TW200911240A - Anti-tumor agent - Google Patents

Abstract

Disclosed is are: an anti-tumor agent comprising, as an active ingredient, a pyrazole derivative represented by the formula (I) [wherein R1 represents an aryl which may have a substituent or the like; R2 represents a cyano or the like; R3 represents a hydrogen atom; R4 represents a hydrogen atom, a lower alkanoyl which may have a substituent or the like; R5 represents an aryl which may have a substituent or an aromatic heterocyclic group which may have a substituent; and X represents -NR9- (wherein R9 represents a hydrogen atom, a lower alkyl which may have a substituent or a lower alkoxycarbonyl which may have a substituent) or -S(O)n- (wherein n represents an integer of 0 to 2)] or a prodrug or pharmaceutically acceptable salt thereof; and others.

Description

[Technical Field] The present invention relates to an antitumor agent or the like, which comprises a pyrazole derivative or a lead drug thereof or a pharmaceutically acceptable salt thereof as an active ingredient. [Prior Art] Among the chemotherapy for cancer, various types such as a microtubule acting such as a taxane or a vinca alkaloid, a topoisomerase inhibitor, and an alkylating agent are used. Antitumor agent. However, these systems have problems with side effects such as bone marrow toxicity or neurological disorders or drug resistance, and new anti-tumor agents for improving the problem of the temple have been required. In the case of a compound having a 3-aminopyrazole structure in the pyran derivative, for example, a compound A which exhibits analgesic activity, antipyretic activity, and anti-inflammatory activity is known (see Non-Patent Document 1). In addition, a compound b (see Non-Patent Document 2), Compound C (see Non-Patent Document 3), and Compound D are known as a compound having a structure of a 3-aminopyrazole or a 3-thiopyrazole (see Non-Patent Document 3). Non-Patent Document 4), Compound E (see Non-Patent Document 5), Compound F (see Non-Patent Document 6), and compounds described in Patent Documents 1 to 6. 200911240

Patent Document 1: International Publication No. 98/5 294 1 pamphlet Patent Document 2: International Publication No. 9 Heart No. 1 345 pamphlet Patent Document 3: International Publication No. 00/7 1 5 3 No. 2 Patent Document 4: International Publication Patent Publication No. 90/002 1 8 Patent Document 5: International Publication No. 97" No. 704 pamphlet Patent Document 6: International Publication No. 20/4,776, pp. Non-Patent Document 1: Indian Journal of Pharmaceutical Science ), 61(1), P.25 - 2 8 '1999 Non-Patent Document 2: Archives of P harmaceutica 1 R esearch, 2 2 (6), p. 5 7 1 - 5 7 4 '1 9 9 9 Non-Patent Document 3: Phosphorous, Sulfur and Silicon, 175 volumes, ρ·1〇9-127, 2001 1 Non-Patent Document 4: Saudi Arabia J 〇urna 1 of Saudi Chemical Society ' 36 (47) Volume ' P-8641-8644 ' 1 995 200911240 Non-Patent Document 5 : Tetrahedron Letters ' 36 (47), ρ·8641-8644, 1995 Non-Patent Document 6: Chemical Journal (Chemis CheBerichte), 127(9), Vol., pp. 1 729- 1 73 3, 1 994. [Problems to be Solved by the Invention] An object of the present invention is to provide an antitumor agent or the like which contains pyrazole A derivative or a lead drug thereof or a pharmaceutically acceptable salt thereof is used as an active ingredient. [Method for Solving the Problem] The present invention relates to the following (1) to (24). (1) An antitumor agent system The pyrazole derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof is contained as an active ingredient, [Chemical 2]

[wherein R1 represents a cycloalkyl group which may have a substituent] an aromatic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or may have an aliphatic heterocyclic group, and R2 represents a cyano group a lower alkyl group which may have a substituent, a lower k-oxy group which may have a substituent of 200911240, an aromatic heterocyclic group which may have a substituent, COR (wherein R represents a thiol group, and may have a substituent a base group, a lower dilute group which may have a substituent, a lower-grade oxy group which may have a substituent, a aryl group which may have a substituent or an aryloxy group which may have a substituent, or CONRY (wherein R 7 and W are the same or Different from each other, a hydrogen atom, a lower-order h group which may have a substituent, a cycloalkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a lower alkenyl group which may have a substituent, may have a fragrance of a substituent Or an aliphatic heterocyclic group which may have a substituent, or R7 and R may form a nitrogen-containing heterocyclic group which may have a substituent together with a nitrogen atom adjacent thereto, R3 represents a hydrogen atom, and R4 represents a hydrogen atom; Lower alkyl alkane group having a substituent, which may have a substitution a lower alkoxycarbonyl group, an aromatic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aryl group which may have a substituent, and R5 represents an aromatic group which may have a substituent or may have a substitution The aromatic heterocyclic group of the group, X represents -nr9- (wherein r9 represents a hydrogen atom, a lower alkyl group which may have a substituent or a lower alkoxycarbonyl group which may have a substituent) or -S(〇) N-(where η represents an integer from 〇 to 2)]. (2) An antitumor agent comprising the pyrazole derivative (1) or a pharmaceutically acceptable salt thereof as an active ingredient. (3) The antitumor agent according to any one of (1) or (2) wherein, in the formula, NR9a- (wherein R9a represents a hydrogen atom or a lower alkyl group which may have a substituent). The antitumor agent according to any one of (1) or (2), wherein X is -S(0)n- (wherein the η is synonymous with the above). (5) The antitumor agent according to any one of (1) to (4) wherein r2 is a cyano group. (6) The antitumor agent according to any one of (1) to (4) wherein R2 is a CONR7R8 (wherein R7 and R8 are each synonymous with the above). (7) The antitumor agent according to any one of (1) to (6) wherein R4 is a hydrogen atom. (8) The antitumor agent according to any one of (1) to (7). An aromatic heterocyclic group which may have a substituent. (9) The antitumor agent according to any one of (1) to (8) wherein R1 is an aromatic group which may have a substituent. (10) A pyrazole derivative or a lead thereof or a pharmaceutically acceptable salt thereof, represented by formula (IA), [Chem. 3]

p3A

N-R^ (ΙΑ), ΧΑ Ν

\ d4A Μ-Π R1 [wherein R1A represents a cycloalkyl group which may have a substituent, an aromatic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aliphatic heterocyclic ring which may have a substituent The R2A group represents a cyano group, a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, and an aromatic heterogeneous group which may have a substituent _ 200911240 COR6Ai^f r+τ "中中' R6A Is a lower group in which a lower alkane 1 which may have a substituent has a substituent, a lower alkoxy group which may have a substituent or an aryloxy group which may have a substituent) or C〇NR7aRsa (wherein, r7a and R) The same or different, representing a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a lower alkenyl group which may have a substituent, may have a substitution An aromatic group or an aliphatic heterocyclic group which may have a substituent, or R7 A and R8A may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom; r3a represents a hydrogen atom; r4A represents a hydrogen atom, a lower alkyl alkane group which may have a substituent, or a lower alkoxycarbonyl group of a substituent, an aromatic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aryl group which may have a substituent; r5a represents an aromatic group which may have a substituent or may have The aromatic heterocyclic group of the substituent; the xA group represents -nr9A- (wherein R 9A represents a hydrogen atom, a lower alkyl group which may have a substituent or a lower alkoxycarbonyl group which may have a substituent) or -S ( 0) nA- (where nA represents an integer from 0 to 2). However, (i) XA is -NH-' and R2a is ethoxycarbonyl, and when r4A is phenyl, R1A is not phenyl, 2-ethoxyphenyl or 4-(diethylamine sulfonyl) Phenyl, (ii) XA is -NH-, and when the ruler is 6-(4-methylphenyl)pyridazinyl, R1A is not phenyl' (iii) XA is -NH-' and R2A is an amine When a fluorenyl group, and r5A is a phenyl group, R1A is not a 2-ethoxyphenyl group or a 4-(diethylamine sulfonyl) phenyl group, -10-200911240 (iv) XA is -NH-, and When R2A is an ethoxycarbonyl group, R5A is not a pyrazolyl group which may have a substituent, (v) XA is -NH-, and R2A is a cyano group or a methoxycarbonyl group, and RM is 1, 2, 3, 4 -tetrahydro-2,4-dioxo-5-pyrimidinyl, R5A is not phenyl or 4-nitrophenyl, (乂丨) and 4 is a sulfur atom, and R2A is a cyano group, and R5A is In the case of phenyl, R1A is not 3-methylphenyl, 4-chlorophenyl or phenyl, (vii) XA is a sulfur atom, and R2A is a cyano group, and when R5A is a 2-benzothiazolyl group, R1A is not Is 3-methylphenyl]. (1) The pyrazole derivative according to any one of (1) or the pharmaceutically acceptable pyrazole derivative according to any one of (1) or (1). Or a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein XA-S(〇)nA_ (wherein nA is synonymous with the foregoing). (1) The pyrazole derivative according to any one of (10) or (1), or a pharmaceutically acceptable salt thereof, wherein XA is _NR9A1_ (wherein R9A1 is represented by An ammonia atom or a lower alkyl group which may have a substituent). (14) The pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of (10) to (13), wherein R2A is a chloro group. (15) A pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of (10) to (13), wherein the formula is 1〇174 and r8A The pyrazole derivative or a pharmaceutically acceptable salt thereof, wherein R4A is a hydrogen atom, or a pharmaceutically acceptable salt thereof, according to any one of the above (10) to (I5), wherein the R4A is a hydrogen atom. -11 - 200911240 ( The pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (6), wherein R5A is an aromatic heterocyclic group which may have a substituent The pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of (1) to (1), wherein R1A is an aromatic group which may have a substituent. (19) A pharmaceutical preparation comprising the pyrazole derivative according to any one of (10) to (18) or a lead drug thereof or a pharmaceutically acceptable salt thereof as an active ingredient. The tumor agent is a pyrazole derivative according to any one of (10) to (18) or a lead drug thereof or a pharmaceutically acceptable salt thereof as effective (2) The therapeutic method of the tumor, which comprises the pyrazole derivative according to any one of (1) to (9) or a prodrug thereof or an pharmaceutically acceptable salt thereof (22) A pyrazole derivative according to any one of (1) to (9), or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of an antitumor agent. (23) A method for treating a tumor, comprising the step of administering an effective amount of the pyrazole derivative or the lead drug thereof or a pharmaceutically acceptable salt thereof according to any one of (10) to (18) (2 4) The use of a pyrazole derivative or a lead drug thereof or a pharmaceutically acceptable salt thereof as described in any one of (1 〇) to (1 8) is used for an antitumor agent [Effect of the Invention] According to the present invention, an antitumor agent or the like can be provided, and a drug or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof can be provided as an embodiment. Hereinafter, the formula (I) will be used. The compound represented by the formula is also the same as the compound of the other formula. In the definition of each group of the formula (I) The lower alkyl moiety of the alkyl group, the lower alkoxy group, the lower alkyl alkoxide group and the carbonyl group may, for example, be a linear or a number of alkyl groups having a number of 1 to 1 fluorene, and more specifically, a methyl group or an ethyl isopropyl group. Base, butyl, isobutyl, t-butyl, tert-butylpentyl, neopentyl, hexyl, heptyl, octyl, decyl, hydrazine: as the cycloalkyl group, for example, carbon number Specific examples of 3 to 8 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclic group, a cyclooctyl group, etc. Examples of the lower alkenyl group include a linear group or a branched group of 10 to 10 alkenyl groups. More specifically, it may, for example, be a vinyl group, an allyl group, a butenyl group, a pentenyl group, a hexenyl group, a heptenyl group, an octyl group or a fluorene group. The aryl group of the aryl group, the aryloxy group and the aryl fluorenyl group is exemplified by an aromatic group having 6 to 14 carbon atoms, and more specifically, an alkyl group, a fluorenyl group or the like. Further, 'aromatic, aryloxy and pyrazole derivative components. Compound (I). A lower alkoxy group, a branched carbon group, a propyl group, a 'pentyl group', and the like. a cycloalkyl group, which is a phenyl group or a naphthyl fluorenyl group, may be exemplified by a phenyl group or a naphthyl fluorenyl group. For example, an aromatic group condensed with a cycloalkyl group such as a dihydroindenyl group or a tetrahydronaphthyl group. The aliphatic heterocyclic group may, for example, be a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a 3 to 8 member ring condensation or snail. a condensed bicyclic or tricyclic ring and containing a fluorene-containing aliphatic heterocyclic group selected from a nitrogen atom, an oxygen atom and a sulfur atom of at least one atom, and more specifically, an aziridine group, an azetidinyl group, Pyrrole H-based, piperidino, piperidinyl, azaheptyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolyl, piperazine Azinyl, homopiperazinyl, pyrazolinyl, ethylene oxide, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, tetrahydro-2H-thiopyridyl Cyclol, chelate D, d-based, N-morpholinyl (m 〇rph ο I i η 〇), morpholine (morph ο 1 iny 1), thior-indole D-based, thiophenanthyl, 1-oxo -thiolaninyl, 1,1 -dioxo-thiomorpholinyl, 2 oxa-oxazolyl, 2 Η-thiazolyl, indanyl, dihydroisoindolyl, dihydrogen Benzofuranyl, benzimidazolyl, dihydrobenzoxazole , dihydrobenzothiazolyl, benzodioxolanyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, dihydro-2-indole-chromoalkyl, dihydro-1 fluorene-chromoalkyl, two Hydrogen-2Η-thiochroman, dihydro-1Η-thiochroman, tetrahydroquinoxaline, tetrahydroquinazolinyl, dihydrobenzodioxan, 2,3-dihydro Snail [茚-1,4'-piperidinyl]-yl and the like. The aromatic heterocyclic group may, for example, be a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom; a bicyclic or tricyclic ring, and a condensed aromatic heterocyclic group-14-200911240 or the like selected from a nitrogen atom, an oxygen atom and a sulfur atom of at least one atom, and more specifically, a furyl group, a thienyl group, Shame, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazinyl, thiadiazolidinyl, tridecyl, tetradecyl, stilbene, -azinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, isodecyl, fluorenyl , carbazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, thiazolopyridyl, pyrrolopyridyl, pyrrolopyrimidinyl, imidazopyridyl, fluorenyl, Quinolinyl, isoquinolinyl, porphyrin, pyridazinyl, quinazolinyl, quinoxalinyl, naphthyridyl ' 6,7-dihydro[1,4]dioxy[ 2,3-f]benzothiazolyl, naphtho[l,2-d]thiazolyl, 4,5,6,7-tetrahydrobenzothiazolyl, 4,5,6,7-tetrahydrothiazolium [5,4-(:]pyridyl, 6,7-dihydro-4^1-indole-pyrano[4,3-(1]thianyl, 6,7-monohydro-411-sulfanyl ratio喃[4,3-called thiazolyl, 5,7-dihydro-4}1-spiro[benzothiazole-6,2'-[1,3]dioxolan]-yl, 5,6, 7,8-tetrahydro-4H-cyclohepta[d]thiazolyl, thiazolo[5,4-b]pyridinyl, 5,6-dihydro-4H-cyclohepta[d]thiazolyl, etc. The nitrogen-containing heterocyclic group formed by the nitrogen atom together may, for example, be a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group may also contain other nitrogen) a cyclized heterocyclic group having a dicyclic or tricyclic nature of a 3 to 8 membered ring condensed and containing at least one nitrogen atom (the condensed heterocyclic group may also contain other nitrogen) Specific examples of the atom, an oxygen atom or a sulfur atom include an aziridine group, a butyl group, a pyrrolidinyl group, a piperidinyl-1 group, an azaheptyl group, a pyrrolyl group, and an imidazole group. Imidazolyl, pyrazolyl, pyrazolinyl, pyrazolyl, piperazinyl, high piperazine Base, oxazolidinyl, 2 Η-oxazolyl, thiazolidine, 2 Η-thiazol-15- 200911240 base, morpholinyl, thiomorpholinyl, indanyl, dihydroiso Sulfhydryl, fluorenyl, isodecyl, tetrahydroquinolyl, tetrahydroisoquinolinyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, benzimidazolyl, benzene Imidazolyl, dihydrocarbazolyl, oxazolyl, benzotriazolyl, pyrrolopyridyl, pyrrolopyrimidinyl, imidazopyridyl, indolyl, etc. lower alkyl which may have a substituent a lower alkenyl group having a substituent, a lower alkoxy group which may have a substituent, a lower alkyl fluorenyl group which may have a substituent, a lower alkoxycarbonyl group which may have a substituent, a cycloalkyl group which may have a substituent, may have The substituent (A) in the nitrogen-containing heterocyclic group which may have a substituent formed by the aliphatic heterocyclic group of the substituent and the adjacent nitrogen atom may be the same or different, and for example, the substitution number 1 may be mentioned. ～3, selected from the group consisting of an oxy group, a halogen, a hydroxyl group, a sulfonyl group, a nitro group, a cyano group, a carboxyl group, an amine carbenyl group, and a Ci-i group which may have a substituent Oalkyl group, which may have a substituent (: 3-8 cycloalkyl group, a C6-14 aryl group which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aromatic heterocyclic group which may have a substituent, may have a substitution a Cl-ίο alkoxy group, a [3-8 ring-oxime oxy group which may have a substituent, a c6-14 aryloxy group which may have a substituent, a c7-16 aralkyloxy group which may have a substituent, and a C2 which may have a substituent -u alkyloxy, c7.15 aryloxy which may have a substituent, Cl_1Q alkylsulfonyl which may have a substituent, -NRXRY (wherein Rx and rY are the same or different 'is a hydrogen atom And a C6.M aromatic group which may have a substituent, an aliphatic heterocyclic group which may have a substituent, an aromatic heterocyclic group, C2. η alkanoyl group which may have a substituent, 5 aryl fluorenyl group which may have a substituent, C^u alkoxy-16-200911240 carbonyl group which may have a substituent or c8-17 aralkyloxy group which may have a substituent a carbonyl group, an alkylsulfonyl group which may have a substituent, a Cm alkano group which may have a substituent, a C7.15 aryl fluorenyl group which may have a substituent, Ch! which may have a substituent, an alkoxycarbonyl group, a c7-15 aryloxycarbonyl group which may have a substituent, a Cl. 1() alkylaminecarbamyl group which may have a substituent, and a second compound which may have a substituent A substituent in a group consisting of a carbamine group. The same may be the same for the aromatic group which may have a substituent, the aryl group which may have a substituent, the aryloxy group which may have a substituent, and the substituent (B) in the aromatic heterocyclic group which may have a substituent Different from each other, for example, the substituents i to 3 are selected from the group consisting of halogen, hydroxy, sulfonyl, nitro, cyano, decyl, residue, amine mercapto, methylenedioxy, and ethylene. An oxy group, a ChM alkyl group which may have a substituent, a c2_1() alkenyl group which may have a substituent, a trifluoromethyl group which may have a substituent, a c38 cycloalkyl group which may have a substituent, and a ce_M aroma which may have a substituent a Cl_IQ alkoxy group which may have a substituent, a C3-8 cycloalkoxy group which may have a substituent, a c6.14 aryloxy group which may have a substituent, an alkyloxy group which may have a substituent, may have a substitution a C7_15 aryloxy group, a C1_1()alkylsulfonyl group which may have a substituent, a Cmo-based sulfonyl group which may have a substituent, -D-NRX1RY1 (wherein D represents a single bond, or a sulfonate) a mercapto group, RX1 and RYi are synonymous with the above Rx and Ry, respectively, a Cm alkanoyl group which may have a substituent, a c7-15 aryl group which may have a substituent, C2-n alkoxycarbonyl group having a substituent, c^5 aryloxycarboyl group which may have a substituent, cllG alkylaminecarbamyl group which may have a substituent, dinonylamino group which may have a substituent An anthracene group, an aliphatic heterocyclic group which may have a substituent, an aliphatic heterocyclic carbonyl group which may have a substituent, an aromatic heterocyclic group which may have a substituent of -17 to 200911240, an aromatic heteroepoxy group which may have a substituent Substituents in the group formed by the group. Further, the 3rd position and the 4th position of the 'aromatic group which may have a substituent are not the same as the alkyl sulfonyl group which may be substituted with a hydroxy'sulfonyl group, a substituent which may have a substituent, or A phenyl group substituted with a different substituent. With respect to the substituent (c) in the substituents (A) and (B), the same or different 'is exemplified by, for example, a substitution number of 1 to 3 selected from the group consisting of a methyl group, an oxy group, a halogen group, a hydroxyl group, and a sulfonium group. Base, nitro, cyano, carboxyl, amine carbaryl, Cl l() fluorenyl, difluoromethyl, C3·8 ring, Cn4 aryl, aliphatic heterocyclic group which may have a substituent Examples of the substituent include cu, a Q-based group, a C2-11 alkoxycarbonyl group, a hydroxy C1〇D alkenyl group (alkylenyl group, a trans group or a Cim aryl group), an aromatic heterocyclic group, and a Cl_1Q alkane. Oxyl, c3-8 ring oxime, C6_l4 aryloxy, C7.l6 aralkyloxy, c2-u alkanomethoxy, c7.15 aryloxy, (:, ·, decylsulfonyl) Base, Cuo alkylsulfonyl, Cl_1(), sulfonyloxy, -NRX2RY2 (wherein RX2 and RY2 are the same or different, and represent a hydrogen atom, a Cl-ίο垸 group, a sulfhydryl group) Dilute base, two Cuo j: complete amine group C^o courtyard dilute base, C3-8 ring yard base, Cn4 aromatic group, aliphatic heterocyclic group, aliphatic heterocyclic carbonyl group, aromatic heterocyclic group, c7_16 Fangyuan Base, C: 2-11 yard brewing base, C7_15 square brewing base, Cl-IQ yard base brewing base, a ChM alkoxy-ChH alkenyl group which may have a substituent (for the substituent, a fluorenyl group or a Cl-IQ alkoxy group), a C2-ll alkoxy group or a Cs-17 house Oxycarbonyl), Cn, alkanoyl, C7-, 5 aryl fluorenyl, c211 alkoxy fluorenyl, C^15 aryloxycarbonyl, a group of amine amines 可-18- 200911240 ( The substituent may be exemplified by a hydroxyl group, a C, a Q alkylamino group, a di C ii fluorenylalkyl group or an alkoxy group, which may have a substituent of a diCl 1()alkylaminecarbamyl group (the substituent may be used. a substituent in the group consisting of a hydroxyl group, an alkylamino group, a diCl 1()alkylamino group or a C 1 .1 G alkoxy group, or an aliphatic heterocyclic carbonyl group. The Cuo alkyl group represented herein, and Cmo alkoxy, Cmo alkylamino, di-Cmo alkylamino, c2_u alkyloxy, Cmo alkylsulfonic acid, Cl-ίο sulfonyl, C|-i Base, C2-I 醯, &, 丨丨 丨丨 丨丨 丨丨 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : The base moiety can be exemplified by the examples exemplified above for the lower alkyl group. The two C 0 alkyl groups of the i 0 alkylamino group and the di C i decylalkylcarbinyl group are the same or different. The c2_1() alkenyl group is exemplified by the above lower alkylene. The exemplified group is exemplified. The alkyl group of the C3-8 cycloalkyl group and the c3.8 cycloalkoxy group can be exemplified by the examples exemplified above for the cycloalkyl group. In the case of C6.14 aryl and C6-14 aryloxy, C7-16 aralkyl, C7-16 aralkyloxy, c8.17 aralkyloxycarbonyl, C7-15 aryl fluorenyl, C7-15 aryl fluorene The aryl group of the oxy group and the C7-1515 allyloxycarbonyl group can be exemplified by a group not enumerated as an example of the aforementioned aromatic group. C7-16 aralkyl, C7.16 aralkyloxy, hydroxyCl-oxaloalkenyl, di-Cm decylamino-C丨-decalkenyl, c-- ίο院--C2 - The sputum base, and the C 8 -, 7 aralkoxycarbonyl group are synonymous with the removal of one hydrogen atom from the aforementioned lower courtyard group. -19- 200911240 Halogen means each atom of fluorine, chlorine, bromine and hydrazine. The aliphatic heterocyclic group of the aliphatic heterocyclic group and the aliphatic heterocyclic carbonyl group, and the aromatic heterocyclic group of the aromatic heterocyclic group and the aromatic heterocyclic oxy group, respectively, are exemplified by the above aliphatic heterocyclic group. And the examples exemplified above for the aromatic heterocyclic group. In the respective groups of the compounds (I) and (IA), R1 is preferably an aliphatic group which may have a substituent or an aliphatic heterocyclic group which may have a substituent, and a phenyl group which may have a substituent is more preferable. The R2 is preferably a lower alkoxycarbonyl group, an amine carbenyl group or a cyano group, and a cyano group is preferred. Each of R3 and R4 is preferably a hydrogen atom, a lower alkyl group or a lower alkyl alkene group. R5 is preferably an aromatic heterocyclic group which may have a substituent. X is preferably -NH- or a sulfur atom. The pharmaceutically acceptable salt of the compound (I) includes, for example, a pharmaceutically acceptable acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, and the like. The pharmaceutically acceptable acid addition salt of the compound (1) may, for example, be a mineral acid salt such as a hydrochloride, a hydrobromide, a nitrate, a sulfate or a phosphate, an acetate, an oxalate or a Malay. An organic acid salt such as a salt, a fumarate, a citrate, a benzoate or a methanesulfonate. The pharmaceutically acceptable metal salt may, for example, be an alkali metal salt such as a sodium salt or a potassium salt. An alkaline earth metal salt such as a magnesium salt or a calcium salt, etc., as the pharmaceutically acceptable ammonium salt, for example, a salt such as ammonium or tetramethylammonium, in terms of a pharmaceutically acceptable organic amine addition salt For example, an addition -20-200911240 salt such as morpholine or piperidine may be mentioned, and in the case of a pharmaceutically acceptable amino acid addition salt, for example, lysine, glycine, phenylalanine, and asparagus may be mentioned. An addition salt of an amine acid, such as glutamic acid. The compound (I) is a compound which is converted into a compound (I) by a reaction such as an enzyme or a gastric acid in a living body. There are many types of synthetic methods that can be applied to the drug of the present invention, and a suitable method can be selected from well-known literature (see, for example, development of pharmaceutical products, Hirokawa Bookstore, Vol. 7 'P. 103, 1990). Compound (I) is synthesized as a lead drug. For example, the compound (I) can be exemplified by a compound in which the amine group is thiolated, alkylated, or phosphorylated in the case where the compound (I) has an amine group; and the compound (1) has a hydroxyl group. The compound wherein the hydroxyl group is subjected to thiolation, alkylation, phosphorylation or boration; and when the compound (I) has a carboxyl group, the carboxyl group thereof is esterified or amided. Further, the compound of the compound (I) may be any of a hydrate, a non-hydrate, and a solvent, and a pharmaceutically acceptable acid or a base and a salt may be formed in the same manner as the compound (I). The cancer of the anti-tumor agent of the present invention may, for example, be cancer caused by a hematopoietic organ tumor, breast cancer, endometrial cancer, cervical cancer, prostate cancer, bladder cancer, kidney cancer, stomach cancer, esophageal cancer, liver cancer, Biliary tract cancer, colorectal cancer, rectal cancer, pancreatic cancer, lung cancer, head and neck cancer, osteosarcoma, melanoma, cancer caused by brain tumors, etc. The hematopoietic organ tumor system means a tumor such as a blood cell, and the pathology caused by the blood cell is, for example, chronic myelogenous leukemia, acute myeloid leukemia, leukemia, multiple myeloma, and the like. - 200911240 Swelling and so on. The following is a description of the production method of the compound (1). Production Method 1 Preparation of Compound (I) The compound (IB) can be produced, for example, by the following steps.

[In the formula, R1, R2, R5 and X are synonymous with the above, respectively, γ-expressin, P-toluenesulfonyloxy, trifluoromethanesulfonyloxy, alkoxycarbonyloxy or -N2 + Ya — wherein Y is a halogen, a lower alkoxy BF 4 or the like, the alkoxy group of the alkoxy group, and the aryl moiety of the aryloxy group are each synonymous with the above, and the halogen and the lower alkoxy group are each Synonymous Compound (IB) can be obtained by reacting compound (11) with 1 to 10 equivalents of compound (III) in the presence of a base in a solvent. Examples of the base include potassium carbonate, sodium carbonate, lithium hydrogencarbonate, carbonic acid planer, sodium hydroxide, potassium hydroxide, potassium hydride, sodium, tripotassium phosphate, trisodium phosphate, triethylamine, hydrazine, hydrazine. -diisopropylacetamidine, hydrazine-dimethylaminopyridine (DMAP), 1,8-diazabicyclo[5.4.-1--7-ene (DBU), 1,5-diazabicyclo[4.3 .0] 壬-5-ene (DBN) -22- shows halogen, aryl, fluorenyl, the above-mentioned compound sodium, hydrogenated amine, 0] ten, preferably 200911240 for use 1 to 10 equivalents. As the solvent, for example, hydrazine, hydrazine-dimethylformamide (DMF), hydrazine, hydrazine-dimethylacetamide (DMA), acetonitrile, tetrahydrofuran (THF), hydrazine-methylpyrrolidone (NMP) may be mentioned. ), etc., these may be used singly or in combination. Alternatively, the reaction may be carried out in the presence of a copper catalyst as necessary. Examples of the copper catalyst include copper (I) iodide, copper (I) iodide, trimethyl phosphite complex, copper (I) bromide, and copper (I) bromide. Sulfide complex, copper (I) bromide, triphenylphosphine complex, copper (II) bromide, copper (I) chloride, copper (π) chloride, copper fluoride (11), copper oxide (I), copper (11) oxide, copper (I) cyanide, copper (I) acetate, copper (II) acetate, etc., copper (I) iodide is preferred. The copper catalyst is preferably used in an amount of 0.1 to 10 equivalents, preferably 0.1 to 1 equivalent, more preferably 0.1 to 3 equivalents. Further, in the case of using a copper catalyst, it is preferred to add a ligand at the same time, and a ligand is used, and W, for example, N,N'-monomethylethylenediamine, trans-Ν, Ν'-dimethylcyclohexane Alkyl-1,2-diamine, 1,10-morpholine, N,N'-dimethylethylenediamine are preferred. The ligand is preferably used in an amount of _ 1 to 1 equivalent, preferably 0.3 to 0.5 · equivalent. The reaction is usually carried out at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 24 hours. In addition, the compound (Π) can be based on well-known methods [e.g., Archives of Pharm. Res, Vol. 22(6), p. 571-574, 1999; Chem. Ber, 127 (9) Vol. 1, p. 1729-1733, 1994; Comprehensive Organic Transformations, second editi ο η, R. C. L arock -23- 200911240 Synthetic by the method described by John Wiley & Sons Inc, (1989). The compound (III) can be obtained from a commercially available product or can be obtained by a known method [for example, J. Heterocyclic chem., Vol. 17, p. 1 325 - 1 327, 1980; comprehensive organic conversion The method described in the second edition or the like] or obtained according to the methods. Production Process 2 Among the compounds (I), the compound (1C) can also be produced, for example, by the following procedure.

(wherein, R1, R2, R5 and R9A1 are each synonymous with the above) The compound (1C) can be obtained by reacting the compound (IV) with 1 to 10 equivalents of the compound (V) in a solventless or solvent. . The solvent may, for example, be an alcohol such as methanol, ethanol or n-butanol, and these may be used singly or in combination. The reaction is usually carried out at a temperature between 〇 °c and the boiling point of the solvent used for 5 minutes to 24 hours. In addition, in the absence of a solvent, 'in 〇~1 0 (TC is carried out for 5 minutes to 24 hours. -24- 200911240 In addition, 'compound (IV) can be based on well-known methods [eg Indian Journal of Pharmaceutical Sciences (Indian Journal) Of Pharmaceutical Science), 61(1), vol. p.25 -2 8,1999; Method for Comprehensive Organic Conversion, Second Edition, etc.] Synthesis. Further 'Compound (V) can be obtained from commercial products, or It can be obtained by a well-known force (for example, the method described in the second edition of Comprehensive Organic Conversion, etc.) or according to the methods described above. Manufacturing Method 3 Compound (I) can also be obtained by compound (ID) For example, the following steps are made.

R5-nhnh2 (V)

(wherein R1, R2 and R5 are each synonymous with the above). The compound (VI), for example, R1 is a methyl group and R2 is a cyano group, which is commercially available, and other compounds of R1 and R2 (VI) are known. The method is manufactured. Further, the compound (ID) can be obtained by reacting the compound (VI) with 1 to 10 equivalents of the compound (V) in a solvent-free or solvent. Suitable solvents, temperatures, reaction times, etc. are based on the manufacturing method 2 -25- 200911240. Alternatively, 'compound (V) may be sold from a towel' or may be known by methods [eg Phosphorous and Sulfur, Vol. 21, p. 307-314' 1985; Tetrahedron Letters, 36(47), p.8641-8644, 1995; method described in the second edition of Comprehensive Organic Conversion, or the like. In the compound (I), the compound (IE) having a substituted amino group at the fifth position can also be produced, for example, by the following procedure.

(wherein, X, Y, R1, R2 'R4 and R5 are each synonymous with the above) The compound (IE) can be obtained by subjecting the compound (IB) obtained in the production methods 1 to 3 to 1 to 1 equivalent of the compound. (νΠ) is obtained by carrying out a reaction in the presence of a base in a solvent. The base may, for example, be potassium carbonate, sodium carbonate, sodium hydrogencarbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, potassium hydride, sodium hydride, triethylamine, hydrazine, hydrazine-diisopropylamine or hydrazine. , hydrazine-diisopropylethylamine, DMAP, DBU, DBN, etc., which may be used singly or in combination. The solvent may, for example, be dichloromethane, acetonitrile, toluene, vinegar -26-200911240 ethyl acrylate, THE, 1,4-dioxane, DMF, NMP or the like, which may be used in combination or in combination. The reaction is usually carried out at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 24 hours. Further, the compound (VII) can be obtained from a commercially available product, or can be obtained by a weekly method (for example, the method described in the second edition of Comprehensive Organic Conversion) or the like. Process 5 Compound (I) can also be produced separately by, for example, the following steps.

(wherein R1B represents an aromatic group which may have a substituent or may have a square aromatic heterocyclic group, and R2, R3, r4, r5, fluorene and γ each may have a substituent with the synonymous 'r1q'. The arylene group may have a heteroaromatic group, the R 1 1 group represents a lower alkyl group which may have a substituent, a lower alkyl group having a substituent, an aromatic group which may have a substituent or an aromatic group which may have a mercapto group The heterocyclic group and the M system represent a tin atom, a boron atom or a sub-portion \A _ R represents a halogen, a hydroxyl group, a lower alkyl group, a lower alkoxy group or an aryloxy group, and the p system represents an integer of 〇 〜3. Lower alkyl' The above-mentioned substituent of the lower substituent may have the same meaning as the above, and the aryl group, the aromatic group, the aromatic heterocyclic group, the halogen, the lower alkoxy group and the aryloxy group are respectively synonymous with the foregoing. The substituent of the lower alkyl group, the lower dilute group which may have a substituent, the aromatic group which may have a substituent, and the aromatic heterocyclic group which may have a substituent are synonymous with the foregoing, and may have a substituent An arylene group or a heteroarylene group which may have a substituent, respectively The aromatic group having a substituent or the aromatic heterocyclic group which may have a substituent is synonymous with the removal of one hydrogen atom) The compound (I) can be obtained by reacting the compound (IF) with 1 to 30 equivalents of the compound (IX) It is obtained by carrying out a reaction in a solvent in the presence of a catalyst. At this time, an additive of 0·0 1 to 30 equivalents may be added to promote the reaction. Examples of the catalyst include [1, bis-bis(dichlorophosphino)iron]dichloropalladium (π), palladium acetate, tetrakis(triphenylphosphine)palladium, palladium chloride, palladium bromide, Palladium catalysts such as bis(triphenylphosphine)palladium, dichlorobis(acetonitrile)palladium, nickel, acetonitrile pyruvate, bis(1,5-cyclooctadiene)nickel, nickel bromide, etc. For the catalyst (IF), it is preferred to use 0. 0 0 1 to 1 equivalent. The reaction is carried out at a temperature between usually 〇 ° c and the boiling point of the solvent used for 10 minutes to 24 hours. The solvent may, for example, be methanol, ethanol, dichloromethane, acetonitrile, toluene, ethyl acetate, THF, 1,4-dioxane, DMF, NMP, 1,2-methoxymethoxy, water. Etc. 'These can be used alone or in combination. Examples of the additive include triphenylphosphine, tris(fluorene-tolyl)phosphine, 1,1'-bis(diphenylphosphino)iron, and 1,2-bis(diphenylphosphino)propane. 2,2'-bis(diphenylphosphinobiphthyl, 1,2-bis(diphenylphosphino)ethane, silver oxide, copper iodide, lithium chloride, fluorinated, triethylamine, diethyl Amine, KOH-28-200911240 Sodium, potassium hydroxide, sodium carbonate, etc., these may be used alone or in addition, the compound (IX) may be obtained from a commercial product, such as the comprehensive organic conversion second edition, etc. The conversion of the R1, R2, R3, r4, and r5 groups in the compound (I) can be carried out by a known method (for example, the method described in the first edition or the like) or according to the methods described above. By the method, the compound (I) having a desired functional group can be obtained. Further, the antitumor agent of the present invention can also be used as a compound. However, the compound used in the present invention is determined. Intermediate and target organic synthesis chemistry commonly used in separation and purification methods, such as net, dry, concentrated, recrystallized, various In addition, in the case of the intermediate (I), a stereoisomer such as a geometric substance or a tautomer may be present in the compound (I). When all possible isomers and the salt of the compound (I) to be obtained are used, when it is obtained in the form, it may be directly purified, and, in addition, by simply dissolving the compound (I) or Suspension in a suitable acid or base to form a salt, which can then be isolated and refined. It can be mixed or used. It can be obtained by well-known method or according to the functional organic conversion contained in X. The position of the above-mentioned table is not limited by these restrictions, and can be delivered to filtration, extraction, and washing for separation purification: can be supplied to the next 'isomer, optically different. Such a mixture. Compound (I) is obtained as a solvent in the form of a free salt of the salt 'Addition -29- 200911240 In addition, the compound (I) and its pharmaceutically acceptable salt are also added by water or various solvents. The form of matter exists The above-mentioned adducts can also be used in the present invention. Specific examples of the compound (I) obtained by the present invention are shown in Table 1. However, the compounds of the present invention are not limited by the above. Me and Et in the table indicate methyl and ethyl, respectively. -30- 200911240 [Table 1]

(ΙΑ) Compound No. 1 ΧΑ R1A Rw R4A 1 ΝΗ ΧΓΜΘ CN HH 2 ΝΗ Me CN HH Gas: 0 3 ΜΗ CN HH ,::0 4 ΝΗ CN HH 5 ΝΗ ^XMe CN HH 6 ΝΗ ΌΙ CN HH ^:X 7 ΝΗ Me CN HH 8 ΝΗ υ CN HH iXXe 9 ΝΗ ΧΤ CN HH 10 ΝΗ CN HH ^O. i -31 - 200911240 [Table 2] Reading (continued) Compound X R1 R2 R3 R4 R5 11 NH U CN HH Gas: 0 12 NH Wide N CN HH 13 NH XT CN HH 14 NH Ότ° CN HH Gas; 〇15 NH CN HH 16 NH Χ7° CN HH 17 NH Wide N, Me CN HH 18 NH rX^ CN HH 19 NH ^ NH CN HH 20 NH CN HH 21 NH "σ° CN HH 22 NH Ό"0. CN H H ^S^〇Me -32- 200911240 [Table 3] Table 1 (continued)

Content XA R1A R2A Ru RM 23 NH Υγ〇γΜβ Me CN HH 24 NH Ότ°Ό CN HH 25 NH "CO卜HH -CO 26 NH -1 XC CN HH gas;〇11 NH CONHj HH ^:X) 2% NH ^0° CN H 29 NH CN HH ,::0 30 m Xr°N CN HH ^:X) 31 NH IT CN HH Gas: 0 32 ! NH XX CN HH Gas X) ! | 33 1 NH | ^γ〇Μβ CN HH ^:X) 34 NH xo CN HH -33- 200911240 m4] Table 1 (continued) ft compound XA R1* rja r*A 35 NH "σ°〇CN HHQ h^h 36 NH conh2 HH -CO 37 NH "(7NH2 CN HH 38 NH Or° CN — HH 39 NH ρ^ΝΗ2 CN HH ^:j〇40 NH N called, 〇^ CN HH 41 NH xyOMe CN HH Me''· . Me \ 42 NH CN HH ^sO 43 NH wide NMe XT" CN HH 44 NH wide N-Me MeSOaH CN HH 45 NH CN HH 46 NH CN i HH -<sX^e 0 -34 - 200911240 [Table 5] 1 table (continued) \ compound» XA R** R3A R8* 47 NH Or0. CN HH 0 48 NH CN HHN 丫Me 0 49 NH CN HH 50 NH Yy^r" OMe CN HH -CO 51 NH CN HH 52 NH .N^OMe CN HH 53 NH "a° COzMe HH 54 NH Me XC;- CN HH Gas: 0 55 NH Me CN H H 56 NH ON H H Gas: 0 57 NH CN H H Gas: 0 58 NH Me v〇^〇Me CN H H Gas: 〇 -35- 200911240 [Table 6] Table 1 (continued)

Compound m XA R1A _ R2A R3* 59 NH , 〇r0 co2h HH ,::0 60 NH Me xx> CN HH 61 NH CN HH ^:X) 62 NH "Or0 H n'n HH 63 NH CN HH 64 MH CN HH 65 NH 广丫〇CN HH ^:X) 66 NH i*9 CN HH 67 NH CN HH 68 NH Me CN HH 69 NH CN HH 4XX i70 ! NH O"oh I CN HH -36- 200911240 [Table 7 Table 1 (continued) Compound XA R1A RM R4* RM 71 NH CN HH 72 NH CN HH 73 NH "OX CN HH 74 NH CN HH ^sXXc〇2Et 75 NH i CN HH OMe ^:xb 76 NH O" ° ° CN HH Cl 77 NH X7N〇 ° CN HH Me 78 S v CN HH 79 SO "0Me CN HH -to 80 S "0Me conh2 HH 8f S CN HH o -37- 200911240 [Table 8] Table 1 (Continued) Compound X* Ru Ru R5* R5A 82 S XT CN H COMe X) 83 1 S CN HH Gas: 0 i -38- 200911240 [Table 9] Reading (continued)

