NZ789384A - Combination comprising EP4 antagonist and immune checkpoint inhibitor - Google Patents

Combination comprising EP4 antagonist and immune checkpoint inhibitor

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Publication number
NZ789384A
NZ789384A NZ789384A NZ78938417A NZ789384A NZ 789384 A NZ789384 A NZ 789384A NZ 789384 A NZ789384 A NZ 789384A NZ 78938417 A NZ78938417 A NZ 78938417A NZ 789384 A NZ789384 A NZ 789384A
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NZ
New Zealand
Prior art keywords
amino
carbonyl
phenyl
chromene
butanoic acid
Prior art date
Application number
NZ789384A
Inventor
Akiko Shoyama
Hirotsugu Takano
Takao Yoshida
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Ono Pharmaceutical Co Ltd
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Application filed by Ono Pharmaceutical Co Ltd filed Critical Ono Pharmaceutical Co Ltd
Publication of NZ789384A publication Critical patent/NZ789384A/en

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Abstract

The present invention addresses the problem of discovering an effective cancer therapy method and providing a medicine. Provided is a medicine comprising a combination of a compound represented by general formula (I), a salt, solvate or N-oxide of the compound or a prodrug of the compound or the salt, solvate or N-oxide and an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody). The combination according to the present invention exhibits a high anti-tumor effect and is therefore useful for the treatment of cancer. t, solvate or N-oxide and an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody). The combination according to the present invention exhibits a high anti-tumor effect and is therefore useful for the treatment of cancer.

Description

COMBINATION COMPRISING EP4 ANTAGONIST AND IMMUNE CHECKPOINT TOR The present application is a divisional of New d patent application 749540, which is the national phase entry of PCT international application (published as TECHNICAL FIELD [0001A] The present invention relates to a medicament comprising a combination of a compound represented by formula (I) [Chem. 1] (in the formula, all the symbols have the same meanings as those described below), a salt thereof, a solvate f, an N-oxide thereof, or a prodrug of these and an immune checkpoint inhibitor.
BACKGROUND ART The glandin E2 (PGE2), a known metabolite of the arachidonic acid e, is known to have cytoprotective effect, effect of uterine contraction, effect of lowering the threshold of pain, effect of promoting peristalsis in the digestive tract, arousal effect, effect of inhibiting stomach acid secretion, hypotensive , diuretic effect, and the like.
Recent studies have found that there are subtypes of PGE2 receptors with different roles.
To date, four broad subtypes are known, and these are called EP1, EP2, EP3, and EP4 (Non-Patent Document 1).
[0006] In these subtypes, the EP4 receptor is thought to be ed in inhibition of MCP-l production from macrophages, inhibition ofTNF-CL, IL—2, and IFN-y tion from lymphocytes, anti—inflammation by enhanced IL-10 production, vasodilatation, angiogenesis, inhibition of elastic fiber formation, and regulation of MMP-9 expression. Other possible involvement of the EP4 receptor includes immune control in cancer via myeloid derived suppressor cells, regulatory T cells, and natural killer cells.
It is therefore t that compounds that strongly bind to the EP4 receptor and show antagonistic activity are useful for the treatment of diseases caused by EP4 receptor activation, ing, for example, a bone disease, a cancer, a systemic omatous e, an immune disease, allergy, atopy, asthma, alveolar pyorrhea, gingivitis, periodontitis, Alzheimer's, Kawasaki disease, burn, multiple organ failure, chronic headache, pain, vasculitis, venous incompetence, varicose veins, aneurysm, aortic sm, anal fistula, diabetes insipidus, stress, endometriosis, uterine adenomyosis, patent ductus arteriosus in neonates, and cholelithiasis (Non-Patent Documents 2-7).
Patent Document 1 describes that a compound ented by the following formula (A) is used as a compound used for the ent of diseases involving glandin B receptors, for example, such as pain, inflammation, and cancer.
[0009] The formula (A) is as follows: [Chem 2] Xa___Qa Ar2< (A) V\/e‘——Ar1a
[0011] (in the formula, Ar1a is an aryl or a heteroaryl group optionally substituted with R13 or R33, wherein R15' is CN, N02, CON(R5“)2, or the like; Wa represents a three- to six-membered linking group containing 0 to 2 heteroatoms selected from O, N, and S, wherein the linking group optionally contains CO, S(0)na, C=C, or an acetylene group; Arzal is an aryl or a heteroaryl group ally substituted with R“, n R321 is halogen, CN, or the like; Xa is a linker attached to Arzal at the position ortho to the bonding site for Wa; and Qa is COOH or the like (these are only a part of the definitions of the groups.)) Patent Document 2 describes that a nd of the following formula (B) binds to the PGEz receptor, particularly EP3 and/or EP4, and has antagonistic activity and that the compound is thus useful for the prevention and/or treatment of diseases such as pain, and The formula (B) is as follows:
[0014] [Chem 3] (RQb)mb Ab_R1b (Qb)nb [Db—Rab (in the formula, R'b ents ~COOH or the like; Ab represents (i) a single bond, (ii) Cl-6 alkylene, (iii) C2—6 alkenylene, (iv) 02-6 alkynylene, or the like; the ring Bb represents a C3- 12 monocyclic or bicyclic carbon ring or a three- to twelve-membered monocyclic or bicyclic heterocyclic ring; R2b represents nitro, cyano, or the like; Qb represents C2-6 alkenyl, C2-6 alkynyl, C1-6 alkyl substituted with l to 3 halogen atoms, cyano, nitro, or the like; D" is a one- or two-membcred linking chain of atoms selected from a carbon atom, a nitrogen atom, an oxygen atom, and a sulfur atom, wherein the linking chain may contain a double bond or a triple bond and may be substituted with one to four R40”, wherein R40b ents an 0x0, halogen, or the like; and R3‘) represents (1) C1-6 alkyl or (2) a C3-15 monocyclic, bicyclic, or tricyclic carbon ring that is substituted with one to five R42b or that is tituted or a three- to fifieen-membered monocyclic, bicyclic, or tricyclic heterocyclic ring, wherein R42b represents C1-6 alkyl, C1-6 alkoxy, halogen, cyano, -NR46"COR47b, or CyclOb (these are only a part of the definitions of the .» Patent Document 3 describes that a compound represented by the following formula (C) is used as a compound used for the ent of diseases involving prostaglandin B receptors, for example, such as pain, inflammation, and cancer.
The formula (C) is as follows: [Chem 4] R10R2°R3°——HET° 0 xc_Bc 20 (in the formula, HETc represents a five- to twelve-membered monocyclic or bicyclic aromatic ring system having 0 to 3 atoms selected from O, S(O)nc, and , wherein me is 0 or 1, and no is 0, 1, or 2; AC is one- or two-atom moiety and is selected from the group consisting of -W°-, -C(O)-, and the like, wherein W° is O, S(O)nc, or NRm; XC represents a five- to ten-membered monocyclic or bicyclic aryl or heteroaryl group having 1 to 3 heteroatoms selected from O, S(O)nc, and N(O)mc, Y0 represents 0, S(O)nc, NR17", a bond, or the like; Bc is -(C(R18°)2)pc-Y°—(C(R13°)2)qc-, wherein pc and qc are independently 0 to 3; Zc is OH or the like; and R”, RR, and R“ independently represent n, ~C02R9°, -CON(R6°)2, or the like (these are only a part of the definitions of the groups.»
[0020] None of Patent Documents 1 to 3 and Non-Patent nts 1 to 7 be or suggest the tricyclic spiro compound used for the t invention.
Various immune checkpoint molecules that prevent the immune response to cancer are in cancer cells or cancer microenvironment. Immune checkpoint tors provide a new therapeutic method which deactivates the immunosuppression mechanism and which activates the immune reaction to cancer. As immune checkpoint inhibitors, an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) antibody, ipilimumab, anti-PD-l (programmed cell death- 1) dies, nivolumab and pembrolizumab, and the like have already been approved in and outside Japan and are used for the treatment of cancer.
ON LIST PATENT LITERATURE Patent Document 1: WO2000/020371 Patent Document 2: W02003/016254 Patent Document 3: WOl999/047497 NON PATENT LITERATURE Non-Patent Document 1: Journal of Lipid Mediators and Cell Signalling, Vol. 12, 379-391, 1995 Non-Patent Document 2: Pharmacological Reviews, Vol. 65, p. 1010-1052, July, 2013 Non-Patent nt 3: 105th Annual Meeting ofAmerican Association for Cancer ch (AACR), Abstract: LB-265, Title of Presentation: ONO-AE3~208 inhibits myeloid derived suppressor cells and glioma growth, Date of Presentation: April 8, 2014 Non-Patent Document 4: FEBS Letters, Vol. 364, p. 1, 1995 Non-Patent Document 5: Cancer Science, Vol. 105, p. 1142-1151, 2014 Non—Patent nt 6: Cancer Research, Vol. 70, p. 1606-1615, 2010 Non-Patent Document 7: Cancer ch, Vol. 62, p. 28-32, 2002 SUMMARY OF INVENTION TECHNICAL PROBLEM An object of the present invention is to find an ive method for treatng cancer and to provide the method in the form of a drug.
SOLUTION TO PROBLEM The present inventors conducted intensive studies to achieve the object. As a result, the inventors have found that a compound represented by the formula (1) below, a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these (hereinafter, sometimes simply referred to as the compound used for the t invention) acts as an EP4 receptor antagonist and that a combination of the compound used for the t invention and an immune checkpoint inhibitor (hereinafter, mes simply referred to as the combination of the present invention) es the object of the present invention. The inventors have thus completed the present invention.
That is, the invention relates to the following subject matters.
A medicament comprising a combination of a compound represented by formula (I), a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor, [Chem 5] (R2)p (R5), (wherein R1 represents COORs, tetrazole, SOsH, z, SOzNHRs", CONHSOst' ', ORs‘l, or hydroxamic acid, wherein R8 represents a hydrogen atom, Cl-4 alkyl, or benzyl, and R8'1 represents 01-4 alkyl, Cl-4 haloalkyl, a C3—10 carbon ring, or a three- to ten- membered heterocyclic ring, wherein the C3-10 carbon ring and the three- to ten-membered heterocyclic ring each may be substituted with C1-4 alkyl, Cl-4 haloalkyl, C1-4 alkoxy, - 0(C1-4 haloalkyl), Cl-4 alkylthio, -S(C1-4 haloalkyl), n, or nitrile (here and below, "- CN"), Ll represents C1~5 alkylene, C2-5 alkenylene, or C2—5 alkynylene, R2 represents halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 hio, C2-4 l, C2-4 alkynyl, -0(C1-4 haloalkyl), -S(C1-4 haloalkyl), -C(O)(CI-4 alkyl), ~SOz(C1-4 alkyl), - CONH(C1-4 alkyl), -CON(C1-4 a1ky1)2, —NHC(0)(C1-4 alkyl), -N(C1—4 C(O)(C1-4 alkyl), -NHSOz(C1-4 alkyl), -N(C1—4 alkyl)SOz(C1—4 alkyl), -SOzNH(C1-4 alkyl), -SOzN(C1- 4 alkyl)2, -NR‘7R17, nitro, e, a hydroxyl group, aldehyde (here and below, fonnyl), or carboxyl, wherein the C1-4 alkyl groups each may be substituted with halogen, and the (C 1 -4 2 in R2 represents two independent C1-4 alkyl groups which may be the same or different, X1 represents CR6 or a nitrogen atom, wherein R6 represents a hydrogen atom or R2, X2 represents CR7 or a nitrogen atom, wherein R7 represents a hydrogen atom, R2, or - L3-R9, n L3 represents methylene, an oxygen atom, or a sulfur atom which may be oxidized, and R9 represents a four- to ten-membered heterocyclic ring which may be tuted with a substituent selected from the group consisting ofhalogen, C 1-4 alkyl, and Cl-4 haloalkyl, L2 represents -CH2CH2~, ~CH=CH-, -CH20-, -OCH2—, ~CH2$-, -SCH2-, ~CH23(0)—, - S(O)CH2—, -CH2S02-, -SOzCH2-, -CH2NH—, -NHCH2-, -NHCO-, -CONH—, -NHSOz-, or - SOzNH—, R3 represents C1-4 alkyl or n, R4 represents halogen, C1-4 alkyl, or C1-4 haloalkyl, X3 represents methylene, an oxygen atom, a sulfilr atom which may be oxidized, or NRIO, wherein R10 represents Cl-4 alkyl, —C(O)(C1-4 alkyl), -C(O)O(Cl—4 alkyl), or -SOz(C1- 4 alkyl), wherein the C 1-4 alkyl groups each may be substituted with halogen, the ring represents a benzene ring or a five- or six-membered monocyclic aromatic heterocyclic ring, [Chem 6] _.___._ represents a single bond or a double bond, R5 represents (1) halogen, (2) Cl-4 alkyl, (3) yl, (4) nitrile, (5) -CONHR”, (6) - C(0)R12, (7) OR”, (8) —S(O)1R‘5, (9) -CH2R'6, (10) —NR”R”, (11) -NHCOR“, (12) a c4-10 carbon ring, or (13) a four- to ten-membered heterocyclic ring, wherein the C4-10 carbon ring or the four- to ten-membered heterocyclic ring may be substituted with one to three R's, wherein, when a plurality of R18 exists, the plurality of R18 each independently may be the same or ent, R” represents C1-6 alkyl, C3-6 cycloalkyl, , or a four- to six-membered heterocyclic ring and may be substituted with one to three R13, wherein, when a plurality of RI3 exists, the plurality of R13 each independently may be the same or different, and R13 represents n, C1—6 alkyl, C3 -6 cycloalkyl, C1-4 alkoxy, a hydroxyl group, - NRZORZI, benzene, or a four- to mbered heterocyclic ring, wherein R20 and R21 each independently represent a hydrogen atom or C1-4 alkyl, R12 ents C1-6 alkyl, C3-6 cycloalkyl, e, or a four- to six-membered heterocyclic ring, wherein the C3-6 cycloalkyl, the benzene, and the four- to six-membered heterocyclic ring each ndently may be substituted with halogen, C1-4 alkyl, or C 1-4 alkoxy, Rl4 represents a hydrogen atom, C1-6 alkyl, C3 -6 cycloalkyl, benzene, or benzyl, wherein the C1-6 alkyl may be substituted with one to three R19, n, when a plurality of R19 exists, the plurality of RI9 each independently may be the same or different, and R19 represents C1-4 alkoxy, -CONH(Cl-4 alkyl), -CON(C1-4 alkyl)2, or a five— or six- membered monocyclic aromatic heterocyclic ring which may be substituted with a substituent selected from the group consisting of C1—4 alkyl and C1-4 kyl, wherein the (C1 -4 alky1)2 in R19 represents two independent Cl-4 alkyl groups which may be the same or different, R15 represents C1-6 alkyl, C3 -6 cycloalkyl, benzene, or , Rl6 represents a hydroxyl group or C1-4 alkoxy, each R17 independently ents a hydrogen atom, Cl-6 alkyl, or C3-6 cycloalkyl, R18 represents halogen, Cl-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxo, nitrile, a hydroxyl group, hydroxymethyl, l-methyl-l-hydroxyethyl, (Cl-4 alkyl)SOz-, a four— to six- membered heterocyclic ring, (Cl-4 alkyl)NH-, or (Cl -4 alkyl)2N-, n the (Cl-4 alky1)2 in R18 represents two independent C1-4 alkyl groups which may be the same or ent, 111 represents an integer of 1 to 4, n represents an integer of 0 to 4, p represents an integer of 0 to 2, q represents an integer of 0 to 6, r represents an integer of 0 to 6, 3 ents an integer of 0 to 4, t represents an integer of 0 to 2, and R2, R3, R4, and RS each independently may be the same or ent when p, q, r, and s are each an integer of2 or more.) The medicament according to item [1], wherein the compound represented by formula (I) is a compound represented by formula (1-1), [Chem. 7] (R5)s (wherein na represents an integer of O or 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, X3“1 represents methylene or an oxygen atom, and the other symbols have the same meanings as the symbols defined in item [1].) The medicament according to item [1] or item [2], wherein s is an integer of 1 to 4, and at least one R5 is -CONHR”.
The ment according to any one of item [1] to item [3], wherein L2 is - NHCO- or -CONH-. [5] The medicament according to any one of item [1] to item [4], wherein the compound represented by formula (I) is a nd represented by formula (1-2), [Chem 8] (R2a)p RGa 1 // L\R1 \ (R4)ra NC NH /‘0 o (I-2) (R3)? 0 N/
[0034] (wherein R2a represents halogen, R6a represents a hydrogen atom or n, and the other symbols have the same meanings as the symbols defined in item [1] and item [2].) The medicament according to item [1], wherein the nd represented by formula (I) is (1 ) 4-[4-cyano({ [(2'R,4S)(methylcarbamoyl)-2,3 ~dihydrospiro[chromene-4, 1 '- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4- {4—cyano[({(2'R,4S)[(cyclopropylmethyl)carbamoy1]-2,3- dihydrospiro[chromene—4,1'-cyclopropan]-2'—y1}carbonyl)amino]phenyl}butanoic acid, (3) 4- {4-cyano[({(2'R,4S)[(2-methoxyethyl)carbamoyl]~2,3- dihydrospiro[chromene—4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (4) 4- {4-cyano[({(2'R,4S)[(2-methylpropany1)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (5) 4-[4-cyano({[(2'R,4S){[(ZS)-l-methoxy—2—propany1]carbamoyl}-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-y1]carbonyl}amino)phcnyl]butan0ic acid, (6) yano[({(2'R,4S)[(1-methyl-1H-pyrazol—3~y1)carbamoy1]-2,3- ospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (7) 4-[4-cyano({ [(2'R,4S)(cyclopropy1carbamoyl)-2,3-dihydrospiro[chromene- yclopropan]-2'—yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano({ [(2'R,4S)(isopropylcarbamoyl)—2,3-dihydrospiro[chromene—4, 1 '- cyclopropan]-2'-yl]carbonyl}amino)pheny1]butanoic acid, (9) 4-[4-cyano({ [(2'R,4S)(cyclopentylcarbamoyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-y1]carbonyl}amino)phenyl]butanoic acid, (10) 4-{2-[({(2'R,4S)[(ZS)butanylcarbamoy1]—2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'—yl}carbony1)amino]cyanophenyl}butanoic acid, (11) 4-{4-cyano[({(2’R,4S)—6-[(transhydroxycyclohexy1)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]—2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-{4-cyano—2-[({(2'R,4S)[(cishydroxycyclohexyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]—2'—yl}carbonyl)amino]phenyl}butanoic acid, (1 3) 4— [4-cyano({ [(2'R,4S)(2-pyridinylcarbamoy1)-2,3-dihydrospir0[chromene- 4,1'-cyclopropan]-2'-y1]carbonyl}amino)phenyl]butanoic acid, (14) 4-[4-cyano({ [(2‘R,4S)(3~pyridazinylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'—y1]carbonyl}amino)phenyl]butanoic acid, (1 5) 4-[4-cyano( { [(2‘R,4S)(cyclobutylcarbamoyl)—2,3-dihydrospiro[chromene- 4, 1 '-cyclopr0pan]-2'-yl]carbonyl} phenyl]butanoic acid, (16) 4-[4-cyano({[(2‘R,4S){ [1 -(2-methylpropany1)~1 H-pyrazol yI] carbamoyl}-2,3-dihydrospiro[chromene—4, 1 '-cyclopropan]-2'— y1]carbonyl}amino)pheny1]butanoic acid, (1 7) 4-[4-cyano({ [(2'R,4S)-6~(tetrahydro—2H-pyran—4-ylcarbam0y1)-2,3 — dihydrospiro[chromene-4,1'-cyclopropan]-2'-y1]carbony1}amino)phenyl]butanoic acid, (1 8) 4-[4-cyano({[(2'R,4S)(propylcarbamoyl)-2,3-dihydrospiro[chromene-4,1 '~ cycIOpropan]-2'—y1]carbonyl}amino)pheny1]butanoic acid, (19) 4- {4-cyano[( { (2'R,4S)—6—[(2-ethoxyethy1)carbamoyl]-2,3 - dihydrospiro[chromenc—4, 1 '-cyclopr0pan]-2'-yl}carbonyl)amino]phenyl }butanoic acid, (20) 4-[4-cyano({[(2'R,4S)(ethylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- rOpan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (21) 4-[4-cyano({[(1R,2R)-6'—(methylcarbamoyI)-2',3'-dihydrospiro[cyclopropane- 1 ,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid, (22) 4-{4-cyan0[({(lR,2R)—6'—[(2—methoxyethyl)carbamoyl]-2',3'- dihydrospiro[cyclopropane—1,1'—inden]—2-yl}carbonyl)amino]phenyl}butanoic acid, (23) 4-{4-cyano-2—[({(lR,2R)—6'-[(1-methy1-1H—pyrazol—4-y1)carbamoy1]-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl}carbony1)amino]phenyl}butanoic acid, (24) 4-[4-cyano({ [(2'R,4S)fluoro(methylcarbamoyl)-2,3- dihydrospiro[chromene-4,l'—cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (25) 4- {4-cyano[({(2'R,4S)—7-fluoro[(2-methoxyethyl)carbamoyl]-2,3- dihydrosPiro[chromene-4,1'-cyc10propan]~2'-yl}carbonyl)amino]phenyl}butanoic acid, (26) yano({ [(2'R,4S)fluoro(isopropylcarbamoyl)—2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-y1]carbony1}amino)phenyl]butanoic acid, (27) 4-[4-cyano~2-({ [(2'R,4S)-7—(methylcarbamoyl)-2,3-dihydrospiro[chromene—4, 1'- cyclopropan]-2'-yl]carbony1}amino)phenyl]butanoic acid, (28) yano[({(2'R,4S)[(2-methoxyethyl)carbamoyl]-2,3~ dihydrospiro[chromene-4,l'-cyclopropan]-2'-yl}carbonyl)amino]pheny1}butanoic acid, (29) 4-[4-cyano({[(2'R,4S)-7—meth0xy-6—(methy1carbamoyl)-2,3- dihydrospiro[chromene-4, l '-cyc10propan]-2'-yI]carbonyl}amino)pheny1]butanoic acid, (30) 4-{4-cyano[({(2'R,4S)methoxy—6—[(2-meth0xyethy1)carbamoy1]-2,3- dihydrospiro[chromene—4,1‘-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (3 1) 4-[4-cyan0({[(2'R,3S)(methylcarbamoyl)-2H—spiro[1-benzofuran-3,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (32) 4-{4-cyan0[({(2'R,3S)[(2-meth0xyethyl)carbamoyl]-2H-spiro[1- benzofuran—3 ,1 '-cyclopropan] -2'-y1 } carbonyl)amino]pheny1 } butanoic acid, (33) 4-[4-cyano-2—({[(1S,2R)-6'-[(2-methoxyethy1)carbamoyl]—3',3'—dimethyl-2',3'— dihydrospiro[cyclopropane-l,1’-inden]-2—yl]carbonyl}amino)phenyl]butanoic acid, or (34) 4-[4-cyano({[(1S,2R)-3',3'-dimethyl-6'-(methy1carbamoyl)-2',3'- dihydrospiro[cyclopropane- 1 , l '-inden]yl]carbonyl}amino)pheny1]butanoic acid.
The medicament according to item [1] or item [2], wherein s is an integer of 1 to 4, and at least one R5 is a C4-10 carbon ring which may be substituted with one to three R18 or a four- to mbered heterocyclic ring which may be substituted with one to three R18, wherein, when a plurality of R18 exists, the plurality of R18 each independently may be the same or different.
The medicament according to item [7], wherein L2 is «NHCO- or -CONH-.
The medicament according to any one of item [1], item [2], item [7], and item [8], wherein the compound represented by formula (I) is a compound represented by formula (L3), [Chem 9] (R23), R // L1\R1 \ (Rm NC NH ‘0 (l-3) (R3)? (wherein R5’3 is a C4-10 carbon ring which may be substituted with one to three R18 or a four- to ten-membered heterocyclic ring which may be substituted with one to three R18, wherein, when a plurality of R18 exists, the plurality of R18 each independently may be the same or different, and the other symbols have the same meanings as the symbols defined in item [1], item [2], and item [5].)
[10] The medicament according to item [1], n the compound represented by formula (I) is (1) 4- [4-cyano-2—({ [(2'R,4S)(5-methyl- l ,3 ,4-0xadiazol—2—yl)—2,3- dihydrospiro[chromene-4 , 1 '-cyclopropan] ]carbonyl}amino)phenyl]butanoic acid, (2) 4-[4—cyano—2-({ 4S)—6-(5-cyclopropyl— 1,3 ,4—0xadiazol—2-yl)-2,3 - dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (3) 4-[4-cyano({ [(2'R,4S)(3 l-1,2,4-oxadiazolyl)—2,3- dihydrospiro[chromene-4, 1 opropan] -2'—yl]carbonyl}amino)phenyl]butanoic acid, (4) 4-[4-cyano({ [(2'R,4S)(3-pyridinyl)-2,3-dihydrospiro[chromene-4, 1 '- ropan]-2'—y1]carbony1}amino)pheny1]butanoic acid, (5) 4-[4-cyano({ [(2'R,4S)(1H—pyrazolyI)-2,3-dihydrospiro[chromene-4,1 '- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (6) 4-[4-cyano({ [(2'R,4S)(1 H—pyrazol~5-yl)—2,3 -dihydrospiro[chromene-4,1 '- cyclopropan]-2'~y1]carbonyl}amino)phenyl]butanoic acid, (7) 4- [4-cyano({ [(2'R,4S)-6—(4-pyridazinyl)-2,3-dihydrospiro[chromene-4, 1 '- cyclopropan]-2'-y1]carbonyl}amino)phenyl]butanoic acid, (8) 4— [4—cyano({ [(2'R,4S)(2-oxo-1 —pyrrolidiny1)—2,3 -dihydrospiro[chromene— 4,1‘-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (9) 4-[4-cyano({ 4S)(6—methoxy—3 -pyridinyl)-2,3 -dihydrospiro[chromene- 4,1‘-cyclopropan]-2'—y1]carbonyl}amino)phenyl]butan0ic acid, . (10) 4-{4-cyano[({(2‘R,4S)[6-(1H-pyrazol—1-y1)pyridinyl]—2,3- ospiro[chromene—4, 1 '-cyclopr0pan]—2'—yl}carbony1)amino]pheny1}butanoic acid, (11) 4- {4-cyano[({(2'R,4S)[6-(dimethy1amino)pyridinyl]-2,3- dihydrospiro[chromene-4, 1 '-cyclopropan]-2'-y1}carbonyl)amino]pheny1}butanoic acid, (12) 4-[4-cyano({ 4S)(6-mcthylpyridiny1)-2,3-dihydrospiro[chromene- 4,l'-cyclopropan]-2'-y1]carbonyl}amino)phenyl]butanoic acid, (13) 4-{4-cyano[({(2'R,4S)[6-(methylamino)pyridinyl]-2,3- dihydroSpiro[chromene—4, l '-cyclopropan]-2'-yl}carbonyl)amino]pheny1}butanoic acid, (14) 4-[4-cyano({[(2'R,4S)(2-pyridinyl)—2,3-dihydrospiro[chromene—4,1'- cyclopropan]-2'-y1]carbonyl}amino)pheny1]butanoic acid, (1 5) 4-[4-cyano({[(2'R,4S)-6—(1,3-thiazolyl)—2,3-dihydrospir0[chromene—4,1 '— cycIopropan]-2'—y1]carbony1}amino)phenyl]butanoic acid, (16) 4—[4-cyano({[(2'R,4S)—6-(1,3-oxazoly1)-2,3~dihydrospiro[chromene-4, 1 '- cycIopropan]~2'-y1]carbony1}amino)phenyl]butanoic acid, (17) 4-[4-cyano-2—({ [(2'R,4S)—6-(1—methyl-1H-1,2,3—triazolyl)-2,3- dihydrospiro[chromene-4,1 opropan] —2'-yl]carbonyl}amino)phenyl]butanoic acid, (1 8) 4-[4-cyano({ [(2'R,4S)—6-(3-pyridazinyl)~2,3-dihydrospiro[chromene-4, l '- cyclopropan]~2'-y1]carbony1}amino)phenyl]butanoic acid, (19) 4-[4-cyano({[(2'R,3 S)—5-(3—pyridinyl)-2H—spiro[1-benzofuran-3,1'— cyclopropan]—2'-yI]carbony1}amino)phenyl]butanoic acid, or (20) 4-[4-cyano({[(1S,2R)-3',3‘-dimethyl—6'—(3—pyridiny1)~2',3'~ dihydrospiro[cyclopropane- l ,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid.
A medicament comprising a combination of 4-[4-cyano({ [(2'R,4S)—6~ (isopropylcarbamoyl)-2,3-dihydrospiro[chromene—4, l opropan]-2'— yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an e thereof, a solvate thereof, or a prodrug of these and an immune oint inhibitor.
A medicament comprising a combination of 4- {4-cyano[({(2'R,4S)—6-[(2— methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1‘-cyclopropan]—2'— yl}carbonyl)amino]phenyl}butanoic acid, a salt thereof, an e thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor.
The medicament according to any one of item [1] to item [12], wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint molecule ed from the group consisting of CTLA-4, PD-l, PD-Ll, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, AZaR, KIR, VISTA, ID01, Arginase I, TIGIT, and CD115.
The medicament according to any one of item [1] to item [13], wherein the immune checkpoint inhibitor is an anti-PD—l antibody.
[15] The medicament according to any one of item [1] to item [13], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.
The medicament according to any one of item [1] to item [15] for the treatment of cancer.
The medicament according to item [16], wherein the cancer is any of ia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, stomach cancer, al cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder/bile duct , biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast , ovarian cancer, cervical cancer, corpus uteri cancer, endometrial cancer, vaginal , vulvar cancer, renal cancer, renal pelvis/ureter cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, osteosarcoma/soft tissue a, malignant bone tumor, skin , thymoma, mesothelioma, and cancer of unknown primary.
A therapeutic agent against cancer comprising a combination of the compound represented by formula (1) according to item [1], a salt thereof, a solvate thereof, an N—oxide thereof, or a prodrug of these and an immune checkpoint inhibitor.
A method for treating cancer characterized by administering effective amounts of the compound represented by formula (1) ing to item [1], a salt thereof, a solvate thereof, an N—oxide thereof, or a prodrug of these and an immune checkpoint inhibitor to a mammal (preferably a human patient).
A combination ofthe compound represented by formula (I) according to item [1], a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug of these and an immune checkpoint inhibitor for the treatment of cancer.
A combination of the compound ented by formula (I) according to item [1], a salt f, a solvate thereof, an N-oxide thereof, or a prodrug ofthese and an immune checkpoint inhibitor for the production of a therapeutic agent against cancer.
A medicament for the treatment of cancer characterized by administering a combination of the compound represented by formula (I) according to item [1], a salt thereof, an N-oxide thereof, a solvate f, or a prodrug of these and an immune checkpoint inhibitor.
A medicament for the treatment of cancer characterized by administering a combination of4—[4-cyano({[(2'R,4S)—6-(isopropylcarbamoyl)-2,3—dihydrospiro[chromene- 4,1'-cyclopropan]-2'-y1]carbonyl}amino)phenyl]butanoic acid, a salt f, an N—oxide thereof, a solvate thereof, or a prodrug ofthese and an immune checkpoint inhibitor.
[24] The medicament according to item [23], wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint molecule selected from the group consisting ofCTLA-4, PD-l, PD-Ll, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDOl, se I, TIGIT, and CD115.
The medicament according to item [23] or item [24], wherein the immune checkpoint inhibitor is an anti-PD-l antibody.
The medicament ing to item [23] or item [24], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.
The medicament according to any one of items [23] to [26], wherein the cancer is stomach cancer, colorectal cancer, lung cancer, renal cancer, or malignant melanoma.
[28] A therapeutic agent against cancer containing the compound represented by a (1) ing to item [1], a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug ofthese as an active ingredient terized by being administered in combination with an immune oint inhibitor.
A therapeutic agent against cancer containing 4-[4-cyano({ [(2'R,4S) (isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1 '-cyclopropan]—2'- yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an N-oxide f, a solvate thereof, or a prodrug e as an active ingredient characterized by being administered in combination with an immune checkpoint inhibitor.
The agent according to item [29], wherein the immune oint tor is an inhibitor of an immune checkpoint molecule selected from the group consisting of CTLA-4, PD-l, PD—Ll, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDOl, Arginase I, TIGIT, and CD115.
The agent according to item [29] or item [30], wherein the immune checkpoint inhibitor is an anti-PD-l dy.
The agent ing to item [29] or item [30], wherein the immune checkpoint inhibitor is an TLA—4 antibody.
