DESCRIPTION
2-cyanopyrrolidine carboxamide compound
TECHNICAL FIELD
This invention relates to the compound and pharmaceutically acceptable salt thereof which inhibit dipeptidyl peptidase-IV (DPP-IV).
Moreover, this invention relates to medicament or pharmaceutical composition comprising the above-mentioned compound or pharmaceutically acceptable salt thereof as an active ingredient, a method for treatment and/or prevention of NIDDM, use of the above compound, and the like.
BACKGROUND ART
It is known that DPP-IV has various physiological functions in living body, especially has the action which inactivates Glucagon-like peptide-1 (GLP-1) by cleaving the terminal dipeptide (His-Ala) and decomposes some cytokines. That is, the resultant peptide is the receptor antagonist of GLP-1 and totally reduces the activity of GLP-1.
This GLP-1 has very important role in sugar metabolism. For example, (1) GLP-1 intensifies the secretion of insulin, (2) express genes which are indispensable for the secretion of insulin, (3) stimulate proliferation of
j3 -cell, (4) sup presses secretion of glucagon, (5) suppresses the function about secretion and motility of digestive organs (especially, peristalsis), and (6) suppresses appetite. That is, GLP-1 restricts food ingestion, postpones the process of digestion and absorption, and raised the use of the sugar in blood-Therefore, the inhibitor of DPP-IV can maintain the activity of GLP-1, so it is expected as a medicine to treat

and prevent various diseases, especially non-insulin dependent diabetes mellitus (NIDDM).
Hitherto, such inhibitors of DPP-IV are known so far. For example in US 6,011,155 and 6,124,305, 2-cyanopyrrolidine compounds having [3.1.1]bicyclo moiety like following are disclosed.

Pyrrolidine, 1 -[(2,6,6-trimethylbicyclo[3.1.1 ]hept-3-yl)amino]acetyl-2-cyano, (S)[lS[lo,2P,3o(S),5a]] monohydrochloride
However, the azabicyclo structure of Compound (I) of the present invention is not described in this prior art. In WO 00/34241, 2-cyanopyrrolidine compounds having substituted adamantyl structure like following are di sclosed.

"LAF-237"
Pyrrolidine, 1 -[(3-hydroxy-1 -adamantyl)amino]acetyl-2-cyano, (S)
However, adamantyl structure is different from the azabicyclo structure of Compound (I) of the present invention.
In WO 03/57666, the azabicyclo compound as following is de scribed.
However, the azabicyclo structure of Compound (I) of the present invention is not described.

The hydroxypyrroridine compound like following is described in WO 02/14271.

In this document, however, the azabicyclo structure of Compound (I) of the present invention is not described.
WO 02/38541 discloses 2-cyanopyrrolicine compound, However, the azabicyclo structure of Compound (I) of the present invention is not described.
WO 03/074500 discloses (2S,4S)-4-fluoro-l-(2-{ [8- (2-pyrazinyl)-8-azabicyclo[3.2.1]oct-3-yl]amino}a cetyl)-2-pyrrolidinecarbonitrile dihycrochloride as Example 2.
By comparison of this compound and Compound (I) of the present invention, the position of nitrogen atom in azabicyclo structure is different, and pyrrolidine ring is connected to azabicyclo structure by the intermediary of only carbonyl group in Compound (I) . Compound (1) of the present invention is different from this compound in that Compound (1) is substituted at 3-position of azabicyclo structure.
WO 03/002553 discloses piperidine compounds such as (2S,4S)-4-fluoro-l- ( { [1-(isopropylsulfonyl) -4-piperid inyl]amino}acetyl)-2-pyrrolidinecarbonitrile hydro chloride.


However, the compounds described in the prior art are substituted by sulfonyl group at the nitrogen atom of piperidine ring.
The pyrroridine compound having piperidine ring substituted by the substituent except sulfonyl group is described in WO 02/30890. However, the pyrroridine ring of this compound is not substituted by fluorine atom, compared with Compound (1) of the present compound.
In US 6,172,081, DPP-IV inhibitor having tetrahydroisoquinoline and pyrrolidine structure is described. This compound is obviously different from Compound (2) having tetrahydroquinoline structure.
DISCLOSURE OF INVENTION
Under the above situation, the inventors of this invention found that the compound of this invention (especially, the compound having specific azabicyclo structure) has the outstanding activity to inhibit DPP-IV, and the inventors completed this invention.
Accordingly, this invention relates to DPP-IV inhibitor. More particularly, this invention relates to DPP-IV inhibitor useful for treating or preventing conditions mediated by DPP-IV, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyperlipidemia, metaboli c acidosis, diabetes mellitus (IDDM and NIDDM) , diabetic neuropathy, nephropathy, and secondary diseases in mammals caused by diabetes mellitus.
That is, one object of this invention is to provide new compound and pharmaceut ically acceptable salt thereof, of which activity to inhibit DPP-IV is remarkably improved against known compounds.
Another object of this invention is to provide a medicament and pharmaceutical composition containing the compound and/or pharmaceutical1y acceptable salt thereof

as an active ingredient.
A further object of this invention is to provide a inhibitor of DPP-IV and a method for inhibiting DPP-IV comprising administering an effective amount of the compound and/or pharmaceutically acceptable salt thereof.
A further object of this invention is to provide a use of the compound and pharmaceutically acceptable salt thereof as medi caments.
A further object of this invention is to provide the compound and pharmaceutically acceptable salt thereof which are useful for the manufacture of medicaments for treating or preventing conditions mediated by DPP-IV inhibition, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus (IDDM and NIDDM), diabetic neuropathy, nephropathy, and secondary diseases in mammal s caused by diabetes mellitus, especially NIDDM.
A further object of this invention is to provide the commercial package compri sing the pharmaceutical composition containing the new compound.
The present invention is directed to the following compound of the formula (I) or pharmaceutically acceptable salt thereof.
[wherein
X1 and X2 each is independently lower alkylene; X3 is =CH2, =CHF or =CF2; R1 is substituent;

R2 and R3 are independently H or lower alkyl; n is 0, 1, 2, 3 or 4 . ]
The present invention is also directed to the following compound having formula (1) orpharmaceutically acceptable salt thereof:
[wherein
Y1 is -O-, -S- or =NR16;
Y2 is =CHF or =CF2;
R11 is lower alkyl or lower alkyl substituted by
hydroxy; R12, R13, R14 and R15 are independently H, lower alkyl
or R13 and R14 may be connected together to make
lower alkylene; R16 is lower alkyl, heteroaryl (optionally
substituted by substituent (i) ) or [straight
chain lower alkyl]sulfonyl; substituent (i) is selected from the group consisting
of lower alkyl, lower alkoxy, amino, carboxy,
hydroxy, cyano and halogen.]
Furthermore, the present invention is directed to the following compound having formula (2) or pharmaceutically acceptable salt thereof:


[wherein
Z1 is -0-, -S- or =NR24;
Z2 is = CH2, =CHF or =CF2;
R21 is H, lower alkyl or lower alkyl substituted by
hydroxy; R22 and R23 are independently H, lower alkyl;
O A
R is lower alkyl, heteroaryl (optionally substituted by substituent (ii)) or [straight chain lower alkyl]sulfonyl;
benzene ring may be optionally substituted by substituent (ii);
substituent (ii) is selected from the group consisting of lower alkyl, lower alkoxy, amino, carboxy, hydroxy, cyano and halogen.]
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail in the following.
The term "lower" is intended to mean a group having 1 to 6 carbon atom(s), unless otherwise provided.
Therefore, the "lower alkylene" means a straight or branched chain aliphatic hydrocarbon divalent group, such as methylene, methylmethylene, ethylmethylene, isopropylmethylene, isobutylmethylene, tert-butylmethylene, dimethylmethylene, isopropylmethylmethylene, ethylene, methylethylene, ethylethylene, isopropylethylene, isobutylethylene, tert-butylethylene, 1,1-dimethylmethylene, 1,2-dimethylmethylene, propylene, methylpropylene, ethylpropylene, isopropylpropylene, and the like. It is preferably (C1-C4)alkylene, more preferably (C1-C3)alkylene, more preferably (C1-C2)alkylene, most preferably methylene or ethylene. Preferably, in the definition of X1 and X2, the lower alkylene is methylene

or ethylene which may be substituted by ( C1-C4)alkyl.
The "lower alkyl" means a straight or branched chain aliphatic hydrocarbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. It is preferably (C1-C4) alkyl, more preferably (C1-C2)alkyl, most preferably methyl.
The "(lower)alkenyl" means a straight or branched
chain aliphatic hydrocarbon group having more than one
double bond between two carbon atoms, such as vinyl,
1-methylvinyl, 1-propenyl, 2-propenyl,
1-methyl-l-propenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, pentenyl, hexenyl, and the like. It is preferably (C2-C5)alkenyl, more preferably (C2-C5)alkenyl, most preferably 2-propenyl (allyl).
The "aryl" means an aromatic hydrocarbon group, such as phenyl, naphthyl, indenyl, and the like, and it is preferably (C6-C10)aryl, more preferably phenyl.
Therefore, the "aryloxy" means oxy group substituted with the above aryl, and includes phenyloxy, naphthyloxy, indenyloxy, and the like, and it is preferably phenyloxy.
The "heteroaryl" means 5- or 6-membered aromatic heterocyclic group which contains at least one hetero atom such as nitrogen, oxygen and sulfur atom. The "heteroaryl"may include 5-membered heteroaryl group such as pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazol, or the like; 6-membered heteroaryl group such as pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, or the like. It is preferably nitrogen containing heteroaryl, more preferably thiadiazol or pyridinyl, most preferably pyridinyl. The "heteroaryloxy" means oxy group substituted said heteroaryl group.
The "lower alkanoyl" means a formyl and a lower alkyl carbonyl group such as acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and

the like. It is preferably (Cl-C4)alkanoyl (including formyl), more preferably (Cl-C2)alkanoyl, most preferably acetyl.
The " (lower alkyl) sulfonyl", xvarylsulfonyl", "heteroarylsulfonyl" means sulfonyl group substituted with the above lower alkyl, aryl, heteroaryl, respectively.
The " (lower)alkoxy" means a straight or branched chain aliphatic hydrocarbon oxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, and the like. It is preferably (Cl-C4)alkoxy, more preferably (C1-C2)alkoxy.
The "aryl (lower alkyl) oxy" means the '"lower alkoxy" group mentioned above substituted by aryl group, and includes benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, naphthylmethoxy, 2-naphthylethoxy, and the like. It is preferably phenyl (lower alkyl)oxy, more preferably phenyl[(Cl-C4)alkyl]oxy, more preferably phenyl[(Cl-C2)alkyl]oxy 1, most preferably benzyloxy.
The "heteroaryl (lower alkyl)oxy" means the "lower
alkoxy" group mentioned above substituted by heteroaryl
group. It is preferably heteroaryl[(Cl-C4)alkyl]oxy,
more preferably heteroaryl[(C1-C2)alkyl]oxy, more
preferably (nitrogen containing
heteroaryl)[(Cl-C2)alkyl]oxy, most preferably pyridinylmethyloxy.
The "saturated heterocyclyl" means 5- or 6-membered saturated heterocyclyl group which contains at least one hetero atom such as nitrogen, oxygen, or sulfur atom. The "saturated heterocyclyl" may be substituted with general substituent such as lower alkyl. The "saturated heterocyclyl" may include 5-membered saturated heterocyclyl group such as pyrrolidinyl,

methylpyrrolidinyl, imidazolidinyl, pyrazolidyl, tetrahydrofuranyl, tetrahydrothiophenyl, oxazolidyl, isoxazolidyl, thiazolidyl, isothiazolidyl, or the like; and 6-membered saturated heterocyclyl group such as piperidyl, piperazinyl, tetrahydropyranyl, pentamethylene sulfide, morpholinyl, or the like. It is preferably nitrogen containing saturated heterocyclyl.
The "halogen" may include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, more preferably a fluorine atom or a chlorine atom, most preferably a fluorine atom.
The "(lower alkyl)amino" means a amino group substituted by the above lower alkyl group, such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, pentylamino, hexylamino, and the like. It is preferably [(C1-C4)alkyl]amino, more preferably [(Cl-C2)alkyl]amino.
The udi(lower alkyl)amino" means a amino group substituted by the same or different above two lower alkyl groups, such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, dipentylamino, dihexylamino, ethylmethylamino, methylpropylamino, butylmethylamino, ethylpropylamino, butylethylamino, and the like, and it is preferably di[ (C1-C4)alkyl]amino, more preferably di[(Cl-C2)alkyl]amino, most preferably dimethy1amino.
The "arylamino" means amino group substituted with the above aryl, and includes phenylamino, naphthylamino, indenyl amino, and the like, and it is preferably phenylamino.
The "heteroarylamino" means amino group substituted said heteroaryl group.
The "halogenated(lower alkyl)" means the above lower alkyl substitutedbyhalogenatom(s) , suchas fluoromethyl,

chloromethyl, di fluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, 2,2,2-trifluoroethyl, 2, 2,2-trichloroethyl, 2,2,3,3,3-pentafluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl, and the like. It is preferably halogenated[(Cl-C4)alkyl], more preferably halogenated[(Cl-C2)alkyl], more preferably fluorinated[(Cl-C4)alkyl], more preferably fluorinated[ (C1-C2)alkyl] , most preferably trifluoromethyl .
The " (lower alkyl)sulfonylamino",
"[halogenated(lower alkyl)]sulfonylamino",
"arylsulfonylamino", "heteroarylsulfonylamino", "di (lower alkyl)aminosulfonylamino" means sulfonylamino group substituted with the above lower alkyl, [halogenated(lower alkyl), aryl, heteroaryl, di(lower alkyl)amino, respectively.
The tt(lower alkanoyl)amino" means amino group substituted with the above lower alkanoyl.
The "lower alkyl substituted by hydroxy" means the above mentioned lower alkyl group substituted by a hydroxy, such as hydroxymethyl, hydroxyethyl, hydroxypropy1, hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl, (hydroxy)tert-buty1, and the like, and it is preferably (C1-C4)alkyl substituted by hydroxy, more preferably (Cl-C2)alkyl substituted by hydroxy, most preferably hydroxymethyl.
The "[straight chain lower alkyl]sulfonyl" in the definition of R16 or R24 is exempli fied methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, and the like, and it is preferably methylsulfonyl or ethylsulfonyl, most preferably methylsulfonyl.
The "substituent" in the definition of Compound (I) is not limited, but means general substituent. The " substituent" can be exempli fied by:

(a) R40- wherein R4 is H, lower alkyl optionally
substituted with substituent a , lower alkenyl, aryl
optionally substituted with substituent a , orheteroaryl
optionally substituted with substituent a ;
(b) R5R6N- wherein R5 and R6 each is independently H, lower
alkyl, lower alkanoyl, (lower alkyl)sulfonyl,
arylsulfonyl optionally substituted with substituent a , or heteroarylsulfonyl optionally substituted with
substituent a ;
(c) R7N= wherein R7 is H, hydroxy, lower alkoxy,
aryl(lower alkyl)oxy optionally substituted with
substituent a on the aryl group, or heteroaryl(lower
alkyl)oxy optionally substituted with substituent a on
the heteroaryl group,
(d) saturated heterocyclyl;
(e) carboxy;
(f) sulfonic acid;
(g) halogen; and
(h) oxo.
The above substituent a is not also limited, but means general substituent. The "substituent a" can be selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, aryloxy optionally substituted with substituent β , heteroaryloxy optionally substituted with substituent β , amino, (lower alkyl) amino, di (lower alkyl)amino, arylamino optionally substituted with
substituent β on the aryl group, heteroarylamino optionally substituted with substituent β on the heteroaryl group, (lower alkyl)sulfonylamino, [halogenated(lower alkyl)]sulfonylamino, arylsulfonylamino optionally substituted with substituent β on the aryl group, heteroarylsulfonylamino optionally substituted with substituent β on the heteroaryl group, di (lower alkyl)aminosulfonylamino, oxo, imino, hydroxyimino, (lower alkyl)sulfonyl,

arylsulfonyl optionally substituted with substituentβ , heteroarylsulfonyl optionally substituted with
substituent β , lower alkanoyl, halogen, cyano, nitro and carboxy.
The above substituent β is not also limited, but means general substituent. The "substituent β" can be selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, (lower alkanoyl)amino, halogen, cyano, nitro and carboxy.
The number of substituent a and β may be two or more if feasible. In case that the number of substituent a or β is plural, they may be identical or different to each other. For example, lower alkyl optionally
substituted with substituent a in the definition of R4 includes lower alkyl substituted with carbamoyl which may be further substituted with such as sulfonyl group, two or more hydroxys, and alkoxycarbonyl.
From another point of view, hydrophilic group is preferable as the "substituent" in the definition of Compound (I) . The "hydrophilic group" means polar group having strong affinity for water and general group substituted by such polar group. The xxhydrophilic group" can be exemplified by hydroxy, amino, carboxy, sulfonic acid, imino, and lower alkoxy substituted by such as hydroxy, or the like.
"R1" in Compound (I) may be located on the azabicyclo moiety directly or on the alkyl group in the X1, X2, R2 or R3, preferably it is located directly on the azabicyclo moiety. In case that the number of R1 is plural (n is 2 , 3 or 4) , R1s may be identical or different to each other.
The "heteroaryl" in the definition of R16 and R24 in
Compound (1) and (2) may be substituted by substituent
(i) and (ii) , respectively. The number of the substituent
depends on the kind of the heteroaryl, and is preferably

1 to 3, more preferably 1 or 2, most preferably 1. In case that the number of substituent (i) or (ii) is plural, they may be same or different each other.
The Compound (I) , (1) and (2) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. This invention includes both mixtures and separate individual isomers. However, in the 2-position of 2-cyanopyrrolidine moiety (the position substituted with cyano group), (2S) isomer is more preferable.
The compounds of the formula (I), (1) and (2) may also exist in tautomeric forms and this invention includes both mixtures and separate individual tautomers.
The Compound (I), (1), (2) and their salts may be in a form of a solvate such as hydrate, which is included within the scope of the present invention.
Also included in the scope of this invention are radiolabelled derivatives of Compound (I), (1) and (2) which are suitable for biological studies.
In the scope of the present invention, the prodrug of the Compound (I), (1) and (2) is included, which prodrug is capable of undergoing metabolic conversion to Compound (I), (1) and (2) following administration in body. Further, in the scope of the present invention, metabolites of Compound (I), (1) and (2) are included, which metabolites are therapeutically active in the treatment of the targeted medical condition.
The compounds of this invention can be converted to salt according to a conventional method. Suitable salts of the compounds (I), (1) and (2) are pharmaceutically acceptable conventional non-toxic salts and include an organic acid salt (e.g., acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, trifluoroacetate, or the like), an inorganic acid salt (e.g., hydrochloride, hydrobromide,

sul f ate, phosphate, or the like), a salt with an ami no acid (e.g., aspartate, glutamate, or the like), or the like.
In the each definition of the Compound (I), pre ferably,
(1) X1 and X2 each is independently (C1-C4)alkylene;
(2) X1 and X2 each is independently ( C1-C3)alkylene;
(3) X1 and X2 each is independently ( C1-C2)alkylene;
(4) X1 is methylene;
(5) X1 is ethylene;
(6) X2 is methylene;
(7) X2 is ethylene;
(8) X3 is =CH2 or =CHF;
(9) X3 is =CH2;

(10) R1 is hydrophilic group;
(11) R1 is selected from the group consisting of hydroxy,
lower alkoxy optionally substituted with hydroxy(s),
lower alkenyloxy, amino optionally substituted with lower
alkanoyl, halogen, oxo, imino and hydroxyimino;
(12) R1 is selected from the group consisting of hydroxy,
amino and halogen;
(13) R1 is selected from the group consisting of hydroxy,
amino, (lower alkyl)amino and di(lower alkyl)amino;
(14) R1 is hydroxy;
(15) R1 is amino, (lower alkyl)amino or di (lower
alkyl)amino;
(16) R1 is amino, [( Cl-C2)alkyl]amino or
di[(Cl-C2)alkyl]amino;
(17) R1 is R4O- wherein R4 is lower alkyl optionally
substituted with substituent α , aryl optionally
substituted with substituent α , or heteroaryl optionally
substituted with substituent α ; the said substituent a
is selected from the group consisting of hydroxy,
arylamino, heteroarylamino, arylsulfonylamino,

heteroarylsulfonylamino, oxo, imino, hydroxyimino, lower alkanoyl, halogen, cyano, nitro and carboxy;
(18) R1 is lower alkoxy optionally substituted with
substituent α , the said substituent α is selected from the group consisting of hydroxy, lower alkoxy, amino,
(lower alkyl)amino, di(lower alkyl)amino, (lower
alkyl)sulfonylamino, [halogenated(lower
alkyl)]sulfonylamino, di(lower
alkyl)aminosulfonylamino, oxo, imino, hydroxyimino and
carboxy;
(19) R1 is selected from the group consisting of lower
alkoxy optionally substitute d with substituent α , the
said substituent α is selected from the group consisting
of aryl (lower alkyl)oxy optionally substituted with
substituted with substituent β , heteroarylamino optionally substituted with substitutedwith substituent
β , heteroarylsulfonylamino optionally substituted with substituted with substituent β , oxo and arylsulfonyl optionally substituted with substitutedwith substituent
β , the said substituent β is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (loweralkanoyl)amino, halogen, cyano, nitro and carboxy;
(20) R1 is lower alkoxy optionally substituted with
substituent a ; the substituent a is selected from the group consisting of heteroarylamino optionally
substituted with substituent β on the heteroaryl group, heteroarylsulfonylamino optionally substituted with
substituent )3 on the heteroaryl group and oxo; the said substituent^ is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di (lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy.
(21) R1 is selected from the group consisting of aryloxy
optionally substituted with substituent a ,
heteroaryloxy optionally substituted with substituent a ,

and saturated heterocyclyl; the said substituent α is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy;
(22) R1 is selected from the group consisting of aryloxy
optionally substituted with substituent α , and heteroaryloxy optionally substituted with substituent
α ; the said substituent α is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di (lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy;
(23) R1 is R5R6N- wherein R5 and R6 each is independently
(lower alkyl)sulfonyl, arylsulfonyl optionally
substituted with substituent α , or heteroarylsulfonyl
optionally substituted with substituent α ; the said
substituent α is selected from the group consisting of
lower alkyl, hydroxy, lower alkoxy, amino, (lower
alkyl)amino, di(lower alkyl)amino, lower alkanoyl,
halogen, cyano, nitro and carboxy;
(24) R1 is R7N= wherein R7 is H, hydroxy, lower alkoxy,
or aryl (lower alkyl) oxy optionally substituted with
substituent a on the aryl group; the said substituent
α is selected from the group consisting of lower alkyl,
hydroxy, lower alkoxy, amino, (lower alkyl)amino,
di (lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy;
(25) R1 is selected from the group consisting of lower
alkoxy, amino and imino, the said lower alkoxy, amino and
imino optionally substituted with substituent α , the said
substituent α is selected from the group consisting of
hydroxy, aryloxy optionally substitutedwith substituent
β , heteroaryloxy optionally substituted with substituent β , aryl (lower alkyl) oxy optionally substituted with substituent β on the aryl group,

arylamino optionally substituted with substituent β on the aryl group, heteroarylamino optionally substituted
with substituent β on the heteroaryl group, arylsulfonylamino optionally substituted with
substituent β on thearyl group, heteroarylsulfonylamino optionally substituted with substituent β on the heteroarylgroup, oxo, imino, hydroxyimino, arylsulfonyl
optionally substituted with substituent β on the aryl group, heteroarylsulfonyl optionally substituted with
substituent β on the heteroaryl group, lower alkanoyl, halogen, cyano, nitro and carboxy; the said substituent
β is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di (lower alkyl)amino, (lower alkanoyl)amino, halogen, cyano, nitro and carboxy;
(26) R1 is selected from the group consisting of lower
alkoxy, amino and imino, the said lower alkoxy, amino and
imino optionally substituted with substituent α ; the said
substituent α is selected from the group consisting of
aryl(lower alkyl)oxy, heteroarylamino,
heteroarylsulfonylamino, oxo, arylsulfonyl, the said
aryl(lower alkyl)oxy, heteroarylamino,
heteroarylsulfonylamino and arylsulfonyl may have
substituent β on the aryl or heteroaryl group, the
substituent β is selected from the group consisting of
lower alkyl, hydroxy, lower alkoxy, amino, (lower
alkanoyl)amino, halogen, cyano, nitro and carboxy;
(27) R2 and R3 each is independently H or (C1-C4 ) alkyl ;
(28) R2 and R3 each is independently H or (C1-C2 ) alkyl ;
(29) R2 and R3 are H;
(30) R2 is H or (Cl-C4)alkyl;
(31) R2 is H;
(32) R2 is (C1-C2)alkyl;
(33) R2 is methyl;
(34) R3 is H or (C1-C4) alkyl;

(35) R3 is H;
(36) R3 is methyl;
(37) R3 is isopropyl;
(38) n is 1, 2, 3 or 4 ;
(39) n is 1 or 2;
(40) n is 1;
(41) n is 2.
The Compound (I) is preferably selected from: (2S)-l-{ [ (lS,3Sf4S,5S,6R)-5, 6-Dihydroxy-2-azabicyclo [ 2.2.2]oct-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride;
(2S)-1-{[(1S,3S,4S,5R)-5-Hydroxy-2-azabieyelo[2.2.2] oct-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride;
(2S)-1-{ [ (lR,3S,4S,6R)-6-Hydroxy-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride;
(2S)-1-{[(1R,3S,4S,6S)-6-Hydroxy-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride; (2S)-l-{ [ (lR,3S,4S,6R)-6-(2-Hydroxyethoxy)-2-
azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride;
(2S) -1-{ [ (lRf3S,4S,6Z)-6-Hydroxyimino-2-azabicyclo[2.
2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile
hydrochloride;
N-( (lRf3S,4S,6R)»3-{ [ (2S)-2-Cyano-l-pyrrolidinyl]
carbonyl}-2-azabicyclo[2.2.l]hept-6-yl)acetamide
hydrochloride;
(2S)-1-{[(1R,3S,4R,6R)- 6-Amino-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile dihydrochloride;
(2S) -1-{ [ (lR,4R,5Rr7S)-4-Hydroxy-6-azabicyclo[3.2.1] oct-7-yl]carbonyl}-2-pyrrolidinecarbonitrile

hydrochloride.
In the each definition of the compound formula (1), pre ferably,
(42) Y1 is -0-;
(43) Y1 is -S-;
(44 ) Y1 is =NR16;

(45) Y2 is =CHF;
(46) R11 is (Cl-C4)alkyl;
(47) R11 is (Cl-C4)alkyl substituted by hydroxy;
(48) R11 is hydroxymethyl;
(49) R12, R13, R14 and R15 are independently H or methyl;
(50) R12 and R15 are independently H or methyl, and R13
and R14 may be connected together to make (C1-C4) alkylene;
(51) R12 and R15 are independently H or methyl, and R13
and R14 may be connected together to make ethylene;
(52) R16 is (C1-C4)alkyl;
(53) R16 is heteroaryl (optionally substituted by
substituent (i));

(54) R16 is heteroaryl;
(55) R16 is nitrogen containing heteroaryl (optionally
substituted by substituent (i) ) ;
(56) R16 is nitrogen containing heteroaryl;
(57) R16 is [(Cl-C2)alkyl]sulfonyl;

(58) substituent (i) is selected from the group
consisting of lower alkoxy, amino and hydroxy;
(59) substituent (i) is selected from the group
consisting of carboxy, cyano and halogen;

(60) substituent (i) is cyano or halogen;
(61) substituent (i) is(are) cyano.
In the each definition of the compound formula (2), pre ferably,
(62) Z1 is - 0 - ;
(63) Z1 is -S-;

(64) Z1 is = NR24;
(65) Z2 is =CH2 or =CHF;
(66) Z2 is =CHF;
(67) R21 is H;
(68) R21 is (Cl-C4)alkyl;
(69) R21 is (Cl-C4)alkyl substituted by hydroxy;
(70) R21 is hydroxymethyl;
(71) R22 and R23 are independently H or methyl;
(72) R22 and R23 are H;
(73) R24 is (Cl-C4)alkyl;
(74) R24 is heteroaryl (optionally substituted by
substituent (ii) ) ;
(75) R24 is heteroaryl;
(76) R24 is nitrogen containing heteroaryl;
(77) R24 is [(Cl-C2)alkyl]sulfonyl;

(78) substituent (ii) is selected from the group
consisting of lower alkoxy, araino and hydroxy;
(79) substituent (ii) is selected from the group
consisting of carboxy, cyano and halogen;

(80) substituent (ii) is cyano or halogen;
(81) substituent (ii) is cyano.

