NZ614218B2 - Dispiropyrrolidine derivatives - Google Patents
Dispiropyrrolidine derivatives Download PDFInfo
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- NZ614218B2 NZ614218B2 NZ614218A NZ61421812A NZ614218B2 NZ 614218 B2 NZ614218 B2 NZ 614218B2 NZ 614218 A NZ614218 A NZ 614218A NZ 61421812 A NZ61421812 A NZ 61421812A NZ 614218 B2 NZ614218 B2 NZ 614218B2
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- 239000008096 xylene Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- ZABJMXWJCDYMGL-UHFFFAOYSA-L zinc;2-chlorobenzoate Chemical compound [Zn+2].[O-]C(=O)C1=CC=CC=C1Cl.[O-]C(=O)C1=CC=CC=C1Cl ZABJMXWJCDYMGL-UHFFFAOYSA-L 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N α-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Abstract
Disclosed is a family of dispiropyrrolidine derivative compounds of formula (1), wherein A, B, R1, R2 and R3 are as defined in the specification. The disclosure also relates to these compound’s use to inhibit interaction between Mdm2 (murine double minute 2) protein and p53 protein and to slow cancer tumors. Examples compounds include: (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide sulfate. (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide methanesulfonate. (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide ethanesulfonate. r tumors. Examples compounds include: (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide sulfate. (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide methanesulfonate. (3'R,4'S,5'R)-N-[(3R,6S)-6-carbamoyltetrahydro-2H-pyran-3-yl]-6"-chloro-4'-(2-chloro-3-fluoropyridin-4-yl)-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide ethanesulfonate.
Description
[Document Name] Description
[Title of Invention] DISPIROPYRROLIDINE DERIVATIVES
[Technical Field]
The present invention relates to a
dispiropyrrolidine compound having anti-tumor activity by
inhibition of murine double minute 2 (Mdm2) or a salt
thereof. NZ710585 is a divisional from the present
application. The description of the present invention
and the invention of NZ710585 is retained herein for
clarity and completeness.
[Background Art]
p53 is known as an important factor for inhibiting
canceration of cells. p53 is a transcription factor that
induces the expression of genes involved in the cell
cycle and cellular apoptosis in response to various
stresses. p53 is thought to inhibit canceration of cells
by a transcription regulating function thereof. In fact,
deletion or mutation of the p53 gene is observed in about
half of human cancer cases.
Meanwhile, overexpression of murine double minute 2
(Mdm2), a type of E3 ubiquitin ligase, is known as a
factor for canceration of cells that are cancerated in
spite of the presence of normal p53. Mdm2 is a protein
of which expression is induced by p53. Mdm2 negatively
regulates p53 by mediating degradation of p53 by binding
to the transcription activity domain of p53 to decrease
the transcription activity of p53, exporting p53 out of
the nucleus, and further acting as a ubiquitination
ligase against p53. Therefore, it is thought that
inactivation of functions of and degradation of p53 are
promoted in cells in which Mdm2 is overexpressed,
resulting in canceration (Non Patent Document 1).
Paying attention to such functions of Mdm2, many
approaches have been attempted using substances that
inhibit the suppression of p53 functions by Mdm2, as
candidate anti-tumor agents. Examples of the Mdm2
inhibitors targeting the Mdm2-p53 binding site have been
reported, which include spirooxindole derivatives (Patent
Document 1-15, Non Patent Document 1-3), indole
derivatives (Patent Document 16), pyrrolidine
carboxamide derivatives (Patent Document 17),
pyrrolidinone derivatives (Patent Document 18) and
isoindolinone derivatives (Patent Document 19, Non Patent
Document 4).
[Citation list]
[Patent Documents]
Patent Document 1: WO2006/091646
Patent Document 2: WO2006/136606
Patent Document 3: WO2007/104664
Patent Document 4: WO2007/104714
Patent Document 5: WO2008/034736
Patent Document 6: WO2008/036168
Patent Document 7: WO2008/055812
Patent Document 8: WO2008/141917
Patent Document 9: WO2008/141975
Patent Document 10: WO2009/077357
Patent Document 11: WO2009/080488
Patent Document 12: WO2010/084097
Patent Document 13: WO2010/091979
Patent Document 14: WO2010/094622
Patent Document 15: WO2010/121995
Patent Document 16: WO2008/119741
Patent Document 17: WO2010/031713
Patent Document 18: WO2010/028862
Patent Document 19: WO2006/024837
[Non Patent Documents]
Non Patent Document 1: J. Am. Chem. Soc., 2005, 127,
10130-10131
Non Patent Document 2: J. Med. Chem., 2006, 49, 3432-
3435
Non Patent Document 3: J. Med. Chem., 2009, 52, 7970-
7973
Non Patent Document 4: J. Med. Chem., 2006, 49, 6209-
6221
[Summary of Invention]
[Problem to be solved by the invention]
The present invention provides a novel Mdm2
inhibiting compound. Furthermore, the present invention
provides an anti-tumor agent containing the Mdm2
inhibiting compound.
[Means for Solving the Problem]
As a result of extensive studies, the present
inventors have found that a compound having a structure
represented by the following general formula (1) or a
salt thereof had potent Mdm2 inhibiting activity and
accomplished the present invention.
More specifically, the present invention provides:
A compound represented by general formula (1) or a
salt thereof:
NH (1)
wherein
ring A represents a spiro-linked 4- to 6-membered
saturated hydrocarbon ring which may have one or more
substituents selected from Group 1, or a spiro-linked 6-
membered saturated heterocyclic ring which may have one
or more substituents selected from Group 1;
ring B represents a benzene ring which may have one or
more substituents selected from Group 2, a pyridine ring
which may have one or more substituents selected from
Group 2, or a pyrimidine ring which may have one or more
substituents selected from Group 2;
R represents an aryl group which may have one or more
substituents selected from Group 3, a heteroaryl group
which may have one or more substituents selected from
Group 3, a C -C cycloalkyl group which may have one or
more substituents selected from Group 3, or a C -C
cycloalkenyl group which may have one or more
substituents selected from Group 3;
R represents a C -C alkyl group which may be substituted
with one to three halogen atoms or one to three hydroxy
groups, or a hydrogen atom; and
R represents a group represented by the following
general formulae (2), (3), or (4):
Z 10
wherein in formula (2),
R and R each independently represent a hydroxy group, a
C -C alkyl group, or a C -C alkoxy group, or R and R
1 6 1 6
together with the carbon atoms to which the R and R
groups are respectively bonded may form a 4- to 6-
membered saturated hydrocarbon ring;
in formula (3),
the broken line in the ring structure indicates that the
bond may be a double bond,
R represents a C -C alkyl group which may have one or
more substituents selected from Group 4, a carbamoyl
group which may have one or more substituents selected
from Group 5, a 5- or 6-membered nitrogen-containing
heteroaryl group which may be substituted with an oxo
group or one or more C -C alkyl groups which may be
substituted with an oxo group or one hydroxy group, a
hydroxy group, or -NR'R'', wherein
R' and R'' each independently represent a C -C alkyl
group which may be substituted with one to three halogen
atoms, an oxo group, or one to three hydroxy groups, a
C -C cycloalkyl group which may be substituted with one
to three halogen atoms or one to three hydroxy groups, or
a hydrogen atom, or R' and R'' together with the nitrogen
atom to which R' and R'' are bonded may form a 4- to 7-
membered nitrogen-containing heterocyclic group which may
have one or more substituents selected from a C -C alkyl
group and a hydroxy group,
R represents a C -C alkyl group which may be substituted
with one hydroxy group, a hydroxy group, or a hydrogen
atom, or
R and R may together form a spiro-linked 4- to 6-
membered hydrocarbon ring or a spiro-linked 4- to 6-
membered nitrogen-containing heterocyclic ring,
R is absent or represents one or more substituents
selected from a hydroxy group, a C -C alkyl group, and a
C -C alkoxy group, and
Z represents CH , NH, or an oxygen atom; and
in formula (4),
R represents a C -C alkyl group which may have one or
more substituents selected from Group 4, a carbamoyl
group which may have one or more substituents selected
from Group 5, a 5- or 6-membered nitrogen-containing
heteroaryl group which may be substituted with an oxo
group or one or more C -C alkyl groups which may be
substituted with an oxo group or one hydroxy group, a
hydroxy group, or -NR'R'', wherein
R' and R'' each independently represent a C -C alkyl
group which may be substituted with one to three halogen
atoms, an oxo group, or one to three hydroxy groups, a
C -C cycloalkyl group which may be substituted with one
to three halogen atoms or one to three hydroxy groups, or
a hydrogen atom, or R' and R'' together with the nitrogen
atom to which R' and R'' are bonded may form a 4- to 7-
membered nitrogen-containing heterocyclic group which may
have one or more substituents selected from a C -C alkyl
group and a hydroxy group,
R represents a C -C alkyl group which may be
substituted with one hydroxy group, a hydroxy group, or a
hydrogen atom, or
9 10
R and R may together form a spiro-linked 4- to 6-
membered hydrocarbon ring or a spiro-linked 4- to 6-
membered nitrogen-containing heterocyclic ring, and
R is absent or represents one or more substituents
selected from a hydroxy group, a C -C alkyl group, and a
C -C alkoxy group:
Group 1: a halogen atom, a C -C alkyl group which
may be substituted with one to three halogen atoms, a C -
C alkoxy group, and a cyano group,
Group 2: a halogen atom, a C -C alkyl group which may be
substituted with one to three halogen atoms, a C -C
cycloalkyl group which may be substituted with one to
three halogen atoms, a vinyl group, an ethynyl group, a
cyano group, and a C -C alkoxy group,
Group 3: a halogen atom, a C -C alkyl group which may be
substituted with one to three halogen atoms or one to
three hydroxy groups, a C -C cycloalkyl group which may
be substituted with one to three halogen atoms or one to
three hydroxy groups, a vinyl group, an ethynyl group, a
cyano group, -OR', -NR'R'', -COOR', and -CONHR', wherein
R' and R'' each independently represent a C -C alkyl
group which may be substituted with one to three halogen
atoms or one to three hydroxy groups, a C -C cycloalkyl
group which may be substituted with one to three halogen
atoms or one to three hydroxy groups, or a hydrogen atom,
or R' and R'' together with the nitrogen atom to which R'
and R'' are bonded may form a 4- to 7-membered nitrogen-
containing heterocyclic group which may have one or more
substituents selected from a C -C alkyl group and a
hydroxy group,
Group 4: a halogen atom, a hydroxy group, a carbamoyl
group, a morpholino group, a C -C alkoxy group, a C -C
1 6 1 6
alkylsulfonyl group, and -NR'R'', wherein
R' and R'' each independently represent a C -C alkyl
group which may be substituted with one to three halogen
atoms, one to three hydroxy groups, or an oxo group, a
C -C cycloalkyl group which may be substituted with one
to three halogen atoms or one to three hydroxy groups, or
a hydrogen atom, or R' and R'' together with the nitrogen
atom to which R' and R'' are bonded may form a 4- to 7-
membered nitrogen-containing heterocyclic group which may
have one or more substituents selected from a C -C alkyl
group and a hydroxy group, and
Group 5: a C -C alkyl group which may be substituted
with one to three halogen atoms, one to three hydroxy
groups, or a C -C alkoxy group, a C -C cycloalkyl group,
1 6 3 6
a C -C alkoxy group, and a tetrahydropyranyl group.
A compound according to [1] represented by general
formula (5) or a salt thereof:
NH (5)
wherein in formula (5),
2 3 2
ring A, R , and R have the same meanings as ring A, R ,
and R , respectively, in [1];
12 13
R and R represent a group selected from a halogen atom,
a C -C alkyl group which may be substituted with one to
three halogen atoms, and a cyano group;
R is absent or represents one or more substituents
selected from a halogen atom, a C -C alkyl group which
may be substituted with one to three halogen atoms, and a
cyano group; and
R is absent or represents one or more substituents
selected from Group 3 (which has the same meaning as
Group 3 in [1]).
A compound according to [1] represented by general
formula (6) or a salt thereof:
NH (6)
wherein in formula (6),
2 3 2
ring A, R , and R have the same meanings as ring A, R ,
and R , respectively, in [1];
12 13 16
R , R , and R represent a group selected from a halogen
atom, a C -C alkyl group which may be substituted with
one to three halogen atoms, and a cyano group; and
R is absent or represents one or more substituents
selected from a halogen atom, a C -C alkyl group which
may be substituted with one to three halogen atoms, and a
cyano group.
A compound according to [1] represented by general
formula (7) or a salt thereof:
NH (7)
wherein in formula (7),
2 3 2
ring A, R , and R have the same meanings as ring A, R ,
and R , respectively, in [1];
12 13 16
R , R , and R represent a group selected from a halogen
atom, a C -C alkyl group which may be substituted with
one to three halogen atoms, and a cyano group; and
R is absent or represents one or more substituents
selected from a halogen atom, a C -C alkyl group which
may be substituted with one to three halogen atoms, and a
cyano group.
A compound according to [1] represented by general
formula (8) or a salt thereof:
NH (8)
wherein in formula (8),
2 3 2
ring A, R , and R have the same meanings as ring A, R ,
and R , respectively, in [1];
12 13 16
R , R , and R represent a group selected from a halogen
atom, a C -C alkyl group which may be substituted with
one to three halogen atoms, and a cyano group; and
R is absent or represents one or more substituents
selected from a halogen atom, a C -C alkyl group which
may be substituted with one to three halogen atoms, and a
cyano group.
A compound selected from the following group or a
salt thereof:
O N O N
Cl Cl Cl
H H H
F OH F F N
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
N N N
O O N O
Cl Cl Cl
H H H
F F OH
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
O N N O N O N
Cl Cl Cl
OH H
F F F
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
N O N N O N N O N
O O O
Cl Cl Cl
H H H
OH NH OH
F F F
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
O N O N O N
Cl Cl Cl
H H H
F F F
N N N
Cl Cl Cl
N O N O N O
H H H
N O N N O N
Cl Cl OH
Cl Cl
N O N O
(3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro-
2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4, 4-dimethyl-2"-oxo-1", 2"-
dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"-
indole]-5'-carboxamide hydrochloride.
(3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro-
2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4, 4-dimethyl-2"-oxo-1", 2"-
dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"-
indole]-5'-carboxamide sulfate.
(3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro-
2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4, 4-dimethyl-2"-oxo-1", 2"-
dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"-
indole]-5'-carboxamide methanesulfonate.
(3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro-
2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4, 4-dimethyl-2"-oxo-1", 2"-
dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"-
indole]-5'-carboxamide ethanesulfonate.
(3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro-
2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4, 4-dimethyl-2"-oxo-1", 2"-
dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"-
indole]-5'-carboxamide benzenesulfonate.
(3'R, 4'S, 5'R)-N-[(3R, 6S)carbamoyltetrahydro-
2H-pyranyl]-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4, 4-dimethyl-2"-oxo-1", 2"-
dihydrodispiro[cyclohexane-1, 2'-pyrrolidine-3', 3"-
indole]-5'-carboxamide p-toluenesulfonate.
(3'R, 4'S, 5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R, 6S)[1-hydroxyethyl]tetrahydro-2H-pyranyl}-4,
4-dimethyl-2"-oxo-1", 2"-dihydrodispiro[cyclohexane-1, 2'-
pyrrolidine-3', 3"-indole]-5'-carboxamide benzenesulfonate.
An inhibitor of Mdm2 comprising a compound according to
any one of [1] to [6] or a salt thereof or a compound
according to any one of [7] to [13].
An inhibitor of Mdm2 ubiquitin ligase comprising a
compound according to any one of [1] to [6] or a salt thereof
or a compound according to any one of [7] to [13].
An inhibitor of p53-Mdm2 binding comprising a compound
according to any one of [1] to [6] or a salt thereof or a
compound according to any one of [7] to [13].
An inhibitor of suppression of p53 transcription activity
comprising a compound according to any one of [1] to [6] or a
salt thereof or a compound according to any one of [7] to [13].
An inhibitor of p53 degradation comprising a compound
according to any one of [1] to [6] or a salt thereof or a
compound according to any one of [7] to [13].
A medicament comprising a compound according to any one
of [1] to [6] or a salt thereof or a compound according to any
one of [7] to [13] as an active ingredient.
An anticancer agent comprising a compound according to
any one of [1] to [6] or a salt thereof or a compound
according to any one of [7] to [13] as an active ingredient.
An anticancer agent according to [20], wherein the cancer
is lung cancer, breast cancer, prostate cancer, colon cancer,
acute myeloid leukemia, malignant lymphoma, malignant melanoma,
retinoblastoma, neuroblastoma, or sarcoma.
A pharmaceutical composition comprising a compound
according to any one of [1] to [6] or a salt thereof or a
compound according to any one of [7] to [13] and a
pharmaceutically acceptable carrier.
A method for treating cancer, comprising administering a
compound according to any one of [1] to [6] or a salt thereof
or a compound according to any one of [7] to [13].
A method for treating cancer according to [23], wherein
the cancer is lung cancer, breast cancer, prostate cancer,
colon cancer, acute myeloid leukemia, malignant lymphoma,
malignant melanoma, retinoblastoma, neuroblastoma, or sarcoma.
Use of a compound according to any one of [1] to [6] or a
salt thereof or a compound according to any one of [7] to [13]
for the manufacture of a medicament.
Use of a compound according to any one of [1] to [6] or a
salt thereof or a compound according to any one of [7] to [13]
for the manufacture of an anticancer agent.
[Advantages of the Invention]
The present invention provides a novel spiroprolinamide
derivative represented by the above formula (1), which has
Mdm2 inhibiting activity. Such a novel compound is useful as
an anti-tumor agent.
[Description of Embodiments]
In the present invention, "Mdm2" means a protein
encoded by the murine double minute 2 gene. "Mdm2"
includes Mdm2 proteins encoded by a complete length of
the Mdm2 gene, Mdm2 proteins encoded by mutated Mdm2
genes (including deletion mutants, substitution mutants,
and addition mutants), and so forth. In the present
invention, "Mdm2" also includes homologues derived from
various animal species such as, for example, human Mdm2
homologue (HDM2).
In the present invention, "p53" means a protein
encoded by the p53 gene. "p53" means the p53 protein
encoded by a full length p53 gene or a p53 protein that
has a mutation (including mutations by deletion,
substitution, and addition), but functions normally.
In the present invention, "Mdm2 inhibitor" means a
factor that restores p53 functions suppressed by Mdm2 by
acting on either Mdm2 or p53, or on both p53 and Mdm2.
The p53 functions are not particularly limited so long as
they are functions which p53 normally has. Examples
thereof include inhibition of canceration of cells by
inducing the expression of genes involved in the cell
cycle or cellular apoptosis. Examples of Mdm2 inhibitors
include factors that inhibit binding of Mdm2 to p53
(hereinafter, referred to as p53-Mdm2 binding inhibitors)
or factors that inhibit ubiquitination of p53 by Mdm2
(hereinafter, referred to as Mdm2 ubiquitin ligase
inhibitors).
In the present invention, "inhibitor of suppression
of p53 transcription activity" means a factor that
restores the functions of p53 as a transcription factor
suppressed by Mdm2.
In the present invention, "inhibitor of p53
degradation" means a factor that inhibits degradation of
p53 in proteasomes by inhibiting ubiquitination of p53 by
Mdm2.
In the present invention, the terms "tumor" and
"cancer" are used interchangeably. Furthermore, in the
present invention, tumor, malignant tumor, cancer,
malignant neoplasm, carcinoma, sarcoma, and the like may
be collectively referred to as "tumor" or "cancer."
In the present invention, "C -C alkyl group" means a
straight or branched alkyl group having 1 to 6 carbon
atoms. Examples of a "C -C alkyl group" include a methyl
group, an ethyl group, a propyl group, an isopropyl group,
a butyl group, and a tert-butyl group.
"C -C alkoxy group" means an alkoxy group having a
straight or branched alkyl group having 1 to 6 carbon
atoms. Examples of a "C -C alkoxy group" include a
methoxy group, an ethoxy group, a propoxy group, an
isopropoxy group, and a butoxy group.
Examples of "halogen atom" include a fluorine atom,
a chlorine atom, a bromine atom, and an iodine atom.
"Oxo group" means a group represented by "=O" unless
otherwise specified.
"Carbamoyl group" also includes a cyclic carbamoyl
group.
Hereafter, each substituent in formula (1) will be
explained.
In the following general formula (1),
NH (1)
ring A represents a spiro-linked 4- to 6-membered
saturated hydrocarbon ring which may have one or more
substituents selected from Group 1 above or a spiro-
linked 6-membered saturated heterocyclic ring which may
have one or more substituents selected from Group 1 above.
Here, "spiro-linked" means that ring A and the
pyrrolidine ring to which ring A is bonded form a spiro
ring, as illustrated in, for example, the compounds of
the Examples.
A substituent bonded to ring A may be positioned at
any position. A plurality of substituents may be the
same or different and two identical substituents are
preferably bonded to the 2- to 6-positions.
The substituent(s) is preferably a C -C alkyl group
which may be substituted with one to three halogen atoms,
more preferably a C -C alkyl group which may be
substituted with one fluorine atom, yet more preferably
two methyl groups, ethyl groups, or fluoromethyl groups
bonded to the 2-position for 4-membered ring A, bonded to
the 3- and 4-positions for 5-membered ring A, or bonded
to the 4-position for 6-membered ring A.
The 6-membered saturated heterocyclic ring
represented by ring A is preferably dioxane or
hexahydropyrimidine. The 5-position in these rings is
preferably bonded to the pyrrolidine ring in the compound
of formula (1).
Ring A is more preferably a 4- or 6-membered
saturated hydrocarbon ring.
Ring B represents a benzene ring which may have one
or more substituents selected from Group 2 above, a
pyridine ring which may have one or more substituents
selected from Group 2 above, or a pyrimidine ring which
may have one or more substituents selected from Group 2
above.
A substituent bonded to ring B may be positioned at
any position. A plurality of substituents may be the
same or different. For the benzene ring, one or two
substituents are preferably bonded to the 5- or 6-
position. For the pyridine ring, one substituent is
preferably bonded to the 6-position. For the pyrimidine
ring, one substituent is more preferably bonded to the 2-
position.
The substituent(s) is preferably a halogen atom, a
C -C alkyl group which may be substituted with one to
three halogen atoms, a cyano group, or a C -C alkoxy
group, more preferably a halogen atom or a cyano group,
yet more preferably a halogen atom. The halogen atom is
preferably a fluorine atom or a chlorine atom.
R represents an aryl group which may have one or
more substituents selected from Group 3 above, a
heteroaryl group which may have one or more substituents
selected from Group 3 above, a C -C cycloalkyl group
which may have one or more substituents selected from
Group 3 above, or a C -C cycloalkenyl group which may
have one or more substituents selected from Group 3 above.
Here, examples of the aryl group include a phenyl
group, a benzyl group, an indenyl group, a naphthyl group,
a fluorenyl group, an anthryl group, and a phenanthryl
group. A phenyl group is particularly preferred.
Here, examples of the heteroaryl group include a
pyrrolyl group, a pyrazolyl group, a triazolyl group, an
oxazolyl group, an oxadiazolyl group, a thiophenyl group,
a thiazolyl group, a thiadiazolyl group, a pyridyl group,
a pyrimidyl group, a pyridazinyl group, a pyrazinyl group,
a benzimidazolyl group, a benzotriazolyl group, a
benzofuranyl group, a benzothiophenyl group, a quinolyl
group, a carbazolyl group, and a dibenzofuranyl group. A
pyridyl group and a benzimidazolyl group are particularly
preferred. The position of binding of the heteroaryl
group to the pyrrolidine ring is not particularly limited
and a pyridyl group, for example, is more preferably
bonded at the 4-position.
Here, examples of the C -C cycloalkyl group include
a cyclopropyl group, a cyclobutyl group, a cyclopentyl
group, and a cyclohexyl group. The C -C cycloalkyl group
is preferably a cyclopentyl group or a cyclohexyl group,
more preferably a cyclohexyl group.
Here, examples of the C -C cycloalkenyl group
include a cyclopropenyl group, a cyclobutenyl group, a
cyclopentenyl group, and a cyclohexenyl group. The C -C
cycloalkenyl group is preferably a cyclopentenyl group or
a cyclohexenyl group, more preferably a cyclohexenyl
group.
The number and position of the substituent(s) bonded
to the aryl group, the heteroaryl group, the cycloalkyl
group, and the cycloalkenyl group are not limited and a
plurality of substituents may be the same or different.
Examples of the types of substituents include a
halogen atom, a C -C alkyl group which may be
substituted with one to three halogen atoms or one to
three hydroxy groups, a C -C cycloalkyl group which may
be substituted with one to three halogen atoms or one to
three hydroxy groups, a vinyl group, an ethynyl group, a
cyano group, -OR', -NR'R'', -COOR', and -CONHR', wherein
R' and R'' each independently represent a C -C alkyl
group which may be substituted with one to three halogen
atoms or one to three hydroxy groups, a C -C cycloalkyl
group which may be substituted with one to three halogen
atoms or one to three hydroxy groups, or a hydrogen atom,
or R' and R'' together with the nitrogen atom to which R'
and R'' are bonded may form a 4- to 7-membered nitrogen-
containing heterocyclic group which may have one or more
substituents selected from a C -C alkyl group and a
hydroxy group.
Here, examples of the "4- to 7-membered nitrogen-
containing heterocyclic group" in the phrase "R' and R''
together with the nitrogen atom to which R' and R'' are
bonded may form a 4- to 7-membered nitrogen-containing
heterocyclic group which may have one or more
substituents selected from a C -C alkyl group, a hydroxy
group, and an oxo group" include an azetidinyl group, a
pyrrolidinyl group, a piperidinyl group, a piperazinyl
group, a morpholinyl group, a hexamethyleneiminyl group,
a homopiperazinyl group, and a homomorpholinyl group.
Examples of preferred substituents include a halogen atom,
a C -C alkyl group which may be substituted with one to
three halogen atoms or one to three hydroxy groups, -
NR'R'', -CONHR', and a cyano group. A halogen atom, a
hydroxy-C -C alkyl group, an amino group, -CONHR'
wherein R' is a C -C alkyl group, or a cyano group is
more preferred.
The position of a substituent on the ring is not
particularly limited. For a phenyl group and cyclohexyl
group, it is particularly preferred that one chlorine
atom is bonded to the 3-position, or a chlorine atom and
a fluorine atom are bonded to the 3- and 2-positions,
respectively. For a cyclohexenyl group, the position of
the double bond is not particularly limited. It is
particularly preferred that one chlorine atom is bonded
to the 3-position with respect to the position of binding
to the pyrrolidine ring, or a chlorine atom and a
fluorine atom are bonded to the 3- and 2-positions,
respectively. For a pyridyl group, it is particularly
preferred that one chlorine atom is bonded to the 2-
position, or a chlorine atom and a fluorine atom are
bonded to the 2- and 3-positions, respectively.
R represents a C -C alkyl group which may be
substituted with one to three halogen atoms or one to
three hydroxy groups, or a hydrogen atom. A substituent
bonded to the C -C alkyl group is preferably a fluorine
atom or a hydroxy group. R is preferably a hydrogen
atom, a methyl group, or an ethyl group, and it is
particularly preferred that it is a hydrogen atom.
R represents a group represented by the following
general formulae (2), (3), or (4):
In formula (2), R and R each independently
represent a hydroxy group, a C -C alkyl group, or a C -C
1 6 1 6
alkoxy group, or R and R together with the carbon atoms
to which the R and R groups are respectively bonded may
form a 4- to 6-membered saturated hydrocarbon ring.
Preferably, both of R and R are a hydroxy group, or
4 5 4
R and R together with the carbon atoms to which the R
and R groups are respectively bonded form a 4- to 6-
membered saturated hydrocarbon ring. More preferably,
both of R and R are a hydroxy group.
In formula (3), the broken line in the ring
structure indicates that the bond may be a double bond;
R represents a C -C alkyl group which may have one or
more substituents selected from Group 4 above, a
carbamoyl group which may have one or more substituents
selected from Group 5 above, a 5- or 6-membered nitrogen-
containing heteroaryl group which may be substituted with
an oxo group or one or more C -C alkyl groups which may
be substituted with an oxo group or one hydroxy group, a
hydroxy group, or -NR'R'', wherein
R' and R'' each independently represent a C -C alkyl
group which may be substituted with one to three halogen
atoms, an oxo group, or one to three hydroxy groups, a
C -C cycloalkyl group which may be substituted with one
to three halogen atoms or one to three hydroxy groups, or
a hydrogen atom, or R' and R'' together with the nitrogen
atom to which R' and R'' are bonded may form a 4- to 7-
membered nitrogen-containing heterocyclic group which may
have one or more substituents selected from a C -C alkyl
group and a hydroxy group;
R represents a C -C alkyl group which may be
substituted with one hydroxy group, a hydroxy group, or a
hydrogen atom, or
R and R may together form a spiro-linked 4- to 6-
membered hydrocarbon ring or a spiro-linked 4- to 6-
membered nitrogen-containing heterocyclic ring (wherein
"spiro-linked" means that a ring formed by R and R
together and the Z-containing 6-membered ring form a
spiro ring);
R is absent or represents one or more substituents
selected from a hydroxy group, a C -C alkyl group, and a
C -C alkoxy group; and
Z represents CH , NH, or an oxygen atom.
When R is a "C -C alkyl group which may have one or
more substituents", examples of the substituent(s)
include a halogen atom, a hydroxy group, a carbamoyl
group, a morpholino group, a C -C alkoxy group, a C -C
1 6 1 6
alkylsulfonyl group, and -NR'R''. Here, R' and R'' each
independently represent a C -C alkyl group which may be
substituted with one to three halogen atoms, one to three
hydroxy groups, or an oxo group, a C -C cycloalkyl group
which may be substituted with one to three halogen atoms
or one to three hydroxy groups, or a hydrogen atom, or R'
and R'' together with the nitrogen atom to which R' and
R'' are bonded may form a 4- to 7-membered nitrogen-
containing heterocyclic group which may have one or more
substituents selected from a C -C alkyl group and a
hydroxy group. Here, examples of the "4- to 7-membered
nitrogen-containing heterocyclic group" when "R' and R''
together with the nitrogen atom to which R' and R'' are
bonded form a 4- to 7-membered nitrogen-containing
heterocyclic group which may have one or more
substituents selected from a C -C alkyl group and a
hydroxy group" include an azetidinyl group, a
pyrrolidinyl group, and a piperidinyl group.
The "C -C alkyl group which may have one or more
substituents", represented by R , is preferably a
hydroxymethyl group, a 1-hydroxyethyl group, a 2-
hydroxypropyl group, a hydroxyethyl group, a 1-hydroxy
methylethyl group, a 3,4-dihydroxybutyl group, a
methoxymethyl group, a methylsulfonylmethyl group, an
aminomethyl group, a di-C -C alkylaminomethyl group, a
(hydroxyethyl)aminomethyl group, a C -C
alkyloxy(hydroxyethyl)aminomethyl group, an aminooxoethyl
group, or a di-C -C alkylaminooxoethyl group.
When R is a "carbamoyl group which may have one or
more substituents", examples of the substituent(s)
include a C -C alkyl group which may be substituted with
one to three halogen atoms, one to three hydroxy groups,
or a C -C alkoxy group, a C -C cycloalkyl group, a C -C
1 6 3 6 1 6
alkoxy group, and a tetrahydropyranyl group.
The " carbamoyl group which may have one or more
substituents", represented by R , is preferably an
unsubstituted carbamoyl group, a methylcarbamoyl group, a
dimethylcarbamoyl group, an ethylcarbamoyl group, a
diethylcarbamoyl group, a methylethylcarbamoyl group, an
isopropylcarbamoyl group, a cyclopropylcarbamoyl group, a
2-hydroxyethylcarbamoyl group, a 2-methoxyethylcarbamoyl
group, a 2-methoxyethyl-C -C alkylcarbamoyl group, or a
2-fluoroethylcarbamoyl group.
When R is a "5- or 6-membered nitrogen-containing
heteroaryl group which may be substituted with an oxo
group or one or more C -C alkyl groups which may be
substituted with an oxo group or one hydroxy group",
examples of the "5- or 6-membered nitrogen-containing
heteroaryl group" include an oxadiazolyl group, a
triazolyl group, an imidazolyl group, a thiazolyl group,
a thiadiazolyl group, a pyrrolyl group, a pyridyl group,
a pyrimidyl group, a pyridazinyl group, and a triazinyl
group. An oxadiazolyl group or a triazolyl group is
preferred. An oxadiazolyl group, for example, is
preferably bonded at the 2-position. The position of the
substituent bonded to the "5- or 6-membered nitrogen-
containing heteroaryl group" is not particularly limited.
For a 6-membered nitrogen-containing heteroaryl group,
the substituent is positioned at any position. For a 5-
membered nitrogen-containing heteroaryl group, the
substituent is preferably substituted at the 5-position.
The "5- or 6-membered nitrogen-containing heteroaryl
group which may be substituted with an oxo group or one
or more C -C alkyl groups which may be substituted with
an oxo group or one hydroxy group", represented by R , is
preferably an unsubstituted oxadiazolyl group, a
triazolyl group, or a pyridyl group, and it is
particularly preferred that it is an oxadiazolyl group.
Furthermore, R may be a hydroxy group or -NR'R''.
When R is "-NR'R''", R' and R'' each independently
represent a C -C alkyl group which may be substituted
with one to three halogen atoms, an oxo group, or one to
three hydroxy groups, a C -C cycloalkyl group which may
be substituted with one to three halogen atoms or one to
three hydroxy groups, or a hydrogen atom, or R' and R''
together with the nitrogen atom to which R' and R'' are
bonded may form a 4- to 7-membered nitrogen-containing
heterocyclic group which may have one or more
substituents selected from a C -C alkyl group and a
hydroxy group. Here, examples of the "4- to 7-membered
nitrogen-containing heterocyclic group" when "R' and R''
together with the nitrogen atom to which R' and R'' are
bonded form a 4- to 7-membered nitrogen-containing
heterocyclic group which may have one or more
substituents selected from a C -C alkyl group and a
hydroxy group" include an azetidinyl group, a
pyrrolidinyl group, a piperidinyl group, a piperazinyl
group, a 2-oxopiperazinyl group, a morpholinyl group, a
homopiperidinyl group, a homopiperazinyl group, and a
1,4-oxazepanyl group.
"-NR'R''" represented by R preferably forms an
azetidinyl group, a piperazinyl group, or a morpholinyl
group.
R is preferably a hydroxymethyl group, a 1-
hydroxyethyl group, a 2-hydroxypropyl group, a
hydroxyethyl group, a 1-hydroxymethylethyl group, an
oxazolyl group, an oxadiazolyl group, an oxathiazolyl
group, or a carbamoyl group which may have an alkyl group
having 1 to 6 carbon atoms as a substituent, more
preferably a 1-hydroxyethyl group, an oxadiazolyl group,
or an unsubstituted carbamoyl group.
R represents a C -C alkyl group which may be
substituted with one hydroxy group, a hydroxy group, or a
hydrogen atom.
R is more preferably a methyl group, an ethyl group,
a hydroxymethyl group, a hydroxyethyl group, a hydroxy
group, or a hydrogen atom, yet more preferably a hydroxy
group or a hydrogen atom.
Furthermore, R and R may together form a 4- to 6-
membered spiro-linked hydrocarbon ring or a 4- to 6-
membered spiro-linked nitrogen-containing heterocyclic
ring. Examples of the ring formed include a cyclobutane
ring, a cyclopentane ring, a cyclohexane ring, an
azetidine ring, a pyrrolidine ring, and a tetrahydropyran
ring. A cyclobutane ring or an azetidine ring is more
preferred.
R is a substituent on the 6-membered ring in
formula (3) and represents one or more substituents
selected from a hydroxy group, a C -C alkyl group, and a
C -C alkoxy group.
The position of R bonded to the 6-membered ring in
formula (3) is not particularly limited so long as it is
other than the position to which R and R are bonded.
The number of the substituents is not limited.
Furthermore, R is not necessarily required to be present.
R is preferably a hydroxy group, a methoxy group, or a
methyl group. More preferably, R is absent, or one R
group is present. Yet more preferably, R is absent, or
a methoxy group is bonded in the same positional
configuration as R on the carbon atom adjacent to the
carbon atom to which R is bonded.
In formula (4),
R represents a C -C alkyl group which may have one
or more substituents selected from Group 4 above, a
carbamoyl group which may have one or more substituents
selected from Group 5 above, a 5- or 6-membered nitrogen-
containing heteroaryl group which may be substituted with
an oxo group or one or more C -C alkyl groups which may
be substituted with an oxo group or one hydroxy group, a
hydroxy group, or -NR'R'', wherein
R' and R'' each independently represent a C -C alkyl
group which may be substituted with one to three halogen
atoms, an oxo group, or one to three hydroxy groups, a
C -C cycloalkyl group which may be substituted with one
to three halogen atoms or one to three hydroxy groups, or
a hydrogen atom, or R' and R'' together with the nitrogen
atom to which R' and R'' are bonded may form a 4- to 7-
membered nitrogen-containing heterocyclic group which may
have one or more substituents selected from a C -C alkyl
group and a hydroxy group.
R represents a C -C alkyl group which may be
substituted with one hydroxy group, a hydroxy group, or a
9 10
hydrogen atom, or R and R may together form a spiro-
linked 4- to 6-membered hydrocarbon ring or a spiro-
linked 4- to 6-membered nitrogen-containing heterocyclic
ring, and
R is absent or represents one or more substituents
selected from a hydroxy group, a C -C alkyl group, and a
C -C alkoxy group.
R has the same meaning as defined above for R in
formula (3) and also has the same preferred examples.
7
R has the same meaning as defined above for R in
formula (3) and also has the same preferred examples.
11 8
R has the same meaning as defined above for R in
formula (3) and also has the same preferred examples.
9 10
The phrase "R and R may together form a spiro-linked 4-
to 6-membered hydrocarbon ring or a spiro-linked 4- to 6-
membered nitrogen-containing heterocyclic ring" means
9 10
that R and R together form a ring structure and this
9 10
ring and the cyclobutane ring to which R and R are
bonded form a spiro ring.
The compound represented by general formula (1) of
the present invention is more preferably a compound
represented by any of the following general formulae (5)
to (8) (in formulae (5) to (8), ring A, R , and R have
the same meanings as defined above and also have the same
preferred examples):
NH (5)
R (6)
NH (7)
NH (8)
12 13 16
R , R , and R represent a group selected from a
halogen atom, a C -C alkyl group which may be
substituted with one to three halogen atoms, and a cyano
group and are preferably a halogen atom or a cyano group,
more preferably a halogen atom, yet more preferably a
chlorine atom or a fluorine atom.
R represents one or more substituents selected from
a halogen atom, a C -C alkyl group which may be
substituted with one to three halogen atoms, and a cyano
group and is not necessarily required to be present.
14 14
Preferably, R is absent or R , if present, is a
fluorine atom. The position of the substituent bonded to
the ring is not limited.
R represents one or more substituents selected from
Group 3 above and is not necessarily required to be
15
present. More preferably, R is absent or R , if
present, is a halogen atom, a hydroxy-C -C alkyl group,
an amino group, -CONHR' wherein R' is a C -C alkyl group,
or a cyano group.
The compound represented by general formula (1) of
the present invention is more preferably a compound
selected from the following group:
H H H
O N O N O N
Cl Cl
H H H
F F F
OH N
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
N O N O N O N
Cl Cl Cl
H H H
F OH
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
O N N O N O N
Cl Cl
H H H
F F F
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
N N N N N N
O O O
O O O
Cl Cl Cl
H H H
OH NH OH
F F F
N N N
Cl Cl Cl
N O N O N O
H H H
H H H
N O N O N N O N
Cl Cl Cl N
H H H
F F F
N N N
Cl Cl Cl
N O N O N O
H H H
O N O N
Cl Cl
Cl Cl
N O N O
A compound represented by formula (1) of the present
invention may have stereoisomers or optical isomers due
to asymmetric carbon atoms, and all these stereoisomers,
optical isomers, and mixtures thereof are included in the
present invention.
In one embodiment of the present invention, a
compound having an absolute configuration represented by
the following formula is preferred:
From the prior art, it is known that in a compound having
a 6-oxo-2,7-diazaspiro[4.4]nonanecarboxamide structure,
the central skeleton of general formula (9), which is
unsubstituted or monosubstituted at the 2-position in the
pyrrolidine ring, cleavage and recyclization at the C2-C3
carbon bond of the pyrrolidine ring occur in a polar
solvent to facilitate isomerization of the spiro ring
structure at the 3-position (Helv. Chim. Acta, 1996, 79,
151-168, etc.). The present inventors have found that
introduction of the spiro ring structure A to the 2-
position of the pyrrolidine ring can prevent the
progression of this isomerization. The present inventors
have also found that the compound group having an
absolute configuration represented by general formula (9)
is far superior in the ability to inhibit Mdm2-p53
binding to that reported in the prior art. Furthermore,
the present inventors have obtained co-crystals with Mdm2
protein from compounds of Examples 18, 38, and 70 of the
present application described later and consequently
found that these compounds bind to Mdm2 protein in a
manner different from that predicted in silico in Non
Patent Document 1 and Non Patent Document 2.
The compound represented by general formula (1) of
the present invention can form a pharmaceutically
acceptable salt, if desired, when having a basic group
such as an amino group. Examples of such salts can
include: hydrohalides such as hydrochloride and
hydroiodide; inorganic acid salts such as nitrate,
perchlorate, sulfate, and phosphate; lower
alkanesulfonates such as methanesulfonate,
trifluoromethanesulfonate, and ethanesulfonate;
arylsulfonates such as benzenesulfonate and p-
toluenesulfonate; organic acid salts such as formic acid,
acetic acid, malic acid, fumarate, succinate, citrate,
tartrate, oxalate, and maleate; and amino acid salts such
as ornithine salt, glutamate, and aspartate.
Hydrohalides and organic acid salts are preferred.
The compound represented by general formula (1) of
the present invention may generally form a base addition
salt when having an acidic group such as a carboxy group.
Examples of pharmaceutically acceptable salts can
include: alkali metal salts such as sodium salt,
potassium salt, and lithium salt; alkaline earth metal
salts such as calcium salt and magnesium salt; inorganic
salts such as ammonium salt; and organic amine salts such
as dibenzylamine salt, morpholine salt, phenylglycine
alkyl ester salt, ethylenediamine salt, N-methylglucamine
salt, diethylamine salt, triethylamine salt,
cyclohexylamine salt, dicyclohexylamine salt, N,N'-
dibenzylethylenediamine salt, diethanolamine salt, N-
benzyl-N-(2-phenylethoxy)amine salt, piperazine salt,
tetramethylammonium salt, and
tris(hydroxymethyl)aminomethane salt.
The compound represented by general formula (1) of
the present invention or the salt thereof may be present
in a free or solvate form. The compound represented by
general formula (1) of the present invention or the salt
thereof may be present in a hydrate form, for example, by
absorbing moisture in the air. The solvate is not
particularly limited so long as it is pharmaceutically
acceptable. Specifically, the solvate is preferably a
hydrate, an ethanol solvate, a 2-propanol solvate, or the
like. Moreover, the compound represented by general
formula (1) of the present invention may be in an N-oxide
form when containing a nitrogen atom. These solvate and
N-oxide forms are also included in the present invention.
The compound represented by general formula (1) of
the present invention may have various isomers such as
geometrical isomers (e.g., cis and trans forms),
tautomers, and optical isomers (e.g., d and l forms),
depending on the types or combinations of substituents.
The compound of the present invention also encompasses
all these isomers, stereoisomers, and mixtures of these
isomers and stereoisomers in any ratio, unless otherwise
specified.
The compound represented by general formula (1) of
the present invention may contain an isotope in a non-
natural proportion as one or more constituent atoms.
Examples of an isotope include deuterium ( H), tritium
3 125 14
( H), iodine-125 ( I), and carbon-14 ( C). These
compounds are useful as a therapeutic or preventive agent,
a research reagent (e.g., an assay reagent), and a
diagnostic agent (e.g., an in vivo diagnostic imaging
agent). All isotopic variants of the compound
represented by general formula (1) are included in the
scope of the present invention, regardless of the
presence or absence of radioactivity.
Moreover, the present invention also encompasses a
compound that is converted to the compound (1) as an
active ingredient in the pharmaceutical composition of
the present invention due to a reaction induced by an
enzyme, gastric acid, or the like under physiological
conditions in vivo, i.e., a compound that is converted to
the compound (1) through enzymatic oxidation, reduction,
hydrolysis, or the like or a "pharmaceutically acceptable
prodrug compound" that is converted to the compound (1)
through hydrolysis or the like induced by gastric acid or
the like.
Examples of a prodrug can include: compounds in
which an amino group in the compound (1) is acylated,
alkylated, or phosphorylated (e.g., compounds in which
the amino group is eicosanoylated, alanylated,
pentylaminocarbonylated, (5-methyloxo-1,3-dioxolen
yl)methoxycarbonylated, tetrahydrofuranylated,
pyrrolidylmethylated, pivaloyloxymethylated, or tert-
butylated); compounds in which a hydroxy group in the
compound (1) is acylated, alkylated, phosphorylated, or
borated (e.g., compounds in which the hydroxy group is
acetylated, palmitoylated, propanoylated, pivaloylated,
succinylated, fumarylated, alanylated, or
dimethylaminomethylcarbonylated); and compounds in which
a carboxy group in the compound (1) is esterified or
amidated (e.g., compounds in which the carboxy group is
ethyl esterified, phenyl esterified, carboxymethyl
esterified, dimethylaminomethyl esterified,
pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl
esterified, amidated, or methylamidated).
A prodrug of the compound of the present invention
can be produced from the compound (1) according to a
method known in the art. Moreover, a prodrug of the
compound of the present invention also includes those
converted to the compound (1) under physiological
conditions as described in "Development of Pharmaceutical
Products", vol. 7, Molecule Design, p. 163-198, Hirokawa-
Shoten Ltd. (1990).
Next, a representative method for producing a
compound represented by general formula (1) will be
explained. A compound of the present invention can be
produced by various production methods and the following
production methods are illustrative and should not be
construed in any limitative way. Reactions shown below
can be performed by protecting substituents with
appropriate protective groups, if necessary, and the
types of protective groups are not particularly limited.
[Production Method 1]
+ + +
( 1 ) ( 2 ) ( 3 ) ( 4 ) ( 5 )
O O N
H R N
( 7 )
( 10 )
( 6 ) ( 8 )
O OH
( 7 )
( 9 )
1 2 3
wherein ring A, ring B, R , R , and R have the same
meanings as defined above.
Synthesis of compound (3)
A compound (3) can be obtained by subjecting an
oxindole compound (1) and an aldehyde compound (2) to a
dehydration reaction through treatment with an organic
base such as pyrrolidine, piperidine, or
diisobutylethylamine as a catalyst. Here, the solvent
used in the reaction is not particularly limited and
examples thereof include lower alcohols such as methanol
and ethanol, and mixed solvents in which any of these
solvents are mixed with water in an arbitrary ratio. The
reaction temperature is not particularly limited and
examples thereof include room temperature to 120 C.
Moreover, the compound can also be obtained by a
cyclodehydration reaction using an organic acid such as
p-toluenesulfonic acid or camphorsulfonic acid as a
catalyst. Here, the solvent used in the reaction is not
particularly limited and examples thereof include benzene,
toluene, and xylene. The reaction temperature is
preferably in the range from 80 C to 100 C or the boiling
point of the solvent.
Synthesis of compound (6)
A compound (6) can be obtained by reacting compound
(3) with a morpholinone compound (4) as a chiral
auxiliary compound and a ketone compound (5) using a
dehydrating agent such as a molecular sieve and a Lewis
acid such as copper sulfate, zinc bromide, or a boron
trifluoride-diethyl ether complex as a catalyst. Here,
the solvent used in the reaction is not particularly
limited and examples thereof include tetrahydrofuran,
dioxane, chloroform, benzene, toluene, and mixed solvents
thereof. However, dried solvents are preferred. The
reaction temperature is usually preferably in the range
from room temperature to 100 C or the boiling point of
the solvent (J. Am. Chem. Soc., 2000, 122, 5666-5667; and
Tetrahedron Lett., 2005, 5949-5951).
Synthesis of compound (8)
A compound (8) can be obtained by reacting compound
(6) with an amine compound (7). In this reaction, an
organic base such as triethylamine, diisopropylethylamine,
4-dimethylaminopyridine, N-methylmorpholine, pyridine,
2,6-lutidine, or diazabicyclo[5.4.0]undecene, or an
inorganic base such as potassium carbonate, sodium
carbonate, potassium bicarbonate, or sodium bicarbonate
can also be added. Here, examples of the solvent used in
the reaction can include dichloromethane, chloroform,
diethyl ether, tetrahydrofuran, toluene, methanol,
ethanol, isopropyl alcohol, and mixed solvents thereof.
The reaction temperature is usually preferably in the
range from 0 C to 100 C or the boiling point of the
solvent.
Synthesis of compound (9)
A compound (9) can be obtained by hydrolyzing
compound (6) with a base such as sodium hydroxide,
potassium hydroxide, lithium hydroxide, potassium tert-
butoxide, potassium carbonate, or sodium carbonate, then
neutralizing the hydrolysate with an acid such as
hydrochloric acid, sulfuric acid, or methanesulfonic acid,
then reacting the reaction mixture with lead (IV) acetate
or cerium (IV) diammonium nitrate, and neutralizing the
reaction product with, for example, an inorganic base
such as sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium carbonate, potassium bicarbonate, or
sodium bicarbonate. Alternatively, the compound can also
be obtained by reacting compound (6) under the hydrolysis
conditions above, then reacting the hydrolysate with lead
(IV) acetate or cerium (IV) diammonium nitrate without
neutralizing it, and then neutralizing the reaction
product under the conditions above. Here, examples of
the solvent used in the reaction include methanol,
ethanol, tetrahydrofuran, dioxane, acetonitrile,
dichloromethane, water, and mixed solvents thereof.
However, organic solvents that can be mixed with water in
an arbitrary ratio are preferred. The reaction
temperature is usually preferably in the range from -20 C
to room temperature.
Synthesis of compound (10) [via compound (8)]
A compound (10) can be obtained by reacting compound
(8) with lead (IV) acetate or cerium (IV) diammonium
nitrate. Here, examples of the solvent used in the
reaction include methanol, ethanol, tetrahydrofuran,
dioxane, acetonitrile, dichloromethane, water, and mixed
solvents thereof. However, organic solvents that can be
mixed with water in an arbitrary ratio are preferred.
The reaction temperature is usually preferably in the
range from -20 C to room temperature. Subsequently, the
reaction mixture is preferably treated with an inorganic
base such as potassium carbonate or sodium carbonate.
The treatment temperature is usually preferably in the
range from -20 C to room temperature.
The product obtained by the production method above
is more preferably converted to a compound that is
thermodynamically stable and has the desired positional
configuration by heating, usually in the range from room
temperature to 80 C or the boiling point of the solvent,
using methanol, ethanol, tetrahydrofuran, dioxane, water,
acetonitrile, or the like or a mixed solvent thereof, or
an organic solvent that can be mixed with water in an
arbitrary ratio.
Synthesis of compound (10) [via compound (9)]
A compound (10) can be obtained by reacting compound
(9) with an amine compound (7) in the presence of a
condensing agent. Here, examples of the condensing agent
used can include N,N'-dicyclohexylcarbodiimide (DCC), 1-
ethyl(3-dimethylaminopropyl)carbodiimide (EDCI),
carbonyldiimidazole (CDI), 2-(2H-benzotriazolyl)
(1,1,3,3-tetramethylbutyl)phenol (BOP), 1H-benzotriazol-
1-yloxytripyrrolidinophosphoniumhexafluorophosphate
(PyBOP), and O-(7-azabenzotriazolyl)-N,N,N',N'-
tetramethyluronium hexafluorophosphate (HATU). The
solvent used in the reaction is not particularly limited
and examples thereof include dichloromethane,
dimethylformamide, tetrahydrofuran, ethyl acetate, and
mixed solvents thereof. The reaction temperature is
usually in the range from -20 C to 100 C or the boiling
point of the solvent, preferably in the range from -5 C
to 50 C. Moreover, an organic base such as triethylamine,
diisopropylethylamine, N-methylmorpholine, or 4-
dimethylaminopyridine, or an inorganic base such as
potassium carbonate, sodium carbonate, potassium
bicarbonate, or sodium bicarbonate can be added, if
necessary. Furthermore, 1-hydroxybenzotriazole, N-
hydroxysuccinimide, or the like may be added as a
reaction accelerator.
The product obtained by the production method above
is more preferably converted to a compound that is
thermodynamically stable and has the desired positional
configuration by heating, usually in the range from room
temperature to 80 C or the boiling point of the solvent,
using methanol, ethanol, tetrahydrofuran, dioxane, water,
acetonitrile, or the like or a mixed solvent thereof, or
an organic solvent that can be mixed with water in an
arbitrary ratio.
[Production Method 2]
+ + H N
( 3 ) ( 11 ) ( 12 )
( 5 )
chiral 1
deprotection
( 7 )
separation
( 9 ) ( 10 )
1 2 3
wherein ring A, ring B, R , R , and R have the same
meanings as defined above, and W means a protective group
for the carboxy group. Examples of the protective group
for the carboxy group include substituted or
unsubstituted alkyl groups or aralkyl groups such as a
methyl group, an ethyl group, a tert-butyl group, and a
benzyl group.
Synthesis of compound (12)
A compound (12) can be obtained by reacting a
compound (3), a ketone compound (5), and a compound (11)
such as a glycine ester or hydrochloride thereof with a
dehydrating agent such as a molecular sieve or magnesium
sulfate. Here, the solvent used in the reaction is not
particularly limited and examples thereof include
tetrahydrofuran, dioxane, chloroform, 1,2-dichloroethane,
benzene, toluene, and mixed solvents thereof. However,
dried solvents are preferred. The reaction temperature
is usually preferably in the range from room temperature
to 100 C or the boiling point of the solvent (Tetrahedron,
2001, 57, 1129-1137). Moreover, silver acetate, silver
fluoride, or the like can also be added as a catalyst in
the reaction (Tetrahedron, 2003, 59, 335-340; and
WO2010/031713).
Synthesis of compound (9)
Since the compound synthesized by the production
method above is a racemate, the compound of interest can
be obtained by optical resolution using a chiral column
or a crystallization method involving formation of an
optically active salt or the like of tartaric acid,
bromocamphorsulfonic acid, chlorocamphorsulfonic acid,
camphorsulfonic acid, or the like, followed by
deprotection of the ester (W). Although reaction
conditions differ depending on the type of W, this
reaction may be hydrolysis. When W is a methyl group, an
ethyl group, a benzyl group, or the like, the compound
can be obtained by treating compound (12) with a base
such as sodium hydroxide, potassium hydroxide, lithium
hydroxide, or potassium tert-butoxide, or an acid such as
hydrochloric acid or p-toluenesulfonic acid. Here,
examples of the solvent used in the reaction include
methanol, ethanol, water, tetrahydrofuran, dioxane, and
mixed solvents thereof. However, organic solvents that
can be mixed with water in an arbitrary ratio are
preferred. The reaction temperature is usually
preferably in the range from -20 C to 100 C or the
boiling point of the solvent. When W is a tert-butyl
group or the like, the compound can be obtained by
treating compound (12) with, for example, trifluoroacetic
acid or hydrochloric acid. Here, the solvent used in the
reaction is not particularly limited and examples thereof
include dichloromethane, chloroform, 1,2-dichloroethane,
and mixed solvents thereof. The reaction temperature is
usually in the range from -20 C to 80 C or the boiling
point of the solvent, preferably in the range from 0 C to
around room temperature.
Synthesis of compound (10)
A compound (10) can be obtained according to the
method for producing compound (10) with compound (9) as a
starting material described in [Production Method 1]
above.
The starting material compounds (1), (2), (3), (4),
(5), (7), (11), and (12) are commercially available
products or can be synthesized according to methods
described in the Reference Examples.
In one embodiment of the present invention, the
compound of the present invention can be used as a p53-
Mdm2 binding inhibitor and/or an Mdm2 ubiquitin ligase
inhibitor because it inhibits the binding of p53 with
Mdm2 and the ubiquitination of p53 by Mdm2.
The condition of the p53-Mdm2 binding can be
examined by a method conventionally used by those skilled
in the art to examine binding conditions between proteins
(for example, immunological techniques, surface plasmon
resonance techniques, etc.). Examples of methods for
examining the condition of the Mdm2-p53 binding using an
immunological technique include an immuno-sedimentation
method and enzyme-linked-immuno-sorbent assay (ELISA).
An antibody used in such immunological techniques may be
an anti-Mdm2 antibody and/or an anti-p53 antibody that
can directly detect Mdm2 and/or p53. When Mdm2 and/or
p53 is labeled with a tag (for example, a GST tag or a
histidine tag) or the like, an antibody suitable for
labeling (for example, an anti-GST antibody or an anti-
histidine antibody) can be used. Methods for examining
the condition of the Mdm2-p53 binding using an
immunological technique are described in, for example,
WO2003/51359, WO2003/51360, U.S. Patent Application
Publication No. 2004/259867 or 2004/259884, and
WO2005/110996. Methods for examining the condition of
the Mdm2-p53 binding using a surface plasmon resonance
technique are described in, for example, Science, vol.
303, p. 844-848, 2004.
Ubiquitin ligase activity of Mdm2 against p53 can be
examined by an ubiquitin ligase assay conventionally used
by those skilled in the art. The ubiquitin ligase
activity can be detected by, for example, comparing
ubiquitination of p53 by ubiquitin activation enzyme (E1),
ubiquitin binding enzyme (E2), and ubiquitin ligase (E3)
(Mdm2) in the presence and absence of a test compound
(for example, refer to WO2001/75145 and WO2003/76608).
In another embodiment, the compound of the present
invention can be used as an inhibitor of suppression of
the p53 transcription activity because it restores
functions of p53 as a transcription factor that is
suppressed by Mdm2 by inhibiting the binding of Mdm2 to
the p53 transcription activation domain. The inhibitor
of suppression of the p53 transcription activity can be
obtained by, for example, measuring the mRNA level or the
protein level of a protein whose transcription is
Waf1/Cip1
regulated by p53 (for example, p21 ) in the presence
or absence of a test compound by an mRNA measuring method
(for example, Northern blot) or a protein measuring
method (for example, Western blot) conventionally used by
those skilled in the art and selecting the test compound
as an inhibitor of suppression of the p53 transcription
activity when the mRNA level or the protein level is
increased in the presence of the test compound as
compared with that in the absence of the test compound.
Furthermore, the inhibitor of suppression of the p53
transcription activity can also be identified by a
reporter assay using the reporter activity of a reporter
gene including a p53 responsive element as an indicator.
In another embodiment, the compound of the present
invention can be used as a p53 degradation inhibitor
because it inhibits ubiquitination of p53 by Mdm2 and
thereby prevents the degradation of p53 in proteasomes.
The p53 degradation inhibitor can be obtained by, for
example, measuring the protein level of p53 in the
presence or absence of a test compound by a protein
measuring method (for example, Western blot)
conventionally used by those skilled in the art and
selecting the test compound as a p53 degradation
inhibitor when the protein level is increased in the
presence of the test compound as compared with that in
the absence of the test compound.
In another embodiment, the compound of the present
invention can be used as an anti-tumor agent because it
normalizes functions of p53 as a cancer-restraining gene
by inhibition of the Mdm2-p53 binding and/or
ubiquitination of p53 by Mdm2.
Cellular growth inhibiting activity can be examined
by methods for testing growth inhibition conventionally
used by those skilled in the art. The cell growth
inhibition activity can be determined by, for example,
comparing the levels of cellular growth (for example,
tumor cells) in the presence or absence of a test
compound as described in the following Test Example 2.
The levels of cellular growth can be examined by using,
for example, a test system for measuring living cells.
Examples of the method for measuring living cells include
the [ H]-thymidine uptake test, the BrdU method, the MTT
assay, and so forth.
Moreover, in vivo anti-tumor activity can be
examined by methods for testing anti-tumor activity
conventionally used by those skilled in the art. The in
vivo anti-tumor activity of the present invention can be
confirmed by, for example, transplanting various tumor
cells to mice, rats, or the like; after confirming the
engraftment of the transplanted cells, orally or
intravenously administering the compound of the present
invention to the animals; a few days or a few weeks later,
comparing tumor growth in a drug-non-administered group
with that in the compound-administered group.
A compound of the present invention can be used for
the treatment of tumors or cancers, for example, lung
cancer, digestive system cancer, ovary cancer, uterine
cancer, breast cancer, prostate cancer, liver cancer,
head/neck region cancer, blood cancer, renal cancer, skin
cancer (malignant melanoma, etc.), retinoblastoma,
testicular tumors, and sarcoma, more preferably lung
cancer, breast cancer, prostate cancer, colon cancer,
acute myeloid leukemia, malignant lymphoma, malignant
melanoma, retinoblastoma, neuroblastoma, and sarcoma.
However, the present invention is not limited to these
cancers.
A pharmaceutical composition of the present
invention can contain a compound of the present invention
and a pharmaceutically acceptable carrier and can be
administered as various injections such as intravenous
injection, intramuscular injection, and subcutaneous
injection or by various methods such as oral
administration or percutaneous administration.
Pharmaceutically acceptable carrier means a
pharmacologically acceptable material that is involved in
transport of the compound of the present invention or a
composition containing the compound of present invention
(for example, an excipient, a diluent, an additive, a
solvent, etc.) from a given organ to another organ.
A formulation can be prepared by selecting a
suitable formulation form (for example, oral formulation
or injection) depending on the administration method and
using various conventionally used methods for preparing a
formulation. Examples of oral formulations include
tablets, powders, granules, capsules, pills, lozenges,
solutions, syrups, elixirs, emulsions, oily or aqueous
suspensions, and so forth. In oral administration, the
free compound or a salt form may be used. An aqueous
formulation can be prepared by forming an acid adduct
with a pharmacologically acceptable acid or by forming an
alkali metal salt such as sodium. As an injection, a
stabilizer, a preservative, a dissolving aid, and the
like can be used in the formulation. After filling a
solution that may contain these aids and the like in a
vessel, a formulation for use may be prepared as a solid
formulation by lyophilization or the like. Furthermore,
one dose may be filled in one vessel, or two or more
doses may be filled in a vessel.
Examples of solid formulations include tablets,
powders, granules, capsules, pills, and lozenges. These
solid formulations may contain pharmaceutically
acceptable additives together with a compound of the
present invention. Examples of additives include fillers,
extenders, binders, disintegrating agents, dissolution
promoting agents, skin wetting agents, and lubricants,
and these can be selected and mixed as required to
prepare a formulation.
Examples of liquid formulations include solutions,
syrups, elixirs, emulsions, and suspensions. These
liquid formulations may contain pharmaceutically
acceptable additives together with a compound of the
present invention. Examples of additives include
suspending agents and emulsifiers, and these are selected
and mixed as required to prepare a formulation.
The compound of the present invention can be used in
cancer treatment of mammals, in particular, humans. The
dose and the administration interval can be suitably
selected depending on the site of the disease, the
patient's height, body weight, sex, or medical history,
according to a physician's judgment. When the compound
of the present invention is administered to a human, the
dose range is approx. 0.01 to 500 mg/kg body weight per
day, preferably, approx. 0.1 to 100 mg/kg body weight.
Preferably, the compound of the present invention is
administered to a human once a day, or the dose is
divided two to four times, and administration is repeated
at an appropriate interval. Furthermore, the daily dose
may exceed the above-mentioned dose at a physician's
discretion, if necessary.
The compound of the present invention may be used in
combination with an additional anti-tumor agent.
Examples thereof include anti-tumor antibiotics, anti-
tumor plant constituents, BRMs (biological response
modifiers), hormones, vitamins, anti-tumor antibodies,
molecular target drugs, and other anti-tumor agents.
More specifically, examples of alkylating agents
include: alkylating agents such as nitrogen mustard,
nitrogen mustard N-oxide, and chlorambucil; aziridine
alkylating agents such as carboquone and thiotepa;
epoxide alkylating agents such as dibromomannitol and
dibromodulcitol; nitrosourea alkylating agents such as
carmustine, lomustine, semustine, nimustine hydrochloride,
streptozocin, chlorozotocin, and ranimustine; and
busulfan, improsulfan tosylate, and dacarbazine.
Examples of various metabolic antagonists include:
purine metabolic antagonists such as 6-mercaptopurine, 6-
thioguanine, and thioinosine; pyrimidine metabolic
antagonists such as fluorouracil, tegafur, tegafur-uracil,
carmofur, doxifluridine, broxuridine, cytarabine, and
enocitabine; and folic acid metabolic antagonists such as
methotrexate and trimetrexate.
Examples of anti-tumor antibiotics include: anti-
tumor anthracycline antibiotics such as mitomycin C,
bleomycin, peplomycin, daunorubicin, aclarubicin,
doxorubicin, pirarubicin, THP-adriamycin, 4'-
epidoxorubicin, and epirubicin; and chromomycin A3 and
actinomycin D.
Examples of anti-tumor plant constituents include:
vinca alkaloids such as vindesine, vincristine, and
vinblastine; taxanes such as paclitaxel and docetaxel;
and epipodophyllotoxins such as etoposide and teniposide.
Examples of BRMs include tumor necrosis factors and
indomethacin.
Examples of hormones include hydrocortisone,
dexamethasone, methylprednisolone, prednisolone,
prasterone, betamethasone, triamcinolone, oxymetholone,
nandrolone, metenolone, fosfestrol, ethinylestradiol,
chlormadinone, and medroxyprogesterone.
Examples of vitamins include vitamin C and vitamin A.
Examples of anti-tumor antibodies and molecular
target drugs include trastuzumab, rituximab, cetuximab,
nimotuzumab, denosumab, bevacizumab, infliximab, imatinib
mesylate, gefitinib, erlotinib, sunitinib, lapatinib, and
sorafenib.
Examples of other anti-tumor agents include
cisplatin, carboplatin, oxaliplatin, tamoxifen,
camptothecin, ifosfamide, cyclophosphamide, melphalan, L-
asparaginase, aceglatone, sizofiran, picibanil,
procarbazine, pipobroman, neocarzinostatin, hydroxyurea,
ubenimex, and krestin.
The present invention also includes a method for
preventing and/or treating cancer, comprising
administering a compound of the present invention or a
salt thereof.
The present invention further includes use of a
compound of the present invention, a salt, or a solvate
thereof for the manufacture of a medicament.
Hereinafter, the present invention will be
specifically explained with reference to the Examples.
However, the present invention is not limited to these
examples, and they should not be construed in any
limitative way. Furthermore, reagents, solvents, and
starting materials in the specification can be readily
obtained from commercially available supply sources
unless otherwise specified.
Examples
Example 1
O Ph
O Ph
Step 1
N Ph
工 程 1
Cl Cl
H N OH OH
2 Step 3
O 工 程 3
Ph N
N Ph
S 工 te 程 p 2 2 Cl
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-dione
(5R,6S)-5,6-diphenylmorpholinone (506 mg, 2.00
mmol), 4,4-dimethylcyclohexanone (252 mg, 2.00 mmol), and
4A molecular sieves (powder) (2 g) were added to a
toluene (20 ml) solution of (3E/Z)chloro(3-chloro-
2-fluorobenzylidene)-1,3-dihydro-2H-indolone
(WO2006/091646) (616 mg, 2.00 mmol) under a nitrogen
atmosphere and the resulting mixture was stirred under
heating at 70 C for 5 days. After cooling, insoluble
matter was removed by filtration through celite and the
filtrate was concentrated under reduced pressure. The
residue was dissolved in ethyl acetate and the organic
layer was washed with 1N hydrochloric acid and brine and
then dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 9:1 fi 6:1 (v/v)] to give 194 mg
(14%) of the title compound as a yellow amorphous solid.
H-NMR (400 MHz, CDCl ) d : 0.19 (3H, s), 0.52 (3H, s),
0.94-1.00 (3H, m), 1.29-1.41 (3H, m), 1.80 (1H, d, J =
11.0 Hz), 2.27 (1H, d, J = 14.2 Hz), 4.61 (1H, d, J =
11.0 Hz), 4.86 (1H, d, J = 2.7 Hz), 5.35 (1H, d, J = 11.4
Hz), 6.23 (1H, d, J = 8.2 Hz), 6.60 (1H, dd, J = 8.2, 1.8
Hz), 6.72-6.78 (2H, m), 6.88 (1H, d, J = 1.8 Hz), 7.07-
7.26 (11H, m), 7.67 (1H, s), 7.77 (1H, t, J = 6.4 Hz).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
transaminocyclohexanol (167 mg, 1.45 mmol) was
added to a tetrahydrofuran (10 ml) solution of the
compound (194 mg, 0.29 mmol) obtained in Step 1 above and
the resulting mixture was heated to reflux for 6 days.
After cooling, saturated ammonium chloride solution was
added, followed by extraction with ethyl acetate. The
organic layer was washed with brine and then dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and the residue was purified by
silica gel column chromatography [chloroform:methanol =
100:0 fi 30:1 (v/v)] to give 230 mg (100%) of the title
compound as a pale yellow amorphous solid.
H-NMR (400 MHz, CDCl ) d : 0.51-0.57 (1H, m), 0.85-0.89
(5H, m), 1.05 (3H, s), 1.29-1.35 (6H, m), 1.69-1.71 (3H,
m), 1.82-1.97 (2H, m), 2.26-2.42 (2H, m), 2.90 (1H, d, J
= 12.8 Hz), 3.43-3.46 (2H, m), 3.73-3.74 (1H, m), 4.15
(1H, d, J = 7.8 Hz), 4.64 (1H, d, J = 11.0 Hz), 4.90 (1H,
d, J = 2.7 Hz), 5.55 (1H, s), 6.13 (1H, s), 6.41 (1H, t,
J = 6.4 Hz), 6.64 (1H, t, J = 7.8 Hz), 6.75 (1H, d, J =
1.8 Hz), 7.00-7.03 (2H, m), 7.09-7.11 (4H, m), 7.19-7.20
(5H, m), 7.36 (1H, s), 7.42 (2H, s).
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (230 mg, 0.29 mmol) obtained in Step 2
above was dissolved in acetonitrile (10 ml) and water (3
ml), cerium (IV) diammonium nitrate (318 mg, 0.58 mmol)
was added under ice cooling and the resulting mixture was
stirred for 10 minutes. Potassium carbonate (160 mg,
1.16 mmol) was added to the reaction mixture, the
resulting mixture was stirred and then insoluble matter
was removed by filtration through celite. The filtrate
was diluted with ethyl acetate, washed with brine and
then dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography
[chloroform:methanol = 100:0 fi 30:1 fi 20:1 (v/v)] to
give 90 mg (53%) of the title compound as a pale yellow
solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.94 (3H, s),
1.06-1.23 (2H, m), 1.25-1.44 (5H, m), 1.48-1.63 (2H, m),
1.71-2.06 (7H, m), 3.50-3.65 (2H, m), 4.48 (1H, d, J =
9.2 Hz), 4.66 (1H, d, J = 9.2 Hz), 6.73 (1H, d, J = 2.3
Hz), 7.00-7.06 (2H, m), 7.16-7.24 (1H, m), 7.39-7.45 (1H,
m), 7.57-7.64 (1H, m).
MS (ESI) m/z: 588 (M + H) .
Example 2
O Ph
O O Ph
Step 1
F 工 程 1
N Ph
Cl N Cl N
Step 3
工 程 3
Ph N
N Ph
工 程 2
Step 2
Cl N
Cl N
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-pyrrolo[2,3-b]pyridine]-1',2"(1"H)-
dione
(5R,6S)-5,6-diphenylmorpholinone (2.62 g, 10.3
mmol), 4,4-dimethylcyclohexanone (1.30 g, 10.3 mmol), and
anhydrous copper sulfate (16.4 g, 103 mmol) were added to
a toluene (80 ml) solution of the compound (2.67 g, 8.60
mmol) obtained in Reference Example 1 and the resulting
mixture was heated to reflux for 24 hours under a
nitrogen atmosphere. After cooling, insoluble matter was
removed by filtration through celite and the filtrate was
concentrated under reduced pressure. The residue was
dissolved in ethyl acetate and the organic layer was
washed with 1N hydrochloric acid solution and brine and
then dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 9:1 fi 6:1 (v/v)] to give 5.1 g
(90%) of the title compound as a yellow amorphous solid.
H-NMR (400 MHz, CDCl ) d : 0.20 (3H, s), 0.55 (3H, s),
0.90-1.08 (3H, m), 1.21-1.32 (1H, m), 1.33-1.47 (2H, m),
1.76-1.86 (1H, m), 2.26-2.36 (1H, m), 4.65 (1H, d, J =
11.2 Hz), 4.88 (1H, d, J = 3.2 Hz), 5.36 (1H, d, J = 11.2
Hz), 6.52 (1H, d, J = 7.8 Hz), 6.64 (1H, d, J = 8.2 Hz),
6.71-6.78 (2H, m), 7.06-7.24 (10H, m), 7.25-7.32 (1H, m),
7.74-7.83 (1H, m), 9.00 (1H, s).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[trans
(hydroxymethyl)cyclohexyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (260 mg, 0.39 mmol) obtained in Step 1
above and (transaminocyclohexyl)methanol (100 mg, 0.77
mmol) were used as starting materials and treated in the
same way as in Step 2 of Example 1 to give 260 mg (83%)
of the title compound as a pale yellow oil.
