U.S. patent application number 13/047660 was filed with the patent office on 2011-07-07 for thienopyrazole derivative having pde7 inhibitory activity.
This patent application is currently assigned to DAIICHI SANKYO COMPANY, LIMITED. Invention is credited to Yasuhiro Hayashi, Hidekazu Inoue, Hidenobu Murafuji.
Application Number | 20110166343 13/047660 |
Document ID | / |
Family ID | 35782844 |
Filed Date | 2011-07-07 |
United States Patent
Application |
20110166343 |
Kind Code |
A1 |
Inoue; Hidekazu ; et
al. |
July 7, 2011 |
THIENOPYRAZOLE DERIVATIVE HAVING PDE7 INHIBITORY ACTIVITY
Abstract
To provide thienopyrazole derivatives inhibiting PDE 7
selectively, and therefore, enhance cellular cAMP level.
Consequently, the compound is useful for treating various kinds of
disease such as allergic diseases, inflammatory diseases or
immunologic diseases. The compound is thienopyrazole compound
represented by the following formula (I): ##STR00001## [wherein,
especially, R.sup.1 is a cyclohexyl, a cycloheptyl group or a
tetrahydropyranyl group; R.sup.2 is methyl; R.sup.3 is a hydrogen
atom; and R.sup.4 is a group: --CONR.sup.5R.sup.6 (in which any one
of R.sup.5 and R.sup.6 is a hydrogen atom)].
Inventors: |
Inoue; Hidekazu;
(Mishima-gun, JP) ; Murafuji; Hidenobu;
(Mishima-gun, JP) ; Hayashi; Yasuhiro;
(Mishima-gun, JP) |
Assignee: |
DAIICHI SANKYO COMPANY,
LIMITED
Tokyo
JP
|
Family ID: |
35782844 |
Appl. No.: |
13/047660 |
Filed: |
March 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11630757 |
May 29, 2008 |
7932250 |
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PCT/JP2005/012208 |
Jul 1, 2005 |
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13047660 |
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Current U.S.
Class: |
540/575 ;
544/140; 544/371; 546/15; 546/16; 546/199; 546/275.7; 548/311.7;
548/360.5; 548/366.1; 548/369.4; 548/374.1 |
Current CPC
Class: |
A61P 25/28 20180101;
A61P 17/04 20180101; A61P 9/00 20180101; A61P 17/06 20180101; A61P
19/00 20180101; A61P 11/06 20180101; A61P 9/10 20180101; A61P 11/00
20180101; A61P 17/00 20180101; A61P 19/02 20180101; A61P 37/06
20180101; A61P 1/16 20180101; A61P 11/02 20180101; A61P 37/00
20180101; A61P 1/04 20180101; A61P 27/16 20180101; A61P 29/00
20180101; A61P 43/00 20180101; C07D 495/04 20130101; A61P 1/18
20180101; A61P 25/00 20180101; A61P 31/04 20180101; A61P 37/02
20180101; A61P 27/02 20180101; A61P 37/08 20180101; A61P 1/00
20180101; A61P 7/00 20180101; C07D 231/18 20130101 |
Class at
Publication: |
540/575 ;
548/366.1; 548/374.1; 548/369.4; 548/360.5; 544/140; 544/371;
546/199; 546/275.7; 546/15; 546/16; 548/311.7 |
International
Class: |
C07D 403/14 20060101
C07D403/14; C07D 231/20 20060101 C07D231/20; C07D 231/16 20060101
C07D231/16; C07D 231/18 20060101 C07D231/18; C07D 487/04 20060101
C07D487/04; C07D 413/14 20060101 C07D413/14; C07D 401/14 20060101
C07D401/14; C07D 471/10 20060101 C07D471/10 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 1, 2004 |
JP |
2004-195836 |
Claims
1-21. (canceled)
22. A compound of the formula (IV): ##STR00545## wherein R.sup.1 is
substituted or unsubstituted C.sub.3-C.sub.8 alkyl group,
substituted or unsubstituted cycloalkyl group or substituted or
unsubstituted heterocycloalkyl group; R.sup.2 is a hydrogen atom or
C.sub.1-C.sub.2 alkyl group; and R.sup.3 is a hydrogen atom.
23. (canceled)
Description
TECHNICAL FIELD
[0001] The present invention relates to thienopyrazole derivatives,
pharmaceutically acceptable salts and solvates thereof, having
selective PDE 7 (phosphodiesterase VII) inhibiting effect. Further,
the present invention relates to an intermediate compounds for
preparing said theinopyrazole derivatives and a process for
producing them. These compounds are effective compounds for
treating various kinds of diseases such as allergic diseases,
inflammatory diseases and immunological diseases.
BACKGROUND ART
[0002] Cyclic AMP (cAMP) or cyclic GMP (cGMP), which is an
intracellular second messenger substance, is decomposed and
inactivated by phosphodiesterases (PDE 1 to PDE 11). The PDE 7
selectively decomposes cAMP, and is characterized as an enzyme
which is not inhibited by rolipram. Rolipram is a selective
inhibitor of PDE 4, which decomposes cAMP similarly.
[0003] It is suggested that PDE 7 plays an important role for
activating T cells (Beavo, et al., Science, 283, 848 (1999)), and
is well known that activation of T-cell is concerned with the
exacerbation of allergic diseases, inflammatory diseases or
immunological diseases. These diseases are for example bronchial
asthma, chronic bronchitis, chronic obstructive pulmonary disease,
allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis,
osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic
lupus erythematosus, inflammatory bowel disease, hepatitis,
pancreatitis, encephalomyelitis, sepsis, Crohn's disease, rejection
reaction in transplantation, graft versus host disease (GVH
disease), and restenosis after angioplasty [J. Allergy Clin.
Immunol., 2000 November; 106(5 Suppl.): S221-6; Am. J. Respir.
Crit. Care Med., 1996 February; 153(2): 629-32; Am. J. Respir.
Crit. Care Med., 1999 November; 160(5 Pt 2): S33-7; Clin. Exp.
Allergy, 2000 Feb.; 30(2): 242-54; Hosp. Med., 1998 July; 59(7):
530-3; Int. Arch. Allergy Immunol., 1998 March; 115(3): 179-90; J.
Immunol., 1991 Feb.; 15; 146(4): 1169-74; Osteoarthritis Cartilage,
1999 Jul.; 7(4): 401-2; Rheum. Dis. Clin. North Am., 2001 May;
27(2): 317-34; J. Autoimmun., 2001 May; 16(3): 187-92; Curr.
Rheumatol. Rep., 2000 Feb.; 2(1): 24-31; Trends Immunol., 2001
Jan.; 22(1): 21-6; Curr. Opin. Immunol., 2000 Aug.; 12(4): 403-8;
Diabetes Care, 2001 Sep.; 24(9): 1661-7; J. Neuroimmunol., 2000
Nov.; 1; 111(1-2): 224-8; Curr. Opin. Immunol., 1997 Dec.; 9(6):
793-9; JAMA, 1999 Sep. 15; 282(11):1076-82; Semin. Cancer Biol.,
1996 Apr.; 7(2): 57-64; J. Interferon Cytokine Res., 2001 Apr.;
21(4): 219-21].
[0004] Therefore, it is considered that a compound having PDE 7
inhibiting effect is useful for treating various kinds of diseases
such as allergic diseases, inflammatory diseases or immunological
diseases concerned with T cells.
[0005] There has been proposed that many compounds selectively
inhibit PDE 7. There can be mentioned the examples such as
imidazopyridine derivatives (Patent Document 1), dihydropurine
derivatives (Patent Document 2), pyrrole derivatives (Patent
Document 3), benzothiopyranoimidazolone derivatives (Patent
Document 4), heterocyclic compounds (Patent Document 5; Patent
Document 6), quinazoline and pyridopyrimidine derivatives (Patent
Document 7), spiro tricyclic compounds (Patent Document 8),
thiazole and oxathiazole derivatives (Patent Document 9),
sulfonamide derivatives (Patent Document 10),
heterobiarylsulfonamide derivatives (Patent Document 11),
dihydroisoquinoline derivatives (Patent Document 12), guanine
derivatives (Non-Patent Document 1), benzothiadiazine derivatives
and benzothienothiadiazine derivatives (Non-Patent Document 2, and
Non-Patent Document 3). However, no curative medicines having PDE 7
inhibiting effect as main pharmacological mechanism have developed
up to now.
[0006] Though some compounds having thienopyrazole skeleton have
been known (Patent Documents 13-24; Non-Patent Documents 4-8),
there is no suggestion that these compounds have PDE 7 inhibiting
effect. Further, the method for producing the thienopyrazole
derivatives of the present invention has been reported (Non-Patent
Documents 9-11); however, the substituents on the thienopyrazole
skeleton are different from those of the present invention.
Patent Document 1: International Patent Publication WO
01/34,601
Patent Document 2: International Patent Publication WO
00/68,203
Patent Document 3: International Patent Publication WO
01/32,618
Patent Document 4: DE Patent 19,950,647
Patent Document 5: International Patent Publications WO
02/88,080
Patent Document 6: International Patent Publications WO
02/87,513
Patent Document 7: International Patent Publication WO
02/102,315
Patent Document 8: International Patent Publication WO
02/74,754
Patent Document 9: International Patent Publication WO
02/28,847
Patent Document 10: International Patent Publication WO
01/98,274
Patent Document 11: International Patent Publication WO
01/74,786
Patent Document 12: International Patent Publication WO
02/40,450
Patent Document 13: International Patent Publication WO
02/100,403
Patent Document 14: International Patent Publication WO
02/79,146
Patent Document 15: International Patent Publication WO
02/66,469
Patent Document 16: International Patent Publication WO
01/90,101
[0007] Patent Document 17: U.S. Pat. No. 6,022,307
Patent Document 18: International Patent Publication WO
03/024,962
Patent Document 19: International Patent Publication WO
03/029,245
Patent Document 20: International Patent Publication WO
03/040,096
Patent Document 21: International Patent Publication WO
03/097,617
Patent Document 22: International Patent Publication WO
03/099,821
Patent Document 23: International Patent Publication WO
97/27,200
[0008] Patent Document 24: U.S. Pat. No. 3,649,641 Non-Patent
Document 1: Bioorg. Med. Chem. Lett., 11 (2001), 1081 Non-Patent
Document 2: J. Med. Chem., 43 (2000), 683 Non-Patent Document 3:
Eur. J. Med. Chem., 36 (2001), 333 Non-Patent Document 4: Russ. J.
Org. Chem., 39 (2003), 893 Non-Patent Document 5: Aknos Consulting
and Solutions GmbH Co., Catalog: Akos samples Non-Patent Document
6: Phosphorus, sulfur and silicon and related Elements, 157 (2000),
107
Non-Patent Document 7: Zhurnal Organisheskoi Khimii., 9 (1973),
2416
Non-Patent Document 8: Zhurnal Organisheskoi Khimii., 5 (1969),
1498
[0009] Non-Patent Document 9: Phosphorus, sulfur and silicon and
related Elements, 157 (2000), 107
Non-Patent Document 10: Chinese Chemical Letters, 10(3), (1999).
189
Non-Patent Document 11: Indian Journal of Chemistry, Section B:
Organic Chemistry Including Medicinal Chemistry, 35B(7), (1996),
715
DISCLOSURE OF INVENTION
The Problem to be Solved in the Invention
[0010] The purpose of the present invention is to provide novel
compounds having PDE 7 inhibiting activity, and PDE 7 inhibitors
containing said inhibitors as an active ingredient. Further, the
present invention provides useful intermediate compounds for
manufacturing the above-mentioned novel compounds.
[0011] The compounds of the present invention inhibit PDE 7
selectively, and therefore, enhance cellular cAMP level.
Consequently, the compounds of the present invention are useful for
treating various kinds of diseases such as allergic diseases,
inflammatory diseases or immunological diseases by inhibiting the
activation of T-cells.
[0012] For example, the compounds of the present invention are
useful for treating or preventing the diseases such as bronchial
asthma, chronic bronchitis, chronic obstructive pulmonary disease,
allergic rhinitis, psoriasis, atopic dermatitis, conjunctivitis,
osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic
lupus erythematosus, inflammatory bowel disease, hepatitis,
pancreatitis, encephalomyelitis, sepsis, Crohn's disease, rejection
reaction in transplantation, GVH disease, restenosis after
angioplasty.
Means to Solve the Problem
[0013] Through extensive investigations of researching compounds
having the capabilities of inhibiting PDE 7, the present inventors
discovered that the compounds having thienopyrazole skeleton in the
molecule represented by the formula (I) mentioned below possess
potent and selective PDE 7 inhibiting effect, and thus, completed
the present invention.
[0014] Accordingly, as one aspect of the present invention, it is
provided thienopyrazole compounds represented by the following
formula (I):
##STR00002##
wherein:
[0015] R.sup.1 is substituted or unsubstituted C.sub.3-C.sub.8
alkyl group, substituted or unsubstituted cycloalkyl group or
substituted or unsubstituted heterocycloalkyl group;
[0016] R.sup.2 is a hydrogen atom or substituted or unsubstituted
C.sub.1-C.sub.3 alkyl group;
[0017] R.sup.3 is a hydrogen atom, substituted or unsubstituted
C.sub.1-C.sub.3 alkyl group, or a halogen atom;
[0018] R.sup.4 is substituted or unsubstituted aryl group,
substituted or unsubstituted heteroaryl group, or a group
--CONR.sup.5R.sup.6 or --CO.sub.2R.sup.7;
[0019] R.sup.5 and R.sup.6 are, same or different from each other,
a hydrogen atom; C.sub.1-C.sub.6 alkyl group which may be
substituted by a halogen atom, substituted or unsubstituted aryl
group, substituted or unsubstituted heteroaryl group, substituted
or unsubstituted heterocycloalkyl group, substituted or
unsubstituted cycloalkyl group, a group-NR.sup.7COR.sup.8,
--COR.sup.8, --NR.sup.9R.sup.10; substituted or unsubstituted
cycloalkyl group; substituted or unsubstituted heterocycloalkyl
group; substituted or unsubstituted aryl group; substituted or
unsubstituted heteroaryl group; or substituted or unsubstituted
heterocycloalkyl group in which the ring is formed together with
the nitrogen atom binding R.sup.5 and R.sup.6;
[0020] R.sup.7 is a hydrogen atom, or substituted or unsubstituted
C.sub.1-C.sub.3 alkyl group;
[0021] R.sup.8 is substituted or unsubstituted heterocycloalkyl
group, or a a group --OH, --OR.sup.7 or --NR.sup.9R.sup.10;
[0022] R.sup.9 and R.sup.10 are, same or different from each other,
a hydrogen atom, substituted or unsubstituted C.sub.1-C.sub.3 alkyl
group, substituted or unsubstituted heterocycloalkyl group;
substituted or unsubstituted acyl group; a group --SO.sub.2R.sup.7,
or substituted or unsubstituted heterocycloalkyl group in which the
ring is formed together with the nitrogen atom binding R.sup.5 and
R.sup.6;
or pharmaceutically acceptable salts or solvates thereof.
[0023] Another aspect of the present invention, it is provided PDE
7 inhibiting composition containing the thienopyrazole compounds
mentioned above, or pharmaceutically acceptable salts or solvates
thereof as an active ingredient.
[0024] Still another aspect of the present invention, it is
provided a method for preparing the thienopyrazole compounds
represented by the formula (I).
[0025] In particular, the method is comprised by chlorination of
pyrazole-5-one derivative represented by the formula (VI):
##STR00003##
[0026] wherein, R.sup.1 and R.sup.2 have the same meanings as
defined above; and then, by an electrophilic substitution reaction
of the resulting compound without separation to give the pyrazole
derivative of the formula (IV):
##STR00004##
[0027] wherein, R.sup.1, R.sup.2 and R.sup.3 have the same meanings
as defined above; then, by reacting the resulting pyrazole
derivative of formula (IV) with the compound of the formula (III)
in the presence of base:
##STR00005##
[0028] wherein, R.sup.4 has the same meanings as defined above; to
give the compound of the formula (II):
##STR00006##
[0029] wherein, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above; and then, by treating the resulting
compound of formula (II) with base to give thienopyrazole compound
of the formula (I):
##STR00007##
[0030] wherein, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the same
meanings as defined above.
[0031] Additionally, the intermediate compound of the formula (IV)
can be obtained by electrophilic substitution reaction of
chloropyrazole compound of the formula (V):
##STR00008##
[0032] wherein, R.sup.1 and R.sup.2 have the same meanings as
defined above.
[0033] Furthermore, the compound of the formula (I) can be obtained
by one pot synthesis from the compound of the formula (IV) without
separation of the intermediate compound of the formula (II). In
particularly, it is provided the manufacturing method for the
compound of the formula (I), in which R.sup.3 is a hydrogen
atom.
EFFECTS OF THE INVENTION
[0034] The compounds of the present invention inhibit PDE 7
selectively, and therefore, the compounds of the present invention
are useful for treating or preventing the diseases such as
bronchial asthma, chronic bronchitis, chronic obstructive pulmonary
disease, allergic rhinitis, psoriasis, atopic dermatitis,
conjunctivitis, osteoarthritis, rheumatoid arthritis, multiple
sclerosis, systemic lupus erythematosus, inflammatory bowel
disease, hepatitis, pancreatitis, encephalomyelitis, septicemia
sepsis, Crohn's disease, rejection reaction of transplantation, GVH
disease, restenosis after angioplasty.
[0035] Further, the compounds of the formula (II) and (IV) are
important intermediate compounds for synthesis of the present
compound of formula (I), and therefore, by using these
intermediates, the compounds of the present invention represented
by the formula (I) can be obtained by simple and easy way.
BEST MODE FOR CARRYING OUT THE INVENTION
[0036] The present invention will now be explained more
specifically as following.
[0037] The term "C.sub.n-C.sub.m alkyl group" of the present
invention includes a straight or a branched-chained alkyl group
having n to m carbon atoms. The term "cycloalkyl group" means
cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and
the like. The term "heterocycloalkyl group" may be 3 to 7 membered
monocyclic or polycyclic heterocyclic group containing the same or
different 1 to 4 hetero atom(s) such as oxygen, nitrogen or sulfur
atom(s), and examples may include piperidinyl, pyrrolidinyl,
piperazinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl,
azetidinyl, imidazolidinyl, oxazolidinyl, hexahydropyrrolidinyl,
octahydroindolidinyl, octahydroquinolidinyl, octahydroindolyl, and
oxo-derivatives thereof.
[0038] The "halogen atom" includes chlorine, fluorine, bromine and
iodine. The term "aryl group" may be aromatic hydrocarbon group,
which consists of mono-benzene ring, or binding or condensed
benzene ring, such as phenyl, naphthyl, biphenyl and the like; and
dicyclic or tricyclic group, which consists of benzene ring
condensed with cycloalkyl or heterocyclic ring, such as
1,2,3,4-tetrahydronaphthalene, 2,3-dihydroindene, indoline,
coumarone and the like.
[0039] The term "heteroaryl group" may be 5 to 7 membered
monocyclic heteroaryl group or polycyclic heteroaryl group, and
having 2 to 8 carbon atoms with 1 to 4 hetero atom(s) such as
oxygen, nitrogen, sulfur atom(s), in which the polycyclic
heteroaryl group has condensed ring system by the same or different
nomocyclic heteroaryl or benzene ring each other; or polycyclic
group which is consisted of heteroaryl group condensed with
cycloalkyl or heterocycloalkyl ring.
[0040] The examples include pyrrole, furyl, thienyl, imidazolyl,
thiazolyl, pyrazinyl, indolyl, indolinyl, quinolinyl,
isoquinolinyl, tetrazolyl, pyridinyl, pyrazolyl, pyridazinyl,
pyrimidinyl, benzothiophenyl, isoxazolyl, indazolyl,
benzoimidazolyl, phthalazinyl, triazolyl, benzooxazolyl,
benzothiazolyl, dihydrocyclopentapyridinyl, dihydro-pyrropyridinyl
and the like.
[0041] Examples of suitable substituent of the present invention
may include straight, branched-chained or cyclic C.sub.1-C.sub.8
alkyl group, which may be substituted by one or more methyl, ethyl,
propyl, isopropyl, n-butyl, t-butyl, cyclohexyl, cycloheptyl,
methoxymethyl, hydroxymethyl, trifluoromethyl, C.sub.1-C.sub.3
alkoxy group, halogen atom, and hydroxyl group; hydroxyl group;
cyano group; substituted or unsubstituted alkoxy group such as
methoxy, ethoxy group; amino group which may be substituted by
C.sub.1-C.sub.6 alkyl group or acyl group such as amino,
methylamino, ethylamino, dimethylamino, acylamino and the like;
carboxylic group; substituted or unsubstituted ester group;
phosphate group; sulfonic group; substituted or unsubstituted aryl
group; substituted or unsubstituted heteroaryl group; saturated or
unsaturated heterocycloalkyl group which may be substituted;
substituted or unsubstituted carbamoyl group; substituted or
unsubstituted amide group; substituted or unsubstituted thioamide
group; halogen atom; nitro group; substituted or unsubstituted
sulfone group; substituted or unsubstituted sulfonylamide group;
oxo group; substituted or unsubstituted urea group; straight,
branched-chained or cyclic alkenyl group such as ethenyl, propenyl,
cyclohexenyl and the like.
[0042] Examples of suitable substituent of "C.sub.3-C.sub.8 alkyl
group which may be substituted" in the group of R.sup.1 may include
hydroxyl group, halogen atom, alkoxy group and the like, and
examples of suitable substituent of "cycloalkyl group which may be
sunstituted" in the group of R.sup.1 include hydroxyl group, alkoxy
group, oxo group, C.sub.1-C.sub.3 alkyl group such as methyl group.
Examples of suitable substituent of "heterocyclo alkyl group which
may be substituted" in the group of R.sup.1 may include
C.sub.1-C.sub.3 alkyl group such as methyl group.
[0043] Examples of suitable substituent of "C.sub.1-C.sub.3 alkyl
group which may be substituted" in the group R.sup.2 may include
hydroxyl group, alkoxy group, halogen atom such as fluorine atom.
Further, examples of suitable substituent of C.sub.1-C.sub.3 alkyl
group which may be substituted" in the group R.sup.3 include
hydroxyl group, alkoxy group, halogen atom such as fluorine
atom.
[0044] Examples of suitable substituent of "aryl group which may be
substituted" and "heteroaryl group which may be substituted" in the
group R.sup.4 may include hydroxyl group, halogen atom,
heterocycloalkyl group which may be substituted by C.sub.1-C.sub.6
alkyl group.
[0045] Examples of suitable substituent of "cycloalkyl group which
may be substituted" in the groups R.sup.5 and R.sup.6 may include
hydroxyl group; oxo group; carboxyl group; carboxyl ester group;
cyano group; C.sub.1-C.sub.6 alkyl group {in which said
C.sub.1-C.sub.6 alkyl group may be substituted by C.sub.1-C.sub.3
alkoxyl group, hydroxyl group, amino group which may be substituted
by C.sub.1-C.sub.6 alkyl group, arylsulfonyloxy group,
heterocycloalkyl group (in which said heterocycloalkyl group may be
substituted by hydroxyl group, C.sub.1-C.sub.6 alkyl group, oxo
group or acetyl group)}; amide group (in which said amide group may
be substituted by cycloalkyl group or C.sub.1-C.sub.6 alkyl group
which may be substituted by hydroxyl group); heterocycloalkylamide
group which may be substituted by C.sub.1-C.sub.6 alkyl group;
heterocycloalkylamide group which may be substituted by hydroxyl
group; amino group (in which said amino group may be substituted by
C.sub.1-C.sub.6 alkyl group which may be substituted by
C.sub.1-C.sub.3 alkoxy group and acyl group); heterocycloalkyl
group {in which said heterocycloalkyl group may be substituted by
C.sub.1-C.sub.6 alkyl group (in which said alkyl group may be
substituted by hydroxyl group), oxo group, acyl group, hydroxyl
group, amino group which may be substituted by C.sub.1-C.sub.6
alkyl group, amino group which may be substituted by acyl group,
C.sub.1-C.sub.3 alkoxy group, alkoxycarbonyl group, carboxyl group,
aminocarbonyl group which may be substituted by C.sub.1-C.sub.6
alkyl group, or sulfonyl group which may be substituted by
C.sub.1-C.sub.6 alkyl group}.
[0046] Examples of suitable substituent of "heterocycloalkyl group
which may be substituted" may include benzyl group; acyl group; oxo
group; heterocycloalkyl group (in which said heterocycloalkyl group
may be substituted by C.sub.1-C.sub.6 alkyl group, acyl group,
sulfonyl group which may be substituted by C.sub.1-C.sub.6 alkyl
group or alkoxycarbonyl group); C.sub.1-C.sub.6 alkyl group which
may be substituted by carboxyl group or carboxylic ester group;
amido group which may be substituted by C.sub.1-C.sub.6 alkyl
group; heterocycloalkylamide group which may be substituted by
C.sub.1-C.sub.6 alkyl group; sulfonyl group which may be
substituted by C.sub.1-C.sub.6 alkyl group; sulfonamide group which
may be substituted by C.sub.1-C.sub.6 alkyl group; cycloalkyl group
which may be substituted by oxo or hydroxyl group; alkoxycarbonyl
group, and the like.
[0047] Further, examples of suitable substituent of "aryl group
which may be substituted" in the group of R.sup.5 and R.sup.6 may
include halogen atom; nitro group; cyano group; acyl group; amino
group which may be substituted by acyl group; amide group (in which
said amide group may be substituted by C.sub.1-C.sub.6 alkyl group
which may be substituted by C.sub.1-C.sub.3 alkoxy group or
C.sub.1-C.sub.6 alkyl group which may be substitute by hydroxyl
group); alkoxycarbonylamino group; alkoxycarbonyl group; alkoxy
group (in which said alkoxy group may be substituted by carboxyl
group, carboxylic ester group, or amide group); carbonyl group;
carboxyl group; carboxylic ester group; carbamoyl group; sulfonic
group; sulfonamide group; aminosulfonyl group; C.sub.1-C.sub.6
alkyl group (in which said alkyl group may be substituted by
C.sub.1-C.sub.3 alkoxy group, hydroxyl group or hetrocycloalkyl
group which may be substituted by C.sub.1-C.sub.6 alkyl group);
heterocycloalkylamide group which may be substituted by
C.sub.1-C.sub.6 alkyl group; heterocycloalkyl group which may be
substituted by hydroxyl group; acetic acid group; acetic acid amide
group; or heterocycloalkyl group (in which said heterocycloalkyl
group may be substituted by hydroxyl group, oxo group, acyl group,
C.sub.1-C.sub.6 alkyl group, amino group which may be substituted
by C.sub.1-C.sub.6 alkyl group, amino group which may be
substituted by acyl group, C.sub.1-C.sub.3 alkoxy group,
alkoxycarbonyl group, and the like).
[0048] Examples of suitable substituent of "heteroaryl group which
may be substituted" in the group of R.sup.5 and R.sup.6 may include
halogen atom; acyl group; amide group {in which said amide group
may be substituted by C.sub.1-C.sub.6 alkyl group (in which said
alkyl group may be further substituted by amino group which may be
substituted by C.sub.1-C.sub.6 alkyl group or hydroxyl group)};
cycloalkyl group which may be substituted by hydroxyl group;
cycloheteroalkyl group which may be substituted by C.sub.1-C.sub.6
alkyl group or acyl group; heterocycloalkylamide group which may be
substituted by C.sub.1-C.sub.6 alkyl group; heterocycloalkylamide
group which may be substituted by hydroxyl group; oxo group;
acylamino group; C.sub.1-C.sub.6 alkyl group (in which said alkyl
group may be substituted by cycloheteroalkyl group which may be
substituted by hydroxyl group, acyl group or cycloheteroalkyl group
which may be substituted hydroxyl group); carboxyl group;
carboxylic ester group; sulfonyl group; heterocycloalkyl group (in
which said heterocycloalkyl group may be substituted by hydroxyl
group, oxo group, acyl group, C.sub.1-C.sub.6 alkyl group, amino
group which may be substituted by C.sub.1-C.sub.6 alkyl group,
amino group which may be substituted by acyl group, C.sub.1-C.sub.3
alkoxy group, alkoxycarbonyl group, and the like).
[0049] Examples of suitable substituent of "substituted or
unsubstituted heterocycloalkyl group which is formed said ring
system together with nitrogen atom which they are bonded" may
include acyl group; amide group; C.sub.1-C.sub.6 alkyl group or
C.sub.1-C.sub.3 alkoxy group; carbonyl group; carboxyl group;
carboxylic ester group; hydroxyl group; carbamoyl group;
sulfonamide group; aminosulfonic group; oxo group; and the
like.
[0050] Examples of suitable substituent of "C.sub.1-C.sub.3 alkyl
group which may be substituted" in the group R.sup.7 may include
hydroxyl group, alkoxy group, halogen atom such as fluorine atom,
and the like.
[0051] Examples of suitable substituent of "heterocycloalkyl group
which may be substituted" in the group R.sup.8 may include hydroxyl
group, alkoxy group, oxo group, acyl group, C.sub.1-C.sub.6alkyl
group, C.sub.1-C.sub.3alkoxy group, carboxyl group, amide group,
and the like.
[0052] In the groups R.sup.9 and R.sup.10, examples of suitable
substituent of "C.sub.1-C.sub.3 alkyl group which may be
substituted" may include hydroxyl group, alkoxy group and the like.
Further, examples of suitable substituent of "heterocycloalkyl
group which may be substituted" may include C.sub.1-C.sub.6 alkyl
group, hydroxyl group, alkoxy group, oxo group, acyl group and the
like, and examples of suitable substituent of "acyl group which may
be substituted" may include C.sub.1-C.sub.6 alkyl group, hydroxyl
group, alkoxy group and the like.
[0053] Examples of suitable substituent of "substituted or
unsubstituted heterocycloalkyl group which is formed said ring
system together with nitrogen atom which they are bonded" include
acyl group, amide group, C.sub.1-C.sub.6 alkyl group,
C.sub.1-C.sub.3 alkoxy group, carbonyl group, carboxyl group,
carboxylic ester group, hydroxyl group, carbamoyl group,
sulfonamide group, aminosulfonic group, and the like.
[0054] Preferable compounds of the formula (I) of the present
invention may include the compounds wherein R.sup.1 is cyclohexyl
group, cycloheptyl group or tetrahydropyranyl group; R.sup.2 is
methyl group; R.sup.3 is a hydrogen atom; and R.sup.4 is the group
--NR.sup.5R.sup.6 (in which one of these R.sup.5 and R.sup.6 is a
hydrogen atom).
[0055] It is understood that when the compounds of the formula (I)
of the present invention exist in the tautomeric mixtures, each
tautomeric isomers per se, as well as the mixture thereof.
Furthermore, the radiolabelled compound of the formula (I) shall be
included within the scope of the compounds of the present
invention.
[0056] The compounds of the present invention may contain one or
more asymmetric carbon atom and therefore, the compounds of the
present invention may exist as optically isomer of (R)-form or
(S)-form, racemic forms, as well as diastereomers. Further, the
compounds of the present invention may exist as geometrical isomer
such as (Z)-form or (E)-form due to the double bond in the
substituent. Therefore, the compounds of the present invention
should include these isomers per se as well as the isomeric
mixtures thereof.
[0057] The compounds of the present invention may form acid
additional salt thereof with various acids. Examples of the acid
additional salt include the salts with inorganic acid such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, nitric acid, phosphoric acid, and the like; salts with
organic acid such as formic acid, acetic acid, propionic acid,
oxalic acid, malonic acid, succinic acid, fumaric acid, maleic
acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic
acid, picric acid, methanesulfonic acid, toluenesulfonic acid,
benzenesulfonic acid, trichloroacetic acid, trifluoroacetic acid,
asparaginic acid, glutamic acid and the like.
[0058] The compounds of the present invention may form
pharmaceutically acceptable salts by treating with various kinds of
metal, especially alkali metal or alkali earth metal. These salts
may include sodium salt, potassium salt, calcium salt and the like.
Further, the compounds of the present invention may include hydrate
thereof or solvate with ethanol or isopropanol thereof, and
polymorphisms thereof.
[0059] The following compounds are preferable thienopyrazole
compounds of the formula (I) of the present invention. [0060] Ethyl
1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate;
[0061]
N-Benzyl-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0062]
1-Cyclohexyl-3-methyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxam-
ide; [0063]
N-{4-[Acetyl(methyl)amino]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]p-
yrazole-5-carboxamide; [0064]
N-[4-(Acetylamino)-3-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0065]
N-(1-Acetyl-2,3-dihydro-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,-
3-c]pyrazole-5-carboxamide; [0066] Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}p-
henylcarbamate; [0067] tert-Butyl
5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}--
1-indolinecarboxylate; [0068]
1-Cyclohexyl-N-(2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyraz-
ole-5-carboxamide; [0069]
1-Cyclohexyl-N-(1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carbo-
xamide; [0070]
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinyl)phenyl]-1H-thieno[2,3-c]pyrazol-
e-5-carboxamide; [0071]
1-Cyclohexyl-3-methyl-N-(3-nitrophenyl)-1H-thieno[2,3-c]-pyrazole-5-carbo-
xamide; [0072]
N-(3-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carbo-
xamide; [0073]
N-[3-(Acetylamino)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole--
5-carboxamide; [0074]
1-Cyclohexyl-3-methyl-N-{4-[(methylamino)carbonyl]phenyl}-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0075]
1-Cyclohexyl-3-methyl-N-(1-propionyl-2,3-dihydro-1H-indol-5-yl)-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0076] Ethyl
5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}--
1-indolinecarboxylate; [0077]
1-Cyclohexyl-N-(1-isobutyryl-2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0078]
N-(1-Butyryl-2,3-dihydro-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2-
,3-c]pyrazole-5-carboxamide; [0079]
1-Cyclohexyl-N-[1-(2,2-dimethylpropanoyl)-2,3-dihydro-1H-indol-5-yl]-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0080]
1-Cyclohexyl-3-methyl-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0081]
N-[4-(Acetylamino)-3-chlorophenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide; [0082]
1-Cyclohexyl-N-{4-[(ethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide; [0083]
1-Cyclohexyl-N-[4-(methoxymethyl)phenyl]-3-methyl-1H-thieno[2,3-c]-pyrazo-
le-5-carboxamide; [0084]
1-Cyclohexyl-N-[4-(hydroxymethyl)phenyl]-3-methyl-1H-thieno-[2,3-c]pyrazo-
le-5-carboxamide; [0085]
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0086]
1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-phenyl}-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0087]
1-Cyclohexyl-3-methyl-N-{4-[(methylsulfonyl)amino]phenyl}-1H-thieno[2,3-c-
]pyrazole-5-carboxyamide; [0088]
1-Cyclohexyl-3-methyl-N-{4-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0089]
N-{1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-2,3--
dihydro-1H-indol-5-yl}acetamide; [0090]
1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0091]
1-Cyclohexyl-N-(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0092]
N-(4-Acetylphenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-carb-
oxamide; [0093]
1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-
-c]pyrazole-5-carboxamide; [0094] Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}b-
enzoate; [0095]
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}b-
enzoic acid; [0096]
1-Cyclohexyl-N-(2-methoxy-4-nitrophenyl)-3-methyl-1H-thieno-[2,3-c]pyrazo-
le-5-carboxamide; [0097]
N-(4-Amino-2-methoxyphenyl)-1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazo-
le-5-carboxamide; [0098]
N-[4-(Acetylamino)-2-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0099]
1-Cyclohexyl-N-{4-[(isopropylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,-
3-c]pyrazole-5-carboxamide; [0100]
1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0101]
N-[6-(Acetylamino)-3-pyridinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide; [0102]
1-Cyclohexyl-N-(4-methoxyphenyl)-3-methyl-1H-thieno[2,3-c]-pyrazole-5-car-
boxamide; [0103]
1-Cyclohexyl-N-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamid-
e; [0104]
N,1-Dicyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide- ;
[0105]
N-{4-[(tert-butylamino)carbonyl]phenyl}-1-cyclohexyl-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0106]
1-Cyclohexyl-N-{5-[(isopropylamino)carbonyl]-2-pyridinyl}-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide; [0107]
1-Cyclohexyl-N-[4-(formylamino)phenyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-
-5-carboxamide; [0108] tert-Butyl
4-[(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amin-
o}phenyl)sulfonyl]-1-piperazinecarboxylate; [0109]
1-Cyclohexyl-3-methyl-N-[4-(1-piperazinylsulfonyl)phenyl]-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0110]
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylsulfonyl)phenyl]-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0111]
1-Cyclohexyl-3-methyl-N-[4-(methylsulfonyl)phenyl]-1H-thieno-[2,3-c]pyraz-
ole-5-carboxamide; [0112]
1-Cyclohexyl-N-[1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indol-5-yl]-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0113]
1-Cyclohexyl-3-methyl-N-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H-
-thieno[2,3-c]pyrazole-5-carboxamide; [0114]
N-(1-Acetyl-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-
e-5-carboxamide; [0115]
1-Cyclohexyl-N-cyclopropyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamid-
e; [0116]
N-(1-Benzyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c-
]-pyrazole-5-carboxamide; [0117]
1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carbox-
amide; [0118]
N-(1-Acetyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazol-
e-5-carboxamide; [0119] Ethyl
(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-
phenoxy)acetate; [0120]
(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-
phenoxy)acetic acid; [0121]
1-Cyclohexyl-3-methyl-N-{4-[2-(methylamino)-2-oxoethoxy]phenyl}-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0122] Ethyl
(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-
phenyl)acetate; [0123]
(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-
phenyl)acetic acid; [0124]
1-Cyclohexyl-3-methyl-N-{4-[2-(methylamino)-2-oxoethyl]phenyl}-1H-thieno[-
2,3-c]pyrazole-5-carboxamide; [0125] tert-Butyl
4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino-
l}phenyl)-1-piperazinecarboxylate; [0126]
1-Cyclohexyl-3-methyl-N-[4-(1-piperazinyl)phenyl]-1H-thieno-[2,3-c]pyrazo-
le-5-carboxamide; [0127]
N-[4-(4-Acetyl-1-piperazinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3--
c]pyrazole-5-carboxamide; [0128]
1-Cyclohexyl-N-(trans-4-hydroxycyclohexyl)-3-methyl-1H-thieno-[2,3-c]pyra-
zole-5-carboxamide; [0129]
1-Cyclohexyl-3-methyl-N-(4-oxocyclohexyl)-1H-thieno[2,3-c]-pyrazole-5-car-
boxamide; [0130]
1-Cyclohexyl-3-methyl-N-{4-[2-(4-methyl-1-piperazinyl)-2-oxoethoxy]phenyl-
}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0131]
1-Cyclohexyl-N-{4-[2-(dimethylamino)-2-oxoethoxy]phenyl}-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0132]
2-{4-[4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mino}phenyl]sulfonyl}-1-piperazinyl}ethyl acetate; [0133]
1-Cyclohexyl-N-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]sulfonyl}-phenyl)-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0134]
N-[trans-4-(Acetylamino)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0135]
1-Cyclohexyl-N,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0136] Ethyl
1-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate;
[0137]
N-[4-(Acetylamino)phenyl]-1-cyclopentyl-3-methyl-1H-thieno[2,3-c]--
pyrazole-5-carboxamide; [0138] Ethyl
1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate;
[0139]
N-[4-(Acetylamino)phenyl]-1-cycloheptyl-3-methyl-1H-thieno-[2,3-c]pyrazol-
e-5-carboxamide; [0140]
1-Cyclohexyl-N,3-dimethyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide-
; [0141]
1-Cyclohexyl-3-methyl-N-(4-pyridinyl)-1H-thieno[2,3-c]pyrazole-5--
carboxamide; [0142]
1-Cyclohexyl-3-methyl-N-(3-pyridinyl)-1H-thieno[2,3-c]pyrazole-5-carboxam-
ide; [0143]
1-Cyclohexyl-3-methyl-N-(4-nitrophenyl)-1H-thieno[2,3-c]pyrazole-5-carbox-
amide; [0144]
N-(4-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carbox-
amide; [0145]
N-[4-(Acetylamino)phenyl-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole--
5-carboxamide; [0146]
1-Cyclohexyl-N-{4-[(methoxyacetyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide; [0147] Methyl
5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}--
2-pyridinecarboxylate; [0148]
5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-aminol}-
-2-pyridinecarboxylic acid; [0149]
1-Cyclohexyl-3-methyl-N-{6-[(methylamino)carbonyl]-3-pyridinyl}-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0150]
1-Cyclohexyl-N-{6-[(dimethylamino)carbonyl]-3-pyridinyl}-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0151]
1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3--
c]pyrazole-5-carboxamide; [0152]
1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3--
c]pyrazole-5-carboxamide methanesulfonate; [0153]
N-(4-Cyanophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carbox-
amide; [0154]
1-Cyclohexyl-3-methyl-N-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0155]
1-Cyclohexyl-3-methyl-N-{3-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0156]
1-Cyclohexyl-3-methyl-N-{3-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0157]
1-Cycloheptyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-
-c]pyrazole-5-carboxamide; [0158]
1-Cyclohexyl-3-methyl-N-(3-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3--
c]pyrazole-5-carboxamide; [0159]
1-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3-
-c]pyrazole-5-carboxamide; [0160]
N-[4-(Acetylamino)-3-methoxyphenyl]-1-cycloheptyl-3-methyl-1H-thieno[2,3--
c]pyrazole-5-carboxamide; [0161]
1-Cyclohexyl-N-(3,5-dichloro-4-pyridinyl)-3-methyl-1H-thieno-[2,3-c]pyraz-
ole-5-carboxamide; [0162]
5-(4-Bromophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole;
[0163]
1-Cyclohexyl-3-methyl-5-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3--
c]pyrazole; [0164]
1-Cyclohexyl-3-methyl-5-[4-(4-methyl-1,4-diazepam-1-yl)phenyl]-1H-thieno[-
2,3-c]pyrazole; [0165]
1-Cyclohexyl-N-{3-fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0166]
1-Cyclohexyl-N-{3-fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide HCl salt; [0167] Ethyl
cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amin-
o}cyclohexanecarboxylate; [0168]
cis-4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]ami-
no}cyclohexanecarboxylic acid; [0169]
1-Cyclohexyl-N-[cis-4-(hydroxymethyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0170] Methyl
trans-4-({[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]a-
mino)methyl}cyclohexanecarboxylate; [0171]
1-Cyclohexyl-N-{[trans-4-(hydroxymethyl)cyclohexyl]methyl}-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0172] tert-Butyl
trans-4-({[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]-
amino}cyclohexylcarbamate; [0173]
N-(trans-4-Aminocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c-pyrazol-
e-5-carboxamide; [0174]
1-Cyclohexyl-3-methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1H-thieno[2,3-
-c]pyrazole-5-carboxamide; [0175]
1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carbox-
amide; [0176]
1-Cyclohexyl-3-methyl-N-(1-tetrahydroro-2H-pyran-4-yl-4-piperidinyl)-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide; [0177]
1-Cyclohexyl-N-[1-(1,4-diazaspiro[4.5]decan-8-yl)-4-piperidinyl]-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0178]
1-Cyclohexyl-3-methyl-N-[1-(4-oxocyclohexyl)-4-piperidinyl]-1H-thieno[2,3-
-c]pyrazole-5-carboxamide; [0179]
1-Cyclohexyl-N-[1-(trans-4-hydroxycyclohexyl)-4-piperidinyl]-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0180] tert-Butyl
4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino-
}phenyl)-1-piperidinecarboxylate; [0181]
1-Cyclohexyl-3-methyl-N-[4-(4-piperidinyl)phenyl]-1H-thieno-[2,3-c]pyrazo-
le-5-carboxamide; [0182]
1-Cyclohexyl-3-methyl-N-[4-(1-methyl-4-piperidinyl)phenyl]-1H-thieno[2,3--
c]pyrazole-5-carboxamide; [0183]
1-Cyclohexyl-N-[4-(4-ethyl-1-piperazinyl)-3-fluorophenyl]-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide; [0184]
1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazepam-1-yl)phenyl]-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide; [0185] Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}--
2-methoxybenzoate; [0186]
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}--
2-methoxybenzoic acid; [0187]
1-Cyclohexyl-N-{3-methoxy-4-[(4-methyl-1-piperazinyl)carbonyl]-phenyl}-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0188]
1-Cyclohexyl-N-[3-methoxy-4-(4-morpholinylcarbonyl)phenyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0189]
1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]-3-methoxyphenyl}-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0190]
1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}-3-methoxy-phenyl)-3-m-
ethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0191]
1-Cyclohexyl-N-(3-methoxy-4-{[(2-methoxyethyl)amino]carbonyl}-phenyl)-3-m-
ethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0192]
1-Cyclohexyl-N-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0193]
1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]-3-methoxyphenyl}-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0194]
1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0195]
N-[3-Chloro-4-(4-methyl-1-piperazinyl)phenyl]-1-cyclohexyl-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0196]
1-cyclohexyl-N-[4-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-3-fluorophenyl]-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0197]
1-Cyclohexyl-N-[3-fluoro-4-(4-oxo-1-piperidinyl)phenyl]-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0198]
1-Cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide; [0199]
N-[3-Chloro-4-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)phenyl]-1-cyclohexyl-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0200]
N-[3-Chloro-4-(4-oxo-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0201]
N-[3-Chloro-4-(4-hydroxy-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide;
[0202]
1-Cyclohexyl-N-{3-fluoro-4-[4-(methylamino)-1-piperidinyl]phenyl}--
3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0203] tert-Butyl
1-(2-chloro-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carb-
onyl]amino}phenyl)-4-piperidinyl(methyl)carbamate; [0204]
N-{3-Chloro-4-[4-(methylamino)-1-piperidinyl]phenyl}-1-cyclohexyl-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0205]
1-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-1-piperazinyl)-cyclohexyl]-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0206]
1-Cyclohexyl-3-methyl-N-{trans-4-(4-methyl-1,4-diazapam-1-yl)-cyclohexyl}-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0207]
1-Cyclohexyl-N-[trans-4-(4-methoxy-1-piperidinyl)cyclohexyl]-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0208] Benzyl
4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl-
]amino}cyclohexyl)-1,4-diazepam-1-carboxylate; [0209]
1-Cyclohexyl-N-[trans-4-(1,4-diazepam-1-yl)cyclohexyl]-3-methyl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0210]
N-[trans-4-(4-Acetyl-1,4-diazepam-1-yl)cyclohexyl]-1-cyclohexyl-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0211]
1-Cyclohexyl-N-{trans-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl}-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0212]
1-Cyclohexyl-N-{cis-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0213]
1-Cyclohexyl-N-[trans-4-(1,4-dioxa-8-azaspiro[4.5]deca-8-yl)-cyclohexyl]--
3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0214]
1-Cyclohexyl-3-methyl-N-[trans-4-(4-oxo-1-piperidinyl)cyclohexyl]-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0215]
1-Cyclohexyl-N-[trans-4-(4-hydroxy-1-piperidinyl)cyclohexyl]-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0216]
1-Cyclohexyl-N-{trans-4-[(2R,6S)-2,6-dimethylmorpholinyl]cyclohexyl}-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0217]
1-Cyclohexyl-N-{cis-4-[(2R,6S)-2,6-dimethylmorpholinyl]cyclohexyl}-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0218]
1-Cyclohexyl-3-methyl-N-{trans-4-[4-(methylamino)-1-piperidinyl]-cyclohex-
yl}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0219]
N-(trans-4-{4-[Acetyl(methyl)amino]-1-piperidinyl}cyclohexyl)-1-cyclohexy-
l-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0220]
1-Cyclohexyl-N-{trans-4-[4-(dimethylamino)-1-piperidinyl]cyclohexyl}-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0221] tert-Butyl
1-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbony-
l]amino}cyclohexyl)-4-piperidinylcarbamate; [0222] tert-Butyl
1-(cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbonyl]-
amino}cyclohexyl)-4-piperidinylcarbamate; [0223]
N-[trans-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0224]
N-[cis-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0225] tert-Butyl
4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)carbony-
l]amino}cyclohexyl)-1-piperazinecarboxylate; [0226] tert-Butyl
4-(cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]a-
mino}cyclohexyl)-1-piperazinecarboxylate; [0227]
1-Cyclohexyl-3-methyl-N-[trans-4-(1-piperazinyl)cyclohexyl]-1H-thieno[2,3-
-c]pyrazole-5-carboxamide; [0228]
1-Cyclohexyl-3-methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0229]
N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide; [0230]
1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazapam-1-yl)phenyl]-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide; [0231] Ethyl
3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazole-5-carboxami-
de; [0232]
3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5--
carboxylic acid; [0233]
3-Methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0234]
N-[3-Fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1-tetrahydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0235]
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylmethyl)phenyl]-1H-thieno[2,3-c]p-
yrazole-5-carboxamide; [0236]
1-Cyclohexyl-N-{4-[2-(dimethylamino)ethyl]phenyl}-3-methyl-1H-thieno[2,3--
c]pyrazole-5-carboxamide; [0237]
1-Cyclohexyl-3-methyl-N-{4-[2-(4-morpholinyl)ethyl]phenyl}-1H-thieno[2,3--
c]pyrazole-5-carboxamide; [0238]
1-Cyclohexyl-3-methyl-N-{4-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]-
phenyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0239]
1-Cyclohexyl-3-methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)-phenyl]--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0240] Methyl
trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]am-
ino}cyclohexanecarboxylate; [0241]
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]-amino}-
cyclohexanecarboxylic acid; [0242]
1-Cyclohexyl-N-[4-(hydroxymethyl)cyclohexyl]-3-methyl-1H-thieno-[2,3-c]py-
razole-5-carboxamide; [0243]
1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-cyclohexyl}-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0244]
1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]cyclohexyl}-3-methyl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0245]
N-(4-Cyanocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazole-5-c-
arboxamide; [0246] tert-Butyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}et-
hyl(methyl)carbamate; [0247]
1-Cyclohexyl-3-methyl-N-[2-(methylamino)ethyl]-1H-thieno-[2,3-c]pyrazole--
5-carboxamide; [0248]
N-{2-[Acetyl(methyl)amino]ethyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0249]
1-Cyclohexyl-3-methyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-1H-thieno[-
2,3-c]pyrazole-5-carboxamide; [0250] Ethyl
(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}-
-1-piperidinyl)acetate; [0251]
(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-
-1-piperidinyl)acetic acid; [0252] Ethyl
2-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amin-
ol}-1-piperidinyl)-2-methylpropanoate; [0253]
2-(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amin-
o}-1-piperidinyl)-2-methylpropanoic acid; [0254]
1-Cyclohexyl-N-[2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)-ethyl]-3-m-
ethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0255]
1-Cyclohexyl-3-methyl-N-{2-[methyl(4-morpholinylcarbonyl)amino]-ethyl}-1H-
-thieno[2,3-c]pyrazole-5-carboxamide; [0256]
1-Cyclohexyl-N-{2-[[(dimethylamino)carbonyl](methyl)amino]ethyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0257] Methyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}e-
thyl(methyl)carbamate; [0258]
1-Cyclohexyl-N-{2-[(methoxyacetyl)(methyl)amino]ethyl}-3-methyl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0259]
1-Cyclohexyl-N-{2-[glycoloyl(methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0260]
1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)(methyl)amino]carbonyl}cyclohexyl)-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0261] Methyl
(1S,3S)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-
amino}cyclopentanecarboxylate; [0262]
(1S,3S)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl-
]amino}cyclopentanecarboxylic acid; [0263]
1-Cyclohexyl-3-methyl-N-[2-(4-methyl-2,3-dioxo-1-piperazinyl)-ethyl]-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide; [0264]
1-Cyclohexyl-N-{(1S,3S)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0265] Methyl
(1R,3R)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-
amino}cyclopentanecarboxylate; [0266]
(1R,3R)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl-
]amino}cyclopentanecarboxylic acid; [0267]
1-Cyclohexyl-N-{(1R,3R)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0268]
1-Cyclohexyl-N-{1-[(dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0269]
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylcarbonyl)cyclohexyl]-1H-thieno[2-
,3-c]pyrazole-5-carboxamide; [0270]
1-Cyclohexyl-3-methyl-N-{4-[(methylamino)carbonyl]cyclohexyl}-1H-thieno[2-
,3-c]pyrazole-5-carboxamide; [0271]
1-Cyclohexyl-N-{4-[(cyclopropylamino)carbonyl]cyclohexyl}-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide; [0272]
1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0273]
1-Cyclohexyl-N-{1-[(dimethylamino)sulfonyl]-4-piperidinyl}-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0274] tert-Butyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]amino}-1-
-piperidinecarboxylate; [0275]
1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carbox-
amide; [0276]
N-[(3S)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyraz-
ole-5-carboxamide; [0277]
1-Cyclohexyl-3-methyl-N-[(3S)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-c-
arboxamide; [0278]
1-Cyclohexyl-N-{(3S)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-
-thieno[2,3-c]pyrazole-5-carboxamide; [0279]
1-Cyclohexyl-N-{4-[(2,5-dioxo-1-imidazolidinyl)methyl]cyclohexyl}-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0280] Ethyl
1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-4-piper-
idinecarboxylate; [0281]
1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-4-piperi-
dinecarboxylic acid; [0282]
1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-N-methyl-
-4-piperidinecarboxamide; [0283] Ethyl
(3S)-1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-3--
piperidinecarboxylate; [0284]
N-[(6S,7aS)-1,3-Dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1-cyclohex-
yl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0285]
N-[(6S,7aS)-2-Methyl-1,3-dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1-
-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0286]
{1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-3-piper-
idinyl}methanol; [0287]
N-{4-[(Dimethylamino)carbonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0288]
1-Cyclohexyl-3-methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-pyridinyl]-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0289]
1-Cyclohexyl-N-[(1S,3S)-3-(hydroxymethyl)cyclopentyl]-3-methyl-1H-thieno[-
2,3-c]pyrazole-5-carboxamide; [0290]
1-Cyclohexyl-N-{(1S,3S)-3-[(2,5-dioxo-1-imidazolidinyl)methyl]-cyclopenty-
l}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0291]
1-Cyclohexyl-N-[4-(2,5-dioxo-1-imidazolidinyl)phenyl]-3-methyl-1H-thieno[-
2,3-c]pyrazole-5-carboxamide; [0292]
3-Methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)phenyl]-1-tetrahydro-2-
H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0293]
3-Methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-pyridinyl]-1-tetrahydro-2H-pyran-
-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0294]
1-Cyclohexyl-N-{4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1H-thieno[-
2,3-c]pyrazole-5-carboxamide; [0295]
1-Cyclohexyl-N-{3-fluoro-4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide; [0296]
1-Cyclohexyl-N-{3-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0297]
N-{4-[4-{[tert-Butyl(dimethyl)silyl]oxy}-1-piperidinyl]sulfonyl}-phenyl}--
1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0298]
1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0299]
1-Cyclohexyl-N-[4-(2-hydroxyethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazo-
le-5-carboxamide; [0300]
N-[3-Fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1-tetrahydro-2H-p-
yran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0301]
1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)ph-
enyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0302]
1-Cyclohexyl-3-methyl-N-[4-(2-oxo-1,3-oxazolidin-3-yl)cyclohexyl]-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0303]
1-Cyclohexyl-3-methyl-N-[4-(2-oxo-1-imidazolidinyl)cyclohexyl]-1H-thieno[-
2,3-c]pyrazole-5-carboxamide; [0304]
4-[(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]ami-
no}cyclohexyl)amino]-4-oxobutanoic acid; [0305]
1-Cyclohexyl-N-[4-(2,5-dioxo-1-pyrrolidinyl)cyclohexyl]-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0306]
1-Cyclohexyl-N-[4-(1,1-dioxide-2-isothiazolidinyl)cyclohexyl]-3-methyl-1H-
-thieno[2,3-c]pyrazole-5-carboxamide; [0307] Benzyl
[{[(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]ami-
no}cyclohexyl)amino]carbonyl}(methyl)amino]acetate; [0308]
1-Cyclohexyl-3-methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)-cyclohex-
yl]-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0309]
1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-1-
H-thieno[2,3-c]pyrazole-5-carboxamide; [0310]
1-Cyclohexyl-3-methyl-N-[3-(3-methyl-2,5-dioxo-1-imidazolidinyl)-propyl]--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0311]
1-Cyclohexyl-N-[4-({[(2-hydroxyethyl)(methyl)amino]carbonyl}amino)-cycloh-
exyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0312]
1-Cyclohexyl-3-methyl-N-[4-(3-methyl-2-oxo-1-imidazolidinyl)-cyclohexyl]--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0313] Ethyl
3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}p-
ropanoate; [0314]
N-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-.beta.-a-
lanine; [0315] tert-Butyl
{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}ace-
tate; [0316]
{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}ace-
tic acid; [0317]
1-Cyclohexyl-3-methyl-N-[3-(4-morpholinyl)-3-oxopropyl]-1H-thieno[2,3-c]p-
yrazole-5-carboxamide; [0318] tert-Butyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}e-
thylcarbamate; [0319]
N-(2-Aminoethyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide; [0320]
1-Cyclohexyl-N-[3-(dimethylamino)-3-oxopropyl]-3-methyl-1H-thieno[2,3-c]p-
yrazole-5-carboxamide; [0321]
1-Cyclohexyl-3-methyl-N-{3-[methyl(1-methyl-4-piperidinyl)amino]-3-oxopro-
pyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0322]
1-Cyclohexyl-N-[3-(4-hydroxy-1-piperidinyl)-3-oxopropyl]-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0323]
1-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl)-2-oxoethyl]-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0324]
1-Cyclohexyl-N-[2-(dimethylamino)-2-oxoethyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0325]
1-Cyclohexyl-3-methyl-N-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0326]
1-Cyclohexyl-N-[2-(4-hydroxy-1-piperidinyl)-2-oxoethyl]-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0327]
1-Cyclohexyl-3-methyl-N-[3-(4-methyl-1-piperazinyl)-3-oxopropyl]-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0328]
1-Cyclohexyl-3-methyl-N-{2-[methyl(1-methyl-4-piperidinyl)amino]-2-oxoeth-
yl}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0329]
1-Cyclohexyl-3-methyl-N-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-1H-thieno[2,-
3-c]pyrazole-5-carboxamide; [0330]
1-Cyclohexyl-N-[2-(1,1-dioxide-2-isothiazolidinyl)ethyl]-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0331]
1-Cyclohexyl-N-[2-({[(2-hydroxyethyl)(methyl)amino]carbonyl}amino)-ethyl]-
-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0332]
1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2-oxo-1-imidazolidinyl)ethyl]-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide;
[0333] Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}b-
utanoate; [0334]
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}b-
utanoic acid; [0335]
1-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2-
,3-c]pyrazole-5-carboxamide; [0336]
1-Cyclohexyl-N-[4-(dimethylamino)-4-oxobutyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0337]
1-Cyclohexyl-3-methyl-N-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)et-
hyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0338]
1-Cyclohexyl-N-[2-(2,4-dioxo-1,3-thiazolidin-3-yl)ethyl]-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0339]
1-Cyclohexyl-N-[1-(hydroxymethyl)cyclopropyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0340]
1-Cyclohexyl-3-methyl-N-{1-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]-
cyclopropyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0341] Methyl
[(2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino-
}ethyl)amino]acetate; [0342] Methyl
[(aminocarbonyl)(2-{[(1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazol-5-yl-
)carbonyl]amino}ethyl)amino]acetate; [0343]
1-Cyclohexyl-N-[2-(2,4-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2-
,3-c]pyrazole-5-carboxamide; [0344]
1-Cyclohexyl-N-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0345]
1-Cyclohexyl-3-methyl-N-[2-(5-methyl-1,1-dioxide-1,2,5-thiadiazolidin-2-y-
l)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0346]
1-Cyclohexyl-N-[2-(3-ethyl-2,4-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0347]
1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,4-dioxo-1-imidazolidinyl)-ethyl]-1-
H-thieno[2,3-c]pyrazole-5-carboxamide; [0348]
1-Cyclohexyl-N-[(1S)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0349]
1-Cyclohexyl-N-[(1S)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0350]
N-[(3R)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyraz-
ole-5-carboxamide; [0351]
1-Cyclohexyl-3-methyl-N-[(3R)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-c-
arboxamide; [0352]
1-Cyclohexyl-N-{(3R)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H-
-thieno[2,3-c]pyrazole-5-carboxamide; [0353]
1-Cyclohexyl-N-[(1R)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0354]
1-Cyclohexyl-N-[(1R)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0355]
1-Cyclohexyl-N-[(2S)-2-hydroxypropyl]-3-methyl-1H-thieno[2,3-c]-pyrazole--
5-carboxamide; [0356]
1-Cyclohexyl-N-[(2R)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0357]
1-Cyclohexyl-N-[(2R)-2-hydroxypropyl]-3-methyl-1H-thieno[2,3-c]-pyrazole--
5-carboxamide; [0358]
1-Cyclohexyl-N-[(2S)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0359]
1-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)propyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide; [0360]
1-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]propyl}-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0361]
1-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-3-methyl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide; [0362]
1-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]-2-methylpropy-
l}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0363]
tert-Butyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}--
2-methylpropylcarbamate; [0364]
N-(2-Amino-1,1-dimethylethyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyraz-
ole-5-carboxamide; [0365]
1-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)-1,1-dimethylethyl]-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0366]
N-(3-Amino-2,2-dimethylpropyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyra-
zole-5-carboxamide; [0367]
1-Cyclohexyl-N-[3-(2,5-dioxo-1-imidazolidinyl)-2,2-dimethylpropyl]-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0368]
(.+-.)-1-Cyclohexyl-N-[trans-2-(hydroxymethyl)cyclopropyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0369]
N-[4-(4-Hydroxy-1-piperidinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0370]
1-Cyclohexyl-3-methyl-N-[4-(3-oxo-1-piperazinyl)phenyl]-1H-thieno[2,3-c]p-
yrazole-5-carboxamide; [0371]
3-Methyl-N-[4-(3-oxo-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H--
thieno[2,3-c]pyrazole-5-carboxamide; [0372] Methyl
3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino)b-
enzoate; [0373]
3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}b-
enzoic acid; [0374]
1-Cyclohexyl-N-{3-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-
-c]pyrazole-5-carboxamide; [0375]
1-Cyclohexyl-3-methyl-N-[3-(4-morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c-
]pyrazole-5-carboxamide; [0376] Methyl
trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-
-yl)carbonyl]amino}cyclohexanecarboxylate; [0377]
trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-
-yl)carbonyl]amino}cyclohexanecarboxylic acid; [0378]
N-{trans-4-[(Dimethylamino)carbonyl]cyclohexyl}-3-methyl-1-tetrahydro-2H--
pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0379]
3-Methyl-N-[trans-4-(4-morpholinylcarbonyl)cyclohexyl]-1-tetrahydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0380]
N-{trans-4-[(4-Hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl-1-tetr-
ahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0381]
3-Methyl-N-{trans-4-[(4-methyl-1-piperazinyl)carbonyl]cyclohexyl}-1-tetra-
hydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0382]
1-Cyclohexyl-3-methyl-N-[3-(4-morpholinyl)propyl]-1H-thieno[2,3-c]pyrazol-
e-5-carboxamide; [0383]
1-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl)ethyl]-1H-thieno[2,3-c]pyrazole-
-5-carboxamide; [0384]
1-Cyclohexyl-3-methyl-N-[2-(1-piperidinyl)ethyl]-1H-thieno[2,3-c]pyrazole-
-5-carboxamide; [0385]
N-[trans-4-(Hydroxymethyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0386]
(trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol--
5-yl)carbonyl]amino}cyclohexyl)methyl p-toluenesulfonate; [0387]
3-Methyl-N-[trans-4-(4-morpholinylmethyl)cyclohexyl]-1-tetrahydro-2H-pyra-
n-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0388]
N-{trans-4-[(Dimethylamino)methyl]cyclohexyl}-3-methyl-1-tetrahydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0389]
N-{trans-4-[(4-Acetyl-1-piperazinyl)methyl]cyclohexyl}-3-methyl-1-tetrahy-
dro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0390]
N-{3-[(Dimethylamino)sulfonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0391]
3-Methyl-N-[3-(methylsulfonyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide; [0392]
N-{3-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]phenyl}-3-methyl--
1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0393]
N-[3-{(2-Hydroxyethyl)sulfonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-y-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0394]
3-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0395]
1-Cyclohexyl-N-[6-(4-hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0396]
1-Cyclohexyl-N-[2,3-difluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0397]
1-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)-3-methylphenyl]-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide; [0398]
N-[3-cyano-4-(4-hydroxy-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide; [0399] Methyl
5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino}--
2-(4-hydroxy-1-piperidinyl)benzoate; [0400]
5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}--
2-(4-hydroxy-1-piperidinyl)benzoic acid; [0401]
N-[6-(4-Hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1-tetrahydro-2H-pyra-
n-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0402]
3-Methyl-1-tetrahydro-2H-pyran-4-yl-N-(1-tetrahydro-2H-pyran-4-yl-4-piper-
idinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0403]
1-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyridinyl}-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0404]
1-Cyclohexyl-N-(6-{[(2-hydroxyethyl)amino]carbonyl}-3-pyridinyl)-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0405]
1-Cyclohexyl-3-methyl-N-{6-[(4-methyl-1-piperazinyl)carbonyl]-3-pyridinyl-
}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0406]
1-Cyclohexyl-N-[6-({[2-(dimethylamino)ethyl]amino}carbonyl)-3-pyridinyl)--
3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0407]
1-Cyclohexyl-N-(6-{[(trans-4-hydroxycyclohexyl)amino]carbonyl}-3-pyridiny-
l]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0408]
1-Cyclohexyl-3-methyl-N-{6-[(4-methyl-1,4-diazepam-1-yl)carbonyl]-3-pyrid-
inyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0409] tert-Butyl
4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)ca-
rbonyl]aminol}-1-piperidinecarboxylate; [0410]
3-Methyl-N-(4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]py-
razole-5-carboxamide; [0411]
N-{1-[(Dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1-tetrahydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0412] tert-Butyl
4-{4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol-5-yl-
)carbonyl]amino}piperidin-1-yl}-1-piperidine-carboxylate; [0413]
3-Methyl-N-(piperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide; [0414]
3-Methyl-N-(1-acetylpiperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-
-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0415]
3-Methyl-N-(1-methanesulfonylpiperidin-4-yl-4-piperidinyl)-1-tetrahydro-2-
H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0416]
tert-Butyl
4-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-
-5-yl)carbonyl]amino}cyclohexyl)-1-piperazine-carboxylate; [0417]
tert-Butyl
4-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-
-yl)carbonyl]amino}cyclohexyl)-1-piperazine-carboxylate; [0418]
3-Methyl-N-[trans-4-(1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0419]
3-Methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide; [0420]
N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-p-
yran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0421]
3-Methyl-N-{trans-4-[4-(methylsulfonyl)-1-piperazinyl]cyclohexyl}-1-tetra-
hydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0422]
N-[cis-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyr-
an-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0423]
3-Methyl-N-[1-(4-morpholinylcarbonyl)-4-piperidinyl]-1-tetrahydro-2H-pyra-
n-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0424]
3-Methyl-N-{1-[(4-methyl-1-piperazinyl)carbonyl]-4-piperidinyl}-1-tetrahy-
dro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0425]
N-(trans-4-Hydroxycyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide; [0426]
3-Methyl-N-(4-oxocyclohexyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]p-
yrazole-5-carboxamide; [0427]
N-[trans-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetrahydro-
-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0428]
N-[cis-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetra-hydro--
2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0429]
1-Cyclohexyl-N-[6-(hydroxymethyl)-3-pyridinyl]-3-methyl-1H-thieno[2,3-c]p-
yrazole-5-carboxamide; [0430] Methyl
5-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)ca-
rbonyl]amino}-2-pyridinecarboxylate; [0431]
5-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-yl)ca-
rbonyl]amino}-2-pyridinecarboxylic acid; [0432]
N-(6-{[(trans-4-Hydroxycyclohexyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1-
-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0433]
N-[6-({[2-(Dimethylamino)ethyl]amino}carbonyl)-3-pyridinyl]-3-methyl-1-te-
trahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0434]
3-Methyl-N-(6-{[(1-methyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-1-te-
trahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0435]
N-(6-{[(1-Acetyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1-te-
trahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0436]
1-Cyclohexyl-3-methyl-N-[6-(4-morpholinylmethyl)-3-pyridinyl]-1H-thieno[2-
,3-c]pyrazole-5-carboxamide; [0437]
1-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)methyl]-3-pyridinyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0438]
N-{6-[(4-Acetyl-1-piperazinyl)methyl]-3-pyridinyl}-1-cyclohexyl-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide; [0439]
3-Methyl-N-[trans-4-(4-methyl-2-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydr-
o-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0440]
1-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-2-oxo-1-piperazinyl)-cyclohexy-
l]-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0441]
3-Methyl-N-[trans-4-(3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyra-
n-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0442]
3-Methyl-N-[cis-4-(3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran--
4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0443]
3-Methyl-N-[trans-4-(4-methyl-3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydr-
o-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0444]
3-Methyl-N-[cis-4-(4-methyl-3-oxo-1-piperazinyl)cyclohexyl]-1-tetra-hydro-
-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0445] Ethyl
1-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazo-
l-5-yl)carbonyl]amino}cyclohexyl)-4-piperidine-carboxylate; [0446]
Ethyl
1-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyrazol--
5-yl)carbonyl]amino}cyclohexyl)-4-piperidine-carboxylate; [0447]
N-{trans-4-[4-(Hydroxymethyl)-1-piperidinyl]cyclohexyl}-3-methyl-1-tetrah-
ydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0448]
N-{cis-4-[4-(Hydroxymethyl)-1-piperidinyl]cyclohexyl}-3-methyl-1-tetrahyd-
ro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0449]
N-[trans-4-(4-Hydroxy-1-piperidinyl)cyclohexyl]-3-methyl-1-tetra-hydro-2H-
-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0450]
N-(cis-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methyl--
1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0451]
1-(trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazo-
l-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylic acid;
[0452]
N-(trans-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methy-
l-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0453] Ethyl
3-methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylat-
e; [0454]
3-Methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-c-
arboxylic acid; [0455]
3-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1-tetrahydro-2H-pyran-3-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0456]
N-[trans-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-
-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0457]
N-[cis-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetra-
-hydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide; [0458]
N-{trans-4-[(4-Ethyl-3-oxo-1-piperazinyl)methyl]cyclohexyl}-3-methyl-1-te-
trahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0459]
3-Methyl-N-{trans-4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-cyclohexyl}-1--
tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0460]
3-Methyl-N-[4-(4-methyl-2-oxo-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-
-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide;
[0461] The compounds represented by the formula (I) of the present
invention may be prepared by the following methods.
##STR00009##
(wherein, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have same meanings
mentioned above; L is C.sub.1-C.sub.3 lower alkyl group)
[0462] First, the compound (VI) obtained from the compound (VIII)
by reacting with R.sup.1NHNH.sub.2 (VII) in accordance with the
known method (e.g., International Patent Publication WO
03/053,975). Namely, the compound (VIII) is reacted with 1 to 2
equivalents, preferably about 1 equivalent of the compound (VII) in
the solvent or absent of the solvent at room temperature to
120.degree. C. The solvent to be used in the reaction is inorganic
acid aqueous solution such as hydrochloric acid or sulfuric acid;
aromatic carbon hydrate such as benzene or toluene; organic acid
such as acetic acid; ethers such as 1,4-dioxane or tetrahydrofuran;
halogenated hydrocarbons such as dichloromethane; alcohols such as
methanol or ethanol; or the mixture solvent there of.
[0463] After the reaction is completed, the reaction mixture is
neutralized and the mixture is extracted with an organic solvent,
which is nonmiscible solvent with water, and the organic layer is
washed sequentially with water and saturated saline solution. Then,
the compound (VI) can be obtained by removal of the solvent. This
compound (VI) can be purified by recrystallization, if
necessary.
[0464] The starting compounds (VII) and (VIII) to be used in this
reaction can be commercially available or can be known compounds
(e.g., J. Org. Chem., 1981, 46, 5414-5415). Further, the compounds
(VII) can be used as salt with acidic compounds, such as
hydrochloric acid salt or acetic acid salt.
