WO2005105790A1 - 4- 2- (cycloalkylamino) pyrimidin-4-yl ! - (phenyl) - imidazolin-2- one derivatives as p38 map- kinase inhibitors for the treatment of inflammatory diseases - Google Patents

Abstract

The present invention is to provide a novel heterocyclic compound of the formula [I]: wherein R1 is a halogen, nitro, an alkyl, etc.; R2 is hydrogen, an alkyl, etc.; Ring A is 2-oxo-4-imidazolin-3,4-diyl, etc.; Ring B is a cycloalkyl, monocyclic saturated heterocyclic group; X is CH, N; Y is a single bond, CO, SO2; Z is O, NH, etc.; and Ring C is an aryl, a heterocyclic group, or a pharmaceutically acceptable salt thereof, which is useful as a p38 MAP kinase inhibitor.

Description

DESCRIPTION

4- 2- (CYCLOALKYLAMINO) PYRIMIDIN-4-YL ! -3 - ( PHENYL ) -IMIDAZOLIN-2-ONE DERIVATIVES AS P38 MAP- KINASE INHIBITORS FOR THE TREATMENT OF INFLAMMATORY DISEASES .

5 Technical field [0001]

The present invention relates to a novel heterocyclic compound having an excellent p38 MAP kinase-inhibitory activity and useful as a medicine.

10

Background art [0002]

Mitogen-activated protein (MAP) kinases is a kind of serine-threonine kinase which transfers a γ-phosphate group

15 of adenosine triphosphoric acid (ATP) to a hydroxyl of specific serine or threonine constituting a protein, and participates in various cell responses against extracellular signals. The p38 MAP kinase is a protein with about 38 kDa which is subjected to cloning as a homologue

20 of a MAP kinase. [0003]

The p38 MAP kinase is activated by an inflammatory cytokines such as tumor necrosis factor (TNF-α) , inter- leukin 1 (IL-1) , etc., or by. stress stimulation such as

25 ultraviolet ray irradiation, etc. Also, it has been clarified that the p38 MAP kinase phosphorylates various transcription factor groups and kinase groups as substrates, these transcription factor groups and kinase groups are activated by the p38 MAP kinase, so that they

30. contribute to progress in transcription, control after the transcription (stabilization of mRNA and progress of translation of protein) and stabilization of proteins, etc. with regard to various proteins which participate in inflammatory reaction such as inflammatory cytokines, etc.

35 From these facts, it has been considered that the p38 MAP kinase deeply involves in various inflammatory reactions, etc. through control of production and/or signal transduction of inflammatory cytokines so that there is a high probability that an inhibitor of the p38 MAP kinase is to be an agent for treatment .of inflammatory diseases and the like. [0004]

As an ihibitor of p38 MAP kinases, imidazole derivatives are known in (Patent Literature 1), 1,3-thiazole derivatives in (Patent Literature 2), 1,3-thiazole deriva- tives and 1,3-oxazole derivatives in (Patent Literature 3), imidazole derivatives, pyrrole derivatives, furan derivatives, 3-pyrazolin-5-one derivatives, pyrazole derivatives and thiophene derivatives, etc. in (Non-patent Literature 1), and 4-imidazolin-2-one compound in (Patent Literature 4), respectively.

[Patent Literature 1] JP 2000-503304-A [Patent Literature 2] JP 2001-114690-A [Patent Literature 3] JP 2001-114779-A [Patent Literature 4] WO 03/035638 [Non-patent Literature 1] Expert Opinion on Therapeutic Patents, 2000, 10(1), p.25-37

Disclosure of the invention [Problems to be solved by the invention] [0005]

The problem to be solved by the present invention is to. provide a novel compound having excellent p38 MAP kinase inhibitory activity and useful as a medicine. [Means to solve the problems] [0006]

To solve the above-mentioned problems, the present inventors have earnestly studied, and as a result, they have found that the compound of the following formula has excellent p38 inhibitory activity whereby the present invention has been accomplished.

That is, the present invention is as follows. [0007]

1. A compound of the formula [I]

wherein R¹ is hydrogen, a halogen, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbamoyl, hydroxy or cyano, p is 1 or 2 , provided that when p is 2 , two R¹s may be the same or different from each other, .

Z is oxygen atom or -N (R² ) -,

R² is hydrogen, an alkyl or an alkanoyl ,

Ring A is a ring selected from the following formulae :

R³, R⁴, R⁶, R⁷ , R¹⁰ and R¹² may be the same or different from each other, and each is (CH₂)_n-R^A, R^A is hydrogen, an optionally substituted alkyl, an optionally substituted alkoxyalkyl, an optionally substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, n is 0 or an integer of 1 to 4,

R⁵, R⁸, R⁹, R¹¹ and R¹³ to R²⁴ may be the same or different from each other, and each is hydrogen, a halogen, an optionally substituted alkyl, alkoxy, alkanoyl, an alkoxycarbonyl, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group,

Q¹ is hydrogen, a halogen, cyano, an optionally substituted alkyl or an optionally substituted heterocyclic group, Ring B is a cycloalkane or a monocyclic saturated nitrogen-containing heterocyclic ring, X is CH or N,

Y is a single bond, S0₂ or CO, Ring C is an aromatic hydrocarbon ring or an optionally substituted heterocyclic^' ring, or a pharmaceutically acceptable salt thereof. [0008]

2. The compound or a pharmaceutically acceptable salt thereof as mentioned in the above 1, wherein Ring A is

wherein R³ and Q¹ have the same meanings as the above. 3. The compound or a pharmaceutically acceptable salt thereof as mentioned n the above 1 or 2, wherein Z is - N(R )- and R has the same meaning as the above.

4. The compound or a pharmaceutically acceptable salt, thereof as mentioned, in any one of the above 1 to 3, wherein R² is hydrogen. ' [0009]

5. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 4, wherein Ring B is a C₅_₇ cycloalkane.

6. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 5, wherein Ring B is cyclohexane.

7. The compound or a pharmaceutically acceptable salt thereof as mentioned in the above 5 or 6, wherein Y is a single bond. 8. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 5 to 7, , wherein Ring C is a heterocyclic ring which may be substituted by 1 to 3 groups independently selected from oxo, an alkyl, alkanoyl, alkylsulfonyl, alkoxycarbonyl, hydroxy and an optionally substituted amino.

9. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 5 to 8, wherein Ring C is a_^ ring selected from the following formulae:

B R²-⁵ D _R225* I

_{R25 R} Jo₂₅e. I _R2«₅

wherein R²⁵, R²⁶, R³¹ to R³⁷ and R⁴¹ may be the same or different from each other, and each is hydrogen, an alkyl, hydroxy, an alkoxy or an alkoxyalkyl, R²⁷ to R³⁰, R³⁸ and R³⁹ may be the same or different from each other, and each is hydrogen, an alkyl or an amino- protective group. 10. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 5 to 9, wherein Ring C is the following groups

wherein R^28a is hydrogen, an alkyl, an alkanoyl, an alkoxycarbonyl or an alkylsulfonyl, and other symbols have the same meanings as the above. [0010]

11. The compound or a pharmaceutically acceptable salt^' thereof as mentioned in any one of the above 1 to 3, , wherein Ring B is a 5 to 7-membered monocyclic saturated nitrogen-containing heterocyclic ring.

12. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 3, wherein Ring B is piperidine. 13. The compound or a pharmaceutically acceptable salt thereof as mentioned in the above 11 or 12, wherein Y is S0₂ or CO.

14. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 11 to 13, wherein Ring C is an aromatic hydrocarbon ring, or a ring selected from the following formulae:

wherein R , R and R have the same meanings as the above. [0011]

15. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 14, wherein R¹ is a halogen or an optionally substituted alkyl. 16.. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 15, wherein R¹ is chlorine, fluorine, methyl or trifluoro- methyl .

17. The compound or a pharmaceutically acceptable salt thereof as mentioned in the above 15 or 16, wherein p is 1, and the binding position of R¹ is 4-position or 3-position.

18. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 15 to 17, wherein p is 1, and the binding position of R¹ is 3- position.

19. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 18, wherein R^A is an optionally substituted alkyl, an optionally substituted heterocyclic group, phenyl or a cycloalkyl, and n ^'is 0 or 1.

20. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 19, wherein R^A is 4-tetrahydropyranyl and n is 0. [0012]

21. A compound of the formula:

wherein R^la is a halogen or an optionally substituted alkyl, p is 1 or 2, provided that when p is 2, two R^las may be the same or different from each other,

R² is hydrogen, an alkyl or an alkanoyl,

R^{B '}is an optionally substituted alkyl or an optionally substituted heterocyclic group, Q¹ is^' hydrogen, a halogen, cyano, an optionally substituted alkyl or an optionally substituted heterocyclic group,

Ring B¹ is a cycloalkane

X is CH or N, Ring C¹ is an optionally substituted heterocyclic ring, or a pharmaceutically acceptable salt thereof. [0013] 22. The compound or a pharmaceutically acceptable salt thereof as mentioned in the above 21, wherein p is 1, and R^la is chlorine, fluorine, methyl or trifluoromethyl.

23. The compound or a pharmaceutically acceptable salt^' thereof as mentioned in the above 21 or 22, wherein p is 1, and the binding position of R^la is 4-position or 3-position.