MS (ESI) m/z: 799 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(hydroxymethyl)cyclohexyl]-4,4-dimethyl-2"-oxo-
1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (260 mg, 0.33 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 63 mg (33%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.71 (3H, s), 0.95 (3H, s),
1.04-1.10 (2H, m), 1.20-1.32 (5H, m), 1.45-1.46 (1H, m),
1.56-1.59 (2H, m), 1.71-1.78 (2H, m), 1.85-2.01 (5H, m),
3.37 (2H, d, J = 6.0 Hz), 3.55-3.57 (1H, m), 4.52 (1H, d,
J = 9.6 Hz), 4.68 (1H, d, J = 9.6 Hz), 7.04-7.07 (2H, m),
7.24 (1H, t, J = 7.1 Hz), 7.59 (1H, t, J = 6.9 Hz), 7.83
(1H, dd, J = 7.8, 2.3 Hz).
MS (ESI) m/z: 603 (M + H) .
Example 3
O O Ph
O OH
H N OH
N Ph
N Ph
S 工 te 程 p 1 1
Cl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (670 mg, 1.00 mmol) obtained in Step 1
of Example 2 and the compound (262 mg, 2.0 mmol) obtained
in Step 3 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 2 of
Example 1 to give 200 mg (25%) of the title compound as a
light brown amorphous solid.
MS (ESI) m/z: 801 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (200 mg, 0.25 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 77 mg (51%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.71 (3H, s), 0.95 (3H, s),
1.16-1.20 (2H, m), 1.36-1.45 (2H, m), 1.58-1.61 (3H, m),
1.71-1.84 (4H, m), 2.01-2.11 (1H, m), 3.15 (1H, t, J =
.5 Hz), 3.36-3.39 (1H, m), 3.49 (2H, d, J = 5.0 Hz),
3.73-3.81 (1H, m), 3.88-3.96 (1H, m), 4.53 (1H, d, J =
9.2 Hz), 4.70 (1H, d, J = 9.2 Hz), 7.03-7.08 (2H, m),
7.21-7.27 (1H, m), 7.57 (1H, t, J = 6.9 Hz), 7.83 (1H, dd,
J = 7.8, 2.3 Hz).
MS (ESI) m/z: 605 (M + H) .
Example 4
O O Ph
Cl Step 1
O O Ph
N Ph
工 程 1
N Ph
Cl Cl
Step 3
H N OH NH OH
工 程 3
N Ph
S 工 te 程 p 2 2
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-3',4'-diphenyl-3',4',8',8a'-tetrahydro-1'H-
dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-
7',3"-indole]-1',2"(1"H)-dione
Cyclohexanone (0.25 ml, 2.40 mmol) was used as a
starting material and treated in the same way as in Step
1 of Example 1 to give 900 mg (70%) of the title compound
as a yellow solid.
H-NMR (400 MHz, CDCl ) d : 1.15-1.32 (8H, m), 2.01 (1H, d,
J = 12.9 Hz), 2.45 (1H, d, J = 13.4 Hz), 4.61 (1H, d, J =
11.0 Hz), 4.88 (1H, d, J = 2.9 Hz), 5.36 (1H, d, J = 11.5
Hz), 6.23 (1H, d, J = 8.3 Hz), 6.60 (1H, dd, J = 8.2, 1.8
Hz), 6.76 (2H, d, J = 6.8 Hz), 6.87 (1H, d, J = 1.7 Hz),
7.05-7.23 (11H, m), 7.42 (1H, s), 7.75 (1H, t, J = 6.6
Hz).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (320 mg, 0.50 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Example 1 to give 228 mg(60%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.49-0.53 (1H, m), 0.82-0.90
(3H, m), 1.28-1.30 (4H, m), 1.58-1.62 (2H, m), 1.80-1.90
(6H, m), 2.09 (1H, t, J = 11.4 Hz), 2.16-2.23 (1H, m),
3.03 (1H, d, J = 14.7 Hz), 3.43-3.45 (2H, m), 3.72-3.73
(1H, m), 4.12 (1H, d, J = 8.2 Hz), 4.65 (1H, d, J = 10.5
Hz), 4.90 (1H, d, J = 3.2 Hz), 5.53 (1H, d, J = 2.7 Hz),
6.18 (1H, s), 6.41 (1H, t, J = 6.6 Hz), 6.64 (1H, t, J =
8.0 Hz), 6.75 (1H, d, J = 1.8 Hz), 7.00-7.03 (2H, m),
7.10 (4H, q, J = 7.6 Hz), 7.17 (3H, t, J = 3.0 Hz), 7.21
(2H, d, J = 7.3 Hz), 7.34 (1H, s), 7.43 (2H, br s).
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (228 mg, 0.30 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 76 mg (45%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.88-0.97 (2H, m), 1.05-1.08
(1H, m), 1.29-1.43 (5H, m), 1.54-1.59 (2H, m), 1.64-1.79
(3H, m), 1.87-1.99 (5H, m), 3.56-3.58 (2H, m), 4.50 (1H,
d, J = 9.2 Hz), 4.65 (1H, d, J = 9.6 Hz), 6.71 (1H, d, J
= 2.3 Hz), 7.00-7.04 (2H, m), 7.18-7.22 (1H, m), 7.39 (1H,
dd, J = 8.2, 2.3 Hz), 7.61 (1H, t, J = 6.6 Hz).
MS (ESI) m/z: 560 (M + H) .
Example 5
O Ph
N Ph NH
F Ph
Step 1
工 程 1
N Ph
Cl N
Cl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-4,4-dimethyl-N-
[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
A methanol (18 ml) solution of the compound (3.61 g,
21.0 mmol) obtained in Step 3 of Reference Example 3 was
added to a methanol (6 ml) solution of the compound (3.42
g, 4.82 mmol) obtained in Step 1 of Example 2 under a
nitrogen atmosphere and the resulting mixture was stirred
under heating at 60 C for 2 days. After cooling,
dichloromethane was added and the organic layer was
washed with saturated ammonium chloride solution. The
organic layer was dried over anhydrous sodium sulfate,
the solvent was concentrated under reduced pressure and
the residue obtained was purified by silica gel column
chromatography [dichloromethane:methanol = 99:1 fi 49/1
(v/v)] to give 3.26 g of the title compound as a mixture
of isomers.
MS (ESI) m/z: 837 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-N-[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (3.26 g, 3.89 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 1.00 g (31%)
of the title compound as a pale yellow solid.
H-NMR (400 MHz, CDCl ) d : 0.71 (3H, s), 0.97 (3H, s),
1.14-1.28 (2H, m), 1.30-1.44 (3H, m), 1.46-1.61 (2H, m),
1.62-1.81 (5H, m), 2.09-2.29 (4H, m), 2.91-2.99 (1H, m),
3.17-3.30 (1H, m), 3.74-3.84 (1H, m), 4.48 (1H, d, J =
9.2 Hz), 4.70 (1H, d, J = 9.2 Hz), 6.97 (1H, t, J = 7.7
Hz), 7.06 (1H, d, J = 8.0 Hz), 7.14-7.19 (1H, m), 7.46-
7.51 (1H, m), 7.56 (1H, d, J = 8.6 Hz), 7.64 (1H, dd, J =
7.5, 2.3 Hz), 7.85 (1H, s), 8.33 (1H, s).
MS (ESI) m/z: 641 (M + H) .
Example 6
O O Ph
NH OH
N Ph
Step 1
工 程 1
Cl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (335 mg, 0.50 mmol) obtained in Step 1
of Example 2 was used as a starting material and treated
in the same way as in Step 2 of Example 1 to give 160 mg
(40%) of the title compound as a pale yellow amorphous
solid.
H-NMR (400 MHz, CDCl ) d : 0.55-0.59 (1H, m), 0.87 (3H,
s), 0.95-1.01 (1H, m), 1.05 (3H, s), 1.25-1.44 (6H, m),
1.63-1.69 (2H, m), 1.85-1.97 (2H, m), 2.29-2.33 (2H, m),
2.82 (1H, d, J = 15.9 Hz), 3.45 (1H, s), 3.70-3.73 (3H,
m), 4.42 (1H, d, J = 7.8 Hz), 4.54 (1H, d, J = 10.5 Hz),
4.85 (1H, d, J = 3.4 Hz), 5.56 (1H, s), 5.67 (1H, s),
6.58 (1H, s), 6.77 (1H, t, J = 7.8 Hz), 6.95 (1H, d, J =
7.8 Hz), 7.03-7.05 (2H, m), 7.14-7.24 (9H, m), 7.38-7.46
(2H, m), 7.48 (1H, s).
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (160 mg, 0.20 mol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 30 mg (25%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.71 (3H, s), 0.95 (3H, s),
1.09-1.25 (2H, m), 1.26-1.43 (5H, m), 1.51-1.63 (2H, m),
1.64-2.02 (7H, m), 3.49-3.64 (2H, m), 4.52 (1H, d, J =
9.3 Hz), 4.68 (1H, d, J = 9.3 Hz), 7.01-7.09 (2H, m),
7.20-7.28 (1H, m), 7.54-7.62 (1H, m), 7.83 (1H, dd, J =
7.9, 2.6 Hz).
MS (ESI) m/z: 589 (M + H) .
Example 7
O Ph
N Ph
S 工 te 程 p 1 1
H OH
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-[(3S)-
3,4-dihydroxybutyl]-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (1.01 g, 1.51 mmol) obtained in Step 1
of Example 1 and (2S)aminobutane-1,2-diol
(WO2007/011162) (475 mg, 4.53 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Example 1 to give 644 mg (55%) of the title compound as a
colorless amorphous solid.
MS (ESI) m/z: 774 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3S)-3,4-dihydroxybutyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (644 mg, 0.83 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 330 mg (67%)
of the title compound as a colorless amorphous solid.
H-NMR (400 MHz, DMSO-d ) d : 0.58 (3H, s), 0.88 (3H, s),
0.94 (1H, td, J = 13.9, 4.3 Hz), 1.09 (1H, d, J = 13.3
Hz), 1.18 (1H, d, J = 13.4 Hz), 1.30-1.63 (5H, m), 1.71-
1.81 (2H, m), 3.05-3.08 (1H, m), 3.19-3.32 (3H, m), 3.40-
3.47 (2H, m), 4.38 (1H, t, J = 9.8 Hz), 4.49 (2H, dd, J =
12.1, 5.3 Hz), 4.55 (1H, d, J = 9.2 Hz), 6.66 (1H, d, J =
1.8 Hz), 7.02 (1H, dd, J = 8.2, 1.8 Hz), 7.09 (1H, t, J =
8.0 Hz), 7.30 (1H, td, J = 7.6, 1.4 Hz), 7.42 (1H, dd, J
= 8.0, 2.1 Hz), 7.56 (1H, t, J = 6.6 Hz), 7.98 (1H, t, J
= 6.2 Hz), 10.50 (1H, br s).
MS (ESI) m/z: 578 (M + H) .
Example 8
NH OH
N Ph
工 程 1
Step 1
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (164 mg, 0.24 mmol) obtained in Step 1
of Example 1 and the compound (79.0 mg, 0.49 mmol)
obtained in Step 3 of Reference Example 2 were used as
starting materials and treated in the same way as in Step
1 of Example 5 to give 92.5 mg of the title compound as a
mixture of isomers.
MS (ESI) m/z: 800 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (92.5 mg, 0.12 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 28.1 mg (19%)
of the title compound as a pale yellow solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.09-1.27 (3H, m), 1.32-1.39 (1H, m), 1.41-1.79 (6H, m),
1.97-2.06 (1H, m), 2.08-2.14 (1H, m), 3.12 (1H, t, J =
.6 Hz), 3.40-3.46 (1H, m), 3.51-3.57 (1H, m), 3.58-3.65
(1H, m), 3.84-3.95 (1H, m), 4.06-4.11 (1H, m), 4.45 (1H,
d, J = 9.2 Hz), 4.67 (1H, d, J = 9.2 Hz), 6.69 (1H, d, J
= 2.0 Hz), 6.88-6.93 (1H, m), 7.05 (1H, dd, J = 8.3, 2.0
Hz), 7.10-7.14 (1H, m), 7.31-7.35 (1H, m), 7.41 (1H, s),
7.47-7.55 (2H, m).
MS (ESI) m/z: 604 (M + H) .
Example 9
O O Ph
Step 1
N Ph
工 程 1
H N OH
NH OH
Step 3 H
O 工 程 3
Ph N
N Ph
Step 2
工 程 2 Cl
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6"-chloro-8'-(2-chloropyridin
yl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-tetrahydro-
1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-
7',3"-indole]-1',2"(1"H)-dione
A boron trifluoride-diethyl ether complex (0.038 ml,
0.30 mmol) and 4A molecular sieves (powder) (3 g) were
added to a tetrahydrofuran (30 ml) solution of the
compound (873 mg, 3.00 mmol) obtained in Reference
Example 4, (5R,6S)-5,6-diphenylmorpholinone (760 mg,
3.00 mmol), and 4,4-dimethylcyclohexanone (379 mg, 3.00
mmol) under a nitrogen atmosphere and the resulting
mixture was stirred under heating at 70 C for 7 days.
After cooling, insoluble matter was removed by filtration
through celite and the filtrate was washed with brine and
then dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 4:1 fi 1:1 (v/v)] to give 1.18 g
(60%) of the title compound as a pale yellow amorphous
solid.
H-NMR (400 MHz, CDCl ) d : 0.54 (3H, s), 0.67 (3H, s),
0.80-0.92 (1H, m), 1.15-1.41 (4H, m), 1.71-1.82 (1H, m),
1.82-1.94 (1H, m), 2.15-2.26 (1H, m), 4.42 (1H, d, J =
.7 Hz), 4.81 (1H, d, J = 3.7 Hz), 5.03 (1H, d, J = 10.7
Hz), 6.60-6.68 (2H, m), 6.78-6.84 (2H, m), 6.85-6.89 (1H,
m), 6.91-6.98 (2H, m), 7.06-7.31 (9H, m), 7.47 (1H, s),
8.14 (1H, d, J = 5.1 Hz).
[Step 2]
(4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-N-(trans
hydroxycyclohexyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (195 mg, 0.30 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Example 1 to give 184 mg (80%)
of the title compound as a yellow amorphous solid.
MS (ESI) m/z: 767 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-N-
(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (184 mg, 0.24 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 81 mg (59%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.94 (3H, s),
1.13-1.19 (2H, m), 1.33-1.41 (5H, m), 1.50-1.60 (2H, m),
1.76-1.78 (3H, m), 1.95-1.99 (4H, m), 3.58-3.60 (2H, m),
4.21 (1H, d, J = 9.2 Hz), 4.60 (1H, d, J = 9.2 Hz), 6.79
(1H, d, J = 1.8 Hz), 7.06 (1H, dd, J = 5.3, 1.6 Hz), 7.10
(1H, dd, J = 8.2, 1.8 Hz), 7.23 (1H, s), 7.52 (1H, d, J =
8.2 Hz), 8.06 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 575 (M + H) .
Example 10
Ph O OH
N Ph
S 工 te 程 p 1 1
N Ph
Step 2 H
工 程 2
[Step 1]
(4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)(1-
hydroxymethylethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (159 mg, 1.00 mmol) obtained in Step 2
of Reference Example 5 and triethylamine (0.14 ml, 1.00
mmol) were added to a 2-propanol (4 ml) solution of the
compound (195 mg, 0.30 mmol) obtained in Step 1 of
Example 9 and the resulting mixture was stirred under
heating at 70 C for 4 days. After cooling, the reaction
mixture was diluted with ethyl acetate, washed with
saturated ammonium chloride solution and brine and then
dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the residue was
purified by silica gel column chromatography
[chloroform:methanol = 100:0 fi 40:1 (v/v)] to give 98 mg
(40%) of the title compound as a pale yellow amorphous
solid.
MS (ESI) m/z: 811 (M + H) .
[Step 2]
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-N-
[(3R,6S)(1-hydroxymethylethyl)tetrahydro-2H-pyran-
3-yl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
Cerium (IV) diammonium nitrate (132 mg, 0.24 mmol)
was added to an acetonitrile (10 ml)/water (3 ml)
solution of the compound (98 mg, 0.12 mmol) obtained in
Step 1 above under ice cooling and the resulting mixture
was stirred for 10 minutes. Potassium carbonate (65 mg,
0.48 mmol) was added to the reaction mixture and
insoluble matter was removed by filtration through celite.
The filtrate was diluted with ethyl acetate, washed with
brine and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure, the
residue was dissolved in chloroform (9 ml) and methanol
(1 ml), silica gel (980 mg) was added and the resulting
mixture was stirred overnight at room temperature.
Insoluble matter was removed by filtration and the
residue was purified by NH-silica gel column
chromatography (chloroform) to give 39 mg (53%) of the
title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.95 (3H, s),
1.14-1.16 (9H, m), 1.31-1.34 (1H, m), 1.48-1.58 (3H, m),
1.77-1.79 (3H, m), 1.83-1.86 (1H, m), 2.06-2.08 (1H, m),
3.11-3.16 (2H, m), 3.74-3.75 (1H, m), 3.98-4.01 (1H, m),
4.23 (1H, d, J = 9.2 Hz), 4.61 (1H, d, J = 8.7 Hz), 6.79
(1H, d, J = 1.8 Hz), 7.06 (1H, dd, J = 5.3, 1.6 Hz), 7.11
(1H, dd, J = 8.0, 2.1 Hz), 7.22-7.30 (1H, m), 7.52 (1H, d,
J = 8.2 Hz), 8.06 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 615 (M + H) .
Example 11
O O O OH
NH OH
N Ph
Step 1
工 程 1
Cl N
Cl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)(1-
hydroxymethylethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
Trimethylaluminum (2.0 mol/l, n-hexane solution, 0.5
ml, 1.00 mmol) was added to a tetrahydrofuran (6.0 ml)
solution of the compound (201 mg, 0.30 mmol) obtained in
Step 1 of Example 2 under ice cooling under a nitrogen
atmosphere and the resulting mixture was stirred for 30
minutes. A tetrahydrofuran (4 ml) solution of the
compound (159 mg, 1.00 mmol) obtained in Step 2 of
Reference Example 5 was added to the reaction mixture and
the resulting mixture was warmed to 50 C and stirred
overnight. After cooling, 1N hydrochloric acid was added,
followed by extraction with ethyl acetate. The organic
layer was washed with brine and then dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel
column chromatography [chloroform:methanol = 50:0 fi 30:1
(v/v)] to give 56 mg (22%) of the title compound as a
purple amorphous solid.
H-NMR (400 MHz, CDCl ) d : 0.86 (3H, s), 1.05 (3H, s),
1.08-1.14 (6H, m), 1.23-1.34 (2H, m), 1.38-1.70 (5H, m),
1.98-2.07 (1H, m), 2.20-2.41 (4H, m), 2.75-2.84 (1H, m),
2.85-2.91 (1H, m), 3.61-3.69 (1H, m), 3.71-3.78 (1H, m),
3.80-3.92 (1H, m), 4.37-4.44 (1H, m), 4.45-4.52 (1H, m),
4.82-4.87 (1H, m), 5.37 (1H, s), 5.52-5.57 (1H, m), 6.56-
6.64 (1H, m), 6.78 (1H, t, J = 7.8 Hz), 6.94 (1H, d, J =
7.8 Hz), 7.02-7.08 (1H, m), 7.09-7.15 (2H, m), 7.16-7.25
(8H, m), 7.38-7.46 (2H, m), 7.64 (1H, s).
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(1-hydroxymethylethyl)tetrahydro-2H-pyran-
3-yl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (56 mg, 0.067 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 30 mg (70%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.71 (3H, s), 0.95 (3H, s),
1.09-1.39 (9H, m), 1.43-1.90 (8H, m), 2.04-2.13 (1H, m),
3.04-3.17 (2H, m), 3.69-3.80 (1H, m), 3.91-3.99 (1H, m),
4.52 (1H, d, J = 9.2 Hz), 4.70 (1H, d, J = 9.2 Hz), 7.02-
7.10 (2H, m), 7.20-7.28 (1H, m), 7.54-7.61 (1H, m), 7.83
(1H, dd, J = 7.8, 2.3 Hz).
MS (ESI) m/z: 633 (M + H) .
Example 12
Ph OH
O O O
Step 1
N Ph 工 程 1
N Cl
N OH O
2 HCl
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxylic acid
1N sodium hydroxide solution (50 ml, 50 mmol) was
added to a methanol (250 ml) solution of the compound
(15.7 g, 23.4 mmol) obtained in Step 1 of Example 1 and
the resulting mixture was heated to reflux overnight.
After cooling, methanol (500 ml) and water (200 ml) were
added to the reaction mixture and then the resulting
mixture was neutralized by addition of 1N hydrochloric
acid (50 ml) under ice cooling. Cerium (IV) diammonium
nitrate (26.9 g, 49.1 mmol) was added under ice cooling,
the resulting mixture was stirred for 20 minutes, then
potassium carbonate (13.6 g, 98.3 mmol) was added and the
resulting mixture was stirred for a further 30 minutes.
Insoluble matter was removed by filtration through celite
and the filtrate was concentrated under reduced pressure.
The residue was diluted with water, followed by
extraction with ethyl acetate. The aqueous layer was
further subjected to extraction with chloroform:methanol
[5:1 (v/v)], the organic layers were combined and dried
over anhydrous sodium sulfate, then the solvent was
evaporated under reduced pressure and the residue was
dried to give 6.54 g (57%) of the title compound as a
pale yellow solid.
H-NMR (400 MHz, CD OD) d : 0.75 (3H, s), 1.02 (3H, s),
1.26-1.36 (1H, m), 1.39-1.45 (1H, m), 1.46-1.54 (1H, m),
1.60-1.67 (1H, m), 1.74-1.83 (1H, m), 1.94-2.00 (1H, m),
2.06-2.14 (1H, m), 2.34-2.43 (1H, m), 4.50-4.98 (2H, m),
6.76 (1H, d, J = 2.3 Hz), 7.08-7.14 (2H, m), 7.28-7.32
(1H, m), 7.56 (1H, dd, J = 8.0, 2.3 Hz), 7.60-7.65 (1H,
MS (ESI) m/z: 491 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(3-hydroxyazetidinyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (146 mg, 0.60 mmol) obtained in Step 2
of Reference Example 13, triethylamine (0.14 ml, 1.00
mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), and 1-
ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride
(105 mg, 0.55 mmol) were added to an N,N-
dimethylformamide (5 ml) solution of the compound (246 mg,
0.50 mmol) obtained in Step 1 above and the resulting
mixture was stirred at room temperature for 18 hours.
The reaction mixture was diluted with ethyl acetate,
washed with water, saturated sodium bicarbonate solution,
and brine in this order and then dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced
pressure, then the residue was purified by silica gel
column chromatography [chloroform:methanol = 70:1 (v/v)]
and the purified product obtained was dissolved in
methanol (10 ml) and stirred at 60 C for 24 hours. The
solvent was evaporated under reduced pressure to give 150
mg (47%) of the title compound as a pale yellow solid.
H-NMR (400 MHz, CD OD) d : 0.71 (3H, s), 0.96 (3H, s),
1.06-1.39 (7H, m), 1.53-1.63 (1H, m), 1.75-2.03 (7H, m),
2.10-2.18 (1H, m), 2.88-2.96 (2H, m), 3.26-3.32 (1H, m),
3.53-3.62 (1H, m), 3.62-3.71 (2H, m), 4.30-4.36 (1H, m),
4.50 (1H, d, J = 9.2 Hz), 4.68 (1H, d, J = 9.7 Hz), 6.75
(1H, d, J = 2.3 Hz), 7.02-7.07 (2H, m), 7.22 (1H, t, J =
8.0 Hz), 7.44 (1H, dd, J = 8.0, 2.3 Hz), 7.63 (1H, t, J =
6.6 Hz).
MS (ESI) m/z: 643 (M + H) .
Example 13
O Ph
O OH
N Ph
N Ph
S 工 te 程 p 1 1
N Ph
Step 2
工 程 2
[Step 1]
(4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (195 mg, 0.30 mmol) obtained in Step 1
of Example 9 and the compound (131 mg, 1.00 mmol)
obtained in Step 3 of Reference Example 2 were used as
starting materials and treated in the same way as in Step
1 of Example 10 to give 233 mg (99%) of the title
compound as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 0.87 (3H, s), 1.05 (3H, s),
1.07-1.19 (1H, m), 1.21-1.32 (1H, m), 1.35-1.54 (2H, m),
1.58-1.76 (3H, m), 1.89-1.98 (1H, m), 2.00-2.08 (1H, m),
2.20-2.37 (2H, m), 2.51 (1H, t, J = 10.5 Hz), 2.75-2.85
(1H, m), 3.19-3.28 (1H, m), 3.43-3.61 (3H, m), 3.68-3.76
(1H, m), 3.84-3.97 (1H, m), 4.12 (1H, d, J = 11.0 Hz),
4.66-4.78 (1H, m), 4.84-4.91 (1H, m), 5.20-5.30 (1H, m),
.50-5.57 (1H, m), 6.51-6.55 (1H, m), 6.71-6.76 (2H, m),
6.92 (1H, d, J = 8.2 Hz), 6.99 (1H, dd, J = 8.2, 1.8 Hz),
7.01-7.08 (1H, m), 7.08-7.18 (4H, m), 7.21-7.28 (4H, m),
7.35 (1H, s), 7.39-7.47 (2H, m), 8.00 (1H, d, J = 5.0 Hz).
[Step 2]
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-N-
[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (233 mg, 0.30 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Example 10 to give 90 mg (52%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.94 (3H, s),
1.17-1.19 (2H, m), 1.31-1.33 (1H, m), 1.41-1.62 (4H, m),
1.75-1.79 (4H, m), 2.05 (1H, d, J = 11.0 Hz), 3.18 (1H, t,
J = 10.5 Hz), 3.37-3.41 (1H, m), 3.50 (2H, d, J = 5.0 Hz),
3.77-3.81 (1H, m), 3.95-3.98 (1H, m), 4.23 (1H, d, J =
8.7 Hz), 4.61 (1H, d, J = 9.2 Hz), 6.79 (1H, d, J = 1.8
Hz), 7.06 (1H, dd, J = 5.3, 1.6 Hz), 7.11 (1H, dd, J =
8.2, 1.8 Hz), 7.22 (1H, s), 7.52 (1H, d, J = 8.2 Hz),
8.06 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 587 (M + H) .
Example 14
O Ph
O O Ph
Step 1
工 程 1
N Ph
N Ph
H N OH OH
NH OH
Step 3 H
工 程 3
N Ph
Step 2
工 程 2
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-dione
The compound (1.55 g, 5.00 mmol) obtained in
Reference Example 6 was used and treated in the same way
as in Step 1 of Example 9 to give 2.03 g (61%) of the
title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.48 (3H, s), 0.64 (3H, s),
0.83-0.92 (1H, m), 1.11-1.29 (3H, m), 1.33-1.41 (1H, m),
1.71-1.83 (2H, m), 2.15-2.24 (1H, m), 4.43 (1H, d, J =
11.0 Hz), 4.80 (1H, d, J = 3.7 Hz), 5.02 (1H, d, J = 11.0
Hz), 6.64 (1H, d, J = 8.7 Hz), 6.73 (2H, dd, J = 6.9, 2.8
Hz), 6.79 (2H, dt, J = 8.4, 2.9 Hz), 6.85-6.93 (4H, m),
7.09-7.18 (5H, m), 7.21-7.28 (3H, m), 7.44 (1H, br s).
MS (APCI) m/z: 669 (M + H) .
[Step 2]
(4'R,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (1.01 g, 1.51 mmol) obtained in Step 1
above was used and treated in the same way as in Step 2
of Example 1 to give 0.75g (63%) of the title compound as
a colorless amorphous solid.
MS (APCI) m/z: 784 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (0.72 g, 0.92 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 213 mg (40%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.93 (3H, s),
1.08-1.41 (8H, m), 1.49-1.62 (2H, m), 1.70-1.82 (3H, m),
1.87-2.02 (4H, m), 3.51-3.65 (2H, m), 4.17 (1H, d, J =
9.2 Hz), 4.52 (1H, d, J = 9.2 Hz), 6.77 (1H, d, J = 1.8
Hz), 6.84-6.89 (1H, m), 6.90-6.95 (1H, m), 6.97 (1H, s),
7.09 (1H, dd, J = 8.0, 2.1 Hz), 7.49 (1H, d, J = 8.3 Hz).
MS (ESI) m/z: 588 (M + H) .
Example 15
O O Ph
O O Ph
Step 1
工 程 1 Ph
N Ph
H N OH OH
2 Step 3
工 程 3
N Ph
工 程 2
Step 2
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-8'-(3-chlorofluorophenyl)-4,4-
dimethyl-1',2"-dioxo-3',4'-diphenyl-1",2",3',4',8',8a'-
hexahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-indole]-6"-carbonitrile
The compound (869 mg, 3.00 mmol) obtained in
Reference Example 7 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
49 mg (2%) of the title compound as a blackish brown
solid.
H-NMR (400 MHz, CDCl ) d : 0.22 (3H, s), 0.53 (3H, s),
0.91-1.09 (3H, m), 1.21-1.28 (1H, m), 1.32-1.45 (2H, m),
1.83-1.89 (1H, m), 2.29-2.35 (1H, m), 4.67 (1H, d, J =
11.5 Hz), 4.89 (1H, d, J = 3.4 Hz), 5.40 (1H, d, J = 11.5
Hz), 6.44 (1H, d, J = 8.0 Hz), 6.77 (2H, m), 6.97 (1H, dd,
J = 8.0, 1.1 Hz), 7.09-7.28 (12H, m), 7.68 (1H, s), 7.84
(1H, t, J = 6.6 Hz).
[Step 2]
(4'S,5'R)-4'-(3-chlorofluorophenyl)-6"-cyano-N-(trans-
4-hydroxycyclohexyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (49 mg, 0.074 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Example 1 to give 46 mg (80%) of
the title compound as a blackish brown oil.
MS (APCI) m/z: 775 (M + H) .
[Step 3]
(3'R,4'S,5'R)-4'-(3-chlorofluorophenyl)-6"-cyano-N-
(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (46 mg, 0.06 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 21 mg (62%) of
the title compound as a pale yellow solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.96 (3H, s),
1.09-1.17 (1H, m), 1.18-1.24 (1H, m), 1.30-1.44 (5H, m),
1.55-1.64 (2H, m), 1.74-1.85 (2H, m), 1.87-2.02 (5H, m),
3.55-3.66 (2H, m), 4.55 (1H, d, J = 9.2 Hz), 4.77 (1H, d,
J = 9.2 Hz), 7.02 (1H, br s), 7.04 (1H, t, J = 8.0 Hz),
7.22 (1H, t, J = 7.7 Hz), 7.44 (1H, d, J = 7.7 Hz), 7.64
(1H, t, J = 7.2 Hz), 7.69 (1H, d, J = 8.0 Hz).
MS (ESI) m/z: 579 (M + H) .
Example 16
O Ph
Step 1
工 程 1
N Ph
N Ph
N OH
2 NH
Step 3
工 程 3
Ph N
N Ph
工 程 2
Step 2
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-dione
The compound (1.86 g, 6.00 mmol) obtained in
Reference Example 8 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
3.39 g (84%) of the title compound as a yellow solid.
H-NMR (400 MHz, CDCl ) d : 0.21 (3H, s), 0.53 (3H, s),
0.89-1.08 (3H, m), 1.28-1.43 (3H, m), 1.73-1.81 (1H, m),
2.23-2.33 (1H, m), 4.58 (1H, d, J = 11.0 Hz), 4.86 (1H, d,
J = 3.2 Hz), 5.31 (1H, d, J = 11.0 Hz), 6.25 (1H, d, J =
8.3 Hz), 6.67 (1H, dd, J = 8.3, 1.8 Hz), 6.72-6.77 (2H,
m), 6.93 (1H, d, J = 1.8 Hz), 7.04-7.17 (6H, m), 7.18-
7.25 (3H, m), 7.79 (1H, t, J = 4.6 Hz), 7.99 (1H, s),
8.29 (1H, d, J = 5.0 Hz).
MS (APCI) m/z: 670 (M + H) .
[Step 2]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-N-
(transhydroxycyclohexyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (671 mg, 1.00 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Example 1 to give 730 mg (93%)
of the title compound as a pale yellow solid.
MS (ESI) m/z: 785 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-
1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (710 mg, 0.90 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 14 to give 357 mg (67%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.94 (3H, s),
1.09-1.24 (2H, m), 1.28-1.42 (5H, m), 1.50-1.63 (2H, m),
1.74-1.82 (3H, m), 1.85-2.02 (4H, m), 3.51-3.65 (2H, m),
4.53 (1H, d, J = 9.2 Hz), 4.65 (1H, d, J = 9.2 Hz), 6.76
(1H, d, J = 1.8 Hz), 7.06 (1H, dd, J = 8.0, 2.1 Hz), 7.45
(1H, dd, J = 8.3, 2.3 Hz), 7.66 (1H, t, J = 5.0 Hz), 8.06
(1H, d, J = 5.0 Hz).
MS (ESI) m/z: 589 (M + H) .
Example 17
Step 1
N Ph
工 程 1
工 Ste 程 p 2 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxylic acid
The compound (630 mg, 0.94 mmol) obtained in Step 1
of Example 16 was dissolved in acetonitrile (10 ml) and
water (4 ml), potassium carbonate (130 mg, 0.94 mmol) was
added and the resulting mixture was heated to reflux at
85 C for 16 hours. After cooling, anhydrous magnesium
sulfate (113 mg, 0.94 mmol) was added and the resulting
mixture was stirred at room temperature for 15 minutes.
After extraction with ethyl acetate, the organic layer
was washed with brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced
pressure to give (4'S,5'R)-6"-chloro-4'-(2-chloro
fluoropyridinyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxylic acid (650 mg, 100%) as a pale
orange amorphous solid [MS (ESI) m/z: 688 (M+H) .]. The
carboxylic acid (650 mg, 0.94 mmol) obtained was
dissolved in methanol (30 ml) and water (8 ml), cerium
(IV) diammonium nitrate (1.55 g, 2.82 mmol) was added
under ice cooling and the resulting mixture was stirred
at the same temperature for 30 minutes. Potassium
carbonate (780 mg, 5.64 mmol) was added under ice cooling
and the resulting mixture was stirred at the same
temperature for 1 hour. Insoluble matter was removed by
filtration through celite, then the filtrate was
concentrated under reduced pressure and water was added
to the residue obtained, followed by extraction with
ethyl acetate. The organic layer was washed with brine
and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the residue
obtained was purified by silica gel column chromatography
[chloroform:methanol = 20:1 fi 4:1 (v/v)] to give 152 mg
(33%) of the title compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 0.74 (3H, s), 0.9 (3H, s),
1.29-1.44 (2H, m), 1.48-1.58 (2H, m), 1.64-1.76 (1H, m),
1.94-2.02 (1H, m), 2.11 (1H, ddd, J = 14.0, 14.0, 4.0 Hz),
2.43-2.53 (1H, m), 5.07 (1H, d, J = 10.3 Hz), 5.32 (1H, d,
J = 10.3 Hz), 6.84 (1H, d, J = 1.7 Hz), 7.16 (1H, dd, J =
8.3, 2.0 Hz), 7.63 (1H, dd, J = 8.0, 2.3 Hz), 7.75 (1H, t,
J = 5.2 Hz), 8.15 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 492 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(1-hydroxymethylethyl)tetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
above and the compound (34 mg, 0.21 mmol) obtained in
Step 2 of Reference Example 5 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 38 mg (42%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.95 (3H, s),
1.09-1.24 (8H, m), 1.29-1.39 (1H, m), 1.44-1.63 (4H, m),
1.74-1.88 (4H, m), 2.05-2.13 (1H, m), 3.07-3.19 (2H, m),
3.71-3.81 (1H, m), 3.93-4.00 (1H, m), 4.54 (1H, d, J =
9.2 Hz), 4.67 (1H, d, J = 9.2 Hz), 6.75-6.78 (1H, m),
7.07 (1H, dd, J = 8.2, 1.8 Hz), 7.43-7.48 (1H, m), 7.65
(1H, t, J = 5.0 Hz), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 633 (M + H) .
Example 18
O O Ph
N OH
Step 1
工 程 1
N Ph
Cl F
Step 2 H
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-4,4-dimethyl-N-
[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (180 mg, 0.27 mmol) obtained in Step 1
of Example 16 and the compound (154 mg, 0.92 mmol)
obtained in Step 3 of Reference Example 3 were used as
starting materials and treated in the same way as in Step
1 of Example 5 to give 134 mg of the title compound as a
pale yellow amorphous solid.
MS (ESI) m/z: 837 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (134 mg, 0.16 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 73 mg (44%) of
the title compound as a pale yellow solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.96 (3H, s),
1.12-1.27 (2H, m), 1.31-1.44 (3H, m), 1.45-1.54 (2H, m),
1.58-1.82 (5H, m), 2.10-2.29 (4H, m), 2.92-3.00 (1H, m),
3.18-3.44 (1H, m), 3.74-3.84 (1H, m), 4.45 (1H, d, J =
8.9 Hz), 4.66 (1H, d, J = 8.9 Hz), 6.73 (1H, d, J = 1.7
Hz), 7.06 (1H, dd, J = 8.0, 1.7 Hz), 7.32 (1H, dd, J =
8.3, 2.0 Hz), 7.51 (1H, t, J = 5.2 Hz), 7.61 (1H, d, J =
8.3 Hz), 7.74 (1H, s), 8.04 (1H, d, J = 5.2 Hz), 8.34 (1H,
MS (ESI) m/z: 641 (M + H) .
Example 19
O OH
O OH N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(hydroxymethyl)-3,6-dihydro-2H-pyranyl]-
4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (60 mg, 0.12 mmol) obtained in Step 1
of Example 12 and the compound obtained in Step 2 of
Reference Example 9 were used as starting materials and
treated in the same way as in Step 2 of Example 12 to
give 59 mg (81%) of the title compound as a colorless
solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.92 (3H, s),
1.13-1.21 (2H, m), 1.29-1.35 (1H, m), 1.47-1.67 (3H, m),
1.73-1.78 (2H, m), 2.00 (1H, t, J = 6.1 Hz), 3.26 (1H, br
s), 3.48 (1H, dd, J = 11.2, 6.3 Hz), 3.65 (2H, t, J = 5.9
Hz), 4.10 (1H, dd, J = 11.4, 4.8 Hz), 4.25-4.29 (1H, m),
4.45-4.52 (2H, m), 4.70 (1H, d, J = 9.0 Hz), 5.84 (1H, dt,
J = 10.3, 1.7 Hz), 5.90 (1H, dt, J = 10.0, 2.6 Hz), 6.69
(1H, d, J = 1.7 Hz), 6.92 (1H, t, J = 8.1 Hz), 7.05 (1H,
dd, J = 8.2, 1.8 Hz), 7.11-7.15 (1H, m), 7.33-7.36 (2H,
m), 7.51 (1H, t, J = 6.6 Hz), 7.79 (1H, d, J = 9.0 Hz).
MS (ESI) m/z: 602 (M + H) .
Example 20
O O Ph
N H N
2 OH
N Ph O
N Ph
N Ph
Step 1
工 程 1
Step 2 H
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (131 mg, 1.00 mmol) obtained in Step 3
of Reference Example 2 and triethylamine (0.14 ml, 1.00
mmol) were added to a methanol (4 ml) solution of the
compound (268 mg, 0.40 mmol) obtained in Step 1 of
Example 16 and the resulting mixture was stirred at 50 C
for 5 days. After cooling, saturated ammonium chloride
solution was added, followed by extraction with ethyl
acetate. The organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography
[chloroform:methanol = 100:0 fi 30:1 (v/v)] to give 288
mg (89%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, CDCl ) d : 0.86 (3H, s), 1.05 (3H, s),
1.12-1.18 (1H, m), 1.26-1.29 (1H, m), 1.41-1.48 (2H, m),
1.58-1.68 (5H, m), 2.05 (1H, d, J = 9.6 Hz), 2.22-2.32
(2H, m), 2.61 (1H, t, J = 10.5 Hz), 2.83 (1H, d, J = 14.2
Hz), 3.26 (1H, s), 3.48-3.51 (1H, m), 3.56-3.58 (1H, m),
3.63 (1H, d, J = 10.5 Hz), 3.82-3.84 (1H, m), 3.89-3.91
(1H, m), 4.58 (1H, d, J = 10.5 Hz), 4.86 (1H, s), 4.97-
.01 (2H, m), 5.53 (1H, s), 6.40 (1H, t, J = 4.6 Hz),
6.79 (1H, s), 6.93 (1H, d, J = 7.8 Hz), 6.98 (1H, d, J =
8.2 Hz), 7.04-7.07 (1H, m), 7.12-7.13 (4H, m), 7.21-7.23
(3H, m), 7.42 (2H, s), 7.67 (1H, s), 7.75 (1H, d, J = 5.0
Hz).
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (288 mg, 0.36 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 140 mg (65%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.95 (3H, s),
1.15-1.21 (2H, m), 1.33-1.35 (1H, m), 1.43-1.48 (1H, m),
1.56-1.59 (3H, m), 1.76-1.79 (4H, m), 2.06 (1H, d, J =
11.9 Hz), 3.17 (1H, t, J = 10.8 Hz), 3.37-3.40 (1H, m),
3.49 (2H, d, J = 5.5 Hz), 3.77-3.80 (1H, m), 3.93 (1H, dd,
J = 9.8, 3.9 Hz), 4.54 (1H, d, J = 8.7 Hz), 4.67 (1H, d,
J = 9.2 Hz), 6.77 (1H, d, J = 1.8 Hz), 7.05-7.07 (1H, m),
7.46 (1H, dd, J = 8.2, 2.3 Hz), 7.65 (1H, t, J = 5.0 Hz),
8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 605 (M + H) .
Example 21
O Ph
O O Ph
Step 1
工 程 1 N Ph
N Ph
H N OH O
Step 2
工 程 2
N Ph Ph
N Ph
S 工 te 程 p 3 3
Step 5
Step 4
工 程 5 H
工 程 4
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-8'-(3-bromochlorophenyl)-6"-
chloro-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-dione
The compound (4.25 g, 11.5 mmol) obtained in
Reference Example 10 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
3.44 g (41%) of the title compound as a yellow solid.
H-NMR (400 MHz, CDCl ) d : 0.49 (3H, s), 0.65 (3H, s),
0.83-0.93 (1H, m), 1.12-1.29 (3H, m), 1.34-1.44 (1H, m),
1.74-1.84 (2H, m), 2.14-2.25 (1H, m), 4.39 (1H, d, J =
11.0 Hz), 4.80 (1H, d, J = 3.7 Hz), 5.00 (1H, d, J = 11.0
Hz), 6.62-6.68 (1H, m), 6.70-6.74 (1H, m), 6.79-6.85 (2H,
m), 6.88-6.94 (2H, m), 6.99-7.03 (1H, m), 7.07-7.19 (6H,
m), 7.20-7.25 (3H, m), 7.28-7.30 (1H, m), 7.48 (1H, s).
MS (FAB) m/z: 729 (M + H) .
[Step 2]
Methyl 3-chloro[(3'S,4'R,8'R,8a'R)-6"-chloro-4,4-
dimethyl-1',2"-dioxo-3',4'-diphenyl-1",2",3',4',8',8a'-
hexahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-indole]-8'-yl]benzoate
The compound (3.14 g, 4.30 mmol) obtained in Step 1
above was dissolved in dimethyl sulfoxide (40 ml) and
methanol (40 ml), triethylamine (0.71 ml, 5.16 mmol) and
a 1,1'-bis(diphenylphosphino)ferrocene-palladium (II)
dichloride dichloromethane complex (351 mg, 0.43 mmol)
were added and the resulting mixture was stirred under
heating at 90 C for 2 days under a carbon monoxide
atmosphere. Saturated sodium bicarbonate solution was
added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with
brine and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the
residue was purified by silica gel column chromatography
[n-hexane:ethyl acetate = 1:1 (v/v)] to give 0.40 g (13%)
of the title compound as a yellow solid.
MS (FAB) m/z: 709 (M + H) .
[Step 3]
Methyl 3-chloro{(4'R,5'R)-6"-chloro-5'-[(trans
hydroxycyclohexyl)carbamoyl]-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-4'-yl}benzoate
The compound (312 mg, 0.44 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 2 of Example 1 to give 302 mg (83%)
of the title compound as a pale yellow solid.
MS (FAB) m/z: 824 (M + H) .
[Step 4]
Methyl 3-chloro{(3'R,4'R,5'R)-6"-chloro-5'-[(trans
hydroxycyclohexyl)carbamoyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-4'-yl}benzoate
The compound (301 mg, 0.37 mmol) obtained in Step 3
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 under ice cooling to
give 104 mg (45%) of the title compound as a colorless
solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.94 (3H, s),
1.11-1.55 (10H, m), 1.59-1.80 (2H, m), 1.93-2.06 (4H, m),
3.26 (1H, s), 3.60-3.75 (2H, m), 3.82 (3H, s), 4.17 (1H,
d, J = 8.6 Hz), 4.52 (1H, d, J = 8.6 Hz), 6.73 (1H, d, J
= 2.3 Hz), 7.10 (1H, dd, J = 8.0, 1.7 Hz), 7.20-7.26 (1H,
m), 7.28-7.33 (2H, m), 7.53-7.58 (1H, m), 7.63 (1H, br s),
7.72-7.77 (1H, m).
MS (ESI) m/z: 628 (M + H) .
[Step 5]
(3'R,4'R,5'R)-6"-chloro-4'-[3-chloro
(methylcarbamoyl)phenyl]-N-(transhydroxycyclohexyl)-
4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
1N sodium hydroxide solution (0.19 ml, 0.19 mmol)
was added to a methanol (4 ml) solution of the compound
(81 mg, 0.13 mmol) obtained in Step 4 above and the
resulting mixture was stirred at 50 C for 4 hours. The
reaction mixture was neutralized by addition of 1N
hydrochloric acid and then the resulting mixture was
concentrated under reduced pressure. Dichloromethane (4
ml) was added to the residue, then methylamine
hydrochloride (26 mg, 0.39 mmol), triethylamine (0.11 ml,
0.77 mmol), and 1-ethyl(3-
dimethylaminopropyl)carbodiimide hydrochloride (74 mg,
0.39 mmol) were added and the resulting mixture was
stirred at room temperature for 24 hours. Saturated
sodium bicarbonate solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The
organic layer was washed with brine and then dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and then the residue was purified
by NH-silica gel column chromatography [methanol:ethyl
acetate = 5:95 (v/v)] to give 42 mg (52%) of the title
compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 0.69 (3H, s), 0.94 (3H, s),
1.08-1.24 (2H, m), 1.27-1.45 (5H, m), 1.48-1.63 (2H, m),
1.72-1.85 (3H, m), 1.87-2.02 (4H, m), 2.85 (3H, s), 3.51-
3.67 (2H, m), 4.21 (1H, d, J = 9.2 Hz), 4.62 (1H, d, J =
9.2 Hz), 6.74 (1H, d, J = 1.7 Hz), 7.09 (1H, dd, J = 8.0,
2.3 Hz), 7.23-7.26 (1H, m), 7.51 (1H, d, J = 8.0 Hz),
7.53-7.56 (2H, m).
MS (ESI) m/z: 627 (M + H) .
Example 22
OH O
N Ph
Cl Ph
工 程 1
Step 1
N Ph
Step 2
工 程 2
[Step 1]
1,5-anhydro[({(4'R,5'R)-6"-chloro-4'-[3-chloro
(methoxycarbonyl)phenyl]-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-indol]-
'-yl}carbonyl)amino]-2,3,4-trideoxy-D-erythro-hexitol
The compound (253 mg, 2.20 mmol) obtained in Step 3
of Reference Example 2 was added to a sulfolane (9 ml)
solution of the compound (1.27 g, 1.79 mmol) obtained in
Step 2 of Example 21 and the resulting mixture was
stirred under heating at 70 C for 28 hours. Saturated
sodium bicarbonate solution was added to the reaction
mixture, followed by extraction with ethyl acetate. The
organic layer was washed with brine and then dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and the residue was purified by
silica gel column chromatography [n-hexane:ethyl acetate
= 1:1 (v/v)] to give 511 mg (34%) of the title compound
as a pale yellow solid.
MS (FAB) m/z: 840 (M + H) .
[Step 2]
1,5-anhydro[({(3'R,4'R,5'R)-6"-chloro-4'-[3-chloro
(methoxycarbonyl)phenyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-yl}carbonyl)amino]-2,3,4-trideoxy-D-erythro-
hexitol
The compound (498 mg, 0.592 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 252 mg (66%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.69 (3H, s), 0.95 (3H, s),
1.11-1.23 (2H, m), 1.26-1.49 (2H, m), 1.50-1.68 (3H, m),
1.71-1.87 (4H, m), 2.01-2.11 (1H, m), 3.10-3.24 (1H, m),
3.34-3.43 (1H, m), 3.44-3.54 (2H, m), 3.72-3.80 (1H, m),
3.83 (3H, s), 3.92-4.00 (1H, m), 4.26 (1H, d, J = 9.2 Hz),
4.59 (1H, d, J = 8.7 Hz), 6.75 (1H, d, J = 1.8 Hz), 7.10
(1H, dd, J = 8.0, 2.1 Hz), 7.38-7.43 (1H, m), 7.53 (1H, d,
J = 8.3 Hz), 7.64-7.69 (1H, m), 7.70-7.74 (1H, m).
MS (ESI) m/z: 644 (M + H) .
Example 23
O O Ph
Step 1
工 程 1 N Ph
N Ph
Cl Cl
Step 3
NH OH
工 程 3
N Ph
Step 2
工 程 2
N Ph F
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(2-chloro
fluoropyridinyl)-5"-fluoro-4,4-dimethyl-3',4'-
diphenyl-3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-
1,6'-pyrrolo[2,1-c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-
dione
The compound (981 mg, 3.0 mmol) obtained in
Reference Example 11 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
1.20 g (58%) of the title compound as a pale pink solid.
H-NMR (400 MHz, CDCl ) d : 0.22 (3H, s), 0.55 (3H, s),
0.97-1.00 (3H, m), 1.29-1.38 (3H, m), 1.74 (1H, d, J =
11.4 Hz), 2.27 (1H, d, J = 11.4 Hz), 4.58 (1H, d, J =
11.4 Hz), 4.83 (1H, d, J = 2.7 Hz), 5.26 (1H, d, J = 11.4
Hz), 6.20 (1H, d, J = 8.7 Hz), 6.74 (2H, d, J = 7.3 Hz),
6.93 (1H, d, J = 6.0 Hz), 7.05-7.07 (3H, m), 7.11-7.16
(3H, m), 7.21-7.22 (3H, m), 7.42 (1H, s), 7.76 (1H, t, J
= 4.8 Hz), 8.32 (1H, d, J = 5.0 Hz).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
"-fluoro-1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-N-
[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (275 mg, 0.40 mmol) obtained in Step 1
above and the compound (131 mg, 1.00 mmol) obtained in
Step 3 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 1 of
Example 22 to give 205 mg (62%) of the title compound as
a pale yellow amorphous solid.
MS (ESI) m/z: 819 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-5"-fluoro-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (205 mg, 0.25 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 73 mg (57%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.70 (3H, s), 0.95 (3H, s),
1.12-1.22 (2H, m), 1.38-1.46 (2H, m), 1.57-1.63 (3H, m),
1.71-1.84 (4H, m), 2.07 (1H, d, J = 11.4 Hz), 3.17 (1H, t,
J = 10.5 Hz), 3.39 (1H, dd, J = 11.0, 5.0 Hz), 3.50 (2H,
d, J = 5.0 Hz), 3.74-3.82 (1H, m), 3.93 (1H, dd, J = 11.0,
4.6 Hz), 4.55 (1H, d, J = 9.2 Hz), 4.67 (1H, d, J = 9.2
Hz), 6.83 (1H, d, J = 6.4 Hz), 7.48 (1H, dd, J = 9.2, 1.8
Hz), 7.65 (1H, t, J = 5.0 Hz), 8.06 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 623 (M + H) .
Example 24
N Ph HCl
F NH OH
工 程 1 Ph
Step 1
N Ph
H Cl
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
{trans[(hydroxyacetyl)amino]cyclohexyl}-1'-[(1R,2S)
hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.22 mmol) obtained in Step 1
of Example 1 and N-(transaminocyclohexyl)
hydroxyacetamide hydrochloride (331 mg, 1.23 mmol) were
used as starting materials and treated in the same way as
in Step 1 of Example 20 to give 58 mg (31%) of the title
compound as a colorless solid.
MS (ESI) m/z: 841 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
{trans[(hydroxyacetyl)amino]cyclohexyl}-4,4-dimethyl-
2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (58 mg, 0.07 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 18 mg (40%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.95 (3H, s),
1.07-1.65 (10H, m), 1.74-2.03 (6H, m), 3.55-3.81 (2H, m),
3.94 (2H, s), 4.49 (1H, d, J = 9.2 Hz), 4.67 (1H, d, J =
9.2 Hz), 6.73 (1H, d, J = 1.8 Hz), 6.99-7.07 (2H, m),
7.16-7.23 (1H, m), 7.39-7.46 (1H, m), 7.57-7.65 (1H, m).
MS (ESI) m/z: 645 (M + H) .
Example 25
O O Ph
O Ph
Step 1
工 程 1
N Ph
Cl N
Cl N
OH N
NH OH
Step 3
工 程 3
N Ph N
N Ph
Step 2
工 程 2 Cl
Cl N
Cl N
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3"-pyrrolo[2,3-b]pyridine]-
1',2"(1"H)-dione
The compound (1.46g, 4.71 mmol) obtained in
Reference Example 12 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
1.90 g (60%) of the title compound as a pale red solid.
H-NMR (500 MHz, CDCl ) d : 0.21 (3H, s), 0.55 (3H, s),
0.93-1.07 (3H, m), 1.22-1.30 (1H, m), 1.33-1.42 (2H, m),
1.72-1.79 (1H, m), 2.24-2.31 (1H, m), 4.58 (1H, d, J =
11.5 Hz), 4.84 (1H, d, J = 3.4 Hz), 5.29 (1H, d, J = 11.5
Hz), 6.53 (1H, d, J = 8.0 Hz), 6.69 (1H, d, J = 7.5 Hz),
6.71-6.75 (2H, m), 7.04-7.08 (3H, m), 7.09-7.18 (3H, m),
7.19-7.25 (3H, m), 7.76-7.82 (1H, m), 8.16 (1H, s), 8.32
(1H, d, J = 4.6 Hz).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (204 mg, 0.30 mmol) obtained in Step 1
above and the compound (120 mg, 0.91 mmol) obtained in
Step 3 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 1 of
Example 5 to give 136 mg of the title compound as a
brownish red amorphous solid of a mixture of isomers.
MS (ESI) m/z: 802 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxamide
The compound (136 mg, 0.17 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 59 mg (32%) of
the title compound as a pale yellow solid.
H-NMR (500 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.13-1.28 (2H, m), 1.33-1.76 (8H, m), 1.99-2.13 (2H, m),
3.13 (1H, t, J = 10.9 Hz), 3.39-3.47 (1H, m), 3.51-3.58
(1H, m), 3.59-3.66 (1H, m), 3.84-3.94 (1H, m), 4.04-4.11
(1H, m), 4.45 (1H, d, J = 9.2 Hz), 4.66 (1H, d, J = 9.2
Hz), 7.07 (1H, d, J = 7.5 Hz), 7.40 (1H, d, J = 8.6 Hz),
7.45 (1H, t, J = 4.9 Hz), 7.61 (1H, dd, J = 7.5, 2.3 Hz),
7.97 (1H, br s), 8.09 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 606 (M + H) .
Example 26
N Ph OH
S 工t 程 ep 1 1
N Ph
Cl N
Cl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-4,4-dimethyl-N-
[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (202 mg, 0.30 mmol) obtained in Step 1
of Example 25 and the compound (176 mg, 1.05 mmol)
obtained in Step 3 of Reference Example 3 were used as
starting materials and treated in the same way as in Step
1 of Example 5 to give 142 mg of the title compound as a
brown amorphous solid.
MS (ESI) m/z: 838 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxamide
The compound (142 mg, 0.17 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 72 mg (37%) of
the title compound as a pale yellow solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.97 (3H, s),
1.14-1.29 (2H, m), 1.31-1.44 (3H, m), 1.46-1.55 (2H, m),
1.57-1.82 (5H, m), 2.09-2.29 (4H, m), 2.92-3.00 (1H, m),
3.17-3.40 (1H, m), 3.74-3.83 (1H, m), 4.47 (1H, d, J =
8.9 Hz), 4.68 (1H, d, J = 8.9 Hz), 7.07 (1H, d, J = 7.5
Hz), 7.48 (1H, t, J = 4.9 Hz), 7.53 (1H, d, J = 8.6 Hz),
7.63 (1H, dd, J = 8.0, 2.3 Hz), 8.08 (1H, d, J = 5.2 Hz),
8.30-8.38 (2H, m).
MS (ESI) m/z: 642 (M + H) .
Example 27
Cl O
H Cl
1,5-anhydro[({(3'R,4'R,5'R)-6"-chloro-4'-[3-chloro
(methylcarbamoyl)phenyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-yl}carbonyl)amino]-2,3,4-trideoxy-D-erythro-
hexitol
The compound (82 mg, 0.13 mmol) obtained in Step 2
of Example 22 was used as a starting material and treated
in the same way as in Step 5 of Example 21 to give 31 mg
(37%) of the title compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 0.69 (3H, s), 0.95 (3H, s),
1.09-1.24 (2H, m), 1.26-1.38 (1H, m), 1.38-1.49 (1H, m),
1.49-1.66 (3H, m), 1.70-1.86 (4H, m), 1.99-2.11 (1H, m),
2.85 (3H, s), 3.12-3.21 (1H, m), 3.35-3.42 (1H, m), 3.49
(2H, d, J = 5.2 Hz), 3.73-3.83 (1H, m), 3.91-3.98 (1H, m),
4.23 (1H, d, J = 9.2 Hz), 4.63 (1H, d, J = 9.2 Hz), 6.74
(1H, d, J = 2.3 Hz), 7.09 (1H, dd, J = 8.0, 1.7 Hz),
7.23-7.26 (1H, m), 7.51 (1H, d, J = 8.0 Hz), 7.52-7.57
(2H, m).
MS (ESI) m/z: 643 (M + H) .
Example 28
(3'R,4'R,5'R)-6"-chloro-4'-[3-chloro
(hydroxymethyl)phenyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
Lithium borohydride (26 mg, 1.25 mmol) was gradually
added to a tetrahydrofuran (4 ml) solution of the
compound (107 mg, 0.17 mmol) obtained in Step 2 of
Example 22 at room temperature and the resulting mixture
was stirred at the same temperature for 18 hours. Water
was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with
brine and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and then
the residue was purified by silica gel column
chromatography [methanol:ethyl acetate = 1:9 (v/v)] to
give 69 mg (68%) of the title compound as a colorless
solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.94 (3H, s),
1.04-1.24 (2H, m), 1.26-1.49 (2H, m), 1.50-1.65 (3H, m),
1.68-1.87 (4H, m), 2.00-2.12 (1H, m), 3.06-3.20 (1H, m),
3.34-3.43 (1H, m), 3.46-3.51 (2H, m), 3.71-3.83 (1H, m),
3.89-3.99 (1H, m), 4.18 (1H, d, J = 9.2 Hz), 4.40 (2H, s),
4.56 (1H, d, J = 9.2 Hz), 6.74 (1H, d, J = 1.8 Hz), 6.97-
7.02 (1H, m), 7.03-7.15 (3H, m), 7.49 (1H, d, J = 7.8 Hz).
MS (ESI) m/z: 616 (M + H) .
Example 29
O OH
O OH H N N
2 OH
N OH
Cl O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,5S,6R)hydroxy(hydroxymethyl)tetrahydro-
2H-pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 17 and the compound (39 mg, 0.27 mmol)
obtained in Step 4 of Reference Example 14 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 68 mg (67%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.10-1.27 (4H, m), 1.36-1.79 (5H, m), 2.32-2.42 (1H, m),
2.55 (1H, br s), 3.04-3.13 (1H, m), 3.14-3.21 (1H, m),
3.68-3.90 (3H, m), 3.95-4.07 (2H, m), 4.45 (1H, d, J =
9.0 Hz), 4.63 (1H, d, J = 9.0 Hz), 6.73 (1H, d, J = 1.8
Hz), 7.05-7.10 (1H, m), 7.29-7.34 (1H, m), 7.47-7.60 (3H,
m), 8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 621 (M + H) .
Example 30
O O Ph
N Ph
N Ph
Step 1
工 程 1
Cl N
Cl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,5S,6R)
hydroxy(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (170 mg, 0.25 mmol) obtained in Step 1
of Example 2 and the compound (145 mg, 0.98 mmol)
obtained in Step 4 of Reference Example 14 were used as
starting materials and treated in the same way as in Step
1 of Example 5 to give 100 mg (50%) of the title compound
as a colorless solid.
MS (ESI) m/z: 815 (M-H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,5S,6R)hydroxy(hydroxymethyl)tetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (99 mg, 0.12 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 44 mg (58%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.12-1.28 (3H, m), 1.35-1.81 (6H, m), 2.31-2.56 (2H, m),
3.03-3.12 (1H, m), 3.13-3.21 (1H, m), 3.68-3.90 (3H, m),
3.94-4.08 (2H, m), 4.48 (1H, d, J = 9.2 Hz), 4.67 (1H, d,
J = 9.2 Hz), 6.94-7.01 (1H, m), 7.06 (1H, d, J = 7.8 Hz),
7.14-7.21 (1H, m), 7.43-7.56 (2H, m), 7.63 (1H, dd, J =
8.0, 2.5 Hz), 7.88 (1H, br s).
MS (ESI) m/z: 621 (M + H) .
Example 31
O O Ph
H N O
N Ph OH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[cishydroxy(hydroxymethyl)cyclohexyl]-4,4-dimethyl-
2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
Triethylamine (0.22 ml, 1.58 mmol) was added to a
methanol (2 ml) solution of the compound (201 mg, 0.30
mmol) obtained in Step 1 of Example 1 and the compound
(278 mg, 1.53 mmol) obtained in Reference Example 15 and
the resulting mixture was stirred under heating overnight
at 60 C. The reaction mixture was diluted with ethyl
acetate, washed with water and brine in this order and
then dried over anhydrous magnesium sulfate. The solvent
was concentrated under reduced pressure and the residue
obtained was purified by silica gel column chromatography
[methanol:chloroform = 5:95 (v/v)]. The solid obtained
was dissolved in acetonitrile (1.8 ml) and water (0.6 ml),
cerium (IV) diammonium nitrate (136 mg, 0.25 mmol) was
added under ice cooling and the resulting mixture was
stirred for 30 minutes. Subsequently, potassium
carbonate (69 mg, 0.50 mmol) was added and the resulting
mixture was stirred for 30 minutes. Water was added,
followed by extraction with chloroform. The organic
layer was dried over anhydrous sodium sulfate. The
solvent was concentrated under reduced pressure,
chloroform (9 ml), methanol (1 ml), and silica gel (1 g)
were added to the residue obtained and the resulting
mixture was stirred at room temperature for 2 hours.
Insoluble matter was removed by filtration through celite
and the filtrate was concentrated under reduced pressure.
The residue obtained was purified by silica gel column
chromatography [methanol:chloroform = 5:95 (v/v)] to give
32 mg (17%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 0.60 (3H, s), 0.89 (3H, s),
0.96 (1H, td, J = 14.1, 4.1 Hz), 1.10-1.14 (1H, m), 1.22-
1.26 (1H, m), 1.35-1.59 (11H, m), 1.67-1.79 (2H, m), 3.14
(2H, d, J = 5.5 Hz), 3.37-3.43 (1H, m), 3.49 (1H, d, J =
.1 Hz), 3.94 (1H, s), 4.36 (1H, t, J = 9.2 Hz), 4.49
(1H, t, J = 5.7 Hz), 4.55 (1H, d, J = 9.6 Hz), 6.67 (1H,
d, J = 2.3 Hz), 7.04 (1H, dd, J = 8.3, 1.8 Hz), 7.11 (1H,
t, J = 8.0 Hz), 7.30-7.34 (1H, m), 7.44 (1H, dd, J = 8.0,
2.1 Hz), 7.56-7.60 (1H, m), 7.72 (1H, d, J = 8.7 Hz),
.52 (1H, s).
MS (ESI) m/z: 618 (M + H) .
Example 32
O O N H
Step 1
工 程 1
N Ph
H Cl
Step 2 H
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-4,4-dimethyl-2"-
oxo-N-[trans(4H-1,2,4-triazolyl)cyclohexyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (154 mg, 0.23 mmol) obtained in Step 1
of Example 16 and the compound (115 mg, 0.69 mmol)
obtained in Step 4 of Reference Example 16 were used as
starting materials and treated in the same way as in Step
1 of Example 5 to give 130 mg (68%) of the title compound
as a colorless solid.
MS (ESI) m/z: 835 (M-H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[trans(4H-1,2,4-triazol
yl)cyclohexyl]-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (130 mg, 0.16 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 77 mg (77%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.10-1.89 (12H, m), 2.08-2.25 (4H, m), 2.79-2.90 (1H, m),
3.72-3.87 (2H, m), 4.46 (1H, d, J = 9.2 Hz), 4.67 (1H, d,
J = 9.2 Hz), 6.74 (1H, d, J = 2.3 Hz), 7.05-7.10 (1H, m),
7.30-7.38 (2H, m), 7.49-7.54 (1H, m), 7.56-7.65 (1H, m),
8.01 (1H, s), 8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 640 (M + H) .
Example 33
OH N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[transhydroxy(hydroxymethyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (108 mg, 0.22 mmol) obtained in Step 1
of Example 12 and the compound (0.27 mmol) obtained in
Step 3 of Reference Example 17 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 93 mg (68%) of the title compound as a
colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 0.60 (3H, s), 0.88 (3H, s),
0.92-1.00 (1H, m), 1.10-1.14 (1H, m), 1.24-1.63 (10H, m),
1.69-1.77 (4H, m), 3.26 (2H, d, J = 6.0 Hz), 3.51 (1H, d,
J = 9.6 Hz), 3.68 (1H, s), 4.02 (1H, s), 4.38-4.45 (2H,
m), 4.52 (1H, d, J = 9.2 Hz), 6.67 (1H, d, J = 1.8 Hz),
7.03 (1H, dd, J = 8.3, 2.3 Hz), 7.11 (1H, t, J = 8.0 Hz),
7.30-7.34 (1H, m), 7.44 (1H, dd, J = 8.3, 1.8 Hz), 7.56-
7.60 (1H, m), 7.85 (1H, d, J = 8.3 Hz), 10.53 (1H, s).
MS (ESI) m/z: 618 (M + H) .
Example 34
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)(1,3,4-oxadiazol
yl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (81 mg, 0.16 mmol) obtained in Step 1
of Example 17 and the compound (34 mg, 0.20 mmol)
obtained in Step 6 of Reference Example 18 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 72 mg (68%) of the title compound
as a pale yellow solid.
H-NMR (500 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.12-1.27 (2H, m), 1.36-1.43 (1H, m), 1.45-1.55 (2H, m),
1.61-1.82 (4H, m), 2.11-2.29 (3H, m), 3.21-3.43 (2H, m),
3.99-4.08 (1H, m), 4.09-4.15 (1H, m), 4.47 (1H, d, J =
9.2 Hz), 4.65 (1H, d, J = 9.2 Hz), 4.78 (1H, dd, J = 9.7,
2.9 Hz), 6.73 (1H, d, J = 1.7 Hz), 7.06 (1H, dd, J = 8.3,
2.0 Hz), 7.31 (1H, dd, J = 8.3, 2.0 Hz), 7.51 (1H, t, J =
4.9 Hz), 7.70 (1H, d, J = 8.6 Hz), 7.92 (1H, s), 8.05 (1H,
d, J = 5.2 Hz), 8.43 (1H, s).
MS (ESI) m/z: 643 (M + H) .
Example 35
O OH
H N O
N NH
Cl N
H Cl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[trans(5-oxo-4,5-dihydro-
1,3,4-oxadiazolyl)cyclohexyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 17 and the compound (31 mg, 0.17 mmol)
obtained in Step 2 of Reference Example 19 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 53 mg (57%) of the title compound
as a pale yellow solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.10-1.80 (12H, m), 2.06-2.19 (4H, m), 2.52-2.61 (1H, m),
3.19-3.40 (1H, m), 3.69-3.80 (1H, m), 4.44 (1H, d, J =
9.2 Hz), 4.65 (1H, d, J = 9.2 Hz), 6.73 (1H, d, J = 2.3
Hz), 7.07 (1H, dd, J = 8.0, 1.7 Hz), 7.32 (1H, dd, J =
8.0, 2.3 Hz), 7.41 (1H, s), 7.50 (1H, t, J = 4.9 Hz),
7.59 (1H, d, J = 8.6 Hz), 8.05 (1H, d, J = 5.2 Hz), 8.76
(1H, s).
MS (ESI) m/z: 657 (M + H) .
Example 36
O NH
O Ph
Step 1
工 程 1
+ + Ph
H N OH O NH
2 Step 3
工 程 3
N Ph
S 工 te 程 p 2 2
O NH
Step 4 H
工 程 4
[Step 1]
tert-Butyl {3-chloro[(3'S,4'R,8'R,8a'R)-6"-chloro-4,4-
dimethyl-1',2"-dioxo-3',4'-diphenyl-1",2",3',4',8',8a'-
hexahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-indole]-8'-yl]phenyl}carbamate
The compound (2.41g, 6.16 mmol) obtained in Step 3
of Reference Example 20 was used as a starting material
and treated in the same way as in Step 1 of Example 9 to
give 859 mg (18%) of the title compound as a yellow solid.
MS (FAB) m/z: 766 (M + H) .
[Step 2]
tert-Butyl (3-chloro{(4'R,5'R)-6"-chloro-5'-[(trans
hydroxycyclohexyl)carbamoyl]-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-4'-yl}phenyl)carbamate
The compound (842 mg, 1.10 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Example 1 to give 621 mg (64%)
of the title compound as a colorless solid.
MS (FAB) m/z: 881 (M + H) .
[Step 3]
tert-Butyl (3-chloro{(3'R,4'R,5'R)-6"-chloro-5'-
[(transhydroxycyclohexyl)carbamoyl]-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-4'-yl}phenyl)carbamate
The compound (610 mg, 0.69 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 338 mg (71%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.93 (3H, s),
1.08-1.64 (18H, m), 1.68-1.84 (3H, m), 1.87-2.02 (4H, m),
3.48-3.68 (2H, m), 4.10 (1H, d, J = 9.2 Hz), 4.51 (1H, d,
J = 8.7 Hz), 6.74-6.79 (2H, m), 6.97-7.02 (1H, m), 7.08
(1H, dd, J = 8.0, 2.1 Hz), 7.30-7.35 (1H, m), 7.45 (1H, d,
J = 8.3 Hz).
MS (FAB) m/z: 685 (M + H) .
[Step 4]
(3'R,4'R,5'R)-4'-(3-aminochlorophenyl)-6"-chloro-N-
(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
4N hydrochloric acid/1,4-dioxane solution (1.16 ml,
4.64 mmol) was added to a 1,4-dioxane (6 ml) solution of
the compound (321 mg, 0.47 mmol) obtained in Step 3 above
and the resulting mixture was stirred at room temperature
for 24 hours. Saturated sodium bicarbonate solution was
added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with
brine and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and then
the residue was purified by silica gel column
chromatography [methanol:ethyl acetate = 1:4 (v/v)] to
give 248 mg (91%) of the title compound as a colorless
solid.
H-NMR (500 MHz, CD OD) d : 0.68 (3H, s), 0.93 (3H, s),
1.05-1.22 (2H, m), 1.24-1.42 (5H, m), 1.48-1.61 (2H, m),
1.69-1.82 (3H, m), 1.86-2.01 (4H, m), 3.51-3.64 (2H, m),
4.02 (1H, d, J = 9.2 Hz), 4.46 (1H, d, J = 9.2 Hz), 6.34-
6.37 (1H, m), 6.41-6.46 (2H, m), 6.76 (1H, d, J = 1.7 Hz),
7.06 (1H, dd, J = 8.3, 2.0 Hz), 7.43 (1H, d, J = 8.0 Hz).
MS (ESI) m/z: 585 (M + H) .
Example 37
(3'R,4'R,5'R)-4'-(3-acetamidochlorophenyl)-6"-chloro-
N-(transhydroxycyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (101 mg, 0.172 mmol) obtained in Step 4
of Example 36 and acetic acid (0.015 ml, 0.26 mmol) were
used as starting materials and treated in the same way as
in Step 2 of Example 12 to give 53 mg (49%) of the title
compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 0.68 (3H, s), 0.93 (3H, s),
1.08-1.22 (2H, m), 1.27-1.42 (5H, m), 1.49-1.61 (2H, m),
1.71-1.82 (3H, m), 1.86-2.02 (4H, m), 2.04 (3H, s), 3.51-
3.66 (2H, m), 4.11 (1H, d, J = 9.2 Hz), 4.51 (1H, d, J =
9.2 Hz), 6.76 (1H, d, J = 1.7 Hz), 6.86-6.88 (1H, m),
7.06-7.10 (2H, m), 7.46 (1H, d, J = 8.0 Hz), 7.57-7.59
(1H, m).
MS (ESI) m/z: 627 (M + H) .