The agent according to any one of items [29] to [32], wherein the cancer is stomach cancer, colorectal cancer, lung cancer, renal cancer, or malignant melanoma.
A therapeutic agent against cancer containing an immune checkpoint inhibitor as an active ingredient characterized by being administered in combination with the compound represented by formula (1) according to item [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these.
[35] A therapeutic agent against cancer containing an immune checkpoint inhibitor as an active ingredient characterized by being administered in combination with 4-[4-cyano ({ [(2'R,4S)(isopropylcarbamoyl)-2,3-dihydr03piro[chromene-4, 1 '-cyclopr0pan]-2'- yl]carbony1}amino)phenyl]butanoic acid, a salt f, an N—oxide thereof, a solvate thereof, or a prodrug of these. [3 6] The agent according to item [35], wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint molecule selected from the group consisting of CTLA-4, PD-l, PD-Ll, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDOl, Arginase I, TIGIT, and CD115. [3 7] The agent according to item [35] or item [36], wherein the immune checkpoint inhibitor is an D-l antibody. [3 8] The agent ing to item [35] or item [36], wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.
The agent according to any one of items [35] to [38], wherein the cancer is stomach cancer, colorectal cancer, lung cancer, renal cancer, or malignant melanoma.
[40] 4-[4—Cyano({[(2'R,4S)(isopropylcarbamoyl)—2,3-dihydrospiro[chromene- 4, 1 '-cyclopropan]—2'-y1]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these for the treatment of cancer characterized by being administered in combination with an immune checkpoint inhibitor.
A method for treating cancer characterized by administering an effective amount of4—[4-cyano({[(2'R,4S)(isopropylcarbamoyl)—2,3-dihydrospiro[chromene—4,1 '- cyclopropan]-2'-y1]carbony1}amino)phenyl]butanoic acid, a salt thereof, an e thereof, a solvate thereof, or a g of these in combination with an immune checkpoint inhibitor to a mammal (preferably a human patient) in need of the treatment of cancer.
A therapeutic agent against cancer characterized by administering a combination of 4-[4-cyano({ [(2'R,4S)(isopr0pylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor.
[43] A therapeutic agent against cancer containing 4-[4-cyano({ [(2'R,4S)—6- opylcarbamoyI)-2,3-dihydrospiro[chromene-4,1'-cyclopropan]-2'— yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an N—oxide f, a e thereof, or a prodrug of these as an active ingredient characterized by being administered to a patient to which an immune checkpoint inhibitor is administered.
[44] A therapeutic agent against cancer ning an immune checkpoint inhibitor as an active ingredient characterized by being administered to a patient to which 4-[4-cyano ({[(2'R,4S)(isopropylcarbamoyl)—2,3-dihydrospiro[chromene—4,1'-cyclopropan]-2'- yl]carbonyl}amino)pheny1]butanoic acid, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these is stered.
[45] Use of a combination of 4-[4-cyano({[(2'R,4S)(isopropylcarbamoyl)~2,3- dihydrospiro[chromene—4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, a salt f, an N-oxide thereof, a e thereof, or a prodrug of these and an immune checkpoint inhibitor for the production of a medicament for the treatment of cancer.
Use of 4-[4-cyano({[(2'R,4S)(isopropylcarbamoyl)—2,3— dihydrospiro[chromene~4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these for the production of a eutic agent against cancer characterized by being administered in combination with an immune checkpoint tor.
Use of an immune checkpoint inhibitor for the production of a therapeutic agent against cancer characterized by being administered in combination with 4-[4-cyano-2— ({[(2'R,4S)(isopropylcarbamoy1)-2,3-dihydrospiro[chromene-4,1'-cyclopropan]-2'— yl]carbonyl}amino)phenyl]butanoic acid, a salt f, an N—oxide thereof, a solvate thereof, or a prodrug of these.
A method for treating cancer terized by administering an effective dose of 4-[4-cyano—2-({[(2'R,4S)(isopropylcarbamoyl)—2,3-dihydrospiro[chromene-4,1'— cyclopropan]-2'-y1]carbony1}amino)phenyl]butanoic acid, a salt thereof, an N-oxide thereof, a solvate thereof, or a g of these to a patient, wherein the patient further receives treatment with an immune checkpoint inhibitor.
A method for treating cancer characterized by stering an effective dose of an immune checkpoint inhibitor to a patient, wherein the patient further receives treatment with 4-[4-cyano-2—({ [(2'R,4S)(isopropy1carbamoyl)-2,3-dihydrospiro[chromene-4, 1 ‘- cyclopropan]-2'—yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an N—oxide thereof, a solvate f, or a prodrug of these.
ADVANTAGEOUS EFFECTS OF INVENTION The ation ofthe invention is useful for the treatment of cancer.
BRIEF DESCRIPTION OF DRAWINGS [FIG 1] shows the effect of the combination y with the compound of Example 2-13 and an anti-mouse PD-l antibody in an allograft model ofmouse colorectal cancer cell line MC38. In the figure, the combination therapy indicates the group of the combination therapy with the compound of Example 2-13 and the anti-mouse PD-l antibody.
[FIG 2] shows the effect of the combination y with the compound of e 2-2 and an anti-mouse PD-l antibody in an allograft model of mouse colorectal cancer cell line MC38. In the figure, the combination therapy indicates the group of the combination therapy with the compound of Example 2-2 and the anti-mouse PD—I antibody. [ shows the effect of the combination therapy with the compound of Example 2-13 and an anti—mouse CTLA-4 antibody in an allograft model of mouse ctal cancer cell line MC38. In the figure, the combination y indicates the group of the ation therapy with the compound of Example 2-13 and the anti-mouse CTLA—4 antibody.
[FIG 4] shows the effect of the combination therapy with the compound of Example 2-13 and an anti-mouse PD-l antibody in an allografi model ofmouse fibrosarcoma cell line SalN. In the figure, the combination therapy indicates the group of the combination therapy with the compound of Example 2-13 and the anti-mouse PD-l antibody.
[FIG 5] shows the effect of the combination therapy with the compound of Example 2-13 and an anti-mouse PD—l dy in an allograft model of mouse colorectal cancer cell line CT26. In the figure, the combination therapy indicates the group of the combination therapy with the compound of Example 2-13 and the anti-mouse PD-l antibody.
DESCRIPTION OF EMBODIMENTS The present invention is explained below in detail.
In the present invention, "Cl-4 alkyl" is, for example, methyl, ethyl, n—prOpyl, isopropyl, n—butyl, sec-butyl, tert—butyl, or isobutyl.
In the t invention, "Cl-3 alkyl" is, for example, methyl, ethyl, n-pl'Opyl, or isopropyl.
[0042] In the present invention, "Cl-5 alkylene" is, for example, methylene, ethylene, propylene, butylene, or pentylene.
In the present ion, "CZ-5 alkenylene" is, for example, ethenylene, 1- propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3—butenylene, 1-pentenylene, 2- pentenylene, 3-pentenylene, 4-penteny1ene, or the like.
In the present invention, "CZ-5 alkynylene" is, for example, ethynylene, 1- propynylene, 2-propynylene, nylene, 2-butynylene, 3-butynylene, yny1ene, 2- pentynylene, 3-pentynylene, 4-pentynylene, or the like.
In the present ion, "halogen" is e, chlorine, bromine, or .
In the present ion, "Cl-4 alkoxy" is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, i-methylpropoxy, tert—butoxy, isobutoxy, or the like.
In the present invention, "Cl-4 alkylthio" is, for example, methylthio, ethylthio, propylthio, isopropylthio, hio, 1-methylpropylthio, tert-butylthio, isobutylthio, or the like.
In the present invention, "CZ—4 alkenyl" is, for example, ethenyl, 1-propenyl, 2- propenyl, 1-butenyl, 2-butenyl, 3-buteny1, or the like.
In the present invention, "CZ-4 alkynyl" is, for e, ethynyl, 1-propynyl, 2- propynyl, 1—butynyl, 2-butynyl, 3-butynyl, or the like.
In the t invention, "Cl-4 haloalkyl" represents halogen-substituted C1—4 alkyl and is, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-flu0roethyl, 1- fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2- trifluoroethyl, 1,1,2-trifluoroethyl, l,2,2,2-tetrafluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1,2-dibromo—1,2,2-trifluoroethyl, 1-ch101'o-l,2,2,2—tetrafluoroethyl, 3- fluoropropyl, 3-chloropropyl, 2-fluoropropyl, 2-chloropropyl, l-fluoropropyl, ropropyl, 3,3-difluoropr0pyl, 2,3-difluoropropyl, 1,3-difluoropropyl, 1,2-difluoropr0pyl, 2,2- difluoropropyl, 1,1-difluoropropy1, 3,3,3-trifluoropropyl, 2,3,3—trifluoropropyl, 1,3,3- trifluoropropyl, 1,2,2-trifluoropropyl, trifluor0propyl, 1,1,3-trifluoropropyl, 1,1,2,2- tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4-fluorobutyl, 4-chlorobuty1, 3-fluorobutyl, 3- butyl, Z-fluorobutyl, 2-chlorobutyl, l-fluorobutyl, l-chlorobutyl, 3,3-difluorobutyl, 2,3- difluorobutyl, 1,3-difluorobutyl, fluorobutyl, 2,2—difluorobuty1, 1,1-difluorobutyl, 3,3,3- trifluorobutyl, 2,3,3-trifluorobutyl, 1,3,3-trifluorobutyl, 1,2,2-trifluorobutyl, 1,1,2- trifluorobutyl, 1,1,3 -trifluorobutyl, 1,1,2,2-tetrafluorobutyl, 2,2,3,3,3-pentafluorobutyl, or the like. [005 1] In the present invention, "sulfur atom that may be oxidized" represents sulfiir (S), sulfoxide (8(0)), or sulfone (802).
In the present invention, "four~ to ten-membered cyclic ring" means a four- to ten-membered monocyclic or bicyclic heterocyclic ring ning 1 to 5 heteroatoms ed from an oxygen atom, a nitrogen atom, and a sulfur atom and is, for example, an oxetane, azetidine, pyrrolidine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiopyran, thiepine, oxazole, isooxazole, thiazole, isothiazole, n, oxadiazole, oxazine, oxadiazine, ine, oxadiazepine, thiadiazole, thiazine, azine, thiazepine, thiadiazepine, indole, isoindole, indolizine, u'an,isobenzofi1ran, benzothiophene, isobenzothiophene, le, quinoline, isoquinoline, quinolizine, purine, phthalazine, pteridin, naphthyridine, quinoxaline, quinazoline, cinnoline, xazole, benzothiazole, benzoimidazole, benzodioxole, benzooxathiol, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, lidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, ydrodiazepine, perhydrodiazepine, dihydrofilran,tetrahydrofi1ran, dihydropyran, tetrahydropyran, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, othiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), oisooxazole, tetrahydroisooxazole (isoxazolidine), dihydrothjazole, ydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), ofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, rothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, tetrahydrotriazolopyrazine, morpholine, thiomorpholine, oxathiane, indoline, oline, dihydrobenzofiuan, perhydrobenzofiuan, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, roisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, ronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, oquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzooxazine, dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzooxazole, perhydrobenzooxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole, an, e, dioxaindan, benzodioxane, thiochromane, dihydrobenzodioxine, dihydrobenzoxathiin, chromane, pyrazolopyrimidine, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, triazolopyridine, or dihydropyridooxazine ring, or the like.
In the present invention, - to ten-membered heterocyclic ring" means a three- to ten-membered monocyclic or bicyclic heterocyclic ring ning 1 t0 5 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom and is, for example, aziridine, oxirane, thiirane, any of the heterocyclic rings exemplified above for the "four- to ten- membered heterocyclic ring", or the like.
In the present ion, "five- to ten-membered aromatic heterocyclic ring" means a five- to ten-membered monocyclic or bicyclic aromatic cyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfilr atom and is, for e, a pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole, thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, uran, zofuran, benzothiophene, isobenzothiophene, le, purine, benzooxazole, benzothiazole, benzoimidazole, benzofurazan, benzothiadiazole, benzotriazole, quinoline, isoquinoline, phthalazine, pteridin, naphthyridine, quinoxaline, oline, or cinnoline ring, or the like.
In the t invention, "five- to six-membered monocyclic aromatic heterocyclic ring" is, for example, a pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, fiJrazan, oxadiazole, or thiadiazole ring, or the like.
In the present invention, "C4-10 carbon ring" means a C4 to 10 monocyclic or bicyclic carbon ring and is, for example, a cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, ropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, alene, onaphthalene, tetrahydronaphthalene, or perhydronaphthalene ring, or the like.
In the present invention, "C3-10 carbon ring" means a C3 to 10 clic or bicyclic carbon ring and is, for example, cyclopropane, any of the carbon rings exemplified above for the "'C4-10 carbon ring", or the like.
In the present invention, "Cl-6 alkyl" is, for example, methyl, ethyl, n-propyl, isoprOpyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 1—methylbutyl, 2-methylbutyl, 3- methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethy1propyl, hexyl, 1- pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1—dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 2,2—dimethylbutyl, 2,3-dimethylbutyl, 1-methyl—l- ethylpropyl, 2-methylethylpropyl, l-ethylbutyl, 2-ethylbutyl, or the like.
In the present invention, "C3-6 cycloalkyl" is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In the t invention, "four- to six-membered heterocyclic ring" means a four— to six-membered monocyclic cyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom and is, for example, an oxetane, azetidine, pyrrolidine, dine, pyrazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, e, imidazole, le, tetrazole, pyrazole, pyridine, pyrimidine, pyridazine, furan, thiophene, oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole, or thiadiazole ring, or the like.
In the t invention, R1 is preferably COORs.
In the present invention, R8 is preferably a hydrogen atom or C1-4 alkyl, more preferably a hydrogen atom.
In the present invention, R8”1 is preferably C1-4 alkyl, benzene, or pyridine. The benzene and the pyridine may be substituted with Cl-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, - 0(C1-4 haloalkyl), C1-4 alkylthio, -S(C1-4 haloalkyl), halogen, or nitrile.
In the present ion, L1 is preferably Cl-S alkylene or C2-5 alkenylene, more preferably C l -5 ne, particularly preferably propylene.
In the present ion, R2 is preferably fluorine.
In the present invention, X1 is preferably CR6.
In the present invention, R6 is preferably a hydrogen atom or fluorine, more preferably a hydrogen atom.
In the present invention, X2 is preferably CR7.
In the present invention, R7 is preferably fluorine, e, -CH2R9, or -OR9, more preferably nitrile.
In the present invention, R9 is preferably a four— to ten-membered heterocyclic ring which may be substituted with methyl or trifluoromethyl. The four- to ten-membered heterocyclic ring is preferably a five- to ten-membered aromatic heterocyclic ring, more preferably a five- to ten-membered nitrogen-containing aromatic heterocyclic ring (for example, le, imidazole, triazole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, imidazopyridazine, imidazopyridine, imidazopyrimidine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, or the like).
[0071] In the present invention, L2 is preferably -CH=CH-, -NHCO-, , -NHSOz-, SOzNH-, more preferably -NHCO- or -CONH—, particularly preferably .
In the present invention, R3 is preferably fluorine.
[0073] In the present invention, R4 is preferably methyl, ethyl, or trifluoromethyl, preferably .
In the present ion, X3 is preferably methylene or an oxygen atom, more ably an oxygen atom.
In the present invention, R10 is preferably methyl, ethyl, methylcarbonyl, ethylcarbonyl, sulfonyl, ethylsulfonyl, or tert-butoxycarbonyl.
In the present invention, the ring is preferably a benzene, thiophene, or le ring, more preferably a benzene ring.
In the present invention, R5 is preferably “, fluorine, methoxy, a benzene ring, or a four- to ten—membered heterocyclic ring. The four- to ten—membered cyclic ring is preferably an azetidine, idine, piperidine, oxazolidine, oxadiazole, le, thiophene, furan, pyrazole, thiazole, e, imidazole, pyridine, pyrazine, pyridazine, dine, pyrazolopyrimidine, pyrrolopyrimidine, pyrazolopyridine, pyrrolopyridine, or dihydropyridooxazine ring.
[0078] In the t invention, R11 is preferably C1-6 alkyl, C3-6 cycloalkyl, or a pyran, pyrrolidine, piperidine, pyrazole, thiazole, oxazole, isooxazole, pyridine, zine, or pyrimidine ring, more preferably Cl-6 alkyl.
In the present invention, R13 is preferably halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, a hydroxyl group, -NR2°R2', or a benzene, oxetane, pyridine, pyrazole, or oxazole ring, more preferably fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, cyclopentyl, cyclobutyl, oxetane, a hydroxyl group, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, or a benzene, pyridine, pyrazole, or oxazole ring.
[0080] In the present invention, R20 is preferably a hydrogen atom or methyl.
In the present invention, R21 is preferably a hydrogen atom or methyl.
In the present invention, R12 is preferably C1-3 alkyl, C3 -6 cycloalkyl, benzene, or a four- to six-membered heterocyclic ring. The four— to six-membered heterocyclic ring is ably an oxetane, azetidine, pyrrolidine, piperidine, pyrazine, pyran, ran, oxazine, oxadiazine, thiazine, thiadiazine, pyrrole, ole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, ene, oxazole, isooxazole, thiazole, isothiazole, furazan, oxadiazole, or thiadiazole ring. The four- to six-membered heterocyclic ring may be substituted with C1-4 alkoxy.
In the present invention, R14 is ably a hydrogen atom, methyl, ethyl, benzene, or benzyl.
In the present invention, R19 is preferably methoxy, -CONHCH3, -CON(CH3)2, or an oxazole, thiazole, pyrazole, or pyridine ring.
In the present invention, R15 is preferably methyl, cyclopropyl, 0r e.
In the present ion, R16 is preferably a hydroxyl group.
In the present invention, R17 is preferably methyl, ethyl, or ropyl, more preferably methyl.
In the present invention, R18 is preferably fluorine, methyl, ethyl, n-propyl, pyl, n-butyl, sec-butyl, tert—butyl, isobutyl, cyclopropyl, methoxy, ethoxy, n—propoxy, isopropoxy, 0x0, nitrile, a hydroxyl group, hydroxymethyl, l-methyl-l-hydroxyethyl, methylsulfonyl, pyridine, or dimethylamino.
In the present invention, m is preferably an integer of 1 or 2, more ably 1.
In the present invention, n is preferably an integer of 0 or 1, more preferably 1.
[0091] In the present invention, p is preferably 0.
In the present invention, q is preferably 0.
In the present invention, r is preferably an integer of 0 to 4, more preferably an integer of 0 to 2. ' In the present ion, 8 is preferably an integer of 0 to 2, more preferably 1 or 2.
In the t invention, t is preferably an integer of 0 to 2.
In the present invention, X3a is preferably an oxygen atom.
In the present invention, na is preferably an r of 0 or 1, more preferably 1.
In the present invention, qa is preferably 0.
In the present invention, ra is ably an integer of 0 to 2.
[0100] In the present invention, formula (I) is preferably a combination of the respective preferred definitions of the ring, R1, R2, R3, R4, R5, R6, R7, R8, R8", R9, R10, R“, R12, R13, R14, R15, R”, R17, R18, R19, R20, R21, L1, L2, L3, X', X2, X3, m, n, p, q, r, s, and t. [01 0 1] In the present ion, the compound represented by formula (I) is preferably a compound represented by formula (I—a), a salt thereof, an N-oxide f, a solvate thereof, or a prodrug of these.
[Chem 10] (In the formula, all the s have the same meanings as the symbols defined in items [1] and [2] above.) More preferred is a compound represented by formula (1—1), a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these.
[0104] [Chem 11] (In the formula, all the symbols have the same gs as the symbols defined in items [1] and [2] above.) [0 1 06] In the present invention, a more preferred aspect of the compound represented by formula (I) is a compound represented by formula (I-b), a salt thereof, an N—oxide thereof, a solvate f, or a prodrug of these. [0 l 07] [Chem 12]
[0108] (In the formula, all the symbols have the same meanings as the symbols defined in items [1] and [2] above.) An even more preferred is a compound represented by formula (I- o), a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these.
[Chem 13] (In the formula, all the symbols have the same gs as the symbols defined in items [1] and [2] above.) Preferred is a compound represented by formula (I-d), a salt thereof, an N—oxide f, a solvate f, or a prodrug of these.
[Chem.14] 16 RF“1 2“” X ( ) \X3 L2 na (l-d) (R3)? 0 N/ (In the formula, all the symbols have the same meanings as the symbols defined in items [1] and [2] above.) Further preferred is a compound ented by formula (I—e), a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these.
[Chem. 15]
[0114] (In the formula, all the symbols have the same gs as the symbols defined in items [1] and [2] above.) Particularly preferred is a compound represented by formula (I—2), a salt thereof, an N—oxide thereof, a solvate f, or a prodrug of these. [01 1 5] [Chem 16] (Rah; R6a //l L\R11 \ (R412 NC NH /‘O 0m: ( l-2) 0 N/ (In the formula, all the symbols have the same meanings as the symbols defined in items [1], [2], and [5] above.) Most preferred is a compound represented by formula (I-4), a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these.
[Chem 17] (In the formula, all the symbols have the same gs as the symbols defined in items [1], [2], and [5] above.) In the present invention, a further preferred aspect of the compound represented by formula (I) is a compound represented by formula (H), a salt f, an N—oxide f, solvate thereof, or a prodrug of these.
[Chem 18] (In the formula, all the symbols have the same meanings as the symbols defined in items [1], [2], and [9] above.) Further preferred is a nd represented by formula (I—g), a salt f, an N-oxide thereof, a solvate thereof, or a prodrug of these.
[Chem 19] (In the a, all the symbols have the same meanings as the symbols defined in items [1], [2], and [9] above.) Preferred is a compound represented by formula (I-h), a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these.
[Chem 20] (In the formula, all the s have the same meanings as the symbols defined in items [1], [2], and [9] above.) Further preferred is a compound represented by formula (I-i), a salt thereof, an N—oxide thereof, a solvate f, or a prodrug of these.
[Chem. 21] (R2)p L\R11 x1” (R4)ra )l( ( ) /\O L2 na (l—i) (R3)? (In the formula, all the symbols have the same meanings as the symbols defined in items [1], [2], and [9] above.) Particularly preferred is a compound represented by a (1-3), a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these.
[Chem. 22] (R2a)p R6a // L\R11 \ (R4)ra NC NH /\o (I-3) (R3)qa (In the formula, all the symbols have the same gs as the symbols defined in items [1], [2], and [9] above.) Most preferred is a compound represented by formula (I-5), a salt thereof, an N~0xide thereof, a solvate thereof, or a prodrug of these.
[Chem. 23] (R23)p //r L1\R1 NC NH 2:4)“ (I-5) (In the formula, all the symbols have the same meanings as the symbols defined in items [1], [2], and [9] ) In the present ion, L1 is independently preferably propylene, and L2 is independently preferably -CH=CH-, -NHCO-, -CONH-, —NHSOz-, or - in a formula selected from the group of a (I-a), a (I-b), formula (I-c), formula (I-d), formula (I-e), formula (I-t), formula (I-g), formula (I-h), formula (I-i), and formula (I-l) above. More preferably, L1 is propylene, and L2 is ~NHCO- or -CONH-. Further preferably, L1 is propylene, and L2 is -NHCO-.
In the present ion, L1 is ndently ably propylene in a formula selected from the group of formula (I-2), formula (I-3), formula (I-4), and formula (I—S) above.
[0134] In the present invention, the most red aspect of formula (I) is any of the compound of Example 1, the compounds of Example 2-1 to Example 2-47, the compound of Example 3, the compounds of Example 4-1 to Example 4-3, the compounds of Examples 5 and 6, the compounds of Example 7-1 to Example 7-28, the compounds of Examples 8 and 9, the compounds ofExample 10-1 to Example 10-12, the compound ofExample 11, the compounds ofExample 12-1 to Example 12-3, the compounds of Examples 13 to 17, the compounds ofExample 18-1 to Example 18-3, the nd ofExample 19, the compounds ofExample 20-1 to Example 20-5, the compounds of Examples 21 and 22, the compounds of Example 23-1 and Example 23 ~2, the compounds of Examples 24 to 27, the compounds of Example 28-1 and Example 28-2, the compounds of Examples 29 and 30, the compounds of Example 31-1 and Example 31-2, the compound ofExample 32, the compounds of Example 33—1 to e 33—5, the compounds of Examples 34 to 36, the compounds of Example and Example 37-2, the compounds of Example 38-1 and Example 38-2, and the compound of Example 39, a salt thereof, an N—oxide thereof, a solvate thereof, or a prodrug of these.
All of s fall within the scope of the present invention, unless otherwise specifically . For example, the alkyl groups, the alkoxy groups, the alkylene groups, and the like e linear and branched chain groups. The present invention also includes all of s due to a double bond, a ring, and a fused ring (E, Z, cis, and trans isomers), isomers due to the presence of an asymmetric carbon or the like (R and S s, 0L and I3 s, enantiomers, and diastereomers), optical isomers involving optical rotation (D, L, d, and l isomers), polar compounds separated by chromatography (high-polarity and low—polarity compounds), equilibrium compounds, rotational isomers, mixtures of any tions of these compounds, and racemic mixtures. The present invention also includes all isomers due to tautomerism.
As is clear for a skilled person, the ing symbols in the present invention have the following meanings, unless otherwise specifically stated.
[Chem. 24] “‘\\\\\\
[0138] represents a bond into the plane of the paper (i.e., the or-configuration).
[Chem 25]
[0140] represents a bond out of the plane of the paper (i.e., the B-configuration).
[Chem 26]
[0142] represents an arbitrary mix of a—configuration and B-configuration.
[Salt] The compound represented by formula (I) is converted into a salt using a known method.
The salt is preferably a pharmaceutically acceptable salt.
Preferably, the salt is water soluble.
Examples ofthe pharmaceutically acceptable salt include acid addition salts, alkali metal salts, alkali-earth metal salts, ammonium salts, amine salts, and the like.
[0146] Examples ofthe acid addition salts e inorganic acid salts such as hydrochloride, hydrobromate, hydroiodide, sulfates, phosphates, and nitrates, or organic acid salts such as acetates, lactates, tartrates, benzoates, es, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionates, glucuronates, and giuconates.
Examples ofthe alkali metal salts include salts with potassium, , and the like.
Examples ofthe alkali-earth metal salts include salts with calcium, magnesium, and the like.
Examples ofthe ammonium salts include salts with tetramethylammonium and the like. [01 50] Examples of the amine salts include salts with triethylamine, methylamine, dimethylamine, cyclopentylamine, amine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, , arginine, N- -D-glucamine, and the like. [01 5 1] The compound used for the present ion may be transformed into an N-oxide using any . N-Oxides refer to compounds represented by formula (I) with oxidized nitrogen atoms.
The compound represented by formula (I) and a salt thereof may be transformed into a solvate.
Preferably, the solvate is non-toxic and water soluble. Examples of suitable es include solvates using water and solvates using alcoholic solvents (for example, ethanol and the like). The solvate is preferably a hydrate.
A prodrug ofthe compound ented by formula (1) refers to a compound that is transformed into the compound represented by a (I) in the body through reaction with an enzyme, stomach acid, or the like. The following are examples of prodrugs of the compounds represented by formula (I): a compound represented by formula (I) with an amino group that is acylated, alkylated, or phosphorylated (for example, a compound represented by formula (I) with an amino group that is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyloxo— l ,3-di0X0lenyl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, yloxymethylated, ymethylated, or tert—butylated, and the like); a compound ented by formula (I) with a hydroxyl group that is acylated, alkylated, phosphorylated, or borated (for example, a compound represented by formula (I) with a hydroxyl group that is acetylated, palmitoylated, oylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated, and the like); a compound represented by formula (I) with a 'carboxy group that is esterified or amidated (for example, a compound represented by formula (I) with a carboxy group that is ethylesterified, phenylesterified, carboxymethylesterified, dimethylaminomethylesterifled, pivaloyloxymethylesterified, hoxycarbonyl)oxy}ethylesterified, phthalidylesterified, (5- —2-oxo-1,3-dioxolen—4-yl)methylesterified, l- {[(cyclohexyloxy)carbonyl]oxy}ethylesterified, or methylamidated, and the like); and the like.
These compounds may be produced by a method known per se. The prodrug of the compound represented by formula (I) may be a e or a nonhydrate. The prodrug of the compound represented by formula (I) may be one that transforms into the nd represented by formula (I) under physiological conditions, such as described in Pharmaceutical research and development, Vol. 7, Molecular Design, pp. 163 - 198, 1990, Hirokawa Publishing Company.
The atoms constituting the compounds ented by formula (I) may be replaced with their isotopes (for example, 2H, 3H, 13C, 14C, lsN, 16N, 17O, 18O, 18F, 358, “Cl, 77Br, 1251, and the like) or the like. d of Production ofCompounds Used for the Present invention] The compounds represented by formula (I) may be produced by known methods, for example, by the methods described below, methods equivalent thereto, or the methods described in the Examples. In the methods of production below, a raw material compound may be in the form of a salt. The salt may be any of the pharmaceutically acceptable salts exemplified for the compounds represented by formula (I).
[0155] The compound represented by formula (I) of which L2 is -NHCO- (a nd represented by formula (IVa)) and the compound represented by a (I) of which L2 is - CONH- (a compound represented by formula (IVb)) can be ed by the methods represented by the following reaction scheme (Ia) and reaction scheme (1b), respectively.
[0156] [Chem 27] Reaction Scheme (la) (R2)p iRkLL2 L1 )fd \W R1 Amrdatlon (R4)r + —-——» X NH A [01 57] (In the formulae, all the s have the same meanings as the symbols defined in item [1] above.) [Chem 28] Reaction Scheme (lb) 1 ,(R )r X X1” L\R1 \Xa I tion X . H2“ + _‘, X OH (R3)q ( (ilb) ( Illb) (R5)s (In the formulae, all the symbols have the same meanings as the symbols defined in item [1] above.) Specifically, the compound represented by formula (IVa) can be produced by amidation reaction of the compound represented by formula (Ila) and the compound represented by formula (IIIa). The compound represented by formula (IVb) can be produced by amidation reaction of the nd represented by formula (11b) and the compound represented by formula (IIIb).
[0160] The amidation reaction is known and may be, for e, (1) a method using an acid halide, (2) a method using a mixed acid anhydride, (3) a method using a condensing agent, or the like.
[0161] The following describes these s in detail. (1) In the method using an acid halide, for example, carboxylic acid is reacted with an acid halide reagent (oxalyl de, l chloride, or the like) at about ~20°C to reflux temperature in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, or the like) or without t. The resulting acid halide is then reacted with an amine in an organic solvent (chloroform, romethane, diethyl ether, tetrahydrofuran, or the like) at about 0 to 40°C in the presence of a base ine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, or the like). Alternatively, the resulting acid halide may be reacted with an amine at about 0 to 40°C in an organic solvent (dioxane, tetrahydrofuran, or the like), using an alkaline aqueous solution (sodium bicarbonate water, a sodium hydroxide solution, or the like). (2) In the method using a mixed acid anhydride, for example, carboxylic acid is reacted with an acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, or the like) or with an acid derivative (ethyl chloroformate, isobutyl chloroformate, or the like) at about 0 to 40°C in an organic solvent oform, dichloromethane, l ether, tetrahydrofilran, or the like) or without solvent, in the ce of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, or the like). The resulting mixed acid anhydride is then reacted with an amine at about 0 to 40°C in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofiiran, or the like).
[0163] (3) In the method using a condensing agent, for example, carboxylic acid is reacted with an amine at about 0°C to reflux temperature in an organic solvent (chloroform, dichloromethane, dimethylformamide, dimethylacetoamide, diethyl ether, tetrahydrofuran, or the like) or without solvent in the presence or absence of a base ine, triethylamine, ylaniline, dimethylaminopyridine, or the like), using a condensing agent (1,3- dicyclohexylcarbodiimide (DCC), 1-ethyl~3-[3-(dimethylamino)propyl]carbodiimide (EDC), l,l'-carbonyldiimidazole (CD1), 2—chloromethylpyridiniumiodine, or 1-propy1phosphonic acid cyclic ide (l-propanephosphonic acid cyclic anhydride (T3P) or the like)), with or without l-hydroxybenzotriazole (HOBt).
[0164] Desirably, the reactions (1), (2), and (3) are all performed under anhydrous ions in an inert gas (argon, en, or the like) atmosphere.
The compound represented by formula (I) of which L2 is —NHSOz- (a compound represented by formula (IVc)) and the compound represented by formula (I) of which L2 is - SOzNH— (a compound represented by formula (IVd)) can be produced by the methods represented by the following reaction scheme (1c) and reaction scheme (Id), respectively.
