U.S. patent application number 17/239191 was filed with the patent office on 2021-09-09 for heterocyclic compound and use thereof.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. The applicant listed for this patent is Takeda Pharmaceutical Company Limited. Invention is credited to Yasushi HATTORI, Yasutaka HOASHI, Keisuke IMAMURA, Yoshiteru ITO, Yuichi KAJITA, Tatsuki KOIKE, Yuhei MIYANOHANA, Tohru MIYAZAKI, Tsuneo ODA, Alexander Martin PAWLICZEK, Takahiro SUGIMOTO, Kohei TAKEUCHI, Norihito TOKUNAGA.
Application Number | 20210276949 17/239191 |
Document ID | / |
Family ID | 1000005539370 |
Filed Date | 2021-09-09 |
United States Patent
Application |
20210276949 |
Kind Code |
A1 |
HATTORI; Yasushi ; et
al. |
September 9, 2021 |
HETEROCYCLIC COMPOUND AND USE THEREOF
Abstract
The present invention provides a heterocyclic compound having an
orexin type 2 receptor agonist activity. A compound represented by
the formula (I): ##STR00001## wherein each symbol is as described
in the specification, or a salt thereof has an orexin type 2
receptor agonist activity, and is useful as an agent for the
prophylaxis or treatment of narcolepsy.
Inventors: |
HATTORI; Yasushi; (Kanagawa,
JP) ; MIYANOHANA; Yuhei; (Kanagawa, JP) ;
KAJITA; Yuichi; (Kanagawa, JP) ; KOIKE; Tatsuki;
(Kanagawa, JP) ; HOASHI; Yasutaka; (Kanagawa,
JP) ; TOKUNAGA; Norihito; (Kanagawa, JP) ;
PAWLICZEK; Alexander Martin; (Kanagawa, JP) ; ODA;
Tsuneo; (Kanagawa, JP) ; MIYAZAKI; Tohru;
(Kanagawa, JP) ; ITO; Yoshiteru; (Kanagawa,
JP) ; TAKEUCHI; Kohei; (Kanagawa, JP) ;
IMAMURA; Keisuke; (Kanagawa, JP) ; SUGIMOTO;
Takahiro; (Kanagawa, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Takeda Pharmaceutical Company Limited |
Osaka |
|
JP |
|
|
Assignee: |
Takeda Pharmaceutical Company
Limited
Osaka
JP
|
Family ID: |
1000005539370 |
Appl. No.: |
17/239191 |
Filed: |
April 23, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
16777273 |
Jan 30, 2020 |
11028048 |
|
|
17239191 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 417/06 20130101;
C07D 407/08 20130101; C07D 207/14 20130101 |
International
Class: |
C07D 207/14 20060101
C07D207/14; C07D 407/08 20060101 C07D407/08; C07D 417/06 20060101
C07D417/06 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 31, 2019 |
JP |
2019-015488 |
Claims
1. A compound represented by the formula (I): ##STR00632## wherein
R.sup.1 is an optionally substituted C.sub.1-6 alkyl group, an
optionally substituted mono- or di-C.sub.1-6 alkylamino group, an
optionally substituted C.sub.3-6 cycloalkyl group, or an optionally
substituted 3- to 14-membered non-aromatic heterocyclic group;
R.sup.2 is a hydrogen atom, a fluorine atom, an optionally
substituted C.sub.1-6 alkyl group, or an optionally substituted
C.sub.3-6 cycloalkyl group; R.sup.3 is an acyl group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
C.sub.3-6 cycloalkyl group, an optionally substituted C.sub.6-14
aryl group, an optionally substituted 3- to 14-membered
non-aromatic heterocyclic group, or an optionally substituted 5- to
14-membered aromatic heterocyclic group; and Ring A is an
optionally further substituted C.sub.6-14 aromatic hydrocarbon
ring, or an optionally further substituted 5- to 14-membered
aromatic heterocycle, or a salt thereof.
2. The compound or salt according to claim 1, wherein R.sup.1 is
(1) a C.sub.1-6 alkyl group, (2) a mono- or di-C.sub.1-6 alkylamino
group, or (3) a C.sub.3-6 cycloalkyl group; R.sup.2 is (1) a
hydrogen atom, (2) a fluorine atom, or (3) a C.sub.1-6 alkyl group;
R.sup.3 is (1) a C.sub.1-6 alkyl-carbonyl group optionally
substituted by 1 to 3 substituents selected from (a) a halogen
atom, (b) a hydroxy group, and (c) a cyano group, (2) a C.sub.1-6
alkoxy-carbonyl group, (3) a C.sub.3-10 cycloalkyl-carbonyl group
(the C.sub.3-10 cycloalkyl moiety of the C.sub.3-10
cycloalkyl-carbonyl group is optionally bridged) optionally
substituted by 1 to 3 substituents selected from (a) a halogen
atom, (b) a hydroxy group, (c) a cyano group, and (d) a C.sub.1-6
alkyl group, (4) a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group optionally substituted by 1 to 3
substituents selected from (a) a halogen atom, (b) a hydroxy group,
and (c) a C.sub.1-6 alkyl group, (5) a mono- or di-C.sub.1-6
alkyl-carbamoyl group, (6) a N--C.sub.1-6 alkyl-N--C.sub.1-6
alkoxy-carbamoyl group, or (7) a N--C.sub.1-6
alkyl-N',N'-di-C.sub.1-6 alkylhydrazine-carbonyl group; and Ring A
is (1) a benzene ring further substituted by one substituent
selected from (a) a C.sub.6-14 aryl group optionally substituted by
1 to 3 substituents selected from (i) a halogen atom, (ii) an
optionally halogenated C.sub.1-6 alkyl group, and (iii) an
optionally halogenated C.sub.1-6 alkoxy group, and (b) a 5- to
14-membered aromatic heterocyclic group optionally substituted by 1
to 3 substituents selected from (i) a C.sub.1-6 alkyl group
optionally substituted by 1 to 3 substituents selected from a
halogen atom and a hydroxy group, (ii) a C.sub.1-6 alkoxy group,
(iii) a halogen atom, and (iv) a C.sub.1-6 alkoxy-carbonyl group,
and optionally further substituted by 1 to 3 halogen atoms, or (2)
a 5- or 6-membered aromatic heterocycle further substituted by one
C.sub.6-14 aryl group optionally substituted by 1 to 3 halogen
atoms.
3. The compound or salt according to claim 1, wherein R.sup.1 is
(1) a C.sub.1-6 alkyl group, (2) a mono- or di-C.sub.1-6 alkylamino
group, or (3) a C.sub.3-6 cycloalkyl group; R.sup.2 is (1) a
hydrogen atom, or (2) a fluorine atom; R.sup.3 is (1) a C.sub.1-6
alkyl-carbonyl group optionally substituted by 1 to 3 hydroxy
groups, (2) a C.sub.3-10 cycloalkyl-carbonyl group (the C.sub.3-10
cycloalkyl moiety of the C.sub.3-10 cycloalkyl-carbonyl group is
optionally bridged) optionally substituted by 1 to 3 substituents
selected from (a) a halogen atom, and (b) a hydroxy group, (3) a 3-
to 8-membered monocyclic non-aromatic heterocyclylcarbonyl group,
or (4) a mono- or di-C.sub.1-6 alkyl-carbamoyl group; and Ring A is
a benzene ring further substituted by one C.sub.6-i.sub.4 aryl
group optionally substituted by 1 to 3 substituents selected from
(i) a halogen atom, and (ii) an optionally halogenated C.sub.1-6
alkyl group, and optionally further substituted by 1 to 3 halogen
atoms.
4. The compound or salt according to claim 1, wherein R.sup.1 is
(1) a C.sub.1-6 alkyl group, or (2) a mono- or di-C.sub.1-6
alkylamino group; R.sup.2 is (1) a hydrogen atom, or (2) a fluorine
atom; R.sup.3 is (1) a C.sub.1-6 alkyl-carbonyl group optionally
substituted by 1 to 3 hydroxy groups, (2) a 3- to 8-membered
monocyclic non-aromatic heterocyclylcarbonyl group, or (3) a mono-
or di-C.sub.1-6 alkyl-carbamoyl group; and Ring A is a benzene ring
further substituted by one C.sub.6-14 aryl group optionally
substituted by 1 to 3 substituents selected from (i) a halogen
atom, and (ii) a C.sub.1-6 alkyl group, and optionally further
substituted by 1 to 3 halogen atoms.
5.-7. (canceled)
8. A medicament comprising the compound or salt according to claim
1.
9. The medicament according to claim 8, which is an orexin type 2
receptor agonist.
10.-11. (canceled)
12. A method of activating an orexin type 2 receptor in a mammal,
which comprises administering an effective amount of the compound
or salt according to claim 1 to the mammal.
13. A method for the prophylaxis or treatment of narcolepsy in a
mammal, which comprises administering an effective amount of the
compound or salt according to claim 1 to the mammal.
14. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to a heterocyclic compound,
particularly, a heterocyclic compound having an orexin type 2
receptor agonist activity.
BACKGROUND OF THE INVENTION
[0002] Orexin is a neuropeptide specifically produced in particular
neurons located sparsely in the lateral hypothalamus and its
surrounding area, and consists of two subtypes, orexin A and orexin
B. Both orexin A and orexin B are endogenous ligands of the orexin
receptors, which are G protein-coupled receptors mainly present in
the brain, and two types of subtypes, type 1 and type 2, are known
for the orexin receptors (non-patent document 1).
[0003] Since orexin-producing neurons (orexin neurons) are
localized in the vicinity of the feeding center, and
intraventricular administration of orexin peptide results in an
increase in food intake, orexin initially attracted attention as a
neuropeptide having a feeding behavioral regulation. Thereafter,
however, it was reported that the cause of dog narcolepsy is
genetic variation of orexin type 2 receptor (non-patent document
2), and the role of orexin in controlling sleep and wakefulness has
been also attracted.
[0004] From the studies using a transgenic mouse having denatured
orexin neurons and a double transgenic mouse obtained by crossing
this mouse with orexin overexpressing transgenic mouse, it was
clarified that narcolepsy-like symptoms that appear by degeneration
of orexin neurons disappear due to sustained expression of orexin.
Similarly, when orexin peptide was intraventricularly administered
to a transgenic mouse having denatured orexin neuron, improvement
of narcolepsy-like symptoms was also observed (non-patent document
3). Studies of orexin type 2 receptor knockout mice have suggested
that orexin type 2 receptor is important for maintaining arousal
(non-patent document 4, non-patent document 5). Such background
suggests that orexin type 2 receptor agonists become therapeutic
drugs for narcolepsy or therapeutic drugs for other sleep disorders
exhibiting excessive sleepiness (non-patent document 6).
[0005] In addition, it is suggested that a peptidic agonist that
selectively acts on the orexin type 2 receptor improves obesity due
to high fat diet load in mice (non-patent document 7).
[0006] In addition, it is suggested that intraventricular
administration of orexin peptide shortens the systemic anesthetic
time of rat (non-patent document 8).
[0007] In addition, it is suggested that patients with sleep apnea
syndrome show low orexin A concentration levels in plasma
(non-patent document 9).
[0008] In addition, it is suggested that intraventricular
administration of orexin peptide improves memory retention of
senescence-accelerated model mouse (SAMP8) with cognitive
dysfunction (non-patent document 10).
[0009] In addition, it is suggested that Orexin type 2 receptor
agonist will be a therapeutic drug for cardiac failure (patent
document 1, non-patent document 11).
[0010] In addition, it is suggested that the daytime sleepiness of
Parkinson's disease patients is caused by orexin nerve fallout
(non-patent document 12). 1 In addition, it is suggested that
orexin regulates bone formation and bone loss, and orexin type 2
receptor agonist will be a therapeutic drug for diseases related to
bone loss such as osteoporosis, rheumatoid arthritis and the like
(patent document 2).
[0011] In addition, it is suggested that orexin receptor agonist is
useful for the prophylaxis or treatment of sepsis, severe sepsis
and septic shock, since the mortality was significantly improved by
mere continuous administration of orexin from the periphery in
septic shock model mouse (patent document 3).
[0012] Therefore, a compound having an orexin type 2 receptor
agonist activity is expected to be useful as a novel therapeutic
drug for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep
apnea syndrome, disturbance of consciousness such as coma and the
like, narcolepsy syndrome accompanied by narcolepsy-like symptoms,
hypersomnia syndrome accompanied by daytime hypersomnia (e.g.,
Parkinson's disease, Guillain-Barre syndrome and Kleine Levin
syndrome), Alzheimer, obesity, insulin resistance syndrome, cardiac
failure, diseases related to bone loss, sepsis and the like,
further, anesthetic antagonist, a prophylactic or therapeutic drug
for side effects' and complications due to anesthesia.
[0013] As sulfonamide derivatives, a compound represented by the
formula
##STR00002##
wherein each symbol is as described in the document (Patent
Document 4) has been reported.
[0014] In addition, as compounds having an orexin type 2 receptor
agonist activity, the following compounds have been reported.
[0015] A compound represented by the formula
##STR00003##
wherein each symbol is as described in the document (Patent
Document 5).
[0016] A compound represented by the formula
##STR00004##
wherein each symbol is as described in the document (Patent
Document 6).
[0017] A compound represented by the formula
##STR00005##
wherein each symbol is as described in the document (Patent
Document 7).
[0018] A compound represented by the formula
##STR00006##
wherein each symbol is as described in the document (Patent
Document 8).
[0019] A compound represented by the formula
##STR00007##
wherein each symbol is as described in the document (Patent
Document 9).
[0020] A compound represented by the formula
##STR00008##
wherein each symbol is as described in the document (Patent
Document 10).
[0021] A compound represented by the formula
##STR00009##
wherein each symbol is as described in the document (Patent
Document 11).
[0022] Development of a novel compound having an orexin type 2
receptor agonist activity is desired.
DOCUMENT LIST
Patent Document
[0023] [Patent Document 1] WO 2015/073707 A1 [0024] [Patent
Document 2] WO 2015/048091 A1 [0025] [Patent Document 3] WO
2015/147240 A1 [0026] [Patent Document 4] WO 2012/137982 A9 [0027]
[Patent Document 5] WO 2017/135306 A1 [0028] [Patent Document 6] WO
2018/164191 A1 [0029] [Patent Document 7] WO 2018/164192 A1 [0030]
[Patent Document 8] WO 2019/027003 A1 [0031] [Patent Document 9] WO
2019/027058 A1 [0032] [Patent Document 10] WO 2020/004536 A1 [0033]
[Patent Document 11] WO 2020/004537 A1
Non-Patent Document
[0033] [0034] [Non-Patent Document 1] Cell, Vol. 92, 573-585, 1998
[0035] [Non-Patent Document 2] Cell, Vol. 98, 365-376, 1999 [0036]
[Non-Patent Document 3] Proc. Natl. Acad. Sci. USA, Vol. 101,
4649-4654, 2004 [0037] [Non-Patent Document 4] Cell, Vol. 98,
437-451, 1999 [0038] [Non-Patent Document 5] Neuron, Vol. 38,
715-730, 2003 [0039] [Non-Patent Document 6] CNS Drugs, Vol. 27,
83-90, 2013 [0040] [Non-Patent Document 7] Cell Metabolism, Vol. 9,
64-76, 2009 [0041] [Non-Patent Document 8] Neuroscience, Vol. 121,
8'55-863, 2003 [0042] [Non-Patent Document 9] Respiration, Vol. 71,
575-579, 2004 [0043] [Non-Patent Document 10] Peptides, Vol. 23,
1683-1688, 2002 [0044] [Non-Patent Document 11] Journal of the
American College of Cardiology. Vol. 66, 2015, Pages 2522-2533
[0045] [Non-Patent Document 12] Brain. Vol. 130, 2007, Pages
1586-1595
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0046] The present invention aims to provide a heterocyclic
compound having an orexin type 2 receptor agonist activity.
Means of Solving the Problems
[0047] The present inventors have found that a compound represented
by the following formula (I) or a salt thereof (sometimes to be
referred to as compound (I) in the present specification) has an
orexin type 2 receptor agonist activity.
[0048] As a result of further studies, they have completed the
present invention.
[0049] Accordingly, the present invention relates to the
followings.
[1]
[0050] A compound represented by the formula (I):
##STR00010##
wherein R.sup.1 is an optionally substituted C.sub.1-6 alkyl group,
an optionally substituted mono- or di-C.sub.1-6 alkylamino group,
an optionally substituted C.sub.3-6 cycloalkyl group, or an
optionally substituted 3- to 14-membered non-aromatic heterocyclic
group; R.sup.2 is a hydrogen atom, a fluorine atom, an optionally
substituted C.sub.1-6 alkyl group, or an optionally substituted
C.sub.3-6 cycloalkyl group; R.sup.3 is an acyl group, an optionally
substituted C.sub.1-6 alkyl group, an optionally substituted
C.sub.3-6 cycloalkyl group, an optionally substituted C.sub.6-14
aryl group, an optionally substituted 3- to 14-membered
non-aromatic heterocyclic group, or an optionally substituted 5- to
14-membered aromatic heterocyclic group; and Ring A is an
optionally further substituted C.sub.6-14 aromatic hydrocarbon
ring, or an optionally further substituted 5- to 14-membered
aromatic heterocycle, or a salt thereof. [2]
[0051] The compound or salt of the above-mentioned [1], wherein
R.sup.1 is
[0052] (1) a C.sub.1-6 alkyl group, (2) a mono- or di-C.sub.1-6
alkylamino group, or (3) a C.sub.3-6 cycloalkyl group;
R.sup.2 is
[0053] (1) a hydrogen atom, (2) a fluorine atom, or (3) a C.sub.1-6
alkyl group;
R.sup.3 is
[0054] (1) a C.sub.1-6 alkyl-carbonyl group optionally substituted
by 1 to 3 substituents selected from [0055] (a) a halogen atom,
[0056] (b) a hydroxy group, and [0057] (c) a cyano group, (2) a
C.sub.1-6 alkoxy-carbonyl group, (3) a C.sub.3-10
cycloalkyl-carbonyl group (the C.sub.3-10 cycloalkyl moiety of the
C.sub.3-10 cycloalkyl-carbonyl group is optionally bridged)
optionally substituted by 1 to 3 substituents selected from [0058]
(a) a halogen atom, [0059] (b) a hydroxy group, [0060] (c) a cyano
group, and [0061] (d) a C.sub.1-6 alkyl group, (4) a 3- to
14-membered non-aromatic heterocyclylcarbonyl group optionally
substituted by 1 to 3 substituents selected from [0062] (a) a
halogen atom, [0063] (b) a hydroxy group, and [0064] (c) a
C.sub.1-6 alkyl group, (5) a mono- or di-C.sub.1-6 alkyl-carbamoyl
group, (6) a N--C.sub.1-6 alkyl-N--C.sub.1-6 alkoxy-carbamoyl
group, or (7) a N--C.sub.1-6 alkyl-N',N'-di-C.sub.1-6
alkylhydrazine-carbonyl group; and
Ring A is
[0065] (1) a benzene ring further substituted by one substituent
selected from [0066] (a) a C.sub.6-14 aryl group optionally
substituted by 1 to 3 substituents selected from [0067] (i) a
halogen atom, [0068] (ii) an optionally halogenated C.sub.1-6 alkyl
group, and [0069] (iii) an optionally halogenated C.sub.1-6 alkoxy
group, and [0070] (b) a 5- to 14-membered aromatic heterocyclic
group optionally substituted by 1 to 3 substituents selected, from
[0071] (i) a C.sub.1-6 alkyl group optionally substituted by 1 to 3
substituents selected from a halogen atom and a hydroxy group,
[0072] (ii) a C.sub.1-6 alkoxy group, [0073] (iii) a halogen atom,
and [0074] (iv) a C.sub.1-6 alkoxy-carbonyl group, and optionally
further substituted by 1 to 3 halogen atoms, or (2) a 5- or
6-membered aromatic heterocycle further substituted by one
C.sub.6-14 aryl group optionally substituted by 1 to 3 halogen
atoms. [3]
[0075] The compound or salt of the above-mentioned [1], wherein
R.sup.1 is
[0076] (1) a C.sub.1-6 alkyl group, (2) a mono- or di-C.sub.1-6
alkylamino group, or (3) a C.sub.3-6 cycloalkyl group;
R.sup.2 is
[0077] (1) a hydrogen atom, or (2) a fluorine atom;
R.sup.3 is
[0078] (1) a C.sub.1-6 alkyl-carbonyl group optionally substituted
by 1 to 3 hydroxy groups, (2) a C.sub.3-10 cycloalkyl-carbonyl
group (the C.sub.3-10 cycloalkyl moiety of the C.sub.3-10
cycloalkyl-carbonyl group is optionally bridged) optionally
substituted by 1 to 3 substituents selected from [0079] (a) a
halogen atom, and [0080] (b) a hydroxy group, (3) a 3- to
8-membered monocyclic non-aromatic heterocyclylcarbonyl group, or
(4) a mono- or di-C.sub.1-6 alkyl-carbamoyl group; and Ring A is a
benzene ring further substituted by one C.sub.6-14 aryl group
optionally substituted by 1 to 3 substituents selected from [0081]
(i) a halogen atom, and [0082] (ii) an optionally halogenated
C.sub.1-6 alkyl group, and optionally further substituted by 1 to 3
halogen atoms. [4]
[0083] The compound or salt of the above-mentioned [1], wherein
R.sup.1 is
[0084] (1) a C.sub.1-6 alkyl group, or (2) a mono- or di-C.sub.1-6
alkylamino group;
R.sup.2 is
[0085] (1) a hydrogen atom, or (2) a fluorine atom;
R.sup.3 is
[0086] (1) a C.sub.1-6 alkyl-carbonyl group optionally substituted
by 1 to 3 hydroxy groups, (2) a 3- to 8-membered monocyclic
non-aromatic heterocyclylcarbonyl group, or (3) a mono- or
di-C.sub.1-6 alkyl-carbamoyl group; and Ring A is a benzene ring
further substituted by one C.sub.6-14 aryl group optionally
substituted by 1 to 3 substituents selected from [0087] (i) a
halogen atom, and [0088] (ii) a C.sub.1-6 alkyl group, and
optionally further substituted by 1 to 3 halogen atoms. [5]
[0089]
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3'-me-
thyl[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl)-N,N-dimethylsulfuric
diamide or a salt thereof.
[6]
[0090]
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluo-
ro-1-(2-methylpropanoyl)pyrrolidin-3-` `-yl]ethanesulfonamide or a
salt thereof.
[7]
[0091]
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-
-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
or a salt thereof.
[8]
[0092] A medicament comprising the compound or salt of any of the
above-mentioned [1] to [7].
[9]
[0093] The medicament of the above-mentioned [8], which is an
orexin type 2 receptor agonist.
[10]
[0094] The medicament of the above-mentioned [8], which is an agent
for the prophylaxis or treatment of narcolepsy.
[11]
[0095] The compound or salt of any of the above-mentioned [1] to
[7] for use in the prophylaxis or treatment of narcolepsy.
[12]
[0096] A method of activating an orexin type 2 receptor in a
mammal, which comprises administering an effective amount of the
compound or salt of any of the above-mentioned [1] to [7] to the
mammal.
[13]
[0097] A method for the prophylaxis or treatment of narcolepsy in a
mammal, which comprises administering an effective amount of the
compound or salt of any of the above-mentioned [1] to [7] to the
mammal.
[14]
[0098] Use of the compound or salt of any of the above-mentioned
[1] to [7] for the manufacture of an agent for the prophylaxis or
treatment of narcolepsy.
Effect of the Invention
[0099] The compound of the present invention has an orexin type 2
receptor agonist activity, and is useful as an agent for the
prophylaxis or treatment of narcolepsy.
DETAILED DESCRIPTION OF THE INVENTION
[0100] The definition of each substituent used in the present
specification is described in detail in the following. Unless
otherwise specified, each substituent has the following
definition.
[0101] In the present specification, examples of the "halogen atom"
include fluorine, chlorine, bromine and iodine.
[0102] In the present specification, examples of the "C.sub.1-6
alkyl group" include methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl.
[0103] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkyl group" include a C.sub.1-6 alkyl group
optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl,
pentafluoroethyl, propyl, 2,2-difluoropropyl,
3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl,
isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,
5,5,5-trifluoropentyl, hexyl and 6,6,6-trifluorohexyl.
[0104] In the present specification, examples of the "C.sub.2-6
alkenyl group" include ethenyl, 1-propenyl, 2-propenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,
3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,
4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
[0105] In the present specification, examples of the "C.sub.2-6
alkynyl group" include ethynyl-, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,
4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl
and 4-methyl-2-pentynyl.
[0106] In the present specification, examples of the "C.sub.3-10
cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl,
bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.
[0107] In the present specification, examples of the "optionally
halogenated C.sub.3-10 cycloalkyl group" include a C.sub.3-10
cycloalkyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include cyclopropyl,
2,2-difluorocyelopropyl, 2,3-difluorocyclopropyl, cyclobutyl,
difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[0108] In the present specification, examples of the "C.sub.3-10
cycloalkenyl group" include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
[0109] In the present specification, examples of the "C.sub.6-14
aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl,
2-anthryl and 9-anthryl.
[0110] In the present specification, examples of the "C.sub.7-16
aralkyl group" include benzyl, phenethyl, naphthylmethyl and
phenylpropyl.
[0111] In the present specification, examples of the "C.sub.1-6
alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
[0112] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkoxy group" include a C.sub.1-6 alkoxy
group optionally having 1 to 7, preferably 1 to 5, halogen
atoms.
[0113] Specific examples thereof include methoxy, difluoromethoxy,
trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy,
isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy,
pentyloxy and hexyloxy.
[0114] In the present specification, examples of the "C.sub.3-10
cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
cyclooctyloxy.
[0115] In the present specification, examples of the "C.sub.1-6
alkylthio group" include methylthio, ethylthio, propylthio,
isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio
and hexylthio.
[0116] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkylthio group" include a C.sub.1-6
alkylthio group optionally having 1 to 7, preferably 1 to 5,
halogen atoms.
[0117] Specific examples thereof include methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio,
isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio and
hexylthio.
[0118] In the present specification, examples of the "C.sub.1-6
alkyl-carbonyl group" include acetyl, propanoyl, butanoyl,
2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl,
2,2-dimethylpropanoyl, hexanoyl and heptanoyl.
[0119] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkyl-carbonyl group" include a C.sub.1-6
alkyl-carbonyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include acetyl,
chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl,
butanoyl, pentanoyl and hexanoyl.
[0120] In the present specification, examples of the "C.sub.1-6
alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl and hexyloxycarbonyl.
[0121] In the present specification, examples of the "C.sub.6-14
aryl-carbonyl group" include benzoyl, 1-naphthoyl and
2-naphthoyl.
[0122] In the present specification, examples of the "C.sub.7-16
aralkyl-carbonyl group" include phenylacetyl and
phenylpropionyl.
[0123] In the present specification, examples of the "5- to
14-membered aromatic heterocyclylcarbonyl group" include
nicotinoyl, isonicotinoyl, thenoyl and furoyl.
[0124] In the present specification, examples of the "3- to
14-membered non-aromatic heterocyclylcarbonyl group" include
morpholinylcarbonyl, piperidinylcarbonyl and
pyrrolidinylcarbonyl.
[0125] In the present specification, examples of the "mono- or
di-C.sub.1-6 alkyl-carbamoyl group" include methylcarbamoyl,
ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and
N-ethyl-N-methylcarbamoyl.
[0126] In the present specification, examples of the "mono- or
di-C.sub.7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and
phenethylcarbamoyl.
[0127] In the present specification, examples of the "C.sub.1-6
alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl
and tert-butylsulfonyl.
[0128] In the present specification, examples of the "optionally
halogenated C.sub.1-6 alkylsulfonyl group" include a C.sub.1-6
alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5,
halogen atoms. Specific examples thereof include methylsulfonyl,
difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl,
4,4,4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.
[0129] In the present specification, examples of the "C.sub.6-14
arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and
2-naphthylsulfonyl.
[0130] In the present specification, examples of the "substituent"
include a halogen atom, a cyano group, a nitro group, an optionally
substituted hydrocarbon group, an optionally substituted
heterocyclic group, an acyl group, an optionally substituted amino
group, an optionally substituted carbamoyl group, an optionally
substituted thiocarbamoyl group, an optionally substituted
sulfamoyl group, an optionally substituted hydroxy group, an
optionally substituted sulfanyl (SH) group and an optionally
substituted silyl group.
[0131] In the present specification, examples of the "hydrocarbon
group" (including "hydrocarbon group" of "optionally substituted
hydrocarbon group") include a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-10 cycloalkyl
group, a C.sub.3-10 cycloalkenyl group, a C.sub.6-14 aryl group and
a C.sub.7-16 aralkyl group.
[0132] In the present specification, examples of the "optionally
substituted hydrocarbon group" include a hydrocarbon group
optionally having substituent(s) selected from the following
Substituent group A.
[Substituent Group A]
[0133] (1) a halogen atom, (2) a nitro group, (3) a cyano group,
(4) an oxo group, (5) a hydroxy group, (6) an optionally
halogenated C.sub.1-6 alkoxy group, (7) a C.sub.6-14 aryloxy group
(e.g., phenoxy, naphthoxy), (8) a C.sub.7-16 aralkyloxy group
(e.g., benzyloxy), (9) a 5- to 14-membered aromatic heterocyclyloxy
group (e.g., pyridyloxy), (10) a 3- to 14-membered non-aromatic
heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy), (11)
a C.sub.1-6 alkyl-carbonyloxy group (e.g., acetoxy, propanoyloxy),
(12) a C.sub.6-14 aryl-carbonyloxy group (e.g., benzoyloxy,
1-naphthoyloxy, 2-naphthoyloxy), (13) a C.sub.1-6
alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy,
ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) a
mono- or di-C.sub.1-6 alkyl-carbamoyloxy group (e.g.,
methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy,
diethylcarbamoyloxy), (15) a C.sub.6-14 aryl-carbamoyloxy group
(e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) a 5- to
14-membered aromatic heterocyclylcarbonyloxy group (e.g.,
nicotinoyloxy), (17) a 3- to 14-membered non-aromatic
heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy,
piperidinylcarbonyloxy), (18) an optionally halogenated C.sub.1-6
alkylsulfonyloxy group (e.g., methylsulfonyloxy,
trifluoromethylsulfonyloxy), (19) a C.sub.6-14 arylsulfonyloxy
group optionally substituted by a C.sub.1-6 alkyl group (e.g.,
phenylsulfonyloxy, toluenesulfonyloxy), (20) an optionally
halogenated C.sub.1-6 alkylthio group, (21) a 5- to 14-membered
aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic
heterocyclic group, (23) a formyl group, (24) a carboxy group, (25)
an optionally halogenated C.sub.1-6 alkyl-carbonyl group, (26) a
C.sub.6-14 aryl-carbonyl group, (27) a 5- to 14-membered aromatic
heterocyclylcarbonyl group, (28) a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, (29) a C.sub.1-6 alkoxy-carbonyl group,
(30) a C.sub.6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31) a C.sub.7-16
aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,
phenethyloxycarbonyl), (32) a carbamoyl group, (33) a thiocarbamoyl
group, (34) a mono- or di-C.sub.1-6 alkyl-carbamoyl group, (35) a
C.sub.6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) a 5-
to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
pyridylcarbamoyl, thienylcarbamoyl), (37) a 3- to 14-membered
non-aromatic heterocyclylcarbamoyl group (e.g.,
morpholinylcarbamoyl, piperidinylcarbamoyl), (38) an optionally
halogenated C.sub.1-6 alkylsulfonyl group, (39) a C.sub.6-14
arylsulfonyl group, (40) a 5- to 14-membered aromatic
heterocyclylsulfonyl group (e.g., pyridylsulfonyl,
thienylsulfonyl), (41) an optionally halogenated C.sub.1-6
alkylsulfinyl group, (42) a C.sub.6-14 arylsulfinyl group (e.g.,
phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) a 5-
to 14-membered aromatic heterocyclylsulfinyl group (e.g.,
pyridylsulfinyl, thienylsulfinyl), (44) an amino group, (45) a
mono- or di-C.sub.1-6 alkylamino group (e.g., methylamino,
ethylamino, propylamino, isopropylamino, butylamino, dimethylamino,
diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),
(46) a mono- or di-C.sub.6-14 arylamino group (e.g., phenylamino),
(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g.,
pyridylamino), (48) a C.sub.7-16 aralkylamino group (e.g.,
benzylamino), (49) a formylamino group, (50) a C.sub.1-6
alkyl-carbonylamino group (e.g., acetylamino, propanoylamino,
butanoylamino), (51) a (C.sub.1-6 alkyl) (C.sub.1-6 alkyl-carbonyl)
amino group (e.g., N-acetyl-N-methylamino), (52) a C.sub.6-14
aryl-carbonylamino group (e.g., phenylcarbonylamino,
naphthylcarbonylamino), (53) a C.sub.1-6 alkoxy-carbonylamino group
(e.g., methoxycarbonylamino, ethoxycarbonylamino,
propoxycarbonylamino, butoxycarbonylamino,
tert-butoxycarbonylamino), (54) a C.sub.7-16
aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)
a C.sub.1-6 alkylsulfonylamino group (e.g., methylsulfonylamino,
ethylsulfonylamino), (56) a C.sub.6-14 arylsulfonylamino group
optionally substituted by a C.sub.1-6 alkyl group (e.g.,
phenylsulfonylamino, toluenesulfonylamino), (57) an optionally
halogenated C.sub.1-6 alkyl group, (58) a C.sub.2-6 alkenyl group,
(59) a C.sub.2-6 alkynyl group, (60) a C.sub.3-10 cycloalkyl group,
(61) a C.sub.3-10 cycloalkenyl group, and (62) a C.sub.6-14 aryl
group.
[0134] The number of the above-mentioned substituents in the
"optionally substituted hydrocarbon group" is, for example, 1 to 5,
preferably 1 to 3. When the number of the substituents is two or
more, the respective substituents may be the same or different.
[0135] In the present specification, examples of the "heterocyclic
group" (including "heterocyclic group" of "optionally substituted
heterocyclic group") include (i) an aromatic heterocyclic group,
(ii) a non-aromatic heterocyclic group and (iii) a 7- to
10-membered bridged heterocyclic group, each containing, as a
ring-constituting atom besides carbon atom, 1 to 4 heteroatoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0136] In the present specification, examples of the "aromatic
heterocyclic group" (including "5- to 14-membered aromatic
heterocyclic group") include a 5- to 14-membered (preferably 5 to
10-membered) aromatic heterocyclic group containing, as a
ring-constituting atom besides carbon atom, 1 to 4 heteroatoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0137] Preferable examples of the "aromatic heterocyclic group"
include 5- or 6-membered monocyclic aromatic heterocyclic groups
such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,
isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl,
triazinyl and the like; and 8- to 14-membered fused polycyclic
(preferably bi- or tri-cyclic) aromatic heterocyclic groups such as
benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl,
benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl,
imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl,
pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl,
imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl,
furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,
oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl,
naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl,
1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl and the like.
[0138] In the present specification, examples of the "non-aromatic
heterocyclic group" (including "3- to 14-membered non-aromatic
heterocyclic group") include a 3- to 14-membered (preferably 4- to
10-membered) non-aromatic heterocyclic group containing, as a
ring-constituting atom besides carbon atom, 1 to 4 heteroatoms
selected from a nitrogen atom, a sulfur atom and an oxygen
atom.
[0139] Preferable examples of the "non-aromatic heterocyclic group"
include 3- to 8-membered monocyclic non-aromatic heterocyclic
groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl,
oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl,
pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl,
oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl,
thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl,
tetrahydroisooxazolyl, piperidinyl, piperazinyl,
tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl,
tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl,
tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl,
thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl,
azocanyl, diazocanyl and the like; and 9- to 14-membered fused
polycyclic (preferably bi- or tri-cyclic) non-aromatic heterocyclic
groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl,
dihydrobenzoxazolyl, dihydrobenzothiazolyl,
dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl,
tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl,
indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl,
tetrahydrobenzazepinyl, tetrahydroquinoxalinyl,
tetrahydrophenanthridinyl, hexahydrophenothiazinyl,
hexahydrophenoxazinyl, tetrahydrophthalazinyl,
tetrahydronaphthyridinyl, tetrahydroquinazolinyl,
tetrahydrocinnolinyl, tetrahydrocarbazolyl,
tetrahydro-.beta.-carbolinyl, tetrahydroacrydinyl,
tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl
and the like.
[0140] In the present specification, preferable examples of the "7-
to 10-membered bridged heterocyclic group" include quinuclidinyl
and 7-azabicyclo[2.2.1]heptanyl.
[0141] In the present specification, examples of the
"nitrogen-containing heterocyclic group" include a "heterocyclic
group" containing at least one nitrogen atom as a ring-constituting
atom.
[0142] In the present specification, examples of the "optionally
substituted heterocyclic group" include a heterocyclic group
optionally having substituent(s) selected from the above-mentioned
Substituent group A.
[0143] The number of the substituents in the "optionally
substituted heterocyclic group" is, for example, 1 to 3. When the
number of the substituents is two or more, the respective
substituents may be the same or different.
[0144] In the present specification, examples of the "acyl group"
include a formyl group, a carboxy group, a carbamoyl group, a
thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl
group and a phosphono group, each optionally having "1 or 2
substituents selected from a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.3-10 cycloalkyl group, a. C.sub.3-10
cycloalkenyl group, a C.sub.6-14 aryl group, a C.sub.7-16 aralkyl
group, a 5- to 14-membered aromatic heterocyclic group, a 3- to
14-membered non-aromatic heterocyclic group, an amino group and a
mono- or di-C.sub.1-6 alkyl-amino group, each of which optionally
has 1 to 3 substituents selected from a halogen atom, an optionally
halogenated C.sub.1-6 alkoxy group, a hydroxy group, a nitro group,
a cyano group, an amino group and a carbamoyl group.
[0145] Examples of the "acyl group" also include a
hydrocarbon-sulfonyl group, a heterocyclylsulfonyl group, a
hydrocarbon-sulfinyl group and a heterocyclylsulfinyl group.
[0146] Here, the hydrocarbon-sulfonyl group means a hydrocarbon
group-bonded sulfonyl group, the heterocyclylsulfonyl group means a
heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl
group means a hydrocarbon group-bonded sulfinyl group and the
heterocyclylsulfinyl group means a heterocyclic group-bonded
sulfinyl group.
[0147] Preferable examples of the "acyl group" include a formyl
group, a carboxy group, a C.sub.1-6 alkyl-carbonyl group, a
C.sub.2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C.sub.3-10
cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl,
cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a
C.sub.3-10 cycloalkenyl-carbonyl group (e.g.,
2-cyclohexenecarbonyl), a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a
C.sub.6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
naphthyloxycarbonyl), a C.sub.7-6 aralkyloxy-carbonyl group (e.g.,
benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl), a
mono- or di-C.sub.3-10 cycloalkyl-carbamoyl group (e.g.,
cyclopropylcarbamoyl), a mono- or di-C.sub.6-14 aryl-carbamoyl
group (e.g., phenylcarbamoyl), a mono- or di-C.sub.7-16
aralkyl-carbamoyl group, a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl), N--C.sub.1-6
alkyl-N',N'-di-C.sub.1-6 alkylhydrazine-carbonyl group, a
thiocarbamoyl group, a mono- or di-C.sub.1-6 alkyl-thiocarbamoyl
group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), a
mono- or di-C.sub.2-6 alkenyl-thiocarbamoyl group (e.g.,
diallylthiocarbamoyl), a mono- or di-C.sub.3-10
cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,
cyclohexylthiocarbamoyl), a mono- or di-C.sub.6-14
aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), a mono- or
di-C.sub.7-16 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl, phenethylthiocarbamoyl), a 5- to 14-membered
aromatic heterocyclylthiocarbamoyl group (e.g.,
pyridylthiocarbamoyl), a sulfino group, a C.sub.1-6 alkylsulfinyl
group (e.g., methylsulfinyl, ethylsulfinyl), a sulfo group, a
C.sub.1-6 alkylsulfonyl group, a C.sub.6-14 arylsulfonyl group, a
phosphono group and a mono- or di-C.sub.1-6 alkylphosphono group
(e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono,
dibutylphosphono).
[0148] In the present specification, examples of the "optionally
substituted amino group" include an amino group optionally having
"1 or 2 substituents selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, a C.sub.1-6 alkylsulfonyl
group and a C.sub.6-14 arylsulfonyl group, each of which optionally
has 1 to 3 substituents selected from Substituent group A".
[0149] Preferable examples of the optionally substituted amino
group include an amino group, a mono- or di-(optionally halogenated
C.sub.1-6 alkyl) amino group (e.g., methylamino,
trifluoromethylamino, dimethylamino, ethylamino, diethylamino,
propylamino, dibutylamino), a mono- or di-C.sub.2-6 alkenylamino
group (e.g., diallylamino), a mono- or di-C.sub.3-10
cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino), a
mono- or di-C.sub.6-14 arylamino group (e.g., phenylamino), a mono-
or di-C.sub.7-16 aralkylamino group (e.g., benzylamino,
dibenzylamino), a mono- or di-(optionally halogenated C.sub.1-6
alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), a
mono- or di-C.sub.6-14 aryl-carbonylamino group (e.g.,
benzoylamino), a mono- or di-C.sub.7-16 aralkyl-carbonylamino group
(e.g., benzylcarbonylamino), a mono- or di-5- to 14-membered
aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino,
isonicotinoylamino), a mono- or di-3- to 14-membered non-aromatic
heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), a
mono- or di-C.sub.1-6 alkoxy-carbonylamino group (e.g.,
tert-butoxycarbonylamino), a 5- to 14-membered aromatic
heterocyclylamino group (e.g., pyridylamino), a carbamoylamino
group, a (mono- or di-C.sub.1-6 alkyl-carbamoyl) amino group (e.g.,
methylcarbamoylamino), a (mono- or di-C.sub.7-16 aralkyl-carbamoyl)
amino group (e.g., benzylcarbamoylamino), a C.sub.1-6
alkylsulfonylamino group (e.g., methylsulfonylamino,
ethylsulfonylamino), a C.sub.6-14 arylsulfonylamino group (e.g.,
phenylsulfonylamino), a (C.sub.1-6 alkyl)(C.sub.1-6 alkyl-carbonyl)
amino group (e.g., N-acetyl-N-methylamino) and a (C.sub.1-6 alkyl)
(C.sub.6-14 aryl-carbonyl) amino group (e.g.,
N-benzoyl-N-methylamino).
[0150] In the present specification, examples of the "optionally
substituted carbamoyl group" include a carbamoyl group optionally
having "1 or 2 substituents selected from a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5 to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from Substituent group A".
[0151] Preferable examples of the optionally substituted carbamoyl
group include a carbamoyl group, a mono- or di-C.sub.1-6
alkyl-carbamoyl group, a mono- or di-C.sub.2-6 alkenyl-carbamoyl
group (e.g., diallylcarbamoyl), a mono- or di-C.sub.3-10
cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl,
cyclohexylcarbamoyl), a mono- or di-C.sub.6-14 aryl-carbamoyl group
(e.g., phenylcarbamoyl), a mono- or di-C.sub.7-16 aralkyl-carbamoyl
group, a mono- or di-C.sub.1-6 alkyl-carbonyl-carbamoyl group
(e.g., acetylcarbamoyl, propionylcarbamoyl), a mono- or
di-C.sub.6-14 aryl-carbonyl-carbamoyl group (e.g.,
benzoylcarbamoyl) and a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl)
[0152] In the present specification, examples of the "optionally
substituted thiocarbamoyl group" include a thiocarbamoyl group
optionally having "1 or 2 substituents selected from a C.sub.1-6
alkyl group, a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl
group, a Ce-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5 to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from Substituent group A".
[0153] Preferable examples of the optionally substituted
thiocarbamoyl group include a thiocarbamoyl group, a mono- or
di-C.sub.1-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl,
ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl,
N-ethyl-N-methylthiocarbamoyl), a mono- or di-C.sub.2-6
alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), a mono-
or di-C.sub.3-10 cycloalkyl-thiocarbamoyl group (e.g.,
cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), a mono- or
di-C.sub.6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl),
a mono- or di-C.sub.7-16 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl, phenethylthiocarbamoyl), a mono- or
di-C.sub.1-6 alkyl-carbonyl-thiocarbamoyl group (e.g.,
acebylthiocarbamoyl, propionylthiocarbamoyl), a mono- or
di-C.sub.6-14 aryl-carbonyl-thiocarbamoyl group (e.g.,
benzoylthiocarbamoyl) and a 5- to 14-membered aromatic
heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl).
[0154] In the present specification, examples of the "optionally
substituted sulfamoyl group" include a sulfamoyl group optionally
having "1 or 2 substituents selected from a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5 to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group and a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, each of which optionally has
1 to 3 substituents selected from Substituent group A".
[0155] Preferable examples of the optionally substituted sulfamoyl
group include a sulfamoyl group, a mono- or di-C.sub.1-6
alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl,
dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), a
mono- or di-C.sub.2-5 alkenyl-sulfamoyl group (e.g.,
diallylsulfamoyl), a mono- or di-C.sub.3-10 cycloalkyl-sulfamoyl
group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), a mono- or
di-C.sub.6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl), a mono-
or di-C.sub.7-16 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl,
phenethylsulfamoyl), a mono- or di-C.sub.1-6
alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,
propionylsulfamoyl), a mono- or di-C.sub.6-14
aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to
14-membered aromatic heterocyclylsulfamoyl group (e.g.,
pyridylsulfamoyl).
[0156] In the present specification, examples of the "optionally
substituted hydroxy group" include a hydroxy group optionally
having "a substituent selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group, a
C.sub.7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic
heterocyclylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a 5-
to 14-membered aromatic heterocyclic group, a carbamoyl group, a
mono- or di-C.sub.1-6 alkyl-carbamoyl group, a mono- or
di-C.sub.7-16 aralkyl-carbamoyl group, a C.sub.1-6 alkylsulfonyl
group and a C.sub.6-14 arylsulfonyl group, each of which optionally
has 1 to 3 substituents selected from Substituent group A".
[0157] Preferable examples of the optionally substituted hydroxy
group include a hydroxy group, a C.sub.1-6 alkoxy group, a
C.sub.2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy,
2-pentenyloxy, 3-hexenyloxy), a C.sub.3-10 cycloalkyloxy group
(e.g., cyclohexyloxy), a C.sub.6-14 aryloxy group (e.g., phenoxy,
naphthyloxy), a C.sub.7-16 aralkyloxy group (e.g., benzyloxy,
phenethyloxy), a C.sub.1-6 alkyl-carbonyloxy group (e.g.,
acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a
C.sub.6-14 aryl-carbonyloxy group (e.g., benzoyloxy), a C.sub.7-6
aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), a 5- to
14-membered aromatic heterocyclylcarbonyloxy group (e.g.,
nicotinoyloxy), a 3- to 14-membered non-aromatic
heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), a
C.sub.1-6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy),
a 5- to 14-membered aromatic heterocyclyloxy group (e.g.,
pyridyloxy), a carbamoyloxy group, a C.sub.1-6 alkyl-carbamoyloxy
group (e.g., methylcarbamoyloxy), a C.sub.7-16 aralkyl-carbamoyloxy
group (e.g., benzylcarbamoyloxy), a C.sub.1-6 alkylsulfonyloxy
group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a C.sub.6-14
arylsulfonyloxy group (e.g., phenylsulfonyloxy).
[0158] In the present specification, examples of the "optionally
substituted sulfanyl group" include a sulfanyl group optionally
having "a substituent selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group, a C.sub.7-16 aralkyl group, a C.sub.1-6
alkyl-carbonyl group, a C.sub.6-14 aryl-carbonyl group and a 5- to
14-membered aromatic heterocyclic group, each of which optionally
has 1 to 3 substituents selected from Substituent group A" and a
halogenated sulfanyl group.
[0159] Preferable examples of the optionally substituted sulfanyl
group include a sulfanyl (--SH) group, a C.sub.1-6 alkylthio group,
a C.sub.2-6 alkenylthio group (e.g., allylthio, 2-butenylthio,
2-pentenylthio, 3-hexenylthio), a C.sub.3-10 cycloalkylthio group
(e.g., cyclohexylthio), a C.sub.6-14 arylthio group (e.g.,
phenylthio, naphthylthio), a C.sub.7-16 aralkylthio group (e.g.,
benzylthio, phenethylthio), a C.sub.1-6 alkyl-carbonylthio group
(e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio,
pivaloylthio), a C.sub.6-14 aryl-carbonylthio group (e.g.,
benzoylthio), a 5- to 14-membered aromatic heterocyclylthio group
(e.g., pyridylthio) and a halogenated thio group (e.g.,
pentafluorothio).
[0160] In the present specification, examples of the "optionally
substituted silyl group" include a silyl group optionally having "1
to 3 substituents selected from a C.sub.1-6 alkyl group, a
C.sub.2-6 alkenyl group, a C.sub.3-10 cycloalkyl group, a
C.sub.6-14 aryl group and a C.sub.7-16 aralkyl group, each of which
optionally has 1 to 3 substituents selected from Substituent group
A".
[0161] Preferable examples of the optionally substituted silyl
group include a tri-C.sub.1-6 alkylsilyl group (e.g.,
trimethylsilyl, tert-butyl(dimethyl)silyl).
[0162] In the present specification, examples of the "hydrocarbon
ring" include a C.sub.6-14 aromatic hydrocarbon ring, C.sub.3-10
cycloalkane and C.sub.3-10 cycloalkene.
[0163] In the present specification, examples of the "C.sub.6-14
aromatic hydrocarbon ring" include benzene and naphthalene.
[0164] In the present specification, examples of the "C.sub.3-10
cycloalkane" include cyclopropane, cyclobutane, cyclopentane,
cyclohexane, cycloheptane and cyclooctane.
[0165] In the present specification, examples of the "C.sub.3-10
cycloalkene" include cyclopropene, cyclobutene, cyclopentene,
cyclohexene, cycloheptene and cyclooctene.
[0166] In the present specification, examples of the "heterocycle"
include an aromatic heterocycle and a non-aromatic heterocycle,
each containing, as a ring-constituting atom besides carbon atom, 1
to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and
an oxygen atom.
[0167] In the present specification, examples of the "aromatic
heterocycle" include a 5- to 14-membered (preferably 5- to
10-membered) aromatic heterocycle containing, as a
ring-constituting atom besides carbon atom, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "aromatic heterocycle" include 5- or
6-membered monocyclic aromatic heterocycles such as thiophene,
furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole,
oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,
1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole,
1,3,4-thiadiazole, triazole, tetrazole, triazine and the like;
and
8- to 14-membered fused polycyclic (preferably bi- or tri-cyclic)
aromatic heterocycles such as benzothiophene, benzofuran,
benzimidazole, benzoxazole, benzisoxazole, benzothiazole,
benzisothiazole, benzotriazole, imidazopyridine, thienopyridine,
furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine,
thiazolopyridine, imidazopyrazine, imidazopyrimidine,
thienopyrimidine, furopyrimidine, pyrrolopyrimidine,
pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine,
pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene,
phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline,
quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline,
cinnoline, carbazole, .beta.-carboline, phenanthridine, acridine,
phenazine, phenothiazine, phenoxazine and the like.
[0168] In the present specification, examples of the "non-aromatic
heterocycle" include a 3- to 14-membered (preferably 4- to
10-membered) non-aromatic heterocycle containing, as a
ring-constituting atom besides carbon atom, 1 to 4 hetero atoms
selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "non-aromatic heterocycle" include 3- to
8-membered monocyclic non-aromatic heterocycles such as aziridine,
oxirane, thiirane, azetidine, oxetane, thietane,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline,
pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole,
tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine,
tetrahydropyridine, dihydropyridine, dihydrothiopyran,
tetrahydropyrimidine, tetrahydropyridazine, dihydropyran,
tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine,
azepane, diazepane, azepine, azocane, diazocane, oxepane and the
like; and 9- to 14-membered fused polycyclic (preferably bi- or
tri-cyclic) non-aromatic heterocycles such as dihydrobenzofuran,
dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole,
dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene,
tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine,
indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine,
tetrahydrobenzazepine, tetrahydroquinoxaline,
tetrahydrophenanthridine, hexahydrophenothiazine,
hexahydrophenoxazine, tetrahydrophthalazine,
tetrahydronaphthyridine, tetrahydroquinazoline,
tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-(3-carboline,
tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene,
octahydroisoquinoline and the like.