_ _ RIA R2A R3* R4* \ β4 S Me CN HH 85 NH W0H GN HH 86 NH "cxo CN HH 87 NH \y°Me CN HH Gas: 0 88 NH *S^W〇Me u GN HH 89 NH •, 〇rT, CN HH 90 NH CN HH 91 NH CN HH , 八 OH H1 92 NH CN HH Gas: 0 93 NH "TY°^N"Me,人I “ CN HH Θ4 NH Xr〇CN HH - 00 95 NH 丫XT, CN HH -39- 200911240 [Table 10] Table 1 (continued)

Compound XA R, A R2A p3A R*A R5A 96 NH ΎΤΪ0Η CN HH 97 NH "CC0H ON HH 98 NH u CN HH Gas XT 99 NH CN HH OMe 100 NH u CN HH 101 NH O^OH〇Y CN HH 102 NH ^oco CN HH 103 NH XX CN HH 104 NH XU CN HH 105 NH u CN HH 106 NH CN HH -40- 200911240 [Table 11] Table 1 (continued) \ Compound XA R1A R2A R3" R4* r5A 107 NH CN HH Gas: 0 108 NH Me CN HH 109 NH xro CN HH -CO 110 NH CN HH Sister 111 NH CN HH 112 NH OCOMe CN HH 113 NH , xro, OH CN HH 114 NH CN HH 115 NH CN HH Gas: 0 116 NH u CN HH 汐, nh2 117 NH CN HH ^:ic; -41 - 200911240 [Table 12] Section 13⁄4)

Compound XA R'A R3A R4A Rs* 118 NH Λ CN HH 119 NH u CN HH 120 NH CN HH -CO 121 NH CN HH 122 NH JO CN HH 123 NH CN HH 124 NH w: , OMe CN HH Gas: 〇125 NH fly ^NH2 CN HH,::0 126 NH 7 OMe CN HH Gas: 0 127 NH XC CN HH Gas: 0 128 NH XX CN HH -42- 200911240 [Table 13] Table 1 (continued) Chemical inclusion XA R'A R3* R4* 129 NH CN HH Off 130 NH Me CN HH 131 NH CN HH , :: 0 132 NH vq. CN HH HD 133 NH Me CN HH 134 NH 丫Όγ〇, 0 CN HH 135 NH 0 肀0 Me CN HH Cut 136 NH X? CN HH Gas X) 137 NH CN HH 138 NH *xr〇H CN HH ^IX) 139 NH u0肀0 Me CN HH 140 NH ΌΜβ CN HH ^:X) -43- 200911240 [Table 14] m (continued) Compound X* 1 R, A R2* R5* p4A rm 141 NH •V^^OMe u CN HH Marriage: 142 NH Xr0Me CN HHN^^5^OCHfr2 Also (10), 143 NH CN HH 144 NH "0〇Me CN HH 145 NH Fly 丫 e . r CN HH Gas: 0 146 NH u CN HH Gas XX : 147 NH Ό CN HH 148 NH X7〇Et CN HH 149 NH CN HH ^:X) 150 NH V0H CN HH 151 NMe rr" ^aNj CN HH Gas: 0 -44- 200911240 [Table 15] m (continued)

^Chemical composition XA ria R2A RJA R,A r5A 152 NH OMe XJ CN HHI 153 NH Me Xy〇Me ON HHI 154 NH XXOo CN HH Gas: 〇155 NH ΎΤΟ MsOH CN HH Gas X) 156 NH o CN HH Gas: 0 157 NH CN H 158 NH CN HH Gas: 〇159 NH CN HH 160 NH xr〇H CN HH 161 NH xr〇CN HH 162 NH "(TO CN HH ^3〇J' -45- 200911240 [Table 16] Reading (continued) i Compound XA ria i R2a R3A R** R5* 163 NH ΊΧ〇CN HH 164 NH xro CN HH 165 NH ry Xf'J CN HH ^s^0k 166 NH CN HH 167 NH CN HH 168 NH CN HH 169 NH "a°〇H HH ^〇y 170 NH xr° CN HH f.] ^〇y 171 NH CN HH ^oS] 172 NH OrN〇CN HH ,OH ^:xxr 173 NH CN HH HXr - 46- 200911240 [Table 17] Table 1 (continued)

Compound XA R'A RJA R3A R4A rsa 174 NH Xr° CN HH 175 NH CN HH 176 NH Or0 CN HH 177 NH Or0 CN HH ^sXX^SMe 178 NH CN HH 179 NH Ό^0Η CN HH 180 NH CN HH Gas: 〇181 NH xro CN HH 182 NH Ότ〇CN HH ^OOh 183 NH ΎΧΟ CN HH gas; 〇184 NH ΎΤΌ CN HH -47- 200911240 [Table 18] Table 1 (continued)

Compound XA R, A R2* R3* R'A 185 NH xro CN HH 186 NH xro CN HH 187 NH OXi CN HH 188 NH OXi CN HH 189 NH CN HH 190 NH . OXi CN HH 191 NH CN HH Gas X) 192 NH xxo MsOH CN HH -<:X) 193 NH Χχ〇Μθ CN HH 194 NH tr CN HH Gas: 0 195 NH v0° CN HH -48- 200911240 [Table 19] m (continued)

196 NH , σ ', ο CN HH Nio 197 NH CN HH 198 NH xro CN HH 199 NH ΎΤΟ CN HH OMe 200 NH ΎΤ.Ο CN HH -CO 201 NH va°", OH CN HH Gas: 〇202 NH ^ 7〇Me CN HH 203 NH Or° CN HH ^C〇204 NH CN HH 205 NH "σ'ο CN HH Gas: 0 206 NH Ό^Ο CN HH to' 207 NH Or°° CN HH -49- 200911240 [Table 20] Table 1 (continued) Compound XA R'A RJA R4* R5* 208 NH CN HH Gas: 0 209 NH x/r CN HH Gas: 0 210 NH CN HH 211 NH ^xro CN HH 212 NH Wide π. CN HH 213 NH "σ'Ό CN HH - 00 214 NH Ό^Ο CN HH -a 215 NH ύΛ:: CN HH - 216 NH CN HH 217 NH CN HH Gas: 〇m NH OMe CN HH 219 NH CN HH Gas: 0 -50- 200911240 [Table 21] Reading (continued)

Compound XA R'* R2* ' R3* R*A p5* 220 NH *1X0 CN HH 221 NH xro CN HH Me Sister 1 222 NH N^\ u CN HH 223 NH Me CN HHO^OMe 224 NH Me CN HHO丫OH 225 NH Me X/Me CN HH . OH 226 NH XT CN HH ^:X) 227 NH Me Me u CN HH,::0 228 NH CN HH ^IX) 229 NH CN HH 230 NH CN HH -51 - 200911240 [Table 22] Table 1 (Continued) 231 NH Me CN Η Η ro° 232 m Me XT曰CN Η 233 233 NH Λ , (丫八❺ CN Η Η 234 NH ·, 〇ΆΜβ CN Η Η Gas: 〇235 NH ----_ CN Η Η :0 Next, the pharmacological action of the representative compound (1) is more specifically described in the test case. Test Example 1: Cell proliferation inhibition test for cervical cancer cells Using human cervical cancer cell line He e a (ATCC No.: CCL - 2 ) As a cervical cancer cell line, the cells were cultured using bovine fetal serum 10% (INVITROGEN, catalog number 1 0 0 9 9 - 1 4 1 ), Ν ο η-Essential Amino Acids Solution 10 mmol /L, liquid 1% (INVITROGEN company, catalog number 1 1 1 4 0 - 0 5 0), Penici 11 i n-Streptomycin, liquid 1% (INVITR〇GEN company, catalog number 1 5 1 40- 1 22) ^ Minimum Essential medium Earle's, liquid (INVITROGEN, catalog number 1 1 0 9 5 - 0 8 0). Cell lines at 3 7 t, 5% The cells were cultured under carbon oxide conditions. HeLa cells (500 cells/well) were inoculated into wells of a 96-well plate (Nunc-52-200911240, catalog number 1 67008) and cultured overnight. The diluted test compound was added in stages. Further culture for 72 hours (final capacity ΙΟΟμί/well). Add 50 μί of the XTT marker mixture of Cell Proliferation Kit II (XTT) (R〇CHE-DIAGNOSTICS, catalog number 1465015) to each well and incubate at 37 °C. After 150 minutes, the absorbance at 490 nm (control wavelength 65 5 nm) was measured with a Plate Reader (Molecular Devices, SpectraMax 340PC384). The cells in the control group treated with dimethyl sulfoxide (DMS0) were treated for 72 hours. The proliferation rate was determined to be 1%, and the proliferation rate of the cells in the wells treated with the test compound was calculated. Compounds 1 to 19, 21 to 34, 36 to 40, 42, 45, 47 to 62, 64 to 66, 68 to 82, 84 to 96, 98, 99, 101 to 103, 106 to 115, 117, 120 to 127 129~140, 142~144, 146~151, 154, 155, 157~177, 179, 180, 182, 184, 186, 188-190, 195, 198~205, 208, 210, 213, 215, 216 218, 220, 222, 225 '226, 229, 230 and 232~235 inhibited the proliferation of more than 30% of the human cervical cancer cell line HeLa cells, ΙΟμηιοΙ/L. From the above, it is understood that the compound (I) has cell proliferation inhibitory activity against human cancer cells. That is, the compound (I) is considered to be useful as an antitumor agent. The compound (I) or a prodrug thereof or a pharmaceutically acceptable salt thereof may be administered alone or separately, but it is desirable to provide as a usual various pharmaceutical preparations. In addition, such pharmaceutical preparations are used in animals or humans. The pharmaceutical preparation of the present invention may contain the compound (I) or its lead drug or a pharmaceutically acceptable salt thereof as an active ingredient, either alone or in a mixture with any other active ingredient for treatment of any of -53-200911240 . Further, such pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.), as is well known in the art of the formulation of the invention. Any method of manufacture. In the case of administration to the urethral route, it is desirable to use the most effective method for the treatment, and examples thereof include oral administration or non-oral administration such as intravenous administration. Examples of the administration form include a tablet, an injection, and the like. A form suitable for oral administration, for example, a tablet or the like, can be produced by using an excipient such as lactose, a breaker such as starch, a lubricant such as magnesium stearate, or a binding agent such as hydroxypropylcellulose. A form suitable for parenteral administration, for example, an injection or the like, can be produced by using a salt solution, a glucose solution, or a diluent such as a mixed solution of saline and a glucose solution, or a solvent. The administration amount and the number of administrations of the compound (I) or its lead drug or a pharmaceutically acceptable salt thereof vary depending on the administration form, the age of the patient, the body weight, the nature or severity of the symptom to be treated, and the like. In the case of oral administration, adults are 0. 01~lOOOOmg (preferably 0. The range of 05~100mg), one day to several times. In the case of non-oral administration such as intravenous administration, adults are 0. 001~1000mg (preferably 0. 01~l〇〇mg) l is administered once to several times a day. However, the amount of such administration and the number of administrations will vary according to the various conditions described above. The invention is further described in detail by the following examples, and the scope of the invention is not limited by the examples. -54- 200911240 In addition, the proton nuclear magnetic resonance spectrum (4 NMR) used in the examples and the reference examples was measured at 270 MHz or 300 MHz, and the exchange protons were not clearly observed due to the compound and the measurement conditions. situation. Further, in terms of the representation of the degree of multiplicity of signals, a user who is a normal user is used, and a signal indicating a wide appearance is used. Example 1 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-methylphenyl)amino-1 Η-pyrazole (Compound 1) (Step 1 ) in [bis(methylthio)methylene]malononitrile (l. 〇g, 5. 9mmol), m-toluidine (〇. 63g, 5. 9mmol) was added to ethanol (20mL) and stirred at 80 °C. 0 hours. The solvent was distilled off under reduced pressure, and the residue was purified from ethyl acetate: ethyl acetate: 4/1 to give 2-[(3-methylphenyl)amino (methylsulfonyl)methylidene] Nitrile (0. 9 7 g, 7 2 %). 'H NMR (270MHz, DMSO-d6) 5 2. 32(s, 3H), 2. 52(s, 3H), 7. 07-7. 10(m, 3H), 7. 30 (m, 1H), 10. 5(s, 1H). (Step 2) 2-[(3-Methylphenyl)amino (methylsulfonyl)methylene]malononitrile obtained in Step 1. L〇g, 〇. 44mmol) added hydrazine monohydrate (0. 025mL, 0. 52mm〇l), stir at 100 °C. 5 hours. The reaction mixture was concentrated under reduced pressure and purified with dichloromethane to afford 5-amino-4-cyano-3-(3-methylphenyl)amino-1 s-pyrazole ( 〇· 〇 9 g, 9 7 %). -55- 200911240 ESIMS m/z: 214 (M + H) + ; 'H NMR (2 7 0 MHz, DMSO-d6) 5 2. 20(s, 3H), 6. 23(s, 2H), 6. 58(m, 1 H), 7. 04(m, 1 H), 7_20(m, 1H), 8_23(s, 1H), ll_0(s, 1H). (Step 3) 5-Amino-4-cyano-3-(3-methylphenyl)amino-lH-fl obtained in Step 2 (1. 4g, 6. 4mmol) with cesium carbonate (5. 3 g, 38 mmol) was suspended in DMF (50 mL) and added to 2-chlorobenzothiazole (〇. 86 mL, 6-6 mmol). Stir at 100 °C 3. After 0 hours, water/methanol = 10/l (50 mL) was added to the mixture to give crude crystals. By further adding the dichloroethane (50 mL), at 8 (TC re-slurry, the compound l (〇. 93g, 42%). ESIMS m/z: 3 47(Μ + Η) + ; *Η NMR (270MHz, DMSO-d6)6 2. 31(s, 3H), 6. 76(d, J = 7. 5Hz, 1H), 7. 18(t, J = 8. 0Hz, 1H), 7. 3 8(t, J = 7. 5Hz, 1H), 7. 49-7. 5 4 (m, 3H), 7. 90 (d, J = 8. 0Hz, 1H), 8. 09(d, J = 8. 0Hz, 1H), 8. 29(s, 2H), 9. 04(s, 1H); Anal.  Calcd for Ci8HmN6S: C, 62. 41; H, 4. 07;N, 24. 26.  Found: C, 62. 26; H, 3 . 83; N, 24. 10. Example 2 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3,5-dimethylphenyl)amino-1 Η-pyrazole (Compound 2) (Step 1) According to the procedure of Example 1, from [bis(methylthio)methylene]malononitrile (0. 50 homes, 2. 9111111〇1), 3,5-dimethylaniline (0. 36§, 2. 9111 «1〇1) and -56- 200911240 Ethanol (10 mL) to give 2-[(3,5-dimethylphenyl)amino (methylsulfonyl)methylene]malononitrile (〇. 50g, 70%). ESIMS m/z: 244 (Μ + Η) + ; *Η NMR (270 MHz, DMSO-d6) 6 2. 27(s,6H), 2. 52(s,3H), 6. 90(s, 3H), 10. 4 (s, 1H). (Step 2) According to Step 2 of Example 1, 2-[(3,5-dimethylphenyl)amino (methylsulfonyl)methylene]malononitrile obtained in Step 1 ( 0. 20g, 〇. 82mmol) with hydrazine monohydrate (0. 048mL, 0. 99 mmol) gives 5-amino-4-cyano-3-(3,5-dimethylphenyl)amino-1H-pyrazole (0. 09g, 4 7%) ° ESIMS m/z: 22 8 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2. 17(s, 6H), 6. 21(s, 2H), 6. 41(s, 1H), 7. 05(s, 2H), 8. 14(s, 1H), 7. 29(s, 1H). (Step 3) The 5-amino-4-cyano-3-(3,5-dimethylphenyl)amino-1H-indole obtained in Step 2 is obtained. 〇6g, 0. 26mmol) with potassium carbonate (0. 26g, 1. 8mmol) was suspended in DMA (1mL) and added to 2-chlorobenzothiazole (0. 045mL, 0. 3 5mmol). Stir at 0 00 ° C. After 5 hours, water (5 mL) was added to the reaction mixture to give crude crystals. By further adding chloroform (l〇mL) and then rewarding, compound 2 (0. 095g, 100%). ESIMS m/z: 361 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 8 2. 27(s, 6H), 6. 59(s, 1H), 7. 32(m, 2H), 7. 38(t, J = 7. 6Hz, -57- 200911240 1H), 7. 51(t, J = 7. 6Hz, 1H), 7. 90 (d, J = 8. 2Hz, 1H), 8. 10(d, J = 7. 6Hz, 1H), 8. 27(s, 2H), 8. 96 (s, 1H). Example 3 5-Amino-1-(benzoxan-2-yl)-3-(biphenyl-3-yl)amino-4-amino-1H-pyrazole (Compound 3) (Step 1) In [bis(methylthio)methylene]malononitrile (〇. 5〇g, 2. 9mmol) '3-aminobiphenyl (0_50g, 2. 9 mmol) was added to ethanol (10 mL) and stirred at 80 ° C for 12 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate = 4/1 to 2/1) to give 2-[(biphenyl-3-ylamino) Methylsulfonylmethylene]malononitrile (〇. 50g, 58%). ESIMS m/z: 290(M-H)'; 1H NMR (270MHz, CDC13) δ 2. 30(s, 3H), 7. 22-7. 26(m, 2H), 7. 3 6-7. 5 9 (m, 7H), 8. 25 (m, 1H). (Step 2) According to Step 2 of Example 1, 2-[(biphenyl-3-ylamino)methylsulfonylmethylene]malononitrile obtained in Step 1 (〇. 49g, 1. 7mm〇l) with hydrazine monohydrate (〇 · 2 7 m L, 5. 6 m m ο 1), 5-amino-3 -(biphenyl-3-yl)amino-4-cyano-1H-pyrazole (0. 3 3g, 73%). ESIMS m/z: 276 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 6. 30(s, 2H), 7. 06(m, 1H), 7. 23 -7. 3 7(m, 2H), 7. 43 -7. 3 8 (m, 3H), 7. 58-7. 61(m, 2H), 7_80(m, 1H), 8. 47 (m, 1H). -58- 200911240 (Step 3) The 5-amino-3-(biphenyl-3-yl)amino-4-cyano-1H-pyrazole obtained in Step 2 (〇. 15g, 0. 55mmol) with potassium carbonate (0. 53 g, l_8 mmol) was suspended in DMA (1 mL), and 2-chlorobenzothiazole (〇 · 〇 9 2 m L, 0. 7 1 m m ο 1). Stir at 1 0 ° ° C 1 .  After 5 hours, saturated brine was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloidal column chromatography (hexane / ethyl acetate = 3 / 1), chloroform (10 mL) was further added, and then slurried to give compound 3 (0. 042g, 19%). ESIMS m/z: 409 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 7. 26(m, 1H), 7. 37-7. 42(m, 3H), 7. 50-7. 5 5(m, 3H), 7. 67- 7. 73(m, 3H), 7. 91(m, 1H), 8. 09-8. 13(m, 2H), 8. 33(s, 2H), 9_25(s, 1H). Example 4 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(5,6,7,8-tetrahydronaphthalen-1-yl)amino-1H-pyridyl Azole (Compound 4) (Step 1) According to Step 1 of Example 3, from [bis(methylthio)methylene]malononitrile (0. 50g, 2. 9mmol), 5,6,7,8-tetrahydronaphthalen-1-ylamine (0 _ 4 3 g, 2. 9 mmol) and ethanol (10 mL) give 2 -[ 3 - ( 5,6,7,8 -tetrahydronaphthalen-1-ylamino)methylsulfonylmethylene]malononitrile (〇. 24g, 30%). ESIMS m/z: 270(M + H)VH N M R (2 7 Ο Μ Η z, D M S Ο - d 6) δ -59- 200911240 1. 71-1. 74 (m, 4H), 2. 51-2. 62 (m, 3H), 2. 75 (m, 1H), 2. 79(s, 3H), 7. 04-7. 18 (m, 3H), 10_l (s, 1H). (Step 2) According to Step 2 of Example 3, 2 [[(5,6,7,8-tetrahydronaphthalen-1-yl)amino)methylsulfonyl) Methyl malononitrile 24g, 0_89mmol) added hydrazine monohydrate (0. 15mL, 3. 09 mmol), stirred at 100 ° C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (hexane/ethyl acetate = 2/1) to give 5-amino-4-cyano-3-(5,6) , 7,8-tetrahydronaphthalen-1-yl)amino-1Η-pyrazole (0. 23g, 100%). ESIMS m/z: 254 (M + H) + (Step 3) 5-Amino-4-cyano-3(5,6,7,8-tetrahydroi-naphthalene-1) obtained in Step 2 -yl)amino-1H-pyrazole (O. Llg, 0. 42mm〇l) with potassium carbonate (0. 40g, 2_9mmol) was suspended in DMA (1mL) and added to 2-chlorobenzothiazole (〇. 〇65mL, 0. 5〇mmol). After stirring at i ° ° C for 5 hours, saturated brine was added, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloidal column chromatography (hexane/ethyl acetate = 3/1) to give compound 4 (0. 005 g, 3%). ESIMS m/z : 3 8 7 ( M + Η) + ; 1 Η N M R (2 7 0 Μ H z, D M S ◦ - d 6) δ 1. 72- 1 , 74 (m, 4 Η), 2 6 5 ( m, 2 Η), 2 · 7 0 (m, 2 Η), 6. 8 3 (d, J = 7. 8Hz, 1Η), 7. 06(t, J = 7. 8Hz, 1H), 7. 36(m, 2H), 7. 50(t, -60- 200911240 J = 7. 8Hz, 1H), 7. 88(d, J = 8. 6Hz, 1H), 7. 94(s, 1H), 8. 〇3 (d, J = 7. 8Hz, 1H), 8. 24(s, 2H). Example 5 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-ethylphenyl)amino-1 Η-pyrazole (Compound 5) (Step 1 According to step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0. 50g, 2_9mmol), 3-ethylaniline (〇. 36g, 2. 9 mmol) and ethanol (10 mL) gave 2-[(3-ethylphenyl)amino (indolylsulfonyl)methylene]malononitrile (0. 50g, 70%). ESIMS m/z: 244 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 6 1. 18(t, J = 7. 6Hz, 3H), 2. 50(s, 3H), 2. 62(q, J-7. 6Hz, 2H), 7. 10-7_12(m, 3H), 7_32(m, 1H), 10. 5 (s, 1H). (Step 2) According to Step 2 of Example 1, 2-[(3-ethylphenyl)amino(methylsulfonyl)methylene]malononitrile obtained in Step 1 (0. 50g, 2. 05mmol) with hydrazine monohydrate (〇. 33mL, 6. 8 mmol) gives 5-amino-4-cyano-3-(3-ethylphenyl)amino-1H-pyrazole (〇. 28g, 60%). ESIMS m/z: 228(Μ + Η) + ;*Η NMR (270MHz, DMSO-d6)8 1. 15(t, J = 7. 6Hz, 3H), 2. 51(q, J-7. 6Hz, 2H), 6. 22(s, 2H), 6. 62(m, 1H), 7. 06(m, 1 H), 7. 23 (m, 1 H), 7. 3 1 (s, 1 H), 8. 25(s, 1 H), 1 1 .  1 (s, 1 H). -61 - 200911240 (Step 3) According to Step 3 of Example 4, 5-amino-4-cyano-3-(3-ethylphenyl)amino-1H-pyrazole obtained in Step 2 (0. 08g, 0_35mmol), 2-chlorobenzothiazole (〇. 〇5mL, 0. 39mm〇l), potassium carbonate (0. 34g, 2. 5 mmol) and DMA (1 mL) gave compound 5 (0. 05g, 39%). ESIMS m/z: 361 (M + H) VH NMR (270 MHz, DMSO-d6) 5 1. 2 1 (t, J-7. 5Hz, 3H), 2. 61 (q, J = 7. 5Hz, 2H), 6. 79(d, J = 7. 2Hz, 1H), 7. 20(t, J = 7. 9Hz, 1H), 7. 38(t, J = 7. 2Hz, 1H), 7. 52(m, 2H), 7. 59(s, 1H), 7. 90 (d, J = 7. 9Hz, 1H), 8. 09(d, J = 7. 9Hz, 1 H), 8. 30(s, 2H), 9. 05(s, 1H). Example 6 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3,4-dimethylphenyl)amino-1 Η-pyrazole (Compound 6) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0. 50 Lu, 2. 9111111〇1), 3,4-dimethylaniline (0. 36§, 2. 9111111〇1) and ethanol (10mL) give 2-[(3,4-dimethylphenyl)amino (methylsulfonyl)methylene]malononitrile (〇. 57g, 80%). ESIMS m/z: 244 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 3 2. 22(s, 3H), 2. 50(s, 3H), 2. 51(s, 3H), 7. 00(m, 1H), 7. 07(s, 1 H), 7. 1 7 (m, 1 H), 1 0-4 (s, 1 H). -62 - 200911240 (Step 2) According to Step 2 of Example 1, 2-[(3,4-dimethylphenyl)amino (methylsulfonyl) methylene group obtained in Step 1] Malononitrile (〇. 56§, 2. 32mmol) with hydrazine monohydrate (〇. 37mL, 7. 6 mmol) gives 5-amino-4-cyano-3-(3,4-dimethylphenyl)amino-1H-pyrazole (0. 39g, 74%) ° ESIMS m/z: 22 8 (M + H)VH NMR (270MHz, DMSO-d6)S 2. 11(s, 3H), 2. 14(s, 3H), 6. 20(s, 2H), 6. 90 (m, 1H), 7. 15(m, 1H), 7. 24(s, 1H), 8_10(s, 1H). (Step 3) According to Step 3 of Example 2, 5-amino-4-cyano-3-(3,4-dimethylphenyl)amino-111-pyrazole obtained in Step 2 ( 0. 088, O_35mmol), 2-chlorobenzothiazole (0_05mL, 0. 39mmol), potassium carbonate (0. 34g, 2. 5 mmol) and DMA (1 mL) gave compound 6 (0. 005g, 4%). ESIMS m/z: 361 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 5 2. 17(s, 3H), 2. 22(s, 3H), 7. 04(d, J = 8. 2Hz, 1H), 7. 39(m, 2H), 7. 51(m, 2H), 7. 89(d, J-8. 2Hz, 1H), 8. 09(d, J = 7. 9Hz, 1H), 8. 27(s, 2H), 8. 92(s, 1H). Example 7 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(dimethylamino)phenyl]amino-1H-pyrazole (Compound 7 -63- 200911240 (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (〇. 50g, 2. 9mmol), hydrazine, hydrazine-dimethyl-1,3-phenylenediamine dihydrochloride (0. 61g, 2. 9mmol), triethylamine (0. 8mL, 5. 9 mmol) and ethanol (10 mL) gave crude 2-[(3-dimethylphenyl)amino (methylsulfonyl)methylene]malononitrile (〇. 96g). ESIMS m/z: 259 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 54(s, 3H), 2. 90(s, 6H), 6. 56-6. 62(m, 3H), 7. 18(m, 1H), 1 〇_4(m, 1 H). (Step 2) According to Step 2 of Example 1, the crude 2-[Π-dimethylphenyl)amino (methylsulfonyl)methylene]malononitrile obtained in Step 1 (0. 96g) with hydrazine monohydrate (0. 47mL, 9. 7 mmol) gave 5-amino-4-cyano-3 -[(3-dimethylamino)phenyl]amino-1 η-pyrazole (0 _ 5 6 g, 7 8 %). ESIMS m/z: 243 (M + H) VH NMR (270 MHz, DMSO-d6) 5 2. 84(s, 6H), 6. 18-6. 21 (m, 3H), 6. 84-6. 99(m, 3H), 8. 03(s, 1 H), 1 1 · 1 (s, 1 H). (Step 3) According to Step 3 of Example 2, 5-amino-4-cyano-3-[(3-dimethylamino)phenyl]amino-1H-pyridyl obtained in Step 2 Azole (0. 20g, 0_82mm〇l), 2-chlorobenzothiazole (0_09mL, 0. 90mmol), potassium carbonate (〇. 79g, 5. 7mmol) and DMA (8mL) gave compound 7 (0. 05g, -64 - 200911240 15%). ESIMS m/z: 3 76 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 6 2. 94(s, 6H), 6. 33 (dd, J = 8. 0, 1. 9Hz, 1 H), 6. 95-7. 1 1 (m, 2H), 7. 26(m, 1H), 7. 38(t, J = 7. 6Hz, 1H), 7. 51(m, 1H), 7. 90 (d, J = 8. 0Hz, 1 H), 8. 08(d, J = 8. 0Hz, 1H), 8. 27(s, 2H), 8. 90 (s, 1 H). Example 8 5-Amino-4-cyano-1-(5,6-dimethylbenzothiazol-2-yl)-3-(3-methoxyphenyl)amino-1H-pyrazole (Compound 8) (Step 1) According to Step 1 of Example 1, m-methoxyaniline (5. 0g, 41mm〇l), [bis(methylthio)methylene]malononitrile (6. 9 g, 41 mmol) and ethanol (80 mL) gave 2-[methylsulfonyl-[(3-methoxyphenyl)aminomethylene]malononitrile (8-9 g, 86%). ESIMS m/z: 246(Μ + Η) + ;*Η NMR (270MHz, DMSO-d6)S 2. 52(s, 3H), 3. 77(s, 3H), 6. 82-6. 8 8 (m, 3H), 7. 32(m, 1H), 1 0. 53(s, 1H) ° (Step 2) According to Step 2 of Example 1, 2-[methylsulfonyl-(3-methoxyphenyl)aminomethylene] obtained in Step 1 Malononitrile (8. 9g, 36mmol), hydrazine monohydrate (2. 1mL, 44mmol) and ethanol (0. 10L), 5-amino-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole (6. 0g, -65- 200911240 7 2%) ° ESIMS m/z: 23 0(Μ + Η) + ; *Η NMR (2 70MHz, DMSO-d6)8 3. 69(s, 3H), 6. 25(s, 2H), 6. 35 (m, 1H), 7. 03 -7. 09(m, 2H), 7. 13(s, 1H), 8_31(s, 1H), 11. 16(s, 1H). (Step 3) According to Step 3 of Example 1, 5-amino-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole (O.) obtained in Step 2. Lg,0. 44 mmol), 2-bromo-5,6-dimethylbenzothiazole (0. 13§, 0. 52«1111〇1), potassium carbonate (0. 30g, 2. 2mmol) and DMF (3mL) gave compound 8 (0. 03 8g, 2 2%) ° ESIMS m/z: 391 (M + H) +; 1H NMR (270MHz, DMSO-d6) 5 2. 33(s, 6H), 3. 78(s, 3H), 6. 50 (m, 1H), 7. 14-7. 19(m, 2H), 7. 46(s, 1H), 7. 68(s, 1H), 7. 82(s, 1H), 8. 23(s, 2H), 9. 09(s, 1H). Example 9 5-Amino-1-(benzosin-2-yl)-4-chloro-3-(3-carbyl)β-aryl-1H-pyrazole (Compound 9) (Step 1) According to step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0-50 g, 2. 9 mmol), 3-amino hydrazine (0. 32g, 2. 9 mmol) and ethanol (10 mL) gave 2-[(3-hydroxyphenyl)amino (methylsulfonyl)methylene]malononitrile (0-49 g, 72%) 〇-66 - 200911240 ESIMS m/z : 25 9(M + H) + ; 'h NMR (2 70MHz, DMS〇-d6)8 2. 52(s, 3H), 6. 63 -6. 73 (m, 3H), 7. 19(m, 1H), 9. 7〇(s, 1H), 10. 5(s, 1 H). (Step 2) According to Step 2 of Example 1, 2-[(3-hydroxyphenyl)amino(methylsulfonyl)methylene]malononitrile obtained in Step 1 (0. 30g) with hydrazine monohydrate (0-20mL, 9. 7 mmol) gave 5-amino-4-cyano-3-(3-hydroxyphenyl)amino-1 hydrazine-pyrazole (0 · 2 4 g, 8 5 %). ESIMS m/z: 243 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 6. 16-6. 23(m, 3H), 6. 80 (m, 1H), 6. 89, 6. 95(m, 2H), 8. 15(s, 1 H), 9. 05(s, 1 H), 1 1 .  1 (s, 1H). (Step 3) According to Step 3 of Example 4, 5-amino-4-cyano-3-(3-hydroxyphenyl)amino-1H-pyrazole obtained in Step 2 (0. 10g, oh. 48mmol), 2-chlorobenzothiazole (〇. 〇6mL, 0. 48 mm 〇l), potassium carbonate (〇_47g, 3'4mmol) and D M A (1 m L) gave compound 9 (〇 _ 0 0 5 g, 3%). ESIMS m/z: 3 4 7 (M-H)·; Ή NMR (270 MHz, DMSO-d6) 5 6. 36(d, J = 7. 6Hz, 1H), 7. 05(t, J = 8. 2Hz, 1H), 7. 12(m, 2H), 7. 38(t, J = 7. 6Hz, 1H), 7. 5l(t> J = 7. 6Hz, lH), 7. 90 (d, J = 8. 0 H z,1 H ), 8. 0 9 (d, J = 8. 0 H z, 1 H ), 8. 2 7 ( s, 2 H ), 8. 9 7 ( s, 1 H), 9. 30 (s, 1 H). -67- 200911240 Example 1 〇5-Amino-1-(benzothiazol-2-yl)-3-[3-(benzothiazol-2-yloxy)phenyl]amino-4-cyanide Base-1 Η-pyrazole (Compound 10) According to Step 3 of Example 4, 5-amino-4-cyano-3-(3-hydroxyphenyl) obtained in Step 2 of Example 9. Amino-1Η-pyrazole (〇. 13g, 0_60mmol) '2-Chlorobenzothiazole (0. 09mL, 0. 69mmol), potassium carbonate (0. 58g, 4. 2mmol) and DMA (lmL)' gave compound 10 (0. 012g, 4%). ESIMS m/z: 4 82(M + H)VH N M R ( 2 7 Ο Μ Η z , D M S Ο - d 6) δ 6. 99(m, 1H), 7. 3 6-7. 40 (m, 2H), 7. 43 -7. 5 0 (m, 3H), 7. 57(m, 1H), 7. 77(m, 1H), 7. 83 -7. 89(m, 3H), 7. 98(m, 1H), 8. 31(s, 2H), 9. 46(s, 1 H). Example 11 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole (Compound 1 1) Compound 9 (34mg, 0. 098 mmol) was dissolved in DMF (1 mL), and potassium carbonate (15 mg, 0.11 mmol) and dimethyl sulfate (0. 0 1 mL, O. Llmmol), stirred for 5 hours. Water was added to the reaction mixture, and the obtained crude product was purified by silica gel column chromatography (chloroform/methanol = 95/1) to give Compound 1 1 (0. 004g, 11%). ESIMS m/z: 3 7 7 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 3. 79(s, 3H), 6. 52(m, 1H), 7. L5-7. 21(m, 2H), 7. 3 9-7. 5 3 (m, 3H), 7. 90 (m, 1H), 8. 10 (m, 1H), 8. 30(s, 2H), 9. 13(s, 1H). -68- 200911240 Example 1 2 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(2-methylpyrimidin-4-ylphenyl)amino -1H-pyrazole (Compound 12) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0-50 g, 2. 9mmol), 3-(2-methylglycidine-4-yl)phenylamine (〇. 54g, 2. 9 mmol) and ethanol (10 mL) give 2-{[3-(2-methylpyrimidin-4-yl)phenyl]amino (methylsulfonyl)methylene}malononitrile (〇. 57g, 63%). ESIMS m/ζ: 3 06(Μ-Η)·;'Η NMR (270MHz, DMSO-d6)5 2. 59(s, 3H), 2. 70(s, 3H), 7. 52(m, 1H), 7. 57(m, 1H), 7. 93(m, 1H), 8. 08(m, 1H), 8. 15(s, 1H), 8. 80(s, 1H), 10. 7(s, 1H). (Step 2) 2 - {[ 3 - (2-methylpyrimidin-4-yl)phenyl]amino (methylsulfonyl) methylene} malononitrile obtained in the step 1. 56g, 1. 8 mmol) was dissolved in ethanol (1 mL) and hydrazine monohydrate was added (〇. 29mL, 6. 0mmol), stirred at 80 t. 5 hours. The reaction mixture was concentrated under reduced pressure and purified with dichloromethane to afford 5-amino-4-cyano-3([2-methylpyrimidin-4-yl)phenyl]amino-indole-pyrazole (0. 3 6 g, 6 6 %). ESIMS m/z: 292 (M + H) + ; 1H NMR (2 70 MHz, DMSO-d6) 8 2. 68(s, 3H), 6. 29(s, 2H), 7. 34(t, J = 7. 8Hz, 1H), 7. 55 (d, J = 7. 8Hz, 1H), 7. 70 (m, 2H), 8. 25(s, 1H), 8. 65(s, 1H), -69- 200911240 8. 73 (d, J = 4_9Hz, 1H), 1 1 .  1 (s, 1H). (Step 3) 5-Amino-4-cyano-3-[(2-methylpyrimidin-4-yl)phenyl]amino-1H-pyrazole obtained in Step 2 (0. 20g, 0. 69mmol) with potassium carbonate (〇. 57g, 4_lmmol) suspended in DMF (5mL), added 2-chlorobenzothiazole (0. 09 8mL, 0. 76mmol). After stirring at 1 ° C for 3 hours, water (5 m L) was added to the reaction mixture to give crude crystals. By further force [] into chloroform (10 m L) and then slurrying, compound 12 (0. 1 7g, 59%). ESIMS m/z: 42 5 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 75(s, 3H), 7. 3 8-7. 5 6 (m, 3H), 7. 42(m, 1H), 7. 83 -7. 86(m, 2H), 7. 92(m, 1H), 8. 09(m, 1H), 8. 32(s, 2H), 8. 72(s, 1H), 8_80(m, 1H), 9. 43(s, 1H); Anal.  Calcd for C22H16N8S · 0. 1H2O: C, 61. 99; H, 3. 83; N, 26. 29.  Found: C, 6 1 . 77; H, 3·52; Ν, 26. 13. Example 1 3 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-iodophenyl)amino-1H-pyrazole (Compound 13) (Step 1) According to step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0-50 g, 2-9 mmol), 3-iodoaniline (0. 35mL, 2. 9 mmol) and ethanol (10 mL) gave 2-[(3-iodophenyl)amino (methyl fluorenyl) methylene] malononitrile (0. 64g, 64%). -70 - 200911240 ESIMS m/z: 3 4 0 (M - H)-;1 Η N M R( 2 7 0 MHz, D M S 0 - d 6) δ 2. 55(s, 3H), 7. 21(t, J-8. 0Hz, 1H), 7. 33(d, J = 8. 0Hz, 1H), 7_62 (d, J = 8. 0Hz, 1H), 7. 68 (s, 1H), 10_53 (s, 1H). (Step 2) According to Step 2 of Example 1, 2 - [(3-Iodophenyl)amino (methylsulfonyl)methylene]malononitrile (0. 64g, 1. 9mmol), hydrazine monohydrate (0-30mL, 6. 2mm〇l) and ethanol (10 m L ) give 5-amino-4-cyano-3(3-iodophenyl)amino-1 Η-pyrazole (0. 24g, 8 5%) ° ESIMS m/z: 243 (M + H) + ;1H NMR (270MHz, DMSO-d6)5 6. 33(s, 2H), 6. 96(t, J = 8. 0Hz, 1H), 7. 10(d, J = 8. 0Hz, 1H), 7. 40 (d, J = 8. 0Hz, 1H), 8. 00(s, 1H), 8. 56(s, 1H). (Step 3) According to Step 3 of Example 12, 5-amino-4-cyano-3-(3-iodophenyl)amino-1H-pyrazole obtained in Step 2 (0. 35g, l_lmmol), 2-chlorobenzothiazepine (0. 12mL, 1. 2mmol), potassium carbonate (〇. 60 g, 4_3 mmol) and DMF (10 mL) gave compound 13 (0. 05g, 39%). ESIMS m/z: 4 5 7(Μ-Η)·;1Η NMR (270MHz, DMSO-d6)5 7. 10(t, J = 8. 1Hz, lH)7. 28(d, J = 7. 6Hz, 1H), 7. 39(t, J = 7. 6Hz, 1H), 7. 52(t, J = 7. 6Hz, 1H), 7. 69 (d, J = 8. 1Hz, 1H), 7. 91(d, J = 8. 1Hz, 1H), 8. 11(d, J = 7. 6Hz, 1H), 8. L7(s, 1H), 8. 33(s, 2H), 9_28(s,1H) 〇-71 - 200911240 Example 1 4 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-( Piperazin-1-yl)phenyl]amino-1 Η-pyrazole (Compound 1 4 ) (Step 1) 3-Fluoronitrobenzene (3. 1 g, 22 mm 〇 l) dissolved in DMSO (35 mL), added piperidine (12. 1 mL of 85 mmol). After stirring at 100 ° C for 7 hours, water (40 mL) was added and ethyl acetate (100 mL) was evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1 / /) to give 1-(3-nitrophenyl)piperidine (4 - 45 g, 97%). ESIMS m/z: 20 7 (M + H) VH NMR (270MHz, CDC13)6 1. 5 7- 1 . 75(m, 6H), 3_26(t, J = 5. 3Hz, 4H), 7. 1 7 (m, 1 H), 7. 33 (m, 1H), 7. 59(m, 1H), 7. 70 (m, 1H). (Step 2) The 1-(3-nitrophenyl)piperidine obtained in Step 1 (4. 4g, 21mmol) dissolved in methanol (114mL), forced into ammonium formate (6. 8g, 118mm〇l) with 10% palladium-carbon (〇.  4 4 0 g). The mixture was stirred under heating and reflux for 3 hours. After the residue was added to water (50 mL), ethyl acetate (0. 200L) extraction. After the organic layer was dried over anhydrous sodium sulfate, EtOAc was evaporated. 3-(piperidin-1-yl)phenylamine was obtained by purifying the residue with a silica gel column chromatography (hexane/ethyl acetate = 4/1). 6g, 96%) ° -72 - 200911240 ESIMS m/z: 177(M + H) + ;1H NMR(270MHz, CDC13)S 1. 5 5 - 1 , 76 (m, 8H), 3 .  1 2 (t, J = 5 · 3 H z, 4 H), 6. 1 8 (m, 1 H), 6_27 (m, 1H), 6. 38 (m, 1H), 7_02 (m, 1H). (Step 3) According to Step 1 of Example 1, 3-(piperidin-1-yl)phenylamine obtained in Step 2 (3. 6g, 20mmol), [bis(methylthio)methylene]malononitrile (3. 4g, 20mmol) and ethanol (40mL) gave 2-{methyl-propenyl-[3-(piperidin-bu)phenyl]aminomethylene}malononitrile (5. 2g, 99%). ESIMS m/z: 299 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 1. 53 - 1. 64 (m, 6H), 2. 51(s, 3H), 3. 16(m, 4H), 6. 64(m, 1H), 6 _ 8 2 (m, 2 H), 7 _ 2 0 (m, 1 H), 1 0 _ 4 3 (s, 1 H). (Step 4) According to Step 2 of Example 1, 2, 2-{methylsulfonyl-[3-(piperidin-1-yl)phenyl]aminomethylene}propane obtained in Step 3 Dinitrile (5. 2g, 17mmol), hydrazine monohydrate (2_9mL, 60mmol) and ethanol (50mL) give 5-amino-4-cyano-3-[3-(indolyl-1-yl)phenyl]amine Base-1H - Sakaguchi sitting (4. 1 g, 8 3 %). ESIMS m/z: 2 8 3 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 1. 5 2- 1. 60 (m, 6H), 3. 07(m, 4H), 6. 24(s, 2H), 6. 36(m, 1H), 6. 89-7_01(m, 2H), 7. 09(s, 1H), 8. 10(s, 1H), ll. l(s, 1H). (Step 5) -73- 200911240 5-Amino-4-cyano-3-[3-(piperidin-1-yl)phenyl]amino-1H-pyrazole obtained in Step 4 (2 . 0g, 7_lmmol) and potassium carbonate (3. 9g, 28mmol) suspended in DMF (10 mL), added 2-chlorobenzothiazole (l. OmL, 7. 8mmol). After stirring at 100 ° C for 3 hours, water (1 mL) was added to the reaction mixture to give crude crystals. The obtained crude crystals were purified by ruthenium dioxide colloidal column chromatography (hexane/ethyl acetate = 3/1), further dichloroethane (20 mL) was added, and the slurry was further slurried at 80 ° C to obtain Compound l4 (〇. 81g, 2 8%) ° ESIMS m/z: 416(M + H) + ; 'H NMR (270MHz? DMSO-d6)8 1. 5 7- 1. 66(m, 6H), 3. 18-3. 21 (m, 4H), 6. 50 (m, 1H), 7. 08- 7.  1 3 (m, 2H), 7. 34-7. 41(m, 2H), 7. 52(t, J = 8. 0Hz, 1H), 7. 90 (d, J = 8. 0Hz, 1H), 8. 08(d, J = 8. 0Hz, 1H), 8. 28(s, 2H), 8. 92(s, lH); Anal.  Calcd for C22H2iN7S: C, 63. 5 9;H, 5. 09;N, 23. 60.  Found: C, 63. 84; H, 4. 82;N, 23. 51. Example 1 5 5-Amino-1-(benzothiazol-2-yl)-4-yl-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1 Η-pyrazole ( Compound 1 5 ) (Step 1) According to Step 1 of Example 14, from 3-fluoronitrobenzene (3. 1 g, 22 mmol), morpholine (ll mL, 122 mmol) and DMSO (35 mL) > 1 g , 90%). ESIMS m/z: 209 (Μ + Η) + ; *Η NMR (270 MHz, DMSO-d6) 5 3. 24(t, J = 4. 7Hz, 4H) 3. 76(t, J = 4. 7Hz, 4H), 7. 41(m, 1H), -74- 200911240 7_50(m, 1 H), 7. 63 (m, 2H). (Step 2) According to the step 2 of Example 1, 4 - (3-nitrophenyl) morphine obtained in the step 1 (4. 1g, 20mmol), tannic acid (6. 2 g, 98 mm 〇l), 10% palladium-carbon (410 mg) and methanol (80 mL) gave 3-(morpholin-4-yl)phenylamine (3-2 g, 92%). ESIMS m/z: 179 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) S 2. 99(t, J = 4. 8Hz, 4H), 3. 70(t, J = 4. 8Hz, 4H), 4. 87(s, 2H), 6. 04-6. 14 (m, 3H), 6. 86(t, J = 7. 7 Hz, 1H) 〇 (Step 3) According to Step 1 of Example 1, 3-(morpholin-4-yl)phenylamine (3_lg, 18 mmol) obtained in Step 2, [bis(methylthio)) Methylene]malononitrile (3. 0g, 18mmol) and ethanol (40mL)' gave 2-{methylsulfonyl-[3-(morpholin-4-yl)phenyl]aminomethylene}malononitrile (4. 4g, 83%). ESIMS m/z: 301 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 22 (m, 7H), 3. 33(m, 4H), 7 · 0 0 - 7 _ 0 7 ( m, 3 H), 7 · 1 7 (d , J = 8. 0Hz, 1 H), 1 0_5(s, 1 H). (Step 4) According to Step 2 of Example 1, 2 -丨methylsulfonyl-[3-(morpholin-4-yl)phenyl]aminomethylene}propyl obtained in Step 3 Dinitrile (4. 3g, 14mmol), hydrazine monohydrate (2. 4mL, 50mmol) and ethanol (7〇mL) '-75- 200911240 to give 5-amino-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (4 · 1 g, 1 0 0 %). ESIMSm/z: 285 (M + H) VH NMR (270 MHz, DMSO-d6) S 3. 03(t, J = 4. 8Hz, 4H), 3. 72(t, J = 4. 8Hz, 4H), 6. 26(s, 2H), 6. 38(d, J = 7. 1Hz, 1H), 6. 95 -7. 05 (m, 2H), 7. 11(s, 1H), 8.  16(s, 1H), 1 1 .  13(s, 1H). (Step 5) According to Step 3 of Example 1, 5-amino-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H- obtained in Step 4. Pyrazole (丨. 5g, 5_3mmol), 2-chlorobenzothiazole (〇_82mL, 6_3mmol), potassium carbonate (4_4g, 32mmol) and DMF (30mL)' gave compound I5 (0. 96g, 44%). ESIMS m/z: 418 (M + H) + ; 1h NMR (2 70 MHz, DMSO-d6) 5 3. 14(t, J = 4. 6Hz, 4H), 3. 79(t, J = 4. 6Hz, 4H), 6. 55(m, 1H), 7. 14(m, 2H), 7. 36(m, 1H), 7. 42(m, 1H), 7. 51(m, 1H), 7. 89(d, J = 8. 0Hz, 1H), 8. 1〇(d, J.  = 7. 0Hz, 1H), 8. 29(s, 2H), 8. 98(s, 1H); Anal.  Calcd for C 2 i H , 9N 7 0 S : C , 6 0. 42; H, 4. 59;N, 23. 49. Found: C, 60. 3 0; H, 4. 33;N, 23. 31. Example 1 6 5 -Amino-1 -(benzothiazol-2-yl)-4-cyano-3 -[ 3 -(pyrrolidin-1-yl)phenyl]amino-1H-pyrazole ( Compound 16) (Step 1) According to Step 1 of Example 14, from 3-fluoronitrobenzene (3.  Lg, -76- 200911240 22mmol), H ratio Π ( (8. 7 g, 122 mmol) and DMSO (35 mL) gave 1-(3-nitrophenyl)pyrrolidine (3. 6 g , 8 3 %). ESIMS m/z: 193(Μ + Η) + ;*Η NMR (270MHz, DMSO-d6)5 1. 96-2. 01(m, 4H), 3. 30 (m, 4H), 6. 95(m, 1H), 7. 22(s, 1H), 7. 3 7-7. 44 (m, 2H Bu (Step 2) According to Step 2 of Example 1, 4 (3 - nitrophenyl) masculine (3 - 5 g, 18 mmol), ammonium formate (5. 7 g, 91 mmol), 10% palladium-carbon (350 mg) and methanol (70 mL) gave 3-(pyrrolidin-1-yl)phenylamine (2 _ 2 g, 7 5 %). ESIMS m/z: 163 (M + H) +; 1H NMR (270MHz, DMSO-d6) 5 1 -92 (m, 4H), 2. 54(s, 2H), 3. 14(m, 4H), 5. 76(m, 2H), 5_85(m, 1H), 6. 75(t, J = 7. 7Hz, 1H). (Step 3) According to Step 1 of Example 1, 3-(pyrrole D-l-yl)phenylamine obtained in Step 2 (2. 2g, 14mmol), [bis(methylthio)methylene]malononitrile (2. 3 g, 14 mmol) and ethanol (70 mL) gave 2-{methylsulfonyl-[3-(pyrrolidin-1-yl)phenyl]aminomethylene}malononitrile (2-6 g, 67%). ESIMS m/z: 28 5 (M + H) +; 'H NMR (2 70 MHz, DMSO-d6) 5 1-93 - 1. 9 8 (m, 4H), 2. 50(s, 3H), 3. 22(t, J = 6. 5Hz, 4H), 6. 40-6. 44(m, 2H), 6. 50 (m, 1H), 7. 16(t, J = 7. 9Hz, 1H), 10. 47(s, 1H). -77- 200911240 (Step 4) According to Step 2 of Example 1, 2 - {methylsulfonyl-[3-(pyrrolidin-1-yl)phenyl]aminocarbide obtained in Step 3 Methyl}malononitrile (2. 6g, 9. 1 mmol), hydrazine monohydrate (i. 5 mL, 32 mmol) and ethanol (50 mL) gave 5-amino-4-cyano-3 -[3-(pyrrolidin-1-yl)phenyl]amino-1 hydrazine-pyrazole (2. 5 g, 1 0 0 %). ESIMS m/z: 269(M + H) + ; 1 Η N M R ( 2 7 0 Μ ζ ζ, D M S Ο - d 6) δ 1. 92(t, J = 6. 2Hz, 4Η), 3.  1 7 (t, J = 6. 2Hz, 4H), 6. 00 (d, J = 8. 0Hz, 1 H), 6. 19(s, 2H), 6. 67-6. 72 (m, 2H), 6. 94(t, J = 8. 0Hz, 1H), 8. 08(s, 1H). (Step 5) According to Step 3 of Example 3, 5-amino-3-[3-(pyrrolidin-1-yl)phenyl]amino-1H-pyrazole obtained in Step 4 (1. Og, 3_5mmol), 2-chlorobenzothiazepine (l. lmL, 8. 4mmol), cesium carbonate (1. 9g, 14mmol) and D M F (1 8 m L) give compound 1 6 (0. 0 5 9 g, 4 %). ESIMS m/z: 402 (Μ + Η) + ; *Η NMR (270 MHz, DMSO-d6) 5 l_99 (t, J = 6. 3Hz, 4H), 3,26 (t, J = 6. 4Hz, 4H), 6. 15(d, J = 7. 9Hz, 1H), 6. 91 (d, J = 7. 9Hz, 1H), 7. 0 2 - 7. 0 8 (m , 2H), 7. 38(t, J = 7. 9Hz, 1H), 7. 51(t, J = 7. 9Hz, 1H), 7. 89 (d, J = 7-9Hz, 1H), 8. 08(d, J = 7. 9Hz, 1H), 8. 26(s, 2H), 8. 87(s, 1H). -78- 200911240 Example 1 7 .  5-amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(4-methylpiperazin-1-yl)phenyl]amino-1H-pyrazole ( Compound I7) (Step 1) According to Step 1 of Example 14, from 3-fluoronitrobenzene (3. 1 g, 22 mmol), N-methylpiperazine (122 g, 122 mmol) and DMSO (35 mL) gave 1-methyl-4-(3-nitrophenyl)piperazine (4·6 g, 93%) ). ESIMS m/z: 222 (M + H) + ; 1H NMR (270MHz, CDC13) 6 2. 36(s,3H), 2. 59(t, J = 5. 1Hz, 4H), 3. 30 (t, J = 5, 1 Hz, 4H), 7.  1 8 (dd, J = 8. 4, 2. 5Hz, 1 H ), 7. 3 7 (t, J = 8 _ 2 H z , 1H), 7. 65 (dd, J = 8. 1,2. 0Hz, 1H), 7. 72(t, J = 2. 2Hz, 1H). (Step 2) According to the step 2 of Example 1 4', 1-methyl-4-(3-nitrophenyl)piperazine obtained in the step 1 (4. 6g, 22mmol), ammonium citrate (6. 8 g, 108 mmol), 10% palladium-carbon (45 〇 mg) and methanol (80 mL) gave 3-(4-methylpiperazin-1-yl)phenylamine (3. 〇g, 72%). ESIMS m/z: 192 (M + H) + ; 'H NMR (270MHz, CDC13) 5 2_33 (s, 3H), 2. 56 (m, 4H), 3_19 (m, 4H), 3. 60(s, 2H), 6_20- 6. 28(m, 2H), 6. 37(m, 1H), 7. 05 (m, 1H). (Step 3) According to Step 1 of Example 1, the 3-(4-methylpiperazin-1-yl)phenylamine obtained in Step 2 (3. 0g, 〗 6mmol), [bis(methylthio)methylene]-79- 200911240 malononitrile (2. 7g, l6mmol) and ethanol (70mL)' gave 2-{[3-(4-methylpiperazin-1-yl)phenyl]amino(methylsulfonyl)methylene}malononitrile (4 . 0g, 8 2%) ° ESIMS m/z: 314 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2. 39(s, 3H), 2. 45(s, 3H), 2. 76(m, 4H), 3. 21 (m, 4H), 6. 56(d, J = 7. 9Hz, 1H), 6. 69-6. 7 5 (m, 2H), 7. 16(t, J = 7. 9 Hz, 1H) ° (Step 4) According to Step 2 of Example 12 '2-{[3-(4-Methylpiperazin-1-yl)phenyl]amine (methyl) obtained in Step 3 Sulfomethyl)methylene}malononitrile (4. 0g, 13mmol), hydrazine monohydrate (2. 1 mL, 44 mmol) and ethanol (60 mL) gave 5-amino-4-cyano-3-[3-(4-methylpiperazin-1-yl)phenyl]amino-1 hydrazine-pyrazole (3 · 6 g , 9 6 %). ESIMS m/z: 29 8 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 6 2. 21(s, 3H), 2. 43(t, J = 4. 7Hz, 4H), 3. 07(t, J = 4. 7Hz, 4H), 6. 24(s, 2H), 6. 37(d, J = 8. 1Hz, 1H), 6. 91(d, J = 8. 1Hz, 1H), 6. 99(t, J = 8. 1Hz, 1H), 7. 07(s, 1H), 8. 15(s, 1H), 9. 10(s, 1H) (Step 5) According to Step 3 of Example 1, 5-amino-4-cyano-3-[3-(4-methylpiperazine-bu-ki) obtained in Step 4 Phenyl]amino-1H-pyrazole (1. 5 g, 5. 0mmol), 2-chlorobenzothiazole (〇. 78mL, 6. 0mmol), potassium carbonate (4. 2g, 30mmol) and DMF (30mL) gave compound 17 (0. 75g, 34%). ESIMS m/z: 431 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 5 - 80 - 200911240 2. 24(s, 3H), 2. 50(t, J = 4. 8Hz, 4H), 3. 18(t, J = 4. 8Hz, 4H), 6. 54(m, 1H), 7. 11(m, 2H), 7. 38(m, 2H), 7. 51(m, 1H), 7. 90 (d, J = 8. 0Hz, 1H), 8. 10(d, J = 8. 0Hz, 1H), 8. 28(s, 2H), 8. 95(s, 1H); Anal.  Calcd for Ci8Hi4N6S · 0. 9H2〇: C, 59. 63; H, 5, 32; N, 25. 29.  Found: C, 5 9. 48; H, 5.  1 5;N, 25. 02. Example 1 8 4 - { 3 - [ 5 -Amino-1 -(benzothiazol-2-yl)-4-cyano-1 Η-pyrazol-3-ylamino]phenyl}piperazine- 1-carboxylic acid tert-butyl ester (Compound 18) (Step 1) According to Step 1 of Example 14, from 3-fluoronitrobenzene (1. 5g, lOmmol), 1-t-butoxycarbonylpiperazine (2_7g, 14mmol) and DMS oxime (50mL) afforded the tert-butyl 4-(3-nitrophenyl)piperazine-1-carboxylate ( 1 .  7 g, 5 2 %). ESIMS m/z: 3 0 8 (M + H) + ; *H NMR (270MHz, CDC13) 5 1-48 (s, 9H), 3. 24(t, J = 5. 2Hz, 4H), 3. 61(t, J = 5. 2Hz, 4H), 7-19 (dd, J = 8. 4, 2. 5Hz, 1H), 7. 39(t, J = 8. 4Hz, 1H), 7. 67- 7. 73 (m, 2H). (Step 2) According to the step 2 of Example 14, the 4:(3 _nitrophenyl)piperazine-b-carboxylic acid tert-butyl ester obtained in the step 1 (1. 7g, 5. 5mm〇l), fort money 〇. 7g, 27mmol), 1% palladium-carbon (170mg) and methanol (30mL)' obtained -81 - 200911240 4-(3-aminophenyl)piperazine-1-carboxylic acid tert-butyl ester (1. 7g, 100%). ESIMS m/z: 278(Μ + Η) + ;*Η NMR(270MHz, CDC13)5 1. 48(s, 9H), 3. 10(t, J = 5. 2Hz, 4H), 3. 55(t, J = 5. 2Hz, 4H), 3. 62(s, 2H), 6. 22-6. 26(m, 2H), 6. 3 5 ( m , 1 H), 7. 04 (m, 1 H). (Step 3) According to Step 1 of Example 1, the 4-(3-aminophenyl)piperazine obtained in Step 2. 1-carboxylic acid tert-butyl ester (1. 7g, 5. 5mmol), [bis(methylthio)methylene]malononitrile (0. 94g, 5. 5mm〇l) and ethanol (30mL) to give 4-[3-(2,2-dicyano-1-methylsulfonylvinylamino)phenyl]piperazine-1-carboxylic acid tertidine Ester (l_9g, 85%). ESIMS m/z: 400 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) S 1. 41(s, 9H), 2. 48(s, 3H), 3. 13(t, J = 4. 5Hz, 4H), 3. 45(t, J = 4. 5 H z , 4 H ), 6 · 6 7 (d, J = 7. 6 H z,1 H ),6 _ 8 1 (m , 2 H),7 · 2 2 (t, J = 7. 6Hz, 1H), 10. 3 (s, 1H). (Step 4) According to Step 2 of Example 1, 2 - [ 3 -(2,2-dicyano-1-methylsulfonylvinylamino)phenyl]piperidyl obtained in Step 3 Pyridine-1-carboxylic acid second butyl vinegar (1. 8g, 4_5mmol), hydrazine monohydrate (〇. 76 mL, 16 mmol) and ethanol (30 mL) 'obtained 4-[3-(5-amino-4-amino-1Η-indolyl-3-amino)phenyl]piperazine-1-carboxylic acid Butyl ester (1. 6g, 91%). ESIMS m/z: 3 84 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 8 -82- 200911240 l-41(s, 9H), 3. 03(t, J = 4. 9Hz, 4H), 3. 44(t, J = 4. 9Hz, 4H), 6. 27(s, 2H), 6. 39(d, J = 7. 1Hz, 1H), 6. 99-7. 04(m, 2H), 711(s, 1H), 8. 17(s, 1H), 11. 14(s, 1H). (Step 5) According to Step 3 of Example 1, 4-[3-(5-Amino-4-cyano-1H-pyrazole-3-ylamino)phenyl]piperidyl obtained in Step 4 Triazine ester of azine-1-carboxylic acid (0. 22g, 0. 57mmol), 2-chlorobenzothiazole (0_09mL, 0. 69 mmol), potassium carbonate (0-48 g, 3_4 mmol) and DMF (5 mL) afforded Compound 18 (0·1 3 g, 42%). ESIMS m/z: 517 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 5 1. 43(s, 9H), 3. 14(t, J = 5. 0Hz, 4H), 3. 50(t, J = 5. 0Hz, 4H), 6. 56(m, 1H), 7. 10-7. 19(m, 2H), 7. 35-7. 41(m, 2H), 7. 51(t, J = 7. 9Hz, 1H), 7. 89 (d, J = 7. 9Hz, 1H), 8. 06(d, J = 7. 3Hz, 1 H), 8. 26(s, 2H), 8. 96(s, 1 H). Example 1 9 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(piperazin-1-yl)phenyl]amino-1H-pyrazole ( Compound 19) Compound 1 8 (100 mg, 0.  1 9 m m ο 1) Suspended in dichloromethane (1 mL), force [] into trifluoroacetic acid (〇. 5 mL) was stirred for 3 hours. After the reaction mixture was concentrated under reduced pressure, a 1 m EtOAc /EtOAc. After the organic layer was dried over anhydrous sodium sulfate, it was concentrated under reduced pressure. By adding dichloroethane (10 m L) to the residue and then slurrying, it is obtained. -83- 200911240 Compound 1 9 (0. 0 1 5 g, 1 9 %). ESIMS m/z: 417 (M + H) +; 'H NMR (270 MHz, DMSO-d6) 5 3. 14(m, 4H), 3. 20 (m, 4H), 6. 57(m, 1H), 7. 15(m, 2H), 7. 36-7. 44 (m, 2H), 7. 51(t, J = 8. 2Hz, 1H), 7. 90d, J = 8. 2Hz, 1H), 8. 09(d, J = 8. 2Hz, 1H), 8. 29(s, 2H), 9_00(s, 1H). Example 2 0 3-[3-(4-Ethylpiperazin-1-yl)phenyl]amino-5-amino-1-(benzothiazol-2-yl)-4-cyano- 1H-pyrazole (Compound 20) Compound 19 (78 mg, 0. 19 mmol) suspended in dichloromethane (1 mL) with pyridine (0. 075mL), add anhydrous acetic acid (〇. 〇 35mL). By stirring at room temperature for 12 hours, hexane/ethyl acetate = 4/l (3. 〇mL), then slurry, to obtain compound 20 (0. 077g, 90%). ESIMS m/z : 45 9(M + H) + ; 'H N M R (2 7 Ο Μ H z, D M S 0 - d 6) δ 2 _ 〇 7 ( s, 3 Η), 3 .  1 7 (m,4 Η),3 , 6 2 (m,4 Η),6 , 5 7 ( m , 1 Η), 711-7. 19(m, 2Η), 7. 36-7. 41(m, 2Η), 7. 52(t, J-7. 8Hz, 1H), 7. 90 (d, J = 7. 8Hz, 1H), 8. 09(d, J = 7. 8Hz, 1 H), 8. 29(s, 2H), 8. 99(s, 1 H). Example 2 1 5-Amino-l-(6-chlorobenzothiazol-2-yl)-4-cyano-3- [3-(morpholin-4-yl)phenyl]amino-1 Η - Pyrazole (Compound 2 1 ) According to Step 3 of Example 1, 5-amino-4-cyano-3-[3-(morpholin-4-yl) obtained in Step 4 of Example 15. Phenyl]amino-1Η-pyrazole-84- 200911240 (0. 1 0 g, 0. 3 5mmol), 2,6-dichlorobenzothiazepine π sitting (O. Llg, 0. 53 mmol), potassium carbonate (〇_29 g, 2-1 mmol) and DMF (5 mL) gave Compound 2 1 (0. 05 3 g, 33%). ESIMS m/z: 452 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 5 3. 14(t, J = 4. 5Hz, 4H) 3. 80(t, J = 4. 5Hz, 4H), 6. 56(m, 1H), 7. 12-7. 14(m, 2H), 7. 42(s, 1H), 7. 54 (dd, J = 8. 7, 2. 1Hz, 1H), 7. 88(d, J = 8. 7Hz, 1H), 8. 26(m, 1H), 8. 27(s, 2H), 9. 00(s, 1 H); Anal.  Calcd for C 2 ι Η 18 N 7 0 S : C , 55. 8 1 ;H, 4. 0 1 ;N, 21. 69.  Found: C, 55. 81; H, 3. 62;N, 21. 60. Example 22 5-Amino-4-cyano-1-(6-methoxybenzothiazol-2-yl)-3-[3-(morpholin-4-yl)phenyl]amino-1H -pyrazole (Compound 22) 5-Amino-4-cyano-3 [3-(morpholin-4-yl) obtained in Step 4 of Example 15 according to Step 3 of Example 1. Phenyl]amino-1H-pyrazole (0. 10g, 0. 35mmol). 2-chloro-6-methoxybenzothiazole (0. 1 lg, 0. 53mmol), potassium carbonate (0. 29g, 2. 1 mmol) and DMF (5 mL) gave compound 22 (0. 0098g, 6%). ESIMS m/z: 44 8 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 3. 15(m, 4H), 3. 80 (m, 4H), 3. 84(s, 3H), 6. 55 (d, J = 7. 2Hz, 1H), 7. 09-7. 13(m, 3H), 7. 44(s, 1H), 7. 71(d, J = 2. 5Hz, 1H), 7. 79(d, J = 8. 9Hz, 1 H), 8. 19(s, 2H), 8. 95(s, 1 H); Anal.

