, lower alkylene-heterocyclic group, lower alkylene-0R°, lower alkylene-O-aryl or lower alkylene-S (0) ₂NH₂; aryl or heterocyclic group for R^B is optionally substituted; R⁰: -H or lower alkyl: n and p: the same or different and each is 0, 1 or 2; J: -C(R⁶) (R⁷)-, -0- or -S-; R², R³, R⁶ and R⁷: the same or different and each is -H, halogen, lower alkyl, -OR⁰, or aryl; R² and R³, R³ and R⁶, and R⁶ and R⁷ each optionally form lower alkylene in combination; R⁴: -H or lower alkyl; X: single bond, -CH-, -(CHz)₂-, -0-, -S-, -S(O)- or -S(O)₂-; Y: -CH- or -C(O)-; Z: C(-*), C(R⁸), N or N(O); * for Z means a bond to L; X¹ and X²: the same or different and each is C(R⁹), N or N(O); X³ and X⁴: the same or different and each is C(R¹⁰), N or N(O); R⁵: lower alkyl, halogen, halogeno lower alkyl, -OR⁰ or -0-halogeno lower alkyl; R⁸, R⁹ and R¹⁰: the same or different and each is - H, lower alkyl, halogen, halogeno lower alkyl, -OR⁰ or -0- halogeno lower alkyl; R⁶ and R¹⁰ optionally form lower alkylene, -0-lower alkylene or lower alkylene-O- in combination; L: -0- lower alkylene, lower alkylene-O-, -N (R¹¹) -lower alkylene, lower alkylene-N (R¹¹) -, -0-lower alkylene-O-, -N (R¹¹) -lower alkylene-N(Rⁿ)-, -0-lower alkylene-N (R¹¹) - or -N (R¹¹) -lower alkylene-O-; R¹¹ :-H, lower alkyl or -C(O)R⁰. [0015]

0021(5) WO2007/123225 describes the following compound as a GPR40 receptor agonist. [0016]

0022<img file="WO2010143733A1_D0007.tif" />

0023[0017] wherein R¹: -H, halogen, -R⁰, halogeno lower alkyl, -0R^z, -S-R⁰ or -0-halogeno lower alkyl; R⁰: lower alkyl; R^z: the same or different and each is -H or lower alkyl; L: *-lower alkylene- 0-, *-lower alkylene-N (R^z) - or *-CON(R^z)-; * for L shows a bond to ring A; ring A: benzene, pyridine, thiophene, piperidine, dihydropyridine, pyrimidine or tetrahydroquinoline; ring B: benzene or pyridine; R²: the same or different and each is - halogen, -R⁰, halogeno lower alkyl, -0R^z, -S-R⁰, -O-halogeno lower alkyl, -0-lower alkylene-aryl or oxo; n: 0, 1 or 2; R³: - halogen, -R⁰, -halogeno lower alkyl, -O-R⁰, -S-R⁰, -0-halogeno lower alkyl, -X- (optionally substituted phenyl) or -X-

0024(optionally substituted heteroaryl) ; X: single bond, 0, S or N(R^Z); R⁴: -H or lower alkyl; or R¹ and R⁴ optionally form lower alkylene in combination.

0025[0018]

0026(6) WO2008/054675 describes the following compound as a GPR40 receptor agonist.

0027[0019]

0028<img file="WO2010143733A1_D0008.tif" />

0029[0020] wherein A is selected from the group consisting of -CH₂-, -CF₂-, -O-, -N(R⁶)-, -S-, -S(O)-, -S(O)₂-, -C(=0)- and -CH(OH)-; B is selected from the group consisting of -CH₂-, -CH₂CH₂- and - CH(CH₃)-; or -A-B- is selected from the group consisting of - N(R⁶)C(=O)- and -C (=0)N (R⁶) -, or -A-B- shows two atoms that are bonded to form a 5-membered heteroaromatic ring having 1 to 3 hetero atoms independently selected from O, N and S, the 5- membered heteroaromatic ring may be substituted by 1 to 3 groups independently selected from halogen, CH₃, CF₃, -OCH₃ and -OCF₃; X is selected from =C(R⁴)- and =N-; Y is selected from =C(R⁵)- and =N-; X and Y are not simultaneously =N-; a hetero ring is a 5- or 6-membered saturated or partially saturated monocyclic heterocycle having 1 to 3 hetero atoms independently selected from 0, N and S; heteroaryl is a 5- or 6-membered monocyclic heteroaromatic ring having 1 to 3 hetero atoms independently selected from 0, N and S; R¹, R², R³, R⁴ and R⁵ are independently selected from the group consisting of H, halogen, -CN, -NO₂, -Ci-C₆ alkyl, -OCi-C₆ alkyl, -SCi-C₆ alkyl, - S(O)₂Ci-C₆ alkyl, -N(R⁶) (R⁶), -N (R⁶) C (=0) Ci-C₆ alkyl, - N (R⁶) S (O) ₂Ci-C₆ alkyl , -C (O) H, -C (=0) 0H, -C f =O) OC₁-C₆ alkyl , -

0030C (=0) Ci-C₆ alkyl, -C (=0) N (R⁶) (R⁶) , phenyICH=CHC (=0) -, phenylC(=0JCH=CH-, -C (=0) phenyl, -C (=0) naphthyl, - C (=0) heterocycle, heterocycle, heteroaryl, C₃~C₇ cycloalkyl, phenyl and naphthyl; -Ci-C₆ alkyl, and alkyl group of -OCi-C₆ alkyl, -SCi-C₆ alkyl, -S(O)₂Ci-C₆ alkyl, -N (R⁶) C (=0) C_x-C₆ alkyl, -N(R⁶JS(O)₂Ci-C₆ alkyl, -C (=0) OC_x-C₆ alkyl and -C (=0) C_x-C₆ alkyl is optionally substituted by 1 to 5 halogens and optionally substituted by 1 or 2 groups independently selected from -OH, -OC₁-C₃ alkyl optionally substituted by 1 to 5 halogens, - S(O)₂Ci-C₃ alkyl, -C (=0) C_x-C₃ alkyl, -OC(O)C_x-C₃ alkyl, - NHC (=0) CH₃, -NHC (=0) OC_x-C₆ alkyl, -NHS(O)₂CH₃, -N(R⁶J(R⁶), heterocycle, heteroaryl, C₃-C₇ cycloalkyl, phenyl and naphthyl; phenyl, phenyl of phenylCHOHC (0) -, phenyl of phenylC (=0) CH=CH-, -C (=0) phenyl, -C (=0) naphthyl, -C (=0) heterocycle, heterocycle, heteroaryl, C₃-C₇ cycloalkyl, phenyl and naphthyl for any of R¹, R², R³, R⁴ and R⁵ or as a substituent for R¹, R², R³, R⁴ or R⁵ are optionally substituted by 1 to 4 substituents independently selected from halogen, -CN, -NO₂, -OH, -C_x-C₃ alkyl, -C (=0) C_x-C₃ alkyl, -S(O)₂C_x-C₃ alkyl and -OC_x-C₃ alkyl, and -C_x-C₃ alkyl, - OC₁-C₃ alkyl, -S(O)₂C₁-C₃ alkyl and -C(O)C₁-C₃ alkyl substituent is optionally substituted by 1 to 5 halogens; where necessary, the pair of substituents R¹ and R² in combination show a 3- or 4-carbon crosslinked group selected from -CH₂CH₂CH₂-, - CH₂CH₂CH₂CH₂- and -CH=CH-CHOH-, form condensed cyclopentyl, cyclohexyl or phenyl ring at the positions of R¹ and R², and the crosslinking group is optionally substituted by 1 to 3 groups independently selected from halogen, -OH, -CN, -NO₂, - C₁-C₃ alkyl, -OC_x-C₃ alkyl, -SC_x-C₃ alkyl, -S(O)₂C_x-C₃ alkyl, -CF₃ and -OCF₃; each R⁶ is independently selected from the group consisting of H and -C₁-C₆ alkyl; R⁷ is selected from the group consisting of H and -C₁-C₃ alkyl; R⁸ is selected from the group consisting of H, -OH, -C₁-C₃ alkyl optionally substituted by 1 to 3 halogens and -OC_x-C₃ alkyl optionally substituted by 1 to 3 halogens and optionally substituted by one -C(O)OR¹⁰ group; and R⁹ and R¹⁰ are independently selected from the group consisting of H and -Ci-Ce alkyl, and -Ci-Cβ alkyl is optionally substituted by 1 to 5 halogens.

0031[0021]

0032(7) WO2007/136573 describes the following compound as a GPR40 receptor agonist.

0033[0022]

0034<img file="WO2010143733A1_D0009.tif" />

0035[0023] wherein Ar is selected from the group consisting of phenyl, naphthyl, a 5- or 6-membered monocyclic heteroaromatic group having 1 to 3 hetero atoms independently selected from O, N and S, and a benzoheteroaromatic group containing a phenyl group condensed with a 5- or 6-membered heteroaromatic ring having 1 to 3 hetero atoms independently selected from 0, N and S; Ar is optionally substituted by 1 or 2 aromatic groups independently selected from phenyl, phenoxy, benzyl and a 5- or 6-membered heteroaromatic ring having 1 to 3 hetero atoms independently selected from O, N and S, and is optionally substituted by 1 to 5 substituents independently selected from halogen, -CN, -NO₂, -OH, -C(O)H, -C(=O)OH, Ci_₆ alkyl, -C₃-₆ cycloalkyl, -0Ci_₆ alkyl, -SCi_₆ alkyl, -C(=O)Ci_₆ alkyl, - 0C(=0)Ci-₆ alkyl, -C(=O)OCi_₆ alkyl, -S(O)₂Ci_₆ alkyl, -NR¹³R¹⁴, - C (=0) N (R¹³) (R¹⁴) , -S(O)₂NR¹³R¹⁴ and -OC₃-₆ cycloalkyl, (a) in all cases, Ci_₆ alkyl is optionally substituted by 1 to 5 halogens, and optionally substituted by one group selected from -OC1-4 alkyl optionally substituted by -OH and 1 to 5 halogens, (b) in all cases, C₃-6 cycloalkyl is optionally substituted by 1 or 2 substituents independently selected from halogen and CH3, (c) aromatic substituents phenyl, phenoxy, benzyl and a 5- or 6- membered heteroaromatic ring having 1 to 3 hetero atoms independently selected from 0, N and S are optionally substituted by 1 to 5 groups independently selected from halogen, -CN, -NO₂, -OH, -C(=O)H, -C(=O)OH, Ci_₆ alkyl, -0Ci_₆ alkyl, -SCi_₆ alkyl, -C(O)Ci_₆ alkyl, -OC (0) Ci_₆ alkyl, -C(O)OCi_₆ alkyl, -S (0) ₂Ci_₆ alkyl, NR¹³R¹⁴, -C (O)N (R¹³) (R¹⁴) , -S(O)₂NR¹³R¹⁴ and -0 (CH₂) _q (4- to 6-membered heterocycle having 1 or 2 hetero atoms independently selected from 0, N and S), in all cases, Ci-₆ alkyl is optionally substituted by 1 to 5 halogens, and optionally substituted by one group selected from -OC₁-₄ alkyl optionally substituted by -OH and 1 to 5 halogens, and 4- to 6-membered heterocycle having 1 or 2 hetero atoms independently selected from 0, N and S is optionally substituted by 1 or 2 groups independently selected from halogen, CH₃ and CF₃; X is selected from the group consisting of -0-, -S-, -S(O)-, -S(O)₂-, -NR⁵-, -OCR¹⁰R¹¹-, -SCR¹⁰R¹¹-, - NR⁵CR¹⁰R¹¹-, -CR¹⁰R¹¹O-, -CR¹⁰R¹¹S-, -CR¹⁰R¹¹NR⁵- and -CR⁶R⁷CR⁸R⁹O-; Y is selected from the group consisting of -0-, -S-, -S(O)-, - S(O)₂-, -NR⁵-, -C(=0)-, -CR⁶R⁷-, -OCR⁶R⁷-, -SCR⁶R⁷- and - CR⁶R⁷CR⁸R⁹-; Z is selected from the group consisting of - C(=O)OR¹², -C (=0) NR¹³R¹⁴ and 5-tetrazolyl; R¹, R² and R³ are each independently selected from the group consisting of H, halogen, Ci-₃ alkyl and -OC₁-₃ alkyl, C₁-₃ alkyl and -OC₁-₃ alkyl are each optionally substituted by 1 to 3 halogens; R⁴ is selected from the group consisting of halogen, -CN, -NO₂, -OH, -C(=O)H, - C(O)OH, Ci-₆ alkyl, -0Ci_₆ alkyl, -SCi_₆ alkyl, -C (=0) Ci_₆ alkyl, -0C(=0)Ci-6 alkyl, -C(O)OCi_₆ alkyl, -S(O)₂Ci_₆ alkyl, -NR¹³R¹⁴, - C(=O)N(R¹³) (R¹⁴) and -S(O)₂NR¹³R¹⁴, in all cases, Ci_₆ alkyl is optionally substituted by 1 to 5 halogens; R⁵, R¹³ and R¹⁴ are each independently selected from the group consisting of H, C₁-₅ alkyl, -C(=O)Ci_₅ alkyl and -S(O)₂Ci_₅ alkyl, in all cases, Ci_₅ alkyl is optionally substituted by 1 to 5 halogens; R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are each independently selected from the group consisting of H, halogen, -OH and C1-3 alkyl optionally- substituted by 1 to 5 halogens; R¹² is selected from the group consisting of H and Ci-₇ alkyl optionally substituted by 1 to 5 halogens; p is an integer of 0 to 3; and q is 0 or 1.

0036[0024]

0037(8) WO2006/083781 describes the following compound as a GPR40 receptor agonist.

0038<img file="WO2010143733A1_D0010.tif" />

0039[0026] wherein A is selected from the group consisting of -CH- and - N-; B is selected from the group consisting of -S-, -0-, -NH-, -C(=0)- and -CH₂-; D is selected from the group consisting of - C(=O), -C(=S)-, -C(=NH)-, -O- and -NH-; W and Z are independently selected from -CH₂-, -CF₂-, -CH₂CH₂- and - CH₂CH₂CH₂-, one of W and Z is optionally selected from -0-, - C(=0), -NR⁶-, -S-, -S(O)- and -S(O)₂S; Y is selected from =CH- and =N-; a hetero ring is a 5- or 6-membered saturated or partially saturated monocyclic heterocycle having 1 to 3 hetero atoms independently selected from 0, N and S; heteroaryl is a 5- or 6-membered monocyclic heteroaromatic ring having 1 to 3 hetero atoms independently selected from 0, N and S; R¹, R², R³ and R⁴ are each independently selected from the group consisting of H, halogen, -CN, -NO₂, -Ci-C₆ alkyl, - OCi-C₆ alkyl, -SCi-C₆ alkyl, -S(O)₂Ci-C₆ alkyl, -N(R⁶J(R⁶), - N (R⁶) C (=0) Ci-C₆ alkyl, -N (R⁶) S (0) ₂Ci-C₆ alkyl, -C(O)H, -C(=O)OH, -C (=0) OCi-C₆ alkyl, -C (=0) C_x-C₆ alkyl, -C (=0) N (R⁶) (R⁶) , - C (=0) phenyl, -C (=0) naphthyl, -C (=0) heterocycle, heterocycle, heteroaryl, C₃-C₇ cycloalkyl, phenyl and naphthyl; -Ci-C₆ alkyl, and alkyl group of -OCi-C₆ alkyl, -SCi-C₆ alkyl, -S(O)₂Ci-C₆ alkyl, -N(R⁶JCt=O)C₁-C₆ alkyl, -N(R⁶JS(O)₂Ci-C₆ alkyl, -C (=0) OCi- Ce alkyl and <img file="WO2010143733A1_D0011.tif" /> alkyl is optionally substituted by 1 to

00405 halogens, and optionally substituted by 1 or 2 groups independently selected from -OH, -OC1-C₃ alkyl optionally substituted by 1 to 5 halogens, -CF₃, -S(O)₂Ci-C₃ alkyl, - CC=O)Ci-C₃ alkyl, -OC(O)Ci-C₃ alkyl, -NHC (=0) CH₃, -NHC (=0) OCi-C₆ alkyl, -NHS(O)₂CH₃, -N(R⁶J(R⁶), heterocycle, heteroaryl, C₃-C₇ cycloalkyl, phenyl and naphthyl; -C (=0) phenyl, -C (=0) naphthyl, -C (=0) heterocycle, heterocycle, heteroaryl, C₃-C₇ cycloalkyl, phenyl or naphthyl as any of R¹, R², R³ and R⁴, or substituent of R¹, R², R³ or R⁴ is optionally substituted by 1 to 4 substituents independently selected from halogen, -CF₃, -OCF₃, -CN, -NO₂, -OH, -Ci-C₃ alkyl, -C (=0) Ci-C₃ alkyl, -S(O)₂Ci-C₃ alkyl and -OCi-C₃ alkyl, -Ci-C₃ alkyl, -OCi-C₃ alkyl, -S(O)₂Ci-C₃ alkyl and -C(O)Ci-C₃ alkyl substituent is optionally substituted by 1 to 3 halogens; where necessary, one pair of ortho substituents selected from (R^R²), (R²-R^x) , (R²-R³) , (R³- R²) , (R³-R⁴) and (R⁴-R³) are bonded to form a divalent crosslinking group having a length of 3-5 atoms, the divalent crosslinking group is selected from -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂CH₂-, -OCH₂CH₂-, -OCH₂CH₂CH₂-, -OCH₂CH₂CH₂CH₂-, - CH₂OCH₂-, -CH₂OCH₂CH₂-, -CH₂OCH₂CH₂CH₂-, -CH₂CH₂OCH₂CH₂- and - SCH₂CH₂-, and the divalent crosslinking group is optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -CN, -NO₂, -Ci-C₃ alkyl, -OCi-C₃ alkyl, -SCi-C₃ alkyl, -S(O)₂C₁-C₃ alkyl, -CF₃ and -OCF₃; or the pair of ortho substituents R¹-R² are bonded by 4-carbon chain -CH=CH-CH=CH- to form condensed phenyl ring at the positions of R¹ and R², or bonded by 4-atom chain selected from -CH=CH-CH=N-, -N=CH- CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-, -CH₂CH₂CH₂C (=0) - and - CC=O)CH₂CH₂CH₂- to optionally form condensed pyridinyl ring or condensed cyclohexanone ring at the positions of R¹ and R², the condensed phenyl ring, condensed pyridinyl ring and condensed cyclohexanone ring are optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -CN, - NO₂, -Ci-C₃ alkyl, -OCi-C₃ alkyl, -SCi-C₃ alkyl, -S(O)₂Ci-C₃ alkyl, -CF3 and -OCF₃; or the pair of ortho substituents R^{1^}-R² are optionally bonded by 3-atom chain selected from -CH=CHO-, - OCH=CH-, -CH=CH-S-, -SCH=CH-, -CH=CHN(R⁶)-, -N(R⁶JCH=CH-, - CH₂CH₂C (=0)- and -C (=0) CH₂CH₂- to form, at the positions of R¹ and R², 5-membered ring condensed with phenyl ring, the condensed 5-membered ring is optionally substituted by 1 to 3 substituents independently selected from halogen, -OH, -CN, - NO₂, -Ci-C₃ alkyl, -OCi-C₃ alkyl, -SCi-C₃ alkyl, -S(O)₂Ci-C₃ alkyl, -CF₃ and -OCF₃; and R⁶ is selected from the group consisting of H and -C_x-C₆ alkyl. [0027]

0041(9) WO2008/001931 describes the following compound as a GPR40 receptor agonist. [0028]

0042<img file="WO2010143733A1_D0012.tif" />

0043[0029] wherein R¹ is R⁶-SO₂- (R⁶ is a substituent) or an optionally substituted 1, 1-dioxidotetrahydrothiopyranyl group; X is a bond or a divalent hydrocarbon group; R² and R³ are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group; R⁴ and R⁵ are the same or different and each is a Ci-₆ alkyl group optionally substituted by a hydroxy group; ring A is a benzene ring further optionally having substituent (s) selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group; ring B is a 5- to 7-membered ring; Y is a bond or CH₂; and R is an optionally substituted hydroxy group.

0044[0030] (10) WO2005/087710 describes the following compound as a GPR40 receptor agonist. [0031]

0045<img file="WO2010143733A1_D0013.tif" />

0046[0032] wherein Ar is an optionally substituted cyclic group other than a 4-piperidinyl group, ring B is an optionally substituted ring other than a thiazole ring and an oxanole ring) , V is a bond or a spacer (excluding -N=N-) having an atom number of the main chain of 1 to 3, W is a bond or an Ci_₆ alkylene group optionally substituted by a Ci-₆ alkoxy group, X and Xa are the same or different and each is CH or N, Y is 0 or CR⁶R⁷ (R⁶ and R⁷ are the same or different and each is a hydrogen atom, a halogen atom, a Ci_₆ alkyl group or an optionally substituted hydroxy group, and R⁷ is bonded to R^la to form a 4- to 8-membered ring) , R¹ and R^la are the same or different and each is a hydrogen atom, a halogen atom, a Ci_₆ alkyl group or a Ci-₆ alkoxy group, R² is a hydrogen atom, a Ci_6 alkyl group or an optionally substituted acyl group, R³ and R⁴ are the same or different and each is a hydrogen atom or a halogen atom, R⁵ is an optionally substituted hydroxy group or an optionally substituted amino group, provided when W is a bond, then ring B is an optionally substituted benzene ring condensed nonaromatic ring other than a tetrahydroquinoline ring.

0047[0033]

0048(11) WO2005/063725 describes the following compound as a GPR40 receptor agonist. [0034]

0049<img file="WO2010143733A1_D0014.tif" />

0050[0035] wherein X is S or 0, R¹ and R² are the same or different and each is a hydrogen atom, an optionally substituted Cβ-n aryl group, an optionally substituted heterocyclic group or an optionally substituted Ci-₆ alkyl group, R¹ and R² are bonded to form a ring together with the carbon atom bonded thereto, E is -W^N(R⁵) -W²-, -W^X-CH(R⁶)-O-W²-, -W^O-CH (R⁶) -W²-, -W^S(O)_n-W²- or -W^X-CH(R⁶)-W²- (W¹ and W² are the same or different and each is a bond or an optionally substituted C₁-₃ alkylene group, R⁵ and R⁶ are each an optionally substituted heterocyclic group or an optionally substituted hydrocarbon group, n is 1 or 2, provided that when X is S, then R⁵ and R⁶ are not Ci_₆ alkyl groups, ring S¹ is a benzene ring or a pyridine ring optionally further having substituent (s) selected from an optionally substituted Ci_₆ alkyl group, an optionally substituted Ci_₆ alkoxy group and a halogen atom, R³ and R⁴ are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted Ci_₆ alkyl group or an optionally substituted Ci-₆ alkoxy group, R⁹ and R¹⁰ are the same or different and each is a hydrogen atom, a halogen atom or a Ci-₆ alkoxy group, and R is an optionally substituted hydroxy group or optionally substituted amino group.

0051(12) WO2005/063729 describes the following compound as a GPR40 receptor agonist. [0036] <img file="WO2010143733A1_D0015.tif" />

0052[0037] wherein R¹, R³, R⁴ and R⁵ are the same or different and each is a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or an optionally substituted hydroxy group; R² is a halogen atom, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group or an optionally substituted heterocyclic group; R¹⁰ and R¹¹ are the same or different and each is a hydrogen atom, a halogen atom or a Ci-₆ alkoxy group; E is a bond, an optionally substituted Ci-₄ alkylene group, -W^O-W²-, -Vl¹S-VI²- or -W^x-N (R⁶) -W²- (W¹ and W² are the same or different and each is a bond or an optionally substituted C₁-₃ alkylene group, and R⁶ is a hydrogen atom, an optionally substituted acyl group or an optionally substituted hydrocarbon group) ; ring S¹ is a benzene ring further optionally having substituent (s) selected from a halogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group and an optionally substituted amino group; and R is an optionally substituted hydroxy group or an optionally substituted amino group; provided R¹ and R³ are not simultaneously hydrogen atoms.

0053(13) WO2004/106276 describes the following compound as a GPR40 receptor agonist.

0054[0038] <img file="WO2010143733A1_D0016.tif" />

0055[ 0039] wherein Ar is an optionally substituted cyclic group, ring A is an optionally further substituted ring other than thiazole, oxazole, imidazole and pyrazole, Xa and Xb are independently a bond or a spacer having an atom number of the main chain of 1 to 5, Xc is 0, S, SO or SO₂, [0040]

0056<img file="WO2010143733A1_D0017.tif" />

0057[0041] is

0058[0042]

0059<img file="WO2010143733A1_D0018.tif" />

0060[0043] ring B is a 5- to 7-membered ring, Xd is a bond, CH or CH₂, is a single bond when Xd is a bond or CH₂, a double bond when Xd is CH, and R¹ is an optionally substituted hydroxy group, provided that (i) when ring A is benzene, a cyclic group for Ar is not a quinolinyl group, (ii) when ring B is a 5- to 7- membered aromatic ring, a ring for ring A is not thiophene or furan, (iii) when ring B is benzene, a ring for ring A is not 5-membered aromatic heterocycle, (iv) when ring B is cyclohexane, Xd is not a bond.

0061(14) WO2004/041266 describes the following compound as a GPR40 receptor agonist.

0062[0044] <img file="WO2010143733A1_D0019.tif" />

0063[ 0045 ] wherein ring A is an optionally substituted benzene ring, ring R is an optionally substituted phenylene group, Xa is a spacer other than an alkylene group, p and q are each an optionally substituted carbon chain having a carbon number of 0 to 4, and Ra is a hydrogen atom or a substituent.

0064As other compounds which are not GPR40 receptor agonists, the following compounds have been reported.

0065(15) WO2005/009975 describes the following compound as an MEK inhibitor. [0046]

0066<img file="WO2010143733A1_D0020.tif" />

0067[0047] wherein W is [0048]

0068<img file="WO2010143733A1_D0021.tif" />

0069[ 0049 ]

0070Q is -0-R₃, -NH₂, -NH[ (CH₂) _kCH₃] or -NH [0 (CH₂) _kCH₃] (-NH₂ is optionally substituted by 1 or 2 substituents independently selected from methyl and -NR₉R₉₃, and - (CH₂) _JcCH₃ moiety of - NH [ (CH₂)_kCH₃] and -NH [0 (CH₂) _kCH₃] group is optionally substituted by 1 to 3 substituents independently selected from -OH, -NR₉R_9a, Ci-₆ alkyl and C₃-C₁₂ cycloalkyl) ; Z is -NH₂, -NH [ (CH₂) _kCH₃] or - NH[O(CH₂J_kCH₃] (-NH₂ is optionally substituted by 1 or 2 substituents independently selected from methyl and -NRgRg₃, and -(CH₂J_kCH₃ moiety of -NH [ (CH₂) _kCH₃] and -NH [0 (CH₂) _kCH₃] group is optionally substituted by 1 to 3 substituents independently selected from -OH and -NRgRg₃) ; Ri is hydrogen, Ci_₆ alkyl, C₂-₆ alkenyl, C₂-₆ alkynyl, C3-C₁₂ cycloalkyl, - (CRioRn) _q (C₆-Ci_O aryl) or -(CRioRn)_q (4- to 10-membered heterocycle) ; Ri is optionally substituted by 1 to 3 substituents selected from the group consisting of -COOH, -COORi₄, -COR₉, - (CR10R11) _q (C₆-Ci₀ aryl), - (CRioRii)_q(4-lO-membered heterocycle) , -SO₂Rn, -SO₂NRi₂Ri₃, -OH, - ORi₄, cyano, halo, -NRgRg_a and -NRgCO(Rn); R₂ is hydrogen, chlorine, fluorine or methyl; R₃ is Ci_₆ alkyl; R₄ is bromine, chlorine, fluorine, iodine, Ci_₆ alkyl, C₂_₄ alkenyl, C₂-₆ alkynyl, C₃-₆ cycloalkyl, - (CH₂) -C₃-₆ cycloalkyl, cyano, -0-(Ci_₄ alkyl), - S- (Ci-₂ alkyl) , -SOCH₃, -SO₂CH₃, -SO₂NR₆R₇, .-C≡C- (CH₂) _nNH₂, -C≡C- (CH₂J_nNHCH₃, -C≡C- (CH₂) _nN(CH₃) ₂, -C≡C-CH₂OCH₃, -C=C (CH₂) _n0H, - C=C- (CH₂) _nNH₂, -CHCHCH₂OCH₃, -CHCH- (CH₂) _nNHCH₃, -CHCH- (CH₂) _nN (CH₃) ₂, -(CH₂)_PCO₂R₆, -C(0)Ci_₃ alkyl, -C(O)NHCH₃, -(CH₂J_1nNH₂, - (CH₂) _mNHCH₃, -(CH₂)_mN(CH₃)₂, - (CH₂) _m0R₆, -CH₂S (CH₂) _t (CH₃) , - (CH₂) _PCF₃, -C≡CCF₃, -CH=CHCF₃, -CH₂CHCF₂, -CH=CF₂, - (CF₂) _VCF₃, -CH₂ (CF₂) _nCF₃, - (CH₂) _tCF (CF₃J₂, -CH(CF₃J₂, -CF₂CF(CF₃J₂ or -C(CF₃J₃ (Ci-₆ alkyl and C₂-₆ alkynyl are optionally substituted by 1 to 3 substituents independently selected from -OH and Ci_₆ alkyl) ; R₅ is hydrogen or fluorine; R₆ and R₇ are each independently hydrogen, methyl or ethyl; Rg_a and Rg are each independently hydrogen or Ci-₆ alkyl; k is 0 to 3; m is 1 to 4; n is 1 to 2; p is 0 to 2; t is 0 or 1; and v is 1 to 5.

0071(16) WO2004/014382 and (17) WO2003/063794 describe the following compound as IgE/IgG receptor modulator. [0050]

0072<img file="WO2010143733A1_D0022.tif" /> [ 0051 ] wherein L¹ and L² are each independently selected from the group consisting of a direct bond and a linker; R² is selected from the group consisting of (Cl-Cβ)alkyl optionally- substituted by one or more, the same or different R⁸ groups, (C3-C8) cycloalkyl optionally substituted by one or more, the same or different R⁸ groups, cyclohexyl optionally substituted by one or more, the same or different R⁸ groups, 3- to 8- membered cycloheteroalkyl optionally substituted by one or more, the same or different R⁸ groups, (C5-C15)aryl optionally substituted by one or more, the same or different R⁸ groups, phenyl optionally substituted by one or more, the same or different R⁸ groups and 5- to 15-membered heteroaryl optionally substituted by one or more, the same or different R⁸ groups; R⁴ is selected from the group consisting of hydrogen, (Cl- C6)alkyl optionally substituted by one or more, the same or different R⁸ groups, (C3-C8) cycloalkyl optionally substituted by one or more, the same or different R⁸ groups, cyclohexyl optionally substituted by one or more, the same or different R⁸ groups, 3- to 8-membered cycloheteroalkyl optionally substituted by one or more, the same or different R⁸ groups, (C5-C15)aryl optionally substituted by one or more, the same or different R⁸ groups, phenyl optionally substituted by one or more, the same or different R⁸ groups and 5- to 15-membered heteroaryl optionally substituted by one or more, the same or different R⁸ groups; R⁵ is selected from the group consisting of R⁶, (Cl-Cβ)alkyl optionally substituted by one or more, the same or different R⁸ groups, (C1-C4) alkanyl optionally substituted by one or more, the same or different W groups, (C2-C4) alkenyl optionally substituted by one or more, the same or different R⁸ groups and (C2-C4) alkynyl optionally substituted by one or more, the same or different R⁸ groups; each R⁶ is independently selected from the group consisting of hydrogen, electric negative group, -0R^d, -SR^d, (Cl- C3)haloalkyloxy, (C1-C3) perhaloalkyloxy, -NR^CR^C, halogen, (Cl- C3)haloalkyl, (C1-C3) perhaloalkyl, -CF₃, -CH₂CF₃, -CF₂CF₃, -CN,

0073-NC, -OCN, -SCN, -NO, -NO₂, -N₃, -S(O)R^d, -S(0)₂R^d, -S(0)₂0R^d, - S(O)NR⁰R⁰; -S (O)₂NR^CR^C, -OS(O)R^d, OS(O)₂R^d, -OS(O)₂OR^d, -0S(O)NR⁰R⁰, -OS(O)₂NR⁰R⁰, -C(O)R^d, -C(O)OR^d, -C(O)NR⁰R⁰, -C(NH)NRcRc, - OC(O)R^d, -SC(O)R^d, -OC(O)OR^d, -SC(O)OR^d, -OC(O)NR⁰R⁰, -SC(O)NR⁰R⁰, -OC(NH)NR⁰R⁰, -SC(NH)NR⁰R⁰, -[NHC(O) ]_nR^d, - [NHC (0) ] _n0R^d, - [NHC(O) ]_nNR^cR° and -[NHC(NH)J_nNR⁰R⁰, (C5-C10)aryl optionally substituted by one or more, the same or different R⁸ groups, phenyl optionally substituted by one or more, the same or different R⁸ groups, (C6-C16) arylalkyl optionally substituted by one or more, the same or different R⁸ groups, 5- to 10- membered heteroaryl optionally substituted by one or more, the same or different R⁸ groups and 6- to 16-membered heteroarylalkyl optionally substituted by one or more, the same or different R⁸ groups; R⁸ is selected from the group consisting of R^a, R^b, R^a substituted by one or more, the same or different R^a or R^b, -0R^a substituted by one or more, the same or different R^a or R^b, -B(OR^a)₂, -B(NR^CR^C)₂, -(CH₂)_m-Rb, -(CHR^a)_m-R^b, -O-(CH₂)_m-R^b, -S-(CH₂)_m-R^b, -O-CHR^aR^b, -O-CR^a(R^b)₂, -0- (CHR^a)_m-R^b, -O-(CH₂)_m-CH[(CH₂)_ffiR^b]R^b, -S- (CHR^a) _m-R^b, -C (0) NH- (CH₂)_m-R^b, - C(O)NH-(CHR^a)_m-R^b, -0-(CH₂Jm-C (O)NH- (CH₂) _m-R^b, -S- (CH₂) _m-C (0) NH- (CH₂) _m-R^b, -O-(CHR^a)_m-C(O)NH-(CHR^a)_m-R^b, -S- (CHR^a)_m-C (0) NH- (CHR^a) _m- R^b, -NH-(CH₂)_m-R^b, -NH-(CHR^a)_m-R^b, -NH [ (CH₂) _mR^b] , -N [ (CH₂) _mR^b] ₂, - NH-C (O)-NH- (CH₂) _m-R^b, -NH-C (0) - (CH₂) _m-CHR^bR^b and -NH- (CH₂) _m-C (0) - NH- (CH₂)_m-R^b; each R^a is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2- to 6-membered heteroalkyl, 3- to 8-membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4- to 11-membered cycloheteroalkylalkyl, 5- to 10-membered heteroaryl and 6- to 16-membered heteroarylalkyl; each R^b is an appropriate group independently selected from the group consisting of =0, -0R^d, (Cl-C3)heteroalkyloxy, =S, -SR^d, =NR^d, =NOR^d, -NR^CR°, halogen, - CF₃, -CN, -NC, -OCN, -SCN, -NO, -NO₂, =N₂, -N₃, -S (0) R^d, -S(O)₂R^d, -S (O) ₂OR^d, -S (O) NR^CR^C, -S (O) ₂NR^CR^C, -OS (O) R^d, -OS (O) ₂R^d, -OS (O) ₂OR^d,

0074-OS(O)₂NR^CR^C, -C(O)R^d, -C(O)OR^d, -C(O)NR⁰R⁰, -C(NH)NR^CR^C, - C(NR^a)NR^cR^c, -C (NOH) R^a, -C (NOH) NR^CR^C, -OC(O)R^d, -0C(0)0R^d, - OC(O)NR^CR^C, -0C(NH)NR^cR^c, -OC (NR^a) NR^CR°, - [NHC (0) ]_nR^d, - [NR³C (0) ] _nR^d, - [NHC (0) ] _n0R^d, - [NR^aC (0) ] _n0R^d, - [NHC (0) ] _nNR^cR^c, - [NR³C(O) ]_nNR^cR°, -[NHC(NH)_nNR⁰R⁰ and - [NR³C (NR^a) ]_nNR^cR°; each R° is independently a protecting group or R³, or each R° form, together with the nitrogen atom bonded thereto, 5- to 8- membered cycloheteroalkyl or heteroaryl, optionally further contains one or more, the same or different hetero atoms, or optionally substituted by one or more, the same or different R^a or appropriate R^h group; each R^d is independently R³; each m is independently an integer of 1 to 3; each n is independently an integer of 0 to 3; provided (1) when L¹ is a direct bond and R⁶ is hydrogen, R² is not 3, 4, 5-tri (C1-C6) alkoxyphenyl; (2) when L¹ and L are each a direct bond and R² is substituted phenyl, and R⁶ is hydrogen, R⁵ is other than cyano or -C(O)NHR (R is hydrogen or (C1-C6) alkyl) ; (3) when L¹ and L² are each a direct bond, and R² and R⁴ are each independently substituted or unsubstituted pyrrole or indole, then R and R⁴ are bonded to molecule residue via a ring carbon atom; (4) the compound is not a compound of the following formula [0052]

0075<img file="WO2010143733A1_D0023.tif" />

0076[ 0053 ] wherein R^e is (C1-C6) alkyl; R^f and R⁹ are each independently straight chain or branched chain (C1-C6) alkyl optionally substituted by one or more, the same or different R⁸ groups; and R⁸ is as defined above. [0054]

0077However, none of these documents specifically disclose the compound of the present invention.

SUMMARY OF THE INVENTION

0079Problems to be Solved by the Invention

0080[0055]

0081The present invention aims to provide a novel fused ring compound having a GPR40 receptor activation action and useful as an insulin secretagogue or a drug for the prophylaxis or treatment of diabetes and the like. Means of Solving the Problems [0056]

0082The present inventors have intensively conducted various studies and found that the compound represented by the following formula (I) unexpectedly has a superior GPR40 receptor agonist activity, shows superior properties as pharmaceutical products such as stability, particularly, high dissolution property, low toxicity, fine pharmacokinetics such as sustainability in blood and the like, and therefore, it can be a safe and useful medicament for the prophylaxis or treatment of GPR40 receptor-related pathology or diseases in mammals, based on which the present inventors have completed the present invention. [0057]

0083Accordingly, the present invention relates to [1] a compound represented by the formula (I) : [0058]

0084<img file="WO2010143733A1_D0024.tif" />

0085[0059] wherein R¹ is a halogen atom, hydroxy, optionally substituted Ci-₆ alkyl or optionally substituted Ci_₆ alkoxy, R² is optionally substituted hydroxy,

0086R³ is a hydrogen atom, a halogen atom or optionally substituted

0087Ci-6 alkyl,

0088X is CH₂ (wherein R¹ and X optionally form an optionally substituted ring) ,

0089Y is CH₂, NH or 0,

0090Z is CH or N, n is an integer selected from 1 to 3,

0091A is a halogen atom, optionally substituted amino, or a 4- to

009213-membered cyclic group optionally substituted by 1 to 5 substituents selected from

0093(1) a halogen atom,

0094(2) optionally substituted amino,

0095(3) optionally substituted Ci-₆ alkylthio,

0096(4) optionally substituted Ci_₆ alkyl,

0097(5) optionally substituted C₃-₁₀ cycloalkyl,

0098(6) optionally substituted Ci_₆ alkoxy,

0099(7) optionally substituted C₆-i₄ aryl,

0100(8) an optionally substituted 4- to 7-membered heterocyclic group, and

0101(9) optionally substituted 4- to 7-membered heterocyclyl-oxy or a salt thereof (hereinafter to be sometimes abbreviated as compound (I) ) ;

0102[IA] a compound represented by the formula (I) : [0060]

0103<img file="WO2010143733A1_D0025.tif" />

0104[0061] wherein R¹ is a halogen atom, hydroxy, optionally substituted Ci-₆ alkyl or optionally substituted Ci_₆ alkoxy, R² is optionally substituted hydroxy,

0105R³ is a hydrogen atom, a halogen atom or optionally substituted

0106Ci-6 alkyl,

0107X is CH₂ (wherein R¹ and X optionally form an optionally substituted ring) ,

0108Y is CH₂, NH or 0,

0109Z is CH or N, n is an integer selected from 1 to 3,

0110A is a halogen atom, optionally substituted amino, or a 4- to

011113-membered cyclic group optionally substituted by 1 to 3 substituents selected from

0112(1) a halogen atom,

0113(2) optionally substituted amino,

0114(3) optionally substituted Ci_₆ alkylthio,

0115(4) optionally substituted Ci_₆ alkyl,

0116(5) optionally substituted C₃-1₀ cycloalkyl,

0117(6) optionally substituted Ci_₆ alkoxy,

0118(7) optionally substituted C₆-_U aryl,

0119(8) an optionally substituted 4- to 7-membered heterocyclic group, and

0120(9) optionally substituted 4- to 7-membered heterocyclyl-oxy, or a salt thereof;

0121[2] the compound or salt of the above-mentioned [1] or [IA] wherein R¹ is Ci_₆ alkyl (wherein R¹ and X optionally form an optionally substituted ring) ;

0122[3] the compound or salt of the above-mentioned [1] represented by the formula (II) :

0123[0062]

0124<img file="WO2010143733A1_D0026.tif" />

0125[0063] wherein R² is optionally substituted hydroxy,

0126R³ is a hydrogen atom, a halogen atom or optionally substituted

0127Ci-₆ alkyl,

0128Y is CH₂, NH or 0,

0129Z is CH or N, n is an integer selected from 1 to 3,

0130A is a halogen atom, optionally substituted amino, or a 4- to

013113-membered cyclic group optionally substituted by 1 to 5 substituents selected from

0132(1) a halogen atom,

0133(2) optionally substituted amino,

0134(3) optionally substituted Ci_₆ alkylthio,

0135(4) optionally substituted Ci-₆ alkyl,

0136(5) optionally substituted C₃-₁₀ cycloalkyl,

0137(6) optionally substituted Cχ-₆ alkoxy,

0138(7) optionally substituted C₆-₁₄ aryl,

0139(8) an optionally substituted 4- to 7-membered heterocyclic group, and

0140(9) optionally substituted 4- to 7-membered heterocyclyl-oxy (hereinafter to be sometimes abbreviated as compound (II) ); [3A] the compound or salt of the above-mentioned [1] , [2] , [3] or [IA], which is represented by the formula (II):

0141[0064]

0142<img file="WO2010143733A1_D0027.tif" />

0143[0065] wherein R² is optionally substituted hydroxy,

0144R³ is a hydrogen atom, a halogen atom or optionally substituted Ci_₆ alkyl, Y is CH₂, NH or O, Z is CH or N, n is an integer selected from 1 to 3,

0145A is a halogen atom, optionally substituted amino, or a 4- to 13-membered cyclic group optionally substituted by 1 to 3 substituents selected from

0146(1) a halogen atom,

0147(2) optionally substituted amino,

0148(3) optionally substituted Ci_₆ alkylthio,

0149(4) optionally substituted Ci-β alkyl,

0150(5) optionally substituted C₃-₁₀ cycloalkyl,

0151(6) optionally substituted Ci-₆ alkoxy,

0152(7) optionally substituted Ce-u aryl,

0153(8) an optionally substituted 4- to 7-membered heterocyclic group, and

0154(9) optionally substituted 4- to 7-membered heterocyclyl-oxy; [4] the compound or salt of the above-mentioned [1], [2], [3], [IA] or [3A] , wherein R² is hydroxy;

0155[5] the compound or salt of the above-mentioned [1], [2], [3],

0156[4], [IA] or [3A], wherein R³ is a hydrogen atom or Ci_₆ alkyl;

0157[6] the compound or salt of the above-mentioned [1], [2], [3],

0158[4], [5], [IA] or [3A], wherein Y is 0;

0159[7] the compound or salt of the above-mentioned [1], [2], [3],

0160[4], [5], [6], [IA] or [3A], wherein Z is CH;

0161[8] the compound or salt of the above-mentioned [1], [2], [3],

0162[4], [5], [6], [7], [IA] or [3A], wherein n is 1;

0163[0066]

0164[9] the compound or salt of the above-mentioned [1], [2], [3],

0165[4], [5], [6], [7] or [8], wherein A is phenyl, benzimidazolyl or a 5- or 6-membered aromatic heterocyclic group (preferably, thienyl, pyrimidinyl) each optionally substituted by 1 to 5 substituents selected from

0166(a) a halogen atom,

0167(b) C₁-₆ alkyl optionally substituted by 1 to 3 halogen atoms,

0168(c) Ci-₆ alkoxy optionally substituted by 1 to 3 substituents selected from (1) a halogen atom,

0169(2) Ci-6 alkylsulfonyl,

0170(3) C₃-_S cycloalkyl,

0171(4) mono- or di-Ci_₆ alkyl-amino,

0172(5) Ci-6 alkoxy,

0173(6) Cε-₁₄ aryl optionally substituted by a halogen atom,

0174(7) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituents selected from Cχ-s alkyl and oxo, and

0175(8) Ci-6 alkylthio,

0176(d) a 4- to 7-membered heterocyclic group, and

0177(e) 4- to 7-membered heterocyclyl-oxy optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo;

0178[10] the compound or salt of the above-mentioned [1], [2], [3], [4], [5], [6], [7], [8] or [9], wherein R² is hydroxy,

0179R³ is a hydrogen atom or Ci-₆ alkyl,

0180Y is 0, /

0181Z is CH, n is 1,

0182A is phenyl, benzimidazolyl or a 5- or 6-membered aromatic heterocyclic group (preferably, thienyl, pyrimidinyl) each optionally substituted by 1 to 5 substituents selected from

0183(a) a halogen atom,

0184(b) Ci-₆ alkyl optionally substituted by 1 to 3 halogen atoms,

0185(c) Ci-₆ alkoxy optionally substituted by 1 to 3 substituents selected from

0186(1) a halogen atom,

0187(2) Ci-₆ alkylsulfonyl,

0188(3) C₃-₈ cycloalkyl,

0189(4) mono- or di-Ci-₆ alkyl-amino,

0190(5) Ci-₆ alkoxy,

0191(6) Cε-₁₄ aryl optionally substituted by a halogen atom,

0192(7) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo, and ( 8 ) Ci-₆ alkylthio ,

0193(d) a 4- to 7-membered heterocyclic group, and

0194(e) 4- to 7-membered heterocyclyl-oxy optionally substituted by 1 to 3 substituents selected from Ci_₆ alkyl and oxo;

0195[0067]

0196[11] the compound or salt of the above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [IA] or [3A], wherein A is phenyl optionally substituted by 1 to 3 substituents selected from

0197(a) Ci-₆ alkyl optionally substituted by 1 to 3 halogen atoms,

0198(b) Ci-₆ alkoxy optionally substituted by 1 to 3 substituents selected from

0199(1) a halogen atom,

0200(2) Ci-₆ alkylsulfonyl,

0201(3) C₃-₈ cycloalkyl,

0202(4) mono- or di-Ci-6 alkyl-amino,

0203(5) Ci_6 alkoxy,

0204(6) Cε-₁₄ aryl optionally substituted by a halogen atom,

0205(7) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo, and

0206(8) Cχ-₆ alkylthio, and

0207(c) 4- to 7-membered heterocyclyl-oxy optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo;

0208[12] the compound or salt of the above-mentioned [1] , [2] , [3] , [4], [5], [6], [7], [8], [9], [10], [IA] or [3A], wherein A is benzimidazolyl or a 5- or 6-membered aromatic heterocyclic group (preferably, thienyl, pyrimidinyl) each optionally substituted by 1 to 3 substituents selected from

0209(a) a halogen atom,

0210(b) Ci-₆ alkyl optionally substituted by 1 to 3 halogen atoms, and

0211(c) a 5- or 6-membered heterocyclic group; [0068]

0212[13] [ (3S) -6- { [(3S)-7-{2,6-dimethyl-4-[3- (methylsulfonyl) propoxy] phenyl} -2, 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid or a salt thereof;

0213[14] [ (3S)-6-{ [ (3S)-7-{4-[ (1, l-dioxidotetrahydro-2H-thiopyran- 4-yl) oxy] -2, 6-dimethylphenyl}-2, 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid or a salt thereof;

0214[15] [ (3S) -6-{ [ (3S) -7- (2-ethyl-6, 7-difluoro-lH-benzimidazol-1- yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetic acid or a salt thereof; [16] [ (3S) -6-{ [ (3S) -7- (2-ethoxy-6, 7-difluoro-lH-benzimidazol- 1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetic acid or a salt thereof; [17] [ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (morpholin-4- yl)pyrimidin-5-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetic acid or a salt thereof; [18] a prodrug of the compound or salt of the above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [IA] or [3A]; [19] a medicament comprising the compound or salt of the above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [IA] or [3A], or a prodrug thereof;

0215[20] the medicament of the above-mentioned [19] for activating a GPR40-mediated signal;

0216[21] the medicament of the above-mentioned [19], which is an agent for the prophylaxis or treatment of diabetes or obesity; [22] a method of activating a GPR40-mediated signal, comprising administering the compound or salt of the above- mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [IA] or [3A] or a prodrug thereof to a mammal;

0217[23] a method for the prophylaxis or treatment of diabetes or obesity, comprising administering the compound or salt of the above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [IA] or [3A] or a prodrug thereof to a mammal;

0218[24] use of the compound or salt of the above-mentioned [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [IA] or [3A] or a prodrug thereof for the production of a medicament that activates a GPR40-mediated signal;

0219[25] use of the compound or salt of the above-mentioned [1] , [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [IA] or [3A] or a prodrug thereof for the production of an agent for the prophylaxis or treatment of diabetes or obesity; and the like. Effect of the Invention [0069]

0220The present compound (I) has a superior GPR40 receptor agonist activity, and further has superior properties as a pharmaceutical product such as stability and the like. Particularly, since the compound shows high dissolution property, low toxicity, good kinetics such as sustainability in blood and the like, it can be a safe and useful drug for the prophylaxis or treatment of GPR40 receptor-related pathology or diseases in mammals. [0070] Detailed Description of the Invention

0221The present invention is explained in detail in the following.

0222Unless otherwise specified, as the "halogen atom" in the present specification, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom can be mentioned. [0071]

0223Unless otherwise specified, as the "optionally substituted hydrocarbon" in the present specification, for example, "optionally substituted Ci_6 alkyl", "optionally substituted C₂-₆ alkenyl", "optionally substituted C₂-6 alkynyl", "optionally substituted C₃_₈ cycloalkyl", "optionally substituted C₆-i₄ aryl", "optionally substituted C₇-_I6 aralkyl" and the like can be mentioned.

0224[0072]

0225Unless otherwise specified, as the "Ci_₆ alkyl" in the present specification, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned. [0073]

0226Unless otherwise specified, as the "C₂-₆ alkenyl" in the present specification, for example, vinyl, propenyl, isopropenyl, 2-buten-l-yl, 4-penten-l-yl, 5-hexen-l-yl and the like can be mentioned. [0074]

0227Unless otherwise specified, as the "C₂-₆ alkynyl" in the present specification, for example, 2-butyn-l-yl, 4-pentyn-l- yl, 5-hexyn-l-yl and the like can be mentioned. [0075]

0228Unless otherwise specified, as the "C₃_g cycloalkyl" in the present specification, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like can be mentioned. [0076]

0229Unless otherwise specified, as the "C₆-_I4 aryl" in the present specification, for example, phenyl, 1-naphthyl, 2- naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthryl and the like can be mentioned. The C₆_i₄ aryl may be saturated partially, and as the partially saturated C₆-_U aryl, for example, tetrahydronaphthyl and the like can be mentioned. [0077]

0230Unless otherwise specified, as the "C₇-_I6 aralkyl" in the present specification, for example, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2- diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 2-biphenylylmethyl, 3-biphenylylmethyl, 4-biphenylylmethyl and the like can be mentioned.

0231[0078]

0232Unless otherwise specified, as the "optionally- substituted hydroxy" in the present specification, for example, "hydroxy", "optionally substituted Ci_₆ alkoxy", "optionally substituted heterocyclyl-oxy", "optionally substituted Cβ-n aryloxy", "optionally substituted C₇-₁₆ aralkyloxy" and the like can be mentioned. [0079]

0233Unless otherwise specified, as the "Ci_₆ alkoxy" in the present specification, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy and the like can be mentioned. [0080]

0234Unless otherwise specified, as the "Ci-6 alkoxy-Ci_₆ alkoxy" in the present specification, for example, methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like can be mentioned. [0081]

0235As the "heterocyclyl-oxy" in the present specification, a hydroxy substituted by a "heterocyclic group" below can be mentioned. As preferable examples of the heterocyclyl-oxy group, tetrahydropyranyloxy, thiazolyloxy, pyridyloxy, pyrazolyloxy, oxazolyloxy, thienyloxy, furyloxy and the like can be mentioned. [0082]

0236Unless otherwise specified, as the "Cε-₁₄ aryloxy" in the present specification, for example, phenoxy, 1-naphthyloxy, 2- naphthyloxy and the like can be mentioned. [0083]

0237Unless otherwise specified, as the "C₇-₁₆ aralkyloxy" in the present specification, for example, benzyloxy, phenethyloxy and the like can be mentioned. [0084]

0238Unless otherwise specified, as the "optionally substituted mercapto" in the present specification, for example, "mercapto", "optionally substituted Ci_₆ alkylthio", "optionally substituted heterocyclyl-thio", "optionally substituted Cβ-u arylthio", "optionally substituted C₇-₁₆ aralkylthio" and the like can be mentioned. [0085]

0239Unless otherwise specified, as the "Ci-₆ alkylthio" in the present specification, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert- butylthio and the like can be mentioned. [0086]

0240Unless otherwise specified, as the "heterocyclyl-thio" in the present specification, mercapto substituted by a "heterocyclic group" below can be mentioned. As preferable examples of the heterocyclyl-thio, tetrahydropyranylthio, thiazolylthio, pyridylthio, pyrazolylthio, oxazolylthio, thienylthio, furylthio and the like can be mentioned. [0087]

0241Unless otherwise specified, as the "Cε-u arylthio" in the present specification, for example, phenylthio, 1-naphthylthio, 2-naphthylthio and the like can be mentioned. [0088]

0242Unless otherwise specified, as the "C₇-₁₆ aralkylthio" in the present specification, for example, benzylthio, phenethylthio and the like can be mentioned. [0089]

0243Unless otherwise specified, as the "heterocyclic group" in the present specification, for example, a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heterocyclic group containing, as a ring-constituting atom besides carbon atoms, one or two kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom, preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) • aromatic heterocyclic group, (ii) a 5- to 10-membered non- aromatic heterocyclic group and the like can be mentioned. Of these, a 5- or 6-membered aromatic heterocyclic group is preferable. Specifically, aromatic heterocyclic groups such as thienyl (e.g., 2-thienyl, 3-thienyl) , furyl (e.g., 2-furyl, 3- furyl) , pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl) , thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , pyrazinyl, pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl) , pyrrolyl

0244(e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) , pyrazolyl (e.g., 1- pyrazolyl, 3-pyrazolyl, 4-pyrazolyl) , triazolyl (e.g., 1- triazolyl, 2-triazolyl) , tetrazolyl, pyridazinyl (e.g., 3- pyridazinyl, 4-pyridazinyl) , isothiazolyl (e.g., 3- isothiazolyl, 4-isothiazolyl, 5-isothiazolyl) , isoxazolyl

0245(e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) , indolyl

0246(e.g., 1-indolyl, 2-indolyl, 3-indolyl) , 2-benzothiazolyl, 2- benzoxazolyl, benzimidazolyl (e.g., 1-benzimidazolyl, 2- benzimidazolyl) , benzo [b] thienyl (e.g., 2-benzo [b] thienyl, 3- benzo[b] thienyl) , benzo [b] furyl (e.g., 2-benzo [b] furanyl, 3- benzo[b] furanyl) , quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4- quinolyl, 5-quinolyl, 8-quinolyl) , isoquinolyl (e.g., 1- isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl) , and the like; non-aromatic heterocyclic groups such as pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl) , oxazolidinyl

0247(e.g., 2-oxazolidinyl) , imidazolinyl (e.g., 1-imidazolinyl, 2- imidazolinyl, 4-imidazolinyl) , piperidinyl (e.g., piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl) , piperazinyl

0248(e.g., 1-piperazinyl, 2-piperazinyl) , morpholinyl (e.g., 2- morpholinyl, 3-morpholinyl, morpholino) , thiomorpholinyl (e.g., 2-thiomorpholinyl, 3-thiomorpholinyl, thiomorpholino) , tetrahydropyranyl and the like, and the like can be mentioned.

0249[0090]

0250Unless otherwise specified, as the "Ci_₆ alkyl-carbonyl" in the present specification, for example, acetyl, isobutanoyl, isopentanoyl and the like can be mentioned.

0251[0091]

0252Unless otherwise specified, as the "Ci_₆ alkoxy-carbonyl" in the present specification, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl and the like can be mentioned. [0092]

0253Unless otherwise specified, as the "C₃-₈ cycloalkyl- carbonyl" in the present specification, for example, cyclopentylcarbonyl, cyclohexylcarbonyl and the like can be mentioned. [0093]

0254Unless otherwise specified, as the "Cβ-₁₄ aryl-carbonyl" in the present specification, for example, benzoyl, 1- naphthoyl, 2-naphthoyl and the like can be mentioned. [0094]

0255Unless otherwise specified, as the "C₇_i6 aralkyl- carbonyl" in the present specification, for example, phenylacetyl, 2-phenylpropanoyl and the like can be mentioned. [0095]

0256Unless otherwise specified, as the "Cε-14 aryloxy- carbonyl" in the present specification, for example, phenoxycarbonyl, naphthyloxycarbonyl and the like can be mentioned. [0096]

0257Unless otherwise specified, as the "C₇_i6 aralkyloxy- carbonyl" in the present specification, for example, benzyloxycarbonyl, phenethyloxycarbonyl and the like can be mentioned. [0097]

0258Unless otherwise specified, as the "nitrogen-containing heterocyclyl-carbonyl" in the present specification, for example, pyrrolidinylcarbonyl, piperidinocarbonyl and the like can be mentioned. [0098] Unless otherwise specified, as the "Ci_₆ alkylsulfonyl" in the present specification, for example, methylsulfonyl, ethylsulfonyl and the like can be mentioned.

0259[0099]

0260Unless otherwise specified, as the "Cβ-ia arylsulfonyl" in the present specification, for example, phenylsulfonyl, 1- naphthylsulfonyl, 2-naphthylsulfonyl and the like can be mentioned.

0261[0100]

0262Unless otherwise specified, as the "Ci_₆ alkylsulfinyl" in the present specification, for example, methylsulfinyl, ethylsulfinyl and the like can be mentioned.

0263[0101]

0264Unless otherwise specified, as the "C_δ-₁₄ arylsulfinyl" in the present specification, for example, phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl and the like can be mentioned.

0265[0102]

0266Unless otherwise specified, as the "optionally esterified carboxyl" in the present specification, for example, carboxyl, Ci-₆ alkoxy-carbonyl, Cβ-u aryloxy-carbonyl, C7-16 aralkyloxy- carbonyl and the like can be mentioned.

0267[0103]

0268Unless otherwise specified, as the "optionally halogenated Ci-₆ alkyl" in the present specification, the above- mentioned "Ci-₆ alkyl" optionally substituted by 1 to 5 above- mentioned "halogen atoms" can be mentioned. For example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, trifluoromethyl and the like can be mentioned.

0269[0104]

0270Unless otherwise specified, as the "optionally halogenated Ci-β alkoxy" in the present specification, the above-mentioned "Ci_₆ alkoxy" optionally substituted by 1 to 5 above-mentioned "halogen atoms" can be mentioned. For example, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethoxy and the like can be mentioned.

0271[0105]

0272Unless otherwise specified, as the "mono- or di-Cχ-₆ alkyl-amino" in the present specification, amino mono- or di- substituted by the above-mentioned "Ci-₆ alkyl" can be mentioned. For example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino and the like can be mentioned. [0106]

0273Unless otherwise specified, as the "mono- or di-Cε-u aryl-amino" in the present specification, amino mono- or di- substituted by the above-mentioned "C₆-14 aryl" can be mentioned. For example, phenylamino, diphenylamino, 1-naphthylamino, 2- naphthylamino and the like can be mentioned. [0107]

0274Unless otherwise specified, as the "mono- or di-C₇-i₆ aralkyl-amino" in the present specification, amino mono- or di-substituted by the above-mentioned "C₇-i₆ aralkyl" can be mentioned. For example, benzylamino, phenethylamino and the like can be mentioned. [0108]

0275Unless otherwise specified, as the "N-Ci-6 alkyl-N-Cε-14 aryl-amino" in the present specification, amino substituted by the above-mentioned "Ci-₆ alkyl" and the above-mentioned "Cε-i4 aryl" can be mentioned. For example, N-methyl-N-phenylamino, N-ethyl-N-phenylamino and the like can be mentioned. [0109]

0276Unless otherwise specified, as the "N-Ci-₆ alkyl-N-C₇_i₆ aralkyl-amino" in the present specification, amino substituted by the above-mentioned "Ci-₆ alkyl" and the above-mentioned "C₇- ₁₆ aralkyl" can be mentioned. For example, N-methyl-N- benzylamino, N-ethyl-N-benzylamino and the like can be mentioned. [0110]

0277Unless otherwise specified, as the "mono- or di-Ci-6 alkyl-carbamoyl" in the present specification, carbamoyl mono- or di-substituted by the above-mentioned "Ci_₆ alkyl group" can be mentioned. For example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl and the like can be mentioned. [0111]

0278Unless otherwise specified, as the "mono- or di-C6-i4 aryl-carbamoyl" in the present specification, carbamoyl mono- or di-substituted by the above-mentioned "Cβ-i₄ aryl" can be mentioned. For example, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl and the like can be mentioned. [0112]

0279Unless otherwise specified, as the "mono- or di-G3-s cycloalkyl-carbamoyl" in the present specification, carbamoyl mono- or di-substituted by the above-mentioned "C₃-₈ cycloalkyl" can be mentioned. For example, cyclopropylcarbamoyl and the like can be mentioned. [0113]

0280Unless otherwise specified, as the "mono- or di-C₇_i₆ aralkyl-carbamoyl", carbamoyl mono- or di-substituted by the above-mentioned "C₇-_I6 aralkyl" can be mentioned. For example, benzylcarbamoyl and the like can be mentioned. [0114]

0281Unless otherwise specified, as the "mono- or di-5- to 7- membered heterocyclyl-carbamoyl" in the present specification, carbamoyl mono- or di-substituted by 5- to 7-membered heterocyclic group can be mentioned. As the 5- to 7-membered heterocyclic group, a heterocyclic group containing, as a ring-constituting atom besides carbon atoms, one or two kinds of 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom can be mentioned. As preferable examples of the "mono- or di-5 to 7-membered heterocyclyl- carbamoyl", 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4- pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl and the like can be mentioned. [0115] Unless otherwise specified, as the "mono- or di-Ci-₆ alkyl-sulfamoyl" in the present specification, sulfamoyl mono- or di-substituted by the above-mentioned "Ci_₆ alkyl" can be used, for example, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like can be mentioned. [0116]

0282Unless otherwise specified, as the "mono- or di-C₆-i₄ aryl-sulfamoyl" in the present specification, sulfamoyl mono- or di-substituted by the above-mentioned "C₆-₁₄ aryl" can be used, for example, phenylsulfamoyl, diphenylsulfamoyl, 1- naphthylsulfamoyl, 2-naphthylsulfamoyl and the like can be mentioned. [0117]

0283Unless otherwise specified, as the "mono- or di-C₇_i₆ aralkyl-sulfamoyl" in the present specification, sulfamoyl mono- or di-substituted by the above-mentioned "C₇_i₆ aralkyl" can be mentioned, for example, benzylsulfamoyl and the like can be mentioned. [0118]

0284Examples of the "optionally substituted Ci_₆ alkyl", "optionally substituted C₂-₆ alkenyl", "optionally substituted C2-6 alkynyl", "optionally substituted Ci_6 alkoxy" and "optionally substituted Ci-₆ alkylthio" in the present specification include "Ci_₆ alkyl", "C₂-₆ alkenyl", "C₂-₆ alkynyl", "C₁-₆ alkoxy" and "Ci_₆ alkylthio", each of which optionally has, at substitutable position (s), 1 to 5 substituents selected from

0285(1) a halogen atom;

0286(2) hydroxy;

0287(3) amino;

0288(4) nitro;

0289(5) cyano;

0290(6) a heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl) optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci-₆ alkyl, mono- or di-Ci-6 alkyl-amino, Cβ-14 aryl, mono- or di-Cε-14 aryl-amino, C3-8 cycloalkyl, Ci-₆ alkoxy, Cχ-₆ alkoxy-Ci-₆ alkoxy, Cχ-₆ alkylthio, Ci-₆ alkylsulfinyl, Cχ-β alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Ci-₆ alkyl- carbamoyl, mono- or di-C₆-i4 aryl-carbamoyl, sulfamoyl, mono- or di-Ci-₆ alkyl-sulfamoyl and mono- or di-C₆-i₄ aryl-sulfamoyl;

0291(7) mono- or di-Ci_₆ alkyl-amino;

0292(8) mono- or di-C₆-i₄ aryl-amino;

0293(9) mono- or di-C₇_i₆ aralkyl-amino;

0294(10) N-Ci_6 alkyl-N-Cδ-14 aryl-amino;

0295(11) N-Ci-6 alkyl-N-C₇-i6 aralkyl-amino;

0296(12) C₃_₈ cycloalkyl;

0297(13) optionally halogenated Ci_₆ alkoxy;

0298(14) Ci-₆ alkylthio;

0299(15) Ci-₆ alkylsulfinyl;

0300(16) Ci-₆ alkylsulfonyl;

0301(17) optionally esterified carboxyl;

0302(18) Ci-₆ alkyl-carbonyl;

0303(19) C₃-₈ cycloalkyl-carbonyl;

0304(20) Cε-14 aryl-carbonyl;

0305(21) carbamoyl;

0306(22) thiocarbamoyl;

0307(23) mono- or di-Ci-₆ alkyl-carbamoyl;

0308(24) mono- or di-C_δ-₁4 aryl-carbamoyl;

0309(25) mono- or di-5- to 7-membered heterocyclyl-carbamoyl;

0310(26) Ci-₆ alkyl-carbonylamino (e.g., acetylamino, propionylamino) optionally substituted by carboxyl;

0311(27) Cβ-₁₄ aryloxy optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci_₆ alkyl, mono- or di-Ci_₆ alkyl-amino, Cβ-14 aryl, mono- or di-Cε-14 aryl-amino, C3-8 cycloalkyl, Ci_6 alkoxy, Ci-₆ alkoxy-Ci-6 alkoxy, Ci-6 alkylthio, Ci-6 alkylsulfinyl, Ci-₆ alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Ci-6 alkyl-carbamoyl, mono- or di-C₆-

0312₁₄ aryl-carbamoyl, sulfamoyl, mono- or di-Ci-₆ alkyl-sulfamoyl and mono- or di-C₆-i₄ aryl-sulfamoyl;

0313(28) Cβ-₁₄ aryl optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci_₆ alkyl, mono- or di-Ci_₆ alkyl-amino, C₆-_I4 aryl, mono- or di-C₆-i₄ aryl-amino, C₃_₈ cycloalkyl, Ci_₆ alkoxy, Ci_₆ alkoxy-Ci-6 alkoxy, Ci-6 alkylthio, Ci_₆ alkylsulfinyl, Ci-₆ alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Ci-₆ alkyl-carbamoyl, mono- or di-C₆- ₁₄ aryl-carbamoyl, sulfamoyl, mono- or di-Ci_₆ alkyl-sulfamoyl and mono- or di-C₆-i₄ aryl-sulfamoyl;

0314(29) heterocyclyl-oxy;

0315(30) sulfamoyl;

0316(31) mono- or di-Ci-₆ alkyl-sulfamoyl;

0317(32) mono- or di-C₆-i₄ aryl-sulfamoyl;

0318(33) C₇-₁₆ aralkyloxy optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci-6 alkyl, mono- or di-Ci-6 alkyl-amino, C₆-i₄ aryl, mono- or di-C₆-i4 aryl-amino, C₃_₈ cycloalkyl, Ci_₆ alkoxy, Ci_₆ alkoxy-Ci_₆ alkoxy, Ci_₆ alkylthio, Ci-₆ alkylsulfinyl, Ci-₆ alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_₆ alkyl- carbamoyl, mono- or di-C₆-i₄ aryl-carbamoyl, sulfamoyl, mono- or di-Ci_₆ alkyl-sulfamoyl and mono- or di-C₆-i₄ aryl-sulfamoyl; and the like. When the number of the substituents is plural, the respective substituents may be the same or different. [0119]

0319Examples of the "optionally substituted C₃-₈ cycloalkyl", "optionally substituted C₆-i₄ aryl", "optionally substituted C₇- ₁₆ aralkyl", "optionally substituted heterocyclic group", "optionally substituted heterocyclyl-oxy", "optionally substituted C₆-i₄ aryloxy", "optionally substituted C7-₁₆ aralkyloxy", "optionally substituted heterocyclyl-thio", "optionally substituted C₆-_U arylthio" and "optionally substituted C₇-_I6 aralkylthio" in the present specification include, "C₃-₈ cycloalkyl", "C₆-_I4 aryl", "C₇_₁₆ aralkyl", "heterocyclic group", "heterocyclyl-oxy", "C₆-_I4 aryloxy", "C₇-_I6 aralkyloxy", "heterocyclyl-thio", "C₆-_I4 arylthio" and "C₇-_I6 aralkylthio", which optionally have, at substitutable position (s), 1 to 5 substituents selected from

0320(1) a halogen atom;

0321(2) hydroxy;

0322(3) amino;

0323(4) nitro;

0324(5) cyano;

0325(6) optionally substituted Ci_₆ alkyl;

0326(7) optionally substituted C₂-6 alkenyl;

0327(8) optionally substituted C₂-6 alkynyl;

0328(9) C₆-i₄ aryl optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci-₆ alkyl, mono- or di-Ci-₆ alkyl-amino, C₆-i₄ aryl, mono- or di-C₆_i₄ aryl-amino, C₃_s cycloalkyl, Ci_₆ alkoxy, Ci_6 alkoxy-Ci_₆ alkoxy, Ci_₆ alkylthio, Ci_₆ alkylsulfinyl, Ci-e alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_₆ alkyl-carbamoyl, mono- or di-C₆_ ₁₄ aryl-carbamoyl, sulfamoyl, mono- or di-Ci_₆ alkyl-sulfamoyl and mono- or di-C₆-i₄ aryl-sulfamoyl;

0329(10) C₆-_I4 aryloxy optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci_₆ alkyl, mono- or di-Ci_₆ alkyl-amino, C₆-_I4 aryl, mono- or di-C₆_i₄ aryl-amino, C₃-₈ cycloalkyl, Ci_₆ alkoxy, Ci_₆ alkoxy-Ci_₆ alkoxy, Ci_₆ alkylthio, Ci_₆ alkylsulfinyl, Ci-₆ alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_₆ alkyl-carbamoyl, mono- or di-C₆_ i₄ aryl-carbamoyl, sulfamoyl, mono- or di-Ci_₆ alkyl-sulfamoyl and mono- or di-C₆_i₄ aryl-sulfamoyl;

0330(11) C₇-_I6 aralkyloxy optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci_₆ alkyl, mono- or di-Ci_₆alkyl-amino, C₆-i₄ aryl, mono- or di-C₆-i4 aryl-amino, C₃-₈ cycloalkyl, Ci-₆ alkoxy, Ci_₆ alkoxy-Ci_6 alkoxy, Cχ-₆ alkylthio, Ci_6 alkylsulfinyl, Cχ-₆ alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Ci_₆ alkyl- carbamoyl, mono- or di-Cβ-u aryl-carbamoyl, sulfamoyl, mono- or di-Ci-₆ alkyl-sulfamoyl and mono- or di-C6-i₄ aryl-sulfamoyl;

0331(12) a heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl) optionally substituted by 1 to 3 substituents selected from a halogen atom, hydroxy, amino, nitro, cyano, optionally halogenated Ci_6 alkyl, mono- or di-Ci-6 alkyl-amino, Cε-i₄ aryl, mono- or di-Cε-₁₄ aryl-amino, C3-8 cycloalkyl, Ci-₆ alkoxy, Cχ-₆ alkoxy-Ci-6 alkoxy, Ci-₆ alkylthio, Ci-₆ alkylsulfinyl, Ci-₆ alkylsulfonyl, optionally esterified carboxyl, carbamoyl, thiocarbamoyl, mono- or di-Cχ-₆ alkyl- carbamoyl, mono- or di-Cβ-₁₄ aryl-carbamoyl, sulfamoyl, mono- or di-Ci-₆ alkyl-sulfamoyl and mono- or di-C₆-i₄ aryl-sulfamoyl;

0332(13) mono- or di-Ci-₆ alkyl-amino;

0333(14) mono- or di-Cε-i₄ aryl-amino;

0334(15) mono- or di-C₇-i₆ aralkyl-amino;

0335(16) N-Ci_6 alkyl-N-Cδ-14 aryl-amino;

0336(17) N-Ci-6 alkyl-N-C₇_i6 aralkyl-amino;

0337(18) C₃-_S cycloalkyl;

0338(19) optionally substituted Ci-₆ alkoxy;

0339(20) optionally substituted Ci-₆ alkylthio;

0340(21) Ci-₆ alkylsulfinyl;

0341(22) Ci-₆ alkylsulfonyl;

0342(23) optionally esterified carboxyl;

0343(24) Ci-₆ alkyl-carbonyl;

0344(25) C₃-₈ cycloalkyl-carbonyl;

0345(26) C₆-i₄ aryl-carbonyl;

0346(27) carbamoyl;

0347(28) thiocarbamoyl;

0348(29) mono- or di-Ci-₆ alkyl-carbamoyl;

0349(30) mono- or di-Cε-₁₄ aryl-carbamoyl;

0350(31) mono- or di-5- to 7-membered heterocyclyl-carbamoyl; (32) sulfamoyl;

0351(33) mono- or di-Cχ-₆ alkyl-sulfamoyl;

0352(34) mono- or di-C6-i4 aryl-sulfamoyl;

0353(35) Ci-₆ alkyl-carbonylamino (e.g.: acetylamino, propionylamino) optionally substituted by carboxyl;

0354(36) heterocyclyl-oxy; and the like. When the number of the substituents is plural, the respective substituents may be the same or different. [0120]

0355Unless otherwise specified, as the "optionally substituted amino" in the present specification, an amino optionally substituted by 1 or 2 substituents selected from

0356(1) optionally substituted Ci-6 alkyl;

0357(2) optionally substituted C2-6 alkenyl;

0358(3) optionally substituted C2-6 alkynyl;

0359(4) optionally substituted C₃-₈ cycloalkyl;

0360(5) optionally substituted Cε-i4 aryl;

0361(6) optionally substituted Ci-6 alkoxy;

0362(7) optionally substituted acyl;

0363(8) an optionally substituted heterocyclic group (preferably furyl, pyridyl, thienyl, pyrazolyl, thiazolyl, oxazolyl) ;

0364(9) sulfamoyl;

0365(10) mono- or di-Cχ-₆ alkyl-sulfamoyl;

0366(11) mono- or di-C₆-i4 aryl-sulfamoyl; and the like, can be mentioned. When the "optionally substituted amino" is amino substituted by two substituents, these substituents may be the same or different, and may form a nitrogen-containing heterocycle together with the adjacent nitrogen atom. As the "nitrogen-containing heterocycle", for example, a 5- to 7-membered nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom and optionally further containing 1 or 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom can be mentioned. As preferable examples of the nitrogen-containing heterocycle, pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like can be mentioned.

