DESCRIPTION
CONDENSED PYRIDINE COMPOUND
TECHNICAL FIELD
The present invention relates to a novel condensed pyridine compound, to a medicament containing the compound as an active ingredient and to diseases caused by undesiable and/or abnormal cytokine signal transduction.
BACKGROUND ART
Janus kinase 3 (hereafter referred to as JAK3) is a Janus family of protein kinases. Although kinases in this family, other than JAK3, are expressed in a wide range of tissues, JAK3 is expressed locally in hematopoietic cells. This is not contradict the fact that JAK3 plays an important role in signal transduction via various receptors, such as interleukin (hereafter referred to as IL) -2, IL-4, IL-7, IL-9, IL-15, and IL-21 by noncovalent association with the common gamma chain (refer to nonpatent literature 1 and 2).
XSCID (X-linked severe combined immunodeficiency)
patient populations have been identified with reduced levels
of JAK3 protein or with genetic defects to gamma chain,
suggesting that immunosupression should result from blocking
signaling through the JAK3 pathway (refer to nonpatent
1

patent publications.)
However, in any literature, the compound according to the present invention is not disclosed specifically. [Nonpatent literature 1] J. J. O'shea et al.. Cell, 2002, l^oi.
109 (suppl.), S121, [Nonpatent literature 2] K. Ozaki et al., Science, 2002, Vol.
298, p. 1630, [Nonpatent literature 3] P. Macchi et al.. Nature, 1995, Vol.
311, p. 65, [Nonpatent literature 4] S. M. Russell et al., Science, 1995,
Vol. 210, p. 797, [Patent literature 1] WO 2004/099205, [Patent literature 2] WO 2004/099204, [Patent literature 3] WO 99/65908, [Patent literature 4] WO 99/65909, [Patent literature 5] WO 01/42246, [Patent literature 6] WO 02/00661, [Patent literature 7] WO 2006/069080, [Patent literature 8] WO 2006/127587, [Patent literature 9] WO 2007/007919.
DISCLOSURE OF THE INVENTION
(Problem to be Solved by the Invention)
As a result of intensive studies with an object of providing a useful pharmaceutical composition having JAK3

-C(=0)-carbamoyl, -C(=0)C(=0)-(5- to 6- membered nitrogen-containing heterocycloalkyl), -C(=0)0-(Ci-Cg alkyl),
each of which may be substituted with one or more identical or different group(s) selected from the group consisting of R";
R" is halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
C1-C6 alkyl, -(C1-C5 alkyl)-CN, -(Ci-Ce alkyl)-OH, -C(=0)0-(Ci-C6 alkyl), -0-(Ci-Ce alkyl), -0-(Ci-Cg alkyl)-CN, 2-pyrroridinone-l-yl or phenyl, wherein phenyl may be substituted with halogen;
Y is N, CH or CH2; and
is a single bond or a double bond,
wherein one is single bond, the other is double bond;
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
The same shall be applied hereinafter.
(Effect of the Invention)
The compound according to the present invention has JAK3 inhibition activity and is thus useful as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transduction (e.g., rejection during live organ/tissue transplantation, autoimmune diseases,
asthma, atopic dermatitis, atherosclerotic disease, psoriasis,
7

and rheumatism), or diseases caused by abnormal cytokine signal transduction (e.g., cancer and leukemia).
(Best modes for carrying out the invention)
The present invention will be explained in more detail herein below.
The term "Ci-Ce alkyl" in the specification is a Ci-Ce straight or branched alkyl and may include (C3-C4)cycloalkyl-(C1-C2) alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, neopentyl, and n-hexyl, preferably methyl, ethyl, n-propyl, isopropyl, cyclopropylmethyl, isobutyl and cyclopropylmethyl, cyclopropylethyl, cyclobytylmethyl, and particularly preferably methyl and ethyl.
The term "alkyl" in the specification is a C1-C12 straight or branched alkyl, that is, an alkyl having 7 to 12 carbon atoms in addition to the Ci-Ce alkyl described above.
The term "halogen" may include fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, and bromo.
The term "C3-C9 cycloalkyl is a C3-C9 monovalent nonaromatic and nonbridged carbocyclic group, and may partially have unsaturated bonds. However, bridged cyclic hydrocarbons are excluded. Cycloalkyl may include, such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclohexenyl, cyclooctadienyl and the like.
8

The term "5- to 7-membered nitrogen-containing heterocycloalkyl " is a monovalent group of a five- to seven-membered nonaromatic ring which may contain one or more nitrogen atom(s) and other hetero atom (s) , and may include, such as pyrrolidinyl, piperazinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, and pyrazolidinyl.
The term "aryl" is a monovalent group of an aromatic ring having carbon atoms and may include, such as phenyl and naphthyl.
The term "5- to 6- membered heteroaryl" is a monovalent group of a 5- to 6-membered aromatic heterocycle having one or more identical or different hetero atom(s) selected from the group consisting of nitrogen, oxygen and sulfur atoms. The "5-to 6- membered heteroaryl" may include, such as pyridyl, pyrazinyl, pyrimidynyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, furyl, oxadiazolyl and thiadiazolyl and the like.
The term "5- to 6- membered nitrogen-containing heteroaryl" is "5- to 6- membered heteroaryl" having at least one nitrogen atom as ring atom. "5- to 6- membered nitrogen-containing heteroaryl" may include, such as pyridyl, pyrazinyl, pyrimidynyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl and thiadiazolyl and the like.