The Compound (I) of the present invention can be prepared according to the following Process A. Proces s A

In the above formula, R1 to R3, X1 to X3 and n represent
the same meanings as defined above. "R1' " represents R1 protected not to inhibit this reaction, if needed. "Pro" represents protective group of amino group.
Process A is the process for preparing the Compound
(I) -
Proces s A-1
This process is carried out by reacting carboxylic acid Compound (II) with pyrrolidine Compound (III) or (III1) in the presence of catalyst in solvent.
Compound (II) may be purchased if it is commercial, or synthesized according to Process B to Process E mentioned after or other general methods obvious to the person skilled in the organic chemistry from commercial compounds. Compound (III) and (III1) may be purchased if it is commercial or synthesized by general methods obvious to the person skilled in the organic chemistry

from commerci al compounds , since the structure of Compound (III) and (III1) is relatively s imple.
In this process, general amide-forming reaction such as the reaction using condensing agent can be employable. The condensing agent employable in this process is not particularly limited so long as it accelerates forming amide bond and may include carbodiimide compounds such as dicyclohexylcarbodiimide (DCC), diisopropyl-carbodiimide (DIPCI) , water solvable carbodiimide (WSCD) such as l-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide.
In this case, additive is generally used. The additive employable in this process is not particularly limited so long as it can mainly make the carboxyl groups of Compound (II) active or suppress the racemization, and may include 1-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy~4-oxo-l,2,3-benzotriazole (HOOBt), l-hydroxy-7-azabenzotriazole (HOAt).
The solvent employable in this process is not particularly limited so long as it is inactive in this reaction and may include amides such as dimethylformamide and dimethylacetamide; alcohol such as methanol and ethanol.
This process is generally carried out by adding Compound (III) or (111 ! ) and base, to the solution of Compound (II), condensing agent and additive.
The base employable in this step may include organic amines such as triethylamine and diisopropylethylamine (DIEA).
The temperature at that time depends on the starting material, the solvent, or the like, and it is usually room temperature.
The reaction time after the adding depends on the starting material, the solvent, or the like, and it is usually from lhr to 24hrs.

After the reaction, the mixture is quenched with water, and extracted with organic solvent insoluble with water such as ethyl acetate, chloroform, or the like. The organic layer is washed by water such as hydrochloric acid, saturated aqueous NaHCO3, brine, or the like. The washed organic layer is dried over anhydrous magnesium sulfate or sodium sulfate, and evaporated in vacuo. The target compound is purified by the conventional method such as silica gel chromatography to obtain Compound (IV) or (IV1).
Process A-2
Then, carbamoyl group of Compound (IV ) is transformed to cyano group to synthesize Compound (IV), i f nece s sary.
In this Process A-2, some general dehydration reactions can be adopted. For example, acid anhydride such as trifluoroacetic anhydride and organic amine are reacted with Compound (IV1) in solvent.
The organic amine employable in this process may include pyridine, triethy1amine, tributylamine, diisopropylethylamine.
The solvent employable in this process is not particularly limited so long as it is inactive in this reaction, and may include ether such as diethyether, tetrahydrofuran and dioxane.
This Process A-2 is generally carried out by adding organic amine and acid anhydride to the solution of Compound (IV1 ) . When organic amine and acid anhydride
were added, the temperature is preferably -10˚C to 20˚. However, after the addition, the temperature can be raised to room temperature. The reaction time after the addition depends on the starting material, the solvent, or the like, and it is usually from lhr to 12hrs.
After the reaction, the mixture is alkalized with

base such as saturated aqueous NaHCO3, and concentrated in vacuo. The residue is diluted with H2O, the mixture is extracted with organic solvent insoluble with water such as ethyl acetate, chloroform, or the like. The organic layer is dried over anhydrous magnesium sulfate or sodium sulfate, and evaporated in vacuo. The target compound is purified by the conventional method such as recrystallization to obtain Compound (IV).
Proces s A-3
Finally, in case that "Pro" is protective group of amino group, Compound (IV) is deprotected to give Compound
(I) .
Concerning the protective group of Compound (IV), the general kind and the condition of cleavage reaction may be referred to FPROTECTIVE GROUPS IN ORGANIC SYNTHESIS Second EditionJ T.W.Green and P.G.M.Wuts, John Wiley & Sons, INC. (the contents of which are hereby incorporated by re ference) .
For example, in case that "Pro" is carbamate such as tert-butoxycarbony1 or methoxycarbonyl, the cleavage reaction is carried out in acidic condition.
The solvent employable in this case is not particularly limited so long as it is inactive in this reaction and may include halogenated hydrocarbon such as dichloromethane, chloroform.
The reagent for making acidic condition is not particularly limited so long as it accelerates cleavage reaction and may include hydrogen chloride solution in solvent such as 4N hydrogen chloride solution in 1,4-dioxane.
This process is generally carried out by adding the reagent for making acidic condition dropwise to the solution of Compound (IV) . The temperature at that time depends on the starting material, the solvent , or the

like, and it is usually from -10˚C to 3 0˚0 , preferably room temperature.
The reaction time after adding the reagent for making acidic condition depends on the starting material, the solvent, or the like, and it is usually from 10 minutes to 2hrs.
After the reaction, the organic solvent was removed, and the target Compound (I) may be obtained by conventional purifying method such as thin layer chromatography, silica gel column chromatography, or the like. After the reaction of Process A-3, the residuemaybe only washedwith solvent, which does not dissolve the target Compound (I) to remove excess acid.
Addition of two hydroxy groups to the azabicyclo moiety can be carried out as following Process B, provided-that following schemes are typical examples and can be applied to the production of Compound (II). Proce s s B

In the above formula, X2 and "Pro" represent the same meanings as defined above. "R" represents lower alkyl such as methyl or ethyl.
Process B is the process for adding two hydroxy groups to the double bond of azabicyclo moiety. Wherever the double bond is in the azabicyclo moiety, this reaction can be applied.
Compound (V) may be purchased if it is commercial,

or synthesized other general methods obvious to the person skilled in the organic chemistry from commercial compounds.
Process B-l
ProcessB-l (synaddition) can be carried out by adding the solution of osmium tetroxide (0s04) to the solution of Compound (V) . This osmium tetroxide gives syn addition from the less-hindered side of the double bond of Compound (V) to give dihydroxy compound.
As the solvent for the solution of osmium tetroxide, water can be employable. The solvent employable for the solution of Compound (V) in this process is not particularly limited so long as it is inactive in this reaction, and may include water; ketones such as acetone and methylethyketone; alcohol such as methanol and ethanol; and mixed solvent thereof.
To reduce the amount of expensive osmium tetroxide, morpholine N-oxide, N-methylmorpholine-N-oxide, or the like can be added to the solution of Compound (V).
The temperature at that time depends on the starting material, the solvent, or the like, and it is usually room temperature.
The reaction time after the adding depends on the starting material, the solvent, or the like, and it is usually from 12hrs to 50days.
After the reaction, decomposing agent such as sodium thiosulfate (Na2S2O3) or sodium sulfite (Na2SO3) is added to give dihydroxide Compound (VIx) by decomposing cyclic ester consisting Compound (V) and osmium tetroxide.
After the addition of the decomposing agent, insoluble residue is filtered off. The obtained filtrate is evaporated, then acidic water such as sulfuric acid is added. The mixture is extracted with organic solvent insoluble with water such as ethyl acetate, chloroform,

or the like, and the organic layer is washed by water, brine, or the like. The organic layer is dried over anhydrous magnes ium sulfate or sodium sulfate, and evaporated in vacuo. The target compound is purified by the conventional method such as silica gel chromatography to obtain Compound (Vlf) .
Proces s B-2
In case of Process B-2 (anti addition) , H202 and acid (such as formic acid) are used. That is, first, epoxide is synthesized from Compound (V) and H2O2, and then Sn2 reaction takes place to give dihydroxide Compound (VI2) . Therefore, the position selectivity and stereo selectivity of hydroxy group mainly depend on the circumstance of the C-C double bond of Compound (V) .
When one hydroxy group is introduced, Compound (VII) can be produced by following Process C. Proce s s C

In the above formula, X2, R and "Pro" represent the same meanings as defined above.
Process C is the process for adding one hydroxy group to the double bond of azabicyclo moiety. Wherever the double bond is in the azabicyclo moiety, this reaction can be applied.
Process C can be generally carried out by adding the solution of borane-tetrahydrofuran complex (BH3-THF) to the solution of Compound (V) under N2 atmosphere, and then basic aqueous solution of H2O2. In this Process C, the position selectivity and stereo selectivity of hydroxy group mainly depend on the circumstance of the C-C double

bond of Compound (V) .
As the solvent for the solution of Compound (V) , tetrahydrofuran can be preferably employable. The base for making basic solution of H2O2 may include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potass ium hydroxide.
When borane-tetrahydrofuran complex or H2O2 was added, the each temperature depends on the starting material,
the solvent, or the like, and it is usually -lOt to 10*0.
The each reaction time after adding borane-tetrahydrofuran complex or H2O2 depends on the starting material the solvent, or the like, and it is usually from 5 minutes to 5hrs.
After the reaction, aqueous solution such as brine is added to the mixture, and the mixture is extracted with organic solvent insoluble with water such as ethyl acetate, chloroform, or the like. The organic layer is separated, washed by water, brine, or the like. The washed organic layer is dried over anhydrous magnesium sulfate or sodium sulfate, and evaporated in vacuo. The target compound is purified by the conventional method such as silica gel chromatography to obtain Compound (VII).
When one R1 is introduced, Compound (VIII) is used as material compound as following Process D. Proce ss D


In the above formula, X2, R and "Pro" represent the s ame meanings as defined above. R8 and R9 each is independently H or lower alkyl.
Process D is the process for conversion from oxo group in the azabicyclo moiety to R1 . Wherever the oxo group is in the azabicyclo moiety, this reaction can be applied.
Compound (VIII) may be purchased if it is commercial, or synthesized other general methods obvious to the person skilled in the organic chemistry from commercial compounds.
Proce ss D-l
Process D-l can be carried out by adding hydrogenation agent to the solution of Compound (VIII).
In this process, mild hydrogenation agent such as NaBH4 is used, because strong hydrogenation agents can have negative effects on ester group of Compound (VIII).
Proce s s D-2
Process D-2 can be carried out by adding ammonia or amines (HNR8R9) to the solution of Compound (VIII) , and then adding hydrogenation agent. As this hydrogenation, the above method used in Process D-l can be employable.
When Compound (I) having three or four R1 is synthesized, other starting compound is used or the combination the above Process B to D can be applied.
In case R1 is amino or (lower alkyl) amino, R1 should be protected on cue-After introducing R1, the protective group of carboxyl group is removed to give Compound (II). Proces s E


In the above formula, R1 to R3, R, Rlf , X1, X2, n and "Pro" represent the same meanings as defined above.
Compound (X) can be synthesized by applying the above Processes B to D or other general methods obvious to the person skilled in the organic chemistry from commercial compounds -
Process E is the process for deprotecting the ester group of Compound (X) to give Compound (II)- In this process, general cleavage methods of ester group can be employable. For example, Compound (X) is dissolved in solvent, and base is added to the solution.
The solvent employable for the solution of Compound (X) in this process is not particularly limited so long as it is inactive in this reaction and may include water; alcohol such as methanol and ethanol; and mixed solvent thereof.
The base employable in this process can be alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal hydrogencarbonates such as 1 itium hydrogencarbonate, sodium hydrogencarbonate and potas sium hydrogencarbonate; alkali metal carbonates such as 1 ithiurn carbonate, sodium carbonate and potass ium carbonate; alkaline earth metal carbonates such as magne s ium carbonate and calcium carbonate.
The temperature at that time depends on the starting material, the solvent, or the like, and it is usually room temperature to reflux condition, preferably room temperature. The reaction time after the adding depends on the starting material, the solvent, or the like, and it is usually from lhr to 24hrs.

The compound of the formula (1) of the present invention can be prepared according to the following Proce s s F. Process F

In the above formula, R11 to R15, Y1 and Y2 represent the s ame meanings as defined above. "Hal" represents halogen atom, especially, chlorine or bromine atom.
Process F is the process for preparing the Compound (1) by condensing Compound (3) and (4) .
Compound (3) and (4) may be purchased if it is commercial, or synthesized according to general methods obvious to the person skilled in the organic chemistry from commercial compounds or following Process G and H, respectively.
This process is generally carried out by adding Compound (4) to the solution or mixture of Compound (3) and base. The temperature at that time depends on the starting material, the solvent, or the like, and it is
usually -10˚0 to 10˚C, preferably the addition is carried out under cooling by ice bath. After the addition, the temperature may be raised to room temperature.
The solvent employable in Process F is not particularly limited so long as it is inactive in this reaction and dissolves moderately substrates, and may include preferably ethers such as diisopropyl ether, tetrahydrofuran and dioxane; alcohols such as methanol

and ethanol.
The base employable in this process for making basic condition is not particularly limited so long as it accelerate this reaction, and may include alkali metal • carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as 1ithium hydrogencarbonate, sodium hydrogencarbonate and potas siurn hydrogencarbonate.
The reaction time after the adding depends on the 1 starting material, the solvent, or the like, and it is usually from 12hr to 2days. To accelerate this reaction, a catalytic amount of Nal may be added.
After the reaction, the mixture is partitioned between water and organic solvent insoluble with water such as ethyl acetate, chloroform, or the like, and the organic layer is separated- The organic layer is washed by water, hydrochloric acid, saturated sodium hydrogencarbonate solution, brine, or the like, dried over anhydrous magnesium sulfate or sodium sulfate, and evaporated in vacuo. The target compound is purified by the conventional method such as silica gel column chromatography, or the like.
Compound (3), which is the starting compound of Process F, can be synthesized by following Process G. Proce ss G

In the above formula, R11 to R15, Y1 and Y2 represent the same meanings as defined above.

Compound (5) and (6) may be purchased if it is commercial, or synthesized according to general methods obvious to the person skilled in the organic chemistry from commercial compounds.
Process G-l can be carried out by applying conventional Grignard reaction method. For example, the solution of Compound (6) is added dropwise to the solution of Compound ( 5 ) .
Then, the hydroxy group in Compound (7) is transformed to amino group by conventional functional group interchange trans forms reaction- For example, the following reaction can be applicable.

Besides Process G, Compound (3T) in which R11 is H can be obtained by Process H.

Compound (8) can be obtained by general oximation reaction. Then, this oxime compound (8) is reduced. The reduction condition is not limited, for example, oxime compound (8) is reduced under hydrogen atmosphere in the presence of catalyst at room temperature.
The solvent employable is not particularly limited,

and may include preferably methanol and ethanol; and the mixture of water and alcohol. As the catalyst, palladium catalyst such as Pd(OH)2 can be used.
The reaction time after the adding depends on the starting material, the solvent, or the like, and it is usually from 30 minutes to 6hrs.
After the reaction, catalyst is removed by filtration, and the filtrate is concentrated to give Compound (31) .
Compound (4) , which is the starting compound of Process F, can be synthesized by following Process I. Proce s s I
In the above formula, Y2 and Hal represent the same meanings as defined above.
Process I is the process for preparing the Compound
(4) . This process is carried out by reacting Compound
(9) and Compound (10) in the presence of base to form amide
bond in solvent. A conventional reaction method to form
amide bond is applicable to this Process I.
Compound (9) and (10) may be purchased if it is commercial, or synthesized by the methods obvious to the person skilled in the organic chemistry from commercial compounds, because Compound (9) and (10) as starting compound have comparatively simple structure.
In the Process I, conventional functional group interchange trans forms reactions can be applicable. Such reactions can be exemplified as followings:


In the above formula, DAST is diethylaminosulfur trifluoride which is fluoridation agent- Concerning fluoridation, L.Demange, et.al., Tetrahedron letters, 39, pp.1169-1172 (1998) (the contents of which are hereby incorporated by reference) can be referred.
By application of the above Processes F to I, Compound (2) can be also synthesized.
Above processes, all starting materials and product compounds may be salts. The compounds of above processes can be converted to salt according to a conventional method.
In the above compounds, which have reactive group, may be protected at the group on cue and be deprotected on cue. In these reactions (protecting or deprotecting steps), concerning the kind of protective group and the condition of the reaction, TpROTECTIVE GROUPS IN ORGANIC SYNTHESIS Second Edition] T.W.Green and P.G.M.Wuts, John Wiley & Sons, INC. (the contents of which are hereby incorporated by reference) may be referred.
The patents, patent applications and publications cited herein are incorporated by reference.
For therapeutic purpose, Compound (I), (1) and (2) a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds as an active

ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration - The pharmaceutical preparations may be capsules, tablets, dragees, granules, inhalant, suppositories, solution, lotion, suspension, emulsion, ointment, gel, cream, or the like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsi fying agents, buffers and other commonly used additives.
While the dosage of therapeutically effective amount of the Compound (I) , (1) and (2) depend upon the age and condition of each individual patient, an average single dose of about 0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the Compound (I) , (1) and (2) may be effective for treating the above-mentioned diseases. In general, amounts between 0.01 mg/body and about 1,000 mg/body may be administered per day.
This application is based on Australian Patent Application No.2003906010 filed on October 31, 2003 and No.2004900961 filed on February 25, 2004, the contents of which are hereby incorporated by references.
Although the present invention has been fully described by way of example, it is to be understood that various changes and modifications will be apparent to those skilled in the art. Therefore, unless otherwise such changes and modifications depart from the scope of the present invention hereinafter defined, they should be construed as being included therein.
THE BEST MODE FOR CARRYING OUT THE INVENTION
The following Examples are given only for the purpose of illustrating the present invention in more detail.

Example 1-1
Ethyl (lS,3S,4S,5S,6R)-5,6-dihydroxy-2-[(1R)-1-
phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate
To a solution of ethyl (lS,3S,4R)-2-[(lR)-l-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (9g) and morpholine N-oxide in acetone/water = 6/1 (90mL), was added 4% solution of osmium tetroxide in water (2mL) with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for 4 days.
To the resulting mixture, Na2S2O3*5H2O and Florisil were added. The solid was then filtered off through a celite pad and washed with acetone. The combined filtrate and washings were concentrated in vacuo. The residue was acidified with 6N H2SO4 (pH2) and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate = 2/1 to 1/1) to give the target compound as a colorless oil (4.2g) .
1H-NMR (CDC13) : 5 7.52-7 . 11 ( 5H, m), 4 . 12-3 . 89 (4H, m), 3.85(1H, q, J=6 . 6 Hz) , 3.48-3.38 (1H, m), 3.06-2.98 (1H,
m) , 2.98-2.86(lH,m), 2.64-2.51 (1H, m) , 2.12-2.01(lH,m), 1.98-1.5B(3flf m), 1.46-1.30(4H,m), 1 . 12 (3H, t, J = 7.2Hz) . MASS (ES+) m/z : 320.46 (M+l).
Example 1-2
Ethyl (lS,3S,4S,5S,6R)-5,6-dihydroxy-2-azabicyclo[2.2.
2]octane-3-carboxylate
Ethyl (lS,3S,4S,5S,6R)-5, 6-dihydroxy-2- [ (1R) -1-phenylethyl]-2-azabicyclo[2.2.2]octane-3-carboxylate obtained in Example 1-1 (4.2g) was dissolved in methanol

(lOmL) , andlO%Pd(OH)2-C (800mg) was addedtothe solution. The mixture was hydrogenated under H2 (4.0atm) at room temperature for 2hrs.
The catalyst was filtered through a celite pad and washed with ethyl acetate. The filtrate and washings were concentrated in vacuo to give the target compound as colorless oil (2.9g) .
1H-NMR (CDCI3) : 5 4.36-4.14(2H, m), 4.14-3 . 97 (2H, m) , 3.67-3.57 (1H, m) , 2.98-2.88(lH, m) f 2.86-2.21(3H, m) , 2 .20-2.10- (1H, m) , 2 . 00-1 . 70 ( 2H, m) , 1 . 65 -1 . 4 9 (1H, m) ,. 1.37-1.20(4H, m). MASS (ES+) m/z : 216.30 (M+l).
Example 1-3
(IS,3S,4S,5S f 6R) -2- (tert-Butoxycarbonyl) -5, 6-dihydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid
Ethyl (lS,3S,4S,5S,6R)-5,6-dihydroxy-2-
azabicyclo[2.2.2]octane-3-carboxylate obtained in Example 1-2 (4.2g) was dissolved in methanol (8mL), and INNaOH (17mL) wa s added to the solution at room temper ature . The solution was stirred at that temperature for 2hrs and the organic solvent (methanol) was removed in vacuo.
To this remaining aqueous solution, 530mg of NaOH and then a solution of di-tert-butyl dicarbonate in dioxane (8mL) were added dropwise at room temperature. The mixture was stirred for 16hrs and then acidified with IN HC1 (pH2). The resulting precipitate was collected with filter paper and the precipitate was washed with chloroform to give the target compound as a white powder ( 2 . 8 1 g ) ,
1H-NMR (DMSO-d6) : 5 4.07-3.92(lH,m),3.92-2.72(2H,m), 3.72-2.55 (1H, m), 2.12 -1.49(4H, m), 1.46-1.25(9H, m) ,

1.24-1 . 01 (1H, m) -
MASS (ES-) m/z : 286.29 (M-l).
Example 1-4
tert-Butyl (lS,3S,4S,5S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-5,6-dihydroxy-2-azabicyclo [2 . 2 .2]octane-2-carboxylate
To a solution of (lS,3S,4S,5S,6R)-2-(tert-butoxycarbonyl)-5,6-dihydroxy-2-azabicyclo[2.2.2] octane-3-carboxylic acid obtained in Example 1-3 (500mg), 1-hydroxybenzotriazole hydrate (415mg) and 1-(3-dimethylaminopropyl)-3-ethy1carbodiimide hydrochloride (493mg) in dimethylformamide (lOmL), were added diisopropylethylamine and
(2S)-2-pyrrolidinecarbonitrile hydrochloride with cooling on an ice bath. The reaction mixture was stirred at that temperature for 3hrs .
The reaction mixture was quenched by water and extracted with ethyl acetate . The combined organic layer was washed with IN HC1, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, and concent rated in vacuo. The residue was purified with silica gel chromatography (chloroform/methanol = 20/1) to give the target compound as a colorless oil (122mg).
1H-NMR (CDC13) : 5 4. 93-4. 82 (1H, m), 4.29-3 . 88 ( 4H , m) , 3.80-3.49(2H, m), 3.27-3.15(lH, m), 3.00-2.80(lH, m) , 2.40-1.53 (8H, m)f 1.53-1.29(10H, m). MASS (ES+) m/z : 366.43 (M+l).
Example 1-5
(2S)-l-{ [ (lS,3S,4S,5S,6R)-5,6-Dihydroxy-2-azabicyclo [2 . 2.2]oct-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride

To a solution of tert-butyl (13,33,43,53, 6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-5,6-dihydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 1-4 (122mg) in chloroform (lmL ) , was added 4NHC1 indioxane ( 3mL ) at room temperature . The reaction mixture was stirred for 15 minutes and the organic solvent was removed in vacuo. The residue was triturated with ethyl acetate to give the target compound as a white powder (lOOmg).
^-NMR (DMSO-d6) : 5 10.38-9.96{lH,m)f8.47-7.98(lH,m), 4.95-4.65(lH, m), 4.58-3.1(8H, m), 2.43-0.97(9H, m) . MS (ES + ) m/z : 266.42 (M+l).
Example 2-1
Ethyl (2Z)-{[(lR)-l-phenylethyl]imino}acetate
To a (lS)-l-phenylethanamine (77.4mL), was added a solution of ethyl glyoxylate in toluene (45-50%, 123mL) at room temperature. After lhr, the mixture was evaporated in vacuo. The residue (120g) was used in the next step without further purification.
1H-NMR (300MHz, CDC13) : 8 1.35(3H, t, J=7.2Hz), 1.62(3H, d, J=6.7Hz), 4.34(2H, q, J=7.2Hz), 4.61(1H, d, J=0.7,
6.7Hz) , 7.21-7.40(5H, m), 7.23(1H, d, J=0.7Hz).
Example 2-2
Ethyl (lS,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo-
[2 . 2 . 2]oct-5-ene-3-carboxylate
To a suspension of ethyl (2Z)-{ [ (1R)-1-phenylethyl] imino}acetate obtained in Example 2-1 (205g) andMolecular sieves 4A (30g) in CH2C12 (2L) , were added t r i f luo r oace t i c

acid (76.9mL) and boron trifluoride diethyl etherate
(127mL) dropwise at -70*0 under N2 atmosphere- After 15 minutes, cyclohexadiene (lOOmL) was added dropwise. The mixture was stirred at room temperature overnight.
To the reaction mixture cooled by an ice-bath, were added NaHCO3 and "water. After 20 minutes, the organic layer was separated and evaporated. The residue was diluted with ethyl acetate (1.5L) and washed with saturated aqueous NaHCO3 solution. The separated organic layer was extracted with 3N HC1. The aqueous layer was alkalized with saturated aqueous NaHCO3, and then extracted with ethyl acetate . The combined organic layer was washed with brine, dried with MgSO4, and filtrated. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/30) to provide the target compound
(220g) as an oil.
1H-NMR (300MHz, CDC13) : 6 0.95-1 . 15 ( 1H, m),1.12(3H, t, J=7.2Hz), 1.22-1.35(1H, m), 1.30(3H, d, J=6.6Hz), 1.52-1.65(1H, m), 1.96-2.1O(1H/ m), 2.68-2.76(lH, m), 2 . 89 (1H, br-s), 3.43 (1H, q, J=6.6Hz), 3.62 1H, br-s), 3.97(2H, q, J=7.2Hz), 6.26(1H, ddd, J=l.l, 5.2, 7.9Hz), 6.39(1H, ddd, J=1.4, 6.6, 7.9Hz), 7 . 1 4-7 . 2 9 ( 3H , m) , 7.41 (2H, br-d, J=7.2Hz). MASS (ES+) m/e : 286 (M+l).
Example 2-3
Ethyl (1S,3S,4S,5R)- 5-hydroxy-2-[ (1R)-1-phenylethyl]-
2-azabicyclo[2.2.2]octane-3-carboxylate
To a solution of ethyl (IS, 3S, 4R) -2- [ (1R) -1-pheny-lethyl] -2-azabicyclo- [2 . 2 . 2 ]oct-5-ene-3-carboxylate obtained in Example 2-2 (5-0g) in tetrahydrofuran (50mL), was added

borane-tetrahydrofuran complex (1 . OM in tetrahydrofuran, 17.5mL) with cooling on an ice bath under N2 atmosphere-After 10 minutes, the bath was removed and the mixture was stirred overnight at room temperature. To this mixture, 3N aqueous NaOH solution (8mL) and 30% H2O2 (8mL) were added with cooling on an ice bath.
After 20 minutes, NaCl was added to the mixture, and then the organic layer was separated- The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/2) to provide the diastereomeric mixture (4.05g) of the target compound as oil. Further purification was not attempted.
XH-NMR (300 MHz, CDC13) : 5 1 . 04 (3H, t, J=7.2Hz), 1.16-2.05(6H, m), 1 . 33 (3H, d, J=6.6Hz), 2.35-2.48 (1H, m) , 3. 10 (1H, br-s), 3.17(1H, br-s), 3.56 (1H, q, J=6.6Hz), 3.89(2H, q, J=7.2Hz), 4.05-4.16(lH,m), 7.12-7.32(3H,m)f 7 . 34-7 . 44 (2H, m) -MASS (ES+) m/e : 304 (M+l).
Example 2-4
Ethyl (IS,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]-
octane-3-carboxylate
To a solution of ethyl (1S,3S,4S,5R)-5-hydroxy-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2-2]octane-3-carboxylate obtained in Example 2-3 (22g) inethanol (300mL), was added Pearlman's catalyst (4g). The mixture was stirred for 3hrs under H2 atmosphere on 4atm.
The catalyst was removed by filtration and washed with ethanol. The combined filtrate and washings were concentrated in vacuo. The res idue was purified by silica gel column chromatography (methano1/CHC13 = 1/20 to 1:5)

to provide the diastereomeric mixture of the target compound (8.9g) as a pale yellow oil. Further purification was not attempted.
1H-NMR (300MHz, CDC13) : 8 1.24(3H, t, J=7 . 2 Hz), 1.35-1.45(2H, m), 1.57-2.04(3H, m) , 2.06-2.11 (1H, m) , 2 . 32-2 . 44 (1H, m), 2.99(1H, br-s), 3.67(1H, t, J=2.3Hz), 4 . 16-4.32 (3H, m) . MASS (ES+) m/e : 200 (M+l).
Example 2-5
(lS,3S,4S,5R)-2-(tert-Butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid
To a solution of ethyl (lS,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.2]-octane-3-carboxylate obtained in Example 2-4 (8.9g) in dioxane (13 OmL) , was added IN aqueous NaOH solution (13 4mL) at room temperature. After 30 minutes, di-tert-butyl dicarbonate (9,75 g) was added to the mixture with cooling on an ice bath. After 10 minutes, the bath was removed and the mixture was stirred for 3hrs at room temperature. The mixture was concentrated in vacuo. The residue was acidified with IN aqueous HC1 and extracted with CHC13. The organic layer was dried over Na2SO4, and evaporated in vacuo. The residue was re crystallized from 2-propanol to provide the target compound ( 6.7 8g) as a white crystal.
1H-NMR (300MHz, DMSO-d6) : 5 1 . 1 5-1.40 (2H, m), 1.33(6H, s), 1.37(3H, s), 1.48-1.62(1H, m), 1.68-2.10(4H, m), 3.80-4.00(3H, m), 4.89(1H, br-s), 12.55(1H, br-s). MASS (ES-) m/e : 270 (M-l).
Example 2-6
tert-Butyl (lS,3Sf4Sr5R)-3-{[(2S)-2-aminocarbonyl-

1-pyrrolidinyl]carbonyl}-5-hydroxy-2-azabicyclo [2.2.2 ]octane-2-carboxylate
To a solution of (lS,3S,4S,5R)-2-(tert-butoxycarbonyl)-5-hydroxy-2-azabicyclo[2.2.2]octane-3-carboxylic acid obtained in Example 2-5 (4.05g), ( 2 S)-2-pyrrolidinecarboxamide (1.7 7 g) and 1-hydroxybenzotriazole hydrate (1.68g), were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 3.15g) and N,N-diisopropy1ethyl amine (5 . 2mL) with cooling on an ice bath. After 5 minutes, the ice bath was removed and the mixture was stirred overnight at room temperature -
The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (methanol/ethyl acetate = 1/5) to provide the target compound (8.7g) as a white solid.
1H-NMR (300MHz, CDC13) : 5 1.20-2.65(11H, m), 1.35-1.47(9H, m), 3.46-3.80(2H, m), 4.02-4.36(4H, m),
4.67-4.76(lH, m) , 5.32 IX 9/1 OH, br-s) , 5 . 53 (1 X 1/10H,
br-s) .
MASS (ES + ) m/e : 368 (M+l).
Example 2-7
tert-Butyl (lS,3S,4S,5R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl] carbonyl}-5-hydroxy-2-azabicyclo [2.2.2]
octane-2-carboxylate
To a solution of tert-butyl (lS,3S,4S,5R)-3-{ [ (2S) -2-aminocarbonyl-1-pyrrolidinyl]carbonyl}-5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 2-6 (8.7g) in te t r ahydr o f uran (90mL) , were added pyridine (9.5 8mL) and trifluoroacetic anhydride (1OmL) with cooling on an ice bath under N2 atmosphere. After

10 minutes, the ice bath was removed and the mixture was stirred for 2hrs at room temperature.
The mixture was alkalized with saturated aqueous NaHCO3, and then concentrated in vacuo. The residue was diluted with water and extracted with CHC13. The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue ( 9 . 7g) was triturated with ethyl acetate and recrystallized from 2-propanol to provide the target compound ( 4 . 15g) as a white crystal.
1H-NMR (30 0MHz, DMSO-d6) : 6 1.20-1.40 (11H, m), 1.42-1.6O(1H, m), 1.74-2.30(8Hf m), 3.48-3.66(2H, m), 3.84-4.08(2Hf m), 4.24(1H, br-s), 4.76-4.90(2H, m). MASS (ES+) m/e : 350 (M+l).
Example 2-8
(2S) -1-{ [ (lS,3S,4S,5R)-5-Hydroxy-2-azabicyclo[2.2.2] oct-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
To a solution of tert-butyl (1S,3S,4S,5R) -3- { [ (2S ) -2-cyano-l-pyrrolidinyl]carbonyl}-5-hydroxy-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 2-7 (2.0g) in dioxane (lOmL), was added 4N HC1 in dioxane (1.43mL) at room temperature.
After lhr, the precipitate was filtered and washed with dioxane. The solid was recrystallized from ethanol-water to provide the target compound (0.8 3g) as a white crystal.
1H-NMR (300MHz, DMSO-d6) : 6 1.10 -1.26 (1H, m), 1.4O(1H, br-d, J=14.5Hz), 1.53-1.68(1H, m), 1.76-2.20(6H, m), 2.24-2.44(2H, m), 3.43(1H, br-s), 3.46-3.60(lH, m) , 3.63-3.75(lH, m), 4.04-4.15(lH, m), 4.19(1H, br-s), 4.86(1H, dd, J=5.9, 7.9Hz), 5.23 (1H, d, J=3.9Hz).

MASS (ES+) m/e : 250 (M+l).
Example 3
(2S)-1-{[(1S,3S,4R,6S)-6-Hydroxy-1,4-dimethyl-2 -azabicyclo[2.2.2]oct-3-yl]carbonyl}-2-pyrrolidinecarbonitrile
Ethyl (1S,3S,4R)-1,4-dimethy1-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct~5-ene-3-carboxylate is used as starting compound, the target compound can be obtained by similar method described in Example 2-3 to 2-8.
Example 4
(2S)-1-{[(1R,3S,4R,6S) -6-Hydroxy-1-isopropy1- 4-methy1 -2-azabicyclo[2.2.2]oct-3-yl]carbonyl}-2-pyrrolidinec arbonitrile
Ethyl (IS,3S, 4R) -1-isopropyl-4-methyl-2-[ (1R)-1-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate is used as starting compound, the target compound can be obtained by similar method described in Example 2-3 to 2-8.
Example 5-1
Ethyl (lS,3S,4R)-2-[(lR)-1-phenylethyl]-2-
azabicyclo[2.2.1]hept-5-ene-3-carboxylate
The title compound was obtained from ethyl (2Z)-{[(1R)-1-phenylethyl]-iminojacetate obtained in Example 2-1 in a manner similar to Example 2-2.
1H-NMR (300MHz, CDC13) : 8 0.95(3H, t, J=7.2Hz), 1.41(3H, d, J=6.6Hz), 2.13(1H, d, J^S.SHz), 2.2O(1H, s), 2.9O(1H, m) , 3.03(lH, q, J=6.6Hz), 3-81(2H, q, J=7.2Hz), 4.3O(1H,

s), 6.26 (1H, m), 6.42(1H, m) , 7.12-7.34(5H, m) .
Example 5-2
Ethyl (!S,3S,4S,6R,7S)-6-hydroxy-7-iodo-2-[(lR)-l-
phenylethyl]-2-azabicyclo[2.2,1]heptane-3-carboxylate
To a solution of ethyl (IS,3S,4R)-2-[ (1R) -1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate obtained in Example 5-1 (2.44g) in dimethyl sulfoxide (12mL) and water (1.5mL), was added N-iodosuccinimide (2.06g). The mixture was stirred at room temperature for 30 minutes.
The resulting mixture was diluted with ethyl acetate, and washed successively with sodium hydrogencarbonate solution and brine- The organic layer was dried over NaSO4 and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give the target compound (1.9 9g) as a solid.
1H-NMR (300MHz, CDC13) : 5 1.09(3H, t, J=7.2Hz), 1.41(3H, d, J=6.6Hz), 1.91(1H, m) , 2.01 (1H, d, J=10 . 2Hz) , 2.15 ( 1H, m) , 2.73(1H, m) , 3 . 29 (1H, m) , 3.51(1H, s) , 3.71(1H, q, J=6.6Hz), 3 . 80 (1H, m) f 3 . 92 (1H, q, J=7.2Hz), 4 . 18 (lHf m) f 7.16-7 . 31 (5H, m) . Mass (m/z) : 416 (M+l).
Example 5-3
Ethyl (lR,3S,4S,6R)-6-hydroxy-2-[ (lR)-l-phenylethyl]-
2-azabicyclo[2.2.1]heptane-3-carboxylate
To a solution of ethyl
(lS,3S,4S,6R,7S)-6-hydroxy-7-iodo-2-[(1R)-1-
phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate
obtained in Example 5-2 (1 . 4 4g) in toluene (2 OmL) , was
added tributyltin hydride (1-llg) and

2,2'-azobisisobutyronitrile (22 8mg) . The mixture was
stirred at lOO'C for 30 minutes.
The resulting mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over NaSO4 and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (951mg).
1H-NMR (300MHz, DMSO-d6) : 6 1.01(3H, t, J=7.2Hz), 0.95-l.l(lH,m), 1.28(3H, d, J=6.6Hz), 1.42-1.57(2H,m), 1 . 6 6 (1H , m) , 2 . 4 4 ( 1H , m), 3 . 1 0 (1H , s ) , 3.2O(1H, m) , 3.63(1H, q, J=6.6Hz), 3.74(1H, m) , 3.84(2H, qf J = 7.2Hz) , 4.63(3H, d, J=3.9Hz), 7.13-7.27 (3H,m), 7.30-7.36(2H,m). Mass (m/z) : 290 (M+l).
Example 5-4
Ethyl (1R,3Sf 4S ,6R)-6-hydroxy-2-azabicyclo-
[2 . 2 . 1]heptane-3-carboxylate
The title compound was obtained from ethyl (lR,3S,4S,6R)-6-hydroxy-2-[(lR)-l-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 5-3 in a manner similar to Example 2-4 .
Example 5-5
2-tert-Butyl 3-ethyl (lR,3S,4S,6R)-6-hydroxy-2-
azabicyclo[2.2.1]heptane-2,3-dicarboxylate
To a solution of ethyl (lR,3S,4S,6R)-6-hydroxy-2-azabicyclo-[2.2.1]heptane-3-carboxylate obtained in Example 5-4 (606mg) in ethanol (1OraL), was added di-tert-butyl dicarbonate (8 57mg). The mixture was stirred at room temperature for 2hrs. The resulting mixture was evaporated in vacuo, and the residue was

chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (602mg) as a solid.
1H-NMR (300MHz, CDC13) (major peak of rotational isomer) :
6 1 . 29 (3H, t , J=7.2Hz) r 1 .2-1 . 4 (1H, m) , 1.39(9H, s) , 1.58-1.64(lH,m), 1.78-1.88 (lH,m), 1.98 (1H, m) , 2 .20 (lHf d, J=3.3Hz), 2 . 76 (1H, m), 4.04-4.28 (5H, m). Mass (m/z) : 286 (M+l)-
Example 5-6 (1R,3S,4S, 6R)-2-(tert-Butoxycarbonyl)-6-hydroxy-2-
azabicyclo[2.2.l]heptane-3-carboxylic acid
To a solution of 2-tert-butyl 3-ethyl (lR,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2, 3-dicarboxylate obtained in Example 5-5 (249mg) indioxane (4.5mL) and water (1.5mL), was added lithium hydroxide monohydrate (llOmg) . The mixture was stirred at 43*C for 12hrs and then 60t for 3hrs . The resulting mixture was evaporated in vacuo. IN Hydrochloric acid (2.7mL) was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over NaSO4/ and evaporated in vacuo. The residue was triturated with ether to give the target compound (164mg) as a solid.
1H-NMR (30 0MHz, DMSO-d6) : 5 1.09-1.20(lH, m), 1.32, 1.39(9H, s), 1.45-1.55(1H, m), 1.66(lHf d, J=llHz), 1.72-1.86(1H/ m), 2.58-2.66(lH, m), 3.74-3.82(lH, m), 3.85-3.96(2H, m), 4.96-5.03(lH, m). MASS (ES-) m/z : 256.2 (M-l).
Example 5-7
tert-Butyl (lR,3S,4S/6R)-3-{[(2S)-2-cyano-l-

pyrrolidinyl]carbonyl}~6-hydroxy-2-azabicyclo[2.2.1] heptane-2-carboxylate
To a solution of (lR,3S,4S,6R)-2-(tert-
butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 5-6 (90mg) in N,N-dimethylformamide (1.6mL) , was added (2S) -2-pyrrolidinecarbonitrile hydrochloride ( 55.7mg) , l-hydroxy-7-azabenzotriazole (57•2mg) and 1-(3-dimethylaminopropy1)-3-ethylcarbodiimide (65mg). The mixture was then stirred at room temperature for 6hrs . The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (85.4mg) as a solid.
1H-NMR (300 MHz, CDC13) : 6 1.23-1.34 (lH,m), 1.34, 1 . 46 (9Hf s), 1.64(1H, d, J=9Hz), 1.82, 1.97(1H, d, J=3Hz), 1.84-1.94(1H, m), 2.03-2.36(5H, m), 2.66-2.76(lH, m), 3.46-3.69(2H, m), 4.08-4.23(2H, m), 4.23-4.35(lH, m), 4 . 76-4.90 (1H, m) . MASS m/z : 336.
Example 5-8
(2S)-l-{[(lR,3S,4S,6R)-6-Hydroxy-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was obtained from tert-butyl (lR,3S,4S,6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 in a manner similar to Example 2 - 8.
1H-NMR (300MHz, DMSO-d6) : 8 1.32(1H, m) , 1.62(1H, ddd,

J=l.8, 6.9, 13.8HZ), 1 . 79 (1H, m) , 1.88-2.33 (5H, m) , 3.03(lH, br-s), 3.53-3 - 71 ( 3H , m) , 3.97(1H, m) , 4.31(1H, m)f 4.82 (1H, dd, J=5.1, 8.lHz), 5.46(1H, d, J = 4.2Hz). MASS (ES+) m/z : 236 (M+l).
Example 6
(2S)-1-{[(1R,3S,4S)-7-Hydroxy-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile
Ethyl (lR,3S,4R)-2-[(lR)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-7-hydroxy-3-carboxylate is used as starting compound, which can be synthesized from ethyl (lR,3S,4R)-2-[(lR)-l-phenylethyl]-2-azabicyclo[2.2.1] hept-7-oxy-3-carboxylate by reductive reaction, the target compound can be obtained by similar method described in Example 2-4 to 2-8.
Example 7-1 4-Methyltetrahydro-2H-pyran-4-ol
To a solution of tetrahydro-4H-pyran-4-one in diethyl ether (1OmL) , was added 0.92M methylmagnes ium bromide in tetrahydrofuran (6.5mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for 2hrs.
The reaction mixture was quenched by adding saturated aqueous NH4C1, and then NaCl was added. The resulting solution was extracted with chloroform, the combined organic layer was washed with saturated aqueous NaCl, and dried overMgSO4. After removal of the solvent, the target compound was given as a colorless oil (595mg).
1H-NMR (30 0MHz, CDC13) : 5 1.29(3H, s), 1.81-1.46(4H,m),
3.87-3. 61 (4H, m) .
Mass (ES+) m/z : 117.09 (M+l).

Example 7-2
2-Chloro-N-(4-methyltetrahydro-2H-pyran-4-yl)
acetamide
To a solution of 4-methyltetrahydro-2H-pyran-4-ol obtained in Example 7-1 in chloroacetonitrile (0.65mL), was added a mixture of acetic acid and cone, sulfuric acid
(1 /1, 1 . 6mL) dropwise with cooling on an ice bath. The reaction mixture was warmed to room temperature and stirred for 3hrs.
The reaction mixture was quenched by adding 3N NaOH. The resulting solution was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel chromatography
(hexane/ethyl acetate = 1/2) to give the target compound as a white powder (630 mg).
1H-NMR (300MHz/CDCl3) : 5 1.46(3H, s), 1.83-1. 67(2H,m), 2.14-2.00(2H, m), 3.67-3.55(2H, m), 3.81-3.67(2H, m) , 4.00(2H, s), 4 . 03 (1H, br-s). Mass (ES+) m/z : 192.16 (M+l).
Example 7-3 (4-Methyltetrahydro-2H-pyran-4-yl)amine hydrochloride
To a solution of 2-chloro-N- (4-methyltetrahydro-2H-pyran-4-yl)acetamide obtained in Example 7-2 (63 Omg) in ethanol/acetic acid (5/1, 6mL) , was added thiourea (275mg) at room temperature. The reaction mixture was heated at reflux for 2hrs.
The resulting mixture was cooled to room temperature, and the precipitate was removed by filtration. After removal of the solvent, the residue was triturated with ethanol to give the target compound as a white powder

(200mg).
1H-NMR (300MHz, DMSO-d6) : 8 1.35(3H, s), 1 . 66-1.53 (2H, m), 1.86-1.70(2H,m), 3.59-3.43(2H,m), 3.83-3.67(2H,m),
8 .25 (3H, br-s) .
Mass "(ES+) m/z : 116.96 (M+l).
Example 7-4
Methyl (2S,4R)-4-hydroxy-2-pyrrolidinecarboxylate
hydrochloride
Hydroxy proline (155g) was dissolved in "Hydrogen Chloride, Methanol Reagent 10" (Tokyo Kasei Kogyo Co. , Ltd. , 900mL) , and this mixture was heated at reflux for 2hrs. The resulting mixture was cooled to room temperature, and the solvent was removed invacuo to give the target compound as white powder (215g).
^-NMR (in DMSO-d6) : 5 2.30~1.99(2H, m) , 3.14-2.97(1H, m), 3.45-3.25(lH, m) , 3.76(3H, s) , 4.57-4.35(2H, m),
9 . 23 (1H, br-s), 10.32 (1H, br-s).
Example 7-5
1-tert-Butyl 2-methyl (2S,4R)-4-hydroxy-l,2-
pyrrolidinedicarboxylate
To a solution of methyl ( 2 S,4R)- 4-hydroxy-2-pyrrolidinecarboxylate hydrochloride obtained in Example 7-4 (215g) in water/dioxane (800/500mL) with cooling on an ice bath, was added a solution of di-tert-butyl dicarbonate (271g) in dioxane (150mL) and 6N NaOH (400mL) dropwise. The reaction mixture was stirred at room temperature for 3hrs and quenched by adding with IN HC1.
The aqueous layer was extracted with ethyl acetate.