Calcd for C22Η2iN7〇2S: C, 58.81; H, 4.76; N, 21.82. Found: C, 58.45; H, 4·47; Ν, 21_48. -85- 200911240 Example 23 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-isopropoxyphenyl)amino-1 Η-pyrazole (Compound 2 3 ) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (1.0 g, 5.9 mmol), 3-isopropoxyaniline (0) 8 9g, 5 9mmo 丨) gave 2-[(3-isopropoxyphenyl)amino (methylsulfonyl)methylene]malononitrile (1. lg, 70%). ESIMS m/z: 274 (M + H) + (Step 2) According to Step 2 of Example 1, 2-[(3-isopropoxyphenyl)amino group obtained in Step 1 Mercapto)methylene]malononitrile (1.Og, 3.7 mmol) and hydrazine monohydrate (0.59 mL, 12 mmol) gave 5-amino-4-cyano-3-(3-isopropoxy) Phenylphenyl)amino-1H-pyrazole (750 mg, 80%). ESIMS m/z: 25 8 (M + H) + (Step 3) According to Step 3 of Example 1, 5-amino-4-cyano-3-(3-isopropoxy) obtained in Step 2 Phenylphenyl)amino-1H-pyrazole (0.7 70 g, 3.0 mmol), potassium carbonate (1.6 g, 12 mmol) and 2-chlorobenzothiazepine (0.34 mL, 2.6 mmol) afforded Compound 23 (0.40 g, 34%). ESIMS m/z: 391 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 -86- 200911240 1.12 (d, J = 7.2 Hz, 3H) 1.15 (d, J = 7.2 Hz, 3H) , 3.90(m, 1H), 7.23(br d, J = 8.3Hz, 1H), 7.29(br d, J = 8.3Hz, 1H), 7.37(t, J = 8.3Hz, 1H), 7.50(t, J = 8.3Hz, 1H), 7.68(br s, 1H), 7.87(d, J = 7.3Hz, 1H), 7.91(t, J = 7.3Hz, 1H), 8.〇〇(d, J = 7.3 Hz, 1H), 8 · 0 9 (brs, 2 H), 9 · 01 ( s , 1 H). Example 2 4 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-phenoxyphenyl)amino- 1 Η-pyrazole (Compound 2 4 ) (Step 1) According to Step 1 of Example 1, 'from [bis(methylthio)methylene]malononitrile (0.80 g, 4.7 mm), 3-phenoxyaniline (0.87 mg, 4.7 mmol) 2-[(3-Phenoxyphenyl)amino (methylsulfonyl)methylene]malononitrile (0.95 g, 66%) ° ESIMS m/z: 3 08 (M + H) + (Step 2) According to Step 2 of Example 1, 2-[(3-phenoxyphenyl)amino (methylsulfonyl)methylene]malononitrile (〇) obtained in Step 1. .95g, 3 · 1 mm ο 1) and hydrazine monohydrate (0.5 0 m L, 10 mm ο 1) to give 5-amino-4-cyano-3-(3-phenoxyphenyl) Amino-1 Η-pyrazole (〇_73 g, 81%). ESIMS m/z: 292 (M + H) + (Step 3) -87- 200911240 According to Step 3 of Example 1, the 5-amino-4-cyano-3-(3-) obtained in Step 2 Phenoxyphenyl)amino-1H-pyrazole (0.64g, 2_2mmol), potassium carbonate (1.2g, 8.7mmol) and 2-chlorobenzothiazole (0.25mL, 1 · 9mm ο 1) ' 2 4 (0 _ 4 8 g, 5 2 %). ESIMS m/z: 425 (M + H)+; 1H NMR (270MHz, DMSO-d6) 5 7.18-7.25 (m, 2H), 7.27 (brd, J = 8.3 Hz, 1H), 7.31-7.40 (m , 5H), 7.45-7.91 (m, 4H), 7.94 (d, J = 7.0 Hz, 1H), 8.00 (br s, 2H), 8 70 (br s, 1 H). Example 2 5 5-Amino-3-(1,3-benzobisoxazol-5-yl)amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazole (Compound 25) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0.50 g, 2.9 mmol) and 3,4-methylenedioxyaniline ( 〇.4〇§, 2.9mm〇l), 2-[(1,3-benzobisoxazol-5-ylamino)methylsulfonylmethylene]malononitrile (〇.79g, 99%). ESIMS m/z: 260 (M + H) + (Step 2) According to Step 2 of Example 1, 2-[(1,3-benzobisoxazol-5-ylamino) obtained in Step 1 Methylsulfonylmethylene]malononitrile (0.79 g, 3.0 mmol) and hydrazine monohydrate (〇.49 mL, 10 mmol) afforded 5-amino-3-(1,3-benzo-2) Oxazol-5-yl)amino-4-cyano-1H-pyrazole-88 - 200911240 (0_65 g, 8 8%). ESIMS m/z: 244 (M + H) + (Step 3) 5-Amino-3-(1,3·benzobisoxazole-5) obtained in Step 2 according to Step 3 of Example 1. -yl)amino-4-cyano-1H-pyrazole (〇.62g, 2.6mmol) and potassium carbonate (1.4g, 10mmol) and 2-chlorobenzothiazole (〇.29mL, 2 · 2 mm ο 1 ), compound 2 5 (0 _ 5 8 g, 60%) was obtained. ESIMS m/z: 3 77 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 6 5.68 (s, 2H), 6.85 (s, 1H), 7.01 (d, J = 7.8 Hz, 1H) , 7.23(br d, J = 8.3Hz, 1 H), 7.2 1 (d, J-7.8Hz, 1 H), 7.29(br d, J = 8.3Hz, 1H), 7.37(t, J-8.3Hz , 1H), 7.50 (t, J = 8.3 Hz, 1H), 8.28 (br s, 2H), 8.70 (br s, 1 H). Example 26 5-Amino-1-(benzothiazol-2-yl)-3-(4-chloro-3-methoxyphenyl)amino-4-cyano-1 Η-pyrazole (Compound) 2 6) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (1.0 g, 5.9 mmol) and 4-chloro-3-methoxyaniline ( 〇.93g, 5.9mmol) gave 2-[(4-chloro-3-methoxyphenyl)amino (methylsulfonyl)methylene]malononitrile (〇.71 g, 44%). ESIMS m/z: 280 (M + H) + -89 - 200911240 (Step 2) 2-[(4-chloro-3-methoxyphenyl) obtained in Step 1 according to Step 2 of Example 1. Amino (methylsulfonyl)methylene]malononitrile (〇.7〇g, 2.5mmol) and hydrazine monohydrate (〇.40mL, 8.3mmol) give 5-amino-3- (4-Chloro-3-methoxyphenyl)amino-4-aryl-1H-shame (〇.55g, 8 3%) ° ESIMS m/z: 264(M + H) + (Step 3 According to step 3 of Example 1, 5-amino-3-(4-chloro-3-methoxyphenyl)amino-4-cyano-1H-pyrazole obtained in step 2 (〇) .55 g, 2.1 mmol), potassium carbonate (1.2 g, 8.4 mmol) and 2-chlorobenzosinium (0.24 mL, 2-3 mmol) afforded Compound 26 (0.32 g, 39%). ESIMS m/z: 3 98 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 3.92 (s, 3H), 7.22 (brd, J = 8.4 Hz, 1 H), 7.3 0 (brd , J = 8 · 4 H z, 1H), 7.39 (t, J = 8.4Hz, 1H), 7.52 (t, J = 8.4Hz, 1H), 7'73(br s, 1 H), 7.90(d , J = 7.3 Hz, 1 H), 8.08 (d, J = 7.3 Hz, 1 H), 8.33 (br s, 2H), 9.32 (s, 1H) Example 2 7 3-(3-ethylammonium Phenyl)amino-5-amino-1-(benzothiazol-2-yl)-4-aminecarbazinyl-1 oxime-pyrazole (Compound 2 7) (Step 1) According to the procedure of Example 1 1, from [bis(methylthio)methylene]propane-90- 200911240 nitrile (5.0 g, 29 mmol), 3-aminoethenylaniline (4.4 g, 29 mmol) and ethanol (80 mL) to give N- {3-[2,2-Dicyano-1-(methylsulfonyl)vinylamino]phenyl}acetamide (6.4 g, 80%). ESIMS m/z: 2 73 (M + H)VH NMR (270MHz, DMSO-d6) S 2.06 (s, 3H), 2.54 (s, 3H), 6.96 (d, J = 6.4, Hz, 1H), 7.32 -7.37(m, 2H), 7.68(s, 1H), l〇_〇7(s, 1H), 10_55(s, 1H). (Step 2) According to Step 2 of Example 1, N-丨3-[2,2-dicyano-1-(methylsulfonyl)vinylamino]phenyl] obtained in Step 1. Acetamine (6.2 g, 23 mmol) and hydrazine monohydrate (3.8 mL, 78 mmol) gave N-[3-(5-amino-4-cyano-1H-pyrazol-3-ylamino) Phenyl]acetamide (5.8 g, 100%) ° ESIMS m/z: 25 7 (Μ + Η) + ; 'Η NMR (2 70 MHz, DMSO-d6) 5 2.01 (s, 3H), 6.22 (s , 1H), 7.01-7.07(m, 3H), 7.60(s, 1H), 8.33(s, 1H), 8_92(s, 2H), 9_75(s, 1H), 11.17(s, 1H). (Step 3) The N-[3-(5-amino-4-cyano-1H-pyrazol-3-yl)aminophenyl]acetamide obtained in the step 2 (1.0 g, 3.9 mmol) and potassium carbonate (2.7 g, 20 mmol) were suspended in DMF (10 mL), and 2-chlorobenzothiazide (〇.53 mL, 4 · 1 mm ο 1) was added. After stirring at 80 ° C for 3 hours, water (5 m L) was added to the reaction mixture to give a crude crystal. Further, 2 m ο 1 / L sodium hydroxide aqueous solution (3 mL) and DMF (10 mL) were added, and the mixture was stirred at 10 ° C for 5 hours, and then water (5 mL) was added to the reaction mixture -91 - 200911240 to obtain crude crystals. . By further adding methanol, it was further slurried at 60 ° C to obtain Compound 2 7 (0.30 g, 19%). ESIMS m/z: 40 8 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2.06 (s, 3H), 7.05 (d, J = 8.2 Hz, 1H), 7.20 (s, 2H) , 7.23(t, J = 8.2Hz, 1 H), 7.37(t, J = 7.0Hz, 1H), 7.4 8-7.54(m, 2H), 7.65(s, 1H), 7.89(d, J = 7.4 Hz, 1H), 7.93(s, 2H), 8.08(d, J = 7.4Hz, 2H), 9.68(s, 1 H), 9 _ 8 8 ( s , 1 H). Example 2 8 1-(Benzoxazol-2-yl)-5-(benzoxazol-2-yl)amino-4-cyano-3-[3-(morpholin-4-yl) Phenyl]amino-1H-pyrazole (Compound 28) According to Step 3 of Example 1, 5-amino-4-cyano-3-[3-() obtained in Step 4 of Example 15. Morpholin-4-yl)phenyl]amino-1H-pyrazole (0.10 g, 0.35 mmol), 2-chlorobenzopyrene (0.06 mL, O.53 mmol), potassium carbonate (〇.29 g, 2.1 mmol) And DMF (2 mL) gave Compound 28 (0.05 g, 22%) <·ESIMS m/z: 519 (M + H) +; 'H NMR (270 MHz, DMSO-d6) 5 3. 1 6 (t , J-4.4Hz, 4H), 3.79(t, J = 4_4Hz, 4H), 6.60(d, J = 6.7Hz, 1H), 7.20(t, J = 8.1Hz, 1H), 7.34(d, J = 8.1 Hz, 1H), 7.42-7.51 (m, 5H), 7.76-7.81 (m, 3H), 8.63 (m, 1H), 8.83 (m, 2H). Example 29 5-Amino-1-(benzoxazol-2-yl)-4-cyano-3-[3-(morpholin-4-yl)phenyl]-92- 200911240 Amino-1H -Pyrazole (Compound 29) 5-Amino-4-cyano_3_[3-(morphin-4-yl)phenyl]amino-lH-_D obtained in Step 4 of Example 15 Separate (〇.l〇g, 〇.35 mmol) and potassium carbonate (029 g, 2.1 mmol) were suspended in DMF (5 mL) and 2-chlorobenzoxazole (0.06 mL, 0.53 mmol). After stirring at room temperature for 2 hours, water (10 mL) was added to the reaction mixture to give crude crystals. By further adding acetone (10 m L), heating and refluxing to re-slurry to give compound 2 9 (0 · 0 5 g, 3 5%) = ESIMS m/z: 402 (M + H) + ; 1H NMR (2 70MHz, DMSO-d6)5 3.12(t, J = 4.6Hz, 4H)3.78(t, J = 4.6Hz, 4H), 6.55(d, J = 8.1Hz, 1H), 7.15(t, J = 8.1 Hz, 1H), 7.26-7.3 3 (m, 2H), 7.37-7.42 (m, 2H), 7.70 (m, 1H), 7.78 (m, 1 H), 5 . 1 8 ( s, 2 H) , 8.8 9 (s, 1 H); A na 1. Calcd for C21H19N7O2 · O.3H2O 0 . 1 acetone : C , 62.00; H, 4.93; N, 23.7 6. Found: C, 61 ,78;H, 4.59 ;N, 23.41. Example 3 0 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(pyridin-3-yl)phenyl]amino-1H-pyrazole (compound) 30) (Step 1) Addition of compound 13 (0.616 g, 1.34 mmol) in acetonitrile (10 mL)