[0169] In the present specification, examples of the
"nitrogen-containing heterocycle" include a heterocycle containing
at least one nitrogen atom as a ring-constituting atom, from among
the "heterocycle".
[0170] In the present specification, examples of the "C.sub.3-6
cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
[0171] In the present specification, examples of the "mono- or
di-C.sub.1-6 alkylamino group" include methylamino, dimethylamino,
ethylamino, diethylamino, propylamino, isopropylamino, butylamino,
isobutylamino, sec-butylamino, tert-butylamino, pentylamino,
isopentylamino, neo-pentylamino, 1-ethylpropylamino, hexylamino,
isohexylamino, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino,
3,3-dimethylbutylamino, 2-ethylbutylamino and the like.
[0172] The definition of each symbol in the formula (I) is
explained in detail in the following.
[0173] R.sup.1 is an optionally substituted C.sub.1-6 alkyl group,
an optionally substituted mono- or di-C.sub.1-6 alkylamino group,
an optionally substituted C.sub.3-6 cycloalkyl group, or an
optionally substituted 3- to 14-membered non-aromatic heterocyclic
group.
[0174] Examples of the substituent of the above-mentioned
"optionally substituted C.sub.1-6 alkyl group", "optionally
substituted mono- or di-C.sub.1-6 alkylamino group", "optionally
substituted C.sub.3-6 cycloalkyl group" and "optionally substituted
3- to 14-membered non-aromatic heterocyclic group" include
substituents selected from Substituent group A. The number of the
substituents is preferably 1 to 3. When the number of the
substituents is 2 or more, the respective substituents may be the
same or different.
[0175] R.sup.1 is preferably
(1) an optionally substituted C.sub.1-6 alkyl group (e.g., methyl,
ethyl), (2) an optionally substituted mono- or di-C.sub.1-6
alkylamino group (e.g., dimethylamino), or (3) an optionally
substituted C.sub.3-6 cycloalkyl group (e.g., cyclopropyl).
[0176] R.sup.1 is more preferably
(1) a C.sub.1-6 alkyl group (e.g., methyl, ethyl), (2) a mono- or
di-C.sub.1-6 alkylamino group (e.g., dimethylamino), or (3) a
C.sub.3-6 cycloalkyl group (e.g., cyclopropyl).
[0177] R.sup.1 is further more preferably
(1) a C.sub.1-6 alkyl group (e.g., methyl, ethyl), or (2) a mono-
or di-C.sub.1-6 alkylamino group (e.g., dimethylamino).
[0178] R.sup.2 is a hydrogen atom, a fluorine atom, an optionally
substituted C.sub.1-6 alkyl group, or an optionally substituted
C.sub.3-6 cycloalkyl group.
[0179] Examples of the substituent of the above-mentioned
"optionally substituted C.sub.1-6 alkyl group" and "optionally
substituted C.sub.3-6 cycloalkyl group" include substituents
selected from Substituent group A. The number of the substituents
is preferably 1 to 3. When the number of the substituents is 2 or
more, the respective substituents may be the same or different.
[0180] R.sup.2 is preferably
(1) a hydrogen atom, (2) a fluorine atom, or (3) an optionally
substituted C.sub.1-6 alkyl group (e.g., methyl).
[0181] R.sup.2 is more preferably
(1) a hydrogen atom, (2) a fluorine atom, or (3) a C.sub.1-6 alkyl
group (e.g., methyl).
[0182] R.sup.2 is further more preferably
(1) a hydrogen atom, or (2) a fluorine atom.
[0183] R.sup.3 is an acyl group, an optionally substituted
C.sub.1-6 alkyl group, an optionally substituted C.sub.3-6
cycloalkyl group, an optionally substituted C.sub.6-14 aryl group,
an optionally substituted 3- to 1.4 membered non-aromatic
heterocyclic group, or an optionally substituted 5- to 14-membered
aromatic heterocyclic group.
[0184] Examples of the substituent of the above-mentioned
"optionally substituted C.sub.1-6 alkyl group", "optionally
substituted C.sub.3-6 cycloalkyl group", "optionally substituted
C.sub.6-14 aryl group", "optionally substituted 3- to 14-membered
non-aromatic heterocyclic group" and "optionally substituted 5- to
14-membered aromatic heterocyclic group" include substituents
selected from Substituent group A. The number of the substituents
is preferably 1 to 3. When the number of the substituents is 2 or
more, the respective substituents may be the same or different.
[0185] R.sup.3 is preferably an acyl group.
[0186] R.sup.3 is more preferably
(1) an optionally substituted C.sub.1-6 alkyl-carbonyl group (e.g.,
2-methylpropanoyl, 2,2-dimethylpropanoyl, butanoyl,
2-methylbutanoyl), (2) an optionally substituted C.sub.1-6
alkoxy-carbonyl group (e.g., ethoxycarbonyl, tert-butoxycarbonyl),
(3) an optionally substituted C.sub.3-10 cycloalkyl-carbonyl group
(the C.sub.3-10 cycloalkyl moiety of the C.sub.3-10
cycloalkyl-carbonyl group is optionally bridged (e.g.,
cyclopropylcarbonyl, cyclobutylcarbonyl,
bicyclo[1.1.1]pentan-1-ylcarbonyl)), (4) an optionally substituted
3- to 14-membered non-aromatic heterocyclylcarbonyl group
(preferably a 3- to 8-membered monocyclic non-aromatic
heterocyclylcarbonyl group (e.g., oxetanylcarbonyl,
tetrahydrofurylcarbonyl, azetidinylcarbonyl)), (5) an optionally
substituted mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
dimethylcarbamoyl), (6) an optionally substituted N--C.sub.1-6
alkyl-N--C.sub.1-6 alkoxy-carbamoyl group (e.g.,
N-methyl-N-methoxycarbamoyl)., or (7) a N--C.sub.1-6
alkyl-N',N'-di-C.sub.1-6 alkylhydrazine-carbonyl group (e.g.,
N-methyl-N',N'-dimethylhydrazinecarbonyl).
[0187] R.sup.3 is further more preferably
(1) a C.sub.1-6 alkyl-carbonyl group (e.g., 2-methylpropanoyl,
2,2-dimethylpropanoyl, butanoyl, 2-methylbutanoyl) optionally
substituted by 1 to 3 substituents selected from
[0188] (a) a halogen atom (e.g., a fluorine atom),
[0189] (b) a hydroxy group, and
[0190] (c) a cyano group,
(2) a C.sub.1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl,
tert-butoxycarbonyl), (3) a C.sub.3-10 cycloalkyl-carbonyl group
(the C.sub.3-10 cycloalkyl moiety of the C.sub.3-10
cycloalkyl-carbonyl group is optionally bridged (e.g.,
cyclopropylcarbonyl, cyclobutylcarbonyl,
bicyclo[1.1.1]pentan-1-ylcarbonyl)) optionally substituted by 1 to
3 substituents selected from
[0191] (a) a halogen atom (e.g., a fluorine atom),
[0192] (b) a hydroxy group,
[0193] (c) a cyano group, and
[0194] (d) a C.sub.1-6 alkyl group (e.g., methyl),
(4) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group
(preferably a 3- to 8-membered monocyclic non-aromatic
heterocyclylcarbonyl group (e.g., oxetanylcarbonyl,
tetrahydrofurylcarbonyl, azetidinylcarbonyl)) optionally
substituted by 1 to 3 substituents selected from
[0195] (a) a halogen atom (e.g., a fluorine atom),
[0196] (b) a hydroxy group, and
[0197] (c) a C.sub.1-6 alkyl group (e.g., methyl),
(5) a mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
dimethylcarbamoyl), (6) a N--C.sub.1-6 alkyl-N--C.sub.1-6
alkoxy-carbamoyl group (e.g., N-methyl-N-methoxycarbamoyl), or (7)
a N--C.sub.1-6 alkyl-N',N'-di-C.sub.1-6 alkylhydrazine-carbonyl
group (e.g., N-methyl-N',N'-dimethylhydrazinecarbonyl).
[0198] R.sup.3 is still more preferably
(1) a C.sub.1-6 alkyl-carbonyl group (e.g., 2-methylpropanoyl,
butanoyl) optionally substituted by 1 to 3 hydroxy groups, (2) a
C.sub.3-10 cycloalkyl-carbonyl group (the C.sub.3-10 cycloalkyl
moiety of the C.sub.3-10 cycloalkyl-carbonyl group is optionally
bridged (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl,
bicyclo[1.1.1]pentan-1-ylcarbonyl)) optionally substituted by 1 to
3 substituents selected from
[0199] (a) a halogen atom (e.g., a fluorine atom), and
[0200] (b) a hydroxy group,
(3) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl
group (e.g., oxetanylcarbonyl, tetrahydrofurylcarbonyl,
azetidinylcarbonyl), or (4) a mono- or di-C.sub.1-6 alkyl-carbamoyl
group (e.g., dimethylcarbamoyl).
[0201] R.sup.3 is even more preferably
(1) a C.sub.1-6 alkyl-carbonyl group (e.g., 2-methylpropanoyl)
optionally substituted by 1 to 3 hydroxy groups, (2) a C.sub.3-10
cycloalkyl-carbonyl group (the C.sub.3-10 cycloalkyl moiety of the
C.sub.3-10 cycloalkyl-carbonyl group is optionally bridged (e.g.,
cyclopropylcarbonyl, cyclobutylcarbonyl,
bicyclo[1.1.1]pentan-1-ylcarbonyl)) optionally substituted by 1 to
3 substituents selected from
[0202] (a) a halogen atom (e.g., a fluorine atom), and
[0203] (b) a hydroxy group,
(3) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl
group (e.g., oxetanylcarbonyl, azetidinylcarbonyl), or (4) a mono-
or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
dimethylcarbamoyl).
[0204] R.sup.3 is particularly preferably
(1) a C.sub.1-6 alkyl-carbonyl group (e.g., 2-methylpropanoyl)
optionally substituted by 1 to 3 hydroxy groups, (2) a 3- to
8-membered monocyclic non-aromatic heterocyclylcarbonyl group
(e.g., oxetanylcarbonyl, azetidinylcarbonyl), or (3) a mono- or
di-C.sub.1-6 alkyl-carbamoyl group (e.g., dimethylcarbamoyl).
[0205] Ring A is an optionally further substituted C.sub.6-14
aromatic hydrocarbon ring, or an optionally further substituted 5-
to 14-membered aromatic heterocycle.
[0206] Ring A optionally has substituent(s) in addition to
--CH.sub.2-- pyrrolidine ring in the formula (I). Examples of the
substituent include the above-mentioned "substituent". The number
of the substituents is preferably 1 to 3. When the number of the
substituents is 2 or more, the respective substituents may be the
same or different.
[0207] Ring A is preferably
(1) an optionally further substituted benzene ring, or (2) an
optionally further substituted. 5- or 6-membered aromatic
heterocycle (e.g., thiazole, pyridine).
[0208] Ring A is more preferably
(1) a benzene ring-further substituted by one substituent selected
from [0209] (a) a C.sub.6-14 aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from [0210] (i) a
halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine
atom), [0211] (ii) an optionally halogenated C.sub.1-6 alkyl group
(e.g., methyl, difluoromethyl), and [0212] (iii) an optionally
halogenated C.sub.1-6 alkoxy group (e.g., methoxy,
difluoromethoxy), and [0213] (b) a 5- to 14-membered aromatic
heterocyclic group (preferably a 5- or 6-membered aromatic
heterocyclic group (e.g., pyridyl, pyrimidinyl, pyridazinyl,
thiazolyl, oxazolyl)) optionally substituted by 1 to 3 substituents
selected from [0214] (i) a C.sub.1-6 alkyl group (e.g., methyl,
ethyl) optionally substituted by 1 to 3 substituents selected from
a halogen atom (e.g., a fluorine atom) and a hydroxy group, [0215]
(ii) a C.sub.1-6 alkoxy group (e.g., methoxy), [0216] (iii) a
halogen atom (e.g., a fluorine atom, a chlorine atom), and [0217]
(iv) a C.sub.1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl), and
optionally further substituted by 1 to 3 halogen atoms (e.g., a
fluorine atom), or (2) a 5- or 6-membered aromatic heterocycle
(e.g., thiazole, pyridine) further substituted by one C.sub.6-14
aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen
atoms (e.g., a fluorine atom).
[0218] Ring A is further more preferably a benzene ring further
substituted by one C.sub.6-14 aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from [0219] (i) a
halogen atom (e.g., a fluorine atom, a chlorine atom), and [0220]
(ii) an optionally halogenated C.sub.1-6 alkyl group (e.g., methyl,
difluoromethyl), and optionally further substituted by 1 to 3
halogen atoms (e.g., a fluorine atom).
[0221] Ring A is particularly preferably a benzene ring further
substituted by one C.sub.6-14 aryl group (e.g., phenyl) optionally
substituted by 1 to 3 substituents selected from
[0222] (i) a halogen atom (e.g., a fluorine atom), and
[0223] (ii) a C.sub.1-6 alkyl group (e.g., methyl), and
optionally further substituted by 1 to 3 halogen atoms (e.g., a
fluorine atom).
[0224] Regarding the pyrrolidine ring of compound (I), the
configuration based on the carbon atom that --NHSO.sub.2R.sup.1 is
bonded to and the carbon atom that --CH.sub.2--Ring A is bonded to
is preferably cis-form. That is, compound (I) is preferably
represented by the formula (IA) or (IB):
##STR00011##
wherein each symbol is as defined above, more preferably
represented by the formula (IA):
##STR00012##
wherein each symbol is as defined above.
[0225] Preferable examples of compound (I) include the following
compounds. These compounds are preferably represented by the above
formula (IA) or (IB), more preferably represented by the formula
(IA).
[Compound A]
[0226] Compound (I) wherein
R.sup.1 is
[0227] (1) an optionally substituted C.sub.1-6 alkyl group (e.g.,
methyl, ethyl), (2) an optionally substituted mono- or di-C.sub.1-6
alkylamino group (e.g., dimethylamino), or (3) an optionally
substituted C.sub.3-6 cycloalkyl group (e.g., cyclopropyl);
R.sup.2 is
[0228] (1) a hydrogen atom, (2) a fluorine atom, or (3) an
optionally substituted C.sub.1-6 alkyl group (e.g., methyl);
R.sup.3 is
[0229] (1) an optionally substituted C.sub.1-6 alkyl-carbonyl group
(e.g., 2-methylpropanoyl, 2,2-dimethylpropanoyl, butanoyl,
2-methylbutanoyl), (2) an optionally substituted C.sub.1-6
alkoxy-carbonyl group (e.g., ethoxycarbonyl, tert-butoxycarbonyl),
(3) an optionally substituted C.sub.3-10 cycloalkyl-carbonyl group
(the C.sub.3-10 cycloalkyl moiety of the C.sub.3-10
cycloalkyl-carbonyl group is optionally bridged (e.g.,
cyclopropylcarbonyl, cyclobutylcarbonyl,
bicyclo[1.1.1]pentan-1-ylcarbonyl)), (4) an optionally substituted
3- to 14-membered non-aromatic heterocyclylcarbonyl group
(preferably a 3- to 8-membered monocyclic non-aromatic
heterocyclylcarbonyl group (e.g., oxetanylcarbonyl,
tetrahydrofurylcarbonyl, azetidinylcarbonyl)), (5) an optionally
substituted mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
dimethylcarbamoyl), (6) an optionally substituted N--C.sub.1-6
alkyl-N--C.sub.1-6 alkoxy-carbamoyl group (e.g.,
N-methyl-N-methoxycarbamoyl), or (7) a N--C.sub.1-6
alkyl-N',N'-di-C.sub.1-6 alkylhydrazine-carbonyl group (e.g.,
N-methyl-N',N'-dimethylhydrazinecarbonyl); and
Ring A is
[0230] (1) an optionally further substituted benzene ring, or (2)
an optionally further substituted 5- or 6-membered aromatic
heterocycle (e.g., thiazole, pyridine).
[Compound B]
[0231] Compound (I) wherein
R.sup.1 is
[0232] (1) a C.sub.1-6 alkyl group (e.g., methyl, ethyl), (2) a
mono- or di-C.sub.1-6 alkylamino group (e.g., dimethylamino), or
(3) a C.sub.3-6 cycloalkyl group (e.g., cyclopropyl);
R.sup.2 is
[0233] (1) a hydrogen atom, (2) a fluorine atom, or (3) a C.sub.1-6
alkyl group (e.g., methyl);
R.sup.3 is
[0234] (1) a C.sub.1-6 alkyl-carbonyl group (e.g.,
2-methylpropanoyl, 2,2-dimethylpropanoyl, butanoyl,
2-methylbutanoyl) optionally substituted by 1 to 3 substituents
selected from
[0235] (a) a halogen atom (e.g., a fluorine atom),
[0236] (b) a hydroxy group, and
[0237] (c) a cyano group,
(2) a C.sub.1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl,
tert-butoxycarbonyl), (3) a C.sub.3-10 cycloalkyl-carbonyl group
(the C.sub.3-10 cycloalkyl moiety of the C.sub.3-10
cycloalkyl-carbonyl group is optionally bridged (e.g.,
cyclopropylcarbonyl, cyclobutylcarbonyl,
bicyclo[1.1.1]pentan-1-ylcarbonyl)) optionally substituted by 1 to
3 substituents selected from
[0238] (a) a halogen atom (e.g., a fluorine atom),
[0239] (b) a hydroxy group,
[0240] (c) a cyano group, and
[0241] (d) a C.sub.1-6 alkyl group (e.g., methyl),
(4) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group
(preferably a 3- to 8-membered monocyclic non-aromatic
heterocyclylcarbonyl group (e.g., oxetanylcarbonyl,
tetrahydrofurylcarbonyl, azetidinylcarbonyl)) optionally
substituted by 1 to 3 substituents selected from
[0242] (a) a halogen atom (e.g., a fluorine atom),
[0243] (b) a hydroxy group, and
[0244] (c) a C.sub.1-6 alkyl group (e.g., methyl),
(5) a mono- or di-C.sub.1-6 alkyl-carbamoyl group (e.g.,
dimethylcarbamoyl), (6) a N--C.sub.1-6 alkyl-N--C.sub.1-6
alkoxy-carbamoyl group (e.g., N-methyl-N-methoxycarbamoyl), or (7)
a N--C.sub.1-6 alkyl-N',N'-di-C.sub.1-6 alkylhydrazine-carbonyl
group (e.g., N-methyl-N',N'-dimethylhydrazinecarbonyl); and
Ring A is
[0245] (1) a benzene ring further substituted by one substituent
selected from [0246] (a) a C.sub.6-14 aryl group (e.g., phenyl)
optionally substituted by 1 to 3 substituents selected from [0247]
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a
bromine atom), [0248] (ii) an optionally halogenated C.sub.1-6
alkyl group (e.g., methyl, difluoromethyl), and [0249] (iii) an
optionally halogenated. C.sub.1-6 alkoxy group (e.g., methoxy,
difluoromethoxy), and [0250] (b) a 5- to 14-membered aromatic
heterocyclic group (preferably a 5- or 6-membered aromatic
heterocyclic group (e.g., pyridyl, pyrimidinyl, pyridazinyl,
thiazolyl, oxazolyl)) optionally substituted by 1 to 3 substituents
selected from. [0251] (i) a C.sub.1-6 alkyl group (e.g., methyl,
ethyl) optionally substituted by 1 to 3 substituents selected from
a halogen atom (e.g., a fluorine atom) and a hydroxy group, [0252]
(ii) a C.sub.1-6 alkoxy group (e.g., methoxy), [0253] (iii) a
halogen atom (e.g., a fluorine atom, a chlorine atom), and [0254]
(iv) a C.sub.1-6 alkoxy-carbonyl group (e.g., ethoxycarbonyl), and
optionally further substituted by 1 to 3 halogen atoms (e.g., a
fluorine atom), or (2) a 5- or 6-membered aromatic heterocycle
(e.g., thiazole, pyridine) further substituted by one C.sub.6-14
aryl group (e.g., phenyl) optionally substituted by 1 to 3 halogen
atoms (e.g., a fluorine atom).
[Compound C]
[0255] Compound (I) wherein
R.sup.1 is
[0256] (1) a C.sub.1-6 alkyl group (e.g., methyl, ethyl), (2) a
mono- or di-C.sub.1-6 alkylamino group (e.g., dimethylamino), or
(3) a C.sub.3-6 cycloalkyl group (e.g., cyclopropyl);
R.sup.2 is
[0257] (1) a hydrogen atom, or (2) a fluorine atom;
R.sup.3 is
[0258] (1) a C.sub.1-6 alkyl-carbonyl group (e.g.,
2-methylpropanoyl, butanoyl) optionally substituted by 1 to 3
hydroxy groups, (2) a C.sub.3-10 cycloalkyl-carbonyl group (the
C.sub.3-10 cycloalkyl moiety of the C.sub.3-10 cycloalkyl-carbonyl
group is optionally bridged (e.g., cyclopropylcarbonyl,
cyclobutylcarbonyl, bicyclo[1.1.1]pentan-1-ylcarbonyl)) optionally
substituted by 1 to 3 substituents selected from
[0259] (a) a halogen atom (e.g., a fluorine atom), and
[0260] (b) a hydroxy group,
(3) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl
group (e.g., oxetanylcarbonyl, tetrahydrofurylcarbonyl,
azetidinylcarbonyl), or (4) a mono- or di-C.sub.1-6 alkyl-carbamoyl
group (e.g., dimethylcarbamoyl); and Ring A is a benzene ring
further substituted by one C.sub.6-14 aryl group (e.g., phenyl)
optionally substituted by 1 to 3 substituents selected from [0261]
(i) a halogen atom (e.g., a fluorine atom, a chlorine atom), and
[0262] (ii) an optionally halogenated C.sub.1-6 alkyl group (e.g.,
methyl, difluoromethyl), and optionally further substituted by 1 to
3 halogen atoms (e.g., a fluorine atom).
[Compound D]
[0263] Compound (I) wherein
R.sup.1 is
[0264] (1) a C.sub.1-6 alkyl group (e.g., methyl, ethyl), or (2) a
mono- or di-C.sub.1-6 alkylamino group (e.g., dimethylamino);
R.sup.2 is
[0265] (1) a hydrogen atom, or (2) a fluorine atom;
R.sup.3 is
[0266] (1) a C.sub.1-6 alkyl-carbonyl group (e.g.,
2-methylpropanoyl) optionally substituted by 1 to 3 hydroxy groups,
(2) a C.sub.3-10 cycloalkyl-carbonyl group (the C.sub.3-10
cycloalkyl moiety of the C.sub.3-10 cycloalkyl-carbonyl group is
optionally bridged (e.g., cyclopropylcarbonyl, cyclobutylcarbonyl,
bicyclo[1.1.1]pentan-1-ylcarbonyl)) optionally substituted by 1 to
3 substituents selected from
[0267] (a) a halogen atom (e.g., a fluorine atom), and
[0268] (b) a hydroxy group,
(3) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl
group (e.g., oxetanylcarbonyl, azetidinylcarbonyl), or (4) a mono-
or di-C.sub.1-6 alkyl-carbamoyl group (e.g., dimethylcarbamoyl);
and Ring A is a benzene ring further substituted by one C.sub.6-14
aryl group (e.g., phenyl) optionally substituted by 1 to 3
substituents selected from
[0269] (i) a halogen atom (e.g., a fluorine atom), and
[0270] (ii) a C.sub.1-6 alkyl group (e.g., methyl), and
optionally further substituted by 1 to 3 halogen atoms (e.g., a
fluorine atom).
[Compound E]
[0271] Compound (I) wherein
R.sup.1 is
[0272] (1) a C.sub.1-6 alkyl group (e.g., ethyl), or (2) a mono- or
di-C.sub.1-6 alkylamino group (e.g., dimethylamino);
R.sup.2 is
[0273] (1) a hydrogen atom, or (2) a fluorine atom;
R.sup.3 is
[0274] (1) a C.sub.1-6 alkyl-carbonyl group (e.g.,
2-methylpropanoyl) optionally substituted by 1 to 3 hydroxy groups,
(2) a 3- to 8-membered monocyclic non-aromatic heterocyclylcarbonyl
group (e.g., oxetanylcarbonyl, azetidinylcarbonyl), or (3) a mono-
or di-C.sub.1-6 alkyl-carbamoyl group (e.g., dimethylcarbamoyl);
and Ring A is a benzene ring further substituted by one C.sub.6-14
aryl group (e.g., phenyl) optionally substituted by 1 to 3
substituents selected from
[0275] (i) a halogen atom (e.g., a fluorine atom), and
[0276] (ii) a C.sub.1-6 alkyl group (e.g., methyl), and
optionally further substituted by 1 to 3 halogen atoms (e.g., a
fluorine atom).
[0277] Specific examples of compound (I) include the compounds of
the below-mentioned Examples 1 to 616.
[0278] Specifically, compound (I) is preferably
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
(2R)-oxetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide or a salt
thereof (Example 1);
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifl-
uoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
or a salt thereof (Example 2);
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifl-
uoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
or a salt thereof (Example 3);
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-hyd-
roxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide or a salt
thereof (Example 5);
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro-
[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide or a
salt thereof (Example 56);
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,2',3'-trifl-
uoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
or a salt thereof (Example 66);
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,2',5'-trifl-
uoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
or a salt thereof (Example 67);
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4,4-difluoro-2-[(2,3',5'--
trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
or a salt thereof (Example 87);
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro-
[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide or a
salt thereof (Example 91);
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide or a salt
thereof (Example 94);
N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,-
1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide or a
salt thereof (Example 144);
N-{(2S,3R)-4,4-difluoro-1-(2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'--
biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide or a salt
thereof (Example 146);
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
(1r,3S)-3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
or a salt thereof (Example 225);
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide or a salt
thereof (Example 236);
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-((2R)-o-
xetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide or a salt
thereof (Example 302);
N-{(2S,3R)-4,4-difluoro-1-((1r,3S)-3-fluorocyclobutane-1-carbonyl)-2-[(2,-
3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonami-
de or a salt thereof (Example 375);
N-{(2S,3R)-4,4-difluoro-1-((1s,3R)-3-fluorocyclobutane-1-carbonyl)-2-[(2,-
3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonami-
de or a salt thereof (Example 380);
N-{(2S,3R)-4,4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)-2-[(2,3',5'-tr-
ifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
or a salt thereof (Example 433);
N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-difluoro-2-[(2-fluoro-3'-methyl[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N, N-dimethylsulfuric
diamide or a salt thereof (Example 443);
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide or a salt
thereof (Example 450);
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3'-methyl[1,-
1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide or a
salt thereof (Example 451);
(2S,3R,4S)-3-[(dimethylsulfamoyl)amino]-4-fluoro-2-[(2-fluoro-3'-methyl[1-
,1'-biphenyl]-3-yl)methyl]-N,N-dimethylpyrrolidine-1-carboxamide or
a salt thereof (Example 459);
N'-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)methyl-
]-1-(1-hydroxycyclobutane-1-carbonyl)pyrrolidin-3-yl]-N,N-dimethylsulfuric
diamide or a salt thereof (Example 462);
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3'-methyl[1-
,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide or a salt thereof (Example 463); or
N'-{(2S,3R)-4,4-difluoro-1-[(2R)-oxetane-2-carbonyl]-2-[(2,3',5'-trifluor-
o[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide or a salt thereof (Example 542).
[0279] Compound (I) is particularly preferably
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
(2R)-oxetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide or a salt
thereof (Example 1);
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifl-
uoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
or a salt thereof (Example 3);
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide or a salt
thereof (Example 94);
N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-difluoro-2-[(2-fluoro-3'-methyl[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide or a salt thereof (Example 443);
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3'-methyl[1,-
1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide or a
salt thereof (Example 451);
(2S,3R,4S)-3-[(dimethylsulfamoyl)amino]-4-fluoro-2-[(2-fluoro-3'-methyl[1-
,1'-biphenyl]-3-yl)methyl]-N,N-dimethylpyrrolidine-1-carboxamide or
a salt thereof (Example 459);
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3'-methyl[1-
,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide or a salt thereof (Example 463); or
N'-{(2S,3R)-4,4-difluoro-1-[(2R)-oxetane-2-carbonyl]-2-[(2,3',5'-trifluor-
o[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide or a salt thereof (Example 542).
[0280] As a salt of a compound represented by the formula (I), a
pharmacologically acceptable salt is preferable, and examples of
such salt include a salt with inorganic base, a salt with organic
base, a salt with inorganic acid, a salt with organic acid, a salt
with basic or acidic amino acid and the like.
[0281] Preferable examples of the salt with inorganic base include
alkali metal salts such as sodium salt, potassium salt and the
like, alkaline earth metal salts such as calcium salt, magnesium
salt and the like, aluminum salt, ammonium salt and the like.
[0282] Preferable examples of the salt with organic base include
salts with trimethylamine, triethylamine, pyridine, picoline,
ethanolamine, diethanolamine, triethanolamine,
tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine,
cyclohexylamine, benzylamine, dicyclohexylamine,
N,N-dibenzylethylenediamine and the like.
[0283] Preferable examples of the salt with inorganic acid include
salts with hydrochloric acid, hydrobromic acid, nitric acid,
sulfuric acid, phosphoric acid and the like.
[0284] Preferable examples of the salt with organic acid include
salts with formic acid, acetic acid, trifluoroacetic acid, phthalic
acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric
acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid and the like.
[0285] Preferable examples of the salt with basic amino acid
include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salt with acidic amino acid include
salts with aspartic acid, glutamic acid and the like.
[0286] The production method of the compound of the present
invention is explained below.
[0287] The raw material compound and reagent used and the compound
obtained in each step in the following production method may be
each in a form of a salt, and examples of such salt include those
similar to the salts of the compound represented by the formula
(I), and the like.
[0288] When the compound obtained in each step is a free form, it
can be converted to the objective salt according to a method known
per se. When the compound obtained in each step is a salt, it can
be converted to the objective free form or the other salt according
to a method known per se.
[0289] The compound obtained in each step can be used directly as
the reaction mixture or as a crude product for the next reaction.
Alternatively, the compound obtained in each step can be isolated
and purified from a reaction mixture according to a method known
per se, for example, a separation means such as concentration,
crystallization, recrystallization, distillation, solvent
extraction, fractional distillation, column chromatography and the
like:
[0290] When the raw material compound and reagent used in each step
are commercially available, the commercially available product can
also be used directly.
[0291] In the reaction in each step, while the reaction time varies
depending on the kind of the reagent and solvent to be used, it is
generally 1 min-48 hr, preferably 10 min-8 hr, unless otherwise
specified.
[0292] In the reaction in each step, while the reaction temperature
varies depending on the kind of the reagent and solvent to be used,
it is generally -78.degree. C.-300.degree. C., preferably
-78.degree. C.-150.degree. C., unless otherwise specified.
[0293] In the reaction in each step, while the pressure varies
depending on the kind of the reagent and solvent to be used, it is
generally 1 atm-20 atm, preferably 1 atm-3 atm, unless otherwise
specified.
[0294] Microwave synthesizer such as Initiator manufactured by
Biotage and the like may be used for the reaction in each step.
[0295] While the reaction temperature varies depending on the kind
of the reagent and solvent to be used, it is generally room
temperature -300.degree. C., preferably 50.degree. C.-250.degree.
C., unless otherwise specified. While the reaction time varies
depending on the kind of the reagent and solvent to be used, it is
generally 1 min-48 hr, preferably 1 min-8 hr, unless otherwise
specified.
[0296] In the reaction in each step, the reagent is used in an
amount of 0.5 equivalents-20 equivalents, preferably 0.8
equivalents-5 equivalents, relative to the substrate, unless
otherwise specified. When the reagent is used as a catalyst, the
reagent is used in an amount of 0.001 equivalent-1 equivalent,
preferably 0.01 equivalent-0.2 equivalent, relative to the
substrate. When the reagent is used as a reaction solvent, the
reagent is used in a solvent amount.
[0297] Unless otherwise specified, the reaction in each step is
carried cut without solvent, or by dissolving or suspending the raw
material compound in a suitable solvent. Examples of the solvent
include those described in Examples and the following solvents.
alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol
and the like; ethers: diethyl ether, diphenyl ether,
tetrahydrofuran, 1,2-dimethoxyethane and the like; aromatic
hydrocarbons: chlorobenzene, toluene, xylene and the like;
saturated hydrocarbons: cyclohexane, hexane and the like; amides:
N,N-dimethylformamide, N-methylpyrrolidone and the like;
halogenated hydrocarbons: dichloromethane, carbon tetrachloride and
the like; nitriles: acetonitrile, and the like; sulfoxides:
dimethyl sulfoxide and the like; aromatic organic bases: pyridine
and the like; anhydrides: acetic anhydride and the like; organic
acids: formic acid, acetic acid, trifluoroacetic acid and the like;
inorganic acids: hydrochloric acid, sulfuric acid and the like;
esters: ethyl acetate and the like; ketones: acetone, methyl ethyl
ketone and the like; water.
[0298] The above-mentioned solvent can be used in a mixture of two
or more kinds thereof in an appropriate ratio.
[0299] When a base is used for the reaction in each step, examples
thereof include those described in Examples and the following
bases.
inorganic bases: sodium hydroxide, magnesium hydroxide, sodium
carbonate, calcium carbonate, sodium hydrogen carbonate and the
like; organic bases: triethylamine, diethylamine, pyridine,
4-dimethylaminopyridine, N,N-dimethylaniline,
1,4-diazabicyclo[2.2.2] octane, 1,8-diazabicyclo[5.4.0]-7-undecene,
imidazole, piperidine and the like; metal alkoxides: sodium
ethoxide, potassium tert-butoxide and the like; alkali metal
hydrides: sodium hydride and the like; metal amides: sodium amide,
lithium diisopropylamide, lithium hexamethyldisilazide and the
like; organic lithiums: n-butyllithium and the like.
[0300] When an acid or an acid catalyst is used for the reaction in
each step, examples thereof include those described in Examples and
the following acids and acid catalysts, inorganic acids:
hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid,
phosphoric acid and the like;
organic acids: acetic acid, trifluoroacetic acid, citric acid,
p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewis
acid: boron trifluoride diethyl ether complex, zinc iodide,
anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous
iron chloride and the like.
[0301] Unless otherwise specified, the reaction in each step is
carried out according to a method known per se, for example, the
method described in Jikken Kagaku Kouza, 5th Edition, vol. 13-19
(the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol.
14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry,
Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic
Name Reactions, the Reaction Mechanism and Essence, Revised Edition
(Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII
(John Wiley & Sons Inc.); Modern Organic Synthesis in the
Laboratory A Collection of Standard Experimental Procedures (Jie
Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry
III, Vol. 1-Vol. 14 (Elsevier Japan); Strategic Applications of
Named Reactions in Organic Synthesis (translated by Kiyoshi
Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH
Publishers Inc.), 1989, or the like, or the method described in
Examples.
[0302] In each step, the protection or deprotection reaction of an
functional group is carried out according to a method known per se,
for example, the method described in "Protective Groups in Organic
Synthesis, 4th Ed", Wiley-Interscience, Inc., 2007 (Theodora W.
Greene, Peter G. M. Wuts); "Protecting Groups 3rd Ed." Thieme, 2004
(P. J. Kocienski), or the like, or the method described in
Examples.
[0303] Examples of the protecting group for a hydroxy group of an
alcohol and the like and a phenolic hydroxy group include
ether-type protecting groups such as methoxymethyl ether, benzyl
ether, tert-butyldimethylsilyl ether, tetrahydropyranyl ether and
the like; carboxylate ester-type protecting groups such as acetate
ester and the like; sulfonate ester-type protecting groups such as
methanesulfonate ester and the like; carbonate ester-type
protecting groups such as tert-butylcarbonate and the like, and the
like.
[0304] Examples of the protecting group for a carbonyl group of an
aldehyde include acetal-type protecting groups such as
dimethylacetal and the like; cyclic acetal-type protecting groups
such as 1,3-dioxane and the like, and the like.
[0305] Examples of the protecting group for a carbonyl group of a
ketone include ketal-type protecting groups such as dimethylketal
and the like; cyclic ketal-type protecting groups such as
1,3-dioxane and the like; oxime-type protecting groups such as
O-methyloxime and the like; hydrazone-type protecting groups such
as N,N-dimethylhydrazone and the like, and the like.
[0306] Examples of the protecting group for a carboxyl group
include ester-type protecting groups such as methyl ester and the
like; amide-type protecting groups such as N,N-dimethylamide and
the like, and the like.
[0307] Examples of the protecting group for a thiol include
ether-type protecting groups such as benzyl thioether and the like;
ester-type protecting groups such as thioacetate ester,
thiocarbonate, thiocarbamate and the like, and the like.
[0308] Examples of the protecting group for an amino group and an
aromatic heterocycle such as imidazole, pyrrole, indole and the
like include carbamate-type protecting groups such as benzyl
carbamate and the like; amide-type protecting groups such as
acetamide and the like; alkyl amine-type protecting groups such as
N-triphenylmethylamine and the like; sulfonamide-type protecting
groups such as methanesulfonamide and the like, and the like.
[0309] The protecting groups can be removed according to a method
known per se, for example, by employing a method using acid, base,
ultraviolet rays, hydrazine, phenylhydrazine, sodium
N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium
acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide,
trimethylsilyl bromide) and the like, a reduction method, and the
like.
[0310] When reduction reaction is carried out in each step,
examples of the reducing agent to be used include metal hydrides
such as lithium aluminum hydride, sodium triacetoxyborohydride,
sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H),
sodium borohydride, tetramethylammonium triacetoxyborohydride and
the like; boranes such as borane tetrahydrofuran complex and the
like; Raney nickel; Raney cobalt; hydrogen; formic acid;
triethylsilane and the like. When carbon-carbon double bond or
triple bond is reduced, a method using a catalyst such as
palladium-carbon, Lindlar's catalyst and the like may be
employed.
[0311] When oxidation reaction is carried out in each step,
examples of the oxidizing agent to be used include peroxides such
as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide,
tert-butylhydroperoxide and the like; perchlorates such as
tetrabutylammonium perchlorate and the like; chlorates such as
sodium chlorate and the like; chlorites such as sodium chlorite and
the like; periodates such as sodium periodate and the like;
hypervalent iodine reagents such as iodosylbenzene and the like;
reagents containing manganese such as manganese dioxide, potassium
permanganate and the like; leads such as lead tetraacetate and the
like; reagents containing chromium such as pyridinium
chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent
and the like; halogen compounds such as N-bromosuccinimide (NBS)
and the like; oxygen; ozone; sulfur trioxide-pyridine complex;
osmium tetroxide; selenium dioxide;
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.
[0312] When radical cyclization reaction is carried out in each
step, examples of the radical initiator to be used include azo
compounds such as azobisisobutyronitrile (AIBN) and the like;
water-soluble radical initiators such as
4-4'-azobis-4-cyanopentanoic acid (ACPA) and the like;
triethylboron in the presence of air or oxygen; benzoyl peroxide
and the like. Examples of the radical reagent to be used include
tributylstannane, tristrimethylsilylsilane,
1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide and
the like.
[0313] When Wittig reaction is carried out in each step, examples
of the Wittig reagent to be used include alkylidene phosphoranes
and the like. The alkylidene phosphoranes can be prepared according
to a method known per se, for example, by reacting a phosphonium
salt with a strong base.
[0314] When Horner-Emmons reaction is carried out in each step,
examples of the reagent to be used include phosphonoacetates such
as methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate
and the like; and bases such as alkali metal hydrides, organic
lithiums and the like.
[0315] When Friedel-Crafts reaction is carried out in each step, a
combination of a Lewis acid and an acid chloride or a combination
of a Lewis acid and an alkylating agent (e.g., an alkyl halide, an
alcohol, an olefin etc.) is used as a reagent. Alternatively, an
organic acid or an inorganic acid can also be used instead of a
Lewis acid, and an anhydride such as acetic anhydride and the like
can also be used instead of an acid chloride.
[0316] When aromatic nucleophilic substitution reaction is carried
out in each step, a nucleophile (e.g., an amine, imidazole etc.)
and a base (e.g., an organic base etc.) are used as a reagent.
[0317] When nucleophilic addition reaction by a carbo anion,
nucleophilic 1,4-addition reaction (Michael addition reaction) by a
carbo anion or nucleophilic substitution reaction by a carbo anion
is carried out in each step, and examples of the base to be used
for generation of the carbo anion include organic lithiums, metal
alkoxides, inorganic bases, organic bases and the like.
[0318] When Grignard reaction is carried out in each step, examples
of the Grignard reagent to be used include arylmagnesium halides
such as phenylmagnesium bromide and the like; and alkylmagnesium
halides such as methylmagnesium bromide and the like. The Grignard
reagent can be prepared according to a method known per se, for
example, by reacting an alkyl halide or an aryl halide with a metal
magnesium in an ether or tetrahydrofuran as a solvent.
[0319] When Knoevenagel condensation reaction is carried out in
each step, a compound having an activated methylene group with two
electron withdrawing groups (e.g., malonic acid, diethyl malonate,
malononitrile etc.) and a base (e.g., an organic base, a metal
alkoxide, an inorganic base) are used as a reagent.
[0320] When Vilsmeier-Haack reaction is carried out in each step,
phosphoryl chloride and an amide derivative (e.g.,
N,N-dimethylformamide etc.) are used as a reagent.
[0321] When azidation reaction of an alcohol, an alkyl halide or a
sulfonate is carried out in each step, examples of the azidating
agent to be used include diphenylphosphorylazide (DPPA),
trimethylsilylazide, sodium azide and the like. For example, for
the azidation reaction, of an alcohol, a method using
diphenylphosphorylazide and 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), a method using trimethylsilylazide and a Lewis acid, and the
like are employed.
[0322] When reductive amination reaction is carried out in each
step, examples of the reducing agent to be used include sodium
triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic
acid and the like. When the substrate is an amine compound,
examples of the carbonyl compound to be used include
paraformaldehyde, aldehydes such as acetaldehyde and the like, and
ketones such as cyclohexanone and the like. When the substrate is a
carbonyl compound, examples of the amine to be used include
ammonia, primary amines such as methylamine and the like; secondary
amines such as dimethylamine and the like, and the like.
[0323] When Mitsunobu reaction is carried out in each step, an
azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD),
diisopropyl azodicarboxylate (DIAD) etc.) and triphenylphosphine
are used as a reagent.
[0324] When esterification reaction, amidation reaction or urea
formation reaction is carried out in each step, examples of the
reagent to be used include acyl halides such as acid chlorides,
acid bromides and the like; activated carboxylic acids such as acid
anhydrides, activated esters, sulfates and the like. Examples of
the activating agent of the carboxylic acid include carbodiimide
condensing agents such as
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD)
and the like; triazine condensing agents such as
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
n-hydrate (DMT-MM) and the like; carbonate condensing agents such
as 1,1-carbonyldiimidazole (CDI) and the like; diphenylphosphoryl
azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium
salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama
reagent); thionyl chloride; lower alkyl haloformates such as ethyl
chloroformate and the like;
0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphorate (HATU); sulfuric acid; combinations thereof
and the like. When carbodiimide condensing agent is used, an
additive such as 1-hydroxybenzotriazole (HOBt),
N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the
like may be added to the reaction system.
[0325] When coupling reaction is carried out in each step, examples
of the metal catalyst to be used include palladium compounds such
as palladium(II) acetate, tetrakis(triphenylphosphine) palladium
(0), dichlorobis(triphenylphosphine)palladium(II),
dichlorobis(triethylphosphine)palladium(II),
tris(dibenzylideneacetone)dipalladium(0),
1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride and the
like; nickel compounds such as
tetrakis(triphenylphosphine)nickel(0) and the like; rhodium
compounds such as tris(triphenylphosphine)rhodium(III) chloride and
the like; cobalt compounds; copper compounds such as copper oxide,
copper(I) iodide and the like; platinum compounds and the like. In
addition, a base can be added to the reaction system, and examples
thereof include inorganic bases and the like.
[0326] When thiocarbonylation reaction, is carried out in each
step, phosphorus pentasulfide is typically used as the
thiocarbonylating agent. Alternatively, a reagent having a
1,3,2,4-dithiadiphosphetane-2,4-disulfide structure (e.g.,
2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide
(Lawesson reagent) etc.) can also be used instead of phosphorus
pentasulfide.
[0327] When Wohl-Ziegler reaction is carried out in each step,
examples of the halogenating agent to be used include
N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide
(NCS), bromine, sulfuryl chloride and the like. In addition, the
reaction can be accelerated by subjecting a radical initiator such
as heat, light, benzoyl peroxide, azobisisobutyronitrile and the
like, to the reaction system reaction.
[0328] When halogenation reaction of a hydroxy group is carried out
in each step, examples of the halogenating agent to be used include
hydrohalic acids and acid halides of inorganic acids, specifically,
hydrochloric acid, thionyl chloride, phosphorus oxychloride and the
like for chlorination, 48% hydrobromic acid and the like for
bromination. In addition, a method of producing an alkyl halide by
reacting an alcohol with triphenylphosphine and carbon
tetrachloride or carbon tetrabromide or the like can be employed.
Alternatively, a method of producing an alkyl halide via two steps
comprising converting an alcohol, to the corresponding sulfonate,
and then reacting the sulfonate with lithium bromide, lithium
chloride or sodium iodide can also be employed.
[0329] When Arbuzov reaction is carried out in each step, examples
of the reagent to be used include alkyl halides such as ethyl
bromoacetate and the like; and phosphites such as triethyl
phosphite, tri(isopropyl) phosphite and the like.
[0330] When sulfonate esterification reaction is carried out in
each step, examples of the sulfonating agent to be used include
methanesulfonyl chloride, p-toluenesulfonyl chloride,
methanesulfonic anhydride, p-toluenesulfonic anhydride and the
like.
[0331] When hydrolysis reaction is carried out in each step, an
acid or a base is used as a reagent. For acid hydrolysis reaction
of tert-butyl ester, formic acid, triethylsilane and the like may
be added to reductively-trap tert-butyl cation which is
by-produced.
[0332] When dehydration reaction is carried out in each step,
examples of the dehydrating agent to be used include sulfuric acid,
diphosphorus pentaoxide, phosphorus oxychloride,
N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the
like.
[0333] Compound (I) can be produced from compound (1) according to
the method shown in the following Reaction Scheme 1. In the
reaction scheme, LG.sup.1 and LG.sup.2 are each independently a
leaving group, R.sup.4 and R.sup.5 are each independently an
optionally substituted C.sub.1-6 alkyl group or an optionally
substituted C.sub.6-14 aryl group, P.sup.1 and P.sup.2 are each
independently a protecting group, and the other symbols are as
defined above.
##STR00013## ##STR00014## ##STR00015##
[0334] Examples of the "leaving group" represented by LG.sup.1 or
LG.sup.2 include halogen atoms, optionally halogenated C.sub.1-6,
alkylsulfonyloxy groups (e.g., methanesulfonyloxy,
ethanesulfonyloxy, trifluoromethanesulfonyloxy), and C.sub.6-14
arylsulfonyloxy groups optionally substituted by C.sub.1-6 alkyl
group(s) (e.g., benzenesulfonyloxy, toluenesulfonyloxy) and the
like.
[0335] Examples of the substituent of the "optionally substituted
C.sub.1-6 alkyl group" and "optionally substituted C.sub.6-14 aryl
group" represented by R.sup.4 or R.sup.5 include substituents
selected from Substituent group A. The number of the substituents
is preferably 0.1 to 3. When the number of the substituents is 2 or
more, the respective substituents may be the same or different.
[0336] Examples of the "protecting group" represented by P.sup.1 or
P.sup.2 include those exemplified as the above-mentioned
"protecting group for an amino group and an aromatic heterocycle
such as imidazole, pyrrole, indole and the like".
[0337] Compound (1) may be commercially available, or can be
produced according to a method known per se or a method analogous
thereto.
[0338] Compound (4) can be produced by subjecting compound (2) to
the Reformatsky reaction with compound (3) in the presence of a
metal. Examples of the metal to be used include zinc, samarium
iodide, indium and the like. Compound (3) may be commercially
available, or can be produced according to a method known per se or
a method analogous thereto.
[0339] Compound (6) can be produced by subjecting compound (5) to a
condensation reaction in the presence of a base. Examples of the
base to be used include inorganic bases, organic bases, alkali
metal hydrides and the like.
[0340] Compound (9) can be produced by subjecting compound (8) to a
sulfonate esterification reaction. Examples of the sulfonating
agent to be used include methanesulfonyl chloride,
p-toluenesulfonyl chloride, methanesulfonic anhydride,
p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride and
the like.
[0341] Compound (10) can be produced by subjecting compound (9) to
an azidation reaction. Examples of the azidating agent to be used
include tetra-n-butylammonium azide, trimethylsilylazide, sodium
azide and the like.
[0342] Compound (13) can be produced by subjecting compound (11) to
a sulfonamidation reaction with compound (12). Examples of compound
(12) to be used include sulfonyl chlorides, sulfamoyl chlorides and
the like. Compound (12) may be commercially available, or can be
produced according to a method known per se or a method analogous
thereto.
[0343] Compound (I) can be produced by subjecting compound (14) to
a condensation reaction with compound (15). Examples of compound
(15) to be used include acyl halides such as acid chlorides, acid
bromides, alkyl chloroformates, carbamoyl chlorides and the like;
and activated carboxylic acids such as acid anhydrides, activated
esters, sulfates and the like. Examples of the activating agent of
the carboxylic acid include carbodiimide condensing agents such as
l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD)
and the like; triazine condensing agents such as
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium
chloride-n-hydrate (DMT-MM) and the like; carbonate ester
condensing agents such as 1,1-carbonyldiimidazole (CDI) and the
like; diphenylphosphoryl azide (DPPA);
benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP
reagent); 2-chloro-1-methyl-pyridinium iodide (Mukaiyama reagent);
thionyl chloride; lower alkyl haloformates such as chloroethyl
formate and the like;
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphorate (HATU); sulfuric acid; combinations thereof,
and the like. In addition, a base may be added to the reaction
system. Examples of the base include inorganic bases, organic bases
and the like. When a carbodiimide condensing agent is used, an
additive such as 1-hydroxybenzotriazole (HOBt),
N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) and the
like may be further added to the reaction system.
[0344] In the thus-obtained compound (I), an intramolecular
functional group can also be converted to an object functional
group by a combination of chemical reactions known per se. Examples
of the chemical reaction include oxidation reaction, reduction
reaction, alkylation reaction, acylation reaction, ureation
reaction, hydrolysis reaction, amination reaction, esterification
reaction, aryl coupling reaction, deprotection reaction and the
like.
[0345] In the above-mentioned production method, when a starting
compound has an amino group, a carboxyl group, a hydroxy group, a
carbonyl group or a mercapto group as a substituent, a protecting
group generally used in the peptide chemistry may be introduced
into these groups, and the object compound can be obtained by
removing the protecting group as necessary after the reaction.
[0346] Compound (I) obtained by the above-mentioned production
method can be isolated and purified by a known means, such as
solvent extraction, liquid conversion, phase transfer,
crystallization, recrystallization, chromatography and the
like.
[0347] When compound (I) contains optical isomer, stereoisomer,
regio isomer and rotamer, these compounds are also included in
compound (I), and each can be obtained as a single product by a
synthesis method or a separation method known per se. For example,
when an optical isomer exists in compound (I), an optical isomer
resolved from the compound is also encompassed in compound (I).
[0348] Here, an optical isomer can be produced by a method known
per se.
[0349] Compound (I) may be a crystal.