One embodiement of suitable group in formula(I) is exemplified
as follows:
R'^ : -H is preferred.
R^: Carbamoyl which may be substituted with Ci-Ce alkyl is
preferred. R^-^ : -H, (lA) or (ID) are preferred. R^ : -H is preferred. R^ : -H is preferred. R^ : -H is preferred. R° : -H or -C(=0)C(=0)NH-(Ci-Cg alkyl) or -C(=0)C(=0)NH-
(Ci-Ce alkyl)-0-(Ci-Ce alkyl) are preferred. R^^ : 5- to 7-membered nitrogen-containing
heterocycloalkyl,
which may be substituted with one or more identical or
different group(s) selected from the group consisting of
are preferred. R^ : Halogen, Ci-Cg alkyl, -0-(Ci-C6 alkyl), aryl,
5- to 6- membered nitrogen-containing heteroaryl and
-C(=0)0-(Ci-Ce alkyl) are preferred. R'*: Halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
-(Ci-Cgalkyl)-OH, -C(=0)0-(Ci-Cgalkyl), -0-(Ci-Cgalkyl)
or -0-(Ci-Ce alkyl)-CN are preferred. Y: N and CH are preferred.
10

-C(=0)-(5- to 6-membered nitrogen-containing heterocycloalkyl), -C(=0)-carbamoyl, -C(=0)C(=0)-(5- to 6- membered nitrogen-containing heterocycloalkyl), -C(=0)0-(Ci-C6 alkyl) ,
each of which may be substituted with one or more identical or different group (s) selected from the group consisting of R^S-
R^''' is halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
Ci-Cg alkyl, -(Ci-Cg alkyl)-CN, - (Ci-Cs alkyl)-OH, -C(=0)0-(Ci-C6 alkyl), -0-(Ci-Cg alkyl), -0-(Ci-Ce alkyl)-CN, 2-pyrroridinone-l-yl or phenyl, wherein phenyl may be substituted with halogen;
R^ is halogen or -0-(Ci-C6 alkyl);
n is an integer from 1 to 6;
Y is N, CH or CH2; and
is a single bond or a double bond,
wherein the one is single bond, the other is double bond;
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
A compound of claim 1 having the following formula (III):
12

alkyl)-CN, 2-pyrroridinone-l-yl or phenyl, wherein phenyl may be substituted with halogen;
X is N, CH or CH2; and
is a single bond or a double bond,
wherein the one is single bond, the other is double bond;
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
One embodiment of suitable groups in formula(II) is exemplified
as follows:
R^: -H is preferred.
R'^: Carbamoyl which may be substituted with Ci-Ce alkyl is
preferred. R^'"': -H or may be bonded with R^ via a certain functional group
to form divalent groups represented by the formula (lA)
are preferred. R^: -H is preferred.
R^: Aryl and 5- to 6-membered heteroaryl are preferred. R^''': Halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
-(Ci-CgalkyD-CN, - (Ci-Cealkyi)-OH, -C (=0) 0-(Ci-Ce alkyl) ,
-0-(Ci-C6 alkyl), -0-(Ci-Ce alkyl)-CN and
2-pyrroridinone-l-yl are preferred. R^: Halogen is more preferred. n: An integer from 1 to 2 is more preferred.
Y: N and CH are more preferred.
16

More preferred compound(s) of formula (II) as follows:
(from [1] to [3]).
[1]. A compound of [II], wherein:
R'' is aryl or 5- to 6-membered nitrogen-containing heteroaryl, or -C(=0)0-(Ci-Ce alkyl) ,
each of which may be substituted with one or more identical or different group(s) selected from the group consisting of R^S-R^^ is halogen, -CN, -CF3, -CH2OH, -CONH2, -C(=0)0-(Ci-C6 alkyl) or -NO2;
or pharmaceutically acceptable salts thereof, or prodrug thereof. [2]. A compound of [1], wherein: R^ is halogen;
or pharmaceutically acceptable salts thereof, or prodrug thereof. [3]. A compound of [2], wherein:
R^ is -CONH2 or -C(=0)NH-(Ci-C6 alkyl) ; Y is CH; and R^ is -H;
or pharmaceutically acceptable salts thereof, or prodrug thereof.
Another preferred compound(s) of formula(II) is(are) :
17

(1) rel-4-{ [(3R,4S)-l-(6-Cyanopyrida2in-3-yl) -3-fluoropiperidin-4-yl]amino}-IH-pyrrolo[2, 3-b]pyridine-5-carboxamide,
(2) rel-4-{[(3R,4S)-1-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(3) Ethyl rel-(3R,4S)-4-[(5-carbamoyl-lH-pyrrolo[2,3-b] pyridin-4-yl)amino]-3-methoxypiperidine-l-carboxylate,
(4) rel-4-{[(3R,4R)-1-(5-Cyanopyridin-2-yl)-3-
fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(5) rel-4-{ [ (3R,4S)-1-(5-Cyanopyridin-2-yl)-3-methoxypiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(6) rel-4-{ [ (3R,4S)-1-(5-Cyano-l,3-thiazol-2-yl)-3-fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-
b]pyridine-5-carboxamide,
(7) rel-4-({(3R,4S)-3-Fluoro-l-[6-
(trif luoromethyl) pyridazin-3-yl] piperidin-4-yl }amino)-
IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(8) 4-{[1-(5-Cyanopyridin-2-yl)-3,3-difluoropiperidin-
4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
18