24. The compound or a pharmaceutically acceptable salt ^• thereof as mentioned in any one of the above 21 to 23, wherein p is 1, and the binding position of R^la is 3- position. 25. The compound or a pharmaceutically acceptable salt thereof as mentioned in -any one of the above 21 to 24, wherein R² is hydrogen. ~ 26. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 21 to 25, wherein R^B is an optionally substituted heterocyclic group.

27. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 21 to 26, wherein R^B is 4-tetrahydropyranyl .

28. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 21 to 27, wherein Q¹ is hydrogen, bromine, chlorine, cyano or aminomethyl . .29. The compound or a pharmaceutically acceptable salt- thereof as mentioned in any one of the above 21 to 28, wherein Ring B¹ is cyclohexane.

30. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 21 to 29, wherein X is N. [0014] 31. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 21 to 30, wherein Ring C¹ is a 5- to 7-membered saturated heterocyclic ring which contains 1 or 2 hetero atoms independently selected from nitrogen atom, oxygen atom and sulfur atom, and which may be substituted by the group selected from the group consisting of oxo(s), alkyl (s), hydroxy (s), alkoxy (s), alkanoyl(s), alkoxycarbonyl (s) and alkylsulfonyl (s) .

32. The Compound or a pharmaceutically acceptable salt^' thexeof as mentioned in the above 31, wherein the heterocyclic ring is pyrrolidine, isothiazolidine, oxazolidine, piperidine, piperazine, morpholine or homopiperidine .

33. The compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 21 to 32, wherein Ring C¹ is the following groups

wherein R^28a is hydrogen, an alkyl, an alkanoyl, an alkoxycarbonyl or an alkylsulfonyl, and other symbols have the same meanings as defined above. [0015]

34. A medicine comprising the compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to, 33.

35. A p38 MAP kinase inihibitor containing the compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 33.

36. A prophylaxis or treatment agent for diseases to which excessive production of inflammatory mediator pertains to which- p38 MAP kinase pertains which comprises the compound or a pharmaceutically acceptable salt thereof as mentioned in any one of the above 1 to 33 as an effective ingredient.

37. The prophylaxis or treatment agent according to the above-mentioned 36, wherein the disease to which excessive production of inflammatory mediator pertains is arthritis. Best mode for carrying out the -invention [0016]

In 'the following, the respective groups represented by the respective symbols in. the present specification will be explained.

"Halogen"includes -fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

"Alkyl" and the alkyl in the "alkoxyalkyl", "alkylthio", "alkylsulfinyl" and "alkylsulfonyl" is exemplified by, for example, a straight or branched chain Cι-6 alkyl, preferably Cι_₄ alkyl, and specifically by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, pentyl, hexyl, etc.

"Alkoxy" and the alkoxy in the "alkoxyalkyl" and "alkoxycarbonyl"is exemplified by, for example, a straight or branched chain Cι_₆ alkoxy, preferably Cι_₄ alkoxy, and specifically by methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.

"Alkanoyl" is exemplified by, for example, a straight or branched chain C₂_₇ alkanoyl, preferably C₂-₅ alkanoyl, and specifically, by acetyl, propionyl, butyryl, pentanoyl, etc.

"Cycloalkyl" ^' is exemplified by, for^' example, C₃_₈, preferably C₃_6 cycloalkyl, and specifically by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

"Cycloalkane" is exemplified by, for example, C₃_₈, preferably C₃_₆ cycloalkane, and specifically by cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc. [0017] ^•-

"Aryl" and the aryl in the "arylsulfonyl" is exemplified by, for example, C₆_ι₄, preferably Cε-io monocyclic, dicyclic or tricyclic aryl, and specifically by phenyl, naphthyl, phenanthryl, anthryl, etc., particularly phenyl and naphthyl are preferred.

"Aromatic hydrocarbon ring" is exemplified by, for example, C6-ι₄, preferably Cg-io monocyclic, dicyclic or tricyclic aromatic hydrocarbon ring, and specifically by benzene, naphthalene, phenanthrene, anthracene, etc., particularly benzene and naphthalene are preferred. [0018]

"Heterocyclic group" is exemplified by, for example, a _. monocyclic, .dicyclic or tricyclic heterocyclic group which contains 1 to .4 hetero atoms independently selected from nitrogen atom, oxygen atom and sulfur atom, and a part or whole portion of which may be saturated. There may be preferably mentioned a 5 or 6-membered monocyclic heterocyclic group, specifically mentioned are furyl, tetrahydro- furyl, tetrahydropyranyl, tetrahydrothiapyranyl, thienyl, tetrahydrothienyl, thiazolyl, isothiazolyl, tetrahydro- isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, tetrazol- yl,- pyrrolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyridyl, pyridazinyl, pyrimidinyl, hexahydropyrimidinyl, pyrazinyl, triazinyl, piperidyl, pyrazolyl, piperazinyl, morpholinyl, dioxanyl, imidazolyl, triazolyl, pyrazolinyl, thiazinyl, tetrahydro- thiazinyl, etc. [0019]

"Heterocyclic ring" is exemplified by, for example, a monocyclic,^' dicyclic or tricyclic heterocyclic ring containing 1 to 4 hetero atoms independently selected from nitrogen atom, oxygen atom and' sulfur atom, a part or whole portion of which may be saturated. There may be preferably mentioned a 5 or 6-membered monocyclic heterocyclic ring, specifically mentioned are furan, tetrahydrofuran, tetra- . hydropyran, tetrahydrothiapyran, thiophene, tetrahydro- thiophene,^' thiazole, isothiazole, tetrahydroisothiazole, oxazole, isoxazole, oxadiazole, tetrazole, pyrrole, pyrrolidine, pyrroline, imid^'azolidine, imidazoline, pyrazolidine, pyridine, pyridazine, pyrimidine, hexahydro- pyrimidine, pyrazine, triazine, piperidine, pyrazole, piperazine, morpholine, dioxane, imidazole, triazole, pyrazoline, thiazine, tetrahydrothiazine, etc.

"Monocyclic saturated nitrogen-containing heterocyclic ring^' " is exemplified by, for example, a 4 to 7- membered monocyclic saturated heterocyclic ring having 1 to 2 nitrogen atoms, and further may have 1 to 2 oxygen atom(s) or sulfur atom(s), and specifically by pyrrolidine, piperidine, homopiperidine, etc.

[0020]

^■ The substituent (s) for "the optionally substituted alkyl" of R¹ is exemplified by, for example, a halogen, hydroxy, amino, etc. The alkyl may be substituted by 1 to 3 substituents mentioned above, and when a number of the substituent (s) is two or more, the respective substituents may be the same or different from each other. Specific examples of the substituted alkyl include hydroxymethyl, trifluoromethyl, aminomethyl, chloroethyl, etc.

The substituent (s) for "the optionally substituted alkoxy" of R¹ is exemplified by, for example, hydroxy, amino, etc. The alkoxy may have 1 to 3 substituents mentioned above, and when a number of the substituent (s) is two or more, the respective substituents may be the same or different from each other. .[0021]

The substituent (s) for "the optionally substituted amino" of R¹ is exemplified by, for example, an alkyl (the alkyl may be substituted by 1 to 3 groups independently selected from the group consisting of an alkoxy, amino and carboxy) , alkanoyl, etc. The amino may be, for example, substituted by 1 or 2 substituent (s) , and when a number of the substituent (s) is two, the respective substituents may be the same or different from each other.

The substituent (s) for "the optionally substituted carbamoyl" of R¹ is exemplified by, for example, an alkyl, etc. The carbamoyl may be substituted by 1 or 2 substituen (s) mentioned above, and when a number of the substituent (s) is two, the respective substituents may be the same or different from each other.

R¹ is preferably a halogen, nitro, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino and cyano. Particularly preferred are a halogen, Ci to C₄ alkyl which may be substituted by halogen(s), Ci to C₄ alkoxy, etc., and specific examples thereof include a fluorine, chlorine, methyl, trifluoro- methyl, methoxy, etc. [0022] The substituent (s) for "the optionally substituted alkyl" of R^A is exemplified by, for example, an alkynyl, cyano, alkoxy, hydroxy, amino (the amino may be substituted by 1 or 2 substituent (s) independently selected from the group consisting of an alkyl, alkanoyl and alkylsulfonyl) , carboxy, alkoxycarbonyl, carbamoyl (the carbamoyl may be substituted by 1 or 2 alkyl (s) ) , phenyl, naphthyl, etc. The alkyl may be, for example, substituted by 1 to 3 substituent (s) mentioned above, and when a number of the substituent (s) is two or more, the respective substituents may be the same or different from each other. Preferred examples of the substituent include cyano, alkoxy, hydroxy, amino, carboxy, carbamoyl which may be substituted by alkyl, phenyl, etc. [0023] The substituent (s) for "the optionally substituted cycloalkyl" of R^A is exemplified by, for example, (1) hydroxy, (2) alkoxy (the alkoxy may be substituted by 1 to 3 alkoxy(s)), (3) amino [the amino may be substituted by the same or different 1 or 2 group (s) independently selected from the groups of the following (i) to (v) : (i) alkyl, (ii) alkanoyl, (iii) alkoxycarbonyl, (iv) carbamoyl (the carbamoyl may be substituted by 1 or 2 alkyl (s)), and (v) alkylsulfonyl], (4) carboxy, (5) alkyl [the alkyl may be substituted by a group selected from the group consist- ing of hydroxy, alkoxy and amino], (6) carbamoyl which may be substituted by alkyl (s), etc. The cycloalkyl may be, for example, substituted by 1 to 3 substituent (s) mentioned above, and when a number of the substituent (s) is two or more, the- respective substituents may be the same or different from each other. [0024]