[Chem. 29] Reaction Scheme (Ic) (R2)p (R4)! 1 Xg’9 L1\R‘ ¥©IL\R1 Sulfouamidation (R4)r + ii (llc) (R3)q( ’ (In the formulae, all the symbols have the same meanings as the symbols defined in item [1] above.)
[0168] [Chem 30] Reaction Scheme (Id) (In the formulae, all the symbols have the same meanings as the symbols defined in item [1] above.) ically, the compound represented by formula (IVc) can be produced by sulfonamidation reaction ofthe compound represented by formula (He) and the compound represented by a (1110). The compound represented by formula (IVd) can be ed by sulfonamidation reaction of the compound represented by formula (11d) and the nd represented by formula (111d). [0 1 70] The sulfonamidation reaction is known. For example, sulfonic acid is reacted with an acid halide (oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oride, or the like) at -20°C to reflux temperature in an c solvent (chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, or the like) or without solvent. The resulting sulfonyl halide is then reacted with an amine at about 0 to 40°C in an c solvent (chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, or the like) in the presence of a base (diisopropylethylamine, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, or the like).
[0171] The compound represented by formula (I) of which L2 is -NHCH2- (a compound used for the present invention represented by formula (IVe)) and the compound represented by formula (I) of which L2 is -CH2NH- (a compound ented by formula (IVD) can be produced by the s represented by the following reaction scheme (Ie) and on scheme (11), respectively.
[Chem 31] Reaction Scheme (Ie) (In the formulae, all the symbols have the same meanings as the symbols defined in item [1] above.) [Chem 32] Reaction Scheme (If) x1” LL >21 R1 + (Ilf) (In the formulae, all the symbols have the same meanings as the symbols defined in item [1] above.) Specifically, the compound represented by formula (We) can be produced by reductive amination reaction of the compound represented by formula (He) and the compound ented by formula (file). The compound represented by formula (IVt) can be produced by reductive amination reaction of the nd represented by formula (Iii) and the compound ented by formula (111i). [01.76] The reductive amination reaction is known. For example, the reaction is performed in an organic solvent (dichloroethane, dichloromethane, dimethylformamide, acetic acid, a mixture of these, or the like) at about 0 to 40°C in the presence of a reducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, or the like).
The compound represented by formula (I) of which L2 is -0CH2~ (a compound used for the present invention represented by formula (IVg)) and the nd ented by formula (I) of which L2 is -CH20- (a compound represented by formula (IVh)) can be produced by the methods represented by the following reaction scheme (1g) and reaction scheme (Ih), tively. [0 l 78] [Chem 33] Reaction Scheme (1g) (In the formulae, Xg is halogen, tosylate, or mesylate, and the other symbols have the same meanings as the symbols defined in item [1] above.) [Chem 34] Reaction Scheme (1h) (R2)p 2 as“)r /\(R )p L1 /\ \R1 >51 [ L1 \Rl HO Etherification X>56 (R4)r X y” Xh (Rafi (llh) (”lh) [01 8 1] (In the formulae, Xh is n, tosylate, or mesylate, and the other symbols have the same meanings as the symbols defined in item [1] above.) cally, the compound represented by formula (IVg) can be produced by etherification reaction of the compound represented by formula (11g) and the compound represented by formula (111g). The compound represented by formula (IVh) can be ed by etherification reaction of the compound represented by formula (IIh) and the compound represented by formula (IIIh). [01 82] The etherification reaction is known. For example, the reaction is performed in an organic solvent (dimethylformamide, ylsulfoxide, chloroform, romethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, or the like) at about 0 to 100°C in the presence of an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like), an alkali earth metal hydroxide (barium hydroxide, m hydroxide, or the like), a carbonate (sodium carbonate, potassium carbonate, or the like), an aqueous solution thereof, or a mixture of these.
The nd represented by formula (I) of which L2 is -SCH2- (a compound used for the present invention represented by formula (IVj )) and the nd represented by formula (I) of which L2 is -CH28- (a compound represented by formula (IVk)) can be produced by the methods represented by the following reaction scheme (Ij) and on scheme (Ik), reSpectively. [01 84] [Chem 35] Reaction Scheme (Ij) (In the ae, Xj is halogen, tosylate, or mesylate, and the other symbols have the same meanings as the symbols defined in item [1] above.) [Chem 36] Reaction Scheme (1k) R4 (R2)P (£12)!J L1 iii/V5?L1 ‘ /(\x3)r HS ’56 X Xk (Rah; ( (llk) (lllk) (In the formulae, Xk is halogen, tosylate, or mesylate, and the other symbols have the same meanings as the symbols defined in item [1] above.) Specifically, the compound ented by formula (IVj) can be produced by herification on of the compound represented by formula (IIj) and the compound represented by formula (IIIj). The compound represented by formula (IVk) can be produced by herification reaction of the compound represented by formula (11k) and the compound represented by formula (111k).
The thioetherification on is known. For example, the reaction is performed in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, or the like) at O to 100°C in the presence of an alkali metal hydroxide (sodium hydroxide, potassium ide, lithium ide, or the like), an alkali earth metal hydroxide (barium hydroxide, m hydroxide, or the like), a carbonate (sodium carbonate, potassium carbonate, or the like), an aqueous solution thereof, or a mixture of these.
The compound represented by formula (I) of which L2 is -S(0)CH2~ or -S02CH2- can be produced by appropriately subjecting the sulfur atom of the nd represented by formula (IV3') above to oxidation reaction.
The compound ented by formula (I) ofwhich L2 is -CH2$(O)— or -CH2302- can be produced by appropriately subjecting the sulfur atom of the compound represented by formula (IVk) above to oxidation reaction. [0 l 9 1] The oxidation reaction (sulfoxidation on: -SCH2— —> -S(O)CH2—, or -CH2S- —> - CH28(O)-) is known. For example, the reaction is performed in an organic solvent (dichloromethane, form, benzene, hexane, methanol, t-butyl alcohol, e, acetonitrile, tetrahydrofuran, acetic acid, N,N-dimethylformamide, or the like), in water, or in a mixed solvent of these at about -40 to 0°C in the presence of l to 1.2 equivalents of an oxidizing agent (hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, sodium 2O hypochlorite, a peracid (3-chloroperbenzoic acid, peracetic acid, or the like), Oxone (trade name, hereinafier, simply ed to as Oxone; potassium peroxymonosulfate), potassium permanganate, c acid, dimethyldioxolan, or the like).
The oxidation reaction (sulfonation reaction: -SCH2— —> ~SOzCH2-, or -CH2$- —> - CH2802-) is known. For example, the reaction is performed in a suitable organic solvent (dichloromethane, form, benzene, hexane, methanol, t-butyl alcohol, acetone, acetonitrile, tetrahydrofuran, acetic acid, N,N—dimethylformamide, or the like), in water, or in a mixed solvent ofthese at about 20 to 60°C in the presence of an excess oxidizing agent gen peroxide, sodium ate, acyl nitrite, sodium perborate, sodium hypochlorite, a peracid (3~chloroperbenzoic acid, peracetic acid, or the like), Oxone (trade name; potassium peroxymonosulfate), potassium permanganate, chromic acid, dimethyldioxolan, or the like).
The compound represented by formula (I) h L2 is -CH=CH— (a compound represented by formula (IVm)) can be produced by the method represented by the following reaction scheme (Im). [0 1 94] [Chem 37] Reaction Scheme (1m) Vinylation reaction Ph3P‘*CH;,Br (R3)q ( 1m [01 95] (In the formulae, all the s have the same meanings as the symbols defined in item [1] above.) Specifically, the compound represented by formula (IVm) can be produced by the Heck reaction ofthe compound represented by formula (11111) with the compound represented by a (Vm) produced by vinylation on ofthe compound represented by formula (111m).
The vinylation on is known. For example, the reaction is performed using the compound represented by formula (Hlm) and methyltriphenylphosphonium bromide in an organic solvent (for example, acetonitrile, methylene chloride, tetrahydrofuran, toluene, benzene, an appropriate mixed t of these organic solvents, or the like) at about 0°C to 120°C in the presence of a base (for example, potassium carbonate, sodium hydride, potassium hydride, n-butyllithium, potassium tert-butoxide, azabicyclo[5.4.0]undecene triethylamine (DBU), or the like).
The Heck reaction is known. For example, the reaction is performed in an organic solvent (for example, toluene, diethyl ether, benzene, dichlorobenzene, dimethylformamide, an appropriate mixed solvent of these organic solvents, or the like) at about 0°C to 120°C in the presence of a base (for example, tripotassium phosphate, sodium bicarbonate, ylamine, or the like) and a catalyst (for example, a ium catalyst (for e, palladium chloride, palladium acetate, tetrakis(triphenylphOSphine)palladium(0), or the like), a nickel catalyst (for example, tetrakis(triphenylphosphine)nickel, bis(triphenylphosphine)nickel(II), or the like), a cobalt catalyst (for example, cobalt chloride, or the like), a copper st (for example, copper chloride, or the like), a zinc catalyst (for example, zinc or the like), an appropriate mixed catalyst ofthese catalysts, or the like), in the presence or absence of a phosphorus reagent (for example, l,3-bis(diphenylphosphino)propane (dppp), Ph2P-(CH2)5-PPh2, or the like).
The compound represented by formula (I) of which L2 is ~CH2CH2- can be ed by riately subjecting the "-CH=CH-" ofthe compound ented by formula (IVm) above to reduction on.
The reduction reaction is known. For example, the on is performed in an organic solvent (for example, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, ethyl acetate, acetic acid, an appropriate mixed solvent of these organic solvents, or the like) in a hydrogen atmosphere under normal or rized pressure condition, in the presence of ammonium formate or in the presence of ine at about 0 to 200°C, in the presence of a hydrogenation catalyst (palladium-carbon, palladium black, ium, palladium hydroxide, platinum dioxide, platinum-carbon, , Raney nickel, ruthenium chloride, or the like), in the presence or absence of an acid (hydrochloric acid, sulfiiric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p- toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, or the like).
[0200] The compound represented by formula (Illa) in reaction scheme (Ia) ofwhich q is 0 and h m is 1 (a compound represented by formula (IIIaa)) can be produced by the method represented by the following reaction scheme (Iaa).
[Chem 38] ‘ Reaction Scheme (Iaa) Vinylation reaction Cyclization reaction RaaOZC Ph3P“CH3Br' N/\002Raa Hydrolysis on HO (In the formulae, Raa is C14 alkyl, and the other s have the same meanings as the symbols defined in items [1] and [2] above.) Specifically, the compound represented by formula (IIIaa) can be produced by subjecting the compound represented by formula (VIaa) produced by vinylation reaction ofthe compound ented by formula (Vaa) to cyclization reaction and then to ysis reaction.
[0203] The vinylation reaction is known. For example, the reaction is med using the compound represented by formula (Vaa) and methyltriphenylphosphonium bromide in an organic solvent (for example, acetonitrile, methylene chloride, tetrahydrofuran, toluene, benzene, an appropriate mixed solvent of these organic solvents, or the like) at about 0°C to 120°C in the presence of a base (for example, potassium carbonate, sodium hydride, potassium hydride, n-butyllithium, ium tert—butoxide, 1,8-diazabicyclo[5.4.0]undecene triethylamine (DBU), or the like). i The cyclization reaction is known. For example, the reaction is med using the compound represented by formula (VIaa) and a diazo nd in an c solvent (for example, toluene, benzene, methylene chloride, diehloroethane, methanol, ethanol, hexane, tetrahydrofuran, water, an appropriate mixed solvent ofthese organic solvents, or the like) at about -78°C to 120°C in the presence of a catalyst (a ruthenium catalyst (for example, a dichloro(cymene)ruthenium dimer ([Ru(p-cymene)C12]2), RuC12(PPh3)3, RuCl(Cp)(PPh3)2, or the like), a rhodium catalyst (for example, ha(O—CO-heptyl)4, CO-tBu)4, Rh2(OAc)4, Rh2(O-Piv)4, ha((S)—PTTL)4, Rh2((S)-DOSP)4, Rh2(esp)2, Rh2((S)-NTTL)4, or the like), a silver catalyst (for example, silver(I) tetrafluoroborate, or the like), a copper catalyst (for example, CuOTf, Cu(OAc)2, [Cu(MeCN)4]PF6, or the like), a tin catalyst (for example, Sn(tpp)(OTf)2, or the like), an iron catalyst (for e, [Fe(Cp)(CO)2(tht)]BF4, or the like), a cobalt st, s(4-isopropyl-4,5-dihydrooxazol—2-yl)pyridine, 2,6-bis((S)—4-isopropyl- 4,5-dihydrooxazolyl)pyridine, or 2,6-bis((R)~4—isopropyl-4,5-dihydrooxazol—2—yl)pyridine).
In the cyclization reaction, an lly active lic spiro nd (an optical isomer of the compound represented by formula (VIIaa)) can be produced by using a known optically active asymmetric catalyst.
The hydrolysis reaction (deprotection reaction of the carboxyl group) is known, and alkali ysis or the like is an e thereof. For example, the deprotection reaction by alkali hydrolysis is performed in an organic solvent (methanol, tetrahydrofuran, dioxane, or the like) at 0 to 100°C using an alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, or the like), an alkali earth metal hydroxide (barium hydroxide, calcium hydroxide, or the like), a ate (sodium ate, potassium carbonate, or the like), an aqueous solution thereof, or a mixture of these.
The compound ented by formula (IIIb) in reaction scheme (Ib), the compound represented by formula (IIId) in reaction scheme (Id), or the compound represented by formula (Hit) in reaction scheme (It) h m is 1 can be produced from the compound represented by formula (IIIaa) in reaction scheme (Iaa) above using a known method, for example, using the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999).
The compound represented by formula (1110) in reaction scheme (Ic) of which m is an integer of 1 can be produced from the compound represented by formula (IIIaa) in reaction scheme (Iaa) above using a known method, for example, using the method described in hensive Organic Transformations: A Guide to Emotional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999).
The nd represented by a (file) in reaction scheme (16) or the compound ented by formula (111m) in on scheme (Inn) of which 111 is 1 can be produced from the compound represented by formula (IIIaa) in reaction scheme (Iaa) above using a known method, for example, using the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999).
The compound represented by formula (111g) in reaction scheme (lg) or the compound represented by formula (Illj) in reaction scheme (Ij) ofwhich m is 1 can be produced from the compound represented by formula ) in reaction scheme (Iaa) above by reducing the carboxylic acid to produce a primary alcohol derivative and then transforming the alcohol derivative into a halogen derivative, a tosylate derivative, or a mesylate tive, using known method, for example, using the method bed in hensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C.
Larock, John Wiley & Sons Inc., 1999).
The compound represented by formula (IIIh) in reaction scheme (Ih) of which m is 1 can be produced from the compound represented by formula (IIIaa) in on scheme (Iaa) above using a known method, for example, using the method bed in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C.
Larock, John Wiley & Sons Inc., 1999) or in Tetrahedron Letter, Vol. 28, pp. 4489-4492, 1987.
The compound represented by formula (IIIk) in reaction scheme (1k) of which m is 1 can be produced by producing a secondary alcohol derivative from the compound represented by formula (IIIaa) in reaction scheme (Iaa) above and then transforming the alcohol derivative into a thiol derivative, using a known , for example, using the method described hensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999) or in Tetrahedron Letter, Vol. 28, pp. 4489-4492, 1987.
[0212] Of the compounds ented by a (Illa), formula (IlIb), formula (lllc), formula (IlId), formula (IIIe), formula (IIIf), formula (111g), formula (IIIh), formula (IIIj), a (IIIk), and formula (IIIm) used as starting materials in the reaction schemes, compounds with an m of l and a q of an integer of 1 to 3 or the compounds with an m of an integer of 2 to 4 and a q of an integer of 1 to 6 are known or can be produced with ease using a known method, for example, using the method described in Comprehensive Organic Transformations: A Guide to onal Group Preparations, 2nd Edition (Richard C. , John Wiley & Sons Inc., 1999).
The nds represented by ae (Ila), (11b), (11c), (IId), (He), (Iii), (Hg), (Kb), (113'), (11k), (Hm), and (Vaa) used as starting materials in the reaction schemes are known or can be produced with ease using a known method, for example, using the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. , John Wiley & Sons Inc., 1999).
The compound used for the present invention having an amino group, a carboxyl group, or a hydroxyl group can be produced using a compound that has been protected, as required, by a ting group ly used for such groups, for example, a protecting group described in hensive Organic Transformations: A Guide to onal Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999), by performing a known deprotection on or, for example, the deprotection reaction described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999) after the completion of the amidation reaction shown in reaction scheme (Ia) or (Ib) above, the sulfonamidation reaction shown in reaction scheme (Ic) or (Id) above, the reductive amination reaction shown in reaction scheme (Ie) or (Ii) above, the etherification reaction shown in reaction scheme (Ig) or (1h) above, the thioetherification reaction shown in reaction scheme (Ij) or (IR) above, or the Heck on shown in reaction scheme (Im) above, or after a suitable reaction process.
[0215] The compounds represented by formula (1) other than the compounds described above may be produced by combining the Examples described in this specification or by combining . known methods, for example, the methods described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc., 1999).
When the compound used for the present invention is an optically active compound, the compound also can be produced using a starting al or a reagent having optical activity or produced by lly separating a racemic intermediate and then converting to the compound used for the present invention therefrom or optically separating a racemic form of the compound used for the present invention.
The optical tion method is known. In an example method, a salt, a complex, or the like is formed with another optically active compound, and the compound of interest is isolated after recrystallization or ly ted using a chiral column or the like. [021 8] In the reactions in this specification, reactions involving heating may be performed using a water bath, an oil bath, a sand bath, or a microwave, as is evident to a skilled person.
[0219] In the ons in this specification, a solid—phase-supported reagent that is supported on a polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like) may be appropriately used.
In the reactions in this specification, the reaction products may be purified by using ordinary purification means, for example, such as distillation under normal pressure or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, methods using an ion-exchange resin or a scavenger resin, column chromatography, g, and tallization. The purification may be performed after each reaction or after several ons.
Preparations are usually formed using the compound used for the present invention and various ves or pharmaceutically able excipients such as solvents and are administered as oral or parenteral preparation systemically or locally. The pharmaceutically acceptable excipients mean materials which are generally used for the preparation of drugs except for the active nces. The pharmaceutically acceptable excipients are preferably harmless excipients which do not Show any pharmacological effect at the dosage ofthe ation and which do not inhibit the treatment efi'ect of the active substances. In addition, the pharmaceutically acceptable excipients can also be used to enhance effectiveness of the active substances and the preparations, make production of the drugs easy, ize quality or improve usability. Specifically, the materials described in “Japanese Pharmaceutical Excipients directory 2016” (Yakuji nippo sha, 2016) (edited by Japan Pharmaceutical Excipients l)”, etc. may be appropriately selected according to intentions.
Dosage forms for administration include, for example, oral preparations (e.g.: tablets, capsules, granules, powders, oral ons, syrups, oral jelly agents, etc.), oro-mucosal preparations (e.g.: tablets for oro-mucosal ation, sprays for oro-rnucosal application, semi-solid preparations for oro-mucosal application, gargles, etc.), ations for injection (e.g.: injections, etc.), preparations for dialysis (e.g.: dialysis agents, etc.), preparations for inhalation (e.g.: inhalations, etc.), preparations for ophthalmic application (e.g.: ophthalmic liquids and solutions, ophthalmic ointments, etc.), preparations for otic ation (e.g.: ear preparation, etc.), preparations for nasal application (e.g.: nasal preparations, etc.), preparations for recta (e.g.: suppositories, semi-solid preparations for rectal application, enemas for rectal application, etc.), preparations for vaginal application (e.g.: tablets for vaginal use, suppositories for l use, etc.), preparations for cutaneous application (e.g.: solid preparations for cutaneous application, liquids and solutions for cutaneous application, sprays, ointment, creams, gels, patches, etc.), and the like.
[0223] The dose of the compound used for the present ion varies with age, body weight, symptom, eutic effect, route of administration, duration of treatment, and the like. In general, an amount in the range of 1 ng to 1000 mg is orally administered per adult per dose once or several times per day. Alternatively, an amount in the range of 0.1 mg to 100 mg is parenterally administered per adult per dose once or several times per day or intravenously administered continuously over between an hour to 24 hours per day. As described above, the dose varies with various conditions. Thus, an amount lower than the dose is sometimes suflicient, or administration of a dose exceeding the ranges is mes required.
[Immune Checkpoint Inhibitor] In the present ion, an immune checkpoint le means a molecule which transmits a ssive cosignal and thus exhibits immunosuppressive function. Known immune checkpoint les are CTLA-4, PD-l, PD-Ll (programmed cell death-ligand 1), PD-L2 (programmed cell death-ligand 2), LAG-3 (Lymphocyte activation gene 3), TIM3 (T cell immunoglobulin and mucin-3), BTLA (B and T lymphocyte attenuator), B7H3, B7H4, CD160, CD39, CD73, A2aR (adenosine A2a or), KIR (killer inhibitory receptor), VISTA (V—domain Ig-containing suppressor ofT cell activation), IDOl eamine 2,3- dioxygenase), Arginase I, TIGIT (T cell immunoglobulin and ITIM domain), CD115, and the like (see, Nature Reviews Cancer, 12, p. 252-264, 2012 and Cancer Cell, 27, p. 450-461, 2015), but the immune checkpoint molecule is not particularly limited as long as the molecule has a function which meets the ion.
The immune checkpoint inhibitor used for the ation of the present invention is a substance which inhibits the fiinction of an immune checkpoint molecule. The immune checkpoint inhibitor is not particularly limited as long as the inhibitor is a substance which can inhibit the function (signal) of an immune checkpoint molecule.
The immune checkpoint inhibitor is preferably a human immune checkpoint molecule inhibitor, further preferably a neutralizing antibody to a human immune checkpoint molecule.
The immune checkpoint inhibitor is, for example, an inhibitor of an immune checkpoint le selected from the group ting of CTLA—4, PD-l, PD-Ll , PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDOl, Arginase I, TIGIT, and CD115. Although examples of the immune checkpoint tor are shown below, the immune checkpoint inhibitor is not limited to the examples.
Examples ofthe immune checkpoint inhibitor include an anti-CTLA—4 antibody (for e, ipilimumab (Yervoy (registered trademark» and Tremelimumab), an anti-PD-l dy (for example, a human anti-human PD-l monoclonal alizing) antibody (for e, nivolumab (Opdivo (registered trademark)) and REGN-2810) and a humanized anti- human PD-l monoclonal (neutralizing) antibody (for example, Pembrolizumab UDA (registered trademark)), 1, BGB-A317, and AMP-514 (MED10680)), an anti-PD-Ll antibody (for example, Atezolizumab (RG7446 and MPDL3280A), Avelurnab (PF~06834635 and 0718C), Durvalumab 736) and EMS-936559), an anti—PD—L2 antibody, PD-Ll fusion protein, PD—L2 fusion n (for example, AMP-224), an anti-Tim-3 antibody (for example, MBG453), an anti-LAG-3 antibody (for example, EMS-986016 and LAGSZS), an anti-KIR antibody (for example, Lirilumab), and the like. Antibodies containing heavy chain and light chain complementarity—determining regions (CDRs) or a variable region (VR) of the known antibodies are also embodiments of the immune checkpoint inhibitor. For example, another embodiment of the anti-PD-l antibody is, for example, an antibody containing the heavy chain and light chain complementarity—detennining regions (CDRs) or a variable region (VR) of nivolumab.
Examples of the antibody containing heavy chain and light chain complementarity— determining regions (CDRs) or a variable region (VR) of nivolumab include (1) anti—PD—l antibodies containing (a) heavy chain variable region CDRl having the amino acid ce of SEQ ID NO: 3, (b) heavy chain variable region CDR2 having the amino acid sequence of SEQ ID NO: 4, (0) heavy chain variable region CDR3 having the amino acid sequence of SEQ ID NO: 5, (d) light chain variable region CDRl having the amino acid sequence of SEQ ID NO: 6, (e) light chain variable region CDR2 having the amino acid sequence of SEQ ID NO: 7, and (f) light chain variable region CDR3 having the amino acid sequence of SEQ ID NO: 8 or (2) anti-PD-l antibodies containing the heavy chain variable region having the amino acid sequence of SEQ ID NO: 1 and the light chain variable region having the amino acid sequence of SEQ ID NO: 2 (preferably, an isolated human monoclonal IgG4 antibody of (1) or (2)).
The immune checkpoint inhibitor used for the combination ofthe present invention is preferably an anti-CTLA—4 antibody, an anti-PD-l dy, an anti-PD-Ll antibody, an anti- PD-L2 antibody, PD-Ll fusion protein, or PD-L2 fusion protein. An TLA—4 dy, an anti-PD-l antibody, an anti-PD-Ll antibody, an anti-PD-L2 antibody, usion protein, and PD-L2 fusion protein are further preferred. An anti-CTLA—4 antibody and an anti-PD-l antibody are particularly preferred. The anti-PD-l antibody is preferably an antibody containing the heavy chain and light chain mentarity-determining regions (CDR3) or a variable region (VR) ofnivolumab (including nivolumab), further preferably nivolumab.
In the t invention, any one kind or any two or more kinds of these immune oint inhibitors can be used in combination with the compound used for the present [023 1] The dose ofthe immune checkpoint inhibitor used for the combination ofthe present invention varies with age, body weight, symptom, therapeutic effect, route of administration, duration of treatment, and the like but is adjusted in a manner that the optimal desired effects are obtained.
[0232] When an anti—PD—l antibody is used for e, an embodiment of the dose is 0.1 to mg/kg body weight. When nivolumab is used for e, an embodiment of the dose is 0.3 to 10 mg/kg body weight, preferably 2 rug/kg, 3 mg/kg, or 6 mg/kg body weight.
When an anti-CTLA-4 antibody is used for example, an embodiment of the dose is 0.1 to 20 mg/kg body weight, preferably 0.1 to 10 mg/kg body weight, more ably 3 mg/kg mg/kg body weight.
[Toxicity] The combination of the present invention has low toxicity and can be thus safely used as a drug.
[Drug Applications] The combination of the present invention is useful for the treatment of cancer.
More specifically, examples of the cancer e leukemia (for example, acute enous leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, and chronic lymphocytic leukemia), ant lymphoma (Hodgkin's lymphoma and Hodgkin's lymphoma (for example, adult T-cell leukemia, follicular lymphoma, and e large B-cell lymphoma)), multiple myeloma, myelodysplastic me, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, stomach cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer (for example, hepatocellular carcinoma), gallbladder/bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer (for e, non-small cell lung cancer (for example, squamous non-small cell lung cancer and non-squamous all cell lung cancer) and small cell lung cancer), breast cancer, ovarian cancer (for example, serous ovarian cancer), cervical cancer, corpus uteri cancer, endometrial cancer, vaginal cancer, vulvar cancer, renal cancer (for example, renal cell carcinoma), renal pelvis/ureter cancer, urothelial cancer (for example, bladder cancer and upper urinary tract cancer), penile cancer, prostate cancer, testicular tumor (for e, germ cell tumor), osteosarcoma/soft tissue sarcoma, malignant bone tumor, sldn cancer (for example, uveal malignant ma, malignant melanoma, and Merkel-cell carcinoma), thymoma, mesothelioma, glioblastoma, blood cancer, cancer ofunknown primary, and the like.
For example, it is expected that the combination of the present invention exhibits its 3o. anti-tumor effect the most especially in a patient with cancer in which the therapeutic effect of an immune checkpoint inhibitor or an EP4 or antagonist alone is not ent ofthese examples. Also, when the combination ofthe present invention is used, the drugs can be administered at lower doses, and it is expected that side effects are reduced. [023 6] In an embodiment, the combination of the present invention can also be applied to the treatment ofmetastatic cancer or the inhibition of metastasis.
In an embodiment, the combination of the present invention inhibits ence.
In the present invention, the treatment means to cause at least one of ion in the tumor size, inhibition (delay or stop) of the growth of a tumor, inhibition (delay or stop) of the metastasis of a tumor, inhibition (prevention or delay) of recurrence, and relief of one symptom or more related to cancer.
[0239] In an ment, the combination ofthe present invention is used for the treatment of Hodgkin's lymphoma, head and neck cancer, esophageal cancer, stomach cancer, colorectal , hepatocellular carcinoma, biliary tract cancer, non-small cell lung cancer, small cell lung cancer, ovarian , renal cancer, urothelial cancer, mesothelioma, malignant melanoma, glioblastoma, or blood cancer.
In an embodiment, the combination ofthe t invention is used for the treatment of Hodgkin's lymphoma, head and neck cancer, esophageal cancer, stomach cancer, ctal , hepatocellular oma, biliary tract cancer, non-small cell lung cancer, small cell lung cancer, n cancer, urothelial cancer, mesothelioma, glioblastoma, or blood cancer.
In an embodiment, the combination ofthe present invention is used for the treatment of stomach cancer, colorectal cancer, lung cancer, renal cancer, or malignant melanoma.
The ation administration of the combination of the present invention includes simultaneous administration of compounds in a same preparation or separate preparations and separate administration of compounds (for example, sequential administration).
In the present ion, the combination of the present invention may be used in combination with another drug (for example, known anticancer treatment) in order to (1) complement and/or enhance the therapeutic , (2) improve the kinetics/absorption and reduce the dose, and/or (3) reduce a side effect.
Unless otherwise defined, all the technical and scientific terms and all the iations used in this specification have the meaning as normally understood by a person skilled in the art of the present invention.
The contents of all the patent documents and the non-patent documents and the contents of the reference documents explicitly cited in this specification are incorporated herein as a part of the specification.
EXAMPLE
[0246] Synthetic Examples: The present invention is described below in detail by way of Examples, but the present invention is not limited by the following descriptions.
The solvents in parentheses shown in connection with the separation in chromatography and with TLC represent the eluting ts or developing solvents used.
The proportions are volume ratios.
The solvents in parentheses shown in connection with NMR represent the solvents used for measurement.
The compound names used in this specification are based on the computer program ACD/Name tered trademark) or the Chemdraw Ultra (version 12.0, Cambridge Soft), which generally te chemical names according to IUPAC rules, or based on the IUPAC nomenclature.
Reference e 1: 4-Methylenechromane [025 1] [Chem. 39] A solution of lithium bis(trimethylsilyl)amide in tetrahydrofiiran (hereinafter, "THF") (1.3 mol/L, 931 mL) was drOpped into a mL THF solution of methyltriphenylphosphonium bromide (435 g) under a stream of nitrogen under ice-cooling, and the e was then stirred at room temperature for 1 h. The mixture was further stirred at room temperature for 1 h after dropping a 180-mL THF solution of 4—chromanone (150 g) -5 °C. After adding a saturated ammonium chloride aqueous solution to the reaction mixture under ice-cooling, the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over ous sodium sulfate and then trated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (75.9 g) having the following physical property values.
TLC: Rf 0.62 (hexanezethyl acetate = 9:1); IH-NMR (CDC13): 8 2.59-2.75, 4.18—4.3 1, 4.89, 5.51, 6.79-6.94, 7.12-7.20, 7.56.
Reference Exam 1e 2: Eth l 2'R 4S -2 3-dih dros iro chromene—4 1'-c 010 ro ane carboxylate [Chem 40] COOEt
[0255] Under a stream of nitrogen, a dichloro(p-cymene)ruthenium(II) dimer (15.8 g) and (S,S)—2,6-bis(4-isopropyloxazoliny1)pyridine (15.6 g) were added to a dichloromethane solution (2,500 mL) of the compound (75.9 g) produced in Reference e 1. A dichloromethane solution (150 mL) of diazoethyl acetate ining 13% of dichloromethane, 134 g) was slowly dropped at room temperature, and the mixture was then d for 1 h.
After adding a saturated ammonium chloride aqueous solution to the reaction mixture, the mixture was extracted with dichloromethane, and the resulting organic layer was dried anhydrous sodium e and then concentrated under d pressure. The resulting residue was d by silica gel column chromatography to obtain the title compound (91.2 g) having the following physical property values. lH--NMR (CDC13): 8 1.26, 1.54-1.67, 2.07-2.22, 4.05-4.21, 4.27, 6.68, 6.78-6.89, 7.04- 7.12.
Reference Exam le 3: 2'R 4S -2'-carbox lic [Chem 41] An aqueous solution (160 mL) of lithium hydroxide drate (29.6 g) was added to a ol (400 mL) and 1,2-dimethoxyethane (400 mL) solution of the compound (91.2 g) produced in Reference Example 2, and the mixture was stirred overnight at room temperature.
