DESCRIPTION AZA-BRIDGED-RING COMPOUND
Technical Field
[0001]
The present invention relates to an aza-bridged-ring compound which is useful as an active ingredient of a pharmaceutical composition, particularly a pharmaceutical composition for treating an inflammatory disease.
Background Art
[0002]
Acetylcholine released from a cholinergic nerve in the peripheral and central nervous systems causes various biological reactions through binding with two types of acetylcholine receptors, a nicotinic receptor and a muscarinic receptor, respectively. Among these, the muscarinic receptor belongs to a seven-pass transmembrane-type G protein-conjugated receptor superfamily, and at the present time, there exist five subtypes of these receptors, Mi, M2, M3, M4, and M5, which are each encoded by different gene sequences. These five types of the receptors are widely distributed in each tissue of a vertebrate body. The muscarinic receptor is known to have both the excitatory and inhibitory actions, depending on its subtype. Specifically, the functional roles of various muscarinic receptors, for example, a contribution of the M3 receptor present in the airway smooth muscle to contraction reactions of the smooth muscle, or other roles, have been reported in General Overview of Caulfield, et al. (Non-Patent Document 1).
In the lung, the muscarinic receptor is present in the tracheal and bronchial smooth muscles, the submucosal glands, and the parasympathetic ganglion. It has been known that the distribution density of the muscarinic receptors is highest in the parasympathetic ganglion, and then in the submucosal glands and the tracheal smooth muscle in this order, and is lowest in the bronchial smooth muscle (Non-Patent Document 2).
As the muscarinic receptor which plays an important role in the lung tissue, three types of Ml, M2, and M3 may be mentioned. The M3 receptor which is present in the airway smooth muscle is involved in the smooth muscle contraction, which causes airway obstruction. If the M3 receptor is activated, a phospholipase C in the cytoplasm is activated through the activation of the stimulatory G protein, subsequently

phosphatidylinositol 3-phosphate is dissociated into phosphatidylinositol 4,5-diphosphate, and finally a contractile protein is phosphorylated. The M3 receptor is present in the submucosal glands, in addition to in the smooth muscle which is present in the lung tissue. If this type of M3 receptor is activated the mucus is secreted.
The M2 receptors constitute about 50 to 80% of the cholinergic receptors which are present in the airway smooth muscle. Details on the role of this subtype of the receptor are still unclear, but the reduction of the amount of the cAMP's produced in the cytoplasm is believed to inhibit the relaxation of the airway smooth muscle due to the sympathetic innervation. The central M2 receptors are distributed in the postganglionic parasympathetic fibers. Under physiological conditions, the central M2 receptor plays a role in the negative regulation of the release of acetylcholine from the parasympathetic. The M2 receptor which is expressed in the cardiac muscle is due to regulation of the chronotropic action. The Mi receptor is found in the parasympathetic ganglion of the lung tissue, and functions to facilitate neurotransmission. The Mi receptors are distributed not only in the ganglion, but also in the peripheral lung parenchymal tissue, but their function is unclear.
In the lung tissues, the abnormal function of the muscarinic receptor is perceived when a large number of pathologic conditions are formed. Particularly, for an inflammatory disease such as a chronic obstructive pulmonary disease (COPD), asthma and the like, a sustained inflammatory response leads to dysfiinction of an inhibitory M2 receptor which is present in a parasympathetic nerve, and increases the release of acetylcholine by vagus neiTc stimulation (Non-Patent Document 3). Therefore, the dysfunction of this receptor causes the relative preference of the M3 receptor-mediated fimction, which leads to the induction of airway hyperreactivity. Therefore, a drug that selectively antagonizes the M3 receptor-mediated fiinction without interfering with the M2 receptor-mediated function is thought to be an effective therapeutic agent.
COPD shows a limit in the airflow, usually by an organic change based on the persistent inflammation in the peripheral airways and primarily, the alveoli, allowing the symptoms of coughing, sputum, breathlessness and the like to be perceived, occupies the fourth leading cause of death as of the year 2005, and is a major cause of death world-wide. Further, by the year 2020, it is expected to be the third leading cause of death. Smoking is a major risk factor of COPD, and recently, in addition to this, air pollution or the like due to dust is also mentioned as a risk factor among other issues. The medical cost required for COPD treatment is very high, and the number of patients is expected to increase in future.

A therapy with an inhaled anticholinergic agent is regarded as a drug firstly chosen for the above-described diseases (Non-Patent Document 4), and in recent years, in each region in the Western countries and Asia, a long-term operating (once a day) anticholinergic agent, tiotropium bromide (Spiriva (registered trademark)), has been launched on the market. However, by taking into account the status of treatment, none of the conventional anticholinergic agents including Spiriva (registered trademark) are complete from the viewpoints of either convenience or safety, and thus, there is a room for improvement at present. Therefore, there is a strong desire to create an oral or inhaled anticholinergic agent which is improved in any of the above-described viewpoints.
[0003]
For example, there has been known a carbamate compound which has an M3 receptor antagonistic action and has an airway contraction inhibitory action, wherein the Ring A of the following formula is an unsubstituted benzene or an unsubstituted pyridine (Patent Document 1). In this Patent Document, the compound of the present invention is not disclosed or suggested.
[0004]

[for the symbols in the formula, refer to this publication]
[0005]
Further, there has been known a carbamate compound as below, which has an M3 receptor antagonistic action and has an airway contraction inhibitory action (Patent Document 2). However, in this Patent Document, the compound of the present invention is not disclosed or suggested.

[0006] [Chem. 2]

R
X
R' R1

[for the symbols in the formula, refer to this publication]
[0007]
[Patent Document 1] Pamphlet of International Publication No. WO 95/21820
[Patent Document 2] Pamphlet of International Publication No. WO WO95/06635
[Non-Patent Document 1] Pharmacology and Therapeutics, 1993, vol. 58, pp. 319-
379
[Non-Patent Document 2] American Joumal Respiratory and Critical Care
Medicine, 1998, 158, pp. 154S-160S
[Non-Patent Document 3] Life Science, 1999, vol. 64(6-7), pp. 449-455 [Non-Patent Document 4] American Joumal Respiratory and Critical Care
Medicine, 2001,163, pp. 1256-1276
DISCLOSURE OF THE INVENTION
PROBLEM THAT THE INVENTION IS TO SOLVE
[0008]
Provided is a compound which is usefiil as an active ingredient of a pharmaceutical composition, particularly, a pharmaceutical composition for treating an inflammatory disease such as a chronic obstructive pulmonary disease (COPD), asthma and the like.
MEANS FOR SOLVING THE PROBLEM
[0009]
The present inventors have made extensive studies on a compound having an antagonistic action on a muscarinic M3 receptor, and as a result, they have found that an aza-bridged-ring compound is useful for an antagonistic action on a muscarinic M3 receptor, thereby completing the present invention.

Specifically, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprismg the compound of the formula (I) or a salt thereof, and an excipient.
[0010]
[Chem. 3]

.'"J<'
V1
w
(I)

[R' is -H or Ci.6 alkyl;
R1 is an aza-bridged-ring selected from the group consisting of the formulae (a), (b), (c), and (d):
[Chem. 4]

(a) (b) (c) (d) ,
wherein the ring carbon in the aza-bridged-ring may be substituted with one or
more R11
m, n, and p are respectively 1 or 2;
r is 0 or 1;
R1' is Ci.6 alkyl, -Ci.6 alkyl-0-aryl, or -Ci.6 alkyl-aryl;
R'11 is -Ci-e alkyl-cycloalkyl or -Ci-6 alkyl-aryl;
R is thienyl, phenyl, pyridyl, pyrazinyl, thiazolyl, or pyrazolyl,
each of which may be substituted with one or more R11;
in which R11 is halogen, -OH, -CN, -CF3, Ci-e alkyl or -O-Ci-e alkyl;
Ring A is an aromatic hydrocarbon ring, a hetero ring, or cycloalkane,
each of which may be substituted with R'1;

in which R1 is halogen, -CN, -NH2, Ci-e alkyl, -O-d-e alkyl, -CONH2, -NH-Ci-6 alkyl, -NH-C1.6 alkyl-O-Ci.6 alkyl-aryl, -NH-Ci-e alkyl-aryl, or -NH-Ci1 alkyl-OH,
in which C\.(, alkyl may be substituted with one or more halogen;
V is -NH- or -0-;
W is-(CH2)q- or -(CH2)s-CH-;
qis 0, 1, or 2;
s is 1 or 2;
X" is a counter anion; and
— is a single bond or a double bond;
provided that in the case where Ring A is a substituted benzene, R1 is phenyl, pyridyl, pyrazinyl, thiazolyl, or pyrazolyl, each of which may be substituted with one or moreR1', and;
in the case where Ring A is an unsubstituted benzene, q is 1 or 2; and
in the case where the Ring A is cycloalkane, R'' is phenyl which may be substituted with one or more R ].
Furthermore, unless specified otherwise, in the case where the symbols in any of the formulae in the present specification are also used in other formulae, the same symbols denote the same meanings.
[0011]
The present invention relates to a pharmaceutical composition for treating an inflammatory disease such as a chronic obstructive pulmonary disease (COPD), asthma and the like, which comprises a compound of the formula (I) or a salt thereof, that is, a therapeutic agent for an inflammatory disease such as a chronic obstructive pulmonary disease (COPD), asthma and the like, which comprises the compound of the formula (I) or a salt thereof
Further, the present invention relates to use of the compound of the formula (I) or a salt thereof for the preparation of a pharmaceutical composition for treating an inflammatory disease such as a chronic obstructive pulmonary disease (COPD), asthma and the like, and to a method for treating an inflammatory disease such as a chronic obstructive pulmonary disease (COPD), asthma and the like, which comprises administering to a patient an effective amount of the compound of the formula (I) or a salt thereof

EFFECT OF THE INVENTION
[0012]
The compound of the formula (I) or a salt thereof has an antagonistic action on the binding of a muscarinic M3 receptor, and can be therefore used as a prophylactic and/or therapeutic agent for an inflammatory disease such as a chronic obstructive pulmonary disease (COPD), asthma and the like.
BEST MODE FOR CARRYING OUT THE INVENTION
[0013]
Hereinbelow, the present invention will be described in detail.
In the present specification, the "halogen" refers to F, CI, Br, or I.
[0014]
In the present specification, the "Ci-e alkyl" refers to linear or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl or the like. In a further embodiment, it is C1.4 alkyl. In an even further embodiment, it is methyl, ethyl, or isopropyl.
[0015]
In the present specification, the "-Ci-e alkyl-" refers to, in cases where it has a prefix and a suffix with hyphens, linear or branched Ci-e alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene or the like. In a further embodiment, it is CM alkylene, and in an even further embodiment, methylene, ethylene, or trimethylene.
[0016]
In the present specification, the "aromatic hydrocarbon ring" means an aromatic hydrocarbon ring having 6 to 14 carbon atoms. In an embodiment, examples thereof include benzenCj naphthalene and the like, and in a further embodiment, benzene.
[0017]
In the present specification, the "hetero ring" means a 5- to 6-membered aromatic hetero ring containing one or more hetero atoms which are the same as or different from each other, selected from the group consisting of nitrogen, oxygen, and sulfur, which may be condensed with a cycloalkyl ring or a benzene ring. Specifically, examples thereof include pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, imidazole, oxalzole, thiazole, thiophene, furan, oxadiazole, isothiazole, isooxazole, thiadiazole, quinoline, isoquinoline.

benzothiazole, benzothiophene, benzoxazole, indole, indazole, cyclopentathiophene and the like. In a further embodiment, the hetero ring is a 5-membered hetero ring, and in an even further embodiment, examples thereof include oxazole, thiophene, thiazole, thiadiazole, and cyclopentathiophene. In an even further embodiment, examples thereof include thiophene and thiazole.
[0018]
In the present specification, the "cycloalkane" means a C3.9 non-aromatic carbon ring, which may have a partially unsaturated bond, and may be condensed with a benzene ring. Further, it comprises a bridged ring. Accordingly, specific examples thereof include cyclopropane, cyclobutane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclohexene, cyclooctadiene, norborane, bomene, indane, tetrahydronaphthalene and the like, and in a further embodiment, cyclohexane.
[0019]
Further, examples of the counter anion of the "X"" include a halide ion, trifluoromethanesulfonate, p-toluenesulfonate, methanesulfonate and the like, and in a further embodiment, it is preferably a halide ion (for example, a chloride ion, a bromide ion, and an iodide ion), but it is not limited thereto. Further, in a further embodiment, examples thereof fiirther include inorganic anions such as a nitric acid ion, a phosphoric acid ion, a carbonic acid ion and the like, carboxylates such as formate (HCOO'), acetate (CH3COO'), propionate, oxalate and the like, and anions of amino acids such as glutamic acid and the like.
[0020]
The "anion exchanger" refers to a different compound of the "X*".
[0021]
In the present specification, the expression "may be substituted" means that it is unsubstituted, or it has 1 to 5 substituents. Furthermore, in the case of having a plurality of substituents, the substituents may be the same as or different firom each other.
[0022]
In the present specification, the substituent, for which the expressions "may be substituted" or "be substituted" are acceptable, can be any substituent which is usually used as a substituent for each group.
For example, examples of the substituent in the Ring A, for which the expressions "may be substituted" or "be substituted" are acceptable, include halogen, -CN, -NH2, Ci-e

alkyl, -O-Ci.6 alkyl, -CONH2, -NH-C1.6 alkyl, -NH-Ci-e alkyl-O-Ci-6 alkyl-aryl, -NH-C1.6 alkyl-aryl, and -NH-Ci-g alkyl-OH.
[0023]
An embodiment [1] according to the present invention is as follows. Regarding the formula (I),
(1) the compound, wherein R' is -H,
(2) the compound, wherein R is an aza-bridged-ring selected from the group consisting of the formulae (a), (b), (c), and (d):
[0024] [Chem. 5]


p I

(a) (b)
(3) the compound, wherein r is 0,
(4) the compound, wherein X is halogen,
(5) the compound, wherein R1 is phenyl which may be substituted with one or more

R11 and
.31 :
R1' is halogen, -OH, -CN, -CF3, -Ci1 alkyl, or -O-C1.6 alkyl,
(6) the compound, wherein Ring A is a hetero ring or cycloalkyl,
each of which may be substituted with a group selected from the group consisting of one or more R ,
(7) the compound, wherein V is -0-,
(8) the compound, wherein W is -(CH2)q- and q is 0 or 1,
(9) the compound, wherein :zii is a single bond,

(10) the compound, wherein m, n, and p are respectively 1 or 2, and
(11) the compound which is a combination of two or more of (1) to (10) as above, or a salt thereof
[0025]
Another embodiment [2] of the present invention is as follows.
The compound or a salt thereof of the embodiment [1], wherein

Ring A is a hetero ring or cycloalkane,
each of which may be substituted with a group selected from the group consisting of one or more R11;
in which R1' is halogen, -CN, -NH2, C1.6 alkyl, -O-C1.6 alkyl, -CONH2, -NH-Ci-e alkyl, -NH-C,.6 alkyl-O-Ci-g alkyl-phenyl, -NH-Ci-e alkyl-phenyl, or -NH-C1.6 alkyl-OH,
in which Ci-e alkyl may be substituted with halogen.
[0026]
Another embodiment [3] of the present invention is as follows.
The compound or a salt thereof of the embodiment [2], wherein
Ring A is a group selected from the group consisting of thiophene, thiazole, isothiazole, thiadiazole, oxazole, isooxazole, cyclohexane, norborane, benzothiophene, and 5,6-dihydro-4H-cyclopentathiophene, each of which may be substituted with a group selected from the group consisting of one or more R'1'.
[0027]
Another embodiment [4] of the present invention is as follows.
The compound or a salt thereof of the embodiment [3], wherein
Ring A is a group selected from the group consisting of thiophene, thiazole, and cyclohexane,
each of which may be substituted with a group selected from the group consisting of oneormoreR'1[0028]
Another embodiment [5] of the present invention is as follows.
The compound or a salt thereof of the embodiment [4], wherein
R' is -H.
[0029]
Another embodiment [6] of the present invention is as follows.
The compound or a salt thereof of the embodiment [5], wherein
R1 is phenyl which may be substituted with one or more R11,
and R1' is halogen, -OH, -CN, -CF3, -Ci-e alkyl, or -O-C1.6 alkyl.
[0030]
Another embodiment [7] of the present invention is as follows.
The compound or a salt thereof of the embodiment [6], wherein

R1 is an aza-bridged-ring selected from the group consisting of the formulae (a), (b), (c), and (d), in which in case of (a) or (c), (m, n, p) is (2, 1, 1), (1,1, 2), or (2, 1,2) for each sequence.
[0031]
Another embodiment [8] of the present invention is as follows.
The compound or a salt thereof of the embodiment [7], wherein
R1 is an aza-bridged-ring selected from the group consisting of the formulae (a) and (b), and
R11 is Ci.6 alkyl, -Ci-e alkyl-0-phenyl, or -Ci-e alkyl-phenyl.
[0032]
Examples of the specific compounds included in the present invention include the following compounds or free bases thereof.
(1) l-azabicyclo[2.2.2]oct-4-ylmethyl(5-phenyl-l,3-thiazol-4-yl)carbamate hydrochloride,
(2) l-azabicyclo[3.2.2]non-5-yl(5-phenyl-l,3-thiazol-4-yl)carbamate hydrochloride,
(3)(3R)-l-azabicyclo[2.2.2]oct-3-yl[(lR,2S)-2-phenylcyclohexyl]carbamate hydrochloride,
(4) 1 -azatricyclo[3.3.1.1 -3,7-]dec-4-yl(5-phenyl-1,3-thiazol-4-yl)carbamate hydrochloride,
(5) l-azabicyclo[2.2.2]oct-3-ylmethyl(2-phenyl-3-thienyl)carbamate hydrochloride,
(6) l-azabicyclo[2.2.2]oct-4-yl[5-(4-fluorophenyl)-l,3-tliiazol-4-yl]carbamate hydrochloride,
(7) l-azabicyclo[3.2.1]oct-6-ylmethyl(5-phenyl-l,3-thiazol-4-yl)carbamate hydrochloride, or
(8) l-azabicyclo[2.2.2]oct-3-ylmethyl[5-(4-fluorophenyl)-l,3-thiazol-4-yl]carbamate fumarate.
[0033]
Examples of the specific compounds included in the present invention include the following compounds or anion exchangers thereof.
(l)4-({[5-(3 -chlorophenyl)-1,3 -thiazol-4-yl]carbamoyl} oxy)-1 -methyl-1 -azoniabicyclo[2.2.2]octane iodide,
(2) l-(3-phenylpropyl)-3-({[(2-phenyl-3-thienyl)carbamoyl]oxy}methyl)-l-azoniabicyclo [2.2.2] octane bromide,

(3) 1 -(2-phenyIethyl)-4- {[(5-phenyl-1,3 -thiazol-4-yl)carbamoyl]oxy} -1 -azomabicyclo[2.2.2]octane bromide,
(4) l-(2-phenoxyethyl)-4-{[(5-phenyl-l,3-thiazol-4-yl)carbamoyl]oxy}-l-azoniabicyclo[2.2.2]octane bromide,
(5)4-({[5-(2,5-difluorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-l-methyl-l-azoniabicyclo [2.2.2] octane iodide,
(6) 1 -methyl-5- {[(5-phenyl-1,3 -thiazol-4-yl)carbamoyl]oxy} -1 -azoniabicyclo[3.2.2]nonane iodide,
(7)4-({[5-(3-chlorophenyl)-l,3-thiazol-4-yl]carbamoyI}oxy)-l-(2-phenoxyethyl)-1 -azoniabicyclo[2.2.2]octane iodide,
(8) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbamoyl}oxy)-1 -methyl-1 -azoniabicyclo [2.2.2]octane bromide,
(9)4-({[5-(3,5-dichlorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-l-methyl-l-azoniabicyclo[2.2.2]octane iodide,
(10)4-({[5-(2,5-difluorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-l-methyl-l-azoniabicyclo [2.2.2]octane bromide,
(ll)4-({[5-(2,4-difluorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-l-methyl-l-azoniabicyclo[2.2.2]octane bromide,
(12) 1 -methyl-4- {[(5-phenyl-1,3-thiazol-4-yl)carbamoyl]oxy} -1 -azoniabicyclo[2.2.2]octane bromide,
(13)4-({[5-(3,5-dichlorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-l-methyl-l-azoniabicyclo[2.2.2]octane bromide, or
(14) 1 -methyl-5- {[(5-phenyl-1,3-thiazol-4-yl)carbamoyl]oxy} -1 -azoniabicyclo [3.2.2]nonane bromide.
[0034]
The compound of the formula (I) may exist in the form of geometrical isomers depending on the kinds of the substituents. In the present specification, the compound of the formula (I) may be described in only one form of an isomer, but the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof
Further, the compound of the formula (I) may have an asymmetric carbon atom, and correspondingly, may exist in the form of optical isomers. The present invention includes an isolated form of these optical isomers of the compound of the formula (I), or a mixture thereof

[0035]
Furthermore, the present invention also includes a pharmaceutically acceptable prodrug of the compound of the formula (I). The pharmaceutically acceptable prodrug refers to a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group and the like by solvolysis or under physiological conditions. Examples of the group to form a prodrug include the groups as described in "Prog. Med., 5, 2157-2161 (1985)", or "lyakuhin no Kaihatsu (Development of Medicines) (Hirokawa Shoten, 1990), vol. 7, Bunshi Sekkei (Molecular Design)", 163-198.
[0036]
Moreover, the salt of the compound of the formula (I) refers to a pharmaceutically acceptable salt of the compound of the formula (I), and in some cases, it forms an acid addition salt or a salt with a base, depending on the kind of substituents. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, flimaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditoluoyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benznesulfonic acid, p-toluenesulfonic acid, asparaginic acid, glutamic acid and the like, and salts with various amino acids and amino acid derivatives such as acetylleucine and the like.
[0037]
Furthermore, the present invention also includes various hydrates or solvates, and polymorphic crystal substances of the compound of the formula (I) and a salt thereof Also, the present invention includes the compounds labeled with various radioactive or non¬radioactive isotopes.
[0038]
The abbreviations in the present specification are as follows.
BINAP: (R)-(+)- or (S)-(-)-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl
CHCI3: chloroform
CS2CO3: cesium carbonate
CuCh: copper chloride
DCE: 1,2-dichloroethane
DCM: dichloromethane
DEAD: diethyl azodicarboxylate