[0350] A crystal of compound (I) (hereinafter sometimes to be
abbreviated as the crystal of the present invention) can be
produced by crystallizing compound (I), by applying a
crystallization method known per se.
[0351] In the present specification, the melting point means a
melting point measured, for example, by micro melting point
apparatus (Yanako, MP-500D or Buchi, B-545), DSC (differential
scanning calorimetry analysis) apparatus (METTLER TOLEDO, DSC1) and
the like.
[0352] Generally, the melting point sometimes varies depending on
the measurement device, measurement condition and the like. The
crystal in the present specification may be a crystal showing a
melting point different from the values described in the present
specification as long as the difference is within a general error
range.
[0353] The crystal of the present invention is superior in the
physicochemical properties (e.g., melting point, solubility,
stability) and biological properties (e.g., pharmacokinetics
(absorbability, distribution, metabolism, excretion), efficacy
expression), and is extremely useful as a medicament.
[0354] Compound (I) may be used as a prodrug. A prodrug of the
compound (I) means a compound which is converted to the compound
(I) of the present invention with a reaction due to an enzyme, an
gastric acid, etc. under the physiological condition in the living
body, that is, a compound which is converted to the compound (I) of
the present invention with oxidation, reduction, hydrolysis, etc.
according to an enzyme; a compound which is converted to the
compound (I) of the present invention by hydrolysis etc. due to
gastric acid, etc.
[0355] A prodrug of compound (I) may be a compound obtained by
subjecting an amino group in compound (I) to an acylation,
alkylation or phosphorylation (e.g., a compound obtained by
subjecting an amino group in compound (I) to an eicosanoylation,
alanylation, pentylaminocarbonylation,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,
tetrahydrofuranylation, pyrrolidylmethylation,
pivaloyloxymethylation and tert-butylation, etc.);
a compound obtained by subjecting a hydroxy group in compound (I)
to an acylation, alkylation, phosphorylation or boration (e.g., a
compound obtained by subjecting an hydroxy group in compound (I) to
an acetylation, palmitoylation, propanoylation, pivaloylation,
succinylation, fumarylation, alanylation,
dimethylaminomethylcarbonylation, etc.); a compound obtained by
subjecting a carboxyl group in compound (I) to an esterification or
amidation (e.g., a compound obtained by subjecting a carboxyl group
in compound (I) to an ethyl esterification, phenyl esterification,
carboxymethyl esterification, dimethylaminomethyl esterification,
pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl
esterification, phthalidyl esterification,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterification,
cyclohexyloxycarbonylethyl esterification and methylamidation,
etc.) and the like. Any of these compounds can be produced from
compound (I) by a method known per se.
[0356] A prodrug for compound (I) may also be one which is
converted into compound (I) under a physiological condition, such
as those described in IYAKUHIN no KAIHATSU (Development of
Pharmaceuticals), Vol. 7, Design of Molecules, p. 163-198,
Published by HIROKAWA SHOTEN (1990).
[0357] In the present specification, a prodrug may form a salt, and
as such salt, those exemplified as a salt of the compound
represented by the above-mentioned formula (I) can be
mentioned.
[0358] Compound (I) may be labeled with an isotope (e.g., .sup.3H,
.sup.13C, .sup.14C, .sup.18F, .sup.35S, .sup.125I) and the
like.
[0359] Compound (I) labeled with or substituted by an isotope can
be used, for example, as a tracer used for Positron Emission
Tomography (PET) (PET tracer), and is useful in the field of
medical diagnosis and the like.
[0360] Furthermore, compound (I) may be a hydrate or a non-hydrate,
or a non-solvate (e.g., anhydride), or a solvate (e.g.,
hydrate).
[0361] Compound (I) also encompasses a deuterium conversion form
wherein .sup.1H is converted to .sup.2H(D).
[0362] Furthermore, compound, (I) may be a pharmaceutically
acceptable cocrystal or cocrystal salt. The cocrystal or cocrystal
salt means a crystalline substance constituted with two or more
special solids at room temperature, each having different physical
properties (e.g., structure, melting point, melting heat,
hygroscopicity, solubility and stability). The cocrystal or
cocrystal salt can be produced by a cocrystallization method known
per se.
[0363] Compound (I) or a prodrug thereof (hereinafter sometimes to
be simply abbreviated as the compound of the present invention) can
be used as it is or in the form of a pharmaceutical composition
(also referred to as a medicament) by mixing with a
pharmacologically acceptable carrier etc. to mammals (e.g., human,
mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an
agent for the prophylaxis or treatment of various diseases
mentioned below.
[0364] As pharmacologically acceptable carriers, various organic or
inorganic carrier substances conventionally used as preparation
materials can be used. These are incorporated as excipient,
lubricant, binder and disintegrant for solid preparations; or
solvent, solubilizing agent, suspending agent, isotonicity agent,
buffer and soothing agent for liquid preparations; and the like;
and preparation, additives such as preservative, antioxidant,
colorant, sweetening agent and the like can be added as
necessary.
[0365] Preferable examples of the excipient include lactose,
sucrose, D-mannitol, D-sorbitol, starch, gelatinated starch,
dextrin, crystalline cellulose, low-substituted
hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic,
pullulan, light anhydrous silicic acid, synthetic aluminum silicate
and magnesium alumino metasilicate.
[0366] Preferable examples of the lubricant include magnesium
stearate, calcium stearate, talc and colloidal silica.
[0367] Preferable examples of the binder include gelatinated
starch, sucrose, gelatin, gum arabic, methylcellulose, IQ
carboxymethylcellulose, sodium carboxymethylcellulose, crystalline
cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan,
hydroxypropylcellulose, hydroxypropylmethylcellulose and
polyvinylpyrrolidone.
[0368] Preferable examples of the disintegrant include lactose,
sucrose, starch, carboxymethylcellulose, calcium
carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl
starch, light anhydrous silicic acid and low-substituted
hydroxypropylcellulose.
[0369] Preferable examples of the solvent include water for
injection, physiological brine, Ringer's solution, alcohol,
propylene glycol, polyethylene glycol, sesame oil, corn oil, olive
oil and cottonseed oil.
[0370] Preferable examples of the solubilizing agent include
polyethylene glycol, propylene glycol, D-mannitol, trehalose,
benzyl benzoate, ethanol, trisaminomethane, cholesterol,
triethanolamine, sodium carbonate, sodium citrate, sodium
salicylate and sodium acetate.
[0371] Preferable examples of the suspending agent include
surfactants such as stearyltriethanolamine, sodium lauryl sulfate,
lauryl aminopropionate, lecithin, benzalkonium chloride,
benzethonium chloride, glycerol monostearate and the like;
hydrophilic polymers such as poly(vinyl alcohol),
polyvinylpyrrolidone, carboxymethylcellulose sodium,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose and the like, polysorbates; and
polyoxyethylene hydrogenated castor oil.
[0372] Preferable examples of the isotonicity agent include sodium
chloride, glycerol, D-mannitol, D-sorbitol and glucose.
[0373] Preferable examples of the buffer include buffers of
phosphate, acetate, carbonate, citrate etc.
[0374] Preferable examples of the soothing agent include benzyl
alcohol.
[0375] Preferable examples of the preservative include
p-oxybenzoate esters, chlorobutanol, benzyl alcohol, phenethyl
alcohol, dehydroacetic acid and sorbic acid.
[0376] Preferable examples of the antioxidant include sulfite salts
and ascorbate salts.
[0377] Preferable examples of the colorant include aqueous food tar
colors (e.g., food colors such as Food Color Red Nos. 2 and 3, Food
Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the
like food colors), water insoluble lake dyes (e.g., aluminum salt
of the above-mentioned aqueous food tar color), natural dyes (e.g.,
.beta.-carotene, chlorophyll, red iron oxide) and the like.
[0378] Preferable examples of the sweetening agent include
saccharin sodium, dipotassium glycyrrhizinate, aspartame and
stevia.
[0379] Examples of the dosage form of the above-mentioned
pharmaceutical composition include oral preparations such as tablet
(including sugar-coated tablet, film-coated tablet, sublingual
tablet, orally disintegrating tablet, buccal tablet), capsule
(including soft capsule, microcapsule), pill, granule, powder,
troche, syrup, liquid, emulsion, suspension, aerosol, films (e.g.,
orally disintegrable films, oral mucosa-adhesive film) and the
like; and parenteral agents such as injection (e.g., subcutaneous
injection, intravenous injection, intramuscular injection,
intraperitoneal injection, drip infusion), external preparation
(e.g., transdermal absorption type preparation, ointment, lotion,
adhesive preparation), suppository (e.g., rectal suppository,
vaginal suppository), pellet, nasal preparation, pulmonary
preparation (inhalant), eye drop and the like. The compound and
medicament of the present invention can be respectively safely
administered orally or parenterally (e.g., intrarectal,
intravenous, intraarterial, intramuscular, subcutaneous,
intraorgan, intranasal, intradermal, instillation, intracerebral,
intravaginal, intraperitoneal, intratumoral, proximal tumor
administrations, and administration to the lesion).
[0380] These preparations may be a release control preparation
(e.g., sustained-release microcapsule) such as an immediate-release
preparation, a sustained-release preparation and the like.
[0381] The pharmaceutical composition can be produced according to
a method conventionally used in the field of pharmaceutical
formulation, for example, the method described in the Japanese
Pharmacopoeia, and the like.
[0382] While the content of the compound of the present invention
in the pharmaceutical composition of the present invention varies
depending on the dosage form, dose of the compound of the present
invention and the like, it is, for example, about 0.1 to 100 wt
%.
[0383] When an oral preparation is produced, coating may be applied
where necessary for the purpose of taste masking, enteric
solubility or sustainability.
[0384] Examples of the coating base used for coating include sugar
coating base, water-soluble film coating base, enteric film coating
base, and sustained-release film coating base.
[0385] As the sugar coating base, sucrose is used, and one or more
kinds selected from talc, and the precipitated calcium carbonate,
gelatin, gum arable, pullulan, carnauba wax and the like may be
further used in combination.
[0386] Examples of the water-soluble film coating base include
cellulose polymers such as hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose,
methylhydroxyethylcellulose and the like; synthetic polymers such
as polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate
copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone and the
like; and polysaccharides such as pullulan and the like.
[0387] Examples of the enteric film coating base include cellulose
polymers such as hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate succinate,
carboxymethylethylcellulose, cellulose acetate phthalate and the
like; acrylic acid polymers such as methacrylic acid copolymer L
[Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit
L-30D-55 (trade name)], methacrylic acid copolymer S [Eudragit S
(trade name)] and the like; and naturally-occurring substances such
as shellac and the like.
[0388] Examples of the sustained-release film coating base include
cellulose polymers such as ethylcellulose and the like; and acrylic
acid polymers such as aminoalkylmethacrylate copolymer RS [Eudragit
RS (trade name)], ethyl acrylate-methyl methacrylate copolymer
suspension [Eudragit NE (trade name)] and the like.
[0389] Two or more kinds of the above-mentioned coating bases may
be used in a mixture at an appropriate ratio. In addition, for
example, light shielding agents such as titanium oxide, red ferric
oxide and the like may also be used during coating.
[0390] Since the compound of the present invention shows low
toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity,
reproductive toxicity, cardiotoxicity, carcinogenicity) and less
side effects, it can be used as a prophylactic or therapeutic
agent, or diagnostic agent for various diseases in mammals (e.g.,
human, bovine, horse, dog, cat, monkey, mouse, rat).
[0391] Moreover, the compound of the present invention is expected
to be superior in central migration.
[0392] The compound of the present invention has an excellent an
orexin type 2 receptor agonist activity, and may treat, prevent or
ameliorate the risk of various neurological and psychiatric
diseases associated with an orexin type 2 receptor. The compound of
the present invention is useful as an agent for the prophylaxis or
treatment of various diseases such as narcolepsy, idiopathic
hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome
accompanied by narcolepsy-like symptoms, hypersomnia syndrome
accompanied by daytime hypersomnia (e.g., Kleine Levin syndrome,
major depression with hypersomnia, Lewy body dementia, Parkinson's
disease, progressive supranuclear paralysis, Prader-Willi syndrome,
Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease
type C, brain contusion, cerebral infarction, brain tumor, muscular
dystrophy, multiple sclerosis, acute disseminated
encephalomyelitis, Guillain-Barre syndrome, Rasmussen's
encephalitis, Wernicke's encephalitis, limbic encephalitis,
Hashimoto's encephalopathy), coma, loss of consciousness, obesity
(e.g., malignant mastocytosis, exogenous obesity, hyperinsulinar
obesity, hyperplasmic obesity, hypop hyseal adiposity, hypoplasmic
obesity, hypothyroid obesity, hypothalamic obesity, symptomatic
obesity, infantile obesity, upper body obesity, alimentary obesity,
hypogonadal obesity, systemic mastocytosis, simple obesity, central
obesity), insulin resistance syndrome, Alzheimer's disease,
disturbance of consciousness such as coma and the like, side
effects and complications due to anesthesia, sleep disturbance,
sleep problem, insomnia, Intermittent sleep, nocturnal myoclonus,
REM sleep interruption, jet lag, jet lag syndrome, sleep disorder
of alternating worker, sleep disorder, night terror, depression,
major depression, sleepwalking disease, enuresis, sleep disorder,
Alzheimer's dusk, diseases associated with circadian rhythm,
fibromyalgia, condition arising from decline in the quality of
sleep, overeating, obsessive compulsive eating disorder,
obesity-related disease, hypertension, diabetes, elevated plasma
insulin concentration and insulin resistance, hyperlipidemia,
hyperlipemia, endometrial cancer, breast cancer, prostate cancer,
colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea,
cholelithiasis, gallstones, cardiac disease, abnormal heartbeat,
arrhythmia, myocardial infarction, congestive cardiac failure,
cardiac failure, coronary heart disease, cardiovascular disorder,
sudden death, polycysticovarian disease, craniopharingioma,
Froelich's syndrome, growth hormone deficient, normal mutant short
stature, Turner's syndrome, children suffering from acute
lymphoblastic leukemia, syndrome X, reproductive hormone
abnormality, declining fertility, infertility, male gonadal
function decline, sexual and reproductive dysfunction such as
female male hirsutism, fetal defects associated with pregnant women
obesity, gastrointestinal motility disorders such as
obesity-related gastroesophageal reflux, obesity hypoventilation
syndrome (Pickwick syndrome), respiratory diseases such as dyspnea,
inflammation such as systemic inflammation of the vascular system,
arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back
pain, gall bladder disease, gout, kidney cancer, risk of secondary
outcomes of obesity such as lowering the risk of left ventricular
hypertrophy, migraine pain, headache, neuropathic pain, Parkinson's
disease, psychosis, schizophrenia, facial flushing, night sweats,
diseases of the genital/urinary system, diseases related to sexual
function or fertility, dysthymic disorder, bipolar disorder,
bipolar I disorder, bipolar II disorder, cyclothymic disorder,
acute stress disorder, agoraphobia, generalized anxiety disorder,
obsessive disorder, panic attack, panic disorder, posttraumatic
stress disorder, separation anxiety disorder, social phobia,
anxiety disorder, acute neurological and psychiatric disorders such
as cardiac bypass surgery and post-transplant cerebral deficit,
stroke, ischemic stroke, cerebral ischemia, spinal cord trauma,
head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve
injury, Huntington's disease, amyotrophic lateral sclerosis,
multiple sclerosis, eye damage, retinopathy, cognitive impairment,
muscle spasm, tremor, epilepsy, disorders associated with muscle
spasticity, delirium, amnestic disorder, age-related cognitive
decline, schizoaffective disorder, delusional disorder, drug
addiction, dyskinesia, chronic fatigue syndrome, fatigue,
medication-induced Parkinsonism syndrome, Jill-do La Tourette's
syndrome, chorea, myoclonus, tic, restless legs syndrome, dystonia,
dyskinesia, attention deficit hyperactivity disorder (ADHD),
behavior disorder, urinary incontinence, withdrawal symptoms,
trigeminal neuralgia, hearing less, tinnitus, nerve damage,
retinopathy, macular degeneration, vomiting, cerebral edema, pain,
bone pain, arthralgia, toothache, cataplexy, and traumatic brain
injury (TBI).
[0393] Particularly, the compound of the present invention is
useful as an agent for the prophylaxis or treatment of narcolepsy,
idiopathic hypersomnia, hypersomnia, sleep apnea syndrome,
narcolepsy syndrome accompanied by narcolepsy-like symptoms,
hypersomnia syndrome accompanied by daytime hypersomnia (e.g.,
Parkinson's disease, Guillain-Barre syndrome and Kleine Levin
syndrome), Alzheimer's disease, obesity, insulin resistance
syndrome, cardiac failure, diseases related to bene loss, sepsis,
disturbance of consciousness such as coma and the like, side
effects and complications due to anesthesia, and the like, or
anesthetic antagonist.
[0394] While the dose of the compound of the present invention
varies depending on the subject of administration, administration
route, target disease, symptom and the like, for example, when the
compound of the present invention is administered orally or
parenterally to an adult patient, its dose is for example, about
0.01 to 100 mg/kg body weight per dose, preferably 0.1 to 50 mg/kg
body weight per dose and more preferably 0.5 to 20 mg/kg body
weight per dose. This amount is desirably administered in one to 3
portions daily.
[0395] The compound of the present invention can be used in
combination with other drugs (hereinafter to be abbreviated as
concomitant drug).
[0396] By combining the compound of the present invention and a
concomitant drug, a superior effect, for example,
(1) the dose can be reduced as compared to single administration of
the compound of the present invention or a concomitant drug, (2)
the drug to be combined with the compound of the present invention
can be selected according to the condition of patients (mild case,
severe case and the like), (3) the period of treatment can be set
longer by selecting a concomitant drug having different action and
mechanism from the compound of the present invention, (4) a
sustained treatment effect can be designed by selecting a
concomitant drug having different action and mechanism from the
compound of the present invention, (5) a synergistic effect can be
afforded by a combined use of the compound of the present invention
and a concomitant drug, and the like, can be achieved.
[0397] In the present specification, the compound of the present
invention and a concomitant drug used in combination are referred
to as the "combination agent of the present invention".
[0398] When using the combination agent of the present invention,
the administration time of the compound of the present invention
and the concomitant drug is not restricted, and the compound of the
present invention or a pharmaceutical composition thereof, or the
concomitant drug or a pharmaceutical composition thereof can be
administered to an administration subject simultaneously, or may be
administered at different times. The dosage of the concomitant drug
may be determined according to the dose clinically used, and can be
appropriately selected depending on an administration subject,
administration route, disease, combination and the like.
[0399] The administration mode of the combination agent of the
present invention and the concomitant drug is not particularly
limited, and the compound of the present invention and the
concomitant drug only need to be combined on administration.
Examples of such administration mode include the following: (1)
administration of a single preparation obtained by simultaneously
processing the compound of the present invention and the
concomitant drug, (2) simultaneous administration of two kinds of
preparations of the compound of the present invention and the
concomitant drug, which have been separately produced, by the same
administration route, (3) administration of two kinds of
preparations of the compound of the present invention and the
concomitant drug, which have been separately produced, by the same
administration route in a staggered manner, (4) simultaneous
administration of two kinds of preparations of the compound of the
present invention and the concomitant drug, which have been
separately produced, by different administration routes, (5)
administration of two kinds of preparations of the compound of the
present invention and the concomitant drug, which have been
separately produced, by different administration routes in a
staggered manner (e.g., administration in the order of the compound
of the present invention and the concomitant drug, or in the
reverse order) and the like.
[0400] The dose of the concomitant drug can be appropriately
determined based on the dose employed in clinical situations. The
mixing ratio of the compound of the present invention and a
concomitant drug can be appropriately determined depending on the
administration subject, administration route, target disease,
symptom, combination and the like.
[0401] For example, the content of the compound of the present
invention in the combination agent of the present invention differs
depending on the form of a preparation, and usually from about 0.01
to about 100 wt %, preferably from about 0.1 to about 50 wt %,
further preferably from about 0.5 to about 20 wt %, based on the
whole preparation.
[0402] The content of the concomitant drug in the combination agent
of the present invention differs depending on the form of a
preparation, and usually from about 0.01 to about 100 wt %,
preferably from about 0.1 to about 50 wt %, further preferably from
about 0.5 to about 20 wt %, based on the whole preparation.
[0403] The content of additives such as a carrier and the like in
the combination agent of the present invention differs depending on
the form of a preparation, and usually from about 1 to about 99.99
wt %, preferably from about 10 to about 90 wt %, based on the
preparation.
[0404] Similar contents may be employed even when the compound of
the present invention and a concomitant drug are separately
formulated into preparations.
[0405] Examples of the concomitant drug include the followings. A
therapeutic drug for narcolepsy (e.g., methylphenidate,
amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate,
modafinil, caffeine), antiobesity drug (amphetamine, benzfetamine,
bromocriptine, bupropion, diethylpropion, exenatide, fenfluramine,
liothyronine, liraglutide, mazindol, methamphetamine, octreotide,
octreotide, orlistat, phendimetrazine, phendimetrazine,
phenmetrazine, phentermine, Qnexa (registered trade mark),
phenylpropanolamine, pramlintide, propylhexedrine, recombinant
leptin, sibutramine, topiramate, zimelidine, zonisamide,
Lorcaserin, metformin), acetylcholine esterase inhibitor (e.g.,
donepezil, rivastigmine, galanthamine, zanapezil, idebenone,
tacrine), antidementia agent (e.g., memantine), inhibitor of P
amyloid protein production, secretion, accumulation, aggregation
and/or deposition, .beta. secretase inhibitor (e.g.,
6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin,
6-(4-biphenylyl) methoxy-2-(N,N-dimethylamino)methyltetralin,
6-(4-biphenylyl) methoxy-2-(N,N-dipropylamino)methyltetralin,
2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin,
6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin,
2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin,
2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin-
, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,
N-dimethylamino)ethyl]tetralin,
6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]t-
etralin,
6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)e-
thyl]tetralin, an optically active form thereof, a salt thereof and
a hydrate thereof, OM99-2 (WO01/00663)), .gamma. secretase
inhibitor, .beta. amyloid protein aggregation inhibitor (e.g.,
PTI-00703, ALZHEMED (NC-531), PPI-368 (National Publication of
International Patent Application No. 11-514333), PPI-5.58 (National
Publication of International Patent Application No. 2001-500852),
SKF-74652 (Biochem. J. (1999), 340(1), 283-289)), .beta. amyloid
vaccine, .beta. amyloid-degrading enzyme and the like, brain
function enhancer (e.g., aniracetam, nicergoline), therapeutic drug
for Parkinson's disease [(e.g., dopamine receptor agonist (e.g.,
L-DOPA, bromocriptine, pergolide, talipexole, pramipexole,
cabergoline, amantadine), monoamine oxidase enzyme (MAO) inhibitor
(e.g., deprenyl, selegiline, remacemide, riluzole), anticholinergic
agent (e.g., trihexyphenidyl, biperiden), COMT inhibitor (e.g.,
entacapone)], therapeutic drug for amyotrophic lateral sclerosis
(e.g., riluzole etc., neurotrophic factor), therapeutic drug for
abnormal behavior accompanying progress of dementia, wandering and
the like (e.g., sedative, anti-anxiety drug), apoptosis inhibitor
(e.g., CPI-1189, IDN-6556, CEP-1347), neuronal
differentiation-regenerate promoter (e.g., leteprinim, xaliproden;
SR-57746-A), SB-216763, Y-128, VX-853, prosaptide,
5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-b-
enzofuran-5-yl]isoindoline,
5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro--
1-benzofuran-5-yl]isoindoline,
6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-
-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and an optically
active form, salt or hydrate thereof), non-steroidal
antiinflammatory agents (meloxicam, tenoxicam, indomethacin,
ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin etc.),
steroid drug (dexamethasone, hexestrol, cortisone acetate etc.),
disease-modifying anti-rheumatic drug (DMARDs), anti-cytokine drug
(e.g., TNF inhibitor, MAP kinase inhibitor), therapeutic agent for
incontinence, frequent urination (e.g., flavoxate hydrochloride,
oxybutynin hydrochloride, propiverine hydrochloride),
phosphodiesterase inhibitor (e.g., sildenafil(citrate)), dopamine
agonist (e.g., apomorphine), antiarrhythmic drugs (e.g.,
mexiletine), sex hormone or a derivative thereof (e.g.,
progesterone, estradiol, estradiol benzoate), therapeutic agent for
osteoporosis (e.g., alfacalcidol, calcitriol, elcatonin, calcitonin
salmon, estriol, ipriflavone, pamidronate disodium, alendronate
sodium hydrate, incadronate disodium), parathyroid hormone (PTH),
calcium receptor antagonists, therapeutic drug for insomnia (e.g.,
benzodiazepines medicament, non-benzodiazepines medicament,
melatonin agonist, orexin receptor antagonists), therapeutic drug
for schizophrenia (e.g., typical antipsychotic agents such as
haloperidol and the like; atypical antipsychotic agents such as
clozapine, olanzapine, risperidone, aripiprazole and the like;
medicament acting on metabotropic glutamate receptor or ion channel
conjugated-type glutamate receptor; phosphodiesterase inhibitor),
benzodiazepines medicament (chlordiazepoxide, diazepam, potassium
clorazepate, lorazepam, clonazepam, alprazolam etc.), L-type
calcium channel inhibitor (pregabalin etc.), tricyclic or
tetracyclic antidepressant (imipramine hydrochloride, amitriptyline
hydrochloride, desipramine hydrochloride, clomipramine
hydrochloride etc.), selective serotonin reuptake inhibitor
(fluvoxamine maleate, fluoxetine hydrochloride, citalopram
hydrobromide, sertraline hydrochloride, paroxetine hydrochloride,
escitalopram oxalate etc.), serotonin-noradrenaline reuptake
inhibitor (venlafaxine hydrochloride, duloxetine hydrochloride,
desvenlafaxine hydrochloride etc.), noradrenaline reuptake
inhibitor (reboxetine mesylate etc.), mirtazapine, trazodone
hydrochloride, nefazodone hydrochloride, bupropion hydrochloride,
setiptiline maleate, 5-HT.sub.1A agonist, (buspirone hydrochloride,
tandospirone citrate, osemozotan hydrochloride etc.), 5-HT.sub.2A
antagonist, 5-HT.sub.2A inverse agonist, 5-HT.sub.3 antagonist
(cyamemazine etc.), heart non-selective .beta. inhibitor
(propranolol hydrochloride, oxprenolol hydrochloride etc.),
histamine Hi antagonist (hydroxyzine hydrochloride etc.), CRF
antagonist, other antianxiety drug (meprobamate etc.), tachykinin
antagonist (MK-869, saredutant etc.), medicament that acts on
metabotropic glutamate receptor, CCK antagonist, .beta.3 adrenaline
antagonist (amibegron hydrochloride etc.), GAT-1 inhibitor
(tiagabine hydrochloride etc.), N-type calcium channel inhibitor,
carbonic anhydrase II inhibitor, NMDA glycine moiety agonist, NMDA
antagonist (memantine etc.), peripheral benzodiazepine receptor
agonist, vasopressin antagonist, vasopressin V1b antagonist,
vasopressin Via antagonist, phosphodiesterase inhibitor, opioid
antagonist, opioid agonist, uridine, nicotinic acid receptor
agonist, thyroid hormone (T3, T4), TSH, TRH, MAO inhibitor
(phenelzine sulfate, tranylcypromine sulfate, moclobemide etc.),
therapeutic drug for bipolar disorder (lithium carbonate, sodium
valproate, lamotrigine, riluzole, felbamate etc.), cannabinoid CB1
antagonist (rimonabant etc.), FAAH inhibitor, sodium channel
inhibitor, anti-ADHD drug (methylphenidate hydrochloride,
methamphetamine hydrochloride etc.), therapeutic drug for
alcoholism, therapeutic drug for autism, therapeutic drug for
chronic fatigue syndrome, therapeutic drug for spasm, therapeutic
drug for fibromyalgia syndrome, therapeutic drug for headache,
therapeutic drug for quitting smoking, therapeutic drug for
myasthenia gravis, therapeutic drug for cerebral infarction,
therapeutic drug for mania, therapeutic drug for hypersomnia,
therapeutic drug for pain, therapeutic drug for dysthymia,
therapeutic drug for autonomic ataxia, therapeutic drug for male
and female sexual dysfunction, therapeutic drug for migraine,
therapeutic, drug for pathological gambler, therapeutic drug for
restless legs syndrome, therapeutic drug for substance addiction,
therapeutic drug for alcohol-related syndrome, therapeutic drug for
irritable bowel syndrome, therapeutic drug for lipid abnormality
such as cholesterol-lowering drug (statin series (pravastatin
sodium, atorvastatin, simvastatin, rosuvastatin etc.), fibrate
(clofibrate etc.), squalene synthetase inhibitor), therapeutic drug
for abnormal behavior or suppressant of dromomania due to dementia
(sedatives, antianxiety drug etc.), therapeutic drug for diabetes,
therapeutic agent for diabetic complications, therapeutic drug for
hypertension, therapeutic drug for hypotension, diuretic,
chemotherapeutic agent, immunotherapeutic agent, antithrombotic
agent, anti-cancer agent and the like.
[0406] Two or more kinds of the above-mentioned concomitant drug
may be used in a mixture at an appropriate ratio.
[0407] When the compound of the present invention is applied to
each of the above-mentioned diseases, it can also be used in
combination with biologies (e.g., antibody drug, nucleic acid or
nucleic acid derivative, aptamer drug, vaccine preparation), or can
be used in combination with a gene therapy method and the like, or
can also be used in combination with a treatment in psychiatric
field without using drugs.
[0408] Examples of the antibody drug and vaccine preparation
include vaccine preparation against angiotensin II, vaccine
preparation against CETP, CETP antibody, antibody against
TNF.alpha. antibody and other cytokines, amyloid P vaccine
preparation, vaccine for type 1 diabetes (e.g., DIAPEP-277 of
Peptor), anti-HIV antibody and HIV vaccine preparation, as well as
antibodies or vaccine preparations against cytokines,
renin-angiotensin type enzymes and products thereof, antibodies or
vaccine preparations against enzymes or proteins involved in blood
lipid metabolism, antibodies or vaccines relating to enzymes and
proteins involved in blood coagulation or fibrinolysis system,
antibodies or vaccine preparations against proteins involved in
sugar metabolism and insulin resistance, and the like. In addition,
it can be used in combination with biologies relating to growth
factors such as GH, IGF and the like.
[0409] Examples of the gene therapy method include a treatment
method using gene relating to cytokine, renin-angiotensin type
enzyme and product thereof, G protein, G protein conjugated
receptor and phosphorylating enzyme thereof, a treatment method
using a DNA decoy such as NF.kappa.B decoy and the like, a
treatment method using antisense, a treatment method using a gene
relating to an enzyme or protein involved in blood lipid metabolism
(e.g., a gene relating to metabolism, excretion and absorption of
cholesterol or triglyceride or HDL-cholesterol or blood
phospholipid), a treatment method using a gene relating to an
enzyme or protein involved in angiogenesis therapy for peripheral
vascular obstruction and the like (e.g., growth factors such as
HGF, VEGF etc.), a treatment method using a gene relating to a
protein involved in glucose metabolism and insulin resistance,
antisense against cytokines such as TNF etc., and the like.
[0410] Examples of the treatment method in the psychiatric field
without using drug include modified electroconvulsive therapy, deep
brain stimulation therapy, repetitive transcranial magnetic
stimulation therapy, psychotherapy including cognitive behavioral
therapy and the like.
[0411] The compound of the present invention can also be used in
combination with various organ regeneration methods such as cardiac
regeneration, renal regeneration, pancreatic regeneration,
revascularization and the like, cell transplantation therapy
utilizing bone marrow cells (bone marrow-derived mononuclear cell,
myelogenic stem cell), or artificial organ utilizing tissue
engineering (e.g., artificial blood vessel, cardiomyocyte
sheet).
EXAMPLES
[0412] The present invention is explained in detail in the
following by referring to Examples, Experimental Examples and
Formulation Examples. However, the examples do not limit the
present invention and the examples can be modified within the scope
of the present invention.
[0413] The "room temperature" in the following Examples is
generally about 10.degree. C. to about 35.degree. C. The ratio for
mixed solvent is, unless otherwise specified, a volume mixing ratio
and % means wt % unless otherwise specified.
[0414] The elution by column chromatography in the Examples was
performed under the observation by TLC (Thin Layer Chromatography)
unless otherwise specified. In the observation by TLC, 60 F.sub.254
manufactured by Merck was used as a TLC plate, the solvent used as
an elution solvent in column chromatography was used as an eluent,
and UV detector was used for the detection. In silica gel column
chromatography, the indication of NH means use of
aminopropylsilane-bonded silica gel and the indication of Diol
means use of 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica
gel. In preparative HPLC (high performance liquid chromatography),
the indication of C18 means use of octadecyl-bonded silica gel.
[0415] The ratio for elution solvent is, unless otherwise
specified, a volume mixing ratio.
[0416] For the analysis of .sup.1H NMR, ACD/SpecManager (trade
name) software and the like were used. Peaks of a hydroxyl group,
an amino group and the like, having very mild proton peak, are not
sometimes described.
[0417] MS was measured by LC/MS. As the ionization method, ESI
method, or APCI method was used. The data indicates actual measured
value (found). While molecular ion peak is generally observed, a
fragment ion is sometimes observed. In the case of a salt, a
molecular ion peak or fragment ion peak of free form is generally
observed.
[0418] The unit of sample concentration (c) for optical rotation
([.alpha.].sub.D) is g/100 mL.
[0419] Elemental analysis value (Anal.) is described as calculated
value (Calcd) and actual measured value (Found).
[0420] The retention time in the Examples was measured by liquid
chromatograph method. The measurement conditions are as follows,
unless otherwise specified.
[0421] column: YMC PackPro C18 2.0 mm i.d..times.75 mm (3 .mu.m)
mobile phase: the solution prepared by adding 0.04 M
Britton-Robinson buffer solution (pH 6.5) to methanol (5:2), and
mixing them well, and adjusting the pH to 7.4 with 0.2 M sodium
hydroxide solution.
[0422] Peaks by powder X-ray diffraction in the Examples mean peaks
measured at room temperature by Ultima IV (Rigaku Corporation,
Japan) using Cu K.alpha. radiation as a radiation source. The
measurement conditions are as follows.
[0423] Electric pressure/Electric current: 40 kV/50 mA
[0424] Scan speed: 6 degrees/min
[0425] Scan range of 2 Theta: 2-35 degrees
[0426] The crystallinity by powder X-ray diffraction in the
Examples was calculated by the Hermans method.
[0427] In the following Examples, the following abbreviations are
used.
mp: melting point MS: mass spectrum M: mol concentration N:
normality CDCl.sub.3: deuterochloroform DMSO-d.sub.6:
deuterodimethyl sulfoxide .sup.1H NMR: proton nuclear magnetic
resonance LC/MS: liquid chromatograph mass spectrometer
ESI: Electrospray Ionization
APCI: Atomospheric Pressure Chemical Ionization
[0428] HATU: (dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]
pyridin-3-yloxy)methaneiminium hexafluorophosphate PPh.sub.3:
triphenylphosphine TFA: trifluoroacetic acid DMAP:
N,N-dimethyl-4-aminopyridine CPME: cyclopentyl methyl ether WSC:
N-(3-(dimethylamino)propyl)-N'-ethylcarbodiimide IPE:
2-isopropoxypropane DIPEA: N-ethyl-N-isopropylpropan-2-amine
DMF: N,N-dimethylformamide
HOBt: 1H-benzotriazol-1-ol
[0429] THF: tetrahydrofuran DME: 1,2-dimethoxyethane MeOH: methanol
WSC--HCl: N-(3-(dimethylamino) propyl)-N'-ethylcarbodiimide
hydrochloride (1:1) EtOH: ethanol BOC.sub.2O: di-tert-butyl
dicarbonate TEA: triethylamine Et.sub.2O: ethoxyethane EtOAc: ethyl
acetate CH.sub.3CN: acetonitrile TMSCl: trimethylsilyl chloride
XPhos Pd G3:
methanesulfonato(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphe-
nyl) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) PdCl.sub.2(dppf):
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride
Example 1
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-((-
2R)-oxetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
A) 3-chloro-2-fluorophenylalanine hydrochloride
[0430] To a mixture of 1-(bromomethyl)-3-chloro-2-fluorobenzene
(55.0 g), diethyl acetamidomalonate (56.1 g) and EtOH (400 mL) was
added 20% sodium ethoxide ethanol solution (88 g) at 0.degree. C.
The mixture was refluxed for 2 hr 30 min, and cooled to room
temperature. The impurity was removed by filtration, the filtrate
was concentrated under reduced pressure, and a mixture of the
residue and 6 M hydrochloric acid (500 mL) was refluxed for 15 hr.
The reaction solution was concentrated under reduced pressure, and
the obtained residue was washed with isopropanol/diisopropyl ether
to give the title compound (67.1 g).
[0431] MS: [M+H].sup.+ 217.8.
B) N-(tert-butoxycarbonyl)-3-chloro-2-fluorophenylalanine
[0432] To a mixture of 3-chloro-2-fluorophenylalanine hydrochloride
(67.1 g), 1 M aqueous sodium hydroxide solution (528 mL) and DME
(480 mL) was added Boc.sub.2O (63.4 g) at room temperature. The
mixture was stirred at room temperature for 2 hr 30 min, and poured
into ice water. The mixture was basified with 1 M aqueous sodium
hydroxide solution, and the aqueous layer was washed with diethyl
ether. The aqueous layer was acidified with 1 M hydrochloric acid,
and extracted with EtOAc. The organic layer was separated, washed
with water and saturated brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The obtained
solid was washed with diisopropyl ether/hexane to give the title
compound (63.8 g).
[0433] MS: [M-H].sup.- 316.0.
C) tert-butyl
{3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}ca-
rbamate
[0434] To a mixture of
N-(tert-butoxycarbonyl)-3-chloro-2-fluorophenylalanine (63.8 g),
N-methoxymethanamine hydrochloride (21.5 g), HOBt (29.8 g), TEA
(44.7 g) and DMF (425 mL) was added WSC--HCl (46.2 g) at 0.degree.
C. The mixture was stirred at room temperature for 15 hr, and the
reaction mixture was added to aqueous sodium hydrogen carbonate
solution, and extracted with EtOAc/THF. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The obtained solid was washed with diisopropyl
ether/hexane to give the title compound (70.0 g).
[0435] MS, found: 260.9.
D) tert-butyl
{3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}(4-
-methoxybenzyl)carbamate
[0436] To a mixture of tert-butyl
{3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}ca-
rbamate (70.0 g) and DMF (390 mL) was added 60% sodium hydride
(10.1 g) at 0.degree. C. The mixture was stirred at 0.degree. C.
for 5 min, and then at room temperature for 10 min, and to the
reaction mixture were added 1-(chloromethyl)-4-methoxybenzene (60.7
g) and tetrabutylammonium iodide (7.16 g) at 0.degree. C. The
mixture was stirred at room temperature for 2 hr 30 min, poured
into ice water, and extracted with EtOAc. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane) to give the title compound (90.7
g).
[0437] MS: [M+H].sup.+ 481.1.
E) tert-butyl
[1-(3-chloro-2-fluorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]ca-
rbamate
[0438] To a mixture of tert-butyl
{3-(3-chloro-2-fluorophenyl)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}(4-
-methoxybenzyl)carbamate (90.7 g) and Et.sub.2O (500 mL) was added
lithium aluminium hydride (9.30 g) by small and small at
-78.degree. C. The mixture was stirred at -15.degree. C. for 1 hr
30 min, and to the reaction mixture were added dropwise
sequentially EtOAc and 10% aqueous potassium hydrogensulfite
solution at -78.degree. C. The mixture was stirred at room
temperature for 15 min, and to the mixture was added water. The
insoluble substance was removed by filtration through Celite, and
the filtrate was extracted with EtOAc. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane) to give the title compound (74.7
g).
[0439] MS: [M-H].sup.- 420.0.
F) ethyl
4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-5-(3-chlo-
ro-2-fluorophenyl)-2,4,5-trideoxy-2,2-difluoropentonate
[0440] To a mixture of zinc (37.0 g) and THF (500 mL) was added
TMSCl (3.85 g) under argon atmosphere at room temperature. The
mixture was stirred at room temperature for 15 min, and ethyl
bromo(difluoro)acetate (71.9 g) was added dropwise to the mixture
with vigorously stirring at room temperature while keeping the
internal temperature of about 50.degree. C. The mixture was stirred
at room temperature for 15 min, and to the mixture was added
dropwise a mixture of tert-butyl
[1-(3-chloro-2-fluorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]ca-
rbamate (74:7 g) and THF (100 mL), while keeping the internal
temperature of about 40.degree. C. The mixture was stirred at room
temperature for 2 hr, and added to 5% aqueous potassium
hydrogensulfite solution under ice cooling, and extracted with
EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (61.6 g).
[0441] MS, found: 490.0.
G)
5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methox-
yphenyl)methyl]pyrrolidin-2-one
[0442] To a mixture of ethyl
4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-5-(3-chloro-2-flu-
orophenyl)-2,4,5-trideoxy-2,2-difluoropentonate (61.6 g) and EtOH
(160 mL) was added 4 M hydrogen chloride CPME solution (282 mL) at
room temperature. The mixture was stirred at room temperature for 2
hr, and the reaction solution was concentrated. To the obtained
residue were added EtOH (360 mL) and DIPEA (43.8 g). The mixture
was stirred at 70.degree. C. for 1 hr 30 min, and the reaction
mixture was poured into ice water, and extracted with EtOAc. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane), and the obtained solid was washed
with diisopropyl ether/hexane to give the title compound (36.1
g).
[0443] MS: [M+H].sup.+ 399.9.
H)
5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxypyrrolidin-2--
one
[0444] To a mixture of
5-[(3-chloro-2-fluorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methoxyp-
henyl)methyl]pyrrolidin-2-one (36.1 g), CH.sub.3CN (315 mL) and
water (105 mL) was added ammonium hexanitratocerate(IV) (99 g) at
room temperature. The mixture was stirred at room temperature for 4
hr, poured into ice water, and extracted with EtOAc. The organic
layer was separated, washed with water and saturated brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane), and then silica gel column
chromatography (NH, methanol/EtOAc) to give the title compound
(22.7 g).
[0445] MS: [M-H].sup.- 278.0.
I) tert-butyl
2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-hydroxypyrrolidine-1-c-
arboxylate
[0446] To a mixture of 5-[(3-chloro-2-fluorophenyl)methyl]-3,3-,
difluoro-4-hydroxypyrrolidin-2-one (22.7 g) and THF (350 mL) was
added, dropwise 1 M borane-THF complex THF solution (284 mL) at
room temperature. The mixture was slowly warmed to 60.degree. C.,
and stirred for 4 hr. Water was added dropwise to the mixture at
0.degree. C., and the mixture was stirred at room temperature for
10 min, and concentrated under reduced pressure. To the residue was
added 1 M hydrochloric acid (500 mL), and the mixture was
vigorously stirred at 60.degree. C. for 1 hr 30 min. The mixture
was slowly added to 1 M aqueous sodium hydroxide solution under ice
cooling, basified with potassium carbonate, saturated with salt,
and extracted with EtOAc/THF. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. To a
mixture of the obtained residue, sodium hydrogen carbonate (6.83 g)
and THF (190 mL)/water (210 mL) was added a solution of Boc.sub.2O
(19.5 g) in THF (20 mL) at room temperature. The mixture was
vigorously stirred at room temperature for 15 hr, poured into
water, and extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(EtOAc/hexane) to give the title compound (22.2 g).
[0447] MS, found: 265.9.
J) rac-tert-butyl
(2S,3S)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(trifluoromet-
hanesulfonyl)oxy]pyrrolidine-1-carboxylate
[0448] To a mixture of tert-butyl
2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-hydroxypyrrolidine-1-c-
arboxylate (22.1 g), pyridine (96 g) and Et.sub.2O (355 mL) was
added dropwise trifluoromethanesulfonic anhydride (51.2 g) under
argon atmosphere at 0.degree. C. The mixture was stirred at room
temperature for 2 hr 30 min, poured into ice water, and extracted
with EtOAc/hexane. The organic layer was separated, washed with 10%
aqueous citric acid solution, aqueous sodium hydrogen carbonate
solution, water and saturated brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (EtOAc/hexane) to give
the title compound (22.4 g).
[0449] MS, found: 397.9.
K) rac-tert-butyl
(2S,3R)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate
[0450] To a mixture of rac-tert-butyl
(2S,3S)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(trifluoromet-
hanesulfonyl)oxy]pyrrolidine-1-carboxylate (22.4 g) and CH.sub.3CN
(265 mL) was added tetra-n-butylammonium azide (38.3 g) at room
temperature. The mixture was slowly warmed to 80.degree. C.,
stirred for 1 hr, poured into ice water, and extracted with EtOAc.
The organic layer was separated, washed with water and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (EtOAc/hexane) to give the title compound
(16.2 g).
[0451] MS, found: 290.9.
L) rac-tert-butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate
[0452] To a mixture of rac-tert-butyl
(2S,3R)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate (16.2 g) and THF (200 mL)/water (5 mL) was added
PPh.sub.3 (13.1 g) under argon atmosphere at room temperature. The
mixture was stirred at 55.degree. C. for 18 hr, added to aqueous
sodium hydrogen carbonate solution under ice cooling, and extracted
with EtOAc/THF. The organic layer was separated, washed with water
and saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, EtOAc/hexane) to give the
title compound and by-product, respectively. To a mixture of the
obtained by-product and THF (100 mL)/water (10 mL) was added 40%
aqueous methanamine solution (3.22 g) at room temperature. The
mixture was stirred at 70.degree. C. for 15 hr, poured into water,
and extracted with EtOAc. The organic layer was separated, washed
with water and saturated brine, dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (NH, EtOAc/hexane) to
give the title compound (14.6 g), combined with the title compound
obtained above.
[0453] MS, found: 308.9.
M) tert-butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrroline-
-1-carboxylate
[0454] rac-tert-Butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate (14.6 g) was resolved by HPLC (column: CHIRALPAK
IA, 50 mmID.times.500 mmL, 20 .mu.m, mobile phase:
hexane/ethanol/diethylamine=800/200/1) to give the title compound
(6.84 g) with shorter retention time (column: CHIRALPAK IA, 4.6
mmID.times.250 mmL, 5 .mu.m, mobile phase:
hexane/ethanol/diethylamine=800/200/1).
[0455] MS, found: 309.1.
N) tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-
-difluoropyrrolidine-1-carboxylate
[0456] To a mixture of tert-butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate (1.04 g), TEA (0.577 g), DMAP (0.174 g) and THF
(30 mL) was added ethanesulfonyl chloride (0.550 g) at 0.degree. C.
The mixture was stirred at room temperature for 5 hr, water was
added to mixture at room temperature, and the mixture was extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, EtOAc/hexane) to give the
title compound (1.25 g).
[0457] MS: [M-H].sup.- 455.1.
O)
N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropy-
rrolidin-3-yl}ethanesulfonamide hydrochloride
[0458] A mixture of tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-
-difluoropyrrolidine-1-carboxylate (24.9 mg),
(3-fluorophenyl)boronic acid (15.3 mg), XPhos Pd G3 (4.61 mg), 1 M
aqueous potassium phosphate solution (0.163 mL) and DME (0.6 mL)
was stirred at 80.degree. C. for 2 hr. The reaction solution was
concentrated, and the residue was purified by silica gel column
chromatography (NH, EtOAc/hexane). A mixture of the obtained
residue (27 mg) and 4 M hydrogen chloride CPME solution (2 mL) was
stirred at room temperature for 4 hr. The insoluble substance was
collected by filtration to give the title compound (17 mg).
[0459] MS: [M+H].sup.+ 417.1.
P)
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-
-((2R)-oxetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
[0460] To a mixture of
N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyrr-
olidin-3-yl}ethanesulfonamide hydrochloride (250 mg),
oxetane-2-carboxylic acid (67.6 mg) and DMF (2 mL) were added HATU
(315 mg) and DIPEA (357 mg) at room temperature. The mixture was
stirred overnight at room temperature, to the mixture was added
saturated aqueous ammonium chloride solution, and the mixture was
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (NH, EtOAc/hexane), and the
obtained solid was crystallized from EtOAc/hexane to give the title
compound (66 mg) with shorter retention time.
[0461] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.27-1.47 (3H, m),
2.68-5.20 (14H, m), 7.03-7.13 (1H, m), 7.16-7.45 (6H, m).
Example 2
[0462]
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-
-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
A) tert-butyl
(2S,3R)-2-(3-chloro-2-fluorobenzyl)-4,4-difluoro-3-(methylsulfonamido)pyr-
rolidine-1-carboxylate
[0463] Methanesulfonic anhydride (143 mg) was added to a mixture of
tert-butyl
(2S,3R)-3-amino-2-(3-chloro-2-fluorobenzyl)-4,4-difluoropyrrolidine-1-car-
boxylate (200 mg), TEA (0.229 mL) and THF (5 mL) at room
temperature. The mixture was stirred overnight at room temperature.
The mixture was concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, EtOAc/hexane) to
give the title compound (244 mg).
[0464] MS: [M-H].sup.- 441.1.
B) tert-butyl
(2S,3R)-4,4-difluoro-3-(methylsulfonamido)-2-((2,3',5'-trifluoro-[1,1'-bi-
phenyl]-3-yl)methyl)pyrrolidine-1-carboxylate
[0465] A mixture of tert-butyl
(2S,3R)-2-(3-chloro-2-fluorobenzyl)-4,4-difluoro-3-(methylsulfonamido)pyr-
rolidine-1-carboxylate (4.52 g), (3,5-difluorophenyl) boronic acid
(3.22 g), XPhos Pd G3 (0.432 g) and 1 M aqueous potassium phosphate
solution (30.6 mL) in DME (100 mL) was stirred at 80.degree. C. for
3 h under nitrogen atmosphere. The mixture was purified by column
chromatography (silica gel, EtOAc/hexane, then NH silica gel,
EtOAc/hexane) to give the title compound (5.30 g).
[0466] MS: [M-H].sup.- 519.1.
C)
N-{(2S,3R)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methy-
l]pyrrolidin-3-yl}methanesulfonamide hydrochloride
[0467] A mixture of tert-butyl
(2S,3R)-4,4-difluoro-3-(methylsulfonamido)-2-((2,3',5'-trifluoro-[1,1'-bi-
phenyl]-3-yl)methyl)pyrrolidine-1-carboxylate (73 mg) and 4 M
HCl/CPME solution (1 mL) was stirred overnight at room temperature.
The mixture was diluted with EtOAc and precipitate was collected by
filtration to give the title compound (50.0 mg).
[0468] MS: [M+H].sup.+ 421.0.
D)
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-tri-
fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0469] To a mixture of
N-{(2S,3R)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]-
pyrrolidin-3-yl}methanesulfonamide hydrochloride (4.3 g) and DIPEA
(8.14 mL) in THF (60 mL) was added alpha-acetoxy-isobutyryl
chloride (1.64 mL) at 0.degree. C., and the mixture was stirred at
same temperature for 10 min. To the mixture were added water (20
mL) and 4 M lithium hydroxide solution (23.5 mL), and the mixture
was stirred overnight at room temperature. The mixture was diluted
with saturated brine and extracted with EtOAc. The extract was
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, EtOAc/hexane) to give the title compound (4.40 g).
[0470] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.31-1.47 (6H, m),
2.25-2.60 (1H, m), 2.88-3.02 (4H, m), 3.10 (1H, dd, J=14.2, 7.5
Hz), 4.01-4.49 (3H, m), 4.92-5.17 (2H, m), 6.75-6.87 (1H, m),
7.01-7.11 (2H, m), 7.16-7.23 (1H, m), 7.26-7.32 (1H, m), 7.36-7.46
(1H, m).
Example 3
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-.