A 10% aqueous solution of citric acid was added to the reaction mixture, and the mixture was then ted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
The resulting residue was recrystallized with dichloromethane to obtain the title compound (55.2 g) having the following al property values. lH—NMR(CDC13): 6 1.59-1.67, 1.68-1.76, 2.15, 2.21-2.29, 4.12-4.23, 4.25-4.36, 6.70, 6.80-6.92, 7.06-7.16; HPLC retention time: 6.9 min (CHIRALPAK [C 4.6 mm x 250 mm hexanezethyl acetatezformic acid = 97:3:1). nce Exam 1e 4: Meth l 2'R 4S —dih dros iro ne—4 1'-c 010 ro ane carboxylate
[0260] [Chem 42] COOMe Under a stream ofnitrogen, potassium carbonate (28.5 g) was added to an N,N— ylformamide (hereinafter, "DMF") on (200 mL) ofthe compound (40.0 g) produced in Reference Example 3. Then, the mixture was stirred overnight at room temperature after dropping iodomethane (31.9 g). The reaction mixture was poured into ice water and extracted with a hexane-ethyl acetate mixed solution. The resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (40.1 g) having the following physical property .
TLC: Rf 0.30 ezethyl acetate = 9:1); lH-NMR (CDC13): 5 1.57-1.69, 2.09-2.22, 3.71, 4074.17, 4.27, 6.68, 6.78-6.90, 7.04- 7.14.
Reference Exam 1e 5: Meth l 2'R 4S -6—iodo-2 3-dih dros iro chromene—4 1'-c clo ro ane — 2'—carboxylate
[0263] [Chem 43] COOMe Under a stream ofnitrogen, 1,3—diiodo-5,5-dimethylhydantoin (35.6 g) and three droplets of concentrated sulfuric acid were added to a methanol solution (320 mL) of the compound (40.1 g) produced in Reference e 4, under ice-cooling. The e was then stirred for 1.5 h under the same condition and for 2.5 h at room ature. The reaction mixture was diluted with a hexane-ethyl acetate mixed solution and then washed with a saturated sodium bicarbonate aqueous solution. The aqueous layer was subjected to extraction with a hexane-ethyl acetate mixed on. The resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (63.8 g) having the following physical property values.
TLC: Rf0.33 (hexanezethyl acetate = 9:1); 'H—NMR ): 5 1.60, 2.06-2.19, 3.71, 4.09, 4.20-4.31, 6.59, 6.93, 7.36.
Reference Exam 1e 6: 2' Iodo-2 3-dih dros iro chromene—41'~c clo ro ane -2'- carboxylic acid [Chem. 44] A sodium hydroxide aqueous solution (2 mol/L, 44 mL) was added to a ol (60 mL) and 1,2-dimethoxyethane (60 mL) solution ofthe compound (15.0 g) produced in Reference e 5, and the mixture was stirred at room temperature for 1.5 h. After adding hydrochloric acid to the reaction mixture, the mixture was ted with ethyl acetate.
The resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (14.4 g) having the following physical property values.
TLC: Rf0.42 (dichloromethanemethanol = 9:1); 'H-NMR (CDC13): 5 1.57-1.74, 2.11, 2.16-2.25, 4.10—4.20, 4.23—4.33, 6.59, 6.94, 7.37. - Reference Example 7: Ethyl 4-{4-formylnitrophenyl oate [Chem 45] mecca OHC N02 Iodine (26.0 g) was added to a 700-mL solution of a zinc powder (99.2 g) in N,N- dimethylacetamide (hereinafter, "DMA") under a stream of nitrogen, and the mixture was stirred for 10 min. After dropping ethyl 4-bromobutyrate (200 g), the mixture was d at 80°C for 2 h to prepare a zinc t. Under a stream ofnitrogen, 2- dicyclohexylphosphino-Z',6'-dimethoxybiphenyl (7.14 g) and palladium acetate (1.96 g) were added to a 500-mL THF on of 3-nitrobr0mobenzaldehyde (100 g), and then the prepared zinc reagent (500 mL) was dropped into the mixture under ice-cooling. This was followed by stirring at room temperature for 30 min. A saturated ammonium chloride mixture was then aqueous solution and water were added to the reaction mixture, and the extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (91.2 g) having the following physical property values.
TLC: Rf0.6l (hexanezethyl acetate = 2:1); 1H-NMR ): 5 1.27, 1.97-2.09, 2.42, 3.01, 4.15, 7.57, 8.04, 8.38, 10.03.
Reference Example 8: Ethyl 4-(4-cyano-2—nitrophenyl)butanoate
[0272] [Chem. 46] NC/©\/\/\CO0EtN02 Hydroxylarnine hydrochloride (26.0 g) was added to a 350-mL DMF solution of the nd (92.0 g) produced in Reference Example 7, and the mixture was stirred at 50°C for 1 h. The mixture was stirred at 90°C for 2 h after adding acetyl chloride (30 mL). Water was added to the reaction mixture, and then the mixture was extracted with ethyl acetate.
The resulting organic layer was washed with water, a saturated sodium bicarbonate aqueous on, and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The ing residue was purified by silica gel column chromatography to obtain the title nd (81.0 g) having the ing physical ty values.
TLC: Rf 0.65 (hexanezethyl acetate = 2:1); lH-NMR(CDC13): 8 1.27, 1.92-2.10, 2.37-2.45, 2.91-3.06, 4.15, 7.55, 7.81, 8.21.
Reference Example 9: Ethyl 4-]2-aminocyanopheny1)butanoate [Chem. 47] NC/©:\/\COOE1NH2 Palladium carbon (50% wet, 8.0 g) was added to an 80—mL ethanol on of the compound (17.0 g) produced in nce Example 8, and the mixture was stirred at room temperature for 9 h in a hydrogen atmosphere. After filtering the reaction mixture with Celite (trade name), the filtrate was concentrated to obtain the title compound (12.0 g) having the following physical ty .
TLC: Rf0.56 (hexanezethyl acetate = 2:1); lH—NMR (CDC13): 8 1.28, 1.79-1.95, 2.38-2.45, 2.50-2.60, 4.09-4.30, 6.89, 6.93-6.98, 7.04—7.10.
Reference Exam 1e 10: Eth 14- .4-c ano iodo—2 3-dih dros iro chromene- 4, l '-cyclopropan |-2'-yl Icarbonyl [amino )phenyl Ibutanoate [Chem 48] mcooa NC NH
[0279] 4-Methylmorpholine (24.0 mL), 4-dimethylaminopyridine (5.33 g), and a propylphosphonic acid anhydride cyclic trimer (hereinafler, "T3P"; 1.7 mol/L, 46.5 mL) were added to a 90-mL DMA on ofthe compound (14.4 g) produced in Reference Example 6 and the compound (10.0 g) produced in Reference e 9, and the mixture was stirred overnight at room temperature. Ethyl acetate, water, and a hydrochloric acid aqueous solution were added to the reaction mixture, and the e was extracted with ethyl acetate.
The resulting organic layer was washed with water, a saturated sodium bicarbonate aqueous solution, and ted brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was washed with a hexane-ethyl acetate mixed on to obtain the title compound (19.3 g) having the following physical property values.
TLC: Rf 0.42 (hexanezethyl acetate = 2:1); lH-NMR (CDC13): 8 1.20, 1.61, 1.66-1.79, 1.83, 2.18-2.28, 2.39-2.49, 2.60, 3.66, 3.90, 4.00-4.12, 4.26, 6.58, 7.05, 7.15-7.22, 7.26-7.31, 7.33, 8.72, 9.39.
Reference Exam le 11: 2'R 4S -oxobut 1 hen lcarbamo l - 2,3-dihydrospirol chromene—4,1'-cyclopropane|carboxylic acid [Chem 49] NC@0003NH Sodium acetate (3.35 g) and a[1,1'-bis(dipheny1phosphino)ferrocene]palladium(II) dichloride romethane complex (555 mg) were added to a 60-mL DMF solution ofthe compound (7.40 g) produced in Reference Example 10, and the mixture was stirred at 80°C for 6 h in a carbon monoxide atmosphere. A potassium carbonate aqueous solution was added to the reaction mixture, and the mixture was stirred for some time. Then, after adding tert-butyl methyl ether and water, the mixture was filtered with Celite (trade name). A hydrochloric acid aqueous solution was added to the filtrate, and then the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and ted brine, dried over anhydrous sodium sulfate and then concentrated under d pressure. The resulting residue was purified by silica gel column chromatography en Autopurification Device) to obtain the title compound (6.14 g) having the following physical property values.
TLC: Rf0.48 (dichloromethane2ethyl ezmethanol = 8:4: 1); IH-NMR(CDC13): 8 1.08, 1.65-1.80, 1.83—1.92, 2.25~2.36, 2.37-2.49, 2.55-2.66, 2.71, 3.55, 3.79, .23, 4.37, 6.88, 7.15 - 7.22, 7.27-7.32, 7.61, 7.83, 8.73, 9.40.
Reference Example 12: Ethyl 4-|4-cyano] i |]2'R,4S 1—6-1methylcarbamoyl )-2,3- dihydrospirol chromene-4, l opropan |-2'-yl |carbony1 Earnino )phenyl Ibutanoate [Chem 50] NC NH CONHMe The title compound (53.0 mg) having the following physical property values was obtained by performing the same procedures as those of Reference Example 10, except that the compound (60.0 mg) ed in Reference Example 11 was used instead ofthe compound produced in Reference Example 6 and that methylamine hydrochloride (87.5 mg) was used instead of the compound produced in Reference Example 9. 1H—NMR ): 6 1.07, 1.64—1.79, 1.81-1.89, 2.20-2.35, 2.40, 2.60, 2.69, 2.98, .59, 3.68-3.83, 4.07-4.19, 4.27-4.38, 6.05, 6.82, 7.15-7.22, 7.27-7.32, 7.35-7.44, 8.72, 9.37.
Exam le 1: 4» meth mo l -2 3-dih dros iro chromene-4 1'- cyclopropan | -2'-yl Icarbonyl [amino [phenyl Ibutanoic‘ acid [Chem. 51] NC NH CONHMe The title compound (45 mg) having the physical property values below was obtained by performing the same ures as those of Reference Example 6 using the compound (53 mg) produced in Reference Example 12, using ethanol instead of methanol.
TLC: Rf 0.45 (dichloromethanezmethanol = 9:1); 1H—NMR(CDC13): 8 1.21-1.30, 1.55, 1.65-1.82, .26, 2.38-2.67, 2.67-2.76, 3.02, 3.57, 4.33, 4.49-4.58, 6.25, 6.81, 7.19, .30, 7.94, 8.87, 9.93.
Example 2 The title compounds having the following physical property values were ed by performing the same procedures as those of Reference Example 12 ——> Example 1, except that the methylamine hydrochloride was replaced with a corresponding amine compound.
Exam 1e 2-1: 4- 4-c ano 2'R 4S -6— c clo ro lmeth 1 carbamo l -2 3- dih dros iro chromene—4 1'-c 010 ro an -2'- 1 carbon lamino hen 1 butanoic acid [Chem 52] NC NH TLC: Rf 0.45 oromethanezmethanol = 9: 1); 1H—NMR (CDC13): 5 0.23-0.31, 0.52-0.63, 0.96-1.14, 1.22-1.30, 1.55, 1.66-1.81, 2.06- 2.24, 2.38-2.66, 2.66-2.76, 3.31, 3.57, 4.34, 4.49-4.59, 6.31, 6.83, 7.19, 7.24-7.29, 7.32, 7.95, 8.87, 9.93.
Exam 1e 2-2: 4- dih dros iro chromene-41'-c clo r0 an -2'- 1 carbon lamino hen 1 butanoic acid [Chem 53] TLC: Rf 0.51 (dichloromethanezmethanol = 9: 1); 1H—NMR (CDC13): 8 1.26, 1.55, 1.67-1.84, 2.06-2.27, 2.39-2.67, 2.67-2.78, 3.39, 3.51- 3.78, 4.33, 4.49-4.59, 6.62, 6.82, 7.19, 7.24-7.29, 7.32, 7.92, 8.86, 9.88.
Exam 16 2-3: 4- dih dros iro ne—4 1'—c 010 to an ~2'- 1 carbon 1 amino hen I butanoic acid [Chem 54] NCmeowNH . NJ< TLC: Rf0.63 (ch10roform:methanol= 19:1); 1H—NMR (DMSO-ds): 5 1.37, 1.57, 1.64—1.85, 2.04-2.25, 2.42—2.48, 2.60—2.71, 4.01- 4.15, .38, 6.80, 7.34-7.45, 7.52-7.66, 7.88, 9.89, 12.11.
Exam 16 2-4: 4- dih dros iro chr0mene—4 1'-c 010 to an -2'- Icarbon 1 amino hen lbutanoic acid [Chem 55] TLC: Rf0.62 (ethyl acetatezmethanol = 19:1); lH-NMR (CD3OD): 5 1.22, 1.65-1.89, 2.12-2.26, 2.33, 2.62-2.77, 330-3 .32, 3.37, 3.41, 3.47, 4.21-4.39, 6.82, 7.37-7.51, 7.58, 8.05.
Exam le 2-5: 4- dih dros iro chromene-4 l'-c clo r0 an -2'— 1 carbon 1 amino hen l butanoic acid TLC: Rf 0.51 (chloroformzmethanol = 9:1); IH—NMR‘(DMSO-d6): 5 1.61, 1661.87, 2.08-2.25, 2.50, 2.59-2.73, 3.81, .19, 4.28-4.42, 6.90, 7.41, 7.49-7.61, 7.73, 7.88, 7.99, 9.91, 10.19, 12.10.
Exam 16 2-6: 4- dihydrosgirol chromene-4,1'-cyclopropan|—2'—yl [carbonyl [amino lphenyl fbutanoic acid TLC: Rf0.54 (ethyl acctate:methanol = 19:1); lH-NMR (DMSO-ds): 8 1.56, 1.67—1.80, 2.04—2.26, 2.45, .72, 3.21, 3.74-3.91, 4.06—4.27, 4.30, 4.37—4.51, 6.83, 7.15, .44, 7.57, 7.88, 9.89, 12.11.
Exam 16 2-7: 4— 4-c ano—2— 2'R 4S —6- 1 3-oxazol—2- dihydrospirol chromene-4,1'-cycloprogan|—2'—yl nyl )amino lphenyl {butanoic acid TLC: Rf 0.64 (ch10roform:methanol= 9: 1); 1H—NMR (DMSO-ds): 8 1.53-1.63, 1.65-1.83, 2.07-2.25, 2.48, 2.58-2.70, 4.03-4.16, 4.27-4.40, 4.47-4.64, 6.87, 7.15, 7.40, 7.48, 7.56, 7.67, 7.87, 8.04, 9.02, 9.90, 12.10. dih dros iro chromene-4 1'-c clo ro an -2'- 1 carbon 1 amino hen 1 butanoic acid TLC: Rf 0.40 (ch10roform:methanol= 9:1); 1H—NMR (DMSO-de): 5 1.61, 1.66-1.80, 1.86, .25, 2.52, 2.61-2.72, 4.14, 4.38, 6.93, 7.19, 7.42, 7.54-7.65, 7.76, 7.88, 7.96, 9.92, 11.38, 12.10. [03 06] Exam 16 2-9: 4- dih dros iro chromene-41'-c 010 ro an -2'- 1 carbon larnino hen 1 butanoic acid [Chem. 56] NC NH o N,L;N\.
H .
TLC: Rf0.62 (chloroformmethanol = 9:1); 1H-NMR (DMSO-dé): 8 1.59, .81, 1.92, 2.10-2.25, 2.54, 2.60-2.72, 3.77, 4.12, 4.35, 6.59, 6.89, 7.42, 7.55-7.62, 7.68, 7.77, 7.88, 9.92, 10.75, 12.10.
Exam 1e 2—10: 4- 4-c ano 2'R 4S c 010 ro lcarbamo 1 -2 3- dih dros iro chromene—41'-c clo to an -2'- lcarbon 1 amino hen Ibutanoic acid [03 10] [Chem 57] NCmaroon-tNH O [031 1] TLC: Rf 0.65 (ethyl acetatezmethanol = 19:1); 1H—NMR(DMSO-d6): 6 0.49-0.59, 0.65-0.75, 1.58, 1.66—1.82, 2.06-2.26, 2.47, 2.61- 2.71, 2.81, 4.09, 4.34, 6.83, 7.36-7.45, 7.54-7.65, 7.88, 8.30, 9.89, 12.09.
Exam le 2-11: 4- 2- -2 3-dih dros iro chromene-4 1‘- cyclopropan |—2'-yl [carbonyl [amino )cxanophenyl lbutanoic acid TLC: Rf0.79 (ethyl acetatezmethanol = 19:1); 'H-NMR (CDC13): 5 0.93—1.00, 1.21—1.83, 2.06-2.25, 2.37-2.77, 3.41-3.50, 3.51-3.63, 4.33, 4.54, 6.18, 6.81, 7.15—7.31, 7.94, 8.87, 9.93.
Example 2-12: 4—| 4-cyan0g { | [2'R,4S 1(cyclohexylcarbamoyl[-2,3- dihydrospirol chromene—4, 1 '—cyclopropan I-2'-11 lcarbonyl [amino )ghenyl lbutanoic acid TLC: Rf0.86 (ethyl ezmethanol = 19:1); lH-NMR (CDC13): 6 1.10-1.87, .26, .79, 3.50-3.64, 3.85-4.04, 4.33, 4.54, 6.04, 6.81, .31, 7.93, 8.87, 9.93.
Exam 162-131: 4- 41'—c clo to an —2‘- n 1 amino hen lbutanoic acid
[0315] [Chem 58] NCmeowNH o N’k TLC: Rf 0.74 (ethyl acetatezmethanol 219:1); lH-NMR (CDC13): 5 1.27, 1.34-1.92, 2.01—2.30, 2.38-2.80, 3.50-3.61, 4.18-4.43, 4.54, 6.00, 6.81, 7.15-7.31, 7.94, 8.87, 9.93.
Exam 162-142 4— 4-c ano-Z- 2'R 4S c clo en lcarbamo l -2 3- dlh dros iro chromene—41'—c clo ro an -2'- lcarbon 1 amino hen lbutanoic acid
[0318] [Chem 59] NCmeowNH TLC: Rf0.83 (ethyl acetatezmethanol = 19:1); lH—NMR (CD013): 8 1.20—1.86, 2.00-2.26, 2.38-2.79, 3.50-3.64, 4.25-4.45, 4.46-4.61, 6.13, 6.81, 7.13-7.31, 7.94, 8.87, 9.93.
Exam 3 4- 4-c ano isobut lcarbamo 1 4,1'—cyclopropan [-2'—y1 |carbonyl [amino )phenyl lbutanoic acid TLC: Rf0.83 (ethyl acetatezmethanol = 19:1); IH-NMR (CDC13): 5 0.84-1.03, 1.21-2.01, .26, 2.37-2.79, 320-33 8, 3.51-3.62, 4.34, 4.49-4.59, 6.18-6.32, 6.82, 7.14~7.32, 7.94, 8.87, 9.93.
Exam 1e 2-16: 4- 41'-c clo ro an -2'- 1 carbon lamino c ano hen l butanoic acid
[0322] [Chem 60] NCmeow-tNH O fi’k/ TLC: Rf 0.84 (ethyl acetatezmethanol = 20: 1); lH—NMR (CDC13): 8 0.95, 1.18-1.91, 2.05-2.25, 2.39—2.78, .64, 4.03-4.20, 4.33, 4.48-4.60, 5.97, 6.81, 7.13—7.32, 7.94, 8.87, 9.93.
Exam 1e 2-17: 4- 41'—c clo r0 an -2'- 1 carbon lamino —4—c ano hen 1 butanoic acid TLC: Rf 0.84 (ethyl acetatetmethanol = 20:1); 1H-NMR (CDC13): 8 0.98, 1.18-1.32, 1.49-1.86, 2.05-2.25, 2.39—2.81, 3.57, 4.11, 4.33, 4.54, 5.95, 6.81, 7.13-7.33, 7.93, 8.81, 8.86, 9.93. benz lcarbamo l -2 3-dih dros iro chromene—4 1'- cyclogropan | -2'-yl |carbony1 [amino 1cyanophenyl |butanoic acid TLC: Rf0.84 (ethyl acetatezmethanol = 20: 1); 1H-NMR (CDC13): 8 1.20-1.86, 2.06-2.26, 2.40-2.79, 3.58, 4.34, 4.48-4.72, 6.47, 6.80, 7.15-7.42, 7.99, 8.87, 9.92.
[0326] Exam 1e 2-19: 4- 4-c an0 dihydrospiro] ne-4, l '-cycloprogan |—2'—yl [carbonyl [amino lphenyl [butanoic acid TLC: Rf0.56 (ethyl acetatezmethanol = 19:1); 1H—NMR (DMSO-ds): 6 1.59, 1.67-1.83, 1.90, 2.07-2.26, 2.46, 2.61-2.71, 3.58, 3.72, 3.82-3.92, 4.10, 4.33, 4.48, 6.85, 7.38-7.48, 7.58, 7.67, 7.88, 8.39, 9.91, 12.11.
Exam 16 2-20: 4- 4-c ano dih dros iro chromene-4 l‘-c clo to an ~2'- 1 carbon lamino hen 1 butanoic acid [O3 28] [Chem. 61] NC NH NvOMOH TLC: Rf 0.57 (ethyl acetatezmethanol = 9:1); 'H—NMR (CDC13): 8 0.77-1.85, 1.95-2.26, .77, 3.48-3.77, .04, 4.33, 4.54, 5.97, 6.81, .35, 7.92, 8.87, 9.92. cish drox c clohex 1 carbamo 1 —2 3— dih dros iro chromene-41'-c clo r0 an -2'- 1 carbon [amino hen l butanoic acid [Chem 62] meow-1 NC NH O N.00“ TLC: Rf0.64 (ethyl acetatezmethanol = 9:1); lH-NMR (CD013): 6 1.20-1.31, 1.51-1.86, 2.05-2.24, 2.38-2.79, 3.51-3.62, 3.94—4.09, 4.33, 4.54, 6.16, 6.82, .31, 7.92, 8.87, 9.92.
Exam 1e 2-22: 4- dih dros iro chromene-4 1'-c 010 ro an -2'- lcarbon 1 amino hen lbutanoic acid TLC: Rf0.17 (ethyl acetatezmethanol = 9:1, Chromatorex diol TLC plate (Fuji Silysia al Ltd.)); 1H—NMR(CDC13): 5 1.19-1.34, 1.59, 1.66-1.84, 2.09-3.16, 3.38, 3.62—3.81, 4.33, 4.52, 6.85, 7.15—7.31, 7.52-7.64, 7.87, 8.80, 9.55.
[0334] Exam 1e 2—23: 4- dih dros iro chromene-41'—c 010 to an -2'— lcarbon 1 amino hen lbutanoic acid [Chem 63] NCWCOOHNH 0 O \ I TLC: Rf0.83 (ethyl acetatezmethanol = 19:1); 1H-NMR (DMSO-ds): 8 1.58, 1.73, 1.88—1.99, .24, 2.60-2.70, 4.06—4.18, 4.30- 4.40, 6.90, 7.14, 7.41, 7.57, 7.72, 7.77—7.90, 8.18, 8.38, 9.91, 10.78, 12.09. dihydrospirol chromene-4,1'—cyclopropanl-2'—yl {carbonyl )amino lphenyl {butanoic acid TLC: Rf 0.62 (ethyl acetatemethanol = 9:1); lH-NMR (DMSO-ds): 8 1.58, 1.63-1.84, .24, 2.59-2.69, .16, 4.27-4.39, 4.55, 6.87, 7.22-7.33, 7.40, 7.55, 7.66-7.80, 7.87, 8.45-8.55, 9.01, 9.90, 12.09. dihydrospirol chromene—4,1'—cyclopropan|—2'~yl |carbonyl iamino )phenyl |butanoic acid TLC: Rf0.76 (ethyl acetatezmethanol = 19:1); 1H—NMR (DMSO-ds): 6 1.12, 1.59, 1.67-1.83, 2.08-2.25, 2.47, 2.61-2.70, 3.23-3.31, 3.40, 4.09, 4.20, 4.33, 6.85, 7.39-7.46, 7.58, 7.65, 7.89, 8.09, 9.90, 12.11.
[0339] Exam 1e 2-26: 4- 4-c ano dihxdrospirol chromene—4,1'-cxclopropanl-2'-yl kcarbonxl [amino l tbutanoic acid TLC: Rf0.56 (chloroformzmethanol = 9:1); 1H-NMR (DMSO-ds): 5 1.59, 1.66-1.80, 2.09-2.25, 2.46, 2.61-2.71, 3.15, 3.52, 4.10 4.28-4.39, 4.63, 6.85, 7.37-7.47, 7.57-7.64, 7.89, 8.50, 9.92, 12.10.
Exam 1e 2-27: 4- 4-c ano -tetrah drofuran lcarbamo 1 -2 3- dihydrospirol chromene—4, l '-cyclopropan |-2'-11 {carbonyl )amino [phenyl [butanoic acid TLC: Rf0.50 (ethyl acetatezmethanol 2 19:1); lH-NMR (DMSO-dg): 5 1.51-1.63, 1.64-1.97, 2.04-2.28, 2.41-2.47, 2.60-2.70, 3.58, .77, 3.80-3.92, 4.02-4.16, 4.26-4.38, 4.38—4.53, 6.84, 7.36-7.48, 7.58, 7.67, 7.87, 8.37, 9.91, 12.10.
Example 2—28: 4-{ 4-cyanol ] { (2'R,4S )| (cyclobuglmethyl )carbamoyl |—2,3- dihydrospirol chromene—4, l'-cyclopropan |-2'-yl } carbonyl [amino l {butanoic acid TLC: Rf0.63 oromethanezmethanol = 9:1); 1H-NMR dé): 8 1.52-1.62, 1.62-1.88, 1.88—2.06, 2.06-2.24, 2.60-2.70, 3.23— 3.30, .14, 4.26-4.37, 6.83, 7.36—7.45, 7.59, 7.88, 8.31, 9.91, 12.10.
Exam 1e 2-29: 4- 4-c ano dih dros iro chromene-41'—c 010 to an -2'- lcarbon 1 amino hen lbutanoic acid [Chem 64] NC NH N \ N TLC: Rf 0.65 (dichloromethanezmethanol = 9:1); 1H-NMR (DMSO-da): 3 1.59, 1.72, 1.87-1.99, 2.05-2.24, 2.54-2.70, 4.05-4.23, 4.30- 4.44, 6.93, 7.41, 7.57, 7.72, 7.76-7.93, 8.38, 9.00, 9.99, 11.45, 12.11.
Exam 16 2-30: 4- dih dros iro ne—4 1'-c 010 ro an -2'- 1 carbon 1 amino hen l butanoic acid TLC: Rf0.21 (dichloromethanezmethanol228% a water = 4: 1 :0. 1); 1H-NMR (DMSO-ds): 8 1.49-1.83, 1.90-2.06, 2.06-2.24, 2.65, 2.81, 3.73, 4.02-4.15, .37, 6.83, 7.37-7.46, 7.56, 7.63, 7.90, 8.14, 10.01.
Exam 162-311 4- 4-c ano dih dros iro chromene-41'-c 010 to an -2'- lcarbon 1 amino hen lbutanoic acid TLC: Rf0.45 (dichloromethanezmethanol = 9:1); lH—NMR (CD3OD): 5 1.65—1.90, 2.24, 2.35, 2.60-2.80, 4.20-4.42, 6.89, .50, 7.59, 7.70, 7.89, 8.03.
Exam 1e 2-32: 4- 2 2-difluoroeth 1 carbamo 1 -2 3- dihydrospirol chromene—4, 1 '-cyc109rogan l—2'-y1 {carbonyl )amino lphenyl ibutanoic acid TLC: Rf0.76 (ethyl acetatezmethanol = 19:1); lH—NMR (DMSO-ds): 5 1.53-1.81, 2.06-2.25, 2.41-2.47, 2.58-2.71, 3.55-3.78, 4.04- 4.17, 4.25-4.40, 5.84-6.36, 6.87, 7.41, 7.48, 7.55, 7.67, 7.87, 8.73, 9.91, 12.10.
Exam le 2-33: 4- dihydrospirol chromene-4,1'-cyclopropan|—2'-yl |carbonyl Eamino [phenyl |butanoic acid TLC: Rf 0.33 (dichloromethanezmethanol = 9:1); 1H-NMR (DMSO-d6): 5 1.50-1.59, .84, 2.06-2.23, 2.37, 2.64, 2.74-2.84, 4.14 4.24-4.36, 4.45, 6.83, 7.35-7.48, 7.55, 7.63, 7.98, 8.45, 10.09.
Exam 16 2-34: 4- dihxdrospirol chromene-4,1'-cyclopropan|-2'-yl |carbonyl {amino [phenyl |butanoic acid TLC: Rf0.68 (dichloromethanezmethanol = 9:1); 1H-NMR(DMSO-d6): 8 1.56-1.64, 1.65-1.81, 1.86-1.96, 2.10-2.24, 2.60-2.70, 4.07- 4.19, 4.32-4.43, 6.94, 7.26, 7.41, 7.53-7.60, 7.79, 7.82-7.90, 9.92, 12.11, 12.53. dihydroSpiro! chromene-4,1'-cxclopropan|-2'-yl Icarbonyl {amino l Ibutanoic acid TLC: Rf0.53 (dichloromethanezmethanol = 9:1); lH-NMR (DMSO-ds): 5 1.58-1.65, 1.72, 1.83, .24, .70, 4.30-4.43, 6.94, 7.35-7.45, 7.57, 7.79, 7.88, 8.11-8.18, 8.30, 8.90, 9.93, 10.24, 12.09.
Exam 1e 2—36: 4— ospirol chromene-4,1'-cyclopropan|-2'-yl Icarbonyl Eamino )phenyl Ibutanoic acid TLC: Rf0.56 oromethanemethanol = 9:1); ‘H—NMR (DMSO-da): 8 1.53-1.63, 1.63-1.80, 1.84—1.95, 2.07-2.24, 2.60-2.70, 4.06- 4.19, 4.29-4.43, 6.90, 7.24, 7.41, 7.57, 7.64, 7.75, 7.86, 8.72, 9.91, 10.94, 12.08.
[0352] Exam 1e 2-37: 4- dihydrospirol chromene-4, 1 '-cyclopropan |-2'-y1 lcarbonyl iamino )phenyl |butanoic acid TLC: Rf 0.65 (dichloromethanezmethanol = 9:1); 'H—NMR da): 8 .50, 1.62, 1.86-2.15, 2.53-2.68, 2.68-2.89, 4.19-4.37, 6.85, 6.91, 7.31-7.41, 741-749, 7.62, 7.79, 8.36, 8.75, 11.61, 12.62.
Example 2-38: 4cyanog i |§2'R,4S )§ cyclobutllcarbamoyl )-2,3- dihydrospirol chromene-4,1 '-cyclopropan |-2'-y1 [carbonyl Eamino )phenyl lbutanoic acid [Chem. 65] NCmeowNH O N’0 TLC: Rf 0.72 (ethyl acetate); lH—NMR (CD30D): 6 1.62-1.90, 2.02-2.44, .80, 4.19-4.30, 4.33, 4.49, 6.82, 7.37-7.51, 7.58, 8.04.
Exam 1e 2-39: 4- xi |carbamoyl dihydrospiro| chromene—4,1'-cyclop_ropan[-2'- 21 |carbonyl [amino )phenyl |butanoic acid [Chem 66] NCmeowNH O N’Q/N
[0358] TLC: Rf0.64 (ethyl acetate); IH-NMR (CD30D): 6 1.59, 1.67-1.92, 2.16-2.29, 2.30-2.41, 2.62—2.78, 4.21—4.32, 4.33-4.46, 6.88, 7.37-7.51, 7.58, 7.65—7.74, 8.03, 8.11.
Exam 1e 2-40: 4— 4-c ano dih dros iro chromene-41'-c C10 to an -2'— lcarbon 1 amino hen lbutanoic acid [Chem 67] NCmeowNH TLC: Rf 0.62 (ethyl acetatezmethanol = 9:1); lH-NMR (DMSO-ds): 6 1.44-1.86, 2.02-2.24, 2.59-2.70, 3.35-3.44, 3.80-4.15, 4.25— 4.37, 6.84, 7.37-7.46, 7.57, 7.64, 7.87, 8.13, 9.90, 12.09.
Exam 16 2-41: 4- 4-c ano dih dros iro chromene-4 1'-c (:10 to an -2'- lcarbon 1 amino hen lbutanoic acid TLC: Rf 0.71 (ethyl acetatezmethanol = 9:1); lH—NMR ds): 8 1.56-1.66, 1.73, 1.87, 2.06-2.25, 2.60-2.70, 4.06-4.19, 4.31- 4.44, 6.39, 6.94, 7.41, 7.57, 7.67, 7.81, 7.87, 8.50, 9.92, 11.90, 12.09.