The substituent (s) for "the optionally substituted phenyl" of R^A is exemplified by, for example,^' (1) a halogen, (2) nitro, (3) alkyl (the alkyl may be substituted by the same or different 1 to 3 group (s) selected from the group consisting of a halogen, hydroxy, amino, carboxy and • phenylsulfonyl) , (4) alkenyl, (5) cyano, (6) hydroxy, (7) alkoxy (the alkoxy may be substituted by the same or different 1 to 3. group (s) independently selected from the group consisting of a halogen, carboxy, alkoxycarbonyl, carbamoyl, phenyl and morpholinylcarbonyl) , (8) amino [the amino may be substituted by the same or different 1 or 2 group (s) independently selected from the groups of the following (i) to (iv) : (i) alkyl, (ii) alkanoyl, (iii) carbamoyl (the carbamoyl may be substituted by the same or different 1 or 2 group (s) independently selected from the group consisting of alkyl and cycloalkyl) , and (iv) alkylsulfonyl],. (9) alkanoyl, (10) carboxy, (11) alkoxycarbonyl, (12) carbamoyl [the carbamoyl may be substituted by one or two group (s) which may be the same or different from each other independently selected from the groups consisting of the following (i) and (ii) : (i) alkyl (the alkyl may be substituted by 1 to 3 hydroxy (s) ),^'■ and (ii) cycloalkyl], (13) alkylthio, (14) alkylsulfinyl, (15) alkylsulfonyl, (16) phenyl,' (17) tetrazolyl, (18) hetero- cyclic group-substituted carbonyl (the heterocyclic group may be substituted by the same or different 1 to 3 group (s) independently selected from the group consisting of alkyl and alkoxycarbonyl), etc. When R¹ is an optionally substituted phenyl, the phenyl- may be, for example, substituted by 1 to 3 group (s) mentioned above, and when a number of the substituent (s) is two or more, the respective substituents may be the same or different from each other. Preferred examples of the substituent include (1) a halogen, (2) alkyl (the alkyl. may be substituted by the same or different 1 to 3 group (s) selected from the group consisting of a halogen, hydroxy, amino, carboxy and phenylsulfonyl) ,- (3) cyano, (4) alkoxy (the alkoxy may be substituted by the same or different 1 to 3 group (s) selected from the group consisting of a halogen, carboxy, alkoxycarbonyl, carbamoyl, phenyl and morpholinylcarbonyl) , ■ etc. As a substituted position (s) of the substituent (s) , it is not limited so long as it is a substitutable position, and particularly preferred position may be mentioned 2-position. [0025] When R^A is "the optionally substituted heterocyclic group",, the heterocyclic group is exemplified by the above- mentipned heterocyclic group, preferably a 5 or 6-membered monocyclic heterocyclic group. Specific examples thereof include furyl, tetrahydrofuryl, thienyl, thiazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, piperidyl, pyrrolidinyl, pyrazolyl, tetrazolyl, tetrahydro- pyranyl, tetrahydrothiapyranyl, etc., particularly preferably piperidyl, •. tetrahydropyranyl, etc. Also, a substituent (s) on the heterocyclic group is exemplified by, for example, a halogen, nitro, alkyl (the alkyl may be substituted by a group selected from the group consisting of hydroxy, alkoxy, carbamoyl optionally substituted by alkyl, and carboxy) , cyano, hydroxy, amino, alkanoyl, carboxy, alkoxycarbonyl, carbamoyl (the carbamoyl may be substituted by.1 or 2 alky (s)), alkylsulfonyl, phenyl, oxo, etc. The heterocyclic group may be, for example, substituted by 1 to 3 substituent (s)' mentioned above, and when a number of the substituent (s) is two or more, the respective substituents may be the same or different frpm each other. [0026] The preferred combination of n and R^A in Compound [I] is exemplified by, for example, (1) those in which n is 0, and R^A is' an optionally substituted alkyl, (2) those in which n is 1/ and R^A is an optionally substituted cyclo- ^' alkyl, (3) those in which n is 1, and R^A is an optionally substituted phen l, (4) those in which n is 1, and R^A is an optionally substituted heterocyclic group, (5) those in which n is 0, and R^A is an optionally substituted cycloalkyl, and (6) those in which n is 0, and' R^A is an optionally substituted heterocyclic group, etc. Particularly preferred are (1) those in which n is 0, and R^A is an optionally substituted alkyl, (2) those in which n is 1, and R^A is an optionally substituted phenyl, (3) those in which n is 0, and R^A is optionally substituted cycloalkyl, and (4) those in which n is 0, and R^A is an optionally substituted heterocyclic group, etc. Further preferred are (1) those in which n is 0, and R^A is a C to C₄ alkyl which . may be substituted by hydroxy, (2) those in which n is 1, and R^A is a phenyl (the phenyl may be substituted by a group (s) selected from the group consisting of a cyano, fluorine, chlorine and methyl) , (3) those in which n is 0, and R^A is a C₃ to C₄ cycloalkyl, and (4) those in which n is 0,.and R^A is- a tetrahydrόpyranyl, etc. [0027] The substituent (s) for "the optionally substituted -alkyl" of R⁵, R⁸, R⁹, R¹¹ and R¹³ to R²⁴ is exemplified by, for example, a halogen, hydroxy, amino (the amino may be mono or di-substituted by a group selected from the group consisting of an alkyl, alkanoyl, alkoxycarbonyl and alkylsulfonyl), etc., and the alkyl may by^' substituted by 1 to 3 substituents mentioned above, and when a number of the substituent (s) is two or more, the respective substituents may be the same or different from each other. [0028] ^" The substituent (s) for "the optionally substituted amino" of R⁵, R⁸, R⁹, R¹¹ and R¹³ to R²⁴ and Ring C is exemplified by, for example, an alkyl, alkanoyl, alkoxycarbonyl, alkylsulfonyl, etc., the amino may be substituted by 1 or 2. substituents mentioned above, and when a number of the- substituent (s) is two, the respective substituents may be the same or different from each other. [0029]

The substituent (s) for "the optionally substituted carbamoyl". of R⁵, R⁸, R⁹, R¹¹ and R¹³ to R²⁴ is exemplified by, for example, an alkyl, etc.,. the carbamoyl may be substituted by 1 or 2 substituents mentioned above, and when a number of the substituent (s) is two, the respective substituents may be the same or different from each other. [0030] ^{' ' '}

The substituent (s) for "the optionally substituted cycloalkyl" of R⁵, R⁸, R⁹, R¹¹ and R¹³ to R²⁴ is exemplified by, for example, a halogen, hydroxy, alkyl, alkoxy, amino (which may be mono- or di-substitute^'d by alkyl or alkanoyl), etc., the cycloalkyl may be substituted by 1 or 2 substituents mentioned above, and when a number of the- substituent (s) is two, the' respective substituents may be the same or different from each other. [0031]

The ^'substituent (s) for "the optionally substitute_.d- aryl" of R⁵, R⁸, R⁹,- R¹¹ and R¹³ to R²⁴ - is exemplified by, for ^• example, a halogen, hydroxy, alkyl optionally substituted by halogen, alkoxy, amino (which may be mono-^' or di-substi- tuted by an alkyl or alkanoyl), etc., the aryl may be substituted by 1 or 2 substituents mentioned above, and when a number ^'of the substituent (s) is two, the respective substituents may be the same or different from each other. [0032]

The substituent (s) for "the optionally substituted heterocyclic group" of R⁵, R⁸, R⁹, R¹¹ and R¹³ to R²⁴ is exemplified by, for example, a halogen, hydroxy, alkyl, alkoxy, amino (which may- be mono-- or di-substituted by alkyl or alkanoyl), etc., the heterocyclic group may be substituted by 1 or 2 substituents mentioned above, and when a number of the substituent (s) is two, the respective substituents may be the same or different from each other. [0033] "The amino-protective group" of R²⁷ to R³⁰, R³⁸ and R³⁹ - is exemplified by, for example, an amino-protective group described in T.W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons Inc. (1981) , specifically by alkanoyl, alkoxycarbonyl, alkylsulfonyl, optionally substi- tuted arylsulfonyl (nitro, etc., are preferred as the substituent (s) ) , etc. [0034]

The substituent (s) for "the optionally substituted aklyl" of Q¹ is exemplified by an amino which may be substituted by an alkyl, an alkanoyl, and the like.

Specific examples of the substituted alkyl include amino- methyl, N-methylaminomethyl, N,N-dimethylaminomethyl, N- acetylaminomethyl, and the like, and preferred is a ino- methyl . . "The optionally^' substituted heterocyclic group" of Q^{1 ■}is preferably monocyclic saturated nitrogen-containing heterocyclic group, more preferably a 4 to 7-membered monocyclic. saturated heterocyclic group having 1 to 2 ^• nitrogen atoms, and further may have 1 to 2 oxygen atom(s) or sulfur^' atom(s.). Examples of such heterocyclic group include pyrrolidine, piperidine, homopiperidine, and the like, preferred are pyrrolidine or piperidine.

