UA102540C2 - 5-membered heterocyclic compounds, condensed derivatives thereof and use thereof in the treatment of diabetes - Google Patents

Abstract

Disclosed is an agent for prevention and treatment of diabetes, which has excellent medicinal effects. Specifically disclosed is a compound represented by formula (I) or (IA), or a salt thereof. (In the formulae, the symbols are as defined in the description.)Provision of a prophylactic or therapeutic agent for diabetes, which has superior efficacy. A compound represented by the formula: wherein each symbol is as described in the specification, or a salt thereof.

Description

3) The compound is represented by the following formula:

IS

АА 2 M. 0 ma НА х

F)

K where M is - (ООН, -С(О)МВ2В, -С(О)МА2гОНУ, -5(0)2О2, on m svya, uh. H

Sho x sen "M. and the same is true in Sh, "Zh a " z zach" Mem zaz Ye pe

In M vn.

IN? ii EZ each is independently H or C. in alkyl; B" is H, halogen, etc.; A is de EI sh- in vi vo i " vecha -СН У-М-нв-- . ss nns, M CH or M 2 and -M Сну (Сн and -Е. (СН. реебОабо1;пе0-3;8Б' is H, С.-.в alkyl, etc.; ЕЗ and Е? each is independently H or C. .in alkyl; U is -C(0)-, -5(0)2-, -O- or a bond; 7 is phenyl, 5 is b6-ene aromatic heterocycle (each optionally substituted halo etc.); E! is H or C. .in alkyl; X is o ,

And (she's dreaming of SV (we, oh and Z Y

I dream a ram, -- (my dreams,

Kk o ; 5

A nd Ya o-skmyauchen , it flows, o o SHO o. a end m svya misnag ; -Hve (svv (Sn. lk z 3.1 ; ii i 131 i - I ov koryn tov yun, in: o 1zrza mm; M -i (yena n- (sv vyt ros uchihnih, vya We -(sndisv sna i ni ni M NN

A -

My oh oh! yaz , (sna dishonest, (snigisv in o-sndt o, ia o and "Y. sndr-v- (svt (SN bo Ya nar ovchyamuchonak- gye 0 or 1; d and 5 are each 0 - 3; B", VZ, DV" and B!" each is independently H or C. alkyl; O is for vk In actions I Hetod this se this zu and in: and in

Al in Kk , ' from vd E M to x d' ve in vii V

M", o. ' dya de ne no ud v. TSI ve

M i - 1 schi" still I Y t v da

And min

Kk and

MM is -0-, -5-, -5(0)2- or -M2O-; МY is -СК20- or -М-; B'5, B", BZ and B" are each independently H, -C(O)MV2 B, -C(O)B2, etc.; CO and 20 are each H, C1-6 alkyl, C3-6 cycloalkyl or C1-6 cycloalkyl-C1-6 alkyl; KB? ii Kk? each is H, -C3, C6 alkyl, aryl, aromatic heterocyclic group, etc.; and E is an optionally substituted 3-9-ene monocycle or bicycle (patent document 3: UMUO00/69810). 4) The compound is represented by the following formula: 6)

AND.

IM E

СО in ху "In deA there are n І and І

NM he ;

X is a bond, -СВ'В"- or -МВ"-; In is »SVZ- or »M-; B", I and EZ are each independently H or

Si is alkyl, or B! and B? does not necessarily form a double bond; E is C1-0 alkyl or C3-10 cycloalkyl, C3-0 cycloalkyl-C-6 alkyl, aryl, aromatic heterocyclic group or aryl-

C-alkyl (each of them can be substituted by halogen, C-alkyl, etc.), etc.; There is

N

M M t t M walked only 7's. x-x x-Mm; I'm sorry

X is -M- or -СВ8-; U has -5-, -O- or MEZ-; IN? is H, or C. alkyl or aryl (each of them may be substituted by halogen, Sci-is alkyl, etc.); KE? is H or C 1 alkyl; O is an aryl or an aromatic heterocyclic group (each optionally substituted with halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 cycloalkyl, aryl (these rings are optionally substituted with halogen, C 1-10 alkyl, etc.), etc. .) (patent document 4: UMO2004/002480).

In addition, the following compound is known. 5) The compound is represented by the following formula

Az Na - -y (Nv)

DL Y, i-th

For min Ff, where C is phenyl or pyridyl; UM is -МН(С-О)(СНВв)-, -СН(На)МН-, -МНОН|(Ез)-, -СНо-О- or --6С-О)0-; BZ is H or alkyl; r is 0, 1 or 2; EC is H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aromatic heterocyclic group, optionally substituted cycloalkyl, optionally substituted nonaromatic heterocyclic group, etc.; BC? is H, optionally substituted alkyl, optionally substituted alkoxy, amino, etc.; Kz is H, -SEz, -OSE", halogen, optionally substituted C--4 alkyl, -OB: and so on. Ka; is H, optionally substituted C-, alkyl, halogen, -SEz, -OSE", -OB with, etc.; VU is -SEz, -OSE", optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclic group, optionally substituted aryl, optionally substituted aromatic heterocyclic group, -OBiz, -C(/ -O) VZchz, -

S(I-O) Ministry of Education, etc.; X is -"С-О)МН-, -МН(С-О)-, -МН(С-О)О-, -502МН-, -СО"- or a bond; КЗ is

H, optionally substituted C..4 alkyl, optionally substituted alkoxy, optionally substituted phenoxy, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclic group, optionally substituted aryl, optionally substituted aromatic heterocyclic group, etc.; Kv and K5 can be connected to each other to form a 5- or b-membered ring; Kch.1, Wis and K:i4 are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted non-aromatic heterocyclic group, optionally substituted aryl or optionally substituted aromatic heterocycle; t is 0, 1, 2 or 3, which is useful as a therapeutic agent in inflammatory diseases, especially the following compound

Jach |c) a (patent document 5: UUO2004/098528). patent document 1: UMO2006/102067 patent document 2: UMO2004/069158 patent document 3: UMO00/69810 patent document 4: UMO2004/002480 patent document 5: UMO2004/098528

Description of the invention

Problems solved by the invention

It is desirable to create a compound that has extraordinary effectiveness and benefit in the prevention or treatment of diabetes, etc.

Means of solving the problem

The inventors found that the compound represented by the following formula (I) or its salt (sometimes hereinafter referred to in the presented description as "compound (I)) and the compound represented by formula (IA) or its salt (sometimes hereinafter referred to in the presented description as "compound ( IA)") has an extraordinary glucagon antagonistic effect and an extraordinary efficacy as an agent for the prevention or treatment of diabetes, etc.. Based on this discovery, the inventors conducted intensive research and created the present invention.

Accordingly, the presented invention relates to (1) a compound represented by the following formula:

Oshi where the AA ring is an optionally substituted benzene ring or an optionally substituted 5- or b-membered aromatic heterocycle; ring AB is an optionally substituted 5-membered aromatic heterocycle; the AC ring is an optionally substituted benzene ring or an optionally substituted 5- or b-membered aromatic heterocycle;

BZ is an optionally substituted C-C alkyl group, an optionally substituted C-C cycloalkyl group, an optionally substituted C-C 4 aryl group, or an optionally substituted heterocyclic group;

A" is a hydrogen atom or C. is an alkyl group;

A is -""СНг2)3--СООВА" or -"МАРЕ-СВАВА-СвВ АОС; vie, di, dya, where Her BA" is each, independently, a hydrogen atom or C.. is an alkyl group; and

BA o is a hydrogen atom, C-.v an alkyl group or a hydroxy group, or its salts; (2) the compound mentioned above in (1), where formula (IA) is the following formula (o; v tu v"

AA

M im (A) in ; and the AA ring is a benzene ring or b--len aromatic heterocycle; (3) the compounds mentioned above in (2), where KZ is an optionally substituted C. alkyl group, an optionally substituted C.sub.3-0 cycloalkyl group or an optionally substituted 5- or 6-membered heterocyclic group;

B" is a hydrogen atom;

And is -""CHg2)3-SOOVA" or -MA"E-(CH2g)"-SOOVA;

DE is a hydrogen atom or methyl; i

BA" is a hydrogen atom, methyl or ethyl; (4) 3-((4-Yacyclohexyl(3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)amino)propanoic acid or its salts; (5) 3-1(6-Hycyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridin-3-yl)ucarbonyl|(methyl)amino)propanoic acid or its salts;

(6) 3-4(4-(2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid or its salt; (7) 3-C4-41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2h-yl|-2-methylpropyl)amino)phenyl]carbonylmethyl)amino|propanoic acid or its salt; (8) 3-X4-(cyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid or its salt; (9) the compound represented by the following formula: (c) in su c

And () in! is a where ring A is an optionally substituted benzene ring or an optionally substituted 5- or b-membered aromatic heterocycle; ring B is pyrazole;

In y 22 each is, independently, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or acyl;

BZ is an optionally substituted C6 alkyl group, an optionally substituted C3-0 cycloalkyl group, an optionally substituted C6-4 aryl group or an optionally substituted heterocyclic group;

B" is a hydrogen atom or C... an alkyl group;

IN? is -"СН2г)з3-СООВ" or -"МАЕ-СВ/ВЗ-СВВ"-СООВ;

Be, B", VU, B KE" are each, independently, a hydrogen atom or C..v alkyl group; and

B" is a hydrogen atom, a C-.v alkyl group or a hydroxy group, with the exception of M-(4-CD1-phenyl-5-propyl-1H-pyrazol-4-yl)methylyl|amino|benzoyl|-p-alanine, or a salt thereof; (10) the compound mentioned in (9) above, wherein formula (I) is the following formula

ЕСЯ прия в ф ча ш-

GA A and EE SHY not for what about OO s i -y | by A- and ko! And local t EI EE:

She M sa abi zasquay , and ring A is a benzene ring or a b-membered aromatic heterocycle; (11) of the compound mentioned above in (9), where EK! is an optionally substituted C-.is alkyl group, an optionally substituted C-4 aryl group or an optionally substituted 5- or b-membered aromatic heterocyclic group;

IN? is an optionally substituted C1-6 alkyl group, an optionally substituted C1-6 alkyl group or an optionally substituted C3-0 cycloalkyl group;

BZ is an optionally substituted C6 alkyl group, an optionally substituted C3-0 cycloalkyl group, or an optionally substituted 5- or 6-membered heterocyclic group;

B" is a hydrogen atom;

IN? is -"СН2г)з3-СООВ" or -МАУ-СНоАСАВЗ-СООВ;

Be is a hydrogen atom or methyl;

VE? is a hydrogen atom, methyl or ethyl;

B" is a hydrogen atom, methyl or ethyl; and

B" is a hydrogen atom, methyl or ethyl; (12) 3-I(4-Kcyclohexyl3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-

yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid or its salts; (13) 3-ICH4-Ccyclohexyl|(1-(3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylUmethyl)amino|propanoic acid or its salt; (14) 3-ICH4-Scyclohexyl|(1-(3-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methyl)amino)phenylIcarbonylUmethyl)amino|propanoic acid or its salt; (15) the prodrug form of the compound mentioned in (1) or (9) above; (16) a medicine containing the compound mentioned above in (1) or (9) or its prodrug form; (17) the medication mentioned in (16) above, which is a glucagon antagonist; (18) the medicine mentioned in (16) above, which is an agent that suppresses the production of sugar; (19) the medicament mentioned in (16) above, which is an agent for the prevention or treatment of diabetes; (20) a method of inhibiting sugar production in a mammal, which includes administering to the mammal the compound mentioned above in (1) or its prodrug form or the compound mentioned above in (9) or its prodrug form; (21) a method of preventing or treating diabetes in a mammal, which includes administering to the mammal the compound mentioned in (1) above or its prodrug form or the compound mentioned in (9) above or its prodrug form; (22) using the compound mentioned above in (1) or its prodrug form or the compound mentioned in (9) above or its prodrug form, to obtain a medicament for inhibiting sugar production; (23) using the compound mentioned in (1) above or a prodrug form thereof or the compound mentioned in (9) above or a prodrug form thereof to produce an agent for the prevention or treatment of diabetes; etc... (Effect of the invention)

Since the compound of the presented invention has a glucagonantagonist effect and extraordinary effectiveness (suppression of the increase of glucose in the blood, hypoglycemic effect, etc.), it is useful for the prevention or treatment of diabetes, etc. (Detailed description of the invention)

In the present description, "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

In the presented description, examples of "Si-O alkyl group" are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1 -dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, etc.

In the presented description, examples of "Si alkyl group" are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl , 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.

In the presented description, examples of "branched C-C alkyl group" are isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, 1-ethylpropyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3 ,3-dimethylbutyl, 2-ethylbutyl, etc.

In the presented description, examples of "C2-o alkenyl group" are ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl ...

In the presented description, examples of "C2b alkenyl group" are ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 - pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, etc.

In the presented description, examples of "C1-0 alkynyl group" are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl , 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, etc.

In the presented description, examples of "Owls of the alkynyl group" are ethynyl, 1-propynyl, 2-

propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and t...

In the presented description, examples of "C. alkoxy groups" are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.

In the presented description, examples of "Sov alkenyloxy group" are ethenyloxy, etc.

In the presented description, examples of "C3-10 cycloalkyl group" are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo|(2.2.1)heptyl, bicyclo/2.2.2|octyl, bicyclo!13.2.octyl, bicycloY3.2.2|nonyl, bicyclo(|3.3.1|nonyl, bicyclo(4.2.1|nonyl, bicyclo(4.3.1)decyl, adamantyl, etc...

In the presented description, examples of "SZe cycloalkyl group" are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

A C3-C cycloalkyl group and a C3-O cycloalkyl group can form a condensed cyclic group with a benzene ring, and examples of such a condensed cyclic group are indanyl, etc.

In the present description, examples of "C3-0 cycloalkenyl group" are cyclopropenyl (e.g., /2-cyclopropen-1-yl), cyclobutenyl (e.g., 2-cyclobuten-1-yl), cyclopentenyl (e.g., 2-cyclopenten-1- yl, 3-cyclopenten-1-yl), cyclohexenyl (e.g. 2-cyclohexen-1-yl, 3-cyclohexen-1-yl), cycloheptenyl (e.g. 2-cyclohepten-1-yl), cyclooctenyl (e.g. 2 -cyclooctene-1-Il) etc...

In the present description, examples of "New cycloalkenyl group" are cyclopropenyl (e.g., /2-cyclopropen-1-yl), cyclobutenyl (e.g., 2-cyclobuten-1-yl), cyclopentenyl (e.g., 2-cyclopenten-1-yl, 3-cyclopenten-1-yl), cyclohexenyl (for example, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl), etc.

Czv cycloalkenyl group and Czio cycloalkenyl group can form a fused cyclic group with a benzene ring, and examples of such a condensed cyclic group are dihydronaphthyl, etc.

In the presented description, examples of "C4-o cycloalkadienyl group" are 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, etc.

A cycloalkadienyl group can form a fused cyclic group with a benzene ring, and examples of such a fused cyclic group are fluorenyl, etc.

In the presented description, examples of "Cv-4 aryl group" are phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, biphenylyl, etc.

In the presented description, examples of "Sv-o aryl group" are phenyl, naphthyl, etc.

In the presented description, examples of "Cv-4 aryloxy groups" are phenyloxy and naphthyloxy.

In the presented description, examples of "C7is aralkyl group" are benzyl, phenethyl, naphthylmethyl, biphenylylmethyl, etc.

In the presented description, examples of "C7-from aralkyloxy group" are benzyloxy, etc.

In the presented description, examples of "Sv-z arylalkenyl group" are styryl, etc.

In the presented description, examples of "heterocyclic group" are the following aromatic heterocyclic groups and non-aromatic heterocyclic groups.

In the presented description, examples of "aromatic heterocyclic group" are 4-12-membered aromatic heterocyclic group, for example, 4-7-membered (predominantly 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as ring-forming atoms other than carbon atoms, 1-4 heteroatoms selected from an oxygen atom, a sulfur atom (optionally oxidized) and a nitrogen atom, and an 8-12-membered condensed aromatic heterocyclic group. Examples of a fused aromatic heterocyclic group are a group derived from a fused ring wherein 1 or 2 rings selected from a 5- or b-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (for example, thiophene) and a benzene ring, and the ring corresponding to a 4-7-membered monocyclic aromatic heterocyclic group is condensed, etc.

Preferred examples of an aromatic heterocyclic group are monocyclic aromatic heterocyclic groups such as furyl (e.g. 2-furyl, 3-furyl), thienyl (e.g. 2-thienyl, 3-thienyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl , 4-pyridyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl

(e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g. 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (e.g. 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g. 3-isothiazolyl , 4-isothiazolyl, 5-isothiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (eg, 1, 2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g. 1,3,4- thiadiazol-2-yl), triazole (e.g. 1,2,4- triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol- 4-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g. 1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) etc.; fused aromatic heterocyclic groups such as quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-quinolyl, b-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl, b-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-benzofuranyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), benzisoxazolyl ( e.g., 7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzotriazole (e.g., 1Hn- 1,2,3 -benzotriazol-5-yl), indolyl (for example, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (for example, 1H-indazol-3-yl), pyrrolopyrazinyl (for example, 1H-pyrrolo(|2,3-

VIpyrazin-2-yl, 1H-pyrrolo|2,3-b|pyrazin-6b-yl), imidazopyridinyl (for example, 1H-imidazoi|4,5-

VIpyridin-2-yl, 1H-imidazo|(4,5-c|Ipyridin-2-yl, 2H-imidazoi|1,2-a|pyridin-Z-yl), thienopyridinyl (e.g. thieno(2,3- b|pyridin-Z-yl), imidazopyrazinyl (for example, 1H-imidazo(|4,5-

bipyrazin-2-yl), pyrazolopyridinyl (e.g. 1H-pyrazolo(4,3-c|Ipyridin-3-yl), pyrazolothienyl (e.g. 2H-pyrazolo|3,4-biHiophen-2-yl), pyrazolotriazinyl (e.g. , pyrazolo!|5,1-c|(1,2,4)triazin-3Z-yl) etc.; etc. 4..

In the presented description, examples of a "non-aromatic heterocyclic group" are a 4-12-membered non-aromatic heterocyclic group, for example, a 4-7-membered (predominantly 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing , as ring-forming atoms in addition to carbon atoms, 1-4 heteroatoms selected from an oxygen atom, a sulfur atom (the sulfur atom is optionally oxidized) and a nitrogen atom, and an 8-12-membered condensed non-aromatic heterocyclic group. Examples of a fused non-aromatic heterocyclic group are a group derived from a fused ring wherein 1 or 2 rings selected from a 5- or b-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocycle containing one sulfur atom (for example, thiophene) and a benzene ring, and a ring corresponding to a 4-7-membered monocyclic non-aromatic heterocyclic group is fused (not necessarily partly additionally saturated), etc.

Preferred examples of a non-aromatic heterocyclic group are monocyclic non-aromatic heterocyclic groups such as oxetanyl (e.g., 3-oxetanyl), pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), piperidinyl (e.g., piperidino, 2-piperidinyl, C -piperidinyl, 4-piperidinyl), morpholinyl (eg, morpholino), thiomorpholinyl (eg, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), hexamethyleneiminyl (eg, hexamethyleneimin-1-yl), oxazolidinyl (eg, oxazolidin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), dihydrothiopyranyl (eg, dihydrothiopyran-z-yl, dihydrothiopyran-4-yl), imidazolidinyl (eg, imidazolidin-2-yl, imidazolidin -Z-yl), oxazolinyl (eg, oxazolin-2-yl), thiazolinyl (eg, thiazolin-2-yl), imidazolinyl (eg, imidazolin-2-yl, imidazolin-3-yl), dioxolyl (eg, 1 ,3-dioxol-4-yl), dioxolanil (for example, 1,3-dioxolan-4-yl), dihydrooxadiazolyl (for example, 4,5-dihydro-1,2, 4-oxadiazol-3-yl), pyranyl (eg, 4-pyranyl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (eg, 4-thiopyranyl), tetrahydrothiopyranyl (eg, 2- tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxidotetrahydrothiopyranyl (eg, 1- oxidotetrahydrothiopyran-4-yl), 1,1-dioxidotetrahydrothiopyranyl (eg, 1,1-

dioxytetrahydrothiopyran-4-yl) tetrahydrofuryl (e.g. tetrahydrofuran-3-yl, tetrahydrofuran-2-yl), pyrazolidinyl (e.g. pyrazolidin-1-yl, pyrazolidin-3-yl), pyrazolinyl (e.g. pyrazolin-1-yl) , tetrahydropyrimidinyl (e.g. tetrahydropyrimidin-1-yl), dihydrotriazole (e.g. 2,3-dihydro-1H-1,2,3-triazol-1-yl), tetrahydrotriazole (e.g. 2,3,4,5- tetrahydro-1H-1,2,3-triazol-1-yl), etc.; fused non-aromatic heterocyclic groups such as dihydroindolyl (e.g. 2,3-dihydro-1H-indol-1-yl), dihydroisoindolyl (e.g. 1,3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl ( e.g., 2,3-dihydro-1-benzofuran-5-yl), dihydrobenzodioxynyl (e.g., 2,3-dihydro-1,4-benzodioxynyl), dihydrobenzodioxypinyl (e.g., 3,4-dihydro-2H-1,5- benzodioxepinyl), tetrahydrobenzofuranyl (e.g. 4,5,6,7-tetrahydro-1-benzofuran-Z-yl), chromenyl (e.g. 4H-chromen-g-yl, 2H-chromen-Z-yl), dihydrochromenyl (e.g. , 3,4-dihydro-2H-chromen-2-yl), dihydroquinolinyl (for example, 1,2- dihydroquinolin-4-yl), tetrahydroquinolinyl (for example, 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg, 1,2-dihydroisoquinolin-4-yl), tetrahydroisoquinolinyl (eg, 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (eg, 1,4-dihydrophthalazin-4-yl), etc. AND.; etc...

In the presented description, examples of "5- or b-membered heterocyclic group" are 5- or b-membered rings from among the above-mentioned monocyclic aromatic heterocyclic groups and monocyclic non-aromatic heterocyclic groups.

In the present description, specific examples of "5- or b-membered aromatic heterocycle are rings corresponding to 5- or b-membered cyclic groups from among the aromatic heterocyclic groups mentioned above, for example, furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, triazine, etc.

In the present description, specific examples of "5-membered aromatic heterocycle" are rings corresponding to a 5-membered cyclic group from among the aromatic heterocyclic groups mentioned above, for example, furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole, thiadiazole, triazole, tetrazole, etc... in the presented description, examples of "4-142-membered aromatic heterocyclyloxy group are groups where the oxy group is connected to the above-mentioned 4-12-membered aromatic heterocyclic group, for example, pyridyloxy, etc., in the presented description, examples of "a-12-membered non-aromatic heterocyclyloxy group are groups where the oxy group is connected to the above-mentioned 4-12-membered non-aromatic heterocyclic group, for example, tetrahydropyranilox, tetrahydrothiopyranilox, 1 ,1-dioxidotetrahydrothiopyranilox, etc.

In the presented description, examples of 7"4-12-membered aromatic heterocyclyl-carbonyl group" are groups where the carbonyl group is connected to the above-mentioned 4-12-membered aromatic heterocyclic group, for example, furylcarbonyl, thienylcarbonyl, pyrazolylcarbonyl, pyrazinylcarbonyl , isoxazolylcarbonyl, pyridylcarbonyl, thiazolylcarbonyl, etc.

In the present description, examples of "4-12-membered non-aromatic heterocyclyl-carbonyl group" are groups where the carbonyl group is linked to the above-mentioned 4-12-membered non-aromatic heterocyclic group, for example, tetrahydrofurylcarbonyl, pyrrolidinylcarbonyl, morpholinylcarbonyl, etc. and..

In the presented description, examples of "Si-alkyl-carbonyl group" are acetyl, propanoyl, butanoyl, isobutanoyl, tert-butanoyl, pentanoyl, isopentanoyl, hesanoyl, etc.

In the presented description, examples of "Ci alkyl-carbonyloxy groups" are acetyloxy, propanoyloxy, butanoyloxy, isobutanoyloxy, tert-butanoyloxy, pentanoyloxy, isopentanoyloxy, hesanoyloxy, etc.

In the presented description, examples of "Alkoxy-carbonyl group" are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.

In the presented description, examples of "C3-O cycloalkyl-carbonyl group" are cyclopropylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.

In the presented description, examples of "Cv-4 aryl carbonyl group" are benzoyl, etc.

In the presented description, examples of "Alkylthio group seeds"7 are methylthio, ethylthio,

isopropylthio, etc. 1..

In the presented description, examples of "Sv-arylthio groups" are phenylthio, naphthylthio, etc.

In the presented description, examples of "C7-from aralkylthio group" are benzylthio, etc.

In the presented description, examples of "Alkylsulfonyl group" are methylsulfonyl, ethylsulfonyl, isopropylsulfonyl, etc.

In the presented description, examples of "Svl-4 arylsulfonyl group are benzenesulfonyl and so on...

In the presented description, examples of "C: from the alkylenedioxy group are methylenedioxy, ethylenedioxy, etc...

In the presented description, examples of an "optionally substituted hydrocarbon group" are an optionally substituted C1-0 alkyl group, an optionally substituted C2-0 alkenyl group, an optionally substituted C2-0 alkynyl group, an optionally substituted C3-0 cycloalkyl group, an optionally substituted C3-0 cycloalkenyl group, an optionally substituted C0 cycloalkadienyl group, and an optionally substituted C1-4 aryl group, an optionally substituted C7:3 aralkyl group, an optionally substituted S8 arylalkenyl group, etc. ..

In the present description, examples of an "optionally substituted hydroxy group" are a hydroxy group optionally substituted with a substituent(s) selected from (1) an optionally substituted C--o alkyl group (preferably, optionally substituted

C. .v alkyl group), (2) optionally substituted C3-:0 alkenyl group, (3) optionally substituted C3-zo cycloalkyl group, (4) optionally substituted C3-zo cycloalkenyl group, ( 5) optionally substituted C6-14 aryl group, (b) optionally substituted C7-3 aralkyl group, (7) optionally substituted C3-33 arylalkenyl group, (8) optionally substituted C6-6 alkyl -carbonyl group, (9) optionally substituted heterocyclic group, etc.

In the presented description, Si is an alkyl group, Ci is an alkyl group, Co is an alkenyl group, is is an alkynyl group, and is an alkyl carbonyl group of an "optionally substituted C-C alkyl group," "optionally" necessarily substituted C.-o alkyl group", "optionally substituted

C»-20 alkenyl group", "optionally substituted C2-20 alkynyl group", and "optionally substituted C1-6 alkyl carbonyl group" optionally have 1-5 (predominantly 1-3) substituents in each possible position(s) to be replaced.

Examples of such substituents are the following substituents of group A: (substituent of group A) (1) C3-O cycloalkyl group; (2) C-14 aryl group optionally substituted 1 - With substituents selected from (a) C-C alkyl group optionally substituted 1 - With halogen atoms, (B) hydroxy group, (c) C 1-C alkyl group optional necessarily substituted 1 - With halogen atoms, and (a) a halogen atom; (3) 4-12-membered aromatic heterocyclic group optionally substituted 1 - With substituents selected from (a) C-C alkyl group optionally substituted 1 - With halogen atoms, (B) hydroxy group, (c ) Siv alkoxy group is optionally substituted 1 - With halogen atoms, and (a) a halogen atom; (4) 4-12-ene non-aromatic heterocyclic group optionally substituted 1 - With substituents selected from (a) C-C alkyl group optionally substituted 1 - With halogen atoms, (B) hydroxy group, (c) Siv alkoxy group optionally substituted 1 - With halogen atoms, (ad) halogen atom, and (e) oxo group;

(5) amino group optionally mono- or di-substituted with substituent(s) selected from (a) C-C alkyl group optionally substituted 1 - With substituents selected from (I) halogen atom, and (its ) C-C is an alkoxy group, (p) C-C alkyl-carbonyl group optionally substituted 1 - With halogen atoms, (c) C-C alkyl-carbonyl group is optionally substituted 1 - With halogen atoms, (a) C.e alkylsulfonyl group optionally substituted 1 - With halogen atoms, (e) carbomoyl group optionally mono- or di-substituted C. alkyl group optionally substituted 1 - With halogen atoms, and () 4-12-membered aromatic heterocyclic group; (6) C-C alkyl-carbonyl group optionally substituted 1 - With halogen atoms; (7) C 1 -C 6 alkoxy-carbonyl group is optionally substituted 1 - With substituents selected from (a) a halogen atom, (p) C 1 -C alkoxy group, and (c) C 1 -a aryl group; (8) Siv alkylsulfonyl group optionally substituted 1 - With halogen atoms; (9) the carbomoyl group is optionally mono- or di-substituted by C. alkyl group, which is optionally substituted by 1 - With halogen atoms; (10) the thiocarbomoyl group is optionally mono- or di-substituted by an alkyl group optionally substituted by 1 - with halogen atoms; (11) the sulfamoyl group is optionally mono- or di-substituted by C-.v alkyl group, which is optionally substituted by 1-C halogen atoms; (12) carboxyl group; (13) hydroxy group; (14) C 1 -C 6 alkoxy group is optionally substituted 1 - With substituents selected from (a) halogen atom, (p) carboxy group, (c) C 1 -C 6 alkoxy group, (a) C 3 -C cycloalkyl group, (e) C 6 -C 6 -carbonyl the group is optionally substituted 1 - With Svl4 aryl groups, () the amino group is optionally mono- or di-substituted with a substituent(s) selected from

C. .in the alkyl group and C-i. is the alkoxy-carbonyl group, (94) 4-12-membered aromatic heterocyclic group is optionally substituted 1 - With substituents selected from (I) a halogen atom, and ( her) Civ alkyl group, (n) 4-12-ene non-aromatic heterocyclic group optionally substituted 1-C Civ alkyl groups, (i) Civ alkylsulfonyl group, (I) C-C alkylthio group, and (K) hydroxy group; (15) Alkenyloxy group optionally substituted 1 - With halogen atoms; (16) C7 with an aralkyloxy group; (17) Sv-4 aryloxy group; (18) Siv alkyl-carbonyloxy group; (19) 4-12-membered aromatic heterocyclyl-oxy group optionally substituted 1 - With substituents selected from (i) Si alkyl group optionally substituted 1 - With halogen atoms, and (ii) cyano group; (20) 4-12-membered non-aromatic heterocyclyl-oxy group; (21) Svl4 aryl-carbonyl group optionally substituted 1 - With substituents selected from (a) a halogen atom, and (p) C-C alkyl group optionally substituted 1 - With halogen atoms;

(22) 4-12-lene aromatic heterocyclyl-carbonyl group optionally substituted 1 - With substituents selected from Si. optionally substituted alkyl group 1 - With halogen atoms; (23) 4-12-membered non-aromatic heterocyclyl-carbonyl group optionally substituted 1 - With substituents selected from C..v alkyl group optionally substituted 1 - With halogen atoms; (24) mercapto group; (25) Siv alkylthio group is optionally substituted 1 - With substituents selected from (a) a halogen atom, and (p) Siv alkoxycarbonyl group; (26) C7iz aralkylthio group; (27) Св-и4 arylthio group; (28) cyano group; (29) nitro group; (30) halogen atom; (31) C-C alkylenedioxy group.

When two or more substituents are used, the corresponding substituents may be the same or different.

In the presented description, a benzene ring, a C-4 aryl group, a C3-0 cycloalkenyl group, a C3-2 cycloalkadienyl group, a C7-3 aralkyl group, and a C2-arylalkenyl group of an "optionally substituted benzene ring", "optionally substituted C -4 aryl group", "optionally substituted C3-o cycloalkenyl group", "optionally substituted

A cycloalkadienyl group", an "optionally substituted C7-3 aralkyl group" and an "optionally substituted C3-3 arylalkenyl group" each optionally have 1-5 (mostly 1-3) substituents in the possible pre-substitution positions.

Examples of such a substituent are the following substituent of group B: (substituent of group B) (1) C3-O cycloalkyl group; (2) C-14 aryl group optionally substituted 1 - With substituents selected from (a) C-C alkyl group optionally substituted 1 - With halogen atoms, (B) hydroxy group, (c) C 1-C alkyl group optional necessarily substituted 1 - With halogen atoms, and (a) a halogen atom; (3) 4-12-membered aromatic heterocyclic group optionally substituted 1 - With substituents selected from (a) C-C alkyl group optionally substituted 1 - With halogen atoms, (p) hydroxy group, (c ) Siv alkoxy group is optionally substituted 1 - With halogen atoms, and (a) a halogen atom; (4) 4-12-ene non-aromatic heterocyclic group optionally substituted 1 - With substituents selected from (a) C-C alkyl group optionally substituted 1 - With halogen atoms, (B) hydroxy group, (c) Siv alkoxy group optionally substituted 1 - With halogen atoms, (ad) halogen atom, and (e) oxo group; (5) amino group optionally mono- or di-substituted with substituent(s) selected from (a) C-C alkyl group optionally substituted 1 - With substituents selected from (I) halogen atom, and (its ) C-C is an alkoxy group, (p) C-C alkyl-carbonyl group optionally substituted 1 - With halogen atoms, (c) C-C alkyl-carbonyl group is optionally substituted 1 - With halogen atoms, (a) C.e alkylsulfonyl group optionally substituted 1 - With halogen atoms, (e) carbomoyl group optionally mono- or di-substituted C. alkyl group optionally substituted 1 - With halogen atoms, () 4-12-membered aromatic heterocyclic group,

(9) C1-4 arylcarbonyl group (eg, benzoyl), (n) C1-4 arylsulfonyl group (eg, benzenesulfonyl), and (I) C73 aralkyl group (eg, benzyl); (6) C-C alkyl-carbonyl group optionally substituted 1 - With halogen atoms; (7) C-C 1-C Alkoxy-carbonyl group is optionally substituted 1 - With substituents selected from (a) a halogen atom, (p) C-C 1-C alkoxy group, and (c) C-C 1-C aryl group; (8) Siv alkylsulfonyl group optionally substituted 1 - With halogen atoms; (9) the carbomoyl group is optionally mono- or di-substituted by C. alkyl group, which is optionally substituted by 1 - With halogen atoms; (10) the thiocarbomoyl group is optionally mono- or di-substituted by an alkyl group optionally substituted by 1 - with halogen atoms; (11) the sulfamoyl group is optionally mono- or di-substituted by C-.v alkyl group, which is optionally substituted by 1-C halogen atoms; (12) carboxyl group; (13) hydroxy group; (14) C 1 -C 6 alkoxy group is optionally substituted 1 - With substituents selected from (a) halogen atom, (p) carboxy group, (c) C 1 -C 6 alkoxy group, (a) C 3 -C cycloalkyl group, (e) C 6 -C 6 -carbonyl the group is optionally substituted 1 - With Svl4 aryl groups, () the amino group is optionally mono- or di-substituted with a substituent(s) selected from

C. .in the alkyl group and C-i. is the alkoxy-carbonyl group, (94) 4-12-membered aromatic heterocyclic group is optionally substituted 1 - With substituents selected from (I) a halogen atom, and ( her) Civ alkyl group, (n) 4-12-ene non-aromatic heterocyclic group optionally substituted 1-C Civ alkyl groups, (i) Civ alkylsulfonyl group, (I) C-C alkylthio group, and (K) hydroxy group; (15) Alkenyloxy group optionally substituted 1 - With halogen atoms; (16) C7 with an aralkyloxy group; (17) Sv-4 aryloxy group; (18) Siv alkyl-carbonyloxy group; (19) 4-12-membered aromatic heterocyclyl-oxy group optionally substituted 1 - With substituents selected from (i) Si alkyl group optionally substituted 1 - With halogen atoms, and (ii) cyano group; (20) 4-12-membered non-aromatic heterocyclyl-oxy group; (21) Svl4 aryl-carbonyl group optionally substituted 1 - With substituents selected from (a) a halogen atom, and (p) C-C alkyl group optionally substituted 1 - With halogen atoms; (22) 4-12-lene aromatic heterocyclyl-carbonyl group optionally substituted 1 - With substituents selected from Si. optionally substituted alkyl group 1 - With halogen atoms; (23) 4-12-membered non-aromatic heterocyclyl-carbonyl group optionally substituted 1 - With substituents selected from C..v alkyl group optionally substituted 1 - With halogen atoms; (24) mercapto group;

(25) Siv alkylthio group is optionally substituted 1 - With substituents selected from (a) a halogen atom, and (p) Siv alkoxycarbonyl group; (26) C7iz aralkylthio group; (27) Св-и4 arylthio group; (28) cyano group; (29) nitro group; (30) halogen atom; (31) C-C alkylenedioxy group; (32) The lower alkyl group is optionally substituted 1 - With substituents selected from (a) a halogen atom, (p) a carboxy group, (c) a hydroxy group, (a) a lower alkyl carbonyl group, (e) a lower alkoxy group, optional necessarily substituted by 1 - C:.6 alkoxy groups, and (y) the amino group is optionally mono- or di-substituted by C. 6 alkyl group(s); (33) Sgv alkenyl group is optionally substituted 1 - With substituents selected from (a) a halogen atom, (p) a carboxy group, (c) a hydroxy group, (a) a Civ alkoxy-carbonyl group, (e) C:-c an alkoxy group, and (y) an amino group is optionally mono- or di-substituted by C. .ve alkyl group(s); and (34) C7z aralkyl group optionally substituted 1 - With substituents selected from (a) C1-C alkyl group optionally substituted 1 - With halogen atoms, (B) hydroxy group, (c) C1 6 alkoxy group, and ( a) halogen atom.

When two or more substituents are used, the corresponding substituents may be the same or different.

In the presented description, the C30 cycloalkyl group "optionally substituted C3-0 cycloalkyl group" does not necessarily have 1-5 (preferably 1-3) substituents in the position(s) suitable for substitution. Examples of such a substituent are the group B substituent mentioned above and the oxo group.

When two or more substituents are used, the corresponding substituents may be the same or different.

In the present description, when "heterocyclic group" and "5- or b-membered heterocyclic group" of "optionally substituted heterocyclic group" and "optionally substituted 5- or b-membered heterocyclic group" are aromatic heterocyclic groups, aromatic heterocyclic groups optionally have 1 - 5 (predominantly 1 - 3) substituents in the position(s) suitable for substitution.

Examples of such a substituent are the group B substituent mentioned above. When two or more substituents are used, the corresponding substituents may be the same or different.

In the presented description, when "heterocyclic group" and "5- or b-membered heterocyclic group" of "optionally substituted heterocyclic group" and "optionally substituted 5- or b-membered heterocyclic group" are non-aromatic heterocyclic groups, non-aromatic heterocyclic groups groups optionally have 1 - 5 (predominantly 1 - 3) substituents in the position(s) suitable for substitution.

Examples of such a substituent are the group B substituent mentioned above and the oxo group. When two or more substituents are used, the corresponding substituents may be the same or different.

In the present description, 5- or b-membered aromatic heterocycle and 5-membered aromatic heterocycle "optionally substituted 5- or b-membered aromatic heterocycle" and "optionally substituted 5-membered aromatic heterocycle" each optionally have 1 - 5 (mostly 1-3) substitutes in a position(s) suitable for substitution. Examples of such a substituent are the group B substituent mentioned above. When two or more substituents are used, the corresponding substituents may be the same or different.

In the presented description, examples of "acyl" are groups represented by the formulas: -СО-

Бе, -СО-ОВ, -5(0)3-В2, -5(0)2-82, -5(0)-8У, -СО-МАВА Бе", -С5-МА ВВ", -5( 0)2-MA"V, etc.

In the formula, KU is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. KE" and ER" are each, independently, a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group, or VK" and ER" form, together with an adjacent nitrogen atom, an optionally substituted nitrogen-containing non-aromatic heterocycle .

Examples of "nitrogen-containing non-aromatic heterocycle" "optionally substituted nitrogen-containing non-aromatic heterocycle" formed by K" and B", together with the adjacent nitrogen atom, are 5-/--lene nitrogen-containing non-aromatic heterocycle containing, as a ring-forming an atom in addition to a carbon atom, at least one nitrogen atom, and optionally additionally contains 1 or 2 heteroatoms selected from an oxygen atom, a sulfur atom (the sulfur atom can be oxidized) and a nitrogen atom. Preferred examples of such a nitrogen-containing non-aromatic heterocycle are pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, etc.

A nitrogen-containing non-aromatic heterocycle optionally has 1 - 5 (preferably 1 - 3) substituents in the position(s) suitable for substitution. As such a substituent, we can mention the group B substituent mentioned above and the oxo group. When two or more substituents are used, the corresponding substituents may be the same or different.

Preferred examples of an "acyl group" are (1) a formyl group; (2) carboxyl group; (3) C 1 -C alkyl carbonyl group optionally substituted 1 - With substituents selected from (a) a halogen atom, (p) C 1 C alkoxy carbonyl group, (c) C 1 -a aryl group, and (a) C. .v alkoxy group; (4) C 1 -C 6 alkoxycarbonyl group optionally substituted 1 - With substituents selected from (a) a halogen atom, (p) C 1 -C aryl group, and (c) C 1 -C 6 alkoxy group; (5) C3-O cycloalkyl-carbonyl group; (6) Св-а4 aryl-carbonyl group optionally substituted 1 - With halogen atoms; (7) carbomoyl group optionally mono- or di-substituted by substituent(s) selected from (a) C-C alkyl group optionally substituted 1 - With substituents selected from (I) halogen atom, (its ) a C 6 -alkoxy-carbonyl group, (iii) a C 6 -a4 aryl group, (im) a C 6 -alkoxy group, and (m) a 4-12-membered aromatic heterocyclic group, (p) a C 3 -a cycloalkyl group, (c) C 1 -a the aryl group is optionally substituted 1 - With substituents selected from (I) a halogen atom, (its) Civ alkyl group is optionally substituted 1 - With halogen atoms, and (iii) C is an alkoxy group, and (a) 4-12-membered aromatic heterocyclic group; (8) C 1 alkylsulfonyl group is optionally substituted 1 - With substituents selected from (a) a halogen atom, and (p) C 1 - aryl group;

(9) Sv-4 arylsulfonyl group optionally substituted 1 - With halogen atoms; (10) the sulfamoyl group is optionally mono- or di-substituted with a substituent(s) selected from (a) a halogen atom, and (p) a C 1 -C alkyl group is optionally substituted 1 - With substituents selected from 4-12 - membered non-aromatic heterocyclic group optionally substituted oxo group; (11) the thiocarbomoyl group is optionally mono- or di-substituted by a substituent(s) selected from C..v alkyl group optionally substituted 1 - With halogen atoms; (12) 4-12-membered aromatic heterocyclyl-carbonyl group optionally substituted 1 - With substituents selected from Si. optionally substituted alkyl group 1 - With halogen atoms; (13) 4-12-membered non-aromatic heterocyclyl-carbonyl group optionally substituted 1 - With substituents selected from C..v alkyl group optionally substituted 1 - With halogen atoms; etc...

Compound (I) is broken.

Ring A is an optionally substituted benzene ring or an optionally substituted 5- or b-lene aromatic heterocycle. The 5- or b-membered aromatic heterocycle for ring A is preferably pyridine. "Benzene ring" or "5- or b-membered aromatic heterocycle" "optionally substituted benzene ring or optionally substituted 5- or b-membered aromatic heterocycle" for ring A optionally additionally has 1 to 4 substituents in a suitable to the replacement of position(s) except "-MA"- group" and -СО-В? group".

Ring A is preferably a benzene ring or a 5- or b-membered aromatic heterocycle (for example, pyridine), more preferably a benzene or a b-membered aromatic heterocycle (for example, pyridine), especially preferably a benzene ring, without a substituent other than "-MV "- group" and -СО-Е? group".

When ring A is benzene or β-ene aromatic heterocycle, the following part containing ring A in formula (1):

That's it

Audis and WHAT

And there is mostly (o) sus in! / A is where symbols other than ring A are as defined above.

Ring B is pyrazole.

Specific examples of pyrazole for ring B are

B

M

Hero -8VZ

Code, 2712Z6e: 1) 271 and 72 are nitrogen atoms and 77 is a carbon atom, or 2) 72 and 73 are nitrogen atoms and 7 is a carbon atom; K! and B? are as defined above, and these groups are substituted at any suitable position of the pyrazole ring.

The following part containing ring B in formula (1):

He r pu vh re 2 is especially 2

And sk

UAZ va p , mostly di ro dz v! in de pec y with 1 H 1. and I

Zoo ro Kk o 4 5 IM 4

M to y Mr K or to wai , more preferably tle myh

Which

KM I ra

М В where each symbol in the formula is as defined above.

In Her 22 each is, independently, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, or an acyl group.

B' is preferably (1) an optionally substituted C6 alkyl group (eg, methyl, 1,1-dimethylpropyl), (2) an optionally substituted C1-14 aryl group (eg, phenyl), or (3) an optional a necessarily substituted 5- or b-membered aromatic heterocyclic group (for example, pyridyl), more preferably

(1) C 1 -C alkyl group (e.g., methyl, 1,1-dimethylpropyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine), (p) C 1 -1" aryl group ( e.g., phenyl), and (c) a C 1 -C 4 alkoxy group (e.g., methoxy), (2) a C 1 -C 4 aryl group (e.g., phenyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine), (b) Civ alkyl group (e.g. methyl) optionally substituted 1 - With halogen atoms (e.g. fluorine), and (c) Civ alkoxy group (e.g. methoxy, ethoxy) optionally substituted 1 - With halogen atoms (e.g., fluorine), or (3) a 5- or b-membered aromatic heterocyclic group (e.g., pyridyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine ), (b) A lower alkyl group (e.g., methyl) optionally substituted 1 - With halogen atoms (e.g., fluorine), and (c) A lower alkyl group (e.g., methoxy) optionally substituted 1 - With halogen atoms (e.g. , ft or).

IN? is preferably (1) an optionally substituted C-6 alkyl group (for example, methyl, ethyl, t-butyl, n-propyl, isopropyl), (2) a hydroxy group substituted by an optionally substituted C-6 alkyl group, namely, an optionally substituted C 1 -alkyl group (e.g., methoxy, isopropoxy), or (3) an optionally substituted C 1 -10 cycloalkyl group (e.g., cyclopropyl, cyclohexyl), more preferably (1) a C 1 -6 alkyl group (e.g., methyl, ethyl, t- butyl, n-propyl, isopropyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine), (p) an aryl group (e.g., phenyl), (c ) C 1 -C 6 alkoxy group (e.g., methoxy), and (ad) 4-12 membered non-aromatic heterocyclic group (e.g., morpholino), (2) C 1 -C 6 alkoxy group (e.g., methoxy, isopropoxy) optionally substituted 1 - With substituents choosing with (a) a halogen atom (e.g., fluorine, chlorine), (p) a C 1-1 aryl group (e.g., phenyl), and (c) a C 1-6 alkoxy group (e.g., methoxy), or (3) a C 3-o cycloalkyl gr upa (for example, cyclopropyl, cyclohexyl).

BZ is an optionally substituted C-C alkyl group, an optionally substituted C-C cycloalkyl group, an optionally substituted C-C 4 aryl group, or an optionally substituted heterocyclic group. "Optionally substituted heterocyclic group" for KZ is preferably an optionally substituted 5- or β-linked heterocyclic group.

VI is preferably (1) an optionally substituted C. alkyl group (preferably a branched C. to C. alkyl group (for example, isopropyl, isobutyl, 1-ethylpropyl)), (2) an optionally substituted C.sub.3-o cycloalkyl group ( e.g., cyclopentyl, cyclohexyl), or (3) an optionally substituted 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl), more preferably (1) C 1 -C 6 alkyl (preferably branched C 1 -C 6 alkyl (eg, isopropyl, isobutyl, 1-ethylpropyl)) is optionally substituted 1 - With substituents selected from (a) C 1 -C 6 alkoxy (eg, methoxy, ethoxy, propoxy) optionally replaced by 1

- C 1 -C 6 alkoxy groups (e.g. methoxy), (p) C 1 -C 4 aryloxy group (e.g. phenyloxy), (c) C 7 -C 6 -aralkyloxy group (e.g. benzyloxy), (a) amino group optionally mono- or di-substituted with C -.is an alkyl group (e.g., methyl), (e) a 4-12-membered non-aromatic heterocyclic group (e.g., piperidyl, morpholinyl), (I) a C-alkylsulfonyl group (e.g., methylsulfonyl, isopropylsulfonyl), and (9) Sv -a4 arylsulfonyl group (e.g., benzenesulfonyl), (2) C3-0 cycloalkyl group (e.g., cyclohexyl), or (3) 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1 ,1-dioxidotetrahydrothiopyranyl) optionally substituted with 1-C С-4 aryl groups (for example, phenyl).

B" is a hydrogen atom or C.. is an alkyl group.

B" is mainly a hydrogen atom.

B: there is a group represented by -(СНg)3-СООВ" or -МНАУ-СВ/НЗ-СВАА"-СООВ", where P, B", U,

In KE" each is, independently, a hydrogen atom or C.. is an alkyl group, and BO is a hydrogen atom, a C--6 alkyl group or a hydroxy group.

A: there is mainly a hydrogen atom or a methyl atom, more preferably a hydrogen atom.

B' is mainly a hydrogen atom.

IN? is mainly a hydrogen atom.

VE? is preferably a hydrogen atom, methyl or ethyl, more preferably a hydrogen atom.

B" is preferably a hydrogen atom, methyl or ethyl, more preferably a hydrogen atom.

B" is preferably a hydrogen atom, methyl or ethyl, more preferably a hydrogen atom.

IN? are mainly -UAU-SV'NU-SVV-SOOV.

Among the compounds (I), the preferred compound is where

IN! is an optionally substituted C-4 alkyl group, an optionally substituted C-4 aryl group or an optionally substituted 5- or b-membered aromatic heterocyclic group;

IN? is an optionally substituted C1-6 alkyl group, an optionally substituted C1-6 alkyl group or an optionally substituted C3-0 cycloalkyl group;

BZ is an optionally substituted C6 alkyl group, an optionally substituted C3-0 cycloalkyl group, or an optionally substituted 5- or 6-membered heterocyclic group;

B" is a hydrogen atom;

IN? is -"СН2г)з3-СООВ" or -МАУ-СНоАСАВЗ-СООВ;

Be is a hydrogen atom or methyl;

VE? is a hydrogen atom, methyl or ethyl;

B" is a hydrogen atom, methyl or ethyl; and

B" is a hydrogen atom, methyl or ethyl.

When ring A is a benzene ring or a b-membered aromatic heterocycle, particularly preferred examples of formula (I) are the following formulas (1), (17 1 (17) o (c) (9) v3 su" d3 su va su

M Ii same Mtv: or -- and where each symbol other than ring A is as defined above; the compound represented by the above formulas (1, (17 1 (17)) and their salts is covered by compound (1).

Formula (I) is more preferably formula (I).

Preferable examples of compound (I) are the following compounds. (compound A)

In formula (I), a compound where ring A is a benzene ring or a 5- or b-membered aromatic heterocycle (preferably pyridine); ring B is pyrazole;

Vie (1) an optionally substituted C. alkyl group (for example, methyl, 1,1-dimethylpropyl),

(2) an optionally substituted Ce-14 aryl group (eg, phenyl), or (3) an optionally substituted 5- or b-membered aromatic heterocyclic group (eg, pyridyl);

Ve is (1) an optionally substituted C. alkyl group (eg, methyl, ethyl, t-butyl, n-propyl, isopropyl), (2) an optionally substituted C:.6 alkoxy group (eg, methoxy, isopropoxy) , or (3) an optionally substituted C3-0 cycloalkyl group (for example, cyclohexyl);

VE is (1) an optionally substituted C-C alkyl group (preferably a branched C-C alkyl group (e.g., isopropyl, isobutyl, 1-ethylpropyl)), (2) an optionally substituted C-C10 cycloalkyl group (e.g., cyclopropyl , cyclohexyl), or (3) an optionally substituted 5- or b-membered heterocyclic group (eg, pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl);

B" is a hydrogen atom; and

IN? is -(CH2g)z3-COOV" or -MAU-(CHg)2-COOV" (preferably -MAY-(CHg)»-COOV") where KE is a hydrogen atom or methyl (preferably a hydrogen atom), and

A" is a hydrogen atom, methyl or ethyl (mostly, a hydrogen atom); or its salt (compound A-1)

A compound of formula (I), which is a compound of formula (I) or (I") (preferably, formula (I), where ring A is a benzene ring or a b-membered aromatic heterocycle (for example, pyridine);

A is (1) C 1 alkyl group (e.g. methyl, 1,1-dimethylpropyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g. fluorine), (p) C-l" an aryl group (e.g., phenyl), and (c) a C 1 -C 6 alkoxy group (e.g., methoxy), (2) a C 1 -a 4 aryl group (e.g., phenyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine), (b) Civ alkyl group (e.g., methyl) optionally substituted 1 - With halogen atoms (e.g., fluorine), and (c) Civ alkyl group (e.g., methoxy) optionally substituted 1 - With halogen atoms (eg, fluorine), or (3) a 5- or b-membered aromatic heterocyclic group (eg, pyridyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (eg, fluorine, chlorine), (B) a C:1-C alkyl group (e.g., methyl) optionally substituted by 1 - With halogen atoms (e.g., fluorine), and (c) a C:1-C 6-alkyl group (e.g., methoxy) optionally substituted by 1 - With halogen atoms (for example, ft or);

B is (1) Civ alkyl group (e.g., methyl, ethyl, t-butyl, n-propyl, isopropyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine), (p) C 1 -C 1 aryl (e.g. phenyl), and (c) C 1 -C 6 alkoxy (e.g. methoxy), (2) C 1 -C 6 alkoxy (e.g. methoxy, isopropoxy) optionally substituted 1 - With substituents selected with (a) a halogen atom (e.g., fluorine, chlorine), (p) a C 1-6 aryl group (e.g., phenyl), and (c) a C 1-6 alkoxy group (e.g., methoxy), or

(3) C3-O cycloalkyl group (for example, cyclopropyl, cyclohexyl);

VE is (1) a C 1 -C 6 alkyl group (preferably a branched C 1 -C 6 alkyl group (e.g., isobutyl, 1-ethylpropyl)) optionally substituted with 1 - With substituents selected from (a) C 1 -C 6 alkyl (e.g., methoxy, ethoxy , propoxy) optionally substituted with 1-C 6 alkyloxy groups (e.g. methoxy), (p) C 1-14 aryloxy group (e.g. phenyloxy), (c) C 7-2 aralkyloxy group (e.g. benzyloxy), (a) amino group is optional necessarily mono- or di-substituted C-.is an alkyl group (e.g. methyl), (c) a 4-12-membered non-aromatic heterocyclic group (e.g. piperidyl, morpholinyl), (I) a C-alkylsulfonyl group (e.g. methylsulfonyl, isopropylsulfonyl), and (9) a C1-a4 arylsulfonyl group (e.g., benzenesulfonyl), (2) a C3-0 cycloalkyl group (e.g., cyclohexyl), or (3) a 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl , tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl) optionally substituted 1 - With Св-4 aryl groups (for example lad, phenyl);

B" is a hydrogen atom; and

In is -"CHg)zZ-COOH or -MAZ-(CHg)2-COOH, preferably -MAU(CHg)2-COOH where EE? there is a hydrogen atom or a methyl (predominantly a hydrogen atom)); or its salt. (compound A-2)

A compound of formula (I), which is a compound of formula (I), (I") or (I") (preferably, formula (GU, where ring A is a benzene ring or a b-membered aromatic heterocycle (for example, pyridine);

Vie (1) C 1 alkyl group (e.g., methyl, 1,1-dimethylpropyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine), (p) C-l" an aryl group (e.g., phenyl), and (c) a C 1 -C 6 alkoxy group (e.g., methoxy), (2) a C 1 -a 4 aryl group (e.g., phenyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine), (b) Lower alkyl group (e.g., methyl) optionally substituted 1 - With halogen atoms (e.g., fluorine), and (c) Lower alkyl group (e.g., methoxy, ethoxy) optionally substituted 1 - With halogen atoms (eg, fluorine), or (3) a 5- or b-membered aromatic heterocyclic group (eg, pyridyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (eg, fluorine, chlorine), (b) Gray alkyl group (for example, methyl) optionally substituted 1 - With halogen atoms (for example, fluorine) and (c) Gray alkoxy group (for example, methoxy) optionally substituted 1 - With halogen atoms (example, fluorine);

B is (1) Civ alkyl group (e.g., methyl, ethyl, t-butyl, n-propyl, isopropyl) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine), (p) C 1-6 aryl group (e.g., phenyl), (c) C 1-6 alkoxy group (e.g., methoxy), and (ad) 4-12 membered non-aromatic heterocyclic group (e.g., morpholino) (2) C 1-6 alkoxy group (e.g. , methoxy, isopropoxy) optionally substituted 1 - With substituents selected from (a) a halogen atom (e.g., fluorine, chlorine), (p) C1-1" aryl group (e.g., phenyl), and (c) Si -C 1 -C 6 oxy group (for example, methoxy), or (3) C3-0 cycloalkyl group (for example, cyclopropyl, cyclohexyl);

BE is (1) C 1 -C 6 alkyl (preferably a branched C 6 alkyl group (eg, isobutyl, 1-ethylpropyl)) optionally substituted with 1 - With substituents selected from (a) C 1 -C 6 oxy (eg, methoxy, ethoxy , propoxy) optionally substituted with 1-C 6 alkyloxy groups (e.g. methoxy), (p) C 1-14 aryloxy group (e.g. phenyloxy), (c) C 7-2 aralkyloxy group (e.g. benzyloxy), (a) amino group is optional necessarily mono- or di-substituted C-.is an alkyl group (for example, methyl), (ev) a 4-12-linked non-aromatic heterocyclic group (for example, piperidyl, morpholinyl), (I) a C-alkylsulfonyl group (for example, methylsulfonyl, isopropylsulfonyl), and (9) a C1-a4 arylsulfonyl group (e.g., benzenesulfonyl), (2) a C3-0 cycloalkyl group (e.g., cyclohexyl), or (3) a 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl , tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl) optionally substituted 1 - C Св-4 aryl groups (for example clade, phenyl);

B" is a hydrogen atom; and

B is -(CHg)-СООВ" or -МАУ-СН»-СВВ'-СООВ', preferably -МА-СНоСВВО- сооВв" where KE is a hydrogen atom or methyl (mostly, a hydrogen atom),

B" is a hydrogen atom, methyl or ethyl (mostly, a hydrogen atom),

B" is a hydrogen atom, methyl or ethyl (mostly, a hydrogen atom),

A" is a hydrogen atom, methyl or ethyl (preferably, a hydrogen atom); or its salt. (compound A-3) 3-II(4-Ccyclohexyl(3-methyl-1-15-(trifluoromethyl)pyridin-2-yl |-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid or its salt (Example 1); 3-D4-Hcyclohexyl(|1-(3-methoxyphenyl)-3-methyl- 1H-pyrazol-4-yl|methyl)amino)phenyl(carbonylmethyl)amino|propanoic acid or its salt (Example 70); or 3-D4-Hcyclohexyl(|1-(3-methoxyphenyl)-4-methyl-1H-pyrazole -3-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid or its salt (Example 76).

Compound (IA) is disclosed further.

The AA ring is an optionally substituted benzene ring or an optionally substituted 5- or b-membered aromatic heterocycle. The 5- or b-membered aromatic heterocycle for the AA ring is preferably pyridine. "Benzene ring" or "5- or b-membered aromatic heterocycle" "optionally substituted benzene ring or optionally substituted 5- or b-membered aromatic heterocycle" for the AA ring optionally additionally has 1 to 4 substituents in a suitable to the replacement of position(s) except "-MA- group" and 4СО-В» group".

The AA ring is preferably a benzene ring or a 5- or b-membered aromatic heterocycle (e.g., pyridine), more preferably a benzene ring or a b-membered aromatic heterocycle (e.g., pyridine), especially preferably a benzene ring that has no substituents other than " -MV"- groups" and -СО-В: groups".

When the AA ring is a benzene ring or a b-membered aromatic heterocycle, the next portion containing the AA ring in formula (IA)

o s AB /

She la is mainly Fr

KO

M dm where every symbol other than the AA ring is as defined above.

The AB ring is an optionally substituted 5-membered aromatic heterocycle.

The β-membered aromatic heterocycle for the AB ring is preferably pyrrole, thiophene, furan, imidazole or pyrazole. The "B-membered aromatic heterocycle" of the "optionally substituted 5-membered aromatic heterocycle" for the AB ring optionally additionally has 1 or 2 substituents in the suitable position(s) for substitution other than the -CH(BZ)- group."

Ring AB is preferably a 5-membered aromatic heterocycle (e.g., pyrrole, thiophene, furan, imidazole, pyrazole, pyrrole) optionally substituted 1 - With substituents selected from (a) Civ alkyl group (e.g., methyl, ethyl ) optionally substituted 1 - With substituents selected from C 1 -C 6 alkoxy groups (for example, »methoxy, ethoxy) optionally substituted 1 - With C:.6 alkoxy groups (for example, methoxy), (p) C 3 -C cycloalkyl group ( e.g., cyclohexyl), (c) C14 aryl group (e.g., phenyl), optionally having 1-C C alkyl groups (e.g., methyl) optionally substituted with 1-C halogen atoms (e.g., fluorine), (a ) a cyano group, (e) a C 1 - 6 alkoxy group (e.g., methoxy), and (I) a halogen atom (e.g., a bromine atom).

The AC ring is an optionally substituted benzene ring or an optionally substituted 5- or b-membered aromatic heterocycle. The 5- or b-membered aromatic heterocycle for the AC ring is mainly pyridine. "Benzene ring" or "5- or b-membered aromatic heterocycle" "optionally substituted benzene ring or optionally substituted 5- or b-membered aromatic heterocycle" for ring AC optionally additionally has 1 to 4 substituents in a suitable to replace position(s).

The AC ring is preferably (1) a benzene ring optionally substituted with 1 - With substituents selected from (a) C, an alkyl group (e.g., methyl, ethyl) optionally substituted 1 - With halogen atoms (e.g., fluorine), ( p) a C3-O cycloalkyl group (for example, cyclopropyl, cyclohexyl), (c) a C 1 -C 6 alkoxy group (for example, methoxy, ethoxy, propoxy, isobutoxy) optionally substituted 1 - With substituents selected from (i) a C 1 , methoxy), (i) A fresh cycloalkyl group (for example, cyclopropyl), (ii) a 4-12-ene aromatic heterocyclic group (for example, oxazolyl, isoxazolyl, pyridyl) optionally substituted

(His) a halogen atom (e.g., fluorine, chlorine), and (i) a lower alkyl group (e.g., methyl), (m) a 4-12-ene non-aromatic heterocyclic group (e.g., oxetanyl, tetrahydrofuryl) optionally substituted 1 - With C 1 -C alkyl groups (e.g. methyl), (m) C 1 alkylsulfonyl group (e.g. methylsulfonyl), (mi) C 1 -C alkylthio group (e.g. methylthio), and (mi) hydroxy group, (8) halogen atom (e.g. fluorine, chlorine), (e) C7-iz aralkyloxy group (for example, benzyloxy), () 4-12-membered non-aromatic heterocyclyloxy group (for example, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, 1,1-dioxidotetrahydrothiopyranyloxy), (9) 4- A 12-membered aromatic heterocyclyloxy group (e.g., pyridyloxy) optionally substituted 1 - With substituents selected from () Siv alkyl group (e.g., methyl) optionally substituted 1 - With halogen atoms (e.g., fluorine), and (ii) a cyano group, (n) a C-a" aryl group (e.g., phenyl), () a 4-12 membered aromatic heterocyclic group (e.g., oxazolyl, isoxazolyl, pyrazolyl, pyridyl) optionally substituted 1 - With substituents selected from (I) a C 1 alkyl group (for example, methyl) and (its) a C 1 alkyl group (e.g. methoxy), () 4-12-h- linoleic non-aromatic heterocyclic group (e.g., morpholino, thiomorpholino), (k) C7- aralkyl group (e.g., benzyl), (I) cyano group, (t) amino group optionally mono- or di-substituted by substituent(s) that selected from () Civ alkyl group (for example, methyl, ethyl) optionally substituted with 1 - C Civ alkoxy groups (for example, methoxy), (its) Civ alkyl-carbonyl group (for example, acetyl), (iii) Civ alkylsulfonyl group ( e.g., methylsulfonyl), (m) carbomoyl group optionally mono- or di-substituted by a C--6 alkyl group (e.g., ethyl), (m) C-a aryl-carbonyl group (e.g., benzoyl), (mi) Sela arylsulfonyl group (eg, benzenesulfonyl), and (m) C7z aralkyl group (eg, benzyl), and (n) C1-4 arylsulfonyl group (eg, benzenesulfonyl), or (2) 5- or b-membered nth aromatic heterocycle (e.g., pyridine) optionally substituted 1 - With substituents selected from (a) Si alkyl group (e.g., methyl, ethyl) optionally substituted 1 - With halogen atoms (e.g., fluorine), (p ) a C 3-0 cycloalkyl group (e.g. cyclohexyl), (c) a C 1 -C 6 alkoxy group (e.g. methoxy, ethoxy) optionally substituted 1 - With substituents selected from () a C 1 -C 6 alkoxy group (e.g. methoxy), and (i) A fresh cycloalkyl group (e.g., cyclopropyl), (ad) a halogen atom (e.g., fluorine, chlorine, bromine), (e) a C7- aralkyloxy group (e.g., benzyloxy), and () a 4- to 12-membered non-aromatic heterocyclyl- an oxy group (for example, tetrahydropyraniloxes).

In formula (IA), the moiety represented is a group derived from a bicyclic ring formed by ring AB and ring AC having one common side in each ring (ie, fused). Here, the side of the ring AB and the side of the ring AC included in the formation of the bicyclic ring are connected with the same multiplicity.

For example, when, in formula (IA), the moiety represented is a group represented by and 2 , ring AB is "pyrazole" and ring AC is "benzene".

In the condensed ring formed by the AC ring and the AB ring, the "-CH(B"Z)- group" is present at any attached position on the AB ring.

BZ is an optionally substituted C-C alkyl group, an optionally substituted C-C cycloalkyl group, an optionally substituted C-C 4 aryl group, or an optionally substituted heterocyclic group. "Optionally substituted heterocyclic group" for KZ is preferably an optionally substituted 5- or b--heterocyclic group.

BZ is mainly (1) an optionally substituted C-C alkyl group (preferably a branched C-C alkyl group (for example, isopropyl, isobutyl, 1-ethylpropyl)), (2) an optionally substituted C3-O cycloalkyl group ( e.g., cyclopentyl, cyclohexyl), or (3) an optionally substituted 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl), more preferably (1) Lower alkyl group (predominantly, methyl, ethyl, butyl, hexyl, branched Lower alkyl group (for example, isopropyl, isobutyl, 1-ethylpropyl)) optionally substituted 1 -

With substituents selected from (a) C 1-6 alkoxy (e.g., methoxy, ethoxy, propoxy) optionally substituted with 1-C 6 alkoxy (e.g., methoxy), (p) C 1-4 aryloxy (e.g., phenyloxy), (c) C7-is aralkyloxy group (for example, benzyloxy), (a) amino group is optionally mono- or di-substituted by a C-.is alkyl group (for example, methyl), (ev) 4-12-ene non-aromatic heterocyclic group (e.g., piperidyl, morpholinyl), (I) C 1 -C alkylsulfonyl group (e.g., methylsulfonyl, isopropylsulfonyl), (9) C 1-4 arylsulfonyl group (e.g., benzenesulfonyl), and (n) C.C alkylthio group (e.g., methylthio),

(2) C3-O cycloalkyl group (e.g., cyclopentyl, cyclohexyl), (3) 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl) optionally substituted 1 - With C1-4 aryl groups (eg, phenyl), or (4) C1-4 aryl (eg, phenyl).

A" is a hydrogen atom or C. is an alkyl group.

B" is mainly a hydrogen atom.

In there is a group represented by -(СНг)--SOOVA" or -MAR-SvВ'A VA SV -SOOVY", where

В, ВА, В, дя Her KA" are each, independently, a hydrogen atom or Si. is an alkyl group, and KA is a hydrogen atom, C..-v is an alkyl group or a hydroxy group.

Be is preferably a hydrogen atom or methyl, more preferably a hydrogen atom.

B" is mainly a hydrogen atom.

VU is mainly a hydrogen atom.

IN? is mainly a hydrogen atom.

BA is mainly a hydrogen atom.

BA" is preferably a hydrogen atom, methyl or ethyl, more preferably a hydrogen atom.

IN? are mainly -"MA"-SVAVA-SsvVyady SOVA",

When the AA ring is a benzene ring or a β-ene aromatic heterocycle, particularly preferred examples of formula (I) are the following formula (IA") (6)

AA

Sv) m PA) (where each symbol other than ring AA is as defined above).

The compound represented by the above-mentioned formula (IA) and its salt are covered by the compound (IA).

Among the compounds represented by the above-mentioned formula (IA"), compound de is preferred

BZ is an optionally substituted C 1 -alkyl group, an optionally substituted C 1 -cycloalkyl group, or an optionally substituted 5- or 6-membered heterocyclic group;

B" is a hydrogen atom;

And is -""CHg2)3-SOOVA" or -MA"E-(CH2g)"-SOOVA;

Be is a hydrogen atom or methyl; and

BA" is a hydrogen atom, methyl or ethyl.

Preferred examples of compound (IA) are the following compounds. (compound AA)

In formula (IA), the compound where the AA ring is a benzene ring or a 5- or b-membered aromatic heterocycle (for example, pyridine); ring AB is an optionally substituted 5-membered aromatic heterocycle (for example, pyrrole, thiophene, furan, imidazole, pyrazole); the AC ring is an optionally substituted benzene ring or an optionally substituted 5- or b-membered aromatic heterocycle (for example, pyridine);

B is (1) an optionally substituted C-C alkyl group (preferably a branched C-C alkyl group (for example, isopropyl, isobutyl, 1-ethylpropyl)), (2) an optionally substituted C3-O cycloalkyl group (for example , cyclohexyl), or (3) an optionally substituted 5- or b-membered heterocyclic group (eg, pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl);

B" is a hydrogen atom; and

Be is -CHg)z--SOOVA" or -MA"E(CH2)".-SOOVY", preferably -MA"U(CHg)"-i-SOOVA" where VK" is a hydrogen atom or a methyl hydrogen),

BA" is a hydrogen atom, methyl or ethyl (mostly, a hydrogen atom); or its salt (compound AA-1)

A compound of formula (IA), which is a compound of formula (IA), wherein ring AA is a benzene ring or a b-membered aromatic heterocycle (eg, pyridine); ring AB is a 5-membered aromatic heterocycle (for example, thiophene, furan, imidazole, pyrazole) optionally substituted with 1 - With substituents selected from (a) C-C alkyl group (for example, methyl, ethyl), ( p) a C3-0 cycloalkyl group (for example, cyclohexyl), and (c) a C3-6 aryl group (for example, phenyl); ring AC is (1) benzene ring optionally substituted 1 - With substituents selected from (a) Civ alkyl group (e.g. methyl) optionally substituted 1 - With halogen atoms (e.g. fluorine), (p) Cz -o cycloalkyl group (e.g., cyclohexyl), (c) C 1-6 alkoxy group (e.g., methoxy), and (8) a halogen atom (e.g., fluorine), or (2) a 5- or b-membered aromatic heterocycle (e.g., pyridine) optionally substituted 1 - With substituents selected from (a) C 1 -C 1 alkyl group (e.g. methyl) optionally substituted 1 - With halogen atoms (e.g. fluorine), (p) C 3-0 cycloalkyl group (e.g. cyclohexyl ), (c) a C 1 - 6 alkoxy group (e.g., methoxy), and (a) a halogen atom (e.g., fluorine); ve is (1) a C 1 -C 6 alkyl group (preferably a branched C 1 -C 6 alkyl group (e.g., isobutyl, 1-ethylpropyl)) optionally substituted with 1 - With substituents selected from (a) C 1 -C 6 alkoxy (e.g., methoxy, ethoxy , propoxy) optionally substituted with 1-C 6 alkyloxy groups (e.g. methoxy), (p) C 1-14 aryloxy group (e.g. phenyloxy), (c) C 7-2 aralkyloxy group (e.g. benzyloxy), (a) amino group is optional necessarily mono- or di-substituted C-.is an alkyl group (e.g. methyl), (c) a 4-12-membered non-aromatic heterocyclic group (e.g. piperidyl, morpholinyl), (I) a C-alkylsulfonyl group (e.g. methylsulfonyl, isopropylsulfonyl), and (9) a C1-a4 arylsulfonyl group (e.g., benzenesulfonyl), (2) a C3-0 cycloalkyl group (e.g., cyclohexyl), or (3) a 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl) optionally substituted 1 - C Св-4 aryl groups (for example lad, phenyl);

B" is a hydrogen atom; and

B is -(CHg)z-COOH or -MA"9-(CHg)"-COOH, preferably -MA"9-(CH").-COOH where K"5 is a hydrogen atom or methyl (mostly, a hydrogen atom) or its salt (compound AA-2)

A compound of formula (IA), which is a compound of formula (IA), wherein ring AA is a benzene ring or a b-membered aromatic heterocycle (eg, pyridine); ring AB is a 5-membered aromatic heterocycle (e.g., thiophene, furan, imidazole, pyrazole) optionally substituted 1 - With substituents selected from (a) C6 alkyl group (e.g., methyl, ethyl) optionally substituted 1 - C 1 -C 6 alkoxy groups (e.g., methoxy), (p) C 3-0 cycloalkyl group (e.g., cyclohexyl), and (c) C 1-1a" aryl group (e.g., phenyl); ring AC is (1) benzene ring optionally substituted 1 - With substituents selected from (a) Civ alkyl group (e.g. methyl) optionally substituted 1 - With halogen atoms (e.g. fluorine), (p) Cz -o cycloalkyl group (e.g., cyclohexyl), (c) C 1 -C 6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted 1 - With substituents selected from () C 1 -C 6 alkoxy group (e.g., methoxy), and (i) C 1 -C 6 cycloalkyl group (e.g., cyclopropyl), (a) a halogen atom (e.g., fluorine), (e) a C7-alkyloxy group (e.g., benzyloxy), and (a) a 4- to 12-membered non-aromatic heterocyclyloxy group (e.g., tetrahydropyranyloxy) . (e.g., fluorine), (p) C 3-0 cycloalkyl group (e.g., cyclohexyl), (c) C 1-6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted 1 - With substituents selected from () C 1 -C 6 alkoxy (e.g. methoxy) and (i) C 1 -C 4 cycloalkyl (e.g. cyclopropyl) for example, benzyloxy), and () a 4-12-membered non-aromatic heterocyclyloxy group (for example, tetrahydropyranyloxy); ve is (1) a C 1 -C 6 alkyl group (preferably a branched C 1 -C 6 alkyl group (eg, isopropyl, isobutyl, 1-ethylpropyl)) optionally substituted 1 - With substituents selected from (a) a C 1 -C 6 alkoxy group (eg, methoxy . an optionally mono- or di-substituted C-.is alkyl group (e.g., methyl), (e) a 4-12-membered non-aromatic heterocyclic group (e.g., piperidyl, morpholinyl), (I) a C-alkylsulfonyl group (e.g., methylsulfonyl, isopropylsulfonyl), and (9) a C1-a4 arylsulfonyl group (e.g., benzenesulfonyl), (2) a C3-0 cycloalkyl group (e.g., cyclopentyl, cyclohexyl), or (3) a 5- or b-membered heterocyclic group (e.g. , pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl) optionally substituted 1 - With Sv-4 ar yl groups (for example, phenyl);

B" is a hydrogen atom; and

Be is -CHg)z--SOOVA" or -MA"E(CH2)".-SOOVY", preferably -MA"U(CHg)"-i-SOOVA" where EC" is a hydrogen atom or a methyl hydrogen), and KA" is a hydrogen atom, methyl or ethyl (mostly, a hydrogen atom)); or its salt. (compound AA-3)

A compound of formula (IA), which is a compound of formula (IA), wherein ring AA is a benzene ring or a b-membered aromatic heterocycle (eg, pyridine);

ring AB is a 5-membered aromatic heterocycle (eg, pyrrole, thiophene, furan, imidazole, pyrazole, pyrrole) optionally substituted with 1 - With substituents selected from

(a) C 1 -C alkyl group (e.g. methyl, ethyl) optionally substituted 1 - With substituents selected from C 1 -C 6 alkoxy groups (e.g. "methoxy, ethoxy) optionally substituted 1 - C 1 -C 6 alkoxy groups (e.g. methoxy)

(p) C3-O cycloalkyl group (for example, cyclohexyl),

(c) C14 aryl group (e.g., phenyl) optionally having 1-C Ci alkyl groups (e.g., methyl) optionally substituted with 1-C halogen atoms (e.g., fluorine),

(a) cyano group,

(e) C 6 alkoxy group (for example, methoxy), i

(And a halogen atom (for example, a bromine atom);

is a ring of AC

(1) benzene ring optionally substituted 1 - With substituents selected from

(a) Si alkyl group (e.g. methyl) optionally substituted 1 - With halogen atoms (e.g. fluorine),

(p) C3-O cycloalkyl group (for example, cyclopropyl, cyclohexyl),

(c) A C 1 -C 6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isobutoxy) is optionally substituted 1 - With substituents selected from

(i) C 1 - alkoxy group (e.g., methoxy),

(i) Fresh cycloalkyl group (for example, cyclopropyl),

(iii) 4-12-ene aromatic heterocyclic group (for example, oxazolyl, isoxazolyl, pyridyl) optionally substituted 1 - With substituents selected from

(Her) halogen atom (for example, fluorine, chlorine), and

(i) An alkyl group (e.g. methyl),

(m) a 4- to 12-membered non-aromatic heterocyclic group (for example, oxetanyl, tetrahydrofuryl) optionally substituted with 1-C alkyl groups (for example, methyl),

(m) Civ alkylsulfonyl group (for example, methylsulfonyl),

(mi) C3-C alkylthio group (for example, methylthio), i

(my) hydroxy group,

(a) a halogen atom (for example, fluorine, chlorine),

(e) C7-iz aralkyloxy group (for example, benzyloxy),

() 4-12-membered non-aromatic heterocyclyl-oxy group (for example, tetrahydropyraniloxes, tetrahydrothiopyraniloxes, 1,1-dioxidotetrahydrothiopyraniloxes),

(9) 4-12-ene aromatic heterocyclyloxy group (e.g., pyridyloxy) optionally substituted 1 - With substituents selected from

() Siv alkyl group (for example, methyl) optionally substituted 1 - With halogen atoms (for example, fluorine), and

(iii) cyano group,

(n) C-a" aryl group (for example, phenyl),

() 4-12 membered aromatic heterocyclic group (eg, oxazolyl, isoxazolyl, pyrazolyl, pyridyl) optionally substituted 1 - With substituents selected from

(I) Siv alkyl group (for example, methyl), and

(its) Si alkoxy group (for example, methoxy),

() 4-12-membered non-aromatic heterocyclic group (for example, morpholino, thiomorpholino),

(k) a C7-aralkyl group (e.g., benzyl),

(I) cyano group,

(t) the amino group is optionally mono- or di-substituted with a substituent(s) selected from

() C 1 -C alkyl group (for example, methyl, ethyl) is optionally substituted with 1 - C 1 C 6 alkoxy groups (e.g., methoxy),

(its) Siv alkyl-carbonyl group (for example, acetyl),

(ii) Civ alkylsulfonyl group (for example, methylsulfonyl),

(m) the carbomoyl group is optionally mono- or di-substituted by a C-6 alkyl group (for example, ethyl),

(m) C-a aryl carbonyl group (e.g., benzoyl), (mi) C-6 arylsulfonyl group (e.g., benzenesulfonyl), and (mi) C 73 aralkyl group (e.g., benzyl), and (n) C-4 arylsulfonyl group (e.g., benzenesulfonyl), or (2) a 5- or b-membered aromatic heterocycle (e.g., pyridine) optionally substituted 1 - With substituents selected from (a) a C6 alkyl group (e.g., methyl) optionally substituted 1 - With halogen atoms (for example, fluorine), (p) C3-0 cycloalkyl group (for example, cyclohexyl), (c) C6-alkyl group (for example, methoxy, ethoxy) optionally substituted 1 - With substituents selected from ( ) a C 1 -C 6 alkoxy group (for example, methoxy), and (i) a C 1 C -cycloalkyl group (for example, cyclopropyl), (ad) a halogen atom (for example, fluorine, chlorine, bromine), (e) a C7-C aralkyloxy group (for example, benzyloxy), and () a 4- to 12-membered non-aromatic heterocyclyloxy group (eg, tetrahydropyranilox);

B is (1) C-C alkyl group (predominantly methyl, ethyl, butyl, hexyl, branched C-C alkyl group (for example, isopropyl, isobutyl, 1-ethylpropyl)) optionally substituted with 1 -

With substituents selected from (a) C 1-6 alkoxy (e.g., methoxy, ethoxy, propoxy) optionally substituted with 1-C 6 alkoxy (e.g., methoxy), (p) C 1-4 aryloxy (e.g., phenyloxy), (c) C7-is aralkyloxy group (for example, benzyloxy), (a) amino group is optionally mono- or di-substituted by a C-.is alkyl group (for example, methyl), (ev) 4-12-ene non-aromatic heterocyclic group (e.g., piperidyl, morpholinyl), (I) C 1 -C alkylsulfonyl group (e.g., methylsulfonyl, isopropylsulfonyl), (9) C 1-4 arylsulfonyl group (e.g., benzenesulfonyl), and (n) C.C alkylthio group (e.g., methylthio), (2) C3-O cycloalkyl group (e.g., cyclopentyl, cyclohexyl), (3) 5- or b-membered heterocyclic group (e.g., pyridyl, piperidyl, tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl) optionally substituted 1 - With C1-4 aryl groups (eg, phenyl), or (4) C1-4 aryl (eg, phenyl);

B" is a hydrogen atom; and

Be is -(CHg)z--SOOVA" or -MA"E(CH2)»-SOOVA", preferably -MA"9-(CHg)--SOOVA" where EC" is a hydrogen atom or a methyl (mostly, hydrogen), and KA" is a hydrogen atom, methyl or ethyl (mostly, a hydrogen atom); or its salt. (compound AA-4) 3-((4-(Cyclohexyl(3-methyl-1-benzofuran-2-yl) )umethylamino)phenyl)carbonyl|(methyl)amino)propanoic acid or its salt (Example A41); 3-1(6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl)amino )pyridin-3-yl)ucarbonyl(methyl)amino)propanoic acid or its salt (Example ABZ); 3-4(4-(2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran- 2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid or its salt (Example A?73); 3-Х4-(11-(-(cyclopropylmethoxy)-3-methyl-1-benzofuran- 2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|Ipropanoic acid or its salt (Example

A78); or 3-((4-(H-Cyclohexyl3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid or its salt (Example A83 ).

As salts of compounds (I) or (IA), pharmacologically acceptable salts are preferred. Examples of such a salt are a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc.

Preferred examples of salts with an inorganic base are alkali metal salts such as sodium salt, potassium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., aluminum, ammonium salt, etc.

Preferred examples of salts with an organic base are salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine (gris(hydroxymethyl)methylamine, tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, M,M-dibenzylethylenediamine, etc. .

Preferred examples of salts with an inorganic acid are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

Preferred examples of organic acid salts are salts 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, etc.

Preferred examples of salts with a basic amino acid are salts with arginine, lysine, ornithine, etc.

Preferred examples of salts with an acidic amino acid are salts with aspartic acid, glutamic acid, etc.

Examples of the prodrug form of compound (I) and compound (IA) are a compound where the amino group of compound (I) and compound (IA) is acylated, alkylated or phosphorylated (for example, a compound where the amino group of compound (I) and compound (IA) is substituted eicosanoyl, alanyl, pentylaminocarbonyl (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl, etc.); a compound where the hydroxy group of compound (I) and compound (IA) is acylated, alkylated, phosphorylated or boronated (for example, a compound where the hydroxy group of compound (I) and compound (IA) is substituted with acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl , alanyl or dimethylaminomethylcarbonyl); and a compound where the carboxyl group of compound (I) and compound (IA) is esterified or amidated (for example, a compound where the carboxyl group of compound (I) and compound (IA) is substituted with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester, cyclohexyloxycarbonylethyl ester or methylamide); etc. Any of these compounds can be obtained from compound (I) and compound (IA) by a method known directly.

The prodrug form of compound (I) and compound (IA) may also be a compound that is converted to compound (I) and compound (IA) under physiological conditions such as those described in

HMAKINIM po KAINATEM, Oemeiyurtepi oi RNaptaseciisaie, Mo. 7, Oevidp oi MoiIesshiev, pp. 163-198, Published by NIKOKAMUMUA ZNOTEM, 1990.

Compounds (I) and (IA) and their prodrugs (further in the present description sometimes collectively referred to as "compound of the present invention") include stereoisomers such as cis, trans isomer, etc., optically active forms such as racemate, K compound and 5 compound, etc. Depending on the type of ring, such as ring A, etc., isomers may be formed due to conformation, and such isomers are also included in the compound of the present invention.

The compound of the present invention can be labeled with an isotope (for example, "H, UN, "C, 355, 1251) and the like. A compound of the present invention may be a hydrate, non-hydrate, solvate or non-solvate.

The compound of the present invention exhibits low toxicity and can be used as a pharmaceutical agent as such or as a pharmaceutical composition in admixture with generally known pharmaceutically acceptable carriers, etc. for the prevention or treatment of various diseases mentioned below in mammals (eg humans, horses, cows, dogs, cats, rats, mice, rabbits, pigs, monkeys, etc.).

Here, examples of a pharmacologically acceptable carrier are various organic or inorganic carrier substances commonly used as formulation materials that are added as an excipient, lubricant, binding agent, or disintegrant for solid dosage forms; as a solvent, solubilizing agent, suspending agent, isotonic agent, buffer or soothing agent for liquid formulation, etc. When necessary, formulation additives such as preservative, antioxidant, colorant, sweetener, etc. can be used.

Preferred examples of excipients are lactose, sucrose, U-mannitol, O-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.

Preferred examples of the lubricating agent are magnesium stearate, calcium stearate, talc, colloidal silica gel.

Preferred examples of the binding agent are pregelatinized starch, sucrose, gelatin, gum arabic methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, SO-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone.

Preferred examples of the disintegrant are lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.

Preferred examples of the solvent are water for injection, physiological saline, solution

Ringer's, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

Preferred examples of solubilizing agents are polyethylene glycol, propylene glycol, O-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

Preferred examples of suspending agents are surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc.; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.; polysorbates and polyoxyethylene hydrogenated castor oil.

Preferred examples of isotonic agents are sodium chloride, glycerol, SO-mannitol, O-sorbitol, and glucose.

Preferred examples of the buffer are buffers such as phosphate, acetate, carbonate, citrate buffer, etc.

Preferred examples of sedative agents are benzyl alcohol t...

Preferred examples of preservatives are p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

Preferred examples of antioxidants are sulfite, ascorbate, etc.

Preferred examples of the colorant are aqueous food resinous colors (e.g., food colors such as Food Red Me 2 and Mo 3, Food Yellow Mo 4 and Mo 5,

Food blue Mo 1 and Mo 2, etc.), water-insoluble pigments (for example, the aluminum salt of the above-mentioned aqueous food resin dye) and natural dyes (for example, D-carotene, chlorophyll, red iron oxide).

Preferred examples of sweeteners are sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

Examples of the dosage form of the above-mentioned pharmaceutical composition are oral formulations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orodispersible tablets), capsules (including soft capsules, microcapsules), granules, powders, pills, syrups, emulsions, suspensions, films (eg orodispersible films), etc.; and parenteral agents such as injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external formulations (eg, dermal formulations, ointments), suppositories (for example, rectal suppositories, vaginal suppositories), dragees, nasal formulations, pulmonary formulations (inhalants), eye drops, etc. They can be safely administered orally or parenterally (eg, topically, rectally, intravenously).

These formulations can be controlled-release formulations (eg, sustained-release microcapsules), such as immediate-release formulations, sustained-release formulations | t...

The pharmaceutical composition can be obtained by a method commonly used in the field of pharmaceutical formulations, for example, by the method described in Japanese

Pharmacopoeias, etc.

While the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the dose of the compound of the present invention, etc., it is, for example, approximately 0.1 - 100 wt.95.

When receiving an oral formulation, a coating may be applied if necessary for the purposes of masking taste, modifying stomach behavior, or stability.

Examples of coating bases used for coating are sugar coating bases, aqueous film coating bases, gastric film coating bases, and sustained release film coating bases.

Sucrose is used as a basis for sugar-containing coatings. However, one or more species selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination.

Examples of bases for aqueous film coatings are cellulose polymers, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc.; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eshagadiy E (trade name)|, polyvinylpyrrolidone, etc.); and polysaccharides, such as pullulan, etc.

Examples of bases for gastric film coatings are cellulose polymers, such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, etc. acrylic polymers, such as methacrylic acid copolymer I (Etsagadiyi I. (trade name)), methacrylic acid copolymer GO (Enagadi I-30055 (trade name)), methacrylic acid copolymer 5 (IEnagadiyi 5 (trade name)), etc. and naturally occurring substances such as shellac, etc.

Examples of bases for sustained release film coatings are cellulose polymers such as ethyl cellulose and acrylic polymers such as aminoalkyl methacrylate copolymer KB (Etsyagadiy K5 (trade name)), ethyl acrylate-methyl methacrylate copolymer suspension (Etsyagadiy ME (trade name)| and those.

The above-mentioned bases for coatings can be used after mixing two or more of their types with an acceptable ratio. For example, a light-shielding agent, such as titanium oxide, iron (I) oxide, etc., can be applied to the coating.

The compound of the present invention exhibits low toxicity (eg, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, etc.) and minor side effects. In addition, it can be used as an agent for the prevention or treatment or diagnosis of various diseases in a mammal (eg, human, cattle, horse, dog, cat, monkey, mouse, rat).

The compound of the present invention has an extraordinary glucagon antagonistic effect.

The compound of the present invention can improve the patient's condition due to the activation of glucagon function (for example, production of excess sugar from the liver, excess secretion of growth hormone, excess inhibition of gastric motility, etc.) by, for example, stopping the action of glucagon. However, the compound of the present invention may be useful as a glucagon antagonist, an agent that inhibits sugar production, a prophylactic or therapeutic agent for diseases caused by the activated action of glucagon, etc.

Specifically, the compound of the present invention can be used as a prophylactic or therapeutic agent for obesity, diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, "smooth" diabetes), hyperlipidemia (e.g., hypertriglyceridemia, hypercholesterolemia, hypoLVHemia, postprandial hyperlipemia), hypertension, heart failure, diabetic complications (eg, neuropathy, nephropathy, retinopathy, diabetic cardiomyopathy, cataract, macroangiopathy, osteopenia, hyperosmolar diabetic coma, infections (eg, respiratory infection,

urinary tract infection, gastrointestinal infection, skin soft tissue infection, lower extremity infection), diabetic gangrene, dry mouth, hypoacusis, cerebrovascular disorder, peripheral blood circulation disorder)|, metabolic syndrome (pathology containing three or more selected from hyper-triglyceride (TO)emia, hypo-

LDL cholesterol (LVH-C)emia, hypertension, abdominal obesity and impaired glucose tolerance), sarcopenia, etc.

For the diagnosis of diabetes criteria, the Japanese Diabetes Society announced a new diagnostic criteria in 1999.

According to this report, diabetes is a condition in which the fasting blood glucose level (intravenous plasma glucose concentration) is at least 126 mg/dL, the 2-h level in the 75 g oral glucose tolerance test (75 4 OST) (concentration intravenous plasma glucose) at least 200 mg/dL, and non-fasting blood glucose (intravenous plasma glucose concentration) at least 200 mg/dL. A condition that does not fall under diabetes mentioned above and differs from "a condition that has a fasting blood glucose level (intravenous plasma glucose concentration) of less than 110 mg/dL or a 2-hour level in a 75-g oral glucose tolerance test (75 d4d OST) (intravenous plasma glucose concentration) less than 140 mg/dL" (normal type) is called "borderline type".

In addition, ABA (American Diabetes Association) in 1997 and M/UNO in 1998 reported a new diagnostic criterion for diabetes.

According to this report, diabetes is defined as having a fasting blood glucose level (intravenous plasma glucose concentration) of at least 126 mg/dL and a 2-h level in the 75 g oral glucose tolerance test (75 d OST) (glucose concentration intravenous plasma) not less than 200 mg/dL.

According to the reports mentioned above, impaired glucose tolerance is a condition in which the 2 h level in the 75 g oral glucose tolerance test (75 9

OST) (intravenous plasma glucose concentration) less than 140 mg/dL and less than 200 mg/dL. According to the AMA, a condition in which the fasting blood glucose level (intravenous plasma glucose concentration) is at least 110 mg/dL and less than 126 mg/dL is called IPO (impaired fasting glucose). According to the report of UUNO, among IPO (Deterioration of fasting glucose level), the condition having a 2-hour level in the 75 g oral glucose tolerance test (intravenous plasma glucose concentration) of less than 140 mg/dL is called IPO (Deterioration of fasting glycemia).

The compound of the present invention can also be used as an agent for the prevention or treatment of diabetes, borderline type, impaired glucose tolerance, IS (Impaired fasting glucose) and IPO (Impaired fasting glycemia), as defined according to the diagnostic criteria presented above.

However, the compound of the present invention can prevent the development of borderline type, impair glucose tolerance, IES (Impaired fasting glucose level) or

IPO (Deterioration of fasting glycemia) in diabetes.

However, the compound of the present invention can also be used as a prophylactic or therapeutic agent in osteoporosis, cachexia (for example, carcinocachesia, tuberculous cachexia, diabetic cachexia, hemopathic cachexia, endocrinopathic cachexia, infectious cachexia, cachexia in heart disease or cachexia caused by acquired immunodeficiency syndrome), fatty infiltration of the liver, polycystic ovary syndrome, kidney diseases (for example, diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, end-stage renal disease), muscular dystrophy, myocardial infarction, angina pectoris, cerebrovascular disorder (for example, cerebral infarction, cerebral apoplexy), ischemia, coronary heart disease, non-0) serrated myocardial infarction (non-0O0 serrated MI), congestive heart failure, ventricular hypertrophy, cardiac arrhythmia, Charcot syndrome, obstructive disease of peripheral arteries (for example, disorder of peripheral arteries), Alzheimer's disease, Parkinson's disease, anxiety, dementia, insulin resistance syndrome, syndrome X, hyperinsulinemia, hyperinsulinemia perception disorder, tumor (eg, leukemia, breast cancer, prostate cancer, skin cancer, epithelial cancer, glandular cancer), irritable bowel syndrome bowel, acute or chronic diarrhea, inflammatory disease (eg, chronic rheumatoid arthritis, spondylitis deformans, ostearthritis, lumbago, gout, gouty arthritis, inflammation after surgery or trauma, edema, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including nonalcoholic steatohepatitis), pneumonia , pancreatitis, enteritis, inflammatory bowel disease (including inflammatory colitis), ulcerative colitis, gastric mucosal injury (including aspirin-induced gastric mucosal injury), Lyme disease, rubella arthritic, psoriatic arthritis, conjunctivitis, gastritis, chronic thyroiditis, chronic active hepatitis, Crohn's disease, synovitis, ankylosing spondylitis ileitis), damage to the mucous membrane of the small intestine, malabsorption, testicular dysfunction, visceral obesity syndrome, sarcopenia, macular degeneration, hypoplastic anemia, thrombocytopenia, multiple sclerosis, periodontal disease, keloid formation, pulmonary sarcoidosis, myasthenia gravis, Reiter's syndrome, influenza, cerebral malaria , silicosis, bone resorption disease, fever, myalgia, multiple myeloma-dependent bone disease, traumatic neurodegenerative disease, traumatic brain injury, gigantism, graft-versus-host reaction, transplant rejection, skin disease (eg, scar tissue formation, eczema , atopic dermatitis, contact dermatitis, urticaria, scleroderma, psoriasis), allergies or respiratory diseases (eg, asthma, respiratory distress syndrome, hay fever, allergic rhinitis, chronic inflammatory lung disease (eg, chronic obstructive pulmonary disease (COPD)), inflammation caused by an autoimmune disease (eg, systemic lupus erythematosus, Addison's disease, polyglandular deficiency syndrome, Grave's disease), an infectious disease (eg, sepsis, septic shock, shigellosis, lPe/isobacteriosis), a viral disease (eg, herpes simplex virus, cytomegalovirus , Epstein-Barr virus, human immunodeficiency virus, hepatitis virus type A, type B, and type C, angiogenic disease (eg, solid tumor, ocular neovascularization, hemangioma, edema, analgesia, pain (eg, neuromuscular pain, headache, pain caused by cancer or surgery, toothache, arthritic pain), irritable bowel syndrome, leukemia, diseases of the central nervous system (for example, due to cerebral ischemia, cerebral infarction, brain edema, etc.), kidney fibrosis, liver fibrosis, prostate fibrosis, lung fibrosis, etc.

However, the compound of the present invention can also be used as an improver of gastrointestinal motility.

The compound of the present invention can also be used for secondary prevention and inhibition of development (for example, secondary prevention and inhibition of the development of cardiovascular conditions, such as myocardial infarction, etc.) of the above-mentioned various diseases.

While the subject of administration of the compound of the present invention is not specifically limited, a mammal (eg, mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, monkeys, humans, etc.) is preferred. .

Although the dose of the compound of the present invention varies depending on the subject to whom it is administered, the route of administration, the target disease, the symptom and the like, for example, in the case of oral administration to adult patients with diabetes, it is generally about 0.01 - 100 mg/ kg body weight, preferably 0.05 - 30 mg/kg body weight, more preferably 0.1 - 10 mg/kg body weight for a single dose, which is preferably administered 1 - 3 times a day.

In order to enhance the effect of the compound of the present invention or to reduce the dose of the compound and those, the compound can be used in combination with drugs such as therapeutic agents for diabetes, therapeutic agents for diabetic complications, therapeutic agents for hyperlipidemia, antihypertensive agents, agents for the treatment of obesity, diuretics , antithrombotic agents, etc. (hereinafter referred to as a concomitant medicine). The time of administration of the compound of the present invention and the accompanying medicinal product is not limited and they can be administered to the subject simultaneously or independently of each other. In addition, the compound of the present invention and the accompanying drug can be administered as formulations of two types containing the respective active ingredients or one formulation containing both active ingredients.

The dose of the concomitant medication can be appropriately determined based on clinically used doses. In addition, the ratio of the compound of the present invention and the accompanying drug can be appropriately determined according to the subject of administration, route of administration, target disease, condition, combination, etc... For example, when the subject for administration is a human, the accompanying drug can be used in the amount of 0.01 - 100 parts by mass per 1 part by mass of the compound of the present invention.

Examples of a therapeutic agent for diabetes are insulin formulations and, for example, animal insulin formulations extracted from the pancreas of cattle and pigs; formulations of human insulin genetically synthesized using EzsNegisnia soy or yeast; insulin zinc; protamine zinc insulin; insulin fragment or derivative (for example, IM5-1, etc.), oral insulin formulation), insulin sensitizers (for example, pioglitazone or its salt (mainly hydrochloride), TAK-379, rosiglitazone or its salt (mainly maleate), tezaglitazar, ragaglitazar, muraglitazar, edaglitazone, metaglidazen, naveglitazar, AMO-131, TNA-0921), o-glucosidase inhibitors (for example, voglibose, acarbose, miglitol, emiglitate), biguanides (for example, phenformin, metformin, buformin or their salts ( (eg, hydrochloride, fumarate, succinate)), insulin secretagogues (sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glibuzole), repaglinide, senaglinide, nateglide, mitiglinide, or its calcium salt hydrate, IM dipeptidyl peptidase inhibitors (eg, alogliptin, vildagliptin, sitagliptin, saxagliptin, T-6666, 115-021), BZ agonist (eg, A.)-9677), agonists

OSRK40, agonists of the SI P-1 receptor (for example, SI P-1, SI P-1ME, MM-2211, AC-2993, (exendin-4), VIM-51077, AiB(8,35)pai P-1 ( 7,37)MH", SusC-1131), amylin agonists (eg, pramlintide), phosphotyrosine phosphatase inhibitors (eg, sodium vanadate), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitor, glucose-β6-phosphatase inhibitor, glucagon antagonist), 501 inhibitors (sodium-glucose cotransporter) (for example, T-1095), 11p-hydroxysteroid dehydrogenase inhibitors (for example,

VMT-3498), adiponectin or its agonist, IKK inhibitor (eg, A5Z-2868), agents to improve leptin resistance, somatostatin receptor agonists, glucokinase activators (eg, Ko-28-1675), CIP (Glucose-dependent insulinotropic peptide ) and the like.

Examples of therapeutic agents for the treatment of diabetic complications are aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, ST-112), neurotrophic factors and agents that increase their levels (eg, MOB, MT-3, VOME, promoters of neurotrophin production-secretion are described in UMO01/14372 (for example, 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-|3-(2-methylphenoxy)propyl|oxazole)), YES -583, promoter of nerve regeneration (for example, U-128),

PKC inhibitor (for example, riboxystaurin mesylate), ACE inhibitor (for example, A! T946, pimagedin, pyratoxanthin, M-phenacylthiazolium bromide (AIT766), A T-711, ECHO-226, pyridorin, pyridoxamine), scavengers of reactive oxygen (for example, lipoic acid), cerebral vasodilators (for example, tiapride, mexiletine), somatostatin receptor agonists (for example, VIM23190) and apoptosis inhibitors of signal-regulating kinase-1 (AB5K-1), etc.

Examples of antihyperlipemic agents are statins (e.g. pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, rosuvastatin, pitavastatin and their salts (e.g. sodium salt, calcium salt)), squalene synthase inhibitors (e.g. lapaquistat acetate or its salt), fibrates (e.g. , bezafibrate, clofibrate, simfibrate, clinofibrate), ACE inhibitor (eg, avasimibe, eflucimibe), anion exchange resins (eg, cholestyramine), probucol, nicotinic acid medicine (eg, nicomol, niceritrol), ethyl laicospentate, phytosterols (eg, soy sterol, gamma-oryzanol (y-oprizanol) and the like.

Examples of an antihypertensive agent are an angiotensin-converting enzyme inhibitor (eg, captopril, enalapril, delapril), an angiotensin II receptor antagonist (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosaratan, 1-C2-(2,5-dihydro- 5-oxo-4H-1,2,4-oxadiazol-3-yl)riphenyl-4-yl|Imethyl|-2-ethoxy-1H-benzimidazole-7-carboxylic acid, TAK-491), calcium channel blockers ( for example, manidipine, nifedipine, amlodipine, fenidipine, nicardipine), opening potassium channels (for example, leucromacalin, I -27152, AI 0671, MIR-121),

Clonidine and the like.

Examples of antiobesity agents are central nervous system antiobesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amfepramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonists (eg, 58-568849; 5MAP- 7941; compounds described in UMO01/82925 and M/001/87834); neuropeptide B antagonists (for example, CpP-422935); cannabinoid receptor antagonists (for example, 5K-141716, 58-147778); ghrelin antagonists; 11p-hydroxychroid dehydrogenase inhibitors ( e.g., BMT-3498)), pancreatic lipase inhibitors (e.g., orlistat, cetilistat), DZ agonist (e.g.,

A)-9677, A740140), peptide agents that reduce appetite (eg, leptin, CMTE (Ciliary Neurotropic Factor)), cholecystokinin agonists (eg, lentitript,

ERI--15849), food retarder (for example, P-57) and the like.

Examples of diuretics are xanthine derivatives (e.g. sodium theobromine salicylate, calcium theobromine salicylate), thiazide receptors (e.g. etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydrochlorothiazide, penfluthiazide, polythiazide, methylclothiazide), antialdosterone formulations (e.g. spironolactone), triamterone , carbonate dehydratase inhibitors (for example, acetazolamide), chlorobenzenesulfonamide formulations (for example, chlorthalidone, mefruside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of antithrombotic agents are heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drugs (eg, aragatroban, dabigatran), thrombolytic agents (eg, urokinase, thysokinase, alteplase, nateplase, monteplase, pamiteplase), platelet aggregation inhibitor (eg, ticlopidine hydrochloride, cilostazol), ethyl eicosapentatate, beraprost sodium, sarpogrelate hydrochloride, Е5555, ЗНОС 530348, prasugrel), EC inhibitor (eg, TAK-442, rivaroxaban, apixaban, ОО-176Б6 , UM150) and the like.

The accompanying medicine mentioned above can be a combination of two or more of their types, combined in an acceptable ratio.

Methods of obtaining the compound of the present invention are disclosed below.

The compound of the present invention can be obtained according to a method known in the art, for example, by the methods described in detail below or by a method similar to it.

In the following preparation methods, the starting compounds may be in the form of salts, and examples of such salts are salts similar to those of compound (I) and compound (IA).

The compound obtained at each stage of the following formulas can be used for the next reaction directly in the form of a reaction mixture or a crude product, or can be isolated and purified by known methods of separation and purification, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc. used in the following reaction.

When compounds of the following formulas are commercially available, such commercially available products may be used directly.

In each of the following reactions, when the starting compound has an amino group, a carboxy group, or a hydroxy group as a substituent, such a group may be protected by a protecting group commonly used in peptide chemistry, etc. In this case, the protecting group is removed, if necessary, after reactions to obtain the target compound.

Examples of an amino-protecting group are a formyl group, a C1-6 alkylcarbonyl group, a C-C alkoxycarbonyl group, a benzoyl group, a C7-o aralkylcarbonyl group (for example, benzylcarbonyl), a C7-4 aralkyloxycarbonyl group group (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, M,M-dimethylaminomethylene group, substituted silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), Co-v alkenyl group (for example, 1-allyl), etc. These groups are optionally substituted 1 - With substituents selected from the halogen atom, C-.v alkoxy group and nitro group.

Examples of a carboxy-protecting group are a C1-6 alkyl group, a C7-4 aralkyl group (for example, benzyl), a phenyl group, a trityl group, a substituted silyl group (for example, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), Sov alkenyl group (for example, 1-allyl), etc.

Examples of a hydroxy-protecting group are a C. alkyl group, a phenyl group, a trityl group, a C.7-o aralkyl group (for example, benzyl), a formyl group, a C..v. alkylcarbonyl group, a benzoyl group, a C.7-o aralkyl-carbonyl group (e.g., benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), Alkenyl group (e.g., 1-allyl), etc. and. These groups are optionally substituted with 1 - C substituents selected from a halogen atom, a C-6 alkyl group, a C-6 alkoxy group, and a nitro group.

The above-mentioned protecting group can be removed according to a technique known in the art, for example, by the method described in Rgoyesiime Ogocirz ip Ogdapis Zupipevziz, dopp Umieu apa

Bopz5 (1980), etc.. Specifically, a method using acid, base, ultraviolet radiation, hydrazine, phenylhydrazine, sodium M-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (eg, trimethylsilyl iodide, trimethylsilyl bromide, etc.) etc., recovery, etc.

In each of the following reactions, the introduction of a substituent and the reaction of the transformation of a functional group can also be carried out using a method known essentially based on the starting material, the intermediate compound and/or the obtained product.

Examples of the substituent conversion reaction are known methods, for example, conversion to carboxy by ester hydrolysis, conversion to carbomoyl by amidation of carboxy, conversion to hydroxymethyl by reduction of carboxy, conversion to alcohol by reduction or alkylation of carbonyl, reductive amination of carbonyl, oximation of carbonyl, acylation, urea, sulfonylation or alkylation of amino, substitution and amination of active halogen with amine, amination by nitro reduction, alkylation of hydroxy, substitution and amination of hydroxy; alkylation of the ring nitrogen atom of a nitrogen-containing heterocycle, introduction of a substituent by a condensation reaction (for example, an aryl condensation reaction); substitution of halogen by amine, hydroxy or thio; etc.

Compound (I) can be obtained, for example, by the methods shown in the following Reaction Scheme 1.

Scheme of the reaction 1 o still Y. t di -on -- no M) Her r: - KO stage i Stage 7 because E Stage Z / in o Kk - a in t 1 Kiy iya in Kk im that ov Fo (MO o t ho she yi vi Zm v! Z ! | Khot . A n v X (I v V

Stage 4 is similar to Stage 5 (M NI where K is an alkyl group (for example, methyl, ethyl, n-hexyl); C) is a leaving group, (e.g. methanesulfonyloxy group, p-toluenesulfonyloxy group, halogen atom (e.g. chlorine, bromine)); KM is an organometallic compound (to be mentioned later) and other symbols are as defined above. stage 1

Compound (I) can be obtained by subjecting the original compound (II) to a reduction reaction. This reduction reaction is carried out using a reducing agent and according to conventional techniques.

Examples of the reducing agent are metal hydrides, such as sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride (SIVAIN), etc.; complex metal hydrides, such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium aluminum hydride, etc. etc.

The amount of the reducing agent used is generally 1 - 20 mol per 1 mol of compound (I).

This reaction is preferably carried out in a solvent inert to the reaction. such a solvent is not specifically limited as long as the reaction continues and, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, etc. can be mentioned; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; mineral acids, such as hydrochloric acid, sulfuric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.; water; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 70 - 150 "C, preferably -20 "C -100 76.

Compound (II) used as a starting material can be synthesized according to a method known in essence, for example, the method of synthesis is described in UUO2007/89031,

ЕРО4154, УМО2003/99793 or ЕР1176140, or a method similar to it. stage 2

Compound (IM) can be obtained by subjecting compound (II) to an oxidation reaction. The oxidation reaction is carried out using an oxidant and according to the usual method.

Examples of oxidizing agents are active manganese dioxide, pyridinium chlorochromate (POC), pyridinium dichromate (POC), Dessa-Martin periodinan, dimethylsulfoxide-acid anhydride (for example, acetic anhydride, trifluoroacetic anhydride), dimethylsulfoxide-thionyl chloride, dimethylsulfoxide-sulfuryl chloride, dimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-chlorine and dimethylsulfoxide-dicyclohexylcarbodiimide (DSC) in the presence of acid (for example, phosphoric acid, trifluoroacetic acid, dichloroacetic acid), etc.

The amount of the oxidant used is generally 1 - 20 mol per 1 mol of the compound (PP).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, ethers such as diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, etc. can be mentioned; ketones such as acetone, methyl ethyl ketone, etc. halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; aromatic hydrocarbons, such as benzene, toluene, etc.; saturated hydrocarbons, such as cyclohexane, hexane, etc.; amides such as M,M-dimethylformamide, M,M-dimethylacetamide, hexamethylphosphoramide, etc.; mineral acids, such as hydrochloric acid, sulfuric acid, etc. organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.; water; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 70 - 150 "C, preferably -20 "C -100 76.

stage Z

The compound (MI) can be obtained by the reaction of the compound (IM) with the organometallic compound (M).

This reaction is carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc. can be mentioned; aliphatic hydrocarbons such as hexane, heptane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; etc.. these solvents can be used in the form of a mixture with an acceptable ratio.

Examples of an organometallic compound (M) are a Grignard reagent (for example, a compound represented by the formula: ЕЗМОаВг), an organolithium reagent (for example, a compound represented by the formula: КИ), an organozinc reagent (for example, a compound represented by the formula: (К)22п), where ЕZ is as defined above), etc.. Such a compound can be obtained according to the method known in fact, for example, the method described by "LkKKep Kadaki Koshyga (Tne Spetisa! Zosieiu oi darap ed.), AF Ediyop, my. 25, Zupipevziz ru

Organometallic reagent" year 9-449, Magigep Rhev 55 1992, or by a method similar to it.

The amount of the organometallic compound (U) used is generally about 1-10 mol, preferably about 1-2 mol, per 1 mol of the compound (IM).

The reaction temperature is generally -80 "C - 100 "C, preferably -20 70 - 50 76.

The reaction time is generally 0.5 - 20 g. stage 4

Compound (MI) can be obtained by converting the hydroxy group of compound (MI) to a leaving group.

Such conversion to a leaving group is carried out according to a conventional technique, for example, reaction with methanesulfonyl chloride in the presence of an acceptable base, or reaction with thionyl chloride.

Examples of the base used for this reaction are M,M-isopropylethylamine (OIEA), triethylamine (TEA), pyridine, M,M-dimethylaniline, etc...

The amount of methanesulfonyl chloride or thionyl chloride used is generally about 1-50 mol, preferably about 1-10 mol, per 1 mol of compound (MI).

The amount of base used is generally about 1-50 mol, preferably about 1-10 mol, per 1 mol of compound (MI).

This reaction is carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc. can be mentioned; halogenated hydrocarbons, such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc. etc... These solvents can be used in the form of a mixture with an acceptable ratio.

The reaction temperature is generally -50 - 150 "C, preferably -10 - 100 70.

The reaction time is generally 0.5 - 20 h. stage 5

Compound (I) can be obtained by reacting compound (MI) with compound (MI) (for example, ethyl 3-((4-aminophenyl)carbonyl)aminopropanoate) in the presence of a base. When necessary, the ester group of the resulting adduct can be hydrolyzed.

Examples of the base used for this reaction are alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. hydroxides of alkaline earth metals, such as magnesium hydroxide, calcium hydroxide, etc.; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, etc.; alkali metal alkoxides having 1 to 6 carbon atoms, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; metal hydrides such as sodium hydride, potassium hydride, calcium hydride, etc. etc.

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not specifically limited as long as the reaction continues and, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, etc.; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; sulfoxides such as dimethyl sulfoxide, etc.; sulfolane; hexamethylphosphoramide; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

In this reaction, 1 equivalent to a large excess (mostly 1 - 10 equivalents) of alkali metal iodide, such as sodium iodide, etc., can be added to the compound (MI) as a reaction promoter.

The amount of compound (MI) used is generally about 1-10 mol, preferably about 1-2 mol, per 1 mol of compound (MI).

The amount of base used is generally 1-10 molar equivalents, preferably 1-5 molar equivalents, per 1 mol of compound (MII).

The reaction temperature is generally -30 - 200 "C, preferably 0 - 150 70.

The reaction time is generally 0.5 - 20 g.

The ester group can be hydrolyzed according to a method known in the art, for example, by the method described by Rgoyesiime Sgoshmrz ip Ogdapis Zupipevzih, Tpiga Eayiop, Umieu-Ipiegzsiepse (1999) or a method similar to it.

Methods of obtaining the starting compounds and their reactive derivatives used for the above-mentioned methods are given below.

Compound (MI) can be prepared according to, for example, the following Reaction Scheme 2.

Reaction scheme 2

ЧЕ - - ож шо кут сут t - stage 4 b і Іі во Ted» i. " ia) o i) svv Uh o v z

Ha! Shy o same v y ; in study 4 GU

Ou on «e su go ke 2 ezadia from Vk

MA A tt For Her t ve | M

1st stage of driving and driving (8-2 (3-2 sl)

Eat at 4 p.m. at 9 p.m

Sa 1 i EK p st u dod dl stage 5 I m stage 6 NM Nostage TNK left vv st (vv) vo) where M/ and M? each is independently an amino protecting group, Kg is an alkyl group, and other symbols are as defined above. stage 1

In this reaction, compound (a1-1) is condensed with compound (a) to obtain compound (a3-1).

The condensation reaction is carried out according to the usual method, for example, the well-known method of peptide condensation. Examples of the method are the direct condensation of the compound (a1-1) and the compound (a2) using a condensing agent, a method that includes the reaction of a reactive derivative of the compound (a1-1) with the compound (ag), etc.

Examples of the condensing agent are carbodiimide condensing reagents, such as dicyclohexylcarbodiimide (OCS), diisopropylcarbodiimide (PIRS), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EOS), their hydrochloride, etc.; condensing reagents based on phosphoric acid, such as diethyl cyanophosphate, diphenylphosphorylazide, etc.; carbonyldiimidazole, 2-xpro-1,3-dimethylimidazolium tetrafluoroborate, 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (NATU), etc.

Examples of the solvent used for the condensation reaction are amides such as

M,M-dimethylformamide, M,M-dimethylacetamide, M-methylpyrrolidine, etc.; cSulfoxides, such as dimethyl sulfoxide, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, etc.; esters such as methyl acetate, ethyl acetate, etc.; nitriles such as acetonitrile, propionitrile, etc.; water; etc. These solvents can be used in the form of a mixture with an acceptable ratio.

The amount of used compound (ag) is generally 1-10 mol, preferably 1-3 mol, per 1 mol of compound (a1-1).

The amount of used condensing agent is generally 0.1 - 10 mol, preferably 0.3 - C mol, per 1 mol of compound (a1-1).

When a carbodiimide condensing reagent is used as a condensing agent, the reaction efficiency can be improved by using a suitable condensation promoter (eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, /-M-hydroxysuccinimide, M-hydroxyphthalimide) if necessary.

When NATO or a phosphoric acid-based reagent is used as a condensing agent, the reaction efficiency can be improved by using an organic amino base such as triethylamine, M,M-diisopropylethylamine, etc...

The amount of used condensation promoter or organic amino base is generally 0.1 - 10 mol, preferably 0.3 - C mol, per 1 mol of compound (a1-1), respectively.

The reaction temperature is generally -30 - 120 "C, preferably -10 - 100 70.

The reaction time is generally 0.5 - 60 g.

Examples of the reactive derivative of compound (a1-1) are acid halide (for example, acid chloride, acid bromide), imidazolide, mixed acid anhydride (for example, anhydride with methyl carbonate, ethyl carbonate or isobutyl carbonate), etc.

For example, when an acid halide is used, the reaction is generally carried out in the presence of a base, and in a solvent that does not adversely affect the reaction.

Examples of bases are amines such as triethylamine, pyridine, M-methylmorpholine, M,M-dimethylaniline, 4-dimethylaminopyridine, etc.; alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, etc.

Examples of a solvent that does not have a harmful effect on the reaction are amides, such as M,M-dimethylformamide, M,M-dimethylacetamide, M-methylpyrrolidine, etc.; sulfoxides such as dimethyl sulfoxide, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, etc.; esters such as methyl acetate, ethyl acetate, etc.; nitriles such as acetonitrile, propionitrile, etc.; water; etc... These solvents can be used in the form of a mixture with an acceptable ratio.

When the above-mentioned amide is used as a solvent, the reaction can also be carried out in the absence of a base.

The amount of the used compound (ag) is generally 1-10 mol, preferably 1-5 mol, per 1 mol of the acid halide of the compound (a1-1).

The amount of base used in general is 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of the acid halide of the compound (a1-1).

The reaction temperature is generally -30 "C - 120 "C, preferably -10 - 100 70.

The reaction time is generally 0.5 - 30 g.

When a mixed acid anhydride is used, compound (a1-1) reacts with chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) in the presence of a base and then reacts with compound (ag).

Examples of the base used for this reaction are the bases mentioned above, and their examples are the bases used for the acid halide reaction of compound (a1-1) with compound (az), etc.

The amount of used compound (ag) is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (a1-1).

The amount of chlorine carbonate used is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of compound (a1-1).

The amount of base used in general is 1 - 10 mol, preferably 1 - 3 mol, per 1 mol of compound (a1-1).

The reaction temperature is generally -30 "C - 120 "C, preferably -10 - 100 70.

The reaction time is generally 0.5 - 20 g.

When an imidazolide is used, compound (a1-1) reacts with, for example, M,M'-carbonyldiimidazole (CO) to give the corresponding imidazolide, which then reacts with compound (ag).

The amount of used compound (ag) is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (a1-1).

The amount of M,M'-carbonyldiimidazole (SOI) used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (a1-1).

The reaction temperature is generally -30 "C - 120 "C, preferably -10 - 100 70.

The reaction time is generally 0.5 - 20 g.

As compound (a1-1) and compound (a2), commercially available products are available, or can be obtained using a commercially available compound according to a technique known in the art or a method similar thereto. Ma stage

Compound (a3-2) can be obtained in the same way as in step 1 and using compound (a1-2) and compound (ag).

A commercially available product can be used as compound (a1-2) or can be obtained using a commercially available compound according to a technique known in essence or a method similar to it. stage 2

Compound (a4) can be obtained by subjecting compound (a3-1) to a reduction reaction in the presence of a metal catalyst and a source of hydrogen. Such a reduction reaction is carried out according to the usual technique in a solvent that does not have a harmful effect on the reaction.

Examples of the metal catalyst used for this reaction are palladium-charcoal, palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, etc.

Examples of hydrogen source are hydrogen, formic acid, formamide salt, phosphinate salt, hydrazine, etc...

Examples of a solvent that does not have a harmful effect on the reaction are methanol, tetrahydrofuran, M,M-dimethylacetamide, etc.

The amount of the metal catalyst used is generally 0.001 - 1000 mol, preferably 0.01 - 100 mol, per 1 mol of the compound (aZ3-1).

The reaction temperature is generally -70 - 150 "C, preferably -20 - 100 70.

The reaction time is generally 0.1 - 100 g, preferably 0.1 - 40 g.

This reaction can also be carried out in the presence of a reducing agent in a solvent that does not have a detrimental effect on the reaction.

Examples of the reducing agent are oxide of iron, zinc, tin, etc., and the compound (ai4) can be obtained by the reaction described in "ikkep Kadaki Koiga (Te Spetisa! bosieiu oi

Huarap ed.), Ap Ediop, my. 20, Ogdapis Zupipeviz II AIsopoi apa Atipe" years 279-280, Magigep

Rgez5 1992, or in a way similar to it. stage Z

The compound (a4) can be obtained by removing the protecting group (M/) from the compound (a3-2) by a method known in essence, for example, by the method described by Rgoyesiime Sgotsir5 ip Ogdapis Zupipeviv,

Tpiga Edyiop, U/Peu-Ipiegzsiepse (1999) or a method similar to it. stage 4

Compound (MI) can be obtained by subjecting compound (a4) or compound (a9) to a reductive amination reaction.

The reductive amination reaction is carried out by a method known in essence, for example, by the method described by "ikkep Kadaki Koshpga (Te Spetisa! bosieiu oi darap ea.), A Eayop, mo!. 20. Ogdapis Zupipezviz II AIsopoi apa Atipe" 300-302, Magigep Rgezz 1992; in the manner described by Kedysiop5 ip Ogdapis Spetivigu Zesopa Eaiop, Ategisaps SPpetisa! 5th edition (1996), pp. 187-189; or in a way similar to it.

stage 5

Compound (a7) can be synthesized by the Friedel-Crafts reaction using compound (ab) and glutaric anhydride (ab) and according to the synthesis method described in, for example,

UO2004/45616, or by a method similar to it. stage 6

Compound (a) can be obtained by removing the protective group from compound (a7) by a method known in the art, for example, by the method described by Rgoyesiime Sgoyrz ip Ogdapis Zupipeviv,

Tpiga Edyiop, UMPeu-Ipiegzsiepse (1999) or a method similar to it. stage 7

Compound (а9) can be obtained by esterification of compound (а) by a method known in essence, for example, by the method described by Rgoyesiime Sgoimrz ip Ogdapis Zupipeviv, Tpiga Edyiop, Umieu-

Iptegzsiepse (1999) or a method similar to it.

Compound (IA) can be obtained, for example, according to the method shown in the following Reaction Scheme A1.

In the following Scheme of the AT reaction, compound (Via) is compound (IA), where BA" is a C..v6 alkyl group, and compound (VIB) is compound (IA), where KA" is a hydrogen atom.

Scheme of the reaction A1 sauce de yi (zhu She HU B (deno ol (DYU de (U

AeUu- her hu K F you Stage 5 M,

Kl (VIV VA A, - (BUV) (vu; re still in Y fen it vit or Vo i i bo, (AVK. NO) (the same shoyu (sut (V n m that (BI) ov nya | VK in So " ve u bktokvan Stage Z y ko ra y. t vm y

Odve Oh dz M ul sody v i LU sor uchy Ne nyu dat ve dme (i v v v Stage 8 ( s - v (Viv) - (VI) ov v v - KM sovtalia z

CIS Henna. | Stage Z

Н (вм) ий se o (BA where X is СНо or МЕ"Э, where": is a C..5 alkyl group, GI is a leaving group, (for example, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a halogen atom (for example, chlorine, bromine)), and other symbols are each as defined above.stage 1

The compound (VII) can be obtained, for example, by converting the hydroxy group of the compound (VII) to a leaving group. Such a conversion to a leaving group is carried out according to a conventional technique, for example, by reaction with methanesulfonyl chloride, phosphoryl chloride or thionyl chloride in the presence of an acceptable base.

Examples of bases are M,M-diisopropylethylamine (OIEA), triethylamine (TEA), pyridine, M,M-

dimethylaniline, etc.

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

The amount of methanesulfonyl chloride, phosphoryl chloride or thionyl chloride used is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of the compound (VII).

This reaction is carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc. can be mentioned; halogenated hydrocarbons, such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc. etc... These solvents can be used in the form of a mixture with an acceptable ratio.

The reaction temperature is generally -80 - 200 "C, preferably -10 - 150 70.

The reaction time is generally 10 min - 20 g, preferably 15 min - 24 g.

The compound (VII) can be obtained using the reaction described below. stage 2

The compound (Via) can be obtained, for example, by the reaction of the compound (VI!) with the compound (VIM) in the presence of a base.

Examples of the base are hydroxides of alkali metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals, such as magnesium hydroxide, calcium hydroxide, etc.; alkali metal carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, etc.; alkoxides of alkali metals having 1 - b carbon atoms, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; metal hydrides such as sodium hydride, potassium hydride, calcium hydride, etc.; etc.

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

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, etc. can be mentioned; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; esters such as ethyl formate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; Sulfoxides, such as dimethyl sulfoxide, etc.; sulfolane; hexamethylphosphoramide; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

In this reaction, alkali metal iodide, such as sodium iodide, potassium iodide, etc., can be added as a reaction promoter, generally in a proportion of 1 - 20 mol, preferably 1 - 10 mol, per 1 mol of the compound (VII).

The amount of the used compound (VIM) is generally 1 - 10 mol, preferably 1 -

From mol, per 1 mol of compound (VII).

The reaction temperature is generally -80 "C - 200 "C, preferably 0 C - 150 70.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The compound (VIM) can be obtained using the reaction described below. stage Z

The compound (Via) can be obtained by a method known in fact, for example, by the method described by Kedysip5 ip Ogdapis Spetizigo Zesopa Eaiiop, Ategisaps Spetisa!| Bosieiu (1996), pp. 187-189; Oi Spetis! bosieiu Regkip Tgapzasiyupv 1, (2000), pp. 145-146, etc., or by a method similar to it, subjecting the compound (VM) and the compound (VIM) to a reductive amination reaction.

The compound (BM) can be obtained using the reaction described below. stage 4

The compound (VMI) can be obtained, for example, by the reaction of the compound (VII) with the compound (VMI) in the presence of a base according to the method of obtaining the compound (Via) from the compound (VII).

A commercially available product can be used as a compound (VMI) or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 5

The compound (VMI) can be obtained by subjecting the compound (BM) and the compound (VMI) to a reductive amination reaction according to the method of obtaining, for example, the compound (Via) from the compound (BM). stage 6

The compound (VMIIII) can be obtained by hydrolysis of the ester of the compound (VMIII) by a method known in fact, for example, by the method described by Rgoyesiime SOhoshmrz ip Ogdapis Zupipeviz, Tpiga Eaiiop,

UmMiieu-Ipiegzsiepse (1999) or a method similar to it. stage 7

The compound (Via) can be obtained, for example, by condensing the compound (VMIII!I) and the compound (VIH).

The condensation reaction is carried out according to the usual method, for example, the well-known method of peptide condensation. Examples of such a method are a method of direct condensation of a compound (BM) and a compound (BH) using a condensing agent, or a method involving the interaction of a reactive derivative of a compound (BH) with a compound (BH), etc.

Examples of the condensing agent are carbodiimide condensing reagents, such as dicyclohexylcarbodiimide (OCS), diisopropylcarbodiimide (PIRS), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EYUS) and their hydrochloride, etc.; condensing reagents based on phosphoric acid, such as diethyl cyanophosphate, diphenylphosphorylazide, etc.; carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolium tetrafluoroborate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (NATU), etc.

Examples of the solvent used for direct condensation using a condensing agent are amides such as M,M-dimethylformamide, M,M-dimethylacetamide, M-methylpyrrolidine, etc.; sulfoxides, such as dimethyl sulfoxide, etc.; halogenated hydrocarbons such as chloroform, dichloromethane, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; aromatic hydrocarbons such as benzene, toluene, etc.; ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, tert-butyl methyl ether, etc.; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; nitriles such as acetonitrile, propionitrile, etc.; water; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The amount of condensing agent used in general is 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of the compound (VMI).

When a carbodiimide condensing reagent is used as a condensing agent, the reaction efficiency can be improved by using a suitable condensation promoter (eg, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole, /-M-hydroxysuccinimide, M-hydroxyphthalimide) if necessary.

When NATO or a phosphoric acid-based reagent is used as a condensing agent, the reaction efficiency can be improved by using an organic amino base such as triethylamine, M,M-diisopropylethylamine, etc...

The amount of condensation promoter or organic amino base used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of the compound (VMI), respectively.

The amount of the used compound (VH) is generally 1 - 10 mol, preferably 1 - mol, per 1 mol of the compound (VMI).

The reaction time is generally 10 min - 60 g, preferably 15 min - 24 g.

The reaction temperature is generally -50 - 150 "C, preferably -10 - 100 70.

Examples of reactive derivative compounds (RECs) are acid halide (for example, acid chloride, acid bromide), imidazolide, mixed acid anhydride (for example, anhydrides with methyl carbonate, ethyl carbonate, isobutyl carbonate, etc.), etc.

When an acid halide is used as a reactive compound derivative (VMIII), the reaction is generally carried out in the presence of a base in a solvent inert to the reaction.

Examples of bases are amines such as triethylamine, M,M-disopropylethylamine, M-

methylmorpholine, M,M-dimethylaniline, 4-dimethylaminopyridine, etc.; alkali metal salts such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, etc.; etc.

The amount of base used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of the acid halide of the compound (VMP).

Examples of the solvent used for this reaction are amides such as M,M-dimethylformamide, M,M-dimethylacetamide, M-methylpyrrolidine, etc.; sulfoxides such as dimethyl sulfoxide, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; aromatic hydrocarbons, such as benzene, toluene, etc.; ethers such as tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, tert-butyl methyl ether, etc.; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; nitriles such as acetonitrile, propionitrile, etc.; water; etc... These solvents can be used in the form of a mixture with an acceptable ratio. When the above-mentioned amide is used as a solvent inert to the reaction, the reaction can also be carried out in the absence of a base.

The amount of the used compound (BIH) is generally 1 - 10 mol, preferably 1 - mol, per 1 mol of the acid halide of the compound (VMIII).

The reaction temperature is generally -30 "C - 150 "C, preferably -10 - 100 70.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

When a mixed acid anhydride is used as a reactive derivative of compound (VIII|), compound (VIII) is reacted with chlorocarbonate (eg, methyl chlorocarbonate, ethyl chlorocarbonate, isobutyl chlorocarbonate) in the presence of a base and then reacts with compound (VIX).

Examples of the base used for this reaction are the bases mentioned as the bases used for the above-mentioned reaction of the acid halide of the compound (BM) with the compound (VIX).

The amount of chlorocarbonate used is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of the compound (VMIII).

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

The amount of the used compound (VH) is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of the compound (VMI).

The reaction temperature is generally -30 "C - 120 "C, preferably -10 - 100 70.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

A commercially available product can be used as a compound (VIX) or it can be obtained from a commercially available compound by a method known in the art or a method similar to it. stage 8

The compound (VIB) can be obtained, for example, by hydrolysis of the ester of the compound (Via) according to the method of obtaining the compound (VMIII).

Compound (VII) and compound (BM), which are the starting compounds of Reaction Scheme Ai1, can be obtained, for example, by the method shown in the following Reaction Scheme Ag.

Reaction scheme A?

KT dnih, lot» byu (lev? KA in, o a po Z Z vi ee No ZI 1 I sStaj 13 nya ' stad Uzh I skhvdya Still vaye S u: pz u po dv re le vami -sAVI-4 (as Av ) with two dreams! de Av) ran (les Yiavu M. they Tem "HOW oo he Stdvya ob y Me y (5) (in o. olake o ti KA ulome b AN so i" Me stdyab Se) her o in that de X" is MBA ", O or 5; KA" is a C. alkyl group; BAZ and BA"! each is, independently, a hydrogen atom or a substituent, which does not necessarily have the AB ring mentioned above; KOM is an organometallic compound (to be mentioned later); GI" is a leaving group (eg, a halogen atom such as chlorine, bromine, etc.), and other symbols are as defined above. stage 1

Compound (2) can be obtained by subjecting compound (1) to a reduction reaction. The reduction reaction is carried out according to the usual method using a reducing agent.

Examples of the reducing agent are metal hydrides, such as sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride (OIVAIN), etc.; complex metal hydrides, such as sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium aluminum hydride, calcium borohydride, etc.; etc.

The amount of the reducing agent used is generally 1 - 20 mol, preferably 1 - 10 mol, per 1 mol of compound (1).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, etc. can be mentioned; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; water; etc...

Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 70 - 150 "C, preferably -20 "C -100 76.

As compound (1), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 2

Compound (3) can be obtained, for example, by subjecting compound (2) to an oxidation reaction.

The oxidation reaction is carried out according to the usual method and using an oxidant.

Examples of oxidizing agents are active manganese dioxide, pyridinium chlorochromate (POC), pyridinium dichromate (POC), Dessa-Martin periodinan, dimethylsulfoxide-acid anhydride (for example, acetic anhydride, trifluoroacetic anhydride), dimethylsulfoxide-thionyl chloride, dimethylsulfoxide-sulfuryl chloride, dimethylsulfoxide-oxalyl chloride,

dimethylsulfoxide-chlorine and dimethylsulfoxide-dicyclohexylcarbodiimide (DSC) in the presence of acid (for example, phosphoric acid, trifluoroacetic acid, dichloroacetic acid), etc.

The amount of the oxidant used is generally 1 - 100 mol, preferably 1 - mol, per 1 mol of compound (2).

This reaction is preferably carried out in a solvent inert to the reaction. Such a 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, tert-butylmethylene, etc. can be mentioned; ketones such as acetone, methyl ethyl ketone, etc. halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichloroethylene, etc. aromatic hydrocarbons such as benzene, toluene, etc. saturated hydrocarbons such as cyclohexane, hexane, etc.; amides, such as M,M-dimethylformamide, M,M-dimethylacetamide, hexamethylphosphoramide, etc.; nitriles, such as acetonitrile, propionitrile, etc.; mineral acids, such as hydrochloric acid, sulfuric acid, etc. organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, etc., water, etc. Two or more kinds of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 - 150 "C, preferably -20 - 100 70. stage C

Compound (3) can be obtained, for example, by treating compound (4) with a base and reacting the compound with a formulating agent.

Examples of the base used for this reaction are organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium, etc., and alkali metal amides such as lithium diisopropylamide, lithium tris(trimethylsilyl)amide, etc. ..

The amount of base used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (4).

Examples of formulating agents are M,M-dimethylformamide, M-formylpiperidine, ethyl orthoformate, etc.

The amount of used formulating agent is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of compound (4).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not specifically limited as long as the reaction continues and, for example, ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc. can be mentioned; hydrocarbons such as n-hexane, n-pentane, etc.; and so on Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 - 100 "C, preferably -80 - 50 70.

As the compound (4), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 4

Compound (6) can be obtained by condensing compound (5) and M,O-dimethylhydroxylamine according to the method of obtaining, for example, compound (B1a) from compound (VMP).

As the compound (5), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 5

Compound (8) can be obtained by reacting, for example, compound (7) with 2-chloro-M-methoxy-M-methylacetamide in the presence of a base according to the method of obtaining compound (Ba) from compound (VI).

As the compound (7), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 6

Compound (6) can be obtained, for example, by reacting compound (8) with a base.

Examples of the base are hydroxides of alkali metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals, such as magnesium hydroxide, calcium hydroxide, etc.; alkali metal carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, etc.; alkoxides of alkali metals having 1 - b carbon atoms, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; metal hydrides, such as sodium hydride, potassium hydride, calcium hydride, etc.; organic bases, such as 1,8-diazabicyclo|5.4.O)undec-/-ene (08), 1,5-diazabicyclo|4.3.O|non-5-ene /(OBM), 1,4-diazabicyclo/ 2.2.2) octane (SAVSO), etc. etc...