[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulf-
onamide
A) tert-butyl
(2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2,3',5'-trifluoro-[1,1'-bip-
henyl]-3-yl)methyl)pyrrolidine-1-carboxylate
[0471] To a mixture of tert-butyl
(2S,3R)-2-(3-chloro-2-fluorobenzyl)-3-(ethylsulfonamido)-4,4-difluoropyrr-
olidine-1-carboxylate (3.70 g), (3,5-difluorophenyl)boronic acid
(2.56 g) and 1 M aqueous potassium phosphate solution (24.3 mL) in
DME (50 mL) was added XPhos Pd G3 (0.343 g) at room temperature.
The mixture was stirred at 90.degree. C. under nitrogen atmosphere
for 15 h. The reaction mixture was poured into water and extracted
with EtOAc. The organic layer was washed with saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, EOAc/hexane) to give the title compound (3.30 g).
[0472] MS: [M-H].sup.- 533.2.
B)
N-((2S,3R)-4,4-difluoro-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)meth-
yl)pyrrolidin-3-yl)ethanesulfonamide hydrochloride
[0473] A mixture of tert-butyl
(2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2,3',5'-trifluoro-[1,1'-bip-
henyl]-3-yl)methyl)pyrrolidine-1-carboxylate (3.30 g) and 4 M
HCl/CPME solution (30 mL) was stirred overnight at room
temperature. By filtration, the title compound (2.86 g) was
obtained.
[0474] MS: [M+H].sup.+ 435.1.
C)
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-tri-
fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0475] To a mixture of
N-((2S,3R)-4,4-difluoro-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl-
)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (200 mg) and DIPEA
(0.367 ml) in THF (3 mL) was added alpha-acetoxy-isobutyryl
chloride (0.074 ml) at 0.degree. C., and the mixture was stirred at
same temperature for 10 min. To the mixture were added water (1 ml)
and 4 M lithium hydroxide solution (1.06 ml), and the mixture was
stirred overnight at room temperature. The mixture was diluted with
saturated brine and extracted with EtOAc. The extract was dried
over magnesium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel,
EtOAc/hexane) and recrystallized from EtOAc/hexane to give the
title compound (154 mg).
[0476] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.32-1.40 (9H, m),
2.27-2.54 (1H, m), 2.88-3.16 (4H, m), 4.02-4.49 (3H, m), 4.86-5.20
(2H, m), 6.78-6.86 (1H, m), 7.02-7.10 (2H, m), 7.16-7.22 (1H, m),
7.27-7.31 (1H, m), 7.35-7.43 (1H, m).
Example 4
[0477]
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1--
(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
A) 2-amino-3-(3-bromo-2-fluorophenyl)propanoic acid
hydrochloride
[0478] Sodium ethoxide (121 g) was added to a solution of
1-bromo-3-(bromomethyl)-2-fluorobenzene (91 g) and diethyl
2-acetamidomalonate (77 g) in EtOH (566 ml) at room temperature.
After being refluxed for 2 h, the reaction mixture was cooled to
room temperature, and the insoluble substance was filtered off. The
filtrate was concentrated under reduced pressure, and the residue
was diluted with 8 M hydrochloric acid (849 ml), and the mixture
was refluxed for 17 h. The reaction mixture was concentrated under
reduced pressure to give crystals, which were collected by
filtration and washed with 2-propanol/IPE to give the title
compound (100 g).
[0479] MS: [M+H].sup.+ 261.9.
B)
3-(3-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic
Acid
[0480] Boc.sub.2O (92 ml) was added to a solution of
2-amino-3-(3-bromo-2-fluorophenyl)propanoic acid hydrochloride (100
g) and 0.75 M sodium hydroxide solution (893 ml) in DME (918 ml) at
0.degree. C. After being vigorously stirred at room temperature for
16 h, the reaction mixture was poured into ice water, basified with
1 M NaOH aqueous solution and washed with Et.sub.2O. The aqueous
layer was acidified to pH 3 with 1 M hydrochloric acid and
extracted with EtOAc. The organic layer was dried over magnesium
sulfate and concentrated under reduced pressure to give the title
compound (105 g).
[0481] MS, found: 261.8.
C) tert-butyl
(3-(2-fluoro-[1,1'-biphenyl]-3-yl)-1-(methoxy(methyl)amino)-1-oxopropan-2-
-yl)carbamate
[0482] To a mixture of
3-(3-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic
acid (250 g) in 1,4-dioxane (1.2 L) were added phenylboronic acid
(101 g) and Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (28.2 g) at
15.degree. C. under nitrogen atmosphere. After stirring for 15 min,
a solution of K.sub.2CO.sub.3 (191 g) in H.sub.2O (600 mL) was
added thereto. The reaction mixture was stirred at 100.degree. C.
for 16 h. The reaction mixture was poured into water and it was
adjusted to pH 2 with 2 M hydrochloric acid and then it was
extracted with EtOAc. The combined organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. Tc a stirred solution of the
obtained residue (250 g) and N,O-dimethylhydroxylamine (71.3 g) in
DMF (2 L) was added HATU (250 g) and then DIPEA (331 g) was added
thereto at 0.degree. C. The reaction mixture was stirred at
15.degree. C. under nitrogen atmosphere for 16 h. The reaction
mixture was poured into water and the organic layer was separated.
The water layer was extracted with EtOAc. The combined organic
layer was washed with saturated brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The residue was
collected by filtration and washed with petroleum ether/EtOAc to
give the title compound (180 g).
[0483] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.38 (9H, s),
3.00-3.18 (2H, m), 3.20 (3H, s), 3.77 (3H, s), 4.91-5.09 (1H, m),
5.17-5.30 (1H, m), 7.09-7.19 (2H, m), 7.28-7.48 (4H, m), 7.50-7.57
(2H, m).
D) ethyl
4-((tert-butoxycarbonyl)amino)-2,2-difluoro-5-(2-fluoro-[1,1'-bip-
henyl]-3-yl)-3-hydroxypentanoate
[0484] To a stirred solution of tert-butyl (3'-(2-fluoro-[1,1
biphenyl]-3-yl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate
(40.0 g) in THF (1.2 L) was added lithium aluminium hydride (4.53
g) in portions at -78.degree. C., and the reaction mixture was
stirred at -10.degree. C. under nitrogen atmosphere for 3 h. The
reaction mixture was poured into cooled aqueous saturated ammonium
chloride solution, and the mixture was filtered. The filter cake
was washed with EtOAc and the filtrate was extracted with EtOAc.
The combined organic layer was washed with 1 M hydrochloric acid,
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure to give the tert-butyl
(1-(2-fluoro-[1,1'-biphenyl]-3-yl)-3-oxopropan-2-yl)carbamate (40.0
g). To the mixture of activated zinc (56.8 g) in THF (300 mL) was
added TMSCl (4.43 g) at 20.degree. C., and the resulting mixture
was stirred at 20.degree. C. for 15 min under nitrogen atmosphere.
Then a solution of ethyl 2-bromo-2,2-difluoroacetate (82.8 g) in
THF (500 mL) was added dropwise to the above, mixture at 40.degree.
C., and it was stirred at 40.degree. C. for another 1.5 h under
nitrogen atmosphere to give 0.51 M
(2-ethoxy-1,1-difluoro-2-oxoethyl)zinc(II) bromide/THF solution
(800 mL). To a stirred solution of tert-butyl
(1-(2-fluoro-[1,1'-biphenyl]-3-yl)-3-oxopropan-2-yl)carbamate (27.0
g) in THF (150 mL) was added. 0.51 M
(2-ethoxy-1,1-difluoro-2-oxoethyl)zinc(II) bromide/THF solution
(385 mL) at 15.degree. C., and the reaction mixture was stirred at
15.degree. C. under nitrogen atmosphere for 20 min. Then it was
stirred at 55.degree. C. for another 20 min. The reaction mixture
was poured into aqueous ammonium chloride solution and it was
extracted with EtOAc. The combined organic layer was washed with
saturated brine, dried over anhydrous sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, EtOAc/petroleum ether) to give
the title compound (12.0 g).
[0485] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.30-1.54 (12H,
m), 3.00-3.35 (2H, m), 3.70-4.55 (3H, m), 4.74-5.19 (1H, m),
7.0&-7.25 (2H, m), 7.35-7.57 (7H, m).
E) ethyl
4-amino-2,2-difluoro-5-(2-fluoro-[1,1'-biphenyl]-3-yl)-3-hydroxyp-
entanoate hydrochloride
[0486] To a stirred solution of ethyl
4-((tert-butoxycarbonyl)amino)-2,2-difluoro-5-(2-fluoro-[1,1'-biphenyl]-3-
-yl)-3-hydroxypentanoate (39.0 g) in 1,4-dioxane (80 mL) was added
4 M HCl/1,4-dioxane solution (250 mL), and the reaction mixture was
stirred at 15.degree. C. for 3 h. The mixture was concentrated
under reduced pressure to give the title compound (34.0 g).
[0487] MS: [M+H].sup.+ 368.1.
F)
3,3-difluoro-5-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-hydroxypyrroli-
din-2-one
[0488] To a stirred solution of ethyl
4-amino-2,2-difluoro-5-(2-fluoro-[1,1'-biphenyl]-3-yl)-3-hydroxypentanoat-
e hydrochloride (66.0 g) in EtOH (850 mL) was added DIPEA (66.0 g),
and the reaction mixture was stirred at 80.degree. C. under
nitrogen atmosphere for 0.5 h. The reaction mixture was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, EtOAc/petroleum ether) to give
the title compound (35.0 g).
[0489] MS: [M+H].sup.+ 322.0.
G)
4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidin-3-ol
[0490] To a stirred solution of
3,3-difluoro-5-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-4-hydroxypyrrolidi-
n-2-one (36.0 g) in THF (400 mL) was added 1 M BH.sub.3-THF
complex/THF solution (336 mL) at 15.degree. C., and the reaction
mixture was stirred at 70.degree. C. for. 16 h under nitrogen
atmosphere. Then the reaction mixture was quenched with water
dropwise at 0.degree. C., and then 1 M hydrochloric acid was added
thereto, and it was stirred at 66.degree. C. for 2 h. The reaction
mixture was adjusted to pH 8 with saturated aqueous sodium hydrogen
carbonate solution and extracted with EtOAc. The combined organic
layer was washed with water, dried over anhydrous sodium sulfate
and concentrated under reduced pressure to give the title compound
(35.0 g).
[0491] MS: [M+H].sup.+ 308.1.
H) rac-tert-butyl
(2S,3S)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-hydroxyp-
yrrolidine-1-carboxylate
[0492] To
4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolidin-
-3-ol (37.0 g) was added tert-butoxycarbonyl tert-butyl carbonate
(26.3 g) in THF (300 mL), and the mixture was basified to pH 8 with
saturated aqueous sodium hydrogen carbonate solution, and the
reaction mixture was stirred at 15.degree. C. for 2 h. The reaction
mixture was poured into water and extracted with EtOAc. The
combined organic layer was washed with saturated brine, dried over
anhydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel,
EtOAc/petroleum ether), and then purified by preparative HPLC
(column: C18, mobile phase: CH.sub.3CN/water (containing 10 mM
ammonium bicarbonate)) to give the title compound (9 g).
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.48 (9H, s),
2.14-2.28 (1H, m), 2.78-3.00 (1H, m), 3.24-3.40 (1H, m), 3.69-4.00
(2H, m), 4.00-4.08 (1H, m), 4.14-4.20 (1H, m), 7.13-7.24 (2H, m),
7.32-7.50 (4H, m), 7.52-7.59 (2H, m).
I) rac-tert-butyl
(2S,3S)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(((trifl-
uoromethyl)sulfonyl)oxy)pyrrolidine-1-carboxylate
[0494] To a stirred solution of rac-tert-butyl
(2S,3S)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-hydroxyp-
yrrolidine-1-carboxylate (9.00 g) in dichloromethane (150 mL) was
added pyridine (8.74 g), and then a solution of
trifluoromethanesulfonic anhydride (15.6 g) in dichloromethane (50
mL) was added dropwise thereto at -10.degree. C., and the reaction
mixture was stirred at -10.degree. C. under nitrogen atmosphere for
1 h. The reaction mixture was poured into water and it was
extracted with dichloromethane. The combined organic layer was
washed with 5% aqueous citric acid solution and saturated brine,
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give the title compound (11.0 g).
[0495] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.51 (9H, s),
2.76-2.97 (1H, m), 3.34-3.52 (1H, m), 3.84-3.99 (2H, m), 4.32-4.51
(1H, m), 4.89-5.05 (1H, m), 7.10-7.25 (2H, m), 7.34-7.56 (6H,
m).
J) rac-tert-butyl
(2S,3R)-3-amino-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate
[0496] To a stirred solution of rac-tert-butyl
(2S,3S)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(((trifl-
uoromethyl)sulfonyl)oxy)pyrrolidine-1-carboxylate (11.0 g) in
N,N-Dimethylacetamide (450 mL) was added sodium azide (5.30 g), and
the reaction mixture was stirred at 130.degree. C. for 3 h. The
mixture was diluted with water and it was adjusted to pH 9-10 with
aqueous sodium hydrogen carbonate solution and extracted with
EtOAc. The combined organic layers were washed with water, dried
over anhydrous sodium sulfate and concentrated reduced pressure to
give rac-tert-butyl
(2S,3R)-3-azido-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate (9.00 g). To a stirred solution of
rac-tert-butyl
(2S,3R)-3-azido-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate (1.00 g) in MeOH (30 mL) was added 10% Pd on
carbon (100 mg), and the mixture was degassed under reduced
pressure and purged with hydrogen several times and then stirred at
25.degree. C. under hydrogen atmosphere (15 psi) for 16 h. The
reaction mixture was filtered through a pad of celite and the
filter cake was washed with MeOH and the combined filtrate was
concentrated under reduced pressure to give crude product as
1.sup.st batch. To a stirred solution of rac-tert-butyl
(2S,3S)-4,4-difluoro-2-((2-fluoro-1,1'-biphenyl]-3-yl)methyl)-3-(((triflu-
oromethyl)sulfonyl)oxy)pyrrolidine-1-carboxylate (8.00 g) in MeOH
(200 mL) was added 10% Pd on carbon (800 mg), and the mixture was
degassed under reduced pressure and purged with hydrogen several
times and then stirred at 25.degree. C. under hydrogen atmosphere
(15 psi) for 3 h. The reaction mixture was filtered through a pad
of celite and the filter cake was washed with MeOH. The combined
filtrate was concentrated under reduced pressure. The residue and
crude product of 1.sup.st batch were purified by column
chromatography (silica gel, EtOAc/petroleum ether) to give the
title compound (6.04 g).
[0497] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.89-1.32 (9H,
m), 1.86-2.01 (2H, m), 2.33-2.18 (1H, m), 2.94-3.13 (1H, m),
3.63-3.95 (3H, m), 4.11-4.36 (1H, m), 7.13-7.55 (8H, m).
K) tert-butyl
(2S,3R)-3-amino-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate
[0498] Optical resolution of rac-tert-butyl
(2S,3R)-3-amino-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate (6.03 g) was performed using preparative
HPLC (Column: CHIRALPAK AD, mobile phase: hexane/EtOH=900/100
(v/v)) to afford the title compound (3.09 g) with shorter retention
time (Column: CHIRALPAK AD-H, eluted with hexane/EtOH=900/100
(v/v)).
[0499] MS, found: 351.1.
L) tert-butyl
(2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methyls-
ulfonamido)pyrrolidine-1-carboxylate
[0500] Methanesulfonic anhydride (292 mg) was added to a stirred
solution of tert-butyl
(2S,3R)-3-amino-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl(methyl)pyr-
rolidine-1-carboxylate (355 mg) and TEA (0.365 ml) in THF (8 mL) at
room temperature. After 0.5 h, the reaction mixture was
concentrated under reduced pressure, and the residue was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (427 mg).
[0501] MS, found: 385.0.
M)
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrol-
idin-3-yl)methanesulfonamide hydrochloride
[0502] A mixture of tert-butyl
(2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)-3-(methyls-
ulfonamido)pyrrolidine-1-carboxylate (427 mg) in 4 M HCl/CPME
solution (12 mL) was stirred at room temperature for 2 h. The solid
was collected by filtration to give the title compound (340
mg).
[0503] MS: [M+H].sup.+ 385.0.
N)
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-h-
ydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0504] A mixture of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)methanesulfonamide hydrochloride (45 mg) and DIPEA (0.092
mL) in THF (1.28 mL) was stirred at room temperature for 30 min. To
the suspension was added dropwise alpha-acetoxy-isobutyryl chloride
(0.0186 mL) at 0.degree. C., and the mixture was stirred overnight
at same temperature. To the mixture were added water (0.855 mL) and
4M lithium hydroxide solution (0.267 mL), and the mixture was
stirred overnight at room temperature. The mixture was quenched
with saturated aqueous sodium hydrogen carbonate solution and
extracted with EtOAc. The extract was washed with saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, EtOAc/hexane) to give the title compound (45 mg).
[0505] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.91-1.26 (6H,
m), 2.62-2.72 (1H, m), 2.97-3.07 (4H, m), 4.09-4.44 (2H, m),
4.59-4.81 (1H, m), 4.82-5.02 (1H, m), 5.27 (1H, s), 7.07-7.17 (1H,
m), 7.25-7.34 (2H, m), 7.34-7.41 (1H, m), 7.42-7.49 (2H, m),
7.49-7.56 (2H, m), 8.09-8.19 (1H, m).
Example 5
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-hydr-
oxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
A) tert-butyl
(2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3--
yl)methyl)pyrrolidine-1-carboxylate
[0506] Ethanesulfonyl chloride (0.233 ml) was added to a solution
of tert-butyl
(2S,3R)-3-amino-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate (500 mg), TEA (0.514 mL) and DMAP (75 mg) in
THF (5 mL) at room temperature. After being stirred at room
temperature for 2 h, the reaction mixture was poured into water and
extracted with EtOAc. The organic layer was washed with saturated
brine, dried over magnesium sulfate and concentrated under reduced
pressure. The residual oil was purified by column chromatography
(silica gel, eluted with EtOAc/hexane) to give the title compound
(441 mg).
[0507] MS, found: 399.1.
B)
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrol-
idin-3-yl)ethanesulfonamide hydrochloride
[0508] A mixture of tert-butyl
(2S,3R)-3-(ethylsulfonamido)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3--
yl)methyl)pyrrolidine-1-carboxylate (441 mg) and 4 M HCl/CPME (5
mL) was stirred at room temperature for 2-h. The mixture was
concentrated under reduced pressure to give the title compound (360
mg).
[0509] MS: [M+H].sup.+ 399.1.
C)
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-h-
ydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0510] A mixture of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)ethanesulfonamide hydrochloride (60 mg) and DIPEA (0.119
mL) in THF (1.66 mL) was stirred at room temperature for 30 min. To
the suspension was added dropwise alpha-acetoxy-isobutyryl chloride
(0.024 mL) at 0.degree. C., and the mixture was stirred overnight
at same temperature. To the mixture were added water (1.10 mL) and
4 M lithium hydroxide solution (0.345 mL), and the mixture was
stirred overnight at room temperature. The mixture was quenched
with saturated aqueous sodium hydrogen carbonate solution and
extracted with EtOAc. The extract was washed with saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, eluted with EtOAc/hexane) to give the title compound (42.0
mg).
[0511] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.95-1.36 (9H,
m), 2.60-2.73 (1H, m), 2.99-3.15 (3H, m), 4.09-4.51 (2H, m),
4.58-4.98 (2H, m), 5.26 (1H, s), 7.07-7.18 (1H, m), 7.24-7.33 (2H,
m), 7.34-7.42 (1H, m), 7.42-7.56 (4H, m), 8.13 (1H, brs).
Example 7
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
A) tert-butyl
(3-(2,3'-difluoro-[1,1'-biphenyl]-3-yl)-1-(methoxy(methyl)amino)-1-oxopro-
pan-2-yl)carbamate
[0512] WSC (63.7 mL) was added to a mixture of
3-(3-bromo-2-fluorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic
acid (105 g), N,O-dimethylhydroxylamine hydrochloride (31.1 g),
HOBt (43.1 g), TEA (48.5 mL) and DMF (580 mL) at 0.degree. C. After
being stirred at room temperature for 15 h, the reaction mixture
was poured into half-saturated aqueous sodium hydrogen carbonate
solution and stirred at room temperature for 20 min to give
crystals, which were collected by filtration and washed
successively with water, 2-propanol and IPE. A mixture of the
obtained solid, (3-fluorophenyl)boronic acid (48.7 g), XPhos Pd G3
(2.45 g), 2 M aqueous potassium phosphate solution (435 mL) and THE
(537 mL) was stirred at 70.degree. C. for 1 h under argon
atmosphere. The reaction mixture was poured into half-saturated
aqueous sodium hydrogen carbonate solution and extracted with
EtOAc. The organic layer was washed with water and saturated brine,
dried over magnesium sulfate, passed through NH silica gel pad
(eluted with EtOAc) and concentrated under reduced pressure to give
crystals, which were collected by filtration and washed with IPE to
give the title compound (92.8 g).
[0513] MS, found: 321.0.
B) tert-butyl
{3-(2,3'-difluoro[1,1'-biphenyl]-3-yl)-1-[methoxy(methyl)amino]-1-oxoprop-
an-2-yl}[(4-methoxyphenyl)methyl]carbamate
[0514] To a stirred suspension of tert-butyl
(3-(2,3'-difluoro-[1,1'-biphenyl]-3-yl)-1-(methoxy(methyl)amino)-1-oxopro-
pan-2-yl)carbamate (77.0 g) in DMF (366 mL) was added NaH (60% in
oil) (9.52 g) at 0.degree. C. After being stirred for 10 min at
room temperature, alpha-chloro-4-methoxytoluene (49.7 mL) and
tetrabutylaminium iodide (6.76 g) were added thereto at 0.degree.
C. After 1.5 h at room temperature, the reaction mixture was poured
into a stirred mixture of EtOAc and 5% KHSO.sub.4 aqueous solution
at 0.degree. C., and the organic layer was separated. The organic
layer was washed with saturated brine, dried over sodium sulfate,
filtrated and concentrated under reduced pressure. The residue was
purified by column chromatography, (silica gel, eluted with
EtOAc/hexane) to give the title compound (83 g).
[0515] MS, found: 441.2.
C) tert-butyl
[1-(2,3'-difluoro[1,1'-biphenyl]-3-yl)-3-oxopropan-2-yl][(4-methoxyphenyl-
)methyl]carbamate
[0516] Lithium aluminium hydride (0.983 g) was added to a stirred
solution of tert-butyl
{3-(2,3'-difluoro[1,1'-biphenyl]-3-yl)-1-[methoxy(methyl)amino]-1-oxoprop-
an-2-yl}[(4-methoxyphenyl)methyl]carbamate (10 g) in Et.sub.2O (83
mL) at -78.degree. C. The mixture was warmed up to 0.degree. C.
After 0.5 h, the reaction mixture was quenched with EtOAc (3.61 mL)
with keeping temperature of the reaction mixture under 10.degree.
C., and a solution of potassium bisulfate (6.30 g) in water (83 mL)
was added to the mixture. The mixture was extracted with Et.sub.2O.
The organic layer was separated, washed with water and a mixture of
saturated brine and aqueous sodium hydrogen carbonate solution, and
through silica gel pad (eluted with EtOAc/hexane) to give the title
compound (8.43 g).
[0517] MS, found: 426.0.
D) ethyl
4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-2,4,5-tri-
deoxy-5-(2,3'-difluoro[1,1'-biphenyl]-3-yl)-2,2-difluoropentonate
[0518] Chlorotrimethylsilane (0.305 mL) was added to a stirred
suspension of zinc (2.75 g) in THF (24 mL) at room temperature.
After 10 min, ethyl 2-bromo-2,2-difluoroacetate (3.08 mL) was added
to the mixture under water bath cooling with keeping temperature of
the reaction mixture under 40.degree. C. After 10 min, a solution
of tert-butyl
[1-(2,3'-difluoro[1,1'-biphenyl]-3-yl)-3-oxopropan-2-yl][(4-methoxyphenyl-
)methyl]carbamate (5.78 g) in THF (6 mL) was added to the mixture
at room temperature. After 1.5 h, the reaction mixture was poured
into a stirred mixture of 10% KHSO.sub.4 aqueous solution (60 mL)
and EtOAc (120 mL). The organic layer was separated, washed with
saturated brine, dried over sodium sulfate, filtrated, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (6.71 g).
[0519] MS, found: 550.1
E)
5-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3,3-difluoro-4-hydroxy-1--
[(4-methoxyphenyl)methyl]pyrrolidin-2-one
[0520] 4 M HCl/CPME (30.1 mL) was added to a solution of ethyl
4-{(tert-butoxycarbonyl)[(4-methoxyphenyl)methyl]amino}-2,4,5-trideoxy-5--
(2,3'-difluoro[1,1'-biphenyl]-3-yl)-2,2-difluoropentonate (7.28 g)
in EtOH (3.8 mL) at room temperature. After being stirred at room
temperature for 1 h, the reaction mixture was concentrated under
reduced pressure. The residual oil was dissolved in EtOH (38 mL),
and DIPEA (6.28 mL) was added thereto at room temperature. After
being stirred at 80.degree. C. for 0.5 h, the reaction mixture was
concentrated under reduced pressure. The residue was poured into
water, and the mixture was extracted with EtOAc. The organic layer
was concentrated under reduced pressure, and the residue was
purified by column chromatography (silica gel, eluted with
EtOAc/hexane) to give the title compound (5.00 g).
[0521] MS: [M+H].sup.+ 460.2.
F)
5-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3,3-difluoro-4-hydroxypyr-
rolidin-2-one
[0522] Ceric ammonium nitrate (14.0 g) in water (15.9 mL) was added
to a solution of
5-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3,3-difluoro-4-hydroxy-1-[(-
4-methoxyphenyl)methyl]pyrrolidin-2-one (5.85 g) in CH.sub.3CN
(47.7 mL) at room temperature. The mixture was stirred at room
temperature for 2 h. The mixture was neutralized with saturated
aqueous sodium hydrogen carbonate solution and diluted with EtOAc.
The insoluble material was removed by filtration, and the filtrate
was extracted with EtOAc. The organic layer was separated, washed
with saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, eluted with EtOAc/hexane) to give the
title compound (3.80 g).
[0523] MS: [M-H].sup.- 338.2.
G) tert-butyl
2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-hydroxypyrro-
lidine-1-carboxylate
[0524] 0.9 M Borane-THF complex (37.3 mL) was added dropwise to a
solution of
5-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3,3-difluoro-4-hydroxypy-
rrolidin-2-one (3.80 g) in THF (37.3 mL) at room temperature. After
being stirred at 60.degree. C. for 3 h, the reaction mixture was
quenched by dropwise addition of water at 0.degree. C. The mixture
was stirred at room temperature for 10 min and concentrated under
reduced pressure. The residue was diluted with EtOH (25 mL) and 1 M
hydrochloric acid (125 mL), and the mixture was stirred at
60.degree. C. for 1 h. The reaction mixture was poured carefully
into iced saturated aqueous sodium hydrogen carbonate solution (250
mL) and extracted with EtOAc. The organic layer was washed with
water and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was mixed with
sodium hydrogen carbonate (0.941 g), THF (28.0 mL) and water (28.0
mL), and Boc.sub.2O (2.83 mL) was added to the mixture at room
temperature. The mixture was stirred at room temperature under
nitrogen atmosphere for 3 h. The mixture was poured into water at
room temperature and extracted with EtOAc. The organic layer was
separated, washed with saturated brine, dried over magnesium
sulfate and concentrated under reduced pressure. The residual oil
was purified by column chromatography (silica gel, eluted with
EtOAc/hexane) to give the title compound (4.00 g).
[0525] MS, found: 326.2.
H) rac-tert-butyl
(2S,3S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-[(tr-
ifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate
[0526] Trifluoromethanesulfonic anhydride (3.16 mL) was added to a
solution of tert-butyl
2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-hydroxypyrro-
lidine-1-carboxylate (4.0 g) and pyridine (3.80 mL) in Et.sub.2O
(47.0 mL) at 0.degree. C. After being stirred at room temperature
for 20 h, the mixture was quenched with water at room temperature
and extracted with EtOAc. The organic layer was separated, washed
with saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The organic layer was purified by column
chromatography (silica gel, eluted with EtOAc/hexane) to give the
title compound (3.22 g).
[0527] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.50 (9H, s),
2.74-2.99 (1H, m), 3.33-3.51 (1H, m), 3.72-4.02 (2H, m), 4.33-4.49
(1H, m), 4.86-5.02 (1H, m), 7.03-7.13 (1H, m), 7.17-7.32 (4H, m),
7.33-7.47 (2H, m).
I) rac-tert-butyl
(2S,3R)-3-azido-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluor-
opyrrolidine-1-carboxylate
[0528] Tetra-n-butylammonium azide (24.9 g) was added to a solution
of rac-tert-butyl
(2S,3S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-[(tr-
ifluoromethanesulfonyl)oxy]pyrrolidine-1-carboxylate (24.4 g) in
CH.sub.3CN (292 mL) at room temperature. After being stirred at
80.degree. C. for 1 h, the reaction mixture was poured into iced
water and extracted with EtOAc. The organic layer was washed with
water and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residual oil was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (19.5 g).
[0529] MS, found: 351.0.
J) rac-tert-butyl
(2S,3R)-3-amino-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluor-
opyrrolidine-1-carboxylate
[0530] A solution of rac-tert-butyl
(2S,3R)-3-azido-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluor-
opyrrolidine-1-carboxylate (19.5 g) in MeOH (433 mL) was
hydrogenated in the presence of 2C % Pd(OH).sub.2 on carbon (50%
wet) (1.95 g) at room temperature under ordinary pressure for 1 h.
After removal of the catalyst by filtration, the filtrate was
concentrated under reduced pressure. The residual oil was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (16.5 g).
[0531] MS, found: 369.0.
K) tert-butyl
(2S,3R)-3-amino-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluor-
opyrrolidine-1-carboxylate
[0532] Optical resolution of rac-tert-butyl
(2S,3R)-3-amino-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluor-
opyrrolidine-1-carboxylate (16.5 g) was performed using preparative
HPLC (Column: CHIRALPAK AD, mobile phase:
hexane/EtOH/diethylamine=900/100/1 (v/v/v)) to afford the title
compound (7.32 g) with shorter retention time (Column: CHIRALPAK
AD-H, mobile phase: hexane/EtOH/diethylamine=900/100/1
(v/v/v)).
[0533] MS, found: 369.1.
L) tert-butyl
(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-[(me-
thanesulfonyl)amino]pyrrolidine-1-carboxylate
[0534] Methanesulfonic anhydride (185 mg) was added to a stirred
mixture of tert-butyl
(2S,3R)-3-amino-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluor-
opyrrolidine-1-carboxylate (300 mg) and TEA (0.296 mL) in THF (5
ml) at room temperature and the mixture was stirred overnight. The
reaction mixture was directly purified by column chromatography
(silica gel, eluted with EtOAc/hexane) to give the title compound
(309 mg).
[0535] MS: [M-H].sup.- 501.1.
M) N-{(2S,3R)-2-[.
(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyrrolidin-3-yl}me-
thanesulfonamide hydrochloride
[0536] A mixture of tert-butyl
(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-[(me-
thanesulfonyl)amino]pyrrolidine-1-carboxylate (309 mg) and 4 M
HCl/EtOAc (3 mL) was stirred at room temperature for 1 h. The
mixture was diluted with EtOAc. The resulting solid was collected
by filtration to give the title compound (230 mg).
[0537] MS: [M-H].sup.- 401.0.
N)
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-
-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0538] A mixture of
N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyrr-
olidin-3-yl}methanesulfonamide hydrochloride (40 mg) and DIPEA
(0.079 mL) in THF (1.09 mL) was stirred at room temperature for 30
min. To the suspension was added dropwise alpha-acetoxy-isobutyryl
chloride (0.159 mL) at 0.degree. C., and the mixture was stirred
overnight at same temperature. To the mixture were added water
(0.729 mL) and 4 M aqueous lithium hydroxide solution (0.228 mL),
and the mixture was stirred overnight at room temperature. The
mixture was quenched with saturated aqueous sodium hydrogen
carbonate solution and extracted with EtOAc. The extract was washed
with saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, eluted with EtOAc/hexane) to give the
title compound (41 mg).
[0539] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.95-1.34 (6H,
m), 2.61-2.75 (1H, m), 2.96-3.10 (4H, m), 4.10-4.47 (2H, m),
4.60-4.81 (1H, m), 4.84-5.01 (1H, m), 5.28 (1H, s), 7.08-7.18 (1H,
m), 7.20-7.28 (1H, m), 7.31-7.41 (4H, m), 7.47-7.56 (1H, m), 8.14
(1H, brs).
Example 8
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0540] To a mixture of
N-((2S,3R)-2-((2,3'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4,4-difluoropyr-
rolidin-3-yl)ethanesulfonamide hydrochloride (57 mg) and DIPEA (81
mg) in THF (2 ml) was added 1-chloro-2-methyl-1-oxopropan-2-yl
acetate (31.1 mg) at room temperature. The mixture was stirred at
room temperature for 1 h. To the mixture were added water (1 ml)
and 4 M aqueous lithium hydroxide solution (0.314 mL) at room
temperature. The mixture was stirred at room temperature for 1 h.
After azeotropic evaporation with toluene, the residue was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (17.0 mg).
[0541] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.87-1.43 (9H,
m), 2.60-2.77 (1H, m), 2.97-3.17 (3H, m), 4.07-5.01 (3H, m), 5.27
(1H, s), 7.03-7.62 (8H, m), 8.14 (1H, brs).
Example 13
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(1-
-hydroxycyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide
[0542] To a solution of
N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyrr-
olidin-3-yl}methanesulfonamide hydrochloride (29 mg), DIPEA (42.7
mg) and 1-hydroxycyclobutane-1-carboxylic acid (9.21 mg) in THF (4
mL) was added HATU (37.7 mg) at room temperature. The mixture was
stirred at room temperature for 15 h. The mixture was quenched with
saturated aqueous sodium hydrogen carbonate solution and extracted
with EtOAc. The organic layer was separated, washed with saturated
brine (5 mL), dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by column chromatography
(silica gel, eluted with EtOAc/hexane) to give the title compound
(29.0 mg).
[0543] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.02-1.17 (1H,
m), 1.44-1.66 (1H, m), 1.79-2.04 (2H, m), 2.16-2.42 (2H, m),
2.65-2.84 (1H, m), 2.95-3.10 (4H, m), 3.91-4.11 (1H, m), 4.25-4.53
(2H, m), 4.82-4.96 (1H, m), 5.95 (1H, s), 7.09-7.42 (6H, m),
7.45-7.59 (1H, m), 8.19 (1H, brs).
Example 21
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4,4-difluoro-2-[(3'-fluoro-
[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
A) tert-butyl
(S)-(3-(3-chlorophenyl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbama-
te
[0544] To a mixture of (S)-2M (tert-butoxycarbonyl)
amino)-3-(3-chlorophenyl)propanoic acid (25.3 g), DIPEA (27.3 g)
and HATU (35.3 g) in THF (250 mL) was added
N,O-dimethylhydroxylamine hydrochloride (12.4 g) at room
temperature. The mixture was stirred at room temperature for 15 h.
The mixture was diluted with EtOAc (250 mL). The mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution
(200 mL) at room temperature. The organic layer was separated,
washed with saturated brine (100 mL), dried over magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (28.5 g).
[0545] MS, found: 243.0.
B) tert-butyl
(S)-(3-(3-chlorophenyl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)(4-meth-
oxybenzyl)carbamate
[0546] To a mixture of tert-butyl
(S)-(3-(3'-chlorophenyl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbam-
ate (13.7 g) in DMF (80 mL) was added sodium hydride (2.08 g) at
0.degree. C. After being stirred for 10 min at room temperature,
1-(chloromethyl)-4-methoxybenzene (12.5 g) and tetrabutylammonium
iodide (1.48 g) were added thereto at 0.degree. C. After being
stirred 1.5 h at room temperature, the reaction mixture was poured
into a stirred mixture of EtOAc (200 mL) and 5% KHSO.sub.4 aqueous
solution (100 mL) at 0.degree. C., and the organic layer was
separated. The organic layer was washed with water and saturated
brine, dried over magnesium sulfate, filtrated and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, eluted with EtOAc/hexane) to give the
title compound (18.3 g).
[0547] MS: [M+H].sup.+ 463.1.
C) tert-butyl
[(2S)-1-(3-chlorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]carbam-
ate
[0548] Aluminum(III) lithium hydride (2.10 g) was added to a
stirred solution of tert-butyl
(S)-(3-(3-chlorophenyl)-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)(4-meth-
oxybenzyl) carbamate (18.3 g) in Et.sub.2O (150 mL) at -78.degree.
C. The mixture was warmed up to 0.degree. C. After 0.5 h, the
reaction mixture was quenched with EtOAc (6.97 g) and a solution of
potassium hydrogen sulfate (13.5 g) in water (150 mL). And then,
EtOAc and water were added thereto. The organic layer was
separated, washed with water and a mixture of saturated brine and
aqueous sodium hydrogen carbonate solution, dried over magnesium
sulfate, filtrated and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, eluted
with EtOAc/hexane) to give the title compound (12.8 g).
[0549] MS: [M-H].sup.- 402.1.
D) ethyl (4S)-4-((tert-butoxycarbonyl)
(4-methoxybenzyl)amino)-5-(3-chlorophenyl)-2,2-difluoro-3-hydroxypentanoa-
te
[0550] To a stirred mixture of zinc (0.456 g) in THF (6 mL) was
added chlorotrimethylsilane (0.051 g) at room temperature. After 5
min, ethyl 2-bromo-2,2-difluoroacetate (0.945 g) was added to the
mixture under water bath cooling. After 10 min, a solution of
tert-butyl
[(2S)-1-(3-chlorophenyl)-3-oxopropan-2-yl][(4-methoxyphenyl)methyl]carbam-
ate (0.94 g) in THF (2 mL) was added to the mixture at room
temperature. The mixture was stirred at room temperature under
nitrogen atmosphere for 2 h. The reaction mixture was poured into a
stirred mixture of 10% aqueous citric acid solution and EtOAc. The
organic layer was separated, washed with saturated brine, dried
over magnesium sulfate, filtrated, and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, eluted with EtOAc/hexane) to give the title compound (1.11
g).
[0551] MS, found: 472.1.
E) ethyl
(4S)-5-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-4-((4-methoxybenzy-
l)amino)pentanoate hydrochloride
[0552] To a mixture of ethyl (4S)-4-((tert-butoxycarbonyl)
(4-methoxybenzyl)amino)-5-(3-chlorophenyl)-2,2-difluoro-3-hydroxypentanoa-
te (1.11 g) in EtOH (3 mL) was added 4 M HCl/CPME solution (5.26
mL) at room temperature. The mixture was stirred at room
temperature for 2 h. Evaporation gave the title compound (0.976
g).
[0553] MS: [M+H].sup.+ 428.0.
F)
(5S)-5-[(3-chlorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methoxyphe-
nyl)methyl]pyrrolidin-2-one
[0554] To a mixture of ethyl
(4S)-5-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-4-((4-methoxybenzyl)amino)-
pentanoate hydrochloride (0.976 g) in EtOH (5 mL) was added DIPEA
(2.72 g) at room temperature. The mixture was stirred at room
temperature for 2 h. After evaporation of the solvent, the residue
was poured into water, and the mixture was extracted with EtOAc.
The organic layer was separated, washed with saturated brine, dried
over magnesium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, eluted
with EtOAc/hexane) to give the title compound (0.770 g).
[0555] MS: [M-H].sup.- 380.1.
G)
(5S)-5-[(3-chlorophenyl)methyl]-3,3-difluoro-4-hydroxypyrrolidin-2-one
[0556] To a mixture of
(5S)-5-[(3-chlorophenyl)methyl]-3,3-difluoro-4-hydroxy-1-[(4-methoxypheny-
l)methyl]pyrrolidin-2-one (0.77 g) in CH.sub.3CN (7 ml) and water
(2.33 ml) was added ammonium cerium(IV) nitrate (2.21 g) at room
temperature. The mixture was stirred at room temperature for 2 h.
The mixture was quenched with saturated aqueous sodium carbonate
solution and extracted with EtOAc. The organic layer was separated,
washed with saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (0.460 g).
[0557] MS: [M-H].sup.- 260.0.
H) (2S)-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidin-3-ol
[0558] To a mixture of
(5S)-5-[(3-chlorophenyl)methyl]-3,3-difluoro-4-hydroxypyrrolidin-2-one
(3.45 g) in THF (40 ml) was added 0.9 M borane-THF complex/THF
solution (44.0 ml) at room temperature. The mixture was stirred at
60.degree. C. under nitrogen atmosphere for 3 h. The mixture was
quenched with water at 0.degree. C. The mixture was stirred at room
temperature for 10 min and concentrated under reduced pressure. The
residue was diluted with EtOH (10 ml) and 1 M hydrochloric acid (50
ml), and the mixture was stirred at 60.degree. C. for 1 h. Sodium
hydrogen carbonate was carefully added to the reaction mixture in
the iced bath to bring the pH of the solution to 8. Evaporation
gave the title compound (3.27 g).
[0559] MS, found: 247.9.
I) tert-butyl
(2S)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-hydroxypyrrolidine-1-carbo-
xylate
[0560] To a crude mixture of
(2S)-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidin-3-ol (2.27
g) and TEA (1.86 g) in THF (30 mL) was added Boc.sub.2O (3.00 g) at
room temperature. The mixture was stirred at room temperature under
nitrogen atmosphere for 3 h. After evaporation, the mixture was
diluted with water and extracted with EtOAc. The organic layer was
separated, washed with saturated brine, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, eluted with
EtOAc/hexane) to give the title compound (2.84 g).
[0561] MS, found: 247.9.
J) tert-butyl
(2S,3S)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(trifluoromethanesulfo-
nyl)oxy]pyrrolidine-1-carboxylate
[0562] Trifluoromethanesulfonic anhydride (406 .mu.L) was added to
a solution of tert-butyl
(2S)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-hydroxypyrrolidine-1-carbo-
xylate (420 mg) and pyridine (488 .mu.L) in Et.sub.2O (6.04 ml) at
0.degree. C. After being stirred at room temperature for 2 h and
then at 40.degree. C. for 2 h, the mixture was quenched with water
at room temperature and extracted with EtOAc. The organic layer was
separated, washed with saturated brine, dried over magnesium
sulfate and concentrated under reduced pressure. The organic layer
was purified by column chromatography (silica gel, eluted with
EtOAc/hexane) to give, the title compound (410 mg).
[0563] MS, found: 379.9.
K) tert-butyl
(2S,3R)-3-azido-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidine-1-carb-
oxylate
[0564] To a mixture of tert-butyl
(2S,3S)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(trifluoromethanesulfo-
nyl)oxy]pyrrolidine-1-carboxylate (2.43 g) in CH.sub.3CN (20 ml)
was added tetrabutylammonium azide (2.16 g) at room temperature.
The mixture was stirred at 80.degree. C. for 1 h. The mixture was
quenched with water at 0.degree. C. and extracted with EtOAc. The
organic layer was separated, washed with water and saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, eluted with EtOAc/hexane) to give the title compound (1.85
g).
[0565] MS, found: 272.9.
L) tert-butyl
(2S,3R)-3-amino-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidine-1-carb-
oxylate
[0566] To a mixture of tert-butyl
(2S,3R)-3-azido-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidine-1-carb-
oxylate (1.57 g) in THF (20 mL) was added PPh.sub.3 (1.33 g) at
room temperature. The mixture was stirred at 50.degree. C. for 15
h. After evaporation, the residue was purified by column
chromatography (silica gel, eluted with EtOAc/hexane). The residue
was further purified by preparative HPLC (Column: CHIRALPAK IA,
mobile phase: hexane/EtOH/diethylamine=650/350/1 (v/v/v)) to afford
the title compound (1.13 g) with shorter retention time (Column:
CHIRALPAK IA, mobile phase: hexane/EtOH/diethylamine=650/350/l
(v/v/v)).
[0567] MS, found: 291.1.
M) tert-butyl
(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino-
]pyrrolidine-1-carboxylate
[0568] Methanesulfonic anhydride (166 mg) was added to a stirred
solution of tert-butyl
(2S,3R)-3-amino-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidine-1-carb-
oxylate (165 mg) and TEA (0.199 mL) in THF (3 mL) at room
temperature. After 0.5 h, the reaction mixture was concentrated
under reduced pressure, and the residue was purified by column
chromatography (silica gel, eluted with EtOAc/hexane) to give the
title compound (186 mg).
[0569] MS: [M-H].sup.- 423.1.
N) tert-butyl
(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(methan-
esulfonyl)amino]pyrrolidine-1-carboxylate
[0570] A mixture of tert-butyl
(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino-
]pyrrolidine-1-carboxylate (186 mg), (3-fluorophenyl)boronic acid
(92 mg), XPhos Pd G3 (37.1 mg) and 1 M aqueous potassium phosphate
solution (1.31 mL) in DME (1.46 mL) was stirred overnight at
90.degree. C. The mixture was purified by column chromatography (NH
silica gel, EtOAc/hexane) to give the title compound (205 mg).
[0571] MS: [M-H]p 483.2.
O)
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrol-
idin-3-yl}methanesulfonamide hydrochloride
[0572] A mixture of tert-butyl
(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(methan-
esulfonyl)amino]pyrrolidine-1-carboxylate (205 mg) and 4 M HCl/CPME
solution (5 mL) was stirred at room temperature for 2 h. The solid
was collected by filtration to give the title compound (175
mg).
[0573] MS: [M+H].sup.+ 385.0.
P)
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4,4-difluoro-2-[(3'-flu-
oro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0574] HATU (43.4 mg) was added to a solution of
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolid-
in-3-yl}methanesulfonamide hydrochloride (40 mg),
bicyclo[1.1.1]pentane-1-carboxylic acid (12.8 mg) and TEA (0.066
mL) in DMF (1 mL) at room temperature. The mixture was stirred at
room temperature under a dry atmosphere for 30 min. The mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution
at room temperature and extracted with EtOAc. The organic layer was
separated, washed with saturated brine, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by column chromatography (NH silica gel, eluted with
EtOAc/hexane) to give the title compound (32.0 mg).
[0575] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.21-1.76 (3H, m),
1.98-3.18 (9H, m), 3.70-5.01 (5H, m), 6.97-7.53 (8H, m).
Example 25
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)methyl]-
-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0576] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-hydroxy--
2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide (35 mg),
m-tolylboronic acid (16.6 mg), XPhos Pd G3 (6.91 mg) and 1 M
aqueous potassium phosphate solution (245 .mu.L) in THF (408 .mu.L)
was stirred at 90.degree. C. for 1 h. The mixture was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane) to
give the title compound (33.0 mg).
[0577] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.97-1.23 (6H,
m), 2.36 (3H, s), 2.61-2.71 (1H, m), 2.99 (3H, s), 3.00-3.08 (1H,
m), 4.08-4.45 (0.2H, m), 4.58-5.02 (2H, m), 5.28 (1H, s), 7.05-7.15
(1H, m), 7.17-7.22 (1H, m), 7.24-7.39 (5H, m), 8.05-8.23 (1H,
m).
Example 26
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-[(2R)--
oxolane-2-carbonyl]pyrrolidin-3-yl}methanesulfonamide
[0578] HATU (43.4 mg) was added to a solution of
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolid-
in-3-yl}methanesulfonamide hydrochloride (40 mg),
(R)-tetrahydrofuran-2-carboxylic acid. (13.2 mg) and TEA (0.066 mL)
in DMF (0.5 mL) at room temperature. The mixture was stirred at
room temperature under a dry atmosphere for 30 min. The mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution
at room temperature and extracted with EtOAc. The organic layer was
separated, washed with saturated brine, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by column chromatography (silica, gel, eluted with EtOAc
then, NH silica gel, eluted with EtOAc/hexane) to give the title
compound (39.0 mg).
[0579] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.54-1.81 (3H,
m), 1.38-2.06 (1H, m), 2.62-3.14 (5H, m), 3.41-4.76 (7H, m),
7.12-7.23 (1H, m), 7.29-7.44 (2H, m), 7.45-7.57 (4H, m), 7.59-7.76
(1H, m), 8.14-8.30 (1H, m).
Example 35
N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
A) tert-butyl
(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-[(m-
ethanesulfonyl)amino]pyrrolidine-1-carboxylate
[0580] A mixture of tert-butyl
(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino-
]pyrrolidine-1-carboxylate (90 mg), (3,5-difluorophenyl)boronic
acid (50.2 mg), XPhos Pd G3 (17.9 mg) and 1 M aqueous potassium
phosphate solution (635 .mu.L) in DME (1.06 mL) was stirred
overnight at 90.degree. C. The mixture, was quenched with saturated
aqueous sodium hydrogen carbonate solution and extracted with
EtOAc. The organic layer was separated, washed with saturated
brine, dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, eluted with EtOAc/hexane) to give the title compound (104
mg).
[0581] MS, found: 403.0.
B) N-{(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4
4-difluoropyrrolidin-3-yl}methanesulfonamide hydrochloride
[0582] A mixture of tert-butyl
(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-3-[(m-
ethanesulfonyl)amino]pyrrolidine-1-carboxylate (104 mg) and 4 M
HCl/CPME solution (2 mL) was stirred at room temperature for 2 h.
The solid was collected by filtration to give the title compound
(85 mg).
[0583] MS: [M+H].sup.+ 403.0.
C)
N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro--
1-(2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0584] To a solution of
N-{(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyr-
rolidin-3-yl}methanesulfonamide hydrochloride (20.0 mg) and
isobutyric acid. (5.09 .mu.L) in DMF (1.5 mL) were added HATU (26.0
mg) and DIPEA (0.032 mL) at room temperature. The mixture was
stirred overnight at room temperature. The mixture was quenched
with saturated aqueous sodium hydrogen carbonate solution and
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane) to
give the title compound (19.7 mg).
[0585] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.11-0.98 (6H,
m), 1.82-1.91 (1H, m), 2.54-3.15 (5H, m), 3.81-4.25 (2H, m),
4.37-4.70 (2H, m), 7.16-7.84 (7H, m), 8.23 (1H, brs).
Example 44
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-
-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
A)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-hydrox-
y-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0586] A mixture of
N-((2S,3R)-2-(3-chloro-2-fluorobenzyl)-4,4-difluoropyrrolidin-3-yl)methan-
esulfonamide hydrochloride (200 mg) and DIPEA (456 .mu.L) in THF
(3.16 mL) was stirred at room temperature for 30 min. To the
suspension was added dropwise alpha-acetoxy-isobutyryl chloride (92
.mu.L) at 0.degree. C., and the mixture was stirred overnight at
same temperature. To the mixture were added water (2.11 mL) and 4 M
aqueous lithium hydroxide solution (1.32 mL), and the mixture was
stirred overnight at room temperature. The mixture was quenched
with saturated aqueous sodium hydrogen carbonate solution and
extracted with EtOAc. The extract was washed with saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (silica
gel, eluted with EtOAc/hexane) to give the title compound (184
mg).
[0587] MS: [M+H].sup.+ 429.0.
B)
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-diflu-
oro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0588] The mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-hydroxy--
2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide (24 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (17.1
mg), XPhos Pd G3 (9.47 mg), potassium acetate (11.0 mg) and toluene
(1 mL) was stirred at 80.degree. C. under nitrogen atmosphere for 4
h. The mixture was quenched with water at room temperature and
extracted with EtOAc. The organic layer was separated, washed with
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The mixture of the obtained residue, cesium
carbonate (58.6 mg), 1-chloro-3-iodobenzene (0.011 mL), PdCl.sub.2
(dppf) (8.78 mg) and DME (1 mL)/water (0.300 mL) was stirred at
80.degree. C. under nitrogen atmosphere for 1 h. The residue was
purified by column chromatography (silica gel, eluted with
EtOAc/hexane). The obtained solid was purified by preparative HPLC
to give the title compound (7.50 mg).