The substituent (s) for "the optionally, substituted heterocyclic group" of Q¹ is exemplified by an alkyl, an alkanoyl, an alkoxycarbonyl, an alkylsulfonyl and the like. [0035]

"Heterocyclic ring" of Ring C is exemplified by, for example, a 3 to 7-membered, -preferably 5 or 6-membered heterocyclic ring containing 1 to 4 hetero atoms independ- ently selected from nitrogen atom, oxygen atom and sulfur atom, a part or whole of which may be saturated. The heterocyclic ring may be substituted by 1 to 3 group (s) independently selected from oxo, alkyl, alkoxyalkyl, alkylsulfonyl, optionally substituted arylsulfonyl, hydroxy, alkoxy, alkanoyl, alkoxycarbonyl and optionally ^' substituted amino as a substituent (s) . Specific examples of the optionally substituted heterocyclic ring include the following groups. ^■• ^'

wherein the respective symbols have the same meanings as defined above. Preferred examples of the- -above-mentioned heterocyclic ring include the following groups.

anings

as defined above. [0036] --

A binding position of -Y-Ring C at Ring B is preferably a 3-position, 4-position, 5-position, etc. , when the binding position of -Z- is 1-position. When Ring B is a 6- membered ring, a 4-position is particularly preferred. When Y is S0₂ or CO, Ring B is preferably a mono- cyclic saturated nitrogen-containing heterocyclic ring containing NH, particularly preferred is a heterocyclic ring in which Y binds to a nitrogen atom of the NH.

When Y is a single bond, Ring C is preferably a heterocyclic ring containing NH in which a part or whole of which is saturated, particularly preferred is a heterocyclic ring in which- Y binds to a nitrogen atom of the NH. A binding position of R¹ is preferably a 3-position or 4-position of phenyl, more preferably 3-position. [0037]-

In Compound [I] of the present invention, there exists an optical i.somer based on an asymmetric carbon (s), and the present invention includes any of these optical isomers and a mixture thereof. Compound [I] can be used for a pharmaceutical use, either in a free form or in a form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt of Compound [I] is exemplified by, for example, inorganic acid salts such as hydrochlor- ide, sulfate, phosphate or hydrobromide, organic acid salts such as acetate, fumarate, oxalate, citrate, methane- sulfonate, benzenesulfonate, tosylate or maleate. Further, when the compound has a substituent such as carboxy, etc., there may be mentioned a salt, with a base^' (for example, alkali metal salts such as a sodium salt, a potassium salt, etc., or alkaline earth metal salts such as a calcium salt, etc. ) .

Compound [I] of the present invention or a salt thereof also includes an internal salt thereof, and a solvate thereof such as a hydrate, and the like. [0038]

Compound [I] of the present invention can be produced by the following method. [Method A]

[I-a] wherein G is a halogen, methylthio, -methylsulfinyl or methylsulfonyl, other symbols have the same meanings as defined above. [0039]

When G in Compound [II] is a halogen, the reaction of Compound [II] and Compound [III] can be carried out in the. presence of a catalyst, a base and an additive in a solvent (Journal of Organic Chemistry, 61, 7240(1996)). Any solvent may be used so long as it has no adverse effect on the reaction, and examples of such solvent include, for example, toluene, xylene, dimethoxyethane, dioxane, etc. Examples of the catalyst include, for example, palladium acetate, dipalladium bis (dibenzylideneacetone) , etc. ' Examples of the base include, for example, sodium tert- butoxide, potassium tert-butoxide, lithium tert-butoxide, triethylamine, etc. Examples of the additive include 2,2'- bis (diphenylphosphino) -1, 1' -binaphthyl, etc. The present reaction suitably proceeds at 30 to 150°C, particularly at 60 to 80°C. [0040]

When G in Compound [II] is methylthio, methylsulfinyl or methylsulfonyl, the reaction of Compound [II] and Compound [III] can be carried out in a solvent. Any solvent may be used so long as it has no adverse effect on the reaction, and examples of such solvent include, for example, dioxane, THF, DMF, DMSO, etc. The present reaction suitably proceeds at 0 to 150 °C, particularly at 50 to 100°C. [0041] [Method B]

The compound of the following formula [I-b] included in Compound [I] of the present -invention can be produced by the following method.

[ VII ] [ i-b ] wherein P¹ and P² may be the same or different from each other, and each is a halogen, chloroformyl, carboxy, alkylsulfonyloxy or isocyanate, Q is an alkyl (the alkyl may be interposed by 1 to 2 oxygen atom, nitrogen atom, sulfur atom, etc. in the alkyl chain) which- may have 1 to 4 groups selected from oxo, alkyl, hydroxy, an optionally substituted amino and double bond, Ring C² is a group selected from the following formulae,

other symbols have the same meanings as defined above. [0042]

The reaction of Compound [II] and Compound [IV] can be ^'carried_. out in the same manner as in Method A. When P¹ of Compound [VI] is a halogen or alkylsulfonyloxy, the reaction of Compound [V] and Compound [VI] can be carried out in the presence of a base- in a solvent. Examples of the solvent include chloroform, dichloro- methane, DMF, DMSO, dioxane, THF, etc. Examples of the base include triethylamine, diisopropylethylamme, 4- methylmorpholine, pyridine, etc. The present reaction suitably proceeds at -40 to 100 °C, particularly at -10 to 30°C_? - .

When P¹ of Compound [VI] is isocyanate, the reaction can be carried out in a solvent. Examples of the solvent include chloroform, dichloromethane, DMF-, DMSO, dioxane,

THF, etc. The present reaction suitably proceed.s at -40 to 100°C, particularly at -10 to 30°C. . ..

[0043]

When P¹ of Compound [VI] is carboxy, the reaction of Compound [V] and Compound [VI] can be carried out by treating with a condensing agent in a solvent. Any solvent may be used so long as it has no ad-verse effect on the reaction, and examples of such solvent include, for example, methylene chloride, chloroform, THF, DMF, etc. Examples of the condensing agent include, for example,

1, 1' -carbonyldiimidazole, 1, 3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloride, etc. The present reaction suitably proceeds at -40 to 100°C, particularly at -10 to 30°C. Compound [VII] is treated with a base in a solvent to give Compound [I-b] . Examples of the solvent include DMF, DMSO, N, N-dimethylacetamide, etc. Examples of the base include sodium hydride, potassium tert-butoxide, etc. The present reaction suitably proceeds at 0 to 100 °C, particu- larly at '30 to 80°C. [0044] [Method C]

The compound of the following formula [I-c] included in Compound [I] of the present invention can be produced by the following method.

[ IX ] [ I-c ] wherein Ring B² is a monocyclic saturated nitrogen- containing heterocyclic ring, Hal is a halogen, ' P³ is an amino-protective group, and other symbols have ^' the same meanings as defined above. [0045]

The reaction of Compound [II] and Compound [VIII] can be carried out in the same manner as in Method A, and the ^' obtained compound is deprotected according to the conven- tional manner to. give Compound [IX] .

The reaction of Compound [IX] and Compound [X] can be carried out in the presence of a base in a solvent. Examples of the solvent include THF, dioxane, dichloro- methane, • chloroform, toluene, xylene, DMF, DMSO, etc. Examples of the . base include .sodium hydride, triethylamine, diisopropylethylamme, pyridine, 4-dimethylaminopyridine, etc. The' present reaction suitably proceeds • at -20 to 100°C, particularly at 0°C to room temperature. ' [0046] - [Method D]

The Compound (I) in which Ring A is

and Q¹ is an optionally substituted aminomethyl can be produced by the following method.

[I-d] [I-e]

- wherein Ra and Rb are the- same or different from each other and each is hydrogen, an alkyl or an alkanoyl, and other symbols have the same meaning as defined above. [0047]

' . Compound [I-d] , which is prepared in the same method as in Method A, is subjected to catalytic hydrogenation reaction or treated with reducing agent according to the conventional manner, and subjected to N-alkylation or N- alkanoylation if necessary to give Compound [I-e] . Examples of the catalyst of catalytic hydrogenation reaction include Raney nickel, and the like. Examples of the reducing agent include, lithium aluminum hydride, sodium borohydride, and the like.

[0048] ' - •

Compound [III] can be generally prepared by a known method. For example, the compound of the following formula [XIV] can be produced by the following method.

P¹-Q-P²

[^XI] [^χm] [XIV] wherein P⁴ is an amino-protective group or a protective group for hydroxy, and other symbols- have the same meanings as defined above. The present reaction can be carried out in the same manner as in Method B, and the obtained compound is . deprotected according to the conventional manner to give

Compound [XIV] .

[0049]

The compound of the following formula^' [XV] can be produced by the following, method..

wherein Ring C³- is a group selected from the

The present reaction can be carried out by reacting Compound [XI] and the corresponding cyclic acid anhydride in the same manner as in the ^' condensation reaction of Method B, and the obtained compound is deprotected to give Compound [XV] . [0050]

The compound of the_. following formula [XIX] can be produced by the following method.