The amount of base used is generally 1-10 mol, preferably 1-5 mol, per 1 mol of compound (8).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, etc. can be mentioned; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; esters such as ethyl formate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; Sulfoxides, such as dimethyl sulfoxide, etc.; sulfolane; hexamethylphosphoramide; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction temperature is generally -80 "C - 200 "C, preferably 0 C - 150 70.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g. stage 7

Compound (3) can be obtained by subjecting, for example, compound (b) to a reduction reaction according to the method of obtaining compound (2). stage 8

Compound (VII) can be obtained by reacting, for example, compound (3) with organometallic compound (12).

Examples of organometallic compound (12) are Grignard reagent (for example, the compound is represented by the formula: BMoVg), organolithium reagent (for example, the compound is represented by the formula: ВЗ), organozinc reagent (for example, the compound is represented by the formula: (К3)22п), where ЕЗ is as defined above, and t...

Such an organometallic compound can be obtained by a method known in fact, for example, by the method described by "ikkep Kadaki Koshpga (Te Spetisa! bosieiu oi darap ea.), A Eayop, my. 25, Zupiyeziz Bu Organometallic reagentu yr. 9-449, Magylep Rgez5 1992, or in a way similar to it.

The amount of used organometallic compound (12) is generally 1 - 10 mol, preferably 1 - 5 mol, per 1 mol of compound (3).

This reaction is carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, etc. can be mentioned; aliphatic hydrocarbons such as hexane, heptane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 - 200 "С, preferably -80 - 150 70. stage 9

Compound (VII) can be obtained, for example, by treating compound (4) with a base and reacting the compound with compound (13).

Examples of bases are bases similar to the bases described in stage 3.

The amount of the used base and compound (13) in general for each is 1-10 mol, preferably 1-5 mol, per 1 mol of compound (4).

This reaction is preferably carried out in a solvent inert to the reaction. Examples of a solvent are a solvent similar to the solvent described in step 3.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 - 100 "C, preferably -80 - 50 70.

As the compound (13), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 10

Compound (VII) can be prepared by treating, for example, compound (9) with a base and then reacting the compound with compound (13).

Examples of bases are organolithium compounds such as n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

The amount of the used base and compound (13) in general for each is 1-10 mol, preferably 1-5 mol, per 1 mol of compound (9).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not specifically limited as long as the reaction continues and, for example, ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc. can be mentioned; hydrocarbons such as n-hexane, n-pentane, etc.; and so on Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 - 100 "C, preferably -80 - 50 70.

As the compound (9), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 11

Compound (BM) can be obtained, for example, by subjecting compound (VII) to an oxidation reaction according to stage 2. stage 12

Compound (BM) can be obtained by reacting compound (b) with organometallic compound (12) according to, for example, stage 8. stage 13

Compound (BM) can be obtained by the Friedel-Crafts reaction of compound (4) and compound (10)

While this reaction is preferably carried out with the addition of an acid catalyst, when necessary, it can be carried out without the addition of an acid catalyst.

Examples of the acid catalyst used for the reaction are mineral acids such as sulfuric acid, anhydrous phosphoric acid, polyphosphoric acid, etc., Lewis acids such as aluminum chloride, tin tetrachloride, titanium tetrachloride, boron trifluoride, triethylaluminum, diethyl aluminum chloride, chloride zinc, etc., etc.

Polyphosphoric acid, aluminum chloride, diethyl aluminum chloride, zinc chloride, etc. are mainly used as an acid catalyst.

The acid catalyst can be used in any equivalent amount, generally 0.1 - 50 mol, preferably 1 - 20 mol, per 1 mol of compound (4). In some cases, an acid catalyst can also be used as a solvent.

The amount of compound (10) used is generally 1 - 20 mol, preferably 1 - mol, per 1 mol of compound (4).

This reaction is carried out without a solvent, or after dissolution or suspension in a solvent inert to the reaction. Such a solvent is not specifically limited as long as the reaction continues and, for example, hydrocarbons such as n-hexane, benzene, toluene, etc. can be mentioned; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, 1,2-dichloroethane, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc. nitrocarbons, such as nitromethane, nitrobenzene, etc.; nitriles such as acetonitrile, propionitrile, etc.; amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, etc.; sulfoxides, such as dimethyl sulfoxide, etc.; sulfolane; hexamethylphosphoramide; sulfur disulfide; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

The reaction temperature is generally -100 - 300 "С, preferably 0 - 200 76.

As the compound (10), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 14

Compound (BM) can be obtained, for example, by reacting compound (11) with an organometallic reagent according to step 8.

As the compound (11), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it.

The compound (VIM), which is the starting compound in the Reaction Scheme Ai, can be obtained, for example, by the method shown in the following Reaction Scheme AZ.

The scheme of the reaction of AZ shyuE vne shi cha a (zhu "a schu so de

ВР ня вени яд вой (ve) (vo) blood And! shi in da with x

Y du kyu Zhov J with soda J my own" manikh slediyai but water to drink Ve Ne sodns nm, A) byud"

M vv 5 (62) and (z) Y vl

Is it going to happen with ore o? on J) i duti se du u Stage 4 K-yaSHCI Stage 5 ni (vv) (vv) Y p where P is an amino protecting group and each other symbol is as defined above. stage 1

Compound (02) can be obtained, for example, by condensing compound (B1) and compound (VIH) according to the method of obtaining compound (Via) from compound (VMI).

As the compound (01), a commercially available product can be used, or it can be obtained from a commercially available compound by a substantially known method or a method similar thereto. stage 2

Compound (63) can be obtained by subjecting compound (p2) to a reduction reaction in the presence of a metal catalyst and a source of hydrogen. Such a reduction reaction is carried out according to the usual technique in a solvent that does not have a harmful effect on the reaction.

Examples of palladium-charcoal metal catalyst are palladium black, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, etc.

Examples of hydrogen source are hydrogen, formic acid, formamide salt, phosphinate salt, hydrazine, etc...

Examples of a solvent that does not have a harmful effect on the reaction are methanol, tetrahydrofuran, M,M-dimethylacetamide, etc.

The amount of metal catalyst used is generally 0.001 - 1000 mol, preferably 0.01 - 100 mol, per 1 mol of compound (02).

The reaction temperature is generally -70 - 150 "C, preferably -20 - 100 70.

The reaction time is generally 0.1 - 100 g, preferably 0.1 - 40 g.

This reaction can also be carried out in the presence of a reducing agent in a solvent that does not have a detrimental effect on the reaction.

As a reducing agent, we can mention oxide of iron, zinc, tin, etc., and compound (63)

can be obtained according to the reaction described in "iKKep Kadaki Kopyga (Te Spetisa! bosieiu oi Uarap eid.), 4 Eayop, my. 20. Ogdapis Zupipevzis II AIsopoY apa Atipe" 279-280,

Magigep Rgez5 1992, or in a way similar to it.

The amount of the reducing agent used is generally 0.1 - 20 mol per 1 mol of compound (02).

Examples of a solvent that does not have a harmful effect on the reaction are alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.; esters such as methyl acetate, ethyl acetate, n-butyl acetate, tert-butyl acetate, etc.; amides such as M,M-dimethylformamide, M,M-dimethylacetamide, M-methylpyrrolidine, etc.; etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction temperature is generally -70 - 150 "C, preferably -20 - 100 70.

The reaction time is generally 0.1 - 100 g, preferably 0.1 - 40 g. stage C

Compound (VIM) can be obtained, for example, by the reductive amination reaction of compound (63) and compound (04) according to the method of obtaining compound (Ba) from compound (VM).

As the compound (64), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in the art or a method similar thereto. stage 4

Compound (57) can be obtained by the Friedel-Crafts reaction of compound (B5) and glutaric anhydride (66) according to the synthesis method described in UUO2004/45616 or a method similar to it.

As the compound (65), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 5

Compound (568) can be obtained by removing the protecting group from compound (67) by a method known in the art, for example, by the method described in Rgoyesiime Sgoimrz ip Ogdapis Zupipezviv,

Tpiga Edyiop, U/Peu-Ipiegzsiepse (1999) or a method similar to it. stage 6

Compound (653) (B, BA, BA, and BA are hydrogen atoms) can be obtained by esterification of compound (68) by a method known in the art, for example, by the method described in Rgoyesiime Sgtoirz ip Ogdapis Zupipeviv, TNiga Eayiop, UMpeu-Ipsegzsiepse (1999) or by the method similar to him stage 7

Compound (510) can be obtained, for example, by condensing compound (69) and compound (VIH) according to the method of obtaining compound (Via) from compound (VMI).

As the compound (69), a commercially available product can be used or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 8

Compound (53) can be prepared, for example, by deprotecting compound (610) according to the procedure of step 5.

Among compounds (IA), the compound represented by the following formula (Via-1) (compound (Via-1)1 can be obtained according to the following Reaction Scheme A4.

Scheme of the reaction of A4 ov in odA where in KK stage uv vv

Vg M. (via-2u h (Viv-1)

where KM is a C1 alkyl group, C14 an aryl group, a 4-12-membered aromatic heterocyclic group (a group attached through a carbon atom on the ring), a 4-12-membered non-aromatic heterocyclic group (a group attached through a carbon atom on the ring) or a cyano group and other symbols are as defined above. stage 1

The compound (Via-ii-) can be obtained, for example, by the reaction of the compound (Via-2) with an organometallic reagent or a metal cyanide in the presence of a metal catalyst.

Examples of a metal catalyst are a palladium catalyst (for example, palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), tetrakis(triphenylphosphine)palladium(0), 1,1- bisidiphenylphosphino)ferrocenedichloropalladium adduct (I) and dichloromethane, bis(tris-tert-butylphosphine)palladium (0), etc.; nickel catalyst (for example, tetrakis(triphenylphosphine)nickel (0), dichloro(1,2-bisidiphenylphosphino)ethanenickel (I), dichloro(|1,3-bis(idiphenylphosphino)propane|nickel (II), dichloro1,4- bisidiphenylphosphino )butane|nickel (III), etc.).

The amount of the metal catalyst used is generally 0.01 - 1 mol, preferably 0.03 - 0.5 mol, per 1 mol of the compound (Via-2g).

Examples of organometallic reagent are boronic acid, boronate ester, reagent

Grinyara, organotin reagent, organozinc reagent, etc...

Examples of metal cyanide are zinc cyanide, etc.

The amount of the used organometallic reagent or metal cyanide is generally 1 - 100 mol, preferably 1 - 10 mol, per 1 mol of the compound (Via-g).

This reaction can be carried out in the presence of a base if necessary.

Examples of such bases are hydroxides of alkali metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals, such as magnesium hydroxide, calcium hydroxide, etc.; alkali metal carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, etc.; alkoxides of alkali metals having 1-b carbon atoms, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., etc.

The amount of the base used is generally 1 - 100 mol, preferably 1 - 10 mol, per 1 mol of the compound (Via-g).

This reaction can be carried out in the presence of a ligand if necessary.

Examples of such a ligand are a phosphorus-containing ligand (eg, triphenylphosphine, 1,3-bis(diphenylphosphino)propane, 1,3-bisidiphenylphosphino)propane, 2,2-bisidiphenylphosphino)-1,1-binaphthyl, and 4,5-bisidiphenylphosphino)-9 ,9-dimethylxanthene, etc.).

The amount of ligand used is generally 0.01 - 2 mol, preferably 0.02 - 1 mol, per 1 mol of the compound (Via-g).

This reaction is preferably carried out in a solvent inert to the reaction.

Such a solvent is not particularly limited as long as the reaction continues and, for example, alcohols such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, etc. can be mentioned; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc. hydrocarbons such as n-hexane, benzene, toluene, etc. amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; Sulfoxides, such as dimethyl sulfoxide, etc.; sulfolane; hexamethylphosphoramide; water, etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction temperature is generally -100 - 180 "C, preferably -80 "C - 150 70.

The reaction time is generally 0.1 g - 48 g, preferably 0.1 g - 24 g.

Compound (Via-2) can be obtained, for example, according to the method of obtaining compound (Via) in Reaction Scheme A1.

Among the compounds (BM) described in Reaction Scheme A2, the compound represented by the following formula (VU-1) (compound (VMU-1)) can be obtained according to the following Reaction Scheme AB.

Scheme of reaction A5 about dee-U. Ve o on (7-2) o v (as) uz --- X I

Stage 1 (as G- z (7-0 (VM-1) where each symbol is as defined above. stage 1

Compound (BM-1) can be obtained, for example, by reacting compound (7-1) with compound (7-2) in the presence of a base.

Examples of the base are hydroxides of alkali metals, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; hydroxides of alkaline earth metals, such as magnesium hydroxide, calcium hydroxide, etc.; alkali metal carbonates, such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, etc.; alkoxides of alkali metals having 1 - b carbon atoms, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.; metal hydrides such as sodium hydride, potassium hydride and calcium hydride; organic bases, such as 1,8-diazabicyclo|5.4.O)undec-/-ene (08), 1,5-diazabicyclo|4.3.O|non-5-ene /(OBM), 1,4-diazabicyclo/ 2.2.2) octane (SAVSO), etc. etc...

The amount of base used is generally 1-50 mol, preferably 1-20 mol, per 1 mol of compound (7-1).

The amount of compound (7-2) used is generally 1 - 10 mol, preferably 1 - mol, per 1 mol of compound (7-1).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, etc. can be mentioned; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; esters such as ethyl formate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; Sulfoxides, such as dimethyl sulfoxide, etc.; sulfolane; hexamethylphosphoramide, etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction temperature is generally -80 "C - 200 "C, preferably 0 C - 150 70.

The reaction time is generally 10 min - 48 g, preferably 15 min - 24 g.

Compound (7-1) can be obtained by a method known in essence or by a method similar to it.

Compound (7-2) can be obtained by a method known in essence or by a method similar to it.

Among the compounds (1), the compound represented by the following formula (1-1) (compound (1-1)) can be obtained according to the following Reaction Scheme Ab.

The scheme of the reaction of Ablig le "Ulozn kh KozvA bila, hudozhio b, sot bru Y. fordva on Stage 1 Ve Stage 2 ozh (1-3) (1-2) (1-1) de de EK" is S..v alkyl group and other symbols are as defined above.

stage 1

Compound (1-2) can be obtained, for example, by bromination of compound (1-3).

Examples of brominating reagents are M-bromamides, such as M-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, etc.

The amount of brominating agent used is generally 1 - 100 mol, preferably 1 - 10 mol, per 1 mol of compound (1-3).

This reaction can be carried out in the presence of a radical initiator when desired.

Examples of such a radical initiator are azobisisobutyronitrile, benzoyl peroxide, etc.

The amount of radical initiator used is generally 0.001 - 10 mol, preferably 0.01 - 5 mol, per 1 mol of compound (1-3).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, esters such as ethyl formate, ethyl acetate, n-butyl acetate, etc. may be mentioned; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc. nitriles such as acetonitrile, propionitrile, etc. and i.e. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

The reaction temperature is generally -100 - 180 "C, preferably -80 "C - 150 70.

The reaction time is generally 0.1 g - 48 g, preferably 0.1 g - 24 g.

Compound (1-3) can be obtained by a method known in essence or by a method similar to it. stage 2

Compound (1-14) can be obtained, for example, by reacting compound (1-2) with an alkali metal alkoxide.

Alternatively, compound (1-1) can also be obtained, for example, by reacting compound (1-2) with compound (1-2a) in the presence of a base.

Examples of alkali metal alkoxide are sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, etc.

The amount of alkali metal alkoxide used is generally 1-50 mol, preferably 1-10 mol, per 1 mol of compound (1-2).

Examples of bases are alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, etc.; alkali metal bicarbonates, such as sodium bicarbonate, potassium bicarbonate, etc.; metal hydrides such as sodium hydride, potassium hydride and calcium hydride, etc...

The amount of base used is generally 1-50 mol, preferably 1-10 mol, per 1 mol of compound (1-2).

The amount of compound (1-2a) used is generally 1-50 mol, preferably 1-10 mol, per 1 mol of compound (1-2).

This reaction is preferably carried out in a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction continues and, for example, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, tert-butanol, etc. can be mentioned; ethers such as 1,4-dioxane, tetrahydrofuran, diethyl ether, dimethoxyethane, tert-butyl methyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; esters such as ethyl formate, ethyl acetate, isopropyl acetate, n-butyl acetate, etc.; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, trichlorethylene, etc.; hydrocarbons such as n-hexane, benzene, toluene, etc.; amides such as formamide, M,M-dimethylformamide, M,M-dimethylacetamide, etc.; nitriles such as acetonitrile, propionitrile, etc.; Sulfoxides, such as dimethyl sulfoxide, etc.; sulfolane; hexamethylphosphoramide, etc. Two or more types of these solvents can be used in the form of a mixture with a suitable ratio.

In this reaction, alkali metal iodides, such as sodium iodide, potassium iodide, etc., can be added as a reaction promoter, in a total amount of 1 - 50 mol, preferably 1 - 10 mol, per 1 mol of compound (1-2) .

The reaction temperature is generally -80 "C - 200 "C, preferably 0 C - 15070. The reaction time is generally 0.1 g - 48 g, preferably 0.1 g - 24 g.

The compound (1-2a) can be obtained by a method known in essence or by a method similar to it.

In the compound (Via) Scheme of the reaction of AT, the compound is represented by the following formula (Via-3)

Ispoluka (Via-3)| and the compound represented by the formula (Via-4) (compound (Via-4)|, and in the compound (VIB) of the AT reaction scheme, the compound represented by the following formula (VIB-1) (compound (VIB-1)) can be obtained, for example, according to the methods shown in the following Reaction Scheme A7.

Scheme of the reaction A7 zen no Stage 1 o kiz av V oo lu v ve ve rai o au go) v o ve ch du show o o Stage o on NO (vm) kish s v" rai (spa (VY-1) y

Stage 4 Stage 6 Stage 8 m sl | ov) h ka Ge) au o v sh o sh v Ko

SO she fdi No kso (VMSH-1) no Ge) diz v so," vez (vsh-)u A ve de u (vu-) oh ne (VIХА1) / stage 10 in odu syusksoya Stage 7 ra y (viM) oh no

AT AV in ne (5) DYU oso Stage 11 o i (muk o DDMA ie prtt sya vas sia ve Stage 12 ve

Ge) vis (Via-3) (19) no (Via-4)

VAS Asi inn 13 on ve in (zh sek o. her eternally ve in Xia (VIiv-1) where VAS! There is (1) C.v alkyl optionally substituted 1 - With substituents selected from (a) atom halogen, (p) a carboxy group, (c) a C 1 -C 6 oxy group, (a) a C 3 -C cycloalkyl group, (e) a C 6 -C 6 -carbonyl group optionally substituted with 1 - C C 1 -C 4 aryl groups, () an amino group optionally mono- or di-substituted with substituent(s) selected from

C. .in the alkyl group and C-i. is the alkoxy-carbonyl group, (94) 4-12-membered aromatic heterocyclic group is optionally substituted 1 - With substituents selected from (I) a halogen atom, and ( her) Civ alkyl group, (n) 4-12-membered non-aromatic heterocyclic group optionally substituted with 1-C C6 alkyl groups, (i) Civ alkylsulfonyl group, (I) C-C alkylthio group, and (K) hydroxy group; (2) C7-iz aralkyl group; (3) St-a« aryl group;

(4) C.v alkyl-carbonyl group; (5) 4-12-membered aromatic heterocyclic group optionally substituted 1 - With substituents selected from (i) C alkyl group optionally substituted 1 - With halogen atoms, and (ii) cyano group; (6) 4-12-membered non-aromatic heterocyclyl-oxy group,

And the Aste leaving group, or hydroxy group,

Its other symbols are as defined above.

Examples of "departing groups" for 22! there is a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, etc... stage 1

At this stage, for example, compound (7-1-14) can be obtained by reacting compound (18) with compound (19).

When 1292! there is a leaving group, this reaction is carried out in the presence of a base in a solvent that does not have a detrimental effect on the reaction.

Examples of the base are amines such as triethylamine, M,M-isopropylethylamine, M-methylmorpholine, M,M-dimethylaniline, 4-dimethylaminopyridine, etc.; alkali metal salts such as sodium bicarbonate, sodium carbonate, potassium carbonate, potassium phosphate, etc.; an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; alkaline earth metal hydroxide, such as magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.; metal hydrides such as potassium hydride, sodium hydride, etc.; Si is an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., etc.

The amount of base used is generally 1-1000 mol, preferably 1-5 mol, per 1 mol of compound (18).

The amount of compound (19) used is generally 1-1000 mol, preferably 1-10 mol, per 1 mol of compound (18).

Examples of a solvent that does not have a harmful effect on the reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; amides such as M,M-dimethylformamide, M,M-dimethylacetamide, etc.; sulfoxides such as dimethyl sulfoxide, etc.; ketones, such as acetone, etc. acetonitrile; water. These solvents can be used in the form of a mixture with an acceptable ratio.

The reaction temperature is generally -80 "C - 150 "C, preferably -10 C -100 76.

The reaction time is generally 0.5 - 20 g.

When And 22! is a hydroxy group, this reaction is carried out by a method known in essence, for example, the method described by Zupipevzih, rad 1 (1981), or a method similar to it. That is, this reaction is generally carried out in the presence of an organophosphorus compound and an electrophile in a solvent that does not have a harmful effect on the reaction.

Examples of organophosphorus compounds are triphenylphosphine, tributylphosphine, etc.

Examples of electrophiles are diethyl azo dicarboxylate, diisopropyl azo dicarboxylate, 1,1-azodicarbonyldipiperidine, etc.

The amount of the used organophosphorus compound and electrophile in each case is generally 1 - 1000 mol, preferably 1 - 5 mol, per 1 mol of the compound (18).

The amount of compound (19) used is generally 1-1000 mol, preferably 1-5 mol, per 1 mol of compound (18).

As a solvent that does not have a harmful effect on the reaction, we can mention solvents similar to those mentioned above.

The reaction temperature is generally -80 - 150 "C, preferably -10 - 100 70.

Compound (18) and compound (19) can be prepared according to a technique known in the art. stage 2

At this stage, for example, compound (7-1-1) reacts with compound (7-2) in the presence of a base to give compound (U-2).

This reaction is carried out in the same way as in Reaction Scheme A5, stage 1.

Compound (7-2) can be obtained according to a method known in the art. stage Z

At this stage, for example, CS! compound (y-2) is removed to obtain compound (BM-2).

When KAS! is a benzyl group, this reaction is carried out, for example, in the presence of a metal catalyst, such as palladium-charcoal, palladium black, palladium-charcoal complex ethylenediamine, palladium chloride, platinum oxide, platinum black, platinum-palladium, Raney nickel, Raney cobalt, etc. .and. and a source of hydrogen in the solvent that does not have a detrimental effect on the reaction.

The amount of the metal catalyst used is generally 0.001 - 1000 mol, preferably 0.01 - 100 mol, per 1 mol of compound (U-2).

Examples of hydrogen source are hydrogen, formic acid, formamide salt, phosphinate salt, hydrazine, etc...

Examples of a solvent that does not have a harmful effect on the reaction are alcohols such as methanol, ethanol, propanol, 2-propanol, 2-methoxyethanol, butanol, isobutanol, tert-butanol, etc.; aromatic hydrocarbons such as benzene, toluene, xylene, etc. aliphatic hydrocarbons such as hexane, heptane, etc.; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like..; halogenated hydrocarbons, such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, etc.; amides such as M,M-dimethylformamide, M,M-dimethylacetamide, M-methylpyrrolidine, etc.; ethyl acetate, acetic acid, etc. These solvents can be used in the form of a mixture with an acceptable ratio.

The reaction temperature is generally 0 - 120 °C, preferably 10 - 80 70.

The reaction time is generally 0.5 - 100 g. stage 4

At this stage, for example, compound (M-2) can be obtained by reacting compound (VU-2) with compound (19). This stage is carried out in the same way as in this reaction, stage 1. stage 5

At this stage, for example, compound (VII-4) can be obtained by subjecting compound (M-2) to a reduction reaction. This reaction is carried out in the same manner as in Reaction Scheme 1, step 1. step 6

At this stage, for example, the compound (VIPI-1) can be obtained by converting the hydroxy group of the compound (VII-1) to the leaving group (I). This reaction is carried out in the same way as in the AT reaction scheme, stage 1. stage 7

At this stage, for example, the compound (Via-3) can be obtained by the reaction of the compound (VIP-1) with the compound (VIM) in the presence of a base. This reaction is carried out in the same way as on

Schemes of reaction A1, stage 2. stage 8

At this stage, for example, the compound (VMII-1) can be obtained by the reaction of the compound (VNPI-1) with the compound (BM) in the presence of a base. This reaction is carried out in the same way as on

Reaction schemes A1, stage 4. stage 9

At this stage, for example, the compound (VMPI-1) can be obtained by hydrolysis of the ester of the compound (VMII-1). This reaction is carried out in the same way as in Reaction Scheme A1, stage 6. stage 10

At this stage, for example, the compound (ViIa-3) can be obtained by condensing the compound (VMP-1) and the compound (VIH-1). This reaction is carried out in the same way as in the Scheme of the AT reaction, stage 7.

A commercially available product can be used as a compound (VIH-1) or it can be obtained from a commercially available compound by a method known in essence or a method similar to it. stage 11

At this stage, for example, the compound (Via-4) can be obtained by removing K/-! from the compound (Via-3). This stage is carried out in the same way as in this reaction, stage 3. stage 12

At this stage, for example, compound (Via-3) can be obtained by reacting (Via-4) with compound (19). This stage is carried out in the same way as in this reaction, stage 1.

stage 13

At this stage, for example, the compound (VIr-1) can be obtained by hydrolysis of the ester of the compound (Via-3) according to the method of obtaining the compound (VMI).

Compound (4-1), which is the starting compound of Reaction Scheme A2, can be obtained, for example, according to the method shown in the following Reaction Scheme AB.

Scheme of reaction AB o o o rez on Me o VE de o. Ko Me pet stcio and ON z venoya ne shk; s rem Stage ve: Stage 2 deya Stage I rez (71-1-2) (14) (16) (4-1) where each Kg and BA is a substituent, optionally having the AB ring mentioned above, and other symbols are as defined above. stage 1

At this stage, for example, compound (14) can be obtained by reacting compound (7-1-2) with compound (15) under basic conditions. This reaction is carried out in the same way as in the AB reaction scheme, stage 1. stage 2

At this stage, for example, compound (16) can be obtained by hydrolysis of the ester of compound (14) according to the method of obtaining compound (VMIII!I) in Reaction Scheme A1. stage Z

At this stage, for example, compound (4-14) can be obtained by reacting compound (16) in acetic anhydride.

At this stage, sodium acetate can be used as an additive.

The amount of sodium acetate used is generally 1 - 1000 mol, preferably 1 - 10 mol, per 1 mol of compound (16).

The reaction temperature is generally -80 - 200 "C, preferably -10 - 150 70.

The reaction time is generally 0.5 - 20 g.

Compound (7-1-2) and compound (15) can be prepared according to a technique known in the art.

In the compound (Via-3) of Reaction Scheme A7, the compound is represented by the following formula (Via-5)

Ispoluk (Via-5)) can be obtained, for example, by the method shown in the following Reaction Scheme A9.

Reaction scheme of AZ9 17

Ov Z so" g zs-me Ov v z v (dug Y e NA (du

Xia sia SY 18 and y ia"- And da no yy (E1a-41 stage dae" o (VIa-5) that

NeS on where the symbols are as defined above. stage 1

At this stage, for example, compound (Via-5) can be obtained by reacting compound (Via-4) with compound (17).

This reaction is carried out in the presence of a base in a solvent that does not have a harmful effect on the reaction.

Examples of the base are amines such as triethylamine, M,M-isopropylethylamine, M-methylmorpholine, M,M-dimethylaniline, 4-dimethylaminopyridine, etc.; alkali metal salts, such as sodium bicarbonate, sodium carbonate, potassium carbonate, etc.; alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.; hydroxides of alkaline earth metals, such as magnesium hydroxide, calcium hydroxide, barium hydroxide, etc.; metal hydrides such as potassium hydride, sodium hydride, etc.; Alkali metal alkoxides, such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc., etc.

The amount of base used is generally 1-50 mol, preferably 1-5 mol, per 1 mol of the compound (Via-4).

The amount of compound (17) used is generally 1-50 mol, preferably 1-5 mol, per 1 mol of compound (Via-4).

In this reaction, sodium iodide or potassium iodide can be added to the solvent.

The amount of used sodium iodide or potassium iodide is generally 1-100 mol, preferably 1-10 mol, per 1 mol of the compound (Via-4).

Examples of a solvent that does not have a harmful effect on the reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; halogenated hydrocarbons, such as chloroform, dichloromethane, etc.; aromatic hydrocarbons, such as benzene, toluene, xylene, etc.; amides such as N,M-dimethylformamide, etc.; sulfoxides such as dimethyl sulfoxide, etc.; ketones, such as acetone, etc.; acetonitrile; water. These solvents can be used in the form of a mixture with an acceptable ratio.

The reaction temperature is generally 0 - 150 °C, preferably 0 - 100 70.

The reaction time is generally 0.5 - 100 g.

The compound (ViIa-4) can be obtained according to Reaction Scheme A7.

Compound (17) can be obtained according to a method known in the art.

Thus obtained compound (I) and compound (A) can be isolated and purified by known means of separation and purification, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography, etc.

In addition, the compound (I) and the compound (IA) are obtained as free compounds and can be converted into the target salts by a known method or a method similar to it.

When they are obtained as salts, they can be converted into free forms or other target salts by a method known in the art or by a method analogous to it.

When compound (I) or compound (IA) is an optical isomer, stereoisomer, regioisomer, or rotamer, they are also covered by compound (I) and compound (IA), and can be obtained as a separate product according to methods of synthesis and separation known in the art.

For example, when compound (I) and compound (IA) have an optical isomer, the optical isomer isolated from this compound is also covered by compound (I) and compound (IA).

The optical isomer can be obtained according to techniques known in the art. Specifically, the optically active synthetic intermediate used or the final racemic product is subjected to optical resolution according to conventional techniques to obtain the optical isomer.

The method of optical separation can be a method known in the art, such as fractional recrystallization, using a chiral column, using a diastereomer, etc. 1) Fractional crystallization

A method in which a racemate salt is formed with an optically active compound (for example, (-4)-mandelic acid, (-)-mandelic acid, (g)-tartaric acid, (-)-tartaric acid, (5)-1-phenethylamine , (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), which is separated by fractional recrystallization, and if desired, the method includes a neutralization step to obtain the free optical isomer. 2) Chiral column

A method where the racemate or its salt is applied to a column to separate the optical isomer (chiral column) followed by separation. In the case of liquid chromatography, for example, a mixture of optical isomers is introduced into a chiral column, such as EMAMTO-OUM (manufactured by To5zoip Sogrogayop), SNIKAI series (manufactured by OyuaseI! SPetisai!

Ipdivigiev, a.) and those. and washed with water, various buffers (for example, phosphate buffer, etc.) and organic solvents (for example, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.) separately or with a mixture to separate the optical isomer. In the case of gas chromatography, for example, a chiral column such as SR-Spigazii-Sech SV (manufactured by

SI Zsieepsez Ips.) etc.

C) diastereomer

A method in which a racemic mixture is converted into a diastereomeric mixture by chemical reaction with an optically active reagent, and which gives a separate substance after conventional separation (eg, fractional crystallization, chromatography, etc.), etc. and subjected to chemical treatment, such as hydrolysis, etc., to separate the optically active reagent, thereby obtaining an optical isomer. For example, when compound (I) or compound (IA) contains hydroxy or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (for example, MTRA (o-methoxy-α-(trifluoromethyl)phenylacetic acid), (-) u-menthoxyacetic acid, etc.) etc. are subjected to a condensation reaction to obtain diastereomers of the ester of the compound or the amide of the compound, respectively. When the compound (I) has a carboxyl group, this compound and an optically active amine or an optionally active alcohol are subjected to a condensation reaction to obtain diastereomers of the amide of the compound or the ester of the compound, respectively. The separated diastereomer is converted to an optical isomer of the original compound using acid hydrolysis or basic hydrolysis.

Examples

The presented invention is disclosed in more detail in the following Examples,

Experimental Examples and Formulation Examples, which should not be construed as limitations.

TN-NMR spectra were recorded using tetramethylsilane as an internal standard and spectrometers Magiap Setipi 200 (200 MHz), 300 (300 MHz), VgyKeg 300 (300 MHz) and all values are shown in ppm. Unless otherwise indicated, numerical values shown for mixed solvents are volumes are ratios of mixed volumes of the respective solvents.

Unless otherwise indicated, 906 means wt.9o. In addition, unless otherwise indicated, the ratio of elution solvents in silica gel chromatography means the ratio of mixed volumes. Room temperature (ambient temperature) in the presented description is a temperature from about 20 "C to about 30 "70.

Each symbol in the Examples means the following.

DMSO: dimethylsulfoxide,

SOSI»z: deuterated chloroform, c: singlet, d: doublet, t: triplet, k: quartet, dd: doublet of doublets, dt: doublet of triplets, quin: quintet, m: multiplet, w: wide, y: splitting constant

LC/MS analyzes in the Examples were performed under the following conditions. device for measurement: RC/MS system Umaiegv

TOP: Adiyepei HP1100

MS: Mistotazz 2MO column: SARSEII. RAK c18005120 5-3 μm, 1.5x35 mm (manufactured by ZPizeido So., la.) solvent: SOLUTION A; 0.0595 aqueous solution of trifluoroacetic acid, SOLUTION B; 0.0495 acetonitrile solution of trifluoroacetic acid gradient cycle; 0 min. (SOLUTION A/SOLUTION B-90/10), 2.00 min. (SOLUTION A/SOLUTION

B-5/95), 2.75 min. (SOLUTION A/SOLUTION B-5/95), 2.76 min. (SOLUTION A/SOLUTION B-90/10), 3.60 min. (SOLUTION A/SOLUTION B-90/10) injection volume: 2 μl, flow rate: 0.5 ml/min, detection method: UV 220 nm,

Conditions of MS ionization method: ESI

Purification by preparative HPLC in the Examples was carried out under the following conditions. device: SiYzop Ips., highly effective purification system column: UMO SotbriRger O0O5-A 5-5 μm, 50x20 mm, or SotriRger Nuagozrpege C18 5-5 μm, 50x20 mm solvent: SOLUTION A; 0.195 aqueous solution of trifluoroacetic acid, SOLUTION B; 0.195 acetonitrile solution of trifluoroacetic acid gradient cycle; 0 min. (SOLUTION A/SOLUTION B-95/5), 1.00 min. (SOLUTION A/SOLUTION

B-95/5), 5.20 min. (SOLUTION A/SOLUTION B-5/95), 6.40 min. (SOLUTION A/SOLUTION B-5/95), 6.50 min. (SOLUTION A/SOLUTION B-95/5), 6.60 min. (SOLUTION A/SOLUTION B-95/5), or 0 min. (SOLUTION A/SOLUTION B:-98/2), 1.00 min. (SOLUTION A/SOLUTION B-98/2), 5.00 min. (SOLUTION

A/SOLUTION B:O0/100), 6.40 min. (SOLUTION A/SOLUTION B: O0/100), 6.50 min. (SOLUTION A/SOLUTION

B-98/2), 6.60 min. (SOLUTION A/SOLUTION B-98/2) flow rate: 20 ml/min, detection method: UV 220 nm

Example 1 3-II(4-Kcyclohexyl3-methyl-1-(5-"trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid o o do

Oh boom

E - M (1) ethyl 3-K(4-nitrobenzoyl)amino|propanoate

To a mixture of 4-nitrobenzoic acid (16.7 g), p-alanine ethyl ester hydrochloride (18.4 g), 1-hydroxybenzotriazole monohydrate (18.4 g), triethylamine (16.7 ml) and M,M- 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 g) was added to dimethylformamide (200 ml) and the mixture was stirred at room temperature for 8 h. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate.

The extract was washed with 1M hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. Recrystallization from ethyl acetate-hexane afforded the title compound (26.6 g, 100905) as white crystals.

IN NMR (300 MHz, SOSI") b m.h. 1.29 (t, 9U-7.2 Hz, Z H), 2.68 (t, 9U-6.1 Hz, 2 H), 3.76 (k,

U-6.1 Hz, 2 H), 4.19 (k, 2-7.1 Hz, 2 H), 7.03 (w s, 1 H), 7.93 (d, 9-9.1 Hz , 2 H), 8.29 (d, 2-8.7

Hz, 2 N). (2) ethyl 3-(4-aminophenyl)carbonyl)|amino)propanoate

A mixture of ethyl 3-(4-nitrobenzoyl)amino|propanoate (26.6 g) synthesized above, 590 palladium charcoal (8.9 g), tetrahydrofuran (150 mL), and ethanol (150 mL) was stirred at room temperature overnight in a hydrogen atmosphere. 595 Palladium charcoal was filtered off and the filtrate was concentrated under reduced pressure to give a white solid. Recrystallization from ethyl acetate-isopropyl ether afforded the title compound (22.6 g, 9590) as white crystals.

IN NMR (300 MHz, SOSI") b m.h. 1.27 (t, 9U-7.2 Hz, ZN), 2.63 (t, U-6.0 Hz, 2 N), 3.70 (k, 3-6.0 Hz, 2 N), 3.p94 (shs, 2 H), 4.17 (k, 9U-7.2 Hz, 2 H), 6.66 (d, U-8.7 Hz, 2 H), 7.60 (d, 9-8.7

Hz, 2 N). (3) methyl 3-methyl-1H-pyrazole-4-carboxylate

A mixture of methyl acetoacetate (30.0 g) and dimethylformamide dimethyl acetal (34.7 mL) was stirred at 100 °C for 12 g, and the mixture was allowed to cool. To the reaction mixture at room temperature were added ethanol (500 mL) and hydrazine monohydrate (12. 6 mL) and the mixture was refluxed for 12 g. The mixture was allowed to cool and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give the title compound (22.3 g, 6195) , as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.56 (s, ЗН), 3.84 (s, ЗН), 7.96 (s, 1Н). (4) methyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate

Sodium hydride (1.9 g, 6095 in oil) was added to a solution of methyl 3-methyl-1H-pyrazole-4-carboxylate (5.3 g) synthesized above in dimethylformamide (70 ml) at 0 C and the mixture was stirred for 10 min. 2-chloro-5-trifluoromethylpyridine (7.5 g) was added and the mixture was stirred at room temperature overnight. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:10, v/v) to give the title compound (3.3 g, 31905) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.57 (s, C H), 3.87 (s, C H), 7.97 - 8.17 (m, 2 H), 8 .63 - 8.74 (m, 1 H), 9.00 (s, 1 H). (5)3-methyl-1-(15-«(trifluoromethyl)pyridin-2-yl|-1H-pyrazole -4-carbaldehyde

Methyl 3-methyl-1-(5-(trifluoromethyl)-pyridin-2-yl|-1H-pyrazole-4-carboxylate (3.3 g), synthesized above, was dissolved in tetrahydrofuran (10 ml) and the solution dropwise lithium aluminum hydride (0.45 g) in tetrahydrofuran was added to the solution (20 ml) at 0 "C. The reaction mixture was stirred at 0 "C for 30 min and water (0.45 ml) was carefully added dropwise. In addition, 1 M aqueous sodium hydroxide solution (2.3 mL) and the mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through celite and the residue was washed with tetrahydrofuran (30 mL). The extracts were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in toluene (50 mL), manganese dioxide (8.8 g) was added and the mixture was heated under reflux for 1 h under dehydrating conditions. After spontaneous cooling, the manganese dioxide was filtered off and the residue was evaporated under reduced pressure to give the title compound ( 2.6 g, 8790), as a pale yellow solid. "N NMR (300 MHz, SOSIZ") b 2.57 (s, C H), 7.97 - 8.17 (m, 2 H), 8.63 - 8.74 (m, 1 H), 9.00 (c, 1 H), 9.95 (c, 1 H). (b) cyclohexyl3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-ylylmethanol

To a solution of 3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (2.6 g), synthesized above, in tetrahydrofuran (40 ml) was added dropwise 1M tetrahydrofuran solution of cyclohexylmagnesium bromide (15 ml) at 00. After stirring at 0 "C for 1 g, an aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, volume ratio) to give the title compound (2.0 g, 36905) as a colorless solid. "H NMR (300 MHz, SOSI") 6 ppm 0.93 - 1.93 (m, 11 H), 2.36 (s, C H), 3.62 (w s, 1 H), 4.44 (dd, 97.2, 3.4 Hz, 1 H), 7.91 - 8, 07 (m, 2 H), 8.43 (s, 1 H), 8.63 (s, 1 H). (7)3-I44-Kcyclohexyl3-methyl-1-(5-(trifluoromethyl)pyridine-2 -yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

To a solution (10 ml) of cyclohexyl3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol (0.75 g), synthesized above, in tetrahydrofuran at room temperature thionyl chloride (0.24 ml) was added and the mixture was stirred for 30 min. The reaction mixture was poured into an aqueous solution of sodium hydrogen carbonate at 0"C and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15 ml) and sodium iodide (0.63 g) carbonate was added. sodium (0.45 g) and ethyl 3-K(4-aminophenyl)carbonyl|aminopropanoate (0.75 g), synthesized in Example 1, (2). The mixture was stirred at 80 "C overnight and allowed to cool. Then, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography

(ethyl acetate:hexane-1:1, volume ratio) to give the title compound in the form of ethyl ester (876 mg). It was dissolved in ethanol (4 ml), at room temperature a 1M aqueous solution of sodium hydroxide (4 ml) was added and the mixture was stirred for 1 h. The ethanol was evaporated under reduced pressure and 1M hydrochloric acid (4 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.78 g, 70905) as a white solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.81 - 2.23 (m, 11 H), 2.34 (s, Z H), 2.50 - 2.68 (m, 2 H), 3.43 - 3.74 (m, 2 H ), 4.20 (d, 2-6.4 Hz, 1 N), 6.47 (d, 2-8.5 Hz, 2 N), 6.68 (w s, 1 N), 7.51 (d, uU-8.5 Hz, 2 N), 7.86 - 8.05 (m, 2 N), 8.31 (s, 1 N), 8.57 (s, 1 N).

Example 2 3-II(4-Kcyclohexyl3-methyl-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid 8) we him

EE

E - and M (1) ethyl 3-Imethyl(4-nitrobenzoyl)amino|propanesate

Using ethyl 3-(methylamino)propanoate (13.1 g) and in the same way as in

Example 1(1), the title compound (28.0 g, 10095) was obtained as an oil.

IN NMR (300 MHz, SOSI") b m.h. 1.26 (t, 9U-7.1 Hz, Z H), 2.51-2.78 (m, 2 H), 2.99-3.10 (m,

ZN), 3.46-3.86 (m, 2 H), 4.03-4.28 (m, 2 H), 7.50-7.65 (m, 2 H), 8.28 (d , U-8.7 Hz, 2 N). (2) ethyl 3-(4-aminophenyl)carbonyl)|(methyl)amino)upropanosate

In the same manner as in Example 1(2), the title compound (26.6 g, 9095) was obtained as an oil.

IN NMR (300 MHz, SOSI") b m.h. 1.26 (t, 9-7.2 Hz, Z H), 2.64 (t, 9U-6.4 Hz, 2 H), 3.05 (s, Z

H), 3.74 (t, U-7.0Hz, 2 H), 3.85 (she, 2 H), 4.14 (k, 20-7.2 Hz, 2 H), 6.59- 6.72 (m, 2 H), 7.23-7.28 (m, 2 H). (3) 3-I(4-Kcyclohexyl3-methyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Using cyclohexyl3-methyl-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol (0.75 g), synthesized in Example 1(6) and ethyl 3-( (4-Aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.80 g), synthesized in Example 2(2), and in the same manner as in Example 1 (7), obtained the target compound indicated in the title (0.74 g , 6595), as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.95 - 2.23 (m, 11 H), 2.37 (s, C H), 2.62 -2.78 (m, 2 H), 3.05 (s, C H), 3, 58 - 3.84 (m, 2 N), 4.21 (d, 2-6.1 Hz, 1 N), 6.49 (d, 2-8.7 Hz, 2 N), 7.24 ( d, 90-8.7

Hz, 2 N), 7.90 - 8.00 (m, 2 N), 8.32 (s, 1 N), 8.59 (s, 1 N).

Example C 3-II(4-Kcyclohexyl3-ethyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid do

E N

E - M (1) methyl 3-ethyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate

A mixture of methyl 3-oxopentanoate (2.6 g) and dimethylformamide of dimethyl acetal (2.8 ml) was stirred at 100 "C for 12 g and allowed to cool. Ethanol (50 ml) and hydrazine monohydrate (1.1 ml) were added to the reaction mixture. and the mixture was treated in the same manner as in Example 1(3) to obtain the crude product methyl 3-ethyl-1H-pyrazole-4-carboxylate.It was dissolved in dimethylformamide (30 ml), potassium carbonate (4.2 g) and 2- chloro-5-trifluoromethylpyridine (3.6 g) and the mixture was stirred at 100 "C for 2 h.

In the same manner as in Example 1(4), the title compound (4.7 g, 79905) was obtained as a yellow solid. "H NMR (300 MHz, SOSI") b m.ch. 1.33 (t, 9U-7.5 Hz, Z H), 3.00 (k, U-7.5 Hz, 2 H), 3 ,87 (c, Z

H), 7.99 - 8.18 (m, 2 H), 8.68 (s, 1 H), 9.00 (s, 1 H). (2) 3-ethyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

Methyl (3-ethyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (4.7 g) synthesized above was treated in the same manner as in Example 1 (5) affording the title compound (1.1 g, 2695) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.35 (t, 9-7.6 Hz, Z H), 3.00 (k, 9U-7.6 Hz, 2 H), 7.98 - 8.23 (m, 2 H), 8, 71 (s, 1 H), 9.04 (s, 1 H), 10.05 (s, 1 H). (3) cyclohexyl3-ethyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-ylylmethanol

3-Ethyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde (1.1 g), synthesized above, was treated in the same manner as in Example 1(6) to obtain the indicated title compound (1.1 g, 79905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.80 - 2.21 (m, 14 N), 2.73 (k, 9-7.3 Hz, 2 N), 4.44 (dd, 7.2, 3.4 Hz, 1 N), 7.87 - 8.16 (m, 2 H), 8.43 (s, 1 H), 8.63 (s, 1 H). (4) 3-I(4-Kcyclohexyl3-ethyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

Using cyclohexyl3-ethyl-1-(15-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (0.55 g) synthesized above and ethyl 3-L-(4-aminophenyl)carbonyl |amino)propanoate (0.37 g), synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.32 g, 3890) was obtained as a white solid substance. "H NMR (300 MHz, SOSI") b m.ch. 0.86 - 2.00 (m, 11 N), 1.32 (t, 9-7.5 Hz, Z H), 2.38 - 2.58 (m, 2 N), 2.70 (k , U-7.5 Hz, 2 N), 3.39 - 3.69 (m, 2 N), 4.22 (d, 9U-6.0 Hz, 1 N), 6.47 (d, 9 -8.5 Hz, 2 N), 6.68 (w s, 1 N), 7.51 (d, 9U-8.5 Hz, 2 N), 7.85 - 8.08 (m, 2 N ), 8.30 (c, 1 N), 8.56 (c, 1 N).

Example 4 3-II(4-Kcyclohexyl3-ethyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

With o du

E E

E-M M

Using cyclohexyl3-ethyl-1-(15-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol (0.55 g), synthesized in Example C(3), and ethyl 3- I((4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.39 g), synthesized in Example 2(2), and in the same way as in Example 1(7), obtained the target compound specified in the title (0, 35 g, 4195), as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.19 - 2.06 (m, 11 N), 1.35 (t, 9U-7.5 Hz, Z H), 2.60 - 2.81 (m, 4 N), 3.05 (s , Z H), 3.72 (d, 9-7.5 Hz, 1 H), 4.24 (d, 92-6.2 Hz, 1 H), 6.50 (d, 9U-8.7 Hz, 2 N), 7.26 (d, 928.7 Hz, 2 N), 7.91 - 8.09 (m, 2 N), 8.31 (s, 1 N), 8.59 (s , 1 H).

Example 5 3-II(4-Ccyclohexyl3-propyl-1-15-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

With IF) gu

IS

Eo-(1) methyl 3-propyl-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate

A mixture of methyl 3-oxohexanoate (2.1 g) and dimethylformamide dimethyl acetal (2.1 ml) was stirred at 100 "С for 12 g and the mixture was left to cool. Ethanol (50 ml) and hydrazine monohydrate (0.75 ml ). In the same way as in Example 1(3), the crude product - methyl 3-propyl-1H-pyrazole-4-carboxylate was obtained. It was dissolved in dimethylformamide (20 ml), potassium carbonate (3.0 g) was added and 2-chloro-5-trifluoromethylpyridine (2.7 g) and the mixture was stirred at 100 "С for 2 h.

In the same manner as in Example 1(4), the title compound (3.3 g, 71905) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.p. 1.02 (t, U-7.4 Hz, Z H), 1.69 - 1.88 (m, 2 H), 2.93 ( d, 9-7,7

Hz, 2 H), 3.87 (s, 3 H), 7.98 - 8.19 (m, 2 H), 8.69 (s, 1 H), 9.00 (s, 1 H). (2) 3-propyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

Methyl 3-propyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate (3.3 g), synthesized above, was treated in the same manner as in Example 1(5) to obtain the title compound (1.1 g, 35905) as a yellow oil. "H NMR (300 MHz, SOCI") 6 ppm 1.03 (t, 9U-7.3 Hz, C H), 1.79 (m, 2 N), 2.94 (d, 9-7.7 Hz, 2

H), 8.00 - 8.23 (m, 2 H), 8.71 (s, 1 H), 9.04 (s, 1 H), 10.05 (s, 1 H). (3) cyclohexyl3-propyl-1-N5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol

C-Propyl-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde (1.1 g), synthesized above, was treated in the same manner as in Example 1(6) to obtain the indicated title compound (1.3 g, 9590) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.80 - 2.21 (m, 16 N), 2.67 (k, 9-7.8 Hz, 2 N), 4.44 (dd, uUE7.5, 3.4 Gu, 1 N), 7.90 - 8.16 (m, 2 H), 8.43 (s, 1 H), 8.63 (s, 1 H). (4) 3-I(4-Kcyclohexyl3-propyl-1-I5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

Using cyclohexyl3-propyl-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (0.65 g) synthesized above and ethyl 3-L(4-aminophenyl)carbonyl| amino)propanoate (0.42 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) gave the title compound (0.38 g, 3990) as a white solid . "H NMR (300 MHz, SOSI") b m.ch. 1.03 (t, 9U-7.4 Hz, Z H), 1.07 - 2.04 (m, 13 H), 2.49 - 2.74 (m, 4 N), 3.52 - 3.72 (m, 2 N), 4.24 (d, 2-6.4 Hz, 1 N), 6.50 (d, 9U-8 .7 Hz, 2 N), 6.55 - 6.68 (m, 1

H), 7.53 (d, U9-8.7 Hz, 2 H), 7.86 - 8.08 (m, 2 H), 8.31 (s, 1 H), 8.57 (s, 1 H).

Example 6 3-II(4-Kcyclohexyl3-propyl-1-15-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid (F (F du

E vo-M M

Using cyclohexyl3-propyl-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol (0.65 g), synthesized in Example 5(3), and ethyl 3-I ((4-

aminophenyl)carbonyl|/methyl)aminopropanoate (0.44 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained (0.34 g, 3495) , as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 1.03 (t, 9U-7.2 Hz, Z H), 1.08 - 2.13 (m, 13 H), 2.54 - 2.78 (m, 4 N), 3.05 (s, C H), 3.71 (t, U-6.2 Gu, 1 H), 4.24 (d, 20-5.7 Hz, 1 N), 6.50 (d, 9-8.7 Hz, 2 N), 7.26 (d, U-8.7 Hz, 2 N), 7.87 - 8.12 (m, 2 N ), 8.31 (c, 1 N), 8.59 (c, 1 N).

Example 7 3-II(4-Kcyclohexyl/13-(1-methylethyl)-1-(15-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl) amino|propanoic acid o o dur

IS

E -- m (1) methyl 3-(1-methylethyl)-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate

Using methyl 4-methyl-3-oxopentanoate (2.9 g), dimethyl acetal dimethylformamide (2.8 ml) and hydrazine monohydrate (1.1 ml) and in the same manner as in

In Example 1(3), crude product methyl 3-(1-methylethyl)-1H-pyrazole-4-carboxylate was obtained. It was dissolved in dimethylformamide (30 ml), potassium carbonate (4.2 g) and 2-chloro-5-trifluoromethylpyridine (3.6 g) were added, and the mixture was stirred at 100 "С for 2 h.

In the same manner as in Example 1(4), the title compound (4.6 g, 73905) was obtained as a white solid.

IN YAMRE (300 MHz, SOSI") b m.h. 1.36 (d, U-6.8 Hz, 6 N), 3.60 (quin, U-6.8 Hz, 1 N), 3.87 (s,

With H), 7.99 - 8.99 (m, 4 H). (2) 3-(1-methylethyl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde

Methyl 3-(1-methylethyl)-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (4.6 g), synthesized above, was treated in the same manner as in Example 1(5) affording the title compound (1.7 g, 4095) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.38 (d, U-6.8 Hz, 6 N), 3.41 - 3.64 (m, 1 N), 8.01 - 8.28 (m, 2 N), 8.70 (s , 1 N), 9.04 (c, 1 N), 10.06 (c, 1 N). (3) cyclohexyl/3-(1-methylethyl)-1-15-"trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol 3-(1-Methylethyl)-1-(5- (trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized above was treated in the same manner as in Example 1(6) to give the title compound (1.5 g , 71905), as yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.80 - 2.21 (m, 17 N), 3.01 (quin, U-6.9 Hz, 1 N), 4.45 (dd, 97.5, 3.6 Hz, 1 N), 7.90 - 8.10 (m, 2 H), 8.43 (s, 1 H), 8.62 (s, 1 H). (4)3-I44-Kcyclohexyl/i3-(1-methylethyl)-1-(I5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino |propanoic acid

Using cyclohexyl 3-(1-methylethyl)-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (0.50 g), synthesized above, and ethyl 3-( (4-aminophenyl)carbonylamino)propanoate (0.32 g), synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound was obtained (0.11 g, 1495) , as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.20 - 2.06 (m, 11 N), 1.28 - 1.40 (m, 6 N), 2.64 (t, U-4.5

Hz, 2 N), 2.91 - 3.17 (m, 1 N), 3.54 - 3.79 (m, 2 N), 4.29 (d, 2-6.2 Hz, 1 N) , 6.43 -6.65 (m, Z H), 7.54 (d, 9U-8.7 Hz, 2 H), 7.86 - 8.11 (m, 2 H), 8.30 ( c, 1 N), 8.58 (c, 1 N).

Example 8 3-II(4-Kcyclohexyl/13-(1-methylethyl)-1-(15-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl )amino|propanoic acid o o

Eh, well, eff

E-M M

Using cyclohexyl[1-(1-methylethyl)-1-(5-trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-ylmethanol (0.65 g), synthesized in Example 7(3), and ethyl 3-K(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.34 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained (0.16 g, 2195) as a white solid.

IN NMR (300 MHz, SOS") b m.h. 1.20 - 2.05 (m, 11 N), 1.32 - 1.37 (m, 6 N), 2.59 - 2.79 (m, 2

H), 2.96 - 3.20 (m, 4 H), 3.73 (t, 9-7.5 Hz, 2 H), 4.28 (d, 9-6.0 Hz, 1 H) , 6.52 (d, 9-8.7 Hz, 2 N), 7.26 (d, U-8.7 Hz, 2 N), 7.88 - 8.11 (m, 2 N), 8 .30 (c, 1 H), 8.59 (c, 1 H).

Example 9 3-II(4-Kcyclohexyl3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

Dt

E E

Joon-O

E - M M (1) methyl 3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate

Using methyl 3-cyclopropyl-3-oxopropanoate (2.8 g), dimethylformamide dimethyl acetal (2.8 ml) and hydrazine monohydrate (1.1 ml) and in the same manner as in

In Example 1(3), the crude product methyl 3-cyclopropyl-1H-pyrazole-4-carboxylate was obtained. It was dissolved in dimethylformamide (30 ml), potassium carbonate (4.2 g) and 2-chloro-5-trifluoromethylpyridine (3.6 g) were added, and the mixture was stirred at 100 "С for 2 h.

In the same manner as in Example 1(4), the title compound (4.8 g, 7790) was obtained as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.02 - 1.10 (m, 4 N), 2.55 - 2.70 (m, 1 N), 3.89 (s, Z H), 8.00 - 8.03 (m, 2 N ), 8.66 (s, 1 N), 8.96 (s, 1 N). (2) 3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

Methyl 3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate (4.8 g), synthesized above, was treated in the same manner as in Example 1 (5 ) to give the title compound (1.5 g, 36905) as a white solid. "H NMR (300 MHz, SOCI") 6 ppm 1.02 - 1.15 (m, 4 H), 2.50 - 2.70 (m, 1 H), 8.00 - 8.10 (m, 2

H), 8.69 (s, 1 H), 8.99 (s, 1 H), 10.10 (s, 1 H). (3) cyclohexyl3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol

3-Cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (1.5.kg) synthesized above was treated in the same manner as in Example 1 ( 6) affording the title compound (2.1 g, 99965) as a white solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.80 - 2.10 (m, 16 N), 4.48 (dd, 9U-7.3, 3.0 Hz, 1 N), 7.90 - 8.10 (m, 2 N), 8 .40 (c, 1 N), 8.60 (c, 1 N). (4) 3-I(4-Kcyclohexyl3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

Using cyclohexyl3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1 H-

pyrazol-4-ylmethanol (0.50 g), synthesized above, and ethyl 3-K4-aminophenyl)carbonylamino)propanoate (0.32 g), synthesized in Example 1(2), and in the same manner as in Example 1 (7), afforded the title compound (0.15 g, 21905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.86 - 2.07 (m, 16 N), 2.64 (t, 9U-5.5 Hz, 2 N), 3.65 (k, 9U-5.9

Hz, 2 N), 4.37 (d, 9-6.4 Hz, 1 N), 6.54 - 6.70 (m, C H), 7.53 (d, U-8.3 Hz, 2 H), 7.93 (s, 2 H), 8.28 (s, 1 H), 8.56 (s, 1 H).

Example 10 3-II(4-Kcyclohexyl3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl1|-1H-pyrazol-4-ylylmethyl)amino|phenyl)carbonyl)(methyl)amino|propanoic acid g tn

E E UN

E-M M

Using cyclohexyl3-cyclopropyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (0.50 g), synthesized in Example 9(3), and ethyl 3-K(4 - aminophenyl)carbonyl|)methyl)aminoisopropanoate (0.34 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound specified in the title was obtained (0.19 g, 2595 ), as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 0.92 - 2.09 (m, 16 N), 2.71 (t, U-6.2 Hz, 2 N), 3.07 ( s, Z H), 3.71 (t, U-6.4 Hz, 2 H), 4.36 (d, 2-6.4 Gu, 1 H), 6.54 (d, 2-8, 7 Hz, 2 N), 7.26 (d, 9-8.7 Hz, 2 N), 7.94 (s, 2 N), 8.28 (s, 1 N), 8.57 (s, 1 H).

Example 11 3-I(4-Kcyclohexyl3-(2-phenylethyl)-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethyl)amino|phenylcarbonyl)amino|propanoic acid and

N

E E

Joo-y

E - M (1) ethyl 3-(2-phenylethyl)-1-(5-«(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate

Using ethyl 3-oxo-5-phenylentanoate (5.88 g), dimethyl acetal dimethylformamide (3.6 ml) and hydrazine monohydrate (1.3 ml) and in the same manner as in

In Example 1(3), the crude product ethyl 3-(2-phenylethyl)-1H-pyrazole-4-carboxylate was obtained. It was dissolved in dimethylformamide (30 ml), potassium carbonate (5.5 g) and 2-chloro-5-trifluoromethylpyridine (4.8 g) were added, and the mixture was stirred at 100 "C overnight.

In the same manner as in Example 1(4), the title compound (5.2 g, 50905) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 1.39 (t, 9U-7.2 Hz, Z H), 3.00 - 3.15 (m, 2 H), 3.22 - 3.39 (m, 2 N), 4.34 (k, 9-7.2 Hz, 2 N), 7.15 - 7.38 (m, 10 N), 7.99 - 8.17 (m , 2 H), 8.69 (s, 1 H), 9.01 (s, 1

N).

(2) 3-(2-phenylethyl)-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

Ethyl 3-(2-phenylethyl)-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate (5.2 g), synthesized above, was treated in the same manner as in Example 1(5) to give the title compound (3.0 g, 65905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.98 - 3.17 (m, 2 H), 3.22 - 3.41 (m, 2 H), 7.11 - 7.47 (m, 5

H), 7.99 - 8.22 (m, 2 H), 8.71 (s, 1 H), 9.04 (s, 1 H), 9.99 (s, 1 H). (3) cyclohexyl[13-(2-phenylethyl)-1-(5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl)umethanol 3-(2-Phenylethyl)-1-(I5 -(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde (1.5 g) synthesized above was treated in the same manner as in Example 1(6) to give the title compound (1, 7 g, 9595), as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.83 - 2.02 (m, 12 N), 2.92 - 3.23 (m, 4 N), 4.28 (dd, 9-7.3, 2.7 Hz, 1 N), 7 .15 - 7.40 (m, 5 N), 7.93 - 8.13 (m, 2 N), 8.42 (s, 1 N), 8.64 (s, 1 N). (4). 3-I44-(cyclohexyl/13-(2-phenylethyl)-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propane acid

Using cyclohexyl3-(2-phenylethyl)-1-(15-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (0.50 g), synthesized above, and ethyl 3-((4- aminophenyl)carbonylamino)propanoate (0.28 g), synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.20 g, 28906) was obtained as a white solid substance. "H NMR (300 MHz, SOSIZ") b m.p. 0.84 - 1.97 (m, 11 N), 2.45 - 2.64 (m, 2 N), 2.87 - 3.18 (m, 4

H), 3.49 - 3.67 (m, 2 H), 4.16 (d, 9U-6.0 Gu, 1 H), 6.41 (d, 9-8.7 Hz, 2 H) , 6.61 (she, 1 N), 7.15-7.34 (m, 5 N), 7.49 (d, 928.7 Hz, 2 N), 7.87 - 8.10 (m, 2 H), 8.31 (s, 1 H), 8.57 (s, 1 H).

Example 12 3-I(4-Kcyclohexyl3-(2-phenylethyl)-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino| propanoic acid

Yi Yi ud theo

Eee

Zoo-

E -kM M

Using cyclohexyl(3-(2-phenylethyl)-1-(15-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-ylmethanol (0.50 g), synthesized in Example 11(3), and ethyl 3-K(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.35 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound indicated in the title was obtained ( 0.30 g, 4195), as a white solid. "H NMR (300 MHz, SOSI") b m.p. 0.93 - 2.01 (m, 11 H), 2.59 - 2.74 ( m, 2 H), 2.89 - 3.20 (m, 7

H), 3.71 (d, 9U-6.0 Hz, 2 H), 4.18 (d, 9-6.0 Hz, 1 H), 6.43 (d, 9U-8.7 Hz, 2 N), 7.16 - 7.37 (m, 5 N), 7.90 - 8.13 (m, 2 N), 8.32 (s, 1 N), 8.60 (s, 1 N ).

Example 13 3-1(4-(/3-tert-butyl-1-15-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)cyclohexyl)methylaminophenyl)carbonylamino)propanoic acid o (8) dol »

N

E E

Ughneg

E -Z- M Mm- OH» sn,

SN. (1) methyl 3-tert-butyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate

Using ethyl 4,4-dimethyl-3-oxopentanoate (3.4 g), dimethylformamide dimethyl acetal (2.8 ml) and hydrazine monohydrate (1.1 ml) and in the same manner as in

In Example 1(3), the crude product methyl 3-tert-butyl-1H-pyrazole-4-carboxylate was obtained. It was dissolved in dimethylformamide (15 ml), potassium carbonate (1.2 g) and 2-chloro-5-trifluoromethylpyridine (1.7 g) were added, and the mixture was stirred at room temperature overnight. In the same manner as in Example 1(4), the title compound (2.8 g, 43905) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.p. 1.38 (t, 9U-7.2 Hz, Z H), 1.49 (s, 9 H), 4.32 (k, 9- 72 Hz, 2

H), 7.98 - 8.21 (m, 2 H), 8.68 (d, 9-1.1 Hz, 1 H), 9.03 (s, 1 H). (2) 3-tert-butyl-1-(5-"(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

Methyl 3-tert-butyl-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate (2.8 g), synthesized above, was treated in the same manner as in Example 1 ( 5) obtaining the title compound (1.7 g, 9395) as a white solid. "H NMR (300 MHz, SOCI") 6 ppm 1.49 (s, 9 H), 7.98 - 8.21 (m, 2 N), 8.68 (d, 9-1.1 Hz, 1 N), 9.09 (s, 1 N), 10.11 (s, 1 N). (3 ) cyclohexyl3-tert-butyl-1-(15-«(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol

3-tert-butyl-1-(5-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde (1.7 g), synthesized above, was treated in the same manner as in Example 1(6) affording the title compound (1.1 g, 49965) as a white solid. "H NMR (300 MHz, SOCI") b m.p. 0.79 - 2.20 (m, 12 N), 1 .43 (s, 9 N), 4.65 (d, 9-9.0 Hz, 1 N), 7.91 - 8.15 (m, 2 N), 8.52 (s, 1 N), 8.62 (s, 1 H). (4) 3-((4-1(3-tert-butyl-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)cyclohexyl )methyliaminophenyl)carbonyl|amino)propanoic acid

Using cyclohexyl3-tert-butyl-1-(15-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (0.53 g) synthesized above and ethyl 3-((4-aminophenyl) carbonylamino)propanoate (0.32 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) afforded the title compound (0.12 g, 1595) as a white solid .

IN NMR (300 MHz, SOSI") b m.h. 1.00 - 2.00 (m, 11 N), 1.27 (s, 9 N), 2.57 - 2.61 (m, 2 N), 3.17 - 3.59 (m, 2 N ), 444 (shs, 1 H), 6.31 - 6.51 (m, 2 H), 7.33 - 7.47 (m, 1 H), 7.49 - 7.62 (m,2

H), 7.74 - 8.07 (m, 2 H), 8.32 - 8.57 (m, 2 H).

Example 14 3-1(4-(/3-tert-butyl-1-15-"trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl-cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino) propanoic acid

Yi Yi dr

EE dream

E - M M - CH; dream

CH,

Using cyclohexyl3-tert-butyl-1-(15-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (0.52 g), synthesized in Example 13(3), and ethyl 3-K (4-Aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.34 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained (0.13 g , 1695), as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.96 - 2.00 (m, 11 H), 1.42 (s, 9H), 2.61 - 2.81 (m, 2 H), 3.08 (s, C H), 3.72 (t, U-6.4 Hz, 2 N), 4.57 (d, 9-61 Hz, 1 N), 6.54 (d, 90-8.7 Hz, 2 N), 7.26 ( d, uU-8.7 Hz, 2 N), 7.89 - 8.13 (m, 2 N), 8.40 (s, 1 N), 8.59 (s, 1 N).

Example 15 3-(X4-Ccyclohexyl(|1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl|methyl)iamino)phenylcarbonylamino)propanoic acid

N oon-y

M

(1) ethyl 1-phenyl-3-(2-phenylethyl)-1H-pyrazole-4-carboxylate

A mixture of ethyl 3-oxo-5-phenylpentanoate (5.8 g) and dimethylformamide of dimethyl acetal (3.6 ml) was stirred at 100 °C overnight and the mixture was allowed to cool to room temperature. Ethanol (30 ml) and phenylhydrazine were added to the reaction mixture. (2.9 g) and the mixture was further stirred at 100 C for 8 h. After spontaneous cooling, the ethanol was evaporated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:10, v/v) to give the title compound (7.1 g, 8490) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.40 (t, 9U-7.2 Hz, Z H), 2.87 (dd, U-9.0, 6.6 Hz, 2 H), 3.15 - 3.32 (m, 2 H ), 4.36 (k, U9-7.2 Hz, 2 N), 6.92 - 7.53 (m, U-7.5, 3.8, 3.8, 3.5 Hz, 10 N ), 8.05 (s, 1 N). (2) 1-phenyl-3-(2-phenylethyl)-1H-pyrazole-4-carbaldehyde

Ethyl 1-phenyl-3-(2-phenylethyl)-1H-pyrazole-4-carboxylate (7.1 g) synthesized above was treated in the same manner as in Example 1(5) to give the title compound (4 .6 g, 75905), as a white solid.

IN YAMRE (300 MHz, SOSIz) 6 m.h. 2.87 (t, 9U-7.8 Hz, 2 N), 3.23 (t, 9U-7.6 Hz, 2 N), 6.84 - 7.58 (m, 10 N), 8, 07 (c, 1 H), 9.93 (c, 1 H). (3) cyclohexyl|1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl|methanol 1-Phenyl-3-(2-phenylethyl)-1H-pyrazole-4-carbaldehyde (2.6 g ), synthesized above, was treated in the same manner as in Example 1(6) to give the title compound (2.9 g, 85905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.75 - 2.19 (m, 12 N), 2.46 - 3.17 (m, 4 N), 4.16 (dd, U-8.3, 2.7 Hz, 1 N), 6 .83 - 7.54 (m, 10 N), 7.58 (s, 1 N). (4) 3-(X4-cyclohexyl(|1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl|methyl)amino)phenyl-carbonylamino)propanoic acid

Using cyclohexyl(|1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl|methanol (0.50 g) synthesized above and ethyl 3-|(4-aminophenyl)carbonylaminoiopropanoate (0. 33 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.31 g, 4195) was obtained as a white solid.

"H NMR (300 MHz, SOSI") 6 m.h. 0.94 - 2.03 (m, 11 N), 2.40 - 2.56 (m, 2 N), 2.67 (t, 9U -5.7

Hz, 2 N), 2.91 - 3.07 (m, 2 N), 3.68 (k, 9U-5.9 Hz, 2 N), 4.20 (d, 2-7.0 Hz, 1 H), 6.52 - 6.58 (m, uU-8.7 Hz, Z H), 6.82 (d, U-8.6 Hz, 2 H), 7.12 - 7.22 ( m, 4 N), 7.35 - 7.65 (m, 11 N).

Example 16 3-D4-Hcyclohexyl(|1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid (8)

Using cyclohexyl(|1-phenyl-3-(2-phenylethyl)-1H-pyrazol-4-yl|methanol (0.50 g), synthesized in Example 15(3), and ethyl 3-((4-aminophenyl )carbonyl)methyl)amino)upropanoate (0.35 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained (0.37 g, 4790) , as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 2.08 (m, 11 H), 2.44 - 2.59 (m, 2 H), 2.73 (d, 9U-6.0

Hz, 2 N), 2.91 - 3.05 (m, 2 N), 3.09 (s, C H), 3.7Z (t, U-6.4 Hz, 2 N), 4.19 (d, 9-68 Hz, 1 N), 6.53 (d, U-8.7 Hz, 2 N), 6.79 - 6.88 (m, 2 N), 7.12 - 7.58 (m, 11 H).

Example 17 3-1(4-Icyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methylamino)phenyl)carbonylamino)propanoic acid! Y AH with On

NN

He

Moosh-

Men, (1) methyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (14.4 g), synthesized in Example 1, (3) was dissolved in dimethylacetamide (200 ml), phenylboronic acid (25.0 g), copper acetate (36.4 d) and pyridine (32 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (100 ml) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane 10:1, v/v) to give the title compound (11.4 g, 5395) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.56 (s, ZN), 3.86 (s, ZN), 7.26-7.70 (m, 5H), 8.34 ( c, 1H). (2) 3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde

Methyl 3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (11.4 g) synthesized above was treated in the same manner as in Example 1(5) to give the title compound (3.8 g , 3995) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.59 (s, ЗН), 7.27-7.72 (m, 5Н), 8.34 (s, 1Н), 10.00 ( with, 1H).

(3) cyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methanol

C3-Methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (3.8 g) synthesized above was treated in the same manner as in Example 1(6) to give the title compound (4.4 g, 7995 ), as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.80-2.20 (m, 11H), 2.34 (s, ZH), 3.61 (shs, 1H), 4.44 (d,

U-7.2 Hz, 1H), 7.20-7.80 (m, 6H). (4) 3-I(4-Iicyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methyliamino)phenyl)carbonylamino)propanoic acid

Using cyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methanol (0.14 g) synthesized above and ethyl 3-|(4-aminophenyl)carbonylaminoiopropanoate (0.15 g), synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.05 g, 3195) was obtained as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.04 - 2.21 (m, 12 H), 2.36 (s, Z H), 2.65 (w s, 2 H), 3.67 (she, 2 H), 4.20 (d , 2-6.0 Hz, 1 N), 6.49 (d, 2-6.0 Hz, 2 N), 6.55 - 6.71 (m, 1 N), 7.14 - 7.74 (m, 8

N).

Example 18 3-1(4-Icyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid a (8)

І ml TON with sn

CA

My

MO tan,

Using cyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methanol (0.14 -"Hg), synthesized in Example 17(3), and ethyl 3-((4-aminophenyl)carbonyl)methyl )amino)propanoate (0.15 g) synthesized in Example 2(2) and in the same manner as in Example 1(7) gave the title compound (0.04 g, 2390) as a white solid substance." H NMR (300 MHz, DMSO-α) 6 m.h. 0.87 - 2.10 (m, 12 N), 2.25 (s, Z H), 2.47 (t, 9-7.4 Hz, 2

H), 2.89 (s, C H), 3.51 (t, 90-7.4 Hz, 2 H), 4.16 (t, 9U-7.6 Gu, 1 H), 6.22 (d, 9-80 Hz, 1 N), 6.58 (d, U-8.7 Hz, 2 N), 7.10 (d, 9-8.7 Hz, 2 N), 7.22 ( t, 9-7.2 Gu, 1 N), 7.43 (t, 9-8.0 Gu, 1 N).

Example 19 3-(X14-31-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methyl)amino)phenylcarbonyl)iamino)propanoic acid

N

More

Jood-y

MO sen, (1) methyl 1-(4-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate

Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.25 g), synthesized in

Example 1(3), 4-chlorophenylboronic acid (13.9 g), copper acetate (16.3 g) and pyridine (14.4 ml) and in the same manner as in Example 17(1), obtained the title the target compound (6.9 g, 62905) as a white solid. "H NMR (300 MHz, DMSO-av) b m.p. 2.54 (s, C H), 3.85 (s, C H), 7.43 (d, 2-8.7 Hz, 2 H), 7.62 (d, U-8.7 Hz, 2 H), 8.31 (s, 1 H).

(2) 1-(4-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde

Methyl 1-(4-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (6.9 g) synthesized above was treated in the same manner as in Example 1(5) to give the title compound ( 4.1 g, 6895), as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 2.58 (s, C H), 7.46 (d, 9-9.0 Hz, 2 H), 7.64 (d, 9-9.0 Hz, 2

H), 8.31 (s, 1 H), 10.00 (s, 1 H). (3) P-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|(cyclohexyl)methanol 1-(4-Chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (4, 2 g) synthesized above was treated in the same manner as in Example 1(6) to give the title compound (4.9 g, 8595) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.88 - 2.00 (m, 11 H), 2.32 (s, 3 H), 3.59 (sh s, 1 H), 4.43 (d, 9U-7.2 Hz, 1 N), 7.38 (d, 9-9.0 Hz, 2 N), 7.58 (d, 9U-9.0 Hz, 2 N) . acid

Using (|1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|(cyclohexyl)methanol (0.46 g) synthesized above and ethyl 3-((4-aminophenyl)carbonyl| iaminoisopropanoate (0.35 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.42 g, 57905) was obtained as a white solid.

IN NMR (300 MHz, DMSO-dv) 5 m.h. 0.86 - 2.09 (m, 12 N), 2.24 (s, Z H), 2.41 (t, 9dU-7.1 Hz, 2

H), 3.28 - 3.44 (m, 2 H), 4.20 (t, 9-7.7 Hz, 1 H), 6.33 (d, 2-7.9 Hz, 1 H) , 6.58 (d, 2U-8.9 Hz, 2 N), 7.39 - 7.60 (m, 4 N), 7.73 (d, 9-9.0 Hz, 2 N), 7 .92 - 8.09 (m, 1 N), 8.29 (s, 1 N).

Example 20 3-X14-(4,1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

AH m He is sn, -y -boo

Man,

Using (|1-(4-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|(cyclohexyl)methanol (0.46 g), synthesized in Example 19(3), and ethyl 3-M(4 - aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.25 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound specified in the title was obtained (0.41 g, 57905 ), as a white solid.

IN NMR (300 MHz, DMSO-IV) 56 m.h. 0.75 - 2.07 (m, 12 H), 2.23 (s, 5 H), 2.85 (sh s, Z H), 3.39 - 3.57 (m, 2 H), 4 ,13 (w s, 1 N), 6.20 (d, 2-7.0 Hz, 1 N), 6.56 (d, U-8.5 Hz, 2 N), 7.09 (d, uU-8.5 Hz, 2 N), 7.46 (d, 2-8.7 Hz, 2 N), 7.71 (d, U-8.7 Hz, 2 N), 8.28 (s , 1 H).

Example 21 3-(14-011-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl)/cyclohexyl)methyl)amino)phenylcarbonylamino)propanoic acid a c) and ІІІ det

N

M

E and y oo and MOotev, sleep

(1) methyl 1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazole-4-carboxylate

Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.25 g), synthesized in

Example 1(3), and 4-fluoro-2-methylphenylboronic acid (13.9 g) and in the same manner as in Example 17(1), the title compound (7.5 g, 68905) was obtained as white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.26 (s, Z H), 2.54 (s, Z H), 3.85 (s, Z H), 6.80 - 7.35 (m, Z

H), 7.97 (s, 1 H). (2) 1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde

Methyl 1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazole-4-carboxylate (7.5 g), synthesized above, was treated in the same manner as in Example 1(5) to obtain the title the target compound (4.3 g, 8395) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.24 (s, Z H), 2.57 (s, Z H), 6.90 - 7.39 (m, Z H), 7.99 (s, 1

H), 10.00 (c, 1 H). (3) cyclohexyl(|1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl|methanol 1-(4-Fluoro-2-methylphenyl)-3-methyl-1H -pyrazole-4-carbaldehyde (4.3 g) synthesized above was treated in the same manner as in Example 1(b) to give the title compound (6.1 g, 98905) as a white solid. NMR (300 MHz, SOSI3) b mp 0.88 - 2.00 (m, 11 N), 2.22 (s, З Н), 2.32 (s, З Н), 4.44 ( dd, 9U-7.3, 3.3 Hz, 1 H), 6.91 - 7.30 (m, C H), 7.41 (s, 1 H). (4) 3-(14-311) -(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methyl)amino)phenylcarbonylamino)propanoic acid

Using cyclohexyl(1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.50 g) synthesized above and ethyl 3-|(4-aminophenyl)carbonyl |amino)propanoate (0.55 g), synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.52 g, 7090) was obtained as a white solid substance

IN NMR (300 MHz, DMSO -dv) 6 m.h. 0.87 - 2.00 (m, 12 N), 2.12 (s, Z H), 2.21 (s, Z H), 2.34 (t, 9U-7.1 Hz, 2 N) , 3.22 - 3.45 (m, 2 N), 4.21 (t, 9О-7.7 Hz, 1 N), 6.31 (d, 92-8.1 Hz, 1 N), 6 .59 (d,

U-8.9 Hz, 2 N), 7.10 - 7.31 (m, Z N), 7.51 (d, 9U-8.7 Hz, 2 N), 7.76 (s, 1 N ), 8.11 (c, 1 H).

Example 22 3-S(4-4-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

M on z

M in-( where H we

M sn, sn,

Using cyclohexyl(1-(4-fluoro-2-methylphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.50 g), synthesized in Example 213), and oethyl o /3-D( 4-aminophenyl)carbonyl|/methyl)aminopropanoate (0.39 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound indicated in the title was obtained (0.48 g, 6095), as a white solid.

IN NMR (300 MHz, DMSO-av) 6 m.h. 0.87 - 1.84 (m, 12 H), 2.10 (s, Z H), 2.22 (s, Z H), 2.48 - 2.50 (m, 2 H), 2, 91 (s, Z H), 3.52 (m, 2 H), 4.16 (d, 2-9.0 Hz, 1 H), 6.59 (d, U-8.7 Hz, 2 H ), 7.00 - 7.32 (m, 6 N), 7.75 (s, 1 N).

Example 23 3-(X4-Hcyclohexyl|1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

N not MI o-- other Y N

MO Sen, (1) methyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate

Using methyl 3-methyl-1H-pyrazole-4-carboxylate (5.7 g), synthesized in

Example 1(3), and 4-methoxyphenylboronic acid (12.4 g) and in the same way as in

Example 17(1), the title compound (6.5 g, 6595) was obtained as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.55 (s, C H), 3.83 (s, C H), 3.85 (s, C H), 6.97 (d , 9U-9.0 Hz, 2 H), 7.57 (d, 99.0 Hz, 2 H), 8.23 (s, 1 H). (2) 1-(4-methoxyphenyl)-3- methyl-1H-pyrazole-4-carbaldehyde

Methyl 1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate (6.6 g) synthesized above was treated in the same manner as in Example 1(5) to give the title compound ( 4.1 g, 7890), as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.58 (s, Z H), 3.86 (s, Z H), 6.99 (d, 9U-9.0 Hz, 2 H), 7.59 (d, uU-8.9 Hz, 2 H), 8.24 (s, 1 H), 9.98 (s, 1 H). (3) cyclohexyl(|1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol 1-(4-Methoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (4, 3 g) synthesized above was treated in the same manner as in Example 1(6) to give the title compound (7.1 g, 9895) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.88 - 1.97 (m, 11 H), 2.33 (s, Z H), 3.59 (sh s, 1 H), 3.83 (s, Z H), 4.43 (dd , U-7.3, 3.0 Hz, 1 N), 6.94 (d, 9U-9.0 Hz, 2 N), 7.53 (d, U-9.2 Hz, 2 N), 7.70 (c, 1

N). (4) 3-(X4-Hcyclohexyl|1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonylamino)propanoic acid

Using cyclohexyl|1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.68 g) synthesized above and ethyl 3-((4-aminophenyl)carbonyl|amino)upropanoate ( 0.55 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.44 g, 39905) was obtained as a white solid. "H NMR (300 MHz, DMSO-dv) 5 m.h. 0.89 - 2.08 (m, 12 H), 2.22 (s, C H), 2.34 -2.45 (m, 2 H), 3.44-3.60 (m, 2H), 3.76 (s, C H), 4.07 - 4.27 (m, 1 H), 6.30 (d, 9U-9 ,0 Hz, 1 N), 6.58 (d, 9-8.9 Hz, 2 N), 6.99 (d, 2-9.2 Hz, 2 N), 7.51 (d, 9U- 8.9 Hz, 2 N), 7.60 (d, 2-92 Hz, 2), 803 (shs, 1 N), 8.14 (s, 1 N).

Example 24 3-D4-Hcyclohexyl(|1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

ХХ

M on sn ne i o-0 in Y i ot

MO Sen,

Using cyclohexyl|1-(4-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.68 g), synthesized in Example 23(3), and ethyl 3-I((4-aminophenyl) carbonyl|(methyl)aminoisopropanoate (0.42 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound (0.28 g, 24905) was obtained as white solid.

IN NMR (300 MHz, DMSO-adv) b m.ch. 0.87 - 2.10 (m, 12 H), 2.23 (s, Z H), 2.45-2.50 (m, 2H), 2.90 (s, Z H), 3.44 - 3.60 (m, 2 H), 3.77 (s, C H), 4.13-4.15 (m, 1 H), 6.21 (d, 957.7 Hz, 1 H), 6.58 (d, U-8.7 Hz, 2 N), 6.99 (d, 9U-9.0 Hz, 2 N), 7.10 (d, 2-8.7 Hz, 2 N) , 7.60 (d, 9U-9.0 Hz, 2 N), 8.14 (s, 1 N).

Example 25 3-II(4-Kcyclohexyl3-methyl-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

Y Y g t ten

E N

-x ra

A ng sh-

SN. (1) methyl 3-methyl-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carboxylate

Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.8 g), synthesized in

Example 1(3), and 4-trifluoromethoxyphenylboronic acid (20.0 g) and in the same manner as in Example 17(1), the title compound (3.9 g, 2790) was obtained as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.55 (s, Z H), 3.86 (s, Z H), 7.32 (d, 9-92 Hz, 2 H), 7.71 (d, u5-9.2 Hz, 2 H ), 8.32 (s, 1 H). (2) 3-methyl-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carbaldehyde

Methyl 3-methyl-1-N4-(trifluoromethoxy)phenyl)-1H-pyrazole-4-carboxylate (3.9 g), synthesized above, was treated in the same manner as in Example 1(5) to obtain the title the title compound (2.3 g, 66905) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.59 (s, C H), 7.36 (d, 9-9.0 Hz, 2 H), 7.73 (d, 9U- 9.0 Hz, 2

H), 8.32 (s, 1 H), 10.01 (s, 1 H). (3) cyclohexyl3-methyl-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylmethanol

3-Methyl-1-I(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carbaldehyde (2.6 g), synthesized above, was treated in the same manner as in Example 1(b) to give the title the target compound (2.2 g, 7290) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 ppm 0.89 - 1.91 (m, 11 H), 2.33 (s, C H), 4.44 (dd, 9-7.2, 3.0 Hz, 1 nH), 7.26 (d, 2-9.2 Hz, 2 H), 7.66 (d , U-9.2 Hz, 2 H), 7.77 (s, 1 H). (4) 3-I(4-Kcyclohexyl3-methyl-1-I4-"trifluoromethoxy)phenyl|-1H-pyrazole -4- yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

Using cyclohexyl3-methyl-1-(4-trifluoromethoxy)phenyl|-1H-pyrazol-4-ylylmethanol (0.59 g) synthesized above and ethyl 3-L(4-aminophenyl)carbonyl|amino)propanoate ( 0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) afforded the title compound (0.50 g, 55905) as a white solid. "H NMR (300 MHz, DMSO-av) 6 m.h. 0.85 - 2.11 (m, 11 N), 2.24 (s, Z H), 2.39 (t, 9-7.2 Hz, 2

H), 3.30 - 3.43 (m, 2 H), 4.20 (t, 9U-7.6 Hz, 1 H), 6.34 (d, 9-76 Hz, 1 H), 6 .58 (d, 2-8.3 Hz, 2 N), 7.34 - 7.61 (m, 4 N), 7.82 (d, 2-91 Hz, 2 N), 8.02 (w with, 1H).

Example 26 3-II(4-Kcyclohexyl3-methyl-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Y Y teshane - p-- M sn, o m And we dv

MO tight,

Using cyclohexyl3-methyl-1-(4-trifluoromethoxy)phenyl-1H-pyrazol-4-ylmethanol (0.97 g), synthesized in Example 25(3), and oethyl o3-D( 4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.63 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound specified in the title was obtained (1.3 g, 63905) as a white solid. "H NMR (300 MHz, DMSO-α) 6 m.h. 0.89 - 2.06 (m, 11 N), 2.24 (s, Z H), 2.40 (t, 9-7.0 Hz, 2

H), 3.28 - 3.45 (m, 5 H), 4.20 (t, 92-7.8 Hz, 1 H), 6.34 (d, 2-7.6 Hz, 1 H) , 6.58 (d, 2-91 Hz, 2 N), 7.35 - 7.57 (m, 4 N), 7.82 (d, 9-9.1 Hz, 2 N), 8.01 (she, 1 H).

Example 27 3-II(4-Kcyclohexyl3-methyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

Yi Yi direct

E E de where, oooya--Ts

E MOsen, (1) methyl 3-methyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazole-4-carboxylate

Using the crude product, methyl 3-methyl-1H-pyrazole-4-carboxylate, (8.9 g) synthesized in Example 1(3), and 4-trifluoromethylphenylboronic acid (13.3 g) and in the same manner as in Example 17(1), the title compound (2.0 g, 1195) was obtained as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.56 (s, Z H), 3.87 (s, Z H), 7.72 (d, 9-92 Hz, 2 H), 7.82 (d, 35-9.2 Hz, 2 H ), 8.41 (s, 1 H). (2) 3-methyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazole-4-carbaldehyde

Methyl 3-methyl-1-N4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate (2.0 g), synthesized above, was treated in the same manner as in Example 1(5) to obtain the title the target compound (0.6 g, 3095) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.56 (s, C H), 7.72 (d, 9-9.0 Hz, 2 H), 7.82 (d, 9U- 9.0 Hz, 2

H), 8.40 (s, 1 H), 9.98 (s, 1 H). (3) cyclohexyl3-methyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazol-4-ylmethanol

3-Methyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazole-4-carbaldehyde (0.6 g), synthesized above, was treated in the same manner as in Example 1(6) to obtain the title target compound (0.7 g, 93905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 1.98 (m, 11 H), 2.34 (s, Z H), 3.53 - 3.69 (m, 1 H), 4.46 (d, 9-7.0 Hz , 1 N), 7.67 (d, 9-9.0 Hz, 2 N), 7.77 (d, U-9.0 Hz, 2 N), 7.85 (s, 1 N). (4) 3-N-44-Ccyclohexyl3-methyl-1-(4-trifluoromethyl)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

Using cyclohexyl3-methyl-1-N4-"trifluoromethyl)phenyl|)|-1H-pyrazol-4-ylylmethanol (0.36 g) synthesized above and ethyl 3-L(4-aminophenyl)carbonyl|amino) propanoate (0.38 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) afforded the title compound (77.5 mg, 790) as a white solid. H NMR (300 MHz, DMSO-av) 6 m.h. 0.90 - 2.12 (m, 11 N), 2.26 (s, Z H), 2.41 (t, 9-7.2 Hz, 2

H), 3.23 - 3.44 (m, 2 H), 4.22 (t, 9-7.6 Hz, 1 H), 6.36 (d, 9-7.9 Hz, 1 H) , 6.60 (d, 9U-8.9 Hz, 2 N), 7.52 - 7.80 (m, 4 N), 7.93 (d, 9-6.0 Hz, 2 N), 7 .97 - 8.10 (c, 1H).

Example 28 3-II(4-Kcyclohexyl3-methyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazol-4-ylmethyl)amino|phenyl)carbonyl)(methyl)amino|propanoic acid o o

EE M sn, in - N

My

R MO zen

WITH

Using cyclohexyl3-methyl-1-14-"trifluoromethyl)phenyl|)|-1H-pyrazol-4-ylmethanol. (0.36 (g), synthesized in Example /27(3), and oethyl o 3-D (4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.40 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound specified in the title was obtained (0.20 g , 3595), as a white solid.

IN NMR (300 MHz, DMSO -adv) 5 m.ch. 0.81 - 2.10 (m, 11 H), 2.28 (s, C H), 2.42 -2.50 (m, 2 H), 2.90 (s, C H), 3, 52 (t, 9-7.3 Hz, 2 N), 4.18 (t, 9U-7.5 Hz, 1 N), 6.26 (d, 2-7.7 Hz, 1 N), 6 .59 (d, uU-8.7 Hz, 2 H), 7.11 (d, 9U-8.7 Hz, 2 H), 7.80 (d, 2 H), 7.94 (d, 2 -8.5 Hz, 2 N), 8.43 (s, 1 N).

Example 29 3-II(4-Kcyclohexyl3-(methoxymethyl)-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

HER

EE M to two units

E -m M (8) nos (1) methyl 3-(methoxymethyl)-1 H-pyrazole-4-carboxylate

A mixture of methyl 4-methoxyacetoacetate (25.0 g) and dimethylformamide dimethyl acetal (22.9 mL) was stirred at 100 C for 2 g and the mixture was allowed to cool to room temperature. Ethanol (250 ml) and hydrazine monohydrate (8.3 ml) were added to the reaction mixture and the mixture was heated under reflux for 12 h. After spontaneous cooling, the reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate to give the crude product (25.08 g), methyl 3-methoxymethyl-1H-pyrazole-4-carboxylate, as a pale yellow solid. The presented compound was directly used for the next reaction. "H NMR (300 MHz, SOSI") 6 m.h. 3.51 (s, C H), 3.84 (s, C H), 4.85 (s, 2 H), 7.99 (s , 1 H). (2) methyl 3-(methoxymethyl)-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate

Using methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (7.4 g) synthesized above and 2-chloro-5-trifluoromethylpyridine (5.8 g) and in the same manner as in

Example 1(4) gave the title compound (5.2 g, 3895) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 3.54 (s, Z H), 3.89 (s, Z H), 4.83 (s, 2 H), 7.90 - 8.36 (m, 2

H), 8.70 (s, 1 H), 9.06 (s, 1 H).

(3) 3-(Methoxymethyl)-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

Methyl (3-(methoxymethyl)-1-(5-trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-carboxylate (5.2 g), synthesized above, was treated in the same manner as in Example 1 (5) affording the title compound (1.9 g, 40965) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 3.53 (s, Z H), 4.83 (s, 2 H), 8.05 - 8.25 (m, 2 H), 8.72 (s, 1

H), 9.11 (c, 1 H), 10.10 (c, 1 H). (4) cyclohexyl3-(methoxymethyl)-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol 3-(Methoxymethyl)-1-(5-(trifluoromethyl)pyridin- 2-yl|-1H-pyrazole-4-carbaldehyde (1.9 g) synthesized above was treated in the same manner as in Example 1(6) to give the title compound (2.4 g, 9995), like butter

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.25 (m, 11 H), 3.02 (d, 9-6.0 Hz, 1 H), 3.46 (s, C H), 4.43 (dd, 9-7 .7, 6.0 Hz, 1 N), 4.52 - 4.69 (m, 2 N), 7.93 - 8.11 (m, 2 N), 8.44 (s, 1 N), 8.65 (c, 1

N). (5). 3-I34-Kcyclohexyl(3-(methoxymethyl)-1-(5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|Iphenyl)icarbonyl)amino|propanoic acid

Using cyclohexyl3-(methoxymethyl)-1-I(I5-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (12 g), synthesized above, and ethyl 3-I((4-aminophenyl) carbonylamino)propanoate (0.94 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) afforded the title compound (0.19 g, 10965) as a white solid .

IN NMR (300 MHz, DMSO-dv) b m.ch. 1.90 - 2.10 (m, 11 N), 2.40 (t, 9-72 Hz, 2 N), 3.24 - 3.45 (m, 5 N), 4.28 - 4.71 (m, Z H), 6.37 (d, 9-8.9 Hz, 1 H), 6.64 (d, 9-8.9 Hz, 2 H), 7.51 (d, 98.9 Hz, 2 N), 8.00 (d, 2-8.9 Hz, 2 N), 8.33 (dd, U-9.0, 2.3 Hz, 1 N).

Example 30 3-II(4-Kcyclohexyl3-(methoxymethyl)-1-(5-trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propano acid

Yi Yi then

EE sn breathes hoo-D

E-M M

She; not

Using cyclohexyl3-(methoxymethyl)-1-I(15-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-ylmethanol (1.2 g), synthesized in Example 29(4), and ethyl 3- K(4-aminophenyl)carbonyl|(methyl)amino)propanoate (1.0 g), synthesized in Example 2(2), and in the same way as in Example 1(7), obtained the target compound specified in the title (0 ,17 g, 895), as a white solid.

IN NMR (300 MHz, DMSO -adv) 5 m.ch. 0.89 - 2.09 (m, 11 H), 2.40 - 2.52 (m, 2 H), 2.89 (s, Z H), 3.33 (s, Z H), 3, 51 (t, U-7.3 Hz, 2 H), 4.28 - 4.74 (m, C H), 6.27 (d, 9-8.7 Hz, 1 H), 6.64 ( d, 9-8,7

Hz, 2 H), 7.09 (d, 9U-8.7 Hz, 2 H), 8.01 (d, 9-8.9 Hz, 1 H), 8.33 (dd, 9U-9, 0, 2.3 Hz, 1 N), 8.58 (s, 1

H), 8.83 (s, 1 H).

Example 31 3-1(4-11-(13-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazol-4-ylUcyclohexyl)methylaminophenyl)carbonylamino)upropanoic acid

AH si su on

E E, where is the office?

P - sn, (1) methyl 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazole-4-carboxylate

Using methyl 3-methyl-1H-pyrazole-4-carboxylate (3.8 g), synthesized in

Example 13) and 2,3-dichloro-5-trifluoromethylpyridine (5.8 g) and in the same way as in

Example 1(4), the title compound (7.0 g, 7895) was obtained as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.60 (s, C H), 3.88 (s, C H), 8.16 (d, 9U-1.5 Hz, 1 H ), 8.67 - 8.72 (m, 2 H). (2) 1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazole-4-carbaldehyde

To a solution (150 ml) of methyl 1-|3-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazole-4-carboxylate (7.0 g), synthesized above, in tetrahydrofuran diisobutylaluminum hydride (1.5M toluene solution, 58.4 ml) was added dropwise at 0"C. After stirring for 30 min, the reaction mixture was poured into 2M hydrochloric acid at 0"C and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated. The residue was treated in the same manner as in Example 1(5) to give the title compound (1.7 g, 27905) as a pale yellow solid. "H NMR (300 MHz, SOSIZ") b m.p. 2.63 (s, C H), 8.19 (s, 1 H), 8.70 - 8.73 (m, 2 H), 10 .07 (c, 1

N). (3)/1-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazol-4-ylUcyclohexyl)methanol 1-(3-Chloro-5-(trifluoromethyl)pyridine -2-yl|-3-methyl-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized above was treated in the same manner as in Example 1(6) to give the title compound (1, 5 g, 66905), as oil. "H NMR (300 MHz, SOSI") b m.p. 0.94 - 2.02 (m, 11 H), 2.39 (s, C H), 4, 47 (d, 9-7.2 Hz, 1 N), 8.05 - 8.14 (m, 1 N), 8.18 (s, 1 N), 8.66 (s, 2 N). 4) 3-14-11-(3-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methylaminophenyl)carbonylamino)propanoic acid

Using 11-13-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazol-4-ylcyclohexyl)methanol (0.74 g) synthesized above and ethyl 3-((4 - aminophenyl)carbonyl|amino)propanoate (0.57 g), synthesized in Example 1(2), and in the same way as in Example 1(7), the target compound indicated in the title was obtained (0.11 g, 1095) , as an amorphous pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 1.98 (m, 11 N), 2.37 (s, C H), 2.50-2.72 (m, 2 N), 3.44 - 3.75 (m, 2 N ), 4.24 (d, 96.2 Hz, 1 H), 6.51 (d, 9-8.1 Hz, 2 H), 6.66 (w s, 1 H), 6.89 (w s, 1 N), 7.52 (d, 98.1 Hz, 2 N), 7.98 - 8.20 (m, 2 N), 8.60 (s, 1 N).

Example 32 3-1(4-11-(13-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino )propanoic acid i -- si de J on

EE with uyu nt

E -mkh MO sen,

Using 11-13-chloro-5-(trifluoromethyl)pyridin-2-yl|-3-methyl-1H-pyrazole-4-

yl(cyclohexyl)methanol (0.74 g), synthesized in Example 31(3), and ethyl 3-(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.60 g), synthesized in Example 2(2), and such in the same manner as in Example 1(7), the title compound (54.4 mg, 595) was obtained as an amorphous pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 1.98 (m, 11 H), 2.36 (s, C H), 2.58 - 2.74 (m, 2 H), 3.04 (s, C H), 3, 59 - 3.82 (m, 2 N), 4.23 (d, 96.0 Hz, 1 N), 6.55 (d, 9-8.5 Hz, 2 N), 7.01 (she, 1

H)U, 7.21 (d, 98.5 Hz, 2 H), 8.08 (s, 1 H), 8.13 (s, 1 H), 8.63 (s, 1 H).

Example 33 3-II(4-Kcyclohexyl3-(methoxymethyl)-1-II4-(trifluoromethoxy)phenyl|)|-1H-pyrazol-4-ylmethyl)amino|phenylcarbonyl)amino|propanoic acid

E N pd their o. sn, (1) methyl 3-(methoxymethyl)-1-(4-(trifluoromethoxy)phenyl|)-1H-pyrazole-4-carboxylate

Using methyl 4-methoxyacetoacetate (3.2 g), dimethylformamide dimethyl acetal (2.9 ml) and 4-trifluoromethoxyphenylhydrazine hydrochloride (5.0 g) and in the same manner as in Example 15(1), the title compound was obtained (3.4 g, 4790) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 3.46 (s, Z H), 3.89 (s, Z H), 4.70 (s, 2 H), 7.37 (d, 9U-9.0 Hz, 2H), 7.73 ( d, 929.0 Hz, 2H), 8.08 (s, 1 H). (2) 3-(Methoxymethyl)-1-(4-(trifluoromethoxy)phenyl|)-1H-pyrazole-4-carbaldehyde

Methyl 3-(methoxymethyl)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazole-4-carboxylate (3.4 g), synthesized above, was treated in the same manner as in Example 1(5) to obtain the indicated title compound (2.9 g, 9395) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 3.41 (s, Z H), 4.70 (s, 2 H), 7.37 - 8.08 (m, 5 H), 10.00 (s, 1

N). (3) cyclohexyl3-(methoxymethyl)-1-I(4-"trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)umethanol 3-(Methoxymethyl)-1-(4-(trifluoromethoxy)phenyl|-1H -pyrazole-4-carbaldehyde (2.29 g, synthesized above) was treated in the same manner as in Example 1(6) to give the title compound (2.8 g, 77905) as a pale yellow solid .

IN NMR (300 MHz, SOSI") b m.h. 0.73 - 2.28 (m, 11 H), 3.41 (s, C H), 4.30 - 4.53 (m, C H), 7.33 (d, 958.5 Hz, 2 H), 7.55 - 7.75 (m, C H). (4) 3-II54-Ccyclohexyl3-(methoxymethyl)-1-I(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

Using cyclohexyl3-(methoxymethyl)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylmethanol (0.75 g) synthesized above and ethyl 3-((4-aminophenyl)carbonylamino)propanoate ( 0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) afforded the title compound (0.43 g, 39905) as a colorless solid. "H NMR (300 MHz, DMSO-av) 6 m.ch 0.90 - 2.08 (m, 11 N), 2.43 (t, 9-7.1 Hz, 2 N), 3.25 - 3, 49 (m, 5 N), 4.29 - 4.31 (m, 1 N), 4.39 - 4.59 (m, 2 N), 6.43 (d, 9-8.5 Hz, 1 H), 6.63 (d, 9d-8.9

Hz, 2 N), 7.45 - 7.58 (m, 4 N), 7.63 - 7.77 (m, Z H), 7.94 - 8.09 (m, 1 N).

Example 34 3-II(4-Kcyclohexyl/13-(methoxymethyl)-1-14-(trifluoromethoxy)phenyl|)|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid re ach

E g - o sn,

E shiv N

M o. dream

Using cyclohexyl3-(methoxymethyl)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylmethanol (0.75 g), synthesized in Example 33(3), and ethyl 3-K(4-aminophenyl )carbonyl|/methyl)aminoisopropanoate (0.59 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound (0.42 g, 3995) was obtained, as a colorless solid.

IN NMR (300 MHz, DMSO-dv) 5 m.h. 0.87 - 2.12 (m, 11 H), 2.40 - 2.50 (m, 2 H), 2.90 (s, Z H), 3.31 (s, Z H), 3, 52 (t, U9-7.2 Hz, 2 N), 4.21 - 4.36 (m, 1 N), 4.36 - 4.59 (m, 2 N), 6.32 (d, 9 -8.7 Hz, 1 N), 6.62 (d, 9-8.7 Gu, 2 N), 7.09 (d, 2-8.5 Hz, 2 N), 7.51 (d, 9U-8.5 Hz, 2 N), 7.64 - 7.79 (m, Z

N).

Example 35 3-(14-Ccyclohexyl(|3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)iamino)phenylcarbonylamino)propanoic acid

Yi Yi can't do it, ooya-yi

KI o "en, (1) methyl 3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate

Using methyl 4-methoxyacetoacetate (5.8 g), dimethylformamide dimethyl acetal (5.4 ml) and 4-methoxyphenylhydrazine hydrochloride (7.0 g) and in the same manner as in Example 15(1), the title compound was obtained (5.5 g, 5090) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 3.42 (c, C H), 3.87 (c, C H), 3.88 (c, C H), 4.64 (c, 2 H), 7.00 (d, 9-9, 0 Hz, 2H), 7.53 (d, 9U-9.0 Hz, 2H), 8.05 (s, 1 H). (2) 3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde

Methyl 3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate (2.8 g), synthesized above, was treated in the same manner as in Example 1(5) to obtain the title target compound (2.0 g, 8395) as a pale yellow solid.

IN NMR (300 MHz, SOSIZ") 6 m.h. 3.42 (s, Z H), 3.87 (s, Z H), 4.64 (s, 2 H), 7.00 - 8.05 (m, 5

H), 10.00 (c, 1 H). (3) cyclohexyl|3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol 3-(Methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (2.0 g) synthesized above was treated in the same manner as in Example 1(b) to give the title compound (2.1 g, 7790) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.73 - 2.28 (m, 11 H), 3.36 (s, C H), 3.86 (s, C H), 4.30 - 4.53 (m, C H), 6, 97 (d, U-8.9 Hz, 2 H), 7.44 (d, 2U-8.9 Hz, 2 H), 7.59 (s, 1 H). (4) 3-(X14-(cyclohexyl|3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

Using cyclohexyl3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole-4-

yl|methanol (0.75 g), synthesized above, and ethyl 3-|(4-aminophenyl)carbonyl|amino)propanoate (0.54 g), synthesized in Example 1(2), and in the same manner as in Example 1(7) gave the title compound (0.39 g, 3390) as a white solid. "H NMR (300 MHz, DMSO-av) 6 m.h. 0.89 - 2.11 (m, 11 N), 2.44 (t, 9-7.2 Hz, 2 N), 3.32 - 3.46 (m, 2 N), 3.80 (s, C H), 4.22 - 4.56 (m, C H), 6.40 (d, 2-8.7 Hz, 1 N ), 6.62 (d, U-8.9 Hz, 2 N), 7.04 (d, 9-9.0 Hz, 2 N), 7.36 - 7.55 (m, 4 N), 7 .57 (s, 1 H), 8.01 (s, 1 H).

Example 36 3-D4-Hcyclohexyl(|3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid 3 AKA dusnily ve IN ant sh -

AND

0. "he

Using cyclohexyl3-(methoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol (0.75 g), synthesized in Example /35(3), and oethyl o 3-(4-aminophenyl) carbonyl|/methyl)aminoisopropanoate (0.57 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound (0.44 g, 36905) was obtained as white solid. "H NMR (300 MHz, DMSO-dv) 5 ppm 0.90 - 2.12 (m, 11 N), 2.42 - 2.50 (m, 2 N), 2.91 (s, With H), 3.26 (s, With H), 3.52 (t, 9-7.4 Hz, 2 H), 3.80 (s, With H), 4.14 - 4.54 (m , Z H), 6.29 (d, 9-8.5 Hz, 1 H), 6.62 (d, 2-8.7 Hz, 2 H), 6.97 - 7.19 (m, 4 H), 7.44 (d, 92-8.9 Hz, 2 H), 7.58 (s, 1 H).

Example 37 3-(14-Ccyclohexyl(|3-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

With AJ

N b-do ooon-ki

M re ne (1) methyl 3-(methoxymethyl)-1-phenyl-1H-pyrazole-4-carboxylate

Using methyl 4-methoxyacetoacetate (7.P9 g), dimethylformamide dimethyl acetal (7.2 ml) and phenylhydrazine hydrochloride (5.8 g) and in the same manner as in

Example 15(1) afforded the title compound (7.3 g, 55905) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 3.44 (s, C H), 3.89 (s, C H), 4.68 (s, 2 H), 7.30 - 7 ,70 (m, 5

H), 8.08 (s, 1 H). (2) 3-(Methoxymethyl)-1-phenyl-1H-pyrazole-4-carbaldehyde

Methyl 3-(methoxymethyl)-1-phenyl-1H-pyrazole-4-carboxylate (3.5 g) synthesized above was treated in the same manner as in Example 1(5) to give the title compound (2, 5 g, 82905), as a pale yellow solid.

"H NMR (300 MHz, SOSI") b m.p. 3.45 (s, 3 H), 4.67 (s, 2 H), 7.40 -8.20 (t6 H), 10.08 (c, 1

N). (3) cyclohexyl|3-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl|methanol 3-(Methoxymethyl)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.5 g), synthesized above was treated in the same manner as in Example 1(6) to give the title compound (3.1 g, 75905) as a white solid. "H NMR (300 MHz, SOSI") b mp 0.73 - 2.40 (m, 11 H), 3.38 (s, 3 H), 4.40 (s, 2 H), 4 .42 - 4.55 (m, 1 H), 7.27 - 7.70 (m, 6H). (4) 3-(14-Ccyclohexyl(|3-(methoxymethyl)-1-phenyl-1 H- pyrazol-4-yl|methyl)amino)phenyl(carbonylamino)propanoic acid

Using cyclohexyl(13-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl|methanol (0.50 g) synthesized above and ethyl 3-((4-aminophenyl)carbonyl|iaminoisopropanoate (0.39 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.37 g, 46905) was obtained as a white solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.97 - 2.17 (m, 11 N), 2.58 - 2.78 (m, 2 N), 3.34 (s, Z H), 3.58 - 3.76 (m, 2 N ), 4.21 - 4.51 (m, Z H), 6.51 - 6.71 (m, Z H), 7.36 - 7.74 (m, 8 H).

Example 38 3-D4-Hcyclohexyl(|3-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid and C

І І Гн он пгтнія тя Z SA ra raki h

It's time to sleep

Using cyclohexyl(III-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl|methanol (0.50 g), synthesized in Example 373), and ethyl 3-M(4-aminophenyl)carbonyl|/methyl )aminoisopropanoate (0.42 g) synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound (0.33 g, 3995) was obtained as a white solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.98 - 2.11 (m, 11 H), 2.61 - 2.79 (m, 2 H), 3.07 (c, C H), 3.34 (c, C H), 3, 72 (t, 9U-6.5 Hz, 2 H), 4.25 - 4.46 (m, Z H), 6.57 (d, 9-8.5 Hz, 2 H), 7.35 - 7.61 (m, 8 N).

Example 39 3-II(4-Kcyclohexyl/13-ethyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid her - ruk nH

IS

E dv

E M sn, (1) methyl 3-ethyl-1H-pyrazole-4-carboxylate

Using methyl 3-oxopentanoate (6.5 g) and in the same manner as in Example 1(3), the title compound (7.0 g, 91905) was obtained as an oil.

IN NMR (300 MHz, SOSI") b m.h. 1.32 (t, 9U-7.6 Hz, Z H), 3.02 (k, U-7.6 Hz, 2 H), 3.84 (s, Z

H), 7.96 (s, 1 H), 11.28 (sh s, 1 H).

(2) methyl 3-ethyl-1-I4-(trifluoromethyl)phenyl)|-1H-pyrazole-4-carboxylate

Using methyl 3-ethyl-1H-pyrazole-4-carboxylate (4.6 g) synthesized above and in the same manner as in Example 17(1), the title compound was obtained (6.0 g, 6790) , as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.33 (t, 9U-7.4 Hz, Z H), 2.99 (k, 9-7.5 Hz, 2 H), 3.87 (s, Z

H), 7.71-7.74 (m, 2 H), 7.82-7.85 (m, 2 H), 8.41 (c, 1 H). (3) 3-ethyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-4-carbaldehyde

Using methyl 3-ethyl-1-(4-(trifluoromethyl)phenyl|)|-1H-pyrazole-4-carboxylate (6.0 g), synthesized above, and in the same manner as in Example 1(5), obtained the title compound (4.2 g, 78905) as a white solid. "H NMR (300 MHz, SOSIv) b m.h. 1.37 (t, U-7.4 Hz, Z H), 3.00 (k, 9U-7.4 Hz, 2 H), 7, 74-7.77 (m, 2H), 7.84-7.87 (m, 2H), 8.42 (s, 1H), 10.03 (s, 1H). (4) cyclohexyl3- ethyl-1-(4-«(trifluoromethyl)phenyl|-1H-pyrazol-4-ylmethanol

Using 3-ethyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazole-4-carbaldehyde (1.6 g), synthesized above, and in the same way as in Example 1(6), the indicated in the title the target compound (1.9 g, 91905) as a white solid. "H NMR (300 MHz, SOSI"v) b m.p. 0.86-1.43 (m, 8 H), 1, 52-1.90 (m, 5 N), 2.05 (shs, 1 N), 2.72 (Kk, 9U-7.5 Hz, 2 N), 4.46 (dd, 9-7.2 , 3.0 Hu, 1 H), 7.60-7.71 (m, 2 H), 7.71-7.82 (m, 2 H), 7.86 (s, 1

N). (5) 3-(14-Kcyclohexyl3-ethyl-1-(4-trifluoromethyl)phenyl)|-1H-pyrazol-4-yl)umethyl)amino|benzoyl)iamino)propanoic acid

Using cyclohexyl3-ethyl-1-4-trifluoromethyl)phenyl (1H-pyrazol-4-ylylmethanol (0.90 g) synthesized above and ethyl 3-L(4-aminophenyl)carbonyl|amino )propanoate (0.75 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (82 mg, 695) was obtained as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.09-1.32 (m, 8 H), 1.45-1.83 (m, 5 H), 1.93-2.11 (m, 1 H), 2.37 (t, U- 7.0 Hz, 2 N), 2.68 (kd, 9-7.5, 4.0 Gu, 2 N), 3.35 (k, 9U-5.7 Hz, 2 N), 4.23 (t, U-7.8 Hz, 1

H), 6.33 (d, 9-7.9 Hz, 1 H), 6.60 (d, 9-8.7 Hz, 2 H), 7.52 (d, 9-8.9 Hz, 2 H), 7.81 (d, 90-8.7 Hz, 2

H), 7.87-7.98 (m, 2 H), 7.98-8.12 (m, 1 H), 8.43 (s, 1 H).

Example 40 3-II(4-Kcyclohexyl/13-ethyl-1-(4-(trifluoromethyl)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid p t G Me le bot zone

E pn av a i Sta i zhi puls zi ON

Using cyclohexyl3-ethyl-1-14-trifluoromethylphenyl)-1H-pyrazol-4-ylmethanol (0.90 g), synthesized in Example /339(4), and oethyl o3-D( 4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.75 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained (85 mg, 695) , as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.88-1.24 (m, 8 H), 1.46-1.80 (m, 5 H), 1.92-2.09 (m, 1 H), 2.46 (t, 9- 7.5 Hz, 2 N), 2.68 (kd, U-7.5, 3.3 Hz, 2 N), 2.98 (s, Z H), 3.50 (t, 9U-7, 2 Hz, 2 N), 420 (t, 9-7.4 Hz, 1 N), 6.22 (d, 9d-7.7 Hz, 1 N), 6.60 (d, U-8.5 Hz, 2 N), 7.10 (d, 9-8.7 Hz, 2 N), 7.81 (d, U-8.7 Hz, 2 N), 7.86-8.05 (m, 2 H), 8.43 (s, 1 H).

Example 41 3-4(4-((1-benzyl-3-methyl-1H-pyrazol-4-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid su OH

N

E

(1) methyl 1-benzyl-3-methyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (5.1 g), synthesized in Example 13, was dissolved in dimethylformamide (50 ml) and at room temperature potassium carbonate (5.3 g) and benzyl bromide (4. 6 ml) and the mixture was stirred overnight. The reaction mixture was poured into water and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, v/v) to give the title compound (5.9 g, 71905) as an oil.

IN NMR (300 MHz, SOSI") 6 m.h. 2.48 (s, Z H), 3.78 (s, Z H), 5.22 (s, 2 H), 6.96 - 7.45 (m, 5

H), 7.77 (s, 1 H). (2) 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde

Using methyl 1-benzyl-3-methyl-1H-pyrazole-4-carboxylate (5.9 g) synthesized above and in the same manner as in Example 1(5), the title compound (5.0 g, 96905), as oil. "IN NMR (300 MHz, SOSI") 6 m.h. 2.50 (s, Z H), 5.25 (s, 2 H), 6.96 - 7.45 (m, 5 H), 7 .76 (c, 1

H), 9.85 (s, 1H). (3) (1-benzyl-3-methyl-1H-pyrazol-4-yl)(cyclohexyl)methanol

Using 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde (5.0 g) synthesized above and in the same manner as in Example 1(b6), the title compound (3.3 g, 47905), as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.75 - 1.97 (m, 11 H), 2.25 (s, Z H), 4.34 (d, 9-74, 3.3 Hz, 1), 5.20 (s, 2H) , 7.00 - 7.50 (m, 6 N). (4) 3-4(4-((1-benzyl-3-methyl-1H-pyrazol-4-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid

Using (1-benzyl-3-methyl-1H-pyrazol-4-yl)(cyclohexyl)methanol. (1.0 g) synthesized above, and ethyl 3-|(4-aminophenyl)carbonylaminoiopropanoate (0.62 g), synthesized in Example 1(2), and in the same way as in Example 1(7) , afforded the title compound (28.6 mg, 4905) as a white solid.

IN NMR (300 MHz, DMSO -adv) 5 m.ch. 0.77 - 2.01 (m, 11 N), 2.12 (s, Z H), 2.38 - 2.46 (m, 2 N), 3.35 - 3.44 (m, 2 N ), 3.99 - 4.21 (m, 1 N), 5.11 - 5.19 (m, 2 N), 6.25 (d, 9U-9.0 Hz, 1 N), 6.52 (d, 98.7 Hz, 2 N), 7.04 (dd, 9-7.5, 1.9 Hz, 2 N), 7.25 - 7.60 (m, 6 N), 7.99 (c, 1 H).

Example 42 3-4(4-((1-benzyl-3-methyl-1H-pyrazol-4-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid Mr. Ye's thing in SN sho te s i pre t y 5 Sa

Using (1-benzyl-3-methyl-1H-pyrazol-4-yl)/ucyclohexyl)umethanol (0.65 g), synthesized in Example 41(3), and ethyl 3-((4-aminophenyl)carbonyl|( methyl)amino)propanoate (0.65 g) synthesized in Example 2(2) and in the same manner as in Example 1(7) gave the title compound (18.2 mg, 2905) as a white solid substance

IN NMR (300 MHz, DMSO -aiv) b m.ch. 1.14 - 2.00 (w s, 11 N), 2.13 (s, Z H), 2.38 - 2.46 (m, 2

H), 2.90 (s, C H), 3.42 - 3.60 (m, 2 H), 4.00 - 4.17 (m, 1 H), 5.16 (s, 2 H) , 6.17 (d, 9-6.0 Hz, 1 N), 6.52 (d, 2-8.5 Hz, 2 N), 6.95 - 7.36 (m, 7 N), 7 .52 (c, 1 H).

Example 43 3-(14-Ccyclohexyl|1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazol-4-yl|methyl)iamino)phenylcarbonylamino)propanoic acid

N

СН, M weight BA Щ sh- ns сн, (1) methyl 1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (10.8 g), synthesized in Example 13, was dissolved in acetonitrile (100 ml) and 2-methyl-2-butene (16.3 ml) and monohydrate p - toluenesulfonic acid (4.4 g) and the mixture was stirred in a closed flask at 12070 for 4 g. The reaction mixture was poured into an aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, v/v) to give the title compound (4.6 g, 2990) as an oil. "H NMR (300 MHz, SOSI") b mp 0.68 (t, 9U-7.5 Hz, Z H), 1.53 (s, 6 H), 1.88 (k, 9- 7.5 Hz, 2

H), 2.46 (c, C H), 3.80 (c, C H), 7.90 (c, 1 H). (2) 1441,1-dimethylpropyl)-3-methyl-1H-pyrazole-4-carbaldehyde

Using methyl 1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazole-4-carboxylate (4.6 g) synthesized above and in the same manner as in Example 1(5), the title compound was obtained the target compound (3.0 g, 7390) as an oil. "H NMR (300 MHz, SOSI") b mp 0.68 (t, 9U-7.5 Hz, Z H), 1.53 (s, 6 H), 1.88 (k, 9U- 7.5 Hz, 2

Н), 2.46 (s, З Н), 7.90 (s, 1 Н), 9.85 (s, 1Н). (3) cyclohexyl(|1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazol-4-yl|methanol

Using 1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazole-4-carbaldehyde (3.0 g) synthesized above and in the same manner as in Example 1(6), the title compound was obtained the target compound (1.4 g, 3290) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.67 (t, 9U-7.4 Hz, Z H), 0.88 - 2.00 (m, 13 H), 1.52 (s, 6 H), 2.24 (s, Z H) , 3.61 (w s, 1 H), 4.34 (dd, U-7.6, 2.0 Hz, 1 H), 7.34 (s, 1 H). (4) 3-(14-Ocyclohexyl|1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

Using cyclohexyl(|1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazol-4-yl|methanol (1.0 g) synthesized above and ethyl 3-(|(4-aminophenyl)carbonyl| amino)upropanoate (0.67 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) gave the title compound (0.41 g, 4695) as a white solid .

IN NMR (300 MHz, SOSI") b m.h. 0.56 (t, 9U-7.6 Hz, Z H), 0.88 - 1.35 (m, 5 H), 1.48 (s, 6 H), 1.55 - 1.98 (m , 8 H), 2.26 (s, C H), 2.67 (t, 9U-5.9 Hz, 2 H), 3.68 (k, 9U-5.8 Hz, 2 H), 4 ,12 (d, 9-61

Hz, 1 N), 6.46 (d, 9-8.7 Hz, 2 N), 6.66 (t, 9U-6.2 Hz, 1 N), 7.19 (s, 1 N), 7.53 (d, 2-91 Hz, 2 N).

Example 44 3-(X14-(1-(3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonyl)iamino)propanoic acid sn, o o o ne - b un

M

(1) methyl 3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate

Using methyl 3-cyclopropyl-3-oxopropanoate (3.7 g), dimethylformamide dimethyl acetal (3.6 ml) and p-methoxyphenylhydrazine monohydrate (4.7 g) and in the same manner as in Example 15(1), the indicated title compound (5.9 g, 8490) as an oil.

IN NMR (300 MHz, SOSI") b m.h. 0.60 - 1.01 (m, 4 H), 1.86 - 2.01 (m, 1 H), 3.85 (s, Z H), 3.87 (s, Z H), 6, 98 (d, 2-8.9 Hz, 2 N), 7.41 (d, 9-9.0 Hz, 2 N), 7.98 (s, 1 N). (2) 3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde

Using methyl 3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate (5.9 g) synthesized above and in the same manner as in Example 1(5), the title compound was obtained (3.6 g, 68905) as butter.

IN NMR (300 MHz, SOSI") b m.h. 0.73 - 1.10 (m, 4 H), 1.87 - 2.07 (m, 1 H), 3.88 (s, C H), 7.01 (d, 9U-8.9 Hz , 2 N), 7.44 (d, U-8.9 Hz, 2 N), 8.03 (s, 1 N), 10.03 (s, 1 N). (3) 1-(3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol

3-Cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1.8 g), synthesized above, was dissolved in tetrahydrofuran (10 ml) and isobutylmagnesium bromide (1M tetrahydrofuran solution) was added dropwise at 0"C , 12 ml). In the same manner as in Example 1(6), the title compound (1.8 g, 82905) was obtained as a white solid. "H NMR (300 MHz, SOCI") b m. h 0.36 - 0.91 (m, 5 N), 0.99 (d, U-6.4 Hz, 6 N), 1.48 - 1.97 (m,

With H), 3.86 (s, With H), 4.89 - 5.05 (m, 1 H), 6.96 (d, 9U-9.0 Hz, 2 H), 7.42 (d , 959.0 Hz, 2 N), 7.60 (s, 1 N). (4) 3-(X14-(1-(3-Cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl(|-3-methylbutyl)amino)phenylcarbonyl)iamino)propanoic acid

Using 1-|3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.5 g) synthesized above and ethyl 3-|(4 -aminophenyl)carbonyl|amino)propanoate (0.31 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (23 mg, 395) was obtained as white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.42 - 0.84 (m, 4 N), 0.99 (dd, y-13.8, 5.7 Hz, 6 N), 1.60 - 1.80 (m, 4 N), 2 .60 - 2.65 (m, 2 H), 3.64 - 3.66 (m, 2 H), 3.84 (s, Z H), 4.69 (s, 1 H), 6.55 (d, y-8.5Hz, 2 H), 6.70 (sh s, 1 H), 6.94 (d, 2-88 Hz, 2 H), 7.39 (d, 9-88 Hz, 2 N), 7.50 (s, 1 N), 7.58 (d, U-8.5 Hz, 2 N).

Example 45 3-X4-(1-|(3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanoic acid g 1 o

Sn 1 St ke i on ste o i ne rn / M. djdett. Izt Na Bosch i

Using 1-|3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.5 g), synthesized in Example 44(3), and ethyl 3-I-((4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.33 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound specified in the title was obtained ( 80 mg, 995) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.34 - 0.90 (m, 4 N), 0.99 (dd, y-14.0, 4.8 Hz, 6 N), 1.70 - 2.00 (m, 4 N), 2 .71 (sh, 2 H), 3.10 (s, C H), 3.74 (s, 2 H), 3.85 (s, C H), 4.68 (sh c, 1 H), 6.55 (d, 8.7 Hz, 2 N), 6.95 (dd, 9U-8.7, 1.3 Hz, 2 N), 7.31 - 7.40 (m, 4 N), 7.50 (c, 1 H).

Example 46 3-(14-Ccyclohexyl|3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

N

Nas Shi M -bn m (1) cyclohexyl|3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol

Using 3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1.8 g), synthesized in Example 44(2), and in the same manner as in Example 1(6), obtained the title compound (2.1 mg, 85905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.29 - 2.27 (m, 16 N), 3.86 (s, Z H), 4.57 (dd, U-8.1, 4.0 Hz, 1 N), 6.96 (d , 2-9.0 Hz, 2 N), 7.42 (d, 2U-8.9 Hz, 2 N), 7.59 (s, 1 N). (2) 3-(14-Ccyclohexyl|3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

Using cyclohexyl3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol (0.5 g) synthesized above and ethyl 3-(4-aminophenyl)carbonyl|amino)propanoate (0 .36 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (43 mg, 595) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 0.30 - 2.20 (m, 16 N), 2.65 (w s, 2 N), 3.66 (w s, 2 N) , 3.85 (s, C H), 4.45 (d, 9-72 Hz, 1 H), 6.55 (d, U-8.9 Hz, 2 H), 6.60 - 6.69 (m, 1 N), 6.94 (d, 9-9.0 Hz, 2 N), 7.38 (d, 9-9.0 Hz, 2 N), 7.47 (s, 1 N) , 7.56 (d, 9-8.9 Hz, 2 N).

Example 47 3-D4-Hcyclohexyl|3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid above: sn. the ashes of SHY b

I M

Using cyclohexyl3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol (0.5 g) synthesized in Example Ab(1) and ethyl 3-D(4-aminophenyl)carbonyl|/ methyl)aminoisopropanoate (0.38 g) synthesized in Example 2(2) and in the same manner as in Example 1(7) afforded the title compound (0.11 g, 1495) as a white solid .

IN NMR (300 MHz, SOSI") b m.h. 0.31 - 2.00 (m, 16 N), 2.70 - 2.74 (m, 2 N), 3.10 (s, Z H), 3.74 (t, U-6.5 Hz , 2 H), 3.85 (s, C H), 4.45 (d, 2-6.8 Hz, 1 H), 6.55 (d, 2-8.7 Hz, 2 H), 6 .95 (d, 9UE9, O Hz, 2 N), 7.30 - 7.42 (m, 4 N), 7.47 (s, 1 N).

Example 48 3-(X14-(1-I(3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonylamino)propanoic acid sn. 8) the nose of the student's wife

N

No, ren І, etc. (1) methyl 3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate

Using methyl 33-oxopentanoate (3.3 g), dimethylformamide dimethyl acetal (3.6 ml) and p-methoxyphenylhydrazine monohydrate (4.7 g) and in the same manner as in Example 15(1), the title compound was obtained (6.0 g, 8495) as butter. "H NMR (300 MHz, SOSI") b m.p. 1.14 (t, 9U-7.5 Hz, Z H), 2.92 (k, 9U-7.3 Hz, 2 H), 3 ,86 (c, Z

H), 3.87 (s, C H), 7.00 (d, 9-9.0 Hz, 2 H), 7.31 (d, 9U-9.0 Hz, 2 H), 7.99 (c, 1 H). (2)3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde

Using methyl 3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carboxylate (6.0 g) synthesized above and in the same manner as in Example 1(5), the title compound was obtained (4.0 g, 7690) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 1.18 (t, 9U-7.5 Hz, Z H), 2.92 (k, 9U-7.5 Hz, 2 H), 3 ,88 (c, Z

H), 6.91 - 7.08 (m, 2 H), 7.12 - 7.22 (m, 2 H), 7.33 (d, 9-9.0 Hz, 2 H), 8, 03 (c, 1 H), 9.97 (c, 1 H). (3) 1-(3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol

Using 3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (2.1 g) synthesized above, and in the same manner as in Example 1(6), the title compound was obtained (1.2 g, 4790) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.98 (6 H, d, U-6.4 Hz), 1.06 (Z H, t, 9U-7.6 Hz), 1.50 (1 H, d, 4-4.3 Hz) , 1.59 - 1.96 (Z3H, m), 2.70 (2 N, k, 9-7.5 Hz), 3.86 (Z H, s), 4.77 (1 N, dt, 9-81, 5.1

Hz), 6.97 (2 N, d, 9U-8.9 Hz), 7.931 (2 N, d, 2-8.9 Hz), 7.60 (1 N, s). (4) 3-(X14-(1-I(3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonyl)iamino)propanoic acid

Using 1-(3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.5 g) synthesized above and ethyl 3-((4- aminophenyl)carbonyl|iaminoisopropanoate (0.41 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) gave the title compound (0.2 g, 2595) as a white solid substance

"H NMR (300 MHz, SOSIz") b mp 0.93 - 1.20 (m, 9 H), 1.70 - 1.90 (m, C H), 2.63 (d, U -6.0 Hz, 4 N), 3.67 (d, 9U-5.5 Hz, 2 N), 3.84 (s, C H), 4.48 (t, 92-68 Hz, 1 N ), 6.58 (d, 9U-8.1 Hz, 2 N), 6.65 - 6.80 (m, 1 N), 6.95 (d, 2-8.9 Hz, 2 N), 7.25 - 7.79 (m, 5 N).

Example 49 3-X14-(1-3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanoic acid sn. | (8) sleep SHY zno

SN their mouth - sh y and Sn.

Sleep

Using 1-(3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.5 g), synthesized in Example 48(3), and ethyl 3 -M(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.44 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), obtained the target compound specified in the title (0, 1 g, 12905), as a white solid.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.90 - 1.09 (m, 9 H), 1.70 - 1.80 (m, Z H), 2.59 - 2.81 (m, 4

H), 3.11 (s, C H), 3.74 (t, 9U-6.5 Hz, 2 H), 3.86 (s, C H), 4.41 - 4.57 (m, 1 N), 6.55 (d, 2-8.7 Hz, 2

H), 6.97 (d, 9-8.9 Hz, 2 H), 7.25 - 7.36 (m, 4 H), 7.53 (s, 1 H).

Example 50 3-(X4-Ccyclohexyl|3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)iamino)phenylcarbonylamino)propanoic acid

N

NS Denne IM

He

M dream (1) cyclohexyl(|3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol

Using 3-ethyl-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (2.1 g), synthesized in Example 48(2), and in the same way as in Example 1(6), obtained the title compound (1.9 g, 6595) as a white solid.

IN NMR (300 MHz, SOSIZ") b m.h. 0.82 - 2.18 (m, 12H), 2.66 (k, 9U-7.6 Hz, 2 H), 3.86 (s, C H), 4.34 (dd, U-8, 2, 3.7 Hz, 1 N), 6.97 (d, 9-9.0 Hz, 2 N), 7.32 (d, 9-90 Hz, 2 N), 7.57 (s, 1 N). (2) 3-(C4-(Hcyclohexyl|3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonylamino)propanoic acid

Using cyclohexyl3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol (0.5 g) synthesized above and ethyl 3-((4-aminophenyl)carbonylaminoisopropanoate (0.38 g) , synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.35 mg, 43905) was obtained as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.93 (t, 9U-7.5 Hz, Z H), 1.02 - 2.07 (m, 11 H), 2.64 (t, 9U-7.3 Gu, 4 H), 3, 58 - 3.74 (m, 2 H), 3.84 (s, Z H), 4.20 (d, 9-7.0 Hz, 1 H), 6.54 (d, 2-8.7 Hz, 2

H), 6.61 - 6.72 (m, 1 H), 6.95 (d, 9-9.0 Hz, 2 H), 7.25 - 7.55 (m, 5 H).

Example 51 3-CD4-Hcyclohexyl|3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)amino)propanoic acid

SE nk s r -7 zhi sna o szishnoi MA KE

SN.

Using cyclohexyl3-ethyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl|methanol (0.5 g), synthesized in Example 5O(1) and ethyl 3-(Х(4-aminophenyl)carbonyl| /methyl)aminoisopropanoate (0.40 g) synthesized in Example 2(2) and in the same manner as in Example 1(7) gave the title compound (0.15 mg, 1895) as a white solid substance "H NMR (300 MHz, SOSI") b m.ch. 0.94 (t, 9U-7.5 Hz, Z H), 1.01 - 2.11 (m, 12 H), 2.56 - 2.83 (m, 4 H), 3.09 (s, C H), 3.73 (t, 9U-6.4 Hu, 2 H), 3.85 (s, C H), 4.19 (d, U-6.8 Hz, 1 N), 6.54 (d, uU-8.7 Hz, 2 N), 6.96 (d, 9-8.9 Hz, 2 N), 7, 27 - 7.37 (m, 4 N), 7.48 (s, 1 N).

Example 52 3-(X4-(cyclohexyl|1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methyl)iamino)phenylcarbonylamino)propanoic acid

AJ du

Don't eat her M Shk N

M ON"

SNU

(1) methyl 1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazole-4-carboxylate

Using methyl 4-methyl-3-oxopentanoate (3.6 g), dimethylformamide of dimethyl acetal (3.5 ml) and p-methoxyphenylhydrazine monohydrochloride (4.5 g) and in the same manner as in Example 15(1), the indicated title compound (3.5 g, 5195) as a pale yellow solid.

IN NMR (300 MHz, SOSIz") 6 m.h. 1.37 (d, 9U-6.0 Hz, 6 N), 3.20 - 3.40 (m, 1 N), 3.86 (s, C H), 3.90 (s, C H) , 6.98 (d, 9-9.0 Hz, 2 N), 7.27 (d, 9-9.0 Hz, 2 N), 7.29 (s, 1 N), 7.99 (s , 1 H). (2) 1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazole-4-carbaldehyde

Using methyl 1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazole-4-carboxylate (3.5 g), synthesized above, and in the same manner as in Example 1(5), the indicated title compound (2.6 g, 8495) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.37 (d, 9U-7.0 Hz, 6 N), 3.12 - 3.25 (m, 1 N), 3.88 ( s, Z H), 7.01 (d, 9-9.0 Hz, 2 H), 7.29 (d, Y-9.0 Hz, 2 H), 8.05 (s, 1 H), 10.06 (s, 1 H). (3) cyclohexyl(|1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methanol

Using 1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazole-4-carbaldehyde (1.3 g), synthesized above, and in the same manner as in Example 1(6), the indicated title compound (1.4 g, 8490) as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 0.81 - 2.21 (m, 18 N), 3.08 (quin, U-7.2 Hz, 1 N), 3.86 ( with, Z

H), 4.52 (dd, U-8.7, 3.8 Hz, 1 H), 6.96 (d, 9U-9.0 Hz, 2 H), 7.27 (d, 959.0 Hz, 2 N), 7.59 (s, 1 N). (4) 3-(X4-cyclohexyl|1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

Using cyclohexyl|1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methanol (0.70 g) synthesized above and ethyl 3-|(4-aminophenyl)carbonyl| amino)propanoate (0.52 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) gave the title compound (0.34 g, 30905) as a white solid .

