NZ789384A - Combination comprising EP4 antagonist and immune checkpoint inhibitor - Google Patents
Combination comprising EP4 antagonist and immune checkpoint inhibitorInfo
- 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
- Authority
- NZ
- New Zealand
- Prior art keywords
- amino
- carbonyl
- phenyl
- chromene
- butanoic acid
- Prior art date
Links
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- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- CQSFZPDGBPHCHV-UHFFFAOYSA-M sodium;cyclopropanesulfinate Chemical compound [Na+].[O-]S(=O)C1CC1 CQSFZPDGBPHCHV-UHFFFAOYSA-M 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003447 supported reagent Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- ODGCEQLVLXJUCC-UHFFFAOYSA-O tetrafluoroboric acid Chemical compound [H+].F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-O 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N tetrahydro-2H-thiopyran Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- ZYXWYDDFNXBTFO-UHFFFAOYSA-N tetrazolidine Chemical compound C1NNNN1 ZYXWYDDFNXBTFO-UHFFFAOYSA-N 0.000 description 1
- RWXZKKKYLRFREK-UHFFFAOYSA-N thiadiazepane Chemical compound C1CCSNNC1 RWXZKKKYLRFREK-UHFFFAOYSA-N 0.000 description 1
- BXVYJQULAWJPSR-UHFFFAOYSA-N thiadiazepine Chemical compound S1C=CC=CN=N1 BXVYJQULAWJPSR-UHFFFAOYSA-N 0.000 description 1
- TVQOEGVBMRCMFR-UHFFFAOYSA-N thiadiazinane Chemical compound C1CNNSC1 TVQOEGVBMRCMFR-UHFFFAOYSA-N 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- AJZGFFKDLABHDD-UHFFFAOYSA-N thiazinane Chemical compound C1CCSNC1 AJZGFFKDLABHDD-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 108010072993 tremelimumab Proteins 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- JFALSRSLKYAFGM-UHFFFAOYSA-N uranium(0) Chemical compound [U] JFALSRSLKYAFGM-UHFFFAOYSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- MNFORVFSTILPAW-UHFFFAOYSA-N Β-Lactam Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 1
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. [ [ [ [ [
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US62/359,504 | 2016-07-07 |
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