[0465] Then, the resulting compound (VI) is converted to the
compound (V) in accordance with the common method. Namely, the
reaction can be conducted by reacting the compound (VI) with 1 to 6
equivalents of halogenating reagent such as phosphorous oxychloride
or thionyl chloride in aromatic hydrocarbon solvent such as benzene
or toluene, or the absence of the solvent, at room temperature to
refluxing temperature of the solvent for 1 to 12 hours. After the
reaction is completed, the compound (V) can be obtained by removal
of the solvent.
[0466] The obtained compound (V) is converted, without further
purification, to the compound (IV) by an electrophilic substitution
reaction. For example, the compound, (V) in which R.sup.3 is a
hydrogen atom, can be obtained by Vilsmeier reaction with the
reaction reagent prepared from 1 to 5 equivalents of phosphorus
oxychloride, in the amide solvent such as N,N-dimethylformamide.
The reaction is carried out at room temperature to 120.degree. C.
for 1 to 12 hours.
[0467] After the reaction is completed, inorganic base aqueous
solution such as sodium hydroxide aqueous solution is added to the
reaction mixture and the mixture is extracted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (IV) can be obtained by removal of the
solvent. This compound (IV) can be purified by column
chromatography or recrystallization, if necessary.
[0468] Further, the compound (IV) can be converted directly from
the compound (IV) by Vilsmeier reaction in single process, or
one-pot synthesis reaction without separation of the intermediate
compound (V). Namely, the compound (VI) is treated with 2 to 5
equivalents of phosphorous oxychloride without using the reaction
solvent at room temperature to 120.degree. C. to obtain the
compound (V) in the reaction mixture. Then, to this reaction
mixture containing the resulting compound (V) is added formamide
solvents such as N,N-dimethylformamide at 0.degree. C. to
120.degree. C., and the Vilsmeier reaction is carried out at room
temperature to 120.degree. C. for 1 to 24 hours.
[0469] After the reaction is completed, inorganic base aqueous
solution such as sodium hydroxide aqueous solution is added to the
reaction mixture and the mixture is extracted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (IV) can be obtained by removal of the
solvent. This compound (IV) can be purified by column
chromatography or recrystallization, if necessary.
[0470] Then, the obtained compound (IV) is converted to the
compound (II). The reaction is carried out by treating the compound
(IV) with 1 to 1.5 equivalents of the compound (III), in the
solvent at room temperature to 80.degree. C. for 0.5 to 8 hours.
The solvent to be used in this reaction is polar solvent such as
acetonitrile or N,N-dimethylformamide; ethers such as 1,4-dioxane
or tetrahydrofuran; halogenated hydrocarbons such as
dichloromethane; alcohols such as methanol or ethanol; or the
mixture solvent thereof. In this reaction, the compound (III) is
previously treated with base such as potassium carbonate, sodium
hydride, potassium tert-butoxide, sodium methylate or sodium
hydroxide.
[0471] After the reaction is completed, water is added to the
reaction mixture and the mixture is extracted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (II) can be obtained by removal of the
solvent. This compound (II) can be purified by column
chromatography or recrystallization, if necessary.
[0472] Then, the obtained compound (II) is converted to the
compound (I) of the present invention by ring formation
reaction.
[0473] The reaction condition of this ring formation may vary
depending on the variety of the group R.sup.4. When the group
R.sup.4 is the group: --CO.sub.2R.sup.7, the compound (I) can be
obtained from the compound (II) by treating with 1 to 1.5
equivalents of the base such as potassium carbonate, sodium
hydride, sodium methylate or sodium hydroxide in the solvent at
0.degree. C. to 80.degree. C. for 0.5 to 24 hours. The solvent to
be used in this reaction is polar solvent such as acetonitrile or
N,N-dimethylformamide; ethers such as 1,4-dioxane or
tetrahydrofuran; halogenated hydrocarbons such as dichloromethane;
alcohols such as methanol or ethanol; or the mixture solvent there
of.
[0474] After the reaction is completed, water is added to the
reaction mixture and the mixture is extracted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (I) can be obtained by removal of the
solvent. This compound (I) can be purified by column
chromatography, if necessary.
[0475] Further, when the group R.sup.4 is the group:
--CO.sub.2R.sup.7, the compound (I) can be obtained from the
compound (IV), without the separation of the compound (II) in the
corresponding stepwise reaction.
[0476] When the group R.sup.4 is an aryl group which may be
substituted or a heteroaryl group which may be substituted, the
compound (I) can be obtained from the compound (II) by treating
with 1 to 3 equivalents of the strong base such as lithium
diisopropylamide or lithium bis(trimethylsilyl) amide in the ethers
such as diethylether or tetrahydrofuran.
[0477] After the reaction is completed, water is added to the
reaction mixture and the mixture is extracted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution, then, the organic solvent is removed off. The resulting
residue is dissolved in alcohols such as methanol or ethanol, and
the acid such as hydrochloric acid is added to the mixture, and
then, the mixture is stirred at room temperature to 60.degree. C.
to obtain the compound (I).
[0478] After the reaction is completed, water is added to the
reaction mixture and the mixture is extracted with an organic
solvent, which is nonmiscible solvent with water, and the organic
layer is washed sequentially with water and saturated saline
solution. Then, the compound (I) can be obtained by removal of the
solvent. This compound (I) can be purified by column chromatography
or recrystallization, if necessary.
[0479] In the case of the group R.sup.4 is the group:
--CONR.sup.5R.sup.6, first, the compound (I) in which the group
R.sup.4 is --CO.sub.2R.sup.7 obtained by the method described
above, is converted to the compound (I) in which the group R.sup.4
is --CO.sub.2H. This convertion reaction is the hydrolysis reaction
of ester compound, and can be carried out in the several manners.
For example, the hydrolysis reaction can be carried out in the
presence of the base such as sodium hydroxide, in the solvent at
room temperature to refluxing temperature of the solvent. The
solvent to be used in the reaction may be alcohols such as methanol
or ethanol; water; or the mixture solvent thereof. After the
reaction is completed, the reaction mixture is condensed, and the
mixture is neutralized by adding hydrochloric acid to obtain the
compound (I) in which the group R.sup.4 is --CO.sub.2H.
[0480] Then, the resulting compound (I) in which the group R.sup.4
is --CO.sub.2H is converted to the compound in which the group
R.sup.4 is --CONR.sup.5R.sup.6 by amidation reaction in accordance
with the several known methods. For example, the compound (I) in
which the group R.sup.4 is --CO.sub.2H is converted to the
corresponding acid chloride by treating with the halogenating
reagent such as phosphorous oxychloride or thionyl chloride. Then,
the obtained acid chloride is treated with the amine compound
HNR.sup.5R.sup.6 in the presence of base catalyst such as
triethylamine in solvent at OOC to room temperature. The solvent to
be used in the reaction may be halogenated hydrocarbons such as
dichloromethane; aromoatic hydrocarbons such as toluene or benzene;
ethers such as diethylether or tetrahydrofurane; or the mixture
solvent thereof.
[0481] After the reaction is completed, the reaction mixture is
diluted with the organic solvent, which is nonmiscible solvent with
water, and the organic layer is washed sequentially with water and
saturated saline solution. Then, the compound (I) in which the
group R.sup.4 is --CONR.sup.5R.sup.6 can be obtained by removal of
the solvent. This compound can be purified by column chromatography
or recrystallization, if necessary.
[0482] All reaction mentioned above are well known, and the
reagents to be used or the reaction conditions to be applied can be
easily established in accordance with the standard text book and
the examples mentioned later. Further, the other methods or
modified methods for obtaining the compound (I) of the present
invention can be easily selected by the person skilled in this
field.
EXAMPLES
[0483] The present invention is illustrated in more detail by way
of the following Biological Test, Examples, and Manufacturing
Examples.
[0484] The synthesis of the compounds of the present invention and
intermediate compounds to be used in the synthesis are illustrated
in the Examples and Manufacturing Examples mentioned later.
Further, the physicochemical data and chemical structure of the
compounds and intermediate compounds obtained by the Examples and
Manufacturing Examples are summarized in the Tables mentions
later.
[0485] The compound numbers in the Examples are identical to those
in the Tables.
[0486] It is to be noted that the present invention is not limited
by those Examples in any way.
Biological Test 1:
Methods for Evaluating the PDE 7 Inhibiting Effect
[0487] The PDE 7 (phosphodiesterase VII) inhibiting effect of the
compounds of the present invention was performed by the following
method, which was modified assay method described in Biochemical.
Pharmacol. 48(6), 1219-1223 (1994).
(1) The active fraction of PDE 7 (phosphodiesterase VII) was
obtained. That is, MOLT-4 (obtainable from ATCC as ATCC No.
CRL-1582), which was cell line of human acute lymphoblastic
lymphoma T cells, was incubated in RPMI1640 culture medium
containing 10% fetal bovine serum to obtain 5.times.10.sup.8 MOLT-4
cells. The cells were collected by centrifugation and suspended
with 10 mL of buffer solution A [25 mM of tris-HCl, 5 mM of
2-mercaptoethnol, 2 mM of benzamidine, 2 mM of EDTA, 0.1 mM of
4-(2-aminoethyl)benzensulfonyl hydrochloride; pH 7.5], then
homogenized by Polytron.RTM. homogenizer. The homogenate were
centrifuged under 25,000.times.G for 10 minutes at 4.degree. C. The
supernatant was separated and thus obtained supernatant was further
centrifuged under 100,000.times.G for 60 minutes at 4.degree. C.,
and then filtrated with 0.2 .mu.m filter to obtain the soluble
fraction. (2) The obtained soluble fraction was filled in
equilibrium HiTrap Q column (5 mL.times.2) with buffer solution A,
and phosphodiesterase fractions were eluted by 300 mL of buffer
solution A with linear gradient from 0 to 0.8 M NaCl concentration.
5 mL each of 60 eluents were collected, and each eluents were
examined for cyclic AMP metabolic activities of phosphodiesterase.
The fraction eluting with about 350 mM NaCl concentration parts,
where metabolic activities were not inactivated by 10 .mu.M of
rolipram (selective inhibitor for phosphodiesterase IV) and 10
.mu.M of milrinone (selective inhibitor for phosphodiesterase III),
were collected as storage solution for using to test PDE 7
inhibiting effect. (3) The tested compound having desired
concentration was reacted in the solution of 20 mM tris-HCl
(pH7.5), 1 mM of MgCl.sub.2, 100 .mu.M of EDTA, 330 .mu.g/mL of
bovine serum albumin, 4 .mu.g/mL of 5'-nucleotidase, 0.1 .mu.Ci of
.sup.3H-CAMP (0.064 .mu.M of cAMP), 10 .mu.M of rolipram in storage
solution of PDE 7 for 2 hours at 25.degree. C. After the reaction,
suspension of Sephadex.RTM.-QAE in 10 mM of HEPES-Na (pH 7.0) was
added to the reaction mixture, and the mixture was left at rest for
5 minutes. Further, Sephadex.RTM.-QAE was added to the obtained
supernatant and the mixture was left at rest for 5 minutes, then,
the radioactivity of the solution was measured. (4) IC.sub.50 was
calculated as 50% inhibiting concentration of the metabolic
activities of phosphodiesterase VII of the tested compound.
[0488] The compounds of the present invention selectively inhibit
PDE 7 and their selectivities are more than 10 times compared to
other phosphodiesterase. Therefore, it is expected that the side
effect of the compounds of the present invention caused by other
isozyme to be less.
[0489] For example, the selectivity against PDE 4
(phosphodiesterase IV) of the compounds of the present invention
was affirmed by means of the following Biological Test.
Biological Test 2:
Methods for Evaluating the PDE 4 Inhibiting Effect
[0490] The PDE 4 (phosphodiesterase IV) inhibiting effect of the
compounds of the present invention was performed by the following
method, which was modified assay method described in Biochemical.
Pharmacol. 48(6), 1219-1223 (1994).
(1) The active fraction of PDE 4 (phosphodiesterase IV) was
obtained. That is, the livers obtained from three Balb/c mice
(male, 12 weeks: obtainable from CLEA Japan, Inc.) were suspended
with 30 mL of buffer solution B [20 mM of bis-tris, 5 mM of
2-mercaptoethnol, 2 mM of benzamidine, 2 mM of EDTA, 0.1 mM of
4-(2-aminoethyl)benzensulfonyl hydrochloride, 50 mM of sodium
acetate; pH 6.5], then homogenized by Polytron.RTM. homogenizer.
The homogenate were centrifuged under 25,000.times.G for 10 minutes
at 4.degree. C. The supernatant was separated and thus obtained
supernatant was further centrifuged under 100,000.times.G for 60
minutes at 4.degree. C., and then filtrated with 0.2 .mu.m filter
to obtain the soluble fraction. (2) The obtained soluble fraction
was filled in equilibrium DEAE sepharose column (1.times.10 cm)
with buffer solution B, and phosphodiesterase fractions were eluted
by 120 mL of buffer solution B with linear gradient from 0.05 to 1M
sodium acetate concentration. 5 mL each of 24 eluents were
collected, and each eluents were examined for cyclic AMP metabolic
activities of phosphodiesterase. The fraction eluting with about
620 mM of sodium acetate concentration parts, where metabolic
activities were inactivated by 3 .mu.M of rolipram (selective
inhibitor for phosphodiesterase IV), were collected as storage
solution to test PDE 4 inhibiting effect. (3) The tested compound
having desired concentration was reacted in the solution of 20 mM
tris-HCl (pH 7.5), 1 mM of MgCl.sub.2, 100 .mu.M of EDTA, 330
.mu.g/mL of bovine serum albumin, 4 .mu.g/mL of 5'-nucleotidase,
0.1 .mu.Ci of .sup.3H-cAMP (0.064 .mu.M of cAMP), and storage
solution of PDE 4 for 2 hours at 25.degree. C. After the reaction,
suspension of Sephadex.RTM.-QAE in 10 mM of HEPES-Na (pH 7.0) was
added to the reaction mixture, and the mixture was left at rest for
5 minutes. Further, Sephadex.RTM.-QAE was added to the obtained
supernatant and the mixture was left at rest for 5 minutes, then,
the radioactivity of the solution was measured. (4) IC.sub.50 was
calculated as 50% inhibiting concentration of the metabolic
activities of phosphodiesterase IV of the tested compound.
[0491] As the results of the mentioned above Biological Test 2, the
IC.sub.50 of the compounds of PDE 4 inhibiting effect of the
present invention was more than 10 times weaker than that of PDE 7
inhibiting effect.
[0492] In the following Tables 1 to 4, the IC.sub.50 values of PDE
7 inhibiting activities and PDE 4 inhibiting activities were
summarized.
TABLE-US-00001 TABLE 1 Compound PD7 PDE4 Compound PDE7 PDE4 No.
IC.sub.50/.mu.M IC.sub.50/.mu.M No. IC.sub.50/.mu.M IC.sub.50/.mu.M
10 0.027 1.8 46 0.03 2 11 0.019 2 47 0.032 3.5 12 0.053 5 51 0.075
9.5 14 0.088 3.7 53 0.055 3.5 16 0.034 2.2 58 0.036 3.6 20 0.033
>30 59 0.08 7 21 0.084 2.5 60 0.065 6.5 23 0.083 4.8 67 0.023
3.5 25 0.098 6.5 70 0.025 4.7 26 0.044 3 72 0.01 1.2 28 0.05 30 73
0.012 1 32 0.095 2.5 74 0.05 7 36 0.04 25 76 0.02 2 37 0.028 2 77
0.02 2 38 0.033 5 79 0.06 -- 39 0.014 3.5 80 0.06 2.5 40 0.075 15
94 0.058 >30 41 0.05 12 99 0.099 5 45 0.05 12 100 0.037
>30
TABLE-US-00002 TABLE 2 Compound PDE7 PDE4 Compound PDE7 PDE4 No.
IC.sub.50/.mu.M IC.sub.50/.mu.M No. IC.sub.50/.mu.M IC.sub.50/.mu.M
101 0.03 1.3 156 0.055 2 102 0.085 5.5 159 0.035 1.6 104 0.058 1.5
162 0.07 2 106 0.009 1.2 163 0.014 0.9 107 0.017 2 165 0.02 0.65
109 0.015 1 166 0.016 1.5 110 0.075 5.5 167 0.015 1 111 0.01 >30
168 0.022 1.5 112 0.008 1.2 170 0.022 1.3 114 0.021 1.5 171 0.037
1.7 115 0.04 1.5 172 0.048 9.4 125 0.075 4 176 0.02 1.7 132 0.088
10 177 0.013 1.6 133 0.009 1.8 179 0.0031 0.75 135 0.053 7.4 180
0.01 1.4 141 0.022 1.6 181 0.0086 0.86 142 0.014 2 184 0.0068 1.1
147 0.085 3 188 0.0065 0.7 149 0.065 2 190 0.0035 1.7 150 0.045 0.7
191 0.0089 0.98 152 0.085 3 196 0.09 7.5 155 0.01 1.5 197 0.079
4.4
TABLE-US-00003 TABLE 3 Compound PDE7 PDE4 Compound PDE7 PDE4 No.
IC.sub.50/.mu.M IC.sub.50/.mu.M No. IC.sub.50/.mu.M IC.sub.50/.mu.M
199 0.056 5.8 255 0.089 12 200 0.016 1.9 256 0.002 0.81 201 0.018
2.2 257 0.068 8.3 202 0.033 2.4 258 0.015 4.7 203 0.0061 1.4 260
0.037 4.5 205 0.091 14 261 0.028 1.9 206 0.05 3.8 262 0.028 3.8 207
0.024 2.4 263 0.054 3.5 208 0.025 3.8 264 0.081 6.3 209 0.077 7.4
266 0.07 11 225 0.018 2 268 0.088 4.8 227 0.056 10 270 0.015 1.8
228 0.051 5.8 271 0.0089 2.1 230 0.023 7 273 0.014 1.6 234 0.013
2.1 274 0.0099 1.7 235 0.017 2.8 276 0.004 1.2 236 0.02 2.7 277
0.032 7.8 237 0.0078 -- 280 0.017 1.9 238 0.0078 2.7 302 0.06 6.1
239 0.015 2.6 305 0.066 6.8 240 0.041 -- 313 0.09 12 246 0.051 6.6
316 0.097 15 247 0.0065 1.4 317 0.067 12
TABLE-US-00004 TABLE 4 Compound PDE7 PDE4 Compound PDE7 PDE4 No.
IC.sub.50/.mu.M IC.sub.50/.mu.M No. IC.sub.50/.mu.M IC.sub.50/.mu.M
323 0.071 6.3 379 0.013 1.2 325 0.034 4 380 0.056 1.5 331 0.029 4.9
381 0.022 0.67 339 0.02 5.1 382 0.025 0.62 340 0.054 28 383 0.074
2.4 341 0.005 1.8 395 0.019 1.4 342 0.028 4.6 396 0.022 0.9 349
0.078 2.8 402 0.019 7.3 358 0.071 11 404 0.032 3.5 360 0.057 7.9
412 0.043 4.9 365 0.041 3.9 413 0.05 2.5 366 0.049 3.6 414 0.035
2.8 367 0.02 2.3 415 0.093 5.1 368 0.026 2.9 416 0.017 1.3 369
0.024 7.6 417 0.063 7 370 0.0087 4.1 419 0.029 5.7 371 0.017 3.6
423 0.072 8.1 372 0.011 4 425 0.09 13 373 0.0045 3.4 428 0.05 9.7
375 0.0072 0.93 436 0.03 7.2 378 0.044 2.5 440 0.097 28
[0493] The compounds of the present invention inhibit PDE 7
selectively, and therefore, enhance cellular cAMP level.
Consequently, the compounds of the present invention are useful for
treating various kinds of diseases such as allergic diseases,
inflammatory diseases or immunological diseases. For example, the
compounds of the present invention are useful for treating or
preventing the diseases such as bronchial asthma, chronic
bronchitis, chronic obstructive pulmonary disease, allergic
rhinitis, psoriasis, atopic dermatitis, conjunctivitis,
osteoarthritis, rheumatoid arthritis, multiple sclerosis, systemic
lupus erythematosus, inflammatory bowel disease, hepatitis,
pancreatitis, encephalomyelitis, sepsis, Crohn's disease, rejection
for organ transplantation, GVH disease, and restenosis after
angioplasty.
[0494] The compounds of the present invention can be used for
preparation of the pharmaceutical composition or PDE 7 inhibitor.
As an active ingredient, one or more compounds may be administered
in the appropriated formulation. The formulation for oral
administration may include for example, capsules, granules, fine
granules, syrups, dry syrups or the like; the formulation for
parenteral administration may include, for example injectable
solution, suppository formulation such as rectal suppository or
vaginal suppository, nasal administration such as sprays, or
percutaneous absorption formulation such as ointment and tapes, and
the like.
[0495] The administration dose may vary depending on the various
kinds of factors. These factors may be the condition of the
patients, the severity of the diseases, ages, existence of a
complication, as well as formulation. A usual recommended daily
dose for oral administration is within the range of 0.1-1,000
mg/day/adult, preferably 0.1-500 mg/day/adult, and more preferably
1-100 mg/day/adult. In the case of parenteral administration, a
usual recommended daily dose is within the range of 1/10 to 1/2
based on dose of oral administration. These doses can be adjusted
depending on age, as well as the patient's condition.
[0496] The toxicological properties of the compounds of the present
invention is low, therefore, the compounds of the present invention
is expected to have high safety margin.
Examples and Manufacturing Examples
[0497] The compounds of the present invention and intermediate
compounds used for the synthesis of the compounds of the present
invention are illustrated in the following Manufacturing Examples
and Examples. The physicochemical data and chemical structure of
the compounds are summarized in the Tables mentions later. The
compound numbers in the Examples and Manufacturing Examples are
identical to those in the Tables.
Manufacturing Example 1
tert-Butyl 5-nitro-1-indolinecarboxylate
[0498] To a solution of 500 mg (3.05 mmol) of 5-nitroindoline in 10
mL of anhydrous dichloromethane was added 798 mg (3.65 mmol) of
di-tert-butyl dicarbonate under ice cooling, and the mixture was
stirred for 1.5 hours. Then, to this mixture was added catalytic
amount of 4-dimethylamiopyridine and the mixture was stirred for 1
hour at room temperature. Water was added to the reaction mixture
and the mixture was extracted with dichloromethane. The organic
layer was washed with saturated saline solution and dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the resulting residue was purified by silica gel
column chromatography (eluent:hexane/ethyl acetate=6/1) to give 800
mg (99%) of the title compound.
Manufacturing Example 2
tert-Butyl 5-amino-1-indolinecarboxylate
[0499] 80 mg of 10% palladium-carbon was added to a solution of 760
mg (2.88 mmol) of the compound obtained in the Manufacturing
Example 1 in 60 mL of methanol, and the reaction atmosphere was
exchanged to hydrogen gas atmosphere. Then, the mixture was stirred
for 30 minutes at room temperature and filtrated by Celite.RTM..
The filtrate was removed under reduced pressure to give 670 mg
(99%) of the title compound.
Manufacturing Example 3
tert-Butyl 5-(acetylamino)-1-indolinecarboxylate
[0500] To a solution of 300 mg (1.28 mmol) of the compound obtained
in the Manufacturing Example 2 in 10 mL of anhydrous
dichloromethane were added 191 .mu.L (2.69 mmol) of acetyl chloride
and 375 .mu.L (2.69 mmol) of triethylamine, and the mixture was
stirred for 1 hour at room temperature. Then, water was added to
the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was dried over with anhydrous
sodium sulfate and removed under reduced pressure. The resulting
residue was purified by silica gel column chromatography
(eluent:hexane/ethyl acetate=1/1 to 1/2) to give 370 mg
(quantitative) of the title compound.
Manufacturing Example 4
N-(2,3-Dihydro-1H-indol-5-yl)acetamide HCl salt
[0501] A mixture solution of 330 mg (1.19 mmol) of the compound
obtained in the Manufacturing Example 3 in 15 mL of 4M-HCl/dioxane
was stirred for 1.5 hours at room temperature. Then, diethylether
was added to the reaction mixture and the resulting precipitates
were collected to give 173 mg (68%) of the title compound.
Manufacturing Example 5
6-Amino-N-isopropylnicotinamide
[0502] To a solution of 300 mg (2.17 mmol) of 6-aminonicotinic acid
in 50 mL of chloroform were added 370 .mu.L (4.34 mmol) of
isopropylamine, 4 mL of anhydrous propanephosphonic acid (25 wt %
solution in ethyl acetate) and 1.4 mL (10 mmol) of triethylamin,
and the mixture was stirred for 6 hours at room temperature. Then,
saturated sodium bicarbonate aqueous solution was added to the
reaction mixture, and the mixture was extracted with
dichloromethane. The organic layer was washed with saturated saline
solution and dried over with anhydrous sodium sulfate. The solvent
was removed under reduced pressure and the residue was purified by
silica gel column chromatography
(eluent:dichloromethane/methanol=10/1 to 5/1) to give 30 mg (8%) of
the title compound.
Manufacturing Example 6
1-(Methylsulfonyl)-5-nitroindoline
[0503] To a solution of 300 mg (1.83 mmol) of 5-nitroindoline in 20
mL of dichloromethane were added 141 .mu.L (2.74 mmol) of
methanesulfonyl chloride and 382 .mu.L (2.74 mmol) of
triethylamine, and the mixture was stirred for 2 hours at room
temperature. 141 .mu.L (2.74 mmol) of methanesulfonyl chloride and
255 .mu.L (1.83 mmol) of triethylamine were further added to the
reaction mixture, and the mixture was stirred for 2 hours at room
temperature. Then, water was added to the reaction mixture and the
mixture was extracted with dichloromethane. The organic layer was
washed with saturated saline solution and dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was treated with diethyl ether, then, the precipitates
were collected by filtration to give 410 mg (92%) of the title
compound.
Manufacturing Example 7
1-(Methylsulfonyl)-5-indolineamine
[0504] The title compound 150 mg (58%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 6, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 8
2-{4-[(4-Nitrophenyl)sulfonyl]-1-piperazinyl}ethanol
[0505] To a solution of 415 .mu.L (3.38 mmol) of
1-piperazineethanol in 20 mL of dichloromethane were added 500 mg
(2.26 mmol) of 4-nitrobenzenesulfonyl chloride and 472 .mu.L (3.38
mmol) of triethylamine under ice cooling, and the mixture was
stirred for 30 minutes at the same temperature. The reaction
mixture was diluted with dichloromethane and the organic layer was
washed with water, saturated sodium bicarbonate aqueous solution
and saturated saline solution and then, dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=30/1) to give 670 mg (94%) of the
title compound.
Manufacturing Example 9
2-{4-[(4-Nitrophenyl)sulfonyl]-1-piperazinyl}ethyl acetate
[0506] The title compound 175 mg (77%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Manufacturing Example 8, instead of the compound
obtained in the Manufacturing Example 2.
Manufacturing Example 10
2-{4-(4-Aminophenyl)sulfonyl}-1-piperazinyl}ethyl acetate
[0507] The title compound 130 mg (95%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 9, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 11
tert-Butyl trans-4-(acetylamino)cyclohexylcarbamate
[0508] The title compound 130 mg (68%) was obtained in a manner
similar to the Manufacturing Example 3 by use of tert-butyl
trans-4-amino-cyclohexylcarbamate, instead of the compound obtained
in the Manufacturing Example 2.
Manufacturing Example 12
N-(trans-4-Aminocyclohexyl)acetamide trifluoroacetic acid salt
[0509] To a solution of 220 mg (0.86 mmol) of the compound obtained
in the Manufacturing Example 11 in 8 mL Of dichloromethane was
added 8 mL of trifluoroacetic acid at room temperature, and the
mixture was stirred for 30 minutes at the same temperature. The
reaction mixture was condensed and the residue was treated with
diethylether. The resulting precipitates were collected by
filtration to give 194 mg (84%) of the title compound.
Manufacturing Example 13
2-Methoxy-N-(4-nitrophenyl)acetamide
[0510] To a mixture solution of 384 .mu.L (5.0 mmol) of
methoxyacetic acid and 691 mg (5.0 mmol) of p-nitroaniline in 10 mL
of dichloromethane were added 1.53 mg (5.5 mmol) of
2-chloro-1,3-dimethylimidazoliumhexafluorophosphate and 1.53 mL
(111.0 mmol) of triethylamine, and the mixture was refluxed for 7
hours. Then, the reaction mixture was extracted with ethyl acetate,
the extract was washed with water and saturated saline solution,
then, dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:hexane/ethyl acetate=2/1)
to give 750 mg (71%) of the title compound.
Manufacturing Example 14
N-(4-Aminophenyl)-2-methoxyacetamide
[0511] The title compound 604 mg (86%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 13, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 15
6-(4-Methyl-1-piperazinyl)-3-pyridinylamine
[0512] The title compound 536 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of
1-methyl-4-(5-nitro-2-pyridinyl)piperazine, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 16
1-Methyl-4-[(3-nitrophenyl)sulfonyl]piperazine
[0513] To a solution of 500 mg (2.26 mmol) of
3-nitrobenzenesulfonyl chloride in 30 mL of dichloromethane were
added 275 .mu.L (2.48 mmol) of N-methylpiperazine and 786 .mu.L
(5.64 mmol) of triethylamine, and the mixture was stirred for 1
hour at room temperature. The reaction mixture was extracted with
dichloromethane and the organic layer was washed with water and
saturated saline solution, and then, dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was treated with diethyl ether to give 510 mg (79%) of
the title compound.
Manufacturing Example 17
3-[(4-Methyl-1-piperazinyl)sulfonyl]aniline
[0514] The title compound 350 mg (98%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 16, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 18
2-[2-Fluoro(methyl)-4-nitroanilino]ethanol
[0515] To a solution of 554 .mu.L (5.0 mmol) of
3,4-difluoronitrobenzene in 10 mL of dimethyl sulfoxide were added
1.38 mg (10.0 mmol) of potassium carbonate and 803 .mu.L (10.0
mmol) of 2-methylaminoetanol, and the mixture was stirred for 1.5
hours at 100.degree. C. The reaction mixture was cooled to room
temperature and extracted with ethyl acetate, then, the extract was
washed with water and saturated saline solution. After dried over
with anhydrous sodium sulfate, the solvent was removed under
reduced pressure ant the residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=1/1) to give 1.06 g
(99%) of the title compound.
Manufacturing Example 19
2-(4-Amino-2-fluoromethylanilino)ethanol
[0516] The title compound 900 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Manufacturing Example 18, instead of the
compound obtained in the Manufacturing Example 1.
Manufacturing Example 20
tert-Butyl 4-(4-nitrophenyl)-1-piperidinecarboxylate
[0517] To a solution of 4.84 g (30 mmol) of 4-phenylpiperidine in
30 mL of conc. sulfuric acid was added gradually a solution of 1.26
mL of fuming nitric acid in 5 mL of conc. sulfuric acid under ice
cooling, and after addition, the reaction mixture was warmed up to
room temperature. Then, the reaction mixture was poured into 200 g
of ice and sodium hydroxide aqueous solution was added slowly until
the mixture to be alkalified. The mixture was extracted with
chloroform and the organic layer was dried over with anhydrous
sodium sulfate. The solvent removed under reduced pressure. Then,
2.18 g (10 mmol) of di-tert-butyl dicarbonate was added to a
solution of the resulting residue in 20 mL of dichloromethane, and
the mixture was stirred for 1 hour at room temperature. The mixture
was concentrated and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=40/1) to give 0.78
g (8%) of the title compound.
Manufacturing Example 21
tert-Butyl 4-(4-aminophenyl)-1-piperidinecarboxylate
[0518] The title compound 392 mg (57%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 20, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 22
1-Ethyl-4-(2-fluoro-4-nitrophenyl)piperazine
[0519] The title compound 2.33 g (92%) was obtained in a manner
similar to the Manufacturing Example 18 by use of N-ethylpiperazine
instead of 2-methylaminoethanol.
Manufacturing Example 23
1-(2-Fluoro-4-nitrophenyl)-4-methyl-1,4-diazepam
[0520] The title compound 2.21 g (87%) was obtained in a manner
similar to the Manufacturing Example 18 by use of
N-methylhomopiperazine, instead of 2-methylaminoethanol.
Manufacturing Example 24
4-(4-Ethyl-1-piperazinyl)-3-fluoroaniline
[0521] The title compound 1.85 g (94%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 22, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 25
1-(2-Fluoro-4-nitrophenyl)-4-methylpiperazine
[0522] To a solution of 3.9 mL (35 mmol) of
3,4-difluoronitrobenzene in 60 mL of dimethyl sulfoxide were added
9.7 mL (87.5 mmol) of N-methylpiperazine and 12.1 g (87.5 mmol) of
potassium carbonate, and the mixture was refluxed for 5 hours at
100.degree. C. The reaction mixture was cooled to room temperature
and poured into 500 mL of ice water, and the resulting precipitates
were collected. The collected precipitates were dissolved in 2M-HCl
aqueous solution and washed with ether. The aqueous layer was
neutralized with 4M-NaOH aqueous solution to give the precipitates.
The precipitates were collected to give 5.71 g (68%) of the title
compound.
Manufacturing Example 26
3-Fluoro-4-(4-methyl-1-piperazinyl)aniline
[0523] The title compound 2.76 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Manufacturing Example 25, instead of the
compound obtained in the Manufacturing Example 1.
Manufacturing Example 27
8-(2-Fluoro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane
[0524] The title compound 2.82 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 25 by use of
1,4-dioxa-8-azaspiro[4.5]decane, instead of N-methylpiperazine.
Manufacturing Example 28
4-(1,4-Dioxa-8-azaspiro[4.5]deca-8-yl)-3-fluoroaniline
[0525] To a solution of 2.0 g (7.09 mmol) of the compound obtained
in the Manufacturing Example 27 in 30 mL of methanol was added 200
mg of platinum on sulfide carbon, and the reaction atmosphere was
changed to hydrogen gas atmosphere. Then, the mixture was stirred
for 5 hours at normal pressures and temperature. The reaction
mixture was filtrated by Celite.RTM., and the filtrate was removed
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent:hexane/ethyl acetate=3/1 to 1/1) to
give 1.71 g (96%) of the title compound.
Manufacturing Example 29
8-(2-Chloro-4-nitrophenyl)-1,4-dioxa-8-azaspiro[4.5]decane
[0526] The title compound 3.05 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 25 by use of
3,4-dichloronitrobenzene and 1,4-dioxa-8-azaspiro[4.5]decane,
instead of 3,4-difluoronitorobenzene and N-methylpiperazine,
respectively.
Manufacturing Example 30
3-Chloro-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)aniline
[0527] The title compound 1.84 g (85%) was obtained in a manner
similar to the Manufacturing Example 28 by use of the compound
obtained in the Manufacturing Example 29, instead of the compound
obtained in the Manufacturing Example 27.
Manufacturing Example 31
3-Fluoro-4-(4-methyl-1,4-diazapam-1-yl)aniline
[0528] The title compound 1.85 g (94%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 23, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 32
4-[2-(4-Morpholinyl)ethyl]aniline
[0529] The title compound 2.17 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of
4-[2-(4-morpholinyl)-ethyl]nitrobenzene, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 33
1-Methyl-3-(4-nitrobenzyl)-2,4-imidazodinedione
[0530] To a mixture solution of 685 mg (6.0 mmol) of
1-methylhydantoin in 10 mL of N,N-dimethylformamide and 10 mL of
tetrahydrofuran was added 240 mg (6.9 mmol) of sodiumhydride (60%
oily) at room temperature, and the mixture was stirred for 30
minutes at the same temperature. Then, 1.08 g (5.0 mmol) of
p-nitrobenzyl bromide was added to the reaction mixture, and the
mixture was stirred for over night at room temperature. Water was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The organic layer was dried over with anhydrous
sodium sulfate and the solvent was removed under reduced pressure
to give 1.38 g (quantitative) of the title compound.
Manufacturing Example 34
3-(4-Aminobenzyl)-1-methyl-2,4-imidazolidinedione
[0531] To a mixture solution of 1.33 g (5.34 mmol) of the compound
obtained in the Manufacturing Example 33 in 12 mL of ethanol and 6
mL of conc. hydrochloric acid was added 5.41 g (24.01 mmol) of tin
chloride (II) dehydrate at room temperature, and the mixture was
stirred for 2 hours at 75.degree. C. The reaction mixture was
cooled to room temperature, alkalized by adding of 4N-sodium
hydroxide aqueous solution and treated with chloroform. The mixture
was filtered with Celite.RTM., and chloroform layer was separated
and dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure to give 1.148 g (98%) of the title
compound.
Manufacturing Example 35
tert-Butyl trans-4-cyanocyclohexylcarbamate
[0532] To a solution of 765 mg (4.99 mmol) of
trans-4-cyanocyclohexane carboxylic acid in 10 mL of tert-butanol
was added 766 .mu.L (5.49 mmol) of triethylamine and 1.13 mL (5.24
mmol) of diphenylphosphorylazide at room temperature, and the
mixture was refluxed for 6 hours. After the reaction mixture was
cooled to room temperature, ethyl acetate was added to this mixture
and the organic layer was washed with saturated sodium bicarbonate
aqueous solution, then, dried over with anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:hexane/ethyl
acetate=2/1) to give 608 mg (54%) of the title compound.
Manufacturing Example 36
trans-4-Aminocyclohexane carbonitrile HCl salt
[0533] The title compound 361 mg (90%) was obtained in a manner
similar to the Manufacturing Example 4 by use of the compound
obtained in the Manufacturing Example 35, instead of the compound
obtained in the Manufacturing Example 3.
Manufacturing Example 37
1-(2-Aminoethyl)-4-methyl-2,3-piperazinedione HCl salt
[0534] To a solution of 3.60 g (11.95 mmol) of
2-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]phthalimide in 30 mL
of ethanol was added 695 .mu.L (14.34 mmol) of hydrazine
monohydrate and the mixture was stirred at 40.degree. C. for over
night. The reaction mixture was cooled to room temperature, then,
25 mL of water and 6 mL of 6N--HCl were added to this mixture and
the mixture was stirred for 5 hours at room temperature. After
removed off the insoluble substances by filtration, the filtrate
was concentrated and the residue was re-crystallized by 2%
water-ethanol solution to give 2.12 g (85%) of the title
compound.
Manufacturing Example 38
tert-Butyl 1-[(dimethylamino)carbonyl]-4-piperidinylcarbamate
[0535] To a solution of 500 mg (2.50 mmol) of tert-butyl
4-piperidinyl-carbamate in 20 mL of dichloromethane was added 522
.mu.L (3.74 mmol) of triethylamine and 276 .mu.L (3.00 mmol) of
dimethylaminocarbonyl chloride and the mixture was stirred for 2
hours at room temperature. Then, the mixture was treated with ethyl
acetate and the organic layer was washed with water and saturated
saline solution, and then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure to give 636
mg (94%) of the title compound.
Manufacturing Example 39
4-Amino-N,N-dimethyl-1-piperidinecarboxamide HCl salt
[0536] The title compound 571 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 4 by use of the
compound obtained in the Manufacturing Example 38, instead of the
compound obtained in the Manufacturing Example 3.
Manufacturing Example 40
tert-Butyl 1-[(dimethylamino)sulfonyl]-4-piperidine-carbamate
[0537] To a solution of 412 mg (2.06 mmol) of tert-butyl
4-piperidinyl-carbamate in 20 mL of dichloromethane were added 430
.mu.L (3.09 mmol) of triethylamine and 265 .mu.L (2.47 mmol) of
dimethylsulfamoyl chloride and the mixture was stirred for 2 hours
at room temperature. Then, the mixture was treated with ethyl
acetate and the organic layer was washed with water and saturated
saline solution, and then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=40/1) to give 536 mg (85%) of the
title compound.
Manufacturing Example 41
4-Amino-N,N-dimethyl-1-piperidinesulfonamide HCl salt
[0538] The title compound 0.42 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 4 by use of the
compound obtained in the Manufacturing Example 40, instead of the
compound obtained in the Manufacturing Example 3.
Manufacturing Example 42
Methyl
(2S,4S)-4-[tert-butoxycarbonyl]amino]-2-pyrrolidinecarboxylate
[0539] The title compound 4.70 g (96%) was obtained in a manner
similar to the Manufacturing Example 2 by using methyl
(2S,4S)-1-benzyloxycarbonyl-4-tert-butoxycarbonylaminopyrrolidine-2-carbo-
xylate, instead of the compound obtained in the Manufacturing
Example 1.
Manufacturing Example 43
Methyl
(2S,4S)-1-(aminocarbonyl)-4-[(tert-butoxycarbonyl)amino]-2-pyrrolid-
inecarboxylate
[0540] To a solution of 4.60 g (18.83 mmol) of the compound
obtained in the Manufacturing Example 42 in 80 mL of dioxane and 80
mL of water were added 2.29 g (28.55 mmol) of potassium isocyanate
and 3.23 mL (56.49 mmol) of acetic acid, and the mixture was
stirred for 17 hour at room temperature. Then, the mixture was
treated with ethyl acetate and the organic layer was washed with
water and saturated saline solution, and then, dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=20/1) to give 2.32
g (43%) of the title compound.
Manufacturing Example 44
tert-Butyl
(6S,7aS)-1,3-dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-ylcarba-
mate
[0541] To a solution of 2.21 g (7.69 mmol) of the compound obtained
in the Manufacturing Example 43 in 150 mL of methanol was added
gradually 615 mg (15.38 mmol) of sodium hydride (60% oily) and the
mixture was stirred for 30 minutes at room temperature. After
condensed the reaction mixture, ethyl acetate and diluted
hydrochloric acid were added to this mixture. The organic layer was
separated and dried over with anhydrous sodium sulfate, and the
solvent removed under reduced pressure to give 1.8 g (92%) of the
title compound.
Manufacturing Example 45
(6S,7aS)-6-Aminotetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione
HCl salt
[0542] The title compound 1.18 g (91%) was obtained in a manner
similar to the Manufacturing Example 4 by use of the compound
obtained in the Manufacturing Example 44, instead of the compound
obtained in the Manufacturing Example 3.
Manufacturing Example 46
1-(5-Amino-2-pyridinyl)-2-imidazolidinone
[0543] The title compound 730 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of
1-(5-nitro-2-pyridinyl)-2-imidazolidinone, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 47
3-(4-Aminophenyl)-2,4-imidazolidinedione
[0544] The title compound 179 mg (69%) was obtained in a manner
similar to the Manufacturing Example 2 by use of
3-(4-nitrophenyl)-2,4-imidazolidinedione, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 48
3-(4-Aminophenyl)-1-methyl-2,4-imidazolidinedione
[0545] The title compound 413 mg (95%) was obtained in a manner
similar to the Manufacturing Example 2 by use of
3-(4-nitrophenyl)-1-methyl-2,4-imidazolidinedione, instead of the
compound obtained in the Manufacturing Example 1.
Manufacturing Example 49
(3R)-1-(4-Aminophenyl)-3-pyrrolidinol
[0546] The title compound 1.98 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of
(3R)-1-(4-nitrophenyl)-3-pyrrolidinol, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 50
(3R)-1-(2-Fluoro-4-nitrophenyl)-3-pyrrolidinol
[0547] The title compound 2.19 g (65%) was obtained in a manner
similar to the Manufacturing Example 18 by use of
(R)-3-pyrrolidinol, instead of 2-methylaminoethanol.
Manufacturing Example 51
(3R)-1-(4-Amino-2-fluorophenyl)-3-pyrrolidinol
[0548] The title compound 1.81 g (99%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 50, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 52
1-[(3-Nitrophenyl)sulfonyl]-4-piperidinol
[0549] The title compound 1.91 g (49%) was obtained in a manner
similar to the Manufacturing Example 16 by use of
4-hydroxypiperidine, instead of N-methylpiperazine.
Manufacturing Example 53
1-[(3-Aminophenyl)sulfonyl]-4-piperidinol
[0550] The title compound 1.56 g (52%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 52, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 54
1-[(4-Nitrophenyl)sulfonyl]-4-piperidinol
[0551] The title compound 1.91 g (49%) was obtained in a manner
similar to the Manufacturing Example 8 by use of
4-hydroxypiperidine, instead of 1-piperazineethanol.
Manufacturing Example 55
4-{[tert-Butyl(dimethyl)silyl]oxy}-1-[(4-nitrophenyl)sulfonyl]-piperidine
[0552] To a solution of 1.5 g (5.24 mmol) of the compound obtained
in the Manufacturing Example 54 in 60 mL of dichloromethane was
added 1.32 mL (5.76 mmol) of tert-butyldimethylsilyl trifluorate at
0.degree. C., and the mixture was stirred overnight at room
temperature. After the reaction, the reaction mixture was washed
with water and the organic layer was dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography
(eluent:hexane/ethyl acetate=5/1) to give 2.04 g (97%) of the title
compound.
Manufacturing Example 56
4-[(4-{[tert-Butyl(dimethyl)silyl]oxy}-1-piperidinyl)sulfonyl]-aniline
[0553] The title compound 1.67 g (98%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 55, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 57
1-Methyl-4-[4-nitro-2-(trifluoromethyl)phenyl]piperazine
[0554] The title compound 2.28 g (82%) was obtained in a manner
similar to the Manufacturing Example 25 by use of
2-fluoro-5-nitrobenzotrifluoride, instead of
3,4-difluoronitrobenzene.
Manufacturing Example 58
4-(4-Methyl-1-piperidinyl)-3-(trifluoromethyl)phenylamine
[0555] The title compound 1.96 g (99%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 57, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 59
2-[2-(5-Methyl-1,1-dioxide-1,2,5-thiadiazolidin-2-yl)ethyl]-1H-isoindole-1-
,3(2H)-dione
[0556] To a solution of 686 mg (5.04 mmol) of
2-methyl-1,2,5-thiadiazolidine 1,1-dioxide in 10 mL of
N,N-dimethylformamide was added 212 mg (5.30 mmol) of sodium
hydride (60% oily) at room temperature, and the mixture was stirred
for 1 hour at the same temperature. Then, 1.41 g (5.54 mmol) of
N-(2-bromoethyl)phthalimide was added to the reaction mixture, and
the mixture was stirred for 1.5 hours at 75.degree. C. After the
reaction, water was
addedtothereactionmixtureandsolventwasremovedunderreducedpressure.
The resulting residue was treated with water and extracted with
dichloromethane and the organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:hexane/ethyl acetate=1/5), and solidified by treating with
ethyl acetate/ether to give 526 mg (34%) of the title compound.
Manufacturing Example 60
2-(5-Methyl-1-1-dioxide-1,2,5-thiadiazolidin-2-yl)ethanamine HCl
salt
[0557] To a suspension of 500 mg (1.62 mmol) of the compound
obtained in the Manufacturing Example 59 in 5 mL of ethanol was
added 94 .mu.L (1.94 mmol) of hydrazine monohydrate, and the
mixture was stirred for 6 hours at 70.degree. C. Then, insoluble
substances were removed off by filtration and the filtrate was
removed under reduced pressure, and 5 mL of water and 1.5 mL of
6M-HCl aqueous solution were added to the residue. Then, the
mixture was stirred for 6 hours at room temperature and insoluble
substances were removed off by filtration and the filtrate was
removed under reduced pressure. The resulting residue was
recrystallized from ethanol to give 287 mg (82%) of the title
compound.
Manufacturing Example 61
1-(2-Fluoro-4-nitrophenyl)-4-piperidinol
[0558] To a solution of 4.77 g (30.0 mmol) of
3,4-difluoronitrobenzene in 100 mL of N,N-dimethylformamide were
added 5.33 g (40.0 mmol) of potassium carbonate and 3.03 g (30.0
mmol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour
at 120.degree. C. After the reaction mixture was cooled to room
temperature, the reaction mixture was diluted with chloroform and
insoluble substances were removed off by filtration. The filtrate
was condensed and the residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=1.5/1) to give 3.1 g
(43%) of the title compound.
Manufacturing Example 62
1-(4-Amino-2-fluorophenyl)-4-piperidinol
[0559] To a solution of 2.95 g (12.28 mmol) of the compound
obtained in the Manufacturing Example 61 in 100 mL of ethanol was
added 600 mg of 5%-palladium carbon, and the atmosphere was
exchanged to hydrogen atmosphere. The mixture was stirred for 2
hours at room temperature and filtered. The filtrate was removed
under reduced pressure to give 2.48 g (96%) of the title
compound.
Manufacturing Example 63
tert-Butyl trans-4-(4-morpholinyl)cyclohexylcarbamate
[0560] To a solution of 21.43 g (0.1 mol) of tert-butyl
N-(trans-4-aminocyclohexyl) carbamate in 250 mL of
N,N-dimethylformamide were added 16.76 mL (0.12 mol) of bis
(2-bromoethyl)ether and 34.85 mL (0.25 mol) of triethylamine, and
the mixture was stirred for 6 hours at 70.degree. C. Then solvent
was removed under reduced pressure and the residue was treated with
ethyl acetate. The organic layer was washed with sodium carbonate
aqueous solution and saturated saline solution, then, dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:chloroform alone to
chloroform/methanol=30/1) to give 19.92 g (70%) of the title
compound.
Manufacturing Example 64
trans-4-(4-Morpholinyl)cyclohexylamine di-HCl salt
[0561] To a solution of 18.53 g (65.16 mmol) of the compound
obtained in the Manufacturing Example 63 in 65 mL of chloroform was
added 130 mL of 4N--HCl/ethyl acetate solution, and the mixture was
stirred for 3 hours at room temperature. The reaction mixture was
treated with 200 mL of diethyl ether and separated precipitates
were collected to give 16.22 g (97%) of the title compound.
Manufacturing Example 65
4-(4-Nitrophenyl)-2-piperazinone
[0562] To a solution of 1.275 g (9.04 mmol) of 4-fluoronitrobenzene
in 30 mL of N,N-dimethylformamide were added 1.87 g (13.56 mmol) of
potassium carbonate and 905 mg (9.04 mmol) of piperazine-2-one, and
the mixture was stirred for 1 hour at 130.degree. C. and for 1 hour
at 140.degree. C. The reaction mixture was cooled to room
temperature and diluted with chloroform, then, insoluble substances
were removed off by filtration. The filtrate was condensed under
reduced pressure and the resulting solid was washed with ethanol to
give 859 mg (43%) of the title compound.
Manufacturing Example 66
4-(4-Aminophenyl)-2-piperadinone
[0563] The title compound 640 mg (89%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 65, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 67
3-Amino-N,N-dimethylbenzenesulfonamide
[0564] The title compound 2.55 g (99%) was obtained in a manner
similar to the Manufacturing Example 2 by use of
N,N-dimethyl-3-nitrobenzene-sulfonamide, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 68
3-[(2-{[tert-Butyl(dimethyl)siliyl]oxy}ethyl)sulfonyl]nitrobenzene
[0565] To a solution of 955 mg (4.13 mmol) of 3-[(2-hydroxyethyl)
sulfonyl]-nitrobenzene in 30 mL of dichloromethane were added 747
mg (4.96 mmol) of tert-butyldimethylsilyl chloride and 10 mg of
4-dimethylaminopyridine, and the mixture was stirred for over night
at room temperature. Then, the reaction mixture was diluted with
dichloromethane and the organic layer was washed with water and
dried over anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=4/1 to 2/1) to give
1.27 g (89%) of the title compound.
Manufacturing Example 69
3-[(2-tert-Butyl(dimethyl)silyl)oxy]ethyl)sulfonyl}aniline
[0566] The title compound 856 mg (94%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 68, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 70
2-[(2-Hydroxyethyl)(methyl)amino]-N-(4-nitrophenyl)acetamide
[0567] To a suspension of 2.946 g (13.73 mmol) of
2-chloro-N-(4-nitrophenyl)acetamide in 30 mL of ethanol was added
3.31 mL (41.18 mmol) of 2-(methylamino)ethanol and the mixture was
refluxed for 4 hours. After the reaction mixture was cooled to room
temperature and condensed, then, the residue was treated with ethyl
acetate. The organic layer was washed with water and dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=40/1) to give 2.05
g (59%) of the title compound.
Manufacturing Example 71
4-Methyl-1-(4-nitrophenyl)-2-piperazinone
[0568] To a solution of 1.48 g (5.84 mmol) of the compound obtained
in the Manufacturing Example 70 in 50 mL of tetrahydrofuran were
added 1.75 mL (7.01 mmol) of tri-n-butylphosphine and 1.21 g (7.01
mmol) of 1,1'-azobis-(N,N-dimethylformamide), and the mixture was
stirred for 4 hours at room temperature. Water was added to the
reaction mixture and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated saline solution and
dried over with anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by silica gel
column chromatography to give 738 mg (54%) of the title
compound.
Manufacturing Example 72
1-(4-Aminophenyl)-4-methyl-2-piperazinone
[0569] The title compound 545 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Manufacturing Example 71, instead of the
compound obtained in the Manufacturing Example 1.
Manufacturing Example 73
1-(5-Nitro-2-pyridinyl)-4-piperidinol
[0570] To a suspension of 11.0 g (6.3 mmol) of
2-chloro-5-nitropyridine in 20 mL of n-propanol was added 1.9 g
(18.9 mmol) of 4-hydroxypiperidine, and the mixture was stirred for
1.5 hours at 100.degree. C. After cooling the reaction mixture, the
solvent was removed under reduced pressure, and the residue was
purified by silica gel column chromatography
(eluent:dichloromethane/methanol=50/1) to give 1.37 g (97%) of the
title compound.
Manufacturing Example 74
1-(5-Amino-2-pyridinyl)-4-piperidinol
[0571] To a suspension of 1.35 g (6.04 mmol) of the compound
obtained in the Manufacturing Example 73 in 18 mL of ethanol and 3
mL of water were added 1.3 g of reduced iron and 0.25 mL of conc.
hydrochloric acid, and the mixture was stirred for 2 hours at
90.degree. C. After cooling the reaction mixture, the mixture was
filtrated by Celite.RTM. and filtrate was condensed under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=10/1) to give 601
mg (51%) of the title compound.
Manufacturing Example 75
1-(2,3-Difluoro-4-nitrophenyl)-4-piperidinol
[0572] To a solution of 1.72 mL (15 mmol) of 2,3,4-trifluorobenzene
in N,N-dimethylformamide were added 1.01 g (10 mmol) of
4-hydroxypiperidine and 2.3 mL (20 mmol) of 2,6-lutidine, and the
mixture was stirred for 24 hours at room temperature. The solvent
was removed under reduced pressure, and saturated sodium
bicarbonate aqueous solution was added to the residue and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated saline solution, and dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=2/1 to ethyl acetate
alone) to give 1.82 g (70%) of the title compound.
Manufacturing Example 76
1-(4-Amino-2,3-difluorophenyl)-4-piperidinol
[0573] The title compound 1.23 g (78%) was obtained in a manner
similar to the Manufacturing Example 74 by use of the compound
obtained in the Manufacturing Example 75, instead of the compound
obtained in the Manufacturing Example 73.
Manufacturing Example 77
1-(2-Methyl-4-nitrophenyl)-4-piperidinol
[0574] To a solution of 1.55 g (10 mmol) of 2-fluoro-5-nitrotoluene
in 35 mL of N,N-dimethylformamide were added 1.01 g (10 mmol) of
4-hydroxypiperidine and 1.8 g (13 mmol) of potassium carbonate, and
the mixture was stirred for 2 hours at 120.degree. C. The reaction
mixture was poured into ice and the mixture was extracted with
ethyl acetate. The organic layer was washed with water and
saturated saline solution, and dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:hexane/ethyl acetate=1/1) to give 1.5 g (63%) of the title
compound.
Manufacturing Example 78
1-(4-Amino-2-methylphenyl)-4-piperidinol
[0575] The title compound 1.2 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Manufacturing Example 77, instead of the
compound obtained in the Manufacturing Example 1.
Manufacturing Example 79
2-(4-Hydroxy-1-piperidinyl)-5-nitrobenzonitrile
[0576] The title compound 2.0 g (81%) was obtained in a manner
similar to the Manufacturing Example 77 by use of
2-fluoro-5-nitrobenzonitrile, instead of
2-fluoro-5-nitrotoluene.
Manufacturing Example 80
5-Amino-2-(4-hydroxy-1-piperidinyl)benzonitrile
[0577] To a suspension of 11.0 g (4.04 mmol) of the compound
obtained in the Manufacturing Example 79 in 10 mL of water were
added 790 mg (14.14 mmol) of iron and 130 mg (2.42 mmol) of
ammonium chloride, and the mixture was refluxed for 3 hours. After
the reaction mixture was cooled to room temperature, water was
added to the reaction mixture, and the mixture was extracted with
chloroform. The organic layer was washed with water and saturated
saline solution, and dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:hexane/ethyl
acetate=1/1 to 1/4) to give 327 mg (37%) of the title compound.
Manufacturing Example 81
Methyl 2-(4-hydroxy-1-piperidinyl)-5-nitrobenzoate
[0578] The title compound 2.30 g (98%) was obtained in a manner
similar to the Manufacturing Example 77 by use of methyl
2-fluoro-5-nitrobenzoate, instead of 2-fluoro-5-nitrotoluene.
Manufacturing Example 82
Methyl 5-amino-2-(4-hydroxy-1-piperidinyl)benzoate
[0579] The title compound 1.83 g (91%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Manufacturing Example 81, instead of the compound
obtained in the Manufacturing Example 1.
Manufacturing Example 83
tert-Butyl 1-tetrahydro-2H-pyran-4-yl-4-piperidinylcarbamate
[0580] To a suspension of 9.5 g (184 mmol) of tert-butyl
piperidin-4-yl carbamate in 200 mL of 1,2-dichloroethane were added
4.4 mL (47.4 mmol) of tetrahydro-4H-pyran-4-one and 1.0 mL of
acetic acid, and the mixture was stirred for 30 minute. The
reaction mixture was cooled to 0.degree. C., and to this mixture
was added 15 g (71.1 mmol) of sodium triacetoxyborohydride and the
mixture was stirred for 4 hours at room temperature, then, 5.0 g
(23.6 mmol) of sodium triacetoxyborohydride was further added to
the mixture and the mixture was stirred for 64 hours at room
temperature. Saturated sodium bicarbonate aqueous solution was
added to the reaction mixture, and the mixture was extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, and dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:hexane/ethyl acetate=2/1) to give 11.54 g (86%) of the
title compound.
Manufacturing Example 84
1-Tetrahydro-2H-pyran-4-yl-4-piperidineamine di-HCl salt
[0581] The title compound 10.8 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 4 by use of the
compound obtained in the Manufacturing Example 83, instead of the
compound obtained in the Manufacturing Example 3.
Manufacturing Example 85
tert-Butyl
4-(4-{[(benzyloxy)carbonyl]amino}cyclohexyl)-1-piperazine-carbo-
xylate
[0582] The title compound 4.0 g (96%) was obtained in a manner
similar to the Manufacturing Example 83 by use of benzyl
4-oxocyclohexylcarbamate and tert-butyl 1-piperazinecarbamate,
instead of tetrahydro-4H-pyran-4-one and tert-butyl
piperidin-4-ylcarbamate, respectively.
Manufacturing Example 86
tert-Butyl 4-(4-aminocyclohexy)-1-piperazinecarboxylate
[0583] The title compound 2.6 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Manufacturing Example 85, instead of the
compound obtained in the Manufacturing Example 1.
Manufacturing Example 87
(5-Amino-2-pyridinyl)methanol di-HCl salt
[0584] The title compound 686 mg (78%) was obtained in a manner
similar to the Manufacturing Example 4 by use of tert-butyl
6-(hydroxylmethyl)pyridin-3-ylcarbamate, instead of the compound
obtained in the Manufacturing Example 3.
Manufacturing Example 88
tert-Butyl trans-4-[(chloroacetyl)amino]cyclohexylcarbamate
[0585] The title compound 604 mg (89%) was obtained in a manner
similar to the Manufacturing Example 3 by use of tert-butyl
trans-4-aminocyclohexylcarbamate and chloroacetyl chloride, instead
of the compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Manufacturing Example 89
tert-Butyl
trans-4-({[(2-hydroxyethyl)(methyl)amino]acetyl}amino)-cyclohex-
ylcarbamate
[0586] To a suspension of 560 mg (1.93 mml) of the compound
obtained in the Manufacturing Example 88 in 5 mL of ethanol was
added 464 .mu.L (5.78 mmol) of 2-(methylamino) ethanol and the
mixture was refluxed for 1 hour. After cooling, the solvent was
removed under reduced pressure and water was added to the residue,
and the mixture was extracted with dichloromethane. The organic
layer was washed with water and saturated saline solution, and
dried over with anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by
recrystallization (isopropanol) to give 391 mg (61%) of the title
compound.
Manufacturing Example 90
tert-Butyl
trans-4-(4-methyl-2-oxo-1-piperazinyl)cyclohexylcarbamate
[0587] 589 mg (5.25 mmol) of potassium t-butoxide was added to a
suspension solution of 560 mg (1.7 mmol) of the compound obtained
in the Manufacturing Example 89 in 10 mL of tetrahydrofuran, and a
solution of 499 mg (2.62 mmol) of p-toluenesulfonyl chloride in 5
mL of tetrahydrofuran was added to this mixture, then, the mixture
was stirred for 2 hours at 0.degree. C. 499 mg (2.62 mmol) of
p-toluenesulfonyl chloride and 589 mg (5.25 mmol) of potassium
t-butoxide were further added to the reaction mixture, and the
mixture was stirred for 30 minutes at room temperature. Water was
added to the reaction mixture and the mixture was extracted with
chloroform. The organic layer was washed with water and saturated
saline solution, and dried over with anhydrous sodium sulfate. The
solvent was removed and the residue was purified by silica gel
column chromatography (eluent:dichloromethane/methanol=10/1) to
give 398 mg (75%) of the title compound.
Manufacturing Example 91
1-(trans-4-Aminocyclohexyl)-4-methyl-2-piperazinone di-HCl salt
[0588] The title compound 349 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 4 by use of the
compound obtained in the Manufacturing Example 90, instead of the
compound obtained in the Manufacturing Example 3.
Manufacturing Example 92
Ethyl
1-(4-{[(benzyloxy)carbonyl]amino}cyclohexyl)-4-piperidine-carboxylat-
e
[0589] The title compound 2.6 g (67%) was obtained in a manner
similar to the Manufacturing Example 83 by use of benzyl
4-oxocyclohexylcarbamate and ethyl isonipecocotinate, instead of
tetrahydro-4H-pyran-4-one and tert-butyl piperidin-4-ylcarbamate,
respectively.
Manufacturing Example 93
Ethyl 1-(4-aminocyclohexyl)-4-pirepidinecarboxylate
[0590] The title compound 1.58 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Manufacturing Example 92, instead the
compound obtained in the Manufacturing Example 1.
Manufacturing Example 94
Ethyl 1-(4-nitrophenyl)-4-pirepidinol
[0591] To a solution of 14.1 g (0.10 mol) of 4-fluoronitrobenzene
in 200 mL of N,N-dimethylformamide were added 20.73 (0.15 mol) of
potassium carbonate and 10.1 g (0.10 mol) of 4-hydroxypiperidine
and the mixture was stirred for 1 hour at 140.degree. C. The
reaction mixture was cooled to room temperature and the mixture was
treated with chloroform, then insoluble substances were removed off
by filtration. The filtrate was condensed and the residue was
recrystallized from ethanol to give 17.27 g (78%) of the title
compound.
Manufacturing Example 95
1-(Aminophenyl)-4-piperidinol
[0592] To a solution of 17.09 g (76.95 mmol) of the compound
obtained in the Manufacturing Example 94 in 300 mL of methanol was
added 2.0 g of 5%-palladium-carbon, and the atmosphere was
exchanged to hydrogen atmosphere. The mixture was stirred for over
night at room temperature and the mixture was filtrated. The
filtrate was removed under reduced pressure to give 13.04 g (88%)
of the title compound.
Example 1
2-Cyclohexyl-5-methyl-2,4-dihydro-3H-pyrazol-3-one
[0593] A mixture solution of 39.88 g (0.265 mol) of
cyclohexylhydazine HCl salt in 28.57 mL (0.265 mol) of methyl
acetoacetate was heated for 1 hour at 120.degree. C. After the
reaction mixture was cooled to room temperature, dichloromethane
was added to this mixture and the mixture was neutralized by
2N-NaOH aqueous solution. The organic layer was dried over with
anhydrous sodium sulfate and the solvent was removed under reduced
pressure. The resulting residue was treated with hexane to give
crystalline and the crystalline was collected by filtration to give
33.84 g (71%) of the title compound.
Example 2
5-Chloro-1-cyclohexyl-3-methyl-1H-pyrazole
[0594] A mixture of 13.5 g (74.9 mmol) of the compound obtained in
the Example 1 and 13.5 mL of phosphorus oxychloride was heated for
2 hours at 110.degree. C. Then, the reaction mixture was cooled to
room temperature and condensed under reduced pressure. The residue
was extracted with ethyl acetate, and the extract was washed with
saturated sodium bicarbonate aqueous solution and saturated saline
solution, then, dried over with anhydrous sodium sulfate. The
solvent removed under reduced pressure to give 9.84 g (66%) of the
title compound.
Example 3-1
5-Chloro-1-cyclohexyl-3-methyl-1H-pyrazole-4-carboaldehyde
[0595] To a solution of 9.84 g (49.52 mmol) of the compound
obtained in the Example 2 in 50 mL of N,N-dimethylformamide was
added 11.5 mL (123.8 mmol) of phosphorous oxychloride under ice
cooling, and the mixture was stirred for 30 minutes at room
temperature and for 1 hour at 80.degree. C. Then, the reaction
mixture was cooled to room temperature and condensed under reduced
pressure. The residue was extracted with ethyl acetate and the
extract was washed with saturated sodium bicarbonate aqueous
solution and saturates saline solution, then, dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=10/1) to give 8.73 g
(76%) of the title compound.
Example 3-2
5-Chloro-1-cyclohexyl-3-methyl-1H-pyrazole-4-carboaldehyde
[0596] A mixture of 10 g (0.61 mol) of the compound obtained in the
Example 1 and 216 mL (2.32 mol) of phosphorus oxychloride was
heated and stirred for 2 hours at 110.degree. C. Then, the reaction
mixture was cooled to room temperature and added gradually to 630
mL of cooled N,N-dimethylformamide. After adding, the mixture was
stirred for 30 minutes at room temperature and for 5 hours at
80.degree. C. The reaction mixture was cooled to room temperature,
and the mixture was poured slowly into ice. Chloroform was added to
this mixture and pH of the mixture was adjusted to about 4 by
4N-NaOH aqueous solution (about 2.3 L). The organic layer was
separated and water layer was extracted with chloroform. The
combined organic layer was washed with water and saturated saline
solution, then, dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:ethyl
acetate/hexane=1/10 to 1/7) to give 100.8 g (73%) of the title
compound.
Example 4
Ethyl
[(1-cyclohexyl-4-formyl-3-methyl-1H-pyrazol-5-yl)sulfanil]-acetate
[0597] To a solution of 8.0 g (35.3 mmol) of the compound obtained
in the Example 3 in 100 mL of acetonitrile were added 4.84 mL (44.1
mmol) of ethyl thioglycolate and 7.32 g (52.93 mmol) of potassium
carbonate, and the mixture was refluxed for 4 hours. Then, 1.93 mL
(17.64 mmol) of ethyl thioglycolate and 2.43 g (17.64 mmol) of
potassium carbonate were further added to the reaction mixture and
the mixture was refluxed for 2 hours. After the reaction mixture
was cooled to room temperature and condensed under reduced
pressure. The residue was extracted with ethyl acetate and the
extract was washed with water and saturated saline solution, then,
dried over with anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by silica gel
column chromatography (eluent:hexane/ethyl acetate=4/1) to give
8.09 g (74%) of the title compound.
Example 5-1
Ethyl
1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate
[0598] To a solution of 7.95 g (25.61 mmol) of the compound
obtained in the Example 4 in 100 mL of N,N-dimethylformamide were
added 5.31 g (38.42 mmol) of potassium carbonate and 677 mg (2.56
mmol) of 18-crown-6, and the mixture was heated for 2 hours at
120.degree. C. to 130.degree. C. After cooling the reaction mixture
to room temperature, the mixture was extracted with ethyl acetate,
and the extract was washed with water and saturated saline
solution, then, dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography
(eluent:hexane/acetone=15/1) to give 2.2 g (29%) of the title
compound.
Example 5-2
Ethyl
1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate
[0599] To a solution of 63.4 mL (0.578 mmol) of ethyl thioglycolate
in 1 L of tetrahydrofuran was added gradually 23 g (0.578 mol) of
sodium hydride (60% oily) under ice cooling, and the mixture was
stirred for 1 hour at room temperature. The reaction mixture was
cooled with ice water, and a solution of 100.8 g (0.444 mol) of the
compound obtained in the Example 3 in 400 mL of tetrahydrofuran was
added gradually to this reaction mixture during 45 minutes, and the
mixture was stirred for 2 hours at room temperature. Then, the
reaction mixture was cooled with ice water, and 23 g (0.578 mol) of
sodium hydride (60% oily) was added gradually to this reaction
mixture, and the mixture was stirred for 30 minutes at 0.degree. C.
After the reaction, the reaction mixture was poured slowly into
ice/ethyl acetate solution, and the organic layer was separated.
The water layer was extracted with ethyl acetate, and the combined
organic layer was washed with water and saturated saline solution,
then dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:ethyl acetate/hexane=1/8
to 1/5) to give 104.7 g (81%) of the title compound.
Example 6
1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylic
acid
[0600] To a solution of 11.89 g (40.66 mmol) of the compound
obtained in the Example 5 in 100 mL of ethanol was added 44.7 mL
(44.7 mmol) of 1N sodium hydroxide solution, and the mixture was
heated for 1 hour at 60.degree. C. Then, the reaction mixture was
cooled to room temperature and condensed under reduced pressure.
Water and diethyl ether were added to the residue and the water
layer was separated. 23 mL of 2N--HCl aqueous solution was added to
the water layer, and the resulting precipitates were collected to
give 10.38 g (97%) of the title compound.
Example 7
N-Benzyl-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0601] To a suspension of 60 mg (0.23 mmol) of the compound
obtained in the Example 6 in 2 mL of dichloromethane was added 33
.mu.L (0.45 mmol) of thionyl chloride, and the mixture was stirred
for 8 hours at 80.degree. C. Then, the solvent was removed under
reduced pressure to give the corresponding acid chloride
intermediate compound.
[0602] Next, 27 .mu.L (0.25 mmol) of benzylamine and 79 .mu.L of
triethylamine were added to the solution of the above acid chloride
intermediate compound in 2 mL of anhydrous dichloromethane under
ice-cooling, and the mixture was stirred for 1.5 hours at room
temperature. Then, water was added to the reaction mixture and the
mixture was extracted with dichloromethane. The organic layer was
dried over with anhydrous sodium sulfate and removed under reduced
pressure. The residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=4/1 to 3/1) to give 75
mg (94%) of the title compound.
Example 8
1-Cyclohexyl-3-methyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0603] The title compound 65 mg (84%) was obtained in a manner
similar to the Example 7 by use of aniline, instead of
benzylamine.
Example 9
N-{4-[Acetyl(methyl)amino]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide
[0604] The title compound 89 mg (82%) was obtained in a manner
similar to the Example 7 by use of
N-(4-aminophenyl)-N-methylacetamide, instead of benzylamine.
Example 10
N-[4-(Acetylamino)-3-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0605] The title compound 73 mg (65%) was obtained in a manner
similar to the Example 7 by use of
N-(4-amino-3-methoxyphenyl)acetamide, instead of benzylamine.
Example 11
N-(1-Acetyl-2,3-dihydror-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[0606] The title compound 30 mg (27%) was obtained in a manner
similar to the Example 7 by use of
1-acetyl-2,3-dihydro-1H-indol-5-ylamine, instead of
benzylamine.
Example 12
Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]am-
ino}phenylcarbamate
[0607] The title compound 101 mg (89%) was obtained in a manner
similar to the Example 7 by use of ethyl 4-aminophenylcarbamate,
instead of benzylamine.
Example 13
tert-Butyl
5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbony-
l]amino}-1-indolinecarboxylate
[0608] The title compound 133 mg (92%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 2, instead of benzylamine.
Example 14
1-Cyclohexyl-N-(2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyrazo-
le-5-carboxamide HCl salt
[0609] The title compound 68 mg (99%) was obtained in a manner
similar to the Manufacturing Example 4 by use of the compound
obtained in the Example 13, instead of the compound obtained in the
Manufacturing Example 3.