"H NMR (300 MHz, SOSI") b m.p. 1.10 (d, 9-7.2 Hz, Z H), 1.18 (d, 9-7.2 Hz, Z H), 1 .20 - 2.06 (m, 12 N), 2.64 (t, 95.5 Hz, 2 N), 3.10 (quin, 9U-7.3 Hz, 1 N), 3.66 (k , U-5.8 Hu, 2 H), 3.85 (s, Z

H), 4.37 (d, 9-7.2 Hz, 1 H), 6.57 (d, 9-8.7 Hz, 2 H), 6.61 - 6.74 (m, 1 H) , 6.94 (d, U-8.7 Hz, 2 N), 7.20 - 7.58 (m, 5 N).

Example 53 3-D4-Hcyclohexyl(|1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methyl)amino)phenyl]carbonylUumethyl)amino|propanoic acid m a sn I "o i sha Se 0 --o zhenie M shii M - r

SN

Using cyclohexyl|1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methanol. (0.70 Kc og), synthesized in Example 523), and oethyl o /3-D(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.55 g), synthesized in Example 2(2), and the same in the same manner as in Example 1(7), the title compound (0.28 g, 24905) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.p. 1.11 (d, 9U-6.8 Hz, Z H), 1.19 (d, 9-7.2 Hz, Z H), 1 ,20 -2.13 (m, 11 N), 2.72 (t, 956.1 Hz, 2 N), 3.03 - 3.23 (m, 4 N), 3.73 (t, 9- 6.6 Hz, 2 H), 3.85 (s, C H), 4.36 (d, 9-7.2 Hz, 1 H), 6.55 (d, 2-8.3 Hz, 2 H), 6.95 (d, 9-91 Hz, 2 H), 7.21-7.35 (m, 4 H), 7.50 (s, 1 H).

Example 54 3-(14-(41-1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonyl)iamino)propanoic acid sn. o o ns s m sho

N

Us, from M alob ch- sn.

SNU

(1) 1-11-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol

Using 1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazole-4-carbaldehyde (1.3 g) synthesized in Example 52(2), and in the same manner as in Example 1( 6), afforded the title compound (1.6 g, 9895) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.99 (d, 9U-5.7 Hz, 6 N), 1.28 (dd, 9U-17.0, 7.2 Hz, 6 N), 1.75 - 1.98 (m, 2 N ), 2.99 - 3.19 (m, 1 H), 3.86 (s, C H), 4.96 (dd, 9U-8.4, 4.4 Hz, 1 H), 6.97 (d, uU-8.9 Hz, 2 N), 7.26 (d, 9U-9.0 Hz, 2 N), 7.62 (s, 1 N). (d) 3-(Х4-(11-(1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonyl)iamino)propanoic acid

Using 1-(1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.57 g) synthesized above and ethyl 3- ((4-aminophenyl)carbonyl|amino)propanoate (0.45 g), synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (28.0 mg , 3905), as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.97 (d, 9U-6.4 Hz, Z H), 1.02 (d, 9-6.4 Hz, Z H), 1.11 - 1.98 (m, 9 H), 2, 67 (t, 95.7 Hz, 2 N), 2.98 - 3.19 (m, 1 N), 3.68 (t, 9U-6.0 Hz, 2 N), 3.85 (s, With H), 4.66

(d, U-9.0 Hz, 1 N), 6.51 -6.77 (m, C H), 6.95 (d, 9-8.9 Hz, 2 N), 7.26 - 7 .59 (m, 5 N).

Example 55 3-Х4-(41-11-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanoic acid her in; Y gde -e- : sia S u ky -Zon sh sn

Sun d th st - th She i "A Kk people. 0-6 ov N x znih "m poh zu

SN

Using 1-(1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.57 g), synthesized in Example 5A(1) and ethyl 3-(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.48 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained ( 8.0 mg, 195) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 0.97 (d, 9U-6.6 Hz, Z H), 1.02 (d, 9U-6.4 Hz, Z H), 1 ,11 - 2.01 (m, 9 H), 2.72 (w s, 9U-6.0 Gu, 2 H), 2.96 - 3.24 (m, 4 H), 3.74 (w s, 2-6.0 Hz, 2 N), 3.86 (s, C H), 4.63 (d, 9U-6.0 Hz, 1 H), 6.50 - 6.70 (m, 2 H), 6.96 (d, 9U-8.9 Hz, 2 H), 7.21 - 7.38 (m, 4 H), 7.59 (shs, 1 H).

Example 56 3-II(4-Ccyclohexyl/1-ethyl-3-(4-trifluoromethyl)phenyl|-1H-pyrazol-5-yl)methyl)amino|phenyl)carbonyl)amino|propanoic acid

N

E E he M

Then, (1) ethyl 1-ethyl-3-(4-(trifluoromethyl)phenyl|-1H-pyrazole-5-carboxylate 1--4-"Trifluoromethyl)phenyl|ethanone (12.0 g) was dissolved in ethanol (100 mL), sodium hydride (6095, in oil, 2.8 g) was carefully added under ice-cooling. After stirring for 5 min, diethyl oxalate (8.7 mL) was added and the mixture was stirred at room temperature overnight. The precipitate (18 .6 g) was collected and ethanol (16 ml), 1M hydrochloric acid (4.3 ml) and ethyl hydrazine (1.6 g) were added to 7.3 g of this precipitate and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, volume ratio) to give the title compound (5.7 g, 78905), as oil.

IN NMR (300 MHz, SOSI") b m.h. 1.42 (t, 9d-7.2 Hz, Z H), 1.50 (t, 9U-7.2 Hz, Z H), 4.39 (k,

U-7.2 Hz, 2 N), 4.66 (k, 9U-7.2 Hz, 2 N), 7.17 (s, 1 N), 7.65 (d, 9-81 Hz, 2 H), 7.92 (d, 9U-8.1 Hz, 2 H). (2) 1-ethyl-3-(4-(trifluoromethyl)phenyl|)-1H-pyrazole-5-carbaldehyde

Using ethyl 1-ethyl-3-(4-(trifluoromethyl)phenyl|-1H-pyrazole-5-carboxylate (5.7 g), synthesized above, and in the same way as in Example 1(5), the indicated title compound (3.2 g, 68905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.48 (t, 9-7.2 Hz, Z H), 4.25 (k, 9-7.2 Hz, 2 H), 6.85 (s, 1

H), 7.54 (d, 9-8.0 Gu, 2 H), 7.77 (d, 9-8.0 Hz, 2 H), 10.01 (s, 1 H). (3) cyclohexyl/1-ethyl-3-(4-(trifluoromethyl)phenyl|-1H-pyrazol-5-ylmethanol

Using 1-ethyl-3-(4-(trifluoromethyl)phenyl|-1H-pyrazole-5-carbaldehyde (2.28 g), synthesized above, and in the same manner as in Example 1(6), the title compound was obtained the target compound (1.2 g, 41905) as a white solid.

IN NMR (300 MHz, SOSI»v) b m.ch. 0.92 - 2.00 (m, 11 N), 1.39 (t, 9U-7.2 Hz, Z H), 2.27 (d,

U-4.7 Hz, 1 N), 4.00 - 4.25 (m, 2 N), 4.53 (dd, U-6.4, 4.7 Hz, 1 N), 6.23 ( s, 1 H), 7.53 (d, 9-7.9

Hz, 2 N), 7.72 (d, 9-7.9 Hz, 2 N). (4) 3-I(4-Kcyclohexyl/1-ethyl-3-(4-(trifluoromethyl)phenyl|-1H-pyrazol-5-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

Using cyclohexyl/1-ethyl-3-14-"-trifluoromethyl)phenyl|)|-1H-pyrazol-5-ylmethanol (0.6 g) synthesized above and ethyl 3-(4-aminophenyl)carbonyl| amino)propanoate (0.42 g) synthesized in Example 1(2) and in the same manner as in Example 1(7) gave the title compound (0.18 g, 2090) as a white solid "H NMR (300 MHz, SOSI") b m.ch. 0.97 - 1.27 (m, 11 N), 1.33 (t, U-7.3 Hz, Z H), 2.68 (t, 9U-5.5 Hz, 2 N), 3, 59 - 3.80 (m, 2 N), 4.11 (k, 9U-7.2 Gu, 2 N), 4.39 (d, 9-6.8 Hz, 1 N), 6.16 ( with, 1

H), 6.64 (d, 2-8.7 Hz, 2 H), 6.70 - 6.83 (m, 1 H), 7.48 (d, 9-8.1 Hz, 2 H) , 7.58 (d, U-8.7 Hz, 2 N), 7.69 (d, U-8.1 Hz, 2 N).

Example 57 3-II(4-Kcyclohexyl/1-ethyl-3-(4-trifluoromethyl)phenyl|-1H-pyrazol-5-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

That's it

From g H. or TON r a i

Her uv Y St v i p o

E M - sleep

Using cyclohexyl/1-ethyl-3-I4-"-trifluoromethyl)phenyl|)|-1H-pyrazol-5-yl)umethanol (0.6 g), synthesized in Example 56(3), and ethyl 3-I ((4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.48 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), obtained the target compound specified in the title (0.19 g, 1995), as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 0.92 - 2.00 (m, 11 N), 1.35 (t, 9U-7.2 Hz, Z H), 2.62 - 2.78 (m, 2 N), 3.09 (s , Z H), 3.75 (t, 9U-6.6 Hz, 2 H), 4.15 (k, 9U-7.2 Hz, 2 H), 4.39 (d, 9-6.6 Hz, 1 N), 6.18 (s, 1 N), 6.61 (d, 90-8.7 Hz, 2 N), 7.25 (d, 9U-8.7 Hz, 2 N), 7.50 (d, 9-81 Hz, 2 N), 7.70 (d, y-8.1 Hz, 2 N).

Example 58 3-II(4-Kcyclohexyl/1-ethyl-3-(4-trifluoromethoxy)phenyl|-1H-pyrazol-5-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Yi Yi govo in

E sia Yi dream. (1) ethyl 1-ethyl-3-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-5-carboxylate

Using 1-(4-"trifluoromethoxy)phenyl|ethanone (13.0 g), sodium hydride (6090, in oil, 2.8 g), diethyl oxalate (8.7 mL) and ethyl hydrazine (4.2 g) I in the same way as in

Example 56(1) gave the title compound (19.4 g, 92905) as an oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.34 - 1.53 (m, 6 N), 4.24 (d, 9-7.2 Hz, 2 N), 423 (k, 20-72

Hz, 2 N), 4.43 (k, 90-7.2 Hz, 2 N), 4.45 (d, 2-7.2 Hz, 2 N), 6.82 (s, 1 N), 7.33 (d, 29-90 Hz, 2 N), 7.44 (d, 9-9.0 Hz, 2 N). (2) 1-ethyl-3-(4-(trifluoromethoxy)phenyl|)-1H-pyrazole-5-carbaldehyde

Using ethyl 1-ethyl-3-(4-«(trifluoromethoxy)phenyl|)|-1H-pyrazole-5-carboxylate (5.0 g) synthesized above, and in the same manner as in Example 1(5) , afforded the title compound (4.9 g, 38905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.48 (t, 9U-7.3 Hz, Z H), 4.23 (k, U-7.3 Hz, 2 H), 6.80 (s, 1

N), 7.30 - 7.58 (m, 4 N), 10.00 (c, 1 N). (3) cyclohexyl/1-ethyl-3-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-5-ylmethanol

Using 1-ethyl-3-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-5-carbaldehyde (2.5 g), synthesized above, and in the same manner as in Example 1(6), the title compound was obtained the target compound (1.7 g, 5490) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 1.26 -2.00 (m, 11 H), 1.39 (t , 9U-7.2 Hz, Z H), 4.12 (d, 9-72

Hz, 2 N), 4.52 (d, 9U-6.4 Hz, 1 N), 6.18 (s, 1 N), 7.30 (d, 2-8.7 Hz, 2 N), 7.43 (d, U-8.7 Hz, 2 N). (4) 3-II54-Kcyclohexyl/1-ethyl-3-14-(trifluoromethoxy)phenyl|-1H-pyrazol-5-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Using cyclohexyl/1-ethyl-3-14-"(trifluoromethoxy)phenyl|)|-1H-pyrazol-5-yl)umethanol (0.39 g) synthesized above and ethyl 3-((4-aminophenyl) carbonyl|/methyl)aminoisopropanoate (0.32 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound (0.06 g, 1195) was obtained as white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.99 - 2.00 (m, 11 N), 1.36 (t, 9U-7.2 Hz, Z H), 2.74 (t,

U-6.2 Hz, 2 H), 3.10 (s, Z H), 3.74 (t, 9-6.2 Hz, 2 H), 4.12 (k, 9d0-7.2 Hz , 2 H), 4.37 (d, 9-6.4 Hz, 1

H), 6.10 (s, 1 H), 6.63 (d, 920-8.7 Hz, 2 H), 7.26 - 7.46 (m, 6 H).

Example 59 3-I54-(1-11-ethyl-3-I4-"trifluoromethoxy)phenyl|-1H-pyrazol-5-yl)-3-methylbutyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid sn. and about

E re roles Dr

E-K n.s | Y Y M On it s she

SNU

(1) 1471-ethyl-3-14-(trifluoromethoxy)phenyl)|-1H-pyrazol-5-yl)u.-3-methylbutan-1-ol 1-Ethyl-3-(4-(trifluoromethoxy)phenyl |)|-1 H-pyrazole-5-carbaldehyde (2.5 g), synthesized in

Example 58(2) was dissolved in tetrahydrofuran (20 ml) and a tetrahydrofuran solution (12 ml) of 1M isobutylmagnesium bromide was added dropwise at 0 "С. In the same way as in Example 1(b6), the target compound indicated in the title was obtained (0 .9 g, 3195), as butter.

IN NMR (300 MHz, SOSIZz) b m.ch. 0.98 (d, 9U-6.4 Hz, 6 H), 1.39 (t, 9U-7.2 Hz, Z H), 1.56 - 1.98 (m, Z H), 2, 21 (d, 90-4.3 Hz, 1 N), 4.10 - 4.30 (k, 9-7.2 Hz, 2 N), 4.86 (ddd, U-8.9, 4, 7, 4.3 Hz, 1

H), 6.22 (s, 1 H), 7.32 - 7.50 (m, 4 H). (d) 3-II5A-(1-1-ethyl-3-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-5-yl)-3-methylbutyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Using 1-(1-ethyl-3-N4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-yl-3-methylbutan-1-ol (0.39 g) synthesized above and ethyl 3-( (4-Aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.28 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained (0.02 g , 4905), as a white solid.

IN NMR (300 MHz, SOSIz) 6 m.h. 0.97 (dd, U-19,1,6,2 Hz, 6 H), 1.34 (t, 9U-7.2 Hz, Z H), 1.55 - 1.97 (m, Z H ), 2.70 (shs, 2 H), 3.07 (s, C H), 3.73 (sh s, 2 H), 4.10 (k, 957.2 Hz, 2 H), 4, 61 (t, 3-6.8 Hz, 1 N), 6.17 (s, 1 N), 6.67 (d, 9U-8.0 Hz, 2 N), 7.34 - 7.49 ( m, 6 H).

Example 60 3-1(4-(/3-(benzyloxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylUcyclohexyl)methylaminophenyl)carbonylamino)propanoic acid

Oh bitch

Mo (1) 3-(benzyloxy)-1-(4-(trifluoromethoxy)phenyl/|-1 H-pyrazole-4-carbaldehyde

Using ethyl 3-(benzyloxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carboxylate (3.1 g) was synthesized according to the method described in EP1394154 and in the same way as in Example 1 (5 ), the title compound (2.1 g, 7590) was obtained as a white solid. "H NMR (300 MHz, SOSIS") b m.p. 5.50 (s, 2 H), 7.27 - 7.70 (m, 9 H), 8.24 (s, 1 H), 10.00 (s, 1

N). (2) (3-"benzyloxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-yl cyclohexyl)methanol

Using 3-(benzyloxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carbaldehyde (2.1 g), synthesized above, and in the same way as in Example 1(b), obtained the title compound (1.9 g, 76905) as a white solid.

IN NMR (300 MHz, SOSI»z) b m.h. 0.92 - 2.00 (m, 12 N), 4.44 (dd, 9-6.8, 5.3 Hz, 1 N), 5.36 (s, 2 N), 7.26 - 7 .51 (m, 9 H), 7.66 (s, 1 H). (3) 3-S(4-1/3-(benzyloxy)-1-I4-(trifluoromethoxy)phenyl/|-1H-pyrazol-4-ylUcyclohexyl)methyl]aminophenyl)carbonylamino)propanoic acid

Using 13-(benzyloxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylUcyclohexyl)methanol (0.50 g) synthesized above and ethyl 3-((4-aminophenyl)carbonylamino) propanoate (0.26 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.39 g, 56905) was obtained as a white solid.

IN NMR (300 MHz, SOS") b m.h. 0.78 - 2.00 (m, 11 N), 2.12 - 2.42 (m, 2 N), 3.30 - 3.57 (m, 2

H), 4.14 (d, 20-7.0 Gu, 1 H), 5.31 (s, 2 H), 6.41 (d, 2-8.5 Hz, 2), 6.77 ( w s, 1 H), 7.12 (d, 9-9.0

Hz, 2 N), 7.29 - 7.67 (m, 10 N).

Example 61 3-1(4-(/3-(benzyloxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylUcyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid to

E--x -y M garden even,

She

Using 13-(benzyloxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylUcyclohexyl)methanol (0.50 g), synthesized in Example 60(2), and ethyl 3-(4- aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.28 g), synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound was obtained (0.37 g, 52905) , as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 0.87 - 2.05 (m, 11 N), 2.52 (t, 9U-6.0 Hz, 2 N), 2.96 ( s, Z H), 3.50 - 3.78 (m, 2 H), 4.20 (d, 9U-6.8 Hz, 1 H), 5.25 - 5.46 (m, 2 H) , 6.47 (d, 9U-8.7 Hz, 2 N), 7.12-7.62 (m, 12 N).

Example 62 3-II(4-Kcyclohexyl3-methoxy-1-I(4-"trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid and its addition

Ezi M garden,

Che (1) 3-methoxy-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carbaldehyde

Using ethyl 3-methoxy-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carboxylate (4.8 g) was synthesized according to the method described in UUO2007/89031 and in the same way as in Example 1 (5 ), the title compound (1.0 g, 35905) was obtained as a white solid. "H NMR (300 MHz, SOCI") b m.p. 4.10 (s, C H), 7.33 (d, 9-9.1 Hz, 2 N), 7.69 (d, 9-91 Hz, 2

H), 8.23 (s, 1 H), 9.87 (s, 1 H). (2) cyclohexyl3-methoxy-1-(4-trifluoromethoxy)phenyl)-1H-pyrazol-4-ylylmethanol

Using 3-methoxy-1-(14-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carbaldehyde (1.0 g), synthesized above, and in the same way as in Example 1(6), the indicated in title compound (1.5 g, 75905) as a white solid. "H NMR (300 MHz, SOSI") 6 ppm 0.90 - 2.02 (m, 11 H), 3.62 ( w s, 1 H), 4.00 (s, Z H), 4.40 (dd, U-7.0, 4.7 HZ, 1 H), 7.24 - 7.62 (m, 4 H ), 7.64 (s, 1 H). (3) ethyl 3-methoxy-1-I(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carboxylate

Using cyclohexyl3-methoxy-1-N4-(trifluoromethoxy)phenyl|)|-1H-pyrazol-4-ylylmethanol (0.75 g) synthesized above and ethyl 3-L(4-aminophenyl)carbonyl|amino)propanoate (0.47 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.10 g, 9905) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 0.88 - 2.00 (m, 11 N), 2.58 (t, U-6.0 Hz, 2 N), 3.54 - 3.68 (m, 2 N), 4.00 (s, Z N), 4.20 (d, 9-66 Hz, 1 N), 6.52 (d, 9-8.7 Hz, 2 N ), 6.56 - 6.68 (m, 1 N), 7.20 (d, U-8.3 Hz, 2 N), 7.48 - 7.59 (m, 5 N).

Example 63 3-II(4-Kcyclohexyl3-methoxy-1-I(4-"trifluoromethoxy)phenyl|-1H-pyrazole-4-

ilumethyl)amino|phenyl)carbonyl)(methyl)amino|propanoic acid

OD don

E-M clade;

Ike;

Using cyclohexyl3-methoxy-1-N4-(trifluoromethoxy)phenyl|)|-1H-pyrazol-4-ylmethanol. (0.75 ml), synthesized in Example 62(2), and oethyl o 3-D(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.50 g), synthesized in Example 2(2), and the same in the same manner as in Example 1(7), the title compound (0.13 g, 1295) was obtained as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.02 (m, 11 N), 2.68 (t, U-6.2 Hz, 2 N), 3.05 (s, C H), 3.71 (t, 9-6 .4 Hz, 2 N), 4.01 (s, Z N), 4.19 (d, 2-66 Hz, 1 N), 6.53 (d, 2-8.7 Hz, 2 N), 7.17 - 7.28 (m, 4 H), 7.47 - 7.61 (m, C H).

Example 64 3-II(4-Kcyclohexyl/13-(1-methylethoxy)-1-14-(trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid? at

HELL

E M writes;

MOoso (1) 3-(1-methylethoxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazole-4-carbaldehyde

Using ethyl 3-(1-methylethoxy)-1-(4-"trifluoromethoxy)phenyl|-1H-pyrazole-4-carboxylate (1.3 g) was synthesized according to the method described in UU/O2007/89031 and the same as in Example 1(5), the title compound (0.43 g, 3790) was obtained as an oil. "H NMR (300 MHz, SOCI") 6 m.h. 1.33 (d, 9-6.2 Hz, 6 N), 5.20 (queen, U-6.2 Hz, 1 N), 7.03 - 7.76 (m, 4 N), 7, 98 (c, 1 H), 9.78 (c, 1 H). (2) cyclohexyl3-(1-methylethoxy)-1-(4-"trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)umethanol

Using 3-(1-methylethoxy)-1-N4-(trifluoromethoxy)phenyl!/|-1H-pyrazole-4-carbaldehyde (0.43 g) synthesized above, and in the same manner as in Example 1(b ), afforded the title compound (0.40 g, 7490) as an oil. "H NMR (300 MHz, SOSI") b mp 1.47 - 2.20 (m, 17 N), 3.61 (shs, 1 N), 4.20 - 440 (m, 2 N) , 7.29 (d, U-8.7 Hz, 2 N), 7.57 (s, 1 N), 7.74 (d, 9-8.7 Hz, 2 N). (3) 3- 1(4-Kcyclohexyl/13-(1-methylethoxy)-1-(4-"trifluoromethoxy)phenyl|-1H-pyrazol-4-yl)methyl)amino|phenyl)carbonyl)amino|propanoic acid

Using cyclohexyl(1-methylethoxy)-1-(4-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylmethanol (0.20 g) synthesized above and ethyl 3-K4-aminophenyl)carbonylamino) propanoate (0.12 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.11 g, 3690) was obtained as a white solid. "H NMR (300 MHz, SOSIZ") b m.ch. 1.00 - 2.08 (m, 11 N), 1.11 - 1.18 (m, 6 N), 2.50 - 2.66 (m, 2

H), 3.54 - 3.70 (m, 2 H), 4.11 - 4.30 (m, 2 H), 6.57 (d, 9U-8.7 Hz, 2 H), 6, 69 (w s, 1 H), 7.26 (d,

uU-8.7 Hz, 2 N), 7.46 (s, 1 N), 7.57 (d, U-8.7 Hz, 2 N).

Example 65 3-II(4-Kcyclohexyl/13-(1-methylethoxy)-1-14-(trifluoromethoxy)phenyl|-1H-pyrazol-4-ylylmethyl)amino|phenyl)carbonyl)(methyl)amino|propanoic acid her ode

E- -y M tegu

Mo

Using cyclohexyl(3-(1-methylethoxy)-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-4-ylmethanol (0.20 g), synthesized in Example 64(2), and ethyl 3-K (4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.13 g), synthesized in Example 2(2), and in the same way as in Example 1(7), the target compound specified in the title was obtained (0.11 g , 3695), as a white solid.

IN NMR (300 MHz, SOS") b m.h. 0.97 - 2.00 (m, 11 N), 1.12 - 1.19 (m, 6 N), 2.53 - 2.70 (m, 2

Н), 3.05 (s, З Н), 3.63 - 3.78 (m, 2 Н), 4.13 - 4.29 (m, 2 Н), 6.57 (d, У-8 .9 Hz, 2 N), 7.27 - 7.32 (m, 4 N), 7.46 (s, 1 N), 7.72 (d, 9-8.9 Hz, 2 N).

Example 66 3-(X4-(13-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl)/cyclohexyl)methyl)amino)phenylcarbonylamino)propanoic acid and

N b

Mo (1) 3-(benzyloxy)-1-phenyl-1H-pyrazole-4-carbaldehyde

Using ethyl 3-(benzyloxy)-1-phenyl-1H-pyrazole-4-carboxylate (1.8 g) synthesized according to the method described in EP1394154 and in the same way as in Example 1(5), the target indicated in the title was obtained compound (1.4 g, 90905) as an oil.

IN NMR (300 MHz, SOSI") b m.h. 5.50 (s, 2 N), 7.29 - 7.78 (m, 10 N), 8.26 (s, 1 N), 9.98 (s, 1

N). (2) (3-"benzyloxy)-1-phenyl-1H-pyrazol-4-yl|(cyclohexyl)methanol

Using 3-(benzyloxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.4 g) synthesized above and in the same manner as in Example 1(6), the title compound (1 .6 g, 91905), as butter.

IN NMR (300 MHz, SOSI") b m.h. 1.58 - 2.20 (m, 12 N), 4.44 (dd, 9-72, 5.3 Hz, 1 N), 5.37 (s, 2 N), 7.10 - 7.62 (m, 10 N), 7.69 (s, 1 N). (3) 3-(14-((3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl)"ucyclohexyl)methyl)amino)phenylcarbonylamino)propanoic acid

Using (|3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl|/cyclohexyl)methanol (0.79 g) synthesized above and ethyl 3-|(4-aminophenyl)carbonylaminoiopropanoate (0. 51 g) synthesized in Example 1(2), and in the same manner as in Example 1(7), the title compound (0.51 g, 43905) was obtained as a white solid.

"H NMR (300 MHz, SOSIZ") b mp 0.84 - 1.97 (m, 11 N), 2.30 - 2.48 (m, 2 N), 3.37 - 3.58 (m, 2

H), 4.18 (d, 9U-6.6 Gu, 1 H), 5.24 - 5.42 (m, 2 H), 6.44 (d, 9-8.7 Hz, 2 H) , 6.66 (w s, 1 N), 7.02 - 7.63 (m, 13 N).

Example 67 3-CI4-(3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl)"ucyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

The day of the show M

Sa

Using (|3-(benzyloxy)-1-phenyl-1H-pyrazol-4-yl|/cyclohexyl)methanol (0.79 g), synthesized in Example 66(2), and ethyl 3-((4-aminophenyl )carbonyl)methyl)amino)propanoate was synthesized in Example 2(2), and in the same manner as in Example 1(7), the title compound (0.68 g, 55905) was obtained as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 2.01 (m, 11 N), 2.71 (d, 9U-6.0 Hz, 1 N), 3.06 (s, C H), 3.71 (t, U-6 .4 Hz, 2 N), 4.23 (d, 9-6.6 Hz, 1 N), 5.28 - 5.47 (m, 2 N), 6.50 (d, 2-8.7 Hz, 2 N), 7.10 - 7.64 (m, 13 N).

Example 68 3-(14-Ccyclohexyl|1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid is not very good;

M

From (1) methyl 4-(morpholin-4-yl)-3-oxobutanoate

Morpholine (34.5 g) was added to a solution (300 ml) of methyl 4-chloro-3-oxobutanoate (27.1 g) under ice cooling in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, 1M hydrochloric acid (100 ml) was added and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:10, v/v) to give the title compound (12.8 g, 3596) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 2.37 - 2.55 (m, 4 H), 3.26 (s, 2 H), 3.52 (s, 2 H), 3.70 - 3.76 (m, 4 H), 3, 74 (c, Z H). (2) methyl 1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazole-4-carboxylate

Dimethylformamide dimethyl acetal (4.9 ml) was added to methyl 4-(morpholin-4-yl)-3-oxobutanoate (7.0 g) synthesized in stage (1) and the mixture was stirred at 100 C for 2 h. The reaction mixture was left to cool to room temperature, ethanol (200 ml) and 4-methoxyphenylhydrazine hydrochloride (6.3 g) were added and the mixture was stirred at 100 C for 3 h. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (10.6 g, 9395) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 2.44 - 2.50 (m, 4 H), 3.60 - 3.65 (m, 4 H), 3.75 (s, 2 H), 3.86 (s, C H), 3, 87 (s, C H), 6.97 (d, 9-9.1 Hz, 2 H), 7.68 (d, 9-91 Hz, 2 H), 8.03 (s, 1 H). (3) 1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazole-4-carbaldehyde

A solution (20 ml) of methyl 1-(4-methoxyphenyl)-3-"morpholin-4-ylmethyl)-1H-pyrazole-4-carboxylate (11.3 g), synthesized in the above mentioned (2), in tetrahydrofuran was added to an ice-cooled solution (80 ml) of lithium aluminum hydride (1.4 g) in tetrahydrofuran.

The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (3.7 ml), 1M aqueous sodium hydroxide solution (18.5 ml) and water (3 .7 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (8.5 g), 1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazol-4-methanol, as a pale yellow oil It was dissolved in toluene (150 ml), manganese dioxide (15 g) was added and the mixture was heated for 30 min with a Dean-Stark nozzle.

The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (7.2 g, 7090) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 2.44 - 2.50 (m, 4 H), 3.60 - 3.65 (m, 4 H), 3.72 (s, 2 H), 3.88 (s, C H), 6, 99 (d, 2-9.1 Hz, 2 N), 7.60 (d, 9U-9.1 Hz, 2 N), 8.08 (s, 1 N), 10.10 (s, 1 N ). (4) cyclohexyl|1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazol-4-yl|methanol

To a solution (15 ml) of 1-(4-methoxyphenyl)-3-"("morpholin-4-ylmethyl)-1H-pyrazole-4-carbaldehyde (2.0 g), synthesized in the above-mentioned (3), in cyclohexylmagnesium bromide (10 ml, 1 mM tetrahydrofuran solution) was added dropwise to tetrahydrofuran while cooling with ice. After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (1.3 g, 5195) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.92 - 2.20 (m, 11 N), 2.24 - 2.50 (m, 4 N), 3.47 (d, 9 -12.0

Hz, 1 N), 3.58 - C3.7Z (m, 5 N), 3.87 (s, C H), 4.43 (d, U-6.6 Hz, 1 N), 6.10 (c, 1 H), 6.98 (d, U-8.9

Hz, 2 N), 7.26 (d, 9U-8.9 Hz, 2 N), 7.49 (s, 1 N). (5) 3-(44-(cyclohexyl|1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

To a solution (15 ml) of cyclohexyl|1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazol-4-yl|methanol (0.65 g), synthesized in the above-mentioned (4), in tetrahydrofuran at room temperature was added thionyl chloride (0.37 ml). The reaction mixture was stirred at room temperature for 30 min and cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (15 mL). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15 ml), sodium iodide (0.37 g), sodium carbonate (0.27 g) and ethyl 3-L(4-aminophenyl)carbonyl|amino)propanoate (0.39 g), synthesized in Example 1(2), and the mixture was stirred at 70 "C for 12 h.

After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(14-(/cyclohexyl(|1-(4-methoxyphenyl)-3-(morpholine) -4-ylmethyl)-1H-pyrazol-4-ylmethyl)amino)phenylcarbonyl)iamino)propanoate (0.35 g) as a pale yellow oil. It was dissolved in ethanol (2 ml), at room temperature a 1 M aqueous solution of sodium hydroxide (1.5 ml) was added, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (1 .5 ml). The precipitate was washed with water to give the title compound (0.22 g, 22905) as a colorless solid. "H NMR (300 MHz, SOSI") b mp 0.92 - 2.00 (m, 11 N), 2.24 - 2.50 (m, 4 N), 2.66 (shs, 2 H), 3.44 (s, 2 H), 3.58 - 3.73 (m, 6 H), 3.85 (s, C H), 4.47 (d, 9-7.2 Hz, 1 H), 6.47 - 6.79 (m, C H), 6.94 (d, 9-8.7 Hz, 2 H), 7.26 - 7.30 (m, 2 H), 7 .50 - 7.60 (m, Z H).

Example 69 3-D4-Hcyclohexyl|1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

GO ne shchi M SN" she; vi o o

To a solution (15 ml) of cyclohexyl|1-(4-methoxyphenyl)-3-(morpholin-4-ylmethyl)-1H-pyrazol-4-ylmethanol (0.65 g), synthesized in Example 68(4), in thionyl chloride (0.37 ml) was added to tetrahydrofuran at room temperature. The reaction mixture was stirred at room temperature for 30 min and cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (15 mL). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15 ml) and sodium iodide (0.37 g), sodium carbonate (0.27 g) and ethyl 3-I(4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.42 g) were added ), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(44-Ccyclohexyl|(1-(4-methoxyphenyl)-3-(morpholine-4 -ylmethyl)-1H-pyrazol-4-yl|methylamino)phenylcarbonylmethyl)amino|propanoate (0.38 g) as a pale yellow oil. It was dissolved in ethanol (2 ml), at room temperature a 1M aqueous solution of sodium hydroxide (1.0 ml) was added, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1 .0 ml). The precipitate was washed with water to give the title compound (0.12 g, 1295) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.89 - 2.10 (m, 11 N), 2.50 - 2.75 (m, 6 N), 3.07 (s, Z H), 3.50 - 3.85 (m, 6 N ), 3.88 (s, C H), 4.17 - 425 (m, 2 H), 4.70 - 4.78 (m, 1 H), 6.83 (d, 2-8.7 Hz , 2

H), 7.02 (d, 959.0 Hz, 2 H), 7.19 - 7.35 (m, 4 H), 7.77 (s, 1 H).

Example 70 3-D4-Hcyclohexyl(|1-(3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid 1.

Shev dia m N

M Sn.

(1) methyl 1-(3-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (4.6 g), synthesized in Example 13, was dissolved in M,M-dimethylacetamide (10 ml), 3-methoxyphenylboronic acid (10.0 g), copper acetate was added (12.0 g) and pyridine (10.6 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (100 ml) was added to the filtrate, and the mixture was extracted with diethyl ether.

The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (3.9 g, 48905) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 2.56 (s, C H), 3.86 (s, C H), 3.87 (s, C H), 6.80 - 8 ,33 (m, 5

N). (2) 1-(3-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde

A solution (20 ml) of methyl 1-(33-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate (3.9 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (80 ml ) of lithium aluminum hydride (0.6 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (16 ml), 1M aqueous sodium hydroxide solution (7.8 ml) and water (1.6 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (1.9 g), 1-(3-methoxyphenyl)-3-methyl-1H-pyrazole-4-methanol, as a pale yellow oil. It was dissolved in toluene (30 mL), manganese dioxide (3.0 g) was added and the mixture was heated for 30 min with a Dean-Stark nozzle. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration.

The solvent was evaporated under reduced pressure to give the title compound (1.2 g, 6495) as a colorless solid. "IN NMR (300 MHz, SOSI") 6 m.h. 2.59 (s, Z H), 3.88 (s, Z H), 6.80 - 7.40 (m, 4 H), 8 ,32 (c, 1

H), 10.00 (c, 1 H). (3) cyclohexyl(|1-(3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol

Cyclohexyl magnesium bromide was added dropwise to a solution (15 ml) of 1-(3-methoxyphenyl)-33-methyl-1H-pyrazole-4-carbaldehyde (0.62 g) synthesized in the above-mentioned (2) in tetrahydrofuran under ice cooling ( 4.3 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.60 g, 7095) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.10 (m, 12 H), 2.34 (s, Z H), 3.87 (s, Z H), 4.43 (d,

U-7.2 Hz, 1 N), 6.70 - 7.40 (m, 4 N), 7.78 (s, 1 N). (4) 3-D4-Hcyclohexyl-1-(33-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenyl(Icarbonyl(Uumethyl)amino)propanoic acid

To a solution (3 ml) of cyclohexyl-1-(3-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.30 g) synthesized in the above-mentioned (3) in tetrahydrofuran at room temperature was added thionyl chloride ( 0.11 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (5 ml). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 ml), sodium iodide (0.23 g), sodium carbonate (0.16 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.25 g) were added. , synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(4-H-cyclohexyl-1-(3-methoxyphenyl)-3-methyl-1H-pyrazole- 4-

yl|methyl)amino)phenylIcarbonylmethyl)amino|propanoate (0.38 g) as a pale yellow oil.

It was dissolved in ethanol (3 ml) at room temperature, 1M aqueous sodium hydroxide solution (1.5 ml) was added, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.5 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.17 g, 34905) as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 0.96 - 2.03 (m, 11 H), 2.35 (s, C H), 2.70 (t, 9-6.2 Hz, 2 H), 3.06 (s, C H), 3.71 (t, U-6.2 Hz, 2 H), 3.85 (s, C H), 4.19 (d, 9 -61 Hz, 1 N), 6.50 (d, 9-8.0 Hz, 2

H), 6.76 (dd, 9-7.8, 2.1 Hz, 1 H), 7.09 - 7.37 (m, 5 H), 7.67 (shes, 1 H).

Example 71 3-S4-(4-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

AH s gu on m SN. lol

Ka

CH, (1) methyl 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (1.6 g), synthesized in Example 13, was dissolved in M,M-dimethylacetamide (30 ml), 3-chlorophenylboronic acid (3.58 g), copper acetate was added (5.0 g) and pyridine (4.0 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (1.9 g, 6790) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 2.55 (s, Z H), 3.86 (s, Z H), 3.87 (s, Z H), 6.70 - 8.35 (m, 5

N). (2) 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde

A solution (20 ml) of methyl 1-(33-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (1.9 g), synthesized in the above-mentioned (1), in tetrahydrofuran was added to an ice-cooled solution (80 ml ) of lithium aluminum hydride (0.29 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (0.80 ml), 1M aqueous sodium hydroxide solution (4.0 ml) and water ( 0.80 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (0.65 g) 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-methanol as a pale yellow oil. It was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added and the mixture was heated for 30 min with a Dean-Stark nozzle. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration.

The solvent was evaporated under reduced pressure to give the title compound (0.35 g, 2395) as a colorless solid. "IN NMR (300 MHz, SOSI") 6 m.h. 2.59 (s, Z H), 3.88 (s, Z H), 7.20 - 7.80 (m, A H), 8 ,34 (c, 1

H), 10.00 (c, 1 H). (3) cyclohexyl|1-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methanol

Cyclohexylmagnesium bromide was added dropwise to a solution (5 ml) of 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.35 g) synthesized in (2) mentioned above in tetrahydrofuran while cooling with ice (2.4 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.25 g, 5195) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 1.97 (m, 12 N), 2.33 (s, Z H), 4.44 (d, 2-72 Hz, 1 N), 7.20 -7.78 (m, 5 N). (4) 3-D4-Hcyclohexyl|1-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenyl(IcarbonylUmethyl)amino|propanoic acid

Thionyl chloride was added to a solution (3 ml) of cyclohexyl-1-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.25 g) synthesized in the above-mentioned (3) in tetrahydrofuran at room temperature (0.10 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (5 mL). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 ml), sodium iodide (0.19 g), sodium carbonate (0.13 g) and ethyl 3-(4 aminophenyl)carbonyl)|(methyl)amino)propanoate (0.20 g) were added. synthesized in Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate.hexane- 1:1, volume ratio) yielding ethyl 3-((4- (cyclohexyl|1-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.35 g) as a pale yellow oil.

It was dissolved in ethanol (3 mL), 1 M aqueous sodium hydroxide solution (1.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.5 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.24 g, 58905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 2.07 (m, 11 N), 2.36 (s, C H), 2.71 (t, U-6.4 Hz, 2 N), 3.07 (s, C H) , 3.72 (t, 9U-6.4 Hz, 2 N), 4.19 (d, 9U-6.1 Hz, 1 N), 6.48 (d, 2-8.7 Hz, 2 N ), 7.12 - 7.73 (m, 7 N).

Example 72 3-C4-9411-(2-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl)/cyclohexyl)methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

Y AH o-sn. gu on -o- M and N

Mt

MO sen, (1) methyl 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (7.3 g), synthesized in Example 13, was dissolved in M,M-dimethylacetamide (150 ml), 2-methoxyphenylboronic acid (15.9 g), copper acetate was added (18.2 g) and pyridine (16.2 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (100 ml) was added to the filtrate, and the mixture was extracted with diethyl ether.

The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (10.3 g, 8095) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 2.55 (s, Z H), 3.85 (s, Z H), 6.80 - 8.50 (m, 5 H). (2) 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde

A solution (50 ml) of methyl 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate (10.3 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (350 ml ) of lithium aluminum hydride (1.6 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice and water (42 ml), 1M aqueous sodium hydroxide solution (21.0 ml) and water (4.2 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (2.5 g), 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-methanol, as a pale yellow oil. It was dissolved in toluene (50 mL), manganese dioxide (1.0 g) was added, and the mixture was heated under reflux with a 1 g Dean-Stark fitting. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (2.2 g, 8790) as a colorless solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.58 (s, C H), 3.92 (s, C H), 7.00 - 7.80 (m, 4 H), 8 .50 (c, 1

H), 9.99 (c, 1 H). (3) cyclohexyl(|1-(2-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol

Cyclohexyl magnesium bromide was added dropwise to a solution (15 ml) of 1-(2-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (1.5 g) synthesized in (2) mentioned above in tetrahydrofuran while cooling with ice (11.0 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (1.1 g, 5395) as a pale yellow oil.

IN NMR (300 MHz, SOSI»z) b m.h. 0.90 - 2.10 (m, 12 H), 2.34 (s, Z H), 3.87 (s, Z H), 4.43 (dd, uU-7.6, 3.0 Hz , 1 N), 7.00 - 7.75 (m, 4 N), 7.92 (s, 1 N). (4) 3-D4-Hcyclohexyl-1-(2-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonylmethyl)amino|propanoic acid

To a solution (5 ml) of cyclohexyl1-(2-methoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.40 g), synthesized in the above-mentioned (3) in tetrahydrofuran at room temperature, thionyl chloride ( 0.15 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (5 ml). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5.0 ml), sodium iodide (0.30 g), sodium carbonate (0.21 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.33 d), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(44-Ccyclohexyl|1-(2-methoxyphenyl)-3-methyl-1 H- pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.10 g) as a pale yellow oil.

It was dissolved in ethanol (1.0 ml), 1M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.04 g, 69b) as a colorless solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.83 - 1.97 (m, 11 H), 2.26 (s, C H), 2.69 (she, 2 H), 3.03 (c, C H), 3.62 - 3, 78 (m, 2 H), 3.82 (s, 3 H), 4.20 (d, 9-6.6 Hz, 1 H), 6.93 - 7.70 (m, 9 H).

Example 73 3-S(4-4-(2-chlorophenyl)-3-methyl-1H-pyrazol-4-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

AJ schu M and N

Moo-yy

MO sen, (1) methyl 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (4.5 g), synthesized in Example 13, was dissolved in M,M-dimethylacetamide (100 ml), 2-chlorophenylboronic acid (10.0 g), acetate copper (11.7 g) and pyridine (10.4 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (100 ml) was added to the filtrate, and the mixture was extracted with diethyl ether.

The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (2.0 g, 25905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 2.55 (s, Z H), 3.85 (s, Z H), 6.79 - 7.40 (m, 5 H). (2) 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde

A solution (20 ml) of methyl 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-carboxylate (2.0 g), synthesized in the above-mentioned (1), in tetrahydrofuran was added to an ice-cooled solution (20 ml ) of lithium aluminum hydride (0.30 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (0.80 ml), 1 M aqueous sodium hydroxide solution (4.0 ml) and water (0 .80 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (0.36 g), 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-methanol, as a pale yellow oil. It was dissolved in toluene (10 mL), manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (0.27 g, 1595) as a colorless solid. "H NMR (300 MHz, SOSIZ") b mp 2.59 (s, C H), 7.00 - 7.70 (m, 4 H), 8.32 (s, 1 H), 10 ,02 (c, 1

N). (3) cyclohexyl|1-(2-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methanol

Cyclohexylmagnesium bromide was added dropwise to a solution (5 ml) of 1-(2-chlorophenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (0.27 g) synthesized in (2) mentioned above in tetrahydrofuran while cooling with ice (2.0 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.29 g, 79905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.20 (m, 12 N), 2.35 (s, Z H), 4.45 (d, 9-7.2 Hz, 1 N), 7.20 - 7.60 (m , 4 H), 7.76 (c, 1 H). (4) 3-D4-Hcyclohexyl(|1-(2-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

Thionyl chloride was added to a solution (5 ml) of cyclohexyl-1-(2-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methanol (0.29 g) synthesized in the above-mentioned (3) in tetrahydrofuran at room temperature (0.11 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (3 ml). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5.0 ml), sodium iodide (0.21 g), sodium carbonate (0.15 g) and ethyl 3-((4-aminophenyl)carbonyl)|(methyl)amino)propanoate (0 , 24 g), synthesized in Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate.hexane-1:1, volume ratio) obtaining ethyl 3-((4- (cyclohexyl|1-(2-chlorophenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino) phenylIcarbonylmethyl)amino|propanoate (0.24 g) as a pale yellow oil.

It was dissolved in ethanol (2.0 ml), 1M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.18 g, 37905) as a colorless solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.94 - 2.08 (m, 11 H), 2.34 (s, C H), 2.65 - 2.80 (m, 2 H), 3.08 (s, C H), 3, 73 (w s, 2 N), 4.23 (d, 9-61 Hz, 1 N), 6.54 (shs, 2 N), 7.29 - 7.79 (m, 7 N).

Example 74 3-D4-Hcyclohexyl(|1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methyl)amino)phenylIcarbonylXmethyl)amino|propanoic acid

(1) ethyl 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate

Ethyl 4-methyl-1H-pyrazole-3-carboxylate (2.58 g) was dissolved in M,M-dimethylacetamide (50 ml), 4-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (2.7 g, 66905) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.p. 1.21 (t, 9U-7.2 Hz, Z H), 2.33 (s, Z H), 3.85 (s, Z H ), 4.22 (k,

U-7.2 Hz, 2 N), 6.94 (d, 2-9.0 Hz, 2 N), 7.28 (d, 9U-9.0 Hz, 2 N), 7.50 (s , 1 N). (2) 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde

A solution (10 ml) of ethyl 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate (2.7 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (20 ml ) of lithium aluminum hydride (0.40 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (1.0 ml), 1 M aqueous sodium hydroxide solution (5.0 ml) and water (1 .0 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (1.38 g) 1-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-methanol as a pale yellow oil. It was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (0.96 g, 43905) as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.41 (s, C H), 3.87 (s, C H), 7.01 (d, 9-8.7 Hz, 2 H ), 7.38 (d, uU-8.7 Hz, 2 N), 7.55 (s, 1 N), 9.88 (s, 1 N).

(3) cyclohexyl(|1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methanol

Cyclohexyl magnesium bromide ( 6.0 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.70 g, 5395) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.p. 0.61 - 1.87 (m, 12 H), 2.19 (s, C H), 3.86 (s, C H), 4 .34 (dd, 929.7, 4.4 Hz, 1 N), 6.95 (d, 2-9.0 Hz, 2 N), 7.32 (d, U-9.0 Hz, 2 N ), 7.41 (s, 1 H). (4)33-C14-Hcyclohexyl|1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propane acid

Thionyl chloride ( 0.15 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (3 ml). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10.0 ml), sodium iodide (0.30 g), sodium carbonate (0.21 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (0. 34 g), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(44-Ccyclohexyl|1-(4-methoxyphenyl)-4-methyl-1H-pyrazole -3-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.06 g) as a pale yellow oil.

It was dissolved in ethanol (1.0 ml), 1M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.04 g, b9b) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.84 - 2.07 (m, 11 H), 2.18 (s, 3 H), 2.71 (sh s, 2 H), 3.08 (s, C H), 3.72 (t, U-6.4 Hu, 2 H), 3.88 (s, C H), 4.24 (d, 2-91 Hz, 1 H ), 6.30 (d, 2-8.7 Hz, 2 N), 6.94 (d, 2-8.7 Hz, 2 N), 7.10 - 7.26 (m, 4 N), 7.37 (c, 1 H).

Example 75 3-D4-Hcyclohexyl(|1-(3-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methyl)amino)phenyl]carbonylUumethyl)amino|propanoic acid

Ah, so what

Oh and M

M rn

CH, (1) ethyl 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate

Ethyl 4-methyl-1H-pyrazole-3-carboxylate (2.58 g) was dissolved in M,M-dimethylacetamide (50 ml), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) was added and pyridine (5.3 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (1.9 g, 46905) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.p. 1.43 (t, 9U-7.2 Hz, Z H), 2.37 (s, Z H), 3.87 (s, Z H ), 4.43 (k,

U-7.2 Hz, 2 N), 6.94 -7.50 (m, 5 N). (2) 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde

A solution (5 ml) of ethyl 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate (1.9 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (20 ml ) of lithium aluminum hydride (0.29 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (0.76 ml), 1M aqueous sodium hydroxide solution (3.8 ml) and water ( 0.76 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (0.99 g), 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-methanol, as a pale yellow oil. It was dissolved in toluene (15 mL), manganese dioxide (0.32 g) was added, and the mixture was heated under reflux with a Dean-Stark attachment for 1 h.

The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.84 g, 54905) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.39 (s, Z H), 3.89 (s, Z H), 6.80 - 7.45 (m, 4 H), 7.74 (s, 1

H), 10.13 (s, 1 H). (3) cyclohexyl(|1-(3-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methanol

To a solution (10 ml) of 1-(3-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde (0.84 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise while cooling with ice cyclohexylmagnesium bromide ( 7.0 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.62 g, 52905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.99 - 2.00 (m, 12 H), 2.12 (s, Z H), 3.86 (s, Z H), 4.52 (t,

U-6.6 Hz, 1 N), 6.75 - 7.32 (m, 4 N), 7.64 (s, 1 N). (4) 3-D4-Hcyclohexyl-1-(33-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

Thionyl chloride ( 0.19 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (3 ml). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10.0 ml), sodium iodide (0.39 g), sodium carbonate (0.28 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (0. 38 g), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(44-Ccyclohexyl|1-(3-methoxyphenyl)-4-methyl-1 H- pyrazol-3-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.16 g) as a pale yellow oil.

It was dissolved in ethanol (2.0 ml), 1 M aqueous sodium hydroxide solution (1.5 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.5 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.09 g, 1195) as a pale yellow solid. "H NMR (300 MHz, SOSI") b mp 0.97 - 2.06 (m, 11 H), 2.09 (s, C H), 2.73 (t, 9-6.2 Hz, 2 N),

3.08 (s, C H), 3.72 (t, U-6.2 Hz, 2 H), 3.87 (s, C H), 4.40 (d, 92-7.2 Hz, 1 H), 6.62 (d, 9-8.7 Hz, 2

H), 6.78 (dd, 9-7.8, 2.1 Hz, 1 H), 7.10 - 7.50 (m, 5 H), 7.57 (s, 1 H).

Example 76 3-D4-Hcyclohexyl(|1-(3-methoxyphenyl)-3-(methoxymethyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

M N so o.

Sn, (1) methyl 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxylate

To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (2.8 g), synthesized in

In Example 29(1), 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 ml) were added to M,M-dimethylacetamide (50 ml) and the mixture was stirred at room temperature for at night The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether.

The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (1.1 g, 23905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 3.51 (s, Z H), 3.87 (s, Z H), 3.92 (s, Z H), 4.80 (s, 2 H), 7.29 - 7.93 (m, 4 H), 8.37 (s, 1 H). (2) 3-(Methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde

A solution (5 ml) of methyl 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxylate (1.1 g), synthesized in the above-mentioned (1), in tetrahydrofuran was added to an ice-cooled solution ( 10 ml) of lithium aluminum hydride (0.25 g) in tetrahydrofuran.

The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (0.38 ml), 1 M aqueous sodium hydroxide solution (1.9 ml) and water ( 0.38 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (0.68 g), 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-methanol, as a pale yellow oil. It was dissolved in toluene (15 mL), manganese dioxide (1.0 g) was added, and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (0.30 g, 3290) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 3.50 (s, Z H), 3.88 (s, Z H), 4.80 (s, 2 H), 6.91 (dd, 9-8.3, 1.5 Hz, 1 H) , 7.16 - 7.49 (m, Z H), 8.40 (s, 1 H), 10.07 (s, 1 H). (3) cyclohexyl|3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methanol

To a solution (5 ml) of 3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (0.30 g), synthesized in the above-mentioned (2), in tetrahydrofuran dropwise while cooling with ice cyclohexylmagnesium bromide (2.0 ml, 1M tetrahydrofuran solution) was added. After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.40 g, quantitative) as a pale yellow oil.

IN NMR (300 MHz, SOS") b m.h. 0.89 - 2.21 (m, 11 H), 3.04 (shs, 1 H), 3.44 (s, Z H), 3.87 (s,

Z H), 441 (d, 957.7 Hz, 1 H), 4.61 (d, 93.6 Hu, 2 H), 6.82 (ddd, 9-81, 2.5, 0.8 Hz , 1 H), 7.14 -

7.40 (m, Z H), 7.77 (s, 1 H). (4) 3-D4-Hcyclohexyl/1-(3-methoxyphenyl)-3-(methoxymethyl)-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

To a solution (5 ml) of cyclohexyl3-(methoxymethyl)-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methanol (0.40 g), synthesized in the above mentioned (3), in tetrahydrofuran at room temperature was added thionyl chloride (0.14 ml). The reaction mixture was stirred at room temperature for 30 min and cooled with ice and carefully poured into a saturated aqueous solution of sodium bicarbonate (3 ml). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5.0 ml), sodium iodide (0.23 g), sodium carbonate (0.18 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (0. 25 g), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-((cyclohexyl|1-(3-methoxyphenyl)-3-(methoxymethyl) )-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonylmethyl)amino|propanoate (0.11 g) as a pale yellow oil.

It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.07 g, 1095) as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 0.94 - 2.12 (m, 11 N), 2.73 (t, 9U-6.5 Hz, 2 N), 3.07 ( s, Z H), 3.41 (s, Z H), 3.72 (t, 9U-6.5 Hz, 2 H), 3.85 (s, Z H), 4.34 (d, 2 -7.2 Hz, 1 N), 4.57 (s, 2 N), 6.57 (d, 9U-8.7 Gu, 2 N), 6.79 (dt, U-8.2, 1 .3 Hz, 1 N), 7.11 - 7.38 (m, 5 N), 7.72 (s, 1 N).

Example 77 3-D4-Hcyclohexyl(|1-(2-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

But Z S

M dream

That's it

Shi

Sleep (1) ethyl 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate

Ethyl 4-methyl-1H-pyrazole-3-carboxylate (4.0 g) was dissolved in M,M-dimethylacetamide (30 ml), 2-methoxyphenylboronic acid (7.9 g), copper acetate (9.5 g) was added and pyridine (8.4 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (1.6 g, 25965) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.p. 1.41 (t, 9U-7.2 Hz, Z H), 2.37 (s, Z H), 3.87 (s, Z H ), 4.43 (k,

U-7.2 Hz, 2 N), 7.00 - 7.45 (m, 4 N), 7.78 (s, 1 N). (2) 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-carbaldehyde

A solution (5 ml) of ethyl 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylate (1.6 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (10 ml ) of lithium aluminum hydride (0.50 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g, cooled again with ice, and water (1.3 ml), 1M aqueous sodium hydroxide solution (6.5 ml) and water (1, 3 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (0.79 g), 1-(2-methoxyphenyl)-4-methyl-1H-pyrazole-3-methanol, as a pale yellow oil. It was dissolved in toluene (20 mL), manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (0.97 g, 7090) as a yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.39 (s, C H), 3.90 (s, C H), 7.00 - 7.45 (m, C H), 7 .64 - 7.84 (m, 2 H), 10.13 (s, 1 H). (3) cyclohexyl(|1-(2-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methanol

Cyclohexyl magnesium bromide ( 5.0 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.56 g, 4095) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.99 - 2.00 (m, 12 H), 2.12 (s, Z H), 3.86 (s, Z H), 4.52 (t,

U-6.6 Hz, 1 N), 6.75 - 7.32 (m, 4 N), 7.64 (s, 1 N). (4) 3-D4-Hcyclohexyl-1-(33-methoxyphenyl)-4-methyl-1H-pyrazol-3-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

Thionyl chloride ( 0.17 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (3 ml) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10.0 ml), sodium iodide (0.33 g), sodium carbonate (0.24 g) and ethyl 3-I(4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.38 d), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(44-Ccyclohexyl|1-(2-methoxyphenyl)-4-methyl-1 H- pyrazol-3-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.09 g) as a pale yellow oil.

It was dissolved in ethanol (2.0 ml), 1M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.06 g, 890) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.ch. 0.98 - 2.07 (m, 11 H), 2.10 (s, C H), 2.73 (t, 9-6.2 Hz, 2 H), 3.09 (s, C H), 3.72 (t, U-6.2 Hz, 2 H), 3.86 (s, C H), 4.41 (d, 92 -7.2 Hz, 1 N), 6.62 (d, 9-8.3 Hz, 2

H), 6.96 - 7.37 (m, 5 H), 7.63 (d, 9U-8.0 Hz, 1 H), 7.70 (s, 1 H).

Example 78 3-CD4-Hcyclohexyl|3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid and DA pa

M Sn.

(1) methyl 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxylate

Methyl 3-ethyl-1H-pyrazole-4-carboxylate (2.5 g), synthesized in Example 39(1) was dissolved in M,M-dimethylacetamide (50 ml), 3-methoxyphenylboronic acid (5.0 g) was added, copper acetate (6.0 g) and pyridine (5.3 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (2.3 g, 54905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.32 (t, 9U-7.5 Hz, Z H), 2.98 (k, 9-7.5 Hz, 2 H), 3.86 (s, Z

H), 3.87 (s, C H), 6.86 (ddd, U-8.2, 2.5,0.9 HZ, 1 H), 7.16 - 7.46 (m, C H ), 8.32 (s, 1 H). (2)3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde

A solution (5 ml) of methyl 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carboxylate (2.3 g), synthesized in the above-mentioned (1), in tetrahydrofuran was added to an ice-cooled solution (15 ml ) of lithium aluminum hydride (0.34 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g, cooled again with ice, and water (0.88 ml), 1 M aqueous sodium hydroxide solution (4.4 ml), water (0. 88 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (2.3 g) 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-methanol as a pale yellow oil. It was dissolved in toluene (50 mL), manganese dioxide (4.0 g) was added, and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature, the manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure to give the title compound (1.9 g, 94905) as a yellow solid. "H NMR (300 MHz, SOSI") b m.p. 1.35 (t, 9U-7.6 Hz, Z H), 2.99 (k, 9U-7.6 Hz, 2 H), 3 ,88 (c, Z

H), 6.89 (dd, 9U-8.3, 1.5 Hz, 1 H), 7.11 - 7.50 (m, C H), 8.33 (s, 1 H), 10, 00 (c, 1 N). (3) cyclohexyl|3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methanol

Cyclohexylmagnesium bromide was added dropwise to a solution (20 ml) of 3-ethyl-1-(3-methoxyphenyl)-1H-pyrazole-4-carbaldehyde (1.9 g) synthesized in the above-mentioned (2) in tetrahydrofuran while cooling with ice ( 12.0 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give the crude product (2.6 g, quant.), the title compound as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.86 - 1.98 (m, 14 N), 2.71 (k, 9U-7.5 Hz, 2 N), 3.60 (shs, 1

H), 3.87 (s, C H), 4.44 (d, 9-73 Hz, 1 H), 6.78 (ddd, 9-81, 2.4,0.9 Hz, 1 H) , 7.14 - 7.38 (m, Z

H), 7.78 (s, 1 H). (4)33-C14-Hcyclohexyl|3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

Thionyl chloride was added to a solution (5 ml) of cyclohexyl|3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methanol (0.31 g) synthesized in the above-mentioned (3) in tetrahydrofuran at room temperature (0.13 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (3 ml) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10.0 ml), sodium iodide (0.23 g), sodium carbonate (0.15 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.25 d), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio)

affording ethyl 3-(44-Ccyclohexyl|3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.16 g) as pale yellow butter.

It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.12 g, 2390) as a pale yellow solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.98 - 2.07 (m, 14 N), 2.62 - 2.81 (m, 4 N), 3.07 (s, C H), 3.72 (t, U-6.0 Hz , 2 H), 3.85 (s, C H), 4.22 (d, 2-5.8 Hz, 1 H), 6.51 (d, 9-8.5 Hz, 2 H), 6 .76 (dt, uU-8.2, 1.2 Hz, 1 N), 7.10 - 7.37 (m, 5 N), 7.65 (s, 1 N).

Example 79 3-D4-Hcyclohexyl(|1-(3-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylmethyl)amino|propanoic acid its pd

M nn sn, (1) methyl 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-carboxylate

Methyl 3-(1-methylethyl)-1H-pyrazole-4-carboxylate (2.8 g), synthesized in Example 7(1), was dissolved in M,M-dimethylacetamide (50 ml), and 3-methoxyphenylboronic acid (5, 0 g), copper acetate (6.0 g) and pyridine (5.3 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (3.4 g, 75905) as a pale yellow oil.

IN NMR (300 MHz, SOSIz") 6 m.h. 1.36 (d, 9U-7.0 Hz, 6 N), 3.56 - 3.59 (m, 1 N), 3.85 (s, C H), 3.87 (s, C H) . (2) 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-carbaldehyde

A solution (15 ml) of methyl 1-(33-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-carboxylate (3.4 g), synthesized in the above mentioned (1), in tetrahydrofuran was added to of an ice-cooled solution (35 ml) of lithium aluminum hydride (0.48 g) in tetrahydrofuran.

The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g, cooled again with ice, and water (1.25 ml), 1M aqueous sodium hydroxide solution (6.3 ml), water (1, 25 ml).

The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (2.7 g) 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-methanol as a pale yellow oil . It was dissolved in toluene (50 mL), manganese dioxide (3.0 g) was added, and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (2.6 g, 8496) as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.39 (d, U-6.8 Hz, 6 N), 3.48 - 3.52 (m, 1 N), 3.88 ( c, C H), 6.88 (dd, U-7.8, 2.1 Hz, 1 H), 7.09 - 7.45 (m, C H), 8.33 (c, 1 H) , 10.02 (s, 1 H). (3Z)cyclohexyl|1-(Z-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazol-4-yl|methanol

To a solution (20 ml) of 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (2.6 g), synthesized in the above-mentioned (2), in tetrahydrofuran dropwise while cooling with ice, cyclohexylmagnesium bromide (15.0 ml, 1 M tetrahydrofuran solution) was added.

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give the crude product (2.6 g, 7590), the title compound as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.15 (m, 17 N), 3.00 - 3.20 (m, 1 N), 3.86 (s, Z H), 4.46 (d, 2-7.6 Hz , 1 N), 6.63 - 7.48 (m, 4 N), 7.77 (c, 1 N). (4)33-C14-Hcyclohexyl|1-(3-Methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylUmethyl)amino|propanoic acid

To a solution (5 ml) of cyclohexyl(/1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazol-4-yl|methanol (0.45 g), synthesized in the above-mentioned (3) , thionyl chloride (0.18 mL) was added in tetrahydrofuran at room temperature. The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous sodium bicarbonate solution (5 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate . The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10.0 ml), sodium iodide (0.30 g), sodium carbonate (0.21 g) and ethyl 3-(( 4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.34 g), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-(cyclohexyl(I1-(33-methoxyphenyl)-3-(1- methylethyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.37 g) as a pale yellow oil.

It was dissolved in ethanol (5.0 ml), 1M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.28 g, 38905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.95 - 1.27 (m, 11 H), 1.30 - 1.40 (m, 6 H), 2.73 (d, 9U-6.0

Hz, 2 N), 2.94 - 3.17 (m, 4 N), 3.73 (d, 9U-6.0 Hz, 2 N), 3.85 (s, C H), 4.26 (d, 9U-6.0 Hz, 1 N), 6.52 (d, 5-8.7 Hz, 2 N), 6.75 (ddd, U-8.2, 2.5, 0.9 Hz, 1 N), 7.10 - 7.32 (m, 5 N), 7.62 (s, 1 N).

Example 80 3-I4-Kcyclohexyl|3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methylUmethyl)amino|phenyl)carbonyl)(methyl)amino|Ipropanoic acid

And oh, oh, and oh

CH,

To a solution of ethyl 3-(44-Ccyclohexyl|3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanosate (1.1 g) synthesized in Example 78(4), sodium hydride (0.16 g) was added to M,M-dimethylacetamide (5 ml) while cooling with ice, and after stirring for 30 min, methyl iodide (0.37 ml) was added. The ice bath was removed, the reaction mixture was stirred at room temperature overnight, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with diethyl ether. The extract was washed with brine to obtain ethyl 3-|((4-Kcyclohexyl3-ethyl-1-(3-methoxyphenyl)-1H-pyrazol-4-ylmethylmethyl)amino|phenylcarbonyl)(methyl)amino|- propanoate (0.23 g, 7595), as a pale yellow oil. It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (1.5 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure, 1 M hydrochloric acid was added to the residue (1.5 ml) and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-10:1, v/v) to give the title compound (0.10 g, 1095) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 1.99 (m, 14 H), 2.17 (s, Z H), 2.72 (k, 9-74 Hz, 2 H), 2.76 - 2.90 (m, 2 H), 3.07 (s, C H), 3.75 - 3.85 (m, 5 H), 4.22 (d, 2-5.3 Hz, 1 H), 6.50 (d, 9-8.7

Hz, 2 N), 6.76 (d, 9-8.3 Hz, 1 N), 7.07 - 7.43 (m, 5 N), 7.65 (s, 1 N).

Example 81 3-D4-Hcyclohexyl|1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

Xia p m N

Mo sten, o sn, (1) methyl 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate

Methyl 3-methyl-1H-pyrazole-4-carboxylate (3.9 g), synthesized in Example 13, was dissolved in M,M-dimethylacetamide (50 ml), 3,5-dimethoxyphenylboronic acid (10.0 g) was added, copper acetate (10.0 g) and pyridine (8.9 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (50 ml) was added to the filtrate, and the mixture was extracted with diethyl ether.

The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (3.0 g, 4095) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 2.55 (s, C H), 3.85 (s, 6 H), 6.41 (t, 9U-2.3 Hz, 1 H), 6.83 (d, 3-2.3 Hz, 2 H), 8.30 (s, 1 H). (2) 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde

A solution (15 ml) of methyl 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carboxylate (3.0 g), synthesized in the above-mentioned (1), in tetrahydrofuran was added to the ice-cooled solution (35 ml) of lithium aluminum hydride (0.42 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g, cooled again with ice, and water (1.1 ml), 1M aqueous sodium hydroxide solution (5.5 ml), water (1, 1 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (2.7 g), 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-methanol, as a pale yellow oil. It was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added, and the mixture was heated under reflux with a Dean-Stark nozzle for 1 h. The reaction mixture was allowed to cool to room temperature, the manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure to give the title compound (2.0 g, 7490) as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.55 (s, 3 H), 3.85 (s, 6 H), 6.44 (s, 1 H), 6.82 - 6 ,84 (m, 2

H), 8.30 (s, 1 H), 9.98 (s, 1 H). (3) cyclohexyl|1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol

To a solution (10 ml) of 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (2.0 g), synthesized in the above-mentioned (2), in tetrahydrofuran dropwise while cooling with ice cyclohexylmagnesium bromide (15.0 ml, 1M tetrahydrofuran solution) was added.

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (2.6 g, 4095) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.89 - 2.00 (m, 12 H), 2.33 (s, Z H), 3.84 (s, 6 H), 4.40 - 4.45 (m, 1 H), 6, 34 (t, 90-2.1 Hz, 1 N), 6.81 (d, 2-2.3 Hz, 2 N), 7.76 (s, 1 N). (4).

To a solution (20 ml) of cyclohexyl|1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (1.0 g), synthesized in the above mentioned (3), in tetrahydrofuran at thionyl chloride (0.40 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (15 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15.0 ml), sodium iodide (0.67 g), sodium carbonate (0.45 g) and ethyl 3-I(4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.75 d), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-ICH4-Ccyclohexyl|1-(3,5-dimethoxyphenyl)-3-methyl-1 H -pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.74 g) as a pale yellow oil.

It was dissolved in ethanol (5.0 ml), 1M aqueous sodium hydroxide solution (3.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (3.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.46 g, 29905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 2.02 (m, 11 H), 2.35 (s, C H), 2.70 (sh c, 2 H), 3.06 (s, C H), 3.71 (t , U-6.4 Hz, 2 N), 3.82 (s, 6 N), 4.18 (d, 2-5.8 Hz, 1 N), 6.32 (t, 9-22 Hz, 1 N), 6.49 (d, 9-8.7 Hz, 2 N), 6.77 (s, 2 N), 7.26 (d, 2 N), 7.64 (s, 1 N) .

Example 82 3-(Х4-(cyclohexyl|1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid M azh;

MO sen, Fr

SN.

To a solution (20 ml) of cyclohexyl|1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazol-4-yl|methanol (1.0 g), synthesized in Example 81(3), in tetrahydrofuran at thionyl chloride (0.40 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (15 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15.0 ml), sodium iodide (0.67 g), sodium carbonate (0.45 g) and ethyl were added. 3-((4-aminophenyl)carbonyl|Iaminopropanoate (0.70 g), synthesized in

Example 1(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(Х4-cyclohexyl|1-(3,5-dimethoxyphenyl)-3-methyl-1 N-pyrazol-4-ylmethylamino)phenyl|carbonylamino)propanoate (1.3 g) as a pale yellow oil. It was dissolved in ethanol (5.0 ml), 1M aqueous sodium hydroxide solution (3.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (3.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.65 g, 42905) as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 0.96 - 1.98 (m, 11 H), 2.35 (s, C H), 2.65 (t, U-6.0 Hz, 2 N), 3.66 (d, U-6.0 Hz, 2 N), 3.80 (s, 6 N), 4.20 (d, 9U-6.0 Gu, 1 N), 6.31 (t, 9-2.2 Hz, 1 N), 6.49 (d, uU-8.7 Hz, 2 N), 6.60 (d, 9U-6.0 Hz, 1 N) , 6.75 (s, 2 N), 7.53 (d, 9U-8.9 Hz, 2 N), 7.62 (s, 1 N).

Example 83 3-D4-Hcyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

OA sh vod sn,

M. Hn ve sn, (1) methyl 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carboxylate

Methyl 3-ethyl-1H-pyrazole-4-carboxylate (6.9 g), synthesized in Example 39(1) was dissolved in M,M-dimethylacetamide (150 ml), 3-ethoxyphenylboronic acid (15.0 g), acetate was added copper (16.4 g) and pyridine (14.5 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1M hydrochloric acid (70 ml) was added to the filtrate, and the mixture was extracted with diethyl ether.

The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (4.4 g, 36905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.32 (t, 9U-7.5 Hz, Z H), 1.44 (t, 9U-7.0 Hz, Z H), 2.98 (k, 9UE7.5 Hz, 2 H), 3 .85 (s, Z H), 4.10 (k, 957.0 Gu, 2 H), 6.84 (dd, 9-82, 1.6 Hz, 1 H), 7.14 - 7.43 (m, Z H), 8.31 (s, 1 H). (2) 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde

A solution (15 ml) of methyl 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carboxylate (4.4 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to an ice-cooled solution (35 ml ) of lithium aluminum hydride (0.61 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, the mixture was cooled again with ice, and water (16 ml), 1 M aqueous sodium hydroxide solution (8.0 ml) and water (1, 6 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (3.5 g) 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-methanol as a pale yellow oil. It was dissolved in toluene (100 mL), manganese dioxide (4.0 g) was added, and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature, the manganese dioxide was collected by filtration, and the solvent was evaporated under reduced pressure to give the title compound (3.4 g, 8790) as a yellow solid. "H NMR (300 MHz, SOSI") b m.ch. 1.29 - 1.50 (m, 6 N), 2.99 (k, 9U-7.5 Hz, 2 N), 4.11 ( k, 9-7.0

Hz, 2 N), 6.88 (ddd, 9U-8.2, 2.4, 0.8 Hz, 1 N), 7.15 - 7.45 (m, C H), 8.32 (s , 1 N), 10.00 (c, 1 N). (3) cyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methanol

To a solution (20 ml) of 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized in the above-mentioned (2) in tetrahydrofuran, while cooling with ice, was added dropwise cyclohexylmagnesium bromide (12.0 ml, 1M tetrahydrofuran solution).

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (2.2 g, 96905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.79 - 1.97 (m, 18 N), 2.71 (k, 9U-7.5 Hz, 2 N), 4.07 - 4.21 (m, 2 N), 4.44 (dd , 9-7.3,2.6 Hz, 1 H), 6.77 (dd, 9U-7.9, 2.1 Hz, 1 H), 7.13 - 7.37 (m, C H) , 7.78 (c, 1 H). (4) 3-D4-Hcyclohexyl|1-(33-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

To a solution (10 ml) of cyclohexyl(1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|imethanol (0.60 g) synthesized in the above-mentioned (3) in tetrahydrofuran at room temperature was added thionyl chloride (0.24 mL). The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (15 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.The residue was dissolved in dimethylacetamide (10.0 mL), sodium iodide (0.27 g), sodium carbonate (0.29 g) and ethyl 3-((4-aminophenyl)carbonyl)( methyl)amino)propanoate (0.45 g), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-(4-Hcyclohexyl(|1-(3-ethoxyphenyl)-3-ethyl-1 H -pyrazol-4-ylmethylamino)phenyl|carbonylmethyl)amino|propanoate (0.7 g) as a pale yellow oil. It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (3.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (3.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.66 g, 69965) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.30 (m, 17 H), 2.60 - 2.75 (m, 4 H), 3.06 (s, Z H), 3.72 (t, 9U-6.4 Gu , 1 H), 4.08 (k, 9U-6.9 Hz, 2 H), 4.22 (d, 9-5.7 Hz, 1 H), 6.50 (d, 2-8.7 Hz, 2 N), 6.74 (dd, U-8.7, 1.9 Hz, 1 N), 7.09 - 7.34 (m, 5 N), 7.64 (s, 1 N) .

Example 84 3-(X4-Hcyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

Sbed me sn,

To a solution (10 ml) of cyclohexyl(1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|imethanol (0.60 g) synthesized in Example 83(3) in tetrahydrofuran at room temperature was added thionyl chloride (0.24 mL). The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and saturated aqueous sodium bicarbonate (15 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.The residue was dissolved in dimethylacetamide (10.0 mL), sodium iodide (0.27 g), sodium carbonate (0.29 g) and ethyl 3-((4-aminophenyl)carbonyl|iamino) were added )propanoate (0.43 g), synthesized in Example 1(2), and the mixture was stirred at 70 "С for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified column chromatography on silica gel (et lactate-hexane-1:1, volume ratio) obtaining ethyl 3-(C4-(/cyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)iamino)phenylIcarbonylamino )propanoate (0.6 g) as a pale yellow oil. It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (3.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid was added to the residue (3.0 ml). The precipitate was washed with water to give the title compound (0.59 g, 6395) as a colorless solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.97 - 2.00 (m, 17 N), 2.56 - 2.81 (m, 4 N), 3.64 (k, U -5.8

Hz, 2 N), 4.06 (k, U-7.0 Hz, 2 N), 4.24 (d, 9-6.0 Gu, 1 N), 6.50 (d, 9U-8, 7 Hz, 2 N), 6.54 - 6.62 (m, 1 N), 6.73 (dd, 9U-7.7, 2.1 Hz, 1 N), 7.07 - 7.32 ( m, Z H), 7.53 (d, 9-8.9 Hz, 2 H), 7.63 (s, 1 H).

Example 85 3-X4-(41-P1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanoic acid not CH; Ii G ho Xia sn, ie;

M sn, (1) 1-11-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|-3-methylbutan-1-ol

To a solution (20 ml) of 1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.7 g) synthesized in Example 83(2) in tetrahydrofuran was added dropwise while cooling with ice (12.0 ml, 1M tetrahydrofuran solution). After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (1.4 g, 6790) as a pale yellow oil. "IN NMR (300 MHz, SOSI") b m.h. 0.98 (dd, uU-6.4, 2.4 Hz, 6 N), 1.18 - 1.90 (m, 9 N), 2.75 (k,

U-7.6 Hz, 2 N), 4.09 (k, 9U-7.0 Hz, 2 N), 4.81 (d, 9U-3.6 Hz, 1 N), 6.77 (ddd , 9U-8,1, 2,4,0,9 Hz, 1

H), 7.11 - 7.38 (m, C H), 7.79 (c, 1 H). (d) 3-X4-(41-P1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanoic acid

To a solution (10 ml) of 1-(1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.71 g), synthesized in the above mentioned ( 1), thionyl chloride (0.39 ml) was added in tetrahydrofuran at room temperature. The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous sodium bicarbonate solution (15 ml) was carefully added. The reaction mixture was stirred for 10 min and the mixture extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15.0 mL), sodium iodide (0.53 g), sodium carbonate (0.35 g), and ethyl 3- ((4-aminophenyl)carbonyl)(methyl)amino)propanoate (0.59 g), synthesized in

Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-K4-(41-P1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazole -4-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|-propanoate (0.55 g) as a pale yellow oil.

It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (3.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (3.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.46 g, 39905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.89 - 2.00 (m, 15 N), 2.56 - 2.82 (m, 4 N), 3.06 (s, Z H), 3.72 (t, U-6.2 Hz , 2 H), 4.08 (k, U-6.8 Hz, 2 H), 4.46 (t, 2-6.8 Hz, 1 H), 6.55 (d, 9-7.2 Hz, 2 N), 6.75 (dd, U-8.0, 1.5 Hz, 1 N), 7.05 - 7.38 (m, 5 N), 7.72 (she, 1 N) .

Example 86 3-(X14-(41-P1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|-3-methylbutyl)amino)phenylcarbonyl)iamino)propanoic acid is not CH; Ii G o not in: pt ten

N

That's it

M, H o sn,

To a solution (10 ml) of 1-(1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|-3-methylbutan-1-ol (0.71 g) synthesized in Example 85 ( 1) thionyl chloride (0.39 mL) was added in tetrahydrofuran at room temperature. The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous sodium bicarbonate solution (15 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15.0 ml), sodium iodide (0.53 g), sodium carbonate (0.35 g) and ethyl 3-( (4-aminophenyl)carbonyl|amino)propanoate (0.55 g), synthesized in Example 1(2), and the mixture was stirred at 70 "С for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (eth acetate:hexane-1:1, volume ratio) obtaining oethyl 3-((C4-(1-(1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|-3-methylbutyl) iamino)phenylcarbonylamino)propanoate (0.56 g) as a pale yellow oil. It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (3.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid was added to the residue (3.0 ml). The precipitate was washed with water to give the title compound (0.54 g, 47965) as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 0.84 - 1.10 (m, 6 H), 1.32 (t, 9U-7.6 Hz, C H), 1.41 ( t, 9-7.0

HC, Z H), 1.57 - 1.87 (m, Z H), 2.58 - 2.80 (m, 4 H), 3.67 (k, 955.9 Hz, 2 H), 4 .07 (k, 9-6.8 Hz, 2

H), 4.48 (t, U-6.6 Hz, 1 H), 4.75 (w s, 1 H), 6.53 (d, 9U-8.7 Hz, 2 H), 6, 66 (t, 95.9 Hz, 1 H), 6.74 (dd, 9U-8.1, 1.7 Hz, 1 H), 7.07 - 7.33 (m, C H), 7, 57 (d, 9U-8.7 Hz, 2 N), 7.68 (s, 1 N).

Example 87 3-D4-Hcyclohexyl(|1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenyl]carbonylUumethyl)amino|propanoic acid,

M. N. vita

E dream (1) methyl 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-carboxylate

A mixture of methyl 33-oxopentanoate (5.2 g) and dimethylformamide dimethyl acetal (5.6 ml) was stirred at 100 C overnight and the mixture was allowed to cool to room temperature. Ethanol (100 ml) and 3,5-difluorophenylhydrazine hydrochloride (7.9 g) were added to the reaction mixture, and the mixture was further stirred at 100 "С for 15 g. After spontaneous cooling, the ethanol was evaporated under reduced pressure, water and the mixture were added to the residue extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1O0, v/v) to give the title compound (6.5 g, 6290 ), as yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.21 (t, 9-74 Hz, Z H), 3.03 (k, 9-7.4 Hz, 2 H), 3.87 (s, Z

H), 6.87 - 7.11 (m, C H), 8.02 (c, 1 H). (2) 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde

A solution (35 ml) of methyl 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-carboxylate (6.5 g), synthesized in the above-mentioned (1), in tetrahydrofuran was added to an ice-cooled solution ( 65 ml) of lithium aluminum hydride (0.94 g) in tetrahydrofuran. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (2.5 ml), 1M aqueous sodium hydroxide solution (12.5 ml), and water (2 .5 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (3.3 g), 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-methanol, as a pale yellow oil. It was dissolved in toluene (100 mL), manganese dioxide (6.0 g) was added, and the mixture was heated under reflux with a Dean-Stark attachment for 1 h.

The reaction mixture was allowed to cool to room temperature, the manganese dioxide was collected by filtration and the solvent was evaporated under reduced pressure to give the title compound (3.1 g, 5190) as a yellow solid. "H NMR (300 MHz, SOSI") b m.p. 1.25 (t, 9U-7.6 Hz, Z H), 3.03 (k, 9U-7.6 Hz, 2 H), 6 .85 - 7.11 (m, C H), 8.07 (s, 1 H), 9.99 (s, 1 H). (3) cyclohexyl(|1-(3,5-difluorophenyl)-3 -ethyl-1H-pyrazol-4-yl|methanol

To a solution (10 ml) of 1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazole-4-carbaldehyde (1.5 g) synthesized in the above-mentioned (2) in tetrahydrofuran dropwise while cooling with ice cyclohexylmagnesium bromide (12.0 ml, 1M tetrahydrofuran solution) was added.

After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (1.9 g, quant.) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.26 (t, 9-7.2 Hz, Z H), 1.32 - 2.14 (m, 12 H), 2.78 (k, uU«7.2

Hu, 2 H), 4.35 (dd, 9U-8.2, 2.9 Hz, 1 H), 6.80 - 7.12 (m, З H), 7.62 (s, 1 H) . (4) 3-D4-Hcyclohexyl(|1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

Thionyl chloride was added to a solution (15 ml) of cyclohexyl1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazol-4-yl|imethanol (0.96 g) synthesized in the above-mentioned (3) in tetrahydrofuran at room temperature (0.40 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice and carefully added with a saturated aqueous solution of sodium hydrogencarbonate (10 ml). The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15.0 ml), sodium iodide (0.68 g), sodium carbonate (0.48 g) and ethyl 3-(4-aminophenyl)carbonyl|(methyl)amino)propanoate (0.75 g) were added ), synthesized in Example 2(2), and the mixture was stirred at 70 "C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate: hexane-1:1, volume ratio) obtaining oethyl 3-((4-(cyclohexyl1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazol-4-yl|methylamino)phenylcarbonylmethyl)amino|propanoate (0.90 g) as a pale yellow oil.This was dissolved in ethanol (3.0 mL), 1 M aqueous sodium hydroxide solution (3.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g . Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (3.0 ml) was added to the residue. The precipitate was washed with water to obtain the target compound indicated in the title (0.70 g, 4495), as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 2.08 (m, 14 N), 2.59 - 2.89 (m, 4 N), 3.08 (s, C H), 3.73 (t, U-6.5 Hz , 2 N), 4.19 (d, 9-68 Hz, 1 N), 6.53 (d, U-8.5 Hz, 2 N), 6.77 - 7.30 (m, 5 N) , 7.52 (c, 1 H).

Example 88 3-(14-Ccyclohexyl|1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)propanoic acid

OH YEAH

E o m ten

N sweat M

M. n pe

R sn,

To a solution (15 ml) of cyclohexyl-1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazol-4-yl|imethanol (0.96 g) synthesized in Example 87(3) in tetrahydrofuran at room temperature was added thionyl chloride (0.40 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (10 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15.0 ml), sodium iodide (0.68 g), sodium carbonate (0.48 g) and ethyl 3-((4-aminophenyl)carbonyl|amino)propanoate (0.70 g) were added. synthesized in Example 1(2), and the mixture was stirred at 70 "C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate-hexane- 1:1, volume ratio) obtaining ethyl 3-(C4-(/cyclohexyl|1-(3,5-difluorophenyl)-3-ethyl-1H-pyrazol-4-yl|methyliamino)phenylcarbonylamino)propanoate (0 .80 g) as a pale yellow oil. It was dissolved in ethanol (3.0 mL), 1 M aqueous sodium hydroxide solution (3.0 mL) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g. Ethanol evaporated under reduced pressure and 1M hydrochloric acid (3.0 mL) was added to the residue.The precipitate was washed with water to give the title compound (0.50 g, 33965) , as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 1.02 (t, 9U-7.5 Hz, Z H), 1.06 - 2.08 (m, 11 H), 2.65 ( t, 95.7 Hz, 2 H), 2.78 (k, U-7.5 Hz, 2 H), 3.67 (k, 9U-7.0 Hz, 2 H), 4.20 (d , 9U-6.8 Hz, 1 N), 6.52 (d,

U-8.7 Hz, 2 N), 6.57 -6.68 (m, 1 N), 6.77 - 7.10 (m, C H), 7.51 (s, 1 N), 7 .55 (d, 2-8.7 Hz, 2 N).

Example 89 3-II(4-Kcyclohexyl3-(methoxymethyl)-1-II4-«"«trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propane its acid

E Re mo tone sn.

Um y - m M- o. sn, (1) methyl 3-(methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate

To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (1.8 g), synthesized in

In Example 29(1), 2-chloro-4-trifluoromethylpyridine (2.0 g) and potassium carbonate (2.3 g) were added to M,M-dimethylformamide (20 ml) and the mixture was stirred at 100 "C overnight. The reaction mixture allowed to cool to room temperature and filtered through celite, water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, vol. "capacity ratio) to give the title compound (0.62 g, 1895) as a pale yellow oil. "H NMR (300 MHz, SOCI") b m.p. 3.54 (s, Z H), 3.89 (s, Z H), 4.83 (s, 2 H), 7.47 (dd, 9-51, 0.9 HZ, 1 H), 8 .31 (s, 1 N), 8.61 (d, 2-5.1 Hz, 1 N), 9.04 (s, 1 N). (2) 3-(Methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

A solution (2 ml) of methyl 3-(methoxymethyl)-1-14-"-trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate (0.62 g) synthesized in the above-mentioned (1), in tetrahydrofuran was added to an ice-cooled solution (5 ml) of lithium aluminum hydride (0.10 g) in tetrahydrofuran.

The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (0.2 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) and water (0 .2 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (0.53 g) 33-(methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl)-1H-pyrazole-4-methanol as pale -yellow oil This was dissolved in toluene (30 mL), manganese dioxide (2.0 g) was added and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (0.59 g, quantitative) as a yellow oil. "H NMR (300 MHz, SOCI") 6 mp 3.53 (s, C H), 4 .83 (s, 2 N), 7.50 (d, 9-49 Hz, 1 N), 8.31 (s, 1 N), 8.63 (d, 2-5.1 Hz, 1 N) , 9.09 (s, 1 H), 10.10 (s, 1 H). (3) cyclohexyl3-(methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol- 4-yl)umethanol

To a solution (10 ml) of 3-(methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde (0.59 g), synthesized in the above-mentioned (2), cyclohexylmagnesium bromide (4.0 mL, 1M tetrahydrofuran solution) was added dropwise in tetrahydrofuran under ice-cooling. After completion of the dropwise addition, the ice bath was removed and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added an aqueous solution of ammonium chloride and a mixture extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (0.23 g, 30905) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.p. 0.94 - 1.96 (m, 12 H), 3.45 (s, C H), 4.43 (d, 9-7.7 Hz, 1 N), 4.58 - 4.65 (m, 2 N), 7.38 (d, 9U-0.9 Hz, 1 N), 8.15 - 8.60 (m, C H) (4). 3-I44-Kcyclohexyl(3-(methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl) amino|propanoic acid

To a solution (5 ml) of cyclohexyl 3-(methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl|-1 H-

pyrazol-4-ilumethanol (0.23 g), synthesized in the above-mentioned (3), in tetrahydrofuran at room temperature was added thionyl chloride (0.10 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5.0 ml), sodium iodide (0.14 g), sodium carbonate (0.10 g) and ethyl 3-I((4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.17 g) were added ), synthesized in Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate: .hexane-1:1, volume ratio) obtaining ethyl 3-|(4- (Ccyclohexyl/3-(methoxymethyl)-1-(4-(trifluoromethyl)pyridin-2-yl|-1 H-pyrazol-4 - yl)umethyl)amino|phenyl)icarbonyl)(methyl)amino|propanoate (0.10 g) as a pale yellow oil.

It was dissolved in ethanol (1.0 ml), 1M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.04 g, 1095) as a pale yellow solid. "H NMR (300 MHz, SOSI") b mp 0.95 - 2.18 (m, 11 N), 2.70 (t, U-6.3 Hz, 2 N), 3.06 ( s, Z H), 3.42 (s, Z H), 3.71 (t, U-6.3 Hz, 2 H), 4.36 (d, 2-7.2 Hz, 1 H), 4.57 (d, 9-21 Hz, 2 N), 6.56 (d, 98.7 Hz, 2 N), 7.24 (d, 92-8.7 Hz, 2 N), 7.37 (d, 9U-5.3 Hz, 1 N), 8.16 (s, 1 N), 8.36 (s, 1 N), 8.53 (d, 9U-5.3 Gu, 1 N) .

Example 90 3-II(4-Kcyclohexyl3-(methoxymethyl)-1-1b-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

M M sn,

Y M Still N -- M- o.

Sn, (1) methyl 3-(methoxymethyl)-1-(b-(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate

To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (5.1 g), synthesized in

In Example 29(1), 2-chloro-b-fluoromethylpyridine (5.0 g) and potassium carbonate (6.2 g) were added to M,M-dimethylformamide (70 ml) and the mixture was stirred at 100 "C overnight. The reaction the mixture was allowed to cool to room temperature and filtered through celite, water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane-1:4, volume ratio) to give the title compound (6.5 g, 6995) as colorless crystals. "H NMR (300 MHz, SOCI") 6 m.h. 3.54 (s, Z H), 3.89 (s, Z H), 4.83 (s, 2 H), 7.62 (d, 9-72 Hz, 1 H), 8.00 - 8 .02 (m, 1 N), 8.25 - 8.30 (m, 1 N), 9.06 (s, 1 N). (2) 3-(Methoxymethyl)-1-16-"(trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde

A solution (10 ml) of methyl 3-(methoxymethyl)-1-(16-trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carboxylate (6.5 g) synthesized in the above mentioned (1 ), in tetrahydrofuran was added to an ice-cooled solution (25 ml) of lithium aluminum hydride (0.79 g) in tetrahydrofuran.

The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled again with ice, and water (2.0 ml), 1M aqueous sodium hydroxide solution (10.0 ml) and water (2 .0 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (6.0 g) 33-(methoxymethyl)-1-(6-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-methanol) as pale -yellow oil This was dissolved in toluene (100 mL), manganese dioxide (3.0 g) was added and the mixture was heated under reflux with a Dean-Stark fitting for 1 h. The reaction mixture was allowed to cool to room temperature and the manganese dioxide was collected by filtration. The solvent was evaporated under reduced pressure to give the title compound (5.3 g, 90905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 3.53 (s, C H), 4.83 (s, 2 H), 7.66 (d, 9-7.5 Hz, 1 H), 8.05 - 8.08 (m, 1 H) , 8.27 (d, 9U-8.3 Hz, 1 N), 9.13 (s, 1 N), 10.10 (s, 1 N). (3) cyclohexyl3-(methoxymethyl)-1-(6-«(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethanol

To a solution (100 ml) of 3-(methoxymethyl)-1-(6-trifluoromethyl)pyridin-2-yl|-1H-pyrazole-4-carbaldehyde (5.3 g), synthesized in the above-mentioned (2), cyclohexylmagnesium bromide (25.0 ml, 1M tetrahydrofuran solution) was added dropwise in tetrahydrofuran while cooling with ice. After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (4.6 g, 67905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 2.22 (m, 11 H), 2.95 (d, 9U-6.0 Hz, 1 H), 3.45 (s, C H), 4.44 (dd, 9-7 ,7.6.0 Hz, 1 N), 4.50 - 4.65 (m, 2 N), 7.53 (d, 9-7.0 Hz, 1 N), 7.93 - 8.00 (m, 1 N), 8.14 (d, 2-8.3 Hz, 1 N), 8.45 (s, 1 N). (4). 3-I44-Kcyclohexyl(3-(methoxymethyl)-1-(6-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

To a solution (5 ml) of cyclohexyl[13-(methoxymethyl)-1-(b-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-ylmethanol (0.50 g), synthesized in the above mentioned ( 3), thionyl chloride (0.15 mL) was added in tetrahydrofuran at room temperature. The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous sodium bicarbonate solution (5 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5.0 ml), sodium iodide (0.37 g), sodium carbonate (0.26 g) and ethyl 3- I((4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.34 g), synthesized in Example 2(2), and the mixture was stirred at 70"С for 12 h. After spontaneous cooling, water and a mixture were added to the reaction mixture extracted with ethyl acetate.The extract was concentrated under reduced pressure and the residue was column purified by chromatography on silica gel (ethyl acetate: hexane-1:1, volume ratio) obtaining ethyl 3-|(4- (Ccyclohexyl/3-(methoxymethyl)-1-(6-(trifluoromethyl)pyridin-2-yl) -1H-pyrazol-4-yl)umethyl)amino|phenyl)carbonyl)x(methyl)amino|propanoate (0.08 g) as a pale yellow oil.

It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.06 g, 790) as a colorless solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.92 - 2.19 (m, 11 H), 2.73 (w s, 2 H), 3.08 (s, Z H), 3.41 (s, Z H), 3.72 (t , 9U-6.2 Hz, 2 N), 4.36 (d, 9U-8.0 Hz, 1 N), 4.57 (d, 9-21 Hz, 2 N), 6.58 (d, 9U-8,7

Hz, 2 H), 7.20 - 7.30 (m, 2 H), 7.51 - 8.12 (m, Z H), 8.40 (s, 1 H).

Example 91 3-II(4-Kcyclohexyl3-(methoxymethyl)-1-1b-(trifluoromethyl)pyridin-2-yl|-1H-pyrazol-4-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid

her

E N

M bod and ---- M" o.

CH,

To a solution (5 ml) of cyclohexyl/N-(methoxymethyl)-1-(b-(trifluoromethyl)pyridin-2-yl)-1H-pyrazol-4-ylmethanol (0.50 g), synthesized in Example 90 ( 3), thionyl chloride (0.15 mL) was added in tetrahydrofuran at room temperature. The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous sodium bicarbonate solution (5 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5.0 ml), sodium iodide (0.37 g), sodium carbonate (0.26 g) and ethyl were added. 3 -((4-aminophenyl)carbonyl|Iaminopropanoate (0.32 g), synthesized in

Example 1(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-|(((4-Kcyclohexyl3-(methoxymethyl)-1-Ib-"trifluoromethyl)pyridine -2-yl|- 1H-pyrazol-4-ylmethyl)amino|phenylcarbonyl)amino|propanoate (0.07 g) as a pale yellow oil. It was dissolved in ethanol (3.0 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure, and 1 M hydrochloric acid was added to the residue. (1.0 ml). The precipitate was washed with water to give the title compound (0.06 g, 8905) as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 0.87 - 2.17 (m, 11 N), 2.67 (t, 9-5.7 Hz, 2 N), 3.41 ( s, Z H), 3.56 - 3.77 (m, 2 H), 4.38 (d, 9U-7.6 Hz, 1 H), 4.56 (d, 9U-2.3 Hz, 2 H), 6.47 - 6.71 (m, C H), 7.46 - 8.11 (m, 5 H), 8.40 (c, 1 H).

Example 92 3-(X4-Hcyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)-2-methylpropanoic acid

ON

YUKZHZHKV SN; lu it

Sa and

M, N University

Sn, (1) methyl 4-(Icyclohexyl-1-(33-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)benzoate

To a solution (5 ml) of cyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methanol (0.64 g) synthesized in Example 83(3) in tetrahydrofuran at room temperature was added thionyl chloride (0.22 ml). The reaction mixture was stirred at room temperature for 30 min, cooled with ice, and a saturated aqueous solution of sodium bicarbonate (10 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10.0 ml), sodium iodide (0.44 g), sodium carbonate (0.30 g) and methyl 4-aminobenzoate (0.35 g) were added, and the mixture was stirred at 70 "C overnight. After after self-cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to give the title compound (0.34 g , 3895), as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.76 - 1.85 (m, 17 N), 2.63 - 2.82 (m, 2 N), 3.82 (s, C H), 4.02-4.11 (m, 2 N ), 4.27 (w s, 1 N), 6.51 (d, U-8.9 Hz, 2 N), 6.75 (dd, 9U-2.4, 0.9 Gu, 1 N) , 7.09 - 7.26 (m, Z H), 7.64 (s, 1 H), 7.80 (d, U-8.9 Hz, 2 H). (2) 4-((cyclohexyl-1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)iamino)benzoic acid

To a solution of methyl 4-((cyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)benzoate (0.34 g), synthesized in the above-mentioned (1), 1 M aqueous solution of sodium hydroxide (6.0 ml) was added in ethanol (6.0 ml) and the mixture was stirred at 60 "C for 2 h. Ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (8.0 ml) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the crude product (0.33 g, quantitative) of the title compound as a yellow oil. "H NMR (300 MHz, SOCI") 6 m .h 0.92 - 2.00 (m, 17 N), 2.72 (k, 9U-7.5 Hz, 2 N), 3.99 - 4.11 (m, 2 N), 4.28 (d , 2-5.8 Hz, 1 H), 6.52 (d, U-8.9 Hz, 2 H), 6.74 (ddd, 9U-8.1, 2.5, 0.8 Hz, 1 H), 7.10 - 7.25 (m, C H), 7.65 (s, 1 H), 7.84 (d, 9-8.9 Hz, 2 H). (3) 3-(X4-Hcyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenylcarbonylamino)-2-methylpropanoic acid 4-(Cyclohexyl (1-( -ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)iamino)benzoic acid (0.18 g), synthesized in the above-mentioned (2), was dissolved in M,M-dimethylformamide (3 ml) at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), 1-hydroxybenzotriazole monohydrate (0.09 g) and methyl 3-amino-2-methylpropanoate (0.07 g) were added and the mixture was stirred overnight. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain methyl 3-(|4-(cyclohexyl|1-(3-ethoxyphenyl)-3-ethyl-1H) -pyrazol-4-yl|methylamino)phenylcarbonylamino)-2-methylpropanoate (0.03 g) as a yellow oil. It was dissolved in ethanol (2.0 ml), 1 M aqueous sodium hydroxide solution (0.5 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g.

Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (0.5 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.02 g, 9905) as a colorless solid. "H NMR (300 MHz, SOSI") b mp 0.96 - 2.00 (m, 20 N), 2.62 - 2.91 (m, Z H), 3.59 - 3.75 (m, 2

H), 4.07 (k, U-6.8 Gu, 2 H), 4.24 (d, 9U-6.0 Hz, 1 H), 6.43 - 6.59 (m, C H) , 6.74 (dd, 9U-8.1, 2.4 Hz, 1 N), 7.08 - 7.66 (m, 6 N).

Example 93 2-I(14-Hcyclohexyl-1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)amino)phenyl-carbonylamino)methyl)|-2-ethylbutanoic acid

II o b C dream

N

M

SN.

4-(Cyclohexyl(1-(3-ethoxyphenyl)-3-ethyl-1H-pyrazol-4-yl|methyl)iamino)benzoic acid (0.18 g), synthesized in Example 92(2), was dissolved in M, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g), 1-hydroxybenzotriazole monohydrate (0.09 g), ethyl 2-(aminomethyl)-2 -ethylbutanoate hydrochloride (0.12 g) and triethylamine (0.09 ml) and the mixture was stirred overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, volume ratio) to obtain oethyl o /2-((4-(cyclohexyl|1-(3-ethoxyphenyl)-3-ethyl) -1H-pyrazol-4-yl|Imethyliamino)phenylcarbonyl)iamino)methyl|-2-ethylbutanoate (0.18 g) as a yellow oil. It was dissolved in ethanol (2.0 ml), at room temperature a 1 M aqueous solution of sodium hydroxide (2.0 ml) was added, and the mixture was stirred at 60 "C overnight. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (2 The precipitate was washed with water to give the title compound (0.17 g, 7490) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (t, 9U-7.4 Hz, 6 N), 1.00 - 1.99 (m, 21 N), 2.72 (Kk, 9U-7.5

HC, 2 H), 3.62 (d, 96.2 Hz, 2 H), 4.07 (k, 927.0 Hz, 2 H), 4.24 (d, 9U-6.0 Hz, 1 H), 6.38 - 6.47 (m, 1 H), 6.51 (d, U-8.9 Hz, 2 H), 6.73 (ddd, 9-71, 1.5, 1, 2 Hz, 1 H), 7.09 - 7.24 (m, 3 H), 7.54 (d, y5-8.9 Hz, 2 H), 7.63 (s, 1 H).

Example A1 3-1(4-(1-benzothiophen-3-yl(cyclohexyl)methyl|amino)phenyl)carbonyl|iaminopropanoic acid (9, (9. ru

N

M

Part (1) 1-benzothiophene-3-yl(cyclohexyl)methanol

To a solution (40 ml) of 1-benzothiophene-3-carbaldehyde (2.25 g) in tetrahydrofuran, a 1.0 M tetrahydrofuran solution of cyclohexylmagnesium bromide (20.9 ml) was added dropwise at 0"C and the mixture was stirred for 1.5 g. after quenching the reaction, M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-3:17, volume ratio) to give the title the target compound (2.37 g, 6995) as an orange oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.91 (m, 5 N), 1.43 - 1.52 (m, 1 N), 1.60 - 1.73 (m, 2

H), 1.74 - 1.83 (m, 1 H), 1.83 - 1.96 (m, 2 H), 1.97 - 2.05 (m, 1 H), 4.83 (dd , 9U-6.8, 3.2 Hz, 1 N), 7.30 - 7.40 (m, Z H), 7.82 - 7.93 (m, 2 N). (2) 3--(chloro(cyclohexyl)methyl|-1-benzothiophene

To a solution of 1-benzothiophene-3-yl(cyclohexyl)methanol (2.32 g) synthesized above in toluene (25 ml) was added dropwise thionyl chloride (824 μl) and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (2.42 g, 9790) as an orange oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.34 (m, 5 N), 1.46 - 1.56 (m, 1 N), 1.60 - 1.72 (m, 2

H), 1.76 - 1.86 (m, 1 H), 2.10 - 2.28 (m, 2 H), 5.03 (d, 9U-8.1 Hz, 1 H), 7, 32 - 7.43 (m, Z H), 7.82 - 7.93 (m, 2 H). (3) 4--P-benzothiophene-3-yl(cyclohexyl)methyl|amino)rbenzoic acid

To the mixture of 3-chloro(cyclohexyl)methyl)-1-benzothiophene (2.42 g) synthesized above,

methyl 4-aminobenzate (2.77 g), sodium iodide (2.74 g) and M,M-dimethylacetamide (50 ml) and sodium carbonate (1.94 g) were added and the mixture was stirred under an argon atmosphere at 10070 overnight. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:3, volume ratio) to obtain a pale yellow oil. Tetrahydrofuran (20 ml) and ethanol (20 ml) and 1M aqueous sodium hydroxide solution (20 ml) were added to the mixture of the obtained oil and the mixture was stirred overnight under reflux. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (40 mL) and 1M hydrochloric acid (20 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (1.80 g, 5495) as a white solid substance

IN NMR (300 MHz, SOSI") b m.h. 1.02 - 1.35 (m, 5 N), 1.60 - 2.03 (m, 6 N), 4.69 (d, 9-5.7 Hz, 1 N), 6.43 - 6 .53 (m, 2 H), 7.22 (s, 1 H), 7.32 - 7.47 (m, 2 H), 7.73 - 7.91 (m, 4 H). (4) 3-1(4-(1-benzothiophen-3-yl(cyclohexyl)methylamino)phenyl)carbonyl|Iamino)propanoic acid

To the mixture of 4-(11-benzothiophen-3-yl(icyclohexyl)methyl|Iaminophenzoic acid (250 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (126 mg), 1-hydroxybenzotriazole monohydrate (126 mg), triethylamine (114 μl) and M,M-dimethylformamide (10 ml) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (157 mg) was added and the mixture was stirred at room temperature for 2 h. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to give a pale yellow oil. To a mixture of the obtained oil, tetrahydrofuran ( 5 ml) and ethanol (5 ml) was added to a 1M aqueous solution of sodium hydroxide (1 ml) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (10 ml) and at 0"C was added 1M hydrochloric acid (1 ml). The resulting precipitate was collected by filtration to afford the title compound (201 mg, 67905) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.32 (m, 5 N), 1.57 - 1.81 (m, 4 N), 1.81 - 1.99 (m, 2

H), 2.57 (t, 9U-5.7 Hz, 2 H), 3.53 - 3.63 (m, 2 H), 4.63 (d, 9U-5.7 Hz, 1 H) , 6.42 (d, 2-8.7 Hz, 2 N), 6.62 (t, 9U-6.1 Hz, 1 N), 7.18 (s, 1 N), 7.31 - 7 .46 (m, A H), 7.80 - 7.89 (m, 2 H).

Example A2 3-1(4-(1-benzothiophen-3-yl(cyclohexyl)methylamino)phenyl)carbonyl|(methyl)amino)propanoic acid

More

N

WITH

Using -4-1-benzothiophene-Z3-yl(icyclohexyl)methyl|iaminobbenzoic acid (250 mg) synthesized in Example A1(3) and ethyl Z-(methylamino)propanoate (108 mg) and in the same manner as in Example A1(4) gave the title compound (220 mg, 71905) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.34 (m, 5 N), 1.61 - 1.83 (m, 4 N), 1.83 - 2.00 (m, 2

H), 2.67 (t, 9-6.4 Hz, 2 H), 3.02 (s, C H), 3.69 (t, 9U-6.4 Hz, 2 H), 4.64 (d, 9-5.7 Hz, 1 N), 6.45 (d, 98.7 Hz, 2 N), 7.19 (d, 9U-8.7 Hz, 2 N), 7.21 ( s, 1 H), 7.33 - 7.45 (m, 2 H), 7.82 - 7.91 (m, 2

N).

Example АЗ 3-Ш(4-(cyclohexyl(1-methyl-1H-benzimidazol-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

N

M

! M

Ca (1) cyclohexyl(1-methyl-1H-benzimidazol-2-yl)umethanol

Using 1-methyl-1H-benzoimidazole-2-carbaldehyde (1.03 g) and in the same manner as in Example AT(1), the title compound (0.58 g, 37905) was obtained as a brown oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.05 - 1.30 (m, 5 N), 1.36 - 1.46 (m, 1 N), 1.58 - 2.03 (m, 5

Н), 3.77 (s, З Н), 4.65 (d, 97.2 Hz, 1 Н), 7.20 - 7.30 (m, З Н), 7.65 - 7.73 ( m, 1 H). (2) 2--(chloro(cyclohexyl)methyl|-1-methyl-1H-benzoimidazole

Using cyclohexyl(1-methyl-1H-benzimidazol-2-yl)methanol (0.58 g) synthesized above, and in the same manner as in Example A1(2), the title compound was obtained (605 mg, 9790) as a brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.91 - 1.45 (m, 5 N), 1.50 - 1.60 (m, 1 N), 1.62 - 1.75 (m, 2

H), 1.81 - 1.92 (m, 1 H), 2.33 - 2.49 (m, 2 H), 3.87 (s, C H), 4.88 (d, 2-9 .9 Hz, 1 N), 7.24 - 7.38 (m, C H), 7.74 - 7.79 (m, 1 N). (3) 4-Hycyclohexyl(1-methyl-1H-benzimidazol-2-yl)methylaminobenzoic acid

Using 2-(chloro(cyclohexyl)methyl|-1-methyl-1H-benzoimidazole (605 mg) synthesized above and in the same manner as in Example A1(3), the title compound (87.0 mg , 1095), as a white solid. "H NMR (300 MHz, SOCIz") 6 ppm 1.04 - 1.32 (m, 5 N), 1.39 - 1.51 (m, 1 N ), 1.60 - 1.84 (m, Z

H), 2.03 - 2.20 (m, 2 H), 3.90 (s, With H), 4.63 - 4.72 (m, 1 H), 5.90 - 6.04 (m , 1 H), 6.69 (d, U-8.7

Hz, 2 N), 7.25 - 7.39 (m, C H), 7.73 - 7.81 (m, 1 H), 7.88 (d, 9U-8.7 Hz, 2 H) . (4) 3-((4-Hycyclohexyl(1-methyl-1H-benzimidazol-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

Using 4-ylcyclohexyl(1-methyl-1H-benzimidazol-2-yl)umethylamino)benzoic acid (78.3 mg), synthesized above, and in the same manner as in Example A1(4), the title target was obtained compound (39.5 mg, 4290) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.98 - 1.40 (m, 6 N), 1.59 - 1.71 (m, 2 N), 1.71 - 1.84 (m, 1

H), 1.92 - 2.08 (m, 1 H), 2.13 - 2.26 (m, 1 H), 2.71 (t, U-5.3 Hu, 2 H), 3, 71 - 3.83 (m, 2 H), 3.93 (s, C H), 4.59 - 4.71 (m, 1 H), 6.74 (d, 9-8.7 Hz, 2 H), 7.20 - 7.40 (m, 4 H), 7.59 - 7.70 (m, C H).

Example A4 3-4(4-(P1-benzofuran-2-yl(cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

M

And N

(1) 1-benzofuran-2-yl(cyclohexyl)methanol

Using 1-benzofuran-2-carbaldehyde (2.52 g) and in the same manner as in

Example AT(1) gave the title compound (2.38 g, 60905) as a yellow oil.

"H NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.36 (m, 5 N), 1.49 - 1.59 (m, 1 N), 1.61 - 2.03 (m, 6

H), 4.50 - 4.57 (m, 1 H), 6.60 (s, 1 H), 7.16 - 7.29 (m, 2 H), 7.43 - 7.47 (m , 1 H), 7.50 - 7.55 (m, 1

N). (2) 2--(chloro(cyclohexyl)methyl|-1-benzofuran

Using 1-benzofuran-2-yl(icyclohexyl)methanol (1.20 g) synthesized above, and in the same manner as in Example A1(2), the title compound (1.17 g, 9095) was obtained, like yellow butter. "H NMR (300 MHz, SOSIz") 6 m.h. 0.98 - 1.38 (m, 5 N), 1.50 - 1.86 (m, 4 N), 2.08 - 2.23 (m, 2

H), 4.78 (d, 98.1 Hz, 1 H), 6.66 (s, 1 H), 7.12 - 7.32 (m, 2 H), 7.45 - 7.56 ( m, 2 N). (3) 4--P-benzofuran-2-yl(cyclohexyl)methyl|amino)benzoic acid

Using 2-Ichloro(cyclohexyl)methyl|-1-benzofuran (1.17 g) synthesized above, and in the same manner as in Example A1(3), the title compound (523 mg, 32905) was obtained as pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.05 - 1.38 (m, 5 N), 1.57 - 1.86 (m, 4 N), 1.88 - 2.03 (m, 2

H), 4.41 - 4.50 (m, 1 H), 4.52 - 4.62 (m, 1 H), 6.53 (s, 1 H), 6.60 (d, 9-8 .9 Hz, 2 N), 7.14 - 7.25 (m, 2 N), 7.41 - 7.50 (m, 2 N), 7.85 (d, 9U-8.9 Hz, 2 N). (4) 3-S(4-11-benzofuran-2-yl(cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

Using 4-11-benzofuran-2-yl(icyclohexyl)methylaminobenzoic acid (250 mg) synthesized above and ethyl 33-(methylamino)propanoate (113 mg) and in the same manner as in Example A1(4), the indicated title compound (226 mg, 73905) as a pale red solid.

IN NMR (300 MHz, DMSO-dv) 5 m.h. 0.98 - 1.29 (m, 5 N), 1.39 - 1.50 (m, 1 N), 1.55 - 1.78 (m,

With H), 1.83 - 2.03 (m, 2 H), 2.43 - 2.54 (m, 2 H), 2.89 (s, With H), 3.51 (t, U- 7.3 Hz, 2 N), 4.38 - 4.49 (m, 1 N), 6.46 (d, 2-8.1 Hz, 1 N), 6.67 (d, 98.7 Hz , 2 H), 6.75 (s, 1 H), 7.11 (d, 9-8.7 HZ, 2 H), 7.14-7.26 (m, 2 H), 7.47 - 7.57 (m, 2 N).

Example A5 3-4(4-(P1-benzothiophen-2-yl(cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

M

N

(1) 1-benzothiophen-2-yl(cyclohexyl)methanol

Using 1-benzothiophene-2-carbaldehyde (2.00 g) and in the same manner as in

Examples of AT(1) provided the title compound (1.93 g, 6495) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.96 - 1.35 (m, 5 N), 1.50 - 1.84 (m, 5 N), 1.99 - 2.10 (m, 2

H), 4.70 (dd, U) - 7.2, 3.9 HZ, 1 H), 7.15 (s, 1 H), 7.24-7.36 (m, 2 H), 7 .67 - 7.73 (m, 1 N), 7.77 - 7.83 (m, 1 N). (2) 2--(chloro(cyclohexyl)methyl|-1-benzothiophene

Using 1-benzothiophen-2-yl(icyclohexyl)methanol (1.93 g) synthesized above and in the same manner as in Example A1(2) gave the title compound (1.94 g, 9495), as a brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.98 - 1.38 (m, 5 N), 1.50 - 2.01 (m, 5 N), 2.15 - 2.25 (m, 1

H), 4.97 (d, 9U-7.8 Hz, 1 H), 7.21 (s, 1 H), 7.26 - 7.37 (m, 2 H), 7.66 - 7, 73 (m, 1 N), 7.74 - 7.82 (m, 1 N). (3) 4--P-benzothiophen-2-yl(cyclohexyl)methyl|aminobenzoic acid

Using 2-|Ichloro(cyclohexyl)methyl|-1-benzothiophene (1.93 g) synthesized above and in the same manner as in Example A1(3) gave the title compound (719 mg, 27905), as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.06 - 1.37 (m, 5 N), 1.61 - 1.90 (m, 5 N), 1.91 - 2.04 (m, 1

H), 4.51 - 4.67 (m, 1 H), 6.61 (d, 9-8.8 Hz, 2 H), 7.16 (s, 1 H), 7.21 - 7, 36 (m, 2 N), 7.67 (d, 9U-7.0 Hz, 1 N), 7.74 (d, 9-7.9 Hz, 1 N), 7.84 (d, 2- 8.8 Hz, 2 N). (4) 3-1(4-(1-benzothiophen-2-yl(cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

Using -4-1-benzothiophen-2-yl(icyclohexyl)methyl|iaminobbenzoic acid (250 mg) synthesized above and ethyl 3-(methylamino)propanoate (108 mg) and in the same manner as in Example A1(4) , afforded the title compound (277 mg, 9095) as a white solid.

IN NMR (300 MHz, DMSO - dv) 5 m.h. 1.06 - 1.36 (m, 5 N), 1.62 - 1.87 (m, 5 N), 1.91 - 2.01 (m, 1 N), 2.65 (t, 9U- 6.4 Hz, 2 H), 3.01 (s, Z H), 3.69 (t, 9U-6.4 Hz, 2 H), 4.49 (d, 9-6.2 Hz, 1 H), 6.58 (d, 9-8.7 Hz, 2 H), 7.15 (s, 1 H), 7.18 - 7.35 (m, 4 H), 7.64 - 7, 70 (m, 1 N), 7.71 - 7.76 (m, 1 N).

Example Ab 3-1(4-(1-benzothiophen-2-yl(cyclohexyl)methyl|amino)phenyl)carbonyl|iaminopropanoic acid

N z

M

! N

Using -4-1-benzothiophen-2-yl(icyclohexyl)methyl|iaminobbenzoic acid (250 mg) synthesized in Example A5(33) in the same way as in Example AT1(4), the target compound indicated in the title was obtained (275 mg, 92905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.06 - 1.35 (m, 5 N), 1.61 - 1.87 (m, 5 N), 1.89 - 2.01 (m, 1

H), 2.60 (t, U5.7 Hz, 2 H), 3.55 - 3.67 (m, 2 H), 4.50 (d, 9-6.2 Hz, 1 H), 6 .53 - 6.64 (m, Z H), 7.14 (s, 1 H), 7.19 - 7.34 (m, 2 H), 7.50 (d, 9-8.7 Hz, 2 N), 7.66 (d, 97.3 Hz, 1 N), 7.72 (d, 97.9

HC, 1 H).

Example A7 3-11(4-Ycyclohexyl(1-methyl-1H-indazol-3-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Her vn

Mm-- / (1) cyclohexyl(1-methyl-1H-indazol-3-yl)methanol

Using 1-methyl-1H-indazole-3-carbaldehyde (1.00 g) and following the same procedure as in Example A1(1), the title compound (799 mg, 5295) was obtained as a pale yellow oil .

IN NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.37 (m, 5 N), 1.45 - 1.54 (m, 1 N), 1.60 - 1.82 (m, C

H), 1.84 - 2.03 (m, 2 H), 2.37 - 2.43 (m, 1 H), 4.02 (s, C H), 4.83 - 4.89 (m , 1 H), 7.09 - 7.16 (m, 1

H), 7.91 - 7.41 (m, 2 H), 7.80 (d, 9-8.1 Hz, 1 H). (2)3-(chloro(cyclohexyl)methyl|)|-1-methyl-1H-indazole

Using cyclohexyl(1-methyl-1H-indazol-3-yl)methanol (799 mg) synthesized above and in the same manner as in Example A1(2) gave the title compound (818 mg, 95905), like yellow butter. "H NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.38 (m, 5 N), 1.40 - 1.50 (m, 1 N), 1.59 - 1.70 (m, 2

H), 1.77 - 1.87 (m, 1 H), 2.18 - 2.40 (m, 2 H), 4.03 (s, C H), 5.06 (d, 9-8 .7 Hz, 1 N), 7.12 - 7.19 (m, 1 N), 7.32 - 7.42 (m, 2 N), 7.87 (d, 928.1 Hz, 1 N) . (3) 3-((4-(cyclohexyl(1-methyl-1H-indazol-3-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of 3-(chloro(cyclohexyl)methyl-1-methyl-1H-indazole (465 mg) synthesized above, ethyl 3-(((4-aminophenyl)carbonyl|(methyl)amino)propanate (531 mg), synthesized in

Example 2(2), sodium iodide (531 mg) and M,M-dimethylacetamide (10 ml) was added sodium carbonate (375 mg) and the mixture was stirred in an argon atmosphere at 100 C overnight.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-3:2, volume ratio) to give a white solid. To a mixture of the obtained solid, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous sodium hydroxide solution (2.00 ml) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (10 mL) and 1M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (356 mg, 45905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.97 - 1.34 (m, 5 N), 1.47 - 1.82 (m, 4 N), 1.89 - 2.10 (m, 2

H), 2.66 (t, 9U-6.5 Hz, 2 H), 3.03 (s, C H), 3.69 (t, 9U-6.5 Hz, 2 H), 4.01 (c, Z H), 4.70 (d, 9-7.0 Hz, 1 H), 6.60 (d, 9-8.6 Gu, 2 H), 7.06 - 7.14 (m , 1 N), 7.20 (d, 9-86 Hz, 2 N), 7.29 - 7.40 (m, 2 N), 7.74 (d, 9-81 Hz, 1 N).

Example AB 3-((4-(cyclohexyl(2-methyl-1-benzothiophen-3-yl)methylamino)phenyl)carbonylamino)propanoic acid

M

N

(1) 3-bromo-2-methyl-1-benzothiophene

Bromine (1.90 ml) was added dropwise to a solution (50 ml) of 2-methyl-1-benzothiophene (5.00 g) in acetic acid at 0 C and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (8.02 g, quantitative) as a brown oil.

IN NMR (300 MHz, SOSI") b m.h. 2.56 (s, Z H), 7.28 - 7.36 (m, 1 H), 7.36 - 7.44 (m, 1 H), 7.67 -7.75 (m, 2 H ). (2) cyclohexyl(2-methyl-1-benzothiophen-3-yl)methanol

C3-Bromo-2-methyl-1-benzothiophene (2.00 g) synthesized above was dissolved in tetrahydrofuran (40 ml) dropwise at -78 "C, and a 1.6M hexane solution of n-butyllithium (6.63 ml) was added dropwise. The mixture was stirred under a nitrogen atmosphere for 10 min, cyclohexanecarbaldehyde (2.50 ml) was added, and the mixture was stirred at -78 °C for 30 min and at room temperature for 30 min. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-3:17, v/v) to give the title compound (1.95 g, 8596) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.95 - 1.42 (m, 5 N), 1.51 - 1.70 (m, 2 N), 1.71 - 1.92 (m, C

H), 1.97 - 2.13 (m, 1 H), 2.24 - 2.35 (m, 1 H), 2.54 (s, C H), 4.74 (dd, 9-91 , 2.2 Hz, 1 N), 7.21 - 7.35 (m, 2 N), 7.71 - 7.77 (m, 1 N), 7.97 - 8.05 (m, 1 N ). (3) 3-(chloro(cyclohexyl)methyl|-2-methyl-1-benzothiophene

Using cyclohexyl(2-methyl-1-benzothiophen-3-yl)methanol (1.95 g) synthesized above, and in the same manner as in Example A1(2), the title compound was obtained (1.98 g , 95905), as brown butter.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.70 - 0.85 (m, 1 N), 0.96 - 1.40 (m, 4 N), 1.49 - 1.91 (m, 4

H), 2.24 - 2.32 (m, 1 H), 2.46 - 2.58 (m, 4 H), 4.94 (d, 9-10.5 Hz, 1 H), 7, 23 - 7.36 (m, 2 H), 7.70 - 7.75 (m, 1 H), 7.99 (d, 9d-7.5 Gu, 1 H). (4) 4-Cyclohexyl(2-methyl-1-benzothiophen-3-yl)methylaminophenzoic acid

Using 33-(chloro(cyclohexyl)methyl|-2-methyl-1-benzothiophene (1.98 g), synthesized above, and in the same manner as in Example A1(3), the title compound (1, 69 g, 63905), as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.96 - 1.34 (m, 5 N), 1.39 - 1.51 (m, 1 N), 1.62 - 1.71 (m, 2

H), 1.78 - 1.89 (m, 1 H), 1.93 - 2.08 (m, 1 H), 2.09 - 2.20 (m, 1 H), 2.58 (s , Z H), 4.56 (d, 9-8.5

Hu, 1 H), 6.46 (d, 9-9.0 Hz, 2 H), 7.21 - 7.36 (m, 2 H), 7.69 - 7.84 (m, A H) . (5) 3-((4-Icyclohexyl(2-methyl-1-benzothiophen-3-yl)methylamino)phenyl)carbonyl|amino)propanoic acid

Using 4-cyclohexyl(2-methyl-1-benzothiophen-3-yl)methyl|amino)dibenzoic acid (300 mg) synthesized above, and in the same manner as in Example AT1(4), the title compound was obtained (323 mg, 9195) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.94 - 1.34 (m, 5 N), 1.40 - 1.51 (m, 1 N), 1.61 - 1.72 (m, 2

H), 1.78 - 1.88 (m, 1 H), 1.92 - 2.07 (m, 1 H), 2.09 - 2.20 (m, 1 H), 2.53 - 2 .65 (m, 5 N), 3.54 - 3.65 (m, 2 N), 4.52 (d, 928.7 Hz, 1 N), 6.39 - 6.55 (m, Z N ), 7.20 - 7.34 (m, 2 H), 7.39 - 7.48 (m, 2

H), 7.72 (d, 9-8.0 Gu, 1 H), 7.81 (d, 9-7.6 Hz, 1 H).

Example A9 3-((4-(cyclohexyl(2-methyl-1-benzothiophen-3-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoic acid

N z

Using 4-cyclohexyl(2-methyl-1-benzothiophen-3-yl)methyl|amino)dibenzoic acid (300 mg), synthesized in Example A8(4), and ethyl 3-(methylamino)propanoate (124 mg) and such in the same manner as in Example A1(4), the title compound (312 mg, 8595) was obtained as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.35 (m, 5 N), 1.39 - 1.50 (m, 1 N), 1.61 - 1.73 (m, 2

H), 1.78 - 1.88 (m, 1 H), 1.91 - 2.06 (m, 1 H), 2.09 - 2.20 (m, 1 H), 2.57 (s , Z H), 2.58 - 2.67 (m, 2

H), 2.99 (s, C H), 3.67 (t, 9-6.4 Hz, 1 H), 4.50 (d, 9U-8.7 Hz, 1 H), 6.44 (d, 2-8.5 Hz, 2 N), 7.17 (d, 9-8.5 Hz, 1 N), 7.21 - 7.35 (m, 2 N), 7.73 (d , 97.2 Hz, 1 N), 7.83 (d, 97.6 Hz, 1 N).

Example of ATO 3-((4-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)phenyl)carbonylamino)propanoic acid of her hands

N

M

H sn, (1) cyclohexyl(3-methyl-1-benzothiophen-2-yl)methanol

Using 3-methyl-1-benzothiophene-2-carbaldehyde (2.00 g) and in the same manner as in Example AT(1), the title compound (1.65 g, 56905) was obtained as a yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.85 - 1.36 (m, 5 N), 1.41 - 1.52 (m, 1 N), 1.60 - 1.86 (m, 4

H)U, 2.01 (d, 93.3 Hz, 1 H), 2.14 - 2.24 (m, 1 H), 2.37 (s, C H), 4.83 (dd, 9 -81, 3.3 Hz, 1 N), 7.27 - 7.39 (m, 2 N), 7.62 - 7.67 (m, 1 N), 7.77 - 7.82 (m, 1 H). (2) 2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzothiophene

Using cyclohexyl(3-methyl-1-benzothiophen-2-yl)umethanol (1.65 g), synthesized above, and in the same manner as in Example A1(2), the title compound was obtained (1.68 g , 95905), as yellow oil.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.84 - 0.99 (m, 1 N), 1.04 - 1.39 (m, 4 N), 1.56 - 1.71 (m, C

H), 1.77 - 1.88 (m, 1 H), 1.88 - 2.03 (m, 1 H), 2.32 - 2.45 (m, 4 H), 5.09 (d , 9-9.6 Hz, 1 N), 7.29 - 7.39 (m, 2 N), 7.62 - 7.67 (m, 1 N), 7.75 - 7.80 (m, 1 H). (3) 4-Icyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl|iaminophenzoic acid

Using 2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzothiophene (1.68 g), synthesized above, and in the same manner as in Example A1(3), the title compound (1, 63 g, 71905), as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.34 (m, 5 N), 1.53 - 1.87 (m, 5 N), 2.03 - 2.16 (m, 1

H), 2.44 (s, C H), 4.54 - 4.63 (m, 1 H), 6.46 (d, 9-8.6 Hz, 2 H), 7.21 - 7, 29 (m, 1 H), 7.30 - 7.38 (m, 1 H), 7.63 (d, 9-7.9 Hz, 1 H), 7.69 (d, 9-7.7 Hz, 1 N), 7.75 (d, U-8.6 Hz, 2 N). (4) 3-((4-Hycyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

Using 4-cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)benzoic acid (300 mg) synthesized above, and in the same manner as in Example A1(4), the title compound (275) was obtained mg, 7,790), as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.01 - 1.34 (m, 5 N), 1.53 - 1.85 (m, 5 N), 2.03 - 2.14 (m, 1

H), 2.44 (s, C H), 2.53 (t, 95.6 Hz, 2 H), 3.50 - 3.61 (m, 2 H), 4.54 (d, 9- 7.7 Gu, 1 N), 6.48 (d, uU-8.8 Gu, 2 N), 6.58 (t, 9U-5.9 Hz, 1 N), 7.20 - 7.27 (m, 1 H), 7.29 - 7.37 (m, 1 H), 7.46 (d, 9-88

Hz, 2 N), 7.62 (d, 9-7.5 Hz, 1 N), 7.67 (d, 9-7.5 Hz, 1 N).

Example A11 3-(X4-Ccyclohexyl5-(trifluoromethyl)-1-benzothiophen-2-yl|methyl)amino)phenylcarbonylamino)propanoic acid

N

With M

And N

IS

IS

IS

(1) 5-(trifluoromethyl)-1-benzothiophene-2-carbaldehyde

Lithium aluminum hydride (292 mg) was added to a solution (40 ml) of methyl 5-(trifluoromethyl)-1-benzothiophene-2-carboxylate (2.00 g) in tetrahydrofuran at 0 "C and the mixture was stirred for 1 h. To quench the reaction, water (300 μl), 1M aqueous sodium hydroxide solution (300 μl) was added, and the mixture was stirred at room temperature for 3 h.

The resulting insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a white solid. To a solution of the obtained solid in tetrahydrofuran (40 mL) was added active manganese dioxide (9.00 g) and the mixture was stirred overnight at room temperature. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (1.15 g, 6595) as a brown solid.

IN NMR (300 MHz, SOSI") b m.h. 7.69 - 7.75 (m, 1 N), 8.00 - 8.06 (m, 1 N), 8.11 (s, 1 N), 8.21 - 8.25 (m, 1 N ), 10.14 (s, 1 N). (2) cyclohexyl(5-(trifluoromethyl)-1-benzothiophen-2-yl|methanol

Using 5B-(trifluoromethyl)-1-benzothiophene-2-carbaldehyde (1.15 g) synthesized above and in the same manner as in Example A1(1) gave the title compound (860 mg, 5595), as a pale yellow solid. "H NMR (300 MHz, SOSIz") 6 m.h. 0.98 - 1.35 (m, 5 N), 1.50 - 1.59 (m, 1 N), 1.62 - 1.85 (m, 4

H), 1.95 - 2.06 (m, 1 H), 2.12 - 2.18 (m, 1 H), 4.75 (d, 9-7.2 Hz, 1 H), 7, 22 (s, 1 H), 7.48 - 7.53 (m, 1 H), 7.87 - 7.92 (m, 1 H), 7.97 (s, 1 H). (3) 2-(chloro(cyclohexyl)methyl|-5-(trifluoromethyl)-1-benzothiophene

To a solution of cyclohexyl5-(trifluoromethyl)-1-benzothiophen-2-yl|methanol (860 mg) synthesized above in toluene (20 ml) was added thionyl chloride (239 μl) and the mixture was stirred at 100 "C for 1 h. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (806 mg, 89905) as a pale brown oil/

IN NMR (300 MHz, SOSI") b m.h. 0.99 - 1.37 (m, 5 N), 1.58 - 2.01 (m, 5 N), 2.13 - 2.23 (m, 1

H), 4.97 (d, 9U-7.8 Hz, 1 H), 7.29 (s, 1 H), 7.51 - 7.56 (m, 1 H), 7.86 - 7, 91 (m, 1 H), 7.96 - 7.99 (m, 1 H). (4) 4-(Icyclohexyl5-(trifluoromethyl)-1-benzothiophen-2-yl|Imethyliamino)benzoic acid

Using 2-|chloro(cyclohexyl)methyl|-5-'(trifluoromethyl)-1-benzothiophene (806 mg) synthesized above, and in the same manner as in Example A1(3), the title compound (68 .7 mg, 7905), as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.37 (m, 5 N), 1.62 - 1.89 (m, 5 N), 1.90 - 2.00 (m, 1

H), 4.58 (d, U-6.3 Hz, 1 H), 6.59 (d, U-8.7 Hz, 2 H), 7.25 (s, 1 H), 7.45 - 7.50 (m, 1 N), 7.82 (d, uU-8.4 Hz, 1 N), 7.84 (d, 9-8.7 Hz, 2 N), 7.93 - 7 .96 (m, 1 N). (5) 3-(X4-Ccyclohexyl5-(trifluoromethyl)-1-benzothiophen-2-yl|methyl)amino)phenylcarbonylamino)propanoic acid

Using 4-(Icyclohexyl15-(trifluoromethyl)-1-benzothiophen-2-yl|methyl)amino)benzoic acid (68.7 mg) synthesized above and in the same manner as in

Example A1(4) gave the title compound (57.8 mg, 73905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.36 (m, 5 N), 1.59 - 1.87 (m, 5 N), 1.88 - 1.99 (m, 1

H), 2.58 (t, 9U-5.3 Hz, 2 H), 3.54 - 3.66 (m, 2 H), 4.51 (d, U-6.4 Hz, 1 H) , 6.56 (d, 9-8.3 Hz, 2 N), 6.63 (t, 9U-5.7 Hz, 1 N), 7.22 (s, 1 N), 7.43 - 7 .49 (m, 1 N), 7.51 (d, 2-8.3 Hz, 2 N), 7.80 (d, 9U-8.7

Gu, 1 N), 7.93 (s, 1 N).

Example A12 3-(Х4-Ccyclohexylylβ-(trifluoromethyl)-1-benzothiophen-2-yl|methyl)amino)phenylcarbonylamino)propanoic acid

N

WITH

EE ate

IS

(1) 6-(trifluoromethyl)-1-benzothiophene-2-carbaldehyde

Using methyl b-(trifluoromethyl)-1-benzothiophene-2-carboxylate (2.07 g) and in the same manner as in Example A11(1), the title compound (1.38 g, 75965) was obtained as brown solid.