Di-tert-butyl dicarbonate (〇.88g, 4.0mmol) and 4-dimethylaminopyridinium (〇_16g, 1.3mmol) were added and stirred at room temperature for 1.0 hour. 1.0 mol/L hydrochloric acid and water were added to the reaction mixture, and extracted with ethyl acetate. The organic layer was dried with MgSO.sub. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1) to give 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl) (3) -iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.71 g, 81%). ESIMS m/z: 65 9 (M + H) + (Step 2) 1-(Benzothiazol-2-yl)-5-t-butoxycarbonylamino 3-(3-) obtained in Step 1. (3-butoxycarbonyl)(3-iodophenyl)amino-4-cyano-1H-pyrazole (0.050 g, 0.076 mmol), 3-pyridineboronic acid (O.Ollg, 0.092 mmol), potassium carbonate ( 0_053 g, 0.38 mmol) and {1,1·-bis(diphenylphosphino)iron hydrazine}dichloropalladium(n) (0.006 g, 0.008 mmol) added to water (0.014 mL) and 1,2-dimethoxy Ethylethane (1.6 mL) was heated under reflux for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate and water were added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by preparative thin-layer chromatography (chloroform / methanol = 20/1) to give 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl)[3-(pyridinyl)- 3-yl)phenyl]amino-5-(t-butoxycarbonylamino)-4-cyano-1H-pyrazole (0.040 g, 86%). ESIMS m/z: 6 1 0 (Μ + Η)+. (Step 3) 1-(Benzothiazol-2-yl)-3-(t-butoxycarbonyl)[3-(pyridin-3-yl)phenyl]amino-5 as obtained in Step 2 -(T-butoxycarbonylamino)-4-cyano-1H-pyrazole (0.025 g, 0.040 mmol) was added to trifluoroacetic acid-94-200911240 (1.0 mL) and dichloromethane (1 mL) , stir at room temperature. After 1 hour, it was concentrated under reduced pressure and the residue was suspended in dichloroethane. After stirring for 1 hour, the precipitated white crystals were filtered and dried to give compound 30 (0.016 g, 98% ESIMS m/z: 410 (M + H) VH NMR (270 MHz, DMSO-d6) S 7.33 (br d , J = 8.2Hz, 1H), 7.39(br d, J = 8.2Hz, 1H), 7.40(t, J = 8.2Hz, 1 H), 7.42-7.91(m, 8H), 8.04(d, J = 7.3 Hz, 1H), 8.14 (br s, 2H), 8.80 (s, 1H). Example 3 1 5-amino-1-(benzothiazol-2-yl)-3-(3-bromophenyl) Amino-4-cyano-1H-pyrazole (Compound 31) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (2.0 g, 12 mmol) 3-bromoaniline (2.0 g, 6.5 mmol) gave 2-[(3-bromophenyl)amino (methylsulfonyl)methylene]malononitrile (1. 9 g, 55%). m/z: 295 (M + H) + (Step 2) According to Step 2 of Example 1, the 2-[(3-bromophenyl)amino (methylsulfonyl) amide obtained in Step 1 Methyl]malononitrile (1.2 g, 4.1 mmol) and hydrazine monohydrate (0.66 mL, 14 mmol) gave 5-amino-3-(3-bromophenyl)amino-4-cyano-1H -pyrazole (1.Og, 89%) ESIMS m/z: 279 (M + H) + -95- 200911240 (Step 3) Step 3 according to Example 1 5-Amino-3-(3-bromophenyl)amino-4-cyano-1H-pyrazole (1.0 g, 3.7 mmol), potassium carbonate (2_0 g, 15 mmol) obtained in Step 2. And 2-chlorobenzothiazole (〇.42 mL, 4_0 mmol) gave Compound 3 1 (0·9 9 g, 6 5 %). ESIMS m/z: 411 (M + H) + ; 'H NMR (2 70 MHz , DMSO-d6)5 7.10 (br d, J = 7.8 Hz, 1H), 7.26 (br t, J = 8.1 Hz, 1H), 7.39 (br t, J = 8.1 Hz, 1H), 7.52 (br t, J = 7.8 Hz, 1H), 7.64 (br d, J = 8. 1 Hz, 1H), 7.93 (br d, J = 8.1 Hz, 1H), 8.01 (s, 1H), 8.11 (br d, J = 7.8 Hz, 1H), 8.34 (br s, 2H), 9.36 (s, 1H). Example 3 2 5-Amino-1-(benzothiazol-2-yl)-4-yl-cyano-3-(4-methyl-3-methoxyphenyl)amino-1 Η-pyrazole ( Compound 3 2) (Step 1) To a solution of 2-methyl-5-nitrophenol (5. 〇g, 32 mmol) in acetone (100 mL) was added potassium carbonate (18 s, 130 mmol) and methyl iodide (2.6 mL, 42mmo1) ), stirring vigorously at room temperature. After 6 hours, 'the reaction mixture was filtered,' and the filtrate was concentrated under reduced pressure to give 2-methyl-5-nitroanisole (4 -7 g, 87%). ESIMS m/z: 1 68 (M + H) + (Step 2) 2 -Methyl-5-nitroanisole (4.7 g, -96 - 200911240 28 mmol) obtained in Step 1 was dissolved in ethyl acetate The ester (40 mL) was charged with 10% palladium on carbon (6. 〇g, 2.8 mm ο 1) and stirred vigorously under a stream of hydrogen. After the reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give 4-methyl-trimethoxyaniline (4.0 g, 100%). ESIMS m/z: 1 3 8 (M + H) + (Step 3) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0.98 g, 5.9 mmol) and 4-Methyl-3-methoxyaniline (1.0 g, 5.9 mmol) obtained in Step 2 gave 2-[(4-methyl-3-methoxyphenyl)amine (methylsulfonate) Methyl)malononitrile (1.2 g, 80%). ESIMS m/z: 260 (M + H)+. (Step 4) According to Step 2 of Example 1, 2-[(4-methyl-3-methoxyphenyl)amino (methylsulfonyl)methylene]c-propyl group obtained in Step 3. Dinitrile (1.2 g, 4-7 mmol) and hydrazine monohydrate (〇.56 mL, 12 mmol) afforded 5-amino-4-cyano-3-(4-methyl-3-methoxyphenyl)amine Base-1H-pyrazole (1.3 g, 91%). ESIMS m/z: 244 (M + H) + ° (Step 5) According to Step 3 of Example 1, 5-amino-4-cyano-3-(4-methyl-) obtained in Step 4. 3-methoxyphenyl)amino-1H-pyrazole (〇.83g, -97- 200911240 3.4mmol), potassium carbonate (1.9g, 14mmol) and 2-chlorobenzothiazepine (〇.39mL, 3.0 Methyl) gave compound 32 (0.30 g, 24%). ESIMS m/z: 3 77 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2.33 (s, 3H), 3.72 (s, 3H), 7. 1 9 (br d, J = 8 1 Hz, 1H), 7.26(d, J = 7.7Hz, 1H), 7.31(br d, J = 8.1Hz, 1H), 7.44(t, J = 8.1Hz, 1H), 7.55(t, J = 8.1 Hz, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.99 (s, 1H), 8.20 (br s, 2H), 8.78 (s, 1H). Example 3 3 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(6-methoxypyridine-3-yl)phenyl]amino-1H -pyrazole (Compound 33) (Step 1) 1-(Benzothiazol-2-yl)-5-tert-butoxide obtained in Step 1 of Example 30 according to Step 2 of Example 30 Carbocarbonylamino-3-(t-butoxycarbonyl)(3-iodophenyl)amino-4-cyano-1H-pyrazole (0.10 g, 0_15 «1111〇1), 2-methoxy -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (〇.72g, 0-30 mmol), potassium carbonate (〇.llg, 〇. 76mm〇l) and U,l'-bis(diphenylphosphino)pyrene}dichloropalladium(II) (〇_025 g, 0.030 mmol) give 1-(benzothiazol-2-yl)-5- (t-butoxycarbonyl)amino-4- 4-cyano-3-(tert-butoxycarbonyl)[3-(2-methoxypyridin-5-yl)phenyl]amino-1 Η - Pyrazole (〇·〇8 8 g, 91%). ESIMS m/z: 640 (M + H)+. (Step 2) -98- 200911240 According to Step 3 of Example 30, the 1-(benzothiazol-2-yl)-5-(t-butoxycarbonyl)amino-4- group obtained in Step 1 Cyano-3-(t-butoxy-based)[3-(2-methoxyindole-pyridin-5-yl)phenyl]amino-iH-tl 哩(0.080g, 〇.13mmol Trifluoroacetic acid (1 〇 mL) and dichloromethane (1 mL) gave compound 3 3 (0.02 lg, 38%). ESIMS m/z: 440 (Μ + Η) + ; NMR (270MHz, DMSO-d6) 5 3.92 (s, 3H), 6.92 (d, J = 7.7 Hz, 1H), 7.21 (brd, J = 8.2 Hz, 1H), 7.3 0-7.70(m, 7H), 7.77(s, 1H), 7.9 0 (d J = 7.7 Η z, 1H), 8.33(br s, 2H), 9.00(s,1 H) . Example 3 4 5 -Amino-1-(benzosin-2-yl)-4-chloro-3-(2,3 -mono-amino-1H-indole- 6-yl)amino group -1H-pyrazole (Compound 34) (Step 1) According to Step 1 ' of Example 1, from [bis(methylthio)methylene]malononitrile (〇.44 g, 2.6 mmol) and 6-amino group- 2,3-dihydroindole-1-carboxylic acid tert-butyl ester (0-60 g, 2.6 mmol) gives 6-[2,2-cyano-indole (methyl extended-branched) vinylamino group] -2,3-Dihydroindole-polycarboxylic acid tert-butyl ester (0.70 g, 77%). ESIMS m/z: 3 5 7 (M + H)+. (Step 2) According to Step 2 of Example 1, 6-[2,2-dicyano-1-(methylsulfonyl)vinylamino]-2,3-dihydrogen obtained in Step 1. 3-(5-amino-4-cyano-1H) -pyrazol-3-yl)amino-2,3-dihydroindole-1-carboxylic acid tert-butyl ester (0.64 §, 97%). ESIMS m/z: 341 (Μ + Η)+. (Step 3) According to Step 3 of Example 1, 6-(5-amino-4-cyano-1Η-pyrazol-3-yl)amino 2,3·dihydrogen obtained in Step 2吲哚-1-carboxylic acid tert-butyl vinegar (0.64 g, 1.9 mmol), potassium carbonate (1. 〇g, 7.5 mmol) and 2-chlorobenzithiazole (0.21 mL, 1.6 mmol) gave 6-[5 -amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-ylamino]-2,3-dihydroindole-1-carboxylic acid tert-butyl ester (0.4 8g, 5 4%). ESIMS m/z: 474 (M + H)+. (Step 4) According to Example 3, Step 3 'from 6 - [5 · Amino-1 -(benzothiazol-2-yl)-4-cyano-1indole-pyrazole obtained in Step 3 -3 -yl]amino-2,3-dihydroindole-1-carboxylic acid tert-butyl ester (0.4 〇g, 〇.85mmo1), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL) The compound 34 (0.15 g, 4 6%) ° ESIMS m/z: 374 (M + H) +; 'H NMR (270 MHz, DMSO-d6) 5 2.61 (m, 2H), 3.91 (m, 2H) ), 4.〇2(br s, 1H), 6.85(s, 1H), 6 _ 9 0 (d, J = 7 _ 9 H z,1 H), 7.2 0 (brd, J = 8.3 H z, 1 H ), 7.2 7 (brd, J = 8.3 Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H), 7.48 (t, J = 8_3 Hz, 1H), 7_58 (d, J = 7.9 Hz, 1H ), 8.29 (br s, 2H), 8.83 (s, 1H). -100- 200911240 Example 3 5 5 -Amino-4-cyano-3-(3-(morpholin-4-yl)phenyl]amino-1-(1-phenyl-1H-tetrazole- 5-yl)-1 -pyrimazole (Compound 35) According to Step 3 of Example 1, 5-amino-4-cyano-3-[3-(?) obtained in Step 4 of Example 15. Phenyl-4-yl)phenyl]amino-1H-pyrazole (0.10 g, 0.35 mmol), 5-chloro-1-phenyl-1H-tetramine (0.06 mL, 0.53 mmol), potassium carbonate (0.29 g) , 2.1 mmol) and DMF (2 mL) gave compound 3 5 ( 0.0 8 2 g, 5 5 %). ESIMS m/z: 429 (M + H) + ; 'H NMR (270MHz, DMSO-d6) S 2.95 (t, J = 4.6 Hz, 4H), 3.70 (t, J = 4.6 Hz, 4H), 6.24 ( d, J = 9.3 Hz, 1H), 6.41 (d, J = 8, 1 Hz, 1H), 6.72 (t, J = 8.1 Hz, 1H), 6.79 (s, 1 H), 7.5 9-7.70 (m, 5H), 7.87(s, 2H), 8.63(s, lH); Anal. Calcd for C 21 H 2 〇N i 〇0 : C , 5 8.87; H, 4.70; N, 32.69. Found: C, 58.78; H, 4.47; N, 32.68. Example 3 6 5 -Amino-1-(benzothiazol-2-yl)-4-aminecarbazino-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyridyl Azole (Compound 36) was added to the compound 1 5 (0.10 g, 〇. 3 5 mm ο 1) to 1,4 -B B hospital (10 mL), 2 mol/L aqueous sodium hydroxide solution (2 mL) at 100 ° C. Stir for 5 hours. After neutralizing with 3.0 mol of 1/L hydrochloric acid, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. By re-slurrying the obtained individual with chloroform, 200911240 Compound 3 6 (0.095 g, 65%) was obtained. ESIMS m/z: 43 6(Μ + Η) + ;*Η NMR (270MHz, DMSO-d6)5 3. 1 8(t, J = 4.7Hz, 4H), 3.80(t, J = 4.7Hz, 4H ), 6.54 (d, J = 8.2 Hz, 1 H), 6.94 (d, J = 9.0 Hz, 1 H), 7 · 1 5 (t, J = 8.2 H z , 1 H), 7.18 (s, 2H) ), 7.3 5-7.40(m, 2H), 7.51(t, J = 7.6Hz, 1H), 7.87-7.91(m, 3H), 8.10(d, J = 7.6Hz, 1H), 9_60(s, 1H ). Example 3 7 5 ·Amino-3-(3-aminophenyl)amino-1-(benzothiazol-2-yl)-4-cyano-1 Η-pyrazole (Compound 3 7) ( Step 1) Add ethyl acetate (50 mL), water (35 mL), dibutyl succinate (6.6 g, 30 mmol) to 1,3-phenylenediamine dihydrochloride, and add carbonic acid thereto at 0 ° C. An aqueous solution of potassium (7.6 g, 55 mmol) (15 mL) was stirred at room temperature for 9 hr. The reaction mixture was diluted with EtOAc EtOAc. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1) to afford 3-aminophenylamine carboxylic acid tributyl ester (3.5 g, 60%). 'Η NMR (270MHz, CDC13)6 1.51(s, 9H), 3.66(br s, 2H), 6.36(ddd, J = 8. 1,2.4, 0.7Hz, 1 H), 6.40(br s, 1 H ), 6.54 (ddd, J = 8.1, 1.4, 0.7 Hz, 1H), 6.97 (br s, 1H), 7.03 (t, J = 8.1 Hz, 1H). (Step 2) -102- 200911240 3 -Aminophenylaminecarboxylic acid tert-butyl ester (3.4 g, 16 mmol) obtained in Step 1 was dissolved in ethanol (34 mL), and [bis(methylthio)) Methyl malononitrile (3.0 g, 1 8 mm ο 1), heated to reflux for 5 hours. Next, hydrazine monohydrate (2.4 m L, 4 9 m m ο 1) was added, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure. ethyl acetate (EtOAc) (EtOAc) The residue was triturated with chloroform to give 3-(5-amino-4-cyano-1H-pyrazol-3-ylamino)phenylaminecarboxylic acid tert-butyl ester (4.5 g, 89%). ESIMS m/z: 315 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 8 1.46 (s, 9H), 6.20 (br s, 2H), 6.77 (brd, J = 7.8 Hz, 1H ), 7.00(t, J = 7.8Hz, 1H), 7.06(br d, J = 7.8Hz, 1H), 7.53(br s, 1H), 8.30(br s, 1H), 9_13(s, 1H), 11.18(br s,1H). (Step 3) 3 -( 5 -Amino-4-cyano-1 H-pyrazol-3-ylamino)phenylaminecarboxylic acid tert-butyl ester (3.8 g, 12 mmol) obtained in Step 2. Dissolved in DMF (75 mL), EtOAc (EtOAc, EtOAc (EtOAc) Ethyl acetate (200 mL), hexane (200 mL), water (200 mL), and brine (300 mL) were added to the mixture, and the organic layer was washed twice with saturated brine (300 mL). The sodium was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-chloroform/methanol = 4/1) to give 3-[5-amino-1 -(benzothiazol-2-yl)-4-cyano- 1 Η-pyrazol-3-ylamino]phenylaminecarboxylic acid tert-butyl ester (1.1 g, 21%). -103- 200911240 ESIMS m/z: 44 8(Μ + Η) + ;*Η NMR (270MHz, DMSO-d6)5 1.51(s, 9H), 6.88(br d, J = 8.4Hz, 1H), 7.14 (t, J = 8.4Hz, 1H), 7.3 4-7.45 (m, 2H), 7.51(t, J = 7.6Hz, 1H), 7.90(d, J-7.6Hz, 1H), 7.91(br s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 8.27 (s, 2H), 9.1 6 (s, 1 H), 9.30 (s, 1 H). (Step 4) 3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-ylamino]phenylamine obtained in Step 3 Tributyl carboxylic acid (0.13 g, 0.29 mmol) was added to dichloromethane (3.3 mL) and trifluoroacetic acid (0.65 mL). To the reaction mixture, THF (0.11 mL), EtOAc (EtOAc) . The residue was triturated with (chloroform / methanol = 6 / 1) to afford compound 3 7 (69mg, 68%). ESIMS m/z: 3 4 8 (Μ + Η) + ; 'Η NMR (2 70 MHz, DMSO-d6) S 4.96 (s, 2H), 6.19 (dt, J = 5.9, 3.0 Hz, 1H), 6.81 ( Br s, 1H), 6.8 8 -6.95 (m, 2H), 7.38 (td, J = 7.5, 1.1 Hz, 1H), 7.51 (td, J = 7.5, 1.1 Hz, 1H), 7.89 (br d, J -7.5 Hz, 1H), 8.06 (br d, J = 7.5 Hz, 1H), 8_24 (s, 2H), 8_77 (s, 1H). Example 3 8 5 -Amino-1 ·(benzothiazol-2-yl)-4-cyano-3 -[ 3 -(pyridin-4-yl)phenyl]amino-1H-pyrazole (compound) 38) (Step 1) -104- 200911240 According to Step 2 of Example 30, 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl) obtained in Step 1 of Example 30 (3-Iodophenyl) Amino-5-t-butoxy-amino-amino-4-cyano-indole-sole (0.10 g, 0.15 mmol), 4-indole ratio B-boric acid (0.037 g) , 0.30 mmol), potassium carbonate (O.llg, 0.76 mmol) and {1,1·-bis(diphenylphosphino)iron hydrazine}dichloropalladium(II) (0.025 g, 0.030 mmol) to give 1-( Benzothiazin-2-yl)-3-(t-butoxycarbonyl)[3-(pyridin-4-yl)phenyl]amino-5-(t-butoxycarbonylamino)-4 -Cyano-1H-pyrazole (0-082 g, 89%). ESIMS m/z: 6 1 0 (Μ + Η)+. (Step 2) According to Step 3 of Example 30, 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl)[3-(pyridine-4-) obtained in Step 1 Phenyl]amino-5-(t-butoxycarbonylamino)-4-cyano-1H-pyrazole (30 mg, 0.049 mmol), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL) gave Compound 38 (0.01 lg, 54%). ESIMS m/z: 410 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 7.1 9 (br d, J = 8.2 Hz, 1H), 7.29 (br d, J = 8.2 Hz, 1 H ), 7.3 0(d, J = 8.4, 2H), 7.3 9- 7.5 2(m, 5H), 7.73(br s, 1H), 8.23(d, J = 8.4Hz, 2H), 8.25(br s, 2H), 8.95 (s, 1H). Example 3 9 5 -Amino-3 -[ 3 - 2 -aminopyridin-5-yl)phenyl]amino-1 -(benzothiazol-2-yl)-4-cyano-1H-pyridyl Azole (Compound 39) -105- 200911240 (Step 1) According to the step 2 of Example 30, '1-(benzothiazol-2-yl)-3_ obtained from the step of Example 30 Butoxycarbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (〇.i〇g, 〇.15mmol), 2-amine Pyridinium-5-boronic acid pinacol ester (0.067 g, 0.30 mmol), potassium carbonate (0.10 g, 〇.76 mmol) and {1,1'-bis(diphenylphosphino)pyrene}dichloropalladium (11 (0. 〇25g, 0_03 0mmol) ' Obtained 3-[3-(2-aminopyridin-5-yl)phenyl](t-butoxycarbonyl)amino-1-(benzothiazole-2 -yl)-5-(t-butoxycarbonylamino)-4-cyano-1H-pyrazole (〇.〇80g, 8 4%) ° ESIMS m/z: 626 (M + H)+. (Step 2) According to Step 3 of Example 30, 3-[3-(2-Aminopyridin-5-yl)phenyl](t-butoxycarbonyl)amino-1 obtained in Step 1. -(Benzothiazol-2-yl)-5-(t-butoxycarbonylamino)-4-cyano-1H-pyrazole (70 mg, O.llmmol), trifluoroacetic acid (1.0 mL) Dichloromethane (1.0 mL) gave compound 3 9 (0.01 9 g, 40%). ESIMS m/z: 424 (M + H) + ; 1H NMR (2 70 MHz, DMSO-d6) 5 4.90 (bs, 2H), 7.24 (brd, J = 8.4 Hz, 1H), 7.3 4-7.42 (m , 4H), 7.62(t, J = 8.4Hz, 1H), 7.73 -7.98 (m, 3H), 8.10(s, 1 H), 8_15(s,1H),8_33(br s, 2H), 9_32( s, 1H). Example 4 0-106-200911240 5-Amino-3-[3-(2-aminopyrimidin-5-yl)phenyl]amino-1-(benzothiazole-2-yl)-4-cyano- 1H-pyrazole (Compound 40) (Step 1) 1-(Benzothazin-2-yl)-3-(Step 1) obtained in Step 1 of Example 30 according to Step 2 of Example 30 Tributyloxyindenyl) (3_Yao Phenyl) Amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 0.15 mmol), 2-amino- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrimidine (〇.〇67g, 0.304mm〇l), potassium carbonate (〇.ng , 〇.760mmol) and {Ι,Γ-bis(diphenylphosphino)iron hydrazine}dichloropalladium(H)(〇.〇25g, 0.030mmol), which gives 3-{3-(2-aminopyrimidine- 5-phenyl)phenyl}(t-butoxy-based)amino-1-(benzothiazin-2-yl)-5-second-butyl-mercapto-amino- 4-cyano-1H-pyrazole (0.068 g, 71%). ESIMS m/z: 627 (M + H)+. (Step 2) According to the step 3 of Example 30, 3 - { 3 -(2-aminopyrimidin-5-yl)phenyl}(t-butoxycarbonyl)amino group obtained in the step 1 - 1-(benzothiazol-2-yl)-5-tert-butoxycarbonylamino-4-cyano-1H-pyrazole (60 mg, 0-096 mmol), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL) gave Compound 40 (0.020 g, 49%). ESIMS m/z: 427 (M + H) +; 'H NMR (2 70 MHz, DMSO-d6) 5 5.11 (br s, 2H), 6.89 (d, J = 7.4 Hz, 1H), 7.22 (brd, J = 8.1 Hz, 1H), 7.30-7.52 (m, 4H), 7.30 (s, 1H), 7.75 (d, J = 7.4 Hz, 1H), 8.33 (br s, 2H), 8.50 (s, 2H) , 9.32(s, 1H). -107- 200911240 Example 4 1 5-Amino-4-cyano-M4-isopropylbenzothiazol-2-yl)-3-(3-methoxyphenyl)amino-1H-pyridyl Azole (Compound 41) 5-Amino-4-cyano-3(3-methoxyphenyl)amino-1H obtained from Step 2 of Example 8 according to Step 3 of Example 1. _ shame (0 · 10 g, 0_44 mmol), 2-bromo-4-isopropylbenzothiazole (〇.13g, 0.52mmo1), potassium carbonate (0.30g, 2.2mmol) and DMF (4 m L ) 'Yield compound 4 1 (0.060 g, 35%) ° ESIMS m/z: 404 (MH)';, NMR (270 MHz, DMSO-d6) 5 1.32 (d, J- 6.8 Hz, 6H), 3.7l q, J = 6.9Hz, 1H), 3.78(s, 3H), 6.49(td, J = 4.7, 2.0Hz, 1H), 7.15-7.23(m, 2H), 7.29-7.3 9(m, 2H), 7.44 (d, J = 2.0 Hz, 1 H), 7.89 (dd, J = 7.3, 2.0 Hz, 1H), 8. 1 9 (s, 2H), 9.1 1 (s, 1 H). Example 42 3-(3-Ethylaminophenyl)amino-5-amino-1-(benzothiazol-2-yl)-4-cyano-1 Η-pyrazole (Compound 4 2) Compound 37 (50 mg, 0.14 mmol) was dissolved in DMF (1 mL). After the end of the reaction, THF (20 m L), saturated aqueous sodium hydrogencarbonate (10 m L), and saturated brine (10 m L) were added to separate the organic layer into saturated brine (20 m L ). It was washed twice and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with THF / diisopropyl ether (1 / 2) to give compound -108 - 200911240 42 (35 mg, 62% ESIMS m/z: 3 90 (M + H) +; 'H NMR (270 MHz , DMSO-d6)5 2.06(s, 3H), 7.04(br d, J = 8.3Hz, 1H), 7.20(t, J = 8.3Hz, 1H), 7.38(br t, J = 7.5Hz, 1H) , 7.49(br d, J = 8.3Hz, 1H), 7.51(br t, J = 7.5Hz, 1H), 7.86-7.93 (m, 2H), 8.08(br d, J = 7.5Hz, 1H), 8.28 (s, 2H), 9_18(s, 1H), 9.86 (s, 1H). Example 4 3 5 -amino-1-(benzothiazol-2-yl)-4 -cyano-3- [3 -(4-methylpiperidin-1-yl)phenyl]amino-1H-pyrazole-hydrochloride (Compound 43) To a solution of compound 17 (0.15 g, 0.35 mm), methanol (2-6 mL) and 1 mol /L Hydrochloric acid (0-38 mL, 0.38 mmol), stirred for 1.5 hours. After distilling off the solvent under reduced pressure, the residue was re-slurryed with ethanol to give compound 43 (0.14 g, 8 4%) 3.40 (m, 6H), 3.57(m, 1H), 3.81(m, 1H), 6.62(m, 1H), 7.18-7.19(m, 2H), 7.3 7-7.56(m, 3H), 7.91(d, J = 7.6 Hz, 1H), 8.10(d, J = 7.2Hz, 1H), 8.30(s, 2H), 9.〇4(s, 1H), 10.29(s, lH); Anal. Calcd for C22H23C1N8S · 〇.4H2 〇: C, 5 5.72; H, 5.06; N, 23.63. Found: C, 5 5.61; H, 4.92; N, 23_26° Example 44 5 -Amino-1·(benzothiazol-2-yl)-4-cyano-3- [3-(4-methyl shouting-I - Phenyl]amino-1H-pyrazole-methanesulfonate (Compound 44) -109- 200911240 From compound 17 (0.15 g, 〇.35 mmol), acetal acid (〇. 〇 34 mL, 0.52 mmol) Methanol (3 mL) gave Compound 44 (0.13 g, 70%). <H NMR (270MHz, DMSO-d6) 5 2.3 3 (s, 3H), 2.90 (d, J = 4.3 Hz, 3H), 3.04 ( t, J=12.〇Hz, 2H), 3.22(m, 2H), 3.60(m, 2H), 3.84(m, 2H), 6.63(m, 1H), 7.18(m, 2H), 7.3 7- 7.56(m, 3H), 7.91(d, J = 8.1Hz, 1H), 8.08(d, J = 7.7Hz, 1H), 8.30(s, 2 H), 9.04(s, 1 H), 9.64(s , 1 H) ; Anal. Calcd for C23H26N8 〇 3S2 * 〇-2H2 〇: C, 52.10; H, 5.02; N, 21.13. Found: C, 5 1 · 70; Η, 4_80; N, 20_78. Example 4 5 5 -Amino-4-cyano-1-(6-fluorobenzothiazol-2-yl)-3-[3-(morpholin-4-yl)phenyl]amino-1 oxime -pyrazole (Compound 4 5 ) 5-Amino-4-cyano-3-[3-(morpholin-4-yl) obtained in Step 4 of Example 15 according to Step 3 of Example 1. Phenyl]amino-1Η-pyrazole (0.20 g, 0.70 mmol), 2-chloro-6-fluorobenzothiazole (0-20 mL, 1.1 mmol), potassium carbonate (〇.58 g, 4-2 mmol) and DMF (5 mL) ' Obtained compound 4 5 (0.1 9 g, 62%). ESIMS m/z: 43 6 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 8 3.14 (t, J = 4.6 Hz, 4H), 3.79 (t, J = 4.6 Hz, 4H), 6.55 ( m, 1H), 7.13(d, J = 5.1Hz, 2H), 7.34-7.41(m, 2H), 7.90(dd, J = 9.0, 4.9Hz, 1 H), 8.〇3(dd, J = 9.0, 2.7 Hz, 1H), 8.24 (s, 2H), 8.9 8 ( s , 1 H); Anal. Calcd for C 2 ι Η 18 FN 7 〇S · 0 · 2 H 2 〇: C , 5 7.44; H, 4.22; N, 2 2.3 3. Found: C, 5 7.3 3 ; H, 3.95; N, -110- 200911240 22.02 ° Example 46 1-(5-Ethyl-4-ylthiazol-2-yl -5-Amino-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1 hydrazine-pyrazole (Compound 4 6) According to Step 3 of Example 1 5-Amino-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1Η-pyrazole (0-10 g, 0-35 mmol) obtained in Step 4 of Example 15. 5-Ethyl-2-bromo-4-methylthiazole (0.12 g, 0.53 mmol), potassium carbonate (yield: 29 g, 2-1 mmol) and DMF (1 mL) afforded Compound 46 (0.04 g, 27%). ESIMS m/z: 424 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2 · 6 5 (s , 3 H), 2.8 9 (s, 3 H), 3 · 1 2 - 3 · 1 5 (m, 4 H), 3 · 7 5 - 3 · 7 8 (m, 4H), 6.54 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 8.4Hz, 1H), 7.5〇(s, 1H), 8.16(s, 2H), 9.03(s, lH); Anal.

Calcd for C20H21N7O2S · 〇_3H2 〇: C, 56.00, H, 5.08, N' 22.86.

Found: C, 55.70; H, 5.〇5; N, 22.66. Example 47 2_{5_Amino-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole-1-yl-4-phenylthiazole-5 -Carboxylic acid ethyl ester (Compound 47) According to Step 3 of Example 1, '5-Amino-4-cyano-3_[3-(?咐_4_yl) obtained in Step 4 of Example 15 Phenyl]amino-1^11 哩 (O.iOg, O.Wmmol), bromo-4-phenylthiazole 5-carboxylate (〇.13g, 0.42mm〇l), potassium carbonate (〇. 29 §, 2.lmm 〇 1) and DMF (3 mL) ' Obtained -111 - 200911240 Compound 47 (0.08 g, 44%). ESIMS m/z: 516 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 8 l_23 (t, J = 7.1 Hz, 3H), 3. 1 6 (t, J = 4.6 Hz, 4H), 3.78(t, J = 4 · 6 Hz, 4H), 4.2 3 (q, J = 7 · 1 Hz, 2 H), 6 · 5 5 ( d , J = 8. 1 Hz, 1 H ), 7.03 ( d, J = 8.1Hz, 1H), 7.15(t, J = 8.1Hz, 1H), 7.45-7.48(m, 3H), 7.58(s, 1H), 7.78-7.81(m, 2H), 8.07(s , 2H), 9.08(s, 1 H). Example 4 8 2-{5-Amino-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazol-1-yl}_4-methylthiazole Ethyl Carboxylate (Compound 48) 5-Amino-4-cyano-3-[3-(morpholin-4-yl) obtained in Step 4 of Example 15 according to Step 3 of Example 1. Phenyl]amino-1H-pyrazole (0.26 g, 0.90 mmol), ethyl 2-bromo-4-methylthiazole-5-carboxylate (0.26 g, 1.1 mmol), potassium carbonate (〇.62 g) , 4_5 mmol) and DMF (5 mL)' gave compound 4 8 (0 · 1 3 g, 31%). ESIMS m/z: 45 4 (M + H) + ; 1H NMR (2 70 MHz, DMSO-d6) 8 1.29 (t, J = 7.1 Hz, 3H), 2.62 (s, 3H), 3.13 (t, J = 4.5Hz, 4H), 3.76(t, J = 4.5Hz, 4H), 4.26(q, J = 7.1Hz2H), 6.53(d, J = 8.1Hz, 1H), 7.01(d, J=8.1Hz, 1H ), 7.11 (d, J = 8.1 Hz, 1H), 7.55 (s, 1 H), 8.1 3 (s, 2H), 9.04 (s, 1 H). Example 49 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-(quinolin-6-yl)phenyl]-112- 200911240 Amino-hydrazine- Pyrazole (Compound 49) (Step 1) 1-(Benzothiazol-2-yl)-3-(t-butoxy) obtained in Step 1 of Example 30 according to Step 2 of Example 30 Carbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 0.15 mmol), 6-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.078 g, 0.30 mmol), potassium carbonate (O.llg, 0.76 mmol) and {1,1,-bis ( Diphenylphosphino)ferricium}dichloropalladium(II) (〇.〇24g, 0.030mmol) gives 1-(benzothiazin-2-yl)-3-(t-butoxycarbonyl){3 -(Salanta-6-yl)phenyl}amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.070 g, 70%) ° ESIMS m/z: 66 1 (M + H)+. (Step 2) According to Step 3 of Example 30, N-[3-(quinolin-6-yl)phenyl]-1-(benzothiazol-2-yl)-5- obtained in Step 1. (T-Butoxycarbonylamino)-4-aryl-1H-pyrazol-3-ylaminecarboxylic acid tert-butyl ester (37 mg, 0.056 mmol), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL) gave Compound 49 (0.024 g, 94%). ESIMS m/z: 461 (M + H) + , 'H NMR (27 〇 MHz, DMSO-d6) 5 6.80 (d, J = 7.8 Hz, 1 H), 7.0 1 -7.52 (m, 1 1 H) , 7.60 (t, J = 8.4 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H), 8.38 (br s, 2H), 9.21 (s, 1H). Example 5 0-113-200911240 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(2-methoxypyridine-3-yl)phenyl] Amino-1H-pyrazole (Compound 50) (Step 1) According to Step 2 of Example 30, 1-(benzothiazol-2-yl)-3 obtained in Step 1 of Example 30 -(t-butoxycarbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 0.15 mmol), 2-A Oxyporosyl D-borate (0.047 g, 0.30 mmol), potassium carbonate (O.llg, 0.76 mmol) and {1,1'-bis(diphenylphosphino)pyrene}dichloropalladium(II) (0.025 g, 0.03 0 mmol) gave 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl){3-(2-methoxypyridin-3-yl)phenyl}amine 5--5-butoxycarbonylamino-4-cyano-1 Η-pyrazole (0 · 0 6 7 g, 69%). ESIMS m/z: 641 (M + H)+. (Step 2) According to Step 3 of Example 30, 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl){3-(2-methoxy) obtained in Step 1 Pyridin-3-yl)phenyl}amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.037 g, 0.059 mmol), trifluoroacetic acid (1.0 mL) Dichloromethane (1.0 mL) gave Compound 50 (0.021 g, 82%). ESIMS m/z: 441 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 3.68 (s, 3H), 6.80-6.92 (m, 3H), 7.08-7.3 0 (m, 4H), 7.40(t, J = 8.3Hz, 1H), 7.55(t, J = 8.3Hz, 1H), 8.05(s, 1H), 8.21(d, J = 7.8Hz, 1 H), 8.40(br s, 2H ), 8.94(s, 1H). -114- 200911240 Example 5 1 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-(pyrimidin-5-yl)phenyl]amino-1 Η -pyrazole (Compound 5 1 ) (Step 1) 1-(Benzothiazol-2-yl)-3-(3) obtained in Step 1 of Example 30 according to Step 2 of Example 30 Butoxycarbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 〇.15 mmol), mute-5-boronic acid (llg, 0.30 mmol), potassium carbonate (O.llg, 〇.76 mmol) and {1,1'-bis(diphenylphosphino)pyrene}dichloropalladium(II) (0_0248 g, 0.03 04 mmol), -(benzothiazol-2-yl)-3-(t-butoxycarbonyl){3-(pyrimidin-5-yl)phenyl}amino-5-t-butoxycarbonylamino-4- Cyano-1 Η-pyrazole (0 · 0 5 4 g, 5 8 %). ESIMS m/z: 6 1 2 (M + H)+. (Step 2) According to Step 3 of Example 30, 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl){3-(pyrimidine-5-) obtained in Step 1 Phenyl}amino-5-tert-butoxycarbonylamino-4-cyano-1H-pyrazole (〇.〇37g, 0.059mmol), trifluoroacetic acid (l.〇mL) and dichloro Methane (1. 〇 mL) gave Compound 5 1 (0 · 0 2 1 g, 8 2 %). ESIMS m/z: 411 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 6.90-7.00 (m, 3H), 7.25-7.3 5 (m, 3H), 7.50 (t, J = 8.3 Hz, 1H), 8.05(s, 1H), 8.33(br s, 2H), 8.81(s, 2H), 9.04(br s, 1H), 9.0 1 (s, 1 H). -115- 200911240 Example 5 2 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(2-methoxypyrimidin-5-yl)phenyl] Amino-1H-pyrazole (Compound 52) (Step 1) 1-(Benzothiazol-2-yl)-3- obtained in Step 1 of Example 30 according to Step 2 of Example 30 (t-butoxycarbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.1 〇g, 0.15 mmol), 2-A Oxy-5-pyrimidineboronic acid (0.038 g, 0.30 mmol), potassium carbonate (O.llg, 0.76 mmol) and {1,1'-bis(diphenylphosphino)pyrene}dichloropalladium(II) (0.025) g, 0.03 0 mmol), 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl){3-(2-methoxypyrimidin-5-yl)phenyl}amino- 5-t-butoxycarbonylamino-4-cyano-1 N-pyrazole (〇.〇 76 g, 78%). ESIMS m/z: 642 (M + H)+. (Step 2) According to Step 3 of Example 30, 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl){3-(2-methoxyl) obtained in Step 1 Pyrimidine _5_yl)phenyl}amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (〇.〇33g, 0.05 2mmol), trifluoroacetic acid (1.0 mL) And dichloromethane (1.0 mL) gave compound 5 2 (0 · 0 2 1 g, 93%). ESIMS m/z: 412 (M + H) + ; H NMR (270MHz, DMSO-d6) S 3.80 (s, 3H), 6.78 (s, 1H), 6.90-7.19 (m, 3H), 7.32 (br) d, J = 8.5Hz, 1H), 7.46(t, J = 8.5Hz, 1H), 7.55(t, J = 8.3Hz, 1H), -116- 200911240 8.15(s,1H), 8.40(br s, 2H), 8.52 (s, 2H), 8.92 (s, 1H). Example 5 3 5-Amino-1-(benzothiazol-2-yl)-4-methoxycarbonyl-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyridyl Azole (Compound 53) (Step 1) According to Step 1 of Example 1, 3-(morpholin-4-yl)phenylamine (2_0 g, ll mmol), 2-cyanide obtained in Step 2 of Example 15. Base-3,3-di(methylthio)propanoic acid methyl ester (2.3g, llmmol) and ethanol (30mL), insult to 2-amino-3-methyl ortho--3-[3- (Methyl-4-yl)phenyl]aminopropionate methyl ester (2.3 g, 61%). ESIMS m/z: 3 32 (MH)'; *H NMR (270MHz, DMSO-d6) 5 2.23 (s, 3H), 3.12 (t, J = 4.6 Hz, 4H), 3.68 (s, 3H), 3.73 (t, J = 4.6 Hz, 4H), 6.79 (d, J = 8.8 Hz, 1 H), 6.8 7 (d, J = 8 · 8 H z, 1 H), 6.93 (s, 1H), 7.26 ( t, J = 8.8 Hz, 1H), 11.0 (s, 1H). (Step 2) According to Step 2 of Example 1, 2, 2-cyano-3-methylsulfonyl-3-[3-(morpholin-4-yl)phenyl]amine obtained in Step 1. Methyl methacrylate (2.2 g, 6.6 mmol), hydrazine monohydrate (〇.42 mL, 8.6 mmol) and ethanol (80 mL) gave 5-amino-4-methoxycarbonyl-3-[3 -(morpholin-4-yl)phenyl]amino-1 Η-pyrazole (1 · 6 g, 7 8 %). ESIMS m/z: 318 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 3.07 (t, J = 4.7 Hz, 4H) 3.33 (s, 3H), 3.73 (t, J = 4.7 Hz , 4H), -117- 200911240 6.06(s, 2H), 6.41(d, J = 8.0Hz, 1H), 6.96(d, J = 8.0Hz, 1H), 7.06(t, J = 8.0Hz, 1H) , 7.23(s, 1H), 7.94(s, 1H), ll.〇5(s, 1 H). (Step 3) According to Step 3 of Example 1, the 5-amino-4-methoxycarbonyl-3-[3-(morpholin-4-yl)phenyl]amino group obtained in Step 2 - 1H-pyrazole (〇.5〇g, 1.6mmol), 2-chlorobenzothiazepine (0-25mL, 1.9mmol), potassium carbonate (1.3g, 9.5mmol) and DMF (10mL) gave compound 53 (0.52g) , 73%). ESIMS m/z: 451 (M + H)+; 1H NMR (270MHz, DMSO-d6) 6 3. 1 9 (t, J = 4.5 Hz, 4H) 3.80 (t, J = 4.5 Hz, 4H), 3.86 (s, 3H), 6.57 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 8. 1 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.42 (s, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.83 (s, 2H), 7.89 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.3 l (s, 1H). Example 5 4 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-dimethylamino-4-fluorophenyl)amino-1H-pyrazole (Compound 54) (Step 1) 2-Fluoro-5-nitroaniline (1. g, 6.4 mmol) was dissolved in THE (40 mL), then sodium borohydride (1.4 g, 3 7mmo 1), Concentrated sulfuric acid (0.341111, 6.4111111〇1) and formalin (2.51111〇' was stirred at room temperature for 5 hours. Water and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture to extract with ethyl acetate-118-200911240. The organic layer was dried and concentrated under reduced pressure. The residue was dissolved in THF (40 mL), and then sodium borohydride (1.4 g, 37 mmol), concentrated sulfuric acid (0.34 ml, 6.4 mmol) and sm. The mixture was stirred at room temperature for 5 hours, and water and a saturated aqueous solution of sodium hydrogencarbonate were added to the mixture, and ethyl acetate was evaporated. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography (hexane: ethyl acetate = 2:1) was purified to give 2-fluoro-5-nitro-N, s-dimethylaniline (.42 g, 35%). ESIMS m/z: 1 85 (M + H) +. ( Step 2) According to Step 2 of Example 3 2, 2-fluoro-5-nitro-indole, fluorene-dimethylaniline (0.40 g, 2.2 mmol) obtained in Step 1, 10% palladium-carbon ( 46.46g, 0.22mm 〇l), 3-3-dimethylamino-4-fluoroaniline (0.33g, 100%) = ESIMS m/z: 1 55(M + H)+ (Step 3) Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0.33 g, 2.0 mmol), and the 3-dimethylamino-4-fluoroaniline obtained in Step 2 ( 〇.30g, 2.0mmol) gave 2-[(3-dimethylamino-4-fluorophenyl)amino (methylsulfonyl)methylene]malononitrile. Next, according to the examples Step 2 of 1 consisting of 2-[(3-dimethylamino-4-fluorophenyl)amino (methylsulfonyl)methylene]malononitrile and hydrazine monohydrate (〇.26mL) , 6.4 -119- 200911240 mmol)' yield of 5-amino-4-yl-3-(3-methylamino-4-ylphenyl)amino-1Η-Π 哩 (〇.33g, 65%) ESIMS m/z: 26 1 (M + H) + (Step 4) According to Step 3 of Example 1, the 5-amino-4-cyano-3- obtained in Step 3 3-dimethylamino-4-fluorophenyl)amino-1H-pyrazole (0.30 g, l_2 mmol), carbonic acid Potassium (0.64, 4.6 mmol) and 2-chlorobenzothiazole (0.13 mL, 1.0 mmol) gave compound 54 (0-17 g, 37%). ESIMS m/z: 3 93 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2.99 (s, 6H), 6.87 (m, 1 H), 6.90-7.30 (m, 4H), 7.39 (t, J = 8.4 Hz, 1H), 7.52 (t, J = 8.4 Hz, 1H), 8.23 (br s, 2H), 8.97 (s, 1 H). Example 5 5 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-dimethylamino-4-methylphenyl)amino-1 Η - Pyrazole (Compound 5 5 ) (Step 1) According to Step 1 of Example 54, '2-methyl-5-nitroaniline (2.0 g, 13 mmol) and sodium borohydride (2.8 g, 130 mmol), concentrated sulfuric acid ( 5.6 ml, 98 mmol) and formalin (2.0 mL) were reacted to further residue with sodium borohydride (2.8 §, 13 〇 111111 〇 1), concentrated sulphuric acid (5.61111, 98 «1111 〇 1) and formalin ( Reaction of 2.0 mL) gave 3-dimethylamino-4-methylnitrobenzene (0.42 g, 3 5%) ° -120 - 200911240 ESIMS m/z: 153 (M + H)+. (Step 2) According to Step 2 of Example 3 2, 3-dimethylamino-4-methylnitrobenzene (0.40 g, 2.2 mmol) obtained in Step 1, 1% palladium-carbon ( 47.47g, 〇22mmol) gave 3-dimethylamino-4-methylaniline (〇.33g, 9 9%) ° ESIMS m/z: 181 (M + H)+. (Step 3) According to Step 1 of Example 1, 3-dimethylamino-4-methylaniline (0.30 g, 2. 〇mmol) and [bis(methylthio)) obtained in Step 2 Methyl]malononitrile (0.34 g, 2.0 mmol) gives 2-[(3-dimethylamino-4-methylphenyl)amino (methylsulfonyl)methylene]malononitrile . Next, according to the step 2 of Example 1, the obtained 2-[(3-dimethylamino-4-methylphenyl)amino (methylsulfonyl)methylene]malononitrile And hydrazine monohydrate (0.32 mL, 6.6 mmol) to give 5-amino-4-cyano-3-(3-dimethylamino-4-methylphenyl)amino-1H-pyrazole (0.37 g, 72%). ESIMS m/z: 25 7 (M + H)+. (Step 4) According to Step 3 of Example 1, 5-amino-4-cyano-3-(3-dimethylamino-4-methylphenyl)amino group obtained in Step 3 - 1H- azozolium (0.35 g, 1.4 mmol), potassium carbonate (〇.76 g, 5.5 mmol) and 2-chlorobenzothiazole-121 - 200911240 (0 _ 1 6 m L, 1 _ 2 mm ο 1), Compound 5 5 (0.17 g, 31%). ESIMS m/z: 3 90 (M + H) + ; 1H NMR (2 7 0 MHz, DMSO-d6) 6 2.34 (s, 3H), 2.85 (s, 6H), 6.67 (s, 1H), 6.75 -7.3 5 (m, 3H), 7.41-7.52 (m, 3H), 8.05 (br s, 2H), 8.87 (s, 1H) Example 5 6 5-Amino-1-(benzothiazol-2-yl) 4-cyano-3(3-(2-hydroxyethyl)amino]phenyl}amino-1 Η-pyrazole (Compound 5 6) (Step 1) 1-Fluoro-3-nitro Benzene (1.0 g, 7.1 mmol) and ethanolamine (2.4 mL, 39 mmol) were dissolved in DMSO (10 mL) and stirred at 110 ° C for 4 hours. After the completion of the reaction, ethyl acetate (30 mL) and water (30 mL) were evaporated, and the organic layer was washed twice with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography ('chloroform / methanol = 19/1 to 4/1) to give 3-(2-hydroxyethylamino) nitrobenzene (0.64 g, 4 9%) ° (Step 2) 3-(2-Hydroxyethylamino)nitrobenzene (0.63 g, 3.5 mmol) obtained in Step 1 was dissolved in methanol (6_3 mL), and ammonium formic acid (1.lg, 17 mmol) was added. And 1 〇% palladium-carbon (0 · 13 g), heated to reflux for 2 _ 5 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj

ESIMS m/z: 153 (M + H) VH NMR (270MHz, DMSO-d6) S -122 - 200911240 3.00 (t, J = 6.8 Hz, 2H), 3.52 (t, J = 6.8 Hz, 2H), 4.76 (br s, 4H), 5.82 (s, 1H), 5.74-5.83 (m, 2H), 6.70 (t, J = 8.9 Hz, 1H). (Step 3) 3-(2-Hydroxyethylamino)aniline (0.13 g, 0-84 mmol) obtained in Step 2 was dissolved in ethanol (2.5 mL), and [bis(methylthio)methylene]propyl Dinitrile (0.1 6 g, 0 _ 9 2 mm ο 1), heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified eluted eluted eluted eluted eluted eluted elution Methylsulfonyl)methylene]malononitrile (〇24 g, 100%). 2-[3-(2-Hydroxyethylamino)phenyl]amino(methylsulfonyl)methylene]malononitrile (〇24g, 0.84mmol) obtained by the above method Dissolved in ethanol (2.4 mL), and added hydrazine monohydrate (〇.13 mL, 2.5 mmol). The reaction mixture was concentrated under reduced pressure, and the residue was purified to silica gel column chromatography (chloroform/methanol = 4/1) to give 5-amino-4-cyano-3-[3-(2-hydroxyethyl) Amino]phenyl]amino-1H-pyrazole (0.1 lg, 5 3%) ◦ ESIMS m/z: 25 9 (m + H) +; 'H NMR (270MHz, DMSO-d6) 6 3, 04(td, J = 5.9, 5.4Hz, 2H), 3.54(td, J = 5.9, 5.0Hz, 2H), 4.35(t, J = 5.0Hz, 1H), 4.64(t, J = 5.4Hz, 1H ), 6.05(br d, J = 8. 1 Hz, 1H), 6.18(br s, 2H), 6.55-6.76(m, 2H), 6.85(t, J = 8. 1 Hz, 1 H), 7.99 (s, 1 H), 1 1 . 1 2 (s, 1 H). (Step 4) -123- 200911240 According to Step 3 of Example 37, the 5-amino-4-cyano-3-[3-(2-hydroxyethylamino)phenyl group obtained in Step 3] Amino-1H-pyrazole (O.llg, 0.44 mm) and 2-chlorobenzothiazole (64 pL, 0.49 mmol), potassium carbonate (0.12 g, 〇.89 mmol) and DMF (2.3 mL) 56 (16 mg, 9%).