The combined organic layer was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with hexane to give the target compound as a white powder (200g).
1H NMR (in CDC13) : 8 1.51-1.32(9H,m),2.39-1.82(2H,m), 3.79-3.38 (5H, m), 4.58-4.31(2H, m) .
Example 7-6
1-tert-Butyl 2-methyl (2S,4S)-4-fluoro-l,2-
pyrrolidinedicarboxylate
1-tert-Butyl 2-methyl (2S,4R)-4-hydroxy-l,2-pyrrolidinedicarboxylate obtained in Example 7-5 (130g) and cesium fluoride (105g) were dissolved in dioxane (600mL), and this mixture was cooled on an ice bath. To the mixture, was added a solution of diethylaminosulfur trifluoride (lOOg) in dioxane (2 OmL) dropwise for 30 minutes. The reaction mixture was warmed to room temperature and stirred for 5hrs.
The resulting mixture was added NaHCO3 (400g) . The reaction mixture was quenched with saturated aqueous NaHCO3/ and then H2O (lOOOmL) andCaCl2 (382g) in H2O (300mL) was added. The resulting suspension was filtered and the filtrate was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo to give the target compound as an yellow oil (127.5g). Further purification was not attempted.
1H-NMR (inCDCl3) : 6 1.55-1.35(9H,m),2.62-2.16(2H,m), 3.94-3.49(5H, m) , 4.6O-4.36(1H, m), 5.20(1H, br-d, J=52.8Hz).
Example 7-7

(2S,4S)-l-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinecarboxylic acid
The crude product of 1-tert-butyl 2-methyl (2S,4S)-4-fluoro-l,2-pyrrolidinedicarboxylate obtained in Example 7-6 (1 2 7 . 5g) was dissolved in methanol (4 00mL) and then IN NaOH (800mL) was added at room temperature.
After stirring for 1 . 5hrs, the resulting mixture was washed with diethyl ether , acidi f led wi th IN HC1 (lOOOmL), and then was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo. The resulting residue was triturated with ethyl acetate to give the target compound as a white powder ( 6 4g) .
1H-NMR (inCDCl3) : 5 1. 62-1 . 31 (9H, m) , 2.94-2 . 09 (2H, m) , 4-01-3.44(2Hf m) , 4.66-4.37 (1H, m) , 5.22(1H, br-d, J=51. 9Hz) .
Example 7-8
tert-Butyl (2 S,4 S)-2-aminocarbonyl- 4-fluoro-1-
pyrrolidinecarboxylate
To a mixture of
(2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinecarboxylic acid obtained in Example 7-7 (66g) and 1-hydroxybenzotriazole hydrate (45g) in acetonitrile (150 OmL) with cooling on an ice bath, was added 1- ( 3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (82g) .
After the mixture was stirred for 45 minutes, 28% aqueous NH3 (43mL) was added at that temperature. The resulting mixture was warmed to room temperature and stirred for 15 minutes. The reactionmixture was filtered

and the filtrate was evaporated in vacuo. After dilution with ethyl acetate, the reaction mixture was washed with IN HC1, saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, and filtered. After removal of the solvent, the target compound was obtained as a white powder ( 4 6g) .
1H-NMR (inCDCl3) : 8 1.58-1.36(9H,m),2.99-2.02(2H,m), 3.99-3.43(2H, m) , 4.57-4.23(lH, m) , 5. 23 (1H, br-d, J=51.6Hz)/ 5 . 69-.5. 40 (1H, m) , 6.79-6.05(lH, m) . Mass (ES+) m/z : 233.10 (M+l).
Example 7-9
( 2 S ,'4 S )-4-Fluoro-2-pyrrolidinecarboxamide
hydrochloride
tert-Butyl (2 S,4 S)-2 -aminocarbony1-4-fluoro-l-pyrrolidinecarboxylate obtained in Example 7-8 (46g) was dissolved in 4N HC1 in dioxane (200mL) and the resulting mixture was stirred for 10 minutes at room temperature-After removal of the solvent, the resulting residue was triturated with ethyl acetate to give the target compound as a white powder (34g) .
1H-NMR (in DMSO-d6) : 5 2 . 8 4 - 2 . 0 0 ( 2H , m) , 4 . 10- 3 . 09 ( 2H, m), 4.44-4.15(lH, m), 5 . 39 (1H, br-d, J=52.5Hz), 7 .73 (1H, br-s), 8.09(lH, br-s), 8.76(1H, br-s), 1O.62(1H, br-s). Mass (ES+) m/z : 132.94 (M+l).
Example 7-10
(2S,4S)-l-Chloroacetyl-4-fluoro-2-pyrrolidinecarboxamide
To a mixture of
(2 S , 4 S) -4-fluoro-2~pyrrolidinecarboxamide

hydrochloride obtained in Example 7-9 (33g) and sodium 2-ethylhexanoate (7 Og) in tetrahydrofuran (50 OmL) with cooling on an ice bath, was added chloroacetyl chloride. After stirring for 2hrs, the resulting residue was then poured onto buchner funnel/filter paper and washed with ethyl acetate. The solvent was removed in vacuo and the resulting residue was triturated with diethyl ether to give the target compound as a white powder (34g) .
1H-NMR (inCDCl3) : 5 2.58-2.03(lH,m),3.05-2.58(lH,m), 4.17-3.68 (4H, m), 4.85-4.54(lH, m) , 5.36(1H, br-d, J=52.5Hz), 5.88-5.49 (1H, m) , 6.63-6.19(lH, m) .
Example 7-11
(2S,4S)-l-Cloroacetyl-4-fluoro-2-pyrrolidinecarbonitrile
To a solution of (2S,4S)-l-chloroacetyl-4-fluoro-2-pyrrolidinecarboxamide obtained in Example 7-10 (34g) in tetrahydrofuran (800mL), was added trifluoroacetic anhydride (2 8mL) at room temperature. After stirring for 15 minutes, the resulting mixture was concentrated in vacuo. The resulting residue was triturated with ethyl acetate to give the target compound as a white powder (22g) .
1H-NMR (inCDCl3) : 5 2.52-2.22(lH,m),2.87-2.59(lH,m), 4.33-3.75(4H, m) , 5.12-4.87(1H, m) f 5.41 (1H, br-d, J=50.7Hz).
Example 7-12
(2S,4S)-4-Fluoro-l-{ [ (4-methy1tetrahydro-2H-pyran-4 -yl)amino]acetyl}-2-pyrrolidinecarbonitrile
To a mixture of
(4-methyltetrahydro~2H-pyran-4-yl)amine hydrochloride

obtained in Example 7-3 (90mg) and K2CO3 (10 Omg) in tetrahydrofuran (3mL) cooled on an ice bath, were added (2S ,4 S )-l-chloroacetyl-4-fluoro-2-pyrrolidinecarbonit rile obtained in Example 7-11 (lOOmg) and a catalytic amount of Nal . The reaction mixture was warmed to room temperature and stirred for 23hrs.
The reaction was quenched with pouring H2O. The aqueous layer was saturated with NaCl and then extracted three times with chloroform. The combined organic layer was dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (ethyl acetate / methanol= 9/1). After removal of the solvent invacuo, the residue was triturated by 2-propanol to give the target compound as a white powder (75mg).
1H-NMR (300MHz, DMSO-d6) : 6 1.04{3H, s), 1.58-1 . 30 ( 4H, m), 1.89-1.58(1H, br-s) , 2.70-2.22(2H, m), 3.55-3.13(4H, m)7 4.10-3.55(4H,m), 5.05-4.89(lH,m), 5.66-5.33(lH,m). Mass (ES+) m/z : 270.36 (M+l).
Example 8-1 4-Methyltetrahydro-2H-thiopyran-4-ol
The title compound was obtained from
tetrahydro-4H-thiopyran-4-one in a manner similar to Example 7-1.
1H-NMR (300MHz, CDC13) : 5 1 . 23 (3H, s) , 1.93-1.58(4H,m), 3.22-2 . 30 (4H, m) .
Example 8-2
2-Chloro-N-(4-methy1tetrahydro-2H-thiopyran-4-yl)
acetamide

The title compound was obtained from 4-methyltetrahydro-2H-thiopyran-4-ol obtained in Example 8-1 in a manner similar to Example 7-2.
1H-NMR (300MHz, CDC 13) : 8 1.41(3H, s), 1.91-1.70(2H,m), 2.47-2.32(2H, m), 2. 61-2 . 47 ( 2H, m)f 2.84-2.64(2H, m) , 3.99(2H, s), 6.27(lHf br-s). Mass (ES+) m/z : 208.26 (M+l).
Example 8-3
(4-Methyltetrahydro-2H-thiopyran-4-yl)amine hydrochloride
The title compound was obtained from 2-chloro-N-(4-methyltetrahydro-2H-thiopyran-4-yl) acetamide obtained in Example 8-2 in a manner similar to Example 7-3.
1H-NMR (300MHz, DMSO-d6) : 6 1.26(3H, s), 2 . 0 1 - 1 . 8 1 ( 4H , m) , 2.77-2.59(4H, m), 8.24(3H, br-s). Mass (ES + ) m/z : 132.02 (M+l).
Example 8-4
(2S,4S)-4-Fluoro-l-{ [ (4-methyltetrahydro-2H-thiopyran-4-yl)amino]acetyl}-2-pyrrolidinecarbonitrile
The title compound was obtained from (2 S , 4S ) -1-chloroacetyl-4-fluoro-2-pyrrolidinecarbonitrile obtained in Example 7-11 and (4-methyltetrahydro-2H-thiopyran-4-yl)amine hydrochloride obtained in Example 8-3 in a manner similar to Example 7-12.
1H-NMR (300MHz, DMSO-d6) : 6 0.97(3H, s), 1 . 9 0 - 1 . 4 5 ( 5H , m), 2.68-2.23(4H,m), 2.94-2.70(2H,m), 4.13-3.12(4H,m),

5.15-4.86(1H, m) , 5.75-5.26(1H, m) . Mass (ES+) m/z : 286.34 (M+l).
Example 9-1
2 , 6-Dimethyltetrahydro-4H-pyran-4-one
2,6-Dimethyl-4H-pyran-4-one (4g) was dissolved in ethanol (20mL) andlO%Pd/C (4 00mg) was added. The mixture was hydrogenated under H2 (latm) at room temperature for 25hrs .
The catalyst was filtered through a celite pad and washed with ethanol. The filtrate was concentrated in vacuo, and the residue was purified with silica gel chromatography (hexane/ethyl acetate = 4/1) to give the target compound as a colorless oil (2.08g).
1H-NMR (300MHz, CDC13) : 5 1.33(3H, d, J=6.0Hz), 2.22(1H, dd, J=ll.4, 14.4Hz), 2 . 36 (1H, dd, J=2.7, 14.4Hz), 3.74 (1H, ddq, J=2.7, 6.0, 11 . 4Hz) .
Example 9-2
2, 4, 6-Trimethyltetrahydro-2H-pyran-4-ol
The title compound was obtained from 2f 6-dimethy1tetrahydro-4H-pyran-4-one obtained in Example 9-1 in a manner similar to Example 7 -1.
1H-NMR (300MHz, CDC13) : 5 1.73-1.10(14H, m), 4 . 01-3.36(2H, m) .
Example 9-3
2-Chloro-N-(2,4,6-1rimethy11etrahydro-2H-pyran-4 -
y1)acetamide
The title compound was obtained from

2,4,6-trimethyltetrahydro-2H-pyran-4-ol obtained in Example 9-2 in a manner similar to Example 7 -2 .
1H-NMR (300 MHz, CDC13) : d 1.29-1.10(8H,m), 1.41 (3H, s) , 2.26-2.06(2H,rn), 3.71-3.51(2H,m), 3.99 (2H, s) , 6.35(1H, br-s) . Mass (ES+) m/z : 220.20 (M+l).
Example 9-4 (2,4,6-Trimethyltetrahydro-2H-pyran-4-yl)amine
To a solution of
2-chloro-N-(2,4,6-trimethyltetrahydro-2H-pyran-4-yl) acetamide obtained in Example 9-3 (1.85g) in ethanol/acetic acid (5/1, 15mL), was added thiourea (7 0 5mg) at room temperature . The reaction mixture was heated at reflux for 2hrs.
The resulting mixture was cooled to room temperature , and the precipitate was removed by filtration. After removal of the solvent, the residual solidwas neutralized with saturated aqueous NaHCO3 and extracted with chloroform. The combined organic layer was dried with MgSO4. After removal of the solvent, the target compound was given as a colorless oil (910mg).
1H-NMR (300MHz, CDC13) : S 1.61-0.99 (15H, m),
3. 85-3 . 43 (2H, m) .
Mass (ES+) m/z : 144.09 (M+l).
Example 9-5
(2S,4S)-4-Fluoro-l-({[2,4,6-trimethyltetrahydro-2H-pyran-4-yl]aminojacetyl)-2-pyrrolidinecarbonitrile
To a mixture of
(2,4,6-Trimethyltetrahydro-2H-pyran-4-yl)amine

obtained in Example 9-4 (900mg) and K2CO3 (1 . 2g) in tetrahydrofuran (lOmL) cooled on an ice bath, were added (2S,4S)-l-(chloroacetyl)-4-fluoro-2-
pyrrolidinecarbonitrile obtained in Example 7-11 (700mg) and a catalytic amount of Nal. The reaction mixture was warmed to room temperature and stirred for 65hrs.
The reaction mixture was quenched with pouring H20. The aqueous layer was saturated with NaCl and then extracted three times with chloroform. The combined organic layer was dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (ethyl acetate / methanol = 9/1) . After removal of the solvent in vacuo, the residue was triturated by diethylether to give the target compound as a white powder (465mg).
1H-NMR (300MHz,CDCl3) : 5 1.28-1.00(llH,m) 1.79-1.45(3H, m), 2.54-2.17 (lH,m), 2.88-2.59(lH,m), 4.12-3.20(6H,m),
5.14-4.9O(1H, m), 5.60-5.21 (1H, m) . Mass (ES + ) m/z : 298.31 (M+l).
Example 10-1 l-Benzyl-4-methyl-4-piperidinol
Under nitrogen atmosphere, methylmagnesium bromide ( 3 . 0M solution in diethyl ether, 10.8mL) was diluted with tetrahydrofuran (HOmL) with cooling on an ice bath. To the solution, was added dropwise a solution of 1-benzyl-4-piperidinone (5.6g) in tetrahydrofuran (40mL), and the mixture was stirred for lhr.
The reaction mixture was quenched by adding IN hydrochloric acid. The aqueous layer was neutralized with sodium hydrogencarbonate and extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated.

The residue was purified by silica gel chromatography (eluent: ethyl acetate/methanol = 50/1) to give the title compound as a pale yellow oil (3.34g).
1H-NMR (300MHz, CDC13) : 8 1.21(1H, br-s), 1.24(3H, s), 1.54-1.73(4H, m), 2.33-2.41(2H, my, 2-53-2.60(2H, m), 3.52(2H, s) , 7.22-7.33(5H, m) . Mass (ES+) m/z : 206 (M+l).
Example 10-2
N- (l-Benzyl-4-methyl-4-piperidinyl)acetamide
To a solution of l-benzyl-4-methyl-4-piperidinol obtained in Example 10-1 (3.34 g) in acetonitrile (19mL) , was addeddropwise cone, sulfuric acid (16mL) with cooling
on an ice bath. The mixture was warmed to 20*0 and stirred for 15hrs. After cooling, the reaction mixture was quenched by adding 3N potassium hydroxide solution, and the resulting solution (pH9) was extracted with ethyl acetate three times. The combined organic extracts were washed with brine, dried over MgSO4f and concentrated. The residual solid was triturated with ether to give the title compound as a white powder (3.55g).
H-NMR (300MHz, CDC13) : 5 1.39(3H, s), 1 . 61-1.71 ( 2H, m) ,
1 . 95 (3H, s), 1.98-2.06(2H, m) , 2.18-2.27 (2H, m),
2.52-2.60(2H, m), 3.49(2H, s), 5.10(1H, br-s),
7 .22-7.33 (5H, m) .
Mass (ES+) m/z : 247 (M+l).
Example 10-3
1-Benzyl-4-methyl-4-piperidinamine
A mixture of N-(l-benzyl-4-methyl-4-piperidinyl)acetamide obtained in Example 10-2 (3.4 5g)

and cone. HCl (4 1mL) was heated under reflux with stirring for 72hrs. After cooling, the mixture was quenched by adding 3N potass ium hydroxide solution, and the resulting solution (pHll) was extracted with chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound as a pale brown oil (2.86g) .
1H-NMR (30 0MHz, CDC13) : S 1.11(3H, s), 1.41-1.49(2H,m), 1.56~1.65(2H, m) , 2.35-2.51(4H, m), 3.52(2H, s), 7.22-7 . 34 (5H, m) . Mass (ES + ) m/z : 205 (M+l).
Example 10-4
tert-Butyl (1-benzyl-4-methyl-4-piperidinyl)carbamate
To a solution of 1-benzyl-4-methyl-4-piperidinamine obtained in Example 10-3 (3.73g) in 1,4-dioxane (65mL), were added IN sodium hydroxide solution (18.3mL) and di-tert-butyl dicarbonate (3.98g). The mixture was
stirred at 20*0 for 12hrs.
The resulting mixture was evaporated in vacuo, and the residue was partitioned between water and chloroform. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the title compound as a white solid (3.68g).
1H-NMR (300MHz, CDC13) : 5 1.33(3H, s), 1.44(9H, s), 1.56-1.66(2H, m), 1.88-1.99(2H, m), 2.20-2.30(2H, m), 2.50-2.60(2H, m), 3.50(2H, s), 4.32 (1H, br-s), 7 . 22-7.34 (5H, m) . Mass (ES+) m/z :305 (M+l).
Example 10-5

tert-Butyl (4-methyl-4-piperidinyl)carbamate
tert-Butyl (1-benzyl-4-methyl-4-piperidinyl)-carbamate obtained in Example 10-4 (l.Olg) was dissolved inmethanol (20mL) , and 20% Pd(OH)2 on carbon (300mg) was added. The mixture was stirred under hydrogen atmosphere
( 4 a tin) at 2013 for 2hrs. The reaction mixture was diluted with ethyl acetate, filtered through a pad of Celite, and concentrated- The residual solid was triturated with hexaneto give the title compound as white crystals ( 42 5mg) .
1H-NMR (300MHz, CDC13) : 8 1 . 35 (3H, s) , 1. 45 (9H, s), 1.48-1.57 (2H, m) , 1.66 (lHf br-s), 1.85-1.98(2H, m)f 2.78-2.85(4H, m) , 4.38(1H, br-s). Mass (ES+) m/z :215 (M+l).
Example 10-6
tert-Butyl [4-methyl-l-(2-pyrazinyl)-4-piperidinyl]-
carbamate
To a mixture of tert-butyl
( 4-methyl-4-piperidinyl)carbamate obtained in Example
10-5 (415mg) and potassium carbonate (321mg) in
N,N-dimethylformamide (4.5mL) , was added chloropyrazine
(665mg) . The mixture was heated at 10 0*0 with stirring for 2 4hrs. The resulting mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate . The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give the title compound as a pale yellow oil (566mg).
1H-NMR (300 MHz, CDC13) : 8 1 . 40 (3H, s), 1 . 44 (9H, s), 1 . 66 (2H, ddd, J = 14, 10, 4Hz) , 2.11 (2H, br-d, J=14Hz),

3.33(2H, ddd, J=14, 10, 3Hz), 3,87(2H, ddd, J=14, 4, 4Hz), 4.43(1H, br-s), 7.82(1H, d, J=2.6Hz), 8 . 05 (1H, dd, J = 2 . 6, 1.5Hz) , 8 . 16 ( 1H, d, J=l.5Hz). Mass (ES+) m/z : 293 (M+l).
Example 10-7
4-Methyl-l-(2-pyrazinyl)- 4-piperidinamine
To a solution of tert-butyl [4-methyl-l-(2-pyrazinyl)-4-piperidinyl]carbamate obtained in Example 1 0-6 (508mg) in dichlorome thane (lmL) , was added trif luoroacetic acid ( 5mL) , and the mixture was
stirred for 30 minutes at 20*0. The resulting mixture was evaporated in vacuo. The residue was neutralized with sodium hydrogencarbonate and extracted with chloroform three times. The organic layer was washed with brine, dried over MgSO4, and concentrated to give the title compound as a pale yellow solid (281mg).
1H-NMR (300MHz, CDC13) : 5 1.21(3H, s), 1.36(2H, br-s), 1.47-1.57(2H, m) , 1.65 (2H, ddd, J=13.2, 8.4, 4 . 4Hz) , 3.54-3.73(4H,m), 7.8O(1H, d, J=2.6Hz), 8.05(lH, dd, J=2.6, 1.5Hz) , 8 - 17 (lHf d, J=l.5Hz) . Mass (ES+) m/z : 193 (M+l).
Example 10-8
(2S,4S)-4-Fluoro-l-({[4-methyl-l-(2-pyrazinyl)-4-pipe ridinyl]amino Jacetyl)-2-pyrrolidinecarbonitrile
To a mixture of
4-methyl-l-(2-pyrazinyl)-4-piperidinamine obtained in Example 10-7 (90mg) and potassium carbonate (78mg) in N,N-dimethy1formamide (1.5mL) , were added a solution of (2S,4S)-l-chloroacetyl-4-fluoro-2-pyrrolidinecarbonitrile obtained in Example 7-11 (89mg)

in N,N-dimethylformamide (0.5mL) and a catalytic amount
of sodium iodide. The mixture was heated at 40^ with stirring for 2hrs.
The resulting mixture was partitioned between saturated aqueous sodium hydrogencarbonate and ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4/ and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: chloroform/methanol = 5/1) . After removal of the solvent, the residual solid was triturated with ethanol to give the title compound as white crystals (58mg).
1H-NMR (300MHz, DMSO-d6) : 6 1.06(3H, s), 1.39-1 . 52 ( 2H ,
m), 1.53-1.65(2H,m), 1.73-1.92(lH,m), 2.27-2.61(2Hfm),
3.22-3.61(4H, m), 3.61-4.06(4H,m), 4.94-5.00(lH, m),
5.32-5.61(lH,m), 7.77(1H, d, J=2.6Hz), 8.03-8.06(lH,m),
8.29-8 . 32 (1H, m) .
Mass (ES+) m/z : 347 (M+l).
MP : 166-167^.
Example 11
(2S,4S)-4-Fluoro-l-({[(1R,5S)-3-methyl-8-(2-pyrazinyl)-8-azabicyclo[3.2.1]oct-3-yl]amino}acety1)-2-pyrrolidinecarbonitrile
The title compound was prepared from [ (1R, 5S)-3-methyl-8-(2-pyrazinyl)-8-azabicyclo[3.2.1] oct-3-yl] amine in a similar manner to that of Example 10-8.
1H-NMR (300MHz, DMSO-d6) : 6 0.80(3H, s), 1 . 5 7 - 1 . 7 5 ( 4 H , m) , 1.76-1.87 (2H, m) , 2.15-2.30 (2H, m) , 2.32-2.61(2H, m) , 3.19-3.40(2H, m), 3.45-4.03(2H,m), 4.50(2H, br-s), 4.96-5.01(lH,m), 5.34-5.61(lH,m), 7.74(1H, d, J=2.6Hz), 8.05(lH, dd, J=2.6, 1.5Hz), 8.17(1H, d, J=l.5Hz). Mass (ES+) m/z : 373 (M+l).

Example 12-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-[(methylsulfonyl)oxy]-2 -azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3~{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 in a similar manner to that of Example 29-1 described later.
1H-NMR (300MHz, CDC13) : 5 1.35 and 1.4 7(9H, s),
1.4-1.5(1H, m) , 1.70-1.93(2H, m) , 2.05-2.55(5H, m),
2 . 79 (1H, m) , 3.03 and 3.05(3H, m) , 3.52-3.68 (2H, m) ,
4.18-4.27(1H, m), 4.52(1H, m), 4 . 88 (1H, m)-
MASS (ES+) m/z : 414 (M+l).
Example 12-2
tert-Butyl (lR,3Sf4Rf6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(1-pyrrolidinyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-3-{ [ (2S) -2-cyano-1-pyrrolidinyl]carbonyl}-6-[(methylsulfonyl) oxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 12-1 (153mg) in dimethylformamide (2.0mL) , was added pyrrolidine (79mg) . The mixture was
stirred at 80˚C for lhr. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (91mg).
1H-NMR (300MHz, CDC13) : 5 1.36 and 1 . 46 ( 9H, s) , 1.50-1.82(7Hf m)f 2.06-2.45(6H, m), 2.40-2.65(4H, m)f 3.54-3.80(3Hrm)/ 4 .20 (lHf s) , 4.00-4.25(2H,m), 4 . 83 (lHf

m) .
MASS (ES+) m/z : 389 (M+l).
Example 12-3
(2S)-l-{[(lR,3S,4S,6R)-6-(l-Pyrrolidinyl)~2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile dihydrochloride
The title compound was prepared from tert-butyl (lR,3S,4R,6R)-3~{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-(1-pyrrolidinyl)-2-azabicyclo[2.2.1] heptane-2~carboxylate obtained in Example 12-2 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 8 1.6O(1H, m) , 1 . 7 0 -2 . 3 6 { 7H , m) , 2.64(1H, m) , 2 . 11 - 3 . 1 4 ( 3H , m) , 3 . 3 0- 3 . 7 0 ( 6H , m) ,
3.77 (1H, m), 3.94 (lHf m) , 4 - 14 (lHf s) , 4 . 38 (1H, s) ,
4.81 (1H, dd, J=5, 8Hz) . MASS (ES + ) m/z : 289 (M+l).
Example 13-1
Methyl (lS,3S,4S,6R,7R)-7-fluoro-6-hydroxy-2-[ (1R)-1-
phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate
To a solution of methyl
(lS/3S,4S/6R/7S)-6-hydroxy-7-iodo-2-[ (1R)-1-
phenylethyl]-2~azabicyclo[2.2.1]heptane-3-carboxylate
(lOOmg) in acetonitrile (8mL) , was added
tetrabutylammonium fluoride hydrate (102mg). The
mixture was stirred at 80^ for 30 minutes. The resulting mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound

(59.5mg).
1H-NMR (300MHz, CDC13) : 6 1.39(3H, dr J=6.6Hz), 1.63(1H, m) , 1.82(1H, m) , 2.19(1H, m) , 2.76(1H, m) , 3.26(1H, m) , 3.47 (1H, m) , 3 . 55 (1H, s) , 3 . 72 (1H, q, J=6.6Hz), 4.10 (1H, m) , 4.78(1H, d, J=5 0Hz), 7.17-7.35(5H, m). MASS (ES+) m/z : 294 (M+l).
Example 13-2
Methyl (1S,3S,4S,6R,7R) -7 -fluoro-6-hydroxy-2-
azabicyclo[2.2.1]heptane-3-carboxylate
The title compound was prepared from methyl (lS,3S,4S,6R,7R)-7-fluoro-6-hydroxy-2-[(lR)-l-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 13-1 in a similar manner to that of Example 2-4.
Example 13-3
2-tert-Butyl 3-methyl (13,38,43,6R,7R)-7-fluoro-6-
hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate
The title compound was prepared from methyl (lS,3S,4S,6R,7R)-7-fluoro-6-hydroxy-2-azabicyclo[2.2. 1]heptane-3-carboxylate obtained in Example 13-2 in a similar manner to that of Example 5-5.
1H-NMR (30 0MHz, CDC13) : 8 1.39 and 1 . 47 (9H, s), 1 . 77 (1H, m) , 1.94(1H, m) , 2.2O(1H, m) , 2.92(1H, m) r 3.76(3H, s), 4.08-4.31(3H, m), 4.95(1H, df J=50Hz). MASS m/z : 312 (M+Na).
Example 13-4
(IS,3S,4S, 6Rf7R) -2- (tert-Butoxycarbonyl) -7-fluoro-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid

The title compound was prepared from 2-tert-butyl 3-methyl (lS,3S,4S,6R,7R)-7-fluoro-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 13-3 in a similar manner to that of Example 5-6.
1H-NMR (30 0MHz, DMSO-d6) : 5 1.32 andl.39(9H, s) , 1 . 62 (1H, m), 1.92 (1H, m), 2.76 (1H, m) , 3.88-4.05(3H, m) , 4 . 84-5 . 08 (2H, m) . MASS (ES+) m/z : 276 (M+l).
Example 13-5
tert-Butyl (lS,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-7-fluoro-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from (1S,3S,4S,6R,7R)-2-(tert-butoxycarbonyl)-7-fluoro-6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 13-4 in a similar manner to that of Example 5-7.
1H-NMR (300MHz, CDC13) : 5 1.34 and 1.45(9H, s), 1.65-2.49(6H,m), 2.88(lH,m), 3 . 58 (1H, m) f 4.16-4.45(2H/ m) , 4.77-5. 07 (1H, m) . MASS (ES+) m/z : 354 (M+l).
Example 13-6
(2S)-l-{[(lS,3S,4S,6R,7R)-7-Fluoro-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lS,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-7-fluoro-6-hydroxy-2-azabicyclo[2.2.1] heptane-2-carboxylate obtained in Example 13-5 in a

similar manner to that of Example 2- 8 .
1H-NMR (300MHz, DMSO-d6) : 8 1.77(2H, m), 1 . 9 0-2 - 3 3 ( 4H f m), 3.22(1H, br-s), 3.50-3.66(3H,m), 4 . 13 (lHf m) , 4.41 (1H, m) , 4.82(1H, del, J=5, 8Hz), 5.16(1H, d, J=50Hz), 5.50(lH, br-s) . MASS (ES+) m/z : 254 (M+l).
Example 14-1
2-tert-Butyl 3-methyl (lR,3R,4S,6R)-6-hydroxy-2-
azabicyclo[2.2.1]heptane-2,3-dicarboxylate
To 2-tert-butyl 3-methyl (1R,33,4s,6R)-6-hydroxy~ 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (3.04g), was added IN sodium methoxide solution in methanol (3 4mL) . The mixture was stirred -at reflux for 4hrs. To the resulting mixture was added ammonium chloride solution and evaporated in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was recrystalized fromhexane-diethyl ether to give the target compound (1.09g) as a solid.
1H-NMR (3 00MHz, CDC13) : 8 1.39 and 1 . 47 ( 9H, s),
1.42-2.01(4H, m), 2 . 68 (1H, m), 3.59 and 3 . 69 (1H, s) ,
3.73(3H, s), 3.96-4.17(2H, m).
MASS (ES + ) m/z : 272 (M+l)
Example 14-2
(1R,3R,4S,6R)-2-(tert-Butoxycarbonyl)-6-hydroxy-2-
azabicyclo[2.2.l]heptane-3-carboxylic acid
The title compound was prepared from 2-tert-butyl 3-methyl (1R,3R,4S,6R)-6-hydroxy-2-azabicyclo[2.2.