[0589] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.93-1.28 (6H,
m), 2.61-2.74 (1H, m), 2.93-3.12 (4H, m), 4.10-4.48 (2H, m),
4.57-4.81 (1H, m), 4.84-5.02 (1H, m), 5.29 (1H, s), 7.10-7.18 (1H,
m), 7.29-7.39 (2H, m), 7.42-7.53 (3H, m), 7.57 (1H, s), 8.16 (1H,
brs).
Example 45
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(oxetan-
e-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide with Shorter
Retention Time
[0590] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)ethanesulfonamide hydrochloride (40.4 mg) and
oxetane-2-carboxylic acid (9.33 .mu.L) 0.25 in DMF (3 mL) were
added HATU (53.0 mg) and DIPEA (0.065 mL) at room temperature. The
mixture was stirred overnight at room temperature. The mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution
and extracted with EtOAc. The organic layer was separated, washed
with water and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane) to
give the title compound (12.1 mg).
[0591] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.19-1.33 (3H,
m), 2.20-2.44 (1H, m), 2.60-3.15 (5H, m), 3.80-5.22 (7H, m),
7.11-7.57 (8H, m), 8.09-8.29 (1H, m).
Example 46
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(oxetan-
e-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide with Longer
Retention Time
[0592] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)ethanesulfonamide hydrochloride (40.4 mg) and
oxetane-2-carboxylic acid (9.33 .mu.L) in DMF (3 mL) were added
HATU (53.0 mg) and DIPEA (0.065 mL) at room temperature. The
mixture was stirred overnight at room temperature. The mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution
and extracted with EtOAc. The organic layer was separated, washed
with water and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane) to
give the title compound (13.3 mg).
[0593] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.15-1.43 (3H,
m), 1.95-2.41 (1H, m), 2.61-3.22 (5H, m), 3.76-5.13 (7H, m),
7.11-7.61 (8H, m), 8.13-8.38 (1H, m).
Example 50
N-[(2S,3R)-2-[([1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(oxetane-2-carb-
onyl)pyrrolidin-3-yl]ethanesulfonamide with Shorter Retention
Time
A) tert-butyl
(2S,3R)-2-[(3-chlorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoro-
pyrrolidine-1-carboxylate
[0594] Ethanesulfonyl chloride (0.065 mL) was added to a mixture of
tert-butyl
(2S,3R)-3-amino-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidine-1-carb-
oxylate (158 mg), TEA (0.127 mL), DMAP (11.2 mg) and THF (5 mL) at
room temperature. After being stirred at room temperature for 2 h,
the reaction mixture was quenched with saturated brine and
concentrated under reduced pressure. The residual oil was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (198 mg).
[0595] MS, found: 338.9.
B)
N-{(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethan-
esulfonamide hydrochloride
[0596] A mixture of tert-butyl
(2S,3R)-2-[(3-chlorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoro-
pyrrolidine-1-carboxylate (191 mg) and 4 M HCl/CPME solution (4 ml)
was stirred at room temperature for 2 h. The solid was collected by
filtration to give the title compound (149 mg).
[0597] MS: [M+H].sup.+ 338.9.
C)
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(oxetane-2-carbony-
l)pyrrolidin-3-yl]ethanesulfonamide
[0598] To a solution of
N-{(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanes-
ulfonamide hydrochloride (145 mg) and oxetane-2-carboxylic acid
(0.049 mL) in DMF (5 mL) were added HATU (220 mg) and DIPEA (0.270
mL) at room temperature. The mixture was stirred overnight at room
temperature. The mixture was quenched with aqueous saturated
ammonium chloride solution and extracted with EtOAc. The organic
layer was separated, washed with water and saturated brine, dried
over sodium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (125 mg).
[0599] MS: [M+H].sup.+ 423.0.
D)
N-[(2S,3R)-2-[([1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(oxetane-2-c-
arbonyl)pyrrolidin-3-yl]ethanesulfonamide with Shorter Retention
Time
[0600] A mixture of
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(oxetane-2-carbonyl)-
pyrrolidin-3-yl]ethanesulfonamide (52.7 mg), phenylboronic acid
(30.4 mg), XPhos Pd G3 (10.6 mg) and 1 M aqueous potassium
phosphate solution (0.374 mL) in DME. (1 mL) was stirred overnight
at 90.degree. C. After cooling back to room temperature, the
solution was diluted with EtOAc and dried over sodium sulfate.
After removal of the solvent under reduced pressure, the residue
was purified by column chromatography (silica gel, eluted with.
EtOAc/hexane), and then by preparative HPLC to give the title
compound (8.7 mg).
[0601] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.01-1.29 (3H,
m), 2.53-3.18 (6H, m), 3.75-5.29 (7H, m), 7.20-7.76 (9H, m), 8.18
(1H, d, J=9.8 Hz).
Example 51
N-[(2S,3R)-2-[([1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(oxetane-2-carb-
onyl)pyrrolidin-3-yl]ethanesulfonamide with Longer Retention
Time
[0602] A mixture of
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(oxetane-2-carbonyl)-
pyrrolidin-3-yl]ethanesulfonamide (52.7 mg), phenylboronic acid
(30.4 mg), XPhos Pd G3 (10.6 mg) and 1 M aqueous potassium
phosphate solution (0.374 mL) in DME (1 mL) was stirred overnight
at 90.degree. C. After cooling back to room temperature, the
solution was diluted with EtOAc and dried over sodium sulfate.
After removal of the solvent under reduced pressure, the residue
was purified by column chromatography (silica gel, eluted with
EtOAc/hexane), and then by preparative HPLC to give the title
compound (11.4 mg).
[0603] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.01-1.32 (3H,
m), 1.75-2.28 (1H, m), 2.52-3.23 (5H, m), 3.73-5.22 (7H, m),
7.18-7.71 (9H, m), 8.07-8.36 (1H, m).
Example 52
N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(oxeta-
ne-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide with Shorter
Retention Time
[0604] A mixture of
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(oxetane-2-carbonyl)-
pyrrolidin-3-yl]ethanesulfonamide (50.9 mg),
(3-fluorophenyl)boronic acid (33.7 mg), XPhos Pd G3 (10.2 mg) and 1
M aqueous potassium phosphate solution (0.361 mL) in DME (1 mL) was
stirred overnight at 90.degree. C. After cooling back to room
temperature, the solution was diluted with EtOAc and dried over
sodium sulfate. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography (silica
gel, eluted with EtOAc/hexane), and then by preparative HPLC to
give the title compound (9.6 mg).
[0605] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.03-1.25 (3H,
m), 2.52-3.19 (6H, m), 3.84-5.25 (7H, m), 7.11-7.82 (8H, m),
8.07-8.30 (1H, m).
Example 56
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
A)
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-
-yl}ethanesulfonamide hydrochloride
[0606] A mixture of tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-
-difluoropyrrolidine-1-carboxylate (580 mg) and 4 M hydrogen
chloride CPME solution (10 mL) was stirred overnight at room
temperature. The insoluble substance was collected by filtration to
give the title compound (464 mg).
[0607] MS, found: 356.9.
B)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(oxetane--
2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
[0608] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}ethanesulfonamide hydrochloride (200 mg), oxetane-2-carboxylic
acid (78 mg) and DMF (3 mL) were added HATU (290 mg) and DIPEA (263
mg) at room temperature. The mixture was stirred overnight at room
temperature, to the mixture was added saturated aqueous ammonium
chloride solution, and the mixture was extracted with EtOAc. The
organic layer was separated, washed with water and saturated brine,
dried over anhydrous sodium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, EtOAc/hexane) to give the title compound (147
mg).
[0609] MS: [M+H].sup.+ 441.0.
C)
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,3',5'-trifluo-
ro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0610] A mixture of
N-[(2S,3R)-2-[_(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(oxetane-2-
-carbonyl)pyrrolidin-3-yl]ethanesulfonamide (147 mg),
(3,5-difluorophenyl)boronic acid (105 mg), XPhos Pd G3 (28.2 mg), 1
M aqueous potassium phosphate solution (1.00 mL) and DME (2 mL) was
stirred at 70.degree. C. for 1 hr. The mixture was cooled to room
temperature, and purified by silica gel column chromatography
(EtOAc/hexane). The obtained solid was crystallized from
EtOAc/hexane to give, the title compound (101 mg) with shorter
retention time.
[0611] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 51.18-1.33 (3H, m),
2.26-2.45 (1H, m), 2.58-2.83 (2H, m), 2.95-3.22 (3H, m), 3.74-5.20
(7H, m), 7.14-7.52 (6H, m), 8.21 (1H, brs).
Example 66
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,2',3'-triflu-
oro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
A)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-hydrox-
y-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0612] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}ethanesulfonamide hydrochloride (160 mg) and DIPEA (0.352 mL) in
THF (2 mL) was added alpha-acetoxy-isobutyryl chloride (0.071 mL)
at 0.degree. C. and the mixture was stirred at same temperature for
10 min. To the mixture were added water (1 mL) and 4 M aqueous
lithium hydroxide solution (1.02 mL) and the mixture was stirred
overnight at room temperature. The mixture was quenched with
saturated aqueous sodium hydrogen carbonate solution and extracted
with EtOAc. The extract was washed with saturated brine, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, eluted
with EtOAc/hexane) to give the title compound (172 mg).
[0613] MS: [M+H].sup.+ 443.0.
B)
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,2',3'-tri-
fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0614] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-hydroxy--
2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide (20 mg),
(2,3-difluorophenyl)boronic acid (14.3 mg), XPhos Pd G3 (7.64 mg)
and 1 M aqueous potassium phosphate solution (0.135 mL) in THF (0.5
mL) was stirred at 90.degree. C. in sealed tube for 6 h. The
mixture was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (19.2 mg).
[0615] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.30-1.43 (9H, m),
2.05-3.25 (5H, m), 3.99-4.53 (3H, m), 4.87 (1H, d, J=9.1 Hz),
4.99-5.33 (1H, m), 7.07-7.30 (0.5H, m), 7.35-7.48 (1H, m).
Example 67
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,2',5'-triflu-
oro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0616] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-hydroxy--
2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide (20 mg),
(2,5-difluorophenyl) boronic acid (14.3 mg), XPhos Pd G3 (7.64 mg)
and 1 M aqueous potassium phosphate solution (0.135 mL) in THF (0.5
mL) was stirred at 90.degree. C. in sealed tube for 6 h. The
mixture was purified by column chromatography (silica gel, eluted
with EtOAc/hexane) to give the title compound (17.4 mg).
[0617] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.28-2.66 (10H,
m), 2.87-3.22 (4H, m), 3.94-4.57 (3H, m), 4.86 (1H, d, J=10.6 Hz),
4.99-5.30 (1H, m), 6.99-7.24 (5H, m), 7.35-7.48 (1H, m).
Example 68
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-
-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
A)
N-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl-
]ethanesulfonamide
[0618] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-hydroxy--
2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide (75 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (51.6
mg), XPhos Pd G3 (28.7 mg) and potassium acetate (33.2 mg) in
toluene (1 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 5 h. The reaction mixture was diluted with water and
extracted with EtOAc. The extract was washed with saturated brine,
dried over magnesium sulfate, filtered and concentrated under
reduced pressure to give the title compound (151 mg).
[0619] MS: [M+H].sup.+ 535.2.
B)
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-diflu-
oro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0620] A mixture of
N-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo-
rolan-2-yl)phenyl]methyl}-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]e-
thanesulfonamide (0.022 g), cesium carbonate (0.040 g),
l-chloro-3-iodobenzene (7.65 .mu.L), PdCl.sub.2(dppf) (6.02 mg) and
DME (0.5 mL)/water (0.150 mL) was stirred overnight at 80.degree.
C. under nitrogen atmosphere. The mixture was purified by column
chromatography (NH silica gel, eluted with EtOAc/hexane) to give
the title compound (0.017 g).
[0621] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 1.31-1.42 (9H, m),
2.21-2.58 (1H, m), 2.86-3.18 (4H, m), 3.99-4.53 (3H, m), 4.90 (1H,
d, J=8.3 Hz), 5.01-5.29 (1H, m), 7.14-7.22 (1H, m), 7.27-7.44 (5H,
m), 7.47-7.56 (1H, m).
Example 73
N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-[(2R)-o-
xolane-2-carbonyl]pyrrolidin-3-yl}methanesulfonamide
A) tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfo-
nyl)amino]pyrrolidine-1-carboxylate
[0622] To a mixture of tert-butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate (200 mg), TEA (166 mg) and THF (5 mL) was added
methanesulfonic anhydride (143 mg) at room temperature. The
reaction mixture was stirred overnight at room temperature, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (244 mg).
[0623] MS: [M-H].sup.- 441.1.
B)
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-
-yl}methanesulfonamide hydrochloride
[0624] A mixture of tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-3-[(methanesulfo-
nyl)amino]pyrrolidine-1-carboxylate (360 mg) and 4 M hydrogen
chloride CPME solution (5 mL) was stirred at room temperature for 2
hr. The reaction solution was concentrated to give the title
compound (300 mg).
[0625] MS, found: 342.9.
C)
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(2R)-oxo-
lan-2-carbonyl]pyrrolidin-3-yl}methanesulfonamide
[0626] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}methanesulfonamide hydrochloride (300 mg), TEA (400 mg),
(2R)-tetrahydrofuran-2-carboxylic acid (110 mg) and DMF (5 mL) was
added HATU (361 mg) at room temperature. The mixture was stirred at
room temperature for 30 min, to the mixture was added saturated
aqueous sodium hydrogen carbonate solution at room temperature, and
the mixture was extracted with EtOAc. The organic layer was
separated, washed with saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(EtOAc/hexane). The obtained solid was washed with IPE to give the
title compound (350 mg).
[0627] MS: [M+H].sup.+ 441.0.
D)
N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-[(2R-
)-oxolan-2-carbonyl]pyrrolidin-3-yl}methanesulfonamide
[0628] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(2R)-oxola-
n-2-carbonyl]pyrrolidin-3-yl}methanesulfonamide (30 mg),
phenylboronic acid (12.5 mg), 1 M aqueous potassium phosphate
solution (0.204 mL), XPhos Pd G3 (5.76 mg) and THF (0.340 mL) was
stirred at 90.degree. C. for 1 hr. The residue was purified by
silica gel column chromatography (NH, EtOAc/hexane) to give the
title compound (22 mg).
[0629] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.1.37-2.08 (4H,
m), 2.60-3.12 (5H, m), 3.31-4.95 (7H, m), 7.08-7.55 (8H, m),
8.14-8.29 (1H, m).
Example 76
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(1-hydr-
oxycyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide
[0630] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)methanesulfonamide hydrochloride (35.0 mg) and
1-hydroxycyclobutane-1-carboxylic acid (9.50 .mu.L) in DMF (1.5 mL)
were added HATU (47.4 mg) and DIPEA (0.058 mL) at room temperature.
The mixture was stirred overnight at room temperature. The mixture
was quenched with saturated aqueous sodium hydrogen carbonate
solution and extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (NH silica gel, eluted with EtOAc/hexane)
to give the title compound (23.5 mg).
[0631] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.79-2.12 (4H, m),
2.51-2.62 (2H, m), 2.87 (3H, s), 2.92-3.14 (2H, m), 3.93-4.13 (1H,
m), 4.19-4.41 (2H, m), 4.97-5.13 (2H, m), 7.16-7.21 (1H, m),
7.27-7.54 (8H, m).
Example 77
[0632]
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1--
(2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0633] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)methanesulfonamide hydrochloride (35.0 mg) and isobutyric
acid (0.012 mL) in DMF (1.5 mL) were added HATU (47.4 mg) and DIPEA
(0.058 mL) at room temperature. The mixture was stirred overnight
at room temperature. The mixture was quenched with, aqueous
saturated ammonium chloride solution and extracted with EtOAc. The
organic layer was separated, washed with water and saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (NH
silica gel, eluted with EtOAc/hexane) to give the title compound
(33.0 mg).
[0634] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.45-1.15 (6H, m),
1.94-2.49 (1H, m), 2.74-3.17 (5H, m), 3.72-4.02 (1H, m), 4.28-4.60
(2H, m), 4.87-5.19 (1H, m), 7.09-7.24 (2H, m), 7.29-7.54 (6H,
m).
Example 78
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4,4-difluoro-2-[(2-fluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0635] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)methanesulfonamide hydrochloride (35.0 mg) and
bicyclo[1.1.1]pentane-1-carboxylic acid (9.17 .mu.L) in DMF (1.5
ml) were added HATU (47.4 mg) and DIPEA (0.058 mL) at room
temperature. The mixture was stirred overnight at room temperature.
The mixture was quenched with aqueous saturated ammonium chloride
solution and extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (NH silica gel, eluted with EtOAc/hexane)
to give the title compound (33.2 mg).
[0636] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.78-1.91 (2H, m),
2.10 (4H, s), 2.26-2.51 (1H, m), 2.77-3.12 (5H, m), 3.92-4.08 (1H,
m), 4.17-4.44 (1H, m), 4.71-5.20 (2H, m), 7.11-7.24 (2H, m),
7.27-7.55 (7H, m).
Example 79
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(oxetan-
e-2-carbonyl)pyrrolidin-3-yl]methanesulfonamide with Shorter
Retention Time
[0637] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)methanesulfonamide hydrochloride (110 mg) and
oxetane-2-carboxylic acid (0.026 mL) in DMF (5 mL) were added HATU
(149 mg) and DIPEA (0.183 mL) at room temperature. The mixture was
stirred overnight at room temperature. The mixture was quenched
with saturated aqueous sodium hydrogen carbonate solution and
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane),
and then by preparative HPLC to give the title compound (33.2
mg).
[0638] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.23-2.47 (1H,
m), 2.61-3.09 (6H, m), 3.72-5.19 (7H, m), 7.11-7.56 (8H, m), 8.23
(1H, brs).
Example 81
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-((-
2R)-oxetane-2-carbonyl)pyrrolidin-3-yl]methanesulfonamide
[0639] To a solution of
N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyrr-
olidin-3-yl}methanesulfonamide hydrochloride (100 mg) and
oxetane-2-carboxylic acid (0.023 mL) in DMF (2 mL) were added HATU
(130 mg) and DIPEA (0.159 mL) at room temperature. The mixture was
stirred at room temperature for 1 h. The mixture was quenched with
saturated aqueous sodium hydrogen carbonate solution and extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (NH silica gel, eluted with EtOAc/hexane) to give
the title compound (41 mg).
[0640] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 2.30-2.47 (1H,
m), 2.64-2.78 (2H, m), 2.96-3.10 (4H, m), 3.75-5.19 (7H, m),
7.11-7.57 (7H, m), 8.14-8.32 (1H, m).
Example 87
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4,4-difluoro-2-[(2,3',5'-t-
rifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
A)
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-2-[(3-chloro-2-fluoroph-
enyl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide
[0641] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}methanesulfonamide hydrochloride (157 mg),
bicyclo[1.1.1]pentane-1-carboxylic acid (55.7 mg), TEA (209 mg) and
DMF (4 mL) was added HATU (236 mg) at room temperature. The mixture
was stirred at room temperature for 1 hr, to the mixture was added
water, and the insoluble substance was collected by filtration to
give the title compound (180 mg).
[0642] MS: [M+H].sup.+ 437.0.
B)
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4,4-difluoro-2-[(2,3',5-
'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0643] A mixture of
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-2-[(3-chloro-2-fluorophen-
yl)methyl]-4,4-difluoropyrrolidin-3-yl}methanesulfonamide (180 mg),
(3,5-difluorophenyl)boronic acid (130 mg), XPhos Pd G3 (69.8 mg), 1
M aqueous potassium phosphate solution (1.24 mL) and DME (3 mL) was
stirred at 90.degree. C. for 2 hr. The residue was purified by
silica gel column chromatography (NH, EtOAc/hexane), and then
silica gel column chromatography (EtOAc/hexane). The obtained
residue was crystallized from ethanol/water to give the title
compound (121 mg).
[0644] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.20-1.68 (2H,
m), 1.90 (4H, s), 2.08-2.40 (1H, m), 2.61-2.77 (1H, m), 2.90-3.16
(4H, m), 3.70-4.31 (2H, m), 4.37-4.86 (2H, m), 7.08-7.57 (6H, m),
8.02-8.30 (1H, m).
Example 88
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-[(2R)--
oxolane-2-carbonyl]pyrrolidin-3-yl}ethanesulfonamide
A) tert-butyl
(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-[(3'-fluoro[1,1'-bipheny-
l]-3-yl)methyl]pyrrolidine-1-carboxylate
[0645] A mixture of tert-butyl
(2S,3R)-2-[(3-chlorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-difluoro-
pyrrolidine-1-carboxylate (97 mg), (3-fluorophenyl)boronic acid
(46.4 mg), XPhos Pd G3 (18.7 mg) and 1 M aqueous potassium
phosphate solution (0.663 mL) in THE (1 mL) was heated, at
80.degree. C. under nitrogen atmosphere for 3 h. The mixture was
purified by column chromatography (NH silica gel, eluted with
EtOAc/hexane) to give the title compound (100 mg).
[0646] MS: [M-H].sup.- 497.2.
B)
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrol-
idin-3-yl}ethanesulfonamide hydrochloride
[0647] A mixture of tert-butyl
(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-difluoro-2-[(3'-fluoro[1,1'-bipheny-
l]-3-yl)methyl]pyrrolidine-1-carboxylate (100 mg) and 4 M HCl/CPME
solution (5 mL) was stirred overnight at room temperature. The
mixture was concentrated under reduced pressure to give the title
compound (86 mg).
[0648] MS: [M+H].sup.+ 399.0.
C)
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-[(2-
R)-oxolane-2-carbonyl]pyrrolidin-3-yl}ethanesulfonamide
[0649] HATU (22.7 mg) was added to a solution of
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolid-
in-3-yl}ethanesulfonamide hydrochloride (20 mg),
(R)-tetrahydrofuran-2-carboxylic acid (6.94 mg) and TEA (0.032 mL)
in DMF (1 mL) at room temperature. The mixture was stirred at room
temperature under a dry atmosphere for 30 min. The mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution
at room temperature and extracted with EtOAc. The organic layer was
separated, washed with saturated brine, dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by column chromatography (NH silica gel, eluted with
EtOAc/hexane) to give the title compound (18.0 mg).
[0650] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 1.03-2.06 (7H,
m), 2.66-3.14 (4H, m), 3.41-4.74 (7H, m), 7.10-7.74 (8H, m),
8.07-8.31 (1H, m).
Example 91
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
A)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-((2R)-oxe-
tane-2-carbonyl)pyrrolidin-3-yl]methanesulfonamide
[0651] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}methanesulfonamide hydrochloride (188 mg), oxetane-2-carboxylic
acid (60.7 mg), TEA (251 mg) and DMF (4 mL) was added HATU (283 mg)
at room temperature. The mixture was stirred at room temperature
for 6 hr, to the mixture was added water, and the mixture was
extracted with EtOAc. The organic layer was separated, washed with
saturated aqueous sodium hydrogen carbonate solution, water and
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane), and then silica
gel column chromatography (NH, EtOAc/hexane), and then HPLC
(column: L-Column2 ODS (3.0 mmI.D..times.50 mm, 3 .mu.m), mobile
phase: water/CH.sub.3CN (containing 5 mM ammonium acetate)) to give
the title compound (65.2 mg) with shorter retention time.
[0652] MS: [M+H].sup.+ 426.9.
B)
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,3',5'-trifluo-
ro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0653] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-((2R)-oxeta-
ne-2-carbonyl)pyrrolidin-3-yl]methanesulfonamide (30 mg),
(3,5-difluorophenyl)boronic acid (22.2 mg), XPhos Pd G3 (11.9 mg),
1 M aqueous potassium phosphate solution (0.211 mL) and THF (0.5
mL) was stirred at 90.degree. C. for 4 hr. The mixture was purified
by silica gel column chromatography (NH, EtOAc/hexane), and
recrystallized from EtOAc/hexane to give the title compound (27.6
mg).
[0654] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.77-3.25 (7H, m),
3.68-3.92 (1H, m), 4.16-4.98 (5'H, m), 5.01-5.21 (2H, m), 6.76-6.87
(1H, m), 7.01-7.10 (2H, m), 7.16-7.50 (3H, m).
Example 92
N-{(2S,3R)-4,4-difluoro-1-((2S)-oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0655] HATU (43.7 mg) was added to a solution of
N-{(2S,3R)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]-
pyrrolidin-3-yl}methanesulfonamide hydrochloride (35 mg),
oxetane-2-carboxylic acid (9.3.9 mg) and TEA (0.053 mL) in DMF (0.5
mL) at room temperature. The mixture was stirred at room
temperature for 30 min, and then additional oxetane-2-carboxylic
acid (9.39 mg) was added to the mixture. The mixture was stirred at
room temperature for 30 min. The mixture was diluted with water and
extracted with EtOAc. The extract was washed with saturated aqueous
sodium hydrogen carbonate solution, water and saturated brine,
dried over magnesium sulfate, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
(silica gel, eluted with EtOAc/hexane) to give the title compound
(10.4 mg).
[0656] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.31-3.21 (7H, m),
3.77-4.66 (6H, m), 4.96-5.11 (2H, m), 6.75-6.89 (1H, m), 6.99-7.15
(2H, m), 7.17-1.47 (3H, m).
Example 94
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0657] To a mixture of
N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyrr-
olidin-3-yl}ethanesulfonamide hydrochloride (15.2 mg), DIPEA (21.7
mg) and THF (0.5 mL) was added 2-methylpropanoyl chloride (5.36 mg)
at room temperature. The mixture was stirred overnight at room
temperature, to the mixture was added saturated aqueous sodium
hydrogen carbonate solution, and the mixture was extracted with
EtOAc. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified, by silica gel
column chromatography (EtOAc/hexane) to give the title compound
(13.6 mg).
[0658] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.17-0.92 (6H,
m), 1.22-1.35 (3H, m), 1.79-2.48 (1H, m), 2.60-2.77 (1H, m),
2.97-3.24 (3H, m), 3.70-4.22 (2H, m), 4.35-4.93 (2H, m), 7.03-7.65
(7H, m), 8.01-8.45 (1H, m).
Example 97
N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-met-
hylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0659] HATU (20.46 mg) was added to a solution of
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolid-
in-3-yl}ethanesulfonamide hydrochloride (18 mg), isobutyric acid
(5.47 mg) and TEA (0.029 mL) in DMF (0.5 mL) at room temperature.
The mixture was stirred at room temperature under a dry atmosphere
for 30 min. The mixture was quenched with saturated aqueous sodium
hydrogen carbonate solution at room temperature and extracted with.
EtOAc. The organic layer was separated, washed with saturated
brine, dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography (NH
silica gel, eluted with EtOAc/hexane) to give the title compound
(12.0 mg).
[0660] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.11-1.38 (9H,
m), 1.75-2.04 (1H, m), 2.52-2.92 (2H, m), 2.96-3.12 (1H, m),
3.15-3.24 (1H, m), 3.81-4.22 (2H, m), 4.35-4.65 (2H, m), 7.12-7.79
(8H, m), 8.10-8.30 (1H, m).
Example 98
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0661] To a solution of
N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoropyrr-
olidin-3-yl}methanesulfonamide hydrochloride (20 mg) and isobutyric
acid (3.95 .mu.L) in DMF (0.5 mL) were added HATU (26.0 mg) and
DIPEA (0.032 mL) at room temperature. The mixture was stirred at
room temperature for 1 h. The mixture was quenched with saturated
aqueous sodium hydrogen carbonate solution and extracted with
EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (NH silica gel, eluted with EtOAc/hexane) to give
the title compound (16 mg).
[0662] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.17-0.92 (6H,
m), 1.11-1.94 (1H, m), 2.58-3.22 (5H, m), 3.65-4.26 (2H, m),
4.36-4.89 (2H, m), 7.06-7.57 (7H, m), 8.13-8.34 (1H, m).
Example 106
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-meth-
ylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0663] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyrrolid-
in-3-yl)ethanesulfonamide hydrochloride (30 mg) and isobutyric acid
(7.29 mg) in DMF (0.5 mL) were added HATU (39.3 mg) and DIPEA
(0.048 mL) at room temperature. The mixture was stirred at room
temperature for 1 h. The mixture was quenched with saturated
aqueous sodium hydrogen carbonate solution and extracted with
EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The residue was purified by column
chromatography (NH silica gel, eluted with EtOAc/hexane) to give
the title compound (29.0 mg).
[0664] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.16-0.94 (6H,
m), 1.19-1.95 (4H, m), 2.59-2.80 (1H, m), 2.97-3.25 (3H, m),
3.65-4.21 (2H, m), 4.33-4.89 (2H, m), 7.05-7.55 (8H, m), 8.03-8.43
(1H, m).
Example 116
N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
A)
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(2-methylpropanoyl-
)pyrrolidin-3-yl]ethanesulfonamide
[0665] To a solution of
N-{(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}ethanes-
ulfonamide hydrochloride (128 mg) and isobutyric acid (0.038 mL) in
DMF (5 mL) were added HATU (195 mg) and DIPEA (0.238 mL) at room
temperature. The mixture was stirred overnight at room temperature.
The mixture was quenched with aqueous saturated ammonium chloride
solution and extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (NH silica gel, eluted with EtOAc/hexane)
to give the title compound (108 mg).
[0666] MS: [M+H].sup.+ 409.0.
B)
N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro--
1-(2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0667] A mixture of
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(2-methylpropanoyl)p-
yrrolidin-3-yl]ethanesulfonamide (17 mg),
(3,5-difluorophenyl)boronic acid (13.1 mg), XPhos Pd G3 (3.52 mg)
and 1 M aqueous potassium phosphate solution-(0.125 mL) in DME (1
mL) was stirred overnight at 80.degree. C. After cooling back to
room temperature, the solution was diluted with EtOAc and dried
over sodium sulfate. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography (silica
gel, eluted with EtOAc/hexane) to give the title, compound (18.2
mg).
[0668] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.12-0.98 (6H,
m), 1.03-1.88 (4H, m), 2.53-3.24 (4H, m), 3.81-4.23 (2H, m),
4.36-4.63 (2H, m), 7.16-7.78 (7H, m), 8.12-8.32 (1H, m).
Example 121
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,2',3'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0669] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-((2R)-oxeta-
ne-2-carbonyl)pyrrolidin-3-yl]methanesulfonamide (17 mg),
(2,3-difluorophenyl)boronic acid (12.6 mg), XPhos Pd G3 (6.74 mg)
and 1 M aqueous potassium phosphate solution (0.119 mL) in THF (0.5
mL) was stirred at 90.degree. C. in sealed tube for 1 h. The
mixture was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (15.3 mg).
[0670] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.67-3.30 (7H, m),
3.67-3.93 (1H, m), 4.18-5.20 (7H, m), 7.06-7.49 (6H, m).
Example 122
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-carbonyl)-2-[(2,2',5'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0671] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-((2R)-oxeta-
ne-2-carbonyl)pyrrolidin-3-yl]methanesulfonamide (17 mg),
(2,5-difluorophenyl)boronic acid (12.6 mg), XPhos Pd G3 (6.74 mg)
and 1 M aqueous potassium phosphate solution (0.119 mL) in THF (0.5
mL) was stirred at 90.degree. C. in sealed tube for 1 h. The
mixture was directly purified by column chromatography (NH silica
gel, eluted with EtOAc/hexane) to give the title compound (10.9
mg).
[0672] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.66-3.32 (7H, m),
3.64-3.91 (1H, m), 4.17-5.21 (7H, m), 6.99-7.17 (3H, m), 7.17-7.30
(2H, m), 7.32-7.49 (1H, m).
Example 124
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(oxetan-
e-2-carbonyl)pyrrolidin-3-yl]cyclopropanesulfonamide with Shorter
Retention Time
A) tert-butyl
(2S,3R)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro[1,1'-bi-
phenyl]-3-yl)methyl]pyrrolidine-1-carboxylate
[0673] Cyclopropanesulfonyl chloride (0.081 mL) was added to a
stirred solution of tert-butyl
(2S,3R)-3-amino-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate (130 mg) and TEA (0.178 mL) in THF (2 mL) at
room temperature. The mixture was stirred at the same temperature
overnight, heated up to at 70.degree. C. and stirred for 1 h.
Additional cyclopropanesulfonyl chloride (0.081 mL) and TEA (0.178
mL) were added to the mixture, and the mixture was stirred
overnight at 70.degree. C. The reaction mixture was purified by
column chromatography on silica gel (eluted with EtOAc/hexane) to
give the title compound (130 mg).
[0674] MS, found: 411.1.
B)
N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrroli-
din-3-yl}cyclopropanesulfonamide hydrochloride
[0675] A mixture of tert-butyl
(2S,3R)-3-[(cyclopropanesulfonyl)amino]-4,4-difluoro-2-[(2-fluoro[1,1'-bi-
phenyl]-3-yl)methyl]pyrrolidine-1-carboxylate (186 mg) and 4 M
HCl/CPME solution (4.0 mL) was stirred overnight at room
temperature, and concentrated under reduced pressure to give the
title compound (150 mg).
[0676] MS: [M+H].sup.+ 411.1.
C)
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(oxe-
tane-2-carbonyl)pyrrolidin-3-yl]cyclopropanesulfonamide with
Shorter Retention Time
[0677] To a mixture of
N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidi-
n-3-yl}cyclopropanesulfonamide hydrochloride (80.0 mg),
oxetane-2-carboxylic acid (29.3 mg), HATU (117 mg) and DMF (2.0 mL)
was added DIPEA (0.200 mL) at room temperature. The mixture was
stirred at room temperature for 1 h. To the mixture was added
saturated aqueous sodium hydrogen carbonate solution, and the
mixture was extracted with EtOAc/hexane. The organic layer was
separated, washed with water and saturated brine, dried over sodium
sulfate and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, eluted with
EtOAc/hexane, then NH silica gel, eluted with EtOAc/hexane) to give
the title compound (21.2 mg).
[0678] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.90-1.08 (3H,
m), 1.21-1.33 (1H, m), 2.24-2.38 (1H, m), 2.54-2.81 (3H, m),
3.01-3.15 (1H, m), 3.70-5.22 (7H, m), 7.07-7.58 (8H, m), 8.05-8.42
(1H, m).
Example 129
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(o-
xetane-2-carbonyl)pyrrolidin-3-yl]cyclopropanesulfonamide with
Shorter Retention Time
A) tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(cyclopropanesulfonyl)amin-
o]-4,4-difluoropyrrolidine-1-carboxylate
[0679] To a mixture of tert-butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate (100 mg), TEA (83 mg) and THF (3 mL) was added
cyclopropanesulfonyl chloride (96 mg) at room temperature. The
mixture was stirred overnight at 70.degree. C., and purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (75 mg).
[0680] MS: [M-H].sup.- 467.0.
B)
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-
-yl}cyclopropanesulfonamide hydrochloride
[0681] A mixture of tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(cyclopropanesulfonyl)amin-
o]-4,4-difluoropyrrolidine-1-carboxylate (328 mg) and 4 M hydrogen
chloride CPME solution (6 mL) was stirred at room temperature for 4
hr. The insoluble substance was collected by filtration to give the
title compound (240 mg).
[0682] MS, found: 369.0.
C)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl.]-4,4-difluoro-1-(oxetane-
-2-carbonyl)pyrrolidin-3-yl]cyclopropanesulfonamide with Shorter
Retention Time (Obtained by HPLC (Column: L-Column2 ODS (3.0
mmI.D..times.50 mm, 3 .mu.m), Mobile Phase: Water/CH.sub.3CN
(Containing 5 mM Ammonium Acetate)))
[0683] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}cyclopropanesulfonamide hydrochloride (35 mg),
oxetane-2-carboxylic acid (13.2 mg) and DMF (1.5 mL) were added
HATU (49.3 mg) and DIPEA (44.6 mg) at room temperature. The mixture
was stirred overnight at room temperature, to the mixture was added
saturated aqueous ammonium chloride solution, and the mixture was
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (11 mg).
[0684] MS: [M+H].sup.+ 453.1.
D)
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-
-(oxetane-2-carbonyl)pyrrolidin-3-yl]cyclopropanesulfonamide with
Shorter Retention Time
[0685] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(oxetane-2--
carbonyl)pyrrolidin-3-yl]cyclopropanesulfonamide (10 mg) with
shorter retention time (obtained by HPLC (column: L-Column2 ODS
(3.0 mmI.D..times.50 mm, 3 .mu.m), mobile phase: water/CH.sub.3CN
(containing 5 mM ammonium acetate))), (3-fluorophenyl)boronic acid
(6.18 mg), Xphos Pd G3 (1.87 mg), 1 M aqueous potassium phosphate
solution (0.066 mL) and DME (0.5 mL) was stirred overnight at
80.degree. C. The mixture was cooled to room temperature, and EtOAc
was added thereto. The mixture was dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (NH, EtOAc/hexane) to
give the title compound (3.6 mg).
[0686] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.91-1.21 (4H, m),
2.15-2.43 (1H, m), 2.71-3.04 (3H, m), 3.08-3.26 (1H, m), 3.68-3.88
(1H, m), 4.16-5.18 (7H, m), 7.03-7.25 (3H, m), 7.27-7.44 (4H,
m).
Example 131
N-[(2S,3R)-2-[(2',3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(-
2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
A)
N-{(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}metha-
nesulfonamide hydrochloride
[0687] A mixture of tert-butyl
(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-3-[(methanesulfonyl)amino-
]pyrrolidine-1-carboxylate (187 mg) and 4 M HCl/CPME solution (5
mL) was stirred at room temperature for 2 h. The solid was
collected by filtration to give the title compound (145 mg).
[0688] MS: [M+H].sup.+ 325.0.
B)
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(2-methylpropanoyl-
)pyrrolidin-3-yl]methanesulfonamide
[0689] To a solution of
N-{(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoropyrrolidin-3-yl}methane-
sulfonamide hydrochloride (51.1 mg) and isobutyric acid (0.020 mL)
in DMF (2 mL) were added HATU (81 mg) and DIPEA (0.099 ml) at room
temperature. The mixture was stirred overnight at room temperature.
The mixture was quenched with aqueous saturated ammonium chloride
solution and extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (53.0 mg).
[0690] MS: [M+H].sup.+ 395.0.
C)
N-[(2S,3R)-2-[(2',3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro--
1-(2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0691] A mixture of
N-[(2S,3R)-2-[(3-chlorophenyl)methyl]-4,4-difluoro-1-(2-methylpropanoyl)p-
yrrolidin-3-yl]methanesulfonamide (14.5 mg),
(2,3-difluorophenyl)boronic acid (11.6 mg), XPhos Pd G3 (3.11 mg)
and 1 M aqueous potassium phosphate solution (0.110 mL) in DME (0.5
mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography (NH silica
gel, eluted with EtOAc/hexane) to give the title compound (17.1
mg).
[0692] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 0.16-0.98 (6H,
m), 1.78-2.36 (1H, m), 2.54-3.13 (5H, m), 3.75-4.72 (4H, m),
7.26-7.64 (7H, m), 8.10-8.36 (1H, m).
Example 133
N-{(2S,3R)-4,4-difluoro-1-((2S)-oxetane-2-carbonyl)-2-[(2,2',3'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
A)
N-((2S,3R)-2-(3-chloro-2-fluorobenzyl)-4,4-difluoro-1-((2S)-oxetane-2-c-
arbonyl)pyrrolidin-3-yl)methanesulfonamide
[0693] HATU (283 mg) was added to a solution of
N-((2S,3R)-2-(3-chloro-2-fluorobenzyl)-4,4-difluoropyrrolidin-3-yl)methan-
esulfonamide hydrochloride (188 mg), oxetane-2-carboxylic acid
(60.7 mg) and TEA (0.345 ml) in DMF (4 mL) at room temperature. The
mixture was stirred at room temperature for 6 h. The mixture was
diluted with water and extracted with EtOAc. The extract was washed
with saturated aqueous sodium hydrogen carbonate solution, water
and saturated brine, dried over magnesium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, eluted with EtOAc/hexane, then
NH silica gel, eluted with EtOAc/hexane) to give the title compound
(84.5 mg).
[0694] MS: [M+H].sup.+ 426.9
B)
N-{(2S,3R)-4,4-difluoro-1-((2S)-oxetane-2-carbonyl)-2-[(2,2',3'-trifluo-
ro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0695] A mixture of
N-((2S,3R)-2-(3-chloro-2-fluorobenzyl)-4,4-difluoro-1-((2S)-oxetane-2-car-
bonyl)pyrrolidin-3-yl)methanesulfonamide (20 mg),
(2,3-difluorophenyl)boronic acid (14.8 mg), XPhos Pd G3 (7.93 mg)
and 1 M aqueous potassium phosphate solution (0.141 mL) in THF (0.5
mL) was stirred at 90.degree. C. in sealed tube for 1 h. The
mixture was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (10.1 mg).
[0696] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.31-3.22 (7H, m),
3.77-3.94 (1H, m), 4.01-4.20 (1H, m), 4.24-5.17 (6H, m), 7.06-7.48
(6H, m).
Example 144
N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
A)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-
-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide
[0697] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}ethanesulfonamide hydrochloride (146 mg), cyclopropanecarboxylic
acid (47.8 mg) and DMF (4 mL) were added
[0698] HATU (211 mg) and DIPEA (191 mg) at room temperature. The
mixture was stirred overnight at room temperature, to the mixture
was added saturated aqueous ammonium chloride solution, and the
mixture was extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (NH, EtOAc/hexane) to
give the title compound (144 mg).
[0699] MS: [M-H].sup.- 423.0.
B)
N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-difluoro-2-[(2,3',5'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0700] To a mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]ethanesulfonamide (16.0 mg),
(3,5-difluorophenyl)boronic acid (12.0 mg), 1 M aqueous potassium
phosphate solution (0.116 mL) and DME (0.500 mL) was added XPhos Pd
G3 (3.2 mg) at room temperature. The mixture was stirred overnight
under nitrogen atmosphere at 90.degree. C., and purified by silica
gel column chromatography (NH, EtOAc/hexane) to give the title
compound (15.0 mg).
[0701] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.43-1.49 (8H, m),
2.85-5.03 (9H, m), 6.72-7.61 (6H, m).
Example 145
N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(1-hyd-
roxycyclobutane-1-carbonyl)pyrrolidin-3-yl]-N,N-dimethylsulfuric
diamide
A) tert-butyl
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro[1,1'-biphe-
nyl]-3-yl)methyl]pyrrolidine-1-carboxylate
[0702] A mixture of dimethylsulfamoyl chloride (3 mL), tert-butyl
(2S,3R)-3-amino-4,4-difluoro-2-((2-fluoro-[1,1'-biphenyl]-3-yl)methyl)pyr-
rolidine-1-carboxylate (400 me) and DMAP (240 mg) was stirred
overnight at 50.degree. C. under nitrogen atmosphere. The reaction
mixture was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (500 mg).
[0703] MS: [M-H].sup.- 512.1.
B)
N'-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrol-
idin-3-yl}-N,N-dimethylsulfuric diamide hydrochloride
[0704] A mixture of 4 M HCl/CPME solution (12.2 mL) and tert-butyl
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro[1,1'-biphe-
nyl]-3-yl)methyl]pyrrolidine-1-carboxylate (500 mg) was stirred
overnight at 45.degree. C. under nitrogen atmosphere. The reaction
mixture was concentrated, and the solids were washed with EtOAc and
filtered to afford the title compound (435 mg).
[0705] MS: [M+H].sup.+ 414.0.
C)
N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(1--
hydroxycyclobutane-1-carbonyl)pyrrolidin-3-yl]-N,N-dimethylsulfuric
diamide
[0706] To a solution of
N'-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolid-
in-3-yl}-N,N-dimethylsulfuric diamide hydrochloride (20 mg),
1-hydroxy-cyclobutanecarboxylic acid (5.16 mg) and DIPEA (7.76
.mu.L) in DMF (1 mL) was added HATU (16.9 mg) at room temperature.
The mixture was stirred overnight at room temperature. The mixture
was quenched with saturated aqueous sodium hydrogen carbonate
solution and extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (NH silica gel, eluted with EtOAc/hexane)
to give the title compound (12.7 mg).
[0707] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.40-1.59 (1H, m),
1.74-1.91 (1H, m), 1.92-2.08 (2H, m), 2.47-2.60 (2H, m), 2.69-2.75
(6H, m), 2.89-3.02 (2H, m), 3.06-3.22 (1H, m), 3.90-4.07 (1H, m),
4.08-4.22, (1H, m), 4.22-4.43 (1H, m), 5.04 (2H, brs), 7.10-7.19
(1H, m), 7.24-7.38 (3H, m), 7.39-7.45 (2H, m), 7.48-7.53 (2H,
m).
Example 146
N-{(2S,3R)-4,4-difluoro-1-(2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-b-
iphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
A)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-methyl-
propanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0708] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}ethanesulfonamide hydrochloride (47.9 mg), isobutyric acid (20.2
mg), DIPEA (0.080 mL) and DMF (0.80 mL) was added HATU (96.2 mg) at
room temperature. The mixture was stirred overnight at room
temperature. The mixture was diluted with saturated aqueous sodium
hydrogen carbonate solution and extracted with EtOAc. The organic
layer was separated, washed with water and saturated brine, dried
over sodium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (44.6 mg).
[0709] MS: [M+H].sup.+ 427.0.
B)
N-{(2S,3R)-4,4-difluoro-1-(2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0710] To a mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-methylpr-
opanoyl)pyrrolidin-3-yl]ethanesulfonamide (15.9 mg),
(3,5-difluorophenyl)boronic acid (12.0 mg), 1 M aqueous potassium
phosphate solution (0.100 mL) and DME (0.300 mL) was added XPhos Pd
G3 (3.0 mg) at room temperature. The mixture was stirred overnight
at 90.degree. C. under nitrogen atmosphere. The mixture was
purified by column chromatography (NH silica gel, eluted with
EtOAc/hexane) to give the title compound (13.4 mg).
[0711] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.52 (1H, d, J=6.4
Hz), 0.85-1.49 (8H, m), 1.82-5.09 (10H, m), 6.75-7.55 (6H, m).
Example 147
N-{(2S,3R)-4,4-difluoro-1-(2-methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-b-
iphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0712] To a mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(2-methylpr-
opanoyl)pyrrolidin-3-yl]ethanesulfonamide (14.5 mg),
(2,5-difluorophenyl)boronic acid (10.0 mg), 1 M aqueous potassium
phosphate solution (0.100 mL) and DME (0.300 mL) was added XPhos Pd
G3 (3.0 mg) at room temperature. The mixture was stirred overnight
under nitrogen atmosphere at 90.degree. C. Additionally, to the
mixture were added (2,5-difluorophenyl)boronic acid (10.0 mg) and
XPhos Pd G3 (3.0 mg) at room temperature. The mixture was stirred
at 120.degree. C. for 20 min under microwave irradiation. The
mixture was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (9.70 mg).
[0713] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.53 (1H, d, J=6.5
Hz), 0.83-1.48 (8H, m), 1.90-5.01 (10H, m), 6.98-7.55 (6H, m).
Example 171
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(2-meth-
ylpropanoyl)pyrrolidin-3-yl]cyclopropanesulfonamide
[0714] To a mixture of
N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidi-
n-3-yl}cyclopropanesulfonamide hydrochloride (44.3 mg), isobutyric
acid (15 .mu.L), DIPEA (50 .mu.L) and DMF (0.80 mL) was added HATU
(60.0 mg) at room temperature. The mixture was stirred at room
temperature for 3 days. To the mixture was added saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by column chromatography
(NH silica gel, eluted with EtOAc/hexane) to give the title
compound (30.6 mg).
[0715] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.52 (1H, d, J=6.5
Hz), 0.76-1.39 (9H, m), 1.84-5.16 (9H, m), 6.98-7.54 (8H, m).
Example 202
N-{(2S,3R)-1-(cyclopropanecarbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)-
methyl]-4,4-difluoropyrrolidin-3-yl}ethanesulfonamide
[0716] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]ethanesulfonamide (15 mg),
(3-fluorophenyl)boronic acid (9.88 mg), XPhos Pd G3 (2.99 mg) and 1
M aqueous potassium phosphate solution (0.106 mL) in DME (1 mL) was
stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (17.1 mg).
[0717] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.05-1.49 (8H, m),
2.86-5.01 (9H, m), 7.04-7.44 (7H, m).
Example 205
N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-difluoro-2-[(2-fluoro[1,1'-bipheny-
l]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0718] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]ethanesulfonamide (13 mg), phenylboronic
acid (7.46 mg), XPhos Pd G3 (2.59 mg) and 1 M aqueous potassium
phosphate solution (0.092 mL) in DME (1 mL) was stirred at
80.degree. C. for 2 h. After cooling back to room temperature, the
solvent was removed under reduced pressure, and the residue was
purified by column chromatography (NH silica gel, eluted with
EtOAc/hexane) to give the title compound (4.90 mg).
[0719] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. -0.13-0.18 (2H,
m), 0.49-1.48 (6H, m), 2.83-4.97 (9H, m), 7.15-7.54 (8H, m).
Example 210
(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(ethanesulfony-
l)amino]-4-fluoro-N,N-dimethylpyrrolidine-1-carboxamide
A) tert-butyl
2-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrrole-1-carboxylate
[0720] To a mixture of 1-(bromomethyl)-3-chloro-2-fluorobenzene
(40.0 g), (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)boronic acid
(49.1 g), 1 M aqueous potassium phosphate solution (537 mL) and THF
(900 mL) was added PdCl.sub.2(dppf) (2.62 g) under argon atmosphere
at room temperature. The mixture was refluxed for 16 hr, poured
into ice water, and extracted with EtOAc. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane) to give the title compound (54.7
g).
[0721] MS: [M-H].sup.- 308.0.
B) 2-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrrole
[0722] To a mixture of tert-butyl
2-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrrole-1-carboxylate (54.7
g) and MeOH (250 ml) was added 28% sodium methoxide methanol
solution (170 g) under argon atmosphere at room temperature. The
mixture was stirred at room temperature for 5 hr, and the reaction
mixture was added to aqueous ammonium chloride, solution under ice
cooling, and extracted with EtOAc. The organic layer was separated,
washed with water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
the title compound (35.9 g).
[0723] MS: [M+H].sup.+ 209.9.
C) benzyl
2-[(3-chloro-2-fluorophenyl)methyl]-2,5-dihydro-1H-pyrrole-1-car-
boxylate
[0724] To a mixture of
2-[(3-chloro-2-fluorophenyl)methyl]-1H-pyrrole (35.9 g), zinc (112
g) and EtOH (500 mL) was added dropwise cone, hydrochloric acid
(171 mL) at 85.degree. C. The mixture was stirred at 85.degree. C.
for 30 min, and the reaction mixture was poured into ice water, and
basified with 8 M aqueous sodium hydroxide solution (pH=8). The
insoluble substance was removed by filtration, and the filtrate was
extracted with EtOAc/THF. The organic layer was separated, washed
with saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. To a mixture of the obtained
residue, THF (400 mL) and water (400 mL) were added sodium hydrogen
carbonate (21.6 g) and
1-(((benzyloxy)carbonyl)oxy)pyrrolidine-2,5-dione (44.8 g) at room
temperature. The mixture was stirred at room temperature for 15 hr,
and the reaction mixture was poured into water, and extracted with
EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane), and then silica
gel column chromatography (NH, EtOAc/hexane) to give the title
compound (25.7 g).
[0725] MS: [M+H].sup.+ 346.0.
D) rac-benzyl
(1S,2S,5R)-2-[(3-chloro-2-fluorophenyl)methyl]-6-oxa-3-azabicyclo[3.1.0]h-
exane-3-carboxylate
[0726] To a mixture of benzyl
2-[(3-chloro-2-fluorophenyl)methyl]-2,5-dihydro-1H-pyrrole-1-carboxylate
(25.7 g), 1,1,1-trifluoroacetone (70.3 g), sodium
2,2'-((2-(bis(carboxymethyl)amino)ethyl)imino)diacetate dihydrate
(0.055 g) and CH.sub.3CN (180 mL)/water (120 mL) were added
potassium peroxymonosulfate (137 g) and sodium hydrogen carbonate
(94 g) over 35 min at 0.degree. C. The mixture was vigorously
stirred at 0.degree. C. for 2 hr 30 min, poured into ice water, and
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (EtOAc/hexane), and then silica
gel column chromatography (NH, EtOAc/hexane) to give the title
compound (24.6 g).