ESIMS m/z: + NMR (270MHz, DMSO-d6) S 3.14 (q, J = 5.9Hz, 2H), 3.5 5 - 3.68 (m, 2H), 4.70 (br s, 1H), 5.41 (t, J = 5.9 Hz, 1H), 6.21 (d, J = 8.1 Hz, 1H), 6.87-7.00 (m, 3H), 7.38 (td, J = 7.5, 1.1 Hz, 1 H ), 7.5 1 (td, J = 7 · 5 , 1 . 1 Hz, 1 H), 7.89 (br d, J = 7.5 Hz, 1H), 8.06 (br d, J = 7.5 Hz, 1H), 8.25 (s, 2H), 8.82 ( s, 1H). Example 5 7 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3 _(3'-methylbiphenyl-3-yl)amino-1 Η-pyrazole ( Compound 5 7 ) (Step 1) 1-(Benzothazol-2-yl)-3-(t-butoxy) obtained in Step 1 of Example 30 according to Step 2 of Example 30 Carbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 0.15 mmol), m-tolylboronic acid (0.025 g, hydrazine) .30 mmol), potassium carbonate (O.llg, 〇.76 mmol) and (Ι, Γ-bis(diphenylphosphino)iron hydrazine}dichloropalladium(II) (0-025 g, 0-030 mmol) to give 1-(benzothiazide)哩-2-yl)-3-(second butoxycarbonyl)(3'-methylbiphenyl-3-yl)amino-5-t-butoxycarbonylamino-4-cyano-1H -pyrazole (0_079g, 84%). -124- 200911240 ESIMS m/z: 623 (M + H) + ° (Step 2) According to Example 3, step 3 'from the 1 obtained in step 1 - ( Benzothiazol-2-yl)-3-(t-butoxycarbonyl)(3'-methylbiphenyl-3-yl)amino-5-t-butoxycarbonylamino-4-cyano -1H-pyrazole (0_033g, 0.053mmol), trifluoroacetic acid (1. 〇mL) and dichloromethane (1.0mL) Compound 5 7 (0 _ 0 2 1 g, 94%) ESIMS m/z: 411 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 2.34 (s, 3H), 7.05 -7.52 (m, 11H), 7.61 (s, 1H), 8.48 (br s, 2H), 9.1 3 (s, 1H). Example 5 8 5 -amino-1-(benzothiazol-2-yl) _4_cyano-3-(3-(N-methyl-2-methoxyethylamino)phenyl]amino-1 H-pyrazole (Compound 5 8 ) (Step 1) According to the examples Step 1 of 56, from 3-nitrofluorobenzene (1.0 g, 7.1 mmol), N-methyl-2-methoxyethylamine (5-2 g, 60 mmol) and DMSO (10 mL) to give 3 - (N - Methyl-2-methoxyethylamino)nitrobenzene (0 · 8 1 g, 5 5 %). JH NMR (270MHz, CDC13) 6 3.06 (s, 3H), 3.36 (s, 3H), 3.58(s, 4H), 6.99(br dd, J = 8_4, 2.4Hz, 1H), 7.3 2(t, J = 8.4Hz, 1H), 7.4 8-7.53 (m, 2H). -125- 200911240 (Step 2) 3·(Ν-Methyl-2-methoxyethylamino)nitrobenzene (0.81 g, 3.9 mmol) obtained in Step 1 was dissolved in methanol (8.1 mL) Ammonium formate (1.2 g, 19 mm 〇l) and 10% palladium-carbon (0.169) were added and heated under reflux for 2 hours. After the completion of the reaction, the palladium-carbon was filtered, and then the mixture was separated from THF (20 mL), ethyl acetate (20 mL) and water (40 mL), and the organic layer was washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-chloroform/methanol = 9 /1) to give 3-(N-methyl-2-methoxyethylamino)aniline (0.47, 68%) . NMR (2 70MHz, DMSO-d6) 5 2.8 2 (s, 3H), 3.25 (s, 3H), 3.3 3 -3.47 (m, 4H), 4.76 (s, 2H), 5.86-5.95 (m, 3H) , 6.79 (t, J = 7.8 Hz, 1H). (Step 3) According to Step 3 of Example 56, 3-(N-methyl-2-methoxyethylamino)aniline obtained in Step 2 (〇.47 g, 2.6 mmol) and [double ( Methylthio)methylene]malononitrile (〇.49g, 2.9mmoi), hydrazine monohydrate (84pL, 1.7mmol) and ethanol (4_4mL) give 5-amino-4-cyano-3- [3-(N-Methyl-2-methoxyethylamino)phenyl]amino-1H-pyrazole (〇_47 g, 100%). *H NMR(270MHz, DMSO-d6)5 2.86(s, 3H), 3.25(s, 3H), 3.37-3.51(m, 4H), 6.16(br d, J = 7.8Hz, 1H), 6.21(br S, 2H), 6.72-6.86 (m, 2H), 6.94 (t, J = 7.8 Hz, 1H), 8.07 (br s, 1H), 1 1 . 1 8 (br s, 1 H). -126- 200911240 (Step 4) According to Step 3 of Example 3, 5-amino-4-cyano-3-[3-(N-methyl-2-methoxy) obtained in Step 3 Ethylamino)phenyl]amino-1Η·pyridinium (0.41 g, 1.4 mmol) with 2-chlorobenzothiazepine (〇.21 mL, 1.6 mmol), potassium carbonate (〇.4〇g, 2-9 mmol) And DMF (8-2 mL)' gave compound 5 8 (0.15 g, 24%). ESIMS m/z: 420 (M + H) VH NMR (2 7 Ο Η Η z, DMS Ο - d 6) δ 2.96 (s, 3H), 3.27 (s, 3H) 3.53 (s, 4H), 6.30 ( Br d, J = 8.1 Hz, 1H), 6.94 (br d, J = 8.1 Hz, 1H), 7.06 (t, J — 8.1 Hz, 1H), 7.23 (br s, 1H), 7.38 (t, J = 7.8Hz, 1H), 7.51(t, J = 7.8Hz, 1H), 7.90(d, J = 7.8Nz, 1H), 8.07(d, J = 7.8Hz, 1H), 8.28(s, 2H), 8.89 (s, 1H). Example 5 9 5 -Amino-1-(benzothiazol-2-yl)-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole-4-carboxylic acid ( Compound 59) To a solution of compound 53 (0.054 g, 0.12 mmol), 1,4-dioxane (1 mL), 2 mol/L aqueous hydrazine hydroxide (5. After neutralizing by adding 3 mol/L hydrochloric acid, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford compound 59 (0.02 lg, 40%). ESIMS m/z: 43 7(M + H) + ;1 Η NMR (2 7 0 Μ ζ , DMS Ο - d 6 ) δ 3. 1 9(t, J = 4.6Hz, 4Η), 3,80 (t, J = 4.6Hz, 4H), 6_57(d, J = 9.7Hz, 1H), 7.02(d, J = 9.2Hz, 1H), 7.17(t, J = 8.1Hz, 1H), -127- 200911240 7.38 (dd, J = 8.2, 5.9 Hz, 2H), 7.51 (t, J = 7_2 Hz, 1H), 7_64 (s, 2H), 7.88 (d, J = 7.9 Hz, 1H), 8.1 〇 (d, J = 7.7 Hz, 1H), 8.53 (s, 1H), 12.9 (s, 1H). Example 6 0 5 -Amino-1_(benzothiazol-2-yl)-4-cyano-3-(1-methyl-2,3-dihydro-1H-indol-6-yl)amine Base-1 Η-pyrazole (Compound 60) (Step 1) According to Step 1 of Example 54 'from 6-nitro-2,3-dihydro-1 fluorene-indole (0.53 g, 3.2 mmol), boron hydride Sodium (〇.98g, 26mmol), anhydrous sulfuric acid (0.17ml, 3.2mmol) and formalin (1.3mL) gave 1-methyl-6-nitro-2,3-dihydro-1 Η-吲哚 ( 0.4 6 g, 9 9 %). ESIMS m/z: 1 79 (M + H)+. (Step 2) According to Step 2 of Example 3 2, 1-methyl-6-nitro-2,3-dihydro-1H-indole (〇.55 g, 3.1 mmol) obtained in Step 1, 10% palladium-carbon (0.66 g 0.31 mmol) gave 6-amino-2,3-dihydro-1-methyl-1H- port oxime (0.46 g, 100%). ESIMS m/z: 149 (M + H)+. (Step 3) According to Step 1 of Example 1, [bis(methylthio)methylene]malononitrile (0.52 g, 3.1 mmol) and 6-amino-2,3 obtained in Step 2 Dihydro--128- 200911240 1-methyl-1H-indole (0_46g, 3.1mmol)' gives 2-[(dimethyl-2,3_monohydro-1 H-indol-6-ylamino)methyl Sulfhydrylmethylene]malononitrile ((K 43 g, 5 2%) ° ESIMS m/z: 1 7 1 (M + H) + ° (Step 4) According to Step 2 of Example 1, by 2·[(1_Methyl-2,3-dihydro-1H-indol-6-ylamino)methylsulfonylmethylene]propanenitrile obtained in Step 3 (0.28 g, 1.0 mmol) And hydrazine monohydrate (0.05 0 mL, yielding 5-amino-4-cyano-3 -(1-methyl-2,3-dihydro-1 Η-D-noise-6-yl)amine -1 Η-pyrazole (0.2 5 g, 9 6 %) ESIMS m/z: 2 5 5 (M + H) + (Step 5) According to Step 3 of Example 1, obtained in Step 4. 5-amino-4-chloro--3-(1-methyl-2,3-diamino-1H-D fluoren-6-yl)amino-1Η-Π 哩 (〇.23g, 0.90mmol) Potassium carbonate (0.50 g, 3.6 mmol) and 2-chlorobenzothiazole (0.1 mL, 0.99 mmol) gave compound 60 (0.12 g, 34%). ESIMS m/z: 3 8 8 (M + H) + ; 1 Η NMR (2 7 0 Μ Η z, DMS Ο - d 6) δ 2.82(m, 2H), 3.93(m, 2H), 3.99(s, 3H), 6.90(s , 1H), 7.01(d, J = 7.8Hz, 1H), 7.24(br d, J = 8.2Hz, 1 H) 7.29(br d, J = 8.2Hz, 1H), 7.36(t, J = 8.2Hz , 1H), 7.52(t, J-8.2Hz, 1H), 7.63(d, J = 7.8Hz, 1 H), 8. 1 9(br s,2H), 8.99(s, 1 H). -129 - 200911240 Example 6 1 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(2-methoxyethylamino)phenyl]amino- 1H-pyrazole (Compound 61) (Step 1) According to Step 1 of Example 56, from <RTI ID=0.0>> And DMSO (20 mL) gave 3-(2-methoxyethylamino) nitrobenzene (1.5 g, 55%). 'H NMR(270MHz, DMSO-d6)5 3.26(q, J = 5.6Hz, 2H), 3.29(s, 3H), 3.50(t, J = 5.6Hz, 2H), 6.41(t, J = 5.6Hz , 1H), 6.9 8-7.06 (m, 1H), 7.3 9-7.27 (m, 3H). (Step 2) According to Step 2 of Example 5, 3-(2-methoxyethylamino)nitrobenzene (1.5 g, 7.9 mmol) obtained in Step 1 and 10% palladium-carbon ( 0.31 g), ammonium ruthenate (2.5 g, 39 mmol) and methanol (15 mL) gave 3-(2-methoxyethylamino)phenylamine (0.60 g, 46%). 'H NMR(270MHz, DMSO-d6)5 3.1〇(td, J = 5.9, 5.8Hz, 2H), 3.27(s, 3H), 3.44(t, J = 5.9Hz, 2H), 4.69(s, 2H ), 5.10 (t, J = 5.8 Hz, 1H), 5.84 - 5.78 (m, 3H), 6_70 (t, J = 8_0 Hz, 1H). (Step 3) According to Step 3 of Example 5, 3 -(2-methoxyethylamino)aniline (0.60 g, 3.6 mmol) obtained in Step 2, [bis(methylthio)) Methyl]malononitrile (〇_67g, 3.9mmol), hydrazine monohydrate (〇.17mL, -130- 200911240 3.4mmol) and ethanol (12mL) give 5-amino-4-cyano-3 -[3-(2-Methoxyethylamino)phenyl]amino-1H-pyrazole (0.80 g, 69%). 1 H NMR (2 70 MHz, DMS Ο - d 6) δ 3 · 1 3 (q, J = 5.9 Η z, 2 Η), 3.27 (s, 3H), 3.47 (t, J = 5.9 Hz, 2H), 5.29(t, J = 5.9Hz, 1H), 6.05(br d, J = 7.9Hz, 1H), 6.18(br s, 2H), 6.5 5 -6.73 (m, 2H), 6.85(t, J-7.9 Hz, 1 H), 7.99 (br s, 1 Η), 1 1 · 1 6 (br s, 1 H). (Step 4) 5-Amino-4-cyano-3-[3-(2-methoxyethylamino)phenyl]amino group obtained in Step 3 according to Step 3 of Example 37 -1H-pyrva (0.6 7 g, 2 _ 5 mm ο 1), 2-chlorobenzothiazole (0.3 5 m L, 2 _ 7 mm ο 1), potassium carbonate (0.68 g, 4.9 mmol) and DMF ( 13 mL) gave compound 6 1 (0.20 g, 2 1%) ° ESIMS m/z: 406 (M + H) + ; 1 NMR (2 7 Μ H z, DMSO - d 6) δ 3.24 (td, J = 5.8, 5.7 Hz, 2H), 3.30 (s, 3H), 3.54 (t, J = 5.8 Hz, 2H), 5_50 (t, J = 5.7 Hz, 1 H), 6 _ 2 3 (brd, J = 8 · 1 H z, 1 H), 6.90 (br d, J = 8.1 Hz, 1H), 6.96 (t, J = 8.1 Hz, 1H), 6.96 (br s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 8.06 (d, J = 7.8 Hz, 1H), 8.25(s, 2H), 8.82 (s, 1H). Example 62 5-Amino-1-(benzothiazol-2-yl)-3-[3-(morpholin-4-yl)phenyl]amino-4-(1 Η-tetrazole-5- Base)-1 Η-pyrazole (Compound 6 2 ) -131 - 200911240 (Step 1) Compound 1 5 (0.80 g, 1 · 9 mm ο 1) was suspended in dichloromethane (20 mL), Triethylamine (1.3 mL, 9.6 mm 〇l), dibutyl butyl dicarbonate (1.8 mL, 7.7 mmol) and 4-dimethylaminopyridine (〇.47 g, 3 · 8 mm ο 1 ). After stirring at room temperature for 1 hour, 3 m ο 1 / L hydrochloric acid (20 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. Concentration by pressure. The residue was purified by ruthenium dioxide colloidal column chromatography (hexane / ethyl acetate = 4 / 1) to give 1-(benzothiazol-2-yl)-3-(t-butoxy) (carbonyl)[3-(morpholin-4-yl)phenyl]amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (1.0 g, 8 7%) ° 1 H NMR (270MHz, CDC 13) δ 1 Η NMR (CDC 13) δ 1 .37 (s, 18H), 3.17 (t, J = 4.8 Hz, 4H), 3.84 (t, J = 4.8 Hz, 4H), 6.78-6.85(m, 2H), 6.96(m, 1H), 7.25(m, 1H), 7.4 0(m, 1H), 7.49(m, 1H), 7.83(d, J = 7.9Hz, 1H), 7.92(d, J = 7.9Hz, 1H), 12.9(s, 1H) (Step 2) 1-(Benzothiazol-2-yl)-3-(t-butoxycarbonyl)[3-(morpholin-4-yl)phenyl]amino-5-tributyl as obtained in step 1. Oxycarbonylamino group 4-cyano-1H-pyrazole (0.20 g, 0.32 mmol) was dissolved in toluene (5 mL), and dibutyltin(IV) oxide (〇, 〇79 g, 4.32 mmol) and azide were added. Methyl sand yard (0 _ 3 8 m L, 2 · 9 mm ο 1 ), stirred at 1 ° C for 10 hours. After adding methanol (〇 _ 5 m L) to the reaction mixture, it was concentrated under reduced pressure. The residue was purified by ruthenium ruthenium colloidal column chromatography (chloroform/methanol = 1 〇〇/〇~9/1) to give 5-amino-1-(benzothiazol-2-yl). --3-(t-butoxycarbonyl)[3-(morpholin-4-yl)phenyl]amino-4 -(1 Η-tetrazol-5-yl)-1 Η-pyrazole (0 · 0 8 g, 4 5 %). ESIMS m/z: 561 (M + H)+; lH NMR (CDC13) 6 1.62 (s, 9H), 3.28 (t, J = 4.7 Hz, 4H), 3.94 (t, J = 4.7 Hz, 4H), 6.61 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7.37-7.54 (m, 5H), 7.83 -7.8 5 (m, 3H), 9.41 (s, 1H), 11.0 (s, 1H). (Step 3) 5-Amino·1_(benzothiazol-2-yl)-3-(t-butoxycarbonyl)[3-(morpholin-4-yl)phenyl obtained in Step 2 Amino-4-(1Η-tetrazol-5-yl)-1Η-pyrazole (0_07 g, 〇.i3 mmol) was added 3 mol/L hydrochloric acid (0-5 mL) and methanol (5.0 rnL), and stirred at 80 ° C for 3 hours. . After adding a saturated aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford compound 6 2 (0.0 4 g, 82%). ESIMS m/z: 459 (MH); 1H NMR (270MHz, DMSO-d6) S 3.17 (s, 1H), 3.22 (t, J = 4.5 Hz, 4H), 3.83 (1, J = 4.5 Hz, 4H) , 6.62 (d, J = 7.7 Hz, 1H), 7.12-7.24 (m, 2H), 7.39 (t, J = 7.7 Hz, 1H), 7.49 (s, 1H), 7.52 (t, J = 7.5 Hz, 1H), 7.89 (s, 1H), 7.91 (s, 2H), 8.11 (d, J = 7.7 Hz, 1H), 8.87 (s, 1H). Example 63 5-Amino-1-(benzothiazepine-2-yl)-4-cyano-3-[3-(quinolin-3-yl)phenyl]amino-1H-pyrazole (Compound 63) -133- 200911240 (Step 1) According to Step 2 of Example 30, 1-(benzothiain-2-yl)-3-(Step 1) obtained in Step 1 of Example 30 Tributoxyalkyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 0.15 mmol), 3-quinoline boric acid (〇.〇53g, 0.304mmol), potassium carbonate (O.llg, 0.76mmol) and {1,1'-bis(diphenylphosphino)pyrene}dichloropalladium (ll) (0_025g, 0.030mmol), Obtaining benzothiazepin-2-yl)-3-(t-butoxycarbonyl){3-(quinolin-3-yl)phenyl}amino-5_t-butoxycarbonylamino-4 -Cyano-1H-pyrazole (0.10 g, 99%). ESIMS m/z: 661 (M + H)+. (Step 2) According to Step 3 of Example 30, 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl){3-(quinoline-3-) obtained in Step 1 Phenyl}amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 0.16 mmol), trifluoroacetic acid (1.0 mL) and dichloromethane .OmL) gave compound 63 (0.051 g, 71%). ESIMS m/z: 461 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 6 6.65 (d, J = 7.2 Hz, 1 H), 6 · 94 - 7 · 6 0 (m, 1 2 H ), 8.2 1 (d, J = 7.9 Hz, 1H), 8_08 (br s, 2H), 8_75 (s, 1H). Example 6 4 5 -Amino-1 -(benzothiazol-2-yl)-4-cyano-3-(3-3-[2-(morpholin-4-yl)pyrimidin-5-yl]phenyl Amino-1H-pyrazole (Compound 64) -134- 200911240 (Step 1) 1-(Benzothiazol-2-) obtained in Step 1 of Example 30 according to Step 2 of Example 30 3-(t-butoxycarbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-4-cyano-1H-pyridinium (0.10 g, 〇.15 mmol ), 2-(4-morphinyl) oxime benzoic acid pinacol (〇.〇89g, 0.30mmol), potassium carbonate (O.llg, 〇.76mmol) and {1,1'-double (two Phenylphosphino) ruthenium}dichloropalladium(II) (0.025 g, 0.030 mmol) 'Get 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl)[{2-(4 -morpholinylpyrimidin-5-yl}phenyl]amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (〇.〇9 5 g, 90%) 〇 ESIMS m/z: 697 (M + H)+. (Step 2) According to Example 3, Example 3, 1-(benzothiazole-2-yl)-3-(t-butoxycarbonyl)[{2-(4-) obtained in Step 1. Morpholinyl)pyrimidine-5-yl}phenyl]amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.090 g, 0.13 mmol), trifluoroacetic acid (1. OmL) and methylene chloride (1.0 m L) gave compound 6 4 (0.0 4 1 g, 64%). ESIMS m/z: 497 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 6 2.70-2.80 (m, 4H), 3.6 5 -3.75 (m, 4H), 6.5 0-6.65 (m, 3H ), 6.91 -7.22(m, 3H), 7.28(br d, J = 8,4Hz, 1H), 7.49(t, J = 8.4Hz, 1 H), 8_30(s, 2H), 8. 1 2( Br s, 2H), 8_89(s, 1 H). Example 6 5 -135- 200911240 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-{3-[2-(piperidin-1-yl)pyrimidine_5_ Phenyl]amino}amino-1H-pyrazole (Compound 65) (Step 1) 1-(Benzothiazol-2-) obtained in Step 1 of Example 30 according to Step 2 of Example 30 3-(tert-butoxycarbonyl)(3-iodophenyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 〇_15 mmol , 2-(piperidin-1-yl)pyrimidine-5-boronic acid pinacol (0.08 8g, 0-30mmol), potassium carbonate (O.llg, 〇.76mmol) and {1,1·-bis(diphenyl) Phosphyl) iron hydrazine} dichloropalladium (ruthenium) (〇.〇25g, 0.030mmol) gives 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl)[3-{2 -(piperidin-1-yl)pyrimidin-5-yl}phenyl]amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 9 6%) 〇 ESIMS m/z: 695 (M + H)+. (Step 2) According to Step 3 of Example 30, 1-(benzothiazole-2-yl)-3-(t-butoxycarbonyl)[3-{2_(piperidine) obtained in Step 1 -1-yl)pyrimidin-5-yl}phenyl]amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (〇·〇90g, 0.13mmol), trifluoroacetic acid (l.OmL) and dichloromethane (1.0 m L) gave compound 6 5 (0.0 4 1 g, 64%). ESIMS m/z: 49 5 (Μ + Η) + ;1 Η NMR (2 7 0 Μ ζ , DMS Ο - d 6) δ 1.3 0- 1.40 (m, 6 Η), 2.79 (m, 4 Η), 6.5 0-6.65 (m, 3H), 7.08-7.22(m, 2H), 7.35(br d, J = 8.4Hz, 1H), 7.45(t, J = 8.4Hz, 1H), 7.51(t, J = 8.4 Hz, 1H), 8.23(s, 2H), 8.11(br s, 2H), -136- 200911240 9.06(s, 1H). Example 6 6 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-(2-dimethylaminofuran-5-yl)phenyl] Amino-1H-pyrazole (Compound 66) (Step 1) 1-(Benzothiazol-2-yl)-3- obtained in Step 1 of Example 30 according to Step 2 of Example 30 (tert-butoxycarbonyl)indole-iodophenyl)amino-5-t-butoxycarbonylamino 4-cyano-1H-pyrazole (0.10 g, 〇.15 mmol), 2-(dimethyl Amino)pyrimidine-5-boronic acid pinacol (〇.〇76g, 0.30mmol), cesium carbonate (O.llg, 0.76mmol) and bis(monophenylene)pyrene}dichloropalladium (11) 0.025g, 0·030ηιιηο1), 1-(benzothiazepine-2-yl)-3-(t-butoxycarbonyl)[3-(2-dimethylaminopyrimidin-5-yl)benzene Amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.10 g, 9 9% ESIMS m/z: 65 5 (M + H) +. (Step 2 According to Step 3 of Example 30, 1-(benzothiazole-2-yl)-3-(t-butoxycarbonyl)[3-(2-dimethylaminopyrimidine) obtained in Step 1 -5-yl)phenyl]amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0-080 g, 0.12 mmol), three Fluoroacetic acid (1.0 mL) and dichloromethane (1 mL) gave Compound 66 (0.042 g, 76%).