DIBOC: di-tert-butyldicarbonate
DIPA: diisopropylamine
DIPEA: N,N-diisopropyIethylamine
DMA: dimethylacetamide
DMA?: N,N-dimethyl-4-aminopyridine
DMF: NjN-dimethylformamide
DMSO: dimethylsulfoxide
DPPA: diphenylphosphoric acid azide
DPPF: diphenylphosphinoferrocene
EtOAc: ethyl acetate
EtOH: ethanol
HCl/dioxane: hydrogen chloride/dioxane solution
HCl/EtOAc: hydrogen chloride/ethyl acetate solution
HCl/MeOH: hydrogen chloride/methanol solution
IPE: diisopropylether
K2CO3: potassium carbonate
KOH: potassium hydroxide
LAH: lithium aluminum hydride
LiBH4: lithium borohydroxide
MCPBA: methachlor-perbenzoic acid
MEK: 2-butanone
MeCN: acetonitrile
MeOH: methanol
MgS04: anhydrous magnesium sulfate
NBS: N-bromosuccinimide
NCS: N-chlorosuccinimide
NMP: N-methylpyrrolidone
NaiCOs: sodium carbonate
Na2S04: anhydrous sodium sulfate
Na2SO4'10H2O: sodium sulfate decaanhydride
NaH: sodium hydride
NaHCOa: sodium hydrogen carbonate
NaOAc: sodium acetate
NaOBu1 sodium tertiary butoxide

NaOEt: sodium ethoxide
NaOH: sodium hydroxide
NaOMe: sodium methoxide
P(Bu')3: tri(tertiary butyl) phosphine
PPhs: triphenylphosphine
Pd(0Ac)2: palladium acetate
PdCl2(PPh3)2: dichlorobistriphenylphosphinepalladium
Pd2dba3: tris(dibenzylideneacetone) dipalladium
Pd(PPh3)4: tetrakis(triphenylphosphine)palladium (0)
rel: relative configuration
Rt: retention time
TEA: triethylamine
TEA: trifluoroacetic acid
THE: tetrahydrofuran
brine: saturated physiological saline
tBuOH: tertiary butanol
tBuOK: potassium tertiary butoxide
[0039] (Preparation Methods)
The compound of the formula (I) and a salt thereof can be prepared by applying various known synthetic methods, by the use of the characteristics based on their basic skeletons or the kinds of substituents. At this time, depending on the kinds of functional groups, it is in some cases effective from the viewpoint of the preparation techniques to substitute the functional group with an appropriate protecting group (a group which is easily capable of being converted into the functional group), during the steps from starting materials to intermediates. Examples of such a functional group include the protectmg groups as described in "Greene's Protective Groups in Organic Synthesis (4* Edition, 2006)", edited by P.G.M. Wuts and T.W. Greene, which may be appropriately selected and used depending on the reaction conditions. In these methods, a desired compound can be obtained by introducing the protecting group to carry out the reaction, and then, if desired, removing the protecting group.
In addition, a prodrug of the compound of the formula (I) can be prepared by introducing a specific group during the steps from the starting materials to the intermediates, in a similar manner to the aforementioned protecting groups, or by further carrying out a

reaction using the resulting compound of the formula (I). The reaction may be carried out by employing a method conventionally known to a person skilled in the art, such as common esterification, amidation, dehydration and the like.
Hereinbelow, representative preparation methods for the compound of the formula (I) are described. Further, the preparation methods of the present invention are not limited to examples shown below.
[0040]
[0041]
[Chem. 6]
W
11nZ R1
(1-a) (1-b) (l-a)
This production process is a process for preparing the compound of the formula (I-a) with R1=H from the compound (l-a).
The step of Step 1 is a reaction for allowing a carboxyl group of the compound (1-a) to undergo a reaction with an azidation agent such as DPPA, sodium azide and the like to constitute a carbamate group or an urea group by a so-called Curtius rearrangement reaction, which is preferably carried out in the presence of a base. As the base, TEA, pyridine or the like can be usually used, and the reaction can be carried out at room temperature, at a room temperature to under heating, or under heating under reflux. Further, the preparation can also be conducted by a process via an isocyanate that is yielded from a carboxylic acid derivative, which uses hydrazoic acid in the presence of concentrated sulfuric acid.
[0042]

[0043] [Chem. 7]
Q111R1 . V'1-"'' 11 (AT V'1w-"1
(2-a) (2-b) (I)
[wherein Lv represents a leaving group].
This production process is a process for preparing the compound of the formula (I) using a compound (2-a) as a starting material.
Step 2 is a reaction for allowing the compound (2-a) to undergo a reaction with a compound (2-b), which is preferably carried out in the presence of a base. As the base, TEA, pyridine or the like can be usually used, and the reaction can be carried out at room temperature, at room temperature to under heating, or under heating under reflux. Here, examples of the leaving group include halogen; methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy; and the like.
[0044]
[0045]
[Chem. 8]

®

R3° 11R3°

(3-a) (1-b) (I)
This production process is a process for preparing the compound of the formula (I)
from a compound (3-a).
The step of Step 3 is a reaction for allowing the compound (3-a) to undergo a
reaction with the compound (1-b), which is preferably carried out in the presence of a base
(for example, NaH, NaOMe, NaOEt, NaOH, KOH and the like) to promote the reaction.
Here, examples of the leaving group, Lv, include halogen, methoxy, ethoxy, phenoxy, p-
nitrophenoxy and the like. [0046]

[0047] [Chem. 9]
1
R1 R
1N1V1 .1R2 3 P1 Step4 1~>/N1V11;,R2
(St T ™ 1 1 -\H -1 QC/ "
Lv 1
(4-a) (4-b) (I)
This reaction is a process for preparing the compound of the formula (I) by reacting a halogenated aryl compound (4-a) with an aryl boric acid compound (4-b), and using a so-called Suzuki coupling. The reaction can be carried out without a solvent, or in a solvent which is inert to the reaction, such as aromatic hydrocarbons (for example, benzene, toluene, xylene and the like), ethers (for example, THF, dioxane and the like); halogenated hydrocarbons (for example, DCM, DCE, CHCI3 and the like); DMF, DMA, NMP; EtOAc, MeCN and the like, at room temperature to under heating under reflux. The reaction is carried out in the coexistence of palladium, phosphine ligands, and metal bases. As palladium, a divalent palladium such as Pd(0Ac)2 and the like, or a nuU-valent palladium such as Pdidbas and the like can be used. As the phosphine ligand, a bidentate ligand such as BINAP, DPPF and the like, a monodentate ligand such as P(Bu*)3 and the like can be used. As the metal base, K2CO3, CS2CO3, potassium phosphate, NaOBu' and the like can be used. Here, examples of the leavmg group, Lv, include halogen, trifluoromethanesulfonyloxy and the like.
[0048]
[0049]
[Chem. 10]

R1 R

1

_11.,1 w1 .'R2 , Steps /-11N111x/vr-1R
/-1 Y 1W-1 + R3-SnBu3 -1 (M1 Y 1
■R31
Lv
O 11DSO
(4-a) (5-b) (l-b)
[wherein Al represents aromatic hydrocarbon or a hetero ring]. This reaction is a process for preparing the compound of the formula (I-b) by reacting a compound (4-a) with a tin compound (5-b), and using a so-called Stille coupling.

The reaction can be carried out without a solvent, or in a solvent which is inert to the reaction, such as aromatic hydrocarbons (for example, benzene, toluene, xylene and the like), ethers (for example, THF, dioxane and the like); halogenated hydrocarbons (for example, DCM, DCE, CHCI3 and the like); DMF, DMA, NMP; EtOAc, MeCN and the like, at room temperature to under heating under reflux. The reaction is carried out in the coexistence of palladium, and phosphine ligands. As palladium, a divalent palladium such as Pd(0Ac)2 and the like, or a nuU-valent palladium such as Pdidbas and the like can be used. As the phosphine ligand, a bidentate ligand such as BINAP, DPPF and the like, a monodentate ligand such as P(Bu')3 and the like can be used. Here, examples of the leaving group include halogen, trifluoromethanesulfonyloxy and the like.
[0050]
[0051]
[Chem. 11]

R1
XT Y w
OCT
R1
W

steps 111
1-1R3°

(l-c)

(l-d)



R11=


(a')

(a)




(b')

In the compound of the formula (I), the compounds (a, b) in which a nitrogen atom of the aza-bridged-ring group forms a quaternary ammonium salt, or the compounds (c, d) in which said nitrogen atom is oxidized can be prepared by subjecting a tertiary amine compound (1-c) of the present invention compound to an N-alkylation or N-oxidation reaction, which can be usually carried out in the final step.
The N-alkylation reaction can be carried out by a conventional method for an N-alkylation reaction, but specifically, it can be carried out by stirring a tertiary amine compound of the present invention with a corresponding amount of an alkylation agent in an inert solvent such as DMF, CHCI3, acetone, MEK, MeCN, THF and the like, from under ice-cooling to at room temperature, or in some cases, with heating under reflux.
Examples of the alkylation agent include alkyl halide, C1.6 alkyl trifluoromethanesulfonate, Ci-e alkyl p-toluenesulfonate, Ci-e alkylmethanesulfonate and the like.
The N-oxidation reaction can be carried out by a conventional method for an oxidization reaction, but specifically, it can be carried by stirring a tertiary amine compound of the present invention with a corresponding amount or excessive amount of an oxidant in an inert solvent such as CHCI3, DCM, DCE and the like, alcohols such as MeOH, EtOH and the like, water, or a mixed solvent thereof, from under cooling to at room temperature, or in some cases, with heating under reflux. Examples of the oxidant include an organic peracid such as MCPBA and the like, sodium periodide, hydrogen peroxide and the like.
[0052] [0056] [Chem. 13]

HjN
fcL.°
Hal OR (8-a)

H,C?'X%.

(8-d)

Step8-1

Step8-4

R—CHO

CI
'1V "-
/=N
L 6R1

or

-R1

?§AK
R1x
R"/ -NH1 \=M
Step8-5
11 OR1

(8-b)

(8-e)

(8-f) J

(8-h)

(4-b)
,1
PH bH
Step8-2

R1-B:
H1N' "NH1
or
Step8-5
H.
R—SnBu,
=N
Step8-6
13 6R1 (8-g)
_ sCX1O Step8-7
Js OR1 Step8-3 13 6H
(8-c) (1-a')

H3C

Step8-3
13 6H
d-a")

Step8-8
{!13 OR1
(8-i)
H3C
H3C-)-0 R1 H3C-)-0 R1
13 6R1 J3 OH
(8-j) (8-k)
[wherein R* represents a Ci-e alkyl group which may be substituted with halogen and R1 represents a Ci-e alkyl group].

[0057]
Further, preparation can be performed in the following method in the case where the Ring A of the carboxylic acid compound (1-a) which is a starting material of Step 1 of Production Process 1 is thiazole.
Step 8-1 is a process for preparing a deaminated product (8-b) by using a compound (8-a) as a starting material. The preparation can be performed by allowing an alkali metal salt of a nitric acid or nitric esters to undergo a reaction under acidic conditions to produce a diazonium salt, with the removal of nitrogen. The reaction can be carried out in a solvent such as sulfuric acid, acetic acid, phosphoric acid, acetone, MeCN, DMSO and the like.
Step 8-2 is a process for preparing a compound (8-c) by allowing an aryl boric acid or alkyl tin compound to undergo a reaction with the compound (8-b). It can be canied out by the same method as Production Processes 4 and 5 above.
Step 8-3 is a reaction for obtaining a carboxylic acid compound (1-a') by subjecting an ester group to hydrolysis or deprotection, and can be canied out by the same method as Step 7-3 above.
In Step 8-4, a compound of the formula (8-e) or the formula (8-f) can be obtained from a compound (8-d) and an aldehyde by a method by TSUBOI, et al. (Bulletin of Chemical Society of Japan., 1987, Vol. 60, p. 2475), and in Step 8-5, a thiazole compound (8-g) or a compound (8-h) can be obtained by the reaction of the compound (8-e) or the compound (8-f) with thiourea or thioamide. The reaction is carried out in an alcohol or MeCN under heating.
Step 8-6 is a process for preparing the deaminated compound (8-c) from a 2-aminothiazole compound (8-g), and can be carried out by the same method as Step 8-1 above.
Step 8-7 is a process for preparing a compound (8-i) from the compound (8-g) having a 2-amino thiazole group, for which the condition for protection of an amino group as described in the above "Protective Groups in Organic Synthesis" can be applied.
Step 8-8 is a process for preparing an N-alkyl N-tert-botoxycarbonyl product from the tert-botoxycarbonyl product (8-i) by a method by KIM, et al. (Synlett., 1999, pp. 1239).
Step 8-9 is a reaction for obtaining a carboxylic acid compound (8-k) by subjecting an ester group to hydrolysis or deprotection, and can be canied out by the same method as Step 7-3 above.

[0058]
Furthermore, the heteroaryl carbamate compound (4-a) used in the step of Production Processes 4 and 5 in which R' is -H can be prepared by the same method as Production Process 1.
[0059]
[Chem. 14]
W
0 H ,

(9-a) (1-b) (4-a)
[0060]
Moreover, several compounds of the formula (I) can be prepared from the compound of the present invention produced as above, by any combination of well-known processes that can be usually employed by a person skilled in the art, such as alkylation, acylation, substitution reaction, oxidation, reduction, hydrolysis, deprotection and the like.
[0061]
The compound of the formula (I) is isolated and purified as its free compound, a salt, a hydrate, a solvate, or a polymorphic crystal substance thereof The salt of the compound of the formula (I) can also be prepared in accordance with a conventional method for a salt formation reaction.
Isolation and purification are carried out by employing common chemical operations such as extraction, firactional crystallization, various types of fi-action chromatography and the like.
Various isomers can be prepared by selecting an appropriate starting compound, or can be separated by making a use of the difference in the physicochemical properties between isomers. For example, the optical isomer can be obtained by means of general optical resolution methods of racemic products (for example, fractional crystallization for inducing diastereomers with optically active bases or acids, chromatography using a chiral column, etc. and the like). In addition, the isomers can also be prepared from an appropriate optically active starting material.

[0062]
The pharmacological activity of the compound of the formula (I) was confirmed by the following test.
Test Example 1: Test of muscarinic receptor affinity (in vitro)
a. Preparation of a membrane specimen
The submandibular gland/heart and the cerebral cortex were harvested from male SD rats (Japan SLC, Inc.) and a 10-fold volume of a 25 mM Tris buffer (pH = 7.4, hereinafter referred to as a Tris buffer) containing 3.75 mM magnesium chloride was added thereto, followed by homogenization under ice-cooling. Centrifugation was performed at 1,000 g, 4°C for 10 minutes, and then ultracentrifugation was performed at 100,000 g, 4°C for 30 minutes. This precipitate was suspended in a Tris buffer and stored at -80°C. After this, it was melted in use, and tested.
b. Experiment of the muscarinic receptor binding
A membrane specimen of any one of the submandibular gland, the heart, and the cerebral cortex, [1H]-N-methylscopolamine (N-methylscopolamine) and a compound to be tested were incubated in 0.3 mL of a Tris buffer at 25°C for 2 hours, and suction-filtered through a glass filter (Whatman GF/B), and the filter was washed 8 times with 0.3 mL of a Tris buffer. The radioactivity of [1H]-N-methylscopolamine adsorbed on the filter was measured with Top Count. Further, the receptor-specific binding was determined by adding 1 1M N-methylscopolamine. The affinity of the compound to be tested for the muscarinic receptor was determined as a dissociation constant (Ki) calculated from a concentration (IC50) of the compound to be tested which inhibits the binding of the [ H]-N-methylscopolamine as a labelled ligand by 50%.
[0063]
As a result, for any one compound of the compounds of the formula (I), the results of the experiment of the receptor binding antagonistic experiments (activity values, Ki values, nM) are shown in Table 1.

[0064]
[Table 1]
Number of Example Ex Ki value (nM) Number of Example Ex Ki value (nM)
2 0.51 95 0.2
6 0.45 110 0.67
12 0.32 130 0.21
26 0.56 136 0.065
32 0.049 139 0.36
35 0.021 153 0.85
46 0.083 246 0.074
[0065]
a. Test Example 2) Test of muscarinic receptor antagonism (in vivo)
a. Test of rat airway contraction
Male SD rats (250 to 400 g) were anesthetized by the intraperitoneal administration of pentobarbital sodium (Nembutal; 50 mg/kg), and the major airway was dissected. An airway cannula was intubated into the trachea, and the pressure in the airway was measured by a pressure transducer. After administration of pancuronium bromide (0.2 mg/kg, i.v.), a stable pressure in the airway was obtained before the experiment was initiated. For the experiment, by administration into the external maxillary vein/administration into the duodenum/oral administration/administration into the airway, physiological saline (in the case of oral administration/administration into the duodenum, distilled water) or a compound to be tested was administered, and after 5 to 30 minutes in the case of intravenous administration, after 0.25 to 6 hours in the case of oral administration into the duodenum, and after 0.25 to 72 hours in the case of administration into the airway, carbachol was intravenously administered at a dose (volume) of 30 [ig/kg (1 mL/kg), and the pressures in the airway were then measured, respectively, for a period of 5 minutes. An inhibition rate of a drug to be tested on the carbachol-induced rise in the pressure in the airway in administration of physiological saline was determined, and a dose of the compound to be tested which inhibited the rise by 50% was taken as an ED50 value.

[0066]
b. Test of rat salivary secretion
Male SD rats (250 to 400 g) were anesthetized by the intraperitoneal administration of pentobarbital sodium (Nembutal; 50 mg/kg). The compound to be tested (for a control group, physiological saline) was administered, and after 5 minutes, carbachol was administered at a dose of 30 )ag/kg (1 mL/kg). The administration of a drug was performed in the same method as for the above-described test method by administration into the external maxillary vein/administration into the duodenum/oral administration/administration into the airway. The saliva secreted for 5 minutes immediately after administration of carbachol was recovered with cotton balls, and its weight was measured. An inhibition rate on the amount of saliva secreted in the control group was determined, and the dose of the compound to be tested which inhibited the amount of the saliva secreted in the control group by 50% was taken as an ID50 value.
[0067]
c. Test of rat bradycardia
Male SD rats (250 to 400 g) were anesthetized by the intraperitoneal administration of pentobarbital sodium (50 mg/kg), the neck was dissected, and the airway was secured by intubating a cannula into the trachea. Under artificial respiration (10 mL/kg at 90 times per minute), the heart rate was monitored from the total maxillary artery. A carmula was intubated into the external maxillary vein, whereby a drug was administered. After intubating a carmula into the trachea, and leaving it to stand for 10 minutes, the compound to be tested was administered intravenously/administered into the duodenum/administered orally/administered into the airway (for the control group, physiological saline was administered in the case of intravenous administration/oral administration, and distilled water was administered in the case of oral administration into the duodenum). After 5 to 30 minutes, carbachol was administered at a dose of 30 1ig/kg (1 mL/kg), and an effect on the reduction of the heart rates in the control group up to 5 minutes from administration was measured. An inhibition rate for the reduction of the heart rates was determined, and the dose of the compound to be tested which inhibited the reduction of the heart rate in the control group by 50% was taken as an ID50 value. For any one compound of the compounds of the formula (I), the results of the carbachol-induced airway contraction inhibitory action are shown in Tables 2 and 3. (Table 2: Evaluation after 3 hours from oral administration and Table 3: Evaluation after 24 hours from administration into the trachea, of 0.5 i1g/kg of a drug, respectively)

[0068]

[Table 2]

Number of Example Ex ID50 (mg/kg)
6 0.1
14 0.027
26 2.45
110 0.41
136 0.68
156 0.091
264 0.21

[0069]

[Table 3]

Number of Example Ex Inhibition rate (%)
32 82
43 64
46 90
50 61
57 64
65 61
66 80

[0070]
From the results of the tests above, it was confirmed that the compound of the formula (I) has an antagonistic action on the binding of a muscarinic M3 receptor. Therefore, it can be used for the treatment of respiratory diseases such as chronic obstructive pulmonary disease (COPD), chronic bronchitis, asthma, chronic airway obstruction, a pulmonary fiber disease, emphysema, rhinitis and the like; diseases of the digestive system such as irritable bowel syndrome, spastic colitis, gastroduodenal ulcers, gastrointestinal seizures or increased motor function, pains due to diverticulitis and contraction of the smooth muscle in the digestive system, and the like; diseases of the urinary system involving dysuria such as urinary incontinence, urgency of urination, urinary

frequency and the like in the diseases such as neurogenic urinary frequency, neurogenic bladder, enuresis noctuma, bladder instability, bladder spasms, chronic cystitis and the like; lifestyle diseases such as obesity, diabetes and the like; motion sickness and the like.
[0071]
A pharmaceutical composition comprising one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared in accordance with a method which is usually used in the art, using an excipient which is usually used in the art, that is, a pharmaceutically acceptable excipient, a pharmaceutically acceptable soluble carrier or the like.
The administration can be carried out in any form of oral administration via tablets, pills, capsules, granules, powders, liquid preparations or the like, or parenteral administration via injections such as infraarticular, intravenous, intramuscular, suppositories, eye drops, eye ointments, percutaneous liquid preparations, ointments, percutaneous patches, transmucosal liquid preparations, fransmucosal patches, inhalations and the like.
[0072]
Regarding the solid composition for oral administration, tablets, powders, granules or the like are used. In such a solid composition, one or two or more kinds of active ingredients are mixed with at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and/or magnesium aluminometasilicate and the like. According to a conventional method, the composition may contain inert additives such as a lubricant such as magnesium stearate, a disintegrator such as carboxymethylstarch sodium and the like, a stabilizing agent, and a solubilizing agent. As occasion demands, the tablets or the pills may be coated with a film of a sugar coating, or a gastric or enteric coatmg agent.
The liquid composition for oral administration includes a pharmaceutically acceptable emulsion, soluble liquid preparation, suspension, syrup, elixir or the like, and contains a generally used inert diluent, for example, purified water or EtOH. In addition to the inert diluent, this liquid composition may contain an auxiliary agent such as a solubilizmg agent, a moistening agent, and a suspending agent, a sweetener, a flavor, an aromatic, or an antiseptic.
[0073]
Injections for parenteral administration contain sterile aqueous or non-aqueous soluble liquid preparations, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection or physiological saline. Examples of the non-

aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as EtOH, Polysorbate 80 (Japanese Pharmacopeia) and the like. This composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by producing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.
[0074]
The drugs for external use includes ointments, plasters, creams, jellies, patches, sprays, lotions, eye drops, eye ointments and the like. The drugs contain generally used ointment bases, lotion bases, aqueous or non-aqueous soluble liquid preparations, suspensions, emulsions and the like. Examples of the ointment bases or the lotion bases include polyethylene glycol, propylene glycol, white vaseline, bleached bee wax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate and the like.
[0075]
Regarding the transmucosal agents such as inhalations, a transnasal agent and the like, those in the form of a solid, liquid, or semi-solid state are used, and may be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a conventionally known device or sprayer, such as a measured administration inhalation device. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a high pressure aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, carbon dioxide and the like, or other forms.
[0076]
In oral administration, the daily dose is generally from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and even more preferably from 0.1 to 10 mg/kg, per body

weight, administered in one portion or in 2 to 4 divided portions. In the case of intravenous administration, the daily dose is suitably from about 0.01 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a drug as a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. In the case of inhalation administration, the daily dose is from about 0.1 to 100 |.tg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to an individual case by taking the symptoms, the age, the gender and the like into consideration.
[0077]
The compound of the formula (I) can be used in combination of various therapeutic agent or prophylactic agents for the diseases for which the compound of the formula (I) is considered to be effective, as described above. The combinations may be administered simultaneously, or separately and continuously, or at a desired time interval. The preparations to be co-administered may be a blend, or may be prepared individually.
[Examples]
[0078]
Hereinbelow, the methods for preparing the compound of the formula (I) are described in more detail with reference to Examples. Also, the present invention is not intended to be limited to the compounds described in Examples below. Further, the production processes for the starting compound are each described with reference to Production Examples. Moreover, the prepai'ation methods for the compound of the formula (I) are not limited to these specific preparation methods of Examples, and thus the compound of the formula (I) can also be prepared by a combination of such preparation methods, or a known production method which is apparent to a skilled person in the art.
[0079]
By using such a preparation method, a method which is apparent to a skilled person in the art, or a modified method thereof, the compounds shown in the Tables below were prepared. The structures and physicochemical data of these compounds of the Examples, and the preparation methods therefor are shown in the Tables. Also, the symbols in the Tables have the following meanings.
[Pr: Production Example number
Ex: Example number