Example 38
O O Ph
O O Ph
Step 1
N Ph
F 工 程 1
+ + F
Cl F
OH N
OH Step 3
NH H
工 程 3
工 程 2
Step 2 N Ph
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclobutane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-dione
The compound (5.44 g, 21.5 mmol) used as a starting
material in Step 1 of Example 1 (WO2006/091646) and the
compound (2.88 g, 21.5 mmol) obtained in Step 2 of
Reference Example 21 were used as starting materials and
treated in the same way as in Step 1 of Example 9 to give
.2 g (87%) of the title compound as a pale yellow
amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.95 (1H, d, J = 14.2 Hz),
2.26 (1H, d, J = 14.2 Hz), 2.79 (1H, d, J = 14.2 Hz),
2.88 (1H, d, J = 14.2 Hz), 3.82-4.02 (2H, m), 4.14-4.34
(2H, m), 4.55 (1H, d, J = 9.6 Hz), 4.73 (1H, d, J = 9.6
Hz), 5.19-5.23 (1H, m), 6.38 (1H, d, J = 4.1 Hz), 6.65
(1H, d, J = 7.8 Hz), 6.85-6.92 (3H, m), 6.95-7.01 (1H, m),
7.10-7.16 (2H, m), 7.18-7.25 (9H, m), 7.56 (1H, s).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (300 mg, 0.44 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Example 20 to give 233 mg (65%)
of the title compound as a pale yellow amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.12-1.27 (1H, m), 1.42-1.69
(3H, m), 2.04-2.13 (1H, m), 2.53-2.66 (2H, m), 2.85 (1H,
d, J = 14.7 Hz), 3.23-3.31 (1H, m), 3.36 (1H, d, J = 14.2
Hz), 3.45-3.53 (1H, m), 3.57 (1H, dd, J = 11.7, 3.0 Hz),
3.79-3.86 (2H, m), 3.91-4.02 (1H, m), 4.06-4.26 (3H, m),
4.43-4.62 (3H, m), 4.85 (1H, d, J = 3.7 Hz), 5.01 (1H, d,
J = 8.2 Hz), 5.59-5.64 (1H, m), 6.49-6.55 (1H, m), 6.74
(1H, t, J = 8.0 Hz), 6.79-6.83 (2H, m), 6.89 (1H, dd, J =
8.2, 1.8 Hz), 7.06-7.30 (10H, m), 7.33-7.40 (2H, m), 7.72
(1H, s).
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(hydroxymethyl)tetrahydro-
2H-pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (200 mg, 0.25 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 66 mg (44%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.37-1.49 (1H, m), 1.52-1.64
(1H, m), 1.64-1.78 (2H, m), 1.88 (1H, d, J = 13.3 Hz),
2.03-2.13 (2H, m), 2.48 (1H, d, J = 12.8 Hz), 3.10 (1H, t,
J = 10.5 Hz), 3.32-3.40 (1H, m), 3.49 (2H, d, J = 5.0 Hz),
3.74-3.94 (4H, m), 4.38 (1H, d, J = 9.4 Hz), 4.45 (1H, d,
J = 9.4 Hz), 4.58-4.78 (2H, m), 6.81 (1H, d, J = 1.8 Hz),
7.02 (1H, t, J = 8.0 Hz), 7.10 (1H, dd, J = 8.0, 2.1 Hz),
7.19-7.26 (1H, m), 7.50 (1H, dd, J = 8.2, 2.3 Hz), 7.52-
7.57 (1H, m).
MS (ESI) m/z: 612 (M + H) .
Example 39
OH H
N OH
H Cl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[cishydroxy(hydroxymethyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 17 and the compound (0.33 mmol) obtained in
Reference Example 15 were used as starting materials and
treated in the same way as in Step 2 of Example 12 to
give 63 mg (62%) of the title compound as a colorless
solid.
H-NMR (400 MHz, DMSO-d ) d : 0.60 (3H, s), 0.89 (3H, s),
0.93-1.00 (1H, m), 1.11-1.15 (1H, m), 1.23-1.25 (1H, m),
1.36-1.60 (11H, m), 1.67-1.77 (2H, m), 3.14 (2H, d, J =
6.0 Hz), 3.38-3.47 (1H, m), 3.54-3.57 (1H, m), 3.96 (1H,
s), 4.43 (1H, t, J = 9.6 Hz), 4.49 (1H, t, J = 5.7 Hz),
4.54 (1H, d, J = 9.2 Hz), 6.71 (1H, d, J = 1.8 Hz), 7.05
(1H, dd, J = 8.0, 2.1 Hz), 7.50 (1H, dd, J = 8.3, 1.8 Hz),
7.63 (1H, t, J = 5.0 Hz), 7.72 (1H, d, J = 8.3 Hz), 8.18
(1H, d, J = 5.0 Hz), 10.61 (1H, s).
MS (ESI) m/z: 619 (M + H) .
Example 40
O OH
H N O
OH H
Cl O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[transhydroxy(hydroxymethyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 17 and the compound (0.24 mmol) obtained in
Step 3 of Reference Example 17 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 67 mg (66%) of the title compound as a
colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 0.60 (3H, s), 0.89 (3H, s),
0.97 (1H, dt, J = 5.5, 13.3 Hz), 1.11-1.15 (1H, m), 1.24-
1.75 (14H, m), 3.27 (2H, d, J = 6.0 Hz), 3.56-3.59 (1H,
m), 3.69 (1H, s), 4.03 (1H, s), 4.43-4.53 (3H, m), 6.71
(1H, d, J = 1.8 Hz), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 7.50
(1H, dd, J = 8.3, 1.8 Hz), 7.63 (1H, t, J = 5.3 Hz), 7.85
(1H, d, J = 8.3 Hz), 8.18 (1H, d, J = 5.5 Hz), 10.62 (1H,
MS (ESI) m/z: 619 (M + H) .
Example 41
O OH
N H N O
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[trans(5-oxo-4,5-dihydro-
1,2,4-oxadiazolyl)cyclohexyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (84 mg, 0.17 mmol) obtained in Step 1
of Example 17 and the compound (46 mg, 0.20 mmol)
obtained in Step 7 of Reference Example 22 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 87 mg (78%) of the title compound
as a pale yellow solid.
H-NMR (500 MHz, CD OD) d : 0.68 (3H, s), 0.94 (3H, s),
1.10-1.24 (2H, m), 1.32-1.67 (7H, m), 1.75-1.84 (3H, m),
1.98-2.12 (4H, m), 2.57-2.66 (1H, m), 3.62-3.71 (1H, m),
4.55 (1H, d, J = 9.2 Hz), 4.67 (1H, d, J = 9.2 Hz), 6.77
(1H, d, J = 2.3 Hz), 7.06 (1H, dd, J = 8.0, 2.3 Hz), 7.46
(1H, dd, J = 8.0, 2.3 Hz), 7.65-7.69 (1H, m), 8.06 (1H, d,
J = 5.2 Hz).
MS (ESI) m/z: 657 (M + H) .
Example 42
OH H
O OH
H N OH
OH N
H Cl
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,5S,6R)hydroxy(hydroxymethyl)tetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 12 and the compound (34 mg, 0.23 mmol)
obtained in Step 4 of Reference Example 14 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 67 mg (66%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.94 (3H, s),
1.07-1.88 (9H, m), 2.24-2.34 (1H, m), 3.04-3.15 (2H, m),
3.45-3.65 (2H, m), 3.80-3.95 (3H, m), 4.50 (1H, d, J =
9.4 Hz), 4.69 (1H, d, J = 9.4 Hz), 6.73 (1H, d, J = 1.8
Hz), 6.98-7.08 (2H, m), 7.17-7.24 (1H, m), 7.39-7.46 (1H,
m), 7.55-7.65 (1H, m).
MS (ESI) m/z: 620 (M + H) .
Example 43
O OH
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,5S,6R)(hydroxymethyl)methoxytetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 12 and the compound (34 mg, 0.21 mmol)
obtained in Step 4 of Reference Example 23 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 69 mg (67%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.69 (3H, s), 0.95 (3H, s),
1.07-1.91 (9H, m), 2.46-2.56 (1H, m), 3.08-3.27 (3H, m),
3.39 (3H, s), 3.61 (1H, dd, J = 11.7, 5.7 Hz), 3.74-3.93
(3H, m), 4.50 (1H, d, J = 9.2 Hz), 4.70 (1H, d, J = 9.2
Hz), 6.73 (1H, d, J = 1.8 Hz), 6.98-7.08 (2H, m), 7.17-
7.24 (1H, m), 7.40-7.47 (1H, m), 7.56-7.64 (1H, m).
MS (ESI) m/z: 634 (M + H) .
Example 44
O OH
O OH
N HO
(3'R,4'S,5'R)-N-[(3R,6S){[acetyl(2-
hydroxyethyl)amino]methyl}tetrahydro-2H-pyranyl]-6"-
chloro-4'-(2-chlorofluoropyridinyl)-4,4-dimethyl-
2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (237 mg, 0.48 mmol) obtained in Step 1
of Example 17 and the compound (142 mg) obtained in Step
6 of Reference Example 24 were used as starting materials
and treated in the same way as in Step 2 of Example 12 to
give 171 mg (47%) of the title compound as a pale yellow
amorphous solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.24 (2H, m), 1.32-1.84 (9H, m), 2.08-2.13 (4H, m),
2.14 (3H, s), 2.82 (1H, dd, J = 14.2, 9.3 Hz), 3.09 (1H,
t, J = 11.1 Hz), 3.18-3.31 (2H, m), 3.38-3.53 (2H, m),
3.62-3.76 (3H, m), 3.82-3.92 (2H, m), 4.02 (1H, dd, J =
.7, 2.9 Hz), 4.40-4.46 (1H, m), 4.63 (1H, dd, J = 9.2,
4.3 Hz), 6.73 (1H, t, J = 1.8 Hz), 7.06 (1H, dd, J = 8.2,
1.8 Hz), 7.30 (1H, dd, J = 8.3, 2.2 Hz), 7.43-7.52 (3H,
m), 8.05 (1H, dd, J = 5.1, 2.2 Hz).
MS (ESI) m/z: 690 (M + H) .
Example 45
O OH
Cl N Ph
工 程 1
Step 1
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,5S,6R)
(hydroxymethyl)methoxytetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (140 mg, 0.21 mmol) obtained in Step 1
of Example 16 and the compound (101 mg, 0.63 mmol)
obtained in Step 4 of Reference Example 23 were used as
starting materials and treated in the same way as in Step
1 of Example 5 to give 48 mg (27%) of the title compound
as a colorless solid.
MS (ESI) m/z: 833 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,5S,6R)(hydroxymethyl)methoxytetrahydro-
2H-pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (48 mg, 0.06 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 26 mg (71%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.09-1.83 (9H, m), 2.09-2.24 (1H, m), 2.48-2.58 (1H, m),
3.08-3.38 (4H, m), 3.40 (3H, s), 3.66-4.06 (4H, m), 4.45
(1H, d, J = 9.0 Hz), 4.64 (1H, d, J = 9.0 Hz), 6.72 (1H,
d, J = 1.8 Hz), 7.03-7.09 (1H, m), 7.28-7.35 (1H, m),
7.47-7.52 (1H, m), 7.60 (1H, d, J = 8.3 Hz), 7.74 (1H, s),
8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 635 (M + H) .
Example 46
O OH
H Cl
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(1-hydroxymethylethyl)tetrahydro-2H-pyran-
3-yl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (40 mg, 0.08 mmol) obtained in Step 1
of Example 12 and the compound (16 mg, 0.10 mmol)
obtained in Step 2 of Reference Example 5 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 15 mg (28%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.09-1.23 (8H, m), 1.32-1.56 (5H, m), 1.57-1.66 (1H, m),
1.69-1.80 (3H, m), 2.08-2.15 (1H, m), 3.07-3.13 (2H, m),
3.82-3.92 (1H, m), 4.06-4.12 (1H, m), 4.45 (1H, d, J =
9.2 Hz), 4.67 (1H, d, J = 9.2 Hz), 6.69 (1H, d, J = 2.3
Hz), 6.87-6.91 (1H, m), 7.05 (1H, dd, J = 8.0, 1.7 Hz),
7.10-7.14 (1H, m), 7.33 (1H, dd, J = 8.0, 2.3 Hz), 7.46-
7.54 (2H, m), 7.72 (1H, s).
MS (ESI) m/z: 632 (M + H) .
Example 47
O Ph
O O OH
Step 1 N
N 工 程 1
N Cl N
Cl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxylic acid
The compound (406 mg, 0.60 mmol) obtained in Step 1
of Example 25 was used as a starting material and treated
in the same way as in Step 1 of Example 12 to give 134 mg
(45%) of the title compound as a brown solid.
MS (ESI) m/z: 493 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(1-hydroxymethylethyl)tetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (65 mg, 0.13 mmol) obtained in Step 1
above and the compound (25 mg, 0.16 mmol) obtained in
Step 2 of Reference Example 5 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 20 mg (24%) of the title compound as a
pale yellow solid.
H-NMR (500 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.07-1.82 (16H, m), 2.05-2.16 (1H, m), 2.37-2.49 (1H, m),
3.05-3.14 (2H, m), 3.17-3.41 (1H, m), 3.80-3.92 (1H, m),
4.04-4.12 (1H, m), 4.45 (1H, d, J = 9.0 Hz), 4.66 (1H, d,
J = 9.0 Hz), 7.07 (1H, d, J = 8.0 Hz), 7.34-7.40 (1H, m),
7.43-7.48 (1H, m), 7.62 (1H, dd, J = 8.0, 2.3 Hz), 7.92
(1H, s), 8.09 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 634 (M + H) .
Example 48
O OH
HCl N O
Cl N
F Cl
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2"-oxo-N-[trans(5-oxo-4,5-dihydro-1,2,4-
oxadiazolyl)cyclohexyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (87 mg, 0.18 mmol) obtained in Step 1
of Example 12 and the compound (48 mg, 0.21 mmol)
obtained in Step 7 of Reference Example 22 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 75 mg (64%) of the title compound
as a pale yellow solid.
H-NMR (500 MHz, CD OD) d : 0.69 (3H, s), 0.94 (3H, s),
1.09-1.23 (2H, m), 1.27-1.50 (4H, m), 1.52-1.66 (4H, m),
1.76-1.88 (2H, m), 1.95-2.12 (4H, m), 2.57-2.65 (1H, m),
3.61-3.70 (1H, m), 4.48-4.53 (1H, m), 4.54-4.60 (1H, m),
4.68 (1H, d, J = 9.2 Hz), 6.73 (1H, d, J = 2.3 Hz), 7.00-
7.06 (2H, m), 7.18-7.23 (1H, m), 7.43 (1H, dd, J = 8.0,
2.3 Hz), 7.59-7.64 (1H, m).
MS (ESI) m/z: 656 (M + H) .
Example 49
O O O OH
Step 1
N Ph
工 程 1
N Cl N
Cl N
H N O
HCl N
Step 2
工 程 2
Cl N
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxylic
acid
The compound (10.6g, 15.7 mmol) obtained in Step 1
of Example 12 was used as a starting material and treated
in the same way as in Step 1 of Example 12 to give 1.79 g
(23%) of the title compound as a colorless solid.
H-NMR (500 MHz, DMSO-d ) d : 0.61-0.69 (3H, m), 0.84-0.92
(3H, m), 0.99-1.29 (3H, m), 1.33-1.67 (3H, m), 1.73-1.83
(1H, m), 1.96-2.05 (1H, m), 4.51-4.58 (1H, m), 4.68-4.74
(1H, m), 6.86-7.30 (3H, m), 7.37-7.43 (1H, m), 7.49-7.56
(1H, m), 7.92-7.99 (1H, m), 11.30-11.38 (1H, m).
MS (ESI) m/z: 492 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2"-oxo-N-[trans(5-oxo-4,5-dihydro-1,2,4-
oxadiazolyl)cyclohexyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (121 mg, 0.25 mmol) obtained in Step 1
above and the compound (66 mg, 0.29 mmol) obtained in
Step 7 of Reference Example 22 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 56 mg (35%) of the title compound as a
light brown solid.
H-NMR (500 MHz, CD OD) d : 0.71 (3H, s), 0.95 (3H, s),
1.11-1.50 (6H, m), 1.52-1.91 (6H, m), 1.96-2.13 (4H, m),
2.54-2.64 (1H, m), 3.60-3.70 (1H, m), 4.51-4.60 (2H, m),
4.70 (1H, d, J = 9.2 Hz), 7.03-7.10 (1H, m), 7.17-7.29
(2H, m), 7.56-7.62 (1H, m), 7.80-7.86 (1H, m).
MS (ESI) m/z: 657 (M + H) .
Example 50
O OH O
Cl N
Cl N
H Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)(1,3,4-oxadiazol
yl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (69 mg, 0.14 mmol) obtained in Step 1
of Example 47 and the compound (28 mg, 0.17 mmol)
obtained in Step 6 of Reference Example 18 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 12 mg (14%) of the title compound
as a light brown solid.
H-NMR (500 MHz, CDCl ) d : 0.71 (3H, s), 0.98 (3H, s),
1.15-1.79 (8H, m), 2.10-2.29 (4H, m), 3.39 (1H, dd, J =
.9, 9.2 Hz), 3.98-4.07 (1H, m), 4.09-4.14 (1H, m), 4.48
(1H, d, J = 9.2 Hz), 4.67 (1H, d, J = 9.2 Hz), 4.78 (1H,
dd, J = 9.7, 2.9 Hz), 7.09 (1H, d, J = 8.0 Hz), 7.44-7.47
(1H, m), 7.58-7.65 (2H, m), 7.67-7.72 (1H, m), 8.10 (1H,
d, J = 5.2 Hz), 8.42 (1H, s).
MS (ESI) m/z: 644 (M + H) .
Example 51
Step 1 N
工 程 1
Cl H
Step 2
工 程 2
[Step 1]
(4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxylic acid
The compound (192 g, 294 mmol) obtained in Step 1 of
Example 9 was used as a starting material and treated in
the same way as in Step 1 of Example 12 to give 53.6 g
(38%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.76 (3H, s), 1.01 (3H, s),
1.33 (1H, td, J = 14.1, 4.3 Hz), 1.41 (1H, dd, J = 14.0,
2.3 Hz), 1.52 (1H, td, J = 14.1, 3.7 Hz), 1.61 (1H, dd, J
= 14.0, 2.3 Hz), 1.80 (1H, td, J = 14.1, 3.4 Hz), 1.95
(1H, dd, J = 14.1, 2.7 Hz), 2.06 (1H, td, J = 14.0, 4.1
Hz), 2.35 (1H, dd, J = 14.2, 3.2 Hz), 4.43 (1H, d, J =
.1 Hz), 5.03 (1H, d, J = 10.1 Hz), 6.82 (1H, d, J = 1.8
Hz), 7.12 (1H, dd, J = 5.5, 1.4 Hz), 7.18 (1H, dd, J =
8.2, 2.3 Hz), 7.28 (1H, s), 7.66 (1H, d, J = 8.2 Hz),
8.14 (1H, d, J = 5.5 Hz).
[Step 2]
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-4,4-
dimethyl-2"-oxo-N-[trans(5-oxo-4,5-dihydro-1,3,4-
oxadiazolyl)cyclohexyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.17 mmol) obtained in Step 1
above and the compound (37 mg, 0.20 mmol) obtained in
Step 2 of Reference Example 19 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 28 mg (26%) of the title compound as a
colorless solid.
H-NMR (500 MHz, CD OD) d : 0.68 (3H, s), 0.95 (3H, s),
1.10-1.82 (12H, m), 1.99-2.19 (4H, m), 2.62-2.67 (1H, m),
3.64-3.68 (1H, m), 4.22 (1H, d, J = 9.2 Hz), 4.62 (1H, d,
J = 9.2 Hz), 6.79 (1H, d, J = 2.3 Hz), 7.05-7.09 (1H, m),
7.11 (1H, dd, J = 8.3, 2.0 Hz), 7.21-7.25 (1H, m), 7.52
(1H, d, J = 8.0 Hz), 8.06 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 639 (M + H) .
Example 52
H N O
Cl N
Cl N
H Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-N-[(3R,6S)(1,3,4-oxadiazolyl)tetrahydro-
2H-pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxamide
The compound (84 mg, 0.17 mmol) obtained in Step 1
of Example 49 and the compound (35 mg, 0.20 mmol)
obtained in Step 6 of Reference Example 18 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 97 mg (89%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.71 (3H, s), 0.97 (3H, s),
1.14-1.27 (2H, m), 1.33-1.44 (1H, m), 1.46-1.58 (2H, m),
1.61-1.86 (4H, m), 2.09-2.29 (3H, m), 3.38 (1H, dd, J =
11.2, 9.5 Hz), 3.99-4.08 (1H, m), 4.09-4.15 (1H, m), 4.51
(1H, d, J = 9.2 Hz), 4.70 (1H, d, J = 9.2 Hz), 4.78 (1H,
dd, J = 10.0, 2.6 Hz), 6.94 (1H, t, J = 8.0 Hz), 7.05 (1H,
d, J = 8.0 Hz), 7.13-7.18 (1H, m), 7.45-7.51 (1H, m),
7.62-7.68 (2H, m), 8.43 (1H, s), 8.72 (1H, s).
MS (ESI) m/z: 643 (M + H) .
Example 53
OH O
H N O
Cl N
H Cl
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-4,4-
dimethyl-N-[(3R,6S)(1,3,4-oxadiazolyl)tetrahydro-
2H-pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (81 mg, 0.17 mmol) obtained in Step 1
of Example 51 and the compound (35 mg, 0.20 mmol)
obtained in Step 6 of Reference Example 18 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 74 mg (69%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.12-1.27 (2H, m), 1.33-1.41 (1H, m), 1.43-1.81 (6H, m),
2.10-2.28 (3H, m), 3.22-3.36 (1H, m), 3.41 (1H, dd, J =
.9, 9.2 Hz), 3.98-4.08 (1H, m), 4.09-4.18 (2H, m), 4.53
(1H, d, J = 9.2 Hz), 4.78 (1H, dd, J = 9.2, 2.9 Hz), 6.78
(1H, d, J = 1.7 Hz), 6.90 (1H, dd, J = 5.2, 1.7 Hz),
7.07-7.09 (1H, m), 7.12 (1H, dd, J = 8.3, 2.0 Hz), 7.29
(1H, d, J = 8.0 Hz), 7.44 (1H, s), 7.72 (1H, d, J = 8.6
Hz), 8.11 (1H, d, J = 5.2 Hz), 8.43 (1H, s).
MS (ESI) m/z: 625 (M + H) .
Example 54
O OH
H Cl
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-4,4-
dimethyl-N-[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (86 mg, 0.18 mmol) obtained in Step 1
of Example 51 and the compound (36 mg, 0.22 mmol)
obtained in Step 3 of Reference Example 3 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 81 mg (72%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.12-1.24 (2H, m), 1.32-1.44 (3H, m), 1.45-1.54 (2H, m),
1.56-1.83 (5H, m), 2.06-2.29 (4H, m), 2.92-3.00 (1H, m),
3.14-3.46 (1H, m), 3.75-3.85 (1H, m), 4.12 (1H, d, J =
8.6 Hz), 4.51 (1H, d, J = 8.6 Hz), 6.78 (1H, d, J = 1.7
Hz), 6.91 (1H, dd, J = 5.15, 1.7 Hz), 7.08-7.12 (2H, m),
7.29 (1H, d, J = 8.0 Hz), 7.66 (1H, d, J = 8.0 Hz), 7.73
(1H, s), 8.09 (1H, d, J = 5.2 Hz), 8.34 (1H, s).
MS (ESI) m/z: 623 (M + H) .
Example 55
O OH
H N O
Cl N
H Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2"-oxo-N-[(3R,6S)(5-oxo-4,5-dihydro-1,3,4-
oxadiazolyl)tetrahydro-2H-pyranyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (76 mg, 0.15 mmol) obtained in Step 1
of Example 49 and the compound (41 mg, 0.18 mmol)
obtained in Step 3 of Reference Example 25 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 67 mg (66%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.71 (3H, s), 0.97 (3H, s),
1.14-1.81 (9H, m), 1.95-2.12 (2H, m), 2.16-2.23 (1H, m),
3.19-3.28 (1H, m), 3.28-3.35 (1H, m), 3.94-4.04 (1H, m),
4.08-4.15 (1H, m), 4.37 (1H, dd, J = 10.0, 3.2 Hz), 4.46-
4.52 (1H, m), 4.69 (1H, d, J = 9.7 Hz), 6.95-7.01 (1H, m),
7.06 (1H, d, J = 8.02 Hz), 7.15-7.20 (1H, m), 7.44-7.50
(1H, m), 7.60-7.66 (2H, m), 7.75-7.92 (1H, m).
MS (ESI) m/z: 659 (M + H) .
Example 56
O OH
Cl N
H Cl
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-4,4-
dimethyl-2"-oxo-N-[(3R,6S)(5-oxo-4,5-dihydro-1,3,4-
oxadiazolyl)tetrahydro-2H-pyranyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (85 mg, 0.18 mmol) obtained in Step 1
of Example 51 and the compound (48 mg, 0.21 mmol)
obtained in Step 3 of Reference Example 25 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 34 mg (29%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.95 (3H, s),
1.11-1.81 (9H, m), 1.94-2.21 (3H, m), 3.30-3.38 (1H, m),
3.93-4.04 (1H, m), 4.08-4.17 (2H, m), 4.38 (1H, dd, J =
9.6, 3.2 Hz), 4.52 (1H, d, J = 8.7 Hz), 6.78 (1H, d, J =
1.8 Hz), 6.90 (1H, dd, J = 5.3, 1.6 Hz), 7.06-7.09 (1H,
m), 7.11 (1H, dd, J = 8.3, 1.8 Hz), 7.29 (1H, d, J = 8.3
Hz), 7.70-7.75 (2H, m), 8.10 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 641 (M + H) .
Example 57
N H N O
Cl N
H Cl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[(3R,6S)(5-oxo-4,5-dihydro-
1,3,4-oxadiazolyl)tetrahydro-2H-pyranyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (81 mg, 0.17 mmol) obtained in Step 1
of Example 17 and the compound (44 mg, 0.20 mmol)
obtained in Step 3 of Reference Example 25 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 57 mg (52%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.09-1.82 (9H, m), 1.95-2.14 (2H, m), 2.15-2.25 (1H, m),
3.21-3.39 (2H, m), 3.94-4.05 (1H, m), 4.07-4.14 (1H, m),
4.38 (1H, dd, J = 9.9, 3.4 Hz), 4.47 (1H, d, J = 8.7 Hz),
4.65 (1H, d, J = 9.2 Hz), 6.73 (1H, d, J = 2.3 Hz), 7.07
(1H, dd, J = 8.3, 1.8 Hz), 7.32 (1H, dd, J = 8.0, 2.1 Hz),
7.50 (1H, t, J = 5.0 Hz), 7.62 (1H, s), 7.68 (1H, d, J =
8.3 Hz), 8.05 (1H, d, J = 5.0 Hz), 9.23 (1H, s).
MS (ESI) m/z: 659 (M + H) .
Example 58
O OH
O OH
H N N
Cl N
Cl N
H Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,5S,6R)(hydroxymethyl)methoxytetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 49 and the compound (30 mg, 0.18 mmol)
obtained in Step 4 of Reference Example 23 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 48 mg (47%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.71 (3H, s), 0.96 (3H, s),
1.16-1.77 (9H, m), 1.98-2.04 (1H, m), 2.48-2.58 (1H, m),
3.07-3.30 (4H, m), 3.40 (3H, s), 3.67-3.74 (1H, m), 3.81-
3.89 (1H, m), 3.94-4.05 (2H, m), 4.44-4.53 (1H, m), 4.68
(1H, d, J = 9.2 Hz), 6.96-7.03 (1H, m), 7.06 (1H, d, J =
7.8 Hz), 7.15-7.22 (1H, m), 7.44-7.66 (4H, m).
MS (ESI) m/z: 635 (M + H) .
Example 59
O H N
Cl N
H Cl
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-N-
[(3R,5S,6R)(hydroxymethyl)methoxytetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.17 mmol) obtained in Step 1
of Example 51 and the compound (36 mg, 0.22 mmol)
obtained in Step 4 of Reference Example 23 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 48 mg (46%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.95 (3H, s),
1.13-1.78 (9H, m), 1.99-2.05 (1H, m), 2.47-2.57 (1H, m),
3.10-3.32 (4H, m), 3.40 (3H, s), 3.67-3.76 (1H, m), 3.82-
4.06 (3H, m), 4.10 (1H, d, J = 8.7 Hz), 4.51 (1H, d, J =
8.7 Hz), 6.78 (1H, d, J = 2.3 Hz), 6.87-6.91 (1H, m),
7.06-7.13 (2H, m), 7.25-7.29 (2H, m), 7.62 (1H, d, J =
8.3 Hz), 8.11 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 617 (M + H) .
Example 60
O OH N
Cl O
H Cl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[trans(5-oxo-4,5-dihydro-
1,3,4-oxadiazolyl)cyclohexyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (96 mg, 0.19 mmol) obtained in Step 1
of Example 47 and the compound (43 mg, 0.23 mmol)
obtained in Step 2 of Reference Example 19 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 51 mg (40%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CD OD) d : 0.71 (3H, s), 0.96 (3H, s),
1.15-1.84 (12H, m), 1.95-2.18 (4H, m), 2.59-2.68 (1H, m),
3.61-3.70 (1H, m), 4.58 (1H, d, J = 9.2 Hz), 4.69 (1H, d,
J = 9.2 Hz), 7.09 (1H, d, J = 8.0 Hz), 7.62-7.67 (1H, m),
7.87 (1H, dd, J = 7.7, 2.0 Hz), 8.09 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 658 (M + H) .
Example 61
O OH
H OH
N HCl
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[cishydroxy(methoxymethyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (100 mg, 0.20 mmol) obtained in Step 1
of Example 17 and the compound (0.31 mmol) obtained in
Step 2 of Reference Example 31 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 80 mg (62%) of the title compound as a
colorless solid.
H-NMR (DMSO-d ) d : 0.60 (3H, s), 0.89 (3H, s), 0.93-1.00
(1H, m), 1.11-1.14 (1H, m), 1.22-1.30 (1H, m), 1.33-1.65
(11H, m), 1.67-1.77 (2H, m), 3.10 (2H, s), 3.26 (3H, s),
3.39-3.44 (1H, m), 3.54-3.56 (1H, m), 4.21 (1H, s), 4.43
(1H, t, J = 9.2 Hz), 4.54 (1H, d, J = 9.2 Hz), 6.71 (1H,
d, J = 1.8 Hz), 7.05 (1H, dd, J = 8.0, 2.1 Hz), 7.50 (1H,
dd, J = 8.3, 1.8 Hz), 7.63 (1H, t, J = 5.0 Hz), 7.72 (1H,
d, J = 8.3 Hz), 8.18 (1H, d, J = 5.0 Hz), 10.61 (1H, s).
MS (ESI) m/z: 633 (M + H) .
Example 62
OH O
F Cl
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-N-[(3R,6S)(1,2,4-oxadiazolyl)tetrahydro-
2H-pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxamide
The compound (87 mg, 0.18 mmol) obtained in Step 1
of Example 49 and the compound (44 mg, 0.21 mmol)
obtained in Step 4 of Reference Example 26 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 91 mg (80%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.71 (3H, s), 0.97 (3H, s),
1.13-1.28 (2H, m), 1.32-1.85 (7H, m), 2.01-2.12 (1H, m),
2.15-2.27 (2H, m), 3.33-3.42 (1H, m), 4.01-4.10 (1H, m),
4.16-4.23 (1H, m), 4.50 (1H, d, J = 9.2 Hz), 4.68-4.74
(2H, m), 6.95 (1H, t, J = 8.0 Hz), 7.06 (1H, d, J = 8.0
Hz), 7.13-7.18 (1H, m), 7.45-7.50 (1H, m), 7.59-7.66 (2H,
m), 8.36 (1H, s), 8.72 (1H, s).
MS (ESI) m/z: 643 (M + H) .
Example 63
H N N
HCl N O
Cl N
H Cl
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyridinyl)-4,4-
dimethyl-N-[(3R,6S)(1,2,4-oxadiazolyl)tetrahydro-
2H-pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (86 mg, 0.18 mmol) obtained in Step 1
of Example 51 and the compound (45 mg, 0.22 mmol)
obtained in Step 4 of Reference Example 26 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 71 mg (63%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.12-1.27 (2H, m), 1.32-1.40 (1H, m), 1.45-1.80 (6H, m),
2.02-2.13 (1H, m), 2.15-2.24 (2H, m), 3.36-3.43 (1H, m),
4.01-4.10 (1H, m), 4.12 (1H, d, J = 8.6 Hz), 4.19-4.25
(1H, m), 4.52 (1H, d, J = 8.6 Hz), 4.72 (1H, dd, J = 10.3,
2.3 Hz), 6.77 (1H, d, J = 2.3 Hz), 6.88-6.92 (1H, m),
7.06-7.09 (1H, m), 7.11 (1H, dd, J = 8.0, 1.7 Hz), 7.29
(1H, d, J = 8.0 Hz), 7.56 (1H, s), 7.69 (1H, d, J = 8.6
Hz), 8.10 (1H, d, J = 5.2 Hz), 8.73 (1H, s).
MS (ESI) m/z: 625 (M + H) .
Example 64
Cl N O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)(1,2,4-oxadiazol
yl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (84 mg, 0.17 mmol) obtained in Step 1
of Example 17 and the compound (42 mg, 0.20 mmol)
obtained in Step 4 of Reference Example 26 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 92 mg (82%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.12-1.27 (2H, m), 1.35-1.42 (1H, m), 1.45-1.55 (2H, m),
1.57-1.83 (4H, m), 2.03-2.13 (1H, m), 2.15-2.28 (2H, m),
3.22-3.45 (2H, m), 4.00-4.11 (1H, m), 4.15-4.22 (1H, m),
4.47 (1H, d, J = 9.2 Hz), 4.65 (1H, d, J = 9.2 Hz), 4.72
(1H, dd, J = 10.3, 2.3 Hz), 6.72 (1H, d, J = 1.7 Hz),
7.06 (1H, dd, J = 8.3, 2.0 Hz), 7.29-7.34 (1H, m), 7.50
(1H, t, J = 5.2 Hz), 7.66 (1H, d, J = 8.6 Hz), 7.82 (1H,
s), 8.04 (1H, d, J = 5.2 Hz), 8.73 (1H, s).
MS (ESI) m/z: 643 (M + H) .
Example 65
O OH
N H N O
NH N
Cl N
Cl H
Cl N
H Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[(3R,6S)(5-oxo-4,5-dihydro-
1,3,4-oxadiazolyl)tetrahydro-2H-pyranyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (87 mg, 0.18 mmol) obtained in Step 1
of Example 47 and the compound (47 mg, 0.21 mmol)
obtained in Step 3 of Reference Example 25 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 54 mg (46%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.71 (3H, s), 0.96 (3H, s),
1.08-2.20 (12H, m), 3.34-3.41 (1H, m), 3.82-3.91 (1H, m),
3.93-4.00 (1H, m), 4.42 (1H, dd, J = 10.1, 3.2 Hz), 4.60
(1H, d, J = 9.2 Hz), 4.71 (1H, d, J = 9.2 Hz), 7.10 (1H,
d, J = 8.0 Hz), 7.61-7.66 (1H, m), 7.87 (1H, dd, J = 8.0,
2.3 Hz), 8.09 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 660 (M + H) .
Example 66
O OH
Cl N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)(1,2,4-oxadiazol
yl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (88 mg, 0.18 mmol) obtained in Step 1
of Example 47 and the compound (44 mg, 0.21 mmol)
obtained in Step 4 of Reference Example 26 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 81 mg (71%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.71 (3H, s), 0.97 (3H, s),
1.15-1.29 (2H, m), 1.35-1.43 (1H, m), 1.45-1.79 (6H, m),
2.02-2.13 (1H, m), 2.16-2.26 (2H, m), 3.20-3.47 (2H, m),
4.00-4.11 (1H, m), 4.16-4.22 (1H, m), 4.48 (1H, d, J =
9.2 Hz), 4.65-4.74 (2H, m), 7.08 (1H, d, J = 8.0 Hz),
7.46 (1H, t, J = 4.9 Hz), 7.57 (1H, d, J = 8.0 Hz), 7.63
(1H, dd, J = 7.5, 2.3 Hz), 8.09 (1H, d, J = 5.2 Hz), 8.28
(1H, br s), 8.73 (1H, s).
MS (ESI) m/z: 644 (M + H) .
Example 67
N H N
HCl N
H Cl
(3'R,4'S,5'R)-N-(transcarbamoylcyclohexyl)-6"-chloro-
4'-(2-chlorofluoropyridinyl)-4,4-dimethyl-2"-oxo-
1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (200 mg, 0.41 mmol) obtained in Step 1
of Example 17 and transaminocyclohexanecarboxamide
hydrochloride (WO2005/058892) (87 mg, 0.49 mmol) were
used as starting materials and treated in the same way as
in Step 2 of Example 12 to give 53 mg (21%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.67 (3H, s), 0.93 (3H, s),
1.09-1.22 (2H, m), 1.26-1.41 (3H, m), 1.49-1.64 (4H, m),
1.76-1.81 (3H, m), 1.86-2.07 (4H, m), 2.18-2.27 (1H, m),
3.57-3.66 (1H, m), 4.52 (1H, d, J = 9.2 Hz), 4.65 (1H, d,
J = 9.2 Hz), 6.76 (1H, d, J = 1.8 Hz), 7.05 (1H, dd, J =
8.0, 2.1 Hz), 7.45 (1H, dd, J = 8.2, 2.3 Hz), 7.65 (1H, t,
J = 5.0 Hz), 8.04 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 616 (M + H) .
Example 68
O OH
H N N
2 OH
Cl N
Cl N
H Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,5R,6R)(hydroxymethyl)methoxytetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 49 and the compound (25 mg, 0.16 mmol)
obtained in Step 5 of Reference Example 27 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 78 mg (86%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.10-1.82 (9H, m), 2.20-2.49 (2H, m), 3.18-3.28 (1H, m),
3.40 (3H, s), 3.45-3.55 (2H, m), 3.63-3.77 (1H, m), 3.84-
3.94 (1H, m), 4.05-4.28 (2H, m), 4.47 (1H, d, J = 9.2 Hz),
4.70 (1H, d, J = 9.2 Hz), 6.91-6.99 (1H, m), 7.05 (1H, d,
J = 7.8 Hz), 7.11-7.19 (1H, m), 7.42-7.69 (3H, m), 8.22-
8.32 (1H, m).
MS (ESI) m/z: 635 (M + H) .
Example 69
O OH
O OH O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,5R,6R)(hydroxymethyl)methoxytetrahydro-
2H-pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 17 and the compound (25 mg, 0.16 mmol)
obtained in Step 5 of Reference Example 27 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 66 mg (73%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.95 (3H, s),
1.10-1.82 (9H, m), 2.16-2.23 (1H, m), 2.38-2.49 (1H, m),
3.20-3.28 (1H, m), 3.41 (3H, s), 3.46-3.55 (2H, m), 3.66-
3.76 (1H, m), 3.85-3.94 (1H, m), 4.06-4.28 (2H, m), 4.44
(1H, d, J = 9.2 Hz), 4.66 (1H, d, J = 9.2 Hz), 6.74 (1H,
d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.3, 1.8 Hz), 7.31-7.54
(4H, m), 8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 635 (M + H) .
Example 70
O OH
O NH N
Cl N
H Cl
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (100 mg, 0.20 mmol) obtained in Step 1
of Example 17 and the compound (35 mg, 0.24 mmol)
obtained in Step 3 of Reference Example 28 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 94 mg (76%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.27 (2H, m), 1.35-1.81 (8H, m), 2.10-2.17 (1H, m),
2.25-2.32 (1H, m), 3.15 (1H, t, J = 10.5 Hz), 3.27 (1H,
br s), 3.80 (1H, dd, J = 11.0, 2.3 Hz), 3.85-3.95 (1H, m),
4.13 (1H, ddd, J = 10.8, 4.5, 1.3 Hz), 4.44 (1H, d, J =
9.2 Hz), 4.64 (1H, d, J = 9.2 Hz), 5.46 (1H, d, J = 3.7
Hz), 6.49 (1H, d, J = 3.7 Hz), 6.74 (1H, d, J = 1.8 Hz),
7.07 (1H, dd, J = 8.2, 1.8 Hz), 7.31 (1H, dd, J = 8.2,
2.3 Hz), 7.48-7.52 (2H, m), 7.62 (1H, s), 8.05 (1H, d, J
= 5.5 Hz).
MS (ESI) m/z: 618 (M + H) .
Example 71
O OH
Cl N
Cl N
H Cl N
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (100 mg, 0.20 mmol) obtained in Step 1
of Example 47 and the compound (35 mg, 0.24 mmol)
obtained in Step 3 of Reference Example 28 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 41 mg (33%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.15-1.27 (2H, m), 1.34-1.40 (1H, m), 1.45-1.73 (7H, m),
2.10-2.16 (1H, m), 2.26-2.32 (1H, m), 3.15 (1H, t, J =
.8 Hz), 3.26 (1H, br s), 3.81 (1H, dd, J = 11.2, 2.5
Hz), 3.87-3.93 (1H, m), 4.12 (1H, dd, J = 11.0, 2.7 Hz),
4.45 (1H, d, J = 8.7 Hz), 4.65 (1H, d, J = 9.2 Hz), 5.52
(1H, d, J = 3.2 Hz), 6.49 (1H, d, J = 3.2 Hz), 7.07 (1H,
d, J = 7.8 Hz), 7.42-7.47 (2H, m), 7.61 (1H, dd, J = 7.8,
2.3 Hz), 8.09 (1H, d, J = 5.0 Hz), 8.20 (1H, br s).
MS (ESI) m/z: 619 (M + H) .
Example 72
O OH
N OH
2 HCl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[trans(3-hydroxyazetidinyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (197 mg, 0.40 mmol) obtained in Step 1
of Example 17 and the compound (117 mg, 0.48 mmol)
obtained in Step 2 of Reference Example 13 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 107 mg (40%) of the title
compound as a pale yellow solid.
H-NMR (400 MHz, CD OD) d : 0.70 (3H, s), 0.97 (3H, s),
1.07-1.41 (7H, m), 1.53-1.64 (2H, m), 1.75-1.83 (2H, m),
1.86-2.02 (4H, m), 2.10-2.18 (1H, m), 2.90-2.96 (2H, m),
3.56-3.64 (2H, m), 3.64-3.69 (2H, m), 4.30-4.36 (1H, m),
4.55 (1H, d, J = 9.2 Hz), 4.67 (1H, d, J = 9.2 Hz), 6.79
(1H, d, J = 2.3 Hz), 7.08 (1H, dd, J = 8.3, 2.0 Hz), 7.47
(1H, dd, J = 8.3, 2.0 Hz), 7.68 (1H, t, J = 4.9 Hz), 8.07
(1H, d, J = 5.7 Hz).
MS (ESI) m/z: 644 (M + H) .
Example 73
O OH
2 OH
Cl O
H Cl
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[cis(hydroxymethyl)methoxycyclohexyl]-4,4-dimethyl-
2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (68 mg, 0.14 mmol) obtained in Step 1
of Example 12 and the compound (0.12 mmol) obtained in
Step 6 of Reference Example 29 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 35 mg (48%) of the title compound as a
colorless amorphous solid.
H-NMR (500 MHz, DMSO-d ) d : 0.60 (3H, s), 0.89 (3H, s),
0.93-0.98 (1H, m), 1.10-1.13 (1H, m), 1.19-1.59 (10H, m),
1.67-1.78 (4H, m), 2.09 (2H, s), 3.11 (3H, s), 3.28-3.49
(4H, m), 4.33-4.37 (1H, m), 4.45-4.47 (1H, m), 4.56 (1H,
d, J = 9.7 Hz), 6.68 (1H, d, J = 1.7 Hz), 7.04 (1H, d, J
= 9.7 Hz), 7.11 (1H, t, J = 7.7 Hz), 7.32 (1H, t, J = 7.2
Hz), 7.44 (1H, d, J = 8.0 Hz), 7.57 (1H, t, J = 6.6 Hz),
7.75 (1H, d, J = 8.6 Hz), 10.52 (1H, s).
MS (ESI) m/z: 632 (M + H) .
Example 74
O OH OH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(hydroxymethyl)methoxycyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (79 mg, 0.16 mmol) obtained in Step 1
of Example 12 and the compound (0.18 mmol) obtained in
Step 4 of Reference Example 29 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 50 mg (51%) of the title compound as a
colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 0.60 (3H, s), 0.88 (3H, s),
0.92-1.00 (1H, m), 1.10-1.14 (1H, m), 1.23-1.26 (1H, m),
1.30-1.37 (1H, m), 1.44-1.79 (12H, m), 3.11 (3H, s), 3.39
(2H, d, J = 5.5 Hz), 3.50 (1H, d, J = 10.1 Hz), 3.65-3.72
(1H, m), 4.38-4.47 (2H, m), 4.53 (1H, d, J = 9.6 Hz),
6.67 (1H, d, J = 1.8 Hz), 7.03 (1H, dd, J = 8.0, 2.1 Hz),
7.11 (1H, t, J = 8.0 Hz), 7.30-7.34 (1H, m), 7.44 (1H, dd,
J = 8.3, 2.3 Hz), 7.56-7.60 (1H, m), 7.88 (1H, d, J = 7.8
Hz), 10.53 (1H, s).
MS (ESI) m/z: 632 (M + H) .
Examples 75 (isomer A) and 76 (isomer B)
O OH
Cl N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[1-hydroxyethyl]tetrahydro-2H-pyran
yl}-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxamide
The compound (200 mg, 0.41 mmol) obtained in Step 1
of Example 47 and the compound (89 mg, 0.49 mmol)
obtained in Step 3 of Reference Example 30 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give a mixture of diastereomers. The
mixture of diastereomers obtained was resolved and
purified by chiral column liquid chromatography
[fractionation conditions: CHIRALPAK IC, n-hexane:ethanol
= 3:2 (v/v)] to separately give 12 mg (5%: isomer A) and
82 mg (32%: isomer B) of the title compounds as colorless
solids.
Isomer A:
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.15 (3H, d, J = 6.9 Hz), 1.16-1.27 (3H, m), 1.37-1.63
(6H, m), 1.70-1.77 (2H, m), 2.05-2.15 (2H, m), 3.12 (1H,
t, J = 10.5 Hz), 3.20-3.28 (2H, m), 3.81-3.90 (2H, m),
4.06 (1H, dd, J = 10.3, 4.4 Hz), 4.45 (1H, d, J = 8.7 Hz),
4.66 (1H, d, J = 9.2 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.38
(1H, d, J = 8.2 Hz), 7.45 (1H, t, J = 4.8 Hz), 7.61 (1H,
d, J = 8.2 Hz), 8.02 (1H, br s), 8.08 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 620 (M + H) .
Isomer B:
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.16 (3H, d, J = 6.0 Hz), 1.17-1.29 (3H, m), 1.34-1.63
(6H, m), 1.71-1.77 (2H, m), 2.07-2.12 (1H, m), 2.64 (1H,
br s), 3.03-3.09 (1H, m), 3.10 (1H, t, J = 10.8 Hz), 3.26
(1H, br s), 3.63 (1H, t, J = 6.2 Hz), 3.83-3.92 (1H, m),
4.04-4.10 (1H, m), 4.45 (1H, d, J = 8.7 Hz), 4.66 (1H, d,
J = 8.7 Hz), 7.07 (1H, d, J = 8.2 Hz), 7.39 (1H, d, J =
8.7 Hz), 7.45 (1H, t, J = 4.8 Hz), 7.61 (1H, dd, J = 7.6,
2.1 Hz), 8.01 (1H, br s), 8.09 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 620 (M + H) .
Example 77(isomer A) and 78(isomer B)
O OH O
O OH
HCl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chloropyridinyl)-N-
{(3R,6S)[1-hydroxyethyl]tetrahydro-2H-pyranyl}-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (300 mg, 0.63 mmol) obtained in Step 1
of Example 51 and the compound (137 mg, 0.76 mmol)
obtained in Step 3 of Reference Example 30 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give a mixture of diastereomers. The
mixture of diastereomers obtained was resolved and
purified by chiral column liquid chromatography
[fractionation conditions: CHIRALCEL OD-H, n-
hexane:ethanol = 4:1 (v/v)] to separately give 45 mg
(12%: isomer A) and 249 mg (66%: isomer B) of the title
compounds as colorless solids.
Isomer A:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.94 (3H, s),
1.14-1.23 (5H, m), 1.31-1.37 (1H, m), 1.40-1.53 (3H, m),
1.55-1.65 (3H, m), 1.69-1.77 (2H, m), 2.06-2.14 (2H, m),
3.14 (1H, t, J = 10.8 Hz), 3.21-3.26 (1H, m), 3.29 (1H,
br s), 3.83-3.90 (2H, m), 4.09 (1H, m), 4.10 (1H, d, J =
8.7 Hz), 4.49 (1H, d, J = 8.2 Hz), 6.76 (1H, d, J = 1.4
Hz), 6.90 (1H, d, J = 5.5 Hz), 7.08 (1H, s), 7.10 (1H, dd,
J = 8.2, 1.4 Hz), 7.28 (1H, d, J = 9.2 Hz), 7.52 (1H, d,
J = 8.7 Hz), 7.57 (1H, s), 8.10 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 601 (M + H) .
Isomer B:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.15-1.27 (5H, m), 1.30-1.36 (1H, m), 1.41-1.53 (4H, m),
1.56-1.63 (2H, m), 1.69-1.77 (2H, m), 2.03-2.11 (1H, m),
2.68 (1H, s), 3.03-3.08 (1H, m), 3.11 (1H, t, J = 10.8
Hz), 3.30 (1H, br s), 3.59-3.67 (1H, m), 3.84-3.93 (1H,
m), 4.09 (1H, m), 4.10 (1H, d, J = 8.7 Hz), 4.49 (1H, d,
J = 8.7 Hz), 6.77 (1H, d, J = 1.8 Hz), 6.90 (1H, dd, J =
.5, 1.4 Hz), 7.08 (1H, s), 7.10 (1H, dd, J = 8.2, 1.8
Hz), 7.28 (1H, d, J = 8.7 Hz), 7.53 (1H, d, J = 8.7 Hz),
7.66 (1H, s), 8.09 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 601 (M + H) .
Example 79
O O Ph
Step 1
工 程 1 N Ph
N Ph
Cl N
Cl N
O OH N
Step 3
工 程 3
N Ph
工 程 2
Step 2
Cl N
Cl N
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-3,3-dimethyl-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclobutane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-pyrrolo[2,3-b]pyridine]-1',2"(1"H)-
dione
The compound (0.93 g, 3.00 mmol) obtained in
Reference Example 1 and 3,3-dimethylcyclobutanone
(Tetrahedron, 1968, 6017-6028) (0.30 g, 3.00 mmol) were
used and treated in the same way as in Step 1 of Example
9 to give 1.10 g (51%) of the title compound as a yellow
solid.
H-NMR (400 MHz, CDCl ) d : 0.71 (3H, s), 0.92 (3H, s),
1.66 (1H, d, J = 13.2 Hz), 1.85 (1H, d, J = 13.2 Hz),
2.45 (1H, d, J = 14.2 Hz), 2.62 (1H, d, J = 14.2 Hz),
4.60 (1H, d, J = 9.3 Hz), 4.83 (1H, d, J = 9.3 Hz), 5.04
(1H, d, J = 4.4 Hz), 6.39 (1H, d, J = 4.4 Hz), 6.86 (1H,
d, J = 7.8 Hz), 6.99 (1H, t, J = 7.8 Hz), 7.04 (1H, d, J
= 7.8 Hz), 7.10-7.25 (12H, m), 7.77 (1H, s).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-3,3-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclobutane-1,2'-pyrrolidine-
3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (430 mg, 0.67 mmol) obtained in Step 1
above and the compound (263 mg, 2.00 mmol) obtained in
Step 3 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 1 of
Example 20 to give 390 mg (76%) of the title compound as
a brown amorphous solid.
MS (ESI) m/z: 773 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyranyl]-3,3-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclobutane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (390 mg, 0.50 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 150 mg (52%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.69 (3H, s), 1.33 (3H, s),
1.38-1.64 (3H, m), 1.71-1.79 (1H, m), 1.83 (1H, dd, J =
12.8, 3.2 Hz), 2.00 (1H, dd, J = 12.4, 3.2 Hz), 2.10 (1H,
d, J = 12.4 Hz), 2.24 (1H, d, J = 12.4 Hz), 3.11 (1H, t,
J = 10.8 Hz), 3.33-3.41 (1H, m), 3.49 (2H, d, J = 5.0 Hz),
3.73-3.83 (1H, m), 3.88-3.94 (1H, m), 4.34 (1H, d, J =
9.2 Hz), 4.45 (1H, d, J = 9.2 Hz), 7.05 (1H, t, J = 8.0
Hz), 7.11 (1H, d, J = 7.8 Hz), 7.23-7.27 (1H, m), 7.52
(1H, t, J = 7.1 Hz), 7.88 (1H, dd, J = 7.8, 2.3 Hz).
MS (ESI) m/z: 577 (M + H) .
Example 80
H OH
Cl N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[cishydroxy(methoxymethyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (79 mg, 0.16 mmol) obtained in Step 1
of Example 47 and the compound (40 mg, 0.20 mmol)
obtained in Step 2 of Reference Example 31 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 63 mg (62%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.80-1.17 (16H, m), 2.19 (1H, s), 3.21 (3H, s), 3.39 (3H,
s), 3.68-3.74 (1H, m), 4.45-4.47 (1H, m), 4.67 (1H, d, J
= 8.7 Hz), 7.06 (1H, d, J = 8.3 Hz), 7.46-7.51 (2H, m),
7.60-7.63 (1H, m), 8.07 (1H, d, J = 5.0 Hz), 8.17 (1H, s).
MS (ESI) m/z: 634 (M + H) .
Example 81
O OH
2 OH
Cl N N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(hydroxymethyl)methoxycyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (71 mg, 0.15 mmol) obtained in Step 1
of Example 49 and the compound (42 mg, 0.21 mmol)
obtained in Step 4 of Reference Example 29 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 65 mg (71%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.70 (3H, s), 0.95 (3H, s),
1.14-1.24 (2H, m), 1.34-1.70 (11H, m), 1.76-1.79 (1H, m),
1.87-1.92 (3H, m), 3.18-3.22 (4H, m), 3.60 (2H, d, J =
.7 Hz), 3.83-3.89 (1H, m), 4.48 (1H, d, J = 9.2 Hz),
4.68 (1H, d, J = 9.7 Hz), 6.96 (1H, t, J = 8.0 Hz), 7.05
(1H, d, J = 8.0 Hz), 7.14-7.18 (1H, m), 7.48 (1H, t, J =
6.3 Hz), 7.63 (2H, dd, J = 8.0, 2.3 Hz), 7.87 (1H, s).
MS (ESI) m/z: 633 (M + H) .
Example 82
O OH
HCl N
Cl N N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[trans(hydroxymethyl)methoxycyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (96 mg, 0.20 mmol) obtained in Step 1
of Example 47 and the compound (42 mg, 0.22 mmol)
obtained in Step 4 of Reference Example 29 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 26 mg (21%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.95 (3H, s),
1.14-1.26 (2H, m), 1.35-1.74 (12H, m), 1.88-1.94 (3H, m),
3.21-3.25 (4H, m), 3.60 (2H, d, J = 5.5 Hz), 3.82-3.90
(1H, m), 4.47 (1H, d, J = 8.7 Hz), 4.65 (1H, d, J = 9.2
Hz), 7.07 (1H, d, J = 7.8 Hz), 7.47 (1H, t, J = 5.0 Hz),
7.59-7.63 (2H, m), 8.02 (1H, s), 8.08 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 634 (M + H) .
Example 83
O OH
Cl N N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[cis(hydroxymethyl)methoxycyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (67 mg, 0.14 mmol) obtained in Step 1
of Example 47 and the compound (0.11 mmol) obtained in
Step 6 of Reference Example 29 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 36 mg (53%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.14-1.83 (15H, m), 1.90-1.99 (2H, m), 3.21-3.26 (4H, m),
3.41-3.53 (2H, m), 3.66-3.76 (1H, m), 4.45 (1H, d, J =
8.7 Hz), 4.68 (1H, d, J = 9.2 Hz), 7.07 (1H, d, J = 7.8
Hz), 7.46-7.50 (2H, m), 7.61-7.63 (1H, m), 8.08 (2H, d, J
= 5.0 Hz).
MS (ESI) m/z: 634 (M + H) .
Example 84
O Ph
O Ph
Step 1
N Ph
F 工 程 1
N Ph
F F O
Cl N Cl N
O OH
NH OH
Step 3
工 程 3
工 程 2
Step 2
Cl N
Cl N
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclobutane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3"-pyrrolo[2,3-b]pyridine]-
1',2"(1"H)-dione
The compound (4.60 g, 15.0 mmol) obtained in
Reference Example 1 above and the compound (2.21 g, 16.5
mmol) obtained in Step 2 of Reference Example 21 were
used as starting materials and treated in the same way as
in Step 1 of Example 9 to give 1.77 g (11%) of the title
compound as a pale yellow solid.
H-NMR (400 MHz, CDCl ) d : 1.87 (1H, d, J = 14.2 Hz),
2.23 (1H, d, J = 14.2 Hz), 2.76 (1H, d, J = 14.2 Hz),
2.88 (1H, d, J = 14.2 Hz), 3.90-3.96 (1H, m), 4.02-4.08
(1H, m), 4.15 (1H, dd, J = 15.3, 9.8 Hz), 4.27 (1H, dd, J
= 15.3, 9.8 Hz), 4.57 (1H, d, J = 9.6 Hz), 4.80 (1H, d, J
= 9.6 Hz), 5.20 (1H, dd, J = 4.1, 1.8 Hz), 6.39 (1H, d, J
= 4.1 Hz), 6.87 (1H, d, J = 7.8 Hz), 6.96 (2H, t, J = 8.0
Hz), 7.05-7.09 (1H, m), 7.10-7.13 (2H, m), 7.14-7.25 (10H,
m), 7.92 (1H, s).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-1,2'-
pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (339 mg, 0.50 mmol) obtained in Step 1
above and the compound (197 mg, 1.50 mmol) obtained in
Step 3 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 1 of
Example 20 to give 198 mg (49%) of the title compound as
a brown amorphous solid.
MS (ESI) m/z: 809 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(hydroxymethyl)tetrahydro-
2H-pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxamide
The compound (198 mg, 0.24 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 2 of Example 10 to give 80 mg (53%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.36-1.48 (1H, m), 1.53-1.64
(1H, m), 1.71-1.81 (2H, m), 1.87-1.93 (1H, m), 2.03-2.13
(2H, m), 2.42 (1H, d, J = 12.8 Hz), 3.11 (1H, t, J = 10.5
Hz), 3.32-3.40 (1H, m), 3.49 (2H, d, J = 5.0 Hz), 3.74-
3.85 (1H, m), 3.86-4.06 (3H, m), 4.41 (1H, d, J = 9.6 Hz),
4.48 (1H, d, J = 9.2 Hz), 4.61-4.80 (2H, m), 7.06 (1H, t,
J = 8.0 Hz), 7.11 (1H, d, J = 7.8 Hz), 7.24-7.28 (1H, m),
7.52 (1H, t, J = 6.6 Hz), 7.92 (1H, dd, J = 8.0, 2.1 Hz).
MS (ESI) m/z: 613 (M + H) .
Example 85(isomer A) and 86(isomer B)
O OH
O OH
O OH
N HO
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6R)hydroxy(hydroxymethyl)
methyltetrahydro-2H-pyranyl]-4,4-dimethyl-2"-oxo-
1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (60 mg, 0.12 mmol) obtained in Step 1
of Example 17 and the compound (21 mg, 0.13 mmol)
obtained in Step 3 of Reference Example 32 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to separately give 35 mg (46%:isomer A)
and 15 mg (20%:isomer B) of the title compound as
colorless solids.
Isomer A:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.09-1.28 (3H, m), 1.32 (3H, s), 1.36-1.76 (5H, m), 1.98-
2.11 (2H, m), 2.33 (1H, s), 3.04-3.27 (2H, m), 3.30-3.38
(1H, m), 3.70-4.10 (4H, m), 4.40-4.50 (1H, m), 4.64 (1H,
d, J = 9.2 Hz), 6.73 (1H, d, J = 1.8 Hz), 7.04-7.12 (1H,
m), 7.29-7.35 (2H, m), 7.46-7.57 (2H, m), 8.06 (1H, d, J
= 5.5 Hz).
MS (ESI) m/z: 635 (M + H) .
Isomer B:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.94 (3H, s),
1.11-1.76 (11H, m), 2.00-2.07 (1H, m), 2.37-2.44 (1H, m),
3.08-3.30 (4H, m), 3.82-3.96 (2H, m), 4.11-4.20 (1H, m),
4.21-4.33 (1H, m), 4.43 (1H, d, J = 9.0 Hz), 4.62 (1H, d,
J = 9.0 Hz), 6.69 (1H, d, J = 1.8 Hz), 7.05-7.10 (1H, m),
7.29-7.34 (1H, m), 7.46-7.62 (3H, m), 8.06 (1H, d, J =
.0 Hz).
MS (ESI) m/z: 635 (M + H) .
Example 87
O OH
HCl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{cishydroxy
[(methylsulfonyl)methyl]cyclohexyl}-4,4-dimethyl-2"-oxo-
1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (89 mg, 0.18 mmol) obtained in Step 1
of Example 17 and the compound (0.20 mmol) obtained in
Step 3 of Reference Example 33 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 84 mg (67%) of the title compound as a
colorless solid.
H-NMR (500 MHz, DMSO-d ) d : 0.60 (3H, s), 0.90 (3H, s),
0.93-1.00 (1H, m), 1.11-1.14 (1H, m), 1.22-1.25 (1H, m),
1.41-1.64 (9H, m), 1.67-1.76 (2H, m), 1.84-1.91 (2H, m),
3.00 (3H, s), 3.22 (2H, s), 3.44-3.49 (1H, m), 3.56 (1H,
d, J = 11.5 Hz), 4.44 (1H, t, J = 9.7 Hz), 4.55 (1H, d, J
= 9.2 Hz), 4.86 (1H, s), 6.71 (1H, d, J = 2.3 Hz), 7.06
(1H, dd, J = 8.3, 2.0 Hz), 7.50 (1H, dd, J = 8.3, 2.0 Hz),
7.63 (1H, t, J = 5.2 Hz), 7.74 (1H, d, J = 8.0 Hz), 8.18
(1H, d, J = 5.2 Hz), 10.61 (1H, s).
MS (ESI) m/z: 681 (M + H) .
Example 88
O OH
H N O
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(ethylcarbamoyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (160 mg, 0.33 mmol) obtained in Step 1
of Example 17 and the compound (87 mg, 0.40 mmol)
obtained in Step 2 of Reference Example 34 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 143 mg (67%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.15 (3H, t, J = 7.2 Hz), 1.16-1.24 (2H, m), 1.35-1.41
(1H, m), 1.43-1.62 (5H, m), 1.70-1.77 (2H, m), 2.09-2.15
(1H, m), 2.28-2.34 (1H, m), 3.13 (1H, t, J = 10.7 Hz),
3.25-3.36 (2H, m), 3.74-3.79 (1H, m), 3.85-3.94 (1H, m),
4.11 (1H, dd, J = 11.7, 3.9 Hz), 4.44 (1H, d, J = 8.8 Hz),
4.64 (1H, d, J = 9.0 Hz), 6.52 (1H, t, J = 5.5 Hz), 6.73
(1H, d, J = 1.7 Hz), 7.07 (1H, dd, J = 8.1, 2.0 Hz), 7.31
(1H, dd, J = 8.2, 2.1 Hz), 7.48-7.52 (2H, m), 7.62 (1H,
s), 8.05 (1H, d, J = 5.1 Hz).
MS (ESI) m/z: 646 (M + H) .
Example 89(isomer A) and 90(isomer B)
O OH H
O OH
N OH
OH H
F OH
Cl Cl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(1,2-dihydroxyethyl)tetrahydro-2H-pyran-
3-yl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (332 mg, 0.67 mmol) obtained in Step 1
of Example 17 and the compound (160 mg, 0.80 mmol)
obtained in Step 3 of Reference Example 35 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give a mixture of diastereomers. The
mixture of diastereomers obtained was resolved and
purified by chiral column liquid chromatography
[fractionation conditions: CHIRALPAK IA, n-hexane:ethanol
= 1:1 (v/v)] to separately give 100 mg (23%: isomer A)
and 174 mg (40%: isomer B) of the title compounds as
colorless solids.
Isomer A:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.26 (2H, m), 1.33-1.39 (1H, m), 1.42-1.63 (5H, m),
1.70-1.76 (2H, m), 1.82-1.89 (1H, m), 2.10-2.16 (2H, m),
2.56 (1H, d, J = 6.4 Hz), 3.09 (1H, t, J = 10.5 Hz), 3.27
(1H, br s), 3.40-3.45 (1H, m), 3.61-3.66 (1H, m), 3.69-
3.75 (2H, m), 3.84-3.93 (1H, m), 4.03-4.08 (1H, m), 4.43
(1H, d, J = 9.2 Hz), 4.64 (1H, d, J = 9.2 Hz), 6.72 (1H,
d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.0, 2.1 Hz), 7.31 (1H,
dd, J = 8.0, 2.1 Hz), 7.43-7.51 (3H, m), 8.05 (1H, d, J =
.0 Hz).
MS (ESI) m/z: 635 (M + H) .
Isomer B:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.10-1.24 (2H, m), 1.33-1.38 (1H, m), 1.43-1.54 (3H, m),
1.57-1.79 (5H, m), 2.09-2.14 (1H, m), 2.20-2.25 (1H, m),
2.77 (1H, d, J = 4.1 Hz), 3.12 (1H, t, J = 10.5 Hz), 3.31
(1H, br s), 3.37-3.43 (1H, m), 3.53-3.59 (1H, m), 3.62-
3.67 (1H, m), 3.71-3.78 (1H, m), 3.86-3.94 (1H, m), 4.06-
4.11 (1H, m), 4.43 (1H, d, J = 9.2 Hz), 4.64 (1H, d, J =
9.2 Hz), 6.73 (1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.2,
1.8 Hz), 7.31 (1H, dd, J = 8.0, 2.1 Hz), 7.46-7.51 (3H,
m), 8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 635 (M + H) .
Example 91
O O Ph
O Ph
Step 1
工 程 1 N Ph
F F O
O OH
Step 3
工 程 3
N Ph
Step 2
工 程 2
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(2-chloro
fluoropyridinyl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclobutane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-dione
The compound (5.0 g, 17.2 mmol) obtained in
Reference Example 8 and the compound (2.88 g, 21.5 mmol)
obtained in Step 2 of Reference Example 21 were used as
starting materials and treated in the same way as in Step
1 of Example 9 to give 10.2 g (87%) of the title compound
as a pale yellow amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.82 (1H, d, J = 14.7 Hz),
2.35 (1H, d, J = 14.7 Hz), 2.84 (1H, d, J = 14.2 Hz),
3.07 (1H, d, J = 14.2 Hz), 3.90-3.98 (1H, m), 4.02-4.10
(1H, m), 4.23-4.30 (1H, m), 4.35-4.42 (1H, m), 4.52 (1H,
d, J = 9.6 Hz), 4.69 (1H, d, J = 9.6 Hz), 5.22-5.25 (1H,
m), 6.30 (1H, d, J = 4.1 Hz), 6.78 (1H, d, J = 8.3 Hz),
6.84 (1H, t, J = 4.8 Hz), 6.89 (1H, d, J = 1.8 Hz), 6.94
(1H, dd, J = 8.3, 1.8 Hz), 7.14-7.27 (10H, m), 7.97 (1H,
d, J = 5.0 Hz), 8.00 (1H, s).
MS (ESI) m/z: 678 (M + H) .
[Step 2]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (203 mg, 0.30 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Example 20 to give 153 mg (63%)
of the title compound as a pale yellow amorphous solid.
MS (ESI) m/z: 809 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-3,3-bis(fluoromethyl)-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (153 mg, 0.19 mmol) obtained in Step 2
above was dissolved in acetonitrile (10 ml) and water (3
ml), cerium (IV) diammonium nitrate (207 mg, 0.38 mmol)
was added under ice cooling and the resulting mixture was
stirred for 10 minutes. Potassium carbonate (104 mg,
0.76 mmol) was added to the reaction mixture and the
precipitated insoluble matter was removed by filtration
through celite. The filtrate was diluted with ethyl
acetate, washed with brine and dried over anhydrous
sodium sulfate. The solvent was evaporated, the residue
was purified by NH-silica gel column chromatography
(chloroform:methanol = 100:0 fi 40:1) and then the
residue was dissolved in 2-propanol (10 ml) and stirred
at 50 C for 2 days. The solvent was evaporated under
reduced pressure and then the residue was purified by
chiral column liquid chromatography [fractionation
conditions: CHIRALPAK IC, n-hexane:ethanol = 2:3 (v/v)]
to give 67 mg (57%) of the title compound as a colorless
solid.
H-NMR (400 MHz, CD OD) d : 1.37-1.49 (1H, m), 1.55-1.78
(2H, m), 1.85-1.91 (1H, m), 2.00-2.20 (2H, m), 2.48 (1H,
d, J = 12.8 Hz), 3.16 (1H, t, J = 10.5 Hz), 3.33-3.41 (1H,
m), 3.45-3.51 (2H, m), 3.74-3.94 (4H, m), 4.39 (1H, d, J
= 9.2 Hz), 4.50 (1H, d, J = 9.2 Hz), 4.60-4.77 (2H, m),
6.84 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J = 8.0, 2.1 Hz),
7.54 (1H, dd, J = 8.0, 2.1 Hz), 7.60 (1H, t, J = 5.0 Hz),
8.06 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 613 (M + H) .
Example 92
O O Ph
O O Ph
Step 2
Step 1
工 程 2
工 程 1
N Ph
OH O
O OH
N OH
Step 3
工 程 3
Cl N
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6"-chloro-8'-(5-chloropyridin
yl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-tetrahydro-
1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-
7',3"-indole]-1',2"(1"H)-dione
The compound (1.35 g, 4.65 mmol) obtained in
Reference Example 36 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
2.35 g (77%) of the title compound as a yellow solid.
H-NMR (400 MHz, CDCl ) d : 0.56 (3H, s), 0.67 (3H, s),
0.81-1.01 (1H, m), 1.16-1.44 (4H, m), 1.74-1.83 (1H, m),
1.86-1.97 (1H, m), 2.16-2.27 (1H, m), 4.48 (1H, d, J =
11.0 Hz), 4.82 (1H, d, J = 3.7 Hz), 5.03 (1H, d, J = 11.0
Hz), 6.61-6.68 (2H, m), 6.77-6.84 (2H, m), 6.92-6.98 (2H,
m), 7.10-7.29 (9H, m), 7.47-7.50 (1H, m), 8.14 (1H, d, J
= 1.4 Hz), 8.34 (1H, d, J = 2.3 Hz).
MS (APCI) m/z: 652 (M + H) .
[Step 2]
(4'R,5'R)-6"-chloro-4'-(5-chloropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxylic acid
The compound (2.29 g, 3.52 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Example 12 to give 827 mg (50%)
of the title compound as a light brown solid.
MS (APCI) m/z: 474 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6"-chloro-4'-(5-chloropyridinyl)-N-
[(3R,6S)(hydroxymethyl)tetrahydro-2H-pyranyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (200 mg, 0.42 mmol) obtained in Step 2
above and the compound (83 mg, 0.63 mmol) obtained in
Step 3 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 23 mg (9%) of the title compound as a
pale yellow solid.
H-NMR (400 MHz, CD OD) d : 0.67-0.71 (3H, m), 0.93-0.96
(3H, m), 1.15-1.24 (2H, m), 1.27-1.66 (5H, m), 1.69-1.86
(4H, m), 2.02-2.10 (1H, m), 3.11-3.53 (4H, m), 3.73-3.82
(1H, m), 3.94-3.98 (1H, m), 4.26 (1H, d, J = 9.2 Hz),
4.61 (1H, d, J = 9.2 Hz), 6.76 (1H, d, J = 1.8 Hz), 7.10
(1H, dd, J = 8.0, 2.1 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.78
(1H, t, J = 2.1 Hz), 8.07 (1H, d, J = 1.8 Hz), 8.28 (1H,
d, J = 2.3 Hz).
MS (ESI) m/z: 587 (M + H) .
Example 93(isomer A) and 94(isomer B)
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[1-hydroxyethyl]tetrahydro-2H-pyran
yl}-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (300 mg, 0.61 mmol) obtained in Step 1
of Example 17 and the compound (133 mg, 0.73 mmol)
obtained in Step 3 of Reference Example 30 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give a mixture of diastereomers. The
mixture of diastereomers obtained was resolved and
purified by chiral column liquid chromatography
[fractionation conditions: CHIRALCEL OD-H, n-
hexane:ethanol = 7:3 (v/v)] to separately give 42 mg
(11%: isomer A) and 233 mg (61%: isomer B) of the title
compounds as colorless solids.
Isomer A:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.09-1.25 (5H, m), 1.34-1.65 (5H, m), 1.69-1.79 (3H, m),
2.07 (1H, d, J = 4.4 Hz), 2.10-2.15 (1H, m), 3.13 (1H, t,
J = 10.6 Hz), 3.20-3.25 (1H, m), 3.27 (1H, br s), 3.82-
3.91 (2H, m), 4.04-4.09 (1H, m), 4.43 (1H, d, J = 9.0 Hz),
4.65 (1H, d, J = 9.0 Hz), 6.72 (1H, d, J = 2.0 Hz), 7.07
(1H, dd, J = 8.1, 2.0 Hz), 7.31 (1H, dd, J = 8.1, 2.2 Hz),
7.40 (1H, s), 7.46 (1H, d, J = 8.8 Hz), 7.49 (1H, t, J =
.0 Hz), 8.05 (1H, d, J = 5.1 Hz).