0367[0121]

0368Unless otherwise specified, as the "optionally substituted acyl" in the present specification, groups represented by the formulas: -COR⁷, -CO-OR⁷, -SO₂R⁷, -SOR⁷, - PO(OR⁷) (OR⁸), -CO-NR^7aR^8a and -CS-NR^7aR^8a, wherein R⁷ and R⁸ are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R^7a and R^8a are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R^7a and R^8a may form an optionally substituted nitrogen-containing heterocycle together with the adjacent nitrogen atom, and the like can be mentioned. [0122]

0369As the "nitrogen-containing heterocycle" of the "optionally substituted nitrogen-containing heterocycle" formed by R^7a and R^8a together with the adjacent nitrogen atom, for example, a 5- to 7-membered nitrogen-containing heterocycle containing, as a ring-constituting atom besides carbon atom, at least one nitrogen atom and optionally further containing 1 to 2 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom can be mentioned. As preferable examples of the "nitrogen-containing heterocycle", pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolidine, oxazolidine and the like can be mentioned. [0123]

0370The nitrogen-containing heterocycle optionally has 1 to 2 substituents at substitutable position (s). As these substituents, hydroxy, optionally halogenated Ci-β alkyl, Cβ-u aryl, C₇-_I6 aralkyl and the like can be mentioned. When the number of the substituents is two, these substituents may be the same or different.

0371[0124]

0372Preferable examples of the "optionally substituted acyl" include formyl; carboxyl; carbamoyl; Ci-₆ alkyl-carbonyl; Ci-₆ alkoxy-carbonyl; C₃-₈ cycloalkyl-carbonyl; Cβ-₁₄ aryl-carbonyl; C₇-i₆ aralkyl-carbonyl; C₆-i₄ aryloxy-carbonyl; C₇-_I6 aralkyloxy-carbonyl; mono- or di-Ci-6 alkyl-carbamoyl; mono- or di-Cδ-i4 aryl-carbamoyl; mono- or di-C3-₈ cycloalkyl-carbamoyl; mono- or di-C₇-i6 aralkyl-carbamoyl; Ci-₆ alkylsulfonyl;

0373C₆-i₄ arylsulfonyl optionally substituted by nitro; nitrogen-containing heterocyclyl-carbonyl; Ci-₆ alkylsulfinyl; C₆-i4 arylsulfinyl; thiocarbamoyl; sulfamoyl; mono- or di-Ci-6 alkyl-sulfamoyl; mono- or di-Cε-i4 aryl-sulfamoyl; mono- or di-C₇_i6 aralkyl-sulfamoyl; and the like. [0125]

0374The definition of each symbol in the formula (I) and (II) is explained in detail in the following.

0375R¹ shows a halogen atom, hydroxy, optionally substituted Ci-₆ alkyl or optionally substituted Ci-6 alkoxy.

0376The "optionally substituted Ci-6 alkyl" or "optionally substituted Ci-₆ alkoxy" for R¹ is optionally substituted by 1 to 3 substituents selected from those exemplified as the substituents of the aforementioned "optionally substituted Ci_₆ alkyl", "optionally substituted C2-₆ alkenyl", "optionally substituted C₂-₆ alkynyl", "optionally substituted Ci_₆ alkoxy" and "optionally substituted Ci-₆ alkylthio". When the number of the substituents is plural, the respective substituents may be the same or different.

0377In addition, when R¹ is optionally substituted Ci_₆ alkyl or optionally substituted Ci-6 alkoxy, R¹ may form an optionally substituted ring together with X. Examples of R¹ and X forming a ring include [0126]

0378<img file="WO2010143733A1_D0028.tif" />

0379[0127]

0380R¹ is preferably Ci_₆ alkyl or Ci-₆ alkoxy which may form an optionally substituted ring together with X, more preferably, methyl which may form an optionally substituted ring together with X, ethyl which may form an optionally substituted ring together with X or methoxy which may form an optionally substituted ring together with X. R¹ particularly preferably forms [0128]

0381<img file="WO2010143733A1_D0029.tif" />

0382[0129] together with X. In other words, in a preferable embodiment, compound (I) is a compound represented by the formula (II) : [ 0130 ]

0383<img file="WO2010143733A1_D0030.tif" />

0384[0131] (compound (II) ) .

0385R² is optionally substituted hydroxy.

0386The "optionally substituted hydroxy" for R² is hydroxy optionally substituted by substituent (s) selected from Ci_₆ alkyl, heterocyclyl-oxy, Cβ-n aryloxy and C₇_i₆ aralkyloxy.

0387R² is preferably hydroxy.

0388R³ is a hydrogen atom, a halogen atom or optionally substituted Ci_6 alkyl.

0389The "optionally substituted Ci-₆ alkyl" for R³ is optionally substituted by 1 to 3 substituents selected from those recited above as the substituents of "optionally substituted Ci_β alkyl", "optionally substituted C₂-₆ alkenyl", "optionally substituted C₂-₆ alkynyl", "optionally substituted Ci-₆ alkoxy" and "optionally substituted Ci_₆ alkylthio". As such substituent, preferred is a halogen atom. When the number of the substituents is plural, the respective substituents may be the same or different.

0390R³ is preferably a hydrogen atom or Ci-₆ alkyl.

0391X is CH₂. Here, X may form an optionally substituted ring together with R¹, and examples of such ring include those mentioned above.

0392X preferably forms [0132] <img file="WO2010143733A1_D0031.tif" />

0393[0133] together with R¹.

0394Y is CH₂, NH or 0.

0395Y is preferably 0. Z is CH or N.

0396Z is preferably CH. n is an integer selected from 1 to 3. n is preferably 1.

0397A is a halogen atom, optionally substituted amino, or a 4- to 13-membered cyclic group optionally substituted by 1 to 5 (preferably 1 to 3) substituents selected from

0398(1) a halogen atom,

0399(2) optionally substituted amino,

0400(3) optionally substituted Ci_₆ alkylthio,

0401(4) optionally substituted Ci_₆ alkyl,

0402(5) optionally substituted C₃-.₁₀ cycloalkyl,

0403(6) optionally substituted Ci-₆ alkoxy,

0404(7) optionally substituted C₆-₁₄ aryl,

0405(8) an optionally substituted 4- to 7-membered heterocyclic group, and

0406(9) optionally substituted 4- to 7-membered heterocyclyl-oxy. When the number of the substituents is plural, the respective substituents may be the same or different.

0407Examples of the ^λΛ4- to 13-membered cyclic group" for A include a 4- to 13-membered cyclic hydrocarbon group and a 4- to 13-membered heterocyclic group.

0408Examples of the "cyclic hydrocarbon group" include an alicyclic hydrocarbon group comprised of 4 to 13 carbon atoms, an aromatic hydrocarbon group comprised of 6 to 14 carbon atoms and the like.

0409Examples of the "alicyclic hydrocarbon group" include C₃-₆cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) , C₃-₆ cycloalkenyl (e.g., cyclopentenyl, cyclohexenyl) , C₅-.₁₄ cycloalkadienyl (e.g., 2, 4-cyclopentadienyl, 1, 3-cyclohexadienyl) , indanyl, adamantyl and the like.

0410Examples of the "aromatic hydrocarbon group" include Cβ-u aryl (e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl) and the like. Preferred is phenyl.

0411Examples of the "heterocyclic group" include those mentioned above. Preferred are pyridyl, pyrimidinyl, piperidinyl, pyrazolyl, thienyl, morpholinyl, dihydropyranyl, 1, 4-dioxaspiro [4.5] dec-7-enyl, 1, 4-dioxa-8- azaspiro [4.5] decanyl, benzimidazolyl, 3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazinyl, imidazo [2, 3-a] pyridyl, imidazo [1, 2-a] pyridyl, furo [2, 3-b] pyridyl, furo [3, 2-b] pyridyl, indolyl and 3, 4-dihydro-2H-l, 4-benzooxazinyl. [0134]

0412The "optionally substituted amino" for A and the "optionally substituted amino" shown as the substituent of the "4- to 13-membered cyclic group" for A are each optionally substituted by 1 or 2 substituents selected from those exemplified as the substituent of the aforementioned "optionally substituted C1-₆ alkyl", "optionally substituted C2-₆ alkenyl", "optionally substituted C₂-₆ alkynyl", "optionally substituted Ci_₆ alkoxy" and "optionally substituted Ci-₆ alkylthio". When the number of the substituents is plural, the respective substituents may be the same or different.

0413The "optionally substituted Ci-₆ alkylthio", "optionally substituted Ci-₆ alkyl" and "optionally substituted Ci-₆ alkoxy" shown as the substituents of the "4- to 13-membered cyclic group" for A is optionally substituted by 1 to 3 substituents selected from those exemplified as the substituents of the aforementioned "optionally substituted Ci_₆ alkyl", "optionally substituted C₂-₆ alkenyl", "optionally substituted C₂-₆ alkynyl", "optionally substituted Ci-₆ alkoxy" and "optionally substituted Ci-₆ alkylthio". When the number of the substituents is plural, the respective substituents may be the same or different.

0414The "optionally substituted C₃-_I0 cycloalkyl", "optionally- substituted C₆-i₄ aryl", "optionally substituted 4- to 7- membered heterocyclic group" and "optionally substituted 4- to 7-membered heterocyclyl-oxy" shown as the substituents of the "4- to 13-membered cyclic group" for A is optionally substituted by 1 to 3 substituents selected from those exemplified as the substituents of the aforementioned "optionally substituted C₃-₈ cycloalkyl", "optionally substituted Cε-i₄ aryl", "optionally substituted C₇_i6 aralkyl", "optionally substituted heterocyclic group", "optionally substituted heterocyclyl-oxy", "optionally substituted Cε-₁₄ aryloxy", "optionally substituted C₇-i₆ aralkyloxy", "optionally substituted heterocyclyl-thio", "optionally substituted C₆-I₄ arylthio" and "optionally substituted C₇-_I6 aralkylthio". When the number of the substituents is plural, the respective substituents may be the same or different. [0135]

0415A is preferably a 4- to 13-membered cyclic group optionally substituted by 1 to 5 (preferably, 1 to 3) substituents selected from

0416(1) a halogen atom,

0417(2) optionally substituted Ci_₆ alkyl (preferably, optionally substituted by a halogen atom or hydroxy) ,

0418(3) optionally substituted Ci-₆ alkoxy (preferably, optionally substituted by a halogen atom, Ci-₆ alkylsulfonyl, C₆-i4 aryl or a heterocyclic group) ,

0419(4) an optionally substituted 4- to 7-membered heterocyclic group, and

0420(5) optionally substituted 4- to 7-membered heterocyclyl-oxy.

0421A is more preferably phenyl or a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, thienyl, pyrimidinyl) , each of which is optionally substituted by 1 to 5 (preferably, 1 to 3) substituents selected from (a) a halogen atom, (b) Ci-₆ alkyl (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

0422(c) Ci-₆ alkoxy (e.g., methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from

0423(1) a halogen atom,

0424(2) Ci-₆ alkylsulfonyl (e.g., methylsulfonyl) ,

0425(3) C₃-₈ cycloalkyl (e.g., cyclopropyl, cyclopentyl) ,

0426(4) mono- or di-Ci-₆ alkyl-amino (e.g., dimethylamino) ,

0427(5) Ci-₆ alkoxy (e.g., methoxy),

0428(6) Cε-₁₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a fluorine atom),

0429(7) a heterocyclic group (e.g., furyl, isoxazolyl, pyridyl, pyrrolidinyl, morpholinyl, piperazinyl, azepanyl) optionally substituted by 1 to 3 substituents selected from

0430(i) Ci-₆ alkyl (e.g., methyl), and (ii) oxo, and

0431(8) Ci_₆ alkylthio (e.g., methylthio) ,

0432(d) a 4- to 7-membered heterocyclic group (e.g., morpholino, pyrrolidinyl) , and

0433(e) 4- to 7-membered heterocyclyl-oxy (e.g., dioxidotetrahydrothiopyranyloxy) .

0434[0136]

0435In another preferable embodiment, A is preferably

0436(a) a halogen atom (e.g., bromine atom),

0437(b) amino optionally substituted by 1 or 2 substituents selected from

0438(i) Ci-₆ alkyl (e.g., ethyl, n-propyl) ,

0439(ii) C₆-_I4 aryl (e.g., phenyl) optionally substituted by substituent (s) selected from a halogen atom (e.g., a fluorine atom), cyano and Ci-₆ alkylsulfonyl (e.g., mesyl) , and

0440(iii) a heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted by substituent (s) selected from a halogen atom (e.g., a fluorine atom, a chlorine atom) and Ci_₆ alkyl (e.g., methyl), or

0441(c) a 4- to 13-membered cyclic group (e.g., phenyl, pyrazolyl, thienyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, dihydropyranyl, indolyl, benzimidazolyl, furo [2, 3-b] pyridinyl, furo[3,2-b]pyridinyl, imidazo [1, 2-a] pyridinyl, 3, 4-dihydro-2H- 1, 4-benzoxazinyl, 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazinyl, 1, 4-dioxaspiro [4.5] dec-7-enyl, 1, 4-dioxa-8- azaspiro [4.5] decanyl) optionally substituted by 1 to 5 (preferably, 1 to 3) substituents selected from

0442(1) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,

0443(2) optionally substituted amino,

0444(3) Ci-₆ alkylthio (e.g., methylthio) optionally substituted by Cβ-i₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a chlorine atom),

0445(4) Ci-₆ alkyl (e.g., methyl, ethyl, isopropyl) optionally substituted by substituent (s) selected from

0446(i) a halogen atom (e.g., a fluorine atom), (ii) optionally substituted hydroxy (e.g., hydroxy, methoxy) , and

0447(iii) Ci-₆ alkylsulfonyl (e.g., mesyl) ,

0448(5) optionally substituted C₃-_I0 cycloalkyl (e.g., cyclopropyl) ,

0449(6) Ci-₆ alkoxy (e.g., methoxy, ethoxy, n-propoxy) optionally substituted by substituent (s) selected from

0450(i) a halogen atom (e.g., a fluorine atom),

0451(ii) C₃-_B cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl) optionally substituted by Ci-₆ alkyl (e.g., methyl),

0452(iii) Ci-₆ alkoxy (e.g., methoxy, ethoxy) optionally substituted by di-Ci-β alkylamino (e.g., dimethylamino) ,

0453(iv) di-Ci-₆ alkylamino (e.g., dimethylamino),

0454(v) Ci-₆ alkylsulfinyl (e.g., methylsulfinyl) ,

0455(vi) mesyl,

0456(vii) C₆-i₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a fluorine atom), and

0457(viii) a heterocyclic group (e.g., furyl, isoxazolyl, pyridyl, pyrrolidinyl, morpholinyl, piperazinyl, azepanyl) optionally substituted by substituent (s) selected from Ci_₆ alkyl (e.g., methyl) and oxo,

0458(7) optionally substituted Cε-n aryl,

0459(8) a 4- to 7-membered heterocyclic group (e.g., tetrahydrofuranyl, morpholino, pyrrolidinyl, tetrahydropyranyl, furanyl, isoxazolyl) optionally substituted by Ci-₆ alkyl (e.g., methyl) , and

0460(9) optionally substituted 4- to 7-membered heterocyclyl-oxy (e.g., dioxidotetrahydrothiopyranyloxy) . [0137]

0461A is more preferably phenyl, benzimidazolyl or a 5- or 6- membered aromatic heterocyclic group (e.g., thienyl, pyrimidinyl) each optionally substituted by 1 to 5 (preferably, 1 to 3) substituents selected from

0462(a) a halogen atom,

0463(b) Ci-₆ alkyl (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

0464(c) Ci-₆ alkoxy (e.g., methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from

0465(1) a halogen atom,

0466(2) Ci-₆ alkylsulfonyl (e.g., methylsulfonyl) ,

0467(3) C₃-₈ cycloalkyl (e.g., cyclopropyl, cyclopentyl) ,

0468(4) mono- or di-Ci-β alkyl-amino (e.g., dimethylamino) ,

0469(5) Ci-₆ alkoxy (e.g., methoxy),

0470(6) Cβ-₁₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a fluorine atom),

0471(7) a 4- to 7-membered heterocyclic group (e.g., furyl, isoxazolyl, pyridyl, pyrrolidinyl, morpholinyl, piperazinyl, azepanyl) optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl (e.g., methyl) and oxo, and

0472(8) Ci-₆ alkylthio (e.g., methylthio) ,

0473(d) a 4- to 7-membered heterocyclic group (e.g., morpholino, pyrrolidinyl) , and

0474(e) 4- to 7-membered heterocyclyl-oxy (e.g., dioxidotetrahydrothiopyranyloxy) optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo.

0475[0138]

0476A is more preferably phenyl optionally substituted by 1 to 3 substituents selected from

0477(a) Ci-₆ alkyl (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

0478(b) Ci-₆ alkoxy (e.g., methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from

0479(1) a halogen atom,

0480(2) Ci-₆ alkylsulfonyl (e.g., methylsulfonyl) ,

0481(3) C₃-₈ cycloalkyl (e.g., cyclopropyl, cyclopentyl) ,

0482(4) mono- or di-Ci-₆ alkyl-amino (e.g., dimethylamino) ,

0483(5) Ci-₆ alkoxy (e.g., methoxy),

0484(6) Cβ-₁₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a fluorine atom),

0485(7) a 4- to 7-membered heterocyclic group (e.g., furyl, isoxazolyl, pyridyl, pyrrolidinyl, morpholinyl, piperazinyl, azepanyl) optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl (e.g., methyl) and oxo, and

0486(8) Ci-₆ alkylthio (e.g., methylthio) , and

0487(c) 4- to 7-membered heterocyclyl-oxy (e.g., dioxidotetrahydrothiopyranyloxy) optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo.

0488[0139]

0489Alternatively, A is more preferably benzimidazolyl or a 5- or 6-membered aromatic heterocyclic group (e.g., thienyl, pyrimidinyl) each optionally substituted by 1 to 3 substituents selected from

0490(a) a halogen atom,

0491(b) Ci-₆ alkyl (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom), and

0492(c) a 5- or 6-membered heterocyclic group (e.g., morpholino, pyrrolidinyl) .

0493[0140]

0494Preferable examples of compound (I) include the following compounds .

0495[Compound A-I]

0496Compound (I) wherein

0497R¹ is Ci-₆ alkyl,

0498R² is hydroxy,

0499R³ is a hydrogen atom or Ci_₆ alkyl,

0500X is CH₂,

0501Y is 0, Z is CH, n is 1, and

0502A is a 4- to 13-membered cyclic group optionally substituted by 1 to 3 substituents selected from

0503(1) a halogen atom,

0504(2) optionally substituted Ci-₆ alkyl (optionally substituted by a halogen atom or hydroxy) ,

0505(3) optionally substituted Ci_₆ alkoxy (optionally substituted by a halogen atom, mesyl, aryl or a heterocyclic group) ,

0506(4) an optionally substituted 4- to 7-membered heterocyclic group, and

0507(5) optionally substituted 4- to 7-membered heterocyclyl-oxy. [0141]

0508[Compound A-2]

0509Compound (I) wherein

0510R¹ is Ci-₆ alkyl (e.g., methyl),

0511R² is hydroxy,

0512R³ is a hydrogen atom or Ci_₆ alkyl (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

0513X is CH₂,

0514Y is 0, Z is CH, n is 1, and A is

0515(a) a halogen atom (e.g., a bromine atom),

0516(b) amino optionally substituted by 1 or 2 substituents selected from ( i ) Ci-₆ alkyl (e . g . , n-propyl ) , and

0517(ii) a heterocyclic group (e.g., pyridyl) optionally substituted by a halogen atom (e.g., a fluorine atom), or (c) a 4- to 13-membered cyclic group (e.g., phenyl, pyrazolyl, thienyl, piperidinyl, pyridyl, pyrimidinyl, dihydropyranyl, indolyl, benzimidazolyl, furo [2, 3-b] pyridinyl, furo[3,2- b]pyridinyl, imidazo [1, 2-a] pyridinyl, 3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazinyl, 1, 4-dioxaspiro [4.5] dec-7-enyl, 1, 4-dioxa-8-azaspiro [4.5] decanyl) optionally substituted by 1 to 3 substituents selected from

0518(1) a halogen atom (e.g., a fluorine atom, a chlorine atom) ,

0519(2) optionally substituted amino,

0520(3) Ci-₆ alkylthio (e.g., methylthio) optionally substituted by Cε-i₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a chlorine atom),

0521(4) Ci-₆ alkyl (e.g., methyl, ethyl, isopropyl) optionally substituted by substituent (s) selected from

0522(i) a halogen atom (e.g., a fluorine atom), (ii) optionally substituted hydroxy (e.g., hydroxy, methoxy) , and

0523(iii) Ci-₆ alkylsulfonyl (e.g., mesyl) ,

0524(5) optionally substituted C₃-₁₀ cycloalkyl (e.g., cyclopropyl) ,

0525(6) Ci-₆ alkoxy (e.g., methoxy, ethoxy, n-propoxy) optionally substituted by substituent (s) selected from

0526(i) a halogen atom (e.g., a fluorine atom),

0527(ii) mesyl,

0528(iii) Cβ-₁₄ aryl (e.g., phenyl), and

0529(iv) a heterocyclic group,

0530(7) optionally substituted C6-14 aryl,

0531(8) an optionally substituted 4- to 7-membered heterocyclic group (e.g., tetrahydrofuryl, morpholino) , and

0532(9) optionally substituted 4- to 7-membered heterocyclyl-oxy. [ 0142 ]

0533[Compound B-I ]

0534Compound ( I ) wherein

0535R¹ forms

0536[ 0143 ]

0537<img file="WO2010143733A1_D0032.tif" />

0538[0144] together with X (that is, compound (II) ) ,

0539R² is hydroxy,

0540R³ is a hydrogen atom or Ci_₆ alkyl,

0541Y is 0,

0542Z is CH, n is 1, and

0543A is a 4- to 13-membered cyclic group optionally substituted by 1 to 3 substituents selected from

0544(1) a halogen atom,

0545(2) optionally substituted Ci_₆ alkyl (optionally substituted by a halogen atom or hydroxy) ,

0546(3) optionally substituted Cχ-₆ alkoxy (optionally substituted by a halogen atom, mesyl, aryl or a heterocyclic group) ,

0547(4) an optionally substituted 4- to 7-membered heterocyclic group, and

0548(5) optionally substituted 4- to 7-membered heterocyclyl-oxy. [0145]

0549[Compound B-2] Compound (I) wherein R¹ forms

0550[0146] <img file="WO2010143733A1_D0033.tif" />

0551[0147] together with X (that is, compound (II) ) ,

0552R² is hydroxy,

0553R³ is a hydrogen atom,

0554Y is 0,

0555Z is CH, n is 1, and

0556A is

0557(a) a halogen atom (e.g., a bromine atom),

0558(b) amino optionally substituted by 1 or 2 substituents selected from

0559(i) Ci-₆ alkyl (e.g., ethyl, n-propyl) ,

0560(ii) Cβ-₁₄ aryl (e.g., phenyl) optionally substituted by substituent (s) selected from a halogen atom (e.g., a fluorine atom), cyano and Ci-₆ alkylsulfonyl (e.g., mesyl) , and

0561(iii) a heterocyclic group (e.g., pyridyl, pyrimidinyl) optionally substituted by substituent (s) selected from a halogen atom (e.g., a fluorine atom, a chlorine atom) and Ci-₆ alkyl (e.g., methyl), or

0562(c) a 4- to 13-membered cyclic group (e.g., phenyl, pyrazolyl, thienyl, piperidinyl, morpholinyl, pyrimidinyl, benzimidazolyl, 3, 4-dihydro-2H-l, 4-benzoxazinyl) optionally substituted by 1 to 3 substituents selected from

0563(1) a halogen atom (e.g., a fluorine atom),

0564(2) optionally substituted amino,

0565(3) optionally substituted Ci-e alkylthio,

0566(4) Ci-₆ alkyl (e.g., methyl, ethyl, isopropyl) optionally substituted by a halogen atom (e.g., a fluorine atom) ,

0567(5) optionally substituted C₃-_I0 cycloalkyl, (6) Ci_6 alkoxy (e.g., methoxy, ethoxy, n-propoxy) optionally substituted by substituent (s) selected from (i) a halogen atom (e.g., a fluorine atom), (ii) C₃-₈ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl) optionally substituted by Cχ-₆ alkyl (e.g., methyl), (iii) Ci-₆ alkoxy (e.g., methoxy, ethoxy) optionally substituted by di-Ci_₆ alkylamino (e.g., dimethylamino) , (iv) di-Ci-₆ alkylamino (e.g., dimethylamino), (v) Ci-₆ alkylsulfinyl (e.g., methylsulfinyl) , (vi) mesyl, (vii) Cε-₁₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a fluorine atom), and

0568(viii) a heterocyclic group (e.g., furyl, isoxazolyl, pyridyl, pyrrolidinyl, morpholinyl, piperazinyl, azepanyl) optionally substituted by substituent (s) selected from Ci-₆ alkyl (e.g., methyl) and oxo,

0569(7) optionally substituted Cβ-i₄ aryl,

0570(8) a 4- to 7-membered heterocyclic group (e.g., morpholino, pyrrolidinyl, tetrahydropyranyl, furanyl, isoxazolyl) optionally substituted by Ci-β alkyl (e.g., methyl), and

0571(9) optionally substituted 4- to 7-membered heterocyclyl-oxy (e.g., dioxidotetrahydrothiopyranyloxy) . [0148]

0572[Compound B-3] Compound (I) wherein R¹ forms

0573[0149]

0574<img file="WO2010143733A1_D0034.tif" />

0575[0150] together with X (that is, compound (II) ) , R² is hydroxy,

0576R³ is a hydrogen atom or Ci-₆ alkyl,

0577Y is 0,

0578Z is CH, n is 1, and

0579A is phenyl, benzimidazolyl or a 5- or 6-membered aromatic heterocyclic group (preferably, thienyl, pyrimidinyl) each optionally substituted by 1 to 5 substituents selected from

0580(a) a halogen atom,

0581(b) Ci-₆ alkyl optionally substituted by 1 to 3 halogen atoms,

0582(c) Ci-₆ alkoxy optionally substituted by 1 to 3 substituents selected from

0583(1) a halogen atom,

0584(2) Ci-₆ alkylsulfonyl,

0585(3) C₃-₈ cycloalkyl,

0586(4) mono- or di-Ci-β alkyl-amino,

0587(5) Ci-6 alkoxy,

0588(6) Cβ-₁₄ aryl optionally substituted by a halogen atom,

0589(7) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo, and

0590(8) Ci-₆ alkylthio,

0591(d) a 4- to 7-membered heterocyclic group, and

0592(e) 4- to 7-membered heterocyclyl-oxy optionally substituted by 1 to 3 substituents selected from Ci-₆ alkyl and oxo. [0151]

0593[Compound B-4] Compound (I) wherein R¹ forms [0152]

0594<img file="WO2010143733A1_D0035.tif" /> [ 0153 ] together with X (that is, compound (II)),

0595R² is hydroxy,

0596R³ is a hydrogen atom or Ci-6 alkyl,

0597Y is O,

0598Z is CH, n is 1, and

0599A is phenyl optionally substituted by 1 to 3 substituents selected from

0600(a) Ci-₆ alkyl optionally substituted by 1 to 3 halogen atoms,

0601(b) Ci-₆ alkoxy optionally substituted by 1 to 3 substituents selected from

0602(1) a halogen atom,

0603(2) Ci-₆ alkylsulfonyl,

0604(3) C₃-_S cycloalkyl,

0605(4) mono- or di-Ci-6 alkyl-amino,

0606(5) Ci_6 alkoxy,

0607(6) C₆-₁₄ aryl optionally substituted by a halogen atom,

0608(7) a 4- to 7-membered heterocyclic group optionally substituted by 1 to 3 substituents selected from Ci_₆ alkyl and oxo, and

0609(8) Ci-₆ alkylthio, and

0610(c) 4- to 7-membered heterocyclyl-oxy optionally substituted by 1 to 3 substituents selected from Cχ-₆ alkyl and oxo.

0611[0154]

0612[Compound B-5] Compound (I) wherein R¹ forms

0613[0155]

0614<img file="WO2010143733A1_D0036.tif" /> together with X (that is , compound ( II ) ) ,

0615R² is hydroxy,

0616R³ is a hydrogen atom or Ci-₆ alkyl,

0617Y is 0,

0618Z is CH, n is 1, and

0619A is benzimidazolyl or a 5- or 6-membered aromatic heterocyclic group (preferably, thienyl, pyrimidinyl) each optionally substituted by 1 to 3 substituents selected from

0620(a) a halogen atom,

0621(b) Ci-₆ alkyl optionally substituted by 1 to 3 halogen atoms, and

0622(c) a 5- or 6-membered heterocyclic group. [0157]

0623[Compound C-I] Compound (I) wherein R¹ forms

0624[0158]

0625<img file="WO2010143733A1_D0037.tif" />

0626[0159] together with X,

0627R² is hydroxy,

0628R³ is a hydrogen atom or Ci_₆ alkyl,

0629Y is 0,

0630Z is CH, n is 1,

0631A is a 4- to 13-membered cyclic group optionally substituted by 1 to 3 substituents selected from

0632(1) a halogen atom,

0633(2) optionally substituted (optionally substituted by a halogen atom or hydroxy) Ci_₆ alkyl, (3) optionally substituted (optionally substituted by a halogen atom, mesyl, aryl or a heterocyclic group) Cχ-₆ alkoxy,

0634(4) an optionally substituted 4- to 7-membered heterocyclic group, and

0635(5) optionally substituted 4- to 7-membered heterocyclyl-oxy. [0160]

0636[Compound C-2] R¹ forms [0161]

0637<img file="WO2010143733A1_D0038.tif" />

0638[0162] together with X,

0639R² is hydroxy,

0640R³ is a hydrogen atom or Cχ-₆ alkyl,

0641Y is 0,

0642Z is CH, and n is 1,

0643A is more preferably phenyl or a 5- or 6-membered aromatic heterocyclic group (e.g., pyrazolyl, thienyl, pyrimidinyl) each optionally substituted by 1 to 3 substituents selected from

0644(a) a halogen atom,

0645(b) Ci-₆ alkyl (e.g., methyl) optionally substituted by 1 to 3 halogen atoms (e.g., a fluorine atom),

0646(c) Ci-₆ alkoxy (e.g., methoxy, ethoxy, propoxy) optionally substituted by 1 to 3 substituents selected from

0647(1) a halogen atom,

0648(2) Ci-₆ alkylsulfonyl (e.g., methylsulfonyl) ,

0649(3) C₃-_S cycloalkyl (e.g., cyclopropyl, cyclopentyl) ,

0650(4) mono- or di-Ci-₆ alkyl-amino (e.g., dimethylamino) ,

0651(5) Ci-₆ alkoxy (e.g., methoxy),

0652(6) Cβ-₁₄ aryl (e.g., phenyl) optionally substituted by a halogen atom (e.g., a fluorine atom),

0653(7) a heterocyclic group (e.g., furyl, isoxazolyl, pyridyl, pyrrolidinyl, morpholinyl, piperazinyl, azepanyl) optionally substituted by 1 to 3 substituents selected from

0654(i) Ci-₆ alkyl (e.g., methyl), and (ii) oxo, and

0655(8) Ci-₆ alkylthio (e.g., methylthio) ,

0656(d) a 4- to 7-membered heterocyclic group (e.g., morpholino, pyrrolidinyl) , and

0657(e) 4- to 7-membered heterocyclyl-oxy (e.g., dioxidotetrahydrothiopyranyloxy) .

0658[0163] [Compound D]

0659^• [ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[3-

0660(methylsulfonyl) propoxy] phenyl } -2 , 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid or a salt thereof;

0661^• [ (3S)-6-{ [ (3S)-7-{4-[ (l,l-dioxidotetrahydro-2H-thiopyran-4- yl) oxy] -2 , 6-dimethylphenyl } -2 , 3-dihydro-l-benzofuran-3- yl] amino } -2, 3-dihydro-l-benzofuran-3-yl] acetic acid or a salt thereof;

0662^• [ (3S)-6-{ [ (3S)-7-(2-ethyl-6,7-difluoro-lH-benzimidazol-l-yl)- 2 , 3-dihydro-l-benzofuran-3-yl] amino } -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid or a salt thereof;

0663^• [ (3S)-6-{ [ (3S)-7-(2-ethoxy-6,7-difluoro-lH-benzimidazol-l-yl)- 2 , 3-dihydro-l-benzofuran-3-yl] amino } -2 , 3-dihydro-l-benzofuran- 3-yl] acetic acid or a salt thereof;

0664^• [ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (morpholin-4-yl) pyrimidin-5- yl] -2, 3-dihydro-l-benzofuran-3-yl}amino) -2, 3-dihydro-l- benzofuran-3-yl] acetic acid or a salt thereof.

0665[0164]

0666Examples of the salt of a compound represented by the formula (I) and (II) include metal salts, an ammonium salt, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like.

0667[0165]

0668Preferable examples of the metal salt include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the like. [0166]

0669Preferable examples of the salt with organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N- dibenzylethylenediamine and the like. [0167]

0670Preferable examples of the salt with inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. [0168]

0671Preferable examples of the salt with organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. [0169]

0672Preferable examples of the salt with basic amino acid include a salt with arginine, lysin, ornithine and the like. Preferable examples of the salt with acidic amino acid include a salt with aspartic acid, glutamic acid and the like. [0170]

0673Among the above-mentioned salts, a pharmaceutically acceptable salt is preferable. [0171]

0674A prodrug of compound (I) is a compound that converts to compound (I) due to the reaction by enzyme, gastric acid and the like under the physiological conditions in the body; that is, a compound that converts to compound (I) by enzymatic oxidation, reduction, hydrolysis and the like, and a compound that converts to compound (I) by hydrolysis and the like by gastric acid and the like. [0172]

0675Examples of a prodrug of compound (I) include a compound wherein amino of compound (I) is acylated, alkylated or phosphorylated (e.g., compound wherein amino of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5- methyl-2-oxo-l, 3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated) ; a compound wherein hydroxy of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound wherein hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated) ; a compound wherein carboxyl of compound (I) is esterified or amidated (e.g., a compound wherein carboxyl of compound (I) is Ci_₆ alkyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5- methyl-2-oxo-l, 3-dioxolen-4-yl) methyl esterified, cyclohexyloxycarbonylethyl esterified or methylamidated) and the like. Of these, a compound wherein carboxyl of compound (I) is esterified by Ci_₆ alkyl such as methyl, ethyl, tert- butyl and the like is preferably used. These compounds can be produced from compound (I) by a method known per se. [0173]

0676A prodrug of compound (I) may be a compound that converts to compound (I) under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990) . [0174]

0677Hereinafter the production methods of the compound (I) or a salt thereof are explained.

0678Each symbol of the compounds in the schematic drawings of the following schemes is as defined above unless particularly described. Each compound described in the schemes may form a salt as long as it does not inhibit the reaction, and as such salt, those similar to the salts of compound (I) can be mentioned.

0679[0175]

0680The compound obtained in each step can also be used as a crude product in the form of a reaction mixture in the next reaction, or can be isolated from the reaction mixture according to a conventional method, and further purified easily by a separation method such as recrystallization, distillation, chromatography and the like.

0681[0176]

0682Compound (I) (e.g., compounds represented by the formulas

0683(Ia) and (Ib) (to be abbreviated as compound (Ia) and compound

0684(Ib), respectively)) can be produced, for example, according to the method as shown in the following Scheme 1 or a method analogous thereto.

0685[0177] Reaction scheme 1

0686<img file="WO2010143733A1_D0039.tif" />

0687[ 0178 ] Step 1

0688Compound (5) can be produced by reacting compound (7a) with compound (8a) .

0689In step 1, L¹ is a leaving group, V is CH, or a carbon atom forming a ring together with R¹, R²' is a substituent, and other symbols are as defined above.

0690Examples of the leaving group for L¹ include a halogen atom (e.g., fluorine, chlorine, bromine, iodine), optionally halogenated Ci_₆ alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trichloromethanesulfonyloxy, trifluoromethanesulfonyloxy) , arylsulfonyloxy optionally having substituent (s) (e.g., C₆-io arylsulfonyloxy (e.g., phenylsulfonyloxy, naphthylsulfonyloxy) optionally substituted by 1 to 3 substituents selected from Ci_₆ alkyl group (e.g., methyl, ethyl), Cχ-₆ alkoxy (e.g., methoxy, ethoxy) and a nitro group, and the like, specific examples include phenylsulfonyloxy, m-nitrophenylsulfonyloxy, p- toluenesulfonyloxy and the like, acyloxy (e.g., trichloroacetoxy, trifluoroacetoxy and the like) and the like.

0691Compound (5) can be produced by subjecting compound (7a) and compound (8a) to a reductive amination reaction (e.g., the methods described in Jikken Kagaku Kouza, the 4th Edition, vol.20, pages 282-284 and 366-368 (The Chemical Society of Japan ed.); J. Am. Chem. Soc, vol. 93, pages 2897-2904, 1971; Synthesis, page 135, 1975, and the like) .

0692In the reductive amination reaction, compound (7a) and compound (8a) are subjected to a dehydration reaction to give an imine form, and the imine form is subjected to a reduction reaction to give compound (5) .

0693The dehydrating reaction is promoted by adding a dehydrating agent such as molecular sieves and the like, or p- toluenesulfonic acid, zinc chloride, phosphoryl chloride, boron trifluoride, titanium tetrachloride, acetic acid, trifluoroacetic acid and the like to the system, removing water from the system by using Dean-Stark apparatus and the like, or a combination of these.

0694The reduction reaction is generally carried out by using a reducing agent according to a conventional method. Examples of the reducing agent include metal hydrides such as aluminum hydride, diisobutylaluminum hydride, tributyltin hydride and the like; metal hydride complex compounds such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium aluminum hydride and the like; borane complexes such as borane tetrahydrofuran complex, borane dimethylsulfide complex, picoline-borane complex and the like; alkylboranes such as hexylborane, disiamylborane and the like; diborane; metals such as zinc, aluminum, tin, iron and the like; alkali metal such as sodium, lithium etc. /liquid ammonia (Birch reduction) and the like.

0695The amount of the reducing agent to be used is appropriately determined depending on the kind of the reducing agent. For example, the amount of the metal hydride, metal hydride complex compound, borane complex, alkylboranes or diborane to be used is each generally about 0.25 - about 10 mol, preferably about 0.5 - about 5 mol, per 1 mol of compound (7a) , and the amount of the metals (containing alkali metal to be used in Birch reduction) is generally about 1 - about 20 mol, preferably about 1 - about 5 mol, per 1 mol of compound (7a).

0696The reduction reaction can also be carried out by a hydrogenation reaction. In this case, for example, catalysts such as palladium carbon, palladium black, platinum dioxide, Raney-nickel, Raney-cobalt and the like can be used. The amount of the catalyst to be used is generally about 5 to about 1000 wt%, preferably about 10 to about 300 wt%, relative to compound (7a) .

0697The hydrogenation reaction can also be carried out using various hydrogen sources instead of gaseous hydrogen. As the hydrogen source, for example, formic acid, ammonium formate, triethylammonium formate, sodium phosphinate, hydrazine and the like can be mentioned. The amount of the hydrogen source to be used is generally about 1 to about 10 mol, preferably about 1 to about 5 mol, per 1 mol of compound (7a) .

0698The reaction is advantageously carried out using a solvent inert to the reaction. While the solvent is not particularly limited as long as the reaction proceeds, for example, halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane and the like) ; alcohols such as methanol, ethanol, 1-propanol, 2- propyl alcohol, tert-butyl alcohol and the like; ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; esters such as ethyl acetate, tert-butyl acetate and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; amides such as N,N-dimethylformamide, N, N- dimethylacetamide, hexamethylphosphoryl amide and the like; organic acids such as formic acid, acetic acid, propanoic acid, trifluoroacetic acid, methanesulfonic acid and the like, a mixed solvent thereof and the like are preferable.

0699The amount of compound (8a) to be used is generally about 0.2 - about 5 mol, preferably about 0.5 - about 2 mol, per 1 mol of compound (7a) .

0700While the reaction time varies depending on the reagent and solvent to be used, it is generally about 10 min to about 100 hr, preferably about 30 min to about 50 hr. The reaction temperature is generally about -20⁰C to about 100⁰C, preferably about 0⁰C to about 8O⁰C. [0179] Step 2

0701Compound (6) can be produced by reacting compound (7b) with compound (8b) .

0702In step 2, L² is hydroxy or a leaving group, P¹ is acyl, and other symbols are as defined above.

0703Examples of the leaving group for L² include those recited for the leaving group L¹.

0704Examples of the acyl for P¹ include carbonyl such as trifluoroacetyl, trichloroacetyl and the like; sulfonyl such as 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, 2,4- dinitrobenzenesulfonyl, methanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl etc. and the like, (i) When L² is hydroxy, compound (6) can be produced by subjecting compound (7b) and compound (8b) to Mitsunobu reaction (for example, the methods described in Synthesis, page 1-27, 1981, Tetrahedron Lett., vol. 36, page 6373-6374, 1995, Tetrahedron Lett., vol. 38, page 5831-5834, 1997 and the like) . In this reaction, compound (7b) is reacted with compound (8b) in the presence of azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, 1,1'- (azodicarbonyl) dipiperidine and the like and phosphine such as triphenylphosphine, tributylphosphine and the like. The reaction is advantageously carried out using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds and, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; amides such as N, N- dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoryl triamide and the like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane arid the like) ; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone and the like; esters such as ethyl acetate, tert- butyl acetate and the like; sulfoxides such as dimethyl sulfoxide and the like and the like, or a mixed solvent thereof and the like are preferable.

0705The reaction time is generally 5 min to 100 hr, preferably 30 min to 72 hr. The reaction temperature is generally -20⁰C to 200⁰C, preferably 0⁰C to 100⁰C.

0706The amount of compound (8b) to be used is about 0.5 - 5 mol, preferably about 0.9 - 2 mol, per 1 mol of compound (7b).

0707The amount of each of the azodicarboxylates and phosphines to be used is about 1 - 5 mol, preferably about 1 - 2 mol, per 1 mol of compound (8b) .

0708(ii) When L² is a leaving group, compound (6) can be produced by reacting compound (7b) with compound (8b) in the presence of a base.

0709Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as barium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and the like; acetates such as sodium acetate, ammonium acetate and the like; aromatic amines such as pyridine, 2,6-lutidine and the like; tertiary amines such as triethylamine, tripropylamine, tributylamine, N, N- diisopropylethylamine, cyclohexyldimethylamine, A- dimethylaminopyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like; alkali metal hydrides such as sodium hydride, potassium hydride and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyl disilazide and the like; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide etc. and the like.

0710The reaction is advantageously carried out using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds and, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; amides such as N, N- dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoryl triamide and the like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane and the like) ; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone and the like; esters such as ethyl acetate, tert- butyl acetate and the like; sulfoxides such as dimethyl sulfoxide and the like; aromatic amines such as pyridine and the like; tertiary amines such as triethylamine, N, N- diisopropylethylamine and the like; and the like or a mixed solvent thereof and the like are preferable.

0711The amount of compound (8b) to be used is about 0.8 - 10 mol, preferably about 0.9 - 2 mol, per 1 mol of compound (7b). In addition, the amount of the base to be used is about 1 - 10 mol, preferably about 1 - 3 mol, per 1 mol of compound (8b) . The reaction time is generally 10 min to 12 hr, preferably 20 min to 6 hr. The reaction temperature is generally -70⁰C to 250⁰C, preferably -20⁰C to 100⁰C.

0712[0180]

0713Step 3

0714Compound (6) can also be produced by reacting compound (5) with compound P^{3^}-L³.

0715In step 3, L³ is a leaving group, and other symbols are as defined above.

0716Examples of the leaving group L³ include those recited for leaving group L¹.

0717Compound (6) can be produced according to a method known per se, for example, by reacting compound (5) with compound P¹- L³ in the presence of a base.

0718Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; organic bases such as trimethylamine, triethylamine, N,N-diisopropylethylamine, pyridine, picoline, 2, 6-lutidine, 4-dimethylaminopyridine, N- methylpyrrolidine, N-methylmorpholine, 1,5- diazabicyclo [4.3.0] -5-nonene, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] -7-undecene etc. and the like.

0719The reaction is advantageously carried out using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; amides such as N, N- dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoryl triamide and the like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane and the like) ; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone and the like; sulfoxides such as dimethyl sulfoxide and the like; and the like or a mixed solvent thereof and the like are preferable.

0720While the reaction time varies depending on the reagent and solvent to be used, it is generally 10 min to 100 hr, preferably 30 min to 50 hr.

0721The reaction temperature is generally -30°C to 100⁰C, preferably 0⁰C to 8O⁰C.

0722The amount of compound P^{1^}-L³ to be used is about 0.5 - 5 mol, preferably about 1 - 3 mol, per 1 mol of compound (5) .

0723The amount of the base to be used is about 0.5 - 10 mol, preferably about 1 - 5 mol, per 1 mol of compound (5) . [0181] Step 4

0724Compound (3) can be produced by reacting compound (5) with a metal or an organic metal reagent.

0725In step 4, M¹ is a metal (e.g., boron, tin, silicon, potassium, sodium, lithium, aluminum, magnesium, copper, mercury, zinc, thallium and the like, which may be formed as a complex), and other symbols are as defined above.

0726Compound (3) can be produced, for example, according to the methods described in Palladium Reagents and Catalysts, John Wiley and Sons, page 289-293 (preparation of organic boron compound) , page 313-317 (preparation of organotin compound) , page 338-340 (preparation of organic silicon compound), 2004 or a method analogous thereto.

0727When M¹ is, for example, boron, compound (5) is reacted with organic boron reagents such as bis (pinacolato) diboron, pinacolborane and the like in the presence of a transition metal catalyst and base.

0728Examples of the transition metal catalyst include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium (0) , bis (triphenylphosphine) palladium (II) dichloride, [1,1'- bis (diphenylphosphino) ferrocene] palladium (II) dichloride and the like. The amount of the transition metal catalyst to be used is about 0.000001 - 5 mol, preferably about 0.0001 - 1 mol, per 1 mol of compound (5) . When a metal catalyst unstable to oxygen is used for the reaction, the reaction is preferably carried out under an inert gas (e.g., argon gas or nitrogen gas) atmosphere or stream. The reaction may be advantageously carried out in the co-presence of about 1 - 50 mol, preferably about 1 - 20 mol, of a phosphine ligand relative to a transition metal catalyst. Examples of the phosphine ligand include triphenylphosphine, 1,1'- bis (diphenylphosphino) ferrocene, 2,2' -bis (diphenylphosphino) - 1, 1' -binaphthyl, bis (2-diphenylphosphinophenyl) ether and the like.

0729Examples of the base include alkali metal acetates such as lithium acetate, sodium acetate, potassium acetate and the like; alkali metal phenoxides such as lithium phenoxide, sodium phenoxide, potassium phenoxide and the like; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal phosphate such as sodium phosphate, potassium phosphate and the like; organic bases such as trimethylamine, triethylamine, N,N-diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5- diazabicyclo [4.3.0] -5-nonene, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] -7-undecene etc. and the like. The reaction proceeds advantageously in a solvent inert to the reaction. Preferable examples of the solvent include ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; amides such as N,N-dimethylformamide, N, N- dimethylacetamide, hexamethylphosphoric triamide and the like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane and the like); nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone and the like; sulfoxides such as dimethyl sulfoxide and the like; water and the like or a mixed solvent thereof and the like.

0730The amount of the organic boron reagent to be used is about 1 - 20 mol, preferably about 1 - 5 mol, per 1 mol of compound (5) . In addition, the amount of the base to be used is about 1 - 20 mol, preferably about 1 - 5 mol, per 1 mol of compound (5) .

0731The reaction temperature is -10⁰C to 250⁰C, preferably 0⁰C to 200⁰C.

0732While the reaction time varies depending on the kind of compound (5) , organic metal reagent, transition metal catalyst, ligand, base or solvent, the reaction temperature and the like, it is generally 1 min - 200 hr, preferably 5 min - 100 hr. [0182] Step 5

0733Compound (Ib) can be produced by reacting compound (3) with compound A-L⁴.

0734In step 5, L⁴ is a leaving group, and other symbols are as defined above.

0735Examples of the leaving group for L⁴ include those recited for leaving group L¹.

0736Compound (3) and compound A-L⁴ are generally reacted in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal phosphates such as sodium phosphate, potassium phosphate and the like; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert- butoxide and the like; organic bases such as trimethylamine, triethylamine, N,N-diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5- diazabicyclo [4.3.0] -5-nonene, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] -7-undecene and the like; organic lithiums such as methyllithium, n-butyllithium, sec- butyllithium, tert-butyllithium and the like; lithium amides such as lithium diisopropylamide etc. and. the like.

0737The reaction is advantageously carried out using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and the like; ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether and the like; esters such as ethyl formate, ethyl acetate, n-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and the like; hydrocarbons such as n-hexane, benzene, toluene and the like; amides such as formamide, N, N- dimethylformamide, N,N-dimethylacetamide and the like; nitriles such as acetonitrile, propionitrile and the like; sulfoxides such as dimethyl sulfoxide and the like; sulfolane; hexamethylphosphoryl amide; water and the like and a mixed solvent thereof and the like are preferable.

0738The reaction can be generally promoted by using a transition metal catalyst. As the transition metal catalyst, a metal complex having various ligands is used and, for example, palladium compounds [e.g., palladium (II) acetate, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium (0) , bis (triphenylphosphine) palladium (II) dichloride, [1,1'- bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis (triethylphosphine) palladium (II) dichloride and the like], nickel compounds [e.g., tetrakis (triphenylphosphine) nickel (0) , bis (triethylphosphine) nickel (II) dichloride, bis (triphenylphosphine) nickel (II) dichloride and the like], rhodium compounds [e.g., tris (triphenylphosphine) rhodium (III) trichloride and the like] , cobalt compound, copper compounds [e.g., copper oxide, copper (II) chloride and the like], platinum compound and the like can be mentioned. Among these, palladium compound, nickel compound and copper compound are preferable. The amount of the transition metal catalyst to be used is about 0.000001 - 5 mol, preferably about 0.0001 - 1 mol, per 1 mol of compound (A-L⁴) . When a metal catalyst unstable to oxygen is used for the reaction, the reaction is preferably carried out under an inert gas (e.g., argon gas or nitrogen gas) atmosphere or stream. The reaction may be advantageously carried out in the co-presence of a ligand such as phosphine and the like relative to a transition metal catalyst. For example, triphenylphosphine, 1,1'- bis (diphenylphosphino) ferrocene, 2,2' -bis (diphenylphosphino) - 1, 1' -binaphthyl, 2-dicyclohexylphosphino-2' , 6' - dimethoxybiphenyl, 2-dicyclohexylphosphino-2' ,4' ,6'- triisopropylbiphenyl, bis (2-diphenylphosphinophenyl) ether, 9, 9-dimethyl-4, 5-bis (diphenylphosphino) xanthene and the like can be mentioned. The amount of the ligand to be used is generally 1 to 50 equivalents, preferably 1 to 10 equivalents, per 1 equivalent of a transition metal catalyst. The amount of compound A-L⁴ to be used is about 0.1 - 10 mol, preferably about 0.5 - 2 mol, per 1 mol of compound (3). In addition, the amount of the base to be used is about 1 - 20 mol, preferably about 1 - 5 mol, per 1 mol of compound (3) .

0739The reaction temperature is -10⁰C - 250⁰C, preferably 0⁰C - 150⁰C.

0740While the reaction time varies depending on the kind of compound (3) , compound A-L⁴, metal catalyst, base or solvent, the reaction temperature and the like, it is generally 1 min - 200 hr, preferably 5 min - 100 hr. [0183] Step 6

0741Compound (Ib) can be produced by reacting compound (5) with compound A-M² according to the method exemplified in step 5 or a method analogous thereto.

0742In step 6, M² is a metal (e.g., boron, tin, silicon, potassium, sodium, lithium, aluminum, magnesium, copper, mercury, zinc, thallium and the like, which may be formed as a complex), and other symbols are as defined above. [0184] Step 7

0743Compound (4) can be produced by reacting compound (6) with compound A' -NH₂.

0744In step 7, A' is an aromatic ring group optionally having substituent (s) or Ci_₆ alkyl optionally having substituent (s) , and other symbols are as defined above.

0745Examples of the aromatic ring group optionally having substituent (s) or Ci_₆ alkyl optionally having substituent (s) for A' include 4-methylpyridin-2-yl, 2-pyrimidinyl, benzyl and the like.

0746Compound (6) and compound A' -NH₂ are generally reacted in the presence of a base. Examples of the base include alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like; alkali metal phosphates such as sodium phosphate, potassium phosphate and the like; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert- butoxide and the like; organic bases such as trimethylamine, triethylamine, N,N-diisopropylethylamine, pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5- diazabicyclo [4.3.0] -5-nonene, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] -7-undecene and the like; organic lithiums such as methyllithium, n-butyllithium, sec- butyllithium, tert-butyllithium and the like; lithium amides such as lithium diisopropylamide etc. and the like.

0747The reaction is advantageously carried out using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol and the like; ethers such as dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol-dimethyl ether and the like; esters such as ethyl formate, ethyl acetate, n-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene and the like; hydrocarbons such as n-hexane, benzene, toluene and the like; amides such as formamide, N, N- dimethylformamide, N,N-dimethylacetamide and the like; nitriles such as acetonitrile, propionitrile and the like; sulfoxides such as dimethyl sulfoxide and the like; sulfolane; hexamethylphosphoryl amide; water and the like and a mixed solvent thereof and the like are preferable.

0748The reaction can be generally promoted by using a transition metal catalyst. As the transition metal catalyst, a metal complex having various ligands, for example, palladium compounds [e.g., palladium (II) acetate, tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium (0) , bis (triphenylphosphine) palladium (II) dichloride, [1,1'- bis (diphenylphosphino) ferrocene] palladium (II) dichloride, bis (triethylphosphine) palladium (II) dichloride and the like], nickel compounds [e.g., tetrakis (triphenylphosphine) nickel (0) , bis (triethylphosphine) nickel (II) dichloride, bis (triphenylphosphine) nickel (II) dichloride and the like], rhodium compounds [e.g., tris (triphenylphosphine) rhodium (III) trichloride and the like] , cobalt compound, copper compounds [e.g., copper oxide, copper (II) chloride and the like], platinum compounds and the like can be mentioned. Among these, palladium compound, nickel compound and copper compound are preferable. The amount of the transition metal catalyst to be used is about 0.000001 - 5 mol, preferably about 0.0001 - 1 mol, per 1 mol of compound (A-L⁴) . When a metal catalyst unstable to oxygen is used for the reaction, a reaction is preferably carried out under an inert gas (e.g., argon gas or nitrogen gas) atmosphere or stream. The reaction may be advantageously carried out in the co-presence of a ligand such as phosphine and the like relative to the above-mentioned transition metal catalyst. For example, triphenylphosphine, 1, 1' -bis (diphenylphosphino) ferrocene, 2,2'- bis (diphenylphosphino) -1, 1' -binaphthyl, 2- dicyclohexylphosphino-2' , 6' -dimethoxybiphenyl, 2- dicyclohexylphosphino-2' , 4' , 6' -triisopropylbiphenyl, bis (2- diphenylphosphinophenyl) ether, 9, 9-dimethyl-4, 5- bis (diphenylphosphino) xanthene and the like can be mentioned. The amount of the ligand to be used is generally 1 to 50 equivalents, preferably 1 to 10 equivalents, per 1 equivalent of a transition metal catalyst.

0749The amount of the compound A' -NH₂ to be used is about 0.5 - 10 mol, preferably about 0.5 - 5 mol, per 1 mol of compound (6) . In addition, the amount of the base to be used is about 1

0750- 20 mol, preferably about 1 - 5 mol, per 1 mol of compound A' -NH₂.

0751The reaction temperature is -10⁰C - 250⁰C, preferably 0⁰C

0752- 150⁰C.

0753While the reaction time varies depending on the kind of compound (6) , compound A' -NH₂, the metal catalyst, base or solvent, the reaction temperature and the like, it is generally 1 min - 200 hr, preferably 5 min - 100 hr. [0185] Step 8

0754Compound (2) can be produced by reacting compound (4) with compound R⁴-L⁵.

0755In step 8, R⁴ is Ci_₆ alkyl optionally having substituent (s) , L⁵ is a leaving group, and other symbols are as defined above.

0756Examples of the Ci_₆ alkyl optionally having substituent (s) for R⁴ include ethyl, n-propyl, cyclopropyl, methoxyethyl and the like.

0757Examples of the leaving group for L⁵ include those recited for leaving group L¹.

0758Compound (2) can be produced according to a method known per se, for example, by reacting compound (4) with compound R⁴- L⁵ in the presence of a base.

0759Examples of the base include alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and the like; organic bases such as trimethylamine, triethylamine, N, N- diisopropylethylamine, pyridine, picoline, 2, 6-lutidine, 4- dimethylaminopyridine, N-methylpyrrolidine, N-methylmorpholine, 1, 5-diazabicyclo [4.3.0] -5-nonene, 1, A- diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] -7-undecene etc. and the like.

0760The reaction is advantageously carried out by using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; amides such as N, N- dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide and the^'like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane and the like) ; nitriles such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone and the like; sulfoxides such as dimethyl sulfoxide and the like and the like or a mixed solvent thereof and the like are preferable.

0761While the reaction time varies depending on the reagent and solvent to be used, generally 10 min - 100 hr, preferably 30 min - 50 hr.

0762The reaction temperature is generally -3O⁰C - 150⁰C, preferably 0⁰C - 100⁰C.

0763The amount of compound R⁴-L⁵ to be used is about 0.5 - 20 mol, preferably about 1 - 10 mol, per 1 mol of compound (4) . [0186] Step 9

0764Compound (2) can be produced by reacting compound (6) with compound A-M² according to the method exemplified in step 5 or a method analogous thereto.

0765In step 9, each symbol is as defined above. [0187] Step 10

0766Compound (2) can be produced by reaction according to the method of reaction scheme 3 to be mentioned below. [0188]

0767Step 11

0768Compound (Ib) can also be produced by eliminating P¹ of compound (2) .

0769The protecting group P¹ can be removed from compound (2) according to a method known per se, for example, the methods described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980), Tetrahedron Lett., vol. 36, page 6373- 6374, 1995, Tetrahedron Lett., vol. 38, page 5831-5834, 1997, Journal of Synthetic Organic Chemistry, Japan, vol. 59, page 779-789, 2001 and the like or a method analogous thereto. For removal of the protecting group P¹, a method using acid, base etc. and the like can be employed. [0189] Step 12

0770Compound (Ia) can be produced by subjecting compound (Ib) or compound (2) to hydrolysis.

0771In step 12, each symbol is as defined above.

0772The hydrolysis is performed according to a conventional method and using an acid or base.

0773Examples of the acid include mineral acids such as hydrochloric acid, sulfuric acid and the like; Lewis acids such as boron trichloride, boron tribromide and the like; organic acids such as trifluoroacetic acid, p-toluenesulfonic acid etc. and the like. Here, Lewis acid can also be used in combination with thiol or sulfide.

0774Examples of the base include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, potassium tert-butoxide etc. and the like. The amount of the acid or base to be used is about 0.5 - 10 mol, preferably about 0.5 - 6 mol, per 1 mol of compound (Ib) or compound (2) . The hydrolysis is carried out without a solvent or using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; alcohols such as methanol, ethanol, 2-propyl alcohol and the like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane and the like); water and the like or a mixed solvent thereof and the like are preferable.

0775The reaction time is generally 10 min - 100 hr, preferably 10 min - 24 hr. The reaction temperature is generally -10⁰C - 200⁰C, preferably 0⁰C - 120⁰C.

0776Compound (7a), (7b), P^x-L³, A-L⁴, A-M², A' -NH₂ and R⁴-L⁵ to be used in the reaction scheme 1 can be obtained as commercially available products, or can be produced according to a method known per se or a method analogous thereto.

0777For example, of compounds (5) , compound (5-1) wherein the ring formed by R¹ and the substituent of X is a 5-membered ring can be produced, for example, according to the method shown in reaction scheme 2 or a method analogous thereto.

0778In reaction scheme 2, each symbol is as defined above.

0779[0190]

0780Reaction scheme 2

0781<img file="WO2010143733A1_D0040.tif" />

0782(7a-1) (8a) (5-1)

0783[0191] Step 13

0784Compound (5-1) can be produced by subjecting an imine compound produced by a dehydrating reaction with compound (7a-l) and compound (8a) to Corey-Chaykovsky reaction. The imine compound can be synthesized from compound (7a-

07851) and compound (8a) in the same manner as in the dehydration reaction of compound (7a) and compound (8a) exemplified in step 1.

0786The Corey-Chaykovsky reaction is generally carried out according to a conventional method and using dimethylsulfoxonium methylide prepared from halogenated trimethylsulfoxonium and a base. Examples of the halogenated trimethylsulfoxonium include trimethylsulfoxonium iodide, trimethylsulfoxonium bromide, trimethylsulfoxonium chloride and the like. In addition, halogenated trimethylsulfonium can be used instead of halogenated trimethylsulfoxonium. The amount of the halogenated trimethylsulfoxonium or halogenated trimethylsulfonium to be used is generally about 1 - 10 mol, preferably about 1 - 5 mol, per 1 mol of compound (7a-l) .

0787Examples of the base include alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metal alkoxides having 1 to 6 carbon atoms such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide and the like; metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyl disilazide etc. and the like. The amount of the base to be used is generally about 1 - 10 mol, preferably about 1 - 5 mol, per 1 mol of compound (7a-l) .

0788The reaction is advantageously carried out by using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; sulfoxides such as dimethyl sulfoxide and the like and the like or a mixed solvent thereof and the like are preferable.

0789The reaction time is generally 5 min - 100 hr, preferably 10 min - 72 hr. The reaction temperature is generally -20⁰C - 200⁰C, preferably -10⁰C - 100⁰C. For example, of compounds (2) shown in reaction scheme 1, compound (2-1) or compound (2-2) wherein A is a benzoimidazole ring can be produced, for example, according to the method shown in reaction scheme 3 or a method analogous thereto. [0192]

0790<img file="WO2010143733A1_D0041.tif" />

0791[0193] Step 1OA

0792Compound (10) can be produced by reacting compound (6) with compound (9) according to the method exemplified in step 7 or a method analogous thereto.

0793In step 1OA, R⁵ is hydrogen, Ci-Cβ alkyl (e.g., methyl, ethyl, n-propyl) optionally having substituent (s) , Ci-C₆ alkoxy (e.g., methoxy, ethoxy, n-propoxy) optionally having substituent (s) , C₃-C₁₀ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl) optionally having substituent (s) , aryl (e.g., phenyl, naphthyl) optionally having substituent (s) , or a 4- to 7-membered heterocyclic group optionally having substituent (s) (e.g., 2-tetrahydrofuranyl, 4-tetrahydro-2H-pyranyl, 5- methylfuran-2-yl) , R⁶ shows 0 to 4 substituents selected from a halogen atom (e.g., fluorine, chlorine, bromine, iodine), a Ci- Ce alkyl group optionally having substituent (s) (e.g., methyl, ethyl, trifluoromethyl) , C₃-C₁₀ cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl) optionally having substituent (s) , Ci-

0794C₆ alkoxy optionally having substituent (s) (e.g., methoxy, trifluoromethoxy, methylsulfonylpropoxy) , Ci-C₆ alkylthio (e.g., methylthio, ethylthio) optionally having substituent (s) , amino optionally having substituent (s) (e.g., dimethylamino, piperidinyl, morpholinyl) , aryl (e.g., phenyl) optionally having substituent (s) , a 4- to 7-membered heterocyclic group optionally having substituent (s) (e.g., 2-tetrahydrofuranyl, 4-tetrahydro-2H-pyranyl, 5-methylfuran-2-yl) , and 4- to 7- membered heterocyclyl-oxy (e.g., tetrahydro-2H-pyran-4-yloxy) optionally having substituent (s) , and other symbols are as defined above. [0194] Step 1OB

0795Compound (12) can be produced by reacting compound (6) with compound (11) according to the method exemplified in step 7 or a method analogous thereto.

0796In step 1OB, each symbol is as defined above. [0195] Step 1OC

0797Compound (14) can be produced by reacting compound (6) with compound (13) according to the method exemplified in step 7 or a method analogous thereto.

0798In step 1OC, each symbol is as defined above. [0196] Step 1OD

0799Compound (14) can be produced by reacting compound (15) with compound (16) according to the method exemplified in step 7 or a method analogous thereto.

0800In step 1OD, L⁶ is a leaving group, and other symbols are as defined above.

0801Examples of the leaving group for L⁶ include those recited for leaving group L¹. [0197] Step 1OE Compound (12) can be produced from compound (14) .

0802In step 1OE, each symbol is as defined above.