(9) rel-6-[(3R,4S)-3-Fluoro-4-(2-oxo-3,6-
dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-
yl)piperidin-l-yl]nicotinonitrile,
(10) 4-{[(3S,4R)-1-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-lH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(11) 4-{[(3S,4R)-1-(6-Cyanopyridazin-3-yl)-3-fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(12) 4-{[(3R,4S)-l-(6-Cyanopyridazin-3-yl)-3-
fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(13) 4-{[(3R,4S)-1-(4-Cyanophenyl)-3-fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide and
(14) rel-6-[(3R,4S)-3-Fluoro-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-l-yl]nicotinonitrile
or pharmaceutically acceptable salts thereof, or prodrug thereof.
One embodiment of suitable groups in formula (III) is exemplified
as follows:
R^: Carbamoyl which may be substituted with Ci-Ce alkyl is
preferred.
19

R~": -H or may be bonded with R^ via a certain functional group to form divalent groups represented by the formula (lA) are preferred.
R^: -H is preferred.
R'': Aryl or 5- to 6- membered heteroaryl are more preferred.
R"*^: Halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
- (Ci-Ce alkyl)-OH, -0- (Ci-Ce alkyl)-CN are more preferred.
More preferred compound(s) of formula (III) as follows: ([4]) .
[4]. A compound of [III], wherein: R^ is -CONH2 or -C(=0)NH-(Ci-Cg alkyl);
or pharmaceutically acceptable salts thereof, or prodrug thereof.
Another preferred compound of formula(III) is:
7-{[1-(5-Cyanopyridin-2-yl)azepan-4-yl]amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide,
or pharmaceutically acceptable salts thereof, or prodrug thereof.
One embodiment of suitable groups in formula(IV) is exemplified as follows:
R-^: -H is preferred. R^''': (ID) is more preferred.
20

R°: -H is more preferred.
R^: -H is more preferred.
R°: -H or -C (=0) C (=0) NH-(Ci-Ce alkyl) are more preferred.
R^^: 5- to 7-membered nitrogen-containing heterocycloalkyl or
C3-C9 cycloalkyl are preferred. R^^: halogen, Ci-Ce alkyl, -0-(Ci-Ce alkyl), aryl or
5- to 6- membered heteroaryl are preferred. R"^: halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
Ci-Ce alkyl, - (Ci-Ce alkyl)-CN, - (Ci-Ce alkyl)-OH,
-C(=0)0-(Ci-C6 alkyl), -0-(Ci-Ce alkyl), -0-(Ci-Cg
alkyl)-CN are preferred.
X: CH is more preferred.
More preferred compound(s) of formula (IV) as follows:
([5]) .
[5] . A com^pound of [IV] , wherein
Y is CH;
R^ is -H;
R^^ and R^ form a group of represented by the formula (ID);
R° is -H or -C(=0)C(=0)NH-(Ci-C6 alkyl); and
R^^ is 5- to 7-membered nitrogen-containing heterocycloalkyl or C3-C9 cycloalkyl,
each of which may be substituted with one or more identical or different group(s) selected from the group consisting
of R^^•
21

or pnarmaceutically acceptable salts thereof, or prodrug thereof.
Another preferred compound of formula(IV) is:
1) rel-(2R,4R)-4-fluoro-l-{[(3S,4S)-4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]carbonyl}pyrrolidine-2-carbonitrile, 2)rel-3-[(3R,4R)-3-(3-aminopyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-l-yl]-3-oxopropanenitrile, 3)rel-3-[(3R,4R)-4-methyl-3-(3-oxo-3,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]-3-oxopropanenitrile, 4)rel-N-{1-[(3R,4R)-1-(cyanoacetyl)-4-methylpiperidin-3-yl]-1,6-dihydropyrazolo[3,4-d]pyrrolo[2, 3-b]pyridin-3-yl}-N'-(cyclopropylmethyl)ethanediamide, 5)rel-6-[(3R,4R)-3-(3-aminopyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-l-yl]pyridazine-3-carbonitrile, 6)rel-N-{1-[(3R,4R)-1-(5-cyanopyridin-2-yl)-4-methylpiperidin-3-yl]-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-3-yl}-N'-(cyclopropylmethyl)ethanediamide,
22