Exam 1e 2-42: 4- dihydrospirol chromene-4, 1 '-cyclopropan |-2'-y1 nyl [amino )phenyl |butanoic acid TLC: Rf 0.53 (dichloromethanezmethanol = 4:1); lH-NMR (DMSO-ds): 5 1.57-1.66, 1.73, 1.83, 2.09-2.24, 2.60-2.70, 4.08-4.21, 4.31- 4.42, 6.95, 7.41, 7.52—7.61, .91, .52, 9.91, 10.38, 12.09.
Exam 1e 2-43: 4— 4-c ano 2O dihydrospirol chromene—4,1'-cyclopropan|—2'-yl [carbonyl [amino Iphenyl [butanoic acid TLC: Rf 0.58 oformzmethanol = 9: 1); 1H-NMR (DMSO-ds): 8 1.55-1.65, 1.66-1.90, 2.06—2.29, 2.50, 2.60—2.74, 3.66, 4.06- 4.22, 4.30-4.46, 6.17, 6.93, 7.35-7.45, 7.52-7.61, 7.77, 7.88, 9.91, 10.15, 12.10.
Exam 1e 2-44: 4- 4,1'—cyclopropan |-2’-y1 Icarbonyl [amino )Qhenyl lbutanoic acid [Chem. 68] NCmeowNH TLC: Rf 0.75 (ethyl e); 1H-NMR (DMSO-ds): 8 0.88, 1.45—1.63, 1.68-1.82, 2.07-2.25, 2.45, 2.61-2.72, 3.15- 3.26, 4.10, 4.32, 6.85, 7.39-7.46, 7.57-7.63, 7.88, 8.32, 9.90, 12.11. dih dros iro chromene-41'-c clo ro an ~2'— 1 carbon lamino hen l butanoic acid
[0369] [Chem 69] NC/©\/\/\COOHNH 0 fimo TLC: Rf 0.51 (ethyl acetate); lH-NMR (DMSO-ds): 5 1.11, 1.59, .83, 2.07-2.26, 2.47, 2.61-2.71, 3.35-3.52, 4.10, 4.33, 6.85, 7.38-7.48, 7.57-7.64, 7.88, 8.42, 9.90, 12.09. cyclopropan |—2'-][l |carbonyl {amino [phenyl Ibutanoic acid
[0372] [Chem 70] NC NH TLC: Rf0.59 (ethyl acetate); lH-NMR (DMSO-ds): 8 1.10, 1.58, 1.65-1.80, 2.07-2.24, 2.45, 2.58-2.69, 3.19—3.33, 4.09, 4.32, 6.84, 7.37-7.45, 7.57, 7.62, 7.88, 8.33, 9.89, 12.09. dih dros iro chromene-41'—c clo ro an ~2'- 1 carbon lamino hen l butanoic acid TLC: Rf 0.72 (hexanezethyl acetate = 1:3); 1H-NMR (DMSO-da): 6 1.33, 1.57, 1.67-1.86, 2.08-2.25, 2.47, 2.62-2.71, 3.27, 3.53, 4.09, 4.32, 6.82, .45, 7.48, 7.57-7.62, 7.88, 9.89, 12.10.
Reference Exam le 13: Eth 14- 4-c ano 2'R 4S ~6- dih dros iro chromene—4 l'-c 010 ro an -2'- lcarbon 1 amino hen l butanoate
[0376] [Chem. 71] NC/©\/\/\COOE’(NH km\,N ylamine (60 uL) and T3P (a 1.7 mol/L ethyl acetate solution, 95 uL) were added at room temperature to a 0.5-mL dichloromethane on ofthe compound (50 mg) produced in Reference Example 11 and acetylhydrazine (16 mg). The reaction e was stirred at room temperature for 1.5 h and then concentrated under reduced pressure. The Burgess reagent (Methyl N-(triethylammoniosulfonyl)carbamate, 117 mg) was added at room temperature to a 5-mL THF solution ofthe compound obtained by purifying the resulting residue by silica gel column tography (Yamazen Autopurification Device). The mixture was stirred at 100°C for 1 h using a microwave reactor (Biotage, Ltd.). A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with ted brine, dried over ous magnesium sulfate and then concentrated under reduced re.
The resulting residue was purified by silica gel column chromatography (Yamazen Autopurification Device) to obtain the title compound (22 mg) having the following physical property values.
TLC: Rf0.53 (hexanezethyl acetate = 1:3); lH-NMR (CDC13): 5 0.94, 1.65-1.83, 1.89, 2.26—2.34, 2.35-2.44, 2.56-2.63, 2.66-2.76 3.12—3.28, 3.36-3.55, 3.58-3.74, 4.07-4.23, 4.30—4.41, 6.92, 7.18, 7.28, 7.54, 7.70, 8.72, 9.39.
Exam 1e 3: 4- 4-0 ano S-meth H 3 4-oxadiazol 1 dih dros iro chromene-4 1'—c 010 ro an -2'- 1 carbon 1 amino hen l butanoic acid [Chem. 72] NC NH 2km\,N
[0380] The title nd having the following physical property values was obtained by performing the same procedures as those of Example 1 using the compound produced in Reference Example 13, instead ofthe compound produced in Reference Example 12.
TLC: Rf0.93 (dichloromethanezmethanol = 9:1); (CDC13): 8 1.27, 1.54, 1.70—1.91, 2.17, 2.32, .90, 3.64, 4.35-4.48, 4.56-4.66, 6.92, 7.20, 7.28, 7.58, 8.15, 8.92, 9.91, 12.68.
The title compounds having the following physical property values were ed by performing the same procedures as those of Reference Example 13 —> Example 1, except that the acetylhydrazine was replaced with a ponding hydrazine compound.
Exam le 4-1: 4- 4-c ano dih dros iro chromene-41'-c clo to an -2'- lcarbon 1 amino hen lbutanoic acid [Chem. 73] NCmeowNH TLC: Rf 0.64 (ethyl acetatezmethanol = 19:1); 1H—NMR(CDC13): 8 1.14-1.32, 1.78, 2.07-2.41, 2.43-2.91, 3.63, 4.33-4.49, 4.61, 6.86- 6.96, 7.16-7.32, 7.54, 8.13, 8.92, 9.91.
[0385] Exam 1e 4-2: 4- 4—e ano dih dros iro chromene-41'—c 010 to an ~2'- 1 carbon lamino hen l butanoic acid TLC: Rf 0.83 (ethyl acetatezrnethanol = 19:1); lH—NMR ): 5 1.19-1.32, 1.44-1.52, 1.64-1.87, 2.10-2.40, 2.44—2.90, 3.64, 4.35- 4.49, 4.56-4.67, 6.93, 7.16-7.35, 7.60, 8.15, 8.92, 9.92.
Exam le 4-3: 4- dihydrospirol chromene-4,1'-cyclopropan]-2'-yl |carbon11 [amino lphenyl |butanoie acid TLC: Rf0.53 (dichloromethanezmethanol = 9:1); lH-NMR (DMSO'dé): 6 1.32, 1.60, 1.66-1.82, 2.10-2.24, 2.60-2.70, 2.92, 4.09-4.21, 4.31-4.42, 6.99, 7.41, 7.46, 7.57, 7.71, 7.88, 9.91, 12.08.
Reference Exam le 14: Eth l4- dih dros iro ne-4 l'-c clo ro an -2'- 1 carbon 1 amino hen 1 butanoate [Chem 74] NCmcooaNH N~\-< Triethylamine (0.144 mL) and T3P (a 1.7 mol/L ethyl acetate solution, 0.380 mL) were added at room temperature to a 0.5-mL ethyl acetate solution of the compound (80 mg) produced in Reference Example 11 and acetamideoxime (32 mg). The reaction mixture was heated under reflux for 4 days and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Yamazen Autopurification Device) to obtain the title nd (49 mg) having the following physical property values.
TLC: Rf 0.55 (hexanezethyl acetate = 1:1); 1H—NMR (CDC13): 8 0.92, 1.64-1.83, .95, 2.22-2.35, 2.36-2.44, 2.45, 2.54—2.65, 2.72, 3.39-3.54, 3.59-3.73, 4.10-4.23, 4.32—4.44, 6.94, 7.20, 7.28, 7.59, 7.84, 8.74, 9.39. dihydrosgirol chromene-4,1'-cyclopropan|-2'-yl |carbonyl [amino l Ibutanoic acid
[0391] [Chem 75] The title nd having the following physical property values was obtained by performing the same ures as those of Example 1 using the compound produced in Reference Example 14, instead ofthe compound produced in Reference Example 12.
TLC: Rf 0.74 (ethyl acetatezmethanol = 20:1); 1H—NMR (DMSO-da): 6 1.55-1.64, 1.67-1.83, 2.11-2.29, 2.39, 2.51-2.60, 2.61-2.73, 4.11-4.25, 4.31-4.44, 7.02, 7.41, 7.52-7.62, 7.83, 7.88, 9.90, 12.10.
Reference Exam 1e 15: Eth 14— 4-c ano 2'R 4S 4—fluoro hen l -2 3- dih dros iro chromene-41'—c clo ro an -2'- learbon 1 amino hen lbutanoate [Chem 76] NCmeccaNH o ‘ O
[0395] Cesium carbonate (84 mg), 4—fluoropheny1boronic acid (36 mg), and purified water (0.4 mL) were added at room ature to a 0.4-mL 1,2-dirnethoxyethane solution of the compound (70 mg) produced in Reference Example 10, and the atmosphere was replaced with argon. A [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (5 mg) was added, and the e was stirred overnight at 85°C. The reaction e was diluted with ethyl acetate and then ted with ethyl e after adding water.
The resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The ing residue was purified by silica gel column chromatography (Yamazen rification Device) to obtain the title compound (54 mg) having the following physical property values.
TLC: Rf 0.48 (hexanezethyl acetate = 2:1); 1H—NMR (CDC13): 8 0.83, 1.64-1.79, 1.82-1.93, 2.29, 2.33-2.43, 2.48-2.74, 3.30, 3.49 4.06-4.19, 4.26-4.38, 6.84-6.91, 6.97, 7.04-7.15, 7.15-7.22, 7.22-7.32, 7.39-7.51, 8.73, 9.30.
[0396] -6— 4—fluoro hen l -2 3-dih dros iro chromene—4 1'- c 010 ro an -2'- lcarbon 1 amino hen lbutanoic acid [Chem 77] NCmeowNH O ‘ O The title compound having the following physical property values was obtained by performing the same procedures as those of Example 1 using the compound produced in Reference Example 15, instead ofthe compound produced in nce Example 12.
TLC: 'Rf 0.58 (dichloromethanezmethanol = 9:1); lH-NMR (DMSO-ds): 8 1.50—1.60, 1.72, 1.87, 2.06-2.24, 2.60-2.69, 4.03—4.15, 4.24— 4.35, 6.87, 7.11, 7.19-7.29, 7.32-7.44, 7.56, 7.61-7.70, 7.87, 9.88, 12.09.
Example 7 The title compounds having the following physical property values were obtained by performing the same procedures as those of nce Example 15 ——) Example 1, except that the 4-fluorophenylboronic acid was replaced with a corresponding boronic acid compound or a corresponding heterocyclic ring.
Exam 1e 7-1: 4- cyclopropan |-2‘-yl Icarbonyl }amino l |butanoic acid TLC: Rf 0.53 (dichloromethanezmethanol = 9:1) lH-NMR (013013): 6 1.58-1.81,2.14-2.27,2.36-2.46,2.49-2.71, 2.78, .37, 6.92, 7.15, 7.16—7.22, 7.26—7.51,7.52—7.61, 8.69, 8.95. —2 3-dih dros iro chromene—4 1'- cyclopropan |—2'-yl Icarbonyl {amino )phenyl |butanoic acid TLC: Rf0.36 (dichloromethanezmethanol = 9:1); lH-NMR ds): 8 1.52-1.63, 1.64-1.79, 1.87-1.99, 2.08-2.30, 2.43-2.73, 3.99— 4.20, 4.25-4.41, 6.93, 7.31, 7.40, 7.56, 7.66-7.71, 7.87, .62, 9.88, 11.90-12.18. -2 3-dih dros iro chromene-4 1'- cyclopropan]-2'-yl |carbonyl {amino )phenyl |butanoic acid
[0403] [Chem 78] NCmeowNH TLC: Rf 0.36 (dichloromethanezmethanol = 9:1); 1H-NMR (DMso-dé): 5 1.56, 1.65-1.77, 1.88-2.00, 2.06-2.30, 2.34-2.75, .19, 4.25—4.39, 6.92, 7.22, 7.37-7.51, 7.57, 7.87, 7.99—8.09, 8.48-8.53, 8.87, 9.87. cyclopropan |—2’-yl ny1 [amino [phenyl Ibutanoic acid [Chem 79] NC NH U TLC: Rf0.45 (dichloromethanezmethanol = 9: 1); 1H-NMR (CDC13): 6 1.23-1.34, 1.62, .83, 2.05-2.23, 2.40-2.59, .82, 3.37- 3.47, 4.22-4.35, 4.44-4.52, 6.49, 6.88, 7.11, 7.20, 7.23, 7.41, 7.71, 8.86, 9.95.
[0408] -2 3-dih dros iro chromene-4 1'- cyclopropanl-2'-yl |carbonyl [amino )phenxl |butanoic acid [Chem 80] NCmeowNH H1? \ TLC: Rf0.35 (dichloromethanezmethanol = 9:1); lH—NMR (DMSO-ds): 8 1.51-1.62, 1.63—1.86, 2.04-2.33, 2.34-2.75, 3.98-4.14, 4.23- 4.35, 6.65, 6.82, 7.29, 7.40, 7.48-7.60, 7.63, 7.87, 9.91, 12.47.
[0411] cyclopropan |-2'-yl |carbonyl [amino )phenyl |butanoic acid [Chem 81] NC NH [‘1 \ TLC: Rf 0.40 (dichloromethanezmethanol = 9:1); 1H—NMR (DMSO—ds): 6 1.53—1.62, 1.63-1.80, 1.95-2.06, 2.09-2.33, .78, 4.01- 4.22, .42, 6.97, 7.42, 7.47, 7.57, 7.71, 7.87, 7.94-8.04, 9.20, 9.60, 9.87, 12.1.
Exam 1e 7-7: 4- dih dros iro chromene-4 1'-c clo r0 an -2'- 1 carbon 1 amino hen 1 butanoic acid TLC: Rf0.25 (ethyl acetatezmethanol = 19:1); 1H-NMR(CDC13): 6 1.44-1.88, .33, 2.48, 2.58-2.76, 3.70, 4.16-4.36, 6.81-6.95, 7.11-7.34, 7.39, 7.56, 8.73, 9.16.
Exam 1e 7-8: 4— cyclopropan I-2'-y1 Icarbonyl [amino )phenyl |butanoic acid TLC: Rf0.44 (dichloromethanczmethanol = 9:1); lH—NMR (DMSO—ds): 8 1.57, 1.65—1.79, 1.92—2.03, 2.06-2.35, 2.36-2.77, .17, 4.27-4.40, 6.94, 7.33, 7.40, 7.50-7.61, 7.87, 9.12, 9.86, 12.08.
[0416] Exam 1e 7-9: 4- cyclopropan |-2'-y1 |carbonyl [amino )phenyl |butanoic acid TLC: Rf 0.44 (dichloromethanemethanol = 9:1); 1H—NMR (DMSO-ds): 5 1.51-1.61, 1.65-1.78, 1.79-1.88, 2.05-2.31, 2.40-2.76, 3.98- 4.14, 4.23—4.36, 6.83, 7.04—7.16, 7.30-7.49, 7.57, 7.86, 9.90, 12.08. 4, 1'-cyclopropan |-2'-yl lcarbonxl [amino [phenyl oic acid [Chem 82] NC NH 07° TLC: Rf0.47 (dichloromethanezmethanol = 9:1); ‘H-NMR (DMSO-ds): s 1.50—1.59, 1.60-1.80, 1.93—2.12, 2.19, 2.31—2.51, 2.54-2.78, 3.78, 3.93—4.09, .31, 6.78, 7.09, 7.29, 7.40, 7.56, 7.85, 9.91, 12.08.
[0420] ropan |-2'-yl |carbonyl [amino )phenyl |butanoic acid TLC: Rf 0.53 (ethyl acetatezmethanol = 20:1); lH—NMR (CDC13): 5 1.20-1.30, 1.58, 1.73-1.90, 2.26-2.37, 2.52, 2.64-2.82, 4.19-4.41, 6.81-6.97, 7.13-7.35, 7.77, 8.60, 8.69, 9.25.
Exam 1e 7 dihydrospiro] chromene-4,1‘-cyclopropan|—2'-yl Icarbonyl }amino [phenyl |butanoic acid TLC: Rf 0.40 (dichloromethanemethanol = 9:1); lH—NMR (CD013): 8 1.59-1.70, 1.76-1.84, 2.31, 2.43-2.53, .80, 4.15-4.44, 6.72, 6.89, 6.97, 7.09-7.36, 7.68, 7.89, 8.43, 8.70, 9.15.
Exam 16 7-13: 4- 4-0 ano dihxdrospirol chromene—4,1'-cyclopropan|—2'-yl |carbonyl [amino Jphenyl Ibutanoic acid
[0423] [Chem 83] TLC: Rf0.56 (ethyl acetate); lH—NMR ): 8 1.65-1.93, 2.14-2.29, 2.33, 2.58, .78, 3.92, 4.21, 4.32, 6.80-6.91, 7.06, 7.30, 7.42, 7.48, 7.84-7.95, 8.31.
Exam 167-142 4- 4-0 ano-Z— 2'R 4S -6— 6- 1H— razol-l— l idin 1-2 3- dih dros iro chromene-4 1'-c 010 ro an -2'- 1 carbon lamino hen l butanoic acid [Chem. 84] NC NH \ / TLC: Rf0.60 (chloroformzmethanol = 9:1); lH—NMR (DMSO-ds): 5 1.57, 1.63-1.79, 1.89-2.01, 2.08-2.25, 2.50-2.56, 2.60-2.72, 4.03-4.18, 4.27-4.40, 6.59, 6.93, 7.27, 7.40, 7.47-7.60, 7.80-7.91, 7.96, 8.27, 8.63, 8.76, 9.88, 12.10.
Exam le 7 dihydrospirol chromene-4, 1'-cycloprogan|—2'-yl [carbonyl [amino Iphenyl [butanoic acid [Chem. 85] NC NH N I TLC: Rf 0.58 (chloroformzmethanol = 9:1); 1H-NMR (DMSO-de): 8 1.51-1.62, 1.63-1.80, 1.84-1.95, .25, 2.51—2.57, 2.60- 2.75, 3.18, 4.02-4.17, 4.23-4.39, 6.88, 7.01-7.21, 7.35-7.47, 7.55, 7.87, 8.10-8.29, 9.92, 12.10.
Exam 1e 7-16: 4- dih dros iro chromene-41'—c 010 to an -2'- lcarbon 1 amino hen Ibutanoic acid [Chem 86] NC/©\/\/\COOHNH TLC: Rf0.63 oromethanezmethanol = 9:1); lH—NMR (DMSO-da): 8 1.46-1.56, 1.56-1.79, 2.03, 2.16, 2.66, 4.15, 4.22-4.33, 6.86, 7.20, 7.27, 7.33—7.44, 7.44-7.52, 8.08—8.21, 8.70, 11.11.
Exam 1e 7-17: 4- 4-0 ano 2'R 4S 6-fluoro 41'—c 010 to an ~2‘- lcarbon 1 amino hen lbutanoic acid TLC: Rf0.59 (dichloromefl1ane:methanol = 9:1); IH-NMR (DMSO-ds): 5 1.52-1.60, 1.65—1.79, 1.93, 2.07—2.23, 2.60-2.70, 4.03-4.15, 4.27-4.37, 6.90, 7.19-7.27, 7.40, 7.45, 7.56, 7.87, 8.25, 8.51, 9.87, 12.09.
Exam 16 7-18: 4- 4-c ano dihydroSpiro] chr0mene-4, 1’-cyclopropan | -2'-yl tcarbonyl )amino l ibutanoic acid TLC: Rf 0.57 (dichloromethanezmethanoi = 9:1); lH-NMR (DMSO-ds): 8 1.58, 1.72, 1.92-2.01, 2.09-2.24, 2.60-2.70, 4.06-4.17, 4.30- 4.40, 6.96, .45, 7.58, 7.88, 8.06, 8.41, 9.09, 9.90, 12.10.
Exam 1e 7-19: 4- 4-0 ano dihydrospirol chromene—4,1'—cyclopropan |-2'-yl |carbonyl {amino )phenyl |butanoic acid TLC: Rf0.55 (dichloromethanezmethanol = 9:1); IH—NMR (DMSO-da): 6 1.51—1.61, 1.65-1.80, 1.91, .24, 2.60-2.70, 4.09, 4.25- 4.36, 6.47, 6.89, 7.18, 7.38-7.45, 7.45-7.50, 7.56, 7.88, 8.17, 8.47, 9.94, 11.65, 12.06.
[0437] 11 Icarbonyl {amino )phenyl Ibutanoic acid TLC: Rf 0.65 (dichloromethanemethanol = 9:1); lH—NMR (DMSO-de): 5 1.48-1.58, 1.65-1.79, 1.88, 2.06-2.14, 2.19, 2.59-2.70, 3.03, 340-3 .47, 3.99-4.11, .33, 6.81, 7.03, 7.23, 7.29, 7.40, 7.56, 7.86, 7.95, 9.87, 12.08.
Exam 16 7-21: 4- dih dros iro chromene-41'—c clo to an -2'- 1 carbon lamino hen 1 butanoic acid
[0439] [Chem 87] TLC: Rf0.53 (dichloromethanczmethanol = 9:1); 1H—NMR (DMSO—da): 5 1.52-1.61, 1.72, 1.84-1.94, 2.06-2.23, 2.60—2.70, 2.94, 4.02- 4.13, 4.25-4.36, 6.88, 6.99, 7.14, 7.34-7.43, 7.56, 7.86, 8.09-8.21, 9.91, 12.13, 13.60.
Exam 1e 7-22: 4- 4-c ano-2— ospirol ne—4,1'—cyclopropan|-2'-yl [carbonyl [amino lphenyl [butanoic acid TLC: Rf0.56 (dichloromethanezmethanol = 9:1); lH—NMR (DMSO-ds): 8 1.46, 1.54-1.62, 1.72, 1.79-1.88, 2.07-2.24, 2.60-2.70, 4.02- 4.15, 4.25-4.36, 5.05, 6.88, 7.09, 7.29-7.46, 7.57, 7.66, 7.87, 9.90, 12.09. 2-oxoazetidin l -2 3-dih dros iro chromene- 41'-c clo r0 an -2'- n 1 amino hen lbutanoic acid TLC: Rf 0.47 (dichloromethanezmethanol = 20:1); R da): 5 1.54-1.79, 2.02-2.11, 2.19, 2.39-2.68, 3.01-3.05, 3.55-3.61, 3.95-4.03, 4.20-4.29, 6.77-6.81, 7.16, 7.41, 7.56, 7.85, 9.90, 12.10.
Exam 1e 7-24: 4- 4-c ano dihydrosgirol chromene-4,1'-cyclopropan|~2'-yl |carbonyl [amino [phenyl Ibutanoic acid TLC: Rf 0.47 oromethanezmethanol 2 20:1); 1H-NMR (DMSO-ds): 6 1.54-1.79, 2.05-2.24, 2.39-2.68, 3.96-4.06, 4.23-4.31, 4.36- 4.45, 6.81, 7.01, 7.27, 7.41, 7.56, 7.86, 9.92, 12.10. le 7-25: 4- dihydrospirol chromene-4, 1'-cyclopropan | -2'-yl [carbonyl )amino Iphenyl [butanoic acid TLC: Rf 0.40 (dichloromethanezmethanol = 20:1); 'H—NMR (DMSO-ds): 8 1.53-1.80, .13, 2.19, 2.37-2.81, 3.47—3.55, 4.00-4.08, 4.20-4.39, 5.29-5.37, 6.78, 7.14, 7.25, 7.40, 7.55, 7.87, 9.91, 12.10. dihxdrospirol chromene-4, 1 '-c1clopropan [-2'-yl [carbonyl [amino lphcnyl [butanoic acid TLC: Rf 0.49 (dichloromethanezmethanol = 9:1); lH—NMR (DMSO-de): 5 1.58, 1.72, 1.92, 2.08—2.24, 2.60-2.70, 3.23, 4.05-4.17, 4.27- 4.39, 6.93, 7.25, 7.41, 7.50, 7.57, 7.84-7.99, 9.88, 12.09.
Exam 1e 7-27: 4— 4—0 ano 2'R 4S -6— 4-0 ano hen 1 -2 3-dih dros iro chromene-4 1'- cyclopropanl-2'—yl nyl [amino [phenyl lbutanoic acid TLC: Rf0.58 (dichloromethanezmethanol = 9:1); IH—NMR (DMSO-de): 5 1.56, 1.72, 1.93, 2.08-2.24, 2.59—2.69, 4.04-4.16, 4.27-4.38, 692,725, 7.40, 7.51, 7.56, 7.87, 9.86, 12.08. dih dros iro chromene-41'-c clo ro an -2'- lcarbon 1 amino hen lbutanoic acid TLC: Rf0.59 (chloroformzmethanol = 9:1); lH—NMR (DMSO-ds): 5 1.51-1.61, 1.64-1.88, 2.08-2.28, 2.39-2.46, 2.58-2.71, 3.82, 4.05-4.17, .39, 6.32, 6.90, 7.00, 7.25, 7.37-7.45, 7.55, 7.86, 9.89, 12.10.
[0448] Reference Exam le 162Eth 14- pflazolyl |-2,3-dihydrospiro] chromene-4,1‘-cyclopropan|—2'- yl [carbonyl [amino l [butanoate [Chem 88] The title compound having the following physical property values was obtained by performing the same procedures as those of Reference Example 15 using a 1-(2- tetrahydr0pyranyl)-1H—pyrazoleboronic acid pinacol ester, d of 4—fluorophenylboronic acid.
TLC: Rf0.62 (hexanezethyl acetate = 1:2); IH—NMR(CDC13): 3 0.86, .79, 1.82-1.90, 2.02—2.16, 2.21-2.29, 2.34-2.43, 2.52- 2.72, 3.28—3.42, 3.45-3.60, 3.65-3.80, 4.03-4.16, 4.25-4.40, 5.35—5.45, 6.81, 6.90, .23, 7.28, 7.71, 7.76, 8.74, 9.36.
Exam 1e 8: 4- cyclopropan |-2'—yl nyl [amino )phenyl |butanoic acid [Chem. 89] A hydrochloric acid-1,4-dioxane solution (4 mol/L, 0.1 mL) was added at room temperature to a l-mL 1,4-dioxane solution of the compound (30 mg) produced in Reference Example 16. The reaction mixture was stirred at 60°C for 3 h. After concentrating the reaction mixture under reduced pressure, the same procedures as those of Example 1 were performed to obtain the title compound having the following physical property values.
TLC: Rf 0.40 (ethyl acetatezmethanol = 20:1); 1H—NMR (DMSO-ds): 8 1.55, 1.64-1.79, 1.81—1.92, 2.04-2.27, 2.35-2.47, 2.52—2.74, 4.02, 4.27, 6.76, 7.09, 7.32, 7.40, 7.56, 7.85, 7.99, 9.89.
[0454] Reference Example 17: Ethyl 4-|4-cyano( { 4S1[4,4,5,5-tetramethyl-1,3,2- dioxaborolan—Z— 1 -2 3-dih dros iro chromene—4 1'-c 010 ro an -2‘— yl [carbonyl [amino l |butanoate [Chem 90] While replacing the atmosphere with argon, potassium acetate (1.44 g), bis(pinacolato)diboron (2.43 g), and a [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (300 mg) were added to a 40-mL yl sulfoxide solution ofthe compound (4.00 g) produced in Reference Example 10, and the mixture was stirred at 90°C for 4 h. After diluting the reaction mixture with ethyl acetate, water was added, and the e was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting e was purified by silica gel column chromatography (Yamazen Autopurification ) to obtain the title compound (3.54 g) having the following physical pr0perty values.
TLC: Rf 0.37 (hexanezethyl acetate = 2:1); 1H—NMR ): 5 1.01, 1.20-1.29, 1.31, 1.63-1.77, 1.84, 2.18-2.27, 2.33—2.42, 2.53- 2.60, .34, 3.45-3.60, 4.00-4.10, 4.25-4.37, 6.78, 7.18, 7.28, 7.52, 8.68, 9.37.
Exam 1e 9: 4- cyclopropan l-2'-yl |carbony1 iamino )phenyl Ibutanoic acid [Chem 9 1] NC NH While replacing the atmosphere with argon, 2-bromopyridine (36 trL), cesium carbonate (120 mg), and a [1,1'—bis(diphenylphosphino)ferrocene]palladium(II) ride dichloromethane complex (7.5 mg) were added to a solution ofthe compound (100 mg) produced in nce Example 17 in 1,2-dimethoxyethane (0.3 mL) and water (0.3 mL), and the mixture was stirred at 95°C for 17 h. The reaction mixture was extracted with ethyl acetate, and the resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was d by silica gel column chromatography (Yamazen AutOpurification Device) to obtain ethyl 4-[4-cyano({[(2'R,4S)(2—pyridinyI)-2,3 -dihydrospiro[chromene—4,l '- cyclopropan]-2'—yl]carbony1}amino)phenyl]butanoate, and the same procedures as those of e 1 were med using this compound to obtain the title compound having the following physical property values.
TLC: Rf 0.44 (dichloromethanezmethanol = 9:1); lH-NMR (DMSO-de): 8 1.54-1.66, 1.68-1.88, 2.07-2.29, 2.54-2.76, 4.04-4.17, 4.26- 4.38, 6.89, 7.23-7.33, 7.40, 7.52-7.64, 7.77-7.99, 8.61, 9.90, 12.10.
Example 10 The title compounds having the following physical property values were obtained by performing the same procedures as those of Example 9, except that the 2-brom0pyridine was replaced with a corresponding halogen-containing heterocyclic ring.
Exam Ie 10-1: 4- 4-c ano cyclopropan | -2'-yl nyl kamino zphenyl oic acid TLC: Rf 0.45 (dichloromethanezmethanol = 9:1); 1H-NMR (DMSO-de): 6 1.54-1.83, 2.07-2.28, 2.35-2.77, 4.05-4.22, 4.26-4.42, 6.93, .45, 7.56, 7.88, 7.94, 8.15, 8.84, 9.93, 12.10.
Exam 16 10-2: 4- 4—0 ano l 3-thiazol -2 3-dih dros iro chromene-4 1'- cyclopropanl-2'-y1 nyl [amino [phenyl |butanoic acid [Chem. 92] NC NH TLC: Rf0.81 (ethyl acetatezmethanol = 20:1); lH-NMR (CD013): 8 1.19-1.32, 1.34-1.85, 2.10-2.25, 2.40-2.79, 3.61, 4.35, 4.48-4.62, 6.88, 7.15-7.30, 7.35, 7.38-7.47, .77, 7.85, 8.88, 10.00.
Exam le 10-3: 4- 4-c ano 2'R 4S l 3-oxazol -2 3-dih dros iro chromene-4 1'- cyclopropan |-2’-y1 |carbonyl {amino [phenyl |butanoic acid [Chem 93] NCmeowNH '13)\ TLC: Rf0.81 (ethyl acetatezmethanol = 20: 1); 1H—NMR (CDC13): 5 1.18-1.29, 1.53, 1.68—1.86, 2.09-2.33, 2.43-2.87, 3.60, 4.39, 4.52- 4.64, 6.90, 7.15, 7.17, 7.28, 7.67, 7.72, 8.05, 8.92, 9.95.
Exam 18 10-4: 4- 4-c ano 2'R 4S -6— l-meth l-lH-l 2 3-triazol 1 -2 3- dih dros iro ne-4 1'-c 010 ro an -2'— lcarbon 1 amino hen lbutanoic acid [Chem 94] NC NH "fl \ TLC: Rf 0.58 (ethyl ezmethanol = 20:1); lH—NMR(CDC13): 6 1.21-1.32, 1.56, 1.69-1.86, 2.14-2.31, 2.44-2.88, 3.64, 4.15-4.20, 4.34, 4.53, 6.86, 7.13-7.31, 7.63, 7.68, 7.79, 8.92, 10.01.