0803Compound (12) is converted to compound (14) according to a method known per se, for example, the method described in Reductions in Organic Chemistry, Second Edition, The American Chemical Society, page 95-97, 1996 or a method analogous thereto. For the substituent conversion, the hydrogenation reaction exemplified in step 1 and the like can be used. [0198] Step 1OF

0804Compound (10) can also be produced by reacting compound (12) with compound (17) .

0805In step 1OF, L⁷ is hydroxy or a leaving group, and other symbols are as defined above.

0806Examples of the leaving group for L⁷ include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), acyloxy (e.g., acetoxy, trifluoroacetoxy) , aromatic heterocyclic groups (e.g., lH-imidazol-1-yl) and the like, (i) When L⁷ is hydroxy, compound (10) can be produced by directly condensing compound (12) and compound (17) using a condensing agent.

0807Examples of the condensing agent include carbodiimide type condensation reagents such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), l-ethyl-3- (3- dimethylaminopropyl) carbodiimide (EDC), or hydrochloride thereof and the like; phosphoric acid type condensation reagents such as diethyl cyanophosphate, diphenylphosphoryl azide and the like; carbonyldiimidazole, 2-chloro-l, 3- dimethylimidazolium tetrafluoroborate, 2-(7-aza-lH- benzotriazol-1-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU) and the like.

0808Examples of the solvent to be used for the condensation reaction include amides such as N,N-dimethylformamide, N, N- dimethylacetamide, N-methylpyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; water; and the like. These solvents may be used in a mixture at an appropriate ratio.

0809The amount of compound (17) to be used is generally 1 - 10 mol, preferably 1 - 3 mol, per 1 mol of compound (12) .

0810The amount of the condensing agent to be used is generally 0.1 - 10 mol, preferably 0.3 - 3 mol, per 1 mol of compound (12) .

0811When a carbodiimide type condensation reagent is used as the condensing agent, the reaction efficiency can be improved by using a suitable condensation promoter (e.g., l-hydroxy-7- azabenzotriazole, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N-hydroxyphthalimide) as necessary.

0812The reaction efficiency of the condensation reaction can be improved by using an organic amine base such as triethylamine, N,N-diisopropylethylamine, 4- (dimethylamino) - pyridine and the like.

0813The amount of each of such condensation promoter and organic amine base to be used is generally 0.1 - 10 mol, preferably 0.3 - 3 mol, per 1 mol of compound (12).

0814The reaction temperature is generally -30⁰C - 120⁰C, preferably -10⁰C - 100⁰C.

0815The reaction time is generally 0.5 - 60 hr. (ii) When L⁷ is a leaving group, the reaction is generally performed in the presence of a base in a solvent that does not adversely influence the reaction.

0816Examples of the base include amines such as triethylamine, pyridine, N-methylmorpholine, N,N-dimethylaniline, 4- dimethylaminopyridine and the like; alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate etc. and the like.

0817Examples of the solvent that does not adversely influence the reaction include amides such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; halogenated hydrocarbons such as chloroform, dichloromethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane and the like; esters such as methyl acetate, ethyl acetate and the like; nitriles such as acetonitrile, propionitrile and the like; water; and the like. These solvents may be used in a mixture at an appropriate ratio.

0818When the above-mentioned amides are used as a solvent, the reaction can also be performed in the absence of a base.

0819The amount of compound (17) to be used is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of compound (12) .

0820The amount of the base to be used is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of compound (12) .

0821The reaction temperature is generally -30⁰C - 120⁰C, preferably -10⁰C - 100⁰C.

0822The reaction time is generally 0.5 - 30 hr. [0199] Step 106 Compound (2-1) can be produced from compound (10) .

0823In step 1OG, each symbol is as defined above.

0824Compound (2-1) can be produced according to a method known per se, for example, by reacting compound (10) in the presence of an acid.

0825Examples of the acid include organic acids such as acetic acid, p-toluenesulfonic acid and the like; mineral acids such as hydrochloric acid and the like; polyphosphoric acid and the like.

0826The reaction is carried our without a solvent or using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane and the like) and the like or a mixed solvent thereof and the like are preferable.

0827The reaction time is generally 10 min - 150 hr, preferably 10 min - 48 hr. The reaction temperature is generally 0⁰C - 200⁰C, preferably 0⁰C - 150⁰C. [0200] Step 1OH

0828Compound (2-1) can be produced by reacting compound (12) with compound (18) .

0829In step 1OH, R⁷ is Ci_₆ alkyl optionally having substituent (s) , and other symbols are as defined above.

0830Examples of the Ci_₆ alkyl optionally having substituent (s) for R⁷ include methyl, ethyl, isopropyl and the like.

0831Compound (12) is generally reacted with compound (18) in a solvent inert to the reaction.

0832While the solvent is not particularly limited as long as the reaction proceeds, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propyl alcohol and the like; ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1, 2-dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; organic acids such as acetic acid, trifluoroacetic acid and the like and the like or a mixed solvent thereof and the like are preferable.

0833Where necessary, moreover, the reaction efficiency can be improved by using an acid such as acetic acid, p- toluenesulfonic acid and the like.

0834The reaction temperature is 0⁰C - 150⁰C, preferably 20⁰C - 80⁰C.

0835The reaction time is generally 5 min - 72 hr, preferably 10 min - 24 hr. [0201] Step 101

0836Compound (20) can be produced by reacting compound (12) with compound (19) .

0837In step 101, W is an oxygen atom or a sulfur atom, L⁸ is a leaving group, ^"and other symbols are as defined above.

0838Examples of the leaving group for L⁸ include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), optionally halogenated Ci-₆ alkyloxy (e.g., methoxy, ethoxy, trichloromethoxy) , aromatic heterocyclic groups (e.g., IH- imidazol-1-yl, IH-I, 2, 4-triazol-l-yl) and the like. [0202] Step 1OJ

0839Compound (2-2) can be produced by reacting compound (20) with compound (R⁸-L⁹) according to the method exemplified in step 8 or a method analogous thereto.

0840In step 10J, R⁸ is Ci_6 alkyl optionally having substituent (s) , L⁹ is a leaving group, and other symbols are as defined above.

0841Examples of the Ci_₆ alkyl optionally having substituent (s) for R⁸ include methyl, ethyl, benzyl and the like.

0842Examples of the leaving group for L⁹ include those recited for leaving group L¹.

0843Compound (9), compound (11), compound (13), compound (16), compound (17), compound (18), compound (19) and compound R⁸-L⁹ to be used in the above-mentioned reaction scheme 3 can be easily obtained as commercially available products, or can be produced according to a method known per se. For example, compound (8a) and compound (8b) shown in reaction scheme 1 can be produced, for example, according to the method shown in reaction scheme 4 or a method analogous thereto. [0203]

0844Reaction scheme 4

0845<img file="WO2010143733A1_D0042.tif" />

0846(21) (22) (8a) <img file="WO2010143733A1_D0043.tif" />

0847[0204] Step 14

0848Compound (22) can be produced by reacting compound (21) with compound (R⁹-L¹⁰) .

0849In step 14, R⁹ is Ci_₆ alkylsulfonyl optionally having substituent (s) , L¹⁰ is a leaving group, and other symbols are as defined above.

0850Examples of the Ci-₆ alkylsulfonyl optionally having substituent (s) for R⁹ include methanesulfonyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl and the like.

0851Examples of the leaving group for L¹⁰ include those recited for leaving group L¹.

0852Compound (22) can be produced according to a method known per se, for example, by reacting compound (21) with compound R⁹-L¹⁰ in the presence of a base.

0853Examples of the base include organic bases such as trimethylamine, triethylamine, diisopropylethylamine, pyridine, picoline, 2, 6-lutidine, 4-dimethylaminopyridine, N- methylpyrrolidine, N-methylmorpholine, 1,5- diazabicyclo [4.3.0] -5-nonene, 1, 4-diazabicyclo [2.2.2] octane,

08541, 8-diazabicyclo [5.4.0] -7-undecene etc. and the like.

0855The reaction is advantageously carried out without a solvent or using a solvent inert to the reaction. While such solvent is not particularly limited as long as the reaction proceeds, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4- dioxane, 1,2-dimethoxyethane and the like; aromatic hydrocarbons such as benzene, toluene and the like; saturated hydrocarbons such as cyclohexane, hexane and the like; halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane and the like); aromatic amines such as pyridine and the like; tertiary amines such as triethylamine, N,N-diisopropylethylamine and the like and the like or a mixed solvent thereof and the like are preferable.

0856While the reaction time varies depending on the reagent and solvent to be used, it is generally 5 min - 100 hr, preferably 30 min - 50 hr.

0857The reaction temperature is generally -80⁰C - 100⁰C, preferably -30⁰C - 50⁰C.

0858The amount of compound R⁹-L¹⁰ to be used is about 1 - 10 mol, preferably about 1 - 3 mol, per 1 mol of compound (21) . [0205] Step 15 Compound (8a) can be produced from compound (22) .

0859Compound (8a) can be produced, for example, according to the method described in Palladium Reagents and Catalysts, John Wiley and Sons, pages 386-387, 2004 or a method analogous thereto. [0206] Step 16

0860Compound (8b) can be produced by reacting compound (8a) with compound (P¹-!.¹¹) according to the method exemplified in step 3 or a method analogous thereto. In step 16, L¹¹ is a leaving group, and other symbols are as defined above.

0861Examples of the leaving group for L¹¹ include those recited for leaving group L¹.

0862Compound (21), compound R⁹-L¹⁰ and compound P^3--L¹¹ to be used in the above-mentioned reaction scheme 4 can be easily obtained as commercially available products, or can be produced according to a method known per se. For example, methyl [ (3S) -6-hydroxy-2, 3-dihydro-l-benzofuran-3-yl] acetate can be produced according to WO2008/001931.

0863In the synthesis of compound (Ib) or (2), the order of syntheses is not limited to that shown in reaction scheme 1 and, for example, the steps may be exchanged as appropriate as shown in reaction scheme 5.

0864In reaction scheme 5, each symbol is as defined above. [0207]

0865Reaction scheme 5

0866<img file="WO2010143733A1_D0044.tif" />

0867[0208] Step 17 Compound (Ib) can also be produced by reacting compound (23-1) with compound (22) according to the method exemplified in step

08687 or a method analogous thereto.

0869Step 18

0870Compound (Ib) can also be produced by reacting compound (23-2) with compound (8a) according to the method exemplified in step

08711 or a method analogous thereto. Step 19

0872Compound (2) can also be produced by reacting compound (23-3) with compound (8b) according to the method exemplified in step

08732 or a method analogous thereto.

0874Compound (23-1), compound (23-2) and compound (23-3) to be used in the above-mentioned reaction scheme 5 can be produced by applying the reactions exemplified above, and further according to methods known per se such as introduction of substituent, functional group conversion reaction, protection and deprotection and the like. [0209]

0875In each of the aforementioned reactions, when the starting material compound has an amino group, a carboxyl group, a hydroxy group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in the peptide chemistry and the like may be introduced into these groups, and the object compound can be obtained by removing the protecting group as necessary after the reaction.

0876Examples of the amino-protecting group include a formyl group, a Ci_₆ alkyl-carbonyl group, a Ci-₆ alkoxy-carbonyl group, a benzoyl group, a C₇_₁₀ aralkyl-carbonyl group (e.g., benzylcarbonyl) , a C₇-_I4 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl) , a trityl group, a phthaloyl group, an N,N-dimethylaminomethylene group, a substituted silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- butyldiethylsilyl) , a C₂-₆ alkenyl group (e.g., 1-allyl) and the like. These groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci_₆ alkoxy group and a nitro group.

0877Examples of the carboxyl-protecting group include a Ci_₆ alkyl group, a C₇-u aralkyl group (e.g., benzyl), a phenyl group, a trityl group, a substituted silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl) , a C₂-₆ alkenyl group (e.g., 1-allyl) and the like. These groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci_₆ alkoxy group and a nitro group.

0878Examples of the hydroxyl-protecting group include a Ci_₆ alkyl group, a phenyl group, a trityl group, a C₇_io aralkyl group (e.g., benzyl), a formyl group, a Ci_₆ alkyl-carbonyl group, a benzoyl group, a C₇-_I0 aralkyl-carbonyl group (e.g., benzylcarbonyl) , a 2-tetrahydropyranyl group, a 2- tetrahydrofuranyl group, a substituted silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl), a C₂-₆ alkenyl group (e.g., 1-allyl) and the like. These groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci_₆ alkyl group, a Ci-₆ alkoxy group and a nitro group.

0879Examples of the carbonyl-protecting group include cyclic acetal (e.g., 1, 3-dioxane) , non-cyclic acetal (e.g., di-Ci_₆ alkylacetal) and the like.

0880Examples of the mercapto-protecting group include a Ci-₆ alkyl group, a phenyl group, a trityl group, a C₇-_I0 aralkyl group (e.g., benzyl), a Ci_₆ alkyl-carbonyl group, a benzoyl group, a C₇-_I0 aralkyl-carbonyl group (e.g., benzylcarbonyl), a Ci-₆ alkoxy-carbonyl group, a Cβ-u aryloxy-carbonyl group (e.g., phenyloxycarbonyl) , a C₇_i₄ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl) , a 2- tetrahydropyranyl group, a Ci-₆ alkylamino-carbonyl group (e.g., methylaminocarbonyl, ethylaminocarbonyl) and the like. These groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci-₆ alkyl group, a Ci-₆ alkoxy group and a nitro group. [0210]

0881The above-mentioned protecting group can be removed according to a method known per se, for example, the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980) . Specific examples include a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method and the like.

0882The present compound (I) obtained in each of the above- mentioned production methods can be isolated and purified by a known method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In addition, each starting material compound to be used in each of the above-mentioned production methods can be isolated and purified by a known method similar to the above. Alternatively, such starting material compound may also be used directly as a starting material without isolation for the next step.

0883When the compound (I) has isomers such as optical isomer, stereoisomer, positional isomer, rotational isomer and the like, and any isomers and mixture of isomers are encompassed in the compound (I) . For example, when the compound (I) has an optical isomer, an optical isomer separated from a racemate is also encompassed in the compound (I) . These isomers can be obtained as independent products by a synthesis means or a separation means (e.g., concentration, solvent extraction, column chromatography, recrystallization and the like) , optical resolution means (e.g., fractional recrystallization method, chiral column method, diastereomer method and the like) and the like known per se. The compound (I) may be a crystal, and both a single crystal and crystal mixtures are encompassed in the compound (I) . Crystals can be produced by crystallization according to crystallization methods known per se.

0884The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate (e.g., non-hydrate), both of which are encompassed in the compound (I) .

0885A compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I etc.) and the like is also encompassed in compound (I).

0886A deuterium-exchanged compound by converting ¹H to ²H(D) is also encompassed in compound (I) . [0211]

0887Compound (I) or a salt thereof or a prodrug thereof (hereinafter to be collectively abbreviated as the compound of the present invention) has a GPR40 receptor function regulating action, particularly, a GPR40 receptor agonist activity. Moreover, since the compound of the present invention shows high solubility, low toxicity (e.g., influence on hematological parameters such as red blood cell count, hematocrit value, hemoglobin concentration, MCH, MCHC, MCV, platelet count, leukocyte count, blood reticulocyte count, leukocyte classification and the like; blood biochemical parameters such as total protein, albumin, A/G ratio, glucose, total cholesterol, triglyceride, urea nitrogen, creatinine, total bilirubin, AST, ALT, LDH, ALP, CK, Na, K, Cl, calcium, inorganic phosphorus, retinol (vitamin A) and the like) , and a few side effects (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction (CYP inhibitory action) , carcinogenicity) , it is useful as a safe GPR40 receptor function regulator, preferably, a GPR40 agonist. [0212]

0888The compound of the present invention shows a superior GPR40 receptor function modulating action in mammals (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human) , and are useful as modulators of physiological function in which GPR40 receptor is involved or agents for the prophylaxis or treatment of disease state or disease in which GPR40 receptor is involved. [0213]

0889To be specific, the compound of the present invention is useful as insulin secretion modulators (preferably insulin secretagogues) , hypoglycemic drugs and pancreatic β cell protectors . [0214]

0890Particularly, the compound of the present invention is useful as a blood glucose level dependent insulin secretagogue based on its GPR40 receptor agonist activity. In other words, the compound of the present invention is useful as an insulin secretagogue that does not cause hypoglycemia, unlike sulfonylurea . [0215]

0891Furthermore, the compound of the present invention is useful as an agent for the prophylaxis or treatment of diseases including, for example, diabetes, glucose tolerance disorders, ketosis, acidosis, diabetic complications (e.g., diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, macroangiopathy, diabetic gangrene) , macular edema, hyperlipidemia, sexual dysfunction, dermatic diseases, arthropathy, osteopenia, arteriosclerosis, thrombotic disease, dyspepsia, deficits in memory and learning, depression, manic- depressive illness, schizophrenia, attention deficit hyperactivity disorder, vision disorder, appetite regulation disorder (e.g., hyperorexia) , obesity, hypoglycemia, hypertension, edema, insulin resistance, unstable diabetes, fatty atrophy, insulin allergy, insulinoma, lipotoxicity, hyperinsulinemia, cancer (e.g., breast cancer), metabolic syndrome, immune diseases (e.g., immunodeficiency), inflammatory diseases (e.g., enteritis, arthritis, allergy), multiple sclerosis, acute renal failure and the like. Here, diabetes includes type 1 diabetes, type 2 diabetes, gestational diabetes and obese diabetes. In addition, hyperlipidemia includes hypertriglyceridemia, hypercholesterolemia, hypoHDL-emia, postprandial hyperlipemia and the like. [0216]

0892For diagnostic criteria of diabetes, Japan Diabetes Society reported diagnostic criteria in 1999. [0217]

0893According to this report, diabetes is a condition showing any of a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test (75 g OGTT) 2 h level (glucose concentration of intravenous plasma) of not less than 200 mg/dl, and a non-fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 200 mg/dl. A condition not falling under the above-mentioned diabetes and different from "a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of less than 110 mg/dl or a 75 g oral glucose tolerance test (75 g OGTT) 2 h level (glucose concentration of intravenous plasma) of less than 140 mg/dl" (normal type) is called a "borderline type". [0218]

0894In addition, ADA (American Diabetes Association) and WHO reported diagnostic criteria of diabetes. [0219]

0895According to these reports, diabetes is a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 126 mg/dl or a 75 g oral glucose tolerance test 2 h level (glucose concentration of intravenous plasma) of not less than 200 mg/dl. [0220]

0896In addition, according to the above-mentioned report of ADA and WHO, the impaired glucose tolerance is a condition showing a 75 g oral glucose tolerance test 2 h level (glucose concentration of intravenous plasma) of not less than 140 mg/dl and less than 200 mg/dl. According to the report of ADA, a condition showing a fasting blood glucose level (glucose concentration of intravenous plasma) of not less than 110 mg/dl and less than 126 mg/dl is called IFG (Impaired Fasting Glucose) . On the other hand, WHO has defined IFG (Impaired Fasting Glucose) as a condition where the fasting blood sugar level (venous plasma glucose concentration) is not less than 110 mg/dl and less than 126 mg/dl, and calls it IFG (Impaired Fasting Glycemia) . [0221]

0897The compound of the present invention can also be used as an agent for the prophylaxis or treatment of diabetes, borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG (Impaired Fasting Glycemia) , as determined according to the above-mentioned diagnostic criteria. Moreover, the compound of the present invention can prevent progress of borderline type, impaired glucose tolerance, IFG (Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) into diabetes.

0898The compound of the present invention is also useful as a therapeutic agent for diabetes with sulfonylurea secondary failure and affords a superior insulin secretion effect and a hypoglycemic effect for diabetic patients for whom sulfonylurea compounds and fast-acting insulin secretagogues fail to provide an insulin secretion effect, and therefore, fail to provide a sufficient hypoglycemic effect.

0899As the sulfonylurea compound here, a compound having a sulfonylurea skeleton or a derivative thereof (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole and the like) can be mentioned.

0900As the fast-acting insulin secretagogue, a compound that promotes insulin secretion from pancreatic β cell in the same manner as a sulfonylurea compound, though it does not have a sulfonylurea skeleton, such as glinide compounds (e.g., repaglinide, senaglinide, nateglinide, mitiglinide, a calcium salt hydrate thereof etc. ) , and the like, can be mentioned.

0901[0222]

0902The medicament containing the compound of the present invention can be safely administered solely or by mixing with a pharmacologically acceptable carrier according to a method known per se (e.g., the method described in the Japanese Pharmacopoeia etc. ) as the production method of a pharmaceutical preparation, and in the form of, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal and the like) , pill, powder, granule, capsule (including soft capsule, microcapsule) , troche, syrup, liquid, emulsion, suspension, release control preparation (e.g., immediate- release preparation, sustained-release preparation, sustained- release microcapsule), aerosol, film (e.g., orally disintegrating film, oral mucosa-adhesive film), injection

0903(e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection) , drip infusion, transdermal absorption type preparation, ointment, lotion, adhesive preparation, suppository (e.g., rectal suppository, vaginal suppository) , pellet, nasal preparation, pulmonary preparation (inhalant) , eye drop and the like orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal and intratumor administrations, administration to the vicinity of tumor, and direct administration to the lesion) .

0904[0223]

0905The content of the compound of the present invention in a pharmaceutical preparation is about 0.01 to about 100 wt% of the whole preparation. While the dose varies depending on the subject of administration, administration route, disease, symptom and the like, for example, when it is orally administered to a diabetic patient (body weight about 60 kg) , the daily dose of the active ingredient [the compound of the present invention] is about 0.01 to about 30 mg/kg body weight, preferably about 0.1 to about 20 mg/kg body weight, more preferably about 1 to about 20 mg/kg body weight, which may be given at once or in several portions a day (1 to 3 times a day) .

0906[0224]

0907As the above-mentioned pharmacologically acceptable carrier, various organic or inorganic carrier substances conventionally used as a preparation material can be mentioned. For example, excipient, lubricant, binder and disintegrant for solid preparations, solvent, solubilizing agents, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations and the like can be mentioned. Where necessary, additives such as conventional preservatives, antioxidants, colorants, sweetening agents, adsorbing agents, wetting agents and the like can be used.

0908[0225]

0909As the excipient, for example, lactose, sucrose, D- mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like can be mentioned.

0910[0226]

0911As the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like can be mentioned.

0912[0227]

0913As the binder, for example, crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, saccharose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like can be mentioned.

0914[0228] As the disintegrant, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, L-hydroxypropylcellulose and the like can be mentioned.

0915[0229]

0916As the solvent, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like can be mentioned.

0917[0230]

0918As the solubilizing agents, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like can be mentioned.

0919[0231]

0920As the suspending agent, for example, surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like, and the like can be mentioned.

0921[0232]

0922As the isotonicity agent, for example, glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol and the like can be mentioned.

0923[0233]

0924As the buffer, for example, buffers such as phosphate, acetate, carbonate, citrate and the like, and the like can be mentioned.

0925[0234]

0926As the soothing agent, for example, benzyl alcohol and the like can be mentioned.

0927[0235] As the preservative, for example, p-hydroxybenzoate esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like can be mentioned. [0236]

0928As the antioxidant, for example, sulfite, ascorbic acid, α-tocopherol and the like can be mentioned.

0929As the colorant, for example, water-soluble edible tar pigments (e.g., foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake pigments (e.g., aluminum salt of the aforementioned water-soluble edible tar pigment) , natural pigments (e.g., β-carotene, chlorophil, ferric oxide red) and the like can be mentioned.

0930As the sweetening agent, for example, saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like can be mentioned. [0237]

0931Furthermore, the compound of the present invention can be used in combination with a drug other than the compound of the present invention. [0238]

0932Examples of the drug that can be used in combination with the compound of the present invention (hereinafter sometimes to be abbreviated as concomitant drug) include other therapeutic agent for diabetes, therapeutic agents for diabetic complications, therapeutic agent for hyperlipidemia, antihypertensive agent, antiobesity agent, diuretic, chemotherapeutic agent, immunotherapeutic agent, antiinflammatory drug, antithrombotic agent, therapeutic agent for osteoporosis, vitamins, anti-dementia, therapeutic drugs for frequent urination or incontinence, therapeutic agent for dysuria and the like. Specifically, the following can be mentioned. [0239]

0933Examples of the therapeutic agent for diabetes include insulin preparations (e.g., animal insulin preparation extracted from pancreas of bovine or swine; human insulin preparation synthesized by genetic engineering using Escherichia coli or yeast; insulin zinc; protamine zinc insulin; insulin fragment or derivative (e.g., INS-I), oral insulin preparation), insulin sensitizers (e.g., pioglitazone or a salt thereof (preferably, hydrochloride) , rosiglitazone or a salt thereof (preferably, maleate) , metaglidasen, AMG-131, balaglitazone, MBX-2044, rivoglitazone, aleglitazar, chiglitazar, lobeglitazon, PLX-204, PN-2034, GFT-505, THR-0921, compounds described in WO2007/013694, WO2007/018314, WO2008/093639 and WO2008/099794) , α-glucosidase inhibitor (e.g., voglibose, acarbose, miglitol, emiglitate) , biguanide (e.g., metformin, buformin or a salt thereof (e.g., hydrochloride, fumarate, succinate) ) , insulin secretagogue (e.g., sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole) , repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof), dipeptidyl peptidase IV inhibitor (e.g., alogliptin or a salt thereof (preferably, benzoate) , vildagliptin, sitagliptin, saxagliptin, BI1356, GRC8200, MP-513, PF-00734200, PHX1149, SK-0403, ALS2-0426, TA-6666, TS-021, KRP-104, 2-[[6- [ (3R) -3-amino-l-piperidinyl] -3, 4-dihydro-3-methyl-2, 4-dioxo- 1 (2H) -pyrimidinyl] methyl] -4-fluorobenzonitrile or a salt thereof), β3 agonist (e.g., N-5984) , GPR40 agonist (e.g., compounds described in WO2004/041266, WO2004/106276, WO2005/063729, WO2005/063725, WO2005/087710, WO2005/095338, WO2007/013689 and WO2008/001931) , GLP-I receptor agonist (e.g., GLP-I, GLP-IMR agent, liraglutide, exenatide, AVE-0010, BIM- 51077, Aib(8,35)hGLP-l(7,37)NH₂, CJC-1131, albiglutide) , amylin agonist (e.g., pramlintide) , phosphotyrosine phosphatase inhibitors (e.g., sodium vanadate), gluconeogenesis inhibitor (e.g., glycogen phosphorylase inhibitor, glucose-6-phosphatase inhibitor, glucagon antagonist, FBPase inhibitor) , SGLT2 (sodium-glucose cotransporter 2) inhibitor (e.g.,

0934Depagliflozin, AVE2268, TS-033, YM543, TA-7284, Remogliflozin, ASP1941) , SGLTl inhibitor, llβ-hydroxysteroid dehydrogenase inhibitor (e.g., BVT-3498, INCB-13739) , adiponectin or an agonist thereof, IKK inhibitor (e.g., AS-2868) , leptin resistance improving drug, somatostatin receptor agonist, glucokinase activator (e.g., Piragliatin, AZD1656, AZD6370, TTP-355, compounds described in WO2006/112549, WO2007/028135, WO2008/047821, WO2008/050821, WO2008/136428 or WO2008/156757) , GIP (Glucose-dependent insulinotropic peptide) , GPRIl9 agonist (e.g., PSN821, MBX-2982, APD597) , FGF21, FGF analogue and the like. [0240]

0935Examples of the therapeutic agents for diabetic complications include aldose reductase inhibitors (e.g., tolrestat, epalrestat, zopolrestat, fidarestat, CT-112, ranirestat (AS-3201) , lidorestat) , neurotrophic factor and a drug for increasing the factor (e.g., NGF, NT-3, BDNF, neurotrophin production-secretion promoter described in WO01/14372 (e.g., 4- (4-chlorophenyl) -2- (2-methyl-l- imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole) , compound described in WO2004/039365) , PKC inhibitor (e.g., ruboxistaurin mesylate), AGE inhibitor (e.g., ALT946, N- phenacylthiazolium bromide (ALT766) , EXO-226, pyridorin, pyridoxamine) , GABA receptor agonist (e.g., gabapentin, pregabalin) , serotonin or noradrenaline reuptake inhibitor (e.g., duloxetine) , sodium channel inhibitor (e.g., lacosamide) , active oxygen scavenger (e.g., thioctic acid), cerebral vasodilator (e.g., tiapuride, mexiletine) , somatostatin receptor agonist (e.g., BIM23190) , apoptosis signal regulating kinase-1 (ASK-I) inhibitor and the like. [0241]

0936Examples of the therapeutic agent for hyperlipidemia include HMG-CoA reductase inhibitor (e.g., pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin or a salt thereof (e.g., sodium salt, calcium salt)), squalene synthase inhibitor (e.g., compound described in WO97/10224, for example, N- [ [ (3R, 5S) -1- (3-acetoxy-2, 2-dimethylpropyl) -7-chloro-5- (2,3- dimethoxyphenyl) -2-oxo-l, 2,3, 5-tetrahydro-4, l-benzoxazepin-3- yl] acetyl] piperidine-4-acetic acid), fibrate compound (e.g., bezafibrate, clofibrate, simfibrate, clinofibrate) , anion exchange resin (e.g., colestyramine) , probucol, nicotinic acid drug (e.g., nicomol, niceritrol, niaspan) , ethyl icosapentate, phytosterol (e.g., soysterol, γ-oryzanol) , cholesterol absorption inhibitor (e.g., zetia) , CETP inhibitor (e.g., dalcetrapib, anacetrapib) , ω-3 fatty acid preparation (e.g., ω-3-acid ethyl esters 90) and the like. [0242]

0937Examples of the antihypertensive agent include angiotensin converting enzyme inhibitor (e.g., captopril, enalapril, delapril and the like) , angiotensin II antagonist (e.g., candesartan cilexetil, candesartan, losartan, losartan potassium, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, olmesartan, olmesartan medoxomil, azilsartan, azilsartan medoxomil and the like), calcium antagonist (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine, amlodipine, cilnidipine and the like), β blocker (e.g., metoprolol, atenolol, propranolol, carvedilol, pindolol and the like), clonidine and the like. [0243]

0938Examples of the antiobesity agent include monoamine uptake inhibitor (e.g., phentermine, sibutramine, mazindol, fluoxetine, tesofensine) , serotonin 2C receptor agonist (e.g., lorcaserin) , serotonin 6 receptor antagonist, histamine H3 receptor modulator, GABA modulator (e.g., topiramate) , neuropeptide Y antagonist (e.g., velneperit) , cannabinoid receptor antagonist (e.g., rimonabant, taranabant) , ghrelin antagonist, ghrelin receptor antagonist, ghrelin acylation enzyme inhibitor, opioid receptor antagonist (e.g., GSK- 1521498) , orexin receptor antagonist, itielanocortin 4 receptor agonist, llβ-hydroxysteroid dehydrogenase inhibitor (e.g., AZD- 4017), pancreatic lipase inhibitor (e.g., orlistat, cetilistat) , β3 agonist (e.g., N-5984) , diacylglycerol acyltransferase 1 (DGATl) inhibitor, acetyl CoA carboxylase

0939(ACC) inhibitor, stearoyl-CoA desaturase inhibitor, microsomal triglyceride transfer protein inhibitor (e.g., R-256918), Na- glucose cotransporter inhibitor (e.g., JNJ-28431754, remogliflozin) , NFK inhibitor (e.g., HE-3286) , PPAR agonist

0940(e.g., GFT-505, DRF-11605) , phosphotyrosine phosphatase inhibitor (e.g., sodium vanadate, Trodusquemin) , GPR119 agonist (e.g., PSN-821) , glucokinase activator (e.g., AZD- 1656), leptin, leptin derivative (e.g., metreleptin) , CNTF

0941(ciliary neurotrophic factor) , BDNF (brain-derived neurotrophic factor) , cholecystokinin agonist, glucagon-like peptide-1 (GLP-I) preparation (e.g., animal GLP-I preparation extracted from pancreas of bovine, swine; human GLP-I preparation synthesized by genetic engineering using Escherichia coli, yeast; GLP-I fragment or derivative (e.g., exenatide, liraglutide) ) , amylin preparation (e.g., pramlintide, AC-2307), neuropeptide Y agonist (e.g., PYY3-36, PYY3-36 derivative, obineptide, TM-30339, TM-30335) , oxyntomodulin preparation: FGF21 preparation (e.g., animal FGF21 preparation extracted from pancreas of bovine, swine; human FGF21 preparation synthesized by genetic engineering using Escherichia coli, yeast; FGF21 fragment or derivative) , anorexigenic agent (e.g., P-57) and the like.

0942[0244]

0943Examples of the diuretics include xanthine derivatives

0944(e.g., sodium salicylate and theobromine, calcium salicylate and theobromine etc.), thiazide preparations (e.g., ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, bentylhydrochlorothiazide, penflutiazide, poly5thiazide, methyclothiazide etc.), antialdosterone preparations (e.g., spironolactone, triamterene etc.), carbonate dehydratase inhibitors (e.g., acetazolamide and the like), chlorobenzenesulfonamide preparations (e.g., chlortalidone, mefruside, indapamide etc.), azosemide, isosorbide, etacrynic acid, piretanide, bumetanide, furosemide and the like.

0945[0245]

0946Examples of the chemotherapeutic agent include alkylating agents (e.g., cyclophosphamide, ifosfamide) , metabolic antagonists (e.g., methotrexate, 5-fluorouracil) , antitumor antibiotics (e.g., mitomycin, adriamycin) , plant-derived antitumor agent (e.g., vincristine, vindesine, Taxol) , cisplatin, carboplatin, etoposide and the like. Of these, Furtulon or NeoFurtulon, which are 5-fluorouracil derivatives, and the like are preferable.

0947[0246]

0948Examples of the immunotherapeutic agent include microorganism or bacterial components (e.g., muramyl dipeptide derivative, Picibanil) , polysaccharides having immunity potentiating activity (e.g., lentinan, schizophyllan, krestin) , cytokines obtained by genetic engineering techniques (e.g., interferon, interleukin (IL) ) , colony stimulating factors

0949(e.g., granulocyte colony stimulating factor, erythropoietin) and the like, with preference given to interleukins such as IL-I, IL-2, IL-12 and the like.

0950[0247]

0951Examples of the antiinflammatory agent include nonsteroidal antiinflammatory agents such as aspirin, acetaminophen, indomethacin and the like.

0952[0248]

0953Examples of the antithrombotic agent include heparin

0954(e.g., heparin sodium, heparin calcium, enoxaparin sodium, dalteparin sodium), warfarin (e.g., warfarin potassium), anti- thrombin drugs (e.g., aragatroban, dabigatran) , FXa inhibitors

0955(e.g., rivaroxaban, apixaban, edoxaban, YM150, the compounds described in WO02/06234, WO2004/048363, WO2005/030740, WO2005/058823 and WO2005/113504) , thrombolytic agents (e.g., urokinase, tisokinase, alteplase, nateplase, monteplase, pamiteplase) , platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, clopidogrel, prasugrel, E5555, SHC530348, cilostazol, ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride) and the like. [0249]

0956Examples of the therapeutic agent for osteoporosis include alfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium, risedronate disodium and the like. [0250]

0957Examples of the vitamin include vitamin Bi, vitamin Bi₂ and the like. [0251]

0958Examples of the antidementia agent include tacrine, donepezil, rivastigmine, galanthamine and the like. [0252]

0959Examples of the therapeutic agent for pollakiuria or urinary incontinence include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride and the like. [0253]

0960Examples of the therapeutic agent for dysuria include acetylcholine esterase inhibitors (e.g., distigmine) and the like. [0254]

0961Furthermore, drugs having a cachexia-ameliorating action established in animal models and clinical situations, such as cyclooxygenase inhibitors (e.g., indomethacin) , progesterone derivatives (e.g., megestrol acetate), glucosteroids (e.g., dexamethasone) , metoclopramide agents, tetrahydrocannabinol agents, fat metabolism improving agents (e.g., eicosapentanoic acid) , growth hormones, IGF-I, or antibodies to a cachexia- inducing factor such as TNF-α, LIF, IL-6, oncostatin M and the like, can be used in combination with the compound of the present invention. [0255]

0962Furthermore, glycosylation inhibitors (e.g., ALT-711) , nerve regeneration promoting drugs (e.g., Y-128, VX853, prosaptide) , antidepressants (e.g., desipramine, amitriptyline, imipramine, etc.), antiepileptics (e.g., lamotrigine, Trileptal, Keppra, Zonegran, Pregabalin, Harkoseride and carbamazepine) , antiarrhythmic agents (e.g., mexiletine) , acetylcholine receptor ligands (e.g., ABT-594) , endothelin receptor antagonists (e.g., ABT-627) , monoamine uptake inhibitors (e.g., tramadol), narcotic analgesics (e.g., morphine), GABA receptor agonists (e.g., gabapentin and gabapentin MR agents), α2 receptor agonists (e.g., clonidine) , local analgesics (e.g., capsaicin), antianxiety drugs (e.g., benzothiazepines) , phosphodiesterase inhibitors (e.g., sildenafil), dopamine receptor agonists (e.g., apomorphine) , midazolam, ketoconazole and the like can also be used in combination with the compound of the present invention. [0256]

0963The concomitant drug is preferably an insulin preparation, a PPAR function regulator (preferably, pioglitazone or hydrochloride thereof) , an α-glucosidase inhibitor (preferably, voglibose) , biguanide (preferably metformin or hydrochloride thereof) , sulfonylurea (preferably glibenclamide, glimepiride) , mitiglinide or calcium salt hydrate thereof, nateglinide, dipeptidyl peptidase IV inhibitor (preferably alogliptin or benzoate thereof, 2- [ [6- [ (3R) -3-amino-l-piperidinyl] -3, 4- dihydro-3-methyl-2, 4-dioxo-l (2H) -pyrimidinyl] methyl] -A- fluorobenzonitrile or succinate thereof, 2- [2- (3- (R) -amino- piperidin-1-yl) -5-fluoro-6-oxo-6H-pyrimidin-l-ylmethyl] - benzonitrile or tartrate thereof) and the like. [0257]

0964A combination of the compound of the present invention and a concomitant drug affords the following effects:

0965(1) the dose can be reduced as compared to a single administration of the compound of the present invention or a concomitant drug,

0966(2) a long treatment period can be set by selecting a concomitant drug having a different mechanism of action from that of the compound of the present invention,

0967(3) a sustained treatment effect can be designed by selecting a concomitant drug having a different mechanism of action from that of the compound of the present invention,

0968(4) a synergistic effect can be afforded by a combined use of the compound of the present invention and a concomitant drug, and the like.

0969[0258]

0970When the compound of the present invention and a concomitant drug are used in combination, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention and the concomitant drug can be administered to an administration subject simultaneously, or may be administered at staggered times. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like. [0259]

0971As the administration mode of the compound of the present invention and a concomitant drug, the following methods can be mentioned: (1) administration of a single preparation obtained by simultaneous formulation of the compound of the present invention and a concomitant drug, (2) simultaneous administration by the same administration route of two kinds of preparations obtained by separate formulation of the compound of the present invention and a concomitant drug, (3) administration by the same administration route at staggered times of two kinds of preparations obtained by separate formulation of the compound of the present invention and a concomitant drug, (4) simultaneous administration by different administration routes of two kinds of preparations obtained by separate formulation of the compound of the present invention and a concomitant drug, (5) administration by different administration routes at staggered times of two kinds of preparations obtained by separate formulation of the compound of the present invention and a concomitant drug (e.g., the compound of the present invention and a concomitant drug are administered in this order, or in the reverse order) , and the like. Examples [0260]

0972The present invention is further explained in detail by referring to the following Reference Examples, Examples, Formulation Examples and Experimental Example, which are mere working examples not to be construed as limitative and may be changed without departing from the scope of the present invention. The term "room temperature" in the following Reference Examples and Examples indicates the range of generally from about 10⁰C to about 35⁰C. As for "%", the yield is in mol/mol%, the solvent used for chromatography is in % by volume and other "%" is in % by weight. OH proton, NH proton etc. that could not be confirmed due to broad peak by proton NMR spectrum are not included in the data.

0973Other symbols used herein mean the following: s: singlet d: doublet t: triplet q: quartet m: multiplet br: broad

0974J: coupling constant Hz: Hertz CDCI3: deuterated chloroform

0975DMSO-d₆: deuterated dimethyl sulfoxide 1H NMR: proton nuclear magnetic resonance

0976In the following Reference Examples and Examples, mass spectrum (MS) , nuclear magnetic resonance spectrum (NMR) and melting point were measured using the following apparatuses. MS measurement device: Waters ZMD, Waters ZQ2000 or Agilent Technologies, Agilent G6100 series. Ionization method: electron impact ionization method (Electron Spray Ionization: ESI) , or atmospheric pressure chemical ionization method (Atmospheric Pressure Chemical Ionization: APCI) . Unless otherwise specified, ESI was used.

0977NMR measurement device: Varian, Varian Gemini 200 (200 MHz), Varian Gemini 300 (300 MHz), Bruker-BioSpin K. K. AVANCE 300.

0978In the present specification, the melting point (m.p.) refers to that measured using, for example, differencial scanning calorimeter EXSTER6000 (DSC6200) manufactured by SII NanoTechnology Inc. or micromelting point measuring apparatus (Bϋchi, B-545) and the like.

0979In general, melting points vary depending on measurement apparatuses, measurement conditions and the like. The crystal in the present specification may show a different melting point from that described in the present specification, as long as it is within general error range. [0261]

0980Reference Example 1 methyl [ (3S) -6-amino-2, 3-dihydro-l-benzofuran-3-yl] acetate [0262]

0981To a solution of methyl [ (3S) -6-hydroxy-2, 3-dihydro-l- benzofuran-3-yl] acetate (41.6 g, 200 mmol) in pyridine (400 mL) was added dropwise under ice-cooling trifluoromethanesulfonic anhydride (40.4 mL, 240 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give methyl [(3S) -6-

0982{ [ (trifluoromethyl) sulfonyl] oxy}-2, 3-dihydro-l-benzofuran-3- yl] acetate (67.3 g) as an oil. To a solution of the obtained oil (67.3 g) and benzophenoneimine (46.5 mL, 277 mmol) and cesium carbonate (194 g, 594 mmol) in tetrahydrofuran (660 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (5.44 g, 5.94 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (6.87 g,

098311.9 mmol), and the mixture was stirred at 80⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure to give a brown oil. To a solution of the obtained oil in tetrahydrofuran (400 mL) was added 3 M hydrochloric acid (330 mL, 990 mmol) , and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with distilled water, and washed with ethyl acetate. The aqueous layer was neutralized with aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give an oil. The obtained oil compound was crystallized from diisopropyl ether (10 mL) and heptane (50 mL) , and the crystals were collected by filtration and washed with heptane to give the title compound (20.6 g, yield 50%) as a white solid. MS m/z 208 (M + H)⁺. [0263]

0984Reference Example 2 methyl [(3S)-6-{ [ (2-nitrophenyl) sulfonyl] amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate [0264] To a solution of methyl [ (3S) -6-amino-2, 3-dihydro-l- benzofuran-3-yl] acetate (3.00 g, 14.5 itunol) in pyridine (24 mL) was added under ice-cooling 2-nitrobenzenesulfonyl chloride (3.92 g, 15.9 mmol) , and the mixture was stirred at room temperature for 16 hr. The mixture was concentrated under reduced pressure to remove pyridine, and 1 M hydrochloric acid and ethyl acetate was added. Insoluble material was filtered off through celite, and the filtrate was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 50:50) to give a yellow solid. The obtained solid was triturated with diisopropyl ether-ethyl acetate, and washed with diisopropyl ether to give the title compound (4.86 g, yield 86%) as a yellow solid. MS m/z 393 (M + H)⁺.

0985[0265]

0986Reference Example 3 methyl [ (3S) -6-{ [ (3-bromo-2-hydroxyphenyl)methylidene] amino }- 2, 3-dihydro-l-benzofuran-3-yl] acetate

0987[0266]

0988A solution of 3-bromo-2-hydroxybenzaldehyde (85.5 g, 425 mmol) and methyl [ (3S) -6-amino-2, 3-dihydro-l-benzofuran-3- yl] acetate (88.1 g, 425 mmol) in toluene (425 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound

0989(yield 100%) as an orange solid. MS m/z 390 (M + H)⁺.

0990[0267]

0991Reference Example 4 methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l-benzofuran-3-yl) amino] - 2, 3-dihydro-l-benzofuran-3-yl}acetate

0992[0268]

0993To a solution (15 - 20⁰C) of trimethylsulfoxonium iodide (187 g, 850 mmol) in dimethyl sulfoxide (1.0 L) was slowly added sodium hydride (50 - 72% oil, 25.0 g) under a nitrogen stream, and the mixture was stirred at 15 - 20⁰C for 1 hr. Thereto was slowly added dropwise (15 - 20⁰C) a solution of methyl [ (3S)-6-{ [ (3-bromo-2-hydroxyphenyl)methylidene] amino}- 2, 3-dihydro-l-benzofuran-3-yl] acetate (425 mmol) in dimethyl sulfoxide (500 mL) , and the mixture was stirred for 2 hr. To the reaction mixture was added aqueous ammonium chloride solution (100 mL) , and the mixture was diluted with ethyl acetate and stirred at room temperature. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium ^"sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 85:15 - 75:25) to give the title compound (118.0 g, yield 69%) as a yellow oil. 1H NMR (300 MHz, CDCl₃) δ 2.55 (IH, dd, J = 16.3, 9.1 Hz), 2.74 (IH, dd, J = 16.3, 5.7 Hz), 3.72 (3H, s) , 3.73-3.85 (IH, m) , 3.97 (IH, d, J = 8.0 Hz), 4.25 (IH, dd, J = 9.5, 6.1 Hz), 4.48 (IH, dd, J = 9.8, 4.2 Hz), 4.68-4.84 (2H, m) , 5.20-5.31 (IH, m) , 6.08-6.16 (2H, m) , 6.76-6.85 (IH, m) , 6.97 (IH, d, J = 8.3 Hz), 7.28 (IH, d, J = 7.6 Hz), 7.41 (IH, d, J = 7.6 Hz). [0269]

0994Reference Example 5 methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l-benzofuran-3- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate [0270]

0995A solution of methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l- benzofuran-3-yl) amino] -2, 3-dihydro-l-benzofuran-3-yl} acetate (118.0 g, 292 mmol) and triethylamine (44.3 g, 438 mmol) in tetrahydrofuran (730 mL) was ice-cooled, and trifluoroacetic anhydride (73.5 g, 350 mmol) was added dropwise (5 - 10⁰C). The reaction mixture was stirred at 5 - 10°C for 1 hr, concentrated under reduced pressure, and diluted -with ethyl acetate. The solution was washed with aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 85:15 - 70:30) to give the title compound (145.0 g, yield 99%) as a yellow oil.

0996¹H NMR (300 MHz, CDCl₃) δ 2.49-2.64 (IH, m) , 2.66-2.83 (IH, m) , 3.71 (3H, s), 3.77-3.89 (IH, m) , 4.18-4.34 (IH, m) , 4.59-4.86 (3H, m) , 5.91-6.04 (IH, m) , 6.36-6.49 (IH, m) , 6.56-6.73 (IH, m) , 6.76-6.85 (IH, m) , 6.86-7.13 (IH, m) , 7.27-7.41 (2H, m) . [0271]

0997Reference Example 6 methyl [ (3S) -6- { [ (3R) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate [0272]

0998Methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l-benzofuran-3- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (10.3 g) was separated by HPLC to give the title compound (4.5 g, >99%d.e., recovery rate 87%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 2.47-2.65 (IH, m) , 2.66-2.82 (IH, m) , 3.64-3.93 (4H, m) , 4.16-4.36 (IH, m) , 4.58-4.86 (3H, m) , 5.91-6.02 (IH, m) , 6.34-6.50 (IH, m) , 6.56-7.15 (3H, m) , 7.28-7.41 (2H, m) .

0999(high performance liquid chromatography conditions) column: CHIRALPAK AD (manufactured by Daicel Chemical Industries, Ltd. ) mobile phase: hexane/isopropyl alcohol (volume ratio: 90/10) flow rate: 80 mL/min detection: UV (220 nm) temperature: 30⁰C retention time: 35 min [0273] Reference Example 7 methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate

1000[0274]

1001Methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l-benzofuran-3- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (10.3 g) was separated by HPLC to give the title compound (4.38 g, 99.8%d.e., recovery rate 85%) as a white solid.

1002¹H NMR (300 MHz, CDCl₃) δ 2.57 (IH, dd, J = 16.7, 9.1 Hz), 2.65-2.82 (IH, m) , 3.60-3.94 (4H, m) , 4.14-4.38 (IH, m) , 4.54-4.87 (3H, m) , 5.89-6.07 (IH, m) , 6.35-6.49 (IH, m) , 6.56-7.18 (3H, m) , 7.28-7.45 (2H, m) . (high performance liquid chromatography conditions) column: CHIRALPAK AD (manufactured by Daicel Chemical Industries, Ltd.) mobile phase: hexane/isopropyl alcohol (volume ratio: 90/10) flow rate: 80 mL/min detection: UV (220 ran) temperature: 30°C retention time: 43 min [0275]

1003Alternatively, to methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l- benzofuran-3-yl) (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (145 g) was added diisopropyl ether

1004(1.0 L), and the mixture was stirred at 95°C for 1 hr. The mixture was allowed to cool to precipitate a white solid, which was collected by filtration. The obtained solid was recrystallized from diisopropyl ether (1.0 L) to give the title compound (40.6 g, 99.9%d.e.) as a white solid. The obtained crystals were applied to single crystal automatic X ray structure analyzer R-AXIS RAPID (manufactured by Rigaku Corporation, measurement temperature: -173°C) to determine the absolute configuration of the title compound as S, S.

1005[0276]

1006Reference Example 8 methyl { (3S)-6-[{ (3S) -7- [ (2R, 6S) -2, 6-dimethylmorpholin-4-yl] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-1-benzofuran-3-yl } acetate

1007[0277]

1008To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (200 mg, 0.400 mmol), (2R,6S)-2,6- dimethylmorpholine (98.5 μL, 0.800 mmol) and cesium carbonate

1009(261 mg, 0.800 mmol) in toluene (2 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0)

1010(14.7 mg, 0.016 mmol) and 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene (18.5 mg, 0.032 mmol), and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (168 mg, yield 79%) as a yellow oil. MS m/z 535 (M + H)⁺.

1011[0278]

1012Reference Example 9 methyl [ (3S) -6-{ [ (3S) -7- (piperidin-1-yl) -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate

1013[0279]

1014To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (200 mg, 0.400 mmol), piperidine

1015(79.3 μL, 0.800 mmol) and cesium carbonate (261 mg, 0.800 mmol) in toluene (2 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (14.7 mg, 0.016 mmol) and (R) -(+) -2, 2' -bis (diphenylphosphino) -1, 1' -binaphthyl

1016(19.9 mg, 0.032 mmol), and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (67.5 mg, yield 33%) as a pale-yellow oil.

1017MS m/z 505 (M + H)⁺. [0280] Reference Example 10 methyl [ (3S) -6-{ [ (3S) -7- (2, 6-dimethyl-4-{ [ (2S) -5- oxopyrrolidin-2-yl]methoxy}phenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate

1018[0281]

1019To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (6.00 g, 12.0 mmol) , [4-

1020(methoxymethoxy) -2, 6-dimethylphenyl]boronic acid (3.02 g, 14.4 mmol) and 2 M aqueous sodium carbonate solution (18.0 mL, 36.0 mmol) in toluene (40 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (439 mg, 0.480 mmol) and dicyclohexyl (2' , 6' -dimethoxybiphenyl-2-yl) phosphane (788 mg, 1.92 mmol) and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1021(hexane: ethyl acetate = 95:5 - 70:30) to give a yellow oil

1022(7.65 g) . To a solution of the obtained oil (7.65 g) in methanol (40 mL) was added 10% hydrogen chloride containing methanol solution (3.8 mL) , and the mixture was stirred at 40⁰C for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, diluted with distilled water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give methyl [(3S)- 6-{ [ (3S)-7-(4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (6.47 g) as a white solid. To a solution of the obtained white solid (3.0O g, 5.54 mmol) and [ (2S) -5-oxopyrrolidin-2-yl] methyl 4-methylbenzenesulfonate

1023(1.94 g, 7.20 irimol) in N,N-dimethylformamide (18 mL) was added tripotassium phosphate (1.76 g, 8.31 mmol) , and the mixture was stirred at 80°C for 3 hr. Then, [ (2S) -5-oxopyrrolidin-2- yl]methyl 4-methylbenzenesulfonate (448 mg) and tripotassium phosphate (470 mg) were added, and the mixture was stirred at 80⁰C for 1 hr. The reaction mixture was neutralized with aqueous ammonium chloride solution, diluted with distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1024(hexane:ethyl acetate = 95:5 - 20:80) to give the title compound (2.92 g, yield 82%) as a white solid. MS m/z 639 (M + H)⁺.

1025[0282]

1026Reference Example 11 methyl { (3S) -6- [ {7- [ (2-aminophenyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate

1027[0283]

1028To a solution of methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l- benzofuran-3-yl) (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (2.00 g, 4.00 mmol), 2-nitroaniline

1029(607 mg, 4.40 mmol) and tripotassium phosphate (1.70 g, 8.00 mmol) in toluene (20 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (183 mg, 0.200 mmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2-yl) biphenyl-2- yl]phosphane (191 mg, 0.400 mmol), and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 67:33) to give an orange solid (2.26 g) . The obtained solid (2.26 g) was dissolved in methanol (20 mL) and tetrahydrofuran (2 mL) , 10% palladium-carbon (50% water-containing product, 226 mg) was added, and the mixture was stirred under a hydrogen atmosphere

1030(balloon pressure) at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanerethyl acetate = 95:5 - 60:40) to give the title compound (1.97 g, yield 93%) as a yellow solid. MS m/z 528 (M + H)⁺.

1031[0284]

1032Reference Example 12 methyl [ (3S) -6-{ [7- (2-methyl-lH-benzimidazol-l-yl) -2,3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate

1033[0285]

1034A solution of methyl { (3S) -6- [ { 7- [ (2-aminophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2,3- dihydro-l-benzofuran-3-yl} acetate (1.97 g, 3.73 mmol) and acetic anhydride (2.82 mL, 29.9 mmol) in acetic acid (12 mL) was stirred overnight at 130⁰C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and diluted with distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1035(hexane: ethyl acetate = 95:5 - 40:60) and HPLC to give the title compound (1.52 g, yield 74%) as a white solid. MS m/z 552 (M + H)⁺.

1036[0286]

1037Reference Example 13 methyl [ (3S) -6-{ [ (3S) -7- (2-methyl-lH-benzimidazol-l-yl) -2,3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate

1038[0287] Methyl [ ( 3S ) -6- { [7- ( 2-methyl-lH-benzimidazol-l-yl ) -2 , 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (1.51 g) was resolved by HPLC to give the title compound (647 mg, recovery rate 86%) as a white solid.

1039MS m/z 552 (M + H)⁺.

1040(high performance liquid chromatography conditions) column: CHIRALPAK IC (manufactured by Daicel Chemical Industries, Ltd.) mobile phase: hexane/ethanol/diethylamine (volume ratio: 500/500/1) flow rate: 60 mL/min detection: UV (220 run) temperature: 40°C retention time: 11.4 min (>99%) . [0288] Reference Example 14 methyl [ (3S)-6-{ [ (3R) -7- (2-methyl-lH-benzimidazol-l-yl) -2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate [0289]

1041Methyl [ (3S) -6-{ [7- (2-methyl-lH-benzimidazol-l-yl) -2,3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (1.51 g) was resolved by HPLC to give the title compound (684 mg, recovery rate 90%) as a solid. MS m/z 552 (M + H)⁺.

1042(high performance liquid chromatography conditions) column: CHIRALPAK IC (manufactured by Daicel Chemical Industries, Ltd.) mobile phase: hexane/ethanol/diethylamine (volume ratio: 500/500/1) flow rate: 60 mL/min detection: UV (220 run) temperature: 40⁰C retention time: 13.8 min (98%) [ 0290 ]

1043Reference Example 15 methyl { (3S) -6- [ { (3R) -7- [ (2-aminophenyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0291]

1044To a solution of methyl [ (3S) -6-{ [ (3R) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- 1-benzofuran-3-yl] acetate (1.00 g, 2.00 mmol) , 2-nitroaniline (304 mg, 2.20 mmol) and tripotassium phosphate (849 mg, 4.00 mmol) in toluene (10 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (91.6 mg, 0.100 mmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2-yl) biphenyl-2- yl]phosphane (95.3 mg, 0.200 mmol), and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give an orange non-crystalline powder (1.19 g) . The obtained non-crystalline powder (1.19 g) was dissolved in methanol (10 mL) , 10% palladium-carbon (50% water-containing product, 120 mg) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (973 mg, yield 92%) as a white solid. MS m/z 528 (M + H)⁺. [0292]

1045Reference Example 16 methyl [ (3S) -6-{ [ (3R) -7- (2-ethyl-lH-benzimidazol-l-yl) -2,3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate [0293] A solution of methyl { (3S) -6- [{ (3R) -7- [ (2- aminophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (300 mg, 0.569 mmol) in N,N-dimethylacetamide (3 mL) was ice-cooled, and propanoyl chloride (59.6 μL, 0.682 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (2 mL) was stirred overnight at 140⁰C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give the title compound (231 mg, yield 72%) as a white solid. MS m/z 566 (M + H)⁺. [0294]

1046Reference Example 17 methyl [ (3S) -6-{ [ (3R) -7- (2-ethoxy-lH-benzimidazol-l-yl) -2,3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate [0295]

1047A solution of methyl { (3S) -6- [ { (3R) -7- [ (2- aminophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (300 mg, 0.569 mmol) and tetraethoxymethane (357 μL, 1.71 mmol) in acetic acid (3 mL) was stirred at 60⁰C for 30 min. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give the title compound (284 mg, yield 86%) as a colorless oil. MS m/z 582 (M + H)⁺. [0296]

1048Reference Example 18 methyl { (3S) -6- [ { (3R) -7- [ (5-fluoro-2-nitrophenyl) amino] -2,3- dihydro-l-benzofύran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0297]

1049To a solution of methyl [ (3S) -6-{ [ (3R) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (1.00 g, 2.00 mmol) and 5-fluoro-2- nitroaniline (343 mg, 2.20 mmol) and tripotassium phosphate (849 mg, 4.00 mmol) in toluene (10 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (91.6 mg, 0.100 mmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2- yl)biphenyl-2-yl]phosphane (95.3 mg, 0.200 mmol) and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (1.16 g, yield 100%) as an orange non-crystalline powder. MS m/z 574 (M - H)^". [0298]

1050Reference Example 19 methyl { (3S) -6-[{ (3R) -7-[ (2-amino-5-fluorophenyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0299] Methyl { (3S) -6- [ { (3R) -7- [ (5-fluoro-2-nitrophenyl) amino] -

10512, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} acetate (2.00 mmol) was dissolved in methanol (10 mL) , 10% palladium-carbon (50% water-containing product, 120 mg) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 2 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (935 mg, yield 86%) as a pale-pink solid. MS m/z 546 (M + H)⁺. [0300]

1052Reference Example 20 methyl [ (3S) -6-{ [ (3R) -7- (2-ethyl-6-fluoro-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate [0301]

1053In the same manner as in Reference Example 16, the title compound (249 mg, yield 78%) was obtained as a white solid from methyl { (3S) -6- [ { (3R) -7- [ (2-amino-5-fluorophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2,3- dihydro-l-benzofuran-3-yl }acetate (300 mg, 0.550 mmol) and propanoyl chloride (57.6 μL, 0.660 mmol). MS m/z 584 (M + H)⁺. [0302] Reference Example 21 methyl [ (3S) -6-{ [ (3R) -7- (2-ethoxy-6-fluoro-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate [0303]

1054In the same manner as in Reference Example 17, the title compound (281 mg, yield 85%) was obtained as a white solid from methyl { (3S) -6- [ { (3R) -7- [ (2-amino-5-fluorophenyl) amino] - 2 , 3-dihydro-l-benzofuran-3-yl } (trifluoroacetyl ) amino] -2 , 3- dihydro-l-benzofuran-3-yl}acetate (300 mg, 0.550 mmol) and tetraethoxymethane (345 μL, 1.65 mmol). MS m/z 600 (M + H)⁺. [0304] Reference Example 22 methyl { (3S) -6- [ { (3S) -7- [ (2-aminophenyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0305]

1055In the same manner as in Reference Example 15, the title compound (553 mg, yield 100%) was obtained as pink crystals from methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (500 mg, 1.00 mmol) and 2-nitroaniline (152 mg, 1.10 mmol) . MS m/z 528 (M + H)⁺. [0306]

1056Reference Example 23 methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-lH-benzimidazol-l-yl) -2,3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- 1-benzofuran-3-yl] acetate [0307]

1057In the same manner as in Reference Example 16, the title compound (177 mg, yield 100%) was obtained as a white solid from methyl { (3S) -6- [{ (3S) -7- [ (2-aminophenyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl} acetate (160 mg, 0.303 mmol) and propanoyl chloride (31.8 μL, 0.364 mmol). MS m/z 566 (M + H)⁺. [0308]

1058Reference Example 24 methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy-lH-benzimidazol-l-yl) -2,3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino } -2, 3-dihydro- 1-benzofuran-3-yl] acetate [0309] In the same manner as in Reference Example 17, the title compound (163 mg, yield 92%) was obtained as a white solid from methyl { (3S) -6- [ { (3S) -7- [ (2-aminophenyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- l-benzofuran-3-yl} acetate (160 mg, 0.303 mmol) and tetraethoxymethane (190 μL, 0.909 mmol). MS m/z 582 (M + H)⁺. [0310]

1059Reference Example 25 methyl { (3S)-6-[{ (3S) -7- [ (2-amino-5-fluorophenyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0311]

1060To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (5.00 g, 10.0 mmol), 5-fluoro-2- nitroaniline (1.87 g, 12.0 mmol) and tripotassium phosphate (4.25 g, 20.0 mmol) in toluene (50 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (458 mg. 0.500 mmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2- yl)biphenyl-2-yl]phosphane (476 mg, 1.00 mmol), and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a red dark oil (6.63 g) . The obtained oil (6.63 g) was dissolved in methanol (50 mL) and tetrahydrofuran (25 mL) , 10% palladium-carbon (50% water- containing product, 1.15 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 5 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give the title compound (4.94 g, yield 91%) as a purple solid. MS m/ z 546 (M + H ) ⁺ .

1061[0312] Reference Example 26 methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-6-fluoro-lH-benzimidazol-1- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate [0313]

1062In the same manner as in Reference Example 16, the title compound (147 mg, yield 80%) was obtained as a white solid from methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5-fluorophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-l-benzofύran-3-yl}acetate (160 mg, 0.293 mmol) and propanoyl chloride (30.7 μL, 0.352 mmol). MS m/z 584 (M + H)⁺. [0314]

1063Reference Example 27 methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy-6-fluoro-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3- dihydro-l-benzofuran-3-yl] acetate [0315]

1064A solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (3.00 g, 5.50 mmol) and tetraethoxymethane (3.45 mL, 16.5 mmol) in acetic acid (28 mL) was stirred at 8O⁰C for 2 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40), and triturated with hexane-ethyl acetate to give the title compound (2.49 g, yield 75%) as a pale-yellow solid. MS m/ z 600 (M + H) ⁺ .

1065[0316] Reference Example 28 methyl { (3S) -6- [ { (3S) -7- [ (4, 5-difluoro-2-nitrophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2,3- dihydro-1-benzofuran-3-yl } acetate [0317]

1066In the same manner as in Reference Example 18, the title compound (370 mg, yield 100%) was obtained as an orange oil from methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (300 mg, 0.600 iranol) and 4, 5-difluoro-2- nitroaniline (115 mg, 0.660 mmol) . MS m/z 592 (M - H)^". [0318]

1067Reference Example 29 methyl { (3S) -6- [ { (3S) -7- [ (2-amino-4, 5-difluorophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-1-benzofuran-3-yl } acetate [0319]

1068In the same manner as in Reference Example 19, the title compound (302 mg, yield 89%) was obtained as a purple oil from methyl { (3S)-6-[{ (3S) -7- [ (4, 5-difluoro-2-nitrophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2,3- dihydro-1-benzofuran-3-yl} acetate (0.600 mmol). MS m/z 564 (M + H)⁺. [0320]

1069Reference Example 30 methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-5, 6-difluoro-lH-benzimidazol- 1-yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} - 2, 3-dihydro-l-benzofuran-3-yl] acetate [0321]

1070In the same manner as in Reference Example 16, the title compound (130 mg, yield 81%) was obtained as a colorless oil from methyl { (3S)-6-[{ (3S) -7- [ (2-amino-4, 5- difluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (151 mg, 0.267 mmol) and propanoyl chloride (28.0 μL, 0.321 mmol) . MS m/z 602 (M + H)⁺. [0322]

1071Reference Example 31 methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy-5, 6-difluoro-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate [0323]

1072In the same manner as in Reference Example 17, the title compound (98.6 mg, yield 60%) was obtained as a pale-pink solid from methyl { (3S) -6- [ { (3S) -7- [ (2-amino-4, 5- difluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (151 mg, 0.267 mmol) and tetraethoxymethane (168 μL, 0.802 mmol) . MS m/z 618 (M + H)⁺. [0324]

1073Reference Example 32 methyl { (3S) -6- [ { (3S) -7- [ (2, 3-difluoro-6-nitrophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2,3- dihydro-1-benzofuran-3-yl } acetate [0325]

1074To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (5.00 g, 10.0 mmol), 2, 3-difluoro-6- nitroaniline (2.09 g, 12.0 mmol) and tripotassium phosphate (4.25 g, 20.0 mmol) in toluene (50 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (459 mg, 0.500 mmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2- yl)biphenyl-2-yl]phosphane (477 mg, 1.00 mmol), and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (5.41 g, yield 91%) as an orange oil. MS m/z 592 (M - H)^". [0326]

1075Reference Example 33 methyl { (3S)-6-[{ (3S) -7- [ (β-amino-2, 3-difluorophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-1-benzofuran-3-yl }acetate [0327]

1076Methyl { (3S)-6-[{ (3S) -7- [ (2, 3-difluoro-6- nitrophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (5.41 g, 9.12 mmol) was dissolved in methanol (50 itiL) and tetrahydrofuran (25 mL) , 10% palladium-carbon (50% water-containing product, 1.08 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 20:80) to give the title compound (4.50 g, yield 88%) as a black solid. MS m/z 564 (M + H)⁺. [0328]

1077Reference Example 34 methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-6, 7-difluoro-lH-benzimidazol- 1-yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}- 2, 3-dihydro-l-benzofuran-3-yl] acetate [0329]

1078A solution of methyl { (3S) -6- [ { (3S) -7- [ (6-amino-2, 3- difluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (3.50 g, 6.21 mmol) in N,N-dimethylacetamide (31 mL) was ice-cooled, and propanoyl chloride (0.651 ITLL, 7.45 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hr, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (20 mL) was stirred overnight at 130⁰C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give the title compound (3.72 g, yield 100%) as a yellow oil. MS m/z 602 (M + H)⁺.

1079[0330]

1080Reference Example 35 methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy-6, 7-difluoro-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate

1081[0331]

1082A solution of methyl { (3S) -6- [ { (3S) -7- [ (6-amino-2, 3- difluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (2.25 g, 4.00 mmol) and tetraethoxymethane (2.51 mL, 12.0 mmol) in acetic acid (20 mL) was stirred at 60⁰C for 2 hr. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) and basic silica gel column chromatography

1083(hexane: ethyl acetate = 95:5 - 40:60) to give the title compound (1.87 g, yield 76%) as a yellow oil. MS m/z 618 (M + H)⁺.

1084[0332]

1085Reference Example 36 methyl { (3S)-6-[{ (3S) -7- [ (3, 5-difluoro-2-nitrophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-1-benzofuran-3-yl }acetate

1086[0333]

1087To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (5.00 g, 10.0 mmol) and 3,5- difluoro-2-nitroaniline (2.09 g, 12.0 mmol) and tripotassium phosphate (4.25 g, 20.0 mmol) in toluene (50 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (458 mg, 0.500 mmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2-yl) biphenyl-2- yl]phosphane (477 mg, 1.00 mmol), and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (6.64 g, yield 100%) as a red orange oil. MS m/z 592 (M - H)^".

1088[0334]

1089Reference Example 37 methyl { (3S) -6- [ { (3S) -7- [ (2-amino-3, 5-difluorophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-1-benzofuran-3-yl } acetate

1090[0335]

1091Methyl { (3S) -6- [ { (3S) -7- [ (3, 5-difluoro-2- nitrophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (10.0 mmol) was dissolved in methanol (50 itiL) and tetrahydrofuran (25 mL) , 10% palladium-carbon (50% water- containing product, 1.33 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) and triturated with hexane-toluene to give the title compound (4.49 g, yield 80%) as a pale-orange solid.

1092MS m/z 564 (M + H)⁺. [0336]

1093Reference Example 38 methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-4, 6-difluoro-lH-benzimidazol- 1-yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino }- 2, 3-dihydro-l-benzofuran-3-yl] acetate [0337]

1094A solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-3, 5- difluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (122 mg, 0.216 mmol) in N,N-dimethylacetamide (1 mL) was ice-cooled, and propanoyl chloride (22.6 μL, 0.259 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (1 mL) was stirred overnight at 140⁰C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give the title compound (106 mg, yield 82%) as a colorless oil. MS m/z 602 (M + H)⁺. [0338]

1095Reference Example 39 methyl { (3S)-6-[{ (3S) -7- [6-fluoro-2- (tetrahydro-2H-pyran-4- yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl }acetate [0339]

1096To a solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (150 mg, 0.275 mmol) and tetrahydro-2H-pyran-4- carboxylic acid (37.6 mg, 0.289 mmol) in tetrahydrofuran (1.4 mL) were added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (63.3 mg, 0.330 mmol) and 1-hydroxybenzotriazole monohydrate (50.5 mg, 0.330 mmol). The reaction mixture was stirred overnight at room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (1.4 mL) was stirred overnight at 13O⁰C. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 30:70) to give the title compound (106 mg, yield 60%) as a pale-yellow solid. MS m/ z 640 (M + H) ⁺ .