[ xvi ] _. [ XVIII ] [ XIX ] wherein Ring C⁴ is

and other symbols have- the same meanings as defined above. • . -

[0051] ^' Compound [XVI] is subjected ^'to reductive amination reaction with Compound [XVII] in the presence of a reducing agent in a solvent to give Compound [XVIII] . Examples of the solvent include water, methariol, ethanol, chloroform, dichloroethane, ethyl acetate, acetic acid, benzene, toluene,^' xylene, DMF, DMSO or a mixture thereof. Examples of the reducing agent include sodium-borohydride, sodium - cyanoborohydride, sodium t'riacetoxyborohydride, etc. The present reaction suitably proceeds at -20 °C to 150 °C for 1 to 24 hours. The obtained Compound [XVIII] is deprotected according to the conventional manner to give Compound - [XIX] . [0O5-2]

Also, the compound of the following [XXII] can be produced by the following method.

Ha^l-Y-{c

[^χχ] [XXII] wherein the respective symbols have -the same meanings as defined above.

The present reaction can be carried out in the same manner as in Method C, and the obtained compound is deprotected to give Compound [XXII] . [0053]

Compound [Il-b], which is the intermediate of Compound [I-d], can be produced by the following method.^'

• . [Il-a] [H-b] wherein Q^la is a- halogen and other symbols have the same meaning as defined above. Compound [Il-a] is reacted with a cyanizing agent in a solvent to give Compound [Il-b] . Examples of the . cyanizing agent include sodium cyanide, cuprous cyanide, and the like. Examples of the solvent include acetonitril.e, DMSO, DMF, a mixture thereof, and the like. The present reaction suitably proceeds at room temperature to 100°C from 1 to 24 hours. Compound [Il-d] may also be prepared using a palladium catalyst such as tetrakis (triphenyl- phosphine) palladium and -a cyanizing • gent such as zinc ' cyanide and potassium cyanide. [0054]

. Compound [II] in which G is methylthio^', methylsulfin- yl or methylsulfonyl, Ring A is

and Q¹ is a halogen, an alkyl or an optionally substituted heterocyclic group, can be produced by the following method. Q^1b-B(ORc)₂ [ XXHI-a]

[II-c] [H-a] _; . [Il-d] wherein G¹ is methylthio, methylsulfinyl or methyl- - sulfonyl, Q^lb is an alkyl or an optionally substi- ' tuted heterocyclic group, Q^lc is an alkyl, Re is ' hydrogen or an alkyl, and other symbols have the same meaning as defined above. [0055]

Compound [II-c] is subjected to halogenation with a •'• halogenating agent according to the conventional manner to give Compound [Il-a] . Examples of the halogenating agent include bromine, chlorine, iodine, N-bromosuccinimide, N- chlorosuccinimide, .and the like.

Compound [Il-d] can be prepared by the following methods . (1) Accroding to the method described in Chem. Rev. 1995, 95,- 2457-2483, Compound [IΪ-a]^'is reacted with Compound - [XXIII-a] in the presence of a palladium catalyst and a base to give Compound. [Il-d] . Example of the palladium catalyst include a zero-valent or divalent palladium catalyst such as [1, 1-bis (diphenylphosphino) ferrocene] dichloropalladium, tetrakis (triphenylphosphine) palladium(O) , bis (triphenylphosphine) palladium (II) dichloride, bis(tri-t- butylphosphine) palladium (0) , bis (tricyclohexylphosphine) - palladium(O) , tris (dibenzylideneacetone) dipalladium(O) and palladium (II) acetate. Examples of the base include an inorganic base. such as alkali metal carbonate (potassium carbonate, cesium carbonate etc.), alkali metal hydroxide (potassium''hydroxide., sodium hydroxide etc.), alkali metal phosphate ^'(potassium phosphate etc.), alkali metal acetate (potassium acetate etc.), alkali metal fluoride (sodium fluoride etc.) and sodium t-butoxide, or an organic base such as triethylamine. Any solvent may -be used as long^' as it has no adverse effect on the reactions. Examples of such solvent include DME, THF, dioxane, DMF, dimethylacet- ■ amide, toluene, benzene, methanol, ethanol, water and a mixture thereof. The present reaction suitably proceeds at 60 to 150°C, preferably 80 to 120°C, for generally from 1 to 24 hours. [0056]

(2) Compound [Il-a] is reacted with Compound [XXIII-b] or Compound [XXIII-c] in the presence of a nickel catalyst or a copper catalyst in a solvent to give Compound_. [Il-d] in which Q^lb is an alkyl. Examples of the nickel catalyst include dichloro [1, 1' -bis (diphenylphosphinb) ferrocene] - nickel (II), bis (triphenylphosphine) nickel (II) chloride, 1, 3-bis (diphenylphosphino) propane nickel chloride. Examples of the copper catalyst include cuprous bromide, cuprous chloride, cuprous cyanide, and the like. Any solvent may be used as long as it has no adverse effect on the reactions, and examples of such solvent include DME, THF, dioxane, toluene, benzene, and a mixture thereof. The present reaction generally proceeds at -78 to 150 °C, suitably at 0 to 100°C, for generally from 1 to 24 hours. [0057] • ,

Compound [Il-a] , Compound [Il-b], Compound [II-c], or Compound [Il-d] are reacted with Compound [III] in the same manner as in Method A to give the corresponding Compound

[I] . ^{■ '} [0058] . ^'

As Compound [II], the known compound may be used directly, or,- for example, .it may be produced by the preparation process -described in . the following publications. •2 (3H)-imidazolone: WO 03/35638 2-Oxo-3H-l,2,4-triazole: J. Heterocyclic Chem. , 23(8), 881(1986) 2-Oxodihydroxazole: JP 10-291982-A

3-Pyrazolone: Bioorg. Med. Chem. Lett., 1998, 8, 2689 2-Oxodihydropyridine: ^"WO 99/32448 4-Oxodihydropyrimidine: WO 98/24780, WO 99/28303 Pyrrole: WO 97/05877, WO 97/05878, WO 97/16^*442 Imidazole: WO 00/63204

Pyrazole: WO 98/56377, WO 99/58523, WO 02/72571 Oxazole: WO 95/13067, .WO 00/63204 Thiazole: JP 2001-114779-A, JP 2001-114690-A 1,2,4-triazole: WO 00/10563

Pyridine: WO 00/40243, WO 99/32448

Pyrazolo[l,5-a]pyridine: WO 02/16359

Pyrimidine: WO 97/33883

Pyridazine: Bioorg. Med. Chem. Lett., 20,02, 12, 689 Pyrazine: WO 00/25791

[Effects of the invention] [0059]

Compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an excellent p38 MAP kinase inhibitory activity, so that it. is useful for prophylaxis or treatment of diseases related to the active- tion of p38 MAP kinase and the excess production of inflammatory mediators concerned with p38.MAP kinase such as TNF- , .IL-1, etc. -Accordingly, Compound [I] of the present invention or^' a pharmaceutically acceptable salt thereof is useful for prophylaxis or treatment of diseases such as inflammatory diseases, etc., for example, arthritis (rheumatoid arthritis, osteoarthiritis, infectious arthritis, gouty arthritis, traumatic arthritis, synovitis, periarthritis, etc.), inflammatory bowel diseases (ulcera- tive colitis, Crohn's disease, etc.), inflammatory dermal diseases [psoriasis, • dermatitis (atopic dermatitis, contact dermatitis, urticaria, eczema, etc.), etc.], inflammatory respiratory diseases (asthma, bronchitis, pneumonia, pleurisy, pharyngitis, rhinitis, etc.), inflammatory eye diseases (conjunctivitis-, keratitis, uveitis, etc.), nephritis, hepatitis, systemic inflammatory diseases (Behςt's syndrome, systemic lupus erythematosus, etc.), shock ^• (septic shock, endotoxin shock, etc.), cerebro- vascular diseases (cerebral hemorrhage, cerebral infarc- tion, cerebral edema, etc.), ischemic heart diseases (angina, cardiac infarction, congestive heart failure, etc.), osteoporosis, multiple sclerosis, diabetes, malignant tumor, cachexia, Alzheimer's disease, Parkinson's disease, aquired immunodeficiency syndrome, arteriosclero- sis, disseminated intravascular coagulation syndrome, rejection by organ transplantation and graft versus host disease (GvHD) , etc..

[0060]

The preferred compound of the present invention or a pharmaceutically- acceptable salt thereof shows superior p38 MAP kinase inhibitory activity and has a strong therapeutic effect on inflammatory diseases such as arthritis, and also shows superior pharmacokinetic profile (e.g. good stability of metabolism, low side-effects, weak inhibitory effect of cytochro e P450) . [0061]

The - compound of the present invention or a pharmaceutically acceptable salt thereof can be formulated into • a pharmaceutical composition comprising a therapeutically effective amount of the compound and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is exemplified by a diluent, a binder (syrup, Gum Arabic, gelatin, sorbitol, tragacanth, polyvinylpyrroli- done) , an excipient (lactose, sucrose, corn starch, potas- sium phosphate, sorbitol, glycine.) , a lubricant (magnesium stearate, talc, polyethylene glycol, silica) , a disinter- grator (potato starch) and a wetting agent (sodium lauryl- sulfate) , and the like. [0062] Compound [I] of the present invention or a pharmaceutically acceptable salt thereof can be administrated orally or parenterally, and can be used as a suitable medicinal preparation. Examples of a. suitable medicinal preparation for oral administration include, for example, a solid preparation such as tablet, granule, capsule, powder, etc., or a liquid preparation, a suspension preparation or an emulsion preparation. Examples of a suitable medicinal preparation for parenteral administration include, for example, a sapository," an injection or an infusion prepa- ration each of which using distilled water for injection, physiological saline or an aqueous glucose solution, or an inhalant, etc. , [0063]

A dose of Compound [I] of the present invention or a pharmaceutically acceptable salt thereof may vary depending on an administration method, or an age, . body weight or ^• conditions of a patient, and generally preferably about

0.003 to 30 mg/kg per day, particularly preferably about

0.01 to 10 mg/kg per day. ■ [Examples] [0064]

In the following, the present invention is explained . in more detail by referring to Examples and Reference examples, but the present invention- is not limited.by • - , these. The following abbreviations used in the present specification mean the following, respectively.