MS (ESI) m/z: 619 (M + H) .
Isomer B:
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.16 (3H, d, J = 6.3 Hz), 1.17-1.24 (3H, m), 1.32-1.39
(1H, m), 1.42-1.64 (4H, m), 1.67-1.79 (3H, m), 2.08-2.14
(1H, m), 2.64 (1H, d, J = 2.4 Hz), 3.02-3.08 (1H, m),
3.10 (1H, t, J = 10.6 Hz), 3.27 (1H, br s), 3.60-3.65 (1H,
m), 3.85-3.91 (1H, m), 4.05-4.10 (1H, m), 4.44 (1H, d, J
= 9.0 Hz), 4.65 (1H, d, J = 9.0 Hz), 6.73 (1H, d, J = 2.0
Hz), 7.07 (1H, dd, J = 8.1, 2.0 Hz), 7.31 (1H, dd, J =
8.1, 2.0 Hz), 7.36 (1H, s), 7.46 (1H, d, J = 8.5 Hz),
7.49 (1H, t, J = 5.0 Hz), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 619 (M + H) .
Example 95
O O Ph
N Ph
Step 1
工 程 1
N Ph
O Cl
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridinyl)-
3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (203 mg, 0.30 mmol) obtained in Step 1
of Example 91 was used as a starting material and treated
in the same way as in Step 1 of Example 5 to give 60 mg
(23%) of the title compound as a colorless amorphous
solid.
MS (ESI) m/z: 845 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-3,3-bis(fluoromethyl)-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (60 mg, 0.07 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 23 mg (58%)
of the title compound as a colorless solid [fractionation
conditions: CHIRALPAK IC, n-hexane:ethanol = 1:4 (v/v)].
H-NMR (400 MHz, CD OD) d : 1.49-1.57 (2H, m), 1.67-1.75
(3H, m), 1.91 (1H, d, J = 12.8 Hz), 2.03-2.11 (3H, m),
2.22 (2H, t, J = 15.6 Hz), 2.49 (1H, d, J = 12.4 Hz),
2.99-3.04 (1H, m), 3.70-3.76 (1H, m), 3.81 (1H, s), 3.92
(1H, s), 4.39 (1H, d, J = 9.2 Hz), 4.52 (1H, d, J = 9.2
Hz), 4.64 (1H, dd, J = 15.6, 9.2 Hz), 4.76 (1H, dd, J =
14.7, 8.7 Hz), 6.85 (1H, d, J = 1.8 Hz), 7.13 (1H, dd, J
= 8.2, 1.8 Hz), 7.55 (1H, dd, J = 8.2, 1.8 Hz), 7.62 (1H,
t, J = 5.0 Hz), 8.07 (1H, d, J = 5.0 Hz), 8.84 (1H, s).
MS (ESI) m/z: 649 (M + H) .
Example 96
O N H
O OH
O N O
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(isopropylcarbamoyl)tetrahydro-2H-pyran-
3-yl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (80 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 37 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 182 mg (92%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.16 (6H, d, J = 6.4 Hz), 1.17-1.22 (2H, m), 1.34-1.39
(1H, m), 1.44-1.77 (7H, m), 2.08-2.16 (1H, m), 2.27-2.34
(1H, m), 3.13 (1H, t, J = 10.8 Hz), 3.28 (1H, br s),
3.71-3.76 (1H, m), 3.84-3.93 (1H, m), 4.01-4.14 (2H, m),
4.44 (1H, d, J = 8.7 Hz), 4.64 (1H, d, J = 9.2 Hz), 6.36
(1H, d, J = 8.2 Hz), 6.73 (1H, d, J = 1.8 Hz), 7.07 (1H,
dd, J = 7.8, 1.8 Hz), 7.31 (1H, dd, J = 8.2, 2.3 Hz),
7.48-7.52 (2H, m), 7.61 (1H, s), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 662 (M + H) .
Example 97
O OH
O N O H
HCl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(cyclopropylcarbamoyl)tetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (79 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 38 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 163 mg (82%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.50-0.55 (2H, m), 0.68 (3H,
s), 0.71-0.80 (2H, m), 0.95 (3H, s), 1.09-1.25 (2H, m),
1.33-1.1.80 (8H, m), 2.09-2.15 (1H, m), 2.27-2.33 (1H, m),
2.69-2.75 (1H, m), 3.11 (1H, t, J = 10.8 Hz), 3.27 (1H,
br s), 3.73-3.78 (1H, m), 3.85-3.91 (1H, m), 4.06-4.12
(1H, m), 4.43 (1H, d, J = 9.2 Hz), 4.63 (1H, d, J = 9.2
Hz), 6.57 (1H, d, J = 3.7 Hz), 6.74 (1H, d, J = 1.8 Hz),
7.07 (1H, dd, J = 8.0, 2.1 Hz), 7.30 (1H, dd, J = 8.2,
2.3 Hz), 7.47-7.52 (2H, m), 7.68 (1H, s), 8.04 (1H, d, J
= 5.0 Hz).
MS (ESI) m/z: 658 (M + H) .
Example 98
O OH O
O N O
N N S
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-{(3R,6S)
[(methylsulfonyl)methyl]tetrahydro-2H-pyranyl}-2"-oxo-
1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (94 mg, 0.19 mmol) obtained in Step 1
of Example 17 and the compound (0.21 mmol) obtained in
Step 2 of Reference Example 39 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 86 mg (68%) of the title compound as a
colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 0.59 (3H, s), 0.90 (3H, s),
0.92-1.00 (1H, m), 1.10-1.13 (1H, m), 1.19-1.22 (1H, m),
1.38-1.88 (9H, m), 2.96 (3H, s), 3.15-3.22 (2H, m), 3.41
(1H, dd, J = 14.9, 8.9 Hz), 3.50-3.52 (1H, m), 3.60-3.77
(3H, m), 4.46 (1H, t, J = 9.4 Hz), 4.57 (1H, d, J = 8.7
Hz), 6.71 (1H, d, J = 2.3 Hz), 7.06 (1H, dd, J = 8.3, 1.8
Hz), 7.50 (1H, dd, J = 8.3, 1.8 Hz), 7.63 (1H, t, J = 5.0
Hz), 7.82 (1H, d, J = 8.3 Hz), 8.18 (1H, d, J = 5.0 Hz),
.61 (1H, s).
MS (ESI) m/z: 667 (M + H) .
Example 99
O OH
O N O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(methylcarbamoyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (70 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 40 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 157 mg (83%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.27 (2H, m), 1.34-1.39 (1H, m), 1.44-1.60 (5H, m),
1.69-1.78 (2H, m), 2.09-2.15 (1H, m), 2.28-2.34 (1H, m),
2.82 (3H, d, J = 5.0 Hz), 3.13 (1H, t, J = 10.5 Hz), 3.27
(1H, br s), 3.76-3.81 (1H, m), 3.85-3.93 (1H, m), 4.12
(1H, dd, J = 10.8, 3.0 Hz), 4.43 (1H, d, J = 8.7 Hz),
4.64 (1H, d, J = 9.2 Hz), 6.52-6.58 (1H, m), 6.73 (1H, d,
J = 1.8 Hz), 7.07 (1H, dd, J = 8.0, 2.1 Hz), 7.31 (1H, dd,
J = 8.2, 2.3 Hz), 7.50 (2H, t, J = 5.0 Hz), 7.62 (1H, s),
8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 632 (M + H) .
Example 100
O OH O N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-pyran-
3-yl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (75 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 41 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 136 mg (70%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.13-1.27 (2H, m), 1.35-1.40 (1H, m), 1.44-1.59 (4H, m),
1.71-1.78 (2H, m), 1.87-2.02 (2H, m), 2.16-2.22 (1H, m),
2.95 (3H, s), 3.09 (3H, s), 3.25 (1H, t, J = 10.1 Hz),
3.27 (1H, br s), 3.89-3.99 (1H, m), 4.06 (1H, dd, J =
.8, 3.4 Hz), 4.12 (1H, dd, J = 9.4, 3.0 Hz), 4.45 (1H,
d, J = 9.2 Hz), 4.65 (1H, d, J = 9.2 Hz), 6.73 (1H, d, J
= 1.8 Hz), 7.06 (1H, dd, J = 8.2, 1.8 Hz), 7.32 (1H, dd,
J = 8.2, 1.8 Hz), 7.50 (1H, t, J = 5.0 Hz), 7.61 (1H, d,
J = 8.7 Hz), 7.69 (1H, s), 8.04 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 646 (M + H) .
Example 101
O N H
O N O
Cl N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)
(methylcarbamoyl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 47 and the compound (59 mg, 0.30 mmol)
obtained in Step 2 of Reference Example 40 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 94 mg (49%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.13-1.27 (2H, m), 1.34-1.40 (1H, m), 1.45-1.74 (7H, m),
2.08-2.14 (1H, m), 2.29-2.34 (1H, m), 2.83 (3H, d, J =
.0 Hz), 3.13 (1H, t, J = 10.8 Hz), 3.21-3.27 (1H, m),
3.77-3.81 (1H, m), 3.84-3.91 (1H, m), 4.08-4.13 (1H, m),
4.41-4.48 (1H, m), 4.65 (1H, d, J = 9.2 Hz), 6.52-6.57
(1H, m), 7.08 (1H, d, J = 8.2 Hz), 7.41-7.47 (2H, m),
7.61 (1H, dd, J = 7.8, 2.3 Hz), 8.08 (2H, d, J = 5.0 Hz).
MS (ESI) m/z: 633 (M + H) .
Example 102
O OH
O N O
2 N N
Cl N N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(cyclopropylcarbamoyl)tetrahydro-2H-
pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 47 and the compound (60 mg, 0.27 mmol)
obtained in Step 2 of Reference Example 38 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 106 mg (54%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.51-0.54 (2H, m), 0.70 (3H,
s), 0.75-0.80 (2H, m), 0.96 (3H, s), 1.13-1.19 (1H, m),
1.20-1.28 (1H, m), 1.34-1.39 (1H, m), 1.43-1.76 (7H, m),
2.07-2.13 (1H, m), 2.27-2.33 (1H, m), 2.70-2.75 (1H, m),
3.11 (1H, t, J = 10.8 Hz), 3.24 (1H, br s), 3.76 (1H, dd,
J = 11.0, 2.3 Hz), 3.85-3.90 (1H, m), 4.08 (1H, dd, J =
.8, 3.0 Hz), 4.45 (1H, d, J = 8.7 Hz), 4.65 (1H, d, J =
9.2 Hz), 6.56 (1H, d, J = 3.7 Hz), 7.07 (1H, d, J = 8.2
Hz), 7.42 (1H, d, J = 8.7 Hz), 7.45 (1H, t, J = 5.0 Hz),
7.61 (1H, dd, J = 7.8, 2.3 Hz), 8.08 (1H, d, J = 5.0 Hz),
8.26 (1H, br s).
MS (ESI) m/z: 659 (M + H) .
Example 103
O OH
H N O
N NH
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[(2-hydroxyethyl)carbamoyl]tetrahydro-
2H-pyranyl}-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (81 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 42 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 86 mg (43%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.13-1.28 (2H, m), 1.33-1.40 (1H, m), 1.45-1.65 (5H, m),
1.68-1.81 (2H, m), 2.10-2.17 (1H, m), 2.27-2.36 (2H, m),
3.14 (1H, t, J = 10.6 Hz), 3.27 (1H, br s), 3.40-3.48 (2H,
m), 3.70-3.75 (2H, m), 3.80 (1H, dd, J = 11.1, 2.3 Hz),
3.86-3.95 (1H, m), 4.11-4.16 (1H, m), 4.44 (1H, d, J =
9.0 Hz), 4.64 (1H, d, J = 9.0 Hz), 6.71 (1H, d, J = 2.0
Hz), 6.85-6.89 (1H, m), 7.07 (1H, dd, J = 8.2, 1.8 Hz),
7.24-7.26 (1H, m), 7.31 (1H, dd, J = 7.9, 2.3 Hz), 7.44
(1H, d, J = 8.1 Hz), 7.47 (1H, t, J = 5.0 Hz), 8.04 (1H,
d, J = 5.1 Hz).
MS (ESI) m/z: 662 (M + H) .
Example 104
O N H
O OH
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-pyran-
3-yl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 47 and the compound (75 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 41 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 105 mg (54%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.13-1.29 (2H, m), 1.36-1.41 (1H, m), 1.46-1.66 (5H, m),
1.72-1.77 (1H, m), 1.88-2.05 (2H, m), 2.15-2.23 (1H, m),
2.96 (3H, s), 3.09 (3H, s), 3.23-3.29 (2H, m), 3.90-3.97
(1H, m), 4.03-4.07 (1H, m), 4.13 (1H, dd, J = 9.6, 3.2
Hz), 4.46 (1H, d, J = 9.2 Hz), 4.67 (1H, d, J = 9.2 Hz),
7.08 (1H, d, J = 7.8 Hz), 7.45 (1H, t, J = 5.0 Hz), 7.54
(1H, d, J = 8.7 Hz), 7.62 (1H, dd, J = 8.0, 2.5 Hz), 8.08
(1H, d, J = 5.0 Hz), 8.12 (1H, br s).
MS (ESI) m/z: 647 (M + H) .
Example 105
O OH
O OH
N OH
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(2R,3R,6S)(hydroxymethyl)methyltetrahydro-
2H-pyranyl]-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (85 mg, 0.17 mmol) obtained in Step 1
of Example 17 and the compound (38 mg, 0.21 mmol)
obtained in Step 7 of Reference Example 43 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 43 mg (40%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.95 (3H, s),
1.12-1.26 (6H, m), 1.35-1.94 (10H, m), 3.28 (1H, br s),
3.47-3.58 (1H, m), 3.68-4.17 (4H, m), 4.49 (1H, d, J =
9.17 Hz), 4.65 (1H, d, J = 9.17 Hz), 6.74 (1H, d, J =
1.83 Hz), 7.07 (1H, dd, J = 8.25, 1.83 Hz), 7.20-7.25 (1H,
m), 7.30-7.35 (1H, m), 7.49-7.53 (1H, m), 7.78 (1H, d, J
= 8.71 Hz), 8.06 (1H, d, J = 5.04 Hz).
MS (ESI) m/z: 619 (M + H) .
Example 106
O OH
O N O
Cl N
(3'R,4'S,5'R)-N-[(3R,6S)(azetidin
ylcarbonyl)tetrahydro-2H-pyranyl]-6"-chloro-4'-(2-
chlorofluoropyridinyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (99 mg, 0.45 mmol)
obtained in Step 2 of Reference Example 44 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 26 mg (13%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.12-1.23 (2H, m), 1.33-1.40 (1H, m), 1.45-1.65 (5H, m),
1.68-1.84 (3H, m), 2.05-2.15 (2H, m), 2.23-2.31 (2H, m),
3.13 (1H, t, J = 10.3 Hz), 3.26 (1H, s), 3.86-3.92 (1H,
m), 3.93 (1H, dd, J = 10.5, 2.3 Hz), 4.04 (2H, t, J = 7.6
Hz), 4.05-4.08 (1H, m), 4.32 (2H, t, J = 7.8 Hz), 4.43
(1H, d, J = 9.6 Hz), 4.64 (1H, d, J = 9.2 Hz), 6.74 (1H,
d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.2, 1.8 Hz), 7.29-7.33
(1H, m), 7.49 (1H, t, J = 4.8 Hz), 7.54 (1H, d, J = 8.2
Hz), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 660 (M + H) .
Example 107
HCl H
O OH
O N O
H H N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[(3-hydroxyazetidin
yl)carbonyl]tetrahydro-2H-pyranyl}-4,4-dimethyl-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (106 mg, 0.45 mmol)
obtained in Step 2 of Reference Example 45 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 60 mg (30%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.23 (2H, m), 1.33-1.40 (1H, m), 1.45-1.65 (4H, m),
1.67-1.83 (3H, m), 2.06-2.17 (2H, m), 2.42-2.58 (1H, m),
3.12 (1H, t, J = 10.3 Hz), 3.25 (1H, br s), 3.83-3.91 (2H,
m), 3.94 (1H, dd, J = 10.5, 1.8 Hz), 4.01-4.07 (1H, m),
4.14 (1H, dd, J = 10.5, 4.1 Hz), 4.23-4.28 (1H, m), 4.44
(1H, d, J = 8.7 Hz), 4.50-4.56 (1H, m), 4.59-4.66 (2H, m),
6.72 (1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.0, 2.1 Hz),
7.31 (1H, dd, J = 8.0, 2.1 Hz), 7.50 (1H, t, J = 4.8 Hz),
7.54-7.58 (2H, m), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 674 (M + H) .
Example 108
O O Ph
O O Ph
Step 1
N Ph
工 程 1
N Ph
Cl Cl
N Step 3
工 程 3 N N
Step 2 N Ph
工 程 2
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6"-chloro-8'-(3-chloro
fluorophenyl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-pyrrolo[3,2-c]pyridine]-1',2"(1"H)-
dione
The compound (3.94 g, 12.7 mmol) obtained in
Reference Example 46 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
6.51 g (76%) of the title compound as a yellow amorphous
solid.
H-NMR (400 MHz, CDCl ) d : 0.20 (3H, s), 0.54 (3H, s),
0.94-1.01 (3H, m), 1.29-1.42 (4H, m), 1.83-1.85 (1H, m),
2.22-2.26 (1H, m), 4.60 (1H, d, J = 11.2 Hz), 4.84 (1H, d,
J = 3.2 Hz), 5.36 (1H, d, J = 11.2 Hz), 6.74 (2H, d, J =
6.6 Hz), 6.87 (1H, s), 7.05-7.32 (10H, m), 7.79 (1H, t, J
= 6.7 Hz), 8.22 (1H, s).
[Step 2]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-1'-
[(1R,2S)hydroxy-1,2-diphenylethyl]-4,4-dimethyl-N-
[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (1.38g, 2.06 mmol) obtained in Step 1
above and the compound (1.03g, 6.17 mmol) obtained in
Step 3 of Reference Example 3 were used as starting
materials and treated in the same way as in Step 1 of
Example 5 to give 0.95 g (55%) of the title compound as a
pale yellow amorphous solid.
MS (ESI) m/z: 837 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-N-[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (950 mg, 1.18 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 350 mg (46%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.73 (3H, s), 0.97 (3H, s),
1.12-1.24 (2H, m), 1.38-2.26 (14H, m), 3.01-3.04 (1H, m),
3.68-3.72 (1H, m), 4.57 (1H, d, J = 9.3 Hz), 4.75 (1H, d,
J = 9.3 Hz), 6.79 (1H, s), 7.05 (1H, t, J = 8.1 Hz),
7.22-7.26 (1H, m), 7.55-7.61 (1H, m), 8.31 (1H, d, J =
2.4 Hz), 8.85 (1H, s).
MS (ESI) m/z: 641 (M + H) .
Example 109
O OH
O NH N
Cl O
Cl Cl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[(3R,6S)(tetrahydro-2H-
pyranylcarbamoyl)tetrahydro-2H-pyranyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (95 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 47 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 121 mg (57%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.25 (2H, m), 1.37 (1H, d, J = 12.8 Hz), 1.47-1.77
(9H, m), 1.83-1.91 (2H, m), 2.10-2.16 (1H, m), 2.28-2.34
(1H, m), 3.14 (1H, t, J = 10.5 Hz), 3.29 (1H, br s),
3.43-3.51 (2H, m), 3.76 (1H, d, J = 8.7 Hz), 3.86-4.02
(4H, m), 4.12 (1H, dd, J = 10.8, 3.4 Hz), 4.44 (1H, d, J
= 8.7 Hz), 4.64 (1H, d, J = 9.2 Hz), 6.46 (1H, d, J = 8.2
Hz), 6.73 (1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.2, 1.8
Hz), 7.31 (1H, dd, J = 8.0, 2.1 Hz), 7.49-7.52 (2H, m),
7.65 (1H, s), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 702 (M + H) .
Example 110
OH O
O N O
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)(morpholin
ylcarbonyl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (112 mg, 0.45 mmol)
obtained in Step 2 of Reference Example 48 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 98 mg (47%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.25 (2H, m), 1.37 (1H, d, J = 12.8 Hz), 1.45-1.65
(4H, m), 1.71-1.81 (2H, m), 1.93-2.01 (2H, m), 2.16-2.23
(1H, m), 3.24 (1H, dd, J = 11.0, 9.2 Hz), 3.26 (1H, br s),
3.52-3.59 (2H, m), 3.63-3.73 (6H, m), 3.90-3.97 (1H, m),
4.03 (1H, dd, J = 10.1, 3.7 Hz), 4.10 (1H, dd, J = 8.0,
3.4 Hz), 4.45 (1H, d, J = 9.2 Hz), 4.64 (1H, d, J = 8.7
Hz), 6.73 (1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.2, 1.8
Hz), 7.31 (1H, dd, J = 8.0, 2.1 Hz), 7.48-7.52 (2H, m),
7.62 (1H, d, J = 8.7 Hz), 8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 688 (M + H) .
Example 111
O OH
O NH O N O
H NH
HCl N
(3'R,4'S,5'R)-N-[(3R,6S)(2-amino
oxoethyl)tetrahydro-2H-pyranyl]-6"-chloro-4'-(2-
chlorofluoropyridinyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (89 mg, 0.18 mmol) obtained in Step 1
of Example 17 and the compound (0.15 mmol) obtained in
Step 3 of Reference Example 49 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 31 mg (32%) of the title compound as a
colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.67 (3H, s), 0.94 (3H, s),
1.11-1.26 (2H, m), 1.36 (1H, dd, J = 12.9, 2.0 Hz), 1.45-
1.82 (8H, m), 2.07-2.10 (1H, m), 2.37-2.46 (2H, m), 3.14
(1H, t, J = 10.6 Hz), 3.29 (1H, s), 3.65-3.71 (1H, m),
3.85-3.93 (1H, m), 4.03-4.06 (1H, m), 4.44 (1H, d, J =
9.2 Hz), 4.62 (1H, d, J = 9.2 Hz), 5.68 (1H, s), 6.29 (1H,
s), 6.71 (1H, d, J = 1.7 Hz), 7.05 (1H, dd, J = 8.3, 2.0
Hz), 7.27-7.30 (2H, m), 7.49-7.53 (2H, m), 8.04 (1H, d, J
= 5.2 Hz), 8.42 (1H, s).
MS (ESI) m/z: 654 (M + Na) .
Example 112
O OH
Cl N N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[trans(1,3,4-oxadiazol
yl)cyclobutyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (1.00 g, 2.03 mmol) obtained in Step 1
of Example 17 and the compound (391 mg, 2.81 mmol)
obtained in Step 3 of Reference Example 50 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 753 mg (60%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.69 (3H, s), 0.98 (3H, s),
1.12-1.24 (2H, m), 1.33-1.40 (1H, m), 1.52-1.69 (2H, m),
1.77-1.92 (3H, m), 2.60-2.80 (4H, m), 3.76-3.82 (1H, m),
4.56 (1H, d, J = 9.2 Hz), 4.57-4.65 (1H, m), 4.70 (1H, d,
J = 9.2 Hz), 6.77 (1H, d, J = 2.3 Hz), 7.07 (1H, dd, J =
8.0, 2.1 Hz), 7.47 (1H, dd, J = 8.2, 2.3 Hz), 7.66 (1H, t,
J = 5.0 Hz), 7.90 (1H, s), 8.06 (1H, d, J = 5.0 Hz), 8.89
(1H, s).
MS (ESI) m/z: 613 (M + H) .
Example 113
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[trans(dimethylcarbamoyl)cyclohexyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (29 mg, 0.06 mmol) obtained in Step 1
of Example 17 and transamino-N,N-
dimethylcyclohexanecarboxamide hydrochloride
(WO2008/068171) (17 mg, 0.08 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 36 mg (100%) of the title compound as
a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.67 (3H, s), 0.95 (3H, s),
1.08-1.40 (6H, m), 1.42-1.55 (2H, m), 1.56-1.91 (6H, m),
2.00-2.13 (2H, m), 2.44-2.55 (1H, m), 2.93 (3H, s), 3.06
(3H, s), 3.66-3.79 (1H, m), 4.44 (1H, d, J = 8.7 Hz),
4.65 (1H, d, J = 8.7 Hz), 6.71 (1H, d, J = 1.8 Hz), 7.05
(1H, dd, J = 8.3, 1.8 Hz), 7.31 (1H, dd, J = 8.3, 2.3 Hz),
7.49-7.57 (2H, m), 8.03 (1H, d, J = 5.0 Hz), 8.09 (1H, s).
MS (ESI) m/z: 644 (M + H) .
Example 114
NH N
Cl Cl
(3'R,4'S,5'R)-N-(transcarbamoylcyclobutyl)-6"-chloro-
4'-(2-chlorofluoropyridinyl)-4,4-dimethyl-2"-oxo-
1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (90 mg, 0.18 mmol) obtained in Step 1
of Example 17 and the compound (21 mg, 0.18 mmol)
obtained in Step 2 of Reference Example 51 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 66 mg (61%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.79 (8H, m), 2.24-2.41 (2H, m), 2.61-2.75 (2H, m),
2.99-3.09 (1H, m), 3.73 (1H, br s), 4.40-4.52 (2H, m),
4.65 (1H, d, J = 9.17 Hz), 5.39 (2H, br s), 6.73 (1H, d,
J = 1.8 Hz), 7.07 (1H, dd, J = 8.25, 1.8 Hz), 7.30-7.35
(1H, m), 7.41 (1H, s), 7.46-7.51 (1H, m), 7.85 (1H, d, J
= 7.8 Hz), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 588 (M + H) .
Example 115
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[trans(dimethylcarbamoyl)cyclobutyl]-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (90 mg, 0.18 mmol) obtained in Step 1
of Example 17 and the compound (26 mg, 0.18 mmol)
obtained in Step 2 of Reference Example 52 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 35 mg (31%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.95 (3H, s),
1.11-1.78 (8H, m), 2.19-2.38 (2H, m), 2.66-2.81 (2H, m),
2.90 (3H, s), 2.96 (3H, s), 3.23-3.37 (2H, m), 4.25-4.36
(1H, m), 4.43 (1H, d, J = 9.0 Hz), 4.66 (1H, d, J = 9.0
Hz), 6.73 (1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 7.8,
1.83 Hz), 7.31-7.41 (2H, m), 7.47-7.51 (1H, m), 7.87 (1H,
d, J = 7.3 Hz), 8.04 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 616 (M + H) .
Example 116
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(diethylcarbamoyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (73 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 53 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 124 mg (61%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.12 (3H, t, J = 7.1 Hz), 1.19 (3H, t, J = 7.1 Hz), 1.20-
1.23 (2H, m), 1.37 (1H, d, J = 11.0 Hz), 1.46-1.67 (4H,
m), 1.71-1.80 (2H, m), 1.86-1.93 (1H, m), 1.97-2.06 (1H,
m), 2.17-2.25 (1H, m), 3.23-3.51 (6H, m), 3.90-3.99 (1H,
m), 4.05 (1H, dd, J = 12.4, 4.6 Hz), 4.09 (1H, dd, J =
9.4, 3.0 Hz), 4.42-4.47 (1H, m), 4.65 (1H, d, J = 9.2 Hz),
6.74 (1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 8.0, 2.1 Hz),
7.32 (1H, dd, J = 8.2, 2.3 Hz), 7.42 (1H, s), 7.49 (1H, t,
J = 5.0 Hz), 7.62 (1H, d, J = 8.2 Hz), 8.05 (1H, d, J =
.5 Hz).
MS (ESI) m/z: 674 (M + H) .
Example 117
O N O
H N N
Cl N
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(diethylcarbamoyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-pyrrolo[2,3-b]pyridine]-5'-
carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 47 and the compound (72 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 53 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 129 mg (68%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.13 (3H, t, J = 7.1 Hz), 1.18 (3H, t, J = 7.1 Hz), 1.20-
1.27 (2H, m), 1.38 (1H, d, J = 9.2 Hz), 1.46-1.66 (5H, m),
1.73-1.77 (1H, m), 1.86-1.92 (1H, m), 1.97-2.07 (1H, m),
2.16-2.23 (1H, m), 3.22-3.48 (6H, m), 3.90-3.98 (1H, m),
4.04 (1H, dd, J = 10.8, 3.0 Hz), 4.09 (1H, dd, J = 9.2,
3.2 Hz), 4.46 (1H, d, J = 8.7 Hz), 4.67 (1H, d, J = 9.2
Hz), 7.07 (1H, d, J = 7.8 Hz), 7.45 (1H, t, J = 5.0 Hz),
7.56 (1H, d, J = 8.2 Hz), 7.63 (1H, dd, J = 7.8, 2.3 Hz),
8.08 (1H, d, J = 5.5 Hz), 8.28 (1H, s).
MS (ESI) m/z: 675 (M + H) .
Example 118
O OH
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[trans(ethylcarbamoyl)cyclobutyl]-4,4-dimethyl-
2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (110 mg, 0.22 mmol) obtained in Step 1
of Example 17 and the compound (41 mg, 0.29 mmol)
obtained in Step 2 of Reference Example 54 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 42 mg (31%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.69 (3H, s), 0.96 (3H, s),
1.07-1.40 (7H, m), 1.51-1.91 (4H, m), 2.22-2.35 (2H, m),
2.47-2.61 (2H, m), 2.96-3.06 (1H, m), 3.20 (2H, q, J =
7.3 Hz), 4.41-4.56 (2H, m), 4.67 (1H, d, J = 9.2 Hz),
6.77 (1H, d, J = 2.1 Hz), 7.06 (1H, dd, J = 8.0, 2.1 Hz),
7.43-7.50 (1H, m), 7.62-7.68 (1H, m), 8.05 (1H, d, J =
.0 Hz).
MS (ESI) m/z: 616 (M + H) .
Example 119
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[trans(hydroxymethyl)cyclobutyl]-4,4-dimethyl-
2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (55 mg, 0.11 mmol) obtained in Step 1
of Example 17 and the compound (11 mg, 0.11 mmol)
obtained in Step 2 of Reference Example 55 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 55 mg (86%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.69 (3H, s), 0.96 (3H, s),
1.08-1.42 (4H, m), 1.51-1.92 (4H, m), 2.05-2.49 (5H, m),
3.60 (2H, d, J = 6.9 Hz), 4.26-4.37 (1H, m), 4.53 (1H, d,
J = 9.2 Hz), 4.66 (1H, d, J = 9.2 Hz), 6.77 (1H, d, J =
1.8 Hz), 7.06 (1H, dd, J = 8.3, 1.83 Hz), 7.43-7.50 (1H,
m), 7.63-7.69 (1H, m), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 575 (M + H)
Example 120
NH H
H H N O
Cl H
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2"-oxo-N-[trans(tetrahydro-2H-pyran-
4-ylcarbamoyl)cyclobutyl]-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (95 mg, 0.19 mmol) obtained in Step 1
of Example 17 and the compound (46 mg, 0.23 mmol)
obtained in Step 2 of Reference Example 56 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 66 mg (51%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.69 (3H, s), 0.96 (3H, s),
1.09-1.91 (12H, m), 2.22-2.36 (2H, m), 2.47-2.61 (2H, m),
2.96-3.06 (1H, m), 3.41-3.52 (2H, m), 3.81-3.97 (3H, m),
4.48 (1H, t, J = 7.8 Hz), 4.54 (1H, d, J = 9.2 Hz), 4.67
(1H, d, J = 9.2 Hz), 6.77 (1H, d, J = 2.1 Hz), 7.06 (1H,
dd, J = 8.1, 2.1 Hz), 7.46 (1H, dd, J = 8.1, 2.1 Hz),
7.62-7.68 (1H, m), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 672 (M + H) .
Example 121
O OH
Step 1
工 程 1
Cl Cl
Cl Cl
H N OH
Step 2
工 程 2
[Step 1]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxylic acid
The compound (1.95 g, 3.70 mmol) obtained in Step 2
of Reference Example 57 was dissolved in ethanol (37 ml),
1N sodium hydroxide solution (7.4 ml, 7.40 mmol) was
added and the resulting mixture was stirred under heating
at 50 C for 1 hour. After cooling, the reaction mixture
was neutralized by addition of 1N hydrochloric acid (7.4
ml, 7.40 mmol) at 0 C and the solvent was evaporated
under reduced pressure. The residue obtained was
collected by filtration and dried to give 2.02 g (100%)
of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.92 (1H, d, J = 14.2 Hz),
2.44 (1H, d, J = 14.2 Hz), 2.69 (1H, d, J = 14.7 Hz),
2.91 (1H, d, J = 14.7 Hz), 3.75 (1H, dd, J = 15.1, 10.5
Hz), 3.87 (1H, dd, J = 14.4, 9.4 Hz), 4.48 (1H, d, J =
.5 Hz), 4.54 (1H, dd, J = 15.8, 9.4 Hz), 4.66 (1H, dd,
J = 15.8, 9.4 Hz), 4.78 (1H, d, J = 10.5 Hz), 6.84 (1H, d,
J = 1.8 Hz), 7.07-7.12 (1H, m), 7.17 (1H, dd, J = 8.2,
1.8 Hz), 7.27-7.33 (1H, m), 7.54-7.59 (1H, m), 7.67 (1H,
dd, J = 8.2, 2.3 Hz).
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-(transhydroxycyclohexyl)-2"-oxo-
1",2"-dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
above and transaminocyclohexanol (19.4 mg, 0.17 mmol)
were used as starting materials and treated in the same
way as in Step 2 of Example 12 to give 56 mg (67%) of the
title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.25-1.42 (5H, m), 1.68 (1H,
dd, J = 13.7, 2.3 Hz), 1.81-2.00 (5H, m), 2.07 (1H, d, J
= 12.8 Hz), 2.47 (1H, d, J = 12.8 Hz), 3.50-3.64 (2H, m),
3.76-3.93 (2H, m), 4.36 (1H, d, J = 9.2 Hz), 4.44 (1H, d,
J = 9.2 Hz), 4.58-4.76 (2H, m), 6.80 (1H, d, J = 2.3 Hz),
7.00-7.05 (1H, m), 7.10 (1H, dd, J = 8.2, 1.8 Hz), 7.20-
7.25 (1H, m), 7.50 (1H, dd, J = 8.2, 2.3 Hz), 7.53-7.58
(1H, m).
MS (ESI) m/z: 596 (M + H) .
Example 122
O OH
O NH
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 121 and the compound (26.8 mg, 0.17 mmol)
obtained in Step 3 of Reference Example 28 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 72 mg (86%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.52-1.71 (3H, m), 1.89 (1H, d,
J = 13.3 Hz), 2.04-2.19 (3H, m), 2.48 (1H, d, J = 13.3
Hz), 3.17 (1H, t, J = 10.5 Hz), 3.74-3.92 (4H, m), 3.94-
4.00 (1H, m), 4.39 (1H, d, J = 9.2 Hz), 4.46 (1H, d, J =
9.2 Hz), 4.59-4.77 (2H, m), 6.81 (1H, d, J = 1.8 Hz),
7.00-7.06 (1H, m), 7.11 (1H, dd, J = 8.2, 1.8 Hz), 7.20-
7.25 (1H, m), 7.50 (1H, dd, J = 8.2, 2.3 Hz), 7.52-7.57
(1H, m).
MS (ESI) m/z: 625 (M + H) .
Example 123
OH O
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 121 and the compound (32 mg, 0.19 mmol)
obtained in Step 3 of Reference Example 3 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 91 mg (87%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.37-1.58 (2H, m), 1.64-1.80
(3H, m), 1.90 (1H, d, J = 13.3 Hz), 1.99 (1H, d, J = 12.4
Hz), 2.07-2.27 (4H, m), 2.49 (1H, d, J = 13.3 Hz), 2.96-
3.04 (1H, m), 3.67-3.75 (1H, m), 3.79-3.91 (2H, m), 4.39
(1H, d, J = 9.2 Hz), 4.47 (1H, d, J = 9.2 Hz), 4.59-4.78
(2H, m), 6.81 (1H, d, J = 2.3 Hz), 7.01-7.06 (1H, m),
7.11 (1H, dd, J = 8.2, 1.8 Hz), 7.20-7.26 (1H, m), 7.51
(1H, dd, J = 8.2, 2.3 Hz), 7.54-7.59 (1H, m), 8.85 (1H, d,
J = 1.4 Hz).
MS (ESI) m/z: 648 (M + H) .
Example 124
O OH
HCl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-pyranyl]-
3,3-bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 121 and the compound (33.1 mg, 0.19 mmol)
obtained in Step 2 of Reference Example 41 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 79 mg (75%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.62-1.73 (2H, m), 1.77-1.92
(3H, m), 2.07 (1H, d, J = 13.3 Hz), 2.11-2.18 (1H, m),
2.49 (1H, d, J = 13.3 Hz), 2.92 (3H, s), 3.09 (3H, s),
3.23 (1H, t, J = 10.1 Hz), 3.77-3.95 (4H, m), 4.22 (1H,
dd, J = 9.8, 3.4 Hz), 4.38 (1H, d, J = 9.2 Hz), 4.46 (1H,
d, J = 9.2 Hz), 4.60-4.77 (2H, m), 6.81 (1H, d, J = 1.8
Hz), 7.00-7.06 (1H, m), 7.11 (1H, dd, J = 8.0, 2.1 Hz),
7.20-7.25 (1H, m), 7.51 (1H, dd, J = 8.0, 2.1 Hz), 7.52-
7.57 (1H, m).
MS (ESI) m/z: 653 (M + H) .
Example 125
O OH O
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[ethyl(methyl)carbamoyl]tetrahydro-2H-
pyranyl}-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (67 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 58 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 122 mg (62%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.26 (5H, m), 1.37 (1H, d, J = 11.0 Hz), 1.45-1.66
(4H, m), 1.70-1.78 (2H, m), 1.88-2.02 (2H, m), 2.15-2.23
(1H, m), 2.91-3.05 (3H, m), 3.25 (1H, t, J = 9.8 Hz),
3.28 (1H, br s), 3.34-3.51 (2H, m), 3.92-3.98 (1H, m),
4.03-4.07 (1H, m), 4.08-4.13 (1H, m), 4.45 (1H, d, J =
9.2 Hz), 4.65 (1H, d, J = 9.2 Hz), 6.73 (1H, d, J = 1.8
Hz), 7.06 (1H, dd, J = 8.2, 1.8 Hz), 7.31 (1H, dd, J =
8.0, 2.1 Hz), 7.50 (1H, t, J = 5.0 Hz), 7.63 (1H, d, J =
8.2 Hz), 7.80 (1H, s), 8.04 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 660 (M + H) .
Example 126
O OH
O NH H
O N O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[(2-fluoroethyl)carbamoyl]tetrahydro-2H-
pyranyl}-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (68 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 59 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 97 mg (49%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.25 (2H, m), 1.32-1.83 (8H, m), 2.11-2.18 (1H, m),
2.27-2.33 (1H, m), 3.15 (1H, t, J = 10.8 Hz), 3.28 (1H,
br s), 3.49-3.69 (2H, m), 3.81 (1H, dd, J = 11.0, 2.3 Hz),
3.86-3.95 (1H, m), 4.07-4.15 (1H, m), 4.40-4.50 (2H, m),
4.52-4.57 (1H, m), 4.64 (1H, d, J = 9.2 Hz), 6.73 (1H, d,
J = 1.8 Hz), 6.91 (1H, t, J = 6.0 Hz), 7.07 (1H, dd, J =
8.2, 1.8 Hz), 7.31 (1H, dd, J = 8.0, 2.1 Hz), 7.48-7.53
(2H, m), 7.60 (1H, s), 8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 664 (M + H) .
Example 127
O N O
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[(2-
methoxyethyl)(methyl)carbamoyl]tetrahydro-2H-pyranyl}-
4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (78 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 60 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 143 mg (69%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.10-1.25 (2H, m), 1.34-1.41 (1H, m), 1.45-1.67 (4H, m),
1.71-1.78 (2H, m), 1.88-2.03 (2H, m), 2.16-2.23 (1H, m),
2.96-3.14 (3H, m), 3.18-3.28 (1H, m), 3.33 (3H, s), 3.38-
3.80 (5H, m), 3.91-3.97 (1H, m), 4.02-4.07 (1H, m), 4.14-
4.21 (1H, m), 4.45 (1H, d, J = 9.2 Hz), 4.65 (1H, d, J =
8.7 Hz), 6.73 (1H, d, J = 2.3 Hz), 7.07 (1H, dd, J = 8.2,
1.8 Hz), 7.32 (1H, dd, J = 8.0, 2.1 Hz), 7.50 (1H, t, J =
.0 Hz), 7.59-7.64 (2H, m), 8.04 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 690 (M + H) .
Example 128
O OH O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[(2-methoxyethyl)carbamoyl]tetrahydro-
2H-pyranyl}-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (73 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 61 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 121 mg (60%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.11-1.81 (10H, m), 2.10-2.16 (1H, m), 2.26-2.33 (1H, m),
3.14 (1H, t, J = 10.5 Hz), 3.27 (1H, br s), 3.36 (3H, s),
3.40-3.53 (4H, m), 3.79 (1H, dd, J = 11.2, 2.5 Hz), 3.86-
3.96 (1H, m), 4.12 (1H, m), 4.44 (1H, d, J = 8.7 Hz),
4.64 (1H, d, J = 9.2 Hz), 6.73 (1H, d, J = 1.8 Hz), 6.84-
6.88 (1H, m), 7.07 (1H, dd, J = 8.0, 2.1 Hz), 7.31 (1H,
dd, J = 8.2, 2.3 Hz), 7.48-7.52 (2H, m), 7.61 (1H, s),
8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 676 (M + H) .
Example 129
O OH
O OH
H N O N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,5R,6R)(hydroxymethyl)
methoxytetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (100 mg, 0.20 mmol) obtained in Step 1
of Example 121 and the compound (65 mg, 0.40 mmol)
obtained in Step 5 of Reference Example 27 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 95 mg (74%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.41-1.50 (1H, m), 1.65-1.86
(2H, m), 2.03-2.17 (2H, m), 2.36-2.52 (2H, m), 3.14-3.22
(1H, m), 3.41 (3H, s), 3.45-3.55 (2H, m), 3.66-4.32 (7H,
m), 4.40 (2H, br s), 4.54-4.82 (2H, m), 6.79 (1H, d, J =
2.3 Hz), 6.93-6.99 (1H, m), 7.11-7.23 (3H, m), 7.36-7.48
(3H, m).
MS (ESI) m/z: 642 (M + H) .
Example 130
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{trans[5-(hydroxymethyl)-1,3,4-oxadiazol
yl]cyclohexyl}-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (64 mg, 0.12 mmol) obtained in Step 1
of Example 17 and the compound (27 mg, 0.13 mmol)
obtained in Step 3 of Reference Example 62 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 55 mg (67%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.96 (3H, s),
1.11-1.28 (2H, m), 1.31-1.43 (3H, m), 1.45-1.81 (7H, m),
2.10-2.28 (4H, m), 2.72-2.86 (1H, m), 2.87-2.97 (1H, m),
3.18-3.43 (1H, m), 3.72-3.82 (1H, m), 4.45 (1H, d, J =
9.2 Hz), 4.66 (1H, d, J = 9.2 Hz), 4.83 (2H, s), 6.74 (1H,
d, J = 2.3 Hz), 7.07 (1H, dd, J = 8.3, 2.0 Hz), 7.30-7.34
(1H, m), 7.49-7.53 (1H, m), 7.57-7.65 (2H, m), 8.05 (1H,
d, J = 5.2 Hz).
MS (ESI) m/z: 671 (M + H) .
Example 131
H N H
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-{trans[5-(hydroxymethyl)-1,3,4-
oxadiazolyl]cyclohexyl}-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (60 mg, 0.12 mmol) obtained in Step 1
of Example 121 and the compound (26 mg, 0.13 mmol)
obtained in Step 3 of Reference Example 62 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 46 mg (57%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CD OD) d : 1.37-1.47 (1H, m), 1.47-1.57
(1H, m), 1.63-1.78 (3H, m), 1.86-1.93 (1H, m), 1.94-2.02
(1H, m), 2.06-2.13 (2H, m), 2.14-2.27 (2H, m), 2.45-2.53
(1H, m), 2.97 (1H, tt, J = 12.0, 3.7 Hz), 3.71 (1H, tt, J
= 11.5, 4.0 Hz), 3.77-3.93 (2H, m), 4.39 (1H, d, J = 9.2
Hz), 4.47 (1H, d, J = 9.2 Hz), 4.61-4.77 (4H, m), 6.81
(1H, d, J = 1.7 Hz), 7.00-7.06 (1H, m), 7.11 (1H, dd, J =
8.0, 1.7 Hz), 7.20-7.25 (1H, m), 7.48-7.53 (1H, m), 7.54-
7.59 (1H, m).
MS (ESI) m/z: 678 (M + H) .
Example 132
O OH O N
N N N
Cl Cl
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-(trans{5-[(1R)hydroxyethyl]-1,3,4-oxadiazol-
2-yl}cyclohexyl)-4,4-dimethyl-2"-oxo-1",2"-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (74 mg, 0.14 mmol) obtained in Step 1
of Example 17 and the compound (33 mg, 0.16 mmol)
obtained in Step 3 of Reference Example 63 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 71 mg (73%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.96 (3H, s),
1.12-1.27 (2H, m), 1.29-1.43 (3H, m), 1.44-1.55 (2H, m),
1.56-1.81 (8H, m), 2.09-2.28 (4H, m), 2.86-2.99 (2H, m),
3.20-3.40 (1H, m), 3.71-3.82 (1H, m), 4.45 (1H, d, J =
9.2 Hz), 4.66 (1H, d, J = 9.2 Hz), 5.01-5.11 (1H, m),
6.74 (1H, d, J = 1.72 Hz), 7.05-7.08 (1H, m), 7.30-7.34
(1H, m), 7.50-7.53 (1H, m), 7.60 (1H, d, J = 8.6 Hz),
7.79 (1H, s), 8.04 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 685 (M + H) .
Example 133
O N O
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(methoxymethyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (70 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 64 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 156 mg (84%) of the title
compound as a pale orange solid.
H-NMR (400 MHz, CDCl ) d : 0.67 (3H, s), 0.95 (3H, s),
1.08-1.65 (8H, m), 1.68-1.77 (3H, m), 2.08-2.14 (1H, m),
3.13 (1H, t, J = 10.8 Hz), 3.27 (1H, br s), 3.33-3.45 (5H,
m), 3.48-3.55 (1H, m), 3.87-3.96 (1H, m), 4.04-4.10 (1H,
m), 4.43 (1H, d, J = 9.2 Hz), 4.65 (1H, d, J = 8.7 Hz),
6.73 (1H, d, J = 1.8 Hz), 7.06 (1H, dd, J = 8.2, 1.8 Hz),
7.31 (1H, dd, J = 8.0, 2.1 Hz), 7.46-7.51 (3H, m), 8.04
(1H, d, J = 5.0 Hz).
MS (ESI) m/z: 619 (M + H) .
Example 134
O OH
H H N
(3'R,4'S,5'R)-N-(transcarbamoylcyclobutyl)-6"-chloro-
4'-(3-chlorofluorophenyl)-3,3-bis(fluoromethyl)-2"-
oxo-1",2"-dihydrodispiro[cyclobutane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (75 mg, 0.15 mmol) obtained in Step 1
of Example 121 and the compound (19 mg, 0.17 mmol)
obtained in Step 2 of Reference Example 51 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 66 mg (74%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.67 (1H, d, J = 13.3 Hz),
1.89 (1H, d, J = 13.3 Hz), 2.08 (1H, d, J = 11.5 Hz),
2.19-2.37 (2H, m), 2.44-2.63 (3H, m), 3.00-3.09 (1H, m),
3.78-3.90 (2H, m), 4.34-4.50 (4H, m), 4.59-4.81 (2H, m),
6.81 (1H, d, J = 2.3 Hz), 7.00-7.13 (1H, m), 7.19-7.26
(1H, m), 7.48-7.59 (2H, m).
MS (ESI) m/z: 595 (M + H) .
Example 135
O OH
NH OH
N Ph
Step 1
工 程 1
N Ph
Cl F
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(1-hydroxy
methylethyl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (200 mg, 0.30 mmol) obtained in Step 1
of Example 38 and the compound (159 mg, 1.00 mmol)
obtained in Step 2 of Reference Example 5 were used as
starting materials and treated in the same way as in Step
1 of Example 20 to give 118 mg (47%) of the title
compound as a brown amorphous solid.
MS (ESI) m/z: 836 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(1-hydroxy
methylethyl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (118 mg, 0.14 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 40 mg (44%)
of the title compound as a colorless solid [fractionation
conditions: CHIRALPAK IC, n-hexane:ethanol = 7:3 (v/v)].
H-NMR (400 MHz, CD OD) d : 1.14 (3H, s), 1.16 (3H, s),
1.44-1.60 (2H, m), 1.68 (1H, d, J = 13.7 Hz), 1.83 (1H, d,
J = 10.5 Hz), 1.89 (1H, d, J = 12.8 Hz), 2.02-2.12 (2H,
m), 2.48 (1H, d, J = 12.8 Hz), 3.05-3.10 (2H, m), 3.71-
3.95 (4H, m), 4.38 (1H, d, J = 9.2 Hz), 4.45 (1H, d, J =
9.2 Hz), 4.59-4.76 (2H, m), 6.81 (1H, d, J = 1.8 Hz),
7.03 (1H, t, J = 8.5 Hz), 7.11 (1H, dd, J = 8.2, 1.8 Hz),
7.21-7.25 (1H, m), 7.50 (1H, dd, J = 8.2, 2.3 Hz), 7.52-
7.56 (1H, m).
MS (ESI) m/z: 640 (M + H) .
Example 136
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(1,3,4-oxadiazol
yl)tetrahydro-2H-pyranyl]-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 121 and the compound (33 mg, 0.19 mmol)
obtained in Step 6 of Reference Example 18 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 79 mg (75%) of the title compound
as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.66-1.76 (2H, m), 1.85 (1H,
dd, J = 13.3, 2.7 Hz), 2.04-2.35 (4H, m), 2.40 (1H, d, J
= 13.3 Hz), 3.33-3.40 (1H, m), 3.78-4.13 (5H, m), 4.36-
4.44 (2H, m), 4.56-4.82 (3H, m), 6.75 (1H, d, J = 1.8 Hz),
6.86-6.91 (1H, m), 7.11-7.16 (2H, m), 7.38 (1H, dd, J =
8.1, 2.2 Hz), 7.41-7.45 (1H, m), 7.66 (1H, d, J = 8.1 Hz),
7.85 (1H, s), 8.43 (1H, s).
MS (ESI) m/z: 650 (M + H) .
Example 137
O NH
2 NH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-2"-oxo-N-[(3R,6S)(tetrahydro-2H-
pyranylcarbamoyl)tetrahydro-2H-pyranyl]-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 121 and the compound (45 mg, 0.17 mmol)
obtained in Step 2 of Reference Example 47 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 79 mg (79%) of the title compound
as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.44-1.71 (5H, m), 1.81-1.91
(3H, m), 2.03 (1H, d, J = 13.3 Hz), 2.14-2.21 (1H, m),
2.27-2.33 (1H, m), 2.39 (1H, d, J = 12.8 Hz), 3.10 (1H, t,
J = 10.8 Hz), 3.43-3.51 (2H, m), 3.74-4.03 (8H, m), 4.09-
4.15 (1H, m), 4.33-4.41 (2H, m), 4.55-4.76 (2H, m), 6.46
(1H, d, J = 8.2 Hz), 6.77 (1H, d, J = 1.8 Hz), 6.87-6.92
(1H, m), 7.11-7.17 (2H, m), 7.37 (1H, dd, J = 8.0, 2.1
Hz), 7.41-7.47 (2H, m), 7.92 (1H, s).
MS (ESI) m/z: 709 (M + H) .
Example 138
O OH
O NH
2 NH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
{(3R,6S)[(2-fluoroethyl)carbamoyl]tetrahydro-2H-pyran-
3-yl}-3,3-bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 121 and the compound (32 mg, 0.17 mmol)
obtained in Step 2 of Reference Example 59 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 64 mg (68%) of the title compound
as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.47-1.71 (3H, m), 1.84 (1H,
dd, J = 13.7, 2.8 Hz), 2.01-2.07 (1H, m), 2.16-2.22 (1H,
m), 2.27-2.33 (1H, m), 2.39 (1H, d, J = 12.8 Hz), 3.12
(1H, t, J = 10.8 Hz), 3.47-3.70 (2H, m), 3.78-4.02 (5H,
m), 4.10-4.16 (1H, m), 4.35-4.40 (2H, m), 4.44 (1H, t, J
= 4.8 Hz), 4.54-4.77 (3H, m), 6.78 (1H, d, J = 1.8 Hz),
6.89 (1H, t, J = 6.0 Hz), 6.93 (1H, t, J = 8.0 Hz), 7.12-
7.18 (2H, m), 7.37 (1H, dd, J = 8.0, 2.2 Hz), 7.41-7.47
(3H, m).
MS (ESI) m/z: 671 (M + H) .
Example 139
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-{(3R,6S)[(2-
methoxyethyl)(methyl)carbamoyl]tetrahydro-2H-pyranyl}-
2"-oxo-1",2"-dihydrodispiro[cyclobutane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 121 and the compound (36 mg, 0.17 mmol)
obtained in Step 2 of Reference Example 60 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 49 mg (52%) of the title compound
as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.39-1.61 (3H, m), 1.70 (1H,
dd, J = 13.4, 2.4 Hz), 1.81-2.11 (4H, m), 2.21-2.30 (1H,
m), 2.41 (1H, d, J = 12.7 Hz), 2.91-3.17 (2H, m), 3.23
(1H, t, J = 9.8 Hz), 3.32 (3H, s), 3.49-3.63 (3H, br s),
3.78-4.23 (6H, m), 4.38 (2H, s), 4.54-4.75 (2H, m), 6.75
(1H, d, J = 1.8 Hz), 6.88-6.93 (1H, m), 7.10-7.16 (2H, m),
7.25-7.30 (1H, m), 7.35-7.47 (3H, m).
MS (ESI) m/z: 697 (M + H) .
Example 140
O Ph
O O Ph
Step 2
Step 1
Ph 工 程 2
工 程 1 N
Cl N
N Ph
O OH
Cl N
Cl N
工 程 3
Step 3
Cl N
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6"-chloro-8'-(2-chloropyrimidin
yl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-tetrahydro-
1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-
7',3"-indole]-1',2"(1"H)-dione
The compound (3.80 g, 13.0 mmol) obtained in
Reference Example 65 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
4.48 g (53%) of the title compound as a pale yellow solid.
H-NMR (500 MHz, CD OD) d : 0.33 (3H, s), 0.59 (3H, s),
0.93-1.55 (6H, m), 2.07-2.16 (1H, m), 2.23-2.32 (1H, m),
4.57 (1H, d, J = 9.7 Hz), 4.93 (1H, d, J = 3.4 Hz), 5.60
(1H, d, J = 9.7 Hz), 6.73-6.76 (1H, m), 6.80-6.93 (4H, m),
6.97-7.10 (3H, m), 7.10-7.37 (7H, m), 8.43 (1H, d, J =
.2 Hz).
MS (FAB) m/z: 653 (M + H) .
[Step 2]
(4'R,5'R)-6"-chloro-4'-(2-chloropyrimidinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxylic acid
The compound (952 mg, 1.46 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Example 12 to give 314 mg (45%)
of the title compound as a brown solid.
MS (FAB) m/z: 475 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6"-chloro-4'-(2-chloropyrimidinyl)-N-
[(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-pyranyl]-
4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (120 mg, 0.25 mmol) obtained in Step 2
above and the compound (51 mg, 0.30 mmol) obtained in
Step 2 of Reference Example 41 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 62 mg (68%) of the title compound as a
colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 0.66 (3H, s), 0.93 (3H, s),
1.13-1.73 (9H, m), 1.90-2.08 (2H, m), 2.17-2.25 (1H, m),
2.97 (3H, s), 3.11 (3H, s), 3.26-3.35 (1H, m), 3.98-4.08
(1H, m), 4.11-4.17 (2H, m), 4.33-4.42 (2H, m), 6.94 (1H,
d, J = 1.7 Hz), 7.01 (1H, dd, J = 8.1, 2.0 Hz), 7.13 (1H,
d, J = 8.1 Hz), 7.67 (1H, d, J = 5.4 Hz), 7.72 (1H, d, J
= 8.3 Hz), 7.85 (1H, s), 8.39 (1H, d, J = 5.1 Hz).
MS (ESI) m/z: 629 (M + H) .
Example 141
OH O NH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[(3R,6S)(ethylcarbamoyl)tetrahydro-2H-pyranyl]-3,3-
bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 121 and the compound (62 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 34 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 94 mg (48%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.15 (3H, t, J = 7.3 Hz),
1.48-1.60 (2H, m), 1.68 (1H, dd, J = 13.5, 2.5 Hz), 1.83-
1.86 (1H, m), 2.03 (1H, d, J = 11.4 Hz), 2.13-2.20 (1H,
m), 2.25-2.35 (1H, m), 2.39 (1H, d, J = 13.3 Hz), 3.10
(1H, t, J = 10.8 Hz), 3.24-3.36 (2H, m), 3.71-3.98 (5H,
m), 4.12 (1H, ddd, J = 10.9, 4.8, 1.3 Hz), 4.37 (2H, s),
4.54-4.75 (2H, m), 6.51 (1H, t, J = 5.7 Hz), 6.77 (1H, d,
J = 1.8 Hz), 6.92 (1H, t, J = 8.0 Hz), 7.10-7.18 (2H, m),
7.37 (1H, dd, J = 8.0, 2.1 Hz), 7.40-7.47 (2H, m), 7.68
(1H, s).
MS (ESI) m/z: 653 (M + H) .
Example 142
O OH O NH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-{(3R,6S)[(2-
methoxyethyl)carbamoyl]tetrahydro-2H-pyranyl}-2"-oxo-
1",2"-dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 121 and the compound (73 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 61 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 116 mg (57%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.47-1.63 (2H, m), 1.68 (1H,
dd, J = 13.3, 2.7 Hz), 1.84 (1H, dd, J = 13.3, 2.7 Hz),
2.03 (1H, d, J = 12.4 Hz), 2.13-2.21 (1H, m), 2.27-2.31
(1H, m), 2.38 (1H, d, J = 12.8 Hz), 3.10 (1H, t, J = 10.8
Hz), 3.36 (3H, s), 3.44-3.47 (4H, m), 3.77-4.01 (5H, m),
4.12 (1H, ddd, J = 10.9, 4.3, 1.4 Hz), 4.37 (2H, s),
4.54-4.75 (2H, m), 6.77 (1H, d, J = 1.8 Hz), 6.82-6.87
(1H, m), 6.92 (1H, t, J = 8.0 Hz), 7.12-7.17 (2H, m),
7.37 (1H, dd, J = 8.0, 2.1 Hz), 7.41-7.46 (2H, m), 7.60
(1H, s).
MS (ESI) m/z: 683 (M + H) .
Example 143
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(methoxymethyl)tetrahydro-
2H-pyranyl]-2"-oxo-1",2"-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (150 mg, 0.30 mmol) obtained in Step 1
of Example 121 and the compound (70 mg, 0.36 mmol)
obtained in Step 2 of Reference Example 64 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 121 mg (64%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.40-1.55 (2H, m), 1.63-1.76
(2H, m), 1.83 (1H, dd, J = 13.5, 3.0 Hz), 2.04 (1H, dd, J
= 12.4, 2.7 Hz), 2.12-2.19 (1H, m), 2.37 (1H, d, J = 12.4
Hz), 3.09 (1H, t, J = 10.8 Hz), 3.34-3.45 (5H, m), 3.48-
3.55 (1H, m), 3.78-4.02 (4H, m), 4.07 (1H, ddd, J = 10.6,
4.3, 1.5 Hz), 4.38 (2H, s), 4.55-4.76 (2H, m), 6.76 (1H,
d, J = 1.8 Hz), 6.88-6.92 (1H, m), 7.11-7.16 (2H, m),
7.35-7.40 (2H, m), 7.41-7.45 (1H, m), 7.53 (1H, s).
MS (ESI) m/z: 626 (M + H) .
Example 144
O O Ph
O O Ph
Step 1
工 程 1 N
N Ph
Step 3 H
工 程 3
OH N
工 程 2
Step 2
N Ph
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6"-chloro-8'-imidazo[1,2-
a]pyridinyl-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3"-indole]-1',2"(1"H)-dione
The compound (550 mg, 1.86 mmol) obtained in
Reference Example 66 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
344 mg (28%) of the title compound as a yellow amorphous
solid.
H-NMR (400 MHz, CDCl ) d : 0.26 (3H, s), 0.54 (3H, s),
0.96-1.00 (2H, m), 1.07-1.10 (2H, m), 1.31-1.39 (4H, m),
1.69-1.71 (4H, m), 1.96-1.99 (1H, m), 2.25-2.28 (1H, m),
4.64 (1H, d, J = 10.7 Hz), 4.91 (1H, d, J = 2.9 Hz), 5.45
(1H, d, J = 10.5 Hz), 6.31 (1H, d, J = 8.3 Hz), 6.46 (1H,
dd, J = 8.3, 1.7 Hz), 6.52 (1H, t, J = 6.8 Hz), 6.78 (1H,
d, J = 1.7 Hz), 6.82-6.84 (2H, m), 7.01-7.28 (16H, m),
7.52 (1H, d, J = 9.0 Hz), 8.02-8.05 (1H, m), 8.21 (1H, br
MS (ESI) m/z: 658 (M + H) .
[Step 2]
(4'R,5'R)-6"-chloro-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-4'-(imidazo[1,2-a]pyridinyl)-4,4-
dimethyl-N-[trans(1,3,4-oxadiazolyl)cyclohexyl]-2"-
oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3"-indole]-5'-carboxamide
The compound (344 mg, 0.52 mmol) obtained in Step 1
above and the compound (265 mg, 1.57 mmol) obtained in
Step 3 of Reference Example 3 were used as starting
materials and treated in the same way as in Step 1 of
Example 5 to give 239 mg (55%) of the title compound as a
pale yellow amorphous solid.
MS (ESI) m/z: 824 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6"-chloro-4'-imidazo[1,2-a]pyridinyl-
4,4-dimethyl-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
The compound (239 mg, 0.29 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 81 mg (44%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 0.70 (3H, s), 0.95 (3H, s),
1.13-1.22 (2H, m), 1.27-1.88 (10H, m), 1.94-2.02 (2H, m),
2.06-2.27 (3H, m), 3.01 (1H, tt, J = 12.1, 4.1 Hz), 3.69
(1H, tt, J = 12.1, 4.1 Hz), 4.49 (1H, d, J = 8.7 Hz),
6.68 (1H, d, J = 1.8 Hz), 6.72 (1H, td, J = 6.9, 0.9 Hz),
6.98 (1H, dd, J = 8.2, 1.8 Hz), 7.13 (1H, td, J = 8.0,
1.4 Hz), 7.36 (1H, d, J = 9.2 Hz), 7.62 (1H, s), 7.66 (1H,
d, J = 7.8 Hz), 7.89 (1H, s), 8.23 (1H, d, J = 7.3 Hz),
8.84 (1H, s).
MS (ESI) m/z: 628 (M + H) .
Example 145
O OH
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(dimethylcarbamoyl)cyclobutyl]-3,3-
bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (80 mg, 0.16 mmol) obtained in Step 1
of Example 121 and the compound (39 mg, 0.27 mmol)
obtained in Step 2 of Reference Example 52 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 72 mg (72%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.69 (1H, dd, J = 13.5, 3.0
Hz), 1.86 (1H, dd, J = 13.5, 3.0 Hz), 2.10 (1H, dd, J =
12.8, 2.8 Hz), 2.21-2.31 (2H, m), 2.40 (1H, d, J = 12.8
Hz), 2.70-2.81 (2H, m), 2.90 (3H, s), 2.96 (3H, s), 2.97
(1H, dd, J = 6.2, 1.6 Hz), 3.28-3.36 (1H, m), 3.79-4.00
(2H, m), 4.30-4.38 (1H, m), 4.39 (2H, s), 4.59-4.82 (2H,
m), 6.78 (1H, d, J = 1.8 Hz), 6.93 (1H, t, J = 8.0 Hz),
7.12-7.17 (2H, m), 7.40 (1H, dd, J = 7.8, 2.3 Hz), 7.43-
7.48 (1H, m), 7.50 (1H, s), 7.77 (1H, d, J = 7.3 Hz).
MS (ESI) m/z: 623 (M + H) .
Example 146(isomer A) and 147(isomer B)
O OH H
O OH
Cl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-N-{(3R,6S)[1-
hydroxyethyl]tetrahydro-2H-pyranyl}-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (300 mg, 0.6 mmol) obtained in Step 1
of Example 121 and the compound (131 mg, 0.72 mmol)
obtained in Step 3 of Reference Example 30 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give a mixture of diastereomers. The
mixture of diastereomers obtained was resolved and
purified by chiral column liquid chromatography
[fractionation conditions: CHIRALPAK IC, n-hexane:ethanol
= 3:2 (v/v)] to separately give 161 mg (42%: isomer A)
and 86 mg (23%: isomer B) of the title compounds as
colorless solids.
Isomer A:
H-NMR (400 MHz, CDCl ) d : 1.15 (3H, d, J = 6.4 Hz), 1.44
(1H, ddd, J = 24.5, 12.1, 4.1 Hz), 1.61-1.75 (3H, m),
1.84 (1H, dd, J = 13.3, 2.7 Hz), 2.01-2.09 (2H, m), 2.13-
2.22 (1H, m), 2.38 (1H, d, J = 13.3 Hz), 3.09 (1H, t, J =
.5 Hz), 3.23 (1H, dt, J = 11.3, 2.9 Hz), 3.79-3.99 (5H,
m), 4.07 (1H, dq, J = 10.5, 2.3 Hz), 4.38 (2H, s), 4.55-
4.76 (2H, m), 6.92 (1H, t, J = 8.0 Hz), 7.12-7.16 (2H, m),
7.36-7.40 (2H, m), 7.43-7.45 (1H, m), 7.52 (1H, s).
MS (ESI) m/z: 626 (M + H) .
Isomer B:
H-NMR (400 MHz, CDCl ) d : 1.16 (3H, d, J = 6.4 Hz),
1.39-1.50 (2H, m), 1.67 (1H, dd, J = 13.3, 2.7 Hz), 1.72-
1.78 (1H, m), 1.83 (1H, dd, J = 13.7, 3.2 Hz), 2.04 (1H,
d, J = 12.8 Hz), 2.12-2.18 (1H, m), 2.38 (1H, d, J = 12.4
Hz), 2.64 (1H, s), 3.03-3.09 (2H, m), 3.58-3.67 (1H, m),
3.83 (1H, dd, J = 23.8, 9.2 Hz), 3.88-4.03 (3H, m), 4.08
(1H, ddd, J = 11.0, 4.2, 1.4 Hz), 4.38 (2H, s), 4.55-4.76
(2H, m), 6.77 (1H, d, J = 1.8 Hz), 6.91 (1H, t, J = 8.0
Hz), 7.12-7.17 (2H, m), 7.35-7.41 (2H, m), 7.44 (1H, t, J
= 6.6 Hz), 7.50 (1H, s).
MS (ESI) m/z: 626 (M + H) .
Example 148
O OH
HCl N
(3'R,4'S,5'R)-6"-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(dimethylcarbamoyl)cyclohexyl]-3,3-
bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxamide
The compound (70 mg, 0.14 mmol) obtained in Step 1
of Example 121 and transamino-N,N-
dimethylcyclohexanecarboxamide hydrochloride
(WO2008/068171) (29 mg, 0.17 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 62 mg (68%) of the title compound as a
colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.15-1.34 (2H, m), 1.61-1.87
(6H, m), 2.01-2.15 (3H, m), 2.36 (1H, d, J = 12.9 Hz),
2.45-2.54 (1H, m), 2.93 (3H, s), 3.06 (3H, s), 3.70-4.03
(4H, m), 4.34-4.40 (2H, m), 4.56-4.79 (2H, m), 6.72 (1H,
d, J = 2.0 Hz), 6.85-6.91 (1H, m), 7.08-7.14 (2H, m),
7.36 (1H, dd, J = 8.2, 2.1 Hz), 7.41-7.47 (2H, m), 8.19
(1H, s).
MS (ESI) m/z: 651 (M + H) .
Example 149
O OH
O NH
NH N
(3'R,4'S,5'R)-N-[(3R,6S)(2-amino
oxoethyl)tetrahydro-2H-pyranyl]-6''-chloro-4'-(3-
chlorofluorophenyl)-3,3-bis(fluoromethyl)-2''-oxo-
1'',2''-dihydrodispiro[cyclobutane-1,2'-pyrrolidine-
3',3''-indole]-5'-carboxamide
The compound (60 mg, 0.12 mmol) obtained in Step 1
of Example 121 and the compound (28 mg, 0.14 mmol)
obtained in Step 3 of Reference Example 49 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 29 mg (38%) of the title compound
as a solid.
H-NMR (500 MHz, CDCl ) d : 1.46-1.57 (2H, m), 1.66-1.69
(1H, m), 1.79-1.85 (2H, m), 2.02-2.05 (1H, m), 2.13-2.15
(1H, m), 2.37-2.46 (3H, m), 3.10 (1H, t, J = 10.9 Hz),
3.66-3.70 (1H, m), 3.80-4.08 (5H, m), 4.35-4.40 (2H, m),
4.56-4.75 (2H, m), 5.35 (1H, s), 6.21 (1H, s), 6.78 (1H,
d, J = 1.7 Hz), 6.94 (1H, t, J = 7.7 Hz), 7.12-7.17 (2H,
m), 7.36-7.40 (2H, m), 7.46-7.43 (1H, m), 7.52 (1H, s).
MS (ESI) m/z: 639 (M + H) .
Example 150
O OH
O N O N
N H N
HCl N
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-{(3R,6S)[2-(methylamino)
oxoethyl]tetrahydro-2H-pyranyl}-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (99 mg, 0.20 mmol) obtained in Step 1
of Example 17 and the compound (180 mg, 0.22 mmol)
obtained in Step 3 of Reference Example 67 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 35 mg (27%) of the title compound
as a solid.
H-NMR (500 MHz, DMSO-d ) d : 0.59 (3H, s), 0.90-0.99 (4H,
m), 1.10-1.13 (1H, m), 1.19-1.33 (2H, m), 1.40-1.43 (1H,
m), 1.48-1.60 (3H, m), 1.70-1.76 (3H, m), 1.82-1.86 (1H,
m), 2.14 (1H, dd, J = 14.3, 5.2 Hz), 2.23 (1H, dd, J =
14.0, 7.7 Hz), 2.54 (3H, d, J = 4.6 Hz), 3.08 (1H, t, J =
.3 Hz), 3.52-3.50 (1H, m), 3.58-3.67 (3H, m), 4.45 (1H,
t, J = 9.5 Hz), 4.56 (1H, d, J = 9.2 Hz), 6.71 (1H, d, J
= 2.3 Hz), 7.06 (1H, dd, J = 8.3, 2.0 Hz), 7.50 (1H, dd,
J = 8.3, 2.0 Hz), 7.63 (1H, t, J = 4.9 Hz), 7.79-7.74 (2H,
m), 8.17 (1H, d, J = 5.2 Hz), 10.62 (1H, s).
MS (ESI) m/z: 646 (M + H) .
Example 151
O O H
O N O
(3'R,4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-
3,3-bis(fluoromethyl)-N-{(3R,6S)[2-(methylamino)
oxoethyl]tetrahydro-2H-pyranyl}-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (81 mg, 0.16 mmol) obtained in Step 1
of Example 121 and the compound (197 mg, 0.24 mmol)
obtained in Step 3 of Reference Example 67 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 28 mg (26%) of the title compound
as a solid.
H-NMR (500 MHz, CDCl ) d : 1.46-1.52 (2H, m), 1.66-1.69
(1H, m), 1.75-1.85 (2H, m), 2.01-2.04 (1H, m), 2.11-2.13
(1H, m), 2.36-2.39 (3H, m), 2.79 (3H, d, J = 4.6 Hz),
3.09 (1H, t, J = 10.9 Hz), 3.67-3.69 (1H, m), 3.80-4.05
(5H, m), 4.35-4.39 (2H, m), 4.56-4.74 (2H, m), 6.15-6.16
(1H, m), 6.78 (1H, s), 6.93 (1H, t, J = 7.7 Hz), 7.16-
7.12 (2H, m), 7.36-7.46 (3H, m), 7.56 (1H, s).
MS (ESI) m/z: 653 (M + H) .
Example 152
O OH
N O N
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[2-(dimethylamino)
oxoethyl]tetrahydro-2H-pyranyl}-4,4-dimethyl-2''-oxo-
1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3''-indole]-5'-carboxamide
The compound (98 mg, 0.20 mmol) obtained in Step 1
of Example 17 and the compound (53 mg, 0.24 mmol)
obtained in Step 2 of Reference Example 68 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 82 mg (62%) of the title compound
as a solid.
H-NMR (500 MHz, CDCl ) d : 0.67 (3H, s), 0.95 (3H, s),
1.11-1.26 (2H, m), 1.34-1.62 (5H, m), 1.71-1.77 (2H, m),
1.91-1.93 (1H, m), 2.07-2.09 (1H, m), 2.34 (1H, dd, J =
.2, 5.4 Hz), 2.67 (1H, dd, J = 15.2, 6.6 Hz), 2.95 (3H,
s), 3.01 (3H, s), 3.13 (1H, t, J = 10.6 Hz), 3.27 (1H, br
s), 3.82-4.00 (3H, m), 4.43 (1H, d, J = 9.2 Hz), 4.64 (1H,
d, J = 9.2 Hz), 6.73 (1H, s), 7.06 (1H, d, J = 6.9 Hz),
7.31 (1H, d, J = 8.0 Hz), 7.51-7.44 (3H, m), 8.05 (1H, d,
J = 5.2 Hz).