ESIMS m/z: 45 5 (1^1 + 11) + ^11 NMR (2 70MHz, DMSO-d6) S-137- 200911240 2.41(s, 6H), 6.63-6.71(m, 3H), 7.04-7.29 (m, 2H), 7.31 (br d, J = 8.4 Hz, 1H), 7.43 (t, J = 8.4 Hz, 1H), 7.58 (t, J = 8.4 Hz, 1H), 8.30 (s, 2H), 8.43 (br s, 2H), 8_89 (s, 1H). Example 67 5-Amino-1-(benzoxan-2-yl)-3-[3-(loweramino)phenyl]amino-4-amino-1 oxime-pyrazole (Compound 6 7) (Step 1) Compound 37 (100 mg, 0.29 mmol) was dissolved in DMF (2.0 mL), and anhydrous trifluoroacetic acid (45 μί, 0.32 mmol) was added at 〇 ° C and stirred at 0 ° C for 1 hour. To the reaction mixture, THF (20 mL), EtOAc (EtOAc m. It was concentrated under reduced pressure. 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(trifluoroethenylamino)phenyl)]amino-1H-pyrazole Not refined, used in the following steps. 1 H NMR (270 MHz, DMSO-d6) 5 7 · 1 3 (brd, J = 8 1 Η z, 1 H), 7.33 (br t, J = 7.9 Hz, 1H), 7.39 (t, J = 8. 1 Hz, 1H), 7.52 (br t, J = 7.9 Hz, 1 H), 7.6 6 (brd, J = 8. 1 H z, 1H), 7.90 (br d, J = 7.9 Hz, 1H), 8.01 (br s, 1 H ), 8 · 0 7 (brd, J = 7.9 Hz, 1 H), 8.31 (s, 2H), 9.33 (s, 1H), 11.23 (s, 1H). (Step 2) The crude 5-amino-1-(benzothiazol-2-yl)-4--138- 200911240 cyano-3-[3-(trifluoroethenylamine) obtained in the first step Base) phenyl)]amino-1H-pyrazole (2.6 mL) was suspended, and ditributyl dicarbonate (〇19 g, 0.86 mm〇l) and 4-(dimethylamino)pyridine (〇) were added. Lg, 〇_86 mmol), stirred at room temperature for 4 hours. The reaction mixture was added with ethyl acetate (3 mL), water (10 mL), and brine (10 mL), and the organic layer was washed twice with saturated brine (20 mL) and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. The residue was purified by silica gel column chromatography (η-hexane / ethyl acetate = 7 / 3) to give 1-(benzothiazol-2-yl)-3-(t-butoxycarbonyl) [3-(Trifluoroethenylamino)phenyl]amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (0.12 g, 66%). (Step 3) 1-(Benzothiazol-2-yl)-3-(t-butoxycarbonyl)[3-(trifluoroethenylamino)phenyl]amino group obtained in Step 2 -5-Tertibutoxycarbonylamino-4-cyano-1H-pyrazole (0.12 g, 0.19 mmol) was suspended in methanol (2.4 mL), and potassium carbonate (O.llg, s. Stir at 70 ° C for 6 hours. To the reaction mixture, ethyl acetate (2 mL), water (10 mL) and saturated brine (1 〇m L) were added, and the organic layer was washed twice with saturated brine (20 mL). Dry over sodium sulfate and concentrate under reduced pressure. The residue was purified by ruthenium dioxide colloidal column chromatography (?-hexane/ethyl acetate = 7/3 to 2/3) to give 3-(3-aminophenyl) (t-butoxycarbonyl) Amino-1-(benzothiazol-2-yl)-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (61 mg, 59%). 'H NMR (270MHz, CDC13)6 1.53 (s, 9H), 1.61 (s, 9H), 3.70 (br s, 2 H), 6.58 (dd, J = 7.9, 2.1 Hz, 1 H), 6.8 0 ( t, J = 2.1Hz, 1H), 6.85(br d, J = 7.9Hz, 1H), 7.14(t, J = 7.9Hz, -139- 200911240 1H), 7.42(t, J = 7.6Hz, 1H) , 7.52(t, J = 7.6Hz, 1H), 7.83(d, J = 7.6Hz, 1H), 7.92(d, J = 7.6Hz, 1H), 10.72(s, 1H)° (Step 4) will be 3-(3-Aminophenyl)(2nd butoxymethyl)amino-1-(benzothiazol-2-yl)-5-t-butoxycarbonylamino group obtained in Step 3 4-Cyano-1H-pyrazole (61 mg, 0.1 mmol) was dissolved in acetonitrile (1.0 mL). Ethyl acetate (20 ml) and a saturated aqueous solution of sodium hydrogencarbonate (10 mL) were added to the mixture, and the organic layer was washed with brine (1 mL) and dried over anhydrous sodium sulfate. The residue was suspended in acetonitrile (2.0 mL). EtOAc (EtOAc m. After the reaction was completed, ethyl acetate (20 mL) and water (20 mL) were evaporated, and the organic layer was washed with saturated aqueous sodium chloride (20 mL) and dried over anhydrous sodium sulfate. The residue was purified by ruthenium dioxide colloidal column chromatography (?-hexane/ethyl acetate = 7/3) to give 1-(benzothiazol-2-yl)-3-[3-(benzylamino) Phenyl](t-butoxycarbonyl)amino-5-t-butoxycarbonylamino-4-cyano-1indole-pyrazole (7 1 mg, 10 0%) ° ESIMS m/z: 63 8(M + H)VH NMR (270MHz, CDC13)S 1.51 (s, 9H), 1.62 (s, 9H), 4.32 (s, 2H), 6.53 (dd, J = 8. 1 , 1 , 9 Hz, 1 H), 6_73 (t, J = 1. 9 Hz, 1 H), 6.82 (dd, J = 8. 1 , 1 _ 9 H z , 1 H ), 7. 5 (t, J = 8 · 1 H z,1 H ), 7.2 0 - 7 _ 4 6 (m,7 H), 7.53 (t, J = 8. 1 Hz, 1 H), 7.83 (d, J = 8. 1 Hz, 1 H) , 7.93 (d, -140- 200911240 J = 8.1 Hz, 1H), 1 0.7 1 (s, 1 H) ° (Step 5) 1-(Benzothiazol-2-yl)- which will be obtained in Step 4. 3-[3-(Benzylamino)phenyl](t-butoxycarbonyl)amino-5-t-butoxycarbonylamino-4-cyano-1H-pyrazole (71 mg, O. Lllmmol) was dissolved in methanol (1 - 5 mL), and then added to a mixture of 3-0 mol/L hydrochloric acid (0.50 mL), and stirred at 60 ° C for 3 hours. After completion of the reaction, THF (20 mL) and EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (chloroform / methanol = 19 / 1) to afford compound 67 (3 6 mg, 75%). ESIMS m/z: 43 8 (M + H) +; 'H NMR (270MHz, DMSO-d6) S 4.32 (d, J = 5.9 Hz, 2H), 6.18 (t, J = 5.9 Hz, 1H), 6.23 (br d, J = 8.6 Hz, 1H), 6.85-7.02 (m, 2H), 6.99 (br s, 1H), 7.18- 7.43 (m, 6H), 7.51 (t, J = 7.8 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1 H), 8 · 2 3 (s , 2 H), 8 · 7 8 (s, 1 H). Example 6 8 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-{3-[N-(2-hydroxyethylmethyl)amino]phenyl}amine Base-1H-pyrazole (Compound 68) (Step 1) According to Step 1 of Example 56, 1-fluoro-3-nitrobenzene (5.0 g, 35 mmol) and N-(2-hydroxyethyl)methylamine (13g, 0_18m〇l) and DMSO (50mL) gave 3-[N-(2-hydroxyethyl)methylamino]nitrobenzene (2.3§, -141 - 200911240 3 4%) ° ESIMS m/ z: 197(M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 3.01 (s, 3H), 3.48 (t, J = 5.4 Hz, 2H), 3.57 (q, J = 5.4 Hz, 2H ), 4.74 (t, J = 5, 4 Hz, 1H), 7.17-7.07 (m, 1 H), 7.43 -7.3 5 (m, 3H). (Step 2) 3-[N-(2-Hydroxyethyl)methylamino]nitrobenzene (2.3 g, 12 mmol) obtained in Step 1 was dissolved in methanol (35 mL), and 10% palladium was added. Carbon (0·23 g) was stirred at room temperature for 3 hours under a hydrogen atmosphere. After completion of the reaction, the palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol = 9/1) to afford 3-[N-( 2-Ethyl)methylamino]aniline (i.8 g, 90%). ESIMS m/z: 167 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 2.83 (s, 3H), 3.28 (t, J = 6.5 Hz, 2H), 3.50 (td, J = 6.5, 4.9 Hz, 2H), 4.60 (t, J = 4.9 Hz, 1H), 4.73 (s, 2H), 5.83 - 5.95 (m, 3H), 6_78 (t, J = 7.9 Hz, 1 H). (Step 3) According to Step 3 of Example 5, 3 - [N-(2-hydroxyethyl)methylamino]aniline (1.8 g, 1 lmmol) obtained in Step 2 and [Double (A) Thio)methylene]malononitrile (2.0 g, 12 mmol), hydrazine monohydrate (0.63 mL, 13 mmol) and ethanol (36 mL) afforded 5-amino-4-cyano-3-3- [N-(2-Hydroxyethyl)methylamino]phenyl}amino-1 Η-pyrazole (3.3 g, 1 〇〇%). -142- 200911240 'η NMR(270MHz, DMSO-d6)5 2.8 8 (s, 3H), 3.31- 3.37(m, 2H), 3.54(td, J = 5.7, 5.3Hz, 2H), 4.61.(t , J = 5.3Hz, 1H), 6. 1 6(br d, J = 8.4Hz, 1H), 6.20(br s, 2H), 6.70-6_89(m, 2H), 6.93(t, J = 8.4Hz , 1H), 8.03 (br s, 1H), 11.09 (br s, 1H). (Step 4) According to Step 3 of Example 3, 5-amino-4-cyano-3-{3-[N-(2-hydroxyethyl)methylamino] obtained in Step 3] Phenyl}amino-1H-pyridinium (2.9 g, iimmol) and 2-chlorobenzothiazepine (1_5 mL, 12 mmol), potassium carbonate (7_4 g, 54 mmol) and DMF (59 mL) afforded Compound 68 (0.20 g, - twenty one%). ESIMS m/z: 406 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 2.98 (s, 3H), 3.42 (t, J = 5.9 Hz, 2H), 3.61 (td, J = 5.9, 5.3 Hz, 2H), 4.67 (t, J = 5.3 Hz, 1 H), 6 · 3 0 (brd, J = 7 · 8 H z, 1 H), i 6.93 (br d, J = 7.8 Hz, 1H ), 7.05(t, J = 7.8Hz, 1H), 7.21(br s, 1H), 7.37(t, J = 8.1Hz, 1H), 7.51(t, J = 8.1Hz, 1H), 7.89(d, J = 8. 1 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 8.26 (s, 2H), 8.87 (s, 1 H); Anal. Calcd for C 2〇H , 9N 7 0 S : C, 59.24; H, 4.72; N, 24.18. Found: C, 5 8.87; H, 4.77; N, 23.87. Example 69 5-Amino-4-cyano-1-(6-methylbenzothiazol-2-yl)-3-[3-(morpholin-4-yl)-phenyl]amino-1H -pyrazole (Compound 69) -143- 200911240 5-Amino-4-cyano-3-[3-(morpholine-) obtained according to Step 3 of Example 1 from Step 4 of Example 15. 4-yl)phenyl]amino-1H-pyrazole (0.25 g, 0-88 mmol), 2-chloro-6-methylbenzothiazole (〇_19 g, 1.1 mmol), potassium carbonate (4.73 g, 5.3 mmol) And DMF (10 mL) gave Compound 6 9 ( Ο. Ο 8 g, 4 4 %). ESIMS m/z: 43 2 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 6 2.44 (s, 3H), 3.15 (t, J = 4.5 Hz, 4H), 3.80 (t, J = 4.5Hz, 4H), 6.55(m, 1H), 7.12-7.15(m, 2H), 7.33(d, J = 8.4Hz, 1H), 7.44(s, 1H), 7.78(d, J = 8.4Hz, 1H), 7.90(s, 1H), 8.24(s, 2H), 8.96(s, lH); Anal. Calcd for C 2 2 H2 i N 7 0 S · 0.1 H 2 〇: C , 60.9 8;H, 4.93 ; N, 22.63 . Found: C, 60.60; H, 4.75; N, 22.25 ° Example 7 0 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3 -(Hydroxymethyl)phenyl]amino-1 hydrazine-pyrazole (Compound 70) (Step 1) According to Step 3 of Example 56, from 3-hydroxymethylaniline (3.0 g, 24 mmol) Bis(methylthio)methylene]malononitrile (4.6 g, 27 mmol), hydrazine monohydrate (1.5 mL, 32 mmol) and ethanol (60 mL) gave 5-amino-4-cyano-3- [3-(Hydroxymethyl)phenyl]amino-1H-pyrazole (4_4 g, 79%). ESIMS m/z: 23 0 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 4.41 (d, J = 5.4 Hz, 2H), 5.05 (t, J = 5.4 Hz, 1H), 6.25 (s, 2H), 6.72 (d, J = 7.6Hz, 1H), 7.10(t, J = 7.6Hz, 1H), 7.28(br d, -144- 200911240 J = 7.6Hz, 1H), 7.45(s , 1H), 8.28 (s, 1H), 11.12 (s, 1H). (Step 2) According to Step 3 of Example 3, '5-Amino-4-cyano-3-[3-(hydroxymethyl)phenyl]amino-1H-pyrazole obtained in Step 1. (4.4 g, 19 mmol) and 2-chlorobenzothiazole (2.5 mL, 21 mmol), potassium carbonate (13 g, 97 mmol) ESIMS m/z: 3 63 (Μ + Η) + ; *Η NMR (2 7 0 MHz, DMSO-d6) 5 4.50 (d, J = 5.7 Hz, 2H), 5.17 (t, J = 5.7 Hz, 1H) , 6.90 (br d, J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.60 (br d, J = 7.6 Hz, 1H), 7.63 (br s, 1H), 7.90 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.28 (s, 2H) ), 9_ 1 2(s, 1 H). Example 7 1 5-Amino-3-(3-aminocyclohexylamino)-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazole (Compound 71) (Step 1 Dissolving [bis(methylthio)methylene]malononitrile (1.5 g, 8.8 mmol) in dichloromethane (40 mL), and adding 1,3 -cyclohexanediamine (l〇.g, 8.8 mmol) ), stirred at room temperature for 1.0 hour. Further, di-tert-butyl dicarbonate (4.4 mL, 19 mmol), triethylamine (5.4 mL, 39 mmol), and 4-dimethylamino oxime ratio (l.lg, 8.8 mmol) were added for 1.0 hour, and 3 mol was added. /L Hydrochloric acid (50 mL) was extracted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate - 145 - 200911240 and dried over anhydrous sodium sulfate. By refining the residue with cerium oxide colloidal column chromatography (hexane/ethyl acetate = 2/1) to give 3-[2,2-dicyano-1-(methylsulfonyl)vinyl Amino]t-butyl cyclohexylaminecarboxylate (2.5 g, 84%). !H NMR(270MHz, CDC13)6 1.45(s, 9H), 1.01-1.20(m, 4H), 1.86-2.04(m, 4H), 2.32(m, 1H), 2.70(s, 3H), 3.52( m, 1H), 4.45 (m, 1H), 6.00 (d, J = 8.1 Hz, 1H). (Step 2) According to Step 2 of Example 1, 2 -[2,2-dicyano-1-(methylsulfonyl)vinylamino]cyclohexylaminecarboxylic acid obtained in Step 1 Tributyl ester (1_6g, 4.7mmol), hydrazine monohydrate (0.28mL, 5.7mmol) and ethanol (50 m L) to give 3-(5-amino-4-cyano-1 Η-pyrazole -3 -aminoamino) tert-butyl cyclohexylaminecarboxylate (〇.65g, 43%). ESIMS m/z: 321 (M + H) VH NMR (270MHz, DMSO-d6) S 〇.99- 1.24 (m, 4H), 1.38 (s, 9H), 1.52-2.00 (m, 5H), 2.00 ( s, 1H), 3.23(d, J = 7, 9Hz, 1H), 3, 63(s, 1H), 6.79(s, 2H), 1 〇. 6(s, 1 H). (Step 3) According to Step 3 of Example 1, 3 - (5-Amino-4-cyano-1H-pyrazol-3-ylamino)cyclohexylaminecarboxylic acid tertidine obtained in Step 2 Ester (0.l0g, 〇.31nimol), 2-chlorobenzothiazepine (0.049mL, 0-37mmol), potassium carbonate (0.26g, 1.9mmol) and DMF (5mL) afforded 3-[5-amino-1 - -146- 200911240 (Benzothiazol-2-yl)-4-cyano-1 Η-pyrazol-3-ylamino]tributyl butyl cyclohexylaminecarboxylate (0.06 g, 42%). ESIMS m/z: 454 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 1.06- 1 , 39 (m, 14H), 1.62- 1.95 (m, 2H), 1.95 -2.23 (m, 2H), 6.16(s, 2H), 6.90(d, J = 6.7Hz, 1H), 7.35(m, 1H), 7.48(m, 1H), 7.83(d, J = 8.1Hz, 1H), 8.02( d, J = 8.1 Hz, 1H), 8.14 (s, 1 H), 8.46 (d, J = 8.6 Hz, 1 H). (Step 4) 3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-ylamino]cyclohexylamine obtained in Step 3. The third butyl formate (0.041 g, 0-09 mmol) was added to 3 mol/L hydrochloric acid (0.2 mL) and methanol (2_0 mL) to stir at 80 ° C for 3 hours. The obtained crude crystals were washed with methanol to give a compound 71 (0.024 g, 75%). ESIMS m/z: 3 54 (M + H) + 1 by adding a 2 mol/L aqueous sodium hydroxide solution. NMR NMR (2 7 Ο Μ Η z, DMS Ο - d 6) δ 0.90- 1.34(m, 4H), 1 _ 7 3 - 2.2 0 (m, 4 Η ), 2 · 5 0 - 2.7 6 (m, 2 Η), 3.57(m, 1H), 3.81(m, 1H), 6.15(s, 2H), 7.34(t, J = 7.6Hz, 1H), 7.48(t, J = 7.6Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1 H), 8 _02 (s, 1 H). Example 72 5-Amino-4-cyano-1-(6-methanesulfonylbenzothiazol-2-yl)-3 _[3-(indol-4-yl)phenyl]amino- 1H-pyrazole (Compound 72) -147- 200911240 5-Amino-4-cyano-3 -[3-(morpholine) obtained in Step 4 of Example 15 according to Step 3 of Example 1. -4 -yl)phenyl]amino-1 Η-pyrazole (0_10g, 0.35mmol), 2-bromo-6-methanesulfonylbenzothiazole (〇_12g, 0.42mmol), potassium carbonate (0.24g) , 1.8 mmol) and DMF (1 mL) gave compound 7 2 (0.0 7 5 g, 43%). ESIMS m/z: 496 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 8 3.14 (t, J = 4.5 Hz, 4H) 3.26 (s, 3H), 3.79 (t, J = 4.5 Hz , 4H), 6.55 (d, J = 7.8Hz, 1H), 7.0 5 - 7.1 6 (m, 2H), 7.46(s, 1 H), 7.9 3 - 8 · 0 8 (m , 2 H), 8 · 3 6 ( s, 2 H), 8.7 6 (d, J = 1 · 7 H z, 1 H ), 9.0 3 (s , 1 H ); A nal C al cd for C 22 H2 l N 7 O3 S 2 · 〇 _ 3 H 2 〇: C, 52.74; H, 4.35; N, 19.57. Found: C, 52.37; H, 4.10; N, 19.28. Example 7 3 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(dimethylaminomethyl)phenyl]amino-1H-pyrazole (Compound 73) (Step 1) Compound 70 (0.30 g, 0.83 mmol) was dissolved in DMF (3.0 mL), and di-dibutyldicarbonate (〇.54 g, 2.5 mmol) and potassium carbonate (〇_34 g, 2.5 mm ο 1), stir at 6 0 °C for 6 hours. After completion of the reaction, THF (60 mL), water (30 mL), and brine (30 mL) were added to separate the mixture. The organic layer was washed twice with saturated brine (60 mL) and dried over anhydrous sodium sulfate. Concentrated by pressure. The residue was tanning with ethyl acetate to give 2_(benzothiazol-2-yl)-4-cyano-5-[3-(hydroxymethyl)phenyl]amino-2H-pyrazol-3-yl Amine-148- 200911240 T-butyl formate (0.38 g, 65%). (Step 2) 2_(Benzothiazol-2-yl)-4.cyano-5-[3-(hydroxymethyl)phenyl]amino-2-indole-pyrazole-3 obtained in Step 1. The butyl carbamic acid tert-butyl ester (〇. 1 〇g, 0.22 mmol) was dissolved in DMF (2.0 mL), and methanesulfonium chloride (22 μί, 0.28 mmol) was added and stirred at room temperature for 2 hours. Thereafter, a 2.0 mol/L dimethylamine-T H F solution (2 · 2 m L, 4 · 3 m m ο 1 ) was added, and the mixture was stirred at room temperature for 1 hour. After the completion of the reaction, THF (20 mL), water (10 mL), and brine (10 mL) were added to the mixture, and the organic layer was washed twice with saturated brine (20 mL) and dried over anhydrous sodium sulfate. . The residue was purified by silica gel column chromatography (chloroform / methanol = 9/1 to 4/1) to give 2-(benzothiazol-2-yl)-4-cyano-5-[3-( Dimethylaminomethyl)phenyl]amino-2H-pyrazol-3-ylaminecarboxylic acid tert-butyl ester (82 mg, 78%). 'H NMR(270MHz, CDC13)8 1.63(s, 9H), 2.30(s, 6H), 3.48(s, 2H), 6.52(s, 1H), 7.01(br d, J = 7.8Hz, 1H), 7.34(t, j = 7.8Hz, 1H), 7.39(td, J = 7.8, 0.8Hz, 1H), 7.42(br s, 1H), 7.51(td, J = 7.8, 0.8Hz, 1H), 7.58( Dd, J = 7.8, 2.0 Hz, 1H), 7.86 (dd, J = 7.8, 0.8 Hz, 1H), 7.89 (dd, J-7.8, 0.8 Hz, 1H), 1 〇_97 (s, 1H). (Step 3) 2-(B-indene-2-)-4-amino-5-[3-(dimethylaminomethyl)phenyl]amino-2H obtained in Step 2 -pyrazol-3-ylaminocarbamic acid tert-butyl-149- 200911240 ester (8 2 mg, 0.17 mmol) dissolved in methanol (2.5 mL) and chloroform (l_〇mL), 3.0 mol/L hydrochloric acid (0.75 mL) Stir at 50 ° C for 14 hours. After the reaction was completed, the mixture of THE (20 mL), ethyl acetate (20 mL) and 2.0 mol/L sodium hydroxide aqueous solution (40 mL) was added, and the organic layer was water (40 m) and brine (40 mL) Each was washed once, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with chloroform to give Compound 73 (40 mg, 62%). ESIMS m/z: 3 90 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2.19 (s, 6H), 3.38 (s, 2H), 6.86 (d, J = 7.3 Hz, 1H) , 7.24 (dd, J = 7.8, 7.3 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.58-7.64 (m, 2H), 7.90 ( (1, J = 7.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8_28 (s, 2H), 9.1 l (s, 1H). Example 7 4 5-Amino-4-cyano -l-[6-(ethoxycarbonyl)benzothiazol-2-yl]-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (Compound 74) Step 3 of Example 1, 5-amino-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H- obtained from Step 4 of Example 15. Pyrazole (0.50 g, 1.76 mmol), ethyl 2-bromobenzothiazepine-6-carboxylate (〇.51 g, 2.1 mmol), potassium carbonate (1.2 g, 8-8 mmol) and DMF (6 mL) (0.090g, 10%) ° ESIMS m/z: 490 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 1.36 (t, J = 7.1 Hz, 3H) 3.15 (t, J = 4.6 Hz, 4H), 3.80(t, J = 4.6Hz, 4H), 4.36(q, J = 7.1Hz, 2H), 6.56(d, J-7.2Hz, 1H), 7.108-7.17(m, 2H), 7.42(s, 1H), 7.96(m, 1H), 8.07(m, 1H), -150- 200911240 8.33(s,2H), 8.78(d,J = 1.5Hz,1H),9.02(s, 1H) Real Example 7 5 5-Amino-4-cyano-1-(4-methoxybenzothiazol-2-yl)-3-[3-(morpholin-4-yl)phenyl]amino- 1H-pyrazole (Compound 75) 5-Amino-4-cyano-3-[3-(morpholin-4-yl) obtained in Step 4 of Example 15 according to Step 3 of Example Phenyl]amino-1H-pyrazole (0.10 g, 0.35 mmol), 2-bromo-4-methoxybenzothiazole (0.13 g, O.53 mmol), potassium carbonate (0.24 g, 1.8 mmol) DMF (3 mL) gave Compound 75 (0.043 g, 27%). ESIMS m/z: 448 (M + H) VH NMR (270MHz, DMSO-d6) 6 3.14 (t, J = 4.5 Hz, 4H) 3.79 (t, J-4.5 Hz, 4H), 3.96 (s, 3H) , 6.56(m, 1 H), 7.0 8 - 7 _ 1 4 (m, 3 H), 7 · 3 4 (t, J = 8 _ 0 H z, 1 H), 7.41(s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 8.24 (s, 2H), 8.99 (s, lH); Anal. Calcd for C 2 2 Η 2 i N 7 O 2 S · 0 . 1 H 2 0 : C , 58.81; H, 4.76; N, 21.82. Found: C, 58.51; H, 4.61; N, 21.54. Example 76 5-Amino-1-(4-chlorobenzothiazol-2-yl)-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyridyl Azole (Compound 76) 5-Amino-4-cyano-3-[3-(morpholin-4-yl)phenyl] obtained in Step 4 of Example 15 according to Step 3 of Example 1. Amino-1H-pyrazole (O.llg, 0.40 mm), 2-bromo-4-chlorobenzothiazole (0.15 g, 0.60 mmol), potassium carbonate (〇.28 g, 2.0 mmol) and DMF (5 mL) Obtained Compound-151 - 200911240 76 (0.12g, 66%) ° ESIMS m/z: 451 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 3.14 (t, J = 4.6Hz, 4H ) 3.79 (t, J = 4.6 Hz, 4H), 6.57 (m, 1H), 7.13-7.15 (m, 2H), 7.35-7.41 (m, 2H), 7.62 (d, J = 7.9 Hz, 1H), 8.09 (d, J = 7.9 Hz, 1H), 8.29 (s, 2H), 9.04 (s, 1H). Example 7 7 5 -Amino-4-cyano-1-(4-ylbenzothiazol-2-yl)-3-[3-(morpholin-4-yl)phenyl]amino-1 oxime -pyrazole (Compound 7 7 ) 5-Amino-4-cyano-3-[3-(morpholin-4-yl) obtained in Step 4 of Example 15 according to Step 3 of Example 1. Phenyl]amino-1Η-pyrazole (0.080 g, 0.28 mmol), 2-bromo-4-methylbenzothiazole (0-096 g, 0.42 mmol), potassium carbonate (〇.19 g, 1.4 mmol) and DMF ( 3 mL) gave compound 7 7 (0 · 0 2 1 g, 1 7 %). ESIMS m/z: 43 2 (M + H) VH NMR (270MHz, DMSO-d6) 5 2.63 (s, 3H), 3.14 (t, J-4.5 Hz, 4H), 3.79 (t, J = 4.5 Hz, 4H), 6.55(s, 1H), 7.13(s, 1H), 7.15(s, 1H), 7.25 -7.34(m, 2H), 7.42(s, 1H), 7.90(d, J = 6.9Hz, 1H ), 8.22(s, 2H), 8.97(s, 1H) Example 7 8 5-Amino-1((benzothiazol-2-yl)-4-cyano-3-(3-methoxyphenyl) Sulfur)-1H-pyrazole (Compound 78) (Step 1) 3-methoxythioindole (1. 〇g, 7 · 2mmo 1) and diphosgene (1 · 7g, -152- 200911240 5.7mmol) It was dissolved in dichloromethane (25 mL), and a solution of triethylamine (1, 2 mL, 8.5 mmol) The reaction mixture was combined with water (25 mL), and the organic layer was washed twice with 2 mol/L hydrochloric acid (15 mL), and washed twice with water (15 mL), and dried over anhydrous sodium sulfate. The obtained thiochloroformic acid-S-(3-methoxyphenyl) ester was used in the next step without purification. (Step 2) 1,1-Dimercapto-2,2-dicyanoethylene dipotassium (0.55 §, 2.9〇1111〇1) was dissolved in acetone (1.4 mL), water (2.0 mL) at 0 °C A solution of the thiochloroformic acid-S-(3-methoxyphenyl) ester in acetone (3.6 mL) obtained in Step 1 was added thereto, and stirred at room temperature for 12 hr. After the reaction was completed, THF (25 mL) and water (25 mL) were evaporated, and the organic layer was washed with brine (25 mL) and dried over anhydrous sodium sulfate. The obtained 2-[bis(3-methoxyphenylamino)]methylenemalononitrile was not purified and used in the following procedure. (Step 3) 2-[Bis(3-methoxyphenylamino)]methylenemalononitrile obtained in Step 2 was dissolved in ethanol (25 mL), and hydrazine monohydrate (0.35 mL, 1 was added) 1 mmol), stirred at room temperature for 30 min. The residue was dissolved in THF (20 mL), and water (10 mL) and saturated brine (1 mL) were separated. The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. concentrate. The residue was purified by ruthenium dioxide colloidal column chromatography (chloroform/methyl-153-200911240 alcohol = 19/1) to give 5-amino-4-cyano-3-(3-methoxyphenylsulfonium). Base) -1 Η -pyrazole (0.3 8 g, 2 2 %). *H NMR(270MHz, CDC 13)6 3.8 0(s, 3H), 4.43(br s, 2H), 6.87(dd, J = 8.4, 2.4Hz, 1H), 6.98(t, J = 2.4Hz, 1H ), 7.0I(br d, J = 8.4Hz, 1H), 7.26(t, J = 8.4Hz, 1H). (Step 4) 5-Amino-4-cyano-3-(3-methoxyphenylsulfonyl)-1Η-pyrazole obtained in Step 3 according to Step 3 of Example 3 7 0.38g, with 2-chlorobenzothiazole (0.22mL, 1.7mmol) gave compound 78 (〇_25g, 42%). ESI MS m/z: 3 80 (M + H) +; 'H NMR (270MHz, DMSO-d6)5 3.78(s, 3H), 6. 95 (ddd, J=8.5, 2.7, 0.9 Hz, 1H), 7.04- 7 . 1 3 (m, 2H), 7.34 (dd, J = 8.5, 7.8 Hz, 1H), 7.44 (td, J=7.6, 1.1 Hz, 1H), 7.55 (td, J = 7.6, 1.1 Hz, 1H), 7.97 (dd, J=7.6, 1.1 Hz , 1H), 8.1 l(dd, J = 7.6, 1.1 Hz, 1H), 8.43(s, 2H); Anal. C a 1 cd for Ci8Hi3N5OS2: C, 56.97; H, 3.45; N, 18.46. : C, 5 6.96; H, 3.24; N, 1 8.59. Example 7 9 5-Amino-(1-benzothiazol-2-yl)-4-cyano-3-(3-methylphenyl) Sulfosyl)-1 Η-pyrazole (compound 7 9) 5-amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-methylphenylsulfonate) Base)-1 Η ·pyridinium (50 mg, 〇. 1 4 mm ο 1) suspended in dichlorocarbyl-154- 200911240 (3.0 mL), adding m-chloroperbenzoic acid (60 mg, 0.35 mmol), Stir at room temperature for 1 hour. After adding 1 〇% aqueous sodium thiosulfate solution, the organic layer was concentrated under reduced pressure in chloroform, and the obtained crude product was purified by preparative chromatography (methanol / chloroform = 1 / 30) to give compound. 7 9 (3 0 mg, 5 7 %) ° E SI - MS m / z : 3 8 0 (M + Η) +; 1 Η NMR (2 7 0 Μ H z, DMS Ο - d 6) δ 2.34( 8, 3Η), 7.43 -7.6 5 (m, 6Η), 7.99(d, J = 8.1Hz, 1Η), 8.14(d, J = 7.9Hz, 1Η), 8.51(s, 2Η). Example 8 0 5-amino-1-(benzothiazol-2-yl)-4-aminemethylmercapto-3- 3-methylphenylthio-1 Η-pyrazole (compound 80) in 5-amino group 1-(Benzothiazol-2-yl)-4-cyano-3(3-methylphenylthio)-1 Η-D is added to sulfuric acid (50 mg, 1 4 mm ο 1) (0.1 2 m L), allowed to react at room temperature for 2 hours. The reaction mixture was added to ice water and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure, and then crystallised from ethyl acetate to afford compound 80 (36 mg, 67%). ESI-MS m/z: 3 82 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 8 2.29 (s, 3H), 7.1 1 -7.3 1 (m, 6H), 7.44 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.77 (s, 2H), 7.95 (d, J = 8.4 Hz, 1H), 8. 1 〇 (d, J = 7.9 Hz, 1 H). Example 8 1 2 - [ 5 -Amino-4-cyano-3 -(3-methylphenylthio)-1 Η-pyridin-1 -yl]-4 -A-155- 200911240 -5-carboxylate (Compound 81)