1097[0340] Reference Example 40 methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy-4, 6-difIuoro-1H- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate

1098[0341]

1099A solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-3, 5- difluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (3.0O g, 5.32 mmol) and tetraethoxymethane (3.35 mL, 16.0 mmol) in acetic acid (27 mL) was stirred at 60°C for 3 hr. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) and triturated with hexane to give the title compound (2.04 g, yield 62%) as a pale-orange solid. MS m/z 618 (M + H)⁺.

1100[0342]

1101Reference Example 41 methyl { (3S) -6- [ { (3S) -7- [ (5-methoxy-2-nitrophenyl) amino] -2, 3- dihydro-l-benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate

1102[0343]

1103To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino } -2, 3-dihydro- l-benzofuran-3-yl] acetate (150 mg, 0.300 mmol) and 5-methoxy- 2-nitroaniline (55.5 mg, 0.330 mmol) and tripotassium phosphate (127 mg, 0.600 mmol) in toluene (1.5 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (13.7 mg, 0.015 inmol) and dicyclohexyl [2' , 4' , 6' -tri (propan-2-yl) biphenyl-2- yl]phosphane (14.3 mg, 0.030 iranol), and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (181 mg, yield 100%) as a yellow oil. MS m/z 588 (M + H)⁺. [0344]

1104Reference Example 42 methyl { (3S)-6-[{ (3S) -7- [ (2-amino-5-methoxyphenyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0345]

1105Methyl { (3S)-6-[{ (3S) -7- [ (5-methoxy-2-nitrophenyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} acetate (0.300 mmol) was dissolved in methanol (1.5 mL) and tetrahydrofuran (0.8 mL) , 10% palladium-carbon (50% water-containing product, 36.0 mg) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 3 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give the title compound (133 mg, yield 79%) as a pale-brown oil.

1106MS m/z 558 (M + H)⁺. [0346]

1107Reference Example 43 methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-6-methoxy-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3- dihydro-1-benzofuran-3-yl] acetate [0347]

1108A solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- methoxyphenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (133 mg, 0.238 mmol) in N,N-dimethylacetamide (1.2 mL) was ice-cooled, and propanoyl chloride (25.0 μL, 0.286 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added acetic acid (1 mL) , and the mixture was stirred at 140⁰C overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give the title compound (101 mg, yield 71%) as a colorless oil. MS m/z 596 (M + H)⁺. [0348]

1109Reference Example 44 methyl { (3S) -6- [ { (3S) -7- [6-fluoro-2- (propan-2-yl) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate [0349]

1110A solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (160 mg, 0.293 mmol) in N,N-dimethylacetamide (1.5 mL) was ice-cooled, and 2-methylpropanoyl chloride (37.5 mg, 0.352 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 20 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (1 mL) was stirred overnight at 140°C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove acetic acid, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give the title compound (134 mg, yield 76%) as a pale-yellow oil. MS m/z 598 (M + H)⁺. [0350]

1111Reference Example 45 methyl { (3S)-6-[{ (3S) -7- [6-fluoro-2- (tetrahydro-2H-pyran-4- yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate [0351]

1112To a solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (150 mg, 0.275 mmol) and tetrahydro-2H-pyran-4- carboxylic acid (37.6 mg, 0.289 mmol) in tetrahydrofuran (1.4 mL) were added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (63.3 mg, 0.330 mmol) and 1-hydroxybenzotriazole monohydrate (50.5 mg, 0.330 mmol). The reaction mixture was stirred overnight at room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (1.4 mL) was stirred overnight at 130⁰C. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 30:70) to give the title compound (106 mg, yield 60%) as a pale-yellow solid. MS m/z 640 (M + H)⁺. [0352]

1113Reference Example 46 methyl { (3S)-6-[{ (3S) -7- [6-fluoro-2- (5-methylfuran-2-yl) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate [0353]

1114To a solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (150 mg, 0.275 mmol) and 5-methylfuran-2-carboxylic acid (36.4 mg, 0.289 mmol) in tetrahydrofuran (1.4 mL) were added N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (63.3 mg, 0.330 mmol) and 1-hydroxybenzotriazole monohydrate (50.5 mg, 0.330 mmol). The reaction mixture was stirred overnight at room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (1.4 mL) was stirred overnight at 130°C. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =

111595:5 - 40:60) to give the title compound (116 mg, yield 66%) as a pale-yellow oil. MS m/z 636 (M + H)⁺.

1116[0354]

1117Reference Example 47 methyl { (3S)-6-[{ (3S) -7- [6-fluoro-2- (5-methylisoxazol-3-yl) - lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate

1118[0355]

1119A solution of methyl { (3S) -6- [ { (3S) -7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (150 mg, 0.275 mmol) in N,N-dimethylacetamide (1.4 mL) was ice-cooled, and 5-methylisoxazole-3-carbonyl chloride

1120(48.0 mg, 0.330 mmol) was added dropwise. The reaction mixture was stirred at 0⁰C for 20 min, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained residue in acetic acid (1 mL) was stirred overnight at 120⁰C. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give the title compound (104 mg, yield 60%) as a white solid. MS m/z 637 (M + H)⁺.

1121[0356]

1122Reference Example 48 methyl { (3S) -6-[{7-[ (4-methyl-2-nitrophenyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-

11231-benzofuran-3-yl } acetate

1124[0357]

1125To a mixture of methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l- benzofuran-3-yl) (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (1.63 g, 3.26 mmol) , 4-methyl-2- nitroaniline (0.545 g, 3.58 mmol) and tripotassium phosphate

1126(1.38 g, 6.52 mmol) in toluene (15 ml) were added tris (dibenzylideneacetone)dipalladium (0) (0.149 g, 0.163 mmol) and 2-dicyclohexylphosphino-2' , 4' , 6' - triisopropylbiphenyl (0.155 g, 0.326 mmol), and the mixture was stirred under an argon atmosphere at 100°C for 13 hr. To the reaction mixture were added water and ethyl acetate, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 5:95-40:60) to give the title compound (1.68 g, yield 90%) as a red-brown viscous oil. MS m/z 572 (M + H)⁺.

1127[0358]

1128Reference Example 49 methyl { (3S) -6- [ {7- [ (2-amino-4-methylphenyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate

1129[0359]

1130Methyl { (3S)-6-[{7-[ (4-methyl-2-nitrophenyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl} acetate (1.68 g, 2.94 mmol) was dissolved in a mixed solution of methanol (10 mL) and tetrahydrofuran (5 mL) , 10% palladium-carbon (50% water-containing product, 0.3 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 21 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 20:80-70:30) to give the title compound (1.38 g, yield 87 %) as a yellow viscous oil. MS m/z 542 (M + H)⁺.

1131[0360]

1132Reference Example 50 methyl [ (3S)-6-{ [7- (2, 5-dimethyl-lH-benzimidazol-l-yl) -2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate

1133[0361]

1134A solution of methyl (3S) -6- [ {7- [ (2-amino-4- methylphenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (1.38 g, 2.55 mmol) and acetic anhydride (2 mL, 21.2 mmol) in acetic acid (8 mL) was heated under reflux for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 40:60-100:0), then preparative HPLC to give the title compound (1.09 g, yield 76 %) as a pale-yellow foam. MS m/z 566 (M + H)⁺.

1135[0362]

1136Reference Example 51 methyl { (3S) -6- [ {7- [ (5-fluoro-2-nitrophenyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate

1137[0363]

1138In the same manner as in Reference Example 48, the title compound was obtained as a brown viscous oil from methyl

1139{ (3S) -6- [ (7-bromo-2, 3-dihydro-l-benzofuran-3- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate and 5-fluoro-2-nitroaniline. yield 97%. MS (ESI-) m/z 574 (M - H)^". [0364] Reference Example 52 methyl { (3S)-6-[{7-[ (2-amino-5-fluorophenyl) amino] -2,3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0365]

1140Methyl { (3S)-6-[{7-[ (5-fluoro-2-nitrophenyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl} acetate (0.676 g, 1.175 mmol) was dissolved in a mixed solution of methanol (4 mL) and tetrahydrofuran (2 mL) , 10% palladium-carbon (50% water-containing product, 0.2 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 22 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 20:80-70:30) to give the title compound (0.483 g, yield 75 %) as a purple viscous oil. MS m/z 546 (M + H)⁺. [0366]

1141Reference Example 53 methyl [ (3S) -6-{ [7- (6-fluoro-2-methyl-lH-benzimidazol-l-yl) - 2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3- dihydro-1-benzofuran-3-yl] acetate [0367]

1142A solution of methyl { (3S) -6- [ { 7- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (0.478 g, 0.876 mmol) and acetic anhydride (1 mL, 10.6 mmol) in acetic acid (4 mL) was heated under reflux for 24 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 40:60-100:0), then preparative HPLC to give the title compound (0.434 g, yield 87 %) as a yellow viscous oil. MS m/z 570 (M + H)⁺. [0368]

1143Reference Example 54 methyl [ (3S) -6-{ [ (3S) -7- (6-fluoro-2-methyl-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3- dihydro-l-benzofuran-3-yl] acetate and methyl [ (3S) -6-{ [ (3R) -7- ( 6-fluoro-2-methyl-lH-benzimidazol-l-yl) -2 , 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate [0369]

1144Methyl [ (3S) -6-{ [7- (6-fluoro-2-methyl-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3- dihydro-l-benzofuran-3-yl] acetate was purified under the following conditions of high performance liquid chromatography to give methyl [ (3S) -6-{ [ (3S) -7- (6-fluoro-2-methyl-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (0.309 g, yield 43%) with an enantiometric excess of 99.9% and methyl [ (3S) -6-{ [ (3R) -7- (6-fluoro-2-methyl-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (0.317 g, yield 44%) with an enantiometric excess of 99.8%.

1145(high performance liquid chromatography conditions) column: CHIRALCEL OJ (manufactured by Daicel Chemical Industries, Ltd.) mobile phase: n-hexane/ethanol (volume ratio: 20/80) flow rate: 30 mL/min detection: UV (220 ran) temperature: 30⁰C [0370] Reference Example 55 methyl { (3S) -6- [ { (3S) -7- [ (5-fluoropyridin-2-yl) amino] -2,3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate

1146[0371]

1147A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.200 g, 0.400 mmol) , 5- fluoropyridin-2-amine (53.8 mg, 0.480 mmol) and cesium carbonate (0.261 g, 0.800 mmol) in toluene (4 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (14.6 mg, 0.0160 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

1148(18.5 mg, 0.0320 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1149(hexane: ethyl acetate = 95:5 - 65:35) to give the title compound (0.186 mg, yield 88%) as a brown oil. MS m/z 532 (M + H)⁺.

1150[0372]

1151Reference Example 56 4- (4, 6-dimethylpyrimidin-2-yl)morpholine

1152[0373]

1153A mixed solution of 2-chloro-4, 6-dimethylpyrimidine (3.00 g, 21.0 mmol) and morpholine (15 mL) was stirred using microwave (Biotage Initiator™ 60) at 21O⁰C for 10 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (3.74 g, yield

115492%) as a pale-yellow solid.

1155¹H NMR (300 MHz, CDCl₃) δ 2.29 (6H, s) , 3.67-3.87 (8H, m) , 6.30 (IH, s). [0374]

1156Reference Example 57

11574- (5-bromo-4, 6-dimethylpyrimidin-2-yl)morpholine [0375]

1158To a solution of 4- (4, 6-dimethylpyrimidin-2-yl)morpholine (10.7 g, 55.6 mmol) in ethyl acetate (80 mL) was added N- bromosuccinimide (10.1 g, 55.6 mmol) at room temperature, and the mixture was heated under reflux for 5 min. The reaction mixture was diluted with 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (14.7 g, yield 97%) as a pale-yellow solid. 1H NMR (300 MHz, CDCl₃) δ 2.45 (6H, s) , 3.69-3.81 (8H, m) . [0376]

1159Reference Example 58

1160(4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) boronic acid [0377]

1161To a solution of 4- (5-bromo-4, 6-dimethylpyrimidin-2- yl)morpholine (14.7 g, 54.0 mmol) in tetrahydrofuran (140 mL) was added dropwise at -78°C a hexane solution (1.6 M, 35.4 mL, 56.7 mmol) of n-butyllithium. The reaction mixture was stirred at the same temperature for 40 min, triisopropyl borate (24.8 mL, 108 mmol) was added, and the mixture was heated to room temperature and stirred for 5 hr. The reaction mixture was poured into aqueous ammonium chloride solution, the mixture was stirred for 4 hr and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue was added diisopropyl ether, and the resulting precipitate was collected by filtration, and dried to give the title compound (7.42 g, yield 58%) as a pale-yellow solid.

1162¹H NMR (300 MHz, DMSO-d₆) δ 2.25 (6H, s) , 3.52-3.73 (8H, m) , 8.19 (2H, s) . [0378] Reference Example 59 methyl [ (3S) -6-{ [ (3S) -7- (4, 6-dimethyl-2-morpholin-4- ylpyrimidin-5-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate

1163[0379]

1164Methyl [(3S)-6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl]acetate (0.450 g, 0.900 mmol) and (4, 6-dimethyl-2- morpholin-4-ylpyrimidin-5-yl)boronic acid (0.256 g, 1.08 mmol) were suspended in a mixed solution of 2 M aqueous sodium carbonate solution (1.08 mL) and toluene (6 mL) and, after argon substitution, tris (dibenzylideneacetone) dipalladium (0)

1165(32.9 mg, 0.0360 mmol) and 2-dicyclohexylphosphino-2' , 6' - dimethoxybiphenyl (60.9 mg, 0.144 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100°C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (0.551 g, yield 100%) as a pale-yellow oil. MS m/z 613 (M + H)⁺. [0380]

1166Reference Example 60

11674 , 6-dimethyl-2-pyrrolidin-l-ylpyrimidine [0381]

1168A solution of 2-chloro-4, 6-dimethylpyrimidine (2.00 g, 14.0 mmol), pyrrolidine (4 mL) and triethylamine (1.96 mL,

116914.0 mmol) in ethanol (10 mL) was stirred by microwave at 150⁰C for 10 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (2.20 g, yield 88%) as a pale-yellow solid.

1170¹H NMR (300 MHz, CDCl₃) δ 1.87-2.01 (4H, m) , 2.29 (6H, s) ,

11713.51-3.65 (4H, m) , 6.23 (IH, s) .

1172MS m/z 178 (M + H)⁺.

1173[0382]

1174Reference Example 61 5-bromo-4 , 6-dimethyl-2-pyrrolidin-l-ylpyrimidine

1175[0383]

1176To a solution of 4, 6-dimethyl-2-pyrrolidin-l-ylpyrimidine

1177(2.20 g, 12.4 iranol) in chloroform (10 mL) was added N- bromosuccinimide (2.25 g, 12.4 mmol) at room temperature and the mixture was heated under reflux for 5 min. The reaction mixture was diluted with 1 M sodium hydroxide, and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1178(hexane:ethyl acetate = 100:0 - 75:25) to give the title compound (3.00 g, yield 94%) as a white solid.

1179¹H NMR (300 MHz, CDCl₃) δ 1.88-2.01 (4H, m) , 2.45 (6H, s) ,

11803.46-3.58 (4H, m) .

1181MS m/z 256 (M + H)⁺.

1182[0384] Reference Example 62

1183(4, 6-dimethyl-2-pyrrolidin-l-ylpyrimidin-5-yl) boronic acid

1184[0385]

1185To a solution of 5-bromo-4, 6-dimethyl-2-pyrrolidin-l- ylpyrimidine (1.52 g, 5.93 mmol) in tetrahydrofuran (20 mL) was added dropwise at -78°C a hexane solution (1.6 M, 3.89 mL, 6.23 mmol) of n-butyllithium. The reaction mixture was stirred at the same temperature for 40 min, triisopropyl borate (2.72 mL, 11.9 mmol) was added, and the mixture was heated to room temperature and stirred for 5 hr. The reaction mixture was poured into aqueous ammonium chloride solution, and the mixture was stirred for 4 hr and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hexane and diisopropyl ether to give the title compound (0.766 g, yield 58%) as a white solid. MS m/z 222 (M + H)⁺. [0386]

1186Reference Example 63 methyl [ (3S) -6-{ [ (3S) -7- (4, 6-dimethyl-2-pyrrolidin-l- ylpyrimidin-5-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate [0387]

1187In the same manner as in Reference Example 59, the title compound was obtained as a pale-yellow non-crystalline powder from methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate and (4, 6-dimethyl-2-pyrrolidin-l-ylpyrimidin-5- yl)boronic acid, yield 96%. MS m/z 597 (M + H)⁺. [0388]

1188Reference Example 64 methyl [ (3S) -6-{ [ (3S) -7-anilino-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate [0389]

1189A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (0.170 g, 0.339 mmol) , aniline (57.0 mL, 0.0270 mmol) and cesium carbonate (0.221 g, 0.678 mmol) in toluene (4 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (12.4 mg, 0.0140 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (15.7 mg, 0.0270 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (0.167 mg, yield 96%) as a yellow solid. MS m/z 513 (M + H)⁺. [0390]

1190Reference Example 65 methyl { (3S)-6-[{ (3S) -7- [ethyl (phenyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0391]

1191To a solution of methyl [ (3S) -6-{ [ (3S) -7-anilino-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (0.167 g, 0.325 mmol) and ethyl iodide (51.0 μg, 0.488 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 15.6 mg, 0.390 mmol) at 0⁰C, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 75:25) to give the title compound (71.9 mg, yield 41%) as a pale-yellow oil. MS m/z 541 (M + H)⁺. [0392]

1192Reference Example 66 methyl { (3S)-6-[{ (3S) -7- [ (4-methylpyridin-2-yl) amino] -2, 3- dihydro-l-benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0393]

1193A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (7.00 g, 14.0 mmol), 4-methylpyridin- 2-amine (1.82 g, 16.8 πunol) and cesium carbonate (9.12 g, 28.0 mmol) in toluene (60 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (0.513 g, 0.560 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (0.648 g, 1.12 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, insoluble material was filtered off, and washed with toluene. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (1.98 g, yield 27%) as a yellow oil. MS m/z 528 (M + H)⁺. [0394]

1194Reference Example 67 methyl [ (3S) -6-{ [ (3S) -7- (2, 3-dihydro-4H-l, 4-benzooxazin-4-yl) - 2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate [0395]

1195A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (200 mg, 0.400 mmol), 3, 4-dihydro-2H- 1, 4-benzooxazine (64.8 mg, 0.480 mmol) and cesium carbonate (390 mg, 1.20 mmol) in toluene (4 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (14.6 mg, 0.0160 mmol) and 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene (18.5 mg, 0.0320 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, and the insoluble material was filtered off, and washed with toluene. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (181 ing, yield 82%) as a yellow oil.

1196MS m/z 555 (M + H)⁺. [0396] Reference Example 68

11977-bromo-2, 3-dihydro-l-benzofuran-3-amine [0397]

1198A mixed solution of 7-bromo-l-benzofuran-3 (2H) -one (0.521 g, 2.45 mmol) , 0-methylhydroxyammonium chloride (0.306 g, 3.67 mmol) and sodium acetate (0.301 g, 3.67 mmol) in methanol (12 mL) was heated under reflux for 10 hr, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated^' under reduced pressure, the residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 80:20) to give 7-bromo-l-benzofuran-3 (2H) -one O- methyloxime (0.468 g, yield 79%) as a yellow solid. To a solution of 7-bromo-l-benzofuran-3 (2H) -one O-methyloxime (0.468 g, 1.93 mmol) obtained above in tetrahydrofuran (9 mL) was slowly added dropwise borane-tetrahydrofuran solution (1 M, 5.80 mL, 5.80 mmol) at room temperature, and the mixture was heated under reflux under a nitrogen atmosphere for 3 hr. The reaction mixture was cooled, ice water was slowly added, 1 M hydrochloric acid was added, and the mixture was stirred at

11998O⁰C for 1.5 hr. The reaction mixture was allowed to cool, 28% aqueous ammonia solution was added to alkalify the solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue (0.402 g) was dissolved in diethyl ether (4 mL) , and 4 M hydrochloric acid-ethyl acetate solution (0.480 mL) was slowly added. The precipitated solid was collected by filtration, and washed with diethyl ether to give 7-bromo-2, 3-dihydro-l-benzofuran-3-amine hydrochloride (0.434 g) as a beige solid. The solid obtained above was dissolved in

120028% aqueous ammonia solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (0.366 g, yield 89%) as a yellow solid.

1201¹H NMR (300 MHz, DMSO-d₆) δ 2.15 (2H, br s), 4.05-4.16 (IH, m) , 4.58-4.72 (2H, m) , 6.78-6.87 (IH, m) , 7.28-7.38 (2H, m) .

1202[0398] Reference Example 69

1203(3S) -7- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2, 3- dihydro-l-benzofuran-3-amine

1204[0399]

1205(2R) -{ [ (3, 5-Dinitrophenyl) carbonyl] amino} (phenyl) ethanoic acid (0.181 g, 0.524 mmol) was dissolved in acetonitrile (38.5 mL) , and a solution of 7-bromo-2, 3-dihydro-l-benzofuran-3- amine (0.112 g, 0.524 mmol) in methanol (10 mL) was added. The mixed solution was stood at room temperature for 1 hr, and further stood in a refrigerator for 1 hr. The precipitated salt was collected by filtration, dried under reduced pressure at 40⁰C for 1 hr to give (3S) -7-bromo-2, 3-dihydro-l-benzofuran- 3-aminium (2R) -{[(3,5- dinitrophenyl) carbonyl] amino} (phenyl) ethanoate (0.120 g, recovery rate 41%, enantiometric excess 96.3%d.e.) as a white solid.

1206(analysis conditions) column: CHIRALCEL OD-RH (DF005) 4.6 mm ID * 150 mm L

1207(manufactured by Daicel Chemical Industries, Ltd.) mobile phase: 50 mM KPF₆ (pH 2, TFA) /acetonitrile (volume ratio: 850/150) flow rate: 1 mL/min detection: UV (220 ran) concentration: 0.25 mg/mL (water/acetonitrile = 85/15) temperature: 30⁰C injection volume: 10 μL To a solution of (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- aminium (2R) -{[(3, 5- dinitrophenyl) carbonyl] amino} (phenyl) ethanoate (0.117 g, 0.208 mmol) obtained above and triethylamine (0.290 mL, 2.08 mmol) in tetrahydrofuran (6 mL) was added di-tert-butyl bicarbonate

1208(0.0580 mL, 0.250 mmol), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with 0.1 M hydrochloric acid solution, then saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure to give a crude product

1209(0.102 g) of tert-butyl [ (3S) -7-bromo-2, 3-dihydro-l- benzofuran-3-yl] carbamate as a white solid. The obtained crude product (0.102 g) of tert-butyl [ (3S) -7-bromo-2, 3-dihydro-l- benzofuran-3-yl] carbamate and (4, 6-dimethyl-2-morpholin-4- ylpyrimidin-5-yl) boronic acid (59.2 mg, 0.250 mmol) were suspended in a mixed solution of 2 M aqueous sodium carbonate solution (0.250 mL) and toluene (4 mL) and, after argon substitution, tris (dibenzylideneacetone) dipalladium (0) (7.62 mg, 0.00833 mmol) and 2-dicyclohexylphosphino-2^f , 6' - dimethoxybiphenyl (14.1 mg, 0.0330 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 65:35) to give tert-butyl [ (3S) -7- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5- yl) -2, 3-dihydro-l-benzofuran-3-yl] carbamate (79.1 mg, yield 89% (2 steps)) as a colorless oil. tert-Butyl [ (3S) -7- (4, 6- dimethyl-2-morpholin-4-ylpyrimidin-5-yl) -2, 3-dihydro-l- benzofuran-3-yl] carbamate (79.1 mg, 0.185 mmol) obtained above was suspended in toluene (2 mL) , and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. To the residue was added sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (58.5 mg, yield 97%) as a pale-yellow oil.

1210¹H NMR (300 MHz, DMSO-d₆) δ 2.03 (3H, s) , 2.06 (3H, s) , 2.24 (2H, br s), 3.60-3.76 (8H, m) , 3.99 (IH, dd, J = 8.3, 5.3 Hz), 4.50-4.67 (2H, m) , 6.90-7.02 (2H, m) , 7.34 (IH, dd, J = 6.6, 1.7 Hz) . [0400]

1211Reference Example 70 methyl { (3S) -6-[{ (3S) -7- [ (5-chloropyrimidin-2-yl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0401]

1212A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (0.300 g, 0.6 mmol) , 5- chloropyrimidine-2-amine (0.093 g, 0.72 mmol), tris (dibenzylideneacetone)dipalladium (0) (22 mg, 0.024 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (27.8 mg, 0.048 mmol) and cesium carbonate (391 mg, 1.2 mmol) in toluene

1213(8 inL) was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (0.146 g, yield 44%) as a pale-yellow solid. MS m/z 549 (M + H)⁺. [0402]

1214Reference Example 71 methyl { (3S) -6-[{ (3S) -7- [ (4-cyano-2-fluorophenyl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [ 0403 ]

1215A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (0.300 g, 0.6 mmol) , 4-amino-3- fluorobenzonitrile (0.098 g, 0.72 mmol), tris (dibenzylideneacetone) dipalladium (0) (22 mg, 0.024 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (27.8 mg, 0.048 mmol) and cesium carbonate (391 mg, 1.2 mmol) in toluene

1216(8 mL) was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (0.160 g, yield 48%) as a solid. MS m/z 556 (M + H)⁺. [0404]

1217Reference Example 72 methyl { (3S)-6-[{ (3S) -7- [ (4-cyanophenyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0405]

1218A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (0.300 g, 0.6 mmol), 4- aminobenzonitrile (0.0851 g, 0.72 mmol), tris (dibenzylideneacetone) dipalladium (0) (22 mg, 0.024 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (27.8 mg, 0.048 mmol) and cesium carbonate (391 mg, 1.2 mmol) in toluene (8 mL) was stirred overnight under an argon atmosphere at 105⁰C. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (0.316 g, yield 98%) as a solid. MS m/z 538 (M + H)⁺. [ 0406 ]

1219Reference Example 73 methyl { (3S) -6- [ { (3S) -7- [ (3-cyanophenyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate

1220[0407]

1221A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (0.400 g, 0.8 mmol) , 3- aminobenzonitrile (0.113 g, 0.72 mmol), tris (dibenzylideneacetone)dipalladium (0) (29 mg, 0.032 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (37 mg, 0.064 mmol) and cesium carbonate (521 mg, 1.6 mmol) in toluene (8 mL) was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (0.331 g, yield 77%) as an oil. MS m/z 538 (M + H)⁺.

1222[0408]

1223Reference Example 74 methyl [ (3S) -6-{ [ (3S) -7- (pyridin-3-ylamino) -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate

1224[0409]

1225A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (0.400 g, 0.8 mmol), pyridin-3-amine

1226(90.4 mg, 0.96 mmol), tris (dibenzylideneacetone) dipalladium

1227(0) (29 mg, 0.032 mmol), 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene (37 mg, 0.064 mmol) and cesium carbonate (521 mg, 1.6 mmol) in toluene (8 mL) was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 50:50) to give the title compound (0.289 g, yield 70%) as an oil. MS m/z 514 (M + H)⁺. [0410] Reference Example 75 methyl { (3S) -6- [ { (3S) -7- [ (6-methylpyridin-3-yl) amino] -2,3- dihydro-l-benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0411]

1228A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (0.400 g, 0.8 mmol) , 6- methylpyridin-3-amine (104 mg, 0.96 mmol), tris (dibenzylideneacetone) dipalladium (0) (29 mg, 0.032 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (37 mg, 0.064 mmol) and cesium carbonate (521 mg, 1.6 mmol) in toluene (8 mL) was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 50:50) to give the title compound (0.219 g, yield 42%) as an oil.

1229MS m/z 528 (M + H)⁺. [0412]

1230Reference Example 76 methyl { (3S)-6-[{ (3S) -7- [ (6-fluoropyridin-3-yl) amino] -2, 3- dihydro-1-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- 1-benzofuran-3-yl } acetate [0413]

1231A suspension of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-1-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (0.400 g, 0.8 mmol), 6- fluoropyridin-3-amine (107 mg, 0.96 mmol), tris (dibenzylideneacetone) dipalladium (0) (29 mg, 0.032 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (37 mg, 0.064 mmol) and cesium carbonate (521 mg, 1.6 mmol) in toluene (8 inL) was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 50:50) to give the title compound (0.263 g, yield 62%) as an oil.

1232MS m/z 532 (M + H)⁺. [0414]

1233Reference Example 77 methyl [ (3S) -6-{ [ (3S) -7-{ [2-amino-3- (benzyloxy) phenyl] amino }- 2, 3-dihydro-l-berizofuran-3-yl] (trifluoroacetyl) amino}-2, 3- dihydro-l-benzofuran-3-yl] acetate [0415]

1234Methyl [(3S)-6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetate (1.0 g, 2.0 mmol), 3- (benzyloxy) -2-nitroaniline (1.0 g, 2.0 mmol) , tris (dibenzylideneacetone) dipalladium (91 mg, 0.1 mmol), 2- (dicyclohexylphosphino) -2' , 4' , 6^f -triisopropyl-1' , 1' -biphenyl (95 mg, 0.2 mmol) and tripotassium phosphate (849 mg, 4.0 mmol) were suspended in toluene (10 mL) , and the suspension was stirred under an argon atmosphere at 100°C overnight. The suspension was allowed to cool, the mixture was diluted with water and extracted with ethyl acetate. The extract was filtered through a celite pad and the filtrate was concentrated. The residue was washed with toluene to give a yellow solid (700 mg, yield 53%) . The obtained solid was suspended in ethanol (40 mL) -water (10 mL) , reduced iron (2.2 g, 40 mmol) and ammonium chloride (2.1 g, 40 mmol) were added and the mixture was stirred at 90⁰C for 4 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate was added and the mixture was filtered through a celite pad. The filtrate was extracted with ethyl acetate, and the extract was washed with aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 50:50) to give the title compound as a pale-yellow solid (580 mg, yield 87%) . MS m/z 634 (M + H)⁺. [0416]

1235Reference Example 78 methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-4-hydroxy-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate [0417]

1236Methyl [ (3S) -6-{ [ (3S) -7-{ [2-amino-3- (benzyloxy) phenyl] amino} -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (317 mg, 0.5 itunol) was dissolved in N, N- dimethylacetamide (10 mL) , propanoyl chloride (56 mg, 0.6 mmol) was added, and the mixture was stirred for 30 min. The mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. Acetic acid (10 mL) was added to the residue, and the mixture was stirred at 90⁰C overnight. Acetic acid was evaporated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate. To the residue were added methanol (10 mL) and 10% palladium-carbon (50% water- containing product, 100 mg) , and the mixture was stirred under a hydrogen atmosphere for 1 hr. The catalyst was filtered through a celite pad and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 90:10 - 50:50) to give the title compound as a white solid (260 mg, yield 89%) . MS m/z 582 (M + H) ⁺ .

1237[0418] Reference Example 79 methyl { (3S)-6-[{ (3S) -7- [2-ethyl-4- (2, 2, 2-trifluoroethoxy) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate

1238[0419]

1239Methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-4-hydroxy-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl]acetate (130 mg, 0.22 mmol) , 2, 2, 2-trifluoroethyl methanesulfonate (59 mg, 0.33 mmol) and potassium carbonate

1240(61 mg, 0.45 mmol) were suspended in N,N-dimethylformamide (2 mL) , and the suspension was stirred at 80⁰C for 2 hr. The suspension was allowed to cool, diluted with saturated brine, extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 20:80) to give the title compound (95 mg, yield 76%) as a colorless solid. MS m/z 664 (M + H)⁺.

1241[0420]

1242Reference Example 80 methyl [ (3S) -6-{ [ (3S) -7-{2-ethyl-4- [3-

1243(methylsulfonyl) propoxy] -lH-benzimidazol-l-yl}-2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

1244[0421]

1245Methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl-4-hydroxy-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (130 mg, 0.22 mmol), 3- (methylsulfonyl) propyl p- toluenesulfonate (98 mg, 0.33 mmol) and potassium carbonate (61 mg, 0.45 rnmol) were suspended in N,N-dimethylformamide (2 mL) , and the suspension was stirred at 80⁰C for 2 hr. The suspension was allowed to cool, diluted with saturated brine, extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 20:80) to give the title compound (110 mg, yield 83%) as a colorless solid. MS m/z 702 (M + H)⁺.

1246[0422]

1247Reference Example 81 methyl { (3S) -6- [ { (3S) -7- [6- (benzyloxy) -2-methyl-lH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate

1248[0423]

1249Methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (195 mg, 0.8 mmol) , 5- (benzyloxy) -2-nitroaniline

1250(400 mg, 0.8 mmol), tris (dibenzylideneacetone) dipalladium (0)

1251(37 mg, 0.04 mmol), 2- (dicyclohexylphosphino) -2' , 4' , 6' - triisopropyl-1' , 1' -biphenyl (38 mg, 0.08 mmol), tripotassium phosphate (340 mg, 1.6 mmol) were suspended in toluene (5 mL) , and the suspension was stirred overnight under an argon atmosphere at 100⁰C. The suspension was allowed to cool, diluted with saturated brine, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography

1252(hexane:ethyl acetate = 70:30 - 20:80) to give an oil (640 mg) . The obtained compound was suspended in ethanol (30 mL) , water

1253(5 mL) and acetic acid (5 mL) , reduced iron (440 mg, 7.8 mmol) and calcium chloride (870 mg, 7.8 mmol) were added and the mixture was stirred at 60⁰C for 2 hr. The reaction mixture was allowed to cool to room temperature, the volatile component was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and the extract was washed with aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 - 0:100) to give the title compound as an oil compound (210 mg, yield 40%) . MS m/z 658 (M + H)⁺. [0424]

1254Reference Example 82 methyl { (3S)-6-[{ (3S) -7- [2-methyl-6- (2, 2, 2-trifluoroethoxy) - lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate [0425]

1255To methyl { (3S) -6- [ { (3S) -7- [6- (benzyloxy) -2-methyl-lH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (210 mg, 0.40 mmol) were added methanol (20 mL) and 10% palladium-carbon (50% water-containing product, 50 mg) , and the mixture was stirred under a hydrogen atmosphere overnight. The catalyst was filtered off and the filtrate was concentrated. The obtained residue (150 mg) , 2,2,2- trifluoroethyl methanesulfonate (59 mg, 0.33 mmol), potassium carbonate (61 mg,0.45 mmol) were suspended in N, N- dimethylformamide (2 mL) , and the suspension was stirred at 60⁰C for 3 hr. The suspension was allowed to cool, diluted with saturated brine, extracted with ethyl acetate and dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 0:100) to give the title compound (150 mg, yield 62%) as a pale-yellow solid. MS m/ z 650 (M + H ) ⁺ .

1256[0426] Reference Example 83

12572-chloro-2' , 6' -dimethylbiphenyl-3-carbaldehyde [0427]

1258To a solution of 2-chloro-3-hydroxybenzaldehyde (1.57 g, 10.0 mmol) in pyridine (30 mL) was added dropwise trifluoromethanesulfonic anhydride (2.02 mL, 12.0 mmol) under a nitrogen atmosphere at 0⁰C, and the mixture was warmed to room temperature and stirred for 0.5 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed successively with IN hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 0:100-25:75) to give 2-chloro-3- formylphenyl trifluoromethanesulfonate (2.65 g, yield 92%) as a colorless oil. This product (2.65 g, 9.18 mmol), 2,6- dimethylphenylboronic acid (1.65 g, 11.0 mmol) and tripotassium phosphate (3.90 g, 18.4 mmol) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and water (10 mL) , palladium (II) acetate (62 mg, 0.275 mmol) and 2- dicyclohexylphosphino-2' , 6' -dimethoxybiphenyl (0.226 g, 0.551 mmol) were added, and the mixture was stirred under an argon atmosphere at 80°C for 21 hr. Ethyl acetate and water were added to the reaction mixture, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 0:100-15:85) and the obtained solid was washed with ethyl acetate-heptane to give colorless crystals (0.393 g) . The mother liquor was purified by preparative HPLC to give colorless crystals (0.292 g) . total 0.685 g (yield 31%) . ¹H NMR (300 MHz, CDCl₃) δ 2.00 (6H, s) , 7.13-7.18 (2H, m) ,

12597.22-7.28 (IH, m) , 7.38-7.43 (IH, m) , 7.45-7.51 (IH, m) , 7.96

1260(IH, dd, J = 7.5, 1.9 Hz) , 10.58 (IH, d, J = 0.8 Hz) .

1261[0428]

1262Reference Example 84

12632-hydroxy-2' , 6' -dimethylbiphenyl-3-carbaldehyde

1264[0429]

1265To a solution of 3-bromo-2-hydroxybenzaldehyde (1.12 g, 5.57 mmol) , 2, 6-dimethylphenylboronic acid (1.00 g, 6.69 irunol) and tripotassium phosphate (3.55 g, 16.7 mmol) in toluene (30 mL) and water (6 mL) were added palladium (II) acetate (38 mg, 0.167 mmol) and 2-dicyclohexylphosphino-2' , 6' - dimethoxybiphenyl (0.137 g, 0.334 mmol), and the mixture was stirred under an argon atmosphere at 100⁰C for 17 hr. Ethyl acetate and water were added to the reaction mixture, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 0:100-20:80) to give the title compound (1.18 g, yield 94%) as a brown oil. MS (ESI-) m/z 225 (M - H)^".

1266[0430]

1267Reference Example 85 methyl 3-bromo-2-methylbenzoate

1268[0431]

1269To a suspension of 3-bromo-2-methylbenzoic acid (3.23 g, 41.6 mmol) in methanol (15 mL) was added dropwise concentrated sulfuric acid (1.60 mL, 30.0 mmol) at room temperature, and the reaction mixture was. heated at 50⁰C for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with diethyl ether, washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 0:100-25:75) to give the title compound (3.20 g, yield 93%) as colorless crystals. ¹H NMR (300 MHz, CDCl₃) δ 2.63 (3H, s) , 3.90 (3H, s) , 7.06-7.13

1270(IH, m) , 7.67-7.75 (2H, m) .

1271[0432]

1272Reference Example 86 methyl 3- [1- (difluoromethyl) -3, 5-dimethyl-lH-pyrazol-4-yl] -2- methylbenzoate

1273[0433]

1274In the same manner as in Reference Example 84, the title compound was obtained as colorless crystals from methyl 2- bromo-3-methylbenzoate and 1- (difluoromethyl) -3, 5-dimethyl-4-

1275(4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -lH-pyrazole. yield 83%.

1276MS m/z 295 (M + H)⁺.

1277[0434] Reference Example 87

1278{3-[l- (difluoromethyl) -3, 5-dimethyl-lH-pyrazol-4-yl] -2- methylphenyl }methanol

1279[0435]

1280Methyl 3- [1- (difluoromethyl) -3, 5-dimethyl-lH-pyrazol-4- yl] -2-methylbenzoate (2.18 g, 7.41 mmol) was dissolved in tetrahydrofuran (30 rtiL) , 1.5 M diisobutylaluminum hydride toluene solution (14.8 mL, 22.2 mmol) was added dropwise under a nitrogen atmosphere at 0⁰C and the mixture was stirred for 16 hr. To the reaction mixture was added sodium sulfate 10 hydrate (7.15 g, 22.2 mmol), and the mixture was stirred at room temperature for 2 hr. Insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 10:90-50:50) to give the title compound (1.82 g, yield 92%) as a colorless oil. MS m/z 267 (M + H)⁺.

1281[0436] Reference Example 88 methyl [ (3S)-6-{ [2-methyl-3- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) benzyl] amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate

1282[0437]

1283To a solution of methyl { (3S) -6- [ (3-bromo-2- methylbenzyl) amino] -2, 3-dihydro-l-benzofuran-3-yl} acetate

1284(0.548 g, 1.40 mmol) , bis (pinacolato) diboron (0.713 g, 2.81 mmol) and potassium acetate (0.482 g, 4.91 mmol) in N, N- dimethylformamide (7 mL) was added [1,1'- bis (diphenylphosphino) ferrocene] palladium dichloride (31 mg, 0.042 mmol), and the mixture was stirred under an argon atmosphere at 100⁰C for 15 hr. Ethyl acetate and water were added to the reaction mixture, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 5:95-40:60) to give the title compound as a yellow viscous oil. MS m/z 438 (M + H)⁺. [0438]

1285Reference Example 89 5-bromo-4 , 6-dimethylpyrimidin-2-ol [0439]

1286To a solution of 2-hydroxy-4, 6-dimethylpyrimidine (13.5 g, 109 mmol) in N,N-dimethylformamide (200 mL) was added N- bromosuccinimide (20.3 g, 114 mmol) by small portions, and the mixture was stirred at room temperature for 3 days. The solvent was evaporated under reduced pressure, and the residue was suspended in ethyl acetate and heated. The suspension was cooled and the precipitate was collected by filtration, and washed with ethanol to give the title compound (11.9 g, yield 54%) as dark gray crystals. MS m/z 203 (M + H)⁺. [0440] Reference Example 90

12875-bromo-2- (difluoromethoxy) -4, 6-dimethylpyrimidine [0441]

12885-Bromo-4, 6-dimethylpyrimidin-2-ol (2.03 g, 10.0 mmol) , sodium chlorodifluoroacetate (3.05 g, 20.0.mmol) , and potassium carbonate (1.73 g, 12.5 mmol) were added to a mixed solution of N,N-dimethylformamide (20 mL) and water (3 mL) , and the mixture was stirred under a nitrogen atmosphere at 100⁰C for 16 hr. The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 0:100-20:80) to give the title compound (0.516 g, yield 20%) as a yellow oil. MS m/z 253 (M + H)⁺. [0442]

1289Reference Example 91

1290[4- (methoxymethoxy) -2, 6-dimethylphenyl]boronic acid [0443]

1291According to WO2008/001931, the title compound was synthesized, yield 91%. [0444]

1292Reference Example 92 methyl 4' - (methoxymethoxy) -2, 2' , 6' -trimethylbiphenyl-3- carboxylate [0445]

1293In the same manner as in Reference Example 84, the title compound was obtained as a yellow oil from methyl 3-bromo-2- methylbenzoate and [4- (methoxymethoxy) -2, 6- dimethylphenyl]boronic acid, yield 94%.

1294¹H NMR (300 MHz, CDCl₃) δ 1.89 (6H, s) , 2.19 (3H, s) , 3.52 (3H, s), 3.91 (3H, s), 5.20 (2H, s) , 6.80 (2H, s) , 7.14-7.20 (IH, m) , 7.25-7.33 (IH, m) , 7.83 (IH, dd, J = 7.6, 1.5 Hz). [ 0446 ]

1295Reference Example 93 methyl 4' -hydroxy-2, 2' , 6' -trimethylbiphenyl-3-carboxylate [0447]

1296To a solution of methyl 4' - (methoxymethoxy) -2, 2' , 6' - trimethylbiphenyl-3-carboxylate (4.14 g, 13.2 mmol) in methanol (60 mL) was added dropwise 5-10% hydrogen chloride/methanol solution (6 mL) , and the mixture was stirred at room temperature for 16 hr. The solvent was evaporated under reduced pressure, and the residue was treated with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 5:95-40:60) to give the title compound (3.40 g, yield 96%) as a colorless viscous oil. MS m/z 271 (M + H)⁺. [0448]

1297Reference Example 94 methyl 2, 2' , 6' -trimethyl-4' - [3- (methylsulfonyl) propoxy] biphenyl-3-carboxylate [0449]

1298To a solution of methyl 4' -hydroxy-2, 2' , 6' - trimethylbiphenyl-3-carboxylate (1.24 g, 4.59 mmol) and 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate (1.41 g, 4.82 mmol) synthesized according to WO2008/001931 in N, N- dimethylformamide (10 mL) was added potassium carbonate (0.761 g, 5.50 mmol), and the mixture was stirred under a nitrogen atmosphere at 80⁰C for 28 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 30:70-70:30) to give the title compound (1.59 g, yield 89%) as a colorless oil. MS m/z 391 (M + H ) ⁺ .

1299[0450] Reference Example 95

1300{2,2' , 6' -trimethyl-4' - [3- (methylsulfonyl) propoxy]biphenyl-3- yljmethanol

1301[0451]

1302In the same manner as in Reference Example 87, the title compound was obtained as colorless crystals from methyl 2, 2' , 6' -trimethyl-4' - [3- (methylsulfonyl) propoxy] biphenyl-3- carboxylate. yield 87%. MS m/z 363 (M + H)⁺. [0452]

1303Reference Example 96 methyl 3- (2, 5-dimethylthiophen-3-yl) -2-fluorobenzoate [0453]

1304To a solution of methyl 3-bromo-2-fluorobenzoate (300 mg, 1.29 mmol) and (2, 5-dimethylthiophen-3-yl)boronic acid (402 mg,

13052.57 mmol) and 2 M aqueous sodium carbonate solution (1.29 mL,

13062.58 mmol) in toluene (6.5 mL) were added under an argon atmosphere tris (dibenzylideneacetone) dipalladium (0) (47.3 mg, 0.0516 mmol) and dicyclohexyl (2' , 6' -dimethoxybiphenyl-2- yl)phosphane (84.7 mg, 0.206 mmol), and the mixture was stirred at 100⁰C overnight The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 90:10) to give the title compound (354 mg, yield 100%) as a colorless oil.

1307¹H NMR (300 MHz, CDCl₃) δ 2.32 (3H, s) , 2.44 (3H, s) , 3.94 (3H, s), 6.64 (IH, s), 7.22 (IH, t, J = 7.7 Hz), 7.39-7.50 (IH, m) , 7.83-7.92 (IH, m) . [0454]

1308Reference Example 97

1309[3- (2, 5-dimethylthiophen-3-yl) -2-fluorophenyl] methanol [0455] To a solution of methyl [3- (2, 5-dimethylthiophen-3-yl) -2- fluoro]benzoate (354 mg, 1.29 mmol) in tetrahydrofuran (6.5 mL) was added under ice-cooling diisobutylaluminum hydride (1.5 M toluene solution, 3.44 mL, 5.16 mmol), and the mixture was stirred for 1 hr. Sodium sulfate 10 hydrate (1.66 g, 5.16 mmol) was slowly added, and the mixture was stirred for 30 min at room temperature. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 67:33) to give the title compound (311 mg, yield 100%) as a colorless oil. 1H NMR (300 MHz, CDCl₃) δ 1.81 (IH, t, J = 6.2 Hz), 2.33 (3H, s), 2.44 (3H, s), 4.81 (2H, d, J = 6.1 Hz), 6.64 (IH, s) , 7.11-7.25 (2H, m) , 7.38 (IH, td, J = 7.1, 2.1 Hz). [0456]

1310Reference Example 98 methyl 3-{ [2- (acetylamino) phenyl] amino }-2-methylbenzoate [0457]

1311N- (2-Aminophenyl) acetamide (750 mg, 5.0 mmol), methyl 3- bromo-2-methylbenzoate (1.1 g, 5.0 mmol), tris (dibenzylideneacetone) dipalladium (230 mg, 0.25 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (290 mg, 0.5 mmol) and cesium carbonate (3.2 g, 10 mmol) were suspended in toluene (25 mL) , and the mixture was stirred under an argon atmosphere at 100⁰C for 4 hr. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 20:80) to give the title compound as a pale-yellow solid (410 mg, yield 27%) .

1312¹H NMR (300 MHz, DMSO-d₆) δ 2.05 (3H, s) , 2.29 (3H, s) , 3.83 (3H, s), 6.85-7.42 (8H, m) , 9.60 (IH, s) . [0458] Reference Example 99

1313[2-methyl-3- (2-methyl-lH-benzimidazol-l-yl) phenyl] methanol [0459]

1314Methyl 3-{ [2- (acetylamino) phenyl] amino }-2-methylbenzoate (410 mg, 1.37 mmol) was dissolved in acetic acid (15 mL) , and the mixture was stirred at 100⁰C overnight. The reaction mixture was allowed to cool, and the volatile component was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL) , lithium aluminum hydride (6.9 mmol, 260 mg) was added at 0⁰C, and the mixture was stirred at room temperature for 30 min. Sodium sulfate 10 hydrate was added, and then ethyl acetate was added, and the mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 20:80) to give the title compound (300 mg, yield 86%) as a colorless solid.

1315¹H NMR (300 MHz, DMSO-d₆) δ 1.77 (3H, s) , 2.28 (3H, s) , 4.60 (2H, d, J = 4.9 Hz), 5.29 (IH, t, J = 5.3 Hz), 6.83 (IH, d, J = 7.2 Hz), 7.10-7.31 (3H, m) , 7.43 (IH, t, J = 7.8 Hz), 7.63 (2H, d, J = 7.2 Hz) . [0460]

1316Reference Example 100 methyl [ (3S) -6-{ [2-methyl-3- (2-methyl-lH-benzimidazol-l- yl) benzyl] [ (2-nitrophenyl) sulfonyl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate [0461]

1317To a solution of [2-methyl-3- (2-methyl-lH-benzimidazol-l- yl) phenyl] methanol (150 mg, 0.6 mmol), methyl [ (3S) -6-{ [ (2- nitrophenyl) sulfonyl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (280 mg, 0.72 mmol) and triphenylphosphine (240 mg, 0.9 mmol) in tetrahydrofuran (15 mL) was added a 2.2 M solution (0.41 mL, 0.9 mmol) of diethyl azodicarboxylate in toluene, and the mixture was stirred overnight at room temperature and diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 - 0:100) to give the title compound (350 mg, yield 93%) as a solid.

1318MS m/z 627 (M + H) ⁺. [0462]

1319Reference Example 101 methyl 2-methyl-3- [2-methyl-6- (trifluoromethyl) -IH- benzimidazol-1-yl] benzoate [0463] methyl 2-methyl-3- [2-methyl-5- (trifluoromethyl) -IH- benzimidazol-1-yl] benzoate [0464]

13204- (Trifluoromethyl)benzene-l,2-diamine (830 mg, 5.0 mmol) and acetic acid (300 mg, 5.0 mmol) were dissolved in N, N- dimethylformamide (10 mL) , o- (7-azabenzotriazol-l-yl) - N, N, N' , N'-tetramethyluronium hexafluorophosphate (2.3 g, 6.0 mmol) and N,N-diisopropylethylamine (1.3 g, 10 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 - 0:100) to give an oil (1.6 g) . The resultant product, methyl 3-bromo- 2-methylbenzoate (1.1 g, 5.0 mmol), tris (dibenzylideneacetone) dipalladium (230 mg, 0.25 mmol), 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (290 mg, 0.5 mmol) and cesium carbonate (3.2 g, 10 mmol) were suspended in toluene (50 mL) , and the mixture was stirred under an argon atmosphere at 100°C overnight. The reaction mixture was allowed to cool, diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 - 0:100) to give methyl 2-methyl-3- [2-methyl- 6- (trifluoromethyl) -lH-benzimidazol-l-yl]benzoate (140 mg, yield 40%) and methyl 2-methyl-3- [2-methyl-5-

1321(trifluoromethyl) -lH-benzimidazol-l-yl]benzoate (140 mg, yield 40%) each as a pale-yellow oil. methyl 2-methyl-3- [2-methyl-6- (trifluoromethyl) -IH- benzimidazol-1-yl] benzoate

1322¹H NMR (300 MHz, DMSO-d₆) δ 2.02 (3H, s) , 2.34 (3H, s) , 3.89 (3H, s), 7.21 (IH, s), 7.54-7.64 (2H, m) , 7.72 (IH, dd, J = 7.9, 1.3 Hz), 7.87 (IH, d, J = 8.3 Hz), 8.06 (IH, dd, J = 7.7, 1.3 Hz) . methyl 2-methyl-3- [2-methyl-5- (trifluoromethyl) -IH- benzimidazol-1-yl] benzoate

1323¹H NMR (300 MHz, DMSO-d₆) δ 2.02 (3H, s) , 2.35 (3H, s) , 3.89 (3H, s), 7.10 (IH, d, J = 8.7 Hz) , 7.51 (IH, d, J = 9.4 Hz) , 7.61 (IH, t, J = 7.7 Hz) , 7.72 (IH, d, J = 6.8 Hz) , 8.00-8.08 (2H, m) . [0465]

1324Reference Example 102 methyl 3-{ [2- (acetylamino) phenyl] amino} -2-fluorobenzoate [0466]

1325In the same manner as in Reference Example 98, the title compound (180 mg, yield 12%) was synthesized from methyl 3- bromo-2-fluorobenzoate (1.17 g, 5.0 mmol) .

1326¹H NMR (300 MHz, DMSO-d₆) δ 2.03 (3H, s) , 3.86 (3H, s) , 7.00- 7.29 (6H, m) , 7.44-7.51 (2H, m) , 9.65 (IH, s) . [0467]

1327Reference Example 103 methyl 2-fluoro-3- (2-methyl-lH-benzimidazol-l-yl) benzoate [0468]

1328A solution of methyl 3-{ [2- (acetylamino) phenyl] amino}-2- fluorobenzoate (180 mg, 0.6 mmol) in acetic acid (20 mL) was stirred overnight at 100⁰C. The volatile component was evaporated under reduced pressure, and the residue was diluted with aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography

1329(hexane: ethyl acetate = 50:50 - 0:100) to give the title compound (130 mg, yield 76%) .

1330¹H NMR (300 MHz, CDCl₃) δ 2.49 (3H, s) , 3.98 (3H, s) , 7.03 (IH, d, J = 8.3 Hz), 7.18-7.24 (IH, m) , 7.28-7.32 (IH, m) , 7.40- 7.48 (IH, m) , 7.56-7.64 (IH, m) , 7.76 (IH, d, J = 7.6 Hz), 8.10-8.18 (IH, m) .

1331[0469]

1332Reference Example 104 methyl 3- [ (5-fluoro-2-nitrophenyl) amino] -2-methylbenzoate

1333[0470]

13342-Bromo-4-fluoro-l-nitrobenzene (1.32 g, 6.0 mmol), methyl 3-amino-2-methylbenzoate (826 mg, 5.0 mmol), tris (dibenzylideneacetone) dipalladium (230 mg, 0.25 mmol), 2, 2' -bis (diphenylphosphino) diphenyl ether (269 mg, 0.5 mmol) and tripotassium phosphate (3.2 g, 15 mmol) were suspended in toluene (25 mL) , and the suspension was stirred under an argon atmosphere at 110⁰C for 3 hr. The reaction mixture was allowed to cool, diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (1.4 g, yield 77%) as a pale-yellow solid. 1H NMR (300 MHz, DMSO-d₆) δ 2.34 (3H, s) , 3.86 (3H, s) , 6.16

1335(IH, dd, J = 11.7, 2.6 Hz), 6.68 (IH, ddd, J = 9.7, 7.3, 2.8 Hz), 7.31-7.86 (3H, m) , 8.26 (IH, dd, J = 9.5, 6.1 Hz), 9.60 ( IH, s ) .

1336[0471] Reference Example 105 methyl 3- [ (2-amino-5-fluorophenyl) amino] -2-methylbenzoate [0472]

1337Methyl 3- [ (5-fluoro-2-nitrophenyl) amino] -2-methylbenzoate (1.4 g, 4.6 mmol) was suspended in methanol (50 mL) , platinum oxide (227 mg, 1 mmol) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature overnight. Platinum oxide was filtered through a celite pad and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 30:70) to give the title compound (880 mg, yield 69%) as a pale-yellow oil.

1338¹H NMR (300 MHz, DMSO-d₆) δ 2.32 (3H, s) , 3.82 (3H, s) , 4.63 (2H, s), 6.44 (IH, dd, J = 10.5, 2.8 Hz), 6.62 (IH, dd, J = 8.5, 2.8 Hz), 6.66-6.75 (2H, m) , 6.81 (IH, dd, J = 7.9, 1.1 Hz), 7.14 (IH, t, J = 7.8 Hz), 7.20-7.26 (IH, m) . [0473]

1339Reference Example 106 methyl 3- (6-fluoro-2-methyl-lH-benzimidazol-l-yl) -2- methylbenzoate [0474]

1340To a solution of methyl 3- [ (2-amino-5- fluorophenyl) amino] -2-methylbenzoate (880 mg, 3.20 mmol) in N,N-dimethylacetamide (20 mL) was added acetyl chloride (299 mg, 3.81 mmol), and the mixture was stirred at room temperature for 30 min. The mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was dissolved in acetic acid (20 mL) , and the obtained solution was stirred at 120⁰C for 2 days. The mixture was allowed to cool, and the volatile component was evaporated under reduced pressure. The obtained residue was diluted with aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure to give the title compound (850 mg, yield 89%) as a solid. MS m/z 299 (M + H) ⁺.

1341[0475]

1342Reference Example 107 methyl 3- [ (2-aminophenyl) amino] -2-methylbenzoate

1343[0476] l-Bromo-2-nitrobenzene (15.0 g, 74.2 mmol) , methyl 3- amino-2-methylbenzoate (11.2 g, 67.5 mmol), tris (dibenzylideneacetone) dipalladium (2.47 g, 2.7 mmol), 2, 2' -bis (diphenylphosphino) diphenyl ether (2.90 g, 5.4 mmol) and tripotassium phosphate (43 g, 203 mmol) were suspended in toluene (300 inL) , and the mixture was stirred under an argon atmosphere at 100⁰C overnight. The reaction mixture was allowed to cool, diluted with ethyl acetate-hexane (1:1) solution, and the mixture was filtered through a silica pad. The filtrate was concentrated and the obtained residue was suspended in methanol (300 mL) . 10% Palladium-carbon (50% water-containing product, 5000 mg) was added, and the mixture was stirred under a hydrogen atmosphere overnight. The catalyst was filtered through a celite pad and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 40:60) to give the title compound (18.4 g, yield 96%) as an oil. 1H NMR (300 MHz, DMSO-d₆) δ 2.34 (3H, s) , 3.82 (3H, s) , 4.74

1344(2H, s), 6.50-6.62 (3H, m) , 6.72-6.82 (2H, m) , 6.83-6.91 (IH, m) , 7.00-7.11 (2H, m) .

1345[0477]

1346Reference Example 108 methyl 3- (2-ethoxy-lH-benzimidazol-l-yl) -2-methylbenzoate

1347[0478]

1348Methyl 3- [ (2-aminophenyl) amino] -2-methylbenzoate (513 mg, 2.0 mmol) and tetraethoxymethane (1.15 g, 6.0 itimol) were stirred in acetic acid (10 mL) at 60°C for 1 hr. The reaction mixture was allowed to cool, and the volatile component was evaporated under reduced pressure. An aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 40:60) to give the title compound (460 mg, yield 74%) as a solid.

1349¹H NMR (300 MHz, ^"DMSO-d₆) δ 1.32 (3H, t, J = 7.0 Hz) , 2.10 (3H, s), 3.88 (3H, s), 4.46-4.64 (2H, m) , 6.81 (IH, d, J = 7.6 Hz), 7.04-7.11 (IH, m), 7.13-7.21 (IH, m) , 7.53 (2H, dd, J = 10.0, 7.8 Hz), 7.60-7.66 (IH, m) , 7.93-7.99 (IH, m) . [0479]

1350Reference Example 109 methyl 3- [ (2-amino-4-methoxyphenyl) amino] -2-methylbenzoate [0480]

1351In the same manner as in Reference Example 107, the title compound was synthesized using l-bromo-4-methoxy-2- nitrobenzene .

1352¹H NMR (300 MHz, DMSO-d₆) δ 2.34 (3H, s) , 3.68 (3H, s), 3.81 (3H, s), 4.79 (2H, s) , 6.15 (IH, dd, J = 8.5, 2.8 Hz), 6.33- 6.41 (2H, m) , 6.45 (IH, s) , 6.78 (IH, d, J = 8.5 Hz), 6.94- 7.02 (2H, m) . [0481]

1353Reference Example 110 methyl 3- [ (2-amino-4-methylphenyl) amino] -2-methylbenzoate [0482]

1354In the same manner as in Reference Example 107, the title compound was synthesized using l-bromo-4-methyl-2-nitrobenzene. ¹H NMR (300 MHz, DMSO-d₆) δ 2.18 (3H, s) , 2.33 (3H, s) , 3.81 (3H, s), 4.67 (2H, br s) , 6.36 (IH, dd, J = 7.7, 1.5 Hz), 6.44-6.52 (2H, m) , 6.57 (IH, d, J = 1.5 Hz), 6.71 (IH, d, J = 7 . 7 Hz ) , 6 . 96-7 . 05 ( 2H, m) .

1355[0483] Reference Example 111 methyl 3- [ (2-amino-6-methylphenyl) amino] -2-methylbenzoate

1356[0484]

1357In the same manner as in Reference Example 107, the title compound was synthesized using l-bromo-6-methyl-2-nitrobenzene. ¹H NMR (300 MHz, DMSO-d₆) δ 1.97 (3H, s) , 2.40 (3H, s) , 3.81

1358(3H, s), 4.76 (2H, s) , 6.09-6.15 (IH, m) , 6.42 (IH, s) , 6.48

1359(IH, d, J = 6.8 Hz), 6.62 (IH, d, J = 8.0 Hz), 6.86-6.95 (3H, m) .

1360[0485]

1361Reference Example 112 methyl 3- [ (2-amino-3-methylphenyl) amino] -2-methylbenzoate

1362[0486]

1363In the same manner as in Reference Example 107, the title compound was synthesized using l-bromo-3-methyl-2-nitrobenzene. ¹H NMR (300 MHz, DMSO-d₆) δ 2.13 (3H, s) , 2.35 (3H, s) , 3.82

1364(3H, s), 4.47 (2H, s) , 6.46-6.54 (2H, m) , 6.61 (IH, s) , 6.69

1365(IH, d, J = 6.8 Hz), 6.81 (IH, d, J = 7.2 Hz), 6.97-7.09 (2H, m) .

1366[0487]

1367Reference Example 113 methyl 3- [ (2-amino-5-methoxyphenyl) amino] -2-methylbenzoate

1368[0488]

1369In the same manner as in Reference Example 107, the title compound (yield 79%) was synthesized using 2-iodo-4-methoxy-l- nitrobenzene as aromatic halide. 1H NMR (300 MHz, DMSO-d₆) δ 2.33 (3H, s) , 3.59 (3H, s) , 3.82

1370(3H, s), 4.31 (2H, s) , 6.37 (IH, d, J = 3.0 Hz), 6.45-6.50 (IH, m) , 6.60-6.73 (3H, m) , 7.04-7.16 (2H, m) .

1371[0489]

1372Reference Example 114 methyl 3- ( 6-methoxy-2-methyl-lH-benzimidazol-l-yl) -2- methylbenzoate [ 0490 ]

1373A solution of methyl 3- [ (2-amino-5-methoxyphenyl) amino] - 2-methylbenzoate (573 mg, 2 mmol) in acetic acid (10 mL)- acetic anhydride (5 mL) was stirred overnight at 100⁰C. The volatile component was evaporated under reduced pressure, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography

1374(hexane: ethyl acetate = 80:20 - 20:80) to give the title compound (620 mg, yield 99%) as an oil.

1375¹H NMR (300 MHz, DMSO-d₆) δ 2.04 (3H, s) , 2.22 (3H, s) , 3.67

1376(3H, s), 3.88 (3H, s) , 6.33 (IH, d, J = 2.3 Hz), 6.81-6.86 (IH, m) , 7.50-7.67 (3H, m) , 8.02 (IH, dd, J = 7.6, 1.5 Hz).

1377[0491]

1378Reference Example 115 methyl 3- (2, 6-dimethyl-lH-benzimidazol-l-yl) -2-methylbenzoate

1379[0492]

1380In the same manner as in Reference Examples 107 and 114, the title compound was synthesized. 1H NMR (300 MHz, DMSO-d₆) δ 2.01 (3H, s) , 2.25 (3H, s) , 2.33

1381(3H, s), 3.88 (3H, s) , 6.65 (IH, s) , 7.03 (IH, d, J = 8.3 Hz), 7.49-7.66 (3H, m) , 8.01 (IH, dd, J = 7.6, 1.5 Hz).

1382[0493]

1383Reference Example 116 methyl 3- [5-methoxy-2- (trifluoromethyl) -lH-benzimidazol-1-yl] - 2-methylbenzoate

1384[0494]

1385Methyl 3- [ (2-amino-4-methoxyphenyl) amino] -2- methylbenzoate (1.15 g, 4.0 mmol) was suspended in trifluoroacetic acid (10 mL) , trifluoroacetic anhydride (2 mL) was added, and the mixture was stirred at 60⁰C for 2 hr. The volatile component was evaporated under reduced pressure, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure to give the title compound (1.5 g, yield - 100%) as an oil. ¹H NMR (300 MHz, DMSOd₆) δ 2.00 (3H, s) , 3.85 (3H, s) , 3.88 (3H, s), 6.98 (IH, d, J = 9.1 Hz), 7.08 (IH, dd, J = 9.1, 2.7 Hz), 7.46 (IH, d, J = 2.3 Hz), 7.56-7.63 (IH, m) , 7.78 (IH, d, J = 7.6 Hz), 8.06 (IH, d, J = 8.0 Hz). [0495]

1386Reference Example 117 methyl 2-methyl-3- (2-thioxo-2, 3-dihydro-lH-benzimidazol-l- yl) benzoate [0496]

1387Methyl 3- [ (2-aminophenyl) amino] -2-methylbenzoate (1.02 g, 4.0 mmol) and di-lH-imidazol-1-ylmethanethion (1.07 g, 6.0 mmol) were mixed in tetrahydrofuran (50 mL) , and the mixture was stirred at room temperature for 1 hr. An aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced "pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 60:40) to give the title compound (1.2 g, yield - 100%) as an oil. [0497]

1388Reference Example 118 methyl 2-methyl-3- [2- (methylsulfanyl) -lH-benzimidazol-1- yl] benzoate [0498]

1389Methyl 2-methyl-3- (2-thioxo-2, 3-dihydro-lH-benzimidazol- l-yl)benzoate (298 mg, 1 mmol), potassium carbonate (276 mg, 2 mmol) and methyl iodide (284 mg, 2 mmol) were suspended in N,N-dimethylformamide (10 mL) , and the mixture was stirred at

139060⁰C for 1 hr. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 40:60) to give the title compound (290 mg, yield 69%). 1H NMR (300 MHz, DMSO-d₆) δ 2.03 (3H, s) , 2.69 (3H, s) , 3.88 (3H, s), 6.88 (IH, d, J = 8.0 Hz), 7.11-7.28 (2H, m) , 7.53- 7.69 (3H, m) , 8.02 (IH, dd, J = 7.6, 1.5 Hz). [0499]

1391Reference Example 119 methyl 3-{2- [ (4-chlorobenzyl) sulfanyl] -lH-benzimidazol-1-yl}- 2-methylbenzoate [0500]

1392In the same manner as in Reference Example 118, the title compound (yield - 100%) was synthesized using 1- (bromomethyl) - 4-chlorobenzene as alkyl halide.

1393¹H NMR (300 MHz, DMSO-d₆) δ 1.93 (3H, s) , 3.86 (3H, s), 4.51- 4.66 (2H, m) , 6.89 (IH, d, J = 7.6 Hz), 7.13-7.20 (IH, m) , 7.22-7.29 (IH, m) , 7.32-7.39 (2H, m) , 7.43-7.50 (2H, m) , 7.51- 7.63 (2H, m) , 7.70 (IH, d, J = 7.6 Hz), 8.00 (IH, dd, J = 7.6, 1.9 Hz) . [0501]

1394Reference Example 120 methyl 2-methyl-3- [ (2-{ [ (2S) -tetrahydrofuran-2- ylcarbonyl] amino}phenyl) amino] benzoate [0502]

1395Methyl 3- [ (2-aminophenyl) amino] -2-methylbenzoate (513 mg, 2.0 mmol) , (2S) -tetrahydrofuran-2-carboxylic acid (255 mg, 2.2 mmol) , N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (422 mg, 2.2 mmol) and 1-hydroxybenzotriazole (367 mg, 2.4 mmol) were mixed in N,N-dimethylformamide (10 mL) , and the mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80:20 - 20:80) to give the title compound (610 mg, yield 69%) .

1396¹H NMR (300 MHz, DMSO-d₆) δ 1.40-1.56 (IH, m) , 1.64-1.87 (2H, m) , 2.04-2.18 (IH, m) , 2.37 (3H, s) , 3.36-3.45 (IH, m) , 3.56- 3.68 (IH, in), 3.83 (3H, s) , 4.27-4.36 (IH, m) , 6.57 (IH, d, J = 6.8 Hz), 7.03-7.22 (6H, m) , 7.89-7.98 (IH, m) , 9.08 (IH, s) .

1397[0503]

1398Reference Example 121 methyl 2-methyl-3- (7-methyl-lH-benzimidazol-l-yl) benzoate

1399[0504]

1400Methyl 3- [ (2-amino-6-methylphenyl) amino] -2-methylbenzoate

1401(270 mg, 1 iranol) and trimethoxymethane (313 mg, 3 mmol) were mixed in acetic acid (10 mL) , and the mixture was stirred at 60⁰C for 3 hr. The volatile component was evaporated under reduced pressure, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 60:40) to give the title compound (310 mg, yield - 100%) . 1H NMR (300 MHz, DMSO-d₆) δ 1.86 (3H, s) , 2.05 (3H, s) , 3.88

1402(3H, s), 7.01 (IH, d, J = 7.2 Hz), 7.17 (IH, t, J = 7.8 Hz), 7.49-7.56 (IH, m) , 7.61 (IH, d, J = 8.3 Hz), 7.73 (IH, d, J = 6.4 Hz), 7.96-8.01 (IH, m) , 8.23 (IH, s) .

1403[0505]

1404Reference Example 122 methyl 3- (2-ethyl-lH-benzimidazol-l-yl) -2-methylbenzoate

1405[0506]

1406Methyl 3- [ (2-aminophenyl) amino] -2-methylbenzoate (541 mg, 2.0 mmol) was dissolved in N,N-dimethylacetamide (10 mL) , propanoyl chloride (222 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature for 30 min. The mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was dissolved in acetic acid (20 mL) , and the obtained solution was stirred overnight at 110⁰C. The mixture was allowed to cool, the volatile component was evaporated, and the residue was diluted with aqueous sodium bicarbonate solution, extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. The volatile component was evaporated under reduced pressure to give the title compound (550 mg, yield 94%) as a solid.