1]heptane-2,3-dicarboxylate obtained in Example 14-1 in a similar manner to that of Example 5-6.
1H-NMR (300 MHz, DM SO-d6) : 5 1.30(lH,m),1.31andl.40(9H, s), 1.53(1H, m) f 1.65(1H, m) , 1.84(1H, m) , 2.55(1H, m) , 3.44 (1H, m) , 3.69 (1H, m) , 3.80 and3.87(lH, br-s), 5.05 (1H, m) . MASS (ES-) m/z : 256 (M-l).
Example 14-3
tert-Butyl (lR,3R,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo [2 .2 , 1] heptane-2-carboxylate
The title compound was prepared from (1R,3R, 4S r 6R) -2- (tert-butoxycarbonyl) -6-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxy1ic acid obtained in Example 14-2 in a similar manner to that of Example 5-7.
1H-NMR (300MHz, CDC13) : 5 1.40 and 1.43 (9H, s) , 1.40-2.78(6H, m) , 2.96 (1H, m) , 3.55-4.21(6H/ m). MASS (ES+) m/z : 336 (M+l).
Example 14-4
(2S)-1-{[(1R,3R,4S,6R)-6-Hydroxy-2-azabicyclo [2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (1R,3R,4S,6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 14-3 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1 . 32-1.55 (4H, m) ,

1.73-1.83(2H, m) , 1.90-2.28 (2H, m) , 2.82 (1H, m) , 3.70-3.87(4H, m) , 4.14-4.25(2H, m) , 5.42 (1H, br-s). MASS (ES+) m/z : 236 (M+l).
Example 15-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(2~ethoxy-2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidiny1] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 in a similar manner to that of Example 35-1 described later.
1H-NMR (300 MHz, CDC13) : 5 1 . 27 (3H, t, J = 7Hz)f 1.32 and 1.34(9H7 s) , 1.44 (1H, s) , 1.66 (1H, m), 1.88(1H, m), 2.05-2.38(5H/m)/ 2 - 72 (lHf m) , 3.55-3.67(2H,m)/ 3 . 91 (1H, m), 4.03-4.38(6H/ m), 4.84(1H, m). MASS (ES+) m/z : 422 (M+l).
Example 15-2
[((lRr3S,4S,6R)-2-(tert-Butoxycarbonyl)-3-{[(2S)-2-
cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo [2 . 2.1]
hept-6-yl)oxy]acetic acid
To a solution of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6- (2-ethoxy-2-oxoethoxy)-2-azabicyclo [2.2 . 1 ]heptane-2-carboxylate obtained in Example 15-1 (249mg) in dioxane (3mL) and water (lmL), was added lithium hydroxide monohydrate (302mg). The mixture was stirred at room temperature for lhr. The resulting mixture was evaporated in vacuo. IN Hydrochloric acid (1.2mL) was added to the residue, and the mixture was extracted with

ethyl acetate- The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the target compound (261mg).
1H-NMR (300MHz, CDC13) : 5 1.34 and 1.46(9H, s ) , 1 . 45 ( 1H, m) , 1.67(1H, m) , 1.87(1H, m) , 2 . 0 5-2 . 3 8 ( 5H, m), 2.75(1H, m) , 3.45-3.70(2H, m) , 3.96(1H, m) , 4.05-4.40(4H, m) , 4.85(1H, m). MASS (ES-) m/z : 392 (M-l).
Example 15-3
tert-Butyl (lR,3S,4S,6R)-6-(2-amino-2-oxoethoxy)-3-
{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo [2.2.1]heptane-2-carboxylate
To a solution of
[((lR,3S,4S,6R)-2-(tert-butoxycarbonyl)-3-{[(2S)-2-
cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo [2.2 . 1]
hept-6-yl)oxy]acetic acid obtained in Example 51-2
(260mg) in dimethylformamide (3.OmL), was added 28%
ammonium hydroxide (0.08mL),
l-hydroxy-7-azabenzotriazole (117mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165mg). The mixture was stirred at room temperature for 12hrs.
The reaction mixture was diluted with ethyl acetate, and washed successively with 0 . 5N hydrochloric acid, sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (174mg).
1H-NMR (300MHz, CDC13) : 5 1.34 and 1 . 4 6 (9H, s), 1 . 42 ( 1H, m) , 1.62-1.84 (2H, m), 2.07-2.38(5H, m), 2 . 74 ( 1H, m),

3.55-3.68(2H, m) , 3.93-4.04 (3H, m) , 4 . 24 (lHf br-s), 4 . 85 (1H, m) f 5.48(1H, br-s), 6. 42 (1H, br-s). MASS (ES+) m/z : 393 (M+l).
Example 15-4
2-[((lR,3S,4S,6R)-3-{[(2S)-2-Cyano-1-pyrrolidiny1]
carbonyl}-2-azabicyclo[2.2,1]hept-6-yl)oxy]acetamide
hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-6-(2-amino-2-oxoethoxy)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1] heptane-2-carboxylate obtained in Example 15-3 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1 . 3 5-1 . 57 (1H , m), 1.56(1H, m) , 1.58-2 . 35 (6H, m) , 3.06(lH, m) , 3.64(1H, m) , 3,82-3. 90(3H, m) , 4 . 01 (1H, s), 4.33(1H, m), 4.83(1H, m) . MASS (ES+) m/z : 293 (M+l).
Example 16-1
tert-Butyl (1R,3S,4S,6R)-6-allyloxy-3-{[(2S)-2-
cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]
heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carb oxylate obtained in Example 5-7 ( 51 Omg ) intetrahydrofuran (5.0mL), were added 1,4-bis (diphenylphosphino)butane ( 6 4.8mg) ,
tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (39.3mg) and allyl ethyl carbonate (0.4mL). The
mixture was stirred at 65^ for 4hrs. The resulting mixture was evaporated in vacuo and the residue was

chromatographed on silica gel eluting with ethyl acetate to give the target compound (408ing) .
1H-NMR (300MHz, CDC13) : 5 1.35 and 1 . 46 (9H, s) , 1.40(1H, m), 1.62(1H, m) , 1 . 82 (1H, m) , 2.05-2.37 (5H, m) , 2.71 (1H,
m) , 3.52-3.67 (2H, m) , 3.89-4.36(5H, m) , 4 . 84 (1H, m) , 5. 16 (1H, m)f 5.27(1H, m)f 5.91(1H, m) . MASS (ES + ) m/z : 376 (M+l).
Example 16-2
(2S)-1-{[(1R,3S,4S,6R)-6-A11yloxy-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-6-allyloxy-3-{ [ (2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 16-1 in a similar manner to that of Example 2-8.
XH-NMR (30 0MHz, DMSO-d6) : 5 1 . 43 (1H, m) , 1 - 64 (1H, m), 1.84(2H, s)f 1 . 90-2 . 35 (4H, m) , 3.06(lH, br-s), 3.63(2Hf m), 3.83 (lHf m) , 3.87-4.08(3H, m), 4.33 (1H, df J = 2Hz), 4.83(lHf dd, J=5, 8Hz), 5-12-5.31(2H, m), 5.89(1H, m). MASS (ES+) m/z : 276 (M+l) .
Example 17-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(2-oxopropoxy)-2-azabicyclo [ 2.2.1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-6-allyloxy-3-{ [ (2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 16-1 (277mg) in

dimethyl form amide ( 5 . OmL ) and water (0.4 5mL ) , were added palladium(2) chloride (10 5mg) and copper(1) chloride
(292mg). The mixture was stirred vigorously in aerobic condition at room temperature for 3hrs.
The reaction mixture was diluted with ethyl acetate, and washed successively with 0.5N hydrochloric acid, sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound
(117mg).
1H-NMR (300MHz, CDC13) : 5 1.35 and 1 . 47 (9H, s), 1 . 42 (1H,
m) , 1.67(1H, m) , 1.86(1H, m) , 2 . 0 5-2 . 3 7 ( 5H, m), 2.14 and
2.17(3H, s), 2.74(1H, m) , 3 . 52 - 3 . 67 ( 2 H, m), 3.88(1H, m) ,
4.07-4.37(4H, m), 4.84(1H, m).
Example 17-2
(2S)-l-{ [ (lR,3S,4S,6R)-6-(2-Oxopropoxy)-2-azabicyclo[ 2.2.l]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6- (2-oxopropoxy) -2-azabicyclo[2.2.1]heptane -2-carboxylate obtained in Example 17-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1.47(1H, m), 1.77(1H, m), 1.85(2H, m) , 1.95-2.33 (4H, m) , 2.04(3H, s), 3.06(lH, m), 3.63 (2H, m), 3.83(1H, m), 3.97(1H, s), 4.22(2H, s), 4.32(1H, m), 4.83(1H, dd, J=5, 8Hz). MASS (ES+) m/z : 292 (M+l).
Example 18-1

tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-{2-[(methylsulfonyl)amino]-2 -oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate
To a solution of
[((lR,3S,4S,6R)-2- (tert-butoxycarbony1)-3-{ [ (2S)-2-
cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]
hept-6-yl)oxy]acetic acid obtained in Example 15-2
(195mg) in dimethylformamide (2.5mL), was added
1, 1 ' -carbonyldiimodazole (165mg) . The mixture was
stirred at room temperature. After 30 minutes,
methanesulfonamide (6 6mg) and
l,8-diazabicyclo[5,4,0]undec-7-ene (106mg) were added, and the resulting mixture was stirred at room temperature for 12hrs.
The reaction mixture was diluted with ethyl acetate, and washed successively with 0.5N hydrochloric acid and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform and methanol (9:1) to give the target compound (171mg).
1H-NMR (30 0MHzf CDC13) : 5 1.35 and 1 . 48 (9H, s), 1.42(1H, m), 1.55-1.85(2H,m), 2.05-2.40 (5H, m) , 2.77 (1H, m) , 3.34 and 3.36 (3H, s), 3.50-3.68(2H, m), 3.99(1H, m), 4.05-4.38(4H, m), 4.84(1H, m). MASS (ES-) m/z : 469 (M-l)
Example 18-2
2- [ ( (lR,3S,4S,6R)-3-{ [ (2S)-2-Cyano-1-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy]-N-(methyl sulfonyl)acetamide hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl]

carbonyl}-6-{2-[(methylsulfonyl)amino]-2-oxoethoxy}-2 -azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 18-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 6 1.52(1H, m) , 1.67(1H, m), 1.78-2.32 (6H, m) , 3.06(lH, m) , 3.27(3H, s), 3.62(2H, m) , 3.91 (1H, m) , 3.95-4.19(3H, m) , 4 . 33 (1H, m) , 4 . 83 (1H, m). MASS (ES+) m/z : 371 (M+l).
Example 19-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(2-{[(dimethylamino)sulfonyl
]amino}-2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-
carboxylate
The title compound was prepared from [ ( (1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-3-{ [ (2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1] hept-6-yl)oxy]acetic acid obtained in Example 15-2 in a similar manner to that of Example 18-1.
1H-NMR (30 0MHz, CDC13) : 5 1.34 and 1.47 (9H, s) , 1 . 42 (1H, m) , 1.60-1.82(2H, m) , 2.05-2.40(5H, m), 2 . 77 (lHf m), 2.98(3H, s), 2.99(3H, s), 3.50-3.68(2H/m), 3.92-4.38(5H, m), 4.83(1H/ m), 8.53(1H, br-s). MASS (ES-) m/z : 498 (M-l).
Example 19-2
2- [ ( (lR,3S,4S,6R)-3-{ [ (2S)-2-Cyano-l-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.l]hept-6-yl)oxy]-N-[(dimethylamino)sulfonyl]acetamide hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-(2-{[(dimethylamino)sulfonyl]amino}-2-oxo

ethoxy)-2-azabicyclo[2.2,1]heptane-2-carboxylate obtained in Example 19-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1.49(1H, m), 1.66(1H, m), 1.76-2 . 32 (6H, m) , 2.82(6H, s), 3.04(lH, m) , 3.62(2H, m) , 3.72-4.40(5H, m), 4.83 (1H, m). MASS (ES+) m/z : 400 (M+l).
Example 2 0-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl] carbonyl}-6- (2-oxo-2-{ [ (tri fluoromethyl)
sulfonyl]amino}ethoxy)-2-azabicyclo[2.2.1]heptane-2-
carboxylate
The title compound was prepared from [((lR,3S,4S,6R)-2- (tert-butoxycarbony1) -3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1] hept-6-yl)oxy]acetic acid obtained in Example 15-2 in a similar manner to that of Example 18-1.
1H-NMR (30 0MHz, CDC13) : 5 1-31 and 1 . 46 (9H, s ) , 1.42(1H/ m) , 1.66(1H, m) , 1.8O(1H, m) , 2.0-2.40(5H, m) , 2.77(1H, m) f 3.52C1H, m) , 3.64(1H/ m) , 3 . 80-4.40 (5H, m) , 4.81(1H, m) . MASS (ES-) m/z : 523 (M-l)
Example 20-2
2-[((lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl]
carbonyl}-2-azabicyclo[2.2.l]hept-6-yl)oxy]-N-
[(trifluoromethyl)sulfonyl]acetamide hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-(2-oxo-2-{[(trifluoromethyl)sulfonyl]

amino}ethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 20-1 in a similar manner to that of Example 2 - 8.
1H-NMR (30 0MHz, DMSO-d6) : 6 1 . 45 (1H, m), 1 . 66 (1H, m) , 1.83(2Hf m) , 2.02(2H, m) , 2 . 05-2.32 (2H, m) , 3-03(lH, m) , 3. 63 (2H, m) , 3,70-4.16(4H/ m) , 4.31 (1H, m) , 4 . 83 (1H, m) . MASS (ES+) m/z : 425 (M+l).
Example 21-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-{[(2R)-2,3-dihydroxypropyl] oxy}-2-azabicyclo[2.2 .1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-6-allyloxy-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 16-1 (323mg) in t-butyl alcohol (4.3mL) and water (4-3mL) , was added AD-mix-a
(1.2g) . The mixture was stirred at 0^ for 4hrs. Sodium sulfite (l.Og) was added to the resulting mixture.
The mixture was then evaporated in vacuo. The residue was diluted with ethyl acetate, and washed successively with 0.5N hydrochloric acid, sodium hydrogen carbonate solution and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (234mg).
1H-NMR (30 0MHz, CDC13) : 5 1.34 and 1 . 46 (9H, s), 1.65(1H, m), 1 .77 (1H, m), 2.05-2.37(6H,m), 2 . 53 (1H, m), 2 . 73 (1H, m) , 3.50-3.77(6H,m), 3.79-3.98(2H,m)f 4.17-4.37(2H,m), 4.84(1H, m). MASS (ES+) m/z : 410 (M+l).

Example 21-2
(2S)-l-[ ( (lR,3S,4S,6R)-6-{ [ (2R)-2,3-dihydroxypropy1] oxy}-2-azabicyclo[2.2.l]hept-3-yl)carbonyl]-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-{[(2R)-2,3-dihydroxypropyl]oxy}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 21-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1.43(1H, m), 1.64(1H, m), 1.70-2.32(6H,m), 3.03 (1H, m) , 3.20-3.96(9H,m), 4.34 (1H, m) , 4.83 (1H, m) . MASS (ES+) m/z : 310 (M+l)-
Example 22-1
tert-Butyl (lR,3S,4S)-3-{ [ (2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-oxo-2-azabicyclo[2.2 . 1]
heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbony 1}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (353mg) in dichloromethane (lOmL), were added sodium hydrogencarbonate (177mg) and Dess-Martin periodinane (6 92mg). The mixture was stirred at room temperature for 4hrs.
The resulting mixture was evaporated in vacuo. To the residue, sodium thiosulfate solution and sodium hydrogen carbonate solution were added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with ethyl acetate to give the target compound (284mg) as a

solid -
1H-NMR (300MHz, CDC13) : 6 1.36 and 1.45(9H, s), 1.83(1H, m) , 1.95-2.40(5H, m) , 2.45-2.57 (1H, m) , 3. 07 (1H, m) , 3.55-3.78 (2H, m) , 4.28 and 4 . 39 (1H, s) , 4.52(1H, m), 4.82-4.95(1H, m). ' ' MASS (ES+) m/z : 334 (M+l).
Example 22-2
(2S)-1-{[(lR,3S,4S)-6-Oxo-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl]carbonyl}-6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 22-1 in a similar manner to that of Example 2-8 .
1H-NMR (300MHz, DMSO-d6) : S 1.44(1H, m) , 1 . 8 0 - 2 . 3 8 ( 5H , m) , 3.05(lH, m) , 3.35-4.0(3H, m) , 4.45(1H, m) , 4.64(1H, m) , 4 . 79-4.91 (2H, m) . MASS (ES+) m/z : 234 (M+l)
Example 2 3-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-{[(2S)-2,3-dihydroxypropyl] oxy}-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from tert-butyl (1R,3S,4S,6R)-6-allyloxy-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.l]heptane-2-carboxylate obtained in Example 16-1 in a similar manner to that of Example 21-1.
1H-NMR (300 MHz, CDC13) : 5 1.34 and 1.46(9H, s), 1 . 65 ( 1H,

m) , 1.77(1H, m) , 2 . 05-2.37 ( 6H, m), 2.53(1H/ m) , 2.73(1H, m), 3.50-3.77 (6H,m), 3.79-3.98(2H,m), 4.17-4.38(2H,m), 4.84(1H, m). MASS (ES+) m/z : 410 (M+l).
Example 23-2
(2S)-1- [ ( (lR,3S,4S,6R)-6-{ [ (2S)-2,3-Dihydroxypropy1] oxy}-2-azabicyclo[2.2.1]hept-3-yl)carbonyl]-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidiny1] carbonyl}-6-{t(2S)-2,3-dihydroxypropyl]oxy}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 23-1 in a similar manner to that of Example 2-8.
1H-NMR (300 MHz, DMSO-d6) : 5 1 . 43 (1H, m), 1 . 64 (1H, m), 1.70-2.32(6H,m), 3.04(lH,m)f 3.20-3.96(9H,m), 4 . 34 (1H, m), 4.83(1H, m). MASS (ES+) m/z : 310 (M+l).
Example 24-1
tert-Butyl (lR,3S,4S,6S)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo [2 .2 . 1]h
eptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-6-oxo-2-azabicyclo [2.2.1]heptane-2-carboxylate obtained in Example 22-1 (80mg) in methanol (8mL), was added sodium borohydride (lOmg) . The mixture was stirred
at 0˚C for lhr. To the reaction mixture, was added citric acid solution. The mixture was extracted with ethyl acetate- The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The

residue was triturated with ether to give the target compound (82mg) as a solid.
1H-NMR (300MHz, CDC13) : 8 1.38 and 1 . 46 (9Hf s) , 1.63 (1H, m) , 1.77(1H, m) , 1.91(1H, m) , 2.05-2 . 41 (5H, m) , 2.74(1H, m) , 3.55-3.75(2H, m) , 4.-15-4.48 (3H, m) f 4.90 (1H, m) . MASS (ES + ) m/z : 336 (M+l).
Example 24-2
(2S)-1-{[(1R,3S,4S,6S)-6-Hydroxy-2-azabicyclo[2.2.1]
hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile
hydrochloride
The title compound was prepared from tert-butyl (lRf3S,4S,6S)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 24-1 in a similar manner to that of Example 2 - 8.
1H-NMR (300MHz, DMSO-d6) : 5 0.91(lHf m), 1 .85-2.35 ( 7H, m) , 2.98 (1H, br-s) , 3.46(1H/ m) , 3 - 70 (lHf m), 3.83 (lHf m) , 4.26(1H, m), 4.48 (1H, m) , 4.86(1H, m) , 5.75 (1H, d, J=4Hz). MASS (ES+) m/z : 236 (M+l)
Example 2 5-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(2-oxoethoxy)-2-azabicyclo[2 . 2 . 1]heptane-2-carboxylate
To a solution of tert-butyl (lRf3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-{[(2S)-2,3-dihydroxypropyl]oxy}-2-azabicy clo[2.2.l]heptane-2-carboxylate obtained in Example 23-1 (250mg) in methanol (5mL) and water (5mL) , was added

sodium periodinate (522mg). The mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo to give the target compound (238mg). This compound was used immediately without purification.
Example 2 5-2
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(2-hydroxyethoxy)-2-azabicyclo[2.2,1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-(2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 25-1 (238mg) inmethanol (6mL) , was added sodium borohydride (26.2mg) . The mixture was stirred at room temperature for 20 minutes. To the resulting mixture, was added citric acid solution. The mixture evaporated in vacuo. The residue was diluted with ethyl acetate, and washed with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo to give the target compound (220mg).
1H-NMR (300MHz, CDC13) : 5 1.35 and 1.46(9H, s), 1.66(1H, m), 1.78(1H, m), 2.05-2.37(6H, m), 2.72(1H, m), 3.52-3.67(4H,m), 3.71(2H,m), 3.93(lH,m), 4.17-4.38(2H, m), 4.85(1H, m). MASS (ES+) m/z : 380 (M+l).
Example 2 5-3
(2S)-1-{[(lR,3S,4S,6R)-6-(2-Hydroxyethoxy)-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride

The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2 -cyano-1-pyrrolidinyl] carbonyl}-6- (2-hydroxyethoxy) -2-azabicyclo [2 .2 . 1] heptane-2-carboxylate obtained in Example 25-2 in a similar manner to that of Example 2 - 8.
1H-NMR (300MHz, DMSO-d6) : 8 1.42(1H, m), 1.64(1H, m), 1.70-2.32(6H,m), 3.04 (1H, m) , 3.30-3.75(5H,m), 3.82(1H, m), 3.93(1H, s), 4.33(1H, m), 4.83(1H, m). MASS (ES+) m/z : 280 (M+l).
Example 26-1
tert-Butyl (lR,3S,4S,6E)-6-[(benzyloxy)imino]-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[ 2.2.1]heptane-2-carboxylate
The title compound was prepared from tert-butyl (lR,3S,4S)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-6-oxo-2-azabicyclo[2.2.l]heptane-2-carboxylate obtained in Example 22-1 in a similar manner to that of Example 28-1 described later.
1H-NMR (300MHz, CDC13) : 5 1.37 and 1 . 43 (9H, s ) , 1.68 (1H, m) f 1.88(1H, m), 2.04-2.36(5H, m), 2.65(1H, m), 2.94(1H, m), 3.57-3.75(4H, m), 4.41(lHf m), 4.65-4.95(2H, m), 5.10(2H, m), 7.20-7.39(5H, m). MASS (ES+) m/z : 439 (M+l).
Example 2 6-2
(2S)-l-({(lR,3S,4S,6E)-6-[(Benzyloxy)imino]-2-azabicyclo[2.2.1]hept-3-yl}carbonyl)-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6E)-6-[ (benzyloxy) imino]-3-{ [ (2S) -2-cyano-l

-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 26-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 8 1 . 90-2 . 55 ( 8H, m), 3.31(1H, m), 3. 66 (2H, t, J = 7Hz), 4.41(1H, s) r 4.55 (1H, m) , 4.84(1H, m) , 5.04-5.17(2H, m) , 7.26-7.40(5H, m). MASS (ES+) m/z : 339 (M+l).
Example 2 7-1
tert-Butyl (lR,3S,4S,6R)-6-[2-({[5-(acetylamino)-
1, 3,4-thiadiazol-2-yl]sulfonyl}amino)-2-oxoethoxy]-3-
{ [ (2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[ 2 . 2 . 1]heptane-2-carboxylate
The title compound was prepared from [ ( (lR,3S,4S,6R)-2-(tert-butoxycarbonyl)-3-{ [ (2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1] hept-6-yl)oxy]acetic acid obtained in Example 15-2 in a similar manner to that of Example 18-1.
1H-NMR (300MHz, CDC13) : 5 1 . 2 6 and 1 . 3 6 ( 9H, s), 1.22(1H, m) , 1.50-1.67(2H, m) , 1.84(1H, m), 1.95-2.30(4Hf m) , 2.20 and 2.23(3H, s), 2 . 77 (1H, m) , 3 . 17 (lHf d, J = 5Hz), 3. 37-3 . 75 (5H, m), 4.09(lH, m) , 4.24(1H7 m) , 4.36(1H, t, J=5Hz), 4.88(1H, m). MASS (ES-) m/z : 596 (M-l).
Example 2 7-2
N-{[5-(Acetylamino)-l,3,4-thiadiazol-2-yl]sulfonyl}-2 -[((1R,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy]acetamide hydrochloride
The title compound was prepared from tert-butyl

(lR,3S,4S,6R)-6-[2-({[5- (acety1 amino)-1,3,4-thiadiazol-2-yl]sulfonyljamino)-2-oxoethoxy]-3-{ [ (2S) -2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo [2.2 . 1] heptane-2-carboxylate obtained in Example 27-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHzf DMSO-d6) : 5 1.47(1H, m), 1.65(1H, m), 1.75-2,29 (6H, m) , 2.25(3H, s), 3.03(lH, m) , 3.62(2H, m) , 3-84-4.13(4Hr m), 4.33(1H, m), 4.82(1H, m). MASS (ES+) m/z : 498 (M+l).
Example 28-1
tert-Butyl (lR,3S,4S,6E)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-hydroxyimino-2-azabicyclo[2.
2.1]heptane-2-carboxylate
To a solution of tert-butyl
(lR,3S,4S)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-
6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate
obtained in Example 2 2-1 (296mg) in ethanol (5mL) andwater
(lmL) , were added hydroxylamine hydrochloride (123mg) and
sodium acetate (153mg). The mixture was stirred at 80^ for 2 0 minutes -
The resulting mixture was evaporated in vacuo. To the residue, was added water. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (10 6mg) as a solid.
1H-NMR (300 MHz, CDC13) : 5 1.36 and 1 . 45 (9H, s), 1.71 (1H, m) , 1.9O(1H, m) , 2.05-2.38 (5H, m) , 2.66(1H, m) , 2.97(1H, m), 3.55-3.74(2H, m), 4.44(1H, m), 4.67 and 4 . 77 (1H, s) , 4 . 90 (1H, m), 7.02(lH, br-s).