7)rel-N-(l-{ (3R,4R)-l-[(cyanomethyl) (methyl)carbamoyl]-4-methylpiperidin-3-yl}-l,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)-N'-isopropylethanediamide, and 8)rel-N-(l-{(3R,4R)-l-[(cyanomethyl)(methyl)carbamoyl]-4-methylpiperidin-3-yl}-l,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-3-yl)-N'-(cyclopropylmethyl)ethanediamide
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
The compound according to the present invention may include geometric isomers and tautomeric isomers depending on the type of substituent. In addition, the compound according to the present invention may have asymmetric carbon atoms. All of these isomers, including separated isomers and mixtures thereof, are included within the scope of the present invention. Furthermore, labeled compounds, that is, compounds afforded by substituting one or more atom(s) of the compound according to the present invention with radioactive or nonradioactive isotopes are also included in the scope of the present invention.
Furthermore, the so-called pharmaceutically acceptable prodrug of the compound of the present invention is also included in the scope of the present invention. The pharmaceutically acceptable prodrug is a compound having a group that can be
23

converted into an amino group, hydroxyl group, carboxyl group, and the like, through solvolysis or under physiological conditions. The groups described in Prog. Med., Vol. 5, p. 2157-2161, 1985 and "lyakuhin No Kaihatsu (Development of Medicines)" (Hirokawa Pub. Co., 1990), Vol. 7, Molecular Design, p. 163-198 are taken as examples of groups forming such prodrugs. The compound represented by the formula (I) may form acid or base addition salts. These salts should only be pharmaceutically acceptable salts. More specifically, the salts may include an acid addition salt with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid), and an acid addition salt with an organic acid (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid) ; a salt with an inorganic base (e.g., sodium, potassium, magnesium, calcium, and aluminum), and a salt with an organic base (e.g., methylamine, ethylamine, ethanolamine, lysine, and ornithine) ; an ammonium salt; and the like.
Still further, various hydrates, solvates, and
crystalline polymorphic forms of the compound represented by
the formula (I) and salts thereof are also included in the scope
of the present invention.
24

The production method of compound (I) was shown below. Each production method can be used in referred to known papaer In addition, the production method of the present invention was not restricted to examples descrived below.
The compound according to the present invention can be produced using the characteristics based on the basic skeleton or the type of substituent thereof and by applying various known synthesis methods. During the production, protecting the relevant functional group with a suitable protective group or replacing the relevant functional group with a group that can be easily converted into the functional group at the stage of a starting substance or an intermediate may occasionally be effective depending on the type of the functional group in production technology. The protective group for such a functional group may include, for example, the protective groups described in "Protective Groups in Organic Synthesis (3rd. Ed, 1999)" written by T. W. Greene and P. G. M. Wuts, and one of these should only be selected and used as necessary depending on reaction conditions. In this kind of method, the desired compound can be afforded by introducing the protective group, by carrying out reaction and by eliminating the protective group as necessary, or by converting the group into a desired group.
In addition, the prodrug of the compound according to the present invention can be produced by introducing a specific group
25

or by carrying out reaction using the afforded compound represented by the formula (I) at the stage of a starting substance or an intermediate, just as in the case of the above-mentioned protective group. The reaction can be carried out using methods known to those skilled in the art, such as ordinary esterification, amidation, and dehydration.

The following abbreviations are used in the present specification:
AcOH: acetic acid,
API-ES: API-ES MS,
GDI: 1,1'-carbonylbis-lH-imidazole,
DCC: N,N'-dicyclohexylcarbodiimide,
DCM: dichloromethane,
DIPEA: N,N'-diisopropylethylamine,
DMA: N,N'-dimethylacetamide
DMAP: 4-(N,N-dimethylamino)pyridine
DMF: N,N'-dimethylformamide,
DMI: 1,3-dimethyl-2-imidazolidinone,
DMSO: dimethylsulfoxide,
DPPA: diphenylphosphoryl azide,
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,
EDCI-HCl: l-ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride,
26

EtOAc: ethyl acetate,
EtOH: ethanol,
HCl aqueous solution:hydrochloric acid aqueous solution ,
HCl/dioxane: hydrogen chloride in dioxane,
HCl/EtOH: hydrogen chloride in ethanol,
HOBt: N-hydroxybenzotriazole,
KHCO3: potassium hydrogencarbonate,
K2CO3: sodium carbonate,
LiAlH4: lithium aluminium hydride,
LiCl: lithium chloride,
MeCN: acetonitrile,
MeOH: methanol,
MgS04: magnesium sulfate,
MEK: methyl ethyl ketone,
n-hexane: normal-hexane,
KOBu^: potassium tert-butoxide,
NHs/MeOH: ammonia in MeOH
NH3: ammonia
NH4CI: ammonium chloride
NMM: N-methylmorpholine
NMP: l-methyl-2-pyrrolidinone,
N2 atmosphere: Nitrogen atmosphere,
Na2C03: potassium carbonate,
Na2S04: sodium sulfate,
NaH: sodium hydride,
27