1407¹H NMR (300 MHz, DMSO-d₆) δ 1.18-1.25 (3H, m) , 1.98-2.01 (3H, m) , 2.53-2.63 (2H, m) , 3.88 (3H, s) , 6.86 (IH, d, J = 7.3 Hz), 7.13-7.27 (2H, m) , 7.54-7.61 (IH, m) , 7.64-7.71 (2H, m) , 8.02 (IH, dd, J = 7.7, 1.5 Hz) . [0507]

1408Reference Example 123 methyl 3- [2- (methoxymethyl) -lH-benzimidazol-1-yl] -2- methylbenzoate [0508]

1409Methyl 3- [ (2-aminophenyl) amino] -2-methylbenzoate (540 mg, 2.0 mmol), methoxyacetic acid (180 mg, 2.2 mmol) , N- (3- dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (422 mg, 2.2 mmol) and 1-hydroxybenzotriazole (367 mg, 2.4 mmol) were suspended in N,N-dimethylformamide (10 mL) , and the suspension was stirred overnight at room temperature. The mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 60:40) to give an oil (380 mg) . The obtained compound was stirred overnight in acetic acid (10 mL) at 110⁰C. The volatile component was evaporated under reduced pressure. The residue was diluted with aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the volatile component was evaporated under reduced pressure to give the title compound (250 mg, yield 89%) as an oil.

1410¹H NMR (300 MHz, DMSO-d₆) δ 2.00 (3H, s) , 3.14 (3H, s) , 3.88 (3H, s), 4.35-4.42 (IH, m) , 4.46-4.52 (IH, m) , 6.90-6.97 (IH, m) , 7.21-7.33 (2H, m) , 7.51-7.60 (IH, m) , 7.63-7.68 (IH, m) , 7.74-7.79 (IH, m) , 7.98-8.04 (IH, m) . [0509]

1411Reference Example 124 methyl 3- (6-chloro-2-ethyl-lH-benzimidazol-l-yl) -2- methylbenzoate [0510]

1412N- (2-Bromo-4-chlorophenyl)propanamide (788 mg, 3.0 mmol) , methyl 3-amino-2-methylbenzoate (496 mg, 3.0 mmol), tris (dibenzylideneacetone) dipalladium (110 mg, 0.12 mmol), 2, 2' -bis (diphenylphosphino) diphenyl ether (129 mg, 0.24 mmol) and tripotassium phosphate (1.91 g, 9.0 mmol) were suspended in toluene (30 mL) , and the mixture was stirred under an argon atmosphere at 11O⁰C for 5 days. The reaction mixture was allowed to cool, diluted with saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 60:40). The obtained solid was dissolved in acetic acid (10 mL) and the mixture was stirred at 110⁰C overnight. The volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 40:60) to give the title compound as an oil (360 mg, yield 36%) .

1413¹H NMR (300 MHz, DMSO-d₆) δ 1.18-1.26 (3H, m) , 2.01 (3H, s) , 2.52-2.60 (2H, m) , 3.88 (3H, s) , 6.93 (IH, d, J = 1.9 Hz), 7 . 26 ( IH, dd, J = 8 . 5 , 2 . 1 Hz ) , 7 . 55-7 . 75 ( 3H, m) , 8 . 02 ( IH, s ) .

1414[0511] Reference Example 125 methyl 3- (2-ethyl-6-fluoro-lH-benzimidazol-l-yl) -2- methylbenzoate [0512]

1415In the same manner as in Reference Example 122, the title compound was synthesized using methyl 3- [ (2-amino-5- fluorophenyl) amino] -2-methylbenzoate.

1416¹H NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J = 7.6 Hz), 2.15 (3H, s), 2.62 (2H, q, J = 7.6 Hz), 3.96 (3H, s) , 6.56 (IH, dd, J = 8.5, 2.5 Hz), 6.96-7.06 (IH, m) , 7.37-7.52 (2H, m) , 7.71 (IH, dd, J = 8.7, 4.5 Hz), 8.07 (IH, dd, J = 7.8, 1.7 Hz). MS m/z 313 (M + H)⁺. [0513]

1417Reference Example 126

1418[3- (2-ethyl-6-fluoro-lH-benzimidazol-1-yl) -2- methylphenyl] methanol [0514]

1419To a solution of methyl 3- (2-ethyl-β-fluoro-lH- benzimidazol-l-yl) -2-methylbenzoate (10 g, 32 mmol) in tetrahydrofuran (300 mL) was added lithium aluminum hydride (2.43 g, 64 mmol), and the mixture was stirred at room temperature for 30 min. Sodium sulfate 10 hydrate was added, and then ethyl acetate was added, and the mixture was filtered through a celite pad. The filtrate was concentrated and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 10:90) to give the title compound (7.9 g, yield 87 %) as an oil.

1420¹H NMR (300 MHz, CDCl₃) δ 1.32 (3H, t, J = 7.5 Hz), 1.92 (3H, s), 2.63 (2H, q, J = 7.5 Hz), 4.83 (2H, d, J = 5.7 Hz), 6.57 (IH, dd, J = 8.7, 2.3 Hz), 6.93-7.24 (2H, m) , 7.41 (IH, t, J = 7.7 Hz) , 7.59-7.74 (2H, m) . MS m/z 285 (M + H)⁺. [ 0515 ]

1421Reference Example 127

14223- (2-ethyl-6-fluoro-lH-benzimidazol-l-yl) -2-methylbenzaldehyde [0516]

1423To a solution of [3- (2-ethyl-6-fluoro-lH-benzimidazol-1- yl) -2-methylphenyl] methanol (6.8 g, 23.4 mmol) in acetonitrile (200 mL) was added Dess-Martin reagent (12.2 g, 28.7 mmol) at 0⁰C, and the mixture was stirred at room temperature for 30 min. An aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 20:80) to give the title compound (5.5 g, yield 83%) as an oil. ¹H NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J = 7.5 Hz), 2.27 (3H, s), 2.62 (2H, q, J = 7.5 Hz), 6.55 (IH, dd, J = 8.3, 2.3 Hz), 6.98-7.07 (IH, m) , 7.47-7.54 (IH, m) , 7.57-7.65 (IH, m) , 7.73 (IH, dd, J = 8.9, 4.7 Hz), 8.05 (IH, dd, J = 7.5, 1.5 Hz), 10.38 (IH, s). MS m/z 283 (M + H)⁺. [0517]

1424Reference Example 128 methyl { (3S) -6- [ (3-bromo-2- methylbenzyl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran- 3-yl} acetate [0518]

1425Methyl { (3S) -6- [ (3-bromo-2-methylbenzyl) amino] -2,3- dihydro-l-benzofuran-3-yl} acetate (13.2 g, 33.8 mmol) and triethylamine (6.8 g, 67.6 mmol) were dissolved in tetrahydrofuran (150 mL) , trifluoroacetic anhydride (852 mg,

142640.6 mmol) was added at 0⁰C and the mixture was stirred for 1 hr. The reaction mixture was diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give the title compound (13.5 g, yield 82%) as an oil.

1427¹H NMR (300 MHz, DMSO-d₆) δ 2.20 (3H, s) , 2.57-2.68 (IH, m) , 2.76-2.87 (IH, m) , 3.61 (3H, s) , 3.70-3.89 (IH, m) , 4.21-4.33 (IH, m) , 4.73 (IH, t, J = 9.2 Hz), 5.00 (2H, s), 6.64 (IH, d, J = 7.9 Hz), 6.75 (IH, s) , 7.00-7.12 (2H, m) , 7.18 (IH, d, J = 7.9 Hz), 7.52 (IH, dd, J = 7.2, 1.9 Hz). [0519]

1428Reference Example 129 methyl {(3S)-6-[(3-{ [2-amino-3- (benzyloxy) phenyl] amino} -2- methylbenzyl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran- 3-yl} acetate [0520]

1429Methyl { (3S) -6- [ (3-bromo-2- methylbenzyl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran- 3-yl}acetate (4.08 g, 8.41 mmol) , 3- (benzyloxy) -2-nitroaniline (1.87 g, 7.65 mmol), tris (dibenzylideneacetone) dipalladium (347 mg, 0.38 mmol), 2- (dicyclohexylphosphino) -2' , 4' , 6' - triisopropyl-1' , 1' -biphenyl (367 mg, 0.77 mmol) and tripotassium phosphate (3.25 g, 15.3 mmol) were suspended in toluene (40 mL) , and the mixture was stirred under an argon atmosphere overnight at 100⁰C. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 60:40) to give an oil (4.04 g, yield 80%). The obtained oil was suspended in ethanol (30 mL) -water (5 mL) -acetic acid (5 mL) , reduced iron (3.43 g, 61.5 mmol) and calcium chloride (6.82 g, 61.5 mmol) were added and the mixture was stirred at 70⁰C for 2 hr. The volatile component was evaporated under reduced pressure, and the residue was extracted with ethyl acetate, and the extract was washed with aqueous sodium bicarbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (2.5 g, yield 53 %) as an oil.

1430[0521]

1431Reference Example 130 methyl [ (3S) -6-{ [3- (2-ethoxy-4-hydroxy-lH-benzimidazol-l-yl) - 2-methylbenzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

1432[0522]

1433Methyl { (3S) -6- [ (3-{ [2-amino-3- (benzyloxy) phenyl] amino}- 2-methylbenzyl) (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (1.23 g, 2.0 mmol) and tetraethoxymethane (883 mg, 6.0 mmol) were dissolved in acetic acid (10 mL) , and the mixture was stirred at 60⁰C for 2 hr. The volatile component was evaporated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The volatile component was evaporated under reduced pressure. The obtained residue was suspended in methanol (30 mL) , palladium-carbon

1434(300 mg) was added, and the mixture was stirred under a hydrogen atmosphere overnight. The catalyst was removed, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80:20 - 20:80) to give the title compound (810 mg, yield 66%) as a solid.

1435[0523]

1436Reference Example 131 methyl [ (3S) -6-{ [3- (2-ethyl-4-hydroxy-lH-benzimidazol-l-yl) -2- methylbenzyl] (trifluoroacetyl) amino } -2 , 3-dihydro-l-benzofuran-

14373-yl] acetate

1438[0524]

1439Methyl { (3S) -6- [ (3-{ [2-amino-3- (benzyloxy) phenyl] amino}- 2-methylbenzyl) (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl}acetate (1.23 g, 2.0 mmol) was dissolved in N,N-dimethylacetamide (20 ml), propanoyl chloride (222 mg, 2.4 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The volatile component was evaporated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. To the obtained residue was added acetic acid (20 mL) and the mixture was stirred at 90⁰C overnight. The volatile component was evaporated under reduced pressure, the residue was diluted with an aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the volatile component was evaporated under reduced pressure. The obtained residue was suspended in methanol (40 mL) , 10% palladium-carbon (50% water-containing product, 200 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 3 hr. The catalyst was removed, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50:50 - 20:80) to give the title compound (880 mg, yield 78 %) as an oil.

1440¹H NMR (300 MHz, DMSO-d₆) δ 1.11-1.21 (3H, m) , 1.49-1.55 (3H, m) , 2.41-2.48 (2H, m) , 2.55-2.66 (IH, m) , 2.76-2.87 (IH, m) , 3.60 (3H, s), 3.73-3.86 (IH, m) , 4.22-4.31 (IH, m) , 4.69-4.79

1441(IH, m) , 5.07 (2H, s) , 6.13 (IH, d, J = 7.9 Hz), 6.56 (IH, d, J = 7.9 Hz), 6.64-6.71 (2H, m) , 6.92 (IH, td, J = 7.9, 1.5 Hz), 7 . 20-7 . 42 ( 4H, m) , 9 . 75 ( IH, s ) .

1442[0525] Reference Example 132

14433-bromo-2, 4-dimethylbenzaldehyde [0526]

1444To a solution of 2-bromo-l, 3-dimethylbenzene (5.00 g, 27.0 mmol) in dichloromethane (5 mL) was slowly added dropwise a solution of dichloro (methoxy) methane (2.69 mL, 29.7 mmol) and titanium tetrachloride (5.96 mL, 54.0 mmol) in dichloromethane (20 mL) at -78°C, the reaction mixture was heated to room temperature and stirred for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 85:15) to give the title compound (5.03 g, yield 87%) as a colorless oil.

1445¹H NMR (300 MHz, CDCl₃) δ 2.50 (3H, s) , 2.78 (3H, s) , 7.26 (IH, d, J = 8.0 Hz), 7.67 (IH, d, J = 7.6 Hz), 10.22 (IH, s) . [0527]

1446Reference Example 133

14471- (difluoromethyl) -3, 5-dimethyl-4- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) -lH-pyrazole [0528]

1448A mixed solution of 3, 5-dimethyl-4- (4, 4, 5, 5-tetramethyl- 1, 3,2-dioxaborolan-2-yl) -lH-pyrazole (0.314 g, 1.41 mmol), sodium chlorodifluoroacetate (0.259 g, 1.70 mmol) and 18- crown-6 (74.7 mg, 0.283 mmol) in acetonitrile (8 mL) was heated under reflux for 2 hr. The reaction mixture was diluted with ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (0.428 g, yield 100%) as a beige solid. ¹H NMR (300 MHz, CDCl₃) δ 1.30 (12H, s) , 2.33 (3H, s) , 2.57 (3H, s) , 7.13 (IH, t, J = 59.1 Hz) . MS m/z 273 (M + H ) ⁺ .

1449[0529] Reference Example 134

14503- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -2, 4-dimethylbenzaldehyde [0530]

1451In the same manner as in Example 184, the title compound was obtained as a yellow oil from 3-bromo-2,4- dimethylbenzaldehyde and 8- (4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl) -1, 4-dioxaspiro [4.5] dec-7-ene. yield 86%. 1H NMR (300 MHz, CDCl₃) δ 1.92 (2H, t, J = 6.4 Hz), 2.24-2.37 (5H, m) , 2.41-2.48 (2H, m) , 2.56 (3H, s) , 4.01-4.07 (4H, m) , 5.34-5.41 (IH, m) , 7.18 (IH, d, J = 7.9 Hz), 7.62 (IH, d, J = 7.9 Hz) , 10.26 (IH, s) . [0531]

1452Reference Example 135

14533- (1, 4-dioxa-8-azaspiro [4.5] dec-8-yl) -2, 4-dimethylbenzaldehyde [0532]

1454A solution of 3-bromo-2, 4-dimethylbenzaldehyde (0.919 g, 4.31 mmol) , 1, 4-dioxa-8-azaspiro [4.5] decane (0.865 g, 6.04 mmol) and cesium carbonate (4.22 g, 12.9 mmol) in toluene (7 ITiL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (0.158 g, 0.173 mmol) and 2, 2' -bis (diphenylphosphino) -1, 1' -binaphthyl (0.215 g, 0.345 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 110⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 85:15) to give the title compound (0.128 g, yield 11%) as a yellow oil.

1455¹H NMR (300 MHz, CDCl₃) δ 1.80-1.89 (4H, m) , 2.39 (3H, s) , 2.63 (3H, s), 3.08-3.26 (4H, m) , 4.02 (4H, s) , 7.13 (IH, d, J = 7.9 Hz), 7.52 (IH, d, J = 7.7 Hz), 10.23 (IH, s) . MS m/z 276 (M + H)⁺. [ 0533 ]

1456Reference Example 136 methyl 2-methyl-3- [2- (trifluoromethyl) -lH-benzimidazol-1- yl]benzoate

1457[0534]

1458A mixed solution of methyl 3- [ (2-aminophenyl) amino] -2- methylbenzoate (1.13 g, 4.40 mmol) in trifluoroacetic acid (10 mL) and trifluoroacetic anhydride (2 mL) was stirred with heating under reflux for 16 hr, and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 50:50) to give the title compound (1.44 g, yield 98%) as a colorless oil.

1459¹H NMR (300 MHz, CDCl₃) δ 2.13 (3H, s) , 3.95 (3H, s) , 6.95-7.00 (IH, m) , 7.34-7.52 (4H, m) , 7.94-8.00 (IH, m) , 8.09-8.16 (IH, m) .

1460MS m/z 335 (M + H)⁺. [0535]

1461Reference Example 137

14622-methyl-3- [2- (trifluoromethyl) -IH-benzimidazol-l- yl] benzaldehyde [0536]

1463To a solution of methyl 2-methyl-3- [2- (trifluoromethyl) - lH-benzimidazol-1-yl] benzoate (1.44 g, 4.31 mmol) in tetrahydrofuran (15 mL) was added dropwise a solution of diisobutylaluminum hydride in toluene (1.6 M, 6.74 mL, 10.8 mmol) at 0⁰C. The reaction mixture was stirred at the same temperature for 1.5 hr, sodium sulfate 10 hydrate (3.48 g, 10.8 mmol) was slowly added, and the mixture was further stirred at room temperature for 1.5 hr. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give {2-methyl-3- [2- (trifluoromethyl) -IH- benzimidazol-1-yl] phenyl }methanol as a colorless crude oil

1464(1.51 g) . To a solution of {2-methyl-3- [2- (trifluoromethyl) - lH-benzimidazol-1-yl] phenyl }methanol (0.444 g, 1.45 mmol) obtained above in acetonitrile (7 mL) was slowly added at 0°C a Dess-Martin reagent (0.738 g, 1.74 iranol) . The reaction mixture was stirred at room temperature for 40 min, aqueous sodium bicarbonate solution and saturated aqueous sodium thiosulfate solution were added, and the mixture was further stirred for 10 min. The reaction mixture was extracted with ethyl acetate, and the obtained extract was dried over sodium sulfate, and concentrated under reduced pressure to give the title compound

1465(0.296 g, yield 67%) as a yellow oil.

1466¹H NMR (300 MHz, CDCl₃) δ 2.24 (3H, s) , 6.94-7.02 (IH, m) ,

14677.36-7.50 (2H, m) , 7.54-7.67 (2H, m) , 7.99 (IH, dd, J = 8.2,

14681.2 Hz), 8.09 (IH, dd, J = 7.2, 2.3 Hz), 10.39 (IH, s) .

1469MS m/z 305 (M + H)⁺.

1470[0537]

1471Reference Example 138 methyl 3- (2-cyclopropyl-lH-benzimidazol-l-yl) -2-methylbenzoate

1472[0538]

1473In the same manner as in Reference Example 122, the title compound was obtained as a purple oil from methyl 3-[(2- aminophenyl) amino] -2-methylbenzoate and cyclopropanecarbonyl chloride, yield 95%.

1474¹H NMR (300 MHz, CDCl₃) δ 0.94-1.05 (2H, m) , 1.25-1.35 (2H, m) , 1.52-1.64 (IH, m) , 2.22 (3H, s) , 3.96 (3H, s) , 6.87 (IH, d, J = 8.0 Hz), 7.11-7.29 (2H, m) , 7.42-7.53 (2H, m) , 7.72 (IH, d, J = 7.6 Hz), 8.06 (IH, dd, J = 7.2, 1.9 Hz). MS m/z 307 (M + H)⁺.

1475[0539]

1476Reference Example 139 3- (2-cyclopropyl-lH-benzimidazol-l-yl) -2-methylbenzaldehyde

1477[0540]

1478In the same manner as in Reference Example 137, the title compound was obtained as a yellow oil from methyl 3- (2- cyclopropyl-lH-benzimidazol-l-yl) -2-methylbenzoate. yield 81%

1479(2 steps) .

1480¹H NMR (300 MHz, CDCl₃) δ 0.95-1.06 (2H, m) , 1.27-1.37 (2H, m) , 1.50-1.62 (IH, m), 2.34 (3H, s) , 6.87 (IH, d, J = 7.6 Hz), 7.12-7.21 (IH, m) , 7.22-7.31 (IH, m) , 7.56-7.64 (2H, m) , 7.74

1481(IH, d, J = 8.0 Hz), 8.00-8.09 (IH, m) , 10.41 (IH, s) . MS m/z 277 (M + H)⁺.

1482[0541]

1483Reference Example 140 methyl [ (3S) -6-{ [2-formyl-3-hydroxy-4-

1484(trifluoromethyl) benzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

1485[0542]

14862- (Dimethoxymethyl) -3- (methoxymethoxy) -4-

1487(trifluoromethyl) benzaldehyde (1.14 g, 3.69 mmol) synthesized according to WO2006/046593 and methyl [ (3S) -6-amino-2, 3- dihydro-l-benzofuran-3-yl] acetate (0.765 g, 3.69 mmol) were dissolved in acetic acid (0.634 mL, 11.1 mmol) and acetonitrile (16 mL) , sodium triacetoxyborohydride (1.57 g, 7.39 mmol) was added at 0°C, and the mixture was stirred at 0⁰C for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1488(hexane: ethyl acetate = 100:0 - 67:33) to give methyl [(3S) -6-

1489{ [2- (dimethoxymethyl) -3- (methoxymethoxy) -4-

1490(trifluoromethyl) benzyl] amino } -2 , 3-dihydro-l-benzofuran-3- yl]acetate (1.51 g) as a yellow oil. To a solution of methyl

1491[ (3S) -6-{ [2- (dimethoxymethyl) -3- (methoxymethoxy) -4-

1492(trifluoromethyl) benzyl] amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (1.51 g, 3.01 mmol) obtained above in methylene chloride (10 mL) were successively added triethylamine (0.630 mL, 4.52 mmol) and trifluoroacetic anhydride (0.511 mL, 3.62 mmol) at O⁰C. The reaction mixture was warmed to room temperature, and stirred for 4 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to give a crude product (1.83 g) of methyl [ (3S) -6-{ [2- (dimethoxymethyl) -3- (methoxymethoxy) -4-

1493(trifluoromethyl) benzyl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate as a yellow oil. To a solution of methyl [ (3S) -6-{ [2- (dimethoxymethyl) -3- (methoxymethoxy) -4-

1494(trifluoromethyl) benzyl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (1.83 g, 3.07 mmol) obtained above in acetone (10 mL) was added p-toluenesulfonic acid monohydrate

1495(0.817 g, 4.29 mmol), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was poured into a mixture of sodium bicarbonate aqueous solution and brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (1.53 g, yield 81% (3 steps) ) as an orange oil. 1H NMR (300 MHz, CDCl₃) δ 2.62 (IH, dd, J = 16.8, 9.0 Hz), 2.78

1496(IH, dd, J = 16.6, 5.7 Hz), 3.73 (3H, s) , 3.82-3.98 (IH, m) , 4.33 (IH, dd, J = 9.3, 6.5 Hz), 4.83 (IH, t, J = 9.2 Hz), 5.23

1497(2H, br s), 6.44 (IH, dd, J = 7.7, 1.1 Hz), 6.52 (IH, d, J = 1.7 Hz), 6.88 (IH, d, J = 7.9 Hz), 7.12 (IH, dd, J = 7.8, 0.8 Hz), 7.73 (IH, d, J = 8.1 Hz), 9.97 (IH, s) , 12.70 (IH, s) . MS m/z 504 (M - H)^".

1498[0543]

1499Reference Example 141 methyl [ (3S) -6-{ [3-hydroxy-2-methyl-4-

1500(trifluoromethyl) benzyl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate

1501[0544] Methyl [ ( 3S ) -6- { [2-formyl-3-hydroxy-4-

1502(trifluoromethyl) benzyl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (1.53 g, 3.03 mmol) was dissolved in methanol (10 mL) , 10% palladium-carbon (50% water-containing product, 1.5 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 16 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (1.36 g, yield 91%) as a pale-yellow oil.

1503¹H NMR (300 MHz, CDCl₃) δ 1.26 (IH, t, J = 7.2 Hz), 2.05 (3H, s), 2.59 (IH, dd, J = 16.3, 8.7 Hz), 2.76 (IH, dd, J = 16.7, 5.7 Hz), 3.71 (3H, s) , 3.81-3.92 (IH, m) , 4.30 (IH, dd, J = 9.1, 6.4 Hz), 4.79 (IH, t, J = 9.3 Hz), 4.96 (2H, s) , 6.41-6.50 (2H, m) , 6.79 (IH, d, J = 8.0 Hz), 7.06 (IH, d, J = 8.7 Hz) , 7.16-7.28 (IH, m) . [0545]

1504Reference Example 142 methyl [ (3S) -6-{ [2-methyl-4- (trifluoromethyl) -3- { [ (trifluoromethyl) sulfonyl] oxyjbenzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [0546]

1505To a solution of methyl [ (3S) -6-{ [3-hydroxy-2-methyl-4- (trifluoromethyl) benzyl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (1.36 g, 2.77 mmol) in pyridine (8 mL) was added dropwise trifluoromethanesulfonic anhydride (1.17 mL, 6.91 mmol) at 0°C. The reaction mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. To the residue was added 1 M aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with 1 M aqueous hydrochloric acid solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 65:35) to give the title compound (1.53 g, yield 89%) as a pale-yellow oil.

1506¹H NMR (300 MHz, CDCl₃) δ 2.19 (3H, s) , 2.59 (IH, dd, J = 16.7, 9.1 Hz), 2.76 (IH, dd, J = 16.7, 5.7 Hz), 3.71 (3H, s) , 3.80-3.96 (IH, m) , 4.31 (IH, dd, J = 9.3, 6.6 Hz), 4.81 (IH, t, J = 9.3 Hz), 5.02 (2H, br s) , 6.40-6.48 (IH, m) , 6.51 (IH, d, J = 1.5 Hz), 7.08 (IH, dd, J = 8.0, 0.8 Hz), 7.36 (IH, d, J = 8.0 Hz), 7.55 (IH, d, J = 8.0 Hz). MS m/z 622 (M - H)^".

1507[0547]

1508Reference Example 143 methyl [ (3S) -6-{ [2-methyl-3- (6-morpholin-4-ylpyridin-3-yl) -A-

1509(trifluoromethyl) benzyl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate

1510[0548]

1511In the same manner as in Example 184, the title compound was obtained as a yellow oil from methyl [ (3S) -6-{ [2-methyl-4-

1512(trifluoromethyl) -3-

1513{ [ (trifluoromethyl) sulfonyl] oxyJbenzyl] (trifluoroacetyl) amino}

1514-2, 3-dihydro-l-benzofuran-3-yl] acetate and (6-morpholin-4- ylpyridin-3-yl)boronic acid, yield 100%.

1515¹H NMR (300 MHz, CDCl₃) δ 1.82 (3H, s) , 2.53-2.66 (IH, m) ,

15162.71-2.82 (IH, m) , 3.52-3.60 (4H, m) , 3.72 (3H, s) , 3.80-3.95

1517(5H, m) , 4.26-4.35 (IH, m) , 4.80 (IH, t, J = 9.3 Hz), 4.89-5.10 (2H, m) , 6.49-6.60 (2H, m) , 6.68 (IH, d, J = 8.7 Hz), 7.09 (IH, d, J = 8.0 Hz), 7.21-7.29 (2H, m) , 7.54 (IH, d, J = 8.3 Hz), 7.91 (IH, d, J = 1.5 Hz). MS m/z 638 (M + H)⁺.

1518[0549]

1519Reference Example 144 methyl [ (3S) -6-{ [3- (6-methoxypyridin-3-yl) -2-methyl-4-

1520(trifluoromethyl) benzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

1521[0550]

1522In the same manner as in Example 184, the title compound was obtained as a colorless oil from methyl [(3S)-6-{[2- methyl-4- (trifluoromethyl) -3-

1523{ [ (trifluoromethyl) sulfonyl] oxy}benzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate and (6-methoxypyridin- 3-yl)boronic acid, yield 95%.

1524¹H NMR (300 MHz, CDCl₃) δ 1.79 (3H, s) , 2.54-2.65 (IH, m) , 2.71-2.82 (IH, m) , 3.72 (3H, s) , 3.81-3.95 (IH, m) , 3.99 (3H, s), 4.26-4.36 (IH, m) , 4.76-4.85 (IH, m) , 4.91-5.10 (2H, m) , 6.49-6.62 (2H, m) , 6.80 (IH, d, J = 8.3 Hz), 7.10 (IH, d, J = 8.0 Hz), 7.24-7.36 (2H, m) , 7.56 (IH, d, J = 8.3 Hz), 7.89 (IH, d, J = 1.9 Hz) . MS m/z 583 (M + H)⁺. [0551]

1525Reference Example 145

15263-bromo-2- (trifluoromethyl) imidazo [1, 2-a] pyridine [0552]

1527To a solution of 2- (trifluoromethyl) imidazo [1, 2- a] pyridine (2.81 g, 15.1 mmol) in ethanol (30 mL) was added dropwise aqueous bromine solution (1.89 M, 8.00 mL, 15.1 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, poured into a mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hexane and diisopropyl ether to give the title compound (2.90 g, yield 73%) as a beige solid.

1528H NMR (300 MHz, CDCl₃) δ 7.02-7.11 (IH, m) , 7.34-7.43 (IH, m) , 7.65-7.74 (IH, m) , 8.17-8.24 (IH, m) . [0553]

1529Reference Example 146

15304- (5-bromo-3-methylpyridin-2-yl) morpholine [0554]

1531A mixed solution of 2, 5-dibromo-3-methylpyridine (3.00 g, 12.0 mmol) and morpholine (15 mL) was stirred by microwave at

1532210⁰C for 10 min. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 75:25) to give the title compound (3.13 g, yield 100%) as a white solid.

1533¹H NMR (300 MHz, CDCl₃) δ 2.26 (3H, s) , 3.08-3.17 (4H, m) , 3.79-3.88 (4H, m) , 7.53 (IH, d, J = 3.0 Hz), 8.19 (IH, d, J = 2.6 Hz) .

1534[0555] Reference Example 147

1535(5-methyl-6-morpholin-4-ylpyridin-3-yl)boronic acid

1536[0556]

1537Under an argon atmosphere, to a suspension of magnesium

1538(0.324 g, 13.4 mmol) in tetrahydrofuran (5 mL) was added dropwise 1, 2-dibromoethane (0.2 mL) , and the mixture was stirred for 1 min. A solution of 4- (5-bromo-3-methylpyridin-2- yl)morpholine (3.12 g, 12.1 mmol) in tetrahydrofuran (15 mL) was slowly added dropwise at 7O⁰C. After completion of the dropwise addition, the reaction mixture was stirred at 70⁰C for 30 min. Then, the reaction mixture was cooled to 0⁰C, and trimethyl borate (2.03 mL, 18.2 mmol) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1.5 hr, neutralized with 1 M aqueous hydrochloric acid solution, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether-ethyl acetate to give the title compound (2.04 g, yield 76%) as a pale-yellow solid. MS m/z 223 (M + H)⁺.

1539[0557]

1540Reference Example 148 4- (5-bromopyridin-2-yl) morpholine [ 0558 ]

1541A mixture of 2, 5-dibromopyridine (20.0 g, 84.4 mmol) , morpholine (106 mL) and copper (I) oxide (0.181 g, 1.23 mmol) was heated under reflux under an argon atmosphere for 3 hr. The reaction mixture was concentrated under reduced pressure, 1 M aqueous sodium hydroxide solution (100 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (15.9 g, yield 78%) as a pale-yellow solid.

1542¹H NMR (300 MHz, CDCl₃) δ 3.36-3.50 (4H, m) , 3.71-3.87 (4H, m) , 6.53 (IH, d, J = 8.7 Hz), 7.56 (IH, dd, J = 9.1, 2.3 Hz), 8.21 (IH, d, J = 2.7 Hz) . MS m/z 243 (M + H)⁺. [0559]

1543Reference Example 149

1544(6-morpholin-4-ylpyridin-3-yl)boronic acid [0560]

1545In the same manner as in Reference Example 147, the title compound was obtained as a pale-yellow solid from 4- (5- bromopyridin-2-yl) morpholine. yield 59%.

1546¹H NMR (300 MHz, DMSO-d₆) δ 3.41-3.54 (4H, m) , 3.61-3.76 (4H, m) , 6.76 (IH, d, J = 8.7 Hz), 7.78-7.93 (IH, m) , 8.48 (IH, d, J = 1.3 Hz) . [0561]

1547Reference Example 150

15484- (5-bromo-3-fluoropyridin-2-yl) morpholine [0562]

1549In the same manner as in Reference Example 146, the title compound was obtained as a white solid from 5-bromo-2-chloro- 3-fluoropyridine and morpholine. yield 80%.

1550¹H NMR (300 MHz, CDCl₃) δ 3.42-3.50 (4H, m) , 3.78-3.86 (4H, m) , 7.39 (IH, dd, J = 12.1, 2.3 Hz), 8.03-8.09 (IH, m) . [0563] Reference Example 151

1551(5-f luoro-6-morpholin-4-ylpyridin-3-yl) boronic acid [0564]

1552In the same manner as in Reference Example 147, the title compound was obtained as a brown solid from 4- (5-bromo-3- f luoropyridin-2-yl)morpholine. yield 39%. MS m/z 227 (M + H)⁺. [0565]

1553Reference Example 152 methyl [ (3S) -6-{ [3- (5-f luoro-6-morpholin-4-ylpyridin-3-yl) -2- methyl-4- (trif luoromethyl) benzyl] (trif luoroacetyl) amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate [0566]

1554In the same manner as in Example 184, the title compound was obtained as a pale-yellow oil from methyl [(3S)-6-{ [2- methyl-4- (trif luoromethyl) -3-

1555{ [ (trif luoromethyl) sulfonyl] oxy}benzyl] (trif luoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate and (5-fluoro-6- morpholin-4-ylpyridin-3-yl) boronic acid, yield 72%. 1H NMR (300 MHz, CDCl₃) δ 2.04 (3H, s) , 2.54-2.66 (IH, m) , 2.71-2.83 (IH, m) , 3.51-3.61 (4H, m) , 3.72 (3H, s) , 3.81-3.92 (5H, m) , 4.27-4.35 (IH, m) , 4.81 (IH, t, J = 9.2 Hz), 5.00 (2H, s), 6.50 (IH, s), 6.58 (IH, d, J = 7.9 Hz), 7.00-7.13 (2H, m) , 7.30 (IH, d, J = 7.9 Hz), 7.56 (IH, d, J = 8.3 Hz), 7.74 (IH, s) .

1556[0567]

1557Reference Example 153 ethyl 3-hydroxypyridine-2-carboxylate [0568]

1558A mixed solution of 3-hydroxypyridine-2-carboxylic acid (8.00 g, 57.5 mmol) and concentrated sulfuric acid (4 mL) in ethanol (160 mL) and toluene (40 mL) was heated under reflux for 16 hr using a Dean-Stark apparatus. The reaction mixture was concentrated under reduced pressure to about 1/4, an aqueous sodium bicarbonate solution was slowly added to basify the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =

155995:5 - 75:25) to give the title compound (5.12 g, yield 53%) as a pale-yellow oil.

1560¹H NMR (300 MHz, CDCl₃) δ 1.49 (3H, t, J = 7.2 Hz), 4.54 (2H, q,

1561J = 6.9 Hz), 7.34-7.46 (2H, m) , 8.30 (IH, dd, J = 4.2, 1.9 Hz),

156210.77 (IH, s).

1563MS m/z 168 (M + H)⁺.

1564[0569]

1565Reference Example 154 ethyl 3- (2-ethoxy-l-methyl-2-oxoethoxy) pyridine-2-carboxylate

1566[0570]

1567A mixed solution of ethyl 3-hydroxypyridine-2-carboxylate

1568(5.12 g, 30.6 mmol) , ethyl 2-bromopropionate (4.77 mL, 36.8 mmol) and potassium carbonate (8.47 g, 61.3 mmol) in N, N- dimethylformamide (80 mL) was stirred at 90°C for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 50:50) to give the title compound (6.01 g, yield 73%) as a yellow oil.

1569¹H NMR (300 MHz, CDCl₃) δ 1.24 (3H, t, J = 7.2 Hz), 1.43 (3H, t, J = 7.2 Hz), 1.68 (3H, d, J = 6.8 Hz), 4.17-4.26 (2H, m) , 4.46

1570(2H, q, J = 7.2 Hz), 4.77 (IH, q, J = 6.8 Hz), 7.22-7.29 (IH, m) , 7.31-7.39 (IH, m) , 8.31-8.35 (IH, m) . MS m/z 268 (M + H)⁺.

1571[0571]

1572Reference Example 155 2-methylfuro [3, 2-b] pyridin-3-ol

1573[0572]

1574To a solution of ethyl 3- (2-ethoxy-l-methyl-2- oxoethoxy) pyridine-2-carboxylate (6.01 g, 22.5 mmol) in toluene (45 inL) was added sodium ethoxide (1.91 g, 28.1 mmol), and the mixture was heated under reflux for 16 hr. The reaction mixture was cooled to room temperature, diluted with water (160 mL) , and acidified with acetic acid. Then, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and 1 M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was -dried over sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether-ethyl acetate to give the title compound (1.45 g, yield 43%) as a brown solid.

1575¹H NMR (300 MHz, CDCl₃) δ 2.54 (3H, s) , 7.14 (IH, dd, J = 8.3, 4.9 Hz), 7.62 (IH, dd, J = 8.1, 1.3 Hz), 8.38 (IH, dd, J = 4.9, 1.1 Hz) . [0573]

1576Reference Example 156

15772-methylfuro [3, 2-b] pyridin-3-yl trifluoromethanesulfonate [0574]

1578To a solution of 2-methylfuro [3, 2-b] pyridin-3-ol (0.483 g, 3.24 mmol) in pyridine (8 mL) was added dropwise trifluoromethanesulfonic anhydride (0.820 mL, 4.86 mmol) at 0⁰C. The reaction mixture was warmed to room temperature, stirred for 16 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 65:35) to give the title compound (0.466 g, yield 51%) as a pale-yellow oil.

1579¹H NMR (300 MHz, CDCl₃) δ 2.58 (3H, s) , 7.23-7.30 (IH, m) , 7.70 (IH, dd, J = 8.7, 1.5 Hz), 8.60 (IH, dd, J = 4.7, 1.3 Hz). MS m/z 282 (M + H)⁺. [0575] Reference Example 157 2-methylfuro [2 , 3-b] pyridin-3 ( 2H) -one

1580[ 0576]

1581To a suspension of sodium hydride (60% in oil, 6.68 g, 0.167 mol) in 1, 2-dimethoxyethane (100 mL) was added dropwise ethyl lactate (16.0 mL, 0.140 mol) at 0°C over 20 min. The reaction mixture was stirred at room temperature for 30 min, and ethyl 2-chloronicotinate (10.0 g, 53.9 mmol) was added at room temperature over 10 min. The reaction mixture was heated to 80⁰C, stirred for 16 hr, and concentrated under reduced pressure. The residue was dissolved in water, washed with toluene, acetic acid was added and, under acidic conditions, the mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (4.50 g, yield 56%) as a red oil.

1582¹H NMR (300 MHz, CDCl₃) δ 1.60 (3H, d, J = 7.2 Hz), 4.80 (IH, d, J = 7.2 Hz), 7.13 (IH, dd) , 8.04 (IH, dd, J = 7.4, 2.1 Hz), 8.59 (IH, dd, J = 4.9, 2.3 Hz). MS m/z 150 (M + H)⁺. [0577]

1583Reference Example 158

15842-methyl-2, 3-dihydrofuro [2, 3-b]pyridin-3-yl acetate [0578]

1585To a mixed solution of 2-methylfuro [2, 3-b]pyridin-3 (2H) - one (4.50 g, 30.2 mmol) in tetrahydrofuran (40 mL) and methanol (20 mL) was added at 0⁰C sodium borohydride (1.14 g, 30.2 mmol), and the mixture was stirred at the same temperature for 45 min. The reaction mixture was concentrated under reduced pressure, diluted with brine, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure to give crude 2-methyl-2, 3-dihydrofuro [2, 3-b] pyridin-3-ol (3.30 g) as a yellow oil. The obtained crude 2-methyl-2, 3- dihydrofuro [2, 3-b] pyridin-3-ol (3.30 g, 21.8 mmol) was dissolved in pyridine (30 mL) , and acetic anhydride (30 mL, 318 iranol) was added at room temperature. The reaction mixture was stirred for 16 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (3.20 g, yield 55% (2 steps)) as a yellow oil.

1586¹H NMR (300 MHz, CDCl₃) δ 1.44-1.56 (3H, m) , 2.09 (3H, s) , 4.76-4.90 (IH, m) , 5.82-6.17 (IH, m) , 6.84-6.93 (IH, in) , 7.71-7.79 (IH, m) , 8.16-8.23 (IH, m) . MS m/z 194 (M + H)⁺. [0579]

1587Reference Example 159 2-methylfuro [2, 3-b] pyridine [0580]

1588To 2-methyl-2, 3-dihydrofuro [2, 3-b]pyridin-3-yl acetate (3.13 g, 16.2 mmol) was added polyphosphoric acid (30 g) , and the mixture was stirred at 100⁰C for 16 hr. The reaction mixture was cooled to room temperature, ice was slowly added, and the mixture was alkalified with 28% aqueous ammonia solution and extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure to give the title compound (2.15 g, yield 100%) as a brown oil.

1589¹H NMR (300 MHz, CDCl₃) δ 2.49 (3H, d, J = 1.1 Hz), 6.38 (IH, q, J = 1.1 Hz), 7.15 (IH, dd, J = 7.6, 4.9 Hz), 7.78 (IH, dd, J = 7.6, 1.9 Hz), 8.21 (IH, dd, J = 4.9, 1.9 Hz). [0581]

1590Reference Example 160 3-bromo-2-methylfuro [2, 3-b] pyridine [0582]

1591A solution of 2-methylfuro [2, 3-b] pyridine (0.504 g, 3.79 mmol) in dichloromethane (4 πiL) was cooled to -15°C, a solution of bromine (0.638 mL, 13.3 mmol) in dichloromethane (3 mL) was slowly added dropwise. The reaction mixture was -stirred at room temperature for 6 hr, and concentrated under reduced pressure. The residue was diluted with 1 M sodium hydroxide, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 75:25) to give the title compound (0.432 g, yield 54%) as a pale-yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 2.52 (3H, s) , 7.22-7.29 (IH, m) , 7.76 (IH, dd, J = 7.9, 1.9 Hz), 8.28 (IH, dd, J = 4.9, 1.9 Hz). [0583]

1592Reference Example 161 methyl { (3S) -6- [ (4-bromo-2, 3-dihydro-lH-inden-l-yl) amino] -2,3- dihydro-l-benzofuran-3-yl}acetate [0584]

1593To a mixed solution of 4-bromoindan-l-one (1.00 g, 4.74 mmol) and methyl [ (3S) -6-amino-2, 3-dihydro-l-benzofuran-3- yl] acetate (1.03 g, 4.97 mmol) in methanol (10 mL) , acetic acid (1 mL) and tetrahydrofuran (2 mL) was added at 0⁰C borane- 2-picoline complex (0.640 g, 5.69 mmol), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, 1 M aqueous hydrochloric acid solution and ethyl acetate were added, and the mixture was stirred for 30 min. Then, sodium carbonate was slowly added to neutralize the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 75:25) to give the title compound (1.75 g, yield 92%) as a pale-yellow oil. ¹H NMR (300 MHz, CDCl₃) δ 1.81-1.99 (IH, m) , 2.48-2.66 (2H, m) , 2.75 (IH, dd, J = 16.7, 5.7 Hz), 2.80-2.96 (IH, m) , 2.96-3.13 (IH, m), 3.67-3.85 (4H, m) , 3.94 (IH, br s), 4.24 (IH, dd, J = 9.3, 5.9 Hz), 4.73 (IH, t, J = 8.9 Hz), 5.03 (IH, t, J = 6.8 Hz), 6.15-6.23 (2H, m) , 6.95 (IH, d, J = 8.7 Hz), 7.07 (IH, t, J = 7.8 Hz), 7.29 (IH, d, J = 6.8 Hz), 7.41 (IH, d, J = 8.0 Hz) . MS m/ z 402 (M + H) ⁺ .

1594[0585] Reference Example 162 methyl { (3S) -6- [ (4-bromo-2, 3-dihydro-lH-inden-l- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate

1595[0586]

1596A mixed solution of methyl { (3S) -6- [ (4-bromo-2, 3-dihydro- IH-inden-l-yl) amino] -2, 3-dihydro-l-benzofuran-3-yl} acetate (1.75 g, 4.35 mmol) and triethylamine (0.910 inL, 6.53 mmol) was cooled to 0⁰C, and trifluoroacetic anhydride (0.738 mL, 5.23 mmol) was slowly added dropwise. The reaction mixture was warmed to room temperature, and stirred for 1.5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 70:30) to give the title compound (1.51 g, yield 70%) as a yellow oil.

1597¹H NMR (300 MHz, CDCl₃) δ 1.91-2.08 (IH, m) , 2.55-2.83 (3H, m) , 2.84-3.01 (IH, m) , 3.02-3.18 (IH, m) , 3.69-3.91 (4H, m) , 4.31-4.43 (IH, m) , 4.80-4.91 (IH, m) , 5.13 (IH, q, J = 7.0 Hz), 6.33 (IH, s), 7.11 (IH, t, J = 7.7 Hz), 7.23-7.33 (IH, m) , 7.44 (IH, d, J = 7.9 Hz), 7.54-7.60 (IH, m) , 9.50 (IH, d, J = 7.2 Hz) . [0587]

1598Reference Example 163 optically active form (A) of methyl { (3S) -6- [ (4-bromo-2, 3- dihydro-lH-inden-1-yl) (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0588]

1599Methyl { (3S) -6- [ (4-bromo-2, 3-dihydro-lH-inden-l- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (1.33 g) was resolved by preparative HPLC to give the title compound (0.633 g, recovery rate 96%, enantiometric excess 99.9%d.e.) as a pale-yellow oil. (high performance liquid chromatography conditions) column: CHIRALCEL OJ (manufactured by Daicel Chemical Industries, Ltd.) mobile phase: hexane/isopropyl alcohol (volume ratio: 90/10) flow rate: 80 mL/min detection: UV (254 run) temperature: 30⁰C retention time: 7.6 min (area ratio: 99.90%) [0589]

1600Reference Example 164 optically active form (B) of methyl { (3S) -6- [ (4-bromo-2, 3- dihydro-lH-inden-1-yl) (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0590]

1601Methyl { (3S) -6- [ (4-bromo-2, 3-dihydro-lH-inden-l- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (1.33 g) was resolved by preparative HPLC to give the title compound (0.609 g, recovery rate 92%, enantiometric excess 99.9%d.e.) as a pale-yellow oil. (high performance liquid chromatography conditions) column: CHIRALCEL OJ (manufactured by Daicel Chemical Industries, Ltd.) mobile phase: hexane/isopropyl alcohol (volume ratio: 90/10) flow rate: 80 mL/min detection: UV (254 run) temperature: 30°C retention time: 9.9 min (area ratio: 99.90%) [0591]

1602Reference Example 165 methyl { (3S)-6-[{4-[ (5-fluoro-2-nitrophenyl) amino] -2, 3- dihydro-lH-inden-1-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0592] Methyl { ( 3S ) -6- [ ( 4-bromo-2 , 3-dihydro-lH-inden-l- yl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (1.51 g, 3.04 πunol) , 5-fluoro-2-nitroaniline (0.522 g, 3.34 mmol) and tripotassium phosphate (1.29 g, 6.08 mmol) were suspended in toluene (20 mL) and, after argon substitution, tris (dibenzylideneacetone) dipalladium (0) (0.139 g, 0.152 mmol) and 2-dicyclohexylphosphino-2' , 4' , 6' - triisopropylbiphenyl (0.145 g, 0.304 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 70:30) to give the title compound (1.64 g, yield 94%) as a brown noncrystalline powder. MS m/z 572 (M - H)^". [0593]

1603Reference Example 166 methyl { (3S) -6- [{4- [ (2-amino-5-fluorophenyl) amino] -2, 3- dihydro-lH-inden-1-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0594]

1604Methyl { (3S) -6-[{4-[ (5-fluoro-2-nitrophenyl) amino] -2, 3- dihydro-lH-inden-1-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (1.64 g, 2.86 mmol) was dissolved in methanol (15 mL) and tetrahydrofuran (5 mL) , 10% palladium- carbon (50% water-containing product, 0.4 g) was added, and the mixture was stirred under a hydrogen atmosphere (balloon pressure) at room temperature for 4 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.47 g, yield 95%) as a purple non-crystalline powder. MS m/z 544 (M + H)⁺. [0595] Reference Example 167 methyl [ ( 3S ) -6- { [ 4- ( 6-f luoro-2-methyl-lH-benzimidazol-l-yl ) - 2 , 3-dihydro-lH-inden-l-yl ] ( trif luoroacetyl ) amino } -2 , 3-dihydro- 1-benzof uran-3-yl ] acetate

1605[ 0596 ]

1606A mixed solution of methyl { (3S) -6- [ {4- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-lH-inden-l- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (0.300 g, 0.552 mmol) in acetic acid (4 mL) and acetic anhydride (2 mL) was heated under reflux for 16 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1607(hexane: ethyl acetate = 90:10 - 0:100) to give the title compound (0.315 g, yield 100%) as a pale-yellow oil. MS m/z 568 (M + H)⁺.

1608[0597]

1609Reference Example 168 methyl [ (3S) -6-{ [4- (2-ethyl-6-fluoro-lH-benzimidazol-1-yl) - 2, 3-dihydro-lH-inden-l-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate

1610[0598]

1611A solution of methyl { (3S) -6- [ { 4- [ (2-amino-5- fluorophenyl) amino] -2, 3-dihydro-lH-inden-l- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (0.590 g, 1.30 mmol) in N,N-dimethylacetamide (5 mL) was cooled to 0⁰C, and propionyl chloride (0.114 mL, 1.30 mmol) was slowly added. The reaction mixture was stirred at room temperature for 5 hr, poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. Then, the residue was dissolved in acetic acid (8 mL) and the mixture was stirred for 16 hr with heating under reflux, and concentrated under reduced pressure. To the residue was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 20:80) to give the title compound (0.617 mg, yield 98%) as a pale-red non-crystalline powder. MS m/z 582 (M + H)⁺. [0599]

1612Reference Example 169 methyl [ (3S) -6-{ [4- (2-ethoxy-6-fluoro-lH-benzimidazol-l-yl) - 2, 3-dihydro-lH-inden-l-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate [0600]

1613Methyl { (3S)-6-[{4-[ (2-amino-5-fluorophenyl) amino] -2, 3- dihydro-lH-inden-1-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (0.567 g, 1.04 mmol) and tetraethoxymethane (0.654 itiL, 3.13 mmol) were dissolved in acetic acid (6 mL) , and the mixture was stirred at 60⁰C for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 50:50) to give the title compound (0.553 g, yield 89%) as a pale-yellow non-crystalline powder. MS m/z 598 (M + H)⁺. [0601]

1614Reference Example 170 methyl 3- (2-ethyl-7-methyl-lH-benzimidazol-l-yl) -2- methylbenzoate [0602]

1615In the same manner as in Reference Example 168, the title compound was obtained as a purple oil from methyl 3-[(2-amino-

16166-methylphenyl) amino] -2-methylbenzoate. yield 82%. 1H NMR (300 MHz, CDCl₃) δ 1.33 (3H, t, J = 7.5 Hz), 1.82 (3H, s), 2.15 (3H, s), 2.54 (2H, q, J = 7.5 Hz), 3.95 (3H, s), 6.88-6.95 (IH, m) , 7.16 (IH, t, J = 7.7 Hz), 7.37-7.50 (2H, m) , 7.66 (IH, d, J = 7.9 Hz), 8.07 (IH, dd, J = 7.5, 1.9 Hz). MS m/z 309 (M + H)⁺. [0603]

1617Reference Example 171 methyl { (3S) -6- [ { 3- [ (5-fluoropyridin-2-yl) amino] -2- methylbenzyl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran- 3-yl} acetate [0604]

1618A solution of methyl { (3S) -6- [ (3-bromo-2- methylbenzyl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran- 3-yl}acetate (0.380 g, 0.781 mmol) , 5-fluoropyridin-2-amine (0.105 g, 0.938 mmol) and cesium carbonate (0.509 g, 1.56 mmol) in toluene (5 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (28.6 mg, 0.0310 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (36.2 mg, 0.0630 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 105⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 65:35), and then preparative HPLC (water: acetonitrile = 60:40 - 0:100) to give the title compound (0.243 g, yield 60%) as a pale-yellow oil. 1H NMR (300 MHz, CDCl₃) δ 2.00 (3H, s) , 2.57 (IH, dd, J = 16.6, 8.7 Hz), 2.75 (IH, dd, J = 16.6, 5.7 Hz), 3.71 (3H, s) , 3.77-3.94 (IH, m) , 4.28 (IH, dd, J = 9.4, 6.4 Hz), 4.78 (IH, t, J = 9.2 Hz), 4.99 (2H, s) , 6.14 (IH, s), 6.38-6.57 (3H, m) , 6.95 (IH, d, J = 7.5 Hz), 7.01-7.16 (2H, m) , 7.17-7.33 (2H, m) , 8.03 (IH, d, J = 3.0 Hz) . MS m/ z 518 (M + H) ⁺ .

1619[0605] Reference Example 172

16203-bromo-5-fluoro-2-methyl-lH-indole [0606]

1621To a solution of 5-fluoro-2-methyl-lH-indole (1.50 g, 10.1 mmol) in dichloromethane (30 mL) was slowly added dropwise a solution of bromine (1.69 g, 10.6 mmol) in dichloromethane (3 mL) . The reaction mixture was stirred at room temperature for 6 hr, and concentrated under reduced pressure. To the residue was added 1 M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 75:25) to give the title compound (1.95 g, yield 85%) as a pale-yellow oil.

1622¹H NMR (300 MHz, CDCl₃) δ 2.41 (3H, s) , 6.82-6.95 (IH, m) , 7.07-7.20 (2H, m) , 8.06 (IH, br s) . [0607]

1623Reference Example 173

16243-bromo-5-fluoro-2-methyl-l- [3- (methylsulfonyl) propyl] -IH- indole [0608]

1625To a solution of 3-bromo-5-fluoro-2-methyl-lH-indole (1.05 g, 4.59 mmol) in N,N-dimethylformamide (14 mL) was slowly added at 0⁰C sodium hydride (60% in oil, 0.220 g, 5.51 mmol) , and the mixture was stirred at the same temperature for 40 min. Further, 3- (methylsulfonyl) propyl 4- methylbenzenesulfonate (1.48 g, 5.05 mmol) obtained according to WO2007/018314 was slowly added at 0°C. The reaction mixture was stirred at room temperature for 16 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 20:80) to give the title compound (0.837 g, yield 55%) as a red oil.

1626¹H NMR (300 MHz, CDCl₃) δ 2.24-2.38 (2H, m) , 2.45 (3H, s) , 2.90

1627(3H, s), 2.97 (2H, t, J = 6.8 Hz), 4.32 (2H, t, J = 7.0 Hz), 6.90-7.00 (IH, m) , 7.12-7.27 (2H, m) . MS m/z 348 (M 4- H)⁺.

1628[0609]

1629Reference Example 174 methyl [ (3S) -6-{ [3- (4, 6-dimethyl-2-morpholin-4-ylpyrimidin-5- yl) -2-methylbenzyl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

1630[0610]

1631Methyl { (3S) -6- [ (3-bromo-2- methylbenzyl) (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran- 3-yl}acetate (4.06 g, 8.35 mmol) , and (4, 6-dimethyl-2- morpholin-4-ylpyrimidin-5-yl) boronic acid (2.38 g, 10.0 mmol) were suspended in a mixed solution of 2 M aqueous sodium carbonate solution (10.0 rtiL) and toluene (50 mL) and, after argon substitution, tris (dibenzylideneacetone) dipalladium (0)

1632(0.306 g, 0.334 mmol) and 2-dicyclohexylphosphino-2' , 6' - dimethoxybiphenyl (0.565 g, 1.34 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (3.63 g, yield 73%) as a white noncrystalline powder.

1633¹H NMR (300 MHz, CDCl₃) δ 1.70 (3H, s) , 1.93 (6H, s) , 2.56 (IH, dd, J = 16.7, 9.1 Hz), 2.74 (IH, dd, J = 15.9, 4.9 Hz), 3.71

1634(3H, s), 3.73-3.91 (9H, m) , 4.25 (IH, dd, J = 9.1, 6.8 Hz), 4.76 (IH, t, J = 9.1 Hz), 5.02 (2H, s) , 6.37 (IH, s) , 6.48 (IH, d, J = 8.0 Hz), 6.94 (IH, d, J = 6.8 Hz), 7.02 (IH, d, J = 7.6 Hz ) , 7 . 11-7 . 23 (2H, m) .

1635MS m/z 599 (M + H)⁺. [0611] Reference Example 175 methyl 3- (2-ethoxy-6-fluoro-lH-benzimidazol-1-yl) -2- methylbenzoate [0612]

1636A solution of methyl 3- [ (2-amino-5-fluorophenyl) amino] -2- methylbenzoate (2.0 g, 7.29 mmol) and tetraethyl orthocarbonate (4.23 g, 22 mmol) in acetic acid (20 mL) was stirred at 60°C for 3 hr. The solvent was concentrated, the residue was poured into an aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 75:25) to give the title compound (1.92 g, yield 80%) as an oil. 1H NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J = 7.2 Hz), 2.25 (3H, s), 3.94 (3H, s), 4.52-4.64 (2H, m) , 6.51-6.54 (IH, m) , 6.89-6.96 (IH, m) , 7.40-7.42 (2H, m) , 7.47-7.52 (IH, m) , 8.00-8.03 (IH, m) . MS m/z 329 (M + H)⁺. [0613]

1637Reference Example 176

1638[3- (2-ethoxy-6-fluoro-lH-benzimidazol-1-yl) -2- methylphenyl] methanol [0614]

1639Lithium aluminum hydride (2.0 M tetrahydrofuran solution,

16404.5 mL, 9.0 mmol) was added dropwise at 0⁰C to a solution of methyl 3- (2-ethoxy-6-fluoro-lH-benzimidazol-l-yl) -2- methylbenzoate (1.92 g, 5.83 mmol) in tetrahydrofuran (200 mL) , and the mixture was stirred at 0⁰C for 1 hr. To the reaction mixture was added sodium sulfate 10 hydrate, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give the title compound (1.80 g, yield quant.) as an oil.

1641¹H NMR (300 MHz, CDCl₃) δ 1.39 (3H, t, J = 7.2 Hz), 2.01 (3H, s), 3.00 (IH, br), 4.50-4.61 (2H, m) , 4.80 (2H, s) , 6.51-6.55 (IH, m) , 6.86-6.94 (IH, m) , 7.18-7.21 (IH, m) , 7.32-7.37 (IH, m) , 7.43-7.48 (IH, m) , 7.56-7.58 (IH, m) . [0615]

1642Reference Example 177 methyl 2-methyl-3-{ [2-nitro-4- (trifluoromethyl) phenyl] amino Jbenzoate [0616]

1643A suspension of l-bromo-2-nitro-4-

1644(trifluoromethyl) benzene (8.1 g, 30 mmol) , methyl 3-amino-2- methylbenzoate (4.13 g, 25 mmol), tris (dibenzylideneacetone) dipalladium (0) (800 mg, 0.87 mmol), bis (2-diphenylphosphinophenyl) ether (942 mg, 1.75 mmol) and tripotassium phosphate (15.9 g, 75 mmol) in toluene (100 mL) was stirred overnight under an argon atmosphere at 105⁰C. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 30:70) to give the title compound (8.0 g, yield 90%) as a solid.

1645¹H NMR (300 MHz, CDCl₃) δ 2.47 (3H, s) , 3.94 (3H, s) , 6.74 (IH, d, J = 9.0 Hz), 7.34-7.44 (2H, m) , 7.49-7.52 (IH, m) , 7.85-7.88 (IH, m) , 8.52 (IH, d, J = 1.2 Hz), 9.55 (IH, s) . [0617]

1646Reference Example 178 methyl 3-{ [2-amino-4- (trifluoromethyl) phenyl] amino}-2- methylbenzoate [0618]

1647A suspension of methyl 2-methyl-3-{ [2-nitro-4- (trifluoromethyl) phenyl] amino }benzoate (8.0 g, 22.5 mmol) and palladium-carbon (1.0 g) in methanol (300 mL) was stirred under a hydrogen atmosphere overnight at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (7.3 g, yield quant.) as a solid.

1648¹H NMR (300 MHz, CDCl₃) 52.45 (3H, s), 3.78 (2H, s) , 3.91 (3H, s) , 5.28 (IH, s) , 6.86-6.93 (2H, m) , 6.97-7.02 (2H, m) , 7.15

1649(IH, t, J = 8.1 Hz) , 7.43-7.46 (IH, m) .

1650[0619]

1651Reference Example 179 methyl 2-methyl-3-{ [2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] amino} -4- (trifluoromethyl) phenyl] amino}benzoate

1652[0620]

1653A solution of methyl 3-{ [2-amino-4-

1654(trifluoromethyl) phenyl] amino }-2-methylbenzoate (7.3 g, 22.5 mmol), (2R) -tetrahydrofuran-2-ylcarboxylic acid (2.79 g, 24 mmol) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.18 g, 27 mmol) and 1-hydroxy-lH-benzotriazole monohydrate (4.13 g, 27 mmol) in acetonitrile (200 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80:20 - 50:50) to give the title compound (9.22 g, yield 97%) as an oil. 1H NMR (300 MHz, CDCl₃) δl.75-1.84 (IH, m) , 1.87-1.96 (IH, m) , 2.06-2.13 (IH, m) , 2.29-2.38 (IH, m) , 2.46 (3H, s) , 3.73-3.89

1655(2H, m) , 3.91 (3H, s) , 4.45-4.49 (IH, m) , 6.29 (IH, s) , 6.99-7.03 (2H, m) , 7.14 (IH, t, J = 8.1 Hz), 7.33 (IH, d, J = 8.7 Hz), 7.48 (IH, d, J = 7.8 Hz), 7.85 (IH, s) , 8.67 (IH, s) .

1656[0621]

1657Reference Example 180 methyl 2-methyl-3-{2- [ (2R) -tetrahydrofuran-2-yl] -5- (trifluoromethyl) -lH-benzimidazol-1-yl }benzoate [0622]

1658Methyl 2-methyl-3-{ [2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] amino} -4- (trifluoromethyl) phenyl] amino }benzoate (9.22 g, 21.8 mmol) and polyphosphoric acid (18 g) were stirred at 130⁰C for 17 min, and the reaction container was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 90:10 - 75:25) to give the title compound (5.76 g, yield 65%) as an oil. 1H NMR (300 MHz, CDCl₃) δl.89-2.00 (IH, m) , 2.12-2.17 (3H, m) , 2.18-2.27 (2H, m) , 2.51-2.62 (IH, m) , 3.78-3.90 (2H, m) , 3.95 (3H, s), 4.79-4.91 (IH, m) , 6.96-6.99 (IH, m) , 7.38-7.56 (3H, m) , 8.07-8.10 (IH, m) , 8.13 (IH, s) . [0623]

1659Reference Example 181

1660(2-methyl-3-{2- [ (2R) -tetrahydrofuran-2-yl] -5- (trifluoromethyl) -lH-benzimidazol-l-yl}phenyl) methanol [0624]

1661Lithium aluminum hydride (2.0 M tetrahydrofuran solution, 8.5 mL, 17 mmol) was added dropwise to a solution of methyl 2- methyl-3-{2- [ (2R) -tetrahydrofuran-2-yl] -5- (trifluoromethyl) - lH-benzimidazol-l-yl}benzoate (5.76 g, 14.2 mmol) in tetrahydrofuran (250 mL) at 0⁰C, and the mixture was stirred at 0⁰C for 1 hr. Sodium sulfate 10 hydrate was added to the reaction mixture at 0⁰C, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give the title compound (5.39 g, yield quant.) as an oil. 1H NMR (300 MHz, CDCl₃) δl.83-2.02 (4H, m) , 2.13-2.27 (2H, m) , 2.30-2.56 (IH, m) , 3.69-3.87 (3H, m) , 4.76-4.88 (3H, m) , 6.96-6.99 (IH, m) , 7.16-7.46 (3H, m) , 7.64 (IH, t, J = 7.2 Hz), 8 . 11 ( IH, s ) .

1662[0625] Reference Example 182

16632-methyl-3-{2- [ (2R) -tetrahydrofuran-2-yl] -5- (trifluoromethyl) - lH-benzimidazol-l-yl}benzaldehyde

1664[0626]

1665To a solution of (2-methyl-3-{2- [ (2R) -tetrahydrofuran-2- yl] -5- (trifluoromethyl) -lH-benzimidazol-1-yl }phenyl) methanol

1666(1.58 g, 4.2 mmol) in acetonitrile (25 mL) was added Dess- Martin periodonane (2.O g, 4.7 mmol) at 0°C, and the mixture was stirred at 0°C for 0.5 hr. An aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80:20 - 50:50) to give the title compound (0.866 g, yield 55%) as an oil.

1667¹H NMR (300 MHz, CDCl₃) δl.91-2.00 (IH, m) , 2.11-2.30 (5H, m) , 2.58-2.65 (IH, m) , 3.78-3.85 (2H, m) , 4.82-4.94 (IH, m) , 6.96-7.00 (IH, m), 7.46-7.67 (3H, m) , 8.03-8.07 (IH, m) , 8.13

1668(IH, s) , 10.36-10.38 (IH, m) .

1669[0627]

1670Reference Example 183 methyl 2-methyl-3-{ [2-nitro-4-

1671(trifluoromethoxy) phenyl] amino}benzoate

1672[0628]

1673A suspension of 2-nitro-4- (trifluoromethoxy) aniline (5.0 g, 22.5 mmol), methyl 3-bromo-2-methylbenzoate (4.81 g, 21 mmol), tris (dibenzylideneacetone) dipalladium (0) (800 mg, 0.87 mmol) , 2-dicyclohexylphosphino-2' , 4' , 6' -triisopropylbiphenyl

1674(834 mg, 1.75 mmol) and tripotassium phosphate (9.34 g, 44 mmol) in toluene (140 mL) was stirred at 105⁰C overnight under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

1675(hexane: ethyl acetate = 98:2 - 90:10) to give the title compound (8.19 g, yield quant.) as a solid.

1676¹H NMR (300 MHz, CDCl₃) δ 2.47 (3H, s) , 3.93 (3H, s) , 6.71 (IH, d, J = 9.3 Hz), 7.20-7.25 (IH, m) , 7.31-7.43 (2H, m) , 7.81-7.84 (IH, m) , 8.12-8.13 (IH, m) , 9.33 (IH, s) .

1677[0629]

1678Reference Example 184 methyl 3-{ [2-amino-4- (trifluoromethoxy) phenyl] amino}-2- methylbenzoate

1679[0630]

1680A suspension of methyl 2-methyl-3-{ [2-nitro-4-

1681(trifluoromethoxy) phenyl] amino }benzoate (8.19 g, 22.1 mmol) and palladium-carbon (1.0 g) in methanol (500 mL) was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (7.25 g, yield quant.) as a solid.

1682¹H NMR (300 MHz, CDCl₃) δ 2.46 (3H, s) , 3.88 (2H, s) , 3.90 (3H, s), 5.07 (IH, s), 6.57-6.61 (IH, m) , 6.65-6.69 (IH, m) , 6.91-6.94 (IH, m) , 7.06-7.16 (IH, m) , 7.20-7.26 (IH, m) , 7.30-7.32 (IH, m) .

1683[0631]

1684Reference Example 185 methyl 2-methyl-3-{ [2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] amino} -4- (trifluoromethoxy) phenyl] amino Jbenzoate

1685[0632]

1686A solution of methyl 3-{ [2-amino-4-

1687(trifluoromethoxy) phenyl] amino} -2-methylbenzoate (7.15 g, 21 mmol), (2R) -tetrahydrofuran-2-ylcarboxylic acid (2.44 g, 21 mmol) , l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.79 g, 25 mmol) and 1-hydroxy-lH-benzotriazole monohydrate (3.83 g, 25 mmol) in acetonitrile (150 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 80:20 - 50:50) to give the title compound (8.1 g, yield 88%) as a solid. 1H NMR (300 MHz, CDCl₃) δl.56-1.67 (IH, m) , 1.76-1.85 (IH, m) , 1.97-2.08 (IH, m), 2.20-2.32 (IH, m) , 2.50 (3H, s) , 3.40-3.47 (IH, m) , 3.68-3.75 (IH, m) , 3.91 (3H, s) , 4.37-4.41 (IH, m) , 5.60 (IH, s), 6.68 (IH, d, J = 8.1 Hz), 6.96-7.00 (IH, m) , 7.04-7.09 (2H, m) , 7.35 (IH, d, J = 7.8 Hz), 8.01 (IH, d, J = 1.8 Hz) , 8.83 (IH, s) . [0633]

1688Reference Example 186 methyl 2-methyl-3-{2- [ (2R) -tetrahydrofuran-2-yl] -5- (trifluoromethoxy) -lH-benzimidazol-1-yl }benzoate [0634]

1689Methyl 2-methyl-3-{ [2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] amino}-4- (trifluoromethoxy) phenyl] aminoJbenzoate (8.1 g, 18.48 mmol) and polyphosphoric acid (16 g) were stirred at 130⁰C for 15 min. The reaction container was cooled to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 90:10 - 80:20) to give the title compound (6.81 g, yield 88%) as an oil. 1H NMR (300 MHz, CDCl₃) δl.89-2.00 (IH, m) , 2.09-2.25 (2H, m) , 2.18 (3H, s), 2.49-2.61 (IH, m) , 3.74-3.91 (2H, m) , 3.95 (3H, s), 4.75-4.88 (IH, m) , 6.85-6.88 (IH, m) , 7.08-7.11 (IH, m) , 7.36-7.55 (2H, m) , 7.71 (IH, s) , 8.05-8.08 (IH, m) . [ 0635 ]

1690Reference Example 187

1691(2-methyl-3-{2- [ (2R) -tetrahydrofuran-2-yl] -5-

1692(trifluoromethoxy) -lH-benzimidazol-l-yl}phenyl) methanol

1693[0636]

1694Lithium aluminum hydride (2.0 M tetrahydrofuran solution, 10 mL, 20 mmol) was added dropwise to a solution of methyl 2- methyl-3-{2-[ (2R) -tetrahydrofuran-2-yl] -5- (trifluoromethoxy)- lH-benzimidazol-l-yl}benzoate (6.83 g, 16.2 mmol) in tetrahydrofuran (200 mL) at 0⁰C, and the mixture was stirred at 0⁰C for 1 hr. Sodium sulfate 10 hydrate was added to the reaction mixture at 0⁰C, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give the title compound (5.55 g, yield 87%) as an oil. 1H NMR (300 MHz, CDCl₃) δl.83-2.03 (4H, m) , 2.14-2.27 (2H, m) , 2.46-2.52 (IH, m) , 3.72-3.88 (2H, m) , 3.94-3.99 (IH, m) , 4.82 (2H, s), 4.84-4.86 (IH, m) , 6.89 (IH, d, J = 8.7 Hz), 7.08-7.32 (2H, m) , 7.37-7.43 (IH, m) , 7.63-7.68 (IH, m) , 7.73 (IH, s). [0637]

1695Reference Example 188

16962-methyl-3-{2-[ (2R) -tetrahydrofuran-2-yl] -5- (trifluoromethoxy) -lH-benzimidazol-l-yl}benzaldehyde [0638]

1697To a solution of (2-methyl-3-{2- [ (2R) -tetrahydrofuran-2- yl] -5- (trifluoromethoxy) -lH-benzimidazol-1-yl}phenyl) methanol (1.0 g, 2.55 mmol) in acetonitrile (10 mL) was added Dess- Martin periodonane (1.23 g, 2.9 mmol) at O⁰C, and the mixture was stirred at O⁰C for 1 hr. An aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give the title compound (0.530 g, yield 53%) as an oil.