Example 15
1-Cyclohexyl-N-(1H-indol-5-yl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide
[0610] The title compound 95 mg (95%) was obtained in a manner
similar to the Example 7 by use of 5-aminoindole, instead of
benzylamine.
Example 16
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinyl)phenyl]-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0611] The title compound 85 mg (89%) was obtained in a manner
similar to the Example 7 by use of 4-(4-morpholinyl) aniline,
instead of benzylamine.
Example 17
1-Cyclohexyl-3-methyl-N-(3-nitrophenyl)-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide
[0612] The title compound 175 mg (60%) was obtained in a manner
similar to the Example 7 by use of 3-nitroaniline, instead of
benzylamine.
Example 18
N-(3-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrozole-5-carboxa-
mide
[0613] The title compound 142 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Example 17, instead of the compound
obtained in the Manufacturing Example 1.
Example 19
N-[3-(Acetylamino)phenyl]-1-cyoclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0614] To a solution of 60 mg (0.17 mmol) of the compound obtained
in the Example 18 in 4 mL of anhydrous tetrahydrofuran were added
25 .mu.L (0.35 mmol) of acetyl chloride and 50 .mu.L (0.35 mmol) of
triethylamine under ice cooling, and the mixture was stirred for 2
hour at room temperature. Then, water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was dried over with anhydrous sodium sulfate and
removed under reduced pressure. The residue was purified by silica
gel column chromatography (eluent:hexane/ethyl acetate=2/1 to 1/2)
to give 15 mg (22%) of the title compound.
Example 20
1-Cyclohexyl-3-methyl-N-{4-(methylamino)carbonyl}phenyl}-1H-thieno[2,3-c]p-
yrazole-5-carboxamide
[0615] The title compound 37 mg (41%) was obtained in a manner
similar to the Example 7 by use of 4-amino-N-methylbenzamide,
instead of benzylamine.
Example 21
1-Cyclohexyl-3-methyl-N-(1-propionyl-2,3-dihydro-1H-indol-5-yl)-1H-thieno[-
2,3-c]pyrazole-5-carboxamide
[0616] The title compound 47 mg (75%) was obtained in a manner
similar to the Example 19 by use of the compound obtained in the
Example 14 and propionyl chloride, instead of using the compound
obtained in the Example 18 and acetyl chloride, respectively.
Example 22
Ethyl
5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]am-
ino}-1-indolinecarboxylate
[0617] The title compound 62 mg (82%) was obtained in a manner
similar to the Example 19 by use of the compound obtained in the
Example 14 and ethyl chlorocarbonate, instead of the compound
obtained in the Example 18 and acetyl chloride, respectively.
Example 23
1-Cyclohexyl-N-(1-isobutyl-2,3-dihydro-1H-indol-5-yl)-3-methyl-1H-thieno[2-
,3-c]pyrazole-5-carboxamide
[0618] The title compound 68 mg (89%) was obtained in a manner
similar to the Example 19 by use of the compound obtained in the
Example 14 and isobutyryl chloride, instead of the compound
obtained in the Example 18 and acetyl chloride, respectively.
Example 24
N-(1-Butyryl-2,3-dihydro-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[0619] The title compound 66 mg (87%) was obtained in a manner
similar to the Example 19 by use of the compound obtained in the
Example 14 and n-butyryl chloride, instead of the compound obtained
in the Example 18 and acetyl chloride, respectively.
Example 25
1-Cyclohexyl-N-[1-(2,2-dimethylpropanoyl)-2,3-dihydro-1H-indol-5-yl]-3-met-
hyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0620] The title compound 59 mg (76%) was obtained in a manner
similar to the Example 19 by use of the compound obtained in the
Example 14 and propanoyl chloride, instead of the compound obtained
in the Example 18 and acetyl chloride, respectively.
Example 26
1-Cyclohexyl-3-methyl-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0621] The title compound 60 mg (58%) was obtained in a manner
similar to the Example 7 by use of
5-amino-1,3-dihydro-2H-indol-2-one, instead of benzylamine.
Example 27
N-[4-(Acetylamino)-3-chlorophenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]p-
yrazole-5-carboxamide
[0622] The title compound 28 mg (43%) was obtained in a manner
similar to the Example 7 by use of
N-(4-amino-2-chlorophenyl)acetamide, instead of benzylamine.
Example 28
1-Cyclohexyl-N-{4-[(ethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-c]p-
yrazole-5-carboxamide
[0623] The title compound 30 mg (32%) was obtained in a manner
similar to the Example 7 by use of 4-amino-N-ethylbenzamide,
instead of benzylamine.
Example 29
1-Cyclohexyl-N-[4-(methoxymethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0624] The title compound 62 mg (70%) was obtained in a manner
similar to the Example 7 by use of 4-(methoxymethyl) aniline,
instead of benzylamine.
Example 30
1-Cyclohexyl-N-[4-(hydroxymethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0625] The title compound 65 mg (76%) was obtained in a manner
similar to the Example 7 by use of (4-aminophenyl)methanol, instead
of benzylamine.
Example 31
1-Cyclohexyl-3-methyl-N-[4-(morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c]py-
razole-5-carboxamide
[0626] The title compound 88 mg (90%) was obtained in a manner
similar to the Example 7 by use of
4-(4-morpholinylcarbonyl)aniline, instead of benzylamine.
Example 32
1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-phenyl}-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0627] The title compound 57 mg (53%) was obtained in a manner
similar to the Example 7 by use of
4-[(4-methyl-1-piperazinyl)carbonyl]aniline, instead of
benzylamine.
Example 33
1-Cyclohexyl-3-methyl-N-{4-[(methylsulfonyl)amino]phenyl}-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0628] The title compound 33 mg (33%) was obtained in a manner
similar to the Example 7 by use of
N-(4-aminophenyl)methanesulfonamide, instead of benzylamine.
Example 34
1-Cyclohexyl-3-methyl-N-{4-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0629] The title compound 22 mg (22%) was obtained in a manner
similar to the Example 7 by use of
4-amino-N-methylbenzenesulfonamide, instead of benzylamine.
Example 35
N-{1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-2,3-di-
hydro-1H-indol-5-yl}acetamide
[0630] The title compound 76 mg (80%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 4, instead of benzylamine.
Example 36
1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0631] The title compound 36 mg (32%) was obtained in a manner
similar to the Example 7 by use of
4-[(4-methyl-1-piperazinyl)sulfonyl]aniline, instead of
benzylamine.
Example 37
1-Cyclohexyl-N-(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0632] The title compound 50 mg (50%) was obtained in a manner
similar to the Example 7 by use of
4-amino-N-(2-methoxyethyl)benzamide, instead of benzylamine.
Example 38
N-(4-Acetylphenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carbox-
amide
[0633] The title compound 54 mg (62%) was obtained in a manner
similar to the Example 7 by use of p-aminoacetophenone, instead of
benzylamine.
Example 39
1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3--
c]pyrazole-5-carboxamide
[0634] The title compound 86 mg (92%) was obtained in a manner
similar to the Example 7 by use of 4-amino-N,N-dimethylbenzamide,
instead of benzylamine.
Example 40
Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]am-
ino}benzoate
[0635] The title compound 80 mg (51%) was obtained in a manner
similar to the Example 7 by use of ethyl 4-aminobenzoate, instead
of benzylamine.
Example 41
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}be-
nzoic Acid
[0636] To a solution of 55 mg (0.13 mmol) of the compound obtained
in the Example 40 in 8 mL of ethanol was added 134 .mu.L of 1M
sodium hydroxide solution, and the mixture was stirred for 1 hour
at room temperature. Then, 20 mL of water was added to the reaction
mixture and the water layer was washed with ethyl acetate. The
water layer was neutralized by adding of 1M-HCl solution, and the
resulting precipitates were collected to give 33 mg (65%) of the
title compound.
Example 42
1-Cyclohexyl-N-(2-methoxy-4-nitrophenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0637] The title compound 73 mg (31%) was obtained in a manner
similar to the Example 7 by use of 2-methoxy-4-nitroaniline,
instead of benzylamine.
Example 43
N-(4-Amino-2-methoxyphenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0638] The title compound 22 mg (37%) was obtained in a manner
similar to the Manufacturing Example 2 by use of the compound
obtained in the Example 42, instead of the compound obtained in the
Manufacturing Example 1.
Example 44
N-[4-(Acetylamino)-2-methoxyphenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0639] The title compound 27 mg (49%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 43, instead of the compound obtained in the
Manufacturing Example 2.
Example 45
1-Cyclohexyl-N-{4-[(isopropylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3-
-c]pyrazole-5-carboxamide
[0640] The title compound 47 mg (49%) was obtained in a manner
similar to the Example 7 by use of 4-amino-N-isopropylbenzamide,
instead of benzylamine.
Example 46
1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}phenyl)-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0641] The title compound 93 mg (72%) was obtained in a manner
similar to the Example 7 by use of
4-amino-N-(2-hydroxyethyl)benzamide, instead of benzylamine.
Example 47
N-[6-(Acetylamino)-3-pyridinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyra-
zole-5-carboxamide
[0642] The title compound 33 mg (37%) was obtained in a manner
similar to the Example 7 by use of
N-(5-amino-2-pyridinyl)acetamide, instead of benzylamine.
Example 48
1-Cyclohexyl-N-(4-methoxyphenyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carbo-
xamide
[0643] The title compound 81 mg (96%) was obtained in a manner
similar to the Example 7 by use of p-anisidine, instead of
benzylamine.
Example 49
1-Cyclohexyl-N-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0644] The title compound 65 mg (85%) was obtained in a manner
similar to the Example 7 by use of cyclopentylamine, instead of
benzylamine.
Example 50
N,1-Dicyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0645] The title compound 82 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of cyclohexylamine, instead
of benzylamine.
Example 51
N-{4-[(tert-Butylamino)carbonyl]phenyl}-1-cyclohexyl-3-methyl-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[0646] The title compound 89 mg (89%) was obtained in a manner
similar to the Example 7 by use of 4-amino-N-(tert-butyl)benzamide,
instead of benzylamine.
Example 52
1-Cyclohexyl-N-{5-[(isopropylamino)carbonyl]-2-pyridinyl}-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide
[0647] The title compound 13 mg (20%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 5, instead of benzylamine.
Example 53
1-Cyclohexyl-N-[4-(fromylamino)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-
-carboxamide
[0648] The title compound 11 mg (19%) was obtained in a manner
similar to the Example 7 by use of 4-aminophenylformamide, instead
of benzylamine.
Example 54
tert-Butyl
4-[(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)car-
bonyl]amino}phenyl)sulfonyl]-1-piperazinecarboxylate
[0649] The title compound 71 mg (32%) was obtained in a manner
similar to the Example 7 by use of tert-butyl
4-[(4-aminophenyl)sulfonyl]-1-piperazinecarboxylate, instead of
benzylamine.
Example 55
1-Cyclohexyl-3-methyl-N-[4-(1-piperazinylsulfonyl)phenyl]-1H-thieno[2,3-c]-
pyrazole-5-carboxamide HCl salt
[0650] The title compound 30 mg (61%) was obtained in a manner
similar to the Manufacturing Example 4 by use of the compound
obtained in the Example 54, instead of the compound obtained in the
Manufacturing Example 3.
Example 56
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylsulfonyl)phenyl]-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0651] The title compound 14 mg (12%) was obtained in a manner
similar to the Example 7 by use of
4-(4-morpholinylsulfonyl)aniline, instead of benzylamine.
Example 57
1-Cyclohexyl-3-methyl-N-[4-(methylsulfonyl)phenyl]-1H-thieno[2,3-c]pyrazol-
e-5-carboxamide
[0652] The title compound 41 mg (43%) was obtained in a manner
similar to the Example 7 by use of 4-(methylsulfonyl) aniline,
instead of benzylamine.
Example 58
1-Cyclohexyl-N-[1-(cyclopropylcarbonyl)-2,3-dihydro-1H-indol-5-yl]-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0653] The title compound 42 mg (49%) was obtained in a manner
similar to the Example 19 by use of the compound obtained in the
Example 14 and cyclopropanecarbonyl chloride, instead of the
compound obtained in the Example 18 and acetyl chloride,
respectively.
Example 59
1-Cyclohexyl-3-methyl-N-[1-(methylsulfonyl)-2,3-dihydro-1H-indol-5-yl]-1H--
thieno[2,3-c]pyrazole-5-carboxamide
[0654] The title compound 106 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of the compound obtained in
the Manufacturing Example 7, instead of benzylamine.
Example 60
N-(1-Acetyl-1H-indol-5-yl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0655] The title compound 94 mg (97%) was obtained in a manner
similar to the Example 7 by use of 1-acetyl-1H-indole-5-amine,
instead of benzylamine.
Example 61
1-Cyclohexyl-N-cyclopropyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0656] The title compound 67 mg (96%) was obtained in a manner
similar to the Example 7 by use of cyclopropylamine, instead of
benzylamine.
Example 62
N-(1-Benzyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0657] The title compound 200 mg (81%) was obtained in a manner
similar to the Example 7 by use of 1-benzyl-4-piperidinylamine,
instead of benzylamine.
Example 63
1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide HCl salt
[0658] To a solution of 180 mg (0.42 mol) of the compound obtained
in the Example 62 in 4 mL of 1,2-dichloroethane was added 50 .mu.L
of 1-chloroethyl chloroformate, and the mixture was refluxed for 2
hours. Then, the reaction mixture was cooled to room temperature
and condensed under reduced pressure. The residue was dissolved in
6 mL of methanol and the mixture was refluxed for 3 hours. After
the reaction mixture was cooled to room temperature, the solvent
was removed under reduced pressure. The residue was washed with
ethyl acetate and the resulting precipitates were collected to give
109 mg (69%) of the title compound.
Example 64
N-(1-Acetyl-4-piperidinyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0659] The title compound 40 mg (78%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 63, instead of the compound obtained in the
Manufacturing Example 2.
Example 65
Ethyl
(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mio}phenoxy)acetate
[0660] The title compound 320 mg (96%) was obtained in a manner
similar to the Example 7 by use of ethyl (4-aminophenoxy)acetate,
instead of benzylamine.
Example 66
(4-{[(1-Cyclohexyl-3-methyl-1H-theino[2,3-c]pyrazol-5-yl)carbonyl]-amino}p-
henoxy)acetic acid
[0661] The title compound 268 mg (95%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 65, instead of the compound obtained in the Example 40.
Example 67
1-Cyclohexyl-3-methyl-N-{[(4-[2-(methylamino)-2-oxoethoxy]phenyl)-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0662] The title compound 24 mg (39%) was obtained in a manner
similar to the Manufacturing Example 5 by use of the compound
obtained in the Example 66 and methylamine (30%-methanol solution),
instead of 6-aminonicotic acid and isopropylamine,
respectively.
Example 68
Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]am-
ino}phenyl)acetate
[0663] The title compound 223 mg (93%) was obtained in a manner
similar to the Example 7 by use of ethyl(4-aminophenyl)acetate,
instead of benzylamine.
Example 69
(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}p-
henyl)acetic acid
[0664] The title compound 157 mg (84%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 68, instead of the compound obtained in the Example 40.
Example 70
1-Cyclohexyl-3-methyl-N-{4-[2-(methylamino)-2-oxoethyl]phenyl}-1H-thieno[2-
,3-c]pyrazole-5-carboxamide
[0665] The title compound 31 mg (50%) was obtained in a manner
similar to the Manufacturing Example 5 by use of the compound
obtained in the Example 69 and methylamine (30%-methanol solution),
instead of 6-aminonicotic acid and isopropylamine,
respectively.
Example 71
tert-Butyl
4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carb-
onyl]amino}phenyl)-1-piperazinecarboxylate
[0666] The title compound 158 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of tert-buty
4-(4-aminophenyl)-1-piperazine-carboxylate, instead of
benzylamine.
Example 72
1-Cyclohexyl-3-methyl-N-[4-(1-piperazinyl)phenyl]-1H-thieno[2,3-c]pyrazole-
-5-carboxamide HCl salt
[0667] The title compound 108 mg (88%) was obtained in a manner
similar to the Manufacturing Example 4 by use of the compound
obtained in the Example 71, instead of the compound obtained in the
Manufacturing Example 3.
Example 73
N-[4-(4-Acetyl-1-piperazinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide
[0668] The title compound 32 mg (63%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 72, instead of the compound obtained in the
Manufacturing Example 2.
Example 74
1-Cyclohexyl-N-(trans-4-hydroxycyclohexyl)-3-methyl-1H-thieno[2,3-c]pyrazo-
le-5-carboxamide
[0669] The title compound 82 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of
trans-4-aminocyclohexanol, instead of benzylamine.
Example 75
1-Cyclohexyl-3-methyl-N-(4-oxocyclohexyl)-1H-thieno[2,3-c]pyrazole-5-carbo-
xamide
[0670] To a solution of 4.0 g (11.1 mmol) of the compound obtained
in the Example 74 in 200 mL of dichloromethane was added 5.0 g
(13.3 mmol) of pyridinium dichromate, and the mixture was stirred
for 6 hours at room temperature. Then, 5.0 g (13.3 mmol) of
pyridinium dichromate was further added to the reaction mixture and
the mixture was stirred for 18 hours. The reaction mixture was
filtrated with Celite.RTM. and the filtrate was removed under
reduced pressure. The residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=40/1) to give the
2.6 g (65%) of the title compound.
Example 76
1-Cyclohexyl-3-methyl-N-{4-[2-(4-methyl-1-piperazinyl)-2-oxoethoxy]-phenyl-
}-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0671] The title compound 65 mg (90%) was obtained in a manner
similar to the Manufacturing Example 5 by use of the compound
obtained in the Example 66 and N-methylpiperazine, instead of
6-aminonicotic acid and isopropylamine, respectively.
Example 77
1-Cyclohexyl-N-{4-[2-(dimethylamino)-2-oxoethoxy]phenyl}-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0672] The title compound 43 mg (67%) was obtained in a manner
similar to the Manufacturing Example 5 by use of the compound
obtained in the Example 66 and dimethylamine HCl salt, instead of
6-aminonicotic acid and isopropylamine, respectively.
Example 78
2-{4-[(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mino}phenyl)sulfonyl]-1-piperazinyl}ethyl acetate
[0673] The title compound 60 mg (28%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 10, instead of benzylamine.
Example 79
1-Cyclohexyl-N-(4-{[4-(2-hydroxyethyl)-1-piperazinyl]sulfonyl}-phenyl)-3-m-
ethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0674] To a solution of 45 mg (0.08 mmol) of the compound obtained
in the Example 78 in 41 mL of ethanol was added 86 .mu.L of 1M
sodium hydroxide aqueous solution, and the mixture was stirred for
1 hour at room temperature. Then, water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated saline solution and dried
over with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=20/1) to give 31 mg
(74%) of the title compound.
Example 80
N-[trans-4-(Acetylamino)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0675] The title compound 28 mg (30%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 12, instead of benzylamine.
Example 81
1-Cyclohexyl-N,3-dimethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0676] The title compound 58 mg (92%) was obtained in a manner
similar to the Example 7 by use of methylamine HCl salt, instead of
benzylamine.
Example 82
2-Cyclopentyl-5-methyl-2,4-dihydro-3H-pyrazole-3-one
[0677] The title compound 9.70 g (80%) was obtained in a manner
similar to the Example 1 by use of cyclopentylhydrazine HCl salt,
instead of cyclohexylhydrazine HCl salt.
Example 83
5-Chloro-1-cyclopentyl-3-methyl-1H-pyrazole
[0678] The title compound 4.5 g (81%) was obtained in a manner
similar to the Example 2 by use of the compound obtained in the
Example 82, instead of the compound obtained in the Example 1.
Example 84
5-Chloro-1-cyclopentyl-3-methyl-1H-pyrazole-4-carboaldehyde
[0679] The title compound 4.0 g (79%) was obtained in a manner
similar to the Example 3-1 by use of the compound obtained in the
Example 83, instead of the compound obtained in the Example 2.
Example 85
Ethyl
[(1-cyclopentyl-4-formyl-3-methyl-1H-pyrazol-5-yl)sulfanil]-acetate
[0680] The title compound 1.9 g (36%) was obtained in a manner
similar to the Example 4 by use of the compound obtained in the
Example 84, instead of the compound obtained in the Example 3.
Example 86
Ethyl
1-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate
[0681] The title compound 1.47 g (87%) was obtained in a manner
similar to the Example 5-1 by use of the compound obtained in the
Example 85, instead of the compound obtained in the Example 4.
Example 87
1-Cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylic
acid
[0682] The title compound 0.49 g (68%) was obtained in a manner
similar to the Example 6 by use of the compound obtained in the
Example 86, instead of the compound obtained in the Example 5.
Example 88
N-[4-(Acetylamino)phenyl]-1-cyclopentyl-3-methyl-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0683] The title compound 88 mg (72%) was obtained in a manner
similar to the Example 7 by use of N-(4-aminophenyl)acetamide and
the compound obtained in the Example 87, instead of benzylamine and
the compound obtained in the Example 6 respectively.
Example 89
2-Cycloheptyl-5-methyl-2,4-dihydro-3H-pyrazole-3-one
[0684] The title compound 16.27 g (52%) was obtained in a manner
similar to the Example 1 by use of cycloheptylhydrazine HCl salt,
instead of using cyclohexylhydrazine HCl salt.
Example 90
5-Chloro-1-cycloheptyl-3-methyl-1H-pyrazole
[0685] The title compound 6.92 g (79%) was obtained in a manner
similar to the Example 2 by use of the compound obtained in the
Example 89, instead of the compound obtained in the Example 1.
Example 91
5-Chloro-1-cycloheptyl-3-methyl-1H-pyrazole-4-carboaldehyde
[0686] The title compound 6.47 g (84%) was obtained in a manner
similar to the Example 3-1 by use of the compound obtained in the
Example 90, instead of the compound obtained in the Example 2.
Example 92
Ethyl
1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylate
[0687] To a solution of 6.4 g (26.6 mmol) of the compound obtained
in the Example 91 in 100 mL of acetonitrile were added 3.06 mL
(27.9 mmol) of ethyl thioglycolate and 7.72 g (55.88 mmol) of
potassium carbonate, and the mixture was refluxed for 23 hours.
Then, 3.06 mL (27.9 mmol) of ethyl thioglycolate was further added
ant the mixture was refluxed for 3 hours. After cooling the
reaction mixture to room temperature, the mixture was condensed and
the residue was extracted with dichloromethane. The organic layer
was washed with water and saturated saline solution, then, dried
over with anhydrous sodium sulfate. The solvent was removed under
reduced pressure, and the residue was purified by silica gel column
chromatography (eluent:hexane/acetone=20/1) to give 2.46 g (30%) of
the title compound.
Example 93
1-Cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxylic
acid
[0688] The title compound 1.40 g (67%) was obtained in a manner
similar to the Example 6 by use of the compound obtained in the
Example 92, instead of the compound obtained in the Example 5.
Example 94
N-[4-(Acetylamino)phenyl]-1-cycloheptyl-3-methyl-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0689] The title compound 71 mg (60%) was obtained in a manner
similar to the Example 7 by use of N-(4-aminophenyl)acetamide and
the compound obtained in the Example 93, instead of benzylamine and
the compound obtained in the Example 6, respectively.
Example 95
1-Cyclohexyl-N,3-dimethyl-N-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0690] The title compound 103 mg (96%) was obtained in a manner
similar to the Example 7 by use of N-methylaniline, instead of
benzylamine.
Example 96
1-Cyclohexyl-3-methyl-N-(4-pyridinyl)-1H-thieno[2,3-c]pyrazole-5-carboxami-
de
[0691] The title compound 80 mg (96%) was obtained in a manner
similar to the Example 7 by use of 4-aminopyridine, instead of
benzylamine.
Example 97
1-Cyclohexyl-3-methyl-N-(3-pyridinyl)-1H-thieno[2,3-c]pyrazole-5-carboxami-
de
[0692] The title compound 48 mg (57%) was obtained in a manner
similar to the Example 7 by use of 3-aminopyridine, instead of
benzylamine.
Example 98
1-Cyclohexyl-3-methyl-N-(4-nitrophenyl)1H-thieno[2,3-c]pyrazole-5-carboxam-
ide
[0693] To a suspension of 170 mg (0.643 mmol) of the compound
obtained in the Example 6 in 3 mL of 1,2-dichloroethane was added
94 .mu.L (1.29 mmol) of thionyl chloride, and the mixture was
stirred for 1.5 hours at 90.degree. C. After cooling the reaction
mixture to room temperature, and the solvent was removed under the
reduced pressure to give the corresponding acid chloride
intermediate compound.
[0694] Then, to a solution of 170 mg (0.643 mmol) of 4-nitroaniline
in 4 mL of tetrahydrofuran was added 77 mg (60% oily; 1.93 mmol) of
sodium borohydride, and the mixture was stirred for 10 minutes at
room temperature. Next, a solution of the above acid chloride in 3
mL of tetrahydrofuran was added to this mixture, and the mixture
was stirred for 30 minutes at room temperature. Water was added to
the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated saline
solution and dried over with anhydrous sodium sulfate. The solvent
was removed under reduced pressure and the resulting solid was
washed with methanol to give 150 mg (61%) of the title
compound.
Example 99
N-(4-Aminophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide
[0695] The title compound 142 mg (quantitative) was obtained in a
manner similar to the Manufacturing Example 2 by use of the
compound obtained in the Example 98, instead of the compound
obtained in the Manufacturing Example 1.
Example 100
N-[4-(Acetylamino)phenyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-
-carboxamide
[0696] The title compound 10 mg (24%) was obtained in a manner
similar to the Example 19 by use of the compound obtained in the
Example 99, instead of the compound obtained in the Example 18.
Example 101
1-Cyclohexyl-N-{4-[(methoxyacetyl)amino]phenyl}-3-methyl-1H-thieno[2,3-c]p-
yrazole-5-carboxamide
[0697] The title compound 92 mg (88%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 14, instead of benzylamine.
Example 102
Methyl
5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mino}-2-pyridinecarboxylate
[0698] The title compound 98 mg (43%) was obtained in a manner
similar to the Example 7 by use of methyl
5-amino-2-pyridinecarboxylate, instead of benzylamine.
Example 103
5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-
-pyridinecarboxylic Acid
[0699] The title compound 160 mg (87%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 102, instead of the compound obtained in the Example
40.
Example 104
1-Cyclohexyl-3-methyl-N-{6-[(methylamino)carbonyl]-3-pyridinyl}-1H-thieno[-
2,3-c]pyrazole-5-carboxamide
[0700] The title compound 44 mg (77%) was obtained in a manner
similar to the Manufacturing Example 5 by use of the compound
obtained in the Example 103 and methylamine (30%-methanol
solution), instead of 6-aminonicotic acid and isopropylamine,
respectively.
Example 105
1-Cyclohexyl-N-{6-[(dimethylamino)carbonyl]-3-pyridinyl}-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0701] The title compound 50 mg (85%) was obtained in a manner
similar to the Manufacturing Example 5 by use of the compound
obtained in the Example 103 and dimethylamine HCl salt, instead of
6-aminonicotic acid and isopropylamine, respectively.
Example 106
1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c-
]pyrazole-5-carboxamide
[0702] The title compound 76 mg (77%) was obtained in a manner
similar to the Example 7 by use of
4-(4-methyl-1-piperazinyl)aniline, instead of benzylamine.
Example 107
1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c-
]pyrazole-5-carboxamide methanesulfonate
[0703] To a suspension of 563 mg (1.287 mmol) of the compound
obtained in the Example 106 in 5.6 mL of methanol was added 85.6
.mu.L (1.319 mmol) of methanesulfonic acid at 50.degree. C., and
the mixture was refluxed. Then, the reaction mixture was gradually
cooled to 0.degree. C. and the resulting precipitates were
collected to give 452 mg (66%) of the title compound.
Example 108
N-(4-Cyanophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide
[0704] The title compound 300 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of 4-cyanoaniline, instead
of benzylamine.
Example 109
1-Cyclohexyl-3-methyl-N-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-thieno-
[2,3-c]pyrazole-5-carboxamide di-HCl salt
[0705]
1-Cyclohexyl-3-methyl-N-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-
-thieno[2,3-c]pyrazole-5-carboxamide 235 mg (79%) was obtained in a
manner similar to the Example 7 by use of 4-cyanoaniline, instead
of benzylamine. Next, to a solution of 132 mg (0.301 mmol) of the
above free base compound in 2 mL of methanol was added 166 .mu.L of
4N--HCl/dioxane, and the mixture was diluted with diethyl ether.
The resulting precipitates were collected to give 140 mg (91%) of
the title compound.
Example 110
1-Cyclohexyl-3-methyl-N-{3-[(4-methyl-1-piperazinyl)sulfonyl]-phenyl}-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide HCl salt
[0706]
1-Cyclohexyl-3-methyl-N-{3-[(4-methyl-1-piperazinyl)sulfonyl]-pheny-
l}-1H-thieno[2,3-c]pyrazole-5-carboxamide 133 mg (87%) was obtained
in a manner similar to the Example 7 by use of the compound
obtained in the Manufacturing Example 17, instead of benzylamine.
Next, to a solution of 133 mg (0.265 mmol) of the above free base
compound in 3 mL of methanol was added 80 .mu.L of 4N--HCl/dioxane,
and the mixture was diluted with diethyl ether. The resulting
precipitates were collected to give 138 mg (97%) of the title
compound.
Example 111
1-Cyclohexyl-3-methyl-N-{3-[(methylamino)sulfonyl]phenyl}-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0707] The title compound 45 mg (34%) was obtained in a manner
similar to the Example 7 by use of
3-amino-N-methylbenzenesulfonamide, instead of benzylamine.
Example 112
1-Cycloheptyl-3-methyl-N-[(4-(4-methyl-1-piperazinyl)phenyl)-1H-thieno[2,3-
-c]pyrazole-5-carboxamide
[0708] The title compound 89 mg (78%) was obtained in a manner
similar to the Example 106 by use of the compound obtained in the
Example 93, instead of the compound obtained in the Example 6.
Example 113
1-Cyclohexyl-3-methyl-N-[(3-(4-methyl-1-piperazinyl)phenyl)-1H-thieno[2,3--
c]pyrazole-5-carboxamide
[0709] The title compound 106 mg (80%) was obtained in a manner
similar to the Example 7 by use of
3-(4-methyl-1-piperazinyl)aniline, instead of benzylamine.
Example 114
1-Cyclohexyl-N-[(4-(4-hydroxy-1-piperidinyl)phenyl)-3-methyl-1H-thieno[2,3-
-c]pyrazole-5-carboxamide
[0710] To a suspension of 4.1 g (15.51 mmol) of the compound
obtained in the Example 6 in 50 mL of 1,2-dichloroethane was added
2.26 mL (31.02 mmol) of thionyl chloride, and the mixture was
refluxed for 1.5 hours. After cooling of the reaction and the
solvent was removed under reduced pressure to give the
corresponding acid chloride intermediate compound.
[0711] Then, 3.04 g (15.82 mmol) of the compound obtained in the
Manufacturing Example 95 and 4.32 mL (31.02 mmol) of triethylamine
were added to a solution of the above acid chloride intermediate
compound in 150 mL of anhydrous dichloromethane under ice cooling,
and the mixture was stirred for 20 hours at room temperature. Water
was added to the reaction mixture, and the mixture was extracted
with dichloromethane. The organic layer was dried over with
anhydrous sodium sulfate and the solvent was removed under reduced
pressure. The residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=40/1 to 30/1) to
give 7.5 g (83%) of the title compound.
Example 115
N-[4-(Acetylamino)-3-methoxyphenyl]-1-cycloheptyl-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide
[0712] The title compound 160 mg (59%) was obtained in a manner
similar to the Example 10 by use of the compound obtained in the
Example 93, instead of the compound obtained in the Example 6.
Example 116
1-Cyclohexyl-N-(3,5-dichloro-4-pyridinyl)-3-methyl-1H-thieno[2,3-c]pyrazol-
e-5-carboxamide
[0713] The title compound 342 mg (88%) was obtained in a manner
similar to the Example 98 by use of 4-amino-3,5-dichloropyridine,
instead of 4-nitoraniline.
Example 117
5-[(4-Bromobenzyl)sulfanil]-1-cyclohexyl-3-methyl-1H-pyrazole-4-carboaldeh-
yde
[0714] To a solution of 1.2 g (5.29 mmol) of the compound obtained
in the Example 3 in 21 mL of ethanol were added 2.07 g (6.35 mmol)
of S-(4-bromobenzyl) isothiourea hydrobromic acid salt and 10.6 mL
of 2N-sodium hydroxide solution, and the mixture was refluxed for 2
hours. After the reaction mixture was cooled to room temperature,
the mixture was condensed and the residue was diluted with ethyl
acetate. The organic layer was washed with saturated saline
solution and dried over with anhydrous sodium sulfate. The solvent
was removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:hexane/ethyl acetate=7/1)
to give 1.723 g (82%) of the title compound.
Example 118
5-(4-Bromophenyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole
[0715] To a solution of 1.623 g (4.13 mmol) of the compound
obtained in the Example 117 in 30 mL of tetrahydrofuran was added
gradually a solution of 10.3 mL (10.3 mmol) of 1M lithium
bis(trimethylsilyl)amide in tetrahydrofuran at -78.degree. C., and
the mixture was stirred for 30 minutes at the same temperature.
Then, the reaction mixture was warmed slowly to 0.degree. C. during
1 hour, and water was added to the reaction mixture. The mixture
was extracted with dichloromethane and the organic layer was dried
over with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and 15 mL of ethanol and 10 mL of 4N--HCl/dioxane
were added to the residue and the mixture was stirred for 30
minutes at room temperature and for 30 minutes at 60.degree. C.
Then, the reaction mixture was cooled to room temperature and
condensed under reduced pressure. The residue was diluted with
ethyl acetate and the organic layer was washed with saturated
sodium bicarbonate aqueous solution, then, dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=8/1) to give 717 mg
(46%) of the title compound.
Example 119
1-Cyclohexyl-3-methyl-5-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c-
]pyrazole
[0716] To a solution of 175 mg (0.466 mmol) of the compound
obtained in the Example 118 in 30 mL of toluene were added 115
.mu.L (1.40 mmol) of N-methylpiperazine, 89.6 mg (0.933 mmol) of
sodium tert-butoxide, 5.2 mg (0.023 mmol) of palladium acetate (II)
and 9.4 mg (0.0466 mmol) of tri-tert-butyl-phosphine, and the
mixture was refluxed for 5 hours. After the mixture was cooled to
room temperature, ethyl acetate was added to the mixture and the
organic layer was washed with water and saturated saline solution,
then, dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography
(eluent:dichloromethane/methanol=40/1) to give 158 mg (86%) of the
title compound.
Example 120
1-Cyclohexyl-3-methyl-5-[4-(4-methyl-1-piperazinyl)phenyl]-1H-thieno[2,3-c-
]pyrazole methanesulfanate
[0717] The title compound 143 mg (94%) was obtained in a manner
similar to the Example 107 by use of the compound obtained in the
Example 119, instead of the compound obtained in the Example
106.
Example 121
1-Cyclohexyl-3-methyl-5-[4-(4-methyl-1,4-diazepam-1-yl)phenyl]-1H-thieno[2-
,3-c]pyrazole
[0718] The title compound 124 mg (65%) was obtained in a manner
similar to the Example 119 by use of N-methylhomopiperazine,
instead of N-methylpiperazine.
Example 122
1-Cyclohexyl-N-(2-hydroxypropyl)-3-methyl-1H-thoieno[2,3-c]pyrazole-5-carb-
oxamide
[0719] The title compound 82 mg (78%) was obtained in a manner
similar to the Example 7 by use of 2-aminoethanol, instead of
benzylamine.
Example 123
1-Cyclohexyl-N-(3-hydroxypropyl)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carbo-
xamide
[0720] The title compound 103 mg (94%) was obtained in a manner
similar to the Example 7 by use of 3-amino-1-propanol, instead of
benzylamine.
Example 124
1-Cyclohexyl-N-{3-fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0721] The title compound 99 mg (68%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 19, instead of benzylamine.
Example 125
1-Cyclohexyl-N-{3-fluoro-4-[(2-hydroxyethyl)(methyl)amino]phenyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide HCl salt
[0722] To a solution of 91 mg (0.211 mmol) of the compound obtained
in the Example 124 in 2 mL of diethyl ether and 1 mL of ethyl
acetate was added 63 .mu.L (0.25 mmol) of 4N--HCl/1,4-dioxane, and
3 mL of diethyl ether was further added to the mixture. The
resulting precipitates were collected to give 86 mg (87%) of the
title compound.
Example 126
Ethyl
cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbony-
l]amino}cyclohexanecarboxylate
[0723] The title compound 365 mg (92%) was obtained in a manner
similar to the Example 7 by use of ethyl
cis-4-aminocyclohexanecarboxylate, instead of benzylamine.
Example 127
[0724]
cis-4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbon-
yl]amino}cyclohenxanecarboxylic acid
[0725] The title compound 123 mg (88%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 126, instead of the compound obtained in the Example
40.
Example 128
1-Cyclohexyl-N-[cis-4-(hydroxymethyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0726] To a solution of 185 mg (0.433 mmol) of the compound
obtained in the Example 126 in 6 mL of tetrahydrofuran were added
56 mg (1.33 mmol) of lithium chloride and 50 mg (1.33 mmol) of
sodium borohydride, and the mixture was stirred for 14 hours at
room temperature. Then, ethyl acetate was added to the mixture and
the organic layer was washed with water and saturated saline
solution, then, dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:hexane/ethyl
acetate=1/3) to give 110 mg (66%) of the title compound.
Example 129
Methyl
trans-4-({[(1-cyclohexyl-3-methyl-1H-thoieno[2,3-c]pyrazol-5-yl)car-
bonyl]amino}methyl)cyclohexanecarboxylate
[0727] The title compound 605 mg (96%) was obtained in a manner
similar to the Example 7 by use of ethyl
trans-4-aminocyclohexanecarboxylate hydrochloric acid salt, instead
of benzylamine.
Example 130
1-Cyclohexyl-N-methyl{[trans-4-(hydroxymethyl)cyclohexyl]methyl}-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0728] The title compound 150 mg (80%) was obtained in a manner
similar to the Example 128 by use of the compound obtained in the
Example 129, instead of the compound obtained in the Example
126.
Example 131
tert-Butyl
trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)c-
arbonyl]amino}cyclohexylcarbamate
[0729] The title compound 90 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of tert-butyl
trans-4-aminocyclohexyl-carbamate, instead of benzylamine.
Example 132
N-(trans-4-Aminocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0730] To a solution of 890 mg (1.93 mmol) of the compound obtained
in the Example 131 in 5 mL of N,N-dimethylformamide was added 9.66
mL of 4N--HCl/dioxane, and the mixture was stirred for 3 hours at
room temperature. Then, the mixture was diluted with
dichloromethane and 50 mL of 1N-sodium hydroxide solution was added
to the mixture. The organic layer was dried over with anhydrous
sodium sulfate and the solvent was removed under reduced pressure.
The residue was purified by alkaline silica gel column
chromatography (eluent:chloroform/methanol=60/1) to give 495 mg
(71%) of the title compound.
Example 133
1-Cyclohexyl-3-methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1H-thieno[2,3--
c]pyrazole-5-carboxamide
[0731] To a solution of 120 mg (0.333 mmol) of the compound
obtained in the Example 132 in 8 mL of N,N-dimethylformamide were
added 46.8 .mu.L (0.333 mmol) of bis(2-chloroethyl)ether, 116 .mu.L
(0.832 mmol) of triethylamine, 50 mg (0.333 mmol) of sodium iodide,
and 6.5 .mu.L (0.333 mmol) of 15-crown-5, and the mixture was
stirred for 24 hours at 100.degree. C. After the reaction mixture
was cooled to room temperature, the mixture was extracted with
ethyl acetate and the organic layer was washed with saturated
sodium bicarbonate aqueous solution and saturated saline solution,
then, dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:chloroform/methanol=20/1)
to give 22 mg (15%) of the title compound.
Example 134
1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide
[0732] Saturated sodium bicarbonate solution and ethyl acetate were
added to the compound obtained in the Example 63, and the organic
layer was dried over with anhydrous sodium sulfate. The solvent was
removed and the residue was purified by alkaline silica gel column
chromatography (eluent:chloroform/methanol=60/1) to give 411 mg
(60%) of the title compound.
Example 135
1-Cyclohexyl-3-methyl-N-(1-tetrahydro-2H-pyran-4-yl-4-piperidinyl)-1H-thie-
no[2,3-c]pyrazole-5-carboxamide
[0733] To a solution of 150 mg (0.433 mmol) of the compound
obtained in the Example 134 in 8 mL of dichloromethane were added
44 .mu.L (0.476 mmol) of tetrahydro-4-pyranone and 128 mg (0.606
mmol) of sodium triacetoxyborohydride, and the mixture was stirred
for 24 hours at room temperature. Then, saturated sodium
bicarbonate solution was added to the reaction mixture and the
mixture was extracted with dichloromethane. The organic layer was
washed with water and saturated saline solution, then, dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=20/1) to give 70 mg
(38%) of the title compound.
Example 136
1-Cyclohexyl-N-[1-(1,4-diazaspiro[4.5]decan-8-yl)-4-piperazdinyl]-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0734] The title compound 180 mg (92%) was obtained in a manner
similar to the Example 135 by use of 1,4-cyclohexanedione
monoethyleneketal, instead of tetrahydro-4-pyranone.
Example 137
1-Cyclohexyl-3-methyl-N-[1-(4-oxocyclohexyl)-4-piperidinyl]-1H-thieno[2,3--
c]pyrazole-5-carboxamide
[0735] To a solution of 153 mg (0.314 mmol) of the compound
obtained in the Example 136 in 3 mL of acetone and 1 mL of water
was added 71.8 mg (0.377 mmol) of p-toluenesulfonic acid
monohydrate, and the mixture was refluxed for 2 days. Then,
saturated sodium bicarbonate aqueous solution was added to the
reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was dried over with anhydrous
sodium sulfate and removed under reduced pressure to give 120 mg
(86%) of the title compound.
Example 138
1-Cyclohexyl-N-[1-(trans-4-hydroxycyclohexyl)-4-piperidinyl]-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0736] To a solution of 109 mg (0.246 mmol) of the compound
obtained in the Example 137 in 8 mL of ethanol was added 14.0 mg
(0.369 mmol) of sodium borohydride, and the mixture was stirred for
1 hour at 0.degree. C. Then, dichloromethane was added to the
reaction mixture and the organic layer was washed with water, then,
dried over with anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by silica gel
column chromatography (eluent:dichloromethane/methanol=20/1) to
give 67 mg (61%) of the title compound.
Example 139
tert-Butyl
4-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carb-
onyl]amino}phenyl)-1-piperidinecarboxylate
[0737] The title compound 649 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of the compound obtained in
the Manufacturing Example 21, instead of benzylamine.
Example 140
1-Cyclohexyl-3-methyl-N-[4-(4-piperidinyl)phenyl]-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0738] To a solution of 584 mg (1.12 mmol) of the compound obtained
in the Example 139 in 3 mL of dichloromethane was added 0.86 mL
(11.2 mmol) of trifluoroacetic acid at room temperature, and the
mixture was stirred for 1.5 hours at the same temperature. Then,
the mixture was extracted with dichloromethane and the organic
layer was washed with 2N sodium hydroxide solution and then, dried
over with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=100/1) to give 437
mg (92%) of the title compound.
Example 141
1-Cyclohexyl-3-methyl-N-[4-(4-piperidinyl)phenyl]-1H-thieno[2,3-c]pyrazole-
-5-carboxamide HCl salt
[0739] The title compound 94 mg (86%) was obtained in a manner
similar to the Example 125 by use of the compound obtained in the
Example 140, instead of the compound obtained in the Example
124.
Example 142
1-Cyclohexyl-3-methyl-N-[4(1-methyl-4-piperidinyl)phenyl]-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0740] To a solution of 174 mg (0.4412 mmol) of the compound
obtained in the Example 140 in 5 mL of chloroform were added 31
.mu.L (0.494 mmol) of methyl iodide and 86 .mu.L (0.618 mmol) of
triethylamine, and the mixture was stirred for 2 hours at room
temperature. Then, saturated sodium bicarbonate aqueous solution
was added to the reaction mixture and the mixture was extracted
with dichloromethane. The organic layer was dried over with
anhydrous sodium sulfate and removed under reduced pressure. The
residue was purified by alkaline silica gel column chromatography
(eluent:dichloromethane/methanol=40/1) to give 46 mg (26%) of the
title compound.
Example 143
1-Cyclohexyl-N-[4-(4-ethyl-1-piperazinyl)-3-fluorophenyl]-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide
[0741] The title compound 90 mg (42%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 24, instead of benzylamine.
Example 144
1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazepam-1-yl)phenyl]-3-methyl-1H-
-thieno[2,3-c]pyrazole-5-carboxamide
[0742] The title compound 161 mg (76%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 31, instead of benzylamine.
Example 145
Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]am-
ino-2-methoxybenzoate
[0743] The title compound 401 mg (80%) was obtained in a manner
similar to the Example 7 by use of ethyl 4-amino-2-methoxybenzoate,
instead of benzylamine.
Example 146
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-
-methoxybenzoic acid
[0744] The title compound 242 mg (59%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 145, instead of the compound obtained in the Example
40.
Example 147
1-Cyclohexyl-N-{3-methoxy-4-[(4-methyl-1-piperazinyl)carbonyl]-phenyl}-3-m-
ethyl-1H-thieno[2,3-c]pyrazole-5-carboxamide HCl Salt
[0745] To a solution of 200 mg (0.48 mmol) of the compound obtained
in the Example 146 in 3 mL of anhydrous dichloromethane were added
64 .mu.L (0.58 mmol) of N-methylpiperazine and 111 mg (0.58 mmol)
of 1-ethyl-3-(3-dimethyl-aminopropyl) carbodiimide HCl salt, and
the mixture was stirred for 3 hours at room temperature. Then,
saturated sodium bicarbonate aqueous solution was added to the
reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution and dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=20/1 to 10/1). The obtained crude
crystalline was dissolved in 4M-HCl/dioxane and the solvent was
removed under reduced pressure. The obtained solid was collected to
give 124 mg (49%) of the title compound.
Example 148
1-Cyclohexyl-N-[3-methoxy-4-(4-morpholinylcarbonyl)phenyl]-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0746] The title compound 76 mg (79%) was obtained in a manner
similar to the Example 147 by use of morpholine, instead of
N-methylpiperazine.
Example 149
1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]phenyl}-3-methoxyphen-
yl}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0747] The title compound 68 mg (69%) was obtained in a manner
similar to the Example 147 by use of 4-hydroxypiperidine, instead
of N-methylpiperazine.
Example 150
1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)amino]carbonyl}-3-methoxy-phenyl)-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0748] The title compound 53 mg (58%) was obtained in a manner
similar to the Example 147 by use of 2-aminoethanol, instead of
N-methylpiperazine.
Example 151
1-Cyclohexyl-N-(3-methoxy-4-{[(2-methoxyethyl)amino]carbonyl}-phenyl)-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0749] The title compound 73 mg (78%) was obtained in a manner
similar to the Example 147 by use of 2-methoxyethylamine, instead
of N-methylpiperazine.
Example 152
1-Cyclohexyl-N-{3-methoxy-4-[(methylamino)carbonyl]phenyl}-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0750] The title compound 31 mg (36%) was obtained in a manner
similar to the Example 147 by use of methylamine HCl salt, instead
of N-methylpiperazine.
Example 153
1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]-3-methoxyphenyl}-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0751] The title compound 70 mg (80%) was obtained in a manner
similar to the Example 147 by use of dimethylamine HCl salt,
instead of N-methyl-piperazine.
Example 154
1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0752] The title compound 136 mg (79%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 26, instead of benzylamine.
Example 155
1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide methanesulfonic acid salt
[0753] A suspension of 100 mg (0.22 mmol) of the compound obtained
in the Example 154 in 2 mL of methanol was heated at 50.degree. C.,
and to this suspension was added 14 mL (0.22 mmol) of
methanesulfonic acid, then, the mixture was refluxed for 10
minutes. The reaction mixture was cooled gradually and the appeared
precipitates were collected to give 68 mg (56%) of the title
compound.
Example 156
N-[3-Chloro-4-(4-methyl-1-piperizinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0754] The title compound 169 mg (95%) was obtained in a manner
similar to the Example 7 by use of
3-chloro-4-(4-methyl-1-piperazinyl)aniline, instead of
benzylamine.
Example 157
1-Cyclohexyl-N-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-3-fluoro-phenyl]-3-
-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0755] The title compound 546 mg (96%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 28, instead of benzylamine.
Example 158
1-Cyclohexyl-N-[3-fluoro-4-(4-oxo-1-piperidinyl)phenyl]-3-methyl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide
[0756] To a solution of 500 mg (1.00 mmol) of the compound obtained
in the Example 157 in a mixture solution of 20 mL of toluene and 2
mL of water was added 229 mg (1.20 mmol) of p-toluenesulfonic acid
monohydrate, and the mixture was refluxed for 8 hours. Then, the
reaction mixture was cooled to room temperature and condensed under
reduced pressure. Saturated sodium bicarbonate aqueous solution was
added to the residue and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and saturated
saline solution, and then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure to give 460
mg (quantitative) of the title compound.
Example 159-1
1-Cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide
[0757] To a suspension of 150 mg (0.33 mmol) of the compound
obtained in the Example 158 in anhydrous methanol was added 15 mg
(0.39 mmol) of sodium borohydride under ice cooling, and the
mixture was stirred for 3 hours at the same temperature and for 2
hours at room temperature. Then, acetone was added to the reaction
mixture and the solvent was removed under reduced pressure. The
residue was diluted with ethyl acetate and the organic layer was
washed with water and saturated saline solution. The solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:hexane/ethyl acetate=1/2 t
0/1) to give 114 mg (76%) of the title compound.
Example 159-2
[0758] To a suspension of 900 mg (3.40 mmol) of the compound
obtained in 15 mL of 1,2-dichloroethane was added 497 .mu.L (6.81
mmol) of thionyl chloride, and the mixture was refluxed for 1.5
hours. After cooling the reaction mixture, the solvent removed
under reduced pressure to give acid chloride intermediate
compound.
[0759] Then, 752 mg (3.57 mmol) of the compound obtained in the
Manufacturing Example 62 and 949 .mu.L (6.81 mmol) of triethylamine
were added to a solution of acid chloride intermediate compound
obtained above in 40 mL of anhydrous dichloromethane, and the
mixture was stirred for 6 hours at room temperature. Water was
added to the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was dried over with anhydrous
sodium sulfate, and the solvent was removed under reduced pressure.
The resulting residue was recrystallized from ethanol to give 0.86
g (55%) of the title compound.
Example 160
N-[3-Chloro-4-(1,4-dioza-8-azaspiro[4.5]decan-8-yl)phenyl]-1-cyclohexyl-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0760] The title compound 565 mg (96%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 30, instead of benzylamine.
Example 161
N-[3-Chloro-4-(4-oxo-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide
[0761] The title compound 282 mg (61%) was obtained in a manner
similar to the Example 158 by use of the compound obtained in the
Example 160, instead of the compound obtained in the Example
157.
Example 162
N-[3-Chloro-4-(4-hydroxy-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide
[0762] The title compound 90 mg (90%) was obtained in a manner
similar to the Example 159-1 by use of the compound obtained in the
Example 161, instead of the compound obtained in the Example
158.
Example 163
1-Cyclohexyl-N-{3-fluoro-4-[4-(methylamino)-1-piperidinyl]phenyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0763] To a suspension of 150 mg (0.33 mmol) of the compound
obtained in the Example 158 in 3 mL of 1,2-dichloroethane were
added 68 .mu.L (0.66 mmol) of trimethylamine (30%-ethanol
solution), 20 .mu.L of acetic acid and 105 mg (0.50 mmol) of sodium
triacetoxyborohydride, and the mixture was stirred for 18 hours at
room temperature. Then, saturated sodium bicarbonate solution was
added to the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, and then, dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by alkaline silica gel column
chromatography (eluent:dichloromethane/methanol=20/1) to give 148
mg (97%) of the title compound.
Example 164
tert-Butyl
1-(2-chloro-4-{[(1-cyclohexyl-3-methyl-3-1H-thieno[2,3-c]-pyraz-
ol-5-yl)carbonyl]amino}phenyl)-4-piperidinyl(methyl)carbamate
[0764] To a suspension of 200 mg (0.43 mmol) of the compound
obtained in the Example 161 in 3 mL of 1,2-dichloroethane were
added 88 .mu.L (0.85 mmol) of trimethylamine (30%-ethanol
solution), 15 .mu.L of acetic acid and 135 mg (0.64 mmol) of sodium
triacetoxyborohydride, and the mixture was stirred for 4 hours at
room temperature. Then, saturated sodium bicarbonate solution was
added to the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, the dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was dissolved in 4 mL of dichloromethane. To this mixture
were added 186 mg (0.85 mmol) of tert-butyldicarbonate and 0.14 mL
(1.02 mmol) of triethylamine, and the mixture was stirred for 1
hour at room temperature. Water was added to the reaction mixture
and the mixture was extracted with dichloromethane. The organic
layer was washed with water and saturated saline solution and dried
over with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:hexane/ethyl acetate=1/1) to give 236 mg
(95%) of the title compound.
Example 165
N-{3-Chloro-4-[4-(methylamino)-1-piperidinyl]phenyl}-1-cyclohexyl-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0765] To a solution of 211 mg (0.36 mmol) of the compound obtained
in the Example 164 in 3 mL of dichloromethane was added 1.5 mL of
trifluoroacetic acid, and the mixture was stirred for 1.5 hours at
room temperature. After removal of the solvent under reduced
pressure, water was added to the residue and the mixture was
extracted with chloroform. The organic layer was washed with water
and saturated saline solution and dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by alkaline silica gel column chromatography
(eluent=dichloromethane/methanol=40/1) to give 116 mg (66%) of the
title compound.
Example 166
1-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-1-piperazinyl)-cyclohexyl]-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0766] To a solution of 150 mg (0.42 mmol) of the compound obtained
in the Example 75 in 3 mL of dichloromethane were added 93 .mu.L
(0.84 mmol) of N-methylpiperazine, 15 .mu.L of acetic acid and 133
mg (0.63 mmol) of sodium triacetoxyborohydride, and the mixture was
stirred for 3 hours at room temperature. Then, saturated sodium
bicarbonate solution was added to the reaction mixture and the
mixture was extracted with dichloromethane. The organic layer was
washed with water and saturated saline solution, then, dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by alkaline silica
gel column chromatography (eluent:ethyl acetate) to give 103 mg
(56%) of the title compound.
Example 167
1-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-1,4-diazepam-1-yl)-cyclohexyl]--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0767] The title compound 101 mg (53%) was obtained in a manner
similar to the Example 166 by use of N-methylhomopiperazine,
instead of N-methylpiperazine.
Example 168
1-Cyclohexyl-N-[trans-4-(4-methoxy]-1-piperidinyl)cyclohexyl]-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide
[0768] The title compound 30 mg (20%) was obtained in a manner
similar to the Example 166 by use of 4-methoxypiperidine
p-toluenesulfonic acid salt, instead of N-methylpiperazine.
Example 169
Benzyl
4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl)c-
arbonyl]amino}cyclohexyl)-1,4-diazepam-1-carboxylate
[0769] The title compound 252 mg (78%) was obtained in a manner
similar to the Example 166 by use of benzyl
1-homopiperazinecarboxylate, instead of N-methylpiperazine.
Example 170
1-Cyclohexyl-N-[trans-4-(1,4-diazepam-1-yl)cyclohexyl]-3-methyl-1H-thieno[-
2,3-c]pyrazole-5-carboxamide
[0770] A mixture solution of 219 mg (0.38 mmol) of the compound
obtained in the Example 169 in 3 mL of 30%-HBr/acetic acid was
stirred for 3 hours at room temperature. Then, the reaction mixture
was neutralized by 4M-sodium hydroxide aqueous solution and the
mixture was extracted with dichloromethane. The organic layer was
washed with water and saturated saline solution and dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by alkaline silica gel column
chromatography (eluent:dichloromethane/methanol=30/1) to give 126
mg (75%) of the title compound.
Example 171
N-[trans-4-(4-Acetyl-1,4-diazepam-1-yl)cyclohexyl]-1-cyclohexyl-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0771] The title compound 96 mg (99%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 170 and acetic anhydride, instead of the
compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Example 172
1-Cyclohexyl-N-{trans-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl}-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0772] The title compound 131 mg (73%) was obtained in a manner
similar to the Example 166 by use of
N-(2-methoxylethyl)methylamine, instead of N-methylpiperazine.
Example 173
1-Cyclohexyl-N-{cis-4-[(2-methoxyethyl)(methyl)amino]cyclohexyl}-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0773] The title compound 34 mg (19%) was obtained as by-product in
the Example 172.
Example 174
1-Cyclohexyl-N-[trans-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-cyclohexyl]--
3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0774] The title compound 664 mg (98%) was obtained in a manner
similar to the Example 166 by use of
1,4-dioxa-8-azaspiro[4.5]decane, instead of N-methylpiperazine.
Example 175
1-Cyclohexyl-3-methyl-N-[trans-4-(4-oxo-1-piperidinyl)cyclohexyl]-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0775] A mixture of 384 mg (0.79 mmol) of the compound obtained in
the Example 174 in 6 mL of 6M-HCl aqueous solution was stirred for
9 days at room temperature. Then, the reaction mixture was
neutralized by saturated sodium bicarbonate aqueous solution and
the mixture was extracted with chloroform. The organic layer was
washed with water and saturated saline solution, and dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure to give 317 mg (91%) of the title compound.
Example 176
1-Cyclohexyl-N-[trans-4-(4-hydroxy-1-piperidinyl)cyclohexyl]-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0776] The title compound 102 mg (quantitative) was obtained in a
manner similar to the Example 159 by use of the compound obtained
in the Example 175, instead of the compound obtained in the Example
158.
Example 177
1-Cyclohexyl-N-{trans-4-[(2R,6S)-2,6-dimethylmorpholinyl]-cyclohexyl}-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0777] The title compound 126 mg (66%) was obtained in a manner
similar to the Example 166 by use of cis-2,6-dimethylmorpholine,
instead of N-methylpiperazine.
Example 178
1-Cyclohexyl-N-{cis-4-[(2R,6S)-2,6-dimethylmorpholinyl]cyclohexyl}-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0778] The title compound 50 mg (26%) was obtained as by-product in
the Example 177.
Example 179
1-Cyclohexyl-3-methyl-N-{trans-4-[4-(methylamino)-1-piperidinyl]-cyclohexy-
l}-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0779] The title compound 182 mg (89%) was obtained in a manner
similar to the Example 166 by use of the compound obtained in the
Example 175 and methylamine (30% ethanol solution), instead of the
compound obtained in the Example 75 and N-methylpiperazine,
respectively.
Example 180
N-(trans-4-{4-[Acetyl(methyl)amino]-1-piperidinyl}cyclohexyl)-1-cyclohexyl-
-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0780] The title compound 35 mg (72%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 179 and acetic anhydride, instead of the
compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Example 181
1-Cyclohexyl-N-{trans-4-[4-(dimethylamino)-1-piperidinyl]-cyclohexyl}-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0781] To a mixture solution of 70 mg (0.15 mmol) of the compound
obtained in the Example 179 in 2 mL of ethanol and 2 mL of water
were added 30 mg of paraformaldehyde and 1 mL of formic acid, and
the mixture was refluxed for 6 hours. Further 30 mg of
paraformaldehyde and 1 mL of formic acid were added to the reaction
mixture, and the mixture was refluxed for 18 hours. Then, the
reaction mixture was cooled to room temperature and neutralized
with saturated sodium bicarbonate aqueous solution, and extracted
with dichloromethane. The organic layer was washed with water and
saturated saline solution, and dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was recrystallized from ethyl acetate to give 32 mg (44%)
of the title compound.
Example 182
tert-Butyl
1-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5--
yl)carbonyl]amino}cyclohexyl)-4-piperidinylcarbamate
[0782] The title compound 176 mg (58%) was obtained in a manner
similar to the Example 166 by use of tert-butyl
4-piperidinecarbamate, instead of N-methylpiperazine.
Example 183
tert-Butyl
1-(cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl-
)carbonyl]amino}cyclohexyl)-4-piperidinylcarbamate
[0783] The title compound 94 mg (31%) was obtained as by-product in
the Example 182.
Example 184
N-[trans-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0784] The title compound 82 mg (60%) was obtained in a manner
similar to the Example 165 by use of the compound obtained in the
Example 182, instead of the compound obtained in the Example
164.
Example 185
N-[cis-4-(4-Amino-1-piperidinyl)cyclohexyl]-1-cyclohexyl-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0785] The title compound 63 mg (95%) was obtained in a manner
similar to the Example 165 by use of the compound obtained in the
Example 183, instead of the compound obtained in the Example
164.
Example 186
tert-Butyl
4-(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5--
yl)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate
[0786] The title compound 218 mg (74%) was obtained in a manner
similar to the Example 166 by use of tert-butyl
1-piperazinecarboxylate, instead of N-methylpiperazine.
Example 187
tert-Butyl
4-(cis-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazol-5-yl-
)carbonyl]amino}cyclohexyl)-1-piperazinecarboxylate
[0787] The title compound 72 mg (14%) was obtained as by-product in
the Example 186.
Example 188
1-Cyclohexyl-3-methyl-N-[trans-4-(1-piperazinyl)cyclohexyl]-1H-thieno[2,3--
c]pyrazole-5-carboxamide
[0788] The title compound 146 mg (86%) was obtained in a manner
similar to the Example 165 by use of the compound obtained in the
Example 186, instead of the compound obtained in the Example
164.
Example 189
1-Cyclohexyl-3-methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0789] The title compound 51 mg (97%) was obtained in a manner
similar to the Example 165 by use of the compound obtained in the
Example 187, instead of the compound obtained in the Example
164.
Example 190
N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-1-cyclohexyl-3-methyl
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0790] The title compound 81 mg (95%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 188, instead of the compound obtained in
the Manufacturing Example 2.
Example 191
1-Cyclohexyl-N-[3-fluoro-4-(4-methyl-1,4-diazepam-1-yl)phenyl]-3-methyl-1H-
-thieno[2,3-c]pyrazole-5-carboxamide hemifumarate
[0791] To a solution of 143 mg (0.305 mmol) of the compound
obtained in the Example 144 in 2 mL of ethanol was added 38.9 mg
(0.335 mmol) of fumaric acid, and the resulting precipitates were
collected to give 139 mg (86%) of the title compound.
Example 192
5-Methyl-2-tetrahydro-2H-pyran-4-yl-2,4-dihydro-3H-pyrazole-3-one
[0792] The title compound 6.93 g (58%) was obtained in a manner
similar to the Example 1 by use of 4-tetrahydropyranylhydrazine,
instead of cyclohexylhydrazine HCl salt.
Example 193
5-Chloro-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-pyrazole-4-carboaldehyde
[0793] A mixture solution of 6.87 g (3.77 mmol) of the compound
obtained in the Example 192 and 14.1 mL (150.8 mmol) of phosphorous
oxychloride was stirred for 1 hour at 110.degree. C. After the
reaction mixture was cooled to room temperature, this mixture was
added gradually to ice-cooled 40 mL of N,N-dimethylformamide, and
the mixture was stirred for 1 hour at room temperature and for 3
hours at 90.degree. C. Then, the reaction mixture was cooled with
ice and diluted with ethyl acetate, and pH of the reaction mixture
was adjusted to 4 by adding 2N-NaOH aqueous solution. The mixture
was extracted with ethyl acetate and the organic layer was washed
with saturated saline solution and then, dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography
(eluent:hexane/ethyl acetate=2/1) to give 4.64 g (54%) of the title
compound.
Example 194
Ethyl
3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carbo-
xylate
[0794] To a solution of 16.54 mL (0.151 mol) of ethyl thioglycolate
in 300 mL of tetrahydrofuran was added 6.03 g (0.151 mol) of sodium
hydride (60% oily) in small portions, and the mixture was stirred
for 3 minutes. Then, 31.36 g (0.137 mol) of the compound obtained
in the Example 193 was added to this mixture at once, and the
mixture was stirred for 1 hour. Further, 6.03 g (0.151 mol) of
sodium hydride (60% oily) was added to this mixture in small
portions at 0.degree. C., and the mixture was stirred for 1 hour.
The reaction mixture was diluted with ethyl acetate and the organic
layer was washed with water and saturated saline solution, and
dried over with anhydrous sodium sulfate. The solvent was removed
under reduced pressure and the residue was purified by silica gel
column chromatography (eluent:hexane/ethyl acetate=3/1 to 2/1) to
give 30.1 g (76%) of the title compound.
Example 195
3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic
acid
[0795] The title compound 4.26 g (99%) was obtained in a manner
similar to the Example 6 by use of the compound obtained in the
Example 194, instead of the compound obtained in the Example 5.
Example 196
3-Methyl-N-[4-(4-methyl-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0796] The title compound 166 mg (84%) was obtained in a manner
similar to the Example 7 by use of
4-(4-methyl-1-piperazinyl)aniline and the compound obtained in
Example 194, instead of benzylamine and the compound obtained in
the Example 6, respectively.
Example 197
N-[3-Fluoro-4-(4-methyl-1-piperazinyl)phenyl]-3-methyl-1-tetra-hydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0797] The title compound 214 mg (83%) was obtained in a manner
similar to the Example 7 by use of
[3-fluoro-4-(4-methyl-1-piperazinyl)]aniline and the compound
obtained in Example 195, instead of benzylamine and the compound
obtained in the Example 6, respectively.
Example 198
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylmethyl)phenyl]-1H-thieno[2,3-c]py-
razole-5-carboxamide
[0798] The title compound 173 mg (87%) was obtained in a manner
similar to the Example 7 by use of 4-(4-morpholinylmethyl)aniline,
instead of benzylamine.
Example 199
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylmethyl)phenyl]-1H-thieno[2,3-c]py-
razole-5-carboxamide fumarate
[0799] 41.7 mg (0.59 mmol) of fumaric acid was added to a mixture
of 150 mg (0.432 mmol) of the compound obtained in the Example 198
in 1 mL of ethanol, and 2 mL of diethyl ether was further added to
the mixture. Then, the mixture was stirred for over night and
appeared precipitates were collected by filtration to give 112 mg
(59%) of the title compound.
Example 200
1-Cyclohexyl-N-{4-[2-(dimethylamino)ethyl]phenyl}-3-methyl-1H-thieno[2,3-c-
]pyrazole-5-carboxamide
[0800] The title compound 83 mg (75%) was obtained in a manner
similar to the Example 7 by use of
4-[(2-dimethylamino)ethyl]aniline, instead of benzylamine.
Example 201
1-Cyclohexyl-3-methyl-N-{4-[2-(4-morpholinyl)ethyl]phenyl}-1H-thieno[2,3-c-
]pyrazole-5-carboxamide
[0801] The title compound 140 mg (68%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Example 32, instead of benzylamine.
Example 202
1-Cyclohexyl-3-methyl-N-{4-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]p-
henyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0802] The title compound 185 mg (88%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Example 34, instead of benzylamine.
Example 203
1-Cyclohexyl-3-methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)-phenyl]-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0803] The title compound 116 mg (57%) was obtained in a manner
similar to the Example 7 by use of
4-(3-methyl-2,5-dioxo-1-imidazolidinyl) aniline, instead of
benzylamine.
Example 204
Methyl
trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbo-
nyl]amino}cyclohexane carboxylate
[0804] The title compound 2.18 g (95%) was obtained in a manner
similar to the Example 7 by use of methyl
trans-4-aminocyclohexanecarboxylate, instead of benzylamine.
Example 205
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}cy-
clohexane carboxylic acid
[0805] The title compound 1.48 g (quantitative) was obtained in a
manner similar to the Example 41 by use of the compound obtained in
the Example 204, instead of the compound obtained in the Example
40.
Example 206
1-Cyclohexyl-N-[4-(hydroxymethyl)cyclohexyl]-3-methyl-1H-thieno[2,3-c]pyra-
zole-5-carboxamide
[0806] To a solution of 200 mg (0.496 mmol) of the compound
obtained in the Example 204 in 5 mL of tetrahydrofuran was added 43
mg (1.98 mmol) of lithium borohydride, and the mixture was stirred
for 1.5 hours under heating at 70.degree. C. The reaction mixture
was cooled to room temperature and water was added to the mixture
and mixture was extracted with dichloromethane. The organic layer
was dried over with anhydrous sodium sulfate and the solvent was
removed under reduced pressure. The resulting residue was
recrystallized from isopropanol/hexane (1/1) to give 76 mg (41%) of
the title compound.
Example 207
1-Cyclohexyl-3-methyl-N-{4-[(4-methyl-1-piperazinyl)carbonyl]-cyclohexyl}--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0807] To a solution of 200 mg (0.513 mmol) of the compound
obtained in the Example 205 in 5 mL of dichloromethane and 1 mL of
N,N-dimethylformamide were added 51.3 .mu.L (0.462 mmol) of
N-methylpiperazine and 750 mg of PS carbodiimide (Argonaut Co.),
and the mixture was stirred for over night at room temperature. The
reagent removed off by filtration and the filtrate was condensed to
give 36 mg (15%) of the title compound.
Example 208
1-Cyclohexyl-N-{4-[(dimethylamino)carbonyl]cyclohexyl}-3-methyl-1H-thieno[-
2,3-c]pyrazole-5-carboxamide
[0808] The title compound 18 mg (8%) was obtained in a manner
similar to the Example 207 by use of 2M-dimethylamine in
tetrahydrofuran, instead of N-methylpiperazine.
Example 209
N-(4-Cyanocyclohexyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]-pyrazole-5-ca-
rboxamide
[0809] The title compound 189 mg (84%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Example 36, instead of benzylamine.
Example 210
tert-Butyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbon-
yl]amino}ethyl(methyl)carbamate
[0810] The title compound 1.89 g (99%) was obtained in a manner
similar to the Example 7 by use of
[2-(N-Boc-N-methyl)amino]ethylamine, instead of benzylamine.
Example 211
1-Cyclohexyl-3-methyl-N-[2-(methylamino)ethyl]-1H-thieno[2,3-c]-pyrazole-5-
-carboxamide 2HCl Salt
[0811] The title compound 1.71 g (quantitative) was obtained in a
manner similar to the Manufacturing Example 4 by use of the
compound obtained in the Example 210, instead of the compound
obtained in the Manufacturing Example 3.
Example 212
N-{2-[Acetyl(methyl)amino]ethyl}-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0812] To a solution of 150 mg (0.381 mmol) of the compound
obtained in the Example 211 in 5 mL of dichloromethane were added
54 .mu.L (0.572 mmol) of acetic anhydride and 123 .mu.L (1.53 mmol)
of pyridine, and the mixture was stirred for 1 hour at room
temperature. Then, 54 .mu.L (0.572 mmol) of acetic anhydride and
123 .mu.L (1.53 mmol) of pyridine were further added to the
reaction mixture, and the mixture was stirred for 1 hour at room
temperature. Water was added to the reaction mixture and the
mixture was extracted with dichloromethane, and the organic layer
was dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure, and the residue was purified by
silica gel column chromatography
(eluent:dichloromethane/methanol=30/1) to give 120 mg (87%) of the
title compound.
Example 213
1-Cyclohexyl-3-methyl-N-{2-[methyl(methylsulfonyl)amino]ethyl}-1H-thieno[2-
,3-c]pyrazole-5-carboxamide HCl Salt
[0813] To a solution of 150 mg (0.381 mmol) of the compound
obtained in the Example 211 in 5 mL of dichloromethane were added
44 .mu.L (0.572 mmol) of methanesulfonyl chloride and 212 .mu.L
(1.53 mmol) of triethylamine, and the mixture was stirred for 1
hour at room temperature. After the reaction, water was added to
the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was dried over with anhydrous
sodium sulfate and the solvent was removed under reduced pressure.
The resulting residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=40/1), and the
eluate was treated with 4N--HCl/dioxane to give 128 mg (77%) of the
title compound.