Syn: Preparation method (the numeral shows that the compound of the Example was prepared using the same preparation method as for the compound having its number as the Example number).
Structure: Structural formula
data: Physicochemical data. For example, NMR and MS are as follows.
• NMR: Signal 6 (ppm) of 'H-NMR, using DMSO-de as a measurement solvent
• NMR (CDCI3): Signal 5 (ppm) of 1H-NMR, using CDCI3 as a measurement solvent
• ESI (+): Values as measured in a positive mode
• ESI (-): Values as measured in a negative mode
[0080]
Production Example 1
Under ice-cooling, to a suspension of CuBr2 in MeCN was added tert-butyl nitrate. Next, methyl 2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate was added portion wise thereto, followed by stirring under ice-cooling for 2 hours and then at room temperature for 3 hours. To the reaction mixture was added hydrochloric acid, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN, YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 2-bromo-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate as a colorless liquid.
[0081]
The compounds of Production Examples 1-1 to 1-2 shown in Tables below were synthesized in the same method as in Production Example 1, using the corresponding starting materials.
[0082]
Production Example 2
To a solution of ethyl 2-amino-5-phenylthiazole-4-carboxylate in MeCN was added CuCb at 0°C, and the isoamyl nitrate was slowly added dropwise thereto, followed by stirring for 1 hour. To the reaction mixture was added CHCI3, followed by stirring at 0°C for 2 hours and then at room temperature for 2 hours. The reaction mixture was neutralized by addition of a 1 M aqueous NaOH solution, and filtered through Celite. The filtrate was extracted with EtOAc, and the organic layer was washed with water and brine in this order and then dried over MgS04. After concentration under reduced pressure, the

residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel YAIvlAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain ethyl 2-chloro-5-phenylthiazole-4-carboxylate as a yellow oil.
[0083]
Production Example 3
To a suspension of methyl 2-bromo-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate, phenyl boronic acid, and Pd(PPh3)4 in dioxane was added a 2 M aqueous Na2C03 solution, followed by stirring at 90°C for 15 hours. Water was added thereto, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgS04 and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate as a colorless liquid.
[0084]
The compounds of Production Examples 3-1 to 3-24 shown in Tables below were synthesized in the same method as in Production Example 3, using the corresponding starting materials.
[0085]
Production Example 4
To a solution of methyl 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate in EtOH was added a 1 M aqueous NaOH solution, followed by heating under reflux for 5 hours. The reaction mixture was adjusted into pH=2 by addition of 1 M hydrochloric acid, and the solid precipitated was collected by filtration, and washed with water to obtain 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid as a white solid.
[0086]
The compounds of Production Examples 4-1 to 4-20 shown in Tables below were synthesized in the same method as in Production Example 4, using the corresponding starting materials.
[0087]
Production Example 5
To a solution of ethyl 2-chloro-5-phenylthiazole-4-carboxylate in THF was added a 1 M aqueous KOH solution, followed by stirring at 60°C for 30 minutes. To the reaction

mixture was added 1 M hydrochloric acid, and the solid precipitated was collected by filtration to obtain 2-chloro-5-phenylthiazole-4-carboxylic acid as a white solid.
[0088]
The compounds of Production Examples 5-1 to 5-23 shown in Tables below were synthesized in the same method as in Production Example 5, using the corresponding starting materials.
[0089]
Production Example 6
To a solution of 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid and TEA in toluene was added a solution of DPPA in toluene, followed by stirring at room temperature for 40 minutes, and then stirring at 90°C for 60 minutes. Furthermore, a solution of (3R)-quinuclidinole in DMF was added thereto, followed by heating under reflux for 15 hours. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The oily substance obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-amine as a pale brown oil, but not a desired (3R)-l-azabicyclo[2.2.2]oct-3-yl(2-phenyl-5,6-dihydro-4H-cyclopenta[b]thien-3-yl)carbamate.
[0090]
Production Example 7
To a solution of 2-bromothiophene-3-carboxylic acid and TEA in toluene was added drop wise a solution of DPPA in toluene. The reaction liquid was stirred at room temperature for 40 minutes, and then stirred at 90°C for 60 minutes. To this solution was added a solution of 3-quiclidinole in DMF, followed by heating under reflux for 15 hours. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHClsMeOH) to obtain l-azabicyclo[2.2.2]oct-3-yl(2-bromo-3-thienyl)carbamate as a pale brown solid.

[0091]
The compounds of Production Examples 7-1 to 7-5 shown in Tables below w:ere synthesized in the same method as in Production Example 7, using the corresponding starting materials.
[0092]
Production Example 8
To a solution of 2-phenylthiophene-3-carboxylic acid and TEA in toluene was added dropwise a solution of DPPA in toluene, followed by stirring at room temperature for 40 minutes, and then stirring at 90°C for 60 minutes. To this solution was added tBuOH, followed by heating under reflux for 15 hours. To the reaction solution was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtam tert-butyl (2-phenyl-3-thienyl)carbamate as a pale brown oil.
[0093]
Production Example 9
To a suspension of LAH in THF was added a solution of tert-butyl (2-phenyl-3-thienyl)carbamate in THF, followed by stirring at room temperature for 30 minutes and the stirring at 70°C for 4 hours. After cooling at room temperature, Na2S04' IOH2O was added thereto, followed by stirring at room temperature for 30 minutes. The reaction mixture was filtered and concentrated under reduced pressure to obtain 3-methylamino-2-phenylthiophene as a colorless oily substance.
[0094]
Production Example 10
To a mixture of methyl 2-chloroisonicotinate, Pd(PPh3)4, and [(E)-2-phenylvinyl]boric acid in dioxane was added a 2 M aqueous Na2C03 solution, followed by stirring at 90°C for 5 hours. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgS04, and the filtrate was then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAG) to obtain methyl 2-[(E)-2-phenylvinyl]isonicotinate as a pale yellow solid.

[0095]
Production Example 11 .
To a solution of methyl 2-[(E)-2-phenylvinyl]isonicotinate in hydrochloric acid and MeOH was added platinum oxide, followed by stirring at room temperature for 8 hours under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite, and the filtrate was then concentrated under reduced pressure. To the residue were added an aqueous Na2C03 solution and xylene, and the aqueous layer was extracted with CHCI3. The organic layer was dried over MgS04 and then concentrated under reduced pressure to obtain methyl 2-(2-cyclohexylethyl)piperidine-4-carboxylate as a colorless oily substance.
[0096]
Production Example 12
To a solution of methyl 2-[(E)-2-phenylvinyl]isonicotinate in acetic acid was added platinum oxide, followed by stirring at room temperature for 8 hours under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite, and the filtrate was then concentrated under reduced pressure. To the residue were added an aqueous Na2C03 solution, and the EtOAc was extracted. The organic layer was dried over MgS04 and then concentrated under reduced pressure to obtain methyl 2-(2-phenylethyl)piperidine-4-carboxylate as a colorless oil.
[0097]
Production Example 13
To a suspension of methyl 2-(2-phenylethyl)piperidine-4-carboxylate in xylene were added ethyl bromoacetate and K2CO3, followed by heating under reflux for 8 hours. The reaction mixture was diluted with EtOAc, the organic layer was washed with water and brine in this order, dried over MgS04, and then filtered. The filtrate was concentrated under reduced pressure. To the residue was added hexane, and the insolubles were removed by filtration, followed by concentration under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl l-(2-ethoxy-2-oxoethyl)-2-(2-phenylethyl)piperidine-4-carboxylate as a pale brown oil.
[0098]
The compound of Production Example 13-1 shown in Tables below was synthesized in the same method as in Production Example 13, using the corresponding starting material.

[0099]
Production Example 14
A suspension of tBuOK in toluene was heated under reflux, and a solution of methyl l-(2-ethoxy-2-oxoethyl)-2-(2-phenylethyl)piperidine-4-carboxylate in toluene was added dropwise thereto, followed by stirring at the same temperature for 15 hours. After cooling to room temperature, concentrated hydrochloric acid was added thereto. The aqueous layer was separated and the organic layer was extracted with concentrated hydrochloric acid. The hydrochloric acid layer was heated under reflux for 15 hours. The reaction mixture was neutralized by addition of K2CO3 and the aqueous layer was extracted with CHCI3. The organic layer was dried and then concentrated under reduced pressure. The residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHChMeOK) to obtain 6-(2-phenylethyl)quinuclidin-3-one as a pale brown oil.
[0100]
The compound of Production Example 14-1 shown in Tables below was synthesized in the same method as in Production Example 14, using the corresponding starting material.
[0101]
Production Example 15
To a suspension of LAH in diethyl ether was added a solution of 6-(2-phenylethyl)quinuclidin-3-one in THF, followed by heating under reflux for 4 hours. To the reaction mixture was added Na2SO4*10H2O, followed by stirring at room temperature for overnight. The reaction mixture was filtered, and the filtrate was then concentrated under reduced pressure to obtain 6-(2-phenyIethyl)quinuclidin-3-oI as a colorless oil.
[0102]
The compounds of Production Examples 15-1 and 15-2 shown in Tables below were synthesized in the same method as in Production Example 15, using the corresponding starting materials.
[0103]
Production Example 16
To l-azatncyclo[3.3.1.1 ' ]decane-4-carbonitrile was added concentrated hydrochloric acid, followed by heating under reflux for 3 hours. The reaction liquid was
T 7
concentrated under reduced pressure to obtain l-azatricyclo[3.3.1.1 ' ]decane-4-carboxylic acid hydrochloride as a solid. It was used in the next reaction without purification.

[0104]
Production Example 17
To a solution of l-azatricyclo[3.3.1.11'1]decane-4-carboxylic acid hydrochloride in EtOH was added concentrated sulfuric acid, followed by heating under reflux for 18 hours. The reaction liquid was concentrated under reduced pressure and then diluted with EtOAc. The EtOAc layer was washed with an aqueous NaHCOa solution and brine in this order, dried over MgS04, and then concentrated under reduced pressure to obtain a yellow oily substance. This was purified by silica gel column chromatography (CHClsiMeOH) to obtain ethyl l-azatricyclo[3.3.1 .l1'1]decane-4-carboxylate as a yellow solid.
[0105]
Production Example 18
To a suspension of LAH in THF was added dropwise a solution of ethyl 1-azatricyclo[3.3.1.11' 1]decane-4-carboxylate in THF at 0 to 5°C, followed by stirring at the same temperature for 1 hour. Under ice-cooling, to the reaction mixture were added water, a 15% aqueous NaOH solution, and then water in this order. The insolubles were removed by filtration through Celite, followed by washing with EtOAc. The filtrate was dried over MgS04 and then concentrated under reduced pressure to obtain 1-azatricyclo[3.3.1.11'']decan-4-yl methanol as a colorless oily substance.
[0106]
The compounds of Production Examples 18-1 to 18-11 shown in Tables below were synthesized in the same method as in Production Example 18, using the corresponding starting materials.
[0107]
Production Example 19
To a solution of methyl 2-phenylthiophene-3-carboxylate and NCS in CHCI3 was added perchloric acid, followed by stirring at 50°C for overnight. To the reaction mixture was added water, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue obtained was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane:EtOAc) to obtain methyl 5-cliloro-2-phenylthiophene-3-carboxylate as a white solid.

[0108]
Production Example 20
To a solution of 60% oily NaH in MeOH was added ethyl 2-chloro-5-phenylthiazole-4-carboxylate, followed by stirring at 70°C for 1 hour. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was - washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHClsrMeOH) to obtain methyl 2-methoxy-5-phenylthiazole-4-carboxylate as a white solid.
[0109]
Production Example 21
To a solution of ethyl 2-methyl-5-phenyl-l,3-thiazole-4-carboxylate in carbon tetrachloride was added NBS, followed by heating under reflux. The reaction liquid was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc = from 8:1 to 6:1) to obtain ethyl 2-(bromomethyl)-5-phenyl-l,3-thiazole-4-carboxylate (21a) and ethyl 2-(dibromomethyl)-5-phenyl-l,3-thiazole-4-carboxylate (21b) as a yellow solid, respectively.
[0110]
The compound of Production Example 21-1 shown in Tables below was synthesized in the same method as in Production Example 21, using the corresponding starting material.
[0111]
Production Example 22
A suspension of ethyl 2-(bromomethyl)-5-phenyl-l,3-thiazole-4-carboxylate obtained in Production Example 21 and NaOAc in MeCN was heated under reflux. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=4:l) to obtain ethyl 2-(acetoxymethyl)-5-phenyl-l,3-thiazole-4-carboxylate as a pale yellow solid.
[0112]
Production Example 23
To a solution of ethyl 2-(acetoxymethyl)-5-phenyl-l,3- thiazole-4-carboxylate obtained in Production Example 22 in EtOH was added a 1 M aqueous NaOH solution,

followed by stirring at room temperature. The reaction liquid was neutralized by addition of 1 M hydrochloric acid, and extracted with CHCI3. The organic layer was washed with brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=l: 1) to obtain ethyl 2-(hydroxymethyl)-5-phenyl-l,3-thiazole-4-carboxylate as a pale yellow solid.
[0113]
Production Example 24
To a solution of ethyl 2-(hydroxymethyl)-5-phenyl-l,3-thiazole-4-carboxylate obtained in Production Example 23 in DCM was added bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor(R)) at 0°C, followed by stirring for 30 minutes. The reaction was stopped by adding aqueous NaHCOa to the reaction mixture, followed by extraction by addition of EtOAc. The organic layer was washed with brine, dried over Na2S04, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc) to obtain ethyl 2-(fluoromethyl)-5-phenyl-l,3-thiazole-4-carboxylate as a pale yellow oily substance.
[0114]
The compounds of Production Examples 24-1 and 24-2 shown in Tables below were synthesized in the same method as in Production Example 24, using the aldehyde compounds of Production Examples 25 and 25-1 as described below as starting materials.
[0115]
Production Example 25
To a solution of an aqueous solution of the dibromo product (21b) obtained in Production Example 21 in EtOH was added an aqueous silver nitrate solution, followed by heating under reflux for 15 minutes. To the reaction liquid was added 1 M hydrochloric acid, the solid precipitated was removed by filtration, and the filtrate was then extracted with CHCI3. The organic layer was washed with brine, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by siHca gel column chromatography (hexane:EtOAc) to obtain ethyl 2-formyl-5-phenyl-l,3-thiazole-4-carboxylate as a pale yellow solid.
[0116]
The compound of Production Examples 25-1 shown in Tables below was synthesized in the same method as in Production Example 25, using the corresponding starting material.

[0117]
Production Example 26
A solution of ethyl 3-chloro-2-oxo-3-phenylpropanoate and trifluorothioacetamide in MeCN was heated under reflux. To the reaction mixture was added an aqueous Na2C03 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried, and then concentrated vmder reduced pressure. Theresidue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 5-phenyl-2-(trifluoromethyl)-l,3-thiazole-4-carboxylate as a white solid.
[0118]
Production Example 27
To a suspension of methyl (2-bromo-4-methylphenyl)carbamate, and quinuclidin-3-ol and MS4A in toluene was added 60% oily NaH, followed by heating under reflux for 36 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCI3: MeOH) to obtain l-azabicyclo[2.2.2]oct-3-yl 2-bromo-4-methylphenyl)carbamate as a white solid.
[0119]
Production Example 28
To a suspension of ethyl 5-bromothiazole-4-carboxylate, l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole and Pd(PPh3)4 in dioxane was added a 2 M aqueous Na2C03 solution, followed by heating under reflux for 4 hours. To the reaction mixture was added water and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgS04 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:EtOAc) to obtain ethyl 5-(1-methyl-IH-pyrazol-4-yl)-l ,3-thiazole-4-carboxylate as a brown solid.
[0120]
Production Example 29
Sodium was portion wise added to EtOH at 60°C under stirring. EtOH was removed by evaporation, and diethyl ether was added thereto, and ethyl 2,2-dichloro-3-oxobutanate was then added dropwise thereto at 0°C. To the reaction mixture was added dropwise 2,6-difluorobenzaldehyde, followed by stirring at 0°C for 30 minutes, and then heating under reflux for 4 hours. To the reaction mixture was added ice-water, followed by neutralization with 2 M HCl and extraction with EtOAc. The organic layer was washed

with brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc = from 85:15 to 6:4) to obtain ethyl 2-chloro-3-(2,6-difluorophenyl)oxirane-2-carboxylate as a yellow oil.
[0121]
Production Example 30
To a solution of ethyl 2-chloro-3-(2,6-difluorophenyl)oxirane-2-carboxylate in EtOH was added thiourea, followed by heating under reflux for 4 hours. To the reaction mixture was added ice-water, followed by addition of K2CO3 to make it basic. The solid precipitated was collected by filtration and washed with water to obtain ethyl 2-amino-5-(2,6-difluorophenyl)-l,3-thiazole-4-carboxylate as a yellow solid.
[0122]
Production Example 31
To a solution of ethyl 2-amino-5-(2,6-difluorophenyl)-l,3-thiazole-4-carboxylate in THF was slowly added dropwise tert-butyl nitrate under heating under reflux. After completion of dropwise addition, it was further stirred at the same temperature for 4 hours. The reaction mixture was cooled to room temperature, followed by addition of water and extraction with EtOAc. The organic layer was washed with brine, dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc=9:1-7:3) to obtain ethyl 5-(2,6-difluorophenyl)-l,3-thiazole-4-carboxylate as a yellow oily substance.
[0123]
Production Example 32
To a mixed solution of ethyl 2-amino-5-phenyl-l,3-thiazole-4-carboxylate, acetic acid, and sulfuric acid was slowly added an aqueous NaN02 solution (5 mL) at 0°C, followed by stirring at the same temperature for 1 hour. This solution was added to an aqueous solution (40 mL) containing CuCN, NaCN, and NaHCOs (30 g) over 30 minutes, followed by stirring at the same temperature for 1 hour. EtOAc was added thereto, and the insolubles were filtered through Celite. The filtrate was extracted with EtOAc, the organic layer was dried, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc = from 5:1 to 3:1 to 2:1) to obtain ethyl 2-cyano-5-phenyl-l,3-thiazole-4-carboxylate as a yellow solid.

[0124]
Production Example 33
To a solution of ethyl 2-cyano-5-phenyl-1,3-thiazole-4-carboxylate in THF was added a 1 M aqueous KOH solution, followed by stirring at room temperature for 12 hours. To the reaction mixture was added 1 M hydrochloric acid, and the solid precipitated was collected by filtration to obtain 2-carbamoyl-5-phenyl-1,3-thiazole-4-carboxylic acid as a -; pale yellow solid.
[0125]
Production Example 34
To a solution of ethyl 5-bromo-l,3-thiazole-4-carboxylate in toluene were added 2-(tributylstannyl)-l,3-thiazole and PdCl2(PPh3)2, followed by heating under reflux for 6 hours. Water was added thereto and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 2,5'-bi-l,3-thiazole-4'-carboxylate as a yellow solid.
[0126]
The compound of Production Examples 34-1 shown in Tables below was synthesized in the same method as in Production Example 34, using the corresponding starting material.
[0127]
Production Example 35
To a solution of ethyl 2-amino-5-phenylthiazole-4-carboxylate in THF were added DIBOC, DMAP, and TEA, followed by stirring at room temperature. To the reaction mixture was added 1 M hydrochloric acid, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 2-[(tert-butoxycarbonyl)amino]-5-phenyl-l,3-thiazole-4-carboxylate as a yellowish white amorphous substance.
[0128]
Production Example 36
To a solution of ethyl 2-[(tert-butoxycarbonyl)amino]-5-phenyl-l,3-thiazole-4-carboxylate in THF were added EtOH, PPhs, and DEAD, followed by stirring at room

temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 2-[(tert-butoxycarbonyl) (ethyl)amino]-5-phenyl-l,3-thiazole-4-carboxylate as a yellow oil.
[0129]
The compounds of Production Examples 36-1 and 36-2 shown in Tables below were synthesized in the same method as in Production Example 36, using the corresponding starting materials.
[0130]
Production Example 37
To a suspension of 60% oily NaH in THF was added diethylphosphonoethyl acetate under ice-cooling. The reaction mixture was stirred for 30 minutes under ice-cooling, and a mixture of quinuclidin-3-one hydrochloride and THF was then added thereto under ice-cooling, followed by stirring at room temperature for 3 hours, and then stirring at 60°C for 3 hours. The reaction mixture was cooled to room temperature, followed by addition of water and extraction with EtOAc. The organic layer was extracted with 1 M hydrochloric acid. The aqueous layer was basified with a 6 M aqueous NaOH solution and extracted with CHCI3. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure to obtain a mixture of ethyl (2E)-1-azabicyclo[2.2.2]oct-3-ylidene acetate and ethyl (2Z)-l-azabicyclo[2.2.2]oct-3-ylidene acetate as a colorless oil.
[0131]
Production Example 38
To quinuclidin-4-yl acetonitrile (500 mg) that had been synthesized by the method as described in Published Japanese translation of PCT application, No. 2001-521033 was added concentrated hydrochloric acid (3 mL), followed by heating under reflux. The reaction mixture was concentrated under reduced pressure, toluene was added, followed by concentration under reduced pressure. To the residue were added EtOH (10 mL) and concentrated sulfuric acid (1 mL), followed by stirring at 100°C. The reaction mixture was concentrated under reduced pressure, neutralized by addition of a 1 M aqueous NaOH solution, and extracted with CHCI3. The organic layer was dried over MgS04 and then concentrated under reduced pressure to obtain ethyl quinuclidin-4-yl acetate (500 mg) as a yellow oily substance.