NaHCOa: sodium hydrogencarbonate
NaOH: sodium hydroxide
Pd(0Ac)2: palladium acetate,
Pd(0H)2: palladium hydroxide,
Pd(PPh3)4: tetrakis(triphenylphosphine) palladium(0)
TBAF: tetrabutylammonium fluoride,
TEA: triethylamine,
TFA: trifluoroacetic acid,
TFAA: trifluoroacetic anhydride,
THF: tetrahydrofuran,
TLC: thin layer chromatography,
brine: saturated sodium chloride aqueous solution
i-PrOH: 2-propanol,
n-BuOH: 1-butanol,
t-BuOH: tert-butanol
Ex: Example Number,
Pr: Preparation Number,
rel: relative structure; either enantiomer is showm.
Syn: process (the number indicates that the compound
corresponding to the Example was produced using a process similar to that for the compound corresponding to the Example identified by the number.)
The compound according to the present invention can be
28

produced using the characteristics based on the basic skeleton or the type of substituent thereof and by applying various known synthesis methods. During the production, protecting the relevant functional group with a suitable protective group or replacing the relevant functional group with a group that can be easily converted into the functional group at the stage of a starting substance or an intermediate may occasionally be effective depending on the type of the functional group in production technology. This kind of functional group may include, for example, amino group, hydroxyl group, and carboxyl group. The protective group for such a functional group may include, for example, the protective groups described in "Protective Groups in Organic Synthesis (3rd. Ed, 1999) " written by T. W. Greene and P. G. M. Wuts, and one of these should only be selected and used as necessary depending on reaction conditions. In this kind of method, the desired compound can be afforded by introducing the protective group, by carrying out reaction and by eliminating the protective group as necessary, or by converting the group into a desired group.
In addition, the prodrug of the compound according to the present invention can be produced by introducing a specific group or by carrying out reaction using the afforded compound represented by the formula (I) at the stage of a starting substance or an intermediate, just as in the case of the above-mentioned protective group. The reaction can be carried
29

and MEK); ethers (e.g., ether, THF, dioxane, and
diethoxyethane); alcohols (e.g., MeOH, EtOH, i-PrOH, and
n-BuOH); halogenated hydrocarbons (e.g., DCM,
1,2-dichloroethane, chloroform, and carbon tetrachloride);
MeCN; aprotic polar solvents (e.g., DMF, DMI, NMP, and DMSO);
water; or a mixture of these. It is preferable that the reaction
is carried out in the presence of a base, and the base may include,
for example, alkaline carbonates (e.g., K2CO3 and NaaCOs) ;
alkaline hydrogencarbonates (e.g., NaHCOs and KHCO3) ;
alkoxides (e.g., sodium methoxide, sodium ethoxide, and KOBu^) ;
tertiary amines (e.g., TEA, tributylamine, and DIPEA); and
organic bases (e.g., 1,8-diazabicyclo[5.4.0]undeca-7-ene,
pyridine, and lutidine). However, an excess amount of the
compound represented by the formula (2b) can also be used.
Although the reaction temperature differs depending on the type
of a starting compound and reaction conditions, the reaction
can usually be carried out at a temperature approximately ranging
from ambient temperature to the refluxing temperature of a
solvent. The reaction can also usually be carried out in the
presence of a base, such as NaH and K2CO3, in an organic solvent
inert to the reaction, such as DMF and DMA, under ambient
temperature to heating. In addition, the amine represented by
the formula (2b) can also be used as a salt thereof for the
reaction.
Furthermore, microwave irradiation can also be carried
32

compound represented by the formula (3c) . The derived compound
is used to produce the compound according to the present
invention represented by the formula (I-d).
The second process can be incorporated in Step 3-1. The
amine represented by the formula (3b) can also be used as a salt
thereof for the reaction.
In Step 3-2 in the case that -R° is -H, an imidazole ring
can be constructed by reacting an orthoformate, such as ethyl
orthoformate, in the presence of an acid catalyst. It is
desirable that the nitro group should be reduced before the
orthoformate is used for the reaction. Furthermore, the method
to be used when -R° is not -H may include, for example, a method
in which the amino group of the compound represented by the
formula (3c) is acylated in advance, a method in which
tetraalkylorthocarbonate or alkylisothiocyanate is used
instead of the orthoformate, and a method in which carboxylic
acid or carboxylic anhydride is reacted with a strong acid, such
as sulfonic acid. These reactions can be carried out in a solvent
inert to the reactions or in the absence of a solvent, under
ambient temperature, under ambient temperature to heating, or
under heating and refluxing.
Process 4
34

afforded by reaction with diphenylphosphoryl chloride or NMM; and the like.
When the compound represented by the formula (4a) is reacted in the form of a free acid or reacted without isolating the activated ester, it is preferable to use a condensing reagent, such as DCC, GDI, DPPA, diethyphosphoryl cyanide, andEDCI-HCl.
The reaction is carried out in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters (e.g., EtOAc), MeCN, DMF, and DMSO, under cooling, under cooling to ambient temperature, or under ambient temperature to heating, although the conditions differ depending on the reactive derivative or the condensing reagent to be used.
In order to smoothly advance the reaction, it is occasionally advantageous that an excess amount of the compound represented by the formula (4b) is used for the reaction or the reaction is carried out in the presence of a base, such as NMM, trimethylamine, TEA, DIPEA, N,N-dimethylaniline, pyridine, DMAP, picoline, and lutidine. Pyridine can also be used as a solvent.
The method used in Step 1 of the first process can be incorporated in Step 4-2. Process 5
36