Example 214
Ethyl
(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mino}-1-piperidinyl)acetate
[0814] To a solution of 250 mg (0.722 mol) of the compound obtained
in the Example 134 in 6 mL of dichloromethane were added 88 .mu.L
(0.794 mmol) of ethyl bromoacetate and 151 .mu.L (1.082 mmol) of
triethylamine, and the mixture was stirred for 3 days at room
temperature. Then, water was added to the reaction mixture and the
mixture was extracted with dichloromethane. The organic layer was
dried over with anhydrous sodium sulfate and the solvent was
removed under reduced pressure. The resulting residue was purified
by silica gel column chromatography
(eluent:dichloromethane/methanol=40/1) to give 237 mg (76%) of the
title compound.
Example 215
(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}--
1-piperidinyl)acetic acid
[0815] The title compound 176 mg (86%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 214, instead of the compound obtained in the Example
40.
Example 216
Ethyl
2-(4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl-
]amino}-1-piperidinyl)-2-methylpropanoate
[0816] To a solution of 252 mg (0.727 mmol) of the compound
obtained in the Example 134 in 5 mL of N,N-dimethylformamide were
added 128 .mu.L (0.873 mmol) of ethyl 2-bromoisobutyrate and 152
.mu.L (1.09 mmol) of triethylamine, and the mixture was stirred for
over night at 70.degree. C. Then, water was added to the reaction
mixture and the mixture was extracted with dichloromethane. The
organic layer was dried over with anhydrous sodium sulfate and the
solvent was removed under reduced pressure. The resulting residue
was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=40/1) to give 115 mg (34%) of the
title compound.
Example 217
2-(4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]amino-
}-1-piperidinyl)-2-methylpropanoic Acid
[0817] The title compound 65 mg (69%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 216, instead of the compound obtained in the Example
40.
Example 218
N-[4-(4-Hydroxy-1-piperidinyl)phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0818] The title compound 198 mg (90%) was obtained in a manner
similar to the Example 7 by use of 1-(4-aminophenyl)-4-piperidinol
and the compound obtained in the Example 195, instead of
benzylamine and the compound obtained in the Example 6,
respectively.
Example 219
1-Cyclohexyl-N-[2-(5,5-dimethyl-2,4-dioxo-1,3-oxazolidin-3-yl)-ethyl]-3-me-
thyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0819] To a solution of 150 mg (0.488 mol) of the compound obtained
in the Example 122 in 5 mL of tetrahydrofuran were added 75.6 mg
(0.586 mmol) of 5,5-dimethyloxazolidine-dione, 154 mg (0.586 mmol)
of triphenylphsophine and 267 .mu.L (0.586 mmol) of diethyl
azodicarboxylate (40% toluene solution), and the mixture was
stirred for 2 hours at room temperature. After the reaction, water
was added to the reaction mixture and the mixture was extracted
with dichloromethane. The organic layer was dried over with
anhydroussodiumsulfateandthesolventwasremovedunderreducedpressu-
re. The resulting residue was purified by silica gel column
chromatography (eluent:dichloromethane/acetone=2/1 for first trial,
and hexane/ethyl acetate=2/1 for second trial) to give 133 mg (65%)
of the title compound.
Example 220
1-Cyclohexyl-3-methyl-N-{[methyl(4-morpholinylcarbonyl)amino]ethyl}-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0820] The title compound 164 mg (99%) was obtained in a manner
similar to the Example 214 by use of the compound obtained in the
Example 211 and 4-morpholinylcarbonyl chloride, instead of the
compound obtained in the Example 134 and ethyl bromoacetate,
respectively.
Example 221
1-Cyclohexyl-N-{2-[[(dimethylamino)carbonyl](methyl)amino]ethyl}-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0821] The title compound 119 mg (80%) was obtained in a manner
similar to the Example 214 by use of the compound obtained in the
Example 211 and dimethylaminocarbonyl chloride, instead of the
compound obtained in the Example 134 and ethyl bromoacetate,
respectively.
Example 222
Methyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mino}ethyl(methyl)carbamate
[0822] To a solution of 150 mg (0.381 mmol) of the compound
obtained in the Example 211 in 5 mL of dichloromethane and 5 mL of
water were added 158 mg (1.14 mmol) of potassium carbonate and 44
.mu.L (0.572 mmol) of ethyl chlorocarbonate, and the mixture was
stirred for over night at room temperature. Then, water was added
to the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was dried over with anhydrous
sodium sulfate and the solvent was removed under reduced pressure.
The resulting residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=40/1) to give 120
mg (83%) of the title compound.
Example 223
1-Cyclohexyl-N-{2-[(methoxyacetyl)(methyl)amino]ethyl}-3-methyl-1H-thieno[-
2,3-c]pyrazole-5-carboxamide
[0823] The title compound 124 mg (83%) was obtained in a manner
similar to the Example 214 by use of the compound obtained in the
Example 211 and methoxyacetyl chloride, instead of the compound
obtained in the Example 134 and ethyl bromoacetate,
respectively.
Example 224
1-Cyclohexyl-N-{2-[glycoloyl(methyl)amino]ethyl}-3-methyl-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0824] To a solution of 150 mg (0.381 mmol) of the compound
obtained in the Example 211 in 6 mL of dichloromethane were added
34.8 mg (0.458 mmol) of hydroxyacetic acid, 186 .mu.L (1.335 mmol)
of triethylamine, 61.8 mg (0.458 mmol) of N-hydroxybenzotriazole
and 80.4 mg (0.419 mmol) of
1-ethyl-3-(3'-di-methylaminopropyl)carbodiimide, and the mixture
was stirred for 3 hours at room temperature. Then, water was added
to the reaction mixture and the mixture was extracted with
dichloromethane. The organic layer was dried over with anhydrous
sodium sulfate and the solvent was removed under reduced pressure.
The resulting residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=40/1) to give 87 mg
(60%) of the title compound.
Example 225
1-Cyclohexyl-N-(4-{[(2-hydroxyethyl)(methyl)amino]carbonyl}-cyclohexyl)-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0825] The title compound 128 mg (74%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 205 and 2-N-methylaminoethanol, instead of the compound
obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 226
Methyl
(1S,3S)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)car-
bonyl]amino}cyclopentanecarboxylate
[0826] The title compound 565 mg (97%) was obtained in a manner
similar to the Example 7 by use of methyl
(1S,3S)-3-aminocyclopentanecarboxylate, instead of benzylamine.
Example 227
(1S,3S)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-
amino}cyclopentanecarboxylic Acid
[0827] The title compound 542 mg (quantitative) was obtained in a
manner similar to the Example 41 by use of the compound obtained in
the Example 226, instead of the compound obtained in the Example
40.
Example 228
1-Cyclohexyl-3-methyl-N-[2-(4-methyl-2,3-dioxo-1-piperazinyl)ethyl]-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0828] The title compound 88 mg (35%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Example 37, instead of benzylamine.
Example 229
1-Cyclohexyl-N-{(1S,3S)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0829] The title compound 176 mg (91%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 227 and 2M-dimethylamine tetrahydrofuran solution, instead
of the compound obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 230
1-Cyclohexyl-N-{(1S,3S)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide HCl Salt
[0830] The title compound 137 mg (84%) was obtained in a manner
similar to the Example 125 by using the compound obtained in the
Example 229, instead of the compound obtained in the Example
124.
Example 231
Methyl
(1R,3R)-3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)car-
bonyl]amino}cyclopentanecarboxylate
[0831] The title compound 772 mg (99%) was obtained in a manner
similar to the Example 7 by use of methyl
(1R,3R)-3-aminocyclopentanecarboxylate, instead of benzylamine.
Example 232
(1R,3R)-3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-
amino}cyclopentanecarboxylic acid
[0832] The title compound 822 mg (quantitative) was obtained in a
manner similar to the Example 41 by use of the compound obtained in
the Example 231, instead of the compound obtained in the Example
40.
Example 233
1-Cyclohexyl-N-{(1R,3R)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0833] The title compound 153 mg (79%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 232 and 2M-dimethylamine tetrahydrofuran solution, instead
of the compound obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 234
1-Cyclohexyl-N-{(1R,3R)-3-[(dimethylamino)carbonyl]cyclopentyl}-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide HCl Salt
[0834] The title compound 80 mg (54%) was obtained in a manner
similar to the Example 125 by use of the compound obtained in the
Example 233, instead of the compound obtained in the Example
124.
Example 235
1-Cyclohexyl-N-{l[(dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide
[0835] The title compound 241 mg (95%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 39, instead of benzylamine.
Example 236
1-Cyclohexyl-3-methyl-N-[4-(4-morpholinylcarbonyl)cyclohexyl]-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[0836] The title compound 236 mg (96%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 205 and morpholine, instead of the compound obtained in the
Example 211 and hydroxyacetic acid, respectively.
Example 237
1-Cyclohexyl-3-methyl-N-{4-[(methylamino)carbonyl]cyclohexyl}-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[0837] The title compound 122 mg (79%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 205 and methylamine (30% ethanol solution), instead of the
compound obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 238
1-Cyclohexyl-N-{4-[(cyclopropylamino)carbonyl]cyclohexyl}-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide HCl Salt
[0838] The title compound 115 mg (64%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 205 and cyclopropylamine, instead of the compound obtained
in the Example 211 and hydroxyacetic acid, respectively.
Example 239
1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0839] The title compound 157 mg (86%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 205 and 4-hydroxypiperidine, instead of the compound
obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 240
1-Cyclohexyl-N-{1-[(dimethylamino)sulfonyl]-4-piperidinyl}-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0840] The title compound 257 mg (99%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 41, instead of benzylamine.
Example 241
tert-Butyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbon-
yl]amino}-1-piperidinecarboxylate
[0841] The title compound 2.57 g (98%) was obtained in a manner
similar to the Example 7 by use of 4-amino-1-Boc-piperidine,
instead of benzylamine.
Example 242
1-Cyclohexyl-3-methyl-N-(4-piperidinyl)-1H-thieno[2,3-c]pyrazole-5-carboxa-
mide di-HCl Salt
[0842] The title compound 2.29 g (97%) was obtained in a manner
similar to the Manufacturing Example 4 by using the compound
obtained in the Example 241, instead of the compound obtained in
the Manufacturing Example 3.
Example 243
N-[(3S)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazo-
le-5-carboxamide
[0843] The title compound 2.32 g (97%) was obtained in a manner
similar to the Example 7 by use of
(3S)-1-benzyl-3-aminopyrrolidine, instead of benzylamine.
Example 244
1-Cyclohexyl-3-methyl-N-[(3S)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-ca-
rboxamide
[0844] To a solution of 2.26 g (5.35 mmol) of the compound obtained
in the Example 243 in 50 mL of 1,2-dichloroethane was added 721
.mu.L (6.68 mmol) of 1-chloroethyl chloroformate, and the mixture
was refluxed for 2 hours. Then, 289 .mu.L (2.67 mmol) of
1-chloroethyl chloroformate was further added to this mixture and
the mixture was refluxed for 1 hour under stirring. The solvent was
removed under reduced pressure and 50 mL of methanol was added to
the residue, and the mixture was refluxed for 30 minutes. The
solvent was removed under reduced pressure and the residue was
treated with saturated sodium bicarbonate aqueous solution, and the
mixture was extracted with dichloromethane. The organic layer was
dried over with anhydrous sodium sulfate, and the solvent was
removed under reduced pressure. The residue was purified by silica
gel column chromatography (eluent:dichloromethane/methanol=20/1) to
give 0.83 g (47%) of the title compound.
Example 245
1-Cyclohexyl-N-{(3S)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide
[0845] The title compound 155 mg (85%) was obtained in a manner
similar to the Example 214 by use of the compound obtained in the
Example 244 and dimethylaminocarbonyl chloride, instead of the
compound obtained in the Example 134 and ethyl bromoacetate,
respectively.
Example 246
1-Cyclohexyl-N-{(3S)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide HCl Salt
[0846] The title compound 155 mg (85%) was obtained in a manner
similar to the Example 125 by use of the compound obtained in the
Example 245, instead of the compound obtained in the Example
124.
Example 247
1-Cyclohexyl-N-{4-[(2,5-dioxo-1-imidazolidinyl)methyl]cyclohexyl}-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0847] To a solution of 136 mg (0.362 mmol) of the compound
obtained in the Example 206 in 10 mL of tetrahydrofuran were added
72 mg (0.724 mmol) of hydantoin, 135 .mu.L (0.543 mmol) of
tri-n-butylphosphine and 1,1'-azobis (N,N-dimethylformamide), and
the mixture was stirred for 3 hours at 60.degree. C. The reaction
mixture was cooled to room temperature, treated with water, and
extracted with ethyl acetate. The organic layer was dried over with
anhydrous sodium sulfate and removed under reduced pressure. The
residue was purified by silica gel column chromatography
(eluent:ethyl acetate) to give 96 mg (58%) of the title
compound.
Example 248
Ethyl
1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]-4--
piperidinecarboxylate
[0848] The title compound 2.73 g (98%) was obtained in a manner
similar to the Example 7 by using ethyl isonipecotic acid, instead
of benzylamine.
Example 249
1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-4-piperid-
inecarboxylic acid
[0849] The title compound 1.1 g (99%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 248, instead of the compound obtained in the Example
40.
Example 250
1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-N-methyl--
4-piperidinecarboxamide
[0850] The title compound 195 mg (94%) was obtained in a manner
similar to the Example 224 by use of methylamine (30% ethanol
solution) and the compound obtained in the Example 249, instead of
the compound obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 251
Ethyl
(3S)-1-[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbony-
l]-3-piperidinecarboxylate
[0851] The title compound 2.29 g (quantitative) was obtained in a
manner similar to the Example 7 by use of ethyl (R)-nipecotic acid,
instead of benzylamine.
Example 252
N-[(6S,7aS)-1,3-Dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1-cyclohexy-
l-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0852] The title compound 595 mg (74%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 45, instead of benzylamine.
Example 253
N-[(6S,7aS)-2-Methyl-1,3-dioxohexahydro-1H-pyrrolo[1,2-c]imidazol-6-yl]-1--
cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide HCl
Salt
[0853] To a solution of 150 mg (0.374 mmol) of the compound
obtained in the Example 252 in 10 mL of tetrahydrofuran were added
30 .mu.L (0.747 mmol) of methanol, 122 mg (0.476 mmol) of
triphenylphosophine and 213 .mu.L (0.467 mmol) of
diethylazodicarboxylate (40% toluene solution), and the mixture was
stirred for 1 hour at room temperature. Then, the solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:hexane/acetone=2/1 for
first trial; dichloromethane/ethyl acetate=1/1 for second trial),
and obtained product was converted to the HCl salt by treating with
100 .mu.L of 4N--HCl/dioxane solution and recrystallized from
methanol-ethanol (1/1) to give 23 mg (15%) of the title
compound.
Example 254
(.+-.)-{1-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]--
3-piperidinyl}methanol
[0854] The title compound 595 mg (74%) was obtained in a manner
similar to the Example 7 by use of
(.+-.)-3-hydroxymethylpiperidine, instead of benzylamine.
Example 255
N-{4-[(Dimethylamino)carbonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0855] The title compound 123 mg (80%) was obtained in a manner
similar to the Example 7 by use of
4-(dimethylaminocarbonyl)aniline, instead of benzylamine.
Example 256
1-Cyclohexyl-3-methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-pyridinyl]-1H-thieno-
[2,3-c]pyrazole-5-carboxamide
[0856] The title compound 199 mg (83%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 46, instead of benzylamine.
Example 257
1-Cyclohexyl-N-[(1S,3S)-3-(hydroxymethyl)cyclopentyl]-3-methyl-1H-tieno[2,-
3-c]pyrazole-5-carboxamide
[0857] The title compound 462 mg (quantitative) was obtained in a
manner similar to the Example 206 by use of the compound obtained
in the Example 226, instead of the compound obtained in the Example
204.
Example 258
1-Cyclohexyl-N-{(1S,3S)-3-[(2,5-dioxo-1-imidazolidinyl)methyl]-cyclopentyl-
}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0858] The title compound 74 mg (40%) was obtained in a manner
similar to the Example 247 by use of the compound obtained in the
Example 257, instead of the compound obtained in the Example
206.
Example 259
1-Cyclohexyl-N-[4-(2,5-dioxo-1-imidazolidinyl)phenyl]-3-methyl-1H-thieno[2-
,3-c]pyrazole-5-carboxamide
[0859] The title compound 54 mg (27%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 47, instead of benzylamine.
Example 260
3-Methyl-N-[4-(3-methyl-2,5-dioxo-1-imidazolidinyl)phenyl]-1-tetrahydro-2H-
-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0860] The title compound 104 mg (61%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 48 and the compound obtained in the Example
195, instead of benzylamine and the compound obtained in the
Example 6, respectively.
Example 261
3-Methyl-N-[6-(2-oxo-1-imidazolidinyl)-3-piperidinyl]-1-tetrahydro-2H-pyra-
n-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0861] The title compound 101 mg (63%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 46 and the compound obtained in the Example
195, instead of benzylamine and the compound obtained in the
Example 6, respectively.
Example 262
1-Cyclohexyl-N-{4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1H-thieno[2-
,3-c]pyrazole-5-carboxamide
[0862] The title compound 308 mg (64%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 49, instead of benzylamine.
Example 263
1-Cyclohexyl-N-{3-fluoro-4-[(3R)-3-hydroxypyrrolidinyl]phenyl}-3-methyl-1H-
-thieno[2,3-c]pyrazole-5-carboxamide
[0863] The title compound 397 mg (79%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 51, instead of benzylamine.
Example 264
1-Cyclohexyl-N-{3-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0864] The title compound 80 mg (35%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 53, instead of benzylamine.
Example 265
N-{4-[4-{[tert-Butyl(dimethyl)silyl]oxy}-1-piperidinyl]sulfonyl}-phenyl}-1-
-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0865] The title compound 243 mg (69%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 56, instead of benzylamine.
Example 266
1-Cyclohexyl-N-{4-[(4-hydroxy-1-piperidinyl)sulfonyl]phenyl}-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0866] To a solution of 231 mg (0.374 mmol) of the compound
obtained in the Example 265 in 5 mL of tetrahydrofuran was added
562 .mu.L (0.562 mmol) of tetrabutylammoniumfluoride
(1M-tetrahydrofuran solution), and the mixture was stirred for over
night at room temperature. Then, the reaction mixture was treated
with ethyl acetate, and the organic layer was washed with water,
saturated saline solution and then, dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography
(eluent:hexane/ethyl acetate=1/2) to give 176 mg (94%) of the title
compound.
Example 267
1-Cyclohexyl-N-[4-(2-hydroxyethyl)phenyl]-3-methyl-1H-thieno[2,3-c]pyrazol-
e-5-carboxamide
[0867] The title compound 139 mg (64%) was obtained in a manner
similar to the Example 7 by use of 4-aminophenethylalcohol, instead
of benzylamine.
Example 268
N-[3-Fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1-tetra-hydro-2H-p-
yran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0868] The title compound 161 mg (96%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 62 and the compound obtained in the Example
195, instead of benzylamine and the compound obtained in the
Example 6, respectively.
Example 269
1-Cyclohexyl-3-methyl-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phe-
nyl]-1H-thieno[2,3-c]]pyrazole-5-carboxamide
[0869] The title compound 229 mg (80%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 58, instead of benzylamine.
Example 270
1-Cyclohexyl-3-methyl-N-[trans-4-(2-oxo-1,3-oxazolidin-3-yl)-cyclohexyl]-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0870] To a suspension of 150 mg (0.416 mmol) of the compound
obtained in the Example 132 in 2.5 mL of tetrahydrofuran were added
52 .mu.L (0.50 mmol) of 2-chloroethyl chloroformate and 87 .mu.L
(0.624 mmol) of triethylamine, and the mixture was stirred for 3
hours at room temperature. Saturated sodium bicarbonate aqueous
solution was added to the reaction mixture and the mixture was
extracted with chloroform. The organic layer was washed with water
and saturated saline solution and dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure to give
urethane intermediate compound.
[0871] Next, to a mixture solution of the urethane intermediate
compound obtained above in 2 mL of ethanol and 4 mL of
tetrahydrofuran was added 2 mL of 4M-NaOH aqueous solution, and the
mixture was stirred for 40 hours at room temperature. The solvent
was removed under reduced pressure and the residue was treated with
water, and the mixture was extracted with chloroform. The organic
layer was washed with water and saturated saline solution and dried
over with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:chloroform/methanol=10/1) to give 180 mg
(quantitative) of the title compound.
Example 271
1-Cyclohexyl-3-methyl-N-[trans-4-(2-oxo-1-imidazolidinyl)-cyclohexyl]-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0872] To a suspension of 150 mg (0.416 mmol) of the compound
obtained in the Example 132 in 4 mL of tetrahydrofuran was added 71
.mu.L (0.832 mmol) of 2-chloroethylsocyanate, and the mixture was
stirred for 3.5 hours at room temperature. 2 mL of 1M-NaOH aqueous
solution was added to the reaction mixture, and the mixture was
stirred. Then, further 5 mL of 4M-NaOH aqueous solution and 15 mL
of tetrahydrofuran were added to the mixture, and the mixture was
stirred for 2 hours. Next, 5 .mu.L of 15-crown-5 was added to the
reaction mixture and the mixture was further stirred for 43 hours
at room temperature, then, 5 mL of ethanol was added to the
reaction mixture and stirred for 6 hours at 80.degree. C. The
solvent was removed under reduced pressure and the residue was
treated with water. The mixture was extracted with chloroform and
the organic layer was washed with water and saturated saline
solution, then, dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography
(eluent:chloroform/methanol=10/1) to give 106 mg (55%) of the title
compound.
Example 272
4-[(trans-4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbony-
l]amino}cyclohexyl)amino]-4-oxobutanoic acid
[0873] To a suspension of 150 mg (0.416 mmol) of the compound
obtained in the Example 132 in 5 mL of xylene was added 62 mg
(0.624 mmol) of succinic anhydride, and the mixture was refluxed
for 5 hours. The solvent was removed under reduced pressure and the
residue was treated with ether. The appeared precipitates were
collected to give 178 mg (93%) of the title compound.
Example 273
1-Cyclohexyl-N-[trans-4-(2,5-dioxo-1-pyrrolidinyl)cyclohexyl]-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide
[0874] A mixture of 141 mg (0.306 mmol) of the compound obtained in
the Example 272, 2 mL of acetic anhydride and 33 mg of sodium
acetate was stirred for 3 hours at 60.degree. C. and for 14 hours
at 80.degree. C., then, 2 mL of acetic anhydride was further added
to the reaction mixture, and the mixture was stirred for 6 hours at
100.degree. C. After the reaction, ice water was added to the
reaction mixture and the mixture was neutralized by adding
saturates sodium bicarbonate aqueous solution, and extracted with
chloroform. The organic layer was washed with water and saturated
saline solution, and dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
treated with ethanol to give 59 mg (49%) of the title compound.
Example 274
1-Cyclohexyl-N-[trans-4-(1,1-dioxide-2-isothiazolidinyl)cyclohexyl]-3-meth-
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0875] To a solution of 150 mg (0.416 mmol) of the compound
obtained in the Example 132 in 10 mL of dichloromethane were added
87 .mu.L (0.624 mmol) of triethylamine and 61 .mu.L (0.50 mmol) of
3-chloropropanesulfonyl chloride, and the mixture was stirred for
1.5 hours at room temperature. Water was added to the reaction
mixture and the mixture was extracted with chloroform. The organic
layer was washed with water and saturated saline solution and dried
over with anhydrous sodium sulfate. The solvent was removed under
reduced pressure to give sulfonamide intermediate compound.
[0876] Next, to a mixture solution of the sulfonamide intermediate
compound obtained above in 5 mL of ethanol was added 2 mL of
4M-NaOH aqueous solution, and the mixture was stirred for 1.5 hours
at room temperature and for 3 hours at 80.degree. C. The reaction
mixture was cooled and treated with water, and then, extracted with
chloroform. The organic layer was washed with water and saturated
saline solution and dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
recrystallized from ethanol to give 112 mg (58%) of the title
compound.
Example 275
Benzyl
[{[(trans-4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)c-
arbonyl]amino}cyclohexyl)amino]carbonyl}(methyl)amino]acetate
[0877] To a solution of 200 mg (0.555 mmol) of the compound
obtained in the Example 132 in 4 mL of tetrahydrofuran were added
66 mg (0.22 mmol) of tri-phosgene and 232 .mu.L (1.66 mmol) of
triethylamine, and the mixture was stirred for 1 hour at room
temperature. Then, 195 mg (0.55 mmol) of p-toluene sulfonic acid
sarcosine benzyl ester and 77 .mu.L (0.555 mmol) of triethylamine
were added to the reaction mixture, and the mixture was stirred for
5 hours at room temperature. Water was added to the reaction
mixture and the mixture was extracted with chloroform, and the
organic layer was washed with water and saturated saline solution,
then, dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:chloroform/methanol=15/1)
to give 227 mg (72%) of the title compound.
Example 276
1-Cyclohexyl-3-methyl-N-[trans-4-(3-methyl-2,5-dioxo-1-imidazolidinyl)cycl-
ohexyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0878] To a solution of 207 mg (0.366 mmol) of the compound
obtained in the Example 275 in 5 mL of ethanol was added 0.5 mL of
6M-HCl aqueous solution and the mixture was refluxed for 4 hours.
After the reaction, the mixture was neutralized by adding saturated
sodium bicarbonate aqueous solution, and extracted with chloroform.
The organic layer was washed with water and saturated saline
solution and dried over with anhydrous sodium sulfate. The solvent
was removed under reduced pressure and the residue was purified by
silica gel column chromatography (eluent:chloroform/methanol=15/1)
to give 169 mg (quantitative) of the title compound.
Example 277
1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-1H-
-thieno[2,3-c]pyrazole-5-carboxamide
[0879] To a solution of 150 mg (0.487 mmol) of the compound
obtained in the Example 122 and 55.6 mg (0.487 mmol) of
1-methylhydantoin 4 mL of tetrahydrofuran were added 12 .mu.L
(0.487 mmol) of n-butylphosphine and 83.8 mg (0.487 mmol) of
1,1'-azobis(N,N-dimethylformamide), and the mixture was stirred for
5 hours at room temperature. The reaction mixture was treated with
water and extracted with chloroform. The organic layer was washed
with water and saturated saline solution, and dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:ethyl acetate) to give 113 mg (58%) of the
title compound.
Example 278
1-Cyclohexyl-3-methyl-N-[3-(3-methyl-2,5-dioxo-1-imidazolidinyl)-propyl]-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0880] The title compound 147 mg (75%) was obtained in a manner
similar to the Example 277 by use of the compound obtained in the
Example 123, instead of the compound obtained in the Example
122.
Example 279
1-Cyclohexyl-N-[trans-[4-({[(2-hydroxyethyl)(methyl)amino]carbonyl}-aminoc-
yclohexyl]-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0881] To a suspension of 200 mg (0.555 mmol) of the compound
obtained in the Example 132 in 4 mL of tetrahydrofuran were added
66 mg (0.22 mmol) of triphosgene and 232 .mu.L (1.66 mmol) of
triethylamine and the mixture was stirred for 1 hour at room
temperature. Then, 54 .mu.L (0.66 mmol) of 2-(methylamino) ethanol
was added to the reaction mixture and the mixture was stirred for 3
hours at room temperature. The reaction mixture was treated with
water and extracted with chloroform, washed with water and
saturated saline solution, and then, dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by silica gel column chromatography
(eluent:chloroform/methanol=15/1) to give 190 mg (74%) of the title
compound.
Example 280
1-Cyclohexyl-3-methyl-N-[trans-[4-(3-methyl-2-oxo-1-imidazolidinyl)-cycloh-
exyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0882] To a suspension of 187 mg (0.519 mmol) of the compound
obtained in the Example 279 in 6 mL of tetrahydrofuran was added
140 mg (1.25 mmol) of potassium tert-butoxide and the mixture was
cooled to 0.degree. C. Then, a solution of 119 mg (0.623 mmol) of
p-toluenesulfonyl chloride in 2 mL of tetrahydrofuran was added
gradually to the reaction mixture and the mixture was stirred for
30 minutes at room temperature. The reaction mixture was treated
with water and extracted with chloroform. The organic layer was
washed with water and saturated saline solution and dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:chloroform/methanol=20/1) to give 115 mg
(64%) of the title compound.
Example 281
Ethyl
3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]am-
ino}propanoate
[0883] The title compound 716 mg (98%) was obtained in a manner
similar to the Example 7 by use of .beta.-alanine ethyl ester HCl
salt, instead of benzylamine.
Example 282
N-[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]-.beta.-a-
lanine
[0884] The title compound 620 mg (99%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 281, instead of the compound obtained in the Example
40.
Example 283
tert-Butyl
{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl-
]amino}acetate
[0885] The title compound 663 mg (88%) was obtained in a manner
similar to the Example 7 by use of glycine tert-butyl ester HCl
salt, instead of benzylamine.
Example 284
{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}acet-
ic acid
[0886] A mixture solution of 637 mg (1.68 mmol) of the compound
obtained in the Example 283 and 5 mL of 4M-HCl/dioxane was stirred
for 5 hours at room temperature, and after the reaction, the
solvent was removed under reduced pressure. The residue was treated
with water and extracted with chloroform, and the organic layer was
washed with water and saturated saline solution, then, dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure to give 556 mg (quantitative) of the title
compound.
Example 285
1-Cyclohexyl-3-methyl-N-[3-(4-morphonyl)-3-oxopropyl]-1H-thieno[2,3-c]pyra-
zole-5-carboxamide
[0887] A suspension solution of 85 mg (0.253 mmol) of the compound
obtained in the Example 282, 246 mg (0.337 mmol) of PS-carbodiimide
(Argonaut Co.), and 39 mg (0.287 mmol) of 1-hydroxybenzotriazole in
4 mL of dichloromethane was stirred for 10 minutes at room
temperature. To the reaction mixture was added 20 .mu.L (0.228
mmol) of morpholine, and the mixture was stirred for 20 hours at
room temperature. Then, 267 mng (0.861 mmol) of MP-carbonate
(Argonaut Co.) was added to the reaction mixture and the mixture
was stirred for 3 hours at room temperature. The reaction mixture
was filtrated and the filtrate was condensed under reduced
pressure. The residue was recrystallized from ethyl acetate/hexane
to give 80 mg (78%) of the title compound.
Example 286
tert-Butyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbon-
yl]amino}ethylcarbamate
[0888] The title compound 2.23 g (97%) was obtained in a manner
similar to the Example 7 by use of N-(2-aminomethyl) carbamic acid
tert-butyl ester, instead of benzylamine.
Example 287
N-(2-Aminoethyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxam-
ide
[0889] To a solution of 2.18 g (5.36 mmol) of the compound obtained
in the Example 286 in 20 mL of dichloromethane was added 5 mL of
4M-HCl/dioxane, and the mixture was stirred for 18 hours at room
temperature. After reaction, the solvent was removed under reduced
pressure and the residue was neutralized with saturated sodium
bicarbonate aqueous solution, and extracted with chloroform. The
organic layer was washed with water and saturated saline solution,
then, dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was treated with
ethanol to give 670 mg (41%) of the title compound.
Example 288
1-Cyclohexyl-N-[3-(dimethylamino)-3-oxopropyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide
[0890] The title compound 52 mg (57%) was obtained in a manner
similar to the Example 285 by use of
2.0M-dimethylamine/tetrahydrofuran, instead of morpholine.
Example 289
1-Cyclohexyl-3-methyl-N-{3-[methyl(1-methyl-4-piperidinyl)amino]-3-oxoprop-
yl}-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0891] The title compound 79 mg (70%) was obtained in a manner
similar to the Example 285 by use of
1-methyl-4-(methylamino)piperidine, instead of morpholine.
Example 290
1-Cyclohexyl-N-[3-(4-hydroxy-1-piperidinyl)-3-oxopropyl]-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0892] The title compound 74 mg (70%) was obtained in a manner
similar to the Example 285 by use of 4-hydroxypiperidine, instead
of morpholine.
Example 291
1-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl)-2-oxoethyl]-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0893] The title compound 62 mg (63%) was obtained in a manner
similar to the Example 285 by use of the compound obtained in the
Example 284, instead of the compound obtained in the Example
282.
Example 292
1-Cyclohexyl-N-[2-(dimethylamino)-2-oxoethyl]-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0894] The title compound 63 mg (71%) was obtained in a manner
similar to the Example 285 by use of the compound obtained in the
Example 284 and 2.0M-dimethylamine/tetrahydrofuran, instead of the
compound obtained in the Example 282 and morpholine,
respectively.
Example 293
1-Cyclohexyl-3-methyl-N-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]-1H-thieno[-
2,3-c]pyrazole-5-carboxamide
[0895] The title compound 68 mg (67%) was obtained in a manner
similar to the Example 285 by use of the compound obtained in the
Example 284 and N-methylpiperazine, instead of the compound
obtained in the Example 282 and morpholine, respectively.
Example 294
1-Cyclohexyl-N-[2-(4-hydroxy-1-piperidinyl)-2-oxoethyl]-3-methyl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide
[0896] The title compound 75 mg (73%) was obtained in a manner
similar to the Example 285 by use of the compound obtained in the
Example 284 and 4-hydroxypiperidine, instead of the compound
obtained in the Example 282 and morpholine, respectively.
Example 295
1-Cyclohexyl-3-methyl-N-[3-(4-methyl-1-piperazinyl)-3-oxopropyl]-1H-thieno-
[2,3-c]pyrazole-5-carboxamide
[0897] The title compound 84 mg (80%) was obtained in a manner
similar to the Example 285 by use of N-methylpiperazine, instead of
morpholine.
Example 296
1-Cyclohexyl-3-methyl-N-{3-[4-methyl-1-piperidinyl]-3-oxopropyl}-1H-thieno-
[2,3-c]pyrazole-5-carboxamide fumarate
[0898] The title compound 41 mg (41%) was obtained in a manner
similar to the Example 191 by use of the compound obtained in the
Example 295, instead of the compound obtained in the Example
144.
Example 297
1-Cyclohexyl-3-methyl-N-{2-[methyl(1-methyl-4-piperidinyl)amino]-2-oxoethy-
l}-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0899] The title compound 81 mg (74%) was obtained in a manner
similar to the Example 285 by use of the compound obtained in the
Example 284 and 1-methyl-4-(methylamino) piperidine, instead of the
compound obtained in the Example 282 and morpholine,
respectively.
Example 298
1-Cyclohexyl-3-methyl-N-{2-[methyl(1-methyl-4-piperidinyl)amino-2-oxoethyl-
}-1H-thieno[2,3-c]pyrazole-5-carboxamide fumarate
[0900] The title compound 74 mg (79%) was obtained in a manner
similar to the Example 191 by use of the compound obtained in the
Example 297, instead of the compound obtained in the Example
144.
Example 299
1-Cyclohexyl-3-methyl-N-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-1H-thieno[2,3-
-c]pyrazole-5-carboxamide
[0901] To a suspension of 150 mg (0.490 mmol) of the compound
obtained in the Example 287 in 3 mL of tetrahydrofuran were added
102 .mu.L (0.735 mmol) of triethylamine and 61 .mu.L (0.590 mmol)
of 2-chloroethyl chloroformate, and the mixture was stirred for 2
hours at room temperature. Then, 210 mg (1.08 mmol) of 28%-sodium
methoxide/methanol solution was added to the reaction mixture and
the mixture was stirred for 2 hours at room temperature, and
further 130 mg (0.674 mmol) of 28%-sodium methoxide/methanol
solution was added to the reaction mixture and the resulting
mixture was stirred for 15 hours at room temperature. Then, the
reaction mixture was treated with water and extracted with
chloroform. The organic layer was washed with water and saturated
saline solution, then, dried over with anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the residue was
recrystallized from ethyl acetate to give 107 mf (58%) of the title
compound.
Example 300
1-Cyclohexyl-N-[2-(1,1-dioxide-2-isothiazolidinyl)ethyl]-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0902] The title compound 125 mg (62%) was obtained in a manner
similar to the Example 274 by use of the compound obtained in the
Example 287, instead of the compound obtained in the Example
132.
Example 301
1-Cyclohexyl-N-[2-({[(2-hydroxyethyl)(methyl)amino]carbonyl}amino)-ethyl]--
3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0903] The title compound 160 mg (60%) was obtained in a manner
similar to the Example 279 by use of the compound obtained in the
Example 287, instead of the compound obtained in the Example
132.
Example 302
1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2-oxo-1-imidazolidinyl)ethyl]-1H-thie-
no[2,3-c]pyrazole-5-carboxamide
[0904] The title compound 110 mg (80%) was obtained in a manner
similar to the Example 280 by use of the compound obtained in the
Example 301, instead of the compound obtained in the Example
279.
Example 303
Ethyl
4-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]am-
ino}butanoate
[0905] The title compound 763 mg (67%) was obtained in a manner
similar to the Example 7 by use of ethyl 4-aminobutyrate HCl salt,
instead of benzylamine.
Example 304
4-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}bu-
tanoic acid
[0906] The title compound 690 mg (quantitative) was obtained in a
manner similar to the Example 41 by use of the compound obtained in
the Example 303, instead of the compound obtained in the Example
40.
Example 305
1-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[0907] The title compound 98 mg (67%) was obtained in a manner
similar to the Example 7 by use of
3-(2-aminoethyl)-2,4-imidazolidinedione, instead of
benzylamine.
Example 306
1-Cyclohexyl-N-[4-(dimethylamino)-4-oxobutyl]-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0908] The title compound 101 mg (85%) was obtained in a manner
similar to the Example 285 by use of the compound obtained in the
Example 304 and 2.0M-dimethylamine/tetrahydrofuran solution,
instead of the compound obtained in the Example 282 and morpholine,
respectively.
Example 307
1-Cyclohexyl-3-methyl-N-[2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)eth-
yl]-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0909] To a solution of 150 mg (0.487 mmol) of the compound
obtained in the Example 122 in 5 mL of tetrahydrofuran were added
90 mg (0.634 mmol) of 1,5,5-trimethylhydantoin, 166 mg (0.634 mmol)
of triphenylphosphine and 289 .mu.L (0.634 mmol) of 40%-diethyl
azodicarboxylate/toluene solution, and the mixture was stirred for
30 minutes at room temperature. After the reaction, the reaction
mixture was treated with water and extracted with dichloromethane.
The organic layer was washed with water and saturated saline
solution, then, dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:hexane/ethyl
acetate=1/2) to give 146 mg (69%) of the title compound.
Example 308
1-Cyclohexyl-N-[2-(2,4-dioxo-1,3-thiazolidine-3-yl)ethyl]-3-methyl-1H-thie-
no[2,3-c]pyrazole-5-carboxamide
[0910] The title compound 106 mg (53%) was obtained in a manner
similar to the Example 307 by use of 2,4-thiazolidinedione, instead
of 1,5,5-trimethylhydantoin.
Example 309
1-Cyclohexyl-N-[1-(hydroxymethyl)cyclopropyl]-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0911] The title compound 766 mg (93%) was obtained in a manner
similar to the Example 7 by use of (1-aminocyclopropyl)methanol,
instead of benzylamine.
Example 310
1-Cyclohexyl-3-methyl-N-{1-[(3-methyl-2,5-dioxo-1-imidazolidinyl)-methyl]c-
yclopropyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0912] The title compound 111 mg (58%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 309 and 1-methylhydantoin, instead of the compound obtained
in the Example 122 and 1,5,5-trimethylhydantoin, respectively.
Example 311
Methyl
[(2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl-
]amino}ethyl)amino]acetate
[0913] To a solution of 170 mg (0.555 mmol) of the compound
obtained in the Example 287 in 5 mL of acetonitrile were added 52.5
.mu.L (0.555 mmol) of methyl bromoacetate and 153 mg (1.11 mmol) of
potassium carbonate, and the mixture was refluxed for 3 hours. The
reaction mixture was cooled and filtrated. The filtrate was treated
with water and extracted with ethyl acetate. The organic layer was
washed with water and saturated saline solution, then, dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=20/1 to 10/1) to
give 93 mg (44%) of the title compound.
Example 312
Methyl
[(aminocarbonyl)(2-{[(1-cyclohexyl-3-methyl-1H-thieno-[2,3-c]pyrazo-
l-5-yl)carbonyl]amino}ethyl)amino]acetate
[0914] To a solution of 78.8 mg (0.208 mmol) of the compound
obtained in the Example 311 in 1.5 mL of dioxane and 1.5 mL of
water were added 25.3 mg (0.312 mmol) of potassium cyanate and 36
.mu.L of acetic acid, and the mixture was stirred for 1.5 hours at
room temperature. The reaction mixture was treated with water and
extracted with ethyl acetate. The organic layer was washed with
water and saturated saline solution, then, dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:ethyl acetate/methanol=20/1 to 10/1) to give
73 mg (84%) of the title compound.
Example 313
1-Cyclohexyl-N-[2-(2,4-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[0915] To a solution of 68 mg (0.161 mmol) of the compound obtained
in the Example 312 in 6 mL of methanol was added 13 mg (60% oily;
0.323 mmol) of sodiumhydride, and the mixture was stirred for 1.5
hour at room temperature. The solvent was removed and the residue
was treated with water and extracted with ethyl acetate. The
organic layer was washed with water and saturated saline solution,
and then, dried over with anhydrous sodium sulfate. The solvent was
removed under reduced pressure and the residue was recrystallized
from ethanol to give 20 mg (32%) of the title compound.
Example 314
1-Cyclohexyl-N-[2-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0916] The title compound 195 mg (96%) was obtained in a manner
similar to the Example 307 by use of 5,5-dimethylhydantoin, instead
of 1,5,5-trimethylhydantoin.
Example 315
1-Cyclohexyl-3-methyl-N-[2-(5-methyl-1,1-dioxide-1,2,5-thiadiazolidin-2-yl-
)ethyl]-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0917] The title compound 227 mg (94%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 60, instead of benzylamine.
Example 316
1-Cyclohexyl-N-[2-(3-ethyl-2,4-dioxo-1-imidazolidinyl)ethyl]-3-methyl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0918] The title compound 84 mg (65%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 313 and ethanol, instead of 1,5,5-trimethylhydantoin and
the compound obtained in the Example 122, respectively.
Example 317
1-Cyclohexyl-3-methyl-N-[2-(3-methyl-2,4-dioxo-1-imidazolidinyl)-ethyl]-1H-
-thieno[2,3-c]pyrazole-5-carboxamide
[0919] The title compound 82 mg (66%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 313 and methanol, instead of 1,5,5-trimethylhydantoin and
the compound obtained in the Example 122, respectively.
Example 318
1-Cyclohexyl-N-[(1S)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0920] The title compound 170 mg (56%) was obtained in a manner
similar to the Example 7 by use of (S)-(+)-2-amino-1-propanol,
instead of benzylamine.
Example 319
1-Cyclohexyl-N-[(1S)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0921] The title compound 46 mg (24%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 318 and hydantoin, instead of the compound obtained in the
Example 122 and 1,5,5-trimethylhydantoin, respectively.
Example 320
N-[(3R)-1-Benzylpyrrolidinyl]-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazo-
le-5-carboxamide
[0922] The title compound 2.32 g (97%) was obtained in a manner
similar to the Example 7 by use of
(3R)-(-)-1-benzyl-3-aminopyrrolidine, instead of benzylamine.
Example 321
1-Cyclohexyl-3-methyl-N-[(3R)-pyrrolidinyl]-1H-thieno[2,3-c]-pyrazole-5-ca-
rboxamide
[0923] To a solution of 2.28 g (5.40 mmol) of the compound obtained
in the Example 320 in 15 mL of dichloromethane was added gradually
1.16 mL (10.8 mmol) of 1-chloroethyl formate at 0.degree. C., and
the mixture was stirred for 1 hour at the same temperature and for
2 hours at room temperature. The solvent was removed under reduced
pressure and 25 mL of ethanol was added to the residue, then, the
mixture was refluxed for 2.5 hours. After cooling, the solvent was
removed under reduced pressure, and the residue was treated with
6M-HCl aqueous solution. Water layer was washed with ether, and
neutralized by 4M-NaOH aqueous solution, and extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by alkaline silica gel column chromatography
(eluent:dichloromethane/methanol=50/1 to 30/1) to give 1.06 g (59%)
of the title compound.
Example 322
1-Cyclohexyl-N-{(3R)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide
[0924] To a solution of 150 mg (0.451 mmol) of the compound
obtained in the Example 321 in 5 mL of dichloromethane were added
50 .mu.L (0.541 mmol) of N,N-dimethylcarbamoyl chloride and 94
.mu.L of (0.677 mmol) of triethylamine, and the mixture was stirred
for 4 hours at room temperature. The reaction mixture was treated
with saturated sodium bicarbonate aqueous solution and extracted
with dichloromethane. The organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by alkaline silica gel column chromatography
(eluent:dichloromethane/methanol=30/1 to 10/1) to give 177 mg (97%)
of the title compound.
Example 323
1-Cyclohexyl-N-{(3R)-1-[(dimethylamino)carbonyl]pyrrolidinyl}-3-methyl-1H--
thieno[2,3-c]pyrazole-5-carboxamide HCl salt
[0925] 0.11 mL (0.44 mmol) of 4M-HCl/ethyl acetate was added to a
solution of 150 mg (0.372 mmol) of the title compound in 1 mL of
ethyl acetate, and the mixture was treated with ether, then,
stirred for 2 hours. The precipitates were collected to give 152 mg
(93%) of the title compound.
Example 324
1-Cyclohexyl-N-[(1R)-2-hydroxy-1-methylethyl]-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0926] The title compound 357 mg (98%) was obtained in a manner
similar to the Example 7 by use of (R)-(-)-2-amino-1-propanol,
instead of benzylamine.
Example 325
1-Cyclohexyl-N-[(1R)-2-(2,5-dioxo-1-imidazolidinyl)-1-methylethyl]-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0927] The title compound 67 mg (18%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 324 and hydantoin, instead of the compound obtained in the
Example 122 and 1,5,5-trimethylhydantoin, respectively.
Example 326
1-Cyclohexyl-N-[(2S)-2-hydroxypropyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-5-
-carboxamide
[0928] The title compound 343 mg (94%) was obtained in a manner
similar to the Example 7 by use of (S)-(-)-1-amino-2-propanol,
instead of benzylamine.
Example 327
1-Cyclohexyl-N-[(2R)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0929] The title compound 57 mg (15%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 326 and hydantoin, instead of the compound obtained in the
Example 122 and 1,5,5-trimethylhydantoin, respectively.
Example 328
1-Cyclohexyl-N-[(2R)-2-hydroxypropyl]-3-methyl-1H-thieno[2,3-c]-pyrazole-5-
-carboxamide
[0930] The title compound 338 mg (93%) was obtained in a manner
similar to the Example 7 by use of (R)-(+)-1-amino-2-propanol,
instead of benzylamine.
Example 329
1-Cyclohexyl-N-[(2S)-2-(2,5-dioxo-1-imidazolidinyl)propyl]-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0931] The title compound 42 mg (11%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 328 and hydantoin, instead of the compound obtained in the
Example 122 and 1,5,5-trimethylhydantoin, respectively.
Example 330
1-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)propyl]-3-methyl-1H-thieno[2,3-c]pyr-
azole-5-carboxamide
[0932] The title compound 355 mg (94%) was obtained in a manner
similar to the Example 7 by use of (R)-(-)-2-mino-1-butanol,
instead of benzylamine.
Example 331
1-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]propyl}-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0933] The title compound 66 mg (18%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 330 and hydantoin, instead of the compound obtained in the
Example 122 and 1,5,5-trimethylhydantoin, respectively.
Example 332
1-Cyclohexyl-N-[(1R)-1-(hydroxymethyl)-2-methylpropyl]-3-methyl-1H-thieno[-
2,3-c]pyrazole-5-carboxamide
[0934] The title compound 392 mg (99%) was obtained in a manner
similar to the Example 7 by use of D-valinol, instead of
benzylamine.
Example 333
1-Cyclohexyl-N-{(1R)-1-[(2,5-dioxo-1-imidazolidinyl)methyl]-2-methylpropyl-
}-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0935] The title compound 97 mg (22%) was obtained in a manner
similar to the Example 307 by use of the compound obtained in the
Example 332 and hydantoin, instead of the compound obtained in the
Example 122 and 1,5,5-trimethylhydantoin, respectively.
Example 334
tert-Butyl
2-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbon-
yl]amino}-2-methylpropylcarbamate
[0936] The title compound 493 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of tert-butyl
2-amino-2-methylpropyl-carbamate, instead of benzylamine.
Example 335
N-(2-Amino-1,1-dimethylethyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazo-
le-5-carboxamide
[0937] A mixture solution of 470 mg (1.08 mmol) of the compound
obtained in the Example 334 in 2 mL of 4M-HCl/dioxane was stirred
for 3 hours at room temperature. Then, the solvent was removed
under reduced pressure and the residue was treated with ether and
the resultant precipitates were collected. The collected
precipitates were dissolved in water and the mixture was
neutralized with saturated sodium bicarbonate aqueous solution, and
extracted with dichloromethane. The organic layer was washed with
water and saturated saline solution and dried over with anhydrous
sodium sulfate. The solvent was removed under reduced pressure to
give 344 mg (92%) of the title compound.
Example 336
1-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)-1,1-dimethylethyl]-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0938] To a solution of 304 mg (0.882 mmol) of the compound
obtained in the Example 335 in 5 mL of ethanol was added gradually
a solution of 114 mg (0.882 mmol) of ethyl isocyanatoacetate in 5
mL of ethanol, and the mixture was stirred for 3 hours at room
temperature. The solvent was removed under reduced pressure and the
residue was dissolved in 5 mL of ethanol, then, 5 mL of 6M-HCl
aqueous solution was added to the mixture. The mixture was refluxed
for 3 hours, and the solvent was removed under reduced pressure.
The residue was neutralized with saturated sodium bicarbonate
aqueous solution and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline
solution and then, dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:ethyl acetate)
to give 336 mg (91%) of the title compound.
Example 337
1-Cyclohexyl-N-[2-(2,5-dioxo-1-imidazolidinyl)-1,1-dimethylethyl]-3-methyl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide HCl Salt
[0939] The title compound 227 mg (70%) was obtained in a manner
similar to the Example 323 by use of the compound obtained in the
Example 336, instead of the compound obtained in the Example
322.
Example 338
N-(3-Amino-2,2-dimethylpropyl)-1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyraz-
ole-5-carboxamide
[0940] The title compound 162 mg (41%) was obtained in a manner
similar to the Example 7 by use of 2,2-dimethyl-1,3-propanediamine,
instead of benzylamine.
Example 339
1-Cyclohexyl-N-[3-(2,5-dioxo-1-imidazolidinyl)-2,2-dimethylpropyl]-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0941] The title compound 123 mg (72%) was obtained in a manner
similar to the Example 336 by use of the compound obtained in the
Example 338, instead of the compound obtained in the Example
335.
Example 340
(.+-.)-1-Cyclohexyl-N-[trans-2-(hydroxymethyl)cyclopropyl]-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0942] The title compound 280 mg (42%) was obtained in a manner
similar to the Example 7 by use of
(.+-.)-trans-(2-aminocyclopropyl)methanol, instead of
benzylamine.
Example 341
1-Cyclohexyl-3-methyl-N-[4-(3-oxo-1-piperazinyl)phenyl]-1H-thieno[2,3-c]py-
razole-5-carboxamide
[0943] The title compound 215 mg (87%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 66, instead of benzylamine.
Example 342
3-Methyl-N-[4-(3-oxo-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-t-
hieno[2,3-c]pyrazole-5-carboxamide
[0944] The title compound 152 mg (77%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 66 and the compound obtained in the Example
195, instead of benzylamine and the compound obtained in the
Example 6, respectively.
Example 343
Methyl
3-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mino}benzoate
[0945] The title compound 1.78 g (95%) was obtained in a manner
similar to the Example 7 by use of methyl m-aminobenzoate, instead
of benzylamine.
Example 344
3-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}be-
nzoic acid
[0946] The title compound 1.67 g (quantitative) was obtained in a
manner similar to the Example 41 by use of the compound obtained in
the Example 343, instead of the compound obtained in the Example
40.
Example 345
1-Cyclohexyl-N-{3-[(dimethylamino)carbonyl]phenyl}-3-methyl-1H-thieno[2,3--
c]pyrazole-5-carboxamide
[0947] The title compound 145 mg (90%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 344 and 2M-dimethylamine/tetrahydrofuran solution, instead
of the compound obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 346
1-Cyclohexyl-3-methyl-N-[3-(4-morpholinylcarbonyl)phenyl]-1H-thieno[2,3-c]-
pyrazole-5-carboxamide
[0948] The title compound 167 mg (94%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 344 and morpholine, instead of the compound obtained in the
Example 211 and hydroxyacetic acid, respectively.
Example 347
Methyl
trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyr-
azol-5-yl)carbonyl]amino}cyclohexanecarboxylate
[0949] The title compound 605 mg (99%) was obtained in a manner
similar to the Example 7 by use of methyl
trans-4-aminocyclohexanecarboxylate HCl salt and the compound
obtained in the Example 195, instead of benzylamine and the
compound obtained in the Example 6, respectively.
Example 348
trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5--
yl)carbonyl]amino}cyclohexanecarboxylic acid
[0950] The title compound 540 mg (98%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 347, instead of the compound obtained in the Example
40.
Example 349
N-{trans-4-[(Dimethylamino)carbonyl]cyclohexyl}-3-methyl-1-tetra-hydro-2H--
pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0951] The title compound 117 mg (91%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 348 and 2M-dimethylamine/tetrahydrofuran solution, instead
of the compound obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 350
3-Methyl-N-[trans-4-(4-morpholinylcarbonyl)cyclohexyl]-1-tetra-hydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0952] The title compound 132 mg (93%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 348 and morpholine, instead of the compound obtained in the
Example 211 and hydroxyacetic acid, respectively.
Example 351
N-{trans-4-[(4-Hydroxy-1-piperidinyl)carbonyl]cyclohexyl}-3-methyl-1-tetra-
hydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0953] The title compound 137 mg (94%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 348 and 4-hydroxypiperidine, instead of the compound
obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 352
3-Methyl-N-{trans-4-[(4-methyl-1-piperazinyl)carbonyl]cyclohexyl}-1-tetrah-
ydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0954] The title compound 97 mg (76%) was obtained in a manner
similar to the Example 224 by use of the compound obtained in the
Example 348 and 1-methylpiperazine, instead of the compound
obtained in the Example 211 and hydroxyacetic acid,
respectively.
Example 353
1-Cyclohexyl-3-methyl-N-[3-(4-morpholinyl)propyl]-1H-thieno[2,3-c]pyrazole-
-5-carboxamide
[0955] The title compound 199 mg (90%) was obtained in a manner
similar to the Example 7 by use of N-(3-aminopropyl)morpholine,
instead of benzylamine.
Example 354
1-Cyclohexyl-3-methyl-N-[2-(4-morpholinyl)ethyl]-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0956] The title compound 174 mg (82%) was obtained in a manner
similar to the Example 7 by use of N-(2-aminoethyl)morpholine,
instead of benzylamine.
Example 355
1-Cyclohexyl-3-methyl-N-[2-(1-piperidinyl)ethyl]-1H-thieno[2,3-c]pyrazole--
5-carboxamide
[0957] The title compound 148 mg (70%) was obtained in a manner
similar to the Example 7 by use of N-(2-aminoethyl)piperidine,
instead of benzylamine.
Example 356
N-[trans-4-(Hydroxymethyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0958] The title compound 628 mg (96%) was obtained in a manner
similar to the Example 206 by use of the compound obtained in the
Example 347, instead of the compound obtained in the Example
204.
Example 357
(trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-
-yl)carbonyl]amino}cyclohexyl)methyl p-toluenesulfonate
[0959] To a suspension solution of 510 mg (1.35 mmol) of the
compound obtained in the Example 356 in 20 mL of dichloromethane
and 20 mL of chloroform were added 270 mg (1.42 mmol) of
p-toluenesulfonyl chloride and 131 .mu.L (1.62 mmol) of pyridine,
and the mixture was stirred for over night at room temperature.
Then, further 270 mg (1.42 mmol) of p-toluenesulfonyl chloride and
131 .mu.L (1.62 mmol) of pyridine were added twice to the reaction
mixture at 50.degree. C., and the mixture was stirred for over
night. Further, 270 mg (1.42 mmol) of p-toluenesulfonyl chloride,
131 .mu.L (1.62 mmol) of pyridine and 226 .mu.L (1.62 mmol) of
triethylamine were added twice to the reaction mixture, and the
mixture was stirred for over night. Then, the reaction mixture was
washed with water and dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography (eluent:hexane/ethyl
acetate=1/1 to ethyl acetate only) to give 402 mg (56%) of the
title compound.
Example 358
3-Methyl-N-[trans-4-(4-morpholinylmethyl)cyclohexyl]-1-tetrahydro-2H-pyran-
-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0960] To a solution of 120 mg (0.226 mmol) of the compound
obtained in the Example 357 in 5 mL of N,N-dimethylformamide was
added 79 .mu.L (0.903 mmol) of morpholine, and the mixture was
stirred for 12 hours at 100.degree. C. Then, the reaction mixture
was cooled to room temperature, and treated with 20 mL of
ethylacetate. The organic layer was washed with water and saturated
saline solution, and dried over with anhydrous sodium sulfate. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography
(eluent:dichloromethane/methanol=40/1) to give 52 mg (52%) of the
title compound.
Example 359
N-{trans-4-[(Dimethylamino)methyl]cyclohexyl}-3-methyl-1-tetra-hydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0961] The title compound 92 mg (quantitative) was obtained in a
manner similar to the Example 358 by use of
2M-dimethylamine/tetrahydrofuran solution, instead of
morpholine.
Example 360
N-{trans-4-[(4-Acetyl-1-piperazinyl)methyl]cyclohexyl}-3-methyl-1-tetrahyd-
ro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0962] The title compound 82 mg (87%) was obtained in a manner
similar to the Example 358 by use of 1-acetylpiperazine, instead of
morpholine.
Example 361
N-{3-[(Dimethylamino)sulfonyl]phenyl}-3-methyl-1-tetrahydro-2H-pyran-4-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0963] The title compound 133 mg (66%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 67 and the compound obtained in the Example
195, instead of benzylamine and the compound obtained in the
Example 6, respectively.
Example 362
3-Methyl-N-[3-(methylsulfonyl)phenyl]-1-tetrahydro-2H-pyran-4-yl-1H-thieno-
[2,3-c]pyrazole-5-carboxamide
[0964] The title compound 74 mg (39%) was obtained in a manner
similar to the Example 7 by use of 3-methylsulfonylaniline HCl salt
and the compound obtained in the Example 195, instead of
benzylamine and the compound obtained in the Example 6,
respectively.
Example 363
N-{3-[(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)sulfonyl]phenyl}-3-methyl-1-
-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0965] The title compound 135 mg (53%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 68 and the compound obtained in the Example
195, instead of benzylamine and the compound obtained in the
Example 6, respectively.
Example 364
N-[3-[(2-Hydroxyethyl)sulfonyl]phenyl]-3-methyl-1-tetrahydro-2H-pyran-4-yl-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0966] The title compound 61 mg (60%) was obtained in a manner
similar to the Example 266 by use of the compound obtained in the
Example 363, instead of the compound obtained in the Example
265.
Example 365
1-Cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide dimethanesulfonate
[0967] A mixture solution of 456.5 mg (1.00 mmol) of the compound
obtained in the Example 159 and 142.8 .mu.L (2.20 mmol) of
methanesulfonic acid in 4 mL of ethanol was condensed under reduced
pressure. The residue was treated with 5 mL of ethanol and the
residue was solved in the solution by heating and refluxing. Then,
2 mL of isopropyl ether was added and the mixture was cooled
gradually to room temperature. The resulting precipitates were
collected by filtration to give 383 mg (59%) of the title
compound.
Example 366
1-Cyclohexyl-N-[3-fluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl
-1H-thieno[2,3-c]pyrazole-5-carboxamide p-toluenesulfonate
[0968] To a solution of 228.3 mg (0.50 mmol) of the compound
obtained in the Example 159 in 2 mL of ethanol was added 104.6 mg
(0.55 mmol) of p-toluenesulfonic acid monohydrate at 50.degree. C.,
and the mixture was condensed under reduced pressure. Then, 1.5 mL
of isopropanol was added to the residue and the residue was solved
in the mixture by heating at 70.degree. C., and the mixture was
cooled gradually to room temperature. The resulting precipitates
were collected by filtration to give 281 mg (89%) of the title
compound.
Example 367
1-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3--
c]pyrazole-5-carboxamide methanesulfonate
[0969] To a solution of 438.6 mg (1.00 mmol) of the compound
obtained in the Example 114 in 4 mL of ethanol was added 71.4 .mu.L
(1.10 mmol) of methanesulfonic acid, and further 0.8 mL of ethyl
acetate was added to the mixture. After refluxing the mixture,
then, the mixture was cooled gradually to room temperature. The
resulting precipitates were collected by filtration to give 424 mg
(79%) of the title compound.
Example 368
1-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1H-thieno[2,3--
c]pyrazole-5-carboxamide p-toluenesulfonate
[0970] To a suspension of 219.3 mg (0.50 mmol) of the compound
obtained in the Example 114 in 3 mL of ethanol was added 104.6 mg
(0.55 mmol) of p-toluenesulfonic acid monohydrate, and the mixture
was refluxed. Then, the separated precipitates were dissolved by
adding 0.6 mL of water and the mixture was cooled gradually to
0.degree. C. The resulting precipitates were collected by
filtration to give 244 mg (80%) of the title compound.
Example 369
3-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0971] To a suspension of 120 mg (0.45 mmol) of the compound
obtained in the Example 195 in 2 mL of 1,2-dichloroethane was added
66 .mu.L (0.90 mmol) of thionyl chloride and the mixture was
refluxed for 2 hours. After cooling the reaction mixture and the
solvent removed under reduced pressure to give acid chloride
intermediate compound.
[0972] 314 .mu.L (2.25 mmol) of triethylamine and 139 mg (0.54
mmol) of the compound obtained in the Manufacturing Example 64 were
added to the solution of the acid chloride intermediate compound in
5 mL of anhydrous dichloromethane, and the mixture was stirred for
3 hours at room temperature. The reaction mixture was treated with
saturated sodium bicarbonate aqueous solution and extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=20/1 to 10/1) to give 172 mg (88%)
of the title compound.
Example 370
1-Cyclohexyl-N-[6-(4-hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[0973] The title compound 216 mg (quantitative) was obtained in a
manner similar to the Example 7 by use of the compound obtained in
the Manufacturing Example 74, instead of benzylamine.
Example 371
1-Cyclohexyl-N-[2,3-difluoro-4-(4-hydroxy-1-piperidinyl)phenyl]-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[0974] The title compound 177 mg (82%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 76, instead of benzylamine.
Example 372
1-Cyclohexyl-N-[4-(4-hydroxy-1-piperidinyl)-3-methylphenyl]-3-methyl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide
[0975] The title compound 189 mg (92%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 78, instead of benzylamine.
Example 373
N-[3-Cyano-4-(4-hydroxy-1-piperidinyl)phenyl]-1-cyclohexyl-3-methyl-1H-thi-
eno[2,3-c]pyrazole-5-carboxamide
[0976] The title compound 209 mg (99%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 80, instead of benzylamine.
Example 374
Methyl
5-{[(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)-carbonyl]a-
mino}-2-(4-hydroxy-1-piperidinyl)benzoate
[0977] The title compound 224 mg (99%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 82, instead of benzylamine.
Example 375
5-{[(1-Cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazol-5-yl)carbonyl]-amino}-2-
-(4-hydroxy-1-piperidinyl)benzoic acid
[0978] The title compound 167 mg (81%) was obtained in a manner
similar to the Example 41 by use of the compound obtained in the
Example 374, instead of the compound obtained in the Example
40.
Example 376
N-[6-(4-Hydroxy-1-piperidinyl)-3-pyridinyl]-3-methyl-1-tetrahydro-2H-pyran-
-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0979] The title compound 202 mg (quantitative) was obtained in a
manner similar to the Example 369 by use of the compound obtained
in the Manufacturing Example 74, instead of the compound obtained
in the Manufacturing Example 64.
Example 377
3-Methyl-1-tetrahydro-2H-pyran-4-yl-N-(1-tetrahydro-2H-pyran-4-yl-4-piperi-
dinyl)-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0980] The title compound 187 mg (96%) was obtained in a manner
similar to the Example 369 by use of the compound obtained in the
Manufacturing Example 84, instead of the compound obtained in the
Manufacturing Example 64.
Example 378
1-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)carbonyl]-3-pyridinyl}-3-methy-
l-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0981] To a suspension of 100 mg (0.26 mmol) of the compound
obtained in the Example 103 in 5 mL of anhydrous dichloromethane
were added 39.4 mg (0.39 mmol) of 4-hydroxypiperidine, 53 mg (0.39
mmol) of 1-hydroxy-benzotriazole, 74.8 mg (0.39 mmol) of
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide HCl salt and 72.5
.mu.L (0.52 mmol) of triethylamine, and the mixture was stirred for
17 hours at room temperature. The reaction mixture was treated with
saturated sodium bicarbonate aqueous solution, and extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=10/1) to give 102 mg (84%) of the
title compound.
Example 379
1-Cyclohexyl-N-(6-{[(2-hydroxyethyl)amino]carbonyl}-3-pyridinyl)-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[0982] The title compound 76 mg (68%) was obtained in a manner
similar to the Example 378 by use of 2-aminoethanol, instead of
4-hydroxypiperidine.
Example 380
1-Cyclohexyl-3-methyl-N-{6-[(4-methyl-1-piperazinyl)carbonyl]-3-pyridinyl}-
-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0983] The title compound 87 mg (72%) was obtained in a manner
similar to the Example 378 by use of N-methylpiperazine, instead of
4-hydroxypiperidine.
Example 381
1-Cyclohexyl-N-[6-({[2-(dimethylamino)ethyl]amino}carbonyl-3-pyridinyl)-3--
methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0984] The title compound 71 mg (60%) was obtained in a manner
similar to the Example 378 by use of N,N-dimethylethylenediamine,
instead of 4-hydroxypiperidine.
Example 382
1-Cyclohexyl-N-(6-{[(trans-4-hydroxycyclohexyl)amino]carbonyl}-3-pyridinyl-
)-3-methyl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0985] The title compound 50 mg (39%) was obtained in a manner
similar to the Example 378 by use of trans-4-aminocyclohexanaol,
instead of 4-hydroxypiperidine.
Example 383
1-Cyclohexyl-3-methyl-N-{6-1(4-methyl-1,4-diazepam-1-yl)carbonyl]-3-pyridi-
nyl}-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0986] The title compound 105 mg (84%) was obtained in a manner
similar to the Example 378 by use of N-methylhomopiperazine,
instead of 4-hydroxypiperidine.
Example 384
tert-Butyl
4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyraz-
ol-5-yl)carbonyl]amino}-1-piperidinecarboxylate
[0987] The title compound 1.86 g (92%) was obtained in a manner
similar to the Example 369 by use of 4-amino-1-Boc-piperidine,
instead of the compound obtained in the Manufacturing Example
64.
Example 385
3-Methyl-N-(4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyr-
azole-5-carboxamide
[0988] A mixture solution of 1.81 g (4.03 mmol) of the compound
obtained in the Example 384 in 10 mL of 4M-HCl/dioxane was stirred
for 30 minutes at room temperature and for 2 hours at 60.degree. C.
After cooling the reaction mixture, the solvent was removed under
reduced pressure and the residue was treated with saturated sodium
bicarbonate aqueous solution, then, the mixture was extracted with
chloroform. The organic layer was washed with water and saturated
saline solution and then, dried over with anhydrous sodium sulfate.
The solvent was removed under reduced pressure to give 1.22 g (87%)
of the title compound.
Example 386
N-{1-[(Dimethylamino)carbonyl]-4-piperidinyl}-3-methyl-1-tetra-hydro-2H-py-
ran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0989] The title compound 132 mg (91%) was obtained in a manner
similar to the Example 322 by use of the compound obtained in the
Example 385, instead of the compound obtained in the Example
321.
Example 387
tert-Butyl
4-{4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]py-
razol-5-yl)carbonyl]amino}piperidin-1-yl}-1-piperidine-carboxylate
[0990] To a suspension of 220 mg (0.63 mmol) of the compound
obtained in the Example 385 in 5 mL of 1,2-dichloroethane were
added 15 .mu.L of acetic acid and 151 mg (0.757 mmol) of
1-Boc-4-piperidone, and the mixture was stirred for 30 minutes at
room temperature. Then, 200 mg (0.95 mmol) of sodium
triacetoxyborohydride was added to the reaction mixture, and the
mixture was stirred for 6 hours at room temperature. The reaction
mixture was treated with saturated sodium bicarbonate aqueous
solution and extracted with dichloromethane. The organic layer was
washed with water and saturated saline solution, then, dried over
with anhydrous sodium sulfate. The solvent was removed under
reduced pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=10/1) to give 230
mg (69%) of the title compound.
Example 388
3-Methyl-N-(piperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4-yl-1H-th-
ieno[2,3-c]pyrazole-5-carboxamide
[0991] The title compound 165 mg (98%) was obtained in a manner
similar to the Example 385 by use of the compound obtained in the
Example 387, instead of the compound obtained in the Example
384.
Example 389
3-Methyl-N-(1-acetylpiperidin-4-yl-4-piperidinyl)-1-tetrahydro-2H-pyran-4--
yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0992] The title compound 51 mg (62%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 388, instead of the compound obtained in
the Manufacturing Example 2.
Example 390
3-Methyl-N-(1-methanesulfonylpiperidin-4-yl-4-piperidinyl)-1-tetra-hydro-2-
H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0993] The title compound 68 mg (77%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 388 and methanesulfonyl chloride, instead
of the compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Example 391
tert-Butyl
4-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-
-c]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazine-carboxylate
[0994] The title compound 456 mg (46%) was obtained in a manner
similar to the Example 369 by use of the compound obtained in the
Manufacturing Example 86, instead of the compound obtained in the
Manufacturing Example 64.
Example 392
tert-Butyl
4-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c-
]pyrazol-5-yl)carbonyl]amino}cyclohexyl)-1-piperazine-carboxylate
[0995] 523 mg (52%) of the title compound was obtained as
by-product in the Example 391.
Example 393
3-Methyl-N-[trans-4-(1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide di-HCl Salt
[0996] A mixture of 419 mg (0.817 mmol) of the compound obtained in
the Example 391 in 3 mL of 4M-HCl/dioxane and 1 mL of methanol was
stirred for 5 hours at room temperature. The solvent was removed
under reduced pressure and the residue was treated with ethanol.
The resulting precipitates were collected by filtration to give 343
mg (83%) of the title compound.
Example 394
3-Methyl-N-[cis-4-(1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-yl-1H-
-thieno[2,3-c]pyrazole-5-carboxamide di-HCl Salt
[0997] The title compound 234 mg (51%) was obtained in a manner
similar to the Example 393 by use of the compound obtained in the
Example 392, instead of the compound obtained in the Example
391.
Example 395
N-[trans-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-1-tetra-hydro-2H-p-
yran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0998] The title compound 100 mg (70%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 388 and acetic anhydride, instead of the
compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Example 396
3-Methyl-N-{trans-4-[4-(methylsulfonyl)-1-piperazinyl]cyclohexyl}-1-tetrah-
ydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[0999] The title compound 109 mg (71%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 393 and methanesulfonyl chloride, instead
of the compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Example 397
N-[cis-4-(4-Acetyl-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro-2H-pyra-
n-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1000] The title compound 113 mg (66%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 394 and acetic anhydride, instead of the
compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Example 398
3-Methyl-N-[1-(4-morpholinylcarbonyl)-4-piperidinyl]-1-tetrahydro-2H-pyran-
-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1001] The title compound 109 mg (69%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 385 and 4-morpholinyl chloride, instead of
the compound obtained in the Manufacturing Example 2 and acetyl
chloride, respectively.
Example 399
3-Methyl-N-{1-[(4-methyl-1-piperazinyl)carbonyl]-4-piperidinyl}-1-tetrahyd-
ro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1002] The title compound 92 mg (56%) was obtained in a manner
similar to the Manufacturing Example 3 by use of the compound
obtained in the Example 385 and 4-methyl-1-piperazinecarbonyl
chloride HCl salt, instead of the compound obtained in the
Manufacturing Example 2 and acetyl chloride, respectively.