[0132]
Production Example 39
To l-benzyl-5-hydroxy-l-azoniabicyclo[3.2.Ijoctane 4-methylbenzenesulfonate (800 mg) that had been synthesized by the method as described in Published Japanese Patent AppUcation No. 63-290878 was added a mixture of EtOH (8 mL), 10% Pd/Carbon with a 50% hydration (200-mg), and ammonium formate (500 mg), followed by heating under reflux. The reaction mixture was alkalified with addition of a 1 M aqueous NaOH solution, and extracted with a mixed solvent (CHCl3:MeOH=9:1). The organic layer was dried over MgS04 and then concentrated under reduced pressure to obtain 1-azabicyclo[3.2.1]octan-5-ol (180 mg) as a colorless oily substance.
[0133]
The compound of Production Example 39-1 in Tables below was prepared in the same method as in Production Example 39, using Production Example 44 to be described below as a starting material.
[0134]
Production Example 40
In an ice-bath, to DIPA (4.1 mL) was added dropwise a 1 M solution of n-butyl lithium in hexane (10.1 mL). The reaction mixture was diluted with diethyl ether (10 mL), followed by stirring for 20 minutes. Next, the reaction mixture was stirred at -78°C, and a solution of ethyl 1-benzyl piperidine-3-carboxylate (6.0 g) in diethyl ether (20 mL) was added dropwise thereto, followed by stirring at -50°C for 15 minutes. Next, after addition of 1,3-dibromopropane (2.8 mL) at 70°C, it was slowly returned to room temperature. Next, it was heated under reflux for 30 minutes. The reaction mixture was cooled, diluted with water, and extracted with diethyl ether. The organic layer was dried over MgS04 and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl l-benzyl-(3-bromopropyl)piperidine-3-carboxylate (1.08 g) as a colorless oily substance.
[0135]
Production Example 41
A mixture of ethyl l-benzyl-(3-bromopropyl)piperidine-3-carboxylate (1.08 g), toluene (10 mL), and CHCI3 (2 mL) was heated under reflux for 2 hours. It was cooled to room temperature and then concentrated under reduced pressure. To the residue was added

EtOAc, and the solid was collected by filtration to obtain l-benzyl-5-(ethoxycarbonyl)-l-azoniabicyclo[3.3.1]nonane bromide (942 mg) as a colorless solid.
[0136]
Production Example 42
A mixture of l-benzyl-5-(ethoxycarbonyl)-l-azomabicyclo[3.3.1]nonane bromide (932 mg), 10% Pd/Carbon with a 50% hydration (25 mg), and EtOH-(15 mL) was stirred at room temperature under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to obtain a colorless solid. To this solid were added CHCI3 and a saturated aqueous NaHCOs solution, and the organic layer was separated. Furthermore, the aqueous layer was extracted with CHCI3. The organic layer was collected, dried over MgS04, and then concentrated under reduced pressure to obtain ethyl l-azabicyclo[3.3.1]nonane-5-carboxylate (376 mg).
[0137]
The compound of Production Example 42-1 in Tables below was prepared in the same method as in Production Example 42, using Production Example 56 to be described below as a starting material.
[0138]
Production Example 42-2
To a solution of l-benzyl-l-azoniabicyclo[2.2.1]heptane-4-carboxylate (3.25 g) in MeOH was added 10% Pd carbon with a 50% hydration (650 mg), followed by stirring at room temperature for 5 hours under a hydrogen atmosphere of 3 atm. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in MeOH and added with sulfuric acid (3 mL), followed by heating under reflux for 1 hour. The reaction mixture was neutralized with an aqueous K2CO3 solution and extracted with EtOAc. The organic layer was washed with water and brine m this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCI3: MeOH: 28% aqueous ammonia) to obtain methyl 1-azabicyclo[2.2.1]heptane-4-carboxylate (890 mg) as a colorless oily substance.
[0139]
Production Example 43
To a solution of DIPA (3.1 mL) in THF (30 mL) was added dropwise a 2.6 M solution (8.6 mL) of n-butyl lithium in hexane at -70°C. After stirring at 0°C for 40 minutes, EtOAc (2.3 mL) was added dropwise thereto at -70°C, followed by stirring for 5

minutes. A solution of 1 -benzylazepan-4-one (3.6 g) in THF (10 mL) was added dropwise thereto, followed by stirring for 40 minutes. To the reaction mixture was added a sattirated aqueous NH4CI solution, followed by addition of water and extraction with EtOAc. The organic layer was washed with brine, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH: aqueous ammonia) to obtain ethyl (l-benzyl-4-hydroxyazepan-4-yl)acetate (5.0 g) as a yellow oily-substance.
[0140]
The compound of Production Example 43-1 shown in Tables below was synthesized in the same method as in Production Example 43, using the corresponding starting material.
[0141]
Production Example 44
To a solution of l-benzyl-4-(2-hydroxyethyl)azepan-4-ol (2.0 g) in DCM (20 mL) were added pyridine (4 mL) and p-toluenesulfonylchloride (1.68 g) at 0°C, followed by stirring at 0°C for 3 hours and then at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, alkalified by addition of a saturated aqueous NaHCOa solution, and then extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure to obtain a pale red solid. EtOAc was added thereto and the solid was pulverized and collected by filtration to obtain l-benzyl-5-hydroxy-l-azoniabicyclo[3.2.2]nonane4-methylbenzenesulfonate (1.85 g) as a pale red powder.
[0142]
Production Example 45
To a solution of tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-hydroxypyrrolidine-l-carboxylate (6.35 g) in THF (100 mL) was added LiBH4 (1.01 g), followed by heating under reflux for 4 hours. The reaction mixture was cooled to room temperature, then added with water, and extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure to obtain tert-butyl 3-hydroxy-3-(2-hydroxyethyl)pyrrolidine-l-carboxylate (4.72 g) as a colorless oily substance.

[0143]
Production Example 46
Under cooling with a cryogen (-10°C to 0°C), to a solution of tert-butyl 3-hydroxy-3-(2-hydroxyethyl)pyrrolidine-l-carboxylate (4.72 g) in pyridine (10 mL) was added p-toluene sulfonylchloride (1.68 g), followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, and 1 M hydrochloric acid was added thereto, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain tert-butyl 3-hydroxy-3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)pyrrolidine-l-carboxylate (3.25 g) as a colorless oily substance.
[0144]
Production Example 47
To a solution of tert-butyl 3-hydroxy-3-(2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)pyrrolidine-l-carboxylate (3.24 g) in EtOH was added 4 M HCl/dioxane, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, followed by addition of an aqueous NaaCOs solution and extraction with EtOAc. The aqueous layer was washed with EtOAc, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH:aqueous ammonia=7:3:0.3) to obtain 1-azabicyclo[2.2.1]heptan-4-ol (950 mg) as a colorless solid.
[0145]
Production Example 48
To DIPA (3.6 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (8.93 mL) at -78°C, followed by stirring for 30 minutes. To the reaction mixture was added ethyl l-benzyl-pyrrolidine-3-carboxylate (5.0 g), followed by stirring for 30 minutes. To the reaction mixture was added dropwise a solution of 1,2-dibromoethane (6.05 g) in THF, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The aqueous layer was concentrated under reduced pressure, and to the residue was added EtOH, followed by stirring at room temperature for 30 minutes. The insolubles were removed by filtration and the filtrate was concentrated under reduced pressure. To the residue was added EtOH, followed by stirring at room temperature for 10 minutes. The

insolubles \\ere removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 1-benzyl-l-azoniabicyclo[2.2.l]heptane-4-carboxylate (3.25 g) as a colorless solid.
[0146]
Production Example 49
To a solution of ethyl 2-methyl-l,3-thiazole-4-carboxylate (14.53 g) in MeCN (150 mL) was added NBS (22.66 g), followed by heating under reflux for 3 hours. To the reaction mixture was added NBS (7.55 g), followed by heating under reflux for 2 hours. Under ice-cooling, to the reaction mixture was added a saturated aqueous NaHCOs solution, followed by stirring for 5 minutes, and then extraction with EtOAc. The organic layer was dried over MgS04 and then concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane:EtOAc = from 100:0 to 60:40) to obtain ethyl 5-bromo-2-methyl-l,3-thiazole-4-carboxylate (8.52 g) as a yellow solid.
[0147]
Production Example 50
Amixture of l-azabicyclo[2.2.1]heptan-3-one (Journal of Medicinal Chemistry, 1990, 33, pp. 2690-2697), hydrochloride (350 mg), platinum oxide (35 mg), and EtOH (5 mL) was stirred at room temperature under a hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain l-azabicyclo[2.2.1]heptan-3-ol hydrochloride as a pale brown solid.
[0148]
The compounds of Production Examples 50-1 and 50-2 sho\\'n in Tables below were synthesized in the same method as in Production Example 50, using the corresponding starting materials.
[0149]
Production Example 51
Amixture of l-azabicyclo[3.3.1]nonane-4-carbonitrile (US 5834499, REFERENCE EXAMPLE 44) (1.7 g) and concentrated hydrochloric acid (10 mL) was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. To the residue were added EtOH (10 mL) and concentrated sulfuric acid (2 drops), followed by heating under reflux for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was added with CHCI3 and a 10% aqueous K2CO3 solution and partitioned. The aqueous layer was extracted with CHCI3, and the organic layer was then

combined, washed with brine, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain ethyl l-azabicyclo[3.3.1]nonane-4-carboxylate (2.2 g) as a pale brown oily substance.
[0150]
The compound of Production Example 51-1 shown in Tables below was >? synthesized in the same method as in Production Example 51, using the corresponding./ starting material.
[0151]
Production Example 52
To a mixture of a hydrochloride (2.3 g) of l-azabicyclo[3.2.1]octan-4-one (Journal of Medicinal Chemistry, 1993, 36, pp. 683-689), dimethoxyethane (23 mL), and tBuOH (4.6 mL) was added tBuOK (1.60 g), followed by stirring at room temperature for 1 hour. To the reaction mixture was added p-toluenesulfonylmethyl isocyanide (3.06 g), followed by stirring in the ice bath. To the reaction mixture was added tBuOK (3.19 g) in two divided portions, followed by stirring for 30 minutes, and then stirring at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction with CHCI3. The organic layer was washed with water and brine in this order, and then extracted with 1 M hydrochloric acid. The aqueous layer was washed with EtOAc, and concentrated under reduced pressure to obtain a pale brown solid (1.9 g). This was added with concentrated hydrochloric acid (10 mL), heated under reflux for 4 hours, cooled to room temperature, and then concentrated under reduced pressure. To the residue were added EtOH (20 mL) and concentrated sulfuric acid (2 drops), followed by heating under reflux for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure, and the residue was neutralized by addition with a 1 M aqueous NaOH solution, and extracted with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCbrMeOHiaqueous ammonia) to obtain ethyl 1-azabicyclo[3.2.1]octane-4-carboxylate (850 mg) as a colorless oily substance.
[0152]
The compound of Production Example 52-1 shown in Tables below was synthesized in the same method as in Production Example 52, using the l-benzylazepan-4-one.

[0153]
Production Example 53
To a mixture of a hydrochloride (21.63 g) of l-azabicyclo[3.2.1]octan-6-one (Joumal of Medicinal Chemistry, 1993, 36, pp. 683-689), dimethoxyethane (210 mL), and tBuOH (43 mL) was added tBuOK (15 g) under ice-cooling, followed by stirring at room temperature for 40 minutes. Next, under ice-cooling; p-toluenesulfonylmethyl isocyanide (28.74 g) was added thereto, to which tBuOK (30 g) was added in two divided portions, followed by stirring for 30 minutes, and stirring at room temperature for 4 hours. To the reaction mixture was added water, followed by extraction with CHCI3. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCbiMeOHiaqueous ammonia) to obtain a low-polarity product (6.17 g) and a high-polarity product (4.9 g) of l-azabicyclo[3.2.1]octane-6-carbonitrile as a yellow oily substance and a diluted brown solid, respectively.
[0154]
Production Example 54
Amixture of the high-polarity product (1.44 g) of 1-azabicyclo [3.2.1 ]octane-6-carbonitrile obtained in Production Example 53 and concentrated hydrochloric acid (15 mL) was heated under reflux for 4 hours, cooled to room temperature, and then concentrated under reduced pressure. Next, to the residue was added MeOH, followed by concentration under reduced pressure. To the residue were added MeOH (25 mL) and sulfuric acid (0.67 mL), followed by heating under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure and solidified to dry, and to the residue were added CHCI3 and a 1 M aqueous K2CO3 solution. The aqueous layer was extracted with CHCI3, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain methyl l-azabicyclo[3.2.1]octane-6-carboxylate (657 mg) as a colorless oily substance.
[0155]
The compound of Production Example 54-1 shown in Tables below was synthesized in the same method as in Production Example 54, using the corresponding starting material.

[0156]
Production Example 55
To DIPA (3.22 mL) was added drop wise a 2.64 M solution of n-butyl lithium in hexane (7.97 mL) at -78°C, followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzylazepane-4-carboxylate (5.0 g), followed by stirring for 30 minutes. Next, a solution of l*i)romo-2-chloroethane (3.02 g) in THF was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHClsiMeOHiaqueous ammonia). Desired fractions were collected, and concentrated under reduced pressure. After concentration under reduced pressure, to the residue, a part of which was solidified, was added EtOAc, followed by purification by silica gel column chromatography (EtOAc) to obtain ethyl 1 -benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.11 g) as a colorless oily substance.
[0157]
Production Example 56
A solution of ethyl l-benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.1 g) in MeCN (200 mL) was stirred at 40°C for 10 hours. The reaction mixture was concentrated under reduced pressure to obtain l-benzyl-5-(ethoxycarbonyl)-l-azoniabicyclo[3.2.2]nonane chloride (4.1 g) as a colorless oily substance.
[0158]
Production Example 57
The compounds of Production Examples 57 to 57-3 shown in Tables below were synthesized in the same method as in Example 6, using the corresponding starting material.

[0159] [Table 4]

Pr

Structure

data

Pr

Structure

data

d CH,

ESI (+): 283

1-1

H3C1CH3
Br Vq
0 1CH3

ESI (+): 301

Ck 1S
■1.
1-2

O CH,

ESI (+): 312 336
ESI (+): 281

3-1

d 1CH.

ESI (+): 290
ESI (+): 262 501

3-2

ESI (+): 283

3-3

0 1CH3

ESI (+): 272

3-4

ESI (+): 297

3-5

0 1CH3

ESI (+): 266

3-6

0 1CH3

ESI (+): 292

3-7

ESI (+): 281

3-8

ESI (+): 286

3-9

0 1CH3

ESI (+): 308

[0160] [Table 5]

Pr

Structure

data

Pr

Structure

data

3-10

ESI (+):
257

3-11

ESI (+): 277

3-12

ESI (+): 270

3-13

ESI (+): 302

3-14

ESI (+): 270

3-15

ESI (+):
257

3-16

ESI (+): 302

3-17

ESI (+): 296

3-18

ESI (+): 270

3-19

ESI (+): 188

3-20

0 1CH3

ESI (+): 308

3-21

ESI (+): 184

3-22

ESI (+): 290

3-23

ESI (+): 184

[0161] Table 6]

Pr

Structure

data

Pr

Structure

data

3-24

ESI (+): 304

ESI (+): 267

4-1

ESI (+): 264

4-2

ESI (+): 255

4-3

ESI (+): 264

4-4

ESI (+): 269

4-5

ESI(-): 238

4-6

ESI (+): 261

1
4-7

ESI(-): 236

4-8

ESI (+): 255

F1,
N
4-9

ESI(-):
254

4-10

ESI(-): 204

4-11

ESI(-): 256

4-12

ESI (+): 264

[0162] [Table 7]

Pr

Structure

data

Pr

Structure

data

4-13

ESI(-): 218

4-14

ESI(+): 264

4-15

ESI(-): 238

4-16

ESI(-):
222

4-17

ESI (+): 234

4-18

ESI (+): 246

F,C- 'S
4-19

ESI(-):
244

4-20

ESI (+): 296

ESI (+}: 262

5-1

ESI (+): 306, 308

5-2

"'I

ESI (+): 258

5-3

ESI(-): 229

5-4

ESI(-): 205

5-5

ESI(-): 256

[0163] [Table 8]

Pr

Structure

data

Pr

Structure

data

5-6

ESI (+): 242

5-7

ESI(-): 208

CF,
5-8

ESI(-):
272

5-9

ESI(-): 247

5-10

ESI(-): 240

5-11

ESI(-):
272 274

i
5-12

ESI (+): 280

5-13

ESI(-): 205

5-14

ESI(-): 220

5-15

VOH O

ESI (+): 235

5-16

ESI (+): 264

5-17

VoH
o

ESI (+): 230

5-18

ESI(-): 236

5-19

ESI (+): 343

[0164] Table 9]

Pr

Structure

data

Pr

Structure

data

5-20

ESI (+): 371

5-21

ESI (+): 461

1H
CI
k N-'(
5-22

"iSi-CH. °'

ESI (+): 477

5-23

ESI (+): 312

ESI (+): 216

XoB
Br H

SB

7-1
7-3

1o-B
Bi1 H
ir H

ESI (+): 331, 333
ESI (+): 345

7-2
7-4

H
Br 1

ESI (+): 343, 345
ESI (+): 339, 341

H 3
7-5

Br 1

ESI (+): 343

ESI (+): 298

[0165] [Table 10]

Pr

Structure

data

Pr

Structure

data

H

ESI (+): 190

10

0.10.

ESI (+): 240

11

0.10

ESI (+): 254

12

0101

ESI (+): 248

13

010

ESI (+): 334

13-1

O.v1O,

ESI (+): 340

14

.1

ESI (+): 230

14-1

ESI (+): 236

15

ESI (+): 232

15-1

HO

ESI (+): 238

15-2

HO

ESI (+): 142

16

HO.
1

...1
HOI

ESI (+): 182

hJ.
17

HaC1O .

ESI (+): 210

18

HO

X>-"

ESI (+): 168

[0166] [Table 11]

Pr

Structure

data

Pr

Structure

data

HO1 >k M
18-1

Ho11N

ESI (+): 154

18-2

ESI (+): 142

N
HO
18-3

HO

ESI (+): 156

18-4

ESI (+): 156

IN-
N
HO
N
HO
N
18-5
18-7
18-9

HO111N

ESI (+): 128
ESI (+): 142
SB

18-6
18-8
18-10

HO

HO
HO1AO

ESI (+): 156
ESI (+): 142
ESI (+): 156

CI
18-11

1OH 11
HO1-1

ESI (+): 250

19

O OH,

SB

20

0 1CH,

ESI (+): 272

21a

011H3

ESI (+): 348, 350

21b

Br

ESI (+): 427

21-1

ESI (+): 461

[0167] [Table 12] Pr

Structure

data

Pr

Structure

data

1CH,
22
24

0 "-CHs

ESI (+): 328
ESI (+): 288

23
24-1


a "-cHs

a °"1H3

ESI
(+): 286
ESI 306

1CH,
24-2

ESI (+): 340

25

HrO
J1C

SB

25-1

SB

26

ESI
324

l.l„1
■CH,
NO H
27

HsC1
Br

ESI (+): 399, 341

28

0 1H3

ESI
(+): 260

H,N1S
29

&f1'

XH,

ESI (+): 285

30

ESI
307

[0168] [Table 13]

Pr

Structure

data

Pr

Structure

data

1-CH,
31

ESI (+) 292

32

ESI (+): 281

If*
33

ESI(-): 247

34

v-CH,

ESI (+): 263

H3
1CH,
34-1

'1

CH,

ESI (+): 258

35

ESI (+): 371

1CH,

36

ESI (+): 399

36-1

ESI (+): 489

36-2

ESI (+): 505

37

Hn-O-1-11

ESI (+): 196

N

38

H3C' "O

ESI (+): 198

39

HO

ESI (+): 128

[0169] [Table 14] Pr

Structure

data

Pr

Structure

data

N
H3C10
39-1

HO

ESI (+): 142

40

ESI (+): 368, 370

H3C10
41

H,C1oA(j Bf-

ESl (+): 288

42

O

ESI (+): 198

,0
42-1

HsC1'

ESI (+): 198

42-2

H3C

/

ESI (+): 156

1

43
44

1CH3 010
Xo
°'l
HO \-y

CH,

ESI (+): 292
ESI (+): 232

43-1
45

1CH3
O1VN1O%
HO
m
.OH <=> PH O
HO

ESI (+): 296
ESI (+): 254

HO1-1

N
46

HO

ESI (+): 408

47

HO

ESI (+): 114

[0170] [Table 15]

Pr

Structure

data

Pr

Structure

data

N
O.
48
50

HO'1"1 HCI

ESI (+): 232, 254
ESI (+): 114

49
50-1

H3C1S B,
d '1CH3
HO HCI

ESI (+): 272, 274
ESI (+): 128

.JV
50-2

HO1-11 HCI

ESI (+): 128

51

T)
H,C1 O

ESI (+): 198

HjC1O.
51-1

ESI (+): 184

52

HaC1O1iO

ESI (+): 184

Kl
52-1

H3C.

o

ESI(+) 262

53

if

SB

54

HsC1/1

SB

55

CI
.rO

ESI (+): 324

[0171] Table 16]

Pr

Structure

data

Pr

Structure

data

CI
56

H3C-

ESI (+): 288

57

H3CPH3 )=N O

ESI (+): 577

57-1

P
)=N

ESI (+): 593

57-2

H,C pHj O, ' >1CH3
HN
K--°1

ESI (+): 459

0"%
57-3

ESI (+): 487

For the sake of saving space in the paper, the descriptions of SB (shown below) in Tables of Production Examples above are denoted as follows. [0172] [Table 17]

Pr data
7 NMR:1.3-1.37(1 H,m), 1.46-1.53(1 H,m), 1.57-1.65(1 H,m), 1.76(1H,brs), 1.94(1 H.brs), 2.55-2.74(5H,m), 3.12(1H,dd,J=8.3,14.4Hz), 4.63-4.67(1 H,m), 7.12(1 H,d,J=5.7Hz), 7.55(1 H,d,J=5.7Hz), 9.06(1 H.brs)
18-9 NMR(CDCl3):1.33-1.41(1H,m), 1.65-1.79(3H,m), 2.09-2.13(1H,m), 2.36-2.46(1 H,m), 2.52(1 H,ddd,J=2.0,6.8,12.4Hz), 2.74-2.82(4H,m), 2.78-2.95(1 H,m), 3.16(1H,dd,J=10.4,12.4Hz), 3.81-3.99(2H,m)
19 NMR:3.67(3H,s), 7.41-7.49(5H,m), 7.65(1 H,d,J=5.4Hz)
25 NMR(CDCl3):1.27(3H,t,J=7.DHz), 4.36(2H,q,J=7.0Hz), 7.39-7.55(5H,m), 10.03(1H,s).
25-1 NMR:1.28(3H,t,J=7.2Hz), 4.36(2H,q,J=7.2Hz), 7.34-7.54(4H,m), 10.03(1 H,s)
53
Low-polarity product NMR(CDCl3)1.47-1.80(4H,m), 2.65-2.67(1 H,m), 2.85-3.01 (5H,m), 3.25(1 H,dd,J=5.2,12.8Hz), 3.38(1 H,ddd,J=2.0,8.4,12.8Hz), ESI(+):137
53
High-polarity product NMR(CDCl3): 1.48-1.54(1 H,m), 1.78-2.01 (3H,m), 2.47-2.50(1 H,m), 2.69-2.74(1H,m), 2.87-3.04(4H,m), 3.22(1H,ddd,J=2.4,5.2,13.0H2), 3.41(1H,dd,J=10.8,13.0Hz), ESI(+):137
54 NMR(CDCl3):1.26-1.30(1H,m), 1.67-1.85(3H,m), 2.44-2.47(1 H,m), 2.78-2.82(1 H,m), 2.87-2.92(3H,m), ESI(+)r170
[0173]
Example 1
To a solution of l-azabicyclo[2.2.2]oct-4-yl (2-phenyl-3-thienyI)carbamate (120 mg) hi DCM (10 mL) was added MCPBA (90 mg) portion wise under ice-cooling. After stirring for 30 mmutes, the reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CHClsiMeOH = from 20:1 to 10:1, subjected to liquid separation by 28% aqueous ammonia) to obtain 1-oxide-1-azabicyclo[2.2.2]oct-4-yl(2-phenyl-3-thienyl)carbamate (105 mg) as a colorless amorphous substance.