IN NMR (300 MHz, SOSIz") 6 m.h. 7.63 - 7.69 (m, 1 N), 8.06 (d, U-8.4 Hz, 1 N), 8.08 (s, 1 N), 8.18 - 8.22 (m , 1 N), 10.15 (c, 1 N). (2) cyclohexyl 1b-(trifluoromethyl)-1-benzothiophen-2-yl|methanol

Using b-(trifluoromethyl)-1-benzothiophene-2-carbaldehyde (1.38 g) synthesized above and in the same manner as in Example A1(1) gave the title compound (668 mg, 35905), as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.99 - 1.35 (m, 5 N), 1.50 - 1.60 (m, 1 N), 1.62 - 1.84 (m, 4

H), 1.94 - 2.04 (m, 1 H), 2.15 - 2.20 (m, 1 H), 4.76 (dd, U-6.9, 3.6 Hz, 1 H ), 7.21 (s, 1 N), 7.52 - 7.58 (m, 1 N), 7.79 (d, 98.1 Hz, 1 N), 8.06 - 8.10 (m , 1 H). (3) 2-(chloro(cyclohexyl)methyl|-6-(trifluoromethyl)-1-benzothiophene

Using cyclohexylib-(trifluoromethyl)-1-benzothiophen-2-yl|methanol (668 mg) synthesized above and in the same manner as in Example A11(3) gave the title compound (659 mg, 93905), like brown butter. "H NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.37 (m, 5 N), 1.58 - 1.86 (m, 4 N), 1.88 - 2.01 (m, 1

H), 2.12 - 2.22 (m, 1 H), 4.97 (d, 9-7.8 Hz, 1 H), 7.28 (s, 1 H), 7.53 - 7, 58 (m, 1 N), 7.80 (d, uU-8.4 HZ, 1 N), 8.05 - 8.08 (m, 1 N). (4) 4-(IcyclohexylIb-(trifluoromethyl)-1-benzothiophen-2-yl|Imethyliamino)benzoic acid

Using 2-|chloro(cyclohexyl)methyl|-6-(trifluoromethyl)-1-benzothiophene (659 mg) synthesized above and in the same manner as in Example A1(3), the title compound (82 .5 mg, 10905), as brown oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.37 (m, 5 N), 1.62 - 1.88 (m, 5 N), 1.90 - 1.99 (m, 1

H), 4.58 (d, 9-6.3 Hz, 1 H), 6.59 (d, 9-8.7 Hz, 2 H), 7.23 (s, 1 H), 7.50 - 7.55 (m, 1 N), 7.76 (d, uU-8.4 Hz, 1 N), 7.84 (d, 9-8.7 Hz, 2 N), 7.99 - 8 .02 (m, 1 N). (5) 3-(X4-Ccyclohexylyl[trifluoromethyl)-1-benzothiophen-2-yl|methyl)amino)phenylcarbonylamino)propanoic acid

Using 4-(IcyclohexylIb-(trifluoromethyl)-1-benzothiophen-2-yl|methyl)amino)benzoic acid (82.5 mg) synthesized above and in the same manner as in

Example A1(4) gave the title compound (54.0 mg, 56905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.35 (m, 5 N), 1.58 - 1.87 (m, 5 N), 1.88 - 1.99 (m, 1

H), 2.53 - 2.63 (m, 2 H), 3.54 - 3.66 (m, 2 H), 4.52 (d, 9-6.1 Gu, 1 H), 6, 56 (d, 2-8.7 Hz, 2 N), 6.58 - 6.66 (m, 1 N), 7.20 (s, 1 N), 7.46 - 7.55 (m, Z H), 7.73 (d, 9-8.3 Hz, 1 H), 7.98 (s, 1 H).

Example A13 3-((4-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid is

E

And N

Using 4-1-cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyliaminophenbenzoic acid (300 mg) synthesized in Example A10(3), and ethyl 3-(methylamino)propanoate (124 mg) and in the same manner as in Example A1(4), the title compound (269 mg, 73905) was obtained as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.34 (m, 5 N), 1.53 - 1.87 (m, 5 N), 2.05 - 2.16 (m, 1

H), 2.45 (s, C H), 2.59 (t, 9U-6.4 Hz, 2 H), 2.97 (s, C H), 3.65 (t, U-6, 4 Hz, 2 N), 4.53 (d, 9-7.5 Gu, 1 N), 6.50 (d, U-8.7 Hz, 2 N), 7.18 (d, 9-8 ,7 Hz, 2 N), 7.22 - 7.29 (m, 1 N), 7.30 - 7.38 (m, 1 N), 7.63 (d, 9U-7.5 Hz, 1 H), 7.70 (d, 9-7.7 Hz, 1 H).

Example A14 3-1(4-Icyclohexyl(1-phenyl-1H-indazol-3-yl)methylamino)phenyl)carbonylamino)propanoic acid

N ate

M-- (1) methyl 1-phenyl-1H-indazole-3-carboxylate

Copper (II) acetate ( 5.32 g) and the mixture was stirred at 30 "C overnight. The insoluble material was filtered off, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate.

The extract was washed with saturated sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (1.58 g, 3295) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 4.07 (s, Z H), 7.35 - 7.60 (m, 5 H), 7.70 - 7.77 (m, Z H), 8.30 - 8.35 (m, 1 H ). (2) 1-phenyl-1H-indazole-3-carbaldehyde

To a solution (40 ml) of methyl 1-phenyl-1H-indazole-3-carboxylate (2.25 g) synthesized above in tetrahydrofuran at 0"C, a 1.5M toluene solution of diisobutylaluminum hydride (26.7 ml) was added dropwise and the mixture was stirred for 1 h. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a colorless oil. To a solution of the obtained oil in tetrahydrofuran (40 ml) active manganese dioxide (8.00 g) was added and the mixture was stirred at 50 "C for 5 h. Active manganese dioxide (1.00 g) was added and the mixture was stirred at 50 "C for 1 g. The manganese dioxide was filtered off and the filtrate was concentrated at The residue was purified by silica gel column chromatography (ethyl acetate:hexane-3:17 v/v) to afford the title compound (926 mg, 4790) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 7.39 - 7.47 (m, 1 H), 7.47 - 7.55 (m, 2 H), 7.57 - 7.64 (m, 2

H), 7.72 - 7.80 (m, With H), 8.37 - 8.42 (m, 1 H), 10.34 (s, 1 H). (3) cyclohexyl(1-phenyl-1H-indazol-3-yl)methanol

Using 1-phenyl-1H-indazole-33-carbaldehyde (926 mg) synthesized above and in the same manner as in Example A1(1), the title compound (716 mg, 5695) was obtained as a pale yellow oil

IN NMR (300 MHz, SOSI") 6 m.h. 1.11 - 1.31 (m, 5 N), 1.51 - 1.84 (m, 4 N), 1.94 - 2.08 (m, 2

H), 2.52 (d, U-4.5 Hz, 1 H), 4.93 - 5.00 (m, 1 H), 7.18 - 7.25 (m, 1 H), 7, 31 - 7.38 (m, 1 H), 7.39 - 7.45 (m, 1 H), 7.49 - 7.56 (m, 2 H), 7.68 - 7.74 (m, With H), 7.87 - 7.92 (m, 1 H). (4) 3-(chloro(cyclohexyl)methyl|-1-phenyl-1H-indazole

To a mixture of cyclohexyl(1-phenyl-1H-indazol-3-yl)methanol (716 mg) synthesized above, pyridine (284 μl) and toluene (20 ml) was added thionyl chloride (256 μl) and the mixture was stirred at room temperature for 2 d. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (767 mg, quantitative) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.99 - 1.38 (m, 5 N), 1.46 - 1.55 (m, 1 N), 1.60 - 1.72 (m, 2

H), 1.80 - 1.90 (m, 1 H), 2.24 - 2.44 (m, 2 H), 5.15 (d, 2-9.0 Gu, 1 H), 7, 21 - 7.27 (m, 1 H), 7.32 - 7.39 (m, 1 H), 7.40 - 7.46 (m, 1 H), 7.49 - 7.56 (m, 2 H), 7.67 - 7.74 (m, With H), 7.96 - 8.00 (m, 1 H). (5) 3-((4-(cyclohexyl(1-phenyl-1H-indazol-3-yl)methylamino)phenyl)carbonylamino)propanoic acid

Using 3-(chloro(cyclohexyl)methyl!|-1-phenyl-1H-indazole (370 mg) synthesized above and ethyl 3-(((4-aminophenyl)carbonyl|aminopropanoate (269 mg) synthesized in Example 1(2), and in the same manner as in Example A7(3), the title compound (79.1 mg, 14965) was obtained as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.01 - 1.36 (m, 5 N), 1.54 - 1.84 (m, 4 N), 1.98 - 2.13 (m, 2

H), 2.52 - 2.64 (m, 2 H), 3.53 - 3.66 (m, 2 H), 4.81 (d, 9U-6.8 Hz, 1 H), 6, 52 - 6.71 (m, Z H), 7.16 (t, 9-7.6 HZ, 1 H), 7.29 - 7.42 (m, 2 H), 7.45 - 7.56 (m, 4 H), 7.62 - 7.71 (m, Z H), 7.81 (d, 9-8.3

HC, 1 H).

Example A15 3-1(4-Icyclohexyl(1-phenyl-1H-indazol-3-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

M--M

Using 3-(chloro(cyclohexyl)methyl!|-1-phenyl-1H-indazole (397 MG), synthesized in Example A14(4), and ethyl 3-(4-aminophenyl)carbonyl)(methyl)amino)propanoate (305 mg) synthesized in Example 2(2) and in the same manner as in Example A?7(3) gave the title compound (76.9 mg, 1295) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.35 (m, 5 N), 1.54 - 1.84 (m, 4 N), 1.98 - 2.13 (m, 2

H), 2.56 - 2.67 (m, 2 H), 2.99 (s, C H), 3.67 (t, U-6.1 Hz, 2 H), 4.80 (d, 9-6.4 Hz, 1 N), 6.66 (d,

U-8.7 Hz, 2 N), 7.13 - 7.18 (m, 1 N), 7.21 (d, 9U-8.7 Hz, 2 N), 7.30 - 7.42 ( m, 2 H), 7.52 (t, U-7.8

Hz, 2 N), 7.64 - 7.72 (m, 2 N), 7.82 (d, 98.3 Hz, 1 N).

Example A16 3-((4-(cyclohexyl(3-methyl-1-benzofuran-2-yl)umethyl|iamino)phenyl)carbonyl|(methyl)amino)propanoic acid

M

N

(1) 3-methyl-1-benzofuran-2-carbaldehyde

A 1.5M toluene solution of diisobutylaluminum hydride (19.6 ml) was added dropwise to a solution (40 ml) of ethyl 3-methyl-1-benzofuran-2-carboxylate (2.00 g) in tetrahydrofuran at 0"C, and the mixture was stirred for 2 g. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. To a solution (40 ml) of the obtained solid in dichloromethane was added Dessa-Martin periodinan ( 4.96 g) at 0 "This mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium sulfite was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:9, v/v) to give the title compound (753 mg, 48905) as a white solid. "IN NMR (300 MHz, SOSI") b m.ch. 2.63 (s, Z H), 7.30 - 7.37 (m, 1 H), 7.48 - 7.58 (m, 2 H), 7.67 - 7.71 (m, 1 H), 10.03 (s, 1 H). (2) cyclohexyl(3-methyl-1-benzofuran-2-yl)umethanol

Using 3-methyl-1-benzofuran-2-carbaldehyde (753 mg) synthesized above and in the same manner as in Example A1(1) gave the title compound (843 mg, 73905) as a pale yellow butter.

IN NMR (300 MHz, SOSI") 6 m.h. 0.85 - 1.03 (m, 1 N), 1.03 - 1.34 (m, 4 N), 1.34 - 1.44 (m, 1

H), 1.60 - 1.71 (m, 2 H), 1.75 - 1.99 (m, Z H), 2.10 - 2.20 (m, 1 H), 2.23 (s , Z H), 4.49 - 4.56 (m, 1

H), 7.18 - 7.29 (m, 2 H), 7.39 - 7.49 (m, 2 H). (3) 2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzofuran

To a mixture of cyclohexyl(3-methyl-1-benzofuran-2-yl)methanol (843 mg) synthesized above and toluene (20 mL) was added thionyl chloride (256 µL) and the mixture was stirred at room temperature for 2.5 g and at 50C for 1.5 g. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (862 mg, 9596) as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.84 - 0.98 (m, 1 N), 1.00 - 1.37 (m, 4 N), 1.42 - 1.53 (m, 1

H), 1.57 - 1.77 (m, 2 H), 1.77 - 1.88 (m, 1 H), 2.12 - 2.28 (m, 4 H), 2.08 - 2 .38 (m, 1 N), 4.82 (d, 99.6 Hz, 1 N), 7.14 - 7.33 (m, 2 N), 7.43 - 7.50 (m, 2 N ). (4) 3-((4-Yacyclohexyl(3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Using 2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzofuran (429 mg) synthesized above and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (408 mg) synthesized in Example 2(2), and in the same manner as in Example A7(3), the title compound (247 mg, 34905) was obtained as a white solid. "H NMR (300 MHz, SOCI") 6 m .parts 0.94 - 1.37 (m, 5 N), 1.47 - 1.58 (m, 1 N), 1.60 - 1.73 (m, 2

H), 1.73 - 1.83 (m, 1 H), 1.84 - 1.98 (m, 1 H), 2.03 - 2.15 (m, 1 H), 2.25 (s , Z H), 2.59 - 2.69 (m, 2

H), 3.01 (c, 2 H), 3.68 (t, U-6.5 Hu, 2 H), 4.38 (d, 9-7.9 Hu, 1 H), 6.56 (d, 9-8.7 Hz, 2 N), 7.16 - 7.27 (m, 4 N), 7.35 - 7.40 (m, 1 N), 7.41 - 7.45 ( m, 1 N).

Example A17 3-((4-(cyclohexyl(3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

N. v

Using 2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzofuran (433 MG), synthesized in Example A16(3), and ethyl 3-((4-aminophenyl)carbonyl|amino)propanoate (390 mg) , synthesized in Example 1(2), and in the same manner as in Example A?7(3), the title compound (268 mg, 37905) was obtained as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.46 - 1.59 (m, 1 N), 1.59 - 1.74 (m, 2

H), 1.74 - 1.84 (m, 1 H), 1.84 - 1.99 (m, 1 H), 2.02 - 2.13 (m, 1 H), 2.25 (s , Z H), 2.55 - 2.66 (m, 2

H), 3.57 - 3.68 (m, 2 H), 4.40 (d, 9-8.1 Hz, 1 H), 6.51 - 6.65 (m, C H), 7, 14 - 7.25 (m, 2 H), 7.34 - 7.39 (m, 1 H), 7.39 - 7.45 (m, 1 H), 7.52 (d, 9-8, 9 Hz, 2 N).

Example A18 3-1(4-cyclohexyl(1-cyclohexyl-1H-indazol-3-yl)umethylamino)phenyl)carbonyl|(methyl)amino)propanoic acid (1) methyl 1-cyclohexyl-1H-indazole -Z3-carboxylate

To a mixture of methyl 1H-indazole-3-carboxylate (5.00 g), cyclohexanol (9.00 ml), triphenylphosphine (14.9 g) and tetrahydrofuran (100 ml) was added 4095 toluene solution of diethyl azodicarboxylate (25.6 ml) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue and the mixture was stirred at 0"C. The precipitate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:9, volume ratio) to obtain the title compound (6.84 g, 93905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.25 - 1.43 (m, 1 N), 1.45 - 1.62 (m, 2 N), 1.72 - 1.82 (m, 1

H), 1.90 - 2.00 (m, 2 H), 2.01 - 2.16 (m, 4 H), 4.03 (s, C H), 5.50 - 5.62 (m , 1 H), 7.24-7.37 (m, 2

H), 7.78 - 7.83 (m, 1 H), 7.99 - 8.04 (m, 1 H). (2) 1-cyclohexyl-1H-indazole-3-carbaldehyde

Using methyl 1-cyclohexyl-1H-indazole-3-carboxylate (3.08 g) synthesized above and in the same manner as in Example A14(2) gave the title compound (1.98 g, 73905 ), as a pale yellow oil.

"H NMR (300 MHz, SOSI") 6 m.h. 1.31 - 1.43 (m, 1 H), 1.45 - 1.63 (m, 2 H), 1.74 - 1.84 (m, 1

H), 1.92 - 2.02 (m, 2 H), 2.06 - 2.18 (m, 4 H), 5.24 - 5.36 (m, 1 H), 7.33 - 7 .43 (m, 2 H), 7.83 - 7.90 (m, 1 H), 7.98 - 8.05 (m, 1 H), 10.32 (s, 1 H). (3) cyclohexyl(1-cyclohexyl-1H-indazol-3-yl)methanol

Using 1-cyclohexyl-1H-indazole-3-carbaldehyde (980 mg) synthesized above and in the same manner as in Example A1(1) gave the title compound (984 mg, 7395) as a white solid substance "H NMR (300 MHz, SOSIZ") b m.ch. 0.82 - 1.00 (m, 1 N), 1.05 - 2.07 (m, 17 N), 2.07 - 2.33 (m, 4

H), 4.48 - 4.62 (m, 1 H), 4.93 (dd, 2U-8.9, 3.6 Hz, 1 H), 6.99 - 7.07 (m, 1 H ), 7.20-728 (m, 1 N), 7.65-7.73 (m, 2 N). (4) 3-(chloro(cyclohexyl)methyl|)-1-cyclohexyl-1H-indazole

Using cyclohexyl(1-cyclohexyl-1H-indazol-3-yl)methanol (934 mg/g), synthesized above, and in the same manner as in Example A14(4), the title compound was obtained (1.05 g, quantitatively), as a pale yellow solid. "H NMR (300 MHz, SOSIZ") b m.p. 0.75 - 0.89 (m, 1 N), 1.06 - 2.08 (m, 16 N), 2.09 - 2.38 (m, Z

H), 2.45 - 2.56 (m, 1 H), 4.41 - 4.54 (m, 1 H), 5.09 (d, 9U-10.5 Hz, 1 H), 7, 04 - 7.11 (m, 1 H), 7.21 - 7.29 (m, 1 H), 7.66 - 7.72 (m, 2 H). (5) 3-((4-(cyclohexyl(1-cyclohexyl-1H-indazol-3-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Using 3-Ichloro(cyclohexyl)methyl|-1-cyclohexyl-1!H-indazole (400 mg) synthesized above and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (303 mg), synthesized in Example 2(2), and in the same manner as in Example A7(3), the title compound (451 mg, 72905) was obtained as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.50 (m, 9 H), 1.61 - 2.04 (m, 9 H), 2.06 - 2.29 (m, Z

H), 2.57 - 2.69 (m, 2 H), 2.99 (s, C H), 3.67 (t, U-6.2 Hz, 2 H), 4.43 - 4, 57 (m, 1 H), 4.72 (d, 9U-8.3

Hz, 1 N), 6.47 (d, 9-8.7 Hz, 2 N), 6.99 - 7.06 (m, 1 N), 7.17 (d, 9-8.7 Hz, 2 H), 7.20 - 7.29 (m, 1

H), 7.65 - 7.73 (m, 4 H).

Example A19 3-1(4-cyclohexyl(1-cyclohexyl-1H-indazol-3-yl)umethyl|amino)phenyl)carbonyl|amino)propanoic acid

Gee stupid

N and sh--M

Using 3-Ichloro(cyclohexyl)methyl|-1-cyclohexyl-1!H-indazole (400 mg), synthesized in Example A18(4), and ethyl 3-((4-aminophenyl)carbonyl|amino)propanoate (286 mg ), synthesized in Example 1(2), and in the same manner as in Example A?7(3), obtained the title compound (441 mg, 72905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.48 (m, 9 H), 1.61 - 2.04 (m, 9 H), 2.03 - 2.29 (m, Z

H), 2.61 (t, 9-5.7 Hz, 2 H), 3.54 - 3.69 (m, 2 H), 4.43 - 4.55 (m, 1 H), 4, 74 (d, 2-83 Hz, 1 N), 6.46 (d, 2-8.7 Hz, 2 N), 6.67 (t, 9U-5.8 Hz, 1 N), 6.97 - 7.06 (m, 1 N), 7.18 - 7.29 (m, 1 N), 7.46 (d, U-8.7 Hz, 2 N), 7.68 (d, 9- 9.4 Hz, 2 N).

Example A2O 3-((4-(cyclohexyl(7-methoxy-1-benzofuran-2-yl)methyl|amino)phenyl)carbonylamino)propanoic acid

N

(1) 7-methoxy-1-benzofuran-2-carbaldehyde

Using ethyl 7-methoxy-1-benzofuran-2-carboxylate (2.00 g) and in the same manner as in Example A14(2), the title compound (950 mg, 5990) was obtained as a brown oil. "IN NMR (300 MHz, SOSI") b m.ch. 4.04 (s, Z H), 6.96 - 7.00 (m, 1 H), 7.22 - 7.34 (m, 2 H), 7.54 (s, 1 H), 9.90 (s, 1 H). (2) cyclohexyl(7-methoxy-1-benzofuran-2-yl)umethanol

Using 7-methoxy-1-benzofuran-2-carbaldehyde (950 mg) synthesized above and in the same manner as in Example A1(1), the title compound (790 mg, 5695) was obtained as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.34 (m, 5 N), 1.49 - 1.60 (m, 1 N), 1.60 - 1.83 (m, Z

H), 1.84 - 2.02 (m, With H), 4.00 (s, With H), 4.53 - 4.59 (m, 1 H), 6.60 (s, 1H), 6.74-681 (m, 1 N), 7.09 - 7.17 (m, 2 N). (3) 2--(chloro(cyclohexyl)methyl|- 7-methoxy-1-benzofuran

Using cyclohexyl(7-methoxy-1-benzofuran-2-yl)methanol (790 mg) synthesized above and in the same manner as in Example A1(2) gave the title compound (823 mg, 9790), like yellow butter. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.37 (m, 5 N), 1.55 - 1.84 (m, 4 N), 2.06 - 2.25 (m, 2

H), 4.01 (s, C H), 4.81 (d, 9-7.8 Hz, 1 H), 6.67 (s, 1 H), 6.75 - 6.83 (m, 1 N), 7.10 - 7.18 (m, 2 N). (4) 3-((4-(cyclohexyl(7-methoxy-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

Using /2-(chloro(cyclohexyl)methyl|-7/-methoxy-i-benzofuran (422 ml) synthesized above and ethyl 3-(((4-aminophenyl)carbonyl|aminoisopropanoate (357 mg) synthesized in Example 1(2), and in the same manner as in Example A7(3), the title compound (64.3 mg, 995) was obtained as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.34 (m, 5 N), 1.54 - 1.82 (m, 4 N), 1.87 - 2.07 (m, 2

H), 2.64 (t, U-5.6 Hz, 2 H), 3.59 - 3.69 (m, 2 H), 4.00 (s, C H), 4.43 (d, 9U-6.4 Hz, 1 N), 6.50 (s, 1

H), 6.53 - 6.61 (m, C H), 6.75 (dd, 9d-7.5, 1.3 Hz, 1 H), 7.02 - 7.13 (m, 2 H ), 7.53 (d, 9-8.7 Hz, 2

N).

Example A21 3-((4-(cyclohexyl(7-methoxy-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

M and N

Using /2-(chloro(cyclohexyl)methyl|-7/-methoxy-i-benzofuran (401 grams), synthesized in Example A2O(3), and ethyl 3-|(4-aminophenyl)carbonyl)(methyl)amino) propanoate (360 mg) synthesized in Example 2(2) and in the same manner as in Example A?7(3) gave the title compound (48.7 mg, 790) as a white solid.

"H NMR (300 MHz, SOSIz") 6 m.h. 1.03 - 1.34 (m, 5 N), 1.54 - 1.82 (m, 4 N), 1.88 - 2.08 (m, 2

H), 2.68 (t, U-6.4 Hz, 2 H), 3.04 (s, C H), 3.71 (t, U-6.4 Hu, 2 H), 4.01 (c, Z H), 4.42 (d, 9-66 Gu, 1H), 6.51 (c, 1 H), 6.57 (d, U-8.7 Hz, 2 H), 6, 76 (dd, 9-7.3, 1.5 Hz, 1 N), 7.04 -715 (m, 2 N), 7.24 (d, 9U-8.7 Hz, 2 N).

Example A22 3-((4-(cyclohexyl(5-methoxy-1-benzofuran-2-yl)umethyl|amino)phenyl)carbonyl|amino)propanoic acid

N o

M

N

- o (1) Y-methoxy-1-benzofuran-2-carbaldehyde

Using ethyl 5-methoxy-1-benzofuran-2-carboxylate (2.00 g) and in the same manner as in Example A14(2), the title compound (914 mg, 5790) was obtained as a brown solid. "IN NMR (300 MHz, SOSI") b m.ch. 3.86 (s, Z H), 7.10 - 7.16 (m, 2 H), 7.46 - 7.52 (m, 2 H), 9.82 (s, 1 H). (2) cyclohexyl(5-methoxy-1-benzofuran-2-yl)umethanol

Using 5-methoxy-1-benzofuran-2-carbaldehyde (914 mg) synthesized above and in the same manner as in Example A1(1), the title compound (702 mg, 52905) was obtained as a brown oil.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.98 - 1.35 (m, 5 N), 1.47 - 1.58 (m, 1 N), 1.60 - 2.02 (m, 6

H), 3.83 (s, C H), 4.47 - 4.53 (m, 1 H), 6.54 (s, 1 H), 6.85 (dd, 9U-8.7, 2 .7 Hz, 1 N), 6.99 (d, 9-2.7

Hz, 1 N), 7.33 (d, 9-8.7 Hz, 1 N). (3) 2-(chloro(cyclohexyl)methyl|-5-methoxy-1-benzofuran

Using cyclohexyl(5-methoxy-1-benzofuran-2-yl)methanol (702 mg) synthesized above and in the same manner as in Example A1(2) gave the title compound (722 mg, 96905), like brown butter.

IN NMR (300 MHz, SOSI") 6 m.h. 0.98 - 1.38 (m, 5 N), 1.51 - 1.86 (m, 4 N), 2.06 - 2.21 (m, 2

H), 3.83 (s, C H), 4.75 (d, 2-8.1 Hz, 1 H), 6.59 - 6.61 (m, 1 H), 6.88 (dd, 9U-8.9, 2.4 Hz, 1 N), 6.97 (d, 9U-2.4 Hz, 1 N), 7.33 - 7.38 (m, 1 N). (4) 3-((4-(cyclohexyl(5-methoxy-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

To the mixture of 2-(chloro(cyclohexyl)methyl|-5-methoxy-1-benzofuran (360 MG), synthesized above, ethyl 3-(((4-aminophenyl)carbonyl|Iaminopropanoate (305 mpgH), synthesized in Example 1) 2), sodium iodide (291 mg) and M,M-dimethylacetamide (10 ml) was added sodium carbonate (206 mg) and the mixture was stirred overnight at 80 C. To quench the reaction, 1 M hydrochloric acid was added and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-11:9, volume ratio) to obtain a yellow oil. A 1M aqueous solution of sodium hydroxide (1 ml) was added to the mixture of the obtained oil, tetrahydrofuran (2.5 ml) and ethanol (2.5 ml), and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (5 mL) and 1 M hydrochloric acid (1 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (96.0 mg, 17905) as a yellow solid. H NMR (300 MHz, SOSI") 6 m.ch. 1.02 - 1.35 (m, 5 N), 1.54 - 1.84 (m, 4 N), 1.85 - 2.01 (m, 2

H), 2.60 - 2.69 (m, 2 H), 3.59 - 3.70 (m, 2 H), 3.80 (s, Z H), 4.38 (d, 9U-6 ,4 Hz, 1 N), 6.44 (s, 1 N), 6.53 - 6.62 (m, C H), 6.82 (dd, 9U-9.1, 2.7 Hz, 1 H), 6.92 (d, 9-2.7 Hz, 1 H), 7.30 (d, 959.1 Hz, 1

H), 7.54 (d, 9-8.7 Hz, 2 H).

Example A23 3-4(4-((3-methyl-1-(3-methyl-1-benzofuran-2-yl)butylamino)phenyl)carbonylamino)propanoic acid (F) - Su

But M

N

(1) M-methoxy-M,3-dimethyl-1-benzofuran-2-carboxamide

To a mixture of 3-methyl-1-benzofuran-2-carboxylic acid (15.0 g), M,O-dimethylhydroxyamine hydrochloride (9.95 g), 1-hydroxybenzotriazole monohydrate (15.6 g), triethylamine (14.2 ml) and M,M-dimethylformamide (150 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.6 g) and the mixture was stirred overnight at room temperature. M,O-dimethylhydroxyamine hydrochloride (4.16 g), 1-hydroxybenzotriazole monohydrate (6.52 g), triethylamine (5.94 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8. 17 g) and the mixture was stirred at room temperature for 4 h. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-3:7, v/v) to give the title compound (16.2 g, 87905) as a colorless oil. "H NMR (300 MHz, SOSI") 6 m.h. 2.51 (s, C H), 3.39 (s, C H), 3.87 (s, C H), 7.25 - 7 ,32 (m, 1

H), 7.37 - 7.50 (m, 2 H), 7.58 - 7.63 (m, 1 H). (2) 3-methyl-1-(3-methyl-1-benzofuran-2-yl)butan-1-one

A 1.0M solution (6.84 ml) of isobutylmagnesium bromide in tetrahydrofuran and the mixture was stirred for 1 g.

Another 1.0M tetrahydrofuran solution of isobutylmagnesium bromide (6.84 ml) was added and the mixture was stirred at 0"C for 1 h and then at room temperature for 2 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:9, v/v) to give the title compound (873 mg, 89905) as a colorless oil.

IN NMR (300 MHz, SOSIz") 6 m.h. 1.02 (d, 9U-6.9 Hz, 6 N), 2.26 - 2.41 (m, 1 N), 2.61 (s, C H), 2.87 (d, 96.9 Hz, 2 N), 7.26 - 7.33 (m, 1 N), 7.42 - 7.53 (m, 2 N), 7.62 - 7.67 (m, 1 N). (3) methyl 4-1|3-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl|amino)benzoate

To the mixture of 3-methyl-1-(3-methyl-1-benzofuran-2-yl)butan-1-one (200 mg) synthesized above, methyl 4-aminobenzoate (140 mg), triethylamine (1.03 ml) and dichloromethane (5 ml) at

Titanium chloride (IM) (122 μl) was added to the solution and the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown solid. Sodium cyanoborohydride (175 mg) was added in small portions to a mixture of the obtained solid, acetic acid (1 ml), methanol (5 ml), and tetrahydrofuran (5 ml), and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution was added to quench the reaction of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (254 mg, 78905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.92 (d, U-6.6 Hz, Z H), 1.01 (d, 9U-6.6 Hz, Z H), 1.49 - 1.64 (m, 1 H), 1, 79 - 1.96 (m, 2 H), 2.29 (s, C H), 3.81 (s, C H), 4.48 (d, 9-7.8 Hz, 1 H), 4 .70 - 4.80 (m, 1 N), 6.58 (d, 9U-8.9 Hz, 2 N), 7.16 - 7.26 (m, 2 N), 7.34 - 7, 39 (m, 1 N), 7.41 - 7.45 (m, 1 N), 7.80 (d, U-8.9 Hz, 2 N). (4) 4-13-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl|iaminorbenzoic acid

To the mixture of methyl 4-1Z3-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl|amino)benzoate (1.38 g), synthesized above, tetrahydrofuran (20 ml) and ethanol (20 ml) 1M aqueous sodium hydroxide solution (20 ml) was added and the mixture was stirred under reflux overnight. Another 1 M aqueous solution of sodium hydroxide (20 ml) was added and the mixture was stirred under reflux with 3 g. The reaction mixture was concentrated under reduced pressure, 1 M hydrochloric acid (40 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with isopropyl ether to give the title compound (1.06 g, 80905) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 0.92 (d, 9U-6.6 Hz, Z H), 1.01 (d, 9U-6.6 Hz, Z H), 1 .49 - 1.64 (m, 1 N), 1.79 - 1.97 (m, 2 N), 2.30 (s, Z H), 4.77 (t, Ue7.5 Hz, 1 N ), 6.59 (d, 959.0 Hz, 2 N), 7.16 - 7.28 (m, 2 N), 7.35 - 7.40 (m, 1 N), 7.42 - 7 .47 (m, 1 H), 7.86 (d, 9U-9.0 Hz, 2 H). (5) 3-((4-(3-methyl-1-(3-methyl-1-benzofuran) -2-yl)butyl|Iamino)phenyl)carbonyl|Iamino)propanoic acid

Using 4-13-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl|aminobenzoic acid (300 mg), synthesized above, and in the same manner as in Example AT1(4), the indicated in title compound (289 mg, 8095) as a white solid.

IN NMR (300 MHz, SOSIz") b m.h. 0.91 (d, 9U-6.6 Hz, Z H), 1.00 (d, 9-6.6 Hz, Z H), 1.48 - 1.64 (m, 1 H), 1, 78 - 1.94 (m, 2 H), 2.28 (s, Z H), 2.64 (t, 95.5 Hz, 2 H), 3.60 - 3.69 (m, 2 H) , 4.73 (t, 97.5 Hz, 1 N), 6.54 - 6.65 (m, Z H), 7.15 - 7.26 (m, 2 N), 7.34 - 7, 39 (m, 1 H), 7.40 - 7.45 (m, 1

H), 7.54 (d, 9-8.7 Hz, 2 H).

Example A24

3-Imethyl(4-(3-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid o m СОН o Her

Using 4-13-methyl-1-(3-methyl-1-benzofuran-2-yl)butyl|aminobenzoic acid (300 mg) synthesized in Example A23(4) and ethyl 33-(methylamino)propanoate (140 mg ) and in the same manner as in Example A1(4), the title compound (221 mg, 5995) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.p. 0.91 (d, 9U-6.6 Hz, Z H), 1.00 (d, 9U-6.6 Hz, Z H), 1 .48 - 1.64 (m, 1 H), 1.81 - 1.92 (m, 2 H), 2.29 (s, C H), 2.61 - 2.71 (m, 2 H) , 3.03 (s, C H), 3.70 (t, 9-6.4 Gu, 2 H), 4.71 (t, 927.5 Hz, 1 H), 6.58 (d, 9 -8.5 Hz, 2 N), 7.16 - 7.29 (m, 6 N), 7.35 - 7.40 (m, 1 N), 7.A1 - 7.Ab (m, 1 N ).

Example A25 3-((4-(cyclohexyl(5-methoxy-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

M

N

-at

Using /2-(chloro(cyclohexyl)methyl|-5-methoxy-1-benzofuran (361 mpgHg), synthesized in Example A22(3), and ethyl 3-|(4-aminophenyl)carbonyl)(methyl)amino)propanoate (325 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4) gave the title compound (87.0 mg, 14905) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.36 (m, 5 N), 1.55 - 1.84 (m, 4 N), 1.86 - 2.01 (m, 2

H), 2.61 - 2.74 (m, 2 H), 3.04 (s, C H), 3.71 (t, U-6.2 Hz, 2 H), 3.81 (s, With H), 4.36 (d, 9-61 Hz, 1

H), 6.45 (s, 1 H), 6.57 (d, 9U-8.7 Hz, 2 H), 6.83 (dd, U-8.9, 2.5 Hz, 1 H) , 6.94 (d, 9-2.5 Hz, 1 N), 7.21 - 7.29 (m, 2 N), 7.31 (d, 9-8.9 Gu, 1 N).

Example A26 3-((4-(cyclohexyl(2-ethyl-1-benzofuran-3-yl)umethyl|iamino)phenyl)carbonyl|(methyl)amino)propanoic acid o o

M

H o (1) cyclohexyl(2-ethyl-1-benzofuran-3-yl)methanol

Using 2-ethyl-1-benzofuran-3-carbaldehyde (1.20 g) and in the same manner as in Example A1(1), the title compound (1.76 g, 9990) was obtained as a yellow oil.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.79 - 0.94 (m, 1 H), 1.01 - 1.19 (m, Z H), 1.20 - 1.34 (m, 4

H), 1.37 - 1.46 (m, 1 H), 1.57 - 1.70 (m, 2 H), 1.77 - 2.02 (m, C H), 2.17 - 2 ,27 (m, 1 H), 2.70 - 2.85 (m, 2 H), 4.54 (dd, 2-8.7, 2.7 HZ, 1 H), 7.14 - 7, 24 (m, 2 H), 7.37 - 7.41 (m, 1 H), 7.60 - 7.65 (m, 1 H). (2) 3--(chloro(cyclohexyl)methyl|-2-ethyl-1-benzofuran

Using cyclohexyl(2-ethyl-1-benzofuran-3-yl)methanol (763 mg) synthesized above and in the same manner as in Example A1(2) gave the title compound (765 mg, 94905), as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.75 - 0.89 (m, 1 N), 1.00 - 1.39 (m, 7 N), 1.43 - 1.53 (m, 1

H), 1.58 - 1.69 (m, 2 H), 1.78 - 1.89 (m, 1 H), 2.12 - 2.26 (m, 1 H), 2.35 - 2 .46 (m, 1 N), 2.70 - 2.85 (m, 2 N), 4.78 (d, 2-9.9 Hz, 1 N), 7.14 - 7.28 (m, 2 H), 7.37 - 7.42 (m, 1 H), 7.67 - 7.72 (m, 1

N). (3) 3-((4-(cyclohexyl(2-ethyl-1-benzofuran-3-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Using 33-(chloro(cyclohexyl)methyl/|-2-ethyl-1-benzofuran (300 mg) synthesized above and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (270 mg), synthesized in Example 2(2), and in the same manner as in Example A22(4), the title compound (287 mg, 57906) was obtained as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.87 - 1.23 (m, 5 N), 1.28 (t, 9-7.5 Hz, C H), 1.55 - 1.75 (m,

With H), 1.75 - 1.98 (m, 2 H), 2.04 - 2.15 (m, 1 H), 2.61-2.71 (m, 2 H), 2.75 - 2.90 (m, 2 H), 3.02 (s,

With H), 3.69 (t, 9U-6.4 Hz, 2 H), 4.30 (d, 9-7.9 Hz, 1 H), 6.49 (d, 2-8.7 Hz , 2 H), 7.12 - 7.24 (m, 4

H), 7.35 - 7.41 (m, 1 H), 7.53 - 7.59 (m, 1 H).

Example A27 3-((4-(cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Z y , -H - (1) methyl 5-methoxy-3-methyl-1-benzofuran-2-carboxylate

To a mixture of 1-(2-hydroxy-5-methoxyphenyl)ethanone (5.00 g), methyl bromoacetate (3.13 ml) and

Potassium carbonate (12.5 g) was added to M,M-dimethylformamide (50 ml) and the mixture was stirred overnight at room temperature. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown oil.

Sodium methoxide (1.63 g) was added to a solution (50 ml) of the obtained oil in methanol, and the mixture was stirred under reflux with 3 g. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (1.25 g, 1995) as a white solid. "H NMR (300 MHz, SOS") 6 m.h. 2.57 (s, C H), 3.87 (s, C H), 3.97 (s, C H), 6.99 (d , 9-26 Hz, 1 N), 7.06 (dd, U-9.0, 2.6 Hz, 1 N), 7.42 (d, 2-9.0 Hz, 1 N). (2 ) 5-methoxy-3-methyl-1-benzofuran-2-carbaldehyde

Lithium aluminum hydride (862 mg) was added to a solution (100 ml) of methyl 5-methoxy-3-methyl-1-benzofuran-2-carboxylate (5.00 g) in tetrahydrofuran at 0 "С and the mixture was stirred for 1.5 g. To quench the reaction, water (860 μl) was added, 1M aqueous sodium hydroxide solution (860 μl) was added, and the mixture was stirred at room temperature for 1 h.

The resulting insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a pale yellow solid. Active manganese dioxide (21.2 g) was added to a solution of the obtained solid in tetrahydrofuran (80 ml) and the mixture was stirred at 50 C overnight. Manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (3.41 g, 7995) as a brown solid. "H NMR (300 MHz, SOSI") b m.p. 2.60 (s, C H), 3.88 (s, C H), 7.03 (d, 9-2.5 Hz, 1 H ), 7.14 (dd, U-9.0, 2.5 Hz, 1 N), 7.44 (d, 9U-9.0 Hz, 1 N), 10.00 (s, 1 N). (3) cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methanol

Using B-methoxy-3-methyl-1-benzofuran-2-carbaldehyde (1.50 g), synthesized above as in Example AT1(1), the title compound (1.54 g, 71965) was obtained as yellow oil

IN NMR (300 MHz, SOSI") 6 m.h. 0.84 - 0.99 (m, 1 N), 1.00 - 1.33 (m, 4 N), 1.33 - 1.44 (m, 1

H), 1.60 - 1.70 (m, 2 H), 1.74 - 1.99 (m, Z H), 2.09 - 2.22 (m, 4 H), 3.85 (s , Z H), 4.50 (dd, 98.6, 6.5 Hu, 1 H), 6.86 (dd, U-8.7, 2.6 Hz, 1 H), 6.91 (d , 9U-2.6 Hz, 1 N), 7.30 (d, U-8.7 Hz, 1 N). (4) 2--(chloro(cyclohexyl)methyl|-5-methoxy-3-methyl-1-benzofuran

Using cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methanol (754 mg) synthesized above, and in the same manner as in Example A1(2), the title compound was obtained (795 mg , 99905), as brown butter.

"H NMR (300 MHz, SOSI") 6 m.h. 0.83 - 0.97 (m, 1 N), 1.00 - 1.40 (m, 4 N), 1.42 - 1.52 (m, 1

H), 1.60 - 1.70 (m, 2 H), 1.77 - 1.87 (m, 1 H), 2.10 - 2.38 (m, 5 H), 3.85 (s , Z H), 4.80 (d, 9U-9.6

Hz, 1 N), 6.86 - 6.91 (m, 2 N), 7.31 - 7.36 (m, 1 N). (5) 3-(S(4-Yacyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Using 2-Ichloro(cyclohexyl)methyl|-5-methoxy-33-methyl-1-benzofuran (395 mg) synthesized above and ethyl. 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (338 mg), synthesized in Example 2(2), and in the same manner as in Example A22(4), the title compound was obtained (305 mg, 47905), as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.47 - 1.57 (m, 1 N), 1.60 - 1.96 (m, 4

H), 2.03 - 2.13 (m, 1 H), 2.23 (s, C H), 2.65 (t, 9U-6.4 Hz, 2 H), 3.02 (s, With H), 3.69 (t, U-6.4 Hz, 2

Н), 3.83 (s, З Н), 4.36 (d, 9-8.0 Hz, 1 Н), 6.55 (d, У-8.7 Hz, 2 Н), 6.82 (dd, U-8.9, 2.4 Hz, 1 H), 6.88 (d, 9-2.4 Hz, 1 H), 7.19 - 7.29 (m, C H).

Example A28 3-((4-(cyclohexyl(b-methoxy-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid of the type

(1) b-methoxy-1-benzofuran-2-carbonitrile

Potassium carbonate (18.1 g) was added to a mixture of 2-hydroxy-4-methoxybenzaldehyde (10.0 g), bromoacetonitrile (5.04 mL), and acetone (100 mL), and the mixture was stirred at room temperature for 3 h. Insoluble material was filtered and the filtrate was concentrated under reduced pressure to give a pale brown solid. 1,8-diazabicycloi|5.4.Fundec-7-ene (9.83 ml) was added to a solution (100 ml) of the obtained solid in M,M-dimethylformamide and the mixture was stirred at 140 "C for 1.5 g.

The reaction mixture was concentrated under reduced pressure, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue, the 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-3:17, v/v) to give the title compound (5.32 g, 47905) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 3.88 (s, Z H), 6.96 - 7.04 (m, 2 H), 7.39 (d, 9-09 Hz, 1 H), 7.52 (d, U-8.5 Hz, 1 N). (2) cyclohexyl(b-methoxy-1-benzofuran-2-yl)methanone

To a solution (20 ml) of b-methoxy-1-benzofuran-2-carbonitrile (1.00 g) synthesized above in tetrahydrofuran was added a 1.0 M tetrahydrofuran solution of cyclohexylmagnesium bromide (11.5 ml) and the mixture was stirred at 50 "C for overnight and stirred under reflux for 1 h. Saturated aqueous ammonium chloride solution was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane-1:9, v/v) to give the title compound (584 mg, 39905) as a yellow solid. "H NMR (300 MHz, SOCI") 6 m.p.h. 1.20 - 1.64 (m, 5 N), 1.69 - 1.79 (m, 1 N), 1.81 - 1.98 (m, 4

H), 3.09 - 3.21 (m, 1 H), 3.87 (s, C H), 6.93 (dd, 9U-8.4, 2.1 Hz, 1 H), 7, 03 - 7.06 (m, 1 H), 7.44 - 7.46 (m, 1 H), 7.54 (d, 9U-8.4 Gu, 1 H). (3) methyl 4-cyclohexyl(b-methoxy-1-benzofuran-2-yl)methyl ylaminobenzoate

Using cyclohexyl(b-methoxy-1-benzofuran-2-yl)methanone (584 mg) synthesized above and in the same manner as in Example A23(3) gave the title compound (682 mg, 7790) , like brown butter. "H NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.36 (m, 5 N), 1.56 - 1.84 (m, 4 N), 1.86 - 2.00 (m, 2

Н), 3.81 (s, З Н), 3.83 (s, З Н), 4.35 - 4.57 (m, 2 Н), 6.44 (s, 1 Н), 6.58 (d, 9U-8.9 Hz, 1 N), 6.81 (dd, U-8.6, 2.3 Hz, 1 N), 6.97 (d, U-2.3 Hz, 1 N ), 7.31 (d, 9U-8.6 Hz, 1 N), 7.80 (d, 9-8.9 Hz, 2 N). (4) 4-Icyclohexyl(b-methoxy-1-benzofuran-2-yl)methyl|amino)dibenzoic acid

Using methyl 4-cyclohexyl(b-methoxy-1-benzofuran-2-yl)methyliamino)benzoate (682 mg) synthesized above and in the same manner as in

Example A23(4) afforded the title compound (633 mg, 9690) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.37 (m, 5 N), 1.56 - 1.86 (m, 4 N), 1.86 - 2.01 (m, 2

H), 3.83 (s, C H), 4.36 - 4.46 (m, 1 H), 4.48 - 4.65 (m, 1 H), 6.45 (s, 1 H) , 6.60 (d, 9-8.9 Hz, 2 H), 6.82 (dd, 9U-8.6, 2.3 Hz, 1 H), 6.98 (d, 9-2.3 Hz, 1 N), 7.33 (d, 9U-8.6 Gu, 1 N), 7.86 (d, 9U-8.9 Hz, 2 N). (5) 3-((4-(cyclohexyl(b-methoxy-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Using 4-ylcyclohexyl(b-methoxy-1-benzofuran-2-yl)methylamino)benzoic acid (300 mg) synthesized above and ethyl 3-(methylamino)propanoate (125 mg) and in the same manner as in Example A1 (4), afforded the title compound (201 mg, 55905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.36 (m, 5 N), 1.55 - 1.84 (m, 4 N), 1.85 - 2.00 (m, 2

H), 2.67 (t, 96.5 Hz, 2 H), 3.03 (s, Z H), 3.70 (t, 9U-6.5 Hz, 2 H), 3.83 (s , Z H), 4.35 (d, 9-66 Hz, 1 H), 6.44 (s, 1 H), 6.57 (d, 9U-8.7 Hz, 2 H), 6.82 (dd, U-8.5, 2.2 Hz, 1 N), 6.98 (d, 9-22 Hz, 1 N), 7.22 - 1.28 (m, 2 N), 7.32 (d, 98.5 Hz, 1 N).

Example A29 3-((4-(cyclohexyl(2-ethyl-1-benzofuran-3-yl)methylamino)phenyl)carbonylamino)propanoic acid (F)

N

M

Her n

Gee)

Using 3-(chloro(cyclohexyl)methyl|-2-ethyl-1-benzofuran (300 mg) synthesized in Example A26(2) and ethyl 3-((4-aminophenyl)carbonyl|amino)propanoate (255 mg) , synthesized in Example 1(2), and in the same manner as in Example A22(4), afforded the title compound (374 mg, 7790) as a pale brown solid. "H NMR (300 MHz, SOCI ») b m.p. 0.92 - 1.23 (m, 5 N), 1.27 (t, 9U-7.5 Hz, Z H), 1.55 - 1.74 (m,

With H), 1.76 - 1.97 (m, 2 H), 2.04 - 2.15 (m, 1 H), 2.56 - 2.66 (m, 2 H), 2.71 - 2.92 (m, 2 N), 3.56 - 3.66 (m, 2 N), 4.31 (d, 9-7.9 Hz, 1 N), 6.48 (d, 9-8 .7 Hz, 2 N), 6.52 - 6.62 (m, 1 N), 7.11 - 7.22 (m, 2 N), 7.34 - 7.40 (m, 1 N), 7.47 (d, 928.7 Hz, 2 N), 7.52 - 7.57 (m, 1 N).

Example of AZO 3-((4-(cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid ra i; Sht, what else?

І |! She and On 0 ra on U

K- her ХО хи , ud - 0

Using 2-Ichloro(cyclohexyl)methyl|-5-methoxy-33-methyl-1-benzofuran (395 mg) synthesized in Example A27(4) and ethyl 3-(4-aminophenyl)carbonyl|amino)propanoate (319 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4) afforded the title compound (413 mg, 66905) as a white solid. "H NMR (300 MHz, SOSIz") 6 m.h. 0.92 - 1.36 (m, 5 N), 1.46 - 1.58 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.01 - 2.13 (m, 1 H), 2.22 (s, C H), 2.61 (t, 955.9 Hz, 2 H), 3.57 - 3.67 ( m, 2 N), 3.82 (s, C H), 4.37 (d, 9U-8.0 Gu, 1 H), 6.55 (d, 9-8.7 Hz, 2 H), 6.61 (t, 9U-6.1 Gu, 1 H), 6.81 (dd, 9-9.1, 2.7 Hz, 1 H), 6.87 (d, 952.3 Hz, 1 H), 7.21 - 7.28 (m, 1 H), 7.52 (d, 9U-8.7 Hz, 2 H).

Example АЗ1 3-4(4-(1-(3-ethyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonyl(methyl)amino)propanoic acid and its derivative

Ken se ply 7 U ha-e (1) methyl 3-ethyl-1-benzofuran-2-carboxylate

Potassium carbonate (18.4 g) was added to a mixture of 1-(2-hydroxyphenyl)propan-1-one (10.0 g), methyl bromoacetate (5.11 mL), and acetone (100 mL), and the mixture was stirred overnight at room temperature. temperature The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, volume ratio) to obtain a colorless oil.

To a solution (150 ml) of the obtained oil in M,M-dimethylformamide was added 1,8-diazabicycloi|5.4.Fundec-7-ene (8.12 ml) and the mixture was stirred at 120 "C for 2 h. To quench the reaction, 1M was added hydrochloric acid and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue, the 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-1:9, v/v) to give the title compound (7.14 g, 52905) as a white solid. "H NMR (300 MHz, SOSI") b m.ch. 1.31 (t, 9U-7.5 Hz, 4 H), 3.12 (k, U-7.5 Hz, 2 H), 3 .99 (c, Z

H), 7.27 - 7.34 (m, 1 H), 7.41 - 7.49 (m, 1 H), 7.53 - 7.58 (m, 1 H), 7.65 - 7 .70 (m, 1 N). (2) 3-ethyl-1-benzofuran-2-carbaldehyde

Using methyl 3-ethyl-1-benzofuran-2-carboxylate (3.00 g) synthesized above and in the same manner as in Example A27(2) gave the title compound (2.27 g, 9095) , like brown butter. "H NMR (300 MHz, SOSI") b m.p. 1.40 (t, 9U-7.6 Hz, Z H), 3.12 (k, 9U-7.6 Hz, 2 H), 7 .30 - 7.37 (m, 1 N), 7.48 - 7.60 (m, 2 N), 7.71 - 7.76 (m, 1 N), 10.04 (s, 1 N) (3) 1-(3-ethyl-1-benzofuran-2-yl)-3-methylbutan-1-ol

A 1.0M tetrahydrofuran solution of isobutylmagnesium bromide (19.5 ml) was added dropwise to a solution (50 ml) of 33-ethyl-1-benzofuran-2-carbaldehyde (2.27 g) synthesized above in tetrahydrofuran at 0"C and a mixture stirred for 1 g. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-3:17 v/v) to give the title compound (1.55 g, 5195) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.94 (d, 9-6.6 Hz, Z H), 0.96 (d, 9U-6.6 Hz, Z H), 1.28 (t, uUE7.5 Hz, Z H), 1 .56 - 1.73 (m, 1 N), 1.74 - 1.86 (m, 2 N), 1.88 - 1.99 (m, 1 N), 2.74 (k, 957.5 Hu, 2 H), 4.91 - 4.99 (m, 1 H), 7.18 - 7.31 (m, 2 H), 7.41 - 7.47 (m, 1 H), 7, 50 - 7.56 (m, 1 N). (4) 2-(1-chloro-3-methylbutyl)-3-ethyl-1-benzofuran

Using 1-(3-ethyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (1.00 g), synthesized above, and in the same manner as in Example A1(2), the indicated in title compound (1.03 g, 96905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.92 - 0.97 (m, 6 N), 1.29 (t, 9-7.5 Hz, Z H), 1.60 - 1.75 (m, 1 N), 2.14 - 2 .21 (m, 2 N), 2.73 (k, 957.5 Hz, 2 N), 5.22 (t, 928.0 Hz, 1 N), 7.19 - 7.33 (m, 2 H), 7.A1 - 7.48 (m, 1 H), 7.51 - 7.55 (m, 1 H). (5) 3-4(4-(1-(3-ethyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Using 2-(1-chloro-3-methylbutyl)-3-ethyl-1-benzofuran (300 mg) synthesized above and ethyl 3-(|(4-aminophenyl)carbonyl|(methyl)amino)propanoate (300 mg ), synthesized in

Example 2(2), and in the same manner as in Example A22(4), obtained the title compound (97.4 mg, 19905) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.92 (d, U-6.6 Hz, Z H), 1.00 (d, 9U-6.4 Hz, Z H), 1.27 (t, 97.6 Gu, Z H), 1 .51 - 1.69 (m, 1 H), 1.82 - 1.89 (m, 2 H), 2.60 - 2.70 (m, 2 H), 2.77 (k, U-7 ,6 Hu, 2 H), 3.02 (s, C H), 3.69 (t, 96.4 Hz, 2 H), 4.72 (t, de7.5 Hz, 1 H), 6, 58 (d, 9-8.7 Hz, 2 N), 7.15-7.28 (m, 4 N), 7.36 - 7.42 (m, 1 N), 7.47 - 7.52 (m, 1 N).

Example AZ32

3-Imethyl(4-3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|Iamino)propanoic acid. (1) 3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butan-1-one

Aluminum (III) chloride (8.98 g) was added to a mixture of 3-methyl-1-benzothiophene (5.00 g), isovaleryl chloride (4.52 ml) and nitromethane (50 ml) at 0"C, the mixture was stirred at 0 " for 30 min and then at room temperature for 4 h. The reaction mixture was poured into ice-cooled water and the mixture was extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:19, v/v) to give the title compound (7.72 g, 99905) as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.03 (d, U-6.8 Hz, 6 N), 2.28 - 2.43 (m, 1 N), 2.77 ( s, Z H), 2.80 (d, 97.0 Hz, 2 H), 7.39 - 7.53 (m, 2 H), 7.81 - 7.90 (m, 2 H). 2) methyl 4-1|3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|aminophenzoate

Using 3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butan-1-one (1.00 g), synthesized above, and in the same manner as in Example A23(3), the indicated title compound (923 mg, 5895) as a pale brown solid.

"H NMR (300 MHz, SOSIZ") b m.p. 0.98 (d, U-6.0 Hz, Z H), 1.02 (d, 9U-6.0 Hz, Z H), 1 .68 - 1.81 (m, 2 H), 1.81 - 1.95 (m, 1 H), 2.47 (c, C H), 3.80 (c, C H), 4.40 - 4.47 (m, 1 N), 4.86 - 4.95 (m, 1

H), 6.54 (d, 98.1 Hz, 2 H), 7.23 - 7.30 (m, 1 H), 7.32 - 7.39 (m, 1 H), 7.62 - 7.67 (m, 2 N), 7.69 - 7.74 (m, 1 N), 7.79 (d, 958.1 Hz, 2 N). (3) 4-3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)benzoic acid

Using methyl 4-1|3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)benzoate (923 mg) synthesized above and in the same manner as in Example A23(4) , afforded the title compound (817 mg, 92905) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 0.98 (d, U-6.2 Hz, Z H), 1.02 (d, 9-6.2 Hz, Z H), 1.67 - 1.96 (m, Z H), 2, 47 (s, Z H), 4.88 - 4.96 (m, 1 H), 6.55 (d, 9-8.9 Hz, 2 H), 7.23 - 7.30 (m, 1 H), 7.32 - 7.39 (m, 1 H), 7.62 - 7.68 (m, 1 H), 7.69 - 7.74 (m, 1 H), 7.84 (d , 958.9 Hz, 2 N). (4) 3-Imethyl|(4-III-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid

Using 4-13-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|aminodibenzoic acid (300 mg) synthesized above and ethyl 3-(methylamino)propanoate (134 mg) and the same as in Example A1(4), the title compound (218 mg, 59905) was obtained as a white solid. "H NMR (300 MHz, SOSI") b m.p. 0.98 (d, 9U-6.2 Hz, Z H), 1.02 (d, 9-6.2 Hz, Z H), 1 .66 - 1.94 (m, C H), 2.46 (s, C H), 2.62 - 2.72 (m, 2 H), 3.02 (s, C H), 3.70 (t, 9U-6.4 Gu, 2 H), 4.82 - 4.89 (m, 1 H), 6.54 (d, 9-8.7 Hz, 2 H), 7.20 - 7 .31 (m, Z H), 7.32 - 7.39 (m, 1 H), 7.65 (d, 957.9 Hz, 1 H), 7.72 (d, UE7, З Hz, 1 N).

Example of AZZ 3-4(4-((3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid about TSO) solution A catch

Ky p ry Hi «i v

Ku or Ii

Using 4-13-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|aminodobenzoic acid (300 mg) synthesized in Example AZ2(3) and in the same manner as in Example

A1(4) afforded the title compound (316 mg, 8895) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 0.97 (d, 9U-6.0 Hz, Z H), 1.01 (d, 9U-6.2 Hz, Z H), 1 .66 - 1.94 (m, Z H), 2.46 (s, Z H), 2.61 (t, 95.7 Hz, 2 H), 3.57 - 3.67 (m, 2 H ), 4.83 - 4.91 (m, 1 H), 6.50 - 6.62 (m, Z H), 7.22 - 7.29 (m, 1 H), 7.31 - 7, 38 (m, 1 N), 7.51 (d, 9U-8.7 Hz, 2 N), 7.64 (d, 957.5

Hu, 1 N), 7.70 (d, 97.9 Hz, 1 N).

Example AZ34 3-4(4-(1-(3-ethyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonyl|Iamino)propanoic acid 8) solution of XX. - g And what Sh

Using 2-(1-chloro-3-methylbutyl)-3-ethyl-1-benzofuran (300 mg), synthesized in Example AZ1(4), and ethyl 3-((4-aminophenyl)carbonylaminoisopropanoate (283 mg),

synthesized in Example 1(2), and in the same manner as in Example A22(4), afforded the title compound (162 mg, 32905) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9-6.6 Hz, Z H), 1.00 (d, 9U-6.6 Hz, Z H), 1.27 (t, uUE7.5 Hz, Z H), 1 .51 - 1.68 (m, 1 N), 1.81 - 1.90 (m, 2 N), 2.58 - 2.68 (m, 2 N), 2.76 (k, 957.5 Hu, 2 H), 3.58 - 3.68 (m, 2 H), 4.73 (t, 957.5 Hz, 1 H), 6.54 - 6.63 (m, C H), 7 .14 - 7.26 (m, 2 H), 7.35 - 7.40 (m, 1 H), 7.46 - 7.51 (m, 1 H), 7.54 (d, 9-8 .7 Hz, 2 N).

Example АЗ5 3-((4-(cyclohexyl(b-methoxy-1-benzofuran-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid of 5 y; sh

Using 4-ylcyclohexyl(b-methoxy-1-benzofuran-2-yl)methylamino)benzoic acid (102 mg) synthesized in Example A28(4) and in the same manner as in Example

A1(4), afforded the title compound (40.0 mg, 3395) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.35 (m, 5 N), 1.54 - 1.84 (m, 4 N), 1.84 - 1.99 (m, 2

H), 2.55 - 2.68 (m, 2 H), 3.56 - 3.69 (m, 2 H), 3.82 (s, C H), 4.36 (d, 9U-6 ,4 Hz, 1 H), 6.42 (s, 1 H), 6.51 - 6.66 (m, C H), 6.81 (dd, 9)-8.5, 2.1 Hz, 1 N), 6.97 (d, 9-2.1 Hz, 1 N), 7.31 (d, 9-8.5 Hz, 1

H), 7.53 (d, U-8.3 Hz, 2 H).

Example AZb 3-4(6-(3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridin-3-yl)ucarbonyl|Iamino)propanoic acid ki nai syt yin shi still; (1) methyl 6-13-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridine-3-carboxylate

To the mixture of 3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butan-1-one (1.00 g), synthesized in

Titanium chloride (IM) (566 μl) was added to Example AZ2(1), methyl b-aminopyridine-3-carboxylate (654 mg), triethylamine (4.79 ml) and dichloromethane (20 ml) at 0"C, and the mixture was stirred for overnight at room temperature.To quench the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown solid. Sodium cyanoborohydride (540 mg) was added to the mixture of the obtained solid, acetic acid (2 ml) and tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 2 h. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, volume ratio) to give a pale brown solid. To the mixture of the obtained solid substance,

of trifluoroacetic acid (1.00 ml) and ethanol (10 ml) was added sodium cyanoborohydride (251 mg) and the mixture was stirred at room temperature for 1 h. Sodium cyanoborohydride (251 mg) was also added and the mixture was stirred at room temperature for

30 min and then at 50 "C for 1 h. A saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (743 mg, 4790), as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.98 (d, 9U-6.3 Hz, Z H), 1.01 (d, 9U-6.3 Hz, Z H), 1.64 - 1.96 (m, Z H), 2, 48 (s, Z H), 3.83 (s, Z H), 5.25 - 5.40 (m, 2 H), 6.28 (d, 9-8.7 Hz, 1 H), 7 .24 - 7.39 (m, 2 H), 7.61 - 7.66 (m, 1 H), 7.71 - 7.76 (m, 1 H), 7.91 (dd, 9U-8 ,7, 2.0 Gu, 1 N), 8.73 (d, 9-20 Hz, 1

N). (2) 6-3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridine-3-carboxylic acid

Using methyl 6-|3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridin-

The 3-carboxylate (743 mg) synthesized above and in the same manner as in Example A23(4) afforded the title compound (236 mg, 33905) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.90 - 0.99 (m, 6 H), 1.58 - 1.78 (m, 2 H), 1.81 - 1.95 (m, 1

H), 2.44 (s, C H), 5.51 - 5.64 (m, 1 H), 6.53 (d, 9-8.7 Hz, 1 H), 7.24 - 7, 38 (m, 2 N), 7.67 (d, 98.1 Hz, 1 N), 7.73 - 7.92 (m, Z H), 8.50 (d, 9-24 Hz, 1 N ), 12.29 (shs, 1 N). (3) 3-1(6-(3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridin-3-yl)ucarbonyl|Iamino)propanoic acid

Using 6-13-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridine-3-carboxylic acid (115 mg) synthesized above and in the same manner as in Example

A1(4), afforded the title compound (112 mg, 8195) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.98 (d, 9U-6.0 Hz, Z H), 1.03 (d, 9-6.2 Hz, Z H), 1.71 - 1.85 (m, 2 H), 1, 95 - 2.11 (m, 1 H), 2.49 (s, C H), 2.57 - 2.67 (m, 2 H), 3.67 - 3.79 (m, 2 H), 4.86 - 4.98 (m, 1 N), 6.48 (d, 2-9.2 Hz, 1 N), 7.24 - 7.33 (m, 1 N), 7.33 - 7 .41 (m, 1 H), 7.61 - 7.75 (m, Z H), 8.10 - 8.20 (m, 2 H), 8.87 - 8.97 (m, 1 H) .

Example АЗ7 3-(1(4-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

IS

(1) 3-fluoro-M-methoxy-M,3-dimethyl-1-benzofuran-2-carboxamide

To a mixture of /1-(5-fluoro-2-hydroxyphenyl)ethanone (10.0 g), 2-chloro-M-methoxy-M-methylacetamide (9.82 g), sodium iodide (19.5 g) and M Potassium carbonate (18.0 g) was added to M-dimethylformamide (200 ml) and the mixture was stirred at 80 C overnight. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a brown solid. 1,8-diazabicycloi|5.4.Fundec-7-ene (9.71 ml) was added to a solution (200 ml) of the obtained solid in M,M-dimethylformamide, and the mixture was stirred at 120 "C for 4 h. To quench the reaction, added 1M hydrochloric acid and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel

(ethyl acetate:hexane-1:3, v/v) to give the title compound (4.37 g, 2895) as a brown oil.

IN NMR (300 MHz, SOSI") 6 m.h. 2.47 (s, Z H), 3.38 (s, Z H), 3.86 (s, Z H), 6.98 - 7.16 (m, 1

H), 7.21 - 7.27 (m, 1 H), 7.37 - 7.43 (m, 1 H). (2) cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanol

To a solution (80 ml) of 5-fluoro-M-methoxy-M,3-dimethyl-1-benzofuran-2-carboxamide (4.37 g) synthesized above in tetrahydrofuran was added dropwise at 0"C with 1.5 M toluene diisobutylaluminum hydride solution (24.5 ml) and the mixture was stirred for 1 h.

1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:9, volume ratio) to give a pale brown solid. A 1.0 M tetrahydrofuran solution of cyclohexylmagnesium bromide (21.8 ml) was added dropwise to a solution (50 ml) of the obtained solid in tetrahydrofuran at 0 C, and the mixture was stirred for 1 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-3:17, v/v) to give the title compound (1.32 g, 27905) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.85 - 1.43 (m, 6 H), 1.61 - 1.71 (m, 2 H), 1.75 - 1.98 (m, Z

H), 2.09 - 2.21 (m, 4 H), 4.51 (dd, 2U-8.4, 6.0 Hz, 1 H), 6.92 - 7.00 (m, 1 H ), 7.08 - 7.13 (m, 1 N), 7.30 - 7.36 (m, 1 N). (3) 2-(chloro(cyclohexyl)methyl|-5-fluoro-3-methyl-1-benzofuran

Using cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanol (1.01 g) synthesized above, and in the same manner as in Example A11(3), the title compound was obtained (900 mg, 8395) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.83 - 1.40 (m, 5 N), 1.40 - 1.50 (m, 1 N), 1.60 - 1.72 (m, 2

H), 1.77 - 1.88 (m, 1 H), 2.10 - 2.25 (m, 4 H), 2.28 - 2.38 (m, 1 H), 4.79 (d , 9-9.6 Hz, 1 N), 6.96 - 7.04 (m, 1 N), 7.09 - 7.14 (m, 1 N), 7.34 - 7.39 (m, 1 H). (4) 3-1(4-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Using 2-Ichloro(cyclohexyl)methyl|-5-fluoro-3-methyl-1-benzofuran (400 mg) synthesized above and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (355 mg ), synthesized in Example 2(2), and in the same manner as in Example A22(4), afforded the title compound (303 mg, 46905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.37 (m, 5 N), 1.45 - 1.56 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.22 (s, C H), 2.64 (t, 9U-6.5 Hz, 2 H), 3.02 (s, With H), 3.69 (t, U-6.5 Hz, 2

N), 4.36 (d, 2-7.9 Hz, 1 N), 6.55 (d, 2-8.7 Hz, 2 N), 6.88 - 6.97 (m, 1 N) , 7.07 (dd, 9U-8.5, 2.6 Gu, 1 H), 7.23 (d, 2-8.7 Hz, 2 H), 7.25 - 7.31 (m, 1 N).

Example of AZ8

Z-Imethyl(6-((Z-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridin-3-yl)ucarbonyl|Iamino)propanoic acid 8. G pt I pe y shi shk;

And zeeeestosge, y

Using 6-13-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|amino)pyridine-3-carboxylic acid (121 mg), synthesized in Example AZb(2), and ethyl 3- ( methylamino)propanoate (67.2 mg) and in the same manner as in Example A1(4) gave the title compound (115 mg, 77905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.97 (d, 9U-6.2 Hz, Z H), 1.01 (d, 9U-6.4 Hz, Z H), 1.67 - 1.86 (m, 2 H), 1, 93 - 2.08 (m, 1 H), 2.47 (s, C H), 2.62 - 2.71 (m, 2 H), 3.08 (s, C H), 3.67 - 3.84 (m, 2

H), 4.84 - 4.95 (m, 1 H), 6.35 (d, U-8.9 Hz, 1 H), 7.24 - 7.31 (m, 1 H), 7, 32 - 7.39 (m, 1 H), 7.51 - 7.59 (m, 1 H), 7.64 (d, 9U-7.7 Hz, 1 H), 7.73 (d, 9 -7.7 Hz, 1 N), 8.05 - 8.17 (m, 1 N).

Example AZ9 3-(1(4-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

N o

M tn

IS

Using 2-Ichloro(cyclohexyl)methyl|-5-fluoro-3-methyl-1-benzofuran (400 mg), synthesized in Example AZ7(3), and ethyl 3-((4-aminophenyl)carbonyl|amino)propanoate ( 336 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4) afforded the title compound (321 mg, 5095) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.91 - 1.36 (m, 5 N), 1.43 - 1.56 (m, 1 N), 1.59 - 1.95 (m, 4

H), 2.00 - 2.12 (m, 1 H), 2.20 (s, C H), 2.59 (t, 9U-5.7 Hz, 2 H), 3.55 - 3, 67 (m, 2 H), 4.37 (d, 9-81

Hz, 1 N), 6.54 (d, 9U-8.8 Hz, 2 N), 6.71 (t, 9U-6.0 Hz, 1 N), 6.87 - 6.95 (m, 1 N), 7.05 (dd, 9U-8.5, 2.4 Hz, 1 N), 7.21 - 7.30 (m, 1 N), 7.52 (d, U-8.8 Hz, 2 N).

Example A40 3-D4-Hcyclohexyl(b-trifluoromethyl)imidazo|1,2-a|pyridin-2-yl|methyl)iamino)phenyl(carbonylmethyl)amino|propanoic acid 6)

M: and m

IS

IS

IS

(1) 6-(trifluoromethyl)imidazo(|1,2-a|Ipyridine-2-carbaldehyde

To a solution of 5-trifluoromethyl)pyridin-2-amine (12.9 g) dissolved in dimethoxyethane (150 ml) at room temperature was added 1,1,3-trichloroacetone (12.7 ml) and the mixture was stirred overnight. The solid precipitate was collected and suspended in ethanol (50 ml) and the mixture was heated under reflux for 3 h. After spontaneous cooling to room temperature, the solvent was evaporated under reduced pressure, saturated aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with ethyl acetate-tetrahydrofuran (1: 11, volume ratio). The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane-1:2, volume ratio) to give /2-(dichloromethyl)-6 - (trifluoromethyl)imidazo|1,2-α|pyridine (10.3 g) as a white solid. The resulting solid was suspended in a mixed solvent of water (100 mL) and tetrahydrofuran (20 mL) and added to the mixture at room temperaturecalcium carbonate (8.0 g) and the mixture was stirred at 100 C for 1 h. The mixture was allowed to cool to room temperature, the insoluble material was filtered off and the filtrate was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. The residue was washed with diisopropyl ether to give the title compound (7.3 g, 4390) as white crystals. "H NMR (300 MHz, SOSI"v) b m.p. 7.43 (d, 9U-9.8 Hz, 1 H), 7.82 (d, 9-9.8 Hz, 1H), 8 ,26 (c, 1

H), 8.58 (s, 1 H), 10.19 (s, 1 H). (2) cyclohexylIb-(trifluoromethyl)imidazo|1,2-a|Ipyridin-2-yl|methanol

Cyclohexylmagnesium bromide (1M tetrahydrofuran solution, 15 After stirring at 0"C for 1 g, an aqueous solution of ammonium chloride was added. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure. The precipitate was washed with ethanol-diisopropyl ether to give the title compound (0.9 g, 30905) as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 1.01 - 1.96 (m, 11 N), 2.43 (d, 9-6.1 Hz, 1 N), 4.66 ( t, 9U-5.9 Hz, 1 H), 7.31 (d, 9-9.8 Hz, 1 H), 7.59 (s, 1 H), 7.66 (d, U-9, 8 Hz, 1 H), 8.46 (s, 1 H). (3) 3-D4-Hcyclohexyl(Ib-«(trifluoromethyl)imidazo|1,2-a|pyridin-2-yl|methyl)amino) phenylIcarbonylXmethyl)amino|propanoic acid

Using cyclohexylIb-(trifluoromethyl)imidazo(|1,2-a|Ipyridin-2-yl|methanol (1.1 g) synthesized above and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (0.94 g) synthesized in Example 2(2), and in the same manner as in Example 4, the title compound (3.0 mg, 2905) was obtained as an oil.

IN NMR (300 MHz, SOSI") b m.h. 0.98 - 2.16 (m, 11 N), 2.50 - 2.75 (m, 2 N), 3.06 (s, Z H), 3.10 - 3.25 (shs, 1 N ), 3.61 - 3.82 (m, 2 N), 4.43 (d, 9-6.0 Hz, 1 N), 6.54 (d, 2-9.0 Hz, 2 N), 7.16 (d, 9U-9.0 Hu, 2 H), 7.45 (d, 9-9.0 Hu, 1 H), 7.63 (c, 1 H), 7.84 (d, 2-9.0 Hz, 1 N), 8.53 (s, 1 N).

Example A41 3-((4-(cyclohexyl(3-methyl-1-benzofuran-2-yl)umethyl|iamino)phenyl)carbonyl|(methyl)amino)propanoic acid o sh o M Sn.

H sn,

Ethyl 3-((4-1-cyclohexyl(3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate (9.85 g), synthesized in Example

A16, separated using high-performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by Oaisei Spetis! Ipdivihiev, Ts., mobile phase: hexane/ethanol (500/500), flow rate: 60 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a shorter retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (4.85 g, 99.995 ee). 1M lithium hydroxide (22 ml) was added to a mixture of the obtained amorphous form, ethanol (20 ml) and tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (20 mL) was added at 0 "C. The resulting precipitate was collected by filtration to give the title compound (4.41 g, 97905.99.995 ee) as a white solid. A white solid (50 mg) was crystallized from ethanol/water to give ethanol-containing crystals (41 mg).The ethanol-containing crystals (35 mg) were recrystallized from diethyl ether to give colorless crystals (18 mg) free of solvent.

IN YAMRE (300 MHz, DMSO-av) 6 m.h. 0.97 - 1.28 (m, 5 N) 1.30 - 1.39 (m, 1 N) 1.52 - 1.81 (m,

With H) 1.81 - 2.00 (m, 1 H) 2.03 - 2.18 (m, 1 H) 2.26 (s, With H) 2.40 - 2.49 (m, 2 H ) 2.88 (s, C H) 3.50 (t, 9-7.38 Hz, 2 H) 4.41 (t, 2U-8.33 Hz, 1 H) 6.48 (d, 2- 7.95 Hz, 1 N) 6.60 (d, 2-8.71 Hz, 2 N) 7.09 (d, U-8.33 Hz, 2 N) 7.14 - 7.29 (m, 2 N) 7.36 - 7.55 (m, 2 N) 12.27 (shs, 1 N).

Example A42 3-((4-(cyclohexyl(3-methyl-1-benzofuran-2-yl)umethyl|iamino)phenyl)carbonyl|(methyl)amino)propanoic acid

Ethyl 3-((4-1-cyclohexyl(3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate (9.85 g), synthesized in Example

A16 was separated using high performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by OaiseI Spetis! Ipdivihiev, Ts., mobile phase: hexane/ethanol (500/500), flow rate: 60 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (4.81 g, 99.995 ee). A 1M aqueous solution of lithium hydroxide (22 ml) was added to a mixture of the obtained amorphous form, ethanol (20 ml) and tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (20 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (4.43 g, 9895.99.995 ee) as a white solid.

IN NMR (300 MHz, DMSO-av) 6 m.h. 0.97 - 1.28 (m, 5 N) 1.30 - 1.39 (m, 1 N) 1.52 - 1.81 (m,

With H) 1.81 - 2.00 (m, 1 H) 2.03 - 2.18 (m, 1 H) 2.26 (s, With H) 2.40 - 2.49 (m, 2 H ) 2.88 (s, C H) 3.50 (t, 9-7.38 Hz, 2 H) 4.41 (t, 2U-8.33 Hz, 1 H) 6.48 (d, 2- 7.95 Hz, 1 N) 6.60 (d, 2-8.71 Hz, 2 N) 7.09 (d, U-8.33 Hz, 2 N) 7.14 - 7.29 (m, 2 N) 7.36 - 7.55 (m, 2 N) 12.27 (shs, 1 N).

Example A4Z3 3-((4-(cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid o

Hol o M sn, yn sn, ne-a (1)4-Icyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methyl|amino)benzoic acid

To the mixture of 2-Ichloro(cyclohexyl)methyl|-5-methoxy-3-methyl-1-benzofuran (748 mg) synthesized in Example A27(4), methyl 4-aminobenzoate (385 mg), sodium iodide (764 mg) and

Sodium carbonate (541 mg) was added to M,M-dimethylformamide (15 ml) and the mixture was stirred at 80 C overnight. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2595 ethyl acetate/hexane) to give a yellow oil. A 1M aqueous solution of sodium hydroxide (20 ml) was added to the mixture of the obtained oil, tetrahydrofuran (20 ml) and ethanol (20 ml), and the mixture was stirred under reflux for 5 g and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and 1M hydrochloric acid (20 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (745 mg, 74905) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.37 (m, 5 N), 1.47 - 1.58 (m, 1 N), 1.61 - 1.98 (m, 4

H), 2.02 - 2.12 (m, 1 H), 2.24 (s, C H), 3.83 (s, C H), 4.42 (d, 90-7.9 Hz, 1 H), 6.57 (d, U-8.9 Hz, 2

H), 6.83 (dd, U-8.8, 2.5 Hz, 1 H), 6.88 (d, 9-2.5 Hz, 1 H), 7.26 (d, U-8 .8 Hz, 1 N), 7.85 (d, 9U-8.9

Hz, 2 N). (2) ethyl 3-((4-1-cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

To the mixture of 4-Icyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)methylIaminobbenzoic acid (745 mg) synthesized above, ethyl 3-(methylamino)propanosate (298 mg), 1-hydroxybenzotriazole monohydrate (348 mg), triethylamine (633 μl) and N,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg) and the mixture was stirred at room temperature overnight and then at 5070 for 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55950 ethyl acetate/hexane) to give the title compound (801 mg, 84905) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.35 (m, 8 N), 1.47 - 1.60 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.02 - 2.14 (m, 1 H), 2.22 (s, With H), 2.61 (t, 9U-7.0 Hz, 2 H), 3.01 (s, With H), 3.70 (t, U9-7.0 Hz, 2

H), 3.84 (s, C H), 4.07 - 4.17 (m, 2 H), 4.30 - 4.40 (m, 2 H), 6.56 (d, 2-8 .7 Hz, 2 N), 6.82 (dd, y-8.9, 2.6 Hz, 1 N), 6.88 (d, 9U-2.6 Hz, 1 N), 7.18 - 7.30 (m, Z H). (3) 3-(S(4-Yacyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Ethyl 3-((4-Ncyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)aminoisopropanoate (795 mg), synthesized above, was separated by high-performance liquid chromatography ( column: SNICAG RAK

Ar (50 mm Hx500 mm D, manufactured by OaiseI Spetis! Ipaivigie5, Ts., mobile phase: hexane/ethanol (400/600), flow rate: 60 ml/min, column temperature: 30 "C). Fractions containing optically the active form, which has a shorter retention time under the conditions of high-performance chromatography mentioned above, was concentrated to give the amorphous form (413 mg, 99.995 ee).To a mixture of the obtained amorphous form, ethanol (5 mL), and tetrahydrofuran (5 mL), 1M aqueous sodium hydroxide was added (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1M hydrochloric acid (2.00 ml) was added at 0"C.

The resulting precipitate was collected by filtration to afford the title compound (355 mg, 47905, 99.995 ee) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.47 - 1.57 (m, 1 N), 1.60 - 1.96 (m, 4

H), 2.03 - 2.13 (m, 1 H), 2.23 (s, C H), 2.65 (t, 9U-6.4 Hz, 2 H), 3.02 (s, With H), 3.69 (t, U-6.4 Hz, 2

H), 3.83 (s, C H), 4.36 (d, 9-8.0 Hz, 1 H), 6.55 (d, 9U-8.7 Hz, 2 H), 6.82 (dd, 9U-8.9, 2.4 Hz, 1 H), 6.88 (d, 9-2.4 Hz, 1 H), 7.19 - 7.29 (m, C H).

Example A44 3-((4-(cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid,

In

SN" no-oh

Ethyl 3-((4-cyclohexyl(5-methoxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoate (795 mg), synthesized in Example

A43(2) was separated using high performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by Oaisei! Spetisa! Ipadiviyev, Ts., mobile phase: hexane/ethanol (400/600), flow rate: 60 ml/min, column temperature: "C). Fractions containing the optically active form, which has a longer retention time under the above-mentioned high-performance chromatography conditions, was concentrated to give the amorphous form (418 mg, 99.995 ee).To a mixture of the obtained amorphous form, ethanol (5 mL), and tetrahydrofuran (5 mL), 1 M aqueous hydroxide solution was added sodium (2.00 ml), the mixture was stirred at room temperature for 1.5 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrochloric acid (2.00 ml) was added at 0 "C. The resulting precipitate was collected by filtration to give the title compound (354 mg, 47905.99.995 ee) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.47 - 1.57 (m, 1 N), 1.60 - 1.96 (m, 4

H), 2.03 - 2.13 (m, 1 H), 2.23 (s, C H), 2.65 (t, 9U-6.4 Hz, 2 H), 3.02 (s, With H), 3.69 (t, U-6.4 Hz, 2

H), 3.83 (s, C H), 4.96 (d, U-8.0 Hz, 1 H), 6.55 (d, U-8.7 Hz, 2 H), 6.82 (dd, U-8.9, 2.4 Gu, 1 H), 6.88 (d, 9-2.4 Hz, 1 H), 7.19 - 7.29 (m, C H).

Example A45 3-(1(4-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid o

M pcs IN A DREAM! about SN,

Her k

CH,

IS

(1) 4-Icyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|iaminobenzoic acid

To the mixture of /2-(chloro(cyclohexyl)methyl|-5-fluoro-3-methyl-II-benzofuran (1.44 -/("Gg), synthesized in Example AZ7(3), methyl 4-aminobenzoate (776 mg ), sodium iodide (1.54 g) and

Sodium carbonate (1.09 g) was added to M,M-dimethylformamide (30 ml) and the mixture was stirred at 80 C overnight. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2095 ethyl acetate/hexane) to give a yellow solid. A 1 M aqueous solution of sodium hydroxide (20 ml) was added to a mixture of the obtained solid, tetrahydrofuran (20 ml) and ethanol (20 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure.

The residue was dissolved in water (40 ml) and 1 M hydrochloric acid (20 ml) was added at 0 "C.

The obtained precipitate was collected by filtration to obtain the target compound specified in the title

(1.06 g, 5495) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.37 (m, 5 N), 1.46 - 1.58 (m, 1 N), 1.60 - 1.99 (m, 4

H), 2.02 - 2.13 (m, 1 H), 2.23 (s, C H), 4.43 (d, 9U-8.0 Hz, 1 H), 4.51 - 4, 73 (m, 1 H), 6.57 (d,

U-8.7 Hz, 2 N), 6.87 - 6.98 (m, 1 N), 7.04 - 7.11 (m, 1 N), 7.24 - 7.32 (m, 1 H), 7.85 (d, 9-8.7 Hz, 2 H). (2) ethyl 3-((4-1-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

To the mixture of 4-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylaminobbenzoic acid (1.06 g) synthesized above, ethyl 3-(methylamino)propanoate (438 mg), monohydrate of 1- 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (640 mg) was added to hydroxybenzotriazole (512 mg), triethylamine (930 μl) and M,M-dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1.5 g . 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5590 ethyl acetate/hexane) to give the title the target compound (564 mg, 4195) as a white solid. "H NMR (300 MHz, SOSI") 6 ppm 0.93 - 1.37 (m, 8 H), 1.46 - 1.56 (m, 1 H), 1.61 - 1.98 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.22 (s, C H), 2.61 (t, 9U-7.0 Hz, 2 H), 3.01 (s, With H), 3.70 (t, U9-7.0 Hz, 2

H), 4.06 - 4.17 (m, 2 H), 4.28 - 4.41 (m, 2 H), 6.56 (d, 2-8.7 Hz, 2 H), 6, 88 - 6.97 (m, 1 N), 7.04 - 7.09 (m, 1 N), 7.22 (d, 9U-8.7 Hz, 2 N), 7.25 - 7.31 (m, 1 H). (3) 3-1(4-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Ethyl 3-((4-Ncyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)phenyl)carbonyl|(methyl)aminoisopropanoate (564 mg), synthesized above, was separated using a high-efficiency liquid chromatography (column: SNIKAG RAK

Ar (50 mm H x 500 mm D, manufactured by Oaise! Spetisa! Ipaivigie5, Ts., mobile phase: hexane/ethanol (400/600), flow rate: 60 ml/min, column temperature: 30 "C). Fractions containing the optically active form, which has a shorter retention time under the above-mentioned high-performance chromatography conditions, was concentrated to give the amorphous form (274 mg, 99.995 ee).To a mixture of the obtained amorphous form, ethanol (5 mL), and tetrahydrofuran (5 mL), 1 M aqueous hydroxide solution was added sodium (1.00 ml), the mixture was stirred at room temperature for 1.5 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1M hydrochloric acid (1.00 ml) was added at 0"C.

The resulting precipitate was collected by filtration to give the title compound (249 mg, 4795.99.995 ee) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.37 (m, 5 N), 1.45 - 1.56 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.22 (s, C H), 2.64 (t, 9U-6.5 Hz, 2 H), 3.02 (s, With H), 3.69 (t, U-6.5 Hz, 2

H), 4.36 (d, 2-7.9 Hz, 1 H), 6.55 (d, U-8.7 Hz, 2 H), 6.88 - 6.97 (m, 1 H) , 7.07 (dd, 9U-8.5, 2.6 Gu, 1 H), 7.23 (d, 2-8.7 Hz, 2 H), 7.25 - 7.31 (m, 1 N).

Example A46 3-(1(4-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid (F) then about M Sn. N

CH,

IS

Ethyl 3-((4-Hycyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-

yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoate (564 mg), synthesized in Example

A45(2) was separated using high performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm H x 500 mm D, manufactured by Oaise! Spetisa! Ipdivigiev, Ts., mobile phase: hexane/ethanol (400/600), flow rate: 60 ml/min, column temperature: "С). Fractions containing the optically active form, which has a longer retention time under the above-mentioned high-performance chromatography conditions, was concentrated to give the amorphous form (273 mg, 99.995 ee).To a mixture of the obtained amorphous form, ethanol (5 mL), and tetrahydrofuran (5 mL), 1 M aqueous hydroxide solution was added sodium (1.00 ml), the mixture was stirred at room temperature for 1.5 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrochloric acid (1.00 ml) was added at 0 "C. The resulting precipitate was collected by filtration to give the title compound (248 mg, 47905, 99.9965 ee) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.37 (m, 5 N), 1.45 - 1.56 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.22 (s, C H), 2.64 (t, 9U-6.5 Hz, 2 H), 3.02 (s, With H), 3.69 (t, 9-6.5 Hz, 2

N), 4.36 (d, 9U-7.9 Hz, 1 N), 6.55 (d, 9-8.7 Hz, 2 N), 6.88 - 6.97 (m, 1 N) , 7.07 (dd, 9U-8.5, 2.6 Hz, 1), 7.23 (d, 98.7 Hz, 2 N), 7.25 - 7.31 (m, 1 N).

Example A47 3-(X4-Ccyclohexyl-5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylamino)propanoic acid (o) du

N o M / n o h

E CH, (1) methyl 5-fluoro-3-methyl-1-benzofuran-2-carboxylate

To a mixture of 1-(5-fluoro-2-hydroxyphenyl)ethanone (100 g), methyl bromoacetate (67.6 ml) and

Potassium carbonate (135 g) was added to M,M-dimethylformamide (500 ml) and the mixture was stirred at 50"C for 2 h. The insoluble material was filtered off, 1,8-diazabicycloi|5.4.Fundec-7-ene (97.1 ml ) and the mixture was stirred at 120 °C for 30 min.

1M hydrochloric acid was added to the reaction mixture at 0"C and the resulting precipitate was collected by filtration to give the title compound (77.9 g, 58905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 2.56 (s, Z H), 3.99 (s, Z H), 7.14 - 7.22 (m, 1 H), 7.24 - 7.30 (m, 1 H), 7, 45 - 7.51 (m, 1 N). (2) methyl 3-(bromomethyl)-5-fluoro-1-benzofuran-2-carboxylate

M-bromosuccinimide (19.8 g) and 2,2-azobis (isobutyronitrile) (1.21 g) and the mixture was stirred under argon at 5070 for 2.5 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (20 - 3095 ethyl acetate/hexane) to give a white solid. The resulting solid was washed with hexane to give the title compound (15.1 g, 71905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 4.02 (s, Z H), 4.96 (s, 2 H), 7.18 - 7.27 (m, 1 H), 7.41 - 7.47 (m, 1 H), 7, 49 - 7.55 (m, 1 N). (3) methyl 5-fluoro-3-(methoxymethyl)-1-benzofuran-2-carboxylate

To a solution (50 ml) of methyl 3-(bromomethyl)-5-fluoro-1-benzofuran-2-carboxylate (5.87 g), synthesized above, in methanol was added 2895 solution (8.33 ml) of sodium methoxide in methanol and the mixture was stirred under reflux with 3 g. 1M hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5090 ethyl acetate/hexane) to give the title compound (3.04 g, 63905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 3.44 (s, Z H), 3.99 (s, Z H), 4.99 (s, 2 H), 7.18 (td, 9-91, 2.7 Hz, 1 H), 7 .46 - 7.52 (m, 1 N), 7.53 - 7.58 (m, 1 N). (4) 5-fluoro-3-(methoxymethyl)-1-benzofuran-2-carbaldehyde

To a mixture of methyl 5-fluoro-3-(methoxymethyl)-1-benzofuran-2-carboxylate (5.01 g) synthesized above, calcium chloride (4.66 g), ethanol (50 ml) and tetrahydrofuran (50 ml) sodium borohydride (3.18 g) was added at 0"C and the mixture was stirred at room temperature for 3 h. A saturated aqueous solution of ammonium chloride was added until the reaction was quenched, the organic solvent was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a colorless oil. Tetrapropylammonium perruthenate (738 mg) was added to a mixture of the obtained oil, 4-methylmorpholine M-oxide (3.69 g) and acetonitrile (50 ml) at 0 "C, and the mixture was stirred for 1 .5 g and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-2095 ethyl acetate/hexane) to give the title compound (2.33 g, 53905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 3.49 (s, Z H), 4.94 (s, 2 H), 7.21 - 7.29 (m, 1 H), 7.47 - 7.54 (m, 2 H), 10, 08 (c, 1 N). (5) cyclohexyl(5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methanone

To a solution (20 ml) of 5-fluoro-3-(methoxymethyl)-1-benzofuran-2-carbaldehyde (1.07 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (7.71 ml) of cyclohexylmagnesium bromide in tetrahydrofuran at 0 "C and the mixture was stirred for 1 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction, tetrahydrofuran was evaporated on evaporators, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 - 5095 ethyl acetate/hexane) to give a pale yellow oil. Tetrapropylammonium perruthenate (126 mg) was added to a mixture of the obtained oil, 4-methylmorpholine M-oxide (841 mg) and acetonitrile (20 ml), and the mixture was stirred at room temperature for 1.5 g and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-2095 ethyl acetate/hexane) to give the title compound (857 mg, 57905) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 1.15 - 1.55 (m, 5 N), 1.69 - 1.80 (m, 1 N), 1.80 - 2.02 (m, 4

H), 3.25 - 3.39 (m, 1 H), 3.44 (s, C H), 5.00 (s, 2 H), 7.15 - 7.23 (m, 1 H) , 7.43 - 7.49 (m, 1 N), 7.57 - 7.62 (m, 1 N). (6) methyl 4-((cyclohexyl 5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)benzoate

To the mixture of cyclohexyl(5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methanone (857 mg) synthesized above, methyl 4-aminobenzoate (491 mg), triethylamine (3.29 ml) and methylene chloride ( 10 ml) titanium chloride (IM) (388 μl) was added and the mixture was stirred under an argon atmosphere at room temperature overnight. A saturated aqueous solution of sodium bicarbonate was added to quench the reaction, methylene chloride was evaporated on the evaporator and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran was added acetic acid (847 μL) and sodium cyanoborohydride (371 mgH) and the mixture was stirred at room temperature for 1 h. Before quenching to the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. alyshok was purified by column chromatography on silica gel (0 - 4095 ethyl acetate/hexane) to give the title compound (454 mg, 3695) as a pale brown oil "H NMR (300 MHz, SOCI") 6 ppm. 0.97 - 1.36 (m, 5 N), 1.43 - 1.54 (m, 1 N), 1.60 - 1.99 (m, 4

H), 2.00 - 2.11 (m, 1 H), 3.37 (s, C H), 3.81 (s, C H), 4.48 - 4.64 (m, 4 H) , 6.60 (d, 2-8.8 Hz, 2 N), 6.90 - 6.99 (m, 1 N), 7.17 - 7.23 (m, 1 N), 7.28 - 7.34 (m, 1 N), 7.79 (d, U-8.8 Hz, 2 N). (7). 4-Iacyclohexyl|5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyliamino)benzoic acid

To a mixture of methyl 4-((cyclohexylib5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)benzoate (454 mg), synthesized above, tetrahydrofuran (10 ml) and ethanol (10 ml) was added 1M aqueous sodium hydroxide solution (10.0 mL) and the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (10.0 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (423 mg, 9695) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.96 - 1.36 (m, 5 N), 1.40 - 1.55 (m, 1 N), 1.60 - 1.99 (m, 4

H), 1.99 - 2.13 (m, 1 H), 3.38 (s, C H), 4.49 - 4.77 (m, 4 H), 6.61 (d, 9-8 .8 Hz, 2 N), 6.90 - 6.99 (m, 1 N), 7.17 - 7.23 (m, 1 N), 7.28 - 7.35 (m, 1 N), 7.84 (d, 9U-8.8 Gu, 2 H). (8) ethyl 3-(C14-(cyclohexyl(5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylamino)propanoate

To the mixture of 4-((cyclohexylIb5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)iamino)benzoic acid (200 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (112 mg), monohydrate 1-Hydroxybenzotriazole (112 mg), triethylamine (203 μl) and N,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg) and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to give the title compound (207 mg, 8395) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.36 (m, 8 N), 1.42 - 1.54 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.01 - 2.13 (m, 1 H), 2.58 (t, 9-5.8 Hz, 2 H), 3.37 (s, C H), 3.61 - 3, 70 (m, 2 H), 4.13 (k, 9-57.1

Hz, 2 N), 4.46 - 4.62 (m, 4 N), 6.56 - 6.65 (m, Z H), 6.90 - 6.99 (m, 1 N), 7, 17 - 7.23 (m, 1 N), 7.27 - 7.33 (m, 1 N), 7.54 (d, 9-8.8 Hz, 2 N). (9) 3-(X4-(cyclohexyl(5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylamino)propanoic acid

To a mixture of ethyl 3-(X4-cyclohexyl|5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylamino)propanoate (207 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (186 mg, 9595) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 0.95 - 1.35 (m, 5 N), 1.41 - 1.53 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.00 - 2.11 (m, 1 H), 2.63 (t, 9-5.7 Hz, 2 H), 3.37 (s, C H), 3.59 - 3, 68 (m, 2 H), 4.50 (d, 2-8.1

Gu, 1 H), 4.54 (d, 9d-12.2 Gu, 1 H), 4.59 (d, 912.2 Hz, 1 H), 6.55 - 6.66 (m, C H ), 6.90 - 6.99 (m, 1 H), 7.16 - 7.23 (m, 1 H), 7.27 - 7.34 (m, 1 H), 7.53 (d, 9U-8.9 Hz, 2 N).

Example A48 3-((4-(H-cyclohexyl-5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenyl-carbonylmethyl)amino|propanoic acid o M CH, n i)

IN

E dream (1) Ethyl 3-Sh4-(cyclohexyl(5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate

To the mixture of 4-((cyclohexylIb5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)iamino)benzoic acid (200 mg), synthesized in Example A47(7), ethyl 3-(methylamino)propanoate (95.6 mg), 1-hydroxybenzotriazole monohydrate (112 mg), triethylamine (203 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg) and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70956 ethyl acetate/hexane) to give the title compound (197 mg, 7790) as a pale yellow oil.

IN NMR (300 MHz, SOSIZ") b m.h. 0.96 - 1.36 (m, 8 N), 1.42 - 1.53 (m, 1 N), 1.59 - 1.97 (m, 4

H), 2.02 - 2.13 (m, 1 H), 2.61 (t, 9-7.0 Hz, 2 H), 3.00 (s, C H), 3.36 (s, With H), 3.70 (t, 9-7.0 Hz, 2

H), 4.11 (k, 9-7.1 Hz, 2 H), 4.35 - 4.51 (m, 2 H), 4.54 (d, 2-12.3 Gu, 1 H) , 4.59 (d, 9U-12.3 Gu, 1

H), 6.59 (d, 9U-8.5 Hz, 2 H), 6.90 - 6.99 (m, 1 H), 7.17 - 7.24 (m, C H), 7, 28 - 7.34 (m, 1 N). (2) 3-((4-(H-Cyclohexyl-5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

To the mixture of ethyl 3-YХ4-(cyclohexyl15-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (197 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 7 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (161 mg, 87905) as a pale yellow solid. NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.36 (m, 5 N), 1.41 - 1.53 (m, 1 N), 1.59 - 1.97 (m, 4

H), 2.01 - 2.13 (m, 1 H), 2.54 - 2.70 (m, 2 H), 3.01 (s, C H), 3.37 (s, C H) , 3.68 (t, U-6.6 Hz, 2 N), 4.47 (d, 9-7.9 Hz, 1 N), 4.55 (d, 9U-12.2 Hz, 1 N ), 4.60 (d, 9-12.2 Hz, 1 N), 6.59 (d, 9U-8.5 Hz, 2

H), 6.89 - 7.00 (m, 1 H), 7.17 - 7.25 (m, Z H), 7.28 - 7.35 (m, 1 H).

Example A49 3-((4-(H-cyclohexyl-5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenyl-carbonylmethyl)amino|propanoic acid o o M CH. / N

F) m

E SN.

Ethyl 3-FSH4-(cyclohexyl5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (1.20 g), synthesized in Example

A48(1), was separated using high performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm H x 500 mm D, manufactured by Oaise! Spetisa! Ipdivigiev, Ts., mobile phase: hexane/ethanol (200/800), flow rate: 60 ml/min, column temperature: "C). Fractions containing the optically active form, which has a shorter retention time under the above-mentioned high-performance chromatography conditions, was concentrated to give the amorphous form (470 mg, 99.995 ee).To a mixture of the obtained amorphous form, ethanol (5 mL), and tetrahydrofuran (5 mL), 1 M aqueous hydroxide solution was added sodium (2.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrochloric acid (2.00 ml) was added at 0 "C. The resulting precipitate was collected by filtration to give the title compound (433 mg, 3895, 99.995 ee) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.36 (m, 5 N), 1.41 - 1.53 (m, 1 N), 1.59 - 1.97 (m, 4

H), 2.01 - 2.13 (m, 1 H), 2.54 - 2.70 (m, 2 H), 3.01 (s, C H), 3.37 (s, C H) , 3.68 (t, U-6.6 Hz, 2 N), 4.47 (d, 9-7.9 Hz, 1 N), 4.55 (d, 9-12.2 Hz, 1 N ), 4.60 (d, 9-12.2 Hz, 1 N), 6.59 (d, 9-8.5 Hz, 2

H), 6.89 - 7.00 (m, 1 H), 7.17 - 7.25 (m, Z H), 7.28 - 7.35 (m, 1 H).

Example OR 3-((4-(Hcyclohexyl-5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylHmethyl)amino|propanoic acid o ru o M CH,

N

)

M

E CH,

Ethyl 3-FSH4-(cyclohexyl5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (1.20 g), synthesized in Example

A48(1), was separated using high performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm H x 500 mm L, manufactured by Oaise! Spetisa! Ipdivigiev, Ts., mobile phase: hexane/ethanol (200/800), flow rate: 60 ml/min, column temperature: 30 "C). Fractions that containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, was concentrated to give the amorphous form (465 mg, 99.995 ee). To a mixture of the obtained amorphous form, ethanol (5 ml) and tetrahydrofuran (5 ml) was added a 1M aqueous solution sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1M hydrochloric acid (2.00 ml) was added at 0 "C. The resulting precipitate was collected by filtration to give the title compound (415 mg, 37905, 99.9965 ee) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.95 - 1.36 (m, 5 N), 1.41 - 1.53 (m, 1 N), 1.59 - 1.97 (m, 4

H), 2.01 - 2.13 (m, 1 H), 2.54 - 2.70 (m, 2 H), 3.01 (s, C H), 3.37 (s, C H) , 3.68 (t, U-6.6 Hz, 2 N), 4.47 (d, 9-7.9 Hz, 1 N), 4.55 (d, 9-12.2 Hz, 1 N ), 4.60 (d, 9-12.2 Hz, 1 N), 6.59 (d, 9-8.5 Hz, 2

H), 6.89 - 7.00 (m, 1 H), 7.17 - 7.25 (m, Z H), 7.28 - 7.35 (m, 1 H).

Example A5BI1 3-1(6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)ucarbonyl|iamino)propanoic acid

F. d m---- BACKGROUND o - | and

M M

/ N

CH,

IS

(1) 2-bromo-1-cyclohexylethanone

Bromine (10.1 ml) was added to a solution (50 ml) of 1-cyclohexylethanone (25.0 g) in methanol at 0 "C, and the mixture was stirred at room temperature for 30 min. To quench the reaction, a saturated aqueous solution of sodium sulfite was added and the mixture extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 1095 ethyl acetate/hexane) to afford the title compound (25.8 g, 63905) as a colorless oil .

IN NMR (300 MHz, SOSI") 6 m.h. 1.10 - 1.50 (m, 5 N), 1.62 - 1.73 (m, 1 N), 1.75 - 1.94 (m, 4

H), 2.64 - 2.79 (m, 1 H), 3.97 (c, 2 H). (2) cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanone

Potassium carbonate (13, 4 g) and the mixture was stirred at room temperature overnight. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-2095 ethyl acetate/hexane) to give the title compound (5.38 g, 64905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.19 - 1.57 (m, 5 N), 1.70 - 2.01 (m, 5 N), 2.56 (s, Z H), 3.25 - 3.36 (m, 1 N ), 7.15 - 7.23 (m, 1 N), 7.24 - 7.30 (m, 1 N), 7.42 - 7.48 (m, 1 N). (3) methyl 6-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridine-3-carboxylate

To the mixture | cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanone (3.00 g), synthesized above, methyl b-aminopyridine-3-carboxylate (1.93 g), triethylamine (12.8 ml ) and methylene chloride (40 ml) at 0 "С, a 1.0 M solution (13.8 ml) of titanium chloride (IM) in methylene chloride was added, and the mixture was stirred in an argon atmosphere at room temperature for 1.5 days. To quench the reaction, saturated aqueous sodium bicarbonate solution, methylene chloride was removed on the evaporator and the residue was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (3.29 ml) and sodium cyanoborohydride (3.61 g) were added to the mixture of the obtained oil, ethanol (40 ml) and tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 3 h. To quench the reaction, saturated aqueous sodium bicarbonate solution, the organic solvent was removed by evaporation and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-CO 90 ethyl acetate/hexane) to give the title compound (547 mg, 1290) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.82 - 1.35 (m, 5 N), 1.44 - 1.55 (m, 1 N), 1.56 - 1.86 (m, Z

H), 1.85 - 2.10 (m, 2 H), 2.24 (s, C H), 3.83 (s, C H), 5.02 - 5.14 (m, 1 H) , 5.42 (d, 2-8.2 Hz, 1 N), 6.33 (d, 98.8 Hz, 1 N), 6.88 - 6.97 (m, 1 N), 7.04 - 7.10 (m, 1 N), 7.26 - 7.32 (m, 1 N), 7.90 (dd, uU-8.8, 2.4 Hz, 1 N), 8.72 ( d, U-2.4 Hz, 1 N). (4) 6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridine-3-carboxylic acid

To a mixture of methyl 6-1-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethyl|amino)pyridine-3-carboxylate (547 mg), synthesized above, ethanol (10 ml) and tetrahydrofuran (10 ml) ) 1M aqueous sodium hydroxide solution (10 ml) was added and the mixture was stirred overnight under reflux. Another 1M aqueous solution of sodium hydroxide (5.00 ml) was added and the mixture was stirred under reflux for 5 g and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (15 mL) was added at 0 "C. The resulting precipitate was collected by filtration and the resulting pale brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (478 mg, 9095) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.98 - 1.41 (m, 5 N), 1.48 - 1.84 (m, 4 N), 2.01 - 2.18 (m, 2

H), 2.23 (s, C H), 4.47 - 4.65 (m, 1 H), 6.34 (d, 2-8.8 Hz, 1 H), 6.87 - 6, 97 (m, 1 H), 7.03 - 7.10 (m, 1 H), 7.26 - 7.33 (m, 1 H), 8.08 (d, 9-8.8 Hz, 1 N), 8.70 - 8.74 (m, 1 N). (5) ethyl 3-((6-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)ucarbonyl|amino)propanoate

To the mixture of 6-ylcyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyliamino)pyridine-3-carboxylic acid (300 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (181 mg), monohydrate 1-Hydroxybenzotriazole (181 mg), triethylamine (328 μl) and N,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to give the title compound (366 mg, 97905) as a pale brown oil "H NMR (300 MHz, SOCI") 6 ppm 0.93 - 1.36 (m, 8 H), 1.43 - 1.55 (m, 1 H), 1.57 - 1.85 (m, Z

H), 1.85 - 2.08 (m, 2 H), 2.24 (s, C H), 2.60 (t, 9U-5.9 Hz, 2 H), 3.62 - 3, 72 (m, 2 H), 4.15 (k, 20-7.1

Hz, 2 N), 5.01 - 5.12 (m, 1 N), 5.25 (d, 2-8.8 Hz, 1 N), 6.35 (d, 9-8.8 Hz, 1 H), 6.65 (t, 9U-6.0 Gu, 1 H), 6.88 - 6.97 (m, 1 H), 7.03 - 7.10 (m, 1 H), 7 .23 - 7.31 (m, 1 N), 7.75 (dd, U-8.8, 2.5 Hz, 1 N), 8.48 (d, 9-2.5 Hz, 1 N) . (6) 3-1(6-Icyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyliamino)pyridin-3-yl)ucarbonyl|Iamino)propanoic acid

To the mixture of ethyl 3-((6-Icyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylylamino)pyridin-3-yl)carbonyl|Iaminopropanoate (366 mg), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (287 mg, 83905) as a white solid. H NMR ( 300 MHz, SOSIz") 6 m.h. 0.84 - 1.41 (m, 5 N), 1.44 - 1.55 (m, 1 N), 1.59 - 1.84 (m, C

H), 1.97 - 2.15 (m, 2 H), 2.23 (s, C H), 2.55 - 2.69 (m, 2 H), 3.65 - 3.78 (m , 2 H), 4.46 (t, 9-78

Hu, 1 N), 6.48 (d, 959.1 Hz, 1 N), 6.89 - 6.99 (m, 1 N), 7.04 - 7.11 (m, 1 N), 7 .27 - 7.35 (m, 1 N), 7.51 - 7.61 (m, 1 N), 8.13 (dd, 9U-9.1, 2.1 Hz, 1 N), 8, 22 (d, 9-21 Hz, 1 N), 8.25 - 8.41 (m, 1 N).

Example A52 3-1(6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)carbonyl|(methyl)amino)propanoic acid CH,

YOU are

SN.

IS

(1) ethyl 3-((6-Tcyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)/ucarbonyl|(methyl)amino)propanoate

To the mixture of 6-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridine-3-carboxylic acid (294 mg), synthesized in Example ABbB1(4), ethyl 3-(methylamino)propanoate (151 mg), 1-hydroxybenzotriazole monohydrate (176 mg), triethylamine (322 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (221 mg) and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 70956 ethyl acetate/hexane) to give the title compound (236 mg, 6295) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.94 - 1.34 (m, 8 N), 1.45 - 1.57 (m, 1 N), 1.58 - 1.83 (m, Z

H), 1.84 - 2.09 (m, 2 H), 2.23 (s, C H), 2.63 (t, 9U-7.0 Hz, 2 H), 3.05 (s, With H), 3.72 (t, U9-7.0 Hz, 2

H), 4.03 - 4.17 (m, 2 H), 4.97 - 5.07 (m, 1 H), 5.08 - 5.18 (m, 1 H), 6.34 (d , 9-8.6 Hz, 1 N), 6.88 - 6.97 (m, 1 N), 7.04 - 7.10 (m, 1 N), 7.23 - 7.31 (m, 1 H), 7.46 (dd, U-8.6, 2.1 Hz, 1 H), 8.18 (d, 9-21 Hz, 1 H). (2) 3-1(6-Hycyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridin-3-yl)ucarbonyl|(methyl)amino)propanoic acid

To the mixture of ethyl 3-((6-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridin-3-yl)carbonyl|/methyl)amino)propanoate (236 mg), synthesized above , tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was dissolved in water (10 ml), 1 M hydrochloric acid (1.00 ml) was added at 0"C and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow solid. the solid was recrystallized from ethyl acetate/hexane to give the title compound (143 mg, 6495) as colorless crystals. "H NMR (300 MHz, SOCI3") 6 m.p. 0.84 - 1.37 (m, 5 N), 1.38 - 1.53 (m, 1 N), 1.55 - 1.82 (m, C

H), 1.87 - 2.12 (m, 2 H), 2.20 (s, C H), 2.48 - 2.68 (m, 2 H), 2.99 (shs, C H) , 3.59 - 3.79 (m, 2 N), 4.54 - 4.76 (m, 1 N), 6.34 (d, 2-88 Hz, 1 N), 6.86 - 6, 97 (m, 1 H), 7.01 - 7.09 (m, 1 H), 7.23 - 7.34 (m, 1 H), 7.51 (d, 9U-8.8 Hz, 1 H), 8.11 (shs, 1 H).

Example ABZ 3-1(6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)ucarbonyl|(methyl)amino)propanoic acid N

Sleep

IS

Ethyl 3-((6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)ucarbonyl|(methyl)amino)propanate (4.06 g) , synthesized in Example AB52(1), was separated using high-performance liquid chromatography (column: SNIKAGRAK AYU (50 mm

H x 500 mm D, manufactured by YuOaise! Spetis! Ipaivigiez, TSY. mobile phase: hexane/2-propanol (700/300-200/800), flow rate: 60 ml/min-50 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a shorter retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (1.94 g, 99.995 ee). A 1M aqueous solution of lithium hydroxide (8 ml) was added to the mixture of the obtained amorphous form, ethanol (10 ml) and tetrahydrofuran (10 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (8 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (1.81 g, 9595, 99.995 ee) as a white solid.

IN NMR (300 MHz, DMSO-av) b m.ch. 0.89 - 1.28 (m, 5 N) 1.34 (d, 2-12.12 Hz, 1 N) 1.49 - 1.80 (m, C H) 1.80 - 2.08 ( m, 2 H) 2.23 (s, C H) 2.50 - 2.54 (m, 2 H) 2.92 (s, C H) 3.53 (t, 9-7.38

Hz, 2 N) 5.15 (t, U-8.90 Hz, 1 N) 6.56 (d, 2-8.71 Hz, 1 N) 7.05 (td, 2-9.28, 2 ,65 Hz, 1 N) 7.31 (dd, U-8.71, 2.65 Hz, 1 N) 7.36 - 7.56 (m, 2 N) 8.04 (d, 90-52, 27 Hz, 1 N) 12.22 (she, 1 N).

Example A5bB4 3-1(6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)ucarbonyl|(methyl)amino)propanoic acid o ev o mm shchi / n

Sleep

IS

Ethyl 3-((6-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)/ucarbonyl|(methyl)amino)propanoate (4.06 g ), synthesized in Example AB2(1), was separated using high-performance liquid chromatography (column: SNIKAGRAK AYU (50 mm

H x 500 mm D, manufactured by YuOaise! Spetis! Ipayivigiez, TSY. mobile phase: hexane/2-propanol (700/300-200/800), flow rate: 60 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (1.96 g, 99.995 ee). A 1M aqueous solution of lithium hydroxide (8 ml) was added to the mixture of the obtained amorphous form, ethanol (10 ml) and tetrahydrofuran (10 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (8 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (1.80 g, 9995.99.995 ee) as a white solid.

IN NMR (300 MHz, DMSO-av) b m.ch. 0.89 - 1.28 (m, 5 N) 1.34 (d, 2-12.12 Hz, 1 N) 1.49 -

1.80 (m, Z H) 1.80 - 2.08 (m, 2 H) 2.23 (s, Z H) 2.50 - 2.54 (m, 2 H) 2.92 (s, With H) 3.53 (t, 9d-7.38

Hz, 2 N) 5.15 (t, U-8.90 Hz, 1 N) 6.56 (d, 2-8.71 Hz, 1 N) 7.05 (td, 2-9.28, 2 ,65 Hz, 1 N) 7.31 (dd, 9U-8.71, 2.65 Hz, 1 N) 7.36 - 7.56 (m, 2 N) 8.04 (d, 9-52, 27 Hz, 1 N) 12.22 (she, 1 N).

Example A55 3-((5-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-2-yl)ucarbonyl|Iamino)propanoic acid / N

SN.

IS

(1) methyl 5-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|iamino)pyridine-2-carboxylate

To a solution (15 ml) of cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanol (1.50 g) synthesized in Example AZ7(2) in toluene was added thionyl chloride (625 μl) and the mixture was stirred at room temperature for 3 h. The reaction mixture was poured into an ice-cooled, saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown oil.

To a mixture of the obtained oil, methyl 5-aminopyridine-2-carboxylate (957 mg), sodium iodide (1.71 g) and M,M-dimethylformamide (15 ml) was added sodium carbonate (1.21 g) and the mixture was stirred at 80 C during the night. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 - 5095 ethyl acetate/hexane) to give the title compound (909 mg, 4090) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.94 - 1.37 (m, 5 N), 1.46 - 1.57 (m, 1 N), 1.60 - 2.00 (m, 4

H), 2.02 - 2.14 (m, 1 H), 2.23 (s, C H), 3.90 (s, C H), 4.39 (t, 9U-8.2 Hz, 1 H), 4.70 (d, 2-8.2 Hz, 1

H), 6.84 (dd, U-8.6, 3.0 Hz, 1 H), 6.89 - 6.97 (m, 1 H), 7.04 - 7.10 (m, 1 H ), 7.22 - 7.30 (m, 1 N), 7.88 (d, U-8.6 Hz, 1 N), 8.08 (d, 9U-3.0 Hz, 1 N). (2) 5-Hycyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridine-2-carboxylic acid

To a mixture of methyl 5-I(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyliamino)pyridine-2-carboxylate (909 mg), synthesized above, ethanol (20 ml) and tetrahydrofuran (20 ml) ) 1M aqueous sodium hydroxide solution (20 ml) was added, the mixture was stirred under reflux for 5 g and concentrated under reduced pressure. 1M hydrochloric acid (20 ml) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (751 mg, 8695) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.94 - 1.39 (m, 5 N), 1.46 - 1.60 (m, 1 N), 1.62 - 2.02 (m, 4

H), 2.02 - 2.15 (m, 1 H), 2.25 (s, C H), 4.41 (t, 2-7.9 Hz, 1 H), 4.72 - 4, 83 (m, 1 H), 6.90 - 7.00 (m, 2 H), 7.07 - 7.13 (m, 1 H), 7.24 - 7.33 (m, 1 H), 7.91 - 7.98 (m, 2 N). (3) ethyl 3-(5-H-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridin-2-yl)ucarbonyl|amino)propanoate

To the mixture of 5-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridine-2-carboxylic acid (300 mg), synthesized above, hydrochloride of ethyl ester of B-alanine

(181 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (328 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) and the mixture was stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to give the title compound (361 mg, 9695) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.94 - 1.39 (m, 8 N), 1.46 - 2.00 (m, 5 N), 2.03 - 2.14 (m, 1

H), 2.24 (s, C H), 2.60 (t, 9-6.2 Hz, 2 H), 3.64 - 3.72 (m, 2 H), 4.15 (k, 9-7.1 Hz, 2 N), 4.34 - 4.42 (m, 1 N), 4.45 - 4.52 (m, 1 N), 6.86 - 6.98 (m, 2 H), 7.05 - 7.10 (m, 1 H), 7.24 - 7.30 (m, 1 H), 7.87 - 7.93 (m, 2 H), 8.06 - 8 ,13 (m, 1 H). (4) 3-1(5-Icyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyliamino)pyridin-2-yl)ucarbonyl|Iamino)propanoic acid

Tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (324 mg, 9595) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.36 (m, 5 N), 1.45 - 1.56 (m, 1 N), 1.61 - 2.00 (m, 4

H), 2.01 - 2.12 (m, 1 H), 2.22 (s, C H), 2.65 (t, 9U-6.1 Hz, 2 H), 3.64 - 3, 75 (m, 2 H), 4.37 (d, U-8.0

Hu, 1 H), 6.85 - 6.99 (m, 2 H), 7.03 - 7.10 (m, 1 H), 7.23 - 7.30 (m, 1 H), 7, 86 - 7.94 (m, 2 N), 8.14 (t, 9-6.2 Hz, 1 N).

Example A5b 3-((5-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-2-yl)ucarbonyl|(methyl)amino)propanoic acid

IF - m-n o z i M sn, to her

CH,

IS

(1) ethyl 3-((5-H-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridin-2-yl)/ucarbonyl|(methyl)amino)propanoate

To the mixture of 5-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridine-2-carboxylic acid (300 mg), synthesized in Example AB5(2), ethyl 3-(methylamino)propanoate (155 mg), 1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (328 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) and the mixture was stirred at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 - 6095 ethyl acetate/hexane) to give the title compound (318 mg, 8295) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.38 (m, 8 N), 1.46 - 1.57 (m, 1 N), 1.60 - 1.99 (m, 4

H), 2.03 - 2.16 (m, 1 H), 2.22 (s, With H), 2.63 -2.78 (m, 2 H), 3.00 - 3.21 (m , Z H), 3.69 - 3.87 (m, 2

H), 4.01 - 4.19 (m, 2 H), 4.32 - 4.40 (m, 1 H), 4.41 - 4.49 (m, 1 H), 6.84 - 6 .98 (m, 2 H), 7.04 -

7.11 (m, 1 N), 7.24 - 7.31 (m, 1 N), 7.44 - 7.59 (m, 1 N), 7.88 - 7.95 (m, 1 N ). (2) 3-1(5-Hycyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridin-2-yl)ucarbonyl|(methyl)amino)propanoic acid

To the mixture ethyl 3-((5-1-cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)pyridin-2-yl)ucarbonyl| 1 M aqueous solution of sodium hydroxide (2.00 ml) was added to methyl)iaminosupropanoate (318 mg) synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (262 mg, 87905) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.46 - 1.56 (m, 1 N), 1.60 - 1.99 (m, 4

Н), 2.03 - 2.13 (m, 1 Н), 2.23 (s, З Н), 2.68 - 2.89 (m, 2 Н), 3.09 (she, З Н) , 3.77 (t, U-6.8 Hz, 2

H), 4.36 (d, 9-8.3 Hz, 1 H), 6.87 - 6.99 (m, 2 H), 7.05 - 7.11 (m, 1 H), 7, 24 - 7.32 (m, 1 N), 7.48 - 7.66 (m, 1 N), 7.90 - 8.00 (m, 1 N).

Example A57 3-((5-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-2-yl)ucarbonyl|(methyl)amino)propanoic acid o d " m -n o M with M CH, in e

SN.

IS

Ethyl 3-((5-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|iamino)pyridin-2-yl)/ucarbonyl|(methyl)amino)propanoate (5.83 g ), synthesized in Example A5B6(1), was separated using high-performance liquid chromatography (column: SNIKAGRAK AYU (50 mm

Wx500 mm D, manufactured by Oaise! Spetisai! Ipdivigie5, Ts., mobile phase: hexane/ethanol (500/500), flow rate; bO ml/min, column temperature: room temperature).

Fractions containing the optically active form, which has a shorter retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (2.90 g, 99.990 ccee). A 1M aqueous solution of lithium hydroxide (12 ml) was added to the mixture of the obtained amorphous form, ethanol (10 ml) and tetrahydrofuran (10 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and 1 M hydrochloric acid (12 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (2.67 g, 9995.99.995 ee) as a white solid.

IN NMR (300 MHz, DMSO-av) 6 m.h. 0.98 - 1.29 (m, 5 N) 1.30 - 1.39 (m, 1 N) 1.63 (shs, 2 N) 1.75 (d, 9-11.36 Gu, 1 N ) 1.82 - 2.00 (m, 1 H) 2.09 (d, 9U-11.74 Gu, 1 H) 2.25 (s, with H) 2.53 - 2.66 (m, 2 H) 2.88 - 3.03 (m, C H) 3.32 (shs, 2 H) 4.51 (t, U-8.33 Hz, 1 H) 6.80 (d, 2-8, 33 Hz, 1 N) 6.96 (dd, 9U-8.71, 2.65 Hz, 1 N) 7.05 (td, 2-9.28, 2.65 Hz, 1 N) 7.26 - 7.39 (m, 2 N) 7.47 (dd, uU-8.90, 3.98 Hz, 1 N) 7.95 (d, 9U-2.27 Hz, 1 N) 12.26 (she , 1 H).

Example A5B 3-((5-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-2-yl)carbonyl|(methyl)amino)propanoic acid o o M z M 00 SN, on

SN.

IS

Ethyl 3-((5-(cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|iamino)pyridin-2-yl)ucarbonyl|(methyl)amino)propanoate (5.83 g) , synthesized in Example A5B6(1), was separated using high-performance liquid chromatography (column: SNIKAGRAK AYU (50 mm

Wx500 mm D, manufactured by Oaise! Spetisai! Ipdivigie5, Ts., mobile phase: hexane/ethanol (500/500), flow rate: bO ml/min, column temperature: room temperature).

Fractions containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (2.82 g, 99.995 ee). A 1M aqueous solution of lithium hydroxide (12 ml) was added to the mixture of the obtained amorphous form, ethanol (10 ml) and tetrahydrofuran (10 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and 1 M hydrochloric acid (12 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (2.64 g, 97905.99.995 ee) as a white solid. H NMR (300 MHz, DMSO-av) 6 m.h. 0.98 - 1.29 (m, 5 N) 1.30 - 1.39 (m, 1 N) 1.63 (shs, 2 N) 1.75 (d, 9-11.36 Gu, 1 N ) 1.82 - 2.00 (m, 1 H) 2.09 (d, 9U-11.74 Gu, 1 H) 2.25 (s, with H) 2.53 - 2.66 (m, 2 H) 2.88 - 3.03 (m, C H) 3.32 (she, 2 H) 4.51 (t, 9-8.33 Hz, 1 H) 6.80 (d, 2-8, 33 Hz, 1 N) 6.96 (dd, 9U-8.71, 2.65 Hz, 1 N) 7.05 (td, 2-9.28, 2.65 Hz, 1 N) 7.26 - 7.39 (m, 2 N) 7.47 (dd, uU-8.90, 3.98 Hz, 1 N) 7.95 (d, 9U-2.27 Hz, 1 N) 12.26 (she , 1 H).

Example A5bB9 3-Ш((5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)ucarbonyl|(methyl)amino)propanoic acid

F that

M with M CH,

Hn sn. (1) methyl 5-cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridine-2-carboxylate

To the mixture of 2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzothiophene (664 mg), synthesized in Example A1F(2), methyl 5-aminopyridine-2-carboxylate (362 mg), sodium iodide (714 mg ) and

Sodium carbonate (505 mg) was added to M,M-dimethylformamide (10 ml) and the mixture was stirred at 80 "C overnight. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70905 ethyl acetate/hexane) to afford the title compound (460 mg, 4995) as a pale yellow solid. "H NMR (300 MHz, SOCI") 6 m.ch. 1.03 - 1.37 (m, 5 N), 1.54 - 1.88 (m, 5 N), 2.07 - 2.18 (m, 1

H), 2.47 (s, C H), 3.88 (s, C H), 4.54 - 468 (m, 2 H), 6.78 (dd, 9U-8.6, 2.7 Hz, 1 N), 7.22 - 7.30 (m,

1 N), 7.91 - 7.38 (m, 1 N), 7.63 (d, 9U-8.0 Gu, 1 N), 7.68 (d, 9-8.0 Hz, 1 N ), 7.84 (d, 2-8.6 Gu, 1

H), 8.05 (d, 9-2.7 Hz, 1 H). (2) 5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl|amino)pyridine-2-carboxylic acid

To a mixture of methyl 5-ylcyclohexyl(3-methyl-1-benzothiophen-2-yl)umethylamino)pyridine-2-carboxylate (460 mg) synthesized above, ethanol (5 ml) and tetrahydrofuran (5 ml) was added a 1 M aqueous solution of hydroxide sodium (5.00 mL), the mixture was stirred overnight under reflux and concentrated under reduced pressure.

The residue was dissolved in water (10 ml), 1 M hydrochloric acid (5.00 ml) was added at 0 "C and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound indicated in the title (452 mg, quantitatively) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.38 (m, 5 N), 1.56 - 1.90 (m, 5 N), 2.08 - 2.18 (m, 1

H), 2.50 (s, C H), 4.56 - 4.64 (m, 1 H), 4.68 - 4.77 (m, 1 H), 6.88 (dd, 9U-8 ,7, 2.6 Gu, 1 H), 7.25 - 7.33 (m, 1 H), 7.34 - 7.41 (m, 1 H), 7.66 (d, 9-7, 4 Hz, 1 N), 7.71 (d, 9-7.7 Hz, 1 N), 7.86 - 7.93 (m, 2 N). (3) ethyl 3-((5-Ycyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)/ucarbonyl|(methyl)amino)ypropanoate

To the mixture of 5-cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridine-2-carboxylic acid (200 mg) synthesized above, ethyl 3-(methylamino)propanoate (104 mg), 1-hydroxybenzotriazole monohydrate (121 mg), triethylamine (220 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151 mg) was added, and the mixture was stirred at room temperature for 4 h. aqueous solution of ammonium chloride to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give the title compound (141 mg, 54905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.35 (m, 8 N), 1.55 - 1.88 (m, 5 N), 2.06 - 2.17 (m, 1

H), 2.46 (c, C H), 2.61 - 2.76 (m, 2 H), 2.98 - 3.18 (m, C H), 3.69 - 3.87 (m , 2 H), 3.98 - 4.18 (m, 2

H), 4.39 (d, 9U-6.0 Hz, 1 H), 4.51 - 4.58 (m, 1 H), 6.81 (dd, U-8.5, 2.7 Hz , 1 N), 7.23 - 7.30 (m, 1

H), 7.91 - 7.38 (m, 1 H), 7.39 - 7.55 (m, 1 H), 7.63 (d, 9U-7.4 Hz, 1 H), 7, 70 (d, 2-7.7 Hz, 1 N), 7.84 - 7.91 (m, 1 N). (4) 3-((5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)ucarbonyl|(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(5-Ycyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl|amino)pyridin-2-yl)ucarbonyl I|(methyl)amino)propanosate (141 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (112 mg, 8495) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 1.01 - 1.37 (m, 5 N), 1.54 - 1.89 (m, 5 N), 2.06 - 2.18 (m, 1

H), 2.47 (s, C H), 2.73 - 2.90 (m, 2 H), 3.08 (shs, C H), 3.76 (t, 9U-6.4 Hz, 2 H), 4.55 (d, 2-8.0 Gu, 1 H), 6.83 - 6.93 (m, 1 H), 7.23 - 7.33 (m, 1 H), 7 .33 - 7.41 (m, 1 H), 7.47 - 7.63 (m, 1 H), 7.65 (d, 9U-7.6 HZ, 1 H), 7.71 (d, 9U-7.6 Hz, 1 N), 7.85 - 7.94 (m, 1 N).

Example AbO 3-Ш((5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)ucarbonyl|(methyl)amino)propanoic acid o -E / m OH

With me M sn, n sn.

Ethyl 3-((5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)/ucarbonyl|(methyl)amino)propanoate (9.31 g), synthesized in Example A5U (3), were separated using high-performance liquid chromatography (column: SNIKAGRAK AYU (50 mm

Wx500 mm D, manufactured by Oaise! Spetis! Ipaivigie5, TSY. mobile phase: hexane/2-propanol (700/300-200/800), flow rate: 60 ml/min-50 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a shorter retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (4.67 g, 99.995 ee). A 1M aqueous solution of lithium hydroxide (20 ml) was added to the mixture of the obtained amorphous form, ethanol (20 ml) and tetrahydrofuran (20 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (20 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (4.17 g, 9995, 99.995 ee) as a white solid.

IN YAMRE (300 MHz, DMSO-av) 6 m.h. 1.00 - 1.32 (m, 5 N) 1.37 - 1.51 (m, 1 N) 1.52 - 1.84 (m, 4 N) 2.07 - 2.20 (m, 1 H) 2.46 (s, C H) 2.50 - 2.57 (m, 2 H) 2.87 - 3.01 (m, C H) 3.27 - 3.36 (m, 5

H) 3.43 - 3.68 (m, 2 H) 4.63 (t, 9U-7.38 Hz, 1 H) 6.87 (d, U-6.82 Hz, 2 H) 7.19 - 7.41 (m, C H) 7.69 (d, 9U-7.19 Hz, 1 H) 7.79 (d, 9-7.57 Hz, 1 H) 7.89 (d, 9- 2.65 Hz, 1 N) 12.16 (shs, 1 N).

Example Ab1 3-Z((5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)/ucarbonyl)/methyl)amino)propanoic acid

F de / m-n!

M -- M sn, yin sn.

Ethyl 3-((5-1-cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)/ucarbonyl|(methyl)amino)propanoate (9.31 g), synthesized in Example A5U ( 3), were separated using high-performance liquid chromatography (column: SNIKAG RAK AYU (50 mm

H x 500 mm D, manufactured by YuOaise! Spetis! Ipaivigiez, TSY. mobile phase: hexane/2-propanol (700/300-200/800), flow rate: 60 ml/min-50 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (4.52 g, 99.995 ee). A 1M aqueous solution of lithium hydroxide (20 ml) was added to the mixture of the obtained amorphous form, ethanol (20 ml) and tetrahydrofuran (20 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1M hydrochloric acid (20 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (4.12 g, 9895, 99.995 ee) as a white solid. IN NMR (300 MHz, DMSO-av) 6 m.h. 1.00 - 1.32 (m, 5 N) 1.37 - 1.51 (m, 1 N) 1.52 - 1.84 (m, 4 N) 2.07 - 2.20 (m, 1 H) 2.46 (s, C H) 2.50 - 2.57 (m, 2 H) 2.87 - 3.01 (m, C H) 3.27 - 3.36 (m, 5

H) 3.43 - 3.68 (m, 2 H) 4.63 (t, 9U-7.38 Hz, 1 H) 6.87 (d, U-6.82 Hz, 2 H) 7.19 - 7.41 (m, Z H) 7.69

(d, 9U-7.19 Hz, 1 H) 7.79 (d, 9-7.57 Hz, 1 H) 7.89 (d, 9-2.65 Hz, 1 H) 12.16 (shs , 1 N).

Example Ab62 3-Ш((5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylIamino)pyridin-2-yl)ucarbonyl|Iamino)propanoic acid o - / th units of KOH

With M with M sn. (1) ethyl 3-((5-Ycyclohexyl(3-methyl-1-benzothiophen-2-yl)methylamino)pyridin-2-yl)ucarbonyl|amino)propanoate

To the mixture of 5-cyclohexyl(3-methyl-1-benzothiophen-2-yl)umethylamino)pyridine-2-carboxylic acid (247 mg), synthesized in Example A5BU(2), hydrochloride of ethyl ester of B-alanine (149 mg), 1-Hydroxybenzotriazole monohydrate (149 mg), triethylamine (270 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (186 mg) and the mixture was stirred at room temperature overnight . A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give the title compound (274 mg, 88905) as a colorless oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.35 (m, 8 N), 1.54 - 1.88 (m, 5 N), 2.06 - 2.18 (m, 1

H), 2.47 (s, C H), 2.58 (t, U-6.3 Hz, 2 H), 3.61 - 3.71 (m, 2 H), 4.13 (k, U-7.1 Hz, 2 N), 4.48 - 4.60 (m, 2 N), 6.80 - 6.87 (m, 1 N), 7.22 - 7.30 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.64 (d, 9-7.4 Hz, 1 H), 7.69 (d, U-8.0 Hz, 1 H) , 7.83 - 7.88 (m, 2 N), 8.07 (t, U-6.3 Hz, 1 N). (2) 3-((5-(cyclohexyl(3-methyl-1-benzothiophen-2-yl)methylIamino)pyridin-2-yl)ucarbonyl|Iamino)propanoic acid

To a mixture of ethyl 3-1(5-cyclohexyl(3-methyl-1-benzothiophen-2-yl)methyl|iamino)pyridin-2-yl)ucarbonylaminopropanoate (274 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 "C. The resulting precipitate was collected by filtration to give the title compound (235 mg, 9195) as a white solid. "H NMR ( 300 MHz, SOSI") 6 m.h. 1.02 - 1.36 (m, 5 N), 1.54 - 1.89 (m, 5 N), 2.06 - 2.18 (m, 1

H), 2.47 (s, C H), 2.64 (t, U-6.0 HZ, 2 H), 3.61 - 3.7Z (m, 2 H), 4.56 (d, 9U-7.9 Hz, 1 N), 6.84 (dd, uU-8.5, 2.4 Hz, 1 N), 7.22 - 7.31 (m, 1 N), 7.31 - 7.40 (m, 1 N), 7.64 (d, 2-7.9 Hz, 1 N), 7.69 (d, 9U-7.9 Hz, 1 N), 7.82 - 7, 91 (m, 2 N), 8.11 (t, U-6.0 Hz, 1 N).

Example AbZ 3-Sh((4-(cyclopentyl(3-methyl-1-benzothiophen-2-yl)methylamino)phenyl)carbonylamino)propanoic acid about m 99Н in Н

M

N

CH,

(1) cyclopentyl(3-methyl-1-benzothiophen-2-yl)methanone

Aluminum chloride (1.35 g) was added to a mixture of 3-methyl-1-benzothiophene (1.00 g), cyclopentanecarbonyl chloride (903 μl) and nitromethane (10 ml) at 0 "C, and the mixture was stirred for 1.5 g. after quenching the reaction, water was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on

MH silica gel (ethyl acetate) to give the title compound (1.54 g, 9390) as a pale brown oil.

IN NMR (300 MHz, SOSI") b m.h. 1.60 - 1.84 (m, 4 H), 1.92 - 2.03 (m, 4 H), 2.78 (s, Z H), 3.48 - 3.60 (m, 1 H ), 7.40 - 7.52 (m, 2 N), 7.81 - 7.91 (m, 2 N). (2) methyl 4-1-cyclopentyl(3-methyl-1-benzothiophen-2-yl)methyliaminobenzoate

To the mixture of cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethanone (1.54 g) synthesized above, methyl 4-aminobenzoate (1.05 g), triethylamine (7.02 ml) and methylene chloride (30 ml ) added titanium chloride (IM) (829 μl) and the mixture was stirred under an argon atmosphere at room temperature for 3 days. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, methylene chloride was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (721 μl) and sodium cyanoborohydride (792 mg) were added to a solution (30 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium bicarbonate was added to quench the reaction, the organic solvent was evaporated on evaporators and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-3095 ethyl acetate/hexane) to give the title compound (1.56 g, 6595) as an orange solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.30 - 1.44 (m, 1 N), 1.45 - 1.82 (m, 6 N), 1.90 - 2.06 (m, 1

H), 2.28 - 2.46 (m, 1 H), 2.50 (s, C H), 3.79 (s, C H), 4.47 - 4.56 (m, 1 H) , 4.62 (d, 9-59.1 Hz, 1 N), 6.51 (d, 9-91 Hz, 2 N), 7.22 - 7.29 (m, 1 N), 7.31 - 7.37 (m, 1 N), 7.61 - 7.66 (m, 1 N), 7.67 - 7.72 (m, 1 N), 7.76 (d, 959.1 Hz, 2 H). (3) 4-Hycyclopentyl(3-methyl-1-benzothiophen-2-yl)methyl|amino)benzoic acid

A 1M aqueous solution of sodium hydroxide (20 .0 ml) and the mixture was stirred under reflux for 4 g and concentrated under reduced pressure. The residue was dissolved in water (40 ml) and 1M hydrochloric acid (20.0 ml) was added at 0"C.