Exam 1e 10-5: 4- ' ' -2 3-dih dros iro chromene—4 1'- cyclopropan | -2'-y1 Icarbonyl [amino [ghenyl lbutanoic acid [Chem 95] NC/£::1:“\/”\000HNH N I TLC: Rf 0.40 (dichloromethanezmcthanol = 9:1); 1H—NMR (CDC13): 5 .31, 1.61, 1.66-1.90, 2.11-2.32, 2.36-2.82, 3.48-3.71, 4.35, 4.54, 6.98, 7.21, 7.28, 7.36, 7.66, 7.83, 7.80-7.83, 8.87, 9.15, 10.07.
Exam 16 10-6: 4- 4-c ano 2'R 4S 2- azin 1 -2 3-dih dros iro chromene-4 1'- cyclopropan |—2'—11 [carbonyl [amino )phenyl lbutanoic acid TLC: Rf 0.40 (dichloromethanezmethanol = 9:1); lH—NMR (CDC13): 5 1.25, 1.61, 1.68-1.88, 2.08-2.29, 2.40-2.87, 3.49, 4.25-4.41, 4.52, 6.97, 7.21, 7.29, 7.46, 7.61, 8.45, 8.62, 8.85, 8.97, 9.93.
Exam 1e 10-7: 4— 4—c ano dihydrospirol chromene-4,1'-cyclopropan|—2'-yl nyl [amino lphenyl [butanoic acid TLC: Rf0.48 (dichloromethanezmethanol = 9: 1); 1H-NMR (DMSO-ds): 8 1.61, 1.73, 1.80-1.92, .28, 2.38-2.75, 3.34, 4.06-4.20, 4.26-4.44, 6.96, 7.41, 7.57, 7.71, 7.88, 7.97, 8.18-8.36, 9.06, 9.91, 12.08.
[0476] Exam le 10-8: 4- 4-c ano dih dros iro chromene—4 1'-c clo r0 an -2'- 1 carbon 1 amino hen l butanoic acid TLC: Rf0.42 (dichloromethanezmethanol = 9:1); lH—NMR (DMSO-ds): 5 1.51~1.62, 1.63-1.87, 2.07—2.30, 2.53—2.75, 4.03-4.19, 4.25- 4.39, 4.54, 5.29, 6.88, 7.40, 7.52-7.64, 7.70-7.94, 8.53, 9.92, 12.07.
Exam 16 10-9: 4- 41'-c clo r0 an -2'- lcarbon 1 amino hen lbutanoic acid TLC: Rf 0.64 (dichloromethanezmethanol = 9:1); lH—NMR (DMSO-ds): 5 .64, 1.65-1.88, 2.06-2.32, .80, 4.00-4.19, 4.24- 4.40, 6.89, 7.40, 7.51-7.65, 7.71-7.84, 7.88, 8.00-8.05, 8.60, 9.92, 12.08.
Exam 1e 10-10: 4- 2'R 4S dih dros iro chromene—4 1'—c clo r0 an —2'- 1 carbon 1 amino hen 1 butanoic acid TLC: Rf 0.50 (dichloromethanemethanol = 9:1); 1H-NMR ds): 8 1.53-1.64, 1.66—1.79, 1.79—1.91, 2.03-2.30, 2.40-2.79, 3.94, 4.02-4.16, 4.26-4.40, 6.70, 6.89, 7.40, 7.48—7.62, 7.73, 7.80-7.89, 9.89, 12.07.
Exam 1e 10-11: 4- 4-c ano dih dros iro chromene-4 1'-c clo ro an -2'- lcarbon 1 amino hen lbutanoic acid TLC: Rf0.70 (dichloromethanezmethanol = 9:1); 1H—NMR ): 8 1.16-1.30, 1.57, 1.70—1.83, 2.04-2.27, 2.52, .73, 2.74-2.92, 3.54, 3.92, 4.30, 4.48, 6.89, 7.19, 7.24-7.31, 7.38, 7.49, 7.52, 8.18, 8.83, 10.06.
Exam 1e 10-12: 4- 4—c ano—2— 2' 4S 5-meth 1-1 2 4-oxadiazol l -2 3- dihydrospirol chromene-4, l'-cyclopropan |-2'-yl Icarbonyl [amino )phenyl |butanoic acid TLC: Rf0.69 (ethyl acetatezmethanol = 9:1); lH—NMR (CDC13): 5 1.19-1.31, 1.56, 1.70-1.88, 2.12-2.32, 2.42-2.84, 3.54, 4.37, 4.56, 6.92, 7.16—7.3 1, 7.71-7.82, 8.91, 9.84. carbonyl [amino [phenyll ic acid The title compound having the following physical property values was obtained by performing the same ures as those of Reference e 10 —-> Example 1 using the compound produced in Reference Example 9 and the compound produced in Reference Example 3.
TLC: Rf 0.62 (chloroformzmethanol = 9: 1); 'H-NMR ): 5 1.66, 1.77-1.91, 2.08-2.28, 2.34, 2.48, 2.71, 4.16, 4.28, 6.74, 6.82-6.91, 7.06, 7.42, 7.48, 7.91.
Reference Exam 1e 18: 2' -4—oxobu lfluoro hen lcarbamo 1 - 2 3-dih dros iro o ran-4 1'—c 010 ro ane carbox lic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Reference Example 7 -—> nce Example 9 —> Reference Example 10 —> Example 1, except that 5-fluoroiodonitrobenzene was used instead of 3-nitro—4—bromobenzaldehyde. lH—NMR (DMSO-ds): 5 1.12, 1.52—1.77, 2.12, 2.26, 2.51-2.62, 3.87-4.02, 4.12, 4.34, 6.86, 6.92, 7.20, 7.41, 7.47, 7.68, 9.68, 12.68.
Example 12 The title compounds having the following al property values were obtained by performing the same procedures as those of Reference Example 12 —> Example 1 using the compound produced in Reference Example 18 instead of the compound produced in Reference Example 11, using methylamine hydrochloride or a corresponding amine compound.
Exam 1e 12-1: 4- 4—fluoro-2— 2'R 4S meth lcarbamo l -2 3-dih dros iro chromene- 4 l'~c clo ro an -2'- 1 carbon 1 amino hen 1 butanoic acid TLC: Rf0.69 (ethyl acetate:methanol = 19:1); lH—NMR (CD30D): 8 1.62-1.87, .28, 2.32, 2.56-2.78, 2.90, 4.23, 4.34, 6.76- 6.89, 7.20, 7.38—7.51, 7.54.
Exam 1e12-2z4- 4-fluoro-2— dih dros iro chromene-4 1'-c 010 ro an -2'- 1 carbon 1 amino hen l butanoic acid TLC: Rf0.67 (ethyl acetate:methanol = 1921); IH—NMR (DMSO-ds): 8 .79, 2.06-2.22, 2.41-2.61, 3.25, 3.36~3.46, 4.07, 4.31, 6.83, 6.95, 7.19, 7.33, 7.43, 7.63, 8.42, 9.74, 12.06.
Exam 1e 12-3: 4- dih dros iro chromene-4 l‘-c 010 ro an -2’— 1 carbon lamino hen l butanoic acid TLC: Rf 0.64 (ethyl acetatezmethanol = 9:1); IH-NMR (CD30D): 6 1.66-1.86, 2.12-2.37, 2.57-2.70, 3.88, 4.25, 4.37, 6.81-6.92, 7.21, 7.45, 7.58, 7.63, 7.68, 8.00.
Reference Exam 1e 19: Eth 14- 2- 1 ,1'—indene |carbonyl [amino 1cyanophenyl )butanoate The title compound having the ing physical property values was obtained by ming the same procedures as those of Reference Example 1 —> Reference Example 2 —> Reference Example 3 —> nce Example 10, using 6—(benzyloxy)-2,3-dihydro—1H—inden— 1-one instead of 4-chromanone.
[0488] [Chem 96] lH-NMR (CDC13): 8 1.25, .45, 1.68—1.81, 1.82-1.87, 2.32-2.46, 2.57-2.67, 2.86- 3.08, 3.82-3.92, 3.97-4.07, 5.00, 6.46, 6.77, 7.12, 7.17, 7.25—7.31, 7.32-7.43, 8.78, 9.15.
Exam 1e 13: 4— lcarbon 1 amino c ano hen lbutanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Example 1 using the compound produced in Reference Example 19, instead of the nd produced in Reference Example 12.
TLC: Rf0.53 (dichloromethanezmethanol = 10:1); lH-NMR (CDC13): 5 1.36-1.43, 1.66-1.77, 1.79-1.85, 2.31, 2.42—2.73, 2.84-3.09, 5.05, 6.49, 6.81, 7.13-7.21, 7.24-7.30, 7.32-7.47, 8.72, 8.92. inden |yl nyl iamino )phenyl lbutanoic acid % ium/carbon (12 mg) was added to a solution of the compound (40 mg) produced in Example 13 in ethyl acetate (3 mL) and 1,4—dioxane (1 mL). After replacing the atmosphere with hydrogen, the mixture was stirred at room temperature for 9 h. The reaction mixture was filtered using , and the filtrate was concentrated under reduced pressure.
The resulting residue was d by silica gel column chromatography to obtain the title compound (32 mg) having the following physical property values.
TLC: Rf0.40 (dichloromethanezmethanol = 10:1); lH-NMR (CD013): 5 1.36—1.43, 1.65-1.85, 2.32, 2.47-2.55, 2.58-2.76, 2.83-3.08, 6.37, 6.62, 7.06, 7.22, .37, 8.74, 8.92.
Reference Example 20 :Eth l4— 4-c ano carbonyl lamino [phenyl )butanoate The title compound having the ing physical property values was ed by performing the same procedures as those of Example 14 using the compound produced in Reference Example 19, instead of the compound produced in Example 13. 1H-NMR (CDC13): 6 1.24, .43, 1.70—1.87, 2.31-2.49, 2.58-2.67, 2.85-3.07, 3.89- 4.01, 4.04-4.16, 4.49, 6.31, 6.58, 7.04, 7.17, 7.26-7.31, 8.78, 9.18.
Reference Exam 1e 21: Eth l4- yl )methoxy |-2',3 drospirol cyclonrogane— 1 , 1'-indene | yl iamino lphenyl |butanoate Under a stream of nitrogen, cyanomethylenetributylphosphorane (0.06 mL) was dropped into a 0.2-mL toluene solution ofthe compound (30 mg) produced in nce Example 20 and (1-methylpyrazolyl)methanol (9.6 mg), and the mixture was stirred overnight at 100°C. The reaction e was concentrated under reduced pressure. The resulting residue was d by silica gel column chromatography to obtain the title compound (7 mg) having the following physical property values. 1H—NMR(CDC13): 5 1.26, 1.39-1.42, 1.68-1.85, 2.28-2.51, 2.55-2.65, 2.83-3.05, 3.87- 4.01, 4.04-4.18, 4.89, 6.40, 6.72-6.79, 7.06-7.38, 7.41, 7.51, 8.77, 9.13.
Exam le 15: 4- dihydrospiro| cyclogropane-l den|-2~y1 icarbonyl )amino lphenyl }butanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Example 1 using the nd produced in Reference Example 21, instead of the compound produced in nce Example 12.
TLC: Rf 0.26 (dichloromethanemethanol = 20:1); 1H-NMR da): 5 1.45-1.57, 1.66-1.79, 2.13-2.25, 2.26-2.75, 2.84-2.92, 3.81, 4.90, 6.51, 6.77, 7.09, 7.39, 7.47, 7.55, 7.77, 7.96.
Reference Exam 1e 22: Eth l4— 4-c ano-2— oxoethox - 2',3 '-dihydrospiro| cyclopropane- 1 , 1'-indene |carbonyl }amino Lphenyl Ibutanoate Potassium carbonate (33 mg) and tetrabutylammonium iodide (4.4 mg) and subsequently 2-chloro—N-methylacetamide (25.7 mg) were added at room temperature to a 0.5- mLDMF solution ofthe compound (50 mg) produced in Reference Example 20. The reaction mixture was stirred overnight at 50°C. The reaction mixture was diluted with ethyl acetate and, after adding a saturated ammonium chloride aqueous solution and water, extracted with ethyl acetate. The resulting organic layer was washed with water and 20% brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The ing residue was purified by silica gel column chromatography (Yamazen Autopurification Device) to obtain the title compound (51 mg) having the following physical property values.
TLC: Rf 0.26 (hexanezethyl acetate = 4:1); lH—NMR (CDC13): 5 1.19, 1.39—1.44, 1.68-1.84, .89, 2.27-2.70, .08, 3.79- 3.93, 3.95—4.06, 4.07, 4.44, 6.38, 6.55, 6.70, 7.13-7.20, 7.26-7.30, 8.75, 9.07.
Exam le 16: 4- 4-c ano dihydrospirol cyclopropane—l ,1'-inden|-2~yl }carbonyl )amino l [butanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Example 1 using the compound produced in Reference Example 22, instead ofthe compound produced in nce e 12.
TLC: Rf 0.59 (ethyl acetatezmethanol = 9:1); IH—NMR (DMSO-de): 8 1.44-1.51, 1.56, 2.07-2.34, 2.66, 2.87, 6.54, 6.76, 7.12, 7.41, 7.56, 7.92, 8.01, 9.75, 12.12.
Exam 1e 17: 4— 4-c ano ospirol cyclopropane—1,1’-inden|yl [carbonyl)amino lphenyl [butanoic acid The title compound having the following physical prOperty values was obtained by performing the same procedures as those of Reference Example 22 —> Example 1, using 2- chloro-N,N-dimethylacetamide instead of 2-chloro-N-methylacetamide.
TLC: Rf0.54 (ethyl acetatezmethanol = 9: 1); 1H—NMR (DMSO—ds): 8 1.47-1.58, 1.71, 2.08-2.32, 2.33-2.70, 2.82-2.91, 3.00, 4.74, 6.49, 6.70, 7.10, 7.41, 7.57, 7.91, 9.79, 12.16.
Reference Exam 1e 23: Eth 14- 4-c ano—2- 1R 2R -6'- trifluoromethanesulfon 1 0x - 2',3 '-dihydrospiro| cyclopropane-1,1 ne |carbonyl [amino )phenyl |butanoate
[0499] [Chem 97] NCmmNH o\s/,° d’ \CF3 In a nitrogen atmosPhere, triethylamine (0.1 mL) and 1,1,l-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl)methanesulfoneamide (128 mg) were added to a 2-mL dichloromethane solution of the compound (100 mg) produced in Reference Example 20, and the mixture was stirred at room temperature for 3 h. The mixture was further stirred at room temperature for 2 h after adding I,1,1-trifluoro-N—phenyl—N— (trifluoromethylsulfonyl)methanesulfoneamide (128 mg) to the reaction . The reaction liquid was purified by silica gel column chromatography to obtain the title nd (130 mg) having the ing al property values. 1H-NMR(CDC13): 5 1.22-1.29, 1.39-1.44, 1.70-1.83, 1.86-1.91, 2.34-2.51, 2.60—2.67, 2.95-3.14, 3.90-4.02, 4.05-4.16, 6.67, 7.03, 7.19, .31, 8.78, 9.19.
Reference Exam 1e 24: IR 2R 5-0 ano 4-ethox oxobu l hen 1 carbamo l - 2'3'—dih dros iro c clo ro ane—l 1‘-indene -6'-carbox lic acid [Chem 98] NCmamaNH The compound (120 mg) produced in Reference Example 23 was dissolved in DMSO (3 mL) and ultrasonically ted under reduced pressure. 1,3- Bis(diphenylphosphino)propane (dppp; 18 mg), palladium(II) e (10 mg), lithium chloride (92 mg), sodium formate (148 mg), diisopropylethylamine (0.34 mL), and an acetic anhydride (0.19 mL) were added to the reaction liquid. The mixture was stirred at 90°C for 4 h while replacing the atmosphere with carbon monoxide. After adding a 0.1 N hydrochloric acid aqueous solution, the reaction mixture was ted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column tography to obtain the title compound (40 mg) having the following physical property . 1H—NMR(CDC13): 6 1.18, 1.44-1.51, .79, 1.85-1.90, 2.35—2.48, 2.57-2.78, 2.99- 3.17, 3.84-3.91,4.03-4.11,7.18,7.24-7.36, 7.52, 7.89, 8.81, 9.29.
Example 18 The title compounds having the following physical property values were obtained by performing the same procedures as those of Reference Example 12 —> Example 1 using the compound produced in Reference Example 24 instead ofthe compound produced in Reference Example 11, using methylamine hydrochloride or a corresponding amine compound.
Exam 1e 18 4-c ano dih dros iro c clo ro ane—l 1'-inden 1 carbon 1 amino hen oic acid [Chem 99] NCmmNH o N’OHS
[0507] TLC: Rf0.29 oromethanezmethanol = 20:1); IH-NMR (CDC13): 8 1.26-1.31, 1.66-1.78, 1.82-1.87, 2.23-2.30, 2.34-2.48, 2.52-2.71, 2.91-3.03, 3.04, 3.13-3.27, 6.21-6.29, 7.17, 7.19-7.35, 7.70, 8.82, 9.56.
Exam 1e 18-2: 4- 4-0 ano dih dros iro c clo ro ane—l 1'-inden 1 carbon 1 amino hen l butanoic acid [Chem 100] TLC: Rf 0.50 (dichloromethanezmethanol = 20: 1); lH-NMR(CDC13): 8 1.25-1.31, 1.65-1.77, 1.81-1.86, 2.23-2.30, 2.35-2.47, 2.51-2.71, 2.91—3.03, 3.13-3.27, 3.41, 3.54-3.78, 6.62-6.67, 7.17, 7.19-7.30, 7.34, 7.66, 8.82, 9.51.
Exam le 18-3: 4- dih dros iro c 010 ro ane—l 1'-inden 1 carbon lamino hen l butanoic acid
[0512] [Chem 101] NC NH Liv—0H3’,N\ ° [1 TLC: Rf 0.28 (dichloromethanezmethanol = 20:1); 1H-NMR ): 6 1.26-1.34, 1.68-1.78, 1.81-1.88, 2.25-2.31, .72, 2.95-3.06, 3.17-3.23, 3.92, 7.16-7.33, 7.42, 7.52, 7.75, 7.86, 7.99, 8.83, 9.54.
Exam 1e 19: 4- 4-c ano inden ly1 nyl {amino )phenyl lbutanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Reference Example 15 —> Example 1 using the compound produced in nce Example 23, using neboronic acid instead of 4- henylboronic acid.
TLC: Rf 0.30 (dichloromethanemethanol = 20: 1); 1H-NMR (CD30D): 5 1.58-1.66, 1.75-1.90, 2.25-2.45, 2.47-2.55, 2.68-2.79, 3.07- 3.16, 7.15, 7.34-7.56, 7.98, 8.10, 8.52, 8.78.
Reference Exam 1e 25: 2'R 4S -2'- fluoro-2,3-dihydrospiro| 1-benzopygan—4, 1 '-cyclopropane rboxylic acid [05 16] [Chem. 102] The title compound having the following al property values was obtained by performing the same procedures as those of Reference Example 1 —> Reference Example 2—) Reference Example 3 —> Reference Example 4 —> Reference Example 5 —> Reference Example 6 —> Reference Example 10 —> Reference Example 11, using 7-fluorochromanone instead of 4-chromanone. lH—NMR(CDC13): 8 1.13, 1.66-1.78, 1.84—1.90, 2.25-2.35, .47, 2.58-2.67, 3.60- 3.73, .90, 4.10—4.22, 4.35-4.44, 6.60, 7.19, 7.26—7.33, 7.50, 8.71, 9.37.
[0518] Example 20 The title compounds having the following physical property values were obtained by performing the same procedures as those of Reference Example 12 —> Example 1 using the compound produced in Reference Example 25 d ofthe compound produced in Reference Example 11, using methylamine hydrochloride or a corresponding amine compound. [05 l 9] Exam 16 20-1: 4- 4-c ano dih dros iro ne-4 1'-c 010 to an -2'- 1 carbon 1 amino hen l butanoic acid [Chem 103] NCmeowNH O O N TLC: Rf0.74 oromethanezmethanol = 10:1); lH—NMR (CD013): 8 1.18-1.29, 1.50-1.62, 1.70-1.80, 2.05-2.15, 2.20-2.27, 2.44-2.76, 3.03, 3.54-3.60, 4.31-4.40, 4.54-4.59, 6.57, 6.82-6.95, 7.20, 7.24-7.33, 8.06, 8.88, 9.94.
[0522] Exam 1e 20-2: 4- 2-methox eth lcarbamo 1 -2 3- dih dros iro chromene-4 1'-c clo r0 an -2'- 1 carbon 1 amino hen l ic acid [Chem 104] NCmeowNH 0 o Eli/VO\CH3 TLC: Rf0.49 (dichloromethanemethanol = 10:1); IH—NMR (CDC13): 8 1.19-1.26, 1.58-1.64, 1.68—1.84, 2.05-2.29, 2.45-2.77, 3.39, 3.53- 3.64, 3.65-3.72, 4.31-4.43, 4.54-4.62, 6.57, 7.17-7.34, 8.05, 8.88, 9.93.
[0525] Exam 1e 20—3: 4— 4-c ano eth lcarbamo 1 dihydrospiro] chr0mene-4,1'-cyclopropan|-2'-yl |carbonyl}amino)pheny1 |butanoic acid TLC: Rf 0.62 (hexanezethyl acetate = 1:3); IH—NMR (DMSO'dé): 8 1.09, 1.55, .78, 2.02-2.28, 2.47, 2.60-2.71, 3.17-3.33, 4.12, 4.33, 6.73, 7.19, 7.41, 7.56, 7.88, 8.07, 9.89, 12.11.
Exam 1e 20-4: 4- 4-c ano dihxdrospirol chromene-4, l '-cyclopropan |-2'-yl [carbonyl }amino)phenyl |butanoic acid TLC: Rf0.56 (hexanezethyl acetate = 1:2); lH—NMR (DMSO—ds): 8 0.87, 1.42-1.58, 1.62-1.78, 2.04-2.23, 2.42, 2.60-2.69, 3.11- 3.23, 4.12, 4.31, 6.73, 7.18, 7.41, 7.56, 7.88, 8.06, 9.90, 12.11.
Exam le 20-5: 4- 4-c ano —7—fluoro—6— iso r0 lcarbamo 1-2 3- dih dros iro chromene-4 1'-c 010 to an ~2'- 1 carbon 1 amino hen lbutanoic acid
[0528] [Chem 105] NCmm“NH O TLC: Rf0.68 (hexanezethyl acetate = 1:3); 1H—NMR (DMSO-da): 8 1.13, 1.53, 1.63-1.79,.2.02—2.24, 2.46, 2.61-2.69, 3.96-4.18, 4.33, 6.72, 7.14, 7.41, 7.56, 7.80-7.92, 9.89, 12.11.
Exam le 21: 4- 4-c ano 2'R 4S ro—2 3-dih dros iro chromene-4 1'-c clo to an - 2'-xl nyl [amino )phenyl |butanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Reference e 1 —> Reference Example 2 —> Reference Example 3 —> Reference Example 10 —> Example 1 using 6-fluorochromanone d of4-chromanone.
TLC: Rf0.38 (dichloromethanemethanol = 10:1); lH-NMR(CDC13): 6 1.46-1.80, 2.18—2.24, 2.48-2.75, 4.09-4.32, 6.55, 6.75-6.87, 7.21, 7.25-7.34, 8.66, 9.00.
Reference Exam 1e 26: Eth l4- cyclopropane |-2'-carbonyl lamino }cyanophenyl)butanoate Phenylboronic acid (10 mg), potassium carbonate (22 mg), and a [1 ,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane x (9 mg) were added to a l-mL anisole solution ofthe compound (30 mg) produced in Reference Example 10, and the mixture was stirred at 80°C for 3 h in a carbon de atmosphere.
A saturated sodium bicarbonate aqueous solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The ing residue was purified by silica gel column tography (Yamazen Autopurification Device) to obtain the title compound (18 mg) having the following physical property values.
TLC: Rf0.38 (hexanezethyl acetate = 1:1); lH—NMR(CDC13): 5 0.99, 1.61-1.80, 1.87, 2.27—2.36, .44, 2.61, 2.71, 3.43-3.56, 3.66, 3.81, 4.11-4.23, 4.32-4.42, 6.86, 7.19, 7.27, 7.42-7.62, 7.73, 8.73, 9.38.
Exam 1e 22: 4- 2- 2'R 4S -6—benzo 1-2 3-dih dros iro chromene—4 1'-c clo to an yl |carbonyl tamin01—4-cyanophenyl |butanoic acid The title nd having the following physical property values was obtained by performing the same procedures as those of Example 1 using the nd produced in nce Example 26, instead ofthe compound produced in Reference Example 12.
TLC: Rf 0.42 (dichloromethanetmethanol = 9:1); lH-NMR (DMSO-de): 8 1.53—1.64, .78, 2.10-2.30, 2.41-2.75, 3.20-3.49, 4.10- 4.23, 4.33-4.45, 6.94, 7.36-7.45, 7.46-7.59, 7.60-7.73, 7.87, 9.89, 12.09.
Example 23 The title compounds having the following physical property values were obtained by performing the same procedures as those of Reference e 26 —> Example 1, except that the phenylboronic acid was replaced with a corresponding boronic acid.
Exam 1e 23-1: 4- -2 3-dih dros iro chromene- 4,1'—cyclopropan |-2'-y1 learbonyl [amino )phenyl |butanoic acid TLC: Rf0.41 (dichloromethanezmethanol = 9:1); lH—NMR ): 8 1.02-1.38, 1.67-1.83, 2.06-2.38, .78, 4.33-4.45, 4.53-4.67, 6.89, 7.19, 7.25-7.30, 7.87, 7.98, 8.88, 9.85.
[0535] acet l~2 3—dih dros iro chromene-41'-c 010 to an yl |carbonyl [amino [cyanophenyl Ibutanoic acid TLC: Rf 0.40 (dichloromethanezmethanol = 9:1); 1H-N"l\/1R(CDC13): 8 1.20-1.31, 1.70-1.85, 2.05-2.20, 2.23-2.33, 2.44-2.83, 4.33—4.45, 4.53-4.65, 6.85, 7.20, 7.28, 7.70, 8.06, 8.89, 9.83.
Reference Exam 1e 27: Eth l4— 4-c ano 2' 4S methanesulfon 1 -2 3- dih dros iro l-benzo ran-4 1'-c 010 ro ane -2'-carbon 1 amino hen l butanoate In an argon atmosphere, sodium hydroxide (2.3 mg) was added to a 2-mL DMSO solution of L-proline (7 mg), and the mixture was stirred at room temperature for 30 min. To the resulting reaction mixture, the compound (40 mg) ed in Reference Example 10, and the mixture was copper iodide (11 mg), and sodium methanesulfinate (37 mg) were added, stirred at 100°C for 1 h using a ave reactor (Biotage, Ltd). The on e was purified by silica gel column chromatography (Yamazen Autopurification Device) to obtain the title compound (33 mg) having the following physical property values.
TLC: Rf0.58 (hexanezethyl acetate = 1:3); 1H—NMR (CDC13): 8 1.13, 1.66-1.80, 1.91, 2.20-2.45, .64, 2.67, 3.01, 3.45-3.60, 3.73-3.86, 4.11-4.20, 4.40, 6.96, 7.20, 7.30, 7.40, 7.63, 8.71, 9.44.
Exam 1e 24: 4- meth lsulfon l ~2 3-dih dros iro chromene—4 1'- cyclopropanl-2'-yl nyl [amino )phenyl lbutanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Example 1 using the compound ed in nce Example 27, instead of the compound produced in Reference Example 12.
TLC: Rf0.42 (dichloromethanezmethanol = 9:1); 1H-NMR (DMSO-ds): 5 1.53-1.64, 1.72, .87, 2.08-2.29, 2.35-2.74, 3.18, 4.05- 4.20, 4.32-4.44, 7.02, 7.40, 7.42, 7.57, 7.64, 7.87, 9.95, 12.10. 4,1'-cyclopropan |—2'-yl |carbonyl {amino )phenyl lbutanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those ofReference Example 27 —> Example 1, using sodium cyclopropanesulfinate instead of sodium methanesulfinate.
TLC: Rf 0.40 (dichloromethanezmethanol = 9:1); (CDC13): 8 1.00-1.15, 1.20-1.43, 1.60-1.82, 2.09-2.35, 2.3 8-2.60, 2.63-2.75, 3.39, 4.35, 4.57, 6.95, 7.20, 7.29, 7.59, 7.71, 8.90, 9.64.
Reference Exam 1e 28: 2'R 4S enz 10x -2 3-dih dros iro l-benzo ran-41'- ropane arboxylic acid [Chem 106] The title compound having the ing physical property values was obtained by performing the same procedures as those of Reference Example 1 -—> Reference Example 2 —> Reference Example 3, using 7-(benzyloxy)-2,3-dihydro-4H-chromen—4-one instead of 4- chromanone.
TLC: Rf 0.21 (hexanezethyl acetate = 1:1); lH-NMR (CDC13): 8 1.53-1.70, 2.07, 2.20, 4.20-4.09, 4.23-4.33, 5.01, 6.46, 6.52, 6.60, 7.27-7.44.
HPLC retention time: 12.2 min (CHIRALPAK IC 4.6 mm x 250 mm hexanezethyl acetatezformic acid = 97:3: 1).
Reference Exam le 29: Eth 14- 41'-c clo r0 ane -2'-carbon lamino c ano hen lbutanoate [Chem 107] NCmegaNH 0 The title compound having the following physical property values was obtained by performing the same procedures as those of nce Example 10 using the compound produced in Reference Example 28, instead of the compound produced in Reference e 1H—NMR (CDC13): 5 1.13, 1.54-1.61, 1.64-1.81, 2.22, .45, 2.51-2.66, 3.55-3.68, 3.72-3.86, 4.03, 4.16, 4.22432, 4.99, 6.42-6.51, 6.73, 7.18, 7.28, 7.29-7.44, 8.72, 9.28. 1 carbon 1 amino ~4-c ano hen lbutanoic acid
[0546] [Chem. 108] NCmm”NH 0 The title compound having the following physical property values was obtained by performing the same ures as those of Example 1 using the compound produced in Reference Example 29, instead of the nd produced in Reference Example 12.
TLC: Rf 0.42 (dichloromethanezmethanol = 9: 1); 1H—NMR (CDC13): 5 1.58, 1.68-1.84, 2.10—2.20, 2.36, 2.46, 2.50-2.75, 4.03-4.16, 4.20- 4.32, 5.02, 6.48, 6.54, 6.71, 7.20, 7.27-7.45, 8.54, 8.82.
Reference Exam 1e 30: Eth l4- benzo an—41'-c 010 ro ane -2'-carbon lamino hen lbutanoate
[0549] [Chem 109] NH 0 ASCA—2 (trade name, 50% wet, 300 mg) was added to a mixed solution of the compound (650 mg) produced in Reference Example 29 in l (50 mL) and ethyl acetate (10 mL), and the e was stirred at room temperature for 8 h in a hydrogen here.
The reaction mixture was filtered using Celite (trade name), and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Yamazen Autopurification Device) and then washed with utyl methyl ether and hexane to obtain the title compound (368 mg) having the following physical property values.
TLC: Rf 0.28 (hexanezethyl acetate = 1:1); lH-NMR (CDC13): 5 1.16, 1.55-1.62, 1.66-1.80, 2.16-2.25, 2.38-2.47, 2.52-2.66, 3.60- 3.73, 3.76-3.87, .15, 4.22-4.32, 4.63, 6.28-6.37, 6.69, 7.18, 7.28, 8.71, 9.28.
[0551] ropan |-2'—yl learbonyl Earnino )phenyl |butanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Reference Example 23 —> Reference Example 15 —) Example 1 using the compound produced in Reference Example 30 instead of the compound produced in Reference Example 20, using pyridineboronic acid instead of 4- fluorophenylboronic acid.
TLC: Rf 0.39 (dichloromethanezmethanol = 9:1); 1H-NMR (DMSO-ds): 8 1.55-1.63, 1.65-1.80, 2.09-2.18, 2.21, 2.40-2.47, 2.53-2.77, .16, .38, 7.05, 7.15, 7.25, 7.41, 7.43-7.50, 7.57, 7.88, 8.02—8.08, 8.55, 8.85, 9.90, 12.10.
Example 28 The title compounds having the following physical property values were ed by ming the same procedures as those of Reference Example 23 —-> Reference Example 24 —> Reference Example 12 —> Example 1 using the nd produced in Reference Example instead ofthe compound produced in Reference Example 20, using methylamine hloride or 2-methoxyethylamine.