MS (ESI) m/z: 660 (M + H) .
Example 153
O OH
N O N
Cl Cl
(3'R,4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-N-
{(3R,6S)[2-(dimethylamino)oxoethyl]tetrahydro-2H-
pyranyl}-3,3-bis(fluoromethyl)-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (81 mg, 0.16 mmol) obtained in Step 1
of Example 121 and the compound (53 mg, 0.24 mmol)
obtained in Step 2 of Reference Example 68 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 58 mg (54%) of the title compound
as a solid.
H-NMR (500 MHz, CDCl ) d : 1.44-1.50 (2H, m), 1.66-1.68
(1H, m), 1.82-1.92 (2H, m), 2.01-2.12 (2H, m), 2.31-2.39
(2H, m), 2.67 (1H, dd, J = 15.5, 6.9 Hz), 2.95 (3H, s),
3.01 (3H, s), 3.09 (1H, t, J = 10.6 Hz), 3.83-3.99 (6H,
m), 4.37 (2H, s), 4.57-4.74 (2H, m), 6.77 (1H, s), 6.92
(1H, t, J = 7.7 Hz), 7.12-7.15 (2H, m), 7.36-7.37 (2H, m),
7.43-7.46 (1H, m), 7.57-7.54 (1H, m).
MS (ESI) m/z: 667 (M + H) .
Example 154
O OH
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-N-[trans(2-hydroxypropanyl)cyclobutyl]-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (45 mg, 0.09 mmol) obtained in Step 1
of Example 17 and the compound (13 mg, 0.10 mmol)
obtained in Step 2 of Reference Example 69 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 38 mg (69%) of the title compound
as a solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.05-2.10 (16H, m), 2.31-2.46 (3H, m), 3.34 (1H, br s),
4.22-4.34 (1H, m), 4.43 (1H, d, J = 8.90 Hz), 4.66 (1H, d,
J = 8.90 Hz), 6.72 (1H, d, J = 1.83 Hz), 7.07 (1H, dd, J
= 8.25, 1.83 Hz), 7.27-7.35 (2H, m), 7.47-7.53 (1H, m),
7.82-7.89 (1H, m), 8.05 (1H, d, J = 5.04 Hz).
MS (ESI) m/z: 603 (M + H) .
Example 155
O OH
NH S
HCl NH
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2''-oxo-N-[trans(1,3,4-thiadiazol
yl)cyclohexyl]-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (84 mg, 0.16 mmol) obtained in Step 1
of Example 17 and the compound (46 mg, 0.18 mmol)
obtained in Step 3 of Reference Example 70 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 76 mg (72%) of the title compound
as a solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.96 (3H, s),
1.12-1.26 (2H, m), 1.34-1.55 (5H, m), 1.60-1.81 (5H, m),
2.10-2.20 (2H, m), 2.25-2.35 (2H, m), 3.18-3.43 (2H, m),
3.76-3.87 (1H, m), 4.46 (1H, d, J = 8.88 Hz), 4.66 (1H, d,
J = 8.88 Hz), 6.73 (1H, d, J = 1.72 Hz), 7.06 (1H, dd, J
= 8.31, 2.00 Hz), 7.29-7.34 (1H, m), 7.50-7.55 (1H, m),
7.63 (1H, d, J = 8.59 Hz), 7.98 (1H, s), 8.04 (1H, d, J =
.15 Hz), 9.05 (1H, s).
MS (ESI) m/z: 657 (M + H) .
Example 156
O OH
Cl O
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)(5-methyl-1,3,4-oxadiazol-
2-yl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (204 mg, 0.39 mmol) obtained in Step 1
of Example 17 and the compound (79 mg, 0.43 mmol)
obtained in Step 2 of Reference Example 71 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 165 mg (64%) of the title
compound as a solid.
H-NMR (500 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.11-1.27 (2H, m), 1.35-1.43 (1H, m), 1.44-1.55 (2H, m),
1.60-1.83 (4H, m), 2.07-2.28 (3H, m), 2.55 (3H, s), 3.14-
3.43 (2H, m), 3.98-4.07 (1H, m), 4.08-4.15 (1H, m), 4.47
(1H, d, J = 9.16 Hz), 4.65 (1H, d, J = 9.16 Hz), 4.69 (1H,
dd, J = 9.74, 2.86 Hz), 6.73 (1H, d, J = 1.72 Hz), 7.06
(1H, dd, J = 8.02, 1.72 Hz), 7.29-7.33 (1H, m), 7.49-7.53
(1H, m), 7.69 (1H, d, J = 8.59 Hz), 8.04 (1H, d, J = 5.15
Hz), 8.08 (1H, s).
MS (ESI) m/z: 657 (M + H) .
Example 157
O OH
工 程 1
Step 1
Cl Ph
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridinyl)-
3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(1-hydroxy
methylethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (267 mg, 1.55 mmol) obtained in Step 2
of Reference Example 5 and triethylamine (0.23 ml, 2.06
mmol) were added to a tetrahydrofuran solution (5.5 ml)
of the compound (350 mg, 0.52 mmol) obtained in Step 1 of
Example 91 and the resulting mixture was stirred at 60 C
for 36 hours. After cooling, saturated ammonium chloride
solution was added, followed by extraction with ethyl
acetate. The organic layer was washed with brine and
then dried over anhydrous magnesium sulfate. The solvent
was evaporated and the residue was purified by silica gel
column chromatography [chloroform:methanol = 100:0 fi
11:1 (v/v)] to give 232 mg (53%) of the title compound as
a solid.
MS (ESI) m/z: 837 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-3,3-bis(fluoromethyl)-N-[(3R,6S)(1-hydroxy
methylethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (162 mg, 0.38 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 58 mg (51%)
of the title compound as a solid [fractionation
conditions: CHIRALPAK IC, n-hexane:ethanol = 1:1 (v/v)].
H-NMR (400 MHz, CDCl ) d : 1.15 (3H, s), 1.19 (3H, s),
1.39-1.59 (2H, m), 1.62-1.88 (3H, m), 2.03 (1H, d, J =
11.9 Hz), 2.16 (1H, d, J = 12.4 Hz), 2.38 (1H, d, J =
12.8 Hz), 2.48 (1H, s), 3.04-3.13 (2H, m), 3.78-4.11 (5H,
m), 4.32-4.41 (2H, m), 4.53-4.79 (2H, m), 6.80 (1H, s),
7.14 (1H, d, J = 7.8 Hz), 7.36 (2H, d, J = 7.8 Hz), 7.44
(1H, t, J = 4.6 Hz), 7.88 (1H, s), 8.04 (1H, d, J = 5.0
Hz).
MS (ESI) m/z: 641 (M + H) .
Example 158
O NH
工 程 1
Step 1
Cl Ph
Step 2 2
工 程 2
[Step 1]
(3'S,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6''-chloro-4'-(2-chlorofluoropyridinyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (300 mg, 0.44 mmol) obtained in Step 1
of Example 91 and the compound (240 mg, 1.33 mmol)
obtained in Step 3 of Reference Example 28 were used as
starting materials and treated in the same way as in Step
1 of Example 20 to give 180 mg (50%) of the title
compound as a solid.
MS (ESI) m/z: 822 (M + H) .
[Step 2]
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6''-chloro-4'-(2-chlorofluoropyridinyl)-3,3-
bis(fluoromethyl)-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (150 mg, 0.18 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 76 mg (59%)
of the title compound as a solid [fractionation
conditions: CHIRALPAK IC, n-hexane:ethanol = 3:2 (v/v)].
H-NMR (400 MHz, CDCl ) d : 1.47-1.74 (3H, m), 1.85 (1H, d,
J = 13.3 Hz), 2.03 (1H, d, J = 12.8 Hz), 2.16-2.43 (3H,
m), 3.14 (1H, t, J = 10.5 Hz), 3.76-4.16 (6H, m), 4.29-
4.43 (2H, m), 4.53-4.76 (2H, m), 5.70 (1H, s), 6.51 (1H,
s), 6.83 (1H, s), 7.14 (1H, d, J = 7.3 Hz), 7.35 (1H, d,
J = 7.8 Hz), 7.41-7.47 (2H, m), 8.05 (1H, d, J = 5.0 Hz),
8.30 (1H, s).
MS (ESI) m/z: 626 (M + H) .
Example 159
O OH O
NH O
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-N-{trans[5-(methoxymethyl)-1,3,4-oxadiazol
yl]cyclohexyl}-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (174 mg, 0.34 mmol) obtained in Step 1
of Example 17 and the compound (78 mg, 0.37 mmol)
obtained in Step 3 of Reference Example 72 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 168 mg,(73%) of the title
compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.96 (3H, s),
1.10-1.26 (2H, m), 1.30-1.55 (5H, m), 1.58-1.82 (5H, m),
2.08-2.29 (4H, m), 2.87-2.97 (1H, m), 3.19-3.39 (1H, m),
3.45 (3H, s), 3.71-3.85 (1H, m), 4.46 (1H, d, J = 8.7 Hz),
4.62 (2H, s), 4.65 (1H, d, J = 8.7 Hz), 6.70 (1H, d, J =
1.8 Hz), 7.01-7.06 (1H, m), 7.28-7.33 (1H, m), 7.50-7.55
(1H, m), 7.64 (1H, d, J = 8.2 Hz), 8.02 (1H, d, J = 5.5
Hz), 8.50 (1H, s).
MS (ESI) m/z: 685 (M + H) .
Example 160
O OH
O OH
H N N
Cl N
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(2-hydroxyethyl)tetrahydro-2H-pyran
yl]-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (101 mg, 0.20 mmol) obtained in Step 1
of Example 17 and the compound (19 mg, 0.10 mmol)
obtained in Step 2 of Reference Example 73 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 21 mg (33%) of the title compound
as a solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.15-1.22 (2H, m), 1.35-1.72 (11H, m), 2.07-2.09 (1H, m),
2.42 (1H, br s), 3.12 (1H, t, J = 10.6 Hz), 3.28 (1H, br
s), 3.53 (1H, br s), 3.77 (2H, br s), 3.89-3.89 (1H, m),
4.02-4.04 (1H, m), 4.43 (1H, d, J = 8.6 Hz), 4.64 (1H, d,
J = 8.6 Hz), 6.72 (1H, br s), 7.07 (1H, d, J = 7.4 Hz),
7.30-7.32 (1H, m), 7.46-7.50 (3H, m), 8.05 (1H, d, J =
4.6 Hz).
MS (ESI) m/z: 619 (M + H) .
Example 161
O OH
O O N O
H N N
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)(1,3,4-oxadiazol
ylmethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (200 mg, 0.41 mmol) obtained in Step 1
of Example 17 and the compound (58 mg, 0.26 mmol)
obtained in Step 3 of Reference Example 74 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 72 mg (42%) of the title compound
as a solid.
H-NMR (500 MHz, DMSO-d ) d : 0.59 (3H, s), 0.90-0.99 (4H,
m), 1.10-1.12 (1H, m), 1.19-1.21 (1H, m), 1.41-1.63 (5H,
m), 1.71-1.76 (2H, m), 1.83-1.88 (2H, m), 3.00-3.15 (3H,
m), 3.51 (1H, d, J = 9.7 Hz), 3.71-3.65 (3H, m), 4.45 (1H,
t, J = 9.2 Hz), 4.57 (1H, d, J = 8.6 Hz), 6.71 (1H, d, J
= 1.7 Hz), 7.06 (1H, d, J = 6.3 Hz), 7.50 (1H, d, J = 7.4
Hz), 7.63 (1H, t, J = 4.6 Hz), 7.80 (1H, d, J = 8.0 Hz),
8.17 (1H, d, J = 5.2 Hz), 9.14 (1H, s), 10.62 (1H, s).
MS (ESI) m/z: 657 (M + H) .
Example 162
O OH
H OH
(3'R,4'S,5'R)-N-[6,6-bis(hydroxymethyl)spiro[3.3]hepta
yl]-6''-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (98 mg, 0.20 mmol) obtained in Step 1
of Example 17 and the compound (38 mg, 0.20 mmol)
obtained in Step 5 of Reference Example 75 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 76 mg (56%) of the title compound
as a solid.
H-NMR (400 MHz, CD OD) d : 0.68 (3H, s), 0.95 (3H, s),
1.13-1.22 (2H, m), 1.33-1.36 (1H, m), 1.55-1.57 (2H, m),
1.72-1.87 (5H, m), 1.97-2.00 (4H, m), 2.36-2.47 (2H, m),
3.46-3.54 (4H, m), 4.09-4.17 (1H, m), 4.51 (1H, d, J =
9.2 Hz), 4.65 (1H, d, J = 9.2 Hz), 6.76 (1H, d, J = 1.8
Hz), 7.06 (1H, dd, J = 8.0, 1.8 Hz), 7.45 (1H, dd, J =
8.0, 2.1 Hz), 7.65 (1H, m), 8.05 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 649 (M + H) .
Example 163
O O Ph
Step 1
工 程 1 N
N Ph
O H F
F F N F
O OH
H N O
Step 3
工 程 3
N Cl
工 程 2
Step 2
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6''-chloro-8'-(2-chloro
fluoropyridinyl)-5''-fluoro-3,3-bis(fluoromethyl)-
3',4'-diphenyl-3',4',8',8a'-tetrahydro-1'H-
dispiro[cyclobutane-1,6'-pyrrolo[2,1-c][1,4]oxazine-
7',3''-indole]-1',2''(1''H)-dione
The compound (402 mg, 3.0 mmol) obtained in Step 2
of Reference Example 21 and the compound (981 mg, 3.00
mmol) obtained in Reference Example 11 were used as
starting materials and treated in the same way as in Step
1 of Example 9 to give 1.20g(57%) of the title compound
as a solid.
H-NMR (400 MHz, CDCl ) d : 1.74 (1H, d, J = 14.2 Hz),
2.42 (1H, d, J = 14.7 Hz), 2.84 (1H, d, J = 14.7 Hz),
3.19 (1H, d, J = 14.2 Hz), 4.00-4.04 (1H, m), 4.12-4.15
(1H, m), 4.31 (1H, t, J = 10.1 Hz), 4.43 (1H, t, J = 9.6
Hz), 4.53 (1H, d, J = 9.6 Hz), 4.65 (1H, d, J = 10.1 Hz),
.26 (1H, t, J = 3.2 Hz), 6.29 (1H, d, J = 4.1 Hz), 6.78-
6.79 (2H, m), 6.90 (1H, d, J = 6.0 Hz), 7.16-7.18 (2H, m),
7.21-7.29 (8H, m), 7.73 (1H, s), 7.98 (1H, d, J = 5.0 Hz).
[Step 2]
(4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridinyl)-
''-fluoro-3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-
1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (348 mg, 0.50 mmol) obtained in Step 1
above and the compound (251 mg, 1.50 mmol) obtained in
Step 1 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 1 of
Example 20 to give 353 mg (85%) of the title compound as
a solid.
MS (ESI) m/z: 827 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-5''-fluoro-3,3-bis(fluoromethyl)-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (353 mg, 0.43 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 140 mg (52%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.42-1.46 (1H, m), 1.59-1.65
(1H, m), 1.71-1.79 (2H, m), 1.84-1.91 (1H, m), 1.99-2.13
(2H, m), 2.46 (1H, d, J = 13.3 Hz), 3.16 (1H, t, J = 10.5
Hz), 3.37-3.39 (1H, m), 3.50 (2H, d, J = 5.0 Hz), 3.76-
3.84 (1H, m), 3.88 (1H, s), 3.90-3.93 (1H, m), 4.00 (1H,
s), 4.40 (1H, d, J = 9.2 Hz), 4.51 (1H, d, J = 9.2 Hz),
4.60-4.82 (2H, m), 6.90 (1H, d, J = 6.0 Hz), 7.60-7.61
(2H, m), 8.08 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 635 (M + H) .
Example 164
O O Ph
Step1
工 程 1 N
N Ph
N F F F
H N N
Step3
工 程 3
N Cl
工 程 2
Step 2
Cl H
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6''-chloro-8'-(3-chloro
fluorophenyl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclobutane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-
dione
The compound (402 mg, 3.00 mmol) obtained in Step 2
of Reference Example 21 and the compound (981 mg, 3.00
mmol) obtained in Reference Example 6 were used as
starting materials and treated in the same way as in Step
1 of Example 9 to give 1.32 g (65%) of the title compound
as a solid.
H-NMR (400 MHz, CDCl ) d : 1.68 (1H, d, J = 15.1 Hz),
2.45 (1H, d, J = 14.2 Hz), 2.88 (1H, d, J = 14.2 Hz),
3.30 (1H, d, J = 14.7 Hz), 4.02 (1H, d, J = 12.4 Hz),
4.07 (1H, d, J = 10.1 Hz), 4.14-4.19 (1H, m), 4.39 (1H,
dd, J = 13.1, 9.4 Hz), 4.50 (1H, dd, J = 12.8, 9.6 Hz),
4.61 (1H, d, J = 9.6 Hz), 5.24 (1H, t, J = 3.4 Hz), 6.18
(1H, d, J = 3.7 Hz), 6.54 (1H, d, J = 9.6 Hz), 6.75 (1H,
s), 6.81 (1H, d, J = 1.8 Hz), 6.87-6.90 (2H, m), 6.97 (1H,
dd, J = 8.2, 1.8 Hz), 7.21-7.30 (10H, m), 7.54 (1H, s).
[Step 2]
(4'R,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2''-oxo-1'',2''-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (338 mg, 0.50 mmol) obtained in Step 1
above and the compound (251 mg, 1.50 mmol) obtained in
Step 1 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 1 of
Example 20 to give 335 mg (83%) of the title compound as
a solid.
MS (ESI) m/z: 808 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-
3,3-bis(fluoromethyl)-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (335 mg, 0.41 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 97 mg (38%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.41-1.45 (1H, m), 1.51-1.78
(3H, m), 1.88 (1H, d, J = 12.8 Hz), 1.98-2.11 (2H, m),
2.46 (1H, d, J = 12.8 Hz), 3.11 (1H, t, J = 10.8 Hz),
3.33-3.40 (1H, m), 3.49 (2H, d, J = 5.0 Hz), 3.74-3.84
(2H, m), 3.87-3.94 (3H, m), 4.47 (1H, d, J = 9.6 Hz),
4.56-4.78 (2H, m), 6.84 (1H, d, J = 2.3 Hz), 6.87 (1H, m),
6.93-6.97 (1H, m), 7.00-7.03 (1H, m), 7.14 (1H, dd, J =
8.2, 1.8 Hz), 7.57 (1H, d, J = 8.2 Hz).
Example 165
O O Ph
Step 1
工 程 1 N
N Ph
O H F
N F F F
H N N
Step 3
工 程 3
N Cl
工 程 2
Step 2
Cl H
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6''-chloro-8'-(2-chloropyridin
yl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclobutane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-dione
The compound (402 mg, 3.00 mmol) obtained in Step 2
of Reference Example 21 and the compound (873 mg, 3.00
mmol) obtained in Reference Example 4 were used as
starting materials and treated in the same way as in Step
1 of Example 9 to give 1.35 g (68%) of the title compound
as a solid.
H-NMR (400 MHz, CDCl ) d : 1.65 (1H, d, J = 14.9 Hz),
2.46 (1H, d, J = 14.9 Hz), 2.88 (1H, d, J = 14.4 Hz),
3.32 (1H, d, J = 13.7 Hz), 4.01-4.10 (2H, m), 4.13-4.21
(1H, m), 4.39 (1H, dd, J = 13.2, 9.5 Hz), 4.51 (1H, dd, J
= 12.9, 9.5 Hz), 4.65 (1H, d, J = 10.0 Hz), 5.26 (1H, t,
J = 3.5 Hz), 6.19 (1H, d, J = 3.9 Hz), 6.76 (1H, dd, J =
.2, 1.6 Hz), 6.80 (1H, d, J = 1.7 Hz), 6.91-6.95 (3H, m),
7.20-7.27 (10H, m), 7.85 (1H, s), 8.11 (1H, d, J = 5.4
Hz).
[Step 2]
(3'S,4'R,5'R)-6''-chloro-4'-(2-chloropyridinyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2''-oxo-1'',2''-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
A methanol solution (5 ml) of the compound (330 mg,
0.50 mmol) obtained in Step 1 above and the compound (251
mg, 1.50 mmol) obtained in Step 1 of Reference Example 2
were used as starting materials and treated in the same
way as in Step 1 of Example 20 to give 222 mg (56%) of
the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.25-1.29 (1H, m), 1.46-1.51
(2H, m), 1.61-1.64 (1H, m), 1.99 (1H, dd, J = 7.3, 4.6
Hz), 2.11 (1H, d, J = 12.2 Hz), 2.63 (1H, d, J = 16.6 Hz),
2.70 (1H, t, J = 10.6 Hz), 2.82 (1H, d, J = 14.9 Hz),
3.27-3.31 (1H, m), 3.46-3.60 (3H, m), 3.81-3.84 (2H, m),
3.93-3.97 (2H, m), 4.05 (1H, d, J = 2.4 Hz), 4.18 (1H, s),
4.30 (1H, s), 4.44 (1H, dd, J = 12.6, 9.6 Hz), 4.56 (1H,
dd, J = 12.5, 9.8 Hz), 4.80 (1H, d, J = 2.9 Hz), 5.32 (1H,
d, J = 8.1 Hz), 5.62 (1H, s), 6.61 (1H, dd, J = 5.4, 1.5
Hz), 6.80-6.83 (3H, m), 6.89 (1H, dd, J = 8.1, 2.0 Hz),
7.05-7.19 (6H, m), 7.29-7.32 (4H, m), 7.65 (1H, s), 8.05
(1H, d, J = 5.1 Hz).
[Step 3]
(3'R,4'R,5'R)-6''-chloro-4'-(2-chloropyridinyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(hydroxymethyl)tetrahydro-
2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (222 mg, 0.28 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 80 mg (56%)
of the title compound as a colorless solid [fractionation
conditions: CHIRALPAK IC, n-hexane:2-propanol = 2:3
(v/v)].
H-NMR (400 MHz, CD OD) d : 1.40-1.46 (1H, m), 1.54-1.80
(3H, m), 1.88 (1H, d, J = 12.4 Hz), 1.98-2.11 (2H, m),
2.47 (1H, d, J = 13.3 Hz), 3.15 (1H, t, J = 10.5 Hz),
3.36-3.39 (1H, m), 3.50 (2H, d, J = 5.0 Hz), 3.75-3.85
(2H, m), 3.88-4.00 (3H, m), 4.55 (1H, d, J = 9.2 Hz),
4.60-4.80 (2H, m), 6.86 (1H, d, J = 1.8 Hz), 7.09-7.18
(2H, m), 7.20-7.30 (1H, m), 7.60 (1H, d, J = 8.2 Hz),
8.10 (1H, d, J = 5.5 Hz).
MS (ESI) m/z: 599 (M + H) .
Example 166
O OH
O N S O
Cl N
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(3R,6S)
{[(methylsulfonyl)amino]methyl}tetrahydro-2H-pyranyl]-
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (199 mg, 0.40 mmol) obtained in Step 1
of Example 17 and the compound (81 mg, 0.33 mmol)
obtained in Step 2 of Reference Example 76 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 184 mg (83%) of the title
compound as a solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.12-1.22 (2H, m), 1.34-1.37 (1H, m), 1.43-1.62 (5H, m),
1.68-1.78 (3H, m), 2.09-2.11 (1H, m), 2.96 (3H, s), 3.02-
3.12 (2H, m), 3.26-3.32 (2H, m), 3.45-3.50 (1H, m), 3.88-
3.88 (1H, m), 4.02-4.05 (1H, m), 4.42-4.45 (1H, m), 4.64
(1H, d, J = 9.2 Hz), 4.74 (1H, dd, J = 8.0, 4.0 Hz), 6.73
(1H, d, J = 1.7 Hz), 7.07 (1H, dd, J = 8.3, 2.0 Hz), 7.31
(1H, dd, J = 8.3, 2.0 Hz), 7.37 (1H, s), 7.50-7.47 (2H,
m), 8.05 (1H, d, J = 5.2 Hz).
MS (ESI) m/z: 682 (M + H) .
Example 167
St 工 e 程 p 1 1
Cl Ph
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridinyl)-
N-[(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-pyran
yl]-3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (350 mg, 0.52 mmol) obtained in Step 1
of Example 91 and the compound (267 mg, 1.55 mmol)
obtained in Step 2 of Reference Example 77 were used as
starting materials and treated in the same way as in Step
1 of Example 157 to give 232 mg (53%) of the title
compound as a solid.
MS (ESI) m/z: 850 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-N-[(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-pyran-
3-yl]-3,3-bis(fluoromethyl)-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (320 mg, 0.38 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 138 mg (56%)
of the title compound as a solid [fractionation
conditions: CHIRALPAK IC, n-hexane:ethanol = 2:3 (v/v)].
H-NMR (400 MHz, CDCl ) d : 1.52-1.63 (2H, m), 1.69 (1H,
dd, J = 13.5, 2.5 Hz), 1.82-2.08 (4H, m), 2.21-2.31 (1H,
m), 2.39 (1H, d, J = 12.8 Hz), 2.96 (3H, s), 3.09 (3H, s),
3.24 (1H, dd, J = 10.5, 8.7 Hz), 3.79-4.09 (4H, m), 4.16
(1H, dd, J = 9.2, 3.2 Hz), 4.34-4.41 (2H, m), 4.54-4.78
(2H, m), 6.83 (1H, d, J = 1.8 Hz), 7.15 (1H, dd, J = 8.3,
1.8 Hz), 7.37 (1H, dd, J = 8.0, 2.1 Hz), 7.44 (1H, t, J =
4.8 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.68 (1H, br s), 8.05
(1H, d, J = 5.0 Hz).
MS (ESI) m/z: 654 (M + H) .
Example 168
工 程 1
Step 1
Cl Ph
Step 2
工 程 2
[Step 1]
(4'R,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(dimethylcarbamoyl)cyclohexyl]-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (339 mg, 0.50 mmol) obtained in Step 1
of Example 164 and transamino-N,N-
dimethylcyclohexanecarboxamide (144 mg, 0.85 mmol) were
used as starting materials and treated in the same way as
in Step 1 of Example 20 to give 178 mg (42%) of the title
compound as a colorless solid.
MS (ESI) m/z: 847 (M + H) .
[Step 2]
(3'R,4'R,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-N-
[trans(dimethylcarbamoyl)cyclohexyl]-3,3-
bis(fluoromethyl)-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (178 mg, 0.21 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 60 mg (44%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.26-1.71 (5H, m), 1.75-2.09
(6H, m), 2.46 (1H, d, J = 12.8 Hz), 2.60-2.72 (1H, m),
2.91 (3H, s), 3.11 (3H, s), 3.59-3.71 (1H, m), 3.79 (1H,
s), 3.88-3.94 (2H, m), 4.46 (1H, d, J = 9.6 Hz), 4.56-
4.76 (2H, m), 6.84 (1H, d, J = 1.8 Hz), 6.87-6.99 (2H, m),
7.02 (1H, br s), 7.14 (1H, dd, J = 8.0, 1.6 Hz), 7.57 (1H,
d, J = 8.2 Hz).
MS (ESI) m/z: 653 (M + H) .
Example 169
O O Ph
Step 1
工 程 1 N
F F N F
O OH
H N O
Step 3
工 程 3
N Cl
工 程 2
Step 2
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6''-chloro-8'-(3,5-
dichlorophenyl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclobutane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-
dione
The compound (402 mg, 3.00 mmol) obtained in Step 2
of Reference Example 21 and the compound (974 mg, 3.00
mmol) obtained in Reference Example 78 were used as
starting materials and treated in the same way as in Step
1 of Example 9 to give 1.27 g (61%) of the title compound
as a solid.
H-NMR (400 MHz, CDCl ) d : 1.70 (1H, d, J = 15.1 Hz),
2.46 (1H, d, J = 14.7 Hz), 2.89 (1H, d, J = 13.3 Hz),
3.30 (1H, d, J = 14.7 Hz), 3.99-4.10 (2H, m), 4.11-4.22
(1H, m), 4.39 (1H, dd, J = 12.8, 9.6 Hz), 4.51 (1H, dd, J
= 12.8, 9.6 Hz), 4.60 (1H, d, J = 10.1 Hz), 5.24 (1H, t,
J = 3.4 Hz), 6.17 (1H, d, J = 4.1 Hz), 6.78-6.84 (3H, m),
6.91 (1H, d, J = 8.2 Hz), 6.98 (1H, dd, J = 8.2, 1.8 Hz),
7.15 (1H, t, J = 1.8 Hz), 7.16-7.34 (10H, m), 7.52 (1H,
[Step 2]
(4'R,5'R)-6''-chloro-4'-(3,5-dichlorophenyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2''-oxo-1'',2''-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (347 mg, 0.50 mmol) obtained in Step 1
above and the compound (197 mg, 1.50 mmol) obtained in
Step 1 of Reference Example 2 were used as starting
materials and treated in the same way as in Step 1 of
Example 20 to give 285 mg (69%) of the title compound as
a solid.
MS (ESI) m/z: 825 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6''-chloro-4'-(3,5-dichlorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(hydroxymethyl)tetrahydro-
2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (285 mg, 0.35 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 99 mg (46%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.38-1.48 (1H, m), 1.53-1.65
(1H, m), 1.68 (1H, dd, J = 13.7, 2.3 Hz), 1.75-1.78 (1H,
m), 1.88 (1H, d, J = 13.7 Hz), 2.01-2.12 (2H, m), 2.46
(1H, d, J = 13.3 Hz), 3.12 (1H, t, J = 10.8 Hz), 3.34-
3.40 (1H, m), 3.49 (2H, d, J = 5.5 Hz), 3.76-3.84 (2H, m),
3.88-3.95 (3H, m), 4.47 (1H, d, J = 9.2 Hz), 4.57-4.76
(2H, m), 6.85 (1H, d, J = 1.8 Hz), 7.12-7.17 (3H, m),
7.18-7.20 (1H, m), 7.57 (1H, d, J = 8.2 Hz).
Example 170
N HCl
工 程 1
Step 1
O Cl
Cl Ph
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridinyl)-
3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-{(3R,6S)[(1R)
hydroxyethyl]tetrahydro-2H-pyranyl}-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (500 mg, 0.74 mmol) obtained in Step 1
of Example 91 and the compound (321 mg, 2.21 mmol)
obtained in Step 4 of Reference Example 79 were used as
starting materials and treated in the same way as in Step
1 of Example 157 to give 378 mg (62%) of the title
compound as a solid.
MS (ESI) m/z: 823 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-3,3-bis(fluoromethyl)-N-{(3R,6S)[(1R)
hydroxyethyl]tetrahydro-2H-pyranyl}-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (360 mg, 0.44 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 186 mg (68%)
of the title compound as a solid [fractionation
conditions: CHIRALPAK IC, n-hexane:ethanol = 3:2 (v/v)].
H-NMR (CDCl ) d : 1.15 (3H, d, J = 6.4 Hz), 1.38-1.89 (5H,
m), 2.00-2.23 (3H, m), 2.38 (1H, d, J = 12.4 Hz), 3.10
(1H, t, J = 10.5 Hz), 3.23 (1H, d, J = 11.0 Hz), 3.77-
4.10 (6H, m), 4.32-4.41 (2H, m), 4.53-4.77 (2H, m), 6.81
(1H, s), 7.15 (1H, d, J = 8.3 Hz), 7.33-7.39 (2H, m),
7.44 (1H, t, J = 4.6 Hz), 7.65 (1H, s), 8.05 (1H, d, J =
.0 Hz).
MS (ESI) m/z: 627 (M + H) .
Example 171
O OH
H N O N
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[(1-methyl-1H-imidazolyl)methyl]-
2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (400 mg, 0.81 mmol) obtained in Step 1
of Example 17 and 1-(1-methyl-1H-imidazol
yl)methanamine (95 mg, 0.98 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 188 mg (41%) of the title compound as
a solid.
H-NMR (400 MHz, CDCl ) d : 0.64 (3H, s), 0.88 (3H, s),
1.09-1.26 (3H, m), 1.37-1.52 (2H, m), 1.59-1.82 (3H, m),
3.21-3.28 (1H, m), 3.62 (3H, s), 4.40-4.53 (3H, m), 4.64
(1H, d, J = 9.2 Hz), 6.72 (1H, s), 7.00-7.08 (2H, m),
7.29 (1H, d, J = 8.7 Hz), 7.45 (1H, s), 7.52 (1H, t, J =
.0 Hz), 7.83 (1H, t, J = 5.0 Hz), 8.05 (1H, d, J = 5.0
Hz), 8.45 (1H, s).
MS (ESI) m/z: 585 (M + H) .
Example 172
O O Ph
Step 1
工 程 1 N
+ + F
N Ph
O H F
F F N F
O OH
H N N
Step 3 OH
工 程 3
工 程 2
Step 2
Cl H
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6''-chloro-8'-(3-chloro-2,4-
difluorophenyl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclobutane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-
dione
The compound (402 mg, 3.00 mmol) obtained in Step 2
of Reference Example 21 and the compound (978 mg, 3.00
mmol) obtained in Reference Example 80 were used as
starting materials and treated in the same way as in Step
1 of Example 9 to give 1.20 g (58%) of the title compound
as a solid.
H-NMR (400 MHz, CDCl ) d : 1.87 (1H, d, J = 13.8 Hz),
2.32 (1H, d, J = 14.2 Hz), 2.83 (1H, d, J = 14.2 Hz),
3.01 (1H, d, J = 14.7 Hz), 3.89-3.95 (1H, m), 4.01-4.07
(1H, m), 4.24 (1H, dd, J = 14.2, 9.6 Hz), 4.36 (1H, dd, J
= 14.0, 9.4 Hz), 4.48 (1H, d, J = 10.1 Hz), 4.68 (1H, d,
J = 10.1 Hz), 5.22 (1H, t, J = 3.2 Hz), 6.32 (1H, d, J =
3.7 Hz), 6.72-6.80 (2H, m), 6.84-6.89 (2H, m), 6.92 (1H,
dd, J = 8.3, 1.8 Hz), 7.09-7.16 (2H, m), 7.20-7.25 (8H,
m), 7.62 (1H, s).
[Step 2]
(3'S,4'S,5'R)-6''-chloro-4'-(3-chloro-2,4-
difluorophenyl)-3,3-bis(fluoromethyl)-1'-[(1R,2S)
hydroxy-1,2-diphenylethyl]-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (348 mg, 0.50 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Example 20 to give 400 mg (96%)
of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.17-1.30 (1H, m), 1.42-1.56
(2H, m), 1.62 (2H, d, J = 11.5 Hz), 2.10 (1H, d, J = 11.0
Hz), 2.58 (1H, d, J = 15.6 Hz), 2.70 (1H, t, J = 10.5 Hz),
2.85 (1H, d, J = 15.1 Hz), 3.25-3.34 (1H, m), 3.40 (1H, d,
J = 14.7 Hz), 3.50 (1H, dd, J = 11.5, 6.9 Hz), 3.58 (1H,
dd, J = 11.7, 3.0 Hz), 3.82 (1H, d, J = 9.6 Hz), 3.88 (1H,
dd, J = 10.5, 2.8 Hz), 3.91-4.03 (1H, m), 4.09 (1H, s),
4.20 (2H, d, J = 9.6 Hz), 4.35 (1H, s), 4.45 (1H, t, J =
.1 Hz), 4.57 (1H, t, J = 10.1 Hz), 4.83 (1H, d, J = 3.2
Hz), 5.22 (1H, d, J = 7.8 Hz), 5.61 (1H, s), 6.47-6.52
(1H, m), 6.63 (1H, dd, J = 8.9, 6.2 Hz), 6.77-6.85 (2H,
m), 6.89 (1H, dd, J = 8.0, 1.6 Hz), 7.08-7.16 (4H, m),
7.20-7.31 (4H, m), 7.36 (2H, d, J = 6.9 Hz), 8.07 (1H, s).
[Step 3]
(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2,4-
difluorophenyl)-3,3-bis(fluoromethyl)-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (400 mg, 0.48 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 120 mg (40%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.37-1.50 (1H, m), 1.53-1.79
(3H, m), 1.88 (1H, d, J = 13.6 Hz), 2.02-2.12 (2H, m),
2.47 (1H, d, J = 13.6 Hz), 3.12 (1H, t, J = 10.4 Hz),
3.35-3.41 (1H, m), 3.49 (2H, d, J = 5.4 Hz), 3.74-3.84
(2H, m), 3.86-3.92 (2H, m), 4.33 (1H, d, J = 9.5 Hz),
4.44 (1H, d, J = 9.5 Hz), 4.57-4.78 (2H, m), 6.82 (1H, br
s), 6.98-7.02 (1H, m), 7.08-7.14 (1H, m), 7.47-7.53 (1H,
m), 7.55-7.63 (1H, m).
MS (ESI) m/z: 632 (M + H) .
Example 173
O OH
Cl N
Methyl (2S,5R)({[(3'R,4'S,5'R)-6''-chloro-4'-(2-
chlorofluoropyridinyl)-4,4-dimethyl-2''-oxo-
1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3''-indole]-5'-yl]carbonyl}amino)tetrahydro-2H-pyran-
2-carboxylate
The compound (34.0 g, 69.1 mmol) obtained in Step 1
of Example 17 and the compound (12.6 g, 64.3 mmol)
obtained in Step 1 of Reference Example 18 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 31.5 g (76%) of the title
compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.68 (3H, s), 0.95 (3H, s),
1.15-1.26 (2H, m), 1.33-1.40 (1H, m), 1.42-2.03 (7H, m),
2.08-2.17 (2H, m), 3.22-3.31 (2H, m), 3.79 (3H, s), 3.91-
4.07 (2H, m), 4.15 (1H, dd, J = 11.3, 4.1 Hz), 4.40-4.49
(1H, m), 4.64 (1H, d, J = 9.1 Hz), 6.73 (1H, d, J = 1.8
Hz), 7.07 (1H, dd, J = 8.2, 2.0 Hz), 7.31 (1H, dd, J =
8.2, 2.0 Hz), 7.49 (2H, t, J = 4.8 Hz), 7.61 (1H, d, J =
8.6 Hz), 8.05 (1H, d, J = 5.4 Hz).
MS (ESI) m/z: 633 (M + H) .
Example 174
O OH
Cl Cl
Cl Cl
(2S,5R)({[(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-yl]carbonyl}amino)tetrahydro-2H-pyran
carboxylic acid
1N sodium hydroxide solution (3 ml) was added to a
methanol (10 ml) solution of the compound (1.00 g, 1.58
mmol) obtained in Example 173 and the resulting mixture
was stirred at room temperature for 18 hours. 1N
hydrochloric acid was added to the reaction mixture to
adjust its pH to approximately 6 to 7, followed by
extraction with ethyl acetate. The organic layer was
washed with brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced
pressure to give 577 mg (60%) of the title compound as a
solid.
H-NMR (400 MHz, DMSO-d ) d : 0.58 (3H, s), 0.89 (3H, s),
0.91-0.99 (1H, m), 1.07-1.13 (1H, m), 1.17-1.23 (1H, m),
1.37-1.76 (7H, m), 1.82-1.88 (1H, m), 1.92-1.99 (1H, m),
3.15-3.22 (1H, m), 3.56-3.91 (3H, m), 4.41-4.57 (2H, m),
6.70 (1H, d, J = 2.3 Hz), 7.05 (1H, dd, J = 8.2, 1.8 Hz),
7.50 (1H, d, J = 7.2 Hz), 7.62 (1H, t, J = 5.0 Hz), 7.84
(1H, d, J = 8.6 Hz), 8.16 (1H, d, J = 5.0 Hz), 10.62 (1H,
br s).
MS (ESI) m/z: 619 (M + H) .
Example 175
O O Ph Step 1
工 程 1 N
N Ph
O H F
F F N F
O OH
H N N O
Ph Step 3
工 程 3
S 工 te 程 p 2 2
Cl H
[Step 1]
(3'S,4'R,7'S,8'R,8a'R)-6''-chloro-8'-(3-chlorophenyl)-
3,3-bis(fluoromethyl)-3',4'-diphenyl-3',4',8',8a'-
tetrahydro-1'H-dispiro[cyclobutane-1,6'-pyrrolo[2,1-
c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-dione
The compound (760 mg, 2.6 mmol) obtained in
Reference Example 81 and the compound (402 mg, 3.00 mmol)
obtained in Step 2 of Reference Example 21 were used as
starting materials and treated in the same way as in Step
1 of Example 9 to give 1.20 g (70%) of the title compound
as a solid.
H-NMR (400 MHz, CDCl ) d : 1.70 (1H, d, J = 14.0 Hz),
2.45 (1H, d, J = 14.5 Hz), 2.90 (1H, d, J = 14.0 Hz),
3.29 (1H, d, J = 14.0 Hz), 3.98-4.18 (3H, m), 4.38 (1H,
dd, J = 14.0, 9.5 Hz), 4.50 (1H, dd, J = 14.0, 9.5 Hz),
4.66 (1H, d, J = 10.0 Hz), 5.24 (1H, t, J = 3.2 Hz), 6.18
(1H, d, J = 3.6 Hz), 6.77-6.82 (2H, m), 6.89 (1H, d, J =
8.2 Hz), 6.93-6.96 (2H, m), 7.03 (1H, t, J = 7.9 Hz),
7.11-7.15 (1H, m), 7.18-7.34 (10H, m), 7.65 (1H, s).
[Step 2]
(4'R,5'R)-6''-chloro-4'-(3-chlorophenyl)-3,3-
bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2''-oxo-1'',2''-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (330 mg, 0.50 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Example 20 to give 343 mg (86%)
of the title compound as a solid.
MS (ESI) m/z: 790 (M + H) .
[Step 3]
(3'R,4'R,5'R)-6''-chloro-4'-(3-chlorophenyl)-3,3-
bis(fluoromethyl)-N-[(3R,6S)(hydroxymethyl)tetrahydro-
2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (343 mg, 0.43 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 90 mg (35%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.36-1.50 (1H, m), 1.53-1.80
(3H, m), 2.06 (2H, d, J = 12.4 Hz), 2.47 (1H, d, J = 12.4
Hz), 3.09 (1H, t, J = 10.5 Hz), 3.34-3.38 (1H, m), 3.49
(2H, d, J = 5.5 Hz), 3.77-3.83 (2H, m), 3.85-3.95 (3H, m),
4.49 (1H, d, J = 9.2 Hz), 4.57-4.78 (2H, m), 6.81 (1H, d,
J = 1.8 Hz), 7.03-7.14 (4H, m), 7.19-7.21 (1H, m), 7.56
(1H, d, J = 8.2 Hz).
Example 176
O O Ph
Step 1
工 程 1 N
N Ph
O H F
F F N F
O OH
F O N
H N O
Ph Step 3
工 程 3
工 程 2
Step 2
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6''-chloro-8'-(3-chloro-2,5-
difluorophenyl)-3,3-bis(fluoromethyl)-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclobutane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-
dione
The compound (978 mg, 3.00 mmol) obtained in
Reference Example 82 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
1.50 g (70%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.93 (1H, d, J = 14.5 Hz),
2.30 (1H, d, J = 14.5 Hz), 2.81 (1H, d, J = 14.0 Hz),
2.92 (1H, d, J = 14.0 Hz), 3.87 (1H, t, J = 11.6 Hz),
3.99 (1H, t, J = 11.8 Hz), 4.21 (1H, dd, J = 14.0, 9.5
Hz), 4.33 (1H, dd, J = 14.3, 9.7 Hz), 4.50 (1H, d, J =
9.5 Hz), 4.61 (1H, d, J = 9.1 Hz), 5.22 (1H, s), 6.34 (1H,
d, J = 3.6 Hz), 6.62-6.72 (2H, m), 6.88-7.02 (3H, m),
7.10-7.17 (2H, m), 7.19-7.31 (8H, m), 7.81 (1H, s).
[Step 2]
(4'S,5'R)-6''-chloro-4'-(3-chloro-2,5-difluorophenyl)-
3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-[(3R,6S)(hydroxymethyl)tetrahydro-2H-
pyranyl]-2''-oxo-1'',2''-dihydrodispiro[cyclobutane-
1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (348 mg, 0.50 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Example 20 to give 321 mg (78%)
of the title compound as a solid.
MS (ESI) m/z: 826 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2,5-
difluorophenyl)-3,3-bis(fluoromethyl)-N-[(3R,6S)
(hydroxymethyl)tetrahydro-2H-pyranyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (321 mg, 0.39 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 125 mg (51%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.37-1.50 (1H, m), 1.53-1.79
(3H, m), 1.88 (1H, d, J = 13.7 Hz), 2.02-2.12 (2H, m),
2.47 (1H, d, J = 12.8 Hz), 3.12 (1H, t, J = 10.5 Hz),
3.33-3.41 (1H, m), 3.49 (2H, d, J = 5.0 Hz), 3.75-3.85
(2H, m), 3.88-3.92 (2H, m), 4.36 (1H, d, J = 9.6 Hz),
4.41 (1H, d, J = 9.2 Hz), 4.58-4.78 (2H, m), 6.83 (1H, d,
J = 1.8 Hz), 7.06-7.14 (2H, m), 7.31-7.35 (1H, m), 7.50
(1H, dd, J = 8.0, 2.1 Hz).
Example 177
O O OH
HCl O
工 程 1
Step 1
Cl Ph
Step 2
工 程 2
[Step 1]
(4'S,5'R)-6''-chloro-4'-(3-chloro-2,5-difluorophenyl)-
3,3-bis(fluoromethyl)-1'-[(1R,2S)hydroxy-1,2-
diphenylethyl]-N-{(3R,6S)[(1R)
hydroxyethyl]tetrahydro-2H-pyranyl}-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (348 mg, 0.50 mmol) obtained in Step 1
of Example 176 and the compound (272 mg, 1.50 mmol)
obtained in Step 4 of Reference Example 79 were used as
starting materials and treated in the same way as in Step
1 of Example 20 to give 303 mg (72%) of the title
compound as a solid.
MS (ESI) m/z: 840 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2,5-
difluorophenyl)-3,3-bis(fluoromethyl)-N-{(3R,6S)[(1R)-
1-hydroxyethyl]tetrahydro-2H-pyranyl}-2''-oxo-1'',2''-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (303 mg, 0.36 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Example 91 to give 135 mg (58%)
of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.15 (3H, d, J = 6.4 Hz),
1.40-1.62 (2H, m), 1.68 (1H, d, J = 13.3 Hz), 1.88 (2H, d,
J = 12.8 Hz), 2.02-2.13 (2H, m), 2.47 (1H, d, J = 12.8
Hz), 3.08-3.13 (2H, m), 3.59-3.65 (1H, m), 3.74-3.82 (2H,
m), 3.86-3.93 (2H, m), 4.36 (1H, d, J = 9.6 Hz), 4.41 (1H,
d, J = 9.2 Hz), 4.56-4.78 (2H, m), 6.83 (1H, d, J = 1.8
Hz), 7.06-7.14 (2H, m), 7.31-7.35 (1H, m), 7.50 (1H, dd,
J = 8.0, 2.1 Hz).
Example 178
O OH
H N N
2HCl
Cl Cl N
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2''-oxo-N-[1-(1H-tetrazol
yl)piperidinyl]-1'',2''-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (148 mg, 0.30 mmol) obtained in Step 1
of Example 17 and the compound (72 mg, 0.30 mmol)
obtained in Step 3 of Reference Example 83 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 170 mg (53%) of the title
compound as a solid.
H-NMR (400 MHz, CD OD) d : 0.67 (3H, s), 0.91 (3H, s),
1.09-1.23 (2H, m), 1.27-1.34 (1H, m), 1.51-1.83 (7H, m),
1.91-2.05 (2H, m), 3.16-3.27 (2H, m), 3.80-3.95 (3H, m),
4.56 (1H, d, J = 9.2 Hz), 4.69 (1H, d, J = 9.2 Hz), 6.77
(1H, d, J = 1.8 Hz), 7.07 (1H, dd, J = 7.8, 1.8 Hz), 7.46
(1H, dd, J = 8.2, 1.8 Hz), 7.67 (1H, t, J = 5.0 Hz), 8.06
(1H, d, J = 5.0 Hz).
Example 179
O O Ph
O OH
Step 1
工 程 1
N Ph
Cl N
Cl N
O NH
工 程 2
Step 2
Cl N
[Step 1]
(4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-pyrrolo[2,3-b]pyridine]-5'-carboxylic
acid
The compound (18.2 g, 27.0 mmol) obtained in Step 1
of Example 2 was used as a starting material and treated
in the same way as in Step 1 of Example 17 to give 3.1 g
(23%) of the title compound as a solid.
H-NMR (500 MHz, DMSO-d ) d : 0.65-0.66 (3H, m), 0.86-0.88
(3H, m), 1.03-1.63 (6.6H, m), 1.77-1.83 (0.7H, m), 1.98-
2.01 (0.7H, m), 4.27 (0.3H, d, J = 9.2 Hz), 4.52-4.55 (1H,
m), 4.72 (0.7H, d, J = 9.7 Hz), 6.88 (0.3H, d, J = 8.0
Hz), 7.11-7.19 (2H, m), 7.38-7.42 (1H, m), 7.51-7.55 (1H,
m), 7.95 (0.7H, dd, J = 8.0, 2.3 Hz), 11.32-11.31 (1H, m).
[Step 2]
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6''-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (248 mg, 0.50 mmol) obtained in Step 1
above and the compound (104 mg, 0.57 mmol) obtained in
Step 2 of Reference Example 84 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 258 mg (83%) of the title compound as
a solid.
H-NMR (500 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.16-1.27 (2H, m), 1.36-1.67 (7H, m), 1.76-1.78 (1H, m),
2.11-2.15 (1H, m), 2.26-2.30 (1H, m), 3.14 (1H, t, J =
.9 Hz), 3.22 (1H, br s), 3.80 (1H, dd, J = 11.5, 2.3
Hz), 3.87-3.93 (1H, m), 4.11-4.14 (1H, m), 4.43-4.50 (1H,
m), 4.68 (1H, d, J = 9.7 Hz), 5.50 (1H, d, J = 4.0 Hz),
6.49 (1H, d, J = 4.6 Hz), 6.97 (1H, t, J = 8.0 Hz), 7.05
(1H, d, J = 7.4 Hz), 7.16-7.19 (1H, m), 7.46-7.49 (2H, m),
7.62 (1H, dd, J = 8.0, 2.3 Hz), 8.13 (1H, s).
MS (ESI) m/z: 618 (M + H) .
Example 180
O OH O OH
Cl N
Cl N
(3'R,4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-N-
{(3R,6S)[(1R)hydroxyethyl]tetrahydro-2H-pyran
yl}-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
pyrrolo[2,3-b]pyridine]-5'-carboxamide
The compound (250 mg, 0.51 mmol) obtained in Step 1
of Example 179 and the compound (104 mg, 0.57 mmol)
obtained in Step 4 of Reference Example 79 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 282 mg (90%) of the title
compound as a solid.
H-NMR (500 MHz, CDCl ) d : 0.70 (3H, s), 0.96 (3H, s),
1.14-1.24 (5H, m), 1.35-1.64 (7H, m), 1.72-1.79 (2H, m),
2.07-2.13 (2H, m), 3.12 (1H, t, J = 10.6 Hz), 3.21-3.24
(2H, m), 3.82-3.90 (2H, m), 4.06-4.09 (1H, m), 4.46 (1H,
d, J = 9.2 Hz), 4.69 (1H, d, J = 9.2 Hz), 6.96 (1H, t, J
= 7.7 Hz), 7.05 (1H, d, J = 8.0 Hz), 7.16 (1H, t, J = 6.9
Hz), 7.43-7.48 (2H, m), 7.63 (1H, dd, J = 7.4, 2.3 Hz),
8.03 (1H, s).
MS (ESI) m/z: 619 (M + H) .
Example 181
O NH
O OH
2 O N
O NH
Cl Cl
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6''-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-indole]-5'-carboxamide
The compound (250 mg, 0.51 mmol) obtained in Step 1
of Example 12 and the compound (100 mg, 0.56 mmol)
obtained in Step 2 of Reference Example 84 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 222 mg (71%) of the title
compound as a solid.
H-NMR (500 MHz, DMSO-d ) d : 0.60 (3H, s), 0.90 (3H, s),
0.95 (1H, td, J = 13.7, 4.0 Hz), 1.10-1.12 (1H, m), 1.20-
1.24 (1H, m), 1.40-1.65 (5H, m), 1.70-1.76 (2H, m), 1.87-
1.91 (1H, m), 1.97-2.01 (1H, m), 3.16 (1H, t, J = 10.6
Hz), 3.48 (1H, d, J = 10.9 Hz), 3.64-3.71 (2H, m), 3.76-
3.79 (1H, m), 4.38 (1H, t, J = 9.7 Hz), 4.58 (1H, d, J =
9.2 Hz), 6.68 (1H, d, J = 1.7 Hz), 7.04 (1H, dd, J = 8.0,
2.3 Hz), 7.15-7.09 (3H, m), 7.31-7.34 (1H, m), 7.45 (1H,
dd, J = 8.3, 2.0 Hz), 7.57 (1H, t, J = 6.6 Hz), 7.83 (1H,
d, J = 8.0 Hz), 10.53 (1H, s).
MS (ESI) m/z: 617 (M + H) .
Example 182
O OH
O OH
(3'R,4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-N-
{(3R,6S)[(1R)hydroxyethyl]tetrahydro-2H-pyran
yl}-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (247 mg, 0.50 mmol) obtained in Step 1
of Example 12 and the compound (104 mg, 0.57 mmol)
obtained in Step 4 of Reference Example 79 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 261 mg (84%) of the title
compound as a solid.
H-NMR (500 MHz, CDCl ) d : 0.68 (3H, s), 0.94 (3H, s),
1.11-1.21 (5H, m), 1.34-1.39 (1H, m), 1.43 (1H, td, J =
12.2, 3.6 Hz), 1.48-1.53 (1H, m), 1.56-1.64 (3H, m),
1.71-1.76 (3H, m), 2.08 (1H, d, J = 4.6 Hz), 2.13 (1H, d,
J = 12.0 Hz), 3.12 (1H, t, J = 10.6 Hz), 3.21-3.25 (2H,
m), 3.82-3.92 (2H, m), 4.06-4.09 (1H, m), 4.44 (1H, d, J
= 8.0 Hz), 4.67 (1H, d, J = 9.2 Hz), 6.68 (1H, d, J = 2.3
Hz), 6.91 (1H, t, J = 8.0 Hz), 7.05 (1H, dd, J = 8.0, 1.7
Hz), 7.11-7.14 (1H, m), 7.33 (1H, dd, J = 8.0, 2.3 Hz),
7.40 (1H, s), 7.47-7.52 (2H, m).
MS (ESI) m/z: 618 (M + H) .
Example 183
Cl Cl
(3'R,4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-
4,4-dimethyl-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (250 mg, 0.51 mmol) obtained in Step 1
of Example 12 and the compound (100 mg, 0.60 mmol)
obtained in Step 3 of Reference Example 3 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 251 mg (77%) of the title
compound as a solid.
H-NMR (500 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.12-1.26 (2H, m), 1.32-1.43 (3H, m), 1.48-1.80 (7H, m),
2.15-2.25 (4H, m), 2.93-2.98 (1H, m), 3.24 (1H, br s),
3.76-3.82 (1H, m), 4.46 (1H, d, J = 9.2 Hz), 4.68 (1H, d,
J = 9.2 Hz), 6.69 (1H, s), 6.89 (1H, t, J = 8.0 Hz), 7.05
(1H, d, J = 6.9 Hz), 7.12 (1H, t, J = 7.2 Hz), 7.33 (1H,
d, J = 6.9 Hz), 7.55-7.50 (2H, m), 7.64 (1H, d, J = 8.6
Hz), 8.34 (1H, s).
MS (ESI) m/z: 640 (M + H) .
Example 184
O OH
Step 1
Ph NH
N 工 程 1
O OH
HCl NH
工 程 2 N
Step 2
[Step 1]
(4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-pyrrolo[3,2-c]pyridine]-5'-carboxylic
acid
1N sodium hydroxide solution (1.8 ml) was added to a
methanol (10 ml) solution of the compound (1.00 g, 1.49
mmol) obtained in Step 1 of Example 108 and the resulting
mixture was stirred at 70 C for 5 hours. 65% aqueous
methanol (15 ml) solution of cerium (IV) diammonium
nitrate (3.2 g, 5.96 mmol) was added dropwise to the
reaction mixture under ice cooling and the resulting
mixture was stirred at the same temperature for 30
minutes. Subsequently, the reaction mixture was rendered
weakly acidic (pH 4 to 5) by addition of 1N sodium
hydroxide solution and then concentrated under reduced
pressure. After extraction with ethyl acetate, the
organic layer was washed with brine. The organic layer
was dried over anhydrous magnesium sulfate and filtered
and then the solvent in the filtrate was evaporated under
reduced pressure. The residue obtained was solidified by
addition of diethyl ether to give 480 mg (65%) of the
title compound as a solid.
MS (ESI) m/z: 492 (M + H) .
[Step 2]
(3'R,4'S,5'R)-6''-chloro-4'-(3-chlorofluorophenyl)-N-
{(3R,6S)[(1R)hydroxyethyl]tetrahydro-2H-pyran
yl}-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (300 mg, 0.61 mmol) obtained in Step 1
above and the compound (111 mg, 0.61 mol) obtained in
Step 4 of Reference Example 79 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 67 mg (18%) of the title compound as a
solid.
H-NMR (400 MHz, CD OD) d : 0.72 (3H, s), 0.96 (3H, s),
1.15 (3H, d, J = 6.3 Hz), 1.17-1.25 (2H, m), 1.28-1.63
(6H, m), 1.73-1.95 (3H, m), 2.06-2.11 (1H, m), 3.13 (2H,
t, J = 10.6 Hz), 3.59-3.65 (1H, m), 3.72-3.80 (1H, m),
3.88-3.95 (1H, m), 4.55 (1H, d, J = 9.1 Hz), 4.75 (1H, d,
J = 9.1 Hz), 6.79 (1H, s), 7.05 (1H, t, J = 8.2 Hz), 7.24
(1H, t, J = 6.8 Hz), 7.56 (1H, t, J = 6.8 Hz), 8.31 (1H,
d, J = 2.7 Hz).
MS (ESI) m/z: 619 (M + H) .
Example 185
O NH
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6''-chloro-4'-(3-chlorofluorophenyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (300 mg, 0.61 mmol) obtained in Step 1
of Example 185 and the compound (110 mg, 0.61mol)
obtained in Step 3 of Reference Example 28 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 155 mg (41%) of the title
compound as a solid.
H-NMR (400 MHz, CD OD) d : 0.72 (3H, s), 0.96 (3H, s),
1.11-1.24 (2H, m), 1.36-1.41 (1H, m), 1.51-1.95 (7H, m),
2.09-2.19 (2H, m), 3.23 (1H, t, J = 10.6 Hz), 3.77-3.86
(2H, m), 4.00 (1H, dq, J = 10.5, 2.1 Hz), 4.56 (1H, d, J
= 9.1 Hz), 4.76 (1H, d, J = 9.1 Hz), 6.79 (1H, s), 7.05
(1H, t, J = 8.2 Hz), 7.22-7.27 (1H, m), 7.57 (1H, t, J =
6.3 Hz), 8.31 (1H, d, J = 2.3 Hz).
MS (ESI) m/z: 618 (M + H) .
Example 186
O OH
Cl Cl
工 程 1
Step 1
Step 2
工 程 2
[Step 1]
Methyl (5R)({[(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-yl]carbonyl}amino)methyltetrahydro-2H-
pyrancarboxylate
The compound (492 mg, 1.0 mmol) obtained in Step 1
of Example 17 and the compound (119 mg, 0.70 mmol)
obtained in Step 3 of Reference Example 85 were used as
starting materials and treated in the same way as in Step
2 of Example 12 to give 321 mg (71%) of the title
compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.14-1.26 (2H, m), 1.36-1.41 (1H, m), 1.46 (3H, s), 1.49-
1.56 (2H, m), 1.63-1.90 (6H, m), 2.19-2.26 (1H, m), 3.19-
3.23 (1H, m), 3.72-3.77 (1H, m), 3.80 (3H, s), 3.84 (1H,
dd, J = 12.7, 2.3 Hz), 3.86-3.91 (1H, m), 4.52-4.57 (1H,
m), 4.64 (1H, d, J = 9.5 Hz), 6.73 (1H, d, J = 1.8 Hz),
7.07 (1H, dd, J = 8.2, 1.8 Hz), 7.34 (1H, dd, J = 8.4,
2.5 Hz), 7.43 (1H, s), 7.51 (1H, t, J = 5.0 Hz), 8.05 (1H,
d, J = 5.4 Hz), 8.14 (1H, d, J = 8.2 Hz).
MS (ESI) m/z: 647 (M + H) .
[Step 2]
(5R)({[(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-yl]carbonyl}amino)methyltetrahydro-2H-
pyrancarboxylic acid
The compound (280 mg, 0.43 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Example 174 to give 222 mg (81%) of the
title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 0.60 (3H, s), 0.89 (3H, s),
0.95-1.01 (1H, m), 1.10-1.18 (1H, m), 1.28-1.86 (12H, m),
1.98-2.04 (1H, m), 3.37-3.39 (1H, m), 3.47-3.59 (1H, m),
3.62-3.80 (2H, m), 4.48-4.54 (1H, m), 6.70 (1H, s), 7.05
(1H, d, J = 8.2 Hz), 7.54 (1H, d, J = 7.7 Hz), 7.58-7.65
(1H, m), 8.10 (1H, d, J = 7.2 Hz), 8.18 (1H, d, J = 4.1
Hz), 10.63 (1H, br s).
MS (ESI) m/z: 633 (M + H) .
Example 187
O N N
N N 2
Cl Cl
(3'R,4'S,5'R)-N-[(3R)carbamoylmethyltetrahydro-2H-
pyranyl]-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (150 mg, 0.24 mmol) obtained in Example
187 was used as a starting material and treated in the
same way as in Step 1 of Reference Example 16 to give 116
mg (76%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.96 (3H, s),
1.16-1.27 (2H, m), 1.38-1.43 (1H, m), 1.47 (3H, s), 1.49-
1.56 (2H, m), 1.68-1.80 (5H, m), 1.83-1.91 (1H, m), 2.15-
2.21 (1H, m), 3.28 (1H, br s), 3.62 (1H, dd, J = 12.0,
4.8 Hz), 3.82-3.93 (2H, m), 4.51 (1H, d, J = 9.5 Hz),
4.64 (1H, d, J = 9.5 Hz), 5.52 (1H, d, J = 3.6 Hz), 6.49
(1H, d, J = 3.6 Hz), 6.73 (1H, d, J = 1.8 Hz), 7.07 (1H,
dd, J = 8.2, 1.8 Hz), 7.34 (1H, dd, J = 8.4, 2.0 Hz),
7.51 (1H, t, J = 5.0 Hz), 7.70 (1H, s), 7.93 (1H, d, J =
7.7 Hz), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 632 (M + H) .
Example 188
O OH
HCl N
工 程 1
Step 1
Step 2 H
工 程 2
[Step 1]
Methyl (2S)({[(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-yl]carbonyl}amino)methyltetrahydro-2H-
pyrancarboxylate
1-Chloro-N,N,2-trimethylpropenamine (0.13 ml,
1.00 mmol) was added to a tetrahydrofuran (8 ml) solution
of the compound (492 mg, 1.00 mmol) obtained in Step 1 of
Example 17, the resulting mixture was stirred for 1
minute, then a tetrahydrofuran (6 ml) solution of the
compound (210 mg, 1.00 mmol) obtained in Step 2 of
Reference Example 85 and triethylamine (0.42 ml, 3.00
mmol) was added dropwise and the resulting mixture was
stirred at room temperature for 16 hours. Subsequently,
1-ethyl(3-dimethylaminopropyl)carbodiimide
hydrochloride (191 mg, 1.00 mmol) was added to the
reaction mixture and the resulting mixture was stirred at
room temperature for 5 hours. The reaction mixture was
diluted with ethyl acetate, then washed with saturated
sodium bicarbonate solution, and brine in this order, and
dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the residue
obtained was purified by silica gel chromatography
[chloroform:methanol = 50:1 (v/v)] to give 62 mg (10%) of
the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.67 (3H, s), 0.93-0.98 (1H,
m), 0.93 (3H, s), 1.10-1.53 (12H, m), 1.94-1.99 (1H, m),
2.31-2.37 (1H, m), 2.92 (1H, br s), 3.28-3.33 (1H, m),
3.75-3.80 (1H, m), 3.81 (3H, s), 3.91-3.96 (1H, m), 4.42
(1H, d, J = 9.1 Hz), 4.64 (1H, d, J = 9.1 Hz), 6.74 (1H,
d, J = 2.3 Hz), 7.07 (1H, dd, J = 8.2, 1.8 Hz), 7.31 (1H,
dd, J = 7.7, 2.7 Hz), 7.41 (1H, s), 7.47-7.53 (2H, m),
8.05 (1H, d, J = 5.4 Hz).
MS (ESI) m/z: 647 (M + H) .
[Step 2]
(2S)({[(3'R,4'S,5'R)-6''-chloro-4'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-yl]carbonyl}amino)methyltetrahydro-2H-
pyrancarboxylic acid
The compound (130 mg, 0.20 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Example 174 to give 35 mg (28%) of the
title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 0.57 (3H, s), 0.86 (3H, s),
0.92-1.23 (4H, m), 1.26 (3H, s), 1.29-1.79 (7H, m), 2.16-
2.22 (1H, m), 3.24-3.30 (1H, m), 3.52-3.58 (1H, m), 3.60-
3.70 (1H, m), 4.42 (1H, d, J = 8.6 Hz), 4.56 (1H, d, J =
9.1 Hz), 6.70 (1H, d, J = 1.8 Hz), 7.04 (1H, dd, J = 8.2,
2.3 Hz), 7.48 (1H, dd, J = 8.2, 1.8 Hz), 7.61 (1H, t, J =
.2 Hz), 7.86 (1H, d, J = 8.6 Hz), 8.16 (1H, d, J = 5.0
Hz), 10.61 (1H, s).
MS (ESI) m/z: 633 (M + H) .
Example 189
O N N
N N 2
Cl Cl
(3'R,4'S,5'R)-N-[(6S)carbamoylmethyltetrahydro-2H-
pyranyl]-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
indole]-5'-carboxamide
The compound (23 mg, 0.04 mmol) obtained in Step 2
of Example 189 was used as a starting material and
treated in the same way as in Step 1 of Reference Example
16 to give 11 mg (48%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.66 (3H, s), 0.92 (3H, s),
1.11-1.40 (4H, m), 1.44 (3H, s), 1.46-1.77 (6H, m), 1.92-
1.97 (1H, m), 2.24-2.29 (1H, m), 3.40 (1H, dd, J = 11.1,
7.0 Hz), 3.85-4.00 (2H, m), 4.47 (1H, d, J = 9.1 Hz),
4.61 (1H, d, J = 9.5 Hz), 5.48 (1H, d, J = 4.1 Hz), 6.53
(1H, d, J = 4.1 Hz), 6.73 (1H, d, J = 1.8 Hz), 7.07 (1H,
dd, J = 8.2, 1.8 Hz), 7.31 (1H, dd, J = 8.2, 2.3 Hz),
7.50 (1H, t, J = 5.0 Hz), 7.60 (1H, s), 7.70 (1H, d, J =
8.2 Hz), 8.05 (1H, d, J = 5.0 Hz).
MS (ESI) m/z: 632 (M + H) .
Example 190
O O Ph
O O Ph
Step 1
N Ph
工 程 1
N Ph
Step 3
NH 工 程 3
工 程 2 N
Step 2
N Ph
[Step 1]
(3'S,4'R,7'S,8'S,8a'R)-6''-chloro-8'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3''-pyrrolo[3,2-
c]pyridine]-1',2''(1''H)-dione
The compound (3.00g, 9.67 mmol) obtained in
Reference Example 86 was used as a starting material and
treated in the same way as in Step 1 of Example 9 to give
.00 g (77%) of the title compound as a solid.
H-NMR (CDCl ) d : 0.22 (3H, s), 0.54 (3H, s), 0.93-1.09
(3H, m), 1.24-1.37 (3H, m), 1.75-1.82 (1H, m), 2.20-2.27
(1H, m), 4.56 (1H, d, J = 11.0 Hz), 4.82 (1H, d, J = 3.2
Hz), 5.29 (1H, d, J = 11.0 Hz), 6.73 (1H, d, J = 6.9 Hz),
6.90-6.93 (1H, m), 7.03-7.06 (1H, m), 7.09-7.25 (10H, m),
7.78 (1H, t, J = 4.8 Hz), 7.93 (1H, s), 8.33 (1H, d, J =
.0 Hz).
MS (ESI) m/z: 671 (M + H) .
[Step 2]
(4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridinyl)-
1'-[(1R,2S)hydroxy-1,2-diphenylethyl]-4,4-dimethyl-N-
[trans(1,3,4-oxadiazolyl)cyclohexyl]-2''-oxo-
1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-
3',3''-pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (300 mg, 0.45 mmol) obtained in Step 1
above and the compound (242 mg, 1.34 mmol) obtained in
Step 3 of Reference Example 3 were used as starting
materials and treated in the same way as in Step 2 of
Example 12 to give 177 mg (47%) of the title compound as
a solid.
MS (ESI) m/z: 838 (M + H) .
[Step 3]
(3'R,4'S,5'R)-6''-chloro-4'-(2-chlorofluoropyridin
yl)-4,4-dimethyl-N-[trans(1,3,4-oxadiazol
yl)cyclohexyl]-2''-oxo-1'',2''-
dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-
pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (145 mg, 0.17 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Example 1 to give 62 mg (56%) of
the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 0.72 (3H, s), 0.97 (3H, s),
1.09-1.26 (2H, m), 1.37-1.94 (10H, m), 2.01-2.29 (4H, m),
2.98-3.09 (1H, m), 3.67-3.75 (1H, m), 4.61 (1H, d, J =
9.2 Hz), 4.75 (1H, d, J = 9.2 Hz), 6.84 (1H, s), 7.64 (1H,
t, J = 5.0 Hz), 8.09 (1H, d, J = 5.0 Hz), 8.36 (1H, s),
8.85 (1H, s).
MS (ESI) m/z: 642 (M + H) .
Example 191
O NH
HCl H
(4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran
yl]-6''-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (60 mg, 0.11 mmol) obtained in Step 3
of Reference Example 87 and the compound (20.5 mg, 0.11
mmol) obtained in Step 3 of Reference Example 28 were
used as starting materials and treated in the same way as
in Step 2 of Example 12 to give 26 mg (37%) of the title
compound as a solid.
H-NMR (400 MHz, CD OD) d : 0.71 (3H, s), 0.96 (3H, s),
1.10-1.41 (4H, m), 1.49-1.91 (7H, m), 2.06-2.20 (2H, m),
3.77-3.87 (2H, m), 3.98-4.04 (1H, m), 4.60 (1H, d, J =
9.2 Hz), 4.76 (1H, d, J = 9.2 Hz), 6.83 (1H, s), 7.62 (1H,
t, J = 5.0 Hz), 8.09 (1H, d, J = 5.0 Hz), 8.35 (1H, d, J
= 1.8 Hz).
MS (ESI) m/z: 619 (M + H) .
Example 192
O OH
O OH
H N O
HCl N
Cl Cl
6''-chloro-4'-(2-chlorofluoropyridinyl)-N-{(3R,6S)-
6-[(1R)hydroxyethyl]tetrahydro-2H-pyranyl}-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-pyrrolo[3,2-c]pyridine]-5'-carboxamide
The compound (40 mg, 0.76 mmol) obtained in Step 3
of Reference Example 87 and the compound (14 mg, 0.76
mmol) obtained in Step 4 of Reference Example 79 were
used as starting materials and treated in the same way as
in Step 2 of Example 12 to give 18 mg (39%) of the title
compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.73 (3H, s), 0.98 (3H, s),
1.13-1.30 (3H, m), 1.18 (3H, d, J = 6.4 Hz), 1.39-1.81
(9H, m), 2.12-2.21 (2H, m), 3.15 (1H, t, J = 10.8 Hz),
3.24-3.29 (1H, m), 3.84-3.93 (2H, m), 4.04-4.09 (1H, m),
4.49 (1H, d, J = 9.2 Hz), 4.71 (1H, d, J = 9.2 Hz), 6.72
(1H, s), 7.45-7.49 (2H, m), 8.09 (1H, d, J = 5.0 Hz),
8.31-8.34 (2H, m).
MS (ESI) m/z: 620 (M + H) .
Example 193
2 O 2
Cl Cl
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide hydrochloride
water/2-propanol (IPA) solvate
Concentrated hydrochloric acid (0.026 ml, 0.31 mmol)
was added to a 2-propanol (2.0 ml) solution of the
compound (192 mg, 0.31 mmol) obtained in Example 70 and
the resulting mixture was dissolved by heating. After
stirring at room temperature for 18 hours, the
precipitate was collected by filtration to give 173 mg
(85%) of the title compound as a solid.