The resulting precipitate was collected by filtration and the resulting pale brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.42 g, 9595) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.30 - 1.45 (m, 1 N), 1.45 - 1.82 (m, 6 N), 1.90 - 2.05 (m, 1

H), 2.27 - 2.45 (m, 1 H), 2.50 (s, C H), 4.63 (d, 9-9.1 Gu, 1 H), 6.52 (d, 9U-8.8 Hz, 2 N), 7.22 - 7.29 (m, 1 N), 7.31 - 7.38 (m, 1 N), 7.61 - 7.66 (m, 1 H), 7.67 - 7.71 (m, 1 H), 7.80 (d, 9-8.8 Hz, 2

N). (4) ethyl 3-((4-1-cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-16cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethyliaminophbenzoic acid (300 mg), synthesized above, p-alanine ethyl ester hydrochloride (189 mg), 1-hydroxybenzotriazole monohydrate (188 mg), triethylamine ( 343 μl) and M,M-dimethylformamide (10 ml) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (236 mg) was added and the mixture was stirred at room temperature for 5 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to give the title compound (331 mg, 8795) as a pale brown oil.

IN NMR (300 MHz, SOSI") b m.h. 1.23 (t, 9-7.1 Hz, Z H), 1.30 - 1.45 (m, 1 H), 1.45 - 1.81 (m, 6 H), 1.90 - 2 .07 (m, 1 N), 2.27 - 2.47 (m, 1 N), 2.50 (s, Z H), 2.56 (t, 9U-5.8 Hz, 2 N), 3.59 - 3.68 (m, 2 H), 4.12 (k, 927.1 Hz, 2 H), 4.42 (d, 95.7 Hz, 1 H), 4.60 (dd, 9-91, 5.7 Hz, 1 H), 6.48 - 6.60 (m, Z H), 7.21 - 7.29 (m, 1 H), 7.30 - 7.37 (m , 1 N), 7.50 (d, 958.8 Hz, 2 N), 7.61 - 7.65 (m, 1

H), 7.66 - 7.72 (m, 1 H). (5) 3-((4-Hycyclopentyl(3-methyl-1-benzothiophen-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

To a mixture of ethyl 3-((4-Hcyclopentyl(3-methyl-1-benzothiophen-2-yl)methyliamino)phenyl)carbonyl|Iaminodipropanoate /(:(331 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) a 1M aqueous sodium hydroxide solution (2.00 ml) was added, the mixture was stirred at room temperature for 1.5 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1M hydrochloric acid (2 .00 mL). The resulting precipitate was collected by filtration to give the title compound (276 mg, 89905) as a white solid. "H NMR (300 MHz, SOSI") 6 ppm 1.28 - 1.43 ( m, 1 H), 1.44 - 1.80 (m, 6 H), 1.89 - 2.03 (m, 1

H), 2.25 - 2.43 (m, 1 H), 2.48 (s, C H), 2.56 (t, 9U-5.3 Hz, 2 H), 3.52 - 3, 63 (m, 2 H), 4.58 (d, U-9.0

Hu, 1 H), 6.45 - 6.60 (m, Z H), 7.20 - 7.28 (m, 1 H), 7.29 - 7.37 (m, 1 H), 7, 46 (d, 9-8.3 Hz, 2 N), 7.62 (d, 9-7.5 Hz, 1 N), 7.68 (d, 9U-7.9 Hz, 1 N).

Example Ab4 3-Ш((4-(cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid o m Son !

M SN. he sleeps (1) ethyl 3-((4-1-cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonyl I|(methyl)amino)propanoate

To the mixture of 4-16cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethyliaminophbenzoic acid (300 mg), synthesized in Example Ab3(3), ethyl 3-(methylamino)upropanoate (161 mg), 1-hydroxybenzotriazole monohydrate ( 188 mg), triethylamine (343 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (236 mg) was added, and the mixture was stirred at room temperature for 5 h. Saturated aqueous ammonium chloride solution to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give the title compound (228 mg, 5895) as a pale brown oil.

IN NMR (300 MHz, SOSI") b m.h. 1.21 (t, 9-7.2 Hz, C H), 1.31 - 1.44 (m, 1 H), 1.45 - 1.83 (m, b H), 1.89 - 2 .04 (m, 1 N), 2.28 - 2.43 (m, 1 N), 2.49 (s, Z H), 2.59 (t, 9-7.1 Hz, 2 N), 2.98 (c, Z

H), 3.68 (t, 957.1 Hz, 2 H), 4.09 (k, d57.2 Hz, 2 H), 4.27 - 4.33 (m, 1 H), 453-461 (m, 1 N), 6.51 (d, 958.5 Hz, 2 N), 7.17 (d, 958.5 Hz, 2 N), 7.22 - 7.29 (m, 1 N) , 7.31 - 7.38 (m, 1 N), 7.61 - 7.66 (m, 1 N), 7.68 - 7.73 (m, 1 N). (d) 3-((4-Ycyclopentyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To a mixture of ethyl 3-((4-Hcyclopentyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonyl(methyl)aminoisopropanoate (228 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml ) added a 1 M aqueous solution of sodium hydroxide

(2.00 ml), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (198 mg, 9295) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.28 - 1.44 (m, 1 N), 1.44 - 1.79 (m, 6 N), 1.89 - 2.04 (m, 1

H), 2.26 - 2.43 (m, 1 H), 2.49 (s, C H), 2.62 (t, 9U-6.2 Hz, 2 H), 2.98 (s, With H), 3.66 (t, U-6.2 Hz, 2

H), 4.57 (d, 9-9.0 Hz, 1 H), 6.51 (d, 9U-8.5 Hz, 2 H), 7.20 (d, 9-8.5 Hz, 2 H), 7.23 - 7.30 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.64 (d, 9-7.5 Hz, 1 H), 7 .71 (d, 9-7.5 Hz, 1 N).

Example Ab5 3-Ш((4-(cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethyl|iamino)phenyl)carbonyl|(methyl)amino)propanoic acid o

M SN.

Monday

CH,

Ethyl 3-((4-1-cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoate (19.7 g), synthesized in Example

AbaA(1), was separated using high-performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by OaiseI Spetis! Ipdivihiev, Tse., mobile phase: hexane/ethanol (500/500), flow rate: 60 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a shorter retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (8.75 g, 99.995 ee). A 1M aqueous solution of sodium hydroxide (30 ml) was added to a mixture of the obtained amorphous form, ethanol (100 ml) and tetrahydrofuran (100 ml), and the mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was dissolved in water (200 ml), 1 M hydrochloric acid (30 ml) was added at 0"C and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound indicated in the title (7.54 g, 4195.99.995 ee) as a white solid. The obtained solid was recrystallized from ethanol/water to give colorless crystals. "H NMR (300 MHz, SOSI") 6 m.p.h. 1.28 - 1.44 (m, 1 N), 1.44 - 1.79 (m, 6 N), 1.89 - 2.04 (m, 1

H), 2.26 - 2.43 (m, 1 H), 2.49 (s, C H), 2.62 (t, 9U-6.2 Hz, 2 H), 2.98 (s, With H), 3.66 (t, U-6.2 Hz, 2

H), 4.57 (d, 9-9.0 Hz, 1 H), 6.51 (d, 9U-8.5 Hz, 2 H), 7.20 (d, 9-8.5 Hz, 2 H), 7.23 - 7.30 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.64 (d, 9-7.5 Hz, 1 H), 7 .71 (d, 9-7.5 Hz, 1 N).

Example Abb 3-Х((4-(cyclopentyl(3-methyl-1-benzothiophen-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid in 5 M CH, / n

SN.

Ethyl 3-((4-1-cyclopentyl(3-methyl-1-benzothiophen-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate (19.7 g), synthesized in Example

AbaA(1), was separated using high-performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by Oaise! Spetisa! Ipdivigiev, Ts., mobile phase: hexane/ethanol (500/500), flow rate: 60 ml/min, column temperature: room temperature). Fractions containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, were concentrated to give the amorphous form (8.95 g, 99.995 ee). A 1 M aqueous solution of sodium hydroxide (30 ml) was added to the mixture of the obtained amorphous form, ethanol (100 ml) and tetrahydrofuran (100 ml), and the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (200 ml), 1M hydrochloric acid (35 ml) was added at 0"C and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound indicated in the title (8.06 g, 4390, 99.995 ee) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.28 - 1.44 (m, 1 N), 1.44 - 1.79 (m, 6 N), 1.89 - 2.04 (m, 1

H), 2.26 - 2.43 (m, 1 H), 2.49 (s, C H), 2.62 (t, 9U-6.2 Hz, 2 H), 2.98 (s, With H), 3.66 (t, U-6.2 Hz, 2

H), 4.57 (d, 9-9.0 Hz, 1 H), 6.51 (d, U-8.5 Hz, 2 H), 7.20 (d, U-8.5 Hz, 2 H), 7.23 - 7.30 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.64 (d, 9-7.5 Hz, 1 H), 7 .71 (d, 9-7.5 Hz, 1 N).

Example Ab7

Ethyl 3-((4-Tcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoate

Her wounds - m -0-

Fe -4 5-

En, (1) (2d-acetyl-4-fluorophenoxy)acetic acid

A solution of 5'-fluoro-2-hydroxyacetophenone (25.0 g), methyl bromoacetate (27.2 g), potassium carbonate (33.6 g) in M,M-dimethylformamide (250 ml) was stirred at room temperature for 1.5 g. The insoluble material was filtered off, 1M hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown oil. Tetrahydrofuran (300 ml), ethanol (300 ml) and 1 M aqueous sodium hydroxide solution (300 ml) were added to the obtained oil, and the mixture was stirred at room temperature for 30 min. The solvent was concentrated under reduced pressure, 1M hydrochloric acid (300 ml) was added, and the resulting crystals were collected by filtration.

The crystals were dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (23.7 g, 6995) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 2.68 (s, C H), 4.75 (s, 2 H), 6.86 - 7.03 (m, 1 H), 7 .13 - 7.30 (m, 1 H), 7.43 - 7.60 (m, 1 H). (2) 5-fluoro-3-methyl-1-benzofuran

A mixture of (2-acetyl-4-fluorophenoxy)acetic acid (22.94 g) synthesized above, sodium acetate (44.38 g) and acetic anhydride (200 ml) was stirred at 110 C for 15 h.

The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate.

After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (MN silica gel, hexane) to give the title compound (14.73 g, 9195) as a yellow oil.

"IN NMR (300 MHz, SOSI") b m.ch. 2.20 (s, Z H), 6.91 - 7.03 (m, 1 H), 7.15 (dd, U-8.3 , 2.7 Hz, 1 H), 7.35 (dd, 9U-8.7, 4.2 Hz, 1 H), 7.42 (s, 1 H). (3) cyclopentyl (5-fluoro- 3-methyl-1-benzofuran-2-yl)methanone

Aluminum chloride (anhydrous) (2.66 g) was added to a solution of 5-fluoro-3-methyl-i-benzofuran (2.0 g) synthesized above, cyclopentanecarbonyl chloride (1.94 g) in nitromethane (40 ml) at 0 "C and the mixture was stirred for 3 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 1000 - 955 , o/o) to give the title compound (2.11 g, 64905) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 1.67 - 2.09 (m, 8 H), 2.57 (s, Z H), 3.64 - 3.91 (m, 1 H), 7.10 - 7.23 (m, 1 H ), 7.25 - 7.31 (m, 1 N), 7.38 - 7.53 (m, 1 N). (4) cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanol

Cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanone (27.15 g), synthesized above, was dissolved in a mixed solvent of methanol (40 ml)-tetrahydrofuran (240 ml), and at 0 C was added sodium tetrahydroborate (9095, 5.5 g). The reaction mixture was stirred at 0 "C for 2 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (29.26 g, 100905) as a yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.20 (m, 1 N), 1.42 - 1.77 (m, 6 N), 1.92 - 2.02 (m, 2

H), 2.21 (s, C H), 2.42 - 2.60 (m, 1 H), 4.56 (dd, U-9.3, 5.9 Hz, 1 H), 6, 97 (td, 9-91, 2.7 Hz, 1

NU, 7.11 (dd, U-8.7, 2.7 Hz, 1 H), 7.33 (dd, U-8.9, 4.0 Hz, 1 H). (5) ethyl 3-((4-Tcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl I|(methyl)amino)propanoate

To a solution of cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methanol (27.31 g) obtained above in tetrahydrofuran (200 ml) was added thionyl chloride (12.0 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h. An aqueous solution of sodium hydrogen carbonate cooled with ice to 0"C was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to the obtained residue added ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (28.90 g), obtained in Example 2(2), sodium iodide (16.48 g), sodium carbonate (23.3 g) and M,M-dimethylacetamide (200 ml) and the mixture was stirred at 80 "C for 18 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound (17.88 g, 3496) as a yellow amorphous substance.

Example Ab8 3-((4-Hcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

I m sh- g r, ly in; and I'm Shnny M o svo --4

ON

Ethyl 3-((4-Tcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethyl|amino)phenyl)carbonyl|(methyl)amino)upropanoate (460 mg), obtained in Example

Ab7(5) was dissolved in ethanol (1.9 ml) and tetrahydrofuran (1.9 ml), 1M aqueous sodium hydroxide solution (1.9 ml) was added, and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure . Water (6 mL) was added and the mixture was neutralized with 1 M hydrochloric acid under ice cooling and stirred for 1 h. The resulting precipitate was collected by filtration and dried to give the title compound (352 mg, 8195) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.23 - 1.74 (m, 8 H), 1.90 - 2.08 (m, 1 H), 2.24 (s, C H), 2.47 (d, 9-8.0 Gu , 1 N), 2.60 - 2.70 (m, 2 N), 3.01 (s, C H), 3.69 (t, 9U-6.6 Hz, 2 N), 4.36 ( d, 9-9.1

Hz, 1 N), 6.55 (d, 9U-8.7 Hz, 2 N), 6.86 - 6.97 (m, 1 N), 7.07 (dd, 9U-8.7, 2 .7 Hz, 1 H), 7.18 - 7.31 (m, C H).

Example Ab69 3-((4-Hcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethyl|iamino)phenyl)carbonyl|(methyl)amino)propanoic acid o;

and 0)

E m- -th dream. M o / not 4 on

Ethyl 3-((4-Tcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)aminoisopropanoate (4.18 g), obtained in Example

Ab7(5), dissolved in hexane-ethanol (1:11, volume ratio), subjected to HPLC using SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by Oaise! Spetisai!

Ipdivigiee5, Tsa.), and eluted with hexane-ethanol (1:1, volume ratio) as the mobile phase at 30 "С and at a flow rate of 60 ml/min. The resulting fraction containing the optically active form, which has shorter retention time, concentrated to obtain the amorphous form (2.07 g, 99.995 ee). The obtained amorphous form was dissolved in ethanol (9 ml) and tetrahydrofuran (9 ml), 1M aqueous sodium hydroxide solution (8.6 ml) was added, and the mixture was stirred at at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (15 mL) was added, and the mixture was neutralized with 1 M hydrochloric acid (8.6 mL) under ice cooling and stirred for 1 h. The resulting precipitate was collected by filtration and dried to give the title compound (1.81 g, 9395, 99.995 ee) as a colorless amorphous form. The obtained colorless amorphous substance (150 mg) was crystallized from 2-propanol/water to give colorless 2-propanol-containing crystals (140 mg). Another colorless amorphous ( 773 mg) of the substance obtained above and crystallized from e ethanol/water to give ethanol-containing crystals (756 mg). Ethanol-containing crystals (756 mg) were recrystallized from diethyl ether to give colorless crystals (553 mg) free of solvent.

IN NMR (300 MHz, SOSI") b m.h. 1.15 - 1.72 (m, 7 N), 1.86 - 2.09 (m, 1 N), 2.24 (s, Z H), 2.40 - 2.53 (m, 1 N ), 2.62 (t, 9-6.2 Hz, 2 N), 3.00 (s, Z H), 3.68 (t, 9-6.6 Hz, 2 N), 4.36 ( d, U-9.0

Hz, 1 N), 6.54 (d, 2-8.7 Hz, 2 N), 6.91 (td, U-8.9, 2.6 Hz, 1 N), 7.06 (dd, 9U-8.7, 2.6 Hz, 1 N), 7.19 - 7.30 (m, C N).

Example A7O0 3-((4-Hcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

E M-th U-th nn

SN, shk; not

ON

Ethyl 3-((4-Tcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)aminoisopropanoate (4.18 g), obtained in Example

Ab7(5), dissolved in hexane-ethanol (1:11, volume ratio), subjected to HPLC using SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by Oaise! Spetisai!

Ipaiviyev, Tsa.), and eluted with hexane-ethanol (1:1, volume ratio) as the mobile phase at 30 "С and at a flow rate of 60 ml/min. The resulting fraction containing an optically active form, which has longer retention time. concentrated to give the amorphous form (2.04 g, 99.995 ee). The resulting amorphous form (2.04 g) was dissolved in ethanol (9 mL) and tetrahydrofuran (9 mL), and 1 M aqueous sodium hydroxide solution (8, 5 ml) and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (15 ml) was added, and the mixture was neutralized with 1 M hydrochloric acid (8.5 ml) under ice cooling and stirred for 1 h. The resulting precipitate was collected by filtration and dried to give the title compound (1.88 g, 9895, 99.995 ee) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 1.23 - 1.75 (m, 7 N), 1.86 - 2.03 (m, 1 N), 2.25 (s, Z H), 2.39 - 2.54 (m, 1 N ), 2.63 (t, 9U-6.4 Hz, 2 H), 3.01 (s, Z H), 3.69 (t, 9U-6.6 Hz, 2 H), 4.36 ( d, 2-9,1

Hz, 1 N), 4.48 (w s, 1 N), 6.55 (d, 2-8.7 Hz, 2 N), 6.92 (td, U-8.9, 2.7 Hz , 1 H), 7.07 (dd, 9-85, 2.5 Hz, 1 H), 7.16 - 7.32 (m, C H).

Example A7/1 ethyl 3-((4-C2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butylamino)phenyl)carbonyl)(methyl)amino)propanoate

I sleep and sleep

Their name is ОН ТУ сн (1) 2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butan-1-one

Aluminum chloride (anhydrous) was added to a solution of 5-fluoro-3-methyl-1-benzofuran (12.0 g) synthesized in Example Ab7(2), 2-ethylbutyryl chloride (9.58 g) in nitromethane (240 ml) ( 12.94 g) at 0 "С and the mixture was stirred for 1.5 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 90:10, v/v) to give the title compound (15.02 g, 93905) as a yellow oil. "H NMR (300 MHz, SOCI") b m.h . 0.91 (t, 9U-7.6 Hz, 6 N), 1.59 - 1.67 (m, 2 N), 1.75 - 1.91 (m, 2 N), 2.58 (s , Z H), 3.26 - 3.42 (m, 1 H), 7.11 - 7.35 (m, 2 H), 7.40 - 7.55 (m, 1 H). (2) 2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butan-1-ol

2-Ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butan-1-one (15.0 g), synthesized above, was dissolved in a mixed solvent of methanol (50 mL)-tetrahydrofuran ( 250 ml), and sodium tetrahydroborate (9095, 5.1 g) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1.5 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (16.17 g, 10095) as a colorless oil. "H NMR (300 MHz, SOSI") b m.p. 0.75 - 0.86 (m, Z H), 0.95 (t, 9U-7.6 Hz, Z H), 1.10 - 1.35 (m, 2 H), 1.66 - 1.94 (m, C H), 2.21 (s, C H), 4.66 - 4.81 (m, 1 H), 6, 90 - 7.02 (m, 1 H), 7.11 (dd, 9uEV,7, 2.7 Hz, 1 H), 7.30 - 7.40 (m, 1 H). (3) methyl 4 -D2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|amino)benzoate

To a solution of / 2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butan-i-ol (1.00 (g), synthesized above, in tetrahydrofuran (10 ml) was added thionyl chloride (320 μl) and the mixture was stirred at room temperature for 3.5 g. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil ( 1.11 g).A solution of this yellow oil (1.11 g), methyl 4-aminobenzoate (638 mg), sodium iodide (1.20 g) and sodium carbonate (852 mg) in M,M-dimethylformamide (10 ml ) were stirred at 100 C for 20 g. Water was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate 90:10, v/ o) obtaining the title compound (790 mg, 5290) as a yellow oil at. "H NMR (300 MHz, SOSI") b m.h. 0.95 (t, 9U-7.5 Hz, 6 N), 1.62 - 1.73 (m, 2 N), 1.84 - 1.94 (m, 2 H), 2.23 (s, Z H), 3.81 (s, Z H), 4.46 - 4.52 (m, 1 H), 4.56 - 4, 65 (m, 1 N), 4.68 - 4.76 (m, 1 N), 6.54 - 6.61 (m, 2 N), 6.85 - 7.00 (m, 1 N), 7.04 - 7.15 (m, 1 H), 7.29 - 7.37 (m, 1 H), 7.80 (d, 959.0

Hz, 2 N). (4) 4-H2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|amino)dbenzoic acid

To a mixture of methyl 4-(2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|iaminophenzoate (709 mg), synthesized above, tetrahydrofuran (b ml) and ethanol (b ml ) a 1M aqueous solution of sodium hydroxide (3.7 ml) was added and the mixture was heated under reflux for 14 h. A 1M aqueous solution of sodium hydroxide (4.0 ml) was added and the mixture was further stirred while heating under reflux for 2 h. To the mixture an 8M aqueous solution of sodium hydroxide (2.0 ml) and ethanol (2 ml) were added, and the mixture was further stirred under reflux for 1 h. The reaction mixture was concentrated under reduced pressure, an 8M aqueous solution of sodium hydroxide (4.0 ml) was added , ethanol (4 ml) and tetrahydrofuran (4 ml) and the mixture was further stirred under reflux for 1 h. The reaction mixture was allowed to cool to room temperature, 1 M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulfate magnesium and concentrated at reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0 - 70:30, v/v) to give the title compound (412 mg, 6195) as a colorless amorphous form. "H NMR (300 MHz, SOSI") 6 m.h. 0.80 - 1.02 (m, 6 H), 1.32 - 1.72 (m, 4 H), 1.83 - 1.97 (m, 1

H), 2.23 (s, C H), 4.51 - 4.71 (m, 2 H), 6.57 (d, 9U-8.7 Hz, 2 H), 6.87 - 6, 98 (m, 1 H), 7.07 (dd, 9UEV,Z3, 2.7 Hz, 1 H), 7.27 - 7.35 (m, 1 H), 7.86 (d, 9-8 ,7 Gu, 2 N). (5) ethyl 3-((4-T2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butylamino)phenyl)carbonyl)(methyl)amino)propanoate

A mixture of 4-C2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|amino)benzoic acid (10.77 g) synthesized above, ethyl 3-(methylamino)propanoate ( 4.59 g), 1-hydroxybenzotriazole monohydrate (5.34 g), triethylamine (3.53 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.69 g) and M,M-dimethylformamide (100 ml) was stirred at room temperature for 14 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0 - 0:100, 0/0) to give the title compound (9.83 g, 70905) as a yellow amorphous substance. "H NMR (300 MHz, SOSI") b mp 0.80 - 0.88 (m, З Н), 0.95 (t, 9U-7.3 Hz, З Н), 1.19 - 1.25 (m,

H), 1.33 - 1.54 (m, 2 H), 1.87 (dt, 2-7.3, 4.9 Hz, 1 H), 2.22 (s, C H), 2, 61 (t, 2-7.0 Hz, 2 H), 3.01 (s, Z H), 3.70 (t, U9-7.2 Hz, 2 H), 4.11 (k, U-6 .9 Hz, 2 N), 4.28 (d, 2-8.7 Hz, 1 N), 4.56 (t, uU-8.3 Gu, 1 N), 6.56 (d, 9U- 8.7 Hz, 2 N), 6.92 (td, 9U-9.0, 2.6 Hz, 1 N), 7.06 (dd, U-8.3, 2.6 Hz, 1

H), 7.22 (d, 98.7 Hz, 2 H), 7.25 - 7.31 (m, 1 H).

Example A72 3-4(4-(2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid i in - - i o

And year Z no sh y

E -7 in N M in Dt x

Sn» B - r on

To the mixture of ethyl 3-1(4-C2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoate (132 mg) , obtained in Example

A71(5), in tetrahydrofuran (1 ml) and ethanol (1 ml) was added a 1 M aqueous solution of sodium hydroxide (0.54 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water (4 ml) and at 07 was added 1M hydrochloric acid (0.54 ml). The mixture was stirred at 0 °C for 1 h and the resulting precipitate was collected by filtration to give the title compound (103 mg, 7090) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 0.79 - 1.01 (m, 6 H), 1.12 - 1.90 (m, 6 H), 2.21 (s, Z H), 2.58 - 2.69 (m, 2 H ), 3.00 (s, C H), 3.66 (d, 2 H), 4.56 (d, 2-8.0 Hz, 1 H), 6.55 (d, 2-8.3 HC, 2 H), 6.92 (td, U-8.9, 2.7 Hz, 1 H), 7.06 (dd, 9U-8.3, 2.7 Gu, 1 H), 7, 19 - 7.36 (m, Z H).

Example A7Z 3-4(4-(2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid

SN

What the hell, -

IT; 4 she Y i r tn is: -dy i nM-k as

Ma M / n- o se 4

He

Ethyl 3-1(4-C2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl|)(methyl)aminoisopropanoate (9.18 g), obtained in Example

А71(5), dissolved in hexane-ethanol (1:11, volume ratio), subjected to VRH using SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by Oaise! Spetisai!

Ipdivigiee5, Tsa.), and eluted with hexane-ethanol (1:1, volume ratio) as the mobile phase at room temperature and at a flow rate of 60 ml/min. The resulting fraction containing the optically active form, which has a shorter retention time, was concentrated to give the amorphous form (4.56 g, 99.995 ee). The obtained amorphous form (4.56 g) was dissolved in ethanol

(19 ml) and tetrahydrofuran (19 ml), 1M aqueous sodium hydroxide solution (18.6 ml) was added and the mixture was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure. Water (30 ml) was added and the mixture was neutralized with 1M hydrochloric acid (18.6 ml) under ice cooling and stirred for 20 min. The resulting precipitate was collected by filtration and dried to give the title compound (3.63 g, 86905, 99.995 ee) as a colorless amorphous form. The obtained colorless amorphous form (1.0 g) was crystallized from 2-propanol/water to give colorless crystals (927 mg). 0.85 (t, 9U-7.3 Hz, Z H), 0.94 (t, 9U-7.5 Hz, Z H), 1.11 -1.72 (m, 4 H), 1, 77 - 1.92 (m, 1 H), 2.22 (s, C H), 2.65 (t, 9U-6.6 Hz, 2 H), 3.02 (s, C H), 3 ,69 (t, 9U-6,8

Hz, 2 N), 4.56 (d, 9-7.9 Gu, 1 N), 6.55 (d, 98.7 Hz, 2 N), 6.92 (td, 99.0, 2, 6 Hz, 1 H), 7.06 (dd, 9UEV,5, 2.4 Gu, 1 H), 7.18 - 7.39 (m, C H).

Example A74 3-4(4-(2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid sn ka bn San U--

SS and 7 Zashchei that - -

SN shi l o sna - on

Ethyl 3-1(4-C2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl|)(methyl)aminoisopropanoate (9.18 g), obtained in Example

А71(5), dissolved in hexane-ethanol (1:11, volume ratio), subjected to VRH using SNIKAGRAK AYU (50 mm Hx500 mm D, manufactured by Oaise! Spetisai!

Ipdivigiee5, Tsa.), and eluted with hexane-ethanol (1:1, volume ratio) as the mobile phase at room temperature and at a flow rate of 60 ml/min. The resulting fraction containing the optically active form, which has a longer retention time, was concentrated to obtain the amorphous form (4.67 g, 99.995 ee). The obtained amorphous form (4.67 g) was dissolved in ethanol (20 ml) and tetrahydrofuran (20 ml), 1M aqueous sodium hydroxide solution (19.4 ml) was added, and the mixture was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure. Water (30 ml) was added and the mixture was neutralized with 1 M hydrochloric acid under ice cooling and stirred for 20 min. The resulting precipitate was collected by filtration and dried to give the title compound (4.21 g, 9690, 99.995 ee). "H NMR (300 MHz, SOSI") b mp 0.80 - 0.89 (m, Z H), 0.94 (t, 9U-7.5 Hz, Z H), 1.16 - 1.71 (m, 4 N), 1.74 - 1.91 (m, 1 N), 2.22 (s, Z H), 2.62 (t, 96.2 Hz, 2 N), 3 ,01 (c, Z H), 3.61 - 3.76 (m, 2

H), 4.56 (d, 9-7.9 Hz, 1 H), 6.55 (d, 9U-8.7 Hz, 2 H), 6.92 (td, 99.0, 2.6 Hz, 1 H), 7.06 (dd, 9UEV,5, 2.4 Gu, 1 H), 7.16 - 7.31 (m, C H).

Example A75 ethyl 3-K4-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanesate not o) sn, in (o)

In M- In (

N sn, shko ne she

CH, (1) 1-bromo-3-methylbutan-2-one

To a solution of 3-methyl-2-butanone (43.0 g) in methanol (300 ml), bromine (80 g) was added dropwise over 20 min while cooling in an ice bath. The ice bath was removed and the mixture was stirred at room temperature for 40 min. Water (450 ml) was added to the reaction mixture and the mixture was stirred for 20 min. The reaction mixture was extracted twice with diethyl ether (500 ml). The extract was washed with water (400 mL), 1095 aqueous potassium carbonate solution (400 mL) and saturated brine (200 mL), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (55.9 g) as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.17 (d, U-6.8 Hz, 6 N), 2.88 - 3.05 (m, 1 N), 3.98 ( c, 2 H). (2) 1-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-one

A solution of 2',5'-dihydroxyacetophenone (25.0 g), bromomethylcyclopropane (24.43 g), potassium carbonate (27.2 g) in acetonitrile (400 ml) was stirred under reflux for 2.5 g. bromomethylcyclopropane (4.4 g) was added to the mixture, and the mixture was further stirred under reflux for 14 g.

The reaction mixture was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate 1000 - 10:90, v/v) to give 1-(5-(cyclopropylmethoxy)-2-hydroxyphenyl|ethanone (35.5 g) as a yellow oil with a purity of 7095. Solution of the obtained 1-|5-(cyclopropylmethoxy)-2-hydroxyphenyl|ethanone (35.5 g), 1-bromo-3-methylbutan-2-one (35.5 g), synthesized above, and potassium carbonate (66.3 d) in M,M-dimethylformamide (350 ml) was stirred at room temperature for 1 h.

Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the resulting residue were added 1,8-diazabicyclo(|5.4.FOIundec-7-ene (22.5 ml) and M,M-dimethylformamide (300 ml) and the mixture was stirred at 100 "C for 30 min. The reaction mixture was cooled to room temperature temperature, 1M hydrochloric acid (300 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate 100:0 - 90:10, v/ o) obtaining the title compound (19.91 g, 4595) as a colorless solid.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.29 - 0.50 (m, 2 H), 0.61 - 0.73 (m, 2 H), 1.01 - 1.46 (m, 7

H), 2.57 (s, C H), 3.44 - 3.68 (m, 1 H), 3.86 (d, 9-7.2 Hz, 2 H), 7.00 (d, 9-2.3 Hz, 1 H), 7.11 (dd, y-9.0, 2.6 Hz, 1 H), 7.39 (d, y-9.0 Gu, 1 H). (3) 1-(5-(Cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol 1-(5-"Cyclopropylmethoxy)-3-methyl-1-benzofuran-2 -yl|-e-methylpropan-i-one (19.91 g), synthesized above, was dissolved in a mixed solvent of methanol (40 ml)-tetrahydrofuran (200 ml) and sodium tetrahydroborate (9095, 5.53 d). The reaction mixture was stirred at 0"C for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the title compound (22.74 g, 100905), as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.32 - 0.42 (m, 2 H), 0.60 - 0.71 (m, 2 H), 0.81 (d, Z H), 1.12 (d, 9-6.4 Hz , Z H), 1.26 - 1.36 (m, 1 H), 1.99 (d, 9U-6.0 Hz, 1 H), 2.17 - 2.28 (m, 4 H), 3.84 (d, 2 H), 4.45 (dd, U-8.3, 6.4 Hz, 1 H), 6.84 - 6.96 (m, 2 H), 7.29 (d , 928.7 Hz, 1 N).

(4) ethyl 3-K4-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2- methylpropyl)amino)phenylcarbonylmethyl)amino|propanesate

Thionyl chloride (6, 4 ml) at room temperature. The reaction mixture was stirred at room temperature for 1.5 g. An aqueous solution of sodium bicarbonate cooled to 0 "C with ice was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, ethyl 3-((4-aminophenyl)carbonyl|(methyl)aminopropanoate (19.2 g), obtained in Example 2(2), sodium iodide (21.9 g), carbonate sodium (15.4 g) and M,M-dimethylacetamide (200 ml) and the mixture was stirred at 80 C for 1.5 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate After filtration, the filtrate was concentrated and the residue was subjected to columns Chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) afforded the title compound (18.34 g, 5096) as a yellow amorphous substance. "H NMR (300 MHz, SOSI") b mp 0.29 - 0.40 (m, 2 H), 0.58 - 0.70 (m, 2 H), 0.91 (d, U -6.8 Hz,

With H), 1.12 (d, 9U-6.8 Hz, With H), 1.19 - 1.33 (m, 4 H), 2.17 - 2.28 (m, 4 H), 2 .61 (t, 2-6.8 Hz, 2 H), 3.01 (s, Z H), 3.70 (t, 927.2 Hz, 2 H), 3.82 (d, 9-7 ,2 Hz, 2 N), 4.05 - 4.16 (m, 2 N), 4.27 - 4.38 (m, 2 N), 6.57 (d, 959.0 Hz, 2 N) , 6.78 - 6.91 (m, 2 H), 7.17 - 7.25 (m, C H).

Example A76 3-N4-(11-(-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoic acid not

And about nN

SN, shk; not him

To the mixture oethyl o 3-Sh4-31-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoate (667 mg), obtained in

Example A75(4), in tetrahydrofuran (3 ml) and ethanol (3 ml) was added 1M aqueous solution of sodium hydroxide (2.6 ml) and the mixture was stirred at room temperature for 30 min.

The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (4 ml) and 1M hydrochloric acid (2.6 ml) was added at 0°C. The mixture was stirred at 0° for 30 min and the resulting precipitate was collected by filtration to give the title compound ( 509 mg, 8195), as a colorless amorphous form. "H NMR (300 MHz, SOSI") b mp 0.28 - 0.40 (m, 2 H), 0.58 - 0.71 (m, 2 H), 0.91 (d, U -6.8 Hz,

With H), 1.11 (d, 9U-6.8 Hz, With H), 1.23 - 1.34 (m, 1 H), 2.17 - 2.28 (m, 4 H), 2 .64 (t, 2-64 Hz, 2 H), 3.02 (s, Z H), 3.69 (t, 9U-6.4 Hz, 2 H), 3.82 (d, 97.2 Hz, 2 N), 4.31 (d, 9U-8.0 Gu, 1 N), 6.56 (d, 9uEB8.7 Hz, 2 N), 6.78 - 6.91 (m, 2 N ), 7.19 - 7.25 (m, Z H).

Example A77 3-X4-(11-(-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|Ipropanoic acid

Sara still uv -- Х шт у; m U and ut sno - n

Ethyl 3-K4-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoate (18.23 g), obtained in

Example A75(4), dissolved in hexane-ethanol (1:11, volume ratio), subjected to

TOP using SNIKAI RAK AYU (50 mm Hx500 mm D, manufactured by Oaisei

Spetisai Ipaivigiev, Tsa.), and eluted with hexane-ethanol (1:1 - 1:4, volume ratio) as a mobile phase, at room temperature and at a flow rate of 60 - 50 ml/min. The resulting fraction containing the optically active form, which has a shorter retention time, was concentrated to obtain the amorphous form (9.08 g, 99.995 ee). The obtained amorphous form (4.72 g) was dissolved in ethanol (19 ml) and tetrahydrofuran (19 ml), 1M aqueous sodium hydroxide solution (183.6 ml) was added, and the mixture was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure. Water (40 ml) was added and the mixture was neutralized with 1M hydrochloric acid (18.6 ml) under ice cooling and stirred for 20 min. The resulting precipitate was collected by filtration and dried to give the title compound (4.27 g, 9695, 99.995 ee) as a colorless amorphous form.

IN NMR (300 MHz, SOS") b m.h. 0.31 - 0.38 (m, 2 N), 0.58 - 0.68 (m, 2 N), 0.90 (d, 9U-6.8 Hz,

Z H), 1.12 (d, 96.4 Hz, Z H), 1.28 (s, 1 H), 2.17 - 2.29 (m, A H), 2.63 (t, 9 -6.4 Hz, 2 N), 3.01 (s,

With H), 3.69 (t, 9U-6.4 Hz, 2 H), 3.82 (d, 9U-6.8 Hz, 2 H), 4.31 (d, 9-7.5 Hz , 1 H), 6.56 (d, 9-8.7 Hz, 2 H), 6.78 - 6.89 (m, 2 H), 7.19 - 7.27 (m, C H).

Example A78 3-Х4-(11-(-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenyl(carbonylmethyl)amino|ipropanoic acid snadit 0 --СНУ

A G G- A Y in tal tOnm r

Sa and re

SN -

ON

Ethyl 3-CH4-41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-g-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoate (18.23 g), obtained in

Example A75(4), dissolved in hexane-ethanol (1:11, volume ratio), subjected to

TOP using SNIKAI RAK AYU (50 mm Hx500 mm D, manufactured by Oyuaisei!

Spetisai Ipaivigiev, Tsa.), and eluted with hexane-ethanol (1:1 - 1:4, volume ratio) as a mobile phase, at room temperature and at a flow rate of 60 - 50 ml/min. The resulting fraction containing the optically active form, which has a longer retention time, was concentrated to give the amorphous form (9.08 g, 99.995 ee). The obtained amorphous form (4.73 g) was dissolved in ethanol (19 ml) and tetrahydrofuran (19 ml), 1M aqueous sodium hydroxide solution (18.7 ml) was added, and the mixture was stirred at room temperature for 20 min. The solvent was evaporated under reduced pressure. Water (40 ml) was added and the mixture was neutralized with 1M hydrochloric acid (18.7 ml) under ice cooling and stirred for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound (4.02 g, 9095, 98.895 ee) as a colorless amorphous form.

The obtained colorless amorphous form (500 mg) was dissolved in ethyl acetate and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate.

After filtration, the filtrate was concentrated to obtain a colorless amorphous substance.

The obtained colorless amorphous form was crystallized from ethyl acetate/hexane to give colorless crystals (401 mg). An amorphous product (60 mg) obtained by separate crystallization from diethyl ether/hexane was added to obtain colorless crystals (45

MG). "H NMR (300 MHz, SOSIz") b mp 0.27 - 0.42 (m, 2 H), 0.56 - 0.66 (m, 2 H), 0.91 (d, U -6.8 Hz,

With H), 1.12 (d, 96.8 Hz, With H), 1.28 (s, 1 H), 2.18 - 2.28 (m, 4 H), 2.66 (t, 9U -6.4 Hz, 2 N), 3.03 (s,

With H), 3.70 (t, U-6.6 Hz, 2 H), 3.82 (d, 9-7.2 Hz, 2 H), 4.31 (d, 9-7.5 Hz , 1 H), 6.56 (d, 9-8.7 Hz, 2 H), 6.73 - 6.89 (m, 2 H), 7.19 - 7.25 (m, C H).

Example A79 3-(4-(H-Cyclohexyl-5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid ro a 7 in Zhran AJ

Y G Her o ON

C "m -- Zshiy x E U. - o - -fOH (1) 1-(2-hydroxy-5-(2-methoxyethoxy)phenyl|ethanone

To a solution (250 mL) of 1-(2,5-dihydroxyphenyl)ethanone (11.0 g) in acetonitrile at room temperature was added 2-methoxyethyl bromide (19.6 mL) and potassium carbonate (12.0 g), and the mixture was heated with under reflux for 15 h. The reaction mixture was allowed to cool to room temperature and was filtered through celite and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:10, v/v) to give the title compound (7.6 g, 5095) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.p. 2.61 (s, C H), 3.46 (s, C H), 3.66 - 4.21 (m, 4 H), 6 .92 (d, 9U9.O Hz, 1 N), 7.15 (d, 959.0 Hz, 1 N), 7.22 - 7.26 (m, 1 N), 11.84 (s, 1 H). (2) cyclohexyl(|5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methanone 1-(2-Hydroxy-5-(2-methoxyethoxy)phenyl|ethanone (7, 0 g) synthesized in the above-mentioned (1) was dissolved in M,M-dimethylformamide (140 ml). Potassium carbonate (13.8 g) and 2-bromo-1-cyclohexylethanone (8.9 g) were added to the reaction mixture at room temperature ), synthesized in Example A5B1(1) and the mixture was stirred for 15 g. The reaction mixture was filtered through celite, water (200 ml) was added and the mixture was extracted with diethyl ether (100 mlx2). The extract was washed with saturated brine, dried over magnesium sulfate and concentrated at under reduced pressure. The residue was dissolved in M,M-dimethylformamide (100 mL), OVI (5.3 mL) was added at room temperature, and the mixture was stirred at 10070 for 1 h. The reaction mixture was allowed to cool to room temperature, 1M was added hydrochloric acid (100 ml) and the mixture was extracted with diethyl ether (100 mlx2). The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:20, v/v) to give the title compound (10.3 g, 9895) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.32 - 2.00 (m, 11 N), 2.56 (s, C H), 3.30 (d, 9U-3.4 Hz, 1 H), 3.48 (s, C H) , 3.75 - 3.85 (m, 2 H), 4.15 - 4.25 (m, 2 H), 7.04 (d, 952.5 Hz, 1 H), 7.13 (dd, 9-8.9, 2.5 Hz, 1 N), 7.40 (d, 9-8.9 Hz, 1 N).

(3) cyclohexyl(|5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methanol

Cyclohexyl(5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methanone (10.3 g) synthesized in the above-mentioned (2) was dissolved in a mixed solvent of tetrahydrofuran (180 ml) and methanol (20 The reaction mixture was cooled with ice, sodium borohydride (90965, 2.7 g) was added and the reaction mixture was stirred at room temperature for 2 h.

The reaction mixture was cooled again with ice, water (10 mL) and 1M hydrochloric acid (100 mL) were carefully added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (10.3 g) of the title compound as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.p. 1.15 - 2.02 (m, 11 H), 2.56 (s, C H), 3.48 (s, C H), 3 .73 - 3.87 (m, 2 H), 4.14 - 4.26 (m, 2 H), 4.44 -4.A46b (m, 1 H), 7.04 (d, 952.6 Hz, 1 H), 7.13 (dd, 959.0, 2.6 Hu, 1 H), 7.40 (d, 2-9.0 Hu, 1 H). (4) ethyl 3-FSH4- (cyclohexyl5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate

Thionyl chloride ( 4.7 ml). The reaction mixture was stirred at room temperature for 30 min and cooled with ice, and a saturated aqueous solution of sodium bicarbonate (100 mL) was carefully added. The reaction mixture was stirred for 1 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (150 ml), sodium iodide (8.0 g), sodium carbonate (5.3 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (8.9 g) were added ), synthesized in

Example 2(2), and the mixture was stirred at 80C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (8.5 g, 4390) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.92 - 2.14 (m, 14 N), 2.21 (s, C H), 2.61 (t, 9-6.8 Hz, 2 N), 3.01 (s, C H) , 3.46 (c, Z H), 3.60 - 3.81 (m, 4 H), 4.01 -4.21 (m, 4 H), 4.27 - 4.46 (m, 2 H), 6.56 (d, U-8.3 Hz, 2 H), 6.76 - 6.95 (m, 2 H), 7.14 - 7.25 (m, C H). (5) 3-X4-(cyclohexyl5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

Ethyl 3-X4-(cyclohexyl15-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylXmethyl)amino|Ipropanoate (5.4 g) was synthesized in the above-mentioned (4), dissolved in ethanol (150 ml), at room temperature a 1 M aqueous solution of sodium hydroxide (15 ml) was added, and the mixture was stirred at 50 "C for 0.5 g. The ethanol was evaporated under reduced pressure, 1 M hydrochloric acid (20 ml) was added to the residue and the mixture was extracted with diethyl ether.The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to afford the title compound (3.0 g, 59905) as a white solid "IN NMR (300 MHz, SOSI") b m.h. 0.92 - 2.14 (m, 12 N), 2.21 (s, C H), 2.66 (t, U-6.1 Hz, 2 N), 3.03 (s, C H) , 3.46 (s, Z H), 3.60 - 3.81 (m, 4 H), 4.01 - 4.21 (m, 4 H), 4.35 (d, 2-7.8 Hz, 2 N), 6.55 (d, 2-8.7 Hz, 2 N), 6.76 - 6.95 (m, 2 N), 7.14 - 7.25 (m, C H) .

Example ABO 3-(4-(Hcyclohexylyl5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

Mo 3-(4-(H-Cyclohexyl-5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenyl-carbonylUumethyl)amino|propanoic acid 3-((4-(Cyclohexyl(5-(2 -methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino)propanoic acid (3.0 g), synthesized in

Examples A79(5) were separated using high-performance liquid chromatography (column: SNIKAG RAK AO (5 mm Wx500 mm D, manufactured by Oaise! Spetisai! Ipdivigiev5, a. mobile phase: hexane/2-propanol/trifluoroacetic acid (500/500/ 1), flow rate: 60 ml/min, column temperature: 30 7C).Triethylamine (10 ml) was added to the fraction containing the optically active form, which has a shorter retention time under the conditions of the above-mentioned high-performance chromatography, and the mixture was concentrated to obtain the triethylamine salt (3.7 g) of the title compound. To this was added 1M hydrochloric acid (30 mL) and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.49 g, 99.9905 ee) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 0.92 - 2.14 (m, 12 N), 2.21 ( s, Z H), 2.66 (t, 9-61 Hz, 2 H), 3.03 (s, Z H), 3.46 (s, Z H), 3.60 - 3.81 (m , 4 H), 4.01 - 4, 21 (m, 4 N), 4.35 (d, 2-7.8 Hz, 2 N), 6.55 (d, 2-8.7 Hz, 2 N), 6.76 - 6.95 ( m, 2 H), 7.14 - 7.25 (m, C H).

Example A81 3-(4-(H-Cyclohexyl-5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)iamino)phenylcarbonylmethyl)amino|propanoic acid o IF. dr o M / n x sha o (1) 3-X4-(cyclohexylyl5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylUumethyl)amino|propanoic acid 3-(( 4-(Cyclohexyl(5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino)propanoic acid (3.0 g), synthesized in

Examples A79(5) were separated using high-performance liquid chromatography (column: SNIKAG RAK AYU (50 mm Wx500 mm D, manufactured by Oaise! Spetisai! Ipaivipev, a. mobile phase: hexane/2-propanol/trifluoroacetic acid (500/500/ 1), flow rate: 60 ml/min, column temperature: 30 7C).Triethylamine (30 ml) was added to the fraction containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, and the mixture was concentrated to obtain the triethylamine salt (9.2 g) of the title compound. To this was added 1M hydrochloric acid (30 mL) and the mixture was extracted with diethyl ether. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.50 g, 99.990 ee) as a white solid.

"H NMR (300 MHz, SOSI") b m.ch. 0.92 - 2.14 (m, 12 N), 2.21 (s, C H), 2.66 (t, 9-61 Hz, 2 H), 3.03 (s, Z H), 3.46 (s, Z H), 3.60 - 3.81 (m, 4 H), 4.01-4.21 (m, 4 H ), 4.35 (d, 2-7.8 Hz, 2 N), 6.55 (d, 9-8.7 Hz, 2 N), 6.76 - 6.95 (m, 2 N), 7.14 - 7.25 (m, Z H).

Example A82 3-((4-(H-Cyclohexyl3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl(IcarbonylHmethyl)amino|propanoic acid? (9) du about M

СА оо ше (1) 1-(5-(benzyloxy)-2-hydroxyphenyl|ethanone

To a solution (400 mL) of 1-(2,5-dihydroxyphenyl)ethanone (25.0 g) in acetonitrile at room temperature was added benzyl bromide (19.6 mL) and potassium carbonate (25.0 g) and the mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a solid. The resulting solid was washed with ethanol-isopropyl ether to give the title compound (31.0 g, 80905) as a yellow-green solid. "H NMR (300 MHz, SOSIZ") b m.p. 2.58 (s, C H), 5.05 (s, 2 H), 7.11 - 7.53 (m, 8 H), 11 .85 (c, 1

N). (2) (5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|(cyclohexyl)methanone

Potassium carbonate (41, 4 g) and 2-bromo-1-cyclohexylethanone (25.0 g), synthesized in Example

AB1(1), and the mixture was stirred at 60"C for 15 g. The reaction mixture was allowed to cool to room temperature, filtered through Celite. Water was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated at under reduced pressure to give a solid. The resulting solid was washed with ethanol-isopropyl ether to give the title compound (18.0 g, 4395) as a pale yellow solid. h 1.17 - 2.10 (m, 10 N), 2.56 (s, Z H), 3.17 - 3.43 (m, 1 H), 5.12 (s, 2 N), 7, 04 - 7.21 (m, 2 N), 7.30 - 7.51 (m, 6 N). (3) cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|(cyclohexyl)methanone (7.3 g ) synthesized in the above-mentioned (2), was dissolved in ethanol (150 ml) and tetrahydrofuran (30 ml) and palladium charcoal-ethylenediamine complex (1.0 g) was added at room temperature. The reaction mixture was stirred at 60 "C for 3 h in under hydrogen (1 atm), allowed to cool to room temperature, and the catalyst was filtered.The filtrate was concentrated under reduced pressure to give the crude product (5.2 g, quant.) of the title compound as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.21 - 2.03 (m, 10 N), 2.54 (s, Z H), 3.22 - 3.38 (m, 1 H), 4.78 (w s, 1 H), 6 .96 - 7.05 (m, 2 N), 7.38 (d, 9-9.5 Hz, 1 N). (4) cyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methanone

Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (5.2 g), synthesized in (3) mentioned above, was dissolved in dimethylformamide (100 ml) and potassium phosphate was added to the mixture at room temperature (7.4 g) and tetrahydro-2H-pyran-4-yl o /-4-methylbenzenesulfonate (9.0 g) synthesized by the method of EP-A-1367058, and the mixture was stirred at 80 "C overnight. The reaction mixture was left cooled to room temperature, water (150 ml) was added and the mixture was extracted with diethyl ether (100 mlx2). The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:10, volume ratio) to give the indicated in title compound (7.1 g, 9995) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.35 - 2.10 (m, 14 N), 2.56 (s, Z H), 3.24 - 3.38 (m, 1 N), 3.50 - 3.65 (m, 2 N ), 3.95 - 4.07 (m, 2 N), 4.50 (tt, 9-7.8, 3.9 Gu, 1 N), 7.04 - 7.16 (m, 2 N) , 7.42 (d, U-8.7 Gu, 1 H). (5) cyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methanol

Cyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methanone (7.1 g) synthesized in the above mentioned (4), dissolved in tetrahydrofuran (200 ml) and methanol (20 ml) and sodium borohydride (9090, 1.6 g) was added under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 h.

The reaction mixture was cooled again with ice, water (10 mL) and 1M hydrochloric acid (100 mL) were carefully added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (6.7 g, 9895) of the title compound as a pale yellow oil.

IN NMR (300 MHz, SOSIZz) b m.ch. 0.82 - 2.14 (m, 15 N), 2.18 (s, Z H), 3.57 (ddd, U-11.6, 8.4, 3.4 Hz, 2 N), 3 .93 - 4.06 (m, 2 N), 4.36 - 4.59 (m, 2 N), 6.89 (dd, 9U-8.7, 2.3 Hz, 1 N), 6, 97 (d, 9-2.3 Hz, 1 N), 7.31 (d, 2-8.7 Hz, 1 N). (b) ethyl. 3-((4-((cyclohexyl13-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate

Cyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methanol (6.7 g) synthesized in the above-mentioned (5), dissolved in tetrahydrofuran (120 ml) , and thionyl chloride (2.6 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (100 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (100 ml), sodium iodide (5.3 g), sodium carbonate (3.5 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate (4.9 g) were added. , synthesized in

Example 2(2), and the mixture was stirred at 80"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (6.1 g, 54906) as a yellow oil. "H NMR (300 MHz, SOSI") b m.ch. 1.00 - 2.10 (m, 18 N), 2.21 (s, C H), 2.61 (t, U-7.0 Hz, 2 H), 3.01 (s, Z H), 3.55 (ddd, 9U-11.7, 8.5, 3.2 Hz, 2 H), 3.70 (t, 9U-7 ,0 Hz, 2 N), 3.90 - 4.05 (m, 2 N), 4.27 - 4.52 (m, 4 N), 6.56 (d, 9-8.7 Hz, 2 H), 6.77 - 6.96 (m, 2 H), 7.15 - 7.25 (m, C H). (7) 3-Х4-(cyclohexyl|3-methyl-5-(tetrahydro- 2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl(carbonylmethyl)amino|propanoic acid

Ethyl 3-F4-(Ccyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylXmethyl)amino|Ipropanoate (0.6 g) synthesized in (b) mentioned above was dissolved in ethanol (20 ml), 1 M aqueous sodium hydroxide solution (3 ml) was added at room temperature and the mixture was stirred at room temperature for 12 h. Ethanol was evaporated under reduced pressure, 1 M hydrochloric acid was added to the residue ( With ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from acetone to give the title compound (0.5 g, 7790) as colorless crystals.

IN NMR (300 MHz, SOSI") b m.h. 0.85 - 2.14 (m, 15 N), 2.21 (s, C H), 2.67 (t, U-6.2 Hz, 2 N), 3.03 (s, C H) , 3.56 (ddd, 9U-11.6, 8.4, 3.0 Hz, 2 N), 3.69 (t, U-6.6 Hz, 2 N), 3.88 - 4.08 (m, 2 H),

4.27 - 4.53 (m, 2 H), 6.55 (d, U-8.7 Hz, 2 H), 6.78 - 6.99 (m, 2 H), 7.17 - 7 ,26 (m, Z H).

Example A83 3-((4-(H-Cyclohexyl-3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl]carbonyl(methyl)amino|propanoic acid

TI F) du o M h o she (1) ethyl. 3-((4-((cyclohexyl13-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate

Ethyl 3-F4-(Ccyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|Ipropanoate (4.0 g), synthesized in Example

A82(6), separated using high-performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm H x 500 mm D, manufactured by Oaise! Spetisa! Ipdivigiev, Ts., mobile phase: hexane/ethanol (200/800), flow rate: 60 ml/min, column temperature: "C). Fractions containing the optically active form, which has a shorter retention time under the above-mentioned high-performance chromatography conditions, was concentrated to give the title compound (1.8 g, 99.9965 ee).

IN NMR (300 MHz, SOSI") b m.h. 1.00 - 2.10 (m, 18 N), 2.21 (s, C H), 2.61 (t, 92-7.0 Hz, 2 N), 3.01 (s, C H) , 3.55 (ddd, 9U-11.7, 8.5, 3.2 Hz, 2 N), 3.70 (t, U-7.0 Hz, 2 N), 3.90 - 4.05 (m, 2 N), 4.27 - 4.52 (m, 4 N), 6.56 (d, U-8.7 Hz, 2 N), 6.77 - 6.96 (m, 2 N ), 7.15 - 7.25 (m, Z H). (2)3-K(4-cyclohexyl(|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl]carbonylmethyl)amino|propanoic acid

Ethyl 3-F4-(Ccyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (1.8 g), optically separated in the above-mentioned (1), dissolved in ethanol (20 ml), at room temperature 1 aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at 50 "C for 0.5 g.

Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (5 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from acetone to give the title compound (1.6 g, 9590, 99.995 ee) as colorless crystals.

IN NMR (300 MHz, SOSI") b m.h. 0.85 - 2.14 (m, 15 N), 2.21 (s, C H), 2.67 (t, 9-6.2 Hz, 2 N), 3.03 (s, C H) , 3.56 (ddd, 9U-11.6, 8.4, 3.0 Hz, 2 N), 3.69 (t, U-6.6 Hz, 2 N), 3.88 - 4.08 (m, 2 N), 4.27 - 4.53 (m, 2 N), 6.55 (d, U-8.7 Hz, 2 N), 6.78 - 6.99 (m, 2 N ), 7.17 - 7.26 (m, Z H).

Example A84 3-((4-(H-Cyclohexyl3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl]carbonyl(methyl)amino|propanoic acid

PI o du schi M g 0)-o che

(1) ethyl. 3-((4-((cyclohexyl13-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate

Ethyl 3-F4-(Ccyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|Ipropanoate (4.0 g), synthesized in Example

A82(6), separated using high-performance liquid chromatography (column:

SNIKAGRAK AYU (50 mm H x 500 mm D, manufactured by Oaise! Spetisa! Ipdivigiev, Ts., mobile phase: hexane/ethanol (200/800), flow rate: 60 ml/min, column temperature: "C). Fractions containing the optically active form, which has a longer retention time under the conditions of the above-mentioned high-performance chromatography, was concentrated to obtain the target compound indicated in the title (1.8 g, 99.9965 ee). "IN NMR (300 MHz, SOSI") b m. 1.00 - 2.10 (m, 18 N), 2.21 (s, C H), 2.61 (t, U-7.0 Hz, 2 N), 3.01 (s, C H), 3.55 (ddd, 9U-11.7, 8.5, 3.2 Hz, 2 H), 3.70 (t, 9U-7.0 Hz, 2 H), 3.90 - 4.05 ( m, 2 N), 4.27 - 4.52 (m, 4 N), 6.56 (d, 9-8.7 Hz, 2 N), 6.77 - 6.96 (m, 2 N) , 7.15 - 7.25 (m, Z H). (2)3-K(4-cyclohexyl(|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl]carbonylUumethyl)amino|propanoic acid

Ethyl 3-F4-(Ccyclohexyl|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (1.8 g), optically separated in the above-mentioned (1), dissolved in ethanol (20 ml), at room temperature 1M aqueous solution of sodium hydroxide (5 ml) was added and the mixture was stirred at 50 "C for 0.5 g.

Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (5 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from acetone to give the title compound (1.5 g, 8895.99.9905 ee) as colorless crystals. "H NMR (300 MHz, SOSI") b mp 0.85 - 2.14 (m, 15 N), 2.21 (s, C H), 2.67 (t, 9-6.2 Hz, 2 N), 3.03 (s, Z H), 3.56 (ddd, 9U-11.6, 8.4, 3.0 Hz, 2 H), 3.69 (t, U-6 .6 Hz, 2 N), 3.88 - 4.08 (m, 2 N), 4.27 - 4.53 (m, 2 N), 6.55 (d, 9-8.7 Hz, 2 H), 6.78 - 6.99 (m, 2 H), 7.17 - 7.26 (m, C H).

Example A85 3-TsCh4-41-(5-(benzyloxy)-3-methyl-1-benzofuran-2g-yl)|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|Ipropanoic acid 7 6) "Ozna o M ov ( 6) (1)1-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-one

Potassium carbonate (27.6 d) and 1-bromo-3-methylbutan-2-one (14.3 g) synthesized in Example A75(1) and the mixture was stirred for 15 g. The reaction mixture was filtered through Celite, water (200 ml) was added and the mixture was extracted diethyl ether (100 mlx2). The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylformamide (100 ml) and OVI (9.9 ml) was added at room temperature. The reaction mixture was stirred at 100 "C for 1 h. The reaction mixture was allowed to cool to room temperature, 1M hydrochloric acid (150 ml) was added, and the mixture was extracted with diethyl ether (100 mlx2). The extract was washed with water, a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, and dried over sulfate magnesium and concentrated under reduced pressure crystallized from ethanol-isopropyl ether to give the title compound (11.7 g, 57905) as pale yellow crystals.

IN NMR (300 MHz, SOSI") b m.h. 1.23 (d, U-6.8 Hz, 6 N), 2.57 (s, Z H), 3.57 (dt, uU-13.8, 6.8

Hz, 1 N), 5.12 (s, 2 N), 7.11 (d, 9-2.6 Gu, 1 N), 7.13 - 7.21 (m, 1 N), 7.30 - 7.55 (m, 6 N). (2)1-(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol 1-(5-(Benzyloxy)-3-methyl-1-benzofuran-2 -yl|-2-methylpropan-1-one (11.7 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (150 ml) and methanol (15 ml) and sodium borohydride (9095, 3.0 d). The ice bath was removed, the reaction mixture was stirred at room temperature for 2 h. The mixture was cooled again with ice, water (10 ml) and 1M hydrochloric acid (100 ml) were carefully added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to afford the title compound (11.3 g, quant.) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.82 (d, 9U-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 1.55 (d, 9U-2.6 Hz, 1 H) , 2.11 - 2.34 (m, 4 N), 4.46 (dd, U-8.3, 6.0 Hz, 1 N), 5.10 (s, 2 N), 6.82 - 7.08 (m, 2

N), 7.28 - 7.55 (m, 6 N). (3) ethyl 3-K4-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2- methylpropyl)amino)phenylcarbonylmethyl)amino|propanesate 1-(5-(Benzyloxy) -3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol (10.2 g) synthesized in the above mentioned (2), dissolved in tetrahydrofuran (150 ml) and at room temperature added thionyl chloride (4 .3 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice and a saturated aqueous solution of sodium hydrogencarbonate (100 ml) was carefully added. The reaction mixture was stirred for min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (200 ml), sodium iodide (7.4 g), sodium carbonate (5.0 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate ( 8.2 g), synthesized in

Example 2(2), and the mixture was stirred at 80C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to give the title compound (6.3 g, 3590) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 1.23 (t, 9U-7.2 Hz, Z H) , 2.13 - 2.33 (m, 4 N), 2.61 (t, 2U-7.2 Hz, 2 N), 3.01 (s, C H), 3.71 (t, U- 7.2 Hz, 2

H), 4.12 (k, d927.2 Hz, 2 H), 4.25 - 4.Ab (m, 2 H), 5.09 (s, 2 H), 6.57 (d, 928, 7 Hz, 2 N), 6.81 - 7.02 (m, 2 N), 7.15 - 7.25 (m, Z H), 7.30 - 7.59 (m, 5 N). (4)3-Ch14-C1-(5-(benzyloxy)-3-methyl-1-benzofuran-2H-yl|-2-methylpropyl)amino)phenyl(Icarbonylmethyl)amino|Ipropanoic acid

Ethyl 3-CH4-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-g-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoate (0.38 g), synthesized in the above-mentioned (3), was dissolved in ethanol (5 ml), at room temperature a 1 M aqueous solution of sodium hydroxide (1.5 ml) was added, and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure, 1 M hydrogen chloride was added to the residue acid (1.5 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.28 g, 79905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, U-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 2.18 - 2.30 (m, 4 H), 2, 66 (t, 9U-6.2 Hz, 2 H), 3.03 (s, Z H), 3.69 (t, 9U-6.2 Hz, 2 H), 4.32 (d, 9- 7.5 Hz, 1 N), 5.08 (s, 2 N), 6.56 (d, 9-8.7 Hz, 2 N), 6.83 - 7.02 (m, 2 N), 7.17 - 7.26 (m, Z H), 7.30 - 7.53 (m, 5

N).

Example A8b6 3-TsCh4-41-(5-(benzyloxy)-3-methyl-1-benzofuran-2h-yl)|-2-methylpropyl)amino)phenyl(carbonylmethyl)amino|ipropanoic acid

7 o "characteristics of Moba o) (1) ethyl 3-K4-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino| Propane

Ethyl 3-CH4-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-g-yl|-2- methylpropyl)iamino)phenylcarbonylmethyl)amino|propanoate (3.0 g), synthesized in

Examples A85(3) were separated using high-performance liquid chromatography (column: SNIKAG RAK AYU (50 mm Wx500 mm D, manufactured by Oaise! Spetisai! Ipaivipev, yes. mobile phase: hexane/ethanol (200/800), flow rate: 60 mL/min, column temperature: 3070.) Fractions containing the optically active form, which has a longer retention time under the above-mentioned high performance chromatography conditions, were concentrated to give the title compound (1.23 g, 99.995 ee).

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9U-6.8 Hz, Z H), 1.12 (d, U-6.8 Hz, Z H), 1.23 (t,

UE7.2 Hz, Z H), 2.13 - 2.33 (m, 4 H), 2.61 (t, 97.2 Hz, 2 H), 3.01 (s, Z H), 3, 71 (t, d9-7.2 Hz, 2

H), 4.12 (k,. 90-7.2 HZ, 2 H), 4.25 - 4.46 (m, 2 H), 5.09 (s, 2 H), 6.57 (d , 9-8.7 Hz, 2 H), 6.81 - 7.02 (m, 2 H), 7.15 - 7.25 (m, Z H), 7.30 - 7.59 (m, 5 H). (2)3-Sh14-Ch1-(5-(benzyloxy)-3-methyl-1-benzofuran-2g-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|Ipropanoic acid

Ethyl 3-CSH4-41-(15-(benzyloxy)-3-methyl-1-benzofuran-2g-yl|-2-methylpropyl)amino)phenyl(IIcarbonylmethyl)amino|propanosate (1.23 g), optically resolved in the above-mentioned (1) was dissolved in ethanol (15 ml), at room temperature a 1 M aqueous solution of sodium hydroxide (4 ml) was added, and the mixture was stirred at 50 "C for 0.5 g.

Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (4 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (1.22 g, 95905, 99.995 ee) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, U-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 2.18 - 2.30 (m, 4 H), 2, 66 (t, 9U-6.2 Hz, 2 H), 3.03 (s, Z H), 3.69 (t, 9U-6.2 Hz, 2 H), 4.32 (d, d9- 7.5 Hz, 1 N), 5.08 (s, 2 N), 6.56 (d, 9-8.7 Hz, 2 N), 6.83 - 7.02 (m, 2 N), 7.17 - 7.26 (m, Z H), 7.30 - 7.53 (m, 5

N).

Example A87.

These about; du o M os o) (1) ethyl 3-K4-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2- methylpropyl)iamino)phenylIcarbonylUmethyl)amino|propanoate

Ethyl 3-CH4-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-g-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoate (3.0 g), synthesized in

Examples A85(3) were separated using high-performance liquid chromatography

(column: SNIKAG RAK AYU (50 mm Hx500 mm D, manufactured by Oaise! Spetisai! Ipaivilev, yes. mobile phase: hexane/ethanol (200/800), flow rate: 60 ml/min, column temperature: 30 "C) Fractions containing the optically active form, which has a shorter retention time under the above-mentioned high performance chromatography conditions, were concentrated to give the title compound (1.25 g, 99.995 ee).

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 1.23 (t, 9U-7.2 Hz, Z H) , 2.13 - 2.33 (m, 4 N), 2.61 (t, 2U-7.2 Hz, 2 N), 3.01 (s, C H), 3.71 (t, U- 7.2 Hz, 2

H), 4.12 (k, 9d0-7.2 HZ, 2 H), 4.25 - 4.46 (m, 2 H), 5.09 (s, 2 H), 6.57 (d, 9-8.7 Hz, 2 N), 6.81 - 7.02 (m, 2 N), 7.15 - 7.25 (m, Z H), 7.30 - 7.59 (m, 5 N). (2)3-Sh14-Ch1-(5-(benzyloxy)-3-methyl-1-benzofuran-2h-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoic acid

Ethyl 3-CH4-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-g-yl|-2- methylpropyl)amino)phenylcarbonylmethyl)amino|propanoate (1.25 g), optically resolved in the mentioned above (1), was dissolved in ethanol (15 ml), at room temperature a 1 M aqueous solution of sodium hydroxide (4 ml) was added and the mixture was stirred at 50 "C for 0.5 g.

Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (4 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (1.08 g, 93905, 99.995 ee) as a colorless solid. "H NMR (300 MHz, SOSI") b m.p. 0.91 (d, 9U-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 2 ,18 - 2.30 (m, 4 N), 2.66 (t, 9U-6.2 Hz, 2 N), 3.03 (s, C H), 3.69 (t, 9U-6, 2 Hz, 2 N), 4.32 (d, 9-7.5 Hz, 1 N), 5.08 (s, 2 N), 6.56 (d, 9-8.7 Hz, 2 N) , 6.83 - 7.02 (m, 2 H), 7.17 - 7.26 (m, Z H), 7.30 - 7.53 (m, 5

N).

Example A88 3-4(4-((5-chloro-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)propanoic acid 6)

SI

(1)5-chloro-M-methoxy-M,3-dimethyl-1-benzofuran-2-carboxamide

Potassium carbonate (8.10 g), sodium iodide (8.78 g) and 2-chloro-M- methoxy-N-methylacetamide (4.43 g) and the mixture was stirred overnight under reflux. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a white solid. 1,8-diazabicyclo(5.4.FTundec-7-ene (4.38 ml) was added to a solution (50 ml) of the obtained solid in M,M-dimethylformamide and the mixture was stirred at 120 "C for 2 h. The reaction mixture was cooled to room temperature, 1M hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3090 ethyl acetate/hexane) to give the title compound (2.15 g , 29905), as a brown solid. "H NMR (300 MHz, SOSI") b m.p. 2.47 (s, З Н), 3.38 (s, З Н), 3.86 (s, With H), 7.35 (dd, 9U-8.9, 1.68 Hu, 1 H), 7.40 (dd, U-8.9, 0.6 Hz, 1 H), 7.57 ( dd, U-1.8, 0.6 Hz, 1 H). (2)5-chloro-3-methyl-1-benzofuran-2-carbaldehyde

Lithium aluminum hydride (322 mg) was added to a solution (40 ml) of 5-chloro-M-methoxy-M,33-dimethyl-1-benzofuran-2-carboxamide (2.15 g) synthesized above in tetrahydrofuran at 0 "Si the mixture was stirred for 1 h. Water (320 μl) was added to quench the reaction, 1 M aqueous sodium hydroxide solution (320 μl) was added, and the mixture was stirred at room temperature for 1 h. The resulting insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column by chromatography on silica gel (tetrahydrofuran) to give a pale yellow solid. The resulting solid was washed with diisopropyl ether to give the title compound (1.21 g, 7395) as a pale yellow solid. "IN NMR (300 MHz, SOCI" ) b m.h. 2.60 (s, Z H), 7.43 - 7.51 (m, 2 H), 7.65 - 7.67 (m, 1 H), 10.02 (s, 1 H). (3)(5-chloro-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanol

To a solution (10 ml) of 5-chloro-3-methyl-1-benzofuran-2-carbaldehyde (600 mg) synthesized above in tetrahydrofuran was added a 1.0 M solution (4.62 ml) of cyclohexylmagnesium bromide in tetrahydrofuran at 0 "С and the mixture was stirred for 1 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15906 ethyl acetate/hexane) to give the title compound (518 mg, 6095) as a pale yellow oil.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.85 - 1.41 (m, 6 N), 1.61 - 1.71 (m, 2 N), 1.75 - 1.98 (m, Z

H), 2.09 - 2.18 (m, 1 H), 2.19 (s, C H), 4.52 (dd, U-8,4,6.0 Hz, 1 H), 7, 20 (dd, U-8.4, 21 Hz, 1

H), 7.33 (dd, U-8.4, 0.6 Hz, 1 H), 7.42 (dd, U-2.1, 0.6 Hz, 1 H). (4)5-chloro-2-(chloro(cyclohexyl)methyl/|-3-methyl-1-benzofuran

To a solution (10 ml) of (5-chloro-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanol (518 mg) synthesized above, thionyl chloride (163 μl) was added in toluene and the mixture was stirred at 100 "С for 1 h. The reaction mixture was poured into an ice-cooled saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (553 mg, quantitative) as a pale yellow oil

IN NMR (300 MHz, SOSI") 6 m.h. 0.83 - 1.48 (m, 6 N), 1.60 - 1.71 (m, 2 N), 1.77 - 1.87 (m, 1

H), 2.10 - 2.24 (m, 4 H), 2.27 - 2.37 (m, 1 H), 4.78 (d, 99.6 Hz, 1 H), 7.20 - 7.26 (m, 1 H), 7.34 - 7.38 (m, 1 H), 7.42 - 7.44 (m, 1 H). (5)3-(I4-1(5-chloro-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid

A mixture of B-chloro-2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzofuran (270 MG), synthesized above, ethyl 3-(((4-aminophenyl)carbonyl|Iaminopropanoate (215 mg), synthesized in Example 1(2), sodium iodide (204 mg), sodium carbonate (144 mg) and M,M-dimethylformamide (10 ml) were stirred overnight at 80 "C. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. Extract washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5095 ethyl acetate/hexane) to give a pale yellow oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 2 g and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrochloric acid was added at 0 "С (1.00 ml).The resulting precipitate was collected and filtration to give the title compound (132 mg, 31905) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.35 (m, 5 N), 1.44 - 1.55 (m, 1 N), 1.60 - 1.96 (m, 4

H), 2.01 - 2.12 (m, 1 H), 2.20 (s, C H), 2.54 - 2.67 (m, 2 H), 3.56 - 3.68 (m , 2 H), 4.37 (d, 957.9

Hu, 1 H), 6.50 - 6.66 (m, Z H), 7.12 - 7.18 (m, 1 H), 7.23 - 7.30 (m, 1 H), 7, 37 (d, 9-1.9 Hz, 1 N), 7.52 (d, U-8.7 Hz, 2 N).

Example A89 3-4(4-((5-chloro-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

SI

A mixture of B-chloro-2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzofuran (283 MG), synthesized in Example AZ88(4), ethyl 3-((4-aminophenyl)carbonyl/methyl)aminopropanoate ( 238 mg), synthesized in Example 2(2), sodium iodide (214 mg), sodium carbonate (152 mg) and M,M-dimethylformamide (10 ml) were stirred overnight at 80 "C. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with sat. (5 ml) and ethanol (5 ml) was added 1 M aqueous sodium hydroxide solution (1.00 ml) and the mixture was stirred at room temperature for 1.5 g, and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and at 0"C, 1M hydrochloric acid (1.00 ml) was added. The precipitate obtained collected by filtration to give the title compound (113 mg, 25905) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.38 (m, 5 N), 1.45 - 1.56 (m, 1 N), 1.61 - 1.97 (m, 4

H), 2.02 - 2.13 (m, 1 H), 2.21 (s, C H), 2.60 - 2.69 (m, 2 H), 3.01 (s, C H) , 3.68 (t, U-6.2 Hz, 2 N), 4.36 (d, 9-7.9 Hz, 1 N), 6.54 (d, 2-8.7 Hz, 2 N ), 7.13 - 7.19 (m, 1 H), 7.20 - 7.31 (m, C H), 7.38 (d, 9U-1.9 Gu, 1 H).

Example of AZO 3-((4-(cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid at

N o M n sn, ne (1)M-methoxy-M,3,5-trimethyl-1-benzofuran-2-carboxamide

Potassium carbonate (9.20 g), sodium iodide (9.98 g) and 2-chloro -M-methoxy-M-methylacetamide (5.04 g) and the mixture was stirred at 50 "C for 5 g and then at 80 "C overnight. The insoluble material was filtered off, 1,8-diazabicycloi|5.4.Fundec-7-ene (5.00 ml) was added to the filtrate and the mixture was stirred at 120 "C for 2 h. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2090 ethyl acetate/hexane) to give the title compound (3.789 g, 49905) as a brown oil.

IN NMR (300 MHz, SOSI") 6 2.47 (s, Z H), 2.49 (s, Z H), 3.38 (s, Z H), 3.86 (s, Z H), 7.19 - 7.24 (m, 1 H), 7.32 - 7.34 (m, 1 H), 7.35 - 7.39 (m, 1 H).

(2) 3,5-dimethyl-1-benzofuran-2-carbaldehyde

Lithium aluminum hydride (307 mg) was added to a solution (50 ml) of M-methoxy-M,3,5-trimethyl-1-benzofuran-2-carboxamide (3.78 g) synthesized above in tetrahydrofuran at -78 C, the mixture stirred for 2 h. Water (350 μl) was added to quench the reaction, 1M aqueous sodium hydroxide solution (700 μl) was added, and the mixture was stirred at room temperature for 1 h. The resulting insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with hexane to give the title compound (2.08 g, 74905) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 2.48 (s, Z H), 2.60 (s, Z H), 7.30 - 7.35 (m, 1 H), 7.40 - 7.47 (m, 2 H), 10, 01 (c, 1 H). (3) cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methanol

To a solution (20 ml) of 3,5-dimethyl-1-benzofuran-2-carbaldehyde (1.00 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (8.61 ml) of cyclohexylmagnesium bromide in tetrahydrofuran at 0"С and the mixture was stirred for 1 g. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated on evaporators and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2595 ethyl acetate/ hexane) to give the title compound (1.13 g, 7695) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.83 - 0.99 (m, 1 N), 1.00 - 1.44 (m, 5 N), 1.58 - 1.70 (m, 2

H), 1.74 - 1.98 (m, C H), 2.09 - 2.22 (m, 4 H), 2.45 (s, C H), 4.51 (dd, U-8 .5, 5.9 Gu, 1 N), 7.03 - 7.11 (m, 1 N), 7.23 - 7.33 (m, 2 N). (4)2-(chloro(cyclohexyl)methyl|-3,5-dimethyl-1-benzofuran

Pyridine (424 μl) and thionyl chloride (382 μl) were added to a solution (20 ml) of cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methanol (1.13 g) synthesized above in toluene, and the mixture was stirred at room temperature for 5 h. A saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.12 g, 93965) as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.82 - 0.97 (m, 1 N), 1.00 - 1.40 (m, 4 N), 1.41 - 1.51 (m, 1

H), 1.59 - 1.70 (m, 2 H), 1.76 - 1.87 (m, 1 H), 2.11 - 2.25 (m, 4 H), 2.28 - 2 .38 (m, 1 N), 2.44 (s, Z

H), 4.80 (d, 9-9.3 Hz, 1 H), 7.07 - 7.12 (m, 1 H), 7.23 - 7.26 (m, 1 H), 7, 32 (d, 98.4 Hz, 1 N). (5) 3-(4-Ycyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

A mixture of 2-(chloro(cyclohexyl)methyl|)|-3,5-dimethyl-1-benzofuran (400 mg), synthesized above, ethyl 3-(4-aminophenyl)carbonyl|Iaminopropanoate (343 mg), synthesized in

Example 1(2), sodium iodide (327 mg), sodium carbonate (231 mg) and M,M-dimethylformamide (10 ml) were stirred at 80 "C for 5 h. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (4595 ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL), and ethanol (5 mL) was added 1 M aqueous sodium hydroxide solution (2.00 ml) and the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrochloric acid (2.00 ml) was added at 0"C. The resulting precipitate was collected by filtration to afford the title compound (436 mg, 67905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.36 (m, 5 N), 1.47 - 1.58 (m, 1 N), 1.59 - 1.97 (m, 4

H), 2.02 - 2.12 (m, 1 H), 2.22 (s, C H), 2.42 (s, C H), 2.61 - 2.69 (m, 2 H) , 3.60 - 3.70 (m, 2 H), 4.38 (d, 9-8.0 Hz, 1 H), 6.49 - 6.60 (m, C H), 7.00 - 7.06 (m, 1 H), 7.19 - 7.24 (m, 2 H), 7.52 (d,

U-7.6 Hz, 2 N).

Example A91 3-((4-(cyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Hn sn, n.e (1) ethyl 3-((4-Ycyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl I|(methyl)amino)propanoate

A mixture of 2-(chloro(cyclohexyl)methyl/|-3,5-dimethyl-1-benzofuran (400 mg), synthesized in Example A9O(4), ethyl 3-(4-aminophenyl)carbonyl)(methyl)aminopropanoate (363 mg) synthesized in Example 2(2), sodium iodide (327 mg), sodium carbonate (231 mg) and M,M-dimethylformamide (10 ml) were stirred at 80 C for 5 h. 1 M hydrogen chloride was added to quench the reaction acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (45905 ethyl acetate/hexane) to give the title compound (471 mg, 669b) as a yellow oil.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.94 - 1.36 (m, 8 N), 1.48 - 1.59 (m, 1 N), 1.60 - 1.96 (m, 4

H), 2.03 - 2.13 (m, 1 H), 2.22 (s, C H), 2.42 (s, C H), 2.57 - 2.65 (m, 2 H) , 3.01 (c, Z H), 3.70 (t,

UET, 1 Hz, 2 N), 4.07 - 4.17 (m, 2 N), 4.32 - 4.40 (m, 2 N), 6.56 (d, 9-8.7 Hz, 2 H), 7.03 (dd, 9UEV,Z3, 1.3 Hu, 1 H), 7.17 - 7.24 (m, 4 H). (2)3-M4-Icyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-Tcyclohexyl(3,5-dimethyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonylI(methyl)aminoisopropanoate (471 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 3 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (407 mg, 92905) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.47 - 1.58 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.02 - 2.14 (m, 1 H), 2.23 (s, C H), 2.42 (s, C H), 2.62 - 2.73 (m, 2 H) , 3.04 (s, C H), 3.70 (t, uU-6.4 Hz, 2 H), 4.37 (d, 2-8.0 Gu, 1 H), 6.56 (d , 2-8.7 Hz, 2 N), 7.00 - 7.06 (m, 1 N), 7.19 - 7.28 (m, 4 N).

Example A9U2 3-4(4-(1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonyl(amino)upropanoic acid

Sleep, oh dew

(1)1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol

To a solution (40 ml) of 5-methoxy-3-methyl-1-benzofuran-2-carbaldehyde (1.91 g) synthesized in Example A27(2) in tetrahydrofuran was added a solution (15.0 ml) of 1.0 M isobutylmagnesium bromide in tetrahydrofuran at 0 C and the mixture was stirred for 1 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction, tetrahydrofuran was evaporated on evaporators, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20905 ethyl acetate/hexane) to give the title compound (1.53 g, 62905) as a yellow oil. "H NMR (300 MHz, SOSI") b m.p. 0.93 (d, 9U-6.6 Hz, Z H), 0.95 (d, U-6.6 Hz, Z H), 1 .54 - 1.69 (m, 1 H), 1.74 - 1.96 (m, C H), 2.23 (c, C H), 3.85 (c, C H), 4.88 - 4.97 (m, 1 N), 6.86 (dd, 9U-8.6, 2.7 Hz, 1 N), 6.91 (d, 952.7 Hz, 1 N), 7.30 (d, 9U-8.6 Hz, 1 H). (2)2-(1-chloro-3-methylbutyl)-5-methoxy-3-methyl-1-benzofuran

To a solution (10 ml) of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (761 mg) synthesized above in toluene was added pyridine (297 μl) and thionyl chloride (268 μl) and the mixture was stirred at room temperature for 3 h. To quench the reaction, a saturated aqueous sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (769 mg, 94905) as a brown oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 0.96 (m, Z H), 1.12 (d, 9-6.8 Hz, Z H), 1.58 - 1.75 (m, 1 H), 2.15 (d , 957.9 Hz, 2 H), 2.24 (s, C H), 3.86 (s, C H), 5.20 (t, 97.8 Hz, 1 H), 6.86 - 6 .93 (m, 2 N), 7.34 (d, 959.4 Hz, 1 N). (3) ethyl 3-1(4-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonylamino)propanoate

A mixture of 2-(1-chloro-3-methylbutyl)-5-methoxy-3-methyl-1-benzofuran (380 MG), synthesized above, ethyl 3-(((4-aminophenyl)carbonylaminoisopropanoate (350 mg), synthesized in Example 1(2), sodium iodide (443 mg), sodium carbonate (314 mg) and M,M-dimethylformamide (10 ml) were stirred at 80 C for 5 h. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel (5090 ethyl acetate/hexane) to give the title compound (266 mg, 40905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, U-6.8 Hz, Z H), 1.00 (d, 9U-6.8 Hz, Z H), 1.20 - 1.30 (m, Z H), 1, 49 - 1.64 (m, 1 N), 1.79 - 1.91 (m, 2 N), 2.26 (s, Z H), 2.59 (t, 925.9 Hz, 2 N) , 3.62 - 3.71 (m, 2 H), 3.83 (s, C H), 4.07 - 4.21 (m, 2 H), 4.30 - 4.44 (m, 1 H), 4.70 (t, 7.4 Hz, 1 H), 6.56 - 6.63 (m, Z H), 6.80 - 6.85 (m, 1 H), 6.88 ( d, 9-2.3 Hz, 1 N), 7.25 (d, 98.7 Hz, 1 N), 7.56 (d, U-8.7 Hz, 2 N). (4)3-(I(4-11-(5-methoxy-3-methyl-1-benzofuran-2h-yl)-3-methylbutylamino)phenyl)carbonyl|Iamino)propanoic acid

To the mixture of ethyl 3-1(4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonylamino)upropanoate (266 mg), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to afford the title compound (216 mg, 8695) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.90 (d, 9U-6.4 Hz, Z H), 0.99 (d, 9U-6.4 Hz, Z H), 1.48 - 1.64 (m, 1 H), 1, 76 - 1.93 (m, 2 H), 2.25 (s, Z H), 2.63 (t, 95.7 Hz, 2 H), 3.59 - 3.69 (m, 2 H) , 3.83 (c,

With H), 4.70 (t, 97.4 Hz, 1 H), 6.54 - 6.65 (m, With H), 6.78 - 6.85 (m, 1 H), 6.87 (d, 9-2.7 Hz, 1 N), 7.20 - 7.30 (m, 1 N), 7.53 (d, 98.7 Hz, 2 N).

Example AZUZ 3-4(4-(1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonylI(methyl)amino)propanoic acid

SN, F)

Roshen (F) M sn, n sn, non-o (1) ethyl 3-1(4-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3- methylbutylamino)phenyl)carbonylI (methyl)amino)propanesate

A mixture of 2-(1-chloro-3-methylbutyl)-5-methoxy-3-methyl-1-benzofuran (380 MG), synthesized in Example AZ9Z2I(2), ethyl 3-((4-aminophenyl)carbonyl|I/ methyl)aminopropanoate (370 mg) synthesized in Example 2(2), sodium iodide (443 mg), sodium carbonate (314 mg) and M,M-dimethylformamide (10 ml) were mixed at 80"C for 5 h. Before quenching 1M hydrochloric acid was added to the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6090 ethyl acetate/hexane) to give the title compound (350 mg, 51905), as yellow oil. "H NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9U-6.4 Hz, Z H), 1.00 (d, 9U-6.8 Hz, Z H), 1.19 - 1.30 (m, Z H), 1, 49 - 1.64 (m, 1 H), 1.80 - 1.89 (m, 2 H), 2.26 (s, Z H), 2.61 (t, 9U-7.0 Hz, 2 H), 3.01 (s,

With H), 3.71 (t, 927.0 Hz, 2 H), 3.84 (s, With H), 4.07 - 4.17 (m, 2 H), 4.68 (t, 9 -7.4 Hz, 1 N), 6.58 (d, 9UE8.7 Hz, 2 N), 6.80 - 6.86 (m, 1 N), 6.88 (d, 9-2.3 Hz, 1 N), 7.23 (d, 9-8.7 Hz, 2 N), 7.26 (d,

U-8.7 Hz, 1 N). (2)3-(IK4-11-(5-methoxy-3-methyl-1-benzofuran-2h-yl)-3-methylbutylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonylI(methyl)amino)propanate (350 mg), synthesized above, of tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (308 mg, 9495) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9U-6.4 Hz, Z H), 1.00 (d, 9-6.4 Hz, Z H), 1.48 - 1.65 (m, 1 H), 1, 81 - 1.89 (m, 2 H), 2.26 (s, Z H), 2.65 - 2.75 (m, 2 H), 3.05 (s, Z H), 3.71 ( t, 9U-6.4 Hu, 2 H), 3.84 (s, C H), 4.69 (t, 97.4 Hz, 1 H), 6.58 (d, 9-8.7 Hu , 2 H), 6.80 - 6.86 (m, 1 H), 6.88 (d, 9uE2, 3 Hz, 1 H), 7.23 - 7.30 (m, 3 H).

Example AZ9U4 3-4(4-(1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethylamino)phenyl)carbonyl|amino)propanoic acid o c m7- Co

N where

Hn sn, (1)1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethanone

Potassium carbonate (655 mg) was added to a mixture of 2-bromo-1-(3-methyl-1-benzofuran-2-yl)ethanone (1.00 g), phenol (446 mg) and M,M-dimethylformamide (20 ml) ) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1095 ethyl acetate/hexane) to give the title compound (697 mg, 6690) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 2.65 (s, Z H), 5.36 (s, 2 H), 6.81 - 6.86 (m, 1 H), 6.98 - 7.06 (m, 2 H), 7, 20 - 7.39 (m, Z H), 7.51 - 7.57 (m, 2 H), 7.67 - 7.73 (m, 1 H). (2) methyl 4-C1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl|aminobenzoate

To the mixture of 1-(33-methyl-1-benzofuran-2-yl)-2-phenoxyethanone (697 mg) synthesized above, methyl 4-aminobenzoate (399 mg), triethylamine (2.93 ml) and methylene chloride (10 ml ) titanium chloride (IM) (344 μl) was added at 0 "C in an argon atmosphere and the mixture was stirred overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, methylene chloride was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine , dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil.To a solution (20 ml) of the obtained oil in tetrahydrofuran was added acetic acid (2 ml) and sodium cyanoborohydride (329 mg) and the mixture was stirred at room temperature for 15 min. Trifluoroacetic acid (2 ml) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 h. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, and the reaction mixture was extracted with ethyl cetate The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2595 ethyl acetate/hexane) to give the title compound (279 mg, 2790) as a yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.29 (s, C H), 3.83 (s, C H), 4.32 - 4.44 (m, 2 H), 4 .91 (d, 96.6 Gu, 1 N), 5.08 - 5.16 (m, 1 N), 6.66 (d, 9U-8.9 Hz, 1 N), 6.81 - 6 .99 (m, Z H), 7.18 - 7.31 (m, 4 H), 7.38 - 7.48 (m, 2 H), 7.84 (d, 2-8.9 Hz, 2 H). (3)4-11-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethylaminobenzoic acid

To a mixture of methyl 4-11-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl|amino)benzoate (279 mg) synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous sodium hydroxide solution (5.00 mL) and the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (5.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (220 mg, 82905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 2.30 (s, Z H), 4.32 - 4.46 (m, 2 H), 4.92 - 5.03 (m, 1 H), 5.09 - 5.20 (m, 1 H ), 6.69 (d, 9U-9.1 Hz, 2 N), 6.90 (d, 9-7.6 Hz, 2 N), 6.93 - 7.01 (m, 1 N), 7.19 - 7.34 (m, 4 N), 7.38 - 7.51 (m, 2 N), 7.90 (d, 98.7 Hz, 2 N). (4) ethyl 3-1(4-11-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethylamino)phenyl)carbonyl|iamino)propanesate

To the mixture of 4-11-(3Z-methyl-1-benzofuran-2-yl)-2-phenoxyethyl|iaminophenoic acid (100 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (59.4 mgG), monohydrate of 1- 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74.2 mg) was added to hydroxybenzotriazole (59.3 mg), triethylamine (72 μl) and M,M-dimethylformamide (10 ml) and the mixture was stirred overnight at room temperature temperature 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4590 ethyl acetate/hexane) to give the title compound (63.0 mg, 5090) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.25 (t, 9U-7.2 Hz, Z H), 2.29 (s, Z H), 2.59 (t, U-5.8 Hz, 2

H), 3.62 - 3.72 (m, 2 H), 4.14 (k, 20-7.2 Hz, 2 H), 4.31 -4.44 (m, 2 H), 4 .78 - 4.88 (m, 1 H), 5.06 -

5.15 (m, 1 H), 6.60 - 6.71 (m, Z H), 6.89 (dd, U-8.8, 1.0 Hz, 2 H), 6.93 - 7 .00 (m, 1 N), 7.18 - 7.31 (m, 4 N), 7.38 - 7.49 (m, 2 N), 7.59 (d, 928.9 Hz, 2 N ). (5)3-(I(4-11-(3-methyl-1-benzofuran-2h-yl)-2-phenoxyethylamino)phenyl)carbonyl|amino)propanoic acid

To the mixture of ethyl 3-((4-11-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethylamino)phenyl)carbonyl|Iaminopropanoate (63.0 mg), synthesized above, tetrahydrofuran (5 ml) and of ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (57.5 mg, 97905) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 2.29 (s, Z H), 2.68 (t, 9U-5.9 Hz, 2 H), 3.63 - 3.72 (m, 2 H), 4.32 - 4.44 (m , 2 H), 5.10 (t, 9-6.1 Hz, 1 H), 6.58 (t, 9-5.7 Hz, 1 H), 6.67 (d, U-8.7 Hz, 2 N), 6.87 - 6.92 (m, 2 N), 6.93 - 7.00 (m, 1 N), 7.18 - 7.31 (m, 4 N), 7, 38 - 7.43 (m, 1 H), 7.44 - 7.49 (m, 1

H), 7.58 (d, 9-8.7 Hz, 2 H).

Example A9U5

3-Imethyl(4-111-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethylamino)phenyl)carbonyl|iamino)propanoic acid o o rula same sn, ron sn, (1) ethyl 3-methyl |((4-11-(3Z-methyl-1-benzofuran-2-yl)-2-phenoxyethylamino)phenyl)carbonyl|iamino)propanate

To the mixture of 4-11-(33-methyl-1-benzofuran-2-yl)-2-phenoxyethyl|iaminophenoic acid (100 mg), synthesized in Example AZ4(3), ethyl 3-(methylamino)upropanoate (50.8 mg), 1-hydroxybenzotriazole monohydrate (59.3 mg), triethylamine (54 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74.2 mg) and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5090 ethyl acetate/hexane) to give the title compound (82.5 mg, 6490) as a yellow oil. "H NMR (300 MHz, SOSI") b m.p. 1.23 (t, 9U-7.2 Hz, Z H), 2.29 (s, Z H), 2.57 - 2.67 ( m, 2 H), 3.02 (s, З H), 3.72 (t, 9-7.1 Hz, 2 H), 4.12 (k, 9d0-7.2 Hz, 2 H), 4.30 - 4.44 (m, 2 N), 5.08 (t, U-6.0

Gu, 1 N), 6.66 (d, U-8.7 Hz, 2 N), 6.90 (dd, 9-8.7, 0.9 Hz, 2 N), 6.93 - 7, 01 (m, 1 N), 7.19 - 7.32 (m, 6 N), 7.38 - 7.50 (m, 2 N). (2)3--methyl(4-11-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethylamino)phenyl)carbonyl|iamino)propanoic acid

To the mixture of ethyl 3-Imethyl(4-11-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethylamino)phenyl)carbonyl|Iaminopropanoate (82.5 mg), synthesized above, tetrahydrofuran (5 ml) and of ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (54.8 mg, 7095) as a white solid.

"H NMR (300 MHz, SOSI»z) b m.p. 2.29 (s, З Н), 2.61 - 2.72 (m, 2 Н), 3.04 (s, З Н), 3.71 (t,

U-6.6 Gu, 2 N), 4.30 - 4.42 (m, 2 N), 5.08 (t, 9U-6.1 Hz, 1 N), 6.66 (d, 9- 8.7 Hz, 2 N), 6.86 - 6.92 (m, 2 N), 6.92 - 7.00 (m, 1 N), 7.18 - 7.31 (m, 6 N) , 7.38 - 7.43 (m, 1 N), 7.44 - 7.49 (m, 1 N).

Example A9Ub 3-1(4-(cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

E and sn, (1) b6-fluoro-M-methoxy-M,3-dimethyl-1-benzofuran-2-carboxamide

To a solution (50 ml) of 1-(4-fluoro-2-hydroxyphenyl)ethanone (5.00 g) in M,M-dimethylformamide was added 2-chloro-M-methoxy-M-methylacetamide (4.90 g), iodide sodium (9.71 g) and potassium carbonate (8.96 g) and the mixture was stirred overnight at 800. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off. 1,8-diazabicyclo(/5.4.F)undec-7-ene (4.85 ml) was added to the filtrate and the mixture was stirred at 120 C for 2 h. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2590 ethyl acetate/hexane) to give the title compound (3.65 g, 47905) as a pale brown oil "IN NMR (300 MHz, SOCI") b 2.50 (s, C H), 3.38 (s, C H), 3.87 (s, C H), 7.01-711 (m, 1 H), 7.18 (dd, 9U-8.8, 1.9 Hz, 1 H), 7.54 (dd, 9U-8.8, 5.5 Hu, 1 H). (2)6-fluoro-3-methyl-1-benzofuran-2-carbaldehyde

Lithium aluminum hydride (292 mg) was added to a solution (50 ml) of b-fluoro-M-methoxy-M,3-dimethyl-1-benzofuran-2-carboxamide (3.65 g) synthesized above in tetrahydrofuran at 0 "Si the mixture was stirred for 1 h. Water (300 μL) was added to quench the reaction, 1 M aqueous sodium hydroxide solution (600 μL) was added, and the mixture was stirred at room temperature for 1 h. The resulting insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2090 ethyl acetate/hexane) to give the title compound (1.88 g, 69905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 2.62 (s, C H), 7.07 - 7.15 (m, 1 H), 7.22-728 (m, 1 H), 7.65 (dd, U-8.8, 5, 4 Gu, 1 H), 9.99 (s, 1 H). (3)cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methanol

To a solution (20 ml) of b-fluoro-3-methyl-1-benzofuran-2-carbaldehyde (940 ml) synthesized above in tetrahydrofuran was added a 1.0 M solution (7.92 ml) of cyclohexylmagnesium bromide in tetrahydrofuran at 0 "С and the mixture was stirred for 1 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction, tetrahydrofuran was evaporated on evaporators, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1595 ethyl acetate/hexane) to give the title compound (931 mg, 6790) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.85 - 1.00 (m, 1 N), 1.00 - 1.44 (m, 5 N), 1.60 - 1.71 (m, 2

H), 1.76 - 1.99 (m, with H), 2.10 - 2.23 (m, 4 H), 4.50 (dd, U-8,3,6,1 Hz, 1 H ), 6.94 - 7.02 (m, 1 N), 7.10 - 7.17 (m, 1 N), 7.34 - 7.40 (m, 1 N). (4)2-(chloro(cyclohexyl)methyl|-6b-fluoro-3-methyl-1-benzofuran

To a solution (20 ml) of cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methanol (931 mg) synthesized above, thionyl chloride (311 μl) was added in toluene, and the mixture was stirred at

100 "С for 1 h. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogencarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound indicated in the title (945 mg, 9590), like yellow butter.

IN NMR (300 MHz, SOSI") 6 m.h. 0.82 - 0.98 (m, 1 N), 0.99 - 1.52 (m, 5 N), 1.60 - 1.72 (m, 2

H), 1.76 - 1.89 (m, 1 H), 2.11 - 2.25 (m, 4 H), 2.26 - 2.39 (m, 1 H), 4.79 (d , 959.6 Hz, 1 N), 6.96 - 7.04 (m, 1 N), 7.15 - 7.20 (m, 1 N), 7.35 - 7.41 (m, 1 N ). (5)4-Cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methyl|iaminobenzoic acid

To the mixture of 2-(chloro(cyclohexyl)methyl|-b-fluoro-33-methyl-I-benzofuran (945 mg) synthesized above, methyl 4-aminobenzoate (508 mg), sodium iodide (1.01 g) and M ,M-dimethylformamide (10 ml) was added sodium carbonate (712 mg) and the mixture was stirred at 80 C overnight. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure . The residue was purified by column chromatography on silica gel (2095 ethyl acetate/hexane) to give a yellow solid. To a mixture of the obtained solid, tetrahydrofuran (20 ml) and ethanol (20 ml) was added 1M aqueous sodium hydroxide solution (10.0 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and 1M hydrochloric acid (10.0 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (722 mg, 5695 ), as a brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.38 (m, 5 N), 1.46 - 1.57 (m, 1 N), 1.61 - 1.98 (m, 4

H), 2.02 - 2.13 (m, 1 H), 2.25 (s, C H), 4.40 (d, 957.9 Hz, 1 H), 4.51 - 4.74 ( m, 1 N), 6.57 (d, 9UE8.8 Hz, 2 N), 6.91 - 7.00 (m, 1 N), 7.06 - 7.12 (m, 1 N), 7 .29 - 7.36 (m, 1 N), 7.85 (d, 9U-8.8 Hz, 2 N). (6) ethyl 3-((4-cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-(cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methylIaminobbenzoic acid (350 mg), synthesized above, p-alanine ethyl ester hydrochloride (212 mg), 1-hydroxybenzotriazole monohydrate (211 mg), triethylamine (383 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg) was added, and the mixture was stirred overnight at room temperature. To quench the reaction, 1M was added hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5095 ethyl acetate/hexane) to give the title compound (403 mg, 91905) as a pale yellow oil.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.94 - 1.39 (m, 8 H), 1.46 - 1.57 (m, 1 H), 1.62 - 1.97 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.24 (s, C H), 2.58 (t, 95.9 Hz, 2 H), 3.61 - 3.70 ( m, 2 H), 4.14 (k, 957.2

Hz, 2 N), 4.32 - 4.47 (m, 2 N), 6.54 - 6.63 (m, Z H), 6.90 - 7.00 (m, 1 N), 7, 05 - 7.12 (m, 1 N), 7.28 - 7.35 (m, 1 N), 7.55 (d, 9U-8.9 Hz, 2 N). (7)3-(4-Hycyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-((4-cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|Iamino)upropanoate (403 mg), synthesized above, tetrahydrofuran (5 ml) and of ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 3 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (355 mg, 9395) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 0.92 - 1.37 (m, 5 N), 1.44 - 1.56 (m, 1 N), 1.60 - 1.96 (m, 4

H), 2.00 - 2.12 (m, 1 H), 2.22 (s, C H), 2.53 - 2.66 (m, 2 H), 3.54 - 3.67 (m , 2 H), 4.35 (d, 9-8.3

Hu, 1 H), 6.48 - 6.64 (m, Z H), 6.89 - 6.99 (m, 1 H), 7.03 - 7.11 (m, 1 H), 7, 27 - 7.34 (m, 1 N), 7.52 (d, U-8.7 Hz, 2 N).

Example A9U7

3-1(4-(cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

IF) el o sn,

And

CH, (1) ethyl 3-((4-1-cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

To the mixture of 4-(cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methylaminobbenzoic acid (350 mg), synthesized in Example AZ9Bb(5), ethyl 33-(methylamino)propanoate (181 mg), 1-hydroxybenzotriazole monohydrate (211 mg), triethylamine (383 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (265 mg) and the mixture was stirred overnight at room temperature . 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5095 ethyl acetate/hexane) to give the title the target compound (432 mg, 9590) as a yellow oil. "H NMR (300 MHz, SOSI") 6 ppm 0.93 - 1.37 (m, 8 H), 1.46 - 1.56 ( m, 1 H), 1.60 - 1.96 (m, 4

H), 2.02 - 2.14 (m, 1 H), 2.23 (s, C H), 2.61 (t, 9U-6.9 Hz, 2 H), 3.01 (s, With H), 3.70 (t, 9-6.9 Hz, 2

H), 4.07 - 4.17 (m, 2 H), 4.27 - 4.39 (m, 2 H), 6.56 (d, 9U-8.7 Hz, 2 H), 6, 91 - 7.00 (m, 1 N), 7.06 - 7.12 (m, 1 N), 7.21 (d, 98.7 Hz, 2 N), 7.28 - 7.35 (m , 1 H). (2)3-M4-Ycyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-cyclohexyl(b-fluoro-3-methyl-1-benzofuran-2-yl)methyliamino)phenyl)carbonyl(methyl)aminoisopropanoate (432 mg), synthesized above, tetrahydrofuran (10 ml) and of ethanol (10 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 4 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (367 mg, 9095) as a pale purple solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.46 - 1.57 (m, 1 N), 1.61 - 1.96 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.23 (s, With H), 2.67 (t, U-6.4 Hz, 2 H), 3.04 (s, With H), 3.70 (t, 9-6.4 Hz, 2

N), 4.35 (d, U-8.0 Hz, 1 N), 6.56 (d, 2-8.7 Gu, 2 N), 6.91 - 7.00 (m, 1 N) , 7.06 - 7.12 (m, 1 H), 7.21-7.28 (m, 2 H), 7.29 - 7.36 (m, 1 H).

Example АЗУВ8 3-4(4-((5-cyano-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminonorphenyl)carbonylamino)propanoic acid,

Me

(1) methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate

Methyl bromoacetate (4.85 ml) and potassium carbonate (12.9 g) were added to a solution (100 ml) of 1-(5-bromo-2-hydroxyphenyl)ethanone (10.00 g) in M,M-dimethylformamide and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, 1,8-diazabicyclo/5.4.O)undec-7-ene (6.95 ml) was added to the filtrate, and the mixture was stirred at 120 "C for 2 h. 1M hydrogen chloride was added to quench the reaction acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1090 ethyl acetate/hexane) to give the title compound (6.06 g, 4895) as a pale - brown solid substance. "H NMR (300 MHz, SOSI") b m.p. 2.56 (s, Z H), 3.99 (s, Z H), 7.39 - 7.44 (m, 1 H), 7.51 - 7.56 (m, 1 H), 7, 76 (d, 9-1.9 Hz, 1 N). (2) methyl 5-cyano-3-methyl-1-benzofuran-2-carboxylate

To a mixture of methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate (6.06 g) synthesized above, zinc cyanide (2.64 g) and M,M-dimethylformamide (60 ml) was added )palladium (0) (1.31 g), and the mixture was deaerated and stirred under an argon atmosphere at 80 C overnight. Water was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (4.20 g, 8790) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 2.61 (s, Z H), 4.01 (s, Z H), 7.61 - 7.66 (m, 1 H), 7.69 - 7.74 (m, 1 H), 8, 00 (d, 2-0.9 Hz, 1 N). (3)5-cyano-3-methyl-1-benzofuran-2-carboxylic acid

Lithium hydroxide monohydrate ( 1.64 g) and the mixture was stirred overnight at room temperature and concentrated under reduced pressure. 1M hydrochloric acid was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (3.58 g, 91905) as a pale brown solid.

IN NMR (300 MHz, DMSO-a6) 5 m.h. 2.55 (s, Z H), 7.85 - 7.89 (m, 1 H), 7.91 - 7.95 (m, 1 H), 8.44 - 8.47 (m, 1 H ), 13.76 (shs, 1 H). (4) 2-formyl-3-methyl-1-benzofuran-5-carbonitrile

To the 5-cyano-3-methyl-1-benzofuran-2-carboxylic acid (2.58 g) synthesized above in tetrahydrofuran (30 ml) was added oxalyl chloride (1.32 ml) and a few drops of M,M-dimethylformamide and the mixture was stirred at room temperature for 5 g.

The reaction mixture was concentrated under reduced pressure and the residue was washed with diisopropyl ether to give a pale brown solid. To a solution (50 ml) of the obtained solid in tetrahydrofuran was added a 1.1 M solution (12.0 ml) of lithium tri(isobutoxy)aluminum hydride in tetrahydrofuran at -78 C and the mixture was stirred at -78 "C for 1.5 g, then at 0 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a pale brown solid. Active manganese dioxide (10.0 g) was added to a solution (40 mL) of the obtained solid in tetrahydrofuran, and the mixture was stirred at 50 °C overnight. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with isopropyl ether to give the title compound compound (1.49 g, 63905) as a white solid. "H NMR (300 MHz, SOSI") b m.p. 2.65 (s, Z H), 7.65 (d, 9-8.7 Hz, 1 H), 7.77 (dd, U-8.7, 1.5

HC, 1 N), 8.05 - 8.08 (m, 1 N), 10.08 (s, 1 N). (5)2-(cyclohexyl(hydroxy)methyl|-3-methyl-1-benzofuran-5-carbonitrile

To a solution (30 ml) of 2-formyl-3-methyl-1-benzofuran-5-carbonitrile (1.49 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (12.1 ml) of cyclohexylmagnesium bromide in tetrahydrofuran at 0 " C and the mixture was stirred for 1 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2590 ethyl acetate/hexane) and then purified by column chromatography on MH silica gel (ethyl acetate) to give the title compound (922 mg, 4395) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.84 - 1.43 (m, 6 N), 1.48 - 1.99 (m, 5 N), 2.03 - 2.19 (m, 1

H), 2.24 (s, C H), 4.56 (dd, 9U-8.4, 5.4 Hz, 1 H), 7.47 - 7.51 (m, 1 H), 7, 52 - 7.57 (m, 1 N), 7.78 - 7.81 (m, 1 N). (6)2-(chloro(cyclohexyl)methyl|-33-methyl-1-benzofuran-5-carbonitrile

To a solution (10 ml) of 2-(cyclohexyl(hydroxy)methyl)|-3-methyl-1-benzofuran-5-carbonitrile (922 mg) synthesized above, thionyl chloride (374 μl) was added in toluene and the mixture was stirred at 100 " C for 1 h. The reaction mixture was poured into ice-cooled saturated aqueous sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (868 mg, 8895) as a pale - yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.85 - 1.55 (m, 6 N), 1.62 - 1.74 (m, 2 N), 1.79 - 1.90 (m, 1

H), 2.10 - 2.22 (m, 1 H), 2.26 (s, C H), 2.28 - 2.39 (m, 1 H), 4.80 (d, 9-9 .6 Hz, 1 N), 7.51 - 7.55 (m, 1 N), 7.56 - 7.61 (m, 1 N), 7.81 - 7.83 (m, 1 N). (74-1(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methylamino)benzoic acid

To the mixture of 2-I(chloro(cyclohexyl)methyl|-3-methyl-1-benzofuran-5-carbonitrile (868 mg), synthesized above, methyl 4-aminobenzoate (546 mg), sodium iodide (902 mg) and M, Sodium carbonate (638 mg) was added to M-dimethylformamide (10 mL) and the mixture was stirred at 80 C overnight. To quench the reaction, 1 M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (3095 ethyl acetate/hexane) to give a pale brown solid. .38 ml) and the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (40 ml) and 1M hydrochloric acid (3.50 ml) was added at 0"C. The resulting precipitate was collected by filtration to give the indicated in the title the target compound (621 mg, 53905) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.90 - 1.41 (m, 5 N), 1.44 - 1.56 (m, 1 N), 1.62 - 2.01 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.28 (s, C H), 4.40 - 4.51 (m, 1 H), 4.52 - 4.67 (m , 1 H), 6.56 (d, 9U-8.8

Hz, 2 N), 7.41 - 7.46 (m, 1 N), 7.49 - 7.54 (m, 1 N), 7.75 - 7.77 (m, 1 N), 7, 85 (d, 9U-8.8 Hz, 2 N). (8) ethyl 3-1(4-((5-cyano-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl|amino)upropanoate

To the mixture of 4-Y(5-cyano-3-methyl-1-benzofuran-2-yl)ucyclohexyl)methyl|aminobbenzoic acid (250 mg), synthesized above, hydrochloride of ethyl ester of β-alanine (148 mg), monohydrate of 1- 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (185 mg) was added to hydroxybenzotriazole (148 mg), triethylamine (269 μl) and M,M-dimethylformamide (10 ml), and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5095 ethyl acetate/hexane) to give the title compound (195 mg, 6290) as a colorless oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.38 (m, 8 H), 1.45 - 1.63 (m, C H), 1.63 - 1.99 (m, 2

H), 2.03 - 2.15 (m, 1 H), 2.27 (s, C H), 2.54 - 2.61 (m, 2 H), 3.61 - 3.70 (m , 2 H), 4.14 (k, 057.2

Hz, 2 H), 4.39 - 4.46 (m, 1 H), 6.53 - 6.64 (m, Z H), 7.41 - 7.45 (m, 1 H), 7, 48 - 7.53 (m, 1 N), 7.55 (d, U-8.7 Hz, 2 N), 7.76 (d, 9-1.5 Gu, 1 N). (9)3-(I(4-4(5-cyano-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid

To the mixture of ethyl 3-X1(4-((5-cyano-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonylaminoisopropanoate (195 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added to a 1 M aqueous solution of lithium hydroxide (800 μl), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (800 µL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (168 mg, 92905) as a white solid. H NMR (300 MHz , SOSI") 6 m.ch. 0.94 - 1.37 (m, 5 N), 1.43 - 1.54 (m, 1 N), 1.62 - 1.98 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.26 (s, C H), 2.57 - 2.67 (m, 2 H), 3.54 - 3.70 (m , 2 H), 4.42 (d, 20-81

HC, 1 H), 6.51 - 6.65 (m, C H), 7.39 - 7.44 (m, 1 H), 7.45 - 7.56 (m, C H), 7, 74 (d, 921.1 Hz, 1 N).

Example AZUZ9 3-4(4-((5-cyano-3-methyl-1-benzofuran-2-yl)Uucyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid (o) o M sn.

Kon sn,

Me (1) ethyl 3-1(4-((5-cyano-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanesate

To the mixture of 4-Y(5-cyano-3-methyl-1-benzofuran-2-yl)ucyclohexyl)methyl|aminobbenzoic acid (250 mg), synthesized in Example АЗ9З8(7), ethyl З-(methylamino)propanoate (127 mg), 1-hydroxybenzotriazole monohydrate (148 mg), triethylamine (269 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (185 mg) was added and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5095 ethyl acetate/hexane) to give the title compound (193 mg, 60905) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.95 - 1.38 (m, 8 N), 1.44 - 1.54 (m, 1 N), 1.62 - 1.98 (m, 4

Н), 2.05 - 2.15 (m, 1 Н), 2.27 (s, З Н), 2.55 - 2.66 (m, 2 Н), 3.00 (s, З Н) , 3.70 (t, 9U-7.1 Hz, 2 H), 4.11 (Kk. 9-7.0 Hz, 2 H), 4.26 - 4.33 (m, 1 H), 4, 40 (t, 92-7.9 Hz, 1 N), 6.55 (d, 9-8.6 Hz, 2 N), 7.21 (d, U-8.6 Hz, 2 N), 7 .40 - 7.46 (m, 1 N), 7.48 - 7.54 (m, 1 N), 7.76 (d, 9-1.5 Hz, 1 N). (2)3-I(4-1(5-cyano-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-Sh1(4-((5-cyano-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (193 MG), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of lithium hydroxide (770 μl), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (770 µL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (163 mg, 90905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 1.37 (m, 5 N), 1.44 - 1.54 (m, 1 N), 1.62 - 1.98 (m, 4

H), 2.04 - 2.15 (m, 1 H), 2.27 (s, C H), 2.61 - 2.70 (m, 2 H), 3.03 (s, C H) , 3.69 (t, 9U-6.5 Hz, 2 N), 4.40 (d, 9-7.9 Hz, 1 N), 6.55 (d, 2-8.9 Hz, 2 N ), 7.24 (d, 9-8.9 Hz, 2 N), 7.40 - 7.46 (m, 1 N), 7.48 - 7.53 (m, 1 N), 7.76 (d, 9-1.1 Gu, 1 H).

Example ATO0 3-4(4-(1-(5-chloro-3-methyl-1-benzofuran-2g-yl)-3-

methylbutylamino)phenyl)carbonyl|Iamino)propanoic acid

СН, о емайл ом / Н сн,

SI

(1)1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol

To a solution (20 ml) of 5-chloro-3-methyl-1-benzofuran-2-carbaldehyde (1.00 g) synthesized in Example A88(2) in tetrahydrofuran was added a 1.0 M solution (10.3 ml) of isobutylmagnesium bromide in tetrahydrofuran at 0 C and the mixture was stirred for 1 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2090 ethyl acetate/hexane) to give the title compound (650 mg, 5095) as a colorless oil.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.91 - 0.98 (m, 6 H), 1.53 - 1.70 (m, 1 H), 1.71 - 1.97 (m, C

H), 2.22 (s, C H), 4.89 - 4.98 (m, 1 H), 7.19 - 7.23 (m, 1 H), 7.31 - 7.35 (m , 1 H), 7.43 (d, 9-22

HC, 1 H). (2)5-chloro-2-(1-chloro-3-methylbutyl)-3-methyl-1-benzofuran

To a solution (10 ml) of 1-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (650 mg) synthesized above in toluene was added thionyl chloride (225 μl) and the mixture was stirred at "C for 2 h. The reaction mixture was poured into an ice-cooled aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (668 mg, 9695 ), as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.93 (d, 9U-2.5 Hz, Z H), 0.95 (d, 9-2.7 Hz, Z H), 1.58 - 1.74 (m, 1 H), 2, 06 - 2.21 (m, 2 N), 2.23 (s, C H), 5.17 (t, 98.0 Hz, 1 N), 7.22-7.27 (m, 1 N) , 7.34 - 7.38 (m, 1 N), 7.44 (d, 9-22 Hz, 1 N). (3)4-111-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl|amino)benzoic acid

To the mixture / 5-chloro-2-(1-chloro-3-methylbutyl)-3-methyl-i-benzofuran (668 mu), synthesized above, methyl 4-aminobenzoate (410 mg), sodium iodide (737 mg) and Sodium carbonate (521 mg) was added to M,M-dimethylformamide (10 ml) and the mixture was stirred at 80 C for 8 h. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1595 ethyl acetate/hexane) to give a yellow oil. A 1M aqueous solution of sodium hydroxide (10.0 ml) was added to the mixture of the obtained oil, tetrahydrofuran (10 ml) and ethanol (10 ml), the mixture was stirred under reflux for 8 g and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (10.0 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (394 mg, 43905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.92 (d, 9U-6.6 Hz, Z H), 1.01 (d, 9U-6.6 Hz, Z H), 1.47 - 1.65 (m, 1 H), 1, 87 (t, 9U-7.4 Hz, 2 H), 2.27 (s, Z H), 4.75 (t, 97.4 Hz, 1 H), 6.58 (d, 2U-8, 7 Hz, 2 N), 7.16 - 7.21 (m, 1 N), 7.27 - 7.31 (m, 1 N), 7.40 (d, 9-52.1 Hz, 1 N ), 7.86 (d, 9-8.7 Hz, 2 N). (4) ethyl 3-((4-11-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonyl|iamino)propanesate

To the mixture of /4-X11-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl|Iaminophenzoic acid (180 mg), synthesized above, pB-alanine ethyl ester hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (111 mg), triethylamine (202 μl) and M,M-

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg) was added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 2.5 days. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5095 ethyl acetate/hexane) to give the title compound (196 mg, 86905) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9-6.3 Hz, Z H), 1.00 (d, 9U-6.6 Hz, Z H), 1.25 (t, 97.1 Hz, Z H), 1 .48 - 1.64 (m, 1 N), 1.85 (t, 957.3 Hz, 2 N), 2.25 (s, C H), 2.55-2.62 (m, 2 N ), 3.61 - 3.69 (m, 2 N), 4.13 (k, 2-7.1 Hz, 2 N), 4.30 - 4.39 (m, 1 N), 4.65 - 4.76 (m, 1 H), 6.53 - 6.65 (m, Z H), 7.13 - 7.19 (m, 1 H), 7.23 - 7.29 (m, 1 H), 7.38 (d, 952.2 Hz, 1 H), 7.55 (d, 9-8.8 Hz, 2

N). (5)3-4I(4-111-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonyl|Iamino)propanoic acid

To the mixture of ethyl 3-1(4-11-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonylamino)upropanoate (196 mg), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.50 ml) and the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (1.50 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (170 mg, 92905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, U-6.8 Hz, Z H), 1.00 (d, 9U-6.4 Hz, Z H), 1.48 - 1.63 (m, 1 H), 1, 85 (t, 9-7.5 Hz, 2 H), 2.24 (s, Z H), 2.64 (t, 9U-5.9 Hz, 2 H), 3.60 - 3.69 ( m, 2 H), 4.70 (t, uE7.5 Gu, 1 H), 6.57 (d, 9-8.7 Hz, 2 H), 6.62 (t, 96.1 Hz, 1 H), 7.14 - 7.19 (m, 1 H), 7.24 - 7.29 (m, 1 H), 7.38 (d, 951.9 Hz, 1 H), 7.54 ( d, 9-8.7 Hz, 2 N).

Example A101 3-4(4-(1-(5-chloro-3-methyl-1-benzofuran-2h-yl)-3-methylbutylamino)phenyl)carbonyl(methyl)amino)propanoic acid sn, (o)no o M SN, in SN,

SI

(1) ethyl 3-((4-11-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonyl(methyl)amino)propanate

To the mixture of /4-Х11-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutyl|Iaminophenzoic acid (180 mg), synthesized in Example A100(3), ethyl 3-(methylamino) propanoate (95.2 mg), 1-hydroxybenzotriazole monohydrate (111 mg), triethylamine (202 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (139 mg) and the mixture was stirred at room temperature for 2.5 days. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5595 ethyl acetate/hexane) to give the title compound (199 mg, 8595) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9-6.6 Hz, Z H), 1.00 (d, U-6.6 Hz, Z H), 1.23 (t, 97.1 Hz, Z H), 1 .49 - 1.64 (m, 1 N), 1.84 (t, 957.3 Hz, 2 N), 2.25 (s, Z H), 2.56 - 2.67 (m, 2 N ), 3.01 (s, C H), 3.70 (t, dU27.0 Hz, 2 H), 4.06 - 4.17 (m, 2 H), 4.19 - 4.29 (m , 1 N), 4.63 - 4.73 (m, 1

H), 6.56 (d, 9-8.5 Hz, 2 H), 7.14 - 7.19 (m, 1 H), 7.22 (d, 98.5 Hz, 2 H), 7 .25 - 7.29 (m, 1 N), 7.38 (d, 9-2.2 Hz, 1 N). (2)3-4IK4-111-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonylI(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(4-11-(5-chloro-3-methyl-1-benzofuran-2-yl)-3-methylbutylamino)phenyl)carbonylI(methyl)amino)propanate (199 mg), synthesized above, 1M aqueous solution of sodium hydroxide (1.50 ml) was added to tetrahydrofuran (5 ml) and ethanol (5 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.50 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (174 mg, 9395) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.92 (d, 9U-6.8 Hz, Z H), 1.00 (d, 9-6.8 Hz, Z H), 1.48 - 1.64 (m, 1 H), 1, 85 (t, 9U-7.2 Hz, 2 H), 2.25 (s, Z H), 2.67 (t, 9-6.3 Hz, 2 H), 3.04 (s, Z H ), 3.71 (t, 9UEb, Z Gu, 2 N), 4.69 (t, U-7.6 Hz, 1 N), 6.57 (d, 9U-8.7 Hz, 2 N) , 7.15 - 7.20 (m, 1 N), 7.22 - 7.31 (m, Z H), 7.39 (d, 9-1.9 Hz, 1 N).

Example A102 3-4(4-((3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid

N o M n

HV ne-o (1)M,5-dimethoxy-M-methyl-1-benzofuran-2-carboxamide

To a solution (100 ml) of 2-hydroxy-5-methoxybenzaldehyde (1000 g) in M,M-dimethylformamide was added 2-chloro-M-methoxy-M-methylacetamide (12.1 g), sodium iodide (24.0 g) and potassium carbonate (22.1 g) and the mixture was stirred at 50 °C overnight. The reaction mixture was cooled to room temperature and the insoluble material was filtered off.

1,8-diazabicyclo/5.4.Oundec-7-ene (9.82 ml) was added to the filtrate and the mixture was stirred at 120 C for 2 h. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4096 ethyl acetate/hexane) to give the title compound (9.42 g, 61905) as a yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 3.42 (s, Z H), 3.83 (s, Z H), 3.85 (s, Z H), 7.01 - 7.06 (m, 1

H), 7.07 - 7.09 (m, 1 H), 7.43 - 7.45 (m, 1 H), 7.46 - 7.51 (m, 1 H). (2)3-bromo-M,5-dimethoxy-M-methyl-1-benzofuran-2-carboxamide

To a solution (100 ml) of M,5-dimethoxy-M-methyl-1-benzofuran-2-carboxamide (9.24 g) synthesized above in acetic acid was added dropwise bromine (2.21 ml) and the mixture was stirred for overnight at room temperature. The resulting precipitate was collected by filtration and washed with diisopropyl ether to afford the title compound (9.48 g, 77905) as an orange solid. "H NMR (300 MHz, SOSI") 6 m.h. 3.43 (s, C H), 3.85 (s, C H), 3.95 (s, C H), 7.09 (d , 9-9.0 Hz, 1 H), 7.46 - 7.54 (m, 2 H). (3)3-bromo-5-methoxy-1-benzofuran-2-carbaldehyde

Lithium aluminum hydride (241 mg) was added to a solution (40 ml) of 3-bromo-M,5-dimethoxy-M-methyl-1-benzofuran-2-carboxamide (4.00 g) synthesized above in tetrahydrofuran at 0 C, and the mixture was stirred for 1 h. Lithium aluminum hydride (241 mg) was added, and the mixture was stirred at 0 "C for 1 h. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2090 ethyl acetate/hexane) to give the title compound (880 mg, 27905) as a pale yellow solid. "H NMR (300 MHz, SOCI") b m.h . 3.96 (s, Z H), 7.17 (d, 9-91 Hz, 1 H), 7.48 - 7.53 (m, 1 H), 7.55 - 7.56 (m, 1 H), 9.85 (s, 1 H). (4)(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanol

To a solution (50 ml) of 3-bromo-5-methoxy-1-benzofuran-2-carbaldehyde (2.26 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (13.3 ml) of cyclohexylmagnesium bromide in tetrahydrofuran at -78 "C and the mixture was stirred at -78 70 for 30 min, then at 0 "C for 1 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction, tetrahydrofuran was evaporated on evaporators and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2090 ethyl acetate/hexane) to give the title compound (1.82 g, 6790) as a yellow oil.

IN NMR (300 MHz, SOSIZ") b m.h. 0.99 - 1.37 (m, 5 N), 1.49 - 1.60 (m, 1 N), 1.62 - 2.02 (m, 6

H), 3.93 (s, Z H), 4.53 (t, 9U-6.0 Hz, 1 H), 6.63 (s, 1 H), 6.89 (d, 9U-8, 8 Hz, 1 N), 7.34 (d, 9-8.8

HC, 1 H). (5)3-bromo-2-|(chloro(cyclohexyl)methyl|-5-methoxy-1-benzofuran

To a solution (20 ml) of (3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanol (1.82 g) synthesized above in toluene was added thionyl chloride (469 μl) and the mixture was stirred at 100 "C for 1.5 g. The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound indicated in the title (1.73 g, 9096) as a yellow solid. "H NMR (300 MHz, SOSIz") 6 m.h. 0.98 - 1.39 (m, 5 N), 1.51 - 1.87 (m, 4 N), 2.03 - 2.21 (m, 2

H), 3.92 (s, C H), 4.74 (d, 9U-8.0 Hu, 1 H), 6.68 (s, 1 H), 6.92 (d, 9-8, 8 Hz, 1 N), 7.36 (d, 9-8.8

HC, 1 H). (6) 4-(3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl|amino)benzoic acid To a mixture of 3-bromo-2-(chloro(cyclohexyl)methyl|-5-methoxy- Sodium carbonate (1.03 g) was added to 1-benzofuran (1.73 g) synthesized above, methyl 4-aminobenzoate (878 mg), sodium iodide (1.45 g) and M,M-dimethylformamide (30 ml) and the mixture was stirred at 80 C for 8 h. 1 M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2595 ethyl acetate/hexane) to give a yellow oil. To a mixture of the obtained oil, tetrahydrofuran (10 ml) and ethanol (10 ml) was added 1M aqueous sodium hydroxide solution (10.0 ml), the mixture was stirred under reflux for 5 g and concentrated under reduced pressure. The residue was dissolved in water (20 ml) and 1M hydrochloric acid (10.0 ml) was added at 0"C. The resulting precipitate was collected by filtration yam to give the title compound (318 mg, 14905) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.37 (m, 5 N), 1.55 - 1.86 (m, 4 N), 1.87 - 2.02 (m, 2

H), 3.90 (s, C H), 4.44 (d, 9-6.6 Hz, 1 H), 6.56 (s, 1 H), 6.61 (d, 9-8, 9 Hz, 2 N), 6.87 (d, 9-9.0

Hu, 1 H), 7.29 - 7.35 (m, 1 H), 7.87 (d, 9U-8.9 Hz, 2 H). (7) ethyl 3-1(4-((3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl|amino)upropanoate

To the mixture of 4-((3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylIaminorphenzoic acid (125 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (63.0 mg), monohydrate of 1- hydroxybenzotriazole (62.9 mg), triethylamine (114 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.6 mg) and the mixture was stirred overnight at at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5095 ethyl acetate/hexane) to give the indicated title compound (134 mg, 8895) as a pale yellow oil."H NMR (300 MHz, SOCI") 6 m.h. 1.03 - 1.37 (m, 8 H), 1.54 - 1.85 (m, 4 H), 1.87 - 1.99 (m, 2

H), 2.56 - 2.61 (m, 2 H), 3.62 - 3.70 (m, 2 H), 3.90 (s, C H), 4.14 (k, 9-7 ,1 Hz, 2 N), 4.36 - 4.41 (m, 2 N), 6.53 (d, 9U-0.8 Hz, 1 N), 6.56 - 6.64 (m, Z H), 6.86 (d, 9U-8.8 Hz, 1 H), 7.29 (dd, 9U-8.8, 0.8 Gu, 1 H), 7.56 (d, 9U-8 .8 Hz, 2 N). (8)3-(I(4-1(3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid

To the mixture of ethyl 3-((4-((3-bromo-5-methoxy-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl|amino)upropanoate (134 mg), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 2.5 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (116 mg, 9195) as a pale brown solid. NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.35 (m, 5 N), 1.53 - 1.84 (m, 4 N), 1.84 - 1.99 (m, 2

H), 2.61 (t, 95.7 Hz, 2 H), 3.59 - 3.68 (m, 2 H), 3.89 (s, C H), 4.38 (d, 9- 6.4 Gu, 1 N), 6.52 - 6.66 (m, 4 N), 6.85 (d, U-8.9 Hz, 1 N), 7.30 (dd, U-8, 9, 0.8 Gu, 1 N), 7.54 (d, 9U-8.7 Hz, 2 N).

Example ATOZ 3-4(4-((3-bromo-5-methoxy-1-benzofuran-2-yl)Uucyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid o mi OH o M sn,

ON

Hg ne-o (1) ethyl 3-1(4-((3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanesate

To the mixture of 4-((3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenzoic acid (125 mg), synthesized in Example A102(6b), ethyl 3-(methylamino)propanoate (53.8 mg), 1-hydroxybenzotriazole monohydrate (62.9 mg), triethylamine (114 μl) and N,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78.6 mg) was added and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3595 ethyl acetate/hexane) to give the title compound (124 mg, 7990) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.36 (m, 8 N), 1.55 - 1.85 (m, 4 N), 1.86 - 2.00 (m, 2

H), 2.62 (t, 927.0 Hz, 2 H), 3.02 (s, C H), 3.72 (t, 9U7.0 Hz, 2 H), 3.91 (s, C H), 4.12 (k, 957.1 Gu, 2 H), 4.24 - 4.A1 (m, 2 H), 6.54 - 6.55 (m, 1 H), 6.58 ( d, 2-8.8 Hz, 2 N), 6.86 (d, U-8.8 Hz, 1 N), 7.24 (d, 98.8 Hz, 2 N), 7.30 (dd , U-8.8, 0.8 Hz, 1 N). (2)3-(IM4-1(3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-(A-((3-bromo-5-methoxy-1-benzofuran-2-yl)cyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (124 MG), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrochloric acid (1.00 ml) was added at 0"C and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (5 ml ), a 1M aqueous sodium hydroxide solution (500 μl) was added and the mixture was concentrated under reduced pressure. The residue was dissolved in water (5 ml) and 1M hydrochloric acid (500 μl) was added at 0"C.

The resulting precipitate was collected by filtration to afford the title compound (107 mg, 9195) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.36 (m, 5 N), 1.53 - 1.84 (m, 4 N), 1.85 - 2.00 (m, 2

Н), 2.62-2.75 (m, 2 Н), 3.05 (s, З Н), 3.70 (t, 9U-6.2 Hz, 2 Н), 3.90 (s, With H), 4.37 (d, 9U-6.4 Hz, 1

H), 6.55 (s, 1 H), 6.58 (d, 2-8.7 Hz, 2 H), 6.87 (d, 9-8.9 Hz, 1 H), 7.22 - 7.35 (m, Z H).

Example A104 3-4(4-(2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid

Sleep SN, oh du

N o M in

SN; non-o (1)X2-acetyl-4-methoxyphenoxy)acetic acid

To a mixture of 1-(2-hydroxy-5-methoxyphenyl)ethanone (25.0 g), methyl bromoacetate (15.5 ml) and

Potassium carbonate (31.1 g) was added to M,M-dimethylformamide (250 ml) and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, 1M hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a brown solid. A 1M aqueous solution of sodium hydroxide (300 ml) was added to a mixture of the obtained solid, tetrahydrofuran (300 ml) and ethanol (300 ml), and the mixture was stirred overnight at room temperature and concentrated under reduced pressure. 1M hydrochloric acid (300 mL) was added to the residue at 0 °C and the resulting precipitate was collected by filtration to give the title compound (34.2 g, quantitative) as a white solid. H NMR (300 MHz, SOSI) 6 m.h. 2.67 (s, Z H), 3.83 (s, Z H), 4.72 (s, 2 H), 6.92 (d, U-9.0 Hz, 1 H), 7.04 - 7.09 (m, 1 H), 7.29 (d, 9U-3.0 Gu, 1 H). (2) 5-methoxy-3-methyl-1-benzofuran

A mixture of (2-acetyl-4-methoxyphenoxy)acetic acid (10.0 g) synthesized above, acetic anhydride (18.3 g) and acetic acid (100 ml) was stirred at 110 "C for 5 g, poured into water and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (590 ethyl acetate/hexane) to give the title compound (5.87 g, 8195 ), as a colorless oil.

IN NMR (300 MHz, SOSIz") 6 m.h. 2.21 (d, 9-1.1 Hz, Z H), 3.86 (s, Z H), 6.85 - 6.91 (m, 1 H), 6.95 (d, 9U-2 .7 Hz, 1 N), 7.33 (d, 9U-8.8 Hz, 1 N), 7.35 - 7.39 (m, 1 N). (3)2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butan-1-one

Aluminum chloride (3.28 g) was added to a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized above, 2-ethylbutanoyl chloride (1.85 ml) and nitromethane (30 ml) and the mixture was stirred at at room temperature for 1.5 g. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (695 ethyl acetate/hexane) to give the title compound (3.12 g, 97965) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.86 - 0.95 (m, 6 N), 1.52 - 1.66 (m, 2 N), 1.72 - 1.88 (m, 2

H), 2.59 (s, C H), 3.29 - 3.41 (m, 1 H), 3.88 (s, C H), 7.00 - 7.02 (m, 1 H) , 7.06 - 7.11 (m, 1 N), 7.37 - 7.42 (m, 1 N). (4) methyl 4-D2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|amino)benzoate

To the mixture of /2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butan-1-one (800 mg) synthesized above, methyl 4-aminobenzoate (464 mg), triethylamine ( 3.43 ml) and methylene chloride (10 ml) was added titanium chloride (IM) (404 μl) and the mixture was stirred overnight at room temperature under an argon atmosphere. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, methylene chloride was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (882 μl) and sodium cyanoborohydride (386 mg) were added to a solution (20 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 g. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. . The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2095 ethyl acetate/hexane) to give the title compound (718 mg, 5990) as a brown oil.