[0727] MS: [M+H].sup.+ 362.0.
E) rac-benzyl
(2S,3S,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-hydroxypyrrolid-
ine-1-carboxylate
[0728] A mixture of rac-benzyl
(1S,2S,5R)-2-[(3-chloro-2-fluorophenyl)methyl]-6-oxa-3-azabicyclo[3.1.0]h-
exane-3-carboxylate (24.0 g) and N,N-diethylethanamine
trihydrofluoride (64.1 g) was stirred at 120.degree. C. for 17 hr.
The mixture was poured into ice water, and extracted with EtOAc.
The organic layer was separated, washed with aqueous sodium
hydrogen carbonate solution and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane) to give the title compound (24.2
g).
[0729] MS: [M+H].sup.+ 382.0.
F) rac-benzyl
(2S,3S,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-[(trifluorometh-
anesulfonyl)oxy]pyrrolidine-1-carboxylate
[0730] To a mixture of rac-benzyl
(2S,3S,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-hydroxypyrrolid-
ine-1-carboxylate (24.2 g), pyridine (100 g) and Et.sub.2O (370 mL)
was added dropwise trifluoromethanesulfonic anhydride (53.6 g)
under argon atmosphere at 0.degree. C. The mixture was stirred at
room temperature for 2 hr 30 min, poured into ice water, and
extracted with EtOAc. The organic layer was separated, washed
successively with 10% aqueous citric acid solution, aqueous sodium
hydrogen carbonate solution and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane) to give the title compound (29.0
g).
[0731] MS: [M+H].sup.+ 514.0.
G) rac-benzyl
(2S,3R,4S)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-
e-1-carboxylate
[0732] To a mixture of rac-benzyl
(2S,3S,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-[(trifluorometh-
anesulfonyl)oxy]pyrrolidine-1-carboxylate (29.0 g) and CH.sub.3CN
(335 mL) was added tetra-n-butylammonium azide (48.2 g) at room
temperature. The mixture was stirred at 80.degree. C. for 1 hr,
poured into ice water, and extracted with EtOAc. The organic layer
was separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (EtOAc/hexane) to give the title compound (22.2
g).
[0733] MS: [M+H].sup.+ 407.0.
H) rac-benzyl
(2S,3R,4S)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-
e-1-carboxylate
[0734] To a mixture of rac-benzyl
(2S,3R,4S)-3-azido-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-
e-1-carboxylate (2.17 g) and THF (42.7 mL)/water (10.7 mL) was
added triphenylphosphine (1.68 g) at room temperature. The mixture
was stirred at 50.degree. C. for 15 hr, to the mixture was added
saturated brine at room temperature, and the mixture was extracted
with EtOAc. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (methanol/EtOAc) to give the title compound
(1.74 g).
[0735] MS: [M+H].sup.+ 381.0.
I) benzyl
(2S,3R,4S)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluorop-
yrrolidine-1-carboxylate
[0736] rac-Benzyl
(2S,3R,4S)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-
e-1-carboxylate (668 mg) was resolved by HPLC (column: CHIRALPAK
ID, 50 mmID.times.500 mmL, 20 .mu.m, mobile phase:
hexane/2-propanol/diethylamine=600/400/1) to give the title
compound (251 mg) with longer retention time.
[0737] MS: [M+H].sup.+ 381.1.
J) benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfony-
l)amino]-4-fluoropyrrolidine-1-carboxylate
[0738] To a mixture, of benzyl
(2S,3R,4S)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-
e-1-carboxylate (289 mg), TEA (189 mg) and THF (4.0 mL) was added
ethanesulfonyl chloride (190 mg) at 0.degree. C. The mixture was
stirred at room temperature for 2 hr, to the mixture was added
water, and the mixture was extracted with EtOAc. The organic layer
was separated, washed with water and saturated brine, dried over
anhydrous sodium sulfate, and concentrated Under reduced pressure.
The residue was purified by silica gel column chromatography
(EtOAc/hexane) to give the title compound (295 mg).
[0739] MS: [M+H].sup.+ 473.0.
K) benzyl
(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(eth-
anesulfonyl)amino]-4-fluoropyrrolidine-1-carboxylate
[0740] To a mixture of benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]--
4-fluoropyrrolidine-1-carboxylate (340 mg), (3-fluorophenyl)boronic
acid (150 mg), XPhos Pd G3 (30.9 mg) and DME (4.0 ml) was added 1 M
aqueous potassium phosphate solution (1.2 mL) at room temperature,
and the mixture was stirred under nitrogen atmosphere at 90.degree.
C. for 2 hr. To the reaction mixture were added 1 M aqueous
potassium phosphate solution (0.4 mL), (3-fluorophenyl)boronic acid
(50.5 mg) and XPhos Pd G3 (15.2 mg) at 90.degree. C. The mixture
was stirred under nitrogen atmosphere at 90.degree. C. for 1 hr, to
the reaction mixture was added water, and the mixture was extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (250 mg).
[0741] MS: [M+H].sup.+ 533.2.
L)
N-{(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluoropyr-
rolidin-3-yl}ethanesulfonamide
[0742] A mixture of benzyl
(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(ethanesulfon-
yl)amino]-4-fluoropyrrolidine-1-carboxylate (240 mg), 10% palladium
on carbon (24.0 mg) and MeOH (5.0 mL)/THF (3.0 mL) was stirred
overnight under normal pressure of hydrogen atmosphere at room
temperature. The catalyst was removed by filtration, and the
filtrate was concentrated under reduced pressure to give the title
compound (178 mg).
[0743] MS: [M+H].sup.+ 399.0.
M)
(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(ethanesulf-
onyl)amino]-4-fluoro-N,N-dimethylpyrrolidine-1-carboxamide
[0744] To a mixture of N-{(2S,3R,4S)-2-[(2-,
3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluoropyrrolidin-3-yl}ethanesul-
fonamide (10.0 mg), DIPEA (22.2 mg) and THF (0.200 mL) was added
dimethylcarbamoyl chloride (11.7 mg) at 0.degree. C. The mixture
was stirred at room temperature for 3 hr, and the reaction solution
was dried by blowing of nitrogen. The residue was purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (6.7 mg).
[0745] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.81-1.44 (3H, m),
2.59-4.17 (13H, m), 4.73-4.90 (2H, m), 5.06-5.27 (1H, m), 6.98-7.53
(7H, m).
Example 211
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-3--
yl)methyl]-4-fluoropyrrolidin-3-yl}ethanesulfonamide
[0746] To a mixture of
N-{(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluoropyrro-
lidin-3-yl}ethanesulfonamide (8.9 mg), bis(trichloromethyl)
carbonate (4.0 mg) and THF (0.200 mL) was added DIPEA (7.40 mg) at
0.degree. C. The mixture was stirred at 0.degree. C. for 30 min,
and the reaction solution was concentrated under reduced pressure.
The obtained residue was diluted with THF (0.200 mL), azetidine
(3.83 mg) was added thereto at room temperature, and the mixture
was stirred at room temperature for 1 hr. The mixture was dried by
blowing of nitrogen, and the residue was purified by silica gel
column chromatography (EtOAc/hexane) to give the title compound
(4.8 mg).
[0747] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.81-1.35 (3H, m),
2.06-2.16 (2H, m), 2.85-4.23 (11H, m), 4.64-5.29 (3H, m), 6.98-7.54
(7H, m).
Example 212
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-3--
yl)methyl]-4-fluoropyrrolidin-3-yl}ethanesulfonamide
[0748] To a mixture of
N-{(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluoropyrro-
lidin-3-yl}ethanesulfonamide (11.6 mg), cyclopropanecarboxylic acid
(4.6 mg), DIPEA (11.8 mg) and DMF (0.200 mL) was added HATU (20.5
mg), at room temperature. The mixture was stirred overnight at room
temperature, to the mixture was added water, and the mixture was
extracted with EtOAc. The organic layer was dried by blowing of
nitrogen. The residue was purified by silica gel column
chromatography (EtOAc/hexane) to give the title compound (8.4
mg).
[0749] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.05-1.47 (7H, m),
2.64-5.43 (11H, m), 6.98-7.54 (7H, m).
Example 220
N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluo-
ro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
A)
N-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3--
yl}ethanesulfonamide hydrobromide
[0750] To benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]--
4-fluoropyrrolidine-1-carboxylate (78 mg) was added 30% hydrogen
bromide-acetic acid solution (0.8 mL) at room temperature. The
mixture was stirred at room temperature for 1 hr, and the reaction
solution was concentrated under reduced pressure. The obtained
residue was subjected to azeotrope with toluene, and suspended in
IPE, and the insoluble substance was collected by filtration to
give the title compound (65 mg).
[0751] MS, found: 338.9.
B)
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-1-(2-hydroxy-
-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0752] To a mixture of
N-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl-
}ethanesulfonamide hydrobromide (65 mg), DIPEA (60.0 mg) and THF
(0.8 mL) was added 1-chloro-2-methyl-1-oxopropan-2-yl acetate (30.6
mg) at 0.degree. C. The mixture was stirred at the same temperature
for 1 hr, and water (0.4 mL) and 4 M aqueous lithium hydroxide
solution (0.387 mL) were added thereto at 0.degree. C. The mixture
was stirred at room temperature for 1 hr, to the mixture was added
water, and the mixture was extracted with EtOAc. The organic layer
was separated, washed with saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
the title compound (66 mg).
[0753] MS: [M+H].sup.+ 425.0.
C)
N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trif-
luoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0754] A mixture of
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-1-(2-hydroxy-2-
-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide (22 mg),
(3,5-difluorophenyl)boronic acid (16.4 mg), XPhos Pd G3 (4.38 mg),
1 M aqueous potassium phosphate solution (0.155 mL) and DME (0.8
mL) was stirred under nitrogen atmosphere at 80.degree. C. for 1
hr. The mixture was purified by silica gel column chromatography
(EtOAc/hexane), and then silica gel column chromatography (NH,
EtOAc/hexane) to give the title compound (20.2 mg).
[0755] .sup.1H NMR (400 MHz, CDCl.sub.3) 51.20 (3H, t, J=7.0 Hz),
1.40 (6H, s), 2.85 (2H, q, J=6.9 Hz), 3.02 (0.2H, dd, J=13.4, 6.1
Hz), 3.22 (1H, dd, J=13.9, 7.8 Hz), 3.96-4.30 (3H, m), 4.75-5.02
(2H, m), 5.10-5.32 (1H, m), 6.82 (1H, t, J=8.9 Hz), 7.02-7.13 (2H,
m), 7.16-7.23 (1H, m), 7.27-7.50 (2H, m).
Example 225
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-((-
1r,3S)-3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
A)
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1r,3S)--
3-fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide
[0756] To a solution of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}ethanesulfonamide hydrochloride (0.310 g) and
3-fluorocyclobutane-1-carboxylic acid (0.128 mL) in DMF (10 mL)
were added HATU (0.450 g) and DIPEA (0.551 mL) at room temperature.
The mixture was stirred overnight at room temperature. The mixture
was quenched with aqueous saturated ammonium chloride solution and
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane),
and then purified by preparative HPLC (Column: CHIRALCEL OD-H,
mobile phase: carbon dioxide/(MeOH/diethylamine=1000/3)=850/150
(v/v) to give the title compound (177 mg) with shorter retention
time by HPLC (Column: CHIRALCEL OD-H, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=850/150 (v/v)).
[0757] MS: [M+H].sup.+ 457.1.
B)
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-
-((1r,3S)-3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
[0758] To a mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1r,3S)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (50
mg), (3-fluorophenyl)boronic acid (30.6 mg) and XPhos Pd G3 (9.26
mg) were added DME (2 mL) and 1 M aqueous potassium phosphate
solution (0.328 mL) at room temperature. The mixture was stirred at
80.degree. C. under nitrogen atmosphere for 1 h. After cooling back
to room temperature, the solvent was removed under reduced
pressure, and the residue was purified by column chromatography (NH
silica gel, eluted with EtOAc/hexane) to give the title compound
(54.1 mg).
[0759] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.29-1.48 (3H, m),
1.55-2.03 (2H, m), 2.25-3.26 (7H, m), 3.33-4.55 (4H, m), 4.88-5.24
(2H, m), 7.03-7.48 (7H, m).
Example 226
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-((-
1s,3R)-3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
A)
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1s,3R)--
3-fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide
[0760] To a solution of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-S-y-
l}ethanesulfonamide hydrochloride (0.310 g) and
3-fluorocyclobutane-1-carboxylic acid (0.128 mL) in DMF (10 mL)
were added HATU (0.450 g) and DIPEA (0.551 mL) at room temperature.
The mixture was stirred overnight at room temperature. The mixture
was quenched with aqueous saturated ammonium chloride solution and
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane),
and then purified by preparative HPLC (Column: CHIRALCEL OD-H,
mobile phase: carbon dioxide/(MeOH/diethylamine=1000/3)=850/150
(v/v) to give the title compound (134 mg) with longer retention
time by HPLC (Column: CHIRALCEL OD-H, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=850/150 (v/v)).
[0761] MS: [M+H].sup.+ 457.1.
B)
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-
-((1s,3R)-3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
[0762] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1s,3R)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (45
mg), (3-fluorophenyl)boronic acid (17.9 mg), XPhos Pd G3 (8.34 mg)
and 1 M aqueous potassium phosphate solution (0.295 mL) in DME (2
mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography (NH silica
gel, eluted with EtOAc/hexane). The residue was crystallized from
EtOAc/hexane to give the title compound (19.5 mg).
[0763] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.29-1.47 (3H, m),
1.80-3.92 (11H, m), 4.19-5.01 (4H, m), 7.02-7.46 (7H, m).
Example 236
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1,1'-
-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
A)
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbon-
yl)-4-fluoropyrrolidin-3-yl]ethanesulfonamide
[0764] A mixture of benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]--
4-fluoropyrrolidine-1-carboxylate (179 mg) and 30% hydrogen
bromide/acetic acid solution (2.0 mL) was stirred overnight at room
temperature. Toluene (20 mL) was added thereto, and the mixture was
concentrated under reduced pressure. The residue was diluted with
EtOAc, and the insoluble substance was collected by filtration, and
washed with EtOAc to give a solid. To a mixture of the obtained
solid, THF (2.0 ml) and 2M aqueous sodium hydroxide solution (0.50
ml) was added cyclopropanecarbonyl chloride (81 mg) at room
temperature. The mixture was stirred at room temperature for 30
min. To the mixture was added water, and the mixture was extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (88.2 mg).
[0765] MS: [M+H].sup.+ 407.0.
B)
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1-
,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0766] To a mixture of
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl-
)-4-fluoropyrrolidin-3-yl]ethanesulfonamide (22.0 mg),
(3,5-difluorophenyl/boronic acid (17.3 mg), 1M aqueous potassium
phosphate solution (0.130 mL) and DME (0.500 mL) was added XPhos Pd
G3 (5.0 mg) at room temperature. The mixture was stirred overnight
under nitrogen atmosphere at 90.degree. C. The mixture was purified
by silica gel column chromatography (NH, EtOAc/hexane), and
recrystallized from EtOAc/hexane to give the title compound (13.5
mg).
[0767] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.05-1.48 (7H, m),
2.68-4.30 (8H, m), 4.60-5.41 (3H, m), 6.76-7.54 (6H, m).
Example 239
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-fluoro-2-[(2-fluoro[1,1'-biphenyl-
]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0768] To a mixture of
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl-
)-4-fluoropyrrolidin-3-yl]ethanesulfonamide (22.0 mg),
phenylboronic acid (17.0 mg), 1 M aqueous potassium phosphate
solution (0.130 mL) and DME (0.500 mL) was added XPhos Pd G3 (6.0
mg) at room temperature. The mixture was stirred overnight under
nitrogen atmosphere at 90.degree. C. The mixture was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane),
then recrystallization (EtOAc/heptane) to give the title compound
(13.2 mg).
[0769] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.09-1.47 (7H, m),
2.60-4.31 (8H, m), 4.60-5.38 (3H, m), 6.98-7.57 (8H, m).
Example 245
N-[(2S,3R)-2-[(3'-chloro-2,5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-1-(cycl-
opropanecarbonyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide
A)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-
-4,4-difluoropyrrolidin-3-yl]methanesulfonamide
[0770] To a solution of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3-y-
l}methanesulfonamide hydrochloride (141 mg) and
cyclopropanecarboxylic acid (0.044 mL) in DMF (4 mL) were added
HATU (212 mg) and DIPEA (0.260 mL) at room temperature. The mixture
was stirred overnight at room temperature. The mixture was quenched
with aqueous saturated ammonium chloride solution and extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by column chromatography
(NH silica gel, eluted with EtOAc/hexane) to give the title
compound (134 mg).
[0771] MS: [M+H].sup.+ 411.0.
B)
N-[(2S,3R)-2-[(3'-chloro-2,5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-1-(c-
yclopropanecarbonyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide
[0772] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]methanesulfonamide (134 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (124
mg), XPhos Pd G3 (55.2 mg) and potassium acetate (64.0 mg) in
toluene (4 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 8 h. The reaction mixture was diluted with water and
extracted with EtOAc. The extract was washed with saturated brine,
dried over magnesium sulfate, filtered and concentrated under
reduced pressure. The mixture of the obtained residue (0.041 g),
cesium carbonate (0.080 g), l-bromo-3-chloro-5-fluorobenzene (0.051
g), PdCl.sub.2(dppf) (0.012 g) and DME (1 mL)/water (0.300 mL) was
stirred in a sealed flask at 80.degree. C. under nitrogen
atmosphere for 1 h. The solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (13.8
mg).
[0773] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.05-1.47 (5H, m),
2.83-5.42 (10H, m), 7.07-7.47 (6H, m).
Example 248
N-[(2S,3R)-2-[(3'-chloro-2,5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-1-(cycl-
opropanecarbonyl)-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide
[0774] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]ethanesulfonamide (144 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (129
mg), XPhos Pd G3 (57.4 mg) and potassium acetate (66.5 mg) in
toluene (4 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 36 h. The reaction mixture was diluted with water
and extracted with EtOAc. The extract was washed with saturated
brine, dried over magnesium sulfate, filtered and concentrated
under reduced pressure. The mixture of the obtained residue (0.043
g), cesium carbonate (0.081 g), l-bromo-3-chloro-5-fluorobenzene
(0.052 g), PdCl.sub.2(dppf) (0.012 g) and DME (1 mL)/water (0.300
mL) was stirred in a sealed flask at 80.degree. C. under nitrogen
atmosphere for 1 h. The solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (6.00
mg).
[0775] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.06-1.51 (8H, m),
2.84-5.44 (9H, m), 7.05-7.48 (6H, m).
Example 249
N-[(2S,3R)-2-[(3'-chloro-2,2'-difluoro[1,1'-biphenyl]-3-yl)methyl]-1-(cycl-
opropanecarbonyl)-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide
[0776] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]ethanesulfonamide (144 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (129
mg), XPhos Pd G3 (57.4 mg) and potassium acetate (66.5 mg) in
toluene (4 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 36 h. The reaction mixture was diluted with water
and extracted with EtOAc. The extract was washed with saturated
brine, dried over magnesium sulfate, filtered and concentrated
under reduced pressure. The mixture of the obtained residue (0.043
g), cesium carbonate (0.081 g), l-bromo-3-chloro-2-fluorobenzene
(0.052 g) and PdCl.sub.2(dppf) (0.012 g) in DME (1 mL)/water (0.300
mL) was stirred in a sealed flask at 80.degree. C. under nitrogen
atmosphere for 1 h. The solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (9.30
mg).
[0777] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.-0.11-0.22 (1H, m),
0.47-1.48 (7H, m), 2.79-4.98 (9H, m), 6.95-7.61 (6H, m).
Example 250
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(cycloprop-
anecarbonyl)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide
[0778] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]methanesulfonamide (134 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (124
mg), XPhos Pd G3 (55.2 mg) and potassium acetate (64.0 mg) in
toluene (4 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 8 h. The reaction mixture was diluted with water and
extracted with EtOAc. The extract was washed with saturated brine,
dried over magnesium sulfate, filtered and concentrated under
reduced pressure. The mixture of the obtained residue (0.041 g),
cesium carbonate (0.080 g), 1-chloro-3-iodobenzene (0.058 g) and
PdCl.sub.2(dppf) (0.012 g) in DME (1 mL)/water (0.300 mL) was
stirred in a sealed flask at 80.degree. C. under nitrogen
atmosphere for 1 h. The solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (0.013
g).
[0779] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.07-1.48 (5H, m),
2.76-5.27 (10H, m), 7.12-7.51 (7H, m).
Example 251
N-[(2S,3R)-2-[(5'-chloro-2,2'-difluoro[1,1'-biphenyl]-3-yl)methyl]-1-(cycl-
opropanecarbonyl)-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide
[0780] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-1-(cyclopropanecarbonyl)-4-
,4-difluoropyrrolidin-3-yl]ethanesulfonamide (144 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (129
mg), XPhos Pd G3 (57.4 mg) and potassium acetate (66.5 mg) in
toluene (4 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 36 h. The reaction mixture was diluted with water
and extracted with EtOAc. The extract was washed with saturated
brine, dried over magnesium sulfate, filtered and concentrated
under reduced pressure. The mixture of the obtained residue (0.043
g), cesium carbonate (0.081 g, 2-bromo-4-chloro-1-fluorobenzene
(0.052 g), PdCl.sub.2(dppf) (0.012 g) and DME (1 mL)/water (0.300
mL) was stirred in a sealed flask at 80.degree. C. under nitrogen
atmosphere for 1 h. The solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (10.6
mg).
[0781] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.11-1.47 (8H, m),
2.77-5.39 (9H, m), 6.97-7.61 (6H, m).
Example 257
N-{(2S,3R)-1-butanoyl-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-di-
fluoropyrrolidin-3-yl}ethanesulfonamide
[0782] To a solution of
N-((2S,3R)-2-((2,3'-difluoro-[1,1'-biphenyl]-3-yl)methyl)-4,4-difluoropyr-
rolidin-3-yl)ethanesulfonamide hydrochloride (0.020 g) and butyric
acid (6.08 .mu.L) in DMF (1 ml) were added HATU (0.025 g) and DIPEA
(0.031 ml) at room temperature. The mixture was stirred overnight
at room temperature. The mixture was quenched with aqueous
saturated ammonium chloride solution and extracted with EtOAc. The
organic layer was separated, washed with water and saturated brine,
dried over sodium sulfate and concentrated under reduced pressure.
The residue was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane), and then purified by preparative HPLC
(Column: YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (9.90
mg).
[0783] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.44-0.69 (3H,
m), 0.70-1.33 (6H, m), 1.81-2.31 (1H, m), 2.56-3.24 (4H, m),
3.64-4.82 (4H, m), 7.08-7.58 (7H, m), 8.11-8.41 (1H, m).
Example 267
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-
-1-(oxetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide with
Shorter Retention Time
A) tert-butyl
(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(ethanesulf-
onyl)amino]-A, 4-difluoropyrrolidine-1-carboxylate
[0784] A mixture of tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4,4-
-difluoropyrrolidine-1-carboxylate (51 mg),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (42.5
mg), XPhos Pd G3 (18.9 mg), potassium acetate (21.9 mg) and toluene
(2 ml) was stirred under nitrogen atmosphere at 80.degree. C. for
36 hr. The reaction mixture was diluted with water, and extracted
with EtOAc. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. A mixture of the obtained residue, cesium
carbonate (108 mg), 1-chloro-3-iodobenzene (39.3 mg),
PdCl.sub.2(dppf) (16.1 mg) and DME (1 ml)/water (0.3 mL) was
stirred under sealed condition, under nitrogen atmosphere at
80.degree. C. for 1 hr. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
chromatography (NH, EtOAc/hexane) to give the title compound (22
mg).
[0785] MS: [M-H].sup.- 531.1.
B)
N-{(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-diflu-
oropyrrolidin-3-yl}ethanesulfonamide hydrochloride
[0786] A mixture of tert-butyl
(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-3-[(ethanesulf-
onyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (22 mg) and 4M
hydrogen chloride/CPME solution (15 mL) was stirred overnight at
room temperature. The insoluble substance was collected by
filtration to give the title compound (4.5 mg).
[0787] MS: [M-H].sup.- 431.0.
C)
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-diflu-
oro-1-(oxetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide with
Shorter Retention Time
[0788] To a mixture of
N-{(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4
4-difluoropyrrolidin-3-yl}ethanesulfonamide hydrochloride (4.5 mg),
oxetane-2-carboxylic acid (1.47 mg) and DMF (1 ml) were added HATU
(5.47 mg) and DIPEA (4.96 mg) at room temperature. The mixture was
stirred overnight at room temperature, and concentrated under
reduced pressure. The residue was purified by HPLC (YMC-Actus
Triant C18 mobile phase: water/CH.sub.3CN (containing 10 mM
ammonium bicarbonate)) to give the title compound (0.4 mg).
[0789] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.18-1.32 (3H,
m), 2.23-2.40 (1H, m), 2.61-3.16 (5H, m), 3.78-5.11 (7H, m),
7.12-7.61 (7H, m), 8.12-8.42 (1H, m).
Example 272
N-{(2S,3R)-4,4-difluoro-1-(1-hydroxycyclobutane-1-carbonyl)-2-[(2,3',5'-tr-
ifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0790] To a solution of
N-((2S,3R)-4,4-difluoro-2-((2,3',5'-trifluoro-[1,1'-biphenyl]-3-yl)methyl-
)pyrrolidin-3-yl)ethanesulfonamide hydrochloride (0.030 g) and
1-hydroxycyclobutane-1-carboxylic acid (10.2 .mu.L) in DMF (1 mL)
were added HATU (0.036 g) and DIPEA (0.045 mL) at room temperature.
The mixture was stirred overnight at room temperature. The mixture
was quenched with aqueous saturated ammonium chloride solution and
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (0.016 g).
[0791] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.36 (3H, t, J=7.3
Hz), 1.77-1.92 (1H, m), 1.96-2.11 (3H, m), 2.45-2.62 (2H, m),
2.90-3.19 (4H, m), 3.35-3.67 (1H, m), 3.98-4.39 (3H, m), 4.86-5.08
(2H, m), 6.78-6.86 (1H, m), 7.02-7.12 (2H, m), 7.15-7.23 (1H, m),
7.24-7.30 (1H, m), 7.35-7.45 (1H, m).
Example 302
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-((2R)-ox-
etane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
A) benzyl
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-[(2-fluoro[1,1'--
biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate
[0792] A mixture of benzyl (2S,3R,4S)-2-[.
(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]-4-fluoropyrrol-
idine-1-carboxylate (129 mg), phenylboronic acid (66.5 mg), XPhos
Pd G3 (23.1 mg) and 1 M aqueous potassium phosphate solution (0.818
mL) in DME (4 mL) was stirred at 80.degree. C. under nitrogen
atmosphere for 1 h. The mixture was diluted with water and
extracted with EtOAc. The combined organic layers were dried over
magnesium sulfate, filtered and concentrated under reduced
pressure. The residue obtained was purified by column
chromatography (silica gel, eluted with EtOAc/hexane) to give the
title compound (92 mg).
[0793] MS: [M+H].sup.+ 515.1.
B)
N-{(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolid-
in-3-yl}ethanesulfonamide hydrobromide
[0794] To benzyl
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-[(2-fluoro[1,1'-biphenyl]-
-3-yl)methyl]pyrrolidine-1-carboxylate (90 mg) was added 30%
HBr/acetic acid solution (1 mL) at room temperature. The mixture
was stirred at room temperature for 1-5 h, and the solvent was
evaporated with toluene. The solid obtained was suspended in IPE
and collected by filtration to give the title compound (80.9
mg).
[0795] MS: [M+H]+ 381.0.
C)
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-((2R)-
-oxetane-2-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
[0796] To a solution of
N-{(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-
-3-yl}ethanesulfonamide hydrobromide (35 mg) and
oxetane-2-carboxylic acid (23.2 mg) in DMF (2 mL) were added HATU
(43.3 mg) and DIPEA (0.053 mL) at 0.degree. C. The mixture was
stirred at room temperature for 1.5 h. The mixture was quenched
with water and extracted with EtOAc. The organic layer was dried
over magnesium sulfate, filtered and concentrated under reduced
pressure. The residue was purified by preparative HPLC (Column:
YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (11.5
mg).
[0797] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.19-1.31 (3H,
m), 2.30-2.46 (1H, m), 2.60-2.86 (2H, m), 3.02-3.20 (3H, m),
3.46-3.68 (1H, m), 3.77-4.28 (4H, m), 4.39-5.40 (3H, m), 7.09-7.61
(8H, m), 7.81 (1H, br s).
Example 304
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-b-
iphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide with Shorter
Retention Time
A) benzyl
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-[(2,3',5'-triflu-
oro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate
[0798] To a mixture of benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]--
4-fluoropyrrolidine-1-carboxylate (129 mg),
(3,5-difluorophenyl)boronic acid (94.6 mg), XPhos Pd G3 (21.9 mg)
and DME (2.0 mL) was added 1 M aqueous potassium phosphate solution
(0.60 mL) at room temperature. The mixture was stirred at
90.degree. C. under nitrogen atmosphere for 4 h. To the mixture was
added water, and the mixture was extracted with EtOAc. The organic
layer was separated, washed with water and saturated brine, dried
over sodium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, eluted
with EtOAc/hexane) to give the title compound (30.4 mg).
[0799] MS: [M+H].sup.+ 551.2.
B)
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide with
Shorter Retention Time
[0800] A mixture of benzyl
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-[(2,3',5'-trifluoro[1,1'--
biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate (30.4 mg) and 10%
Pd--C (3.0 mg) in MeOH (1.0 mL) was hydrogenated under balloon
pressure overnight at room temperature. The catalyst was removed by
filtration, and the filtrate was concentrated under reduced
pressure. To a mixture of the obtained residue, 2-oxetanecarboxylic
acid (10.2 mg), DIPEA (0.030 mL) and DMF (1.0 mL) was added HATU
(36.1 mg) at room temperature. The mixture was stirred at room
temperature for 1 h. To the mixture was added saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
with EtOAc. The organic layer was separated, washed with water and
saturated, brine, dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by preparative HPLC
(Column: YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (5.2
mg).
[0801] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.17-1.33 (3H,
m), 2.22-2.45 (1H, m), 2.58-3.20 (5H, m), 3.48-5.42 (8H, m),
7.13-7.51 (6H, m), 7.73-7.91 (1H, m).
Example 305
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-carbonyl)-2-[(2,3',5'-trifluoro[1,1'-b-
iphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide with Longer
Retention Time
[0802] A mixture of benzyl
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-[(2,3',5'-trifluoro[1,1'--
biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate (30.4 mg) and 10%
Pd--C (3.0 mg) in MeOH (1.0 mL) was hydrogenated under balloon
pressure overnight at room temperature. The catalyst was removed by
filtration, and the filtrate was concentrated under reduced
pressure. To a mixture of the obtained residue, 2-oxetanecarboxylic
acid (10.2 mg), DIPEA (0.030 mL) and DMF (1.0 mL) was added HATH
(36.1 mg) at room temperature. The mixture was stirred at room
temperature for 1 h. To the mixture was added saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by preparative HPLC
(Column: YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (4.1
mg).
[0803] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.19-1.33 (3H,
m), 2.22-2.44 (1H, m), 2.61-3.22 (4H, m), 3.42-5.41 (9H, m),
7.12-7.56 (6H, m), 7.73-8.00 (1H, m).
Example 307
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-carbonyl)-2-[(2,2',3'-trifluoro[1,1'-b-
iphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide with Shorter
Retention Time
A) benzyl
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-[(2,2',3'-triflu-
oro[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate
[0804] To a mixture of benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]--
4-fluoropyrrolidine-1-carboxylate (129 mg),
(2,3-difluorophenyl)boronic acid (91.9 mg), XPhos Pd G3 (21.9 mg)
and DME (2.0 mL) was added 1 M aqueous potassium phosphate solution
(0.60 mL) at room temperature. After being stirred at 90.degree. C.
under nitrogen atmosphere for 4 h, the mixture was concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, eluted with EtOAc/hexane) to give the
title compound (32.7 mg).
[0805] MS: [M+H].sup.+ 551.2.
B)
N-{(2S,3R,4S)-4-fluoro-2-[(2,2',3'-trifluoro[1,1'-biphenyl]-3-yl)methyl-
]pyrrolidin-3-yl}ethanesulfonamide
[0806] A mixture of benzyl
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-fluoro-2-[(2,2',3'-trifluoro[1,1'--
biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate (32.7 mg) and 10%
Pd--C (3.0 mg) in MeOH (1.0 mL) was hydrogenated under balloon
pressure overnight at room temperature. The catalyst was removed by
filtration, and the filtrate was concentrated under reduced
pressure to give the title compound (23.6 mg).
[0807] MS: [M+H].sup.+ 417.1.
C)
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-carbonyl)-2-[(2,2',3'-trifluoro[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide with
Shorter Retention Time
[0808] To a mixture of
N-{(2S,3R,4S)-4-fluoro-2-[(2,2',3'-trifluoro[1,1'-biphenyl]-3-yl)methyl]p-
yrrolidin-3-yl}ethanesulfonamide (23.6 mg), 2-oxetanecarboxylic
acid (16.1 mg), DIPEA (0.050 mL) and DMF (1.0 mL) was added HATU
(26.0 mg) at room temperature. After being stirred at room
temperature for 1 h, the mixture was concentrated under reduced
pressure. The residue was purified by preparative HPLC (Column:
YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (8.7
mg).
[0809] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.24 (3H, t,
J=7.3 Hz), 2.23-2.45 (1H, m), 2.58-2.89 (2H, m), 3.00-3.18 (3H, m),
3.41-5.39 (8H, m), 7.07-7.59 (6H, m), 7.82 (1H, br s).
Example 346
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluoro--
1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
A)
N-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3--
yl}ethanesulfonamide hydrobromide
[0810] To benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(ethanesulfonyl)amino]--
4-fluoropyrrolidine-1-carboxylate (2.18 g) was added 30% HBr/acetic
acid solution (20 mL) at 0.degree. C. After being stirred at room
temperature for 30 min, the mixture was concentrated under reduced
pressure with heptane, and the residue was diluted with IPE. The
insoluble material was collected by filtration, and washed with IPE
to give the title compound (1.83 g).
[0811] MS: [M+H].sup.+ 339.0.
B)
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-T-(2-hydroxy-
-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0812] To a mixture of
N-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl-
}ethanesulfonamide hydrobromide (195 mg) and DIPEA (0.402 mL) in
THF (4 mL) was added alpha-acetoxy-isobutyryl chloride (0.081 mL)
at 0.degree. C., and the mixture was stirred at same temperature
for 10 min. To the mixture were added water (1 mL) and 4 M aqueous
lithium hydroxide solution (1.16 mL), and the mixture was stirred
overnight at room temperature. The mixture was quenched with
saturated aqueous sodium hydrogen carbonate solution, and extracted
with EtOAc. The extract was washed with saturated brine, dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, eluted
with EtOAc/hexane) to give the title compound (180 mg).
[0813] MS: [M+H].sup.+ 425.0.
C)
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluo-
ro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide
[0814] A mixture of
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-1-(2-hydroxy-2-
-methylpropanoyl)pyrrolidin-3-yl]ethanesulfonamide (45 mg),
(3-chlorophenyl)boronic acid (21.5 mg), XPhos Pd G3 (8.96 mg) and 1
M aqueous potassium phosphate solution (0.318 mL) in DME (2 mL) was
stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) and then column chromatography (NH
silica gel, eluted with EtOAc/hexane) to give the title compound
(11.4 mg).
[0815] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.10-1.22 (3H, m),
1.40 (6H, s), 2.73-3.27 (5H, m), 3.94-4.31 (3H, m), 4.76-5.33 (3H,
m), 7.13-7.55 (7H, m).
Example 374
N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4-fluoro-2-[(2,3',5'-tr-
ifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
A)
N-((2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-2-(3-chloro-2-fluoro-
benzyl)-4-fluoropyrrolidin-3-yl)methanesulfonamide
[0816] To a solution of
N-((2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl-
)methanesulfonamide hydrobromide (100 mg) and
bicyclo[1.1.1]pentane-1-carboxylic acid (0.044 mL) in DMF (3 mL)
were added HATU (141 mg) and DIPEA (0.129 mL) at 0.degree. C. The
mixture was stirred at room temperature for 1.5 h, then it was
quenched with a saturated aqueous sodium hydrogen carbonate
solution and extracted with EtOAc. The combined organic layers were
washed with saturated brine, dried over magnesium sulfate, filtered
and concentrated. The residue was purified by column chromatography
(silica gel, eluted with EtOAc/hexane) to give the title compound
(102 mg).
[0817] MS: [M+H].sup.+ 419.0.
B)
N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-4-fluoro-2-[(2,3',5'-
-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
[0818] A mixture of
N-((2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-carbonyl)-2-(3-chloro-2-fluorobe-
nzyl)-4-fluoropyrrolidin-3-yl)methanesulfonamide (20 mg),
(3,5-difluorophenyl)boronic acid (15.1 mg), XPhos Pd G3 (4.04 mg)
and 1 M aqueous potassium phosphate solution (0.143 mL) in DME (0.8
mL) was stirred at 80.degree. C. under nitrogen atmosphere for 2 h.
The mixture was purified by column chromatography (silica gel,
eluted with EtOAc/hexane) followed by preparative HPLC ((Column:
L-Column 2 ODS, mobile phase: H.sub.2O 5 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (15.5
mg).
[0819] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.75-1.94 (1H, m),
2.07-2.38 (5H, m), 2.53 (3H, d, J=26.2 Hz), 2.88-3.31 (3H, m),
3.62-4.47 (3H, m), 4.65-5.35 (3H, m), 6.78-6.88 (1H, m), 7.02-7.12
(2H, m), 7.16-7.26 (2H, m), 7.46-7.55 (1H, m).
Example 375
N-{(2S,3R)-4,4-difluoro-1-((1r,3S)-3-fluorocyclobutane-1-carbonyl)-2-[(2,3-
',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamid-
e
[0820] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1r,3S)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (28
mg), (3,5-difluorophenyl)boronic acid (19.4 mg), XPhos Pd G3 (5.19
mg) and 1 M aqueous potassium phosphate solution (0.184 mL) in DME
(2 mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography (NH silica
gel, eluted with EtOAc/hexane) and preparative HPLC (Column:
YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (28.3
mg).
[0821] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.21-1.73 (4H,
m), 2.00-2.42 (3H, m), 2.60-3.26 (5H, m), 3.68-5.13 (5H, m),
7.11-7.55 (6H, m), 8.09-8.40 (1H, m).
Example 376
N-{(2S,3R)-4,4-difluoro-1-((1r,3S)-3-fluorocyclobutane-1-carbonyl)-2-[(2,2-
',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamid-
e
[0822] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1r,3S)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (28
mg), (2',5-difluorophenyl) boronic acid (19.4 mg), XPhos Pd G3
(5.19 mg) and 1 M aqueous potassium phosphate solution (0.184 mL)
in DME (2 mL) was stirred at 80.degree. C. for 2 h. After cooling
back to room temperature, the solvent was removed under reduced
pressure, and the residue was purified by column chromatography (NH
silica gel, eluted with EtOAc/hexane) and preparative HPLC (Column:
YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (18.2
mg).
[0823] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.19-1.74 (4H,
m), 2.01-2.42 (3H, m), 2.57-3.22 (5H, m), 3.66-5.17 (5H, m),
7.13-7.48 (6H, m), 8.11-8.37 (1H, m).
Example 378
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-((1r,3S-
)-3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
[0824] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1r,3S)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (28
mg), phenylboronic acid (14.9 mg), XPhos Pd G3 (5.19 mg) and 1 M
aqueous potassium phosphate solution (0.184 mL) in DME (2 mL) was
stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue, was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) and preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (26.9
mg).
[0825] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.20-1.71 (4H,
m), 1.99-2.43 (3H, m), 2.60-3.23 (5H, m), 3.68-5.14 (5H, m),
7.09-7.56 (8H, m), 8.11-8.38 (1H, m).
Example 380
N-{(2S,3R)-4,4-difluoro-1-((1s,3R)-3-fluorocyclobutane-1-carbonyl)-2-[(2,3-
',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamid-
e
[0826] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1s,3R)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (17
mg), (3,5-difluorophenyl)boronic acid (11.8 mg), XPhos Pd G3 (3.15
mg) and 1 M aqueous potassium phosphate solution (0.112 mL) in DME
(1 mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography (NH silica
gel, eluted with EtOAc/hexane) and preparative HPLC (Column:
YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (15.8
mg).
[0827] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.11-3.20 (12H,
m), 3.73-5.00 (5H, m), 7.11-7.52 (6H, m), 8.14-8.35 (1H, m).
Example 381
N-{(2S,3R)-4,4-difluoro-1-((1s,3R)-3-fluorocyclobutane-1-carbonyl)-2-[(2,2-
',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamid-
e
[0828] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1s,3R)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (17
mg), (2,5-difluorophenyl)boronic acid (7.64 mg), XPhos Pd G3 (3.15
mg) and 1 M aqueous potassium phosphate solution (0.112 mL) in DME
(1 mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by column chromatography (NH silica
gel, eluted with EtOAc/hexane) and preparative HPLC (Column:
YMC-Actus Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (12.0
mg).
[0829] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.19-1.30 (3H,
m), 1.70-2.44 (5H, m), 2.54-3.22 (4H, m), 3.70-5.12 (5H, m),
7.10-7.49 (6H, m), 8.10-8.38 (1H, m).
Example 383
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-((1s,3R-
)-3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfonamide
[0830] A mixture of
N-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(1s,3R)-3--
fluorocyclobutane-1-carbonyl]pyrrolidin-3-yl}ethanesulfonamide (17
mg), phenylboronic acid (9.07 mg), XPhos Pd G3 (3.15 mg) and 1 M
aqueous potassium phosphate solution (0.112 mL) in DME (1 mL) was
stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) and preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 10 mM
NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (8.00
mg).
[0831] .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 1.12-3.24 (12H,
m), 3.68-5.03 (5H, m), 7.06-7.59 (8H, m), 8.10-8.40 (1H, m).
Example 388
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluoro--
1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
A) benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-[(meth-
anesulfonyl)amino]pyrrolidine-1-carboxylate
[0832] Methanesulfonic anhydride (225 mg) was added to a stirred
solution of benzyl
(2S,3R,4S)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-
pyrrolidine-1-carboxylate (328 mg) and TEA (0.360 mL) in THF (10
mL) at room temperature. After 0.5 h, the reaction mixture was
concentrated under reduced pressure, and the residue was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) to
give the title compound (336 mg).
[0833] MS: [M+H].sup.+ 459.0.
B)
N-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3--
yl}methanesulfonamide hydrobromide
[0834] To benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-3-[(methanesulfon-
yl)amino]pyrrolidine-1-carboxylate (1.17 g) was added 30%
HBr/acetic acid solution (10 mL) at room temperature. The mixture
was stirred at room temperature for 30 min. The mixture was
evaporated with toluene, and the residue was suspended in IPE, and
the insoluble substance was collected by filtration and washed with
IPE to give the title compound (0.974 g).
[0835] MS, found: 325.1.
C)
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-1-(2-hydroxy-
-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0836] To a mixture of
N-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl-
}methanesulfonamide hydrobromide (100 mg) and DIPEA (0.299 mL) in
THF (3 mL) was added alpha-acetoxy-isobutyryl chloride (0.071 mL)
at 0.degree. C., and the mixture was stirred at the same
temperature for 10 min. To the mixture were added water (1 mL) and
4 M aqueous lithium hydroxide solution (1 mL), and the mixture was
stirred at room temperature for 4 h. The mixture was quenched with
saturated aqueous sodium hydrogen carbonate solution and extracted
with EtOAc. The extract was washed with saturated brine, dried over
sodium sulfate and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, eluted with
EtOAc/hexane) to give the title compound (96 mg).
[0837] MS: [M+H].sup.+ 411.1.
D)
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-biphenyl]-3-yl)methyl]-4-fluo-
ro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide
[0838] A mixture of
N-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-1-(2-hydroxy-2-
-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide (23 mg),
(3-chlorophenyl)boronic acid (17.5 mg), XPhos Pd G3 (4.74 mg) and 1
M aqueous potassium phosphate solution (0.168 mL) in DME (2 mL) was
stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TEA)
and column chromatography (NH silica gel, eluted with EtOAc/hexane)
to give the title compound (5.40 mg).
[0839] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.42 (6H, s), 2.60
(6H, brs), 4.01-4.30 (3H, m), 4.77-5.34 (3H, m), 7.16-7.23 (1H, m),
7.27-7.55 (6H, m).
Example 392
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(3-
-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide
with Longer Retention Time
A)
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluoro-
cyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide
[0840] To a solution of
N-((2S,3R)-2-(3-chloro-2-fluorobenzyl)-4,4-difluoropyrrolidin-3-yl)methan-
esulfonamide hydrochloride (0.310 g) and
3-fluorocyclobutane-1-carboxylic acid (0.133 mL) in DMF (10 mL)
were added HATU (0.466 g) and DIPEA (0.571 mL) at room temperature.
The mixture was stirred overnight at room temperature. The mixture
was quenched with aqueous saturated ammonium chloride solution and
extracted with EtOAc. The organic layer was separated, washed with
water and saturated brine, dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane, and
then silica gel, eluted with EtOAc/hexane) to give the title
compound (0.196 g).
[0841] MS: [M+H].sup.+ 443.0.
B)
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-
-(3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide
with Longer Retention Time
[0842] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
(3-fluorophenyl)boronic acid (18.3 mg), XPhos Pd G3 (5.54 mg) and 1
M aqueous potassium phosphate solution (0.19'6 mL) in DME (2 mL)
was stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA,
and then Column: CHIRALPAK IB, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (11.3 mg).
[0843] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.56-1.72 (1H, m),
1.95-3.14 (9H, m), 3.36-3.92 (2H, m), 4.26-4.53 (2H, m), 4.88-5.24
(2H, m), 7.26 (7H, s).
Example 393
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-difluoro-1-(3-
-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide
with Shorter Retention Time
[0844] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
(3-fluorophenyl)boronic acid (18.3 mg), XPhos Pd G3 (5.54 mg) and 1
M aqueous potassium phosphate solution (0.196 mL) in DME (2 mL) was
stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA,
and then Column: CHIRALPAK IB, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (10.2 mg).
[0845] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.84-3.14 (10H,
m), 3.32-3.94 (2H, m), 4.27-5.13 (4H, m), 7.03-7.46 (7H, m).
Example 431
N-{(2S,3R)-4,4-difluoro-1-((1r,3S)-3-fluorocyclobutane-1-carbonyl)-2-[(2,3-
',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonami-
de
[0846] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
(3,5-difluorophenyl)boronic acid (20.7 mg), XPhos Pd G3 (5.54 mg)
and 1 M aqueous potassium phosphate solution (0.196 mL) in DME (2
mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA,
and then Column: CHIRALPAK IB, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (9.90 mg).
[0847] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.56-1.70 (1H, m),
1.98-3.14 (9H, m), 3.27-3.98 (2H, m), 4.25-4.52 (2H, m), 4.88-5.23
(2H, m), 6.78-6.88 (1H, m), 6.99-7.09 (2H, m), 7.16-7.45 (3H,
m).
Example 433
N-{(2S,3R)-4,4-difluoro-1-((1s,3R)-3-fluorocyclobutane-1-carbonyl)-2-[(2,3-
',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonami-
de
[0848] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
(3,5-difluorophenyl)boronic acid (20.7 mg), XPhos Pd G3 (5.54 mg)
and 1 M aqueous potassium phosphate solution (0.196 mL) in DME (2
mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA,
and then Column: CHIRALPAK IB, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (12.3 mg).
[0849] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.29-3.22 (10H,
m), 3.30-5.24 (6H, m), 6.77-7.47 (6H, m).
Example 435
N-{(2S,3R)-4,4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)-2-[(2,2',3'-tri-
fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
with Longer Retention Time
[0850] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
(3,5-difluorophenyl)boronic acid (20.7 mg), XPhos Pd G3 (5.54 mg)
and 1 M aqueous potassium phosphate solution (0.196 mL) in DME (2
mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA,
and then Column: CHIRALPAK IB, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (9 mg).
[0851] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.60-3.18 (10H,
m), 3.36-3.94 (2H, m), 4.28-4.53 (2H, m), 4.92-5.24 (2H, m),
7.05-7.46 (6H, m).
Example 436
N-{(2S,3R)-4,4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)-2-[(2,2',3'-tri-
fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
with Shorter Retention Time
[0852] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4
4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfo-
namide (29 mg), (3,5-difluorophenyl)boronic acid (20.7 mg), XPhos
Pd G3 (5.54 mg) and 1 M aqueous potassium phosphate solution (0.196
mL) in DME (2 mL) was stirred at 80.degree. C. for 2 h. After
cooling back to room temperature, the solvent was removed under
reduced pressure, and the residue was purified by preparative HPLC
(Column: YMC-Actus Triant C18, mobile phase: H.sub.2O 0.1%
TFA/CH.sub.3CN 0.1% TFA, and then Column: CHIRALPAK IB, mobile
phase: carbon dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to
give the title compound (7.6 mg).
[0853] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.54-3.23 (10H,
m), 3.27-5.08 (6H, m), 7.04-7.47 (6H, m).
Example 437
N-{(2S,3R)-4,4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)-2-[(2,2',5'-tri-
fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
with Longer Retention Time
[0854] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
(2,5-difluorophenyl)boronic acid (20.7 mg), XPhos Pd G3 (5.54 mg)
and 1 M aqueous potassium phosphate solution (0.196 mL) in DME (2
mL) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA,
and then Column: CHIRALPAK IA, mobile phase 1 carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (6.1 mg).
[0855] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.54-3.36 (10H,
m), 3.33-3.94 (2H, m), 4.27-4.53 (2H, m), 4.91-5.24 (2H, m),
7.02-7.46 (6H, m).
Example 439
N-{(2S,3R)-4,4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)-2-[(2,2',5'-tri-
fluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide
with Shorter Retention Time
[0856] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
(2,5-difluorophenyl)boronic acid (20.7 mg), XPhos Pd G3 (5.54 mg)
and 1 M aqueous potassium phosphate solution (0.196 ml) in DME (2
ml) was stirred at 80.degree. C. for 2 h. After cooling back to
room temperature, the solvent was removed under reduced pressure,
and the residue was purified by preparative HPLC (Column: YMC-Actus
Triant C18, mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA,
and then Column: CHIRALPAK IA, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (8.4 mg).
[0857] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.30-3.21 (10H,
m), 3.25-5.07 (6H, m), 6.97-7.47 (6H, m).
Example 440
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(3-fluo-
rocyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide with
Longer Retention Time
[0858] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
phenylboronic acid (16.0 mg), XPhos Pd G3 (5.54 mg) and 1 M aqueous
potassium phosphate solution (0.196 mL) in DME (2 mL) was stirred
at 80.degree. C. for 2 h. After cooling back to room temperature,
the solvent was removed under reduced pressure, and the residue was
purified by preparative HPLC (Column: YMC-Actus Triant C18, mobile
phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA, and then Column:
CHIRALPAK OJ-H, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (11.8 mg).
[0859] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.54-3.15 (10H,
m), 3.32-3.93 (2H, m), 4.27-4.52 (2H, m), 4.91-5.23 (2H, m),
7.09-7.53 (8H, m).