[0174]
Example 2
To a solution of 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-amine (110 mg) in pyridine (2 mL) was added (3R)-quinuclidin-3-ol and (3R)-l-azabicyclo[2.2.2]octa-3-yl chlorocarbonate hydrochloride (231 mg) synthesized from triphosgene, followed by stirring at room temperature for 30 minutes, and then stirring at 80°C for 15 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, then dried over MgS04, and concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCbiMeOH) to obtain a colorless oily substance (135 mg). This was dissolved in EtOH, and fiamaric acid (38 mg) was added thereto. The crystal precipitated was collected by filtration to obtain (3R)-1-azabicyclo[2.2.2]oct-3-yl (2-phenyl-5,6-dihydro-4H-cyclopenta[b]thien-3-yl)carbamate fumarate (103 mg) as a white sohd.
[0175]
Example 3
To a solution of triphosgene (362 mg) in DCM (3 mL) was added pyridine (162 mg) at 0°C, and subsequently a solution of cis-2-phenylcyclohexyl amine (300 mg) in DCM (3 mL) was added dropwise thereto, followed by stirring at room temperature for 40 minutes. To a suspension of 60% oily NaH (110 mg) in THF (1.5 mL) was added 1-azabicyclo[2.2.2]oct-3-yl methanol (363 mg) at 0°C, followed by stirring at room temperature for 20 minutes, and to the mixture was added dropwise the above-described DCM solution at 0°C, followed by stirring at 80°C for 1 hour. To the reaction mixture was added a saturated aqueous NaHCOa solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH:28% aqueous ammonia=80:10:l) to obtain a colorless oily substance (100 mg). The oily substance obtained was dissolved in a mixed solvent (EtOAc:EtOH=l: 1) and fumaric acid (32 mg) was added thereto. The mixture was concentrated under reduced pressure, a mixed solvent (EtOAc:IPE) was then added thereto, and the solid precipitated was collected by filtration to obtain l-azabicyclo[2.2.2]oct-3-ylmethyl rel-[(lR,2R)-2-phenylcyclohexyl] carbamate fumarate (103 mg) as a colorless solid.

[0176]
Example 4
To a solution of l-azabicyclo[2.2.2]oct-3-yImethyl (2-phenyI-3-thienyl)carbamate (100 mg) in EtOAc(2 mL) was added iodomethane (36 1iL) at room temperature, followed by stirring for overnight. The reaction mixture was filtered, then concentrated under reduced pressure, and freeze-dried to obtain l-methyl-3-({[(2-phenyl-3-thienyl)carbamoyl]oxy}methyl)-l-azoniabicyclo[2.2.2]octane iodide (88 mg) as a yellow amorphous substance.
[0177]
Example 5
A solution of a mixture of l-azabicyclo[2.2.2]oct-3-yl(2-bromo-3-thienyl)carbamate (295 mg), Pd(PPh3)4 (103 mg), 4-fluorophenyl boric acid (187 mg), and 1,4-dioxane (3 mL) was added a 2 M aqueous Na2C03 solution (0.89 mL), followed by stirring under heating at 90°C for 5 hours. The reaction mixture was diluted with water, and extracted with EtO Ac. The organic layer was washed with water, and adjusted into pH=l with 1 M hydrochloric acid. Next, the aqueous layer was washed with EtOAc and adjusted to pH=10 with an aqueous NaOH solution, and the aqueous layer was extracted with CHCI3. The organic layer was dried over MgS04, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (manufactured by Fuji Silysia Chemical Ltd., YAMAZEN YFLC WPrep2XY, CHCI3). The collected fraction was concentrated under reduced pressure and the oil obtained was dissolved in EtO Ac, followed by addition of 4 M HCl/EtOAc, concentration under reduced pressure, and solidification to dry. To the residue obtained were added EtOH and EtOAc for crystallization to obtain l-azabicyclo[2.2.2]oct-3-yl [2-(4-fluorophenyl)-3-thienyl]carbamate hydrochloride (135 mg) as a white solid.
[0178]
Example 6
To a solution of 5-phenyl-l,3-thiazole-4-carboxylic acid (250 mg) in toluene (6 mL) were added dropwise TEA (221 fiL) and DPPA (315 \iL) at room temperature, followed by stirring at the same temperature for 40 minutes. Next, after stirring at 90°C for 40 minutes, a solution of l-azabicyclo[2.2.2]oct-4-yl methanol (241 mg) in DMF (2 niL)/toluene (2 mL) was added thereto, followed by heating under reflux for 2 hours. To the reaction liquid was added a saturated aqueous NaHC03 solution, followed by extraction v1th EtOAc. The organic layer was washed with water and brine in this order, dried over

MgS04, and then filtered, and the filtrate was concentrated under reduced presswe. The residue was purified by medium-pressure preparative liquid chromatography (YAM'\ZEN YFLC WPreplXY, eluent; CHCl3:MeOH:28% aqueous ammonia=80:10:l) to obtain a yellow oily substance. To this solution in EtOH (2 mL) was added 4 M HCl/EtOAc (1 mL) at room temperature, followed by stirring, and the solvent was concentrated under reduced pressure. The residue obtained was recrystallized firom EtOH/ether to obtain 1 -azabicyclo[2.2.2]oct-4-ylmethyl(5-phenyl-l ,3-thiazol-4-yl)carbamate hydrochloride (145 mg) as a yellow solid.
[0179]
Example 7
To a solution of l-azabicyclo[2.2.2]oct-4-ylmethyl (2-carbamoyl-5-phenyl-l,3 thiazol-4-yl)carbamate (100 mg) in DMF (5 mL) was added phosphorous oxychloride (48 |j,L) at 0°C, followed by stirring for 1 hour. To the reaction mixture was added EtOAc, followed by dilution, addition of an aqueous NaHCOa solution, and extraction with EtOAc. The organic layer was washed with water and brine in this order, then dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH:28% aqueous ammonia=9:l :0.1), and the brown oily substance obtained was dissolved in EtOAc, followed by addition of 4 M HCl/EtOAc and stirring. The mixture was concentrated under reduced pressure, EtOAc was added thereto, and the solid precipitated was collected by filtration to obtain l-azabicyclo[2.2.2]oct-4-ylmethyl (2-cyano-5-phenyl-l,3-thiazol-4-yl)carbamate hydrochloride (33 mg) as a pale brown solid.
[0180]
Example 8
l-azabicyclo[2.2.2]oct-3-ylmethyl [5-(4-fluorophenyl)-l,3-thiazol-4-yl]carbamate (120 mg) was subjected to HPLC (CHIRALPAK AD-H, 0.46 cm x 25 cm) to separately collect an enantiomer 8a (retention time: about 12.8 minutes, 51 mg) and an enantiomer 8b (retention time: about 16.9 minutes, 54 mg) as a white solid, respectively.
Conditions: mobile phase; hexane:EtOH:diethyl amine=50:50:0.1, flow rate; 0.5 mL/minute, column temperature; 40°C, detection wavelength; 254 nm.
Each of the enantiomers was dissolved in EtOH, and fiimaric acid was added thereto to yield a fiimarate, respectively.

[0181]
Example 9
In a mixed solvent (MeOH:EtOAc=5 mL:5 mL), to l-azabicyclo[2.2.2]oct-4-ylmethyl tert-butyl(5-phenyl-l,3-thiazole-2,4-diyl)biscarbamate was added 4 M HCl/EtOAc (7 mL), followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, to the residue was added EtOAc, and the solid was collected by filtration to obtain l-azabicyclo[2.2.2]oct-4-ylmethyl (2-amino-5-phenyl-l,3-thiazol-4-yl)carbamate dihydrochloride as a white solid.
[0182]
Example 10
To a solution of 5-phenyl-l,3-thiazole-4-carboxylic acid (300 mg) in toluene (6 mL) were added dropwise TEA (672 [iL) and DPPA (409 |xL) at room temperature, followed by stirring at the same temperature for 20 minutes. Next, after stirring at 90°C for 5 minutes, a mixture of 3-aminoquinuclidine dihydrochloride (407 mg) and DMF (2 mL) was added thereto, followed by heating under reflux for 1 hour. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated,under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (YAMAZEN YFLC WPrep2XY, eluent; CHCl3:MeOH:28% aqueous ammonia=80:10:l) to obtain an oily substance. This was dissolved in EtOH, followed by addition of 10% HCl/MeOH at room temperature and concentration under reduced pressure. The residue obtained was added with EtOH and EtOAc, and left to stand, and the solid precipitated was collected by filtration, and washed with EtOAc to obtain l-(l-azabicyclo[2.2.2]oct-3-yl)-3-(5-phenyl-l,3-thiazol-4-yl) urea hydrochloride (15 mg) as a white solid.
[0183]
Example 11
To a solution of 5-phenyl-l,3-thiazole-4-carboxylic acid (400 mg) in toluene (5 mL) was added TEA (380 1iL) at room temperature. To the reaction liquid was added dropwise a solution of DPPA (546 i1L) in toluene (5 mL), followed by stirring at the same temperature for 20 minutes. After stirring at 90°C for 5 minutes, a mixture of 1-azabicyclo[3.2.1]oct-5-yl methanol (357 mg) and DMF (2 mL) was added thereto, followed by heating under reflux for 1 hour. To the reaction liquid was added water, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was

purified by medium-pressure preparative liquid chromatography (YAMAZEN YFLC \1Trep2XY, CHCl3:MeOH:28%aqueous ammonia-80:10:l) to obtain an oily substance. This was dissolved in EtOAc, followed by addition of 4 M HCl/dioxane at room temperature. The solid precipitated was collected by filtration and washed with EtOAc to obtain 1 -azabicyclo[3.2.1 ]oct-5-ylmethyl (5-phenyl-1,3-thiazol-4-yl)carbamate hydrochloride (174 mg) as a white solid.
[0184]
Example 12
To a solution of 5-phenyl-1,3-thiazole-4-carboxylic acid (385 mg) in toluene (5 mL) was added TEA (314 )iL) at room temperature. Next, DPPA(486 1L) was added dropwise, followed by stirring at the same temperature for 30 minutes. After stirring at 90°C for 5 minutes, a mixture of l-azabicyclo[3.3.1]non-5-yl methanol (291 mg), DMF (1 mL), and toluene (4 mL) was added thereto, followed by stirring at 90°C for 30 minutes. The reaction mixture was cooled to room temperature, and CHCI3 and water were then added thereto to separate the organic layer. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHChiMeOH:aqueous ammonia). The collected fraction was concentrated under reduced pressure, followed by addition of 4 M HCl/EtOAc and concentration under reduced pressure. To the residue were added EtOAc and water to separate the aqueous layer. The aqueous layer was neutralized with NaHCOs and extracted with CHCI3. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure to obtain a tacky substance (129 mg). This was dissolved in EtOH, followed by addition of a solution of fumaric acid (40 mg) in EtOH and concentrated under reduced pressure to obtain l-azabicyclo[3.3.1]non-5-ylmethyl(5-phenyl-l,3-thiazol-4-yl)carbamate fumarate (161 mg) as a colorless amorphous fluorescent substance.
[0185]
Example 13
To a mixture of l-azabicyclo[2.2.2]oct-4-ylmethyl(2-{[2-(benzyloxy)ethyl]amino}-5-phenyl-l,3-thiazol-4-yl)carbamate dihydrochloride (350 mg) and TEA (3.5 mL) was added thioanisole (362 |iL) under a nitrogen atmosphere, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure, alkalified with addition of a 1 M aqueous NaOH solution, and extracted with a mixed

solvent (CHCl3:MeOH=8.T). The organic layer was dried over MgS04 and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). The collected fraction was concentrated under reduced pressure, EtOAc was then added to the residue, and the solid precipitated was pulverized, collected by filtration, and washed with EtOAc to obtain l-azabicyclo[2.2.2]oct-4-ylmethyl {2-[(2-hydroxyethyl)amino]-5-phenyl-l,3-thiazol-4-yl}carbamate (110 mg) as a colorless solid.
[0186]
Example 14
To a solution of 5-phenyl-l,3-thiazole-4-carboxylic acid (385 mg) in toluene (8 mL) was added TEA (285 p,L) at room temperature. To the reaction mixture was added dropwise DPPA (404 p,L), followed by stirring at the same temperature for 40 minutes. In addition, after stirring at 90°C for 5 minutes, a mixture of l-azabicyclo[3.2.2]nonan-5-ol (313 mg) and DMF (3 mL) was added thereto, followed by stirring at 110°C for 1 hour. The reaction mixture was cooled to room temperature, followed by addition with 1 M hydrochloric acid for acidification, and extraction with EtOAc. The aqueous layer was alkalified with addition of a 1 M aqueous NaOH solution, and extracted with CHCI3. The organic layer was washed with water and brine in this order, dried over MgS04, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia) to obtain a yellow amorphous fluorescent substance. To this was added EtOAc, and the resulting solid was collected by filtration, and washed with EtOAc to obtain l-azabicyclo[3.2.2]non-5-yl(5-phenyl-l,3-thiazol-4-yl)carbamate (238 mg) as a colorless powder.
[0187]
Example 15
A solution of l-azabicyclo[3.2.l]oct-6-ylmethyl(5-phenyl-l ,3-thiazol-4-yl)carbamate in EtOH (1 mL) was prepared, and subjected to preparative HPLC (CHIRALCEL OD, 0.46 cm x 25 cm) to separately collect an enantiomer 15a (retention time: about 6.2 minutes) and an enantiomer 15b (retention time: about 7.9 minutes). Each was recrystallized from a mixed solvent (hexane:EtOH) to obtain a colorless solid.
Conditions: mobile phase; hexane:EtOH:diethyl amine=50:50:0.1, flow rate; 0.9 mL/minute, column temperature; 40°C, detection wavelength; 254nm.

[0188]
By using the abo\'e-described preparation method, a method which is apparent to a skilled person in the art, or a modified method thereof, the compounds shown in Tables 18 to 41 below were prepared. The Example numbers (Syn) indicating that the compounds can be prepared in the same manner as the structure of the compounds of Examples are shown in Tables. The physicochemical data are shown in Tables 42 to 57 below.

[0

891 [Table 18]

Ex

Syn

Structure

Ex

Syn

Structure

NO H
,11

,0

\J HO"
0.5- Chiral 6

HoA1-1OH O

O
N1O1I1C1j1J

+yC\13

KS.
HCI

/1N O
1 HCI 1N

%J . .1X.1 .OH
)=N


w1ra

8a

1
_/=N
HO-11111 Chiral 0

, " 2HCI1N
8b

_/=*N
'■''v'1
HO
OH
Chiral °

MN O

N O " HCI
N H H
HCI

10

/=N

,1.1

11

/=N

.1

[0190] [Table 19]

Ex

Syn

Structure

Ex

Syn

Structure

OH
12

/=N 0 1

HO
0
s X A r1

13

OH
HN

N
14

/=N O

15a

/=N O
SAX
Chiral

15b

/=N 0
Chiral

16

( // 113

HCI

N1O'
H Q
H,C

17

18

'1
HO
N'1O H

OH
N

H

19

CH,
N-1O H
0.5- 1
HO

OH
N

20

lo-1
OH
HO
21

22

6

-N-1O1'11 H O
H011-1=1°" Chiral O

[0191] [Table 20]

Ex

Svn

Structure

Ex

Syn

Structure

HCI
1z' Chiral
23

1 HCI Chiral

24

L1
HCI Chiral
25

HCI Chiral

26

1 H ,,1,

HCI Chiral
OH
27

i H . .„,

28

HO-11' Chiral 0

'"N H
OH
HO
29

Chiral O

30

KB
Chiral O

31

6"'

32

1CH3
1\KB
"CI

9
// "1 '"
33

34

/CH3

[0

192] [Table 21]

Ex

Syn

Structure

Ex

Syn

Structure

35

N' O
XM'

XH,

36

XH,

s: 11 1_
N,
37

Br 11

38

CH3

1°7S
H
//A I
39

40

N.

CH,

N

1CH3

H
II 1
41

SJ 1

Br

42

F3C

r1
Br
43

44

1CH3
.1N O r1N

')
s; :i 9 J
\ II 1'~
45

46

[0193] [Table 22]

Ex

Syn

Structure

Ex

Syn

Structure

/==N O


r°
47

CH,

48

./1N

,L0
Br

49

- 1H*'
11
6H,

50

61.

f1

CO

51

0"

I Chiral

52

53

11j1l Chiral

54

1/=*N 0
6"

Br'

N.

55

CI.
Vi Chi.,

CH,

56

[0194] [Table 23]

Ex

Syn

Structure

Ex

Syn

Structure

57

. 101


+/CH3

58

Chiral

+1CH3
59

60

./=*N


X1-r
H „ Chiral
a

,/1N
y
H
F / 1N O
61

LB

1CH,

62

Chiral

J
63

"A1-1"

64

>=N


=N O
o
N1 I IV1l

125

1 HC!
L 1 Chiral

126

11NV"-.
H HCI 1"1

127

X.S
H HCI
. /] Chiral

128

H,C

Chiral o

129

,10-1
HCI

130

131

132

[0201] [Table 30]

Ex

Syn

Structure

Ex

Syn

Structure

N OH
133

Hjq PH3
N
H
0.5
HO

k11

134

CI.
Q- 1 o r1N
H
1N-1O'
HOI

IJD

■XB
H H
OS1iC1OH

136

'" HOI V

N N H H
HCI

137

CI.

N

138

N-1O Ho
V1 HO

OH

H H
/yo.5
HO
OH
139

140

H
1-1VoB
HCI
Chiral

A1
141

142

H3C CH
1AQJC1
H %J Ho'-1-1-OH

H H
143

CI

N

144

H3C
Ho Chiral O

[0202] [Table 31]

Ex

Syn

Structure

Ex

Syn

Structure

145

/=N 0
1 HCI kbN

146

/=N O
" HCI kbN

N
N
F, J K °
P / NO
147

148

r-0
149

A " HC,
F

150

H
1/1N

X.J&
HCI

,/=*N
1 HCI
F'1J' Chiral
151

SJ{ Chiral

152

XB

153

N=N

f1ScTa

154

-/=N
/°-1
HO
OH

155

1/==N O
9


HCIX1N

156

0" ™

[0203] [Table 32]

Ex

Syn

Structure

Ex

Syn

Structure

157

1,
.'1N
11«\70

158

H


Chiral O

,/1N
1 H
ioy

HCI

lOU

/ // 0.5-9

161

Wo

N

162

-11 X

N OH
163

si ?
y

164

Chiral o

165

./1N O
=1ff1Sc?8

166

y11N1o"11"1
" HCI
1J' Chiral

167

y
r\ " HCI

168

,/=*N O
1«''H;B
F-AJ
F

[0204] [Table 33]

Ex

Syn

Structure

Ex

Syn

Structure

1 H
169

CI
HCI

170

g/1N 0

171

Chiral

172

1'11 l,J&
P4 " ""

173

>=N

«\?a

174

5X
_f\ " HCI
F-VA Chiral
F

N

175

!„,..
>=N
A " HCI
\1 Chiral

176

CI

177

>=N

1h'1

178

CI

179

>=N

AB
H .,1.
HCI Chiral

180

C"a
OH
0.5
VAHO
CI

[0205] [Table 34]

Ex

SNTI

Structure

Ex

Syn

Structure

1 H
1.5 HO
OH

181

11Vo-'111
CH,
HCI Chiral

182

F CI

153

ff Chiral O

184

/=N O N'

/=N
H,C
185

«\?a
CF,

186

/=N

1 HCI kf1N

187

/=N
H ,.1,
HCI Chiral
CF,

ST 9
CH,

'\ 1 HCI
189

CF,

190

S J 9 CH,

//-\ HCI \1
191

/=1 5
CF,

192

111
A«HcTa

[0206] [Table 35]

Ex

S>T1

Structure

Ex

Syn

Structure

H
HCI
193

CI

194

H
// 1 11'
Chiral
F

H
// 1 HCI
195

/=N 0
F. 'r1r °11
-1 HCI 11
1Cl

% HCI 11
HCI "11N
197

./*1N
1""1

198

199

./=1N
1,
"11"1

200

/=N O
yX " HCI "1N CI

i„,.a
201

vi
/ // 11Cl
1■J' Chiral

202

P 1/o-1'1

203

S 1 9

204

[0207] [Table 36]

Ex

Syn

Structure

Ex

Syn

Structure

./=*N
205

206

=N
OH
207

C
CH

208

131

=S> 1 HOI

/=N
N'"0
H
N OH
1.5-
HO
CH3 6
209

,1
O
•1-Y'

210

/=N O
U

OH
211

d1A'B
O
H 0.5
VJ: HO
P111CHj Chiral

212

-/=N

OH
Chiral
213

n
1o1
CH

214

215

Br
>=N

216

./1N
IJ9I
"1'

[0208] [Table 37]

Ex

Syn

Structure

Ex

Syn

Structure

N OH
%Jl HO
217

Chirai 6

218

Ho
CN Chiral O

OH

N
Cl-1
219

/=N

O
N-1O n

/N /I

220

CNHO'111*11 0

OH

\j °-1
221

CH,

222

1
_/=N
=rc1
-A1OH

HCI Chiral
223

224

/=N O

CH,

225

226

A " HCI 1N

/=N
N
M HO-111-1O1
CN O

227

11-1 XB
HCI
Chiral

228

d°1

[0209] [Table 38]

Ex

Syn

Structure

Ex

Syn

Structure

229

230

CN Chiral 6
3"! XB

CI
23 i

/==N

XJ

OH
N

232

M O
1\.0H
\Jl HO
CN 0

/=N
/=N
NO H I
CN
O
233

H 0.5-
-AB
HO
O
CI

OH

234

LB'

.CH,

235

.1N

KB

236

CI
237

" 2HCl'NbN

238

I1JHO1OH

239

S T 9
'i

240

[0210] [Table 39]

Ex

Syn

Structure

Ex

Syn

Structure

241

S, J 11
S CI

HCI 1N

242

CI

1 HCI
Chiral

" HCI 11
243

244

/=N O

OH
OH
HO
HO
245

O

246

O

O

H H [IJ
247

HCI

248

HCI

'1&
249

,1
H H I'1fil HCI

250

€1 X
N-1O-1 H HCL

NO H HCI
H

251

sCi

252

=N 9

[0211] [Table 40]

Ex

S>'n

Structure

Ex

Syn

Structure

1 HCI

253

/=N

N

254

1 HCI

255

S1 ? TA-'N
HCI

256

1
257

O
HN
-11 A
1 2HCI kU

258

/==N O
1 HCI
N

259

A i11
HCI

260

11

/=N

,1

N O H
HCI
N

261

11

CI

feM

.1

262

11

/=1N Q
s- -i .A,
HCI kbN

263

11

264

11

/=*N O

[0212] [Table 41]

Ex

Syn

Structure

Ex

Syn

Structure

265

11

266

12

1\1H0
11OH
26/

12

N

<1x-d

268

14

F,HC
1X1
N O H

269

14

270

14

[0213

[Table 42]
Ex data
1 NMR:2.27(6H,br), 3.31(6H,br), 7.04(1 H,s), 7.31-7.37(1 H,m), 7.40-7.50(5H,m), 9.11(1H,br), ESI(+):345.
2 NMR:1.42(1H,brs), 1.53(1H,brs), 1.63(1H,brs), 1.81(1H,brs), 1.99(1H,brs), 2.32-2.39(2H,m), 2.58-2.62(2H,m), 2.67-2.81 (2H,m), 2.86-2.89(2H,m), 3.17(1H,brs), 4.61(1H,brs), 6.51(1H,s), 7.27-7.31 (1H,m), 7.38-7.42(2H,m), 7.47-7.49(2H,m), 8.99(1 H.brs), ESI(+):369.
3 ESI(+):343
4 NMR:1.76-1.9(5H,m), 2.4(1H,brs), 2.9(3H,s), 3.09(1H,brs), 3.3-
3.4(5H,m), 2.04(2H,d,J=-1632.5Hz), 7.11(1H,brs),
7.35(1 H,t,J=7.3Hz), 7.44(2H,t,J=7.6Hz), 7.5-7.53(3H,m), 9.1(1H,brs),
ESI(+):357.
5 NMR:1.8-2.22(5H,m), 3.13-3.24(5H,m), 3.6-3.65(1 H,m), 4.87(1H,brs), 7.15(1 H,d,J=5.4Hz), 7.28(1 H,t,J=8.9Hz), 7.51(1H,d,J=5.4Hz), 7.54-7.55(2H,m), 9.22(1 H.brs). 10.08(1 H.brs), ESI:347.