[0553] 4,1'-cyclopropan|—2'—yl |carbonyl [amino [phenyl lbutanoic acid [0554} [Chem 1 10] NcmeowNH 0 0 TLC: Rf0.40 (dichloromethanemethanol = 9:1); IH-NMR (DMSO-de): 8 1.56, 1.63-1.80, 2.02-2.15, 2.20, 2.42, 2.57-2.69, 2.74, 4.01- 4.13, 4.23-4.37, 6.99, 7.24, 7.36, 7.40, 7.56, 7.86, 8.34, 9.89, 12.11.
[0556] Exam 1e 28-2: 4- dihydrospirol chromene-4, 1 '-cyclopropan |-2'-yl [carbonyl [amino Iphenyl Ebutanoic acid [Chem 111] “\/\0’CH3 TLC: Rf0.40 (dichloromethanezmethanol = 9:1); lH—NMR (CDC13): 8 1.63-1.89, 2.00-2.13, 2.25-2.47, 2.48—2.73, 2.78-2.93, 3.24—3.39, 3.51, 3.55—3.65, 3.85—4.06, 6.68, 6.79, 7.06, 7.20, 7.29, 7.98, 8.78, 9.84.
Exam le 29: 4— 2- yl |carbony1 Earnino 1cyanophenyl oic acid The title compound having the following physical property values was obtained by performing the same ures as those of Reference Example 1 —> Reference Example 2 —> Reference Example 3 —> Reference Example 4 ——> Reference Example 6 —> Reference e 10 —> Example I, using 6-(benzyloxy)-3,4-dihydro-2Hbenzopyranone instead of 4-chromanone, using iodoethane instead of iodomethane.
TLC: Rf 0.47 (dichloromethanezmethanol = 9:1); lH—NMR (CDC13): 5 1.46-1.55, 1.62-1.80, 2.12-2.18, 2.43-2.48, 2.51-2.76, 4.18-4.26, 495-5.07, 6.62, 6.75-6.80, 7.18, 7.28, 7.31-7.45, 8.68, 9.14. nce Exam 1e 31: Eth 14- benzopyran-4, 1 '—cyclopropane |-2'-carbony1 lamino Ephenyl )butanoate The title compound having the following al ty values was obtained by performing the same procedures as those of Reference Example 1 —9 Reference Example 2 —-> Reference Example 3 —> Reference Example 4 —> Reference Example 6 —> Reference Example 10 —> Reference Example 30, using zyloxy)-3,4-dihydro-2H-1~benzopyran—4- one instead of 4-chromanone.
TLC: Rf0.66 (hexanezethyl acetate = 1:2); 1H—NMR (CD013): 8 1.16, 1.52—1.58, 1.66—1.83, 2.21, 2.41, .73, 3.65-3.78, 3.84- 3.98, 4.02-4.13, 4.17-4.27, 4.54, 6.33, 6.55, 6.68, 7.19, 7.28, 8.74, 9.38. cyclopropan |-2'-yl [carbonyl [amino [phenyl [butanoic acid The title compound having the following physical property values was obtained by performing the same procedures as those of Example 1, using the compound produced in Reference e 31 instead of the compound produced in Reference Example 12.
TLC: Rf 0.38 oromethanezmethanol = 9:1); 1H—NMR (CD3OD): 8 1.55-1.70, 1.77-1.90, 2.11-2.20, 2.33, 2.40-2.48, 2.67-2.78, 4.04-4.15, 4.17-4.26, 6.28, 6.53, 6.64, 7.41, 7.48, 7.90.
Example 31 The title compounds having the following physical property values were obtained by performing the same procedures as those of Reference Example 21 —> Example 1, using the compound produced in Reference Example 31 instead ofthe compound produced in nce Example 20, using 2-oxazolemethanol or methanol instead of (1 ~methylpyrazol yl)methanol.
Exam 1e 31-1: 4- 4—c ano dihydrospirol chromene-4,1'-cyc102ropan|-2'-yl [carbonyl [amino [phenyl [butanoic acid TLC: Rf 0.45 (dichloromethanezmethanol = 9:1); lH—NMR (CD30D): 5 1.58-1.76, 1.77—1.90, 2.09-2.21, 2.33, 2.47, 2.72, 4.08-4.17, 4.18-4.29, 5.11, 6.53, 6.70, 6.77, 7.21, 7.42, 7.48, 7.92, 7.96. cyclopropane |—2‘-carbony1 [amino [phenyl [butanoic acid TLC: Rf 0.35 (ethyl acetate); IH—NMR d5)8 1.50-1.56, 1.65-1.80, .09, 2.20, 2.35-2.47, 2.55-2.60, .69, 2.70-2.75, 3.69, 3.92-4.04, .26, 6.43, 6.71, 7.40, 7.56, 7.85, 9.86, 12.11. ospirol chromene-4,1'-cyclopropan|—2'-yl [carbonyl {amino )phenyl lbutanoic acid The title compound having the following physical property values was obtained by ming the same procedures as those of Reference Example 21 —) Example 1, using the compound produced in Reference Example 30 instead of the compound produced in Reference Example 20, using 2—oxazolemethanol instead of (1-methy1pyrazolyl)methanol.
TLC: Rf 0.47 (dichloromethanezmethanol = 9:1); lH—NMR (CD013): 8 1.58-1.68, 1.68-1.80, 2.03-2.15, 2.18-2.46, 2.41-2.50, 2.50—2.63, 2.64-2.83, 4.00-4.13, 4.20-4.31, 5.05, 5.17, 6.33, 6.48, 6.63, 7.10, 7.20, 7.28, 7.73, 8.62, 8.91.
Reference Exam le 32: Eth l 2‘R 4S methox cyclopropane|~2'-carboxylate [Chem. 112] EtOZC The same procedures as those of Reference Example 4 were performed using the nd produced in Reference Example 28 instead of the compound produced in Reference Example 3, using iodoethane instead of iodomethane. Palladium hydroxide/carbon (10% wet, 0.2 g) was added to a S-mL ethyl acetate solution of the resulting compound (2.] g), and the mixture was stirred at room temperature for 30 min in a hydrogen atmosphere. The reaction mixture was filtered using Celite (trade name), and then the filtrate was concentrated under d pressure. After adding ium carbonate (1.46 g) to a S-mL DMF solution ofthe ing residue (1.31 g), iodomethane (1.5 g) was dropped, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with a hexane-ethyl acetate mixed solution. The resulting c layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (1.38 g) having the following physical ty .
TLC: Rf 0.69 (hexanezethyl acetate = 1:1); lH—NMR (CDC13): 8 1.25, 1.55-1.60, 2.05, 2.13-2.20, 3.75, .20, 4.23-4.31, 6.38, 6.45, 6.59.
Example 33 The title compounds having the following physical property values were obtained by performing the same procedures as those of Reference Example 5 —> Reference Example 6 -—> Reference Example 10 —> nce e 11 —> Reference Example 12 —) Example 1, using the compound ed in Reference e 32 instead of the compound produced in Reference Example 4, using methylamine hydrochloride or a corresponding amine compound.
Exam 1e 33-1: 4- 4-c ano—2- dih dros iro chromene—4 1'-c clo r0 an -2'- lcarbon 1 amino hen lbutanoic acid
[0571] [Chem 113] NCmm“NH O 0 if” TLC: Rf 0.39 (dichloromethanezmethanol = 9:1); lH—NMR (DMSO-ds): 8 1.42-1.60, 1.65-1.79, 2.00-2.29, 2.32-2.74, 2.77, 3.83, 4.05- 4.17, 4.24-4.38, 6.54, 7.35-7.45, 7.55, 7.89, 7.98, 9.88, 12.12.
Exam 1e 33-2: 4- dih dros iro chromene-4 1'-c clo ro an -2'- 1 carbon 1 amino hen 1 butanoic acid
[0574] [Chem 114] NC NH O TLC: Rf0.39 oromethanezmethanol = 9:1); lH—NMR (DMSO‘d6)Z 6 1.46-1.60, .81, 2.00-2.29, .76, 3.27, 3.3 8-3.48, 3.85, 4.06-4.18, 4.25-4.36, 6.56, 7.40, 7.41, 7.55, 7.89, 8.09, 9.87, 12.10.
Exam 1e 33-3: 4- dihydrospirol chromene—4,1'-cyclopropan|-2'-yl |carbonyl [amino l |butanoic acid TLC: Rf 0.54 (hexanezethyl e = 1:3); 1H—NMR (DMSO-ds): 8 1.09, 1.47-1.58, 1.65—1.78, 2.04-2.23, 2.47, 2.60-2.69, 3.21- 3.30, 3.84, 4.11, 4.30, 6.54, 7.35-7.44, 7.56, 7.89, 8.04, 9.88, 12.11.
Exam 1e 33—4: 4- 4-c ano ~7—methox r0 oSpiro] chromene-4,1'-cyclopropan|—2'—yl [carbonyl [amino [phenyl lbutanoic acid TLC: Rf0.70 e:ethyl acetate = 1:3); lH-NMR (DMSO-de): 8 0.87, 1.41-1.58, 1.63-1.76, 2.00-2.23, 2.43, 2.59-2.70, 3.13- 3.28, 3.84, 4.11, 4.29, 6.55, 7.32-7.42, 7.56, 7.90, 8.02, 9.88, 12.11.
Exam 1e 33-5: 4- dihydrospirol chromene—4,1'—cyclopropan |-2'-y1 Icarbonyl [amino )phenyl lbutanoic acid TLC: Rf 0.68 (hexanezethyl acetate = 1:3); lH—NMR (DMSO-de): 5 1.14, 1.46—1.58, 1.63-1.78, 2.01-2.22, 2.46, 2.58—2.69, 3.84, 3.97—4.16, 4.31, 6.55, 7.34-7.43, 7.56, 7.74, 7.89, 9.87, 12.09.
Exam le 34: 4- dihydrospirol chromene-4,1'-cyclopropan|—2'—yl |carbony1 [amino )phenyl [butanoic acid The title compound having the following physical property values was obtained by performing the same ures as those of Reference Example 5 —> Reference Example 6 —-> Reference Example 10 -—> Reference e 11 —> Reference Example 13 —> Example 1, using the compound produced in Reference Example 32 instead ofthe compound produced in Reference Example 4.
TLC: Rf0.38 (dichloromethanemethanol = 9:1); IH—NMR (CDC13): 8 1.16-1.27, 1.50-1.58, 1.66-1.85, 2.09-2.30, 2.42-2.83, 3.46, 3.85, 4.35, 4.55, 6.48, 7.19, 7.27, 7.68, 8.88, 9.90.
Exam 1e 35: 4- ‘ -2 3—dih dros iro chromene—4 1'- cyclopropan |-2'-y1 |carbonyl {amino )phenyl |butanoic acid Cesium carbonate (129 mg), [(2—dicyclohexylphosphino-2',4',6'-triisopr0pyl—1,1'- biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) chloride (9 mg), and morpholine (34 mg) were added to a l-mL DMF solution of the compound (72 mg) produced in Reference Example 10, and the mixture was stirred at 110°C for l h using a microwave reactor (Biotage, Ltd.). A potassium carbonate aqueous solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Yamazen Autopurification Device) to obtain an ethyl ester (46 mg). The title compound was obtained by performing the same reaction as that of Example 1 using the resulting ethyl ester, instead of the compound produced in Reference Example 12.
TLC: Rf 0.36 (dichloromethanezmethanol = 9:1); 1H-NMR (DMSO-ds): 8 1.45-1.55, 1.62-1.80, 2.00-2.10, 2.16-2.26, .77, 2.89- 3.06, 3.65—3.78, 3.90-4.05, 4.13-4.26, 6.39, 6.67, 6.74, 7.40, 7.56, 7.84, 9.87, 12.08.
Reference Exam le 33: Eth 14- 4-c ano iodo-2H—s iro l-benzofuran-3 1'- cyclopropane |-2'-carbonyl lamino iphenyl oate [Chem. 115] NC NH 0 The title compound having the following al property values was obtained by performing the same procedures as those of Reference e 1 —> nce e 2 —> nce Example 3 —> Reference Example 4 —> Reference Example 5 —> Reference Example 6 —> Reference Example 10, using 3-coumaranone d of 4-chromanone, using iodoethane instead of iodomethane. lH-NMR (CDC13): 5 1.32, 1.57, 1.66-1.82, 2.36-2.70, 2.79, .22, 4.70, 6.60, 7.02, 7.20, .32, 7.38, 8.74, 9.40. -2H—s iro 1-benzofuran-3 1‘- cycloprogan |-2'-yl |carbonyl {amino )phenyl oic acid [Chem 116] NC NH The title compound having the following physical property values was ed by ming the same procedures as those of Reference Example 15 —> Example 1 using the compound produced in nce Example 33 instead ofthe compound produced in Reference Example 10, using pyridineboronic acid instead of 4-fluorophenylboronic acid.
TLC: Rf 0.42 (dichloromethanezmethanol = 9:1); 1H—NMR (CDC13): 8 1.06, 1.62-1.92, 2.58, 2.78, 2.94, 4.85, 6.47, 6.87, 7.01-7.40, 8.41, 8.61, 8.79, 9.75. [05 87] Example 37 The title compounds having the following physical property values were obtained by performing the same procedures as those of Reference Example 11 —> Reference Example 12 —> Example 1, using the compound produced in Reference Example 33 instead of the compound produced in Reference Example 10, using methylamine hydrochloride or 2- methoxyethylamine. [05 88] Exam 1e 37-1: 4- 4-c ano -2H—s iro 1-benzofuran-3 1'- cyclopropan |-2‘-3[1 Icarbonyl [amino )phenyl lbutanoic acid [Chem 117] NC NH TLC: Rf0.47 (dichloromethanezmethanol = 9:1); lH—NMR (CDC13): 5 1.57, 1.61-1.86, 2.30-2.73, 3.02, 3.22, 4.59, 4.73, 6.18, 6.76, 7.18, 7.20-7.32, 7.59, 8.70, 9.51.
[0591] Exam 1e 37-2: 4- benzofuran-3 ,1 '-cyclopropan|-2'-y1[carbonyUaminolphenyl [butanoic acid [Chem. 118] NC NH /\/O\CH3 o 151 TLC: Rf0.57 (dichloromethanezmethanol = 9:1); lH-NMR (CDC13): 5 1.58, .85, 2.30-2.75, 3.19, 3.41, 3.50-3.73, 4.61, 4.74, 6.47-6.62, 6.77, 7.19, 7.21-7.40, 7.56, 8.72, 9.47.
[0594] Reference Example 34: 6-iodo-3,3-dimethyl-2,3—dihydro- l H—inden-I -one [Chem 119] A sodium nitrite aqueous solution (4.5 mol/L, 4 mL) was dropped into a hydrochloric acid aqueous solution (5 moi/L, 15 mL) of 6-amino-3,3-dimethyl-indanone (2.1 g) under ice-cooling, and then the mixture was stirred for 30 min. After confirming the disappearance of the raw materials, a potassium iodide aqueous solution (4 mol/L, 6 mL) was dropped into the mixture under ice-cooling. The mixture was then stirred at room temperature for l h after adding acetonitrile (20 mL). A saturated sodium bicarbonate aqueous solution was added to the reaction e under ice-cooling, and then the mixture was extracted with ethyl e.
The resulting organic layer was washed with a saturated sodium thiosulfate aqueous solution, dried over ous sodium sulfate and then concentrated under d pressure. The resulting residue was purified by silica gel column tography to obtain the title compound (2.66 g) having the following physical property values.
TLC: Rf 0.86 (hexanezethyl acetate = 1:1); 1H—NMR (CD013): 8 1.38-1.44, 2.59, 7.25-7.30, 7.90, 8.03.
Reference Exam le 35: Eth 14- 4-c ano IS 2R -6'-iodo-3' 3'-dimeth 1-2' dihydrospirol cyclopropane—l ,1'—indenelcarbonyl lamino Ephenyl [butanoate
[0598] [Chem 120] c0251 NC NH CH3 The title compound having the following physical property values was obtained by ming the same procedures as those of Reference Example 1 —> Reference Example 2 —> Reference Example 3 —> nce e 10, using the compound produced in Reference Example 34 instead of 4-chromanone. 1H—NMR (CD013): 5 1.14-1.35, 1.44, 1.64-1.79, 1.79-1.88, 2.17, 2.28-2.50, 2.50-2.71, 3.83, 4.05, 6.91, 7.11, 7.19, 7.22—7.31, 7.45-7.53, 8.79, 9.28.
Example 3 8 The title compounds having the following physical property values were obtained by performing the same procedures as those of Reference Example 11 —) Reference Example 12 —> e 1, using the compound produced in Reference Example 35 instead ofthe compound produced in Reference Example 10, using methylamine hloride or 2- methoxyethylamine. [060 1] Exam le 38-1: 4- 4-0 ano 2-methox eth lcarbamo 1 -3' 3'-dimeth 1-2' dih dros iro c clo ro ane-l 1'-inden 1 carbon 1 amino hen l butanoic acid [Chem 121] NC NH (:H3 NO\CH3 0 ll
[0603] TLC: Rf 0.64 (ethyl acetatezmethanol = 9:1); 1H-NMR (CDC13): 8 1.28-1.40, 1.72, 1.86, 2.01-2.10, .23, 2.63, 3.16, 3.40, 3.53—3.81, 6.64, 7.17, .31, 7.33-7.44, 7.70, 8.82, 9.51.
Exam 1e 38—2: 4- 4-c ano—2- 3'-dimeth l-6'- meth lcarbamo 1 dih dros iro c clo r0 ane—l 1'-inden lcarbon 1 amino hen lbutanoic acid [Chem. 122] NC NH CH TLC: Rf0.55 (ethyl acetatezmethanol = 9:1); lH—NMR (CDC13): 8 1.29-1.42, 1.63-1.80, 1.83-1.90, .11, 2.11-2.24, 2.32—2.56, 2.57-2.69, 3.04, 3.19, 6.24, 7.11-7.19, 7.21—7.34, 7.72, 8.82, 9.57.
Exam le 39: 4- eth 1-6'- 3- idin l dih dros iro c 010 ro ane-l 1'-inden —2- lcarbon 1 amino hen lbutanoic acid [Chem. 123] NC NH CH3 The title compound having the following physical property values was obtained by performing the same procedures as those of Reference Example 15 —> e 1 using the compound produced in Reference Example 35 instead ofthe compound produced in Reference Example 10, using pyridineboronic acid instead of4-fluorophenylboronic acid.
TLC: Rf 0.62 (ethyl acetatezmethanol = 9:1); lH-NMR (CDC13): 5 0.59, .43, 1.55-1.69, 1.79, 2.18-2.38, 2.52-2.64, 2.64-2.91, 6.53, 7.16-7.35, 7.54, 8.39-8.50, 8.75-8.84, 9.35.
[0610] Pharmacological Examples: Pharmacological Example 1: EP4 Antagonistic Activifl Measurement Experiment Using noid Receptor Subtype-Expressing Cells CHO cells expressing rat EP4 receptor es were prepared according to the methods ofNishigaki et a1. (Non—Patent Document 4) and used for experiment. Cultured subconfluent cells were detached and suspended in an assay medium (MEM containing 1 mmol/L IBMX, 1% HSA) in a concentration of 1 x 106 cells/mL. To start the reaction, PGEz was added to the cell suspension (25 uL) in a final concentration of 10 , either alone or as a 25-pL PGEz solution containing a test compound. After 30 minutes ofreaction at room temperature, the amount ofcAMP in the cells was quantified according to the method in the descriptions of the CAMP assay kit (CISBIO).
The antagonistic effect (ICso value) of the test compound was calculated as a value that ents an inhibition rate against a reaction with PGEz alone at 10 nM, a concentration that produces a submaximal cAMP producing effect.
[0612] As a , the compounds used for the present invention were shown to have strong EP4 receptor antagonistic activity. For example, the IC50 values of some of the compounds used for the present invention were as shown in Table 1 below. The EP4 receptor antagonistic ty of Example 8-128 of Patent Document 2 was very weak, 2,800 nM.
[0613] [Table 1] EP4 antagonistic EP4 antagonistic EP4 antagonistic Example activity activity 1050, 11M) i W7 7 ,, (__50a 11M) ___—_- ___—_—3.0 ___—_—2-5 I 3 3 0 2 7 ___—_— ___-— ___—__! ___—_— ___—_1“ ___-“1— ___—_—1 ___—_—___—_- ___—_- The ing test was conducted using 4-[4-cyano({[(2'R,4S) opylcarbamoyl)-2,3-dihydrospiro[chromene-4,l'-cyclopropan]-2'— yl]carbonyl}amino)phenyl]butanoic acid (the compound of Example 2-13) as an EP4 receptor antagonist represented by formula (I). [06 1 5] Pharmacological Example 2-1: Effect of Combination Therapy with Compound of Example 2- 13 and Anti-Mouse PD-l dy in Allografl Model ofMouse Colorectal Cancer Cell Line The effect ofthe combination therapy with the compound of Example 2-13 and an anti-mouse PD-l antibody was evaluated in an allografi model of a mouse colorectal cancer cell line, MC38 (Cancer Res. (1975), 35(9), p2434-9). The MC38 cells were ed in a DMEM medium containing 10 vol% FBS, 100 units/mL penicillin, and 100 ug/mL streptomycin in a C02 incubator. On the day of lantation, the culture supernatant was removed, and then the MC38 cells were washed with PBS and collected. The collected MC38 cells were suspended in PBS and used as transplant cells. Under anesthesia, 200,000 transplant cells were subcutaneously transplanted into the right lateral abdominal regions of female C57BL/6 mice. On day 7 afier the lantation, the mice were divided into four groups of a vehicle group, an Example 2-13 compound-single therapy group, an anti—mouse PD-l antibody-single therapy group, and a combination therapy group (the compound of e 2-13 and the anti-mouse PD-l antibody), each containing 10 individuals. The compound of Example 2-13 was edly orally administered to the mice of the Example 2— 13 nd-single therapy group and the ation therapy group at 3 mg/kg, once on day 7 after the transplantation and twice a day from day 8 after the transplantation to day 28 afier the transplantation. The anti-mouse PD-l antibody was intraperitoneally administered to the mice ofthe anti-mouse PD-l antibody-single therapy group and the combination therapy group at a dose of 20 mg/kg on day 7 after the tranSplantation and at a dose of 10 mg/kg on day 13 and day 19 after the transplantation. Distilled water was repeatedly orally administered to the mice of the vehicle group and the ouse PD-l antibody group for the same period as that of the compound of Example 2-13. PBS was intraperitoneally administered to the mice of the e group and the Example 2-13 compound group at the same timings as those of the anti-mouse PD-l antibody. The tumor volumes (mm3) were calculated by the following equation from the tumor lengths along the minor axis and the major axis which were measured using a digital caliper.
[Math 1] Tumor Volume = [(Minor Axis)2 x Major Axis]/2 The changes in the tumor volumes of the groups with time are shown in FIG. I. The results of the cases in which the tumor disappeared are shown in Table 2.
[Table 2] Cases of Disappearance of Tumor/Cases Combination Therapy with Compound of Example 2—] 3 8/10 and Anti-Mouse PD—lAntibody [06 1 8] The above s show that the compound of Example 2-13 inhibited the tumor growth alone and further strongly inhibited the tumor growth when used in combination with the anti—mouse PD-I antibody.
Pharmacological Example 2-2: Effect of Combination Therapy with Compound of Example 2- 2 and Anti-Mouse PD-l Antibody in afi Model of Mouse ctal Cancer Cell Line The effect of the combination therapy with the compound of Example 2—2 and an anti- mouse PD—l antibody was evaluated in an allograft model of a mouse ctal cancer cell line, MC38 (Cancer Res. (1975), 35(9), p2434-9). The MC38 cells were cultured in a DMEM medium ning 10 vol% FBS, 100 units/mL penicillin, and 100 ug/mL streptomycin in a C02 incubator. On the day of transplantation, the culture supernatant was removed, and then the MC38 cells were washed with PBS and collected. The collected MC38 cells were suspended in PBS and used as lant cells. Under anesthesia, 1,000,000 tranSplant cells were subcutaneously transplanted into the right lateral abdominal regions of female C57BL/6 mice. On day 8 alter the transplantation, the mice were divided into four groups of a vehicle group, an Example 2-2 compound-single therapy group, an anti- mouse PD-l antibody-single therapy group, and a combination therapy group (the nd of Example 2-2 and the anti-mouse PD-l antibody), each containing 10 individuals. The compound of Example 2-2 was repeatedly orally administered to the mice of the Example 2-2 compound-single therapy group and the ation y group at 3 mg/kg twice a day from day 8 after the transplantation to day 24 after the transplantation. The anti-mouse PD-l antibody was intraperitoneally administered to the mice of the ouse PD-l antibody- single therapy group and the combination therapy group at a dose of 20 mg/kg on day 8 after the transplantation and at a dose of 10 mg/kg on day 14 and day 20 afier the transplantation.
Distilled water was repeatedly orally administered to the mice of the vehicle group and the anti-mouse PD-l antibody group for the same period as that ofthe compound of Example 2-2.
PBS was intraperitoneally administered to the mice of the e group and the Example 2-2 compound group at the same timings as those ofthe anti-mouse PD-l antibody. The tumor s (mm3) were calculated by the following equation from the tumor lengths along the minor axis and the major axis which were measured using a digital caliper.
[Math. 2] Tumor Volume 2 [(Minor Axis)2 x Major Axis]/2 The changes in the tumor volumes of the groups with time are shown in The results show that the compound of Example 2—2 inhibited the tumor growth alone and further strongly ted the tumor growth when used in ation with the anti-mouse PD-l antibody.
Pharmacological Example 3: Effect of Combination Therapy with Compound of Example 2- 13 and ouse CTLA-4 Antibody in Allograft Model ofMouse Colorectal Cancer Cell Line MC38 The effect ofthe combination therapy with the compound of e 2-13 and an anti-mouse CTLA—4 antibody was evaluated in an allograft model of a mouse ctal cancer cell line, MC38. The MC38 cells were cultured using a DMEM medium containing 10 vol% PBS, 2 mmol/L Glutamax, 100 units/mL llin, and 100 ug/mL streptomycin in a C02 incubator. On the day of transplantation, the culture supernatant was removed, and then the MC38 cells were washed with PBS and collected. The collected MC38 cells were suspended in PBS and used as transplant cells. Under anesthesia, 1,000,000 transplant cells were subcutaneously transplanted into the right lateral abdominal regions of female C57BL/6 mice. On day 7 after the transplantation, the mice were divided into four groups of a vehicle group, an Example 2-13 compound-single therapy group, an anti-mouse CTLA-4 antibody- single therapy group, and a combination therapy group (the compound of e 2-13 and the anti-mouse CTLA—4 antibody), each containing 15 individuals. The compound of Example 2-13 was repeatedly orally administered to the mice ofthe Example 2-13 compound- single therapy group and the combination therapy group at 5 mg/kg twice a day from day 7 after the transplantation to day 28 after the transplantation. The anti-mouse CTLA-4 antibody was intraperitoneally administered to the mice of the anti-mouse CTLA-4 dy- single therapy group and the combination therapy group at a dose of 10 mg/kg on day 7, day , day 14, and day 17 after the transplantation. led water was repeatedly orally administered to the mice ofthe vehicle group and the anti-mouse CTLA-4 antibody group for the same period as that of the compound of Example 2—13. Amouse IgGl antibody was intraperitoneally administered to the mice of the vehicle group at the same timings as those of the anti-CTLA—4 antibody. The tumor volumes (mm3) were calculated by the following on from the tumor s along the minor axis and the major axis and the tumor height which were measured using a digital caliper.
[Math 3] Tumor Volume = Minor Axis x Major Axis x Height x 0.52 The changes in the tumor volumes of the groups with time are shown in The results show that the compound of Example 2-13 inhibited the tumor growth alone and further strongly inhibited the tumor growth when used in combination with the anti-mouse CTLA-4 antibody. cological Example 4: Effect of Combination Therapy with nd of Example 2- 13 and Anti-Mouse PD-l Antibody in Allograft Model ofMouse Fibrosarcoma Cell Line The effect ofthe combination therapy with the compound of Example 2-13 and anti-mouse PD—l antibody was evaluated in an allografi model of a mouse fibrosarcoma cell line, SalN (Cancer Res. (2012), 72(4), p917-27). The SalN cells were cultured using a DMEM medium containing 10 vol% PBS, 2 mmol/L Glutamax, 100 mL penicillin, and 100 ug/mL streptomycin in a C02 tor. On the day of transplantation, the culture supernatant was removed, and then the SalN cells were washed with PBS and collected. The ted SalN cells were suspended in PBS and used as transplant cells. Under anesthesia, 2,000,000 transplant cells were subcutaneously transplanted into the right lateral abdominal regions of female All mice. On day 7 after the transplantation, the mice were divided into four groups of a vehicle group, an Example 2-13 compound-single therapy group, an anti- mouse PD-l antibody-single therapy group, and a combination therapy group (the compound ofExample 2-13 and the anti-mouse PD-I antibody), each containing 15 individuals. The compound ofExample 2-13 was edly orally administered to the mice of the Example 2- 13 compound-single therapy group and the combination therapy group at 5 mg/kg twice a day from day 7 after the lantation to day 21 after the transplantation. The anti-mouse PD-l antibody was intraperitoneally administered to the mice of the anti-mouse PD-l antibody- single therapy group and the combination therapy group at a dose of 3 mg/kg on day 7, day 10, day 14, and day 17 after the transplantation. Distilled water was repeatedly orally administered to the mice of the vehicle group and the ouse PD—l antibody-single therapy group for the same period as that of the compound of Example 2-13. A mouse IgGl antibody was intraperitoneally administered to the mice ofthe vehicle group and the e 2-13 compound-single therapy group at the same s as those of the anti-mouse PD-l antibody. The tumor volumes (mm3) were calculated by the following equation from the tumor lengths along the minor axis and the major axis and the tumor height which were measured using a l caliper.
[Math. 4] Tumor Volume = Minor Axis × Major Axis × Height × 0.52 The changes in the tumor volumes of the groups with time are shown in As a result, the compound of Example 2-13 inhibited the tumor growth alone and further strongly inhibited the tumor growth when used in combination with the anti-mouse PD-1 antibody.
Pharmacological e 5: Effect of Combination Therapy with Compound of Example 2- 13 and Anti-Mouse PD-1 Antibody in Allograft Model of Mouse Colorectal Cancer Cell Line The effect of the combination therapy with the compound of Example 2-13 and an anti-mouse PD-1 antibody was evaluated in an allograft model of a mouse colorectal cancer cell line, CT26 (Cancer Res. (2013), 73(12), p3591-603). The CT26 cells were cultured using a RPMI medium containing 10 vol% FBS, 2 mmol/L Glutamax, 100 mL penicillin, and 100 µg/mL omycin in a CO2 incubator. On the day of lantation, the culture supernatant was removed, and then the CT26 cells were washed with PBS and collected. The collected CT26 cells were suspended in PBS and used as transplant cells. Under anesthesia, 1,000,000 transplant cells were subcutaneously lanted into the right lateral abdominal s of female BALB/c mice. On day 7 after the transplantation, the mice were divided into four groups of a vehicle group, an Example 2-13 compound-single therapy group, an anti- mouse PD-1 antibody-single therapy group, and a combination therapy group (the compound of Example 2-13 and the anti-mouse PD-1 antibody), each containing 15 to 18 individuals.
The compound of Example 2-13 was repeatedly orally administered to the mice of the Example 2-13 compound-single therapy group and the combination therapy group at 5 mg/kg twice a day from day 7 after the transplantation to day 21 after the transplantation. The anti- mouse PD-1 dy was intraperitoneally administered to the mice of the ouse PD-1 antibody-single therapy group and the combination therapy group at a dose of 3 mg/kg on day 7, day 10, day 14, and day 17 after the transplantation. led water was repeatedly orally administered to the mice of the vehicle group and the anti-mouse PD-1 antibody-single therapy group for the same period as that of the compound of Example 2-13. A mouse IgG1 dy was intraperitoneally administered to the mice of the vehicle group and the Example 2-13 compound-single y group at the same timings as those of the anti-mouse PD-1 antibody. The tumor volumes (mm3) were calculated by the following equation from the tumor lengths along the minor axis and the major axis and the tumor height which were measured using a digital caliper.
[Math. 5] Tumor Volume = Minor Axis × Major Axis × Height × 0.52 The changes in the tumor volumes of the groups with time are shown in
[0627] As a result, the compound of Example 2-13 inhibited the tumor growth alone and further strongly inhibited the tumor growth when used in ation with the anti-mouse PD-1 antibody.