IN YAMRE (300 MHz, SOSIz) b m.ch. 0.85 (t, 9U-7.4 Hz, Z H), 0.95 (t, 9U-7.3 Hz, Z H), 1.14 - 1.74 (m, 4 H), 1, 81 - 1.95 (m, 1 H), 2.23 (s, Z H), 3.81 (s, Z H), 3.83 (s, Z H), 4.47 - 4.53 ( m, 1 N), 4.59 (t, 9-81 Gu, 1 N), 6.56 (d, U-8.8 Hz, 2 N), 6.81 (dd, U-8.8, 2.6 Hz, 1 N), 6.86 (d, 9-26 Hz, 1 N), 7.24 (d, 98.8 Hz, 1 N), 7.79 (d, 98.8 Hz, 2 H). (5)4-P2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|Iaminophenzoic acid

To a mixture of methyl 4-T2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|iaminobenzoate (718 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) 1M aqueous sodium hydroxide solution (5.00 ml) was added, the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (5.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (574 mg, 8395) as a white solid. H NMR ( 300 MHz, SOSI") b m.h. 0.85 (t, 9U-7.4 Hz, Z H), 0.95 (t, U-7.3 Hz, Z H), 1.16 - 1.74 (m, 4 H), 1, 82 - 1.95 (m, 1 H), 2.24 (s, Z H), 3.83 (s, Z H), 4.54 - 4.66 (m, 2 H), 6.58 ( d, 9-8.8 Hu, 2 H), 6.83 (dd, U-8.8, 2.6 Hu, 1 H), 6.88 (d, 9-26 Hz, 1 H), 7 .25 (d, 9-8.8 Hz, 1 N), 7.85 (d, 9uEv8.8 Hz, 2 N). (6) ethyl 3-1(4-C2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoate

To the mixture of 4-ShT2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butylamino)bbenzoic acid (250 mg), synthesized above, p-alanine ethyl ester hydrochloride (151 mg), 1-hydroxybenzotriazole monohydrate (151 mg), triethylamine (275 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg) and the mixture was stirred at room temperature for 1 day 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55950 ethyl acetate/hexane) to give the title compound (85.0 mg, 2790) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.87 (t, 9U-7.4 Hz, Z H), 0.95 (t, 9U-7.4 Hz, Z H), 1.24 (t, 97.1 Hz, Z H), 1 .30 - 1.74 (m, 4 H), 1.81 - 1.93 (m, 1 H), 2.23 (s, C H), 2.54 - 2.62 (m, 2 H) , 3.65 (k, 9-6.1 Hz, 2 H), 3.83 (s, C H), 4.13 (k, 957.1 Hz, 2 H), 4.40 (d, 928 .8 Hz, 1 N), 4.52 - 4.60 (m, 1

H), 6.53 - 6.62 (m, C H), 6.78 - 6.84 (m, 1 H), 6.86 (d, 9U-2.7 Hz, 1 H), 7, 22 (s, 1 N), 7.54 (d, 3-8.8 Hz, 2 N). (7)3--(4-C2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-

yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid

To the mixture of ethyl 3-4(4-(2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl|Iaminosupropanoate (85.0 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (75.4 mg, 9495) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.84 (t, 9U-7.3 Hz, Z H), 0.94 (t, 9U-7.3 Hz, Z H), 1.14 - 1.72 (m, 4 H), 1, 79 - 1.93 (m, 1 N), 2.22 (s, Z H), 2.62 (t, 95.7 Hz, 2 N), 3.58 - 3.68 (m, 2 N) , 3.82 (c,

With H), 4.57 (d, 9-7.7 Hz, 1 H), 6.52 - 6.62 (m, With H), 6.81 (dd, U-8.9, 2.5 Hz, 1 N), 6.86 (d, 9-2.5

Hu, 1 N), 7.24 (d, 9-8.9 Hz, 1 N), 7.52 (d, 928.9 Hz, 2 N).

Example A1T105 3-4(4-(2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid sn. sn, o du o M sn, / n sn, ne-o (1) ethyl 3-1(4-C2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butylamino) phenyl)carbonyl)(methyl)amino)propanoate

To the mixture of 4-ShT2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butylamino)bbenzoic acid (250 mg), synthesized in Example A104(5), ethyl 3-(methylamino) of propanoate (129 mg), 1-hydroxybenzotriazole monohydrate (151 mg), triethylamine (275 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (188 mg) and a mixture stirred at room temperature for 1 day. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (55950 ethyl acetate/hexane) to give the title compound (261 mg, 81905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.85 (t, 9-7.4 Hz, Z H), 0.94 (t, 9U-7.4 Hz, Z H), 1.23 (t, 97.1 Hz, Z H), 1 .29 - 1.73 (m, 4 N), 1.79 - 1.93 (m, 1 N), 2.22 (s, Z H), 2.61 (t, 957.1 Hz, 2 N ), 3.01 (s, C H), 3.70 (t, 927.1 Hz, 2 H), 3.83 (s, C H), 4.11 (k, 957.1 Hz, 2 H ), 4.28 (d, 9-8.5 Hz, 1

H), 4.50 - 4.58 (m, 1 H), 6.55 (d, 2-8.7 Hz, 2 H), 6.79 - 6.83 (m, 1 H), 6, 86 (d, 9-2.5 Hz, 1 N), 7.20 (d, 9-8.7 Hz, 2 N), 7.24 (d, U-8.8 Hz, 1 N). (2)3-I(4-C2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-4(4-(2-ethyl-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)butylamino)phenyl)carbonyl|)(methyl)aminopropanoate (261 mg), synthesized above, to tetrahydrofuran (5 ml) and ethanol (5 ml) was added a 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (231 mg, 9495) as a pale brown solid. NMR (300 MHz, SOSI") b m.ch. 0.85 (t, 9U-7.3 Hz, Z H), 0.94 (t, U-7.4 Hz, Z H), 1.15 - 1.73 (m, 4 H), 1, 80 - 1.93 (m, 1 H), 2.23 (s, Z H), 2.65 (t, 9U-6.6 Hz, 2 H), 3.03 (s, Z H), 3 ,69 (t, 9U-6,6

Hz, 2 H), 3.83 (s, C H), 4.55 (d, 9U-7.7 Hz, 1 H), 6.56 (d, 9U-8.9 Hz, 2 H), 6.82 (dd, 9U-8.8, 2.4 Hz, 1

Н), 6.87 (d, 9-2.4 Gu, 1 Н), 7.20 - 7.28 (m, З Н).

Example ATO6b 3-I44-(1-(5-chloro-1-3-"(trifluoromethyl)phenyl|-1H-indol-2-yl)heptyl)amino|phenyl)icarbonyl)amino|Ipropanoic acid sn. 8, fool

N ov s M. y

Te (1)5-chloro-M-methoxy-M-methyl-1H-indole-2-carboxamide

To a mixture of 5-chloro-1H-indole-2-carboxylic acid (15.0 g), M.O-dimethylhydroxylamine hydrochloride (8.97 g), 1-hydroxybenzotriazole monohydrate (14.1 g), triethylamine (25.6 ml) and M,M-dimethylformamide (200 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17.6 g) and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the resulting precipitate was collected by filtration to give the title compound (15.5 g, 84905) as a pale brown solid. "H NMR (300 MHz, SOSI") b m.p. 3.43 (s, C H), 3.85 (s, C H), 7.14 - 7.18 (m, 1 H), 7 .25 (dd, uU-8.7, 1.9 Hz, 1 N), 7.36 (d, U-8.7 Gu, 1 N), 7.66 (d, 9U-1.9 Hz, 1 H), 9.32 (shs, 1 H). (2)1-(5-chloro-1H-indol-2-yl)heptan-1-one

A 2.3 M solution (50.0 ml) of hexyllithium was added to a solution (100 ml) of 5-chloro-M-methoxy-M-methyl-1H-indole-2-carboxamide (9.14 g) synthesized above in tetrahydrofuran in hexane at -78 "C and the mixture was stirred in a nitrogen atmosphere for 1.5 h. Another 2.3M solution (38.3 ml) of hexyllithium in hexane was added and the mixture was stirred at -78 "C for 2 h.

1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (6.90 g, 6895) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.86 - 0.95 (m, Z H), 1.26 - 1.48 (m, 6 H), 1.71 - 1.85 (m, 2

H), 2.92 (t, 9-7.7 Hz, 2 H), 7.11 - 7.14 (m, 1 H), 7.29 (dd, U-8.8, 1.9 Gu , 1 N), 7.36 (d, U-8.8 Hz, 1 N), 7.66 - 7.70 (m, 1 N), 9.05 - 9.19 (m, 1 N). (3) 1-15-chloro-1-3-[(trifluoromethyl)phenyl]-1H-indol-2-yluheptan-1-one

A mixture of /1-(b-chloro-1H-indol-2-yl)heptan-i-one (9.14 g) synthesized above, 3-iodobenzotrifluoride (1.97 ml), copper (I) bromide (327 mg ), potassium carbonate (2.36 g) and M-methyl-2-pyrrolidone (30 ml) were deaerated and the mixture was stirred in an argon atmosphere at 180 "C for 1 day. 1 M hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. Extract washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (1090 ethyl acetate/hexane) to give the title compound (0.78 g, 17905) as a brown oil. "H NMR (300 MHz, SOSIz") 6 m.h. 0.84 - 0.92 (m, Z H), 1.22 - 1.41 (m, 6 H), 1.62 - 1.74 (m, 2

H), 2.90 - 2.97 (m, 2 H), 6.95 (d, U-8.8 Hz, 1 H), 7.25 (dd, U-8.8, 1.9 Hz , 1 H), 7.35 (s, 1 H), 7.42 - 7.47 (m, 1 H), 7.49 - 7.53 (m, 1 H), 7.59 - 7.66 (m, 1 N), 7.69 - 7.74 (m, 2 N). (4) methyl 4-K1-/5-chloro-1-3-"(trifluoromethyl)phenyl|-1H-indol-2-yl)heptyl)amino|benzoate

To the mixture of 1-(5-chloro-1-3-"trifluoromethyl)phenyl|-1H-indol-2-yl)uheptan-1-one (709 ml),

synthesized above, methyl 4-aminobenzoate (263 mg), triethylamine (1.94 ml) and methylene chloride (10 ml) was added titanium chloride (IM) (229 μl) and the mixture was stirred under an argon atmosphere overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (498 μl) and sodium cyanoborohydride (219 mg) were added to a solution (10 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 g. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. . The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (1590 ethyl acetate/hexane) to give the title compound (645 mg, 68905) as a brown oil. "H NMR (300 MHz, SOSI") b m.ch. 0.84 (t, 9U-6.9 Hz, Z H), 1.12 - 1.41 (m, 8 H), 1.74 - 1.93 (m, 2 H), 3.83 (s, C H), 4.03 - 4.15 (m, 1 H), 4.41 - 4.52 (m, 1 H), 6, 33 (d, 9-8.8 Hz, 2 N), 6.57 (s, 1

H), 6.88 (d, 9U-8.8 Hz, 1 H), 7.09 (dd, 9U-8.8, 1.9 Hz, 1 H), 7.45 - 7.52 (m , 1 H), 7.54 - 7.65 (m, Z

H), 7.68 - 7.79 (m, C H). (5)4-K1-(5-chloro-1-3-trifluoromethyl)phenyl)-1H-indol-2-yl/heptyl)amino|benzoic acid

To the mixture of methyl 4-(1-(5-chloro-1-3-"(trifluoromethyl)phenyl|-1H-indol-2-yl)uheptyl)amino|benzoate (645 mg), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (5.00 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (5.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (589 mg, 9495) as a white solid. H NMR ( 300 MHz, SOSI") b m.h. 0.80 (t, U-6.8 Hz, Z H), 1.03 - 1.34 (m, 6 H), 1.63 - 1.83 (m, 2 H), 4.29 - 4 .44 (m, 1 N), 6.18 (d, 9U-8.3 Hz, 2 N), 6.49 (s, 1 N), 6.82 (d, 9-8.5 Hz, 1 H), 7.02 (dd, 9U-8.5, 1.9 Hz, 1 H), 7.34 - 7.56 (m, 4 H), 7.60 (d, 9-7.6 Hz , 1 N), 7.70 (d, 9-8.3 Hz, 2 N). (6) ethyl 3-134-(/1-(5-chloro-1-3-trifluoromethyl)phenyl!|-1H-indol-2-yl)heptyl)amino|phenyl)carbonyl)amino|Ipropanoate

To the mixture of 4-((/1-(5-chloro-1-3-trifluoromethyl)phenyl|-1H-indol-2-yl)heptyl)amino|benzoic acid (250 mg), synthesized above, ethyl ester hydrochloride 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (136 mg) was added to β-alanine (109 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (198 μl) and M,M-dimethylformamide (10 ml). and the mixture was stirred at room temperature for 3 days. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5095 ethyl acetate/hexane) to give the title compound (272 mg, 9290) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.83 (t, 9U-6.7 Hz, Z H), 1.11 - 1.39 (m, 11 H), 1.75 - 1.90 (m, 2 H), 2.60 (t , 9U-5.8 Hz, 2 N), 3.63 - 3.72 (m, 2 N), 3.93 - 4.04 (m, 1 N), 4.15 (k, 9-7, 1 Hz, 2

H), 4.38 - 4.50 (m, 1 H), 6.35 (d, 2-8.5 Hz, 2 H), 6.53 - 6.64 (m, 2 H), 6, 87 (d, 9-8.6 Hz, 1 N), 7.08 (dd, U-8.6, 2.1 Gu, 1 N), 7.45 - 7.66 (m, 6 N), 7.70 (d, 9de7.1 Hz, 1 N). (7)3-I44-(/1-(5-chloro-1-3-"trifluoromethyl)phenyl|-1H-indol-2-yl)heptyl)amino|phenyl)carbonyl)amino|Ipropanoic acid

To the mixture of ethyl 3-134-(O1-(5-chloro-1-3-trifluoromethyl)phenyl!|-1H-indol-2-yl)heptyl)amino|phenylcarbonyl)amino|propanoate (273 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added to a 1 M aqueous solution of sodium hydroxide (5.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (5.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (253 mg, 97905) as a white solid. H NMR ( 300 MHz, SOSI") b m.h. 0.78 (t, 9U-6.8 Hz, Z H), 1.01 - 1.32 (m, 8 H), 1.64 - 1.78 (m,

2 H), 2.30 - 2.43 (m, 2 H), 3.37 - 3.53 (m, 2 H), 4.29 - 4.43 (m, 1 H), 6.27 ( d, 9U-8.7 Hz, 2 N), 6.47 (s, 1 N), 6.76 - 6.89 (m, 2 N), 7.00 (dd, 9U-8.7, 1 .9 Hz, 1 N), 7.39 - 7.59 (m, 6 N), 7.63 (d, 9-7.6

HC, 1 H).

Example A107 3-I44-(1-(5-chloro-1-3-"(trifluoromethyl)phenyl|-1H-indol-2-yl)heptyl)amino|phenylcarbonyl)(methyl)amino|Ipropanoic acid sn du - M Sn.

SI M,

IS

EE

(1) ethyl 3-134-(/1-(5-chloro-1-3-trifluoromethyl)phenyl!|-1H-indol-2-yl)heptyl)amino|phenylcarbonyl)(methyl)amino|Ipropanoate

To the mixture of 4-((/1-(5-chloro-1-3-trifluoromethyl)phenyl|-1H-indol-2-yl)heptyl)amino|Ibenzoic acid (250 mg), synthesized in Example A106 (5 ), ethyl 3-(methylamino)propanoate (93.1 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (198 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3- (Z -dimethylaminopropyl)carbodiimide (136 mg) and the mixture was stirred at room temperature for 3 days. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (4095 ethyl acetate/hexane) to give the title compound (254 mg, 8490) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.ch. 0.83 (t, 9U-6.9 Hz, Z H), 1.11 - 1.37 (m, 11 H), 1.76 - 1.86 (m, 2 N), 2.62 (t, 9-7.3 Hz, 2 N), 3.02 (s, C H), 3.72 (t, 9U-7.3 Hz, 2 N), 3.88 (d, 9-7.7 Hz, 1 N), 4.07 - 4.17 (m, 2 N), 4.35 - 4.46 (m, 1 N), 6 .34 (d, 2-8.5 Hz, 2 N), 6.56 (s, 1 N), 6.88 (d, 2-88

Hz, 1 N), 7.08 (dd, 9U-8.8, 2.0 Hz, 1 N), 7.17 (d, 9-8.5 Hz, 2 N), 7.51 (d, 9U-7.7 Gu, 1 H), 7.56 (d, 9-2.0 HZ, 1 H), 7.57 - 7.66 (m, 2 H), 7.71 (d, 9- 7.7 Gu, 1 N). (2)3-I44-(/1-(5-chloro-1-3-trifluoromethyl)phenyl|-1H-indol-2-yl)heptyl)amino|phenyl)carbonyl)(methyl)amino|propanoic acid

To the mixture of ethyl 3-134-(01-(5-chloro-1-3-trifluoromethyl)phenyl!|-1H-indol-2-yl)heptyl)amino|phenyl)carbonyl)(methyl)amino|Ipropanoate (254 mg) synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added with a 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (223 mg, 92905) as a white solid. H NMR ( 300 MHz, SOSI") b m.h. 0.81 (t, U-6.8 Hz, Z H), 1.06 - 1.35 (m, 8 H), 1.70 - 1.82 (m, 2 H), 2.39 - 2 .49 (m, 2 H), 2.92 (s, З H), 3.51 - 3.72 (m, 2 H), 4.38 (t, 9U-6.8 Hz, 1 H), 6.32 (d, 98.5 Hz, 2 H), 6.53 (s, 1 H), 6.86 (d, 9U-8.7 Hz, 1 H), 7.05 (dd, 9U- 8.7, 1.9 Hz, 1 N), 7.14 (d, 3U-8.5 Hz, 2 N), 7.47 - 7.55 (m, 2 N), 7.55 - 7, 67 (m, 2 N), 7.70 (d, 9-7.6 Hz, 1 N).

Example ATO8 3-4(4-((3-cyano-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid o duet

To us

ON

SM non-o (1XX3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanone

Trifluoroacetic anhydride (1.63 ml) was added to a mixture of dimethylsulfoxide (831 ml) and tetrahydrofuran (20 ml) at -78°C, the mixture was stirred for 30 min and a solution (20 ml) (3-bromo-5-methoxy- 1-benzofuran-2-yl)(cyclohexyl)methanol (2.03 g), synthesized in Example A102(4), in tetrahydrofuran. The reaction mixture was stirred in an argon atmosphere at -78 "C for 1 g, triethylamine (3, 33 ml) and the mixture was stirred at room temperature for 1 g. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (1590 ethyl acetate/hexane) to give the title compound (1.52 g, 7590) as a white solid substance "H NMR (300 MHz, SOSI") 6 m.h. 1.20 - 1.63 (m, 5 N), 1.70 - 1.81 (m, 1 N), 1.82 - 2.00 (m, 4

H), 3.13 - 3.24 (m, 1 H), 3.95 (s, C H), 7.12 (d, 2-9.3 Hz, 1 H), 7.46 - 7, 50 (m, 2 N). (2) methyl 4-1 (3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methylamino)benzoate

To the mixture of (3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanone (1.52 g) synthesized above, methyl 4-aminobenzoate (682 mg), triethylamine (5.03 ml) and methylene chloride (20 ml) was added titanium chloride (IM) (593 μl) and the mixture was stirred under an argon atmosphere overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (1.29 ml) and sodium cyanoborohydride (567 mg) were added to a solution (20 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 g. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the tetrahydrofuran was evaporated on the evaporator and the residue was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2590 ethyl acetate/hexane) to give the title compound (1.46 g, 6995) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.38 (m, 5 N), 1.54 - 1.85 (m, 4 N), 1.85 - 2.01 (m, 2

Н), 3.82 (s, З Н), 3.90 (s, З Н), 4.36 - 4.56 (m, 2 Н), 6.54 (s, 1 Н), 6.58 (d, 959.0 Hu, 2 H), 6.86 (d, U-8.8 Hu, 1 H), 7.30 (d, 9-8.8 Hz, 1 H), 7.81 ( d, 92-9.0 Hz, 2 N). (3)4-I(3-cyano-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl|amino)benzoic acid

To the mixture of methyl 4-1(3-bromo-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methyl Iaminorenzoate (1.46 g), synthesized above, zinc cyanide (362 mg) and

To M,M-dimethylformamide (30 mL) was added tetrakis(triphenylphosphine)palladium (0) (357 mg), and after deaeration, the mixture was stirred under argon at 80 C overnight. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (4095 ethyl acetate/hexane) to give a yellow solid. A 1 M aqueous solution of lithium hydroxide (2.88 ml) was added to a solution (10 ml) of the obtained solid in tetrahydrofuran and the mixture was stirred overnight under reflux. Ethanol (10 ml) and water (10 ml) were added to the reaction mixture, and the mixture was stirred under reflux for 3 h. Another 1 M aqueous solution of lithium hydroxide (1.44 ml) was added, the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1M hydrochloric acid (4.35 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (547 mg, 94905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.05 - 1.38 (m, 5 N), 1.53 - 1.87 (m, 4 N), 1.87 - 2.01 (m, 2

H), 3.94 (s, C H), 4.42 - 4.60 (m, 2 H), 6.58 (d, 9U-8.8 Hz, 2 H), 6.68 (d, 9U-0.8 Hz, 1 N), 6.84 (d, 99.1 Hz, 1 N), 7.53 (dd, 9U-9.1, 0.8 Hz, 1 N), 7.87 (d, 9U-8.8 Hz, 2 N). (4) ethyl 3-1(4-((3-cyano-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl|amino)upropanoate

To the mixture of 4-((3-cyano-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylIiaminophenzoic acid (240 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (137 mg), 1-hydroxybenzotriazole monohydrate ( 136 mgH), triethylamine (248 μl) and N,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg) and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6095 ethyl acetate/hexane) to give the title compound (285 mg, 95905) as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.05 - 1.37 (m, 8 N), 1.53 - 1.86 (m, 4 N), 1.86 - 2.00 (m, 2

H), 2.59 (t, U-6.3 Hz, 2 H), 3.62 - 3.70 (m, 2 H), 3.93 (s, C H), 4.14 (k, 9-7.1 Hz, 2 N), 4.35 - 4.445 (m, 2 N), 6.57 (d, U-8.8 Hz, 2 N), 6.60 (t, 9U-5, 2 Hz, 1 N), 6.65 (d, U-0.5 Hz, 1 N), 6.83 (d, 9-9.1

HC, 1 N), 7.51 - 7.60 (m, C H). (5)3-(I(4-1(3-cyano-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid

To the mixture of ethyl 3-1(4-((3-cyano-5-methoxy-1-benzofuran-2-yl)cyclohexyl)methylylamino)phenyl)carbonyl|iaminopropanoate (285 mg), synthesized above, tetrahydrofuran (5 ml) and 1 M aqueous solution of sodium hydroxide (1.00 ml) was added to ethanol (5 ml), the mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (246 mg, 92905) as a pale yellow solid. NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.37 (m, 5 N), 1.50 - 1.63 (m, 1 N), 1.63 - 1.85 (m, C

H), 1.85 - 2.01 (m, 2 H), 2.64 (t, 9U-5.7 Hz, 2 H), 3.60 - 3.70 (m, 2 H), 3, 93 (c, Z H), 4.42 (d, 2-64

Hz, 1 N), 6.58 (d, 9-8.7 Hz, 2 N), 6.62 - 6.70 (m, 2 N), 6.83 (d, 9-9.2 Hz, 1 H), 7.50 - 7.59 (m, Z

N).

Example A109 3-4(4-((3-cyano-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid o pkt o M sn, n

SM ne-o (1) ethyl 3-1(4-((3-cyano-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoate

To the mixture of 4-((3-cyano-5-methoxy-1-benzofuran-2-

yl)Uucyclohexyl)methylaminophenzoic acid (240 mg), synthesized in Example A108(3), ethyl 3-(methylamino)propanoate (117 mg), 1-hydroxybenzotriazole monohydrate (136 mg), triethylamine (248 μl) and M,M- 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg) was added to dimethylformamide (10 ml) and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6095 ethyl acetate/hexane) to give the title compound (253 mg, 8290) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.36 (m, 8 N), 1.52 - 1.85 (m, 4 N), 1.85 - 1.99 (m, 2

H), 2.62 (t, U-6.9 Hz, 2 H), 3.02 (s, C H), 3.71 (t, 9U-6.9 Hz, 2 H), 3.94 (s, C H), 4.11 (k, 9-71 Hz, 2 H), 4.27 - 4.33 (m, 1 H), 4.35 - 4.43 (m, 1 H), 6.56 (d, 9-8.5 Hz, 2 N), 6.66 - 6.67 (m, 1 N), 6.83 (d, 9U-9.1 Gu, 1 N), 7, 23 (d, 9-8.5 Gu, 2 N), 7.52 (dd, U-9.1, 0.8 Hz, 1 N). (2)3-I(4-1(3-cyano-5-methoxy-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(4-((3-cyano-5-methoxy-1-benzofuran-2-yl)cyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (253 MG), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (218 mg, 9195) as a pale yellow solid. NMR (300 MHz, SOSIz") 6 m.h. 1.04 - 1.36 (m, 5 N), 1.53 - 1.63 (m, 1 N), 1.63 - 1.84 (m, C

H), 1.85 - 2.00 (m, 2 H), 2.61 - 2.73 (m, 2 H), 3.05 (s, Z H), 3.71 (t, U-6 .6 Hz, 2 N), 3.94 (s, C H), 4.40 (d, 9U-6.4 Hz, 1 N), 6.57 (d, 9U-8.7 Hz, 2 N ), 6.67 (d, 9U-0.8 Gu, 1 N), 6.84 (d, 2-91 Hz, 1 N), 7.26 (d, 928.7 Hz, 2 N), 7 .55 (dd, U-9.1, 0.8 Hz, 1 N).

Example A110 3-C4-((5-(acetylamino)-3-methyl-1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid o then o M sn.

Mon at midnight

In m neo (1)cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methanone

The carbonate potassium (7.63 g) and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with isopropyl ether to give the title compound (4.18 g, 53905) as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.19 - 1.54 (m, 5 N), 1.70 - 1.81 (m, 1 N), 1.82 - 1.92 (m, 2

H), 1.92 - 2.02 (m, 2 H), 2.65 (s, C H), 3.24 - 3.36 (m, 1 H), 7.62 (d, 9-9 .2 Hz, 1 H), 8.37 (dd, y-9.2, 2.4 Hz, 1 H), 8.59 (d, y-2.4 Gu, 1 H). (2) methyl 4-cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methyl|amino)benzoate

To the mixture /cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-ylumethanone (3.00 g), synthesized above, methyl 4-aminobenzoate (1.57 g), triethylamine (11.6 ml) and methylene chloride ( 40 ml) was added titanium chloride (IM) (1.37 ml) and the mixture was stirred overnight under an argon atmosphere at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulfate magnesium and concentrated under reduced pressure to give a dark brown oil.To a solution (40 mL) of the obtained oil in tetrahydrofuran was added acetic acid (2.98 mL) and sodium cyanoborohydride (1.31 g) and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium hydrogencarbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (2590 ethyl acetate/hexane) to give the title compound (2.66 g, 6195) as an orange solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.96 - 1.38 (m, 5 N), 1.45 - 1.59 (m, 1 N), 1.62 - 2.01 (m, 4

H), 2.05 - 2.15 (m, 1 H), 2.32 (s, C H), 3.81 (s, C H), 4.41 - 4.56 (m, 2 H) , 6.55 (d, 9-91 Hz, 2 N), 7.43 (d, 9-8.9 Hz, 1 N), 7.80 (d, 9-91 Hz, 2 N), 8, 16 (dd, U-8.9, 2.4 Hz, 1 N), 8.36 (d, 9-24 Gu, 1 N). (3)4-Cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methylamino)benzoic acid

To a mixture of methyl 4-ylcyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methyliamino)benzoate (2.66 g) synthesized above, tetrahydrofuran (20 ml) and ethanol (20 ml) was added 1M aqueous sodium hydroxide solution (20.0 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (40 ml) and 1 M hydrochloric acid (20.0 ml) was added at 0 "C. The resulting precipitate was collected by filtration and the resulting solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure The residue was washed with isopropyl ether to give the title compound (2.22 g, 86905) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 0.96 - 1.40 (m, 5 N), 1.45 - 1.58 (m, 1 N), 1.63 - 2.02 (m, 4

H), 2.04 - 2.16 (m, 1 H), 2.33 (s, C H), 4.48 (d, 9-8.0 Hz, 1 H), 6.57 (d, 959.1 Hz, 2 N), 7.43 (d,

U8.9 Hz, 1 N), 7.86 (d, 9-91 Hz, 2 N), 8.17 (dd, U-8.9, 2.4 Hz, 1 N), 8.37 (d , U-2.4 Hz, 1 N). (4) ethyl 3-((4-1-cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

To the mixture of 4-(cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)umethyl|Iaminophenzoic acid (1.54 g) synthesized above, ethyl 3-(methylamino)propanosate (593 mg), monohydrate 1-Hydroxybenzotriazole (692 mg), triethylamine (1.26 mL) and N,M-dimethylformamide (15 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (867 mg) and the mixture was stirred overnight at room temperature. temperature. To quench the reaction, 1M hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50906 ethyl acetate/hexane) to give the indicated in title compound (1.41 g, 72905) as a yellow solid. "H NMR (300 MHz, SOCI") 6 ppm 0.96 - 1.40 (m, 8 H), 1.44 - 1.56 (m, 1 H), 1.58 - 2.00 (m, Z

H), 2.06 - 2.17 (m, 1 H), 2.31 (s, C H), 2.61 (t, 9U-7.0 Hz, 2 H), 3.01 (s, With H), 3.70 (t, U9-7.0 Hz, 2

H), 4.06 - 4.16 (m, 2 H), 4.28 - 4.34 (m, 1 H), 4.42 (t, 2-8.0 Hz, 1 H), 6, 55 (d, 2-8.7 Hz, 2 N), 7.22 (d, 9-8.7 Hz, 2 N), 7.43 (d, 9U-9.1 Hz, 1 N), 8 .16 (dd, 9-91, 2.5 Hz, 1 N), 8.35 - 8.37 (m, 1

N). (5) ethyl 3-((4-((5-amino-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanesate

To a solution (20 ml) of ethyl 3-1(4-cyclohexyl(3-methyl-5-nitro-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)amino)propanoate (600 mg), synthesized above , platinum oxide (IM) (60.0 mg) in ethanol was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 h. The platinum oxide was filtered off and the filtrate was concentrated to give the title compound (579 mg, quantitative) as a white solid substance

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.35 (m, 8 N), 1.49 - 1.60 (m, 1 N), 1.60 - 1.95 (m, 4

H), 2.01 - 2.12 (m, 1 H), 2.17 (s, C H), 2.61 (t, U-7.1 Hz, 2 H), 3.01 (s, With H), 3.56 (shs, 2 H), 3.70 (t,9U-7.1 Hz, 2 H), 4.11 (k, 9О-7.1 Gu, 2 H), 4, 30 - 4.34 (m, 2 N), 6.55 (d, 9U-8.7 Hz, 2 N), 6.59 (dd, u-8.5, 2.5 Hz, 1 N), 6.69 (d, 9U-2.5 Hz, 1 N), 7.14 (d, 9U-8.5 Hz, 1 N), 7.20 (d, 9-8.7 Hz, 2 N) . (6) ethyl 3-SHA-(5-(acetylamino)-3-methyl-1-benzofuran-2-yl)" cyclohexyl)methyl)amino)phenylcarbonylKmethyl)amino|propanesate

To a solution (10 ml) of ethyl 3-(Х4А-1(5-amino-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (480 MG), synthesized above, triethylamine (204 μl) and acetic anhydride (138 μl) were added in tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 days. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (9090 ethyl acetate/hexane) to give the title compound (366 mg, 7095) as a pale brown oil "H NMR (300 MHz, SOCI") 6 ppm 0.92 - 1 .38 (m, 8 N), 1.45 - 1.57 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.01 - 2.13 (m, 1 H), 2.17 (s, C H), 2.22 (s, C H), 2.61 (t, 9-7.1 Hz, 2 H), 3.01 (s, C H), 3.71 (t, 9U-7.1 Gu, 2 NN), 4.06 - 4.17 (m, 2 H), 4.31 - 4 .41 (m, 2 N), 6.55 (d, 9U-8.5 Hz, 2 N), 7.09 (dd, uU-8.8, 2.1 Hz, 1 N), 7.20 (d, 2-8.5 Hz, 2 N), 7.26 (d, 2-8.8 Hz, 1 N), 7.39 - 7.50 (m, 1 N), 7.71 (d , 9-21 Hz, 1 N). (7)3-SHA-Ch(5-(acetylamino)-3-methyl-1-benzofuran-2-yl)"ucyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

To the mixture of ethyl 3-KSH4-(5-(acetylamino)-3-methyl-1-benzofuran-2-yl)/ucyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|Ipropanate (366 MG), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added a 1M aqueous solution of lithium hydroxide (1.00 ml) and the mixture was stirred at room temperature for 1 h. Another 1M aqueous solution of lithium hydroxide (1.00 ml) was added, the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1M hydrochloric acid (2.00 ml) was added at 0"C.

The resulting precipitate was collected by filtration to afford the title compound (292 mg, 84905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.37 (m, 5 N), 1.45 - 1.57 (m, 1 N), 1.60 - 1.99 (m, 4

H), 2.04 - 2.25 (m, 7 H), 2.44 - 2.68 (m, 2 H), 2.99 (s, C H), 3.45 - 3.7Z (m , 2 H), 4.35 (d, 9-7.9

Hu, 1 H), 6.54 (d, 9-8.7 Hz, 2 H), 7.03 - 7.11 (m, 1 H), 7.12 - 7.28 (m, C H) , 7.57 - 7.68 (m, 2 N).

Example A111 3-I44-Kcyclohexyl(3-methyl-5-(methylsulfonyl)amino!|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid o then o M sn.

Mon at midnight o-5-M neo

To a solution (10 ml) of ethyl 3-(Х4А-1(5-amino-3-methyl-1-benzofuran-2-yl)/cyclohexyl)methylaminophenyl)carbonyl|(methyl)amino)propanoate (412 MG), synthesized in Example A110(5), triethylamine (160 μl) and methanesulfonyl chloride (89.0 μl) were added to M,M-dimethylacetamide and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (6095 ethyl acetate/hexane) to give a yellow oil. A 4M aqueous solution of lithium hydroxide (500 μl) was added to a mixture of the obtained oil, tetrahydrofuran (5 ml), ethanol (5 ml) and water (1 ml), and the mixture was stirred at room temperature for 4 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (379 mg, 91905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.92 - 1.39 (m, 5 N), 1.45 - 1.57 (m, 1 N), 1.62 - 1.98 (m, 4

H), 2.06 - 2.15 (m, 1 H), 2.22 (s, C H), 2.64 (t, U-6.2 Hz, 2 H), 2.93 (s, With H), 3.03 (s, With H), 3.68 (t, 9-6.2 Hz, 2 H), 4.37 (d, 9-8.0 Hz, 1 H), 6, 55 (d, 2-8.7 Hz, 2 N), 6.65 -6.71 (m, 1 N), 7.06 (dd, uU-8.6, 2.2 Hz, 1 N), 7.23 (d, 9U-8.7 Hz, 2 N), 7.31 (d, U-8.6 Hz, 1 N), 7.34 (d, 9-2.2 Gu, 1 N) .

Example A112:

But M

In N

-х CH, (1)cyclohexyl(3-methylfuroyl3,2-p|pyridin-2-yl)umethanone

To a mixture of 1-(3-hydroxypyridin-2-yl)ethanone (4.37 g), 2-bromo-1-cyclohexylethanone (9.82 g) synthesized in Example A51(1) and M,M-dimethylformamide (50 ml) potassium carbonate (13.2 g) was added and the mixture was stirred at room temperature for 2.5 days. 1M hydrochloric acid was added to quench the reaction and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (2090 ethyl acetate/hexane) to give the title compound (4.09 g, 5390) as a brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.19 - 1.59 (m, 5 H), 1.70 - 1.92 (m, Z H), 1.92 - 2.03 (m, 2

H), 2.69 (s, C H), 3.26 - 3.39 (m, 1 H), 7.39 (dd, 9U-8.3, 4.6 Hz, 1 H), 7, 82 (dd, 9U-8.3, 1.4 Hz, 1

H), 8.65 (dd, y-4.6, 1.4 Hz, 1 H). (2) methyl 4-1-cyclohexyl(3-methylfuroyl|3,2-ylpyridin-2-yl)methyl-1-amino)benzoate

To the mixture of cyclohexyl(3-methylfuroyl3,2-B|pyridin-2-yl)methanone (1.08 g) synthesized above, methyl 4-aminobenzoate (738 mg), triethylamine (4.95 ml) and methylene chloride (20 ml) ) was added titanium chloride (TM) (584 μl) and the mixture was stirred under an argon atmosphere overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (1.27 ml) and sodium cyanoborohydride (558 mg) were added to a solution (20 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the tetrahydrofuran was evaporated on the evaporator and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5095 ethyl acetate/hexane) to give the title compound (789 mg, 47905) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.99 - 1.38 (m, 5 N), 1.42 - 1.53 (m, 1 N), 1.64 - 2.01 (m, 4

H), 2.06 - 2.16 (m, 1 H), 2.77 (s, C H), 3.81 (s, C H), 4.50 - 4.63 (m, 2 H) , 6.54 (d, 2-9.1 Hz, 2 H), 7.37 (dd, U-8.2, 5.8 Hz, 1 H), 7.81 (d, 2-91 Hz, 2 H), 7.98 (dd, 9U-8.2, 1.1 Hz, 1 H), 8.49 (dd,

95.8, 1.1 Hz, 1 N). (3)4-Ycyclohexyl(3-methylfuro|3,2-in|Ipyridin-2-ylmethyl|Iaminophenzoic acid

A 1 M aqueous solution of sodium hydroxide (10, 0 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 ml) and 1M hydrochloric acid (10.0 ml) was added at 0"C.

The resulting precipitate was collected by filtration to afford the title compound (718 mg, 94905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.96 - 1.39 (m, 5 N), 1.47 - 1.60 (m, 1 N), 1.62 - 2.02 (m, 4

H), 2.03 - 2.17 (m, 1 H), 2.38 (s, C H), 4.47 - 4.72 (m, 2 H), 6.58 (d, 9U-8 .9 Hz, 2 N), 7.18 (dd, uU-8.3, 4.9 Hz, 1 N), 7.65 (dd, 9U-8.3, 1.2 Gu, 1 N), 7.86 (d, U-8.9 Hz, 2 H), 8.51 (dd, 9-49, 1.2

HC, 1 H). (4) ethyl 3-((4-cyclohexyl(3-methylfuroyl3,2-yl)pyridin-2-yl)methylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-cyclohexyl(3-methylfuroyl3,2-B|Ipyridin-2-yl)umethylamino)benzoic acid (330 mg), synthesized above, p-alanine ethyl ester hydrochloride (209 mg), 1-hydroxybenzotriazole monohydrate (208 mg ), triethylamine (379 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (261 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (7095 ethyl acetate/hexane) to give the title compound (383 mg, 91965) as a pale brown oil

IN NMR (300 MHz, SOSIZ") b m.h. 0.96 - 1.38 (m, 8 N), 1.47 - 1.58 (m, 1 N), 1.61 - 2.00 (m, 4

H), 2.05 - 2.16 (m, 1 H), 2.35 (s, C H), 2.58 (t, U-5.8 Hz, 2 H), 3.61 - 3, 69 (m, 2 H), 4.13 (k, 2-7.1

Hz, 2 H), 4.42 -4.52 (m, 2 H), 6.53 - 6.65 (m, Z H), 7.13 (dd, 9U-8.2, 4.7 Hz , 1 N), 7.54 (d, 9-8.8

Hz, 2 N), 7.58 - 7.62 (m, 1 N), 8.45 - 8.49 (m, 1 N). (5)3-I((4-Icyclohexyl(3-methylfuro!3,2-p|pyridin-2-yl)methylIamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-((4-Ycyclohexyl(3-methylfuroyl3,2-B|Ipyridin-2-yl)umethylamino)phenyl)carbonyl|Iamino)propanoate (383 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (315 mg, 88905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.97 - 1.38 (m, 5 N), 1.44 - 1.57 (m, 1 N), 1.61 - 2.00 (m, 4

H), 2.05 - 2.18 (m, 1 H), 2.35 (s, C H), 2.64 (t, 9U-5.7 Hz, 2 H), 3.56 - 3, 78 (m, 2 H), 4.46 (d, 2-8.0

Hz, 1 N), 6.55 (d, 9U-8.7 Hz, 2 N), 6.72 (t, 9-61 Hz, 1 N), 7.18 (dd, 9U-8.3, 4.9 Hz, 1 N), 7.54 (d, uU-8.7 Hz, 2 N), 7.66 (dd, 9U-8.3, 1.3 Gu, 1 N), 8.49 (dd, 9-4.9, 1.3 Hz, 1 N).

Example A113 3-11(4-N-Cyclohexyl(3-methylfuroyl3,2-B|pyridin-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid,

In n -k sn,

(1) ethyl 3-((4-Ycyclohexyl(3-methylfuroyl3,2-B|pyridin-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

To the mixture of 4-cyclohexyl(3-methylfuroyl3,2-B|Ipyridin-2-yl)umethylamino)benzoic acid (330 mg), synthesized in Example A112(3), ethyl 3-(methylamino)propanosate (178 mg), monohydrate 1-Hydroxybenzotriazole (208 mg), triethylamine (379 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (261 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (8095 ethyl acetate/hexane) to give the title compound (292 mg, 67906) as a pale brown oil

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.97 - 1.38 (m, 8 N), 1.47 - 1.58 (m, 1 N), 1.61 - 2.00 (m, 4

H), 2.05 - 2.16 (m, 1 H), 2.35 (s, With H), 2.60 (t, 9U-6.9 Hz, 2 H), 3.00 (s, With H), 3.69 (t, U-6.9 Hz, 2

H), 4.10 (k, U-7.0 Gu, 2 H), 4.35 (d, 9U-8.3 Hz, 1 H), 4.45 (t, U-8.3 Hz, 1 H), 6.56 (d, 9-8.5 Hz, 2

H), 7.13 (dd, 9U-8.2, 4.9 Hz, 1 H), 7.20 (d, U-8.5 Hz, 2 H), 7.60 (dd, 9U-8 ,2, 1.4 Hz, 1 N), 8.47 (dd, y-4.9, 1.4 Hz, 1 N). (2)3--(4-Ycyclohexyl(3-methylfuro!3,2-p|pyridin-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-Ycyclohexyl(3-methylfuroyl3,2-B|Ipyridin-2-yl)umethylamino)phenyl)carbonylI(methyl)aminoisopropanoate (292 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and the mixture was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (278 mg, quantitative) as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.39 (m, 5 N), 1.47 - 1.58 (m, 1 N), 1.61 - 2.00 (m, 4

H), 2.06 - 2.16 (m, 1 H), 2.34 (s, C H), 2.60 - 2.73 (m, 2 H), 3.03 (s, C H) , 3.70 (t, 9-6.8 Hz, 2 N), 4.45 (d, 9-8.0 Hz, 1 N), 6.56 (d, 9U-8.5 Hz, 2 N ), 7.17 (dd, U-8.2, 4.8 Hz, 1 H), 7.23 (d, 9-8.5 Gu, 2 H), 7.65 (dd, 9-82, 1.3 Hz, 1 N), 8.50 (dd, 9U-4.8, 1.3 Hz, 1 N).

Example A114 3-4(4-((5-methoxy-3-methyl-1-benzofuran-2-ylphenyl)methylamino)phenyl)carbonyl(methyl)amino)propanoic acid 3

T g Y wine a. Highness St

IN

Ul Sn no (1X5-methoxy-3-methyl-1-benzofuran-2-yl)(phenyl)methanone

To the mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized in Example

Aluminum chloride (3.28 g) was added to A104(2), benzoyl chloride (1.68 ml) and nitromethane (20 ml) and the mixture was stirred at room temperature for 2 h. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3095 ethyl acetate/hexane) and further silica gel column chromatography (2090 ethyl acetate/hexane) to give the title compound (2.03 g, 6290) as a yellow oil. "H NMR (300 MHz, SOSI") b m.p. 2.62 (s, C H), 3.89 (s, C H), 7.05 (d, 9-2.5 Hz, 1 H ), 7.10 (dd, U-9.1, 2.5 HZ, 1 H), 7.42 (d, 9U-9.1 Hu, 1 H), 7.47 - 7.63 (m, With H), 8.04 - 8.09 (m, 2 H).

(2) methyl 4-(5-methoxy-3-methyl-1-benzofuran-2-yl)u(phenyl)methyl|aminophenzoate

To the mixture of (5-methoxy-3-methyl-1-benzofuran-2-ylluphenyl)methanone (2.03 g) synthesized above, methyl 4-aminobenzoate (1.27 g) triethylamine (8.50 ml) and methylene chloride ( 30 mL) was added titanium chloride (IM) (1.00 mL) and the mixture was stirred under argon overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, methylene chloride was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (2.18 ml) and sodium cyanoborohydride (955 mg) were added to a solution (30 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 2.5 g. To quench the reaction, a saturated aqueous solution of sodium hydrogen carbonate, an organic solvent was added evaporated and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (3095 ethyl acetate/hexane) to give the title compound (2.36 g, 77905) as a brown solid. "H NMR (300 MHz, SOS") 6 m.h. 2.26 (s, C H), 3.82 (s, C H), 3.84 (s, C H), 4.98 (d , U-6.0 Hz, 1 N), 5.82 (d, 9U-6.0 Hz, 1 N), 6.60 (d, 9U-8.7 Hz, 2 N), 6.84 ( dd, 9-88, 2.6 Hz, 1 N), 6.90 (d, 92.6 Hz, 1 N), 7.23 - 7.37 (m, 4 N), 7.39 - 7, 44 (m, 2 H), 7.82 (d, 98.7 Hz, 2 H). (3)4--(5-Methoxy-3-methyl-1-benzofuran-2-yl)(phenyl)methyl-amino )rbenzoic acid

To a mixture of methyl 4-((5-methoxy-3-methyl-1-benzofuran-2-ylphenyl)methylamino)benzoate (2.36 g) synthesized above, tetrahydrofuran (20 ml) and ethanol (20 ml) was added 1M aqueous sodium hydroxide solution (20.0 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (40 mL), and 1 M hydrochloric acid (20.0 mL) was added at 0°C. The resulting precipitate was collected by filtration and the resulting solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.09 g, 4895) as a pale red solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.27 (s, Z H), 3.84 (s, Z H), 5.00 - 5.11 (m, 1 H), 5.84 (shs, 1 H), 6.61 (d, 9-8.8 Hz, 2 N), 6.81 - 6.88 (m, 1 N), 6.91 (d, 9-2.7 Hz, 1 N), 7.24 -7.38( m, 4 N), 7.39 - 7.45 (m, 2 N), 7.88 (d, 9-8.8 Hz, 2 N). (4) ethyl 3-((4-1(5-methoxy-3-methyl-1-benzofuran-2-ylphenyl)methylamino)phenyl)carbonyl(methyl)amino)propanate

To the mixture of /4-((5-methoxy-3-methyl-1-benzofuran-2-yl)N(phenyl)methylIaminobdbenzoic acid (400 mg), synthesized above, ethyl 3-(methylamino)propanosate (203 mg), monohydrate 1-Hydroxybenzotriazole (237 mg), triethylamine (431 μl) and M,N-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (297 mg) and the mixture was stirred overnight at room temperature . Water was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give the title the target compound (486 mg, 9495) as a pale brown oil "H NMR (300 MHz, SOSI") b m.p. 1.24 (t, 9U-7.1 Hz, Z H), 2.26 ( s, With H), 2.56 - 2.67 (m, 2 H), 3.02 (s, With H), 3.71 (t, 927.1 Hz, 2 H), 3.84 (s , Z H), 4.12 (k, 957.1 Hz, 2 H), 4.76 (d, 9-6.0 Hz, 1

H), 5.77 (d, U-6.0 Hz, 1 H), 6.60 (d, 9U-8.5 Hz, 2 H), 6.84 (dd, 9U-8.9, 2 .6 Hz, 1 N), 6.90 (d, 9-26

Hz, 1 N), 7.20 - 7.37 (m, 6 N), 7.39 - 7.45 (m, 2 N). (5)3-(I4-1(5-methoxy-3-methyl-1-benzofuran-2-ylphenyl)methylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-((5-methoxy-3-methyl-1-benzofuran-2-ylphenyl)methylamino)phenyl)carbonyl(methyl)amino)upropanoate (486 mg), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (412 mg, 90905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 2.26 (s, C H), 2.68 (t, 9U-6.4 Hz, 2 H), 3.05 (s, C H), 3.72 (t, uU-6.4 Hz, 2 H), 3.84 (s, C H), 5.78 (s, 1 H), 6.60 (d, 2-8.7 Hz, 2 H), 6.84 (dd, 9U-8 ,9.2.5 Hz, 1 N), 6.91 (d, 92.5 Hz, 1 N), 7.23 - 7.39 (m, 6 N), 7.39 - 7.47 (m , 2 H).

Example A115 3-(144-K(cyclohexyl5-Ketylcarbomoyl)amino|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

IN o sn, m p not (1) ethyl 3-(ChA-Kcyclohexyl5-Ketylcarbomoyl)amino|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)(methyl)amino|propanoate

To a solution (10 ml) of ethyl 3-(Х4А-1(5-amino-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (280 MG), synthesized in Example A110(5), triethylamine (95 μl) and ethyl isocyanate (54 μl) were added in tetrahydrofuran and the mixture was stirred at room temperature for 1 day.

Triethylamine (95 μl) and ethyl isocyanate (54 μl) were added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (60 - 100905 ethyl acetate/hexane) to give the title compound (304 mg, 9590) as a colorless oil. "H NMR (300 MHz, SOSIZ") b mp 0.93 - 1.37 (m, 11 N), 1.44 - 1.57 (m, 1 N), 1.59 - 1.96 (m, 4

H), 2.04 - 2.15 (m, 1 H), 2.19 (s, C H), 2.56 - 2.66 (m, 2 H), 3.02 (s, C H) . - 4.45 (m, 2 N), 6.55 (d, 2-8.8 Hz, 2 N), 6.72 - 6.83 (m, 1 N), 7.15 - 7.23 ( m, Z H), 7.43 - 7.48 (m, 1 H). (2)3-(I44-Kcyclohexyl5-K(ethylcarbomoyl)amino|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

To the mixture of ethyl 3-((4-(cyclohexyl5-(ethylcarbomoyl)amino|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)x(methyl)amino|propanoate (304 mg), synthesized above , tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of lithium hydroxide (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (258 mg, 8995) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.93 - 1.39 (m, 8 N), 1.45 - 1.57 (m, 1 N), 1.61 - 1.98 (m, 4

H), 2.06 - 2.20 (m, 4 H), 2.47 - 2.65 (m, 2 H), 2.99 (s, C H), 3.12 - 3.25 (m , 2 H), 3.52 - 3.70 (m, 2

H), 4.34 (d, 2-8.1 Hz, 1 H), 4.94 - 5.06 (m, 1 H), 6.53 (d, 2-8.7 Hz, 2 H) , 6.88 (dd, 9-8.7, 2.0 Gu, 1 H), 7.14 - 7.24 (m, C H), 7.35 (d, 9U-2.0 Hz, 1 N).

Example A116 3-((4-(cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid du

M. M g i

CH, non-o (1)5-methoxy-M-methyl-2-nitroaniline

A mixture of formic acid (7.64 g) and acetic anhydride (16.9 g) was stirred at 607 for 2 g and then a solution (100 mL) of 5-methoxy-2-nitroaniline (9.30 g) in tetrahydrofuran was added dropwise. and the mixture was stirred overnight at room temperature.

The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate.

The solution was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, dried over sodium sulfate and concentrated under reduced pressure. To a solution (200 ml) of the residue in tetrahydrofuran was added a 1.0 M solution (140 ml) of the borane-tetrahydrofuran complex in tetrahydrofuran at 0 "С and the mixture was stirred under reflux for 2 h. Methanol was added to the reaction mixture at 0 "С. and the mixture was stirred at room temperature for 30 min. After mixing, 1M hydrochloric acid was added to bring it to pH-2. The reaction mixture was stirred under reflux for 1 g, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (6.30 g, 6295) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 3.01 (d, ) - 5.1 Hz, ЗН), 3.88 (s, ЗН), 6.12 (d, ) - 2.7 Hz, 1Н), 6.24 (dd, U - 9 ,6, 2.4 Gu, 1H), 8.14 (d, y - 9.6 Hz, 1H), 8.29 (w, 1H). (2) 6-methoxy-1-methyl-1H-benzoimidazole

To a solution (200 mL) of 5-methoxy-M-methyl-2-nitroaniline (6.30 g) synthesized above in methanol was added 1095 palladium/charcoal (1.00 g) and the mixture was stirred under a hydrogen atmosphere overnight at room temperature. temperature The palladium/charcoal was filtered off and the filtrate was concentrated. A solution (150 mL) of the residue in formic acid was stirred overnight under reflux and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (2590 ethyl acetate/petroleum ether) to give the title compound (4.07 g, 60905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 3.78 (s, ЗН), 3.87 (s, ЗН), 6.81 (d, у - 2.4 Hz, 1Н), 6.91 (dd, У - 8.7, 2.4 Hz , 1H), 7.66 (d, U - 9.0 Hz, 1H), 7.75 (s, 1H). (3) M-methoxy-M-methylcyclohexanecarboxamide

A mixture of cyclohexanecarboxylic acid (6.10 g), M.O-dimethylhydroxyamine hydrochloride (7.31 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (14.4 g), M,M-diisopropylethylamine (9 .68 g), 4-dimethylaminopyridine (600 mg) and methylene chloride (150 ml) were stirred overnight at room temperature. Water was added to quench the reaction and the reaction mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound (7.57 g, 88905).

IN NMR (300 MHz, SOSI") b m.h. 1.21-1.30 (m, ЗН), 1.42-1.50 (m, 2Н), 1.64-1.80 (m, 5Н), 2.65 (m, 1Н), 3, 14 (c, ZN), 3.66 (c, ZN). (4) cyclohexyl (b-methoxy-1-methyl-1 H-benzimidazol-2-yl)methanone

A 1.6 M solution (30.1 ml) of n-butyllithium in hexane was added to a solution (100 ml) of b-methoxy-1-methyl-1H-benzoimidazole (4.07 g) synthesized in the above mentioned (2) in tetrahydrofuran at -78 "C and the mixture was stirred in a nitrogen atmosphere for 30 min. A solution (50 ml) was added

M-methoxy-M-methylcyclohexanecarboxamide (5.15 g), synthesized in the above-mentioned (3), in tetrahydrofuran and the mixture was stirred at -78 C for 1 g and at room temperature for 2 g. A saturated aqueous solution of ammonium chloride was added to quench reactions and the reaction 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 column chromatography on silica gel (ethyl acetate/petroleum ether-1:5, v/v) to give the title compound (5.80 g, 8595) as white crystals.

IN NMR (300 MHz, SOSI") b m.h. 1.23-1.33 (m, 1H), 1.45-1.52 (m, 4H), 1.64-1.72 (m, 1H), 1.78-1.86 (m, 2H ), 1.96-2.01 (m, 2H), 3.82-3.90 (m, 1H), 3.91 (s, ЗН), 4.09 (s, ЗН), 6.77 ( d, U 2.4 Hz, 1H), 7.00 (dd, U - 9.0, 2.4 Hz, 1H), 7.76 (dd, U) - 9.0, 2.4 Hz, 1H ). (5) methyl 4-cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)methylamino)benzoate

To the mixture of cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)umethanone (1.00 g) synthesized above, methyl 4-aminobenzoate (611 mg), triethylamine (4.10 ml) and methylene chloride ( 20 ml) was added titanium chloride (IM) (482 μl) and the mixture was stirred under an argon atmosphere overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, methylene chloride was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown solid. Acetic acid (1.05 ml) and sodium cyanoborohydride (461 mg) were added to a solution (20 ml) of the obtained solid in tetrahydrofuran, and the mixture was stirred at room temperature for 1 h. To quench the reaction, a saturated aqueous solution of sodium hydrogen carbonate was added, the tetrahydrofuran was evaporated to evaporators and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 70905 ethyl acetate/hexane) to give the title compound (625 mg, 4295) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.34 (m, 5 N), 1.46 - 1.58 (m, 1 N), 1.59 - 1.84 (m, 4

H), 1.95 - 2.11 (m, 1 H), 3.77 (s, Z H), 3.82 (s, Z H), 3.86 (s, Z H), 4.59 (t, 928.0 Gu, 1 N), 5.04 (d, U-8.0 Hz, 1 N), 6.63 (d, 9-8.8 Hz, 2 N), 6.76 ( d, 2-2.4 Hz, 1 N), 6.88 (dd, 9U-8.7, 2.4 Hz, 1 N), 7.59 (d, U-8.7 Hz, 1 N) , 7.80 (d, U-8.8 Hz, 2 N). (6)4-cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)methyl|iamino)dibenzoic acid

To a mixture of methyl 4-Hycyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)methyliamino)benzoate (625 mg) synthesized above, tetrahydrofuran (10 ml) and ethanol (10 ml) was added a 1M aqueous solution of hydroxide sodium (5.00 mL), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (5.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to afford the title compound (600 mg, quantitative) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.01 - 1.36 (m, 5 N), 1.40 - 1.53 (m, 1 N), 1.56 - 1.86 (m, C

H), 1.98 - 2.19 (m, 2 H), 3.83 (s, C H), 3.87 (s, C H), 4.59 - 4.69 (m, 1 H) , 5.82 - 5.96 (m, 1 N), 6.68 (d, U-8.9 Hz, 2 N), 6.78 (d, 9U-2.3 Hz, 1 N), 6 .91 (dd, U-8.9, 2.3 Hz, 1 H), 7.64 (d, 9U-8.9 Gu, 1 H), 7.88 (d, 9U-8.9 Hz, 2 H). (7) ethyl 3-((4-(cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)umethylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)umethylamino)benzoic acid (270 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (158 mg), 1-hydroxybenzotriazole monohydrate (158 mg), triethylamine (287 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 - 10095 ethyl acetate/hexane) to give the title compound (151 mg, 45905) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.03 - 1.35 (m, 8 N), 1.45 - 1.55 (m, 1 N), 1.58 - 1.85 (m, Z

H), 1.94 - 2.11 (m, 2 H), 2.58 (t, 9U-6.1 Hz, 2 H), 3.66 (k, U-6.1 Hz, 2 H) , 3.76 (c, Z H), 3.86 (c, Z

H), 4.14 (k, 90-71 Hz, 2 H), 4.56 (t, 9U-7.8 Hz, 1 H), 4.90 (d, 2-7.8 Hz, 1 H ), 6.58 - 6.67 (m, Z H), 6.75 (d, 9U-2.5 Hz, 1 H), 6.88 (dd, U-8.8, 2.5 Hz, 1 N), 7.55 (d, 9U-8.8 Hz, 2 N), 7.58 (d, U-8.8 Hz, 1 N). (8)3-(I(4-Yacyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-((4-(cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)methyliamino)phenyl)carbonyl|Iamino)dupropanoate (151 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 2.5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (124 mg, 87905) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 0.96 - 1.30 (m, 5 N), 1.30 - 1.40 (m, 1 N), 1.60 - 1.70 (m, 2

H), 1.71 - 1.83 (m, 1 H), 1.90 - 2.05 (m, 1 H), 2.12 - 2.23 (m, 1 H), 2.71 (t , 95.4 Hz, 2 H), 3.72 - 3.84 (m, 2 H), 3.86 (s, Z H), 3.87 (s, Z H), 4.57 - 4, 66 (m, 1 H), 6.74 (d, 9-8.9 Hz, 2 H), 6.78 (d, 92.4 Hz, 1 H), 6.90 (dd, 9U-8, 9, 2.4 Gu, 1 H), 7.24 - 7.32 (m, 1 H), 7.52 (d, 9-8.9 Hz, 1 H), 7.66 (d, U- 8.9 Hz, 2 N).

Example A117 3-((4-(cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid 6) m СОН

M. M Sn,

WITH

Сн, не-о (1) ethyl 3-((4-(cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)umethylamino)phenyl)carbonyl|methyl)amino)upropanoate

To the mixture of 4-cyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)umethylamino)benzoic acid (270 mg), synthesized in Example A116(6), ethyl 3-(methylamino)propanoate (135 mg ), 1-hydroxybenzotriazole monohydrate (158 mg), triethylamine (287 μL), and M,M-dimethylformamide (10 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg) was added, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with 1M hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 - 10095 ethyl acetate/hexane) to give the title compound (103 mg, 30905) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.33 (m, 8 N), 1.45 - 1.55 (m, 1 N), 1.59 - 1.92 (m, Z

H), 1.92 - 2.13 (m, 2 H), 2.61 (t, 9U-7.0 Hu, 2 H), 3.01 (s, C H), 3.70 (t, 2-7.0 Hz, 2 H), 3.76 (s, Z

H), 3.86 (s, C H), 4.11 (k, 9-7.1 Hz, 2 H), 4.49 - 4.57 (m, 1 H), 4.75 (d, 9-8.2 Hz, 1 N), 6.63 (d, 98.5 Hz, 2 N), 6.76 (d, 9U-2.4 Hz, 1 N), 6.88 (dd, 9U -8.8, 2.4 Hz, 1 N), 7.22 (d, U-8.5 Hz, 2 N), 7.59 (d, U-8.8 Hz, 1 N). (2)3-(-(4-Yacyclohexyl(b-methoxy-1-methyl-1H-benzimidazol-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1M hydrogen chloride was added at 0 "С acid (1.00 mL). The resulting precipitate was collected by filtration to afford the title compound (72.1 mg, 74905) as a pale brown solid. "H NMR (300 MHz, SOCI3") 6 ppm 1 .00 - 1.30 (m, 5 N), 1.31 - 1.41 (m, 1 N), 1.57 - 1.81 (m, Z

H), 1.88 - 2.03 (m, 1 H), 2.07 - 2.19 (m, 1 H), 2.69 - 2.81 (m, 2 H), 3.10 (s , Z H), 3.73 - 3.82 (m, 2

H), 3.84 (s, C H), 3.85 (s, C H), 4.54 (d, 9U-8.1 Gu, 1 H), 6.59 (d, 2-8, 5 Hz, 2 N), 6.77 (d, 9-24

Gu, 1 H), 6.88 (dd, 9U-8.9, 2.4 Hz, 1 H), 7.20 - 7.28 (m, 2 H), 7.54 (d, 98.9 Hz, 1 N).

Example A118 3-4(4-(1-(5-methoxy-3-methyl-1-benzofuran-2-yl)ugeptylamino)phenyl)carbonylamino)propanoic acid

N o M n sn. non-o (1)1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptan-1-one

To the mixture of 5-methoxy-3-methyl-1-benzofuran (1.87 g) synthesized in Example

Aluminum chloride (3.07 g) was added to A104(2), heptanoyl chloride (2.14 mL) and nitromethane (20 mL) and the mixture was stirred overnight at room temperature. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (790 ethyl acetate/hexane) to give the title compound (2.34 g, 74905) as a pale yellow solid. "H NMR (300 MHz, SOSIz") 6 m.h. 0.84 - 0.95 (m, C H), 1.24 - 1.48 (m, 6 H), 1.67 - 1.82 (m, 2

H), 2.57 (s, C H), 2.96 (t, 97.4 Hz, 2 H), 3.87 (s, C H), 7.00 (d, 9-2.6 Hz , 1 H), 7.07 (dd, 959.1, 2.6 Hu, 1 H), 7.38 (d, 20-9.1 Hu, 1 H). (2) methyl 4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptyl|amino)benzoate

To the mixture of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptan-1-one (1.18 g) synthesized above, methyl 4-aminobenzoate (715 mg), triethylamine (4.79 ml) and methylene chloride (20 ml) was added titanium chloride (IM) (566 μl) and the mixture was stirred under an argon atmosphere overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, methylene chloride was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (1.23 ml) and sodium cyanoborohydride (540 mg) were added to a solution (20 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. . The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 2095 ethyl acetate/hexane) to afford the title compound (1.17 g, 6695) as a pale brown oil

IN NMR (300 MHz, SOSI") 6 m.h. 0.82 - 0.88 (m, Z H), 1.18 - 1.40 (m, 8 H), 1.88 - 2.03 (m, 2

H), 2.24 (s, C H), 3.81 (s, C H), 3.83 (s, C H), 4.51 (d, 957.7 Hz, 1 H), 4, 58 - 4.68 (m, 1 N), 6.56 (d, U-8.8 Hz, 2 N), 6.82 (dd, U-8.8, 2.5 Hz, 1 N), 6.87 (d, 9-2.5 Hz, 1 N), 7.25 (d, 9-88 Hz, 1 N), 7.80 (d, U-8.8 Hz, 2 N). (3)4-11-(5-Methoxy-3-methyl-1-benzofuran-2-yl)heptyl|amino)benzoic acid

To the mixture of methyl 4-1C1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptylaminobenzoate

(1.17 g) synthesized above, tetrahydrofuran (20 ml) and ethanol (20 ml) was added with a 1 M aqueous solution of sodium hydroxide (20.0 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 ml), and 1M hydrochloric acid (20.0 ml) was added at 0"C.

The resulting precipitate was collected by filtration to afford the title compound (1.02 g, 9095) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.80 - 0.92 (m, Z H), 1.16 - 1.44 (m, 8 H), 1.90 - 2.03 (m, 2

H), 2.25 (s, C H), 3.84 (s, C H), 4.65 (t, 957.3 Hz, 1 H), 6.58 (d, 9U-8.8 Hz , 2 H), 6.84 (dd, 9-8.9, 2.5 Hz, 1 H), 6.89 (d, 2-2.5 Hz, 1 H), 7.26 (d, 2 -8.9 Hz, 1 N), 7.87 (d, U-8.8 Hz, 2 N). (4) ethyl 3-((4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)uheptylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-Sh1-(5-methoxy-3-methyl-1-benzofuran-2-yl)uheptylaminophenzoic acid (300 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (175 mgG), 1-hydroxybenzotriazole monohydrate (175 mg), triethylamine (318 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (219 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 10095 ethyl acetate/hexane) to give the title compound (320 mg, 8595) as a colorless oil.

IN NMR (300 MHz, SOS") b m.h. 0.81 - 0.90 (m, Z H), 1.17 - 1.44 (m, 11 H), 1.89 - 2.00 (m, 2

H), 2.24 (s, C H), 2.58 (t, 9U-6.0 Hz, 2 H), 3.66 (k, 9U-6.0 Gu, 2 H), 3.83 (c, Z H), 4.14 (k, 9571 Hz, 2 H), 4.37 - 4.44 (m, 1 H), 4.55 - 4.66 (m, 1 H), 6, 53 - 6.64 (m, Z H), 6.82 (dd, 9U-8.8, 2.4 Hz, 1 H), 6.87 (d, 9-2.4 Hz, 1 H), 7.24 (d, 2-8.8 Hz, 1 N), 7.55 (d, U-8.8 Hz, 2 N). (5)3-(I(4-11-(5-Methoxy-3-methyl-1-benzofuran-2-yl)ugeptylamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-1((4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)uheptylamino)phenyl)carbonylaminoisopropanoate (320 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 3 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (213 mg, 7195) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 0.85 (t, 9U-6.8 Hz, Z H), 1.16 - 1.43 (m, 8 H), 1.85 - 2.03 (m, 2 H), 2.23 (s , with H), 2.63 (t, 95.8 Hz, 2 H), 3.59 - 3.69 (m, 2 H), 3.83 (s, with H), 4.60 (t, 957.3 Hz, 1 H), 6.56 (d, 9-8.9 Hz, 2 H), 6.64 (t, 9-6.1 Hz, 1 H), 6.82 (dd, . -8.9, 2.5 Hz, 1 N), 6.88 (d, 92.5 Hz, 1 N), 7.23 - 7.27 (m, 1 N), 7.53 (d, 9U -8.9 Hz, 2 N).

Example A119 3-4(4-(1-(5-methoxy-3-methyl-1-benzofuran-2-yl)ugeptylamino)phenyl)carbonyl|)methyl)amino)propanoic acid sn, o m-n o M sn ,

And n

SN, no-oh

(1) ethyl 3-((4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)ugeptylamino)phenyl)carbonyl)/methyl)amino)propanoate

To the mixture of 4-Sh1-(5-methoxy-3-methyl-1-benzofuran-2-yl)heptylaminophenzoic acid (300 mg), synthesized in Example A118(3), ethyl C3-(methylamino)upropanoate (150 mg), 1-hydroxybenzotriazole monohydrate (175 mg), triethylamine (318 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (219 mg) and the mixture was stirred overnight at room temperature . A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70956 ethyl acetate/hexane) to give the title compound (289 mg, 75905) as a colorless oil. "H NMR (300 MHz, SOSI") b m.ch. 0.86 (t, U-6.9 Hz, Z H), 1.17 - 1.45 (m, 11 H), 1.88 - 2.01 (m, 2 H), 2.24 (s, Z H), 2.61 (t, 97.0 Hz, 2 H), 3.01 (s, Z H), 3.70 (t , 957.0 Hz, 2 N), 3.84 (s, Z

H)U, 4.11 (k, 957.1 Hz, 2 N), 4.23 - 4.37 (m, 1 N), 4.54 - 4.63 (m, 1 N), 6.56 (d, 9-88 Hz, 2 H), 6.82 (dd, 9U-8.8, 2.4 Hz, 1 H), 6.88 (d, 9-2.4 Hz, 1 H), 7.22 (d, 9-8.8 Hz, 2 N), 7.25 (d, U-8.8 Hz, 1 N). (2)3-(IC4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)ugeptylamino)phenyl)carbonyl)|)methyl)amino)propanoic acid

To the mixture of ethyl 3-1((4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)ugeptylamino)phenyl)carbonyl|/methyl)aminoisopropanoate (289 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (153 mg, 56905) as a pale yellow solid. NMR (300 MHz, SOSI") b m.ch. 0.85 (t, U-6.6 Hz, Z H), 1.16 - 1.44 (m, 8 H), 1.86 - 2.02 (m, 2 H), 2.24 (s , Z H), 2.64 (t, 9-66 Hz, 2 H), 3.02 (s, Z H), 3.69 (t, 9U-6.6 Gu, 2 H), 3.84 (c, Z H), 4.59 (t, 9U-7.3 Hu, 1 H), 6.56 (d, 9U-8.7 Hu, 2 H), 6.83 (dd, U-8 .8, 2.5 Hz, 1 N), 6.89 (d, 9-2.5 Gu, 1 N), 7.20 - 7.29 (m, C H).

Example A120 3-4(4-(1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|Iamino)phenyl)carbonyl|iamino)propanoic acid 57 UN» o very

N o M / n sn, ne-o (1)B5-chloro-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one

Aluminum chloride (2, 47 g) at 0 "С, and the mixture was stirred for 2 h. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (590 ethyl acetate /hexane) to give the title compound (2.63 g, 76905) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.83 - 1.97 (m, 4 H), 2.58 (s, C H), 2.98 - 3.05 (m, 2 H),

3.56 - 3.63 (m, 2 H), 3.87 (s, C H), 7.00 (d, 952.7 Hz, 1 H), 7.08 (dd, 99.0, 2 .7 Hz, 1 N), 7.38 (d, y-9.0 Hz, 1 N). (2)1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentan-1-one

To a mixture of /5-chloro-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)upentan-1-one (1.30 g), synthesized above, in (15 ml) and tetrahydrofuran (15 ml) 1595 aqueous solution (4.33 ml) of sodium methanethiolate was added, the mixture was stirred at room temperature for 1 h and at 50 "C for 1 h. Sodium methanethiolate (325 mg) was also added and the mixture was stirred at 50 "C for 1 h. Sodium methanethiolate (325 mg) was added again and the mixture was stirred at 50 C for 1 h. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (492 mg, 3690) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.64 - 1.79 (m, 2 H), 1.79 - 1.92 (m, 2 H), 2.11 (s, Z H), 2.51 - 2.62 (m, 5 H ), 3.00 (t, U-7.3 Hz, 2 N), 3.87 (s, C H), 7.00 (d, 9-2.5 Hz, 1 N), 7.08 ( dd, uU-9.1, 2.5 Hz, 1 N), 7.38 (d, 9U-9.1 Gu, 1 N). (3) methyl 4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|Iaminobenzoate

To the mixture of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentan-1-one (658 mg), synthesized above, methyl 4-aminobenzoate (375 mg), triethylamine (2.50 ml) and methylene chloride (10 ml) was added to a 1.0 M solution (2.70 ml) of titanium chloride (IM) in methylene chloride at 0"C and the mixture was stirred in an argon atmosphere at room temperature for 3.5 days. after quenching the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added, methylene chloride was evaporated on the evaporator and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. To a solution (10 ml) of the obtained oil in tetrahydrofuran, acetic acid was added acid (647 μl) and sodium cyanoborohydride (283 mg) and the mixture was stirred at room temperature for 1 h. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over sulfate of magnesium and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5095 ethyl acetate/hexane) to give the title compound (645 mg, 6790) as a brown oil.

IN NMR (300 MHz, SOSI") b m.h. 1.30 - 1.71 (m, 4 H), 1.91 - 2.08 (m, 5 H), 2.25 (s, Z H), 2.46 (t, 9U-7.3 Hz , 2 H), 3.81 (s, C H), 3.83 (s, C H), 4.52 (d, 9U-8.0 Hz, 1 H), 4.59 - 4.70 ( m, 1 N), 6.57 (d, U-8.8 Hz, 2 N), 6.83 (dd, U-8.7, 2.5 Hz, 1 N), 6.87 (d, 9-2.5 Hz, 1 N), 7.25 (d, U-8.7 Hz, 1 N), 7.80 (d, 2-8.8 Hz, 2 N). (4)4-(1-(5-Methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentylaminophenzoic acid

To a mixture of methyl 4-Sh1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|Iaminobenzoate (1.01 g), synthesized above, tetrahydrofuran (10 ml) and ethanol (10 ml) was added 1 M aqueous solution of sodium hydroxide (10.0 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1M hydrochloric acid (10.0 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (915 mg, 9495) as a brown solid.

IN NMR (300 MHz, SOSI") b m.h. 1.29 - 1.70 (m, 4 N), 1.93 - 2.09 (m, 5 N), 2.25 (s, C H), 2.46 (t, 9-7.3 Hz , 2 H), 3.83 (s, C H), 4.65 (t, 9-7.3 Hz, 1 H), 6.57 (d, 9U-8.8 Hz, 2 H), 6 .83 (dd, uU-8.8, 2.5 Hz, 1 H), 6.88 (d, 9U-2.5 Hz, 1 H), 7.25 (d, U-8.8 Hz, 1 N), 7.86 (d, 9-8.8 Hz, 2 N). (5) ethyl 3-1(4-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|amino)phenyl)carbonyl|iamino)propanoate

To the mixture of 4-(11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|Iaminobbenzoic acid (450 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (252 mg), 1-hydroxybenzotriazole monohydrate (251 mg), triethylamine (456 μl) and N,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (314 mg) was added and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 70956 ethyl acetate/hexane) to give the title compound (518 mg, 93905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.25 (t, 9-7.1 Hz, Z H), 1.31 - 1.72 (m, 4 H), 1.91 - 2.10 (m,

H), 2.25 (s, C H), 2.42 - 2.50 (m, 2 H), 2.59 (t, 925.8 Hz, 2 H), 3.61 - 3.71 ( m, 2 H), 3.84 (s, Z

H), 4.07 - 4.19 (m, 2 H), 4.38 - 4.45 (m, 1 H), 4.57 - 4.68 (m, 1 H), 6.54 - 6 .66 (m, Z H), 6.83 (dd, uU-8.7, 2.5 Hz, 1 H), 6.88 (d, 9U-2.5 Hz, 1 H), 7.25 (d, 9U-8.7 Hz, 1 N), 7.56 (d, 9U-8.8 Hz, 2 N). (6)3-(I(4-11-(5-methoxy-3-methyl-1-benzofuran-2h-yl)-5-(methylsulfanyl)pentyl|Iamino)phenyl)carbonyl|iamino)propanoic acid

To the mixture of ethyl 3-1(4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|amino)phenyl)carbonyl|iamino)upropanoate (253 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (133 mg, 5695) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 1.30 - 1.69 (m, 4 H), 1.90 - 2.04 (m, 2 H), 2.05 (s, Z H), 2.24 (s, Z H), 2, 41 - 2.50 (m, 2 H), 2.63 (t, 95.8 Hz, 2 H), 3.59 - 3.69 (m, 2 H), 3.83 (s, C H) , 4.62 (t, 9-7.3 Hz, 1 N), 6.57 (d, U-8.7 Hz, 2 N), 6.65 (t, U-5.9 Hz, 1 N ), 6.83 (dd, 9U-8.8, 2.5 Hz, 1 N), 6.88 (d, 2-2.5 Hz, 1 N), 7.22 - 7.28 (m, 1 N), 7.54 (d, 9-8.7 Hz, 2 N).

Example A121 3-4(4-(1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|amino)phenyl)carbonyl)(methyl)amino)propanoic acid vn , oh that van

IF) M Sn, n sn, non-o (1) ethyl 3-1(4-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|amino) phenyl)carbonyl)(methyl)amino)propanoate

To the mixture of 4-(11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|Iaminobbenzoic acid (460 mg), synthesized in Example

A120(4), ethyl 3-(methylamino)propanoate (219 mg), 1-hydroxybenzotriazole monohydrate (256 mg), triethylamine (464 μl) and M,M-dimethylformamide (10 ml) was added with 1-ethyl-3-( C-dimethylaminopropyl)carbodiimide (320 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 50956 ethyl acetate/hexane) to give the title compound (514 mg, 8895) as a pale brown oil "H NMR (300 MHz, SOCI") b m.p. 1.23 (t, 9U-7.1 Hz, Z H), 1.30 - 1.73 (m, 4 H), 1.88 - 2.10 (m, 5 H), 2.24 (s, Z H ), 2.41 - 2.50 (m, 2 H), 2.55 - 2.67 (m, 2 H), 3.01 (s, C H), 3.70 (t, 957.3 Hz , 2

H), 3.84 (s, C H), 4.11 (k, 9-7.1 Hz, 2 H), 4.27 - 4.35 (m, 1 H), 4.54 - 4, 65 (m, 1 H), 6.57 (d, U-8.8

Hz, 2 N), 6.83 (dd, U-8.8, 2.6 Hz, 1 N), 6.88 (d, 9-26 Hz, 1 N), 7.18 - 7.30 ( m, Z H).

(2)3-(IC4-11-(5-methoxy-3-methyl-1-benzofuran-2h-yl)-5-(methylsulfanyl)pentyl|amino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|amino)phenyl)carbonyl|)(methyl)amino)propanate ( 251 MG), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added with a 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (74.8 mg, 33905) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 1.30 - 1.69 (m, 4 H), 1.90 - 2.05 (m, 2 H), 2.06 (s, Z H), 2.24 (s, Z H), 2, 46 (t, 9U-6.8 Hz, 2 H), 2.66 (t, U-6.6 Hz, 2 H), 3.03 (s, C H), 3.70 (t, U- 6.6 Hz, 2

H), 3.84 (s, C H), 4.60 (t, 2-7.3 Hz, 1 H), 6.57 (d, U-8.9 Hu, 2 H), 6.84 (dd, 9U-8.9, 2.5 Hz, 1 H), 6.89 (d, 9-2.5 Hz, 1 H), 7.21 - 7.30 (m, C H).

Example A122 3-4(4-(1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfonyl)pentyl|amino)phenyl)carbonyl)(methyl)amino)propanoic acid o d-57 U, o ev o M sn,

Гн сн, не-о (1) ethyl 3-1(4-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5- (methylsulfonyl)pentyl|amino)phenyl)carbonyl)( methyl)amino)propanoate

To the solution (10 ml) ethyl 3-Ш(4-Ш1Т1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl|amino)phenyl)carbonyl|)(methyl) of amino)propanate (263 mg) synthesized in Example A121(1) in acetone was added m-chlorobenzoic acid (water-containing, purity 69-7595) (344 mg) at 0 "C and the mixture was stirred overnight at room temperature. Before quenching the reaction saturated aqueous sodium sulfite solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane), then by column chromatography on MH silica gel (ethyl acetate) to give the title compound (104 mg, 3790) as a pale yellow oil. "H NMR (300 MHz, SOCI") b m.p. 1.24 (t, 9U-7.1 Hz, Z H), 1.34 - 1.69 (m, 2 H), 1.76 - 2.14 (m, 4 H), 2.24 (s , Z H), 2.62 (t, U-6.9 Hz, 2 H), 2.85 (s, Z H), 2.97 (t, 9-8.0 Hz, 2 H), 3 .02 (s, C H), 3.71 (t, 9U-6.9 Gu, 2 H), 3.84 (s, C H), 4.12 (k, U-7.1 Hz, 2 H), 4.30 (d, 2-8.0 Gu, 1 H), 4.57 - 4.68 (m, 1 H), 6.58 (d, U-8.7 Hz, 2 H) , 6.85 (dd, U-8.7, 2.5 Hz, 1 H), 6.89 (d, 9U-2.5 Hz, 1 H), 7.19 - 7.31 (m, Z N). (2)3-(IC4-11-(5-methoxy-3-methyl-1-benzofuran-2h-yl)-5-(methylsulfonyl)pentyl|amino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(4-11-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfonyl)pentyl|amino)phenyl)carbonyl|)(methyl)amino)propanate ( 104 MG) synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added with a 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (52.7 mg, 53905) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.34 - 1.69 (m, 2 H), 1.76 - 2.13 (m, 4 H), 2.23 (s, C H), 2.66 (t, 9U-6.4 Hz , 2 H), 2.85 (s, C H), 2.96 (t, U-7.8 Hz, 2 H), 3.04 (s, C H), 3.70 (t, 9- 64 Hz, 2

H), 3.84 (s, C H), 4.59 - 4.66 (m, 1 H), 6.58 (d, 2-8.7 Hz, 2 H), 6.85 (dd, 9U-9.1, 2.5 Hz, 1 H), 6.89 (d, 9U-2.5 Hz, 1 H), 7.21 - 7.30 (m, C H).

Example A123 3-4(4-(5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonylamino)propanoic acid o: o du

N o M n sn, ne-o (1)5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one

To a solution (20 ml) of 5-chloro-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentan-1-one (1.93 g) synthesized in Example A120(1) in methanol sodium iodide (1.54 g) and sodium methoxide (1.86 g) were added, the mixture was stirred overnight under reflux and concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-2095 ethyl acetate/hexane) to give the title compound (797 mg, 42905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.62 - 1.75 (m, 2 H), 1.76 - 1.89 (m, 2 H), 2.58 (s, C H), 3.00 (t, 927.3 Hz, 2 H), 3.33 (s, C H), 3.43 (t, 9U-6.3 Hz, 2 H), 3.87 (s, C H), 7.00 (d, 952.4 Hz , 1

H), 7.07 (dd, 99.0, 2.4 Hz, 1 H), 7.38 (d, 99.0 Hz, 1 H). (2) methyl 4-C5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl|iamino)benzoate

To the mixture of 5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)upentan-1-one (797 mg) synthesized above, methyl 4-aminobenzoate (479 mg), triethylamine (3 .21 ml) and methylene chloride (10 ml) was added to a 1.0 M solution (3.46 ml) of titanium chloride (IM) in methylene chloride at 0"C and the mixture was stirred in an argon atmosphere at room temperature for 3.5 days. Until the reaction quenched saturated aqueous sodium bicarbonate solution was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. To a solution (10 ml) of the obtained oil in tetrahydrofuran was added acetic acid (824 μl) and sodium cyanoborohydride (362 mg) and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium bicarbonate was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure The residue was purified by silica gel column chromatography (0-4095 ethyl acetate/hexane) to give the title compound (1.07 g, 90965) as a brown oil.

IN NMR (300 MHz, SOSI") b m.h. 1.27 - 1.67 (m, 4 H), 1.91 - 2.08 (m, 2 H), 2.24 (s, Z H), 3.30 (s, Z H), 3, 31 - 3.37 (m, 2 H), 3.81 (s, Z H), 3.83 (s, Z H), 4.51 - 4.56 (m, 1 H), 4.60 - 4.69 (m, 1 N), 6.56 (d, U-8.8 Hz, 2 N), 6.83 (dd, U-8.8, 2.5 Hz, 1 N), 6, 87 (d, U-2.5 Hz, 1 N), 7.25 (d, uU-8.8 Hz, 1 N), 7.80 (d, 2-8.8 Hz, 2 N). (3)4-ShCh5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl|amino)benzoic acid

To a mixture of methyl 4-C5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)rbenzoate (1.07 g) synthesized above, tetrahydrofuran (10 ml) and ethanol (10 ml) 1M aqueous sodium hydroxide solution (10.0 ml) was added and the mixture was stirred under reflux for 1 day and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (10.0 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (875 mg, 8595) as a brown solid.

IN NMR (300 MHz, SOSI") b m.h. 1.26 - 1.68 (m, 4 H), 1.90 - 2.10 (m, 2 H), 2.25 (s, Z H), 3.30 (s, Z H), 3, 35 (t, 9U-6.5 Hz, 2 H), 3.84 (s, Z H), 4.66 (t, 9-7.3 Hz, 1 H), 6.58 (d, U- 8.8 Hz, 2

H), 6.84 (dd, 9U-8.9, 2.5 Hz, 1 H), 6.89 (d, 9U-2.5 Hz, 1 H), 7.26 (d, 9-8 .9 Hz, 1 N), 7.86 (d, 9-8.8

Hz, 2 N). (4) ethyl 3-1(4-C5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonylamino)upropanoate

To the mixture of 4-ShCh5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)upentylamino)benzoic acid (400 mg) synthesized above, B-alanine ethyl ester hydrochloride (234 mg), 1-hydroxybenzotriazole monohydrate (233 mg), triethylamine (422 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (291 mg) and the mixture was stirred at room temperature for 2 ,5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (40 - 8095 ethyl acetate/hexane) to give the title compound (489 mg, 97905) as a pale brown oil "H NMR (300 MHz, SOCI") b m.p. 1.25 (t, 9U-7.1 Hz, Z H), 1.30 - 1.69 (m, 4 H), 1.88 - 2.08 (m, 2 H), 2.24 (s, Z H ), 2.55 - 2.62 (m, 2 H), 3.30 (s, Z H), 3.34 (t, 96.7 Hz, 2 H), 3.62 - 3.70 (m , 2

H), 3.83 (s, C H), 4.14 (k, 20-7.1 Hz, 2 H), 4.39 - 4.47 (m, 1 H), 4.57 - 4, 68 (m, 1 H), 6.54 - 6.64 (m, Z H), 6.82 (dd, U-8.8, 2.4 Hz, 1 H), 6.87 (d, 9 -2.4 Hz, 1 N), 7.24 (d, 9-8.8 Hz, 1 N), 7.55 (d, 3-8.8 Hz, 2 N). (5)3-(I(4-C5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-1(4-P5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonyl|Iaminosupropanoate (489 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 "C. The resulting precipitate was collected by filtration and the resulting solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure affording the title compound (453 mg, 9895) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 1.27 - 1.67 (m, 4 H), 1.91 - 2.03 (m, 2 H), 2.23 (s, C H), 2.63 (t, 9U-5.7 Hz , 2 H), 3.30 (s, C H), 3.35 (td, 9U-6.3, 1.2 Hz, 2 H), 3.60 - 3.69 (m, 2 H), 3.83 (c,

With H), 4.61 (t, 9-7.2 Hu, 1 H), 6.56 (d, 9U-8.8 Hu, 2 H), 6.66 (t, U-6.0 Hz , 1 H), 6.82 (dd, 9U-8.9, 2.5 Hz, 1 H), 6.87 (d, 9-2.5 Hz, 1 H), 7.22 - 7.27 (m, 1 N), 7.54 (d, 2-8.8 Hz, 2 N).

Example A124 3-4(4-(5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

Ge dsh o M sn, n

SN. non-α (1) ethyl 3-1(4-C5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonyl|(methyl)amino)propanoate

Ethyl 3-(methylamino)propanoate ( 199 mg), 1-hydroxybenzotriazole monohydrate (233 mg), triethylamine (422 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (291 mg) was added and the mixture was stirred at at room temperature for 2.5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40 - 8095 ethyl acetate/hexane) to give the title compound (460 mg, 8995) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.24 (t, 9-7.1 Hz, Z H), 1.30 - 1.67 (m, 4 H), 1.88 - 2.06 (m, 2 H), 2.24 (s , Z H), 2.62 (t, U-7.0HZ, 2 H), 3.02 (s, Z H), 3.30 (s, Z H), 3.35 (t, 9U-6 ,3 Hz, 2 N), 3.71 (t, 9-7.0 Hz, 2 N), 3.84 (s, Z H), 4.12 (k, 2-7.1 Hz, 2 N ), 4.27 - 4.36 (m, 1 N), 4.55 - 4.66 (m, 1 N), 6.57 (d, 9U-8.8 Hz, 2 N), 6.83 (dd, 98.8, 2.5 Hz, 1 H), 6.88 (d, 9U-2.5 Hz, 1 H), 7.18 - 7.28 (m, C H). (2)3--К4-Ц5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(4-P5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentylamino)phenyl)carbonyl)(methyl)amino)upropanoate (460 mg), synthesized above, to tetrahydrofuran (5 ml) and ethanol (5 ml) was added a 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (428 mg, 99965) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.27 - 1.67 (m, 4 H), 1.88 - 2.06 (m, 2 H), 2.23 (s, Z H), 2.67 (t, U-6.6 Gu , 2 H), 3.04 (s, Z H), 3.30 (s, Z H), 3.35 (td, U-6.4, 1.0 Hz, 2 H), 3.70 ( t, 9U-6,6

Hz, 2 H), 3.84 (s, C H), 4.61 (t, 9-7.2 Gu, 1 H), 6.56 (d, 9U-8.7 Hz, 2 H), 6.83 (dd, 9-8.8, 2.4 Hz, 1

Н), 6.88 (d, 9-24 Gu, 1 Н), 7.21 - 7.30 (m, З Н).

Example A125:

But M

Ex I N -m SN,

Be (1)3-(benzyloxy)-6-bromopyridine-2-carbonitrile

M-bromosuccinimide (17.8 g) was added to a mixture of 2-cyano-3-hydroxypyridine (10.0 g), water (40 ml) and acetonitrile (200 ml) at 0 "C, the mixture was stirred at 0 "C for 2 h at room temperature for 1 h. Ethyl acetate was added to the reaction mixture. The solution was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. To a solution (200 ml) of the obtained solid in acetone was added benzyl bromide (11.9 ml) and potassium carbonate (23.1 g) and the mixture was stirred overnight under reflux.

The insoluble material was filtered off and the filtrate was concentrated under reduced pressure.

The residue was washed with methanol and toluene to give the title compound (3.17 g, 1395) as a white solid. "H NMR (300 MHz, DMSO-a) b m.p. 5.36 (s, 2 N), 7.32 - 7.50 (m, 5 N), 7.87 (d, 9-9, 1 Hz, 1

H), 7.96 (d, 9-9.1 Gu, 1 H). (2) 1-(3-(benzyloxy)-6-bromopyridin-2-yl|ethanone

To a solution (40 ml) of 3-(benzyloxy)-6-bromopyridine-2-carbonitrile (4.00 g) synthesized above in tetrahydrofuran was added a 1.0M solution (27.6 ml) of methylmagnesium bromide in tetrahydrofuran at 0"C and the mixture was stirred at room temperature for 5 h. Another 1.0 M solution (13.8 ml) of methylmagnesium bromide in tetrahydrofuran was added, the mixture was further stirred at room temperature for 1 g, then 1 M hydrochloric acid (80 ml) was added. The mixture was stirred overnight at at room temperature, 1 M aqueous sodium hydroxide solution (100 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 - 9095 ethyl acetate/hexane) to give the indicated in title compound (1.45 g, 34905) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 2.65 (s, C H), 5.18 (s, 2 H), 7.25 (d, 9-8.5 Hz, 1 H), 7.28 - 7.46 (m, 5 H) , 7.48 (d, 98.5 Hz, 1 N). (3) 1-(6-bromo-3-hydroxypyridin-2-yl)ethanone

Trimethylammonium chloride (1.32 g) was added to a suspension (30 ml) of aluminum chloride (3.96 g) in toluene, and the mixture was stirred in an argon atmosphere at room temperature for 1 g. A solution (30 ml) of 1-|3 -(benzyloxy)-6-bromopyridin-2-yl|iethanone (2.81 g), synthesized above, in toluene and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous salt solution was added to the residue Rochelle and the mixture were extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-590 ethyl acetate/hexane) to give the title compound (1.64 g, 8395) as a yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.74 (s, C H), 7.23 (d, 9U-8.8 Hz, 1 H), 7.52 (d, 9U- 8.8 Hz, 1

H), 11.77 (s, 1 H). (4)(5-bromo-3-methylfuroyl3,2-pyridin-2-yl)(cyclohexyl)methanone

To a mixture of 1-(6-bromo-3-hydroxypyridin-2-yl)ethanone (1.64 g) synthesized above, 2-bromo-1-cyclohexylethanone (2.34 g) synthesized in Example AB1(1) and Potassium carbonate (3.15 g) was added to M,M-dimethylformamide (20 ml) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (865 mg, 3595) as a white solid. "H NMR (300 MHz, SOSIz") 6 m.h. 1.19 - 1.54 (m, 5 N), 1.70 - 1.81 (m, 1 N), 1.81 - 2.00 (m, 4

H), 2.63 (s, C H), 3.23 - 3.35 (m, 1 H), 7.52 (d, 98.7 Hz, 1 H), 7.69 (d, 9- 8.7 Hz, 1 N). (5) methyl 4-((5-bromo-3-methylfuroyl3,2-bipyridin-2-yl)cyclohexyl)methylaminobenzoate

To the mixture of (5-bromo-3-methylfuro|3,2-in|Ipyridin-2-yl)ucyclohexyl)methanone (1.46 g) synthesized above, methyl 4-aminobenzoate (753 mg), triethylamine (5.05 ml) and methylene chloride (15 ml) was added to a 1.0M solution (5.44 ml) of titanium chloride (IM) in methylene chloride at 0 "C and the mixture was stirred in an argon atmosphere overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (20 mL) of the obtained oil in tetrahydrofuran was added acetic acid (1.30 mL) and sodium cyanoborohydride (569 mg") and the mixture was stirred at room temperature for 2 h. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-4095 ethyl acetate/hexane) to give the title compound (1.86 g, 9095) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.35 (m, 5 N), 1.45 - 1.55 (m, 1 N), 1.63 - 2.00 (m, 4

H), 2.04 - 2.14 (m, 1 H), 2.33 (s, C H), 3.82 (s, C H), 4.43 - 4.54 (m, 2 H) , 6.55 (d, 2U-59.0 Hz, 2 N), 7.29 (d, 9U-8.5 Hz, 1 N), 7.48 (d, 9U-8.5 Hz, 1 N ), 7.80 (d, 9-9.0 Gu, 2 N). (6)4-(5-bromo-3-methylfuro|3,2-B|pyridin-2-yl)u(cyclohexyl)methyl|amino)benzoic acid

A 2M aqueous solution of lithium hydroxide (10 .2 ml) and the mixture was stirred under reflux for 2 h. Another 4M aqueous solution of lithium hydroxide (5.10 ml) was added and the mixture was stirred under reflux for 4 h. Another 4M aqueous solution of lithium hydroxide (5 ,10 ml) and ethanol (20 ml) and the mixture was stirred under reflux for 4 g and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and 1M hydrochloric acid (61.2 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (1.74 g, 9695) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 0.95 - 1.41 (m, 6 H), 1.54 - 1.81 (m, Z H), 1.87 - 2.02 (m, 1

H), 2.02 - 2.15 (m, 1 H), 2.27 (s, C H), 4.52 - 4.62 (m, 1 H), 6.63 (d, 9-8 ,7 Hz, 2 N), 6.92 (d, uU-8.0 Hz, 1 N), 7.43 (d, 9U-8.7 Gu, 1 N), 7.61 (d, U- 8.7 Hz, 2 N), 7.90 (d, 9-8.7 Hz, 1 N), 12.01 (shs, 1 N). (7) ethyl 3-((4-1(5-bromo-3-methylfuroyl)3,2-yl)pyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonyl|amino)propanoate

To the mixture of 4-((5-bromo-3-methylfuroyl)3,2-bipyridin-2-yl)cyclohexyl)methylaminophenzoic acid (300 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (157 mg), 1-hydroxybenzotriazole monohydrate ( 156 mg), triethylamine (283 μl) and N,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg) and the mixture was stirred at room temperature for 1.5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20 - b0O9Uo ethyl acetate/hexane) to give the title compound (343 mg, 93905) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.37 (m, 8 N), 1.44 - 1.55 (m, 1 N), 1.61 - 1.98 (m, 4

H), 2.02 - 2.13 (m, 1 H), 2.31 (s, C H), 2.58 (t, U-5.9 Hz, 2 H), 3.61 - 3, 70 (m, 2 H), 4.13 (k, 2-7.1

Hz, 2 N), 4.40 - 4.50 (m, 2 N), 6.55 (d, 2-8.8 Hz, 2 N), 6.63 (t, 9U-5.9 Hz, 1 H), 7.27 (d, 9U-8.5 Hz, 1 H), 7.47 (d, 2-8.5 Hz, 1 H), 7.54 (d, U-8.8 Hz , 2 H). (8)3-4I(4-1(5-bromo-3-methylfuroyl|3,2-b|pyridin-2-yl)Hycyclohexyl)methylylamino)phenyl)carbonylamino)upropanoic acid

To the mixture of ethyl 3-((4-1(5-bromo-3-methylfuroyl/|3,2-v|pyridin-2-yl)Hycyclohexyl)methylylamino)phenyl)carbonyl|aminopropanoate (343 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of lithium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (307 mg, 9495) as a pale yellow solid. NMR (300 MHz, DMSO-ab) 6 m.h. 0.94 - 1.30 (m, 5 N), 1.30 - 1.42 (m, 1 N), 1.53 - 1.82 (m, Z H), 1.86 - 2.02 ( m, 1 N), 2.03 - 2.15 (m, 1 N), 2.26 (s, C H), 2.41 (t, 9-7.1 Hz, 2 N), 3.29 - 3.41 (m, 2 N), 4.56 (t, U-8.2 Hz, 1 N), 6.60 (d, 9U-8.9 Hz, 2 N), 6.66 (d , 9U-8.2 Hz, 1 N), 7.42 (d, uU-8.6 Hz, 1 N), 7.52 (d, 9U-8.9 Hz, 2 N), 7.89 ( d, 9U-8.6 Hu, 1 H), 8.01 (t, U-5.5 Hu, 1 H).

Example A126 3-1(4-((5-bromo-3-methylfuroyl|3,2-b|pyridin-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid b A. a drunkard

N

That Ko I ZM r sn.

In three of you"

IN

(1) ethyl 3-((4-1(5-bromo-3-methylfuroyl)3,2-yl)pyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanate

To the mixture of 4-((5-bromo-3-methylfuroyl)3,2-bipyridin-2-yl)cyclohexyl)methylaminophenzoic acid (300 mg), synthesized in Example A125(6b), ethyl 3-(methylamino)propanate (134 mg) , 1-hydroxybenzotriazole monohydrate (156 mg"), triethylamine (283 μl) and M,M-dimethylformamide (10 ml) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg) was added and the mixture was stirred at room temperature for 1.5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20 - b0O9Uo ethyl acetate/hexane) to give the title compound (317 mg, 84905) as a pale yellow oil. "H NMR (300 MHz, SOCI") 6 m.p.h. 0.94 - 1.38 (m, 8 N), 1.44 - 1.55 (m, 1 N), 1.59 - 2.00 (m, 4

Н), 2.02 - 2.14 (m, 1 Н), 2.32 (s, З Н), 2.56 - 2.66 (m, 2 Н), 3.00 (s, З Н) , 3.69 (t, 97.0 Hz, 2 N), 4.06 - 4.17 (m, 2 N), 4.27 - 4.34 (m, 1 N), 4.39 - 4, 46 (m, 1 N), 6.53 (d, 9U-8.7 Hz, 2 N), 7.20 (d, uU-8.7 Hz, 2 N), 7.28 (d, 9U- 8.5 Hz, 1 N), 7.48 (d, U-8.5 Hz, 1 N). (2)3-4-K4-1(5-bromo-3-methylfuroyl|3,2-b|pyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-1(5-bromo-3-methylfuroyl/|3,2-v|pyridin-2-yl)/Hycyclohexyl)methylaminophenyl)carbonyl(methyl)amino)propanoate (271 MG), synthesized above, to tetrahydrofuran (5 ml) and ethanol (5 ml) was added a 1 M aqueous solution of lithium hydroxide (1.00 ml), the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (271 mg, 9095) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.95 - 1.37 (m, 5 N), 1.44 - 1.55 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.31 (s, With H), 2.64 (t, 9U-6.3 Hz, 2 H), 3.02 (s, With H), 3.69 (t, U-6.3 Hz, 2

H), 4.43 (d, 9-7.9 Hz, 1 H), 6.54 (d, 2-8.6 Gu, 2 H), 7.23 (d, U-8.6 Hz, 2 H), 7.29 (d, 9U-8.6 Gu, 1

H), 7.49 (d, 2-8.6 Hu, 1 H).

Example A127 3-1(4-1(5-chloro-3-methylfuroyl3,2-p|pyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonylamino)propanoic acid 6)

SI

(1)3-(benzyloxy)-6-chloro-2-iodopyridine

Sodium carbonate (16.3 g) and iodine (10.8 g) were added to an aqueous solution (100 ml) of 2-chloro-5-hydroxypyridine (10.0 g) and the mixture was stirred at room temperature for 5 days. The reaction mixture was acidified to pH-b5 with 1M hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow solid. The resulting solid was recrystallized from methanol to give a brown solid. To a solution (200 ml) of the obtained solid in acetone was added benzyl bromide (8.02 ml) and potassium carbonate (15.5 g) and the mixture was stirred overnight under reflux. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30905 ethyl acetate/hexane) to give the title compound (18.4 g, 69905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 5.17 (s, 2 N), 6.97 (d, 9-84 Hz, 1 N), 7.15 (d, 9U-8.4 Hz, 1

N), 7.30 - 7.47 (m, 5 N). (2) 1-(3-(benzyloxy)-6b-chloropyridin-2-yl)ethanol

To a solution (100 ml) of 3-(benzyloxy)-b-chloro-2-iodopyridine (17.4 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (60.2 ml) of isopropylmagnesium bromide in tetrahydrofuran at -45 " C and the mixture was stirred at the same temperature for 1 h. Acetaldehyde (10.2 ml) was added to the reaction mixture and the mixture was stirred at -457C for 30 min, then at room temperature for 2 h. A saturated aqueous solution of ammonium chloride was added until quenching reaction, the tetrahydrofuran was evaporated and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 - 3095 ethyl acetate/hexane) to give the title compound (6.82 g, 52905), as a pale yellow oil. "H NMR (300 MHz, SOSIZ") b m.ch. 1.46 (d, 9U-6.6 Hz, Z H), 3.95 (d, 9-7.7 Hz, 1 H), 5.06 - 5.18 (m, Z H), 7, 14 (d, 92-8.5 Hz, 1 N), 7.17 (d, 9-8.5 Hz, 1 N), 7.31 - 7.44 (m, 5 N). (3) 1-(3-(benzyloxy)-6b-chloropyridin-2-yl)ethanone

Tetrapropylammonium perruthenate was added to a mixture of 1-3-(benzyloxy)-b-chloropyridin-2-ylethanol (7.04 g) synthesized above, 4-methylmorpholine M-oxide (6.26 g) and acetonitrile (140 ml) (938 mg), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-1095 ethyl acetate/hexane) to give the title compound (6.26 g, 9095) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 2.66 (s, Z H), 5.19 (s, 2 H), 7.27 - 7.47 (m, 7 H). (4) 1-(b-chloro-3-hydroxypyridin-2-yl)ethanone

Trimethylammonium chloride (4.75 g) was added to a suspension (80 ml) of aluminum chloride (14.3 g) in toluene, and the mixture was stirred under an argon atmosphere at room temperature for 1 h. A solution (80 ml) of 1-|3 -(benzyloxy)-6-chloropyridin-2-yl|Iethanone (8.66 g), synthesized above, in toluene and the mixture was stirred at room temperature for 4 g. The reaction mixture was concentrated under reduced pressure, a saturated aqueous salt solution was added to the residue Rochelle and the mixture were extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-590 ethyl acetate/hexane) to give the title compound (4.89 g, 8695) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.74 (s, C H), 7.31 (d, 9U-8.8 Hz, 1 H), 7.39 (d, 9U- 8.8 Hz, 1

H), 11.77 (s, 1 H). (5)(X5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)(cyclohexyl)methanone

To the mixture of 1-(b-chloro-3-hydroxypyridin-2-yl)ethanone (4.89 g) synthesized above, 2-bromo-1-cyclohexylethanone (7.01 g) synthesized in Example AB1(1) and Potassium carbonate (11.8 g) was added to M,M-dimethylformamide (50 ml) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (5.78 g, 73905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.19 - 1.61 (m, 5 N), 1.70 - 1.80 (m, 1 N), 1.81 - 2.01 (m, 4

H), 2.63 (s, C H), 5.23 - 3.35 (m, 1 H), 7.39 (d, 2-8.7 Hz, 1 H), 7.78 (d, 9-8.7 Hz, 1 N). (b) methyl 4-(5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)(cyclohexyl)methyl|aminophenzoate

To the mixture of (5-chloro-3-methylfuroyl3,2-B|Ipyridin-2-yl)ucyclohexyl)methanone (1.00 g) synthesized above, methyl 4-aminobenzoate (599 mg), triethylamine (4.01 ml) to methylene chloride (10 ml) was added a 1.0 M solution (4.32 ml) of titanium chloride (IM) in methylene chloride at 0 "C, and the mixture was stirred in an argon atmosphere overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium hydrogen carbonate and the reaction the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (15 mL) of the obtained oil in tetrahydrofuran was added acetic acid (1.03 mL) and sodium cyanoborohydride (452 mg) and the mixture was stirred at room temperature for 2 h. A saturated aqueous solution of sodium bicarbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure in. The residue was purified by silica gel column chromatography (0-4095 ethyl acetate/hexane) to give the title compound (1.31 g, 8195) as an orange solid.

IN NMR (300 MHz, SOSI") b m.h. 0.96 - 1.37 (m, 5 N), 1.45 - 1.56 (m, 1 N), 1.63 - 1.99 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.32 (s, C H), 3.81 (s, C H), 4.43 - 4.56 (m, 2 H) , 6.54 (d, 2-9.0 Gu, 2 N), 7.14 (d, 9-8.5 Hz, 1 N), 7.56 (d, 9U-8.5 Hz, 1 N ), 7.79 (d, 9-9.0 Gu, 2 N). (74-1(5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)(cyclohexyl)methyliaminophenbenzoic acid

1M was added to a mixture of methyl 4-(5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)cyclohexyl)methylaminophenzoate (1.31 g) synthesized above, ethanol (20 ml) and tetrahydrofuran (20 ml) aqueous solution of lithium hydroxide (20 ml), the mixture was stirred under reflux with 3 g and concentrated under reduced pressure. The residue was dissolved in water (40 mL) and 1 M hydrochloric acid (20 mL) was added at 0 "C. The resulting precipitate was collected by filtration and the resulting solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue washed with isopropyl ether to give the title compound (1.21 g, 9695) as a pale yellow solid.

IN NMR (300 MHz, DMSO-ab) 5 m.h. 0.96 - 1.42 (m, 6 H), 1.54 - 1.82 (m, Z H), 1.87 - 2.03 (m, 1 H), 2.04 - 2.16 ( m, 1 H), 2.28 (s, C H), 4.53 - 4.64 (m, 1 H), 6.64 (d, U-8.9 Hz, 2 H), 6.95 (d,

9U-7.9 Hz, 1 N), 7.32 (d, 9U-8.6 Gu, 1 N), 7.62 (d, 9U-8.9 Hz, 2 N), 7.99 (d , 9-8.6 Gu, 1 N), 12.02 (shs, 1 N). (8) ethyl 3-(Х(4-1(5-chloro-3-methylfuroyl|3,2-B|pyridin-2-yl)Hycyclohexyl)methylamino)phenyl)carbonylaminopropanoate

To the mixture of 4-1(5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)Hycyclohexyl)methylIaminophenzoic acid (300 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (174 mg), monohydrate of 1- 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg) was added to hydroxybenzotriazole (173 mg), triethylamine (315 μl) and M,M-dimethylformamide (10 ml) and the mixture was stirred at room temperature for 2.5 days . A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70956 ethyl acetate/hexane) to give the title compound (383 mg, quantitative) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.96 - 1.37 (m, 8 N), 1.45 - 1.56 (m, 1 N), 1.61 - 1.99 (m, 4

H), 2.02 - 2.14 (m, 1 H), 2.31 (s, C H), 2.54 - 2.62 (m, 2 H), 3.60 - 3.69 (m , 2 H), 4.13 (k, 9-57.1

Hz, 2 N), 4.40 - 4.50 (m, 2 N), 6.55 (d, 2-8.8 Hz, 2 N), 6.62 (t, 9-5.9 Hz, 1 H), 7.14 (d, 9-8.5 Hz, 1 H), 7.54 (d, 2-8.8 Hz, 2 H), 7.55 (d, U-8.5 Hz , 1 H). (9)3-((4-X1(5-chloro-3-methylfuroyl)3,2-bipyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonylamino)upropanoic acid

To the mixture of ethyl 3-1(4-1(5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonylaminoisopropanoate (383 mg), synthesized above, tetrahydrofuran (5 ml) and 1M aqueous solution of sodium hydroxide (2.00 ml) was added to ethanol (5 ml), the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (328 mg, 93905) as a white solid.

IN NMR (300 MHz, DMSO-ab) 5 m.h. 0.95 - 1.30 (m, 5 N), 1.30 - 1.41 (m, 1 N), 1.55 - 1.82 (m, Z H), 1.87 - 2.01 ( m, 1 N), 2.04 - 2.16 (m, 1 N), 2.26 (s, Z H), 2.42 (t, 97.2 Hz, 2 N), 3.26 - 3 .42 (m, 2 N), 4.56 (t, U-8.2 Hz, 1 N), 6.60 (d, 2U-8.9 Hz, 2 N), 6.68 (d, 9U -8.2 Hz, 1 N), 7.31 (d, uU-8.5 Hz, 1 N), 7.52 (d, U-8.9 Hz, 2 N), 7.93 - 8, 06 (m, 2 N).

Example A128 3-1(4-1(5-Chloro-3-methylfuroyl3,2-p|pyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid. University of SN

SI

(1) ethyl 3-(S(4-1(5-chloro-3-methylfuroyl|3,2-B|pyridin-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanate

To the mixture of 4-1(5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)Hycyclohexyl)methylaminophenzoic acid (300 mg), synthesized in Example A127(7), ethyl 3-(methylamino)propanoate (148 mg), 1-hydroxybenzotriazole monohydrate (173 mg), triethylamine (315 μl) and N,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg) was added, and the mixture was stirred at room temperature temperature for 2.5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70956 ethyl acetate/hexane) to give the title compound (332 mg, 86905) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.96 - 1.38 (m, 8 N), 1.44 - 1.56 (m, 1 N), 1.61 - 1.99 (m, 4

H), 2.03 - 2.15 (m, 1 H), 2.31 (s, With H), 2.61 (t, 9U-6.9 Hz, 2 H), 3.00 (s, With H), 3.69 (t, U-6.9 Hz, 2

H), 4.06 - 4.17 (m, 2 H), 4.29 - 4.36 (m, 1 H), 4.39 - 4.47 (m, 1 H), 6.54 (d , 2-8.7 Hz, 2 N), 7.14 (d, U-8.5 Gu, 1 N), 7.21 (d, 9-8.7 Hz, 2 N), 7.56 ( d, 9-8.5 Hz, 1 N). (2)3-(4-X1(5-chloro-3-methylfuroyl3,2-bipyridin-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-1(4-1(5-chloro-3-methylfuroyl3,2-B|pyridin-2-yl)cyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (332 MG), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of lithium hydroxide (3.00 ml), the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (3.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (278 mg, 8995) as a pale yellow solid. NMR (300 MHz, SOSI") 6 m.h. 0.94 - 1.38 (m, 5 N), 1.44 - 1.56 (m, 1 N), 1.61 - 1.98 (m, 4

H), 2.02 - 2.15 (m, 1 H), 2.31 (s, With H), 2.62 (t, 9U-6.3 Hz, 2 H), 3.00 (s, With H), 3.68 (t, U-6.3 Hz, 2

H), 4.43 (d, 2-8.0 Hz, 1 H), 6.54 (d, 2-8.5 Hz, 2 H), 7.14 (d, 2-8.5 Hz, 1 H), 7.22 (d, 90-8.5 Hz, 2

H), 7.57 (d, 9-8.5 Gu, 1 H).

Example A129 3-(I44-K(cyclohexyl3-methyl-5-(phenylcarbonyl)amino|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid o m-n o M sn. yin o sn, y

N

To a solution (10 ml) of ethyl 3-(Х4А-1(5-amino-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (280 MG), synthesized in Example A110(5), in M,M-dimethylacetamide was added benzoyl chloride (99 μl) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give a pale yellow oil. A 1M aqueous solution of lithium hydroxide (2.00 ml) was added to the mixture of the obtained oil, tetrahydrofuran (5 ml) and ethanol (5 ml), the mixture was stirred at room temperature for 5 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (303 mg, 94905) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 0.93 - 1.38 (m, 5 N), 1.46 - 1.58 (m, 1 N), 1.60 - 1.99 (m, 4

Н), 2.03 - 2.16 (m, 1 Н), 2.19 (s, З Н), 2.44 - 2.60 (m, 2 Н), 2.96 (s, З Н) , 3.49 - 3.64 (m, 2 N), 4.36 (d, 9-8.0 Hz, 1 N), 6.54 (d, 9-8.7 Hz, 2 N), 7 .13 - 7.33 (m, 4 H), 7.39 - 7.56 (m, C H), 7.80 (s, 1 H), 7.85 - 7.92 (m, 2 H) , 8.21 (c, 1 H).

Example A130

3-(44-K(cyclohexyl3-methyl-5-(phenylsulfonyl)amino|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid o oda o M sn, yn o sn, o-5-M o (1) ethyl 3-(44-Kcyclohexyl3-methyl-5-((phenylsulfonyl)amino|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)(methyl)amino|propanoate

To a solution (10 ml) of ethyl 3-(Х4А-1(5-amino-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminonorphenyl)carbonyl)(methyl)amino)propanate (254 MG), synthesized in Example A119(5), in M,M-dimethylacetamide was added benzenesulfonyl chloride (99 μl) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give the title compound (312 mg, 96905) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.95 - 1.34 (m, 8 N), 1.41 - 1.54 (m, 1 N), 1.58 - 1.95 (m, 4

H), 2.04 - 2.12 (m, 1 H), 2.18 (s, C H), 2.56 - 2.68 (m, 2 H), 3.02 (s, C H) , 3.71 (t, 92-6.7 Hz, 2 N), 4.12 (Kk, udE7.1 Hz, 2 N), 4.28 - 4.39 (m, 2 N), 6.51 - 6.58 (m, Z H), 6.78 (dd, 9-8.8, 2.2 Hz, 1 H), 7.14-7.24 (m, 4 H), 7.37 - 7.46 (m, 2 N), 7.48 - 7.56 (m, 1 N), 7.68 - 7.74 (m, 2 N). (2)3-(144-Kcyclohexyl/3-methyl-5-|(phenylsulfonyl)amino|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

To the mixture of ethyl 3-((4-(cyclohexyl/3-methyl-5-((phenylsulfonyl)amino|-1-benzofuran-2-ylmethyl)amino|phenylcarbonyl)(methyl)amino|Ipropanoate (312 mg) synthesized above , tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous sodium hydroxide solution (2.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and at 0 1M hydrochloric acid (2.00 mL) was added to C. The resulting precipitate was collected by filtration to give the title compound (240 mg, 8095) as a white solid. 0.89 - 1.37 (m, 5 N), 1.40 - 1.55 (m, 1 N), 1.58 - 1.97 (m, 4

H), 2.02 - 2.13 (m, 1 H), 2.16 (s, C H), 2.62 (t, 9U-6.1 Hz, 2 H), 3.01 (s, With H), 3.68 (t, 9-61 Hz, 2

H), 4.34 (d, 9U-8.0 Gu, 1 H), 6.53 (d, 9U-8.7 Hz, 2 H), 6.79 (dd, 9U-8.7, 2 ,3 Hz, 1 N), 6.84 - 6.98 (m, 1 N), 7.11 - 7.25 (m, 4 N), 7.34 - 7.42 (m, 2 N), 7.45 - 7.53 (m, 1 N), 7.67 - 7.74 (m, 2 N).

Example A131 3-C4-((5-(benzylamino)-3-methyl-1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid o m7--- YAN (F) M CH in

Sleep

Mo (1) ethyl 3-SHA-(5-(benzylamino)-3-methyl-1-benzofuran-2-yl)" cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoate

To the mixture of ethyl 3-((4-((5-amino-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (322 MG), synthesized in Example A110 (5 ), benzaldehyde (100 μl) and ethanol (10 ml), acetic acid (56 μl) and sodium cyanoborohydride (61.6 mg) were added, and the mixture was stirred at room temperature for 1.5 g. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give the title compound (354 mg, 9390) as a colorless oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.92 - 1.37 (m, 8 N), 1.47 - 1.96 (m, 5 N), 2.01 - 2.12 (m, 1

H), 2.17 (s, C H), 2.56 - 2.67 (m, 2 H), 3.02 (s, C H), 3.66 - 3.77 (m, C H) , 4.06 - 4.18 (m, 2 H), 4.29 - 4.39 (m, A H), 6.51 - 6.64 (m, 4 H), 7.14 - 7 AZ ( m, 8 H). (2)3-ShIA-H(5-(benzylamino)-3-methyl-1-benzofuran-2-yl)"ucyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

To the mixture of ethyl 3-CI4-(SHT5-(benzylamino)-3-methyl-1-benzofuran-2-yl)/ucyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|Ipropanate (354 MG), synthesized above, tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 1.5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (310 mg, 92905) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 0.92 - 1.34 (m, 5 N), 1.47 - 1.58 (m, 1 N), 1.60 - 1.97 (m, 4

H), 2.01 - 2.12 (m, 1 H), 2.17 (s, With H), 2.67 (t, 96.4 Hz, 2 H), 3.04 (s, With H ), 3.65 - 3.73 (m, 2 H), 4.30 - 4.36 (m, Z H), 6.55 (d, U-8.7 Hz, 2 H), 6.59 (dd, U-8.7, 2.7 Hz, 1 N), 6.63 -6.67 (m, 1 N), 7.17 (d, 98.7 Hz, 1 N), 7.20 - 7.42 (m, 7 N).

Example A132 3-(44-Kcyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl/|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid o duet

N o M nn o to d-sn,

IS

(1) methyl 5-fluoro-3-(2-methoxyethoxy)methyl)|-1-benzofuran-2-carboxylate

To a solution (25 ml) of 2-methoxyethanol (2.74 ml) in M,M-dimethylformamide was added sodium hydride (6095, in oil, 835 mg) at 0 "C and the mixture was stirred at room temperature for 30 min. After stirring, at 0 "C, a solution (25 ml) of methyl 3-(bromomethyl)-5-fluoro-1-benzofuran-2-carboxylate (5.00 g) synthesized in

Example A47(2) in M,M-dimethylformamide. The reaction mixture was stirred at 807 for 5 g, then a saturated aqueous solution of ammonium chloride was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-4095 ethyl acetate/hexane) to give the title compound (1.54 g, 3195) as a pale yellow oil. "IN NMR (300 MHz, SOSI") b m.ch. 3.40 (s, Z H), 3.57 - 3.62 (m, 2 H), 3.66 - 3.72 (m, 2 H), 3.99 (s, C H), 5.11 (s, 2 H), 7.14 - 7.22 (m, 1 H), 7.45 - 7.51 (m, 1 H) , 7.60 - 7.65 (m, 1 H). (25-fluoro-3-(2-methoxyethoxy)methyl!|-1-benzofuran-2-ylmethanol

To a mixture of methyl 5-fluoro-3-(2-methoxyethoxy)methyl)|-1-benzofuran-2-carboxylate (1.54 g) synthesized above, calcium chloride (1.21 g), ethanol (15 ml) and sodium borohydride (825 mg) was added to tetrahydrofuran (15 ml) at 0 "C and the mixture was stirred at room temperature for 3 h. A saturated aqueous solution of sodium bicarbonate was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.34 g, 97905) as a pale yellow oil. "IN NMR (300 MHz, SOSI") b m.p. 3.38 (s, Z H), 3.55 - 3.60 (m, 2 H), 3.63 - 3.68 (m, 2 H), 4.73 (s, 2 H), 4, 76 (shs, 2 H), 6.95 - 7.04 (m, 1 H), 7.17 - 7.23 (m, 1 H), 7.33 - 7.40 (m, 1 H). (3)5-fluoro-3-(2-methoxyethoxy)methyl/)|-1-benzofuran-2-carbaldehyde

To a mixture of "5-fluoro-3-(2-methoxyethoxy)methyl|-1-benzofuran-2-ylmethanol (2.65 g) synthesized above, 4-methylmorpholine M-oxide (2.44 g) and acetonitrile (50 ml) tetrapropylammonium perruthenate (366 mg) was added, the mixture was stirred for 5 g and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-3090 ethyl acetate/hexane) to give the title compound (1.33 g, 5190) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 3.41 (s, Z H), 3.58 - 3.64 (m, 2 H), 3.72 - 3.77 (m, 2 H), 5.07 (s, 2 H), 7, 21 - 7.29 (m, 1 H), 7.48 - 7.57 (m, 2 H), 10.09 (s, 1 H). (4) cyclohexyl5-fluoro-3-((2-methoxyethoxy)methyl|/|-1-benzofuran-2-yl)methanone

To a solution (20 ml) of 5-fluoro-3-(2-methoxyethoxy)methyl|-1-benzofuran-2-carbaldehyde (1.33 g) synthesized above, a 1.0 M solution (7.91 ml) in tetrahydrofuran was added of cyclohexylmagnesium bromide in tetrahydrofuran at 0 "C and the mixture was stirred for 2 g. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 - 4095 ethyl acetate/hexane) to give a pale yellow oil.

Tetrapropylammonium perruthenate (140 mg) was added to the mixture of the obtained oil, 4-methylmorpholine M-oxide (933 mg) and acetonitrile (20 ml), the mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-2095 ethyl acetate/hexane) to give the title compound (881 mg, 5095) as a colorless oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.17 - 1.55 (m, 5 N), 1.70 - 1.80 (m, 1 N), 1.80 - 2.01 (m, 4

H), 3.24 - 3.37 (m, 1 H), 3.40 (s, C H), 3.57 - 3.63 (m, 2 H), 3.66 - 3.72 (m ,2H), 5.11 (s, 2 H), 7.14 - 7.23 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.64 - 7.70 ( m, 1 H). (5) methyl 4-(cyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl|-1-benzofuran-2-yl)umethyl)amino|benzoate

To the mixture of cyclohexyl5-fluoro-3-(2-methoxyethoxy)methyl|-1-benzofuran-2-ylumethanone (881 mg) synthesized above, methyl 4-aminobenzoate (440 mg), triethylamine (2.93 ml) and methylene chloride ( 10 ml) was added to a 1.0 M solution (3.16 ml) of titanium chloride (IM) in methylene chloride and the mixture was stirred under an argon atmosphere overnight at room temperature. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a dark

brown solid. Acetic acid (301 μl) and sodium cyanoborohydride (331 mg) were added to a solution (10 ml) of the obtained solid in tetrahydrofuran, and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-4095 ethyl acetate/hexane) to give the title compound (482 mg, 3995) as a brown oil.

IN NMR (300 MHz, SOSI") b m.h. 0.96 - 1.35 (m, 5 N), 1.41 - 1.51 (m, 1 N), 1.58 - 1.85 (m, C

H), 1.86 - 2.01 (m, 1 H), 2.01 - 2.13 (m, 1 H), 3.43 (s, C H), 3.53 - 3.60 (m , 2 H), 3.60 - 3.67 (m, 2

H), 3.80 (s, C H), 4.46 - 4.72 (m, C H), 4.99 (d, 9-8.8 Hz, 1 H), 6.60 (d, 9U-9.0 Hz, 2 N), 6.88 - 6.98 (m, 1 N), 7.13 - 7.19 (m, 1 N), 7.27 - 7.34 (m, 1 H), 7.78 (d, 959.0 Hz, 2 H). (6)4-Ccyclohexyl/5-fluoro-3-|(2-methoxyethoxy)methyl/|-1-benzofuran-2-yl)umethyl)amino|benzoic acid

To the mixture of methyl 4-(cyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl|-1-benzofuran-2-yl)umethyl)amino|benzoate (482 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1M aqueous solution of sodium hydroxide (5.00 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (5.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (437 mg, 9395) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.99 - 1.35 (m, 5 N), 1.40 - 1.53 (m, 1 N), 1.59 - 1.85 (m, Z

H), 1.86 - 2.14 (m, 2 H), 3.44 (s, C H), 3.52 - 3.70 (m, 4 H), 4.49 - 4.73 (m , Z H), 6.62 (d, 9U-8.9

Hz, 2 N), 6.91 - 7.00 (m, 1 N), 7.14 - 7.20 (m, 1 N), 7.29 - 7.36 (m, 1 N), 7, 84 (d, 958.9 Hz, 2 N). (7) ethyl 3-(CH-Ccyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|Ipropanoate

To the mixture of 4-(cyclohexyl5-fluoro-3-((2-methoxyethoxy)methyl|)|-1-benzofuran-2-yl)methyl)amino|benzoic acid (200 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (101 mg), 1-hydroxybenzotriazole monohydrate (101 mg), triethylamine (184 μl) and M,M-dimethylformamide (10 ml) was added with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (126 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70905 ethyl acetate/hexane) to give the title compound (216 mg, 89905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.34 (m, 8 N), 1.41 - 1.52 (m, 1 N), 1.60 - 2.01 (m, 4

H), 2.03 - 2.13 (m, 1 H), 2.58 (t, 9-5.9 Hz, 2 H), 3.43 (s, C H), 3.54 - 3, 69 (m, 6 H), 4.13 (k, 9-7.1

Hz, 2 N), 4.45 - 4.53 (m, 1 N), 4.57 (d, 9-12.1 Hz, 1 N), 4.65 (d, 9-12.1 Hz, 1 H), 4.87 (d, 9-8.5

Hu, 1 H), 6.56 - 6.65 (m, Z H), 6.88 - 6.98 (m, 1 H), 7.14 - 7.20 (m, 1 H), 7, 28 - 7.34 (m, 1 N), 7.53 (d, U-8.8 Hz, 2 N). (8)3-(44-Kcyclohexyl5-fluoro-3-((2-methoxyethoxy)methyl|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

To the mixture of ethyl 3-((/4-Kcyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)lamino|propanoate (216 mg), synthesized above, 1 M aqueous sodium hydroxide solution (1.00 ml) was added to tetrahydrofuran (5 ml) and ethanol (5 ml), the mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (69.6 mg, 34905) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.99 - 1.35 (m, 5 N), 1.40 - 1.51 (m, 1 N), 1.59 - 1.85 (m, C

H), 1.84 - 2.00 (m, 1 H), 2.01 - 2.12 (m, 1 H), 2.63 (t, 9-5.7 Hz, 2 H), 3, 42 (s, Z H), 3.54 - 3.69 (m, 6 H), 4.49 (d, 90-8.3 Hz, 1 H), 4.56 (d, 9-12.1 Hz, 1 N), 4.64 (d, 9-12.1 Hz, 1 N), 6.53-6.67 (m, Z H), 6.88 - 6.99 (m, 1 N) , 7.12 - 7.20 (m, 1 N), 7.27 - 7.34 (m, 1 N), 7.52 (d, 928.7 Hz, 2 N).

Example A133 3-(44-Kcyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl/|-1-benzofuran-2-

yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid o tel o M сn, yin o td сН,

IS

(1) ethyl 3-(CH-Ccyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)(methyl)amino|propanoate

To the mixture of 4-(cyclohexyl5-fluoro-3-((2-methoxyethoxy)methyl|)|-1-benzofuran-2-yl)umethyl)amino|benzoic acid (200 mg), synthesized in Example A132(6), ethyl 1-ethyl-3-(3-dimethylaminopropyl) hydrochloride was added to 3-(methylamino)propanoate (86.4 mg), 1-hydroxybenzotriazole monohydrate (101 mg), triethylamine (184 μl) and M,M-dimethylformamide (10 ml). carbodiimide (126 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 70905 ethyl acetate/hexane) to give the title compound (175 mg, 70905) as a pale brown oil "H NMR (300 MHz, SOCI") 6 ppm 1.00 - 1.37 (m, 8 N), 1.42 - 1.53 (m, 1 N), 1.59 - 2.00 (m, 4

H), 2.03 - 2.14 (m, 1 H), 2.61 (t, U-7.0 Gu, 2 H), 3.01 (s, C H), 3.42 (s, With H), 3.54 -3.75 (m, 6 H), 4.11 (k, 9d9-7.1 HZ, 2 H), 4.42 - 4.51 (m, 1 H), 4 .59 (d, 9U-12.1 Hz, 1 N), 4.65 (d, 20-121 Hz, 1 N), 4.71 (d, 9U-8.5 Gu, 1 N), 6, 59 (d, 2U-8.8 Gu, 2 H), 6.89 - 6.98 (m, 1 H), 7.16 - 7.23 (m, C H), 7.28 - 7.34 (m, 1 N). (2)3-(144-Kcyclohexyl5-fluoro-3-((2-methoxyethoxy)methyl|-1-benzofuran-2-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

To the mixture of ethyl 3-((/4-Kcyclohexyl5-fluoro-3-|(2-methoxyethoxy)methyl|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)x(methyl)amino|propanoate (175 mg) , synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added with a 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml), 1 M hydrochloric acid (1.00 ml) was added at 0 "C and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain the target compound indicated in the title (143 mg, 82905), as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.99 - 1.35 (m, 5 N), 1.40 - 1.51 (m, 1 N), 1.60 - 2.00 (m, 4

H), 2.02 - 2.15 (m, 1 H), 2.64 (t, 9-6.4 Hz, 2 H), 3.02 (s, C H), 3.42 (s, With H), 3.54 - 3.75 (m, 6 H), 4.47 (d, 20-8.3 Hz, 1 H), 4.59 (d, 9-12.3 Hz, 1 H ), 4.66 (d, 9-12.3 Hz, 1 N), 6.60 (d, 9-8.7 Hz, 2

H), 6.89 - 6.99 (m, 1 H), 7.16 - 7.25 (m, Z H), 7.28 - 7.35 (m, 1 H).

Example A134 3-4(4-(2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid sn. SN, 6) and others

N

Min

Sn

(1)2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butan-1-one

Aluminum chloride (1.35 g) was added to a mixture of 3-methyl-1-benzothiophene (1.00 g), 2-ethylbutyryl chloride (1.02 ml) and nitromethane (10 ml) at 0 "C, and the mixture was stirred for 3 h . Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0 - 1095 ethyl acetate/hexane) to give the title compound (1, 65 g, 9995), as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.93 (t, 9-74 Hz, 6 N), 1.51 - 1.67 (m, 2 N), 1.75 - 1.92 (m, 2 N), 2.78 (s, Z H), 2.97 - 3.08 (m, 1 H), 7.40 - 7.53 (m, 2 H), 7.81 - 7.91 (m, 2 H). (2) methyl 4-D2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|aminobenzoate

To the mixture of 2-ethyl-1-(33-methyl-1-benzothiophen-2-yl)butan-1-one (1.65 g) synthesized above, methyl 4-aminobenzoate (1.15 g), triethylamine (7 .47 ml) and methylene chloride (15 ml) was added to a 1.0M solution (8.04 ml) of titanium chloride (IM) in methylene chloride and the mixture was stirred under an argon atmosphere overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, methylene chloride was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. To a mixture of the obtained oil, methyl 4-aminobenzoate (506 mg), triethylamine (7.47 ml) and methylene chloride (30 ml) was added titanium chloride (IM) (882 μl) and the mixture was stirred under an argon atmosphere overnight at room temperature until quenching a saturated aqueous solution of sodium bicarbonate was added to the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (797 μl) and sodium cyanoborohydride (842 mg) were added to a solution (30 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature. 1.5 g was stirred. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added, and the organic solvent was evaporated to evaporators, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 - 4095 ethyl acetate/hexane) to give the title compound (580 mg, 2390) as a pale brown solid. "H NMR (300 MHz, SOSIz") 6 m.h. 0.84 - 0.99 (m, 6 H), 1.33 - 1.56 (m, C H), 1.67 - 1.84 (m, 2

H), 2.46 (s, C H), 3.79 (s, C H), 4.45 (d, 9-6.6 Hz, 1 H), 4.81 - 4.89 (m, 1 H), 6.52 (d, 959.0 Hz, 2

H), 7.22 - 7.29 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.61 - 7.66 (m, 1 H), 7.67 - 7 .71 (m, 1 N), 7.77 (d, 9E9, O Hz, 2 N). (3)4-(2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|iaminophenzoic acid

To a mixture of methyl 4-[C2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]iaminoisobenzoate (580 mg) synthesized above, tetrahydrofuran (10 ml) and ethanol (10 ml) was added 1M aqueous sodium hydroxide solution (10.0 mL), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1M hydrochloric acid (10.0 mL) was added at 0°C. The resulting precipitate was collected by filtration to afford the title compound (529 mg, 95905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.87 - 0.99 (m, 6 H), 1.32 - 1.56 (m, Z H), 1.67 - 1.83 (m, 2

H), 2.46 (s, C H), 4.46 - 4.54 (m, 1 H), 4.82 - 4.91 (m, 1 H), 6.53 (d, 9-8 .7 Hz, 2 N), 7.22 - 7.30 (m, 1 N), 7.32 - 7.39 (m, 1 N), 7.65 (d, 9-7.6 Hz, 1 H), 7.70 (d, 927.6 Hz, 1 H), 7.81 (d, 9-8.7 Hz, 2 H). (4) ethyl 3-((4-C2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoate

To the mixture of 4-HT2-ethyl-1-(33-methyl-1-benzothiophen-2-yl)butylamino)benzoic acid (250 mg), synthesized above, hydrochloride of the ethyl ester of β-alanine (157 mg), 1-hydroxybenzotriazole monohydrate (156 mg), triethylamine (284 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg) and the mixture was stirred at room temperature for 2.5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 70950 ethyl acetate/hexane) to give the title compound (330 mg, quantitative) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.86 - 0.97 (m, 6 N), 1.24 (t, 9-71 Hz, Z H), 1.33 - 1.55 (m,

With H), 1.67 - 1.83 (m, 2 H), 2.46 (s, With H), 2.54 - 2.60 (m, 2 H), 3.60 - 3.68 ( m, 2 H), 4.12 (k, 957.1

Hz, 2 N), 4.35 (d, 9-6.6 Hz, 1 N), 4.79 - 4.86 (m, 1 N), 6.50-661 (m, C H), 7 ,22-7.29(m, 1 N), 7.31 - 7.37 (m, 1 N), 7.52 (d, 958.5 Hz, 2 N), 7.61 - 7.66 ( m, 1 N), 7.66 - 7.71 (m, 1 N). (5)3-(I(4-C2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid

To the mixture of ethyl 3-S((4-(2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|iIaminosupropanoate (330 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and at 0 "С added 1M hydrochloric acid (2.00 mL).The resulting precipitate was collected by filtration to afford the title compound (272 mg, 9195) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.86 - 0.97 (m, 6 H), 1.32 - 1.56 (m, Z H), 1.66 - 1.83 (m, 2

H), 2.45 (s, C H), 2.60 (t, 95.5 Hz, 2 H), 3.57 - 3.66 (m, 2 H), 4.82 (d, 9- 6.0 Hz, 1 N), 6.47 - 6.58 (m, Z H), 7.22 - 7.29 (m, 1 N), 7.31 - 7.38 (m, 1 N) , 7.50 (d, 98.7 Hz, 2 N), 7.64 (d, 957.5

Gu, 1 N), 7.69 (d, 9-7.9 Hz, 1 N).