H-NMR (500 MHz, DMSO-d ) d : 0.62 (3H, s), 0.92 (3H, s),
1.09-1.58 (6H, m), 1.65-2.07 (5H, m), 2.53-2.94 (1H, m),
3.29-3.73 (5H, m), 4.56-4.76 (1H, m), 4.85-5.23 (1H, m),
6.80 (1H, s), 7.01-7.13 (2H, m), 7.14-7.20 (1H, m), 7.49-
7.74 (2H, m), 8.19-8.42 (1H, m), 8.61-9.08 (1H, m), 10.41
(1H, br s), 11.25 (1H, br s).
Anal. Calcd for C H Cl FN O HCl 0.75H O IPA: C,
34 2 5 4 2
54.48; H, 6.03; N, 9.63. Found: C, 54.47; H, 6.14; N,
9.65.
Example 194
2 O 2
H H SO
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide sulfate water/2-
propanol (IPA) solvate
Concentrated sulfuric acid (0.005 ml, 0.08 mmol) was
added to a 2-propanol (0.5 ml) solution of the compound
(52 mg, 0.08 mmol) obtained in Example 70 and the
resulting mixture was dissolved by heating. After
stirring at room temperature for 2 days, the precipitate
was collected by filtration to give 20 mg (34%) of the
title compound as a solid.
H-NMR (500 MHz, DMSO-d ) d : 0.62 (3H, s), 0.92 (3H, s),
1.13-1.61 (6H, m), 1.67-2.09 (5H, m), 2.45-2.88 (1H, m),
3.47-4.01 (5H, m), 4.58-4.77 (1H, m), 4.83-5.11 (1H, m),
6.79 (1H, s), 6.98-7.25 (3H, m), 7.51-7.73 (2H, m), 8.20-
8.41 (1H, m), 8.51-8.73 (1H, m), 8.79-9.05 (1H, m), 10.35
(1H, br s), 11.18 (1H, br s).
Anal. Calcd for C H Cl FN O H SO 0.25H O IPA: C,
34 2 5 4 2 4 2
49.94; H, 5.71; N, 8.82. Found: C, 49.74; H, 5.71; N,
8.85.
Example 195
NH NH
O 2 O 2
Cl Cl
O S OH
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide methanesulfonate
hydrate
Methanesulfonic acid (0.006 ml, 0.09 mmol) was added
to a 2-propanol (0.5 ml) solution of the compound (54 mg,
0.09 mmol) obtained in Example 70 and the resulting
mixture was dissolved by heating. After stirring at room
temperature for 3 days, the precipitate was collected by
filtration to give 27 mg (43%) of the title compound as a
solid.
H-NMR (400 MHz, CDCl ) d : 0.74 (3H, s), 1.03 (3H, s),
1.28-1.43 (2H, m), 1.44-1.82 (4H, m), 1.84-2.10 (3H, m),
2.14-2.28 (2H, m), 2.56-2.79 (4H, m), 3.09-3.25 (1H, m),
3.72-3.80 (1H, m), 3.81-3.94 (2H, m), 4.72-4.85 (1H, m),
.35-5.54 (1H, m), 5.69-5.88 (1H, m), 6.55-6.68 (1H, m),
6.90 (1H, s), 7.08 (1H, dd, J = 7.8, 1.8 Hz), 7.28-7.35
(1H, m), 7.81-7.95 (1H, m), 8.14-8.36 (2H, m), 8.44-8.89
(1H, m), 9.83 (1H, br s), 11.03 (1H, br s).
Anal. Calcd for C H Cl FN O CH SO H H O: C, 50.82; H,
34 2 5 4 3 3 2
.50; N, 9.56. Found: C, 50.78; H, 5.51; N, 9.53.
Example 196
O 2 O
Cl Cl
Cl Cl
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide ethanesulfonate
hydrate
Ethanesulfonic acid (0.024 ml, 0.30 mmol) was added
to a 2-propanol (2.4 ml) solution of the compound (183 mg,
0.30 mmol) obtained in Example 70 and the resulting
mixture was dissolved by heating. After stirring at room
temperature for 23 hours, the precipitate was collected
by filtration to give 177 mg (82%) of the title compound
as a solid.
H-NMR (400 MHz, DMSO-d ) d : 0.62 (3H, s), 0.92 (3H, s),
1.05 (3H, t, J = 7.4 Hz), 1.09-1.59 (6H, m), 1.62-2.06
(5H, m), 2.38 (2H, q, J = 7.4 Hz), 2.59-3.07 (1H, m),
3.27-3.79 (5H, m), 4.53-4.76 (1H, m), 4.78-5.16 (1H, m),
6.79 (1H, s), 7.00-7.23 (3H, m), 7.51-7.75 (2H, m), 8.21-
8.41 (1H, m), 8.48-9.07 (1H, m), 10.35 (1H, br s), 11.19
(1H, br s).
Anal. Calcd for C H Cl FN O C H SO H H O: C, 51.54; H,
34 2 5 4 2 5 3 2
.54; N, 9.39. Found: C, 51.42; H, 5.65; N, 9.35.
Example 197
NH NH
O 2 O
Cl Cl
S OH
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide benzenesulfonate
hydrate
Benzenesulfonic acid monohydrate (30 mg, 0.17 mmol)
was added to a 2-propanol (1.0 ml) solution of the
compound (104 mg, 0.17 mmol) obtained in Example 70 and
the resulting mixture was dissolved by heating. After
stirring at room temperature for 24 hours, the
precipitate was collected by filtration to give 116 mg
(89%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.69 (3H, s), 0.88 (3H, s),
1.09-1.85 (7H, m), 1.88-2.19 (4H, m), 2.53-2.77 (1H, m),
2.95-3.10 (1H, m), 3.53-3.69 (1H, m), 3.71-3.89 (2H, m),
4.68-4.85 (1H, m), 5.47-5.80 (2H, m), 6.52 (1H, s), 6.77-
6.90 (1H, m), 7.03-7.11 (1H, m), 7.24-7.44 (5H, m), 7.63-
7.98 (4H, m), 8.09-8.43 (1H, m), 10.16 (1H, br s), 10.96
(1H, br s).
Anal. Calcd for C H Cl FN O C H SO H 1.5H O: C, 53.80;
34 2 5 4 6 5 3 2
H, 5.39; N, 8.71. Found: C, 53.89; H, 5.40; N, 8.80.
Example 198
2 O 2
S OH
(3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3"-indole]-5'-carboxamide p-
toluenesulfonate hydrate
p-toluenesulfonic acid monohydrate (16 mg, 0.08
mmol) was added to a 2-propanol (0.5 ml) solution of the
compound (52 mg, 0.08 mmol) obtained in Example 70 and
the resulting mixture was dissolved by heating. After
stirring at room temperature for 4 hours, the precipitate
was collected by filtration to give 48 mg (72%) of the
title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 0.63 (3H, s), 0.92 (3H, s),
1.09-1.59 (6H, m), 1.66-2.03 (5H, m), 2.29 (3H, s), 2.70-
2.91 (1H, m), 3.34-3.74 (5H, m), 4.67 (1H, d, J = 10.1
Hz), 4.80-5.11 (1H, m), 6.80 (1H, s), 7.02-7.22 (5H, m),
7.43-7.52 (2H, m), 7.55-7.70 (2H, m), 8.23-8.39 (1H, m),
8.45-8.74 (1H, m), 10.33 (1H, br s), 11.14 (1H, br s).
Anal. Calcd for C H Cl FN O C H CH SO H 1.5H O: C,
34 2 5 4 6 4 3 3 2
54.34; H, 5.55; N, 8.56. Found: C, 54.06; H, 5.45; N,
8.50.
Example 199
O N O
N OH
O S OH
(3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin
yl)-N-{(3R,6S)[1-hydroxyethyl]tetrahydro-2H-pyran
yl}-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-
1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide
benzenesulfonate hydrate
Benzenesulfonic acid monohydrate (19 mg, 0.11 mmol)
was added to an acetonitrile (0.6 ml) solution of the
compound (isomer A) (67 mg, 0.11 mmol) obtained in
Example 93 and the resulting mixture was dissolved by
heating. After stirring at room temperature for 26 hours,
the precipitate was collected by filtration to give 62 mg
(80%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 0.72 (3H, s), 0.98 (3H, s),
1.04 (3H, d, J = 6.4 Hz), 1.21-2.09 (12H, m), 2.59-2.73
(1H, m), 2.86-3.05 (2H, m), 3.67-3.87 (3H, m), 4.74 (1H,
d, J = 10.5 Hz), 5.52-5.70 (1H, m), 6.84 (1H, s), 7.05
(1H, dd, J = 8.2, 1.8 Hz), 7.23-7.29 (1H, m), 7.30-7.40
(3H, m), 7.69 (2H, d, J = 6.4 Hz), 7.83-7.98 (2H, m),
8.04-8.17 (1H, m), 8.44 (1H, br s), 9.88 (1H, br s),
.93 (1H, br s).
Anal. Calcd for C H Cl FN O C H SO H 1.75H O: C,
31 37 2 4 4 6 5 3 2
55.09; H, 5.87; N, 8.24. Found: C, 54.68; H, 5.62; N,
8.73.
Reference Examples
Reference Example 1
Cl N
(3E/Z)chloro(3-chlorofluorobenzylidene)-1,3-
dihydro-2H-pyrrolo[2,3-b]pyridinone
N,N-Diisopropylethylamine (0.10 ml) was added to a
methanol (30 ml) solution of 6-chloro-1,3-dihydro-2H-
pyrrolo[2,3-b]pyridinone (633 mg, 3.75 mmol) and 3-
chlorofluorobenzaldehyde (0.45 ml, 3.83 mmol) and the
resulting mixture was heated to reflux for 18 hours.
After cooling, the precipitate was collected by
filtration, washed with cold methanol, and dried to give
920 mg (79%) of the title compound as a yellow solid.
H-NMR (400 MHz, DMSO-d ) d : 7.02 (1H, d, J = 8.0 Hz),
7.30 (1H, t, J = 8.0 Hz), 7.53 (1H, d, J = 7.8 Hz), 7.66-
7.78 (3H, m), 11.4 (1H, s).
Reference Example 2
Step 1
H N Step 2
工 程 1 工 程 2
O OH
Step 3
工 程 3
O OH
[Step 1]
2-amino-1,5-anhydro-2,3,4-trideoxy-D-erythro-hexitol
hydrochloride
1,5-Anhydro[(tert-butoxycarbonyl)amino]-2,3,4-
trideoxy-D-erythro-hexitol (Eur. J. Org. Chem., 2003,
2418-2427) (6.00 g, 0.03 mol) was dissolved in methanol
(20 ml), 4N hydrochloric acid/1,4-dioxane solution (60
ml) was added and the resulting mixture was stirred at
room temperature for 1 hour. The reaction solvent was
evaporated under reduced pressure to give 4.5 g (100%) of
the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.25 (1H, ddd, J = 24.3,
13.3, 3.7 Hz), 1.52 (1H, ddd, J = 24.7, 12.4, 3.9 Hz),
1.66-1.72 (1H, m), 2.03-2.09 (1H, m), 2.97-3.06 (1H, m),
3.19-3.37 (4H, m), 3.96-4.00 (1H, m).
MS (ESI) m/z: 132 (M + H) .
[Step 2]
1,5-anhydro{[(benzyloxy)carbonyl]amino}-2,3,4-
trideoxy-D-erythro-hexitol
The compound (3.5 g, 21.0 mmol) obtained in Step 1
above was dissolved in 5N aqueous sodium hydroxide
solution (40 ml) and benzyloxycarbonyl chloride (3.3 ml,
23.0 mmol) was added dropwise at 0 C. After stirring at
room temperature for 16 hours, the reaction mixture was
rendered acidic by addition of 1N hydrochloric acid,
followed by extraction with ethyl acetate. The organic
layer was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated under
reduced pressure, diethyl ether and hexane were added to
the residue obtained and then the slurry was filtered and
dried to give 2.06 g (37%) of the title compound as a
colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.33 (1H, ddd, J = 24.5,
12.3, 3.9 Hz), 1.48 (1H, ddd, J = 24.3, 13.2, 3.5 Hz),
1.61-1.67 (1H, m), 1.95-2.00 (1H, m), 2.09-2.16 (1H, m),
3.05 (1H, t, J = 10.6 Hz), 3.34-3.41 (1H, m), 3.50-3.55
(1H, m), 3.57-3.64 (1H, m), 3.65-3.72 (1H, m), 4.11-4.17
(1H, m), 4.48 (1H, br s), 5.06-5.13 (2H, m), 7.32-7.38
(5H, m).
MS (ESI) m/z: 266 (M + H) .
[Step 3]
2-amino-1,5-anhydro-2,3,4-trideoxy-D-erythro-hexitol
The compound (2.00 g, 7.54 mmol) obtained in Step 2
above was dissolved in methanol (30 ml), 10% palladium
carbon (300 mg) was added and the resulting mixture was
stirred at room temperature for 4 hours in a hydrogen
atmosphere. The catalyst was removed by filtration
through celite and then the filtrate was concentrated
under reduced pressure and dried to give 1.13 g (100%) of
the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.07-1.20 (2H, m), 1.54-1.61
(1H, m), 1.82-1.88 (1H, m), 2.50-2.56 (1H, m), 2.82 (1H,
t, J = 10.5 Hz), 3.08-3.14 (1H, m), 3.24 (1H, dd, J =
11.2, 4.8 Hz), 3.33 (1H, dd, J = 11.0, 6.0 Hz), 3.73 (1H,
dq, J = 10.8, 2.2 Hz).
MS (ESI) m/z: 132 (M + H) .
Reference Example 3
O N O N
Step 2
Step 1
O OH O N
工 程 2
工 程 1
Step 3
工 程 3
[Step 1]
Benzyl [trans(hydrazinocarbonyl)cyclohexyl]carbamate
Hydrazine monohydrate (1.42 ml, 23.4 mmol), 1-
hydroxybenzotriazole (2.44 g, 18.0 mmol), and 1-ethyl
(3-dimethylaminopropyl)carbodiimide hydrochloride (4.49 g,
23.4 mmol) were added to an N,N-dimethylformamide (75 ml)
solution of trans
(carbobenzoxyamino)cyclohexanecarboxylic acid (5.00 g,
18.0 mmol) at room temperature and the resulting mixture
was stirred for 3 days. Water (150 ml) was added to the
reaction mixture and the precipitated solid was collected
by filtration and dried under reduced pressure to give
4.52 g (86%) of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.09-1.20 (2H, m), 1.56-1.67
(2H, m), 1.86-1.94 (2H, m), 1.96-2.05 (1H, m), 2.07-2.17
(2H, m), 3.43-3.57 (1H, m), 3.65-4.05 (2H, m), 4.54-4.63
(1H, m), 5.08 (2H, s), 6.68 (1H, s), 7.30-7.39 (5H, m).
[Step 2]
Benzyl [trans(1,3,4-oxadiazol
yl)cyclohexyl]carbamate
Trimethyl orthoformate (2 ml) and a boron
trifluoride-diethyl ether complex (0.02 ml, 0.17 mmol)
were added to an N,N-dimethylacetamide (20 ml) solution
of the compound (1.00 g, 3.43 mmol) obtained in Step 1
above at room temperature and the resulting mixture was
stirred at 50 C for 8 hours under a nitrogen atmosphere.
The reaction mixture was cooled, triethylamine (0.29 ml,
2.06 mmol) was added at room temperature, the resulting
mixture was stirred overnight, then water was added and
the precipitated solid was collected by filtration and
dried to give 0.91 g (88%) of the title compound as a
colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.23-1.34 (2H, m), 1.67-1.80
(2H, m), 2.15-2.24 (4H, m), 2.85-2.95 (1H, m), 3.52-3.65
(1H, m), 4.59-4.69 (1H, m), 5.10 (2H, s), 7.30-7.38 (5H,
m), 8.33 (1H, s).
[Step 3]
trans(1,3,4-oxadiazolyl)cyclohexanamine
The compound (2.85 g, 9.45 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 1.55
g (98%) of the title compound as a pale yellow solid.
H-NMR (500 MHz, CDCl ) d : 1.21-1.31 (2H, m), 1.62-1.72
(2H, m), 1.74-1.90 (2H, m), 1.98-2.05 (2H, m), 2.14-2.21
(2H, m), 2.73-2.80 (1H, m), 2.85-2.93 (1H, m), 8.38 (1H,
Reference Example 4
(3E/Z)chloro[(2-chloropyridinyl)methylene]-1,3-
dihydro-2H-indolone
N,N-Diisopropylethylamine (22.5 ml, 135 mmol) was
added to a methanol (2000 ml) solution of 6-chloro-1,3-
dihydro-2H-indolone (141 g, 841 mmol) and 2-
chloroisonicotinaldehyde (131 g, 925 mmol) and the
resulting mixture was heated to reflux for 16 hours.
After cooling, the precipitate was collected by
filtration, washed with cold methanol, and dried to give
194 g (79%) of the title compound as an orange solid.
MS (ESI) m/z: 291 (M + H) .
Reference Example 5
Step 1 Step 2
工 程 2
工 程 1
[Step 1]
2-[(2S,5R)(dibenzylamino)tetrahydro-2H-pyran
yl]propanol
Methyl 2,6-anhydro-3,4,5-trideoxy(dibenzylamino)-
L-erythro-hexonate (16.0 g, 47.0 mmol) was dissolved in
tetrahydrofuran (200 ml) under a nitrogen atmosphere,
methyl magnesium bromide/tetrahydrofuran solution (1.06
mol/l, 300 ml, 0.32 mol) was added dropwise at 0 C and
then the resulting mixture was stirred at room
temperature for 16 hours. After ice cooling again,
aqueous ammonium chloride solution (300 ml) was gradually
added to the reaction mixture and the resulting mixture
was stirred for 30 minutes. The reaction mixture was
diluted with ethyl acetate and the organic layer was
washed with brine. The organic layer was dried over
anhydrous magnesium sulfate and the solvent was
evaporated under reduced pressure. The residue obtained
was purified by silica gel column chromatography [n-
hexane:ethyl acetate = 3:1 (v/v)] to give 15.5 g (97%) of
the title compound as a pale yellow oil.
H-NMR (400 MHz, CDCl ) d : 1.08 (3H, s), 1.14 (3H, s),
1.26-1.36 (1H, m), 1.53-1.62 (1H, m), 1.69-1.75 (1H, m),
2.04-2.10 (1H, m), 2.40 (1H, s), 2.69-2.77 (1H, m), 3.00
(1H, dd, J = 11.4, 1.8 Hz), 3.41 (1H, t, J = 10.8 Hz),
3.61-3.71 (4H, m), 4.03-4.08 (1H, m), 7.20-7.37 (10H, m).
MS (ESI) m/z: 340 (M + H) .
[Step 2]
2-[(2S,5R)aminotetrahydro-2H-pyranyl]propanol
The compound (15.5 g, 46.0 mmol) obtained in Step 1
above was dissolved in ethanol (300 ml), 20% palladium
hydroxide (3.0 g) was added and the resulting mixture was
stirred at room temperature for 2 days in a hydrogen
atmosphere. The catalyst was removed by filtration
through celite and then the solvent in the filtrate was
evaporated under reduced pressure and dried to give 7.10
g (98%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.00 (3H, s), 1.06 (3H, s),
1.27-1.37 (1H, m), 1.45-1.54 (1H, m), 1.74-1.80 (1H, m),
2.04-2.12 (1H, m), 2.92 (1H, d, J = 11.4 Hz), 2.96-3.01
(1H, m), 3.24 (1H, t, J = 10.8 Hz), 4.00-4.05 (1H, m),
4.28 (1H, br s), 8.16 (2H, br s).
MS (ESI) m/z: 160 (M + H) .
Reference Example 6
(3E/Z)chloro(3-chlorofluorobenzylidene)-1,3-
dihydro-2H-indolone
3-Chlorofluorobenzaldehyde (3.00 g, 18.9 mmol)
was used as a starting material and treated in the same
way as in Reference Example 4 to give 3.19 g (56%) of the
title compound as a yellow solid.
H-NMR (400 MHz, DMSO-d ) d : 6.89-6.91 (1H, m), 6.93-6.97
(1H, m), 7.34 (1H, d, J = 8.3 Hz), 7.52-7.58 (2H, m),
7.58-7.62 (2H, m), 10.84 (1H, s).
MS (APCI) m/z: 308 (M + H) .
Reference Example 7
N Cl
(3E/Z)(3-chlorofluorobenzylidene)oxo-2,3-
dihydro-1H-indolecarbonitrile
2-Oxo-2,3-dihydro-1H-indolecarbonitrile (400 mg,
2.53 mmol) was used as a starting material and treated in
the same way as in Reference Example 1 to give 685 mg
(91%) of the title compound as a brown solid.
H-NMR (400 MHz, DMSO-d ) d : 7.24-7.42 (4H, m), 7.72-7.80
(3H, m), 11.07 (1H, s).
Reference Example 8
(3E/Z)chloro[(2-chlorofluoropyridin
yl)methylene]-1,3-dihydro-2H-indolone
2-Chlorofluoroisonicotinaldehyde (2.20 g, 13.8
mmol) was used as a starting material and treated in the
same way as in Reference Example 4 to give 3.37 g (83%)
of the title compound as a yellow solid.
MS (APCI) m/z: 309 (M + H) .
Reference Example 9
Step 1 Step 2
工 程 1 工 程 2 H N
[Step 1]
2-amino-1,5-anhydroO-[tert-butyl(dimethyl)silyl]-
2,3,4-trideoxy-D-erythro-hexenitol
1,5-Anhydro[(tert-butoxycarbonyl)amino]O-
[tert-butyl(dimethyl)silyl]-2,3,4-trideoxy-D-erythro-hex-
3-enitol (Eur. J. Org. Chem., 2003, 2418-2427) (1.02 g,
2.97 mmol), tert-butyldimethylsilyl
trifluoromethanesulfonate (4.10 ml, 17.8 mmol), and 2,6-
lutidine (1.73 ml, 14.9 mmol) were mixed with
dichloromethane (3 ml) and the resulting mixture was
stirred at room temperature for 2 hours. Saturated
ammonium chloride solution (50 ml) was added to the
reaction mixture, followed by extraction with
dichloromethane. The organic layer was washed with brine
and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the residue
obtained was purified by silica gel column chromatography
[chloroform:methanol = 40:1 fi 9:1 (v/v)] to give 295 mg
(41%) of the title compound as a light brown oil.
H-NMR (400 MHz, CDCl ) d : 0.07 (6H, s), 0.90 (9H, s),
1.43 (2H, br s), 3.23 (1H, dd, J = 10.9, 7.9 Hz), 3.39-
3.44 (1H, m), 3.54 (1H, dd, J = 10.3, 5.9 Hz), 3.69 (1H,
dd, J = 10.3, 6.1 Hz), 4.06 (1H, dd, J = 11.5, 5.6 Hz),
4.08-4.12 (1H, m), 5.78 (1H, dt, J = 10.4, 1.8 Hz), 5.83-
.87 (1H, m).
MS (ESI) m/z: 244 (M + H) .
[Step 2]
2-amino-1,5-anhydro-2,3,4-trideoxy-D-erythro-hexenitol
hydrochloride
The compound (1.0 g, 3.0 mmol) obtained in Step 1
above was dissolved in 1,4-dioxane (4 ml), 4N
hydrochloric acid/1,4-dioxane solution (10 ml) was added
and the resulting mixture was stirred at room temperature
for 2 hours. The solvent was evaporated under reduced
pressure to give 620 mg (100%) of the title compound as a
light brown solid.
H-NMR (400 MHz, DMSO-d ) d : 3.38 (1H, dd, J = 11.2, 4.8
Hz), 3.46 (1H, dd, J = 11.4, 6.4 Hz), 3.52-3.59 (1H, m),
3.64-3.70 (1H, m), 4.04 (1H, dd, J = 11.4, 4.6 Hz), 4.05-
4.09 (1H, m), 5.89 (1H, dt, J = 10.5, 2.7 Hz), 6.05-6.08
(1H, m), 8.31 (2H, br s).
MS (ESI) m/z: 130 (M + H) .
Reference Example 10
(3E/Z)(3-bromochlorobenzylidene)chloro-1,3-
dihydro-2H-indolone
3-Bromochlorobenzaldehyde (4.90 g, 22.4 mmol) was
used and treated in the same way as in Reference Example
4 to give 8.11 g (98%) of the title compound as a yellow
solid.
MS (FAB) m/z: 367 (M + H) .
Reference Example 11
(3E/Z)chloro[(2-chlorofluoropyridin
yl)methylene]fluoro-1,3-dihydro-2H-indolone
6-Chlorofluoro-1,3-dihydro-2H-indolone (928 mg,
.0 mmol) was used as a starting material and treated in
the same way as in Reference Example 8 to give 1.6 g
(97%) of the title compound as a yellow solid.
H-NMR (400 MHz, DMSO-d ) d : 7.03 (1H, dd, J = 6.3, 0.7
Hz), 7.18 (1H, d, J = 9.3 Hz), 7.55 (1H, s), 7.79 (1H, t,
J = 5.0 Hz), 8.41 (1H, d, J = 4.9 Hz), 10.94 (1H, s).
Reference Example 12
Cl N
Cl N
(3E/Z)chloro[(2-chlorofluoropyridin
yl)methylene]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridinone
2-Chlorofluoroisonicotinaldehyde (1.14 g, 7.16
mmol) was used as a starting material and treated in the
same way as in Reference Example 1 to give 1.46 g (69%)
of the title compound as a brown solid.
H-NMR (500 MHz, DMSO-d ) d : 7.02 (0.7H, d, J = 8.0 Hz),
7.18 (0.3H, d, J = 8.0 Hz), 7.54 (0.7H, d, J = 8.0 Hz),
7.63 (0.7H, s), 7.78 (0.7H, t, J = 4.9 Hz), 7.89 (0.3H,
s), 7.99 (0.3H, d, J = 5.2 Hz), 8.18 (0.3H, d, J = 8.0
Hz), 8.33 (0.3H, d, J = 5.2 Hz), 8.40 (0.7H, d, J = 5.2
Hz).
Reference Example 13
Step 1
工 程 1
NH Si
N N N O
Step 2
工 程 2
H N N
2 HCl
[Step 1]
tert-butyl [trans(3-{[tert-
butyl(diphenyl)silyl]oxy}azetidin
yl)cyclohexyl]carbamate
1,3-Dibromopropanol (1.70 ml, 16.5 mmol) and
sodium carbonate (15.9 g, 150 mmol) were added to an
ethanol (300 ml) solution of tert-butyl (trans
aminocyclohexyl)carbamate (3.21 g, 15.0 mmol) and the
resulting mixture was stirred under heating to reflux
overnight. After cooling, insoluble matter was removed
by filtration through celite and then the filtrate was
concentrated under reduced pressure. The residue was
diluted with water, followed by extraction with ethyl
acetate. Then, the organic layer was washed with brine.
The organic layer was dried over anhydrous sodium sulfate
and then the solvent was evaporated under reduced
pressure. The residue was dissolved in N,N-
dimethylformamide (15 ml) and imidazole (2.45 g, 36.0
mmol) and tert-butyldiphenylchlorosilane (4.29 ml, 16.5
mmol) were added under ice cooling. After stirring at
room temperature for 1 hour, the reaction mixture was
diluted with ethyl acetate and washed with water and
brine in this order. The organic layer was dried over
anhydrous magnesium sulfate, then the solvent was
evaporated under reduced pressure and the residue was
purified by silica gel column chromatography
[chloroform:methanol = 10:0 fi 10:1 (v/v)] to give 2.45 g
(32%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.01-1.13 (4H, m), 1.06 (9H,
s), 1.46 (9H, s), 1.74-1.80 (2H, m), 1.93-2.03 (3H, m),
2.87 (2H, t, J = 7.2 Hz), 3.35-3.43 (1H, m), 3.51 (2H, t,
J = 6.9 Hz), 4.42 (1H, t, J = 6.3 Hz), 7.37-7.41 (4H, m),
7.42-7.47 (2H, m), 7.61-7.65 (4H, m).
[Step 2]
1-(transaminocyclohexyl)azetidinol dihydrochloride
The compound (2.45 g, 4.82 mmol) obtained in Step 1
above was suspended in methanol (9 ml), 4N hydrochloric
acid/1,4-dioxane solution (18 ml) was added and the
resulting mixture was stirred at room temperature. After
48 hours, diethyl ether was added to the reaction mixture
and the precipitated solid was collected by filtration
and dried to give 1.08 g (92%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CD OD) d : 1.33-1.56 (4H, m), 2.11-2.21
(4H, m), 3.13-3.15 (1H, m), 3.22-3.26 (1H, m), 3.92-3.99
(2H, m), 4.36-4.39 (2H, m), 4.56-4.67 (1H, m).
Reference Example 14
HO N
Step 1 Step 2 Step 3
工 程 2
工 程 1 工 程 3
O O O O
N H N
O Step 4 O
工 程 4
OH OH
OH OH
[Step 1]
1,5-anhydro-4,6-O-benzylidenedeoxyO-
(methylsulfonyl)-D-arabino-hexitol
Methanesulfonyl chloride (4.70 ml, 61.0 mmol) was
added to a dichloromethane (250 ml) solution of 1,5-
anhydro-4,6-O-benzylidenedeoxy-D-arabino-hexitol
(WO2005/049582) (12.0 g, 50.8 mmol) and triethylamine
(8.50 ml, 61.0 mmol) under ice cooling. After stirring
at the same temperature for 45 minutes, water was added
and the resulting mixture was subjected to extraction
with chloroform. The organic layer was washed with brine
and dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give the title
compound.
[Step 2]
1,5-anhydroazido-4,6-O-benzylidene-2,3-dideoxy-D-ribo-
hexitol
An N,N-dimethylformamide (380 ml) solution of the
compound (16.0 g, 50.8 mmol) obtained in Step 1 above and
sodium azide (6.60 g, 102 mmol) was stirred at 80 C for
66 hours. N,N-dimethylformamide was evaporated under
reduced pressure, then ether was added and the organic
layer was washed with water and brine and then dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure, n-hexane was added and the
precipitated solid was collected by filtration to give
7.50 g (56%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.68-1.79 (1H, m), 2.49-2.57
(1H, m), 3.23-3.35 (2H, m), 3.54-3.72 (3H, m), 4.01-4.09
(1H, m), 4.31 (1H, dd, J = 10.6, 4.6 Hz), 5.54 (1H, s),
7.33-7.52 (5H, m).
[Step 3]
1,5-anhydroazido-2,3-dideoxy-D-ribo-hexitol
The compound (8.00 g, 30.6 mmol) obtained in Step 2
above was dissolved in acetic acid (160 ml) and water (40
ml) and the resulting solution was stirred at 90 C for 1
hour and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
[n-hexane:ethyl acetate = 3:1 fi 1:3 (v/v)] to give 4.70
g (89%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.47-1.58 (1H, m), 1.95-2.02
(1H, m), 2.26 (1H, d, J = 5.0 Hz), 2.45-2.53 (1H, m),
3.11-3.21 (2H, m), 3.47-3.57 (1H, m), 3.66-3.75 (1H, m),
3.77-3.91 (2H, m), 3.97-4.04 (1H, m).
[Step 4]
2-amino-1,5-anhydro-2,3-dideoxy-D-ribo-hexitol
% Palladium carbon (120 mg) was added to a
methanol (14 ml) solution of the compound (500 mg, 2.89
mmol) obtained in Step 3 above and the resulting mixture
was stirred for 6 hours under a hydrogen atmosphere. The
catalyst was removed by filtration through celite and
then the solvent was evaporated under reduced pressure to
give 341 mg (80%) of the title compound as a colorless
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.00-1.10 (1H, m), 1.38 (2H,
br s), 2.01-2.10 (1H, m), 2.55-2.65 (1H, m), 2.71-2.78
(1H, m), 2.78-2.85 (1H, m), 3.13-3.24 (1H, m), 3.29-3.39
(1H, m), 3.61-3.72 (2H, m), 4.36-4.44 (1H, m), 4.70 (1H,
d, J = 5.50 Hz).
MS (ESI) m/z: 148 (M + H) .
Reference Example 15
O N 2
Cisamino(hydroxymethyl)cyclohexanol hydrochloride
tert-Butyl[cishydroxy
(hydroxymethyl)cyclohexyl]carbamate (WO2010/027500) (376
mg, 1.53 mmol) was used as a starting material and
treated in the same way as in Step 1 of Reference Example
2 to give the title compound as a colorless solid.
Reference Example 16
Step 1
Step 2
O N O N
工 程 1 工 程 2
O OH O NH
Step 3
O N O N
工 程 3
O N N O
Step 4
工 程 4
[Step 1]
Benzyl (transcarbamoylcyclohexyl)carbamate
Triethylamine (1.4 ml, 10.1 mmol) was added to an
N,N-dimethylformamide (120 ml) solution of trans
{[(benzyloxy)carbonyl]amino}cyclohexanecarboxylic acid
(1.40 g, 5.10 mmol), ammonium chloride (0.54 g, 10.1
mmol), 1-hydroxybenzotriazole (0.39 g, 2.50 mmol), and 1-
ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride
(1.35 g, 7.10 mmol) and the resulting mixture was stirred
at room temperature for 19 hours. Water was added and
the precipitated solid was collected by filtration to
give 1.20 g (86%) of the title compound as a colorless
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.07-1.21 (2H, m), 1.26-1.41
(2H, m), 1.68-1.87 (4H, m), 1.92-2.04 (1H, m), 3.15-3.27
(1H, m), 4.99 (2H, s), 6.67 (1H, br s), 7.12-7.21 (2H, m),
7.27-7.40 (5H, m).
MS (ESI) m/z: 277 (M + H) .
[Step 2]
Benzyl (trans{[(E)-
(dimethylamino)methylidene]carbamoyl}cyclohexyl)carbamate
An N,N-dimethylformamide dimethyl acetal (20 ml)
solution of the compound (1.20 g, 4.34 mmol) obtained in
Step 1 above was stirred at 120 C for 3 hours. The
solvent was evaporated under reduced pressure, then
diethyl ether was added and the precipitated solid was
collected by filtration to give 0.97 g (67%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.09-1.22 (2H, m), 1.51-1.60
(2H, m), 1.97-2.14 (4H, m), 2.22-2.34 (1H, m), 3.06 (3H,
s), 3.10 (3H, s), 3.41-3.58 (1H, m), 4.53-4.64 (1H, m),
.09 (2H, s), 7.29-7.37 (5H, m), 8.39 (1H, s).
MS (ESI) m/z: 332 (M + H) .
[Step 3]
Benzyl [trans(4H-1,2,4-triazol
yl)cyclohexyl]carbamate
Hydrazine monohydrate (0.21 ml, 3.51 mmol) was added
to an acetic acid (25 ml) solution of the compound (970
mg, 2.93 mmol) obtained in Step 2 above and the resulting
mixture was stirred at room temperature for 2 hours.
Water was added and the precipitated solid was collected
by filtration to give 717 mg (82%) of the title compound
as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.23-1.58 (4H, m), 1.85-2.05
(4H, m), 2.47-2.55 (1H, m), 3.29-3.36 (1H, m), 5.01 (2H,
s), 7.22-7.40 (6H, m).
MS (ESI) m/z: 301 (M + H) .
[Step 4]
trans(4H-1,2,4-triazolyl)cyclohexanamine
The compound (360 mg, 1.20 mmol) obtained in Step 3
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 63
mg (31%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.22-1.38 (2H, m), 1.56-1.70
(2H, m), 1.95-2.11 (4H, m), 2.67-2.84 (2H, m), 8.05 (1H,
Reference Example 17
Step 1
工 程 1
O Si
( B )
( A )
Step 2
工 程 2
Step 3
工 程 3
[Step 1]
tert-Butyl [trans({[tert-
butyl(diphenyl)silyl]oxy}methyl)
hydroxycyclohexyl]carbamate (A)
cis-tert-Butyloxaspiro[2.5]octylcarbamate
(WO2010/027500) (4.15 g, 18.3 mmol) was dissolved in 1,2-
dimethoxyethane (50 ml) and water (200 ml), potassium
hydroxide (5.13 g, 91.5 mmol) was added and the resulting
mixture was heated to reflux for 3 hours. After cooling,
the precipitate was removed by filtration and the
filtrate was subjected to extraction with ethyl acetate.
The organic layer was washed with brine and then dried
over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure to give 2.33 g of a
mixture of tert-butyl [cishydroxy
(hydroxymethyl)cyclohexyl]carbamate and tert-butyl
[transhydroxy(hydroxymethyl)cyclohexyl]carbamate as
a colorless solid. The above mixture was dissolved in
N,N-dimethylformamide (20 ml), tert-
butyldiphenylchlorosilane (4.13 g, 15.0 mmol) and
imidazole (2.74 g, 40.0 mmol) were added and the
resulting mixture was stirred at room temperature for 1
hour. The reaction mixture was diluted with ethyl
acetate, washed with water and brine, and dried over
anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography
[acetonitrile:benzene = 1:9 (v/v)] to give 0.81 g (9%) of
the title compound as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.07 (9H, s), 1.17-1.27 (2H,
m), 1.43 (9H, s), 1.53-1.66 (4H, m), 1.85-1.91 (2H, m),
2.54 (1H, s), 3.53 (2H, s), 3.61 (1H, m), 4.38 (1H, m),
7.38-7.47 (6H, m), 7.64-7.66 (4H, m).
MS (APCI) m/z: 482 (M-H) .
[Step 2]
tert-Butyl [transhydroxy
(hydroxymethyl)cyclohexyl]carbamate
Tetrabutylammonium fluoride/tetrahydrofuran solution
(1.0 mol/l, 2.0 ml) was added to a tetrahydrofuran (8 ml)
solution of the compound (0.80 g, 1.65 mmol) obtained in
Step 1 above and the resulting mixture was stirred at
room temperature for 1 hour. The solvent was evaporated
under reduced pressure and the residue was purified by
silica gel column chromatography [chloroform:methanol =
9:1 (v/v)] to give 372 mg (92%) of the title compound as
a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.19-1.31 (4H, m), 1.37 (9H,
s), 1.61-1.67 (4H, m), 3.24 (2H, d, J = 5.5 Hz), 3.34 (1H,
m), 3.94 (1H, s), 4.33 (1H, t, J = 6.0 Hz), 6.63 (1H, d,
J = 6.9 Hz).
MS (FAB) m/z: 246 (M + H) .
[Step 3]
transamino(hydroxymethyl)cyclohexanol hydrochloride
The compound (67 mg, 0.27 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a colorless solid.
Reference Example 18
O N 2
Step 1 Step 2
工 程 1
工 程 2
O OH
Step 3
工 程 3
O O O OH
Step 4 Step 5
工 程 4 工 程 5
N Step 6
工 程 6
[Step 1]
Methyl 5-amino-2,6-anhydro-3,4,5-trideoxy-L-erythro-
hexonate hydrochloride
4N Hydrochloric acid/1,4-dioxane solution (20 ml)
was added to a methanol (5 ml) solution of 2,6-anhydro
[(tert-butoxycarbonyl)amino]-3,4,5-trideoxy-L-erythro-
hexonic acid (Eur. J. Org. Chem., 2003, 2418-2427) (1.00
g, 4.08 mmol) at room temperature and the resulting
mixture was stirred for 20 hours. The reaction mixture
was concentrated under reduced pressure to give 0.80 g
(100%) of the title compound.
MS (ESI) m/z: 160 (M + H) .
[Step 2]
Methyl 2,6-anhydro{[(benzyloxy)carbonyl]amino}-3,4,5-
trideoxy-L-erythro-hexonate
The compound (0.80 g, 4.08 mmol) obtained in Step 1
above was dissolved in acetonitrile (10 ml) and water (20
ml), sodium bicarbonate (1.71 g, 30.4 mmol) and
carbobenzoxy chloride (0.72 ml, 4.89 mmol) were added
under ice cooling and the resulting mixture was stirred
at 5 C for 21 hours. Saturated sodium bicarbonate
solution was added to the reaction mixture, followed by
extraction with dichloromethane:methanol [10:1 (v/v)].
The organic layer was dried over anhydrous sodium sulfate.
The solvent was concentrated under reduced pressure and
the residue obtained was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 17:3 fi 3:2
(v/v)] to give 0.97 g (81%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.38-1.54 (1H, m), 1.66-1.85
(1H, m), 2.03-2.16 (2H, m), 3.12-3.23 (1H, m), 3.70-3.80
(4H, m), 3.91-4.01 (1H, m), 4.15-4.25 (1H, m), 4.66-4.79
(1H, m), 5.01-5.17 (2H, m), 7.29-7.39 (5H, m).
[Step 3]
2,6-anhydro{[(benzyloxy)carbonyl]amino}-3,4,5-
trideoxy-L-erythro-hexonic acid
1N Sodium hydroxide solution (55.4 ml, 55.4 mmol)
was added to a tetrahydrofuran (110 ml) solution of the
compound (8.12 g, 27.7 mmol) obtained in Step 2 above at
room temperature and the resulting mixture was stirred
for 2 hours. 10% citric acid solution was added under
ice cooling, followed by extraction with ethyl acetate.
Then, the organic layer was washed with brine. The
organic layer was dried over anhydrous sodium sulfate,
then the solvent was concentrated under reduced pressure
and the residue was dried under reduced pressure to give
7.78 g (100%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.45-1.73 (2H, m), 1.98-2.16
(2H, m), 3.10-3.20 (1H, m), 3.51-3.64 (1H, m), 3.85-3.95
(1H, m), 4.00-4.09 (1H, m), 5.06 (2H, s), 6.93-7.08 (1H,
m), 7.22-7.44 (5H, m).
[Step 4]
Benzyl [(3R,6S)(hydrazinocarbonyl)tetrahydro-2H-pyran-
3-yl]carbamate
Hydrazine monohydrate (0.23 ml, 3.86 mmol), 1-
hydroxybenzotriazole (434 mg, 3.21 mmol), and 1-ethyl
(3-dimethylaminopropyl)carbodiimide hydrochloride (740 mg,
3.86 mmol) were added to an N,N-dimethylformamide (16 ml)
solution of the compound (898 mg, 3.21 mmol) obtained in
Step 3 above at room temperature and the resulting
mixture was stirred for 18 hours. The reaction mixture
was subjected to extraction with chloroform:methanol
[10:1 (v/v)] and the organic layer was washed with
saturated sodium bicarbonate solution and then dried over
anhydrous sodium sulfate. The solvent was concentrated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography
[dichloromethane:methanol = 49:1 fi 13:1 (v/v)] to give
811 mg (86%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.42-1.60 (2H, m), 2.00-2.16
(2H, m), 3.11 (1H, t, J = 10.8 Hz), 3.50-3.62 (1H, m),
3.75-3.83 (1H, m), 4.02-4.11 (1H, m), 5.06 (2H, s), 7.26-
7.37 (5H, m).
MS (ESI) m/z: 294 (M + H) .
[Step 5]
Benzyl [(3R,6S)(1,3,4-oxadiazolyl)tetrahydro-2H-
pyranyl]carbamate
The compound (2.27 g, 7.74 mmol) obtained in Step 4
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 3 at room
temperature to give 2.00 g (85%) of the title compound as
a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.49-1.63 (1H, m), 2.04-2.30
(3H, m), 3.27-3.37 (1H, m), 3.76-3.90 (1H, m), 4.14-4.22
(1H, m), 4.66-4.77 (2H, m), 5.04-5.19 (2H, m), 7.31-7.40
(5H, m), 8.41 (1H, s).
MS (ESI) m/z: 304 (M + H) .
[Step 6]
(3R,6S)(1,3,4-oxadiazolyl)tetrahydro-2H-pyran
amine
The compound (749 mg, 2.47 mmol) obtained in Step 5
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 418
mg (100%) of the title compound as a light brown solid.
H-NMR (500 MHz, CDCl ) d : 1.36-1.48 (1H, m), 1.98-2.10
(1H, m), 2.12-2.25 (2H, m), 2.93-3.02 (1H, m), 3.18-3.25
(1H, m), 4.04-4.11 (1H, m), 4.63-4.69 (1H, m), 8.42 (1H,
Reference Example 19
Step 1 O N Step 2
O N 工 程 1
工 程 2
[Step 1]
Benzyl [trans(5-oxo-4,5-dihydro-1,3,4-oxadiazol
yl)cyclohexyl]carbamate
Triphosgene (0.36 g, 1.17 mmol) was added to a 1,4-
dioxane (15 ml) suspension of the compound (1.00 g, 3.43
mmol) obtained in Step 1 of Reference Example 3 under ice
cooling and the resulting mixture was stirred at room
temperature for 20 hours. Water was added to the
reaction mixture, the resulting mixture was stirred for
70 minutes and then the solid was collected by filtration
and dried under reduced pressure to give 685 mg (63%) of
the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.17-1.28 (2H, m), 1.54-1.65
(2H, m), 2.05-2.21 (4H, m), 2.46-2.56 (1H, m), 3.47-3.61
(1H, m), 4.58-4.66 (1H, m), 5.09 (2H, s), 7.29-7.39 (5H,
m), 8.12 (1H, s).
[Step 2]
-(transaminocyclohexyl)-1,3,4-oxadiazol-2(3H)-one
The compound (685 mg, 2.16 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 341
mg (86%) of the title compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 1.21-1.32 (2H, m), 1.40-1.51
(2H, m), 1.88-2.05 (4H, m), 2.43-2.51 (1H, m), 2.75-2.83
(1H, m).
Reference Example 20
O NH
Step 1 Step 2
工 程 1 工 程 2
O NH
Step 3
工 程 3
[Step 1]
Methyl 3-[(tert-butoxycarbonyl)amino]
chlorobenzoate
Zinc powder (7.54 g, 116 mmol) and acetic acid (23
ml) were added to a methanol (230 ml) solution of methyl
3-chloronitrobenzoate (5.00 g, 23.0 mmol) under ice
cooling and the resulting mixture was heated to reflux
for 4 hours. The reaction mixture was filtered through
celite and then saturated sodium bicarbonate solution was
added to the filtrate, followed by extraction with ethyl
acetate. The organic layer was dried over anhydrous
sodium sulfate, then the solvent was concentrated under
reduced pressure, the residue obtained was dissolved in
tetrahydrofuran (250 ml), di-tert-butyl dicarbonate (7.52
g, 34.5 mmol) and 4-dimethylaminopyridine (141 mg, 1.16
mmol) were added and the resulting mixture was heated at
50 C for 16 hours. Saturated sodium bicarbonate solution
was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 2:1 (v/v)] to give 2.77 g (41%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.51 (9H, s), 3.91 (3H, s),
6.61 (1H, br s), 7.66-7.68 (1H, m), 7.74-7.77 (1H, m),
7.80-7.85 (1H, m).
MS (FAB) m/z: 286 (M + H) .
[Step 2]
tert-Butyl (3-chloroformylphenyl)carbamate
Lithium borohydride (294 mg, 1.40 mmol) was added to
a tetrahydrofuran (100 ml) solution of the compound (2.67
g, 9.36 mmol) obtained in Step 1 above under ice cooling
and the resulting mixture was stirred at room temperature
for 3 days and then stirred at 50 C for 2 hours. Water
was added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with
brine and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure, the
residue was dissolved in dichloromethane (100 ml),
dimethyl sulfoxide (2.00 ml, 28.1 mmol), N,N-
diisopropylethylamine (4.81 ml, 28.1 mmol), and a sulfur
trioxide-pyridine complex (4.38 g, 28.1 mmol) were added
and the resulting mixture was stirred at room temperature
for 16 hours. Saturated sodium bicarbonate solution was
added to the reaction mixture, followed by extraction
with ethyl acetate. The organic layer was washed with
brine and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the
residue obtained was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 4:1 (v/v)] to
give 2.21 g (92%) of the title compound as a colorless
solid.
H-NMR (400 MHz, CDCl ) d : 1.53 (9H, s), 6.65 (1H, br s),
7.50-7.54 (1H, m), 7.71-7.74 (1H, m), 7.75-7.78 (1H, m),
9.92 (1H, s).
MS (FAB) m/z: 256 (M + H) .
[Step 3]
tert-Butyl {3-chloro[(3E/Z)-(6-chlorooxo-1,2-
dihydro-3H-indolylidene)methyl]phenyl}carbamate
6-Chloro-1,3-dihydro-2H-indolone (1.31 g, 7.85
mmol) and the compound (2.01 g, 7.85 mmol) obtained in
Step 2 above were dissolved in methanol (40 ml) at room
temperature and N,N-diisopropylethylamine (0.21 ml, 1.25
mmol) was added. After heating to reflux for 24 hours,
saturated sodium bicarbonate solution was added to the
reaction mixture, followed by extraction with ethyl
acetate. The organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 4:1 (v/v)] to give 2.53 g (82%) of
the title compound as an orange solid.
MS (FAB) m/z: 405 (M + H) .
Reference Example 21
Step 1 Step 2
工 程 1 工 程 2
[Step 1]
1,1-bis(fluoromethyl)-3,3-dimethoxycyclobutane
Tetrabutylammonium fluoride/tetrahydrofuran solution
(1.0 mol/l, 74.3 ml, 74.3 mmol) was added to a
tetrahydrofuran (5 ml) solution of (3,3-
dimethoxycyclobutane-1,1-diyl)bis(methylene)bis(4-
methylbenzenesulfonate) (9.0 g, 18.6 mmol) and the
resulting mixture was stirred at 50 C for 20 hours.
After cooling, tetrabutylammonium
fluoride/tetrahydrofuran solution (1.0 mol/l, 37.1 ml,
37.1 mmol) was further added and the resulting mixture
was stirred at 50 C for 12 hours. After cooling,
saturated sodium bicarbonate solution was added at 0 C,
followed by extraction with diethyl ether. The organic
layer was washed with saturated ammonium chloride
solution and brine and then dried over anhydrous
magnesium sulfate. The solvent was evaporated under
reduced pressure (80 mmHg, 17 C) and the residue was
purified by silica gel column chromatography [n-
hexane:ether = 9:1 fi 1:1 (v/v)] to give 3.90 g (95%) of
the title compound as a colorless oil.
H-NMR (400 MHz, CDCl ) d : 2.05 (4H, m), 3.15 (6H, s),
4.39-4.51 (4H, m).
[Step 2]
3,3-bis(fluoromethyl)cyclobutanone
1N Hydrochloric acid (61.7 ml, 61.7 mmol) was added
to a tetrahydrofuran (42 ml) solution of the compound
(2.8 g, 12.3 mmol) obtained in Step 1 above at 0 C.
After stirring at room temperature for 13 hours, the
reaction mixture was diluted with diethyl ether at 0 C
and saturated sodium bicarbonate solution was added for
extraction. The organic layer was washed with brine and
then dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure (110 mmHg, 17 C) to
give 3.63 g (100%) of the title compound as a colorless
oil.
H-NMR (400 MHz, CDCl ) d : 2.99-3.04 (4H, m), 4.53-4.66
(4H, m).
Reference Example 22
Step 1
Step 2
工 程 1 Si
工 程 2
O Step 4
Step 3 O N
工 程 4
Si 工 程 3
O OH
O NH
Step 5
O N Step 6
工 程 5 工 程 6
Step 7
工 程 7
[Step 1]
Ethyl trans({[2-
(trimethylsilyl)ethoxy]carbonyl}amino)cyclohexanecarboxyl
Ethyl transaminocyclohexanecarboxylate (J. Med.
Chem., 1971, 14, 600-614) (29.5 g, 143 mmol) was
dissolved in 1,4-dioxane (290 ml) and water (290 ml),
triethylamine (30.0 ml, 215 mmol) and 1-[2-
(trimethylsilyl)ethoxycarbonyloxy]pyrrolidine-2,5-dione
(40.8 g, 157 mmol) were added under ice cooling and the
resulting mixture was stirred at room temperature for 2
days. The reaction mixture was concentrated and then the
residue was diluted with ethyl acetate and washed with
% aqueous citric acid solution, saturated sodium
bicarbonate solution, and brine in this order. The
organic layer was dried over anhydrous sodium sulfate and
the solvent was concentrated under reduced pressure to
give 44.3 g (98%) of the title compound as colorless
needle-like crystals.
H-NMR (500 MHz, CDCl ) d : 0.03 (9H, s), 0.92-1.01 (2H,
m), 1.08-1.18 (2H, m), 1.25 (3H, t, J = 7.2 Hz), 1.48-
1.59 (2H, m), 1.97-2.11 (4H, m), 2.21 (1H, tt, J = 12.3,
3.7 Hz), 3.38-3.54 (1H, m), 4.07-4.19 (4H, m), 4.38-4.49
(1H, m).
[Step 2]
trans({[2-
(trimethylsilyl)ethoxy]carbonyl}amino)cyclohexanecarboxyl
ic acid
The compound (44.3 g, 140 mmol) obtained in Step 1
above was dissolved in tetrahydrofuran (500 ml) and water
(100 ml), lithium hydroxide monohydrate (11.8 g, 281
mmol) was added at room temperature and the resulting
mixture was stirred for 2 days. Lithium hydroxide
monohydrate (2.95 g, 70.2 mmol) was further added, the
resulting mixture was further stirred for 27 hours, then
the reaction mixture was concentrated and 10% aqueous
citric acid solution was added to the residue, followed
by extraction with ethyl acetate. The organic layer was
washed with brine and then dried over anhydrous sodium
sulfate and the solvent was concentrated under reduced
pressure to give 40.0 g (99%) of the title compound as a
colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.04 (9H, s), 0.92-1.02 (2H,
m), 1.10-1.20 (2H, m), 1.47-1.63 (2H, m), 2.01-2.13 (4H,
m), 2.23-2.31 (1H, m), 3.40-3.55 (1H, m), 4.08-4.20 (2H,
m), 4.41-4.50 (1H, m).
[Step 3]
2-(Trimethylsilyl)ethyl (trans
carbamoylcyclohexyl)carbamate
The compound (3.23 g, 11.2 mmol) obtained in Step 2
above and ammonium chloride (1.20 g, 22.5 mmol) were used
as starting materials and treated in the same way as in
Step 1 of Reference Example 16 to give 3.16 g (98%) of
the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.04 (9H, s), 0.92-1.01 (2H,
m), 1.09-1.20 (2H, m), 1.52-1.62 (2H, m), 1.95-2.02 (2H,
m), 2.06-2.15 (2H, m), 3.40-3.54 (2H, m), 4.08-4.19 (2H,
m), 4.38-4.49 (1H, m), 5.17-5.27 (1H, m), 5.35-5.45 (1H,
[Step 4]
2-(Trimethylsilyl)ethyl (trans
cyanocyclohexyl)carbamate
Anhydrous trifluoroacetic acid (2.30 ml, 16.6 mmol)
was added to a dichloromethane (60 ml) solution of the
compound (3.16 g, 11.0 mmol) obtained in Step 3 above and
triethylamine (3.10 ml, 22.1 mmol) under ice cooling.
After stirring at room temperature for 75 minutes,
saturated sodium bicarbonate solution was added to the
reaction mixture. After extraction with dichloromethane,
the organic layer was dried over anhydrous sodium sulfate.
The solvent was concentrated under reduced pressure and
the residue obtained was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 19:1 fi 3:2
(v/v)] to give 3.06 g (100%) of the title compound as a
pale yellow solid.
H-NMR (500 MHz, CDCl ) d : 0.04 (9H, s), 0.92-1.01 (2H,
m), 1.14-1.24 (2H, m), 1.64-1.75 (2H, m), 2.05-2.15 (4H,
m), 2.37-2.45 (1H, m), 3.43-3.59 (1H, m), 4.10-4.18 (2H,
m), 4.39-4.52 (1H, m).
[Step 5]
2-(Trimethylsilyl)ethyl {trans[(Z)-
amino(hydroxyimino)methyl]cyclohexyl}carbamate
Aqueous hydroxylamine solution (50% w/w, 0.68 ml,
11.1 mmol) was added to an ethanol (40 ml) solution of
the compound (1.03 g, 3.71 mmol) obtained in Step 4 above
at room temperature and the resulting mixture was heated
to reflux for 21 hours. After cooling, the reaction
mixture was concentrated under reduced pressure to give
the title compound as a colorless solid.
[Step 6]
2-(Trimethylsilyl)ethyl [trans(5-oxo-4,5-dihydro-
1,2,4-oxadiazolyl)cyclohexyl]carbamate
Carbonyldiimidazole (1.24 g, 7.43 mmol) was added to
a tetrahydrofuran (20 ml) solution of the compound (1.12
g, 3.71 mmol) obtained in Step 5 above under ice cooling
and the resulting mixture was stirred at 50 C for 24
hours. The reaction mixture was diluted with
dichloromethane:methanol [10:1 (v/v)] and washed with 10%
aqueous citric acid solution and saturated sodium
bicarbonate solution in this order and then the organic
layer was dried over anhydrous sodium sulfate. The
solvent was concentrated under reduced pressure and the
residue obtained was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 9:1 fi 13:7 fi
dichloromethane:methanol = 49:1 fi 19:1 (v/v)] to give
757 mg (62%) of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 0.05 (9H, s), 0.94-1.02 (2H,
m), 1.22-1.33 (2H, m), 1.62-1.75 (2H, m), 2.00-2.09 (2H,
m), 2.14-2.22 (2H, m), 2.55-2.65 (1H, m), 3.44-3.58 (1H,
m), 4.18-4.24 (2H, m), 4.61 (1H, d, J = 8.0 Hz).
[Step 7]
3-(transaminocyclohexyl)-1,2,4-oxadiazol-5(4H)-one
hydrochloride
4N Hydrochloric acid/1,4-dioxane solution (3.5 ml)
was added to the compound (349 mg, 1.06 mmol) obtained in
Step 6 above at room temperature and the resulting
mixture was stirred for 23 hours. The reaction mixture
was concentrated under reduced pressure to give 234 mg
(100%) of the title compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 1.45-1.67 (4H, m), 2.11-2.19
(4H, m), 2.59-2.68 (1H, m), 3.10-3.19 (1H, m).
Reference Example 23
Step 1 Step 2
O H O
Step 3 Step 4
[Step 1]
1,5-anhydroazidoO-[tert-butyl(dimethyl)silyl]-2,3-
dideoxy-D-ribo-hexitol
A dichloromethane (4 ml) solution of tert-
butyldimethylchlorosilane (381 mg, 2.54 mmol) was added
to a dichloromethane (10 ml) solution of 1,5-anhydro
azido-2,3-dideoxy-D-ribo-hexitol (440 mg, 2.54 mmol) and
triethylamine (0.46 ml, 3.30 mmol) under ice cooling.
After stirring at room temperature for 50 hours, the
reaction mixture was diluted with chloroform and the
organic layer was washed with water and brine. The
organic layer was dried over anhydrous sodium sulfate,
then the solvent was evaporated under reduced pressure
and the residue was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 10:1 fi 4:1
(v/v)] to give 650 mg (89%) of the title compound as a
colorless oil.
H-NMR (400 MHz, CDCl ) d : 0.07-0.10 (6H, m), 0.88 (9H,
s), 1.41-1.53 (1H, m), 2.39-2.49 (1H, m), 3.06-3.18 (2H,
m), 3.41-3.57 (2H, m), 3.62-3.71 (2H, m), 3.88-3.96 (2H,
MS (ESI) m/z: 310 (M + Na) .
[Step 2]
1,5-anhydroazidoO-[tert-butyl(dimethyl)silyl]-2,3-
dideoxyO-methyl-D-ribo-hexitol
Sodium hydride (60% oily, 136 mg, 3.39 mmol) was
added to a tetrahydrofuran (11 ml) solution of the
compound (650 mg, 2.26 mmol) obtained in Step 1 above
under ice cooling, the resulting mixture was stirred for
minutes and then methyl iodide (0.42 ml, 6.78 mmol) was
added. After stirring at the same temperature for 1 hour,
saturated ammonium chloride solution was added, the
resulting mixture was subjected to extraction with ethyl
acetate and the organic layer was washed with brine. The
organic layer was dried over anhydrous sodium sulfate and
then the solvent was evaporated under reduced pressure to
give the title compound.
[Step 3]
1,5-anhydroazido-2,3-dideoxyO-methyl-D-ribo-hexitol
Tetrabutylammonium fluoride/tetrahydrofuran solution
(1.0 mol/l, 3.6 ml, 3.60 mmol) was added to a
tetrahydrofuran (7 ml) solution of the compound (2.26
mmol) obtained in Step 2 above and the resulting mixture
was stirred at room temperature for 16 hours. The
solvent was evaporated under reduced pressure and water
was added, followed by extraction with ethyl acetate.
The organic solvent was dried over anhydrous sodium
sulfate, the solvent was evaporated under reduced
pressure and the residue obtained was purified by silica
gel column chromatography [n-hexane:ethyl acetate = 4:1
fi 1:1 (v/v)] to give 329 mg (78%) of the title compound
as a colorless oil.
H-NMR (400 MHz, CDCl ) d : 1.34-1.44 (1H, m), 1.90-1.97
(1H, m), 2.61-2.69 (1H, m), 3.13-3.29 (3H, m), 3.39 (3H,
s), 3.42-3.53 (1H, m), 3.65-3.73 (1H, m), 3.81-3.89 (1H,
m), 3.97-4.04 (1H, m).
[Step 4]
2-amino-1,5-anhydro-2,3-dideoxyO-methyl-D-ribo-hexitol
The compound (329 mg, 1.76 mmol) obtained in Step 3
above was used as a starting material and treated in the
same way as in Step 4 of Reference Example 14 to give 283
mg (100%) of the title compound as a colorless oil.
H-NMR (400 MHz, CD OD) d : 1.04-1.15 (1H, m), 2.45-2.54
(1H, m), 2.73-2.84 (1H, m), 2.94-3.08 (2H, m), 3.11-3.21
(1H, m), 3.35 (3H, s), 3.58 (1H, dd, J = 11.69, 5.73 Hz),
3.74-3.81 (1H, m), 3.84-3.92 (1H, m).
MS (ESI) m/z: 162 (M + H) .
Reference Example 24
N Step 2
Step 1
工 程 2
工 程 1 O
O OH
Step 4
Step 3
O N 工 程 3 N 工 程 4
O NH
Step 5
O N O N O
工 程 5
O N O N
H N O
Step 6
工 程 6
[Step 1]
1,5-anhydro[(tert-butoxycarbonyl)amino]-2,3,4-
trideoxyO-(methylsulfonyl)-D-erythro-hexitol
The same starting material (2.38 g, 10.30 mmol) as
in Step 1 of Reference Example 2 was used and treated in
the same way as in Step 1 of Reference Example 14 to give
1.34 g (42%) of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.28-1.36 (1H, m), 1.44-1.54
(9H, m), 1.72 (1H, dq, J = 13.0, 3.1 Hz), 2.12-2.17 (1H,
m), 3.02 (1H, t, J = 10.6 Hz), 3.05 (3H, s), 3.53-3.64
(2H, m), 4.13-4.10 (1H, m), 4.28-4.15 (3H, m).
MS (FAB) m/z: 310 (M + H) .
[Step 2]
1,5-anhydroazido[(tert-butoxycarbonyl)amino]-
2,3,4,6-tetradeoxy-D-erythro-hexitol
The compound obtained in Step 1 above was used as a
starting material and treated in the same way as in Step
2 of Reference Example 14 to give the title compound.
H-NMR (400 MHz, CDCl ) d : 1.23-1.34 (1H, m), 1.44 (9H,
s), 1.46-1.53 (1H, m), 1.66-1.71 (1H, m), 2.09-2.15 (1H,
m), 3.02 (1H, t, J = 10.8 Hz), 3.21 (1H, dd, J = 12.6,
3.9 Hz), 3.30 (1H, dd, J = 12.8, 6.9 Hz), 3.39-3.45 (1H,
m), 3.60-3.64 (1H, m), 4.12 (1H, dq, J = 10.9, 2.3 Hz),
4.24 (1H, br s).
MS (ESI) m/z: 279 (M + Na) .
[Step 3]
6-amino-1,5-anhydro[(tert-butoxycarbonyl)amino]-
2,3,4,6-tetradeoxy-D-erythro-hexitol
The compound obtained in Step 2 above was used as a
starting material and treated in the same way as in Step
4 of Reference Example 14 to give the title compound.
H-NMR (400 MHz, DMSO-d ) d : 1.13-1.32 (2H, m), 1.35 (9H,
s), 1.60-1.65 (1H, m), 1.78-1.84 (1H, m), 2.50 (2H, d, J
= 5.9 Hz), 2.91 (1H, t, J = 10.6 Hz), 3.01-3.08 (1H, m),
3.25-3.30 (1H, m), 3.74-3.78 (1H, m), 6.72 (1H, d, J =
8.1 Hz).
[Step 4]
6-[(2-acetoxyethyl)amino]-1,5-anhydro[(tert-
butoxycarbonyl)amino]-2,3,4,6-tetradeoxy-D-erythro-
hexitol
The compound (500 mg, 2.17 mmol) obtained in Step 3
above was dissolved in dichloromethane (10 ml), 2-
oxoethyl acetate (243 mg, 2.39 mmol) was added and the
resulting mixture was stirred at room temperature for 1
hour. Then, sodium triacetoxyborohydride (920 mg, 4.34
mmol) was added and the resulting mixture was stirred at
room temperature for 3 hours. After reaction, saturated
sodium bicarbonate solution (50 ml) was added and the
resulting mixture was further stirred for 1 hour. The
reaction mixture was diluted with dichloromethane and the
organic layer was washed with brine. The organic layer
was dried over anhydrous sodium sulfate and the solvent
was evaporated under reduced pressure. The residue
obtained was purified by silica gel column chromatography
[chloroform:methanol = 40:1 fi 20:1 (v/v)] to give 544 mg
(64%) of the title compound as a colorless oil.
H-NMR (400 MHz, CDCl ) d : 1.23-1.33 (1H, m), 1.39-1.49
(10H, m), 1.65-1.71 (1H, m), 2.06-2.15 (4H, m), 2.61-2.70
(2H, m), 2.80-2.90 (2H, m), 2.99 (1H, t, J = 10.5 Hz),
3.34-3.40 (1H, m), 3.56-3.62 (1H, m), 4.05-4.19 (3H, m),
4.24 (1H, br s).
MS (ESI) m/z: 317 (M + H) .
[Step 5]
6-[(2-acetoxyethyl)(acetyl)amino]-1,5-anhydro[(tert-
butoxycarbonyl)amino]-2,3,4,6-tetradeoxy-D-erythro-
hexitol
The compound (264 mg, 0.83 mmol) obtained in Step 4
above was dissolved in dichloromethane (8 ml), acetic
anhydride (0.50 ml, 5.30 mmol) was added and the
resulting mixture was stirred at room temperature for 1
hour. Then, pyridine (0.10 ml, 1.24 mmol) was added and
the resulting mixture was stirred for a further 1 hour.
Saturated brine (20 ml) was added to the reaction mixture
and the resulting mixture was stirred for 1 hour,
followed by extraction with dichloromethane. The organic
layer was washed with saturated sodium bicarbonate
solution, and brine in this order and dried over
anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography
[chloroform:methanol = 40:1 (v/v)] to give 244 mg (82%)
of the title compound as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.15-1.40 (3H, m), 1.43 (9H,
s), 1.71-1.76 (1H, m), 2.05 and 2.06 (total 3H, each s),
2.11 and 2.15 (total 3H, each s), 2.82-3.02 (2H, m),
3.24-3.78 (5H, m), 4.01-4.30 (4H, m).
MS (ESI) m/z: 359 (M + H) .
[Step 6]
6-[(2-acetoxyethyl)(acetyl)amino]amino-1,5-anhydro-
2,3,4,6-tetradeoxy-D-erythro-hexitol hydrochloride
The compound (240 mg, 0.67 mmol) obtained in Step 5
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a colorless amorphous solid.
Reference Example 25
Step 1
Step 2
工 程 1 工 程 2
O OH
Step 3
工 程 3
[Step 1]
tert-Butyl [(3R,6S)(hydrazinocarbonyl)tetrahydro-2H-
pyranyl]carbamate
The same starting material (1.52 g, 6.20 mmol) as in
Step 1 of Reference Example 18 was used and treated in
the same way as in Step 4 of Reference Example 18 to give
1.33 g (83%) of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.30-1.60 (11H, m), 2.10-2.18
(1H, m), 2.20-2.28 (1H, m), 3.03 (1H, t, J = 10.9 Hz),
3.55-3.68 (1H, m), 3.81 (1H, dd, J = 11.7, 2.6 Hz), 4.12-
4.19 (1H, m), 4.27-4.38 (1H, m), 7.63 (1H, s).
MS (ESI) m/z: 260 (M + H) .
[Step 2]
tert-Butyl [(3R,6S)(5-oxo-4,5-dihydro-1,3,4-oxadiazol-
2-yl)tetrahydro-2H-pyranyl]carbamate
The compound (1.33 g, 5.13 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 19 to give
1.10 g (75%) of the title compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 1.38-1.58 (10H, m), 1.84-1.95
(1H, m), 1.96-2.03 (1H, m), 2.05-2.13 (1H, m), 3.20 (1H,
t, J = 10.6 Hz), 3.48-3.59 (1H, m), 3.97-4.05 (1H, m),
4.28 (1H, dd, J = 10.6, 2.6 Hz), 6.59-6.71 (1H, m).
MS (ESI) m/z: 286 (M + H) .
[Step 3]
-[(2S,5R)aminotetrahydro-2H-pyranyl]-1,3,4-
oxadiazol-2(3H)-one hydrochloride
The compound (1.10 g, 3.86 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 688
mg (81%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.70-1.82 (1H, m), 1.94-2.06
(1H, m), 2.08-2.17 (1H, m), 2.25-2.34 (1H, m), 3.29-3.38
(1H, m), 3.54 (1H, dd, J = 11.5, 9.16 Hz), 4.07-4.15 (1H,
m), 4.49 (1H, dd, J = 9.6, 3.2 Hz).
MS (ESI) m/z: 186 (M + H) .
Reference Example 26
Step 1 Step 2
工 程 1
工 程 2
O NH
Step 3
Step 4
工 程 3 工 程 4
[Step 1]
tert-Butyl [(3R,6S)cyanotetrahydro-2H-pyran
yl]carbamate
tert-Butyl [(3R,6S)carbamoyltetrahydro-2H-pyran-
3-yl]carbamate (WO2006/125974) (1.54 g, 6.30 mmol) was
used as a starting material and treated in the same way
as in Step 4 of Reference Example 22 to give 1.39 g (97%)
of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.45 (9H, s), 1.74-1.90 (2H,
m), 2.00-2.20 (2H, m), 3.52-3.67 (1H, m), 3.70-3.83 (1H,
m), 4.05 (1H, dd, J = 12.0, 2.9 Hz), 4.56-4.67 (1H, m),
4.85-4.98 (1H, m).
[Step 2]
tert-Butyl {(3R,6S)[(Z)-
amino(hydroxyimino)methyl]tetrahydro-2H-pyran
yl}carbamate
The compound (1.39 g, 6.14 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 5 of Reference Example 22 to give
1.59 g (100%) of the title compound as a colorless solid.
[Step 3]
tert-Butyl [(3R,6S)(1,2,4-oxadiazolyl)tetrahydro-
2H-pyranyl]carbamate
Trimethyl orthoformate (6.0 ml) was added to an N,N-
dimethylacetamide (20 ml) solution of the compound (1.59
g, 6.14 mmol) obtained in Step 2 above at room
temperature under a nitrogen atmosphere and then a boron
trifluoride-diethyl ether complex (0.08 ml, 0.61 mmol)
was added. After stirring at 50 C for 21 hours, the
reaction mixture was cooled, triethylamine (0.86 ml, 6.14
mmol) was added at room temperature and the resulting
mixture was stirred for 80 minutes. The reaction mixture
was diluted with dichloromethane:methanol [10:1 (v/v)]
and washed with saturated sodium bicarbonate solution and
then the organic layer was dried over anhydrous sodium
sulfate. The solvent was concentrated under reduced
pressure and the residue obtained was purified by silica
gel column chromatography [n-hexane:ethyl acetate = 9:1
fi 7:3 (v/v)] to give 1.46 g (89%) of the title compound
as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.39-1.63 (10H, m), 1.95-2.29
(3H, m), 3.20-3.36 (1H, m), 3.68-3.86 (1H, m), 4.17-4.29
(1H, m), 4.43-4.58 (1H, m), 4.60-4.68 (1H, m), 8.74 (1H,
[Step 4]
(3R,6S)(1,2,4-oxadiazolyl)tetrahydro-2H-pyran
amine hydrochloride
The compound (1.46 g, 5.43 mmol) obtained in Step 3
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 988
mg (88%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.75-1.88 (1H, m), 1.99-2.11
(1H, m), 2.16-2.25 (1H, m), 2.26-2.35 (1H, m), 3.32-3.41
(1H, m), 3.58 (1H, dd, J = 11.5, 9.6 Hz), 4.14-4.21 (1H,
m), 4.76-4.81 (1H, m), 9.28 (1H, s).
Reference Example 27
Step 2
Step 1
工 程 2
工 程 1
Step 3 Step 4
工 程 3 工 程 4
Si Si
OH O
O Step 5
工 程 5
[Step 1]
2,6-anhydroazidoO-[tert-butyl(dimethyl)silyl]-4,5-
dideoxy-L-erythro-hexulose
A Dess-Martin reagent (876 mg, 2.00 mmol) was added
to a dichloromethane (10 ml) solution of 1,5-anhydro
azidoO-[tert-butyl(dimethyl)silyl]-2,3-dideoxy-D-ribo-
hexitol (450 mg, 1.25 mmol) under ice cooling and the
resulting mixture was stirred for 75 minutes. Aqueous
sodium thiosulfate solution was added under ice cooling,
then the resulting mixture was subjected to extraction
with ether and the organic layer was washed with brine.
The organic layer was dried over anhydrous sodium sulfate,
then the solvent was evaporated under reduced pressure
and the residue was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 50:1 fi 20:1
(v/v)] to give 272 mg (76%) of the title compound as a
colorless oil.