Me.: methyl .

Et: ethyl

THF: tetrahydrofuran DMF: N, -dimethylformamide

DMSO: dimethylsulfoxide

Bn:- benzyl

Ns: 2-nitrobenzenesulfonyl

[0065] Example 1

( 3 ) - _, ( 4 )

(1) A mixture .comprising 112 mg of Compound (1) which can be prepared by the same method as described in WO 03/035638, 110 mg of Compound (2) and 3 ml of dioxane was stirred at 90 °C for 5 days. Water was added to the_. reaction mixture, and the mixture was extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. ^"After concentration under reduced pressure, the residue was •purified by silica gel- column chromatography (chloroform: methanol=19 : 1) to give 49 mg of Compound (3) as colorless crystals . MS: 507 ([M+H]⁺) [0066] (2) To 47 mg of Compound (3) were added 2 ml of methanol and 2^"6 μl of 4N hydrogen chloride-ethyl acetate solution, and the. mixture was stirred at room temperature for 5 ^■ ', minutes. The. reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the mixture and powder was collected by filtration to give 47 mg of Compound (4). MS: 507 ([M+H]⁺) .

[0067] .

Example

(1) To 10 ml of chloroform solution containing 500 mg of

- Compound (1) and 204 μl of- triethylamine was added dropwise 172 mg of' 4-chlorobutyryl chloride under ice-cooling-, and the mixture was stirred under, ice-cooling for an hour. The reaction mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over^' anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was crystallized from ethyl acetate to give 370 mg of Compound (2) as colorless crystals. MS: ^'515 ( [M+H]⁺) [0068] ,

(2) In 10 ml of N,N-dimethylacetamide was dissolved 360 mg - of Compound (2), and after adding 28.1 mg of sodium hydride (62.7% in oil) to the mixutre, the resulting mixture was stirred at -room temperature for an hour. Water was- added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol=19: 1) to give 263 mg of Compound (3) as colorless crystals. MS: ^'479 ■ ([M+H]⁺) . ^{' ''} [0069] ^"

(3) In the same manner as in Example 1(2), 253 mg of Compound (3) was treated to 'give 265 mg of hydrochloride of- Compound (3). MS: 479 ([M+H]⁺)

[0070] • Example 3

(1) ^'To 3 ml of chloroform solution containing 200 mg of Compound^' (1) and 102 μl of triethylamine was added dropwise 86.3 mg of 3-chloropropanesulfonyl chloride, and the - ^' mixture was stirred at room temperature for an hour. The .reaction mixture -was washed with water, and dried over anhydrous magnesium sulfate.. After concentration under reduced pressure, the residue was_. crystallized from ethyl acetate to give 180 mg of Compound (2) as colorless crystals. MS: 551 ([M+H]⁺) [0071]

(2) In 20 ml of THF was dissolved 173 mg of Compound (2), 47.5 mg of potassium tert-butoxide was added to the solution, and the mixture was stirred 'at room temperature overnight. Water was -added to the reaction mixture and the resulting mixture was extracted .with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol=19: 1) to give 77.9. mg of Compound (3) as colorless crystals.. MS-: 515 ([M+H]⁺)^' [0072]^{' •}

(3) In the same manner as in Example 1(2), 75 mg of Compound (3) was treated ^'to give 65 mg^' of hydrochloride of Compound (3). MS: 515 ([ +H]⁺) [0073] Example ^'4

(1) To 3 ml of chloroform solution containing 150 mg of Compound (1) and 76.4 μl of triethylamine was added drop- wise 52.2 mg of 2-chloroethyl chloroformate under ice- cooling, and the mixture was stirred under ice-cooling for 30 minutes. The mixture was washed with water, and dried over anhydrous magnesium sulfate.^' After concentration under reduced pressure, the residue was crystallized from ethyl acetate. to give 130 mg of Compound (2) as colorless crystals. MS: 517 ([M+H]⁺) [0074]

(2) In 3 ml of THF was dissolved 125 mg of Compound (2), 47.5 mg of potassium tert-butoxide was added to the solution, and the mixture was stirred at room temperature overnight. Water was. added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The . extract was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol=l? : 1) to give 80.1 mg of Compound (3) as colorless crystals. MS: 481 ([M+H]⁺) '[0075] ^' . ^•

(3) In the same manner as in Example 1(2), 76 mg of " Compound (3) was treated to give 64 m.g of a hydrochloride of Compound (3). MS: 481 ([M+H]⁺) [0076] Example 5

To 6.0 ml of dichloromethane solution containing 300 mg of Compound (1) which can be prepared by the same method as described in WO 03/035638, and 0.185 ml of triethylamine

• 5 was added dropwise under ice-cooling 1.0 ml of dichloromethane solution containing 105-mg'of 2-chloroethylisocyan- ate, and the mixture was stirred under ice-cooling for 15^' minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was

10 extracted with chloroform. 'The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained crude product was dissolved in 6.0 ml of DMF, 84 mg of sodium hydride (62.7% in oil) was added to the solution,

15 and the resulting mixture was stirred at 60°C for 20 hours. .Saturated aqueous sodium bicarbonate solution was added -to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous

20 sodium sulfate. After concentration under reduced pressure, the residue was- purified by NH silica gel column chromatography (ethyl acetate: methanol=2^'4 : 1) , ^'and crystallized from chloroform-ethyl acetate to give 70.0 mg of Compoμnd (2) as colorless crystals. MS: 522 ([M+H]⁺)

25 [0077]

Example 6

-In a mixed solvent of 1.0 ml of THF and 0.25 ml of water were dissolved 136 mg of Compound (1), 47.2 mg of bis (2-chloroethyl) ether, 104- mg of potassium carbonate and 45 mg of sodium iodide, and the mixture was refluxed for 7 days. After cooling by allowing to stand, the reaction^' mixture was concentrated under reduced pressure. Water was^' added to the residue, the mixture was extracted with chloroform, and dried over anhydrous sodium sulfate. After concentration under reduced .pressure, the residue was purified by silica gel^' column chromatography (chloroform: methanol=19 : 1) , and then, treated by using hydrochloric acid in the same manner as in Example 1(2) to give 68.0 mg of Compound (2) as pale yellow crystals. MS: 523 ([M+H]⁺) [0078]

Example 7

(1) (2)

(1) To 3 ml of chloroform solution containing 100 mg of - Compound (1) which can be prepared by the same method, as described. in WO 03/035638 and 52.7 μl of triethylamine was added dropwise 50.7 mg of thiophene 2-sulfonyl chloride, and the mixture was stirred at room temperature overnight.- The mixture was washed with water, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was crystallized from ethyl acetate to give 110 mg of Compound (2) as colorless crystals. (2) In the same manner as in Example 1(2), 107 mg of Compound (2) was treated to give 108 mg of a hydrochloride 5 of Compound (2). MS: 543 ([M+H]⁺) [0079] Examples 8 to 54

In the same manner as mention in the above Examples, the following .compounds were prepared. 10_. [0080]

Example R³ Ring C MS([M+H]⁺)

17* — C° "γ 521

O

18^* — C⁰ ' ° 523

. O

*: monohydrochloride, **: dihydrochlόride

[0081]

Example R Ring C MS([M+H]⁺)

22* X 475

24* X •^°>_Λ 529

O O

27* x> 527 o*^S o

*: monohydrochloride, **: dihydrochloride 2]

Example R¹ Ring C MS([M+H]⁺)

34* Me ^"~^N-_S 553 o" "O

35* CI — IN, J 573 o'^AV

36* Me -^Nv.O . 519

O

37* CI -^N?° 539

41** CI -N O 539 monohydrochloride, **: dihydrochloride] ■

Example R³ Ring C MS([M+H]⁺)

O.

46^* — ( "^{N 521}

O

47^* /— ( '^NX ⁵³⁵

O O.