1698¹H NMR (300 MHz, CDCl₃) δ 1.90-1.99 (IH, m) , 2.11-2.30 (5H, m) , 2.55-2.67 (IH, m) , 3.78-3.86 (2H, m) , 4.79-4.90 (IH, m) , 6.86-6.89 (IH, m) , 7.10-7.13 (IH, m) , 7.48-7.67 (2H, m) , 7.73 (IH, s), 8.03-8.07 (IH, m) , 10.36-10.39 (IH, m) . [0639]

1699Reference Example 189 methyl 3- [ (4-fluoro-2-nitrophenyl) amino] -2-methylbenzoate [0640]

1700A suspension of l-bromo-4-fluoro-2-nitrobenzene (15 g, 68.2 mmol) , methyl 3-amino-2-methylbenzoate (9.58 g, 58 mmol) , tris (dibenzylideneacetone)dipalladium (0) (800 mg, 0.87 mmol), bis (2-diphenylphosphinophenyl) ether (942 mg, 1.75 mmol) and tripotassium phosphate (38.2 g, 180 mmol) in toluene (200 mL) was stirred at 105⁰C overnight under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 85:15) to give the title compound (18.4 g, yield quant.) as a solid.

1701¹H NMR (300 MHz, CDCl₃) δ 2.46 (3H, s) , 3.93 (3H, s) , 6.68-6.72 (IH, m) , 7.11-7.17 (IH, m) , 7.29-7.32 (IH, m) , 7.40-7.43 (IH, m) , 7.80 (IH, d, J = 7.8 Hz), 7.91-7.95 (IH, m) , 9.20 (IH, s) . [0641]

1702Reference Example 190 methyl 3- [ (2-amino-4-fluorophenyl) amino] -2-methylbenzoate [0642]

1703A suspension of methyl 3- [ (4-fluoro-2-nitrophenyl) amino] - 2-methylbenzoate (18.4 g, 60.5 mmol) and palladium-carbon (0.5 g) in methanol (700 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (16.4 g, yield 99%) as a solid. 1H NMR (300 MHz, CDCl₃) δ 2.46 (3H, s) , 3.89 (5H, s) , 5.03 (IH, s), 6.39-6.57 (3H, m) , 6.88-6.93 (IH, m) , 7.05 (IH, t, J = 8.1 Hz) , 7.23-7.26 (IH, m) .

1704[0643]

1705Reference Example 191 methyl 3- [ (4-fluoro-2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] aminojphenyl) amino] -2-methylbenzoate

1706[0644]

1707A solution ^"of methyl 3- [ (2-amino-4-fluorophenyl) amino] -2- methylbenzoate (16.40 g, 59.8 mmol) , (2R) -tetrahydrofuran-2- ylcarboxylic acid (6.97 g, 60.0 mmol), l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (13.8 g, 72 mmol) and 1-hydroxy-lH-benzotriazole monohydrate (11.0 g, 72 mmol) in acetonitrile (300 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography

1708(hexanerethyl acetate = 90:10 - 70:30) to give the title compound (20.71 g, yield 93%) as an oil.

1709¹H NMR (300 MHz, CDCl₃) δ 1.43-1.55 (IH, m) , 1.70-1.79 (IH, m) , 1.94-2.04 (IH, m), 2.15-2.77 (IH, m) , 2.52 (3H, s) , 3.25-3.32

1710(IH, m) , 3.61-3.69 (IH, m) , 3.91 (3H, s) , 4.34-4.38 (IH, m) , 5.31 (IH, s), 6.49-6.51 (IH, m) , 6.80-6.86 (IH, m) , 7.00-7.10

1711(2H, m) , 7.28-7.31 (IH, m) , 8.06-8.11 (IH, m) , 8.95 (IH, br s) .

1712[0645]

1713Reference Example 192 methyl 3-{ 5-fluoro-2- [ (2R) -tetrahydrofuran-2-yl] -IH- benzimidazol-1-yl } -2-methylbenzoate

1714[0646]

1715Methyl 3- [ (4-fluoro-2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] amino}phenyl) amino] -2-methylbenzoate (20.7 g, 55.6 mmol) and polyphosphoric acid (41 g) were stirred at 130⁰C for 20 min, and the reaction container was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane: ethyl acetate = 95:5 - 75:25) to give the title compound (11.5 g, yield 59%) as an oil.

1716¹H NMR (300 MHz, CDCl₃) δ 1.89-1.96 (IH, m) , 2.04-2.23 (5H, m) , 2.50-2.59 (IH, m) , 3.77-3.91 (2H, m) , 3.94 (3H, s) , 4.73-4.86 (IH, m) , 6.77-6.82 (IH, m) , 6.94-7.00 (IH, m) , 7.37-7.55 (3H, m) , 8.04-8.07 (IH, m) . [0647]

1717Reference Example 193

17183-{5-fluoro-2-[ (2R) -tetrahydrofuran-2-yl] -IH-benzimidazol-l- yl } -2-methylbenzaldehyde [0648]

1719Lithium aluminum hydride (2.0 M tetrahydrofuran solution, 17 rtiL, 34 mmol) was added dropwise to a solution of methyl 3- {5-fluoro-2-[ (2R) -tetrahydrofuran-2-yl] -lH-benzimidazol-1-yl}- 2-methylbenzoate (11.54 g, 32.6 mmol) in tetrahydrofuran (250 mL) at 0⁰C, and the mixture was stirred at 0⁰C for 1 hr. Sodium sulfate 10 hydrate was added to the reaction mixture at

17200⁰C, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give an oil.

1721To a solution of the obtained oil in acetonitrile (300 mL) was added Dess-Martin periodonane (14.4 g, 34 mmol) at 0⁰C, and the mixture was stirred at 0⁰C for 1 hr. An aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 60:40) to give the title compound (6.78 g, yield 64%, 2 steps) as an oil.

1722¹H NMR (300 MHz, CDCl₃) δl.83-1.98 (IH, m) , 2.00-2.29 (5H, m) , 2.56-2.62 (IH, m) , 3.72-3.85 (2H, m) , 4.76-4.88 (IH, m) , 6.77-6.83 (IH, m) , 6.94-7.01 (IH, m) , 7.47-7.65 (3H, m) , 8.01-8.04 (IH, m) , 10.35-10.39 (IH, m) . [0649]

1723Reference Example 194 methyl 3- [ (4-chloro-2-nitrophenyl) amino] -2-methylbenzoate [0650]

1724A suspension of l-bromo-4-chloro-2-nitrobenzene (14.2 g, 60.0 mmol) , methyl 3-amino-2-methylbenzoate (8.26 g, 50 mmol) , tris (dibenzylideneacetone) dipalladium (0) (1.6 g, 1.74 mmol), bis (2-diphenylphosphinophenyl) ether (1.88 g, 3.48 mmol) and tripotassium phosphate (31.8 g, 150 mmol) in toluene (200 mL) was stirred at 105⁰C overnight under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 50:50) to give the title compound (15.7 g, yield 98%) as a solid.

1725¹H NMR (300 MHz, CDCl₃) δ 2.45 (3H, s) , 3.93 (3H, s) , 6.65 (IH, d, J = 9.3 Hz), 7.25-7.42 (3H, m) , 7.80-7.83 (IH, m) , 8.22 (IH, d, J = 1.8 Hz), 9.29 (IH, br s) . [0651]

1726Reference Example 195 methyl 3- [ (4-chloro-2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] amino}phenyl) amino] -2-methylbenzoate [0652]

1727A suspension of methyl 3- [ (4-chloro-2-nitrophenyl) amino] - 2-methylbenzoate (15.7 g, 49.0 πunol) , reduced iron (13.96 g,

1728250.0 mmol) , calcium chloride (2.77 g, 25.0 itimol) in ethanol (700 mL) and water (85 mL) was stirred at 95°C for 7 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a solid. The solid was washed with water and dried under reduced pressure to give a solid (14.0 g) . A solution of the obtained solid (14.0 g) , (2R) -tetrahydrofuran- 2-ylcarboxylic acid (6.15 g, 53.0 mmol), l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (11.11 g, 58 mmol) and 1-hydroxy-lH-benzotriazole monohydrate (8.88 g, 58 mmol) in acetonitrile (200 mL) was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 80:20) to give the title compound (17.1 g, yield 90%) as an oil.

1729¹H NMR (300 MHz, CDCl₃) δl.54-1.63 (IH, m) , 1.75-1.84 (IH, m) , 1.95-2.06 (IH, m) , 2.19-2.31 (IH, m) , 2.48 (3H, s) , 3.41-3.47 (IH, m) , 3.67-3.75 (IH, m) , 3.90 (3H, s) , 4.36-4.41 (IH, m) , 5.62 (IH, s), 6.67-6.70 (IH, m) , 6.98-7.10 (3H, m) , 7.33-7.36 (IH, m) , 8.07 (IH, d, J = 2.4 Hz), 8.78 (IH, s) . [0653]

1730Reference Example 196 methyl 3-{ 5-chloro-2- [ (2R) -tetrahydrofuran-2-yl] -IH- benzimidazol-1-yl } -2-methylbenzoate [0654]

1731Methyl 3- [ (4-chloro-2-{ [ (2R) -tetrahydrofuran-2- ylcarbonyl] amino}phenyl) amino] -2-methylbenzoate (17.1 g, 44.0 mmol) and polyphosphoric acid (33 g) were stirred at 13O⁰C for 20 min, and the reaction container was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography

1732(hexane: ethyl acetate = 90:10 - 75:25) to give the title compound (13.2 g, yield 81%) as an oil.

1733¹H NMR (300 MHz, CDCl₃) δ 1.89-1.98 (IH, m) , 2.10-2.24 (5H, m) , 2.47-2.59 (IH, m) , 3.76-3.91 (2H, m) , 3.94 (3H, s) , 4.74-4.87

1734(IH, m) , 6.78-6.82 (IH, m) , 7.16-7.20 (IH, m) , 7.36-7.54 (2H, m) , 7.80-7.81 (IH, m) , 8.05-8.08 (IH, m) .

1735[0655]

1736Reference Example 197

17373-{5-chloro-2-[ (2R) -tetrahydrofuran-2-yl] -lH-benzimidazol-1- yl } -2-methylbenzaldehyde

1738[0656]

1739Lithium aluminum hydride (2.0 M tetrahydrofuran solution, 20 mL, 40 mmol) was added dropwise to a solution of methyl 3-

1740{ 5-chloro-2- [ (2R) -tetrahydrofuran-2-yl] -IH-benzimidazol-l-yl } - 2-methylbenzoate (13.2 g, 35.6 mmol) in tetrahydrofuran (200 mL) at 0⁰C, and the mixture was stirred at 0⁰C for 0.5 hr. Sodium sulfate 10 hydrate was added to the reaction mixture at

17410⁰C, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give a solid.

1742To a solution of the obtained solid in acetonitrile (200 mL) was added Dess-Martin periodonane (15.3 g, 36 mmol) at 0⁰C, and the mixture was stirred at O⁰C for 1 hr. An aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 75:25) to give the title compound (8.7 g, yield 72%, 2 steps) as a solid.

1743¹H NMR (300 MHz, CDCl₃) δl.88-1.98 (IH, m) , 2.09-2.27 (5H, m) , 2 . 52-2 . 61 ( IH, m) , 3 . 76-3 . 84 ( 2H, m) , 4 . 77 -4 . 89 ( IH, m) ,

17446.78-6.81 (IH, m) , 7.17-7.27 (IH, m) , 7.47-7.65 (2H, m) , 7.82-7.83 (IH, m) , 8.01-8.05 (IH, m) , 10.35-10.38 (IH, m) . [0657] Example 1

1745[ (3S) -6- { [ (3R) -7-bromo-2, 3-dihydro-l-benzofuran-3-yl] amino}- 2 , 3-dihydro-l-benzofuran-3-yl] acetic acid [0658]

1746<img file="WO2010143733A1_D0045.tif" />

1747[0659]

1748To a mixed solution of methyl [ (3S) -6-{ [ (3R) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (60.0 mg, 0.120 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (360 μL) , and the mixture was stirred at 50°C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound

1749(48.8 mg, yield 100%) as a white solid.

1750¹H NMR (300 MHz, CDCl₃) δ 2.61 (IH, dd, J = 17.0, 9.5 Hz), 2.80

1751(IH, dd, J = 16.7, 5.3 Hz), 3.72-3.86 (IH, m) , 4.27 (IH, dd, J = 9.1, 6.1 Hz), 4.47 (IH, dd, J = 9.5, 4.2 Hz), 4.68-4.84 (2H, m) , 5.26 (IH, dd, J = 7.2, 4.2 Hz), 6.10-6.19 (2H, m) , 6.80

1752(IH, t, J = 7.8 Hz), 7.00 (IH, d, J = 8.0 Hz), 7.24-7.34 (IH, m) , 7.40 (IH, d, J = 8.0 Hz) . MS m/z 390 (M + H)⁺.

1753[0660] Example 2

1754[ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro-l-benzofuran-3-yl] amino}- 2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0661]

1755<img file="WO2010143733A1_D0046.tif" />

1756[0662]

1757To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro- l-benzofuran-3-yl] acetate (60.0 mg, 0.120 mmol) in tetrahydrofuran (1.0 πiL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (360 μL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound

1758(52.3 mg, yield 100%) as a white solid.

1759¹H NMR (300 MHz, CDCl₃) δ 2.61 (IH, dd, J = 17.0, 9.5 Hz), 2.80

1760(IH, dd, J = 17.0, 5.3 Hz), 3.72-3.86 (IH, m) , 4.27 (IH, dd, J = 9.1, 6.1 Hz), 4.47 (IH, dd, J = 9.8, 4.2 Hz), 4.69-4.85 (2H, m) , 5.26 (IH, dd, J = 7.4, 4.0 Hz), 6.09-6.17 (2H, m) , 6.81

1761(IH, t, J = 7.6 Hz), 7.00 (IH, d, J = 8.7 Hz), 7.28 (IH, d, J = 7.2 Hz), 7.41 (IH, d, J = 8.0 Hz). MS m/z 390 (M + H)⁺.

1762[0663] Example 3

1763[ (3S)-6-{ [ (3S)-7-(2,5-dimethylthiophen-3-yl)-2,3-dihydro-l- benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

1764[0664] <img file="WO2010143733A1_D0047.tif" />

1765[ 0665 ]

1766To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (200 mg, 0.400 mmol) , (2,5- dimethylthiophen-3-yl) boronic acid (74.8 mg, 0.480 mmol) and 2 M aqueous sodium carbonate solution (0.600 mL, 1.20 mmol) in toluene (2 mL) were added tris (dibenzylideneacetone) dipalladium (0) (14.7 mg, 0.016 mmol) and dicyclohexyl (2' , 6' -dimethoxybiphenyl-2-yl) phosphane

1767(26.3 mg, 0.064 mmol) under an argon atmosphere, and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a colorless oil (230 mg) . To a mixed solution of the obtained oil (230 mg) in tetrahydrofuran (2.7 mL) and methanol (1.35 mL) was added 1 M aqueous sodium hydroxide solution (1.30 mL) , and the mixture was stirred at 5O⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound

1768(114 mg, yield 61%) as a white solid.

1769¹H NMR (300 MHz, CDCl₃) δ 2.37 (3H, br s) , 2.44 (3H, br s) , 2.53-2.72 (IH, m) , 2.73-2.91 (IH, m) , 3.79 (IH, br s) , 4.20-4.35 (IH, m) , 4.35-4.50 (IH, m) , 4.73 (2H, d, J = 8.3 Hz), 5.20 (IH, br s) , 6.14 (2H, br s) , 6.74 (IH, br s) , 6.86-7.11

1770(2H, m), 7.13-7.41 (2H, m) . MS m/z 422 (M + H)⁺. [0666]

1771Example 4

1772[ (3S)-6-({ (3S) -7- [ (2R,6S)-2,6-dimethylmorpholin-4-yl]-2,3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid [0667]

1773<img file="WO2010143733A1_D0048.tif" />

1774[0668]

1775To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [ (2R, 6S) - 2, 6-dimethylmorpholin-4-yl] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (168 mg, 0.315 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (945 μL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (89.7 mg, yield 67%) as a pale-yellow solid.

1776¹H NMR (300 MHz, CDCl₃) δ 1.19-1.27 (6H, m) , 2.38 (2H, td, J = 10.9, 4.0 Hz), 2.60 (IH, dd, J = 16.7, 9.5 Hz), 2.79 (IH, dd, J = 16.7, 5.3 Hz), 3.40-3.54 (2H, m) , 3.71-3.96 (3H, m) , 4.26

1777(IH, dd, J = 9.1, 6.1 Hz), 4.44 (IH, dd, J = 9.5, 3.8 Hz), 4.67-4.78 (2H, m) , 5.13 (IH, dd, J = 7.2, 3.8 Hz), 6.07-6.16

1778(2H, m) , 6.76-6.82 (IH, m) , 6.88 (IH, t, J = 7.8 Hz), 6.95-7.03 (2H, m) . MS m/z 425 (M + H)⁺.

1779[0669] Example 5

1780[ (3S)-6-{ [ (3S)-7-(piperidin-l-yl)-2,3-dihydro-l-benzofuran-3- yl ] amino } -2 , 3-dihydro-l-benzofuran-3-yl ] acetic acid

1781[0670] <img file="WO2010143733A1_D0049.tif" />

1782[ 0671 ]

1783To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7-

1784(piperidin-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (67.5 mg, 0.134 mmol) in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (401 μL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (32.2 mg, yield 61%) as a pale-yellow solid.

1785¹H NMR (300 MHz, CDCl₃) δ 1.51-1.63 (2H, m) , 1.68-1.83 (4H, m) , 2.59 (IH, dd, J = 16.7, 9.1 Hz), 2.78 (IH, dd, J = 16.7, 5.3 Hz), 2.99-3.17 (4H, m) , 3.70-3.85 (IH, m) , 4.25 (IH, dd, J = 9.3, 6.2 Hz), 4.43 (IH, dd, J = 9.5, 3.8 Hz), 4.64-4.79 (2H, m) , 5.13 (IH, dd, J = 7.2, 3.8 Hz), 6.05-6.15 (2H, m) , 6.78-6.92 (2H, m) , 6.97 (2H, d, J = 8.3 Hz). MS m/z 395 (M + H)⁺.

1786[0672] Example 6

1787[ (3S)-6-{ [ (3R)-7-{2,6-dimethyl-4-[3-

1788(methylsulfonyl) propoxy] phenyl } -2 , 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

1789[0673] <img file="WO2010143733A1_D0050.tif" />

1790[ 0674 ]

1791To a solution of methyl [ (3S) -6-{ [ (3R) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (200 mg, 0.400 mmol) , {2, 6-dimethyl- 4- [3- (methylthio)propoxy] phenyl }boronic acid (229 mg, 0.800 mmol) synthesized according to WO2008/001931 and 2 M aqueous sodium carbonate solution (0.600 mL, 1.2 mmol) in toluene (1.3 inL) were added tris (dibenzylideneacetone) dipalladium (0) (14.7 mg, 0.016 mmol) and dicyclohexyl (2' , 6' -dimethoxybiphenyl-2- yl)phosphane (26.3 mg, 0.064 mmol) under an argon atmosphere, and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a pale-yellow oil (209 mg) . To a solution of the obtained oil (209 mg) in ethyl acetate (1.7 mL) was added m-chloroperbenzoic acid (65%, 120 mg, 0.453 mmol) under ice-cooling, and the mixture was stirred at 0⁰C for 30 min. Then, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give a colorless oil (157 mg) . To a mixed solution of the obtained oil (157 mg) in tetrahydrofuran (1.5 mL) and methanol (0.75 mL) was added 1 M aqueous sodium hydroxide solution (714 μL) , and the mixture was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (111 mg, yield 50%) as a white solid. 1H NMR (300 MHz, CDCl₃) δ 2.05 (3H, s) , 2.08 (3H, s) , 2.27-2.41

1792(2H, m) , 2.61 (IH, dd, J = 16.7, 9.1 Hz), 2.80 (IH, dd, J = 16.7, 5.3 Hz), 2.96 (3H, s) , 3.20-3.30 (2H, m) , 3.72-3.86 (IH, m) , 4.11 (2H, t, J = 5.7 Hz), 4.22-4.38 (2H, m) , 4.67 (IH, dd, J = 9.7, 7.4 Hz), 4.74 (IH, t, J = 9.1 Hz), 5.22 (IH, dd, J = 7.2, 4.2 Hz), 6.10-6.20 (2H, m) , 6.66 (2H, s) , 6.94-7.06 (3H, m) , 7.34 (IH, dd, J = 6.8, 1.5 Hz). MS m/z 552 (M + H)⁺.

1793[0675] Example 7

1794[ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[3-

1795(methylsulfonyl) propoxy] phenyl } -2 , 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid

1796[0676]

1797<img file="WO2010143733A1_D0051.tif" />

1798[0677]

1799To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (2.00 g, 4.00 mmol), {2, 6-dimethyl- 4- [3- (methylthio) propoxy] phenyl }boronic acid (1.72 g, 6.00 mmol) and 2 M aqueous sodium carbonate solution (6.00 mL, 12.0 mmol) in toluene (13 mL) were added tris (dibenzylideneacetone)dipalladium (0) (147 mg, 0.160 mmol) and dicyclohexyl (2' , 6' -dimethoxybiphenyl-2-yl) phosphane (263 mg, 0.640 mmol) under an argon atmosphere, and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 - 70:30) to give a yellow oil (2.75 g) . To a solution of the oil (2.75 g) obtained above in ethyl acetate (20 mL) was added m- chloroperbenzoic acid (65%, 1.45 g, 5.46 mmol) under ice- cooling, and the mixture was stirred at 0⁰C for 1 hr. Then, saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give a yellow solid (1.59 g) . To a mixed solution of the obtained yellow solid (1.59 g) in tetrahydrofuran (15 mL) and methanol (7.5 mL) was added 1 M aqueous sodium hydroxide solution (7.22 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a pale-yellow solid. This was recrystallized from ethyl acetate-heptane to give the title compound (1.16 g, yield 52%) as white crystals.

1800¹H NMR (300 MHz, CDCl₃) δ 2.05 (3H, s) , 2.08 (3H, s) , 2.26-2.43 (2H, m) , 2.61 (IH, dd, J = 16.6, 9.0 Hz), 2.81 (IH, dd, J = 17.0, 5.3 Hz), 2.96 (3H, s) , 3.19-3.33 (2H, m) , 3.73-3.88 (IH, m) , 4.11 (2H, t, J = 5.8 Hz), 4.23-4.41 (2H, m) , 4.63-4.83 (2H, m) , 5.22 (IH, dd, J = 7.2, 4.5 Hz), 6.10-6.23 (2H, m) , 6.66 (2H, s), 6.94-7.09 (3H, m) , 7.32-7.43 (IH, m) . MS m/z 552 (M + H)⁺. elemental analysis value for C₃₀H₃₃NO7S Calculated: C, 65.32; H, 6.03; N, 2.54. Found: C, 65.13; H, 5.98; N, 2.29. melting point 169°C. [0678]

1801Example 8

1802[ (3S) -6-{ [ (3S) -7- (2, 6-dimethyl-4-{ [ (2S) -5-oxopyrrolidin-2- yl]methoxy}phenyl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid [0679]

1803<img file="WO2010143733A1_D0052.tif" />

1804[0680]

1805To a solution of methyl [ (3S) -6-{ [ (3S) -7- (2, 6-dimethyl-4-

1806{ [ (2S) -5-oxopyrrolidin-2-yl]methoxy}phenyl) -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (2.92 g, 4.58 mmol) in methanol (23 mL) was added potassium carbonate (1.90 g, 13.7 mmol), and the mixture was stirred at 50⁰C for 3 hr. The reaction mixture was filtered and concentrated under reduced pressure to give an oil compound. This was dissolved in tetrahydrofuran (30 mL) and methanol (15 mL) , 1 M aqueous sodium hydroxide solution

1807(13.7 mL) was added, and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a white solid. This was recrystallized from ethanol-water to give the title compound

1808(1.63 g, yield 67%) as a pale-gray solid.

1809¹H NMR (300 MHz, CDCl₃) δ 1.81-2.13 (7H, m) , 2.22-2.64 (4H, m) ,

18102.78 (IH, dd, J = 16.7, 5.3 Hz), 3.68-3.90 (2H, m) , 3.94-4.18

1811(2H, m), 4.19-4.37 (2H, m) , 4.64 (IH, dd, J = 9.8, 7.2 Hz), 4.75 (IH, t, J = 8.9 Hz), 5.11-5.26 (IH, m) , 6.02-6.16 (2H, m) , 6.59-6.74 (2H, m) , 6.89-7.06 (3H, m) , 7.19-7.38 (2H, m) . MS m/z 529 (M + H)⁺. elemental analysis value for C₃₁H₃₂N2O₆

1812Calculated: C, 70.44; H, 6.10; N, 5.30. Found: C, 70.34; H, 6.12; N, 5.30. melting point 161°C. [0681] Example 9

1813[ (3S) -6-{ [ (3S) -7-{4- [ (1, l-dioxidotetrahydro-2H-thiopyran-4- yl) oxy] -2, 6-dimethylphenyl } -2 , 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0682]

1814<img file="WO2010143733A1_D0053.tif" />

1815[0683]

1816To a solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3- dihydro-l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate (6.00 g, 12.0 mmol) , [4-

1817(methoxymethoxy) -2, 6-dimethylphenyl] boronic acid (3.02 g, 14.4 mmol) and 2 M aqueous sodium carbonate solution (18.0 mL, 36.0 mmol) in toluene (40 mL) were added tris (dibenzylideneacetone)dipalladium (0) (439 mg, 0.480 mmol) and dicyclohexyl (2' , 6' -dimethoxybiphenyl-2-yl) phosphane (788 mg, 1.92 mmol) under an argon atmosphere, and the mixture was stirred at 100⁰C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a yellow oil (7.65 g) . To a solution of the obtained oil

1818(7.65 g) in methanol (40 mL) was added 10% hydrogen chloride containing methanol solution (3.8 mL) , and the mixture was stirred at 40⁰C for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give a white solid (6.47 g) . To a solution of the obtained solid (2.00 g) , tetrahydro-2H-thiopyran-4-ol (480 mg, 4.06 mmol) and triphenylphosphine (1.26 g, 4.81 mmol) in tetrahydrofuran (19 mL) was added diethyl azodicarboxylate (40% toluene solution, 2.19 mL, 4.81 mmol). The mixture was stirred at room temperature for 2 hr, diethyl azodicarboxylate (2.19 mL) and triphenylphosphine (1.26 g) were added, and the mixture was further stirred for 1 hr. Diethyl azodicarboxylate (2.19 mL) and triphenylphosphine (1.26 g) were further added, and the mixture was stirred for 10 min and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a white solid (1.86 g). To a solution of the obtained solid (1.86 g) in ethyl acetate (15 mL) was added m- chloroperbenzoic acid (65%, 1.5O g, 5.65 mmol) under ice- cooling, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 30:70) to give a white solid (1.57 g) . To a mixed solution of the obtained solid (1.57 g) in tetrahydrofuran (15 mL) and methanol (7.5 mL) was added 1 M aqueous sodium hydroxide solution (7.01 mL) , and the mixture was stirred at 50°C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a white solid. This was triturated with hexane-ethyl acetate, and recrystallized from ethyl acetate-heptane to give the title compound (911 mg, yield 44%) as a white solid.

1819¹H NMR (300 MHz, CDCl₃) δ 2.07 (6H, d, J = 9.0 Hz), 2.27-2.71 (5H, in), 2.81 (IH, dd, J = 16.6, 5.3 Hz), 2.88-3.04 (2H, m) , 3.35-3.55 (2H, m) , 3.74-3.88 (IH, m) , 4.23-4.42 (2H, m) , 4.62-4.83 (3H, m) , 5.17-5.31 (IH, m) , 6.09-6.21 (2H, m) , 6.69 (2H, s), 6.95-7.11 (3H, m) , 7.32-7.44 (IH, m) . MS m/z 564 (M + H)⁺. melting point 176°C. [0684] Example 10

1820[ (3S) -6-{ [ (3R) -7- (2-methyl-lH-benzimidazol-l-yl) -2, 3-dihydro- l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0685]

1821<img file="WO2010143733A1_D0054.tif" />

1822[0686]

1823To a mixed solution of methyl [ (3S) -6-{ [ (3R) -7- (2-methyl- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl]acetate (684 mg, 1.24 mmol) in tetrahydrofuran (7.8 mL) and methanol (3.9 mL) was added 1 M aqueous sodium hydroxide solution (3.72 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (485 mg, yield 89%) as a white solid.

1824¹H NMR (300 MHz, DMSO-d₆) δ 2.38-2.54 (4H, m) , 2.60-2.77 (IH, m) , 3.52-3.67 (IH, m) , 4.13 (IH, dd, J = 8.7, 6.8 Hz), 4 . 21-4 . 31 ( IH, m) , 4 . 57-4 . 67 ( IH, m) , 4 . 76-4 . 88 ( IH, m) ,

18255.34-5.45 (IH, m) , 6.13-6.27 (3H, m) , 6.97 (IH, d, J = 7.9 Hz), 7.06-7.33 (4H, m) , 7.45 (IH, d, J = 7.9 Hz), 7.55 (IH, d, J = 7.5 Hz), 7.65 (IH, d, J = 6.8 Hz), 12.30 (IH, br s) . MS m/z 442 (M + H)⁺.

1826[0687] Example 11

1827[ (3S) -6-{ [ (3R) -7- (2-ethyl-lH-benzimidazol-l-yl) -2, 3-dihydro-l- benzofuran-3-yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid

1828[0688]

1829<img file="WO2010143733A1_D0055.tif" />

1830[0689]

1831To a mixed solution of methyl [ (3S) -6-{ [ (3R) -7- (2-ethyl- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (231 mg, 0.408 mmol) in tetrahydrofuran (2.6 mL) and methanol (1.3 mL) was added 1 M aqueous sodium hydroxide solution (1.22 mL) , and the mixture was stirred at 50°C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (159 mg, yield 86%) as a white solid.

1832¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, q, J = 7.5 Hz), 2.39-2.47 (IH, m) , 2.60-2.77 (3H, m) , 3.54-3.68 (IH, m) , 4.12 (IH, dd, J = 9.0, 6.8 Hz), 4.18-4.29 (IH, m) , 4.62 (IH, t, J = 9.0 Hz), 4.73-4.84 (IH, m) , 5.33-5.45 (IH, m) , 6.15-6.27 (3H, m) , 6.92-7.26 (5H, m) , 7.41 (IH, d, J = 7.9 Hz), 7.53 (IH, d, J = 7.5 Hz), 7.61-7.67 (IH, m) , 12.31 (IH, br s) . elemental analysis value for C₂₇H_2SN₃O₄ Calculated: C, 71.19; H, 5.53; N, 9.22. Found: C, 71.32; H, 5.65; N, 9.07. MS m/z 456 (M + H)⁺. [0690] Example 12

1833[ (3S) -6- { [ (3R)-7-(2-ethoxy-lH-benzimidazol-l-yl)-2,3-dihydro- l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0691]

1834<img file="WO2010143733A1_D0056.tif" />

1835[0692]

1836To a mixed solution of methyl [ (3S) -6-{ [ (3R) -7- (2-ethoxy- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (284 mg, 0.489 mmol) in tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was added 1 M aqueous sodium hydroxide solution (1.47 mL) , and the mixture was stirred at 5O⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (207 mg, yield 90%) as a white solid.

1837¹H NMR (300 MHz, DMSOd₆) δ 1.35 (3H, t, J = 7.0 Hz), 2.38-2.47 (IH, m) , 2.65 (IH, dd, J = 16.6, 5.7 Hz), 3.55-3.68 (IH, m) , 4.12 (IH, dd, J = 8.9, 6.6 Hz), 4.18-4.28 (IH, m) , 4.54 (2H, q, J = 7.2 Hz), 4.62 (IH, t, J = 9.0 Hz), 4.71-4.90 (IH, m) , 5.32-5.43 (IH, m) , 6.16-6.29 (3H, m) , 6.90-7.03 (2H, m) , 7 . 04-7 . 19 ( 3H, m) , 7 . 38 ( IH, d, J = 7 . 5 Hz ) , 7 . 47 ( 2H, d, J =

18387.2 Hz) , 12.33 (IH, br s) . MS m/z 472 (M + H)⁺. [0693] Example 13

1839[ (3S)-6-{ [ (3R)-7-(2-ethyl-6-fluoro-lH-benzimidazol-l-yl)-2,3- dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

1840[ 0694 ]

1841<img file="WO2010143733A1_D0057.tif" />

1842[0695]

1843To a mixed solution of methyl [ (3S) -6-{ [ (3R) -7- (2-ethyl- 6-fluoro-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (249 mg, 0.427 mmol) in tetrahydrofuran (2.6 mL) and methanol (1.3 mL) was added 1 M aqueous sodium hydroxide solution (1.28 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (172 mg, yield 85%) as a white solid.

1844¹H NMR (300 MHz, DMSOd₆) δ 1.24 (3H, q, J = 7.5 Hz), 2.39-2.49 (IH, m) , 2.59-2.77 (3H, m) , 3.55-3.69 (IH, m) , 4.07-4.17 (IH, m) , 4.20-4.29 (IH, m) , 4.62 (IH, td, J = 8.9, 1.5 Hz), 4.72-4.86 (IH, m) , 5.33-5.44 (IH, m) , 6.13-6.26 (3H, m) , 6.79-6.90 (IH, m) , 6.97 (IH, dd, J = 7.9, 2.6 Hz), 7.01-7.17 (2H, m) , 7.43 (IH, d, J = 7.9 Hz), 7.54 (IH, d, J = 7.5 Hz), 7.65 (IH, dd, J = 8.7, 4.9 Hz), 12.31 (IH, br s) . MS m/ z 474 (M + H) ⁺ .

1845[0696] Example 14

1846[ (3S)-6-{ [ (3R) -7- (2-ethoxy-6-fluoro-lH-benzimidazol-l-yl)-2,3- dihydro-1-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

1847<img file="WO2010143733A1_D0058.tif" />

1848[0698]

1849To a mixed solution of methyl [ (3S) -6-{ [ (3R) -7- (2-ethoxy- 6-fluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (281 mg, 0.468 mmol) in tetrahydrofuran (3.0 mL) and methanol (1.5 mL) was added 1 M aqueous sodium hydroxide solution (1.40 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (193 mg, yield 84%) as a white solid.

1850¹H NMR (300 MHz, DMSO-d₆) δ 1.34 (3H, t, J = 7.2 Hz), 2.38-2.49 (IH, m) , 2.66 (IH, dd, J = 16.6, 5.7 Hz), 3.54-3.69 (IH, m) , 4.12 (IH, dd, J = 8.7, 6.8 Hz), 4.18-4.35 (IH, m) , 4.53 (2H, q, J = 6.9 Hz), 4.62 (IH, t, J = 9.0 Hz), 4.70-4.97 (IH, m) , 5.31-5.43 (IH, m) , 6.13-6.31 (3H, m) , 6.74-6.90 (IH, m) , 6.93-7.03 (2H, m) , 7.08 (IH, t, J = 7.7 Hz), 7.39 (IH, d, J = 7.9 Hz), 7.43-7.52 (2H, m) , 12.32 (IH, br s) . MS m/z 490 (M + H)⁺. [0699] Example 15

1851[ (3S) -6-{ [ (3S) -7- (2-methyl-lH-benzimidazol-l-yl) -2, 3-dihydro- l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

1852[0700]

1853<img file="WO2010143733A1_D0059.tif" />

1854[0701]

1855To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-methyl- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (647 mg, 1.17 mmol) in tetrahydrofuran (7.3 mL) and methanol (3.7 mL) was added 1 M aqueous sodium hydroxide solution (3.51 mL) , and the mixture was stirred at 50⁰C for 1 hr. I M Hydrochloric acid and 10% aqueous citric acid solution were added to the reaction mixture. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (369 mg, yield 71%) as a white solid.

1856¹H NMR (300 MHz, DMSO-d₆) δ 2.36-2.46 (4H, m) , 2.66 (IH, dd, J = 16.2, 5.3 Hz), 3.52-3.70 (IH, m) , 4.07-4.19 (IH, m) , 4.19-4.32 (IH, m) , 4.63 (IH, t, J = 8.9 Hz), 4.74-4.88 (IH, m) , 5.31-5.47 (IH, m) , 6.11-6.28 (3H, m) , 6.91-7.28 (5H, m) , 7.42

1857(IH, d, J = 7.9 Hz), 7.53 (IH, d, J = 7.5 Hz), 7.57-7.66 (IH, m) , 12.32 (IH, br s) . MS m/z 442 (M + H)⁺.

1858[0702] Example 16 sodium [ (3S) -6-{ [ (3S) -7- (2-methyl-lH-benzimidazol-l-yl) -2,3- dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate [0703]

1859<img file="WO2010143733A1_D0060.tif" />

1860[0704]

1861To a suspension of [ (3S) -6-{ [ (3S) -7- (2-methyl-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid (369 mg, 0.836 mmol) in water (4 mL) was added 1 M aqueous sodium hydroxide solution

1862(0.836 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (286 mg, yield 74%) as a pale-brown solid.

1863¹H NMR (300 MHz, DMSO-d₆) δ 2.01 (IH, dd, J = 15.1, 10.2 Hz), 2.29-2.45 (4H, m) , 3.49-3.65 (IH, m) , 4.08 (IH, t, J = 7.9 Hz), 4.19-4.32 (IH, m) , 4.62 (IH, t, J = 9.0 Hz), 4.80 (IH, q, J = 7.9 Hz), 5.32-5.44 (IH, m) , 6.04-6.23 (3H, m) , 6.94 (IH, d, J = 7.9 Hz), 7.00-7.27 (4H, m) , 7.41 (IH, d, J = 7.5 Hz), 7.52

1864(IH, d, J = 7.2 Hz), 7.58-7.67 (IH, m) . MS m/z 442 (M + H)⁺ (as free form).

1865[0705] Example 17 sodium [ (3S) -6-{ [ (3S) -7- (6-fluoro-2-methyl-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

1866[0706] <img file="WO2010143733A1_D0061.tif" />

1867[ 0707 ]

1868To a suspension of [ (3S) -6-{ [ (3S) -7- (6-fluoro-2-methyl- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino}- 2, 3-dihydro-l-benzofuran-3-yl] acetic acid (100 mg, 0.218 mmol) in water (1.1 mL) was added 1 M aqueous sodium hydroxide solution (0.218 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (96.8 mg, yield 92%) as a white solid.

1869¹H NMR (300 MHz, DMSO-d₆) δ 1.98 (IH, dd, J = 14.9, 10.0 Hz), 2.32 (IH, dd, J = 15.1, 4.9 Hz), 2.40 (3H, d, J = 5.7 Hz), 3.47-3.65 (IH, m) , 4.03-4.13 (IH, m) , 4.26 (IH, dd, J = 9.4, 4.5 Hz), 4.61 (IH, t, J = 8.9 Hz), 4.73-4.87 (IH, m) , 5.30-5.44 (IH, m) , 6.08 (IH, dd, J = 8.1, 6.6 Hz), 6.12-6.21 (2H, m) , 6.81-6.98 (2H, m) , 7.00-7.17 (2H, m) , 7.43 (IH, d, J = 7.9 Hz), 7.53 (IH, d, J = 7.2 Hz), 7.61 (IH, dd, J = 8.7, 4.9 Hz) .

1870MS m/z 460 (M + H) ⁺ (as free form). [0708] Example 18

1871[ (3S) -6-{ [ (3S) -7- (2-ethyl-lH-benzimidazol-l-yl) -2, 3-dihydro-l- benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0709] <img file="WO2010143733A1_D0062.tif" />

1872[ 0710 ]

1873To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (0.303 πunol) in tetrahydrofuran (2.0 itiL) and methanol (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.909 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (77.7 mg, yield 56%) as a white solid. 1H NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, q, J = 7.5 Hz), 2.37-2.47

1874(IH, m) , 2.59-2.79 (3H, m) , 3.55-3.69 (IH, m) , 4.08-4.17 (IH, m) , 4.18-4.28 (IH, m) , 4.63 (IH, t, J = 8.9 Hz), 4.74-4.85 (IH, m) , 5.32-5.46 (IH, m) , 6.14-6.28 (3H, m) , 6.92-7.26 (5H, m) , 7.41 (IH, d, J = 7.9 Hz), 7.53 (IH, d, J = 7.5 Hz), 7.60-7.68

1875(IH, m) , 12.31 (IH, br s) . MS m/z 456 (M + H)⁺.

1876[0711] Example 19 sodium [ (3S) -6-{ [ (3S) -7- (2-ethyl-lH-benzimidazol-l-yl) -2,3- dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate

1877[0712] <img file="WO2010143733A1_D0063.tif" />

1878[ 0713 ]

1879To a suspension of [ (3S) -6-{ [ (3S) -7- (2-ethyl-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid (77.7 mg, 0.171 mmol) in water (1.0 inL) was added 1 M aqueous sodium hydroxide solution

1880(0.171 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. This was triturated with acetonitrile to give the title compound (61.9 mg, yield 76%) as a white solid. 1H NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, q, J = 7.8 Hz), 1.85-1.99

1881(IH, m), 2.20-2.33 (IH, m) , 2.65-2.78 (2H, m) , 3.43-3.57 (IH, m) , 4.01-4.11 (IH, m) , 4.18-4.29 (IH, m) , 4.59 (IH, t, J = 8.9 Hz), 4.73-4.85 (IH, m) , 5.32-5.44 (IH, m) , 6.02-6.21 (3H, m) , 6.91 (IH, d, J = 8.0 Hz), 6.98-7.28 (4H, m) , 7.40 (IH, d, J = 7.2 Hz), 7.53 (IH, d, J = 8.0 Hz), 7.64 (IH, d, J = 7.6 Hz). MS m/z 456 (M + H)⁺ (as free form).

1882[0714] Example 20

1883[ (3S) -6-{ [ (3S) -7- (2-ethoxy-lH-benzimidazol-l-yl) -2, 3-dihydro- l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

1884[0715]

1885<img file="WO2010143733A1_D0064.tif" />

1886[0716]

1887To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (163 mg, 0.280 iranol) in tetrahydrofuran (1.8 mL) and methanol (0.9 mL) was added 1 M aqueous sodium hydroxide solution (0.839 mL) , and the mixture was stirred at 50°C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (90.6 mg, yield 69%) as a white solid.

1888¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (3H, t, J = 7.2 Hz), 2.37-2.47

1889(IH, m) , 2.65 (IH, dd, J = 16.2, 5.7 Hz), 3.55-3.67 (IH, m) , 4.12 (IH, dd, J = 8.7, 6.8 Hz), 4.18-4.27 (IH, m) , 4.54 (2H, q, J = 7.0 Hz), 4.62 (IH, t, J = 8.9 Hz), 4.74-4.88 (IH, m) , 5.33-5.42 (IH, m) , 6.16-6.26 (3H, m) , 6.96 (2H, d, J = 7.9 Hz), 7.04-7.18 (3H, m) , 7.38 (IH, d, J = 7.9 Hz), 7.47 (2H, d, J = 7.5 Hz) , 12.34 (IH, br s) . MS m/z 472 (M + H)⁺.

1890[0717] Example 21 sodium [ (3S) -6-{ [ (3S) -7- (2-ethoxy-lH-benzimidazol-l-yl) -2, 3- dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate

1891[0718]

1892<img file="WO2010143733A1_D0065.tif" />

1893[0719]

1894To a suspension of [ (3S) -6-{ [ (3S) -7- (2-ethoxy-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid (90.6 mg, 0.192 mmol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution

1895(0.192 mL), and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. This was triturated with acetonitrile to give the title compound (93.5 mg, yield 99%) as a white solid. 1H NMR (300 MHz, DMSOd₆) δ 1.30-1.40 (3H, m) , 1.91-2.09 (IH, m) , 2.32 (IH, dd, J = 15.0, 4.7 Hz), 3.47-3.63 (IH, m) , 4.07

1896(IH, t, J = 8.0 Hz), 4.17-4.30 (IH, m) , 4.47-4.67 (3H, m) , 4.70-4.89 (IH, m) , 5.28-5.43 (IH, m) , 6.01-6.23 (3H, m) , 6.84-7.20 (5H, m) , 7.37 (IH, d, J = 8.0 Hz), 7.47 (2H, d, J = 7.6 Hz) . MS m/z 472 (M + H)⁺ (as free form).

1897[0720] Example 22

1898[ (3S) -6-{ [ (3S) -7- (2-ethyl-6-fluoro-lH-benzimidazol-l-yl) -2, 3- dihydro-l-benzofuran-3-yl] amino}-2, 3-dihydro-l-benzofuran-3- yl] acetic acid

1899[ 0721 ]

1900<img file="WO2010143733A1_D0066.tif" />

1901[0722]

1902To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl- 6-fluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (147 mg, 0.253 mmol) in tetrahydrofuran (1.6 mL) and methanol (0.8 mL) was added 1 M aqueous sodium hydroxide solution (0.758 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (99.3 mg, yield 83%) as a white solid.

1903¹H NMR (300 MHz, DMSO-d₆) δ 1.24 (3H, q, J = 7.5 Hz), 2.37-2.47

1904(IH, m) , 2.58-2.77 (3H, m) , 3.55-3.69 (IH, m) , 4.12 (IH, t, J = 7.2 Hz), 4.20-4.29 (IH, m) , 4.63 (IH, t, J = 8.7 Hz), 4.73-4.86 (IH, m) , 5.32-5.44 (IH, m) , 6.14-6.26 (3H, m) , 6.79-6.89 (IH, m) , 6.96 (IH, dd, J = 7.9, 2.6 Hz), 7.01-7.17

1905(2H, m) , 7.43 (IH, d, J = 7.9 Hz), 7.53 (IH, d, J = 7.5 Hz), 7.65 (IH, dd, J = 8.7, 4.9 Hz), 12.31 (IH, br s) . MS m/z 474 (M + H)⁺.

1906[0723] Example 23 sodium [ (3S) -6-{ [ (3S) -7- (2-ethyl-6-fluoro-lH-benzimidazol-1- yl) -2, 3-dihydro-l-benzofuran-3-yl] amino } -2 , 3-dihydro-l- benzofuran-3-yl] acetate

1907[0724]

1908<img file="WO2010143733A1_D0067.tif" />

1909[0725]

1910To a mixed solution of [ (3S) -6-{ [ (3S) -7- (2-ethyl-6- fluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid (93.8 mg, 0.198 mmol) in tetrahydrofuran (2.0 mL) and acetonitrile (2.0 mL) was added 1 M aqueous sodium hydroxide solution (0.198 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. This was triturated with acetonitrile to give the title compound (87.3 mg, yield 89%) as a white solid.

1911¹H NMR (300 MHz, DMSO-d₆) δ 1.24 (3H, q, J = 7.7 Hz), 1.96 (IH, dd, J = 15.0, 10.0 Hz), 2.30 (IH, dd, J = 15.0, 4.4 Hz), 2 . 62-2 . 78 ( 2H , m) , 3 . 4 6-3 . 62 ( IH, m) , 4 . 07 ( IH, t , J = 8 . 0 Hz ) ,

19124.19-4.30 (IH, m) , 4.60 (IH, t, J = 8.9 Hz), 4.79 (IH, q, J = 9.3 Hz), 5.30-5.43 (IH, m) , 6.02-6.21 (3H, m) , 6.78-6.97 (2H, m) , 7.00-7.17 (2H, m) , 7.42 (IH, d, J = 8.0 Hz), 7.53 (IH, d, J = 7.6 Hz), 7.65 (IH, dd, J = 8.5, 4.7 Hz). MS m/z 474 (M + H)⁺ (as free form). [0726] Example 24

1913[ (3S)-6-{ [ (3S)-7-(2-ethoxy-6-fluoro-lH-benzimidazol-l-yl)-2,3- dihydro-l-benzofuran-3-yl] amino}-2, 3-dihydro-l-benzofuran-3- yl] acetic acid

1914<img file="WO2010143733A1_D0068.tif" />

1915[0728]

1916To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy- 6-fluoro-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (2.49 g, 4.15 mmol) in tetrahydrofuran (26 mL) and methanol (13 mL) was added 1 M aqueous sodium hydroxide solution (12.4 mL) , and the mixture was stirred at 5O⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (2.00 g, yield 99%) as a pale-pink solid.

1917¹H NMR (300 MHz, DMSO-d₆) δ 1.34 (3H, t, J = 7.0 Hz), 2.37-2.47 (IH, m) , 2.61-2.72 (IH, m) , 3.54-3.69 (IH, m) , 4.12 (IH, dd, J = 9.0, 6.8 Hz), 4.25 (IH, br s) , 4.53 (2H, q, J = 6.8 Hz), 4.63 (IH, t, J = 9.0 Hz) , 4.70-4.97 (IH, m) , 5.31-5.43 (IH, m) ,

19186.13-6.28 (3H, m) , 6.82 (IH, br s) , 6.92-7.05 (2H, m) , 7.08

1919(IH, t, J = 7.7 Hz), 7.39 (IH, d, J = 7.9 Hz), 7.43-7.52 (2H, m) , 12.32 (IH, br s) . MS m/z 490 (M + H)⁺.

1920[0729] Example 25

1921" sodium [ (3S)-6-{ [ (3S) -7- (2-ethoxy-6-fluoro-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

1922[0730]

1923<img file="WO2010143733A1_D0069.tif" />

1924[0731]

1925To a mixed solution of [ (3S) -6-{ [ (3S) -7- (2-ethoxy-6- fluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (1.70 g, 3.47 mmol) in tetrahydrofuran (18 mL) and acetonitrile (18 mL) was added 1 M aqueous sodium hydroxide solution (3.47 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. This was recrystallized from methanol-acetonitrile to give the title compound (1.30 g, yield 73%) as a white solid. 1H NMR (300 MHz, DMSO-d₆) δ 1.34 (3H, t, J = 7.0 Hz), 1.96 (IH, dd, J = 15.1, 9.8 Hz), 2.30 (IH, dd, J = 14.7, 4.9 Hz), 3.44-3.63 (IH, m) , 4.07 (IH, t, J = 8.7 Hz), 4.16-4.32 (IH, m) , 4.47-4.66 (3H, m) , 4.70-4.96 (IH, m) , 5.30-5.41 (IH, m) , 6.02-6.22 (3H, m) , 6.74-7.13 (4H, m) , 7.38 (IH, d, J = 7.9 Hz), 7.43-7.54 (2H, m) . elemental analysis value for C₂₇H₂SNsO₅FNa Calculated: C, 63.40; H, 4.53; N, 8.22. Found: C, 63.28; H, 4.30; N, 8.19. MS m/z 490 (M + H)⁺ (as free form), melting point not less than 300°C. [0732] Example 26

1926[ (3S)-6-{ [ (3S)-7-(2-ethyl-5,6-difluoro-lH-benzimidazol-l-yl)- 2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

1927<img file="WO2010143733A1_D0070.tif" />

1928[0734]

1929To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl- 5, 6-difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (130 mg, 0.215 mmol) in tetrahydrofuran (1.4 πiL) and methanol (0.7 mL) was added 1 M aqueous sodium hydroxide solution (0.646 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (89.1 mg, yield 84%) as a white solid.

1930¹H NMR (300 MHz, DMSOd₆) δ 1.19-1.29 (3H, m) , 2.36-2.46 (IH, m) , 2.58-2.79 (3H, m) , 3.53-3.69 (IH, m) , 4.08-4.17 (IH, m) , 4.20-4.30 (IH, m) , 4.63 (IH, td, J = 9.1, 1.9 Hz), 4.72-4.87

1931(IH, m) , 5.32-5.44 (IH, m) , 6.11-6.26 (3H, m) , 6.96 (IH, dd, J = 8.0, 3.4 Hz), 7.05-7.17 (2H, m) , 7.43 (IH, dd, J = 7.4, 2.5 Hz), 7.54 (IH, d, J = 7.2 Hz), 7.67-7.78 (IH, m) . MS m/z 492 (M + H)⁺.

1932[0735] Example 27 sodium [ (3S) -6-{ [ (3S) -7- (2-ethyl-5, 6-difluoro-lH-benzimidazol- 1-yl) -2, 3-dihydro-l-benzofuran-3-yl]amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate [0736]

1933<img file="WO2010143733A1_D0071.tif" />

1934[0737]

1935To a suspension of [ (3S) -6-{ [ (3S) -7- (2-ethyl-5, 6- difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid (89.1 mg, 0.181 mmol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.181 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (82.2 mg, yield 88%) as a white solid.

1936¹H NMR (300 MHz, DMSO-d₆) δ 1.12-1.35 (3H, m) , 1.90-2.06 (IH, m) , 2.25-2.41 (IH, m) , 2.60-2.80 (2H, m) , 3.49-3.65 (IH, m) , 3.98-4.17 (IH, m) , 4.18-4.36 (IH, m) , 4.51-4.69 (IH, m) , 4.71-4.90 (IH, m) , 5.29-5.45 (IH, m) , 5.99-6.28 (3H, m) , 6.88-7.01 (IH, m) , 7.04-7.21 (2H, m) , 7.42 (IH, d, J = 6.4 Hz), 7.54 (IH, d, J = 6.8 Hz), 7.67-7.82 (IH, m) . MS m/z 492 (M + H)⁺ (as free form).

1937[0738] Example 28

1938[ (3S) -6-{ [ (3S) -7- (2-ethoxy-5, 6-difluoro-lH-benzimidazol-1-yl) - 2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

1939[0739] <img file="WO2010143733A1_D0072.tif" />

1940[0740]

1941To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy- 5, 6-difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (98.6 mg, 0.160 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.479 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (100 mg, yield 100%) as a pale-purple solid.

1942¹H NMR (300 MHz, CDCl₃) δ 1.39-1.46 (4H, m) , 2.62 (IH, dd, J = 16.7, 9.1 Hz), 2.75-2.86 (IH, m) , 3.73-3.87 (IH, m) , 4.29 (IH, dd, J = 9.3, 5.9 Hz), 4.44 (IH, dd, J = 9.7, 4.4 Hz), 4.60 (2H, q, J = 7.2 Hz), 4.71-4.84 (2H, m) , 5.31 (IH, dd, J = 7.2, 4.2 Hz), 6.14-6.21 (2H, m) , 6.80 (IH, dd, J = 9.8, 7.2 Hz), 6.99-7.12 (2H, m) , 7.25-7.32 (2H, m) , 7.36 (IH, dd, J = 10.6, 7.2 Hz), 7.47 (IH, d, J = 7.6 Hz). MS m/z 508 (M + H)⁺.

1943[0741] Example 29 sodium [ (3S) -6-{ [ (3S) -7- (2-ethoxy-5, 6-difIuoro-1H- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate

1944[0742] <img file="WO2010143733A1_D0073.tif" />

1945[ 0743 ]

1946To a suspension of [ (3S) -6-{ [ (3S) -7- (2-ethoxy-5, 6- difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.160 mmol) in water (1.0 πiL) was added 1 M aqueous sodium hydroxide solution (0.160 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (80.9 mg, yield 95%) as a pale-pink solid.

1947¹H NMR (300 MHz, DMSO-d₆) δ 1.34 (3H, t, J = 7.0 Hz), 1.98 (IH, dd, J = 15.1, 9.8 Hz), 2.32 (IH, dd, J = 15.1, 4.9 Hz), 3.46-3.62 (IH, m) , 4.03-4.13 (IH, m) , 4.17-4.36 (IH, m) , 4.48-4.66 (3H, m) , 4.68-4.94 (IH, m) , 5.29-5.41 (IH, m) , 5.98-6.23 (3H, m) , 6.93 (IH, d, J = 7.9 Hz), 7.01-7.15 (2H, m) , 7.39 (IH, d, J = 7.9 Hz), 7.48 (IH, d, J = 7.5 Hz), 7.57 (IH, dd, J = 11.1, 7.3 Hz) . MS m/z 508 (M + H)⁺ (as free form). [0744] Example 30

1948[ (3S)-6-{ [ (3S)-7-(2-ethyl-6,7-difluoro-lH-benzimidazol-l-yl)- 2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

1949<img file="WO2010143733A1_D0074.tif" />

1950[0746] To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl- 6, 7-difluoro-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (3.72 g, 6.19 mmol) in tetrahydrofuran (40 mL) and methanol (20 mL) was added 1 M aqueous sodium hydroxide solution (18.6 mL) , and the mixture was stirred at 50°C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. This was triturated with hexane-ethyl acetate to give the title compound (2.44 g, yield 80%) as a white solid.

1951¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (3H, t, J = 7.6 Hz), 2.37-2.47 (IH, m) , 2.57-2.71 (3H, m) , 3.54-3.68 (IH, m) , 4.12 (IH, dd, J = 9.1, 6.8 Hz), 4.22 (IH, dd, J = 9.3, 5.5 Hz), 4.62 (IH, t, J = 9.1 Hz), 4.86 (IH, t, J = 8.5 Hz), 5.33-5.45 (IH, m) , 6.16-6.30 (3H, m) , 6.95 (IH, d, J = 7.6 Hz), 7.10 (IH, t, J = 7.8 Hz), 7.19-7.33 (IH, m) , 7.42-7.57 (3H, m) , 12.30 (IH, br s) .

1952MS m/z 492 (M + H)⁺. [0747] Example 31 sodium [ (3S) -6-{ [ (3S) -7- (2-ethyl-6, 7-difluoro-lH-benzimidazol- 1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate [0748]

1953<img file="WO2010143733A1_D0075.tif" />

1954[0749]

1955To a mixed solution of [ (3S) -6-{ [ (3S) -7- (2-ethyl-6, 7- difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid (2.00 g, 4.07 mmol) in tetrahydrofuran (30 inL) and acetonitrile (30 mL) was added 1 M aqueous sodium hydroxide solution (4.07 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. This was triturated with acetonitrile and recrystallized from methanol-acetonitrile to give the title compound (1.10 g, yield 53%) as a white solid.

1956¹H NMR (300 MHz, DMSO-d₆) δ 1.22 (3H, t, J = 7.5 Hz), 1.93 (IH, dd, J = 15.1, 10.2 Hz), 2.27 (IH, dd, J = 15.1, 4.9 Hz), 2.63 (2H, q, J = 7.4 Hz), 3.44-3.58 (IH, m) , 4.05 (IH, dd, J = 8.7, 7.2 Hz), 4.22 (IH, dd, J = 9.0, 5.7 Hz), 4.59 (IH, t, J = 8.9 Hz), 4.85 (IH, t, J = 8.7 Hz), 5.32-5.45 (IH, m) , 6.07-6.21 (3H, m) , 6.91 (IH, d, J = 7.5 Hz), 7.09 (IH, t, J = 7.5 Hz), 7.20-7.32 (IH, m) , 7.45-7.56 (3H, m) . MS m/z 492 (M + H)⁺ (as free form), elemental analysis value for 0₂-₇H₂₂NaO₄F₂Na Calculated: C, 63.16; H, 4.32; N, 8.18. Found: C, 63.10; H, 4.33; N, 8.06. melting point not less than 300⁰C. [0750] Example 32

1957[ (3S) -6-{ [ (3S) -7- (2-ethoxy-6, 7-difluoro-lH-benzimidazol-1-yl) - 2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

1958<img file="WO2010143733A1_D0076.tif" />

1959[0752]

1960To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy- 6, 7-difluoro-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl]acetate (1.87 g, 3.02 mmol) in tetrahydrofuran (20 mL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide solution (9.07 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. The solid was triturated with hexane-ethyl acetate to give the title compound (1.35 g, yield 88%) as a white solid.

1961¹H NMR (300 MHz, DMSO-d₆) δ 1.33 (3H, td, J = 7.1, 3.6 Hz), 2.42 (IH, dd, J = 16.3, 8.7 Hz), 2.64 (IH, dd, J = 16.5, 5.5 Hz), 3.52-3.68 (IH, m) , 4.11 (IH, dd, J = 8.7, 6.8 Hz), 4.16-4.29 (IH, m) , 4.45-4.67 (3H, m) , 4.74-4.90 (IH, m) , 5.31-5.43 (IH, m) , 6.15-6.27 (3H, m) , 6.95 (IH, d, J = 8.0 Hz), 7.06 (IH, t, J = 7.8 Hz), 7.11-7.24 (IH, m) , 7.26-7.33 (IH, m) , 7.47 (2H, d, J = 8.3 Hz), 12.11-12.49 (IH, m) . MS m/z 508 (M + H)⁺. [0753] Example 33 sodium [ (3S) -6-{ [ (3S) -7- (2-ethoxy-6, 7-difluoro-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetate [0754]

1962<img file="WO2010143733A1_D0077.tif" />

1963[0755]

1964To a mixed solution of [ (3S) -6-{ [ (3S) -7- (2-ethoxy-6, 7- difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (1.10 g, 2.17 πunol) in tetrahydrofuran (15 mL) and acetonitrile (15 mL) was added 1 M aqueous sodium hydroxide solution (2.17 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. The solid was triturated with acetonitrile and recrystallized from methanol-acetonitrile to give the title compound (803 mg, yield 70%) as a white solid.

1965¹H NMR (300 MHz, DMSO-d₆) δ 1.33 (3H, td, J = 7.2, 3.4 Hz), 1.96 (IH, dd, J = 15.1, 9.8 Hz), 2.30 (IH, dd, J = 15.1, 4.9 Hz), 3.45-3.60 (IH, m) , 4.06 (IH, t, J = 8.1 Hz), 4.17-4.29 (IH, m) , 4.46-4.65 (3H, m) , 4.81 (IH, dt, J = 13.3, 8.6 Hz), 5.30-5.42 (IH, m) , 6.06-6.21 (3H, m) , 6.92 (IH, d, J = 7.9 Hz), 7.05 (IH, t, J = 7.5 Hz), 7.11-7.25 (IH, m) , 7.26-7.34 (IH, m) , 7.43-7.52 (2H, m) .

1966MS m/z 508 (M + H)⁺ (as free form), elemental analysis value for C₂₇H₂₂NsOsF₂Na Calculated: C, 61.25; H, 4.19; N, 7.94. Found: C, 61.01; H, 4.25; N, 7.98. melting point not less than 300⁰C. [0756] Example 34

1967[ (3S)-6-{ [ (3S)-7-(2-ethyl-4,6-difluoro-lH-benzimidazol-l-yl)- 2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

1968<img file="WO2010143733A1_D0078.tif" />

1969[0758]

1970To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl- 4, 6-difluoro-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (106 mg, 0.177 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.531 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (89.1 mg, yield 100%) as a colorless oil.

1971¹H NMR (300 MHz, CDCl₃) δ 1.31-1.41 (3H, m) , 2.55-2.89 (4H, m) , 3.74-3.89 (IH, m) , 4.29 (IH, dd, J = 9.3, 5.9 Hz), 4.37-4.49 (IH, m) , 4.70-4.85 (2H, m) , 5.34 (IH, td, J = 7.5, 4.7 Hz), 6.13-6.21 (2H, m) , 6.51-6.63 (IH, m) , 6.76 (IH, td, J = 10.0, 2.3 Hz), 7.03 (IH, d, J = 7.6 Hz), 7.06-7.17 (IH, m) , 7.21-7.28 (2H, m) , 7.54 (IH, d, J = 7.2 Hz). MS m/z 492 (M + H)⁺. [0759] Example 35 sodium [ (3S) -6-{ [ (3S) -7- (2-ethyl-4, 6-difluoro-lH-benzimidazol- 1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate [0760]

1972<img file="WO2010143733A1_D0079.tif" />

1973[0761]

1974To a suspension of [ (3S) -6-{ [ (3S) -7- (2-ethyl-4, 6- difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.177 mmol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.177 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (76.1 mg, yield

197584%) as a white solid.

1976¹H NMR (300 MHz, DMSCHd₆) δ 1.24 (3H, q, J = 7.7 Hz), 1.99 (IH, dd, J = 14.9, 10.0 Hz), 2.33 (IH, dd, J = 15.1, 4.5 Hz), 2.64-2.80 (2H, m) , 3.48-3.63 (IH, m) , 4.08 (IH, t, J = 7.9 Hz), 4.20-4.31 (IH, m) , 4.62 (IH, t, J = 9.0 Hz), 4.73-4.87 (IH, m) , 5.31-5.44 (IH, m) , 6.01-6.22 (3H, m) , 6.70-6.82 (IH, m) , 6.94 (IH, d, J = 7.5 Hz), 7.03-7.18 (2H, m) , 7.44 (IH, d, J = 7.5 Hz), 7.55 (IH, d, J = 7.2 Hz). MS m/z 492 (M + H)⁺ (as free form). [0762] Example 36

1977[ (3S) -6-{ [ (3S) -7- (2-ethoxy-4, 6-difluoro-lH-benzimidazol-l-yl) - 2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

1978<img file="WO2010143733A1_D0080.tif" />

1979[0764]

1980To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethoxy- 4, 6-difluoro-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (2.04 g, 3.30 mmol) in tetrahydrofuran (21 mL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide solution (9.91 mL) , and the mixture was stirred at 50°C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. The solid was recrystallized from hexane-ethyl acetate to give the title compound (1.48 g, yield 88%) as a pale-pink solid. ¹H NMR (300 MHz, DMSO-d₆) δ 1.35 (3H, t, J = 7.2 Hz), 2.38-2.47

1981(IH, m) , 2.65 (IH, dd, J = 16.3, 5.3 Hz), 3.55-3.69 (IH, m) , 4.12 (IH, dd, J = 8.7, 6.8 Hz), 4.17-4.32 (IH, m) , 4.49-4.68

1982(3H, m) , 4.70-4.98 (IH, m) , 5.30-5.43 (IH, m) , 6.14-6.30 (3H, m) , 6.74 (IH, br s) , 6.96 (IH, d, J = 7.6 Hz), 7.00-7.14 (2H, m) , 7.41 (IH, d, J = 7.6 Hz), 7.49 (IH, d, J = 7.2 Hz), 12.32

1983(IH, br s) . MS m/z 508 (M + H)⁺.

1984[0765] Example 37 sodium [ (3S) -6-{ [ (3S) -7- (2-ethoxy-4, 6-difluoro-lH- benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-1-benzofuran-3-yl] acetate

1985[0766]

1986<img file="WO2010143733A1_D0081.tif" />

1987[0767]

1988To a mixed solution of [ (3S) -6-{ [ (3S) -7- (2-ethoxy-4, 6- difluoro-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl]amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid (1.48 g, 2.92 mmol) in tetrahydrofuran (20 mL) and acetonitrile (20 mL) was added 1 M aqueous sodium hydroxide solution (2.92 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give a solid. The solid was triturated with acetonitrile and recrystallized from methanol-acetonitrile to give the title compound (1.07 g, yield 69%) as a white solid.

1989¹H NMR (300 MHz, DMSOd₆) δ 1.35 (3H, t, J = 7.2 Hz), 1.97 (IH, dd, J = 15.0, 10.0 Hz), 2.31 (IH, dd, J = 15.1, 4.9 Hz), 3.45-3.60 (IH, m) , 4.00-4.12 (IH, m) , 4.18-4.33 (IH, m) , 4.50-4.65 (3H, m) , 4.70-4.94 (IH, m) , 5.30-5.41 (IH, m) , 6.01-6.22 (3H, m) , 6.68-6.80 (IH, m) , 6.93 (IH, d, J = 7.6 Hz) , 7.00-7.13 (2H, m) , 7.40 (IH, d, J = 7.6 Hz) , 7.49 (IH, d, J = 7.2 Hz) .

1990MS m/z 508 (M + H)⁺ (as free form). [0768] Example 38

1991[ (3S) -6-{ [ (3S) -7- (2-ethyl-6-methoxy-lH-benzimidazol-l-yl) -2,3- dihydro-1-benzofuran-3-yl] amino } -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

1992<img file="WO2010143733A1_D0082.tif" />

1993[0770]

1994To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2-ethyl- 6-methoxy-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (101 mg, 0.169 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.507 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (86.0 mg, yield 100%) as a colorless oil.

1995¹H NMR (300 MHz, CDCl₃) δ 1.29-1.39 (3H, m) , 2.55-2.89 (4H, m) , 3.72-3.89 (4H, m) , 4.30 (IH, dd, J = 9.2, 6.2 Hz), 4.36-4.47

1996(IH, m), 4.71-4.84 (2H, m) , 5.27-5.39 (IH, m) , 6.13-6.20 (2H, m) , 6.53 (IH, dd, J = 15.6, 2.4 Hz), 6.85-6.93 (IH, m) , 7.03

1997(IH, d, J = 8.3 Hz), 7.07-7.16 (IH, m) , 7.26-7.29 (IH, m) , 7.52 (IH, d, J = 7.5 Hz), 7.67 (IH, d, J = 9.0 Hz). MS m/z 486 (M + H)⁺. [0771]

1998Example 39 sodium [ (3S) -6-{ [ (3S) -7- (2-ethyl-6-methoxy-lH-benzimidazol-l- yl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate [0772]

1999<img file="WO2010143733A1_D0083.tif" />

2000[0773]

2001To a suspension of [ (3S) -6-{ [ (3S) -7- (2-ethyl-6-methoxy- lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino}- 2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.169 mmol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution

2002(0.169 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (63.8 mg, yield 74%) as a white solid.