Example 400
N-(trans-4-Hydroxycyclohexyl)-3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thien-
o[2,3-c]pyrazole-5-carboxamide
[1003] The title compound 843 mg (52%) was obtained in a manner
similar to the Example 396 by use of trans-4-aminocyclohexanol,
instead of the compound obtained in the Manufacturing Example
64.
Example 401
3-Methyl-N-(4-oxocyclohexyl)-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]py-
razole-5-carboxamide
[1004] To a solution of 828 mg (2.28 mmol) of the compound obtained
in the Example 400 in 30 mL of dichloromethane were added 983 mg
(4.56 mmol) of pyridinium chlorocromate and 2 g of Molecular sieves
4A, and the mixture was stirred for 4 hours at room temperature.
The reaction mixture was filtrated by Celite.RTM., and the filtrate
was removed under reduced pressure. The residue was purified by
silica gel column chromatography (eluent:dichloromethane/ethyl
acetate) and further purified by silica gel column chromatography
(eluent:ethyl acetate) to give 668 mg (81%) of the title
compound.
Example 402
N-[trans-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetrahydro--
2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1005] To a solution of 150 mg (0.415 mmol) of the compound
obtained in the Example 401 in 3 mL of 1,2-dichloroethane were
added 103 .mu.L (0.83 mmol) of cis-2,6-dimethylmorpholine and 15
.mu.L of acetic acid, and the mixture was stirred for 30 minutes at
room temperature. Then, 132 mg (0.623 mmol) of sodium
triacetoxyborohydride was added to the reaction mixture and the
mixture was stirred for 4 hours at room temperature. The reaction
mixture was treated with saturated sodium bicarbonate aqueous
solution and extracted with dichloromethane. The organic layer was
washed with water and saturated saline solution, then, dried over
with anhydrous sodium sulfate. The organic layer was removed under
reduced pressure and the residue was purified by alkaline silica
gel column chromatography (eluent:ethyl acetate/hexane=1/1) to give
132 mg (69%) of the title compound.
Example 403
N-[cis-4-(cis-2,6-Dimethylmorpholinyl)cyclohexyl]-3-methyl-1-tetra-hydro-2-
H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1006] The title compound 46 mg (24%) was obtained in the Example
402 as by-product.
Example 404
1-Cyclohexyl-N-[6-(hydroxymethyl)-3-pyridinyl]-3-methyl-1H-thieno[2,3-c]py-
razole-5-carboxamide
[1007] The title compound 215 mg (58%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 87, instead of benzylamine.
Example 405
Methyl
5-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-5-
-yl)carbonyl]amino}-2-pyridinecarboxylate
[1008] To a suspension of 700 mg (2.63 mmol) of the compound
obtained in the Example 195 in 6 mL of 1,2-dichloroethane was added
384 .mu.L (5.26 mmol) of thionyl chloride, and the mixture was
refluxed for 2 hours. After reaction mixture was cooled, the
solvent was removed under reduced pressure to give acid chloride
intermediate compound.
[1009] Then, to a solution of the acid chloride intermediate
compound obtained above in 8 mL of pyridine was added 400 mg (2.63
mmol) of methyl 5-amino-2-pyridinecarboxylate, and the mixture was
stirred for 2 hours at room temperature. The reaction mixture was
treated with saturated sodium bicarbonate aqueous solution and
extracted with dichloromethane. The organic layer was washed with
water and saturated saline solution, then, dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:ethyl acetate) to give 956 mg (91%) of the
title compound.
Example 406
5-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-yl)carb-
onyl]amino}-2-pyridinecarboxylic acid
[1010] To a solution of 923 mg (2.30 mmol) of the compound obtained
in the Example 405 in 5 mL of methanol was added 5 mL of 1M-NaOH
aqueous solution, and the mixture was stirred for 1.5 hours at
60.degree. C. After cooling the reaction mixture, the solvent was
removed under reduced pressure and the residue was neutralized by
adding 2.5 mL of 2M-HCl aqueous solution. The resulting
precipitates were collected to give 870 mg (98%) of the title
compound.
Example 407
N-(6-{[(trans-4-Hydroxycyclohexyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1--
tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1011] The title compound 118 mg (94%) was obtained in a manner
similar to the Example 378 by use of the compound obtained in the
Example 406 and trans-4-aminocyclohexanol, instead of the compound
obtained in the Example 103 and 4-hydroxypiperidine,
respectively.
Example 408
N-[6-({[2-(Dimethylamino)ethyl]amino}carbonyl)-3-pyridinyl]-3-methyl-1-tet-
rahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1012] The title compound 108 mg (91%) was obtained in a manner
similar to the Example 378 by use of the compound obtained in the
Example 406 and N,N-dimethylethylenediamine, instead of the
compound obtained in the Example 103 and 4-hydroxypiperidine,
respectively.
Example 409
3-Methyl-N-(6-{[(1-methyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-1-tet-
rahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1013] The title compound 35.6 mg (36%) was obtained in a manner
similar to the Example 378 by use of the compound obtained in the
Example 406 and 4-amino-1-methylpiperidine, instead of the compound
obtained in the Example 103 and 4-hydroxypiperidine,
respectively.
Example 410
N-(6-{[(1-Acetyl-4-piperidinyl)amino]carbonyl}-3-pyridinyl)-3-methyl-1-tet-
rahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1014] The title compound 109 mg (82%) was obtained in a manner
similar to the Example 378 by use of the compound obtained in the
Example 406 and 4-amino-1-acetylpiperidine, instead of the compound
obtained in the Example 103 and 4-hydroxypiperidine,
respectively.
Example 411
1-Cyclohexyl-3-methyl-N-[6-(4-morpholinylmethyl)-3-pyridinyl]-1H-thieno[2,-
3-c]pyrazole-5-carboxamide
[1015] To a suspension of 120 mg (0.324 mmol) of the compound
obtained in the Example 404 in 3 mL of ethyl acetate were added 90
.mu.L (0.648 mmol) of triethylamine and 38 .mu.L (0.486 mmol) of
methanesulfonyl chloride, and the mixture was stirred for 30
minutes at room temperature. The reaction mixture was treated with
ethyl acetate, and the organic layer was washed with saturated
sodium bicarbonate aqueous solution, water and saturated saline
solution, respectively, then, dried over with anhydrous sodium
sulfate. Sodium sulfate was removed off by filtration, and the
filtrate was treated with 1 mL of 4M-HCl/dioxane, and the solvent
was removed to give
(5-{(1-cyclohexyl-3-methyl-1H-thieno[2,3-c]pyrazole-5-yl)carbonyl]amino}--
2-pyridinyl)methyl methanesulfonate HCl salt as the intermediate
compound.
[1016] To a suspension of the intermediate compound obtained above
in 3 mL of acetonitrile were added 162 mg (1.17 mmol) of potassium
carbonate, 28.8 .mu.L (0.33 mmol) of morpholine and 5.8 mg (0.035
mmol) of potassium iodide, and then, the mixture was stirred for 2
hours at 70.degree. C. and for 15 hours at room temperature. Then,
the reaction mixture was treated with water and extracted with
ethyl acetate. The organic layer was washed with water and
saturated saline solution, and dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=10/1) to give 114 mg (80%) of the
title compound.
Example 412
1-Cyclohexyl-3-methyl-N-[6-(4-morpholinylmethyl)-3-pyridinyl]-1H-thieno[2,-
3-c]pyrazole-5-carboxamide methanesulfonate
[1017] To a solution of 100 mg (0.227 mmol) of the compound
obtained in the Example 411 in 2 mL of ethanol was added 14.8 .mu.L
of methanesulfonic acid and the solvent was removed. The residue
was recrystallized from isopropanol to give 77 mg (63%) of the
title compound.
Example 413
1-Cyclohexyl-N-{6-[(4-hydroxy-1-piperidinyl)methyl]-3-pyridinyl}-3-methyl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[1018] The title compound 104 mg (71%) was obtained in a manner
similar to the Example 411 by use of 4-hydroxypiperidine, instead
of morpholine.
Example 414
N-{6-[(4-Acetyl-1-piperazinyl)methyl]-3-pyridinyl}-1-cyclohexyl-3-methyl-1-
H-thieno[2,3-c]pyrazole-5-carboxamide
[1019] The title compound 102 mg (66%) was obtained in a manner
similar to the Example 411 by use of 1-acetylpiperazine, instead of
morpholine.
Example 415
3-Methyl-N-[trans-4-(4-methyl-2-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-
-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1020] The title compound 124 mg (72%) was obtained in a manner
similar to the Example 369 by use of the compound obtained in the
Manufacturing Example 91, instead of the compound obtained in the
Manufacturing Example 64.
Example 416
1-Cyclohexyl-3-methyl-N-[trans-4-(4-methyl-2-oxo-1-piperazinyl)-cyclohexyl-
]-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1021] The title compound 130 mg (75%) was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 91, instead of benzylamine.
Example 417
3-Methyl-N-[trans-4-(3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-
-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1022] The title compound 115 mg (62%) was obtained in a manner
similar to the Example 402 by use of 2-piperazine, instead of
cis-2,6-dimethyl-morpholine.
Example 418
3-Methyl-N-[cis-4-(3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-2H-pyran-4-
-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1023] The title compound 43 mg (23%) was obtained in the Example
471, as by-product.
Example 419
3-Methyl-N-[trans-4-(4-methyl-3-oxo-1-piperazinyl)cyclohexyl]-1-tetrahydro-
-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1024] To a suspension of 150 mg (0.415 mmol) of the compound
obtained in the Example 401 in 3 mL of 1,2-dichloroethane were
added 125 mg (0.83 mmol) of 1-methyl-2-piperazinone HCl salt, 15
.mu.L of acetic acid, and 82 mg (1.0 mmol) of sodium acetate, and
the mixture was stirred for 30 minutes at room temperature. Then,
132 mg (0.623 mmol) of sodium triacetoxyborohydride was added to
the reaction mixture, and the mixture was stirred for 1 hour at
room temperature. The reaction mixture was diluted by saturated
sodium bicarbonate aqueous solution and extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:dichloromethane/methanol=10/1) to give 131 mg (69%) of the
title compound.
Example 420
3-Methyl-N-[cis-4-(4-methyl-3-oxo-1-piperazinyl)cyclohexyl]-1-tetra-hydro--
2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1025] The title compound 21 ng (11%) was obtained in the Example
419, as by-product.
Example 421
Ethyl
1-(trans-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]p-
yrazol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidine-carboxylate
[1026] The title compound 690 mg (37%) was obtained in a manner
similar to the Example 369 by use of the compound obtained in the
manufacturing Example 93, instead of the compound obtained in the
Manufacturing Example 64.
Example 422
Ethyl
1-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno-[2,3-c]pyr-
azol-5-yl)carbonyl]amino}cyclohexyl)-4-piperidine-carboxylate
[1027] The title compound 10.10 g (58%) was obtained in the Example
421, as by-product.
Example 423
N-{trans-4-[4-(Hydroxymethyl)-1-piperidinyl]cyclohexyl}-3-methyl-1-tetrahy-
dro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1028] The title compound 59 mg (54%) was obtained in a manner
similar to the Example 206 by use of the compound obtained in the
Example 421, instead of the compound obtained in the Example
204.
Example 424
N-{cis-4-[4-(Hydroxymethyl)-1-piperidinyl]cyclohexyl}-3-methyl-1-tetrahydr-
o-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1029] The title compound 61 mg (55%) was obtained in a manner
similar to the Example 206 by use of the compound obtained in the
Example 422, instead of the compound obtained in the Example
204.
Example 425
N-[trans-4-(4-Hydroxy-1-piperidinyl)cyclohexyl]-3-methyl-1-tetra-hydro-2H--
pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1030] The title compound 76 mg (42%) was obtained in a manner
similar to the Example 402 by use of 4-hydroxypiperidine, instead
of cis-2,6-di-methylmorpholine.
Example 426
N-(cis-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methyl-1-
-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1031] A mixture solution of 400 mg (0.795 mmol) of the compound
obtained in the Example 422 in 8 mL of 6M-HCl aqueous solution was
refluxed for 2.5 hours. After cooling the reaction mixture, the
solvent was removed under reduced pressure to give
1-(cis-4-{[(3-methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazol-5-
-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylic acid HCl salt
as intermediate compound.
[1032] Then, to a suspension of the intermediate compound obtained
above in dichloromethane were added 0.60 mL (1.2 mmol) of
2M-dimethylamine/tetrahydrofuran, 229 mg (1.19 mmol) of
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide HCl salt, 746 .mu.L
(5.35 mmol) of triethylamine and 182 mg (1.19 mmol) of
1-hydroxybenzotriazole, and the mixture was stirred for 95 hours at
room temperature. The saturated sodium bicarbonate aqueous solution
was added to the reaction mixture, and the mixture was extracted
with dichloromethane. The organic layer was washed water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by alkaline silica gel column chromatography
(eluent:ethyl acetate) to give 196 mg (49%) of the title
compound.
Example 427
1-(trans-4-{[(3-Methyl-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]-pyrazol-
-5-yl)carbonyl]amino}cyclohexyl)-4-piperidinecarboxylic Acid HCl
Salt
[1033] A mixture solution of 400 mg (0.795 mmol) of the compound
obtained in the Example 421 in 6M-HCl aqueous solution was stirred
for 2 hours at 70.degree. C. The solvent was removed to give 465 mg
(quantitative) of the title compound.
Example 428
N-(trans-4-{4-[(Dimethylamino)carbonyl]-1-piperidinyl}cyclohexyl)-3-methyl-
-1-tetrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1034] The title compound 195 mg (78%) was obtained in a manner
similar to the Example 378 by use of the compound obtained in the
Example 427 and 2M-dimethylamine/tetrahydrofuran, instead of the
compound obtained in the Example 103 and 4-hydroxypiperidine,
respectively.
Example 429
N'-(Dihydro-2H-pyran-3(4H)-ilidene)benzohydrazide
[1035] To a solution of 3.48 g (34.1 mmol) of
tetrahydro-2H-pyran-3-ol in 350 mL of dichloromethane were added
11.1 g (51.2 mmol) of pyridinium chlorochromate, 3.16 g (38.5 mmol)
of sodium acetate, and 30 g of molecular sieve 4A, and the mixture
was stirred for 4 hours at room temperature. Then, the reaction
mixture was filtrated by Celite.RTM. and the filtrate was condensed
under reduced pressure. The residue was purified by silica gel
column chromatography (eluent:hexane/ethyl acetate=2/1) to give
dihydro-2H-pyran-3(4H)-one as intermediate compound.
[1036] A mixture solution of the intermediate compound obtained
above and 4.6 g (34.1 mmol) of benzoylhydrazine in 20 mL of
methanol was stirred for 4 hours at 60.degree. C. After cooling the
reaction mixture, the solvent was removed and the residue was
purified by silica gel column chromatography
(eluent:dichloromethane/methanol=30/1) to give 1.75 g (24%) of the
title compound.
Example 430
N'-Tetrahydro-2H-pyran-3-ylbenzohydrazide
[1037] To a solution of 1.64 g (7.51 mmol) of the compound obtained
in the Example 429 in methanol was added 257 mg (6.76 mmol) of
sodium borohydride at 0.degree. C., and the mixture was stirred for
3 hours at the same temperature. The solvent was removed and the
residue was treated with water and the mixture was extracted with
dichloromethane. The organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed and the residue was purified by
silica gel column chromatography
(eluent:dichloromethane/methanol=30/1) to give 1.46 g (88%) of the
title compound.
Example 431
5-Methyl-2-tetrahydro-2H-pyran-3-yl-2,4-dihydro-3H-pyrazol-3-one
[1038] To a solution of 1.44 g (6.53 mmol) of the compound obtained
in the Example 430 in 10 mL of water was added 20 mL of conc. HCl,
and the mixture was stirred for 24 hours at 100.degree. C. After
cooling the reaction mixture, the insoluble substances were removed
off by filtration, and the filtrate was condensed to give
1-(tetrahydro-2H-pyran-3-yl)hydrazine HCl salt as intermediate
compound.
[1039] A mixture of the intermediate compound obtained above and
705 .mu.L (6.53 mmol) of methyl acetoacetate was stirred for 2
hours at 110.degree. C. The reaction mixture was cooled and diluted
with water and ethyl acetate, then, neutralized by 1M-NaOH aqueous
solution. The solvent was removed and the residue was purified by
silica gel column chromatography
(eluent:dichloromethane/methanol=20/1) to give 793 mg (67%) of the
title compound.
Example 432
5-Chloro-3-methyl-1-tetrahydro-2H-pyran-3-yl-1H-pyrazole-4-carboaldehyde
[1040] The title compound 452 mg (47%) was obtained in a manner
similar to the Example 193 by use of the compound obtained in the
Example 431, instead of the compound obtained in the Example
192.
Example 433
Ethyl
3-methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carbo-
xylate
[1041] To a solution of 259 .mu.L (2.36 mmol) of ethyl
thioglycolate in 4 mL of tetrahydrofuran was added 94 mg (2.36
mmol) of sodium borohydride (60% oily) at 0.degree. C., and the
mixture was stirred for 30 minutes at room temperature. Then, the
reaction mixture was cooled to 0.degree. C. and 415 mg (1.81 mmol)
of the compound obtained in the Example 432 in 4 mL of
tetrahydrofuran was added gradually to this mixture, and the
mixture was stirred for 2 hours at room temperature. Then, the
reaction mixture was cooled to 0.degree. C. and 94 mg (2.36 mmol)
of sodium borohydride (60% oily) was added to this mixture, and the
mixture was stirred for 30 minutes at room temperature. The
reaction mixture was treated with ice water and extracted with
ethyl acetate. The organic layer was washed with water and
saturated saline solution, then, dried over with anhydrous sodium
sulfate. The solvent was removed under reduced pressure and the
residue was purified by silica gel column chromatography
(eluent:hexane/ethyl aceteta=3/1) to give 413 mg (78%) of the title
compound.
Example 434
3-Methyl-1-tetrahydro-2H-pyran-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic
Acid
[1042] The title compound 320 mg (89%) was obtained in a manner
similar to the Example 6 by use of the compound obtained in the
Example 433, instead of the compound obtained in the Example 5.
Example 435
3-Methyl-N-[trans-4-(4-morpholinyl)cyclohexyl]-1-tetrahydro-2H-pyran-3-yl--
1H-thieno[2,3-c]pyrazole-5-carboxamide
[1043] The title compound 185 mg (95%) was obtained in a manner
similar to the Example 369 by use of the compound obtained in the
Example 434, instead of the compound obtained in the Example
195.
Example 436
N-[trans-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetrahydro--
2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1044] The title compound 140 mg (71%) was obtained in a manner
similar to the Example 419 by use of 1-ethyl-2-piperazinone HCl
salt, instead of 1-methyl-2-piperazinone HCl salt.
Example 437
N-[cis-4-(4-Ethyl-3-oxo-1-piperazinyl)cyclohexyl]-3-methyl-1-tetra-hydro-2-
H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1045] The title compound 41 mg (21%) was obtained in the Example
436, as by-product.
Example 438
N-{trans-4-[(4-Ethyl-3-oxo-1-piperazinyl)methyl]cyclohexyl}-3-methyl-1-tet-
rahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1046] To a solution of 150 mg (0.282 mmol) of the compound
obtained in the Example 357 in 3 mL of N,N-dimethylformamide were
added 93 mg (0.564 mmol) of 1-ethyl-2-piperazinone HCl salt, and
236 .mu.L (1.7 mmol) of triethylamine, and the mixture was stirred
for 5 hours at 100.degree. C. Then, 43 mg (0.282 mmol) of sodium
iodide was added to the reaction mixture and the mixture was
stirred for 40 hours at 100.degree. C. Further, 100 mg (0.61 mmol)
of 1-ethyl-2-piperazinone HCl salt and 50 mg (0.33 mmol) of sodium
iodide were added to the reaction mixture, and the mixture was
stirred for 15 minutes at 120.degree. C. using microwave. After the
reaction, water was added to the reaction mixture and the mixture
was extracted with dichloromethane. The organic layer was washed
with water and saturated saline solution, then, dried over with
anhydrous sodium sulfate. The solvent was removed under reduced
pressure and the residue was purified by silica gel column
chromatography (eluent:dichloromethane/methanol=20/1 to 15/1), and
further alkaline silica gel column chromatography (eluent:ethyl
acetate) to give 63 mg (46%) of the title compound.
Example 439
3-Methyl-N-{trans-4-[(4-methyl-3-oxo-1-piperazinyl)methyl]-cyclohexyl}-1-t-
etrahydro-2H-pyran-4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1047] The title compound 24 mg (18%) was obtained in a manner
similar to the Example 438 by use of 1-methyl-2-piperazinone HCl
salt, instead of 1-ethyl-2-piperazinone HCl salt.
Example 440
3-Methyl-N-[4-(4-methyl-2-oxo-1-piperazinyl)phenyl]-1-tetrahydro-2H-pyran--
4-yl-1H-thieno[2,3-c]pyrazole-5-carboxamide
[1048] The free base of the title compound was obtained in a manner
similar to the Example 7 by use of the compound obtained in the
Manufacturing Example 72 and the compound obtained in the Example
195, instead of benzylamine and the compound obtained in the
Example 6, respectively. Then, 30.7 .mu.L (0.473 mmol) of
methanesulfonic acid was added to a solution of the free base of
the compound obtained above in 2.5 mL of isopropanol, and the
mixture was refluxed. The reaction mixture was cooled to room
temperature and the resultant precipitates were collected to give
206 mg (83%) of the title compound.
[1049] Chemical structure and physicochemical data of the compounds
obtained by the above-mentioned Manufacturing Examples and Examples
are summarized in the following Tables.
TABLE-US-00005 TABLE 5 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 1 ##STR00010## pale yellow cryst. 98-100
CDCl.sub.31.58(9H, s), 3.17(2H, t, J = 8.8 Hz), 4.09(2H, t, J = 8.8
Hz), 7.76-7.82(1H, m), 8.00-8.02(1H, m), 8.10(1H, m) 265 2
##STR00011## brown oil CDCl.sub.3 1.53(9H, s), 3.00(2H, t, J = 8.6
Hz), 3.45(2H, brs), 3.88-3.98(2H, m), 6.45-6.56(2H, m),
7.58-7.65(1H, m) 234 3 ##STR00012## colorless cryst. 134-138
CDCl.sub.3 1.57(9H, s), 2.15(3H, s), 3.08(2H, t, J = 8.7 Hz),
3.91-4.05(2H, m), 6.90-7.11(2H, m), 7.50-7.71(1H, m) 277 4
##STR00013## pale pink cryst. 195-210 DMSO 2.06(3H, s), 3.18(2H, t,
J = 7.8 Hz), 3.70(2H, t, J = 7.8 Hz), 7.35-7.38(1H, m),
7.50-7.53(1H, m), 7.76- 7.78(1H, m), 10.24(1H, brs), 11.18(2H, brs)
177
TABLE-US-00006 TABLE 6 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 5 ##STR00014## colorless cryst. 247-249
DMSO 1.13(6H, d, J = 6.6 Hz), 3.99-4.09(1H, m), 6.38- 6.41 (3H, m),
7.79(1H, dd, J = 2.3 and 8.6 Hz), 7.84(1H, d, J = 7.6 Hz), 8.43(1H,
d, J = 2.3 Hz) 180 6 ##STR00015## pale yellow 190-192 CDCl.sub.3
2.99(3H, s), 3.26(2H, t, J = 8.6 Hz), 4.13(2H. t, J = 8.6 Hz),
7.47(1H, d, J = 8.9 Hz), 8.07-8.09(1H, m), 8.13-8.16(1H, m) 243 7
##STR00016## yellow crys. 117-118 CDCl.sub.3 2.79(3H, s), 3.05(2H,
t, J = 8.3 Hz), 3.57(2H, brs), 3.94(2H, t, J = 8.3 Hz), 6.53(1H,
dd, J = 2.2 and 8.4 Hz), 6.58-6.60(1H, m), 7.21(1H, d, J = 8.4 Hz)
212 8 ##STR00017## pale yellow cryst. 146-148 CDCl.sub.3 2.22(1H,
t, J = 5.3 Hz), 2.56(2H. t, J = 5.3 Hz), 2.59-2.63(4H, m),
3.08-3.13 (4H, m), 2.56-2.61(2H. m), 7.94-7.97(2H, m),
8.39-8.42(2H, m) 316
TABLE-US-00007 TABLE 7 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 9 ##STR00018## pale yellow cryst. 114-116
CDCl.sub.3 2.02(3H, s), 2.55-2.69 (6H, m), 3.04-3.15(4H, m),
4.13(2H, t, J = 5.7 Hz), 7.94(2H, dd, J = 1.8 and 7.0 Hz), 8.39(2H,
dd, J = 1.8 and 7.0 Hz) 358 10 ##STR00019## colorless cryst.
109-112 CDCl.sub.3 2.03(3H, s), 2.53-2.68 (6H, m), 2.94-3.07(4H,
m), 4.07-4.19(4H, m), 6.67-6.70(2H, m), 7.51-7.54(2H, m) 328 11
##STR00020## colorless cryst. 210(dec.) CDCl.sub.3 1.12-1.28(4H,
m), .44(9H, s), 1.92-2.05(4H, m), 1.95(3H, s), 3.33-3.45 (1H, m),
3.68-3.78(1H, m), 4.32-4.42(1H, m), 5.21-5.29(1H, m) 257 12
##STR00021## colorless cryst. 230(dec.) MeOH 1.26-1.55(4H, m),
1.91(3H, s), 1.94-2.11 (4H, m), 3.01-3.12(1H, m), 3.55-3.67(1H, m),
7.99(1H, d, J = 6.8 Hz) 157
TABLE-US-00008 TABLE 8 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 13 ##STR00022## yellow solid 107-110
CDCl.sub.3 3.53(3H, s), 4.06(2H, m), 7.77(2H, d, J = 9.1 Hz),
8.22(2H, d, J = 9.1 Hz), 8.56(1H, brs) 211 14 ##STR00023## brown
solid 82-83 CDCl.sub.3 3.49(3H, s), 3.61(2H, brs), 3.99(2H, s),
6.66(2H, d, J = 8.6 Hz), 7.33(2H, d, J = 8.6 Hz), 8.06(1H, brs) 181
15 ##STR00024## brown solid 73-78 CDCl.sub.3 2.34(3H, s),
2.51-2.56(4H, m), 3.29(2H, brs), 3.38-3.43(4H, m), 6.57(1H, d, J =
8.8 Hz), 6.98(1H, dd, J = 3.0 and 8.8 Hz), 7.79(1H, d, J = 3.0 Hz)
193 16 ##STR00025## pale yellow solid 104-105 CDCl.sub.3 2.28(3H,
s), 2.48-2.53(4H, m), 3.08-3.13(4H, m), 7.73-7.80(1H, m),
8.07-8.12(1H, m), 8.44-8.49(1H, m), 8.60-6.62(1H, m) 286
TABLE-US-00009 TABLE 9 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 17 ##STR00026## colorless solid 141-142
CDCl.sub.3 2.27(3H, s), 2.45-2.50(4H, m), 3.01-3.06(4H, m),
3.89(2H, brs), 6.82-6.87(1H, m), 7.00-7.03(1H, m), 7.08-7.12(1H,
m), 7.24-7.27(1H, m) 256 18 ##STR00027## yellow solid 49-50
CDCl.sub.3 3.13(3H, s), 3.58-3.64(2H, m), 3.87-3.93(2H, m),
6.80-6.86(1H, m), 7.89(1H, dd, J = 1.5 and 14.3 Hz), 7.95-8.00(1H,
m) 215 19 ##STR00028## brown oil CDCl.sub.3 2.73(3H, s),
3.06-3.11(2H, m), 3.59(2H, brs), 3.88-3.93(2H, m), 6.37-6.454(2H,
m), 6.88-6.95(1H, m) 185 20 ##STR00029## yellow oil CDCl.sub.3
1.47(9H, s), 1.57-1.70(2H, m), 1.78-1.90(2H, m), 2.70-2.86(3H, m),
4.20-4.32(2H, m), 7.34(2H, d, J = 8.7 Hz), 8.15(2H, d, J = 8.7 Hz)
307
TABLE-US-00010 TABLE 10 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 21 ##STR00030## pale yellow solid 109-112
CDCl.sub.3 1.46(9H, s), 1.51-1.61(2H, m), 1.72-1.79(2H, m),
2.47-2.57(1H, m), 2.70-2.81 (2H, m), 3.56(2H, brs), 4.14-4.26(1H,
m), 6.63(2H, d, J = 8.4 Hz), 6.97(2H, d, J = 8.3 Hz) 277 22
##STR00031## yellow solid 64-65 CDCl.sub.3 1.12 (3H, t, J = 7.2
Hz), 2.47(2H, q, J = 7.2 Hz), 2.58-2.63(4H, m), 3.29-3.34(4H, m),
6.89(1H, dd, J = 8.8 and 8.8 Hz), 7.88(1H, dd, J = 2.6 and 13.2
Hz), 7.95- 8.00(1H, m) 254 23 ##STR00032## yellow solid 49-50
CDCl.sub.3 2.00-2.07(2H, m), 2.39(3H, s), 2.58-2.63(2H, m),
2.73-2.79(2H, m), 3.54-3.60(2H, m), 3.61-3.66(2H, m), 6.68-6.74(1H,
m), 7.83-7.94(2H, m) 254 24 ##STR00033## pale yellow solid 58-60
CDCl.sub.3 1.11 (3H, t, J = 7.2 Hz), 2.46(2H, q, J = 7.2 Hz),
2.57-2.64(4H, m), 2.97-3.03(4H, m), 3.51(2H, brs), 6.35-6.45(2H,
m), 7.77-7.84(1H, m) 224
TABLE-US-00011 TABLE 11 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 25 ##STR00034## pale yellow solid 71-71.5
CDCl.sub.3 2.36(3H, s), 2.57-2.64(4H, m), 3.30-3.38(4H, m),
6.88-6.94(1H, m), 7.90(1H, dd, J = 2.5 and 13.2 Hz), 7.98(1H, dd, J
= 2.5 and 9.0 Hz) 240 26 ##STR00035## pale reddish brown solid
93-94.5 CDCl.sub.3 2.34(3H, s), 2.51-2.69(4H, m), 2.96-3.09(4H, m),
3.53(2H, brs), 6.37-6.48(2H, m), 6.78-6.87(1H, m) 210 27
##STR00036## pale yellow solid 129-131 (AcOEt/hexane) CDCl.sub.3
1.84-1.92(4H, m), 3.38-3.47(4H, m), 4.01(4H, s), 6.89-6.97(1H, m),
7.90(1H, dd, J = 2.6 and 13.1 Hz), 7.97(1H, dd, J = 2.6 and 8.8 Hz)
284 28 ##STR00037## colorless solid 100.5-101.5 (EtOH) CDCl.sub.3
1.83-1.92(4H, m), 3.01-3.09(4H, m), 3.53(2H, brs), 3.99(4H, s),
6.37-6.47(2H, m), 6.79-6.88(1H, m) 253
TABLE-US-00012 TABLE 12 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 29 ##STR00038## yellow solid 121-122
(AcOEt/hexane) CDCl.sub.3 1.89-1.98(4H, m), 3.27-3.34(4H, m),
4.02(4H, s), 7.05(1H, d, J = 8.9 Hz), 8.08(1H, dd, J = 2.7 and 8.9
Hz), 8.25(1H, d, J = 2.7 Hz) 299 30 ##STR00039## pale yellow solid
139.5-140.5 CDCl.sub.3 1.83-1.92(4H, m), 2.97-3.04(4H, m), 3.52(2H,
brs), 4.00(4H, s), 6.54(1H, dd, J = 2.6 and 8.5 Hz), 6.74(1H, d, J
= 2.6 Hz), 6.91(1H, d, J = 8.5 Hz) 269 31 ##STR00040## reddish
brown solid 40-42 CDCl.sub.3 1.90-1.97(2H, m), 2.39(3H, s),
2.65-2.75(4H, m), 3.23-3.30(4H, m), 3.43(2H, brs), 6.32-6.42(2H,
m), 6.72-6.78(1H, m) 224 32 ##STR00041## pale brown solid
CDCl.sub.3 2.46-2.56(6H, m), 2.66-2.73(2H, m), 3.58(2H, brs),
3.70-3.76(4H, m), 6.59-6.65(2H, m), 6.96- 7.02(2H, m) 207
TABLE-US-00013 TABLE 13 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 33 ##STR00042## pale yellow viscous solid
CDCl.sub.3 3.02(3H, s), 3.92(2H, s), 4.74(2H, s), 7.54- 7.59(2H,
m), 8.15-8.20(2H, m) 250 34 ##STR00043## pale yellow viscous solid
CDCl.sub.3 2.96(3H, s), 3.65(2H, brs), 3.82(2H, s), 4.53(2H, s),
6.57-6.62(2H, m), 7.22-7.27(2H, m) 220 35 ##STR00044## pale yellow
solid CDCl.sub.3 1.10-1.22(2H, m), 1.44(9H, s), 1.61-1.73(2H, m),
2.04-2.15(4H, m), 2.36-2.45(1H, m), 3.46(1H, br), 4.38(1H, br) 225
36 ##STR00045## colorless solid DMSO-d.sub.6 1.27-1.40(2H, m),
1.51-1.65(2H, m), 1.90- 1.98(2H, m), 2.03-2.11(2H, m), 2.67(1H, tt,
J = 3.7 and 11.7 Hz), 2.94-3.07(1H, m), 8.06(3H, br) 125
TABLE-US-00014 TABLE 14 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 37 ##STR00046## colorless solid D.sub.2O
3.06(3H, brs), 3.25-3.32(2H, m), 3.67-3.99(6H, m) 172 38
##STR00047## colorless solid CDCl.sub.3 1.29-1.40(2H, m), 1.45(9H,
s), 1.89-1.96(2H, m), 2.88(6H, s), 2.82-2.88(2H, m), 3.57-3.65(3H,
m), 4.43(1H, br) 272 39 ##STR00048## colorless foamy solid
DMSO-d.sub.6 1.39-1.51 (2H, m), 1.83-1.92(2H, m), 2.50(3H, s),
2.68-2.78(2H, m), 2.72(3H, s), 3.08- 3.21(1H, m), 3.51-3.59(2H, m)
172 40 ##STR00049## colorless solid CDCl.sub.3 1.39-1.49(2H, m),
1.44(9H, s), 1.93-2.02(2H, m), 2.81(6H, s), 2.88-2.89(2H, m),
3.50-3.68(3H, m), 4.46(1H, br) 308
TABLE-US-00015 TABLE 15 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 41 ##STR00050## colorless solid
DMSO-d.sub.6 1.45-1.56(2H, m), 1.88-1.96(2H, m), 2.74(6H, s),
2.86-2.96(2H, m), 3.11-3.21(1H, m), 3.56- 3.62)2H, m), 8.02(3H, br)
208 42 ##STR00051## colorless solid CDCl.sub.3 1.43(9H, s),
1.80-1.87(1H, m), 2.41(1H, ddd, J = 7.2, 9.4 and 14.7 Hz),
2.92-2.99(1H, m), 3.12(1H, dd, J = 5.7 and 11.0 Hz), 3.76(3H, s),
3.82(1H, dd, J = 4.8 and 9.4 Hz), 4.12(1H, br), 4.92(1H, br) 245 43
##STR00052## colorless solid CDCl.sub.3 1.44(9H, s), 1.97-2.06(1H,
m), 2.47(1H, ddd, J = 6.5, 9.5 and 13.9 Hz), 3.33-3.39(1H, m),
3.70(1H, dd, J = 6.0 and 9.9 Hz), 3.79(3H, s), 4.36-4.46(1H, m),
4.43(1H, dd, J = 2.7 and 9.5 Hz), 4.60(2H, brs). 5.52- 5.58(1H, m)
288 44 ##STR00053## colorless solid CDCl.sub.3 1.45(9H, s),
1.80-2.65(2H, br), 3.25-4.80(5H, br) 256
TABLE-US-00016 TABLE 16 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 45 ##STR00054## colorless solid D.sub.2O
1.94-2.04(1H, m), 2.70-2.78(1H, m), 3.64- 3.75(2H, m), 3.76(1H, s),
4.25-4.34(1H, m), 4.51(1H, dd, J = 7.3 and 10.5 Hz) 156 46
##STR00055## pale reddish brown solid CDCl.sub.3 3.42-3.58(4H, m),
4.07-4.14(2H, m), 4.58(1H, br), 7.06(1H, dd, J = 2.9 and 8.9 Hz),
7.79(1H, dd, J = 0.7 and 2.9 Hz), 8.04(1H, dd, J = 0.7 and 8.9 Hz)
179 47 ##STR00056## pale brown solid DMSO-d.sub.6 3.99(2H, s),
5.24(2H, brs), 6.57(2H, dd, J = 2.0 and 6.6 Hz), 6.89(1H, dd, J =
2.0 and 6.6 Hz), 8.10(1H, brs) 192 48 ##STR00057## pale brown solid
DMSO-d.sub.6 2.89(3H, s), 4.04(2H, s), 5.27(2H, brs), 6.55-6.60(2H,
m), 6.86-6.91(2H, m) 206
TABLE-US-00017 TABLE 17 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 49 ##STR00058## reddish brown solid
CDCl.sub.3 1.98-2.06(1H, m), 2.13-2.24(1H, m), 3.18- 3.50(6H, m),
4.52-4.58(1H, m), 6.45-6.51(1H, m), 6.64-6.70(1H, m) 179 50
##STR00059## brown solid (EtOH) DMSO-d.sub.6 1.86-2.05(2H, m),
3.38-3.45(1H, m), 3.55- 3.74(3H, m), 4.36-4.42(1H, m), 5.05(1H, d,
J = 3.5 Hz), 6.74-6.80(1H, m), 7.89-7.97(2H, m) 227 51 ##STR00060##
purple oil CDCl.sub.3 1.90-1.99(1H, m), 2.14-2.25(1H, m), 3.06-
3.27(2H, m), 3.35-3.56(2H, m), 4.47-4.52(1H, m), 6.36-6.48(2H, m),
6.57-6.64(1H, m) 197 52 ##STR00061## pale brown solid DMSO-d.sub.6
1.38-1.48(2H, m), 1.70-1.78(2H, m), 2.78- 2.85(2H, m),
3.19-3.26(2H, m), 3.50-3.58(1H, m), 4.69(1H, d, J = 4.0 Hz),
7.93-7.99(1H, m), 8.17-8.21(1H, m), 8.36-8.38(1H, m), 8.54-8.58(1H,
m) 287
TABLE-US-00018 TABLE 18 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 53 ##STR00062## colorless solid
DMSO-d.sub.6 1.39-1.48(2H, m), 1.69-1.77(2H, m), 2.65- 2.73(2H, m),
3.06-3.15 (2H, m), 3.50-3.58(1H, m), 4.65(1H, d, J = 3.8 Hz), 5.61
(2H, brs), 6.76-6.84(2H, m), 6.89-6.92(1H, m), 7.20-7.26(1H, m) 257
54 ##STR00063## colorless solid DMSO-d.sub.6 1.38-1.48(2H, m),
1.71-1.79(2H, m), 2.81- 2.88(2H, m), 3.18-3.26 (2H, m),
3.52-3.59(1H, m), 4.68(1H, d, J = 4.0 Hz), 8.00-8.05 (2H, m),
8.42-8.47(2H, m) 287 55 ##STR00064## colorless solid CDCl.sub.3
-0.01(6H, s), 0.77 (9H, s), 1.59-1.68(2H, m), 1.77-1.87(2H, m),
3.07-3.15 (2H, m), 3.17-3.24(2H, m), 3.82-3.89(1H, m), 7.93-7.98
(2H, m), 8.37-8.42(2H, m) 401 56 ##STR00065## colorless solid
CDCl.sub.3 -0.01(6H, s), 0.80 (9H, s), 1.56-1.65(2H, m),
1.75-1.84(2H, m), 2.89-2.96 (2H, m), 3.12-3.19(2H, m),
3.72-3.78(1H, m), 4.10 (2H, br), 6.68-6.73(2H, m), 7.52-7.57(2H, m)
371
TABLE-US-00019 TABLE 19 Properties Manufacturing m.p. (.degree. C.)
MS(FAB) Exmple No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 57 ##STR00066## yellow solid 56.5-57.5
CDCl.sub.3 2.36(3H, s), 2.52-2.64(4H, m), 3.11-3.22(4H, m),
7.27(1H, d, J = 9.1 Hz), 8.31 (1H, dd, J = 2.6 and 9.1 Hz),
8.50(1H, d, J = 2.6 Hz) 290 58 ##STR00067## reddish brown solid
123-125 CDCl.sub.3 2.32(3H, s), 2.40-2.60(4H, m), 2.80-2.89(4H, m),
3.69(2H, brs), 6.78(1H, dd, J = 2.7 and 8.5 Hz), 6.89(1H, d, J =
2.7 Hz), 7.19(1H, d, J = 8.5 Hz) 260 59 ##STR00068## colorless
solid 154-156.5 CDCl.sub.3 2.66(3H, s), 3.28(2H, t, J = 6.5 Hz),
3.35- 3.42(2H, m), 3.51(2H, t, J = 6.5 Hz), 3.88-3.95(2H, m),
7.69-7.76(2H, m), 7.82-7.89(2H, m) 310 60 ##STR00069## colorless
solid 142-145 (EtOH) DMSO-d.sub.6 2.63(3H, s), 2.98-3.03(2H, m),
3.17- 3.43(6H, m), 8.02(3H, brs) 180(free)
TABLE-US-00020 TABLE 20 properties Manufacturing m.p. (.degree. C,)
MS(FAB) Example No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 61 ##STR00070## yellow solid 53-57
CDCl.sub.3 1.69-1.79(2H, m), 2.01-2.09(2H, m), 3.05- 3.15(2H, m),
3.55-3.64(2H, m), 3.91-4.00(1H, m), 6.89- 6.96(1H, m),
7.87-8.04(2H, m) 241 62 ##STR00071## pale reddish brown solid
112-116 CDCl.sub.3 1.58(1H, br), 1.71-1.81(2H. m), 1.98-2.06(2H,
m), 2.71-2.81(2H, m), 3.17-3.25(2H, m), 3.53(2H, br), 3.77-3.86(1H,
m), 6.37-6.47(2H, m), 6.79-6.86(1H, m) 211 63 ##STR00072## pale
yellow solid 147-149 CDCl.sub.3 1.05-1.16(2H, m), 1.24-1.40(2H, m),
1.43(9H, s), 1.88-1.97(2H, m), 2.02-2.10(2H, m), 2.16(1H. tt, J =
3.5 and 11.4 Hz), 2.50-2.56(4H, m), 3.37(1H, br), 3.67-3.72(4H, m),
4.36(1H, br) 285 64 ##STR00073## colorless solid >250
DMSO-d.sub.6 1.32-1.48(2H, m), 1.51-1.66(2H, m), 2.03- 2.12(2H, m),
2.17-2.26(2H, m), 2.90-3.20(4H, m). 3.33- 3.41(2H, m),
3.82-3.99(4H, m), 8.10-8.28(3H, m), 11.17-11.46(1H, m) 185
TABLE-US-00021 TABLE 21 properties Manufacturing m.p. (.degree. C.)
MS(FAB) Example No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 65 ##STR00074## pale brown solid 195-199
DMSO-d.sub.6 3.32-3.37(2H, m), 3.62-3.67(2H, m), 3.98(2H, s),
6.96-7.02(2H, m), 8.06-8.12(2H, m). 8.26(1H, brs) 222 66
##STR00075## pale brown solid CDCl.sub.3 3.28-3.33(2H, m),
3.45-3.51(2H, m), 3.74(2H, s), 6.00(1H, brs), 6.65-6.71 (2H, m),
6.77-6.83(2H, m). 192 67 ##STR00076## pale purple solid 151-154
CDCl.sub.3 2.71(6H, s), 3.91(2H, br), 6.84-6.88(1H, m),
7.05-7.07(1H, m), 7.11-7.16(1H, m), 7.28-7.33(1H, m) 201 68
##STR00077## colorless solid 87-88 CDCl.sub.3 -0.08(6H, s),
0.72(9H, s), 3.43(2H, t, J = 5.6 Hz), 4.07(2H, t, J = 5.6 Hz),
7.74-7.80(1H, m), 8.24-8.28(1H, m), 8.47-8.52(1H, m), 8.77-8.79(1H,
m) 346
TABLE-US-00022 TABLE 22 properties Manufacturing m.p. (.degree. C.)
MS(FAB) Example No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 69 ##STR00078## colorless viscous solid
CDCl.sub.3 -0.01(6H, s), 0.81(9H, s), 3.33(2H, t, J = 6.6 Hz),
3.94(2H. br), 3.98(2H, t, J = 6.6 Hz), 6.85-6.91(1H, m),
7.15-7.17(1H, m), 7.22-7.32(2H, m) 316 70 ##STR00079## pale yellow
solid CDCl.sub.3 1.77(1H, brs), 2.48(3H, s), 2.70(2H, t, J = 5.0
Hz), 3.27(2H, s), 3.80 (2H, brs), 7.78-7.84(2H, m), 8.28-8.34(2H,
m), 9.97(1H, brs) 254 71 ##STR00080## pale yellow solid 100-101
CDCl.sub.3 2.42(3H, s), 2.83(2H, t, J = 5.3 Hz), 3.32(2H, s),
3.79(2H, t, J = 5.3 Hz), 7.53-7.59(2H, m), 8.24-8.30(2H, m) 236 72
##STR00081## colorless solid 156-160 CDCl.sub.3 2.39(3H, s),
2.74-2.79 (2H, m), 3.25(2H, s), 3.61-3.74(4H, m), 6.66-6.73 (2H,
m), 7.00-7.07(2H, m) 206
TABLE-US-00023 TABLE 23 properties Manufacturing m.p. (.degree. C.)
MS(FAB) Example No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 73 ##STR00082## yellow solid 149-151
CDCl.sub.3 1.56-1.70(2H, m), 1.93-2.06(2H, m), 3.44- 3.58(2H, m),
4.00-4.09(1H, m), 4.11-4.22(2H, m), 6.60(1H, d, J = 9.6 Hz),
8.19(1H, dd, J = 2.8 and 9.6 Hz), 9.03(1H, d, J = 2.8 Hz) 224 74
##STR00083## reddish brown solid 140-140 CD.sub.3OD 1.50-1.61(2H,
m), 1.88-1.96(2H, m), 2.88- 2.97(2H, m), 3.70-3.81(3H, m), 6.73(1H,
d, J = 8.8 Hz), 7.10(1H, dd, J = 2.7 and 8.8 Hz), 7.70(1H, d, J =
2.7 Hz) 194 75 ##STR00084## yellow solid 90.5-91.5 CDCl.sub.3
1.66-1.80(2H, m), 1.97-2.11(2H, m), 3.09- 3.23(2H, m),
3.53-3.71(2H, m), 3.91-4.06(1H, m), 6.61- 6.72(1H, m),
7.79-7.90(1H, m) 259 76 ##STR00085## pale yellow solid 148-150
CD.sub.3OD 1.62-1.73(2H, m), 1.90-2.00(2H, m), 2.69- 2.79(2H, m),
3.12-3.21(2H, m), 3.65-3.74(1H, m), 6.52(1H, dt, J = 2.2 and 8.9
Hz), 6.65(1H, dt, J = 2.2 and 8.8 Hz) 229
TABLE-US-00024 TABLE 24 properties Manufacturing m.p. (.degree. C.)
MS(FAB) Example No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 81 ##STR00086## pale yellow oil
CDCl.sub.3 1.69-1.80(2H, m), 1.99-2.10(2H, m), 3.08- 3.19(2H, m),
3.45-3.56 (2H, m), 3.93(3H, s), 3.94- 4.004(1H, m), 6.98(1H, d, J =
9.3 Hz), 8.19(1H, dd, J = 2.8 and 9.3 Hz), 8.60(1H, d, J = 2.8 Hz)
281 82 ##STR00087## pale yellow solid 123-124.5 CDCl.sub.3
1.47-1.53(1H, m), 1.67-1.78(2H, m), 1.95- 2.02(2H, m),
2.70-2.79(2H, m), 3.10-3.19(2H, m), 3.50- 3.63(2H, m),
3.74-3.83(1H, m), 3.88(3H, s), 6.75(1H, dd, J = 2.9 and 8.6 Hz),
6.91-6.98 (1H, m), 7.03(1H, d, J = 2.9 Hz) 251 83 ##STR00088##
colorless solid 142-145 (EtOH) CDCl.sub.3 1.33-1.49(2H, m),
1.44(9H, s), 1.52-1.63(2H, m), 1.70-1.79(2H, m), 1.90-1.99 (2H, m),
2.19-2.28(2H, m), 2.44(1H, tt, J = 3.8 and 11.4 Hz), 2.83-2.92(2H,
m), 3.36(2H, dt, J = 1.9 and 11.9 Hz), 3.41-3.50(1H, m),
3.99-4.05(2H, m), 4.39-4.48(1H, m) 285 84 ##STR00089## colorless
solid DMSO-d.sub.6 1.67-1.80(2H, m), 1.95-2.20(6H, m), 2.93-
3.09(2H, m), 3.23-3.39(4H, m), 3.45-3.57(2H, m), 3.90- 4.02(2H, m),
8.40-8.68 (3H, m), 10.95-11.22(1H, m) 185(free)
TABLE-US-00025 TABLE 25 properties Manufacturing m.p. (.degree. C.)
MS(FAB) Example No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 81 ##STR00090## pale yellow oil
CDCl.sub.3 1.69-1.80(2H, m), 1.99-2.10(2H, m), 3.08- 3.19(2H, m),
3.45-3.56 (2H, m), 3.93(3H, s), 3.94- 4.004(1H, m), 6.98(1H, d, J =
9.3 Hz), 8.19(1H, dd, J = 2.8 and 9.3 Hz), 8.60(1H, d, J = 2.8 Hz)
281 82 ##STR00091## pale yellow solid 123-124.5 CDCl.sub.3
1.47-1.53(1H, m), 1.67-1.78(2H, m), 1.95- 2.02(2H, m),
2.70-2.79(2H, m), 3.10-3.19(2H, m), 3.50- 3.63(2H, m), 3.74-3.83
(1H, m), 3.88(3H, s), 6.75(1H, dd, J = 2.9 and 8.6 Hz), 6.91-
6.98(1H, m), 7.03(1H, d, J = 2.9 Hz) 251 83 ##STR00092## colorless
solid 142-145 (EtOH) CDCl.sub.3 1.33-1.49(2H, m), 1.44(9H, s),
1.52-1.63(2H, m), 1.70-1.79(2H, m), 1.90- 1.99(2H, m),
2.19-2.28(2H, m), 2.44(1H, tt, J = 3.8 and 11.4 Hz), 2.83-2.92(2H,
m), 3.36(2H, dt, J = 1.9 and 11.9 Hz), 3.41-3.50(1H, m),
3.99-4.05(2H, m), 4.39-4.48(1H, m) 265 84 ##STR00093## colorless
solid DMSO-d.sub.6 1.67-1.80(2H, m), 1.95-2.20(6H, m), 2.93-
3.09(2H, m), 3.23-3.39 (4H, m), 3.45-3.57(2H, m), 3.90- 4.02(2H,
m), 8.40-8.68 (3H, m), 10.95-11.22(1H, m) 185(free)
TABLE-US-00026 TABLE 26 Manu- facturing properties Example m.p.
(.degree. C.) MS(FAB) No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 85 ##STR00094## pale yellow oil
CDCl.sub.3 1.08-1.92(7H, m), 1.45(9H, s), 2.03-2.12(1H, m),
2.19-2.31(1H, m), 2.42-2.53(4H, m), 3.37- 3.50(4.5H, m), 3.74-3.83
(0.5H, m), 4.57-4.64(0.5H, m), 4.83-4.91 (0.5H, m), 5.05- 5.14(2H,
m), 7.29-7.41(5H, m) 418 86 ##STR00095## colorless oil CDCl.sub.3
1.05-1.78(6H, m), 1.45 and 1.46(9H, each s), 1.82-1.98(2H, m),
2.17-2.31 (1H, m), 2.43-2.68(4.5H, m), 2.98-3.04(0.5H, m),
3.37-3.47(4H, m) 284 87 ##STR00096## brown solid 145-148
DMSO-d.sub.6 4.66(2H, s), 7.60- 7.70(2H, m), 7.94(1H, d, 2.4 Hz)
125(free) 88 ##STR00097## colorless solid 215-217 (EtOH) CDCl.sub.3
1.18-1.38(4H, m), 1.44(9H, s), 1.99-2.10(4H, m), 3.39-3.51(1H, m),
3.69- 3.80(1H, m), 4.03(2H, s), 4.37-4.46(1H, m), 6.35-6.42(1H, m)
291
TABLE-US-00027 TABLE 27 Manu- properties facturing m.p. (.degree.
C.) Example (recryst. MS(FAB) No. Chemical Structure solvent)
.sup.1H-NMR (M + 1).sup.+ 89 ##STR00098## colorless solid 161-163
(iso-PrOH) CDCl.sub.3 1.17-1.37(4H, m), 1.44(9H, s), 1.92-2.13(5H,
m), 2.33(1H, s), 2.58(2H, t, J = 5.2 Hz), 3.06(2H, s), 3.35-
3.48(1H, m), 3.69(2H, t, J = 5.2 Hz), 3.71-180(1H, m),
4.38-4.48(1H, m), 7.09-7.16(1H, m) 330 90 ##STR00099## pale brown
solid 162.5-165 CDCl.sub.3 1.21-1.37(2H, m), 1.44(9H, s),
1.48-1.60(2H, m), 1.63-1.74(2H, m), 2.01- 2.10(2H, m), 2.32(3H, s),
2.59-2.65(2H, m), 3.11(2H, s), 3.20-3.27(2H, m), 3.30- 3.44(1H, m),
4.38-4.50(2H, m) 312 91 ##STR00100## colorless solid DMSO-d.sub.6
1.38-1.71(6H, m), 1.98-2.09(2H, m), 3.17(3H, s), 2.90-3.01(1H, m),
3.20-3.90(6H, m), 4.11- 4.22(1H, m), 8.09-8.28 (3H, m), 11.92(1H,
brs) 212(free) 92 ##STR00101## colorless gum CDCl.sub.3
1.06-1.97(14H, m), 2.02-2.31(5H, m), 2.81- 2.98(2H, m),
3.37-3.49(0.4H, m), 3.74-3.87(0.6H, m), 4.08-4.18(2H, m), 4.53-4.62
(0.4H, m), 4.83-4.93(0.6H, m), 5.04-5.19(2H, m), 7.28-7.43(5H, m)
389
TABLE-US-00028 TABLE 28 properties Manufacturing m.p. (.degree. C.)
MS(FAB) Example No. Chemical Structure (recryst. solvent)
.sup.1H-NMR (M + 1).sup.+ 93 ##STR00102## colorless oil CDCl.sub.3
1.05-1.19(1H, m), 1.20-1.39(4H, m), 1.50- 1.97(12H, m), 2.12-2.32
(4H, m), 2.62(0.4H, tt, J = 3.9 and 11.1 Hz), 2.74-3.00 (2H, m),
3.01-3.09(0.6H, m), 4.08-4.19(2H, m) 255 94 ##STR00103## yellow
solid 106-107 (EtOH) CDCl.sub.3 1.53-1.56(1H, m), 1.62-1.72(2H, m),
1.98- 2.06(2H, m) 3.21-3.29(2H, m), 3.76-3.84(2H, m), 3.97-
4.06(1H, m), 6.81-6.87 (2H, m), 8.10-8.16(2H, m) 223 95
##STR00104## pale purple solid 171-173 CDCl.sub.3 1.45(1H, br),
1.68-1.77 (2H, m), 1.98-2.06(2H, m), 2.74-2.83(2H, m),
3.32-3.40(2H, m), 3.42(2H, br), 3.76-3.85(1H, m), 6.63-6.68 (2H,
m), 6.81-6.86(2H, m) 193
TABLE-US-00029 TABLE 29 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 1 ##STR00105## colorless cryst. 147.6-150.4 CDCl.sub.3
1.21-1.36(1H, m), 1.39-1.52(2H, m), 1.71- 1.98(7H, m), 2.09(3H, s),
3.20(2H, s), 3.95-4.02(1H, m) 181 2 ##STR00106## pale brown oil
CDCI.sub.3 1.21-1.47(3H, m), 1.65-1.75(1H, m), 1.83- 1.95(6H, m),
2.23(3H, s), 4.10-4.20(1H, m), 5.95(1H, s) 3 ##STR00107## colorless
cryst. 86.0-87.6 CDCl.sub.3 1.21-1.50(3H, m), 1.71-1.79(1H, m),
1.90- 1.98(6H, m), 2.46(3H, s), 4.18-4.28(1H, m), 9.88(1H, s) 227 4
##STR00108## colorless oil CDCl.sub.3 1.21(3H, t, J = 7.1 Hz),
1.22-1.50(3H, m), 1.71- 2.01(7H, m), 2.48(3H, s), 3.59(2H, s),
4.12(2H, q, J = 7.1 Hz), 4.58-4.60(1H, m), 10.02(1H, s) 311
TABLE-US-00030 TABLE 30 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 5 ##STR00109## colorless oil CDCl.sub.3 1.22-1.34(1H, m),
1.38(3H, t, J = 7.1 Hz), 1.38- 1.52(2H, m), 1.70-1.88(3H, m),
1.89-1.98(2H, m), 2.15- 2.22(2H, m), 2.45(3H, s), 4.12-4.21(1H, m),
4.35(2H, q, J = 7.1 Hz), 7.70(1H, s) 293 6 ##STR00110## colorless
cryst. 231.5-235.0 CDCl.sub.3 1.22-1.37(1H, m), 1.39-1.51(2H, m),
1.72- l.89(3H, m), 1.91-1.98(2H, m), 2.16-2.24(2H, m), 2.47(3H, s),
4.16-4.25(1H, m), 7.79(1H, s) 265 7 ##STR00111## colorless cryst.
128.4-130.1 CDCl.sub.3 1.21-1.33(1H, m), 1.38-1.51(2H, m), 1.70-
1.87(3H. m), 1.89-1.95(2H, m), 2.14-2.24(2H, m), 2.42(3H, s),
4.10-4.21(1H, m), 4.63(1H, d, J = 5.7 Hz), 6.11-6.17(1H, m),
7.29-7.37(6H, m) 354 8 ##STR00112## colorless cryst. 149.0-150.0
CDCl.sub.3 1.24-1.35(1H, m), 1.40-1.52(2H, m), 1.72- 1.99(5H, m),
2.15-2.23(2H, m), 2.47(3H, s), 4.15- 4.26(1H, m), 7.12-7.16(1H, m),
7.35-7.40(2H, m), 7.47(1H, s), 7.49-7.51(3H, m) 340
TABLE-US-00031 TABLE 31 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 9 ##STR00113## colorless cryst. 221.8-224.2 CDCl.sub.3
1.25-1.53(3H, m), 1.74-1.96(5H, m), 1.89(3H, s), 2.19-2.23(2H, m),
2.47 (3H, s), 3.26(3H, s), 4.18- 4.23(1H, m), 7.17-7.20 (2H, m),
7.49(1H, s), 7.64- 7.67(3H, m) 411 10 ##STR00114## colorless cryst.
241.5-242.8 CDCl.sub.3 1.23-1.33(1H, m), 1.40-1.52(2H, m), 1.70-
1.97(5H, m), 2.17-2.23(2H, m), 2.20(3H, s), 2.46(3H, s), 3.93(3H,
s), 4.13-4.20 (1H, m), 6.73-6.76(1H, m), 7.46(1H, s), 7.59-7.61(1H,
m), 7.67-7.69(1H, m), 7.77- 7.79(1H, m), 8.30-8.34(1H, m) 427 11
##STR00115## colorless cryst. >270 CDCl.sub.3 1.23-1.33(1H, m),
1.40-1.52(2H, m), 1.71- 1.97(5H, m), 2.15-2.22(2H, m), 2.22(3H, s),
2.46(3H, s), 3.22(2H, t, J = 8.5 Hz), 4.08(2H, t, J = 8.5 Hz).
4.13- 4.21(1H, m), 7.05-7.08 (1H, m), 7.44(1H, s), 7.53- 7.55(1H,
m), 7.79(1H, brs), 8.16-8.19(1H, m) 423 12 ##STR00116## colorless
cryst. 195.9-197.9 CDCl.sub.3 1.23-1.33(1H, m), 1.31(3H, t, J = 7.1
Hz), 1.41- 1.54(2H, m), 1.71-1.95 (5H, m), 2.15-2.22(2H, m),
2.46(3H, s), 4.15-4.22(1H, m), 4.23(2H, q, J = 7.1 Hz), 6.52(1H,
brs), 7.36-7.38 (2H, m), 7.45(1H, s), 7.52- 7.55(3H, m) 427
TABLE-US-00032 TABLE 32 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 13 ##STR00117## colorless cryst/ 200.3-200.8 CDCl.sub.3
1.23-1.32(1H, m), 1.39-1.52(2H, m), 1.53(9H, s), 1.73-1.96(5H, m),
216-2.24(2H, m), 2.46(3H, s), 3.10(2H, t, J = 8.5 Hz), 3.99(2H, t,
J = 8.5 Hz), 4.15- 4.22(1H, m), 7.08-7.20(1H, m), 7.44(1H, s),
7.53(1H, brs), 7.58-7.72(1H, m) 481 14 ##STR00118## colorless
cryst. 268.3-271.2 DMSO 1.23-1.33(1H, m), 1.40-1.51 (2H, m), 1.66-
1.90(5H, m), 2.04-2.13(2H, m), 2.40(3H, s), 3.23(2H, t, J = 7.7
Hz), 3.74(2H, t, J = 7.7 Hz), 4.29-4.31(1H, m), 7.41- 7.45(1H, m),
7.69-7.72 (1H, m), 7.90-7.92(1H, m), 8.17(1H, s), 10.49-10.51 (1H,
m), 11.18(1H, brs) 381 15 ##STR00119## pale brown cryst.
234.3-235.6 CDCl.sub.3 1.23-1.32(1H, m), 1.39-1.52(2H, m), 1.72-
1.98(5H, m), 2.16-2.23 (2H, m), 2.46(3H, s), 4.13- 4.22(1H, m),
6.53-6.55(1H, m), 7.21-7.23(1H, m), 7.31- 7.38(2H, m), 7.47(1H, s),
7.67(1H, brs), 7.89-7.91(1H, m), 8.20(1H, brs) 379 16 ##STR00120##
pale yellow cryst. 216.9-218.4 CDCl.sub.3 1.23-1.32(1H, m),
1.40-1.52(2H, m), 1.71- 1.88(3H, m), 1.90-1.98 (2H, m),
2.15-2.22(2H, m), 2.46(3H, s), 3.12-3.16(4H, m), 3.85-3.88(4H, m),
4.13- 4.22(1H, m), 6.90-6.93 (2H, m), 7.43(1H, s), 7.47- 7.51(3H,
m) 424
TABLE-US-00033 TABLE 33 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 17 ##STR00121## pale yellow cryst. 193.1-194.8 CDCl.sub.3
1.23-1.35(1H, m), 1.40-1.52(2H, m), 1.72- 1.89(3H, m), 1.90-1.98
(2H, m), 2.17-2.23(2H, m), 2.48(3H, s), 4.16-4.24 (1H, m),
7.51-7.57(2H, m), 7.80(1H, brs), 8.00(1H, dd, J = 1.8 and 8.2 Hz),
8.07(1H, dd, J = 1.8 and 8.2 Hz), 8.43(1H, s) 385 18 ##STR00122##
yellow cryst. 150.0-153.8 CDCl.sub.3 1-23-1.35(1H, m),
1.39-1.55(2H, m), 1.72- 1.98(5H, m), 2.16-2.23 (2H, m), 2.46(3H,
s), 3.49(2H, brs), 4.15-4.24(1H, m), 6.75-6.84(2H, m), 7.06-
7.09(1H, m), 7.43-7.46 (2H, m), 7.60(1H, brs) 355 19 ##STR00123##
pale yellow cryst. >270 DMSO 1.20-1.30(1H, m), 1.39-1.51(2H, m),
1.65- 1.88(5H, m), 2.01-2.11(2H, m), 2.05(3H, s), 2.40(3H, s),
4.18-4-26(1H, m), 7.21-7.29 (2H, m), 7.39-7.42(1H, m),
8.06-8.11(2H, m), 9.93 (1H, brs), 10.21(1H, brs) 397 20
##STR00124## colorless cryst. >270 (EtOH) DMSO 1.19-1.30(1H, m),
1.37-1.50(2H, m), 1.63- 1.87(5H, m), 2.04-2.11(2H, m), 2.40(3H, s),
2.78(3H, d, J = 4.4 Hz), 4.16-4.22(1H, m), 7.78-7.85(4H, m),
8.10(1H, s), 8.30-8.32(1H, m), 10.38(1H, brs) 397
TABLE-US-00034 TABLE 34 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 21 ##STR00125## colorless cryst. 223.2-226.5 CDCl.sub.3
1.25(3H, t, J = 7.3 Hz), 1.23-1.35(1H, m), 1.39- 1.55(2H, m),
1.72-1.89(3H, m), 1.90-1.98(2H, m), 2.18- 2.24(2H, m),
2.41-2.49(2H, m), 2.46(3H, s), 3.22(2H, t, J = 8.5Hz), 4.07(2H, t,
J = 8.5 Hz), 4.17-4.25(1H, m), 7.06- 7.09(1H, m), 7.45(1H, s),
7.59-7.61(1H, m), 7.78- 7.80(1H, m), 8.19-8.22(1H, m) 437 22
##STR00126## pale yellow cryst. 155.0-159.0 CDCl.sub.3 0.88(3H, t,
J = 6.8 Hz), 1.23-1.52(3H, m), 1.73- 1.98(5H, m), 2.17-2.22(2H, m),
2.45(3H, s), 3.13(2H, t, J = 8.6 Hz), 4.03(2H, t, J = 8.6 Hz),
4.15-4.23(1H, m), 4.22- 4.37(2H, m), 7.11-7.18(1H, m), 7.45(1H, s),
7.59(1H, brs), 7.63-7.74(1H, m), 7.75-7.89(1H, m) 453 23
##STR00127## colorless cryst. 192.8-196.6 CDCl.sub.3 1.23(6H, d, J
= 6.7 Hz), 1.23-1.35(1H, m), 1.38- 1.52(2H, m), 1.72-1.99(5H, m),
2.17-2.22(2H, m), 2.46(3H, s), 2.74-2.83(1H, m), 3.22(2H, t, J =
8.4 Hz), 4.09-4.24(1H, m), 4.15(2H, t, J = 8.4 Hz), 7.05-7.09(1H,
m), 7.45(1H, s), 7.59-7.61 (1H, m), 7.79-7.81(1H, m), 8.22-8.25(1H,
m) 451 24 ##STR00128## colorless cryst. 179.9-183.1 CDCl.sub.3
1.03(3H, t, J = 7.3 Hz), 1.23-1.35(1H, m), 1.38- 1.52(2H, m),
1.74-1.99(7H, m), 2.18-2.24(2H, m), 2.40(2H, t, J = 7.3 Hz),
2.46(3H, s), 3.21 (2H, t, J = 8.5 Hz), 4.08(2H, t, J = 8.5 Hz),
4.12- 4.27(1H, m), 7.06-7.09(1H, m), 7.45(1H, s), 7.59-7.61 (1H,
m), 7.79-7.81(1H, m), 8.20-8.23(1H, m) 451
TABLE-US-00035 TABLE 35 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 25 ##STR00129## colorless cryst. 162.8-167.3 CDCl.sub.3
1.21-1.51(3H, m), 1.38(9H, s), 1.72-1.99(5H, m), 2.18-2.22(2H, m),
2.45 (3H, s), 3.15(2H, t, J = 8.1 Hz), 4.12-4.27(1H, m), 4.25(2H,
t, J = 8.1 Hz), 7.08(1H, dd, J = 2.1 and 8.7 Hz), 7.45(1H, s),
7.62-7.65(1H, m), 7.79- 7.81(1H, m), 8.19-8.22(1H, m) 465 26
##STR00130## pale yellow cryst. 171.8-176.3 CDCl.sub.3
1.22-1.37(1H, m), 1.39-1.52(2H, m), 1.72- 1.89(3H, m),
1.90-1.99(2H, m), 2.18-2.24(2H, m), 2.46(3H, s), 3.56(2H, s),
4.14-4.22(1H, m), 6.81- 6.84(1H, m), 7.28-7.31 (1H, m), 7.46(1H,
s), 7.50- 7.52(1H, m), 7.55-7.58 (1H, m), 7.62-7.64(1H m) 395 27
##STR00131## vcolorless cryst. >270 EtOH DMSO 1.19-1.30(1H, m),
1.37-1.50(2H, m), 1.63- 1.88(5H, m), 2.04-2.11(2H, m), 2.08(3H, s),
2.40(3H, s), 4.19-4.28(1H, m), 7.60-7.65 (2H, m), 7.96-7.98(1H, m),
8.06(1H, s), 9.49(1H, brs), 10.36(1H, brs) 431 28 ##STR00132##
colorless cryst. 262.2-263.8 EtOH DMSO 1.12(3H, t, J = 7.2 Hz),
1.21-1.30(1H, m), 1.38- 1.50(2H, m), 1.63-1.88(5H, m),
2.04-2.11(2H, m), 2.40(3H, s), 3.23-3.32(2H, m), 4.19-4.28(1H, m),
7.78- 7.86(4H, m), 8.11(1H, s), 8.35-8.36(1H, m), 10.46(1H, brs)
411
TABLE-US-00036 TABLE 36 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 29 ##STR00133## pale yellow cryst. 135.2-136.3 CDCl.sub.3
1.22-1.35(1H, m), 1.39-1.52(2H, m), 1.72- 1.98(5H, m),
2.16-2.22(2H, m), 2.46(3H, s), 3.39(3H, s), 4.14-4.22(1H, m),
4.44(2H, s), 7.33-7.36(2H, m), 7.47(1H, s), 7.57-7.60(3H, m) 384 30
##STR00134## pale yellow cryst. 190.0-191.9 CDCl.sub.3
1.22-1.35(1H, m), 1.39-1.51(2H, m), 1.72- 1.98(5H, m), 2.17-2.22
(2H, m), 2.47(3H, s), 4.12- 4.22(1H, m), 4.68(2H, d, J = 5.1 Hz),
7.35-7.39(2H, m), 7.48(1H, s), 7.58-7.61 (2H, m), 7.64(1H, brs) 370
31 ##STR00135## colorless cryst. 246.5-248.3 CDCl.sub.3
1.22-1.35(1H, m), 1.39-1.51(2H, m), 1.72- 1.89(3H, m),
1.90-1.98(2H, m), 2.17-2.22(2H, m), 2.47(3H, s), 3.39-3.89(8H, m),
4.13-4.25(1H, m), 7.40- 7.43(2H, m), 7.55(1H, s), 7.61-7.64(2H, m),
7.85(1H, brs) 453 32 ##STR00136## colorless cryst. 193.2-196.0
CDCl.sub.3 1.22-1.34(1H, m), 1.39-1.51(2H, m), 1.72- 1.89(3H, m),
1.90-1.98(2H, m), 2.16-2.25(2H, m), 2.38- 2.56(4H, m), 2.36(3H, s),
2.47(3H, s), 3.36-3.90(4H, m), 4.15-4.25(1H, m), 7.39-7.42 (2H, m),
7.56(1H, s), 7.59- 7.62(2H, m), 7.91(1H, brs) 466
TABLE-US-00037 TABLE 37 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 33 ##STR00137## colorless cryst. 240.0-243.1 EtOH DMSO
1.17-1.30(1H, m), 1.38-1.50(2H, m), 1.62- 1.88(5H, m),
2.03-2.11(2H, m), 2.40(3H, s), 2.95(3H, s), 4.17-4.25(1H, m),
7.18-7.21 (2H, m), 7.66-7.69(2H, m), 8.05(1H, s), 9.60(1H, brs),
10.23(1H, brs) 433 34 ##STR00138## pale yellow cryst. 338.7-240.0
AcOEt/ hexane CDCl.sub.3 1.20-1.31(1H, m), 1.39-1.50(2H, m), 1.63-
1.89(5H, m), 2.03-2.12(2H, m), 2.41(3H, s), 2.42(3H, s),
4.19-4.29(1H, m), 7.31-7.36 (1H, m), 7.75-7.78(2H, m),
7.93-7.96(2H, m), 8.13 (1H, s), 10.55(1H, brs) 433 35 ##STR00139##
colorless cryst. 203.9-207.1 EtOH DMSO 1.18-1.31(1H, m),
1.36-1.51(2H, m), 1.61- 1.89(5H, m), 2.00-2.11(2H, m), 2.03(3H, s),
2.39(3H, s), 3.22(2H, t, J = 8.0 Hz), 4.15- 4.26(1H, m), 4.49(2H,
t, J = 8.0 Hz), 7.28-7.31(1H, m), 7.60-7.62(1H, m), 7.79(1H, s),
7.95-7.98(1H, m), 9.91 (1H, brs) 423 36 ##STR00140## colorless
cryst. 223.5-225.0 CDCl.sub.3 1.21-1.38(1H, m), 1.41-1.55(2H, m),
1.73- 1.91(3H, m), 1.91-2.00(2H, m), 2.16-2.25(2H, m), 2.27(3H, s),
2.42-2.55(4H, m), 3.00-3.12(4H, m), 4.16- 4.25(1H, m), 7.52(1H, s),
7.73-7.80(5H, m) 502
TABLE-US-00038 TABLE 38 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 37 ##STR00141## colorless cryst. 203.2-205.8 CDCl.sub.3
1.22-1.38(1H, m), 1.40-1.53(2H, m), 1.72- 1.90(3H, m),
1.91-1.99(2H, m), 2.16-2.22(2H, m), 2.40(3H, s), 3.40(3H, s),
3.55-3.60(2H, m), 3.64- 3.69(2H, m), 4.15-4.25(1H, m),
6.48-6.52(1H, m), 7.52(1H, s), 7.67-7.71(2H, m), 7.78-7.81(2H, m),
7.83(1H, brs) 441 38 ##STR00142## colorless cryst. 177.8-179.4
CDCl.sub.3 1.22-1.36(1H, m), 1.40-1.53(2H, m), 1.72- 1.89(3H, m),
1.91-1.99(2H, m), 2.16-2.23(2H, m), 2.47(3H, s), 2.60(3H, s), 4.15-
4.25(1H, m), 7.51(1H, s), 7.71-7.74(2H, m), 7.78(1H, brs),
7.97-8.01(2H, m) 382 39 ##STR00143## colorless cryst. 239.0-243.8
CDCl.sub.3 1.22-1.36(1H, m), 1.40-1.52(2H, m), 1.72- 1.89(3H, m),
1.90-1.99(2H, m), 2.17-2.24(2H, m), 2.47(3H, s), 3.02(3H, brs),
3.12(3H, brs), 4.15-4.25(1H, m), 7.37(2H, dd, J = 1.8 and 8.5 Hz),
7.55(2H, dd, J = 1.8 and 8.5 Hz), 7.64(1H, s), 8.17(1H, brs) 411 40
##STR00144## colorless cryst. 159.5-163.3 CDCl.sub.3 1.22-1.36(1H,
m), 1.40(3H, t, J = 7.1 Hz), 1.40- 1.52(2H, m), 1.72-1.89(3H, m),
1.90-1.99(2H, m), 2.17- 2.24(2H, m), 2.47(3H, s), 4.15- 4.25(1H,
m), 4.37(2H, q, J = 7.1 Hz), 7.50(1H, s), 7.68- 7.71(2H, m),
7.74(1H, brs), 8.04-8.08(2H, m) 412
TABLE-US-00039 TABLE 39 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 41 ##STR00145## colorless cryst. 265.9-268.8 DMSO
1.18-1.31(1H, m), 1.39-1.51(2H, m), 1.62- 1.89(5H, m),
2.04-2.11(2H, m), 2.41(3H, s), 4.18- 4.26(1H, m), 7.84-7.87(2H, m),
7.92-7.95(2H, m), 8.13(1H, s), 10.48(1H, brs) 384 42 ##STR00146##
colorless cryst. 215.8-216.8 CDCl.sub.3 1.22-1.38(1H, m),
1.40-1.52(2H, m), 1.72- 1.89(3H, m), 1.90-1.99(2H, m),
2.18-2.24(2H, m), 2.50(3H, s), 4.09(3H, s), 4.15- 4.25(1H, m),
7.50(1H, s), 7.81(1H, d, J = 2.3 Hz), 7.97 (1H, dd, J = 2.3 and 9.0
Hz), 8.54(1H, brs), 8.65 (1H, d, J = 9.0 Hz) 415 43 ##STR00147##
yellow cryst. 102.2-105.0 CDCl.sub.3 1.22-1.37(1H, m),
1.39-1.52(2H, m), 1.70- 1.98(5H, m), 2.17-2.23(2H, m), 2.47(3H, s),
3.62(2H, brs), 3.90(3H, s), 4.13-4.24 (1H, m), 6.30-6.35(2H, m),
7.40(1H, s), 8.06(1H, brs), 8.12-8.15(1H, m) 384(M+) 44
##STR00148## pale yellow cryst. 263.1-365.3 EtOH DMSO 1.18-1.31(1H,
m), 1.38-1.51(2H, m), 1.63- 1.88(5H, m), 2.04-2.11(2H, m), 2.05(3H,
s), 2.38(3H, s), 3.79(3H, s), 4.15-4.29(1H, m), 7.08-7.11(1H, m),
7.45- 7.51(2H, m), 8.02(1H, s), 9.45(1H, brs), 9.97(1H, brs)
427
TABLE-US-00040 TABLE 40 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 45 ##STR00149## ccolorless cryst. 255.7-259.5 EtOH DMSO
1.16(6H, d, J = 6.6 Hz), 1.18-1.31(1H, m), 1.38- 1.51(2H, m),
1.63-1.88(5H, m), 2.03-2.12(2H, m), 2.41(3H, s), 4.04-4.15(1H, m),
4.19-4.28(1H, m), 7.78- 7.81(2H, m), 7.84-7.87(2H, m), 8.09(1H, d,
J = 7.4 Hz), 8.11(1H, s), 10.39(1H, brs) 425 46 ##STR00150##
colorless cryst. 194.2-196.0 DMSO 1.20-1.33(1H, m), 1.39-1.54(2H,
m), 1.65- 1.95(5H, m), 2.05-2.15(2H, m), 2.41(3H, s), 3.26-
3.40(2H, m), 3.49-3.59(2H, m), 4.18-4.29(1H, m), 4.69- 4.73(1H, m),
7.79-7.88(4H, m), 8.11(1H, s), 8.31- 8.35(1H, m), 10.40(1H, brs)
427 47 ##STR00151## colorless cryst. >270 EtOH DMSO
1.19-1.33(1H, m), 1.39-1.52(2H, m), 1.63- 1.90(5H, m),
2.05-2.12(2H, m), 2.08(3H, s), 2.40(3H, s), 4.18-4.28(1H, m),
8.01-8.08 (2H, m), 8.04(1H, s), 8.65- 8.67(1H, m), 10.36(1H, brs),
10.45(1H, brs) 398 48 ##STR00152## colorless crys. 133.5-136.0
CDCl.sub.3 1.22-1.37(1H, m), 1.39-1.52(2H, m), 1.71- 1.98(5H, m),
2.16-2.23(2H, m), 2.46(3H, s), 3.81(3H, s), 4.13-4.25(1H, m),
6.91(2H, dd, J = 2.1 and 6.9 Hz), 7.44(1H, s), 7.49(2H, dd, J = 2.1
and 6.9 Hz), 10.51(1H, brs) 370
TABLE-US-00041 TABLE 41 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 49 ##STR00153## colorless cryst. 161.0-164.2 CDCl.sub.3
1.22-1.35(1H, m), 1.39-1.54(4H, m), 1.61- 1.98(9H, m), 2.04-2.21
(4H, m), 2.43(3H, s), 4.13- 4.22(1H, m), 4.31-4.42(1H, m), 5.80(1H,
d, J = 6.6 Hz), 7.29(1H, s) 332 50 ##STR00154## colorless cryst.