48^* — jD -^N < 563

O

. * : monohydrochloride [0084]

Example Y Ring C MS([M+Hf)

Me

51* SO, 556

Me^'

52* SO, -o 537 53* SO, 587

54* CO — «T) 502

* : monohydrochloride [0085] Example 55

Compound (1) which can be prepared by the same method, as described in WO 03/035638 and Compound (4) of Reference example 1 were treated in the same manner as in Example 1 to give Compound (2). MS: 52Ϊ([M+H]⁺) [0086] Example 56

(1) In accordance with the method described in -Tetrahedron Lett., 1995, 6373-74, etc., 1.1 g of Compound (1) (which can be prepared by the same method as described in WO 03/035638), 900 mg of N, N-bis- (2-chloroethyl) -2-nitro- benzenesulfonamide, 860 mg of potassium carbonate and 345 mg .of sodium iodide were dissolved in a mixed solvent of 7.5 ml of ethanol and 1/9 ml of water, and the mixture was stirred under microwave irradiation at 150 °C for 75 minutes. After concentration under reduced pressure, water was added to the residue, the mixture was extracted with chloroform, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography^'" (chloroform: methanol=93 : 7) to .give 578 mg of Compound (2) as pale yellow powder. MS: 703 ( [M+H] ⁺) [0087] "

(2) In 3 ml of DMF were dissolved 550 mg of Compound (2), 216 mg^' of potassium carbonate and 97 mg of thiophenol, and the mixture was stirred at room temperature for an hour.

Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column • chromatography (chloroform: methanol=93 : 7) to give 338 mg of Compound (3) as pale yellow powder. MS: 518 ( [M+H]⁺) [0088] Example 57

To ^'2 ml 'of dichloromethane solution obtaining 52 mg of Compound (1) was. ^'added dropwise 14 mg of methanesulfonyl chloride, and the mixture was stirred at room temperature for 15 minutes.. Saturated aqueous sodium bicarbonate solution^" was added to the reaction mixture, and the resulting mixture was extracted with chloroform, and dried over anhydrous magnesium sulfate. After concentration .under reduced pressure, the residue was crystallized from ethyl acetate-diisopropyl ether to give 57 mg of Compound (2) as pale yellow crystals. MS: 596([M+H]⁺) [0089]

Example - 58

To 2 ml of dichloromethane solution containing 80 mg of Compound (1) was added dropwise 9.4 mg of acetyl chloride, -and the mixture was stirred at room temperature for 15 minutes. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the resulting - mixture was extracted with chloroform, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was crystallized from ethyl acetate-diisopropyl ether to give 77 mg of Compound (2) as pale yellow crystals. MS: 560([M+H]⁺) [0090] Example 5-9

In 1 ml -of methanol were dissolved 52 mg of Compound (1)^' and 11 mg of sodium cyanoborohydride, then, 10 mg of IN aqueous hydrochloric acid and 13 mg of formalin were added dropwise -to the solution, and the resulting mixture was stirred at room temperature for 40 minutes. After concen- tration under reduced pressure, aqueous ammonia was added to the residue, the mixture was extracted with chloroform, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol= 75:25) to give 35 mg of Compound (2). as pale yellow powder. MS: 532 ([M+H]⁺) [0091]-

Example 60 .

To 2 ml of DMF solution containing 52 mg of Compound (1) was added dropwise 19 mg of iodoethane, and the mixture was stirred .at room temperature for 5 minutes. After concentration under reduced pressure, water was added to the residue, and the resulting mixture was extracted- with chloroform and dried over anhydrous magnesium sulfate. • After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol=97 : 3) to give 38 mg .of Compound (2) as pale yellow powder.

MS: 546 ([M+H]⁺) , [0092] Examples 61 to 83

-In the same manner as in the above-mentioned Examples by using Compound (4) obtained in Reference example 1 and corresponding starting compounds, the following compounds were- prepared.

Example R¹ Ring C MS([M+H]⁺)

61 4-F DIN r> 521

67 4-F ^•"UN N-Boc 622

,5-OH

69 4-F "'0 537

71 4-F ^••MIN NH 536

O

* : monohydrochloride 3] r

Example Ring C MS([M+H]⁺)

73 — N~o 521

75 — N^O 507

[0094]

Example R¹ R³ Ring C MS([M+H]⁺)

v OH

7788 Me -Ό . 491

_ΛOH^'

79 Me v OH

Me -? 505

80

_ -Ώ 541 o""⁰

_\OH _/-v.

83 Me _^V— . — N^N-COMe 548

[0095] ^■ Example 84

(1 ) (2)

In 2.5 ml of 1,4-dioxane were dissolved 90 mg of Compound (1) which is prepared by reference example 4 and 64.mg of trans-4-morpholin-4-yl-cyclohexylamine, and the mixture was stirred at 90 °-C for 144 hours. After cooling by allowing to stand, Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the resulting mixture was extracted with chloroform and dried over anhydrous- magnesium .sulfate. After concentration under reduced pressure, the residue was purified by NH-silica gel column chromatography (hexane: ethyl . acetate= 50:50 -> 0:100). After concentration under reduced pressure, the residue was crystallized from ethyl acetate to give 44 mg of Compound (2) as pale yellowish crystals. MS: 481 UM+H]⁺) [0096] . >

Example 85

( 2 )

In the same manner as in example 84, 214 mg of Compound (1) , which was prepared by reference example 5,_. was reacted and treated to give 172 mg of Compound (2) as -colorless 'crystals. • ^• >

MS:- 5^'48 ( [M+H]⁺) [0097] -

Example 86 ^{' •}

CD ^{( 2 )}

Raney-Ni was added to a solution of 141 mg of

Compound (1) in 7N ammonia-methanol at room temperature, and the mixture was stirred at room temperature for 20 hours under hydrogen flow. After removing the catalyst, the filtrate was concentrated under reduced pressure.. - Chloroform was added to the residue and the mixture was dried .over anhydrous sodium sulfate. After concentration under reduced pressure, the crude product was purified by NH silica gel column chromatography (chloroform: methanol= 19:1) and crystallized from chloroform-ethyl acetate to give 80.0 mg of Compound (2) as colorless crystals. MS: 552 ( [M+H]⁺) [0098]

Examples 87 to 136

The following compounds were prepared by carrying out a reaction and a treatment in the same manner as in the above-mentioned Examples.

Example R RingC Q R³ MS([M+H]⁺)

87 3-Me -"UN N-Me H -Q^{3 532}

92 3-Me ^■"UN O CN Et 488 93 3-Me •■UN O CN Et 502

94 3-Me /"H ^— OH H -Q^{3 533} 95 4-F ^•"IIN N-Me H -Q^{3 550}

96 4-F ""O H -Q^{3 535}

Example R¹ RingC Q¹ R³ MS([M+H]⁺)

^--OH

98 3-Me ^■" - H - 533

99 3-Me ^■"" H -o> 517

100 4-F ^■'HIN^_ N-COMe H o 564

101 4-F ^■'UlN^^N-SOzMe H - 600

^OH

_,106 4-F ^■" Me Et^' 495

107 3-Me ^•■ιllN^~0 Me

X - 547

109 3-Me v°

^■""G Me -O 567

Example Q¹ Ring C MS([M+H]⁺)

112 Me — N N-Me 504

113 Me -O 489

[0101]

Example R¹ R³ Q¹ Ring C MS([M+H]^÷)

116 4-F — C° Me ^~N^ 535

120 3-Me — ζ - Me -N^-OH 547.

121 3-Me - _P Me -N NH 546

122 3-Me. — / ^ Me _ ^<VN°^""Y ' 525 =

123 3-Me — ^ ^' Me -N~ > 491

124^. 4-F "O^{3 Me -}C° ⁵³⁷

125 3-Me —{^^{3 Me} -r^χf l-COMe 574.

126 3-Me —^ ^{3 Me} →T l-S0₂Me 610

[0102]

Example R¹ R³ Q¹ Ring C MS([M+H]⁺)

132 3-Me ~(^J Me — * ) 531

O

133 3-Me. ^"Y?" Me -N^O 535 p

134 4-F ^~ _P ^{Me -N N_Me} - 564

135 4-F — (^~ > Me — N^~ l-Me 550^' o 136 4.F — < p H -N > 535

[0103]

The following- compounds are prepared by carrying out a reaction and a treatment in the same manner as in the^' above-mentioned Examples.

-N N- -OOHH

[0104]

^N^ -N^ ^{OH •}-N^V^0Me^N' '^0Et

O O O

^N NMe^N NEt or "-N O \ I \_

[0105]

106]

[0107]

The following compound (I-l) to compound (1-69) are prepared by carrying out a reaction and a treatment in the same manner as in the above-mentioned Examples.

[0108]

[0109]

[0110]

44) (1-45)

[0111]

[0112]

[0113]

O O O o o O '

X X X "s A

-N NH ^N NMe^N NEt ^^NX_) or ^N O 114]

[0115 ]

Reference example 1

Bn₂N-<^ =0 _*- Bn₂N- ^ N^> + Bn₂N- ^ -N ^

(1) (2) (1) A mixture of 10 g of 4-dibenzylaminocyclohexanone, 3.19 g of piperidine,' ^'2.93 ml of acetic acid and 100 ml of 1,2- dichloroethane was stirred at room temperature for 20 minutes, then, 8.67 g of sodium triacetoxyborohydride was added to the mixture and the resulting mixture was stirred overnight. After saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the resulting mixture was stirred for an hour. The organic layer was separated and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate =10:1) to give 3.10 g of Compound (1) and 6.37 g of Compound (2) as colorless solid. Compound (1): MS: 363 ([M+H]⁺) Compound (2):^' MS: 363 ([M+H]⁺) BnzN-^ N^> »- H₂N-<^ N^>

(1) (3) . ^'

Bn₂N-^ -N^ - — >- H₂N-<^ -N^>

(2) (4)

[ 0116]

(2) In a mixed solvent of 20 ml of methanol and 10 ml of THF was dissolved 2.92 g of Compound (1), 0.8 g of 10% palladium carbon was added to the solution, and the mixture was stirred at room temperature overnight under hydrogen flow. Insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure to give 1.30 g of Compound (3) as colorless solid. MS: 183([M+H]⁺) Compound (2) was reacted and treated in the same manner as mentioned above to give 1.30 g of Compound (4) as pale yellowish oily substance. MS: 183 ([M+H]⁺)

[0117]

Reference example 2

( 1 ) . ^' ( 2 )

In 400 ml of chloroform was dissolved 33.0 g of Compound (1) which can be prepared by the same method as described in WO 03/035638, 36.5 g of N-bromosuccinimide was added thereto and the mixture was stirred at room tempera- ture for 7 hours. To the reaction mixture was added 10% aqueous sodium thiosulfate solution, the mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate= 67:33 -> 62:38) to give 16.7 g of Compound (2) as pale yellowish crystals .