2003¹H NMR (300 MHz, DMSO-d₆) δ 1.16-1.28 (3H, m) , 2.00 (IH, dd, J = 15.1, 9.8 Hz), 2.33 (IH, dd, J = 15.1, 4.9 Hz), 2.58-2.74

2004(2H, m) , 3.46-3.62 (IH, m) , 3.70 (3H, d, J = 2.6 Hz),

20054.02-4.12 (IH, m) , 4.18-4.30 (IH, m) , 4.61 (IH, t, J = 8.9 Hz),

20064.80 (IH, t, J = 8.7 Hz), 5.31-5.44 (IH, m) , 6.07-6.22 (3H, m) ,

20076.50 (IH, dd, J = 17.7, 2.3 Hz), 6.78-6.87 (IH, m) , 6.93 (IH, d, J = 7.9 Hz), 7.13 (IH, t, J = 7.5 Hz), 7.32-7.44 (IH, m) ,

20087.52 (2H, d, J = 8.7 Hz) .

2009MS m/z 486 (M + H)⁺ (as free form).

2010[0774] Example 40

2011[ (3S) -6- ( { (3S) -7- [6-fluoro-2- (propan-2-yl) -lH-benzimidazol-1- yl] -2, 3-dihydro-l-benzofuran-3-yl}amino) -2, 3-dihydro-l- benzofuran-3-yl] acetic acid [ 0775 ]

2012<img file="WO2010143733A1_D0084.tif" />

2013[0776]

2014To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [6-fluoro- 2- (propan-2-yl) -IH-benzimidazol-l-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (134 mg, 0.223 mmol) in tetrahydrofuran (1.4 mL) and methanol (0.7 mL) was added 1 M aqueous sodium hydroxide solution (0.670 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (116 mg, yield 100%) as a colorless oil. 1H NMR (300 MHz, CDCl₃) δ 1.21-1.41 (6H, m) , 2.62 (IH, dd, J = 16.7, 9.5 Hz), 2.81 (IH, dd, J = 17.0, 5.3 Hz), 2.91-3.08 (IH, m) , 3.74-3.89 (IH, m) , 4.30 (IH, dd, J = 9.5, 6.1 Hz), 4.36-4.47 (IH, m) , 4.72-4.82 (2H, m) , 5.29-5.39 (IH, m) , 6.12-6.22 (2H, m) , 6.65-6.78 (IH, m) , 6.94-7.07 (2H, m) , 7.07-7.16 (IH, m) , 7.22-7.26 (IH, m) , 7.54 (IH, d, J = 7.2 Hz), 7.73 (IH, dd, J = 8.9, 4.7 Hz) . MS m/z 488 (M + H)⁺.

2015[0777] Example 41 sodium [ (3S) -6- ( { (3S) -7- [6-fluoro-2- (propan-2-yl) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetate

2016[0778] <img file="WO2010143733A1_D0085.tif" />

2017[ 0779 ]

2018To a suspension of [ (3S) -6- ( { (3S) -7- [6-fluoro-2- (propan- 2-yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.223 itimol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.238 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (93.3 mg, yield 82%) as a white solid.

2019¹H NMR (300 MHz, DMSO-d₆) δ 1.14-1.30 (6H, m) , 1.96-2.11 (IH, m) , 2.36 (IH, dd, J = 15.1, 4.5 Hz), 2.88-3.07 (IH, m) , 3.33-3.44 (IH, m) , 3.97-4.13 (IH, m) , 4.16-4.31 (IH, m) , 4.62

2020(IH, t, J = 8.9 Hz), 4.70-4.86 (IH, m) , 5.31-5.46 (IH, m) , 6.04-6.23 (3H, m) , 6.72-7.21 (4H, m) , 7.42 (IH, d, J = 7.5 Hz), 7.54 (IH, d, J = 7.5 Hz), 7.66 (IH, dd, J = 8.5, 4.7 Hz). MS m/z 488 (M + H)⁺ (as free form).

2021[0780] Example 42

2022[ (3S) -6- ( { (3S) -7- [6-fluoro-2- (tetrahydro-2H-pyran-4-yl) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3-yl) amino) -2,3- dihydro-l-benzofuran-3-yl] acetic acid

2023[0781]

2024<img file="WO2010143733A1_D0086.tif" />

2025[0782]

2026To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [6-fluoro- 2- (tetrahydro-2H-pyran-4-yl) -lH-benzimidazol-1-yl] -2,3- dihydro-l-benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro- l-benzofuran-3-yl} acetate (106 mg, 0.165 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.495 mL) , and the mixture was stirred at 5O⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (89.5 mg, yield 100%) as a pale-yellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ 1.60-1.93 (4H, m) , 2.25-2.46 (2H, m) , 2.56-2.67 (IH, m) , 2.87-3.02 (IH, m) , 3.38-3.45 (IH, m) , 3.53-3.68 (IH, m) , 3.82-3.96 (2H, m) , 4.07-4.16 (IH, m) , 4.17-4.30 (IH, m) , 4.56-4.67 (IH, m) , 4.71-4.87 (IH, m) , 5.33-5.45 (IH, m) , 6.10-6.28 (3H, m) , 6.74-6.88 (IH, m) , 6.96 (IH, d, J = 8.0 Hz), 7.02-7.19 (2H, m) , 7.44 (IH, d, J = 8.0 Hz), 7.55 (IH, d, J = 7.6 Hz), 7.63-7.73 (IH, m) . MS m/z 530 (M + H)⁺. [0783] Example 43 sodium [ (3S) -6- ( { (3S) -7- [6-fluoro-2- (tetrahydro-2H-pyran-4- yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3- yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate [0784]

2027<img file="WO2010143733A1_D0087.tif" />

2028[0785]

2029To a suspension of [ (3S) -6- ( { (3S) -7- [6-fluoro-2- (tetrahydro-2H-pyran-4-yl) -lH-benzimidazol-1-yl] -2, 3-dihydro- l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.165 mmol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.165 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (78.0 mg, yield 86%) as a white solid.

2030¹H NMR (300 MHz, DMSO-d₆) δ 1.70-2.05 (5H, m) , 2.27-2.42 (2H, m) , 2.82-3.05 (2H, m) , 3.77-3.96 (2H, m) , 3.98-4.14 (IH, m) , 4.15-4.33 (IH, m) , 4.50-4.67 (IH, m) , 4.68-4.88 (IH, m) , 5.28-5.45 (IH, m) , 5.97-6.27 (3H, m) , 6.71-6.99 (2H, m) , 6.99-7.24 (2H, m) , 7.36-7.60 (2H, m) , 7.61-7.78 (IH, m) . MS m/z 530 (M + H)⁺ (as free form). [0786] Example 44

2031[ (3S) -6- ( { (3S) -7- [6-fluoro-2- (5-methylfuran-2-yl) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetic acid [0787]

2032<img file="WO2010143733A1_D0088.tif" />

2033[0788]

2034To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [6-fluoro- 2- (5-methylfuran-2-yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (116 mg, 0.182 mmol) in tetrahydrofuran (1.2 mL) and methanol (0.6 mL) was added 1 M aqueous sodium hydroxide solution (0.545 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (99.7 mg, yield 100%) as a pale-yellow oil. ¹H NMR (300 MHz, DMSO-d₆) δ 2.24-2.32 (3H, m) , 2.32-2.46 (2H, m) , 2.55-2.67 (IH, m) , 3.54-3.68 (IH, m) , 4.07-4.27 (2H, m) , 4.56-4.86 (2H, m) , 5.29-5.45 (IH, m) , 6.09-6.25 (5H, m) , 6.79-6.91 (IH, m) , 6.95 (IH, d, J = 8.0 Hz) , 7.09-7.20 (2H, m) , 7.40 (IH, t, J = 6.6 Hz) , 7.59 (IH, d, J = 7.2 Hz) , 7.68-7.77

2035(IH, m) . MS m/z 526 (M + H)⁺.

2036[0789] Example 45 sodium [ (3S)-6-({ (3S) -7- [6-fluoro-2- (5-methylfuran-2-yl) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3-yl}amino) -2,3- dihydro-l-benzofuran-3-yl] acetate

2037[0790]

2038<img file="WO2010143733A1_D0089.tif" />

2039[0791]

2040To a suspension of [ (3S) -6- ( { (3S) -7- [6-fluoro-2- (5- methylfuran-2-yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.182 mmol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.182 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound

2041(85.5 mg, yield 86%) as a white solid.

2042¹H NMR (300 MHz, DMSO-d₆) δ 1.99 (IH, dd, J = 15.0, 10.0 Hz), 2.24-2.39 (4H, m) , 3.48-3.63 (IH, m) , 4.07 (IH, t, J = 8.0 Hz), 4.11-4.28 (IH, m) , 4.54-4.86 (2H, m) , 5.28-5.43 (IH, m) , 6.06

2043(IH, t, J = 7.6 Hz), 6.10-6.24 (4H, m) , 6.80-6.97 (2H, m) , 7.07-7.20 (2H, m) , 7.40 (IH, t, J = 6.8 Hz), 7.59 (IH, d, J = 7.2 Hz) , 7.67-7.77 (IH, m) . MS m/z 526 (M + H)⁺ (as free form). [0792]

2044Example 46

2045[ (3S) -6- ( { (3S) -7- [6-fluoro-2- (5-methylisoxazol-3-yl) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetic acid

2046[0793]

2047<img file="WO2010143733A1_D0090.tif" />

2048[0794]

2049To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [6-fluoro- 2- (5-methylisoxazol-3-yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (104 mg, 0.164 mmol) in tetrahydrofuran (1.0 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.492 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with distilled water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (76.2 mg, yield 88%) as a white solid. 1H NMR (300 MHz, DMSO-d₆) δ 2.38-2.47 (4H, m) , 2.58-2.76 (IH, m) , 3.54-3.69 (IH, m) , 4.08-4.25 (2H, m) , 4.57-4.87 (2H, m) , 5.30-5.41 (IH, m) , 6.10-6.25 (3H, m) , 6.65-6.72 (IH, m) , 6.90-7.02 (2H, m) , 7.03-7.12 (IH, m) , 7.17-7.29 (IH, m) , 7.40 (IH, d, J = 7.9 Hz), 7.52 (IH, d, J = 7.5 Hz), 7.80-7.92 (IH, m) .

2050MS m/z 527 (M + H)⁺. [0795] Example 47 sodium [ (3S) -6- ( { (3S) -7- [6-fluoro-2- (5-methylisoxazol-3-yl) - IH-benzimidazol-l-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) - 2 , 3-dihydro-l-benzofuran-3-yl ] acetate

2051[ 0796] <img file="WO2010143733A1_D0091.tif" />

2052[0797]

2053To a suspension of [ (3S) -6- ( { (3S) -7- [6-fluoro-2- (5- methylisoxazol-3-yl) -lH-benzimidazol-1-yl] -2, 3-dihydro-l- benzofuran-3-yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (76.2 mg, 0.145 mmol) in water (1.0 mL) was added 1 M aqueous sodium hydroxide solution (0.145 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound

2054(68.1 mg, yield 86%) as a white solid.

2055¹H NMR (300 MHz, DMSO-d₆) δ 2.33 (IH, dd, J = 14.9, 4.7 Hz),

20562.45 (3H, s), 3.47-3.68 (2H, m) , 3.97-4.27 (2H, m) , 4.54-4.88

2057(2H, m) , 5.26-5.43 (IH, m) , 5.97-6.34 (3H, m) , 6.62-6.77 (IH, m) , 6.87-7.16 (3H, m) , 7.17-7.32 (IH, m) , 7.39 (IH, d, J = 7.9 Hz), 7.53 (IH, d, J = 7.2 Hz), 7.83-7.98 (IH, m) . MS m/z 527 (M + H)⁺ (as free form).

2058[0798] Example 48

2059[ (3S) -6- ( { (3S) -7- [4- (cyclopropylmethoxy) -2, 6-dimethylphenyl] - 2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

2060[0799]

2061<img file="WO2010143733A1_D0092.tif" />

2062[0800] A 0.20 M solution (500 μL, 100 μmol) of methyl [(3S) -6- { [ (3S) -7- (4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate obtained in the process of obtaining Reference Example 10 in toluene, a 0.40 M solution (500 μL, 200 μmol) of triphenylphosphine in toluene and a 0.30 M solution (500 μL, 150 μmol) of cyclopropanemethanol in toluene were mixed, and to the mixture was added at room temperature diisopropyl azodicarboxylate (38 μL, 200 μmol) and the mixture was stirred for 16 hr. The mixture was neutralized and extracted with ethyl acetate (3.5 mL) -2% aqueous sodium hydrogen carbonate solution (1 mL) , and the organic layer was separated by upper layer PhaseSep tube (manufactured by Wako Pure Chemical Industries, Ltd.). The solvent was evaporated under reduced pressure, and the residue was dissolved in DMSO- methanol (1:1, 1 mL) , and purified by preparative HPLC. The solvent was evaporated to give purified alkyloxy intermediate. The obtained alkyloxy intermediate was dissolved in tetrahydrofuran-methanol (1:1, 0.5 mL) , 2 M aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 16 hr. I M Aqueous ammonium chloride solution (2.0 mL) was added, and methanol was further added. The residue was completely dissolved, and the solution was purified by preparative HPLC to give the title compound (13.3 mg, yield 27%) as a colorless oil.

2063¹H NMR (300 MHz, CDCl₃) δ 0.29-0.39 (2H, m) , 0.57-0.73 (2H, m) , 1.20-1.36 (IH, m) , 2.04 (3H, s) , 2.07 (3H, s) , 2.53-2.62 (IH, m) , 2.79 (IH, dd, J = 16.7, 5.3 Hz), 3.72-3.89 (3H, m) , 4.21-4.40 (2H, m) , 4.62-4.80 (2H, m) , 5.17-5.29 (IH, m) , 6.09-6.24 (2H, m) , 6.68 (2H, s) , 6.92-7.12 (3H, m) , 7.34 (IH, d, J = 6.8 Hz) . MS m/z 486 (M + H)⁺. [0801] Example 49

2064[ (3S) -6- ( { (3S) -7- [4- (2-methoxyethoxy) -2, 6-dimethylphenyl] -2,3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid [0802]

2065<img file="WO2010143733A1_D0093.tif" />

2066[0803]

2067In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7-

2068(4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference

2069Example 10 and 2-methoxyethanol.

2070¹H NMR (300 MHz, CDCl₃) δ 2.04 (3H, s) , 2.07 (3H, s) , 2.58 (IH, dd, J = 16.7, 9.1 Hz), 2.78 (IH, dd, J = 16.7, 5.3 Hz), 3.45

2071(3H, s), 3.71-3.86 (3H, m) , 4.09-4.16 (2H, m) , 4.21-4.39 (2H, m) , 4.61-4.79 (2H, m) , 5.17-5.25 (IH, m) , 6.08-6.19 (2H, m) , 6.70 (2H, s), 6.92-7.07 (3H, m) , 7.33 (IH, d, J = 6.8 Hz). MS m/z 490 (M + H)⁺.

2072[0804] Example 50

2073[ (3S)-6-{ [ (3S)-7-{4-[2-(dimethylamino)ethoxy]-2,6- dimethylphenyl}-2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3- dihydro-l-benzofuran-3-yl] acetic acid

2074[0805]

2075<img file="WO2010143733A1_D0094.tif" />

2076[0806]

2077In the same manner as in Example 48, the title compound was obtained as a white solid from methyl [ (3S) -6-{ [ (3S) -7- (4- hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and N,N-dimethylethanolamine.

2078¹H NMR (300 MHz, CDCl₃) δ 2.03 (3H, s) , 2.05 (3H, s) , 2.38-2.93 (8H, m), 2.95-3.11 (2H, m) , 3.68-3.88 (IH, m) , 4.12-4.34 (4H, m) , 4.61 (IH, dd, J = 9.7, 7.4 Hz), 4.74 (IH, t, J = 8.9 Hz), 5.17 (IH, dd, J = 7.0, 4.4 Hz), 6.00-6.13 (2H, m) , 6.67 (2H, s), 6.91-7.05 (3H, m) , 7.30-7.36 (IH, m) . MS m/z 503 (M + H)⁺. [0807] Example 51

2079[ (3S)-6-({ (3S) -7-[4-(furan-2-ylmethoxy)-2, 6-dimethylphenyl] - 2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid [0808]

2080<img file="WO2010143733A1_D0095.tif" />

2081[0809]

2082In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7- (4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and furfuryl alcohol.

2083¹H NMR (300 MHz, CDCl₃) δ 2.05 (3H, s) , 2.08 (3H, s) , 2.51-2.65 (IH, m) , 2.79 (IH, dd, J = 16.7, 5.3 Hz), 3.72-3.87 (IH, m) , 4.17-4.41 (2H, m) , 4.61-4.81 (2H, m) , 4.99 (2H, s) , 5.22 (IH, dd, J = 7.2, 4.2 Hz), 6.11-6.18 (2H, m) , 6.34-6.47 (2H, m) , 6.76 (2H, s), 6.92-7.08 (3H, m) , 7.34 (IH, d, J = 6.1 Hz), 7.45 (IH, s) . MS m/z 512 (M + H)⁺. [0810]

2084Example 52

2085[ (3S) -6- ( { (3S) -7- [2, 6-dimethyl-4- (pyridin-3-ylmethoxy) phenyl] - 2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid [0811]

2086<img file="WO2010143733A1_D0096.tif" />

2087[0812]

2088In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7-

2089(4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference

2090Example 10 and 3-pyridinemethanol.

2091¹H NMR (300 MHz, CDCl₃) δ 2.06 (3H, s) , 2.09 (3H, s) , 2.52-2.64

2092(IH, m) , 2.80 (IH, dd, J = 16.7, 5.3 Hz), 3.74-3.89 (IH, m) , 4.22-4.39 (2H, m) , 4.68 (IH, dd, J = 9.7, 7.4 Hz), 4.77 (IH, t, J = 8.9 Hz), 5.09 (2H, s) , 5.22 (IH, dd, J = 7.2, 4.5 Hz), 6.10-6.20 (2H, m) , 6.76 (2H, s) , 6.93-7.07 (3H, m) , 7.31-7.42

2093(2H, m) , 7.84 (IH, d, J = 7.6 Hz), 8.60 (IH, dd, J = 4.9, 1.5 Hz) , 8.70 (IH, d, J = 1.9 Hz) . MS m/z 523 (M + H)⁺.

2094[0813] Example 53

2095[ (3S) -6-{ [ (3S) -7-{2, 6-dimethyl-4- [2- (2-oxopyrrolidin-l- yl) ethoxy] phenyl} -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid

2096[0814] <img file="WO2010143733A1_D0097.tif" />

2097[ 0815 ]

2098In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7-

2099(4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and 1- (2-hydroxyethyl) -2-pyrrolidone. 1H NMR (300 MHz, CDCl₃) δ 1.98-2.10 (8H, m) , 2.34-2.47 (2H, m) , 2.60 (IH, dd, J = 16.7, 9.1 Hz), 2.79 (IH, dd, J = 16.7, 5.3 Hz), 3.61 (2H, t, J = 7.2 Hz), 3.69 (2H, t, J = 4.9 Hz), 3.73-3.86 (IH, m) , 4.11 (2H, t, J = 5.1 Hz), 4.22-4.38 (2H, m) , 4.67 (IH, dd, J = 9.7, 7.4 Hz), 4.74 (IH, t, J = 9.1 Hz), 5.22

2100(IH, dd, J = 7.2, 4.2 Hz), 6.09-6.19 (2H, m) , 6.59-6.68 (2H, m) , 6.92-7.06 (3H, m) , 7.34 (IH, d, J = 7.2 Hz) . MS m/z 543 (M + H)⁺.

2101[0816] Example 54

2102[ (3S) -6-{ [ (3S) -7-{2, 6-dimethyl-4- [3- (pyridin-3- yl ) propoxy] phenyl } -2, 3-dihydro-l-benzofuran-3-yl] amino } -2 , 3- dihydro-l-benzofuran-3-yl] acetic acid

2103[0817]

2104<img file="WO2010143733A1_D0098.tif" />

2105[0818]

2106In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7- (4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and 3-pyridinepropanol .

2107¹H NMR (300 MHz, CDCl₃) δ 2.02-2.19 (8H, m) , 2.59 (IH, dd, J = 16.7, 9.5 Hz), 2.73-2.92 (3H, m) , 3.72-3.90 (IH, m) , 3.97 (2H, t, J = 5.9 Hz), 4.23-4.40 (2H, m) , 4.67 (IH, dd, J = 9.7, 7.4 Hz), 4.77 (IH, t, J = 9.1 Hz), 5.22 (IH, dd, J = 7.0, 4.4 Hz), 6.11-6.21 (2H, m) , 6.66 (2H, s) , 6.90-7.08 (3H, m) , 7.28-7.39 (2H, m) , 7.62 (IH, d, J = 8.0 Hz), 8.44-8.57 (2H, m) . MS m/z 551 (M + H)⁺. [0819] Example 55

2108[ (3S) -6-{ [ (3S) -7-{2, 6-dimethyl-4- [3- (2-oxopyrrolidin-l- yl)propoxy] phenyl} -2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3- dihydro-l-benzofuran-3-yl] acetic acid [0820]

2109<img file="WO2010143733A1_D0099.tif" />

2110[0821]

2111In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7- (4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and 1- (3-hydroxypropyl) -2-pyrrolidone. 1H NMR (300 MHz, CDCl₃) δ 1.96-2.10 (1OH, m) , 2.37-2.47 (2H, m) , 2.56 (IH, dd, J = 16.3, 9.1 Hz), 2.77 (IH, dd, J = 16.7, 4.9 Hz), 3.46 (4H, q, J = 7.4 Hz), 3.71-3.85 (IH, m) , 3.98 (2H, t, J = 6.2 Hz), 4.20-4.37 (2H, m) , 4.66 (IH, dd, J = 9.7, 7.4 Hz), 4.74 (IH, t, J = 9.1 Hz), 5.21 (IH, dd, J = 7.2, 4.2 Hz), 6.08-6.18 (2H, m) , 6.66 (2H, s) , 6.92-7.05 (3H, m) , 7.31-7.37 (IH, m) . MS m/z 557 (M + H)⁺. [0822] Example 56

2112[ (3S)-6-{ [ (3S)-7-{4-[2-(2-fluorophenyl)ethoxy]-2,6- dimethylphenyl}-2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid [0823]

2113<img file="WO2010143733A1_D0100.tif" />

2114[0824]

2115In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7-

2116(4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference

2117Example 10 and 2-fluorophenethyl alcohol.

2118¹H NMR (300 MHz, CDCl₃) δ 2.03 (3H, s) , 2.06 (3H, s) , 2.56 (IH, dd, J = 16.7, 9.5 Hz), 2.76 (IH, dd, J = 16.7, 5.3 Hz), 3.13

2119(2H, t, J = 6.8 Hz), 3.69-3.85 (IH, m) , 4.18 (2H, t, J = 6.8 Hz), 4.22-4.38 (2H, m) , 4.65 (IH, dd, J = 9.5, 7.6 Hz), 4.72

2120(IH, t, J = 9.1 Hz), 5.20 (IH, dd, J = 7.2, 4.2 Hz), 6.09-6.18

2121(2H, m) , 6.67 (2H, s) , 6.89-7.13 (5H, m) , 7.15-7.24 (IH, m) , 7.27-7.37 (2H, m) . MS m/z 554 (M + H)⁺.

2122[0825] Example 57

2123[ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[2-(4-methylpiperazin-l- yl) ethoxy] phenyl} -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid

2124[0826] <img file="WO2010143733A1_D0101.tif" />

2125[ 0827 ]

2126In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7- (4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and 1- (2-hydroxyethyl) -4-methylpiperazine. 1H NMR (300 MHz, CDCl₃) δ 2.03 (3H, s) , 2.06 (3H, s) , 2.40-2.57 (4H, m) , 2.65-2.85 (9H, m) , 2.89 (2H, t, J = 5.1 Hz), 3.69-3.88 (IH, m) , 4.13 (2H, t, J = 5.1 Hz), 4.20-4.35 (2H, m) , 4.64 (IH, dd, J = 9.5, 7.6 Hz), 4.76 (IH, t, J = 9.1 Hz), 5.20 (IH, dd, J = 7.0, 4.4 Hz), 6.06-6.18 (2H, m) , 6.66 (2H, s) , 6.90-7.06 (3H, m) , 7.33 (IH, d, J = 5.3 Hz). MS m/z 558 (M + H)⁺. [0828] Example 58

2127[ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[3-

2128(methylsulfanyl) propoxy] phenyl} -2, 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0829]

2129<img file="WO2010143733A1_D0102.tif" />

2130[0830]

2131In the same manner as in Example 48, the title compound was obtained as a white solid from methyl [ (3S) -6-{ [ (3S) -7- (4- hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference

2132Example 10 and 3- (methylmercapto) propan-1-ol. 1H NMR (300 MHz, CDCl₃) δ 2.00-2.12 (8H, m) , 2.13 (3H, s) , 2.54-2.74 (3H, m) , 2.79 (IH, dd, J = 16.7, 5.3 Hz), 3.72-3.86 (IH, m) , 4.06 (2H, t, J = 6.1 Hz), 4.20-4.38 (2H, m),^~4.67 (IH, dd, J = 9.7, 7.4 Hz), 4.74 (IH, t, J = 9.1 Hz), 5.22 (IH, dd, J = 7.2, 4.2 Hz), 6.10-6.19 (2H, m) , 6.68 (2H, s) , 6.92-7.06 (3H, m) , 7.33 (IH, d, J = 5.7 Hz). MS m/z 520 (M + H)⁺. [0831] Example 59

2133[ (3S)-6-{ [ (3S)-7-{4-[2-(azepan-l-yl)ethoxy]-2,6- dimethylphenyl } -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid [0832]

2134<img file="WO2010143733A1_D0103.tif" />

2135[0833]

2136In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7- (4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and N- (2-hydroxyethyl) hexamethyleneimine. 1H NMR (300 MHz, CDCl₃) δ 1.61-1.74 (4H, m) , 1.76-1.91 (4H, m) ,

21372.03 (3H, s), 2.05 (3H, s) , 2.47 (IH, dd, J = 15.9, 9.1 Hz), 2.62-2.73 (IH, m) , 3.09-3.18 (4H, m) , 3.20-3.33 (2H, m) , 3.71-3.86 (IH, m) , 4.21-4.33 (4H, m) , 4.61 (IH, dd, J = 9.3,

21387.4 Hz), 4.74 (IH, t, J = 8.9 Hz), 5.17 (IH, dd, J = 6.6, 4.4 Hz), 5.99-6.13 (2H, m) , 6.66 (2H, s) , 6.88-7.04 (3H, m) , 7.28-7.36 (IH, m) .

2139MS m/z 557 (M + H)⁺. [0834]

2140Example 60

2141[ (3S)-6-{ [ (3S)-7-(4-{2-[2-(dimethylamino)ethoxy]ethoxy}-2,6- dimethylphenyl) -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-1-benzofuran-3-yl] acetic acid

2142[0835]

2143<img file="WO2010143733A1_D0104.tif" />

2144[0836]

2145In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7-

2146(4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference

2147Example 10 and 2- (2-dimethylaminoethoxy) ethanol.

2148¹H NMR (300 MHz, CDCl₃) δ 2.02 (3H, s) , 2.05 (3H, s) , 2.46 (IH, dd, J = 15.9, 9.1 Hz), 2.56 (6H, s) , 2.68 (IH, dd, J = 16.3,

21495.3 Hz), 2.86-2.97 (2H, m) , 3.70-3.87 (5H, m) , 4.08-4.17 (2H, m) , 4.22-4.34 (2H, m) , 4.62 (IH, t, J = 8.5 Hz), 4.76 (IH, t,

2150J = 9.1 Hz), 5.18 (IH, dd, J = 7.2, 4.5 Hz), 6.04-6.14 (2H, m) ,

21516.67 (2H, s), 6.89-7.04 (3H, m) , 7.32 (IH, dd, J = 6.8, 1.5

2152Hz) .

2153MS m/z 547 (M + H)⁺.

2154[0837] Example 61

2155[ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[ (5-methylisoxazol-3- yl) methoxy] phenyl } -2 , 3-dihydro-l-benzofuran-3-yl] amino} -2 , 3- dihydro-1-benzofuran-3-yl] acetic acid

2156[0838] <img file="WO2010143733A1_D0105.tif" />

2157[0839]

2158In the same manner as in Example 48, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (3S) -7-

2159(4-hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and 3-hydroxymethyl-5-methylisoxazole. 1H NMR (300 MHz, CDCl₃) δ 2.04 (3H, s) , 2.07 (3H, s) , 2.43 (3H, s), 2.56 (IH, dd, J = 16.3, 9.1 Hz), 2.77 (IH, dd, J = 16.7, 4.9 Hz), 3.69-3.84 (IH, m) , 4.20-4.38 (2H, m) , 4.61-4.78 (2H, m) , 5.10 (2H, s), 5.21 (IH, dd, J = 7.0, 4.4 Hz), 6.08-6.18

2160(3H, m) , 6.74 (2H, s) , 6.91-7.06 (3H, m) , 7.33 (IH, d, J = 5.7 Hz) . MS m/z 527 (M + H)⁺.

2161[0840] Example 62

2162[ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[2-(morpholin-4- yl) ethoxy] phenyl } -2 , 3-dihydro-l-benzofuran-3-yl] amino } -2 , 3- dihydro-l-benzofuran-3-yl] acetic acid

2163[0841]

2164<img file="WO2010143733A1_D0106.tif" />

2165[0842]

2166In the same manner as in Example 48, the title compound was obtained as a white solid from methyl [ (3S) -6-{ [ (3S) -7- (4- hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference

2167Example 10 and N- (2-hydroxyethyl)morpholine.

2168¹H NMR (300 MHz, CDCl₃) δ 2.04 (3H, s) , 2.07 (3H, s) , 2.57 (IH, dd, J = 16.7, 9.5 Hz), 2.63-2.70 (4H, m) , 2.76 (IH, dd, J = 16.7, 5.3 Hz), 2.85 (2H, t, J = 5.7 Hz), 3.70-3.83 (5H, m) , 4.14 (2H, t, J = 5.5 Hz), 4.21-4.37 (2H, m) , 4.65 (IH, dd, J = 9.7, 7.4 Hz), 4.74 (IH, t, J = 9.1 Hz), 5.20 (IH, dd, J = 7.4, 4.4 Hz), 6.08-6.16 (2H, m) , 6.68 (2H, s) , 6.87-7.06 (3H, m) , 7.33 (IH, d, J = 5.3 Hz) . MS m/z 545 (M + H)⁺. [0843] Example 63

2169[ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[ (3-methyloxetan-3- yl)methoxy] phenyl} -2, 3-dihydro-l-benzofuran-3-yl] amino} -2, 3- dihydro-l-benzofuran-3-yl] acetic acid [0844]

2170<img file="WO2010143733A1_D0107.tif" />

2171[ 0845 ]

2172In the same manner as in Example 48, the title compound was obtained as a white solid from methyl [ (3S) -6-{ [ (3S) -7- (4- hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and 3-methyl-3-oxetanemethanol.

2173¹H NMR (300 MHz, CDCl₃) δ 1.43 (3H, s) , 2.06 (3H, s) , 2.09 (3H, s), 2.61 (IH, dd, J = 16.7, 9.1 Hz), 2.80 (IH, dd, J = 16.7, 5.3 Hz), 3.73-3.87 (IH, m) , 4.03 (2H, s) , 4.23-4.38 (2H, m) , 4.46 (2H, d, J = 6.1 Hz), 4.59-4.81 (4H, m) , 5.22 (IH, dd, J = 7.0, 4.4 Hz), 6.10-6.22 (2H, m) , 6.72 (2H, s) , 6.93-7.08 (3H, m) , 7.34 (IH, d, J = 5.7 Hz) .

2174[0846] Example 64

2175[ (3S)-6-{ [ (3S)-7-{2,6-dimethyl-4-[3-(morpholin-4- yl)propoxy] phenyl} -2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3- dihydro-l-benzofuran-3-yl] acetic acid [0847]

2176<img file="WO2010143733A1_D0108.tif" />

2177In the same manner as in Example 48, the title compound was obtained as a white solid from methyl [ (3S) -6-{ [ (3S) -7- (4- hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and 3-morpholinopropanol.

2178¹H NMR (300 MHz, CDCl₃) δ 1.96-2.09 (8H, m) , 2.52 (IH, dd, J = 16.6, 8.7 Hz), 2.58-2.78 (7H, m) , 3.70-3.85 (5H, m) , 4.02 (2H, t, J = 6.0 Hz), 4.20-4.29 (2H, m) , 4.54 (IH, dd, J = 9.6, 7.3 Hz), 4.72 (IH, t, J = 9.0 Hz), 5.15 (IH, dd, J = 7.2, 4.1 Hz), 6.03-6.14 (2H, m) , 6.67 (2H, s) , 6.90-7.05 (3H, m) , 7.32 (IH, dd, J = 6.6, 2.1 Hz) . MS m/z 559 (M + H)⁺.

2179[0849] Example 65

2180[ (3S) -6- ( { (3S) -7- [4- (cyclopentylmethoxy) -2, 6-dimethylphenyl] - 2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid

2181[0850]

2182<img file="WO2010143733A1_D0109.tif" /> [ 0851 ]

2183In the same manner as in Example 48, the title compound was obtained as a white solid from methyl [ (3S) -6-{ [ (3S) -7- (4- hydroxy-2, 6-dimethylphenyl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate obtained in the process of obtaining Reference Example 10 and cyclopentanemethanol.

2184¹H NMR (300 MHz, CDCl₃) δ 1.27-1.46 (2H, m) , 1.52-1.70 (4H, m) , 1.75-1.95 (2H, m) , 2.04 (3H, s) , 2.07 (3H, s) , 2.29-2.46 (IH, m) , 2.54-2.71 (IH, m) , 2.80 (IH, dd, J = 16.6, 5.3 Hz), 3.73-3.89 (3H, m) , 4.20-4.39 (2H, m) , 4.67 (IH, dd, J = 9.6, 7.3 Hz), 4.74 (IH, t, J = 9.0 Hz), 5.22 (IH, dd, J = 7.3, 4.3 Hz), 6.10-6.19 (2H, m) , 6.63-6.75 (2H, m) , 6.92-7.12 (3H, m) , 7.28-7.39 (IH, m) . MS m/z 514 (M + H)⁺. [0852] Example 66 methyl [ (3S) -6- ( {7- [1- (difluoromethyl) -3, 5-dimethyl-lH- pyrazol-4-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3- dihydro-l-benzofuran-3-yl] acetate [0853]

2185<img file="WO2010143733A1_D0110.tif" />

2186[0854]

2187To a mixed solution of methyl { (3S) -6- [ (7-bromo-2, 3- dihydro-l-benzofuran-3-yl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (0.323 g, 0.800 mmol) , 1- (difluoromethyl) -3, 5- dimethyl-4- (4,4,5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl) -IH- pyrazole (0.327 g, 1.20 mmol) and tripotassium phosphate (0.340 g, 1.60 mmol) in toluene (4 mL) and water (1 mL) were added palladium (II) acetate (0.018 g, 0.080 mmol) and 2- dicyclohexylphosphino-2' , 6' -dimethoxybiphenyl (0.033 g, 0.080 irunol) , and the mixture was stirred at 100⁰C for 22 hr under an argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 5:95-40:60) to give the title compound (0.276 g, yield 74 %) as a pale-yellow viscous oil.

2188¹H NMR (300 MHz, CDCl₃) δ 2.20 (3H, s) , 2.36 (3H, s) , 2.50-2.61 (IH, m) , 2.69-2.80 (IH, m) , 3.72 (3H, s) , 3.73-3.85 (IH, m) , 4.03 (IH, d, J = 7.3 Hz), 4.25 (IH, dd, J = 9.1, 5.9 Hz), 4.41 (IH, dd, J = 9.7, 4.2 Hz), 4.68-4.78 (2H, m) , 5.18-5.28 (IH, m) , 6.10-6.19 (2H, m) , 6.95-7.39 (5H, m) . MS m/z 470 (M + H)⁺. [0855] Example 67

2189[ (3S) -6- ( { 7- [1- (difluoromethyl) -3, 5-dimethyl-lH-pyrazol-4-yl] - 2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran- 3-yl] acetic acid [0856]

2190<img file="WO2010143733A1_D0111.tif" />

2191[0857]

2192To a mixed solution of methyl [ (3S) -6- ( {7- [1- (difluoromethyl) -3, 5-dimethyl-lH-pyrazol-4-yl] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate (0.272 g, 0.579 mmol) in methanol (1.2 mL) and tetrahydrofuran (1.2 mL) was added 1 M aqueous sodium hydroxide solution (1.2 mL) , and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1 M hydrochloric acid, and the precipitated solid was collected by filtration and dried to give the title compound (0.231 g, yield 88%) as a colorless powder. 1H NMR (300 MHz, CDCl₃) δ 2.20 (3H, s) , 2.36 (3H, s) , 2.55-2.68

2193(IH, m) , 2.74-2.87 (IH, m) , 3.73-3.87 (IH, m) , 4.28 (IH, dd, J = 9.2, 6.0 Hz), 4.41 (IH, dd, J = 9.6, 4.1 Hz), 4.68-4.80 (2H, m) , 5.24 (IH, dd, J = 7.2, 4.1 Hz), 6.11-6.20 (2H, m) , 6.96-7.41 (5H, m) . MS (ESI-) m/z 454 (M - H)^".

2194[0858] Example 68 methyl [ (3S) -6-{ [7- (2-methyl-lH-benzimidazol-l-yl) -2, 3- dihydro-1-benzofuran-3-yl] amino } -2 , 3-dihydro-l-benzofuran-3- yl] acetate

2195[0859]

2196<img file="WO2010143733A1_D0112.tif" />

2197[0860]

2198To a mixture of methyl { (3S) -6- [ (7-bromo-2, 3-dihydro-l- benzofuran-3-yl) amino] -2, 3-dihydro-l-benzofuran-3-yl} acetate (0.555 g, 1.37 mmol) , o-aminoacetanilide (0.309 g, 2.06 mmol) and cesium carbonate (0.280 g, 2.75 mmol) in toluene (8 ml) were added tris (dibenzylideneacetone) dipalladium (0) (0.063 g, 0.069 mmol) and 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene (0.079 g, 0.137 mmol), and the mixture was stirred at 100°C for 18 hr under an argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 40:100-100:0) to give the title compound (56.3 mg, yield 9%) as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ 2.49-2.61 (4H, m) , 2.70-2.80 (IH, m) , 3.72 (3H, s), 3.74-3.85 (IH, m) , 4.06 (IH, d, J = 7.6 Hz), 4.26 (IH, dd, J = 9.1, 6.1 Hz), 4.37-4.48 (IH, m) , 4.70-4.84

2199(2H, m) , 5.26-5.39 (IH, m) , 6.13-6.20 (2H, m) , 6.99 (IH, d, J = 8.3 Hz), 7.04-7.14 (2H, m) , 7.16-7.31 (3H, m) , 7.51 (IH, dd, J = 7.2, 0.8 Hz), 7.71-7.76 (IH, m) . MS m/z 456 (M + H)⁺.

2200[0861] Example 69

2201[ (3S) -6-{ [7- (2-methyl-lH-benzimidazol-l-yl) -2, 3-dihydro-l- benzofuran-3-yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2202[0862]

2203<img file="WO2010143733A1_D0113.tif" />

2204[0863]

2205In the same manner as in Example 67, the title compound was obtained as a colorless powder from methyl [ (3S) -6-{ [7- (2- methyl-lH-benzimidazol-1-yl) -2, 3-dihydro-l-benzofuran-3- yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate, yield 66%. ¹H NMR (300 MHz, CDCl₃) δ 2.53 and 2.55 (3H, s) , 2.57-2.69 (IH, m) , 2.77-2.87 (IH, m) , 3.78-3.91 (IH, m) , 4.31 (IH, dd, J = 9.1, 6.1 Hz), 4.37-4.49 (IH, m) , 4.70-4.85 (2H, m) , 5.27-5.38

2206(IH, m) , 6.12-6.21 (2H, m) , 7.01-7.16 (3H, m) , 7.17-7.32 (3H, m) , 7.52 (IH, d, J = 7.3 Hz), 7.77 (IH, d, J = 7.9 Hz). MS m/z 442 (M + H)⁺.

2207[0864] Example 70 [ (3S) -6-{ [7- (2, 5-dimethyl-lH-benzimidazol-l-yl) -2, 3-dihydro-l- benzofuran-3-yl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2208[0865]

2209<img file="WO2010143733A1_D0114.tif" />

2210[0866]

2211To a mixed solution of methyl [ (3S) -6-{ [7- (2, 5-dimethyl- IH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (0.101 g, 0.179 mmol) in methanol (0.5 mL) and tetrahydrofuran (1 mL) was added 1 M aqueous sodium hydroxide solution (0.5 mL) , and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1 M hydrochloric acid, and the precipitated solid was collected by filtration and dried to give the title compound (56.4 mg, yield 69%) as a colorless powder. 1H NMR (300 MHz, CDCl₃) δ 2.47 (3H, s) , 2.52 (3H, d, J = 5.7 Hz), 2.57-2.69 (IH, m) , 2.76-2.87 (IH, m) , 3.79-3.91 (IH, m) , 4.32 (IH, dd, J = 9.3, 6.2 Hz), 4.36-4.48 (IH, m) , 4.70-4.84

2212(2H, m) , 5.27-5.37 (IH, m) , 6.12-6.20 (2H, m) , 6.93-7.14 (4H, m) , 7.23-7.30 (IH, m) , 7.51 (IH, d, J = 6.8 Hz), 7.56 (IH, s) . MS m/z 456 (M + H)⁺.

2213[0867] Example 71

2214[ (3S)-6-{ [7-(6-fluoro-2-methyl-lH-benzimidazol-l-yl)-2,3- dihydro-1-benzofuran-3-yl] amino } -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2215[0868] <img file="WO2010143733A1_D0115.tif" />

2216[0869]

2217In the same manner as in Example 70, the title compound was obtained as a colorless powder from methyl [ (3S) -6-{ [7- (6- fluoro-2-methyl-lH-benzimidazol-l-yl) -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate, yield 76%. 1H NMR (300 MHz, CDCl₃) δ 2.51 (3H, d, J = 6.4 Hz), 2.57-2.69

2218(IH, m) , 2.76-2.87 (IH, m) , 3.77-3.90 (IH, m) , 4.31 (IH, dd, J = 9.1, 6.1 Hz), 4.44 (IH, td, J = 10.2, 4.5 Hz), 4.73-4.85 (2H, m) , 5.28-5.40 (IH, m) , 6.13-6.22 (2H, m) , 6.78 (IH, ddd, J = 13.1, 8.5, 2.7 Hz), 6.96-7.16 (3H, m) , 7.23-7.31 (IH, m) , 7.53

2219(IH, d, J = 7.2 Hz), 7.68 (IH, dd, J = 8.7, 4.9 Hz). MS m/z 460 (M + H)⁺.

2220[0870] Example 72

2221[ (3S)-6-{ [ (3S)-7-(6-fluoro-2-methyl-lH-benzimidazol-l-yl)-2,3- dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2222[0871]

2223<img file="WO2010143733A1_D0116.tif" />

2224[0872]

2225To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (6-fluoro- 2-methyl-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (0.305 g, 0.536 iratiol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 M aqueous sodium hydroxide solution (2 mL) , and the mixture was stirred at 50°C for 2 hr. The reaction mixture was diluted with water, weak acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The precipitated crystals were recrystallized from heptane-ethyl acetate to give the title compound (0.206 g, yield 84%) as colorless crystals.

2226¹H NMR (300 MHz, DMSO-d₆) δ 2.37-2.51 (4H, m) , 2.60-2.71 (IH, m) , 3.56-3.69 (IH, m) , 4.08-4.16 (IH, m) , 4.22-4.30 (IH, m) , 4.58-4.67 (IH, m) , 4.75-4.87 (IH, m) , 5.33-5.44 (IH, m) , 6.15- 6.26 (3H, m) , 6.86 (IH, ddd, J = 11.5, 9.0, 2.4 Hz), 6.97 (IH, dd, J = 8.1, 2.4 Hz), 7.01-7.17 (2H, m) , 7.41-7.47 (IH, m) , 7.53 (IH, d, J = 7.5 Hz), 7.61 (IH, dd, J = 8.9, 5.1 Hz), 12.31 (IH, br s) . MS m/z 460 (M + H)⁺.

2227[0873] Example 73

2228[ (3S)-6-{ [ (3R)-7-(6-fluoro-2-methyl-lH-benzimidazol-l-yl)-2,3- dihydro-l-benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2229[0874]

2230<img file="WO2010143733A1_D0117.tif" />

2231[0875]

2232To a mixed solution of methyl [ (3S) -6-{ [ (3R) -7- (6-fluoro- 2-methyl-lH-benzimidazol-l-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (0.314 g, 0.551 iranol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 M aqueous sodium hydroxide solution (2 mL) , and the mixture was stirred at 50°C for 2 hr. The reaction mixture was diluted with water, weak acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.257 g, quantitative) as an off-white powder.

2233¹H NMR (300 MHz, DMSO-d₆) δ 2.38-2.50 (4H, m) , 2.60-2.71 (IH, m) , 3.55-3.69 (IH, m) , 4.08-4.16 (IH, m) , 4.26 (IH, ddd, J = 9.4, 4.7, 1.7 Hz), 4.62 (IH, td, J = 9.0, 1.5 Hz), 4.75-4.87 (IH, m), 5.34-5.44 (IH, m) , 6.14-6.26 (3H, m) , 6.85-6.94 (IH, m) , 6.97 (IH, dd, J = 7.9, 2.6 Hz), 7.03-7.18 (2H, m) , 7.42- 7.48 (IH, m) , 7.54 (IH, d, J = 7.2 Hz), 7.63 (IH, dd, J = 8.7, 4.9 Hz) .

2234MS m/z 460 (M + H)⁺. [0876] Example 74

2235[ (3S) -6- ( { (3S) -7- [ (5-fluoropyridin-2-yl) (propyl) amino] -2,3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2236<img file="WO2010143733A1_D0118.tif" />

2237[0878]

2238To a solution of methyl { (3S) -6- [{ (3S) -7- [ (5- fluoropyridin-2-yl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (0.186 g, 0.351 mmol) and n-propyl iodide (89.0 mg,

22390.526 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 16.8 mg, 0.421 mmol) at 0⁰C, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 95:5 - 70:30) to give a mixture (0.125 g) of methyl { (3S) -6- [{ (3S) -7- [ (5- fluoropyridin-2-yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate and methyl [ (3S) -6- ( { (3S) -7- [ (5-fluoropyridin-2- yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3- dihydro-l-benzofuran-3-yl] acetate as a pale-yellow oil. To a mixed solution of the mixture (0.125 g) obtained above in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.787 mL) , and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound

2240(0.109 g, yield 67%, 2 steps) as a pale-yellow solid.

2241¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J = 7.2 Hz), 1.55-1.74

2242(2H, m) , 2.59 (IH, dd, J = 16.7, 9.1 Hz), 2.79 (IH, dd, J = 16.7, 5.3 Hz), 3.71-3.89 (3H, m) , 4.27 (IH, dd, J = 9.1, 6.1 Hz), 4.37 (IH, dd, J = 9.7, 4.4 Hz), 4.64-4.82 (2H, m) , 5.21

2243(IH, dd, J = 7.6, 4.2 Hz), 6.09-6.19 (2H, m) , 6.27 (IH, dd, J = 9.3, 3.6 Hz), 6.90-7.20 (4H, m) , 7.21-7.32 (IH, m) , 8.03 (IH, d, J = 3.4 Hz) . MS m/z 464 (M + H)⁺.

2244[0879] Example 75 sodium [ (3S) -6- ( { (3S) -7- [ (5-fluoropyridin-2-yl) (propyl) amino] - 2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-

22453-yl] acetate [0880]

2246<img file="WO2010143733A1_D0119.tif" />

2247[0881]

2248To a suspension of [ (3S) -6- ( { (3S) -7- [ (5-fluoropyridin-2- yl) (propyl) aminoJ-2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetic acid (75.7 mg, 0.163 mmol) in water (1 mL) was added 1 M aqueous sodium hydroxide solution

2249(0.163 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (75.7 mg, yield 95%) as a pale- yellow solid. 1H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J = 7.4 Hz), 1.47-1.64

2250(2H, m) , 1.98 (IH, dd, J = 15.0, 10.0 Hz), 2.32 (IH, dd, J = 15.0, 4.7 Hz), 3.45-3.63 (IH, m) , 3.68-3.85 (2H, m) , 4.01-4.12

2251(IH, m) , 4.17 (IH, dd, J = 9.5, 4.9 Hz), 4.60 (IH, t, J = 8.9 Hz), 4.72 (IH, t, J = 8.7 Hz), 5.19-5.34 (IH, m) , 6.00 (IH, d, J = 8.0 Hz), 6.06-6.29 (3H, m) , 6.84-7.03 (2H, m) , 7.16 (IH, d, J = 7.6 Hz), 7.22-7.42 (2H, m) , 8.08 (IH, d, J = 3.0 Hz). MS m/z 464 (M + H)⁺ (as free form).

2252[0882] Example 76 methyl { (3S) -6- [ { (3S) -7- [4, 6-dimethyl-2- (morpholin-4- yl) pyrimidin-5-yl] -2, 3-dihydro-l-benzofuran-3-yl}amino] -2, 3- dihydro-1-benzofuran-3-yl } acetate

2253[0883] <img file="WO2010143733A1_D0120.tif" />

2254[0884]

2255A solution of (3S) -7- (4, 6-dimethyl-2-morpholin-4- ylpyrimidin-5-yl) -2, 3-dihydro-l-benzofuran-3-amine (55.7 mg, 0.171 mmol), methyl [ (3S) -6-{ [ (trifluoromethyl) sulfonyl] oxy}- 2, 3-dihydro-l-benzofuran-3-yl] acetate (63.9 mg, 0.188 mmol) obtained in the process of obtaining Reference Example 1 and cesium carbonate (0.167 g, 0.512 mmol) in toluene (3 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (6.25 mg, 0.00683 mmol) and 2-dicyclohexylphosphino-2' , 4' , 6' - triisopropylbiphenyl (6.51 mg, 0.0140 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100°C for 16 hr. The reaction mixture was cooled, insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give the title compound (69.8 mg, yield 79%) as a yellow oil.

2256¹H NMR (300 MHz, DMSO-d₆) δ 2.05 (3H, s) , 2.09 (3H, s) , 2.50-2.61 (IH, m) , 2.72 (IH, dd, J = 16.6, 6.0 Hz), 3.56-3.77

2257(12H, m) , 4.08-4.21 (2H, m) , 4.61 (IH, t, J = 8.9 Hz), 4.67-4.78 (IH, m) , 5.21-5.34 (IH, m) , 6.09-6.24 (3H, m) , 6.91

2258(IH, d, J = 8.7 Hz), 6.93-7.02 (IH, m) , 7.03-7.11 (IH, m) , 7.34 (IH, d, J = 6.8 Hz) .

2259[0885] Example 77

2260[ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (morpholin-4-yl) pyrimidin-5- yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l- benzofuran-3-yl] acetic acid

2261[0886] <img file="WO2010143733A1_D0121.tif" />

2262To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [4, 6- dimethyl-2- (morpholin-4-yl) pyrimidin-5-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (3.90 g, 6.37 mmol) in tetrahydrofuran

2263(20 mL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide solution (19.1 mL) , and the mixture was stirred at 50°C for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 70:30 - 0:100) and crystallized from methanol. The obtained crystals were recrystallized from ethanol-water to give the title compound

2264(2.26 g, yield 71%) as white crystals.

2265¹H NMR (300 MHz, DMSO-d₆) δ 2.05 (3H, s) , 2.09 (3H, s) , 2.44

2266(IH, dd, J = 16.6, 9.0 Hz) , 2.65 (IH, dd, J = 16.6, 5.7 Hz) , 3.53-3.76 (9H, m) , 4.05-4.20 (2H, m) , 4.62 (IH, t, J = 9.0 Hz) , 4.67-4.78 (IH, m) , 5.22-5.35 (IH, m) , 6.06-6.24 (3H, m) , 6.90-7.02 (2H, m) , 7.03-7.11 (IH, m) , 7.34 (IH, d, J = 7.2 Hz) , 12.31 (IH, br s) . MS m/z 503 (M + H)⁺. melting point: 168°C. elemental analysis value for C₂₈H₃₀N₄O₅

2267Calculated: C, 66.92; H, 6.02; N, 11.15.

2268Found: C, 66.84; H, 6.12; N, 11.08.

2269[0888]

2270Alternatively, to a mixed solution of methyl {(3S)-6- [ { (3S) -7- [4, 6-dimethyl-2- (morpholin-4-yl) pyrimidin-5-yl] -2,3- dihydro-l-benzofuran-3-yl}amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (67.8 mg, 0.131 mmol) in tetrahydrofuran (1.5 iriL) and methanol (0.75 mL) was added 1 M aqueous sodium hydroxide solution (0.394 mL) , and the mixture was stirred at 50°C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid (0.394 mL) , diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate:methanol = 90:10:0 - 0:100:0 - 0:85:15), and crystallized from methanol-hexane to give the title compound (32.5 mg, yield 49%) as pale-yellow crystals . [0889]

2271Example 77-1

2272Hydrate of [ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (morpholin-4- yl)pyrimidin-5-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetic acid [0890]

2273To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [4, 6- dimethyl-2- (morpholin-4-yl) pyrimidin-5-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (2.24 g, 3.66 mmol) in tetrahydrofuran (14 mL) and methanol (7 mL) was added 1 M aqueous sodium hydroxide solution (11.0 mL) , and the mixture was stirred at 50°C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol- diisopropyl ether to give a first crystal (1.10 g) . Mother liquor was concentrated, and the obtained solid was triturated with methanol. The solid was collected by filtration, and dried to give a second crystal (0.460 g) . Furthermore, a similar operation was repeated to give a third crystal (0.109 g) . The first to third crystals were combined and recrystallized from ethanol to give the title compound (1.30 g, yield 71%) as pale-yellow crystals.

2274¹H NMR (300 MHz, DMSOd₆) δ 2.05 (3H, s) , 2.09 (3H, s) , 2.44 (IH, dd, J = 16.6, 9.0 Hz), 2.65 (IH, dd, J = 16.6, 5.7 Hz), 3.53-3.76 (9H, m) , 4.05-4.20 (2H, m) , 4.62 (IH, t, J = 9.0 Hz), 4.67-4.78 (IH, m) , 5.22-5.35 (IH, m) , 6.06-6.24 (3H, m) , 6.90-7.02 (2H, m) , 7.03-7.11 (IH, m) , 7.34 (IH, d, J = 7.2 Hz), 12.31 (IH, br s) . MS m/z 503 (M + H)⁺. melting point: 133°C. elemental analysis value for C₂₈H₃oN₄CVO .5 H₂O Calculated: C, 65.74; H, 6.11; N, 10.95. Found: C, 65.79; H, 6.18; N, 10.96. [0891]

2275Example 77-2

2276[ (3S) -6- ( { (3S) -7- [4 , 6-dimethyl-2- (morpholin-4-yl) pyrimidin-5- yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l- benzofuran-3-yl] acetic acid [0892]

2277To a mixed solution of methyl { (3S) -6- [ { (3S) -7- [4, 6- dimethyl-2- (-morpholin-4-yl) pyrimidin-5-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (0.191 g, 0.312 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.937 mL) , and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 90:10 - 20:80) to give the title compound (0.122 g, yield 78%) as a white amorphous solid.

2278¹H NMR (300 MHz, CDCl₃) δ 2.14 (3H, s) , 2.17 (3H, s) , 2.61 (IH, dd, J = 16.6, 9.0 Hz) , 2.80 (IH, dd, J = 16.6, 5.3 Hz) ,

22793.71-3.90 (9H, m) , 4.27 (IH, dd, J = 9.4, 6.0 Hz), 4.36 (IH, dd, J = 9.6, 4.3 Hz) , 4.64-4.80 (2H, m) , 5.23 (IH, dd, J = 7.3, 4.3 Hz), 6.10-6.21 (2H, m) , 6.93-7.07 (3H, m) , 7.32-7.40 (IH, m) . MS m/z 503 (M + H)⁺.

2280[0893] Example 78 sodium [ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (morpholin-4- yl) pyrimidin-5-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetate

2281[0894]

2282<img file="WO2010143733A1_D0122.tif" />

2283[0895]

2284To a suspension of [ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (morpholin-4-yl) pyrimidin-5-yl] -2, 3-dihydro-l-benzofuran-3- yl } amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (87.3 mg, 0.174 mmol) in water (1 mL) was added 1 M aqueous sodium hydroxide solution (0.174 mL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (90.2 mg, yield 99%) as a beige solid.

2285¹H NMR (300 MHz, DMSOd₆) δ 1.92-2.13 (7H, m) , 2.33 (IH, dd, J = 14.8, 4.9 Hz), 3.47-3.60 (IH, m) , 3.60-3.78 (8H, m) , 4.07 (IH, dd, J = 8.7, 7.2 Hz), 4.16 (IH, dd, J = 9.5, 4.9 Hz), 4.60 (IH, t, J = 8.9 Hz), 4.72 (IH, t, J = 8.5 Hz), 5.20-5.33 (IH, m) , 5.99 (IH, d, J = 7.6 Hz), 6.08-6.20 (2H, m) , 6.87-7.01 (2H, m) , 7.03-7.10 (IH, m) , 7.34 (IH, d, J = 7.2 Hz). MS m/z 503 (M + H)⁺ (as free form). [0896] Example 79

2286[ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (pyrrolidin-1-yl) pyrimidin-5- yl] -2, 3-dihydro-l-benzofuran-3-yl }amino) -2, 3-dihydro-l- benzofuran-3-yl] acetic acid

2287[0897]

2288<img file="WO2010143733A1_D0123.tif" />

2289[0898]

2290To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (4, 6- dimethyl-2-pyrrolidin-l-ylpyrimidin-5-yl) -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (1.45 g, 2.43 mmol) in tetrahydrofuran

2291(10 inL) and methanol (5 inL) was added 1 M aqueous sodium hydroxide solution (7.28 mL) , and the mixture was stirred at 5O⁰C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol, and the obtained crystals were recrystallized from methanol to give the title compound (0.908 g, yield 77%) as a pale-yellow solid. 1H NMR (300 MHz, CDCl₃) δ 1.91-2.01 (4H, m) , 2.14 (3H, s) , 2.17

2292(3H, s), 2.61 (IH, dd, J = 16.6, 9.0 Hz), 2.80 (IH, dd, J = 16.6, 5.3 Hz), 3.54-3.66 (4H, m) , 3.73-3.86 (IH, m) , 4.27 (IH, dd, J = 9.2, 5.8 Hz), 4.35 (IH, dd, J = 9.6, 4.3 Hz), 4.64-4.80 (2H, m) , 5.23 (IH, dd, J = 7.3, 4.3 Hz), 6.10-6.19

2293(2H, m) , 6.93-7.07 (3H, m) , 7.31-7.37 (IH, m) . MS m/z 487 (M + H)⁺. melting point : 169°C . elemental analysis value for C₂₈H₃₀N₄CV 0 . 2H₂O Calculated : C, 68 . 61 ; H, 6 . 25 ; N, 11 . 43 . Found : C , 68 . 67 ; H, 6 . 27 ; N , 11 . 36 .

2294[0899] Example 80 sodium [ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2- (pyrrolidin-1- yl) pyrimidin-5-yl] -2, 3-dihydro-l-benzofuran-3-yl}amino) -2, 3- dihydro-l-benzofuran-3-yl] acetate

2295[0900]

2296<img file="WO2010143733A1_D0124.tif" />

2297[0901]

2298To a solution of [ (3S) -6- ( { (3S) -7- [4, 6-dimethyl-2-

2299(pyrrolidin-1-yl) pyrimidin-5-yl] -2, 3-dihydro-l-benzofuran-3- yljamino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.105 mg, 0.215 mmol) in methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.251 mL) . The mixture was stirred at room temperature for 1 min, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (99.6 mg, yield 91%) as a pale-yellow solid. 1H NMR (300 MHz, DMSOd₆) δ 1.82-2.13 (HH, m) , 2.34 (IH, dd, J = 15.1, 4.9 Hz), 3.42-3.65 (5H, m) , 4.01-4.22 (2H, m) , 4.61

2300(IH, t, J = 8.9 Hz), 4.71 (IH, t, J = 8.7 Hz), 5.18-5.35 (IH, m) , 5.99 (IH, d, J = 7.9 Hz), 6.09-6.19 (2H, m) , 6.87-7.09 (3H, m) , 7.33 (IH, d, J = 6.8 Hz) . MS m/z 487 (M + H)⁺ (as free form).

2301[0902] Example 81

2302[ (3S) -6- ( { (3S) -7- [ethyl (phenyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2303[0903] <img file="WO2010143733A1_D0125.tif" />

2304[0904]

2305To a mixed solution of methyl { (3S) -6- [ { (3S) -7-

2306[ethyl (phenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (71.9 mg, 0.133 mmol) in tetrahydrofuran (1 mL) and methanol (0.5 mL) was added 1 M aqueous sodium hydroxide solution (0.399 mL) , and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was concentrated under reduced pressure, and water was added to dissolve the residue, and 1 M hydrochloric acid (0.266 mL) was slowly added. The obtained precipitate was collected by filtration, washed with water, and dried to give the title compound (54.3 mg, yield 95%) as a pale-yellow solid.

2307¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J = 7.2 Hz), 2.57 (IH, dd, J = 16.6, 9.0 Hz), 2.76 (IH, dd, J = 16.6, 5.3 Hz), 3.66-3.85 (3H, m) , 4.25 (IH, dd, J = 9.4, 6.0 Hz), 4.34 (IH, dd, J = 9.6, 4.3 Hz), 4.62-4.77 (2H, m) , 5.17 (IH, dd, J = 7.2, 4.1 Hz), 6.06-6.16 (2H, m) , 6.68-6.78 (3H, m) , 6.89 (IH, t, J = 7.5 Hz), 6.97 (IH, d, J = 8.7 Hz), 7.08-7.22 (4H, m) . MS m/z 429 (M - H)^".

2308[0905] Example 82

2309[ (3S) -6- ( { (3S) -7- [ (4-methylpyridin-2-yl) (propyl) amino] -2,3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2310[0906] <img file="WO2010143733A1_D0126.tif" />

2311To a solution of methyl { (3S) -6- [{ (3S) -7- [ (4- methylpyridin-2-yl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (1.98 g, 3.75 mmol) and n-propyl iodide (0.549 mL, 5.63 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.180 g, 4.50 mmol) at 0⁰C, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 70:30) to give a mixture (1.76 g) of methyl { (3S)-6-[{ (3S) -7- [ (4-methylpyridin-2-yl) (propyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- l-benzofuran-3-yl}acetate and methyl [ (3S) -6- ( { (3S) -7- [ (4- methylpyridin-2-yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate as a white non-crystalline powder. To a mixed solution of the mixture (1.76 g) obtained above in tetrahydrofuran (14 mL) and methanol (7 mL) was added 1 M aqueous sodium hydroxide solution (9.25 mL) , and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 100:0 - 70:30) and crystallized from 90% ethanol-water to give the title compound

2312(1.23 g, yield 71%, 2 steps) as a white solid.

2313¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J = 7.4 Hz), 1.45-1.63

2314(2H, m) , 2.08 (3H, s) , 2.44 (IH, dd, J = 16.7, 9.1 Hz), 2.65

2315(IH, dd, J = 16.3, 5.7 Hz), 3.53-3.69 (IH, m) , 3.70-3.85 (2H, m) , 4.05-4.21 (2H, m) , 4.62 (IH, t, J = 8.9 Hz), 4.73 (IH, t, J = 8.5 Hz), 5.22-5.35 (IH, m) , 6.04 (IH, s) , 6.10-6.25 (3H, m) , 6.44 (IH, d, J = 4.9 Hz), 6.88-7.03 (2H, m) , 7.14 (IH, d, J = 6.8 Hz), 7.28 (IH, d, J = 7.2 Hz), 7.96 (IH, d, J = 5.3 Hz) , 12.32 (IH, br s) . MS m/z 460 (M + H)⁺. melting point : i46°C. elemental analysis value for C₂7H₂₉N₃O₄ Calculated: C, 70.57; H, 6.36; N, 9.14. Found: C, 70.47; H, 6.34; N, 9.06.

2316[0908] Example 83

2317[ (3S) -6-{ [ (3S) -7- (pyridin-2-ylamino) -2, 3-dihydro-l-benzofuran- 3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2318[0909]

2319<img file="WO2010143733A1_D0127.tif" />

2320[0910]

2321A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (0.176 g, 0.422 mmol) , pyridin-2-amine

2322(39.7 mg, 0.422 mmol) and cesium carbonate (0.229 g, 0.704 mmol) in toluene (4 inL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (12.9 mg, 0.0140 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

2323(16.3 mg, 0.0280 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100°C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 65:35) to give methyl [(3S)-6- { [ (3S) -7- (pyridin-2-ylamino) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl]acetate (49.5 mg, yield 27%) and methyl [ (3S) -6-{ [ (3S) -7- (pyridin-2-ylamino) -2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3- dihydro-l-benzofuran-3-yl] acetate (15.0 mg, yield 10%) each as a brown oil. To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (pyridin-2-ylamino) -2, 3-dihydro-l-benzofuran-3-yl] amino}-2, 3- dihydro-l-benzofuran-3-yl] acetate (15.0 mg, 0.0360 mmol) obtained above in tetrahydrofuran (0.5 mL) and methanol (0.25 mL) was added 1 M aqueous sodium hydroxide solution (0.108 mL) , and the mixture was stirred at 50°C for 1 hr. The reaction mixture was concentrated under reduced pressure, and water was added to dissolve the residue, and 1 M hydrochloric acid (0.108 mL) was slowly added. The obtained precipitate was collected by filtration, washed with water, and dried to give the title compound (13.1 mg, yield 90%) as a pale-yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 2.59 (IH, dd, J = 16.2, 8.3 Hz), 2.75 (IH, dd, J = 16.2, 6.4 Hz), 3.74-3.91 (IH, m) , 4.25 (IH, dd, J = 9.0, 6.4 Hz), 4.46 (IH, dd, J = 9.8, 4.1 Hz), 4.68-4.82 (2H, m) , 5.17-5.26 (IH, m) , 6.04-6.17 (2H, m) , 6.70-6.86 (2H, m) , 6.88-7.00 (IH, m) , 7.03-7.15 (2H, m) , 7.50-7.61 (2H, m) , 8.03-8.13 (IH, m) . MS m/z 404 (M + H)⁺. [0911] Example 84

2324[ (3S) -6- ( { (3S) -7- [ (4-methylpyridin-2-yl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0912] <img file="WO2010143733A1_D0128.tif" />

2325[0913]

2326A solution of methyl [ (3S) -6-{ [ (3S) -7-broπιo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.203 g, 0.487 mmol) , 4- methylpyridin-2-amine (52.6 mg, 0.487 mmol) and cesium carbonate (0.264 g, 0.811 mmol) in toluene (4 mL) was substituted with argon, and tris (dibenzylideneacetone) dipalladium (0) (14.9 mg, 0.0160 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

2327(18.8 mg, 0.0320 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography

2328(hexane: ethyl acetate = 95:5 - 65:35) to give methyl {(3S)-6-

2329[{ (3S) -7-[ (4-methylpyridin-2-yl)amino]-2,3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (55.5 mg, yield 26%) and methyl [(3S)- 6- ( { (3S) -7- [ (4-methylpyridin-2-yl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate

2330(24.9 mg, yield 14%) each as a brown oil. To a mixed solution of methyl [ (3S) -6- ( { (3S) -7- [ (4-methylpyridin-2-yl) amino] -2, 3- dihydro-1-benzofuran-3-yl } amino) -2 , 3-dihydro-l-benzofuran-3- yl] acetate (24.9 mg, 0.0580 mmol) obtained above in tetrahydrofuran (0.5 mL) and methanol (0.25 mL) was added 1 M aqueous sodium hydroxide solution (0.173 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was concentrated under reduced pressure, water was added to dissolve the residue, and 1 M hydrochloric acid was slowly added to neutralize the mixture. The obtained precipitate was collected by filtration, washed with water, and dried to give the title compound (21.3 mg, yield 88%) as a pale-yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 2.28 (3H, s) , 2.52 (IH, dd, J = 16.4, 9.6 Hz), 2.74 (IH, dd, J = 16.2, 5.3 Hz), 3.71-3.86 (IH, m) , 4.27 (IH, dd, J = 9.0, 6.4 Hz), 4.46 (IH, dd, J = 9.6, 4.0 Hz), 4.70-4.80 (2H, m) , 5.21 (IH, dd, J = 7.2, 4.1 Hz), 6.10-6.18 (2H, m) , 6.57-6.64 (2H, m) , 6.89-7.10 (3H, m) , 7.77 (IH, d, J = 7.9 Hz), 8.03 (IH, d, J = 5.7 Hz). MS m/z 418 (M + H)⁺. [0914] Example 85 sodium [ (3S)-6-({ (3S) -7- [propyl (pyridin-2-yl) amino] -2, 3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetate [0915]

2331<img file="WO2010143733A1_D0129.tif" />

2332To a solution of methyl [ (3S) -6-{ [ (3S) -7- (pyridin-2- ylamino) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino} -2, 3-dihydro-l-benzofuran-3- yl] acetate (0.310 g, 0.604 mmol) obtained in the process of obtaining Example 83 and n-propyl iodide (154 mg, 0.906 mmol) in N,N-dimethylformamide (4 πιL) was added sodium hydride (60% in oil, 29.0 mg, 0.725 mmol) at 0⁰C, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 60:40) to give a mixture (0.143 g, a colorless oil) of methyl { (3S) -6- [ { (3S) -7- [propyl (pyridin-2- yl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate and methyl [ (3S) -6- ( { (3S) -7- [propyl (pyridin-2- yl) amino] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l- benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.143 g) obtained above in tetrahydrofuran (2 mL) and methanol (4 mL) was added 1 M aqueous sodium hydroxide solution (0.934 mL) , and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [ (3S) -6- ( { (3S) -7- [propyl (pyridin-2-yl) amino] -2, 3-dihydro-l-benzofuran-3- yljamino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.140 g, yield 52%, 2 steps) as a pale-yellow oil. To a solution of [ (3S) -6- ( { (3S) -7- [propyl (pyridin-2-yl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.140 g, 0.314 mmol) obtained above in methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.314 mL) , and the mixture was stirred at room temperature for 1 min. Then, acetonitrile was added, and the mixture was concentrated under reduced pressure to give the title compound (132 mg, yield 90%) as a pale-yellow solid.