[0214] [Table 43]

Ex data
6 NMR:1.50-1.61(6H,m), 3.13-3.21(6H,m), 3.83(2H,s), 7.36-7.41(1H,m), 7.44-7.49(2H,m), 7.55-7.58(2H,m), 9.01 (1H,s), 9.48(1 H,s), 10.46(1 H,brs).ESI(+)344
7 ESI(+):369
8a ESI(+):362(free) [a]D1'*=-36.0°(c=0.1,MeOH)
8b ESI(+):362(free) [a]D11=+32.0°(c=0.1,MeOH)
9 ESI(+):359
10 NMR:1.72-2.01 (5H,m), 2.87-2.92(1 H,m), 3.11-3.2(4H,m), 3.95(1H,b.s), 7.15(1 H,d,J=6.5Hz), 7.33-7.37(1H,m), 7.41-7.44(2H,m), 7.55-7.57(2H,m), 8.44(1 H,s), 8.99(1 H,s), 9.79(1 H.brs), ESi(+);329
11 NMR:1.45-1.76(7H,m), 2.93-3.35(5H,m), 4.01 (2H,s), 7.37-7.4(1 H,m), 7.45-7.48(2H,m), 7.55-7.57(2H,m), 9.01(1H,s), 9.5(1H,s), 10.1(1H,b.s), ESI(+):344.
12 NMR:1.52-1.64(6H,m), 2.10(2H,br), 2.78(2H,br), 3.03-3.07(2H.m), 3.18-3.22(2H,m), 3.70(2H,s), 6.52(2H,s), 7.35-7.38(1 H,m), 7.44-7.47(2H,m), 7.55-7.57(2H,m), 9.01(1H,s), 9.46(1H,s), ESI(+):359
13 NMR:1.52-1.64(6H,m), 3.16-3.57(10H,m), 3.82(2H,s), 7.17-7.57(5H,m), 7.82(1 H,t,d=6.0Hz), 9.08(1H,s), 9.66(1H,s), ESI(+):403
14 NMR:1.48-1.62(4H,m), 2.00-2.09(2H,m), 2.17-2.28(2H,m), 2.71-2.92(6H,m), 7.34-7.55(5H,m), 8.96(1H,s), 9.11(1H,s), ESI(+):344
15a ESI(+):344 [a]D"=-7.8°(c=1.05, CHCI3)
15b ESI(+):344 [a]D1'=+5.2°(c=0.2,CHCl3)
16 NMR:1.79-1.82(4.8H,m), 2.21(1.2H,brs), 3.02(0.6H,s), 3.09(2.4H,s), 3.21-3.25(4.8H,m), 3.39(1.2H,s), 7.12(1H,d,J=5.3Hz), 7.38-7.4(3H,m), 7.46-7.5(2H,m), 7.55(1 H,d,J=5.3Hz), 10.04(1 H,brs).ESI(+):343
17 ESI(+):337
18 ESI(+):341
19 ESI(+):337

[0215

] [Tab! e44]
Ex data
20 ESI(+):341
21 ESI(+):329
22 NMR:1.27-2.32(14H,m), 2.75-3.30(6H,m), 3.91-3.97(1 H,m), 4.33-4.51(1H,m), 6.52(2H,s), 6.97-7.27(6H,m).ESI(+):329, [a]D1'=+34.65°(c=1.0.MeOH)
23 ESI(+):329. [a]D11=+80.4°(c=1.0,MeOH)
24 NMR:1.29-2.12(14H,m), 2.77-3.55(6H,m), 3.92-3.98(1 H,m), 4.50-4.60(1 H,m), 7.11-7.30(6H,m), 10.39(1H,brs).ESI(+):329. [a]D11=-75.3°(c=1.0,MeOH)
25 ESI(+):329. [a]D11=-44.75''(c=1.0,MeOH)
26 NMR:1.20-1.91(14H,m), 2.86-3.22(5H,m), 3.46-3.60(2H,m), 4.54-4.60(1 H,m), 7.09-7.29(6H,m), 10.35(1 H,brs).ESI(+):329. [a]D'1=-24.85°(c=1.0,MeOH)
27 ESI(+):329. [a]D1'=+9.25°(c=1.0,MeOH)
28 ESI(+):329. [a]D"=-7.30°(c=1.0,MeOH)
29 NMR:1.19-1.50(4H,m), 1.66-1.88(10H,m), 2.43-2.50(1 H,m), 3.00-3.07(6H,m), 3.43-3.53(1 H,m), 6.50(2H,s), 6.80-6.83(1 H,m), 7.11-7.29(5H,m).ESI(+):329. [a]D1''=+11.5°(c=1.0.MeOH)
30 ESI(+):329. [a]D11=-11.7°(c=1.0,MeOH)
31 NMR:1.20-2.11(14H,m), 2.45-2.67(2H,m), 3.02-3.22(5H,m), 3.50-3.59(1 H,m), 3.69-3.95(2H,m), 6.92-7.28(6H,m), 10.09(1 H,brs).ESI(+):343
32 NMR:2.25(6H,brs), 2.92(3H,s), 3.59-3.63(6H,m), 7.44-7.51 (3H,m), 7.57(1H,s), 9.05(1H,s), 9,68(1H,brs), ESI(+):378
33 NMR:1.75-1.99(5H,m), 2.39(1 H.brs), 3.04(1 H.brs), 3.29-3.42(4H,m), 4.07(2H,brs), 4.41-4.45(2H,m), 7.09(1 H.brs), 7.34(1 H,t,J=7.3Hz), 7.43(2H,t.J=7.6Hz), 7.49-7.52(8H,m), 9.1(1H,brs).ESI(+):433
34 ESI(+):362
35 NMR:2.32(6H,brs), 2.93(3H,brs), 3.61(6H,brs), 7.05(1 H.brs), 7.34(1 H,t,J=7.3Hz), 7.44(2H,t,J=7.6Hz), 7.49-7.51 (2H,m), 9.14(1H,brs).ESI(+):343
36 ESI(+):413
37 NMR:1.79-1.94(5H,m), 2.44(1 H.brs), 3(2H,brs), 3.15(1 H.brs), 3.37-3.6(6H,m), 4.08-4.14(2H,m), 7.13(1H,brs), 7.26-7.38(6H,m), 7.44(2H,t,J=7.7Hz), 7.51-7.54(3H,m), 9.11(1H,brs).ESI(+):447
38 ESI(+):376

[02

Ex
16] [Table 45]
data

39
40
41
42
43
44
45
46
47
48
49
50
51
52

NMR:1.78-1.93(5H,m), 2.42(1 H.brs), 3.23(1 H.brs), 3.54-3.63(7H,m),
4.09(2H,brs), 4.42(2H,brs), 6.98-7.02(3H,m), 7.1(1H,brs), 7.31-
7.36(3H,m), 7.43(2H,t,J=7.6Hz), 7.51(3H,t,J=7.5Hz),
9.10(1H,brs).ESI(+):463
ESI(+):394
NMR:1.77-2.13(7H,m), 2.42(1H,brs), 3.1(1H,brs), 3.3-3.54(6H,m), 4-4.13(4H,m), 6.93-9.98(3H,m), 7.12(1H,brs), 7.29-7.36(3H,m), 7.44(2H,t,J=7.7Hz), 7.5-7.54(3H,m), 9.10(1 H,brs).ESI(+):477
ESI(+):412
NMR:1.73-1.97(7H,m), 2.39(1 H.brs), 2.59(2H,t,J=7.7Hz), 3.04-
3.14(3H,m), 3.29-3.38(5H,m), 4.09(2H,brs), 7.1(1H,brs), 7.21-7.26(3H,m),
7.3-7.35(3H,m), 7.42(2H,t,J=7.6Hz), 7.51(3H,t,J=7.3Hz),
9.07(1 H,brs).ESI(+):461
NMR:2.15-2.30(6H,m), 2.92(3H,s), 3.56-3.63(6H,m), 7.36-7.41(1H,m),
7.44-7.48(2H,m), 7.51-7.54(2H,m), 9.00(1 H,s), 9.53(1 H,brs).ESI:344
NMR:0.89(3H,t,J=7.2Hz), 1.21-1.36(4H,m), 1.6-1.89(7H,m), 2.39(1 H.brs),
3.09(3H,brs), 3.27-3.41 (5H,m), 4.09(2H,brs), 7.11(1H,brs),
7.34(1 H,t,J=7.3Hz), 7.43(2H,t,J=7.6Hz), 7.5-7.53(3H,m),
9.08(1 H,brs).ESI(+):413
NMR:2.19-2.32(6H,m), 3.62-3.77(8H,m), 4.37-4.41 (2H,m), 6.97-7.02(3H,m)7.31-7.41(3H,m), 7.43-7.48(2H,m), 7.51-7.55(2H,m), 9.00(1 H,s), 9.54(1 H,brs).ESI(+):450
NMR:1.60-1.69(6H,m), 2.92(3H,s), 3.37-3.44(6H,m), 3.87(2H,s)r7.37-
7.41 (1H,m), 7.44-7.49(2H,m), 7.54-7.58(2H,m), 9.01 (1H,s), 9.47(1 H.brs).
ESI(+):358
NMR:2.08-2.33(8H,m), 3.31-3.36(2H,m), 3.57-3.66(6H,m),
4.02(2H,t,J=6.0Hz), 6.92-6.97(3H,m)7.27-7.33(2H,m), 7.36-7.55(5H,m),
9.01 (1 H,s), 9.55(1 H,brs).ESI(+):464
NMR:1.71-1.91(5H,m), 2.39(1H,m), 2.89(3H,s), 3.03(1H,m), 3.34-
3.47(5H,m), 3.98-4.10(2H,m), 7.37-7.56(5H,m), 9.00(1H,s),
9.48(1 H,br).ESI(+):358
NMR:2.20-2.32(6H,m), 2.96-3.02(2H,m), 3.34-3.45(2H,m), 3.62-
3.70(6H,m), 7.25-7.41 (6H,m)7.44-7.55(4H,m), 9.01 (IH.s),
9.56(1 H,brs).ESI(+):434
NMR1.81-1.93(4H,m), 2.16(1H,brs), 2.93(3H,s), 3.26-3.42(5H,m), 3.77-
3.82(1 H.m), 4.88-4.9(1 H,m), 7.39(1 H,t,J=7.4Hz), 7.47(2H,t,J=7.6Hz),
7.57(2H.d,J=7.6Hz), 9.02(1 H,s), 9.68(1 H,brs).ESI(+):344
ESI(+):448

♦ 53

NMR:1.83-1.95(4H,m), 2.19(1H,brs), 2.95(3H,s), 3.27-3.44(5H,m), 3.79-
3.85(1 H,m), 4.9-4.93(1 H,m), 7.45-7.51 (3H,m), 7.62(1 H,s), 9.07(1 H,s),
9.8(1 H,brs).ESI(+):378

[0217] [Table 46]
Ex
data

54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69

ESI(+):420
ESI(+):378
ESI(+):434
ESI(+):380
ESI1+):450
ESI(+):380
ESI(+):464
NMR:2.19(6H,brs), 2.91 (3H,s), 3.56-3.6(6H,m),
7.2(1 H,dt,J=2.5,8.3Hz), 7.37-7.43(1 H,m), 7.53(1H,q,J=8.3Hz),
9.11(1H,br), 9.73(1 H.brs), ESI(+):380
ESI(+):384
NMR:2.20-2.31(6H,m), 2.93(3H,s), 3.58-3.64(6H,m),
7.31(1H,t,J=54Hz), 7.52-7.53(3H,m), 7.63-7.65(1 H,tn), 9.92(1 H,s),
ESI(+):428
NMR:2.23-2.33(6H,m), 3.62-3.67(2H,m), 3.71-3.78(6H,m), 4.37-
4.42(2H,m), 6.97-7.02(3H,m), 7.23-7.54(6H,m), 7.63-7.65(1 H,m),
9.93(1 H,s),ESI(+):534
NMR:1.87-2.47(8H,m), 3.06(3H,s), 3.44-3.61 (6H,m), 7.36-7.55(5H,m),
8.99(1 H,s), 9.39(1 H,s), ESI(+):358
NMR:2.28(6H,br), 3.64(2H,br), 3.72-3.76(6H,m), 4.39(2H,br), 6.98-
7.02(3H,m), 7.32-7.35(2H,m), 7.44-7.49(4H,m), 7.56(1 H,s),
9.05(1 H,s),ESI(+):484,486
NMR:1.90-2.23(6H,m), 2.39-2.50(2H,m), 3.06(3H,s), 3.46-3.64(6H,m), 7.44-7.51 (3H,m), 7.57-7.59(1 H,m), 9.04(1 H,s), 9.55(1 H,s), ESI(+):392 NMR:1.80-1.88(3H,m), 2.03(1H,brs), 2.24(1H,brs), 3.15(5H,brs), 3.62(1 H,brs), 4.89(1 H,brs). 7.17-7.21 (2H,m), 7.35-7.39(2H,m), 7.46-7.52(1 H,m), 7.57(1 H,d,J=5.4Hz), 9.37(1 H.brs), 10.2(1 H,brs).ESI(+):347
NMR:1.81(3H,brs), 2.08(1H,brs), 2.28(1H,brs), 3.14(5H,brs), 3.64(1 H.brs), 4.91(1H,brs), 7.08(1 H,d,J=5.4Hz), 7.11 (1 H,dd,J=3.6,5.1 Hz), 7.3(1 H,dd,J=1.1,3.6Hz), 7.46(1 H,d,J=5.4Hz), 7.57(1H,dd,J=1.1,5.1Hz), 9.25(1H,brs), 10.2(1 H,brs).ESI(+):335

70
71

NMR:1.72-1.99(4H,m), 2.2(1 H.brs), 3.07-3.24(5H,m), 3.6-3.65(1 H,m), 4.85-4.87(1 H,m), 7.23-7.33(3H,m), 7.41-7.49(2H,m), 7.63(1 H,d,J=5.4Hz), 9.29(1 H.brs), 9.95(1 H,brs).ESI(+)347
NMR;1.47(1H,brs), 1.62(1H,brs), 1.71(1H,brs), 1.83(1H,brs),
2.02(1 H.brs), 2.82-2.89(5H,m), 3.29(1 H.brs), 3.78(3H,s),
4.72(1H,brs), 6.52(2H,s), 7.01(1H,t,J=7.5Hz), 7.12(1H,d,J=8.2Hz),
7.2(1 H.brs), 7.32-7.38(2H,m), 7.5(1 H,d,J=5.4Hz),
8.63(1 H,brs).ESI(+):359

[0218] [Table 47]

Ex

data

72
73
74

NMR:1.81(3H,brs), 2.09(1H,brs), 2.29(1H,brs), 2.46(3H,d,J=.3Hz),
3.13(5H,brs), 3.64(1H,brs), 4.91(1H,brs), 6.8(1H,dd,J=1.1,3.6Hz),
7.04(1 H,d,J=5.3Hz), 7.08(1 H,d,J=3.6Hz), 7.41(1H,d,J=5.3Hz),
9.17(1H,brs), 10.19(1H,brs).ESI(+):349
NMR:1.24-1.57(3H,m), 1.74(1H,br), 1.90(1H,br), 2.56-2.70(5H,m),
3.07(1H,br), 4.60(1H,br), 7.10(1H,br), 7.29-7.32(2H,m), 7.39-
7.43(2H,m), 7.48-7.50(2H,m), 9.42(1 H,br).ESI(+):329
NMR:1.41(1H,brs), 1.55(1H,brs), 1.65(1 H.brs), 1.83(1H,brs),
1.97(1H,brs), 2.72-2.82(5H,m), 3.19(1H,brs), 3.7(3H,s), 4.64(1 H.brs),
6.5(1H,s), 6.98-7.02(2H,m), 7.07(1H,brs), 7.41(1H,d,J=5.4Hz),
7.45(2H,d,J=8.7Hz), 8.97(1 H,brs).ESI(+):359

7R

ESI(+):337

76

NMR:1.45(1H,brs), 1.59(1H,brs), 1.68(1H,brs), 1.85(1H,brs),
1.99(1H,brs), 2.77-2.86(5H,m), 3.26(1 H.brs), 3.78(3H,s), 4.68(1 H.brs),
6.53(2H,s), 6.91-6.93(1 H,m), 7.07-7.09(3H,m), 7.34(1 H,t,J=8Hz),
7.49(1 H,d,J=5.2Hz), 9.11 (1 H.brs).
ESI(+):359

77
78
79
80

ESI(+):337
NMR:1.8-1.88(3H,m), 2.04(1 H.brs), 2.25(1 H.brs), 2.33(3H,s),
3.14(5H,brs), 3.62(1H,brs), 4.88(1H,brs), 7.13(1H,d,J=5.4Hz),
7.25(2H,d,J=7.8Hz), 7.42(2H,d,J=7.8Hz), 7.47(1 H,d,J=5.4Hz),
9.19(1H,brs), 10.04(1 H,brs).ESI(+):343
ESI(+):341
NMR:1.78-1.87(3H,m), 2.02(1H,brs), 2.24(1H,brs), 2.34(3H,s), 3.13(5H,brs), 3.61(1H,brs), 4.88(1H,brs), 7.13-7.17(2H,m), 7.3-7.34(3H,m), 7.5(1 H.d.J=5.4Hz), 9.21(1H,brs), 10.2(1H,brs).ESI(+):343

81
82

ESI(+):341
NMR:1.69-1.91(4H,m), 2.16(4H,brs), 3.05-3.26(5H,m), 3.59-3.65(1H,m), 4.84-4.86(1 H,m), 7.21-7.28(3H,m), 7.31-7.32(2H,m), 7.54(1 H.d,J=5.4Hz), 8.98(1 H.brs), 9.79(1 H,brs).ESI(+):343

83

ESI(+):341

84

NMR:1.81-1.87(4H,m), 2.24(1 H.brs), 3.14(5H,brs), 3.64(1 H.brs), 4.91(1H,brs), 7.4(1 H,t,J=7.6Hz), 7.5(2H,t,J=7.6Hz), 7.67(2H,d.J=7.6Hz), 8.4(1 H,s), 9.62(1 H.brs), 9.87(1 H.brs), ESI(+):314

85

ESI(+):439,
less polar(10%MeOH in CHCl3,Rf=0.25)

86

NMR:1.64(6H,brs), 3.2(6H,brs), 3.91(2H,brs), 7.39(1 H,t,J=7.6Hz),
7.5(2H,t,J=7.6Hz), 7.66(2H,d,J=7.6Hz), 8.39(1 H,s), 9.46(1 H.brs),
10.3(1 H,brs).ESI(+):328

87

ESI(+):439,
more polar(10%MeOH in CHCl3,Rf=0.20)

[0219] [Tab

e48]

Ex

data

88
89
90
91
92
93
94
95
96
97
98
99

NMR:1.64-1.89(5H,m), 2.33(1H,brs), 2.81(1H,brs), 3.17(5H,brs), 4.07-
4.17(2H,m), 7.39(1 H,t,J=7.5H2), 7.5(2H,t,J=7.5Hz),
7.65(2H,d,J=7.5Hz), 8.39(1H,s), 9.46(1H,brs), 10.03(1H,brs),
ESI(+):328
NMR:1.48-2.27(6H,m), 2.61-2.67(2H,m), 3.01-3.32(4H,m),
3.74(1 H.brs), 4.89(1 H.brs), 7.16-7,25(4H,m), 7.29-7.37(4H,m),
7.45(2H,t,J=7.6Hz), 7.51-7.55(3H,m), 9.22(1 H.brs),
10.00(1 H,brs).ESI(+):433
less polar(10%MeOH in CHCl3,Rf=0.25)
NMR:1.60-2.20(7H,m), 2.63(3H,s), 3.32-3.38(6H,m), 4.88-4.92(2H,m),
7.20-7.54(5H,m), 9.48(1 H,s), 10.49(1 H,brs).ESI(+):370
NMR:1.46-2.32(6H,m), 2.67(2H,brs), 3.00-3.65(5H,m), 4.83-
4.89(1H,m), 7.14-7.54(12H,m), 9.3(1H,brs), 10.27(1 H,brs).ESI(+):433
more polar(10%MeOH in CHCl3,Rf=0.20)
NMR:2.14(6H,brs), 2.62(3H,s), 3.26-3.42(6H,m), 7.26-7.50(5H,m),
9.41(1H,s), 10.46(1 H,brs).ESI(+):344
NMR:1.53-1.86(5H,m), 2.14-2.22(1 H,m), 2.65-2.72(1 H,m), 3.01-3.26(5H,m), 3.97-4.09(2H,m), 6.54(2H,s), 7.35-7.40(1 H,m), 7.43-7.47(2H,m), 7.53-7.56(2H,m), 9.00(1 H,s), 9.44(1 H,brs).ESI(+):344
NMR:1.60-1.94(4H,m), 2.14(1H,brs), 2.63(3H,s), 2.82-3.26(4H,m),
3.48-3.64(2H,m), 4.80-4.86(1 H,m), 7.32-7.54(5H,m), 9.58(1 H,s),
10.44(1 H,brs).ESI(+):344
NMR:1.76(6H,brs), 2.78-2.82(6H,m), 7.36(1 H,t,J=7.3Hz),
7.44(2H,t,J=7.7Hz), 7.52-7.54(2H,m), 8.96(1 H,s),
9.16(1H,brs).ESI(+):330
NIVIR:1.8(3H,brs), 2.05(1 H.brs), 2.29(1 H,brs), 3.16-3.23(5H,m),
3.64(1 H.brs), 4.97(1 H.brs), 7.37(1 H,t,J=7.4Hz), 7.47(2H,t,J=7.7Hz),
7.78(2H,d,J=7.4Hz), 8.92(1 H,s), 10.92(1 H.brs),
10.4(1 H.brs).ESI(+):330
NMR:1.18-1.40(6H,m), 2.64-2.76(6H,m), 3.66-3.72(2H,m),
7.08(1 H.brs), 7.31-7.36(1 H,m), 7.40-7.45(2H,m), 7.48-7.54(3H,m),
8.96(1 H,brs).ESI(+):343
NMR:1.69-2.04(5H,m), 2.37(1H,brs), 2.86(1H,brs), 3.19-3.34(5H,m),
4.17(2H,brs), 7.36(1 H,t,J=7.6Hz), 7.46(2H,t,J=7.6Hz),
7.77(2H,d,J=7.6Hz), 8.92(1 H.brs), 9.96(1 H.brs),
10.2(1 H,brs).ESi(+):344
NMR:1.80-2.26(6H,m), 3.28-3.40(6H,m), 7.31-7.44(5H,m), 7.52-
7.53(1H,m), 8.85(1H,s), 10.52(1 H,brs).ESI(+):329