[Bis(3-methylphenylthio)methylene]malononitrile (50 mg, 0-16 mmol) was dissolved in ethanol (1. 〇mL), add 2-mercapto-4-methylthiazole-5-carboxylic acid ethyl ester (72mg, 〇. 44mmol). The compound 8 1 was obtained by preparative thin layer chromatography (hexane/ethyl acetate = 2/1) by a microwave reaction apparatus (CEM Microwave Focused Chemical Synthesis Apparatus) at 110 ° C for 20 minutes. 5 mg , 2 4 %) ° ESI-MS m/z: 400 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 6 1. 23 - 1. 3 5 (m, 3H), 2. 3 1 (s, 3H), 2. 60(s, 3H), 4. 28(q, J = 7. 1Hz, 2H), 7. 20-7_34(m, 4H) 8. 27(s, 2H). Example 8 2 5-Ethylamino-1-((benzothiazol-2-yl)-4-cyano-3-(3-methylphenylthio)-1Η-pyrazole (Compound 82) 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-methylphenylthio)-1Η-pyrazole (20 mg, 0_06 mmol) was dissolved in pyridine (0-30 mL) ), adding anhydrous acetic acid (1〇μί, 0. 12 mmol), 4-dimethylaminopyridine (1. Omg), stirred at room temperature for 4 hours. The compound 82 (78 mg, 99%) was obtained by ethyl acetate. ESI-MS m/z: 406 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 2 8 ( s , 3 Η ), 2 · 3 1 ( s, 3 Η), 7 _ 2 4 (m, 1 Η ), 7 _ 3 3 - 7 · 4 0 (m, 3 Η), 7. 47-7. 62 (m, 2H), 8. 04(d, J = 8. 1Hz, 1H), 8. 15(d, J = 8. 1Hz, 1 H), 1 1 . 3(s, 1 H). -156- 200911240 Example 8 3 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3-(4-methylphenylthio)-1H-pyrazole (Compound 83 ) [Bis(4-methylphenylthio)methylene]malononitrile (〇_12g, 0. 37mmol) dissolved in ethanol (l_〇mL), force into 2-mercaptobenzothiazepine (72mg, 0. 44mmol). The reaction was carried out by a microwave reaction apparatus (CEM Microwave Focusing Chemical Synthesis Apparatus) at 150 ° C for 1 hour to obtain Compound 83 (30 mg, 22%) 〇ESI-MSm/z: 3 64 (M + H) + ;1H NMR (2 7 0 Μ Η z , DMS Ο - d 6) δ 2. 33(s, 3H), 7. 25(d, J = 8. 4Hz, 2H), 7. 40-7. 45 (m, 3H), 7. 54(t, J = 7. 9Hz, 1H), 7. 96(d, J = 8.  1Hz, 1H), 8. 09(d, J = 7. 9Hz, 1H), 8. 40(s, 2H). Example 84 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-dimethylaminophenylthio)-1Η-pyrazole (Compound 84) ( Step 1) According to Step 1 of Example 78, from 3-methoxythiophenol (〇. 50g, 3. 3mmol), triphosgene (0. 78g, 2. 6mmol), diethylamine (0. 45mL, 3. 9 mmol) and dichlorocarbyl (14 mL) gave crude thiochloroformic acid-S-(3-dimethylaminophenyl) ester (0. 66 g). Further according to the step 2 of Example 78, the thiochloroformic acid-S-(3-dimethylaminophenyl) ester and the 1,1-dimercapto-2,2-dicyanide obtained in the previous step. Ethylene dipotassium (0. 24§, 1. 3111111〇1), acetone (2. 5mL) and water (l. OmL) gave crude 2-{bis-[(3-dimethylamino)phenyl-157-200911240 thio]methylene}malononitrile. 2-({2-[3-dimethylamino)phenylthio]methylene]malononitrile, hydrazine monohydrate obtained from the previous step according to step 3 of Example 78 ( 0. 16mL, 3. 3mmol) and ethanol (6. 2mL), compound 84 (0. 24g, 57%). (Step 2) 5-Amino-4-cyano-3-(3-dimethylaminophenylthio)-1Η-pyrazole obtained in Step 2 according to Step 3 of Example 37 0. 24g, 0. 93mmol), 2-chlorobenzothiazole (〇. L3mL, l. Ommol), potassium carbonate (〇. 64g, 4. 6mmol) and hydrazine, hydrazine-dimethylformamide (3. 6 mL) to give the compound 8 4 (0 · 2 1 g, 5 8 %). Example 8 5 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-bis(2-hydroxyethyl)amino]phenyl}amino-1H- Pyrazole (Compound 85) (Step 1) Synthesis according to Step 2 of Example 56, from 3-[bis(2-hydroxyethyl)amino]nitrobenzene (〇. 5〇g, 2_2mmol) and methanol (7. 5mL), palladium-carbon (〇. 〇 5g) and hydrogen to give 3-[bis(2-hydroxyethyl)amino]aniline (〇. 27g, 62%) ° 1 H NMR (270MHz, D M S Ο - d 6) δ 3 · 3 2 (t, J = 5. 8 Η z, 4 Η ), 3. 50 (q, J = 5. 8Hz, 4H), 4. 77-4. 65 (m, 4H), 5. 77-5. 94(m, 3H), 6. 76(t, J = 8. 0Hz, 1H). -158· 200911240 (Step 2) According to Step 3 of Example 56, from 3-[bis(2-hydroxyethyl)amino]aniline (〇_27g, 1. 4mmol) with [bis(methylthio)methylene]malononitrile (0. 33g, 1. 9mmol), hydrazine monohydrate (0. 13mL, 2. 7mmol) and ethanol (5. 41111〇, 5-amino-3-{3-[bis(2-hydroxyethyl)amino]phenyl}amine-4-cyano-1H-pyrazole (0. 42g, 100%). Further according to step 4 of Example 56, 5-amino-3-{3-[bis(2-hydroxyethyl)amino]phenyl}amino-4-cyano-1H-pyrazole (0. 42g, 1. 4mmol) and 2-chlorobenzothiazole (0. 27mL, 2. 1mm〇l), potassium carbonate (l. Lg, 8. 2mmol) and hydrazine, hydrazine-dimethylformamide (8 · 3 mL), to give compound 8 5 (0. 1 3 g, 2 2 %). ESIMS m/z: 43 6 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 3. 46(t, J = 6. 2Hz, 4H), 3. 61(td, J = 6. 2, 5. 3Hz, 4H), 4. 77(t, J = 5. 3Hz, 2H), 6. 28(br d, J = 8. 1Hz, 1 H), 6. 9 3 ( b r d, J = 8 .  1 H z, 1H), 7. 04(t, J = 8. 1Hz, 1H), 7. 13(br s, 1H), 7. 38(t, J = 7. 8Hz, 1H), 7. 51(t, J = 7. 8Hz, 1H), 7. 89 (d, J = 7. 8Hz, 1H), 8. 04(d, J = 7. 8Hz, 1H), 8. 26(s, 2H), 8. 83(s, lH); Anal.  Calcd for C2iH21N7〇2S:C, 5 7. 92; H, 4. 86;N, 22. 5 1.  Found: C, 5 7. 77; H, 4_70; N, 22_49. Example 8 6 5 -Monthyl-l-(indolyl-2-pyridin-2-yl)-4-chloro-3-(3-(morphin-4-ylmethyl)phenyl]amino- 1 Η-pyrazole (Compound 8 6) According to Step 2 of Example 7 3, from 5-(benzothiazol-2-yl)-4-cyano-5-[3-(hydroxymethyl)phenyl] Amino-2 Η-pyrazole-3-ylcarbamic acid tert-butyl ester-159- 200911240 (0. 10g, 0. 22mmol) with N,N-dimethylformamide (2. 0mL), methane sulfonate 醯 chlorine (0. 022mL, 0. 28mmol) and morpholine (〇. 38mL, 4. 3nimol), unpurified tert-butyl 5-amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl[3-(hydroxymethyl)benzene Amino acid ester. According to step 3 of Example 73, the third butyl 5-amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazole-3-yl group obtained from the previous step [3] -(Hydroxymethyl)phenyl]carbamate with methanol (2-3 mL), dichloromethane (1. 5mL) and 3. 0m〇l/L hydrochloric acid (1. 2 m L) gave compound 8 6 (3 6 m g, 39%). ESIMS m/z: 43 2 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2. 40(br t, J = 4. 3Hz, 4H), 3. 46(s, 2H), 3. 61(br t, J = 4. 3Hz, 4H), 6. 88(br d, J=7. 6Hz, 1H), 7. 24(t, J = 7. 6Hz, 1H), 7. 39(td, J = 7. 5, 1. 3Hz, 1H), 7. 52(td, J = 7. 5, 1. 3Hz, 1H), 7. 5 9-7. 66(m, 2H), 7. 90(br d, J = 7. 5Hz, 1H), 8. 07(br d, J = 7. 5Hz, 1H), 8. 28(s, 2H), 9. 12(s, lH); Anal.  Calcd for C22H21N7OS · 0.  1 EtOAc: C, 61-15; H, 4. 97;N, 22. 49.  Found: C, 60_80; H, 4. 83;N, 22. 27 . Example 8 7 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(methoxymethyl)phenyl]amino-1H-pyrazole (Compound 87 ) Compound 70 (0. 13g, 〇. 36 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (2_6 mL), and methane sulfonium chloride (0. 053mL, 〇. 68 mm 〇l), stirred at room temperature for 2 hours. Thereafter, a 28% sodium methoxide-methanol solution (2 · 1 m L, 1 1 m m ο 1) was added and stirred at room temperature for 3 hours. After the reaction is over, add -160- 200911240 ethyl acetate (l〇mL), tetrahydrofuran (8. The organic layer was washed twice with saturated brine (18 mL) and dried over anhydrous sodium sulfate. The obtained residue was purified by chromatography on silica gel column chromatography (chloroform/methanol = 9/1), and then purified to yield (chloroform/methanol = 10/1) to afford compound 87 (42 mg, 31%). ESIMS m/z: 3 77 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 8 3. 33(s, 3H), 4. 42(s, 2H), 6. 88(br , J = 7. 6Hz, 1H), 7. 27(t, J = 7. 6Hz, 1 H), 7. 39(td, J = 8.  1 , 1 .  1 Hz, 1 H), 7. 52(td, J = 8. 1,1. 1Hz, 1H), 7. 68-7. 61(m, 2H), 7. 90 (dd, J = 8. 1,1. 1Hz, 1 H), 8. 09 (dd, J = 8. 1,1. 1Hz, 1H), 8. 29(s, 2H), 9. 15(s, 1H). Example 8 8 5-Amino-4-cyano-l-[4,6-difluorobenzothiazol-2-yl]-3-(3-methoxyphenyl)amino-1H-pyrazole (Compound 88) 5-Amino-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole obtained in Step 2 of Example 8. lOg, O. 44mmol) with potassium carbonate (03 0g, 2. 2 mmol) was suspended in hydrazine, hydrazine-dimethylformamide (3 mL), and 2-bromo-4,6-difluorobenzothiazole (0. 16g, 0. 65mmol). After stirring at 4 °t for 5 hours, water was added to the reaction solution to obtain a crude crystal. The obtained crude crystals were washed with methanol to give Compound 88 (0. 1 lg, 63%). ESIMS m/z: 3 99 (M + H) VH NMR (270 MHz, DMSO-d6) 6 3. 78(s, 3H), 6. 51(td, J = 4. 6,2. 3Hz, 1H), 7. 12-7. 21(m, 2H), 7. 42-7. 50 (m, 2H), 7. 86-7. 90 (m, 1H), 8. 19(s, 2H), 9. 16(s, -161 - 200911240 1H). Example 89 2-{3-[5-Amino-1-(benzothiazin-2-yl)-4-cyano-1H-pyrazol-3-yl]aminophenyl}acetic acid ethyl ester ( Compound 89) (Step 1) 2-(3-Aminophenyl)acetic acid (6. 6g, 44mmol) dissolved in ethanol (0. 13L) 'Add [bis(methylthio)methylene]propane-lath (8. 2 g, 48 mmol), heated to reflux for 8 hours. After cooling to room temperature, add concentrated sulfuric acid (1. 4 m L, 4 4 m m ο 1 ), stirred at room temperature for 14 hours. After the end of the reaction, the mixture was concentrated under reduced pressure and ethyl acetate (0. 20L), 2. 0mol/L sodium hydroxide solution (0. 20L) Dispensing 'The organic layer is a mixture of water (0 · 10 L) and saturated brine (〇 _ 1 〇 L) with saturated brine (0. 20 L) Washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by ruthenium dioxide colloidal column chromatography (chloroform / methanol = 19 / 1) to give 2-[3-(2,2-dicyano-1-methylsulfonylvinyl) Aminophenyl]ethyl acetate (1 lg, 86%). ESIMS m/z: 3 02 (M + H) + ; 1H NMR (270MHz, CDC13) 8 1. 27(t, J = 7. 2H > , 3H), 2. 27(s, 3H), 3. 64(s, 2H), 4. 17(q, J = 7. 2Hz, 2H), 7. 13-7. 24(m, 3H), 7. 37(t, J = 8. 1Hz, 1H), 8. 1 4 (s, 1 H). (Step 2) Ethyl 2-[3-(2,2-dicyano-indole-methylsulfonylvinyl)aminophenyl]acetate (llg, 37 mmol) was dissolved in ethanol (0. 11L), adding hydrazine-162- 200911240 hydrate (8. 2 g, 48 mmol), stirred at room temperature for 2 hours. After the end of the reaction, it was concentrated under reduced pressure and water was added (5.  OmL) was filtered. The obtained crystal was dissolved in ethanol at 50 ° C (0. 10 L), cooled to room temperature, recrystallized to give ethyl 2-[3-(5-amino-4-cyano-1H-pyrazol-3-yl)aminophenyl]acetate (5 · 1 g , 4 8 %). ESIMS m/z: 2 8 6 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 1. 18(t, J = 7. 1Hz, 3H), 3. 52(s, 2H), 4. 07(q, J = 7. 1Hz, 2H), 6. 27(s, 2H), 6. 65(br d, J = 7. 8Hz, 1H), 7. 11(t, J = 7. 8Hz, 1H), 7. 33(br d, J = 7. 8Hz, 1H), 7. 39(br s, 1H), 8. 34(s, 1H), 1 1 .  1 4 (s, 1 H). (Step 3) Ethyl 2-[3-(5-amino-4-cyano-1 H-pyrazol-3-yl)aminophenyl]acetate (4. 9g, 17mm〇l) dissolved in hydrazine, hydrazine-dimethylformamide (73mL), added 2-chlorobenzothiazole (2. 2 mL, 19 mmol) and potassium carbonate (12 g, 85 mmol) were stirred at 70 ° C for 2 hours. After the completion of the reaction, the crystals were washed by water (50 mL), and the crystals were washed with water and ethanol to give Compound 8 9 (5. 0g, 7 0%) ° ESIMS m/z: 419 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 1. 21(t, J = 7. 0Hz, 3H), 3. 63(s, 2H), 4. 11(q, J = 7. 0Hz, 2H), 6. 84(br d, J = 7. 8Hz, 1H), 7. 25(t, J = 7. 8Hz, 1H), 7. 38(br t, J = 8. 1Hz, 1H), 7. 51(br t, J = 8. 1Hz, 1H), 7. 57(br s, 1H), 7. 64 (br d, J = 7. 8Hz, 1H), 7. 89(br d, J = 8.  1 Hz, 1H), 8. 07(br d, J = 8_lHz, 1H), 8. 29(s, 2H), 9_15(s, 1H). -163- 200911240 Example 90 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-([(2-hydroxyethyl)methylamino)methyl }Phenyl)amino-1H-pyrazole (Compound 90) According to Example 87, from Compound 70 (0. 10g, 0. 28 mm ο 1) with sulfonium chloride (〇_〇38mL, 0. 50mmol) '(2-hydroxyethyl)methylamine (〇. 44mL, 5. 5mmol) and N,N-dimethylformamide (2. 0 mL), gave compound 90 (9 1 mg, 7 9%) ° ESIMS m/z: 420 (M + H) + ; 'H NMR (27 〇 MHz, DMSO-d6) 5 2. 20(s, 3H), 2. 45-2. 53 m, 2H), 3. 49(s, 2H), 3. 56(td, J = 6. 2, 5 · 1 H z , 2 H ), 4 _ 3 7 (b r t, J : 5 _ 1 H z, 1 H ), 6. 8 8 (b r d, J = 7. 7 H z, 1H), 7. 23(t, J = 7. 7Hz, 1H), 7. 38(br t, J = 7. 8Hz, 1H), 7. 52br t, J = 7. 8Hz, 1H), 7. 61(br d, J = 7. 7Hz, 1H), 7. 65(br s, 1H), 7. 90(br d, J = 7. 8Hz, 1H), 8. 07(br d, J = 7. 8Hz, 1H), 8. 28(s, 2H), 9. 1i(s,iH);Anal.  Calcd for C21H21N7OS: C, 60. 12; H, 5. 05;N, 23. 3 7.  Found: C, 5 9. 82; H, 4. 89;N, 23. 29. Example 9 1 5-Amino-4·cyano-hydroxyethyl)benzothiazol-2-yl]-3-(3-methoxyphenyl)amino-1 Η-pyrazole (Compound 9 1 (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (5. 〇g, 4〇_6mmol), m-methoxyaniline (6. 9g, 40. 6 mmol) and ethanol to give 2_[(3-methoxyphenyl)amino (methylsulfonyl) methylene]-164- 200911240 malononitrile (8. 9g, 86%). ESIMS m/z: 244 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 6 2. 27(s, 6H), 2. 52(s, 3H), 6_90(s, 3H), 10. 4(s, 1H). (Step 2) According to Step 2 of Example 1, 2-[(3-methoxyphenyl)amino (methylsulfonyl)methylene]malononitrile obtained in Step 1 (8. 9g, 3 6. 3 mm ο 1) with hydrazine monohydrate (2 _ 1 m L , 4 3 · 5 mm ο 1) to give 5-amino-4-cyano-3-(3-methoxyphenyl)amine Base-1H-pyrazole (6_0g, 72%). ESIMS m/z: 23 0 (M + H) VH NMR (270 MHz, DMSO-d6) 5 3. 69(s, 3H), 6. 25(s, 2H), 6. 34 (dd, J = 9. 0, 2. 2Hz, 1H), 7. 00-7. 09(m, 2H), 7.  1 3 (s, 1 H), 8 . 3 1 (s, 1 H), 1 1 . 1 6 (s, 1 H). (Step 3) According to Step 3 of Example 4, the 5-amino-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole obtained in Step 2 (〇. I〇g, 0. 44 mmol), 2-bromo-4-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzoquinone thiazole (0. 26g, 0. 52mmol), potassium carbonate (〇. 3〇g, 2. 2 mmol) and N,N-dimethylformamide (5 mL) gave 5-amino-indole-{4-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzothiazole- 2-yl}-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole (0. 12g, 4 4%). ESIMS m/z: 643 (Μ-Η)·;1Η NMR (270MHz, DMSO-d6)6 0. 93(s, 9H), 3. 80(s, 3H), 4. 〇5(t, J = 5. 5Hz, 2H), 4. 33(t, -165 - 200911240 J = 5. 5Hz, 2H), 6. 36(m, 1H), 6. 55 (dd, J^8. 2, 2. 4Hz, 1H), 6. 87 (dd, J = 8. twenty one. 4Hz, 1H), 6. 97(s, 1H), 7. 〇8-7. 44(m, 12H), 7. 5 2-7. 5 5 (m, 4H), 9. 19(s, 1H). (Step 4) 5-Amino-1 - { 4 -[ 2 -(t-butyldiphenylphosphonyloxy)ethyl]benzothiazol-2-yl]-4- obtained in Step 3 Cyano 3-(3-methoxyphenyl)amino-1 Η-pyrazole (0. 1 3 g , 0. 2 0 m m 〇丨) dissolved in tetrahydrofuran (〗 〖m L ), added 70% tetrabutyl fluorinated money (80 μL, 0 _ 2 1 m m ο 1), and stirred for 1 _ 5 hours. After the reaction solution was added with water, it was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The obtained residue was purified by ruthenium dioxide colloidal column chromatography (chloroform/methanol = 95/5), and then purified from diisopropyl ether to give compound 91 (0. 05 lg, 65%). ESIMS m/z: 407 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 3. 74(s, 3H), 3_80(m, 2H), 4. 27-4. 3 5 (m, 2H), 4. 94(t, J = 5. 0Hz, 1H), 6. 48(d, J = 7. 1Hz, 1H), 6. 64(s, 1H), 7. 13- 7. 19(m, 3H), 7. 3 5 -7. 46(m, 2H), 7. 69 (d, J = 7. 6Hz, 1H), 9. 02(s, 1 H), 1 2. 65(s, 1H) 〇 Example 92 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(4-fluoro-3-methoxyphenyl)amino- 1H-pyrazole (Compound 92) (Step 1) [Bis(methylthio)methylene]malononitrile (6_6 g, 39_0 mmol), 4-fluoro-m--166-200911240 methoxyaniline (5. 0 g, 35 mmol) was added to ethanol (50 mL) and stirred at 80 ° C for 5 hours. Add hydrazine monohydrate at room temperature (2. 6 mL, 53 mmol), stirred at 50 ° C for 2 hours. By adding water to the reaction solution, the resulting crude crystals are reslurryed with ethanol to give 5-amino-4-cyano-3-(4-fluoro-3-methoxyphenyl)amino-1 Η- Π 哩 (6 · 1 g, 70%). ESIMS m/z: 24 8 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 6 3. 77(s, 3H), 6. 27(s, 2H), 6. 95-7. 06(m, 2H), 7. 33(d, J = 6. 7Hz, 1H), 8. 36(s, 1H), 11. 14(s, 1H). (Step 2) According to Step 3 of Example 4, 5-amino-4-cyano-3-(4-fluoro-3-methoxyphenyl)amino-1H-pyridyl obtained in Step 1. Azole (0. 70g, 2, 8mmol), 2-chlorobenzothiazepine (〇. 44mL, 3. 4 mmol), cesium carbonate llmmol) and hydrazine, hydrazine-dimethylformamide (30 mL) gave compound 92 (0. 58g, 54%). ESIMS m/z: 381 (M + H) + ; *H NMR (270 MHz, DMF-d7) 6 3. 90(s, 3H), 7. 08-7. 18(m, 2H), 7. 39(t, J = 7. 6Hz, 1H), 7. 52(t, J = 7. 6Hz, 1H), 7. 69 (dd, J = 8. 1,2. 1Hz, 1H), 7. 9〇(d, J = 8. 1Hz, 1H), 8. 08(d, J = 8. 1Hz, 1H), 8. 31(s, 2H), 9. 17(s, 1H). Example 93 5-Amino-(1-benzothiazol-2-yl)-3-[4-chloro-3-(2-dimethylaminoethoxy)phenyl]amino]_cyanide Base-1H-pyrazole (Compound 93) -167- 200911240 (Step 1) 2-Chloro-5-nitrophenol (2. 0g, 12mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (401111 〇, at 0 it was added sodium hydride (0. 92§, 23111111〇1) Stirring. After the mixture was stirred at room temperature, it was suspended by ultrasonication to make it 〇 ° C, and 2-chloro- hydrazine, hydrazine-dimethylethylamine hydrochloride (1. 8 g, 13 mmol) was stirred at room temperature for 15 hours. After completion of the reaction, ethyl acetate (3 mL) and water (30 mL) were evaporated, and the organic layer was washed with saturated aqueous sodium chloride (10 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chloroform / methanol = 20/1) to give 4-chloro-3-(2-dimethylaminoethyloxy) nitrobenzene (0. 5 8 g, 2 1 %). ESIMS m/z: 245 (M + H)+. (Step 2) 4-Chloro-3-(2-dimethylaminoethoxy)nitrobenzene obtained in Step 1. 58g, 2. 4 mmol) was dissolved in ethanol (10 mL), and tin dichloride (2 _ 7 g, 1 2 m ο 1) was added, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was evaporated under reduced pressure, and ethyl acetate (20 mL) and water (20 mL) was added to the mixture. The organic layer was washed with saturated brine (1 mL) and dried over anhydrous sodium sulfate. Concentrate to obtain a residue. The residue was dissolved in ethanol (8. 0m L), adding [bis(methylthio)methylene]malononitrile (0. 40g, 2. 4 mmol), heated to reflux for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to give a residue. This residue was dissolved in ethanol (8. 0mL), adding hydrazine monohydrate (0. 38 mL, 7-8 mmol), heated at 6 Torr for 1 Torr. After completion of the reaction, the mixture was stirred at room temperature for 15 hours, and the precipitated crystals were filtered and dried under reduced pressure to give -168-200911240 5 -amino-3-[4-chloro-3-(2-dimethylamine) Ethyl ethoxy)phenyl]amino-4-cyano-1 Η-pyrazole (〇· 4 2 g, 5 5 %). ES IM S m / z : 3 1 9 (Μ - 广 广. (Step 3) According to the step 3 of Example 4 'from 5-amino-3-[4-chloro-3-( 2-Dimethylaminoethoxy)phenyl]amino-4-cyano-1Η-pyridinium (0. 41g, 1. 3mmol), 2-chlorobenzothiazepine (〇. L〇mL, 0_97mmol), potassium carbonate (0. 54g, 3_9mmol) and N,N-dimethylformamide (8. 0mL)' obtained compound 9 3 (0. 0 2 4 g, 4 %). ESIMS m/z: 452 (M-H)'; 'H NMR (270 MHz, DMSO-d6) 5 2. 89(s, 6H), 3. 31(m, 2H), 3. 77(m, 2H), 7. 08-7. 25 (m, 2H), 7. 39(t, J = 7. 1Hz, 1H), 7. 51(t, J = 7. 1Hz, 1H), 7. 60 (m, 1H), 7. 91 (d, J = 7. 7Hz, 1H), 8. 07(d, J = 7. 7Hz, 1H), 8. 31(br s, 2H), 9.  1 4 (br s, 1 H). Example 94 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(piperidin-1-ylmethyl)phenyl]amino-1H-pyrazole (Compound 94) on Compound 70 (0. 10g, 0. 28 mmol), Ν-dimethylformamide (2. 0mL) solution added to methane sulfonium chloride (〇. 〇32mL, 0. 41 mmol), stirred at room temperature for 30 minutes. Further, methane sulfonium chloride (O. OllmL, 0. 14mmol), after stirring at room temperature for 30 minutes, add piperidine (〇. 55mL, 5 _ 5 m m ο 1). After stirring at room temperature for 2 hours, the reaction mixture was quenched with water, and the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The residue was purified by ruthenium dioxide colloidal column chromatography (chloroform / methanol = 9 / 1), and crystallized (chloroform / methanol = 2 0/1) to give compound 94 (0. 023 g, 19%). ESIMS m/z: 43 0 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 1. 3 3 - 1. 45 (m, 2H), 1. 4 5 -1 · 5 9 (m, 4 H), 2. 3 0 - 2. 4 3 (m, 4 H), 3. 41(s, 2H), 6. 85(br d, J = 7. 6Hz, 1H), 7. 22(t, J = 7. 6Hz, 1H), 7. 38(br t, J = 8. 1Hz, 1H), 7. 52(br t, J = 8. 1Hz, 1H), 7. 60 (br d, J = 7. 6Hz, 1H), 7. 62(br s, 1H), 7. 89(br d, J = 8. 1Hz, 1H), 8. 06(br d, J = 8. 1Hz, 1H), 8_27(s, 2H), 9. 10(s, 1H). Example 95 5-Amino-1-(benzoindole-2-yl)-4-chloro-3--3-{3-[(2-ethyl)isopropylamino]methylphenyl} Amino-1H-pyrazole (Compound 95) According to Example 87, from Compound 70 (0. 10g, 0. 28mmol) with methanesulfonyl chloride (〇. 〇43mL, 0. 55mmol), (2-hydroxyethyl) isopropylamine (0. 62mL, 5. 5mmol) and hydrazine, hydrazine-dimethyl ketoamine (2. 0 mL) gave Compound 95 (0_083 g, 68%). ESIMS m/z: 448 (M + H) + ; 丨 H NMR (270 MHz, DMSO-d6) 6 1. 0 1 (d, J = 6. 5Hz, 6H), 2. 4 4 - 2. 5 6 (m, 2H), 2. 92 (sept, J = 6. 5 H z, 1H), 3. 40(td, J = 6. 8, 5. 4Hz, 2H), 3. 55s, 2H), 4. 20(t, J = 5, 4Hz, 1H), 6. 89(br d, J = 7. 6Hz, 1H), 7. 21(t, J = 7. 6 H z, 1 H), 7. 39(br t, J = = 7. 8Hz, 1 H), 7. 52(br t, J = 7. 8Hz31H), 7. 61(br d, J = 7. 6Hz, 1H), 7. 66(br s, 1H), -170- 200911240 7. 91(br d, J = 7. 8Hz, 1H), 8. 07(br d, J = 7. 8Hz, 1H), 8. 28(s, 2H), 9. 08(s, lH); Anal.  Calcd for C23H25N7OS · O. l EtOAc • 0. 3H2〇: C, 60. 86; H, 5. 76; N, 21. twenty three.  Found: C, 60. 65; H, 5. 54; N, 21. 14. Example 9 6 2-{3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminophenyl}acetic acid (Compound 9 6) Compound 89 (2. 0g, 4. 8mmol) was dissolved in tetrahydrofuran (35mL), added 2. A 0 mol/L aqueous sodium hydroxide solution (60 mL) was stirred at room temperature for 20 hours. After the reaction was completed, 3 · 0 m ο 1 / L hydrochloric acid (0 _ 1 9 L), tetrahydrofuran (170 mL) and saturated brine (50 mL) were added, and the organic layer was water (0. 10L) and saturated saline solution (0. 10 L) mixed solution and saturated brine (0. 20 L) Washed and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with chloroform to give compound 9 6 (1.  7 g, 90%). ESIMS m/z: 391 (M + H) + ; 1H NMR (2 70 MHz, DMSO-d6) 8 3. 54(s, 2H), 6. 84(br d, J = 7. 8Hz, 1H), 7. 24(t, J = 7. SHz, 1H), 7. 38(td, J = 7. 9, 0. 8Hz, 1H), 7. 51(td, J = 7. 9, 1. 1Hz, 1H), 7. 59(br s, 1H), 7. 62(br d, J = 7. 8Hz, 1 H), 7. 9 0 (b r d, J = 7. 9Hz, 1H), 8. 07(br d, J = 7. 9Hz, 1H), 8. 29(s, 2H), 9. 15(s, 1 H), 12. 34(br s, 1H). Example 9 7 5-Amino-1-(benzothiazol-2-yl)-3-[4-chloro-3-(hydroxymethyl)phenyl]amino--171 - 200911240 4-cyano- 1H-pyrazole (Compound 97) (Step 1) 4-Chloro-3-(methyl)aniline (1. Og, 6. 4 mmol) was dissolved in ethanol (20 mL) and [bis(methylthio)methylene]malononitrile (i. Ig, 6 · 4 m m ο 1)' was heated to reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to give a residue. The residue was added to ethanol to suspend it, and stirred for 15 hours. The suspension was filtered and dried to give 2-{[4-chloro-3-(hydroxymethyl)phenyl]amino (methylsulfonyl)methylene}malononitrile. Further, the obtained 2-[4-chloro-3-(hydroxymethylphenyl)amino (methylsulfonyl)methylene]malononitrile was dissolved in ethanol 'addition of hydrazine monohydrate (1 . OmL, 21 mmol) was heated at 60 °C for 1 hour. After completion of the reaction, the mixture was stirred at room temperature for 15 hours, and the precipitated crystals were filtered and dried to give 5-amino-3-[4-chloro-3-(hydroxymethyl)phenyl]amino-4-cyano- 1 Η - 卩 哇 wow (1 · 〇g, 60%). ESIMS m/z: 262 (M-H)_. (Step 2) According to Step 3 of Example 4, 5-amino-3-[4-chloro-3-(hydroxymethyl)phenyl]amino-4-cyano-1H obtained in Step 1. -pyrazole (l. Og, 3. 8mmol), 2-chlorobenzothiazole (〇. 49mL, 3. 8mmol), potassium carbonate (2. 1 g, 15 mmol) and N,N-dimethylformamide (2 〇 m L ) gave compound 97 (0. 694g, 46%). ESIMS m/z: 262 (Μ-Η)·;1Η NMR (270MHz, DMSO-d6)5 4. 56(br s, 2H), 5. 39(br s, 1H), 7. 30 (d, J = 8. 2Hz, 1H), 7. 39(t, J = 7. 7Hz, 1H), 7. 5 1 (j = 7. 7 Η z, 1H), 7. 67(d, J = 8. 2Hz, -172- 200911240 1H), 7. 89(s, 1H), 7. 92(d, J-7. 7Hz, 1H), 8. 06(d, J = 7. 7Hz, 1H), 8. 31 (br s, 2H), 9_35 (s, 1H). Example 9 8 5-Amino-4-cyano- l-(5-methylbenzothiazol-2-yl)-3-(3-methoxyphenyl)amino-1 Η-pyrazole ( Compound 9 8 ) 5-Amino-4-cyano-3-(3-methoxyphenyl)amino-1-1 obtained in Step 2 of Example 91 according to Step 3 of Example 4. -pyrazole (〇. 1〇8, 〇. 61mmol), 2-bromo-5-methylbenzothiazole (〇. 17g, 0. 73mmol), potassium carbonate (0_42g, 3. 0mm〇l) and N,N-dimethylformamide (2mL) gave compound 9 8 (0. 0 3 6 g, 1 6 %). ESIMS m/z: 3 7 7 (M + H) VH NMR (270 MHz, DMSO-d6) S 2. 44(s, 3H), 3. 79(s, 3N), 6. 51(m, 1H), 7. 16-7. 21(m, 3H), 7. 43(m, 1H), 7. 74 (m, 1H), 7. 95(d, J = 8. 1Hz, 1H), 8. 29(d, J= 1 0_2Hz, 2H), 9. 1 1 (s, 1 H). Example 9 9 5-Amino-4-cyano-1-(4-methoxybenzothiazol-2-yl)-3-(4-fluoro-3-methoxyphenyl)amino-1H -pyrazole (Compound 99) According to Step 3 of Example 4, 5-amino-4-cyano-3(4-fluoro-3-methoxybenzene) obtained in Step 1 of Example 92 Amino-1 H-specific oxime (0. 026g, O. Lllmmol), 2-bromo-4-methoxybenzothiazol (〇. 〇31g, 〇. 13mmol), potassium carbonate (〇. 〇73g,0. 53 mmol) and hydrazine, hydrazine-methyl-methylamine (1 mL) give compound 99 (0. 014g, 33%). -173- 200911240 ESIMS m/z: 410 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 3. 89(s, 3H), 3. 96(s, 3H), 7. 08-7. 1 8 (m, 3H), 7. 34(t, J = 8. 0Hz, 1H), 7. 63(d, J = 8. 0Hz, 1H), 7. 68 (dd, J = 8. 0, 2. 2Hz, 1 H), 8. 27(s, 2H), 9_ 1 8(s, 1 H). Example 100 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(4-phenylpiperazin-1-ylmethyl)phenyl]amino- 1H-pyrazole (Compound 100) According to Example 87, from Compound 70 (0. 10g, 0. 28mmol), a hospital sulfonium chloride (〇. 〇23mL, 0. 30mmol), 1-phenyl xiaoxiao (0. 42mL, 2. 8mmol) and hydrazine, hydrazine-dimethylformamide (2. 0mL), get compound 100 (0. 08 8g, 63%). ESIMS m/z: 5 07 (M + H) VH NMR (270 MHz, DMSO-d6) 5 2. 57(br s, 4H), 3. 19(br s4H), 3. 53(s, 2H), 6. 76(t, J = 7. 1Hz, 1 H), 6. 86-6. 97(m, 3H), 7.  14-7. 29(m, 3H), 7_34(br t, J = 7. 7Hz, 1 H), 7. 50(br t, J = 7. 7Hz, 1H), 7. 59(br d, J = 7. 8Hz, 1H), 7. 74(br s, 1H), 7. 84-7. 94(m, 2H), 8. 28(s, 2H), 9. 12(s, lH); Anal.  Calcd for C28H26N8S: C, 66. 3 8;H, 5_17;N, 22. 12.  Found: C, 66. 44; H, 4. 81;N, 22. 18. Example 1 0 1 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-{3-[4-(3-hydroxy-3-methylbutyl)piperazine- 1-methylmethyl]phenyl}amino-1H-pyrazole (Compound 101) was synthesized according to Example 87 from Compound 70 (0. 10g, 0. 28mmol) -174- 200911240 with methane sulfonium chloride (23μί,0. 30mmol), 1-(3-hydroxy-3-methylbutyl) warm 嚷 (〇. 48g, 2. 8mmol) and N,N-dimethylformamide (2. 0mL)' obtained compound 1 0 1 (0. 036g, 25%). ESIMS m/z: 517 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 6 1. 07(s, 6H), 1. 50(t, J = 7. 3Hz, 2H), 2. 30-2. 5 3 (m, 1 OH), 3. 45(s, 2H), 4. 65(s, 1H), 6. 85(br d, J = 7. 7Hz, 1H), 7. 23(t, J = 7. 7Hz, 1H), 7. 38(br t, J = 8. 3Hz, 1 H), 7. 52(br t, J = 8. 3Hz, 1H), 7. 58(br d, J = 7. 7Hz, 1H), 7. 67(br s, 1H), 7. 90 (br d, J = 8. 3Hz, 1 H), 8. 07(br d, J = 8. 3Hz, 1H), 8. 28(s, 2H), 9. 11(s, 1 H). Example 102 5-Amino-1-(benzoxazol-2-yl)-3-[4-chloro-3-(morpholin-4-yl)methylphenyl]amino-4-cyano -1H-pyrazole (Compound 102) Compound 97 (0. 10g, 0. 25mm〇l) dissolved in N,N-dimethylformamide (2. 0mL), adding methane sulfonium chloride (0_078mL, l. Olmmol), stirred at room temperature for 1 hour. Next, add morpholine (〇. 26mL, 3. 0 mmol), stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (3 mL) and water (30 mL) were evaporated, and the organic layer was washed with saturated aqueous sodium chloride (10 mL), and dried over anhydrous sodium sulfate. Ethyl alcohol was added to the residue obtained, suspended, stirred for 15 hours, filtered and dried to give Compound 102 (0. 081g, 69%) ° ESIMS m/z: 464 (M-H): 1H NMR (270MHz, DMSO-d6)S 3. 98(s, 2H), 2. 95-3. 10(m, 4H), 3. 71-3. 90 (m, 4H), 7. 28(d, -175- 200911240 J-8. 2Hz, 1H), 7. 36(t, J = 7. 8Hz, 1H), 7. 50(t, J = 7. 8Hz, 1H), 7. 60 (d, J = 8. 2Hz, 1H), 7. 92(s, 1H), 7. 94 (d, J = 7. 8Hz, 1H), 8_10 (d, J = 7_8Hz, 1H), 8. 39(br s, 2H), 9_10(s, 1H). Example 103 5-Amino-1-(benzothiazol-2-yl)-3-(4-chlorophenyl)amino-4-cyano-1H-pyrazole (Compound 1 〇3) (Step 1 According to step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (l. Og, 5. 9mmol), 4-chloroaniline (0. 75g, 5. 9 mmol) and ethanol (20 mL) gave 2-[(4-chlorophenyl)amino (methylsulfonyl)methylene]malononitrile (0. 69g, 47%). ESIMS m/z: 248 (MH), (Step 2) 2-[(4-chlorophenyl)amino (methylsulfonyl)-methyl group obtained in step 1 according to step 2 of Example 1. Base] malononitrile (0. 67, 2. 70mmol) with hydrazine monohydrate (〇_43mL, 8. 9 mmol) gave 5-amino-3-(4-chlorophenyl)amino-4-cyano-1 Η-pyrazole (0 · 5 8 g, 92%). ESIMS m/z: 23 2 (MH), (Step 3) 5-Amino-3-(4-chlorophenyl)amino-4-cyanide obtained in Step 2 according to Step 3 of Example 4. keto-1H-pyrazole (0. 23g, l. Ommol), 2-chloro-176- 200911240 Benzothiazole (0. 14mL, l. Lmmol), potassium carbonate (〇. 55g, 4_0mmol) and N,N-dimethylformamide (4mL) gave compound l〇3 (〇. 21g, 57%). ESIMS m/z: 3 6 5 (M-H)'; 'H NMR (270 MHz, DMSO-d6) 8 7. 35 (d, J two 8. 1Hz, 2H)t7. 39(t, J = 7. 3Hz, 1H), 7. 49(t, J = 7. 3Hz, 1H), 7. 70 (d, J = 8. 1Hz, 2H), 7. 90 (d, J = 7. 3Hz, 1H), 8_08 (d, J = 7. 3Hz, 1H), 8. 32(br s, 2H), 9_29 (br s, 1H). Example 104 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(4-methoxyphenyl)amino-1H-pyrazole (Compound 104) (Step 1 According to step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (l_〇g, 5. 9mmol), 4-methoxyaniline (〇. 72g, 5. 9 mmol) and ethanol (20 mL) give 2-[(4-methoxyphenyl)amino (methylsulfonyl)methylene]malononitrile (〇. 96g, 67%). ESIMS m/z: 244 (Μ-ΗΓ. (Step 2) According to Step 2 of Example 1, 2-[(4-methoxyphenyl)amino group (methylsulfonyl) obtained in Step 1. Methylene]malononitrile (0_95g, 3. 9 m m ο 1) with hydrazine monohydrate (〇.  6 2 m L , 1 3 m m ο 1), 5-amino-4-cyano-3-(4-methoxyphenyl)amino-1H-D is obtained. 68g, 76%). ESIMS m/z: 228 (M-HK. -177- 200911240 (Step 3) According to Step 3 of Example 4, the 5-amino group 4- 4-cyano-3-(4-A obtained in Step 2 Oxyphenyl)amino-1H-pyrazole (〇23g, 1. 00 mmol), 2-chlorobenzothiazole (〇_i4mL, l. Lmmol), potassium carbonate (〇. 55g, 4_0mmol) and N,N-dimethylformamide (4. 〇mL), get compound 1〇4 (0. 1 7g, 4 8%) 〇 ESIMS m/z: ΒόΙίΜ-Η)'; ^ NMR (270MHz, DMSO-d6) 5 3. 99(s, 3H), 6. 98 (d, J = 7. 9Hz, 2H), 7. 40(t, 1=7. 2Hz, 1H), 7. 45 (d, J = 7. 9Hz, 2H), 7. 57(t, J = 7. 2Hz 1H), 7. 90 (d, J = 7. 2Hz, 1H), 8. 05(d, J = 7. 2Hz, 1H), 8. 32(br s, 2H), 9. 20 (br s, 1H). Example 1 5 5 -Amino-1-(1-benzyl-1H-benzimidazol-2-yl)-4-yl-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole (Compound 105) (Step 1) on 1-benzyl-2-chloro-1H-benzimidazole (0. 10g, 041mm〇1) Add triethylol monomethyl ether (3. 0mL), fluorinated planer (〇. 〇63g, 〇. 41mmol), 2,6-lut steep (0. 0531111>,0. 45111111〇1), 5 - fl-fanta-4-cyano-3-(3-methoxyphenyl)amino group _ 1 η - fluorene obtained in step 2 of Example 91 (0. 094g, 0. 4 1mmol) 'At 13 (rc was stirred for 72 hours. After adding water to the reaction mixture to draw with ethyl acetate), the solvent was distilled off under reduced pressure. The obtained residue was chromatographed on a silica gel column. Purification with chloroform/methanol = 9 5 / 5 ) gave Compound 1 〇5 (2 1 mg, 12%). -178- 200911240 ESIMS m/z: 43 4(MH)';1H NMR (270MHz, DMSO-d6 )6 3. 71(s, 3H), 5. 53(s, 2H), 6. 07(s, 2H), 6. 90-6. 99(m, 5H), 7. 14-7. 16(m, 4H), 7. 3 8 -7. 42(m, 2H), 7. 57(d, J = 9. 5 Hz, 1H), 7 · 7 2 (d, J = 8 · 7 H z, 1 H), 7 8 3 (d, J = 8 · 7 H z, 1 H). Example 106 5-Amino-4-cyano-3-(3-methoxyphenyl)amino-1-(n-naphtho[l,2-d]thiazol-2-yl)-1 Η-pyridyl Azole (Compound 1 〇6) 5-Amino-4-cyano-3-(3-methoxyphenyl)amino group obtained in Step 2 of Example 91 according to Step 3 of Example 4. 1Η-pyrazole (0. 10g, 0. 44 mmol), 2-bromonaphtho[l,2-d]thiazole (0. 17g, 0. 65mmol), potassium carbonate (0. 30g, 2. 2 mmol) and hydrazine, hydrazine-dimethylformamide (5_0 mL) gave compound 1 0 6 (0 _ 0 3 5 g, 19%). ESIMS m/z: 413 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 3. 81(s, 3H), 6. 52 (d, J = 7. 9Hz, 1 H), 7 · 1 6 - 7 · 2 7 (m, 2 H), 7. 49(s, 1H), 7. 60-7. 72(m, 2H), 7. 90 (d, J = 8. 9Hz, 1 H), 8. 06(d, J = 7. 7Hz, 1H), 8. 16(d, J = 8. 9Hz, 1H), 8. 34(s, 2H), 8. 82 (d, J = 7. 7Hz, 1H), 9_13(s, 1H). Example 107 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-{[2-(2-hydroxyethoxy)ethylamino]methylbenzene Amino-1H-pyrazole (Compound 107) According to Example 87, from Compound 70 (0. 10g, 0. 28mmol) with methanesulfonyl chloride (〇. 〇32mL, 0. 41 mmol) ' 2-(2-hydroxyethoxy)ethylamine -179- 200911240 (0. 28mL, 2. 8mmol) and hydrazine, hydrazine-dimethylformamide (2. 0 mL) to give the compound 1 07 (47 mg, 3 8%) ° ESIMS m/z: 450 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 70(t, J = 5. 7Hz, 2N), 3. 18(d, J = 4. 6Hz, 1H), 3. 36-3. 56(m, 6H), 3. 72(s, 2H), 4. 60(br s, 1H), 6. 90(br d, J = 7_8Hz, 1H), 7. 23(t, J = 7. 8Hz, 1H), 7. 38(br t, J = 7. 8Hz, 1H), 7. 52(br t, J = 7. 8Hz, 1H), 7. 59(br d, J = 7. 8Hz, 1H), 7. 64(br s, 1H), 7. 90(br d, J = 7. 8Hz, 1H), 8. 07(br d, J = 7. 8Hz, 1H), 8. 28(s, 2H), 9. 09(s, 1H). Example 1 0 8 • 2-{3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl].  Aminophenyl}-N,N-dimethylacetamide (Compound 108) Compound 96 (0. 10g, 0. 26mmol) dissolved in hydrazine, hydrazine-dimethylacetamide (0. 20mL) and tetrahydrofuran (1. 6mL), adding 1-hydroxybenzotriazole-water compound (0. 042g, 0. 31mmol), 2. 0 mol / L dimethylamine - tetrahydrofuran solution (〇. 19mL, 0. 38 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (〇. 〇59g,0. 31 mmol), stirred at room temperature for 2 hours. After the completion of the reaction, the mixture was combined with EtOAc (EtOAc) (EtOAc) The residue thus obtained was purified by chromatography on silica gel column chromatography (chloroform/methanol = 19/1) to afford THF (yield: 6 g, 65%). ESIMS m/z: 418 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 -180 - 200911240 2. 86(s, 3H), 3. 03(s,3H), 3. 67(s, 2H), 6. 82 (br d, J = 7. 6Hz, 1H), 7. 24 (dd, J two 8. 1, 7. 6Hz, 1H), 7. 38(td, J = 8. 0, l. IHz 1H), 7. 45 -7. 5 5 (m, 2H), 7. 64 (dd, J = 8. 1,1. 4Hz, 1H), 7. 9〇(br d, J = 8. 0Hz, 1H), 8. 07(br d, J = 8. 0Hz, 1H), 8. 29(s, 2H), 9. 14(s, 1 H). Example 1 〇9 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(thiomorpholin-4-ylmethyl)phenyl]amino- 1 Η-pyrazole (Compound 1 〇9) According to Example 87, from Compound 70 (0-10 g, 〇. 28mmol) with methanesulfonyl chloride (〇. 〇23mL, 0. 30mmol), thiomorpholine (〇. 26mL, 2. 8 mmol) and N,N-dimethylformamide (2. 0 mL) gave the compound ι〇9 (0 _ 1 1 g, 8 7 %). ESIMS m/z: 448 (M + H) +; 'H NMR (270 MHz, DMSO-d6) 6 2. 61-2. 72(m, 8H), 3. 49(s, 2H), 6. 85(br d, J = 7. 7Hz, 1H), 7. 23(t, J = 7. 7Hz, 1H), 7. 39(br t, J = 7. 8Hz, 1H), 7. 52(br t, J = 7. 8Hz, 1H), 7. 55 (dd, J = 7. 7, 1. 9Hz, 1H), 7. 69(br s, 1H), 7. 90(br d, J = 7. 8Hz, 1H), 8. 06(br d, J = 7. 8Hz, 1H), 8. 28(s, 2H), 9. 12(s, lH); Anal.  Calcd for C22H21N7S2: C, 59_04; H, 4_73; N, 21. 91.  Found: C, 5 8. 66; H, 4. 48; N, 21_72. Example 11 〇5-Amino-4-cyano-1-(6,7-dihydro[1,4]dioxy[2,3-f] [1,3]benzothiazol-2-yl -3-(3-methoxyphenyl)amino-1H-pyrazole (Compound 1 10) 200911240 According to Step 3 of Example 4, the 5-amino group obtained in Step 2 of Example 91 - 4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole (0. 042g, 0. 18 mmol), 2-bromo-6,7-dihydro[1,4]dioxy[2,3-f][l,3]benzothiazole (0. 075g, 0_28mmol), potassium carbonate (〇3g, 0·92 mmol) and N,N-dimethylformamide (5. 0mL), get compound 110 (〇. 〇13g, 17%) ° ESIMS m/z: 421 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 8 3. 78(s, 3H), 4. 30(s, 4H), 6. 50 (m, 1H), 7. 17-7. 19(m, 2H), 7. 38(s, 1H), 7. 43(m, 1H), 7. 58(s, 1H), 8. 19(s, 2H), 9. 08(s, 1 H). Example 111 5-Amino-1-(6-butylbenzothiazole-2.yl)-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole (Compound 1 1 1) 5-Amino-4-cyano-3-(3-methoxyphenyl)amine·lH-pyrazole obtained in Step 2 of Example 91 according to Step 3 of Example 4. (0. 05g, 〇. 22mmol), 2-bromo-6-butylbenzothiazole (〇. 〇71g, 0. 26mmol), potassium carbonate (0. 15g, l. Lmmol) and hydrazine, hydrazine-dimethylformamide (5. 0mL), get compound lll (0. 016g, 18%). ESIMS m/z: 419 (M + H) + : :H NMR (270MHz, DMSO-ά6) δ 0. 91(t, J = 7. 3Hz, 3H), 1. 33(td, J=14. 8, 7. 3Hz, 2H), 1. 5 6- 1. 66(m, 2H), 2. 7 0 (t, J = 7 · 3 H z, 2H), 3. 79(s, 3H), 6. 51(m, 1H), 7. 18-7. 20(m, 2H), 7. 34 (dd, J = 8. 3, 1. 7Hz, 1H), 7. 47(t, J = 1. 7Hz, 1H), 7. 79(d, J-8. 3Hz, 1H), 7. 90(d, -182- 200911240 J=1. 7Hz, 1H), 8_26(s, 2H), 9. 