heteroaryl), -C(=0)-(5- to 5- membered nitrogen-containing heterocycloalkyl), -C(=0)-carbamoyl, -C(=0)C(=0)-(5- to 6-membered nitrogen-containing heterocycloalkyl can be synthesized as described above by appropriately combining processes usually used by those skilled in the art.
In addition, some of the compounds represented by the formula (I) can also be produced from the compound according to the present invention produced as described above by appropriately combining processes usually used by those skilled in the art, such as known alkylation, acylation, substitution, oxidation, reduction, hydrolysis, deprotection, halogenation, and Mannich reaction. For example, when producing the compound (I) wherein -R* is Ci-Ce alkyl from compound (I) wherein -R^ is -H, alkylation can be used referring to the method described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Ed., 2003)." Furthermore, the processes capable of being usually used by those skilled in the art are not only used for the compound according to the present invention but can also be used for intermediates formed during production. The processes can also advance to subsequent processes.
The compound produced as described above is in a free form
or subjected to salt-forming processing using a conventional
method and isolated and purified as a salt thereof. The
isolation and purification are carried out by performing
ordinary chemical operations, such as extraction, concentration,
38

evaporation, crystallization, filtration, recrystallization, and various types of chromatography.
Various types of isomers can be isolated by utilizing the difference in physicochemical properties between the isomers using a conventional method. For example, a racemic mixture can be converted into an optically pure isomer using a general racemic resolution method, such as a method in which the racemic mixture is converted into a diastereomer salt with a general optically-active acid or optically-active base, and subjected to optical resolution. Furthermore, the diastereo mixture can be separated by fractional crystallization or various types of chromatography, for example. Still further, the optically-active compound can also be produced using a suitable optically-active material.
The pharmacological activity of the compound according to the present invention was verified by carrying out the following test. Test example 1 JAK3 inhibition test
The JAK3 inhibition test was performed as described below (1) Preparation of human JAK3
Purified human JAK3 kinase domain was purchased from Carna Biosciences, Inc. (Kobe, Japan). This was afforded as described below. His-tag (41 kDa) was attached to the N-terminal of the 796-1124 (C-terminal) fragment of the human JAK3 protein (accession number #NM_000215), expressed using baculovirus
39

expression system, and then purified using Ni-NTA affinity
column chromatography.
(2) Measurement of JAK3 activity
As substrates, Biotin-Lyn-Substrate-2 (Biotin-XEQED EPEGF YFEWL EPE), X = e -Acp (PEPTIDE INSTITUTE, INC., Osaka, Japan) and ATP were used. As an assay buffer, 15mM Tris-HCl pH 7.5 containing 0.01% Tween 20 and 2mM DTT (dithiothreitol) was used. Normally, 20 yL of a substrate solution (an assay buffer containing 627 nM Biotin-Lyn-Substrate-2, 20pM ATP, and 25mM MgCla) , an assay buffer containing 10 ]iL of a compound to be tested, and 20 yL of an enzyme solution were added to a microplate, and stirred sufficiently.
After incubation at ambient temperature for one hour, the plate was washed with a cleaning buffer (50mM Tris-HCl pH 7.5, ISOmM NaCl, 0.02% Tween 20), and a blocking buffer (a cleaning buffer containing 0.1% bovine serum albumin) was added to the plate. After incubation at ambient temperature for 30 minutes, the blocking buffer was removed, and an HRP-py-20 solution (afforded by diluting HRP-PY-20 solution with the blocking buffer 500 times) was added. After incubation at ambient temperature for 30 minutes, the plate was washed four times, and a TMB substrate solution (Sigma) was added to the plate. After incubation at ambient temperature for 4 minutes, IM sulfuric acid was added to stop the reaction. Enzyme activity was measured as absorbance at 450 nm. The JAK3 inhibitory

CLAIMS 1. A condensed pyridine compound represented by the following
a. ^ -^

alkyl), -C(=0)C(=0)NH-(Ci-C6alkyl), -C (=0) C (=0) NH-(C1-C5 alkyl)-0-(Ci-C6 alkyl) or -C(=0)0-(alkyl);
R is 5- to 7-membered nitrogen-containing
heterocycloalkyl, C3-C9 cycloalkyl, benzopyranyl or
benzyl,
each of which may be substituted with one or more identical
or different group(s) selected from the group consisting
of R\-
R^ is halogen, Ci-Ce alkyl, -0-(Ci-C6 alkyl), aryl,
5- to 6- membered nitrogen-containing heteroaryl,
benzyl, carbamoyl, - (C=0)- (Ci-Cg alkyl),
-C(=0)-(5- to 6- membered heteroaryl), -C(=0)-(5- to 6-
membered nitrogen-containing heterocycloalkyl),
-C(=0)-carbamoyl, -C(=0)C (=0)-(5- to 6-membered
nitrogen-containing heterocycloalkyl), -C(=0)0-(Ci-Ce
alkyl);
each of which may be substituted with one or more identical
or different group(s) selected from the group consisting
of R";
R" is halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
Ci-Ce alkyl, - (Ci-Cg alkyl)-CN, -(Ci-Cg alkyl)-OH,
-C(=0)0-(Ci-C6 alkyl), -0-(Ci-Ce alkyl), -0-(Ci-Ce
alkyl)-CN, 2-pyrroridinone-l-yl or phenyl,
wherein phenyl may be substituted with halogen;
Y is N, CH or CH2; and
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is a single bond or a double bond,
wherein the one is single bond, the other is double bond; or pharmaceutically acceptable salts thereof, or prodrug thereof.
2. A compound of. claim 1 having the following formula (II):

wherein
R^ is -H or =0;
R^ is carbamoyl or oxadiazolyl,
each of which may be substituted with Ci-Cs alkyl; R^-^ is -H or may be bonded with R^ via a certain functional group
to form divalent groups represented by the following
formula (lA):
N-RA
(lA) ,.
141