MASS (ES+) m/z : 349 (M+l).
Example 28-2
(2S)-l-{[(lR,3S,4S,6Z)-6-Hydroxyimino-2-azabicyclo[2. 2 . 1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6E)-3-{[(2S)-2-cyano-1-pyrrolidiny1] carbonyl}-6-hydroxyimino-2-azabicyclo[2.2.1]heptane-2 -carboxylate obtained in Example 28-1 in a similar manner to that of Example 2-8 .
1H-NMR (300MHz, DMSO-d6) : 6 1.87-2.43 ( 8H, m), 3.28(1H, m) , 3 . 66 (2H, t, J=7Hz), 4 . 35 (1H, s) , 4.53 (1H, m) , 4 . 83 (1H, m) . MASS (ES + ) m/z : 249 (M+l).
Example 2 9-1
2-tert-Butyl 3-methyl (!R,3S,4S,6R)-6-
[ (methylsulfonyl)oxy]-2-azabicyclo[2.2.1]heptane-2,3-
dicarboxylate
To a solution of 2-tert-butyl 3-methyl (lR,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2, 3-dicarboxylate (185mg) in pyridine (2mL), was added methanesulfonyl chloride (117mg)• The mixture was stirred at room temperature for 2hrs. The resulting mixture was evaporated in vacuo. To the residue, water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (237mg).

XH-NMR (30 0MHz, CDC13)- : 5 1-39 and 1 . 4 8 (9H, s) ,
1.58-l.BB(3Hf m) , 2 . 83 (1H, m) , 3.04 and 3. 06 (3H, s) ,
3.75(3H, s), 4.12(1H, m), 4.45(1H, br-s), 4.84(1H, m).
MASS (ES+) m/z : 350 (M+l).
Example 29-2
2-tert-Butyl 3-methyl (lR,3S,4S,6R)-6-azido-2-
azabicyclo[2.2.l]heptane-2,3-dicarboxylate
To a solution of 2-tert-butyl 3-methyl
(1R,3S,4S, 6R) -6-[ (methylsulfonyl)oxy]-2-azabicyclo [2.
2.l]heptane-2,3-dicarboxylate obtained in Example 29-1
(2 32mg) in dimethylformamide (2.OmL) and water ( 0.4mL) ,
was added sodium azide (108mg). The mixture was stirred
at 80^ for lhr. The resulting mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (4:1) to give the target compound (175mg).
TH-NMR (300MHz, CDC13) : 5 1.40 and 1 . 49 (9H, s) , 1.40-1.71(3H, m), 1.87-2.02(2H, m), 2.72(1H, m),
3.63-3.77(1H, m), 3.73(3H, s), 4.1O-4.33(1H, m). MASS (ES+) m/z : 297 (M+l).
Example 29-3
2-tert-butyl 3-methyl (1R,3S,4R,6R)-6-amino-2-
azabicyclo[2.2.1]heptane-2,3-dicarboxylate
To a solution of 2-tert-butyl 3-methyl (lR,3S,4S,6R)-6-azido-2-azabicyclo[2.2.1]heptane-2,3-
dicarboxylate obtained in Example 29-2 (1 7 Omg ) in methanol (4mL), was added 10% palladium on carbon (30mg). The
mixture was stirred under latm of hydrogen for 1 .5hrs at

room temperature. The resulting mixture was filtered through celite and washed with methanol. The filtrate and washings were evaporated in vacuo to give the target compound (155mg).
Example 29-4
2-tert-Butyl 3-methyl (lR,3S,4R,6R)-6-acetylamino-2-
azabicyclo[2.2.1]heptane-2,3-dicarboxylate
To a solution of 2-tert-butyl 3-methyl
(1R,3S,4R,6R)-6-amino-2-azabicyclo[2.2.1]heptane-2,3-
di carboxylate obtained in Example 2 9-3 (155mg) inmethanol
(lOmL), was added acetic anhydride (30mg). The mixture
was stirred at room temperature for lhr. The resulting
mixture was evaporated in vacuo and chromatographed on
silica gel eluting with chloro form and methanol (19:1)
to give the target compound (153mg).
2H-NMR (300MHz, CDCl3) : 5 1.39 and 1.51(9H, s), 1.30-1.55(2H, m) f 1.95 and 1. 97 (3Hf s) , 2.04-2.20 (2H, m) , 2.71 (1H, m) , 3.67-3.80(lHf m)f 3.73 (3H, s) , 3.98-4.28 (2H, m) . MASS (ES+) m/z : 313 (M+l).
Example 29-5
(1R,3S,4R,6R)-6-Acetylamino-2-(tert-butoxycarbonyl)-2
-azabicyclo[2,2.1]heptane-3-carboxylic acid
The title compound was prepared from tert-butyl 3-methyl (1R, 3S,4Rf 6R) -6-acetylamino-2-azabicyclo[2.2. 1]heptane-2,3-dicarboxylate obtained in Example 29-4 in a similar manner to that of Example 5-6.
1H-NMR (300MHz, DMSO-d6) : 5 1.32 and 1.41(9H, s), 1.33-1.50(2H, m) , 1.68(1H, m) f 1 . 78 (3Hf s) , 1 . 92 (1H, m) ,

2.59 (1H, m), 3.57(1H, s) , 3.70-3.98(2H, m) , 7.74 (1H, m) . MASS (ES-) m/z : 297 (M-l).
Example 29-6
tert-Butyl (1R,3R,4R,6R) - 6-acetylamino-3-{ [ (2S)-2-
cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]
heptane-2-carboxylate
The title compound was prepared from
(1R,3S,4R, 6R) -6-acetylamino-2- (tert-butoxycarbonyl)-2
-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in
Example 29-5 in a similar manner to that of Example 5-7.
1H-NMR (300MHz, CDC13) : 5 1.35 and 1 . 4 9 (9H, s) , 1.4-1.6(2H, m) 7 .1.98 (3H, s), 2.0-2.42(6H, m) , 2.6O(1H, m) , 3 . 55-3 . 82 (3H, m) , 4 . 0 0 - 4 . 2 5 ( 2H , m) , 4.83(1H, m) , 5.25 (1H, m) . MASS (ES+) m/z : 377 (M+l).
Example 29-7
N-((lR,3S,4S,6R)-3-{[(2S)-2-Cyano-l-pyrrolidinyl]
carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)acetamide
hydrochloride
The title compound was prepared from tert-butyl (1R,3R,4R,6R)- 6-acety1amino-3-{ [ (2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.l]heptane-2-carboxylate obtained in Example 29-6 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1 . 32 -1.65 (2H, m), 1.67-2.32(6H, m) , 1.83(3H, s), 2 . 96 (1H, m) , 3.58-3.70(2H, m) , 3.83(1H, m) , 4.07(lH, m) , 4.17(1H, m) , 4.8O(1H, dd, J=5.1, 8.1Hz), 8.14(1H, d, J=8Hz), 8.53(1H, m). MASS (ES+) m/z : 277 (M+l).

Example 3 0-1
3-Benzyl 2-tert-butyl (1R,3S,4S,6R)-6-hydroxy-2-
azabicyclo[2.2.1]heptane-2,3-dicarboxylate
To a solution of (1R,3S,4S,6R)-2- (tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2 . 1] heptane-3-carboxylic acid obtained in Example 5-6 (1.Og) in dichloromethane (8mL), were added benzyl alcohol (50 4mg)/ dicyclohexylcarbodiimide (9 62mg) and 4 - ( dimethyl ami no )pyridine ( 12 ing ). The mixture was stirred at room temperature for 2 Ohrs-
The resulting mixture was filtered through celite and washed with dichloromethane. The filtrate and washings were evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (597mg).
^-NMR (300MHz, CDC13) : 5 1.32 and 1 . 46 (9H, s) , 1.60-2.03(3H, m), 2.77(1H, m), 4.07-4.22(3H, m) , 5.06-5.28(2H, m), 7.25-7.37(5H, m). MASS m/z : 370 (M+Na).
Example 30-2
3-Benzyl 2-tert-butyl (1R,3S, 4S,6R) - 6-{ [ (IE) -3-ethoxy-3-oxo-l-propen-l-yl]oxy}-2-azabicyclo[2.2.1]heptane-2 , 3-dicarboxylate
To a solution of 3-benzyl 2-tert-butyl
(1R,3S ,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,
3-dicarboxylate obtained in Example 30-1 (593mg) in
dichloromethane (1OmL), were added ethyl propiolate
(670mg) and 4-methylmorphorine (190mg) . The mixture was
stirred at room temperature for 3hrs. The resulting
mixture was evaporated in vacuo and the residue was
chromatographed on silica gel eluting with hexane and

ethyl acetate (4:1) to give the target compound (760mg).
1H-NMR (300MHz,CDCl3) : 6 1.26(3H, m) , 1.34 and 1.50 (9H, s) , 1.42(1H, m) , 1,63-1.78 (2H, m) , 1.97(1H, m) , 2.82 (1H, m) , 4.07-4.43(5H,m), 5.07-5.37(3H,m), 7 . 28-7 . 42 (5H, m) , 7.48 (1H, m) .
Example 3 0-3
(lR,3S,4S,6R)-2-(tert-Butoxycarbonyl)-6-(3-ethoxy-3-oxopropoxy)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid
To a solution of 3-benzyl 2-tert-butyl (lR,3S,4S,6R)-6-{ [ (lE)-3-ethoxy-3-oxo-l-propen-l-yl] oxy}-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 30-2 (316mg) in ethanol (8mL), was added 10% palladium on carbon (60mg). The mixture was stirred under 4atm of hydrogen for lhr at room temperature . The resulting mixture was filtered through celite and washed with ethanol. The filtrate and washings were evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform andmethanol (19:1) to give the target compound (210mg)-
1H-NMR (30 0MHz, DMSO-d6) : 5 1 . 26 (3H, t, J=7Hz), 1.3-1.55 (1H, m) , 1.59(1H, m), 1.73(1H, m) , 2.06(lH, m) , 2.54(2H, t, J=6Hz), "2.84 (1H, m) f 3.61-3.81{3Hf m) , 4.09-4.18(3H, m)f 4.35(1H, m).
Example 30-4
tert-Butyl (lR,3R,4Sf6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(3-ethoxy-3-oxopropoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from

(lR,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-(3-ethoxy-3-oxopropoxy)-2-azabicyclo[2 - 2.1]heptane-3-carboxylic acid obtained in Example 30-3 in a similar manner to that of Example 5-7.
1H-NMR (30 0MHz, CDC 13) : 8 1 . 27 (3H, m) , 1.34 and 1 . 47 ( 9Hf s) , 1.44 (1H, m) , 1.63(1H, m) , 1.76(1H, m), 2.05-2.38 (5H, m) , 2.54 (2H, m) , 2.68 (lHf m) , 3.50-3.93(5H, m) , 4.09-4.38(4H, m) , 4 . 85 (lHf m).
Example 3 0-5
Ethyl 3-[((lR,3R,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.l]hept-6-yl) oxyjpropionate hydrochloride
The title compound was prepared from tert-butyl (lR,3R,4S,6R)-3-{[(2S)-2 -cyano-1-pyrrolidinyl] carbonyl}-6- (3-ethoxy-3-oxopropoxy)-2-azabicyclo[2.2. l]heptane-2-carboxylate obtained in Example 30-4 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1.18(1H, t, J=7Hz), 1.37(1H, m) , 1 . 62 (lHr m) f 1 . 73 (lHr m), 1 . 84 (1H, m) , 1.90-2.32(4H, m) , 2.53(2H, m), 3 - 03 (1H, m), 3 • 54-3.75(4H, m), 3 - 81 (lHf m) , 3.92 (1H, br-s) , 4.07(2H, qf J = 7Hz), 4.33 (1H, m) , 4.83 (1H, dd, J=5f 8Hz) . MASS (ES+) m/z : 336 (M+l).
Example 31
Ethyl [((lR,3Sf4S,6R)-3-{t(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]hept-6-yl) oxy]acetate hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl]

carbonyl}-6-(2-ethoxy-2-oxoethoxy)-2-azabicyclo[2.2.1 ]heptane-2-carboxylate obtained in Example 15-1 in a similar manner to that of Example 2-8.
1H-NMR (300 MHz, DMSO-d6) : 6 1 . 22 (1H, t, J=7Hz), 1.48 (1H, m) , 1.68(1H, m) , 1.81(1H, m) , 1.93-2.32(5H, m) , 3.05(1H, br-s), 3.53-3.71(2H, m) , 3.90 (1H, m), 4.02(1H, br-s), 4.07-4.20 (4H, m), 4.33(1H, m) , 4.82(1H, ddf J=5, 8Hz). MASS (ES+) m/z : 322 (M+l).
Example 32-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-{[(2E)-2-(hydroxyimino)ethyl ]oxy}-2-azabicyclo[2.2.1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6- (2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 25-1 (163mg) in ethanol (6mL) and water (lmL), were added hydroxylamine hydrochloride (36mg) and sodium acetate (46mg). The mixture was stirred at reflux for 20 minutes. To the resulting mixture, brine was added. The mixture extracted with ethyl acetate . The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (131mg).
1H-NMR (300MHz, CDC13) : 5 1.35 and 1 . 47 (9H, s) , 1.3-1.5(1H, m) , 1.65(1H, m) , 1.8O(1H, m) , 2.05-2.37 ( 5H, m), 2.72(1H, m), 3.49-3.67(2H, m), 3.93(1H, m), 4.07-4.26(3H, m), 4.85(1H, m), 6.85 and 7.46(1H, m). MASS (ES+) m/z : 393 (M+l).

Example 32-2
(2S)-1- [ ( (lR,3S,4S,6R)-6-{ [ (2E)-2- (Hydroxyimino)ethyl ]oxy}-2-azabicyclo[2.2.1]hept-3-yl)carbonyl]-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-{ t (2E)-2- (hydroxyimino)ethyl]oxy}-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 32-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1.4-2.32(8H, m) , 3 . 06 (7H, m) , 3.5-4.4{5H, m) , 4.83(1H, m) , 6.78 and 7.36(1H, m) . MASS (ES + ) m/z : 293 (M+l).
Example 33-1
2-tert-Butyl 3-methyl (lR,3S,4R,6R)-6-[ (tert-
butoxycarbonyl)amino]-2-azabicyclo[2.2.1]heptane-2,3-
dicarboxylate
The title compound was prepared from 2-tert-butyl 3-methyl (lRf3S,4R/6R)-6-amino-2-azabicyclo[2.2. 1]heptane-2,3-dicarboxylate obtained in Example 29-3 in a similar manner to that of Example 29-4.
1H-NMR (300MHz, CDC13) : 5 1.39 and 1 . 50 (9H, s ) , 1 . 45 ( 9H, s), 1 . 30-1.55 (2H, m) , 1.93(1H, m) , 2.06(lH, m), 2.77(1H, m) , 3.7-3.83(lH, m) f 3.72 and 3.73(3H, s) , 4.03-4.40(2H, m) . MASS (ES+) m/z : 371 (M+l).
Example 3 3-2
(1R,3S, 4R, 6R)-2- (tert-Butoxycarbonyl)-6-[ (tert-butoxy carbonyl)amino] -2-azabicyclo [2 . 2 . 1]heptane-3-carboxylic acid

The title compound was prepared from 2-tert-butyl 3-methyl (lR,3S,4R,6R)-6-[ (tert-butoxycarbonyl) amino]-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 33-1 in a similar manner to that of Example 5-6.
1H-NMR (300MHz, DMSO-d6) : 6 1,32 and 1 . 42 (9H, s) , 1 . 39 (9Hf s), 1.2-1.54(2H, m) , 1.62(1H, m) , 1.87(1H, m) , 2.53(1H, m) , 3.45-3.58 (2H, m) , 3.77-3.96(lH, m) , 6. 89 (1H, m) . MASS (ES-) m/z : 355 (M-l).
Example 33-3
tert-Butyl (lR,3R,4R,6R)-6-[ (tert-butoxycarbonyl) amino]-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from (1R,3S,4R, 6R) -2- (tert-butoxycarbonyl)-6-[ (tert-butoxy carbonyl)amino]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 33-2 in a similar manner to that of Example 5-7.
1H-NMR (300MHzf CDC13) : 8 1.35 and 1.48(9H, s), 1 . 45 ( 9Hf s) , 1-33-1.53(2Hf m) , 1.97-2.37(6H, m), 2 . 58 (lHf m), 3.56-3.88(4H, m) f 4.09(lHf m) , 4 . 34 (1H, m) , 4 . 83 (1H, m). MASS (ES+) m/z : 435 (M+l).
Example 33-4
(2S)-l-{[(lRf3Sf4R,6R) - 6-Amino-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile dihydrochloride
The title compound was prepared from tert-butyl (lR,3Rf4R,6R)-6-[(tert-butoxycarbonyl)amino]-3-{[(2S) -2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]

heptane-2-carboxylate obtained in Example 33-3 in a similar manner to that of Example 2 - 8.
1H-NMR (300MHz, DMSO-d6) : 6 1.53(1H, m) , 1 . 6 7 -2 . 3 2 ( 7H , m) , 3 . 06 (1H, m) , 3.45-3.71(2H, m) , 3 . 89 (1H, m) , 4.12(1H, m), 4 .26 (1H, m) , 4 . 80 (1H, dd, J=5, 8Hz) . MASS (ES+) m/z : 235 (M+l).
Example 34-1
2-tert-Butyl 3-methyl (lR,3S,4S,6R)-6-{[(4-methylphenyl)sulfonyl]amino}-2-azabicyclo[2,2.1] heptane-2,3-dicarboxylate
To a solution of 2-tert-butyl 3-methyl (lR,3S,4R,6R)-6-amino-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 29-3 (32lmg) inpyridine (4mL) , was added p-toluenesulfonyl chloride (249mg) . The mixture was stirred at room temperature for lhr. The resulting mixture was evaporated in vacuo, and the re si due chromatographed on silica gel eluting with hexane and ethyl acetate (1:1) to give the target compound (440mg).
1H-NMR (300MHz, CDC13) : 8 1.37 and 1 . 4 7 (9H, s) , 1 . 30-1 . 55 (2H, m) , 1.84-1.99(2H, m), 2.44(3Hf s)f 2.61-2.74(1H, m), 3.26-3.68(2H, m) , 3.70(3H, s) , 4 . 06-4.50 (2H, m) , 7.33(2H, df J = 8Hz)f 7.75-7.85(2H, m) . MASS (ES+) m/z : 425 (M+l).
Example 34-2
(lR,3S,4S,6R)-2-(tert-Butoxycarbonyl)-6-{[(4-methylphenyl)sulfonyl]amino}-2-azabicyclo[2.2.1] heptane-3-carboxylic acid
The title compound was prepared from 2-tert-butyl 3-methyl (lR/3S/4S,6R)-6-{[(4-methylphenyl)sulfonyl]

amino}-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 34-1 in a similar manner to that of Example 5-6.
1H-NMR (300MHz,CDCl3):S 1.23-1.92(4H,m),1.51(9H,s), 2.45(3H, s) , 2.94(1H, m) , 3 . 35 (1H, m) , 3 . 67 (1H, m), 4.15(lHf m) , 4.68(1H, m) , 7.33(2H, d, J=8Hz), 7.77(2H, d, J=8Hz). MASS (ES-) m/z : 409 (M-l).
Example 3 4-3
tert-Butyl (1R,3R,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-{[(4-methylpheny1)sulfonyl] amino}-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from (lR,3S,4S,6R)-2-(tert-butoxycarbonyl)-6-{ [ (4-methylphenyl) sulfonyl]amino}-2-azabicyclo[2.2 . 1] heptane-3-carboxylic acid obtained in Example 34-2 in a similar manner to that of Example 5-7.
1H-NMR (30 0MHz, CDC13):5 1.35-1.48(2H,m),1.43(9H, s), 1.91(1H, m) , 2.05-2.28(5H, m) , 2.44(3H, s) f 2.55(1H/ m) ,
3. 38 (lHf m) , 3.42-3.73(3H, m), 4 . 11 (1H, m) , 4 . 65 (1H, m) r
4.80(lHr m), 7.32(2H/ d, J=8Hz), 7.78(2H, d, J=8Hz). MASS (ES-) m/z : 487 (M-l).
Example 34-4
N-((lR,3S,4S,6R)-3-{[(2S)-2-Cyano-l-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)-4-methylbenzenesulfonamide hydrochloride
The title compound was prepared from tert-butyl (lR,3R,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-{[(4-methylphenyl)sulfonyl]amino}-2-

azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 34-3 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 8 1.37-1.50(2H, m), 1.70-2.30(6H, m) , 2.41 (3H, s) , 2.88 (1H, m) , 3.57 (2H, m) ,
3.67-3.81(2H, m), 3.98(1H, s), 4.77(1H, dd, J=5, 8Hz) , 7.44 (2H, df J=8Hz), 7.74(2H, d, J=8Hz), 7.97 (lHf d, J = 7Hz) . MASS (ES+) m/z : 389 (M+l).
Example 3 5-1
tert-Butyl (lR,3S,4S,6R)-6-(2-tert~butoxy-2-
oxoethoxy)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2,1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (322mg) in dichloromethane (6mL), were added rhodium acetate dimer (4.24mg) and tert-butyl diazoacetate (0.27mL). The mixture was stirred at room temperature for 4hrs. The resulting mixture was evaporated in vacuo and the residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (2 3 6mg) .
1H-NMR (300MHz, CDC13) : 6 1.43(1H, m), 1.47(9Hf s), 1.49(9H, s), 1.64(1H, m) , 1.9O(1H, m) , 2.05-2.38 (5H, m) , 2 . 72 (1H, m) , 3.55-3.67(2H,m), 3,85-4.05(3H,m), 4.19(1H, m), 4.32 (1H, m), 4.84 (1H, m). MASS (ES+) m/z : 450 (M+l).
Example 3 5-2
[((lR,3S,4S,6R)-3-{[(2S)-2-Cyano-l-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy]acetic acid hydrochloride

The title compound was prepared from tert-butyl (lR,3S,4S,6R)-6-(2-tert-butoxy-2-oxoethoxy)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1] heptane-2-carboxylate obtained in Example 35-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 6 1 . 3 0-2 . 35 ( 8H, m) , 3.05(lH, m), 3. 45(1H, m) , 3.63(1H, m) r 3-78-4.ll(4Hf m) , 4.32(1H, m), 4 . 83 (1H, m). MASS (ES+) m/z : 294 (M+l).
Example 3 6-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl] carbonyl}-6-[2-oxo-2-(2-pyridinylamino) ethoxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from [((lR,3S,4S,6R)-2-(tert-butoxycarbony1)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl)-2-azabicyclo[2.2 - 1] hept-6-yl)oxy]acetic acid obtained in Example 15-2 in a similar manner to that of Example 15-3.
1H-NMR (300 MHz, CDC13) : 8 1.35 and 1.47(9Hf s ) , 1 . 47 (1H, m) , 1.73(1H, m) r 1.86(1H, m) , 2 . 0 8 -2 . 3 8 { 5H, m) , 2-77(lH.f m) , 3.53-3.69(2H, m) , 3.99-4.42(5H, m) f 4 . 85 (1H, m) , 7.07(lH, m), 7.73(lHr m)r 8.25(1H, d, J=8Hz), 8.29(1H, m) , 8.75 (1H, br-s) . MASS (ES+) m/z : 470 (M+l).
Example 3 6-2
2-[ ( (lR,3S,4S,6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.l]hept-6-yl)oxy]-N-2-pyridinylacetamide dihydrochloride
The title compound was prepared from tert-butyl

(lR,3S,4S,6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-[2-oxo-2-(2-pyridinylamino)ethoxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 36-1 in a similar manner to that of Example 2-8.
1H-NMR (300 MHz, DMSO-d6) : 6 1.4-2.32 (8H, m), 3 . 08 (1H, m) , 3.56-4.10(4H,m), 4.20-4.37(3H,m), 4 . 83 (lHf dd, J = 5, 8Hz) , 7 . 26 (1H, m), 7 . 96 (1H, m) , 8 . 07 (1H, m) , 8•37(1H, m). MASS (ES+) m/z :370 (M+l).
Example 37-1
Ethyl (lS,4Rf5S,7S,8S)-8-bromo-4-hydroxy-6-[ (1R) -1-
phenylethyl]-6-azabicyclo[3.2.1]octane-7-carboxylate
The title compound was prepared from ethyl (1S,3S,4R)~2-[(1R)-1-phenylethyl]-2-azabicyclo-[2.2.2 ]oct-5-ene-3-carboxylate obtained in Example 2-2 in a similar manner to that of Example 5-2.
1H-NMR (300MHz, CDC13) : 5 1.26(3H, t, J=7Hz), 1.41(3H, df J=7Hz), 1 . 42-1 . 55 (2H, m) , 2 . 12-2 . 41 ( 2H, ia) , 2.46(1H, d, J=llHz) , 2 - 77 (lHf m) f 3.32(1H, m), 3 - 47 (lHf m), 3 . 80 (1H, d, J=7Hz), 4 . 96-4 . 06 (2H, m) , 4.17(2H, m) , 7 . 2 0 -7 . 3 5 ( 3H, m) , 7.49 (2H, dr J = 7Hz) -MASS (ES+) m/z : 382, 384 (M+l)
Example 37-2
Ethyl (1R,4R,5R,7S)- 4-hydroxy-6-[ (1R) -1-phenylethyl]-
6-azabicyclo[3.2.1]octane-7-carboxylate
The title compound was prepared from ethyl (1S,4R,5S,7S,8S) - 8-bromo-4-hydroxy-6-[ (1R) -1-phenylethyl]-6-azabicyclo[3.2.1]octane-7-carboxylate obtained in Example 37-1 in a similar manner to that of Example 5-3.