2333¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J = 7.3 Hz), 1.45-1.69 (2H, m) , 1.99 (IH, dd, J = 15.1, 10.2 Hz), 2.33 (IH, dd, J = 15.3, 5.1 Hz), 3.47-3.63 (IH, m) , 3.70-3.89 (2H, m) , 4.07 (IH, dd, J = 8.9, 7.3 Hz), 4.17 (IH, dd, J = 9.4, 4.9 Hz), 4.61 (IH, t, J = 8.9 Hz), 4.72 (IH, t, J = 8.7 Hz), 5.19-5.35 (IH, m) , 6.02 (IH, d, J = 7.5 Hz), 6.06-6.27 (3H, m) , 6.54-6.64 (IH, m) , 6.86-7.03 (2H, m) , 7.15 (IH, d, J = 7.2 Hz), 7.22-7.43 (2H, m) , 8.05-8.16 (IH, m) .

2334MS m/z 446 (M + H)⁺ (as free form). [0917]

2335Example 86 sodium [ (3S) -6-{ [ (3S) -7- (2, 3-dihydro-4H-l, 4-benzooxazin-4-yl) - 2 , 3-dihydro-l-benzofuran-3-yl] amino } -2 , 3-dihydro-l-benzofuran- 3-yl] acetate [0918]

2336<img file="WO2010143733A1_D0130.tif" />

2337[0919]

2338To a mixed solution of methyl [ (3S) -6-{ [ (3S) -7- (2, 3- dihydro-4H-l, 4-benzooxazin-4-yl) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate (0.181 g, 0.327 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.980 mL) , and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [ (3S) -6-{ [ (3S) -7- (2, 3-dihydro- 4H-I, 4-benzooxazin-4-yl) -2, 3-dihydro-l-benzofuran-3-yl] amino }- 2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.152 g, yield 100%) as a pale-yellow solid. To a solution of [ (3S) -6-{ [ (3S) - 7- (2, 3-dihydro-4H-l, 4-benzooxazin-4-yl) -2, 3-dihydro-l- benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetic acid (0.152 g, 0.342 mmol) obtained above in methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.342 mL) , and the mixture was stirred at room temperature for 1 min. Then, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (97.3 mg, yield 61%) as a pale-yellow solid.

2339¹H NMR (300 MHz, DMSO-d₆) δ 1.98 (IH, dd, J = 15.1, 10.2 Hz), 2.33 (IH, dd, J = 15.1, 4.9 Hz) , 3.46-3.69 (3H, m) , 4.02-4.12

2340(IH, m), 4.15-4.31 (3H, m) , 4.61 (IH, t, J = 8.9 Hz) , 4.70-4.81 (IH, m) , 5.19-5.31 (IH, m) , 5.98 (IH, d, J = 7.9 Hz) , 6.09-6.20 (2H, m) , 6.45 (IH, dd, J = 7.7, 2.1 Hz), 6.58-6.72 (2H, m) , 6.74-6.81 (IH, m) , 6.86-6.98 (2H, m) , 7.08-7.23 (2H, in) .

2341MS m/z 443 (M - H)^" (as free form) . [0920]

2342Example 87 sodium [ (3S)-6-{ [ (3S)-7-{ [4-

2343(methylsulfonyl) phenyl] (propyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [0921]

2344<img file="WO2010143733A1_D0131.tif" />

2345[0922]

2346A solution of methyl [ (3S) -6-{ [ (3S) -7-bromo-2, 3-dihydro- l-benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.300 g, 0.600 mmol) , 4-

2347(methylsulfonyl) aniline (123 mg, 0.720 mmol) and cesium carbonate (0.585 g, 1.80 mmol) in toluene (4 rαL) was substituted with argon, and tris (dibenzylideneacetone)dipalladium (0) (22.0 mg, 0.0240 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

2348(27.8 mg, 0.0480 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 100⁰C for 16 hr. The reaction mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 40:60) to give a mixture (0.161 g, a yellow solid) containing methyl [ (3S) -6-{ [ (3S) -7-{ [4- (methylsulfonyl) phenyl] amino} -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl] acetate. To a solution of the solid (0.161 g) obtained above and n-propyl iodide (69.4 mg, 0.408 mmol) in N, N- dimethylformamide (3 inL) was added sodium hydride (60% in oil,

234913.1 mg, 0.327 mmol) at 0⁰C, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a mixture (96.7 mg, a yellow oil) of methyl [ (3S) -6-{ [ (3S) -7-{ [4-

2350(methylsulfonyl) phenyl] (propyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate and methyl [ (3S) -6-{ [ (3S) -7-{ [4- (methylsulfonyl) phenyl] (propyl) amino} -2, 3-dihydro-l- benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (96.7 mg) obtained above in tetrahydrofuran (2 mL) and methanol (1 inL) was added 1 M aqueous sodium hydroxide solution (0.459 mL) , and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, diluted with brine, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil (84.6 mg) . To a solution of the oil (84.6 mg) obtained above in methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.162 mL) , and the mixture was stirred at room temperature for 1 min. Then, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (73.4 mg, yield 23% (4 steps)) as a pale-yellow solid.

2351¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J = 7.4 Hz), 1.50-1.70 (2H, m) , 1.98 (IH, dd, J = 15.0, 10.0 Hz), 2.32 (IH, dd, J = 15.1, 4.9 Hz), 2.50 (3H, s) , 3.44-3.72 (3H, m) , 4.07 (IH, t, J = 8.0 Hz), 4.18 (IH, dd, J = 9.5, 4.9 Hz), 4.61 (IH, t, J = 9.1 Hz), 4.72 (IH, t, J = 8.7 Hz), 5.21-5.35 (IH, m) , 6.01 (IH, d, J = 7.6 Hz), 6.07-6.20 (2H, m) , 6.69 (2H, d, J = 9.1 Hz), 6.87-7.05 (2H, m) , 7.16 (IH, d, J = 7.6 Hz), 7.32 (IH, d, J = 7.6 Hz), 7.60 (2H, d, J = 8.7 Hz). MS m/z 523 (M + H)⁺ (as free form). [0923] Example 88

2352[ (3S) -6- ({ (3S) -7- [ (5-chloropyrimidin-2-yl) (propyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2353<img file="WO2010143733A1_D0132.tif" />

2354[0925]

2355To a solution of methyl { (3S) -6- [ { (3S) -7- [ (5- chloropyrimidin-2-yl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (0.146 g, 0.266 mmol) and n-propyl iodide (62.0 mg, 0.399 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 12.8 mg, 0.319 mmol), and the mixture was stirred at room temperature for 20 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a mixture (0.098 g, a solid) of methyl { (3S) -6- [ { (3S) -7- [ (5-chloropyrimidin-2- yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate and methyl [ (3S) -6- ( { (3S) -7- [ (5-chloropyrimidin-2- yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.098 g) obtained above in tetrahydrofuran (5 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (3 mL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.078 g, yield 61%, 2 steps) as a solid.

2356¹H NMR (300 MHz, CDCl₃) δ 1.21-1.30 (3H, m) , 1.59-1.69 (2H, m) , 2.53-2.61 (IH, m) , 2.72-2.80 (IH, m) , 3.74-3.79 (IH, m) , 3.80-3.87 (2H, m) , 4.23-4.28 (IH, m) , 4.35-4.40 (IH, m) , 4.67-4.76 (2H, m) , 5.20-5.23 (IH, m) , 5.94 (2H, br s) , 6.13-6.16 (2H, m) , 6.94-6.99 (2H, m) , 7.14 (IH, d, J = 7.5 Hz), 7.29 (IH, d, J = 7.2 Hz), 8.23 (2H, s) .

2357[0926] Example 89

2358[ (3S)-6-({ (3S) -7- [ (4-cyano-2-fluorophenyl) (ethyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2359<img file="WO2010143733A1_D0133.tif" />

2360[0928]

2361To a solution of methyl { (3S) -6- [ { (3S) -7- [ (4-cyano-2- fluorophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (0.160 g, 0.288 mmol) and ethyl iodide (67.3 mg, 0.43 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 13.8 mg, 0.35 mmol) , and the mixture was stirred at room temperature for 20 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a mixture (0.085 g, an oil) of methyl { (3S) -6- [ { (3S) -7- [ (4-cyano-2- fluorophenyl) (ethyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate and methyl [ (3S) -6- ( { (3S) -7- [ (4-cyano-2- fluorophenyl) (ethyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.085 g) obtained above in tetrahydrofuran (5 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (3 mL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.058 g, yield 43%, 2 steps) as a solid.

2362¹H NMR (300 MHz, CDCl₃) δ 1.22 (3H, t, J = 7.2 Hz), 2.57-2.65 (IH, m), 2.76-2.83 (IH, m) , 3.77-3.84 (3H, m) , 4.24-4.30 (IH, m) , 4.38-4.43 (IH, m) , 4.62-4.77 (2H, m) , 5.17-5.21 (IH, m) , 6.02 (2H, br s) , 6.16-6.20 (2H, m) , 6.82-6.92 (2H, m) , 6.97-7.01 (2H, m) , 7.17-7.28 (3H, m) . [0929] Example 90

2363[ (3S) -6- ( { (3S) -7- [ (4-cyanophenyl) (ethyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0930] <img file="WO2010143733A1_D0134.tif" />

2364[0931]

2365To a solution of methyl { (3S) -6- [{ (3S) -7- [ (4- cyanophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (0.316 g, 0.59 mmol) and ethyl iodide (138 mg, 0.88 iranol) in N,N-dimethylformamide (2 mL) was added sodium hydride

2366(60% in oil, 28 mg, 0.71 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a mixture (0.140 g, a solid) of methyl { (3S) -6- [ { (3S) -7- [ (4-cyanophenyl) (ethyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate and methyl [ (3S) -6- ( { (3S) -7- [ (4- cyanophenyl) (ethyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.140 g) obtained above in tetrahydrofuran (5 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (2 mL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.100 g, yield 37%, 2 steps) as a solid.

2367¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J = 6.9 Hz), 1.43 (IH, br s), 2.57-2.65 (IH, m) , 2.77-2.84 (IH, m) , 3.70-3.79 (3H, m) , 4.25-4.30 (IH, m) , 4.36-4.41 (IH, m) , 4.69-4.77 (2H, m) , 5.23-5.25 (IH, m) , 6.14-6.17 (2H, m) , 6.60-6.69 (2H, m) ,

23686.94-7.01 (3H, m) , 7.11 (IH, d, J = 7.2 Hz) , 7.31 (IH, d, J = 7.2 Hz) , 7.39 (2H, d, J = 8.4 Hz) .

2369[0932] Example 91

2370[ (3S)-6-({ (3S) -7- [ (3-cyanophenyl) (ethyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2371[0933]

2372<img file="WO2010143733A1_D0135.tif" />

2373[0934]

2374To a solution of methyl { (3S) -6- [{ (3S) -7- [ (3- cyanophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate (0.156 g, 0.29 mmol) and ethyl iodide (69 mg, 0.44 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 14 mg, 0.36 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a mixture (0.057 g, an oil) of methyl { (3S) -6- [ { (3S) -7- [ (3-cyanophenyl) (ethyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate and methyl [ (3S) -6- ( { (3S) -7- [ (3- cyanophenyl) (ethyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.057 g) obtained above in tetrahydrofuran (5 mL) and methanol (5 mL) was added 2 M aqueous sodium hydroxide solution (2 mL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid to give a white solid as a precipitate. The obtained white solid was dried under reduced pressure to give the title compound (0.042 g, yield 32%, 2 steps) as a white solid.

2375¹H NMR (300 MHz, CDCl₃) δ 1.20 (3H, t, J = 7.2 Hz), 2.50-2.66 (IH, m) , 2.71-2.84 (IH, m) , 3.65-3.80 (4H, m) , 4.22-4.30 (IH, m) , 4.45-4.47 (IH, m) , 4.67-4.78 (2H, m) , 5.23-5.27 (IH, m) , 6.19-6.25 (2H, m) , 6.85-6.86 (2H, m) , 6.93-7.03 (3H, m) , 7.10 (IH, d, J = 7.5 Hz), 7.18-7.23 (2H, m) , 7.33 (IH, d, J = 7.2 Hz) . [0935] Example 92

2376[ (3S) -6- ({ (3S) -7- [ (3-cyanophenyl) (propyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0936]

2377<img file="WO2010143733A1_D0136.tif" />

2378[0937]

2379To a solution of methyl { (3S) -6- [ { (3S) -7- [ (3- cyanophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (0.331 g, 0.616 mmol) and n-propyl iodide (126 mg, 0.74 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% in oil, 37 mg, 0.924 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a mixture (0.100 g, an oil) of methyl { (3S) -6- [ { (3S) -7- [ (3-cyanophenyl) (propyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro- l-benzofuran-3-yl} acetate and methyl [ (3S) -6- ( { (3S) -7- [ (3- cyanophenyl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3- yljamino) -2, 3-dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.100 g) obtained above in tetrahydrofuran (10 πiL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide solution (6 mL) , and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and neutralized with 1 M hydrochloric acid to give a solid precipitate. The obtained solid was washed with water, and dried under reduced pressure to give the title compound (0.084 g, yield 29%, 2 steps) as a solid. 1H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J = 7.8 Hz), 1.60-1.71

2380(2H, m) , 2.57-2.66 (IH, m) , 2.77-2.84 (IH, m) , 3.55-3.60 (2H, m) , 3.77-3.82 (IH, m) , 4.25-4.30 (IH, m) , 4.36-4.41 (IH, m) , 4.69-4.78 (2H, m) , 5.22-5.26 (IH, m) , 6.15-6.18 (2H, m) , 6.82-6.86 (2H, m) , 6.94-7.02 (3H, m) , 7.09-7.12 (IH, m) , 7.17-7.30 (3H, m) , 12.52 (IH, br s) . MS m/z 470 (M + H)⁺.

2381[0938] Example 93

2382[ (3S) -6- ( { (3S) -7- [propyl (pyridin-3-yl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2383[0939]

2384<img file="WO2010143733A1_D0137.tif" />

2385[0940]

2386To a- solution of methyl [ (3S) -6-{ [ (3S) -7- (pyridin-3- ylamino) -2, 3-dihydro-l-benzofuran-3- yl] (trifluoroacetyl) amino}-2, 3-dihydro-l-benzofuran-3- yl]acetate (0.289 g, 0.56 mmol) and n-propyl iodide (116 mg, 0.68 mmol) in N,N-dimethylformamide (2 πiL) was added sodium hydride (60% in oil, 33.6 mg, 0.84 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85:15 - 50:50) to give a mixture (0.105 g, an oil) of methyl { (3S) -6- [{ (3S) -7- [propyl (pyridin-3-yl) amino] -2, 3- dihydro-l-benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro- l-benzofuran-3-yl} acetate and methyl [ (3S) -6- ( { (3S) -7- [propyl (pyridin-3-yl) amino] -2, 3-dihydro-l-benzofuran-3- yl }amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.105 g) obtained above in tetrahydrofuran (10 mL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide solution (4 mL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and neutralized with 1 M hydrochloric acid to give a solid precipitate. The obtained solid was dried under reduced pressure to give the title compound (0.042 g, yield 17%, 2 steps) as a solid.

2387¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J = 7.5 Hz), 1.64-1.69 (2H, m) , 2.48-2.60 (IH, m) , 2.69-2.76 (IH, m) , 3.62 (2H, t, J = 7.5 Hz), 3.70-3.80 (IH, m) , 4.17-4.24 (IH, m) , 4.32-4.40 (IH, m) , 4.67-4.72 (2H, m) , 5.05 (2H, br s) , 5.17-5.21 (IH, m) , 6.10-6.13 (2H, m) , 6.94-7.12 (5H, m) , 7.24-7.26 (IH, m) , 7.93-7.97 (2H, m) . MS m/z 446 (M + H)⁺. [0941] Example 94

2388[ (3S)-6-({ (3S) -7- [ (6-methylpyridin-3-yl) (propyl) amino] -2, 3- dihydro-l-benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid [0942] <img file="WO2010143733A1_D0138.tif" />

2389[0943]

2390To a solution of methyl { (3S) -6- [{ (3S) -7- [ (6- methylpyridin-3-yl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (0.219 g, 0.42 mmol) and n-propyl iodide (85 mg, 0.5 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 25.2 mg, 0.63 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85:15 - 50:50) to give a mixture (0.063 g, an oil) of methyl { (3S) -6- [ { (3S) -7- [ (6-methylpyridin-3- yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yljacetate and methyl [ (3S) -6- ( { (3S) -7- [ (6-methylpyridin-3- yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3-yl}amino) -2,3- dihydro-l-benzofuran-3-yl] acetate . To a mixed solution of the mixture (0.063 g) obtained above in tetrahydrofuran (10 mL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide solution (4 mL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and neutralized with 1 M hydrochloric acid to give a solid precipitate. The obtained solid was dried under reduced pressure to give the title compound (0.024 g, yield 12%, 2 steps) as a solid. 1H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J = 7.5 Hz), 1.61-1.71

2391(2H, in), 2.46 (3H, s) , 2.50-2.55 (IH, m) , 2.70-2.77 (IH, m) , 3.62 (2H, t, J = 7.5 Hz), 3.76-3.81 (IH, m) , 4.18-4.23 (IH, m) , 4.34-4.39 (IH, m) , 4.64-4.73 (2H, m) , 5.18-5.22 (IH, m) , 5.34 ( 2H, br s ) , 6. 12-6. 14 ( 2H, m) , 6. 91-7 . 11 ( 4H, m) , 7 . 23-7 . 26

2392( 2H, m) , 7 . 90-7 . 91 ( IH, m) . MS m/z 460 (M + H) ⁺ .

2393[0944] Example 95

2394[ (3S)-6-({ (3S) -7- [ (6-fluoropyridin-3-yl) (propyl) amino] -2, 3- dihydro-1-benzofuran-3-yl }amino) -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2395<img file="WO2010143733A1_D0139.tif" />

2396[0946]

2397To a solution of methyl { (3S) -6- [{ (3S) -7- [ (6- fluoropyridin-3-yl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate (0.263 g, 0.495 mmol) and n-propyl iodide (100 mg, 0.59 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in oil, 30 mg, 0.74 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5 - 70:30) to give a mixture (0.103 g, an oil) of methyl { (3S) -6- [ { (3S) -7- [ (6-fluoropyridin-3- yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}acetate and methyl [ (3S) -6- ( { (3S) -7- [ (6-fluoropyridin-3- yl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-1-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.103 g) obtained above in tetrahydrofuran (10 mL) and methanol (10 mL) was added 1 M aqueous sodium hydroxide solution (4 itiL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and neutralized with 1 M hydrochloric acid to give a solid precipitate. The obtained solid was dried under reduced pressure to give the title compound (0.078 g, yield 32%, 2 steps) as a solid.

2398¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J = 7.5 Hz), 1.62-1.70 (2H, m) , 2.57-2.65 (IH, m) , 2.76-2.84 (IH, m) , 3.59 (2H, t, J = 7.5 Hz), 3.77-3.83 (IH, m) , 4.24-4.30 (IH, m) , 4.36-4.40 (IH, m) , 4.66-4.77 (2H, m) , 5.18-5.22 (IH, m) , 6.14-6.17 (2H, m) , 6.71-6.75 (IH, m) , 6.91-7.01 (3H, m) , 7.06-7.12 (2H, m) , 7.22-7.25 (IH, m)^' , 7.57 (IH, s) , 12.48 (IH, br s) . MS m/z 464 (M + H)⁺. [0947] Example 96

2399[ (3S)-6-({ (3S) -7-[ (4-cyanophenyl) (propyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2400<img file="WO2010143733A1_D0140.tif" />

2401[0949]

2402To a solution of methyl { (3S) -6- [ { (3S) -7- [ (4- cyanophenyl) amino] -2, 3-dihydro-l-benzofuran-3- yl } (trifluoroacetyl) amino] -2, 3-dihydro-l-benzofuran-3- yl} acetate (0.403 g, 0.75 mmol) and n-propyl iodide (153 mg, 0.9 mmol) in N,N-dimethylformamide (3 inL) was added sodium hydride (60% in oil, 45 mg, 1.125 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give a mixture (0.20 g, an oil) of methyl { (3S) -6- [ { (3S) -7- [ (4-cyanophenyl) (propyl) amino] -2,3- dihydro-l-benzofuran-3-yl } (trifluoroacetyl) amino] -2, 3-dihydro- l-benzofuran-3-yl} acetate and methyl [ (3S) -6- ( { (3S) -7- [ (4- cyanophenyl) (propyl) amino] -2, 3-dihydro-l-benzofuran-3- yl}amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate. To a mixed solution of the mixture (0.20 g) obtained above in tetrahydrofuran (5 mL) and methanol (5 mL) was added 1 M aqueous sodium hydroxide solution (6 mL) , and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated, and neutralized with 1 M hydrochloric acid to give a solid precipitate. The obtained solid was washed with water, and dried under reduced pressure to give the title compound (0.16 g, yield 45%, 2 steps) as a solid. 1H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J = 7.2 Hz), 1.65-1.72 (2H, m) , 2.54-2.65 (IH, m) , 2.71-2.84 (IH, m) , 3.60 (2H, t, J = 7.8 Hz), 3.72-3.79 (2H, m) , 4.22-4.30 (IH, m) , 4.35-4.40 (IH, m) , 4.69-4.78 (2H, m) , 5.21-5.24 (IH, m) , 6.13-6.15 (2H, m) , 6.59 (2H, d, J = 9.0 Hz), 6.95-7.01 (2H, m) , 7.10 (IH, d, J = 7.5 Hz), 7.31 (IH, d, J = 7.2 Hz), 7.38 (2H, d, J = 9.0), 12.49 (IH, br s) . [0950] Example 97 sodium [ (3S)-6-({ (3S) -7- [2-ethyl-4- (2, 2, 2-trifluoroethoxy) -IH- benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) -2,3- dihydro-1-benzofuran-3-yl] acetate [0951]

2403<img file="WO2010143733A1_D0141.tif" />

2404[0952]

2405Methyl { (3S)-6-[{ (3S) -7- [2-ethyl-4- (2, 2, 2- trifluoroethoxy) -lH-benzimidazol-1-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (95 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL) , IN aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 50⁰C for 1 hr. The volatile component was evaporated under reduced pressure, and IN aqueous hydrochloric acid solution (1 mL) was added. The mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the volatile component was evaporated under reduced pressure to give a white solid (76 mg, yield ~100%) . The obtained solid (55 mg, 0.1 mmol) was dissolved in tetrahydrofuran (2 mL) , and 1 M aqueous sodium hydroxide solution (0.1 mL) was added. The volatile component was evaporated under reduced pressure, and the solid was precipitated to give the title compound (50 mg) as a white solid.

2406¹H NMR (300 MHz, DMSO-d₆) δ 1.18-1.28 (3H, m) , 1.95 (IH, dd, J = 14.9, 10.0 Hz), 2.29 (IH, dd, J = 14.9, 5.1 Hz), 2.65-2.77 (2H, m) , 3.53 (IH, br s) , 4.03-4.11 (IH, m) , 4.19-4.28 (IH, m) , 4.60 (IH, t, J = 8.9 Hz), 4.79 (IH, dd, J = 8.5, 3.2 Hz), 5.13 (2H, q, J = 9.0 Hz), 5.37 (IH, d, J = 7.5 Hz), 6.05-6.21 (3H, m) , 6.73 (IH, dd, J = 19.4, 7.7 Hz), 6.90 (2H, dd, J = 15.6, 8.1 Hz), 7.06-7.17 (2H, m) , 7.39 (IH, d, J = 7.5 Hz), 7.53 (IH, d, J = 7.5 Hz) .

2407MS m/z 554 (M + H) ⁺ (as free form). [0953] Example 98 sodium [ (3S)-6-{ [ (3S) -7-{2-ethyl-4- [3-

2408(methylsulfonyl) propoxy] -lH-benzimidazol-1-yl } -2 , 3-dihydro-l- benzofuran-3-yl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [0954] <img file="WO2010143733A1_D0142.tif" />

2409[0955]

2410Methyl [ (3S) -6-{ [ (3S) -7-{2-ethyl-4- [3-

2411(methylsulfonyl) propoxy] -lH-benzimidazol-l-yl}-2, 3-dihydro-l- benzofuran-3-yl] (trifluoroacetyl) amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (110 mg, 0.16 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL) , IN aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 50°C for 1 hr. The volatile component was evaporated under reduced pressure, and 1 M aqueous hydrochloric acid solution (1 mL) was added. The mixture was diluted with saturated brine, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the volatile component was evaporated under reduced pressure to give a white solid (96 mg, yield - 100%) . The obtained solid (59 mg, 0.1 mmol) was dissolved in tetrahydrofuran (2 mL) , and 1 M aqueous sodium hydroxide solution (0.1 mL) was added. The volatile component was evaporated under reduced pressure, and the solid was precipitated to give the title compound (46 mg) as a white solid.

2412¹H NMR (300 MHz, DMSO-d₆) δ 1.15-1.29 (m, 3 H), 2.01-2.14 (m, 1 H), 2.17-2.29 (2H, m) , 2.35-2.45 (IH, m) , 2.62-2.75 (2H, m) , 3.05 (3H, s), 3.30-3.40 (3H, m) , 3.50-3.62 (2H, m) , 4.07 (IH, t, J = 7.9 Hz), 4.18-4.27 (IH, m) , 4.60 (IH, t, J = 8.9 Hz), 4.72-4.85 (IH, m) , 5.32-5.42 (IH, m) , 6.06-6.22 (3H, m) , 6.64 (IH, dd, J = 20.0, 7.9 Hz), 6.76 (IH, d, J = 8.3 Hz), 6.93 (IH, d, J = 7.5 Hz), 7.02-7.17 (2H, m) , 7.37 (IH, d, J = 7.9 Hz), 7'.52 (IH, d, J = 7.5 Hz) . MS m/z 592 (M + H)⁺ (as free form). [0956] Example 99 sodium [ (3S)-6-({ (3S) -7- [2-methyl-6- (2, 2, 2-trifluoroethoxy) - lH-benzimidazol-1-yl] -2, 3-dihydro-l-benzofuran-3-yl} amino) - 2, 3-dihydro-l-benzofuran-3-yl] acetate [0957]

2413<img file="WO2010143733A1_D0143.tif" />

2414[0958]

2415Methyl { (3S)-6-[{ (3S) -7- [2-methyl-6- (2,2,2- trifluoroethoxy) -lH-benzimidazol-1-yl] -2, 3-dihydro-l- benzofuran-3-yl} (trifluoroacetyl) amino] -2, 3-dihydro-l- benzofuran-3-yl} acetate (150 mg, 0.24 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 rtiL) , 1 M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at 50⁰C for 2 hr. The volatile component was evaporated under reduced pressure, and 1 M aqueous hydrochloric acid solution (1 mL) was added to allow precipitation of a white solid. The resulting solid was collected (110 mg, 0.17 mmol). The solid (74 mg, 0.12 mmol) was dissolved in tetrahydrofuran (2 mL) , and 1 M aqueous sodium hydroxide solution (0.12 mL) was added. The volatile component was evaporated under reduced pressure and the solid was precipitated, whereby the title compound (75 mg) was obtained as a white solid.

2416¹H NMR (300 MHz, DMSO-d₆) δ 2.04-2.15 (IH, m) , 2.34-2.45 (4H, m) , 3.53-3.58 (IH, m) , 4.04-4.11 (IH, m) , 4.26 (IH, dd, J = 9.5, 4.5 Hz), 4.56-4.87 (4H, m) , 5.31-5.43 (IH, m) , 6.05-6.21

2417(3H, m) , 6.71 (IH, t, J = 2.8 Hz), 6.90-6.99 (2H, m) , 7.09- 7.18 (IH, m) , 7.41 (IH, d, J = 8.0 Hz), 7.50-7.57 (2H, m) . MS m/z 540 (M + H)⁺ (as free form).

2418[0959]

2419Example 100 methyl [ (3S) -6-{ [ (2-chloro-2' , 6' -dimethylbiphenyl-3- yl) methyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [0960]

2420<img file="WO2010143733A1_D0144.tif" />

2421[0961]

2422A solution of 2-chloro-2' , 6' -dimethylbiphenyl-3- carbaldehyde (0.184 g, 0.750 mmol) , methyl [ (3S) -6-amino-2, 3- dihydro-l-benzofuran-3-yl] acetate (0.155 g, 0.750 mmol), and acetic acid (0.086 mL, 1.50 mmol) in acetonitrile (4 mL) was stirred under a nitrogen atmosphere at room temperature for 2 hr. Sodium triacetoxyborohydride (0.397 g, 1.50 mmol) was added to the reaction mixture, and the mixture was further stirred for 3 hr. The reaction mixture was treated with water and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate ihexane = 5:95-30:70) and preparative HPLC to give the title compound

2423(0.294 g, yield 90%) as a colorless oil.

2424¹H NMR (300 MHz, CDCl₃) δ 1.99 (6H, s) , 2.49-2.59 (IH, m) ,

24252.69-2.78 (IH, m) , 3.69-3.82 (4H, m) , 4.18-4.29 (2H, m) , 4.47

2426(2H, s), 4.71 (IH, t, J = 8.9 Hz), 6.14 (IH, d, J = 2.1 Hz), 6.18 (IH, dd, J = 7.9, 2.1 Hz), 6.94 (IH, d, J = 7.9 Hz), 7.06

2427(IH, dd, J = 7.5, 1.7 Hz), 7.10-7.16 (2H, m) , 7.18-7.25 (IH, m) , 7.25-7.31 (IH, m) , 7.41 (IH, dd, J = 7.7, 1.7 Hz). MS m/z 436 (M + H)⁺.

2428[0962] Example 101

2429[ (3S)-6-{ [ (2-chloro-2' , 6' -dimethylbiphenyl-3-yl) methyl] amino}- 2, 3-dihydro-l-benzofuran-3-yl] acetic acid [ 0963 ]

2430<img file="WO2010143733A1_D0145.tif" />

2431[0964]

2432To a mixed solution of methyl [ (3S) -6-{ [ (2-chloro-2' , 6' - dimethylbiphenyl-3-yl) methyl] amino} -2, 3-dihydro-l-benzofuran- 3-yl]acetate (0.290 g, 0.665 mmol) in methanol (1.3 mL) and tetrahydrofuran (2.6 mL) was added 1 M aqueous sodium hydroxide solution (1.3 mL) , and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 20:80-80:20), and the obtained oil was dissolved in a mixed solution of methanol (1.3 mL) and tetrahydrofuran (2.6 mL) . The mixture was treated with 1 M aqueous sodium hydroxide solution (1.3 mL) , and concentrated under reduced pressure. The residue was dissolved in water, and neutralized with 1 N hydrochloric acid. The precipitated solid was collected by filtration, and dried to give the title compound (0.233 g, yield 83%) as a colorless powder. 1H NMR (300 MHz, CDCl₃) δ 1.99 (6H, s) , 2.54-2.66 (IH, m) , 2.74-2.85 (IH, m) , 3.72-3.84 (IH, m) , 4.25 (IH, dd, J = 9.2, 6.0 Hz), 4.47 (2H, s) , 4.72 (IH, t, J = 9.0 Hz), 6.14 (IH, d, J = 2.1 Hz), 6.19 (IH, dd, J = 8.0, 2.1 Hz), 6.97 (IH, d, J = 8.0 Hz), 7.06 (IH, dd, J = 7.3, 1.7 Hz), 7.10-7.16 (2H, m) , 7.18-7.25 (IH, m) , 7.25-7.32 (IH, m) , 7.41 (IH, dd, J = 7.5, 1.7 Hz) .

2433MS m/z 422 (M + H)⁺. [0965] Example 102 methyl [ (3S) -6-{ [ (2-hydroxy-2' , 6' -dimethylbiphenyl-3- yl) methyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [0966]

2434<img file="WO2010143733A1_D0146.tif" />

2435[0967]

2436A solution of 2-hydroxy-2^f , 6' -dimethylbiphenyl-3- carbaldehyde (0.453 g, 2.00 iranol) , methyl [ (3S) -6-amino-2, 3- dihydro-l-benzofύran-3-yl] acetate (0.414 g, 2.00 mmol), and acetic acid (0.343 mL, 6.00 mmol) in acetonitrile (10 mL) was stirred under a nitrogen atmosphere at room temperature for 2 hr. Sodium triacetoxyborohydride (0.397 g, 1.50 mmol) was added to the reaction mixture, and the mixture was further stirred for 3 hr. The reaction mixture was treated with water and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 10:90-50:50) to give the title compound

2437(0.714 g, yield 86%) as a yellow oil.

2438¹H NMR (300 MHz, CDCl₃) δ 2.04 (6H, s) , 2.48-2.59 (IH, m) , 2.68-2.78 (IH, m) , 3.71 (4H, s) , 4.09 (IH, s) , 4.22 (IH, dd, J = 9.1, 6.1 Hz), 4.40 (2H, s) , 4.71 (IH, t, J = 9.1 Hz), 6.24- 6.30 (2H, m) , 6.58 (IH, br s) , 6.90-7.00 (3H, m) , 7.11-7.25

2439(4H, m) . MS m/z 418 (M + H)⁺.

2440[0968]

2441Example 103 methyl [ (3S) -6-{ [ (2-methoxy-2' , 6' -dimethylbiphenyl-3- yl) methyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [ 0969 ]

2442<img file="WO2010143733A1_D0147.tif" />

2443[0970]

2444A solution of methyl [ (3S) -6-{ [ (2-hydroxy-2' , 6' - dimethylbiphenyl-3-yl) methyl] amino} -2, 3-dihydro-l-benzofuran- 3-yl]acetate (0.265 g, 0.635 mmol) , methanol (0.031 mL, 0.762 mmol) and tributylphosphine (0.253 mL, 1.02 mmol) in tetrahydrofuran (5 mL) was stirred, 1,1'-

2445(azodicarbonyl) dipiperidine (0.256 g, 1.02 mmol) was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 3 hr. Hexane (5 mL) was added to the reaction mixture, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 5:95-30:70) to give the title compound (0.252 g, yield 92%) as a colorless oil. 1H NMR (300 MHz, CDCl₃) δ 2.08 (6H, s) , 2.48-2.59 (IH, m) , 2.69-2.78 (IH, m) , 3.34 (3H, s) , 3.69-3.82 (4H, m) , 4.15 (IH, br s), 4.22 (IH, dd, J = 9.1, 6.1 Hz), 4.36 (2H, s), 4.71 (IH, t, J = 9.1 Hz), 6.16-6.23 (2H, m) , 6.93 (IH, d, J = 7.6 Hz), 6.98 (IH, dd, J = 7.6, 1.9 Hz), 7.07-7.14 (3H, m) , 7.15-7.21

2446(IH, m) , 7.33 (IH, dd, J = 7.4, 1.7 Hz). MS m/z 432 (M + H)⁺.

2447[0971] Example 104

2448[ (3S)-6-{ [ (2-methoxy-2' , 6' -dimethylbiphenyl-3- yl)methyl] amino } -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2449[0972] <img file="WO2010143733A1_D0148.tif" />

2450[0973]

2451To a mixed solution of methyl [ (3S) -6-{ [ (2-methoxy-2' , 6' - dimethylbiphenyl-3-yl) methyl] amino} -2, 3-dihydro-l-benzofuran- 3-yl] acetate (0.248 g, 0.575 iranol) in methanol (1.2 mL) and tetrahydrofuran (2.4 mL) was added 1 M aqueous sodium hydroxide solution (1.2 mL) , and the mixture was stirred at 50⁰C for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1 M hydrochloric acid, and the precipitated solid was collected by filtration, and dried to give the title compound (0.217 g, yield 90%) as a colorless powder.

2452¹H NMR (300 MHz, CDCl₃) δ 2.08 (6H, s) , 2.53-2.65 (IH, m) , 2.74-2.84 (IH, m) , 3.34 (3H, s) , 3.71-3.83 (IH, m) , 4.24 (IH, dd, J = 9.1, 6.0 Hz), 4.36 (2H, s) , 4.72 (IH, t, J = 9.1 Hz), 6.17-6.25 (2H, m) , 6.93-7.01 (2H, m) , 7.07-7.14 (3H, m) , 7.15- 7.22 (IH, m) , 7.33 (IH, dd, J = 7.5, 1.9 Hz). MS m/z 418 (M + H)⁺. [0974]

2453Example 105 methyl [(3S)-6-({ [2' , 6' -dimethyl-2- (l-methylethoxy)biphenyl-3- yl] methyl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate [0975]

2454<img file="WO2010143733A1_D0149.tif" />

2455[0976]

2456In the same manner as in Example 103, the title compound was obtained as a colorless oil from methyl [ (3S) -6-{ [ (2- hydroxy-2' , 6' -dimethylbiphenyl-3-yl) methyl] amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate and 2-propanol. yield 88%. 1H NMR (300 MHz, CDCl₃) δ 0.93 (6H, d, J = 6.1 Hz), 2.10 (6H, s), 2.48-2.58 (IH, m) , 2.69-2.78 (IH, m) , 3.56-3.66 (IH, m) , 3.69-3.82 (4H, m) , 4.17-4.26 (2H, m) , 4.37 (2H, s) , 4.71 (IH, t, J = 8.9 Hz), 6.15-6.22 (2H, m) , 6.92 (IH, d, J = 7.6 Hz), 6.96-7.01 (IH, m) , 7.04-7.13 (3H, m) , 7.13-7.20 (IH, m) , 7.32

2457(IH, dd, J = 7.4, 1.7 Hz) . MS m/z 460 (M + H)⁺.

2458[0977] Example 106

2459[ (3S) -6- ( { [2' , 6' -dimethyl-2- (1-methylethoxy) biphenyl-3- yl]methyl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2460[0978]

2461<img file="WO2010143733A1_D0150.tif" />

2462[0979]

2463In the same manner as in Example 104, the title compound was obtained as a colorless powder from methyl [(3S) -6-

2464({ [2' ,6' -dimethyl-2- (1-methylethoxy) biphenyl-3- yl] methyl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate, yield

246588%.

2466¹H NMR (300 MHz, CDCl₃) δ 0.93 (6H, d, J = 6.0 Hz), 2.10 (6H, s), 2.54-2.65 (IH, m) , 2.75-2.84 (IH, m) , 3.54-3.68 (IH, m) ,

24673.71-3.82 (IH, m) , 4.24 (IH, dd, J = 9.0, 6.0 Hz), 4.38 (2H, s), 4.72 (IH, t, J = 9.0 Hz), 6.16-6.23 (2H, m) , 6.93-7.01 (2H, m) , 7.04-7.13 (3H, m) , 7.13-7.20 (IH, m) , 7.32 (IH, dd, J =

24687:5, 1.7 Hz) .

2469MS m/z 446 (M + H)⁺.

2470[0980] Example 107 [ (3S) -6- { [ (2-hydroxy-2' , 6' -dimethylbiphenyl-3- yl) methyl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0981]

2471<img file="WO2010143733A1_D0151.tif" />

2472[0982]

2473In the same manner as in Example 101, the title compound was obtained as a beige powder from methyl [ (3S) -6-{ [ (2- hydroxy-2' , 6' -dimethylbiphenyl-3-yl) methyl] amino} -2, 3-dihydro- l-benzofuran-3-yl] acetate, yield 46%.

2474¹H NMR (300 MHz, CDCl₃) δ 2.04 (6H, s) , 2.53-2.65 (IH, m) , 2.73-2.84 (IH, m) , 3.72-3.83 (IH, m) , 4.25 (IH, dd, J = 9.1, 6.0 Hz), 4.40 (2H, s) , 4.72 (IH, t, J = 9.1 Hz), 6.24-6.32 (2H, m) , 6.90-7.01 (3H, m) , 7.10-7.25 (4H, m) . MS m/z 404 (M + H)⁺. [0983]

2475Example 108 methyl [ (3S) -6- ( {3- [1- (difluoromethyl) -3, 5-dimethyl-lH- pyrazol-4-yl] -2-methylbenzyl} amino) -2, 3-dihydro-l-benzofuran- 3-yl] acetate [0984]

2476<img file="WO2010143733A1_D0152.tif" />

2477[0985]

2478To a solution of { 3- [1- (difluoromethyl) -3, 5-dimethyl-lH- pyrazol-4-yl] -2-methylphenyl}methanol (0.133 g, 0.500 mmol) , methyl [ (3S) -6-{ [ (2-nitrophenyl) sulfonyl] amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.196 g, 0.500 mmol) and triphenylphosphine (0.210 g, 0.800 mmol) in tetrahydrofuran (4 inL) was added 40% diethyl azodicarboxylate toluene solution

2479(0.317 mL, 0.800 mmol) at room temperature, and the mixture was stirred for 5 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate rhexane = 20:80-60:40) to give a yellow foam. To a solution of this product and mercaptoacetic acid (0.070 mL, 1.00 mmol) in N,N-dimethylformamide (1 mL) was added lithium hydroxide monohydrate (0.084 g, 2.00 mmol), and the mixture was stirred at room temperature for 3 hr. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate :hexane = 5:95-40:60) to give the title compound (0.155 g, yield 68%, 2 steps) as a colorless oil.

2480¹H NMR (300 MHz, CDCl₃) δ 2.07 (3H, s) , 2.11 (3H, s) , 2.24 (3H, s), 2.49-2.60 (IH, m) , 2.70-2.79 (IH, m) , 3.71 (3H, s) , 3.73- 3.83 (IH, m) , 3.94 (IH, br s) , 4.23 (IH, dd, J = 9.0, 6.0 Hz), 4.29 (2H, s), 4.72 (IH, t, J = 9.0 Hz), 6.14 (IH, d, J = 2.2 Hz), 6.19 (IH, dd, J = 8.0, 2.2 Hz), 6.96 (IH, d, J = 7.5 Hz), 6.98-7.39 (4H, m) . MS m/z 456 (M + H)⁺. [0986]

2481Example 109

2482[ (3S) -6- ( { 3- [1- (difluoromethyl) -3, 5-dimethyl-lH-pyrazol-4-yl] - 2-methylbenzyl } amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid [0987]

2483<img file="WO2010143733A1_D0153.tif" /> [ 0988 ]

2484In the same manner as in Example 104, the title compound was obtained as a colorless powder from methyl [ (3S) -6- ( { 3- [1- (difluoromethyl) -3, 5-dimethyl-lH-pyrazol-4-yl] -2- methylbenzyl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate, yield 75%.

2485¹H NMR (300 MHz, CDCl₃) δ 2.07 (3H, s) , 2.11 (3H, s) , 2.24 (3H, s), 2.55-2.67 (IH, m) , 2.75-2.86 (IH, m) , 3.73-3.85 (IH, m) , 4.22-4.33 (3H, m) , 4.74 (IH, t, J = 9.0 Hz), 6.15 (IH, d, J = 2.1 Hz), 6.20 (IH, dd, J = 8.1, 2.1 Hz), 6.99 (IH, d, J = 8.1 Hz) , 7.01-7.44 (4H, m) . MS m/z 442 (M + H)⁺. [0989]

2486Example 110 methyl { (3S) -6- [ (3-bromo-2-methylbenzyl) amino] -2, 3-dihydro-l- benzofuran-3-yl } acetate [0990]

2487<img file="WO2010143733A1_D0154.tif" />

2488[0991]

2489Methyl 3-bromo-2-methylbenzoate (2.29 g, 10.0 mmol) was dissolved in tetrahydrofuran (50 mL) , under ice-cooling, lithium aluminum hydride (0.285 g, 7.50 mmol) was added by small portions, and the mixture was stirred under a nitrogen atmosphere for 2 hr. Sodium sulfate 10 hydrate (2.42 g, 7.50 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr. Insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained solid was recrystallized from heptane-ethyl acetate to give 3-bromo-2-methylbenzyl alcohol (1.76 g, yield 88%) as colorless crystals. This product (0.943 g, 4.69 mmol) was dissolved in acetonitrile (25 mL) , a Dess-Martin reagent (2.39 g, 5.63 mmol) was added by small portions under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. The reaction mixture was treated with saturated aqueous sodium hydrogen carbonate and aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the obtained colorless oil, methyl [ (3S) -6-amino-2, 3-dihydro-l- benzofuran-3-yl] acetate (0.972 g, 4.69 mmol) and acetic acid

2490(0.537 mL, 9.38 mmol) in acetonitrile (25 mL) was stirred under a nitrogen atmosphere at room temperature for 0.5 hr. Sodium triacetoxyborohydride (1.99 g, 9.38 mmol) was added to the reaction mixture, and the mixture was further stirred for 12 hr. The reaction mixture was treated with water and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate rhexane = 5:95-40:60) to give the title compound (1.59 g, yield 87%, 2 steps) as a colorless oil.

2491¹H NMR (300 MHz, CDCl₃) δ 2.42 (3H, s) , 2.48-2.59 (IH, m) , 2.68-2.78 (IH, m) , 3.68-3.83 (4H, m) , 3.89 (IH, br s) , 4.18- 4.30 (3H, m) , 4.71 (IH, t, J = 9.1 Hz), 6.07-6.16 (2H, m) , 6.93 (IH, d, J = 8.0 Hz), 7.01 (IH, t, J = 7.9 Hz), 7.23-7.30

2492(IH, m) , 7.49 (IH, dd, J = 7.9, 1.1 Hz). MS m/z 390 (M + H)⁺.

2493[0992]

2494Example 111 methyl [ (3S) -6-{ [2-methyl-3- (6-methyl-2, 3-dihydro-4H- pyrido [3, 2-b] [1,4] oxazin-4-yl) benzyl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate

2495[0993] <img file="WO2010143733A1_D0155.tif" />

2496[0994]

2497To a mixture of methyl { (3S) -6- [ (3-bromo-2- methylbenzyl) amino] -2, 3-dihydro-1-benzofuran-3-yl} acetate

2498(0.312 g, 0.800 mmol) , 6-methyl-3, 4-dihydro-2H-pyrido [3, 2- b] [l,4]oxazine (0.180 g, 1.20 mmol) and cesium carbonate

2499(0.521 g, 1.60 mmol) in toluene (8 mL) were added tris (dibenzylideneacetone) dipalladium (0) (0.037 g, 0.040 mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

2500(0.046 g, 0.080 mmol), and the mixture was stirred under an argon atmosphere at 100⁰C for 21 hr. To the reaction mixture were added water and ethyl acetate, and the insoluble material was filtered off through celite. The organic layer of the filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel- column chromatography

2501(ethyl acetate :hexane = 10:90-50:50) to give the title compound (0.310 g, yield 84%) as a yellow foam.

2502¹H NMR (300 MHz, CDCl₃) δ 2.17 (3H, s) , 2.19 (3H, s) , 2.48-2.60

2503(IH, m) , 2.69-2.79 (IH, m) , 3.60-3.89 (6H, m) , 3.95 (IH, br s) , 4.19-4.36 (5H, m) , 4.72 (IH, t, J = 8.9 Hz), 6.12-6.20 (2H, m) , 6.40 (IH, d, J = 8.1 Hz), 6.90-6.97 (2H, m) , 7.12-7.29 (3H, m) . MS m/z 460 (M + H)⁺.

2504[0995] Example 112

2505[ (3S) -6-{ [2-methyl-3- (6-methyl-2, 3-dihydro-4H-pyrido [3, 2- b] [1, 4] oxazin-4-yl) benzyl] amino} -2, 3-dihydro-l-benzofuran-3- yl] acetic acid

2506[0996] <img file="WO2010143733A1_D0156.tif" />

2507[0997]

2508In the same manner as in Example 104, the title compound was obtained as a beige powder from methyl [ (3S) -6-{ [2-methyl- 3- ( 6-methyl-2, 3-dihydro-4H-pyrido [3, 2-b] [1,4] oxazin-4- yl) benzyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate, yield 84%.

2509¹H NMR (300 MHz, CDCl₃) δ 2.15 (3H, d, J = 4.2 Hz), 2.21 (3H, s), 2.31-2.48 (IH, m) , 2.58-2.70 (IH, m) , 3.60-3.88 (3H, m) , 4.13-4.36 (5H, m) , 4.63-4.75 (IH, m) , 6.12-6.19 (2H, m) , 6.41

2510(IH, d, J = 7.6 Hz), 6.90 (IH, dd, J = 8.5, 2.8 Hz), 6.96 (IH, d, J = 8.0 Hz), 7.11-7.31 (3H, m) . MS m/z 446 (M + H)⁺.

2511[0998]

2512Example 113 methyl [ (3S) -6- ( {3- [2- (difluoromethoxy) -4, 6-dimethylpyrimidin- 5-yl] -2-methylbenzyl} amino) -2, 3-dihydro-l-benzofuran-3- yl] acetate

2513[0999]

2514<img file="WO2010143733A1_D0157.tif" />

2515[1000]

2516In the same manner as in Reference Example 84, the title compound was obtained as a colorless oil from methyl [(3S) -6- { [2-methyl-3- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl) benzyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate and 5- bromo-2- (difluoromethoxy) -4, 6-dimethylpyrimidine. yield 15% (2 steps) .

2517¹H NMR (300 MHz, CDCl₃) δ 2.01 (3H, s) , 2.17 (6H, s) , 2.49-2.60

2518(IH, m) , 2.69-2.80 (IH, m) , 3.69-3.84 (4H, m) , 3.89-3.98 (IH, m) , 4.23 (IH, dd, J = 9.0, 5.9 Hz), 4.27-4.34 (2H, m) , 4.72

2519(IH, t, J = 9.0 Hz), 6.14 (IH, d, J = 2.1 Hz), 6.18 (IH, dd, J = 8.1, 2.1 Hz), 6.92-7.00 (2H, m) , 7.22-7.79 (3H, m) . MS m/z 484 (M + H)⁺.

2520[1001] Example 114

2521[ (3S) -6- ( { 3- [2- (difluoromethoxy) -4, 6-dimethylpyrimidin-5-yl] - 2-methylbenzyl } amino) -2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2522[1002]

2523<img file="WO2010143733A1_D0158.tif" />

2524[1003]

2525To a mixed solution of methyl [ (3S) -6- ( { 3- [2-

2526(difluoromethoxy) -4, 6-dimethylpyrimidin-5-yl] -2- methylbenzyl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate

2527(0.102 g, 0.211 mmol) in methanol (0.5 mL) and tetrahydrofuran

2528(1 mL) was added 1 M aqueous sodium hydroxide solution (0.5 mL) , and the mixture was stirred at 50⁰C for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1 M hydrochloric acid, and the precipitated solid was purified by preparative HPLC to give the title compound (29.0 mg, yield 29%) as an orange non-crystalline powder. 1H NMR (300 MHz, CDCl₃) δ 2.01 (3H, s) , 2.17 (6H, s) , 2.55-2.67

2529(IH, m) , 2.74-2.86 (IH, m) , 3.72-3.85 (IH, m) , 4.21-4.35 (3H, m) , 4.74 (IH, t, J = 8.9 Hz), 6.15 (IH, d, J = 1.9 Hz), 6.20

2530(IH, dd, J = 8.0, 1.9 Hz), 6.91-7.03 (2H, m) , 7.22-7.79 (3H, m) .

2531MS m/z 470 (M + H)⁺. [1004] Example 115 calcium [ (3S) -6- ( {3- [2- (difluoromethoxy) -4, 6- dimethylpyrimidin-5-yl] -2-methylbenzyl}amino) -2, 3-dihydro-l- benzofuran-3-yl] acetate

2532[1005]

2533<img file="WO2010143733A1_D0159.tif" />

2534[1006]

2535To a mixed solution of methyl [ (3S) -6- ( { 3- [2- (difluoromethoxy) -4, 6-dimethylpyrimidin-5-yl] -2- methylbenzyl} amino) -2, 3-dihydro-l-benzofuran-3-yl] acetate (0.328 g, 0.678 mmol) in methanol (1.5 mL) and tetrahydrofuran (3 mL) was added 1 M aqueous sodium hydroxide solution (1.3 mL) , and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give an oil. The oil was dissolved in water, and treated with 1 M aqueous sodium hydroxide solution (0.515 mL) , and then 1 M aqueous calcium chloride solution (0.262 mL) was added. The precipitated solid was collected by filtration to give the title compound (0.147 g, yield 44%) as a beige powder.

2536¹H NMR (300 MHz, DMSO-d₆) δ 1.95 (3H, s) , 2.03-2.21 (7H, m) , 2.34-2.47 (IH, m) , 3.51-3.65 (IH, m) , 4.06 (IH, dd, J = 8.5, 7.5 Hz), 4.21 (IH, d, J = 5.1 Hz), 4.59 (IH, t, J = 8.9 Hz), 5.90-6.04 (2H, m) , 6.09 (IH, dd, J = 8.1, 1.5 Hz), 6.91 (IH, d, J = 8.1 Hz), 7.01 (IH, d, J = 7.0 Hz), 7.25 (IH, t, J = 7.5 Hz), 7.31-7.40 (IH, m) , 7.47-8.02 (IH, m) . elemental analysis value for C_2SH₂₄F₂N₃O₄S-O-S Ca²⁺- 1.5 H₂O Calculated: C, 58.24; H, 5.28; N, 8.15. Found: C, 58.33; H, 5.25; N, 8.04.

2537[1007]

2538Example 116 methyl { (3S) -6- [ ({2,2' , 6' -trimethyl-4' - [3-

2539(methylsulfonyl) propoxy]biphenyl-3-yl}methyl) amino] -2, 3- dihydro-1-benzofuran-3-yl } acetate

2540[1008]

2541<img file="WO2010143733A1_D0160.tif" />

2542[1009]

2543In the same manner as in Example 108, the title compound was obtained as a pale-yellow oil from {2, 2' , 6' -trimethyl-4' - [3- (methylsulfonyl) propoxy]biphenyl-3-yl}methanol and methyl [ (3S)-6-{ [ (2-nitrophenyl) sulfonyl] amino}-2, 3-dihydro-l- benzofuran-3-yl] acetate, yield 98% (2 steps).

2544¹H NMR (300 MHz, CDCl₃) δ 1.92 (6H, s) , 1.96 (3H, s) , 2.30-2.41 (2H, m) , 2.48-2.60 (IH, m) , 2.69-2.79 (IH, m) , 2.97 (3H, s) , 3.24-3.32 (2H, m) , 3.69-3.83 (4H, m) , 3.89 (IH, br s) , 4.09- 4.17 (2H, m) , 4.19-4.31 (3H, m) , 4.72 (IH, t, J = 8.9 Hz), 6.13-6.22 (2H, m) , 6.65 (2H, s) , 6.92-6.98 (2H, m) , 7.16-7.24 (IH, m) , 7.28-7.34 (IH, m) . MS m/z 552 (M + H)⁺. [1010]

2545Example 117

2546{ (3S) -6- [ ({2,2' , 6' -trimethyl-4'- [3-

2547(methylsulfonyl) propoxy] biphenyl-3-yl}methyl) amino] -2,3- dihydro-l-benzofuran-3-yl }acetic acid [1011] <img file="WO2010143733A1_D0161.tif" />

2548[ 1012 ]

2549In the same manner as in Example 101, the title compound was obtained as beige crystals from methyl { (3S) -6- [ ( {2, 2' , 6^f - trimethyl-4' - [3- (methylsulfonyl) propoxy] biphenyl-3- yl}methyl) amino] -2, 3-dihydro-l-benzofuran-3-yl}acetate, yield 73%. 1H NMR (300 MHz, CDCl₃) δ 1.92 (6H, s) , 1.96 (3H, s) , 2.30-2.42

2550(2H, m) , 2.54-2.66 (IH, m) , 2.75-2.85 (IH, m) , 2.97 (3H, s) , 3.24-3.33 (2H, m) , 3.73-3.84 (IH, m) , 4.13 (2H, t, J = 5.7 Hz), 4.22-4.31 (3H, m) , 4.73 (IH, t, J = 8.9 Hz), 6.14-6.23 (2H, m) , 6.66 (2H, s), 6.93-7.01 (2H, m) , 7.17-7.24 (IH, m) , 7.29-7.34

2551(IH, m) . MS m/z 538 (M + H)⁺.

2552[1013]

2553Example 118 ethyl (3-{ [3- (6-fluoro-2-methyl-lH-benzimidazol-l-yl) -2- methylbenzyl] amino} -6, 7-dihydro-5H-cyclopenta [b]pyridin-7- yl) acetate

2554[1014]

2555<img file="WO2010143733A1_D0162.tif" />

2556[1015]

2557To a mixed solution of 3- (6-fluoro-2-methyl-lH- benzimidazol-1-yl) -2-methylbenzaldehyde (0.268 g, 1.00 mmol) synthesized, by an operation similar to Reference Example 126 and Reference Example 127, from methyl 3- (6-fluoro-2-methyl- lH-benzimidazol-1-yl) -2-methylbenzoate, ethyl (3-amino-6, 7- dihydro-5H-cyclopenta [b]pyridin-7-yl) acetate (0.242 g, 1.10 iranol) synthesized according to the method described in WO2006/083612, and acetic acid (0.114 mL, 2.00 mmol) in acetonitrile (10 mL) and tetrahydrofuran (10 mL) was added under ice-cooling sodium triacetoxyborohydride (0.424 g, 2.00 mmol) , and the mixture was warmed to room temperature and stirred for 12 hr. The reaction mixture was treated with water and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate ihexane = 50:50-100:0, then methanol: ethyl acetate= 0:100-10:90) to give the title compound (0.246 g, yield 52%) as a yellow viscous oil. 1H NMR (300 MHz, CDCl₃) δ 1.26 (3H, t, J = 7.2 Hz), 1.69-1.85

2558(IH, m) , 1.95 (3H, s) , 2.32-2.52 (5H, m) , 2.74-2.91 (2H, m) , 3.06 (IH, dd, J = 15.5, 4.2 Hz), 3.43-3.57 (IH, m) , 3.95 (IH, br s), 4.07-4.21 (2H, m) , 4.39 (2H, s) , 6.59 (IH, dd, J = 8.6, 2.5 Hz), 6.82 (IH, d, J = 2.7 Hz), 6.96-7.05 (IH, m) , 7.16- 7.22 (IH, m) , 7.38 (IH, t, J = 7.7 Hz), 7.55 (IH, d, J = 7.7 Hz), 7.67 (IH, dd, J = 8.6, 4.5 Hz), 7.86 (IH, d, J = 2.7 Hz). MS m/z 473 (M + H)⁺.

2559[1016] Example 119

2560(3-{ [3- (6-fluoro-2-methyl-lH-benzimidazol-l-yl) -2- methylbenzyl] amino} -6, 7-dihydro-5H-cyclopenta [b] pyridin-7- yl) acetic acid

2561[1017] <img file="WO2010143733A1_D0163.tif" />

2562[1018]

2563In the same manner as in Example 104, the title compound was obtained as a colorless powder from ethyl (3-{[3-(6- fluoro-2-methyl-lH-benzimidazol-l-yl) -2-methylbenzyl] amino} - 6, 7-dihydro-5H-cyclopenta [b]pyridin-7-yl) acetate, yield 67%. ¹H NMR (300 MHz, CDCl₃) δ 1.60-1.77 (IH, m) , 1.95 (3H, s) , 2.34-2.53 (4H, m) , 2.61-2.72 (IH, m) , 2.73-2.82 (IH, m) , 2.83- 2.94 (2H, m) , 3.39-3.52 (IH, m) , 4.20 (IH, br s) , 4.42 (2H, s) , 6.59 (IH, dd, J = 8.7, 2.4 Hz), 6.93-7.06 (2H, m) , 7.23 (IH, d, J = 7.7 Hz), 7.40 (IH, t, J = 7.7 Hz), 7.53 (IH, d, J = 7.7 Hz), 7.68 (IH, dd, J = 8.7, 4.7 Hz), 7.73 (IH, d, J = 2.4 Hz). MS m/z 445 (M + H)⁺.

2564[1019]

2565Example 120 methyl [ (3S) -6-{ [3- (2, 5-dimethylthiophen-3-yl) -2- fluorobenzyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate

2566[1020]

2567<img file="WO2010143733A1_D0164.tif" />

2568[1021]

2569To a solution of [3- (2, 5-dimethylthiophen-3-yl) -2- fluorophenyl] methanol (311 mg, 1.29 mmol) , methyl [(3S) -6- {'[ (2-nitrophenyl) sulfonyl] amino} -2, 3-dihydro-l-benzofuran-3- yl]acetate (455 mg, 1.29 mmol) and triphenylphosphine (677 mg, 2.58 mmol) in tetrahydrofuran (10 inL) was added diethyl azodicarboxylate (40% toluene solution, 1.52 mL, 3.87 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 50:50) to give a pale-yellow solid (1.05 g) . To a solution of the obtained solid (1.05 g) and mercaptoacetic acid (179 μL) in N,N-dimethylformamide (6.5 mL) was added lithium hydroxide monohydrate (217 mg, 5.16 mmol) , and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 70:30) to give the title compound (356 mg, yield 65%) as a pale-yellow oil.

2570¹H NMR (300 MHz, CDCl₃) δ 2.33 (3H, s) , 2.45 (3H, s) , 2.53 (IH, dd, J = 16.2, 9.2 Hz), 2.73 (IH, dd, J = 16.4, 5.3 Hz), 3.68-3.82 (4H, m) , 4.08-4.17 (IH, m) , 4.21 (IH, dd, J = 9.0, 6.0 Hz), 4.35-4.44 (2H, m) , 4.70 (IH, t, J = 8.9 Hz), 6.12-6.21 (2H, m) , 6.65 (IH, s) , 6.93 (IH, d, J = 7.9 Hz), 7.06-7.14 (IH, m) , 7.14-7.22 (IH, m) , 7.31 (IH, td, J = 7.2, 2.0 Hz) .

2571MS m/z 426 . 2 (M + H) ⁺ . [ 1022 ]

2572Example 121

2573[ (3S)-6-{ [3- (2,5-dimethylthiophen-3-yl)-2-fluorobenzyl]amino}- 2, 3-dihydro-l-benzofuran-3-yl] acetic acid [1023]

2574<img file="WO2010143733A1_D0165.tif" />

2575[1024] To a mixed solution of methyl [ (3S) -6-{ [3- (2, 5- dimethylthiophen-3-yl) -2-fluorobenzyl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (356 mg, 0.836 mmol) in tetrahydrofuran (5.2 mL) and methanol (2.6 mL) was added 1 M aqueous sodium hydroxide solution (2.51 mL) , and the mixture was stirred at 5O⁰C for 1 hr. The reaction mixture was concentrated under reduced pressure, dissolved in distilled water, and cooled to 0⁰C. Thereto was slowly added 1 M hydrochloric acid to give a solid. The solid was collected by filtration, and washed with distilled water to give the title compound (301 mg, yield 87%) as a white solid.

2576¹H NMR (300 MHz, CDCl₃) δ 2.32 (3H, s) , 2.44 (3H, s) , 2.54 (IH, dd, J = 16.5, 9.3 Hz), 2.73 (IH, dd, J = 16.5, 5.2 Hz), 3.64-3.80 (IH, m) , 4.21 (IH, dd, J = 9.0, 6.0 Hz), 4.38 (2H, s), 4.67 (IH, t, J = 8.9 Hz), 6.09-6.19 (2H, m) , 6.64 (IH, s) , 6.93 (IH, d, J = 7.9 Hz), 7.03-7.13 (IH, m) , 7.12-7.21 (IH, m) , 7.24-7.34 (IH, m) . MS m/z 412 (M + H)⁺. [1025]

2577Example 122 methyl [ (3S)-6-{ [3- (2, 5-dimethylthiophen-3-yl) -2- methylbenzyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [1026]

2578<img file="WO2010143733A1_D0166.tif" />

2579[1027]

2580To a solution of methyl { (3S) -6- [ (3-bromo-2- methylbenzyl) amino] -2, 3-dihydro-l-benzofuran-3-yl} acetate (150 mg, 0.384 mmol), (2, 5-dimethylthiophen-3-yl) boronic acid (120 mg, 0.769 mmol) and 2 M aqueous sodium carbonate solution (0.576 mL, 1.15 mmol) in toluene (2 mL) were added tris (dibenzylideneacetone)dipalladium (0) (10.5 mg. 0.012 mmol) and dicyclohexyl (2' , 6' -dimethoxybiphenyl-2-yl) phosphane

2581(18.9 mg, 0.046 mmol) under an argon atmosphere, and the mixture was stirred at 100°C overnight. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95:5 - 67:33) to give the title compound (140 mg, yield 86%) as a yellow oil.

2582¹H NMR (300 MHz, CDCl₃) δ 2.15 (3H, s) , 2.18 (3H, s) , 2.45 (3H, s), 2.54 (IH, dd, J = 16.3, 9.1 Hz), 2.74 (IH, dd, J = 16.3, 5.7 Hz), 3.71 (3H, s) , 3.73-3.83 (IH, m) , 3.91 (IH, br s) , 4.23 (IH, dd, J = 9.1, 6.1 Hz), 4.27 (2H, s) , 4.72 (IH, t, J = 8.9 Hz), 6.13-6.22 (2H, m) , 6.50 (IH, s) , 6.95 (IH, d, J = 8.0 Hz), 7.05-7.12 (IH, m) , 7.17 (IH, t, J = 7.6 Hz), 7.23-7.34

2583(IH, m) . MS m/z 422 (M + H)⁺.

2584[1028] Example 123

2585[ (3S) -6- { [ 3- (2 , 5-dimethylthiophen-3-yl) -2-methylbenzyl] amino} - 2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2586[1029]

2587<img file="WO2010143733A1_D0167.tif" />

2588[1030]

2589To a mixed solution of methyl [ (3S) -6-{ [3- (2, 5- dimethylthiophen-3-yl) -2-methylbenzyl] amino} -2, 3-dihydro-l- benzofuran-3-yl] acetate (140 mg, 0.331 mmol) in tetrahydrofuran (2 mL) and methanol (1 mL) was added 1 M aqueous sodium hydroxide solution (0.994 mL) , and the mixture was stirred at 5O⁰C for 1 hr. The reaction mixture was concentrated under reduced pressure, dissolved in distilled water, and cooled to 0°C. Thereto was slowly added 1 M hydrochloric acid to give a solid. The solid was filtered, and washed with distilled water to give the title compound (115 mg, yield 85%) as a white solid.

2590¹H NMR (300 MHz, CDCl₃) δ 2.16 (3H, s) , 2.18 (3H, s) , 2.44 (3H, s), 2.60 (IH, dd, J = 16.8, 9.4 Hz), 2.80 (IH, dd, J = 16.6, 5.3 Hz), 3.71-3.85 (IH, m) , 4.21-4.31 (3H, m) , 4.73 (IH, t, J = 8.9 Hz), 6.11-6.23 (2H, m) , 6.50 (IH, d, J = 0.9 Hz), 6.98

2591(IH, d, J = 8.1 Hz), 7.07-7.13 (IH, m) , 7.17 (IH, t, J = 7.4 Hz) , 7.27-7.33 (IH, m) . MS m/z 408 (M + H)⁺.

2592[1031] Example 124

2593[ (3S) -6-{ [3- (2-ethyl-6-fluoro-lH-benzimidazol-l-yl) -2- methylbenzyl] amino}-2, 3-dihydro-l-benzofuran-3-yl] acetic acid

2594[1032]

2595<img file="WO2010143733A1_D0168.tif" />

2596[1033]

2597To a mixed solution of methyl [ (3S) -6-{ [3- (2-ethyl-6- fluoro-lH-benzimidazol-1-yl) -2-methylbenzyl] amino} -2 , 3- dihydro-l-benzofuran-3-yl] acetate (348 mg, 0.735 mmol) in tetrahydrofuran (4.6 mL) and methanol (2.3 mL) was added 1 M aqueous sodium hydroxide solution (2.21 mL) , and the mixture was stirred at 50⁰C for 1 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and diluted with distilled water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a solid. The solid was triturated with hexane-ethyl acetate to give the title compound (279 mg, yield 83%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.32 (3H, s) , 1.92 (3H, s) , 2.55-2.72

2598(3H, m) , 2.82 (IH, dd, J = 16.7, 5.3 Hz) , 3.75-3.89 (IH, m) , 4.29 (IH, dd, J = 9.5, 6.1 Hz), 4.36 (2H, s) , 4.76 (IH, t, J = 9.1 Hz), 6.12-6.25 (2H, m) , 6.59 (IH, dd, J = 8.5, 2.5 Hz), 6.96-7.06 (2H, in) , 7.17 (IH, d, J = 7.6 Hz) , 7.36 (IH, t, J = 7.8 Hz) , 7.56 (IH, d, J = 7.6 Hz) , 7.74 (IH, dd, J = 8.7, 4.9 Hz) .

2599MS m/z 460 (M + H)⁺. [1034]

2600Example 125 sodium [ (3S) -6-{ [3- (2-ethyl-6-fluoro-lH-benzimidazol-1-yl) -2- methylbenzyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate [1035]

2601<img file="WO2010143733A1_D0169.tif" />

2602[1036]

2603To a suspension of [ (3S) -6-{ [3- (2-ethyl-6-fluoro-lH- benzimidazol-1-yl) -2-methylbenzyl] amino}-2, 3-dihydro-l- benzofuran-3-yl] acetic acid (220 mg, 0.479 mmol) in water (2.4 ml) was added 1 M aqueous sodium hydroxide solution (0.479 itiL) , and the mixture was stirred at room temperature. After dissolution of insoluble material, acetonitrile was added and the mixture was concentrated under reduced pressure to give the title compound (225 mg, yield 98%) as a white solid. 1H NMR (300 MHz, DMSO-d₆) δ 1.21 (3H, t, J = 7.5 Hz), 1.84 (3H, s), 1.95 (IH, dd, J = 14.7, 10.2 Hz), 2.29 (IH, dd, J = 14.7, 4.5 Hz), 2.53-2.64 (2H, m) , 3.44-3.60 (IH, m) , 4.05 (IH, t, J = 7.9 Hz), 4.26 (2H, d, J = 4.5 Hz), 4.58 (IH, t, J = 8.7 Hz), 5.91-6.18 (3H, m) , 6.69 (IH, d, J = 7.2 Hz), 6.89 (IH, d, J = 7.9 Hz), 7.07 (IH, t, J = 8.3 Hz), 7.24-7.33 (IH, m) , 7.39 (IH, t, J = 7.5 Hz), 7.45-7.56 (IH, m) , 7.67 (IH, dd, J = 8.7, 4.9 Hz) .

2604MS m/z 460 (M + H)⁺ (as free form).

2605[1037]

2606Example 126 methyl [ (3S) -6-{ [2-methyl-3- (2-methyl-lH-benzimidazol-l- yl) benzyl] amino} -2, 3-dihydro-l-benzofuran-3-yl] acetate

2607[1038]

2608<img file="WO2010143733A1_D0170.tif" />