[0628] Particular features of the present disclosure are set out in the following numbered paragraphs: [Paragraph 1] A medicament comprising a combination of a compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor, [Chem. 1] (wherein R1 represents COOR8, tetrazole, SO3H, SO2NH2, SO2NHR8-1, CONHSO2R8- 1, SO 8-1, or hydroxamic acid, 2NHCOR wherein R8 represents a hydrogen atom, C1-4 alkyl, or , and R8-1 represents C1-4 alkyl, C1-4 haloalkyl, a C3-10 carbon ring, or a three- to tenmembered cyclic ring, wherein the C3-10 carbon ring and the three- to ten-membered cyclic ring each may be substituted with C1-4 alkyl, C1-4 kyl, C1-4 alkoxy, - O(C1-4 haloalkyl), C1-4 alkylthio, -S(C1-4 haloalkyl), halogen, or e (here and below, "- CN"), L1 represents C1-5 alkylene, C2-5 alkenylene, or C2-5 alkynylene, R2 represents halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C2-4 alkenyl, C2-4 alkynyl, -O(C1-4 haloalkyl), -S(C1-4 haloalkyl), -C(O)(C1-4 alkyl), -SO 2(C1-4 alkyl), - CONH(C1-4 alkyl), 1-4 alkyl)2, )(C1-4 alkyl), -N(C1-4 alkyl)C(O)(C1-4 alkyl), -NHSO2(C1-4 alkyl), -N(C1-4 alkyl)SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1- 4 alkyl)2, 17, nitro, nitrile, a hydroxyl group, aldehyde (here and below, formyl), or carboxyl, wherein the C1-4 alkyl groups each may be substituted with n, and the (C1-4 alkyl)2 in R2 represents two independent C1-4 alkyl groups which may be the same or different, X1 represents CR6 or a nitrogen atom, wherein R6 represents a hydrogen atom or R2, X2 represents CR7 or a nitrogen atom, wherein R7 represents a hydrogen atom, R2, or - L3-R9, wherein L3 represents methylene, an oxygen atom, or a sulfur atom which may be oxidized, and R9 represents a four- to ten-membered heterocyclic ring which may be substituted with a tuent ed from the group consisting of halogen, C1-4 alkyl, and C1-4 haloalkyl, L2 represents -CH2CH2-, -CH=CH-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2S(O)-, - S(O)CH2-, -CH2SO2-, -SO2CH2-, -CH2NH-, -NHCH2-, -NHCO-, , -NHSO2-, or - SO2NH-, R3 represents C1-4 alkyl or halogen, R4 represents halogen, C1-4 alkyl, or C1-4 haloalkyl, X3 represents methylene, an oxygen atom, a sulfur atom which may be oxidized, or NR10, wherein R10 represents C1-4 alkyl, C1-4 alkyl), -C(O)O(C1-4 alkyl), or 1- 4 alkyl), wherein the C1-4 alkyl groups each may be substituted with halogen, the ring represents a benzene ring or a five- or six-membered monocyclic aromatic heterocyclic ring, [Chem. 2] represents a single bond or a double bond, R5 represents (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5) -CONHR11, (6) - C(O)R12, (7) -OR14, (8) -S(O)tR15, (9) -CH2R16, (10) -NR17R17, (11) -NHCOR11, (12) a C4-10 carbon ring, or (13) a four- to ten-membered cyclic ring, wherein the C4-10 carbon ring or the four- to ten-membered heterocyclic ring may be substituted with one to three R18, n, when a plurality of R18 exists, the plurality of R18 each independently may be the same or different, R11 represents C1-6 alkyl, C3-6 cycloalkyl, phenyl, or a four- to six-membered heterocyclic ring and may be substituted with one to three R13 , wherein, when a ity of R13 exists, the plurality of R13 each independently may be the same or ent, and R13 represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, a hydroxyl group, - NR 20 R21 , benzene, or a four- to six-membered heterocyclic ring, wherein R20 and R21 each independently represent a hydrogen atom or C1-4 alkyl, R12 ents C1-6 alkyl, C3-6 cycloalkyl, benzene, or a four- to six-membered cyclic ring, wherein the C3-6 cycloalkyl, the benzene, and the four- to six-membered heterocyclic ring each independently may be substituted with halogen, C1-4 alkyl, or C1-4 alkoxy, R14 represents a en atom, C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl, wherein the C1-6 alkyl may be substituted with one to three R19 , wherein, when a plurality of R19 exists, the ity of R19 each independently may be the same or different, and R19 represents C1-4 alkoxy, -CONH(C1-4 alkyl), -CON(C1-4 alkyl)2, or a five- or six- membered monocyclic ic heterocyclic ring which may be substituted with a substituent selected from the group consisting of C1-4 alkyl and C1-4 haloalkyl, wherein the (C1-4 alkyl)2 in R19 represents two independent C1-4 alkyl groups which may be the same or different, R15 represents C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl, R16 represents a hydroxyl group or C1-4 alkoxy, each R17 independently ents a hydrogen atom, C1-6 alkyl, or C3-6 cycloalkyl, R18 represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxo, nitrile, a hydroxyl group, hydroxymethyl, 1-methylhydroxyethyl, (C1-4 alkyl)SO2-, a four- to six- membered cyclic ring, (C1-4 alkyl)NH-, or (C1-4 alkyl)2N-, wherein the (C1-4 alkyl)2 in R18 represents two ndent C1-4 alkyl groups which may be the same or different, m represents an integer of 1 to 4, n represents an integer of 0 to 4, p represents an integer of 0 to 2, q represents an integer of 0 to 6, r represents an integer of 0 to 6, s represents an integer of 0 to 4, t represents an integer of 0 to 2, and R2, R3, R4, and R5 each independently may be the same or different when p, q, r, and s are each an integer of 2 or more.) [Paragraph 2] The medicament ing to paragraph 1, wherein the compound represented by formula (I) is a compound represented by formula (I-1), [Chem. 3] (wherein na represents an integer of 0 or 1, qa represents an r of 0 to 3, ra represents an integer of 0 to 4, X3a represents methylene or an oxygen atom, and the other symbols have the same meanings as the symbols defined in paragraph 1.) [Paragraph 3] The medicament according to paragraph 1 or paragraph 2, wherein s is an integer of 1 to 4, and at least one R5 is 11.
[Paragraph 4] The ment according to any one of paragraph 1 to paragraph 3, wherein L 2 is - NHCO- or -CONH-.
[Paragraph 5] The medicament ing to any one of paragraph 1 to paragraph 4, wherein the compound represented by formula (I) is a compound represented by formula (I-2), [Chem. 4] (wherein R2a represents halogen, R6a represents a hydrogen atom or halogen, and the other symbols have the same meanings as the symbols defined in paragraph 1 and paragraph [Paragraph 6] The ment according to paragraph 1, wherein the compound represented by formula (I) is (1) 4-[4-cyano({[(2'R,4S)(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4-{4-cyano[({(2'R,4S)[(cyclopropylmethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (3) 4-{4-cyano[({(2'R,4S)[(2-methoxyethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (4) 4-{4-cyano[({(2'R,4S)[(2-methylpropanyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (5) 4-[4-cyano({[(2'R,4S){[(2S)methoxypropanyl]carbamoyl}-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (6) 4-{4-cyano[({(2'R,4S)[(1-methyl-1H-pyrazolyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (7) 4-[4-cyano({[(2'R,4S)(cyclopropylcarbamoyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano({[(2'R,4S)(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (9) 4-[4-cyano({[(2'R,4S)(cyclopentylcarbamoyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) ({(2'R,4S)[(2S)butanylcarbamoyl]-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl}carbonyl)amino]cyanophenyl}butanoic acid, (11) 4-{4-cyano[({(2'R,4S)[(transhydroxycyclohexyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-{4-cyano[({(2'R,4S)[(cishydroxycyclohexyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (13) 4-[4-cyano({[(2'R,4S)(2-pyridinylcarbamoyl)-2,3-dihydrospiro[chromene- yclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (14) 4-[4-cyano({[(2'R,4S)(3-pyridazinylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (15) 4-[4-cyano({[(2'R,4S)(cyclobutylcarbamoyl)-2,3-dihydrospiro[chromene- yclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano({[(2'R,4S){[1-(2-methylpropanyl)-1H-pyrazol yl]carbamoyl}-2,3-dihydrospiro[chromene-4,1'-cyclopropan]-2'- yl]carbonyl}amino)phenyl]butanoic acid, (17) 4-[4-cyano({[(2'R,4S)(tetrahydro-2H-pyranylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) 4-[4-cyano({[(2'R,4S)(propylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (19) 4-{4-cyano[({(2'R,4S)[(2-ethoxyethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (20) 4-[4-cyano({[(2'R,4S)(ethylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (21) 4-[4-cyano({[(1R,2R)-6'-(methylcarbamoyl)-2',3'-dihydrospiro[cyclopropane- 1,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid, (22) 4-{4-cyano[({(1R,2R)-6'-[(2-methoxyethyl)carbamoyl]-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl}carbonyl)amino]phenyl}butanoic acid, (23) 4-{4-cyano[({(1R,2R)-6'-[(1-methyl-1H-pyrazolyl)carbamoyl]-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl}carbonyl)amino]phenyl}butanoic acid, (24) 4-[4-cyano({[(2'R,4S)fluoro(methylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (25) 4-{4-cyano[({(2'R,4S)fluoro[(2-methoxyethyl)carbamoyl]-2,3- ospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (26) 4-[4-cyano({[(2'R,4S)fluoro(isopropylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (27) yano({[(2'R,4S)(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (28) 4-{4-cyano[({(2'R,4S)[(2-methoxyethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (29) 4-[4-cyano({[(2'R,4S)methoxy(methylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (30) 4-{4-cyano[({(2'R,4S)methoxy[(2-methoxyethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (31) 4-[4-cyano({[(2'R,3S)(methylcarbamoyl)-2H-spiro[1-benzofuran-3,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (32) 4-{4-cyano[({(2'R,3S)[(2-methoxyethyl)carbamoyl]-2H-spiro[1- benzofuran-3,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (33) 4-[4-cyano({[(1S,2R)-6'-[(2-methoxyethyl)carbamoyl]-3',3'-dimethyl-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid, or (34) 4-[4-cyano({[(1S,2R)-3',3'-dimethyl-6'-(methylcarbamoyl)-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid.
[Paragraph 7] The medicament according to paragraph 1 or paragraph 2, wherein s is an integer of 1 to 4, and at least one R5 is a C4-10 carbon ring which may be substituted with one to three R18 or a four- to ten-membered heterocyclic ring which may be tuted with one to three R18, wherein, when a plurality of R18 exists, the plurality of R18 each independently may be the same or different. raph 8] The medicament according to paragraph 7, wherein L2 is -NHCO- or .
[Paragraph 9] The medicament according to any one of paragraph 1, paragraph 2, aph 7, and paragraph 8, wherein the compound ented by a (I) is a compound represented by formula (I-3), [Chem. 5] (wherein R5a is a C4-10 carbon ring which may be substituted with one to three R18 or a four- to ten-membered heterocyclic ring which may be substituted with one to three R18, wherein, when a plurality of R18 exists, the plurality of R18 each independently may be the same or different, and the other symbols have the same meanings as the symbols defined in paragraph 1, paragraph 2, and paragraph 5.) [Paragraph 10] The medicament according to paragraph 1, wherein the compound represented by formula (I) is (1) 4-[4-cyano({[(2'R,4S)(5-methyl-1,3,4-oxadiazolyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4-[4-cyano({[(2'R,4S)(5-cyclopropyl-1,3,4-oxadiazolyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (3) 4-[4-cyano({[(2'R,4S)(3-methyl-1,2,4-oxadiazolyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (4) 4-[4-cyano({[(2'R,4S)(3-pyridinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (5) 4-[4-cyano({[(2'R,4S)(1H-pyrazolyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (6) yano({[(2'R,4S)(1H-pyrazolyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (7) 4-[4-cyano({[(2'R,4S)(4-pyridazinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano({[(2'R,4S)(2-oxopyrrolidinyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (9) 4-[4-cyano({[(2'R,4S)(6-methoxypyridinyl)-2,3-dihydrospiro[chromene- yclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) 4-{4-cyano[({(2'R,4S)[6-(1H-pyrazolyl)pyridinyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (11) 4-{4-cyano[({(2'R,4S)[6-(dimethylamino)pyridinyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-[4-cyano({[(2'R,4S)(6-methylpyridinyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (13) 4-{4-cyano[({(2'R,4S)[6-(methylamino)pyridinyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (14) 4-[4-cyano({[(2'R,4S)(2-pyridinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (15) yano({[(2'R,4S)(1,3-thiazolyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano({[(2'R,4S)(1,3-oxazolyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (17) yano({[(2'R,4S)(1-methyl-1H-1,2,3-triazolyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) 4-[4-cyano({[(2'R,4S)(3-pyridazinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (19) 4-[4-cyano({[(2'R,3S)(3-pyridinyl)-2H-spiro[1-benzofuran-3,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, or (20) 4-[4-cyano({[(1S,2R)-3',3'-dimethyl-6'-(3-pyridinyl)-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid.
[Paragraph 11] A medicament comprising a combination of yano({[(2'R,4S) (isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'-cyclopropan]-2'- yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, an N-oxide f, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor.
[Paragraph 12] A ment comprising a combination of 4-{4-cyano[({(2'R,4S)[(2- methoxyethyl)carbamoyl]-2,3-dihydrospiro[chromene-4,1'-cyclopropan]-2'- yl}carbonyl)amino]phenyl}butanoic acid, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor.
[Paragraph 13] The medicament according to any one of paragraph 1 to paragraph 12, wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint molecule selected from the group ting of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDO1, Arginase I, TIGIT, and CD115.
[Paragraph 14] The medicament according to any one of paragraph 1 to paragraph 13, n the immune checkpoint inhibitor is an D-1 antibody.
[Paragraph 15] The medicament according to any one of paragraph 1 to paragraph 13, wherein the immune checkpoint tor is an anti-CTLA-4 antibody.
[Paragraph 16] The medicament according to any one of paragraph 1 to paragraph 15 for the treatment of cancer.
[Paragraph 17] The medicament according to paragraph 16, wherein the cancer is stomach cancer, colorectal , lung cancer, renal cancer, or malignant melanoma.
[Paragraph 18] A eutic agent against cancer comprising a combination of the compound represented by formula (I) according to paragraph 1, a salt thereof, a solvate thereof, an N- oxide f, or a prodrug of these and an immune checkpoint inhibitor.
[Paragraph 19] A method for treating cancer characterized by administering effective amounts of the compound represented by formula (I) according to paragraph 1, a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug of these and an immune checkpoint inhibitor to a [Paragraph 20] A combination of the compound represented by formula (I) according to paragraph 1, a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug of these and an immune oint inhibitor for the treatment of cancer.
[Paragraph 21] Use of a combination of the compound represented by formula (I) according to paragraph 1, a salt thereof, a e thereof, an N-oxide thereof, or a prodrug of these and an immune checkpoint inhibitor for the production of a therapeutic agent against cancer.
[Paragraph 22] A ment for the treatment of cancer characterized by administering a ation of the compound represented by formula (I) according to paragraph 1, a salt thereof, an N-oxide f, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor.
[Paragraph 23] A therapeutic agent against cancer containing the compound represented by a (I) according to paragraph 1, a salt thereof, an e thereof, a solvate thereof, or a prodrug of these as an active ingredient characterized by being administered in combination with an immune checkpoint inhibitor.
[Paragraph 24] A therapeutic agent against cancer containing an immune oint inhibitor as an active ient characterized by being administered in combination with the compound represented by formula (I) according to aph 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these.
INDUSTRIAL APPLICABILITY
[0629] The combination of the present invention exhibits a strong anti-tumor effect and thus is useful for the treatment of cancer.

Claims (28)

1. A medicament comprising a combination of a compound ented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these and an immune 5 checkpoint inhibitor, wherein R1 represents COOR8, tetrazole, SO3H, SO2NH2, SO2NHR8-1, CONHSO2R8-1, SO2NHCOR8-1, or hydroxamic acid, 10 wherein R8 represents a hydrogen atom, C1-4 alkyl, or benzyl, and R8-1 represents C1-4 alkyl, C1-4 kyl, a C3-10 carbon ring, or a three- to tenmembered heterocyclic ring, wherein the C3-10 carbon ring and the three- to ten-membered heterocyclic ring each may be substituted with C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, - O(C1-4 haloalkyl), C1-4 alkylthio, -S(C1-4 haloalkyl), halogen, or nitrile (here and below, "- 15 CN"), L1 ents C1-5 alkylene, C2-5 alkenylene, or C2-5 alkynylene, R2 represents halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C2-4 alkenyl, C2-4 alkynyl, -O(C1-4 haloalkyl), -S(C1-4 kyl), -C(O)(C1-4 alkyl), -SO 2(C1-4 alkyl), - CONH(C1-4 alkyl), -CON(C1-4 alkyl)2, -NHC(O)(C1-4 alkyl), -N(C1-4 alkyl)C(O)(C1-4 20 alkyl), (C1-4 alkyl), -N(C1-4 alkyl)SO2(C1-4 alkyl), -SO2NH(C1-4 alkyl), -SO2N(C1- 4 alkyl)2, -NR17R17, nitro, e, a yl group, aldehyde (here and below, formyl), or carboxyl, wherein the C1-4 alkyl groups each may be substituted with halogen, and the (C1-4 alkyl)2 in R2 represents two independent C1-4 alkyl groups which may be the same or ent, 25 X1 represents CR6 or a en atom, wherein R6 represents a hydrogen atom or R2, X2 represents CR7 or a nitrogen atom, wherein R7 represents a hydrogen atom, R2, or - L3-R9, wherein L3 represents ene, an oxygen atom, or a sulfur atom which may be oxidized, and R9 represents a four- to ten-membered heterocyclic ring which may be substituted with a substituent ed from the group consisting of halogen, C1-4 alkyl, and C1-4 haloalkyl, L2 represents -CH2CH 2-, -CH=CH-, , -OCH2-, , -SCH2-, -CH2S(O)-, - S(O)CH 2-, -CH2SO 2-, -SO2CH 2-, -CH2NH-, -, , -CONH-, -NHSO2-, or - 5 SO 2NH-, R3 represents C1-4 alkyl or halogen, R4 represents halogen, C1-4 alkyl, or C1-4 haloalkyl, X3 represents methylene, an oxygen atom, a sulfur atom which may be oxidized, or NR 10 , wherein R10 represents C1-4 alkyl, -C(O)(C1-4 alkyl), -C(O)O(C1-4 alkyl), or -SO 2(C1- 10 4 alkyl), n the C1-4 alkyl groups each may be substituted with halogen, the ring represents a benzene ring or a five- or six-membered monocyclic aromatic heterocyclic ring, represents a single bond or a double bond, R5 represents (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5) -CONHR11 , (6) - 15 C(O)R 12 , (7) -OR14 , (8) -S(O)tR15 , (9) -CH2R16 , (10) -NR17 R17 , (11) -NHCOR11 , (12) a C4-10 carbon ring, or (13) a four- to ten-membered heterocyclic ring, wherein the C4-10 carbon ring or the four- to ten-membered cyclic ring may be substituted with one to three R18 , wherein, when a plurality of R18 exists, the ity of R18 each independently may be the same or different, 20 R11 represents C1-6 alkyl, C3-6 cycloalkyl, phenyl, or a four- to six-membered heterocyclic ring and may be substituted with one to three R13 , wherein, when a plurality of R13 exists, the plurality of R13 each independently may be the same or different, and R13 ents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, a hydroxyl group, - NR 20 R21 , benzene, or a four- to six-membered heterocyclic ring, 25 wherein R20 and R21 each independently represent a hydrogen atom or C1-4 alkyl, R12 represents C1-6 alkyl, C3-6 cycloalkyl, benzene, or a four- to six-membered heterocyclic ring, wherein the C3-6 cycloalkyl, the benzene, and the four- to mbered heterocyclic ring each independently may be substituted with halogen, C1-4 alkyl, or C1-4 alkoxy, 30 R14 represents a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, benzene, or benzyl, wherein the C1-6 alkyl may be substituted with one to three R19 , wherein, when a plurality of R19 exists, the plurality of R19 each independently may be the same or different, and R19 represents C1-4 alkoxy, -CONH(C1-4 alkyl), 1-4 alkyl)2, or a five- or sixmembered monocyclic aromatic heterocyclic ring which may be substituted with a substituent selected from the group consisting of C1-4 alkyl and C1-4 kyl, wherein the (C1-4 alkyl)2 in R19 represents two independent C1-4 alkyl groups which 5 may be the same or different, R15 represents C1-6 alkyl, C3-6 cycloalkyl, benzene, or , R16 represents a hydroxyl group or C1-4 alkoxy, each R17 independently represents a hydrogen atom, C1-6 alkyl, or C3-6 cycloalkyl, 10 R18 represents halogen, C1-6 alkyl, C3-6 cycloalkyl, C1-4 alkoxy, oxo, nitrile, a hydroxyl group, hydroxymethyl, 1-methylhydroxyethyl, (C1-4 alkyl)SO2-, a four- to sixmembered heterocyclic ring, (C1-4 alkyl)NH-, or (C1-4 alkyl)2N-, wherein the (C1-4 alkyl)2 in R18 ents two independent C1-4 alkyl groups which may be the same or different, 15 m represents an integer of 1 to 4, n represents an integer of 0 to 4, p ents an integer of 0 to 2, q represents an integer of 0 to 6, r represents an integer of 0 to 6, 20 s represents an integer of 0 to 4, t ents an integer of 0 to 2, and R2, R3, R4, and R5 each ndently may be the same or different when p, q, r, and s are each an integer of 2 or more. 25
2. The medicament according to claim 1, wherein the compound represented by formula (I) is a compound represented by formula (I-1), wherein na represents an integer of 0 or 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, X3a represents ene or an oxygen atom, and the other symbols have the same meanings as the symbols defined in claim 1. 5
3. The medicament ing to claim 1 or 2, wherein s is an integer of 1 to 4, and at least one R5 is -CONHR11.
4. The medicament according to any one of claims 1 to 3, wherein L2 is -NHCO- or - CONH-.
5. The medicament according to any one of claims 1 to 4, wherein the compound represented by formula (I) is a compound represented by formula (I-2), 15 wherein R2a represents halogen, R6a represents a hydrogen atom or n, and the other symbols have the same meanings as the symbols defined in claim 1 and 2.
6. The medicament according to claim 1, n the compound represented by formula (I) is 20 (1) 4-[4-cyano({[(2'R,4S)(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4-{4-cyano[({(2'R,4S)[(cyclopropylmethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (3) 4-{4-cyano[({(2'R,4S)[(2-methoxyethyl)carbamoyl]-2,3- 25 ospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (4) 4-{4-cyano[({(2'R,4S)[(2-methylpropanyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (5) yano({[(2'R,4S){[(2S)methoxypropanyl]carbamoyl}-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (6) 4-{4-cyano[({(2'R,4S)[(1-methyl-1H-pyrazolyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, 5 (7) 4-[4-cyano({[(2'R,4S)(cyclopropylcarbamoyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano({[(2'R,4S)(isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (9) 4-[4-cyano({[(2'R,4S)(cyclopentylcarbamoyl)-2,3-dihydrospiro[chromene- 10 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) 4-{2-[({(2'R,4S)[(2S)butanylcarbamoyl]-2,3-dihydrospiro[chromene-4,1'- ropan]-2'-yl}carbonyl)amino]cyanophenyl}butanoic acid, (11) 4-{4-cyano[({(2'R,4S)[(transhydroxycyclohexyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, 15 (12) 4-{4-cyano[({(2'R,4S)[(cishydroxycyclohexyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (13) 4-[4-cyano({[(2'R,4S)(pyridineyl-carbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (14) 4-[4-cyano({[(2'R,4S)(3-pyridazinylcarbamoyl)-2,3- 20 dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (15) 4-[4-cyano({[(2'R,4S)(cyclobutylcarbamoyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano({[(2'R,4S){[1-(2-methylpropanyl)-1H-pyrazol yl]carbamoyl}-2,3-dihydrospiro[chromene-4,1'-cyclopropan]-2'- 25 yl]carbonyl}amino)phenyl]butanoic acid, (17) 4-[4-cyano({[(2'R,4S)(tetrahydro-2H-pyranylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) 4-[4-cyano({[(2'R,4S)(propylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, 30 (19) 4-{4-cyano[({(2'R,4S)[(2-ethoxyethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (20) yano({[(2'R,4S)(ethylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (21) 4-[4-cyano({[(1R,2R)-6'-(methylcarbamoyl)-2',3'-dihydrospiro[cyclopropane- nden]yl]carbonyl}amino)phenyl]butanoic acid, (22) 4-{4-cyano[({(1R,2R)-6'-[(2-methoxyethyl)carbamoyl]-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl}carbonyl)amino]phenyl}butanoic acid, 5 (23) 4-{4-cyano[({(1R,2R)-6'-[(1-methyl-1H-pyrazolyl)carbamoyl]-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl}carbonyl)amino]phenyl}butanoic acid, (24) 4-[4-cyano({[(2'R,4S)fluoro(methylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (25) 4-{4-cyano[({(2'R,4S)fluoro[(2-methoxyethyl)carbamoyl]-2,3- 10 dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (26) 4-[4-cyano({[(2'R,4S)fluoro(isopropylcarbamoyl)-2,3- ospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (27) 4-[4-cyano({[(2'R,4S)(methylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, 15 (28) 4-{4-cyano[({(2'R,4S)[(2-methoxyethyl)carbamoyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (29) 4-[4-cyano({[(2'R,4S)methoxy(methylcarbamoyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (30) 4-{4-cyano[({(2'R,4S)methoxy[(2-methoxyethyl)carbamoyl]-2,3- 20 ospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (31) 4-[4-cyano({[(2'R,3S)(methylcarbamoyl)-2H-spiro[1-benzofuran-3,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (32) 4-{4-cyano[({(2'R,3S)[(2-methoxyethyl)carbamoyl]-2H-spiro[1- benzofuran-3,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, 25 (33) 4-[4-cyano({[(1S,2R)-6'-[(2-methoxyethyl)carbamoyl]-3',3'-dimethyl-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid, or (34) 4-[4-cyano({[(1S,2R)-3',3'-dimethyl-6'-(methylcarbamoyl)-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid. 30
7. The medicament according to claim 1 or 2, wherein s is an integer of 1 to 4, and at least one R5 is a C4-10 carbon ring which may be substituted with one to three R18 or a four- to ten-membered cyclic ring which may be substituted with one to three R18 , wherein, when a plurality of R18 exists, the plurality of R18 each independently may be the same or different.
8. The medicament according to claim 7, wherein L2 is -NHCO- or .
9. The medicament according to any one of claims 1, 2, 7, and 8, wherein the compound 5 represented by formula (I) is a compound represented by formula (I-3), wherein R5a is a C4-10 carbon ring which may be substituted with one to three R18 or a four- to ten-membered heterocyclic ring which may be tuted with one to three R18, wherein, when a plurality of R18 exists, the plurality of R18 each independently may be the 10 same or different, and the other symbols have the same meanings as the symbols defined in claim 1, 2, and 5.
10. The medicament ing to claim 1, n the compound represented by formula (I) is 15 (1) 4-[4-cyano({[(2'R,4S)(5-methyl-1,3,4-oxadiazolyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (2) 4-[4-cyano({[(2'R,4S)(5-cyclopropyl-1,3,4-oxadiazolyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (3) 4-[4-cyano({[(2'R,4S)(3-methyl-1,2,4-oxadiazolyl)-2,3- 20 dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (4) 4-[4-cyano({[(2'R,4S)(3-pyridinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (5) 4-[4-cyano({[(2'R,4S)(1H-pyrazolyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, 25 (6) 4-[4-cyano({[(2'R,4S)(1H-pyrazolyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (7) 4-[4-cyano({[(2'R,4S)(4-pyridazinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (8) 4-[4-cyano({[(2'R,4S)(2-oxopyrrolidinyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, 5 (9) 4-[4-cyano({[(2'R,4S)(6-methoxypyridinyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (10) yano[({(2'R,4S)[6-(1H-pyrazolyl)pyridinyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (11) 4-{4-cyano[({(2'R,4S)[6-(dimethylamino)pyridinyl]-2,3- 10 dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, (12) 4-[4-cyano({[(2'R,4S)(6-methylpyridinyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (13) 4-{4-cyano[({(2'R,4S)[6-(methylamino)pyridinyl]-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl}carbonyl)amino]phenyl}butanoic acid, 15 (14) 4-[4-cyano({[(2'R,4S)(2-pyridinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (15) yano({[(2'R,4S)(1,3-thiazolyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (16) 4-[4-cyano({[(2'R,4S)(1,3-oxazolyl)-2,3-dihydrospiro[chromene-4,1'- 20 cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (17) yano({[(2'R,4S)(1-methyl-1H-1,2,3-triazolyl)-2,3- dihydrospiro[chromene-4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, (18) yano({[(2'R,4S)(3-pyridazinyl)-2,3-dihydrospiro[chromene-4,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, 25 (19) 4-[4-cyano({[(2'R,3S)(3-pyridinyl)-2H-spiro[1-benzofuran-3,1'- cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, or (20) 4-[4-cyano({[(1S,2R)-3',3'-dimethyl-6'-(3-pyridinyl)-2',3'- dihydrospiro[cyclopropane-1,1'-inden]yl]carbonyl}amino)phenyl]butanoic acid. 30
11. A medicament comprising a combination of 4-[4-cyano({[(2'R,4S) (isopropylcarbamoyl)-2,3-dihydrospiro[chromene-4,1'-cyclopropan]-2'- yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor.
12. The medicament according to any one of claims 1 to 11, wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint molecule selected from the group ting of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39, CD73, A2aR, KIR, VISTA, IDO1, Arginase I, TIGIT, and CD115.
13. The medicament according to any one of claims 1 to 12, wherein the immune oint inhibitor is an anti-PD-1 antibody.
14. The medicament according to any one of claims 1 to 12, wherein the immune 10 checkpoint inhibitor is an anti-CTLA-4 antibody.
15. The ment according to any one of claims 1 to 14 for the treatment of cancer.
16. The medicament according to claim 15, wherein the cancer is malignant lymphoma, 15 head and neck cancer, esophageal cancer, stomach , colorectal , pancreatic cancer, lung cancer, renal cancer, or malignant melanoma.
17. A therapeutic agent against cancer comprising a combination of the compound represented by formula (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide 20 thereof, or a prodrug of these and an immune checkpoint inhibitor.
18. A combination of the compound represented by a (I) according to claim 1, a salt thereof, a solvate thereof, an N-oxide thereof, or a prodrug of these and an immune checkpoint inhibitor for the treatment of cancer.
19. Use of a combination of the compound represented by formula (I) according to claim 1, a salt thereof, a e f, an N-oxide thereof, or a prodrug of these and an immune checkpoint inhibitor in the manufacture of a medicament for treating cancer. 30
20. Use of a compound represented by a (I), a salt thereof, an N-oxide thereof, a solvate f, or a prodrug of these and an immune checkpoint inhibitor in the manufacture of ments for treating cancer wherein the medicaments are to be administered in combination.
21. Use of 4-[4-cyano({[(2'R,4S)(isopropylcarbamoyl)-2,3-dihydrospiro[chromene- 4,1'-cyclopropan]-2'-yl]carbonyl}amino)phenyl]butanoic acid, a salt thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor in the manufacture of medicaments for treating cancer n the medicaments are to be administered in combination.
22. The use of any one of claims 19 to 21, wherein the cancer is malignant lymphoma, head and neck cancer, esophageal cancer, stomach cancer, ctal cancer, pancreatic cancer, lung cancer, renal cancer, or malignant melanoma. 10
23. The use according to any one of claims 19 to 22, wherein the immune checkpoint inhibitor is an inhibitor of an immune checkpoint molecule selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM3, BTLA, B7H3, B7H4, CD160, CD39,
24. CD73, A2aR, KIR, VISTA, IDO1, Arginase I, TIGIT, and CD115. 15 24. The use according to any one of claims 19 to 23, n the immune checkpoint inhibitor is an anti-PD-1 antibody.
25. The use according to any one of claims 19 to 23, wherein the immune checkpoint tor is an anti-CTLA-4 antibody.
26. A medicament for the ent of cancer, wherein the medicament is formulated for administration of a combination of the compound represented by a (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these and an immune checkpoint inhibitor.
27. A therapeutic agent against cancer containing the compound represented by formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug of these as an active ient , wherein the agent is to be administered in combination with an immune checkpoint tor.
28. A therapeutic agent against cancer containing an immune checkpoint tor as an active ingredient, wherein the agent is to be administered in combination with the compound represented by formula (I) according to claim 1, a salt thereof, an e thereof, a solvate thereof, or a prodrug of these. [ [ [ [ [
NZ789384A 2016-07-07 2017-07-06 Combination comprising EP4 antagonist and immune checkpoint inhibitor NZ789384A (en)

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