184.0-185.8 CDCl.sub.3 1.15-1.35(4H, m), 1.37-1.52(4H, m), 1.61-
1.70(1H, m), 1.71-1.98(7H, m), 2.00-2.09(2H, m), 2.14- 2.21(2H, m),
2.43(3H, s), 3.88-3.98(1H, m), 4.13- 4.22(1H, m), 5.73(1H, d, J =
8.0 Hz), 7.30(1H, s) 346 51 ##STR00155## colorless cryst.
256.0-257.3 CDCl.sub.3 1.21-1.37(1H, m), 1.40-1.52(2H, m), 1.48(9H,
s), 1.71-1.89(3H, m), 1.91- 1.99(2H, m), 2.18-2.25(2H, m), 2.46(3H,
s), 4.15-4.22 (1H, m), 5.92(1H, brs), 7.53(1H, s), 7.63-7.66(2H,
m), 7.70-7.73(2H, m), 7.85(1H, brs) 439 52 ##STR00156## colorless
cryst. >270 CDCl.sub.3 1.21-1.36(1H, m), 1.29(6H, d, J = 6.6
Hz), 1.40- 1.52(2H, m), 1.71-1.89(3H, m), 1.91-1.99(2H, m), 2.18-
2.24(2H, m), 2.47(3H, s), 4.15-4.24(1H, m), 4.28- 4.35(1H, m),
5.85(1H, d, J = 7.6 Hz), 7.57(1H, s), 8.08(1H, dd, J = 2.2 and 8.7
Hz), 8.36(1H, d, J = 8.7 Hz), 8.56(1H, brs), 8.71-8.72(1H, m)
426
TABLE-US-00042 TABLE 42 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 53 ##STR00157## pale brown cryst. 216.9-218.5
EtOH/Et.sub.2O DMSO 1.19-1.31(1H, m), 1.39-1.52(2H, m), 1.63-
1.89(5H, m), 2.05-2.11(2H, m), 2.39(3H, s), 4.18- 4.27(1H, m),
7.54-7.58(2H, m), 7.64-7.68(2H, m), 8.04(1H, s), 8.24(1H, brs),
10.14(1H, brs), 10.21(1H, brs) 383 54 ##STR00158## colorless cryst.
226.0-227.8 CDCl.sub.3 1.21-1.36(1H, m), 1.41(9H, s), 1.40-1.52(2H,
m), 1.71-1.89(3H, m), 1.91- 1.99(2H, m), 2.18-2.25(2H, m), 2.48(3H,
s), 2.97-3.01 (4H, m), 3.50-3.55(4H, m), 4.18-4.27(1H, m), 7.53(1H,
s), 7.73-7.76(2H, m), 7.78- 7.81(2H, m), 7.82(1H, brs) 588 55
##STR00159## colorless cryst. >270 DMSO 1.19-1.31(1H, m),
1.39-1.50(2H, m), 1.63- 1.89(5H, m), 2.05-2.11(2H, m), 2.41(3H, s),
3.09- 3.22(8H, m), 4.19-4.30(1H, m), 7.77-7.80(2H, m), 8.05-
8.08(2H, m), 8.22(1H, s), 8.84(1H, brs), 10.74(1H, brs) 488 56
##STR00160## colorless cryst. >270 CDCl.sub.3 1.21-1.35(1H, m),
1.39-1.51(2H, m), 1.74- 1.99(5H, m), 2.17-2.26(2H, m), 2.48(3H, s),
3.00- 3.03(4H, m), 3.72-3.77(4H, m), 4.18-4.26(1H, m), 7.53(1H, s),
7.71-7.83(5H, m) 489
TABLE-US-00043 TABLE 43 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 57 ##STR00161## colorless cryst. >270 CDCl.sub.3
1.21-1.35(1H, m), 1.37-1.51(2H, m), 1.73- 1.99(5H, m),
2.17-2.26(2H, m), 2.48(3H, s), 3.06(3H, s), 4.14-4.26(1H, m),
7.54(1H, s), 7.81-7.84(3H, m), 7.93- 7.96(2H, m) 418 58
##STR00162## colorless cryst. 217.7-219.9 EtOH DMSO 0.80-0.91(4H,
m), 1.15-1.30(1H, m), 1.39- 1.50(2H, m), 1.63-1.88(5H, m),
1.90-1.99(1H, m), 2.02- 2.10(2H, m), 2.39(3H, s), 3.15-3.22(2H, m),
4.18- 4.35(3H, m), 7.38-7.41(1H, m), 7.67-7.69(1H, m), 7.94-
7.99(1H, m), 8.03(1H, s), 10.16(1H, brs) 449 59 ##STR00163##
colorless cryst. 132.8-137.4 CDCl.sub.3 1.21-1.37(1H, m),
1.39-1.53(2H, m), 1.72- 1.98(5H, m), 2.17-2.23(2H, m), 2.47(3H, s),
2.86(3H, s), 3.18(2H, t, J = 8.4 Hz), 4.01 (2H, t, J = 8.4 Hz),
4.15- 4.27(1H, m), 7.14-7.18 (1H, m), 7.37-7.40(1H, m), 7.47(1H,
s), 7.58(1H, brs), 7.74(1H, brs) 459 60 ##STR00164## colorless
cryst. 213.1-217.5 CDCl.sub.3 1.22-1.36(1H, m), 1.40-1.52(2H, m),
1.72- 1.98(5H, m), 2.18-2.23(2H, m), 2.47(3H, s), 2.64(3H, s),
4.15-4.27(1H, m), 6.63-6.64(1H, m), 7.29(1H, dd, J = 1.8 and 8.9
Hz), 7.42-7.44(1H, m), 7.50(1H, s), 7.75(1H, brs), 8.10(1H, d, J =
1.8 Hz), 8.38-8.42(1H, m) 421
TABLE-US-00044 TABLE 44 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 61 ##STR00165## colorless cryst. 178.9-181.5 CDCl.sub.3
0.60-0.64(2H, m), 0.82-0.89(2H, m), 1.21- 1.32(1H, m),
1.38-1.50(2H, m), 1.72-1.88(3H, m), 1.89- 1.95(2H, m),
2.13-2.20(2H, m), 2.42(3H, s), 2.85- 2.91(1H, m), 4.12-4.20(1H, m),
6.02(1H, brs), 7.29(1H, s) 304 62 ##STR00166## colorless cryst.
170.2-172.2 CDCl.sub.3 1.21-1.50(5H, m), 1.70-1.95(5H, m), 1.98-
2.04(2H, m), 2.12-2.23(4H, m), 2.43(3H, s), 2.84- 2.90(2H, m),
3.52(2H, s), 3.91-4.02(1H, m), 4.12- 4.21(1H, m), 5.73(1H, d, J =
7.2 Hz), 7.26-7.33(6H, m) 437 63 ##STR00167## colorless cryst.
164.1-167.3 DMSO 1.17-1.30(1H, m), 1.39-1.50(2H, m), 1.64- 1.87(7H,
m), 1.92-2.00(2H, m), 2.02-2.10(2H, m), 2.36(3H, s), 2.95-3.01(2H,
m), 3.29-3.36(2H, m), 3.96- 4.05(1H, m), 4.15-4.22(1H, m), 7.88(1H,
s), 8.51(1H, d, J = 7.5 Hz), 8.72(1H, brs) 347 64 ##STR00168##
colorless cryst. 249.2-250.8 CDCl.sub.3 1.21-1.50(5H, m),
1.71-1.88(3H, m), 1.89- 1.98(2H, m), 2.01-2.07(1H, m), 2.12(3H, s),
2.14- 2.21(3H, m), 2.44(3H, s), 2.72-2.80(1H, m), 3.18- 3.25(1H,
m), 3.79-3.88(1H, m), 4.12-4.21(2H, m), 4.59- 4.66(1H, m), 5.78(1H,
d, J = 7.7 Hz), 7.34(1H, s) 389
TABLE-US-00045 TABLE 45 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 65 ##STR00169## colorless cryst. 137.1-138.1 CDCl.sub.3
1.25-1.34(1H, m), 1.31(3H, t, J = 7.1 Hz), 1.38- 1.50(2H, m),
1.71-1.88(3H, m), 1.89-1.98(2H, m), 2.16- 2.22(2H, m), 2.46(3H, s),
4.15-4.22(1H, m), 4.28(2H, q, J = 7.1 Hz), 4.62(2H, s), 6.90-
6.94(2H, m), 7.45(1H, s), 7.49-7.53(2H, m), 7.55(1H, brs) 442 66
##STR00170## colorless cryst. 181.0-182.6 DMSO 1.18-1.30(1H, m),
1.38-1.50(2H, m), 1.64- 1.90(5H, m), 2.04-2.10(2H, m), 2.39(3H, s),
4.18- 4.27(1H, m), 4.64(2H, s), 6.89-6.92(2H, m), 7.59- 7.62(2H,
m), 8.01(1H, s), 10.13(1H, brs) 414 67 ##STR00171## colorless
cryst. 233.2-235.0 CDCl.sub.3 1.25-1.35(1H, m), 1.40-1.52(2H, m),
1.72- 1.98(5H, m), 2.18-2.23(2H, m), 2.46(3H, s), 2.92(3H, d, J =
5.0 Hz), 4.15-4.24(1H, m), 4.49(2H, s), 6.53-6.63(1H, m), 6.92(2H,
dd, J = 2.1 and 6.9 Hz), 7.47(1H, s), 7.53(2H, dd, J = 2.1 and 6.9
Hz), 7.57(1H, brs) 427 68 ##STR00172## colorless cryst. 149.3-151.2
CDCl.sub.3 1.22-1.35(1H, m), 1.26(3H, t, J = 7.2 Hz), 1.38-
1.53(2H, m), 1.71-1.98 (5H, m), 2.15-2.22(2H, m), 2.47(3H, s),
3.60(2H, s), 4.15-4.22(1H, m), 4.16(2H, q, J = 7.2 Hz),
7.27-7.30(2H, m), 7.46(1H, s), 7.54-7.57(2H, m), 7.58(1H, brs)
426
TABLE-US-00046 TABLE 46 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 69 ##STR00173## colorless cryst. 233.2-234.7 DMSO
1.18-1.30(1H, m), 1.38-1.51(2H, m), 1.61- 1.89(5H, m),
2.05-2.11(2H, m), 2.40(3H, s), 3.53(2H, s), 4.18-4.29(1H, m), 7.21-
7.25(2H, m), 7.63-7.66(2H, m), 8.06(1H, s), 10.20(1H, brs) 398 70
##STR00174## colorless cryst. 257.3-258.8 DMSO 1.18-1.32(1H, m),
1.37-1.50(2H, m), 1.61- 1.89(5H, m), 2.05-2.09(2H, m), 2.39(3H, s),
2.57(3H, d, J = 4.6 Hz), 3.35(2H, s), 4.19- 4.27(1H, m),
7.20-7.23(2H, m), 7.61-7.64(2H, m), 7.88- 7.91(1H, m), 8.06(1H, s),
10.18(1H, brs) 411 71 ##STR00175## colorless cryst. 228.3-229.6
CDCl.sub.3 1.24-1.35(1H, m), 1.38-1.52(2H, m), 1.49(9H, s),
1.72-1.98(5H, m), 2.15- 2.21(2H, m), 2.46(3H, s), 3.09-3.12(4H, m),
3.58-3.61 (4H, m), 4.12-4.25(1H, m), 6.91-6.94(2H, m), 7.44 (1H,
s), 7.47-7.50(2H, m), 7.53(1H, brs) 523 72 ##STR00176## colorless
cryst. 248.5-252.6 DMSO 1.19-1.31(1H, m), 1.38-1.51(2H, m), 1.63-
1.89(5H, m), 2.04-2.10(2H, m), 2.39(3H, s), 3.19- 3.22(4H, m),
3.30-3.33(4H, m), 4.05-4.15(1H, m), 6.98- 7.01(2H, m),
7.61-7.64(2H, m), 8.07(1H, s), 9.08- 9.15(2H, m), 10.17(1H, brs)
424
TABLE-US-00047 TABLE 47 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 73 ##STR00177## colorless cryst. >270 EtOH DMSO
1.18-1.32(1H, m), 1.35-1.51(2H, m), 1.65- 1.90(5H, m), 2.04(3H, s),
2.05-2.11(2H, m), 2.39(3H, s), 3.02-3.13(4H, m), 3.55- 3.60(4H, m),
4.15-4.28(1H, m), 6.94-6.98(2H, m), 7.56- 7.59(2H, m), 8.01(1H, s),
10.07(1H, brs) 466 74 ##STR00178## colorless cryst. 181.3-182.8
CDCl.sub.3 1.22-1.52(7H, m), 1.72-1.88(3H, m), 1.89- 1.98(2H, m),
2.00-2.08(2H, m), 2.10-2.22(4H, m), 2.43(3H, s), 3.60-3.71(1H, m),
3.90-4.00(1H, m), 4.12- 4.21(1H, m), 5.68(1H, d, J = 7.8 Hz),
7.30(1H, s) 362 75 ##STR00179## colorless cryst. 177.2-178.5
CDCl.sub.3 1.21-1.35(1H, m), 1.39-1.50(2H, m), 1.72- 1.88(5H, m),
1.90-1.98(2H, m), 2.15-2.23(2H, m), 2.32- 2.60(6H, m), 2.43(3H, s),
4.14-4.22(1H, m), 4.40- 4.50(1H, m), 5.86(1H, d, J = 7.6 Hz),
7.35(1H, s) 360 76 ##STR00180## colorless cryst. 117.2-121.2
CDCl.sub.3 1.21-1.35(1H, m), 1.40-1.52(2H, m), 1.72- 1.89(3H, m),
1.90-1.98(2H, m), 2.16-2.22(2H, m), 2.30(3H, s), 2.34-2.42(4H, m),
2.46(3H, s), 3.59- 3.68(4H, m), 4.14-4.25(1H, m), 4.68(2H, s),
6.93- 6.97(2H, m), 7.46(1H, s), 7.49-7.52(2H, m), 7.60(1H, brs)
496
TABLE-US-00048 TABLE 48 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst solvent) .sup.1H-NMR (M +
1).sup.+ 77 ##STR00181## colorless cryst. 178.2-180.8 CDCl.sub.3
1.22-1.35(1H, m), 1.37-1.52(2H, m), 1.72- 1.89(3H, m),
1.90-1.98(2H, m), 2.15-2.22(2H, m), 2.46(3H, s), 2.99(3H, s), 3.10
(3H, s), 4.15-4.23(1H, m), 4.69(2H, s), 6.94-6.98(2H, m), 7.46(1H,
s), 7.48- 7.51(2H, m), 7.56(1H, brs) 441 78 ##STR00182## colorless
cryst. 202.2-203.8 CDCl.sub.3 1.22-1.35(1H, m), 1.40-1.52(2H, m),
1.72- 1.89(3H, m), 1.91-1.99(2H, m), 2.03(3H, s), 2.19- 2.25(2H,
m), 2.48(3H, s), 2.59-2.64(6H, m), 3.02- 3.08(4H, m), 4.13(2H, t, J
= 5.7 Hz), 4.15-4.26(1H, m), 7.53(1H, s), 7.73-7.81 (4H, m),
7.84(1H, brs) 574 79 ##STR00183## colorless cryst. 141.4-145.8
CDCl.sub.3 1.22-1.35(1H, m), 1.39-1.53(2H, m), 1.72- 1.98(5H, m),
2.18-2.22(2H, m), 2.34(1H, brs), 2.48(3H, s), 2.52-2.58(2H, m),
2.60- 2.63(4H, m), 3.03-3.09(4H, m), 3.58-3.61(2H, m), 4.17-
4.26(1H, m), 7.54(1H, s), 7.74-7.82(4H, m), 7.84(1H, brs) 532 80
##STR00184## colorless cryst. >270 EtOH DMSO 1.17-1.50(7H, m),
1.63-1.90(9H, m), 1.78(3H, s), 2.00-2.08(2H, m), 2.35 (3H, s),
3.41-3.57(1H, m), 3.60-3.72(1H, m), 4.12- 4.24(1H, m), 7.73(1H, d,
J = 7.6 Hz), 7.79(1H, s), 8.24(1H, d, J = 7.7 Hz) 403
TABLE-US-00049 TABLE 49 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 81 ##STR00185## colorless cryst. 217.5-218.3 CDCl.sub.3
1.21-1.32 (1H, m), 1.37-1.51 (2H, m), 1.70-1.88 (3H, m), 1.89-1.97
(2H, m), 2.13-2.21 (2H, m), 2.43 (3H, s), 3.00 (3H, d, J = 4.9 Hz),
4.10-4.21 (1H, m), 5.85-5.93 (1H, m), 7.30 (1H, s) 278 82
##STR00186## colorless cryst. 125.1-127.8 CDCl.sub.3 1.54-1.69 (2H,
m), 1.75-1.93 (6H, m), 2.09 (3H, s), 3.19 (2H, s), 4.51-4.60 (1H,
m) 167 83 ##STR00187## browm oil CDCl.sub.3 1.60-1.72 (2H, m),
1.86-1.98 (2H, m), 2.00-2.10 (4H, m), 2.23 (3H, s), 4.68-4.75 (1H,
m), 5.95 (1H, s) 84 ##STR00188## colorless oil CDCl.sub.3 1.65-1.75
(2H, m), 1.92-2.02 (2H, m), 2.14-2.13 (4H, m), 2.45 (3H, s),
4.72-4.80 (1H, m), 9.85 (1H, s) 213
TABLE-US-00050 TABLE 50 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 85 ##STR00189## colorless oil CDCl.sub.3 1.20 (3H, t, J =
7.1 Hz), 1.65-1.75 (2H, m), 1.92-2.11 (6H, m), 2.48 (3H, s), 3.58
(2H, s), 4.10 (2H, q, J = 7.1 Hz), 5.17-5.22 (1H, m), 10.01 (1H, s)
297 86 ##STR00190## colorless oil CDCl.sub.3 1.38 (3H, t, J = 7.1
Hz), 1.68-1.78 (2H, m), 1.83-1.95 (2H, m), 2.05-2.24 (4H, m), 2.44
(3H, s), 4.35 (2H, q, J = 7.1 Hz), 4.66-4.72 (1H, m), 7.69 (1H, s)
279 87 ##STR00191## colorless cryst. 167.5-168.9 CDCl.sub.3
1.68-1.80 (2H, m), 1.84-1.96 (2H, m), 2.08-2.25 (4H, m), 2.47 (3H,
s), 4.66-4.75 (1H, m), 7.80 (1H, s) 251 88 ##STR00192## colorless
cryst. >270 EtOH DMSO 1.62-1.72 (2H, m), 1.75-1.85 (2H, m),
1.94-2.04 (2H, m), 2.02 (3H, s), 2.09-2.19 (2H, m), 2.40 (3H, s),
4.70-4.79 (1H, m), 7.52-7.55 (2H, m), 7.60-7.63 (2H, m), 8.03 (1H,
s), 9.88 (1H, brs), 10.16 (1H, brs) 383
TABLE-US-00051 TABLE 51 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 89 ##STR00193## pale yellow cryst. 134.0-137.7 CDCl.sub.3
1.45-1.71 (6H, m), 1.72-1.97 (6H, m), 2.09 (3H, s), 3.16 (2H, s),
4.15-4.21 (1H, m), 195 90 ##STR00194## brown oil CDCl.sub.3
1.48-1.72 (6H, m), 1.78-1.88 (2H, m), 1.91-2.00 (2H, m), 2.01-2.11
(2H, m), 2.23 (3H, s), 4.30-4.38 (1H, m), 5.93 (1H, s) 91
##STR00195## colorless cryst. 75.0-76.3 CDCl.sub.3 1.50-1.73 (6H,
m), 1.81-1.91 (2H, m), 1.93-2.02 (2H, m), 2.03-2.14 (2H, m), 2.45
(3H, s), 4.39-4.46 (1H, m), 9.87 (1H, s) 241 92 ##STR00196##
colorless oil CDCl.sub.3 1.38 (3H, t, J = 7.1 Hz), 1.51-1.73 (6H,
m), 1.79-1.89 (2H, m), 1.99-2.10 (2H, m), 2.15-2.23 (2H, m), 2.44
(3H, s), 4.35 (2H, q, J = 7.1 Hz), 4.32-4.42 (1H, m), 7.69 (1H, s)
307
TABLE-US-00052 TABLE 52 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 93 ##STR00197## colorless cryst. 239.8-241.4 CDCl.sub.3
1.52-1.75 (6H, m), 1.80-1.90 (2H, m), 2.00-2.10 (2H, m), 2.16-2.25
(2H, m), 2.46 (3H, s), 4.35-4.41 (1H, m), 7.79 (1H, s) 279 94
##STR00198## colorless cryst. >270 EtOH DMSO-d.sub.6 1.50-1.82
(8H, m), 1.88-2.12 (4H, m), 1.97 (3H, s), 2.39 (3H, s), 4.32-4.46
(1H, m), 7.52-7.55 (2H, m), 7.60-7.63 (2H, m), 8.03 (1H, s), 9.88
(1H, brs), 10.15 (1H, brs) 411 95 ##STR00199## colorless cryst.
157-159 CDCl.sub.3 1.18-1.45 (3H, m), 1.68-1.82 (3H, m), 1.84-1.93
(2H, m), 2.04-2.13 (2H, m), 2.21 (3H, s), 3.45 (3H, s), 4.04-4.14
(1H, m), 6.11 (1H, s), 7.27-7.33 (2H, m), 7.39-7.49 (3H, m) 354 96
##STR00200## colorless cyrst. 223-224 CDCl.sub.3 1.22-1.36 (1H, m),
1.40-1.53 (2H, m), 1.72-1.89 (3H, m), 1.91-2.00 (2H, m), 2.15-2.25
(2H, m), 2.47 (3H, s), 4.15-4.25 (1H, m), 7.53 (1H, s), 7.54-7.58
(2H, m), 7.74 (1H, brs), 8.53-8.58 (2H, m) 341
TABLE-US-00053 TABLE 53 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 97 ##STR00201## colorless solid 178-180 CDCl.sub.3
1.23-1.35 (1H, m), 1.39-1.42 (2H, m), 1.72-1.89 (3H, m), 1.90-1.97
(2H, m), 2.16-2.25 (2H, m), 2.48 (3H, s), 4.15-4.25 (1H, m),
7.29-7.35 (1H, m), 7.53 (1H, s), 7.68 (1H, brs), 8.24-8.29 (1H, m),
8.38-8.42 (1H, m), 8.63-8.66 (1H, m) 341 98 ##STR00202## pale
yellow cryst. 210-212 CDCl.sub.3 1.22-1.52 (3H, m), 1.72-1.89 (3H,
m), 1.91-1.98 (2H, m), 2.17-2.26 (2H, m), 2.48 (3H, s), 4.15-4.25
(1H, m), 7.54 (1H, s), 7.77-7.81 (2H, m), 7.87 (1H, brs), 8.24-2.29
(2H, m) 385 99 ##STR00203## pale yellow foamy solid CDCl.sub.3
1.22-1.34 (1H, m), 1.38-1.51 (2H, m), 1.71-1.98 (5H, m), 2.14-2.23
(2H, m), 2.45 (3H, s), 4.14-4.24 (1H, m), 6.65-6.72 (2H, m),
7.33-7.38 (2H, m), 7.42 (1H, s), 7.48 (1H, s) 355 100 ##STR00204##
colorless solid >300 CDCl.sub.3 1.19-1.30 (1H, m), 1.36-1.50
(2H, m), 1.63-1.86 (5H, m), 2.03 (3H, s), 2.03-2.10 (2H, m), 2.39
(3H, s), 4.15-4.26 (1H, m), 7.51-7.56 (2H, m), 7.59-7.64 (2H, m),
8.04 (1H, s), 9.91 (1H, brs), 10.18 (1H, brs) 397
TABLE-US-00054 TABLE 54 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 101 ##STR00205## pale yellow cryst. 233-236 CDCl.sub.3
1.23-1.35 (1H, m), 1.38-1.54 (2H, m), 1.72-1.97 (5H, m), 2.15-2.24
(2H, m), 2.47 (3H, s), 3.52 (3H, s), 4.03 (2H, s), 4.15-4.25 (1H,
m), 7.47 (1H, s), 7.56-7.65 (4H, m), 8.25 (1H, brs) 427 102
##STR00206## colorless solid 120-123 CDCl.sub.3 1.23-1.36 (1H, m),
1.39-1.52 (2H, m), 1.72-1.98 (5H, m), 2.16-2.24 (2H, m), 2.48 (3H,
s), 4.01 (3H, s), 4.15-4.25 (1H, m), 7.58 (1H, s), 7.88 (1H, brs),
8.18 (1H, d, J = 8.6 Hz), 8.51 (1H, dd, J = 2.6 and 8.6 Hz), 8.71
(1H, d, J = 2.6 Hz) 399 103 ##STR00207## pale yellow solid 161-166
DMSO-d.sub.6 1.18-1.42 (1H, m), 1.38-1.51 (2H, m), 1.65-1.89 (5H,
m), 2.05-2.13 (2H, m), 2.42 (3H, s), 4.19-4.28 (1H, m), 8.07 (1H,
d, J = 8.6 Hz), 8.14 (1H, s), 8.35 (1H, dd, J = 2.4 and 8.6 Hz),
8.99 (1H, d, J = 2.4 Hz), 10.71 (1H, brs) 385 104 ##STR00208##
colorless solid 255-257 CDCl.sub.3 1.21-1.35 (1H, m), 1.40-1.60
(2H, m), 1.72-1.97 (5H, m), 2.16-2.25 (2H, m), 2.47 (3H, s), 3.04
(3H, d, J = 5.1 Hz), 4.15-4.25 (1H, m), 7.55 (1H, s), 7.79 (1H,
brs), 7.86-7.92 (2H, m), 8.21-8.24 (2H, m), 8.76 (1H, brs) 398
TABLE-US-00055 TABLE 55 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 105 ##STR00209## colorless cryst. 243-245 CDCl.sub.3
1.23-1.35 (1H, m), 1.39-1.52 (2H, m), 1.72-1.98 (5H, m), 2.16-2.24
(2H, m), 2.48 (3H, s), 3.11 (3H, s), 3.17 (3H, s), 4.15-4.25 (1H,
m), 7.51 (1H, d, J = 8.5 Hz), 7.78 (1H, s), 8.00 (1H, dd, J = 2.5
and 8.5 Hz), 8.57-8.60 (2H, m) 412 106 ##STR00210## yellow solid
206-208 CDCl.sub.3 1.22-1.35 (1H, m), 1.38-1.50 (2H, m), 1.70-1.97
(5H, m), 2.15-2.23 (2H, m), 2.36 (3H, s), 2.46 (3H, s), 2.56-2.63
(4H, m), 3.17-3.23 (4H, m), 4.14-4.23 (1H, m), 6.93 (2H, d, J = 8.9
Hz), 7.44 (1H, s), 7.47 (2H, d, J = 8.9 Hz), 7.53 (1H, brs) 438 107
##STR00211## colorless cryst 175 (dec.) (MeOH) D.sub.2O 1.05-1.18
(1H, m), 1.25-1.39 (2H, m), 1.48-1.69 (3H, m), 1.73-1.83 (2H, m),
1.93-2.01 (2H, m), 2.31 (3H, s), 2.86 (3H, s), 2.96 (3H, s),
3.25-3.55 (8H, m), 3.90-4.00 (1H, m), 6.96 (2H, d, J = 8.6 Hz),
7.34 (1H, d, J = 8.6 Hz), 7.50 (1H, brs) 438 108 ##STR00212##
colorless solid 98-103 CDCl.sub.3 1.21-1.36 (1H, m), 1.38-1.52 (2H,
m), 1.72-1.98 (5H, m), 2.15-2.24 (2H, m), 2.36 (3H, s), 4.13-4.23
(1H, m), 7.53 (1H, s), 7.64 (2H, d, J = 8.6 Hz), 7.75 (2H, d, J =
8.6 Hz), 7.89 (1H, brs) 365
TABLE-US-00056 TABLE 56 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 109 ##STR00213## colorless solid 250 (decpt.) D.sub.2O
1.12-1.26 (1H, m), 1.31-1.44 (2H, m), 1.54-1.64 (3H, m), 1.80-1.88
(2H, m), 1.96-2.05 (2H, m), 2.32 (3H, s), 3.00 (3H, s), 3.17-3.30
(2H, m), 3.34-3.45 (2H, m), 3.63-3.74 (2H, m), 3.95-4.05 (1H, m),
4.18-4.29 (2H, m), 7.03 (1H, d, J = 9.4 Hz), 7.55 (1H, s), 7.82
(1H, dd, J = 2.4 and 9.4 Hz), 8.25 (1H, d, J = 2.4 Hz) 439 110
##STR00214## colorless cryst. 164-170 DMSO-d.sub.6 1.28-1.32 (1H,
m), 1.38-1.52 (2H, m), 1.64-1.89 (5H, m), 2.05-2.12 (2H, m), 2.41
(3H, s), 2.63-2.74 (2H, m), 2.76 (3H, s), 3.09-3.12 (2H, m),
3.41-3.50 (2H, m), 373-3.82 (2H, m), 4.20-4.30 (1H, m), 7.47-7.51
(1H, m), 7.65-7.71 (1H, m), 8.08-8.13 (1H, m), 8.17 (1H, s),
8.26-8.28 (1H, m), 10.22 (1H, brs), 10.68 (1H, brs) 502 111
##STR00215## coloeless solid 255-256 DMSO-d.sub.6 1.28-1.31 (1H,
m), 1.38-1.52 (2H, m), 1.64-1.89 (5H, m), 2.04-2.12 (2H, m), 2.41
(3H, s), 2.45 (3H, s), 4.17-4.27 (1H, m), 7.44 (1H, brs), 7.47-7.51
(1H, m), 7.55-7.61 (1H, m), 7.99-8.04 (1H, m), 8.11 (1H, s),
8.22-8.26 (1H, m), 10.51 (1H, brs) 433 112 ##STR00216## pale yellow
solid 203-205 CDCl.sub.3 1.52-1.75 (6H, m), 1.78-1.88 (2H, m),
1.99-2.11 (2H, m), 2.15-2.24 (2H, m), 2.35 (3H, s), 2.45 (3H, s),
2.55-2.61 (4H, m), 3.16-3.22 (4H, m), 4.34-4.43 (1H, m), 6.92 (2H,
d, J = 9.0 Hz), 7.43 (1H, s), 7.46 (2H, d, J = 9.0 Hz), 7.49 (1H,
brs) 452
TABLE-US-00057 TABLE 57 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 113 ##STR00217## colorless foamy solid CDCl.sub.3
1.22-1.36 (1H, m), 1.39-1.52 (2H, m), 1.69-1.98 (5H, m), 2.15-2.24
(2H, m), 2.35 (3H, s), 2.46 (3H, s), 2.53-2.59 (4H, m), 3.21-3.27
(4H, m), 4.13-4.23 (1H, m), 6.67-6.72 (1H, m), 6.88-6.93 (1H, m),
7.19-7.25 (1H, m), 7.40-7.43 (1H, m), 7.45 (1H, s), 7.45 (1H, brs)
438 114 ##STR00218## yellow cryst. 165-167 (iPrOH) DMSO-d.sub.6
1.18-1.32 (1H, m), 1.37-1.53 (4H, m), 1.64-1.88 (7H, m), 2.03-2.10
(2H, m), 2.39 (3H, s), 2.75-2.84 (2H, m), 3.45-3.52 (2H, m),
3.56-3.65 (1H, m), 4.16-4.26 (1H, m), 4.65 (1H, d, J = 4.2 Hz),
6.91 (2H, d, J = 9.0 Hz), 7.52 (2H, d, J = 9.0 Hz), 7.99 (1H, s),
10.02 (1H, brs) 439 115 ##STR00219## colorless cryst. 205-207
(EtOH) CDCl.sub.3 1.56-1.75 (6H, m), 1.80-1.88 (2H, m), 2.00-2.10
(2H, m), 2.15-2.25 (5H, m), 2.46 (3H, s), 3.93 (3H, s), 4.33-4.43
(1H, m), 6.74 (1H, dd, J = 2.2 and 8.7 Hz), 7.47 (1H, s), 7.65 (1H,
brs), 7.70 (1H, brs), 7.78 (1H, d, J = 2.2 Hz), 8.31 (1H, d, J =
8.7 Hz) 441 116 ##STR00220## colorless cryst. 201-202
(iPr.sub.2O/EtOAc) CDCl.sub.3 1.21-1.35 (1H, m), 1.38-1.52 (2H, m),
1.71-1.98 (5H, m), 2.15-2.23 (2H, m), 2.48 (3H, s), 4.15-4.25 (1H,
m), 7.64 (1H, s), 7.64 (1H, brs), 8.55 (2H, s) 409
TABLE-US-00058 TABLE 58 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 117 ##STR00221## colorless solid 93-96 CDCl.sub.3
1.16-1.31 (4H, m), 1.38-1.47 (2H, m), 1.65-1.89 (4H, m), 2.47 (3H,
s), 3.92 (3H, s), 4.16-4.26 (1H, m), 6.94 (2H, d, J = 8.3 Hz), 7.38
(2H, d, J = 8.3 Hz), 9.90 (1H, s) 393 118 ##STR00222## colorless
solid 118-120 CDCl.sub.3 1.22-1.34 (1H, m), 1.37-1.52 (2H, m),
1.72-1.98 (5H, m), 2.15-2.24 (2H, m), 2.45 (3H, s), 4.14-4.24 (1H,
m), 7.13 (1H, s), 7.39-7.44 (2H, m), 7.47-7.52 (2H, m) 375 119
##STR00223## pale yellow solid 182-183 CDCl.sub.3 1.22-1.48 (3H,
m), 1.70-1.95 (5H, m), 2.15-2.24 (2H, m), 2.36 (3H, s), 2.44 (3H,
s), 2.56-2.61 (4H, m), 3.23-3.28 (4H, m), 4.12-4.22 (1H, m),
6.88-6.94 (2H, m), 6.98 (1H, s), 7.42-7.48 (2H, m) 395 120
##STR00224## colorless cryst. 210-214 (EtOH/Et.sub.2O) DMSO-d.sub.6
1.16-1.28 (1H, m), 1.38-1.50 (2H, m), 1.65-1.87 (5H, m), 2.04-2.13
(2H, m), 2.30 (3H, s), 2.34 (3H, s), 2.85-2.88 (3H, m), 2.93-3.21
(4H, m), 3.40-3.58 (2H, m), 3.82-3.97 (2H, m), 4.12-4.22 (1H, m),
7.01-7.06 (2H, m), 7.31 (1H, s), 7.48-7.53 (2H, m), 9.55 (1H, brs)
395
TABLE-US-00059 TABLE 59 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 121 ##STR00225## pale yellow solid 112-114 CDCl.sub.3
1.22-1.53 (3H, m), 1.70-1.96 (5H, m), 1.99-2.07 (2H, m), 2.15-2.24
(2H, m), 2.39 (3H, s), 2.43 (3H, s), 2.56-2.61 (2H, m), 2.71-2.76
(2H, m), 3.47-3.53 (2H, m), 3.57-3.62 (2H, m), 4.12-4.22 (1H, m),
6.66-6.71 (2H, m), 6.91 (1H, s), 7.38-7.43 (2H, m) 409 122
##STR00226## colorless cryst. 127-129 CDCl.sub.3 1.22-1.33 (1H, m),
1.37-1.50 (2H, m), 1.70-1.96 (5H, m), 2.13-2.21 (2H, m), 2.41-2.46
(1H, brs), 2.44 (3H, s), 3.59-3.65 (2H, m), 3.81-3.87 (2H, m), 4.18
(1H, tt, J = 3.8 and 11.8 Hz), 6.36-6.44 (1H, m), 7.36 (1H, s) 308
123 ##STR00227## colorless viscous solid CDCl.sub.3 1.20-1.33 (1H,
m), 1.37-1.50 (2H, m), 1.71-1.97 (7H, m), 2.14-2.22 (2H, m), 2.43
(3H, s), 2.85-2.91 (1H, m), 3.59-3.65 (2H, m), 3.72-3.79 (2H, m),
4.18 (1H, tt, J = 3.8 and 11.8 Hz), 6.42-6.48 (1H, m), 7.34 (1H, s)
322 124 ##STR00228## pale yellow foamy solid CDCl.sub.3 1.22-1.35
(1H, m), 1.39-1.53 (2H, m), 1.71-1.97 (5H, m), 2.15-2.25 (3H, m),
2.46 (3H, s), 2.84 (3H, s), 3.20-3.26 (2H, m), 3.72-3.79 (2H, m),
4.20 (1H, tt, J = 3.8 and 11.8 Hz), 6.97-7.04 (1H, m), 7.18 (1H,
dd, J = 1.9 and 8.6 Hz), 7.47 (1H, s), 7.50 (1H, dd, J = 2.3 and
13.8 Hz), 7.58 (1H, brs) 431
TABLE-US-00060 TABLE 60 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 125 ##STR00229## colorless solid 112-125 DMSO-d.sub.6
1.18-1.30 (1H, m), 1.37-1.50 (2H, m), 1.63-1.88 (5H, m), 2.02-2.10
(2H, m), 2.40 (3H, s), 2.89 (3H, s), 3.20-3.26 (2H, m), 3.52-3.58
(2H, m), 4.22 (1H, tt, J = 3.8 and 11.7 Hz), 7.18-7.26 (1H, m),
7.39-7.45 (1H, m), 7.64 (1H, dd, J = 2.0 and 15.3 Hz), 8.06 (1H,
s), 10.30 (1H, brs) 431 126 ##STR00230## colorless foamy solid
CDCl.sub.3 1.22-1.34 (1H, m), 1.28 (3H, t, J = 7.1 Hz), 1.37-1.50
(2H, m), 1.62-2.00 (13H, m), 2.14-2.22 (2H, m), 2.44 (3H, s),
2.49-2.57 (1H, m), 4.08-4.22 (2H, m), 4.16 (2H, q, J = 7.1 Hz),
5.84-5.90 (1H, m), 7.32 (1H, s) 418 127 ##STR00231## colorless
solid 212-213 CDCl.sub.3 1.20-2.06 (16H, m), 2.13-2.22 (2H, m),
2.44 (3H, s), 2.60-2.68 (1H, m), 4.06-4.23 (2H, m), 5.82-5.89 (1H,
m), 7.32 (1H, s) 390 128 ##STR00232## colorless solid 150-153
CDCl.sub.3 1.22-1.97 (17H, m), 2.13-2.21 (2H, m), 2.45 (3H, s),
3.57-3.61 (2H, m), 4.09-4.27 (2H, m), 5.93-5.98 (1H, m), 7.32 (1H,
s) 376
TABLE-US-00061 TABLE 61 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 129 ##STR00233## colorless solid 147-148 CDCl.sub.3
0.98-1.11 (2H, m), 1.21-1.35 (1H, m), 1.38-1.50 (4H, m), 1.53-1.65
(1H, m), 1.72-1.97 (7H, m), 2.00-2.08 (2H, m), 2.14-2.21 (2H, m),
2.26 (1H, tt, J = 3.6 and 12.2 Hz), 2.44 (3H, s), 3.28-3.34 (2H,
m), 3.67 (3H, s), 4.18 (1H, tt, J = 3.8 and 11.8 Hz), 5.92-6.00
(1H, m), 7.33 (1H, s) 418 130 ##STR00234## colorless cryst. 101-104
(EtOAc) CDCl.sub.3 0.92-1.10 (4H, m), 1.21-1.34 (2H, m), 1.36-1.55
(3H, m), 1.70-1.97 (9H, m), 2.13-2.21 (2H, m), 2.44 (3H, s),
3.28-3.34 (2H, m), 3.46-3.51 (2H, m), 4.18 (1H, tt, J = 3.8 and
11.9 Hz), 5.92-6.00 (1H, m), 7.33 (1H, s) 390 131 ##STR00235##
colorless solid 265 (dec.) CDCl.sub.3 1.21-2.22 (18H, m), 1.45 (9H,
s), 2.43 (3H, s), 3.37-3.53 (1H, m), 3.87-3.97 (1H, m), 4.17 (1H,
tt, J = 3.8 and 11.9 Hz), 4.37-4.45 (1H, m), 5.66-5.72 (1H, m),
7.31 (1H, s) 461 132 ##STR00236## colorless cryst. 154-156
(Et.sub.2O) CDCl.sub.3 1.20-1.98 (14H, m), 2.05-2.23 (4H, s), 2.44
(3H, s), 2.65-2.74 (1H, m), 3.86-3.96 (1H, m), 4.18 (1H, tt, J =
3.8 and 11.8 Hz), 5.64-5.69 (1H, m), 7.30 (1H, s) 361
TABLE-US-00062 TABLE 62 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 133 ##STR00237## colorless solid 211-214 CDCl.sub.3
1.19-1.49 (7H, m), 1.71-2.03 (7H, m), 2.13-2.29 (5H, m), 2.44 (3H,
s), 2.56-2.61 (4H, m), 3.72-3.77 (4H, m), 3.85-3.94 (1H, m), 4.17
(1H, tt, J = 3.9 and 11.8 Hz), 5.66-5.71 (1H, m), 7.30 (1H, s) 431
134 ##STR00238## colorless solid 184-187 CDCl.sub.3 1.21-1.52 (5H,
m), 1.71-1.97 (5H, m), 2.01-2.08 (2H, m), 2.04-2.11 (2H, m), 2.44
(3H, s), 2.70-2.80 (2H, m), 3.08-3.15 (2H, m), 3.99-4.10 (1H, m),
4.18 (1H, tt, J = 3.9 and 11.8 Hz), 5.72-5.79 (1H, m), 7.32 (1H, s)
347 135 ##STR00239## colorless solid 207-208 CDCl.sub.3 1.22-1.34
(1H, m), 1.38-1.68 (6H, m), 1.71-1.96 (7H, m), 2.03-2.11 (2H, m),
2.13-2.21 (2H, m), 2.30-2.39 (2H, m), 2.44 (3H, s), 2.46-2.55 (1H,
m), 2.92-3.00 (2H, m), 3.35-3.45 (2H, m), 3.92-4.07 (3H, m), 4.17
(1H, tt, J = 3.8 and 11.8 Hz), 5.71-5.77 (1H, m), 7.31 (1H, s) 431
136 ##STR00240## colorless solid 217-220 CDCl.sub.3 1.22-1.96 (18H,
m), 2.01-2.09 (2H, m), 2.13-2.21 (2H, m), 2.36-2.49 (3H, m), 2.44
(3H, s), 2.87-2.94 (2H, m), 3.77-3.84 (1H, m), 3.91-4.01 (8H, m),
4.17 (1H, tt, J = 3.8 and 11.8 Hz), 5.76-5.80 (1H, m), 7.31 (1H, s)
487
TABLE-US-00063 TABLE 63 properties m.p. (.degree. C.) MS Example
(recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 137 ##STR00241## colorless solid 207-210 CDCl.sub.3
1.21-2.22 (18H, m), 2.28-2.54 (4H, m), 2.44 (3H, s), 2.58-2.66 (1H,
m), 2.72-2.82 (1H, m), 2.93-3.01 (2H, m), 3.93-4.02 (1H, m), 4.18
(1H, tt, J = 3.8 and 11.8 Hz), 5.73-5.79 (1H, m), 7.32 (1H, s) 443
138 ##STR00242## colorless solid 150-160 CDCl.sub.3 1.20-1.65 (8H,
m), 1.69-1.98 (8H, m), 2.00-2.10 (4H, m), 2.13-2.20 (2H, m),
2.30-2.41 (3H, m), 2.44 (3H, s), 2.95-3.96 (2H, m), 3.55-3.64 (1H,
m), 3.88-4.01 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),
5.70-5.77 (1H, m), 7.31 (1H, s) 445 139 ##STR00243## colorless
solid 197 (dec.) CDCl.sub.3 1.22-1.33 (1H, m), 1.37-1.64 (4H, m),
1.48 (9H, s), 1.70-1.96 (7H, m), 2.15-2.21 (2H, m), 2.45 (3H, s),
2.57-2.67 (1H, m), 2.72-2.84 (2H, m), 4.12-4.30 (3H, m), 7.18 (2H,
d, J = 8.5 Hz), 7.46 (1H, s), 7.51 (2H, d, J = 8.5 Hz), 7.63 (1H,
brs) 523 140 ##STR00244## pale yellow foamy solid CDCl.sub.3
1.22-1.33 (1H, m), 1.37-1.50 (2H, m), 1.52-1.67 (1H, m), 1.70-1.95
(8H, m), 2.13-2.21 (2H, m), 2.44 (3H, s), 2.55-2.64 (1H, m),
2.68-2.78 (2H, m), 3.13-3.21 (2H, m), 4.18 (1H, tt, J = 3.8 and
11.8 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.45 (1H, s), 7.50 (2H, d, J =
8.4 Hz), 7.60 (1H, brs) 423
TABLE-US-00064 TABLE 64 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 141 ##STR00245## colorless cryst. 270 (dec.)
(EtOH/Et.sub.2O) DMSO-d.sub.6 1.14-1.28(1H, m), 1.35-1.48(2H, m),
1.59- 1.93(9H, m), 1.99-2.07(2H, m), 2.47(3H, s), 2.74- 2.84(1H,
m), 2.90-3.01(2H, m), 3.26-3.36(2H, m), 4.18(1H, tt, J = 3.8 and
11.8 Hz), 7.18(2H, d, J = 8.5 Hz), 7.65(2H, d, J = 8.5 Hz), 8.06
(1H, s), 8.42-8.58(1H, m), 8.63-8.77(1H, m), 10.21(1H, brs) 423 142
##STR00246## colorless foamy solid CDCl.sub.3 1.20-1.33(1H, m),
1.37-1.51(2H, m), 1.69- 1.95(9H, m), 1.98-2.07(2H, m),
2.12-2.21(2H, m), 2.31(3H, s), 2.39-2.49(1H, m), 2.45(3H, s), 2.92-
3.00(2H, m), 4.18(1H, tt, J = 3.8 and 11.8 Hz), 7.21(2H, d, J = 8.5
Hz), 7.44(1H, s), 7.50 (2H, d, J = 8.5 Hz), 7.57(1H, brs) 437 143
##STR00247## pale brown solid 197-198 CDCl.sub.3 1.12(3H, t, J =
7.3 Hz), 1.21-1.33(1H, m), 1.37- 1.51(2H, m), 1.69-1.96(5H, m),
2.15-2.22(2H, m), 2.45(3H, s), 2.48(2H, q, J = 7.3 Hz),
2.58-2.66(4H, m), 3.07-3.14(4H, m), 4.18(1H, tt, J = 3.8 and 11.8
Hz), 6.89-6.97(1H, m), 7.15(1H, dd, J = 1.6 and 8.6 Hz), 7.43(1H,
s), 7.46-7.53(1H, m), 7.51(1H, brs) 470 144 ##STR00248## brown
foamy solid CDCl.sub.3 1.21-1.33(1H, m), 1.37-1.50(2H, m), 1.69-
2.04(7H, m), 2.12-2.21(2H, m), 2.39(3H, s), 2.44(3H, s),
2.62-2.67(2H, m), 2.73- 2.78(2H, m), 3.35-3.44(4H, m), 4.17(1H, tt,
J = 3.8 and 11.8 Hz), 6.76-6.83(1H, m), 7.09(1H, dd, J = 1.9 and
8.9 Hz), 7.43(1H, s), 7.48(1H, dd, J = 2.4 and 11.6 Hz), 7.42(1H,
s), 7.51(1H, brs) 470
TABLE-US-00065 TABLE 65 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 145 ##STR00249## colorless solid 216-218 (AcOEt/ hexane)
CDCl.sub.3 1.21-1.52(3H, m), 1.38(3H, t, J = 7.1 Hz), 1.71-
1.99(5H, m), 2.16-2.25(2H, m), 2.45(3H, s), 3.92(3H, s),
4.13-4.22(1H, m), 4.35(2H, q, J = 7.1 Hz), 6.95(1H, dd, J = 1.8 and
8.4 Hz), 7.52(1H, s), 7.72(1H, d, 1.8 Hz), 7.84(1H, d, J = 8.4 Hz),
7.92(1H, brs) 442 146 ##STR00250## colorless solid 223-224.5
(AcOEt) DMSO-d.sub.6 1.15-1.30(1H, m), 1.38-1.51(2H, m), 1.62-
1.90(5H, m), 2.02-2.13(2H, m), 2.41(3H, s), 3.83(3H, s),
4.17-4.29(1H, m), 7.43(1H, dd, J = 1.6 and 8.5 Hz), 7.59(1H, d, 1.6
Hz), 7.72(1H, d, J = 8.5 Hz), 8.12(1H, s), 10.41(1H, brs),
12.31(1H, brs) 414 147 ##STR00251## colorless solid 193.5-198
DMSO-d.sub.6 1.17-1.31(1H, m), 1.39-1.51(2H, m), 1.62- 1.90(5H, m),
2.02-2.13(2H, m), 2.41(3H, s), 2.78(3H, s), 2.88-3.08(2H, m),
3.19-3.60 (5H, m), 3.84(3H, s), 4.17- 4.29(1H, m), 4.51-4.64(1H,
m), 7.19-7.29(1H, m), 7.41- 7.54(1H, m), 7.59-7.68(1H, m), 8.21(1H,
s), 10.50(1H, brs), 11.20(1H, brs) 496 148 ##STR00252## colorless
solid 188.5-190 (AcOEt/ hexane) CDCl.sub.3 1.21-1.35(1H, m),
1.39-1.1.52(2H, m), 1.71- 2.00(5H, m), 2.13-2.25(2H, m), 2.50(3H,
s), 3.19- 3.39(2H, m), 3.51-3.65(2H, m), 3.70-3.97(4H, m), 3.77(3H,
s), 4.14-4.26(1H, m), 6.80(1H, dd, J = 1.8 and 8.1 Hz), 7.04(1H, d,
J = 8.1 Hz), 7.37(1H, d, J = 1.7 Hz), 7.76(1H, s), 8.72(1H, brs)
483
TABLE-US-00066 TABLE 66 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 149 ##STR00253## colorless solid 242.5-245.5 CDCl.sub.3
1.21-1.69(6H, m), 1.71-2.00(7H, m), 2.13- 2.25(2H, m), 4.46(3H, s),
2.99-3.18(1H, m), 3.34- 3.59(2H, m), 3.70-3.80(3H, m),
3.90-4.00(1H, m), 4.13- 4.34(2H, m), 6.77-6.82(1H, m),
6.95-7.03(1H, m), 7.29- 7.36(1H, m), 7.82(1H, s), 8.84(1H, brs) 497
150 ##STR00254## colorless solid 243-245.5 CDCl.sub.3 1.21-1.36(1H,
m), 1.39-1.51(2H, m), 1.70- 2.00(5H, m), 2.15-2.25(2H, m), 3.27(1H,
brt, J = 5.2 Hz), 3.60-3.69(2H, m), 3.79-3.89 (2H, m), 3.99(3H, s),
4.13- 4.25(1H, m), 6.88(1H, dd, J = 1.8 and 8.5 Hz), 7.58(1H, s),
7.93(1H, d, J = 1.8 Hz), 8.13 (1H, d, J = 8.5 Hz), 8.15(1H, brs),
8.26(1H, brt, 5.5 Hz) 457 151 ##STR00255## colorless solid 187-188
CDCl.sub.3 1.21-1.35(1H, m), 1.39-1.52(2H, m), 1.71- 1.99(5H, m),
2.14-2.24(2H, m), 2.44(3H, s), 3.41(3H, s), 3.52-3.60(2H, m),
3.62-3.70 (2H, m), 3.99(3H, s), 4.13- 4.24(1H, m), 6.89(1H, dd, J =
1.5 and 8.5 Hz), 7.57(1H, s), 7.95(1H, d, J = 1.5 Hz), 8.11(1H,
brs), 8.16(1H, d, J = 8.5 Hz), 8.19(1H, brt, 5.3 Hz) 471 152
##STR00256## colorless solid 279-281 (AcOEt) CDCl.sub.3
1.22-1.36(1H, m), 1.39-1.52(2H, m), 1.71- 1.99(5H, m),
2.14-2.23(2H, m), 2.45(3H, s), 3.01(3H, d, J = 4.8 Hz), 4.00(3H,
s), 4.13- 4.23(1H, m), 6.87(1H, dd, J = 1.8 and 8.5 Hz), 7.56(1H,
s), 7.81(1H, brq, J = 4.8 Hz), 7.97(1H, d, J = 1.8 Hz), 8.04 (1H,
brs), 8.19(1H, d, J = 8.5 Hz) 427
TABLE-US-00067 TABLE 67 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 153 ##STR00257## colorless solid 216-218 (AcOEt)
CDCl.sub.3 1.21-1.37(1H, m), 1.39-1.52(2H, m), 1.70- 1.98(5H, m),
2.15-2.25(2H, m), 2.47(3H, s), 2.87(3H, s), 3.16(3H, s), 3.73(3H,
s), 4.13- 4.24(1H, m), 6.79(1H, dd, J = 1.4 and 8.1 Hz), 6.98(1H,
d, J = 8.1 Hz), 7.28(1H, d, J = 1.4 Hz), 7.88(1H, s), 8.98(1H, brs)
441 154 ##STR00258## colorless solid 169-172.5 (EtOH) CDCl.sub.3
1.21-1.34(1H, m), 1.38-1.51(2H, m), 1.69- 1.97(5H, m),
2.12-2.21(2H, m), 2.34(3H, s), 2.44(3H, s), 2.53-2.64(4H, m),
3.03-3.14 (4H, m), 4.11-4.21(1H, m), 6.89-6.96(1H, m), 7.15(1H, dd
J = 2.4 and 8.6 Hz), 7.43(1H, s), 7.49(1H, dd J = 2.4 and 14.0 Hz),
7.53(1H, brs) 456 155 ##STR00259## colorless solid 270(dec.)