1H-NMR (300MHz, CDC13) : 5 1.24(3H, t, J=7Hz), 1.22-1.49(3H,m), 1.38 (3H, d, J=7Hz), 1 . 64 (1H, m) , 1.99(1H, d, J=llHz), 2.30 (1H, m) , 2.61 (1H, m) , 3.13 (1H, m) , 3 . 49 (1H, m) , 3.84(1H, d, J=5Hz) , 3.97(1H, q, J=7Hz), 4.13(2H, m) , 7-17-7.33(3Hf m), 7.54(2Hf d, J=7Hz). MASS (ES+) m/z : 304 (M+l).
Example 37-3
Ethyl (lRf4R,5R/7S)-4-hydroxy-6-azabicyclo[3.2.
1]octane-7-carboxylate
The title compound was prepared from ethyl (lR,4R,5R,7S)-4-hydroxy-6~[(lR)-l-phenylethyl]-6-azabicyclo[3.2.1]octane-7-carboxylate obtained in Example 37-2 in a similar manner to that of Example 2-4.
Example 37-4
6-tert-Butyl 7-ethyl (lR,4R,5R,7S)-4-hydroxy-6-
azabicyclo[3.2 - 1]octane-6,7-dicarboxylate
The title compound was prepared from ethyl (lRf4R,5R,7S)-4-hydroxy-6-azabicyclo[3.2.1]octane-7-carboxylate obtained in Example 37-3 in a similar manner to that of Example 5-5,
1H-NMR (300MHz, CDCl3) : 5 1.29(3H, m), 1.23-1.50(2H,m)f 1.41 and 1.47(9H, s) , 1 - 66 (1H, m) f 1 . 80 (1H, m), 2 . 20 (1H, m), 2.34(1H, m), 2.64(1H, m), 4.03-4.37(5H, m). MASS (ES+) m/z : 300 (M+l).
Example 3 7-5 (1R,4Rf5R,7S) -6- (tert-Butoxycarbonyl) -4-hydroxy-6-
azabicyclo[3.2.1]octane-7-carboxylic acid
The title compound was prepared from 6-tert-butyl

7-ethyl (lR,4R,5R,7S)-4-hydroxy-6-azabicyclo[3.2.1] octane-6,7-dicarboxylate obtained in Example 37-4 in a similar manner to that of Example 5- 6 .
1H-NMR (300MHz,CDCl3) : 6 1.16(lH,m), 1.43 and 1.47(9H, s) , 1.54-1.75(3H, m) , 1.78-1.95(2H, m) , 2. 09 (1H, m) , 2.4-2.7 (2H, m) , 3.95-4.15(3H, m). MASS (ES-) m/z : 270 (M-l).
Example 37-6
tert-Butyl (lR,4R,5R,7S)-7-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-4-hydroxy-6-azabicyclo[3.2.1]
octane-6-carboxylate
The title compound was prepared from
(1R,4R,5R,7S)-6-(tert-butoxycarbonyl)-4-hydroxy-6-azabicyclo[3.2.1]octane-7-carboxylic acid obtained in Example 37-5 in a similar manner to that of Example 5-7.
1H-NMR (300MHz, CDC13) : 5 1.44 and 1 . 4 6 (9H, s) , 1.50-2.53 (12H, m) , 3.35-3 . 88 ( 2H, m) , 4 . 01-4 . 29 ( 3H, m) , 2.73(lH,m),4.67-4.83(lH,m). MASS (ES+) m/z : 350 (M+l).
Example 37-7
(2S)-1-{[(1R,4R,5R,7S)-4-Hydroxy-6-azabicyclo[3.2.1] oct-7-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,4R,5R,7S)-7-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-4-hydroxy-6-azabicyclo[3.2.1]octane-6-carboxylate obtained in Example 37-6 in a similar manner to that of Example 2-8.

2H-NMR (300MHz, DMSO-d6) : 5 1 . 38-2.35 ( 1 OH, m), 2.66(1H, m), 3.3-3.5(lH,m), 3.84-3.95(2H,m), 4.01(lH,m), 4.52(1H, s), 4.82(1H, m). MASS (ES+) m/z : 250 (M+l).
Example 3 8-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-(2-pyridinyloxy)-2 -azabicyclo[2.2.1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 (209mg) in dimethylformamide (2.5ml) , were added 2 -fluoropyridine (109mg) and sodium hydride (60 % in mineral oil, 25mg). The mixture was then stirred at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate, and washed successively with water and brine. The organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (162mg).
1H-NMR (300MHz, CDC13) : 5 1.37, 1.46 and 1.49(9H, s), 1.55(1H, m), 1.72(1H, m), 1.96(1H, m), 2.08-2.42 (5H, m), 2.68-2.83(lH, m), 3.45-3.83(2H, m), 4.24-4.34(lH, m), 4.45-4.53(lH,m), 4.73-5.05(lH,m), 5.13(lH,m), 6.76(1H, m), 6.86(1H, m), 7.57 (1H, m), 8.17(1H, m). MASS (ES+) m/z : 413 (M+l).
Example 38-2
(2S)-1-{[(lR,3S,4S,6R)-6-(2-pyridinyloxy)-2-azabicyclo[2.2.l]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile dihydrochloride

The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-(2-pyridinyloxy)-2-azabicyclo[2.2.1] heptane-2-carboxylate obtained in Example 38-1 in a similar manner to that of Example 2-8.
1H-NMR (30 0MHz, DMSO-d6) : 8 1.42-1.61(1H, m) , 1.85-2.35(7H, m)f 3.05-3.17(lHf m) , 3.40-3.88(2H, m) , 4.03(1H, m), 4.35-4.52(lH, m) , 4.84-4.98 (1H, m) , 5.14-5.28(1H, m) , 6. 84 (lHr m) , 7.04(1H, m) , 7 _ 74 (1H, m),
8 . 19 (1H, m) .
MASS (ES + ) m/z : 313 (M+l).
Example 3 9-1
tert-Butyl (1R,3S,4Sf6R) -6-[ (5-cyano-2-pyridinyl) oxy]-3-{ [ (2 S) -2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2 - 2.1]heptane-2-carboxylate obtained in Example 5-7 in a similar manner to that of Example 38-1.
1H-NMR (300MHz, CDC13) : 5 1.36, 1.46 and 1.49(9H/ s), 1.52(1H, m) , 1.76(1H, m) , 1.92(1H, m) , 2 . 0 7-2 . 4 4 ( 5H, m) , 2.7O-2.84(1H, m), 3.53-3.84(2H, m), 4.25-4. 35(1H, m) , 4.42-4.53(lH,m), 4.72-4.97(lH,m), 5.28(lH,m), 6.78(1H, m), 7.78(1H, m), 8.47(1H, m). MASS (ES+) m/z : 438 (M+l).
Example 3 9-2
6-[((!R,3S,4S,6R)-3-{[(2S)-2-Cyano-l-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy] nicotinonitrile dihydrochloride

The title compound was prepared from tert-butyl (lR,3S,4S,6R)-6-[ (5-cyano-2-pyridinyl)oxy]-3-{[(2S)-2 -cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2„1] heptane-2-carboxylate obtained in Example 39-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1.45-1.67 (1H, m) , 1.85-2.35(7H, m) , 3.06-3.18(lH, m)f 3.35-3.88 (2H, m) , 4.08(1H, m), 4.35-4.52(lH, m) , 4.84-4.98 (1H, m) , 5.20-5 . 35 (1H, m) , 7.04(lH, m) , 8.21(1H, m) , 8.74(1H, m) . MASS (ES+) m/z : 338 (M+l).
Example 4 0-1
2-tert-Butyl 3-methyl (lR,3S,4S,6R)-6-
[ (phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.1] heptan e-2 ,3-dicarboxylate
To a solution of2-tert-butyl 3-methyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (4.5g) in pyridine (1OmL), was added O-phenyl chlorothiocarbonate (3.15g) - The mixture was then stirred at room temperature for 3hrs. The resulting mixture was evaporated in vacuo. To the residue, water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed successively with diluted hydrochloric acid, sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give the target compound (5.22g) .
1H-NMR (300MHz, CDC13) : 5 1.41 and 1.47(9H, s), 1.58-1.92(3H, m) , 2.24 (1H, m), 2.88(1H, m), 3.76(3H, s) , 4 . 17 (1H, m), 4.58(1H, m), 5.34(1H, m), 7.09(2H, m), 7.29 (1H, m) , 7.43 (2H, m) .

MASS (ES+) m/z : 408 (M+l).
Example 4 0-2
2-tert-Butyl 3-methyl (lS,3S,4R)-2-azabicyclo[2.2.
l]heptane-2,3-dicarboxylate
The title compound was prepared from 2-tert-butyl 3-methyl (1R, 3S ,4S ,6R)-6-[ (phenoxycarbonothioyl)oxy]-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 40-1 in a similar manner to that of Example 5-3.
1H-NMR (300MHz, CDC13) : 5 1.39 and 1.4 6 (9H, s) , 1.23-1.72 (5H, m) , 1.85(1H, m) , 2.77(1H, m) , 3.74(3H, s), 4 , 17-4.40 (2H, m) . MASS (ES + ) m/z :256 (M+l).
Example 4 0-3
(1S,3S,4R)-2-(tert-Butoxycarbonyl)-2-azabicyclo [2.2.1
]heptane-3-carboxylic acid
The title compound was prepared from 2-tert-butyl 3-methyl (IS,3S,4R)-2-azabicyclo[2.2.1]heptane-2,3 -dicarboxylate obtained in Example 40-2 in a similar manner to that of Example 5-6.
1H-NMR (300MHz, DMSO-d6) : 5 1 . 2 6-1 . 65 ( 6H, m) , 1.32 and 1 . 38 (9H, s), 2 . 68 (1H, m) , 4 . 03 (1H, m) , 4 . 15 (1H, m) . MASS (ES-) m/z : 240 (M-l).
Example 40-4
tert-Butyl (lS,3S,4R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]heptane-2-c
arboxylate

The title compound was prepared from (IS,3S,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid obtained in Example 40-3 in a similar manner to that of Example 5-7.
1H-NMR (300MHz, CDCl3) : 5 1.35 and 1 . 45 ( 9H, s) , 1.36-1.55(3H, m) , 1.62-1.75(2H, m), 1.91 (1H, m) , 2.05-2.37(4H, m), 2.68-2.78(lH, m)f 3.50-3. 67 (2H, m), 4.1-4.4 (2H, m) , 4.88 (1H, m). MASS (ES+) m/z : 320 (M+l)-
Example 4 0-5
(2S)-l-[(lS,3S,4R)-2-Azabicyclo[2.2.1]hept-3-yl-carbonyl]-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lS,3S,4R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.l]heptane-2-carboxylate obtained in Example 40-4 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 5 1.15-1.38 (1H, m), 1.52-2.35(9H, m), 3 - 05 (1H, br-s), 3.64-3.71(2H, m), 3.95(1H, m), 4.37(1H, m), 4.84(1H, m) . MASS (ES+) m/z : 220 (M+l).
Example 41-1
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-6-(4-nitrophenoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 5-7 in a similar manner to that of Example 38-1.

1H-NMR (300MHzf CDC13) : 5 1.48 and 1.1.52(9H, s) , 1.55(1H, m) , 1.74-1.93 (2H, m)f 2.08-2.50(5H, m) , 2 . 75 ( 1H, m) , 3.44-3.88 (2H, m) , 4.31-4.52(1H, m) , 4.68-4.81 (2H, m) , 7.03-7.1K2H, m) , 8.16-8.24(2H, m) . MASS (ES + ) m/z : 457 (M+l).
Example 41-2
(2S)-l-{ [ (lR,3S,4S,6R)-6- ( 4-Nitrophenoxy)-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecar bonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)~3-{ [ (2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-(4-nitrophenoxy)-2-azabicyclo[2.2.1] heptane-2-carboxylate obtained in Example 41-1 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 8 1.66(1H, m) , 1 . 8 4-2 . 3 3 ( 7 H , m) , 3.13(1H, m) , 3.48(1H, m) , 3.84(1H, m) , 4.04(lH, m) , 4 . 50 (lHf m) f 4 .77 (1H, m) , 4.91(1H, m), 7.26(2H, m), 8.26 (2H, m) . MASS (ES+) m/z : 357 (M+l).
Example 42-1
Methyl (2Z)-{[(1R)-1-phenylethyl]imino}acetate
To a solution of 2-hydroxy-2-methoxyacetic acid methyl ester (151g) in toluene (300mL), was added (R)-(+)-1-phenylethylamine (150g) dropwise. The mixture was then stirred for Ihr at room temperature . The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to obtain the target compound as a yellow oil. The target compound was used in the next step without further purification.

1H-NMR (300MHz, CDC13) : 6 1.63{3H, d, J=6.6Hz), 3.87(3H, s) , 4 . 61 (1H, dq, J=6.6, 0.7Hz) , 7.22-7.36(5H,m), 7 . 75 (1H, d, J=0.7Hz) .
Example 42-2
Methyl (lS,3S,4R)-2-[(lR)-1-phenylethyl]-2-
azabicyclo[2.2 - 1]hept-5-ene-3-carboxylate
To a solution of methyl (2Z)-{[(lR)-l-phenylethyl]imino}acetate obtained in Example 42-1 (238g) in 2,2,2-trifluoroethanol, was added
trifluoromethylacetic acid (95.9mL) at -10 "C . The mixture was then stirred at the same temperature. After
lhr, cyclopentadiene was added dropwise at -lot over 30 minutes.
The mixture was stirred at the same temperature and then the solution was concentrated. The residue was diluted with 3N hydrochloric acid (12 0 OmL) and washed with ether- The ether layer was extracted with 3Nhydrochloric acid (300mL). The combined aqueous layer was basified with 2 8 % ammonium hydroxide (3 OOmL) and extracted with
ethyl acetate ( X 2, 12 0 0mL + 200mL) . The combined organic layer was washed with brine, dried over MgSO4, and concentrated to obtain a crude oil.
The crude oil was placed in a refrigerator overnight. The solid which crystallized from the oil was washed with pre-cooled hexane to obtain yellow crystal (96.4g) . The mother liquid was evaporated and placed in a refrigerator 2days, The solid which crystallized from the liquid was washed similarly to obtain yellow crystal (12.4g). The mother liquid (c.a. 18 Og) was purified by short column chromatogr aphy on silica gel eluting with 10% ethyl ace tat e/hexane to give an colorless oil, which was
crystallized in a refrigerator and washed similarly (X 2) to obtain colorless crystal (24.Og, 18.3g).

1H-NMR (300MHz, CDC13) : 5 1 . 35-1 . 4 7 ( 1H, m), 1.42(3H, d, J=6.6Hz) , 2.06-2.13(lH, m)f 2.18-2.23(1H, m) , 2.86-2.93(lH, m) , 3.04 (1H, q, J=6.6Hz), 3.35 (3H, s) , 4.31(1H, s) , 6.21-6.3O(1H, m) , 6.37-6.45(lH, m) , 7.11-7.32(5H, m). MASS m/z : 258.25.
Example 42-3
Methyl (lS,3S,4S,6R,7S)~6-acetyloxy-7-iodo-2-[(1R) -
1-phenylethyl]-2-azabicyclo[2 - 2.1]heptane-3-
carboxylate
To a solution of methyl (lS,3S,4R)-2-[(lR)-1-phenylethyl]-2-azabicyclo[2.2.1] hept-5-ene-3-carboxylate obtained in Example 42-2 (1.Og) in acetic acid (9mL), was added portionwise 1,3-diiodo-5, 5-dimethylhydantoin (782mg). The mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate, and washed successively with sodium hydrogencarbonate solution, sodium thiosulfate solution, sodium hydrogen carbonate solution and brine. The organic layer was dried over MgSO4 and evaporated in vacuo to give the target compound as a solid (1.74g).
1H-NMR (300MHz, CDC13) : 8 1.42(3H, d, J=6Hz), 2.05(3H, s), 2.02-2.15(2H,m), 2. 66-2 .72 (1H, m) , 3.30-3.40 (1H, m) , 3.46(3H, s), 3.67(1H, s), 3.72(1H, q, J=6Hz), 3.83(1H, s),4.88-4.95(lH, m), 7.20-7.31(5H, m). MASS (ES+) m/z : 444.0 (M+l)-
Example 42-4
Methyl (lR,3S,4S,6R)-6-acetyloxy-2-[(lR)-l-
phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate

A solution of methyl
(lS,3S,4S,6R,7S)-6-acetyloxy-7-iodo-2-[(lR)-l-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-3 (1 . 7 3g) in methanol (2 OraL) containing 20% Pd(OH)2 (173mg) and triethylamine (0.6mL) was stirred at room temperature for 1.5hrs under latm pressure with hydrogen.
The reaction mixture was filtered through a bed of Celite and concentrated. The residue was diluted with ethyl acetate, and washed successively with sodium hydrogencarbonate solution, sodium thiosulfate solution, sodium hydrogencarbonate solution and brine. The organic layer was dried over MgSO4 and evaporated in vacuo to give the target compound as a brawn oil (1.28g) -
1-H-NMR (300MHz, CDC13) : 6 1 . 2 3 - 1 . 3 2 (1H , m) , 1.40(3H, d, J=6Hz), 1.45-1.56(2H, m), 1.99(3H, s), 2.00-2.08(lH, m), 2 . 60 (1H, br-s), 3.35(1H, d, J=2Hz), 3. 43 (1H, s), 3.49(3H, s), 3.71(1H, q, J=6Hz), 4.84(1H, d, J=7Hz), 7.19-7 . 38 ( 5H, m) . MASS (ES+) m/z : 318.2 (M+l).
Example 4 2-5
Methyl (lR,3S,4S,6R)-6-acetyloxy-2-azabicyclo[2.2.
1]heptane-3-carboxylate
A solution of methyl
(lR,3S,4S,6R)-6-acetyloxy-2-[(lR)-l-phenylethyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-4 (1.25g) in methanol (20mL) containing 20% Pd(OH)2 (250mg) was stirred at room temperature for 17hrs under 4atm pressure with hydrogen.
The reaction mixture was filtered through a bed of Celite and concentrated. The residue was dissolved with IN hydrochloric acid and washed with diethylether. The

aqueous phase was basified with sodium hydrogencarbonate and extracted with chloroform. The organic layer was dried over MgSO4 and evaporated in vacuo. The res idue was dissolved with methanol (2 OmL) containing 20% Pd(OH)2 (160mg) was stirred at room temperature for 3hrs under 4 a tin pressure with hydrogen. The reaction mixture was filtered through a bed of Celite and concentrated to give the target compound as an oil (750mg).
1H-NMR (300MHz, CDC13) : 6 1.38-1. 47 (lH,m),l. 68-1.85(4H, m), 2.01 (3H, m) , 2.69 (1H, br-s), 3.43(1H, s), 3.75(3H, s) , 3.74-3.78(lH, m) , 4.62-4.68(lH/ m) . MASS (ES + ) m/z : 214.2 (M+l).
Example 42-6
(1R,3S,4S , 6R) -2- (tert-Butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2. l]heptane-3-carboxylic acid
To a solution of methyl (lR,3S,4S,6R)-6-acetyloxy-2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 42-5 (744mg) in dioxane
( 8mL) , was added IN sodium hydroxide (12 . 2mL) atO'C. The
mixture was stirred at the same temperature for lhr. To
this mixture, di-tert-butyl dicarbonate (777mg) in
dioxane (2mL) was added. The mixture was then stirred
at room temperature for 14hrs.
The resulting mixture was evaporated in vacuo. To
the residue, IN hydrochloric acid was added, and the
mixture was extracted with chloroform (60mLX2). The combined organic phase was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with dii sopropylether to give the target compound as a white solid (615mg).
1H-NMR (300MHz, DMSO-d6) : 6 1 . 0 9 - 1 . 2 0 (1H , m) , 1.32 and

1.39(9H, s) , 1.45-1.55(1H, m) , 1.66 (1H, d, J=llHz),
1.72-1.86(1H, m) , 2.58-2.66(lH, m) , 3.74-3.82 (1H, m) ,
3.85-3.96(2H, m) f 4.96-5.03(lH, in).
MASS (ES-) m/z : 256.2 (M-l).
Example 42-7
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-aminocarbony1-1-
pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]
heptane-2-carboxylate
To a suspension of (lR,3S,4S,6R)-2-(tert-
butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2.1]heptane-
3-carboxylic acid obtained in Example 42-6 (45g) in
chloroform (450mL), were added
(2S) -2-pyrrolidine carboxamide (2lg) ,
1-hydroxybenzotriazole hydrate (29.5g), 1-(3-dimethyl aminopropyl)-3-ethylcarbodiimide hydrochloride ( 3 6 . 9g) anddii sopropy1ethylamine ( 4 5 . 3g ) in water bath. The mixture was stirred at room temperature for 5hrs. The precipitate collected by vacuum filtration and washed with ethyl acetate to give the target compound as a solid (51.5g).
1H-NMR (300MHz, DMSO-d6) : 5 0 . 9 1 - 1 . 0 4 (1H , m), 1.24 and 1.35(9H, s), 1.4O-1.54(1H, m), 1.58-1.69(lH,m), 1,69-2.05(5H, m), 2.69-2.79 (1H, m) , 3.45-3.59(2H, m) f 3.70-3.88(2H, m), 4.13-4.25(2Hf m), 4.79-4.86(lHf m) f 6.79-6.89(lH, m), 7.20(1H, br-s). MASS m/z : 354.
Example 42-8
tert-Butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-
pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]
heptane-2-carboxylate