100
101
102

ESI(+):344
NMR:1.26(6H,brs), 2.69(6H,brs), 3.69(2H,brs), 7.15(1H,s),
7.36(1 H,t,J=7.2Hz), 7.44(2H,t,J=7.6Hz), 7.48-7.5(2H,m),
9.14(1 H,brs).ESI(+):377
NMR:1.48(6H,br), 2.61 (3H,s), 2.93(6H,br), 3.83(2H,brs), 6.42(1 H,s), 7.34(1 H,t,J=7Hz), 7.43(2H,t,J=7Hz), 7.75(2H,d,J=7Hz).ESI(+):358

[0220] [Table 49]
Ex
data

103
104
105
106
107
108
109
110
111
112
113
114
115
116

NMR:1.27(1H,brs), 1.41(1H,brs), 1.51-1.65(3H,m), 1.85(1 H.brs), 2.2-
2.25(1 H,m), 2.61-2.66(3H,m), 2.82(1 H,brs), 3.97-4.04(2H,m),
7.15(1H,s), 7.34-7.38(1 H,m), 7.43(2H,t,J=7.6Hz), 7.47-7.49(2H,m),
9.16(1 H,brs).ESI(+):377
NMR:1.5-1.9(4H,m), 2.61(3H,s), 3.0(4H,br), 4.11(2H,m), 6.47(2H,s),
7.33(1 H,t,J=7Hz), 7.43(2H.t,J=7Hz), 7.75(2H,d,J=7Hz).ESI(+):358
NMR:1.85(6H,brs), 2.84(6H,brs), 7.06(1 H,d,J=5.6Hz), 7.27-
7.32(2H,m), 7.41(2H,t,J=7.6Hz), 7.46-7.47(2H,m),
9.17(1H,brs).ESI(+)329.
NMR:1.9(6H,br), 2.60(3H,s), 2.9(6H,br), 6.5(1 H,s), 7.32(1 H,t,J=7Hz),
7.42(2H,t,J=7Hz), 7.73(2H.brd,J=7Hz).ESI(+)344
NMR:1.3(6H,brs), 2.7(6H,brs), 3.72(2H,brs), 7.1(1H,brs),
7.31(2H,t,J=7.2Hz), 7.41(2H,t,J=7.6Hz), 7.48-7.5(2H,m),
9.38(1 H,brs).ESI(+):343
NMR:1.4-2.1(6H,m), 2.6(3H,s), 2.78-2.91 (3H,m), 4.76(1H,br),
6.55(2H,s), 7.33(1 H,t,J=7.5Hz), 7.43(2H,t,J=7.5Hz),
7.75(2H,d,J=7.5Hz).ESI(+):344
NMR:1.27-1.89(6H,m), 2.23(1 H.brs), 2.66(4H.brs), 2.84(1 H.brs),
4.02(2H,brs), 7.09(1 H,d,J=5.6Hz), 7.29-7.32(2H,m), 7.38-7.43(2H,m),
7.47-7.48(2H,m), 9.38(1 H.brs), ESI(+):343
NMR:1.69-2.14(7H,m), 3.30-3.46(6H,m), 4.76-4.48(0.4H,m), 4.89-4.92(0.6H,m), 7.35-7.40(1 H,m), 7.42-7.48(2H,m), 7.54-7.58(2H,m), 9.02(1 H.brs), 9.56(0.6H,brs), 9.62(0.4H,brs), 10.46(0.6H,brs), 10.69(0.4H,brs).ESI(+):356
NMR:1.24-1.88(5H,m), 2.55-2.67(5H,m), 3.05(1H,brs), 4.57(1H,brs),
7.16(1H,s), 7.36(1 H,t,J=7.2Hz), 7.44(2H,t,J=7.6Hz), 7.47-7.51 (2H,m),
9.17(1H,brs).ESI(+)363
NMR;1.58-1.90(5H,m), 2.20-2.29(1 H,m), 2.73-2.80(1 H,m), 3.08-
3.31(5H,m), 3.99-4.13(2H,m), 7.35-7.55(5H,m), 9.65(1H,brs),
10.3(1H,brs).ESI(+):378
NMR:1.15-1.36(6H,m), 2.64-2.75(6H,m), 3.65(2H,brs), 7.31-
7.53(7H,m), 8.72(1 H,brs).ESI(+):343
NMR:1.53-1.62(6H,m), 3.14-3.23(6H,m), 3.85(2H,s), 7.40-7.56(5H,m),
9.64(1 H.brs), 10.20(1 H.brs).ESI(+):378
NMR:2.21(6H,brs), 2.41(3H,d,J=1.1Hz), 3.37(6H,brs), 6.77(1H,brs),
7.28-7.32(1 H,m), 7.4-7.46(4H,m), 9.04(1 H.brs),
9.98(1 H,brs).ESI(+):343
NMR:1.62-1.96(4H,m), 2.11-2.20(1H,m), 2.90-3.26(5H,m), 3.54-
3.63(1 H,m), 4.82-4.88(1 H,m), 7.37-7.58(5H,m), 9.82(1 H.brs),
10.33(1 H,brs).ESI(+)364

[0221] [Tab Ex
117
118
119
120
121
122
123
124
125
126
127
128
129

e50]
data
NMR:1.19-2.07(5H,m), 1.93(3H,s), 2.34(3H,s), 2.74-2.96(5H,m), 3.3-
3.35(1 H,m), 4.55(0.3H,brs), 4.72(0.7H,brs), 6.58(2H,s), 7.27-
7.31 (1H,m), 7.38-7.47(4H,m), 8.67(0.3H,brs),
8.93(0.7H,brs).ESI(+):357
NMR:2.08-2.19(6H,m), 3.30-3.40(6H,m), 7.39-7.53(5H,m),
9.66(1 H.brs), 10.37(1 H,brs).ESI(+):364
NMR:1.17-1.92(5H,m), 2.43-2.74(5H,m), 2.94-3.09(1 H,m), 4.42-
4.60(1 H,m), 7.30-7.53(7H,m), 8.75(1 H,brs).ESI(+):329
NMR:1.22-1.88(5H,m), 2.19-2.26(1H,m), 2.62-2.86(5H,m), 3.25-
3.48(1 H,m), 3.91-4.02(5H,m), 7.29-7.47(5H,m),
9.26(1 H,brs).ESI(+):374
.NMR:1.60-1.96(3H,m), 2.04-2.15(1 H,m), 2.24-2.32(1 H,m), 2.91-
3.39(5H,m), 3.60-3.68(1 H,nn), 4.88-4.95(1 H,m), 7.41-7.56(5H,m),
7.64-7.77(3H,m), 7.98-8.01 (1H,m), 9.50(1 H.brs),
10.25(1 H,brs).ESI(+):379
NMR:1.54-1.92(5H,m), 2.14-2.39(1 H,m), 2.62(3H,s), 2.70-2.80(1 H,m),
3.04-3.30(5H,m), 3.94-4.12(2H,m), 7.32-7.52(5H,m), 9.40(1H,s),
10.32(1 H,brs).ESI(+):358
NMR:1.79-1.90(3H,m), 2.00(1 H.br), 2.23(1 H,br), 3.12-3.20(5H,m), 3.60(1H,br), 4.87(1H,br), 7.15(1 H,d,J=5.2Hz), 7.32-7.36(1 H,m), 7.42-7.46(2H,m), 7.51-7.55(3H,m), 9.26(1H,br), 10.41(1H,br).ESI(+):329
NMR:1.46-1.70(6H,m), 2.63(3H,s), 3.12-3.25(6H,m), 3.83(2H,brs),
7.32-7.54(5H.m), 9.40(1 H,s), 10.25(1 H,brs).ESI(+):358
NMR:1.79-1.90(3H,m), 2.00(1H,br), 2.23(1H,br), 3.12-3.20(5H,m), 3.60(1 H,br), 4.87(1 H,br), 7.15(1H,d,J=5.2H2), 7.32-7.36(1 H,m), 7.42-7.46(2H,m), 7.51-7.55(3H,m), 9.26(1H,br), 10.55(1H,br).ESI(+)329 [a]"26=-9.2°(C=1.0,MeOH).
NMR(CDCl3)6:1.64-2.14(8H,m), 3.18-3.52(6H,m), 4.12-4.28(2H,tn),
6.55(2H,s), 7.24-7.54(5H,m), 8.64(1 H,s), 9.08(1 H,brs).ESI(+):369
NMR:1.79-1.90(3H,m), 2.00(1H,br), 2.23(1H,br), 3.12-3.20(5H,m),
3.60(1H,br), 4.87(1H,br), 7.15(1 H,d,J=5.2H2), 7.32-7.36(1 H.m), 7.42-
7.46(2H,m), 7.51-7.55(3H,m), 9.25(1 H,br), 10.23(1 H,br).ESI(+):329
[a]%=+9.4°(C=1.0,MeOH)
NMR:1.24(3H,t,J=7.6Hz), 1.43(1H,brs), 1.57(1H,brs), 1.66(1H,brs),
1.83(1H,brs), 1.99(1H,brs), 2.67-2.85(4H,m), 2.74-2.8(2H,m),
4.65(1 H.brs), 6.52(1 H,s), 6.85(1 H.brs), 7.27-7.32(1 H,m), 7.39-
7.42(2H,m), 7.48-7.49(2H.m), 9.03(1 H,brs).ESI(+):357
NMR:2.26(6H,br), 3.36(6H,br), 7.07(1 H.br), 7.31-7.34(2H,m), 7.41-
7.51(4H,m), 9.12(1H,br). 10.42(1 H,br).ESI(+):329

[0222]

[Tab Ex
130
131
132
133

e51]
data
NMR:1.70-2.10(7H,m), 2.42(1.5H,s), 2.43(1.5H,s), 3.1-3.3(6H,m),
4.81(0.5H,brs), 4.86(0.5H,brs), 6.50(2H,s), 6.83(0.5H,brs),
6.90(0.5H,brs), 7.30(1 H,t,J=7.5Hz), 7.40(2H,dt,J=2.7,7.5Hz), 7.46-
7.49(2H,m).ESI(+):369.
NMR:1.49(1H,brs), 1.6(1H,brs), 1.69(1H,brs), 1.87(1H,brs), 2.04(1 H.brs), 2.42(3H,d,J=2Hz), 2.82-2.91 (5H,m), 3.29(1 H.brs), 4.69(1 H.brs), 6.53(2H,s), 6.83(1 H.brs), 7.27-7.32(1 H,m), 7.39-7.43(2H.m), 7.48(2H,d,J=7.3Hz), 9.08(1 H,brs).ESI(+):343
NMR:1.28(6H,d,J=6.7Hz), 1.42(1H,brs), 1.55(1 H.brs), 1.66(1 H.brs),
1.82(1H,brs), 1.99(1H,brs), 2.64-2.84(4H,m), 3.1(1H,q,J=6.8Hz),
3.21(1H,brs), 4.65(1 H.brs), 6.52(1 H,s), 6.86(1 H.brs), 7.28-
7.31(1H,m), 7.38-7.42(2H,m), 7.48-7.5(2H,m),
9.01(1H,brs).ESI(+):371
NMR:1.47-1.55(2H,m), 1.66(1H,brs), 1.84(1H,brs), 1.91(3H,s), 1.93(1H,brs), 1.17(3H,d,J=-932.3Hz), 2.62-2.85(5H,m), 3.18-3.24(1 H,m), 4.65(1 H,brs), 6.51 (1H,s), 7.29(1 H,t,J=7.2Hz), 7.4(2H,t,J=6.7Hz), 7.46(2H,d,J=7.2Hz), 8.88(1 H.s).ESI(+):357

134
135
136
137
138
139
140

NMR:2.2(6H,brs), 3.37(6H,brs), 7.13(1H,s), 7.35-7.38(1 H,m), 7.42-
7.49(4H,m), 9.27(1 H.brs), 9.91(1H,brs).ESI(+):363
NMR:1.42-1.49(1H,m), 1.57-1.77(3H,m), 1.83(1H,q,J=3Hz), 2.75-2.87(4H,m), 3.27(1 H,dd,J=9.6,13.2Hz), 3.74(1 H.brs), 6.45(1 H,s), 6.94(1 H,d,J=6.9Hz), 7.34-7.39(1 H,m), 7.44(1 H,d,J=5.4Hz), 7.47(2H,s), 7.48(2H.s), 7.53(1 H,d,J=5.4Hz), 8.02(1 H,s).ESI(+):328
NMR:1.59-2.02(5H,m), 2.21-2.38(1 H,m), 2.76-2.86(1 H,m), 3.06-3.37(5H,m), 4.00-4.15(2H,m), 7.11(1H,brs), 7.32-7.36(1 H,m), 7.41-7.46(2H,m), 7.50-7.54(3H,m), 9.12(1 H.brs), 10.37(1 H,brs).ESI(+):343
NMR:1.74(1H,brs), 1.85-1.91 (3H,m), 2.01-2.03(1H,m), 2.91(1H,dd,J=4.4,12.9Hz), 3.16-3.2(4H,m),
3.59(1H,dd,J=9.7,13.3Hz), 3.97(1H,brs), 7.25(1 H,d,J=6.2Hz), 7.37-7.41(1H,m), 7.48(4H,d,J=4.3Hz), 7.51(1H,s), 8.2(1H,s), 9.8(1 H,brs).ESI(+):362
NMR:1.42-1.72(4H,m), 1.96(1H,br), 2.63(1 H,br), 2,73-2.93(4H,m), 3.24-3.30(1 H,m), 4.67-4.69(1 H,m), 6.53(2H,s), 7.35-7.39(1 H,m), 7.44-7.47(2H,m), 7.54-7.57(2H,m), 9.00(1 H,s), 9.51(1H,s).ESI(+):330
NMR:1.86-1.90(6H,in), 3.01-3.05(6H,m), 6.44(1 H,s), 6.54(1 H,br),
7.33-7.37(1 H,m), 7.42(1 H,d,J=5.4Hz), 7.43-7.49(5H,m),
7.51 (1 H.d,J=5.4Hz).ESI(+):328
NMR:1.72-1.91(4H,m), 2.14(1H,brs), 2.93-3.21 (5H,m), 3.56-
3.61 (1H,m), 4.83-4.85(1 H,m), 7.39(1 H,t,J=7.3Hz).
7.46(2H,t,J=7.6Hz), 7.56(2H,d,J=7.4Hz), 9.02(1 H,s), 9.65(1 H.brs),
10.21(1H.brs).ESI(+):330

[0223;
] [Tab e52]
Ex data
141 NMR:1.52-1.59(6H,m), 2.99(2H,d,J=6.4Hz), 3.12-3.18(6H,m), 6.70(1 H,t,J=6.4Hz), 7.33-7.38(1 H,m), 7.43-7.51 (6H,m), 8.06(1 H,s).ESI(+):342
142 NMR:1.62(1.2H,brs), 1.91(3H,s), 1.95(4.8H,brs), 2.32(3H,brs), 2.84(1.2H,brs), 2.97(4.8H,brs), 6.51(1H,s), 7.27-7.31 (1H,m), 7.39(2H,t,J=7.6Hz), 7.44-7.46(2H,m), 8.34(0.2H,brs), 8.66(0.8H,brs).ESI(+);357
143 NMR:1.67-1.71(6H,m), 2.76-2.8(6H,m), 6.34(1H,s), 7.36-7.5(5H,m), 7.56(1 H,s), 7.95(1 H,s).ESI(+):362
144 NMR:1.49-2.03(5H,m), 2.42(3H,s), 2.81-2.91(5H,m), 3.29(1H,brs), 4.69(1 H.brs), 6.53(2H,s), 6.83(1 H.brs), 7.29(1 H,t,J=7.3Hz), 7.4(2H,t,J=7.7Hz), 7.47-7.49(2H,m), 9.07(1 H,brs).ESI(+):343
145 NMR:1.56-1.62(6H,m), 3.17-3.23(6H,m), 3.83(2H,s), 7.28-7.34(1 H,m), 7.38-7.44(2H,m), 9.16(1H,s), 9.76(1H,brs), 10.35(1 H,brs).ESl:(+)380
146 NMR: 1.56-1.61 (6H,m), 3.17-3.22(6H,m), 3.82(2H,s), 7.27-7.35(2H,m), 7.44-7.51 (IH.tn), 9.16(1H,s), 9.80(1H,brs), 10.30(1 H,brs).ESI:(+)380
147 NMR:1.18-1.26(1H,m), 1.33-1.42(1 H,m), 1.46-1.59(3H,m), 1.72-1.82(1H,m), 2.13-2.19(1H,m), 2.58-2.72(4H,m), 2.74-2.82(1 H,m), 3.87(1H,dd.J=10.8,6.4Hz), 3.97(1H,dd,J=10.8,9.2Hz), 7.27-7.41(3H,m), 9.13(1H,s), 9.64(1 H,brs).ESI(+):380
148 NMR:1.56-1.89(5H,m), 2.18-2.26(1H,m), 2.71-2.78(1 H,m), 3.07-3.21(4H,m), 3.24-3.32(1 H,m), 3.97(1 H,dd,J=11.2,7.2Hz), 4.07(1 H,dd,J=11.2,8.8Hz), 7.26-7.34(2H,m), 7.45-7.52(1 H,m), 9.16(1H,s), 9.79(1H,brs), 10.20(1 H,brs).ESI(+):380
149 NMR:2.08-2.15(6H,m), 3.30-3.37(6H,m), 7.28-7.42(3H,m), 9.14(1 H,s), 9.81 (1 H.brs), 10.46(1 H,brs).ESI(+):366
150 NMR:2.08-2.14(6H,m), 3.31-3.35(6H,m), 7.25-7.32(2H,m), 7.44-7.51(1H,m), 9.15(1H,s), 9.85(1H,brs), 10.51(1 H,brs).ESI(+):366
151 NMR: 1.67-1.96(4H,m), 2.11-2.16(1H,m), 2.90-2.96(1 H,m), 3.03-3.28(4H,m), 3.54-3.62(1 H,m), 4.80-4.84(1 H,m), 7.28-7.35(1 H,m), 7.38-7.44(2H,m), 9.17(1H,s), 9.93(1H,brs), 10.51(1H,brs).ESI(+):366
152 NMR: 1.67-1.95(4H,m), 2.11-2.16(1H,m), 2.88-2.95(1 H,m), 3.03-3.28(4H,m), 3.54-3.61 (1H,m), 4.78-4.83(1 H,m), 7.27-7.38(2H,m), 7.45-7.52(1 H,m), 9.18(1H,s), 9.96(1H,brs), 10.48(1 H,brs).ESI(+):366
153 NMR:1.40-1.76(6H,m), 3.11-3.25(6H,m), 3.88(2H,s), 7.50-7.68(5H,m), 10.11(1H,s), 10.38(1 H,brs).ESI(+):345
154 NMR: 1.50-1.82(5H,m), 2.14(1 H,br), 2.59-2.64(1 H,m), 2.96-3.07(4H,m), 3.15-3.20(1H,m), 3.96-4.09(2H,m), 6.47(2H,s), 7.28-7.32(2H,m), 7.56-7.59(2H,m), 9.00(1 H,s), 9.46(1 H,s).ESI(+):362

[0224] [Tab

e53]