R^ is -H or Ci-Cs alkyl;
R"^ is aryl, 5- to 6- membered heteroaryl,
benzyl, carbamoyl, -C (=0) - (5- to 6- membered heteroaryl) , -C(=0)-(5- to 6-membered nitrogen-containing heterocycloalkyl), -C(=0)-carbamoyl, -C (=0)C(=0)- (5- to 6- membered nitrogen-containing heterocycloalkyl), -C(=0)0-(Ci-C6 alkyl) ,
each of which may be substituted with one or more identical or different group(s) selected from the group consisting of R^\-
R^"'' is halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime, Ci-Ce alkyl, - (Ci-Cg alkyl)-CN, - (Ci-Cg alkyl)-OH, -C(=0)0-(Ci-C6 alkyl) , -0-(Ci-Cg alkyl) , -0-(Ci-C6 alkyl)-CN, 2-pyrroridinone-l-yl or phenyl, wherein phenyl may be substituted with halogen;
R^ is halogen or -0-(Ci-Ce alkyl);
n is an integer from 1 to 6;
Y is N, CH or CH2; and
is a single bond or a double bond,
wherein the one is single bond, the other is double bond;
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
3. A compound of claim 2, wherein:
R^ is aryl or 5- to 6-membered nitrogen-containing heteroaryl,
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or -C(=0)0-(Ci-Ce alkyl) ,
each of which may be substituted with one or more identical
or different group (s) selected from the group consisting
of R^^• and R^^ is halogen, -CN, -CF3, -CH2OH, -CONH2, -C (=0) 0-(Ci-Cg alkyl)
or -NO2; or pharmaceutically acceptable salts thereof, or prodrug thereof.
4. A compound of claim 3, wherein:
R^ is halogen;
or pharmaceutically acceptable salts thereof, or prodrug thereof.
5. A compound of claim 4, wherein:
R^ is -CONH2 or -C(=0)NH-(Ci-C6 alkyl) ; Y is CH; and R^ is -H;
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
6. A compound of claim 5, which is :
(1) rel-4-{[(3R,4S)-1-(6-Cyanopyridazin-3-yl)-3-
fluoropiperidin-4-yl]amino}-lH-pyrrolo[2, 3-b]pyridine-
5-carboxamide,
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(2) rel-4-{[(3R,4S)-1-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-lH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(3) Ethyl rel-(3R,4S)-4-[(5-carbamoyl-lH-pyrrolo[2,3-b]pyridin-4-yl) amino]-3-methoxypiperidine-l-carboxylate,
(4) rel-4-{[(3R,4R)-1-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-lH-pyrrolo[2, 3-b]pyridine-5-carboxamide,
(5) rel-4-{[(3R,4S)-1-(5-Cyanopyridin-2-yl)-3-methoxypiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(6) rel-4-{[(3R,4S)-1-(5-Cyano-l,3-thiazol-2-yl)-3-fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-
b]pyridine-5-carboxamide,
(7) rel-4-({ (3R,4S)-3-Fluoro-l-[6-
(trifluoromethyl)pyridazin-3-yl]piperidin-4-yl}amino)-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(8) 4-{[1-(5-Cyanopyridin-2-yl)-3,3-difluoropiperidin-4-yl] amino} -IH-pyrrolo [2,3-b]pyridine-5-carboxamide,
(9) rel-6-[(3R,4S)-3-Fluoro-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]nicotinonitrile,
144