H-NMR (400 MHz, CDCl ) d : 0.02 (3H, s), 0.04 (3H, s),
0.85 (9H, s), 2.55 (1H, dd, J = 16.1, 6.4 Hz), 2.86 (1H,
dd, J = 16.1, 5.7 Hz), 3.58-3.67 (1H, m), 3.87-4.00 (3H,
m), 4.06-4.16 (1H, m), 4.31-4.39 (1H, m).
MS (ESI) m/z: 308 (M + Na) .
[Step 2]
1,5-anhydroazidoO-[tert-butyl(dimethyl)silyl]-2,3-
dideoxy-D-xylo-hexitol
Lithium tri-sec-butylborohydride/tetrahydrofuran
solution (1.0 mol/l, 0.83 ml, 0.83 mmol) was added to a
tetrahydrofuran (2.5 ml) solution of the compound (169 mg,
0.59 mmol) obtained in Step 1 above at -78 C and the
resulting mixture was stirred at -78 C for 45 minutes.
1N hydrochloric acid was added, the resulting mixture was
subjected to extraction with ethyl acetate and the
organic layer was washed with brine. The organic layer
was dried over anhydrous sodium sulfate, then the solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 20:1 fi 12:1 (v/v)] to give 101 mg
(59%) of the title compound as a colorless oil.
H-NMR (400 MHz, CDCl ) d : 0.07 (3H, s), 0.08 (3H, s),
0.88 (9H, s), 1.49-1.58 (1H, m), 2.28-2.36 (1H, m), 3.14-
3.27 (2H, m), 3.43-3.48 (1H, m), 3.85-3.96 (3H, m), 4.03-
4.15 (2H, m).
MS (ESI) m/z: 288 (M + H) .
[Step 3]
1,5-anhydroazidoO-[tert-butyl(dimethyl)silyl]-2,3-
dideoxyO-methyl-D-xylo-hexitol
The compound (160 mg, 0.56 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 23 to give the
title compound.
[Step 4]
1,5-anhydroazido-2,3-dideoxyO-methyl-D-xylo-hexitol
The compound (0.56 mmol) obtained in Step 3 above
was used as a starting material and treated in the same
way as in Step 3 of Reference Example 23 to give 62 mg
(60%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.43-1.52 (1H, m), 2.10 (1H,
dd, J = 9.2, 2.8 Hz), 2.47-2.56 (1H, m), 3.21-3.29 (1H,
m), 3.40 (3H, s), 3.41-3.46 (1H, m), 3.51-3.55 (1H, m),
3.64-3.91 (3H, m), 4.09-4.17 (1H, m).
[Step 5]
2-amino-1,5-anhydro-2,3-dideoxyO-methyl-D-xylo-hexitol
The compound (62 mg, 0.33 mmol) obtained in Step 4
above was used as a starting material and treated in the
same way as in Step 4 of Reference Example 14 to give 53
mg (100%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.19-1.30 (1H, m), 2.35-2.44
(1H, m), 2.93-3.10 (2H, m), 3.28-3.32 (1H, m), 3.35 (3H,
s), 3.45-3.51 (1H, m), 3.56-3.67 (2H, m), 3.87-3.96 (1H,
MS (ESI) m/z: 162 (M + H) .
Reference Example 28
Step 1
Step 2
工 程 1 工 程 2
O OH
Step 3
工 程 3
N NH
NH O
[Step 1]
2,6-anhydro-3,4,5-trideoxy(dibenzylamino)-L-erythro-
hexonic acid
The same starting material (1.60 g, 4.70 mmol) as in
Step 1 of Reference Example 5 was dissolved in methanol
(30 ml), 1N sodium hydroxide solution (10 ml) was
gradually added under ice cooling and then the resulting
mixture was stirred at room temperature for 3 hours.
Dowex 50W-X8 was added to the reaction mixture to adjust
its pH to 5 to 6, insoluble matter was removed by
filtration and then the filtrate was concentrated under
reduced pressure to give 1.7 g (100%) of the title
compound as a colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.18-1.26 (1H, m), 1.36-1.48
(1H, m), 1.79-1.97 (2H, m), 2.62 (1H, t, J = 11.0 Hz),
3.18 (1H, t, J = 10.4 Hz), 3.40 (1H, d, J = 11.5 Hz),
3.51-3.61 (4H, m), 3.90-3.99 (1H, m), 7.12-7.38 (10H, m).
MS (ESI) m/z: 326 (M + H) .
[Step 2]
(2S,5R)(dibenzylamino)tetrahydro-2H-pyran
carboxamide
The compound (870 mg, 2.67 mmol) obtained in Step 1
above was dissolved in N,N-dimethylformamide (30 ml), 1-
hydroxybenzotriazole (361 mg, 2.67 mmol) and 1-ethyl
(3-dimethylaminopropyl)carbodiimide hydrochloride (614 mg,
3.20 mmol) were added and the resulting mixture was
stirred at room temperature for 15 minutes. Ammonium
chloride (285 mg, 5.44 mmol) and N,N-
diisopropylethylamine (l.86 ml, 10.7 mmol) were added and
the resulting mixture was stirred at room temperature for
8 hours. The reaction mixture was diluted with ethyl
acetate and the organic layer was washed with saturated
sodium bicarbonate solution and brine in this order and
dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give 495 mg (57%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.35-1.45 (1H, m), 1.60-1.70
(1H, m), 2.10-2.18 (1H, m), 2.21-2.28 (1H, m), 2.76 (1H,
tt, J = 11.4, 4.0 Hz), 3.44 (1H, t, J = 10.9 Hz), 3.67
(4H, q, J = 14.2 Hz), 3.71-3.73 (1H, m), 4.04 (1H, dq, J
= 11.0, 2.1 Hz), 5.35 (1H, s), 6.40 (1H, s), 7.21-7.36
(10H, m).
MS (ESI) m/z: 325 (M + H) .
[Step 3]
(2S,5R)aminotetrahydro-2H-pyrancarboxamide
The compound (490 mg, 1.51 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 5 to give 215
mg (99%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.11-1.22 (1H, m), 1.25-1.35
(1H, m), 1.83-1.91 (2H, m), 2.51-2.60 (1H, m), 2.90 (1H,
t, J = 10.5 Hz), 3.52 (1H, d, J = 11.9 Hz), 3.78-3.84 (1H,
m), 6.99 (1H, br s), 7.09 (1H, br s).
MS (ESI) m/z: 145 (M + H) .
Reference Example 29
Step 1
工 程 1
O OH
O OH
( A ) ( B )
S 工 te 程 p 2 2
O O Si +
O O Si
( C ) ( D )
工 St 程 ep 3 3 工 程 5
Step 5
O OH
O OH
Step 4
Step 6
工 程 4
工 程 6
HCl O HCl
[Step 1]
tert-Butyl [4-(hydroxymethyl)
methoxycyclohexyl]carbamate (A)
Concentrated sulfuric acid (0.10 ml, 1.90 mmol) was
added to a methanol (10 ml) solution of the same starting
material (1.14 g, 5.02 mmol) as in Step 1 of Reference
Example 17 and the resulting mixture was stirred
overnight at room temperature. Potassium carbonate (1.34
g, 9.70 mmol) was added, followed by extraction with
chloroform. The organic layer was washed with water and
brine and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the
residue obtained was purified by silica gel column
chromatography (ethyl acetate) to separately give 422 mg
(34%) of the title compound and 239 mg (18%) of the
compound (B) as colorless amorphous solids.
H-NMR (500 MHz, CDCl ) d : 1.22-1.38 (3H, m), 1.44 (9H,
s), 1.63 (3H, t, J = 6.3 Hz), 1.80-1.83 (1H, m), 1.87-
1.93 (2H, m), 3.19 (0.6H, s), 3.21 (2.4H, s), 3.45 (0.4H,
d, J = 5.7 Hz), 3.55-3.61 (2.6H, m), 4.41-4.52 (1H, m).
[Step 2]
tert-Butyl [trans({[tert-
butyl(diphenyl)silyl]oxy}methyl)
methoxycyclohexyl]carbamate (C) and tert-butyl [cis
({[tert-butyl(diphenyl)silyl]oxy}methyl)
methoxycyclohexyl]carbamate (D)
tert-Butyldiphenylchlorosilane (667 mg, 2.4 mmol)
and imidazole (441 mg, 6.5 mmol) were added to an N,N-
dimethylformamide (4 ml) solution of the compound (A)
(413 mg, 1.59 mmol) obtained in Step 1 above and the
resulting mixture was stirred overnight at room
temperature. The reaction mixture was diluted with ethyl
acetate, washed with water and brine and then dried over
anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 90:10 (v/v)] to separately give
513 mg of the title compound (C) (65%, highly polar
compound) and 123 mg of the title compound (D) (16%, low
polar compound) as colorless amorphous solids.
Compound (C):
H-NMR (400 MHz, CDCl ) d : 1.08 (9H, s), 1.25-1.33 (2H,
m), 1.45 (9H, s), 1.52-1.59 (2H, m), 1.63-1.70 (2H, m),
1.76-1.84 (2H, m), 3.23 (3H, s), 3.58 (2H, s), 3.61-3.67
(1H, m), 4.42-4.48 (1H, m), 7.37-7.47 (6H, m), 7.66-7.68
(4H, m).
Compound (D):
H-NMR (400 MHz, CDCl ) d : 1.05 (9H, s), 1.31-1.44 (13H,
m), 1.77-1.85 (4H, m), 3.18 (3H, s), 3.39 (1H, m), 3.49
(2H, s), 4.42 (1H, d, J = 6.9 Hz), 7.36-7.45 (6H, m),
7.64-7.66 (4H, m).
[Step 3]
tert-Butyl [trans(hydroxymethyl)
methoxycyclohexyl]carbamate
The compound (C) (511 mg, 1.03 mmol) obtained in
Step 2 above was used as a starting material and treated
in the same way as in Step 2 of Reference Example 17 to
give 243 mg (91%) of the title compound as a colorless
amorphous solid.
H-NMR (500 MHz, CDCl ) d : 1.31-1.38 (2H, m), 1.44 (9H,
s), 1.63 (4H, t, J = 6.3 Hz), 1.83 (1H, t, J = 6.0 Hz),
1.87-1.93 (2H, m), 3.21 (3H, s), 3.55-3.60 (3H, m), 4.47-
4.51 (1H, m).
MS (FAB) m/z: 260 (M + H) .
[Step 4]
(transaminomethoxycyclohexyl)methanol hydrochloride
The compound (46 mg, 0.175 mmol) obtained in Step 3
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a colorless solid.
[Step 5]
tert-Butyl [cis(hydroxymethyl)
methoxycyclohexyl]carbamate
The compound (D) (127 mg, 0.254 mmol) obtained in
Step 2 above was used as a starting material and treated
in the same way as in Step 2 of Reference Example 17 to
give 59 mg (89%) of the title compound as a colorless
amorphous solid.
H-NMR (500 MHz, CDCl ) d : 1.25 (2H, td, J = 13.6, 3.6
Hz), 1.37 (2H, dq, J = 3.4, 12.6 Hz), 1.44 (9H, s), 1.71
(1H, t, J = 5.7 Hz), 1.80-1.83 (2H, m), 1.88-1.93 (2H, m),
3.19 (3H, s), 3.41-3.45 (3H, m), 4.43-4.46 (1H, m).
MS (FAB) m/z: 260 (M + H) .
[Step 6]
(cisaminomethoxycyclohexyl)methanol hydrochloride
The compound (30 mg, 0.115 mmol) obtained in Step 5
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a colorless solid.
Reference Example 30
Step 1 Step 2
O 工 程 2
工 程 1 N
O OH
Step 3
工 程 3 2
O OH
[Step 1]
2,6-anhydro[(tert-butoxycarbonyl)amino]-3,4,5-
trideoxy-L-erythro-hexose
Dichloromethane (5 ml) and dimethyl sulfoxide (0.21
ml, 2.85 mmol) were mixed under a nitrogen atmosphere, a
dichloromethane (5 ml) solution of oxalyl chloride (0.21
ml, 2.50 mmol) was added dropwise at -78 C and the
resulting mixture was stirred for 30 minutes. A
dichloromethane (5 ml) solution of the same starting
material (440 mg, 1.90 mmol) as in Step 1 of Reference
Example 2 was added dropwise at the same temperature and
the resulting mixture was stirred for 1 hour. Then, a
dichloromethane (4 ml) solution of N,N-
diisopropylethylamine (1.65 ml, 9.50 mmol) was added
dropwise and the resulting mixture was stirred at the
same temperature for 1 hour, warmed to room temperature,
and stirred for a further 1 hour. The reaction solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 1:1 fi 1:2 (v/v)] to give 347 mg
(80%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.36-1.44 (1H, m), 1.45 (9H,
s), 1.53-1.63 (1H, m), 1.94-2.01 (1H, m), 2.10-2.17 (1H,
m), 3.15 (1H, t, J = 10.5 Hz), 3.59-3.67 (1H, m), 3.73
(1H, dd, J = 11.0, 2.7 Hz), 4.17 (1H, dq, J = 11.0, 2.1
Hz), 4.38 (1H, br s), 9.65 (1H, s).
[Step 2]
1,5-anhydro[(tert-butoxycarbonyl)amino]-2,3,4,7-
trideoxy-D-erythro-heptitol
The compound (2.80 g) obtained in Step 1 above was
dissolved in diethyl ether (30 ml), methyl magnesium
bromide/tetrahydrofuran solution (1.1 mol/l, 54.0 ml,
59.4 mmol) was added dropwise at 0 C under a nitrogen
atmosphere and then the resulting mixture was stirred at
room temperature for 16 hours. Methanol (5 ml) was
gradually added, followed by extraction with ethyl
acetate. The organic layer was washed with aqueous
ammonium chloride solution and brine in this order and
dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 2:1 fi 1:1 (v/v)] to give 1.07 g
(73%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.14 (3H, d, J = 6.4 Hz),
1.23-1.32 (1H, m), 1.34-1.43 (1H, m), 1.44 (9H, s), 1.66-
1.72 (1H, m), 2.08-2.14 (1H, m), 2.64 (1H, br s), 2.99
(1H, t, J = 10.8 Hz), 3.56-3.64 (2H, m), 4.09-4.15 (1H,
m), 4.25 (1H, br s).
MS (ESI) m/z: 268 (M + Na) .
[Step 3]
2-amino-1,5-anhydro-2,3,4,7-tetradeoxy-D-erythro-heptitol
hydrochloride
The mixture (700 mg, 2.85 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 484
mg (93%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.06 (3H, d, J = 6.4 Hz),
1.35-1.46 (1H, m), 1.53-1.64 (1H, m), 1.66-1.73 (1H, m),
2.11-2.18 (1H, m), 2.99-3.14 (2H, m), 3.31 (1H, t, J =
.8 Hz), 3.55-3.63 (1H, m), 4.05-4.12 (1H, m).
MS (ESI) m/z: 146 (M + H) .
Reference Example 31
O N Step 2 2
工 程 2
O N Step 1
工 程 1 HCl
( A ) OH
( B )
[Step 1]
tert-Butyl [cishydroxy
(methoxymethyl)cyclohexyl]carbamate (A) and tert-butyl
[transhydroxy(methoxymethyl)cyclohexyl]carbamate
Sodium methylate/methanol solution (28% w/w, 2.0 ml,
.0 mmol) was added to a methanol (7 ml) solution of the
same starting material (0.75 g, 3.31 mmol) as in Step 1
of Reference Example 17 and the resulting mixture was
stirred at 60 C for 2 hours. Water was added, followed
by extraction with ethyl acetate. The organic layer was
washed with brine and then dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced
pressure and the residue obtained was purified by silica
gel column chromatography [n-hexane:ethyl acetate = 1:1
(v/v)] to give 619 mg of the title compound (A) (72%, low
polar compound) as a colorless amorphous solid. Also, 61
mg of the title compound (B) (7%, highly polar compound)
was obtained as a colorless amorphous solid.
Compound (A):
H-NMR (400 MHz, CDCl ) d : 1.35 (2H, td, J = 13.3, 4.0
Hz), 1.44 (9H, s), 1.47-1.57 (2H, m), 1.70-1.75 (2H, m),
1.79-1.83 (2H, m), 2.06 (1H, s), 3.20 (2H, s), 3.38-3.43
(4H, m), 4.45-4.43 (1H, m).
MS (FAB) m/z: 260 (M + H) .
Compound (B):
H-NMR (500 MHz, CDCl ) d : 1.33-1.40 (2H, m), 1.44 (9H,
s), 1.51-1.56 (2H, m), 1.64-1.69 (2H, m), 1.91-1.96 (2H,
m), 2.33 (1H, s), 3.31 (2H, s), 3.40 (3H, s), 3.61-3.64
(1H, m), 4.49-4.53 (1H, m).
MS (FAB) m/z: 260 (M + H) .
[Step 2]
cisamino(methoxymethyl)cyclohexanol hydrochloride
The compound (A) (80 mg, 0.31 mmol) obtained in Step
1 above was used as a starting material and treated in
the same way as in Step 1 of Reference Example 2 to give
the title compound as a colorless solid.
Reference Example 32
Step 1 O Step 2
工 程 2
工 程 1
Step 3
工 程 3
[Step 1]
1,5-anhydroazidoO-[tert-butyl(dimethyl)silyl]-2,3-
dideoxyC-methyl-D-erythro-hexitol
Methylmagnesium bromide (1.06 mol/l, 0.47 ml, 0.50
mmol) was added to a tetrahydrofuran (1.4 ml) solution of
the compound (80 mg, 0.28 mmol) obtained in Step 1 of
Reference Example 27 at -40 C and the resulting mixture
was gradually warmed to -10 C. 1N hydrochloric acid was
added and the resulting mixture was subjected to
extraction with ethyl acetate. The organic layer was
washed with saturated sodium bicarbonate solution and
brine and dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the
residue was purified by silica gel column chromatography
[n-hexane:ethyl acetate = 50:1 fi 20:1 (v/v)] to give 58
mg of a mixture of the title diastereomers (69%) as a
colorless oil.
MS (ESI) m/z: 324 (M + Na) .
[Step 2]
1,5-anhydroazido-2,3-dideoxyC-methyl-D-erythro-
hexitol
The mixture (58 mg, 0.19 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 23 to give 25
mg (70%) of the title compound as a colorless oil.
[Step 3]
2-amino-1,5-anhydro-2,3-dideoxyC-methyl-D-erythro-
hexitol
The mixture (25 mg, 0.13 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 4 of Reference Example 14 to give 21
mg (100%) of the title compound as a colorless oil.
MS (ESI) m/z: 162 (M + H) .
Reference Example 33
Step 1 Step 2
工 程 1 工 程 2
Step 3
工 程 3
O HCl
[Step 1]
tert-Butyl {cishydroxy
[(methylthio)methyl]cyclohexyl}carbamate
A methanol (5 ml) solution of the same starting
material (1.00 g, 4.41 mmol) as in Step 1 of Reference
Example 17 and sodium methanethiolate (465 mg, 6.64 mmol)
was stirred for 1 hour. The reaction mixture was diluted
with ethyl acetate, washed with water, saturated sodium
bicarbonate solution, and brine in this order and then
dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the residue
obtained was purified by silica gel column chromatography
[ethyl acetate:benzene = 3:7 (v/v)] to give 766 mg (63%)
of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.37-1.44 (11H, m), 1.49-1.57
(2H, m), 1.74 (2H, dq, J = 14.2, 3.1 Hz), 1.80-1.83 (2H,
m), 2.15 (1H, s), 2.17 (3H, s), 2.61 (2H, s), 3.37-3.44
(1H, m), 4.43-4.45 (1H, m).
MS (FAB) m/z: 276 (M + H) .
[Step 2]
tert-Butyl {cishydroxy
[(methylsulfonyl)methyl]cyclohexyl}carbamate
m-Chloroperbenzoic acid (25% hydrated, 538 mg, 2.34
mmol) was added to a dichloromethane (5 ml) solution of
the compound (276 mg, 1.00 mmol) obtained in Step 1 above
under ice cooling and the resulting mixture was stirred
for 1 hour. The reaction mixture was diluted with ethyl
acetate, washed with water, saturated sodium bicarbonate
solution, and brine in this order and then dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography [ethyl
acetate:n-hexane = 7:3 (v/v)] to give 292 mg (95%) of the
title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.44 (9H, s), 1.51-1.62 (4H,
m), 1.80-1.86 (2H, m), 2.03-2.10 (2H, m), 3.00 (3H, s),
3.19-3.21 (3H, m), 3.40-3.46 (1H, m), 4.40-4.46 (1H, m).
MS (FAB) m/z: 308 (M + H) .
[Step 3]
cisamino[(methylsulfonyl)methyl]cyclohexanol
hydrochloride
The compound (62 mg, 0.20 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a colorless solid.
Reference Example 34
O N O N
Step 1
O 工 程 1 O
O OH O N
Step 2 O
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(ethylcarbamoyl)tetrahydro-2H-
pyranyl]carbamate
The same starting material (500 mg, 2.04 mmol) as in
Step 1 of Reference Example 18 and ethylamine
hydrochloride (250 mg, 3.06 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Reference Example 28 to give 123 mg (22%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.16 (3H, t, J = 7.3 Hz),
1.32-1.54 (11H, m), 2.09-2.15 (1H, m), 2.21-2.28 (1H, m),
3.04 (1H, t, J = 10.7 Hz), 3.25-3.36 (2H, m), 3.60 (1H,
br s), 3.70 (1H, dd, J = 11.6, 2.6 Hz), 4.12-4.18 (1H, m),
4.30 (1H, s), 6.50 (1H, br s).
MS (ESI) m/z: 295 (M + Na) .
[Step 2]
(2S,5R)amino-N-ethyltetrahydro-2H-pyrancarboxamide
hydrochloride
The compound (120 mg, 0.44 mmol) obtained in Step 1
above was used and treated in the same way as in Step 1
of Reference Example 2 to give 87 mg (95%) of the title
compound as a colorless amorphous solid.
H-NMR (400 MHz, DMSO-d ) d : 0.98 (3H, t, J = 7.2 Hz),
1.37-1.47 (1H, m), 1.56 (1H, ddd, J = 23.8, 12.2, 3.7 Hz),
1.96-2.08 (2H, m), 3.04-3.13 (3H, m), 3.54-3.59 (1H, m),
3.71 (1H, dd, J = 11.2, 2.4 Hz), 4.02-4.07 (1H, m), 7.69
(1H, t, J = 5.5 Hz).
MS (ESI) m/z: 173 (M + H) .
Reference Example 35
O N O
Step 2
Step 1
O 工 程 1 O
工 程 2
O H O
Step 3
工 程 3
O OH
[Step 1]
tert-Butyl [(3R,6S)vinyltetrahydro-2H-pyran
yl]carbamate
n-Butyllithium/n-hexane solution (1.65 mol/l, 6.60
ml, 10.9 mmol) was added dropwise to a tetrahydrofuran
(100 ml) suspension of methyltriphenylphosphonium bromide
(3.90 g, 10.9 mmol) at -78 C under a nitrogen atmosphere
and the resulting mixture was stirred for 15 minutes and
then stirred at 0 C for 45 minutes. After cooling to
-78 C again, a tetrahydrofuran (6
ml)/hexamethylphosphoric acid triamide (3 ml) solution of
the compound (1.00 g, 4.36 mmol) obtained in Step 1 of
Reference Example 30 was added dropwise and the resulting
mixture was stirred at the same temperature for 30
minutes and then stirred at room temperature for 1 hour.
Water (100 ml) was added, followed by extraction with
diethyl ether. The organic layer was washed with brine
and dried over anhydrous magnesium sulfate. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 4:1 (v/v)] to give 553 mg (56%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.33 (1H, ddd, J = 24.0, 12.4,
3.9 Hz), 1.44 (9H, s), 1.47-1.56 (1H, m), 1.78 (1H, dq, J
= 13.6, 3.3 Hz), 2.06-2.14 (1H, m), 3.06 (1H, t, J = 10.5
Hz), 3.61 (1H, br s), 3.71-3.77 (1H, m), 4.08-4.13 (1H,
m), 4.28 (1H, br s), 5.12 (1H, dt, J = 10.7, 1.3 Hz),
.24 (1H, dt, J = 17.4, 1.6 Hz), 5.85 (1H, dq, J = 17.4,
.3 Hz).
MS (ESI) m/z: 228 (M + H) .
[Step 2]
1,5-anhydro[(tert-butoxycarbonyl)amino]-2,3,4-
trideoxy-D-erythro-heptitol
The compound (230 mg, 1.01 mmol) obtained in Step 1
above was dissolved in a mixture of tert-butanol (5 ml),
ethyl acetate (1.5 ml), and water (6 ml),
methanesulfonamide (115 mg, 1.2 mmol) and AD-mix-a (1.7
g) were added and the resulting mixture was stirred at
room temperature for 16 hours. Sodium bisulfite (2 g)
was gradually added and the resulting mixture was further
stirred for 15 minutes. After extraction with ethyl
acetate, the organic layer was washed with brine and
dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the residue was
purified by silica gel column chromatography
[chloroform:methanol = 9:1 (v/v)] to give 206 mg (79%) of
the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.23-1.36 (1H, m), 1.44 (9H,
s), 1.51-1.82 (3H, m), 2.09-2.16 (1H, m), 2.22-2.29 (1H,
m), 2.61 and 2.78 (total 1H, each d, J = 5.0 and 3.7 Hz),
3.01 (1H, t, J = 10.3 Hz), 3.30-3.35 (1H, m), 3.51-3.56
(1H, m), 3.59-3.65 (1H, m), 3.69-3.75 (1H, m), 4.08-4.16
(1H, m), 4.27 (1H, br s).
MS (ESI) m/z: 284 (M + Na) .
[Step 3]
2-amino-1,5-anhydro-2,3,4-trideoxy-D-erythro-heptitol
hydrochloride
The compound (200 mg, 0.77 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 166
mg (100%) of the title compound as a colorless amorphous
solid.
MS (ESI) m/z: 162 (M + H) .
Reference Example 36
6-chloro[(5-chloropyridinyl)methylene]-1,3-dihydro-
2H-indolone
-Chloronicotinaldehyde (2.04 g, 14.4 mmol) was used
as a starting material and treated in the same way as in
Reference Example 4 to give 3.48 g (87%) of the title
compound as a yellow solid.
MS (APCI) m/z: 291 (M + H) .
Reference Example 37
O N O N
Step 1
O 工 程 1 O
O OH O N
Step 2 O
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(isopropylcarbamoyl)tetrahydro-2H-
pyranyl]carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and isopropylamine (0.21
ml, 2.45 mmol) were used as starting materials and
treated in the same way as in Step 2 of Reference Example
28 to give 363 mg (78%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.16 (6H, d, J = 6.4 Hz), 1.33
(1H, ddd, J = 24.7, 12.4, 3.9 Hz), 1.43-1.54 (10H, m),
2.09-2.16 (1H, m), 2.21-2.27 (1H, m), 3.03 (1H, t, J =
.5 Hz), 3.60 (1H, br s), 3.67 (1H, dd, J = 11.4, 2.7
Hz), 4.01-4.11 (1H, m), 4.12-4.17 (1H, m), 4.29 (1H, br
s), 6.34 (1H, d, J = 7.3 Hz).
MS (ESI) m/z: 309 (M + Na) .
[Step 2]
(2S,5R)amino-N-isopropyltetrahydro-2H-pyran
carboxamide hydrochloride
The compound (350 mg, 1.22 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 198
mg (73%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.04 (6H, d, J = 6.6 Hz),
1.42 (1H, ddd, J = 24.4, 13.0, 3.6 Hz), 1.58 (1H, ddd, J
= 24.4, 12.3, 3.8 Hz), 1.93-1.99 (1H, m), 2.06-2.11 (1H,
m), 3.04-3.12 (1H, m), 3.31-3.33 (1H, m), 3.69 (1H, dd, J
= 11.2, 2.4 Hz), 3.82-3.90 (1H, m), 4.07-4.12 (1H, m),
7.43 (1H, d, J = 8.1 Hz).
MS (ESI) m/z: 187 (M + H) .
Reference Example 38
O O N
Step 1
O 工 程 1 O
O OH O N
Step 1
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(cyclopropylcarbamoyl)tetrahydro-
2H-pyranyl]carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and cyclopropylamine (0.21
ml, 2.45 mmol) were used as starting materials and
treated in the same way as in Step 2 of Reference Example
28 to give 231 mg (50%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CDCl ) d : 0.49-0.54 (2H, m), 0.74-0.80
(2H, m), 1.27-1.38 (1H, m), 1.42-1.53 (10H, m), 2.08-2.14
(1H, m), 2.20-2.27 (1H, m), 2.68-2.74 (1H, m), 3.01 (1H,
t, J = 10.6 Hz), 3.57 (1H, br s), 3.68 (1H, dd, J = 11.5,
2.4 Hz), 4.09-4.14 (1H, m), 4.29 (1H, br s), 6.54 (1H, s).
MS (ESI) m/z: 307 (M + Na) .
[Step 2]
(2S,5R)amino-N-cyclopropyltetrahydro-2H-pyran
carboxamide hydrochloride
The compound (220 mg, 0.77 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 128
mg (75%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 0.43-0.47 (2H, m), 0.56-0.60
(2H, m), 1.39-1.50 (1H, m), 1.57 (1H, ddd, J = 23.6, 12.1,
3.4 Hz), 1.92-1.99 (1H, m), 2.03-2.11 (1H, m), 2.60-2.67
(1H, m), 3.02-3.12 (1H, m), 3.28-3.32 (1H, m), 3.69 (1H,
dd, J = 11.0, 2.3 Hz), 4.05 (1H, dq, J = 11.0, 2.3 Hz),
7.72 (1H, d, J = 4.6 Hz).
MS (ESI) m/z: 185 (M + H) .
Reference Example 39
Step 1 Step 2
工 程 1 工 程 2
S O S
[Step 1]
tert-Butyl {(3R,6S)[(methylsulfonyl)methyl]tetrahydro-
2H-pyranyl}carbamate
An N,N-dimethylformamide (5 ml) solution of the
compound (621 mg, 2.01 mmol) obtained in Step 1 of
Reference Example 24 and sodium methanethiolate (297 mg,
4.24 mmol) was stirred overnight at room temperature.
The reaction mixture was diluted with ethyl acetate,
washed with water, 1N hydrochloric acid, saturated sodium
bicarbonate solution, and brine in this order and then
dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure, the residue obtained
was dissolved in dichloromethane (20 ml), m-
chloroperbenzoic acid (25% hydrated, 1.9 g, 8.2 mmol) was
added and the resulting mixture was stirred for 1 hour.
The reaction mixture was diluted with ethyl acetate,
washed with water, saturated sodium bicarbonate solution,
and brine in this order and then dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced
pressure and the residue obtained was purified by silica
gel column chromatography [ethyl acetate:n-hexane = 1:1
(v/v)] and subsequently purified by NH-silica gel column
chromatography [ethyl acetate:n-hexane = 1:1 (v/v)] to
give 505 mg (86%) of the title compound as a colorless
solid.
H-NMR (400 MHz, CDCl ) d : 1.30-1.56 (11H, m), 1.76 (1H,
dq, J = 13.4, 3.1 Hz), 2.10-2.16 (1H, m), 2.92-2.99 (4H,
m), 3.05 (1H, t, J = 10.8 Hz), 3.23 (1H, dd, J = 15.1,
9.6 Hz), 3.57-3.64 (1H, m), 3.83-3.89 (1H, m), 4.07-4.12
(1H, m), 4.23-4.29 (1H, m).
MS (FAB) m/z: 294 (M + H) .
[Step 2]
(3R,6S)[(methylsulfonyl)methyl]tetrahydro-2H-pyran
amine hydrochloride
The compound (61 mg, 0.21 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a colorless solid.
Reference Example 40
O N O N
Step 1
O 工 程 1 O
O OH O N
Step 2 O
工 程 2
[Step 1]
tert-Butyl[(3R,6S)(methylcarbamoyl)tetrahydro-2H-
pyranyl]carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and aqueous methylamine
solution (40% w/w, 0.27 ml, 3.26 mmol) were used as
starting materials and treated in the same way as in Step
2 of Reference Example 28 to give 191 mg (45%) of the
title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.32-1.55 (11H, m), 2.08-2.16
(1H, m), 2.20-2.29 (1H, m), 2.82 (3H, d, J = 5.1 Hz),
3.04 (1H, t, J = 10.6 Hz), 3.57-3.64 (1H, m), 3.72 (1H,
dd, J = 11.5, 2.4 Hz), 4.13-4.19 (1H, m), 4.28 (1H, br s),
6.53 (1H, s).
MS (ESI) m/z: 259 (M + H) .
[Step 2]
(2S,5R)amino-N-methyltetrahydro-2H-pyrancarboxamide
hydrochloride
The compound (190 mg, 0.74 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 124
mg (86%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.36-1.47 (1H, m), 1.58 (1H,
ddd, J = 24.0, 12.1, 3.7 Hz), 1.96-2.02 (1H, m), 2.04-
2.10 (1H, m), 2.57 (3H, d, J = 4.6 Hz), 3.04-3.12 (1H, m),
3.35 (1H, t, J = 10.3 Hz), 3.72 (1H, dd, J = 11.2, 2.5
Hz), 4.05-4.09 (1H, m), 7.67 (1H, d, J = 4.6 Hz).
MS (ESI) m/z: 159 (M + H) .
Reference Example 41
O N O N
Step 1
O 工 程 1 O
O OH O N
Step 2
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-
pyranyl]carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and aqueous dimethylamine
solution (50% w/w, 0.29 ml, 3.26 mmol) were used as
starting materials and treated in the same way as in Step
2 of Reference Example 28 to give 328 mg (74%) of the
title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.41-1.42 (1H, m), 1.44 (9H,
s), 1.83-2.00 (2H, m), 2.16-2.22 (1H, m), 2.95 (3H, s),
3.07 (3H, s), 3.08-3.15 (1H, m), 3.66 (1H, br s), 4.04
(1H, dd, J = 10.0, 3.2 Hz), 4.11 (1H, dd, J = 10.7, 3.2
Hz), 4.40 (1H, br s).
MS (ESI) m/z: 273 (M + H) .
[Step 2]
(2S,5R)amino-N,N-dimethyltetrahydro-2H-pyran
carboxamide hydrochloride
The compound (320 mg, 1.17 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 289
mg (78%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.55-1.75 (3H, m), 2.07-2.13
(1H, m), 2.99 (3H, s), 3.07-3.13 (1H, m), 3.15 (3H, s),
3.38 (1H, t, J = 10.5 Hz), 3.97-4.01 (1H, m), 4.13 (1H,
dd, J = 8.9, 3.4 Hz).
MS (ESI) m/z: 173 (M + H) .
Reference Example 42
O N O N
Step 1
O 工 程 1 O
O OH
Step 2 O
工 程 2
[Step 1]
tert-Butyl {(3R,6S)[(2-
hydroxyethyl)carbamoyl]tetrahydro-2H-pyranyl}carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and 2-aminoethanol (0.15
ml, 2.45 mmol) were used as starting materials and
treated in the same way as in Step 2 of Reference Example
28 to give 313 mg (67%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.33-1.41 (1H, m), 1.44 (9H,
s), 1.48-1.57 (1H, m), 2.10-2.18 (1H, m), 2.21-2.28 (1H,
m), 2.78 (1H, br s), 3.05 (1H, t, J = 10.8 Hz), 3.38-3.51
(2H, m), 3.58-3.63 (1H, m), 3.70-3.77 (3H, m), 4.13-4.19
(1H, m), 4.33 (1H, br s), 6.97 (1H, br s).
MS (ESI) m/z: 289 (M + H) .
[Step 2]
(2S,5R)amino-N-(2-hydroxyethyl)tetrahydro-2H-pyran
carboxamide hydrochloride
The compound (310 mg, 1.07 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 310
mg (100%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.38-1.48 (1H, m), 1.54-1.64
(1H, m), 1.97-2.04 (1H, m), 2.06-2.12 (1H, m), 3.06-3.17
(2H, m), 3.34-3.47 (4H, m), 3.71-3.79 (1H, m), 4.07-4.13
(1H, m), 7.56 (1H, t, J = 5.7 Hz).
MS (ESI) m/z: 189 (M + H) .
Reference Example 43
Step 1
Step 2
工 程 1 O 工 程 2 O
OH OH
Cl H
Step 3 Step 4
工 程 3
工 程 4
Step 5 Step 6 H
工 程 5
O 工 程 6
O OH
Step 7
工 程 7
[Step 1]
2,6-anhydro-1,3,4-trideoxy-D-arabino-heptenitol
Sodium methoxide/methanol solution (28% w/w, 0.40 ml,
2.1 mmol) was added to a methanol (15 ml) solution of
,7-di-O-acetyl-2,6-anhydro-1,3,4-trideoxy-D-arabino-
heptenitol (Synlett, 1996, 185; and Tetrahedron:
Asymm., 2003, 14, 757) (1.56 g, 6.83 mmol) and the
resulting mixture was stirred at room temperature for 3
hours. DOWEX 50WX8-200 was added to the reaction mixture
to adjust its pH to 4 and then insoluble matter was
removed by filtration. The filtrate was concentrated
under reduced pressure to give the title compound.
[Step 2]
2,6-anhydroO-[tert-butyl(dimethyl)silyl]-1,3,4-
trideoxy-D-arabino-heptenitol
The compound (6.83 mmol) obtained in Step 1 above
was used as a starting material and treated in the same
way as in Step 1 of Reference Example 23 to give the
title compound.
[Step 3]
2,6-anhydroO-[tert-butyl(dimethyl)silyl]-1,3,4-
trideoxyO-(2,2,2-trichloroethanimidoyl)-D-arabino-
heptenitol
1,8-Diazabicyclo[5.4.0]undecene (1.00 ml, 6.83
mmol) was added to a dichloromethane (22 ml) solution of
the compound (6.83 mmol) obtained in Step 2 above and
trichloroacetonitrile (0.82 ml, 8.20 mmol) under ice
cooling and the resulting mixture was stirred at room
temperature for 1 hour. The solvent in the reaction
mixture was evaporated under reduced pressure and the
residue was dissolved in chloroform and added dropwise
into n-hexane:ethyl acetate [4:1 (v/v)] mixed solvent.
The resulting insoluble matter was removed by filtration
through celite and the solvent in the filtrate was
evaporated under reduced pressure. The residue obtained
was purified by silica gel column chromatography [n-
hexane:ethyl acetate = 99:1 fi 10:1 (v/v)] to give 2.1 g
(77%) of the title compound as a colorless oil.
H-NMR (400 MHz, CDCl ) d : 0.04 (6H, s), 0.87 (9H, s),
1.30 (3H, d, J = 6.4 Hz), 3.74-3.91 (3H, m), 4.36-4.46
(1H, m), 5.25-5.30 (1H, m), 5.86-5.93 (2H, m), 8.34 (1H,
[Step 4]
2,6-anhydroO-[tert-butyl(dimethyl)silyl]-1,3,4,5-
tetradeoxy[(trichloroacetyl)amino]-D-arabino-hept
enitol
Potassium carbonate (50 mg, 0.36 mmol) was added to
an o-dichlorobenzene (11 ml) solution of the compound
(2.13 g, 5.29 mmol) obtained in Step 3 above and the
resulting mixture was stirred under heating at 180 C for
4 hours. After cooling to room temperature, insoluble
matter was removed by filtration through celite and then
the solvent in the filtrate was evaporated under reduced
pressure to give the title compound.
[Step 5]
2,6-anhydro[(tert-butoxycarbonyl)amino]O-[tert-
butyl(dimethyl)silyl]-1,3,4,5-tetradeoxy-D-arabino-hept-
4-enitol
Potassium hydroxide (0.89 g) was added to a 2-
propanol (9 ml) solution of the compound (5.29 mmol)
obtained in Step 4 above and the resulting mixture was
stirred for 28 hours. Insoluble matter was removed by
filtration through celite, the solvent was evaporated
under reduced pressure and the residue obtained was
dissolved in dichloromethane (9 ml). Di-tert-butyl
dicarbonate (1.38 g, 6.35 mmol) was added under ice
cooling and the resulting mixture was stirred at room
temperature for 4 hours. Water was added, the resulting
mixture was subjected to extraction with chloroform and
the organic layer was washed with brine and then dried
over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the residue was
purified by silica gel column chromatography [n-
hexane:ethyl acetate = 30:1 fi 10:1 (v/v)] to give 1.3 g
(71%) of the title compound as a colorless oil.
H-NMR (400 MHz, CDCl ) d : 0.04 (3H, s), 0.04 (3H, s),
0.87 (9H, s), 1.15 (3H, d, J = 6.0 Hz), 1.42 (9H, s),
3.62 (1H, dd, J = 10.6, 5.50 Hz), 3.72 (1H, dd, J = 10.6,
6.4 Hz), 3.84-3.92 (1H, m), 3.96-4.04 (1H, m), 4.13-4.20
(1H, m), 4.59 (1H, d, J = 9.6 Hz), 5.83-5.89 (1H, m),
.92-6.01 (1H, m).
[Step 6]
2,6-anhydro[(tert-butoxycarbonyl)amino]-1,3,4,5-
tetradeoxy-D-arabino-heptitol
The compound (960 mg, 2.68 mmol) obtained in Step 5
above was dissolved in ethyl acetate (5 ml) and ethanol
(5 ml), platinum (IV) oxide (18 mg, 0.08 mmol) was added
and the resulting mixture was stirred for 19 hours under
a hydrogen atmosphere. The catalyst was removed by
filtration through celite, then the solvent in the
filtrate was evaporated under reduced pressure and the
residue was purified by silica gel column chromatography
[n-hexane:ethyl acetate = 9:1 fi 2:3 (v/v)] to give 524
mg (79%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.17 (3H, d, J = 6.9 Hz),
1.41-1.93 (14H, m), 3.45-3.83 (4H, m), 4.08-4.18 (1H, m),
4.54-4.66 (1H, m).
[Step 7]
3-amino-2,6-anhydro-1,3,4,5-tetradeoxy-D-arabino-heptitol
hydrochloride
The compound (524 mg, 2.14 mmol) obtained in Step 6
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 355
mg (92%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.24 (3H, d, J = 6.9 Hz),
1.44-1.55 (1H, m), 1.76-2.04 (3H, m), 3.27-3.34 (1H, m),
3.52 (1H, dd, J = 11.5, 4.6 Hz), 3.61-3.69 (1H, m), 3.75-
3.84 (1H, m), 4.11-4.19 (1H, m).
Reference Example 44
O N O N
Step 1
O 工 程 1 O
O OH O N
Step 2
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(azetidinylcarbonyl)tetrahydro-
2H-pyranyl]carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and azetidine
hydrochloride (305 mg, 3.26 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Reference Example 28 to give 244 mg (53%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.29-1.39 (1H, m), 1.44 (9H,
s), 1.68-1.78 (1H, m), 1.98-2.05 (1H, m), 2.08-2.16 (1H,
m), 2.23-2.30 (2H, m), 3.02 (1H, t, J = 10.3 Hz), 3.56-
3.66 (1H, m), 3.86 (1H, dd, J = 11.2, 2.5 Hz), 4.04 (2H,
t, J = 7.8 Hz), 4.10 (1H, dq, J = 10.6, 2.1 Hz), 4.31 (2H,
t, J = 7.8 Hz), 4.33 (1H, br s).
MS (ESI) m/z: 285 (M + H) .
[Step 2]
(3R,6S)(azetidinylcarbonyl)tetrahydro-2H-pyran
amine hydrochloride
The compound obtained in Step 1 above was used as a
starting material and treated in the same way as in Step
1 of Reference Example 2 to give 210 mg (100%) of the
title compound as a colorless amorphous solid.
H-NMR (400 MHz, DMSO-d ) d : 1.42-1.51 (1H, m), 1.55-1.61
(1H, m), 1.78-1.85 (1H, m), 1.95-2.03 (1H, m), 2.14-2.22
(2H, m), 3.07-3.11 (1H, m), 3.59 (1H, t, J = 6.7 Hz),
3.84 (2H, t, J = 7.6 Hz), 3.95-4.01 (1H, m), 4.04-4.10
(1H, m), 4.20 (2H, t, J = 7.8 Hz).
MS (ESI) m/z: 185 (M + H) .
Reference Example 45
O N O N
Step 1
工 程 1
O OH O N
2 OH
Step 2
工 程 2
[Step 1]
tert-Butyl {(3R,6S)[(3-hydroxyazetidin
yl)carbonyl]tetrahydro-2H-pyranyl}carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and 3-hydroxyazetidine
hydrochloride (267 mg, 2.45 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Reference Example 28 to give 261 mg (53%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.33-1.42 (1H, m), 1.44 (9H,
s), 1.64-1.76 (1H, m), 2.01-2.07 (1H, m), 2.08-2.15 (1H,
m), 2.37 (1H, d, J = 5.6 Hz), 3.01 (1H, td, J = 10.5, 2.8
Hz), 3.60 (1H, br s), 3.82-3.91 (2H, m), 4.06-4.17 (2H,
m), 4.23-4.30 (1H, m), 4.35 (1H, br s), 4.51-4.57 (1H, m),
4.60-4.68 (1H, m).
MS (ESI) m/z: 301 (M + H) .
[Step 2]
1-{[(2S,5R)aminotetrahydro-2H-pyran
yl]carbonyl}azetidinol hydrochloride
The compound (310 mg, 1.03 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 249
mg (100%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.53-1.61 (2H, m), 1.78-1.83
(1H, m), 2.04-2.07 (1H, m), 3.05-3.13 (1H, m), 3.30 (1H,
dd, J = 10.9, 6.0 Hz), 3.57 (1H, dd, J = 11.2, 3.7 Hz),
3.85-4.07 (4H, m), 4.34-4.46 (2H, m).
MS (ESI) m/z: 201 (M + H) .
Reference Example 46
(3E/Z)chloro(3-chlorofluorobenzylidene)-1,3-
dihydro-2H-pyrrolo[3,2-c]pyridinone
6-Chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyridinone
(3.00 g, 17.8 mmol) was used as a starting material and
treated in the same way as in Reference Example 1 to give
3.94 g (72%) of the title compound as a yellow solid.
H-NMR (DMSO-d ) d : 6.98 (1H, s), 7.41 (1H, t, J = 7.9
Hz), 7.70 (1H, s), 7.78 (2H, q, J = 7.0 Hz), 8.09 (1H, s),
11.38 (1H, br s).
MS (ESI) m/z: 309 (M + H) .
Reference Example 47
O N O N
Step 1
O 工 程 1 O
O OH
O O O
Step 2
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(tetrahydro-2H-pyran
ylcarbamoyl)tetrahydro-2H-pyranyl]carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and tetrahydropyran
ylamine hydrochloride (270 mg, 1.96 mmol) were used as
starting materials and treated in the same way as in Step
2 of Reference Example 28 to give 355 mg (66%) of the
title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.35 (1H, ddd, J = 24.6, 12.3,
3.8 Hz), 1.44 (9H, s), 1.45-1.56 (3H, m), 1.84-1.92 (2H,
m), 2.10-2.16 (1H, m), 2.22-2.27 (1H, m), 3.04 (1H, t, J
= 10.8 Hz), 3.48 (2H, td, J = 11.7, 2.1 Hz), 3.59-3.63
(1H, m), 3.70 (1H, dd, J = 11.4, 2.3 Hz), 3.92-4.02 (3H,
m), 4.13-4.19 (1H, m), 4.30-4.32 (1H, m), 6.45 (1H, d, J
= 7.8 Hz).
MS (ESI) m/z: 351 (M + H) .
[Step 2]
(2S,5R)amino-N-(tetrahydro-2H-pyranyl)tetrahydro-
2H-pyrancarboxamide hydrochloride
The compound (350 mg, 1.07 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 236
mg (83%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.40-1.64 (6H, m), 1.93-1.99
(1H, m), 2.06-2.13 (1H, m), 3.04-3.12 (1H, m), 3.30 (2H,
td, J = 11.7, 2.3 Hz), 3.37 (1H, t, J = 9.4 Hz), 3.72 (1H,
dd, J = 11.2, 2.5 Hz), 3.74-3.82 (3H, m), 4.11 (1H, dq, J
= 10.5, 2.1 Hz), 7.63 (1H, d, J = 7.8 Hz).
MS (ESI) m/z: 229 (M + H) .
Reference Example 48
O O N
Step 1
O O O
工 程 1
O OH O N
Step 2
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(morpholinylcarbonyl)tetrahydro-
2H-pyranyl]carbamate
The same starting material (400 mg, 1.63 mmol) as in
Step 1 of Reference Example 18 and morpholine (0.17 ml,
1.96 mmol) were used as starting materials and treated in
the same way as in Step 2 of Reference Example 28 to give
344 mg (67%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.37-1.43 (1H, m), 1.44 (9H,
s), 1.87-1.99 (2H, m), 2.15-2.22 (1H, m), 3.11 (1H, t, J
= 10.1 Hz), 3.50-3.74 (9H, m), 4.01 (1H, dd, J = 8.5, 3.9
Hz), 4.06-4.12 (1H, m), 4.41 (1H, s).
MS (ESI) m/z: 315 (M + H) .
[Step 2]
(3R,6S)(morpholinylcarbonyl)tetrahydro-2H-pyran
amine hydrochloride
The compound (340 mg, 1.08 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 283
mg (100%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.58-1.78 (3H, m), 2.08-2.13
(1H, m), 3.06-3.13 (1H, m), 3.41-3.58 (9H, m), 3.99 (1H,
dd, J = 10.8, 2.5 Hz), 4.15 (1H, dd, J = 9.6, 3.2 Hz).
MS (ESI) m/z: 215 (M + H) .
Reference Example 49
Step 2
Step 1
O 工 程 2
工 程 1
O N Step 3
工 程 3
[Step 1]
tert-Butyl [(3R,6S)(cyanomethyl)tetrahydro-2H-pyran
yl]carbamate
Potassium cyanide (741 mg, 11.4 mmol) was added to
an N,N-dimethylformamide (10 ml) solution of the compound
(678 mg, 2.19 mmol) obtained in Step 1 of Reference
Example 24 and the resulting mixture was stirred
overnight at 100 C. The reaction mixture was diluted
with ethyl acetate, washed with brine and then dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography [ethyl
acetate:chloroform = 1:4 (v/v)] to give 392 mg (74%) of
the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.28-1.57 (11H, m), 1.87 (1H,
dq, J = 13.5, 3.1 Hz), 2.13-2.16 (1H, m), 2.48-2.58 (2H,
m), 3.04 (1H, t, J = 10.9 Hz), 3.50-3.56 (1H, m), 3.60-
3.65 (1H, m), 4.09-4.12 (1H, m), 4.23-4.28 (1H, m).
MS (FAB) m/z: 241 (M + H) .
[Step 2]
tert-Butyl [(3R,6S)(2-aminooxoethyl)tetrahydro-2H-
pyranyl]carbamate
The compound (60 mg, 0.25 mmol) obtained in Step 1
above was added to a mixture of sodium hydroxide (94 mg,
2.36 mmol), ethanol (5 ml), and 30% aqueous hydrogen
peroxide solution (5 ml) and the resulting mixture was
stirred overnight at room temperature. The reaction
mixture was diluted with ethyl acetate, washed with brine
and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the
residue obtained was purified by silica gel column
chromatography [methanol:chloroform = 5:95 (v/v)] to give
9 mg (13%) of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.28-1.54 (11H, m), 1.73-1.76
(1H, m), 2.08-2.10 (1H, m), 2.35-2.44 (2H, m), 3.04 (1H,
t, J = 10.9 Hz), 3.59-3.64 (2H, m), 4.09-4.12 (1H, m),
4.32 (1H, d, J = 8.0 Hz), 5.46 (1H, br s), 6.30 (1H, br
MS (FAB) m/z: 259 (M + H) .
[Step 3]
2-[(2S,5R)aminotetrahydro-2H-pyranyl]acetamide
hydrochloride
The compound (39 mg, 0.15 mmol) obtained in Step 2
above was used and treated in the same way as in Step 1
of Reference Example 2 to give the title compound as a
colorless solid.
Reference Example 50
Step 1
工 程 1
O O O N NH
Step 3
Step 2
O N N
工 程 2
工 程 3
[Step 1]
Benzyl [trans(hydrazinocarbonyl)cyclobutyl]carbamate
Hydrazine monohydrate (10 ml) was added to a
methanol (50 ml) solution of methyl trans
{[(benzyloxy)carbonyl]amino}cyclobutanecarboxylate
(Neurochemical Research, 1980, 5, 393-400) (995 mg, 3.78
mmol) at room temperature and the resulting mixture was
stirred for 24 hours. The precipitated solid was
collected by filtration, washed with water and then dried
to give 760 mg (76%) of the title compound as a colorless
solid.
H-NMR (400 MHz, CDCl ) d : 2.21-2.25 (2H, m), 2.61-2.64
(2H, m), 2.81-2.87 (1H, m), 3.87 (2H, br s), 4.36 (1H, q,
J = 7.5 Hz), 4.83 (1H, br s), 5.09 (2H, s), 6.54 (1H, br
s), 7.30-7.35 (5H, m).
MS (ESI) m/z: 265 (M + H) .
[Step 2]
Benzyl [trans(1,3,4-oxadiazol
yl)cyclobutyl]carbamate
The compound (760 mg, 2.89 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 3 to give 1.00
g (99%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 2.52-2.58 (2H, m), 2.76-2.79
(2H, m), 3.67-3.72 (1H, m), 4.48-4.52 (1H, m), 5.10 (2H,
s), 5.15 (1H, br s), 7.30-7.41 (5H, m), 8.37 (1H, s).
MS (ESI) m/z: 274 (M + H) .
[Step 3]
trans(1,3,4-oxadiazolyl)cyclobutanamine
The compound (1.00 g, 3.66 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 391
mg (77%) of the title compound as a colorless oil.
H-NMR (400 MHz, CDCl ) d : 2.21-2.29 (2H, m), 2.67-2.74
(2H, m), 3.64-3.71 (1H, m), 3.83-3.91 (1H, m), 8.35 (1H,
MS (ESI) m/z: 140 (M + H) .
Reference Example 51
O N 2
Step 2
Step 1
工 程 1 工 程 2
[Step 1]
Benzyl (transcarbamoylcyclobutyl)carbamate
trans
{[(Benzyloxy)carbonyl]amino}cyclobutanecarboxylic acid
(110 mg, 0.44 mmol) was used as a starting material and
treated in the same way as in Step 1 of Reference Example
16 to give 47 mg (43%) of the title compound as a
colorless solid.
H-NMR (400 MHz, CDCl ) d : 2.10-2.34 (2H, m), 2.59-2.71
(2H, m), 2.90-3.01 (1H, m), 4.29-4.41 (1H, m), 4.95 (1H,
br s), 5.09 (2H, s), 5.30 (2H, br s), 7.29-7.40 (5H, m).
MS (ESI) m/z: 249 (M + H) .
[Step 2]
transaminocyclobutanecarboxamide
The compound (21 mg, 0.19 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 21
mg (97%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.96-2.09 (2H, m), 2.39-2.52
(2H, m), 2.94-3.04 (1H, m), 3.54-3.69 (1H, m).
Reference Example 52
O N 2
Step 2
Step 1
工 程 2
工 程 1
[Step 1]
Benzyl [trans(dimethylcarbamoyl)cyclobutyl]carbamate
The same starting material as in Step 1 of Reference
Example 51 and aqueous dimethylamine solution (50% w/w,
0.16 ml, 1.77 mmol) were used as starting materials and
treated in the same way as in Step 2 of Reference Example
28 to give 48 mg (39%) of the title compound as a
colorless solid.
MS (ESI) m/z: 277 (M + H) .
[Step 2]
transamino-N,N-dimethylcyclobutanecarboxamide
The compound (48 mg, 0.17 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 26
mg (100%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 2.07-2.17 (2H, m), 2.45-2.56
(2H, m), 2.93 (3H, s), 2.95 (3H, s), 3.33-3.42 (1H, m),
3.51-3.62 (1H, m).
MS (ESI) m/z: 143 (M + H) .
Reference Example 53
Step 1
工 程 1
O OH
Step 2
工 程 2
[Step 1]
Benzyl [(3R,6S)(diethylcarbamoyl)tetrahydro-2H-pyran-
3-yl]carbamate
The compound (400 mg, 1.43 mmol) obtained in Step 3
of Reference Example 18 and diethylamine (0.22 ml, 2.15
mmol) were used as starting materials and treated in the
same way as in Step 2 of Reference Example 28 to give 514
mg (100%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, CDCl ) d : 1.12 (3H, t, J = 7.1 Hz), 1.18
(3H, t, J = 7.1 Hz), 1.41-1.48 (1H, m), 1.80-1.87 (1H, m),
1.93-2.03 (1H, m), 2.18-2.23 (1H, m), 3.13-3.20 (1H, m),
3.28-3.47 (4H, m), 3.71-3.76 (1H, m), 4.02 (1H, dd, J =
8.9, 2.6 Hz), 4.12 (1H, dd, J = 11.2, 3.2 Hz), 4.69-4.73
(1H, m), 5.06-5.12 (2H, m), 7.30-7.39 (5H, m).
MS (ESI) m/z: 335 (M + H) .
[Step 2]
(2S,5R)amino-N,N-diethyltetrahydro-2H-pyran
carboxamide
The compound (480 mg, 1.43 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 282
mg (98%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, DMSO-d ) d : 0.98 (3H, t, J = 6.9 Hz),
1.10 (3H, t, J = 6.9 Hz), 1.50 (1H, ddd, J = 23.5, 11.8,
4.7 Hz), 1.63-1.75 (2H, m), 2.01-2.08 (1H, m), 2.92-3.00
(1H, m), 3.12-3.20 (1H, m), 3.23-3.39 (4H, m), 3.92 (1H,
dq, J = 10.8, 2.1 Hz), 4.02 (1H, dd, J = 9.6, 3.7 Hz).
MS (ESI) m/z: 201 (M + H) .
Reference Example 54
O N Step 1
工 程 1
Step 2
工 程 2
[Step 1]
Benzyl [trans(ethylcarbamoyl)cyclobutyl]carbamate
The same starting material as in Step 1 of Reference
Example 51 and ethylamine hydrochloride (79 mg, 0.96
mmol) were used as starting materials and treated in the
same way as in Step 2 of Reference Example 28 to give 85
mg (64%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.13 (3H, t, J = 7.3 Hz),
2.04-2.30 (2H, m), 2.57-2.67 (2H, m), 2.77-2.91 (1H, m),
3.25-3.35 (2H, m), 4.29-4.41 (1H, m), 4.91-5.15 (3H, m),
.37 (1H, br s), 7.29-7.39 (5H, m).
MS (ESI) m/z: 277 (M + H) .
[Step 2]
transamino-N-ethylcyclobutanecarboxamide
The compound (84 mg, 0.30 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 43
mg (100%) of the title compound as a colorless oil.
H-NMR (400 MHz, CD OD) d : 1.10 (3H, t, J = 7.1 Hz),
1.95-2.06 (2H, m), 2.38-2.49 (2H, m), 2.87-2.99 (1H, m),
3.14-3.23 (2H, m), 3.57-3.68 (1H, m).
MS (ESI) m/z: 143 (M + H) .
Reference Example 55
Step 1 O N
工 程 1
Step 2
工 程 2
[Step 1]
Benzyl [trans(hydroxymethyl)cyclobutyl]carbamate
Isobutyl chloroformate (0.14 ml, 1.04 mmol) and
triethylamine (0.15 ml, 1.04 mmol) were added in this
order to a tetrahydrofuran (4 ml) solution of the same
starting material (260 mg, 1.04 mmol) as in Step 1 of
Reference Example 51 under ice cooling and the resulting
mixture was stirred at the same temperature for 10
minutes. Insoluble matter was removed by filtration
through celite, methanol (1 ml) was added to the filtrate
and sodium borohydride (79 mg, 2.09 mmol) was added under
ice cooling. After stirring for 30 minutes, 1N
hydrochloric acid was added. The solvent was evaporated
under reduced pressure, the residue was subjected to
extraction with ethyl acetate and the organic layer was
washed with brine and then dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel
column chromatography [n-hexane:ethyl acetate = 3:1 fi
1:1 (v/v)] to give 111 mg (45%) of the title compound as
a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.36 (1H, br s), 1.95-2.08 (2H,
m), 2.15-2.27 (2H, m), 2.32-2.47 (1H, m), 3.68 (2H, d, J
= 7.3 Hz), 4.17-4.33 (1H, m), 4.93 (1H, br s), 5.08 (2H,
s), 7.29-7.39 (5H, m).
MS (ESI) m/z: 236 (M + H) .
[Step 2]
(transaminocyclobutyl)methanol
The compound (34 mg, 0.14 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 11
mg (75%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.83-1.94 (2H, m), 2.04-2.15
(2H, m), 2.26-2.39 (1H, m), 3.42-3.52 (1H, m), 3.55 (2H,
d, J = 7.3 Hz).
Reference Example 56
Step 1 O N
工 程 1
Step 2
工 程 2
[Step 1]
Benzyl [trans(tetrahydro-2H-pyran
ylcarbamoyl)cyclobutyl]carbamate
The same starting material as in Step 1 of Reference
Example 51 and 4-aminotetrahydropyran hydrochloride (99
mg, 0.72 mmol) were used as starting materials and
treated in the same way as in Step 2 of Reference Example
28 to give 104 mg (65%) of the title compound as a
colorless solid.
H-NMR (DMSO-d ) d : 1.27-1.41 (2H, m), 1.61-1.71 (2H, m),
2.01-2.13 (2H, m), 2.22-2.31 (2H, m), 2.72-2.82 (1H, m),
3.28-3.35 (2H, m), 3.67-3.86 (3H, m), 4.09-4.22 (1H, m),
4.99 (2H, s), 7.28-7.40 (5H, m), 7.58 (1H, d, J = 8.3 Hz),
7.70 (1H, d, J = 7.8 Hz).
MS (ESI) m/z: 333 (M + H) .
[Step 2]
transamino-N-(tetrahydro-2H-pyran
yl)cyclobutanecarboxamide
The compound (78 mg, 0.23 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 47
mg (100%) of the title compound as a colorless solid.
H-NMR (400 MHz, CD OD) d : 1.41-1.56 (2H, m), 1.74-1.84
(2H, m), 1.95-2.06 (2H, m), 2.38-2.48 (2H, m), 2.88-2.98
(1H, m), 3.41-3.51 (2H, m), 3.58-3.68 (1H, m), 3.80-3.97
(3H, m).
MS (ESI) m/z: 199 (M + H) .
Reference Example 57
O O O
Step 1
Step 2
+ 工 程 1
工 程 2
Cl F
[Step 1]
Ethyl 6"-chloro-4'-(3-chlorofluorophenyl)-3,3-
bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxylate (racemate)
Glycine ethyl ester hydrochloride (6.98 g, 50 mmol)
and the compound (6.70 g, 50.0 mmol) obtained in Step 2
of Reference Example 21 were dissolved in tetrahydrofuran
(210 ml) and N,N-dimethylformamide (210 ml),
triethylamine (7.6 ml, 54.5 mmol) and 4A molecular sieves
(powder) (18.8 g) were added and the resulting mixture
was stirred at 70 C for 1 hour. (3E/Z)chloro(3-
chlorofluorobenzylidene)-1,3-dihydro-2H-indolone
(WO2006/091646) (14.0 g, 45.4 mmol) was added to the
reaction mixture and the resulting mixture was stirred at
70 C for 14 hours. Glycine ethyl ester hydrochloride
(1.58 g, 11.4 mmol) and the compound (1.52 g, 11.4 mmol)
obtained in Step 2 of Reference Example 21 were further
added to the reaction mixture and the resulting mixture
was further stirred at 70 C for 18 hours. After cooling,
insoluble matter was removed by filtration through celite
and the filtrate was concentrated under reduced pressure.
Saturated sodium bicarbonate solution was added to the
residue, followed by extraction with ethyl acetate. The
organic layer was washed with water and brine and then
dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the residue
obtained was purified by silica gel column chromatography
[n-hexane:ethyl acetate = 9:1 fi 1:1 (v/v)] to give 5.31
g (22%) of the title compound.
[Step 2]
Ethyl (3'R,4'S,5'R)-6"-chloro-4'-(3-chloro
fluorophenyl)-3,3-bis(fluoromethyl)-2"-oxo-1",2"-
dihydrodispiro[cyclobutane-1,2'-pyrrolidine-3',3"-
indole]-5'-carboxylate
The racemate (5.31 g, 10.1 mmol) obtained in Step 1
above was fractionated and purified by chiral column
liquid chromatography [fractionation conditions:
CHIRALPAK IC, n-hexane:tetrahydrofuran = 4:1 (v/v)] to
give 2.33 g (44%) of the title compound.
H-NMR (400 MHz, CDCl ) d : 1.19 (3H, t, J = 7.1 Hz), 1.70
(1H, d, J = 13.7 Hz), 1.83-1.89 (1H, m), 2.20 (1H, d, J =
12.8 Hz), 2.42 (1H, dd, J = 12.8, 2.7 Hz), 3.66-3.76 (1H,
m), 3.77-3.96 (2H, m), 4.09-4.22 (2H, m), 4.45 (1H, d, J
= 9.5 Hz), 4.48 (1H, d, J = 9.5 Hz), 4.54-4.78 (2H, m),
6.81 (1H, d, J = 1.8 Hz), 6.96 (1H, td, J = 8.0, 1.2 Hz),
7.13 (1H, dd, J = 8.0, 2.1 Hz), 7.16-7.21 (1H, m), 7.36
(1H, br s), 7.40 (1H, dd, J = 8.1, 2.0 Hz), 7.44-7.48 (1H,
Reference Example 58
Step 1
工 程 1
O OH
Step 2
工 程 2
[Step 1]
Benzyl {(3R,6S)[ethyl(methyl)carbamoyl]tetrahydro-2H-
pyranyl}carbamate
The compound (400 mg, 1.43 mmol) obtained in Step 3
of Reference Example 18 and N-methylethanamine (0.19 ml,
2.15 mmol) were used as starting materials and treated in
the same way as in Step 2 of Reference Example 28 to give
466 mg (100%) of the title compound as a colorless
amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.11 and 1.18 (total 3H, each
t, J = 7.1 Hz), 1.39-1.50 (1H, m), 1.82-1.90 (1H, m),
1.92-2.01 (1H, m), 2.16-2.25 (1H, m), 2.91 and 3.03
(total 3H, each s), 3.17 (1H, t, J = 10.3 Hz), 3.33-3.49
(2H, m), 3.71-3.78 (1H, m), 4.01-4.07 (1H, m), 4.10-4.15
(1H, m), 4.68 (1H, d, J = 6.9 Hz), 5.06-5.13 (2H, m),
7.31-7.38 (5H, m).
MS (ESI) m/z: 321 (M + H) .
[Step 2]
(2S,5R)amino-N-ethyl-N-methyltetrahydro-2H-pyran
carboxamide
The compound (450 mg, 1.40 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 240
mg (92%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.00-1.12 (3H, m), 1.49-1.55
(1H, m), 1.68-1.75 (2H, m), 2.04-2.11 (1H, m), 2.76-2.83
(1H, m), 2.91-3.00 (1H, m), 3.19 (3H, s), 3.27 (1H, t, J
= 10.3 Hz), 3.31-3.38 (1H, m), 3.94 (1H, dd, J = 11.0,
4.6 Hz), 4.06 (1H, t, J = 6.4 Hz).
MS (ESI) m/z: 187 (M + H) .
Reference Example 59
Step 1
工 程 1
O OH
Step 2
工 程 2 H
[Step 1]
Benzyl {(3R,6S)[(2-fluoroethyl)carbamoyl]tetrahydro-
2H-pyranyl}carbamate
The compound (400 mg, 1.43 mmol) obtained in Step 3
of Reference Example 18 and 2-fluoroethanamine
hydrochloride (214 mg, 2.15 mmol) were used as starting
materials and treated in the same way as in Step 2 of
Reference Example 28 to give 310 mg (96%) of the title
compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.32-1.45 (1H, m), 1.50-1.59
(1H, m), 2.13-2.19 (1H, m), 2.26 (1H, dq, J = 13.7, 3.2
Hz), 3.08 (1H, t, J = 10.8 Hz), 3.48-3.78 (4H, m), 4.18-
4.23 (1H, m), 4.42-4.57 (3H, m), 5.06-5.14 (2H, m), 6.89
(1H, br s), 7.31-7.39 (5H, m).
MS (ESI) m/z: 325 (M + H) .
[Step 2]
(2S,5R)amino-N-(2-fluoroethyl)tetrahydro-2H-pyran
carboxamide
The compound (300 mg, 0.92 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 140
mg (80%) of the title compound as a colorless solid.
H-NMR (400 MHz, DMSO-d ) d : 1.13-1.36 (2H, m), 1.86-1.93
(2H, m), 2.53-2.61 (1H, m), 2.93 (1H, t, J = 10.5 Hz),
3.30-3.44 (2H, m), 3.61 (1H, dd, J = 11.2, 2.5 Hz), 3.84
(1H, dq, J = 11.0, 2.1 Hz), 4.33-4.80 (2H, m), 7.74 (1H,
br s).
MS (ESI) m/z: 191 (M + H) .
Reference Example 60
Step 1
工 程 1
O OH
Step 2
工 程 2
[Step 1]
Benzyl {(3R,6S)[(2-
methoxyethyl)(methyl)carbamoyl]tetrahydro-2H-pyran
yl}carbamate
The compound (400 mg, 1.43 mmol) obtained in Step 3
of Reference Example 18 and (2-methoxyethyl)methylamine
(191 mg, 2.15 mmol) were used as starting materials and
treated in the same way as in Step 2 of Reference Example
28 to give 442 mg (88%) of the title compound as a
colorless amorphous solid.
H-NMR (400 MHz, CDCl ) d : 1.41-1.46 (1H, m), 1.82-1.99
(2H, m), 2.17-2.23 (1H, m), 2.96 and 3.12 (total 3H, each
s), 3.15-3.20 (1H, m), 3.33 and 3.33 (total 3H, each s),
3.48-3.56 (3H, m), 3.70-3.78 (2H, m), 4.04-4.17 (2H, m),
4.67 (1H, br s), 5.05-5.14 (2H, m), 7.30-7.39 (5H, m).
MS (ESI) m/z: 351 (M + H) .
[Step 2]
(2S,5R)amino-N-(2-methoxyethyl)-N-methyltetrahydro-2H-
pyrancarboxamide
The compound (440 mg, 1.26 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 264
mg (97%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.53-1.73 (3H, m), 2.06-2.12
(1H, m), 2.80 and 3.02 (total 3H, each s), 3.05-3.13 (1H,
m), 3.21 and 3.25 (total 3H, each s), 3.35-3.41 (3H, m),
3.42-3.67 (2H, m), 3.95-4.01 (1H, m), 4.11-4.17 (1H, m),
8.10 (2H, br s).
MS (ESI) m/z: 217 (M + H) .
Reference Example 61
Step 1
工 程 1
O OH
Step 2
工 程 2
[Step 1]
Benzyl {(3R,6S)[(2-methoxyethyl)carbamoyl]tetrahydro-
2H-pyranyl}carbamate
The compound (600 mg, 2.15 mmol) obtained in Step 3
of Reference Example 18 and 2-methoxyethylamine (0.28 ml,
3.23 mmol) were used as starting materials and treated in
the same way as in Step 2 of Reference Example 28 to give
359 mg (50%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.33-1.42 (1H, m), 1.50-1.57
(1H, m), 2.12-2.17 (1H, m), 2.25 (1H, dq, J = 13.6, 3.2
Hz), 3.07 (1H, t, J = 10.6 Hz), 3.37 (3H, s), 3.41-3.50
(4H, m), 3.68-3.72 (1H, m), 3.74 (1H, dd, J = 11.5, 2.4
Hz), 4.17-4.22 (1H, m), 4.52 (1H, d, J = 6.6 Hz), 5.06-
.14 (2H, m), 6.84 (1H, br s), 7.31-7.39 (5H, m).
MS (ESI) m/z: 337 (M + H) .
[Step 2]
(2S,5R)amino-N-(2-methoxyethyl)tetrahydro-2H-pyran
carboxamide
The compound (350 mg, 1.04 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 220
mg (100%) of the title compound as a colorless oil.
H-NMR (400 MHz, DMSO-d ) d : 1.12-1.22 (1H, m), 1.24-1.34
(1H, m), 1.85-1.92 (2H, m), 2.53-2.60 (1H, m), 2.91 (1H,
t, J = 10.5 Hz), 3.16-3.27 (5H, m), 3.32 (2H, t, J = 6.0
Hz), 3.58 (1H, dd, J = 11.4, 2.3 Hz), 3.83 (1H, ddd, J =
11.0, 4.2, 1.8 Hz), 7.46 (1H, s).
MS (ESI) m/z: 203 (M + H) .
Reference Example 62
Step 1
工 程 1
Step 2 Step 3
工 程 2 工 程 3
[Step 1]
Benzyl [trans({2-[(benzyloxy)acetyl]hydrazino}-
carbonyl)cyclohexyl]carbamate
The compound (507 mg, 1.74 mmol) obtained in Step 1
of Reference Example 3 and benzyloxyacetic acid (0.28 ml,
1.92 mmol) were used as starting materials and treated in
the same way as in Step 2 of Reference Example 28 to give
695 mg (91%) of the title compound as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.08-1.21 (2H, m), 1.61-1.72
(2H, m), 1.90-2.02 (2H, m), 2.06-2.21 (3H, m), 3.39-3.63
(1H, m), 4.10 (2H, s), 4.50-4.70 (3H, m), 5.08 (2H, s),
7.29-7.42 (10H, m), 7.94-8.03 (1H, m), 8.80-8.88 (1H, m).