Ex

data

155
156
157
158
159
160
161
162
163
164
165
166
167

NMR:1.58(6H,br), 3.20(6H,br), 3.84(2H,s), 7.30-7.34(2H,m), 7.57-7.61(2H,m), 9.01(1H,S), 9.48(1H,s), 10.18(1H,br).ESI(+):362
NMR:2.14(6H,br), 3.35-3.37(6H,br), 7.28-7.34(2H,m), 7.53-7.58(2H,m), 8.99(1H,s), 9.51(1H,br), 10.35(1 H,br).ESI(+):348
NMR:1.54-1.58(6H,m), 3.17-3.21 (6H,m), 3.8(2H,s), 7.27-7.36(2H,m),
7.43-7.48(1 H,m), 7.52-7.55(1 H,m), 9.12(1H,s), 9.6(1H,brs),
10.09(1 H,brs).ESI(+):362
NMR:1.42-1.72(4H,m), 1.96(1H,br), 2.66(1H,br), 2.76-2.93(4H,m),
3.26-3.31 (1H,m), 4.68-4.70(1 H,m), 6.53(2H,s), 7.29-7.33(2H,m), 7.58-
7.60(2H,m), 9.00(1 H,s), 9.52(1 H,s).ESI(+):348
NMR:1.58-1.64(1H,m), 1.74-1.84(4H,m), 2.19-2.23(1H,m), 2.73-
2.78(1H,m), 3.12-3.3(5H,m), 3.94-4.07(2H,m), 7.27-7.36(2H,m), 7.43-
7.49(1H,m), 7.53(1 H,dt,J=1.6,7.7Hz), 9.11(1H,s), 9.6(1H,brs),
9.91(1H,brs).ESI(+):362
NMR:1.39(6H,m), 2.92(6H,m), 3.76(2H,s), 6.42(1H,s),
7.24(1 H,dt,J=8.8Hz,2.6Hz), 7.37-7.43(2H,m), 7.48-7.53(1 H,m),
9.04(1 H,s), 9.51 (1 H,br).ESI(+):362
NMR:1.54-1.58(6H,m), 3.16-3.2(6H,m), 3.85(2H,s), 7.48-7.55(3H,m),
7.64-7.65(2H,m), 9.85(1H,s), 10.03(1H,brs).ESI(+):412
NMR:1.3-1.7(5H,m), 1.9-2.0(1 H,m), 2.3-2.4(1H,m), 2.7-3.0(5H,m), 3.9-4.1 (2H,m), 6.41(1H,s), 7.23(1 H,dt,J=8.8Hz,2.5Hz), 7.35-7.40(2H,m), 7.46-7.52(1 H,m), 9.03(1 H,s), 9.50(1 H,brs).ESI(+):362
NMR:1.56-1.6(6H,m), 3.1913.23(6H,m), 3.81(2H,s),
7.21(1 H,dt,J=2.3,8.4Hz), 7.38-7.44(1 H,m), 7.56(1 H,dt,J=6.5,8.6Hz),
9.12(1H,s), 9.64(1 H.brs), 9.83(1 H,brs).ESI(+):380
NMR:1.47-1.69(4H,m), 1.96(1H,m), 2.61-2.93(5H,m), 3.27(1H,m), 4.68(1 H,m), 6.56(2H,s), 7.19-7.25(1 H,m), 7.37-7.42(2H,m), 7.47-7.53(1H,m), 9.04(1H,s), 9.60(1 H,br).ESI(+):348
NMR:1.59-1.65(1 H,m), 1.74-1.85(4H,m), 2.2-2.24(1 H,m), 2.74-
2.78(1H,m), 3.13-3.32(5H,m), 3.94-4.08(2H,m),
7.21(2H,dt,J=2.3,8.3Hz), 7.38-7.44(1 H,m), 7.55(1 H,dt,J=6.5,8.6Hz),
9.12(1H,s), 9.64(1H,brs), 9.93(1 H.brs).ESI(+):380
NMR:1.72-1.89(4H,m), 2,14(1 H.brs), 2.94(1 H,d,J=13.2Hz), 3.09-
3.24(4H,m), 3.55-3.61 (1H,m), 4.79-4.81(1H,m),
7.21 (1 H,dt,J=2.5,8.5Hz), 7.38-7.44(1 H,m), 7.58(1 H,dt.J=6.5,8.5Hz),
9.13(1H,s), 9.82(1H,brs), 10.24(1 H.brs).ESI(+):366
NMR:2.08-2.11(6H,m), 3.32-3.35(6H,m), 7.2(1 H,dt,J=2.4,8.6Hz),
7.36-7.42(1 H,m), 7.53(1 H,dt,J=6.5,8.6Hz), 9.11(1H,s), 9.68(1 H.brs),
10(1H.brs).ESI(+):366

[02:

Ex 168
[Table 54]
data
NMR:1.59-1.62(6H,m), 3.19-3.23(6H,m), 3.87(2H,s), 7.29-
7.33(3H,m), 9.09(1H,s), 9.68(1H,brs), 9.91(1H,brs), ESI(+):380

169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189

NMR:2.17(6H,brs), 3.34-3.39(6H,m), 7.44-7.49(3H,m), 7.58-7.58(1H,m), 9.04(1H,s), 9.64(1H,brs), 10.2(1H,brs), ESI(+):364
NMR: 1.59-1.65(1 H,m), 1.75-1.91 (4H,m), 2.24-2.28(1 H,m),
2.77(1 H,dd,J=6.5,13Hz), 3.14-3.17(4H,m), 3.27-3.29(1 H,m), 4-
4.14(2H,m), 7.28-7.34(3H,m), 9.08(1H,s), 9.68(1H,brs),
9.97(1 H.brs).ESI(+):380
NMR: 1.73-1.91 (4H,m), 2.16(1 H,brs), 2.93-3.23(5H,m), 3.57-
3.63(1H,m), 4.85-4.87(1 H,m), 7.44-7.51 (3H,m), 7.61(1H,brs),
9.07(1 H,s), 9.79(1 H.brs), 10.47(1 H,brs).ESI(+):364
NMR:2.14-2.18(6H,m), 3.35-3.39(6H,m), 7.24-7.33(3H,m), 9.08(1H,s), 9.72(1H,brs), 10.06(1 H,brs).ESI(+):366
NMR:1.48-1.64(6H,m), 3.13-3.22(6H,m), 3.84(2H,s),
5.67(2H,d,J=46.9Hz), 7.38-7.60(5H,m), 9.56(1 H,s),
10.05(1 H,brs).ESI(+):376
NMR: 1.74-1.91 (4H,m), 2.17(1H,brs), 2.98-3.24(5H,m), 3.59-
3.64(1H,m), 4.86-4.89(1 H,m), 7.29-7.33(3H,m), 9.1(1H,s),
9.85(1H.brs), 10.22(1H,brs).ESI(+):366
NMR:1.62-2.20(5H,m). 2.80-3.64(6H,m), 4.80-4.88(1 H,m),
5.67(2H,d,J=47.2Hz), 7.38-7.62(5H,m), 9.76(1 H,s),
10.45(1H.brs).ESI(+):362
NMR:1.58-1.61(6H,m), 3.18-3.22(6H,m), 3.86(2H,s), 7.44-
7.51(3H,m), 7.63(1H,brs), 9.06(1H,s), 9.61(1H,brs),
10.26(1H,brs).ESI(+):378
NMR:1.48-1.62(6H,m), 3.12-3.22(6H,tn), 3.85(2H,s),
7.36(1 H,t,J=54.2Hz), 7.43-7.65(5H,m), 9.71 (1H,s),
10.32(1 H,brs).ESI(+):394
NMR:1.61(1H,brs), 1.74-1.86(4H,m), 2.24(1H,brs), 2.75-2.79(1 H,m), 3.15-3.2(4H,m), 3.26-3.29(1 H,m), 3.99-4.13(2H,m), 7.44-7.5(3H,m), 7.61(1H,brs), 9.05(1 H,s), 9.61(1H,brs), 9.89(1 H,brs).ESI(+):378
NMR:1.60-2.20(5H,m), 2.80-3.26(5H,m), 3.50-3.62(1 H,m), 4.81-
4.87(1 H,m), 7.36(1 H,t,J=54.2Hz), 7.42-7.65(5H,m), 9.91 (1 H,s),
10.66(1 H,brs).ESI(+):380 '
ESI(+):396
ESI(+):344
ESI(+):396
ESI(+):382
ESI(+):345
ESI(+):412
ESI(+):358
ESI(+):398
ESI(+):358
ESI(+):398

[0226;
[Table 55]
Ex data
190 ESI(+) :358
191 ESI(+) :412
192 ESI(+) :380
193 ESI(+) 382
194 ESI(+) ■366
195 ESI(+) 396
196 ESI(+) 366
197 ESI(+) 378
198 ESI(+) 380
199 ESI(+) 378
200 ESI(+) 396
201 ESi(+) 364
202 ESI(+) 382
203 ESI(+) 350
204 ESI(+) 360
205 ESI(+) 350
206 ESI(+) 360
207 ESI(+) 376
208 ESI(+) 344
209 ESI(+) 376
210 ESI(+) 358
211 ES1(+) 362
212 ESI(+) 380
213 ESI(+) 362
214 ESI(+) 366
215 ESI(+) 424
216 ESI(+) 344
217 ESI(+) 410
218 ESI(+) 355
219 ESI(+) 396
220 ES1(+) 369
221 ESI(+) 348
222 ESI(+) 369
223 ESI(+) 334
224 ESI(+) 380
225 ESI(+) 387
226 ESI(+) 396
227 ESI(+) 336
228 ESI(+) 387

[02271 [Table 56]

Ex data
229 ESl(+):387
230 ESI(+):373
231 ESI(+):398
232 ESI(+):373
233 ESI(+):398
234 ESI(+):387
235 ESI(+):366
236 ESI(+):413
237 ESI(+):345
/LOO ESI(+):413
239 ESI(+):346
240 ESI(+):384
241 ESI(+);384
242 ESI(+):370
243 NMR:1.50-1.57(6H,m), 3.14-3.20(6H,m), 3.78(2H,s), 7.29-7.46(9H,m), 8.77(1 H,s), 10.26(1 H,brs).ESI(+):337
244 ESI(+):351
245 ESI(+):336
246 NMR: 1.47-1.81 (5H,m), 2.03-2.13(1 H,m), 2.54-2.61(1 H,m), 2.91-3.17(5H,m), 3.89-4.04(2H,m), 6.47(2H,s), 7.27-7.45(9H,m), 8.76(1H,s).ESI(+):337
247 ESI(+):362
248 ESl(+):336
249 ESI(+):362
250 NMR:1.57-2.00(8H,m), 2.67-2.76(1 H,m), 3.02-3.21 (4H,m), 3.24-3.32(1 H,m), 3.98(2H,t,d=8.0Hz), 7.36-7.41 (1H,m), 7.44-7.48(2H,m), 7.54-7.57(2H,m), 9.01(1H,s), 9.41(1H,brs), 10.25(1H,brs).ESI(+):358
251 NMR:1.41-1.70(4H,m), 2.28-2.32(1 H,m), 2.62-2.82(4H,m), 3.27-3.40(2H,m), 4.39-4.50(1 H.m), 4.39-4.50(1 H,m), 5.18(1H,brs), 7.35-7.47(3H,m), 7.52-7.56(2H,m), 8.98-9.00(1 H,m), 9.33-9.39(1 H,m), ESI(+):356
252 NMR: 1.44-1.65(8H,m), 3.13-3.20(6H,m), 3.98-4.03(2H,m), 7.35-7.48(3H.m), 7.53-7.57(2H,m), 8.99(1 H,s), 9.35(1H,s), 10.20(1 H,s).ESI(+):358
253 NMR:1.79-2.38(6H,m), 3.09-3.53(6H,m), 7.36-7.55(5H,m), 9.01(1H,s), 9.67(1 H,s), 11.06(1 H,s).ESI(+):330
254 NMR:1.87(2H,brs), 2.82-3.33(6H,m), 3.59-3.64(2H,m), 5.01-5.04(1H,m), 7.37-7.41(1H,m), 7.45-7.49(2H,m), 7.54-7.57(2H,m), 9.02(1H,s), 9.73(1H,s), 10.33(1H,brs).ESI(+):316
255 NMR:1.69-1.96(4H,m), 2.57(1H,b.s), 3.19-3.33(6H,m), 4.76-4.81 (1H,m), 7.36-7.4(1 H.m), 7.43-7.47(2H,m), 7.53-7.55(2H,m), 9(1 H,s), 9.51 (IH.s), 10.57(1 H.brs), ESI(+):330

[0228;

[Tab Ex
256

e57]
data
ESI(+):387

257
258
259
260
261
262
263
264
265
266
267
268
269
270

NMR:1.57(6H,brs), 3.14-3.20(6H,m), 3.49(2H,t,d=5.2Hz), 3.61(2H,t,d=5.2H2), 3.83(2H,s), 4.53(2H,s), 5.71(1H,brs), 7.22-7.43(10H,m), 8.42(1H,brs), 9.25(1H,s), 10.32(1H,s).ESI(+):493
NMR:1.57(6H,brs), 1.84-1.91 (2H,m), 2.67(2H,t,d=7.2H2), 3.17(6H,brs), 3.26(2H,t,d=7.2Hz), 3.83(2H,s), 4.72(1 H.brs), 7.17-7.43(1 OH,m), 8.50(1 H.brs), 9.26(1 H,s), 10.32(1 H,s).ESI(+):477
NMR:2.04(2H,brs), 2.18(2H,brs), 3.41(4H,brs), 3.52(2H,brs), 7.37-
7.41(1H,m), 7.44-7.48(2H,m), 7.53-7.55(2H,m), 9.02(1H,s),
9.82(1H,s), 10.61(1H,brs).ESI(+):316
NMR:1.6(2H,brs), 1.82(2H,brs), 2.89(2H,brs), 3.29(4H,brs),
4.27(2H,s), 7.37-7.4(1 H,m), 7.45-7.48(2H,m), 7.55-7.58(2H,m),
9.02(1 H,s), 9.54(1 H,s), 10.24(1 H.brs), ESI(+):330
NMR:1.55-1.64(6H,m), 3.17-3.24(6H,m), 3.87(2H,s),
7.38(1 H,t,J=54Hz), 7.52-7.58(3H,m), 7.69-7.71 (1H,m), 9.85(1 H,s),
10.23(1 H.s).ESI(+):428
NMR;1.46-2.4(6H,m), 2.86-3.38(6H,m), 3.83-4.17(2H,m), 7.36-
7.4(1H,m), 7.44-7.47(2H,m), 7.54-7.56(2H,m), 9(0.6H,s), 9.01(0.4H,s),
9.44(0.6H,brs), 9.47(0.4H,brs), 10.32(0.4H,brs),
10.41(0.6H,brs).ESI(+):344
NMR:1.65(3H,brs), 1.89(1H,brs), 2.58(1H,brs), 3.11-3.27(4H,m), 3.69-3.76(1H,m), 5.16-5.21 (1H,m), 7.37-7.41(1H,m), 7.45-7.48(2H,m), 7.56-7.58(2H,m), 9.02(1 H,s), 9.7(1 H.brs), 10.26(1 H,brs).ESI(+):330
NMR:1.6-1.68(3H,m), 1.86(1H,brs), 2.33-2.4(1 H,m), 2.7(1H,brs), 3.05-3.26(4H,m), 4.14-4.23(2H,m), 7.36-7.4(1 H,m), 7.44-7.48(2H,m), 7.54-7.56(2H,m), 9.00(1 H.s), 9.48(1 H.brs), 10.09(1 H,brs).ESI(+):344
NI\/IR:1,53-1.63(6H,m), 1.79(2H,brs), 3.18-3.26(6H,m), 3,74(2H,s),
7.36-7.4(1 H,m), 7.44-7.48(2H,m), 7.55-7.57(2H,m), 9.01(1H,s),
9.44(1 H.brs). 10.58(1 H,brs).ESI(+):358
NMR:1.5-2.1(8H,m), 2.97-3.24(6H,m), 4.00(2H,m), 6.49(2H,s),
7.38(1H,m), 7.45(2H.m), 7.55(2H,m), 9.00(1H,s),
9.42(1 H,brs).ESI(+):358
NMR:1.5-1.9(7H,m), 3.0-3.2(6H,m), 4.90(1 H,m), 6.52(2H,s),
7.37(1 H,s), 7.44(2H,m), 7.55(2H,m), 9.00(1 H,s),
9.47(1 H,brs).ESI(+):344
NMR:1.73-1.83(6H,m), 2.79-2.86(6H,m), 7.35(1 H,t,J=54Hz), 7.50-
7.53(3H,m). 7.64-7.65(1 H,m), 9.57(1 H,s).ESI(+):414
NMR:1.49-1.66(4H,m), 2.03-2.10(2H,m), 2.18-2.30(2H,m), 2.73-
2.94(6H,m), 7.42-7.50(3H,m), 7.58-7.60(1 H,m), 9.01(1H,s),
9.27(1H.s).ESI(+):378
NMR:1.17-1.27(1H,m), 1.41-1.68(3H,m), 1.84-1.98(1H,m), 2.10-
2.16(1 H,m), 2.28-2.37(2H,m), 2.48-2.73(4H,m), 3.68-3.76(2H,m),
7.35-7.57(5H,m), 8.99(1H,s). 9.35(1 H,s).ESI(+):344

Industrial A%aiiabilit>'
[0233]
The compound of the formula (I) or a salt thereof has an antagonistic action on the binding of a muscarinic M3 receptor, and can be therefore used as a prophylactic and/or therapeutic agent for an inflammatory disease such as chronic obstructive pulmonary disease (COPD), asthma and the like.

CLAIMS
1. A compound of the formula (I) or a salt thereof:
[Chem. 15]

is an aza-bridged-ring selected from the group consisting of the formulae (a), (b),(c),and(d):
[Chem. 16]


R-1 is halogen, -CN, -NH2, C1.6 alkyl, -O-C1.6 alkyl, -CONH2, -NH-C,.6 alkyl, -NH-C,.6 alkyl-O-Ci.6 alkyl-aryl, -NH-C1.6 alkyl-aryl, or -NH-Ci-e alkyl-OH,
in which C1.6 alkyl may be substituted with one or more halogen;
V is -NH- or -0-;
Wis-(CH2)q-or-(CH2)s-CH=;
qis 0, 1, or 2;
s is 1 or 2;
X" is a counter anion; and
— is a single bond or a double bond;
provided thai in the case where Ring A is a substituted benzene, R is phenyl, pyridyl, pyrazinyl, thiazolyl, or pyrazolyl, each of which may be substituted with one or more R11;
in the case where Ring A is an unsubstituted benzene, q is 1 or 2; and
in the case where the Ring A is cycloalkane, R is phenyl which may be substituted with one or more
2. The compound or a salt thereof as described in claim 1, wherein Ring A
is a hetero ring or cycloalkane,
each of which may be substituted with a group selected from the group consisting of one or more R ;
in which R1' is halogen, -CN, -NH2, C,.6 alkyl, -O-Ce alkyl, -CONH2, -NH-C,. 6 alkyl, -NH-Ci1 alkyl-O-Ci.6 alkyl-phenyl, -NH-C1.6 alkyl-phenyl, or -NH-Ci-e alkyl-OH,
in which Ci-e alkyl may be substituted with one or more halogen.
3. The compound or a salt thereof as described in claim 2, wherein Ring A is a group selected from the group consisting of thiophene, thiazole, isothiazole, thiadiazole, oxazole, isooxazole, cyclohexane, norborane, benzothiophene, and 5,6-dihydro-4H-cyclopentathiophene, each of which may be substituted with a group selected from the group consisting of one or more
4. The compound or a salt thereof as described in claim 3, wherein Ring A is a group selected from the group consisting of thiophene, thiazole, and cyclohexane.

each of which may be substituted with a group selected from the group consisting ot one or more R .
The compound or a salt thereof as described in claim 4, wherein R' is
H.
6. The compound or a salt thereof as described in claim 5, wherein
R is phenyl which may be substituted with one or more R ,
in which R1' is halogen, -OH, -CN, -CF3, -Ci-e alkyl, or -O-C1.6 alkyl.
7. The compound or a salt thereof as described in claim 6, wherein R'1 is an aza-bridged-ring selected from the group consisting of the formulae (a), (b), (c), and (d), in which in case of (a) or (c), (m, n, p) is (2, 1, 1), (1, 1, 2), or (2, 1, 2) for each sequence.
8. The compound or a salt thereof as described in claim 7, wherein R1 is an aza-bridged-ring selected from the group consisting of the formulae (a) and (b), and
R"1' is Ci-e alkyl, -C1.6 alkyl-0-phenyl, or -Ci-e alkyl-phenyl.
9. The compound or a salt thereof as described in claim 8, wherein Ring A is a thiazole which may be substituted with a group selected from the group consisting of one or more R .
10. The compound or a free base thereof as described in claim 4, which is

(1) l-azabicyclo[2.2.2]oct-4-ylmethyl(5-phenyl-l,3-thiazol-4-yl)carbamate hydrochloride,
(2) l-azabicyclo[3.2.2]non-5-yl(5-phenyl-l,3-thiazol-4-yl)carbamate hydrochloride,
(3)(3R)-l-azabicyclo[2.2.2]oct-3-yl[(lR,2S)-2-phenylcyclohexyl]carbamate hydrochloride,
(4) l-azatricyclo[3.3.1.1-3,7-]dec-4-yl(5-phenyl-l,3-thiazol-4-yl)carbamate hydrochloride,

(5) l-azabicyclo[2.2.2]oct-3-ylmethyl(2-phenyl-3-thienyl)carbamate hydrochloride,
(6) l-azabicyclo[2.2.2]oct-4-yl[5-(4-fluorophenyl)-l,3-thiazol-4-yl]carbamate hydrochloride,
(7) 1 -azabicyclo[3.2.1 ]oct-6-ylmethyl(5-phenyl-1,3-thiazol-4-yl)carbamate hydrochloride, or
(8) l-azabicyclo[2.2.2]oct-3-ylmethyl[5-(4-fluorophenyl)-l,3-thiazol-4-yl] carbamate fumarate.
11. The compound or an anionic exchanger thereof as described in claim 4,
which is
(l)4-({[5-(3 -chlorophenyl)-1,3 -thiazol-4-yl] carbamoyl} oxy)-1 -methyl-1 -azoniabicyclo [2.2.2] octane iodide,
(2) l-(3-phenylpropyl)-3-({[(2-phenyl-3-thienyl)carbamoyl]oxy}methyl)-l-azoniabicyclo [2.2.2] octane bromide,
(3) l-(2-phenylethyl)-4-{[(5-phenyl-l,3-thiazol-4-yl)carbamoyl]oxy}-l-azoniabicyclo[2.2.2]octane bromide,
(4) 1 -(2-phenoxyethyl)-4- {[(5 -phenyl-1,3 -thiazol-4-yl)carbamoyl] oxy} -1 -azoniabicyclo[2.2.2]octane bromide,
(5) 4-({[5-(2,5-difluorophenyl)-l,3-tliiazol-4-yl]carbamoyl}oxy)-l-methyl-l-azoniabicyclo [2.2.2] octane iodide,
(6) 1 -methyl-5-{ [(5-phenyl-l ,3-thiazol-4-yl)carbamoyl]oxy} -1 -azoniabicyclo[3.2.2]nonane iodide,
(7) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbamoyl}oxy)-1 -(2-phenoxyethyl)-1 -azoniabicyclo [2.2.2]octane iodide,
(8) 4-({[5-(3-chlorophenyl)-1,3-thiazol-4-yl]carbamoyl}oxy)-1 -methyl-1 -azoniabicyclo [2.2.2] octane bromide,
(9) 4-({[5-(3,5-dichlorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-1 -methyl-1 -azoniabicyclo[2.2.2]octane iodide,
(10)4-({[5-(2,5-difluorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-l-methyl-l-azoniabicyclo[2.2.2]octane bromide,
(11) 4-({[5-(2,4-difluorophenyl)-1,3-thiazol-4-yl]carbamoyl}oxy)-1 -methyl-1 -azoniabicyclo [2.2.2] octane bromide,

(12) l-methyl-4-{[(5-phen\i-l,3-thiazol-4-yl)carbainoyl]oxy}-l-
azoniabicyclo[2.2.2]octane bromide,
(13) 4-({[5-(3,5-dichlorophenyl)-l,3-thiazol-4-yl]carbamoyl}oxy)-l-methyl-l-
azoniabicyclo[2.2.2]octane bromide, or
(14) l-methyl-5-{[(5-phenyl-l,3-thiazol-4-yl)carbamoyl]oxy}-l-
azoniabicyclo[3.2.2]nonane bromide.
12. A pharmaceutical composition comprising the compound or a salt thereof as described in claim 1, and a pharmaceutically acceptable excipient.
13. A pharmaceutical composition for preventing or treating an inflammatory disease, comprising the compound or a salt thereof as described in claim 1.
14. Use of the compound or a salt thereof as described in claim 1 for the
preparation of a pharmaceutical composition for preventing or treating an inflammatory
disease.
15. Use of the compound or a salt thereof as described in claim 1 for
prevention or treatment of an inflammatory disease.
16. A method for preventing or treating an inflammatory disease,
comprising administering to a patient an effective amount of the compound or a salt
thereof as described in claim 1.