MS : 409 , 411 C[M+H] ⁺)

[ 0118 ]

Reference example 3

(1) .(2)

In 1,4-dioxane were suspended 6.1 g of Compound (1), 1.4 g of methylboronic acid, 613 mg of [1, 1' -bis (diphenyl- phosphino) ferrocene] dichloropalladium methylene chloride complex and 9.8 g of cesium carbonate, and the mixture was stirred at 80°C for 13 hours. After cooling by allowing to stand, water was added to the reaction mixture, the resulting mixture was extracted- with ethyl^' acetate and the extract was dried over anhydrous magnesium sulfate.^" After concentration under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate= 50:50 -> 10:90). After concentration under reduced pressure, the residue was crystallized from isopropyl ether to give 4.5 g of Compound (2) as pale yellowish crystals . MS: 345 ([M+H]⁺) [-0119] Reference example 4

(1) . (2)

In 40 ml of chloroform was dissolved 3.4 g of Compound (1), 3.9 g of m-chloroperbenzoic acid was dropwise added thereto and the mixture was stirred for 5 minutes under ice-cooling. The mixture was stirred at room temperature for 45 minutes, and to the reaction solution were added 10% aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol= 99:1 -> 94:6) to give 3.0^' g of Compound (2) as a pale yellowish powder. MS: 361 ([M+H]⁺) [0120] Reference example.5

(1) Compound (1) was reacted and treated in the same manner as in Reference example 2 to give Compound (2) as pale yellowish crystals. MS:. 465, 467 f[M+H]⁺)

(2) To a solution of 20.94 g of Compound (2) in 180 ml of DMF was added 2.65 g of sodium cyanide at room temperature and the mixture was stirred at ^'90°C for 26. hours. After cooling by allowing to stand, saturated aqueous sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained crude product was crystallized from ethyl acetate-diethyl ether to give 12.85 g of Compound (3) as pale yellowish crystals. MS: 412 ([M+H]⁺)

(3) Compound (3) was reacted and treated^' in the same manner as in Reference example 4 to give Compound (4) as colorless crystals.

^"MS: 428 ([M+H]⁺) [0121]

Experimental example 1 (Pharmacological test) : Inhibitory effects on lipo-polysaccharide (LPS) induced TNF-α production in rat ( In vivo)

This test is a method to assess the inhibitory effects of the compounds of the present invention against TNF-α production- induced by LPS in rats.

Rats (LEW/Crj, 6-8 weeks-old, female, available from Charles River Japan, Inc.) were administered with a test compounds (5 mg/kg, p.o.) dissolved by 0.5% methylcellulose, and 0.2% PEG-60 hydrogenated castor oil (HCO60, available from IKKO CHEMICALS, Co., Ltd.), and after 30 minutes, LPS (E. coli 0111 :B4, available from SI.GMA, the final concen- tration was adjusted to 0.16 mg/ml by a phosphate buffered physiological saline solution, 6.25 ml/kg, i.p.) was inoculated to rats. After 90 minutes, blood was collected from abdominal vein under diethyl ether anesthesia. The collected blood was centrifuged at 3000g, and serum was recovered. TNF-α in the serum was measured by ELISA (rat TNF-α ELISA Development_. Kits, available from genzyme TECHNE) .

As a result, as shown in the following table, the following compounds of Examples of the present invention inhibited significantly production of TNF-α. [0122]

Table 1

Industrial applicability [0123]

The ' compound or a pharmaceutically acceptable salt thereof of the present invention has an excellent p38 MAP kinase inhibitory activity, so that an agent for prophylaxis or treatment of diseases to which ,p38 MAP kinase pertains can be provided.

Claims

Claims

1. A compound of the formula [I]

wherein R¹ is- hydrogen, a halogen, nitro, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted amino, an optionally substituted carbamoyl, hydroxy or cyano, p is 1 or 2, provided that when p is 2, two R¹s may be the same or different from each other,

Z is oxygen atom or -N(R²)-,'

R² is hydrogen, an alkyl or an alkanoyl,

Ring A is a ring selected from the ^• following formulae :

R³, R⁴, R⁶, R⁷, R¹⁰ and R¹² may be the same or different from each other, and each is (CH₂)_n-R^A, R^A is hydrogen, an optionally substituted alkyl, an optionally substituted alkoxyalkyl, an optionally 5 " substituted cycloalkyl, an optionally substituted phenyl or an optionally substituted heterocyclic group, n is 0 or an integer of 1 to 4, R⁵, R⁸, R⁹, R¹¹ and R¹³ to R²⁴ may be the same or

10 different from each other, and each is hydrogen, a^' halogen, an optionally substituted alkyl, alkoxy, alkanoyl, an alkoxycarbonyl, an optionally substituted amino, an optionally substituted carbamoyl, an optionally substituted cycloalkyl, an

15 optionally substituted aryl or an optionally substituted heterocyclic group,

Q¹ is hydrogen, a halogen, cyano, an optionally • substituted alkyl or an optionally substituted heterocyclic group,

20 Ring B is a cycloalkane or a monocyclic saturated nitrogen-containing heterocyclic ring, . X is.CH or N,

Y is a single bond, S0₂ or CO,

Ring C is an aromatic hydrocarbon ring or an

■25 optionally substituted heterocyclic ring, or a pharmaceutically acceptable salt thereof. '

2. The compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein Ring A is

wherein R³ and Q¹ have the same meanings as defined in claim 1.

3. The compound or a pharmaceutically acceptable salt thereof according to Claim 1 or 2, wherein Z is -N(R²)- and R² has the same meaning as defined in claim 1.^'

4. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 3, wherein R² is hydrogen.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 4, wherein Ring B is a C₅_₇ cycloalkane.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 5, wherein Ring B is cyclohexane.

,

7. The compound or a pharmaceutically acceptable salt thereof according to Claim 5 or 6, wherein Y is a single bond.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 5 to 7, wherein Ring. C is a heterocyclic ring which may be substituted by 1-to 3 groups independently selected from oxo, an alkyl, alkanoyl, alkylsulfonyl, alkoxycarbonyl, hydroxy and an optionally substituted amino.

9. The compound or a pharmaceutically acceptable salt

, thereof according to any one of Claims 5 to 8, wherein Ring C is a ring selected from the following formulae:

wherein R²⁵, R²⁶, R³¹ to R³⁷ and R⁴¹ may be the same or different from each other, and each is hydrogen, an alkyl, hydroxy, an alkoxy or an alkoxyalkyl, R²⁷ to R³⁰, R³⁸ and R³⁹.may be the same or different from each other, and each is hydrogen, an alkyl or an amino- protective group.

' 10. The compound or a pharmace^'utically acceptable salt thereof according to any one of Claims 5 to 9, wherein Ring C is the

alkoxycarbonyl or an alkylsulfonyl, and other symbols have the same meanings as defined in claim 9.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 10, wherein R¹ is a halogen or an optionally substituted alkyl.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11, wherein R¹ is chlorine, fluorine, methyl or trifluoromethyl .

13. The compound or a^' pharmaceutically acceptable salt thereof according to any one . of Claims- 1 to 12, wherein p is 1, and the binding position of R¹ is 4-position or 3- position. -

14.. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 12, wherein p is 1, and the binding position of R¹ is 3-position.

15. The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 14, wherein R^A is an optionally substituted alkyl, an optionally substituted heterocyclic group, phenyl or a cycloalkyl, and n is 0 or 1.

16. The compound or a pharmaceutically acceptable- salt thereof according to^" any one- of Claims 1 to 15, wherein R^A is 4-tetrahydropyranyl and n is 0.

17. A compound of the. formula:

wherein R^la is a halogen or an optionally substituted alkyl, p is 1 or 2, provided that when p is 2, two R^las may "be the same or different from each other,

R² is hydrogen, an alkyl or an alkanoyl,

R^B is an optionally substituted alkyl or an optionally substituted heterocyclic group,

Q¹ is hydrogen, a halogen, cyano, an optionally substituted alkyl or an optionally substituted heterocyclic. group,

Ring B¹ is a cycloalkane,

X is CH or N,

Ring C¹ is an optionally substituted heterocyclic , . ring, or a pharmaceutically acceptable salt thereof.