DMSO-d.sub.6 1.15-1.29(1H, m), 1.34-1.49(2H, m), 1.60- 1.88(5H, m),
1.99-2.09(2H, m), 2.30(3H, s), 2.37(3H, s), 2.84(3H, s),
2.90-3.62(8H, m), 4.13-4.27(1H, m), 7.08- 7.14(1H, m),
7.39-7.45(1H, m), 7.62-7.71(1H, m), 8.02(1H, s), 9.56(1H, brs),
10.28(1H, brs) 456 156 ##STR00260## colorless solid 114-118 (EtOH)
CDCl.sub.3 1.21-1.35(1H, m), 1.40-1.52(2H, m), 1.71- 1.98(5H, m),
2.14-2.23(2H, m), 2.39(3H, s), 2.46(3H, s), 2.54-2.72(4H, m),
3.00-3.17 (4H, m), 4.14-4.26(1H, m), 7.05(1H, d, J = 8.7 Hz), 7.43
(1H, dd, J = 2.4 and 8.7 Hz), 7.46(1H, s), 7.57(1H, brs), 7.69(1H,
d, J = 2.4 Hz) 472
TABLE-US-00068 TABLE 68 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 157 ##STR00261## colorless solid 188-189.5 (EtOH)
CDCl.sub.3 1.21-1.35(1H, m), 1.39-1.51(2H, m), 1.70- 1.98(9H, m),
2.14-2.23(2H, m), 2.45(3H, s), 3.11- 3.19(4H, m), 4.00(4H, s),
4.12-4.24(1H, m), 6.91- 6.98(1H, m), 7.16(1H, dd J = 2.4 and 8.6
Hz), 7.46(1H, s), 7.49(1H, dd, J = 2.4 and 13.9 Hz), 7.61(1H, brs)
499 158 ##STR00262## colorless solid 198-199 (EtOH) CDCl.sub.3
1.21-1.35(1H, m), 1.39-1.52(2H, m), 1.70- 1.99(5H, m),
2.16-2.25(2H, m), 2.46(3H, s), 2.59- 2.68(4H, m), 3.34-3.43(4H, m),
4.14-4.25(1H, m), 6.94- 7.01(1H, m), 7.18-7.23(1H, m), 7.47(1H, s),
7.56(1H, dd, J = 2.4 and 13.7 Hz), 7.62(1H, brs) 455 159
##STR00263## colorless solid 210-212 (EtOH) CDCl.sub.3
1.21-1.34(1H, m), 1.39-1.52(3H, m), 1.70- 1.98(7H, m),
2.00-2.09(2H, m), 2.16-2.24(2H, m), 2.46(3H, s), 279-2.89(2H, m),
3.29-3.39(2H, m), 3.81- 3.91(1H, m), 4.13-4.24(1H, m),
6.91-7.00(1H, m), 7.17(1H, dd, J = 2.5 and 8.6 Hz), 7.46(1H, s),
7.48(1H, dd, J = 2.5 and 13.9 Hz), 7.58(1H, brs) 457 160
##STR00264## colorless solid 230.5-232 (EtOH) CDCl.sub.3
1.22-1.36(1H, m), 1.39-1.52(2H, m), 1.71- 1.98(9H, m),
2.15-2.23(2H, m), 2.45(3H, s), 3.05- 3.16(4H, m), 4.01(4H, s),
4.15- 4.24(1H, m), 7.05(1H, d, J = 8.7 Hz), 7.44(1H, dd, J = 2.5
and 8.7 Hz), 7.46(1H, s), 7.58(1H, brs), 7.66 (1H, d, J = 2.5 Hz)
515
TABLE-US-00069 TABLE 69 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 161 ##STR00265## colorless solid 217.5-219 (EtOH)
CDCl.sub.3 1.21-1.37(1H, m), 1.40-1.52(2H, m), 1.71- 1.99(5H, m),
2.15-2.24(2H, m), 2.46(3H, s), 2.60- 2.70(4H, m), 3.29-3.38(4H, m),
4.13-4.26(1H, m), 7.05(1H, d, J = 8.7 Hz), 7.47 (1H, dd, J = 2.5
and 8.7 Hz), 7.48(1H, s), 7.64(1H, brs), 7.73(1H, d, J = 2.5 Hz)
471 162 ##STR00266## colorless solid 153.5-156 (AcOEt/ hexane)
CDCl.sub.3 1.21-1.36(1H, m), 1.39-1.53(3H, m), 1.71- 1.99(7H, m),
2.01-2.10(2H, m), 2.16-2.24(2H, m), 2.45(3H, s), 275-2.87(2H, m),
3.21-3.31(2H, m), 3.82- 3.92(1H, m), 4.14-4.26(1H, m), 7.03(1H, d,
J = 8.7 Hz), 7.44(1H, dd, J = 2.5 and 8.7 Hz), 7.47(1H, s),
7.63(1H, brs), 7.65(1H, d, J = 2.5 Hz) 473 163 ##STR00267##
colorless solid 174-176 (AcOEt/ hexane) CDCl.sub.3 1.22-1.36(1H,
m), 1.39-1.63(4H, m), 1.71- 2.07(7H, m), 2.14-2.23(2H, m),
2.41-2.56(1H, m), 2.46(3H, s), 2.48(3H, s), 2.68-2.80(2H, m), 3.38-
3.45(2H, m), 4.14-4.23(1H, m), 6.90-6.99(1H, m), 7.17(1H, dd, J =
2.4 and 8.6 Hz), 7.42-7.51(2H, m), 7.58(1H, brs) 470 164
##STR00268## colorless solid 99.5-106.5 CDCl.sub.3 1.22-1.36(1H,
m), 1.39-1.52(2H, m), 1.49(9H, s), 1.70-2.00(9H, m), 2.14- 2.24(2H,
m), 2.46(3H, s), 2.67-2.77(2H, m), 2.81(3H, s), 3.37-3.46(2H, m),
4.10- 4.26(2H, m), 7.00-7.07(1H, m), 7.39-7.45(1H, m), 7.47(1H, s),
7.59-7.62(1H, m), 7.69(1H, brs) 586
TABLE-US-00070 TABLE 70 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 165 ##STR00269## colorless solid 112-121 CDCl.sub.3
1.22-1.37(1H, m), 1.39-1.65(4H, m), 1.71- 2.08(7H, m),
2.16-2.25(2H, m), 2.46(3H, s), 2.49(3H, s), 2.50-2.58(1H, m),
265-2.76 (2H, m), 3.30-3.39(2H, m), 4.12-4.24(1H, m), 7.04(1H, d, J
= 8.7 Hz), 7.45(1H, dd, J = 2.4 and 8.7 Hz), 7.46(1H, s), 7.56(1H,
brs), 7.64(1H, d, J = 2.4 Hz) 486 166 ##STR00270## colorless solid
230-233.5 (AcOEt) CDCl.sub.3 1.17-1.32(3H, m), 1.36-1.49(4H, m),
1.69- 2.00(7H, m), 2.10-2.20(4H, m), 2.22-2.30(1H, m), 2.27(3H, s),
2.37-2.70(8H, m), 2.41(3H, s), 3.81- 3.92(1H, m), 4.09-4.21(1H, m),
5.62-5.69(1H, m), 7.28(1H, s) 444 167 ##STR00271## colorless solid
195-199 (AcOEt) CDCl.sub.3 1.17-1.32(3H, m), 1.36-1.50(4H, m),
1.69- 1.95(9H, m), 2.09-2.20(4H, m), 2.34(3H, s), 2.41(3H, s),
2.42-2.50(1H, m), 2.52-2.62 (4H, m), 2.71-2.80(4H, m),
3.80-3.91(1H, m), 4.10-4.20 (1H, m), 5.61-5.69(1H, m), 7.28(1H, s)
458 168 ##STR00272## colorless solid 204.5-207 (AcOEt/ hexane)
CDCl.sub.3 1.18-1.32(3H, m), 1.36-1.49(4H, m), 1.51- 1.61(2H, m),
1.69-1.95(9H, m), 2.10-2.20(4H, m), 2.25- 2.38(3H, m), 2.41(3H, s),
2.72-2.81(2H, m), 3.13- 3.22(1H, m), 3.32(3H, s), 3.80-3.93(1H, m),
4.11- 4.21(1H, m), 5.62-5.69 (1H, m), 7.28(1H, s) 459
TABLE-US-00071 TABLE 71 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 169 ##STR00273## colorless solid 61-63 CDCl.sub.3
1.12-1.50(7H, m), 1.68-1.95(9H, m), 2.05- 2.20(4H, m),
2.35-2.50(1H, m), 2.41(3H, s), 2.57- 2.78(4H, m), 3.41-3.59(4H, m),
3.76-3.90(1H, m), 4.08- 4.21(1H, m), 5.13(2H, s), 5.60-5.71(1H, m),
7.28- 7.40(6H, m) 578 170 ##STR00274## colorless solid 115-120
CDCl.sub.3 1.17-1.32(3H, m), 1.36-1.50(4H, m), 1.64- 1.96(9H, m),
2.09-2.21(4H, m), 2.41(3H, s), 2.43- 2.54(1H, m), 2.68-2.77(4H, m),
2.83-2.94(4H, m), 3.80- 3.92(1H, m), 4.10-4.21(1H, m),
5.61-5.70(1H, m), 7.28(1H, s) 444 171 ##STR00275## colorless foamy
solid CDCl.sub.3 1.17-1.50(7H, m), 1.69-1.97(9H, m), 2.07 and
2.08(total 3H, each s), 2.10-2.21(4H, m), 2.41(3H, s),
2.44-2.54(1H, m), 2.61-2.69 (2H, m), 2.71-2.79(2H, m),
3.41-3.52(2H, m), 3.55-3.12 (2H, m), 3.79-3.92(1H, m),
4.11-4.21(1H, m), 5.64- 5.72(1H, m), 7.28(1H, s) 486 172
##STR00276## colorless solid 142-143.5 (AcOEt/ hexane) CDCl.sub.3
1.17-1.32(3H, m), 1.35-1.49(4H, m), 1.69- 1.96(7H, m),
2.10-2.20(4H, m), 2.30(3H, s), 2.39- 2.48(1H, m), 2.41(3H, s), 2.63
(2H, t, J = 5.9 Hz), 3.35(3H, s), 3.45(2H, t, J = 5.9 Hz),
3.80-3.92(1H, m), 4.10- 4.20(1H, m), 5.61-5.69 (1H, m), 7.28(1H, s)
433
TABLE-US-00072 TABLE 72 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 173 ##STR00277## colorless foamy solid CDCl.sub.3
1.20-1.97(16H, m), 2.11-2.20(2H, m), 2.28- 2.47(1H, m), 2.33(3H,
s), 2.44(3H, s), 2.68(2H, t, J = 6.0 Hz), 3.35(3H, s), 3.47(2H, t,
J = 6.0 Hz), 4.11- 4.24(2H, m), 5.93-6.00 (1H, m), 7.30(1H, s) 433
174 ##STR00278## colorless solid 222-224.5 (EtOH) CDCl.sub.3
1.16-1.31(3H, m), 1.35-1.50(4H, m), 1.68- 1.96(11H, m), 2.09-2.19
(4H, m), 2.31-2.40(1H, m), 2.41(3H, s), 2.58-2.67(4H, m),
3.80-3.92(1H, m), 3.94(4H, s), 4.10-4.20(1H, m), 5.62-5.71(1H, m),
7.28(1H, s) 487 175 ##STR00279## colorless solid 197-199 (AcOEt)
CDCl.sub.3 1.19-1.32(3H, m), 1.36-1.52(4H, m), 1.69- 2.00(7H, m),
2.10-2.23(4H, m), 2.36-2.56(8H, m), 2.79- 2.89(4H, m),
3.82-3.95(1H, m), 4.10-4.20(1H, m), 5.66- 5.76(1H, m), 7.29(1H, s)
443 176 ##STR00280## colorless solid 200-202 (AcOEt) CDCl.sub.3
1.18-1.31(3H, m), 1.36-1.97(16H, m), 2.10- 2.20(4H, m),
2.27-2.38(3H, m), 2.41(3H, s), 2.75- 2.85(2H, m), 3.61-3.71(1H, m),
3.80-3.92(1H, m), 4.10- 4.20(1H, m), 5.64-5.73 (1H, m), 7.28(1H, s)
445
TABLE-US-00073 TABLE 73 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 177 ##STR00281## colorless solid 226-228 (EtOH) CDCl.sub.3
1.15(6H, d, J = 6.2 Hz), 1.17-1.32(3H, m), 1.34- 1.50(4H, m),
1.69-1.99(9H, m), 2.11-2.27(5H, m), 2.41(3H, s), 2.68-2.78(2H, m),
3.59-3.69(2H, m), 3.81- 3.93(1H, m), 4.11-4.20(1H, m),
5.63-5.70(1H, m), 7.28(1H, s) 459 178 ##STR00282## colorless solid
199.5-200.5 (EtOH) CDCl.sub.3 1.17(6H, d, J = 6.2 Hz),
1.20-1.33(1H, m), 1.36- 1.50(2H, m), 1.53-1.96(15H, m),
2.09-2.20(3H, m), 2.43(3H, s), 2.80-2.89(2H, m), 3.60-3.70(2H, m),
4.10- 4.22(2H, m), 5.89-5.96 (1H, m), 7.30(1H, s) 459 179
##STR00283## colorless solid 201.5-203 (AcOEt/ hexane) CDCl.sub.3
1.17-1.98(18H, m), 2.10-2.38(8H, m), 2.41(6H, s), 2.81-2.90(2H, m),
3.80- 3.92(1H, m), 4.11-4.20(1H, m), 5.62-5.69(1H, m), 7.29(1H, s)
458 180 ##STR00284## colorless solid 253-255 (AcOEt/EtOH)
CDCl.sub.3 1.18-1.31(3H, m), 1.35-1.50(4H, m), 1.57- 2.00(11H, m),
2.07 and 2.10(total 3H, each s), 2.11- 2.21(4H, m), 2.24-2.40 (3H,
m), 2.41(3H, s), 2.81 and 2.85(total 3H, each s), 2.90-3.01(2H, m),
3.41- 3.51(0.4H, m), 3.81-3.94 (1H, m), 4.10-4.21(1H, m),
4.41-4.52(0.6H, m), 5.67- 5.74(1H, m), 7.29(1H, s) 500
TABLE-US-00074 TABLE 74 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 181 ##STR00285## colorless solid 204-208.5 (AcOEt)
CDCl.sub.3 1.18-1.33(3H, m), 1.36-1.50(4H, m), 1.55- 1.99(11H, m),
2.10-2.20 (4H, m), 2.23-2.48(4H, m), 2.38(6H, s), 2.41(3H, s),
2.95-3.05(2H, m), 3.80- 3.92(1H, m), 4.10-4.20(1H, m),
5.68-5.74(1H, m), 7.29(1H, s) 472 182 ##STR00286## colorless solid
215.5-224 CDCl.sub.3 1.16-1.50(9H, m), 1.43(9H, s), 1.69-1.99(9H,
m), 2.10-2.19(4H, m), 2.22- 2.36(3H, m), 2.41(3H, s), 2.78-2.87(2H,
m), 3.36-3.49 (1H, m), 3.81-3.92(1H, m), 4.09-4.20(1H, m),
4.35-4.44 (1H, m), 5.62-5.69(1H, m), 7.28(1H, s) 544 183
##STR00287## colorless solid CDCl.sub.3 1.20-2.00(20H, m), 1.44(9H,
s), 2.11-2.28(5H, m), 2.43(3H, s), 2.40-2.49 (2H, m), 3.38-3.51(1H,
m), 4.11-4.22(2H, m), 4.33-4.46 (1H, m), 5.90-5.97(1H, m), 7.30(1H,
s) 544 184 ##STR00288## colorless solid 219-221.5 (AcOEt/ hexane)
CDCl.sub.3 1.16-1.52(9H, m), 1.69-1.96(9H, m), 2.10- 2.38(7H, m),
2.41(3H, s), 2.57-2.68(1H, m), 2.80- 2.89(2H, m), 3.80-3.92(1H, m),
4.10-4.21(1H, m), 5.62- 5.70(1H, m), 7.28(1H, s) 444
TABLE-US-00075 TABLE 75 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 185 ##STR00289## colorless solid 83-86.5 CDCl.sub.3
1.20-1.95(20H, m), 2.02-2.36(5H, s), 2.43(3H, s), 2.60-2.70(1H, m),
2.92- 3.03(2H, m), 4.11-4.22(2H, m), 5.91-6.00(1H, m), 7.30(1H, s)
444 186 ##STR00290## colorless solid 190.5-193.5 CDCl.sub.3
1.17-1.32(3H, m), 1.36-1.49(4H, m), 1.45(9H, s), 1.69-1.96(7H, m),
2.11- 2.21(4H, m), 2.25-2.36(1H, m), 2.41(3H, s), 2.45-2.53 (4H,
m), 3.38-3.45(4H, m), 3.81-3.93(1H, m), 4.10-4.20 (1H, m),
5.63-5.70(1H, m), 7.28(1H, s) 530 187 ##STR00291## colorless foamy
solid CDCl.sub.3 1.20-1.96(16H, m), 1.45(9H, s), 2.11-2.24(3H, m),
2.43(3H, s), 2.45-2.51 (4H, m), 3.39-3.47(4H, m), 4.10-4.21(2H, m),
5.88- 5.93(1H, m), 7.30(1H, s) 530 188 ##STR00292## colorless solid
180.5-182 (AcOEt) CDCl.sub.3 1.18-1.32(3H, m), 1.34-1.49(4H, m),
1.69- 1.99(7H, m), 2.10-2.19(4H, m), 2.20-2.29(1H, m), 2.41(3H, s),
2.48-2.58(4H, m), 2.82-2.91(4H, m), 3.80- 3.93(1H, m),
4.10-4.20(1H, m), 5.63-5.70(1H, m), 7.28(1H, s) 430
TABLE-US-00076 TABLE 76 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 189 ##STR00293## colorless solid 161-164.5 CDCl.sub.3
1.20-1.96(16H, m), 2.11-2.21(3H, m), 2.43(3H, s), 2.46-2.58(4H, m),
2.87- 2.96(4H, m), 4.10-4.22(2H, m), 5.90-5.99(1H, m), 7.30(1H, s)
430 190 ##STR00294## colorless solid 242-243.5 (AcOEt/EtOH)
CDCl.sub.3 1.18-1.32(3H, m), 1.35-1.50(4H, m), 1.69- 1.96(7H, m),
2.07(3H, s), 2.11-2.21(4H, m), 2.27- 2.38(1H, m), 2.41(3H, s),
2.49-2.59(4H, m), 3.40- 3.47(2H, m), 3.57-3.63(2H, m),
3.81-3.93(1H, m), 4.10- 4.21(1H, m), 5.64-5.71 (1H, m), 7.28(1H, s)
472 191 ##STR00295## pale brown solid 237(dec.) DMSO-d.sub.6
1.16-1.29(1H, m), 1.35-1.50(2H, m), 1.61- 1.84(5H, m), 1.881.96(2H,
m), 2.00-2.08(2H, m), 2.35(3H, s), 2.36(3H, s), 2.63-2.69(2H, m),
2.72- 2.77(2H, m), 3.25-3.35(4H, m), 4.19(1H, tt, J = 3.8 and 11.7
Hz), 6.51(1H, s), 6.88- 6.95(1H, m), 7.29(1H, dd, J = 2.0 and 8.8
Hz), 7.55(1H, dd, J = 2.3 and 15.7 Hz), 7.98(1H, s), 10.15(1H, brs)
470 192 ##STR00296## colorless solid CDCl.sub.3 1.64-1.73(2H, m),
2.00-2.10(2H, m), 2.10(3H, s), 3.22(2H, s), 3.43-3.52 (2H, m),
4.02-4.09(2H, m), 4.23(1H, tt, J = 11.7 and 4.2 Hz) 183
TABLE-US-00077 TABLE 77 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 193 ##STR00297## colorless solid CDCl.sub.3 1.80-1.88(2H,
m), 2.22-2.35(2H, m), 2.46(3H, s), 3.50-3.58(2H, m), 4.09- 4.15(2H,
m), 4.48(1H, tt, J = 11.6 and 4.2 Hz), 9.89(1H, s) 229 194
##STR00298## colorless solid 78-80 CDCl.sub.3 1.38(3H, t, J = 7.1
Hz), 2.08-2.25(4H, m), 2.45(3H, s), 3.52-3.61(2H, m), 4.10-4.17(2H,
m), 4.35(2H, q, J = 7.1 Hz), 4.38- 4.47(1H, m), 7.71(1H, s) 295 195
##STR00299## colorless solid 240-242 DMSO-d.sub.6 1.90-2.05(4H, m),
2.38(3H, s), 3.44- 3.52(2H, m), 3.92-4.00(2H, m), 4.43-4.54(1H, m),
7.66(1H, s) 267 196 ##STR00300## colorless solid 107-109 (EtOH)
CDCl.sub.3 2.08-2.26(4H, m), 2.36(3H, s), 2.46(3H, s),
2.55-2.61(4H, m), 3.16-3.23 (4H, m), 3.52-3.61(2H, m),
4.09-4.16(2H, m), 4.37-4.47 (1H, m), 6.90-6.95(2H, m), 7.45(1H, s),
7.45-7.50 (2H, m), 7.53(1H, brs) 440
TABLE-US-00078 TABLE 78 properties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 197 ##STR00301## colorless solid 98-102 (EtOH) CDCl.sub.3
2.07-2.25(4H, m), 2.36(3H, s), 2.46(3H, s), 2.57-2.63(4H, m),
3.06-3.12 (4H, m), 3.50-3.58(2H, m), 4.08-4.15(2H, m), 4.36-4.47
(1H, m), 6.89-6.96(1H, m), 7.12-7.16(1H, m), 7.45(1H, s),
7.47-7.52(1H, m), 7.52(1H, brs) 458 198 ##STR00302## colorless
foamy solid CDCl.sub.3 1.23-1.36(1H, m), 1.38-1.52(2H, m), 1.72-
1.98(5H, m), 2.15-2.25(2H, m), 2.41-2.47(4H, m), 2.46(3H, s),
3.48(2H, s), 3.69- 3.75(4H, m), 4.19(1H, tt, J = 3.8 and 11.8 Hz),
7.32(2H, d, J = 8.4 Hz), 7.47(1H, s), 7.54(2H, d, J = 8.4 Hz),
7.65(1H, brs) 439 199 ##STR00303## colorless solid 198-202
(Et.sub.2O/EtOH) DMSO-d.sub.6 1.16-1.31(1H, m), 1.38-1.52(2H, m),
1.62- 1.86(5H, m), 2.01-2.11(2H, m), 2.31-2.39(4H, m), 2.40(3H, s),
3.44(2H, s), 3.54- 3.60(4H, m), 4.22(1H, tt, J = 3.8 and 11.6 Hz),
6.62(2H, s), 7.27(2H, d, J = 8.5 Hz), 7.67(2H, d, J = 8.5 Hz),
8.06(1H, s), 10.21(1H, s) 439 200 ##STR00304## colorless solid
140-144 (Et.sub.2O/ hexane) CDCl.sub.3 1.21-1.33(1H, m),
1.38-1.51(2H, m), 1.71- 1.96(5H, m), 2.14-2.23(2H, m), 2.31(6H, m),
2.46(3H, s), 2.50-2.56(2H, m), 2.65- 2.71(2H, m), 4.19(1H, tt, J =
3.9 and 11.8 Hz), 7.18- 7.23(2H, m), 7.46(1H, s), 7.49-7.54(2H, m),
7.58(1H, brs) 411
TABLE-US-00079 TABLE 79 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 201 ##STR00305## colorless solid 162-164 CDCl.sub.3 1.24-
1.36(1H, m), 1.39-1.52(2H, m), 1.72-1.98(5H, m), 2.15-2.24(2H, m),
2.46(3H, s), 2.49-2.55(4H, m), 2.56-2.62(2H, m), 2.76-2.83(2H, m),
3.73-3.78(4H, m), 4.19(1H,tt, J = 3.9 and 11.8 Hz), 7.20(2H, d, J =
8.4 Hz), 7.46(1H, s), 7.51(2H, d, J = 8.4 Hz), 7.61(1H, brs) 453
202 ##STR00306## colorless foamy solid 216-218 CDCl.sub.3 1.24-
1.35(1H, m), 1.39-1.52(2H, m), 1.72-1.99(5H, m), 2.16-2.24(2H, m),
2.46(3H, s), 2.99(3H, s), 3.86(2H, s), 4.19(1H, tt, J = 3.9 and
11.8 Hz), 4.63(2H, s), 7.41-7.46(2H, m), 7.47(1H, s), 7.53-7.57(2H,
m), 7.63(1H, brs) 466 203 ##STR00307## colorless solid (AcOEt)
CDCl.sub.3 1.22- 1.53(3H, m), 1.72-1.99(5H, m), 2.16-2.24(2H, m),
2.47(3H, s), 3.10(3H, s), 4.04(2H, s), 4.19(1H, tt, J = 3.9 and
11.8 Hz), 7.36-7.42(2H, m), 7.51(1H, s), 7.66-7.72(2H, m), 7.79(1H,
brs) 452 204 ##STR00308## colorless solid 153-156 CDCl.sub.3 1.18-
1.33(3H, m), 1.38-1.51(2H, m), 1.55-1.67(2H, m), 1.71-1.96(5H, m),
2.03-2.22(6H, m), 2.28(1H, tt, J = 3.6 and 12.1 Hz), 2.43(3H, s),
3.68(3H, s), 3.88-4.00(1H, m), 4.16(1H, tt, J = 3.9 and 11.9 Hz),
5.69-5.75 (1H, m), 7.30(1H, s) 404
TABLE-US-00080 TABLE 80 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 205 ##STR00309## colorless solid 280-288 DMSO-d.sub.6
1.16-1.49(7H, m), 1.62-2.08(11H, m), 2.17(1H, tt, J = 3.4 and 11.5
Hz), 2.35(3H, s), 3.60-3.72(1H, m), 4.18(1H, tt, J = 3.8 and 11.5
Hz), 7.80(1H, s), 8.26(1H, d, J = 7.8 Hz), 12.12(1H, brs) 390 206
##STR00310## colorless solid 180-182 CDCl.sub.3 1.07-1.56(8H, m),
1.70-1.95(7H, m), 2.11- 2.20(4H, m), 2.43(3H, s), 3.46-3.52(2H, m),
3.85- 3.97(1H, m), 4.17(1H, tt, J = 3.8 and 11.9 Hz), 5.66-
5.72(1H, m), 7.30(1H, s) 376 207 ##STR00311## colorless foamy solid
CDCl.sub.3 1.19-1.35(3H, m), 1.37-1.51(2H, m), 1.69- 1.96(9H, m),
2.13-2.25(4H, m), 2.32(3H, s), 2.34- 2.49(5H, m), 2.43(3H, s),
3.47-3.55(2H, m), 3.60- 367(2H, m), 3.88-4.01(1H, m), 4.17(1H, tt,
J = 3.9 and 11.9 Hz), 5.65-5.71(1H, m), 7.31(1H, s) 472 208
##STR00312## colorless solid 224-228 CDCl.sub.3 1.21-1.52(5H, m),
1.67-1.96(9H, m), 2.13- 2.23(4H, m), 2.43(3H, s), 2.49(1H, tt, J =
3.5 and 11.7 Hz), 2.95(3H, s), 3.06(3H, s), 3.90-4.02(1H, m),
4.17(1H, tt, J = 3.8 and 11.9 Hz), 5.64-5.70(1H, m), 7.29(1H, s)
417
TABLE-US-00081 TABLE 81 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 209 ##STR00313## colorless solid 134-136 CDCl.sub.3
1.22-1.34(3H, m), 1.37-1.51(2H, m), 1.70- 1.87(5H, m),
1.89-1.96(2H, m), 2.13-2.23(6H, m), 2.40- 2.49(1H, m), 2.43(3H, s),
3.92-4.02(1H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 5.66-5.72(1H,
m), 7.30(1H, s) 371 210 ##STR00314## colorless foamy solid
CDCl.sub.3 1.21-1.33(1H, m), 1.37-1.50(2H, m), 1.47(9H, s),
1.69-1.95(5H, m), 2.12- 2.21(2H, m), 2.41(3H, s), 2.92(3H, s),
3.47-3.60(4H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 7.26-7.36(1H,
m), 7.34(1H, s) 421 211 ##STR00315## colorless solid 130-142
DMSO-d.sub.6 1.17-1.30(1H, m), 1.37-1.50(2H, m), 1.50- 1.86(5H, m),
2.02-2.10(2H, m), 2.36(3H, s), 2.56- 2.61(2H, m), 3.03-3.12(2H, m),
3.51-3.57(1H, m), 3.57(3H, s), 4.20(1H, tt, J = 3.8 and 11.6 Hz),
7.86(1H, s), 8.72-8.87(3H, m) 321 212 ##STR00316## colorless solid
153-154 CDCl.sub.3 1.21-1.34(1H, m), 1.37-1.49(2H, m), 1.70-
1.96(5H, m), 2.12(3H, s), 2.13-2.22(2H, m), 2.44(3H, s), 3.08(3H,
s), 3.58- 3.71(4H, m), 4.16(1H, tt, J = 3.8 and 11.8 Hz), 7.30-
7.37(1H, m), 7.31(1H, s) 363
TABLE-US-00082 TABLE 82 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 213 ##STR00317## colorless solid 120-130 DMSO-d.sub.6
1.14-1.28(1H, m), 1.35-1.48(2H, m), 1.62- 1.85(5H, m),
2.01-2.08(2H, m), 2.35(3H, s), 2.81(3H, s), 2.86(3H, s),
3.18-3.23(2H, m), 3.38-3.44(2H, m), 4.19(1H, tt, J = 3.8 and 11.5
Hz), 7.75(1H, s), 8.62- 8.68(1H, m) 399 214 ##STR00318## colorless
foamy solid CDCl.sub.3 1.21-1.34(1H, m), 1.28(3H, t, J = 7.1 Hz),
1.38-1.51(2H, m), 1.57- 1.97(7H, m), 2.01-2.08(2H, m),
2.14-2.21(2H, m), 2.36(2H, dt, J = 2.3 and 11.6 Hz), 2.44(3H, s),
2.93- 3.00(2H, m), 3.24(2H, s), 3.94-4.04(1H, m), 4.12- 4.22(1H,
m), 4.19(2H, q, J = 7.1 Hz), 5.72-5.77(1H, m), 7.32(1H, s) 433 215
##STR00319## colorless solid 230-236 DMSO-d.sub.6 1.16-130(1H, m),
1.36-1.49(2H, m), 1.61- 1.88(7H, m), 2.01-2.08(2H, m), 2.36(3H, s),
2.41- 2.59(4H, m), 3.07-3.14(2H, m), 3.17-3.20(2H, m), 3.73-
3.84(1H, m), 4.18(1H, tt, J = 3.9 and 11.5 Hz), 7.83(1H, s),
8.31-8.35(1H, m) 405 216 ##STR00320## pale yellow solid 156-158
CDCl.sub.3 1.21-1.34(1H, m), 1.29(3H, t, J = 7.1 Hz), 1.33(6H, s),
1.37-1.69(4H, m), 1.69-1.97(5H, m), 2.01- 2.08(2H, m),
2.13-2.21(2H, m), 2.31-2.41(2H, m), 2.43(3H, s), 2.92-2.99(2H, m),
3.91-4.01(1H, m), 4.12- 4.22(1H, m), 4.19(2H, q, J = 7.1 Hz),
5.70-5.75(1H, m), 7.30(1H, s) 461
TABLE-US-00083 TABLE 83 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 217 ##STR00321## colorless solid 251-256 DMSO-d.sub.6
1.16-1.30(1H, m), 1.25(6H, s), 1.34- 1.51(2H, m), 1.62- 1.86(7H,
m), 1.92- 1.99(2H, m), 2.02- 2.09(2H, m), 2.36(3H, s),
2.65-2.76(2H, m), 3.13-3.20(2H, m), 3.81- 3.91(1H, m), 4.19(1H, tt,
J = 3.7 and 11.5 Hz), 7.86(1H, s), 8.34- 8.39(1H, m) 433 218
##STR00322## colorless solid 125-127 CDCl.sub.3 1.21-1.34(1H, m),
1.38-1.50(2H, m), 1.72- 1.77(5H, m), 2.14- 2.22(2H, m), 2.36-
2.46(1H, m), 2.44(3H, s), 3.60-3.66(2H, m), 3.83- 3.88(2H, m),
4.18(1H, tt, J = 3.8 and 11.8 Hz), 6.36- 6.44(1H, m), 7.36(1H, s)
308 219 ##STR00323## colorless solid 207-208 CDCl.sub.3
1.21-1.34(1H, m), 1.38-1.51(2H, m), 1.57(6H, s), 1.71-1.97(5H, m),
2.12-2.20(2H, m), 2.44(3H, s), 3.72- 3.77(2H, m), 3.78- 3.83(2H,
m), 4.16(1H, tt, J = 3.8 and 11.8 Hz), 6.40- 6.46(1H, m), 7.31(1H,
s) 419 220 ##STR00324## colorless solid 169-171 CDCl.sub.3
1.21-1.33(1H, m), 1.37-1.48(2H, m), 1.68- 1.96(5H, m), 2.11-
2.21(2H, m), 2.44(3H, s), 2.94(3H, s), 3.23-3.29(4H, m),
3.47-3.52(2H, m), 3.58-3.64(2H, m), 3.66- 3.71 (4H, m), 4.16(1H,
tt, J = 3.8 and 11.8 Hz), 7.34(1H, s), 7.94- 7.99(1H, m) 434
TABLE-US-00084 TABLE 84 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 221 ##STR00325## colorless solid 103-105
(Et.sub.2O/hexane) CDCl.sub.3 1.18-1.32(1 H, m), 1.36-1.50(2H, m),
1.68- 1.95(5H, m), 2.12-2.20(2H, m), 2.44(3H, s), 2.86(6H, s),
2.90(3H, s), 3.44-3.49(2H, s), 3.56-3.62(2H, m), 4.16(1H, tt, J =
3.8 and 11.8 Hz), 7.39(1H, s), 8.37-8.43(1H, m) 392 222
##STR00326## colorless solid 109-113 (Et.sub.2O/hexane) CDCl.sub.3
1.18-1.33(1H, m), 1.36-1.50(2H, m), 1.69- 1.96(5H, m),
2.12-2.20(2H, m), 2.44(3H, s), 2.96(3H, brs), 3.46-3.64(4H, s),
3.72(3H, s), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 6.05-6.15(0.2H, m),
7.00-7.08(0.8H, m), 7.32(1H, s) 379 223 ##STR00327## colorless
solid 136-137 (Et.sub.2O/hexane) CDCl.sub.3 1.18-1.33(1H, m),
1.36-1.50(2H, m), 1.69- 1.96(5H, m), 2.12-2.20(2H, m), 2.44(3H, s),
2.99(0.5H, s), 3.06(2.5H, s), 3.41(2.5H, s), 3.44(0.5H, s), 3.56-
3.70(4H, s), 4.10-4.21(3H, m), 6.65-6.72(0.17H, m),
7.12-7.18(0.83H, m), 7.33(1H, s) 393 224 ##STR00328## colorless
foamy solid CDCl.sub.3 1.21-1.34(1H, m), 1.37-1.52(2H, m), 1.70-
1.96(5H, m), 2.13-2.22(2H, m), 2.43(0.3H, s), 2.44(2.7H, s),
2.97(2.7H, s), 3.08(0.3H, s), 3.38-3.74(5H, s), 4.11- 4.22(3H, m),
6.17-6.24(0.1H, m), 6.78-6.84(0.9H, m), 7.29(0.9H, s), 7.34(0.1H,
s) 379
TABLE-US-00085 TABLE 85 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 225 ##STR00329## colorless solid 190-194 CDCl.sub.3 1.20-
1.50(5H, m), 1.66-1.96(9H, m), 2.12-2.26(4H, m), 2.43(3H, s), 2.44-
2.68(1H, m), 2.96(0.6H, s), 3.13(2.4H, s), 3.48- 3.59(2H, m), 3.76-
3.83(2H, m), 3.91- 4.03(1H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz),
5.68- 5.74(1H, m), 7.30(1H, s) 447 226 ##STR00330## colorless solid
190-194 CDCl.sub.3 1.21-1.33(1H, m), 1.37-1.50(2H, m),
1.54-1.64(1H, m), 1.70-1.98(7H, m), 2.05-2.40(5H, m), 2.43(3H, s),
2.92-3.02(1H, m), 3.70(3H, s), 4.17(1H, tt, J = 3.8 and 11.8 Hz),
4.46-4.55(1H, m), 5.77-5.84(1H, m), 7.30(1H, s) 390 227
##STR00331## colorless solid 164-167 DMSO-d.sub.6 1.16- 1.31(1H,
m), 1.37- 1.86(10H, m), 1.93- 2.08(5H, m), 2.35(3H, s), 2.87-
2.97(1H, m), 4.18(1H, tt, J = 3.8 and 11.7 Hz), 4.23-4.32(1H, m),
7.81(1H, s), 8.32-8.36(1H, m), 12.14(1H, brs) 376 228 ##STR00332##
colorless solid >300 DMSO-d.sub.6 1.16- 1.29(1H, m), 1.36-
1.49(2H, m), 1.62- 1.86(5H, m), 2.00- 2.07(2H, m), 2.35(3H, s),
2.91(3H, s), 3.39- 3.58(8H, m), 4.19(1H, tt, J = 3.8 and 11.6 Hz),
7.69(1H, s), 8.60- 8.66(1H, m) 418
TABLE-US-00086 TABLE 86 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 229 ##STR00333## colorless foamy solid CDCl.sub.3
1.21-1.33(1H, m), 1.38- 1.51(2H, m), 1.58-1.68(1H, m),
1.70-2.05(8H, m), 2.13-2.21(2H, m), 2.23-2.40(2H, m), 2.43(3H, s),
2.96(3H, s), 3.05(3H, s), 3.12- 3.22(1H, m), 4.17(1H, tt, J = 3.8
and 11.8 Hz), 4.43-4.52(1H, m), 5.83-5.89(1H, m), 7.31(1H, s) 403
231 ##STR00334## colorless solid 75-90 DMSO-d.sub.6 1.15-1.28(1H,
m), 1.36- 1.48(2H, m), 1.51-1.85(8H, m), 1.92-2.07(5H, m), 2.36(3H,
s), 2.83(3H, s), 3.02(3H, s), 3.18- 3.29(1H, m), 4.18(1H, tt, J =
3.8 and 11.6 Hz), 4.22-4.32(1H, m), 7.81(1H, s), 8.30-8.35(1H, m)
403 231 ##STR00335## colorless solid 95-101 CDCl.sub.3
1.21-1.33(1H, m), 1.37- 1.50(2H, m), 1.54-1.64(1H, m),
1.70-1.98(7H, m), 2.05-2.40(5H, m), 2.43(3H, s), 2.92-3.02(1H, m),
3.70(3H, s), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 4.46-4.55(1H, m),
5.84-5.89(1H, m), 7.31(1H, s) 390 232 ##STR00336## colorless solid
165-168 DMSO-d.sub.6 1.16-1.30(1H, m), 1.37- 1.86(10H, m),
1.93-2.09(5H, m), 2.35(3H, s), 2.87-2.96(1H, m), 4.19(1H, tt, J =
3.8 and 11.7 Hz), 4.23-4.31(1H, m), 7.81(1H, s), 8.32-8.36(1H, m),
12.14(1H, brs) 376
TABLE-US-00087 TABLE 87 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 233 ##STR00337## colorless foamy solid CDCl.sub.3 1.21-
1.33(1H, m), 1.38-1.51(2H, m), 1.59-1.68(1H, m), 1.70-2.04(8H, m),
2.13-2.21(2H, m), 2.23-2.40(2H, m), 2.43(3H, s), 2.96(3H, s),
3.05(3H, s), 3.12-3.22(1H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz),
4.42- 4.52(1H, m), 5.83-5.89(1H, m), 7.30(1H, s) 403 234
##STR00338## colorless solid 96-105 DMSO-d.sub.6 1.15- 1.28(1H, m),
1.36-1.48(2H, m), 1.51-1.85(8H, m), 1.92-2.07(5H, m), 2.36(3H, s),
2.83(3H, s), 3.02(3H, s), 3.18-3.29(1H, m), 4.18(1H, tt, J = 3.8
and 11.6 Hz), 4.22-4.31(1H, m), 7.81(1H, s), 8.30-8.35(1H, m) 403
235 ##STR00339## colorless solid 210-212 CDCl.sub.3 1.22- 1.33(1H,
m), 1.38-1.56(4H, m), 1.70-1.96(5H, m), 2.00-2.08(2H, m),
2.14-2.22(2H, m), 2.44(3H, s), 2.84(6H, s), 2.89-2.99(2H, m),
3.65-3.73(2H, m), 4.08-4.22(2H, m), 5.78-5.84(1H, m), 7.32(1H, s)
418 236 ##STR00340## colorless solid 235-238 CDCl.sub.3 1.20-
1.35(3H, m), 1.38-1.51(2H, m), 1.72-1.97(9H, m), 2.13-2.26(4H, m),
2.43(3H, s), 3.49-3.54(2H, m), 3.60-3.72(6H, m), 3.90-4.02(1H, m),
4.17(1H, tt,J = 3.8 and 11.8 Hz), 5.67- 5.72(1H, m), 7.30(1H, s)
459
TABLE-US-00088 TABLE 88 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 237 ##STR00341## colorless solid >300 DMSO-d.sub.6
1.17-1.49(7H, m), 1.63-1.92(9H, m), 2.01- 2.11(3H, m), 2.35(3H, s),
2.55(3H, d, J = 4.5 Hz), 3.59-3.71(1H, m), 4.18(1H, tt, J = 3.8 and
11.6 Hz), 7.64-7.70(1H, m), 7.79(1H, s), 8.22-8.27(1H, m) 403 238
##STR00342## colorless solid >300 DMSO-d.sub.6 0.33-0.39(2H, m),
0.56-0.62(2H, m), 1.16- 1.49(7H, m), 1.63-1.91(9H, m),
1.96-2.08(3H, m), 2.35(3H, s), 2.57-2.63(1H, m), 3.60-3.72(1H, m),
4.13- 4.22(1H, m), 7.75-7.78(1H, m), 7.78(1H, s), 8.21- 8.26(1H, m)
429 239 ##STR00343## colorless solid 260-263 CDCl.sub.3
1.21-1.34(3H, m), 1.37-1.60(4H, m), 1.68- 1.98(11H, m), 2.14-
2.26(4H, m), 2.43(3H, s), 2.48(1H, tt, J = 3.7 and 11.6 Hz),
3.15-3.31(2H, m), 3.74- 3.83(1H, m), 3.91-4.02(2H, m),
4.08-4.16(1H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 5.68-5.73(1H,
m), 7.30(1H, s) 473 240 ##STR00344## colorless solid 230-231
CDCl.sub.3 1.21-1.34(1H, m), 1.38-1.51(2H, m), 1.57- 1.66(2H, m),
1.72-1.97(5H, m), 2.05-2.13(2H, m), 2.15- 2.23(2H, m), 2.44(3H, s),
2.83(6H, s), 2.96-3.06(2H, m), 3.72-3.80(2H, m), 4.06- 4.16(1H, m),
4.18(1H, tt, J = 3.8 and 11.8 Hz), 5.78- 5.93(1H, m), 7.34(1H, s)
454
TABLE-US-00089 TABLE 89 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 241 ##STR00345## colorless solid 83-87 CDCl.sub.3
1.21-1.50(5H, m), 1.47(9H, s), 1.70-2.06(7H, m), 2.13-2.21(2H, m),
2.43(3H, s), 2.80-2.96(2H, m), 4.04-4.17(2H, m), 4.18(1H, tt, J =
3.9 and 11.8 Hz), 5.74-5.81(1H, m), 7.33(1H, s) 447 242
##STR00346## pale yellow solid 153-160 DMSO-d.sub.6 1.15-1.29(1H,
m), 1.36-1.49(2H, m), 1.62- 1.86(7H, m), 1.91-1.99(2H, m),
2.00-2.08(2H, m), 2.36(3H, s), 2.89-3.06(2H, m), 3.26-3.35(2H, m),
3.97-4.06(1H, m), 4.19(1H, tt, J = 3.8 and 11.6 Hz), 7.89(1H, s),
8.50-8.55(1H, m), 8.76(1H, brs) 347 243 ##STR00347## colorless
foamy solid CDCl.sub.3 1.22-1.33(1H, m), 1.38-1.50(2H, m), 1.69-
1.97(6H, m), 2.13-2.22(2H, m), 2.26-2.43(2H, m), 2.44(3H, s),
2.58-2.64(1H, m), 2.72-2.77(1H, m), 2.91- 2.98(1H, m), 3.64 and
3.65(total 2H, each s), 4.17(1H, tt, J = 3.8 and 11.8 Hz),
6.34-6.40(1H, m), 7.26- 7.38(6H, m) 423 244 ##STR00348## colorless
foamy solid CDCl.sub.3 1.21-1.34(1H, m), 1.38-1.50(2H, m), 1.69-
1.97(6H, m), 2.10-2.28(3H, m), 2.42(3H, s), 2.90- 3.02(2H, m),
3.09-3.22(2H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz), 4.54-4.63(1H,
m), 6.33-6.39(1H, m), 7.38(1H, m) 333
TABLE-US-00090 TABLE 90 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 245 ##STR00349## colorless foamy solid CDCl.sub.3
1.21-1.34(1H, m), 1.38-1.50(2H, m), 1.71- 1.96(5H, m),
1.99-2.08(1H, m), 2.12-2.23(3H, m), 2.43(3H, s), 2.89(6H, s),
3.42-3.62(4H, m), 4.17(1H, tt, J = 3.9 and 11.8 Hz), 4.50- 4.58(1H,
m), 6.60-6.65(1H, m), 7.35(1H, s) 404 246 ##STR00350## colorless
solid 110-114 DMSO-d.sub.6 1.16-1.30(1H, m), 1.36-1.50(2H, m),
1.62- 1.91(6H, m), 2.00-2.10(3H, m), 2.35(3H, s), 2.74(6H, s),
3.21(1H, dd, J = 5.4 and 10.6 Hz), 3.29-3.47(2H, m), 3.55(1H, dd, J
= 7.6 and 10.6 Hz), 4.19(1H, tt, J = 3.8 and 11.6 Hz),
4.28-4.36(1H, m), 7.86(1H, s), 8.50-8.55(1H, m) 404 247
##STR00351## colorless solid 251-254 CDCl.sub.3 1.12-1.50(7H, m),
1.69-1.96(8H, m), 2.07- 2.21(4H, m), 2.43(3H, s), 3.38-3.43(2H, m),
3.85- 3.95(1H, m), 4.00(2H, brs), 4.17(1H, tt, J = 3.9 and 11.9
Hz), 5.21(1H, brs), 5.63- 5.69(1H, m), 7.30(1H, s) 458 248
##STR00352## pale yellow oil CDCl.sub.3 1.21-1.33(1H, m), 1.28(3H,
t, J = 7.1 Hz), 1.37- 1.51(2H, m), 1.70-2.06(9H, m), 2.15-2.23(2H,
m), 2.44(3H, s), 2.57-2.67(1H, m), 3.14-3.24(2H, m), 4.11- 4.22(1H,
m), 4.17(2H, q, J = 7.1 Hz), 4.35-4.45(2H, m), 7.12(1H, s) 404
TABLE-US-00091 TABLE 91 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 249 ##STR00353## colorless solid 94-96 CDCl.sub.3
1.20-1.33(1H, m), 1.37-1.50(2H, m), 1.70-1.96(7H, m), 2.02-2.10(2H,
m), 2.12-2.20(2H, m), 2.44(3H, s), 2.65- 2.75(1H, m), 3.17-3.28(2H,
m), 4.18(1H, tt, J = 3.8 and 11.9 Hz), 4.36- 4.45(2H, m), 7.13(1H,
s) 376 250 ##STR00354## colorless solid 211-214 CDCl.sub.3
1.21-1.33(1H, m), 1.37-1.51(2H, m), 1.70-1.99(9H, m), 2.12-2.22(2H,
m), 2.39(1H, tt, J = 4.0 and 11.3 Hz), 2.44(3H, s), 2.84(3H, d, J =
4.8 Hz), 3.00-3.12(2H, m), 4.17(1H, tt, J = 3.8 and 11.8 Hz),
4.48-4.57(2H, m), 5.46- 5.55(1H, m), 7.13(1H, s) 389 251
##STR00355## colorless oil CDCl.sub.3 1.20-1.32(1H, m), 1.26(3H, t,
J = 7.1 Hz), 1.37-1.50(2H, m), 1.55- 1.66(1H, m), 1.70-1.97(7H, m),
2.10- 2.20(3H, m), 2.44(3H, s), 2.53-2.63(1H, m), 3.12-3.21(1H, m),
3.27-3.38(1H, m), 4.12-4.22(1H, m), 4.15(2H, q, J = 7.1 Hz),
4.25-4.34(1H, m), 4.47-4.56(1H, m), 7.16(1H, s) 404 252
##STR00356## colorless solid 262-266 DMSO-d.sub.6 1.16-1.29(1H, m),
1.36- 1.50(2H, m), 1.62-1.92(6H, m), 2.01- 2.09(2H, m), 2.35(3H,
s), 2.35-2.45(1H, m), 3.27-3.34(1H, m), 3.55(1H, dd, J = 5.5 and
11.3 Hz), 4.19(1H, tt, J = 3.8 and 11.6 Hz), 4.24-4.30(1H, m),
4.55- 4.65(1H, m), 7.73(1H, s), 8.52-8.56(1H, m), 10.90(1H, brs)
402
TABLE-US-00092 TABLE 92 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 253 ##STR00357## colorless solid 221-223 DMSO-d.sub.6
1.16-1.28(1H, m), 1.36-1.50(2H, m), 1.62- 1.91(6H, m),
2.00-2.08(2H, m), 2.35(3H, s), 2.40-2.48(1H, m), 2.87(3H, s),
3.39(1H, dd, J = 6.9 and 11.4 Hz), 3.58(1H, tt, J = 5.4 and 11.4
Hz), 4.19(1H, tt, J = 3.8 and 11.6 Hz), 4.33(1H, t, J = 8.4 Hz),
4.56-4.64(1H, m), 7.71(1H, s), 8.51-8.56(1H, m) 416 254
##STR00358## pale yellow foamy solid CDCl.sub.3 1.21-1.34(1H, m),
1.37-1.49(3H, m), 1.52- 1.63(1H, m), 1.70-1.97(8H, m),
2.12-2.20(2H, m), 2.43(3H, s), 2.44-2.60(1H, m), 3.26- 3.61(4H, m),
4.05-4.17(2H, m), 4.17(1H, tt, J = 3.8 and 11.9 Hz), 7.18(1H, s)
362 255 ##STR00359## colorless solid 247-248.5 CDCl.sub.3
2.11-2.27(4H, m), 2.48(3H, s), 2.97-3.16(6H, m), 3.57(2H, dt, J =
2.4 and 11.6 Hz), 4.11-4.18(2H, m), 4.39- 4.49(1H, m),
7.36-7.41(2H, m), 7.54-7.59(2H, m), 7.65(1H, s), 8.11(1H, brs) 413
256 ##STR00360## colorless solid 148-150 DMSO-d.sub.6 1.16-1.31(1H,
m), 1.37-1.51(2H, m), 1.62- 1.88(5H, m), 2.03-2.12(2H, m), 2.40(3H,
s), 3.37-3.43(2H, m), 3.95-4.02(2H, m), 4.22(1H, tt, J = 3.8 and
11.5 Hz), 7.15(1H, brs), 8.00(1H, dd, J = 2.6 and 9.1 Hz), 8.03(1H,
s), 8.16(1H, d, J = 9.1 Hz), 8.59(1H, d, J = 2.6 Hz), 10.3(1H, brs)
425
TABLE-US-00093 TABLE 93 properties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 257 ##STR00361## colorless foamy solid CDCl.sub.3 1.21-
1.59(5H, m), 1.67-2.00(8H, m), 2.12-2.22(3H, m), 2.28-2.38(1H, m),
2.43(3H, s), 3.56(2H, d, J = 6.8 Hz), 4.17(1H, tt, J = 3.8 and
11.9Hz), 4.38-4.48(1H, m), 5.82-5.86(1H, m), 7.30(1H, s) 362 258
##STR00362## colorless solid 183-185 (toluene) CDCl.sub.3 1.20-
1.58(6H, m), 1.69-1.96(7H, m), 2.12-2.30(3H, m), 2.43(3H, s),
2.49-2.61(1H, m), 3.50-3.55(2H, m), 3.98(2H, s), 4.17(1H, tt, J =
3.8 and 11.9Hz), 4.43-4.53(1H, m), 5.26(1H, brs), 5.76-5.82(1H, m),
7.29(1H, s) 444 259 ##STR00363## colorless solid 218-222 CDCl.sub.3
1.21- 1.33(1H, m), 1.37-1.51(2H, m), 1.70-1.97(5H, m),
2.15-2.21(2H, m), 2.43(3H, s), 4.18(1H, tt, J = 3.8 and 11.8 Hz),
4.63(2H, s), 6.75-6.79(2H, m), 7.13-7.17(2H, m), 8.28(1H, s) 438
260 ##STR00364## colorless solid 204-206 CDCl.sub.3 2.11- 2.27(4H,
m), 2.48(3H, s), 3.10(3H, s), 3.57(2H, dt, J = 2.4 and 11.6 Hz),
4.05(2H, s), 4.11-4.18(2H, m), 4.37-4.48(1H, m), 7.40-7.45(2H, m),
7.50(1H, s), 7.68(1H, brs), 7.70-7.75(2H, m) 454
TABLE-US-00094 TABLE 94 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 261 ##STR00365## pale brown solid 252-254
(EtOH) DMSO-d.sub.6 1.91-2.07 (4H, m), 2.41 (3H, s), 3.38-3.44 (2H,
s), 3.51 (2H, dt, J = 2.4 and 11.6 Hz), 3.95-4.03 (4H, m),
4.47-4.57 (1H, m), 7.16 (1H, brs), 8.00 (1H, dd, J = 2.7 and 9.1
Hz), 8.05 (1H, s), 8.16 (1H, d, J = 9.1 Hz), 8.60 (1H, d, J = 2.7
Hz), 10.33 (1H, brs) 427 262 ##STR00366## pale yellow solid 164-166
(iso-PrOH) CDCl.sub.3 1.22-1.35 (1H, m), 1.38-1.53 (2H, m),
1.70-1.97 (5H, m), 2.04-2.12 (1H, m), 2.15-2.25 (3H, m), 2.45 (3H,
s), 3.25-3.41 (2H, m), 3.46-3.57 (2H, m), 4.19 (1H, tt, J = 3.9 and
11.8 Hz), 4.58-4.65 (1H, m), 6.53-6.59 (2H, m), 7.40-7.51 (4H, m)
425 263 ##STR00367## pale yellow solid 167-168 (hexane/ AcOEt)
CDCl.sub.3 1.22-1.35 (1H, m), 1.38-1.52 (2H, m), 1.71-2.05 (7H, m),
2.11-2.23 (3H, m), 2.45 (3H, s), 3.29-3.39 (2H, m), 3.57-3.68 (2H,
m), 4.19 (1H, tt, J = 3.9 and 11.8 Hz), 4.52-4.58 (1H, m),
6.61-6.67 (1H, m), 7.10 (1H, dd, J = 2.2 and 8.7 Hz), 7.42 (1H, dd,
J = 2.5 and 14.8 Hz), 7.44 (1H, s), 7.52 (1H, brs) 443 264
##STR00368## colorless solid 216-218 CDCl.sub.3 1.23-1.67 (5H, m),
1.72-1.98 (7H, m), 2.15-2.23 (2H, m), 2.50 (3H, s), 2.85- 2.95 (2H,
m), 3.31-3.40 (2H, m), 3.72-3.80 (1H, m), 4.20 (1H, tt, J = 3.8 and
11.8 Hz), 7.49-7.57 (2H, m), 7.64 (1H, s), 7.93 (1H, d, J = 1.7
Hz), 8.11-8.17 (1H, m), 8.19 (1H, brs) 503
TABLE-US-00095 TABLE 95 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 265 ##STR00369## colorless solid 226-228
CDCl.sub.3 -0.01 (6H, s), 0.80 (9H, s), 1.22-1.36 (1H, s),
1.40-1.68 (4H, m), 1.72-1.99 (7H, m), 2.16-2.26 (2H, m), 2.48 (3H,
s), 2.97-3.05 (2H, m), 3.15- 3.25 (2H, m), 3.75-3.81 (1H, m),
4.16-4.26 (1H, m), 7.53 (1H, s), 7.75- 7.81 (5H, m) 617 266
##STR00370## colorless solid 229-233 CDCl.sub.3 1.24-1.55 (4H, m),
1.60-1.98 (9H, m), 2.18-2.25 (2H, s), 2.47 (3H, s), 2.85-2.93 (2H,
m), 3.29-3.38 (2H, m), 3.75-3.82 (1H, m), 4.20 (1H, tt, J = 3.8 and
11.8 Hz), 7.54 (1H, s), 7.73-7.81 (4H, m), 7.84 (1H, brs) 503 267
##STR00371## colorless solid 162-165 CDCl.sub.3 1.22-1.35 (1H, m),
1.38-1.55 (2H, m), 1.72-1.98 (5H, s), 2.17-2.24 (2H, m), 2.46 (3H,
s), 2.86 (2H, t, J = 6.5 Hz), 3.86 (2H, t, J = 6.5 Hz), 4.19 (1H,
tt, J = 3.9 and 11.8 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.47 (1H, s),
7.53 (2H, d, J = 8.4 Hz), 7.60 (1H, brs) 384 268 ##STR00372## pale
yellow solid 211-213 CDCl.sub.3 1.43-1.47 (1H, m), 1.72-1.82 (2H,
m), 2.00-2.27 (6H, m), 2.47 (3H, s), 2.81-2.91 (2H, m), 3.30-3.37
(2H, m), 3.56 (2H, dt, J = 2.4 and 11.6 Hz), 3.83-3.91 (1H, m),
4.11-4.18 (2H, m), 4.38- 4.48 (1H, m), 6.90-7.00 (1H, m), 7.16-7.21
(1H, m), 7.45 (1H, s), 7.47-7.52 (1H, m), 7.53 (1H, brs) 459
TABLE-US-00096 TABLE 96 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 269 ##STR00373## colorless solid 205-206.5
(AcOEt/ hexane) CDCl3 1.19-1.33 (1H, m), 1.38-1.50 (2H, m),
1.70-1.97 (5H, m), 2.12-2.21 (2H, m), 2.34 (3H, s), 2.45 (3H, s),
2.48-2.63 (4H, m), 2.88-2.96 (4H, m), 4.12-4.22 (1H, m), 7.37 (1H,
d, J = 8.7 Hz), 7.48 (1H, s), 7.66 (1H, brs), 7.75 (1H, d, J = 2.5
Hz), 7.83 (1H, dd, J = 2.5 and 8.7 Hz) 506 270 ##STR00374##
colorless solid >300 (EtOH) CDCl.sub.3 1.21-1.34 (1H, m),
1.47-1.50 (4H, m), 1.54-1.67 (2H, m), 1.71-1.96 (7H, m), 2.13-2.22
(4H, m), 2.43 (3H, s), 3.51-3.59 (2H, m), 3.79 (1H, tt, J = 3.9 and
12.1 Hz), 3.89-4.01 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),
4.32-4.38 (2H, m), 6.08-6.12 (1H, m), 7.44 (1H, s) 431 271
##STR00375## colorless solid 290 (dec.) (EtOH) CDCl.sub.3 1.20-1.50
(7H, m), 1.70-1.97 (5H, m), 2.06-2.21 (6H, m), 2.43 (3H, s),
3.40-3.50 (1H, m), 3.79 (2H, t, J = 8.5 Hz), 3.88- 3.99 (1H, m),
4.17 (1H, tt, J = 3.8 and 11.9 Hz), 4.25 (2H, t, J = 8.5 Hz),
5.69-5.77 (1H, m), 7.32 (1H, s) 430 272 ##STR00376## colorless
solid 268 (dec.) CD.sub.3OD 1.24-1.56 (7H, m), 1.72-2.03 (9H, m),
2.09-2.17 (2H, m), 2.42 (3H, s), 2.44 (2H, t, J = 7.0 Hz), 2.58
(2H, t, J = 7.0 Hz), 3.61-3.70 (1H, m), 3.77-3.86 (1H, m), 4.18
(1H, tt, J = 3.8 and 11.8 Hz), 7.66 (1H, s) 461
TABLE-US-00097 TABLE 97 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 273 ##STR00377## pale brown solid >300
CDCl.sub.3 1.21-1.51 (5H, m), 1.61-1.97 (7H, m), 2.12-2.24 (4H, m),
2.37-2.49 (2H, m), 2.43 (3H, s), 2.67 (4H, s), 3.98-4.09 (2H, m),
4.17 (1H, tt, J = 3.8 and 11.8 Hz), 5.68-5.73 (1H, m), 7.32 (1H, s)
443 274 ##STR00378## colorless solid 279-280 (EtOH) CDCl.sub.3
1.21-1.50 (5H, m), 1.58-1.87 (7H, m), 1.88-1.96 (2H, m), 2.12-2.21
(4H, m), 2.31-2.40 (2H, m), 2.43 (3H, s), 3.14 (2H, t, J = 7.5 Hz),
3.29 (2H, t, J = 6.7 Hz), 3.50 (1H, tt, J = 3.8 and 11.8 Hz),
3.84-3.97 (1H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 5.78-5.83
(1H, m), 7.34 (1H, s) 465 275 ##STR00379## colorless solid 251-254
CDCl.sub.3 1.20-1.50 (7H, m), 1.70-1.98 (5H, m), 2.03-2.21 (6H, m),
2.42 (3H, s), 2.94 (3H, s), 3.60-3.71 (1H, m), 3.88-3.99 (1H, m),
4.11 (2H, s), 4.17 (1H, tt, J = 3.8 and 11.8 Hz), 4.34-4.40 (1H,
m), 5.17 (2H, s), 5.78-5.84 (1H, m), 7.29-7.41 (6H, s) 566 276
##STR00380## colorless solid 274-276 (EtOH) CDCl.sub.3 1.21-1.50
(5H, m), 1.70-1.97 (7H, m), 2.11-2.23 (4H, m), 2.33-2.49 (2H, m),
2.43 (3H, s), 2.98 (3H, s), 3.81 (2H, s), 3.90-4.08 (2H, m), 4.17
(1H, tt, J = 3.9 and 11.9 Hz), 5.69-5.75 (1H, m), 7.32 (1H, s)
458
TABLE-US-00098 TABLE 98 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 277 ##STR00381## colorless solid 156-157.5
(AcOEt/ hexane) CDCl.sub.3 1.21-1.33 (1H, m), 1.37-1.50 (2H, m),
1.69-1.97 (5H, m), 2.12-2.21 (2H, m), 2.45 (3H, s), 3.02 (3H, s),
3.61-3.69 (2H, m), 3.79-3.88 (2H, m), 3.93 (2H, s), 4.16 (1H, tt, J
= 3.9 and 11.8 Hz), 6.98-7.06 (1H, m), 7.34 (1H, s) 404 278
##STR00382## colorless solid 170-171 (AcOEt) CDCl.sub.3 1.21-1.33
(1H, m), 1.38-1.51 (2H, m), 1.70-1.98 (7H, m), 2.12-2.22 (2H, m),
2.45 (3H, s), 3.04 (3H, s), 3.38-3.46 (2H, m), 3.67 (2H, t, J = 6.0
Hz), 3.94 (2H, s), 4.17 (1H, tt, J = 3.9 and 11.8 Hz), 7.15-7.22
(1H, m), 7.43 (1H, s) 418 279 ##STR00383## colorless solid >300
CDCl.sub.3 1.20-1.50 (7H, m), 1.69-1.96 (5H, m), 2.03-2.21 (6H, m),
2.41 (3H, s), 2.93 (3H, s), 3.44 (2H, t, J = 4.6 Hz), 3.49- 3.53
(1H, m), 3.58-3.69 (1H, m), 3.72- 3.80 (2H, m), 3.87-3.99 (1H, m),
4.16 (1H, tt, J = 3.9 and 11.8 Hz), 4.70-4.78 (1H, m), 5.88- 5.95
(1H, m), 7.35 (1H, s) 462 280 ##STR00384## colorless solid
274-276.5 (EtOH) CDCl.sub.3 1.20-1.68 (7H, m), 1.70-1.98 (7H, m),
2.09-2.22 (4H, m), 2.43 (3H, s), 2.79 (3H, s), 3.28 (4H, s), 3.79
(1H, tt, J = 3.9 and), 3.87-3.98 (1H, m), 4.17 (1H, tt, J = 3.9 and
11.8 Hz), 5.93-6.01 (1H, m), 7.36 (1H, s) 444
TABLE-US-00099 TABLE 99 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 281 ##STR00385## colorless solid 98.5-99.5
CDCl.sub.3 1.21-1.35 (1H, m), 1.29 (3H, t, J = 7.1 Hz), 1.38-1.51
(2H, m), 1.70-1.98 (5H, m), 2.12-2.22 (2H, m), 2.44 (3H, s), 2.64
(2H, t, J = 6.0 Hz), 3.67-3.76 (2H, m), 4.11-4.25 (1H, m), 4.19
(2H, q, J = 7.1 Hz), 6.68-6.74 (1H, m), 7.37 (1H, s) 364 282
##STR00386## colorless solid 161-162 (AcOEt) CDCl.sub.3 1.20-1.33
(1H, m), 1.38-1.50 (2H, m), 1.69- 1.96 (5H, m), 2.10-2.20 (2H, m),
2.42 (3H, s), 2.72 (2H, t, J = 5.9 Hz), 3.68-3.74 (2H, m), 4.18
(1H, tt, J = 3.9 and 11.9 Hz), 6.68-6.74 (1H, m), 7.34 (1H, s) 336
283 ##STR00387## colorless solid 141-142.5 CDCl.sub.3 1.21-1.50
(3H, m), 1.51 (9H, s), 1.71-1.97 (5H, m), 2.13-2.22 (2H, m), 2.44
(3H, s), 4.12 (2H, d, J = 4.8 Hz), 4.17 (1H, tt, J = 3.8 and 11.9
Hz), 6.43- 6.49 (1H, m), 7.40 (1H, s) 378 284 ##STR00388##
colorless solid 194-195 (AcOEt) CDCl.sub.3 1.20-1.33 (1H, m),
1.38-1.51 (2H, m), 1.70- 1.98 (5H, m), 2.12-2.21 (2H, m), 2.44 (3H,
s), 4.19 (1H, tt, J = 3.9 and 11.9 Hz), 4.27 (2H, d, J = 5.1 Hz),
6.55- 6.61 (1H, m), 7.45 (1H, s) 322
TABLE-US-00100 TABLE 100 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 285 ##STR00389## colorless solid 138.5-139.5
(AcOEt/ hexane) CDCl.sub.3 1.21-1.33 (1H, m), 1.38-1.50 (2H, m),
1.70- 1.98 (5H, m), 2.11-2.21 (2H, m), 2.43 (3H, s), 2.61 (2H, t, J
= 5.5 Hz), 3.41-3.49 (2H, m), 3.60-3.71 (6H, m), 3.71- 3.78 (2H,
m), 4.17 (1H, tt, J = 3.9 and 11.8 Hz), 6.95- 7.02 (1H, m), 7.32
(1H, s) 405 286 ##STR00390## colorless solid 183.5-185 CDCl.sub.3
1.20-1.32 (1H, m), 1.37-1.51 (2H, m), 1.45 (9H, s), 1.70-1.96 (5H,
m), 2.12-2.21 (2H, m), 2.42 (3H, s), 3.38-3.45 (2H, m), 3.50-3.56
(2H, m), 4.17 (1H, tt, J = 3.9 and 11.8 Hz), 4.97-5.03 (1H, m),
7.09-7.16 (1H, m), 7.36 (1H, s) 407 287 ##STR00391## colorless
solid 157-158 CDCl.sub.3 1.20-1.32 (1H, m), 1.371.37-1.52 (2H, m),
1.70-1.97 (5H, m), 2.12-2.21 (2H, m), 2.43 (3H, s), 2.94 (2H, t, J
= 5.7 Hz), 3.45-3.52 (2H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),
6.53-6.61 (1H, m), 7.36 (1H, s) 307 288 ##STR00392## colorless
solid 154-155 (AcOEt) CDCl.sub.3 1.21-1.33 (1H, m), 1.38-1.50 (2H,
m), 1.69- 1.96 (5H, m), 2.11-2.20 (2H, m), 2.43 (3H, s), 2.61 (2H,
t, J = 5.4 Hz), 2.98 (3H, s), 3.00 (3H, s), 3.70-3.78 (2H, m), 4.16
(1H, tt, J = 3.9 and 11.9 Hz), 7.10-7.17 (1H, m), 7.33 (1H, s)
363
TABLE-US-00101 TABLE 101 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 289 ##STR00393## colorless solid 164.5-168
(AcOEt/hexane) CDCl.sub.3 1.21-1.33 (1H, m), 1.37-1.50 (2H, m),
1.56-1.65 (2H, m), 1.70-2.20 (11H, m), 2.29 and 2.30 (total 3H,
each s), 2.42 and 2.43 (total 3H, each s), 2.57- 2.68 (2H, m), 2.83
and 2.85 (total 3H, each s), 2.89-2.99 (2H, m), 3.51 (0.4H, tt, J =
4.1 and 11.6 Hz), 3.70-3.79 (2H, m), 4.16 (1H, tt, J = 3.8 and 11.8
Hz), 4.47 (0.6H, tt, J = 4.2 and 12.2 Hz), 7.08-7.16 (1H, m), 7.32
and 7.33 (total 1H, each s) 446 290 ##STR00394## colorless solid
173-175.5 (AcOEt) CDCl.sub.3 1.21-1.34 (1H, m), 1.38-1.59 (4H, m),
1.69-1.98 (7H, m), 2.11-2.20 (2H, m), 2.43 (3H, s), 2.63 (2H, d, J
= 5.5 Hz), 3.18-3.31 (2H, m), 3.65-3.78 (3H, m), 3.91-4.00 (1H, m),
4.01-4.21 (2H, m), 7.03-7.10 (1H, m), 7.33 (1H, s) 419 291
##STR00395## colorless solid 214-215 (AcOEt) CDCl.sub.3 1.20-1.33
(1H, m), 1.38-1.52 (2H, m), 1.69-1.98 (5H, m), 2.13-2.23 (2H, m),
2.44 (3H, s), 3.43-3.52 (2H, m), 3.68- 3.79 (6H, m), 4.18 (1H, tt,
J = 3.9 and 11.8 Hz), 4.23 (2H, d, J = 3.9 Hz), 7.08-7.15 (1H, m),
7.44 (1H, s) 391 292 ##STR00396## colorless solid 130-131.5
CDCl.sub.3 1.20-1.34 (1H, m), 1.38-1.51 (2H, m), 1.70-1.98 (5H, m),
2.13-2.22 (2H, m), 2.44 (3H, s), 3.04 (3H, s), 3.05 (H, s), 4.18
(1H, tt, J = 3.9 and 11.8 Hz), 4.21 (2H, d, J = 3.9 Hz), 7.11- 7.18
(1H, m), 7.44 (1H, s) 349
TABLE-US-00102 TABLE 102 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 293 ##STR00397## colorless solid 157-159
CDCl.sub.3 1.20-1.34 (1H, m), 1.38-1.50 (2H, m), 1.70-1.98 (5H, m),
2.13-2.22 (2H, m), 2.33 (3H, s), 2.40-2.50 (4H, m), 2.44 (3H, s),
3.46-3.51 (2H, m), 3.69- 3.75 (2H, m), 4.18 (1H, tt, J = 3.9 and
11.8 Hz), 4.22 (2H, d, J = 3.9 Hz), 7.10-7.16 (1H, m), 7.44 (1H, s)
404 294 ##STR00398## colorless solid 175-176 CDCl.sub.3 1.20-1.33
(1H, m), 1.39-1.50 (2H, m), 1.53-1.64 (3H, m), 1.70-1.99 (7H, m),
2.15-2.21 (2H, m), 2.44 (3H, s), 3.21-3.31 (1H, m), 3.37-3.46 (1H,
m), 3.66-3.74 (1H, m), 3.99-4.09 (2H, m), 4.18 (1H, tt, J = 3.9 and
11.8 Hz), 4.23 (2H, d, J = 3.9 Hz), 7.12-7.18 (1H, m), 7.44 (1H, s)
405 295 ##STR00399## colorless foamy solid CDCl.sub.3 1.20-1.32
(1H, m), 1.38-1.50 (2H, m), 1.68-1.98 (5H, m), 2.11-2.21 (2H, m),
2.30 (3H, s), 2.36-2.51 (4H, m), 2.43 (3H, s), 2.61 (2H, t, J = 5.5
Hz), 3.42-3.51 (2H, m), 3.61-3.69 (2H, m), 3.70-3.80 (2H, m), 4.16
(1H, tt, J = 3.9 and 11.8 Hz), 7.00-7.09 (1H, m), 7.33 (1H, s) 418
296 ##STR00400## colorless 91-96 CD.sub.3OD 1.22-1.38 (1H, m),
1.43-1.59 (2H, m), 1.72-2.99 (5H, m), 2.09-2.18 (2H, m), 2.42 (3H,
s), 2.63 (3H, s), 2.74 (2H, t, J = 6.7 Hz), 2.86-3.00 (4H, m), 3.62
(2H, t, J = 6.7 Hz), 3.70-3.80 (4H, m), 4.16 (1H, tt, J = 3.9 and
11.8 Hz), 6.72 (2H, s), 7.60 (1H, s) 418 (free)
TABLE-US-00103 TABLE 103 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 297 ##STR00401## colorless foamy solid
CDCl.sub.3 1.20-1.34 (1H, m), 1.38-1.50 (2H, m), 1.60- 1.69 (2H,
m), 1.72-2.21 (11H, m), 2.30 and 2.32 (total 3H, each s), 2.44 (3H,
s), 2.88 and 2.92 (total 3H, each s), 2.90-2.99 (2H, m), 3.43-3.53
(0.4H, m), 4.12- 4.28 (3H, m), 4.47 (0.6H, tt, J = 4.2 and 12.2
Hz), 7.14- 7.27 (1H, m), 7.44 and 7.45 (total 1H, each s) 432 298
##STR00402## colorless solid 107-116.5 CD.sub.3OD 1.23-1.38 (1H,
m), 1.43-1.57 (2H, m), 1.71- 2.21 (11H, m), 2.43 (3H, s), 2.83 (3H,
s), 2.87 and 2.99 (total 3H, each s), 3.02-3.13 (2H, m), 3.49- 3.58
(2H, m), 4.01-4.13 (0.3H, m), 4.15-4.24 (1H, m), 4.21 and 4.31
(total 2H, each s), 4.50-4.60 (0.7H, m), 6.70 (2H, s), 7.70 (1H, s)
432 (free) 299 ##STR00403## colorless solid 182-183 (AcOEt)
CDCl.sub.3 1.20-1.33 (1H, m), 1.36-1.50 (2H, m), 1.69- 1.98 (5H,
m), 2.11-2.21 (2H, m), 2.43 (3H, s), 3.51- 3.59 (2H, m), 3.64-3.76
(4H, m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 4.33-4.42 (2H, m),
6.79-6.87 (1H, m), 7.37 (1H, s) 377 300 ##STR00404## colorless
solid 158-160 (EtOH) CDCl.sub.3 1.20-1.33 (1H, m), 1.38-1.51 (2H,
m), 1.69- 1.96 (5H, m), 2.12-2.21 (2H, m), 2.37-2.48 (2H, m), 2.44
(3H, s), 3.21 (2H, t, J = 7.5 Hz), 3.34-3.42 (4H, m), 3.61-3.69
(2H, m), 4.17 (1H, tt, J = 3.9 and 11.8 Hz), 6.20-6.27 (1H, m),
7.40 (1H, s) 411
TABLE-US-00104 TABLE 104 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 301 ##STR00405## colorless foamy solid
CDCl.sub.3 1.19-1.32 (1H, m), 1.37-1.50 (2H, m), 1.69- 1.97 (5H,
m), 2.09-2.11 (2H, m), 2.43 (3H, s), 2.92 (3H, s), 3.38-3.55 (6H,
m), 3.61-3.67 (1H, m), 3.72-3.79 (2H, m), 4.16 (1H, tt, J = 3.9 and
11.8 Hz), 5.81-5.89 (1H, m), 7.43 (1H, s), 7.63-7.72 (1H, m) 408
302 ##STR00406## colorless solid 182-183 (AcOEt) CDCl.sub.3
1.21-1.33 (1H, m), 1.37-1.50 (2H, m), 1.69- 1.97 (5H, m), 2.11-2.21
(2H, m), 2.44 (3H, s), 2.79 (3H, s), 3.31-3.49 (6H, m), 3.54-3.61
(2H, m), 4.16 (1H, tt, J = 3.8 and 11.8 Hz), 7.37-3.43 (1H, m),
7.38 (1H, s) 390 303 ##STR00407## colorless solid 110-111
CDCl.sub.3 1.20-1.33 (1H, m), 1.96 (3H, t, J = 6.7 Hz), 1.38- 1.51
(2H, m), 1.70-2.01 (7H, m), 2.12-2.21 (2H, m), 2.38- 2.51 (2H, m),
2.44 (3H, s), 3.45-3.53 (2H, m), 4.10- 4.22 (3H, m), 6.39-6.44 (1H,
m), 7.32 (1H, s) 378 304 ##STR00408## colorless solid 170-171
(AcOEt/ benzene) CDCl.sub.3 1.19-1.32 (1H, m), 1.37-1.51 (2H, m),
1.70- 1.84 (3H, m), 1.88-2.01 (4H, m), 2.11-2.20 (2H, m), 2.28 (3H,
s), 2.49 (2H, t, J = 6.4 Hz), 3.50-3.58 (2H, m), 4.18 (1H, tt, J =
3.8 and 11.9 Hz), 6.54-6.61 (1H, m), 7.30 (1H, s) 350
TABLE-US-00105 TABLE 105 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 305 ##STR00409## colorless solid 233-234
(EtOH) DMSO-d.sub.6 1.16-1.30 (1H, m), 1.37-1.49 (2H, m), 1.62-1.87
(5H, m), 2.00-2.09 (2H, m), 2.35 (3H, s), 3.33- 3.42 (2H, m),
3.46-3.52 (2H, m), 3.85 (2H, s), 4.18 (1H, tt, J = 3.8 and 11.6
Hz), 7.64 (1H, s), 8.03 (1H, s), 8.57- 8.62 (1H, m) 390 306
##STR00410## colorless solid 114.5-116 (AcOEt/hexane) CDCl.sub.3
1.20-1.33 (1H, m), 1.38-1.50 (2H, m), 1.70- 1.96 (5H, m), 1.99-2.06
(2H, m), 2.11-2.20 (2H, m), 2.43 (3H, s), 2.48-2.53 (2H, m), 2.97
(3H, s), 3.02 (3H, s), 3.44-3.51 (2H, m), 4.16 (1H, tt, J = 3.9 and
11.8 Hz), 7.39 (1H, s), 7.49-7.56 (1H, m) 377 307 ##STR00411##
colorless solid 162-163 (AcOEt/hexane) CDCl.sub.3 1.21-1.34 (1H,
m), 1.37-1.49 (2H, m), 1.39 (6H, s), 1.69-1.97 (5H, m), 2.12-2.20
(2H, m), 2.45 (3H, s), 2.90 (3H, s), 3.62-3.69 (2H, m), 3.80-3.86
(2H, m), 4.16 (1H, tt, J = 3.8 and 11.8 Hz), 6.99-7.05 (1H, m),
7.34 (1H, s) 432 308 ##STR00412## colorless solid 168-169 (AcOEt)
CDCl.sub.3 1.21-1.33 (1H, m), 1.37-1.51 (2H, m), 1.70- 1.98 (5H,
m), 2.12-2.20 (2H, m), 2.44 (3H, s), 3.66- 3.72 (2H, m), 3.89-3.96
(2H, m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 6.39-6.47 (1H, m),
7.29 (1H, s) 407
TABLE-US-00106 TABLE 106 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 309 ##STR00413## colorless solid 173-174
(AcOEt/ hexane) CDCl.sub.3 0.92-1.02 (4H, m), 1.20-1.32 (1H, m),
1.37- 1.50 (2H, m), 1.70-1.84 (3H, m), 1.88-1.97 (2H, m), 2.11-
2.20 (2H, m), 2.42 (3H, s), 3.70 (2H, d, J = 5.1 Hz), 3.92 (1H, t,
J = 5.1 Hz), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 6.60 (1H, brs),
7.33 (1H, s) 334 310 ##STR00414## colorless solid 208-209 (AcOEt/
hexane) CDCl.sub.3 0.98-1.14 (4H, m), 1.20-1.33 (1H, m), 1.38- 1.50
(2H, m), 1.69-1.99 (5H, m), 2.11-2.21 (2H, m), 2.40 (3H, s), 2.99
(3H, s), 3.73 (2H, s), 3.87 (2H, s), 4.14 (1H, tt, J = 3.9 and 11.8
Hz), 6.53 (1H, brs), 7.27 (1H, s) 430 311 ##STR00415## colorless
solid 113-114 CDCl.sub.3 1.20-1.33 (1H, m), 1.39-1.51 (2H, m),
1.65- 1.98 (5H, m), 2.12-2.21 (2H, m), 2.44 (3H, s), 2.86- 2.92
(2H, m), 3.44-3.56 (2H, m), 3.47 (2H, s), 3.76 (3H, s), 4.14 (1H,
tt, J = 3.8 and 11.8 Hz), 6.80-6.89 (1H, m), 7.40 (1H, s) 379 312
##STR00416## colorless solid 83-87 CDCl.sub.3 1.21-1.34 (1H, m),
1.38-1.50 (2H, m), 1.69- 1.97 (5H, m), 2.12-2.21 (2H, m), 2.44 (3H,
s), 3.48- 3.64 (4H, m), 3.79 (3H, s), 4.06 (2H, s), 4.17 (1H, tt, J
= 3.8 and 11.8 Hz), 4.93 (2H, brs), 7.31-7.42 (1H, m), 7.39 (1H, s)
422
TABLE-US-00107 TABLE 107 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 313 ##STR00417## colorless solid 233-235
(EtOH) CDCl.sub.3 1.20-1.32 (1H, m), 1.38-1.50 (2H, m), 1.70- 1.98
(5H, m), 2.11-2.21 (2H, m), 2.42 (3H, s), 3.57- 3.70 (4H, m), 4.07
(2H, s), 4.14 (1H, tt, J = 3.9 and 11.9 Hz), 6.62-6.70 (1H, m),
7.35 (1H, s), 7.97 (1H, brs) 390 314 ##STR00418## colorless solid
207-2113 (EtOH) CDCl.sub.3 1.20-1.32 (1H, m), 1.37-1.51 (2H, m),
1.45 (6H, s), 1.69-1.96 (5H, m), 2.11-2.20 (2H, m), 2.44 (3H, s),
3.64-71 (2H, m), 3.79-3.85 (2H, m), 4.16 (1H, tt, J = 3.9 and 11.9
Hz), 5.51 (1H, brs), 6.89-6.96 (1H, m), 7.33 (1H, s) 418 315
##STR00419## colorless solid 149-150 (AcOEt/ hexane) CDCl.sub.3
1.21-1.33 (1H, m), 1.38-1.51 (2H, m), 1.70- 1.98 (5H, m), 2.13-2.21
(2H, m), 2.44 (3H, s), 2.78 (3H, s), 3.31-3.48 (6H, m), 3.68-3.75
(2H, m), 4.17 (1H, tt, J = 3.8 and 11.9 Hz), 6.62-6.70 (1H, m),
7.38 (1H, s) 426 316 ##STR00420## colorless solid 148.5-150 (AcOEt/
hexane) CDCl.sub.3 1.13 (3H, t, J = 7.2 Hz), 1.20-1.33 (1H, m),
1.38-1.50 (2H, m), 1.70-1.98 (5H, m), 2.11-2.21 (2H, m), 2.44 (3H,
s), 3.53 (2H, q, J = 7.2 Hz), 3.60-3.72 (4H, m), 3.99 (2H, s), 4.16
(1H, tt, J = 3.9 and 11.9 Hz), 6.57- 6.65 (1H, m), 7.33 (1H, s)
418
TABLE-US-00108 TABLE 108 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 317 ##STR00421## colorless solid 154-155
(AcOEt/ hexane) CDCl.sub.3 1.20-1.33 (1H, m), 1.37-1.50 (2H, m),
1.69-1.97 (5H, m), 2.11-2.21 (2H, m), 2.44 (3H, s), 2.99 (3H, s),
3.59-3.74 (4H, m), 4.01 (2H, s), 4.17 (1H, tt, J = 3.9 and 11.9
Hz), 6.57-6.67 (1H, m), 7.34 (1H, s) 404 318 ##STR00422## colorless
solid 152-153 (AcOEt/ hexane) CDCl.sub.3 1.20-1.34 (1H, m), 1.30
(3H, d, J = 6.8 Hz), 1.38-1.50 (2H, m), 1.69-1.98 (5H, m),
2.12-2.21 (2H, m), 2.42 (3H, s), 2.75 (1H, t, J = 5.5 Hz),
3.61-3.68 (2H, m), 3.74-3.82 (2H, m), 4.17 (1H, tt, J = 3.9 and
11.9 Hz), 4.21-4.31 (1H, m), 6.13-6.21 (1H, m), 7.35 (1H, s) 322
319 ##STR00423## colorless solid 172.5-175 (AcOEt/ hexane)
CDCl.sub.3 1.20-1.34 (1H, m), 1.29 (3H, d, J = 6.8 Hz), 1.38-1.50
(2H, m), 1.69-1.96 (5H, m), 2.11-2.20 (2H, m), 2.43 (3H, s),
3.61-3.77 (2H, m), 3.96-4.08 (2H, m), 4.16 (1H, tt, J = 3.9 and
11.9 Hz), 4.36-4.48 (1H, m), 5.46 (1H, brs), 6.79-6.86 (1H, m),
7.32 (1H, s) 404 320 ##STR00424## colorless foamy solid CDCl.sub.3
1.21-1.33 (1H, m), 1.38-1.50 (2H, m), 1.68-1.97 (6H, m), 2.11-2.21
(2H, m), 2.26-2.42 (2H, m), 2.44 (3H, s), 2.58-2.63 (1H, m),
2.70-2.78 (1H, m), 2.90-2.99 (1H, m), 3.59-3.69 (2H, m), 4.16 (1H,
tt, J = 3.9 and 11.8 Hz), 4.59-4.69 (1H, m), 6.34-6.42 (1H, m),
7.23-7.40 (6H, m) 423
TABLE-US-00109 TABLE 109 Ex- properties am- m.p. (.degree. C.) ple
(recryst. MS(FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 321 ##STR00425## colorless solid 119-123 CDCl.sub.3
1.20-1.32 (1H, m), 1.37-1.50(2H, m), 1.70- 1.98(6H, m),
2.11-2.31(3H, m), 2.42 (3H, s), 2.93- 3.04 (2H, m), 3.11-3.25 (2H,
m), 4.16 (1H, tt, J = 3.9 and 11.9 Hz), 4.55-4.65 (1H, m),
6.48-6.55 (1H, m), 7.41 (1H, s) 333 322 ##STR00426## colorless
foamy solid CDCl.sub.3 1.21-1.32 (1H, m), 1.37-1.50 (2H, m), 1.70-
1.96 (5H, m), 1.98-2.08 (1H, m), 2.11-2.24 (3H, m), 2.43 (3H, s),
2.89(6H, s), 3.41-3.62 (4H, m), 4.17 (1H, tt, J = 3.8 and 11.8 Hz),
4.50-4.59 (1H, m), 6.61-6.69 (1H, m), 7.35 (1H, s) 404 323
##STR00427## colorless solid 126-128 DMSO-d.sub.6 1.16-1.29 (1H,
m), 1.38-1.50 (2H, m), 1.61-1.91 (6H, m), 2.00-2.10 (3H, m), 2.35
(3H, s), 2.74 (6H, s), 3.19-3.25 (1H, m), 3.30-3.49 (2H, m), 3.51-
3.60 (1H, m), 4.19 (1H, tt, J = 3.8 and 11.6 Hz), 4.28- 4.38 (1H,
m), 7.88 (1H, s), 8.52-8.59 (1H, m) 404 (free) 324 ##STR00428##
colorless solid 146.5-148 CDCl.sub.3 1.20-1.34 (1H, m), 1.30 (3H,
d, J = 6.8 Hz), 1.38-1.50 (2H, m), 1.69-1.98 (5H, m), 2.12-2.21
(2H, m), 2.42 (3H, s), 2.68-2.73 (1H, m), 3.61-3.68 (2H, m), 3.74-
3.82 (2H, m), 4.17 (1H, tt, J = 3.9 and 11.9 Hz), 4.21- 4.31 (1H,
m), 6.11-6.19 (1H, m), 7.35 (1H, s) 322
TABLE-US-00110 TABLE 110 Ex- properties am- m.p. (.degree. C.) ple
(recryst. MS(FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 325 ##STR00429## colorless solid 170-173 CDCl.sub.3
1.20-1.34 (1H, m), 1.29 (3H, d, J = 6.8 Hz), 1.38-1.50 (2H, m),
1.69-1.96 (5H, m), 2.11-2.20 (2H, m), 2.43 (3H, s), 3.61-3.77 (2H,
m), 3.96-4.08 (2H, m), 4.16 (1H, tt, J = 3.9 and 11.9 Hz),
4.36-4.48 (1H, m), 5.44 (1H, brs), 6.79-6.86 (1H, m), 7.32 (1H, s)
404 326 ##STR00430## colorless solid 116-117.5 CDCl.sub.3 1.20-1.33
(1H, m), 1.26 (3H, d, J = 6.3 Hz), 1.38-1.51 (1H, m), 1.70-1.97
(5H, m), 2.12-2.21 (2H, m), 2.42 (3H, s), 2.49-2.54 (1H, m),
3.23-3.32 (1H, m), 3.61- 3.70 (1H, m), 3.99-4.09 (1H, m), 4.17 (1H,
tt, J = 3.9 and 11.8 Hz), 6.42-6.50 (1H, m), 7.37 (1H, s) 322 327
##STR00431## colorless solid 213-215 CDCl.sub.3 1.20-1.34 (1H, m),
1.38-1.50 (2H, m), 1.47 (3H, d, J = 7.1 Hz), 1.69-1.97 (5H, m),
2.12-2.20 (2H, m), 2.44 (3H, s), 3.37-3.44 (1H, m), 3.98 (2H, s),
4.10- 4.23 (2H, m), 4.47-4.58 (1H, m), 5.42 (1H, brs), 7.10- 7.18
(1H, m), 7.36 (1H, s) 404 328 ##STR00432## colorless solid
115.5-117 CDCl.sub.3 1.20-1.33 (1H, m), 1.26 (3H, d, J = 6.3 Hz),
1.38-1.51 (2H, m), 1.70-1.97 (5H, m), 2.12-2.21 (2H, m), 2.42 (3H,
s), 2.44-2.49 (1H, m), 3.23-3.32 (1H, m), 3.61- 3.70 (1H, m),
3.99-4.09 (1H, m), 4.17 (1H, tt, J = 3.9 and 11.8 Hz), 6.40-6.48
(1H, m), 7.37 (1H, s) 322
TABLE-US-00111 TABLE 111 Ex- properties am- m.p. (.degree. C.) ple
(recryst. MS(FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 329 ##STR00433## colorless solid 214-216 (AcOEt/hexane)
CDCl.sub.3 1.20-1.34 (1H, m), 1.38-1.50 (2H, m), 1.47 (3H, d, J =
7.1 Hz), 1.69-1.97 (5H, m), 2.12-2.20 (2H, m), 2.44 (3H, s),
3.37-3.44 (1H, m), 3.98 (2H, s), 4.10- 4.23 (2H, m), 4.47-4.58 (1H,
m), 5.46 (1H, brs), 7.12- 7.20 (1H, m), 7.36 (1H, s) 404 330
##STR00434## colorless solid 147-149.5 CDCl.sub.3 1.02 (3H, t, J =
7.5 Hz), 1.20-1.32 (1H, m), 1.38-1.51 (2H, m), 1.58-1.97 (7H, m),
2.12-2.21 (2H, m), 2.43 (3H, s), 2.51-2.59 (1H, m), 3.68-3.74 (1H,
m), 3.78- 3.83 (1H, m), 4.00-4.10 (1H, m), 4.17 (1H, tt, J = 3.8
and 11.9 Hz), 6.07-6.14 (1H, m), 7.36 (1H, s) 336 331 ##STR00435##
colorless solid 180-183 CDCl.sub.3 1.03 (3H, t, J = 7.5 Hz),
1.20-1.33 (1H, m), 1.37-1.50 (2H, m), 1.55-1.97 (7H, m), 2.11-2.19
(2H, m), 2.43 (3H, s), 3.62-3.77 (2H, m), 3.91-4.04 (2H, m), 4.16
(1H, tt, J = 3.8 and 11.8 Hz), 4.25-4.37 (1H, m), 5.45 (1H, brs),
6.53-6.60 (1H, m), 7.33 (1H, s) 418 332 ##STR00436## colorless
solid 148.5-149.5 CDCl.sub.3 0.99-1.08 (6H, m), 1.19-1.32 (1H, m),
1.38- 1.51 (2H, m), 1.70-2.07 (6H, m), 2.12-2.21 (2H, m), 2.43 (3H,
s), 2.51-2.60 (1H, m), 3.77-3.83 (2H, m), 3.86- 3.95 (1H, m), 4.17
(1H, tt, J = 3.9 and 11.8 Hz), 6.12- 6.20 (1H, m), 7.56 (1H, s)
350
TABLE-US-00112 TABLE 112 Ex- properties am- m.p. (.degree. C.) MS
ple (recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M
+ 1).sup.+ 333 ##STR00437## colorless solid 180-184 CDCl.sub.3 1.05
(6H, d, J = 6.8 Hz), 1.19-1.33 (1H, m), 1.38-1.51 (2H, m),
1.69-2.01 (6H, m), 2.10-2.20 (2H, m), 2.44 (3H, s), 3.59-3.80 (2H,
m), 3.88-4.02 (2H, m), 4.11- 4.31 (2H, m), 5.45 (1H, brs),
6.32-6.41 (1H, m), 7.34 (1H, s) 432 334 ##STR00438## colorless
foamy solid CDCl.sub.3 1.20-1.33 (1H, m), 1.38-1.53 (2H, m), 1.47
(6H, s), 1.50 (9H, s), 1.69-1.95 (5H, m), 2.11-2.20 (2H, m), 2.40
(3H, s), 3.22 (2H, d, J = 6.7 Hz), 4.16 (1H, tt, J = 3.9 and 11.8
Hz), 5.15-5.20 (1H, m), 7.36 (1H, s), 7.58 (1H, brs) 435 335
##STR00439## colorless solid 134-136.5 CDCl.sub.3 1.20-1.50 (3H,
m), 1.43 (6H, s), 1.70-1.97 (5H, m), 2.11-2.20 (2H, m), 2.43 (3H,
s), 2.83 (2H, s), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 6.70 (1H,
brs), 7.28 (1H, s) 335 336 ##STR00440## colorless foamy solid
CDCl.sub.3 1.21-1.32 (1H, m), 1.38-1.51 (2H, m), 1.55 (6H, s),
1.69-1.96 (5H, m), 2.10-2.19 (2H, m), 2.44 (3H, s), 3.66 (2H, s),
4.10-4.20 (3H, m), 5.55 (1H, brs), 7.34 (1H, s), 7.74 (1H, brs)
418
TABLE-US-00113 TABLE 113 Ex- properties am- m.p. (.degree. C.) ple
(recryst. MS(FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 337 ##STR00441## colorless solid 141.5-143 DMSO-d.sub.6
1.18-1.31 (1H, m), 1.34-1.51 (2H, m), 1.35 (6H, s), 1.61-1.88 (5H,
m), 2.00-2.09 (2H, m), 2.35 (3H, s), 3.62 (2H, s), 3.98 (2H, m),
4.18 (1H, t, J = 3.8 and 11.5 Hz), 7.60 (1H, s), 8.01 (1H, s), 8.28
(1H, s) 418 (free) 338 ##STR00442## colorless solid 145-147
CDCl.sub.3 0.97 (6H, s), 1.20-1.33 (1H, m), 1.39-1.53 (2H, m),
1.70-1.98 (5H, m), 2.12-2.21 (2H, m), 2.44 (3H, s), 2.72 (2H, s),
3.37 (2H, d, J = 5.2 Hz), 4.17 (1H, tt, J = 3.9 and 11.8 Hz), 7.29
(1H, s), 8.38-8.53 (1H, m) 349 339 ##STR00443## colorless solid
180-182 CDCl.sub.3 1.00 (6H, s), 1.20-1.34 (1H, m), 1.38-1.50 (2H,
m), 1.70-1.98 (5H, m), 2.12-2.21 (2H, m), 2.45 (3H, s), 3.17 (2H,
d, J = 6.7 Hz), 3.43 (2H, s), 4.09-4.13 (2H, m), 4.17 (1H, tt, J =
3.8 and 11.8 Hz), 5.60 (1H, brs), 7.44 (1H, s), 7.83-7.89 (1H, m)
432 340 ##STR00444## colorless solid 153-154 CDCl.sub.3 0.83-0.91
(1H, m), 0.94-1.00 (1H, m), 1.20- 1.50 (4H, m), 1.70-1.97 (5H, m),
2.12-2.21 (2H, m), 2.42 (3H, s), 2.57-2.62 (1H, m), 3.05-3.19 (2H,
m), 3.90- 3.98 (1H, m), 4.16 (1H, tt, J = 3.9 and 11.8 Hz), 6.35
(1H, brs), 7.32 (1H, s) 334
TABLE-US-00114 TABLE 114 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 341 ##STR00445## pale brown solid 220 (dec.)