Example 441
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-yl)methyl]-1-(3-fluo-
rocyclobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide with
Shorter Retention Time
[0860] A mixture of
N-[(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-(3-fluorocy-
clobutane-1-carbonyl)pyrrolidin-3-yl]methanesulfonamide (29 mg),
phenylboronic acid (16.0 mg), XPhos Pd. G3 (5.54 mg) and 1 M
aqueous potassium phosphate solution (0.196 mL) in DME (2 mL) was
stirred at 80.degree. C. for 2 h. After cooling back to room
temperature, the solvent was removed under reduced pressure, and
the residue was purified by HPLC (Column: YMC-Actus Triant C18,
mobile phase: H.sub.2O 0.1% TFA/CH.sub.3CN 0.1% TFA, and then
Column: CHIRALPAK OJ-H, mobile phase: carbon
dioxide/(MeOH/diethylamine=1000/3)=900/100 (v/v)) to give the title
compound (8 mg).
[0861] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.29-3.20 (10H,
m), 3.35-5.19 (6H, m), 7.10-7.53 (8H, m).
Example 442
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro-3'-methyl[1-
,1'-biphenyl]-3-yl)methyl]-N,N-dimethylpyrrolidine-1-carboxamide
A) tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amino]--
4,4-difluoropyrrolidine-1-carboxylate
[0862] A mixture of tert-butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate (300 mg), dimethylsulfamoyl chloride (800 mg) and
DMAP (201 mg) was stirred overnight under nitrogen atmosphere at
50.degree. C. The reaction mixture was diluted with saturated
aqueous sodium hydrogen carbonate solution, and extracted with
EtOAc. The organic layer was separated, washed with saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (EtOAc/hexane) to give the title compound
(225 mg).
[0863] MS: [M-H]470.1.
B) tert-butyl
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro-3'-methyl[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate
[0864] A mixture of tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amino]--
4,4-difluoropyrrolidine-1-carboxylate (200 mg),
(3-methylphenyl)boronic acid (86 mg), XPhos Pd G3 (35.9 mg), 1M
aqueous potassium phosphate solution (0.636 mL) and THF (3 ml) was
irradiated with microwave at 80.degree. C. for 1 hr. The mixture
was neutralized with saturated aqueous sodium hydrogen carbonate
solution at 0.degree. C., and extracted with EtOAc. The organic
layer was separated, washed with water and saturated brine, dried
over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (NH, EtOAc/hexane) to give the title compound (150
mg).
[0865] MS: [M-H].sup.- 526.2.
C)
N'-{(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)met-
hyl]pyrrolidin-3-yl}-N, N-dimethylsulfuric diamide
hydrochloride
[0866] A mixture of tert-butyl
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro-3'-methyl[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carboxylate (145 mg) and
4M hydrogen chloride/CPME solution (5 mL) was stirred at 60.degree.
C. for 4 hr. The reaction mixture was concentrated under reduced
pressure to give the title compound (125 mg).
[0867] MS, found: 428.1.
D)
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro-3'-methy-
l[1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carbonyl chloride
[0868] To a mixture of
N'-{(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)methy-
l]pyrrolidin-3-yl}-N,N-dimethylsulfuric diamide hydrochloride (50
mg), DIPEA (27.9 mg) and THF (4.7 ml) was added
bis(trichloromethyl) carbonate (25.6 mg) at 0.degree. C. The
reaction mixture was stirred at 0.degree. C. for 10 min, and then
stirred at room temperature for 10 min. The mixture was neutralized
with saturated aqueous sodium hydrogen carbonate solution at
0.degree. C., and extracted with EtOAc. The organic layer was
separated, washed with water and saturated brine, dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure to give the title compound (48 mg).
[0869] MS: [M+H].sup.+490.1.
E)
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro-3'-methy-
l[1,1'-biphenyl]-3-yl)methyl]-N,N-dimethylpyrrolidine-1-carboxamide
[0870] To a mixture of
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro-3'-methyl[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carbonyl chloride (48 mg)
and THF (0.5 ml) was added 2M N-methylmethanamine/THF solution (0.5
mL) at 0.degree. C. The mixture was stirred at room temperature for
2 hr, and purified by silica gel column chromatography
(EtOAc/hexane) to give the title compound (35 mg).
[0871] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.40 (3H, s), 2.60
(6H, s), 2.76-2.88 (7H, m), 2.98-3.05 (1H, m), 3.66-3.78 (1H, m),
3.88-4.00 (1H, m), 4.14-4.27 (1H, m), 4.82-4.90 (1H, m), 5.05 (1H,
d, J=9.7 Hz), 7.09-7.34 (7H, m).
Example 443
N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-difluoro-2-[(2-fluoro-3'-methyl[1-
,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide
[0872] To a mixture of
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-difluoro-2-[(2-fluoro-3'-methyl[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidine-1-carbonyl chloride (50 mg)
and THF (0.5 ml) was added azetidine (17.5 mg) at 0.degree. C. The
mixture was stirred at room temperature for 2 hr, and purified by
silica gel column chromatography (EtOAc/hexane) to give the title
compound (20 mg).
[0873] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.99-2.11 (2H, m),
2.41 (3H, s), 2.78 (6H, s), 2.83-2.93 (1H, m), 2.96-3.09 (1H, m),
3.58-3.91 (6H, m), 4.10-4.26 (1H, m), 4.69-4.87 (1H, m), 4.87-5.01
(1H, m), 7.12-7.23 (2H, m), 7.24-7.36 (5H, m).
Example 450
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1,1'-
-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
A)
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-[(3-chloro-2-fluorophenyl)meth-
yl]-4-fluoropyrrolidin-3-yl}ethanesulfonamide
[0874] To a mixture of
N-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-yl-
}ethanesulfonamide hydrobromide (60 mg),
bis(trichloromethyl)carbonate (25.5 mg) and THF (1.4 mL) was added
DIPEA (0.075 mL) at 0.degree. C. After being stirred at 0.degree.
C. for 30 min, the mixture was poured into water and extracted with
EtOAc. The combined organic layers were dried over sodium sulfate,
filtered and concentrated under reduced pressure. The residue was
diluted with THF (1.4 mL), and azetidine (0.029 mL) was added
thereto at room temperature. After being stirred at room
temperature for 2 h, the mixture was poured into aqueous saturated
ammonium chloride solution and extracted with EtOAc. The combined
organic layers were dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
preparative HPLC (Column: L-Column 2 ODS, mobile phase: H.sub.2O 10
mM NH.sub.4HCO.sub.3/CH.sub.3CN) to give the title compound (49.0
mg).
[0875] MS: [M+H].sup.+ 422.1.
B)
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1-
,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0876] A mixture of
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-[(3-chloro-2-fluorophenyl)methyl-
]-4-fluoropyrrolidin-3-yl}ethanesulfonamide (23 mg),
(3,5-difluorophenyl)boronic acid (17.2 mg), XPhos Pd G3 (4.61 mg)
and 1 M aqueous potassium phosphate solution (0.164 mL) in DME (0.8
mL) was stirred at 80.degree. C. under nitrogen atmosphere for 2 h.
The mixture was directly purified by column chromatography (NH
silica gel, eluted, with EtOAc/hexane) to give the title compound
(24.5 mg).
[0877] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.28 (3H, t, J=7.4
Hz), 2.13 (2H, quin, J=8.0 Hz), 2.95 (3H, q, J=7.3 Hz), 3.04-3.14
(1H, m), 3.61-3.79 (4H, m), 3.89-4.08 (3H, m), 4.66-4.75 (1H, m),
4.86 (1H, d, J=10.3 Hz), 5.06-5.27 (1H, m), 6.82 (1H, t, J=8.9 Hz),
7.08 (2H, d, J=7.0 Hz), 7.15-7.22 (1H, m), 7.27-7.31 (1H, m), 7.36
(1H, t, J=7.1 Hz).
Example 451
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3'-methyl[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide
[0878] A mixture of
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-[(3-chloro-2-fluorophenyl)methyl-
]-4-fluoropyrrolidin-3-yl}ethanesulfonamide (23-mg), m-tolylboronic
acid (14.8 mg), XPhos Pd G3 (4.61 mg) and 1 M aqueous potassium
phosphate solution (0.164 mL) in DME (0.8 mL) was stirred at
80.degree. C. under nitrogen atmosphere for 2 h. The mixture was
directly purified by column chromatography (NH silica gel, eluted
with EtOAc/hexane) to give the title compound (23.5 mg).
[0879] .sup.1H NMR (400 MHz, CDCl.sub.3) 51.22 (3H, t, J=7.3 Hz),
2.06-2.18 (2H, m), 2.38-2.45 (3H, m), 2.87 (2H, q, J=7.2 Hz),
2.92-3.01 (1H, m), 3.05-3.14 (1H, m), 3.60-3.82 (4H, m), 3.88-4.09
(3H, m), 4.68 (1H, q, J=7.3 Hz), 4.88 (1H, d, J=10.3 Hz), 5.04-5.27
(1H, m), 7.13-7.21 (2H, m), 7.27-7.37 (5H, m).
Example 458
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1,1-
'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide
A) benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfa-
moyl)amino]-4-fluoropyrrolidine-1-carboxylate
[0880] A mixture of benzyl
(2S,3R,4S)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-
e-1-carboxylate (100 mg), DMAP (64.2 mg) and dimethylsulfamoyl
chloride (3 mL) was stirred overnight under nitrogen atmosphere at
50.degree. C. The reaction mixture was purified by column
chromatography (NH silica gel, eluted with EtOAc/hexane) to give
the title compound (114 mg).
[0881] MS: [M+H].sup.+ 488.1.
B)
N'-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-
-yl}-N,N-dimethylsulfuric diamide hydrobromide
[0882] To benzyl
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amin-
o]-4-fluoropyrrolidine-1-carboxylate (225 mg) was added 30%
HBr/acetic acid solution (10 mL) at room temperature. The mixture
was stirred at room temperature 16 h then the solvent was
evaporated with toluene. The solid obtained was suspended in IPE
and collected by filtration to give the title compound (180
mg).
[0883] MS: [M+H].sup.+ 354.0.
C)
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)am-
ino]-4-fluoropyrrolidine-1-carbonyl chloride
[0884] Bis(trichloromethyl) carbonate (76 mg) was added to a
solution of
N'-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-y-
l}-N,N-dimethylsulfuric diamide hydrobromide (140 mg) and DIPEA
(0.112 mL) in THF (4.7 mL) at 0.degree. C. After being stirred at
0.degree. C. for 10 min and at room temperature for 10 min, the
mixture was neutralized with saturated aqueous sodium hydrogen
carbonate solution at 0.degree. C. and extracted with EtOAc. The
organic layer was separated, washed 0.15 with water and saturated
brine, dried over magnesium sulfate and concentrated under reduced
pressure to give the title compound (120 mg).
[0885] MS: [M-H].sup.+ 414.0.
D)
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-[(3-chloro-2-fluorophenyl)met-
hyl]-4-fluoropyrrolidin-3-yl}-N,N-dimethylsulfuric diamide
[0886] Azetidine (300 .mu.L) was added to a solution of
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amin-
o]-4-fluoropyrrolidine-1-carbonyl chloride (80 mg) in THF (3 mL) at
0.degree. C. The mixture was stirred at room temperature under a
dry atmosphere for 2 h. The mixture was neutralized with 0.05 M
hydrochloric acid at 0.degree. C. and extracted with EtOAc. The
organic layer was separated, washed with saturated aqueous sodium
hydrogen carbonate solution, water and saturated brine, dried over
magnesium sulfate and concentrated under reduced pressure to give
the title compound (70.0 mg).
[0887] MS: [M+H].sup.+ 437.1.
E)
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[-
1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide
[0888] A mixture of
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-[(3-chloro-2-fluorophenyl)methy-
l]-4-fluoropyrrolidin-3-yl}-N, N-dimethylsulfuric diamide (35 mg),
(3,5-difluorophenyl)boronic acid (19.0 mg), XPhos Pd G3 (6.78 mg)
and 1 M aqueous potassium phosphate solution (0.120 mL) in THF (3
mL) was heated at 80.degree. C. for 1 h under microwave
irradiation. The mixture was neutralized with aqueous saturated
ammonium chloride solution at 0.degree. C. and extracted with
EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over magnesium sulfate and concentrated
under reduced pressure. The crude was purified by preparative TLC
(silica gel, eluted with EtOAc/hexane) to give the title compound
(20.0 mg).
[0889] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.99-2.21 (2H, m),
2.71 (6H, s), 2.84-3.00 (1H, m), 3.00-3.18 (1H, m), 3.63-3.80 (4H,
m), 3.80-4.01 (3H, m), 4.58-4.81 (1H, m), 4.77-4.97 (1H, m),
5.05-5.37 (1H, m), 6.70-6.90 (1H, m), 7.02-7.21 (3H, m), 7.25-7.30
(1H, m), 7.32-7.45 (1H, m).
Example 459
(2S,3R,4S)-3-[(dimethylsulfamoyl)amino]-4-fluoro-2-[(2-fluoro-3'-methyl[1,-
1'-biphenyl]-3-yl)methyl]-N,N-dimethylpyrrolidine-1-carboxamide
A)
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)am-
ino]-4-fluoro-N,N-dimethylpyrrolidine-1-carboxamide
[0890] Dimethylamine (366 .mu.L) was added to a solution of
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amin-
o]-4-fluoropyrrolidine-1-carbonyl chloride (40 mg) in THF (2-mL) at
0.degree. C. The mixture was stirred at room temperature under a
dry atmosphere for 2 h. The mixture-55 was neutralized with 0.05 M
hydrochloric acid at 0.degree. C. and extracted with EtOAc. The
organic layer was separated, washed with water and saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure to give the title compound (35.0 mg).
[0891] MS: [M+H].sup.+ 425.0.
B)
(2S,3R,4S)-3-[(dimethylsulfamoyl)amino]-4-fluoro-2-[(2-fluoro-3'-methyl-
[1,1'-biphenyl]-3-yl)methyl]-N,N-dimethylpyrrolidine-1-carboxamide
[0892] A mixture of
(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amin-
o]-4-fluoro-N,N-dimethylpyrrolidine-1-carboxamide (35 mg),
m-tolylboronic acid (16.8 mg), XPhos Pd G3 (6.97 mg) and 1 M
potassium phosphate, aqueous solution (0.247 mL) in THF (3 mL) was
heated at 85.degree. C. for 3 h under microwave irradiation. The
mixture was neutralized with saturated aqueous sodium hydrogen
carbonate solution at 0.degree. C. and extracted with EtOAc. The
organic layer was separated, washed with water and saturated brine,
dried over magnesium sulfate and concentrated under reduced
pressure. The crude was purified by column chromatography (NH
silica gel, eluted with EtOAc/hexane) to give the title compound
(13.0 mg).
[0893] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.41 (3H, s), 2.65
(6H, s), 2.80 (6H, s), 2.82-2.90 (1H, m), 3.00-3.08 (1H, m),
3.58-3.76 (1H, m), 3.78-4.04 (2H, m), 4.75-4.89 (2H, m), 5.01-5.39
(1H, m), 7.07-7.15 (1H, m), 7.15-7.23 (2H, m), 7.24-7.27 (1H, m),
7.28-7.36 (3H, m).
Example 462
N'-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)methyl]-
-1-(1-hydroxycyclobutane-1-carbonyl)pyrrolidin-3-yl]-N,N-dimethylsulfuric
diamide
A)
N'-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-1-(1-hydrox-
ycyclobutane-1-carbonyl)pyrrolidin-3-yl]-N,N-dimethylsulfuric
diamide
[0894] To a solution of
N'-{(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoropyrrolidin-3-y-
l}-N,N-dimethylsulfuric diamide hydrobromide (40 mg) and
1-hydroxycyclobutane-1-carboxylic acid (12.8 mg) in DMF (1 mL) were
added HATU (52.5 mg) and DIPEA (0.048 mL) at room temperature. The
mixture was stirred overnight at room temperature. The mixture was
quenched with saturated aqueous sodium hydrogen carbonate solution
and extracted with EtOAc. The organic layer was separated, washed
with water and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography (NH silica gel, eluted with EtOAc/hexane) to
give the title compound (40.0 mg).
[0895] MS: [M+H].sup.+ 452.0.
B)
N'-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-yl)meth-
yl]-1-(1-hydroxycyclobutane-1-carbonyl)pyrrolidin-3-yl]-N,N-dimethylsulfur-
ic diamide
[0896] A mixture of
N'-[(2S,3R,4S)-2-[(3-chloro-2-fluorophenyl)methyl]-4-fluoro-1-(1-hydroxyc-
yclobutane-1-carbonyl)pyrrolidin-3-yl]-N,N-dimethylsulfuric diamide
(40 mg), m-tolylboronic acid (18.1 mg), XPhos Pd G3 (7.49 mg) and 1
M aqueous potassium phosphate solution (0.266 mL) in THF (3 mL) was
heated at 85.degree. C. for 3 h under microwave irradiation. The
mixture was neutralized with aqueous saturated ammonium chloride
solution at 0.degree. C. and extracted with EtOAc. The organic
layer was separated, washed with water and saturated brine, dried
over magnesium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (32.0 mg).
[0897] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.59-1.70 (1H, m),
1.82-1.97 (1H, m), 1.97-2.14 (2H, m), 2.15-2.20 (1H, m), 2.41 (3H,
s), 2.57 (8H, s), 2.98-3.11 (1H, m), 3.11-3.27 (1H, m), 3.74-4.30
(3H, m), 4.72-4.84 (1H, m), 4.85-5.01 (1H, m), 5.09-5.34 (1H, m),
7.10-7.23 (2H, m), 7.26-7.30 (1H, m), 7.31 (3H, s), 7.36-7.47 (1H,
m).
Example 463
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-fluoro-2-[(2-fluoro-3'-methyl[1,-
1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide
[0898] A mixture of
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-[(3-chloro-2-fluorophenyl)methy-
l]-4-fluoropyrrolidin-3-yl}-N,N-dimethylsulfuric diamide (35 mg),
m-tolylboronic acid (16.3 mg), XPhos Pd G3 (6.78 mg) and 1 M
aqueous potassium phosphate solution (0.240 m) in THF (3 mL) was
heated at 85.degree. C. for 3 h under microwave irradiation. The
mixture was neutralized with aqueous saturated ammonium chloride
solution at 0.degree. C. and extracted with EtOAc. The organic
layer was separated, washed with water and saturated brine, dried
over magnesium sulfate and concentrated under reduced pressure. The
residue was purified by column chromatography (NH silica gel,
eluted with EtOAc/hexane) to give the title compound (13.0 mg).
[0899] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.03-2.16 (2H, m),
2.41 (3H, s), 2.63-2.69 (6H, m), 2.90-2.99 (1H, m), 3.03-3.15 (1H,
m), 3.59-4.01 (7H, m), 4.63-4.76 (1H, m), 4.76-4.91 (1H, m),
5.03-5.41 (1H, m), 7.10-7.21 (2H, m), 7.26-7.37 (5H, m).
Example 505
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-3-yl]methyl}-4,-
4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulfona-
mide with Longer Retention Time
A) tert-butyl
(2S,3R)-2-{[3'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-3-yl]methyl}-3-[(-
ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate
[0900] A mixture of tert-butyl
(2S,3R)-2-(3-chloro-2-fluorobenzyl)-3-(ethylsulfonamido)-4,4-difluoropyrr-
olidine-1-carboxylate (270 mg), (3-(difluoromethyl)phenyl)boronic
acid (203 mg), XPhos Pd G3 (50.0 mg) and 1 M aqueous potassium
phosphate solution (1.77 mL) in THF (7 ml) was stirred overnight at
90.degree. C. in sealed tube. The mixture was quenched with
saturated aqueous sodium hydrogen carbonate solution and extracted
with EtOAc. The organic layer was separated, washed with saturated
brine, dried over sodium sulfate and concentrated under reduced
pressure. The mixture was purified by column chromatography (silica
gel, eluted with EtOAc/hexane) to give the title compound (231
mg).
[0901] MS: [M-H].sup.- 547.2.
B)
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-3-yl]methyl}-
-4,4-difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride
[0902] The mixture of tert-butyl
(2S,3R)-2-{[3'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-3-yl]methyl}-3-[(-
ethanesulfonyl)amino]-4,4-difluoropyrrolidine-1-carboxylate (231
mg) and 4 M HCl/CPME solution (5 mL) was stirred at room
temperature for 2 h. White solid was collected by filtration to
give the title compound (195 mg).
[0903] MS: [M+H].sup.+ 449.1.
C)
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-3-yl]methyl}-
-4,4-difluoro-1-(3-fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl]ethanesulf-
onamide with Longer Retention Time
[0904] To a mixture of 3-fluorocyclobutanecarboxylic acid (29.2
mg),
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-fluoro[1,1'-biphenyl]-3-yl]methyl}-4-
,4-difluoropyrrolidin-3-yl]ethanesulfonamide hydrochloride (60 mg),
DIPEA (0.130 mL) and DMF (1 mL) was added HATH (75 mg) at room
temperature. The mixture was stirred at room temperature for 3 h.
The mixture was quenched with aqueous saturated ammonium chloride
solution at room temperature and extracted with EtOAc. The organic
layer was separated, washed with saturated aqueous sodium hydrogen
carbonate solution and saturated brine, dried over sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography (silica gel, eluted with EtOAc/hexane) and
then preparative HPLC (Column: CHIRALCEL 0J-H, mobile phase: carbon
dioxide/MeOH=900/100 (v/v)) to give the title compound (25.6
mg).
[0905] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 1.25-1.48 (3H, m),
1.63-3.30 (9H, m), 3.70-5.30 (6H, m), 6.53-6.88 (1H, m), 7.14-7.71
(7H, m).
Example 542
N'-{(2S,3R)-4,4-difluoro-1-[(2R)-oxetane-2-carbonyl]-2-[(2,3',5'-trifluoro-
[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide
A) (2R)-oxetane-2-carboxylic Acid
[0906] Iodobenzene diacetate (8.04 g),
(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (0.532 g) and
(R)-oxetan-2-ylmethanol (1.00 g) were combined, and to this mixture
were added CH.sub.3CN (50 mL) and water (50.0 mL) and then the
mixture was stirred for 3 h at room temperature. The mixture was
neutralized with 1 M NaOH aqueous solution at 0.degree. C. and the
aqueous layer was washed with IPE. The aqueous layer was acidified
with 2 M hydrochloric acid at 0.degree. C. To the mixture was added
NaCl and the mixture was extracted with THF/EtOAc). The organic
layer was separated, dried over magnesium sulfate and concentrated
under reduced pressure. To the residue was added toluene and the
mixture was concentrated under reduced pressure to give the title
compound (0.510 g).
[0907] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.69-2.90 (1H, m),
3.00-3.22 (1H, m), 4.68-4.88 (2H, m), 5.07-5.33 (1H, m).
B) tert-butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amino]--
4,4-difluoropyrrolidine-1-carboxylate
[0908] A mixture of tert-butyl
(2S,3R)-3-amino-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidi-
ne-1-carboxylate (500 mg) and DMAP (335 mg) in dimethylsulfamoyl
chloride (4 mL) was stirred at 65.degree. C. for 5 h under nitrogen
atmosphere. The reaction mixture was cooled to room temperature and
purified by column chromatography (NH silica gel, eluted with
EtOAc/hexane) to give the title compound (541 mg).
[0909] MS, found: 416.0.
C)
N'-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin--
3-yl}-N,N-dimethylsulfuric diamide hydrochloride
[0910] tert-Butyl
(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-3-[(dimethylsulfamoyl)amino]--
4,4-difluoropyrrolidine-1-carboxylate (541 mg) was stirred in 4 M
HCl/CPME solution (10 mL) at 60.degree. C. for 1 h. The mixture was
concentrated under reduced pressure, triturated with IPE and
collected by filtration to give the title compound (439 mg).
[0911] MS: [M+H].sup.+ 372.0.
D)
N'-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(2R)-ox-
etane-2-carbonyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric diamide
[0912] To a solution of
N'-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoropyrrolidin-3--
yl}-N,N-dimethylsulfuric diamide hydrochloride (100 mg) and
(2R)-oxetane-2-carboxylic acid (0.034 mL) in DMF (5 mL) were added
HATU (140 mg) and DIPEA (0.171 mL) at room temperature. The mixture
was stirred overnight at room temperature. The mixture was quenched
with aqueous saturated ammonium chloride solution and extracted
with EtOAc. The organic layer was separated, washed with water and
saturated brine, dried over sodium sulfate and concentrated under
reduced pressure. The residue was purified by column chromatography
(NH silica gel, eluted with EtOAc/hexane) to give the title
compound (109 mg).
[0913] MS: [M+H].sup.+ 456.0.
E)
N'-{(2S,3R)-4,4-difluoro-1-[(2R)-oxetane-2-carbonyl]-2-[(2,3',5'-triflu-
oro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric
diamide
[0914] A mixture of
N'-{(2S,3R)-2-[(3-chloro-2-fluorophenyl)methyl]-4,4-difluoro-1-[(2R)-oxet-
ane-2-carbonyl]pyrrolidin-3-yl}-N,N-dimethylsulfuric diamide (22
mg), (3,5-difluorophenyl)boronic acid (15.2 mg), XPhos Pd G3 (4.08
mg) and 1M aqueous potassium phosphate solution (0.145 mL) in DME
(0.8 mL) was stirred at 80.degree. C. under nitrogen atmosphere for
2 h. The mixture was purified by column chromatography (silica gel,
eluted with EtOAc/hexane) to give the title compound (16.4 mg).
[0915] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 2.71-3.06 (9H, m),
3.06-3.25 (1H, 1), 3.69-3.90 (1H, m), 4.05-5.17 (7H, m), 6.77-6.87
(1H, m), 7.06 (2H, d, J=7.0 Hz), 7.21 (1H, q, J=7.3 Hz), 7.27-7.48
(2H, m).
[0916] The compounds of Examples are shown in the following tables.
MS in the tables means actual measured value. The compounds of
Examples 6, 9-12, 14-20, 22-24, 27-34, 36-43, 47-49, 53-55, 57-65,
69-72, 74, 75, 80, 82-86, 89, 90, 93, 95, 96, 99-105, 107-115,
117-120, 123, 125-128, 130, 132, 134-143, 148-170, 172-201, 203,
204, 206-209, 213-219, 221-224, 227-235, 237, 238, 240-244, 246,
247, 252-256, 258-266, 268-271, 273-301, 303, 306, 308-345,
347-373, 377, 379, 382, 384-387, 389-391, 394-430, 432, 434, 438,
444-449, 452-457, 460, 461, 464-504, 506-541 and 543-616 in the
following tables were produced according to the methods described
in the above-mentioned Examples, or methods analogous thereto.
TABLE-US-00001 TABLE 1-1 EX. IUPAC NAME Structure ADDITIVE MS 1
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-((2R)-oxetane- 2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00016## 501.4 2
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00017## 507.1 3 N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00018## 521.1 4 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00019##
471.2 5 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00020##
485.2 6 N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-3,3,3- trifluoro-2-hydroxy-2-
methylpropanoyl]pyrrolidin-3- yl}methanesulfonamide ##STR00021##
523.3 7 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00022##
487.2 8 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00023##
503.1 9 N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-[(2R)-oxolane- 2-carbonyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00024## 501.1 10
(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-3- [(methanesulfonyl)amino]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00025## 474.1 11
N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4,4-difluoropyrrolidin-3- yl}methanesulfonamide ##STR00026## 486.1
12 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(3-
fluoroazetidine-1-carbonyl)pyrrolidin-3- yl]methanesulfonamide
##STR00027## 504.1 13 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]methanesulfonamide
##STR00028## 501.1 14 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00029## 503.1 15 rac-N-[(2S,3R,4R)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00030## 471.2 16 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-hydroxy-2-
methylbutanoyl)pyrrolidin-3- yl]methanesulfonamide with shorter
retention time ##STR00031## 503.2 17
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-hydroxy-2-
methylbutanoyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00032## 503.2 18
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00033## 481.2 19 N-[(2S,3R)-2-[(2',3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00034## 503.2 20 N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00035##
485.2 21 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00036## 479.2 22 N-{(2S,3R)-1-(1-cyanocyclobutane-1-
carbonyl)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00037## 490.2 23 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00038## 497.2 24 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(3-
hydroxyazetidine-1-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00039## 498.2 25 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl [1,1'-biphenyl]-3-yl) methyl]-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00040## 485.2 26 N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-oxolane-2- carbonyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00041## 483.2 27
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4- difluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00042##
521.2 28 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoropyrrolidin-3- yl}methanesulfonamide
##STR00043## 497.2 29 N-{(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-[(2R)-oxolane-2- carbonyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00044## 465.2 30
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[([1,1'-biphenyl]-3-yl)methyl]-
4,4-difluoropyrrolidin-3- yl}methanesulfonamide ##STR00045## 461.2
31 N-[(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00046## 503.2 32 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00047## 475.2 33 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methoxy[1,1'-biphenyl]-3-yl)methyl]-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00048## 501.2 34 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(1-
methylcyclopropane-1-carbonyl)pyrrolidin- 3-yl]methanesulfonamide
##STR00049## 483.2 35 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00050##
473.2 36 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxolane-2-carbonyl]pyrrolidin-3- yl}methanesulfonamide
##STR00051## 501.2 37 N-[(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methynpyrrolidin-3- yl}methanesulfonamide
##STR00052## 507.1 38 N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00053## 507.2 39 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]cyclopropanesulfonamide
##STR00054## 515.2 40 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]cyclopropanesulfonamide
##STR00055## 497.2 41 N-[(2S,3R)-2-([3'-(difluoromethoxy)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4- difluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00056##
537.1 42 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[(3'-chloro[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3- yl}methanesulfonamide
##STR00057## 495.1 43 N-{(2S,3R)-2-[(3'-chloro[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-[(2R)-oxolane-2- carbonyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00058## 499.1 44
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00059## 505.1 45 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with shorter retention
time ##STR00060## 483.2 46
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with longer retention
time ##STR00061## 483.1 47 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1- (oxetane-2-carbonyl)-3-
yl]methanesulfonamide with shorter retention time ##STR00062##
487.2 48 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00063## 487.1 49
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-((2S)-oxetane- 2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00064## 501.1 50
N-[(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with shorter retention
time ##STR00065## 465.2 51 N-[(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with longer retention
time ##STR00066## 465.2 52
N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with shorter retention
time ##STR00067## 483.2 53
N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with longer retention
time ##STR00068## 483.2 54 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00069## 501.2 55
N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00070## 501.1 56
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00071## 519.1 57 N-{(2S,3R)-4,4-difluoro-1-((2S)-oxetane-
carbonyl)-2-[(2,3',5'-trifluoro[1,1-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00072## 519.1 58 N-{(2S,3R)-1-(cyclobutanecarbonyl)-4,4-
difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00073## 467.2 59
(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'- biphenyl]-3-yl)methyl]-3-
[(methanesulfonyl)amino]-N,N- dimethylpyrrolidine-1-carboxamide
##STR00074## 456.2 60 N-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(3'-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00075## 468.2 61
N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide with shorter retention time ##STR00076##
469.2 62 N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide with longer retention time ##STR00077## 469.2
63 N-[(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide with shorter retention time ##STR00078##
451.2 64 N-[(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide with longer retention time ##STR00079## 451.2
65 N-[(2S,3R)-2-[(2,2'-difluoro-3-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00080## 517.2 66 N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00081## 521.1 67 N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00082## 521.1 68 N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00083## 519.1 69 N-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(6-
methylpyridin-2-yl)phenyl]methyl}-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00084## 500.2 70 N-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4-
methylpyridin-2-yl)phenyl]methyl}-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00085## 500.2 71 N-[(2S,3R)-2-{[3-(4,6-dimethylpyridin-2-
yl)-2-fluorophenyl]methyl}-4,4-difluoro-1-
(2-hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00086## 514.2 72 N-{(2S,3R)-4,4-difluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00087## 519.1 73 N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-oxolane-2- carbonyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00088## 483.2 74
N-{(2S,3R)-4,4-difluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00089## 519.1 75 N-{(2S,3R)-4,4-difluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00090## 519.1 76 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]methanesulfonamide
##STR00091## 483.2 77 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00092## 455.2 78
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00093## 479.2 79 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide with shorter retention time ##STR00094##
469.2 80 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide with longer retention time ##STR00095## 469.2
81 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-((2R)-oxetane- 2-carbonyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00096## 487.2 82
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-((2S)-oxetane- 2-carbonyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00097## 487.2 83
N-{(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00098## 479.2 84
N-{(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxolane-2-carbonyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00099## 515.2 85 N-{(2S,3R)-2-[(2',3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxolane-2-carbonyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00100## 515.2 86 N-{(2S,3R)-2-[(2',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxolane-2-carbonyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00101## 515.2 87 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2,3',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}methanesulfonamide ##STR00102## 515.3 88
N-{(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00103## 497.2 89
N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methyloxolane-2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with shorter retention time ##STR00104## 511.2
90 N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methyloxolane-2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with longer retention time ##STR00105## 511.2
91 N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00106## 505.1 92 N-{(2S,3R)-4,4-difluoro-1-((2S)-oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00107## 505.1 93 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoropyrrolidin-3- yl}ethanesulfonamide
##STR00108## 511.2 94 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00109## 487.2 95
rac-N-[(2S,3R,4S)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4-fluoro-1-(2-hydroxy-2- methylpropanoyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00110## 435.2 96
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00111## 493.2 97 N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00112## 469.2 98
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00113## 473.2 99
N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-{[2-fluoro-3-(6- methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]methanesulfonamide ##STR00114##
494.2 100 N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-{[2-fluoro-3-(4- methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]methanesulfonamide ##STR00115##
494.2 101 N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[3-(4,6-dimethylpyridin-2-yl)-
2-fluorophenyl]methyl}-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00116## 508.2 102
N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[3-(2,6-dimethylpyridin-4-yl)-
2-fluorophenyl]methyl]-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00117## 508.2 103
N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-{[2-fluoro-3-(6- methoxypyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]methanesulfonamide ##STR00118##
510.2 104 N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-4,4-
difluoro-2-{[3-(4-methylpyridin-2- yl)phenyl]methyl}pyrrolidin-3-
yl]ethanesulfonamide ##STR00119## 480,2 105
N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00120## 497.1 106
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00121## 469.2 107
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[([1,1'-biphenyl]-3-yl)methyl]-
4,4-difluoropyrrolidin-3- yl}ethanesulfonamide ##STR00122## 475.2
108 N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-{[3-(6- methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]ethanesulfonamide ##STR00123##
490.2 109 N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[3-(4,6-dimethylpyridin-2-
yl)phenyl]methyl}-4,4-difluoropyrrolidin-3- yl]ethanesulfonamide
##STR00124## 504.2 110 N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-{[3-(4- methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]ethanesulfonamide ##STR00125##
490.2 111 N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[3-(2,6-dimethylpyrimidin-4-
yl)-2-fluorophenyl]methyl}-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00126## 509.1 112
N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[3-(4,6-dimethylpyrimidin-2-
yl)phenyl]methyl}-4,4-difluoropyrrolidin-3- yl]ethanesulfonamide
##STR00127## 505.2 113 N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-{[3-(6- methoxypyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]ethanesulfonamide ##STR00128##
506.2
114 N-[(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-{[3-(4-methylpyridin-
2-yl)phenyl]methyl}pyrrolidin-3- yl]ethanesulfonamide ##STR00129##
466.2 115 N-[(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00130## 451.2 116
N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00131##
487.2 117 N-[(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-{[3-(6-methylpyridin-
2-yl)phenymethyl}pyrrolidin-3- yl]ethanesulfonamide ##STR00132##
466.2 118 N-[(2S,3R)-2-{[3-(4,6-dimethylpyridin-2-
yl)phenyl]methyl}-4,4-difluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00133## 480.2 119
N-[(2S,3R)-2-[([1,1'-biphenyl]-3- yl)methyl]-4,4-difluoro-1-(2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00134##
437.2 120 N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00135## 453.2 121
N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00136## 505.1 122 N-{(2S,3R)-4,4-difluoro-1-((2R)-oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00137## 505.1 123 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00138## 493.3 124 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00139##
495.2 125 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00140##
495.2 126 N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-oxolane-2- carbonyl]pyrrolidin-3-
yl}cyclopropanesulfonamide ##STR00141## 509.2 127
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methyloxetane-2-carbonyl)pyrrolidin-3-
yl]methanesulfonamide with shorter retention time by HPLC (column
CHIRALPAK IC (4.6 mmI.D. .times. 250 mmL, 5 .mu.m), mobile phase:
hexane/EtOH/diethylamine = 550/450/1 (v/v/v)) ##STR00142## 483.2
128 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methyloxetane-2-carbonyl)pyrrolidin-3-
yl]methanesulfonamide with longer retention time by HPLC (column:
CHIRALPAK IC (4.6 mmI.D. .times. 250 mmL, 5 .mu.m), mobile phase:
hexane/EtOH/diethylamine = 550/450/1 (v/v/v)) ##STR00143## 483.2
129 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-{oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00144##
513.2 130 N-[(2S,3R)-2-[(2,3-difluoro[1,1-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00145##
513.1 131 N-[(2S,3R)-2-[(2',3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00146##
473.2 132 N-[(2S,3R)-2-[(2',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00147##
473.2 133 N-{(2S,3R)-4,4-difluoro-1-((2S)-oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
bipheny]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00148## 505.1 134 N-{(2S,3R)-4,4-difluoro-1-((2S)-oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00149## 505.1 135 N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-yl]-N,N-
dimethylsulfuric diamide with shorter retention time ##STR00150##
498.1 136 rac-N-[(2S,3R)-2-{[2-(3,5-difluorophenyl)-
1,3-thiazol-4-yl]methyl}-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]methanesulfonamide
##STR00151## 508.1 137 N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-yl]-N,N-
dimethylsulfuric diamide with longer retention time ##STR00152##
498.1 138 (2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-
yl)methyl]-N,N-dimethylpyrrolidine-1- carboxamide ##STR00153##
485.2 139 N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric diamide
##STR00154## 497.2 140 N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3-yl]N,N- dimethylsulfuric diamide
##STR00155## 500.3 141 N'-{(2S,3R)-1-(cyclobutanecarbonyl)-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric diamide
##STR00156## 496.2 142 (2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-
yl)methyl]-N-methoxy-N-methylpyrrolidine- 1-carboxamide
##STR00157## 501.2 143 N'-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric
diamide ##STR00158## 508.2 144
N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-
difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-
3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00159## 500.8
145 N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00160## 512.2 146
N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00161## 505.2 147 N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00162## 505.2 148 N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00163## 505.2 149 N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-yl]-N,N-
dimethylsulfuric diamide ##STR00164## 484.2 150
N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-4,4-
difluoro-2-{[2-fluoro-3-(4-methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]methanesulfonamide ##STR00165##
484.2 151 N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-2-
{[3-(4,6-dimethylpyrimidin-2-yl)-2-
fluorophenyl]methyl}-4,4-difluoropyrrolidin-
3-yl]methanesulfonamide ##STR00166## 499.3 152
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methyloxetane-2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with shorter retention time by SFC (column:
CHIRALPAK IC (4.6 mmI.D. .times. 150 mmL, 5 .mu.m), mobile phase:
carbon dioxide/(MeOH/diethylamine) = 1000/1) = 750/250 (v/v))
##STR00167## 497.2 153 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
longer retention time ##STR00168## 531.1 154
N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-2-
{[3-(4,6-dimethylpyridin-2-yl)-2-
fluorophenyl]methyl}-4,4-difluoropyrrolidin-
3-yl]methanesulfonamide ##STR00169## CF.sub.3COOH 498.2 155
N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-4,4-
difluoro-2-{[2-fluoro-3-(6-methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]methanesulfonamide ##STR00170##
CF.sub.3COOH 484.2 156 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methylipyrrolidin-3- yl}cyclopropanesulfonamide with
longer retention time ##STR00171## 531.1 157
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
shorter retention time ##STR00172## 531.1 158
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-
methyloxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
longer retention time ##STR00173## 501.2 159
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
longer retention time ##STR00174## 531.2 160
N-[(2S,3R)-2-[(3',4'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00175##
471.2 161 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methyloxetane-2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with longer retention time by SFC (column:
CHIRALPAK IC (4.6 mmI.D. .times. 150 mmL, 5 .mu.m), mobile phase:
carbon dioxide/(MeOH/diethylamine) = 1000/1) = 750/250 (v/v))
##STR00176## 497.2 162 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
shorter retention time ##STR00177## 531.2 163
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]cyclopropanesulfonamide ##STR00178## 499.2 164
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-
methyloxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
shorter retention time ##STR00179## 501.1 165
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
shorter retention time ##STR00180## 531.1 166
N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00181## 517.2 167 N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00182## 517.1
168 N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00183## 517.2 169 N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
shorter retention time ##STR00184## 513.1 170
N-[(2S,3R)-2-[(3',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
longer retention time ##STR00185## 513.2 171
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]cyclopropanesulfonamide ##STR00186## 481.2 172
N-[(2S,3R)-2-[(2',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00187## 501.1 173
N-[(2S,3R)-2-[(2',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00188## 501.1 174
N-[(2S,3R)-2-[(2',3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00189## 501.2 175
N-[(2S,3R)-2-[(2',3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00190## 501.2 176
N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-4,4-
difluoro-2-{[2-fluoro-3-(4-methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]ethanesulfonamide ##STR00191##
498.2 177 N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-4,4-
difluoro-2-{[2-fluoro-3-(6-methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]ethanesulfonamide ##STR00192##
498.2 178 N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-2-
{[3-(4,6-dimethylpyridin-2-yl)-2-
fluorophenyl]methyl}-4,4-difluoropyrrolidin- 3-yl]ethanesulfonamide
##STR00193## 512.2 179 N-[(2S,3R)-1-(2,2-dimethylpropanoyl)-2-
{[3-(4,6-dimethylpyrimidin-2-yl)-2-
fluorophenyl]methyl}-4,4-difluoropyrrolidin- 3-yl]ethanesulfonamide
##STR00194## 513.3 180 N-[(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00195##
477.2 181 N-[(2S,3R)-2-[([1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoro-1-(oxetane- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00196##
477.2 182 N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00197## 489.2 183 N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00198## 491.1 184 N-{(2S,3R)-4,4-difluoro-1-(2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00199## 491.2 185 N-{(2S,3R)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-[(2R)-oxolane- 2-carbonyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00200## 515.2 186
N-[(2S,3R)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00201## 487.2 187
N-[(2S,3R)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with shorter retention
time ##STR00202## 501.2 188
N-[(2S,3R)-2[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with longer retention
time ##STR00203## 501.1 189
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-
methyloxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with
longer retention time ##STR00204## 515.2 190
N-[(2S,3R)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]cyclopropanesulfonamide ##STR00205## 499.2 191
N-[(2S,3R)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00206##
513.2 192 N-[(2S,3R)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00207##
513.2 193 N-{(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2S)-oxolane-2- carbonyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00208## 483.2 194
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(2-
methyloxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with
shorter retention time ##STR00209## 515.1 195
rac-N-{(2S,3R,4R)-4-fluoro-1-(2-hydroxy-
2-methylpropanoyl)-4-methyl-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00210## 503.2 196
N-[(2S,3R)-2-[(3-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00211##
489.2 197 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2,2',3'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}methanesulfonamide ##STR00212## 515.2
198 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2,2',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}methanesulfonamide ##STR00213## 515.2
199 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoropyrrolidin-3- yl}ethanesulfonamide
##STR00214## 511.2 200 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2,2',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00215## 529.0 201
N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-
difluoro-2-[(2,2',5'-trifluoro[1,1'-biphenyl]-
3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00216## 503.1
202 N-{(2S,3R)-1-(cyclopropanecarbonyl)-2-
[(2,3-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4,4-difluoropyrrolidin-3- yl}ethanesulfonamide ##STR00217## 485.1
203 N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2,2',3'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00218## 529.1 204
N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-
difluoro-2-[(2,2',3'-trifluoro[1,1'-biphenyl]-
3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00219## 503.2
205 N-{(2S,3R)-1-(cyclopropanecarbonyl)-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00220## 467.2 206
N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(3-hydroxy-2,2-
dimethylpropanoyl)pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
##STR00221## 514.2 207 N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00222## 485.2 208 N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00223## 497.1 209 N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00224## 469.2 210
(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-3-[(ethanesulfonyl)amino]-4-
fluoro-N,N-dimethylpyrrolidine-1- carboxamide ##STR00225## 470.2
211 N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4-fluoropyrrolidin-3-yl}ethanesulfonamide ##STR00226## 482.2 212
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4-fluoropyrrolidin-3-yl}ethanesulfonamide ##STR00227## 467.2 213
N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4-fluoropyrrolidin-3- yl}ethanesulfonamide
##STR00228## 493.2 214 N-{(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-[(2R)-
oxolane-2-carbonyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00229##
497.3 215 N-{(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-[(2S)-
oxolane-2-carbonyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00230##
497.3 216 N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00231## 483.2 217
N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00232## 483.2 218
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-1-(3,3-difluorocyclobutane-1-
carbonyl)-4,4-difluoropyrrolidin-3- yl]ethanesulfonamide
##STR00233## 533.3 219 N-{(2S,3R)-1-(3,3-difluoroazetidine-1-
carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoropyrrolidin-3- yl}ethanesulfonamide
##STR00234## 536.4 220 N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00235## 503.4 221 N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00236## 503.4 222 N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00237## 503.4 223 N-{(2S,3R)-1-(cyclobutanecarbonyl)-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00238## 481.4 224
rac-N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-
2-methylpropanoyl)-4-methyl-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00239## 503.4 225
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-((1r,3S)-3-
fluorocyclobutane-1-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00240## 515.2 226 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-((1s,3R)-3-
fluorocyclobutane-1-carbonyl)pyrrolidin yl]ethanesulfonamide
##STR00241## 515.2 227 (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-
yl)methyl]-N,N-dimethylpyrrolidine-1- carboxamide ##STR00242##
470.4 228 N-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00243## 482.4 229
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00244##
467.4 230 N-[(2S,3R,4S)-2-[(2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00245## 485.5 231 N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4-fluoropyrrolidin-3- yl}methanesulfonamide
##STR00246## 479.4 232 N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00247## 455.4 233
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]- 4-fluoropyrrolidin-3-
yl}methanesulfonamide ##STR00248## 453.4 234
(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-
difluoro-2-[(2-fluoro[1,1'-biphenyl]-3-
yl)methyl]-N-methoxy-N-methylpyrrolidine- 1-carboxamide
##STR00249## 486.4 235 N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00250## 471.4 236 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00251## 485.4 237
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,2',3'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00252## 485.4 238
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,2',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00253## 485.4 239
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00254## 449.4 240
N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00255## 489.3 241 N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00256## 489.4 242 N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00257## 489.4 243 N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00258##
453.4 244 N-[(2S,3R,4S)-2-[(2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00259## 471.4 245 N-[(2S,3R)-2-[(3'-chloro-2,5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-1- (cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00260## 503.1 246
N-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(6-
methylpyridin-2-yl)phenyl]methyl}-1-(1-
methylcyclopropane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00261## 496.2 247 N-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4-
methylpyridin-2-yl)phenyl]methyl}-1-(1-
methylcyclopropane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00262## 496.1 248 N-[(2S,3R)-2-[(3'-chloro-2,5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-1- (cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00263## 519.1 249
N-[(2S,3R)-2-[(3'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-1- (cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00264## 519.1 250
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'- biphenyl]-3-yl)methyl]-1-
(cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00265## 487.1 251
N-[(2S,3R)-2-[(5'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-1- (cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00266## 519.1 252
N-[(2S,3R)-2-[(5'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-1- (cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00267## 505.1 253
N-[(2S,3R)-2-[(3'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-1- (cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00268## 505.1 254
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'- biphenyl]-3-yl)methyl]-1-
(cyclopropanecarbonyl)-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00269## 501.1 255
N-[(2S,3R)-2-{[3-(4,6-dimethylpyrimidin-
2-yl)-2-fluorophenyl]methyl}-4,4-difluoro-
1-(1-methylcyclopropane-1-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00270## 511.2 256
ethyl (2S,3R)-2-[(2,3'-difluoro[1,1'- biphenyl]-3-yl)methyl]-3-
[(ethanesulfonyl)amino]-4,4- difluoropyrrolidine-1-carboxylate
##STR00271## 487.2 257 N-[(2S,3R)-1-butanoyl-2-[(2,3'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-
difluoropyrrolidin-3-yl}ethanesulfonamide ##STR00272## 487.4 258
N-{(2S,3R)-1-(2-cyano-2- methylpropanoyl)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-
difluoropyrrolidin-3-yl}ethanesulfonamide ##STR00273## 510.2 259
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
shorter retention time ##STR00274## 503.4 260
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00275## 503.4 261
N-[(2S,3R)-2-[(5'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
shorter retention time ##STR00276## 521.3 262
N-[(2S,3R)-2-[(5'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00277## 521.3 263
N-[(2S,3R)-2-[(3'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
shorter retention time ##STR00278## 521.3 264
N-[(2S,3R)-2-[(3'-chloro-2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00279## 521.3 265
N-[(2S,3R)-2-[(3'-chloro-2,5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
shorter retention time ##STR00280## 521.3 266
N-[(2S,3R)-2-[(3'-chloro-2,5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00281## 521.3 267
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00282## 517.4 268
N-[(2S,3R)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00283## 517.4 269
rac-N-[(2S,3R)-2-{[2-(3,5-difluorophenyl)-
1,3-thiazol-4-yl]methyl}-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00284## 510.2 270 rac-N-[(2S,3R)-2-{[2-(3,5-difluorophenyl)-
1,3-thiazol-4-yl]methy}-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00285## 522.1 271 rac-N-{(2S,3R,4R)-4-fluoro-1-(2-hydroxy-
2-methylpropanoyl)-4-methyl-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00286## 517.2 272
N-{(2S,3R)-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00287## 531.2 273
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00288## 515.2 274 N-{(2S,3R)-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)-2-[(2,2',3'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00289## 533.2 275
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00290## 511.2 276 N-[(2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00291## 529.2 277 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00292## 497.2 278
N-[(2S,3R)-2-[(2,2'-difluoro-3-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00293## 515.2 279
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00294## 497.2 280
N-[(2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00295## 515.2 281
N-[(2S,3R)-2-{[3-(4,6-dimethylpyridin-2-
yl)-2-fluorophenyl]methyl}-4,4-difluoro-1- (1-methylcyclopropane-1-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00296## 510.2 282
(2S,3R)-3-[(ethanesulfonyl)amino]-4,4-
difluoro-N,N-dimethyl-2-[(2,3',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00297## 506.2
283 N-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-
3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00298## 518.2
284 (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-
difluoro-2-[(2-fluoro-3'-methyl[1,1'- biphenyl]-3-yl)methyl]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00299## 484.2 285
N-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00300## 496.2 286 (2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-
yl)methyl]-3-[(ethanesulfonyl)amino]-4,4-
difluoro-N,N-dimethylpyrrolidine-1- carboxamide ##STR00301## 488.2
287 N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4,4-difluoropyrrolidin-3- yl}ethanesulfonamide ##STR00302## 500.2
288 (2S,3R)-3-[(ethanesulfonyl)amino]-4,4-
difluoro-N,N-dimethyl-2-[(2,2',3'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00303## 506.2 289
N-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2,2',3'-trifluoro[1,1'-biphenyl]-
3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00304## 518.1
290 (2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-3- [(ethanesulfonyl)amino]-4,4-difluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00305## 502.2 291
N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,2'-difluoro-3'-methyl[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3- yl}ethanesulfonamide
##STR00306## 514.1 292 N-{(2S,3R,4S)-4-fluoro-1-(2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00307## 487.2 293 N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00308## 451.3 294
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-
fluoro-N,N-dimethyl-2-[(2,2',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00309## 488.2 295
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-
fluoro-2-[(2-fluoro[1,1'-biphenyl]-3-
yl)methyl]-N,N-dimethylpyrrolidine-1- carboxamide ##STR00310##
452.2 296 N-{(2S,3R,4S)-4-fluoro-1-(2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00311## 487.2 297 N-{(2S,3R,4S)-4-fluoro-1-(2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00312## 487.2 298 N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methy]-4-fluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00313## 485.2 299
N-[(2S,3R,4S)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00314##
467.2 300 N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
shorter retention time ##STR00315## 501.2 301
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
longer retention time ##STR00316## 501.1 302
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-((2R)-oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00317## 465.2 303
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-((2S)-oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00318## 465.2 304
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
shorter retention time ##STR00319## 501.2 305
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
longer retention time ##STR00320## 501.1 306
N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00321## 511.2 307 N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
shorter retention time ##STR00322## 501.1 308
N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00323## 475.3 309 N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
longer retention time ##STR00324## 501.1 310
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(3'-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00325## 449.0 311
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}methanesulfonamide ##STR00326## 468.9
312 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,2',3'-trifluoro[1,1'-biphenyl] yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00327## 471.0 313
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,2',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}methanesulfonamide ##STR00328## 471.0
314 N-{(2S,3R,4S)-4-fluoro-1-(2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00329## 473.0 315 N-{(2S,3R,4S)-4-fluoro-1-(2-
methylpropanoyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00330## 473.0 316 N-{(2S,3R,4S)-4-fluoro-1-(2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00331## 473.0 317 N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00332## 437.1 318
N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00333## 469.0 319
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide with
longer retention time ##STR00334## 484.8 320
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide with
longer retention time ##STR00335## 486.9 321
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide with
longer retention time ##STR00336## 486.9 322
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with longer
retention time ##STR00337## 484.9 323
N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
shorter retention time ##STR00338## 469.0 324
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide with
shorter retention time ##STR00339## 486.9 325
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide with
shorter retention time ##STR00340## 486.9 326
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide with
shorter retention time ##STR00341## 486.9 327
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide derived from N- [(2S,3R,4S)-2-[(3-chloro-2-
fluorophenyl)methyl-4-fluoro-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]methanesulfonamide with shorter retention time by HPLC (column:
L- Column2 ODS (3.0 mml.D. .times. 50 mmL, 3 .mu.m), mobile phase:
water/acetonitrile (including 0.05% TFA) ##STR00342## 451.0 328
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]methanesulfonamide with
shorter retention time ##STR00343## 484.9 329
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-
fluoro-N,N-dimethyl-2-[(2,3',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00344## 488.0 330
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-
fluoro-N,N-dimethyl-2-[(2,2',3'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00345## 488.0 331
(2S,3R,4S)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-3-[(ethanesulfonyl)amino]-4-
fluoro-N,N-dimethylpyrrolidine-1- carboxamide ##STR00346## 470.0
332 (2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-3- [(ethanesulfonyl)amino]-4-fluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00347## 485.9 333
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-
fluoro-2-[(2-fluoro-3'-methyl[1,1'- biphenyl]-3-yl)methyl]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00348## 466.0 334
(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'- biphenyl]-3-yl)methyl]-3-
[(methanesulfonyl)amino]-N,N- dimethylpyrrolidine-1-carboxamide
##STR00349## 438.1 335 (2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4-fluoro-3- [(methanesulfonyl)amino]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00350## 456.0 336
(2S,3R,4S)-4-fluoro-3- [(methanesulfonyl)amino]-N,N-dimethyl-2-
[(2,3',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00351## 474.0 337
(2S,3R,4S)-4-fluoro-3- [(methanesulfonyl)amino]-N,N-dimethyl-2-
[(2,2',3'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00352## 474.0 338
(2S,3R,4S)-4-fluoro-3- [(methanesulfonyl)amino]-N,N-dimethyl-2-
[(2,2',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00353## 474.0 339
(2S,3R,4S)-2-[(2,2'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4-fluoro-3- [(methanesulfonyl)amino]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00354## 456.0 340
(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-3- [(methanesulfonyl)amino]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00355## 452.0 341
(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-3- [(methanesulfonyl)amino]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00356## 471.9 342
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2,2'-difluoro[1,1'-biphenyl]-3-yl)methyl]- 4-fluoropyrrolidin-3-
yl}methanesulfonamide ##STR00357## 452.9
343 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00358## 435.1 344
(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-biphenyl]- 3-yl)methyl]-3-
[(dimethylsulfamoyl)amino]-4-fluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00359## 485.0 345
N-[(2S,3R,4S)-2-[(3'-chloro-2,5'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00360##
516.8 346 N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00361## 501.0 347 N-[(2S,3R,4S)-2-[(3'-chloro-2,2'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00362##
518.9 348 N-[(2S,3R,4S)-2-[(5'-chloro-2,2'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00363##
518.9 349 N-{(2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',3'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide with longer retention time ##STR00364## 532.9
350 N-{(2S,3R,4S)-1-(cyclobutanecarbonyl)-4-
fluoro-2-[(3'-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00365## 463.0 351
N-{(2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',3'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide with shorter retention time ##STR00366## 532.9
352 N-{(2S,3R)-2-[(2',5'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxolane-2-carbonyl]pyrrolidin-3- yl}methanesulfonamide
##STR00367## 501.2 353 rac-N-[(2S,3R)-2-{[2-(3,5-difluorophenyl)-
1,3-thiazol-4-yl]methyl}-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00368## 496.1 354 N-{(2S,3R)-2-[(2',3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxolane-2-carbonyl]pyrrolidin-3- yl}methanesulfonamide
##STR00369## 501.2 355 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide derived
from N- [(2S,3R)-2-[(3-chloro-2-
fluorophenyl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time by HPLC (column: L-Column2 ODS (3.0 mml.D. .times.