Example A135 3-4(4-(2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid

Sleep bachelor's degree, 9) M.Sc

M sn,

Кн сн, (1) ethyl 3-((4-T2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoate

To the mixture of 4-HT2-ethyl-1-(33-methyl-1-benzothiophen-2-yl)butylamino)benzoic acid (250 mg) synthesized in Example A134(3) oethyl 33-(methylamino)propanoate (134 ml) , 1-hydroxybenzotriazole monohydrate (156 mg), triethylamine (284 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (196 mg) was added, and the mixture was stirred at room temperature for 2 ,5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine and saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to give the title compound (253 mg, 7790) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.87 - 0.97 (m, 6 N), 1.22 (t, 97.1 Hz, Z H), 1.32 - 1.54 (m,

With H), 1.67 - 1.82 (m, 2 H), 2.45 (s, With H), 2.60 (t, 927.0 Hz, 2 H), 3.00 (s, With H), 3.69 (t, 927.0 Hz, 2 H), 4.10 (k, 957.1 Gu, 2 H), 4.23 (d, 9-6.3 Hz, 1 H), 4.76 - 4.83 (m, 1 N), 6.51 (d, 9-8.8 Hz, 2

H), 7.19 (d, 928.8 Hz, 2 H), 7.22 - 7.29 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.61 - 7.66 (m, 1 N), 7.68 - 7.72 (m, 1 N). (2)3-(I(4-C2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To the mixture of ethyl 3-S((4-(2-ethyl-1-(3-methyl-1-benzothiophen-2-yl)butyl|Iamino)phenyl)carbonyl|)(methyl)aminopropanoate (253 mg), synthesized above ,

of tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to afford the title compound (225 mg, 9595) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.84 - 0.99 (m, 6 H), 1.30 - 1.56 (m, Z H), 1.66 - 1.81 (m, 2

H), 2.45 (s, C H), 2.64 (t, 2-6.4 Hz, 2 H), 3.01 (s, C H), 3.68 (t, U-6, 4 Hz, 2 N), 4.80 (d, 9U-6.4 Gu, 1 N), 6.52 (d, 9-8.7 Hz, 2 N), 7.21 (d, 9-8 .7 Hz, 2 N), 7.23 - 7.30 (m, 1 N), 7.31 - 7.38 (m, 1 N), 7.64 (d, 9-7.9 Hz, 1 H), 7.71 (d, 9U-7.5 Hz, 1 H).

Example A136 3-1(4-Icyclohexyl(3-methylthieno(|2,3-c|Ipyridin-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid M sn,

M

- sn, (1) ethyl 3-methylthieno(2,3-c|Ipyridine-2-carboxylate

To a solution (120 ml) of 3-chloropyridine-4-carbonitrile (10.3 g) in tetrahydrofuran was added a 3.00 M solution (49.8 ml) of methylmagnesium chloride in tetrahydrofuran under a nitrogen atmosphere at 0 "C and the mixture was stirred at room temperature for 2 g. Water (50 mL) was added to the reaction mixture, then 1095 sulfuric acid (100 mL) was added to the reaction mixture and the mixture was stirred overnight. Sodium carbonate was added to acidify the solution to pH." 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 column chromatography on silica gel to give a colorless oil (6.10 g). To a mixture of the obtained oil (6.00 g), ethyl mercaptoacetate (11.6 mL) and anhydrous M,M-dimethylformamide (100 ml) at 5 °C for 30 min, sodium hydride (6095, in oil, 4.0 g) was added, and the mixture was stirred at 5 °C for 20 min, then at room temperature overnight. after quenching the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was poured into water. The solid precipitate was collected by filtration and recrystallized from petroleum ether/(ethyl acetate) to give the title compound (5.12 g, 3190) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 1.42 (t, U - 7.2 Hz, ZN), 2.76 (s, ZN), 4.41 (ku - 7.2 Hz, 2H), 7.69 (dd, U - 5.7 , 0.9 Hz, 1H), 8.57 (d, ) - 5.7 Hz, 1H), 9.14 (d, 2 - 0.6 Hz, 1H). (2)3-methylthieno(|2,3-s|Ipyridine-2-carbaldehyde

To a mixture of ethyl 3-methylthienoI2,3-c|Ipyridine-2-carboxylate (2.00 g) synthesized above, calcium chloride (2.01 g), ethanol (30 ml) and tetrahydrofuran (30 ml) at 0 "С sodium borohydride (1.37 g) was added and the mixture was stirred at room temperature for 3 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow solid. Active manganese dioxide (8.10 g) was added to a solution (40 ml) of the obtained solid in tetrahydrofuran and the mixture was stirred at 50 °C for 8 g. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure to obtain the target compound indicated in the title (1, 39 g, 87905), as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 2.81 (s, Z H), 7.75 (dd, 45.5, 1.1 Hz, 1 H), 8.61 (d, U-5.5

Hu, 1 N), 9.20 (d, 91.1 Hz, 1 N), 10.41 (s, 1 N). (Z)cyclohexyl(Z-methylthienoi|2,3-s|Ipyridin-2-yl)umethanone

To a solution (30 ml) of 3-methylthieno(2,3-c|pyridine-2-carbaldehyde (1.39 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (15.7 ml) of cyclohexyl magnesium bromide in tetrahydrofuran at 0" C and the mixture was stirred for 1.5 g. Saturated aqueous ammonium chloride solution was added to quench the reaction, tetrahydrofuran was evaporated on the evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. (30 - 70905 ethyl acetate/hexane) to give a pale yellow solid. To a mixture of the obtained solid, 4-methylmorpholine M-oxide (680 mg) and acetonitrile (20 ml) was added tetrapropylammonium perruthenate (113 mg), the mixture was stirred at room temperature concentrated under reduced pressure for 1 h The residue was purified by silica gel column chromatography (0 - 4095 ethyl acetate/hexane) to give the title compound (628 mg, 3195) as colorless oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.22 - 1.62 (m, 5 N), 1.70 - 1.81 (m, 1 N), 1.82 - 1.94 (m, 2

H), 1.95 - 2.06 (m, 2 H), 2.73 (s, C H), 2.97 - 3.09 (m, 1 H), 7.71 (dd, 9U-5 .5, 1.1 Hz, 1 N), 8.58 (d, 9U-5.5 Hz, 1 N), 9.16 (d, 9-1.1 Hz, 1 N). (4)4-Hycyclohexyl(3-methylthieno(2,3-c|Ipyridin-2-yl)umethyl|Iaminophenzoic acid

To the mixture of cyclohexyl(3-methylthieno(2,3-Cs|Ipyridin-2-yl)methanone (628 mg), synthesized above, methyl 4-aminobenzoate (402 mg), triethylamine (2.70 ml) and methylene chloride (10 ml ) titanium chloride (IM) (318 μL) was added and the mixture was stirred under an argon atmosphere overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated at under reduced pressure to give a dark brown oil. To a solution (30 mL) of the obtained oil in tetrahydrofuran was added acetic acid (277 μL) and sodium cyanoborohydride (304 mg), and the mixture was stirred at room temperature for 2 h. To quench the reaction, a saturated aqueous solution of hydrogen carbonate was added sodium, the organic solvent was evaporated and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. the residue was purified by column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give an orange solid. A 1M aqueous solution of sodium hydroxide (5.00 ml) was added to a mixture of the obtained solid, tetrahydrofuran (5 ml) and ethanol (5 ml) and the mixture was stirred under reflux for 4 h. 1M hydrochloric acid (5 .00 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40 - 10095 ethyl acetate/hexane) to give the title compound (202 mg, 2290) as a yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.34 (m, 5 N), 1.40 - 1.93 (m, 5 N), 2.01 - 2.16 (m, 1

H), 2.50 (s, C H), 4.58 - 4.69 (m, 2 H), 6.51 (d, 2-8.8 Hz, 2 H), 7.52 (dd, U-5.6, 0.9 Hz, 1 N), 7.82 (d, U-8.8 Gu, 2 N), 8.49 (d, 2-5.6 Hz, 1 N), 8 .95 (d, 2-0.9 Hz, 1 N). (5) ethyl 3--(4-Tcyclohexyl(3-methylthienoi|2,3-c|Ipyridin-2-yl)methylIamino)phenyl)carbonylI|(methyl)amino)propanoate

To the mixture of 4-Ycyclohexyl(3-methylthieno|2,3-c|Ipyridin-2-yl)umethylamino)benzoic acid (202 mg) synthesized above, ethyl 3-(methylamino)propanoate (104 mg), 1-hydroxybenzotriazole monohydrate (122 mg), triethylamine (222 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (152 mg) and the mixture was stirred at room temperature for 1 day. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 10095 ethyl acetate/hexane, then 0 - 1095 methanol/acetic acid) to give the title compound (151 mg, 58905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.06 - 1.36 (m, 8 N), 1.53 - 1.88 (m, 5 N), 2.03 - 2.16 (m, 1

H), 2.48 (s, C H), 2.60 (t, U-7.0 Hz, 2 H), 2.99 (s, C H), 3.69 (t, 9U-7, 0 Hz, 2 H), 4.10 (k, 9-71 Gu, 2 H), 4.35 (d, 9-5.7 Hz, 1 H), 4.58 (dd, 9-7.3 , 5.7 Hz, 1 N), 6.49 (d, 2-8.7 Hz, 2 N), 7.19 (d,

U-8.7 Hz, 2 N), 7.51 (dd, 9U-5.7, 1.1 Gu, 1 N), 8.48 (d, 2-5.7 Hz, 1 N), 8 .95 (d, 9-1.1 Gu, 1 H).

(6)3--I(4-YTcyclohexyl(3-methylthieno(|2,3-c|Ipyridin-2-yl)umethylamino)phenyl)carbonylI(methyl)amino)propanoic acid

To the mixture of ethyl 3--(4-Tcyclohexyl(3-methylthienoi|2,3-c|Ipyridin-2-yl)umethylamino)phenyl)carbonylI(methyl)aminoisopropanoate (151 mg), synthesized above, tetrahydrofuran (5 ml) and of ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 5 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (80.2 mg, 5695) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.34 (m, 5 N), 1.50 - 1.62 (m, 1 N), 1.63 - 1.88 (m, 4

Н), 2.02 - 2.14 (m, 1 Н), 2.48 (s, З Н), 2.53 - 2.68 (m, 2 Н), 3.00 (s, З Н) , 3.58 - 3.74 (m, 2 N), 4.57 (d, 97.5 Hz, 1 N), 6.47 (d, 9-8.5 Hz, 2 N), 7.19 (d, 2-8.5 Gu, 2 N), 7.55 (d, 9U-5.7 Hz, 1 N), 8.43 (d, 9-5.7 Hz, 1 N), 8, 94 (p. 1 H).

Example A137 3-1(4-Icyclohexyl(3-methylthieno(|2,3-c|Ipyridin-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid

N i m -sch Sn. (1) ethyl 3-(4-Tcyclohexyl(3-methylthienoi|2,3-c|Ipyridin-2-yl)umethylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-cyclohexyl(3-methylthieno|2,3-c|Ipyridin-2-yl)umethylamino)benzoic acid (201 mg), synthesized in Example A136(4), p-alanine ethyl ester hydrochloride (122 mg), 1-hydroxybenzotriazole monohydrate (121 mg), triethylamine (220 μl) and

1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (152 mg) was added to M,M-dimethylformamide (10 ml) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (60 - 10095 ethyl acetate/hexane) to give the title compound (209 mg, 83905) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.06 - 1.37 (m, 8 N), 1.53 - 1.89 (m, 5 N), 2.05 - 2.16 (m, 1

H), 2.48 (s, C H), 2.56 (t, 95.8 Gu, 2 H), 3.59 - 3.68 (m, 2 H), 4.12 (k, 97, 1 Hz, 2 N), 4.50 (d, uU-5.8 Hz, 1 N), 4.58 - 4.64 (m, 1 N), 6.50 (d, 2-8.8 Hz , 2 H), 6.61 (t, 9U-5.9 Hz, 1 H), 7.51 (dd, 95.5, 1.1 Hz, 1 H), 7.52 (d, U-8 .8 Hz, 2 N), 8.47 (d, 9U-5.5 Hz, 1 N), 8.93 (d, 9-1.1 Hz, 1 N). (2)3--(4-Ycyclohexyl(3-methylthieno(|2,3-c|Ipyridin-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3--(4-Tcyclohexyl(3-methylthienoi|2,3-c|Ipyridin-2-yl)umethyliamino)phenyl)carbonyl|Iamino)upropanoate (209 mg), synthesized above, tetrahydrofuran (5 ml) and of ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (169 mg, 8695) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 1.04 - 1.36 (m, 5 N), 1.49 - 1.89 (m, 5 N), 2.02 - 2.14 (m, 1

H), 2.48 (s, C H), 2.59 (t, 95.7 Hz, 2 H), 3.51 - 3.77 (m, 2 H), 4.59 (d, 9- 7.2 Gu, 1 N), 6.47 (d, uU-8.7 Hz, 2 N), 6.85 (t, 2-5.8 Hz, 1 N), 7.48 - 7.60 (m, C H), 8.42 (d, 9-5.7 Hz, 1 H), 8.88 (s, 1

N).

Example A138 3-1(4-Icyclohexyl(3-methylthienoyl3,2-c|Ipyridin-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid

N

M

In n

M- sn, (1) ethyl Z-methylthieno|3,2-s|Ipyridine-2-carboxylate

Thionyl chloride (100 mL) was added to 4-chloronicotinic acid (22.4 g) and the mixture was stirred under reflux for 4 g and concentrated under reduced pressure. M,O-dimethylhydroxylamine hydrochloride (13.8 g) and triethylamine (60 ml) were added to a solution (300 ml) of the residue in methylene chloride, and the mixture was stirred at room temperature for 5 h. Water was added to the reaction mixture and the reaction mixture was extracted with methylene chloride. The extract was dried over sodium sulfate and concentrated under reduced pressure. To a solution (300 ml) of the residue in tetrahydrofuran was added a 3.00 M solution (54 ml) of methylmagnesium chloride in ether at -78"C and the mixture was stirred in a nitrogen atmosphere at room temperature for 10 g. The reaction mixture was acidified with an aqueous solution of sodium carbonate to pH Н- C and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated under reduced pressure to give a colorless oil. To a mixture of the obtained oil, ethyl mercaptoacetate (21 ml) and anhydrous MM-dimethylformamide (200 ml) was added sodium hydride (6095, in oil, 7 ,34 g) at 5 "C for 30 min and the mixture was stirred at 5 "C for 20 min and then at room temperature for 18 g. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate (4 concentrated at The resulting solid was recrystallized from petroleum ether/(ethyl acetate) to give the title compound (5.45 g, 1795) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.43 (t, U - 7.2 Hz, ZN), 2.85 (s, ZN), 4.42 (Kk, - 7.2 Gu, 2H), 7.74 (dd, U - 5, 7, 0.9 Hz, 1H), 8.55 (d, 9 -6.0 Hz, 1H), 9.14 (d, 2) - 1.2 Hz, 1H). (2)3-methylthieno|C3,2-c|Ipyridine-2-carbaldehyde

Borohydride was added to a mixture of ethyl 3-methylthieno|3,2-c|pyridine-2-carboxylate (3.40 g) synthesized above, calcium chloride (3.42 g), ethanol (30 ml) and tetrahydrofuran (30 ml) sodium (2.33 g) at 0 "С, and the mixture was stirred at room temperature for 3 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow oil.

Active manganese dioxide (14.4 g) was added to a solution (60 ml) of the obtained oil in tetrahydrofuran and the mixture was stirred at 50 C overnight. Manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (1.54 g, 56905) as a pale brown solid.

IN NMR (300 MHz, SOS") b m.h. 2.89 (s, Z H), 7.79 (dd, -5.5, 0.8 Hz, 1 H), 8.58 (d, .)-5.5

Hz, 1 N), 9.21 (d, 9U-0.8 Hz, 1 N), 10.35 (s, 1 N). (Z)cyclohexyl(Z-methylthienoyl3,2-c|pyridin-2-yl)umethanone

A 1.0M solution (21.2 ml) of cyclohexylmagnesium bromide in tetrahydrofuran was added to a solution (40 ml) of 3-methylthienoyl3,2-c|pyridine-2-carbaldehyde (1.87 g) synthesized above in tetrahydrofuran at 0 "С and the mixture was stirred for 1 h. Another 1.0 M solution (10.0 ml) of cyclohexylmagnesium bromide in tetrahydrofuran was added and the mixture was further stirred at 0 C for 1 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine,

dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 9095 ethyl acetate/hexane) to give a pale yellow solid. Tetrapropylammonium perruthenate (164 mg) was added to a mixture of the obtained solid, 4-methylmorpholine M-oxide (1.24 mg) and acetonitrile (30 ml), and the mixture was stirred at room temperature for 4 g and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 - 5095 ethyl acetate/hexane) to give the title compound (864 mg, 31905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.19 - 1.61 (m, 5 N), 1.69 - 1.80 (m, 1 N), 1.81 - 1.92 (m, 2

H), 1.93 - 2.04 (m, 2 H), 2.82 (s, C H), 2.93 - 3.05 (m, 1 H), 7.75 (dd, 9-5 .7, 1.0 Hz, 1 N), 8.55 (d, 95.7 Hz, 1 N), 9.17 (d, 9-1.0 Hz, 1 N). (4)4-Icyclohexyl(3-methylthieno|3,2-c|Ipyridin-2-yl)umethyl|Iaminophenzoic acid

To the mixture of cyclohexyl(3-methylthienoi3,2-c|pyridin-2-yl)methanone (864 mg) synthesized above, methyl 4-aminobenzoate (553 mg), triethylamine (3.71 ml) and methylene chloride (20 ml) at At 0"C, titanium chloride (IM) (439 μl) was added and the mixture was stirred under an argon atmosphere overnight at room temperature. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and was concentrated under reduced pressure to obtain a dark brown oil. To a solution (20 ml) of the obtained oil in tetrahydrofuran was added acetic acid (268 μl) and sodium cyanoborohydride (419 mg) and the mixture was stirred at room temperature, stirred 1.5 g. To quench the reaction was added saturated aqueous sodium bicarbonate solution, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 70905 ethyl acetate/hexane) to give a pale brown solid. To a mixture of the resulting solid, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1M aqueous sodium hydroxide solution (5.00 mL) and the mixture was stirred overnight under reflux.

Tetrahydrofuran (5 ml), ethanol (5 ml) and 1 M aqueous sodium hydroxide solution (5.00 ml) were added, the mixture was stirred under reflux for 2.5 g and ethylenediamine (1.00 ml) was added. The mixture was stirred under reflux for 4 g and concentrated under reduced pressure. The residue was acidified with 1M hydrochloric acid to pH 4 and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 - 10095 ethyl acetate/hexane) to give the title compound (432 mg, 34905) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.37 (m, 5 N), 1.53 - 1.90 (m, 5 N), 2.03 - 2.15 (m, 1

H), 2.56 (s, C H), 4.55 - 4.66 (m, 2 H), 6.51 (d, 92-8.7 Hz, 2 H), 7.63 (dd, 9U-5.5, 1.1 Hz, 1 N), 7.84 (d, U-8.7 Gu, 2 N), 8.39 (d, 9-5.5 Hz, 1 N), 8 .97 (d, 9-1.1 Hz, 1 N). (5) ethyl 3-(4-Tcyclohexyl(3-methylthienoyl3,2-c|pyridin-2-yl)methylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-Hcyclohexyl(3-methylthienoyl3,2-c|Ipyridin-2-yl)methyl|amino)benzoic acid (211 mg), synthesized above, p-alanine ethyl ester hydrochloride (128 mg), 1-hydroxybenzotriazole monohydrate ( 128 mg), triethylamine (233 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (160 mg) was added and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 - 10095 ethyl acetate/hexane) to give the title compound (214 mg, 8095) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.05 - 1.37 (m, 8 N), 1.53 - 1.91 (m, 5 N), 2.04 - 2.16 (m, 1

H), 2.50 - 2.63 (m, 5 H), 3.58 - 3.70 (m, 2 H), 4.12 (k, 9-7.1 Hz, 2 H), 4, 42 (d, 2-5.8 Hz, 1 N), 4.52 - 4.62 (m, 1 N), 6.51 (d, 2-8.7 Hz, 2 N), 6.59 ( t, 9-5.8 Hz, 1 N), 7.52 (d, 9-8.7/ Hz, 2 N),

7.60 (d, 9U-5.5 Hz, 1 N), 8.37 (d, 9U-5.5 Hz, 1 N), 8.93 (s, 1 N). (6) 3--I(4-YTcyclohexyl(3-methylthienoyl3,2-c|Ipyridin-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3--(4-Tcyclohexyl(3-methylthienoyl3,2-c|pyridin-2-yl)methyliamino)phenyl)carbonyl|Iamino)propanoate (186 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (186 mg, 9395) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 1.05 - 1.36 (m, 5 N), 1.55 - 1.64 (m, 1 N), 1.65 - 1.90 (m, 4

H), 2.03 - 2.15 (m, 1 H), 2.56 (s, C H), 2.61 (t, 2-51 Hz, 2 H), 3.52 - 3.67 ( m, 1 H), 3.73 - 3.89 (m, 1 H), 4.56 (d, 9U-7.2 Hz, 1 H), 6.48 (d, 2-8.7 Gu, 2 N), 6.89 - 6.99 (m, 1 N), 7.58 (d, 9U-8.7 Hz, 2 N), 7.69 (d, 9-5.7 Hz, 1 N ), 8.31 (d, 2-5.7 Hz, 1 N), 8.96 (s, 1 N).

Example A139:

M SN.

AK nn h- CH, (1) ethyl 3-(4-Tcyclohexyl(3-methylthienoyl3,2-c|pyridin-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoate

To the mixture of 4-cyclohexyl(3-methylthienoyl3,2-c|pyridin-2-yl)methylamino)benzoic acid (209 mg), synthesized in Example A138(4), ethyl 33-(methylamino)propanoate (108 mg), monohydrate 1-Hydroxybenzotriazole (126 mg), triethylamine (229 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (158 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 - 10095 ethyl acetate/hexane, then 0 - 1095 methanol/ethyl acetate) to give the title compound (180 mg, 6690) as a colorless oil. "H NMR (300 MHz, SOSIz) 6 m.h. 1.04 - 1.38 (m, 8 N), 1.52 - 1.94 (m, 5 N), 2.02 - 2.16 ( m, 1

H), 2.55 (s, C H), 2.60 (t, U-6.9 Hz, 2 H), 2.99 (s, C H), 3.69 (t, 9U-6, 9 Hz, 2 N), 4.10 (k, 92-68 Hz, 2 N), 4.27 - 4.39 (m, 1 N), 4.49 - 4.59 (m, 1 N), 6.49 (d, 2-8.5 Hz, 2 N), 7.19 (d, 9U-8.5 Hz, 2 N), 7.62 (d, 9U-5.5 Hz, 1 N) , 8.38 (d, 9U-5.5 Hz, 1 N), 8.93 (s, 1 N). (2)3--(4-Cyclohexyl(3-methylthienoyl),2-c|pyridin-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To a mixture of ethyl 3-(4-Tcyclohexyl(3-methylthienoyl3,2-c|pyridin-2-yl)methylamino)phenyl)carbonyl(methyl)aminoisopropanoate (180 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (1.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (1.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (136 mg, 8095) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 1.03 - 1.32 (m, 5 N), 1.52 - 1.63 (m, 1 N), 1.63 - 1.89 (m, 4

H), 2.03 - 2.15 (m, 1 H), 2.53 (s, C H), 2.58 - 2.74 (m, 2 H), 3.03 (s, C H) , 3.62 - 3.79 (m, 2 N),

4.54 (d, 9-7.5 Hz, 1 N), 6.48 (d, 9-8.7 Hz, 2 N), 7.22 (d, 2-8.7 Hz, 2 N) , 7.67 (d, 9U-5.5 Hz, 1 N), 8.34 (d, 2-5.5 Hz, 1 N), 8.93 (c, 1 N).

Example A140 3-1(4-(11-(5-chloro-1-methyl-1H-indol-2-yl)heptylamino)phenyl)carbonyl|amino)propanoic acid sn.

Oh, you fool

N ov s M. sn. (1)1-(5-chloro-1-methyl-1H-indol-g-yl)heptan-1-one

To a solution (10 ml) of 1-(5-chloro-1H-indol-2-yl)heptan-i-one (1.00 g) synthesized in

Sodium hydride (6095, in oil, 182 mg) was added to Example A106(2) in M,M-dimethylformamide at 0 C and the mixture was stirred under an argon atmosphere for 30 min. After stirring, methyl iodide (354 μL) was added. The reaction mixture was stirred at room temperature overnight, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (367 mg, 3595) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.85 - 0.94 (m, Z H), 1.24 - 1.46 (m, 6 H), 1.68 - 1.81 (m, 2

H), 2.90 - 2.98 (m, 2 H), 4.05 (s, C H), 7.19 (s, 1 H), 7.28 - 7.31 (m, 2 H) , 7.63 - 7.66 (m, 1 N). (2) methyl 4-C11-(5-chloro-1-methyl-1H-indol-2-yl)heptylaminophenzoate

To the mixture of 1-(5-chloro-1-methyl-1H-indol-2-yl)heptan-1-one (1.05 g) synthesized above, methyl 4-aminobenzoate (629 mg), triethylamine (4.21 ml) and methylene chloride (10 ml) was added to a 1.0M solution (4.54 ml) of titanium chloride (IM) in methylene chloride at 0 "C, and the mixture was stirred overnight at room temperature in an argon atmosphere. To quench the reaction, a saturated aqueous solution of hydrogen carbonate was added of sodium and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a solution (10 mL) of the obtained solid in tetrahydrofuran was added acetic acid (1.08 mL) and cyanoborohydride of sodium (475 mg) and the mixture was stirred at room temperature for 1 h. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated at reduced temperature lawsuit The residue was purified by silica gel column chromatography (0 - 30 O ethyl acetate/hexane) to give the title compound (1.15 g, 74905) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.83 - 0.91 (m, Z H), 1.21 - 1.53 (m, 8 H), 1.88 - 2.08 (m, 2

Н), 3.68 (s, З Н), 3.83 (s, З Н), 4.25 (d, 927.1 Gu, 1 Н), 4.60 - 4.70 (m, 1 Н ), 6.37 (s, 1 N), 6.55 (d, -8.8 Hz, 2 N), 7.13 (dd, 9U-8.7, 1.9 Hz, 1 N), 7 .19 (d, 9-8.7 Hz, 1 N), 7.49 (d, 2-1.9 Gu, 1 N), 7.83 (d, U-8.8 Hz, 2 N). (3)4-(11-(5-chloro-1-methyl-1H-indol-2-yl)/heptylaminophenzoic acid

1M was added to the mixture of methyl 4-11-(5-chloro-1-methyl-1H-indol-2-yl)heptyl|Iaminobbenzoate (1.15 g) synthesized above, tetrahydrofuran (15 ml) and ethanol (15 ml) aqueous sodium hydroxide solution (15 ml), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (30 mL) and 1M hydrochloric acid (15 mL) was added at 0°C. The resulting precipitate was collected by filtration to give the title compound (1.09 g, 9895) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 0.86 (t, 9U-6.5 Hz, Z H), 1.11 - 1.51 (m, 8 H), 1.79 - 2.04 (m, 2 H), 3.58 (s , Z H), 4.49 - 4.63 (m, 1 H), 6.31 (s, 1 H), 6.42 (d, 9-8.3 Hz, 2 H), 7.05 - 7.17 (m, 2

H), 7.46 (s, 1 H), 7.80 (d, 90-8.3 Hz, 2 H). (4) ethyl 3-(SHA-11-(5-chloro-1-methyl-1H-indol-2-yl)ugeptylamino)phenyl)carbonyl|iamino)propanoate

To the mixture of 4-X11-(5-chloro-1-methyl-1H-indol-2-yl)heptylaminobenzoic acid (300 mg), synthesized above, hydrochloride of ethyl ester of B-alanine (174 mg), 1-hydroxybenzotriazole monohydrate (173 mg), triethylamine (158 μl) and N,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70905 ethyl acetate/hexane) to give the title compound (349 mg, 93965) as a pale yellow oil. "H NMR (300 MHz, SOSI") b m.ch. 0.88 (t, U-6.9 Hz, Z H), 1.18 - 1.55 (m, 11 H), 1.87 - 2.10 (m, 2 N), 2.60 (t, 9-5.8 Hz, 2 N), 3.61 - 3.76 (m, 5 N), 4.06 - 4.23 (m , Z H), 4.57 - 4.69 (m, 1 H), 6.37 (s, 1 H), 6.57 (d, 9-8.5 Hz, 2 H), 6.64 ( t, 92-5.8 Hz, 1 N), 7.11 - 7.16 (m, 1 N), 7.17 - 7.23 (m, 1 N), 7.50 (d, 2-1 .6 Hz, 1 H), 7.59 (d, U-8.5 Hz, 2 H). (5)3-44-111-(5-chloro-1-methyl-1 H-indole-2- yl)heptylamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-((4-11-(5-chloro-1-methyl-1H-indol-2-yl)uheptylamino)phenyl)carbonylaminoisopropanoate (349 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 3 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (302 mg, 9295) as a pale brown solid.

IN NMR (300 MHz, SOSI") b m.h. 0.86 (t, 9U-6.4 Hz, Z H), 1.17 - 1.55 (m, 8 H), 1.84 - 2.05 (m, 2 H), 2.62 (t , 9U-5.7 Hz, 2 N), 3.58 - 3.72 (m, 5 N), 4.60 (t, U-6.8 Hz, 1 N), 6.33 (s, 1 H), 6.52 (d,

U8.7 Hu, 2 H), 6.69 (t, U-5.8 Hz, 1 H), 7.12 (dd, 9U-9.0, 2.1 Hu, 1 H), 7.17 (d, 9U-9.0 Gu, 1 N), 7.47 (d, 9-21 Hz, 1 N), 7.55 (d, U-8.7 Hz, 2 N).

Example A141 3-4(4-11-(5-chloro-1-methyl-1H-indol-2-yl)heptylamino)phenyl)carbonyl|)methyl)amino)propanoic acid

Sn, Fr

Kt w- M sn,

SI M, sn, (1) ethyl 3-(SHA-11-(5-chloro-1-methyl-1H-indol-2-yl)ugeptylamino)phenyl)carbonyl)/methyl)amino)propanoate

To the mixture of 4-X11-(5-chloro-1-methyl-1H-indol-2-yl)heptylaminobenzoic acid (300 mg), synthesized in Example A140(3), ethyl 3-(methylamino)propanoate (148 mg), 1-hydroxybenzotriazole monohydrate (173 mg), triethylamine (158 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (217 mg) and the mixture was stirred overnight at room temperature . A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate.

The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70905 ethyl acetate/hexane) to give the title compound (235 mg, 61905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.87 (t, U-6.6 Hz, Z H), 1.17 - 1.53 (m, 11 H), 1.89 - 2.06 (m, 2 H), 2.63 (t , 9-6.7 Hz, 2 N), 3.04 (s, C H), 3.65 - 3.79 (m, 5 N), 4.02 (d, 957.1 Hz, 1 N) , 4.12 (Kk, uU7.1 Hz, 2 N), 4.54 - 4.65 (m, 1 N), 6.37 (s, 1 N), 6.55 (d, 9U-8, 4 Hz, 2 H), 7.13 (dd, 9-88, 1.68 Hu, 1 H), 7.20 (d, 98.8 Hu, 1 H), 7.25 (d, 9-84 Hz, 2 N), 7.50 (d, 9-1.8 Gu, 1 N). (2)3-(4-11-(5-chloro-1-methyl-1H-indol-2-yl)heptylamino)phenyl)carbonyl|)methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-11-(5-chloro-1-methyl-1H-indol-2-yl)ugeptylamino)phenyl)carbonyl/methyl)aminoisopropanoate (235 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (211 mg, 9595) as a pale yellow solid. NMR (300 MHz, SOSI") b m.ch. 0.87 (t, U-6.8 Hz, Z H), 1.16 - 1.54 (m, 8 H), 1.84 - 2.05 (m, 2 H), 2.63 (t , 95.8 Hz, 2 N), 3.02 (s, Z H), 3.62 - 3.76 (m, 5 N), 4.59 (t, 9U-6.8 Hz, 1 N) , 6.35 (s, 1 N), 6.53 (d, 9-8.5 Hz, 2 N), 7.12 (dd, 9U-8.7, 1.9 Hz, 1 N), 7 .19 (d, 9-8.7 Hz, 1 N), 7.24 (d, uU-8.5 Hz, 2 N), 7.49 (d, 2-1.9 Hz, 1 N).

Example A142 3-1(4-cyclohexyl(3-methylthieno(|2,3-b|pyridin-2-yl)methylamino)phenyl)carbonylamino)propanoic acid in

Dx - sn, (1) ethyl 3-methylthieno|(2,3-b|Ipyridine-2-carboxylate

To a solution (300 ml) of 2-chloropyridine-3-carbonitrile (15.0 g) in tetrahydrofuran was added a 3.0 M solution (72.5 ml) of methylmagnesium chloride in tetrahydrofuran at -78 C and the mixture was stirred at room temperature for 10 g in an atmosphere nitrogen Water (50 mL) was added to the reaction mixture and then 1095 sulfuric acid (100 mL) was added and the mixture was stirred overnight. Sodium carbonate was added to acidify the reaction mixture to pH. and the mixture was extracted with ethyl acetate. The extract was dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to obtain a colorless oil (7.68 g). To a mixture of the obtained oil (7.00 g), ethyl mercaptoacetate (13 ml) and anhydrous M,M-dimethylformamide (200 ml) was added sodium hydride (6095, in oil, 4.68 g) at 5"C for 30 min and the mixture was stirred at 57 for 20 min then at room temperature for 18 h. Saturated aqueous sodium bicarbonate solution was added to quench the reaction and the mixture was poured into water. The solid precipitate was collected by filtration and recrystallized from petroleum ether/ethyl acetate to give the title compound (6, 14 g, 29905), as a white solid.

IN NMR (400 MHz, SOSI") 6 m.h. 1.45 (t, ) - 7.2 Hz, ЗН), 2.78 (s, ЗН), 4.43 (k, 9 - 7.2 Hz, 2Н), 7.38-7.40 (m , 1H), 8.11-8.13 (m, 1H), 8.70-8.72 (m, 1H). (2)3-methylthieno(|2,3-B|pyridine-2-carbaldehyde

Borohydride was added to a mixture of ethyl 3-methylthieno(2,3-b|pyridine-2-carboxylate (3.00 g) synthesized above, calcium chloride (3.02 g), ethanol (50 ml) and tetrahydrofuran (50 ml) of sodium (2.06 g) at 0 "С and the mixture was stirred at room temperature for 4 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. Active manganese dioxide (12.5 g) was added to a solution (50 ml) of the obtained solid in tetrahydrofuran, and the mixture was stirred at 50 °C overnight. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The residue was washed with isopropyl ether to give the title compound compound (2.07 g, 8695) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 2.79 (s, C H), 7.39 (dd, U-8.2, 4.5 Hz, 1 H), 8.16 (dd, 98.2, 1.6 Hu, 1 H), 8.72 (dd, U-4.5, 1.6 Hz, 1 N), 10.36 (s, 1 N). (Z)cyclohexyl(Z-methylthienoy2,3-b|Ipyridin-2-yl)umethanone

To a solution (60 ml) of 3-methylthieno(2,3-b|Ipyridine-2-carbaldehyde (2.07 g) synthesized above in tetrahydrofuran was added a 1.0 M solution (17.6 ml) of cyclohexyl magnesium bromide in tetrahydrofuran at 0" C and the mixture was stirred for 1 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 - 5095 ethyl acetate/ hexane) to give a yellow solid. To a mixture of the obtained solid, 4-methylmorpholine M-oxide (1.81 g) and acetonitrile (40 ml) was added tetrapropylammonium perruthenate (238 mg), the mixture was stirred at room temperature for 3 h and concentrated at The residue was purified by silica gel column chromatography (0-3095 ethyl acetate/hexane) to give the title compound (1.50 g, 8595) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.18 - 1.62 (m, 5 N), 1.69 - 1.80 (m, 1 N), 1.81 - 1.91 (m, 2

H), 1.95 - 2.06 (m, 2 H), 2.73 (s, C H), 2.95 - 3.07 (m, 1 H), 7.37 (m, U-8 ,2, 4.4 Hz, 1 N), 8.13 (dd, 98.2, 1.6 Hz, 1 N), 8.70 (dd, 9-44, 1.6 Gu, 1 N). (4) methyl 4-Icyclohexyl(3-methylthieno|2,3-B|Ipyridin-2-yl)umethylIaminophenbenzoate

To the mixture of cyclohexyl(3-methylthieno(2,3-B|pyridin-2-yl)methanone (1.00 g) synthesized above, methyl 4-aminobenzoate (642 mg), triethylamine (4.31 ml) and methylene chloride ( 20 ml) was added titanium chloride (IM) (508 μl) at 0"C and the mixture was stirred at room temperature for 1.5 days in an argon atmosphere. To quench the reaction, a saturated aqueous solution of sodium bicarbonate was added and the reaction mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown solid. Acetic acid (442 μl) and sodium cyanoborohydride (485 mg) were added to a solution (20 ml) of the obtained solid in tetrahydrofuran, and the mixture was stirred at room temperature for 1.5 g. To quench the reaction, a saturated aqueous sodium bicarbonate solution was added and the reaction mixture was extracted ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to give the title compound (975 mg, 64905) as a pale brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.35 (m, 5 N), 1.48 - 1.96 (m, 5 N), 2.02 - 2.19 (m, 1

H), 2.55 (s, C H), 3.81 (s, C H), 4.54 - 4.70 (m, 2 H), 6.51 (d, 9-8.8 Hz, 2 H), 7.59 (dd, 957.6, 5.7

Hz, 1 N), 7.78 (d, 9U-8.8 Hz, 2 N), 8.22 (d, 2-7.6 Hz, 1 N), 8.63 (d, 2-5, 7 Hz, 1 N). (5) 4-Hycyclohexyl(3-methylthieno(2,3-B|Ipyridin-2-yl)umethylamino)benzoic acid

A 1M aqueous solution of sodium hydroxide ( 10 mL), the mixture was stirred overnight under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 mL), 1 M hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to afford the title compound (701 mg, 7595) as a pale yellow solid. "H NMR (300 MHz, SOCI") 6 m.h. 1.01 - 1.39 (m, 5 N), 1.53 - 1.92 (m, 5 N), 2.07 - 2.20 (m, 1

H), 2.46 (s, C H), 4.60 (d, 9U-8.0 Hz, 1 H), 6.53 (d, 9U-8.5 Hz, 2 H), 7.21 - 7.31 (m, 1 N), 7.82 (d, uU-8.5 Hz, 2 N), 7.87 (dd, 9U-8.1, 1.3 Gu, 1 N), 8 ,47 (dd, U-4.4, 1.3 Hz, 1 N).

(6) ethyl 3-((4-Ycyclohexyl(3-methylthieno|2,3-B|pyridin-2-yl)umethylamino)phenyl)carbonylamino)propanoate

To the mixture of 4-Ycyclohexyl(3-methylthieno|2,3-B|Ipyridin-2-yl)umethyliaminophbenzoic acid (300 mg), synthesized above, p-alanine ethyl ester hydrochloride (181 mg), 1-hydroxybenzotriazole monohydrate (181 mg ), triethylamine (329 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 10095 ethyl acetate/hexane) to give the title compound (335 mg, 8995) as a pale yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.02 - 1.38 (m, 8 N), 1.54 - 1.90 (m, 5 N), 2.08 - 2.21 (m, 1

H), 2.45 (s, C H), 2.56 (t, 955.9 Gu, 2 H), 3.59 - 3.69 (m, 2 H), 4.12 (k, 957, 1 Hz, 2 H), 4.40 (d, 9UEb, Z Gu, 1 H), 4.53 - 4.61 (m, 1 H), 6.48 - 6.64 (m, Z H), 7.21 - 7.30 (m, 1 N), 7.52 (d, 9U-8.5 Hz, 2 N), 7.86 (dd, 9U-8.1, 1.5 Hz, 1 N ), 8.45 (dd, 9U-4.5, 1.5 Hz, 1 N). (7)3--(4-Ycyclohexyl(3-methylthieno|2,3-B|pyridin-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-((4-YTcyclohexyl(3-methylthieno(2,3-b|pyridin-2-yl)umethylamino)phenyl)carbonyl|Iamino)upropanoate (335 mg), synthesized above, tetrahydrofuran (5 ml) and of ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (281 mg, 8995) as a white solid. H NMR ( 300 MHz, SOSI") 6 m.h. 1.00 - 1.34 (m, 5 N), 1.51 - 1.87 (m, 5 N), 2.06 - 2.19 (m, 1

H)U, 2.44 (s, C H), 2.52 - 2.64 (m, 2 H), 3.53 - 3.68 (m, 2 H), 4.55 (d, 9- 8.0 Hz, 1 N), 6.49 (d,

U-8.7 Hz, 2 N), 6.71 (t, U-5.3 Hz, 1 N), 7.23 - 7.31 (m, 1 N), 7.49 (d, 2- 8.7 Hz, 2 N), 7.88 (dd,

U-8.0, 1.1 HZ, 1 N), 8.45 (dd, 9-45, 1.1 Gu, 1 N).

Example A143 3-1(4-cyclohexyl(3-methylthieno(|2,3-b|pyridin-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid in 5 M CH,

Di | H - CH, (1) ethyl 3-((4-Ycyclohexyl(3-methylthieno|2,3-B|pyridin-2-yl)umethylamino)phenyl)carbonyl| methyl)aminopropansoate

To the mixture of 4-Ycyclohexyl(3-methylthieno|2,3-B|Ipyridin-2-yl)umethyliaminofbenzoic acid (300 mg), synthesized in Example A142(5), ethyl 3-(methylamino)propanoate (155 mg), monohydrate 1-Hydroxybenzotriazole (181 mg), triethylamine (329 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40 - 10095 ethyl acetate/hexane) to give the title compound (333 mg, 85905) as a pale yellow oil.

"H NMR (300 MHz, SOSI") 6 m.h. 1.00 - 1.37 (m, 8 N), 1.52 - 1.89 (m, 5 N), 2.07 - 2.21 (m, 1

H), 2.45 (s, C H), 2.60 (t, 9U-6.8 Hz, 2 H), 2.99 (s, C H), 3.69 (t, 9U-6, 8 Hz, 2 N), 4.02 - 4.17 (m, 2

H), 4.32 (d, 2-5.8 Hz, 1 H), 4.49 - 4.58 (m, 1 H), 6.52 (d, 92-8.5 Hz, 2 H) , 7.19 (d, U-8.5 Hz, 2 N), 7.22 - 7.31 (m, 1 N), 7.86 (dd, 9U-8.0, 1.1 Gu, 1 N), 8.43 - 8.50 (m, 1 N). (2)3--(4-Ycyclohexyl(3-methylthienoy|2,3-Y|pyridin-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-YTcyclohexyl(3-methylthieno(2,3-b|pyridin-2-yl)umethyliamino)phenyl)carbonyl I|(methyl)aminoisopropanoate (333 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml) and the mixture was stirred at room temperature for 4 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrochloric acid was added at 0"C (2.00 mL). The resulting precipitate was collected by filtration to afford the title compound (275 mg, 88905) as a white solid. "H NMR (300 MHz, SOCI") 6 ppm 1.02 - 1, 35 (m, 5 N), 1.54 - 1.88 (m, 5 N), 2.07 - 2.19 (m, 1

H), 2.45 (s, C H), 2.58 - 2.70 (m, 2 H), 3.01 (s, C H), 3.68 (t, 9U-6.6 Hz, 2 H), 4.54 (d, 9-7.6 Hz, 1

NU, 6.51 (d, 9U-8.7 Hz, 2 H), 7.20 (d, 98.7 Hz, 2 H), 7.27 (dd, 9U-8.1, 4.7 Hz , 1 H), 7.88 (dd, 98.1, 1.6 HZ, 1 H), 8.47 (dd, U-4.7, 1.6 Hu, 1 H).

Example A144 3-1(4-cyclohexyl(3-methylthienoyl)3,2-b|pyridin-2-yl)methylamino)phenyl)carbonylamino)propanoic acid (F) du

N

M u Dn -k sn, (1) ethyl З-methylthieno|З3,2-б|Ipyridine-2-carboxylate

To a solution (100 ml) of 3-chloropyridine-2-carbonitrile (10.0 g) in tetrahydrofuran was added a ZOM solution (48.0 ml) of methylmagnesium bromide in diethyl ether and the mixture was stirred at room temperature for 3 h. 2M hydrogen chloride was added to the reaction mixture acid (300 ml), tetrahydrofuran was evaporated and the residue 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 column chromatography on silica gel (30 - 7095 ethyl acetate/hexane) to give a pale yellow oil. Potassium carbonate (16.0 g) was added to a mixture of the obtained oil, ethyl mercaptoacetate (4.23 ml) and M,M-dimethylformamide (60 ml) and the mixture was stirred overnight at 50°C. Water and a solid precipitate were added to quench the reaction collected by filtration to give the title compound (6.75 g, 7995) as a white solid.

IN NMR (400 MHz, SOSI") b m.h. 1.44 (t, 9-7.2 Hz, Z H), 2.87 (s, Z H), 4.44 (k, 92-7.2 Hz, 2

H), 7.37 (dd, U-8.3, 4.4 Hz, 1 H), 8.17 (dd, 9U-8.3, 1.5 Hz, 1 H), 8.78 (dd , 9-44, 1.5 Hz, 1 N). (2) 3-methylthieno-3,2-B|pyridine-2-carbaldehyde

Borohydride was added to a mixture of ethyl 3-methylthieno|YZ3,2-in|Ipyridine-2-carboxylate (3.00 g) synthesized above, calcium chloride (3.02 g), ethanol (30 ml) and tetrahydrofuran (30 ml) of sodium (2.06 g) at 0 "С and the mixture was stirred at room temperature for 5 g.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. To a solution (50 ml) of the obtained solid in tetrahydrofuran was added active manganese dioxide (12.2 g) and the mixture was stirred at 50 "C overnight. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (2.24 g, 93905), as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 2.90 (s, C H), 7.40 (dd, 9U-8.2, 4.6 Hz, 1 H), 8.21 (dd, 98.2, 1.4 Gu, 1 H), 8.79 (dd, 9-46, 1.4 Hz, 1 N), 10.43 (s, 1 N). (Z)cyclohexyl(Z-methylthienoy3,2-b|Ipyridin-2-yl)umethanone

A 1.0M solution (18.9 ml) of cyclohexylmagnesium bromide in tetrahydrofuran was added to a solution (50 ml) of 3-methylthienoyl3,2-B|pyridine-2-carbaldehyde (2.24 g) synthesized above in tetrahydrofuran at 0"С and the mixture was stirred at 0 "C for 1.5 g in an argon atmosphere. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 - 5095 ethyl acetate/hexane) to give a pale yellow oil. Tetrapropylammonium perruthenate (238 mg) was added to a mixture of the obtained oil, 4-methylmorpholine M-oxide (1.81 g) and acetonitrile (40 ml), the mixture was stirred at room temperature for 2 g and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-30905 ethyl acetate/hexane) to give the title compound (1.38 g, 7995) as a colorless oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.19 - 1.65 (m, 5 N), 1.70 - 1.81 (m, 1 N), 1.82 - 1.94 (m, 2

H), 1.94 - 2.08 (m, 2 H), 2.86 (s, C H), 3.01 - 3.15 (m, 1 H), 7.37 (dd, 9U-8 ,2, 4.4 Hu, 1 H), 8.17 (dd, U-8.2, 1.5 Hz, 1 H), 8.78 (dd, U-4.4, 1.5 Hz, 1 H). (4) methyl 4-Icyclohexyl(3-methylthienoi|3,2-in|Ipyridin-2-yl)umethylIiaminophenbenzoate

To the mixture of cyclohexyl(3-methylthienoyl3,2-B|pyridin-2-yl)methanone (1.38 g) synthesized above, methyl 4-aminobenzoate (884 mg), triethylamine (5.94 ml) and methylene chloride (30 ml ) titanium chloride (IM) (700 μl) was added at 0"C and the mixture was stirred at room temperature for 3.5 days in an argon atmosphere. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (607 μl) and sodium cyanoborohydride (666 mg) were added to a solution (30 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10 - 5095 ethyl acetate/hexane) to give the title compound (1.31 g, 62965) as a brown solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.37 (m, 5 N), 1.55 - 1.90 (m, 5 N), 2.03 - 2.16 (m, 1

H), 2.59 (s, C H), 3.79 (s, C H), 4.56 (d, 95.8 Hz, 1 H), 4.63 - 4.72 (m, 1 H ), 6.51 (d, 9-8.5 Hz, 2

H), 7.16 (dd, 9U-8.1, 4.6 Hz, 1 H), 7.77 (d, U-8.5 Hz, 2 H), 7.98 (dd, 9-8 ,1, 1.2 Hz, 1 N), 8.64 (dd, y-4.6, 1.2 Hz, 1 N). (5) 4-Hycyclohexyl(3-methylthieno|3,2-b|Ipyridin-2-yl)umethyliamino)benzoic acid

A 1 M aqueous solution of sodium hydroxide ( 10 ml) and the mixture was stirred overnight under reflux. Another 1 M aqueous solution of sodium hydroxide (5 ml) was added, the mixture was further stirred under reflux for 7 h and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and 1 M hydrochloric acid (15 mL) was added at 0"C. The resulting precipitate was collected by filtration and the resulting brown solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (804 mg, 6495) as a brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.36 (m, 5 N), 1.55 - 1.91 (m, 5 N), 2.02 - 2.15 (m, 1

H), 2.60 (s, C H), 4.52 - 4.74 (m, 2 H), 6.52 (d, 2-8.7 Hz, 2 H), 7.17 (dd, U-8.0, 4.6 Hz, 1 N), 7.82 (d, 9-8.7 Hz, 2 N), 7.99 (dd, U-8.0, 1.4 Hz, 1 H), 8.66 (dd, 9U-4.6, 1.4 Hz, 1 H). (6) ethyl 3-((4-cyclohexyl(3-methylthienoyl3,2-yl)pyridin-2-yl)methylamino)phenyl)carbonylamino)propanesate

To the mixture of 4-Ycyclohexyl(3-methylthienoyl3,2-B|Ipyridin-2-yl)umethyliaminofbenzoic acid (300 mg), synthesized above, p-alanine ethyl ester hydrochloride (181 mg),

1-hydroxybenzotriazole monohydrate (181 mg), triethylamine (329 μl) and M,M-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) and the mixture was stirred at room temperature for 1 day A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (60 - 10095 ethyl acetate/hexane) to give the title compound (330 mg, 8795) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.36 (m, 8 N), 1.56 - 1.90 (m, 5 N), 2.02 - 2.16 (m, 1

H), 2.52 - 2.63 (m, 5 H), 3.59 - 3.68 (m, 2 H), 4.12 (k, 9-7.1 Hz, 2 H), 4, 49 (d, 2-5.8 Hz, 1 N), 4.62 - 4.69 (m, 1 N), 6.52 (d, 2-8.5 Hz, 2 N), 6.59 ( t, 9-5.8 Hz, 1 N), 7.16 (dd, 9-81, 4.6 Gu, 1

H), 7.52 (d, U-8.5 Hz, 2 H), 7.99 (dd, U-8.1, 1.4 Hz, 1 H), 8.64 (dd, 9U-4 ,6, 1.4 Hz, 1 N). (7) 3--(4-Cyclohexyl(3-methylthienoyl3,2-B|pyridin-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

To the mixture of ethyl 3-((4-YTcyclohexyl(3-methylthienoyl)3,2-b|pyridin-2-yl)methyliamino)phenyl)carbonyl|Iamino)upropanoate (330 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (291 mg, 94905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.36 (m, 5 N), 1.55 - 1.89 (m, 5 N), 2.03 - 2.14 (m, 1

H), 2.57 (s, C H), 2.63 (t, 9-5.7 Hz, 2 H), 3.55 - 3.77 (m, 2 H), 4.64 (d, 90-7.2 Hz, 1 N), 6.49 (d, 98.9 Hz, 2 N), 6.78 (t, U-6.0 Gu, 1 N), 7.19 (dd, U -8.0, 4.6 Gu, 1 N), 7.53 (d, U-8.9 Hz, 2 N), 8.01 (dd, 9U-8.0, 1.5 Hz, 1 N ), 8.64 (dd, 9-46, 1.5 Gu, 1 H).

Example A145 3-1(4-cyclohexyl(3-methylthienoyl),2-b|pyridin-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoic acid

M Sn,

HUK n -k Sn. (1) ethyl 3-((4-Ycyclohexyl(3-methylthienoyl3,2-B|pyridin-2-yl)umethyl|amino)phenyl)carbonyl|(methyl)amino)propanoate

To the mixture of 4-cyclohexyl(3-methylthienoic acid, 2-b|pyridin-2-ylmethylaminobenzoic acid (300 mg), synthesized in Example A144(5), ethyl 3-(methylamino)propanoate (155 mg), 1-hydroxybenzotriazole monohydrate ( 181 mg), triethylamine (329 μl) and M,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (226 mg) was added, and the mixture was stirred at room temperature for 1 day. Saturated aq. ammonium chloride solution to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50 - 10095 ethyl acetate/hexane) to obtain the indicated in title compound (325 mg, 8495) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.36 (m, 8 N), 1.54 - 1.92 (m, 5 N), 2.01 - 2.16 (m, 1

H), 2.51 - 2.68 (m, 5 H), 2.99 (s, C H), 3.69 (t, 9U-7.0 Hz, 2 H), 4.10 (k, 2-6.9 Hz, 2 N), 4.36 (d, 95.2 Hz, 1 N), 4.58 - 4.67 (m, 1 N), 6.51 (d, U-8, 5 Hz, 2 N), 7.13 - 7.23 (m, Z H), 8.00 (d, U-8.0

Hz, 1 N), 8.64 (d, 9-44 Hz, 1 N).

(2)3--(4-Ycyclohexyl(3-methylthienoyl3,2-yl)pyridin-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoic acid

To the mixture of ethyl 3-((4-YTcyclohexyl(3-methylthienoyl)3,2-b|pyridin-2-yl)umethylamino)phenyl)carbonyl(methyl)aminoisopropanoate (325 mg), synthesized above, tetrahydrofuran (5 ml) and ethanol ( 5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL) and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (277 mg, 9095) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.06 - 1.34 (m, 5 N), 1.55 - 1.88 (m, 5 N), 2.03 - 2.15 (m, 1

H), 2.58 (s, C H), 2.66 (t, 9U-6.3 Hz, 2 H), 3.02 (s, C H), 3.70 (t, U-6, 3 Hz, 2 N), 4.62 (d, 9-7.5 Gu, 1 N), 6.50 (d, U-8.7 Hz, 2 N), 7.15 - 7.25 (m , Z H), 8.01 (dd, U-8.3, 1.5 Hz, 1 H), 8.66 (dd, 9-45, 1.5 Gu, 1 H).

Example A146 3-D4-Hcyclohexyl|3-methyl-6-(trifluoromethyl)thienoic3,2-b|Ipyridin-2-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid M sn, sin -ki C (1) ethyl 3-methyl-6-(trifluoromethyl)thieno|3,2-b|pyridine-2-carboxylate

To a solution (50 ml) of 3-chloro-5-(trifluoromethyl)pyridine-2-carbonitrile (5.00 g) in tetrahydrofuran was added a 3.0 M solution (16.1 ml) of methylmagnesium bromide in diethyl ether at 0 "С and the mixture was stirred for 3 h in an argon atmosphere. 1 M hydrochloric acid (300 ml) was added to the reaction mixture to acidify the solution to pHeEZ - 4, 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 column chromatography on silica gel (0 - 1095 ethyl acetate/hexane) to give a pale yellow solid.To a mixture of the obtained solid, ethyl mercaptoacetate (1.61 ml) and MM-dimethylformamide (30 ml) was added potassium carbonate (5.56 g) and the mixture was stirred at 50 "C for 10 g. Water was added to quench the reaction and the solid precipitate was collected by filtration to give the title compound (3.76 g, 54905) as a white solid.

IN NMR (300 MHz, SOSI") b m.h. 1.45 (t, 9-7.1 Hz, Z H), 2.88 (s, Z H), 4.45 (k, 9-7.1 Hz, 2

H), 8.39 - 8.45 (m, 1 H), 8.94 - 9.02 (m, 1 H). (2)3-methyl-6-(trifluoromethyl)thieno|3,2-b|Ipyridine-2-carbaldehyde

To a mixture of ethyl 3-methyl-6-(trifluoromethyl)thieno-3,2-pyridine-2-carboxylate (3.69 g) synthesized above, calcium chloride (2.84 g), ethanol (40 ml) and tetrahydrofuran ( 40 ml) sodium borohydride (1.94 g) was added at 0"C and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. To a solution (60 ml) of the obtained solid in tetrahydrofuran was added active manganese dioxide (16.3 g) and the mixture was stirred at

C for 5 g. Manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (2.88 g, 9295) as a white solid.

IN NMR (300 MHz, SOSIz") 6 m.h. 2.93 (s, Z H), 8.47 - 8.50 (m, 1 H), 9.00 (d, 9U-1.6 Hz, 1 H), 10.46 (s, 1 H) . (3) cyclohexyl|3-methyl-6b-(trifluoromethyl)thienoyl3,2-b|Ipyridin-2-yl|methanone

A 1.0 M solution (8.81 ml) of cyclohexylmagnesium bromide was added to a solution (15 ml) of 3-methyl-6-(trifluoromethyl)thieno-3,2-b|pyridine-2-carbaldehyde (1.44 g) synthesized above in tetrahydrofuran in tetrahydrofuran at 0 "C and the mixture was stirred for 1 g under an argon atmosphere. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10 - 5095 ethyl acetate/hexane) to give a yellow oil.To a mixture of the obtained oil, 4-methylmorpholine M-oxide (817 mg) and acetonitrile (20 ml) was added tetrapropylammonium perruthenate (108 mg), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 - 1095 ethyl acetate/hexane) to give the title compound (805 mg, 4290) as a yellow solid. R (300 MHz, SOSIz") 6 m.h. 1.19 - 1.65 (m, 5 N), 1.70 - 1.81 (m, 1 N), 1.82 - 2.07 (m, 4

H), 2.86 (s, 3 H), 3.01 - 3.15 (m, 1 H), 8.42 (s, 1 H), 8.98 (s, 1 H). (4) methyl 4-(Icyclohexyl3-methyl-6-(trifluoromethyl)thienoyl3,2-B|pyridin-2-yl|methyl)amino)benzoate

To the mixture of cyclohexyl3-methyl-6-trifluoromethyl)thieno|3,2-B|pyridin-2-yl|methanone (805 mg), synthesized above, methyl 4-aminobenzoate (410 mg), triethylamine (2.75 ml) and methylene chloride (10 ml) was added titanium chloride (IM) (323 μl) at 0"C and the mixture was stirred at room temperature for 1 day in an argon atmosphere. A saturated aqueous sodium bicarbonate solution was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil. Acetic acid (282 μl) and sodium cyanoborohydride (309 mg) were added to a solution (10 ml) of the obtained oil in tetrahydrofuran, and the mixture was stirred at room temperature for 1 h. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-4095 ethyl acetate/hexane) to give the title compound (775 mg, 6895) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.05 - 1.36 (m, 5 N), 1.53 - 1.91 (m, 5 N), 2.02 - 2.15 (m, 1

H), 2.62 (s, C H), 3.79 (s, C H), 4.58 (d, 9-5.5 Hz, 1 H), 4.66 - 4.74 (m, 1 H), 6.50 (d, 2-8.8 Hz, 2

H), 7.77 (d, 9-8.8 Gu, 2 H), 8.23 (d, 9-1.3 Hz, 1 H), 8.87 (d, 9U-1.3 Hz, 1 H). (5) 4-((cyclohexyl|3-methyl-6b-(trifluoromethyl)thienoyl)3,2-B|pyridin-2-yl|methyl)amino)benzoic acid

To the mixture of methyl 4-(Ccyclohexyl|3-methyl-b-(trifluoromethyl)thienoyl3,2-b|pyridin-2-yl|methyl)amino)benzoate (775 mg), synthesized above, tetrahydrofuran (10 ml) and ethanol ( 10 ml) was added with a 1M aqueous solution of sodium hydroxide (10 ml), the mixture was stirred for 1 day under reflux and concentrated under reduced pressure. The residue was dissolved in water (20 ml), 1 M hydrochloric acid (10 ml) was added at 0 "С and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (30 - 70905 ethyl acetate/hexane) to give the title compound (671 mg, 8795) as a pale brown solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.38 (m, 5 N), 1.53 - 1.93 (m, 5 N), 2.00 - 2.14 (m, 1

H), 2.62 (s, C H), 4.55 - 4.80 (m, 2 H), 6.50 (d, 9U-8.8 Hz, 2 H), 7.82 (d, U-8.8 Hz, 2 N), 8.23 (d,

U-1.3 Hz, 1 N), 8.88 (d, 9-1.3 Hz, 1 N). (6) ethyl 3-(44-OCcyclohexyl|3-methyl-6-trifluoromethyl)thienoyl 3,2-B|pyridin-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate

To the mixture of 4-(Icyclohexyl33-methyl-6-(trifluoromethyl)thienoyl3,2-B|pyridin-2-yl|methyl)amino)benzoic acid (343 mg), synthesized above, ethyl /3-(methylamino)propanoate (151 mg), 1-hydroxybenzotriazole monohydrate (176 mg), triethylamine (321 μl) and N,M-dimethylformamide (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (221 mg) was added, and the mixture was stirred at room temperature temperature for 2.5 days. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 7095 ethyl acetate/hexane) to give the title compound (310 mg, 72905) as a white solid. "H NMR (300 MHz, SOSIz") 6 m.h. 1.08 - 1.35 (m, 8 N), 1.54 - 1.92 (m, 5 N), 2.01 - 2.13 (m, 1

H), 2.51 - 2.68 (m, 5 H), 2.99 (s, C H), 3.69 (t, 9U-7.0 Hz, 2 H), 4.10 (k, 20-7.1 Gu, 2 H), 4.37 - 4.46 (m, 1 H), 4.60 - 4.68 (m, 1 H), 6.49 (d, 9U-8.7 Hz, 2 N), 7.19 (d, 9-8.7 Hz, 2 N), 8.24 (s, 1 N), 8.87 (s, 1 N). (7)3-TsCh4-Hcyclohexyl|3-methyl-6-(trifluoromethyl)thienoyl3,2-b|Ipyridin-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

To the mixture of ethyl 3-C4-(cyclohexyl|3-methyl-b-(trifluoromethyl)thienoyl3,2-b|pyridin-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (310 mg), synthesized above, tetrahydrofuran ( 5 ml) and ethanol (5 ml) was added 1M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1 M hydrochloric acid (2.00 mL) was added at 0 °C. The resulting precipitate was collected by filtration to give the title compound (284 mg, 96905) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.07 - 1.35 (m, 5 N), 1.53 - 1.89 (m, 5 N), 2.00 - 2.12 (m, 1

H), 2.54 - 2.69 (m, 5 H), 3.00 (s, C H), 3.68 (t, U-6.6 Hz, 2 H), 4.64 (d, 2-7.2 Hz, 1 N), 6.49 (d, uU-8.3 Hz, 2 N), 7.20 (d, 9U-8.3 Hz, 2 N), 8.25 (s , 1 N), 8.88 (c, 1 N).

Example A147 3-(I44-K(cyclohexyl3-methyl-5-(2-(methylthio)ethoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid Art

(1)cyclohexyl3-methyl-5-(2-(methylsulfanyl)ethoxy|-1-benzofuran-2-ylumethanone)

Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (0.76 g), synthesized in

Example A8F2(3) was dissolved in tetrahydrofuran (15 ml) and 2-(methylthio)ethanol (0.26 ml), tributylphosphine (1.5 ml) and 1,1-(azodicarbonyl)udipiperidine (1 .46 g) The ice bath was removed and the reaction mixture was stirred at room temperature for 12 h. Hexane (15 mL) was added to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (0.73 g, 7695) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.18 - 2.01 (m, 10 H), 2.24 (s, Z H), 2.57 (s, Z H), 2.92 (t, 3-6.8 HZ, 2 H) , 3.25 - 3.40 (m, 1 N), 4.21 (t, U-6.8 Hz, 2 N), 7.03 - 7.41 (m, C H). (2) cyclohexyl3-methyl-5-(2-(methylsulfanyl)ethoxy|-1-benzofuran-2-ylmethanol

Cyclohexyl3-methyl-5-(2-(methylsulfanyl)ethoxy|-1-benzofuran-2-ylumethanone (0.73 g) synthesized in the above mentioned (1) was dissolved in tetrahydrofuran (10 ml) and methanol (5 ml) and until sodium borohydride (9090, 0.18 g) was added to the solution while cooling with ice.The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h.

The mixture was cooled again with ice, water (1 mL) and 1M hydrochloric acid (5 mL) were carefully added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (0.67 g, 9195) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.86 - 1.99 (m, 11 H), 2.19 (s, C H), 2.23 (s, C H), 2.91 (t, 3-6.9 Gu, 2 H) , 4.20 (t, U-6.9 Hz, 2 N), 4.51 (dd, U-8.5, 6.0 Hz, 1 N), 6.79 - 6.98 (m, 2 H), 7.31 (d, U-9.0 Gu, 1 H). (3) ethyl 3-|(4-K(cyclohexyl(3-methyl-5-(2-(methylsulfanyl)ethoxy|-1-benzofuran-2-yl)methyl)amino|phenyl)carbonyl)(methyl)amino| propanoate

Cyclohexyl3-methyl-5-(2-(methylsulfanyl)ethoxy|-1-benzofuran-2-ylmethanol (0.34 g) synthesized in the above-mentioned (2) was dissolved in tetrahydrofuran (5 mL), and to solution at room temperature thionyl chloride (0.13 mL) was added. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous sodium bicarbonate solution (10 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (5 ml), sodium iodide (0.23 g), sodium carbonate (0.15 g) and ethyl 3-K (4 - aminophenyl)carbonyl|I/methyl)aminoisopropanoate (0.25 g), synthesized in Example 2(2), and the mixture was stirred at 80 "C for 12 g. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:.hexane-1:1, v/v) to give the title compound (0.33 g, 59905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.00 - 2.00 (m, 15 N), 2.05 (s, Z H), 2.22 (s, Z H), 2.61 (t,

U-6.8 Hz, 2 H), 2.89 (t, 9U-6.9 Hz, 2 H), 3.01 (s, Z H), 3.70 (t, 9U-6.8 Hz , 2 N), 4.00 - 4.20 (m, 4

H), 4.36 (d, 9U-8.0 Gu, 1 H), 6.56 (d, 9-8.7 Hz, 2 H), 6.78 - 6.94 (m, 2 H) , 7.14 - 7.25 (m, Z H). (4)3-(144-Kcyclohexyl/3-methyl-5-(2-(methylthio)ethoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|Ipropanoic acid

Ethyl 3-(144-Kcyclohexyl/3-methyl-5-(2-(methylsulfanyl)ethoxy!|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoate (0.33 g) , synthesized in the above-mentioned (3), was dissolved in ethanol (2 ml), 1M aqueous sodium hydroxide solution (1.5 ml) was added to the solution at room temperature, and the mixture was stirred at 50 "C for 0.5 g.

Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (1.5 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.20 g, 6390) as a colorless solid.

IN NMR (300 MHz, DMSO-av) 6 m.h. 0.88 - 2.11 (m, 12 H), 2.15 (s, Z H), 2.23 (s, Z H), 2.40 - 2.46 (m, 2 H), 2, 76 - 2.96 (m, 5 N), 3.50 (t, U-7.3 Hz, 2 N), 4.15 (t, 9U-6.7 Hz, 2 N), 4.37 ( t, 9U-8,3

Hz, 1 N), 6.46 (d, 9U-8.1 Hz, 1 N), 6.59 (d, 2U-8.7 Hz, 2 N), 6.80 (dd, U-8, 7, 2.6 Hz, 1 N), 7.03 (d, uU-2.6 Hz, 1 N), 7.09 (d, 9-8.7 Hz, 2 N), 7.32 (d , 9-8.7 Gu, 1 N).

Example A148 3-(I44-K(cyclohexyl3-methyl-5-(2-(methylthio)ethoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid and

But M

And he

HM Fr

Cyclohexyl3-methyl-5-(2-(methylsulfanyl)ethoxy|-1-benzofuran-2-ylmethanol synthesized in Example A147(2) was dissolved in tetrahydrofuran (5 ml), and thionyl chloride (0.13 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (10 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (5 ml), sodium iodide (0.23 g), sodium carbonate (0.15 g) and ethyl 3-L(4-aminophenyl)carbonyl|amino) were added propanoate (0.25 g) synthesized in Example 1(2), and the mixture was stirred at 80 C for 12 h.

After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.38 g, 6995) as a yellow oil. It was dissolved in ethanol (2 ml), a 1 M aqueous solution of sodium hydroxide (1.5 ml) was added to the solution at room temperature, and the mixture was stirred at 50 "C for 0.5 g. The ethanol was evaporated under reduced pressure, 1 M hydrogen chloride was added to the residue acid (1.5 mL) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to afford the title compound (0.18 g, 49905) as a colorless solid substance

IN NMR (300 MHz, DMSO-dv) b m.ch. 0.88 - 2.10 (m, 12 N), 2.15 (s, Z H), 2.23 (s, Z H), 2.42 (t, uU7.2 Hz, 2 N), 2 .84 (t, 9-6.5 Hz, 2 N), 3.47 - 3.55 (m, 2 N), 4.15 (t, 9-6.6 Hz, 2 N), 4.41 (t, 9-84 Gu, 1 H), 6.49 - 6.64 (m, C H), 6.79 (dd, 9U-8.9, 2.5 Hz, 1 H), 7.03 (d, 9-24 Gu, 1 N), 7.32 (d, U-8.9 Hz, 1 N), 7.51 (d, 9U-8.7 Hz, 2 N), 7.99 ( t, 955.5 Hz, 1 N).

Example A149 3-(4-(H-Cyclohexyl-5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylamino|Ipropanoic acid

N

9 And yin them

Mo

Thionyl chloride ( 0.35 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (20 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (15 ml) and sodium iodide (0.61 g), sodium carbonate (0.41 g) and ethyl 3-((4-aminophenyl)carbonylamino)upropanoate (0.64 g) were added to the solution ), synthesized in Example 1(2), and the mixture was stirred at 80 C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain oethyl 3-((4-(cyclohexyl(I|5-(2-methoxyethoxy)-3-methyl -1- Benzofuran-2-yl|Imethyliamino)phenylIcarbonyl)iamino)propanoate (0.62 g, 4395) as a yellow oil. It was dissolved in ethanol (5 mL), and to the solution at room temperature was added 1M aqueous sodium hydroxide solution ( 3.0 ml) and the mixture was stirred at 50 "C for 0.5 g. Ethanol was evaporated under reduced pressure, 1 M hydrochloric acid (3.0 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.The residue was washed with ethanol-water to give the title compound (0.54 g, 91905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.93 - 2.13 (m, 12 N), 2.21 (s, C H), 2.66 (t, 9-5.7 Hz, 2 N), 3.46 (s, C H) , 3.58 - 3.71 (m, 2 H), 3.76 (dd, 9-56, 4.1 Hz, 2 H), 4.14 (dd, 9U-5,7,4.1 Hz , 2 N), 4.38 (d, 9-7.9 Hz, 1 N), 6.57 - 6.65 (m, Z H), 6.80 - 6.98 (m, 2 N), 7.22 - 7.26 (m, 1H), 7.53 (d,

U-8.7 Hz, 2 N).

Example A150 3-(I44-K(cyclohexyl3-methyl-5-(3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

І B) du o M g - 5 where and (1)cyclohexyl3-methyl-5-|3-(methylsulfanyl)propoxy|-1-benzofuran-2-ylumethanone

Cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methanone (2.4 g), synthesized in

Example A82(3) was dissolved in tetrahydrofuran (50 ml) and 3-(methylthio)propanol (1.0 ml), tributylphosphine (4.7 ml) and 1,1-(azodicarbonyl)udipiperidine (4 .7 g) The ice bath was removed and the reaction mixture was stirred at room temperature for 12 h. Hexane (50 ml) was added to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (3.1 g, 9595) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.18 - 2.01 (m, 12 H), 2.14 (s, Z H), 2.56 (s, Z H), 2.72 (t,

U-7.2 Hz, 2 H), 3.25 - 3.40 (m, 1 H), 4.08 - 4.20 (m, 2 H), 7.03 - 7.42 (m, Z N). (2) cyclohexyl3-methyl-5-|3-(methylsulfanyl)propoxy|-1-benzofuran-2-ylmethanol

Cyclohexyl3-methyl-5-|13-(methylsulfanyl)propoxy|-1-benzofuran-2-ylumethanone (3.1 g) synthesized in the above mentioned (1) was dissolved in tetrahydrofuran (50 ml) and methanol (10 ml) and sodium borohydride (9095, 0.73 g) was added to the solution while cooling with ice. The ice bath was removed, the reaction mixture was stirred at room temperature for 1 g, then cooled again with ice, and water (5 ml) and 1 M hydrochloric acid ( 25 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, volume ratio) to give the title compound ( 3.0 g, 9595), as a pale yellow oil. "H NMR (300 MHz, SOSIZ") b m.h. 1.18 - 2.01 (m, 14 H), 2.13 (s, Z H), 2.19 (s, Z H), 2.72 (t,

U-7.2 Hz, 2 N), 4.11 (t, 20-7.2 Hz, 2 N), 4.40 - 4.55 (m, 1 N), 6.80 - 7.42 ( m, Z H). (3) ethyl. 3-((4-Kcyclohexyl3-methyl-5-3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)(methyl)amino|propanoate

Cyclohexyl3-methyl-5-|13-"methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethanol (1.5 g) synthesized in the above-mentioned (2), was dissolved in tetrahydrofuran (10 ml), and to the solution thionyl chloride (0.56 mL) was added at room temperature.The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (30 mL) was carefully added to the mixture.

The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml), sodium iodide (0.95 g), sodium carbonate (063 g) and ethyl 3-K(4-aminophenyl)carbonyl|)(methyl)amino)propanoate (1) were added to the solution ,1 g), synthesized in Example 2(2), and the mixture was stirred at 80 "С for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (1.4 g, 5695) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.00 - 2.00 (m, 17 H), 2.12 (s, Z H), 2.21 (s, Z H), 2.52 - 2.79 (m, 4 H), 3, 01 (s, Z H), 3.70 (t, 90-7.2 Hz, 2 H), 4.00 - 4.36 (m, 5 H), 6.56 (d, 9-8.7 Hz, 2 H), 6.78 - 6.94 (m, 2 H), 7.14 - 7.25 (m, C H). (4)3-(44-Kcyclohexyl3-methyl-5-|3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Ethyl 3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)(methyl)amino|propanoate (0.37 g ), synthesized in the above mentioned (3), was dissolved in ethanol (5 ml), 1 M aqueous solution of sodium hydroxide (2.0 ml) was added to the solution at room temperature and the mixture was stirred at 50 "C for 0.5 g.

Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (2.0 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.28 g, 7990) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.89 - 2.10 (m, 14 H), 2.12 (s, Z H), 2.21 (s, Z H), 2.52 - 2.81 (m, 4 H), 3, 04 (s, Z H), 3.70 (k, 9U-6.4 Hz, 2 H), 4.09 (t, 9U-6.4 Hz, 2 H), 4.36 (d, 9- 7.9 Hz, 1

Н), 6.56 (d, 9-8.7 Hz, 2Н), 6.77 - 6.96 (m, 2 Н), 7.20 - 7.26 (m, З Н).

Example A151 3-(I44-K(cyclohexyl3-methyl-5-(3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)icarbonyl)amino|propanoic acid g. M

SA

- 5

C b (1) ethyl 3-((4-Kcyclohexyl3-methyl-5-3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)methyl)amino|phenyl)icarbonyl)amino|Ipropanoate

Cyclohexyl3-methyl-5-|13-"methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethanol (1.5 g), synthesized in Example A150(2), was dissolved in tetrahydrofuran (10 ml) and until the solution thionyl chloride (0.56 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (30 mL) was cautiously added. The reaction mixture was stirred for 10 min and extracted with ethyl acetate. The extract was washed saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml), sodium iodide (0.95 g), sodium carbonate (0.63 g) and ethyl 3-L were added to the solution (4-aminophenyl)carbonyl|amino)propanoate (1.0 g), synthesized in Example 1(2), and the mixture was stirred at 80 "С for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (1.8 g, 7790) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.00 - 2.00 (m, 17 H), 2.12 (s, Z H), 2.21 (s, Z H), 2.52 -

2.79 (m, 4 N), 3.66 (k, 9U-6.0 Hz, 2 N), 4.00 - 4.60 (m, 5 N), 6.56 (d, U-8 .9 Hz, 2 N), 6.58 (shs, 1

H), 6.78 - 6.94 (m, 2 H), 7.20 - 7.60 (m, C H). (2)3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

Ethyl 3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoate (0.25 g) was synthesized in mentioned above (1) was dissolved in ethanol (5 ml), a 1 M aqueous solution of sodium hydroxide (2.0 ml) was added to the solution at room temperature, and the mixture was stirred at 50 "C for 0.5 g. Ethanol was evaporated under reduced pressure until 1M hydrochloric acid (2.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.07 g, 3195) , as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 0.82 - 2.16 (m, 14 H), 2.22 (s, Z H), 2.52 -2.81 (m, A H), 3.66 (k, U-6.0 Hz , 2 H), 4.08 (t, 9U-6.0 Hz, 2 H), 4.38 (d, 9-7.9 Hz, 1 H), 6.43 -6.66 (m, Z H), 6.74 - 6.96 (m, 2 H), 7.20 - 7.26 (m, 1 H), 7.53 (d, 2-8.9 Hz, 2 H).

Example A152 3-(I44-K(cyclohexyl3-methyl-5-(3-(methylsulfonyl)propoxy|-1-benzofuran-2-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Yi S

(o; - 5 E60

(1) ethyl 3-((4-Kcyclohexyl3-methyl-5-3-(methylsulfonyl)propoxy|-1-benzofuran-2-yl)methyl)amino|phenyl)carbonyl)(methyl)amino|propanoate

Ethyl 3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfanyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoate (0.61 g), synthesized in Example

A150(3) was dissolved in methanol (15 ml) and water (2 ml), oxone (2.1 g) was added to the solution at room temperature, and the mixture was stirred for 30 min. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.48 g, 75906) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 2.01 (m, 17 H), 2.21 (s, C H), 2.28 -2.42 (m, 2 H), 2.61 (t, U-6.9 Gu , 2 H), 2.95 (s, C H), 3.01 (s, C H), 3.20 - 3.36 (m, 2 H), 3.70 (t, U-6.9 Hz, 2 N), 4.04 - 4.19 (m, 2 N), 4.26 - 4.44 (m, 1 N), 6.56 (d, 9U-8.7 Hz, 2 N) , 6.74 - 6.91 (m, 2 H), 7.15 - 7.25 (m, C H). (2)3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfonyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Ethyl 3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfonyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoate (0.48 g) synthesized in the above-mentioned (1) was dissolved in ethanol (5 ml), 1 M aqueous sodium hydroxide solution (1.5 ml) was added to the solution at room temperature and the mixture was stirred at 50 "C for 0.5 g.

Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (1.5 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.35 g, 7890) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.87 - 2.15 (m, 12 H), 2.21 (s, Z H), 2.25 - 2.45 (m, 2 H), 2.67 (w s, 2 H), 2 .95 (s, Z H), 3.04 (s, Z H), 3.17 - 3.36 (m, 2 H), 3.69 (t, 9U-6.5 Hz, 2 H), 4.13 (t,

95.7 Hz, 2 N), 4.36 (d, 2-7.9 Gu, 1 N), 6.56 (d, 2-8.7 Hz, 2 N), 6.70 - 6.93 (m, 2 H), 7.16 - 7.26 (m, C H).

Example A153 3-(I44-K(cyclohexyl3-methyl-5-(3-(methylsulfonyl)propoxy|-1-benzofuran-2-yl)methyl)amino|phenyl)carbonyl)amino|propanoic acid

Her mother is M o. Oh H -5p 0

Z o (1) ethyl 3-((4-Kcyclohexyl3-methyl-5-3-(methylsulfonyl)propoxy|-1-benzofuran-2-ylmethyl)amino|phenylcarbonyl)amino|propanoate

Ethyl 3-(144-Kcyclohexyl/3-methyl-5-|13-(methylsulfanyl)propoxy|-1-benzofuran-2-ylmethyl)amino|phenylcarbonyl)amino|propanoate (0.16 g), synthesized in Example A151 ( 1) was dissolved in acetone (5 ml), metachloroperbenzoic acid (0.2 g) was added to the solution while cooling with ice, and the mixture was stirred for 15 min. An aqueous solution of sodium sulfite was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.11 g, 68905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.89 - 1.92 (m, 17 N), 2.22 (s, C H), 2.25 - 2.44 (m, 2 H), 2.58 (t, U-5.8 Hz , 2 H), 2.95 (s, C H), 3.14 - 3.35 (m, 2 H), 3.66 (k, 9U-6.8 Hz, 2 H), 4.13 ( k, 9-72

Hz, 2 N), 4.38 (d, 9-7.9 Hz, 1 N), 6.43-6.64 (m, Z H), 6.73 -6.90 (m, 2 N) , 7.16 - 7.25 (m, 1 N), 7.54 (d, U-8.7 Hz, 2 N). (2)3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfonyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid

Ethyl 3-(144-Kcyclohexyl/3-methyl-5-|3-(methylsulfonyl)propoxy|-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoate (0.11 g) was synthesized in mentioned above (1) was dissolved in ethanol (3 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added to the solution at room temperature and the mixture was stirred at 50 "C for 0.5 g. Ethanol was evaporated under reduced pressure until 1M hydrochloric acid (1.0 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.9 g, 8095) , as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.14 (m, 14 H), 2.22 (s, 3 NN), 226-242 (M, 2 H), 2.60 - 2.72 (m, 2 H), 2, 95 (s, Z H), 3.17 - 3.33 (m, 2 H), 3.66 (k, U-5.7 Hz, 2 H), 4.13 (t, 2-5.7 Hz, 2 H), 4.38 (d, 97.9 Gu, 1 H), 6.47 - 6.62 (m, Z H), 6.74 - 6.90 (m, 2 H), 7 .20 - 7.26 (m, 1 N), 7.53 (d, U-8.7 Hz, 2 N).

Example A154 3-C4-((5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

(1)(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|(cyclohexyl)methanol (5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|cyclohexyl)methanone (1 .5 g), synthesized in Example A82(2), was dissolved in tetrahydrofuran (25 ml) and methanol (5 ml) and sodium borohydride (9095, 0.36 g) was added to the solution while cooling with ice. The ice bath was removed, the reaction the mixture was stirred at room temperature for 1 g, then cooled again with ice and water (5 mL) and 1M hydrochloric acid (10 mL) were carefully added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (1.4 g, 95965) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.81 - 2.00 (m, 12 N), 2.18 (s, C H), 4.51 (d, U-8.3 Hz, 1 N), 5.10 (s, 2 N) , 6.87 - 7.06 (m, 2 N), 7.29 - 7.58 (m, 6 N). (2) ethyl 3-SHA-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)"ucyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propansate (5-(Benzyloxy)-3-methyl- 1-benzofuran-2-yl|cyclohexyl)methanol (1.5 g) synthesized in (1) mentioned above was dissolved in tetrahydrofuran (20 ml) and thionyl chloride (0.57 ml) was added to the solution at room temperature. The reaction mixture was stirred at at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (30 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (15 ml), sodium iodide (0.98 g), sodium carbonate (0.65 g) and ethyl 3-|(4-aminophenyl)carbonyl|(methyl)amino)propanoate (1, 1 g), synthesized in Example 2(2), and the mixture was stirred at 80 for 12 g. After spontaneous cooling, the reaction mixture was added water was added and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to give the title compound (1.8 g, 7290) as a yellow oil. "H NMR (300 MHz, SOSI") b mp 0.86 - 2.00 (m, 15 N), 2.21 (s, C H), 2.61 (t, 9-7.1 Hz, 2 N), 3.01 (s, C H), 3.70 (t, U-7.1 Hz, 2 H), 4.12 (k, d-7.2 Hz, 2 H), 4.27 - 443 (m, 2 H), 5.08 (s, 2 H), 6.56 (d, 9U-8.7 Hz, 2 H), 6.79 - 7.01 (m, 2 H), 7.13 - 7.24 (m, C H), 7.30 - 7.59 (m, 5 H). (3)3-Х14-Х(5-(benzyloxy)-3-methyl- 1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

Ethyl 3-CH4-(CH5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)"ucyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|Ipropanoate (0.2 g) was synthesized in the above-mentioned (2), was dissolved in ethanol (5 ml), a 1 M aqueous solution of sodium hydroxide (1.5 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure, 1 M hydrochloric acid was added to the residue ( 1.5 mL) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to afford the title compound (0.18 g, 9495) as a colorless solid. "H NMR (300 MHz, SOSI") b m.h. 0.79 - 2.14 (m, 12 N), 2.21 (s, C H), 2.63 (t, 9-6.2 Hz, 2 N), 3.01 (s, C H) , 3.68 (t, U-6.2 Hz, 2 N), 4.36 (d, 9-7.9 Hz, 1 N), 5.08 (s, 2 N), 6.55 (d , 9-8.7 Hz, 2

H), 6.80 - 7.03 (m, 2 H), 7.13 - 7.52 (m, 8 H).

Example A155 3-((4-(H-Cyclohexyl3-methyl-5-(pyridin-2-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenyl]carbonyl(methyl)amino|propanoic acid

(1) ethyl 3-((4-cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl|(methyl)aminopropanoate

Ethyl 3-CH4-(CH5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)" cyclohexyl)methyl)amino)phenylcarbonylKmethyl)amino|propanate (2.46 g), synthesized in Example A154(2) , was dissolved in ethanol (50 mL) and platinum oxide (0.33 g) was added to the solution. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to afford the title compound (1.64 g, 79906) as a yellow oil. "H NMR (300 MHz, SOCI") b m.h. 0.91 - 1.91 (m, 15 N), 2.18 (s, C H), 2.61 (t, 9-7.1 Hz, 2 N), 3.01 (s, C H) , 3.71 (t, 0-7.1 Hz, 2H), 4.02 -4.18 (m, 21H), 4.28 -4.41 (m, 1 H), 4.86 (s, 1 H), 6.55 (d, 2-8.7 Hz, 2 H), 6.66 - 6.87 (m, 2 H), 7.14 - 7.25 (m, C H). (2) ethyl 3-KSH4-(cyclohexyl|3-methyl-5-(pyridin-2-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoate (0.23 g) synthesized in the aforementioned (1) was dissolved in tetrahydrofuran (5 ml) and 2-pyridinemethanol (62 mg), tributylphosphine (0.21 ml) and 1,1-(azodicarbonyl)udipiperidine (0.21 g) were added to the solution under ice cooling. The ice bath was removed, the reaction mixture was stirred at at room temperature for 12 g, then hexane (15 mL) was added to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.19 g, 70905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.88 - 1.95 (m, 15 N), 2.21 (s, C H), 2.54-2.72 (m, 2 H), 3.01 (s, C H), 3, 70 (t, 0-72 Hz, 2H), 4.01-421 (m, 2H), 4.22-4.54 (m, 1H), 510 (s, 2H), 6.56 (d, U-8.7 Hz, 2 N), 6.80 - 7.05 (m, 2 N), 7.21 (d, 9-8.7 Hz, 2 N), 7.28 - 7.40 ( m, 2 N), 7.79 (d, U-8.0 Gu, 1 N), 8.58 (d, 2-4.5 Hz, 1 N), 8.70 (s, 1 N). (3)3-K(4-Cyclohexyl|3-methyl-5-(pyridin-2-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

Ethyl 3-KSH4-(cyclohexyl|3-methyl-5-(pyridin-2-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylXmethyl)amino|propanoate (0.19 g) was synthesized in the above mentioned ( 2), was dissolved in ethanol (5 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure, 1 M was added to the residue hydrochloric acid (1.0 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.11 g, 4195) as a yellow solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.92 - 2.16 (m, 12 H), 2.20 (s, 3 H), 2.62 (she, 2 H), 3 .02 (s, C H), 3.65 (shs, 2 H), 4.34 (d, 9-7.9 Hz, 1 H), 5.15 (s, 2 H), 6.54 ( d, U-8.3 Hz, 2 N), 6.75 - 6.98 (m, 2 N), 7.11 - 7.30 (m, 4 N), 7.35 - 7.52 (m , 1 N), 7.93 (d, 9-7.9 Hz, 1 N), 8.50 - 8.70 (m, 2

N).

Example A156 3-((4-(Hcyclohexylyl3-methyl-5-(pyridin-3-ylmethoxy)-1-benzofuran-2-

yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid (1) ethyl 3-KSH4-(cyclohexyl|3-methyl-5-(pyridin-3-ylmethoxy)-1-benzofuran-2 - yl|methyl)amino)phenylIcarbonylmethyl)amino|propanoate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonylI|(methyl)amino)propanoate (0.23 g), synthesized in Example

A155(1) was dissolved in tetrahydrofuran (5 ml), and 3-pyridinemethanol (62 mg), tributylphosphine (021 ml) and 1,1-(azodicarbonyl)udipiperidine (0.21 g) were added to the solution under ice cooling. Ice bath was removed, the reaction mixture was stirred at room temperature for 12 g, then hexane (5 ml) was added to the mixture, and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.13 g, 4995) as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.85 - 1.95 (m, 15 H), 2.19 (s, 3 H), 2.61 (sh s, 2 H), 3.01 (s, Z H), 3.70 (t, 9-7.2 Hz, 2 H), 4.12 (k.0-7.2,2.8 Hz, 2 H), 425-445 ( m, 2 N), 524 (s, 2 N), 6.55 (d, 9-8.7 Hz, 2 N), 6.84 - 7.02 (m, 2 N), 7.13 - 7 .30 (m, 4 N), 7.55 (d, 9U-7.9 Hz, 1 N), 7.67 - 7.82 (m, 1 N), 8.48 - 8.71 (m, 1 H). (2)3-K(4-Cyclohexyl|3-methyl-5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

Ethyl 3-KSH4-(cyclohexyl|3-methyl-5-(pyridin-3-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenyl IcarbonylXmethyl)amino|propanoate (0.13 g) was synthesized in the above mentioned ( 1) was dissolved in ethanol (5 ml), a 1M aqueous solution of sodium hydroxide (3.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure, 1M hydrogen chloride was added to the residue acid (3.0 mL) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.08 g, 9595) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.83 - 2.13 (m, 12 H), 2.18 (s, C H), 2.50-2.75 (sh c, 2H), 3.01 (s, C H), 3, 64 (she, 2 N), 4.35 (d, 9-7.9 Hz, 1 N), 5.44 (s, 2 N), 6.55 (d, U-8.7 Hz, 2 N ), 6.79 - 7.09 (m, 2 H), 7.12 - 7.25 (m, Z H), 7.45 - 8.01 (m, Z H), 8.66 (w s , 1 N).

Example A157 3-((4-(H-Cyclohexyl3-methyl-5-(pyridin-4-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid o 8, c AZ o

IR

M - Y N o d o (1) ethyl 3-KSH4-(cyclohexyl|3-methyl-5-(pyridin-4-ylmethoxy)-1-benzofuran-2-

yl|methyl)amino)phenylIcarbonylmethyl)amino|propanoate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonylI|(methyl)amino)propanoate (0.23 g), synthesized in Example

A155(1) was dissolved in tetrahydrofuran (5 ml), and 4-pyridinemethanol (62 mg), tributylphosphine (021 ml) and 1,1-(azodicarbonyl)udipiperidine (0.21 g) were added to the solution under ice-cooling. Ice bath was removed, the reaction mixture was stirred at room temperature for 12 g, then hexane (5 ml) was added to the mixture, and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.18 g, 6495) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.89 - 1.97 (m, 15 N), 2.20 (s, Z H), 2.61 (t, 9-72 Hz, 2 N), 3.01 (s, Z H), 3 .70 (t, 9-7.2 Hz, 2 N), 4.06 - 4.18 (k, 2-7.2 Hz, 2 N), 4.74 (d, 9-40 Hz, 1 N ), 5.11 (s, 2 N), 6.56 (d, 9U-8.7 Hz, 2 N), 6.82 - 6.99 (m, 2 N), 7.14 - 7.31 (m, Z H), 7.38 (d, U-6.0 Hz, 2

H), 8.60 - 8.69 (m, 2 H). (2)3-K(4-Cyclohexyl|3-methyl-5-(pyridin-4-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

Ethyl 3-KSH4-(cyclohexyl|3-methyl-5-(pyridin-4-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylXmethyl)amino|propanoate (0.17 g) was synthesized in the above mentioned ( 1) was dissolved in ethanol (5 ml), a 1M aqueous solution of sodium hydroxide (3.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure, 1M hydrogen chloride was added to the residue acid (3.0 mL) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.13 g, 7790) as a pale yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.81 - 2.13 (m, 12 H), 2.19 (s, C H), 2.50-2.75 (sh c, 2H), 3.03 (s, C H), 3, 60 - 3.75 (m, 2 N), 4.34 (d, 9-7.9 Hz, 1 N), 5.16 (s, 2 N), 6.53 (d, 2U-8.5 Hz ,2 H), 6.78 -6.97 (m, 2 H), 7.12 - 7.31 (m, Z H), 7.44 (d, 2-5.8 Hz, 2 H), 8.60 (d, 9-5.8 Hz, 2 N).

Example A158 3-(C4-(15-(benzyloxy)-3-methyl-1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylamino)propanoic acid

Oso 0 (1) ethyl 3-(C4-(C5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)"ucyclohexyl)methyl)amino)phenylcarbonylamino)upropanoate (5-(Benzyloxy)-3-methyl -1-benzofuran-2-yl|cyclohexyl)methanol (1.0 g) synthesized in Example A154(1) was dissolved in tetrahydrofuran (15 ml) and thionyl chloride (0.38 ml) was added to the solution at room temperature. was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (30 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (20 ml), sodium iodide (0.65 g), sodium carbonate (0.43 g) and ethyl 3-L(4-aminophenyl)carbonyl|amino)propanoate ( 0.68 g), synthesized in Example 1(2), and the mixture was stirred at 80 C for 12 g.

After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.78 g, 4895) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.92 - 1.98 (m, 15 N), 2.21 (s, Z H), 2.58 (t, 9U-5.7 Hz, 2 N), 3.48 (k, U-7 ,0 Hu, 1 N), 3.66 (k, 9U-5.7 Hz, 2 N), 4.11 (k, 9-7.2 Hz, 2 N), 4.30 - 4.54 ( m, 2 H), 5.08 (c, 2 H), 6.57 - 6.62 (m, C H), 6.82 - 7.02 (m, 2 H), 7.18 - 7, 60 (m, 8 N). (2)3-Cl4-Ch(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|propanoic acid

Ethyl 3-(C4-(T15-(benzyloxy)-3-methyl-1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylamino)upropanoate (0.78 g) synthesized in the above mentioned (1) was dissolved in ethanol (5 ml), a 1M aqueous solution of sodium hydroxide (3.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure, and 1M hydrochloric acid (3, 0 mL) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to afford the title compound (0.70 g, 9495) as a colorless solid.

IN NMR (300 MHz, SOS") b m.h. 0.81 - 2.10 (m, 12 H), 2.17 (s, Z H), 2.50 (w s, 2H), 3.55 (w s, 2 H), 4.32 (w s, 1 H), 5.04 (s, 2 H), 6.51 (d, 9U-8.7 Hz, 2 H), 6.68 (w s, 1 H), 6.81 - 6, 99 (m, 2

H), 7.23 - 7.59 (m, 8 H).

Example A159. 5-(Benzyloxy)-3-methyl-1-benzofuran-2-carboxylate

Potassium carbonate (13.1 g) was added to a solution (200 ml) of 1-(5-(benzyloxy)-2-hydroxyphenyl|ethanone (15.3 g) synthesized in Example A8B2(1) in M,M-dimethylformamide and ethyl bromoacetate (7.7 ml) at room temperature and the mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure, the resulting residue was redissolved in M,M-dimethylformamide (100 ml) and 1,8-diazabicyclo|5.4.O)undec-/-ene (12.2 ml) was added to the solution. The reaction mixture was stirred at 807 overnight. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the resulting solid was washed with ethanol-isopropyl ether to give the title compound (3.3 g, 1795) as a colorless solid. "H NMR (300 MHz, SOSI") b m.p. 1.44 (t, 9U-7.2 Hz, Z H), 2.55 (s, Z H), 4.45 (k, 90- 72 Hz, 2

H), 5.12 (s, 2 H), 7.01 - 7.21 (m, 2 H), 7.30 - 7.60 (m, 6 H). (2)(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|methanol

Lithium aluminum hydride (0.42 g) was added to a solution (50 ml) of ethyl 5-(benzyloxy)-3-methyl-1-benzofuran-2-carboxylate (3.3 g) synthesized in (1) mentioned above in tetrahydrofuran when cooled with ice. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice. Water (1.1 ml), 1 M aqueous solution of sodium hydroxide (5.5 ml) and water (1.1 ml) were successively added dropwise to quench the reaction. The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the title compound (2.8 g, quantitative) as a pale yellow solid.

IN NMR (300 MHz, SOSI") 6 m.h. 1.70 - 1.90 (w s, 1 H), 2.22 (s, Z H), 4.73 (d, 9-6.0 Hz, 2

H), 5.10 (s, 2 H), 6.88 - 7.06 (m, 2 H), 7.28 - 7.56 (m, 6 H). (3)5-(benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde

Manganese dioxide (5 g ) and the mixture was heated under reflux with a Dean-Stark attachment for 1 g. The reaction mixture was allowed to cool to room temperature, the catalyst was filtered through Celite. The filtrate was concentrated under reduced pressure to give the title compound (2.68 g, 94905) as colorless solid. "H NMR (300 MHz, SOSI") b m.p. 2.58 (s, C H), 5.12 (s, 2 H), 7.06 - 7.25 (m, 2 H), 7.32 - 7.57 (m, 6 H), 10.00 (s, 1 H). (4) ethyl 3-K4-(41-(5-(benzyloxy)-3-methyl-1 -benzofuran-2-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanesate

Isobutyl magnesium bromide (1M, tetrahydrofuran solution) was added dropwise to a solution (15 ml) of 5-(benzyloxy)-3-methyl-1-benzofuran-2-carbaldehyde (1.2 g) synthesized in (3) mentioned above in tetrahydrofuran. when cooled with ice. The ice bath was removed, the reaction mixture was stirred at room temperature for 15 min, and an aqueous solution of ammonium chloride was added to quench the reaction. The reaction mixture was extracted with ethyl acetate and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane--1:4, volume ratio) to give 1-|5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-3 -methylbutan-1-ol (0.82 g, 56965) as a pale yellow oil. It was dissolved in tetrahydrofuran (15 ml) and thionyl chloride (0.35 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (15 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (15 ml) and sodium iodide (0.56 g), sodium carbonate (0.38 g) and ethyl 3-((4-aminophenyl)carbonyl)(methyl)amino)propanoate were added to the solution (0.63 g), synthesized in

Example 2(2), and the mixture was stirred at 80C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.46 g, 3390) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.76 - 1.05 (m, 6 H), 1.11 - 1.90 (m, 6 H), 2.24 (s, Z H), 2.A7 - 2.69 (m, 2 H ), 3.01 (s, C H), 3.56 - 3.80 (m, 2 H), 3.95 - 4.32 (m, C H), 4.56 - 4.78 (m, 1 N), 5.09 (s, 2 N), 6.57 (d, 9-8.7 Hz, 2 N), 6.80 - 7.02 (m, 2 N), 7.12 - 7 .53 (m, 8 N). (5)3-CH14-CH1-(5-(benzyloxy)-3-methyl-1-benzofuran-2H-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanoic acid

Ethyl 3-CH4-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-2h-yl|-3-methylbutyl)amino)phenylcarbonylmethyl)amino|propanoate (0.46 g) was synthesized in the above mentioned ( 4), was dissolved in ethanol (5 ml), a 1M aqueous solution of sodium hydroxide (1.5 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure, 1M hydrogen chloride was added to the residue acid (1.5 ml) and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title compound (0.45 g, quantitative) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.90 (d, Z H, U-6.0 Hz), 0.99 (d, Z H, U-6.0 Hz), 1.25 - 2.00 (m, 4 H), 2, 24 (c, Z H), 2.67 (she, 2 H), 3.03 (s, C H), 3.71 (shs, 2 H), 4.20 - 4.40 (m, 2 H ), 5.08 (s, 2 N), 6.59 - 7.05 (m, 4 N), 7.31 - 7.57 (m, 8 N).

Example A160 3-((4-(H-Cyclohexyl3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylcarbonylylmethyl)amino|propanoic acid, 9 m

AND

8-9 as (1) ethyl 3-((4-((cyclohexyl|3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl)|methyl)iamino)phenyl IicarbonylXmethyl )amino|propansate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonylI|(methyl)amino)propanoate (0.50 g), synthesized in Example

A155(1) was dissolved in tetrahydrofuran (10 ml) and tetrahydrothiopyran-4-ol (142 mg), tributylphosphine (045 ml) and 1,1-(azodicarbonyl)udipiperidine (0.45 g) were added to the solution under ice cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 g, then hexane (10 mL) was added to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.14 g, 2395) as a yellow oil.

IN NMR (300 MHz, SOSI") 6 0.91 - 2.14 (m, 18 N), 2.20 (s, Z H), 2.46 - 2.99 (m, 6 N), 3, 01 (c,

With H), 3.33 - 3.49 (m, 1 H), 3.70 (t, 9U-7.1 Hz, 2 H), 4.12 (Kk. 0-72 Hz, 2 H), 425 -440 (m, 1 N), 6.56 (d, 2-8.7 Hz, 2 N), 6.78 - 6.94 (m, 2 N), 7.16 - 7.30 (m, With N). (2)3-C4-cyclohexyl|3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

Ethyl 3-(44-(cyclohexyl|3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|methyl)amino)phenyl IcarbonylXmethyl)amino|propanoate (0.14 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure, 1M hydrochloric acid (1.0 ml) was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-3:1, v/v) to give the title compound (0.06 g, 4695) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.86 - 2.15 (m, 16 H), 2.21 (s, Z H), 2.41 - 2.95 (m, 6 H), 3.06 (s, Z H), 3, 72 (t, 9-6.4 Hz, 2 N), 4.21 - 4.46 (m, 2 N), 6.56 (d, 2-8.7 Hz, 2 N), 6.76 - 6.95 (m, 2 H), 7.22 - 7.26 (m, C H).

Example A161 3-(1(4-(cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

N o m

SA

IS

(1) cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)methanone

Potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone were added to a solution (50 ml) of 1-(2-fluoro-b-hydroxyphenyl)ethanone (2.5 g) in M,M-dimethylformamide at room temperature (4.0 g) synthesized in Example A51(1) and the mixture was stirred at room temperature for 16 g. The reaction mixture was allowed to cool to room temperature and filtered through celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was again dissolved in M,M-dimethylformamide (50 ml), 1,8-diazabicyclo/5.4.O)undec-7-ene (2.6 ml) was added to the solution, and the mixture was stirred at 110 "C for 1 g at heating. After cooling to room temperature, the reaction mixture was quenched with 1M hydrochloric acid and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title compound (2.6 g, 6290), as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.20 - 2.07 (m, 10 N), 2.73 (s, C H), 3.20 - 3.36 (m, 1 H), 6.92 (ddd, U-10.0, 7.8, 0.8 Hz, 1 N), 7.27 - 7.44 (m, 2 N). (2) cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)methanol

Cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)umethanone (2.6 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (40 ml) and methanol (4 ml) and dissolved under cooling sodium borohydride (9095, 0.83 g) was added with ice. The ice bath was removed, the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, and water (5 ml) and 1M hydrochloric acid (10 ml) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (2.5 g, quantitative) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.72 - 2.22 (m, 12 H), 2.35 (s, C H), 4.50 (dd, U-8.6, 6.1 Hz, 1 H), 6.86 (ddd , 9-10.1, 7.6, 1.3 Hz, 1 N), 7.11 - 7.24 (m, 2 N). (3)3--(4-Hycyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid

Cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)umethanol (0.52 g) synthesized in (2) mentioned above, was dissolved in tetrahydrofuran (10 ml) and thionyl chloride (0 .27 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml) and sodium iodide (0.45 g), sodium carbonate (0.30 g) and ethyl 3-L(4-aminophenyl)carbonyl|amino)propanoate (0. 45 g), synthesized in Example 1(2), and the mixture was stirred at 80 C for 12 g.

After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-(cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2 - yl)umethyl|amino)phenyl)carbonyl|amino)propanoate (0.12 g, 1395) as a yellow oil. The obtained oil was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.11 g, 9595) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.85 - 2.18 (m, 12 N), 2.37 (s, Z H), 2.54 (t, 9-56 Hz, 2 N), 3.41 - 3.75 (m, 2 H), 4.35 (d, 2-81 Hz, 1 H), 6.44 - 6.64 (m, Z H), 6.72 - 6.89 (m, 1 H), 7.02 - 7.19 (m, 2 N), 7.52 (d, U-8.5 Hz, 2 N).

Example A162 3-(1(4-(cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Dt o m b

IS

Cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)umethanol (520 mg), synthesized in

Example A161(2) was dissolved in tetrahydrofuran (10 ml) and thionyl chloride (0.27 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (10 mL) was carefully added to the mixture. The mixture was stirred for 10 min and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml), sodium iodide (0.45 g), sodium carbonate (0.30 g) and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate were added to the solution (0.50 g), synthesized in Example 2(2), and the mixture was stirred at 80 for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-(cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2 - yl)methylamino)phenyl)carbonyl(methyl)aminopropanoate (0.15 g, 1595), as a yellow oil.

The obtained oil was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue acid (1.0 ml). The precipitate was washed with water to give the title compound (0.14 g, 9595) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.88 - 2.16 (m, 12 N), 2.38 (s, C H), 2.65 (t, 9-6.4 Hz, 2 N), 3.03 (s, C H) , 3.69 (t, 9U-6.4 Hz, 2 N), 4.35 (d, 2-8.3 Hz, 1 N), 6.56 (d, 2-8.7 Hz, 2 N ), 6.75 - 6.91 (m, 1 N), 7.03 - 7.18 (m, 2 N), 7.23 (d, 928.7 Hz, 2 N).

Example A163 3-((4-(cyclohexyl(5, 7-difluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acid and its molecule

M ha

IS

(1) cyclohexyl (5, 7-difluoro-3-methyl-1-benzofuran-2-yl) methanone

Potassium carbonate (6.7 g) and 2-bromo-1-cyclohexylethanone were added to a solution (50 ml) of 1-(3,5-difluoro-2-hydroxyphenyl)ethanone (2.8 g) in MM-dimethylformamide at room temperature (4.0 g) synthesized in Example A5B1(1) and the mixture was stirred at room temperature for 16 g. The reaction mixture was allowed to cool to room temperature and filtered through celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved again in M,M-dimethylformamide (50 ml), 1,8-diazabicycloi|5.4.Fundec-7-ene (2.6 ml) was added to the solution, and the mixture was stirred at 110 C for 1 g under heating.

After cooling to room temperature, the reaction mixture was quenched with 1M hydrochloric acid and the reaction mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title compound (3.1 g, 7095) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.09 - 2.09 (m, 10 N), 2.56 (s, Z H), 3.17 - 3.47 (m, 1 N), 6.93 - 7.16 (m, 2 N ). (2) cyclohexyl (5, 7-difluoro-3-methyl-1-benzofuran-2-yl) methanol

Cyclohexyl(5, 7-difluoro-3-methyl-1-benzofuran-2-ylumethanone (3.1 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (50 ml) and methanol (5 ml) and dissolved under cooling sodium borohydride (9095, 0.93 g) was added over ice.The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g, then cooled again with ice and water (5 mL) and 1M hydrochloric acid (10 mL) were cautiously added to the mixture. and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:4, v/v) to give the title compound (3.1 g, quantitative), as a pale yellow oil. "H NMR (300 MHz, SOSI") 6 ppm 0.83 - 2.00 (m, 12 H), 2.20 (s, C H), 4.52 (dd, U-8.5, 6.8 Hz, 1 H), 6.79 - 6.93 (m, 2 H). (3)3--:(4-Ycyclohexyl(5, 7 -difluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoic acids and

Cyclohexyl(5, 7-difluoro-3-methyl-1-benzofuran-2-ylmethanol (0.56 g) synthesized in (2) mentioned above was dissolved in tetrahydrofuran (10 ml) and thionyl chloride (0 .26 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (10 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml), sodium iodide (0.45 g), sodium carbonate (0.30 g) and ethyl 3-1(4-aminophenyl )carbonyl|amino)propanoate (0.45 g) synthesized in Example 1(2), and the mixture was stirred at 80 C for 12 h.

After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-(cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2 - yl)umethyl|amino)phenyl)carbonyl|amino)propanoate (0.17 g, 1795) as a yellow oil. The obtained oil was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.16 g, 9595) as a colorless solid. "H NMR (300 MHz, SOSI") b mp 0.87 - 2.14 (m, 12 H), 2.21 (s, C H), 2.61 (t, 9-5.7 HC, 2 N), 3.63 (k, 9U-5.7 Hz, 2 N), 4.39 (d, 9-8.3 Hz, 1 N), 6.45 - 6.64 (m, With H), 6.67 - 6.81 (m, 1 H), 6.87 (dd, U-8.3, 2.3 Hz, 1 H), 7.53 (d, U-8.7 Hz, 2 N).

Example A164 3-((4-(cyclohexyl(5, 7-difluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

E o M ha

IS

Cyclohexyl(5, 7-difluoro-3-methyl-1-benzofuran-2-yl)methanol (0.56 g), synthesized in

Example A163(2) was dissolved in tetrahydrofuran (10 ml) and thionyl chloride (0.26 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min. then it was cooled with ice and a saturated aqueous solution of sodium bicarbonate (10 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml) and sodium iodide (0.45 g), sodium carbonate (0.30 g) and ethyl 3-I-((4-aminophenyl)carbonyl | methyl)aminopropanoate (0 .50 g), synthesized in Example 2(2), and the mixture was stirred at 80 "С for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:.hexane-1:1, volume ratio) obtaining ethyl 3-(|(4-

Tricyclohexyl(4-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)aminoisopropanoate (0.17 g, 1790) as a yellow oil.

The obtained oil was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue acid (1.0 ml). The precipitate was washed with water to give the title compound (0.15 g, 9395) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.88 - 2.16 (m, 12 N), 2.21 (s, Z H), 2.67 (t, 9-64 Hz, 2 N), 3.04 (s, Z H), 3 .70 (t, 9U-6.4 Hz, 2 N), 4.38 (d, 9U-8.1 Hz, 1 N), 6.56 (d, 2-8.7 Hz, 2 N), 6.75 - 6.688 (m, 2 N), 7.23 (d, 9-8.7 Hz, 2 N).

Example A165 3-(14-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|styl)iamino)phenylcarbonylamino)propanoic acid

AND

(1)1-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|ethanone)

To a solution (120 ml) of 1-(5-(benzyloxy)-2-hydroxyphenyl|ethanone (6.4 g), synthesized in

Potassium carbonate (10.8 g) and bromoacetone (4.8 g) were added to Example A82(1) in M,M-dimethylformamide at room temperature, and the mixture was stirred at 80" for 1 g. Water was added to the reaction mixture and the mixture was extracted diethyl ether. The extract was concentrated under reduced pressure and the obtained residue was redissolved in M,M-dimethylformamide (120 ml) and 1,8-diazabicyclo/5.4.F)undec-7-ene (5.1 ml) was added to the solution. the mixture was stirred at 80"C for 2 h. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the resulting solid was washed with ethanol-isopropyl ether to give the title compound (2.5 g, 3495) as a colorless solid. "H NMR (300 MHz, SOSI") 6 m.h. 2.56 (s, C H), 2.60 (s, C H), 5.12 (s, 2 H), 7.11 (d , 9-23 Hz, 1 H), 7.17 (dd, 9U-8.9, 2.3 Hz, 1 H), 7.30 - 7.55 (m, 6H). (2)1-( 5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|ethanol 1-(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|ethanone (0.53 g) was synthesized in the mentioned above (1) was dissolved in tetrahydrofuran (10 ml) and methanol (1 ml) and sodium borohydride (9095, 0.16 g) was added to the solution under ice cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g, then cooled again with ice and water (1 mL) and 1M hydrochloric acid (5 mL) were cautiously added to the mixture and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the crude product (0.53 g, quantitatively) the title compound as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.62 (d, U-6.6 Hz, Z H), 1.91 (w s, 1 H), 2.21 (s, Z H), 4.95 - 5.21 (m, Z H ), 6.87 - 7.07 (m, 2 N), 7.28 - 7.58 (m, 6 N). (3)3-4Х14-(11-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|styl)iamino)phenylcarbonylamino)propanoic acid 1-(5-(Benzyloxy)-3-methyl- 1-Benzofuran-2-yl|ethanol (0.27 g) synthesized in (2) mentioned above was dissolved in tetrahydrofuran (5 mL), and thionyl chloride (0.13 mL) was added to the solution at room temperature. The reaction mixture was stirred at at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (10 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml) and sodium iodide (0.21 g), sodium carbonate (0.14 g) and ethyl 3-((4-aminophenyl)carbonylamino)upropanoate (0.23 g) were added to the solution ), synthesized in Example 1(2), and the mixture was stirred at 80 C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl /3-(14-(1-(5-(benzyloxy)-3-methyl-1- benzofuran-2-yl|styl)iamino)phenylcarbonylamino)propanoate (0.15 g, 3195) as a yellow oil. The obtained oil was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.13 g, 8895) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.62 (d, 9U-7.0 Hz, Z H), 2.22 (s, Z H), 2.69 (d, 9-5.7 Hz, 2

H), 3.57 - 3.76 (m, 2 H), 4.65 - 4.88 (m, 1 H), 5.08 (s, 2 H), 6.59 - 6.75 (m , Z H), 6.82 - 7.04 (m, 2

H), 7.29 - 7.62 (m, 8 H).

Example A166 3-CI4-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2- yl )-3-methyl-1-benzofuran-2-yl|ethanol (0.27 g), synthesized in Example

A165(2) was dissolved in tetrahydrofuran (5 ml) and thionyl chloride (0.13 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (10 ml), sodium iodide (0.21 g), sodium carbonate (0.14 g) and ethyl 3-(4-aminophenyl)carbonyl|(methyl)amino)propanoate ( 0.24 g), synthesized in Example 2(2), and the mixture was stirred at 80 for 12 g. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-(cyclohexyl(4-fluoro-3-methyl-1-benzofuran-2 - yl)umethylamino)phenyl)carbonyl(methyl)aminoisopropanoate (0.10 g, 20965), as a yellow oil.

The obtained oil was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue acid (1.0 ml). The precipitate was washed with water to give the title compound (0.09 g, 9095) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.63 (d, 9U-6.8 Hz, Z H), 2.21 (s, Z H), 2.69 (t, 9U-6.5 Hz, 2

H), 3.05 (s, C H), 3.71 (t, 9U-6.5 Hz, 2 H), 4.79 (k, 9U-6.9 Hz, 1 H), 5.09 (c, 2 H), 6.60 (d, 9-83 Gu, 2 H), 6.84 - 7.02 (m, 2 H), 7.27 - 7.51 (m, 8 H).

Example A167 3-(I44-K(cyclohexyl5-((2-fluoropyridin-4-yl)methoxy|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoic acid (8)

M-in (8) (1) ethyl 3-((4-Ycyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonylamino)propanesate

Ethyl 3-CH4-(CH5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)"ucyclohexyl)methyl)amino)phenylcarbonylamino|propanoate (5.6 g), synthesized in

Example A158(1) was dissolved in ethanol (100 ml) and platinum oxide (0.50 g) was added to the solution. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to give the title compound (3.2 g, 6890) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 1.94 (m, 14 H), 2.16 (s, Z H), 2.59 (t, 9U-5.8 Hz, 2 H), 3.66 (k, U-5 .8 Hz, 2 N), 4.03 - 4.14 (m, 2 N), 4.26 - 4.56 (m, 2 N), 5.57 (w s, 1 N), 6.56 (d, 9-8,7

Hz, 2 N), 6.61 - 6.68 - 6.71 (m, 1 N), 6.73 (dd, 9U-8.7, 2.3 Hz, 1 N), 6.83 (d , 9-2.3 Hz, 1 N), 7.19 (d, U-8.7 Gu, 1 N), 7.55 (d, 9-8.7 Hz, 2 N). (2) ethyl 3-((4-K(cyclohexyl/5-|(2-fluoropyridin-4-yl)methoxy|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenyl)icarbonyl)amino Ipropanoate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|Iamino)upropanoate (0.36 g) synthesized in the above mentioned (1) was dissolved in tetrahydrofuran (5 ml) and 2-fluoro-4-pyridinemethanol (114 mg), tributylphosphine (0.35 ml) and 1,7-(azodicarbonyl)udipiperidine (0.34 g) were added to the solution under ice cooling. The ice bath was removed, the reaction mixture was stirred at room temperature for 12 g, then hexane (5 ml) was added to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.23 g, 5495) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.00 (m, 14 N), 2.22 (s, Z H), 2.58 (t, 9-5.8 Hz, 2 N), 3.66 (k, U-5 .8 Hz, 2 N), 4.15 (k, 2-7.0 Hz, 2 N), 4.30 - 4.54 (m, 2 N), 5.13 (s, 2 N), 6, 57 -6.75 (m,

With H), 6.83 - 6.96 (m, 2 H), 7.05 (s, 1 H), 7.18 - 7.32 (m, 2 H), 7.55 (d, 9- 8.9 Hz, 2 N), 8.22 (d, 9-51 Hz, 1 N). (3)3-(44-Kcyclohexyl)-[(2-fluoropyridin-4-yl)methoxy]-3-methyl-1-benzofuran-2-

yl)umethyl)amino|phenylcarbonyl)(methyl)amino|Ipropanoic acid

Ethyl 3-(144-Kcyclohexyl5-|(2-fluoropyridin-4-yl)methoxy|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenyl)carbonyl)amino|propanoate (0.24 g) synthesized in the above mentioned (2), was dissolved in ethanol (3 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.17 g, 75905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.83 - 2.13 (m, 12 H), 2.20 (s, 3 H), 2.52-2.77 (m, 2 H), 3.52. - 3.77 (m, 2 N), 4.38 (d, U-8.0 Hz, 1 N), 5.14 (s, 2 N), 6.38 - 6.93 (m, 5 N ), 7.04 (s, 1 N), 7.17 - 7.25 (m, 2 N), 7.53 (d, 9-8.7 Hz, 2 N), 8.21 (d, 2 -5.3 Hz, 1 N).

Example A168 3-(I44-K(cyclohexyl5-((2-fluoropyridin-4-yl)methoxy|-3-methyl-1-benzofuran-2-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid at

M-- writes a

B) (1) ethyl. 3-((4-K(cyclohexyl/5-|(2-fluoropyridin-4-yl)methoxy|-3-methyl-1-benzofuran-2-ylmethyl)amino|phenyl)carbonyl)(methyl)amino|propanosate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethyl|amino)phenyl)carbonyl|(methyl)amino)propanoate (0.35 g), synthesized in Example

A155(1) was dissolved in tetrahydrofuran (5 ml) and 2-fluoro-4-pyridinemethanol (108 mg), tributylphosphine (0.32 ml) and 1,1-(azodicarbonyl)udipiperidine (0.32 d) The ice bath was removed, the reaction mixture was stirred at room temperature for 12 g, then hexane (5 mL) was added to the mixture and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate-hexane-1:2 v/v) to give the title compound (0.27 g, 6290) as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 0.94 - 1.99 (m, 14 H), 2.21 (s, 3 H), 2.61 (sh s, 2 H), 3.01 (s, C H), 3.70 (t, 9-7.1 Hz, 2 H), 4.12 (k, 9U-7.0 Gu, 2 H), 4.24 - 4, 49 (m, 2 H), 5.14 (s, 2 H), 6.56 (d, 9U-8.5 Hz, 2 H), 6.83 - 6.95 (m, 2 H), 7 .06 (s, 1 H), 7.21 - 7.28 (m, 4 H), 8.22 (d, 2-51 Gu, 1

N). (2)3-(144-Kcyclohexyl/15-|(2-fluoropyridin-4-yl)methoxy|-3-methyl-1-benzofuran-2-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

Ethyl 3-(144-Kcyclohexyl5-|(2-fluoropyridin-4-yl)methoxy|-3-methyl-1-benzofuran-2-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoate (0.27 g ) synthesized in the above-mentioned (1) was dissolved in ethanol (3 ml), a 1 M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.21 g, 8295) as a colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 0.86 - 2.14 (m, 12 H), 2.21 (s, C H), 2.67 (t, U9-6.4 Hz, 2 N), 3.04 (s, C H), 3.70 (t, U-6.4 Hz, 2 H), 4.36 (d, 92-8.0 Gu, 1 H), 5.14 (s, 2 H), 6.55 (d, 90-8.7 Hz, 2

H), 6.79 - 6.96 (m, 2 H), 7.05 (s, 1 H), 7.20 - 7.35 (m, 4 H), 8.21 (d, U-5 ,3 Hz, 1 N).

Example A169 3-4(4-((5-(6b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-ylUcyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanoic acid we him

SI about and - Ge

M

B) (1) ethyl 3-((4-1(5-(b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl|iamino)upropanoate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methyl|amino)phenyl)carbonyl|Iamino)propanoate (0.35 g), synthesized in Example A167(1) was dissolved in tetrahydrofuran (5 ml) and 56-chloro-3-pyridinemethanol (0.13 g), tributylphosphine (0.33 ml) and 1,7-(azodicarbonyl)udipiperidine (0.33 g) were added to the solution under ice cooling The ice bath was removed, the reaction mixture was stirred at room temperature for 12 g, then hexane (5 mL) was added to the mixture, and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.31 g, 6595) as a yellow oil. "H NMR (300 MHz, SOSI") b m.ch. 0.95 - 2.13 (m, 14 N), 2.22 (s, 2 N), 2.58 (t, 9-5.9 Hz, 2 N), 3.65 (k, U-5.9 Hz, 2 N), 4.25 (k, 9-7.0 Hz, 2 N), 4.29 - 4.54 (m, 1 N), 4.71 (d, 2-5.3 Hz, 1 N), 5.07 (s, 2 N), 6.48 -6.68 (m, C H), 6.77 - 7 .03 (m, 2 H), 7.25 (s, 1 H), 7.24 - 7.40 (m, 2 H), 7.54 (d,

U-8.7 Hz, 2 N), 7.68 - 7.76 (m, 1 N), 8.34 - 8.47 (m, 1 N). (2)3-(IM4-1(5-K(b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylaminophenyl)carbonylamino)upropanoic acid

Ethyl 3-1(4-((5-((b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-ylUcyclohexyl)methylIamino)phenyl)carbonyl|iaminoipropanoate (0.31 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 ml), a 1 M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and until 1M hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title compound (0.22 g, 74905) as a colorless solid. "H NMR (300 MHz, SOCI") b m.p. 0.88 - 2.13 (m, 12 N), 2.21 (s, Z H), 2.62 (t, 9-5.7 Hz, 2 N), 3.45- 3.77 (m , 2 H), 4.37 (d, U-8.0 Hz, 1 H), 5.07 (s, 2 H), 6.43 - 6.64 (m, C H), 6.75 - 6.99 (m, 2

H), 7.23 - 7.26 (m, 1 H), 7.35 (d, U-8.0 Hz, 1 H), 7.52 (d, 9U-8.7 Hz, 2 H) , 7.76 (dd, 9U-8.0, 1.9 Gu, 1 N), 8.43 (d, 2-1.9 Hz, 1 N).

Example A170 3-4(4-((5-(6b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid thanks

C o M - I N o (1) ethyl 3-((4-1(5-(b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-ylHUcyclohexyl)methyl|amino)phenyl )carbonyl|(methyl)amino)propanoate

Ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethyl|amino)phenyl)carbonyl|(methyl)amino)propanoate (0.39 g), synthesized in Example

A155(1) was dissolved in tetrahydrofuran (5 ml), b-chloro-3-pyridinemethanol (140 mg), tributylphosphine (0.35 ml) and 1,7-(azodicarbonyl)udipiperidine (0.36 g) were added to the solution under ice cooling ) The ice bath was removed, the reaction mixture was stirred at room temperature for 12 g, then hexane (5 ml) was added to the mixture, and the precipitate was filtered through celite. Water was added to the filtrate and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.32 g, 6690) as a yellow oil.

IN YAMRE (300 MHz, SOSI") b m.h. 0.95 - 2.13 (m, 14 N), 2.22 (s, ЗН), 2.61 (t, U-5.9 Hz, 2 N), 3.01 (s, З Н), 3.70 (t, 95.9 Hz, 2 N), 4.25 (k, 927.0 Hz, 2 N), 4.29 - 4.71 (m, 2 N), 5.07 (s, 2 N), 6.55 (d, 9U-8.7 Hz, 2 N), 6.77 - 7.03 (m, 2 N), 7.10 - 7.40 (m, 4 N), 7 .68 - 7.76 (m, 1 N), 8.34 - 8.47 (m, 1 N). (2)3-(IM4-1(5-K(b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

Ethyl 3-1(4-((5-((b-chloropyridin-3-yl)methoxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoate (0 .32 g) synthesized in the above-mentioned (1) was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.26 g, 8595) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.86 - 2.15 (m, 12 H), 2.21 (s, C H), 2.52-2.77 (m, 2 H), 3.04 (s, C H), 3, 69 (t, U-6.4 Hz, 2 N), 4.36 (d, 9U-8.0 Hz, 1 N), 5.08 (s, 2 N), 6.56 (d, 9- 8.7 Hz, 2

H), 6.71 - 7.00 (m, 2 H), 7.14 - 7.26 (m, Z H), 7.36 (d, 9U-8.0 Hz, 1 H), 7, 77 (dd, 9U-8.0, 1.9 Hz, 1

H), 8.44 (d, 2-1.9 Gu, 1 H).

Example A171 3-(C4-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylamino)propanoic acid (1 ) ethyl 3-(Ч4-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylamino)propanoate 1-(5-(Benzyloxy)-3- methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol (1.0 g), synthesized in Example A85(2), was dissolved in tetrahydrofuran (15 ml) and thionyl chloride (0 .43 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (15 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (15 ml), sodium iodide (0.74 g), sodium carbonate (0.50 g) and ethyl 3-K(4-aminophenyl) were added to the solution carbonylIaminoduprop anoate (0.76 g), synthesized in Example 1(2), and the mixture was stirred at 80 "C for 12 g. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.43 g, 2590) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9U-6.4 Hz, Z H), 1.12 (d, 9-7.0 Hz, Z H), 1.25 (t,

97.0 Hz, Z H), 2.16 - 2.34 (m, 4 H), 2.58 (t, U-6.0 Hz, 2 H), 3.66 (k, U-6, 0 Hz, 2 N), 4.15 (k,

UE7, O Hz, 2 H), 4.25 - 4.54 (m, 2 H), 5.08 (s, 2 H), 6.48 - 6.66 (m, C H), 6.80 - 7.04 (m, 2 H), 7.20 - 7.48 (m, 6 H), 7.55 (d, 929.0 Gu, 2 H). (2)3-414-411-(5-(benzyloxy)-3-methyl-1-benzofuran-g-yl|-2-methylpropyl)amino)phenylcarbonylamino)propanoic acid

Ethyl 3-(14-41-(5-(benzyloxy)-3-methyl-1-benzofuran-2h-yl|-2-methylpropyl)amino)phenylcarbonylamino)upropanoate (0.43 g) was synthesized in the above-mentioned (1) was dissolved in ethanol (10 ml), a 1 M aqueous solution of sodium hydroxide (2.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid was added to the residue ( 2.0 ml). The precipitate was washed with water to give the title compound (0.36 g, 8995) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.93 (d, 9-6.4 Hz, Z H), 1.13 (d, 9U-6.4 Hz, Z H), 2.10 - 2.40 (m, 4 H), 2, 67 (shs, 2 H), 3.66 (shs, 2 H), 4.35 (sh s, 1 H), 5.08 (s, 2 H), 6.44 - 6.69 (m, Z N), 6.79 - 7.68 (m, 10 N).

Example A172 3-(15-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-2-yl|carbonylmethyl)amino|propanoic acid o o (1) methyl 5-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-2-carboxylate 1 -(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol (1.0 g), synthesized in Example A58(2), was dissolved in tetrahydrofuran (15 ml) and thionyl chloride (0.43 mL) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (15 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylacetamide (15 ml), sodium iodide (0.74 g), sodium carbonate (0.50 g ) and methyl 5-aminopyridine-2-carboxylate (0.50 g) and the mixture was stirred at 80 C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to give the title compound (0.22 g, 1596) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.93 (d, U-6.8 Hz, Z H), 1.15 (d, U-6.8 Hz, Z H), 2.16 - 2.40 (m, 4 H), 3, 91 (s, Z H), 4.35 (t, U-8.1 Hz, 1 H), 4.65 (d, 9-8.7 Hz, 1 H), 5.08 (s, 2 H ), 6.72 - 7.03 (m, Z H), 7.18 - 7.53 (m, 6 H), 7.89 (d, 2-8.3 Hz, 1 H), 8.10 (d, 9U-2.6 Hz, 1 N). (2) ethyl 3-K15-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-2-ylcarbonylmethyl)amino|Ipropanate

Methyl 5-(11-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-2-carboxylate (0.22 g) was synthesized in the above-mentioned (1) was dissolved in ethanol (5 ml) and a 1 M aqueous solution of sodium hydroxide (1 ml) was added to the solution at room temperature.

The reaction mixture was stirred at 70 "C for 30 min, allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylformamide (1 ml) and 1-ethyl-3-(Z) hydrochloride was added to the solution at room temperature -dimethylaminopropyl)carbodiimide (0.17 g), 1-hydroxybenzotriazole monohydrate (0.14 g) and ethyl 3-(methylamino)propanate (0.10 g) and the mixture was stirred overnight. Water was added to the reaction mixture and the mixture was extracted with diethyl The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to afford the title compound (0.15 g, 56905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.93 (d, 9-6.4 Hz, Z H), 1.14 (d, 9U-6.4 Hz, Z H), 1.26 (t, 9U-7.2 Hz, Z H) , 2.16 - 2.36 (m, 4 N), 2.60 - 2.80 (m, 2 N), 3.80 (shs, 2 N), 4.12 (k,. 00-72 Hz , H), 4.22 - 4 AB (m, 2 H), 5.09 (s, 2 H), 6.79 - 7.05 (m, C H), 7.24 - 7.51 (m , 7 H), 7.93 (sh s, 1 H). (3)3-К15-(1-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)iamino)pyridin-2-yl|carbonylUmethyl)amino|propanoic acid

Ethyl 3-CI5-41-(5-(benzyloxy)-3-methyl-1-benzofuran-g-yl|-2-methylpropyl)amino)pyridin-2-ylcarbonylmethyl)amino|Ipropanoate (0.15 g) was synthesized in mentioned above (2), was dissolved in ethanol (3 ml), a 1 M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and until 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.14 g, quant.) as a colorless solid. "H NMR (300 MHz, SOSI") b m.p. 0.93 (d, U-6.8 Hz, Z H), 1.15 (d, U-6.8 Hz, Z H), 2 ,24 (c, Z

H), 2.27 - 2.39 (m, 1 H), 2.82 (shs, 2 H), 3.10 (s, C H), 3.77 (t, U-6.4 Gu, 2 H ), 4.31 (d, 2-7.9 Hu, 1 H), 5.09 (c, 2 H), 6.85 - 7.03 (m, C H), 7.29 - 7.61 (m, 7 H), 8.04 (w s, 1 H).

Example A173 3-CI4-(41-I(5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|propanoic acid (8) (8) thanks 9 I

Yi N

Oh ma CHI

B) (1)1-(5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-one

Potassium carbonate (1.1 d) and 1-bromo-33-methylbutan-2-one (0.56 g), synthesized in Example A75(1) at room temperature and the mixture was stirred for 15 g. The reaction mixture was filtered through celite, water (200 ml) was added and the mixture was extracted with diethyl ether (10 mLxh2).

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylformamide (10 mL), and 1,8-diazabicyclo/5.4.Oundec-7-ene (0.41 mL) was added to the solution at room temperature. The reaction mixture was stirred at 100 "C for 1 h. The reaction mixture was left to cool to room temperature, 1M hydrochloric acid (10 ml) was added, and the mixture was extracted with diethyl ether (10 mlx2). The extract was washed with water, saturated aqueous solution of sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, v/v) to afford the title compound (0.71 g, 98905) as a pale yellow oil .

IN NMR (300 MHz, SOSI") b m.h. 1.23 (d, 9U-6.8 Hz, 6 H), 2.57 (s, Z H), 3.48 (s, Z H), 3.56 (quin, U-6.8 Gu, 1 N), 3.74 - 3.85 (m, 2 N), 4.10 - 4.24 (m, 2 N), 7.05 (d, 9-26 Hz, 1 N), 7.14 (dd, 99.0, 2.6 Hz, 1 N), 7.39 (d, 9-9.0 Hz, 1 N). (2)1-(5-(2-Methoxyethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol 1-(5-(2-Methoxyethoxy)-3-methyl-1 -benzofuran-2-yl|-α-methylpropan-1-one (0.71 g) synthesized in (1) mentioned above was dissolved in tetrahydrofuran (5 ml) and methanol (0.5 ml) and added to the solution under ice cooling sodium borohydride (90905, 0.21 g).The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g,

then cooled again with ice and water (1 ml) and 1M hydrochloric acid (5 ml) were carefully added to the mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (0.70 g, quantitative) of the title compound as a pale yellow oil.

IN YAMRE (300 MHz, SOSI") b m.h. 0.82 (d, 9-6.8 Hz, Z H), 1.12 (d, U-6.8 Hz, Z H), 1.96 (sh s, 1H), 2.12 - 2, 33 (m, A H), 3.47 (s, C H), 3.70 - 3.85 (m, 2 H), 4.10 - 4.23 (m, 2 H), 4.46 ( d, 90-8,3

HC, 1 N), 6.79 - 7.01 (m, 2 N), 7.30 (d, 9-8.7 Hz, 1 N). (3)3-CH14-Ch1-(5-(2-methoxyethoxy)-3-methyl-1-benzofuran-g-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|Ipropanoic acid 1-(5-(2 -Methoxyethoxy)-3-methyl-1-benzofuran-2-yl|-α-methylpropan-1-ol (0.70 g) synthesized in the above-mentioned (2), dissolved in tetrahydrofuran (10 ml) and dissolved at room temperature thionyl chloride (0.34 mL) was added at room temperature.The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium hydrogencarbonate (5 mL) was cautiously added to the mixture.

The reaction mixture was stirred for 10 min and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10 ml), sodium iodide (0.56 g), sodium carbonate (0.38 g) and ethyl 3-(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.63 g) were added to the solution. synthesized in Example 2(2), and the mixture was stirred at 80 "С for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane- 1:1, volume ratio) yielding ethyl 3-((4-(1-(5-(2-methoxyethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenylcarbonylmethyl) amino|Ipropanoate (0.10 g, 895) as a yellow oil.