To a mixture of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-aminocarbonyl-1-pyrrolidinyl ]carbonyl}-6~hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 42-7 (53. 4 g) and pyridine (71.7g) in tetrahydrofuran (55 OmL) , was added
trifluoroacetic anhydride (95.2g) dropwise at O'C under nitrogen.
The mixture was stirred at the same temperature for 10 minutes and was then stirred at room temperature for 1.5hrs. The reaction mixture was adjusted with aqueous sodium hydrogencarbonate solution (ca.500mL) to pH8 and concentrated in vacuo. The res idue was partitioned between water and chloroform. The organic layer was separated, washed with 0.5mol/L hydrochloric acid, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with isopropylether, and a mixture of hexane and ethyl acetate (2:1) to give the target compound as a solid (43.5g).
1H-NMR (3 00MHz, CDC13) : 5 1.23-1.34 (1H, m), 1.34 and 1.46(9H, s), 1.64(1H, d, J=9Hz), 1.82 and 1.97(1H, d, J=3Hz)7 1.84-1.94(lH,m), 2.03-2.36(5H,m), 2.66-2.76(lH, m), 3.46-3.69(2H,m), 4.08-4.23(2H,m), 4.23-4.35(lH,m), 4 .76-4.90 (1H, m) . MASS m/z : 336.
Example 42-9
(2S)-1-{[(1R,3S,4S,6R)-6-Hydroxy-2-azabicyclo[2.2.1]
hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile
hydrochloride
To a solid of tert-butyl (lR,3S,4S,6R)-3-{[(2S)-2-cyano-l-pyrrolidinyl] carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 42-8 (796mg) , was added

amixture of 4N hydrochloride in dioxane (1.8 7mL) andwater (0.13mL). The mixture was stirred at room temperature for 5 minutes. The resulting mixture was evaporated in vacuo and the residual solid was washed with i sopropyl alcohol. The solid was recrystalized from ethanol-water to give the target compound as a white crystal (367mg).
1H-NMR (300MHz, DMSO-d6) : 5 1.32(1H, m) , 1.62(1H, ddd, J=l.8 , 6.9, 13.8HZ), 1 . 79 (1H, m), 1.88-2.33(5H, m), 3.03(lH, br-s), 3.53-3 . 71 (3H, m) , 3.97(1H, m) r 4.31(1H, m), 4.82 (1H, dd, J=5 . 1, 8.lHz) , 5.4 6 (1H, d, J = 4.2Hz) . MASS (ES+) m/z : 236 (M+l).
Example 4 3-1
1-Methyl-l,2 ,3,4-tetrahydro-4-quinolinamine
1-Methyl-2,3-dihydro-4(lH)-quinolinone oxime (360mg)'was dissolved in methanol (25mL) and 20% Pd(OH)2 oncarbon (lOOmg) was added* Themixturewas stirredunder hydrogen atmosphere at room temperature for 1.5hrs. The reaction mixture was filtered through a bed of Celite and washed with methanol. The filtrate was concentrated in vacuo to give the target compound as a colorless oil (330mg) .
1H-NMR (300MHz, CDC13) : 5 1.57(2H, br-s), 1.87(1H, m) , 2 . 07 (1H, m), 2 . 91 (3H, s) , 3.22(1H, m), 3 . 33 (1H, m), 3.98(1H, t, J=4Hz), 6.62(1H, d, J=8Hz), 6.67(1H/ dd, J=8, 8Hz), 7.14(1H, dd, J=8, 8Hz), 7.19(1H, d, J=8Hz).
Example 4 3-2
(2S,4S)-4-Fluoro-l-{[(1-methyl-1,2,3,4-tetrahydro-4-
quinolinyl)amino]acetyl}-2-pyrrolidinecarbonitrile
To a solution of 1-methyl-1,2,3,4-tetrahydro-4-quinolinamine obtained in Example 43-1

(329mg) in tetrahydrofuran (4mL), were added (2S,4S)-l-chloroacetyl-4-fluoro-2-
pyrrolidinecarbonitrile obtained in Example 7-11 (193mg) and a catalytic amount of Nal . The reaction mixture was stirred for 2 2hrs.
The reaction mixture was diluted with tetrahydrofuran (1OmL) and washed with tetrahydrofuran. The combined organic layer was concentrated in vacuo. The residue was purifiedwith silica gel chromatography (SiO2: 25g, ethyl acetate then me thanol/CHCl3 = 10/0-20/1) to give the target compound as a pale brawn amorphous (137mg).
1H-NMR (300MHz,CDCl3):S 2.15-2.43(lH,m),2.66(lH,m), 2 . 91 (3H, s) , 3 . 16 (1H, m) , 3.31-4.06(lH,m), 4.86-5.50(2H, m) , 6.55-6.66(2H, m) , 7.05-7.22(2H, m). MASS" (ES + ) m/z : 317.2 (M+l) .
Example 4 4-1
3,4-Dihydro-2H-chromen-4-ylamine
The title compound was prepared from 4-chromanone oxime in a similar manner to that of Example 43-1.
1H-NMR (300MHz, CDC13) : 5 1 . 86 (1H, m) , 2 . 16 (1H, m) , 4.05(lH,m), 4.18-4.33(2H,m), 6.82(1H, d, J = 8Hz), 6. 90 (1H, dd, J = 8, 8Hz), 7 . 15 (lHf ddf J=8f 8Hz), 7.3O(1H, d, J=8Hz).
Example 4 4-2
(2S,4S)-1- [ (3,4-Dihydro-2H-chromen-4-ylamino)acetyl]-4-fluoro-2-pyrrolidinecarbonitrile
The title compound was prepared from 3,4-dihydro-2H-chromen-4-ylamine obtained in Example 44-1 in a similar manner to that of Example 43-2.

1H-NMR (300MHz,CDCI3) : 8 1. 83-2 . 07 ( 2H, m), 2.32(1H, m), 2 .70 (1H, m) , 3.40-3.95(5H,m), 4.16-4 . 40 (2H, m) , 4.97(1H, d, J=8Hz), 5.25~5.52(lH,m), 6.82(1H, d, J=8Hz), 6.90(1H, dd, J = 8, 8Hz), 7.17(1H, dd, J=8, 8Hz), 7.35(1H, dd, J=8, 8Hz) . MASS (ES+), m/z : 304.2 (M+l).
Example 4 5-1
tert-Butyl (lR,3S,4Sf6R)-3-{ [ (2Sf 4S)-2-aminocarbonyl-
4-fluoro-1-pyrrolidinyl]carbonyl}^6-hydroxy-2-
azabicyclo[2.2.1]heptane-2-carboxylate
The title compound was prepared from (1R,3S,4S f6R)-2-(tert-butoxycarbonyl)-6-hydroxy-2-azabicyclo[2.2,1]heptane-3-carboxylic acid obtained in Example 5-6 in a similar manner to that of Example 5-7.
1H-NMR (300MHz, CDC13) : 8 1.34-1.15(lHfm), 1 . 44 (9H, s) , 1-61-1.72(1H/ m), 1.82-1.94(lHf m), 1.98-3.04(4H, m) , 3.66-4.46(6H, m), 5.11-5.34(1H, m)f 5.62-5.77(lH, m), 6. 69-6.76(2H, br-s) .
Example 4 5-2
tert-Butyl (lR,3S,4S,6R)-3-{ [ (2S,4S) -2-cyano-4-fluoro-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate
To a solution of tert-butyl (lR,3Sf4S,6R)-3-{[(2Sf4S)-2-aminocarbonyl-4-fluoro-l-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1] heptane-2-carboxylate obtained in Example 45-1 (689mg) in tetrahydrofuran ( 6.9mL) , was added trifluoroacetic anhydride (0.6 6mL) at room temperature.
After stirring for 15 minutes, IN NaOH (14mL) was added. After stirring for 10 minutes, the resulting

solution was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous NaCl and dried over MgSO4. After removal of the solvent, the target compound was obtained as a white powder (475mg) . Further purification was not attempted.
1H-NMR (300MHz, CDC13) : 6 1.20-1.99(13H, m) ,
2.16-2.46(2H, m) , 2.51-2.83(2H, m), 3.80-4.37 (5H, m) ,
4.98-5.10(lH, m), 5.33-5.58 (1H, m) .
MASS (ES+) m/z : 354.46 (M+l).
Example 4 5-3
(2S,4S)-4-Fluoro-l-{[(1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (lR,3S,4S,6R)-3-{ [ (2S,4S) -2 -cyano-4-fluoro-1-pyrrolidinyl]carbonyl}-6-hydroxy-2-azabicyclo[2.2.1] heptane-2-carboxylate obtained in Example 45-2 in a similar manner to that of Example 2-8.
1H-NMR (300MHz, DMSO-d6) : 8 1.17-1.41(1H, m),
1.55-1.70(lHf m), 1.72-1-85(1H, m), 1.87-2.65(4H, m),
2.99-3.18(lH, m), 3.52-3.70(lH, m), 3.7O-3.86(1H, m),
3.86-4.07(2H, m), 4.21(1H, br-s), 5.00-5.19(lH, m),
5.40-5.73 (1H, m) , 7.67-8.05 (1H, m) , 10.16-10.61 (1H, m) .
Example 4 6-1
Ethyl ( 3S)-2-azabicyclo[2.2.2]octane-3-carboxylate
A solution of ethyl (lS,3S,4R)-2-[(lR)-l-phenylethyl]-2-azabicyclo[2.2.2]oct-5-ene-3-carboxylate (l.lg) in ethanol (20mL) was hydrogenated under H2 atmosphere (4atm) for 2hrs. After removal of

the catalyst by filtration, the solvent was removed in vacuo to give the target compound as a colorless oil (700mg).
1H-NMR (CDCI3) : 8 1.20(3H, t, J=7.5Hz), 1.47-2.04 (7H, m) , 2.90-3.10 (2H, m) , 3.73-4.08 (2H, m) , 4.23(2H, q, J=7.5Hz). MASS m/z : 184.25.
Example 4 6-2
(3S)-2-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.2] octane-3-carboxylic acid
Ethyl (3S)-2-azabicyclo[2.2.2]octane-3-
carboxylate obtained in Example 46-1 (0.7g) was dissolved indioxane (1 OmL) and IN NaOH (7. 7mL ) at room temperature , and the reaction mixture was stirred at room temperature for lhr. After removal of the organic solvent in vacuo, the aqueous residue was washed with diethylether (lOmL) to remove the impurities, and the aqueous layer was diluted with dioxane (1OmL). To the mixture di-tert-butyl dicarbonate was added (840mg). The reaction mixture was stirred at room temperature overnight.
The reaction mixture was neutralized with-IN HClf and the organic solvent was removed in vacuo. The aqueous re si due was acidified with IN HCl . The resulting precipitate was collected by filtration, washed with water to give the target compound as a whi te powder ( 2 0 Omg) .
1H-NMR (CDCI3) : 5 1 . 44 (9H, s), 1.55-2.31(10H, m), 3.98-4 . 27 (2H, m) . MASS m/z : 256.36.
Example 4 6-3
tert-Butyl (3S)-3~1 [ (2S)-2-aminocarbonyl-l-

pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.2]octane-2-carboxylate
The title compound was prepared from (3S>-2-(tert-butoxycarbonyl) -2-azabicyclo[2.2 .2] octane-3-carboxylic acid obtained in Example 46-2 in a similar manne r to that of Example 5-7.
1H-NMR (CDC13) : 8 1.40(9H , s), 1.55-2 . 31 (12H, m) , 3.46-3.77 (2H, m) , 4.00-4.37 (2H, m) , 4.68-4.75(lH, m) , 5.21-5. 50 (1H, m) . MASS m/z : 352 . 41 .
Example 4 6-4
tert-Butyl (3S)-3-{[(2S)-2-cyano-l-pyrrolidinyl]
carbonyl}-2-azabicyclo[2.2 - 2]octane-2-carboxylate
The title compound was prepared from tert-butyl ( 3S)-3-{ [ (2 S)-2-aminocarbonyl-l-pyrrolidinyl]carbonyl }-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 45-2 in a similar manner to that of Example 5-7.
1H-NMR (CDCI3) : 5 1.38(9H, s) , 1.50-2.35(13H, m) , 3.52-3.78 (2H, m) , 4.03-4.30(2H, m), 4.85-4.93(lH, m). MASS m/z : 334.40.
Example 4 6-5
(2S)-l-[(3S)-2-Azabicyclo[2.2.2]oct-3-ylcarbonyl]-2-pyrrolidinecarbonitrile hydrochloride
The title compound was prepared from tert-butyl (3S)-3-{[(2S)-2-cyano-l-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.2]octane-2-carboxylate obtained in Example 46-4 in a similar manner to that of Example 2-8.

1H-NMR (DMSO-d6) 1.33-2.35{13H, m) , 3-40-3.46 (1H, m) , 3.52-3.71 (2H, m) , 4.20-4.27 (1H, m), 4.82-4.90(lH, m) , 8 . 03 (1H, br-s), 9.90(1H, br-s). MASS (ES + ) xn/z : 234.30 (M+l) .
In"order to illustrate the usefulness of the object Compound (I), (1) and (2), the pharmacological test is carried out as shown in the following.
Inhibition test of human plasma DPP-IV : (i) Material and Method :
The effect of test compounds on DPP-IV activity in human plasma was evaluated with a modified version of the assay d escribed by Hughes et al (Biochemistry, 38, ppll597-11603 (1999) ) .
Briefly, 20U L of human plasma were mixed with 20 iLof 80mM MgCl2 in assay buffer (25mM HEPES, 140mM NaCl, 1% RIA-grade BSA, pH7 . 8) , and were incubated in a room . temperature for 60 minutes. Then the reaction was initiated by the addition of both 2 0 U L of test compounds and 20 JU L of 0 . 2mM substrate (H-glycine-proline-AMC; AMC is 7~amino-4-methylcoumarine) , they were dissolved in the as say buffer•
After 2 0 minutes incubation in a room temperature (kept in the dark) , fluorescence was measured (Excitation 3 8 Onrn, Emi s s ion 4 6 0nm) . A fluorescence-concentration curve of free AMC was obtained using AMC solution in the assay buffer with appropriate concentration. Plasma DPP-IV activities, with or without the test compounds, were expressed as the amount of product per minute per mL. The potency of the test compounds as DPP-IV inhibitor was expressed as IC50.
( ii) Results :
The following IC50 values were obtained.


It appeared, from the above-mentioned inhibition test, that the compound (I), (1) and (2) or pharmaceutical ly acceptable salts thereof of the present invention have an inhibiting activity against DPP-IV.
Therefore, the compound (I) , (1) and (2) or pharmaceutically acceptable salts thereof are useful for treating or preventing disease mediated by DPP-IV, more particularly useful for treating or preventing altered glucose tolerance, glucosuria, hyperlipidemia, metabolic acidosis, diabetes mellitus (IDDM and NIDDM), diabetic neuropathy, nephropathy, and secondarydiseases in mammals caused by diabetes mellitus.
Further, the compound (I), (1) and (2) or pharmaceutically acceptable salts thereof are useful for treating or preventing autoimmune disease, arthritis, rejection of transplanted organs, systemic lupus erythematosus (SLE) , acquired immunodeficiency syndrome (AIDS), hypertension, atherosclerosis, gallbladder disease, cancer, intestinal disease and dwarfism.

CLAIMS
1 . A compound of the formula (I) or pharmaceutically acceptable salt thereof.

[wherein
X1 and X2 each is independently lower alkylene;
X3 is =CH2, =CHF or =CF2;
R1 is substituent;
R2 and R3 are independently H or lower alkyl;
n is 0, 1, 2, 3 or 4.]
2. The compound of Claim 1, wherein R1 is selected from the group consisting of:
(a) R4O- wherein R4 is H, lower alkyl optionally
substituted with substituent a , lower alkenyl,
aryl optionally substituted with substituent a ,
or heteroaryl optionally substituted with
substituent α ;
(b) R5R6N- wherein R5 and R6 each is independently
H, lower alkyl, lower alkanoyl, (lower
alkyl)sulfonyl, arylsulfonyl optionally
substituted with substituent a , or heteroarylsulfonyl optionally substituted with
substituent α ;
(c) R7N= wherein • R7 is H, hydroxy, lower alkoxy,
aryl (lower alkyl)oxy optionally substituted with
substituent α on the aryl group, or heteroaryl(lower alkyl)oxy optionally
substituted with substituent a on the heteroaryl group,

(d) saturated heterocyclyl;
(e) carboxy;
(f) sulfonic acid;
(g) halogen; and
(h) oxo .
3. The compound of Claim 2, wherein the said substituent
α is selected from the group consisting of: lower alkyl, hydroxy, lower alkoxy,
aryloxy optionally substituted with substituent β , heteroaryloxy optionally substituted with
substituent β , amino,
(lower alkyl)amino, di (lower alkyl)amino, arylamino optionally substituted with substituent
j3 on the aryl group, heteroarylamino optionally substituted with
substituent ]3 on the heteroaryl group, (lower alkyl)sulfonylamino, [halogenated(lower alkyl)]sulfonylamino, arylsulfonylamino optionally substituted with
substituent β on the aryl group, heteroarylsulfonylamino optionally substituted
with substituent β on the heteroaryl group, di (lower alkyl)aminosulfonylamino, oxo, imino,
hydroxyimino, (lower alkyl)sulfonyl, arylsulfonyl optionally substituted with
substituent β , heteroarylsulfonyl optionally substituted with

substituent β , lower alkanoyl, halogen, cyano, nitro and carboxy;
the said substituent β is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, (lower alkanoyl)amino, halogen, cyano, nitro and carboxy.
4. The compound of Claim 3, wherein R1 is selected from
the group consisting of hydroxy, lower alkoxy optionally
substituted with hydroxy (s), lower alkenyloxy, amino
optionally substituted with substituent lower alkanoyl,
halogen, oxo, imino and hydroxyimino.
5. The compound of Claim 4, wherein R1 is selected from
the group consisting of hydroxy, amino and halogen.
6 . The compound of Claim 5, wherein R1 is hydroxy.
7. The compound of Claim 3, wherein R1 is R40- wherein
R4 is lower alkyl optionally substituted with substituent
a , aryl optionally substituted with substituent a , or
heteroaryl optionally substituted with substituent a ;
the said substituent a is selected from the group consisting of hydroxy, arylamino, heteroarylamino, arylsulfonylamino, heteroarylsulfonylamino, oxo, imino, hydroxyimino, lower alkanoyl, halogen, cyano, nitro and carboxy.
8. The compound of Claim 3, wherein R1 is lower alkoxy
optionally substituted with substituent a ;
the said substituent a is selected from the group

consisting of hydroxy, lower alkoxy, amino, (lower
alkyl)amino, di(lower alkyl)amino, (lower
alkyl)sulfonylamino, fhalogenated(lower
alkyl)]sulfonylamino, di(lower
alkyl)aminosulfonylamino, oxo, imino, hydroxyimino and
carboxy.
9. The compound of Claim 3, wherein R1 is lower alkoxy
optionally substituted with substituent a ;
the substituent a is selected from the group consisting of heteroarylamino optionally substituted
with substituent j3 on the heteroaryl group,
heteroarylsulfonylamino optionally substituted with
substituent j3 on the heteroaryl group and oxo;
the said substituent β is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino,
(lower alkyl)amino, di(lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy.
10. The compound of Claim 3, wherein R1 is selected from
the group consisting of aryloxy optionally substituted
with substituent a , heteroaryloxy optionally
substituted with substituent a , and saturated
heterocyclyl;
the said substituent a is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di (lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy.
11. The compound of Claim 10, wherein R1 is selected from
the group consisting of aryloxy optionally substituted
with substituent a , and heteroaryloxy optionally
substituted with substituent a ;
the said substituent a is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino,

(lower alkyl)amino, di (lower alkyl) ami no, lower alkanoyl, halogen, cyano, nitro and carboxy.
12. The compound of Claim 3, wherein R1 is R5R6N- wherein
R5 and R6 each is independently (lower alkyl)sulfonyl,
arylsulfonyl optionally substituted with substituent a , or heteroarylsulfonyl optionally substituted with
substituent a ;
the said substituent a is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di (lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy.
13. The compound of Claim 3, wherein R1 is R7N= wherein
R7 is H, hydroxy, lower alkoxy, aryl(lower alkyl)oxy
optionally substituted with substituent a on the aryl group;
the said substituent a is selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, lower alkanoyl, halogen, cyano, nitro and carboxy.
14. The compound of any one of Claims 1 to 13, wherein
X1 and X2 each is independently (Cl-C4)alkylene.
15. The compound of any one of Claims 1 to 13, wherein
X1 and X2 each is independently (C1-C2)alkylene.
16. The compound of any one of Claims 1 to 15, wherein
X3 is =CH2 or =CHF.
17 . The compound of any one of Claims 1 to 15, wherein X3 is =CH2-
18. The compound of any one of Claims 1 to 17, wherein

R2 and R3 each is independently H or (Cl-C4)alkyl.
19. The compound of any one of Claims 1 to 17 , wherein
R2 and R3 each is independently H or (C1-C2)alkyl.
20. The compound of any one of Claims 1 to 17, wherein
R2 and R3 are H.

21 . The compound of any one of Claims 1 to 20, wherein
n is 1, 2, 3 or 4 .
22 . The compound of any one of Claims 1 to 20, wherein
n is 1 or 2.
23. The compound of any one of Claims 1 to 20, wherein n is 1 .
2 4. A compound selected from:
(2S)-l-{[(lS,3S,4S,5S,6R)-5,6-Dihydroxy-2-azabicyclo[ 2.2.2]oct-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydro chloride;
(2S)-1-{[(1S,3S,4S,5R)-5-Hydroxy-2-azabicyclo [2.2.2] oct-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride;
(2S)-1-{[(1R,3S,4S,6R)-6-Hydroxy-2-azabicyclo [2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride;
(2S)-1-{[(1R,3S,4S,6S) -6-Hydroxy-2- azabicyclo [2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride;
(2S)-l-{[(lR,3S,4S,6R)-6-(2-Hydroxyethoxy)-2-azabicyclo[2.2.1]hept-3-yl]carbonyl}-2 -pyrrolidinecarbonitrile hydrochloride;
(2S)-1-{[(1R,3S,4S,6Z) -6-Hydroxyimino-2-azabieyelo [2. 2.1]hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile

.hydrochloride;
N-( (lR,3S,4S,6R)-3-{ [ (2S)-2-Cyano-1-pyrrolidinyl] carbonyl}-2-azabicyclo[2.2.l]hept-6-yl)acetamide hydrochloride;
(2S)-1-{[(1R,3S,4R,6R)- 6-Amino-2-azabicyclo[2.2.1] hept-3-yl]carbonyl}-2-pyrrolidinecarbonitrile dihydrochloride;
(2S)-1-{[(1R,4R,5R,7S)-4-Hydroxy-6-azabicyclo[3.2.1] oct-7-yl]carbonyl}-2-pyrrolidinecarbonitrile hydrochloride.
25. A method for producing Compound (1) characterized in deprotecting Compound (IV):

[wherein
X1 and X2 each is independently lower alkylene;
X3 is =CH2, =CHF or =CF2;
R1 is substituent;
R2 and R3 are independently H or lower alkyl;
n is 0, 1, 2, 3 or 4;
R1' is R1 protected not to inhibit this reaction, if
needed; Pro is protective group of amino group.]
2 6. A compound of the formula (1) or pharmaceuti cally acceptable salt thereof.


[wherein
Y1 is -0-, -S- or = NR16;
Y2 is =CHF or =CF2;
R11 is lower alkyl or lower alkyl substituted by
hydroxy; R12, R13, R14 and R15 are independently H, lower alkyl
or R13 and R14 may be connected together to make
lower alkylene; R16 is lower alkyl, heteroaryl (optionally
substituted by substituent (i) ) or [straight
chain lower alkyl]sulfonyl; substituent (i) is selected from the group consisting
of lower alkyl, lower alkoxy, amino, carboxy,
hydroxy, cyano and halogen.]
2 7. The compound of Claim 2 6, wherein Y1 is -0- . 2 8. The compound of Claim 26, wherein Y1 is -S-.
29. The compound of Claim 26, wherein Y1 is =NR16, and R16 is heteroaryl.
30 . The compound of Claim 29, wherein R16 is nitrogen containing heteroaryl.
31. The compound of any one of Claims 26 to 30, wherein
Y2 is =CHF.
32. The compound of any one of Claims 26 to 31, wherein
R11 is lower alkyl.
33. The compound of any one of Claims 26 to 32, wherein
R12, R13, R14 and R15 are independently H or lower alkyl
34. The compound of any one of Claims 26 to 32, wherein

R12 and R15 are independently H or methyl, and R13 and R14 may be connected together to make (C1-C4)alkylene.
3 5. A compound of the formula (2) or pharmaceuti cally acceptable salt thereof.
[wherein
Z1 is -0-, -S- or = NR24;
Z2 is =CH2, =CHF or =CF2;
R21 is H, lower alkyl or lower alkyl substituted by
hydroxy;
R22 and R23 are independently H, lower alkyl; R24 is lower alkyl, heteroaryl (optionally
substituted by substituent ( ii ) ) or [straight
chain lower alkyl]sulfonyl; benzene ring may be optionally substituted by
substituent (ii); substituent (ii) is selected from the group
consisting of loweralkyl, loweralkoxy, amino,
carboxy, hydroxy, cyano and halogen.]
36. The compound of Claim 35, wherein Z1 is -0-.
37 , The compound of Claim 35, wherein Z1 is =NR24, and R24 is lower alkyl.
38. The compound of any one of Claims 35 to 37, wherein
Z2 is =CHF.
39. The compound of any one of Claims 35 to 38, wherein
R21 is H.

40. The compound of any one of Claims 35 to 38, wherein R22 and R23 are H.
41 . A compound of any one of Claims 1 to 2 4 and 2 6 to
40 for use as a medicament.
42 . The compound of Claim 41 for use in the treatment
and/or prevention of NIDDM in human beings or animals.
43, A medicament comprising a compound of any one of
Claims 1 to 24 and 26 to 40 as an active ingredient.
44. A pharmaceutical composition comprising a compound
of any one of Claims 1 to 24 and 26 to 40 as an active
ingredient, in association with a pharmaceutically
acceptable carrier or excipient.
4 5. An inhibitor of DPP-IV consisting of a compound of any one of Claims 1 to 24 and 26 to 40.
4 6. A method for treatment and/or prevention of NIDDM which comprises administering an effective amount of the compound of any one of Claims 1 to 24 and 26 to 40 to human
beings or animals.
47. Use of the compound of any one of Claims 1 to 24 and
26 to 40 for treatment and/or prevention of NIDDM in human
beings or animals.
48. A commercial package comprising the pharmaceutical
composition containing the compound identified in any one
of Claims 1 to 24 and 26 to 40 and a writtenmatter associated
therewith, wherein the written matter states that the
compound (I) can or should be used for preventing or
treatinaNIDDM.