[Step 2]
Benzyl (trans{5-[(benzyloxy)methyl]-1,3,4-oxadiazol
yl}cyclohexyl)carbamate
Hexachloroethane (205 mg, 0.87 mmol), triethylamine
(0.29 ml, 2.08 mmol), and the compound (152 mg, 0.35
mmol) obtained in Step 1 above were added to a
dichloromethane (9 ml) solution of triphenylphosphine
(273 mg, 1.04 mmol) under ice cooling and the resulting
mixture was stirred at room temperature for 24 hours.
The reaction mixture was diluted with
dichloromethane:methanol [10:1 (v/v)], washed with 10%
aqueous citric acid solution, and dried over anhydrous
sodium sulfate. The solvent was concentrated under
reduced pressure and the residue was purified by silica
gel column chromatography [n-hexane:ethyl acetate = 2:1
fi 1:1 (v/v)] to give 125 mg (86%) of the title compound
as a colorless solid.
H-NMR (500 MHz, CDCl ) d : 1.20-1.33 (2H, m), 1.64-1.82
(2H, m), 2.11-2.23 (4H, m), 2.78-2.88 (1H, m), 3.50-3.64
(1H, m), 4.62 (2H, s), 4.67 (2H, s), 4.71-4.79 (1H, m),
.09 (2H, s), 7.28-7.39 (10H, m).
MS (ESI) m/z: 422 (M + H) .
[Step 3]
[5-(transaminocyclohexyl)-1,3,4-oxadiazol
yl]methanol
The compound (125 mg, 0.30 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 52
mg (89%) of the title compound as a colorless solid.
H-NMR (500 MHz, CD OD) d : 1.22-1.35 (2H, m), 1.58-1.69
(2H, m), 1.97-2.04 (2H, m), 2.11-2.22 (2H, m), 2.64-2.72
(1H, m), 2.85-2.95 (1H, m), 4.71 (2H, s).
Reference Example 63
Step 1
工 程 1
H H N
Step 3
Step 2
工 程 3
工 程 2
[Step 1]
Benzyl [trans({2-[(2R)(benzyloxy)propanoyl]-
hydrazino}carbonyl)cyclohexyl]carbamate
The compound (504 mg, 1.73 mmol) obtained in Step 1
of Reference Example 3 and (R)-(+)(benzyloxy)propionic
acid (386 mg, 2.08 mmol) were used as starting materials
and treated in the same way as in Step 2 of Reference
Example 28 to give 687 mg (88%) of the title compound as
a colorless solid.
H-NMR (500 MHz, DMSO-d ) d : 1.28-1.39 (2H, m), 1.44 (3H,
d, J = 6.4 Hz), 1.50-1.64 (2H, m), 1.87-1.96 (2H, m),
1.96-2.06 (2H, m), 2.21-2.32 (1H, m), 3.33-3.46 (1H, m),
4.12 (1H, q, J = 6.4 Hz), 4.57 (1H, d, J = 12.0 Hz), 4.75
(1H, d, J = 12.0 Hz), 5.15 (2H, s), 7.37 (1H, d, J = 7.5
Hz), 7.41-7.57 (10H, m), 9.86-9.90 (1H, m), 9.92-9.97 (1H,
[Step 2]
Benzyl (trans{5-[(1R)(benzyloxy)ethyl]-1,3,4-
oxadiazolyl}cyclohexyl)carbamate
The compound (687 mg, 1.52 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 62 to give 606
mg (92%) of the title compound as a colorless oil.
H-NMR (500 MHz, CDCl ) d : 1.22-1.33 (2H, m), 1.61 (3H, d,
J = 6.9 Hz), 1.65-1.78 (2H, m), 2.12-2.25 (4H, m), 2.78-
2.88 (1H, m), 3.51-3.65 (1H, m), 4.51 (1H, d, J = 11.5
Hz), 4.56 (1H, d, J = 11.5 Hz), 4.59-4.69 (1H, m), 4.80
(1H, q, J = 6.7 Hz), 5.10 (2H, s), 7.23-7.43 (10H, m).
MS (ESI) m/z: 436 (M + H) .
[Step 3]
(1R)[5-(transaminocyclohexyl)-1,3,4-oxadiazol
yl]ethanol
The compound (606 mg, 1.39 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 288
mg (98%) of the title compound as a light brown oil.
H-NMR (400 MHz, CD OD) d : 1.21-1.36 (2H, m), 1.53-1.70
(5H, m), 1.95-2.05 (2H, m), 2.11-2.22 (2H, m), 2.64-2.74
(1H, m), 2.84-2.96 (1H, m), 4.98 (1H, q, J = 6.7 Hz).
Reference Example 64
O O N
Step 1
O 工 程 1
O OH
Step 2
工 程 2 2
[Step 1]
1,5-anhydro[(tert-butoxycarbonyl)amino]-2,3,4-
trideoxyO-methyl-D-erythro-hexitol
The same starting material (500 mg, 2.16 mmol) as in
Step 1 of Reference Example 2 was used and treated in the
same way as in Step 2 of Reference Example 23 to give 433
mg (82%) of the title compound as a colorless solid.
H-NMR (400 MHz, CDCl ) d : 1.28 (1H, ddd, J = 24.6, 12.5,
4.0 Hz), 1.41-1.48 (10H, m), 1.65-1.73 (1H, m), 2.08-2.15
(1H, m), 3.02 (1H, t, J = 10.8 Hz), 3.34-3.46 (6H, m),
3.60-3.65 (1H, m), 4.11 (1H, dd, J = 11.2, 3.4 Hz), 4.24
(1H, br s).
MS (ESI) m/z: 268 (M + Na) .
[Step 2]
2-amino-1,5-anhydro-2,3,4-trideoxyO-methyl-D-erythro-
hexitol hydrochloride
The compound (420 mg, 1.71 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 360
mg (100%) of the title compound as a colorless amorphous
solid.
H-NMR (400 MHz, DMSO-d ) d : 1.24-1.35 (1H, m), 1.47-1.56
(1H, m), 1.64-1.69 (1H, m), 2.01-2.07 (1H, m), 3.00-3.07
(1H, m), 3.22 (3H, s), 3.24-3.31 (2H, m), 3.40-3.46 (2H,
m), 3.97 (1H, dq, J = 10.9, 2.2 Hz).
MS (ESI) m/z: 146 (M + H) .
Reference Example 65
Cl N
6-chloro[(2-chloropyrimidinyl)methylene]-1,3-
dihydro-2H-indolone
2-Chloropyrimidinecarbaldehyde (3.05 g, 21.4
mmol) was used as a starting material and treated in the
same way as in Reference Example 4 to give 5.02 g (80%)
of the title compound as a red solid.
H-NMR (500 MHz, DMSO-d ) d : 6.92 (1H, d, J = 2.3 Hz),
7.10 (1H, dd, J = 8.3, 2.0 Hz), 7.52 (1H, s), 8.00 (1H, d,
J = 5.2 Hz), 8.83 (1H, d, J = 8.0 Hz), 8.95 (1H, d, J =
4.6 Hz), 10.94 (1H, s).
MS (EI) m/z: 291 (M + H) .
Reference Example 66
(3E/Z)chloro(imidazo[1,2-a]pyridinylmethylene)-
1,3-dihydro-2H-indolone
Imidazo[1,2-a]pyridinecarbaldehyde (2.67 g, 18.3
mmol) was used as a starting material and treated in the
same way as in Reference Example 4 to give 2.44 g (45%)
of the title compound as an orange solid.
MS (ESI) m/z: 295 (M + H) .
Reference Example 67
O N O N
Step 1
工 程 1
O OH
Step 2 Step 3
工 程 2 工 程 3
O N H
[Step 1]
tert-Butyl {(3R,6S)[2-(1H-benzotriazolyloxy)
oxoethyl]tetrahydro-2H-pyranyl}carbamate
Concentrated hydrochloric acid (40 ml) was added to
the compound (1.99 g, 8.28 mmol) obtained in Step 1 of
Reference Example 49, concentrated sulfuric acid (20 ml)
was added under ice cooling and then the resulting
mixture was stirred at 100 C for 2 hours. Ice (300 g)
was added to the reaction mixture under ice cooling and
then the resulting mixture was rendered basic by gradual
addition of sodium bicarbonate (84 g). The reaction
mixture was diluted with dioxane (400 ml), di-t-butyl
dicarbonate (11.5 g, 53.0 mmol) was added under ice
cooling and then the resulting mixture was stirred at
room temperature for 24 hours. The reaction mixture was
rendered acidic by addition of citric acid (53 g),
followed by extraction with ethyl acetate. The organic
layer was washed with brine and then dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced
pressure, the residue obtained was dissolved in methylene
chloride (20 ml), 1-hydroxybenzotriazole (2.24 g, 16.6
mmol) and 1-ethyl(3-dimethylaminopropyl)carbodiimide
hydrochloride (3.17 g, 16.5 mmol) were added and the
resulting mixture was stirred at room temperature for 24
hours. Brine was added to the reaction mixture, followed
by extraction with ethyl acetate. The organic layer was
washed with saturated sodium bicarbonate solution and
brine in this order and then dried over anhydrous
magnesium sulfate. The solvent was evaporated under
reduced pressure and the residue obtained was purified by
silica gel column chromatography [methanol:chloroform =
:95 (v/v)] to give 2.27 g (73%) of the title compound as
a solid.
MS (FAB) m/z: 377 (M + H) .
[Step 2]
tert-Butyl {(3R,6S)[2-(methylamino)
oxoethyl]tetrahydro-2H-pyranyl}carbamate
Methylamine/tetrahydrofuran solution (2.0 mol/l, 1
ml) was added to a tetrahydrofuran (5 ml) solution of the
compound (378 mg, 1.00 mmol) obtained in Step 1 above and
the resulting mixture was stirred at room temperature for
1 hour. The reaction mixture was diluted with ethyl
acetate, washed with water, saturated sodium bicarbonate
solution, and brine in this order and then dried over
anhydrous sodium sulfate. The solvent was evaporated
under reduced pressure and the residue obtained was
purified by silica gel column chromatography
[methanol:ethyl acetate = 5:95 (v/v)] to give 135 mg
(49%) of the title compound as a solid.
H-NMR (500 MHz, CDCl ) d : 1.27-1.35 (1H, m), 1.44-1.50
(10H, m), 1.72-1.75 (1H, m), 2.06-2.10 (1H, m), 2.36 (2H,
d, J = 6.3 Hz), 2.80 (3H, d, J = 5.2 Hz), 3.02 (1H, t, J
= 10.6 Hz), 3.58-3.63 (2H, m), 4.07-4.11 (1H, m), 4.28
(1H, br s), 6.22 (1H, br s).
MS (FAB) m/z: 273 (M + H) .
[Step 3]
2-[(2S,5R)aminotetrahydro-2H-pyranyl]-N-
methylacetamide
The compound (60 mg, 0.22 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a solid.
Reference Example 68
O H N
Step 2
Step 1
工 程 2
工 程 1
[Step 1]
tert-Butyl {(3R,6S)[2-(dimethylmethylamino)
oxoethyl]tetrahydro-2H-pyranyl}carbamate
The compound (385 mg, 1.00 mmol) obtained in Step 1
of Reference Example 67 and aqueous dimethylamine
solution (40 wt%, 0.25 ml, 2.00 mmol) were used as
starting materials and treated in the same way as in Step
2 of Reference Example 67 to give 168 mg (57%) of the
title compound as a solid.
H-NMR (500 MHz, CDCl ) d : 1.28-1.45 (11H, m), 1.85-1.88
(1H, m), 2.06-2.09 (1H, m), 2.32 (1H, dd, J = 15.2, 5.4
Hz), 2.66 (1H, dd, J = 15.2, 7.2 Hz), 2.95 (3H, s), 3.00-
3.05 (4H, m), 3.59-3.62 (1H, m), 3.74-3.79 (1H, m), 4.01-
4.04 (1H, m), 4.32-4.30 (1H, m).
MS (FAB) m/z: 287 (M + H) .
[Step 2]
2-[(2S,5R)aminotetrahydro-2H-pyranyl]-N,N-
dimethylacetamide
The compound (69 mg, 0.24 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a solid.
Reference Example 69
Step 1 O NH Step 2
O NH
工 程 1 工 程 2
[Step 1]
Benzyl [trans(2-hydroxypropan
yl)cyclobutyl]carbamate
The same starting material (99 mg, 0.38 mmol) as in
Step 1 of Reference Example 50 was used and treated in
the same way as in Step 1 of Reference Example 5 to give
55 mg (55%) of the title compound as an oil.
H-NMR (400 MHz, CDCl ) d : 1.16 (6H, s), 1.87-2.01 (2H,
m), 2.27-2.41 (4H, m), 4.06-4.18 (1H, m), 4.94 (1H, br s),
.09 (2H, s), 7.30-7.39 (5H, m).
MS (ESI) m/z: 264 (M + H) .
[Step 2]
2-(transaminocyclobutyl)propanol
The compound (55 mg, 0.21 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 24
mg (89%) of the title compound as an oil.
H-NMR (400 MHz, CD OD) d : 1.11 (6H, s), 1.76-1.86 (2H,
m), 2.24-2.42 (3H, m), 3.36-3.46 (1H, m).
Reference Example 70
Step 1
O N Step 2
工 程 1 工 程 2
O OH
Step 3
工 程 3
[Step 1]
tert-Butyl {trans[(2-
formylhydrazino)carbonyl]cyclohexyl}carbamate
The same starting material (500 mg, 2.06 mmol) as in
Step 1 of Reference Example 3 and formohydrazide (123 mg,
2.06 mmol) were used as starting materials and treated in
the same way as in Step 4 of Reference Example 18 to give
459 mg (78%) of the title compound as a solid.
MS (ESI) m/z: 286 (M + H) .
[Step 2]
tert-Butyl [trans(1,3,4-thiazol
yl)cyclohexyl]carbamate
Lawesson's reagent (651 mg, 1.61 mmol) was added to
a toluene (18 ml) suspension of the compound (459 mg,
1.61 mmol) obtained in Step 1 above at room temperature
and the resulting mixture was heated to reflux for 2.5
hours. After cooling, insoluble matter was removed by
filtration and the filtrate was concentrated under
reduced pressure. The residue obtained was purified by
medium pressure silica gel column chromatography
(hexane/ethyl acetate = 3/1 fi 1/1) to give 225 mg (49%)
of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.26-1.37 (2H, m), 1.45 (9H,
s), 1.64-1.75 (2H, m), 2.11-2.31 (4H, m), 3.13-3.23 (1H,
m), 3.44-3.61 (1H, m), 4.40-4.57 (1H, m), 9.04 (1H, s).
[Step 3]
trans(1,3,4-thiazolyl)cyclohexanamine hydrochloride
4N Hydrochloric acid/1,4-dioxane (2.0 ml) and
dichloromethane (0.5 ml) were added to the compound (51
mg, 0.18 mmol) obtained in Step 2 above at room
temperature and the resulting mixture was stirred for 3
hours. The reaction mixture was concentrated under
reduced pressure to give 46 mg (99%) of the title
compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.56-1.66 (2H, m), 1.72-1.83
(2H, m), 2.15-2.22 (2H, m), 2.28-2.35 (2H, m), 3.18-3.34
(2H, m), 9.38 (1H, s).
Reference Example 71
Step 1
O N N
工 程 1
Step 2
工 程 2
[Step 1]
Benzyl [(3R,6S)(5-methyl-1,3,4-oxazolyl)tetrahydro-
2H-pyranyl]carbamate
The compound (401 mg, 1.37 mmol) obtained in Step 4
of Reference Example 18 and trimethyl orthoacetate (1.01
ml, 7.94 mmol) were used as starting materials and
treated in the same way as in Step 2 of Reference Example
3 to give 139 mg (30%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.48-1.63 (1H, m), 1.99-2.29
(3H, m), 2.54 (3H, s), 3.24-3.36 (1H, m), 3.74-3.90 (1H,
m), 4.12-4.23 (1H, m), 4.55-4.69 (1H, m), 4.72-4.85 (1H,
m), 5.02-5.20 (2H, m), 7.29-7.43 (5H, m).
[Step 2]
(3R,6S)(5-methyl-1,3,4-oxazolyl)tetrahydro-2H-
pyranamine
The compound (139 mg, 0.44 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 79
mg (99%) of the title compound as an oil.
H-NMR (400 MHz, CD OD) d : 1.40-1.50 (1H, m), 1.89-1.99
(1H, m), 2.03-2.10 (1H, m), 2.10-2.18 (1H, m), 2.53 (3H,
s), 2.78-2.86 (1H, m), 3.18-3.26 (1H, m), 3.97-4.03 (1H,
m), 4.59 (1H, dd, J = 11.17, 2.58 Hz).
Reference Example 72
Step 1
工 程 1
O O N
Step 2 O N Step 3
工 程 2
工 程 3
[Step 1]
Benzyl (trans{[2-
(methoxyacetyl)hydrazino]carbonyl}cyclohexylcarbamate
1-Hydroxybenzotriazole (231 mg, 1.71 mmol) and 1-
ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride
(394 mg, 2.05 mmol) were added to an N,N-
dimethylformamide(10 ml) suspension of the compound (499
mg, 1.71 mmol) obtained in Step 1 of Reference Example 3
and methoxyacetic acid (0.16 ml, 2.05 mmol) and the
resulting mixture was stirred at room temperature for 24
hours. Water was added to the reaction mixture and the
precipitated solid was collected by filtration and dried
to give 553 mg (89%) of the title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 1.11-1.23 (2H, m), 1.34-1.47
(2H, m), 1.70-1.79 (2H, m), 1.80-1.90 (2H, m), 2.05-2.15
(1H, m), 3.18-3.28 (1H, m), 3.31 (3H, s), 3.88 (2H, s),
.00 (2H, s), 7.21 (1H, d, J = 8.02 Hz), 7.27-7.41 (5H,
m), 9.61-9.74 (2H, m).
[Step 2]
Benzyl {trans[5-(methoxymethyl)-1,3,4-oxazol
yl]cyclohexyl}carbamate
The compound (199 mg, 0.55 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 62 to give the
title compound as a mixture with triphenylphosphine oxide.
[Step 3]
trans[5-(methoxymethyl)-1,3,4-oxazol
yl]cyclohexanamine
% Palladium carbon (200 mg) was added to a
methanol (8 ml) solution of the mixture (399 mg) obtained
in Step 2 above and the resulting mixture was stirred for
2 hours under a hydrogen atmosphere. The catalyst was
removed by filtration through celite and then the
filtrate was concentrated under reduced pressure. The
residue obtained was dissolved in ethyl acetate, followed
by extraction with 1N hydrochloric acid. Subsequently,
the aqueous layer was rendered basic by addition of 1N
sodium hydroxide solution, followed by extraction with
chloroform:methanol [5:1 (v/v)]. The organic layer was
dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give 78 mg (67%) of
the title compound as an oil.
H-NMR (400 MHz, CD OD) d : 1.22-1.36 (2H, m), 1.57-1.71
(2H, m), 1.96-2.05 (2H, m), 2.12-2.21 (2H, m), 2.65-2.75
(1H, m), 2.85-2.96 (1H, m), 3.42 (3H, s), 4.62 (2H, s).
Reference Example 73
O H N
Step 1
Step 2
工 程 1
工 程 2
[Step 1]
tert-Butyl [(3R,6S)(2-hydroxyethyl)tetrahydro-2H-
pyranyl]carbamate
The compound (106 mg, 0.28 mmol) obtained in Step 1
of Reference Example 67 was added to a tetrahydrofuran (5
ml) suspension of lithium aluminum hydride (103 mg, 2.70
mmol) under ice cooling and the resulting mixture was
stirred at room temperature for 24 hours. Water (0.1 ml)
and 5N aqueous sodium hydroxide solution (0.1 ml) were
added in this order to the reaction mixture, water (0.1
ml) was further added and the resulting mixture was
stirred for 1 hour. After removal by filtration through
celite, the solvent was concentrated under reduced
pressure. The residue obtained was purified by silica
gel column chromatography [ethyl acetate:n-hexane = 10:0
(v/v)] to give 15 mg (21%) of the title compound as a
solid.
H-NMR (500 MHz, CDCl ) d : 1.24-1.33 (1H, m), 1.44-1.54
(10H, m), 1.68-1.78 (3H, m), 2.07-2.09 (1H, m), 2.60 (1H,
br s), 3.01 (1H, t, J = 10.6 Hz), 3.43-3.48 (1H, m),
3.54-3.62 (1H, m), 3.73-3.79 (2H, m), 4.06-4.09 (1H, m),
4.30 (1H, br s).
MS (FAB) m/z: 246 (M + H) .
[Step 2]
2-[(2S,5R)aminotetrahydro-2H-pyranyl]ethanol
The compound (25 mg, 0.10 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a solid.
Reference Example 74
O N O
Step 1
工 程 1
O NH
O NH
O NH
Step 3
Step 2
工 程 2 工 程 3
[Step 1]
tert-Butyl {(3R,6S)[2-(2-formylhydrazino)
oxoethyl]tetrahydro-2H-pyranyl}carbamate
Hydrazine monohydrate (0.06 ml, 1.2 mmol) was added
to a tetrahydrofuran (5 ml) solution of the compound (397
mg, 1.10 mmol) obtained in Step 1 of Reference Example 67
and the resulting mixture was stirred at room temperature
for 2 hours. Formic acid (0.09 ml, 2.40 mmol) and 1-
ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride
(461 mg, 2.40 mmol) were added to the reaction mixture
and the resulting mixture was stirred at room temperature
for 24 hours. Water was added to the reaction mixture,
followed by extraction with chloroform:2-propanol [3:1
(v/v)]. The organic layer was washed with saturated
sodium bicarbonate solution and brine in this order and
dried over anhydrous sodium sulfate. The solvent was
concentrated under reduced pressure and the residue
obtained was purified by silica gel column chromatography
[chloroform:methanol = 90:10 (v/v)] to give 118 mg (37%)
of the title compound as a solid.
H-NMR (500 MHz, DMSO-d ) d : 1.21-1.41 (11H, m), 1.69-
1.72 (1H, m), 1.81-1.84 (1H, m), 2.19-2.34 (2H, m), 2.92
(1H, t, J = 10.8 Hz), 3.28-3.33 (1H, m), 3.49-3.55 (1H,
m), 3.74-3.71 (1H, m), 6.74 (1H, d, J = 7.8 Hz), 7.97 (1H,
s), 9.93 (2H, s).
MS (FAB) m/z: 302 (M + H) .
[Step 2]
tert-Butyl [(3R,6S)(1,3,4-oxazol
ylmethyl)tetrahydro-2H-pyranyl]carbamate
The compound (114 mg, 0.38 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 62 to give 73
mg (68%) of the title compound as a solid.
H-NMR (500 MHz, CDCl ) d : 1.27-1.37 (1H, m), 1.43-1.58
(10H, m), 1.82-1.87 (1H, m), 2.10-2.15 (1H, m), 2.98-3.15
(3H, m), 3.61-3.61 (1H, m), 3.70-3.77 (1H, m), 4.03-4.08
(1H, m), 4.24-4.24 (1H, m), 8.35 (1H, s).
[Step 3]
(3R,6S)(1,3,4-oxazolylmethyl)tetrahydro-2H-pyran
amine
The compound (73 mg, 0.26 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a solid.
Reference Example 75
Step 2 Step 3
Step 1
工 程 2 工 程 3
工 程 1
HO OH
O O Ph
O Ph NH
Step 4 Step 5
工 程 4 工 程 5
HO OH
Ph O O Ph Ph O O Ph
[Step 1]
(6,6-dimethoxyspiro[3.3]heptane-2,2-diyl)dimethanol
Diisopropyl 6,6-dimethoxyspiro[3.3]heptane-2,2-
dicarboxylate (5.60 g, 17.1 mmol) was used as a starting
material and treated in the same way as in Step 1 of
Reference Example 73 to give 1.56 g (42%) of the title
compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.92 (4H, s), 2.21 (5H, s),
2.36 (2H, br s), 3.12 (6H, s), 3.69 (4H, d, J = 4.6 Hz).
[Step 2]
2,2-bis[(benzyloxy)methyl]-6,6-dimethoxyspiro[3.3]heptane
Sodium hydride (755 mg, 17.3 mmol) was added to a
dimethylformamide (40 ml)/tetrahydrofuran (20 ml)
solution of the compound (1.56 g, 7.20 mmol) obtained in
Step 1 above under ice cooling, the resulting mixture was
stirred at room temperature for 10 minutes, then benzyl
bromide (2.06 ml, 17.3 mmol) was added and the resulting
mixture was stirred for 24 hours. Saturated ammonium
chloride solution was added to the reaction mixture,
followed by extraction with ethyl acetate. The organic
layer was washed with brine and then dried over anhydrous
sodium sulfate. The solvent was evaporated under reduced
pressure and the residue obtained was purified by silica
gel column chromatography [n-hexane:ethyl acetate = 4:1
(v/v)] to give 2.25 g (79%) of the title compound as an
oil.
H-NMR (400 MHz, CDCl ) d : 1.96 (4H, s), 2.12 (4H, s),
3.10 (6H, s), 3.43 (4H, s), 4.51 (4H, s), 7.26-7.32 (10H,
[Step 3]
6,6-bis[(benzyloxy)methyl]spiro[3.3]heptanone
The compound (2.25 g, 5.67 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 2 of Reference Example 21 to give
1.70 g (86%) of the title compound as an oil.
H-NMR (400 MHz, CDCl ) d : 2.17 (4H, s), 3.01 (4H, s),
3.47 (4H, s), 4.52 (4H, s), 7.27-7.36 (10H, m).
[Step 4]
N-benzyl-6,6-bis[(benzyloxy)methyl]spiro[3.3]heptan
amine
Benzylamine (1.06 ml, 9.70 mmol) and acetic acid
(0.56 ml, 9.70 mmol) were added to a dichloromethane (50
ml) solution of the compound (1.70 g, 4.85 mmol) obtained
in Step 3 above, the resulting mixture was stirred for 10
minutes under ice cooling and then sodium
cyanoborohydride (610 mg, 9.70 mmol) was added to the
reaction mixture. After stirring at room temperature for
24 hours, saturated sodium bicarbonate solution was added
to the reaction mixture, followed by extraction with
ethyl acetate. The organic layer was washed with brine
and then dried over anhydrous sodium sulfate. The
solvent was evaporated under reduced pressure and the
residue obtained was purified by silica gel column
chromatography [chloroform:methanol = 40:1 (v/v)] to give
1.27 g (60%) of the title compound as an oil.
H-NMR (400 MHz, CDCl ) d : 1.49 (2H, br s), 1.67-1.69 (2H,
m), 1.85 (2H, s), 1.93 (2H, s), 2.23-2.28 (2H, m), 3.12-
3.19 (1H, m), 3.42 (4H, s), 3.65 (2H, s), 4.50 (4H, s),
7.21-7.38 (15H, m).
[Step 5]
(6-aminospiro[3.3]heptane-2,2-diyl)dimethanol
% Palladium hydroxide (254 mg) was added to an
ethanol (30 ml) solution of the compound (1.27 g, 2.88
mmol) obtained in Step 4 above and the resulting mixture
was stirred at room temperature for 3 days under a
hydrogen atmosphere. The catalyst was removed by
filtration through celite and then the filtrate was
concentrated under reduced pressure to give 517 mg (99%)
of the title compound as an oil.
H-NMR (400 MHz, CDCl ) d : 1.62-1.86 (5H, m), 2.17-2.22
(2H, m), 3.15-3.17 (6H, m), 4.58 (4H, br s)
Reference Example 76
O N 2
Step 1 Step 2
工 程 1
O N 工 程 2
HN HCl
[Step 1]
1,5-anhydro[(tert-butoxycarbonyl)amino]-2,3,4,6-
tetradeoxy[(methylsulfonyl)amino]-D-erythro-hexitol
Triethylamine (0.12 ml, 0.88 mmol) and
methanesulfonyl chloride (0.05 ml, 0.67 mmol) were added
to a dichloromethane (4 ml) solution of the compound (101
mg, 0.44 mmol) obtained in Step 3 of Reference Example 24
under ice cooling and the resulting mixture was stirred
for 30 minutes. Water was added, followed by extraction
with dichloromethane. The organic layer was washed with
saturated ammonium chloride solution, saturated sodium
bicarbonate solution, and brine in this order and then
dried over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure and the residue
obtained was purified by silica gel column chromatography
[chloroform:methanol = 95:5 (v/v)] to give 105 mg (77%)
of the title compound as a solid.
H-NMR (500 MHz, CDCl ) d : 1.25-1.35 (1H, m), 1.44-1.51
(10H, m), 1.66-1.72 (1H, m), 2.09-2.12 (1H, m), 2.97-3.06
(5H, m), 3.25-3.31 (1H, m), 3.37-3.43 (1H, m), 3.58 (1H,
br s), 4.06-4.10 (1H, m), 4.25 (1H, br s), 4.67 (1H, br
MS (FAB) m/z: 309 (M + H) .
[Step 2]
2-amino-1,5-anhydro-2,3,4,6-tetradeoxy
[(methylsulfonyl)amino]-D-erythro-hexitol
The compound (101 mg, 0.33 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give the
title compound as a solid.
Reference Example 77
Step 1
Step 2
H 工 程 1
工 程 2 2
O N O
O OH
[Step 1]
Benzyl [(3R,6S)(dimethylcarbamoyl)tetrahydro-2H-pyran-
3-yl]carbamate
The compound (200 mg, 0.72 mmol) obtained in Step 3
of Reference Example 18 and dimethylamine hydrochloride
(88 mg, 1.07 mmol) were used as starting materials and
treated in the same way as in Step 1 of Reference Example
72 to give 177 mg (81%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.43 (1H, m), 1.84-2.00 (2H,
m), 2.19-2.21 (1H, m), 2.95 (3H, s), 3.07 (3H, s), 3.15-
3.18 (1H, m), 3.72-3.75 (1H, m), 4.06 (1H, dd, J = 9.8,
2.4 Hz), 4.13 (1H, dd, J = 11.0, 4.3 Hz), 4.64-4.66 (1H,
m), 5.09 (2H, br s), 7.30-7.40 (5H, m).
MS (ESI) m/z: 307 (M + H) .
[Step 2]
(2S,5R)amino-N,N-dimethyltetrahydro-2H-pyran
carboxamide
The compound (177 mg, 0.58 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 3 of Reference Example 2 to give 99
mg (99%) of the title compound as an oil.
H-NMR (400 MHz, CDCl ) d : 1.22-1.35 (1H, m), 1.75-2.17
(5H, m), 2.93 (1H, m), 2.95 (3H, s), 3.05 (3H, s), 3.07
(1H, m), 3.98-4.04 (2H, m).
MS (ESI) m/z: 173 (M + H) .
Reference Example 78
(3E/Z)chloro(3,5-dichlorobenzylidene)-1,3-dihydro-
2H-indolone
3,5-Dichlorobenzaldehyde (3.50 g, 20.0 mmol) was
used as a starting material and treated in the same way
as in Reference Example 4 to give 2.60 g (40%) of the
title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 6.90 (1H, d, J = 2.3 Hz),
6.95 (1H, dd, J = 8.2, 1.8 Hz), 7.29 (1H, d, J = 8.2 Hz),
7.59 (1H, s), 7.73 (3H, s), 10.83 (1H, s).
Reference Example 79
Step 1 Step 2
工 程 2
工 程 1 O N
O OH
Step 4
Step 3
工 程 4
工 程 3
O OH
[Step 1]
tert-Butyl {(3R,6S)
[methoxy(methyl)carbamoyl]tetrahydro-2H-pyran
yl}carbamate
The same starting material (70.0 g, 0.29 mol) as in
Step 1 of Reference Example 18 and N,O-
dimethylhydroxylamine hydrochloride (34.0 g, 0.35 mol)
were used as starting materials and treated in the same
way as in Step 2 of Example 12 to give 61.0 g (73%) of
the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.44-1.50 (1H, m), 1.44 (9H,
s), 1.77-1.93 (2H, m), 2.14-2.22 (1H, m), 3.14-3.19 (1H,
m), 3.21 (3H, s), 3.67-3.72 (1H, m), 3.72 (3H, s), 4.20
(2H, dd, J = 10.4, 3.6 Hz), 4.39 (1H, br s).
MS (ESI) m/z: 233 (M-55) .
[Step 2]
tert-Butyl [(3R,6S)acetyltetrahydro-2H-pyran
yl]carbamate
Methylmagnesium bromide/diethyl ether solution (3.0
mol/l, 176 ml, 0.53 mol) was added dropwise to a
tetrahydrofuran (600 ml) solution of the compound (61.0 g,
0.21 mol) obtained in Step 1 above under ice cooling
under a nitrogen atmosphere and then the resulting
mixture was stirred at room temperature for 3 hours.
Water (200 ml) was added to the reaction mixture under
ice cooling, the resulting mixture was stirred and then
saturated ammonium chloride solution (100 ml) was added,
followed by extraction with ethyl acetate. The organic
layer was washed with brine and then dried over anhydrous
magnesium sulfate. The solvent was evaporated under
reduced pressure and the residue obtained was purified by
silica gel column chromatography [n-hexane:ethyl acetate
= 2:1 (v/v)] to give 38 g (75%) of the title compound as
a solid.
H-NMR (400 MHz, CDCl ) d : 1.30-1.40 (1H, m), 1.44 (9H,
s), 1.48-1.56 (1H, m), 1.96-2.04 (1H, m), 2.11-2.18 (1H,
m), 2.20 (3H, s), 3.06 (1H, t, J = 10.6 Hz), 3.61-3.65
(1H, m), 3.69 (1H, dd, J = 11.3, 2.7 Hz), 4.15 (1H, ddd,
J = 10.6, 5.0, 2.0 Hz), 4.30 (1H, br s).
MS (ESI) m/z: 266 (M + Na) .
[Step 3]
1,5-anhydro[(tert-butoxycarbonyl)amino]-2,3,4,7-
tetradeoxy-D-ribo-heptitol
The compound (20.0 g, 82.0 mmol) obtained in Step 2
above was suspended in 0.1 mol/l phosphate buffer
solution (pH 6.4; 200 ml) and nicotinamide adenine
dinucleotide (oxidized form) (133 mg, 0.20 mmol),
ammonium formate (1.26 g, 19.7 mmol), magnesium chloride
(19 mg, 0.20 mmol), and isopropyl alcohol (10 ml) were
added. Subsequently, 0.1 mol/l phosphate buffer solution
(pH 6.4, 10 ml) of Chiralscreen-OH E039 kit (Daicel
Corp.) (1.0 g) was added dropwise and then the resulting
mixture was stirred at 30 C for 16 hours. Dimethyl
sulfoxide (8 ml), isopropyl alcohol (2 ml), and 0.1 mol/l
phosphate buffer solution (20 ml) were added to the
reaction mixture, then formic acid was added to the
reaction mixture to adjust its pH to 6.2 to 6.4 and the
resulting mixture was stirred at 37°C for 8 hours. After
extraction with ethyl acetate, insoluble matter was
removed by filtration through celite, the filtrate was
washed with brine twice and then dried over anhydrous
magnesium sulfate and the solvent was evaporated under
reduced pressure. The residue obtained was purified by
silica gel column chromatography [n-hexane:ethyl acetate
= 2:1 fi 1:1 (v/v)] to give 17.9 g (89%) of the title
compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.14 (3H, d, J = 6.4 Hz), 1.26
(1H, ddd, J = 24.7, 12.4, 4.1 Hz), 1.44 (9H, s), 1.50-
1.60 (1H, m), 1.65-1.71 (1H, m), 2.00-2.04 (1H, m), 2.10-
2.17 (1H, m), 3.02 (1H, t, J = 10.8 Hz), 3.14-3.19 (1H,
m), 3.55-3.62 (1H, m), 3.80-3.87 (1H, m), 4.11 (1H, dq, J
= 10.6, 2.3 Hz), 4.21-4.26 (1H, m).
MS (ESI) m/z: 268 (M + Na) .
[Step 4]
2-amino-1,5-anhydro-2,3,4,7-tetradeoxy-D-ribo-heptitol
hydrochloride
The compound (17.5 g, 71.0 mmol) obtained in Step 3
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 12.6
g (98%) of the title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 1.03 (3H, d, J = 6.3 Hz),
1.21-1.33 (1H, m), 1.44-1.55 (1H, m), 1.80-1.87 (1H, m),
2.04-2.11 (1H, m), 2.91-2.95 (1H, m), 2.96-3.03 (1H, m),
3.24 (1H, t, J = 10.6 Hz), 3.40-3.45 (1H, m), 3.97-4.02
(1H, m), 4.63 (1H, br s).
MS (ESI) m/z: 146 (M + H) .
Reference Example 80
(3E/Z)chloro(3-chloro-2,4-difluorobenzylidene)-1,3-
dihydro-2H-indolone
3-Chloro-2,4-difluorobenzaldehyde (4.90 g, 44.9
mmol) was used as a starting material and treated in the
same way as in Reference Example 4 to give 8.03 g (56%)
of the title compound as a solid.
MS (APCI) m/z: 326 (M + H) .
Reference Example 81
(3E/Z)chloro(3-chlorobenzylidene)-1,3-dihydro-2H-
indolone
6-Chloro-1,3-dihydro-2H-indolone (1.67 g, 10.0
mmol) was used as a starting material and treated in the
same way as in Reference Example 4 to give 760 mg (26%)
of the title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 6.90 (1H, d, J = 1.8 Hz),
6.94 (1H, dd, J = 8.2, 2.3 Hz), 7.39 (1H, d, J = 8.2 Hz),
7.55-7.56 (2H, m), 7.64 (1H, s), 7.65-7.69 (1H, m), 7.74
(1H, s), 10.82 (1H, s).
Reference Example 82
(3E/Z)chloro(3-chloro-2,5-difluorobenzylidene)-1,3-
dihydro-2H-indolone
3-Chloro-2,5-difluorobenzaldehyde (6.00 g, 22.0
mmol) was used as a starting material and treated in the
same way as in Reference Example 4 to give 2.46 g (34%)
of the title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 6.87-7.10 (2H, m), 7.14-9.17
(4H, m), 10.89-10.96 (1H, m).
Reference Example 83
O NH
O NH
N Step 1 Step 2
工 程 1 工 程 2
N N N
HN N
Step 3
工 程 3
N N H N N
O N N
2HCl
[Step 1]
tert-Butyl {1-[1H-benzotriazol
yl(imino)methyl]piperidinyl}carbamate
A dichloromethane (50 ml) solution of tert-butyl
piperidinylcarbamate (7.50 g, 37.9 mmol) was added
dropwise to a dichloromethane (150 ml) solution of 1-(1H-
benzotriazolyl)(2H-benzotriazolyl)methanamine (J.
Org. Chem. 2000, 65, 8080; and J. Org. Chem. 2003, 68,
4941) (10.0 g, 37.9 mmol) and the resulting mixture was
stirred at room temperature for 3 days. 10% aqueous
sodium carbonate solution was added to the reaction
mixture, followed by extraction with dichloromethane.
The organic layer was washed with brine and then dried
over anhydrous sodium sulfate. The solvent was
evaporated under reduced pressure to give 10.6 g (81%) of
the title compound as an oil.
H-NMR (400 MHz, CDCl ) d : 1.45 (9H, s), 1.57-1.62 (2H,
m), 2.04 (2H, d, J = 11.4 Hz), 3.05-3.12 (2H, m), 3.71
(3H, d, J = 13.3 Hz), 4.53 (1H, s), 7.00 (1H, s), 7.46
(1H, t, J = 8.2 Hz), 7.60 (1H, t, J = 7.6 Hz), 7.71 (1H,
s), 8.12 (1H, d, J = 8.2 Hz).
[Step 2]
tert-Butyl [1-(1H-tetrazolyl)piperidinyl]carbamate
Sodium azide (2.00 g, 30.7 mmol) and acetic acid
(1.70 ml, 30.7 mmol) were added to a chloroform (300 ml)
solution of the compound (10.6 g, 30.7 mmol) obtained in
Step 1 above and the resulting mixture was stirred at
room temperature for 25 hours. Insoluble matter was
removed by filtration and the filtrate was concentrated
under reduced pressure. The residue obtained was
purified by silica gel column chromatography
[chloroform:methanol = 30:1 fi 10:1 (v/v)] to give 8.20 g
(94%) of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 1.56-1.44 (11H, m), 1.96-1.92
(2H, m), 3.21-3.14 (2H, m), 3.57 (1H, s), 3.84-3.81 (2H,
[Step 3]
1-(1H-tetrazolyl)piperidinamine dihydrochloride
The compound (8.20 g, 28.6 mmol) obtained in Step 2
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 6.90
g (92%) of the title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 1.57 (2H, ddd, J = 24.2,
12.3, 4.0 Hz), 1.98 (2H, d, J = 10.1 Hz), 3.09 (2H, td, J
= 12.8, 2.0 Hz), 3.25 (1H, d, J = 4.6 Hz), 3.93 (2H, d, J
= 13.3 Hz), 8.30 (3H, s).
Reference Example 84
Step 1
Step 2
工 程 1
工 程 2
O NH
O OH
O NH
[Step 1]
tert-Butyl [(3R,6S)carbamoyltetrahydro-2H-pyran
yl]carbamate
The same starting material (2.54 g, 10.3 mmol) as in
Step 1 of Reference Example 18 and ammonium chloride
(1.07 g, 20.0 mmol) were used as starting materials and
treated in the same way as in Step 2 of Example 12 to
give 1.83 g (75%) of the title compound as a solid.
H-NMR (400 MHz, CDCl ) d : 1.35 (1H, ddd, J = 24.7, 12.7,
3.9 Hz), 1.44 (9H, s), 1.53-1.63 (1H, m), 2.11-2.18 (1H,
m), 2.23 (1H, dq, J = 13.6, 3.3 Hz), 3.06 (1H, t, J =
.7 Hz), 3.58-3.67 (1H, m), 3.74 (1H, dd, J = 11.5, 2.4
Hz), 4.14-4.20 (1H, m), 4.29 (1H, br s), 5.37 (1H, br s),
6.47 (1H, br s).
MS (ESI) m/z: 267 (M + Na) .
[Step 2]
(2S,5R)aminotetrahydro-2H-pyrancarboxamide
hydrochloride
The compound (1.82 g, 7.45 mmol) obtained in Step 1
above was used as a starting material and treated in the
same way as in Step 1 of Reference Example 2 to give 1.31
g (97%) of the title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 1.39-1.48 (1H, m), 1.57 (1H,
ddd, J = 23.8, 12.5, 3.9 Hz), 1.95-2.01 (1H, m), 2.04-
2.11 (1H, m), 3.07-3.09 (1H, m), 3.31-3.36 (1H, m), 3.67
(1H, dd, J = 11.1, 2.6 Hz), 4.03-4.08 (1H, m), 7.12 (2H,
s), 7.20 (2H, s).
MS (ESI) m/z: 145 (M + H) .
Reference Example 85
Step 1
工 程 1
N N N
O O O
O O O
(A) (B)
工 S 程 te 3p 3
工 程 2
Step 2
H N H N
(C) (D)
[Step 1]
Methyl 2,6-anhydro-3,4,5-trideoxy(dibenzylamino)
methyl-L-glycero-hexonate (A) and methyl 2,6-anhydro-
3,4,5-trideoxy(dibenzylamino)methyl-L-glycero-
hexonate (B)
Lithium bis(trimethylsilyl)amide/tetrahydrofuran
solution (1.0 mol/l, 37 ml, 37.0 mmol) was added dropwise
to a tetrahydrofuran (70 ml) solution of the same
starting material (6.20 g, 18.0 mmol) as in Step 1 of
Reference Example 5 and hexamethylphosphoric acid
triamide (6.40 ml, 36.0 mmol) at -78 C under a nitrogen
atmosphere and then the resulting mixture was stirred at
room temperature for 1 hour. After cooling to -78 C
again, methyl iodide (5.6 ml, 90.0 mmol) was added
dropwise and the resulting mixture was stirred at room
temperature for 16 hours. The reaction mixture was
diluted with ethyl acetate and the organic layer was
washed with saturated ammonium chloride solution and
brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure and the
residue obtained was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 93:7 (v/v)] to
give a mixture of the compounds A and B. The mixture
obtained was fractionated and purified by chiral column
liquid chromatography [fractionation conditions:
CHIRALCEL OD-H, n-hexane:ethanol = 90:10 (v/v)] to give
1.10 g (17%) of the title compound A as an oil. The
residue was fractionated and purified by chiral column
liquid chromatography [fractionation conditions:
CHIRALPAK IC, n-hexane:ethanol = 90:10 (v/v)] to give 299
mg (5%) of the title compound B as an oil.
Compound A:
H-NMR (400 MHz, CDCl ) d : 1.32 (3H, s), 1.36-1.55 (2H,
m), 1.88-1.94 (1H, m), 2.36 (1H, dt, J = 13.1, 3.2 Hz),
2.75-2.82 (1H, m), 3.56 (1H, t, J = 11.3 Hz), 3.58 (2H, d,
J = 14.0 Hz), 3.65 (2H, d, J = 14.0 Hz), 3.76 (3H, s),
3.87 (1H, dq, J = 11.4, 2.2 Hz), 7.19-7.36 (10H, m).
MS (ESI) m/z: 354 (M + H) .
Compound B:
H-NMR (400 MHz, CDCl ) d : 1.45 (3H, s), 1.76-1.92 (4H,
m), 2.76-2.83 (1H, m), 3.67 (2H, d, J = 14.0 Hz), 3.73
(3H, s), 3.73-3.78 (3H, m), 3.86 (1H, dd, J = 11.8, 5.0
Hz), 7.19-7.23 (2H, m), 7.26-7.35 (8H, m).
MS (ESI) m/z: 354 (M + H) .
[Step 2]
Methyl 5-amino-2,6-anhydro-3,4,5-trideoxymethyl-L-
glycero-hexonate hydrochloride (C)
4N Hydrochloric acid/dioxane solution (2 ml) and 10%
palladium carbon (200 mg) were added to a methanol (20
ml) solution of the compound A (1.10 g, 3.11 mmol)
obtained in Step 1 above and the resulting mixture was
stirred at room temperature for 16 hours under a hydrogen
atmosphere. 20% palladium hydroxide carbon (200 mg) was
further added to the reaction mixture and the resulting
mixture was stirred at room temperature for 48 hours
under a hydrogen atmosphere. The catalyst was removed by
filtration through celite and then the filtrate was
concentrated under reduced pressure to give 703 mg (100%)
of the title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 1.27 (3H, s), 1.39-1.54 (2H,
m), 1.93-2.00 (1H, m), 2.17-2.23 (1H, m), 3.04-3.12 (1H,
m), 3.41 (1H, t, J = 11.1 Hz), 3.69 (3H, s), 3.83-3.89
(1H, m), 8.17 (2H, br s).
MS (ESI) m/z: 174 (M + H) .
[Step 3]
Methyl 5-amino-2,6-anhydro-3,4,5-trideoxymethyl-L-
glycero-hexonate (D)
% Palladium hydroxide carbon (200 mg) was added to
a methanol (6 ml) solution of the compound B (295 mg,
0.83 mmol) obtained in Step 1 above and the resulting
mixture was stirred at room temperature for 5 hours under
a hydrogen atmosphere. The catalyst was removed by
filtration through celite and then the filtrate was
concentrated under reduced pressure to give 119 mg (83%)
of the title compound as an oil.
H-NMR (400 MHz, DMSO-d ) d : 1.29 (3H, s), 1.55-1.66 (2H,
m), 1.73-1.80 (1H, m), 1.84-1.90 (1H, m), 2.84-2.87 (1H,
m), 3.46-3.50 (1H, m), 3.60 (1H, dd, J = 12.4, 2.7 Hz),
3.65 (3H, s).
MS (ESI) m/z: 174 (M + H) .
Reference Example 86
N Cl
(3E/Z)chloro[(2-chlorofluoropyridin
yl)methylene]-1,3-dihydro-2H-pyrrolo[3,2-c]pyrrolidin
6-Chloro-1,3-dihydro-2H-pyrrolo[3,2-c]pyrrolidin
one (7.00 g, 41.5 mmol) and 2-chloro
fluoroisonicotinaldehyde monohydrate (7.37 g, 41.5 mmol)
were used as starting materials and treated in the same
way as in Reference Example 1 to give 5.17 g (40%) of the
title compound as a solid.
H-NMR (400 MHz, DMSO-d ) d : 7.00 (1H, s), 7.62 (1H, s),
7.84 (1H, t, J = 4.8 Hz), 8.10 (1H, s), 8.42 (1H, d, J =
4.6 Hz), 11.47 (1H, br s).
MS (ESI) m/z: 310 (M + H) .
Reference Example 87
Step 1 Cl
工 程 1
O OH
Step 2 Step 3
工 程 2 工 程 3
Cl N
[Step 1]
6''-chloro-8'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-3',4'-diphenyl-3',4',8',8a'-tetrahydro-1'H-
dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-
7',3''-pyrrolo[3,2-c]pyridine]-1',2''(1''H)-dione
Triethylamine (0.50 ml, 3.56 mmol) and 4A molecular
sieves (powder) (1.34 g) were added to a toluene (30 ml)
solution of glycine tert-butyl ester (467 mg, 3.56 mmol)
and 4,4-dimethylcyclohexanone (449 mg, 3.56 mmol) and the
resulting mixture was stirred at 70 C for 1.5 hours. The
compound (1.00 g, 3.23 mmol) obtained in Reference
Example 86 was added to the reaction mixture and the
resulting mixture was stirred at 70 C for 3 hours.
Glycine tert-butyl ester (106 mg, 0.81 mmol) and 4,4-
dimethylcyclohexanone (102 mg, 0.81 mmol) were further
added to the reaction mixture and the resulting mixture
was stirred at 80 C for 24 hours. After cooling,
insoluble matter was removed by filtration through celite
and the filtrate was concentrated under reduced pressure.
The residue obtained was purified by silica gel column
chromatography [n-hexane:ethyl acetate = 100:0 fi 0:100
(v/v)] to give 613 mg (35%) of the title mixture as a
solid.
MS (ESI) m/z: 549 (M + H) .
[Step 2]
(3'S,4'R,7'S,8'S,8a'R)-6''-chloro-8'-(2-chloro
fluoropyridinyl)-4,4-dimethyl-3',4'-diphenyl-
3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-1,6'-
pyrrolo[2,1-c][1,4]oxazine-7',3''-pyrrolo[3,2-
c]pyridine]-1',2''(1''H)-dione
The mixture of isomers (480 mg) obtained in Step 1
above was fractionated and purified by chiral column
liquid chromatography [fractionation conditions:
CHIRALPAK IA, n-hexane:tetrahydrofuran:ethanol = 85:15:5
(v/v)] to give 187 mg (39%) of the title compound as a
solid.
H-NMR (400 MHz, CDCl ) d : 1.19 (3H, t, J = 7.1 Hz), 1.70
(1H, d, J = 13.7 Hz), 1.87 (1H, d, J = 13.7 Hz), 2.20 (1H,
d, J = 12.8 Hz), 2.42 (1H, dd, J = 12.8, 2.7 Hz), 3.70
(1H, s), 3.81 (1H, q, J = 9.2 Hz), 3.93 (1H, q, J = 9.2
Hz), 4.09-4.22 (2H, m), 4.47 (2H, s), 4.54-4.78 (2H, m),
6.81 (1H, d, J = 1.8 Hz), 6.96 (1H, td, J = 8.0, 1.2 Hz),
7.13 (1H, dd, J = 8.0, 2.1 Hz), 7.16-7.21 (1H, m), 7.38-
7.42 (2H, m), 7.44-7.48 (1H, m).
MS (ESI) m/z: 549 (M + H) .
[Step 3]
6''-chloro-4'-(2-chlorofluoropyridinyl)-4,4-
dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-
pyrrolidine-3',3''-pyrrolo[3,2-c]pyridine]-5'-carboxylic
acid hydrochloride
Concentrated hydrochloric acid (1.12 ml, 13.7 mmol)
was added to the compound (150 mg, 0.27 mmol) obtained in
Step 2 above under ice cooling and the resulting mixture
was stirred at room temperature for 1 hour. The reaction
mixture was concentrated under reduced pressure to give
137 mg (94%) of the title compound as a solid.
H-NMR (400 MHz, CD OD) d : 0.79 (3H, s), 1.04 (3H, s),
1.39-1.66 (4H, m), 1.87-2.12 (3H, m), 2.50 (1H, dd, J =
14.2, 3.2 Hz), 5.16 (1H, d, J = 10.1 Hz), 5.47 (1H, d, J
= 10.5 Hz), 6.95 (1H, s), 7.67 (1H, t, J = 5.0 Hz), 8.24
(1H, d, J = 5.0 Hz), 8.57 (1H, d, J = 1.8 Hz).
MS (ESI) m/z: 493 (M + H) .
[Preparation Examples]
(Preparation Example 1) Powder
g of the compound of Example 1, 895 g of lactose,
and 100 g of corn starch can be mixed using a blender to
give powders.
(Preparation Example 2) Granule
g of the compound of Example 5, 895 g of lactose,
and 100 g of low-substituted hydroxypropylcellulose are
mixed, then 300 g of 10% aqueous hydroxypropylcellulose
solution is added and the resulting mixture is kneaded.
This product can be granulated using an extrusion
granulator and dried to give granules.
(Preparation Example 3) Tablet
g of the compound of Example 12, 90 g of lactose,
34 g of corn starch, 20 g of crystalline cellulose, and 1
g of magnesium stearate can be mixed using a blender and
then compressed in a tableting machine to give tablets.
(Test Example 1 Mdm2/p53 binding assay)
A protein dilution containing 6.25 nM each of His-
p53 (fusion protein of a p53 partial protein having p53
amino acids at positions 1 to 132, with a histidine
protein) and GST-Mdm2 (fusion protein of a Mdm2 partial
protein, having Mdm2 amino acids at positions 25 to 108
with leucine residue 33 substituted by glutamic acid,
with glutathione transferase) proteins was prepared using
a protein buffer solution (20 mM HEPES pH 7.4, 150 mM
NaCl, 0.1% BSA). This protein dilution was added in an
amount of 8 m L/well to a 384-well plate (384-well low
volume NBC, Corning Inc., catalog No: 3676).
Next, a test compound was diluted with DMSO to
produce protein buffer solution containing 10% dilution,
and this buffer solution was added in an amount of 4
m L/well to the plate.
Subsequently, a solution containing an XL665-labeled
anti-His antibody (HTRF monoclonal anti-6HIS antibody
labeled with XL665 (catalog No: 61HISXLB),
Schering/Cisbio Bioassays) and a europium (Eu)-labeled
anti-GST antibody (HTRF monoclonal anti-GST antibody
labeled with europium cryptate, Schering/Cisbio Bioassays,
catalog No: 61GSTKLB) at concentrations of 2.5 m g/mL and
0.325 m g/mL, respectively, was prepared using an antibody
diluting buffer solution (20 mM HEPES pH 7.4, 150 mM NaCl,
0.1% BSA, 0.5 M KF). These dilutions were added in an
amount of 8 m L/well (total reaction solution volume: 20
m l/well). Then, the plate was left at 25 C for 1 hour.
Time-resolved fluorescence at 620 and 665 nm was
measured at an excitation wavelength of 320 nm using a
plate reader (ARVOsx, PerkinElmer Co., Ltd. or PHERAstar,
BMG LABTECH). Ratio (R) was calculated using the
measured values (RFU 620 nm and RFU 665 nm) according to
the following formula:
R = (RFU 665 nm-BI-C· RFU 620 nm)/RFU 620 nm
BI: measured value at 665 nm of reaction solution (only
each buffer solution) nonsupplemented with each protein,
the compound, and the antibodies
C (correction factor) = (A-BI)/D
A and D: each measured value at 665 nm and 620 nm of
reaction solution supplemented with only Eu-labeled anti-
GST antibody solution.
The R value calculated from the well supplemented
with His-p53, GST-Mdm2, the test compound, and each
antibody was defined as R (sample). The R value
calculated from the well supplemented with His-p53, GST-
Mdm2, and each antibody but without the test compound was
defined as R (control). The R value calculated from the
well supplemented with GST-Mdm2, the test compound, and
each antibody but without His-p53 was defined as R
(background). T/C was calculated from the formula shown
below. An IC value for Mdm2/p53 binding was calculated
by sigmoid fitting. The results are shown in Table 1.
T/C = (R (sample)-R (background))/(R (control)-R
(background))
The IC value of the compound of each Example was as
follows:
0.001 £ IC (m M) < 0.05: Examples Nos. 3, 6, 7, 8, 9, 11,
12, 13, 16, 20, 21, 23, 25, 27, 28, 29,30, 33, 34, 36,38,
40, 41, 42, 44, 46, 48, 49, 53, 55, 56, 57, 65, 67, 68,
69, 70, 71, 72, 75, 76, 77, 78, 81, 82, 83, 85, 86, 87,
89, 90, 92, 97, 99, 100, 101, 102, 103, 104, 105, 106,
107, 108, 109, 110, 111, 113, 114, 115,116, 117, 118, 119,
120, 122, 124, 125, 126, 127, 128, 129, 130, 134, 136,
139, 141, 142, 144, 146, 148, 150, 151, 152, 153, 156,
158, 167, 172, 174, 176, 178, 179, 180, 181, 182, 185,
186, 187, 188, 189, 191, 192, 193.
0.05 £ IC (m M) < 0.1: Examples Nos. 1, 2, 5, 10, 15, 17,
18, 19, 22, 24, 26, 31, 32, 35, 37, 39, 45, 47, 50, 51,
52, 54, 58, 59, 60, 61, 62, 63, 64, 66, 73, 74, 79, 80,
84, 88, 91, 93, 94, 95, 96, 98, 112, 121, 123, 131, 132,
133, 137, 138, 140, 143, 145, 147, 149, 154, 155, 157,
159, 160, 161, 162, 163, 165, 166, 166, 169, 170, 171,
173, 175, 177, 183, 184, 190.
0.1 £ IC (m M) < 0.5: Examples Nos. 4, 14, 43, 135, 164,
168.
(Test Example 2 Cell growth inhibition assay)
A cell growth inhibition assay was conducted using
human lung cancer-derived cell line NCI-H460 having wild-
type p53.
NCI-H460 cells were suspended in a medium (RPMI1640
medium containing 10% fetal bovine serum) and the
suspension was inoculated in an amount of 500 cells/150
m L/well to a 96-well multiwell plate. A test compound
was dissolved in DMSO and this solution was diluted with
medium to prepare a sample solution (DMSO concentration:
1% or lower). On the next day of inoculation, medium
nonsupplemented with the test compound or the sample
solution was added in an amount of 50 m L/well. The MTT
assay was conducted immediately after the medium was
added in an amount of 50 m L on the next day of cell
inoculation, and after the sample solution or the medium
was added to cells followed by culturing at 37 C for 3
days in a 5% CO atmosphere. The MTT assay was conducted
as shown below.
A 5 mg/mL MTT (3-(4,5-dimethylthiazolyl)-2,5-
diphenyltetrazolium bromide, Sigma-Aldrich Co., M-2128)
solution was prepared using a phosphate buffer solution
(Dulbecco's Phosphate-buffered Saline). This MTT
solution was added in an amount of 20 m L/well. Then, the
plate was cultured at 37 C for 4 hours in a 5% CO
atmosphere. The plate was centrifuged at 1200 rpm for 5
minutes and then the culture supernatant was removed by
aspiration using a dispenser. DMSO was added in an
amount of 150 m L/well to dissolve generated formazan.
The plate was stirred using a plate mixer for uniform
color development from each well. The absorbance of each
well was measured under conditions of OD 540 nm and
reference 660 nm using a plate reader (SpectraMax PLUS384,
Molecular Devices, CA, USA).
The OD value measured on the day of adding the
sample solution was defined as S. The OD value measured
three days after addition of the sample solution was
defined as T. The OD value measured three days after
addition of the DMSO dilution was defined as C. T/C (%)
was determined at each concentration according to the
calculation formula shown below to prepare a dose
response curve, from which 50% growth inhibition
concentration (GI value) was calculated.
T/C (%) = (T-S)/(C-S)· 100
The GI values of the compounds of Examples
subjected to this test were as follows:
GI (m M) < 0.1: Examples Nos. 20, 31, 35, 70, 99, 100,
110, 113, 116, 156, 160, 182.
0.1 £ GI (m M) < 0.5: Examples Nos. 1, 8, 13, 16, 17, 18,
23, 24, 32, 34, 38, 51, 57, 67, 69, 77, 88, 90, 93, 94,
96, 97, 107, 109, 111, 112, 115, 117, 154, 161, 162, 183,
184, 185, 188, 191.
0.5 £ GI (m M) < 1.0: Examples Nos. 3, 7, 11, 14, 25, 26,
40, 47, 53, 54, 108, 114.
1.0 £ GI (m M) < 5.0: Examples Nos. 2, 4, 5, 6, 28, 29,
, 164, 179, 180, 186.
.0 < GI (m M): Example No. 174
(Test Example 3 Anti-tumor activity test)
A human osteosarcoma cell line SJSA-1 or SJSARE
(cells in which a p53 reporter gene is incorporated in
SJSA-1) is subcutaneously transplanted to nude mice
(BALB/C-nu/nu SLC, male, Japan SLC, Inc.). At the point
in time when the tumor size reaches approximately 100 to
200 mm , the mice are divided into groups (6 mice/group).
A test compound was suspended in 0.5% methylcellulose
solution and orally administered twice a day (bid) at a
dose of 50 mg/kg, once a day (qd) at a dose of 50 mg/kg,
or once a day (qd) at a dose of 25 mg/kg for 4
consecutive days. After a 2-day drug holiday, the mice
are dissected, the tumors are excised and then their
weights are measured.
The anti-tumor effect (IR (%)) is calculated
according to the following formula:
IR (%) = [1-(average tumor weight of compound-
administered group/average tumor weight of untreated
control group)]· 100.
(Test Example 4 Metabolic stability test)
100 m L of 100 mM phosphate buffer solution (pH 7.4)
containing 3 m M test compound was added to 100 m L of
reaction solution containing 100 mM phosphate buffer
solution (pH 7.4), 30 mM glucose 6-phosphate, 10 mM
MgCl 6H O, 3 units/mL glucose 6-phosphate 1-dehydrogenase,
and 0.3 to 1.5 mgP/mL human liver microsomes and the
mixture was incubated at 37 C for 20 minutes. Then, 70
m L of 100 mM phosphate buffer solution (pH 7.4)
containing 3 mM NADP+ was added and the mixture was
further incubated at 37 C for 30 minutes to conduct a
microsomal metabolism test. The compound was quantified
by the internal standard method using a quadrupole mass
spectrometer connected to a high performance liquid
chromatography apparatus. The metabolic stability
(residual percentage of compound: MS%) was determined
according to the following formula:
MS (human) (%) = (peak area ratio of test compound
after addition of NADP+ and incubation for 30
minutes)/(peak area ratio of test compound before
addition of NADP+)· 100.
(peak area ratio: peak area of test compound divided by
that of internal standard substance)
Of the compounds of Examples subjected to this test,
the following compounds exhibited MS% of 30 or more:
70 £ MS% £ 100: Examples Nos. 1, 2, 3, 4, 6, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 20, 23, 24, 25, 29, 30, 31,
34, 36, 38, 39, 40, 41, 43, 45, 46, 51, 53, 54, 56, 57,
60, 63, 64, 65, 67, 69, 70, 76, 77, 79, 84, 85, 87, 88,
90, 91, 92, 93, 94, 95, 98, 103, 106, 107, 108, 109, 110,
122, 123, 124, 125, 126, 149, 151, 156, 157, 158, 159,
163, 164, 165.
50 £ MS% < 70: Examples Nos. 5, 32, 35, 37, 47, 48, 55,
59, 68, 71, 99, 128, 155.
£ MS% < 50: Examples Nos. 7, 19, 26, 52, 62, 66, 100,
101, 127, 153.
Claims (33)
1. A compound represented by general formula (1) or a salt thereof: wherein ring A represents a spiro-linked 4- to 6-membered saturated hydrocarbon ring which may have one or more substituents selected from Group 1, or a spiro-linked 6- membered saturated heterocyclic ring which may have one or more substituents selected from Group 1; ring B represents a benzene ring which may have one or more substituents selected from Group 2, a pyridine ring which may have one or more substituents selected from Group 2, or a pyrimidine ring which may have one or more substituents selected from Group 2; R represents an aryl group which may have one or more substituents selected from Group 3, a heteroaryl group which may have one or more substituents selected from Group 3, a C -C cycloalkyl group which may have one or more substituents selected from Group 3, or a C -C cycloalkenyl group which may have one or more substituents selected from Group 3; R represents a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom; and R represents a group represented by the following general formulae (2), (3), or (4): wherein in formula (2), R and R each independently represent a hydroxy group, a C -C alkyl group, or a C -C alkoxy group, or R and R 1 6 1 6 together with the carbon atoms to which the R and R groups are respectively bonded may form a 4- to 6- membered saturated hydrocarbon ring; in formula (3), the broken line in the ring structure indicates that the bond may be a double bond, R represents a C -C alkyl group which may have one or more substituents selected from Group 4, a carbamoyl group which may have one or more substituents selected from Group 5, a 5- or 6-membered nitrogen-containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group, a hydroxy group, or -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C -C cycloalkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R' and R'' together with the nitrogen atom to which R' and R'' are bonded may form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, R represents a C -C alkyl group which may be substituted with one hydroxy group, a hydroxy group, or a hydrogen atom, or R and R may together form a spiro-linked 4- to 6- membered hydrocarbon ring or a spiro-linked 4- to 6- membered nitrogen-containing heterocyclic ring, R is absent or represents one or more substituents selected from a hydroxy group, a C -C alkyl group, and a C -C alkoxy group, and Z represents CH , NH, or an oxygen atom; and in formula (4), R represents a C -C alkyl group which may have one or more substituents selected from Group 4, a carbamoyl group which may have one or more substituents selected from Group 5, a 5- or 6-membered nitrogen-containing heteroaryl group which may be substituted with an oxo group or one or more C -C alkyl groups which may be substituted with an oxo group or one hydroxy group, a hydroxy group, or -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, an oxo group, or one to three hydroxy groups, a C -C cycloalkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R' and R'' together with the nitrogen atom to which R' and R'' are bonded may form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, R represents a C -C alkyl group which may be substituted with one hydroxy group, a hydroxy group, or a hydrogen atom, or 9 10 R and R may together form a spiro-linked 4- to 6- membered hydrocarbon ring or a spiro-linked 4- to 6- membered nitrogen-containing heterocyclic ring, and R is absent or represents one or more substituents selected from a hydroxy group, a C -C alkyl group, and a C -C alkoxy group: Group 1: a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, a C -C alkoxy group, and a cyano group, Group 2: a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, a C -C cycloalkyl group which may be substituted with one to three halogen atoms, a vinyl group, an ethynyl group, a cyano group, and a C -C alkoxy group, Group 3: a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a C -C cycloalkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a vinyl group, an ethynyl group, a cyano group, -OR', -NR'R'', -COOR', and -CONHR', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, a C -C cycloalkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R' and R'' together with the nitrogen atom to which R' and R'' are bonded may form a 4- to 7-membered nitrogen- containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, Group 4: a halogen atom, a hydroxy group, a carbamoyl group, a morpholino group, a C -C alkoxy group, a C -C 1 6 1 6 alkylsulfonyl group, and -NR'R'', wherein R' and R'' each independently represent a C -C alkyl group which may be substituted with one to three halogen atoms, one to three hydroxy groups, or an oxo group, a C -C cycloalkyl group which may be substituted with one to three halogen atoms or one to three hydroxy groups, or a hydrogen atom, or R' and R'' together with the nitrogen atom to which R' and R'' are bonded may form a 4- to 7- membered nitrogen-containing heterocyclic group which may have one or more substituents selected from a C -C alkyl group and a hydroxy group, and Group 5: a C -C alkyl group which may be substituted with one to three halogen atoms, one to three hydroxy groups, or a C -C alkoxy group, a C -C cycloalkyl group, 1 6 3 6 a C -C alkoxy group, and a tetrahydropyranyl group.
2. A compound according to claim 1 in which ring B represents a benzene ring which may have one or two substituents bonded to the 5- or 6-position selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, a cyano group, and a C -C alkoxy group.
3. A compound according to claim 1 in which ring B represents a pyridine ring which may have one substituent bonded to the 6-position selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, a cyano group, and a C -C alkoxy group.
4. A compound according to any one of the preceding claims in which R represents a phenyl group which may have one chlorine atom bonded to the 3-position or a chlorine atom and a fluorine atom bonded to the 3- and 2- positions respectively.
5. A compound according to any one of claims 1 to 3 in which R represents a pyridyl group which may have one chlorine atom bonded to the 2-position or a chlorine atom and a fluorine atom bonded to the 2- and 3-positions respectively.
6. A compound according to claim 1 represented by general formula (7) or a salt thereof: NH (7) wherein 2 3 2 ring A, R , and R have the same meanings as ring A, R , and R , respectively, in claim 1; 12 13 16 R , R , and R represent a group selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group; and R is absent or represents one or more substituents selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atomss, and a cyano group.
7. A compound according to claim 1 represented by general formula (8) or a salt thereof: NH (8) wherein 2 3 2 ring A, R , and R have the same meanings as ring A, R , and R , respectively, in claim 1; 12 13 16 R , R , and R represent a group selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group; and R is absent or represents one or more substituents selected from a halogen atom, a C -C alkyl group which may be substituted with one to three halogen atoms, and a cyano group.
8. A compound according to claim 1 which is selected from the following group or a salt thereof: O N N O N Cl Cl Cl H H H OH F N Cl Cl Cl N O N O N O H H H H H H N N N N O O O Cl Cl Cl H H H F F OH N N N Cl Cl N O N N H H H H H H O N N O N O N Cl Cl Cl OH H F F F N N N Cl Cl Cl N O N O N O H H H H H H N N N N N N O O O O O O Cl Cl Cl H H H OH NH OH F F F N N N Cl Cl Cl O O O N N N H H H H H H O N O N O N Cl Cl Cl H OH H H F F F N N N Cl Cl Cl N O N O N O H H H N O N N O N Cl Cl OH Cl Cl N O N O
9. A compound according to claim 1 which is (3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran- 3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4- dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'- pyrrolidine-3',3"-indole]-5'-carboxamide hydrochloride.
10. A compound according to claim 1 which is (3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran- 3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4- dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'- pyrrolidine-3',3"-indole]-5'-carboxamide sulfate.
11. A compound according to claim 1 which is (3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran- 3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4- dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'- pyrrolidine-3',3"-indole]-5'-carboxamide methanesulfonate.
12. A compound according to claim 1 which is (3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran- 3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4- dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'- pyrrolidine-3',3"-indole]-5'-carboxamide ethanesulfonate.
13. A compound according to claim 1 which is (3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran- 3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4- dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'- pyrrolidine-3',3"-indole]-5'-carboxamide benzenesulfonate.
14. A compound according to claim 1 which is (3'R,4'S,5'R)-N-[(3R,6S)carbamoyltetrahydro-2H-pyran- 3-yl]-6"-chloro-4'-(2-chlorofluoropyridinyl)-4,4- dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane-1,2'- pyrrolidine-3',3"-indole]-5'-carboxamide p- toluenesulfonate.
15. A compound according to claim 1 which is (3'R,4'S,5'R)-6"-chloro-4'-(2-chlorofluoropyridin yl)-N-{(3R,6S)[1-hydroxyethyl]tetrahydro-2H-pyran yl}-4,4-dimethyl-2"-oxo-1",2"-dihydrodispiro[cyclohexane- 1,2'-pyrrolidine-3',3"-indole]-5'-carboxamide benzenesulfonate.
16. An inhibitor of Mdm2 comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15.
17. An inhibitor of Mdm2 ubiquitin ligase comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to
18. An inhibitor of p53-Mdm2 binding comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to
19. An inhibitor of suppression of p53 transcription activity comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15.
20. An inhibitor of p53 degradation comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to
21. A medicament comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15 as an active ingredient.
22. An anticancer agent comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15 as an active ingredient.
23. An anticancer agent according to claim 22, wherein the cancer is lung cancer, breast cancer, prostate cancer, colon cancer, acute myeloid leukemia, malignant lymphoma, malignant melanoma, retinoblastoma, neuroblastoma, or sarcoma.
24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15 and a pharmaceutically acceptable carrier.
25. Use of a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15 for the manufacture of a medicament.
26. Use of a compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15 for the manufacture of an anticancer agent.
27. A compound according to claim 1, substantially as herein described with reference to any one of the Examples thereof.
28. A compound according to any one of claims 1 to 8 or a salt thereof or a compound according to any one of claims 9 to 15, substantially as herein described.
29. An inhibitor according to any one of claims 16 to 20, substantially as herein described.
30. A medicament according to claim 21, substantially as herein described.
31. An anticancer agent according to claim 22 or 23, substantially as herein described.
32. A pharmaceutical composition according to claim 24, substantially as herein described.
33. Use according to claim 25 or 26, substantially as herein described.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ710585A NZ710585B2 (en) | 2011-03-10 | 2012-03-09 | Dispiropyrrolidine derivatives |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011-052687 | 2011-03-10 | ||
JP2011052687 | 2011-03-10 | ||
US201161546805P | 2011-10-13 | 2011-10-13 | |
US61/546805 | 2011-10-13 | ||
PCT/JP2012/056066 WO2012121361A1 (en) | 2011-03-10 | 2012-03-09 | Dispiropyrrolidine derivative |
Publications (2)
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NZ614218A NZ614218A (en) | 2015-08-28 |
NZ614218B2 true NZ614218B2 (en) | 2015-12-01 |
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