DMSO-d.sub.6 1.16-1.32 (1H, m), 1.38-1.51 (2H, m), 1.63-1.87 (5H,
m), 2.02-2.11 (2H, m), 2.39 (3H, s), 3.26-3.39 (4H, m), 3.67 (2H,
s), 4.16-4.26 (1H, m), 6.91-6.96 (2H, m), 7.56-7.61 (2H, m), 8.00
(1H, s), 8.01-8.03 (1H, m), 10.06 (1H, brs) 438 342 ##STR00446##
pale brown solid 155 (dec.) CDCl.sub.3 2.11-2.28 (4H, m), 2.47 (3H,
s), 3.45-3.49 (2H, m), 3.52-3.61 (4H, m), 3.87 (2H, s), 4.12-4.18
(2H, m), 4.39-4.49 (1H, m), 6.01 (1H, brs), 6.87-6.93 (2H, m), 7.47
(1H, s), 7.50-7.56 (2H, m), 7.58 (1H, brs) 440 343 ##STR00447##
colorless solid 155.5-157 CDCl.sub.3 1.22-1.35 (1H, m), 1.39-1.52
(2H, m), 1.72-1.98 (5H, m), 2.16-2.24 (2H, m), 2.47 (3H, s), 3.93
(3H, s), 4.20 (1H, tt, J = 3.8 and 11.8 Hz), 7.45 (1H, t, J = 7.9
Hz), 7.50 (1H, s), 7.74 (1H, brs), 7.81 (1H, dt, J = 7.9 and 1.3
Hz), 7.99-8.04 (1H, m), 8.11-8.13 (1H, m) 398 344 ##STR00448##
colorless foamy solid CDCl.sub.3 1.20-1.32 (1H, m), 1.36-1.50 (2H,
m), 1.71-1.96 (5H, m), 2.15-2.22 (2H, m), 2.42 (3H, s), 4.18 (1H,
tt, J = 3.8 and 11.8 Hz), 7.42 (1H, t, J = 7.9 Hz), 7.64 (1H, s),
7.80-7.85 (1H, m), 8.05-8.10 (1H, m), 8.13-8.16 (1H, m), 8.30 (1H,
brs) 384
TABLE-US-00115 TABLE 115 Ex- properties am- m.p. (.degree. C.) MS
ple (recryst. (FAB) No. Chemical Structure solvent) .sup.1H-NMR (M
+ 1).sup.+ 345 ##STR00449## colorless solid 226-228 CDCl.sub.3
1.25-1.35 (1H, m), 1.39-1.52 (2H, m), 1.72- 1.98 (5H, m), 2.16-2.24
(2H, m), 2.47 (3H, s), 3.02 (3H, brs), 3.13 (3H, brs), 4.19 (1H,
tt, J = 3.9 and 11.8 Hz), 7.12-7.16 (1H, m), 7.34-7.39 (1H, m),
7.57 (1H, s), 7.60 (1H, brs), 7.64-7.68 (1H, m), 8.15 (1H, brs) 411
346 ##STR00450## colorless solid 218-220 CDCl.sub.3 1.24-1.36 (1H,
m), 1.39-1.52 (2H, m), 1.72- 1.98 (5H, m), 2.17-2.25 (2H, m), 2.47
(3H, s), 3.45- 3.89 (8H, m), 4.15-4.25 (1H, m), 7.15-7.20 (1H, m),
7.38- 7.43 (1H, m), 7.51 (1H, s), 7.59-7.64 (1H, m), 7.71- 7.74
(1H, m), 7.81 (1H, brs) 453 347 ##STR00451## colorless solid
185-187 CDCl.sub.3 1.18-1.32 (2H, m), 1.55-1.67 (2H, m), 2.04- 2.33
(9H, m), 2.43 (3H, s), 3.55 (2H, dt, J = 2.4 and 11.7 Hz), 3.69
(3H, s), 3.88-3.99 (1H, m), 4.09-4.16 (2H, m), 4.36-4.45 (1H, m),
5.69-5.74 (1H, m), 7.31 (1H, s) 406 348 ##STR00452## colorless
solid 267-270 DMSO-d.sub.6 1.27-1.47 (4H, m), 1.85-2.04 (8H, m),
2.12-2.22 (1H, m), 2.33 (3H, s), 3.49 (2H, dt, J = 2.4 and 11.6
Hz), 3.63-3.72 (1H, m), 3.95-4.00 (2H, m), 4.43- 4.52 (1H, m), 7.81
(1H, s), 8.25-8.29 (1H, m) 392
TABLE-US-00116 TABLE 116 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 349 ##STR00453## colorless solid 232-234
CDCl.sub.3 1.22-1.34 (2H, m), 1.69-1.90 (4H, m), 2.08-2.26 (6H, m),
2.44 (3H, s), 2.49 (1H, tt, J = 3.6 and 11.6 Hz), 2.94 (3H, s),
3.06 (3H, s), 3.55 (2H, dt, J = 2.4 and 11.7 Hz), 3.90-4.03 (1H,
m), 4.10-4.17 (2H, m), 4.36-4.46 (1H, m), 5.69-5.74 (1H, m), 7.31
(1H, s) 419 350 ##STR00454## colorless solid 220-222 CDCl.sub.3
1.20-1.35 (2H, m), 1.71-1.89 (4H, m), 2.08-2.27 (6H, m), 2.40-2.48
(1H, m), 2.44 (3H, s), 3.47-3.72 (10H, m), 3.91-4.01 (1H, m),
4.09-4.17 (2H, m), 4.37-4.46 (1H, m), 5.67-5.72 (1H, m), 7.31 (1H,
s) 461 351 ##STR00455## colorless solid 255-260 DMSO-d.sub.6
1.17-1.53 (6H, m), 1.62-2.07 (10H, m), 2.36 (3H, s), 2.48-2.54 (1H,
m), 2.91-3.03 (1H, m), 3.13-3.24 (1H, m), 3.47-3.55 (2H, m), 3.61-
3.79 (3H, m), 3.88-4.00 (3H, m), 4.43-4.53 (1H, m), 4.72-7.75 (1H,
m), 7.83 (1H, s), 8.26-8.29 (1H, m) 475 352 ##STR00456## colorless
solid 200-203 CDCl.sub.3 2.20-1.33 (2H, m), 1.70-1.88 (4H, m),
2.08-2.27 (6H, m), 2.31 (3H, s), 2.35-2.48 (5H, m), 2.43 (3H, s),
3.48-3.66 (6H, m), 3.90- 4.02 (1H, m), 4.10-4.16 (2H, m), 4.36-4.47
(1H, m), 5.65-5.71 (1H, m), 7.31 (1H, s) 474
TABLE-US-00117 TABLE 117 Ex- properties am- m.p. (.degree. C.) ple
(recryst. MS(FAB) No. Chemical Structure solvent) .sup.1H-NMR (M +
1).sup.+ 353 ##STR00457## colorless solid 128-129 CDCl.sub.3
1.21-1.35 (1H, m), 1.38-1.52 (2H, m), 1.71- 2.96 (7H, m), 2.05-2.22
(2H, m), 2.44 (3H, s), 2.50- 2.59 (6H, m), 3.52-3.57 (2H, m),
3.76-3.81 (4H, m), 4.14- 4.24 (1H, m), 7.38 (1H, s), 7.67-7.73 (1H,
m) 391 354 ##STR00458## colorless solid 138-138.5 CDCl.sub.3
1.22-1.34 (1H, m), 1.37-1.51 (2H, m), 1.72- 1.96 (5H, m), 2.14-2.21
(2H, m), 2.45 (3H, s), 2.49- 2.54 (4H, m), 2.59 (2H, t, J = 5.9
Hz), 3.51-3.57 (2H, m), 3.74-3.78 (4H, m), 4.17 (1H, tt, J = 3.8
and 11.8 Hz), 6.50-6.55 (1H, m), 7.32 (1H, s) 377 355 ##STR00459##
colorless solid 122-123 CDCl.sub.3 1.22-1.53 (5H, m), 1.59-1.65
(4H, m), 1.71- 1.97 (5H, m), 2.14-2.22 (2H, m), 2.40-2.48 (4H, m),
2.45 (3H, s), 2.52-2.56 (2H, m), 3.47-3.54 (2H, m), 4.17 (1H, tt, J
= 3.8 and 11.8 Hz), 6.73-6.79 (1H, m), 7.31 (1H, s) 375 356
##STR00460## colorless solid 175-178 DMSO-d.sub.6 0.90-1.03 (2H,
m), 1.23-1.37 (3H, m), 1.75-2.06 (8H, m), 2.36 (3H, s), 3.20-3.26
(2H, m), 3.46- 3.54 (2H, m), 3.59-3.72 (1H, m), 3.94-4.01 (2H, m),
4.38- 4.52 (2H, m), 7.81 (1H, s), 8.23-8.28 (1H, m) 378
TABLE-US-00118 TABLE 118 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 357 ##STR00461## colorless solid 193-195
CDCl.sub.3 1.02-1.27 (4H, m), 1.62-1.87 (3H, m), 2.06-2.25 (6H, m),
2.43 (3H, s), 2.46 (3H, s), 3.55 (2H, dt, J = 2.5 and 11.7 Hz),
3.80-3.92 (3H, m), 4.10-4.16 (2H, m), 4.36-4.46 (1H, m), 5.67-5.72
(1H, m), 7.30 (1H, s), 7.34-7.39 (2H, m), 7.78-7.93 (2H, m) 532 358
##STR00462## colorless solid 165-167 CDCl.sub.3 1.01-1.28 (4H, m),
1.43-1.56 (1H, m), 1.84-1.95 (2H, m), 2.08-2.25 (8H, m), 2.38-2.42
(4H, m), 2.44 (3H, s), 3.55 (2H, dt, J = 2.4 and 11.8 Hz),
3.68-3.73 (4H, m), 3.85- 3.95 (1H, m), 4.09-4.17 (2H, m), 4.35-
4.46 (1H, m), 5.68-5.73 (1H, m), 7.31 (1H, s) 447 359 ##STR00463##
pale yellow solid 158-160 CDCl.sub.3 1.00-1.27 (4H, m), 1.36-1.50
(1H, m), 1.84-1.92 (2H, m), 2.06-2.17 (8H, m), 2.20 (6H, s), 2.44
(3H, s), 3.55 (2H, dt, J = 2.4 and 11.7 Hz), 3.83-3.98 (1H, m),
4.10-4.17 (2H, m), 4.36-4.47 (1H, m), 5.68-5.73 (1H, m), 7.31 (1H,
s) 405 360 ##STR00464## pale yellow solid CDCl.sub.3 1.01-1.28 (4H,
m), 1.42-1.55 (1H, m), 1.85-1.93 (2H, m), 2.08-2.25 (8H, m), 2.09
(3H, s), 2.33-2.42 (4H, m), 2.44 (3H, s), 3.43-3.48 (2H, m), 3.55
(2H, dt, J = 2.3 and 11.7 Hz), 3.59-3.63 (2H, m), 4.10-4.17 (2H,
m), 4.37-4.47 (1H, m), 5.70-5.75 (1H, m), 7.32 (1H, s) 488
TABLE-US-00119 TABLE 119 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 361 ##STR00465## colorless solid 224-225
DMSO-d.sub.6 1.92-2.10 (4H, m), 2.42 (3H, s), 2.64 (6H, s), 3.51
(2H, dt, J = 2.4 and 11.5 Hz), 3.96-4.02 (2H, m), 4.50-4.60 (1H,
m), 7.44-7.49 (1H, m), 7.62-7.67 (1H, m), 8.10-8.16 (1H, m), 8.17
(1H, s), 8.18-8.20 (1H, m), 10.57 (1H, brs) 449 362 ##STR00466##
colorless solid 226-227 DMSO-d.sub.6 1.91-2.10 (4H, m), 2.42 (3H,
s), 3.22 (3H, s), 3.48-3.57 (2H, m), 3.96-4.03 (2H, m), 4.50-4.60
(1H, m), 7.64-7.68 (2H, m), 8.06-8.12 (1H, m), 8.14 (1H, s), 8.34
(1H, brs), 10.61 (1H, brs) 420 363 ##STR00467## colorless solid
181-182 CDCl.sub.3 -0.04 (6H, s), 0.77 (9H, s), 2.12-2.28 (4H, m),
2.50 (3H, s), 3.37-3.43 (2H, m), 3.57 (2H, dt, J = 2.5 and 11.7
Hz), 3.99-4.05 (2H, m), 4.12-4.18 (2H, m), 4.40-4.50 (1H, m),
7.55-7.61 (1H, m), 7.60 (1H, s), 7.67-7.71 (1H, m), 8.01-8.04 (1H,
m), 8.09 (1H, brs), 8.22- 8.26 (1H, m) 564 364 ##STR00468##
colorless solid 229-232 DMSO-d.sub.6 1.92-2.09 (4H, m), 2.42 (3H,
s), 3.43- 3.48 (2H, m), 3.51 (2H, dt, J = 2.4 and 11.6 Hz),
3.66-3.74 (2H, m), 3.96-4.03 (2H, m), 4.49-4.60 (1H, m), 4.88-4.93
(1H, m), 7.59-7.67 (2H, m), 8.08-8.13 (1H, m), 8.14 (1H, s),
8.30-8.32 (1H, m), 10.61 (1H, brs) 450
TABLE-US-00120 TABLE 120 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 365 ##STR00469## colorless solid 201-206
(EtOH/ iso- Pr).sub.2O) DMSO-d.sub.6 1.16-1.30 (1H, m), 1.36-1.51
(2H, m), 1.54-1.92 (9H, m), 2.02-2.10 (2H, m), 2.34 (6H, s), 2.40
(3H, s), 2.82-2.92 (2H, m), 3.25- 3.33 (2H, m), 3.62-3.70 (1H, m),
4.10-4.25 (1H, m), 7.12-7.21 (1H, m), 7.39-7.45 (1H, m), 7.62-7.70
(1H, m), 8.03 (1H, s), 10.29 (1H, brs) 457 366 ##STR00470##
colorless solid 211-213 (iso- PrOH) DMSO-d.sub.6 1.16-1.31 (1H, m),
1.36-1.91 (11H, m), 2.02-2.10 (2H, m), 2.29 (3H, s), 2.40 (3H, s),
2.77-2.87 (2H, m), 3.22-3.30 (2H, m), 3.58- 3.67 (1H, m), 4.15-4.26
(1H, m), 7.08-7.18 (3H, m), 7.38-7.44 (1H, m), 7.45-7.50 (2H, m),
7.61-7.69 (1H, m), 8.03 (1H, s), 10.29 (1H, brs) 457 367
##STR00471## colorless solid (Et.sub.2O/ AcOEt) CD.sub.3OD
1.26-1.41 (1H, m), 1.46-1.60 (2H, m), 1.73-2.07 (7H, m), 2.12-2.28
(4H, m), 2.46 (3H, s), 2.70 (3H, s), 3.53-3.66 (2H, br), 3.74- 3.91
(2H, br), 4.02-4.14 (1H, br), 4.22 (1H, tt, J = 3.9 and 11.8 Hz),
7.60-7.66 (2H, m), 7.89-7.96 (2H, m), 7.91 (1H, s), 10.26 (1H, brs)
439 368 ##STR00472## colorless solid 255 (dec.) (EtOH/ H.sub.2O)
DMSO-d.sub.6 1.19-1.31 (1H, m), 1.39-1.52 (2H, m), 1.65-1.89 (7H,
m), 1.96-2.13 (4H, m), 2.29 (3H, s), 2.40 (3H, s), 3.22-3.95 (4H,
m), 4.23 (1H, tt, J = 3.8 and 11.6 Hz), 7.11 (2H, d, J = 8.0 Hz),
7.35-7.66 (1H, br), 7.47 (2H, d, J = 8.0 Hz), 7.72-7.91 (2H, br),
8.07 (1H, br), 10.38 (1H, brs) 439
TABLE-US-00121 TABLE 121 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 369 ##STR00473## colorless solid 226-227.5
(EtOH) CDCl.sub.3 1.19-1.32 (2H, m), 1.36-1.48 (2H, m), 1.93-2.02
(2H, m), 2.07-2.28 (7H, m), 2.43 (3H, s), 2.53-2.60 (4H, m), 3.55
(2H, dt, J = 2.4 and 11.6 Hz), 3.70-3.77 (4H, m), 3.83-3.97 (1H,
m), 4.10-4.18 (2H, m), 4.37-4.47 (1H, m), 5.70-5.77 (1H, m), 7.31
(1H, s) 433 370 ##STR00474## yellow solid 189-190.5 (EtOH)
CDCl.sub.3 1.21-1.33 (1H, m), 1.39-1.51 (2H, m), 1.53-2.03 (10H,
m), 2.15-2.24 (2H, m), 2.44 (3H, s), 3.10-3.21 (2H, m), 3.88-3.96
(1H, m), 3.98-4.09 (2H, m), 4.19 (1H, tt, J = 3.8 and 11.8 Hz),
6.69 (1H, d, J = 9.1 Hz), 7.49 (1H, s), 7.63 (1H, brs), 7.90 (1H,
dd, J = 2.7 and 9.1 Hz), 8.19 (1H, d, J = 2.7 Hz) 440 371
##STR00475## colorless solid 191-193 CDCl.sub.3 1.22-1.37 (1H, m),
1.40-1.56 (3H, m), 1.71-2.10 (9H, m), 2.17-2.247 (2H, m), 2.47 (3H,
s), 2.83-2.94 (2H, m), 3.31-3.41 (2H, m), 3.82-3.93 (1H, m), 4.19
(1H, tt, J = 3.8 and 11.8 Hz), 6.71-6.68 (1H, m), 7.48 (1H, s),
7.67 (1H, brs), 7.90-7.99 (1H, m) 475 372 ##STR00476## colorless
solid 232-233 (EtOH) CDCl.sub.3 1.21-1.35 (1H, m), 1.39-1.52 (3H,
m), 1.69-2.06 (9H, m), 2.13-2.23 (2H, m), 2.30 (3H, s), 2.45 (3H,
s), 2.67-2.76 (2H, m), 3.02- 3.11 (2H, m), 3.79-3.89 (1H, m), 4.19
(1H, tt, J = 3.8 and 11.8 Hz), 7.00 (1H, d, J = 8.4 Hz), 7.32-7.41
(2H, m), 7.44 (1H, s), 7.56 (1H, brs) 453
TABLE-US-00122 TABLE 122 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 373 ##STR00477## colorless solid 255-256.5
(EtOH) CDCl.sub.3 1.21-1.35 (1H, m), 1.39-1.57 (3H, m), 1.71-1.98
(7H, m), 2.03-2.12 (2H, m), 2.16-2.23 (2H, m), 2.45 (3H, s), 2.94-
3.03 (2H, m), 3.39-3.48 (2H, m), 3.88- 3.97 (1H, m), 4.19 (1H, tt,
J = 3.8 and 11.8 Hz), 7.02 (1H, d, J = 8.9 Hz), 7.50 (1H, s),
7.70-7.82 (3H, m) 464 374 ##STR00478## pale yellow foamy solid
CDCl.sub.3 1.22-1.34 (1H, m), 1.38-1.57 (3H, m), 1.69-2.08 (9H, m),
2.14-2.23 (2H, m), 2.45 (3H, s), 2.80-2.90 (2H, m), 3.21-3.31 (2H,
m), 3.80-3.88 (1H, m), 3.89 (3H, s), 4.19 (1H, tt, J = 3.8 and 11.8
Hz), 7.05 (1H, d, J = 8.8 Hz), 7.48 (1H, s), 7.71 (1H, brs), 7.77
(1H, dd, J = 2.6 and 8.8 Hz), 7.84 (1H, d, J = 2.6 Hz) 497 375
##STR00479## colorless solid >300 DMSO-d.sub.6 1.19-1.32 (1H,
m), 1.39-1.51 (2H, m), 1.59-1.87 (7H, m), 1.93-2.02 (2H, m),
2.03-2.11 (2H, m), 2.40 (3H, s), 2.98-3.09 (2H, m), 3.12-3.21 (2H,
m), 3.76-3.85 (1H, m), 4.23 (1H, tt, J = 3.8 and 11.5 Hz), 4.92
(1H, d, J = 4.2 Hz), 7.70 (1H, d, J = 8.8 Hz), 8.08- 8.14 (2H, m),
8.35 (1H, d, J = 2.6 Hz), 10.47 (1H, brs), 483 376 ##STR00480##
yellow solid 121-123 DMSO-d.sub.6 1.30-1.42 (2H, m), 1.73-1.83 (2H,
m), 1.91-2.09 (4H, m), 2.41 (3H, s), 2.99-3.10 (2H, m), 3.51 (2H,
dt, J = 2.3 and 11.6 Hz), 3.63-3.72 (1H, m), 3.91-4.03 (4H, m),
4.44-4.54 (1H, m), 4.67 (1H, d, J = 4.2 Hz), 6.85 (1H, d, J = 9.2
Hz), 7.82 (1H, dd, J = 2.7 and 9.2 Hz), 8.37 (1H, d, J = 2.7 Hz),
10.13 (1H, brs), 442
TABLE-US-00123 TABLE 123 Ex- properties MS am- m.p. (.degree. C.)
(FAB) ple (recryst. (M + No. Chemical Structure solvent)
.sup.1H-NMR 1).sup.+ 377 ##STR00481## colorless solid 194-195
(EtOH) CDCl.sub.3 1.53-1.69 (4H, m), 1.74-1.82 (2H, m), 1.97-2.25
(6H, m), 2.31-2.40 (2H, m), 2.44 (3H, s), 2.50-2.59 (1H, m),
2.94-3.03 (2H, m), 3.41 (2H, dt, J = 1.7 and 11.8 Hz), 3.55 (2H,
dt, J = 2.4 and 11.6 Hz), 3.92-4.08 (3H, m), 4.10-4.18 (2H, m),
4.36-4.47 (1H, m), 5.82-5.90 (1H, m), 7.33 (1H, s) 433 378
##STR00482## colorless solid 268-269.5 (EtOH) DMSO-d.sub.6
1.19-1.50 (5H, m), 1.62-1.88 (7H, m), 2.03-2.12 (2H, m), 2.41 (3H,
s), 3.14-3.28 (2H, m), 3.61-3.80 (2H, m), 3.99-4.09 (1H, m), 4.24
(1H, tt, J = 3.8 and 11.5 Hz), 4.77 (1H, d, J = 4.2 Hz), 7.58 (1H,
d, J = 8.6 Hz), 8.10 (1H, s), 8.24 (1H, dd, J = 2.4 and 8.6 Hz),
8.88 (1H, d, J = 2.4 Hz), 10.58 (1H, brs), 468 379 ##STR00483##
colorless solid 249-251.5 (EtOH) DMSO-d.sub.6 1.19-1.32 (1H, m),
1.39-1.51 (2H, m), 1.63-1.89 (5H, m), 2.03-2.12 (2H, m), 2.41 (3H,
s), 3.33-3.41 (2H, m), 3.50- 3.58 (2H, m), 4.23 (1H, tt, J = 3.8
and 11.4 Hz), 4.79 (1H, d, J = 5.4 Hz), 8.04 (1H, d, J = 8.6 Hz),
8.12 (1H, s), 8.34 (1H, dd, J = 2.4 and 8.6 Hz), 8.55-8.63 (1H, m),
8.95 (1H, d, J = 2.4 Hz), 10.67 (1H, brs), 428 380 ##STR00484##
colorless solid 207-209 DMSO-d.sub.6 1.19-1.32 (1H, m), 1.39-1.51
(2H, m), 1.63-1.89 (5H, m), 2.03-2.12 (2H, m), 2.19 (3H, s),
2.24-2.40 (4H, m), 2.41 (3H, s), 3.42-3.51 (2H, m), 3.60-3.69 (2H,
m), 4.24 (1H, tt, J = 3.9 and 11.5 Hz), 7.61 (1H, d, J = 8.6 Hz),
8.10 (1H, s), 8.25 (1H, dd, J = 2.5 and 8.6 Hz), 8.89 (1H, d, J =
2.5 Hz), 10.60 (1H, brs), 467
TABLE-US-00124 TABLE 124 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 381 ##STR00485## colorless solid 214-215.5 CDCl.sub.3
1.22-1.33(1H, m), 1.38-1.51(2H, m), 1.71-1.98(5H, m), 2.15-23(2H,
m), 2.29(6H, s), 2.43(3H, s), 2.53(2H, t, J = 6.2 Hz),
3.52-3.60(2H, m), 4.19(1H, tt, J = 3.8 and 11.8 Hz), 7.62(1H, s),
8.12-8.34(4H, m), 8.78-8.82(1H, m) 455 382 ##STR00486## colorless
solid 252-254 DMSO-d.sub.6 1.18-1.32(3H, m), 1.39-1.53(4H, m),
1.64-1.89(9H, m), 2.02-2.12(2H, m), 2.41 (3H, s), 3.36-3.46(1H, m),
3.68-3.80(1H, m), 4.24(1H, tt, J = 3.8 and 11.5 Hz), 4.55(1H, d, J
= 4.4 Hz), 8.03(1H, d, J = 8.6 Hz), 8.12(1H, s), 8.30-8.38(2H, m),
8.94(1H, d, J = 2.4 Hz), 10.67(1H, brs), 482 383 ##STR00487##
colorless solid 197.5-199.5 CDCl.sub.3 1.22-1.35(1H, m),
1.39-1.51(2H, m), 1.71-2.08(7H, m), 2.13-2.25(2H, m), 2.36(1.5H,
s), 2.40(1.5H, s), 247(3H, s), 256-2.2.70(3H, m), 2.73-2.83(1H, m),
3.52-3.68(2H, m), 3.82-3.91(2H, m), 4.20(1H, tt, J = 3.8 and 11.8
Hz), 7.31-7.38(1H, m), 7.76-7.87(1H, m), 7.95(1H, s), 8.48-8.58(1H,
m), 9.33(1H, brs) 481 384 ##STR00488## colorless solid 175-180
CDCl.sub.3 1.33-1.54(2H, m), 1.45(9H, s), 1.98-2.06(2H, m),
2.09-2.25(4H, m), 2.44(3H, s), 2.83-2.97(2H, m), 3.51-3.61(2H, m),
4.02-4.19(5H, m), 4.35-4.48(1H, m), 5.82-5.89(1H, m), 7.35(1H, s)
449
TABLE-US-00125 TABLE 125 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 385 ##STR00489## colorless solid 205-214 CDCl.sub.3
1.37-1.9(2H, m), 2.00-2.25(6H, m), 2.44(3H, s), 2.70-2.80(2H, m),
3.08-3.17(2H, m), 3.55(2H, dt, J = 2.4 and 11.6 Hz), 4.00-4.19(3H,
m), 4.36-4.48(1H, m), 5.81-5.90(1H, m), 7.34(1H, s) 349 386
##STR00490## colorless solid 239-240 (EtOH) CDCl.sub.3
1.46-1.59(2H, m), 2.00-2.25(6H, m), 2.44(3H, s), 2.83(6H, s),
2.89-2.99(2H, m), 3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.64-3.73(2H,
m), 4.08-4.19(3H, m), 4.37-4.47(1H, m), 5.91-5.98(1H, m), 7.35(1H,
s) 420 387 ##STR00491## colorless solid 214.5-217 CDCl.sub.3
1.37-1.60(4H, m), 1.46(9H, s), 1.73-1.85(2H, m), 2.01-2.25(6H, m),
2.32-2.51(3H, m), 2.44(3H, s), 2.63-2.76(2H, m), 2.89-2.97(2H, m),
3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.90-4.01(1H, m), 4.08-4.22(4H,
m), 4.36-4.48(1H, m), 5.79-5.86(1H, m), 7.33(1H, s) 532 388
##STR00492## colorless solid 180-182.5 CDCl.sub.3 1.36-1.59(4H, m),
1.78-1.88(2H, m), 2.00-2.25(6H, m), 2.31-2.50(3H, m), 2.44(3H, s),
2.55-2.65(2H, m), 2.89-2.99(2H, m), 3.11-3.20(2H, m), 3.55(2H, dt,
J = 2.4 and 11.6 Hz), 3.90-4.01(1H, m), 4.09-4.19(2H, m),
4.37-4.48(1H, m), 5.73-5.81(1H, m), 7.32(1H, s) 432
TABLE-US-00126 TABLE 126 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 389 ##STR00493## colorless solid 235.5-237 (EtOH)
CDCl.sub.3 1.38-1.58(4H, m), 1.80-1.91(2H, m), 2.01-2.25(6H, m),
2.09(3H, s), 2.30-2.40(2H, m), 2.44(3H, s), 2.47-2.60(2H, m),
2.87-2.94(2H, m), 2.99-3.09(2H, m), 3.55(2H, dt, J= 2.4 and 11.6
Hz), 3.81-4.00(2H, m), 4.09-4.18(2H, m), 4.35-4.46(1H, m),
4.62-4.70(1H, m), 5.75-5.81(1H, m), 7.33(1H, s) 474 390
##STR00494## colorless solid 273-275.5 CDCl.sub.3 1.46-1.58(2H, m),
1.60-1.72(2H, m), 1.88-1.96(2H, m), 2.02-2.24(6H, m), 2.32-2.49(3H,
m), 2.44(3H, s), 2.64-2.74(2H, m), 2.78(3H, s), 2.88-2.96(2H, m),
3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.81-4.01(3H, m), 4.10-4.18(2H,
m), 4.38-4.48(1H, m), 5.73-5.80(1H, m), 7.33(1H, s) 510 391
##STR00495## colorless solid 141-145 CDCl.sub.3 1.20-1.32(2H, m),
1.38-1.52(2H, m), 1.46(9H, s), 1.89-1.98(2H, m), 2.08-2.24(6H, m),
2.28-2.38(1H, m), 2.43(3H, s), 2.49-2.55(4H, m), 3.39-3.47(4H, m),
3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.82-3.93(1H, m), 4.09-4.16(2H,
m), 4.37-4.47(1H, m), 5.71-5.78(1H, m), 7.31(1H, s) 532 392
##STR00496## colorless solid 209-210.5 CDCl.sub.3 1.47(9H, s),
1.54-1.80(6H, m), 1.83-1.92(2H, m), 2.09-2.28(5H, m), 2.45(3H, s),
2.48-2.56(4H, m), 3.41-3.49(4H, m), 3.56(2H, dt, J = 2.4 and 11.6
Hz), 4.10-4.22(3H, m), 4.37-4.48(1H, m), 5.93-6.00(1H, m), 7.33(1H,
s) 532
TABLE-US-00127 TABLE 127 propeties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 393 ##STR00497## colorless solid 270(dec.) DMSO-d.sub.6
1.31-1.48(2H, m), 1.55-1.71(2H, m), 1.88-2.08(6H, m), 2.11-2.20(2H,
m), 2.36(3H, s), 3.42-3.80(10H, m), 3.93-4.00(2H, m), 4.41-4.51(1H,
m), 7.84(1H, s), 8.35-8.40(1H, m), 9.40-9.74(2H, m),
11.79-11.91(1H, m) 432(free) 394 ##STR00498## colorless solid
209-220 DMSO-d.sub.6 1.56-1.69(2H, m), 1.85-2.07(10H, m), 2.38(3H,
s), 3.29-3.68(11H, m), 3.92-4.09(3H, m), 4.42-4.53(1H, m), 8.04(1H,
s), 8.07-8.11(1H, m), 9.37-10.00(2H, m), 11.69-11.81 (1H, m)
432(free) 395 ##STR00499## colorless solid 255-256 (EtOH)
CDCl.sub.3 1.20-1.32(2H, m), 1.36-1.49(2H, m), 1.89-1.98(2H, m),
2.07-2.24(6H, m), 2.09(3H, s), 2.28-2.40(1H, m), 2.43(3H, s),
2.50-2.60(4H, m), 3.41-3.49(2H, m), 3.55(2H, dt, J = 2.4 and 11.6
Hz), 3.59-3.66(2H, m), 3.82-3.95(1H, m), 4.09-4.17(2H, m),
4.35-4.47(1H, m), 5.22-5.29(1H, m), 7.32(1H, s) 474 396
##STR00500## colorless solid 245-246.5 (EtOH) CDCl.sub.3
1.20-1.32(2H, m), 1.37-1.49(2H, m), 1.89-1.99(2H, m), 2.08-2.25(6H,
m), 2.30-2.40(1H, m), 2.43(3H, s), 2.63-2.73(4H, m), 2.77(3H, s),
3.19-3.31(4H, m), 3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.82-3.95(1H,
m), 4.09-4.19(2H, m), 4.37-4.47(1H, m), 5.69-5.78(1H, m), 7.32(1H,
s) 510
TABLE-US-00128 TABLE 128 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 397 ##STR00501## colorless solid 226.5-227.5 (EtOH)
CDCl.sub.3 1.58-1.79(6H, m), 1.81-1.92(2H, m), 2.08-2.29(5H, m),
2.09(3H, s), 2.45(3H, s), 2.48-2.60(4H, m), 3.43-3.51(2H, m),
3.56(2H, dt, J = 2.4 and 11.6 Hz), 3.60-3.69(2H, m), 4.09-4.22(3H,
m), 4.38-4.48(1H, m), 5.90-5.99(1H, m), 7.33(1H, s) 474 398
##STR00502## colorless solid 198-199 (EtOH) CDCl.sub.3
1.43-1.57(2H, m), 2.00-2.25(6H, m), 2.44(3H, s), 2.90-3.01(2H, m),
3.24-3.31(4H, m), 3.55(2H, dt, J = 2.5 and 11.6 Hz), 3.65-3.78(6H,
m), 4.08-4.20(3H, m), 4.36-4.48(1H, m), 5.80-5.87(1H, m), 7.33(1H,
s) 462 399 ##STR00503## colorless solid 211.5-213 (AcOEt)
CDCl.sub.3 1.431.59(2H, m), 2.00-1.99-1.27(6H, m), 2.30(3H, s),
2.36-2.42(4H, m), 2.44(3H, s), 2.90-3.01(2H, m), 3.25-3.34(4H, m),
3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.67-3.78(2H, m), 4.08-4.20(3H,
m), 4.36-4.47(1H, m), 5.98-6.06(1H, m), 7.36(1H, s) 475 400
##STR00504## pale reddish brown solid 199-204 CDCl.sub.3
1.23-1.39(2H, m), 1.41-1.53(3H, m), 2.00-2.24(8H, m), 2.43(3H, s),
3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.60-3.71(1H, m), 3.89-4.00(1H,
m), 4.09-4.17(2H, m), 4.36-4.47(1H, m), 5.69-5.75(1H, m), 7.31(1H,
s) 364
TABLE-US-00129 TABLE 129 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 401 ##STR00505## colorless solid 177-178.5 CDCl.sub.3
1.71-1.83(2H, m), 2.09-2.25(4H, m), 2.32-2.41(2H, m), 2.44(3H, s),
2.47-2.59(4H, m), 3.56(2H, dt, J = 2.5 and 11.6 Hz), 4.09-4.18(2H,
m), 4.38-4.50(2H, m), 5.89-5.96(1H, m), 7.37(1H, s) 362 402
##STR00506## colorless solid 199-200 (iso-PrOH) CDCl.sub.3 1.17(6H,
d, J = 6.3 Hz), 1.19-1.31(2H, m), 1.36-1.49(2H, m), 1.90-2.00(4H,
m), 2.08-2.28(7H, m), 2.43(3H, s), 2.70-2.78(2H, m), 3.55(2H, dt, J
= 2.4 and 11.7 Hz), 3.60-3.70(2H, m), 3.82-3.95(1H, m),
4.09-4.17(2H, m), 4.35-4.46(1H, m), 5.66-5.72(1H, m), 7.31(1H, s)
461 403 ##STR00507## colorless solid 202-208 CDCl.sub.3 1.19(6H, d,
J = 6.2 Hz), 1.56-1.92(10H, m), 2.09-2.27(5H, m), 2.45(3H, s),
2.83-2.90(2H, m), 3.56(2H, dt, J = 2.4 and 11.6 Hz), 3.61-3.71(2H,
m), 4.09-4.23(3H, m), 4.37-4.48(1H, m), 5.91-6.00(1H, m), 7.33(1H,
s) 461 404 ##STR00508## colorless solid 170.5-172 (AcOEt)
CDCl.sub.3 1.21-1.35(1H, m), 1.39-1.52(2H, m), 1.71-1.99(5H, m),
2.14-2.25(2H, m), 2.45(3H, s), 4.19(1H, tt, J = 3.8 and 11.8 Hz),
4.75(2H, s), 7.27(1H, d, J = 8.5 Hz), 7.56(1H, s), 7.88(1H, brs),
8.19(1H, dd, J = 2.4 and 8.5 Hz), 8.61(1H, d, J = 2.4 Hz) 371
TABLE-US-00130 TABLE 130 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 405 ##STR00509## colorless solid 232-233 CDCl.sub.3
2.10-2.26(4H, m), 2.45(3H, s), 3.57(2H, dt, J = 2.5 and 11.5 Hz),
4.00(3H, s), 4.10-4.19(2H, m), 4.39-4.49(1H, m), 7.63(1H, s),
8.17(1H, d, J = 8.6 Hz), 8.20(1H, brs), 8.53(1H, dd, J = 2.7 and
8.6Hz), 8.71(1H, d, J = 2.7 Hz) 401 406 ##STR00510## colorless
solid 262-264 DMSO-d.sub.6 1.90-2.10(4H, m), 2.43(3H, s), 3.51(2H,
dt, J = 2.3 and 11.6 Hz), 3.93-4.03(2H, m), 4.49-4.59(1H, m),
8.07(1H, d, J = 8.6 Hz), 8.16(1H, s), 8.35(1H, dd, J = 2.3 and 8.6
Hz), 9.00(1H, d, J = 2.3 Hz), 10.74(1H, brs), 387 407 ##STR00511##
colorless solid 258-259.5 (EtOH) DMSO-d.sub.6 1.20-1.32(2H, m),
1.40-1.54(2H, m), 1.73-1.89(4H, m), 1.91-2.10(4H, m), 2.43(3H, s),
3.34-3.45(1H, m), 3.51(2H, dt, J = 2.3 and 11.6 Hz), 3.69-3.80(1H,
m), 3.94-4.03(2H, m), 4.49-4.58(2H, m), 8.03(1H, d, J = 8.7 Hz),
8.13(1H, s), 8.29-8.38(1H, m), 8.95(1H, d, J = 2.4 Hz), 10.67(1 H,
brs), 484 408 ##STR00512## colorless solid 185-186 (AcOEt)
CDCl.sub.3 2.10-2.27(4H, m), 2.32(6H, s), 2.45(3H, s), 2.58(2H, t,
J = 6.2 Hz), 3.51-3.61(4H, m), 4.10-4.19(2H, m), 4.39-4.50(1H, m),
7.66(1H, s), 8.14-8.19(1H, m), 8.20-8.31(3H, m), 8.78(1H, d, J =
2.3 Hz) 457
TABLE-US-00131 TABLE 131 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 409 ##STR00513## colorless solid 240-242 (AcOEt)
CDCl.sub.3 1.60-1.73(2H, m), 1.98-2.07(2H, m), 2.10-2.29(6H, m),
2.30(3H, s), 2.46(3H, s), 2.78-2.88(2H, m), 3.57(2H, dt, J = 2.5
and 11.6 Hz), 3.90-4.02(1H, m), 4.10-4.19(2H, m), 4.39-4.49(1H, m),
7.62(1H, s), 7.80-7.87(1H, m), 8.12-8.29(3H, m), 8.77(1H, d, J =
2.3 Hz) 483 410 ##STR00514## colorlesds solid >300 DMSO-d.sub.6
1.41-1.66(2H, m), 1.71-1.87(2H, m), 1.91-2.10(4H, m), 2.01(3H, s),
2.43(3H, s), 2.60-2.71(1H, m), 3.09-3.20(1H, m), 3.51(2H, dt, J =
2.3 and 11.6 Hz), 3.79-3.89(1H, m), 3.96-4.10(3H, m), 4.31-4.40(1H,
m), 4.47-4.59(1H, m), 8.02-8.08(1H, m), 8.14(1H, s), 8.31-8.38(1H,
m), 8.52-8.59(1H, m), 8.96(1H, d, J = 2.4Hz), 10.68(1H, brs), 511
411 ##STR00515## pale brown foam CDCl.sub.3 1.22-1.35(1H, m),
1.39-1.51(2H, m), 1.70-1.98(5H, m), 2.14-2.25(2H, m), 2.46(3H, s),
2.49-2.57(4H, m), 3.64(2H, s), 3.70-3.79(4H, m), 4.20(1H, tt, J =
3.8 and 11.8 Hz), 7.42(1H, d, J = 8.5 Hz), 7.53(1H, s), 7.74(1H,
brs), 8.24(1H, dd, J = 2.7 and 8.5 Hz), 8.58(1H, d, J = 2.7 Hz) 440
412 ##STR00516## pale browm solid 225.5-227.5 (iso-PrOH)
DMSO-d.sub.6 1.19-1.31(1H, m), 1.39-1.52(2H, m), 1.63-1.89(5H, m),
2.03-2.13(2H, m), 2.32(3H, s), 2.41(3H, s), 3.20-3.32(4H, m),
3.79-3.91(4H, m), 4.24(1H, tt, J = 3.8 and 11.5 Hz), 4.41-4.51(2H,
m), 7.55(1H, d, J = 8.5 Hz), 8.13(1H, s), 8.26(1H, dd, J = 2.4 and
8.5 Hz), 9.03(1H, d, J = 2.4 Hz), 10.29(1H, brs), 10.62(1H, brs),
440(free)
TABLE-US-00132 TABLE 132 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 413 ##STR00517## pale yellow solid 214.5-216 (EtOH)
CDCl.sub.3 1.22-1.35(1H, m), 1.39-1.51(3H, m), 1.56-1.69(2H, m),
1.71-1.99(7H, m), 2.16-2.29(4H, m), 2.46(3H, s), 2.74-2.83(2H, m),
3.63(2H, s), 3.66-3.76(1H, m), 4.20(1H, tt, J = 3.8 and 11.8 Hz),
7.42(1H, d, J = 8.5 Hz), 7.54(1H, s), 7.79(1H, brs), 8.22(1H, dd, J
= 2.5 and 8.5 Hz), 8.57(1H, d, J = 2.5Hz) 454 414 ##STR00518##
colorless solid 229-230.5 (AcOEt) CDCl.sub.3 1.22-1.35(1H, m),
1.40-1.51(2H, m), 1.71-1.99(5H, m), 2.09(3H, m), 2.16-2.22(2H, m),
2.41-2.56(4H, m), 2.46(3H, s), 3.47-3.52(2H, m), 3.61-3.69(2H, m),
3.66(2H, s), 4.20(1H, tt, J = 3.8 and 11.8 Hz), 7.40(1H, d, J = 8.5
Hz), 7.58(1H, s), 8.00(1H brs), 8.25(1H, dd, J = 2.6 and 8.5 Hz),
8.60(1H, d, J = 2.6 Hz) 481 415 ##STR00519## colorless solid
266-268 (EtOH) CDCl.sub.3 1.42-1.53(2H, m), 1.58-1.80(4H, m),
2.07-2.25(6H, m), 2.33(3H, s), 2.44(3H, s), 2.61-2.69(2H, m),
3.15(2H, s), 3.23-3.31(2H, m), 3.55(2H, dt, J = 2.3 and 11.6 Hz),
3.88-4.00(1H, m), 4.09-4.17(2H, m), 4.37-4.46(1H, m), 4.51-4.61(1H,
m), 6.48-6.56(1H, m), 7.46(1 H, s) 460 416 ##STR00520## colorless
solid 263-265 (EtOH) CDCl.sub.3 1.21-1.33(1H, m), 1.37-1.52(4H, m),
1.58-1.98(9H, m), 2.11-2.21(4H, m), 2.33(3H, s), 2.44(3H, s),
2.61-2.68(2H, m), 3.14(2H, s), 3.23-3.31(2H, m), 3.88-3.99(1H, m),
4.17(1H, tt, J = 3.9 and 11.9 Hz), 4.49-4.60(1H, m), 6.21-6.29(1H,
m), 7.41(1H, s) 458
TABLE-US-00133 TABLE 133 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 417 ##STR00521## colorless solid 229.5-232 CDCl.sub.3
1.21-1.34(2H, m), 1.38-1.50(2H, m), 1.91-2.00(2H, m), 2.09-2.26(6H,
m), 2.34-2.43(1H, m), 2.44(3H, s), 2.71-2.79(2H, m), 3.29(2H, s),
3.32-3.39(2H, m), 3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.84-3.97(1H,
m), 4.09-4.18(2H, m), 4.37-4.48(1H, m), 5.71-5.79(1H, m), 5.94(1H,
brs), 7.32(1H, s) 446 418 ##STR00522## colorless solid 109-118
CDCl.sub.3 1.64-1.89(8H, m), 2.09-2.26(4H, m), 2.32-2.40(1H, m),
2.45(3H, s), 2.71-2.80(2H, m), 3.26(2H, s), 3.32-3.42(2H, m),
3.56(2H, dt, J = 2.4 and 11.7 Hz), 4.09-4.20(3H, m), 4.37-4.49(1H,
m), 5.93-6.01 (1H, m), 6.14(1H, brs), 7.56(1H, s) 446 419
##STR00523## colorless solid 242-244 (EtOH) CDCl.sub.3
1.21-1.33(2H, m), 1.36-1.49(2H, m), 1.92-2.01 (2H, m),
2.08-2.25(6H, m), 2.29-2.39(1H, m), 2.43(3H, s), 2.73-2.81(2H, m),
2.95(3H, s), 3.28(2H, s), 3.29-3.34(2H, m), 3.55(2H, dt, J = 2.4
and 11.6 Hz), 3.83-3.97(1H, m), 4.10-4.18(2H, m), 4.36-4.47(1H, m),
5.73-5.81(1H, m), 7.33(1H, s) 460 420 ##STR00524## colorless solid
181-182 CDCl.sub.3 1.67-1.89(8H, m), 2.09-2.25(4H, m),
2.28-2.35(1H, m), 2.45(3H, s), 2.74-2.82(2H, m), 2.98(3H, s),
3.25(2H, s), 3.30-3.39(2H, m), 3.56(2H, dt, J = 2.3 and 11.6 Hz),
4.09-4.21(3H, m), 4.37-4.47(1H, m), 5.88-5.94(1H, m), 7.33(1H, s)
460
TABLE-US-00134 TABLE 134 propeties Example m.p.(.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 421 ##STR00525## colorless solid 206-208.5 CDCl.sub.3
1.19-1.31(2H, m), 1.25(3H, t, J = 7.1 Hz), 1.39-1.51(2H, m),
1.68-1.80(2H, m), 1.88-1.98(4H, m), 2.08-2.39(10H, m), 2.43(3H, s),
2.83-2.92(2H, m), 3.55(2H, dt, J = 2.4 and 11.7 Hz), 3.81-3.93(1H,
m), 4.09-4.18(4H, m), 4.36-4.46(1H, m), 5.67-5.73(1H, m), 7.31(1H,
s) 503 422 ##STR00526## colorless foam CDCl.sub.3 1.26(3H, t, J =
7.1 Hz), 1.54-4.81(8H, m), 1.84-1.99(4H, m), 2.05-2.34(8H, m),
2.45(3H, s), 2.99-3.08(2H, m), 3.56(2H, dt, J = 2.4 and 11.7 Hz),
4.10-4.24(5H, m), 4.38-4.48(1H, m), 5.95-6.01(1H, m), 7.33(1H, s)
503 423 ##STR00527## colorless solid 201-202 CDCl.sub.3
1.19-1.31(4H, m), 1.33-1.57(4H, m), 1.72-1.81(2H, m), 1.90-1.99(2H,
m), 2.09-2.28(8H, m), 2.30-2.39(1H, m), 2.43(3H, s), 2.88-2.98(2H,
m), 3.50(2H, d, J = 6.4 Hz), 3.55(2H, dt, J = 2.3 and 11.6 Hz),
3.81-3.94(1H, m), 4.09-4.17(2H, m), 4.37-4.48(1H, m), 5.67-5.74(1H,
m), 7.31(1H, s) 461 424 ##STR00528## colorless solid 119-122
CDCl.sub.3 1.21-1.33(2H, m), 1.40-1.71(6H, m), 1.75-1.85(4H, m),
1.87-1.97(2H, m), 2.00-2.28(7H, m), 2.45(3H, s), 3.05-3.13(2H, m),
3.48-3.60(4H, m), 4.09-4.17(2H, m), 4.19-4.27(1H, m), 4.36-4.48(1H,
m), 5.99-6.07(1H, m), 7.33(1H, s) 461
TABLE-US-00135 TABLE 135 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 425 ##STR00529## colorless solid 211-213.5 (EtOH)
CDCl.sub.3 1.19-1.31(2H, m), 1.39-1.69(5H, m), 1.89-1.98(4H, m),
2.08-2.25(6H, m), 2.30-2.40(3H, m), 2.43(3H, s), 2.78-2.88(2H, m),
3.55(2H, dt, J = 2.4 and 11.7 Hz), 3.62-3.75(1H, m), 3.82-3.93(1H,
m), 4.09-4.17(2H, m), 4.37-4.47(1H, m), 5.69-5.76(1H, m), 7.31(1H,
s) 447 426 ##STR00530## colorless solid 234.5-237 (EtOH) CDCl.sub.3
1.62-1.78(8H, m), 1.79-1.91(4H, m), 1.98-2.07(2H, m), 2.09-2.26(5H,
m), 2.46(3H, s), 2.47-2.55(1H, m), 2.95(3H, s), 3.06(3H, s),
3.10-3.18(2H, m), 3.56(2H, dt, J = 2.4 and 11.7 Hz), 4.09-4.21(3H,
m), 4.38-4.46(1H, m), 5.98-6.06(1H, m), 7.36(1H, s) 502 427
##STR00531## colorless solid 211-218 DMSO-d.sub.6 1.32-1.49(2H, m),
1.53-1.69(2H, m), 1.88-2.21(12H, m), 2.36(3H, s), 2.49-2.61(1H, m),
2.89-3.06(2H, m), 3.11-3.22(1H, m), 3.30-3.54(4H, m), 3.64-3.77(1H,
m), 3.91-4.00(2H, m), 4.40-4.52(1H, m), 7.87(1H, s), 8.40-8.49(1H,
m), 10.50-10.74(1H, m), 475(free) 428 ##STR00532## colorless solid
233.5-234.5 (AcOEt/EtOH) CDCl.sub.3 1.19-1.31(2H, m), 1.39-1.52(2H,
m), 1.68-1.98(6H, m), 2.07-2.51(10H. m), 2.43(3H, s), 2.90-2.99(2H,
m), 2.94(3H, s), 3.05(3H, s), 3.55(2H, dt J = 2.3 and 11.6 Hz),
3.81-3.94(1H, m), 4.09-4.18(2H, m), 4.35-4.47(1H, m), 5.71-5.79(1H,
m), 7.32(1H, s) 502
TABLE-US-00136 TABLE 136 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 429 ##STR00533## pale reddish brown viscous solid
CDCl.sub.3 1.89-2.02(2H, m), 2.49-2.61(2H, m), 2.76- 2.88(2H, m),
4.21-4.40(2H, m), 7.40-7.59(3H, m), 7.71- 7.90(2H, m),
8.70-8.91(1H, m) 219 430 ##STR00534## colorless solid 127-130.5
CDCl.sub.3 1.49-1.65(2H, m), 1.76-1.88(1H, m), 1.92- 2.03(1H, m),
3.05-3.13(1H, m), 3.39-3.46(1H, m), 3.49- 3.58(1H, m),
3.72-3.80(1H, m), 3.87-3.95(1H, m), 7.41- 7.49(2H, m),
7.50-7.59(1H, m), 7.63(1H, brs), 7.71- 7.80(2H, m) 221 431
##STR00535## pale brown solid 170-181 CDCl.sub.3 1.71-1.81(2H, m),
1.91-2.01(2H, m), 2.09(3H, s), 3.20(2H, s), 3.33-3.42(1H, m),
3.56(1H, t, J = 10.7 Hz), 3.84-3.94(2H, m), 4.15-4.25(1H, m) 183
432 ##STR00536## colorless solid 124-129 CDCl.sub.3 1.80-1.90(2H,
m), 2.07-2.15(1H, m), 2.19- 2.30(1H, m), 2.45(3H, s), 3.41-3.51(1H,
m), 3.72(1H, t, J = 10.7 Hz), 3.94-4.01(2H, m), 4.39-4.49(1H, m),
9.89(1H, s) 229
TABLE-US-00137 TABLE 137 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 433 ##STR00537## pale yellow oil CDCl.sub.3 1.38(3H, t, J
= 7.1 Hz), 1.72-1.90(2H, m), 2.18-2.31(2H, m), 2.45(3H, s),
3.60(1H, ddd, J = 3.4 and 9.6 and 11.5 Hz), 3.82(1H, dd, J = 8.7
and 11.3 Hz), 3.89-3.96(1H, m), 4.11-4.18(1H, m), 4.32-4.40(3H, m),
7.69(1H, s) 295 434 ##STR00538## colorless solid 174-176
DMSO-d.sub.6 1.59-1.78(2H, m), 2.05-2.22(2H, m), 2.38(3H, s),
3.49-3.58(1H, m), 3.70-3.81(2H, m), 4.00(1H, dd, J = 3.4 and 11.4
Hz), 4.32-4.40(1H, m), 7.76(1H, s), 13.10(1H, brs) 267 435
##STR00539## colorless solid 211.5-212.5 (EtOH) CDCl.sub.3
1.20-1.31(2H, m), 1.36-1.49(2H, m), 1.70-1.90(2H, m), 1.93-2.02(2H,
m), 2.13-2.31(5H, m), 2.43(3H, s), 2.53-2.61(4H, m), 3.54-3.63(1H,
m), 3.69-3.75(4H, m), 3.81(1H, dd, J = 8.7 and 11.3 Hz),
3.84-3.95(2H, m), 4.10-4.16(1H, m), 4.31-4.40(1H, m), 5.69-5.76(1H,
m), 7.31(1H, s) 433 436 ##STR00540## colorless solid 223-225 (EtOH)
CDCl.sub.3 1.14(3H, t, J = 7.2 Hz), 1.20-1.33(2H, m), 1.35-1.49(2H,
m), 1.92-2.02(2H, m), 2.08-2.38(7H, m), 2.43(3H, s), 2.72-2.81(2H,
m), 3.27(2H, s), 3.29-3.36(2H, m), 3.43(2H, q, J = 7.2 Hz),
3.55(2H, dt, J = 2.4 and 11.6 Hz), 3.83-3.97(1H, m), 4.09-4.20(2H,
m), 4.37-4.48(1H, m), 5.76-5.83(1H, m), 7.33(1H, s) 474
TABLE-US-00138 TABLE 138 propeties Example m.p. (.degree. C.)
MS(FAB) No. Chemical Structure (recryst. solvent) .sup.1H-NMR (M +
1).sup.+ 437 ##STR00541## colorless solid 187-190 CDCl.sub.3
1.16(3H, t, J = 7.2 Hz), 1.65-1.90(8H, m), 2.08-2.35(5H, m),
2.45(3H, s), 2.72-2.83(2H, m), 3.24(2H, s), 3.30-3.39(2H, m),
3.45(2H, q, J = 7.2 Hz), 3.56(2H, dt, J = 2.5 and 11.6 Hz),
4.08-4.21(3H, m), 4.37-4.47(1H, m), 5.37-5.94(1H, m), 7.33(1H, s)
474 438 ##STR00542## colorless solid 180-186 CDCl.sub.3
1.01-1.29(4H, m), 1.14(3H, t, J = 7.2 Hz), 1.40- 1.53(1H, m),
1.86-1.94(2H, m), 2.07-2.27(8H, m), 2.43(3H, s), 2.62-2.69(2H, m),
3.08(2H, s), 3.29- 3.33(2H, m), 3.43(2H, q, J = 7.2 Hz), 3.55(2H,
dt, J = 2.4 and 11.6 Hz), 3.82-3.98(1H, m), 4.09-4.18(2H, m),
4.36-4.47(1H, m), 5.75-5.81(1H, m), 7.33(1H, s) 488 439
##STR00543## colorless solid 194-197 CDC1.sub.3 1.01-1.30(4H, m),
1.40-1.54(1H, m), 1.83-1.95(2H, m), 2.07-2.29(8H, m), 2.44(3H, s),
2.51-2.60(2H, m), 2.96(3H, s), 3.09(2H, s), 3.29-3.38(2H, m),
3.55(2H, dt, J = 2.3 and 11.6 Hz), 3.84-3.98(1H, m), 4.09-4.19(2H,
m), 4.36-4.48(1H, m), 5.78-5.86(1H, m), 7.33(1H, s) 474 440
##STR00544## pale yellow solid 255(dec.) (iso-PrOH) DMSO-d.sub.6
1.90-2.08(4H, m), 2.30(3H, s), 2.42(3H, s), 2.93(3H, brs), 3.51(2H,
dt, J = 2.3 and 11.7 Hz), 3.50-4.07(8H, m), 4.47-4.57(1H, m),
7.31-7.36(2H, m), 7.76-7.81(2H, m), 8.10(1H, s), 10.36(1H, brs)
454
INDUSTRIAL APPLICABILITY
[1050] The present invention provides thienopyrazole derivatives
having selective PDE 7 (phosphodiesterase VII) inhibiting effect.
These compounds are effective compounds for treating various kinds
of diseases such as allergic diseases, inflammatory diseases and
immunologic diseases.
* * * * *