The obtained oil was dissolved in ethanol (3 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue acid (1.0 ml). The precipitate was washed with water to give the title compound (0.05 g, 52905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9U-6.4 Hz, Z H), 1.12 (d, 9-64 Hz, Z H), 2.21 (s, Z

H), 2.23 - 2.36 (m, 1 H), 2.67 (t, 9U-6.4 Hz, 2 H), 3.04 (s, C H), 3.46 (s, With H), 3.69 (t, U-6.4 Hz, 2

H), 3.73 - 3.84 (m, 2 H), 4.15 (dd, 955.7, 3.8 Hz, 2 H), 4.32 (d, 957.5 Hz, 1 H) , 6.57 (d, 9-8.7 Hz, 2 H), 6.76 - 6.98 (m, 2 H), 7.15 - 7.25 (m, C H).

Example A174 3-((4-H-Cyclohexyl-5-(b-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenyl]carbonyl(methyl)amino|propanoic acid

More M / H o x (1X5-bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanone 1-(3-Bromo-2-hydroxyphenyl|ethanone) (13.4 g) was dissolved in M, M-dimethylformamide (300 ml).

Potassium carbonate (25.8 g) and 2-bromo-1-cyclohexylethanone (19.0 g) synthesized in Example A5b1(1) were added to the reaction mixture at room temperature, and the mixture was stirred for 3 h. The reaction mixture was filtered through celite, water (200 ml) was added and the mixture was extracted with diethyl ether (100 mlx2). The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylformamide (150 ml), 1,8-diazabicyclo/5.4.FO)undec-7-ene (9.3 ml) was added to the solution at room temperature, and the mixture was stirred at 10070 for 1 h. the mixture was allowed to cool to room temperature, 1M hydrochloric acid (70 ml) was added and the mixture was extracted with diethyl ether (100 mlx2). The extract was washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title compound (15.4 g, 77905) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 1.16 - 2.05 (m, 10 N), 2.56 (s, C H), 3.20 - 3.36 (m, 1 H), 7.40 (d, U-8.9 Hz, 1 H), 7.55 (dd, U-8.9, 1.5 Hz, 1 H), 7.77 (d, 91.5 Hz, 1 H). (2)(5-Bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methanol (5-Bromo-3-methyl-1-benzofuran-2-yl)(cyclohexyl) methanone (7.5 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (100 ml) and methanol (15 ml) and sodium borohydride (90965, 1.9 g) was added to the solution while cooling with ice. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 g, then cooled again with ice, and water (10 mL) and 1 M hydrochloric acid (50 mL) were cautiously added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford the crude product (7.4 g, quant.) of the title compound as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.83 - 2.11 (m, 11 H), 2.19 (s, C H), 3.62 - 3.85 (m, 1 H), 4.51 (she, 1 H), 7, 27 - 7.59 (m, Z H). (3) ethyl 3-(4-((5-bromo-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoate (5-Bromo-3-methyl- 1-benzofuran-2-yl)(cyclohexyl)methanol (7.5 g) synthesized in (2) mentioned above, was dissolved in tetrahydrofuran (150 ml) and thionyl chloride (3.1 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (75 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (100 ml) and sodium iodide (5.2 g), sodium carbonate (3.5 g) and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (5.8 d), synthesized in Example 2(2), and the mixture was stirred at 80 C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:1, v/v) to give the title compound (6.0 g, 47905) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.ch. 0.88 - 1.97 (m, 14 H), 2.22 (s, C H), 2.61 (t, U-7.1 Hz, 2 N), 3.01 (s, Z H), 3.70 (t, 9-7.1 Hz, 2 N), 3.99 - 4.17 (m, 2 N), 4.23 - 4.47 (m, 2 H), 6.55 (d, U-8.7 Hu, 2 H), 7.11 - 7.37 (m, 4 H), 7.54 (d, 9d9- 1.7 Hz, 1 N). propanoic acid

To the solution (5 ml) ethyl 3-((4-((5-bromo-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanesatz (0.25 g ), synthesized in (3) mentioned above, (6-methoxypyridin-3-yl)boronic acid (0.14 g), potassium carbonate (0.13 g) and tetrakistriphenylphosphinepalladium (0.05 g) were added to M,M-dimethylacetamide and the mixture was stirred at 90 "C for 12 g under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite and the residue was washed with diethyl ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate :hexane-1:1, volume ratio) obtaining ethyl 3-(4-(/cyclohexyl(5-(b-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-

yl|methyl)amino)phenylIcarbonylmethyl)amino|propanoate (0.15 g, 5895) as a pale yellow oil. The resulting oil was dissolved in ethanol (1 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid was added to the residue ( 1.0 ml). The precipitate was washed with water to give the title compound (0.12 g, 8595) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 1.27 - 2.19 (m, 12 H), 2.29 (s, C H), 2.69 (t, 9-6.4 Hz, 2 H), 3.05 (s, C H), 3.70 (t, U-6.4 Hz, 2 H), 3.99 (s, C H), 4.41 (d, 2 -7.9 Hz, 1 N), 6.58 (d, 9-8.7 Hz, 2

H), 6.83 (d, 9-9.0 Hz, 1 H), 7.19 - 7.26 (m, 2 H), 7.32 - 7.53 (m, C H), 7, 81 (dd, 9-8.5, 2.4 Hz, 1

H), 8.38 (d, 9-23 Gu, 1 H).

Example A175 3-4(4-(1-(4-fluoro-3-methyl-1-benzofuran-2h-yl)-2-methylpropylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

SYA

IS

(1)1-(4-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one

Potassium carbonate (3.5 g) and 1-bromo-33-methylbutane-2- it (1.7 g), synthesized in

Example A75(1) at room temperature and the mixture was stirred at room temperature for 3 h. The reaction mixture was allowed to cool to room temperature and filtered through celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was again dissolved in

M,M-dimethylformamide (15 ml), 1,8-diazabicyclo/5.4.Fundec-7-ene (1.3 ml) was added to the mixture, and the mixture was stirred at 110 "C for 1 h under heating. After cooling to room temperature , the reaction mixture was quenched with 1M hydrochloric acid and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the precipitated compound was recrystallized from diisopropyl ether-hexane to give the title compound (1.4 g, 7790) as a colorless solid. "H NMR (300 MHz, SOSI") 6 m.h. 1.24 (d, 9U-6.8 Hz, 6 N), 2.74 (s, Z H), 3.50 - 3.66 (m, 1 H), 6.93 (dd, 9U-10 ,2, 7.9 Hz, 1 N), 7.28 - 7.50 (m, 2 N). (2)1-(4-Fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol 1-(4-Fluoro-3-methyl-1-benzofuran-2-yl)- 2-methylpropan-1-one (1.4 g) synthesized in (1) mentioned above was dissolved in tetrahydrofuran (20 ml) and methanol (2 ml) and sodium borohydride (9095, 0.53 g) was added to the solution while cooling with ice . The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, water (2 ml) and 1M hydrochloric acid (5 ml) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (1.4 g, quantitative) of the title compound as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.82 (d, 9U-6.8 Hz, Z H), 1.13 (d, 9U-6.8 Hz, Z H), 1.99 (d,

U-5.7 HZ, 1 H), 2.22 (dt, 98.3, 6.8 Gu, 1 H), 2.36 (s, З H), 4.46 (dd, 9U-8, 3, 5.7 Hz, 1 N), 6.77 - 7.23 (m, C H). (3)3-(IC4-11-(4-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropylamino)phenyl)carbonyl)(methyl)amino)propanoic acid 1-(4-Fluoro- 3-methyl-1-benzofuran-2-yl)-2-methylpropan-i-ol (1.4 g) synthesized in the above-mentioned (2), was dissolved in tetrahydrofuran (20 ml) and thionyl chloride was added to the solution at room temperature ( 0.84 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (20 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (30 ml) and sodium iodide (1.4 g), sodium carbonate (0.96 g) and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (1.6 g), synthesized in Example 2(2), and the mixture was stirred at 80 "C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate :hexane-1:1, volume ratio) obtaining ethyl (-3-(4-1X11-(4-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropylamino)phenyl)carbonyl)( methyl)amino)propanoate (0.20 g, 795) as a yellow oil.

The obtained oil was dissolved in ethanol (2 ml), a 1M aqueous solution of sodium hydroxide (2.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (2.0 ml). The precipitate was washed with water to give the title compound (0.06 g, 32905) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 0.92 (d, 9U-6.4 Hz, Z H), 1.14 (d, 9U-6.4 Hz, Z H), 2 .09 - 2.32 (m, 1 N), 2.39 (s, C H), 2.69 (t, U-6.2 Hz, 2 H), 3.05 (s, C H), 3.71 (t, 9U-6.2 Hz, 2 N), 4.31 (d, 9U-7.9 Hz, 1 N), 6.58 (d, 2-8.7 Hz, 2 N) , 6.76 - 7.19 (m, C H), 7.25 (d, 9-8.7 Hz, 2 H).

Example A176 3-((4-(cyclohexyl(3-methyl-5-phenyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

C) C) 9 IR vai

To a solution (5 ml) of ethyl 3-((4-((5-bromo-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanate (0.28 g ), synthesized in Example A174(3), phenylboronic acid (0.12 g), potassium carbonate (0.14 g) and tetrakistriphenylphosphinepalladium (0.10 g) were added to M,M-dimethylacetamide, and the mixture was stirred at 70 "C for 12 g under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane-1:1, vol. volume ratio) to give ethyl 3-1-(4-ylcyclohexyl(3-methyl-5-phenyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl)(methyl)amino)propanate (0.15 g, 5495) , as a pale yellow oil. The obtained oil was dissolved in ethanol (1 ml), 1 M aqueous sodium hydroxide solution (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature ature for 0.5 g. Ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.09 g, 6790) as a colorless solid. "IN NMR (300 MHz, SOSI") b m.ch. 0.97 - 2.16 (m, 11 H), 2.29 (s, Z H), 2.69 (t, U-6.2 Hz, 2 N), 3.05 (s, C H), 3.72 (t, 9U-6.2 Hz, 2 H), 4.41 (d, 2-7.9 Hz, 1 H), 6.58 (d, 2-8.7 Hz, 2 N), 7.23 - 7.66 (m, 10 N).

Example A177 3-((4-Hcyclohexyl5-(2-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoic acid M vo y - y o

Mind

To a solution (15 ml) of ethyl 3-(ЧА-(5-bromo-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (0.53 g), synthesized in Example A174(3), in M,M-dimethylacetamide was added (2-methoxypyridine-

Z-yl)boronic acid (0.29 g), potassium carbonate (0.27 g) and tetrakistriphenylphosphine palladium (0.05 g) and the mixture was stirred at 90 "C for 12 g under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, was filtered through celite and the residue was washed with diethyl ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane-1:1, volume ratio) to give ethyl 3-|((4- (cyclohexyl|5-(2d-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylcarbonylmethyl)amino|propanoate (0.50 g, 8995), as a pale yellow oil The resulting oil was dissolved in ethanol (1 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M was added to the residue hydrochloric acid (1.0 mL).The precipitate was washed with water to give the title compound (0.47 g, quantitatively), as a colorless solid. "H NMR (300 MHz, SOSIz") b mp 0.97 - 2.15 (m, 11 H), 2.27 (s, C H), 2.49 - 2.65 (m, 2 H), 2.99 (s, C H), 3.65 (w s, 2 H), 3.95 (s, C H), 4.39 (d, 9-7.9 Hz, 1 H) , 6.56 (d, U-8.7 Hz, 2 N), 6.97 (dd, 97.2, 4.9 Hz, 1 N), 7.23 (d, 928.7 Hz, 2 N ), 7.38 - 7.66 (m, 4 H), 8.15 (dd, 95.1, 2.1 Hz, 1

N).

Example A178 3-((4-((cyclohexyl|5-(3,5-dimethylisoxazol-4-yl)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid its 0 M wad o

To a solution (15 ml) of ethyl 3-(ЧА-(5-bromo-3-methyl-1-benzofuran-2-yl)Hycyclohexyl)methylaminophenyl)carbonyl)(methyl)amino)propanate (0.54 g), synthesized in (3,5-dimethylisoxazol-4-yl)boronic acid (0.41 g) and 2M aqueous sodium carbonate solution (1.46 ml) were added to Example A174(3) in toluene, and the mixture was stirred at room temperature for 10 min in an atmosphere argon 2-dicyclohexylphosphino-2'b'-dimethoxybiphenyl (0.05 g) and tris(dibenzylideneacetone)idipalladium (0) (0.03 g) were added to the reaction mixture, and the mixture was heated under reflux under argon overnight. The reaction mixture was cooled to room temperature, filtered through celite and the residue was washed with diethyl ether.

Water was added to the filtrate and the organic layer was concentrated under reduced pressure.

The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-(cyclohexyl5-(3,5-dimethylisoxazol-4-yl)-3-methyl-1-benzofuran -2-yl|methylamino)phenylIcarbonylmethyl)amino|Ipropanoate (0.13 g, 2395) as a pale yellow oil. The obtained oil was dissolved in ethanol (1 mL), and 1 M aqueous sodium hydroxide solution (1 .0 mL) and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title compound (0.12 g, 96905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.93 - 2.19 (m, 11 H), 2.26 (s, Z H), 2.27 (s, Z H), 2.39 (s, Z

H)U, 2.71 (t, 96.2 Hz, 2 H), 3.07 (s, C H), 3.73 (t, 926.2 Hz, 2 H), 4.41 (d, 957.9 Hz, 1 N), 6.58 (d, 9-8.7 Hz, 2 N), 7.08 (dd, 9U-8.3, 1.5 Hz, 1 N), 7.20 - 7.26 (m, C H), 7.42 (d, 98.3 Hz, 1 H).

Example A179 3-CI4-(41-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|Ipropylamino)phenylcarbonylKmethyl)amino|Ipropanoic acid 9 mg ha o (1)1-(Z- (benzyloxy)-3-methyl-1-benzofuran-2-yl|Ipropan-1-one

To a solution (150 ml) of 1-(5-(benzyloxy)-2-hydroxyphenyl|ethanone (7.8 g), synthesized in

Potassium carbonate (13.2 g) and 1-bromobutan-2-one (5.0 ml) were added to Example 82(1) in M,M-dimethylformamide at room temperature and the mixture was stirred at room temperature for 3 h. The reaction mixture was left cooled to room temperature and filtered through celite. Water was added to the filtrate and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was again dissolved in M,M-dimethylformamide (100 ml), 1,8-diazabicyclo|5.4.O)undec-7-ene (4.9 ml) was added to the solution, and the mixture was stirred at 110 "C with heating for 1 g. After cooling to room temperature, the reaction mixture was quenched with 1M hydrochloric acid and the mixture was extracted with diethyl ether. colorless solid. "H NMR (300 MHz, SOSI") b m.ch. 1.22 (t, 9U-7.2 Hz, Z H), 2.57 (s, Z H), 3.01 (k, 9-72 Hz, 2

H), 5.12 (s, 2 H), 7.04 - 7.52 (m, 8 H). (2)1-(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|Ipropan-1-ol 1-(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl| Ipropan-1-one (0.88 g) synthesized in (1) mentioned above was dissolved in tetrahydrofuran (15 ml) and methanol (1 ml) and sodium borohydride (9095, 0.25 g) was added to the solution while cooling with ice. with ice was removed and the reaction mixture was stirred at room temperature for 1 g, then cooled again with ice, water (2 ml) and 1 M hydrochloric acid (5 ml) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (0.85 g, quantitative) of the title compound as a pale yellow oil. 7.4 Hz, Z H), 1.92 - 2.03 (m, Z H), 2.21 (s, Z H), 4.69 - 4.87 (m, 1 H), 5.11 (c, 2 H), 6.89 - 7.51 (m, 8 H). (3)3-Х4-Х1-(5-(benzyloxy)-3-methyl-1-benzofuran-2-

yl|Ipropylamino)phenylIcarbonylmethyl)amino|propanoic acid 1-(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|propan-y-ol (0.85 g) was synthesized in the above-mentioned (2), was dissolved in tetrahydrofuran (15 mL) and thionyl chloride (0.40 mL) was added to the solution at room temperature. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15 mL), sodium iodide (0.67 g), sodium carbonate (0 .45 g) and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (0.75 g), synthesized in Example 2(2), and the mixture was stirred at 80 "С for 4 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate t was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl /3-((14-(31-(5-(benzyloxy)-3-methyl-1 -benzofuran-2-yl|Ipropylamino)phenyl(Icarbonylmethyl)amino|propanoate (0.15 g, 995) as a yellow oil.

The obtained oil was dissolved in ethanol (2 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.10 g, 7195) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 (t, 9U-7.3 Hz, Z H), 1.87 - 2.08 (m, 2 H), 2.23 (s, Z H), 2.66 (t, U-6 ,2 Hz, 2 H), 3.03 (s, Z H), 3.70 (t, 9U-6.2 Hz, 2 H), 4.52 (dd, U-8,3,6,2 Hz, 1 N), 5.09 (s, 2 N), 6.57 (d, U-8.7 Hz, 2 N), 6.82 - 7.02 (m, 2 N), 7.18 - 7.51 (m, 8 N).

Example A180

3-(methylT4-(2-methyl-1-|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|Ipropylamino)phenyl|carbonylamino)propanoic acid

Io o. (1)1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one

To a solution of 1-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|-e-methylpropan-1-one (11.4 g) synthesized in Example A85(1) in ethanol (200 ml ) at room temperature, a palladium charcoal-ethylenediamine complex (1.1 g) was added.The reaction mixture was stirred in a hydrogen atmosphere (1 atm) at room temperature for 16 g, and the catalyst was filtered off.

The filtrate was concentrated under reduced pressure to give the crude product (8.0 g, quant.), the title compound, as a colorless solid.

IN NMR (300 MHz, SOSIz") 6 m.h. 1.24 (d, 9U-6.8 Hz, 6 N), 2.55 (s, C H), 3.48 - 3.63 (m, 1 H), 6.95 - 7.40 (m , Z H). (2)3-(methylT4-(2-methyl-1-3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2-yl|Ipropylamino)phenyl|carbonylamino)propanoic acid 1 -(5-Hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.1 g) synthesized in (1) mentioned above was dissolved in M,M-dimethylformamide (20 ml) and potassium phosphate (1.3 g) and tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (2.8 g) were added at room temperature. The reaction mixture was stirred at 80 "C for 4 hours, and potassium phosphate (1.3 g) and tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate (2.8 g) were added again. After stirring for 12 hours at 80 "C , cooled to room temperature and quenched with water. The mixture was extracted with diethyl ether, then washed with saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate-hexane - 1:4, volume ratio) to obtain 1-(5-(tetrahydro-2H-pyran-4-yl)-3-methyl-1-benzofuran-2-yl)- 2-methylpropan-1-one (1.1 g, 7895) as a colorless oil.

The obtained oil (1.1 g) was dissolved in tetrahydrofuran (15 ml) and methanol (1 ml), and sodium boron hydride (90905, 0.30 g) was added to the solution while cooling. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, water (5 mL) and 1M hydrochloric acid (15 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain /1-(5-(tetrahydro-2H-pyran-4-yl)-3-methyl-1-benzofuran-2-yl)-2-methylpropan- 1- ol (0.71 g, 65905), as a pale yellow oil. The obtained oil was dissolved in tetrahydrofuran (15 ml) and thionyl chloride (0.30 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (20 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15 ml), sodium iodide (0.52 g), sodium carbonate (0.35 g) and ethyl 3-D(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.58 g) were added to the mixture. , synthesized in Example 2(2), and the mixture was stirred at 70"C for 4 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane -1:1, volume ratio) obtaining ethyl 3-(methyl|4-(2-methyl-1-|3-methyl-5-(tetrahydro-2H-pyran-4-yloxy)-1-benzofuran-2 - yl|Ipropylamino)phenylIcarbonylamino)propanoate (0.54 g, 4695) as a yellow oil. The resulting oil was dissolved in ethanol (3 mL), 1M aqueous sodium hydroxide solution (3.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (3.0 ml) was added to the residue. The precipitate was washed with water to obtain affording the title compound (0.53 g, 9895) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.92 (d, U-6.8 Hz, Z H), 1.13 (d, 9U-6.8 Hz, Z H), 1.70 - 2.09 (m, 4 H), 2, 21 (s, C H), 2.22 - 2.27 (m, 1 H), 2.67 (t, 9-6.2 Hz, 2 H), 3.04 (s, C H), 3 .56 (ddd, 9U-11.5, 8.5, 3.4 Hz, 2 N), 3.70 (t, 9U-6.2 Hz, 2 N), 3.91 - 4.08 (m , 2 H), 4.32 (d, 2-7.6 Hz, 1 H), 4.43 (tt, 9U-7.9, 3.8 Hz, 1 H), 6.57 (d, 9U -8.7 Hz, 2 N), 6.85 (dd, 9U-8.7, 2.7 Hz, 1 N), 6.93 (d, 9-2.3 Hz, 1 N), 7, 19 - 7.26 (m, Z H).

Example A181. o M wad N

And x and

To a solution (15 ml) of ethyl 3-S(A-((5-bromo-3-methyl-1-benzofuran-2-yl)/cyclohexyl)methylaminophenyl)carbonyl|(methyl)amino)propanoate (0.59 g) , synthesized in Example A174(3), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole ( . ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to give ethyl 3-((4-(cyclohexyl|3-methyl-5 -(1-Methyl-1H-pyrazol-4-yl)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylmethyl)amino|propanoate (0.23 g, 3995) as a pale yellow oil. was dissolved in ethanol (1 ml), a 1 M aqueous solution was added to the solution at room temperature sodium hydroxide (1.0 ml) and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to give the title compound (0.04 g, 1695) as a colorless solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.93 - 2.11 (m, 11 H), 2.27 (s, 3 H), 2.67 (sh s, 2 H), 3.03 (s, C H), 3.70 (t, 9U-6.2 Hz, 2 H), 3.94 (s, C H), 4.38 (d, 9U-7.8 Hz, 1 N), 6.57 (d, 9-8.6 Hz, 2 N), 7.23 (d, U-8.6 Hz, 2 N), 7.29 - 7.39 (m, 2 N ), 7.49 (s, 1 H), 7.59 (s, 1 H), 7.75 (s, 1 H).

Example A182 3-CI4-(11-(15-(6-Methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenyl]carbonylmethyl)amino|Ipropanoic acid 0. M n o x (1)1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one 1-(3-Bromo-2-hydroxyphenyl|ethanone) (8 .4 g) was dissolved in M,M-dimethylformamide (50 ml).

Potassium carbonate (16.2 g) and 1-bromo-3-methylbutan-2-one (8.4 g) synthesized in Example A75(1) were added to the reaction mixture at room temperature and the mixture was stirred at 607 for 1 h. The reaction mixture was filtered through celite, water (100 ml) was added and the mixture was extracted with diethyl ether (50 mlx2). The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitate was washed with diisopropyl ether to give the title compound (10.2 g, 7790) as a pale yellow solid.

IN NMR (300 MHz, SOSIZ") b m.h. 1.25 (d, U-6.8 Hz, 6 H), 2.57 (s, Z H), 3.48 - 3.70 (t. 1 H), 7.39 (d, U-8 .7 Hz, 1 N), 7.55 (dd, U-8.7, 1.9 Hz, 1 N), 7.78 (d, 9U-1.9 Hz, 1 N). (2) ethyl 3-((4-11-(5-bromo-3-methyl-1-benzofuran-2-yl)-2- methylpropylamino)phenyl)carbonyl)(methyl)amino)propanate 1-(5-Bromo -3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (6.2 g) synthesized in the aforementioned (1) was dissolved in tetrahydrofuran (100 ml) and methanol (10 ml) and until the solution while cooling with ice, sodium borohydride (90965, 1.8 g) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, water (10 mL) and 1M hydrochloric acid (50 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (6.1 g, quantitative) , as a pale yellow oil. The obtained oil was dissolved in tetrahydrofuran (50 ml) and thionyl chloride (2.3 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (30 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (100 ml) and sodium iodide (3.9 g), sodium carbonate (2.7 g) and ethyl 3-((4-aminophenyl)carbonyl|)(methyl)amino)propanoate (4.4 g) were added to the solution ), synthesized in Example 2(2), and the mixture was stirred at 70 "C for 4 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate: hexane-1:1, v/v) to give the title compound (1.12 g, 1296) as a yellow oil. "H NMR (300 MHz, SOCI") b m.p. 0.91 (d, 9U-6.4 Hz, Z H), 1.13 (d, 9U-6.4 Hz, Z H), 1.18 - 1.26 (t, 97.2 Hz, Z H), 2.20 - 2.35 (m, 4 H), 2.61 (t, 9-7.0 Hz, 2 H), 3.01 (s, 4 H), 3.70 (t, d9-7.0 Hz, 2

H), 4.09 - 4.17 (m, 2 H), 4.24 - 4.A1 (m, 2 H), 6.56 (d, 98.7 Hz, 2 H), 7.15 - 7.36 (m, 4 H), 7.55 (d, 9U-1.9 Gu, 1 H). (3)3-Ch14-Ch1-(5-(6-methoxypyridin-3-yl)-3-methyl-1-benzofuran-g-yl|-2-methylpropyl)amino)phenylcarbonylmethyl)amino|ipropanoic acid

To a solution (10 ml) of ethyl 3-((4-11-(5-bromo-3-methyl-1-benzofuran-2-yl)-2- methylpropylamino)phenyl)carbonyl)(methyl)aminodupropanoate (0.55 g), synthesized in the above-mentioned (2), in M,M-dimethylacetamide was added (b-methoxypyridin-3-yl)/boronic acid (0.33 g), potassium carbonate (0.29 g) and tetrakistriphenylphosphine palladium (0. 12 g) and the mixture was stirred at 70 "C for 24 g in an argon atmosphere. The reaction mixture was cooled to room temperature, filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) obtaining ethyl 3-C(4-(1-(5-(6-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl |-2- methylpropyl)amino)phenylcarbonylmethyl)amino|propanosate (0.10 g) as a pale yellow oil.

The resulting oil was dissolved in ethanol (1 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.06 g, 1095) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 (d, 9U-6.8 Hz, Z H), 1.15 (d, 9U-6.8 Hz, Z H), 2.15 - 2.37 (m, 1 H), 2, 29 (s, C H), 2.66 (t, 9U-6.2 Hz, 2 H), 3.03 (s, C H), 3.70 (t, 9U-6.2 Hz, 2 H ), 3.98 (c, Z

H), 4.36 (d, 9-7.5 Hz, 1 H), 6.58 (d, 9-8.7 Hz, 2 H), 6.82 (d, 9-8.7 Hz, 1 H), 7.23 (d, 90-8.7 Hz, 2

H), 7.30 - 7.46 (m, 2 H), 7.53 (d, 9U-1.9 Hz, 1 H), 7.79 (dd, U-8.5, 2.4 Hz , 1 N), 8.38 (d, 9-24 Hz, 1 N).

Example A183 3-CI4-41-I(I5-(2-Methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)phenyl]carbonylmethyl)amino|Ipropanoic acid its

Bosch 9 IC

On

I am and: M

To a solution (10 ml) of ethyl 3-((4-11-(5-bromo-3-methyl-1-benzofuran-2-yl)-2- methylpropylamino)phenyl)carbonyl)(methyl)aminodupropanoate (0.55 d), synthesized in

(2-Methoxypyridin-3-yl)boronic acid (0.33 g), potassium carbonate (0.29 g) and tetrakistriphenylphosphine palladium (0.12 g) were added to Example A182(2) in M,M-dimethylacetamide, and the mixture was stirred at 70 "C for 24 g in an argon atmosphere. The reaction mixture was cooled to room temperature, filtered through celite and the residue was washed with diethyl ether. Water was added to the filtrate and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1 :1, volume ratio) yielding ethyl 3-C(4-(1-(5-(2-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino )phenylcarbonylmethyl)amino|propanosate (0.10 g) as a pale yellow oil.

The obtained oil was dissolved in ethanol (1 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure, and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.18 g, 3395) as a colorless solid. "H NMR (300 MHz, SOSI") b m.p. 0.94 (d, 9U-6.4 Hz, Z H), 1.15 (d, 9U-6.4 Hz, Z H), 2 ,12 - 2.40 (m, 1 N), 2.27 (s, C H), 2.67 (t, 9U-6.2 Hz, 2 N), 3.04 (s, C H), 3.70 (t, 9U-6.2 Hz, 2 N), 3.96 (s, Z

H), 4.36 (d, 9U-7.9 Hz, 1 H), 6.58 (d, 9U-8.7 Hz, 2 H), 6.97 (dd, 9U-7.2, 4 .9 Hz, 1 N), 7.23 (d, 9-8.7

Hz, 2 N), 7.33 - 7.77 (m, 4 N), 8.16 (dd, U-4.9, 1.9 Hz, 1 N).

Example A184 3-4(4-(1-(5-cyclopropyl-3-methyl-1-benzofuran-2-yl)-2-

methylpropylamino)phenyl)carbonyl)(methyl)amino)propanoic acid (1)1-(5-cyclopropyl-33-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one

To a solution (20 ml) of 1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.0 g) synthesized in Example A182(1) in toluene was added cyclopropaneboronic acid (0.92 g) 2M aqueous solution of sodium carbonate (5.3 ml) and the mixture was stirred at room temperature for 10 min in an argon atmosphere. 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.18 g) and tris(dibenzylideneacetone)idipalladium (0) (0.10 g) were added to the reaction mixture, and the mixture was heated under reflux under argon overnight. The reaction mixture was cooled to room temperature, filtered through celite and the residue was washed with diethyl ether.

Water was added to the filtrate and the organic layer was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:10, v/v) to give the title compound (0.80 g, 93905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.59 - 1.08 (m, 4 N), 1.23 (d, 9-6.8 Hz, 6 N), 1.91 - 2.11 (m, 1 N), 2.35 (s , 1 H), 2.58 (s, C H), 7.07 - 7.51 (m, C H). (2)1-(5-cyclopropyl-33-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol 1-(5-Cyclopropyl-33-methyl-1-benzofuran-2-yl)- 2-methylpropan-1-one (0.80 g) synthesized in (1) mentioned above was dissolved in tetrahydrofuran (10 ml) and methanol (1 ml) and sodium borohydride (9095, 0.34 g) was added to the solution while cooling with ice . The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, water (1 ml) and 1 M hydrochloric acid (5 ml) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (0.4 g, 50905) as a yellow oil. "H NMR (300 MHz, SOSIz") b m.p. 0.63 - 0.75 (m, 2 H), 0.80 (d, U-6.8 Hz, C H), 0.88 - 1.01 (m, 2 H), 1.11 (d, 9-6.8 Gu, Z H), 1.20 - 1.30 (m, 1 H), 1.93 - 2.03 (m , 1 H), 2.12 - 2.30 (m, 4 H), 4.46 (d, U-8.3 Gu, 1 H), 7.01 (dd, U-8.3, 1, 9 Hz, 1 N), 7.17 (d, 9U-1.9 Hz, 1 N), 7.29 (d, 9-8.3 Gu, 1 N). (3)3-4I(4- 111-(5-cyclopropyl-3-methyl-1-benzofuran-2-yl)-2-methylpropylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

To a solution (5 ml) of 1-(5-cyclopropyl-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (0.40 g), synthesized in the above mentioned (2), in tetrahydrofuran thionyl chloride (0.22 ml) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 ml), sodium iodide (0.373 g), sodium carbonate (0.25 g) and ethyl 3-M(4-aminophenyl)carbonyl|/methyl)aminoisopropanoate (0.41 g), synthesized, were added to the solution in Example 2(2), and the mixture was stirred at 70"C for 12 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1 :1, volume ratio) obtaining ethyl 3-1(4-(P1-(5-cyclopropyl-3-methyl-1-benzofuran-2-yl)-2-methylpropylamino)phenyl)carbonyl)(methyl)amino) propanoate (0.25 g) as a pale yellow oil.

The obtained oil was dissolved in ethanol (2 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.24 g, 32905) as a colorless solid. "H NMR (300 MHz, SOSIz") b mp 0.62 - 0.73 (m, 2 N), 0.82 - 1.00 (m, 5 N), 1.12 (d, 9U -6.8 Hz,

With H), 1.90 - 2.07 (m, 1 H), 2.14 - 2.32 (m, 4 H), 2.67 (t, 9U-6.2 Hz, 2 H), 3 .03 (c, Z H), 3.70 (t,

U-6.2 Hz, 2 N), 4.32 (d, 9-7.9 Gu, 1 N), 6.56 (d, U-8.7 Hz, 2 N), 6.98 (dd , U-8.7, 1.9 Hz, 1 H), 7.13 (d, 9-1.9 Hz, 1 H), 7.19 - 7.25 (m, C H).

Example A185 3-((6-(cyclohexyl(5, 7-difluoro-3-methyl-1-benzofuran-2-yl)methyl|amino)pyridin-3-yl)ucarbonyl|(methyl)amino)propanoic acid

Eat and drink

M mm g

IS

Cyclohexyl(5, 7-difluoro-3-methyl-1-benzofuran-2-yl)methanol (0.52 g), synthesized in

Example A163(2) was dissolved in tetrahydrofuran (5 ml) and thionyl chloride (0.24 ml) was added to the solution at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (3 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 ml), sodium iodide (0.45 g), sodium carbonate (0.30 g), ethyl b-aminopyridine-3-carboxylate (0.45 g) were added to the solution, and the mixture was stirred at 60 "С overnight. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with diethyl ether. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to give ethyl 6-ylcyclohexyl( 5,7-difluoro-3-methyl-1-benzofuran-2-yl)methyl-amino)pyridine-3-carboxylate (0.10 g) as a yellow oil.The obtained oil was dissolved in tetrahydrofuran (2 mL) and ethanol (2 mL ) and the mixture was stirred in the presence of 1M aqueous sodium hydroxide solution (2 mL) at 10070 for 12 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in M,M-dimethylformamide (20 mL) and ethyl was added to the solution. 3-(methylamino)propanoate (0.24 g), 1-ethyl-3-(3- dime) hydrochloride ethylaminopropyl)carbodiimide (0.48 g) and hydroxybenzotriazole monohydrate (0.38 g) and the mixture was stirred at 70 °C for 4 h. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted with diethyl ether.

The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, ethanol (5 ml) and 1M aqueous sodium hydroxide solution (1.0 ml) were added to the residue, and the mixture was stirred at room temperature for 1 h.

The reaction mixture was concentrated under reduced pressure, neutralized with 1M hydrochloric acid (1.0 ml) and extracted with ethyl acetate. The extract was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (0.05 g, 6905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.00 - 1.93 (m, 11 H), 2.22 (s, C H), 2.68 - 2.75 (m, 2 H), 3.09 (s, C H), 3, 70 - 3.80 (m, 2 N), 4.10 - 4.20 (m, 1 N), 6.36 (d, 9U-8.7 Hz, 1 N), 6.69 - 6.94 (m, 2

H), 7.50 - 7.58 (m, 1 H), 8.15 (d, 9U-1.9 Hz, 1 H).

Example A186 3-((4-(H-Cyclohexyl3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid and (B

M

I U ad (1) methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate

Potassium carbonate (24.0 g) and methyl bromoacetate (11.5 ml) were added to a solution (200 ml) of 1-(5-bromo-2-hydroxyphenyl)ethanone (25.0 g) in MM-dimethylformamide at room temperature and the mixture was stirred at room temperature for 15 g.

The reaction mixture was filtered, 1,8-diazabicyclo|5.4.O)undec-7-ene (23.2 ml) was added to the filtrate and the mixture was stirred at 100 C for 3 h. The reaction mixture was allowed to cool to room temperature and ice water was added. The precipitate was washed with ethanol-water to give the title compound (16.8 g, 52905) as a pale red solid.

IN NMR (300 MHz, SOSI") b m.h. 2.56 (s, Z H), 3.99 (s, Z H), 7.36 - 7.46 (m, 1 H), 7.49 - 7.60 (m, 1 H), 7, 77 (d, 9-2.3 Hz, 1 N). (2) methyl 3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-carboxylate

Morpholine (5.2 ml), cesium carbonate was added to a solution (100 ml) of methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate (5.4 g) synthesized in the above mentioned (1) in toluene (13.0 g), tris(dibenzylideneacetone)dipalladium (0) (0.92 g) and 9,9-dimethyl-4,5- bisidiphenylphosphino)xanthene (1.1 g) and the mixture was heated under reflux in an argon atmosphere 20 g. The reaction mixture was cooled to room temperature and filtered through Celite. Water was added to the residue and the mixture was extracted with ethyl acetate.

The extract was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.69 g, 1396) as a yellow oil. "IN NMR (300 MHz, SOSI") b m.ch. 2.57 (s, Z H), 3.06 - 3.22 (m, 4 H), 3.83 - 3.94 (m, 4 Н), 3.97 (s, З Н), 7.02 (d, 9-23 Hz, 1 Н), 7.15 (dd, У-9.0, 2.3 Hz, 1 Н), 7 .45 (d, 9U-9.0 Hz, 1 H). (3)3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-carbaldehyde

A solution (2 ml) of methyl 3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-carboxylate (0.69 g), synthesized in the above-mentioned (2), in tetrahydrofuran was added to an ice-cooled solution ( 5 ml) of lithium aluminum hydride (0.25 g) in tetrahydrofuran. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then it was cooled again with ice, and water (0.65 ml), 1M aqueous sodium hydroxide solution (3.2 ml) and water (0 .65 ml). The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product (0.48 g) |3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl|methanol as a pale yellow oil. The obtained oil was dissolved in acetonitrile (5 ml), tetrapropylammonium perruthenate (0.07 g) and M-methylmorpholine M-oxide (0.46 g) were added to the solution at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.24 g, 40905) as a yellow oil. "IN NMR (300 MHz, SOSI") b m.ch. 2.59 (s, Z H), 3.09 - 3.22 (m, 4 H), 3.79 - 3.98 (m, 4 H), 7.05 (d, 9U-2.3 Hz, 1 H), 7.23 (dd, 9-9.2, 2.3 Hz, 1 H), 7.46 (d, 2-9 .2 Hz, 1 N), 10.00 (s, 1 N). (4) cyclohexyl|3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl|methanol

Cyclohexylmagnesium bromide (2 ml, 1M tetrahydrofuran solution) under ice cooling. After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, volume ratio) to give cyclohexyl|3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl |methanol (0.39 g, quantitative) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 1.07 - 2.01 (m, 12 H), 2.19 (s, Z H), 3.11 - 3.21 (m, 4 H), 3.83 - 3.95 (m, 4 H ), 4.50 (d, U-8.7 Hz, 1 N), 6.90 - 7.01 (m, 2 N), 7.33 (d, 9-9.8 Gu, 1 N). (5)33-Cl4-cyclohexyl|3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

To a solution (5 ml) of cyclohexyl|3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl|methanol (0.39 g), synthesized in the above-mentioned (4), in tetrahydrofuran at room temperature temperature, thionyl chloride (0.13 ml) was added. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 mL) was carefully added. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 ml), sodium iodide (0.23 g), sodium carbonate (0.15 g) and ethyl 3-((4-aminophenyl)carbonyl/methyl)aminopropanoate (0.25 g) were added to the solution. synthesized in Example 2(2), and the mixture was stirred at 70"C for 15 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane- 1:1, volume ratio) obtaining ethyl /3-((4-(cyclohexyl3-methyl-5-(morpholin-4-yl)-1-benzofuran-2-yl|Imethyliamino)phenylcarbonyl/methyl)amino|Ipropanoate (0.25 g) as a pale yellow oil. The resulting oil was dissolved in ethanol (2 mL), 1 M aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. Ethanol was evaporated under reduced pressure and 1M hydrochloric acid (1.0 ml) was added to the residue. The precipitate was washed with water to obtain the title compound (0.19 g, 33965) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.90 - 2.16 (m, 11 N), 2.22 (s, Z H), 2.68 (sh s, 2 H), 3.04 (s, Z H), 3.14 (shs , 4 H), 3.58 - 3.77 (m, 2 H), 3.89 (w s, 4 H), 4.36 (d, 9U-8.3 Hz, 1 H), 6.56 (d, 9E9, O Hz, 2 H), 6.84 - 7.02 (m, 2 H), 7.17 - 7.27 (m, C H).

Example A187 3-((4-(H-Cyclohexyl3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl|methyl)amino)phenyl(IcarbonylUumethyl)amino|propanoic acid its 9 IR

IR g M v / (1)cyclohexyl|3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl|methanone

Thiomorpholine (0.72 g ), cesium carbonate (2.3 g), tris(dibenzylideneacetone)idipalladium (0) (0.16 g) and 9,9-dimethyl-4,5-

bisidiphenylphosphino)xanthene (0.2 g), and the mixture was heated under reflux under argon for 18 h. The reaction mixture was cooled to room temperature and filtered through celite, water was added to the residue, and the mixture was extracted with ethyl acetate.

The extract was concentrated to give the crude product (0.83 g, quant.), the title compound as a yellow oil. "H NMR (300 MHz, SOSI»z) b m.ch. 1.37 - 2.01 (m, 10 H), 2.56 (s, 3 H), 2.70 - 2.88 (m, 4 H), 3.25 - 3.40 (m, 1 H), 3.42 - 3.70 (m, 4 H), 7.00 - 7.78 (m, 3 H). (2) cyclohexyl |3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl|methanol

Cyclohexyl|3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl|methanone (0.83 g) synthesized in the above mentioned (1) was dissolved in tetrahydrofuran (10 ml) and methanol (1 ml ) and sodium borohydride (9095, 0.2 g) was added to the solution while cooling with ice. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, water (1 mL) and 1M hydrochloric acid (5 mL) were cautiously added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (0.18 g, 22905) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.81 - 1.93 (m, 11 H), 2.20 (s, Z H), 2.70 - 2.91 (m, 4 H), 3.34 - 3.53 (m, 4 H ), 4.50 (d, 9U-8.3 Hz, 1 H), 4.99 (t, 9U-6.4 Hz, 1 H), 6.90 - 7.40 (m, C H). (3)3-C4-cyclohexyl|3-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl|methyl)amino)phenyl(carbonyl)methyl)amino|propanoic acid

To a solution (5 ml) of cyclohexyl13-methyl-5-(thiomorpholin-4-yl)-1-benzofuran-2-yl|methanol (0.18 g), synthesized in the above-mentioned (2), in tetrahydrofuran at room temperature was added thionyl chloride (0.07 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 ml) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (5 ml) and sodium iodide (0.15 g), sodium carbonate (0.10 g) and ethyl 3-((4-aminophenyl)carbonyl|(methyl)amino)propanoate (0.13 g), synthesized in Example 2(2), and the mixture was stirred at 70 "C for 15 g.

After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:1, volume ratio) to obtain ethyl 3-((4-((cyclohexyl33-methyl-5-(thiomorpholin-4-yl)- 1- Benzofuran-2-yl|Imethylamino)phenylcarbonyl/methyl)amino|Ipropanoate (0.08 g) as a pale yellow oil. The resulting oil was dissolved in ethanol (2 mL), and 1 M aqueous hydroxide solution was added to the solution at room temperature sodium (1.0 mL) and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title compound (0, 05 g, 1895), as a colorless solid.

IN NMR (300 MHz, SOSIZ") 6 m.h. 0.88 - 2.17 (m, 11 H), 2.20 (s, Z H), 2.59 (sh s, 2 H), 2.80 - 3.20 (m, 7 H), 3 .50 - 3.70 (m, 6 N), 4.38 (d, 9-7.9 Hz, 1 N), 6.55 (d, 9U-8.7 Hz, 2 N), 7.08 - 7.47 (m, 5 N).

Example A188 3-(I44-K(cyclohexyl5-((2-methoxyethyl)(methyl)amino|-33-methyl-1-benzofuran-2-yl)methyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid (1) methyl 5-(2-methoxyethyl)(methyl)amino|-3-methyl-1-benzofuran-2-carboxylate

2-Methoxy-M-methylethanamine (2.7 g), cesium carbonate (9.8 g), tris(dibenzylideneacetone)dipalladium (0) (0.69 g) and 9,9-dimethyl-4,5-bisidiphenylphosphino)xanthene (0.87 g) and the mixture was heated with under reflux in an argon atmosphere for 6 h. The reaction mixture was cooled to room temperature, filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate.

The extract was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:4, v/v) to give the title compound (2.7 g, quant.) as a yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 2.55 (s, Z H), 3.01 (s, Z H), 3.37 (s, Z H), 3.40 - 3.70 (m, 4

Н), 3.97 (s, 3 Н), 6.77 - 7.15 (m, З Н). (2)5-K(2-methoxyethyl)(methyl)amino|-3-methyl-1-benzofuran-2-carbaldehyde

A solution (10 ml) of methyl 5-(2-methoxyethyl)(methyl)amino|-3-methyl-1-benzofuran-2-carboxylate (2.7 g) synthesized in the above-mentioned (1) in tetrahydrofuran was added to the ice-cooled solution (40 ml) of lithium aluminum hydride (0.38 g) in tetrahydrofuran.

The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, and water (1.0 ml), 1M aqueous sodium hydroxide solution (5.0 ml) and water (1 .0 ml).

The residue was filtered through celite and the filtrate was concentrated under reduced pressure to give the crude product, (0.41 g) 45-(2-methoxyethyl)(methyl)amino|-3-methyl-1-benzofuran-2-ylmethanol as a pale yellow oil. . The obtained oil was dissolved in acetonitrile (20 ml), tetrapropylammonium perruthenate (0.07 g) and M-methylmorpholine M-oxide (0.46 g) were added to the solution at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.09 g, 390) as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 2.58 (s, C H), 3.02 (s, C H), 3.38 (s, C H), 3.47 - 3 ,66 (m, 4

H), 6.81 (d, 9-26 Gu, 1 H), 7.10 (dd, 9U-9.0, 2.6 Hz, 1 H), 7.40 (d, 2-9.0 Hz, 1 N), 9.97 (s, 1 N). (Z)cyclohexyl5-|(2-methoxyethyl) (methyl)amino)|-3-methyl-1-benzofuran-2-yl)umethanol

To a solution (5 ml) of 5-MK2-methoxyethyl)(methyl)amino|-3-methyl-1-benzofuran-2-carbaldehyde (0.09 g), synthesized in the above-mentioned (2), in tetrahydrofuran under ice cooling cyclohexylmagnesium bromide (2 ml, 1M tetrahydrofuran solution) was added dropwise. After the dropwise addition was complete, the ice bath was removed and the mixture was stirred at room temperature for 15 min. An aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane-1:2, v/v) to give the title compound (0.11 g, quantitative) as a yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.99 - 1.96 (m, 12 H), 2.18 (s, Z H), 2.99 (s, Z H), 3.37 (s, Z

H), 3.45 - 3.72 (m, A H), 4.49 (d, 2-8.7 Hz, 1 H), 6.77 - 7.30 (m, C H). (4)3-(44-Kcyclohexyl/5-|(2-methoxyethyl) (methyl)amino|-3-methyl-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

To a solution (10 ml) of cyclohexyl5-|((2-methoxyethyl)(methyl)amino|-3-methyl-1-benzofuran-2-ylmethanol (0.11 g), synthesized in the above-mentioned (3), in tetrahydrofuran at thionyl chloride (0.10 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (5 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (10 ml), sodium iodide (0.14 g), sodium carbonate (0.09 g) and ethyl 3-K(4-aminophenyl)carbonyl|/methyl)aminopropanoate (0.15 g) were added to the solution. , synthesized in Example 2(2), and the mixture was stirred at 70"C for 4 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate.hexane -1:1, volume ratio) obtaining ethyl 3-|(4- (cyclohexyl/5-|(2-methoxyethyl)(methyl)amino|-3-methyl-1-benzofuran-2-yl)methyl)amino |phenyl)icarbonyl)(methyl)amino|propanoate (0.03 g) as a pale yellow oil.

The obtained oil was dissolved in ethanol (2 ml), a 1M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1M hydrogen chloride was added to the residue. acid (1.0 ml). The precipitate was washed with water to give the title compound (0.02 g, 1195) as a colorless solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.90 - 2.13 (m, 11 H), 2.21 (s, 3 H), 2.68 (sh s, 2 H), 2.98 (s, Z H), 3.05 (s, Z H), 3.36 (s, Z H), 3.41 - 3.62 (m, 4 H), 3.68 (w s , 2 N), 4.35 (d, 9U-8.0 Hz, 1 N), 6.56 (d, 9-8.7 Hz, 2 N), 6.67 - 6.88 (m, 2 H), 7.13 - 7.25 (m, C H).

Example A189 ethyl 3-((4-1-cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonylamino)propanoate

C) o i Nu sna hi shi de (1) methyl 4-cyclopentyl (5-fluoro-3-methyl-1-benzofuran-2-yl) methyl|amino)benzoate

To the mixture | cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethanone (1,3. "(Hg), synthesized in Example Ab7(3), methyl 4-aminobenzoate (798 mg), triethylamine (5, 88 ml) and dichloromethane (13 ml) was added titanium chloride (IM) (1.0 M dichloromethane solution, 6.3 ml) at 0 "C and the mixture was stirred at room temperature for 2 g under a nitrogen atmosphere. To quench the reaction, saturated aqueous sodium bicarbonate solution.

The solvent was concentrated under reduced pressure and the residue was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown solid. Sodium cyanoborohydride (657 mg) and acetic acid (1.50 ml) were added to a solution of the obtained solid in tetrahydrofuran (20 ml) and the mixture was stirred at room temperature for 16 h. A saturated aqueous solution of sodium hydrogen carbonate was added to quench the reaction and the mixture was extracted with ethyl acetate . The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 90:10) to give the title compound (1.27 g, 6395) as a yellow amorphous substance.

IN NMR (300 MHz, SOSI") b m.h. 1.49 - 1.69 (m, 8 H), 2.26 (s, C H), 2.43 - 2.56 (m, 1 H), 3.82 (s, C H), 4, 34 - 4.45 (m, 1 N), 4.55 (d, 2-8.3 Hz, 1 N), 6.56 (d, 9-9.0 Hz, 2 N), 6.86 - 6.98 (m, 1 N), 7.02 - 7.14 (m, 1 N), 7.23 - 7.35 (m, 1 N), 7.79 (d, 959.0 Hz, 2 N).

(2)4--"cyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|Iamino)benzoic acid

To a mixture of methyl 4-PCcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyliamino)benzoate (1.19 g) synthesized above, tetrahydrofuran (6 ml) and ethanol (b ml) was added 1M aqueous sodium hydroxide solution (b ml) and the mixture was stirred under reflux for 3.5 g. Another 1M aqueous solution of sodium hydroxide (b ml) was added to the mixture and the mixture was stirred under reflux for 14 g. The reaction mixture was concentrated at under reduced pressure, 1M hydrochloric acid (11 ml) was added to the residue and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.08 g, 9495) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 1.39 - 1.76 (m, 8 H), 1.89 - 1.99 (m, 1 H), 2.24 (s, Z H), 2.40 - 2.55 (m, 1 H ), 4.40 (d, 20-9.1 Hz, 1 N), 6.52 (d, 9-8.7 Hz, 2 N), 6.82 - 6.98 (m, 1 N), 7.02 - 7.13 (m, 1 H), 7.03 - 7.11 (m, 1 H), 7.22 - 7.29 (m, 1 H), 7.81 (d, 9- 8.7 Hz, 2 N). (3) ethyl 3-((4-Tcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonylamino)propanoate

A solution of 4-Pcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl|Iaminophenzoic acid (483 mg), synthesized above, p-alanine ethyl ester hydrochloride (241 mg), 1-hydroxybenzotriazole monohydrate (240 mg), triethylamine (438 μl) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (301 mg) in N,M-dimethylformamide (10 ml) were stirred at room temperature for 3 h. A saturated aqueous solution of ammonium chloride was added before quenching the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 60:40, v/v) to give the title compound (397 mg, 6590) as a colorless amorphous form. "H NMR (300 MHz, SOSI") 6 m.h. 1.21 - 1.31 (m, Z H), 1.50 - 1.70 (m, 8 H), 1.92 - 2.01 (m, 1

H), 2.25 (s, C H), 2.42 - 2.55 (m, 1 H), 2.58 (t, 2-5.9 Hz, 2 H), 3.65 (k, 9U-6.1 Hz, 2 H), 4.31 - 4.49 (m, 2 H), 6.57 (d, 9-8.7 Hz, C H), 6.84 - 6.98 ( m, 1 H), 7.06 (dd, 9-8.3, 2.7 Hz, 1 H), 7.21 - 7.32 (m, 1 H), 7.54 (d, 9-8 .7 Hz, 2 N).

Example A190 3-((4-Hcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyliamino)phenyl)carbonylamino)propanoic acid

IV) r, (8)

SN. shi;

He

Ethyl 3-((4-Tcyclopentyl(5-fluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|I(amino)upropanoate (363 mg), synthesized in Example A189, was dissolved in ethanol (1 .5 ml) and tetrahydrofuran (1.5 ml), 1M aqueous sodium hydroxide solution (1.5 ml) was added to the solution and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 ml) was added to the mixture, the mixture was neutralized with 1M hydrochloric acid under ice cooling, and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound (283 mg, 83905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.21 - 1.72 (m, 7 N), 1.91 - 2.04 (m, 1 N), 2.24 (s, C H), 2.47 (k, 9U-8.1 Hz , 1 N), 2.62 (t, 9U-5.9 Hz, 2 N), 3.63 (k, U-6.1 Gu, 2 N), 4.38 (d, 9-91 Hz, 1 H), 6.51 - 6.64 (m, C H), 6.86 - 6.97 (m, 1 H), 7.06 (dd, 9U-8.5, 2.5 Hz, 1 H), 7.19 - 7.32 (m, 2 H), 7.52 (d, U-8.7 Hz, 2 H).

Example A191

3-4(4-(2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|Iamino)phenyl)carbonyl|iamino)propanoic acid sn tsn.

Iv) uh o

SN. in

ON

A solution of 4-C2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl|amino)benzoic acid (180 mg), synthesized in Example A71(4), hydrochloride of ethyl ester p- alanine (89 mg), 1-hydroxybenzotriazole monohydrate (89 mg), triethylamine (163 μl) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (111 mg) in N,M-dimethylformamide (5 ml) were stirred at at room temperature for 6 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 60:40, v/v) to give a colorless oil (159 mg). The obtained colorless oil (159 mg) was dissolved in ethanol (1.0 ml) and tetrahydrofuran (1.0 ml), 1M aqueous sodium hydroxide solution (0.66 ml) was added to the solution, and the mixture was stirred at room temperature for 1 h. Solvent evaporated under reduced pressure, water (4 ml) was added, neutralized with 1M hydrochloric acid under ice cooling and the mixture was stirred for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound (87 mg, 4195) as a colorless solid.

IN YAMRE (300 MHz, SOSIz) b m.ch. 0.85 (t, 9U-7.4 Hz, Z H), 0.94 (t, 9U-7.6 Hz, Z H), 1.14 - 1.68 (m, 4 H), 1, 80 - 1.92 (m, 1 H), 2.21 (s, C H), 2.63 (t, 925.7 Hz, 2 H), 3.64 (k, 9-6.1 Hz, 2 H), 4.58 (d, 9U-7.6 Hu, 1 H), 6.49 - 6.64 (m, Z H), 6.92 (td, 929.1, 2.7 Hu, 1 H), 7.05 (dd, 9-8.5, 2.5 Hz, 1

H), 7.22 - 7.29 (m, 1 H), 7.53 (d, 98.7 Hz, 2 H).

Example A192 3-4(4-(1-(5-fluoro-3-methyl-1-benzofuran-2h-yl)-2-methylpropylamino)phenyl)carbonyl)(methyl)amino)propanoic acid not about CH»

(1)1-(5-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one

Aluminum chloride (anhydrous) (2 .66 g) at 0 "C, the mixture was stirred at 0 "C for 1 g and at room temperature for 12 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0 - 90:10, v/v) to give the title compound (1.933 g, 66905) as a colorless oil.

IN NMR (300 MHz, SOSIz") 6 m.h. 1.24 (d, 9-7.2 Hz, 6 N), 2.57 (s, C H), 3.44 - 3.65 (m, 1 H), 7.11 - 7.33 (m , 2 H), 7.41 - 7.50 (m, 1 H) (2)1-(5-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol 1- (5-Fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (11.66 g), synthesized above, was dissolved in methanol (4 ml)-tetrahydrofuran (20 ml) and sodium tetrahydroborate (9095) (446 mg) was added to the solution at 0 C. The reaction mixture was stirred at 07 for 1 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (1.193 g, 10095) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.82 (d, 9U-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 1.99 - 2.06 (m, 1 H), 2, 15 - 2.27 (m, 4 H), 4.43 - 4.52 (m, 1 H), 6.91 - 7.01 (m, 1 H), 7.11 (dd, 9U-8, 7, 2.6 Hz, 1

H), 7.33 (dd, 1 H). (3)3-(IK4-11-(5-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

Thionyl chloride (0.45 ml). The reaction mixture was stirred at room temperature for 2 h. An aqueous solution of sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give crude 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (1.10 g).

Ethyl 3-((4-aminophenyl)carbonyl)/methyl)amino)propanoate (546 mg), obtained in

Example 2 (2), sodium iodide (623 mg), sodium carbonate (441 mg) and M,M-dimethylformamide (5 ml) and the mixture was stirred at 80 "C for 13 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.After filtration, the filtrate was concentrated.

The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to give a yellow amorphous compound (287 mg). The obtained amorphous compound (280 mg) was dissolved in ethanol (2.4 ml) and tetrahydrofuran (2.4 ml) and 1M aqueous sodium hydroxide solution (1.2 ml) was added to the solution and the mixture was stirred at room temperature for 1.5 g The solvent was evaporated under reduced pressure, water (4 ml) was added, the mixture was neutralized with 1M hydrochloric acid (1.2 ml) under ice cooling, and the mixture was stirred for 1.5 g. The resulting precipitate was collected by filtration and dried to give the title compound (231 mg, 2390), as a yellow amorphous substance.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, Z H), 1.13 (d, 9U-6.4 Hz, Z H), 2.18 -2.30 (m, 4 H), 2.66 (t, 9U-6 .4 Hz, 2 N), 3.03 (s, C H), 3.70 (t, 9U-6.6 Gu, 2 N), 4.33 (d, 9-7.5 Hz, 1 N ), 6.56 (d, 428.7 Hz, 2 N), 6.93 (td, U-9.0, 2.6 Hz, 1 N), 7.07 (dd, 9U-8.7, 2.6 Hz, 1 N), 7.22 - 7.32 (m, C N).

Example A193 3-4(4-(1-(5-fluoro-3-methyl-1-benzofuran-2h-yl)-2-methylpropylamino)phenyl)carbonylamino)propanoic acid not (B, CH,

In Ya and N: in sleep, shu

ON

To a solution of 1-(5-fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-ol (1.128 g) obtained in Example A192(2) in tetrahydrofuran (10 ml) at room temperature temperature, thionyl chloride (0.45 ml) was added. The reaction mixture was stirred at room temperature for 2 h. An aqueous solution of sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give crude /2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (1.10 g). To the obtained 2-(1-chloro-2-methylpropyl)-5-fluoro-3-methyl-1-benzofuran (485 mg) was added ethyl 3-|(4-aminophenyl)carbonyl|amino)propanoate (500 mg), the obtained in Example 1(2), sodium iodide (599 mg), sodium carbonate (424 mg) and M,M-dimethylformamide (5 ml) and the mixture was stirred at 80 C for 13 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to obtain a colorless amorphous substance (123 mg).

The obtained amorphous compound (123 mg) was dissolved in ethanol (2.0 ml) and tetrahydrofuran (2.0 ml), 1M aqueous sodium hydroxide solution (1.0 ml) was added to the solution, and the mixture was stirred at room temperature for 1 h. Solvent evaporated under reduced pressure, water (4 ml) was added to the residue and the mixture was neutralized with 1M hydrochloric acid (1.0 ml) under ice cooling and the mixture was stirred for min. The resulting precipitate was collected by filtration and dried to give the title compound (97 mg, 1195) as a yellow amorphous substance. "H NMR (300 MHz, CHLOROFORM-a) b m.p. 0.91 (d, C H), 1.13 (d, 9U-6.8 Hz, C H), 2.18 - 2.29 (m, 4 N), 2.64 (t, 925.7 Hz, 2 N), 3.65 (k, 96.0 Hz, 2 N), 4.35 (d, 9-7.9 Hz, 1 H), 6.57 (d, 48.7 Hz, Z H), 6.92 (td, U-9.0, 2.6 Hz, 1 H), 7.06 (dd, U-8, 5, 2.4 Hz, 1 N), 7.23 - 7.30 (m, 1 N), 7.54 (d, U-8.7 Hz, 2 N).

Example A194 3-I44-K(cyclohexyl3-methyl-5-|(5-methylisoxazol-3-yl)methoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid o ( 8) 0 N - sn. M o

And with what;

Nas on (1)(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl|(cyclohexyl)methanol (5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|(cyclohexyl) methanone (23.4 g), synthesized in Example A82(2), was dissolved in methanol (40 ml)-tetrahydrofuran (400 ml) and sodium tetrahydroborate (9095) (5.64 g) was added to the solution at 0 "С. the mixture was stirred at 0 "C for 1 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the title compound (25.17 g, 100905) , as a colorless oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.88 - 1.40 (m, 7 N), 1.61 - 1.70 (m, 2 N), 1.75 - 1.92 (m, 2

H), 1.95 - 1.99 (m, 1 H), 2.18 (s, C H), 4.45 - 4.54 (m, 1 H), 5.10 (s, 2 H) , 6.94 (dd, 9-9.0, 2.6 Hz, 1 H), 7.00 (d, 9-2.3 Hz, 1 H), 7.28 - 7.49 (m, 6 N). (2)5-(benzyloxy)-2-(chloro(cyclohexyl)methyl|-3-methyl-1-benzofuran

Thionyl chloride (9.44 ml). The reaction mixture was stirred at room temperature for 1 h. An aqueous solution of sodium bicarbonate cooled to 0 "C was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the title compound (25.39 g, 9696) as a yellow solid.

IN NMR (300 MHz, SOSI") b m.h. 0.87 - 1.52 (m, 6 H), 1.58 - 1.71 (m, 4 H), 2.19 (s, Z H), 2.29 - 2.38 (m, 1 H ), 4.80 (d, 1 N), 5.10 (c, 2 N), 6.94 - 7.02 (m, 2 N), 7.32 - 7.56 (m, 6 N). (3) ethyl 3-SHA-(5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)" cyclohexyl)methyl)amino)phenylcarbonylKmethyl)amino|propanesate

Ethyl 3-/|(4-aminophenyl)carbonyl|(methyl)amino) propanoate (12.5 g) obtained in Example 2(2), sodium iodide (7.62 g), sodium carbonate (5.39 mg) and M,M-dimethylacetamide (125 ml) and the mixture was stirred at 60 "C for 14 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, 0/0) to give the title compound (14.20 g, 7290) as a yellow amorphous substance.

IN NMR (300 MHz, SOSI") b m.h. 0.88 - 1.26 (m, 5 N), 1.50 - 2.09 (m, 7 N), 2.21 (s, Z H), 2.56 - 2.73 (m, 2 N ), 3.01 (s, C H), 3.70 (t, 927.0 Hz, 2 H), 4.06 - 4.18 (m, 2 H), 4.32 -4.42 (m ,2

H), 4.32 - 4.39 (m, 2 H), 5.08 (s, 2 H), 6.56 (d, 9U-8.7 Hz, 2 H), 6.86 - 6, 92 (m, 1 N), 6.97 (d, 9uE2, 3 Hz, 1 N), 7.17 - 7.53 (m, 8 N). (4) ethyl 3-((4-cyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl|(methyl)amino)propanoate

Ethyl 3-CH4-(CH5-(benzyloxy)-3-methyl-1-benzofuran-2-yl)cyclohexyl)methyl)amino)phenylcarbonylmethyl)amino|Ipropanoate (10.11 g) obtained above was dissolved in ethanol (200 ml ) and 1090 palladium-carbon (containing water) (1.0 g) was added to the solution at room temperature. The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 24 g and the catalyst was filtered off.

The filtrate was concentrated under reduced pressure to give the title compound (8.98 g, 10095) as a brown amorphous compound.

IN NMR (300 MHz, SOSI") b m.h. 0.93 - 1.16 (m, Z H), 1.22 - 1.27 (m, 5 H), 1.52 (d, 9-12.5

Hu, 1 H), 1.65 - 1.95 (m, 4 H), 2.08 - 2.13 (m, 1 H), 2.15 (s, C H), 2.62 (t, 9U-6.8 Hz, 2 N), 3.02 (s,

With H), 3.72 (t, U7.0HZ, 2 H), 4.05 - 4.17 (m, 2 H), 4.30 - 4.38 (m, 2 H), 5.58 ( s, 1 H), 6.55 (d, 9UE8.7 Hz, 2 H), 6.70 (dd, 98.5, 2.5 Hz, 1 H), 6.80 (d, 952.7 Hz , 1 N), 7.17 (d, 9-8.7 Hz, 1 N), 7.22 (d, U-8.3 Hz, 2 N). (5)3-(144-Ccyclohexyl/3-methyl-5-|(5-methylisoxazol-3-yl)methoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid

A solution of ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)aminopropanoate (300 mg) obtained above, (5-methylisoxazole-Z3- yl)methanol (83 mg) and tributylphosphine (308 mg) in tetrahydrofuran (30 ml) were cooled to 0"C in an ice bath and 1,1-(azodicarbonyl)udipiperidine (308 mg) was added to the solution. The reaction mixture was stirred at room temperature temperature for 3.5 g. (5-methylisoxazol-3-yl)methanol (83 mg), tributylphosphine (154 mg) and 1,1-(azodicarbonyl)udipiperidine (154 mg) were added to the mixture, and the mixture was stirred at room temperature for 14 h. Hexane (60 ml) was added to the reaction mixture. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 1000 - 50:50, 0/0) to obtain a colorless amorphous substance (105 mgH).

The obtained colorless amorphous form of the compound (105 mg) was dissolved in ethanol (0.5 ml) and tetrahydrofuran (0.5 ml), 1M aqueous sodium hydroxide solution (0.36 ml) was added to the solution, and the mixture was stirred at room temperature for 30 min . The solvent was evaporated under reduced pressure, water (2 ml) was added to the residue and the mixture was neutralized with 1M hydrochloric acid (0.36 ml) under ice cooling. The resulting precipitate was collected by filtration and dried to give the title compound (72 mg, 2190) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 1.01 - 1.25 (m, 5 H), 1.42 - 1.83 (m, 6 H), 2.07 (shs, 1 H), 2.21 (s, C H), 2, 41 (s, Z H), 2.61 - 2.69 (m, 2 H), 3.02 (s, Z H), 3.68 (t, 9U-6.4 Hz, 2 H), 4 .35 (d, 9U-7.9 Hz, 1 H), 5.13 (s, 2 H), 6.11 (s, 1 H), 6.55 (d, 2-8.3 Hz, 2 H), 6.87 (dd, U-8,9,2,4 Hz, 1 H), 6.97 (d, 92.6 Hz, 1 H), 7.19 - 7.26 (m, Z N).

Example A195 3-((4-(H-Cyclohexyl-5-(2-hydroxy-2-methylpropoxy)-3-methyl-1-benzofuran-2-yl|methyl)amino)phenyl]carbonylUumethyl)amino|propanoic acid - - ns sn, Sn, M o not

ON

Solution of ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl| of methyl)amino)propanoate (300 mg) obtained in Example

A194(4), isobutylene oxide (439 mg), potassium carbonate (422 mg) and sodium iodide (457 mg) in

M,M-dimethylformamide (E ml) was stirred at 80 "C for 9 g. Isobutylene oxide (2.0 g) was added to the mixture and the mixture was stirred at 120 C for 14 g. Isobutylene oxide (2.0 g) was added to the mixture and the mixture was stirred at 120 "С for 5 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to give a colorless oil (103 mg").

The obtained colorless oil (103 mg) was dissolved in ethanol (0.5 ml) and tetrahydrofuran (0.5 ml), 1M aqueous sodium hydroxide solution (0.36 ml) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 ml) was added to the residue and the mixture was neutralized with 1M hydrochloric acid (0.36 ml) under ice cooling. The resulting precipitate was collected by filtration and dried to give the title compound (88 mg, 2690) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.85 - 1.27 (m, 6 N), 1.35 (s, 6 N), 1.47 - 1.91 (m, 5 N), 2.04 - 2.13 (m, 1 N ), 2.21 (s, C H), 2.62 (t, 96.2 Hz, 2 H), 3.01 (s, C H), 3.67 (t, U-6.6 Hz, 2 H), 3.82 (s, 2 H), 4.35 (d, 9-7.9 Hz, 1 H), 6.55 (d, U-9.0 Hz, 2 H), 6, 84 (dd, 9U-8.7, 2.6 Hz, 1 H), 6.90 (d, 9U-2.3 Hz, 1 H), 7.22 (d, 9-9.8 Hz, 2 H), 7.26 - 7.28 (m, 1 H).

Example A196 3-IIIa4-Ccyclohexyl(3-methyl-5-((3-methyloxetan-3-yl)methoxy|-1-benzofuran-2-yl)umethyl)amino|phenylcarbonyl)(methyl)amino|propanoic acid c) not in about ; nN gu sn, y M o

AND

ON

A solution of ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethyl|amino)phenyl)carbonyl|(methyl)amino)propanoate (300 mg) obtained in Example

A194(4), (3-methyloxetan-3-yl)umethanol (75 mg) and tributylphosphine (308 mg) in tetrahydrofuran (30 ml) was cooled to 0 "C in an ice bath and 1,1-"azodicarbonyl was added to the solution )dipiperidine (308 mg). The reaction mixture was stirred at room temperature for 18 h. Hexane (60 ml) was added to the reaction mixture. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (MN silica gel, hexane-ethyl acetate 100:0

- BO:50, o/o), and then by preparative HPLC" device: biosop Ips., system of preparative

TOP; column: Oemeiosii 005-00-10, 5-5 μm, 50 x 100 mm; solvent: SOLUTION A; 0.190 trifluoroacetic acid-water SOLUTION B; 0.195 trifluoroacetic acid-acetonitrile, (SOLUTION A : SOLUTION B-95:5 - 0:100); flow rate: 150 ml/min; method of detection:

UV 220 nm". The selected fractions were concentrated and the acetonitrile was evaporated. A saturated aqueous solution of sodium bicarbonate (0 C) was added to the aqueous layer and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain a colorless oil. (100 mg). The obtained colorless oil (100 mg) was dissolved in ethanol (0.5 ml) and tetrahydrofuran (0.5 ml), 1M aqueous sodium hydroxide solution (0.34 ml) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 ml) was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid (0.34 ml) under ice cooling and stirred at 0" for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound (73 mg, 22905) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 1.33 (m, 5 H), 1.45 (s, Z H), 1.52 - 1.95 (m, 5 H), 2.09 (d, 98.7 Gu, 1 H), 2.22 (s, C H), 2.55 - 2.74 (m, 2 H), 3.03 (s, C H), 3.65 - 3.76 (m, C H) , 4.05 (s, 2 N), 4.36 (d, 9-7.9 Hz, 1 N), 4.47 (d, 9U-6.0 Hz, 2 N), 4.64 (d , 20-5.7 Hz, 2 N), 6.56 (d, 98.7 Hz, 2 N), 6.80 - 6.89 (m, 1 N), 6.92 (d, 9-2 .6 Hz, 1 H), 7.14 - 7.32 (m, C H).

Example A197 ethyl 3-((4-1(5-(3-cyanopyridin-2-yl)oxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanesate

M

Her o and h / o Her

My

SN M o i ne i ( sn.

A solution of ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethyl|amino)phenyl)carbonyl|(methyl)amino)propanoate (300 mg) obtained in Example

A194(4), 2-chloro-3Z-cyanopyridine (126 mg) and potassium carbonate (125 mg) in M,M-dimethylformamide (3 ml) were stirred at 80 "C for 2.5 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound ( 250 mg, 6995), as a colorless amorphous form.

IN NMR (300 MHz, SOSI") 6 m.h. 0.99 - 1.31 (m, 6 N), 1.48 - 1.96 (m, 6 N), 2.06 - 2.14 (m, 2

H), 2.23 (s, C H), 2.62 (t, 927.0 Hz, 2 H), 3.02 (s, C H), 3.71 (t, 957.0 Hz, 2 H), 4.12 (k, 957.2 Gu, 2 H), 4.31 - 4.44 (m, 2 H), 6.56 (d, 9-8.3 Hz, 2 H), 6 .98 - 7.11 (m, 2 H), 7.19 - 7.25 (m, Z H), 7.40 (d, U-8.7 Hz, 1 H), 8.00 (dd, 9U-7.6, 1.9 Hz, 1 N), 8.29 (dd, 9-4.9, 1.9 Hz, 1 N).

Example A198 3-4(4-((5-(3-cyanopyridin-2-yl)oxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

M ra o

M o i sn, /j o on

Ethyl 3-((4-1(5-(3-cyanopyridin-2-yl)oxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoate (234 mg ), obtained in Example A197 was dissolved in ethanol (1.5 ml) and tetrahydrofuranz (1.5 ml), 1 M aqueous sodium hydroxide solution (0.78 ml) was added to the solution and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 ml) was added and the mixture was neutralized with 1M hydrochloric acid (0.78 ml) under ice cooling. The precipitate obtained was collected by filtration and dried. The obtained residue was purified by preparative HPLC "device: Syizop Ips., system of preparative

TOP; column: Oemeiosii 005-00-10, 5-5 μm, 50 x 100 mm; solvent: SOLUTION A; 0.190 trifluoroacetic acid-water SOLUTION B; 0.195 trifluoroacetic acid-acetonitrile, (SOLUTION A" SOLUTION B-95:5 - 0:100); flow rate: 150 ml/min; method of detection:

OM 220 nm". Saturated aqueous sodium hydrogencarbonate was added to the selected fractions and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (73 mg, 33905) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 1.12 (w s, 4 H), 1.42 - 1.91 (m, 6 H), 2.04 (s, Z H), 2.20 (s,

With H), 2.39 - 2.63 (m, 1 H), 2.89 - 3.03 (m, With H), 3.58 (m, 2 H), 4.37 (d, 9- 8.0 Hz, 1 N), 6.54 (d, 9uEV8, З Hz, 2 Н), 6.94 - 7.10 (m, 2 Н), 7.17 - 7.24 (m, З Н ), 7.37 (d, 9-8.7 Hz, 1 H), 7.99 (dd, uU-7.6, 1.9 Hz, 1 H), 8.28 (d, U-3, 4 Hz, 1 N).

Example A199 3-II(4-Kcyclohexyl5-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy|-3-methyl-1-benzofuran-2-ylmethyl)amino|phenylcarbonyl) (methyl)amino| propanoic acid x v ! shchi / and sn. Shk, not he (1)1,1-dioxidotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate

To a solution of tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (3.0 g) in acetic acid (U ml) was added 3095 hydrogen peroxide (3 ml) and the mixture was stirred at 5070 for 3.5 g. The reaction mixture was cooled to at room temperature, water (30 mL) was added to the mixture, and the mixture was stirred at 0 °C for 5 min. The resulting solid was collected by filtration and washed with water to give the title compound (2.84 g, 8595) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 2.26 - 2.36 (m, 4 H), 2.47 (s, C H), 2.84 - 300 (m, 2 H), 3.10 - 3.43 (m, 2 H), 4.74 - 4.86 (m, 1 N), 7.38 (d, 9-8.0 Hz, 2 N), 7.81 (d, 9-8.3 Hz, 2 N). (2)3-I44-Kcyclohexyl3i5-|(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxy|-3-methyl-1-benzofuran-2-ylmethyl)amino|phenylcarbonyl)(methyl)amino|propane acid

A solution of ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl|(methyl)amino)propanoate (400 mg) obtained in Example

A194(4), 1,1-dioxytetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (593 mg) synthesized above, and potassium triphosphate (223 mg) in M,M-dimethylformamide (4 ml) were stirred at 100 "C for 14 g. 1,1-dioxytetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (593 mg) and potassium triphosphate (112 mg) were added to the mixture, and the mixture was stirred at 100 "C for 2 g and then at 120 C for 3 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 34: 66, o/o) obtaining a colorless amorphous substance (200 mg).

The colorless amorphous form (200 mg) was dissolved in ethanol (1.5 ml) and tetrahydrofuran (1.5 ml), 1 M aqueous sodium hydroxide solution (0.64 ml) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 mL) was added to the residue, and the mixture was neutralized with 1M hydrochloric acid (0.64 mL) under ice-cooling and stirred at 0" for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound ( 136 mg, 2995), as a colorless amorphous form.

IN NMR (300 MHz, SOSIz") b m.h. 0.99 - 2.00 (m, 8 N), 2.21 (s, Z H), 2.31 - 2.73 (m, 10 N), 2.86 - 2.99 (m, 1 N ), 3.03 (s, Z H), 3.36 - 3.53 (m, 2 H), 3.65 - 3.76 (m, 2 H), 4.36 (d, 9U-8, 3 Hz, 1

H), 4.54 - 4.82 (m, C H), 6.55 (d, 2-8.3 Hz, 2 H), 6.78 - 6.87 (m, 1 H), 6, 93 (d, 9-2.6 Hz, 1 N), 7.17 - 7.30 (m, C H).

Example A2O00 3-((4-(H-Cyclohexyl(13-methyl-5-(pyridin-2-yloxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid dk o) (g

M o E sn, M o /

ON

A solution of ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)aminopropanoate (300 mg), obtained in Example

A194(4), 2-fluoropyridine (88 mg) and potassium carbonate (126 mg) in M,M-dimethylformamide (3 ml) were stirred at 80 "С for 8 g, then at room temperature for 48 g. To the mixture was added 2 -fluoropyridine (88 mg) and the mixture was stirred at 120 "C for 4 h. 2-fluoropyridine (352 mg) was added to the mixture and the mixture was stirred at 120 "C for 10 h.

Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, 0/0) to give a colorless oil (35 mg").

The obtained oil (35 mg) was dissolved in tetrahydrofuran (0.5 ml), 1 M aqueous sodium hydroxide solution (0.12 ml) was added to the solution, and the mixture was stirred at 50 °C for 1 h.

The solvent was evaporated under reduced pressure, water (4 ml) was added to the residue, and the mixture was neutralized with 1 M hydrochloric acid (0.12 ml) under ice cooling and stirred at 0 "C for 20 min. The resulting precipitate was collected by filtration and dried to give the title compound (22 mg, 795), as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 0.86 - 1.42 (m, 6 H), 1.51 - 1.96 (m, 5 H), 2.13 (she, 1 H), 2.19 (s, C H), 2.36 - 2.69 (m, 2 H), 3.01 (s, C H), 3.54 (she, 2 H), 4.39 (d, 9-7.9 Gu, 1 H), 6.58 (d,

U-8.7 Hz, 2 H), 6.88 - 7.05 (m, C H), 7.12 - 7.24 (m, C H), 7.33 (d, 9U-8.7 Hz, 1 N), 7.65 - 7.74 (m, 1 N), 8.09 - 8.20 (m, 1 N).

Example A2O1

Ethyl 3-((4-1(5-(5-cyanopyridin-2-yl)oxy|-3-methyl-1-benzofuran-2-

yl (cyclohexyl) methyl (amino) phenyl) carbonyl (methyl) amino) propanoate

IR

Oh oh oh / Her

Mm' to i sn, M o 4 g sn.

A solution of ethyl 3-((4-Tcyclohexyl(5-hydroxy-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate (400 mg) obtained in Example

A194(4), 2-chloro-5-cyanopyridine (167 mg) and potassium carbonate (168 mg) in M,M-dimethylformamide (4 ml) were stirred at 80 "C for 14 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound ( 340 mg, 7090), as a colorless amorphous form.

IN NMR (300 MHz, SOSI") 6 m.h. 1.01 - 1.30 (m, 8 N), 1.55 - 1.96 (m, 5 N), 2.09 - 2.15 (m, 1

H), 2.22 (s, C H), 2.62 (t, 96.8 Hz, 2 H), 3.03 (s, C H), 3.71 (t, 97.0 Hz, 2 H), 4.04 - 4.18 (m, 2

H), 4.27 - 4.48 (m, 2 H), 6.56 (d, 2-8.7 Hz, 2 H), 6.90 - 7.07 (m, 2 H), 7, 17 (d, 9-2.3 Hz, 1 N), 7.22 (d, 9-8.7 Hz, 2 N), 7.40 (d, 9-8.7 Hz, 1 N), 7 .90 (dd, U-8.7, 2.3 Hz, 1 N), 8.46 (d, 2-23 Gu, 1 N).

Example A202 3-4(4-((5-(5-cyanopyridin-2-yl)oxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoic acid

M

Her about and

And / /Y

M' so and sn, M o v

ON

Ethyl 3-((4-1(5-(5-cyanopyridin-2-yl)oxy|-3-methyl-1-benzofuran-2-yl)cyclohexyl)methylamino)phenyl)carbonyl)(methyl)amino)propanoate (300 mg) ), obtained in Example A2O1 was dissolved in tetrahydrofuran (4.0 ml), a 1M aqueous solution of sodium hydroxide (1.1 ml) was added to the solution, and the mixture was stirred at 50 "С for 1 h. The solvent was evaporated under reduced pressure, and the residue was added water (4 ml) and the mixture was neutralized with 1M hydrochloric acid (1.1 ml) under ice cooling and stirred at 0 "C for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound (271 mg, 87905) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 0.93 - 1.36 (m, 5 H), 1.52 - 2.11 (m, 7 H), 2.22 (s, C H), 2.81 (she, 2 H), 3, 03 (s, Z H), 3.66 (w s, 2 H), 4.39 (d, 9-7.9 Hz, 1 H), 6.56 (d, 9-8.7 Hz, 2 H), 6.91 - 7.08 (m, 2 H), 7.12 - 7.25 (m, Z H), 7.39 (d, 928.7 Hz, 1 H), 7.90 ( dd, 9-8.7, 2.3 Hz, 1 N), 8.45 (d, 9-2.3 Hz, 1 N).

Example A2OZ3 ethyl 3-(methyl/T4-(T2-methyl-1-|13-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-

benzofuran-2-yl|Ipropyl)iamino)phenylIcarbonyl)amino)propanoate not

Z o UN, lac o o Y sn, and (B) in and sh sn, (1)1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one 1 -(5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-one (4.0 g), synthesized in Example A85(1) was dissolved in ethanol (80 ml) and palladium charcoal-ethylenediamine complex (400 mg) was added to the solution at room temperature.The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at room temperature for 9.5 g.

The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give the title compound (2.82 g, 10095) as a colorless solid.

IN NMR (300 MHz, SOSIz") 6 m.h. 1.24 (d, 9U-6.8 Hz, 6 N), 2.55 (s, C H), 3.48 - 3.63 (m, 1 H), 6.95 - 7.08 (m , 2 N), 7.32 - 7.40 (m, 1 N). (2)2-methyl-1-3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|Ipropan-1-one

A solution of 1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (1.0 g) synthesized above, tetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate (2.99 g) and potassium triphosphate (1.26 g) in M,M-dimethylformamide (10 ml) was stirred at 807 for 3 g and then at 100 "C for 14 g. Tetrahydro-2H-thiopyran- 4-yl 4-methylbenzenesulfonate (2.99 g) and the mixture was stirred at 100 "C for 20 min. Potassium triphosphate (600 mg) was added to the mixture and the mixture was stirred at 100 "C for 2 h, then at 120 "C for 3 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0 - 90:10, v/v) to give the title compound (886 mg, 61905) as an orange oil. "H NMR (300 MHz, SOSIz") b m.p. 1.23 (d, U-6.8 Hz, 5 N), 1.82 - 2.29 (m, 4 N), 2.49 - 2.68 (m, 6 N), 2.88 - 3.00 (m, 2 N), 3.38 - 3.71 (m, 1 N), 4.25 - 4.50 (m, 1 N ), 6.99 - 7.16 (m, 2 H), 7.40 (d, uU-9.5 Hz, 1 H). (3)2-methyl-1-3-methyl-5-(tetrahydro -2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|Ipropan-1-ol 2-Methyl-1-|3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1- benzofuran-2-yl|Ipropan-1-one (849 mg), synthesized above, was dissolved in methanol (3 ml)-tetrahydrofuran (15 ml) and sodium tetrahydroborate (9090) (202 mg) was added to the solution at 0"C. The reaction mixture was stirred at 0"C for 30 min. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100 :0 - 85:15, v/v) to give the title compound (621 mg, 73905) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.82 (d, 9U-6.8 Hz, Z H), 1.12 (d, 9U-6.4 Hz, Z H), 1.92 - 2.13 (m, 2 H), 2, 16 - 2.27 (m, 6 H), 2.48 - 2.70 (m, 2 H), 2.89 - 3.01 (m, 2 H), 4.28 - 4.37 (m, 1 H), 4.46 (dd, U-8,3,6.0 Hz, 1 H), 6.87 (dd, 1 H), 6.96 (d, 9-2.6 Hz, 1 H ), 7.30 (d, 9-8.7 Hz, 1 N). (4) ethyl 3-(methyl/T4-(T2-methyl-1-|13-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|propylamino)phenylIcarbonyl)amino ) propanoate

To a solution of /2-methyl-1-(3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|propan-1-ol (621 mg) obtained above in tetrahydrofuran ( 5 mL) was added thionyl chloride (0.17 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. An aqueous sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a colorless oil (648 mg).To the obtained colorless oil (648 mg) was added ethyl 3-(4-aminophenyl)carbonyl|(methyl)amino)propanate (509 mg) obtained in Example 2 (2) , sodium iodide (581 mg), sodium carbonate (411 mg) and M,M-dimethylacetamide (5 ml) and the mixture was stirred at 80 "C for 19 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.After filtration, the filtrate conc fell The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound (495 mg, 46905) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.92 (d, U-6.8 Hz, Z H), 1.13 (d, 9U-6.8 Hz, Z H), 1.21 - 1.30 (m, Z H), 1, 95 - 2.09 (m, 2 H), 2.13 - 2.27 (m, 6 H), 2.49 - 2.67 (m, 4 H), 2.87 - 2.96 (m, 2 H), 3.01 (s, C H), 3.70 (t, d9-7.2 Hz, 2 H), 4.07 - 4.16 (m, 2 H), 4.26 - 4 .36 (m, Z H), 6.57 (d, 9U-8.7 Hz, 2

H), 6.83 (dd, 9U-8.7, 2.6 Hz, 1 H), 6.91 (d, 9-2.6 Hz, 1 H), 7.16 - 7.25 (m , Z H).

Example A204

3-(methyl/T4-(2-methyl-1-|3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl|Ipropylamino)phenylcarbonylamino)propanoic acid not about CH . sh / i o -- 7z shk, ns on

Ethyl 3-(methyl/T4-(T2-methyl-1-|13-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1- benzofuran-2-yl|Ipropyl)iamino)phenylI|carbonylamino) propanoate (485 mg), synthesized in

Example A2OZ was dissolved in ethanol (2.0 ml) and tetrahydrofuran (2.0 ml), 1M aqueous sodium hydroxide solution (1.96 ml) was added to the solution, and the mixture was stirred at room temperature for 0.5 g. The solvent was evaporated at reduced pressure, water (4 ml) was added to the residue and the mixture was neutralized with 1M hydrochloric acid (1.96 ml) while cooling with ice, stirred for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound (421 mg, 9190) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 0.91 (d, 9U-6.8 Hz, Z H), 1.12 (d, 9U-6.8 Hz, Z H), 1.96 - 2.07 (m, 2 H), 2, 15 - 2.28 (m, 6 H), 2.48 - 2.71 (m, 5 H), 3.02 (s, Z H), 3.62 - 3.75 (m, 2 H), 4.21 - 4.35 (m, 2 H), 4.55 - 4.73 (m, 2 H), 6.56 (d, 9-8.7 Hz, 2 H), 6.83 (dd , 9U-8.7, 2.7 Hz, 1 H), 6.91 (d, 92.7 Hz, 1 H), 7.20 - 7.26 (m, C H).

Example A2O5 ethyl 3-methyl-1-(3-methyl-5-15-(trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)propylamino)phenyl)carbonylamino) propanoate in ns

I heard about SNU / 5-4

My sleep, My sleep,

(1)2-methyl-1-(3-methyl-5-5-(trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)propan-1-one

Solution // 1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-i-one (900 mg) synthesized in Example A2O3(1), 2-chloro-5- (trifluoromethyl)pyridine (898 mg) and potassium carbonate (854 mg) in M,M-dimethylformamide (5 ml) was stirred at 120 °C for 1 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 90:10, v/0v) to give the title compound (1.23 g, 8295) as colorless solid substance

IN NMR (300 MHz, SOSIz") 6 m.h. 1.25 (d, 9U-6.8 Hz, 6 N), 2.58 (s, C H), 3.47 - 3.71 (m, 1 H), 7.06 (d, 98.7 Hu, 1 H), 7.21 - 7.29 (m, 1 H), 7.42 (d, 9-2.6 Hu, 1 H), 7.55 (d, 9-8.7 Hz, 1 H), 7.92 (dd, 9U-8.7, 1.9 Hu, 1 H), 8.43 (s, 1 H). (2)2-methyl-1-(3-methyl-5-5-(trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)propan-1-ol 2-Methyl-1-( 3-methyl-5-T5-(trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)propan-1-one (1.22 g), synthesized above, was dissolved in methanol (40 ml) -tetrahydrofuran (4 ml) and sodium tetrahydroborate (9095) (253 mg) was added to the solution at 0 "C. The reaction mixture was stirred at 0 "C for 2 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (1.22 g, 10095) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 0.85 (d, Z H), 1.13 (d, 9U-6.4 Hz, Z H), 1.98 - 2.04 (m, 1 H), 2.15 - 2.30 (m , 4 N), 4.50 (dd, 9-7.9, 3.8 Hz, 1 N), 6.94 - 7.09 (m, 2 N), 7.24 (d, 952.3 Hz , 1 N), 7.45 (d, U-9.0 Hz, 1 N), 7.89 (dd, U-8.7, 2.3 Hz, 1 N), 8.45 (s, 1 N). (3) ethyl 3-Imethyl(4-C2-methyl-1-(3-methyl-5-15-trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)propylamino)phenyl) carbonylamino)upropanoate

To a solution of 2-methyl-1-(3-methyl-5-C5-(trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)upropan-1-ol (776 mg) obtained above in tetrahydrofuran (5 ml) at room temperature was added thionyl chloride (0.19 ml). The reaction mixture was stirred at room temperature for 3 h. An aqueous solution of sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. Ethyl 3-((4-aminophenyl)carbonyl|(methyl)aminopropanoate (557 mg), obtained in Example 2 (2), sodium iodide (636 mg), sodium carbonate (449 mg) and M,M- dimethylacetamide (5 ml) and the mixture was stirred at 80 C for 14 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel ( hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound (436 mg, 3490) as a yellow amorphous substance.

IN NMR (300 MHz, SOSI") b m.h. 0.94 (d, 9-6.4 Hz, Z H), 1.15 (d, 9U-6.8 Hz, Z H), 1.21 - 1.29 (m, Z H), 1, 60 (s, Z H), 2.20 - 2.31 (m, 4 H), 2.62 (t, 9-6.8 Hz, 2 H), 3.72 (t, 957.2 Hz, 2 H), 4.12 (Kk, 97.2 Hz, 2 H), 4.34 (d, 2 H), 6.58 (d, 2 H), 6.99 (td, U-5.8 , 3.0 Hz, 2 N), 7.15 - 7.25 (m, Z H), 7.39 (d, U-9.0 Hz, 1 N), 7.88 (dd, U-8 .7, 2.3 Hz, 1 N), 8.43 (d, U-2.6 Hz, 1 N).

Example A2O6

3-Imethyl(4-CH2-methyl-1-(3-methyl-5-((5-(trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)propylamino)phenyl)carbonyl| iamino)propanoic acid, etc

And where is SN? - / g Her and o m sn. her oh oh shcha;

ON

Ethyl 3-methyl(4-CH2-methyl-1-(3-methyl-5-15-(trifluoromethyl)pyridin-2-yl|oxy)-1-benzofuran-2-yl)propylamino)phenyl)carbonyl|iaminopropanoate ( 425 mg), synthesized in

Example A2O5 was dissolved in tetrahydrofuran (4.0 ml), 1M aqueous sodium hydroxide solution (1.4 ml) was added to the solution and the mixture was stirred at 50 for 1.5 g.

The solvent was evaporated under reduced pressure, water (4 ml) was added to the residue, and the mixture was neutralized with 1M hydrochloric acid (1.4 ml) under ice cooling and stirred for 20 min. The resulting precipitate was collected by filtration and dried to give the title compound (378 mg, 94905) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") b m.h. 0.93 (d, U-6.8 Hz, Z H), 1.14 (d, 9U-6.4 Hz, Z H), 2.16 - 2.30 (m, 4 H), 2, 52 (w s, 2 H), 2.99 (s, Z H), 3.62 (w s, 2 H), 4.34 (d, 957.5 Hz, 1 H), 6.57 (d , 98.7

Hz, 2 N), 6.89 - 7.05 (m, 2 N), 7.14 - 7.25 (m, Z H), 7.37 (d, 99.0 Hz, 1 N), 7 .89 (dd, 9U-8.9, 2.4

Gu, 1 H), 8.42 (s, 1 H).

Example A207 ethyl 3-((4-1-cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

E c) uy TO sn. not until; 7

SN. (1) X2-acetyl-4,6-difluorophenoxy)acetic acid

A solution of 3,5'-difluoro-2-hydroxyacetophenone (5.0 g), methyl bromoacetate (4.89 g) and potassium carbonate (6.01 g) in MM-dimethylformamide (50 ml) was stirred at room temperature for 4 d. The insoluble material was filtered off, 1M hydrochloric acid was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown oil. Tetrahydrofuran (60 ml), ethanol (60 ml) and 1 M aqueous sodium hydroxide solution (60 ml) were added to the obtained oil, and the mixture was stirred at room temperature for 30 min. The solvent was concentrated under reduced pressure, 1M hydrochloric acid (60 ml) was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (6.67 g, 10095) as a pale yellow solid. "H NMR (300 MHz, SOSI") b m.p. 2.67 (s, C H), 4.81 (s, 2 H), 7.01 - 7.12 (m, 1 H), 7 .20 - 7.26 (m, 1 H), 9.19 (w s, 1 H). (2) 5,7-difluoro-3-methyl-1-benzofuran

A mixture of (2-acetyl-4,6-difluorophenoxy)acetic acid (6.60 g) obtained above, sodium acetate (11.76 g) and acetic anhydride (40 ml) was stirred at 110 C for 8 h.

The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, saturated brine and dried over anhydrous magnesium sulfate.

After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (MN silica gel, hexane) to give the title compound (2.42 g, 5095) as a colorless solid. "IN NMR (300 MHz, SOSI") b m.ch. 2.21 (s, Z H), 6.70 - 6.90 (m, 1 H), 6.97 (dd, U-8.0 , 2.3 Hz, 1 H), 7.46 (s, 1 H). (Z)cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methanone

Aluminum chloride (anhydrous) (1.19 g) was added to a solution of 5,7-difluoro-3-methyl-1-benzofuran (1.0 g) synthesized above and cyclopentanecarbonyl chloride (867 mg) in nitromethane (20 mL) at 0"C and the mixture was stirred for 2 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 1000 - 955, o/o) to give the title compound (1.25 g, 8090) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.62 - 2.16 (m, 8 H), 2.57 (s, Z H), 3.66 - 3.85 (m, 1 H), 6.90 - 7.05 (m, 1 H ), 7.10 (dd, 9-73, 2.8 Hz, 1 N). (4) cyclopentyl (5, 7-difluoro-3-methyl-1-benzofuran-2-yl) methanol

Cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methanone (1.24 g), synthesized above, was dissolved in methanol (4 ml)-tetrahydrofuran (20 ml) and added to the solution at 0 C sodium tetrahydroborate (9095) (355 mg). The reaction mixture was stirred at 0" for 2 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (1.18 g, 10095) as a yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.04 - 1.22 (m, 1 N), 1.43 - 1.75 (m, 6 N), 1.93 - 2.03 (m, 2

H), 2.22 (s, C H), 2.40 - 2.63 (m, 1 H), 4.56 (dd, 2U-9.0, 6.4 Hz, 1 H), 6, 72 - 6.85 (m, 1 N), 6.87 - 6.95 (m, 1 N). (5) ethyl 3-((4-1-cyclopentyl(5, 7-difluoro-3-methyl-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

Thionyl chloride (0.46 ml) was added to a solution of cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)methanol (1.1 g) obtained above in tetrahydrofuran (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h. Thionyl chloride (0.46 ml) was added to the mixture and the mixture was stirred at room temperature for 30 min. An aqueous solution of sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. Ethyl 3-I((4-aminophenyl)carbonyl|(methyl)amino)propanoate (1.09 g), obtained in Example 2 (2), sodium iodide (1.24 g), sodium carbonate (875 mg) and M,M-dimethylacetamide (10 ml) and the mixture was stirred at 80"C for 2 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated . The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound (252 mg, 1290) as a yellow amorphous substance. "H NMR (300 MHz, SOCI") b m.h. 1.24 (dt, 9-94, 7.1 Hz, Z H), 1.46 - 1.79 (m, 7 H), 1.91 - 2.02 (m, 1 H), 2.25 (c, C H), 2.42 - 2.67 (m, C H), 3.01 (c, C H), 3.70 (t, 957.2 Hz, 2 H), 4.04 - 4.16 (m, 2 N), 4.31 - 4.41 (m, 2 N), 6.56 (d, 9-8.7 Hz, 2 N), 6.68 - 6.79 (m , 1 H), 6.88 (dd, 9U-8.0, 2.3 Hz, 1 H), 7.22 (d, 9d9-8.3 Hz, 2 H).

Example А2О8 3-Х(4-(cyclopentyl(5, 7-difluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

IS

H o; and BUT

SN, SH; PS

He

Ethyl 3-((4-cyclopentyl(5,7-difluoro-3-methyl-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl|(methyl)amino)propanoate (240 mg), synthesized in Example

A207 was dissolved in ethanol (1.0 ml)-tetrahydrofuran (1.0 ml), 1 M aqueous sodium hydroxide solution (0.96 ml) was added to the solution, and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, water (4 ml) was added to the residue, and the mixture was neutralized with 1M hydrochloric acid (0.96 ml) under ice cooling and stirred for 15 min. The resulting precipitate was collected by filtration and dried to give the title compound (185 mg, 8295) as a colorless amorphous form.

IN NMR (300 MHz, SOSI") 6 m.h. 1.16 - 1.39 (m, 1 N), 1.43 - 1.75 (m, 7 N), 1.86 - 2.06 (m, 1

H), 2.24 (s, C H), 2.38 - 2.56 (m, 1 H), 2.66 (t, 9-6.4 Hz, 2 H), 3.03 (s, With H), 3.70 (t, 9U-6.8 Hz, 2

H), 4.37 (d, 9U-9.4 Hz, 1 H), 6.55 (d, 9-8.7 Hz, 2 H), 6.68 - 6.80 (m, 1 H) , 6.88 (dd, 9-7.9, 2.3 Hz, 1 N), 7.24 (d, 2-8.7 Hz, 2 N).

Example A209 3-((4-(Hcyclohexyl13-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid , M o on (1)cyclohexyl|3-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl|methanone

Solution // 1-(5-hydroxy-3-methyl-1-benzofuran-2-yl)-2-methylpropan-i-one (300 mg), synthesized in Example A2O3(1), tetrahydrofurfuryl bromide (230 mg), carbonate potassium (240 mg) in M,M-dimethylformamide (3 ml) was stirred at 80 °C for 2 h and then at 120 °C for 4 h. Tetrahydrofurfuryl bromide (230 mg) was added to the mixture and the mixture was stirred at 120 °C for 60 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 90:10, v/v) affording the title compound (275 mg, 69905) as a colorless oil.

IN NMR (300 MHz, SOSI") b m.h. 1.20 - 1.51 (m, 5 N), 1.68 - 2.17 (m, 9 N), 2.56 (s, Z H), 3.20 - 3.39 (m, 1 N ), 3.76 - 3.98 (m, 2 N), 4.02 (d, 9-5.3 Hz, 2 N), 4.24 - 4.37 (m, 1 N), 7.03 (d, 92.6 Hz, 1 N), 7.13 (dd, 9U-9.0, 2.6 Hz, 1 N), 7.39 (d, 928.7 Hz, 1 N). (2) cyclohexyl|3-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl|methanol

Cyclohexyl|3-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl|methanone (260 mg), synthesized above, was dissolved in methanol (0.5 mL)-tetrahydrofuran (2.5 mL) , and sodium tetrahydroborate (9095) (64 mg) was added to the solution at 0"C. The reaction mixture was stirred at 0"C for 2.5 g. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (235 mg, 9095) as a colorless oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.77 - 1.46 (m, 8 H), 1.61 - 1.69 (m, 2 H), 1.72 - 2.01 (m, 6

H), 2.18 (s, C H), 3.78 - 3.89 (m, 1 H), 3.92 - 4.05 (m, C H), 4.22 - 4.39 (m , 1 N), 4.50 (d, 9-8.7

Hz, 1 N), 6.87 - 6.92 (m, 1 N), 6.94 (d, 9-2.6 Hz, 1 N), 7.29 (d, 959.1 Hz, 1 N ). (3)3-K(4-Cyclohexyl|3-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl|methyl)amino)phenylIcarbonylUumethyl)amino|propanoic acid

To a solution of cyclohexyl3-methyl-5-(tetrahydrofuran-2-ylmethoxy)-1-benzofuran-2-yl|methanol (220 mg) obtained above in tetrahydrofuran (2 ml) was added thionyl chloride (70 μl) at room temperature. The reaction mixture was stirred at room temperature for 2 h. An aqueous solution of sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. Ethyl 3-I((4-aminophenyl)carbonyl|methyl)amino)propanoate (168 mg), obtained in Example 2 (2), sodium iodide (192 mg), sodium carbonate (136 mg) and M, were added to the obtained residue. M-dimethylacetamide (3.0 ml) and the mixture was stirred at 80 C for 14 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 0100, v/v) to obtain a colorless amorphous substance (120 mg). The obtained colorless amorphous form (120 mg) was dissolved in ethanol (1.0 ml)-tetrahydrofuran (1.0 ml), 1 M aqueous sodium hydroxide solution (0.44 ml) was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, water (1 ml) was added to the residue, and the mixture was neutralized with TM hydrochloric acid (0.44 ml) under ice cooling and stirred for 10 min. The resulting precipitate was collected by filtration and dried to give the title compound (97 mg, 8095) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.93 - 1.29 (m, 5 N), 1.47 - 2.14 (m, 11 N), 2.20 (s, Z H), 2.54 - 2.72 (m, 2 N ), 3.02 (s, C H), 3.67 (t, 9U-6.4 Hz, 2 H), 3.77 - 3.90 (m, 1 H), 3.91 - 4.03 (m, Z

H), 4.19 - 4.32 (m, 1 H), 4.35 (d, 9-7.9 Hz, 1 H), 6.55 (d, 9U-8.7 Hz, 2 H) , 6.79 - 6.95 (m, 2 H), 7.16 - 7.25 (m, C H).

Example A210 ethyl 3-K16-41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-3-ylcarbonylUmethyl)amino|propanoate not 0) CH. but

NN and

SN. M t f

Not shk

SN. (1) methyl 6-(11-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2- methylpropylamino)pyridine-3-carboxylate

To a solution of 1-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol (1.41 g), obtained in Example A75(3), in tetrahydrofuran (10 ml) was added thionyl chloride (0.45 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h. An aqueous solution of sodium bicarbonate was added to the reaction mixture, cooled with ice to 0 "С and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a colorless solid (1.42 g). Methyl 6-aminopyridine-3-carboxylate (411 mg), sodium iodide (770 mg), sodium carbonate (545 mg) and

M,M-dimethylacetamide (6 ml) and the mixture was stirred at 80 "C for 22 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound (265 mg, 2590) as a brown oil. "H NMR (300 MHz, SOCI") 6 m.h . 0.33 - 0.39 (m, 2 H), 0.60 - 0.69 (m, 2 H), 0.88 - 0.95 (m, C

H)U, 1.10 (d, 9U-6.8 Hz, Z H), 2.94 (s, Z H), 3.01 (s, Z H), 3.82 - 3.88 (m , 4 N), 5.01 (t, 1 N), 5.40 (d, 9U-8.7 Gu, 1 N), 6.34 (d, 9-83 Hz, 1 N), 6.85 - 6.95 (m, 2 H), 7.21 - 7.27 (m, 1 H), 7.91 (dd, 99.0, 2.3 Hz, 1 H), 8.74 (d, 9-1.9 Hz, 1 N). (2)6-(1-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-3-carboxylic acid

To the mixture of methyl 6-(11-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-3-carboxylate (260 mg) obtained above, tetrahydrofuran (1, 2 ml) and ethanol (1.2 ml) was added 1M aqueous sodium hydroxide solution (1.2 ml) and the mixture was stirred under reflux for 5 h. 1M aqueous sodium hydroxide solution (1.2 ml) was added to the mixture and the mixture was stirred under reflux for 16 g. An 8M aqueous solution of sodium hydroxide (1.2 ml) was added to the mixture, and the mixture was further stirred under reflux for 1 g. The reaction mixture was concentrated under reduced pressure, water was added to the residue ( 4 ml) and 1M hydrochloric acid (10.8 ml) was added to the mixture while cooling with ice, and the mixture was stirred for 10 min. The resulting precipitate was collected by filtration and dried to give the title compound (145 mg, 5895) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.31 - 0.37 (m, 2 N), 0.61 - 0.66 (m, 2 N), 0.94 (d, 9U-6.8 Hz,

With H), 1.15 (d, 9U-6.8 Gu, With H), 1.21 - 1.37 (m, 1 H), 2.22 (s, With H), 2.31 - 2 .48 (m, 1 N), 3.82 (d, 9UEb, 8 Hz, 2 N), 4.66 (sh s, 1 N), 6.36 (d, 9-8.7 Hz, 1 N ), 6.79-6.92 (m, 2 N), 7.22-7.29 (m, 1 N), 8.05 (dd, 9U-9.1, 1.9 Hz, 1 N) , 8.75 (d, 9-1.9 Gu, 1 N). (3) ethyl 3-K16-41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2- methylpropyl)amino)pyridin-3-ylcarbonylUmethyl)amino|propanoate

A mixture of 6-(1-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-3-carboxylic acid (145 mg), synthesized above, ethyl 3- ( methylamino)propanoate (58 mg), 1-hydroxybenzotriazole monohydrate (67 mg), triethylamine (122 μl), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (84 mg) and M,M-dimethylformamide (2 ml) stirred at room temperature for 18 h.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate 100:0 - 0100, v/v) to give the title compound (104 mg, 5695) as a colorless amorphous form. "H NMR (300 MHz, SOSI") 6 m.h. 0.26 - 0.49 (m, 2 H), 0.58 - 0.70 (m, 2 H), 0.86 - 1.00 (m, Z

H), 1.04 - 1.15 (m, Z H), 1.18 - 1.31 (m, 4 H), 2.18 - 2.30 (m, 4 H), 2.63 (t , 9U-6.8 Hz, 2 H), 3.06 (s, Z H), 3.73 (t, 9U-7.0 Hz, 2 H), 3.82 (d, 9U-6.8 Hz, 2 N), 4.13 (k, 9-7.2 Hz, 2 N), 4.94 (t, 2-8.5

Hz, 1 N), 5.18 (d, 9-8.7 Hz, 1 N), 6.34 (d, 2U-8.3 Hz, 1 N), 6.79 -6.91 (m, 2 H), 7.22 - 7.26 (m, 1

H), 7.47 (dd, U-8.3, 2.3 Hz, 1 H).

Example A211 3-(16-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-3-ylcarbonylmethyl)amino|propanoic acid not about sn. h

Ua sn. and M / M o not What; he

Ethyl 3-K16-41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-3-ylcarbonylmethyl)amino|propanoate (100 mg), synthesized in

Example A21O0 was dissolved in ethanol (0.5 ml)-tetrahydrofuran (0.5 ml), 1M aqueous sodium hydroxide solution (0.4 ml) was added to the solution, and the mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure, water (0.5 ml) was added to the residue, the mixture was neutralized with 1M hydrochloric acid (0.4 ml) while cooling with ice, and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration and dried to give the title compound (77 mg, 8090) as a colorless solid. "H NMR (300 MHz, SOSI") b mp 0.30 - 0.43 (m, 2 H), 0.57 - 0.69 (m, 2 H), 0.92 (d, 9 -64 Hz,

With H), 1.15 (d, 9U-6.4 Hz, With H), 1.23 - 1.35 (m, 1 H), 2.21 (s, With H), 2.30 - 2 ,43 (m, 1 H), 2.66 (t, 96.2 Gu, 2 H), 3.06 (s, C H), 3.70 - 3.77 (m, 2 H), 3, 82 (d, 9d9-7.2 Hz, 2 N), 4.43 (w s, 1 N), 6.38 (d, 959.1 Gu, 1 N), 6.80 - 6.91 (m , 2 H), 7.26 - 7.30 (m, 1 H), 7.57 (dd, 9-8.7, 1.9 Hz, 1 H), 8.10 (she, 1 H).

Example A212 ethyl 3-K15-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-2-ylcarbonylmethyl)amino|Ipropanate not pure -05- sn, M M oh nothing; а, сн, (1) methyl 5-31-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-2-carboxylate

To a solution of 1-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropan-1-ol (1.41 g), obtained in Example A75(3), in tetrahydrofuran (10 ml) was added thionyl chloride (0.45 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h. An aqueous solution of sodium bicarbonate cooled with ice to 0 "C was added to the reaction mixture and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give a colorless solid (1.42 g). Methyl 5-aminopyridine-2-carboxylate (411 mg), sodium iodide (770 mg), sodium carbonate (545 mg/g) and

M,M-dimethylacetamide (6 ml) and the mixture was stirred at 80 "C for 2 h. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 100:0 - 50:50, v/v) to give the title compound (424 mg, 4090) as a brown oil. "H NMR (300 MHz, SOCI") b m.h . 0.29 - 0.40 (m, 2 N), 0.60 - 0.69 (m, 2 N), 0.93 (d, U-6.8 Hz,

With H), 1.14 (d, 9-6.8 Hz, With H), 2.20 - 2.31 (m, 4 H), 3.82 (d, 96.8 Hz, 2 H), 3.91 (s, C H), 4.34 (t, uU-8.0 Gu, 1 H), 4.65 (d, 9-8.3 Hz, 1 H), 6.81 - 6, 91 (m, Z H), 7.23 (d, 9-9.5 Gu, 1 H), 7.89 (d, 98.3 HZ, 1 H), 8.10 (d, 2-2, 7 Hz, 1 N). (2)5-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-2-carboxylic acid

To the mixture of methyl 5-41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-2-carboxylate (410 MG), synthesized above, tetrahydrofuran (2, 0 ml) and ethanol (2.0 ml) was added 1 M aqueous solution of sodium hydroxide (2.0 ml) and the mixture was stirred under reflux for 14 h. The reaction mixture was concentrated under reduced pressure, water (4 ml) was added to the residue , while cooling with ice, 1M hydrochloric acid (2 ml) was added and the mixture was stirred for 20 min. The resulting precipitate was collected by filtration and dried to give the title compound (323 mg, 80905) as a colorless solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.35 (k, 2 H), 0.60 - 0.68 (m, 2 H), 0.94 (d, 9-6.8 Hz, Z H), 1.15 (d, 9U-6 .8 Hz, Z H), 1.24 - 1.35 (m, 1 H), 2.18 - 2.38 (m, 4 H), 3.82 (d, 9-7.2 Hz, 2 H), 4.35 (she, 1 H), 498 (shs, 1 H), 6.82 - 6.90 (m, 2 H), 6.96 (dd, U-8.7, 2.6 Hz, 1 N), 7.20 - 7.28 (m, 1

H), 7.95 (d, U-8.7 Hz, 1 H), 8.08 (w s, 1 H). (3) ethyl 3-K15-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-2-ylcarbonylmethyl)amino|Ipropanate

A mixture of 5-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridine-2-carboxylic acid (311 mg) synthesized above, ethyl 3- ( methylamino)propanoate (131 mg), 1-hydroxybenzotriazole monohydrate (145 mg), triethylamine (265 μl), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (182 mg) and M,M-dimethylformamide (2 ml) stirred at room temperature for 16 h. A saturated aqueous solution of ammonium chloride was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate 100:0 - 0100, v/v) to give the title compound (291 mg, 7395) as a colorless amorphous form. "H NMR (300 MHz, SOSI") b m.ch. 0.31 - 0.39 (m, 2 H), 0.64 (k, 9U-6.1 Hz, 2 H), 0.92 ( d, U-6,8

Hu, Z H), 1.14 (d, Z H), 1.22 - 1.31 (m, Z H), 1.63 (s, Z H), 2.17 - 2.30 (m, 4 N), 2.62-2.75 (m, 2

H), 3.71 - 3.93 (m, 4 H), 4.01 - 4.18 (m, Z H), 4.24 - 4.36 (m, 1 H), 4.40 - 4 .47 (m, 1 H), 6.75 - 6.92 (m, Z H), 7.20 - 7.25 (m, 1 H), 7.53 (sh s, 1 H), 7, 93 (w s, 1 N).

Example A213 3-(15-(41-(-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2- methylpropyl)amino)pyridin-2-ylcarbonylmethyl)amino|Ipropanoic acid с а CH, ut and purely M- and

SN. MI A (8) no

ON

Ethyl 3-K15-(41-(5-(cyclopropylmethoxy)-3-methyl-1-benzofuran-2-yl|-2-methylpropyl)amino)pyridin-2-ylcarbonylmethyl)amino|propanoate (280 mg), synthesized in

Example A212 was dissolved in ethanol (1.0 ml)-tetrahydrofuran (1.0 ml), 1 M aqueous sodium hydroxide solution (1.1 ml) was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, water (2.0 ml) was added to the residue and the mixture was neutralized with 1 M hydrochloric acid (1.1 ml) under ice cooling and stirred for 30 min. The resulting precipitate was collected by filtration and dried to give the title compound (238 mg, 9095) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.28 - 0.41 (m, 2 N), 0.57 - 0.68 (m, 2 N), 0.91 (d, 9U-6.4 Hz,

With H), 1.12 (d, 9-6.4 Hz, With H), 2.18-2.31 (m, 4 H), 2.77 (shs, 2 H), 3.06 (sh s, Z H), 3.68 - 3.77 (m, 2 H), 3.80 - 3.85 (m, 2 H), 4.29 (d, 2-7.6 Hz, 2 H) , 4.66 (w s, 1 H), 6.80 - 7.00 (m, Z H), 7.24 (d, 9U-8.7 Hz, 1 H), 7.61 (w s, 1 H), 7.93 (sh s, 1 H).

Example A214 3-((4-(cyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid,

E ne (1)cyclohexyl(5-fluoro-3-hydroxy-1-benzofuran-2-yl)methanone 1-(5-Fluoro-2-hydroxyphenyl)ethanone (4.0 g) was dissolved in acetonitrile (80 ml). Potassium carbonate (4.8 g) and 2-bromo-1-cyclohexylethanone (7.3 g) synthesized in Example A51(1) were added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 8 g. The reaction mixture was filtered through celite, washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was dissolved in M,M-dimethylformamide (50 ml), 1,8-diazabicyclo/5.4.Oundec-7-ene (5.3 ml) was added to the solution, and the mixture was stirred while heating at 110 "С for 1 h. After cooling to room temperature, the reaction mixture was quenched with 1M hydrochloric acid and the mixture was extracted with diethyl ether.The extract was concentrated under reduced pressure and the precipitated compound was recrystallized from diisopropyl ether-ethanol to give the title compound (4.7 g, 7690) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.03 - 2.12 (m, 10 N), 3.00 - 3.26 (m, 1 N), 5.24 (s, 1 N), 7.14 - 7.50 (m, C H ). (2) cyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)methanone

Cyclohexyl(5-fluoro-3-hydroxy-1-benzofuran-2-yl)methanone (3.0 g) synthesized in (1) mentioned above was dissolved in tetrahydrofuran (15 ml) and M,M-dimethylformamide (15 ml). The reaction mixture was cooled with ice, sodium hydride (0.69 mg) was added to the solution, and the mixture was stirred for 15 min. Dimethyl sulfate (1.6 mL) was added to the mixture and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate.

The extract was concentrated under reduced pressure and the precipitate was recrystallized from diisopropyl ether-hexane to give the title compound (2.0 g, 63965) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 1.16 - 2.03 (m, 10 N), 3.23 (tt, 9U-11.2, 3.1 Hz, 1 N), 4.26 (s, C H), 7.20 - 7 .54 (m, Z H). (3)cyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)methanol

Cyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)umethanone (2.0 g) synthesized in (2) mentioned above, was dissolved in tetrahydrofuran (15 ml) and methanol (3 ml) and dissolved at after cooling with ice, sodium borohydride (9095, 0.59 g) was added. The ice bath was removed and the reaction mixture was stirred at room temperature for 1 h, then cooled again with ice, water (2 mL) and 1M hydrochloric acid (10 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (1.9 g, quantitative) of the title compound as a yellow oil. "H NMR (300 MHz, SOSI") b m.ch. 0.86 - 2.19 (m, 12 H), 3.97 (s, C H), 4.61 (d, 9U-8.3 Hz, 1 H), 6.98 - 7.33 (m, C H). (4) ethyl 3-((4-1-cyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)umethyliamino) phenyl)carbonylI|(methyl)amino)propanoate

Thionyl chloride (0, 48 ml). The reaction mixture was stirred at room temperature for 30 min, then cooled with ice, and a saturated aqueous solution of sodium bicarbonate (15 mL) was carefully added to the mixture. The reaction mixture was stirred for 10 min and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in dimethylacetamide (15 ml) and sodium iodide (0.98 g), sodium carbonate (0.65 g) and ethyl 3-(4-aminophenyl)carbonyl|(methyl)amino)propanate (0.90 g) were added to the solution ), synthesized in Example 2(2), and the mixture was stirred at 70 "C for 4 h. After spontaneous cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate: hexane-1:1, v/v) to give the title compound (0.30 g, 1695) as a pale yellow oil.

IN NMR (300 MHz, SOSI") b m.h. 0.91 - 2.19 (m, 14 N), 2.61 (t, 9-7.2 Hz, 2 N), 3.01 (s, C H), 3.70 (t, U-7 ,2 Hz, 2 N), 3.94 (s, C H), 4.11 (k, 0-7.2 Hz, 2 H), 4.30 - 4.46 (m, 2 H), 6 ,63 (d, 9-8,7

Hz, 2 N), 6.93 - 7.25 (m, 5 N). (5)33-((4-Hycyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Ethyl 3-(4-Tcyclohexyl(5-fluoro-3-methoxy-1-benzofuran-2-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoate (0.30 g) synthesized in the above-mentioned (4), dissolved in ethanol (5 ml), a 1 M aqueous solution of sodium hydroxide (1.0 ml) was added to the solution at room temperature and the mixture was stirred at room temperature for 0.5 g. The ethanol was evaporated under reduced pressure and 1 M hydrochloric acid (1 .0 ml). The precipitate was washed with water to give the title compound (0.15 g, 5295) as a colorless solid.

IN NMR (300 MHz, SOSI") b m.h. 0.94 - 2.20 (m, 11 N), 2.70 (t, 9-6.4 Hz, 2 N), 3.05 (s, C H), 3.71 (t, U-6 .4 Hz, 2 N), 3.94 (s, Z H), 4.46 (d, 2-8.3 Hz, 1 N), 6.64 (d, 2-9.0 Hz, 2 N ), 6.94 (td, 99.0, 2.6 Hz, 1 N), 7.14 - 7.31 (m, 4 N).

Example A215 3-((4-(cyclohexyl(b-methoxy-2-methyl-1-benzofuran-3-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid o

Year lshi and ! not M sleep,

Y n o sn. (1) cyclohexyl (b-methoxy-2-methyl-1-benzofuran-3-yl) methanone

To a mixture of b-methoxy-2-methyl-1-benzofuran (1.50 g), cyclohexane carbonyl chloride (1.36 ml) and nitromethane (15 ml) was added aluminum chloride (1.85 g) at 0" and the mixture was stirred for 1 g. Water was added to quench the reaction and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 - 1095 ethyl acetate/hexane) to give the target compound indicated in the title (1 ,18 g, 47905), as yellow oil. "H NMR (300 MHz, SOSI") 6 m.h. 1.20 - 1.62 (m, 5 N), 1.69 - 1.81 (m, 1 N), 1.82 - 2.02 (m, 4

H), 2.73 (s, C H), 2.95 - 3.09 (m, 1 H), 3.85 (s, C H), 6.93 (dd, 9U-8.7, 2 ,2 Hz, 1 N), 6.97 (d, 9-22

Hz, 1 N), 7.68 (d, 9-8.7 Hz, 1 N). (2) cyclohexyl (b-methoxy-2-methyl-1-benzofuran-3-yl) methanol

To the mixture of cyclohexyl (b-methoxy-2-methyl-1-benzofuran-3-yl)umethanone (1.18 g),

synthesized above, methanol (1 ml) and tetrahydrofuran (10 ml) was added sodium borohydride (246 mg) at 0 "С and the mixture was stirred for 30 min. 1 M hydrochloric acid was added to quench the reaction, the organic solvent was evaporated on evaporators and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (906 mg, 7695) as a pale yellow oil. "H NMR (300 MHz, SOCI") 6 m.p.h. 0.76 - 0.97 (m, 1 H), 0.99 - 1.38 (m, 4 H), 1.37 - 1.50 (m, 1

H), 1.51 - 1.72 (m, 2 H), 1.74 - 2.00 (m, 2 H), 2.11 - 2.24 (m, 1 H), 2.38 (s , Z H), 3.83 (s, Z H), 4.50 (d, U-8.0 Hz, 1 H), 6.81 (dd, U-8.5, 2.2 Hu, 1 H), 6.93 (d, 9-2.2 Hz, 1 H), 7.51 (d, 9-8.5 Hz, 1 H). (3)3-(chloro(cyclohexyl)methyl|-b-methoxy-2-methyl-1-benzofuran

To a solution (10 ml) of cyclohexyl(b-methoxy-2-methyl-1-benzofuran-3-yl)methanol (499 mg) synthesized above, thionyl chloride (159 μl) was added in toluene and the mixture was stirred at room temperature for 1 h The reaction mixture was poured into an ice-cooled saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate.

The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (530 mg, 99905) as a pale yellow oil.

IN NMR (300 MHz, SOSI") 6 m.h. 0.72 - 0.92 (m, 1 H), 0.97 - 1.40 (m, 4 H), 1.44 - 1.72 (m, C

H), 1.76 - 1.89 (m, 1 H), 2.05 - 2.22 (m, 1 H), 2.29 - 2.Ab (m, 4 H), 3.83 (s , Z H), 4.74 (d, 2-9.3

Hz, 1 N), 6.84 (dd, 9U-8.5, 2.4 Hz, 1 N), 6.93 (d, 9-24 Gu, 1 N), 7.55 (d, U- 8.5 Hz, 1 N). (4) ethyl 3-((4-cyclohexyl(b-methoxy-2-methyl-1-benzofuran-3-yl)methylamino)phenyl)carbonyl(methyl)amino)propanoate

To the mixture of 3-Ichloro(cyclohexyl)methyl|-b-methoxy-2-methyl-1-benzofuran (530 mg) synthesized above, ethyl 3-((4-aminophenyl)carbonyl)/methyl)amino)propanoate (498 mg ), synthesized in Example 2(2), and M,M-dimethylformamide (10 ml) were added sodium iodide (408 mg) and sodium carbonate (288 mg) and the mixture was stirred at 80 "C overnight.

A saturated aqueous solution of ammonium chloride was added to quench the reaction and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 - 70956 ethyl acetate/hexane) to give the title compound (781 mg, 8595) as a white solid. "H NMR (300 MHz, SOSI") 6 m.h. 0.91 - 1.37 (m, 8 N), 1.54 - 1.96 (m, 5 N), 1.99 - 2.12 (m, 1

H), 2.42 (s, C H), 2.60 (t, U-6.9 Hz, 2 H), 3.00 (s, C H), 3.69 (t, 2U-6, 9 Hz, 2 H), 3.82 (s, C H), 4.11 (k, 90-7.1 Gu, 2 H), 4.19 - 4.32 (m, 2 H), 6, 47 (d, 9U-8.5 Hz, 2 H), 6.79 (dd, 9-8.5, 2.2 Hz, 1

H), 6.91 (d, 9-2.2 Hz, 1 H), 7.17 (d, 9-8.5 Hz, 2 H), 7.40 (d, U-8.5 Hz, 1 H). (5)3-((4-Icyclohexyl(b-methoxy-2-methyl-1-benzofuran-3-yl)umethylamino)phenyl)carbonyl(methyl)amino)propanoic acid

Tetrahydrofuran (5 ml ) and ethanol (5 ml) was added 1 M aqueous solution of sodium hydroxide (2.00 ml), the mixture was stirred at room temperature for 1 g and concentrated under reduced pressure. The residue was dissolved in water (10 ml) and 1 M hydrogen chloride was added at 0 "С acid (2.00 mL).The resulting precipitate was collected by filtration to afford the title compound (702 mg, 9595) as a white solid.

IN NMR (300 MHz, SOSI") 6 m.h. 0.91 - 1.36 (m, 5 N), 1.57 - 1.97 (m, 5 N), 1.99 - 2.11 (m, 1

Н), 2.А1 (с, З Н), 2.64 (t, У-6.6 Hz, 2 Н), 3.01 (с, З Н), 3.68 (t, 2У-6, 6 Hz, 2 H), 3.81 (s, C H), 4.24 (d, 9-7.5 Hz, 1 H), 6.47 (d, 9U-8.7 Hz, 2 H) , 6.79 (dd, 9U-8.7, 2.3 Hz, 1 H), 6.91 (d, 9-23 Hz, 1 H), 7.18 (d, 2-8.7 Hz, 2 H), 7.40 (d, U-8.7 Gu, 1 H).

Experimental Example 1

The inhibition of glucagon binding by the compound of the present invention was evaluated according to the following method. (1) cloning of the human glucagon receptor gene

The human glucagon receptor gene was cloned by means of a PCR reaction using the cDNA of the pancreas of Marathon Red (Siopies!) as a template and the following primer.

sav-y: 5-ААТАСАААТТСАТЯСССССССССАССАЯ-3 (5EO I MO: 1) sav-y: 5-STAdaSsassSsastAaaAldasvsaastsТСАассСААТСТ-3 (ZEO IO MO: 2)

The PCR reaction was performed using Admapiade 2 polymerase (Siopiesi) and according to the attached protocol. The resulting PCR product was electrophoresed on an agarose gel (195). Approximately 1.4 kb DNA fragment containing the glucagon receptor was isolated from the gel and treated with restriction enzymes Esoki!I and Moi. DNA treated with restriction enzymes was electrophoresed on an agarose gel (195). A DNA fragment of approximately 1.4 KB was isolated and ligated to the pM5Kapeo plasmid treated with the restriction enzymes EsokKiI and Moi! for the construction of a DNA plasmid expressing the human glucagon receptor "pRM5Kapeo/poSoOk". The base sequence of the inserted fragment was confirmed and the confirmed base sequence was consistent with the target sequence. (2) obtaining the glucagon receptor membrane protein

The human glucagon receptor was perfused using the Ehrgez|cie CHO Ehrgezviop

Zuziet (Ipiygodep). Short-term expression was carried out in Egeebz (Tsue CHO cells) using a DNA plasmid expressing the human glucagon receptor "zhRM5Kapeo/poSok" and according to the instructions attached to EgeezCie CHO Ehrgezviop

Zuziet The DNA mentioned above was transfected and cultured with shaking for 2 days (37 "С, 895 СО", 125 rpm). 2400 ml of the culture medium was centrifuged at 2000 rpm for 10 min and the cells were collected. The collected cells were washed with RVB5, suspended in homogenized buffer (10 mM MansoOz (pH 7.4), 1 mM EOTA, complete

EOTA-free (Cospe, 1 tablet/5O0 ml)| and destroyed using a polytron cell destroyer (Kipetaiysa AS). The destroyed solution was centrifuged at 2000 rpm for 10 min and the supernatant was collected. The supernatant was centrifuged at 35,000 rpm. for 60 min and the sediment was suspended in buffer (20 mM Tris-HClII (pH 7.4), 5 mM

EOTA, complete EOTA-free (Cospe, 1 tablet/50 ml)| receiving glucagon receptor membrane protein (452 mg). (3) measurement of inhibition of glucagon binding

25 μl of the tested compound (containing 0.495 DMSO), 50 μl of the membrane protein of the glucagon receptor diluted with a reaction buffer of 50 mM Tigyl-HCII (pH 7.4), 5 mM ESTA, 5 mM magnesium chloride, 0.195 VBA, 0.00595 Hmeep20i to 100 μg/ml, and 25 μl of radiolabeled glucagon (G2C-Glucagon of receptor quality; Regkip EITeg Ips.) diluted with reaction buffer to 200 pM, thus starting the reaction. The tablet was stored for 90 minutes at room temperature. The reaction solution was transferred from the reaction plate to a 96-well filter CE/C plate (RegKkip EIteg Ips.) using a cell collector (Regkip EIteg Ips.) and the membrane fraction was collected on a suction filter. The filter was pre-soaked with 2 mg/ml polyethyleneimine to prevent non-specific absorption of the labeled ligand. The filter was washed 4 times with reaction buffer and dried 2 g at 42 °C. 25 μl of scintillator (Misgossipuo; Regkip EItag Ips.) was added to each well, and fluorescence was measured using a microplate scintillation counter (TorSoshpi MHT M; Regkip EItag Ips.). inhibition of glucagon binding (IC value) of test compound added to wells (containing 0.495 DMSO), using the response coefficient in wells to which only 0.495 DMSO was added as 095 inhibition, and the response coefficient to wells to which unlabeled glucagon was added (final concentration 1

MKM), as 10095 inhibition. The results are shown in Table 1.

Table 1 about Example A73. 77779002

In addition, the coefficient of inhibition (90) in wells to which the test compound (10 μM; containing 0.495 DMSO) was added was calculated, using the reaction coefficient in wells to which only 0.495 DMSO was added as 095 inhibition, and the reaction coefficient in wells, to to which unlabeled glucagon (1 µM final concentration) was added as 10095 inhibition.

The results are shown in Table 2.

Table 2 (95) at 10 μm o Example 17, | - 80 zh5Kyu about Example 9// | - 80 J o Example 3b.i/// | -: 695 Ж o Example4her/// | -( 60 J o Example 44.// | -( 69 2 sh zhKE« o Example 45 | - 60 J YumrgZ ( o Example 47.//-/ | - 66 D zhGIZH o Example 5Ob,./// | -( 68 КХКЗК o Example/// | -( 60 Ж жХУВ|Z about Example 586 | -( 69 Ж Х КЯХ about Example 2/// | - 68 Ш НкмЮХЖЖ about Example 8/// | - 66 D KzhKM about Example Б/// | -( 68 2 shDsh "KE on Example 78/// | -:( 69 g D "Ж on Example 85 | - 68 sh zhE on Example/// | -( 66 D zh"ГШ on PrimladAi.///| -: / 66 g D Xsv6 about Example 7./// | 2 -:/ 60 SS about Example AtOi | -( 80 Du zhENM about Example 22// | - 66 YamU about Example 25// | -( 60 Х КЕІ about Example 2u. | - 80 Ж жВе about Example!.// | -( 86 Ж Я about Example 43.// | -:(/ 80 "УК about Example 48 | - 66 ЧГЭ about Example 49.// | - 86 2 ЯЖЭ about Example 55id//- /| -( 90 Дю жЕЖ about Example 3.// | -:( 90 Дю жЖШ about Example б9и// | -:( 89 жеРМБ about Example 78) | -:( 90 Дю "B about Example 82) | -( 89 UKVE about Example Ав86/ / | -:( 89 2 / about Example 89.i | -( 80 "GI about Example 9.i// | -(/ 80 2 D NUMZh about Example A102 | 68 yuK about Example At03 | 66 BF about Example A104 | 68 Kh(mfF about Example of ATO6 | - 69 ZhyuKmK about Example A!!13 | - 68 ХуеБМ о Example AT25 | - 69 kfemM about Example AT26 | - 68 sh yubK about Example A!33 | - 80 Du KZhKz about ExampleAT4! | - 86 shD CC SKZ about Example AT47 | -( 99 2 sh ЖЖЗВ о Example AT49. | - 695 ЖК ГГ

Example Ai56. | 80 g of NRML for Example 57. | 80 g in Example A1b7. | 86 g Example A1b68. 774. | -: 98 2 яЯ1Л about Example A175 | 68 (сК(K about Example A176. | -:( 96 MzhmBmMm about Example A!777 | -: 90 ж Bzhk4kzh. I about Example A178. | 86 РМЖ0ГЗSK about Example A!187 | -: K 90 g / ZrHKE about Example A190 | 86 g (rbee about Example A193 | 80 g (r about Example 200 | - 89 ( about Example 20?2 | - 86 ЖНИШГ about Example 2o4.// | - 86 З about Example 209)// | - 9 g (rOFi

As mentioned above, it has been shown that the compound of the present invention has an extraordinary ability to inhibit the binding of glucagon.

Experimental Example 2 Glucagon-induced blood glucose inhibition test (rats)

50 well-fed rats (male, 7-9 weeks old) were orally administered a 0.595 methylcellulose suspension containing the test compound (10 mg/kg body weight) (compound administration group, 5 rats per group) or a 0.595 methylcellulose suspension (group without the introduction of the compound, 12 rats in the group) and after 60 min glucagon was injected subcutaneously (15 μg/kg of body weight, Momo Mogaizk Rpagta Tsa.). 20 minutes after the introduction of glucagon, blood samples were taken from the tail vein of rats and the level of glucose in the blood was measured using a set for self-determination of glucose level ASSO-SNEK (Nospe Oiadpoviiyisv K.K.).

In addition, as the untreated group (5 rats per group), blood glucose levels were measured in the same manner in rats (no compound group) that were not given glucagon.

The difference between the blood glucose level of the group that did not receive the compound or the group that received the compound and the glucose level of the untreated group was calculated. The percentage of the "difference between the blood glucose level of the compound-treated group and the untreated group" was obtained as "the ratio of increase in glucose level (90 control)" where "the difference between the glucose level of the untreated group, and the "untreated group" is 10,095. The results are shown in Table 3.

Table C. blood glucose level (mg/kg) o (90 control)

As mentioned above, the compound of the present invention has been shown to have an extraordinary ability to inhibit the increase in blood glucose levels.

Example 1 Recipes (capsule preparation) 1) compound of Example 1 30 mg 2) finely dispersed cellulose powder 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg

A total of 60 mg of 1), 2), 3) and 4) were mixed and filled with the mixture into a gelatin capsule.

Example 2 Recipes (tablet preparation) 1) compound of Example 1 30 g 2) lactose 50 g 3) corn starch 15 g 4) calcium carboxymethyl cellulose 44 g 5) magnesium stearate 1 g 1000 tablets in total 140 g

The total amount of 1), 2), 3) and 3 g 4) was mixed with water, dried in a vacuum and sieved.

This sifted powder was mixed with 14 g of 4) and 1 g of 5) and the mixture was pressed on a tableting machine. Thus, 1000 tablets containing 30 mg of the compound of Example 1 per tablet were obtained.

Industrial suitability

The compound of the present invention has a glucagon antagonistic effect and is useful for the prevention or treatment of diabetes, etc.

This application is based on patent applications Me 2008-055250 and 2009-025511 filed in

of Japan, the contents of which are incorporated herein by reference in their entirety.

LIST OF SEQUENCES

"1102" Takeda Pharmaceutical Company Limited "1205 Heterocyclic compound "130" 091369 "1505 UR2008-055250 "1515 2008-03-05 "1502 ЗР?2О09-025511 "151" 2009-02-08 "1605 2 "170" Ragvist 3.4 "2105 1 "112 Z "0122 DNA "13" Artificial "R kveZ" PDR primer "00" 1 self-explanatory vidssssssi dosadssasa Z "2102 2 "vi" 36 "212 DNA "2132: Artificial "2205 "a" PCR primer ka » 2 saadsodss asisaovachae chasisisads savisi Coll