50 mmL, 3 .mu.m), mobile phase: water/acetonitrile (including 0.05%
TFA) ##STR00370## 519.1 356 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide derived
from N- [(2S,3R)-2-[(3-chloro-2-
fluorophenyl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time by HPLC (column: L-Column2 ODS (3.0 mml.D. .times.
50 mmL, 3 .mu.m), mobile phase: water/acetonitrile (including 0.05%
TFA) ##STR00371## 519.2 357
N-[(2S,3R)-4,4-difluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00372##
495.2 358 N-[(2S,3R)-4,4-difluoro-2-[(3-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00373##
495.2 359 rac-N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-
2-methylpropanoyl)-4-methyl-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00374## 517.3 360
N-[(2S,3R,4S)-2-[(2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00375## 455.2 361
N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00376## 497.2 362 N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00377## 461.2 363 N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00378## 497.2 364 N-[(2S,3R,4S)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00379## 479.2 365 N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00380## 511.2 366 N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00381## 511.1 367 N-[(2S,3R,4S)-2-[(2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00382## 483.2 368
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesufonamide with longer
retention time ##STR00383## 499.2 369
N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]cyclopropanesulfonamide
##STR00384## 497.2 370 N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00385## 515.2 371 N-{(2S,3R,4S)-4-fluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00386## 515.1 372 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]- 4-fluoropyrrolidin-3-
yl}cyclopropanesulfonamide ##STR00387## 479.2 373
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide ##STR00388##
497.2 374 N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}methanesulfonamide
##STR00389## 497.2 375 N-{(2S,3R)-4,4-difluoro-1-((1r,3S)-3-
fluorocyclobutane-1-carbonyl)-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00390## 533.2 376
N-{(2S,3R)-4,4-difluoro-1-((1r,3S)-3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00391## 533.2 377
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,2',3'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide ##STR00392##
497.2 378 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-((1r,3S)-3-
fluorocyclobutane-1-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00393## 497.2 379 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2,2',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide ##STR00394##
497.2 380 N-{(2S,3R)-4,4-difluoro-1-((1s,3R)-3-
fluorocyclobutane-1-carbonyl)-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00395## 533.2 381
N-{(2S,3R)-4,4-difluoro-1-((1s,3R)-3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00396## 533.2 382
N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2- methylpropanoyl)pyrrolidin-3-
yl]cyclopropanesulfonamide ##STR00397## 481.2 383
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-((1s,3R)-3-
fluorocyclobutane-1-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00398## 499.2 384 N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4-fluoropyrrolidin-3- yl}cyclopropanesulfonamide
##STR00399## 505.2 385 N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
shorter retention time ##STR00400## 495.1 386
N-[(2S,3R,4S)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
longer retention time ##STR00401## 495.2 387 (2S,3R,4S)-3-
[(cyclopropanesulfonyl)amino]-2-[(2,3-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-N,N-dimethylpyrrolidine-1- carboxamide ##STR00402## 482.2
388 N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide
##STR00403## 487.1 389 N-[(2S,3R,4S)-2-[(3'-chloro-2,2'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00404##
505.1 390 N-[(2S,3R,4S)-2-[(5'-chloro-2,2'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00405##
505.1 391 N-[(2S,3R,4S)-2-[(3'-chloro-2,5'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin- yl]methanesulfonamide ##STR00406##
505.1 392 N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)pyrrolidin-3- yl]methanesulfonamide
with longer retention time ##STR00407## 501.2 393
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)pyrrolidin-3- yl]methanesulfonamide
with shorter retention time ##STR00408## 501.2 394
N-[(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00409## 529.1 395 N-[(2S,3R,4S)-2-[([1,1'-biphenyl]-3-
yl)methyl]-1-(cyclopropanecarbonyl)-4-
fluoropyrrolidin-3-yl]ethanesulfonamide ##STR00410## 431.1 396
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(3',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4-fluoropyrrolidin-3-yl}ethanesulfonamide ##STR00411## 467.0
397 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2',3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4-fluoropyrrolidin-3-yl}ethanesulfonamide ##STR00412## 467.0 398
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2',5'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4-fluoropyrrolidin-3-yl}ethanesulfonamide ##STR00413## 467.0 399
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2'-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00414## 449.1 400
N-[(2S,3R,4S)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00415## 451.1 401
N-{(2S,3R,4S)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00416## 475.0 402 N-((2S,3R,4S)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2S)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00417## 479.0 403
N-((2S,3R,4S)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00418## 479.0 404
(2S,3R,4S)-3-[(ethanesulfonyl)amino]-4-
fluoro-2-[(3'-fluoro[1,1'-biphenyl]-3-
yl)methyl]-N,N-dimethylpyrrolidine-1- carboxamide ##STR00419##
452.0 405 N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-
fluoro-2-[(3'-fluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00420## 464.0 406
N-[(2S,3R,4S)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with longer retention
time ##STR00421## 465.0 407
N-[(2S,3R,4S)-4-fluoro-2-[(3'-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide with shorter retention
time ##STR00422## 465.0 408
(2S,3R,4S)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-3- [(ethanesulfonyl)amino]-4-fluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00423## 484.0 409
(2S,3R,4S)-2-[(2,4'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-3- [(ethanesulfonyl)amino]-4-fluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00424## 484.0 410
(2S,3R,4S)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-3- [(ethanesulfonyl)amino]-4-fluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00425## 484.0 411
(2S,3R,4S)-2-[(2,2'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-3- [(ethanesulfonyl)amino]-4-fluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00426## 484.0 412
(2S,3R,4S)-2-[(2,4'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-3-[(ethanesulfonyl)amino]-4-
fluoro-N,N-dimethylpyrrolidine-1- carboxamide ##STR00427## 470.0
413 N-{(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00428## 479.0 414
N-{(2S,3R,4S)-4-fluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,3',5'-trifluoro[1,1'-
bipheny]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00429## 515.0 415 N-{(2S,3R,4S)-4-fluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00430## 515.0 416 N-{(2S,3R,4S)-4-fluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00431## 515.0 417 N-{(2S,3R,48)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
[(2R)-oxolane-2-carbonyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00432## 493.0 418 N-{(2S,3R,43)-2-[(2,2'-difluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00433## 511.0 419
N-{(2S,3R,48)-2-[(2,3'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00434## 511.0 420
N-{(2S,3R,4S)-2-[(2,2'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4- fluoro-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00435## 511.0 421
N-[(2S,3R,43)-2-[(2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00436## 483.0 422
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00437## 498.9 423
N-[(2S,3R,4S)-2-[(3'-chloro-2,2'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
derived from N- [(2S,3R,4S)-2-[(3-chloro-2-
fluorophenyl)methyl]-4-fluoro-1-(oxetane- 2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with shorter retention time by HPLC (column:
L-Column2 ODS (3.0 mml.D. .times. 50 mmL, 3 .mu.m), mobile phase:
water/acetonitrile (including 0.05% TFA) ##STR00438## 516.9 424
N-{(2S,3R)-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)-2-[(2,2',3'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}cyclopropanesulfonamide ##STR00439## 544.9 425
(2S,3R)-3-[(cyclopropanesulfonyl)amino]-
4,4-difluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-N,N- dimethylpyrrolidine-1-carboxamide
##STR00440## 496.0 426 N-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00441## 508.0 427 N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00442## 526.0 428
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
shorter retention time ##STR00443## 509.0 429
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
longer retention time ##STR00444## 509.0 430
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]cyclopropanesulfonamide ##STR00445## 523.0 431
N-{(2S,3R)-4,4-difluoro-1-((1r,3S)-3-
fluorocyclobutane-1-carbonyl)-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00446## 518.8 432
N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
with shorter retention time ##STR00447## 512.0 433
N-{(2S,3R)-4,4-difluoro-1-((1s,3R)-3-
fluorocyclobutane-1-carbonyl)-2-[(2,3',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide ##STR00448## 518.9 434
N'-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
with longer retention time ##STR00449## 512.0 435
N-{(2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',3'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide with longer retention time ##STR00450## 518.8
436 N-{(2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',3'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide with shorter retention time ##STR00451##
518.9 437 N-((2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide with longer retention time ##STR00452## 518.8
438 N'-{(2S,3R)-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)-2-[(2,2',3'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-yl}-N,N-
dimethylsulfuric diamide ##STR00453## 547.9 439
N-{(2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2,2',5'-
trifluoro[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}methanesulfonamide with shorter retention time ##STR00454##
518.9 440 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(3-
fluorocyclobutane-1-carbonyl)pyrrolidin-3- yl]methanesulfonamide
with longer retention time ##STR00455## 482.9 441
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(3-
fluorocyclobutane-1-carbonyl)pyrrolidin-3- yl]methanesulfonamide
with shorter retention time ##STR00456## 482.9 442
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-
difluoro-2-[(2-fluoro-3'-methyl[1,1'- biphenyl]-3-yl)methyl]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00457## 499.0 443
N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric
diamide ##STR00458## 511.0 444
N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro-5'-methyl[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3- yl}ethanesulfonamide
##STR00459## 514.0 445 N-[(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00460## 515.0 446
N-[(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00461## 515.0 447
(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'- biphenyl]-3-yl)methyl]-3-
[(ethanesulfonyl)amino]-4,4-difluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00462## 501.9 448
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3',5'-
dimethyl[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00463## 525.0 449 N-[(2S,3R,4S)-2-[(3'-chloro-2,5'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
derived from N- [(2S,3R,4S)-2-[(3-chloro-2-
fluorophenyl)methyl]-4-fluoro-1-(oxetane- 2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with shorter retention time by HPLC (column:
L-Column2 ODS (3.0 mml.D. .times. 50 mmL, 3 .mu.m), mobile phase:
water/acetonitrile (including 0.05% TFA) ##STR00464## 517.0 450
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-
fluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00465## 500.2 451
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-
fluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00466## 478.3 452 N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00467## 479.2
453 N-{(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-[(2R)-oxolane- 2-carbonyl]pyrrolidin-3-
yl}ethanesulfonamide ##STR00468## 515.2 454
N-{(2S,3R)-4,4-difluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00469## 533.2 455 N-{(2S,3R)-4,4-difluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00470## 533.2 456 N-{(2S,3R)-4,4-difluoro-1-[(2R)-oxolane-2-
carbonyl]-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00471## 533.2 457 N-{(2S,3R)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4- difluoro-1-[(2R)-oxolane-2-
carbonyl]pyrrolidin-3-yl}ethanesufonamide ##STR00472## 547.2 458
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-
fluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric diamide
##STR00473## 515.2 459 (2S,3R,4S)-3-[(dimethylsulfamoyl)amino]-
4-fluoro-2-[(2-fluoro-3'-methyl[1,1'- biphenyl]-3-yl)methyl]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00474## 481.3 460
N-[(2S,3R,4S)-2-[(2,2'-difluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
with shorter retention time ##STR00475## 497.2 461
N-[(2S,3R,4S)-2-[(2,3'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
with shorter retention time ##STR00476## 497.2 462
N'-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00477## 508.2 463
N'-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-
fluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric
diamide ##STR00478## 493.3 464 N-[(2S,3R,4S)-2-[(2,2'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
with shorter retention time ##STR00479## 497.2 465
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00480## 499.2 466 N-[(2S,3R)-2-[(2,4'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(2-
hydroxy-2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00481## 517.1 467 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',4'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
longer retention time ##STR00482## 517.2 468
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',4'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
shorter retention time ##STR00483## 519.2 469
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',4',5'-tetrafluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
longer retention time ##STR00484## 535.1 470
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3',4'-tetrafluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
shorter retention time ##STR00485## 537.1 471
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3',4'-tetrafluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
longer retention time ##STR00486## 537.1 472
N-[(2S,3R)-2-[(2,4'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00487## 515.2 473
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',4',5'-tetrafluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
longer retention time ##STR00488## 535.1 474
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',4'-trifluoro-3'- methyl[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with longer retention
time ##STR00489## 533.2 475 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',4',5'-tetrafluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with
shorter retention time ##STR00490## 535.2 476
N-[(2S,3R)-2-[(2,4'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with shorter
retention time ##STR00491## 515.2 477
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',4',5'-tetrafluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl)ethanesulfonamide with
shorter retention time ##STR00492## 537.2 478
N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',4'-trifluoro-3'- methyl[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl)ethanesulfonamide with shorter retention
time ##STR00493## 533.2 479 N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
shorter retention time ##STR00494## 513.2 480
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
shorter retention time ##STR00495## 513.2 481
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
shorter retention time ##STR00496## 513.2 482
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00497##
477.2 483 N-[(2S,3R,4S)-2-[(2,2'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide
derived from N-[(2S,3R,4S)-2-[(3-chloro-2-
fluorophenyl)methyl]-4-fluoro-1-(oxetane- 2-carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time by HPLC
(column: L- Column2 ODS (3.0 mml.D. .times. 50 mmL, 3 .mu.m),
mobile phase: water/acetonitrile (including 0.05% TFA) ##STR00498##
495.2 484 N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
shorter retention time ##STR00499## 491.2 485
N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
shorter retention time ##STR00500## 511.1 486
N-[(2S,3R,4S)-2-[(2,3'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00501##
509.2 487 N-[(2S,3R,4S)-2-[(2,2'-difluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00502##
509.2 488 N-[(2S,3R,4S)-2-[(2,2'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with shorter retention time ##STR00503##
509.2 489 N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
longer retention time ##STR00504## 491.2 490
N-[(2S,3R,4S)-2-[(2,2'-difluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00505##
509.2 491 N-[(2S,3R,4S)-2-[(2,3'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00506##
509.2 492 N-[(2S,3R,4S)-2-[(2,2'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00507##
509.1 493 N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
longer retention time ##STR00508## 513.1 494
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',3'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
longer retention time ##STR00509## 513.1 495
N-{(2S,3R,4S)-4-fluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide with
longer retention time ##STR00510## 513.2 496
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-(oxetane-2- carbonyl)pyrrolidin-3-
yl]cyclopropanesulfonamide with longer retention time ##STR00511##
477.2 497 N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-4-fluoro-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]cyclopropanesulfonamide with
longer retention time ##STR00512## 511.1 498
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-
(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide with longer
retention time ##STR00513## 479.2 499
N-[(2S,3R,4S)-2-[(2,2'-difluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
with longer retention time ##STR00514## 497.2 500
N-[(2S,3R,4S)-2-[(2,4'-difluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin- yl]ethanesulfonamide
derived from N- [(2S,3R,4S)-2-[3-chloro-2-
fluorophenyl)methyl]-4-fluoro-1-(oxetane- 2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with longer retention time by HPLC (column:
L-Column2 ODS (3.0 mml.D. .times. 50 mmL, 3 .mu.m), mobile phase:
water/acetonitrile (including 0.05% TFA) ##STR00515## 497.2 501
N-[(2S,3R,4S)-2-[(2,3'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
with longer retention time ##STR00516## 497.2 502
N-[(2S,3R,4S)-2-[(2,2'-difluoro-5'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4-
fluoro-1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
with longer retention time ##STR00517## 497.2 503
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoro-1-(oxetane-2-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
with longer retention time ##STR00518## 533.1
504 N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoro-1-(oxetane-2-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
with shorter retention time ##STR00519## 533.2 505
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoro-1-(3-fluorocyclobutane-1-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00520## 547.2 506
N-[(2S,3R)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoro-1-(3-fluorocyclobutane-1-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00521## 547.2 507
N-[(2S,3R)-2-([3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoro-1-(2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00522## 519.2 508 N-[(2S,3R)-1-(cyclopropanecarbonyl)-2-
{[3'-(difluoromethyl)-2-fluoro[1,1'- biphenyl]-3-yl]methyl}-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00523## 517.1 509
N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00524## 543.2 510
N-{(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-4,4-difluoro-2-[(2-fluoro-3'- methoxy[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00525## 523.2 511
N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methoxy[1,1'-biphenyl]-3-yl)methyl]-1-(2-
methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide ##STR00526##
499.1 512 N-[(2S,3R)-1-(cyclopropanecarbonyl)-4,4-
difluoro-2-[(2-fluoro-3'-methoxy[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00527## 497.2 513 N-[(2S,3R)-4,4-difluoro-2-[(2-fluoro-3'-
methoxy[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00528## 527.2 514 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-4-
fluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00529## 463.2 515 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2,3'-difluoro-5'-methyl[1,1'-biphenyl]-3-
yl)methyl]-4-fluoropyrrolidin-3- yl}ethanesulfonamide ##STR00530##
481.2 516 N-[(2S,3R,4S)-2-[(3'-chloro-2-fluoro[1,1'-
biphenyl]-3-yl)methyl]-1-
(cyclopropanecarbonyl)-4-fluoropyrrolidin- 3-yl]ethanesulfonamide
##STR00531## 483.2 517 N-[(2S,3R,4S)-2-[(3'-chloro-2,5'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-1-
(cyclopropanecarbonyl)-4-fluoropyrrolidin- 3-yl]ethanesulfonamide
##STR00532## 501.1 518 N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2,2'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4-fluoropyrrolidin-3-yl}ethanesulfonamide ##STR00533## 467.1 519
N-{(2S,3R,4S)-1-(cyclopropanecarbonyl)-2-
[(2,2'-difluoro-3'-methyl[1,1'-biphenyl]-3-
yl)methyl}-4-fluoropyrrolidin-3- yl}ethanesulfonamide ##STR00534##
481.1 520 N-[(2S,3R,4S)-2-[(3'-chloro-2,2'-
difluoro[1,1'-biphenyl]-3-yl)methyl]-1-
(cyclopropanecarbonyl)-4-fluoropyrrolidin- 3-yl]ethanesulfonamide
##STR00535## 501.1 521 (2S,3R)-3-[(cyclopropanesulfonyl)amino]-
2-[(2,2'-difluoro-3]-methyl[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-N,N- dimethylpyrrolidine-1-carboxamide
##STR00536## 514.2 522 (2S,3R)-3-[(cyclopropanesulfonyl)amino]-
2-[(2,3'-difluoro-5'-methyl[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-N,N- dimethylpyrrolidine-1-carboxamide
##STR00537## 514.2 523 (2S,3R)-3-[(cyclopropanesulfonyl)amino]-
2-[(2,3-difluoro[1,1'-biphenyl]-3- yl)methyl]-4,4-difluoro-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00538## 500.2 524
(2S,3R)-3-[(cyclopropanesulfonyl)amino]-
4,4-difluoro-N,N-dimethyl-2-[(2,3',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00539## 518.2 525
N-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-
3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide ##STR00540##
530.1 526 (2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-3- [(dimethylsulfamoyl)amino]-4,4-difluoro-
N,N-dimethylpyrrolidine-1-carboxamide ##STR00541## 517.2 527
N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,2'-difluoro-3'-methyl[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3- yl}cyclopropanesulfonamide
##STR00542## 526.1 528 (2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-3-
yl)methyl]-3-[(dimethylsulfamoyl)amino]-
4,4-difluoro-N,N-dimethylpyrrolidine-1- carboxamide ##STR00543##
503.2 529 N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro-5'-methyl[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3- yl}cyclopropanesulfonamide
##STR00544## 526.2 530 N-{(2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxetane-2-carbonyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00545## 527.2 531 (2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-3- [(dimethylsulfamoyl)amino]-4,4-difluoro-
N,N-dimethylpyrrolidine-1-carboxamide ##STR00546## 517.2 532
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-
difluoro-N,N-dimethyl-2-[(2,3',5'- trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidine-1-carboxamide ##STR00547## 521.2 533
N-{(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxetane-2-carbonyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00548## 527.1 534 N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4,4-difluoropyrrolidin-3- yl}cyclopropanesulfonamide ##STR00549##
512.2 535 N-[(2S,3R,4S)-2-{[3'-(difluoromethyl)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4-fluoro-
1-(oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide derived
from N- [(2S,3R,4S)-2-[(3-chloro-2-
fluorophenyl)methyl]-4-fluoro-1-(oxetane- 2-carbonyl)pyrrolidin-3-
yl]ethanesulfonamide with shorter retention time by HPLC (column:
L-Column2 ODS (3.0 mml.D. .times. 50 mmL, 3 .mu.m), mobile phase:
water/acetonitrile (including 0.05% TFA) ##STR00550## 515.1 536
N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00551## 493.2 537 N-[(2S,3R,4S)-4-fluoro-2-[(2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]cyclopropanesulfonamide ##STR00552## 505.3 538 (2S,3R,4S)-3-
[(cyclopropanesulfonyl)amino]-4-fluoro-2-
[(2-fluoro-3'-methyl[1,1'-biphenyl]-3-
yl)methyl]-N,N-dimethylpyrrolidine-1- carboxamide ##STR00553##
478.2 539 N'-{(2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxetane-2-carbonyl]pyrrolidin-3-yl}- N,N-dimethylsulfuric
diamide ##STR00554## 530.2 540
N'-((2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxetane-2-carbonyl]pyrrolidin-3-yl)- N,N-dimethylsulfuric
diamide ##STR00555## 530.2 541 N'-{(2S,3R)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2R)-oxetane-2-carbonyl]pyrrolidin-3-yl}- N,N-dimethylsulfuric
diamide ##STR00556## 516.2 542
N'-{(2S,3R)-4,4-difluoro-1-[(2R)-oxetane-
2-carbonyl]-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric
diamide ##STR00557## 534.1 543
N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-
fluoro-2-[(2-fluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00558## 490.1 544 N-{(2S,3R,4S)-1-(azetidine-1-carbonyl)-4-
fluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}cyclopropanesulfonamide ##STR00559##
512.2 545 N'-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,2'-difluoro-3'-methyl[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3-yl}-N,N- dimethylsulfuric
diamide ##STR00560## 529.2 546
N'-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro-5'-methyl[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3-yl}-N,N- dimethylsulfuric
diamide ##STR00561## 529.2 547
N'-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(2,3'-difluoro[1,1'-biphenyl]-3-yl)methyl]-
4,4-difluoropyrrolidin-3-yl}-N,N- dimethylsulfuric diamide
##STR00562## 515.2 548 N'-{(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-
3-yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric diamide
##STR00563## 533.2 549 N-[(2S,3R)-2-{[3'-(difluoromethoxy)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoro-1-(2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00564## 535.1 550 N-[(2S,3R)-1-(cyclopropanecarbonyl)-2-
{[3'-(difluoromethoxy)-2-fluoro[1,1'- biphenyl]-3-yl]methyl}-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00565## 533.2 551
N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[3'-(difluoromethoxy)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00566## 559.2 552
N-[(2S,3R)-2-{[3'-(difluoromethoxy)-2-
fluoro[1,1'-biphenyl]-3-yl]methyl}-4,4-
difluoro-1-(1-hydroxycyclobutane-1-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00567## 563.1 553
N-[(2S,3R)-2-[(3'-chloro-2,4'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
((2S)-oxetane-2-carbonyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00568## 535.0 554 N-{(2S,3R)-2-[(3'-chloro-2,4'-difluoro[1,1'-
biphenyl]-3-yl)methyl}-4,4-difluoro-1-
[(2R)-oxetane-2-carbonyl]pyrrolidin-3- yl}ethanesulfonamide
##STR00569## 535.1 555 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',4'-trifluoro-5'- methyl[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with longer retention
time ##STR00570## 533.1 556 N-{(2S,3R)-4,4-difluoro-1-(oxetane-2-
carbonyl)-2-[(2,2',4'-trifluoro-5'- methyl[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide with shorter retention
time
##STR00571## 533.1 557 N-{(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(4'-bromo-2,3'-difluoro[1,1'-biphenyl]-3-
yl)methyl]-4,4-difluoropyrrolidin-3- yl}methanesulfonamide
##STR00572## 564.0 558 N-{(2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2-
fluoro-3'-methoxy[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide with longer retention time ##STR00573## 529.1
559 N-{(2S,3R)-4,4-difluoro-1-(3-
fluorocyclobutane-1-carbonyl)-2-[(2-
fluoro-3'-methoxy[1,1'-biphenyl]-3- yl)methyl]pyrrolidin-3-
yl}ethanesulfonamide with shorter retention time ##STR00574## 529.1
560 N'-[(2S,3R)-1-(azetidine-1-carbonyl)-2-
[(3-chloro-2-fluorophenyl)methyl]-4,4-
difluoropyrrolidin-3-yl}-N,N- dimethylsulfuric diamide ##STR00575##
455.1 561 rac-N-[(2S,3R)-2-{[6-(3,5-
difluorophenyl)pyridin-2-yl]methyl}-4,4- difluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00576##
490.1 562 rac-N-[(2S,3R)-2-{[6-(3,5-
difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(1-hydroxycyclobutane-1- carbonyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00577## 502.1 563
N-{(2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2S)-oxetane-2-carbonyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00578## 527.1 564 N-{(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2S)-oxetane-2-carbonyl]pyrrolidin-3- yl}cyclopropanesulfonamide
##STR00579## 527.1 565 N'-[(2S,3R)-2-[(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00580## 530.1 566
N'-[(2S,3R)-2-[(4'-bromo-2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00581## 608.0 567
N-[(2SR,3RS)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(oxetane-2-carbonyl)pyrrolidin- 3-yl]methanesulfonamide
##STR00582## 488.1 568 rac-N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoropyrrolidin-3-yl]methanesulfonamide ##STR00583## 498.2 569
[(2SR,3RS)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(oxetane-2-carbonyl)pyrrolidin- 3-yl]methanesulfonamide
##STR00584## 488.1 570 N-{(2S,3R)-2-[(5'-chloro-2,2',4'-
trifluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-
difluoro-1-[(2R)-oxetane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00585## 553.1 571
N-{(2S,3R)-2-[(3'-chloro-2,2',4'-
trifluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-
difluoro-1-[(2R)-oxetane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00586## 553.0 572
rac-N-[(2S,3R)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(2-hydroxy-2- methylpropanoyl)pyrrolidin-3-
yl]ethanesulfonamide ##STR00587## 504.1 573
rac-N-[(2S,3R)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(2-methylpropanoyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00588## 488.1 574 rac-N-[(2S,3R)-1-(bicyclo[1.1.1]pentane-1-
carbonyl)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoropyrrolidin-3-yl]ethanesulfonamide ##STR00589## 512.1 575
N'-{(2S,3R)-2-[(2,2'-difluoro-3'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2S)-oxetane-2-carbonyl]pyrrolidin-3-yl)- N,N-dimethylsulfuric
diamide ##STR00590## 530.2 576
N'-{(2S,3R)-2-[(2,3'-difluoro-5'-methyl[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2S)-oxetane-2-carbonyl]pyrrolidin-3-yl)- N,N-dimethylsulfuric
diamide ##STR00591## 530.1 577 N'-{(2S,3R)-2-{(2,3'-difluoro[1,1'-
biphenyl]-3-yl)methyl]-4,4-difluoro-1-
[(2S)-oxetane-2-carbonyl]pyrrolidin-3-yl}- N,N-dimethylsulfuric
diamide ##STR00592## 516.1 578
N'-{(2S,3R)-4,4-difluoro-1-[(2S)-oxetane-
2-carbonyl]-2-[(2,3',5'-trifluoro[1,1'-
biphenyl]-3-yl)methyl]pyrrolidin-3-yl}-N,N- dimethylsulfuric
diamide ##STR00593## 534.1 579
N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-
methylpropanoyl)-2-[(2,2',4'-trifluoro-3- methyl[1,1'-biphenyl]-3-
yl)methyl]pyrrolidin-3- yl}ethanesulfonamide ##STR00594## 535.1 580
rac-N-[(2S,3R)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(1-hydroxycyclobutane-1-
carbonyl)pyrrolidin-3-yl]ethanesulfonamide ##STR00595## 516.1 581
N-[(2SR,3RS)-2-{[6-(3,5- difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(oxetane-2-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00596## 502.1 582 N-[(2SR,3RS)-2-{[6-(3,5-
difluorophenyl)pyridin-2-yl]methyl}-4,4-
difluoro-1-(oxetane-2-carbonyl)pyrrolidin- 3-yl]ethanesulfonamide
##STR00597## 502.1 583 N'-[(2S,3R)-2-[(4'-bromo-2-fluoro-3'-
methyl[1,1'-biphenyl]-3-yl)methyl]-4,4-
difluoro-1-(1-hydroxycyclobutane-1- carbonyl) pyrrolidin-3-yl]-N,N-
dimethylsulfuric diamide ##STR00598## 602.1 584
rac-N-[(2S,3R,4S)-2-{[2-(3,5-
difluorophenyl)-1,3-thiazol-4-yl]methyl}-4- fluoro-1-(2-hydroxy-2-
methylpropanoyl)pyrrolidin-3- yl]methanesulfonamide ##STR00599##
478.1 585 rac-N-[(2S,3R,4S)-1- (cyclobutanecarbonyl)-2-{[2-(3,5-
difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-
fluoropyrrolidin-3-yl]methanesulfonamide ##STR00600## 474.1 586
rac-(2S,3R,4S)-2-{[2-(3,5-difluorophenyl)-
1,3-thiazol-4-yl]methyl}-4-fluoro-3- [(methanesulfonyl)amino]-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00601## 463.1 587
rac-N-[(2S,3R,4S)-2-{[2-(3,5-
difluorophenyl)-1,3-thiazol-4-yl]methyl}-4-
fluoro-1-(1-hydroxycyclobutane-1- carbonyl)pyrrolidin-3-
yl]methanesulfonamide ##STR00602## 490.0 588
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-
(trimethylhydrazinecarbonyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00603## 517.0 589 N'-[(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-{[2-fluoro-3-(6-methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
##STR00604## 512.0 590 (2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-
difluoro-2-{[2-fluoro-3-(6-methylpyridin-2-
yl)phenyl]methyl}-N,N-dimethylpyrrolidine- 1-carboxamide
##STR00605## 500.0 591 N'-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(6-
methylpyridin-2-yl)phenyl]methyl}-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00606## 527.0 592
N-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(6-
methylpyridin-2-yl)phenyl]methyl}-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]cyclopropanesulfonamide ##STR00607## 523.9 593
N-[(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-{[2-fluoro-3-(6-methylpyridin-2-
yl)phenyl]methyl}pyrrolidin-3- yl]cyclopropanesulfonamide
##STR00608## 509.0 594 (2S,3R)-3-[(cyclopropanesulfonyl)amino]-
4,4-difluoro-2-{[2-fluoro-3-(6-
methylpyridin-2-yl)phenyl]methyl}-N,N-
dimethylpyrrolidine-1-carboxamide ##STR00609## 497.0 595
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-
difluoro-2-{[2-fluoro-3-(6-methylpyridin-2-
yl)phenyl]methyl}-N,N-dimethylpyrrolidine- 1-carboxamide
##STR00610## HCl 500.2 596
(2S,3R)-3-[(dimethylsulfamoyl)amino]-4,4-
difluoro-2-{[2-fluoro-3-(5-methylpyridazin-
3-yl)phenyl]methyl}-N,N- dimethylpyrrolidine-1-carboxamide
##STR00611## 501.2 597 N'-[(2S,3R)-1-(azetidine-1-carbonyl)-4,4-
difluoro-2-{[2-fluoro-3-(5-methylpyridazin-
3-yl)phenyl]methyl}pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
##STR00612## 513.2 598 N'-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(5-
methylpyridazin-3-yl)phenyl]methyl}-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00613## 528.2 599
N-[(2S,3R)-2-[(2,3'-difluoro[1,1'-biphenyl]-
3-yl)methyl]-4,4-difluoro-1-
(trimethylhydrazinecarbonyl)pyrrolidin-3- yl]ethanesulfonamide
##STR00614## HCl 517.2 600
N'-[(2S,3R)-2-{[3-(6-ethylpyridin-2-yl)-2-
fluorophenyl]methyl}-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00615## 540.9 601
N'-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(5-
fluoro-6-methylpyridin-2- yl)phenyl]methyl}-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00616## 544.9 602
N'-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(3-
fluoro-6-methylpyridin-2- yl)phenyl]methyl}-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00617## 544.9 603
N'-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(2-
methyl-1,3-thiazol-4-yl)phenyl]methyl}-1- (1-hydroxycyclobutane-1-
carbonyl)pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
##STR00618## 532.9 604 N'-[(2S,3R)-4,4-difluoro-2-({2-fluoro-3-[6-
(trifluoromethyl)pyridin-2- yl]phenyl}methyl)-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00619## 580.9 605
N'-[(2S,3R)-2-({3-[6- (difluoromethyl)pyridin-2-yl]-2-
fluorophenyl}methyl)-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00620## 562.9 606
N'-[(2S,3R)-2-{[3-(4,6-dimethylpyridin-2-
yl)-2-fluorophenyl]methyl}-4,4-difluoro-1- (1-hydroxycyclobutane-1-
carbonyl)pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
##STR00621## 540.9 607 ethyl 2-[3-({(2S,3R)-1-(tert-
butoxycarbonyl)-3- [(dimethylsulfamoyl)amino]-4,4-
difluoropyrrolidin-2-yl}methyl)-2-
fluorophenyl]-1,3-oxazole-4-carboxylate ##STR00622## 577.2 608
N'-[(2S,3R)-2-[(3-chloro-2- fluorophenyl)methyl]-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00623## 468.1 609
N'-[(2S,3R)-4,4-difluoro-2-({2-fluoro-3-[4-
(hydroxymethyl)-1,3-oxazol-2- yl]phenyl}methyl)-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00624## 532.9 610
N'-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(4-
methyl-1,3-oxazol-2-yl)phenyl]methyl}-1- (1-hydroxycyclobutane-1-
carbonyl)pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
##STR00625## 517.2 611 N'-[(2S,3R)-2-{[3-(5-chloro-2-methyl-1,3-
thiazol-4-yl)-2-fluorophenyl]methyl}-4,4-
difluoro-1-(1-hydroxycyclobutane-1- carbonyl)pyrrolidin-3-yl]-N,N-
dimethylsulfuric diamide ##STR00626## 567.1 612
N'-[(2S,3R)-4,4-difluoro-2-{[2-fluoro-3-(2-
methyl-1,3-oxazol-4-yl)phenyl]methyl}-1- (1-hydroxycyclobutane-1-
carbonyl)pyrrolidin-3-yl]-N,N- dimethylsulfuric diamide
##STR00627## 517.2 613 N'-[(2S,3R)-2-{[3-(5-chloro-2-methyl-1,3-
oxazol-4-yl)-2-fluorophenyl]methyl}-4,4-
difluoro-1-(1-hydroxycyclobutane-1- carbonyl)pyrrolidin-3-yl]-N,N-
dimethylsulfuric diamide ##STR00628## 551.1 614
N'-[(2S,3R)-2-{[3-(4-ethyl-6- methylpyridin-2-yl)-2-
fluorophenyl]methyl}-4,4-difluoro-1-(1-
hydroxycyclobutane-1-carbonyl)pyrrolidin-
3-yl]-N,N-dimethylsulfuric diamide ##STR00629## 555.1 615
N-{(2S,3R)-2-[(3'-chloro-2,4',5'-
trifluoro[1,1'-biphenyl]-3-yl)methyl]-4,4-
difluoro-1-[(2R)-oxetane-2-
carbonyl]pyrrolidin-3-yl}ethanesulfonamide ##STR00630## 553.0 616
[3-({(2S,3R)-3-[(N,N- dimethylsulfamoyl)amino]-4,4-difluoro-1-
(1-hydroxycyclobutane-1- carbonyl)pyrrolidin-2-yl}methyl)-2-
fluorophenyl]boronic acid ##STR00631## 480.16
Experimental Example 1: Obtainment of Cell Stably Expressing Human
Orexin Type 2 Receptor (hOX2R)
[0917] To obtain a cell clone stably expressing human orexin type 2
receptor, human orexin type 2 receptor cDNA was inserted into
pcDNA3.1(+) plasmid vector (Invitrogen), and a plasmid DNA for
expression of human orexin type 2 receptor (pcDNA3.1(+)/hOX2R) was
cloned. The plasmid DNA was introduced into CHO-dhfr cell by an
electroporation method, and human orexin type 2 receptor expressing
clone cells were obtained by limiting dilution method by using G418
drug resistance as a selection marker.
Experimental Example 2: Measurement of Orexin Type 2 Receptor
Agonist Activity
[0918] CHO cells forcibly expressing human OX2 receptor were seeded
in each well of 384 well black transparent bottom plate (BD Falcon)
at 7,500 cells/well, and cultured for one day in a 5% CO.sub.2
incubator at 37.degree. C. After removal of the medium in the cell
plate, assay buffer A containing a calcium indicator (HBSS (Thermo
Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1%
BSA (Sigma-Aldrich), 2.5 .mu.g/mL Fluo-4 AM (DOJINDO Chemical),
0.08% Pluronic F127 (DOJINDO Chemical), 1.25 mM probenecid (DOJINDO
Chemical)) was added at 30 .mu.L/well. The plate was stood for 30
min in a 5% CO.sub.2 incubator at 37.degree. C., and further stood
at room temperature for 30 min. A test compound prepared by
diluting with assay buffer B (HBSS, 20 mM HEPES, 0.1% BSA) was
added at 10 .mu.L/well, and the fluorescence value was measured by
FDSS.mu.CELL (Hamamatsu Photonics K.K.) every one sec for 1 min,
and thereafter every two sec for 1 min sec. The activity (%) of the
test compound was calculated assuming that variation in the
fluorescence value when DMSO was added instead of the test compound
was 0%, and variation in the fluorescence value when orexin A
(human) (PEPTIDE INSTITUTE, INC.) was added at the final
concentration of 10 nM was 100%. The activity of each compound at
the concentration of 3 .mu.M was shown in Table 2. As is clear from
the results, the compound of the present invention was shown to
have an agonist activity on human orexin type 2 receptor.
TABLE-US-00002 TABLE 2 Test OX2R agonist compound activity (3
.mu.M, %) 1 100 2 106 3 106 4 101 5 117 7 101 8 99 11 85 13 93 21
102 23 100 25 108 26 100 35 96 44 98 45 98 46 102 50 99 51 99 52
100 56 95 65 100 66 104 67 111 68 106 73 104 76 98 77 95 78 93 79
102 81 95 87 93 88 98 91 94 92 99 93 98 94 99 97 90 98 91 105 99
106 97 116 86 121 94 122 89 124 89 129 92 131 94 133 96 136 87 138
97 139 93 144 88 145 99 146 92 147 91 162 92 163 105 166 98 171 99
174 90 175 95 202 94 204 89 205 91 207 88 210 95 211 94 212 96 216
95 217 96 220 90 222 97 225 96 226 100 228 99 231 95 236 100 238 98
239 102 245 94 248 90 249 90 250 96 251 91 257 96 259 96 263 103
264 98 265 96 266 83 267 92 268 94 272 88 273 83 274 93 275 85 276
88 277 94 282 96 283 93 284 92 285 98 287 94 289 80 291 90 292 87
293 83 294 96 295 95 296 96 297 95 298 96 302 85 304 99 305 103 306
89 307 100 308 94 314 109 316 101 323 92 324 91 328 86 329 88 330
98 332 95 333 78 344 102 345 92 346 93 347 102 348 103 349 98 356
97 365 93 366 96 368 95 369 85 370 91 371 94 372 89 373 88 374 93
375 91 376 99 377 95 378 106 379 93 380 93 381 95 382 102 383 94
384 98 385 95 387 85 388 89 389 89 391 92 392 97 393 94 394 86 408
88 409 92 413 99 414 95 415 107 416 101 422 102 423 90 424 95 425
95 426 90 427 99 428 100 430 96 431 106 432 95 433 101 434 101 435
88 436 92 437 84 438 95 439 93 440 94 441 93 442 96 443 90 444 98
447 95 450 86 451 82 453 85 454 84 455 85 456 77 457 80 458 84 459
78 462 78 463 79 465 106 466 103 467 105 468 102 469 91 470 103 471
94 472 95 473 97 474 96 475 100 476 100 477 96 478 103 479 93 480
101 481 104 482 100 483 108 484 90 485 93 486 88 487 95 488 95 489
92 490 93 491 93 492 90 493 95 494 96 495 92 496 95 497 91 498 99
499 96 500 98 501 96 502 96 503 89 504 90 505 88 506 100 507 97
508 96 509 85 510 97 511 98 512 95 513 97 514 95 515 98 516 102 517
100 518 98 519 98 520 94 521 97 522 97 523 86 524 87 525 85 526 83
527 95 528 83 529 95 530 94 531 95 532 96 533 101 534 98 535 102
536 98 537 100 538 106 539 101 540 100 541 100 542 100 543 99 544
90 545 93 546 96 547 98 548 94 549 94 550 93 551 93 552 94
Experimental Example 3: Evaluation of Microsome Stability in
Human
[0919] Human liver microsomes were purchased from Xenotech, LLC
(Lenexa, Kans.). An incubation mixture consisted of microsomes in
50 mmol/L KH.sub.2PO.sub.4--K.sub.2HPO.sub.4 phosphate buffer (pH
7.4) and 1 .mu.mol/L test compound. The concentration of microsomal
protein was 0.2 mg/mL. An NADPH-generating system (5 mmol/L
MgCl.sub.2, 5 mmol/L glucose-6-phosphate, 0.5 mmol/L beta-NADP+ and
1.5 unit/mL glucose-6-phosphate dehydrogenase) was added to the
incubation-mixture with a half volume of the reaction mixture to
initiate the enzyme reaction. The reaction was terminated 15 and 30
minutes after the initiation of the reaction by mixing the reaction
mixture with acetonitrile, followed by centrifugation at 2500 rpm
for 10 min. The supernatant was subjected to LC/MS/MS analysis. The
metabolic rate constant was calculated as the slope of the
remaining rate-time plot. The in vitro intrinsic metabolic
clearance was calculated by dividing initial metabolic rate
constant by microsomal protein in the incubation mixture. The
results were shown in Table 3.
TABLE-US-00003 TABLE 3 Test Clearance compound (.mu.L/min/mg) 1 75
2 40 3 -3 5 12 56 135 66 61 67 4 87 9 91 65 94 44 144 13 146 83 225
60 236 67 302 3 375 35 380 39 433 16
Experimental Example 4: Evaluation of Wake-Promoting Effects in
Cynomolgus Monkeys
[0920] The wake-promoting effects were evaluated by measuring the
electroencephalogram (EEG) and electromyogram (EMG) in cynomolgus
monkeys. Under isoflurane anesthesia (1-5%, Pfizer Japan Inc.,
Tokyo, Japan), male cynomolgus monkeys (3-5 years old, Hamri Co.,
Ltd., Ibaraki, Japan) were surgically implanted with
radio-telemetry transmitters (TL10M3-D70-EEE, Data Sciences
International Inc., MN, USA). EEG electrodes were screwed into the
skull at the parietal area. EMG electrodes were implanted on the
cervical muscles. After the surgery, each monkey was given
penicillin (100,000 units/head, i.m., Meiji Seika Pharma Co., Ltd.,
Tokyo, Japan), buprenorphine (0.02 mg/kg, i.m., Otsuka
Pharmaceutical Co., Ltd., Tokyo, Japan) and prednisolone (1 mg/kg,
s.c., Kyoritsu Seiyaku Co., Ltd., Tokyo, Japan) daily for one week.
After at least a 1-month recovery period in home cages, the monkeys
were habituated to the recording chamber placed in a soundproof
room. EEG and EMG signals were recorded using the telemetry system
(Dataquest ART software, Data Sciences International Inc., MN, USA)
and the signals were analyzed using SleepSign software (Kissei
Comtec Co., Ltd., Nagano, Japan). After confirming long sleep in
dark phase in the experimental room, we used animals to examine the
wake-promoting effect of compounds.
[0921] Oral test compounds (3 or 10 mg/kg) suspended in 0.5%
methylcellulose aqueous solution, or vehicle (i.e., 0.5%
methylcellulose aqueous solution) was administered orally (p.o.) to
monkeys at zeitgeber time 12 (ZT12) in a volume of 5 mL/kg body
weight in cross-over design or pre-post design (n=1-4). EEG and EMG
recordings were performed for 4 h after the compound
administration. The time spent in wakefulness for 4 h after
administration (% of vehicle treatment) was calculated by using
SleepSign. The results are shown in Table 4.
[0922] Parenteral test compounds (0.1 or 0.3 mg/kg) dissolved in a
mixed solution comprising 5% DMSO, 5% Cremophor EL, 20% PEG400 and
70% soluplus (1% (w/v)), or vehicle (i.e., a mixed solution
comprising 5% DMSO, 5% Cremophor EL, 20% PEG400 and 70% soluplus
(1% (w/v))) was administered subcutaneously (s.c.) to monkeys at
ZT12 in a volume of 0.5 mL/kg body weight in a pre-post design
(n=1-2). EEG and EMG recordings were performed for 4 h after the
compound administration. The time spent in wakefulness for 4 h
after administration (% of vehicle treatment) was calculated by
using SleepSign. The results are shown in Table 5.
TABLE-US-00004 TABLE 4 Wakefulness time Example Dose (% of vehicle
No (mg/kg) treatment) (Mean) 1 3 233.91 2 3 599.68 3 3 612.62 5 10
411.70 56 3 417.22 66 3 463.00 67 3 355.56 87 3 832.34 91 10 548.00
94 3 441.88 144 3 649.41 146 3 426.26 225 3 317.65 236 10 716.00
302 10 287.88 375 3 396.49 380 3 483.53 433 3 727.27
TABLE-US-00005 TABLE 5 Wakefulness time Example Dose (% of vehicle
No (mg/kg) treatment) (Mean) 443 0.1 532.00 450 0.3 813.51 451 0.1
225.10 459 0.3 431.39 462 0.3 365.46 463 0.1 483.15 542 0.3
505.45
[0923] As is clear from Table 4 and Table 5, the test compounds of
the present invention increased the wakefulness time compared to
the vehicle treatment group in cynomolgus monkeys. That is, these
compounds were suggested to be potential therapeutics for
narcolepsy.
Formulation Example 1 (Production of Capsule)
TABLE-US-00006 [0924] 1) compound of Example 1 30 mg 2) crystalline
cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate 1 mg total
60 mg
[0925] 1), 2), 3) and 4) are mixed and filled in a gelatin
capsule.
Formulation Example 2 (Production of Tablet)
TABLE-US-00007 [0926] 1) compound of Example 1 30 g 2) lactose 50 g
3) cornstarch 15 g 4) calcium carboxymethylcellulose 44 g 5)
magnesium stearate 1 g 1000 tablets 140 g in total
[0927] The total amount of 1), 2), 3) and 30 g of 4) are kneaded
with water, vacuum dried and sieved. The sieved powder is mixed
with 14 g of 4) and 1 g of 5), and the mixture is punched by a
tableting machine. In this way, 1000 tablets containing 30 mg of
the compound of Example 1 per tablet are obtained.
INDUSTRIAL APPLICABILITY
[0928] The compound of the present invention has an orexin type 2
receptor agonist activity, and is useful as an agent for the
prophylaxis or treatment of narcolepsy.
[0929] This application is based on patent application No.
2019-015488 filed on Jan. 31, 2019 in Japan, the contents of which
are encompassed in full herein.
* * * * *