(10) 4-{[(3S,4R)-l-(5-Cyanopyridin-2-yl)-3-fluoropiperidin-4-yl]amino}-lH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(11) 4-{[(3S,4R)-l-(6-Cyanopyridazin-3-yl)-3-
fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(12) 4-{[(3R,4S)-l-(6-Cyanopyridazin-3-yl)-3-f luoropiperidin-4-yl] amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide,
(13) 4-{[(3R,4S)-1-(4-Cyanophenyl)-3-fluoropiperidin-4-yl]amino}-IH-pyrrolo[2,3-b]pyridine-5-carboxamide, and
(14) rel-6-[(3R,4S)-3-Fluoro-4-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-l(2H)-yl)piperidin-l-yl]nicotinonitrile
or pharmaceutically acceptable salts thereof, or prodrug thereof.
7. A compound of claim 1 having the following formula (IIi;
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of R^S- and
R^^ is halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
Ci-Cg alkyl, -(Ci-Cg alkyl)-CN, -(Ci-Cg alkyl)-OH, -C(=0)0-(Ci-C6 alkyl), -0-(Ci-C6 alkyl), -0-(Ci-Cg alkyl)-CN, 2-pyrroridinone-l-yl or phenyl, wherein phenyl may be substituted with halogen;
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
8. A compound of claim 7, wherein:
R^ is -CONH2 or -C(=0)NH-(Ci-C6 alkyl) ;
or pharmaceutically acceptable salts thereof, or prodrug thereof.
9. A compound of claim 8, which is
7-{[1-(5-Cyanopyridin-2-yl)azepan-4-yl]amino}-3H-imidazo[4,5-b]pyridine-6-carboxamide,
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
10. A compound of claim 1 having the following formula (IV):
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R^^ is halogen, Ci-Cg alkyl, -0-(Ci-Cg alkyl) , aryl,
5- to 6- membered heteroaryl, -(C=0)- (Ci-Ce alkyl), -(C=0)-(5- to 6- membered nitrogen-containing heterocycloalkyl), -(C=0)0- (Ci-Cg alkyl), or carbamoyl, each of which may be substituted with one or more identical or different group (s) selected from the group consisting of R"^;
R^^ is halogen, -CN, -CF3, -OH, =0, -NO2, carbamoyl, oxime,
Ci-Cg alkyl, -(Ci-Ce alkyl)-CN, - (Ci-Cg alkyl)-OH, -C(=0)0-(Ci-C6 alkyl), -0-(Ci-Cg alkyl), -0-(Ci-C6 alkyl)-CN, 2-pyrroridinone-l-yl or phenyl, wherein phenyl may be substituted with halogen;
X is N, CH or CH2; and
is a single bond or a double bond,
wherein the one is single bond, the other is double bond;
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
11. A compound of claim 10, wherein
Y is CH;
R^ is -H;
R^^ and R^ form a group of represented by the formula (ID);
R° is -H or -C(=0)C(=0)NH-(Ci-C6 alkyl); and
R^^ is 5- to 7-membered nitrogen-containing heterocycloalkyl or
C3-C9 cycloalkyl,
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each of which may be substituted with one or more identical or different group(s) selected from the group consisting of R^S-
or pharmaceutically acceptable salts thereof, or prodrug
thereof.
12. A compound of claim 11,
which is selected from the group consisting of: (1) rel-(2R,4R)-4-fluoro-l-{[(3S,4S)-4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]carbonyl}pyrrolidine-2-carbonitrile, (2)rel-3-[(3R,4R)-3-(3-aminopyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)-4-methylpiperidin-l-yl]-3-oxopropanenitrile, (3)rel-3-[(3R,4R)-4-methyl-3-(3-oxo-3, 6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)piperidin-1-yl]-3-oxopropanenitrile, (4)rel-N-{l-[(3R,4R)-1-(cyanoacetyl)-4-methylpiperidin-3-yl]-1,6-dihydropyrazolo[3,4-d]pyrrolo[2, 3-b]pyridin-3-yl}-N'-(cyclopropylmethyl)ethanediamide, (5)rel-6-[(3R,4R)-3-(3-aminopyrazolo[3,4-d]pyrrolo [2,3-b]pyridin-l(6H)-yl)-4-methylpiperidin-l-yl]pyridazine-3-carbonitrile,
150

(6)rel-N-{l-[(3R,4R)-1-(5-cyanopyridin-2-yl)-4-
methylpiperidin-3-yl]-1,6-dihydropyrazolo[3,4-
djpyrrolo[2,3-b]pyridin-3-yl}-N'-
(cyclopropylmethyl)ethanediamide, (7)rel-N-(l-{(3R,4R)-l-[(cyanomethyl)(methyl)carbamoyl]-
4-methylpiperidin-3-yl}-l,6-dihydropyrazolo [3,4-
d]pyrrolo[2,3-b]pyridin-3-yl)-N'-
isopropylethanediamide, and (8)rel-N-(l-{(3R,4R)-1-[(cyanomethyl)(methyl)carbamoyl]-
4-methylpiperidin-3-yl}-l,6-dihydropyrazolo[3,4-
d]pyrrolo[2,3-b]pyridin-3-yl)-N'-
(cyclopropylmethyl)ethanediamide, or pharmaceutically acceptable salts thereof, or prodrug thereof.
13. The compound according to any one of claims 1 to 12, said
compound being used as a medicament.
14. The compound according to any one of claims 1 to 12, said
compound being used to treat and/or prevent diseases including rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, tumors, plasmacytic myeloma and leukemia in human beings or animals.
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15. A medicament containing the compound according to any one
of claims 1 to 12 as an active ingredient.
16. A medicament containing the compound according to any one
of claims 1 to 12 as an active ingredient, with a pharmaceutically acceptable carrier or excipient.
17. A janus kinase 3 (JAK3) inhibitor comprising the compound
according to any one of claims 1 to 12.
18. A method for treating and/or preventing diseases including
rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, tumors, plasmacytic myeloma and leukemia in human beings or animals, said method comprising administration of the compound according to any one of claims 1 to 12 to human beings or animals.
19. A use of the compound according to any one of claims 1 to
12 to treat and/or prevent diseases including rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, tumors, plasmacytic myeloma and leukemia
in human beings or animals.
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20. A product comprising a pharmaceutical composition
containing the compound according to any one of claims 1 to 12 and a written notice regarding the pharmaceutical composition, said written notice stating that the compound (I) can be or should be used to treat and/or prevent diseases including rejection during organ/tissue transplantation, autoimmune diseases, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopy, tumors, plasmacytic myeloma and leukemia in human beings or animals.