11 (s, 1H). Example 1 1 2 5-Amino-1-(benzothiazol-2-yl)-3-[4-chloro-3-(methoxymethyl)phenyl]amino-4-cyano-1H -pyrazole (Compound 112) Compound 97 (0. 10g, 0. 252 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (2 mL), and methane sulfonium chloride (0. 078 mL, l_〇mmol), stirred at room temperature for 4 hours. Next, add sodium methoxide 28% methanol solution (1. 46mL, 7. 5 6 mmol), stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate (30 mL) and water (30 mL) were evaporated. The residue obtained was chromatographed on a silica gel column (hexane / ethyl acetate).  =2/1) Refined to give compound 1 12 (0. 3 9g, 38%). ESIMS m/z: 409(Μ-Η)·;'Η NMR (270MHz, DMSO-d6)6 3. 60(s, 3H), 3. 98(br s, 2H), 7. 21(d, J = 8. 0Hz, 1H), 7. 34(t, l J = 7. 8Hz, 1H), 7. 48(t, J = 7. 8Hz, 1H), 7, 61(d, J = 8. 0Hz, 1H), 7. 90(s, 1H), 7. 99(d, J = 7. 8Hz, 1H), 8. 25(d, J = 7. 8Hz, 1H), 8. 40 (br s, 2H), 9_40 (s, 1H). Example 1 1 3 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-(4-piperidinyl-1-yl)phenyl]amino -1 Η-pyrazole (Compound 1 1 3 ) According to Example 87, from compound 7 〇 (〇·1 〇g, 0. 28 mmol) with methanesulfonium chloride (〇_〇 23 mL, 〇. 3〇mmol), 4-hydroxypiperidin D (0. 28g, 2. 8mmol) -183- 200911240 and N,N-dimethylformamide (2. 0 mL) to give the compound U3 (0. 10 g, 8 3%) ° ESIMS m/z: 446 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 1. 45 (qd, J = 9. 6, 3. 5Hz, 2H), 1 .  7 3 (b r d , J = 9 _ 6 H z, 2 H), 2. 06(br t, J = 9. 6Hz, 2H), 2. 64-2. 77(m, 2H), 3. 3 8 - 3. 5 3 (m, 1H), 3. 43(s, 2H), 4. 56(d, J = 4.  1 Hz, 1H), 6. 85(br d, J = 7. 8Hz, 1H), 7. 22(t, J = 7. 8Hz, 1 H ), 7 _ 3 8 ( b r t, J = 7. 8 H z, 1 H), 7. 52(td, J = 7. 8, 1. 3Hz, 1H), 7. 58 (dd, J = 7. 8, 1. 6Hz, 1H), 7. 67(br s, 1H), 7. 90(br d, J II 7. 8Hz, 1H), 8. 07(br d, J = 7. 8Hz, 1H), 8_27(s, 2H), 9. 10(s, 1H). Example 1 1 4 3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminobenzoic acid ethyl ester (Compound 1 I4) (Step 1) According to Step 1 of Example 89, from 3-aminobenzoic acid (1. Og, 7. 3mmol), [bis(methylthio)methylene]malononitrile (1. 4g, 8. 0mm〇l), concentrated sulfuric acid (〇. 681111^, 22111111〇1) and ethanol (2〇1111^)' gave 3-(2,2-cyano-p-methylsulfonylvinylamino)benzoic acid ethyl ester (〇. 48g, 23% b *H NMR (2 70MHz, CDC13)6 1. 42(t, J = 7. 1Hz, 3H), 2. 32 (s, 3H), 4. 41(q, J = 7. 1Hz, 2H), 7. 46 (dt, J = 8. 0, 1. 8Hz, 1H), 7. 52 (dd, J = 8. 0, 7. 3Hz, 1H), 7. 93(dd, J=l-8, 1. 5Hz, 1H), 7. 99 (dt, J = 7. 3, 1. 5Hz, 1H), 8. 12(s, 1H). -184- 200911240 (Step 2) According to Step 2 of Example 89, the ethyl 3-(2,2-dicyano-1-methylsulfonylvinylamino)benzoate obtained in Step 1 (〇. 21g, 0. 73mmol), hydrazine monohydrate (0_036mL, 0. 73mmol) and ethanol (2.  LmL) to give ethyl 3-(5-amino-4-cyano-1 Η-pyrazol-3-yl)aminobenzoate (〇. 19g, 95%). ESIMS m/z: 2 72 (M + H) VH NMR (270 MHz, DMSO-d6) S 1. 31(t, J = 7. 0Hz, 3H), 4. 29(q, J = 7. 0Hz, 2H), 6. 31(s, 2H), 7. 31(t, J = 7. 6Hz, 1H), 7. 37 (dt, J = 7. 6, 1. 4Hz, 1H), 7. 73 (br d, J = 7. 6Hz, 1H), 8. 15(br s, 1H), 8. 68(s, 1H), 11. 24(s, 1H). (Step 3) According to Step 3 of Example 89, the ethyl 3-(5-amino-4-cyano-1H-pyrazol-3-yl)aminobenzoate obtained in Step 2 (0. 16g, 0. 59 mmol), 2-chlorobenzothiazepine (〇. 〇84mL, 0. 65mmol), potassium carbonate (0. 41g, 2. 9mmol) and N,N-dimethylformamide (2. 4 mL) to give the compound 1 1 4 (80 mg, 3 4%) ° ESIMS m/z: 405 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 8 1. 39(t, J = 7. 0Hz, 3H), 4. 36(q, J = 7. 0Hz, 2H), 7. 40(br t, J = 8. 1Hz, 1H), 7. 45(t, J = 7. 8Hz, 1H), 7. 48-7. 57(m, 2H), 7. 91(br d, J = 8. 1Hz, 1H), 7. 94(br dd, J = 7. 8, 1. 9Hz, 1H), 8. 07(br d, J = 8. 1Hz, 1H), 8. 32(s, 2H), 8. 45(t, J=1. 9Hz, 1H), 9. 45 (s, 1H). -185- 200911240 Example 1 1 5 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-{[(2-methoxyethyl)methylamine Methyl]phenyl)amino-1H-pyrazole (Compound II5) According to Example 87, compound 70 (0. 10g, 0. 28mm〇l) dissolved in hydrazine, hydrazine-dimethylformamide (2. 0mL), adding methane sulfonium chloride (0. 024mL, 0. 30 mmol), stirred at room temperature for 2 hours. Thereafter, (2-methoxyethyl)methylamine (0. 30mL, 2. 8 mmol), stirred at room temperature for 3 hours. After completion of the reaction, tetrahydrofuran (20 mL), water (10 mL), and brine (10 mL) were added, and the organic layer was washed twice with saturated brine (20 mL) and dried over anhydrous sodium sulfate. concentrate. The obtained residue was purified by ruthenium dioxide colloidal column chromatography (chloroform/methanol = 19/1), and then chloroform was used to obtain compound 1 15 (0. 083g, 69%). ESIMS m/z: 434 (M + H) +; lH NMR (270MHz, DMSO-d6) 5 2. 20(s, 3H), 2. 56(t, J = 5. 9Hz, 2H), 3. 24(s, 3H), 3. 49(t, J = 5. 9Hz, 2H), 3. 49(s, 2H), 6. 86(br d, J = 7. 5Hz, 1H), 7. 23(t, J = 7. 5Hz, 1H), 7. 39(br t, J = 8.  1Hz, 1 H), 7. 52(br t, J = 8.  1 Hz, 1H), 7. 5 8-7. 66(m, 2H), 7. 90 (br d, J = 8. 1Hz, 1 H), 8 · 0 7 (br d, J = 8,1Hz, 1H), 8. 29(s, 2H), 9. 13(s, 1H). Example 1 1 6 2-[5-Amino-4-cyano-3-(3-methoxyphenyl)amino-1H-pyrazole-buyl]benzothiazole-6-sulfonamide Compound 1 1 6) According to Step 3 of Example 4, from -186 to 200911240 obtained in Step 2 of Example 91 to 5-amino-4-cyano-3-(3-methoxyphenyl)amine keto-1H-pyrazole (0. 1 〇g, 0. 44mmol), 2-bromobenzothiazole-6-sulfonamide (0. 15g, 0. 52mmol), potassium carbonate (0. 30g, 2_2mmol) and hydrazine, hydrazine-dimethylformamide (5. 0 mL), compound 1 1 6 (0. 063g, 33%). ESIMS m/z: 440 (M-H)'; 1H NMR (270 MHz, DMSO-d6) S 3. 79(s, 3H), 6. 46 (dt, J = 7. 8, 1. 2Hz, 1H), 7. 11-7. 22(m, 4H), 7. 51(t, J = 2_lHz, 1H), 7. 83 -7. 8 6 (m, 3H), 8. 43(s, 1H). Example 1 1 7 5-Amino-4-chloro-3-3-(3-methoxyphenyl)amino-1-(4,5,6-dioxabenzothiazole-2-yl)-1 Η-pyrazole (Compound 1 17) 5-Amino-4-cyano-3-(3-methoxyphenyl)amino-1Η-pyrazole obtained in Step 2 of Example 91 ( 0. 10g, 0. 44mm〇l) with potassium carbonate (0. 3 0g, 2. 2 mmol) was suspended in hydrazine, hydrazine-dimethylformamide (5 mL), and 2-bromo-4,5,6-trifluorobenzothiazole (0. 138,0. 481 «111〇1). After stirring at 40 ° C for 5 hours, water was added to the reaction solution to obtain a crude crystal. The compound 1 17 (0.) was obtained by washing the obtained crude crystals with methanol. 16g, 89%). ESIMS m/z: 417 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 3. 78(s, 3H), 6. 53 (dt, J = 6. 7, 2. 3Hz, 1H), 7. 15-7. 20(m, 2H), 7. 43(d, J = 2. 0Hz, 1H), 8. 15(m, 1H), 8. 21(s, 2H), 9. 20(s, 1H). Example 1 1 8 5-Amino-1-(benzothiazol-2-yl)-3-(2-chlorophenyl)amino-4-cyano-1H--187- 200911240 Pyrazole (Compound 1 1 8 ) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (1. Og, 5. 9mmol), 2-chloroaniline (0. 62g, 5. 9 mmol) and ethanol (20 mL) gave 2-[(2-chlorophenyl)amino (methylsulfonyl)methylene]malononitrile. Next, according to the step 2 of Example 1, 2-[(2-chlorophenyl)amino (methylsulfonyl)methylene]malononitrile and hydrazine monohydrate obtained above ( Hey. 93 mL, 19 mmol) and ethanol (20 mL) gave 5-amino-3-(2-chlorophenyl)amino-4-cyano-1H-pyrazole (0. 83g, 61%). ESIMS m/z: 232 (M-H)-. (Step 2) According to Step 3 of Example 4, 5-amino-3-(2-phenylphenyl)amino-4-cyano-1H-disgust D obtained in Step 1 (〇_23g) l. Ommol), 2-chlorobenzothiazole (〇_14mL, l. Lmmol), potassium carbonate (0_55g, 4. 0mmol) and hydrazine, hydrazine-dimethylformamide (4. 0m L), get compound 1 18 (0. 1 6g, 44%) ° ESIMS m/z: 3 65 (M-H); 'H NMR (270MHz, DMSO-d6) 5 6. 90 (d, J = 7. 7Hz, 1H), 7. 10(t, J = 7. 7Hz, 1H), 7. 25-7. 48(m, 4H), 7. 85 (d, J 2 7.4, 1H), 8. 05(d, J = 7. 4Hz, 1H), 8. 30(br s, 2H), 9. 38 (br s, 1H). Example 1 1 9 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(trifluoromethoxy)phenyl]-188- 200911240 Amino-1 Η-pyrazole (Compound 1 1 9) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (l_0g, 5-9 mmol), 3-trifluoromethoxy Aniline (0. 79mL, 5. 9 mmol) and ethanol (20 mL) gave 2-[(3-trifluoromethoxyphenyl)amino (methylsulfonyl)methylene]malononitrile. Next, according to the step 2 of Example 1, the obtained 2-[(3-trifluoromethoxyphenyl)amino (methylsulfonyl)methylene]malononitrile and hydrazine monohydrate Object (〇. 94 mL, 19 mmol) and ethanol (20 mL) gave 5-amino-4-cyano-3-[3-(trifluoromethoxy)phenyl]amino-1 hydrazine-pyrazole (0. 8 9 g, 5 3 % ). ESIMS m/z: 282 (M-H)·. (Step 2) According to Step 3 of Example 4, 5-amino-4-cyano-3-[3-(trifluoromethoxy)phenyl]amino-1H-pyridyl obtained in Step 1. Azole (0. 28g, 1. 0 mmol), 2-chlorobenzothiazole (〇. 14mL, l. Lmmol), potassium carbonate (0. 55g, 4. 0mmol) and hydrazine, hydrazine-dimethylformamide (4. 0 mL), gave compound 1 1 9 (0 · 0 7 1 g, 17%) ° ESIMS m/z: 415 (Μ-Η)·; 1 NMR (270 MHz, DMSO-d6) 5 7. 3 0-7. 5 7 (m, 4H), 7. 60-7. 80 (m, 2H), 7. 90 (d, J = 7. 2Hz, 1H), 8. 09(d, J = 7. 2Hz, 1 H), 8. 3 0 (b r s, 2 H), 9 · 0 1 (b r s, 1 H). Example 120 5-Amino-1-(benzothiazol-2-yl)-3-(3-chlorophenyl)amino-4-cyano-1H--189- 200911240 Pyrazole (Compound 1 2 0 (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (l. Og, 5. 9mm〇l), 3-chloroaniline (4. 62mL, 5. 9 mmol) and ethanol (20 mL) were obtained as 2-[(3-chlorophenyl)amino (methylsulfonyl)methylene]malononitrile. Next, according to the step 2 of the example, the 2-[(3-chlorophenyl)amino (methylsulfonyl)methylene]malononitrile and the hydrazine monohydrate obtained in the step 1 are obtained. (0. 94 mL, 19 mmol) gave 5-amino-3-(3-chlorophenyl)amino-4-cyano-1 Η-pyrazole (〇.  6 4 g, 4 7 %). E S IM S m / z : 2 3 2 (Μ - Η)-. (Step 2) According to Step 3 of Example 4, 5-amino-3-(3-chlorophenyl)amino-4-cyano-1H-indole hydrazine obtained in Step 1 (0-23 g, l . Ommol), 2-chlorobenzothiazepine (〇. 14mL, l. Lmmol), potassium carbonate (0_55g, 4. 0mmol) and hydrazine, hydrazine-dimethylformamide (4. 0 mL), compound 120 (0. 081g, 2 2%) ° ESIMS m/z: 3 65 (M-H)'; 'H NMR (270MHz, DMSO-d6) 5 6_97 (d, J = 8. 0Hz, 1 H) 7. 34(t, J = 8. 0Hz, 1 H), 7. 3 8 (t, J = 7. 2 Hz, 1 H), 7. 57(t, J = 7. 2Hz, 1H), 7. 6 1 (d, J = 8 _ 0 Hz, 1 H ), 7. 8 8 (br s, 1H), 7. 94 (d, J = 7. 2Hz, 1H), 8. 13(d, J = 7. 2Hz, 1H), 8. 36(br s, 2H), 9. 38(s, 1 H). Example 1 2 1 -190- 200911240 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(5-methoxy-2-methylphenyl)amino group- 1H-pyrazole (Compound 121) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (3. 7g, 22mmol), 5-methoxy-2-methylaniline (3〇g, 22mm〇1) & ethanol (50mL)' gave 2-[(5-methoxy-2-methylphenyl) Amino (methylsulfonyl) methylene] malononitrile (3. 7g, 65%). ESIMS m/z: 25 8 (M-H)·. (Step 2) According to Step 2 of Example 1, 2-[(5-methoxy-2-methylphenyl)amino (methylsulfonyl)methylene]c-propyl group obtained in Step 1. Dinitrile (1. 5g, 5. 2mmol) with hydrazine monohydrate (〇. 83 mL, 17 mmol) gave 5-amino-4-cyano-3-(5-methoxy-2-methylphenyl)amino-1H-U than hydrazine. Next, according to the step 3 of Example 4, the 5-amino-4-cyano-3-(5-methoxy-2-methylphenyl)amino-1H-pyrazole obtained above was obtained. , 2-chlorobenzothiazole (0_54mL, 41mmol), potassium carbonate (〇. 57g, 4. 1mmol) and hydrazine, hydrazine-dimethylformamide (4. 0 mL) gave Compound 121 (0-010 g, 6%). ESIMS m/z: 3 75 (M-H)";1H NMR (270MHz, DMSO-d6)5 2. 10(s, 3H), 3. 71(s, 3H), 6. 84(s, 1H), 6. 91 (d, J = 7. 7Hz, 1H), 7. 30 (d, J = 7. 7Hz, 1H), 7. 40(t, J = 7. 2Hz, 1H), 7. 49(t, J = 7. 2Hz, 1H), 7. 89 (d, J = 7. 2Hz, 1H), 8. 04(d, J = 7. 2Hz, 1H), 8. 30(br s,2H), 9. 38(br s, 1H). -191 - 200911240 Example 122 5-Amino-1_(benzothiazol-2-yl)-4-cyano-3-(2-methoxyphenyl)amino-1H-pyrazole (Compound 122) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (l. Og, 5. 9mm01), 2-methoxyaniline (〇. 72g, 5. 9 mmol) and ethanol (20 mL) gave 2-[(2-methoxyphenyl)amino (methylsulfonyl)methylene]malononitrile. Next, according to the step 2 of Example 1, the 2-[(2-methoxyphenyl)amino (methylsulfonyl)methylene]malononitrile obtained in the step 1 is combined with the hydrazine. Hydrate (0 · 9 3 m L , 1 9 mm ο 1) to give 5-amino-4 -cyano-3-(2-methoxyphenyl)amino-1 hydrazine-pyrazole (0. 5 4 g, 4 1 %). ESIMS m/z: 22 8 (M-H)·. (Step 2) 5-Amino-4-cyano-3-(2-methoxyphenyl)amino-1H-pyrazole obtained in Step 1 according to Step 3 of Example 4. . 050g, 0. 22 mmol), 2-chlorobenzothiazole (〇. 〇23mL, 0 · 1 7 m m ο 1), potassium carbonate (0. 12g, 0. 87mmol) and N,N-dimethylformamide (l. OmL) gave the compound 1 2 2 (0 · 0 2 4 g, 31%). ESIMS m/z: 361 (M-H); 'H NMR (270 MHz, DMSO-d8) 5 3. 68(s, 3H), 6. 88(d, J = 7. 8Hz, 1H), 6. 98 (1, J = 7. 8Hz, 1H), 7. 10(d, J = 7. 8Hz, 1H), 7. 29(t, J = 7. 8HzlH), 7. 40(t, J = 7. 2Hz, 1 H), 7. 48(t, J = 7. 2Hz, 1 H), 7_90 (d, J = 7. 2Hz, 1H), 8. 01 (dJ = 7. 2Hz, 1H), 8. 30(br s, 2H), 9. 10(br s, 1H). -192- 200911240 Example 123 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-(4-methylpiperazin-1-yl)methylphenyl Amino-1 Η-pyrazole (Compound 1 2 3 ) According to Example 86, from Compound 70 (0. 1g, 0. 28mm〇l) with methane sulfonium chloride (〇_〇23mL, 0. 30 mmol), 1-methylpiperazine (〇_31 mL, 2. 8 mmol) and hydrazine, hydrazine-dimethylformamide (2. 0 mL) gave compound 123 (5 1 m g, 42%). ESIMS m/z: 445 (M + H) VH NMR (270 MHz, DMSO-d6) 5 2. 15(s, 3H), 2. 27-2. 48 (m, 8H), 3. 44(s, 2H), 6. 86(br d, J = 7. SHz, 1H), 7. 23(t, J = 7. 8Hz, 1H), 7. 39(td, J = 7. 3, 1. 3Hz, ' 1H), 7. 52(td, J = 7. 3, 1. 3Hz, 1H), 7. 60 (br d, J = 7. 8Hz, 1H), 7. 65(br s, 1 H), 7·90(br d , J = 7. 3Hz, 1 H), 8·06 (br d, J = 7. 3Hz, 1H), 8. 28(s, 2H), 9. 11(s, lH); Anal.  Calcd for C23H24N8S · 0. 1 H2〇: C, 61. 89; H, 5. 46;N, 25. 10.  Found: C, i 61. 73; H, 5. 12;N, 25. 20. Example 124 2-{3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminophenyl}-N-(2 -Methoxyethyl)-N-methylacetamide (Compound 124) According to Example 1〇8' from Compound 96 (0. 10g, 0_26mmol), hydroxybenzotriazole monohydrate (〇. 〇42g, 〇. 31 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (〇. 〇59g, 0. 31 mmol), N-(2-methoxyethyl)methylamine (〇. 〇55mL, 0. 51mmol), hydrazine, hydrazine-dimethyl acetamide -193- 200911240 (0. 2mL) and tetrahydrofuran (1. 8 mL), compound 1 24 (0. 043 g, 3 7%) ° ESIMS m/z: 462 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 87and3. 04(s, 3H), 3. 2 8 an d 3 .  3 2 ( s , 3H), 3. 40-3 .  56(m, 4H), 3,67and3,69(s, 2H), 6. 75 -6. 85 (m, 1 H), 7. 2 3 a n d 7. 2 3 (t, J = 8. 1Hz, 1H), 7. 39(t, J = 8. 1Hz, 3. H), 7. 44-7. 55(m, 2H), 7. 63brd, J = 8. 1Hz, 1H), 7. 90 (br d, J: 8. 1Hz, 1 H), 8. 06(br d, J = 8.  1 Hz, 1H), 8. 28(s, 2H), 9.  13(s, 1H). Example 1 2 5 5-Amino-3-(3-aminomethylphenyl)amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazole (Compound 125) (Step 1) Compound 70 (0. 3 0g, 0. 83mmol) is dissolved in hydrazine, hydrazine-dimethylformamide (6. 0mL), added to the hospital to expand chlorine (〇. 〇80mL, l. Ommol), stirred at room temperature for 4 hours. After the reaction was completed, tetrahydrofuran (20 mL), a saturated aqueous solution of sodium hydrogencarbonate (10 mL), and brine (1 mL) were added, and the organic layer was water (1OmL) and brine (1OmL) The mixed solution was washed with brine (20 mL), dried over anhydrous sodium sulfate This chloromethyl group was dissolved in hydrazine, hydrazine-dimethylformamide (6. OmL), added to dissolve in water (0. 20mL) of sodium azide (〇. 〇70g, l. Lmmol), stirring at room temperature 1. 5h. After the reaction was completed, tetrahydrofuran (20 mL), water (10 mL) and saturated brine (10 mL) were added to separate the mixture. The organic layer was washed twice with saturated brine (2 〇m L) and dried over anhydrous sodium sulfate. And concentrated under reduced pressure. The obtained residue of -194-200911240 was purified by ruthenium dioxide colloidal column chromatography (chloroform/methanol = 19/1) to give 5-amino-3-(3-azidomethylphenyl)amino group. -1-(benzothiazol-2-yl)-4-cyano-1H-pyrazole (0. 27g, 83%). ESIMS m/z: 3 8 8 (M + H)VH N M R (2 7 0 Μ Η z, D M S Ο - d 6) δ 4. 45(s, 2H), 6. 93(br d, J = 7. 6Hz, 1H), 7. 27-7. 43 (m, 2H), 7. 52(td, J = 7. 5, 1. 3Hz, 1H), 7. 65-7. 73 (m, 2H), 7. 90(br d, J = 7. 5Hz, 1H), 8. 08(br d, J = 7. 5Hz, 1H), 8. 31(s, 2H), 9. 25(s, 1H). (Step 2) 5-Amino-3-(3-azidomethylphenyl)amino-1-(benzothiazol-2-yl)-4-cyano-1H- obtained in Step 1. Pyrazole (0. 27g, 0. 69mmol) dissolved in tetrahydrofuran (2. 5mL) and methanol (2. 5 mL), palladium-carbon (50 m g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, palladium-carbon was removed by filtration and concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (8 mL) and added. 0 mol / L hydrochloric acid (80 mL) was separated, and the aqueous layer was further added to 2. 0mol/L sodium hydroxide solution (0. 16L) and tetrahydrofuran (0. 20L) Dispensing. The organic layer was mixed with water (50 mL) and saturated brine (50 mL) with saturated brine (0.  1 0 L) Washed, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was triturated with tetrahydrofuran to give Compound 1 25 (0. 055g, 15%). ESIMS m/z: 362 (M + H) VH NMR (270 MHz, DMSO-d6) S 3. 73(s, 2H), 6. 93(br d, J = 7. 8Hz, 1H), 7. 23(t, J = 7. 8Hz, 1H), 7. 3 8(td, J = 8.  1 , 1 . 0Hz, 1 H), 7. 5 1 (td, J = 5 .  1 ,1 . 0Hz, 1 H), -195- 200911240 7. 55 (dd, J = 7_8, 1. 4Ηζ, 1H), 7. 64(br s, 1H), 7. 89 (dd J = 8. 1,1. 0Hz, 1H), 8. 09 (dd, J-8. 1, l. 〇Hz, 1H), 9. 08(s, 1H). Example 126 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3,5-dimethoxyphenyl)amino-1 hydrazine-pyrazole (Compound 1 2 6) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (l. Og, 5. 9 mmol), 3,5-dimethoxyaniline (〇9()g, 5 9mm〇1) & ethanol (20mL)' gives 2_[(3,5-dimethoxyphenyl)amine (A Sulfosyl)methylene]malononitrile. Next, according to the step 2 of Example 1, the 2-[(3,5-dimethoxyphenyl)amino (methylsulfonyl)methylene]malononitrile obtained in the above was combined with Amine monohydrate (0. 9 3 m L , 1 9 m mo 1), 5-amino-4-cyano-3-(3,5-monomethoxyphenyl)aminol-1^_卩 嗤 (得到. 93 Lu, 6 1%). ESIMS m/z: 2 5 8 (M-H)-. (Step 2) 5-Amino-4-cyano-3-(3,5-dimethoxyphenyl)amino-11-pyrazole obtained in Step 2 according to Step 3 of Example 4. 0. 26 £, 1_〇〇 mmol), 2-chlorobenzothiazole (0. 14mL, l. Lmmol), potassium carbonate (0_55g, 4. 0mmol) and N,N-dimethylformamide (4. 0 mL), compound 126 (0. 26g, 67%) 〇 -196- 200911240 ESIMS m/z: 391 (M-Hv i "; H NMR (270MHz, DMSO-d6) 6 3. 79(s, 6H), 6. 10(s, 1H) 7 n ^ 7〇2(s, 2H), 7. 38(t, J = 7. 3Hz, 1H), 7. 49(t, J = 7. 3Hz, 1H) 7 ^ 7-89 (d, J = 7. 3Hz, 1H), 8. 1 l(d, J = 7. 3Hz, 1H), 8. 30 (br s, 9. 69(s, 1H) ° Example 1 2 7 5-Amino-1-(benzothiazol-2-yl)& % gas-based _3_(3,4·dimethoxyphenyl)amino group- 1 Η-pyrazole (compound 1 2 7 ) (step 1) 'from [bis(methylthio)methylene]propane according to the step i of Example 1 nitrile (l. Og, 5. 9mmol), methoxyphenyl)amine (methylsulfonate - ^^*K (0. 90g, 5. 9ininol) & Ethanol (20 mL) gave 2-[(3,4-yl)methylene]malononitrile. Next, according to the step 2 of Example 1, the 2-[(3,4 -二申智# oxyphenyl)amino group (methylsulfonyl)methylene]-propanoid obtained in the above Deprotection with hydrazine monohydrate (0 _ 9 4 m L, 丨 9 mm 〇丨) gives 5 _ amino-4-cyano-3_(3,5-dimethoxyphenyl)amino-1H _pyrazole (i 3g, 8 7%) ° ESIMS m/z: 25 8 (MH)·. (Step 2) According to Step 3 of Example 4, 5-Amino-4-cyano-3-(3,5-dimethoxyphenyl)amino-1H•pyrazole obtained in Step 2 (〇26g, l. Ommol), 2-chlorobenzothiazole (0. L4mL, 丨. 111101〇1), potassium carbonate (0_55g, 4. 0 0 mmol) and N,N-dimethylformamide (4 〇 mL) were compounded -197- 200911240 Compound 1 2 7 (0 _ 1 6 g, 42 %). ESIMS m/z: 391 (Μ-Η)·;'Η NMR (270MHz, CDC13)6 3. 89(s, 3H), 4. 01(8, 3H), 6. 18(s, 1H), 6. 89(br s, 2H), 7. 3 2 (t, J = 7. 2Hz, 1 H ), 7. 4 8 (t, J = 7. 2 Hz, 1 H), 7. 5 1 (d, J = 7. 8 Hz , 1 H), 7 · 8 0 ( d, J = 7 _ 2 Hz, 1 H ), 7. 84 (d, J = 7. 8 Hz, 1 H), 8. 01(d, J = 7. 3Hz, 1H), 8. 03(br s, 1H). Example 1 2 8 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(4-fluorophenyl)amino-1H-pyrazole (Compound 1 2 8 ) ( Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (1. Og, 5. 9mmol), 4-fluoroaniline (0. 66 g, 5-9 mmol) and ethanol (20 mL) gave 2-[(4-fluorophenyl)amino (methylsulfonyl)methylene]malononitrile. Next, according to the step 2 of Example 1, 2-[(4-fluorophenyl)amino (methylsulfonyl)methylene]malononitrile and hydrazine monohydrate obtained above ( Hey. 94 mL, 19 mmol) gave 5-amino-4-cyano-3-(4-fluorophenyl)amino-1 hydrazine-pyrazole (0. 9 1 g, 7 1 %). ESIMS m/z: 26 1 (M-Η)-. (Step 2) According to Step 3 of Example 4, the 5-amino-4-cyano-3-(4-carbene)amino-1H-D obtained in Step 1 is 哩(0. 22g, l. OOmmol), 2_chlorobenzothiazepine (0. 13mL, l. Ommol), potassium carbonate (〇. 55g, 4. 0mmol) -198- 200911240 and hydrazine, hydrazine-dimethylformamide (4. 0mL), compound 128 (0. 13g, 3 8%) ° ESIMS m/z: 349(M-H); 1H NMR (270MHz, DMSD-d6)6 7. 3 0-7. 5 0 (m, 3H), 7. 60-7. 80 (m, 3H), 7. 98 (d, J = 7. 4Hz, 1 H), 8. 06(d, J = 7. 4Hz, 1H), 8. 36(br s, 2H), 9. 20 (br s, 1H). Example 129 5-Amino-4-cyano-1-(4,6-difluorobenzothiazol-2-yl)-3-[3-(piperidin-1-yl)phenyl]amino- 1H-pyrazole (Compound 129) 5-Amino-4-cyano-3-(3-methoxyphenyl)amine obtained in Step 2 of Example 91 according to Step 2 of Example 8 keto-1H-pyrazole (0. 05g, 0. 18 mmol), 2-bromo-4,6-difluorobenzothiazole (〇. 〇53g, 〇_21mmol), potassium carbonate (〇. 〇98g, 0_71mmol) and N,N-dimethylformamide (3. 0 m L) gives compound 1 2 9 (0 _ 0 6 g, 7 5 %). ESIMS m/z: 45 2 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 1 . 5 8- 1. 65 (m, 6H), 3. 1B(t, J = 4. 9Hz, 4H), 6. 53(td, J = 4. 4, 2. 1Hz, 1H), 7. 08(s, 1H), 7. 10(s, 1H), 7. 35(s, 1H), 7. 49(m, 1H), 7. 92(m, 1H), 8. 18(s, 2H), 8_96(s, 1H). Example 1 3 0 5 -Amino-1-(benzothiazol-2-yl)-4-yl-3-(3-isopropylphenyl)amino-1H-pyrazole (Compound 130) (Step 1) According to the step 1' of Example 92 from 3-isopropylaniline (〇_50g, 3. 7 -199- 200911240 mmol) with [bis(methylthio)methylene]malononitrile (〇. 69g, 4. 1 mmol), hydrazine monohydrate (0. 36mL, 7. 4 mmol) and ethanol (10 mL) give 5-amino-4-cyano-3-(3-isopropylphenyl)amino-1H-D than hydrazine. 57g, 63%). ESIMS ra/z: 242(M + H)+; 'H NMR (270MHz, DMS〇-d6)5 1. 17(d, J = 6. 8Hz, 6H), 2. 68-2. 86(m, 1 H), 6. 2 5 (s, 2 H), 6. 64 (br d, J = 7. 7Hz, 1H), 7. 07(t, J = 7. 7Hz, 1H), 7. 28(br d, J = 7. 7Hz, 1H), 7. 33(br s, 1H), 8_22(s, 1H), 1 1. 2 (s, 1H). (Step 2) 5-Amino-4-cyano-3-(3-isopropylphenyl)amino-1H-pyrazole obtained in Step 1 according to Step 2 of Example 92 (0. 26g, l. Lmmol) with 2-chlorobenzothiazepine (〇_15mL, l_2mmol), potassium carbonate (0. 75g, 5. 4mmol) and N,N-dimethylformamide (3. 9mL), get compound 130 (0. 0 4 6 g, 11%) ° ESIMS m/z: 3 75(M + H)VH N M R (2 7 0 Μ Η z, D M S Ο - d 6) δ 1. 25(d, J = 6. 8Hz, 6H), 2. 79-2. 96(m, 1H), 6. 82(br d, J = 7. 9Hz, 1H), 7. 20(t, J = 7. 9Hz, 1H), 7. 38(td, J = 7. 8, 0. 8Hz, 1H), 7. 44-7. 5 6(m, 2H), 7. 66(t, J = 1. 7Hz, 1 H ), 7 · 9 0 (b r d, J = 7. 8Hz, 1H), 8. 09 (dd, J = 7. 8, 0. 8Hz, 1H), 8. 29(s, 2H), 9. 05(s, lH); Anal.  Calcd for C2〇Hi8N6S:C, 64. 15; H, 4. 85;N, 22. 44.  Found: C, 64. 08; H, 4. 55;N, 22. 46. Example 1 3 1 5-Amino-(1-benzothiazol-2-yl)-4-cyano-3-[3-(methylthiomethyl)phenyl]-200- 200911240 Amino-1 Η-pyrazole (compound 1 3 1) According to Example 87, from compound 70 (0. 3 0 g,0. 83mm〇l) with methanesulfonyl chloride (〇. 〇83mL, l. Lmmol), sodium thiomethoxide (〇. 58g, 8. 3mmol) and hydrazine, hydrazine-dimethylformamide (6. 0mL), compound 131 (0. 2 8g, 8 7%). ESIMS m/z: 3 93 (Μ + Η) + ; *Η NMR (270MHz, DMSO-d6)5 2. 02(s, 3H), 3. 68(s, 2H), 6. 88(br d, J = 7. 8Hz, 1H), 7. 25(t, J = 7. 8Hz, 1 H), 7. 38(br t, J = 7. 9Hz, 1H), 7. 51(td, J = 7. 9, 1. 1Hz, 1H), 7. 59(br d, J = 7. 8Hz, 1H), 7. 65(s, 1H), 7. 90 (br d, J7. 9Hz, 1H), 8. 09(br d, J = 7. 9Hz, 1H), 8. 30(s, 2H), 9_ 1 5(s, 1H). Example 1 3 2 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(1,1-dioxothiomorpholin-4-ylmethyl) Phenyl]amino-1H-pyrazole (Compound 132) According to Example 87, from Compound 70 (0. 10g, 〇. 28mmol) with methanesulfonyl chloride (〇. 〇23mL, 0. 30 mmol), thiomorpholine-1,1-dioxide (0. 37g, 2. 8mmol) and hydrazine, hydrazine-dimethylformamide (2. 0mL), to get the compound 1 3 2 (0. 1 1 g, 8 5 %). ESIMS m/z: 480 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 5 2. 8 7-2. 99(m, 4H), 3. 12-3. 22(m, 4H), 3. 68(s, 2H), 6. 89(br d, J = 7. 8Hz, 1H), 7. 26(t, J = 7. 8Hz, 1H), 7. 39(td, J = 7. 3, 1 .  1 Hz, 1H), 7. 52(td, J = 7. 3, 1. 1Hz, 1H), 7. 58 (dd, J = 7. 8, 1 , 5Hz, 1H), 7. 74(br s, 1H), 7. 90(br d, J = 7. 3Hz, 1H), -201 - 200911240 8. 06(br d, J = 7. 3Hz, 1H), 8 · 3 0 (s, 2 H), 9. 1 2 (s, 1H). Example 1 3 3 2-{3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminophenyl}-N- (2-Dimethylaminoethyl)-N-methylacetamide (Compound 133) According to Example 108, Compound 96 (0. 10g, 0_26mmol), 1-benzotriazine monohydrate (0. 042g, 0. 31 mmol), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (〇. 〇59g, 0. 31mmol), hydrazine, hydrazine, Ν'-trimethylethylenediamine (0. 043mL, 0. 33 mmol), hydrazine, hydrazine-dimethylacetamide (0. 2mL) and tetrahydrofuran (1. 8 mL) to give compound 1 3 3 (0. 067g, 5 5%) ° ESIMS m/z: 47 5 (Μ + Η) + ; *Η NMR (270MHz, DMSO-d6)5 2. 1 3and2. 1 5(s, 6H), 2. 33(t, J = 6. 9Hz, 2H), 2. 8 6 an d 3. 0 1 ( s , 3H), 3 .  3 9 and3. 4 0 (t, J = 6. 9Hz, 2H), 3. 6 5 and 3. 6 8 (s , 2H), 6 · 8 1 (b r d, J = 7 _ 9 H z, 1 H), 7 _ 2 3 (t, J = 7 _ 9 H z, 1 H), 7. 3 9 (b r t, J-7. 4Hz, 1H), 7. 45-7. 5 7(m, 2H), 7. 57-7. 67(m, 1H), 7. 90(br d, J = 7. 4Hz, 1H), 8. 07(br d, J = 7. 4Hz, 1 H), 8. 28(s, 2H), 9. 1 3and9.  1 4 (s, 1 H). Example 134 l-{3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminobenzyl}piperidine-4- Methyl carboxylate (compound 134) according to Example 87' from compound 70 (0. 10g, 0_28mmol) with methanesulfonyl chloride (〇. 023mL, 0_30mmo1), 4_ piperidinecarboxylic acid methyl ester (0. 37mL, -202- 200911240 2. 8mmol) and N,N-dimethylformamide (2. 0m L), get compound 134 (0. 067 g, 50% 卜 ESIMS m/z: 48 8 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 1. 5 5 - 1. 88(m, 4H), 1. 9 5 - 2. 0 8 (m, 2H), 2. 27-2. 40 (m, 1H), 2. 82(br d, J=11. 0Hz, . 2H), 3. 45(s, 2H), 3. 59(s, 3H), 6. 84(br d, J = 7. 8Hz, 1H), 7. 22(t, J = 7. 8Hz, 1H), 7. 39(td, J = 8. 0, 1 .  1 Hz, 1H), 7. 47-7. 60 (m, 2H), 7. 70(br s, 1H), 7. 90 (br d, J = 8. 0Hz, 1H), 8. 06(br d, J = 8. 0Hz, 1H), 8. 29(s, 2H), 9. 1 1 (s, 1 H). Example 1 3 5 N-{ 3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminobenzyl}methanesulfonate Amine (Compound 135) Compound 7 〇 (〇. 〇20g, 0. 05 5mmol) dissolved in hydrazine, hydrazine-dimethylacetamide (l. OmL), force into the hospital to expand chlorine (0. 012mL, 0. 15 mmol) and potassium carbonate (0 · 0 5 4 g, 0 · 3 9 m m ο 1), stirred at room temperature for 4 hours. After the reaction was completed, tetrahydrofuran (2 mL), water (10 mL) and saturated brine (10 mL) were added, and the organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. And concentrated under reduced pressure. The obtained residue was triturated with ethanol to give Compound 135 (0. 016g, 65%). ESIMS m/z: 440 (M + H) + ; 1H NMR (2 70 MHz, DMSO-d6) S 2. 90(s, 3H), 4. 15(d, J = 6. 2Hz, 2H), 6. 92(br d, J = 7. 3Hz, 1 H), 7. 28(t, J = 7. 3Hz, 1 H), 7 · 3 9 (b r t, J = 8. 0 H z, 1 H), 7. 52(br t, J = 8. 0Hz, 1H), 7. 56(t, J = 6. 2Hz, 1H), 7. 63- -203- 200911240 7. 70 (m, 2H), 7. 90 (br d, J = 8. 0Hz, 1H), 8. 〇5(br d, J-8. 0Hz, 1 H), 8. 28(s, 2H), 9. 2 1 (s, 1 H). Example 1 3 6 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(pyridin-3-yl)amino-1H-pyrazole (Compound 1 3 6) (Step 1) According to step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (0. 90g, 5. 3 mmol), 3-aminopyridine (0-50 g, 5. 3 mmol) and ethanol (15 mL) give 3,3-bis(methylthio)-2-(pyridin-3-ylamino)acrylonitrile (0. 5 0g, 43%). ESIMS m/z: 217 (M + H) +; 1H NMR (270MHz, DMSO-d6) 3 2, 57 (s, 3H), 7. 48 (ddd, J = 8. 2,4. 8, 0. 7Hz, 1H), 7. 77 (ddd, J = 8. twenty one. 4, 0. 7Hz, 1H), 8. 45 (dd, J = 4. 8, 1. 4, 0. 7Hz, 1H), 8. 54(m, 1H), l〇. 72(s, 1H). (Step 2) According to Step 2 of Example 1, 3,3-bis(methylthio)-2-(pyridin-3-ylamino)acrylonitrile obtained in Step 1 (0. 50g, 2. 3mmol) with hydrazine monohydrate (〇_13mL, 2. 8 mmol) gave 5-amino-4-cyano-3-(n-pyridin-3-yl)amino-1 hydrazine-pyrazole (0 · 4 1 g, 8 9 %). ESIMS m/z: 201 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 6. 32(s, 2H), 7. 19(m, 1 H), 7. 92(m, 1H), 7_98(m, 1H), 8_63(s,1H), 8. 69 (d, J = 2_6 Hz, 1H). -204- 200911240 (Step 3) The 5-amino-4-cyano-3-(pyridin-3-yl)amino-1H-pyrazole obtained in Step 2 (0. 10g, 0. 50mmol) with potassium carbonate (0. 35g, 2. 5mmol) suspended in N,N-dimethylformamide (5. 0 mL), 2-chlorobenzothiazole (0 · 0 7 8 m L, 0. 6 0 m m ο 1). After stirring at 80 ° C for 3 hours, water was added to the reaction solution to obtain a crude crystal. The obtained crude crystals are recrystallized from a mixed solvent of hydrazine, hydrazine-dimethylformamide-water (10:1), and the obtained crystals are further slurried with ethanol to obtain a compound 1 3 6 ( 0. 077g, 46%). ESIMS m/z: 3 34 (M + H) VH NMR (270 MHz, DMSO-d6) 5 7. 32-7. 42(m, 2H), 7. 52 (dt, J=10. 6, 3. 9Hz, 1H), 7. 91(d, J = 8.  1Hz, 1H), 8. 07-8. 13(m, 2H), 8. 16 (dd, J = 4. 6, 1. 5Hz, 1H), 8. 34(s, 2H), 8_90(s, 1H), 9. 38(s, 1H). Example 1 3 7 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(methanesulfonylmethyl)phenyl]amino-1H-pyrazole (Compound 137) Compound 131 (50 mg, 0. 13mmol) dissolved in tetrahydrofuran (l. OmL) and dichloromethane (2. 0mL), add 3-chloroperbenzoic acid (〇. 12 g, 0 · 4 5 m m ο 1 ), stirred at room temperature for 24 hours. After the reaction was completed, tetrahydrofuran (20 mL) was added. 0 mol / L aqueous sodium hydroxide solution (15 mL) and saturated salt water (5. The organic layer was washed with a mixed solution of water (10 mL) and brine (2 mL) and brine (20 mL), and dried over anhydrous sodium sulfate. The obtained residue was subjected to hydrazine-205-200911240 in tetrahydrofuran to give Compound 1 3 7 (0. 0 3 5 g, 6 5 %). ESIMS m/z: 42 5 (M + H)VH NMR (2 70 MHz, DMS 0-d6) 5 2. 50(s, 3H), 4. 45(s, 2H), 7. 00 (br d, J = 7. 6Hz, 1H), 7. 33(t, J = 7, 6Hz, 1 H), 7. 38(br t, J = 8. 3Hz, 1H), 7. 51(br t, J = 8. 3Hz, 3H), 7. 65(br s, 1H), 7. 77(br d, J = 7. 6Hz, 1H), 7. 90 (br d, J = 8. 3Hz, 1H), 8. 07(br dJ = 8. 3Hz, 1H), 8. 31(s, 2H), 9. 28(s, 1H). Example 1 3 8 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(piperazin-1-yl)-methylphenyl]amino-1H -pyrazole (compound 138) according to Example 87, from compound 70 (0. 10g, 0_28mmol) and the expansion of chlorine in the hospital (〇. 〇23mL, 0. 30mmol), chlorpyrifos (〇. 71g, 8. 3mmol) and hydrazine, hydrazine-dimethylformamide (2. 0 mL), compound 1 3 8 (0. 03 5g, 2 9%) ° ESIMS m/z: 431(M + H) + ;1H NMR (2 70MHz, DMSO-d6)5 2. 2 7-2. 3 8 (m, 4H), 2. 71(br t, J = 4. 9Hz, 4H), 3. 41(s, 2H), 6. 86(br d, J = 7. 6Hz, 1H), 7. 23(t, J = 7. 6Hz, 1H), 7. 39(td, J = 8. 1,1. 1Hz, 1H), 7. 52(td, J = 8. 1,1. 1Hz, 1H), 7. 60 (br d, J = 7. 6Hz, 1H), 7. 64(br s, 1H), 7. 90 (br d, J = 8. 1Hz, 1H), 8. 07(br d, J = 8. 1Hz, 1H), 8. 28(s, 2H), 9. 12(s, 1H). Example 1 3 9 N - { 3 - [ 5 -Amino-1 -(benzothiazol-2-yl)-4-cyano-1 H-pyrazol-3-yl]-amine-206- 200911240 Benzyl}-N-methylmethanesulfonamide (Compound 139) Compound 70 (0-50 g, 1. 4 mmol) was dissolved in N,N-dimethylformamide (10 mL) and added to methanesulfonyl chloride (0. 15mL, 1. 9mmol), stir at room temperature 4. 5 hours. Thereafter, a 40% aqueous solution of methylamine was added (2. 4 mL, 2 8 m m ο 1 ), stirred at room temperature for 2 hours. After completion of the reaction, the mixture was poured into tetrahydrofuran (50 mL), water (20 mL), and brine (2 mL), and the organic layer was washed twice with saturated brine (4 〇m L). It was dried and concentrated under reduced pressure. The obtained residue was purified by ruthenium dioxide colloidal column chromatography (chloroform / methanol = 19 / 1 ) to give 5-amino-1 -(benzothiazol-2-yl)-4-cyano-3 -{3-[(Methylamino)methyl]phenyl}amino-1H-pyrazole (0. 60 g, HPLC area: 81%). a portion of 5-amino-1-(benzothiazol-2-yl)-4-cyano-3-{3-[(methylamino)methyl]phenyl}amino-1H-pyrazole (0. 15g) dissolved in hydrazine, hydrazine - dimethyl acetamide (3. 0mL), adding methane sulfonium chloride (0. 062mL, 0. 80mmol) and potassium carbonate (0. 28 g, 2_0 mmol), stirred at room temperature for 5 hours. After completion of the reaction, tetrahydrofuran (2 mL), water (10 mL), and brine (10 mL) were added, and the organic layer was washed twice with saturated brine (2 mL) and dried over anhydrous sodium sulfate. Concentrated by pressure. The obtained residue was purified by ruthenium dioxide colloidal column chromatography (chloroform / methanol = 19 / 1) to give compound 1 3 9 (0. 0 5 7 g, 3 6 % , 2 s t e p s). ESIMS m/z: 454(M + H)VH N MR (2 7 Ο Μ H z, D M S 0 - d6 ) δ 2. 73(s, 3H), 2. 97(s, 3H)4. 24(s, 2H), 6. 90(br d, J = 7. 7Hz, 1 H), 7. 31(t, J = 7. 7Hz, 1 H), 7 · 3 9 (t d, J = 7 · 8 r 1. 4 H z, 1 H), 7. 52 (tdJ = 7. 8, 1 , 4 Hz, 1 H), 7 · 6 8 ( b r d , J = 7. 7 H z,1H), 7. 72(br s, 1 H), 7. 90(br d, J = 7. 8Hz, 1H), 8. 03(br d, J = 7. 8Hz, 1H), -207- 200911240 8. 29(s, 2H), 9. 25 (s, 1H). Example 1 4 0 2-{3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminophenyl}-N, N-bis(2-methoxyethyl)acetamide (Compound 14A) According to Example 108, from compound 96 (0. 05 g, 0. 13 mmol), 1-benzotriazine monohydrate (0. 021 §, 0. 16111111〇1), 1''1-ethyl-]^'-(3-dimethylaminopropyl)carbodiimide (0. 029g, 0. 16 mmol), bis(2-methoxyethyl)amine (0. 038!!1[,0. 261^11〇1) and tetrahydrofuran (1. 01111 〇 gave compound 1 4 0 (0 _ 0 2 7 g , 42 %). ESIMS m/z: 5 06 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 3. 21(s, 3H), 3. 28(s, 3 H) 3 .  3 8 - 3. 5 8 (m, 8H), 3. 71(s, 2H), 6. 79(br d, J = 8. 0Hz, 1H), 7. 23(t, J = 8. 0Hz, 1H), 7. 39(br t, J = 7. 6Hz, 1 H), 7. 46-7. 5 6(m, 2H), 7. 62(br d, J = 8. 0Hz, 1H), 7. 90(br d, J = 7. 6Hz, 1H), 8. 05(br d, J = 7. 6Hz, 1H), 8. 28(s, 2H), 9_ 1 3(s, 1 H). Example 1 4 1 5-Amino-4-cyano-1-(5,6-difluorobenzothiazol-2-yl)-3-(3-methoxyphenyl)amino-1 Η - Pyrazole (Compound 141) 5-Amino-4-cyano-3-(3-methoxyphenyl)amino-1 oxime obtained according to the procedure of Example 8 8 '. -pyrazole (0. 16g, 0. 72 mmol), 2-bromo-5,6-difluorobenzothiazole (0. 20g, 0. 79mmol), potassium carbonate (0. 40g, 2. 86 mmol) and hydrazine, hydrazine-dimethylformamide (10 mL), obtained -208- 2009-11240 141 (0. 088g, 31%). 'H NMR (270MHz, DMSO-d6) 5 3. 79(s, 3H), 6. 52 (dt, J = 6. 8, 2. 4Hz, 1H), 7. 14-7. 23(m, 2H), 7. 44(m, 1H), 7. 98 (dd, J=11. 2,7. 3Hz, 1H), 8. 21-8. 28 (m, 3H), 9_15 (s, 1H). Example 142 5-Amino- l-[5,6-bis(difluoromethoxy)benzothiazepine-yl]-4-cyano-3-(3-methoxyphenyl)amino- 1H-pyrazole (Compound 142) 5-Amino-4-cyano-3-(3-methoxyphenyl)amine obtained according to Step 2 of Example 4 from Step 2 of Example 91 keto-1H-pyrazole (0. 15g, 0. 67111111〇1), 2-bromo-5,6-bis(difluoromethoxy)benzothiazole (〇. 27§, 0_79mmol), potassium carbonate (〇. 37g, 2. 7mmol) and hydrazine, hydrazine-dimethylformamide (5. 0 mL), compound 1 42 (0. 098g, 29%). ESIMS m / z: 49 5 (M + H) + ; *H NMR (270MHz, DMSO-d6) 6 3. 79(s, 3H), 6. 52(m, 1H), 6. 93 -7. 5 5 (m, 5H), 7. 87(s, 1H), 8_18(s, 1H), 8_30(s, 2H), 9. 15 (s, 1H). Example 1 4 3 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[4-fluoro-3-(2-methoxyethoxy)phenyl]amine Base-1H-pyrazole (Compound M3) (Step 1) 4-Fluoro-3-hydroxybenzoic acid (4. 9g, 31mmol) was dissolved in tetrahydrofuran (0. 10 L), next, triphenylphosphine (16 g, 6 3 mmol), diethyl azodicarboxylate (llg, 63 mmol) and 2-methoxyethanol (5. 4 m L , -209- 200911240 69mm〇l) ' was stirred at room temperature for 5 hours. After the reaction was completed, ethyl acetate was added (0. 10L), water (0. 10L) Dispensing 'The organic layer was washed with saturated brine (5 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-fluoro-3-(2-methoxyethoxy). Benzoic acid-2-methoxyethyl ester (8〇g, 93% ESIMS m/z: 271(MH)-. (Step 2) 4-fluoro-3 - (2) obtained in step 1. -methoxyethoxy)benzoic acid-2-methoxyethyl vinegar (8. 0g, 29mmol) was dissolved in ethanol (50 mL), then added to make sodium hydroxide (1.  8 g) A solution of water (30 m L) was dissolved and refluxed for 1 hour. After the reaction, ethyl acetate (〇 · 10 L ), 1 · 〇 mol / L hydrochloric acid (0. 10L), the organic layer was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate (6_0g, 96%). ESIMS m/z: 2 1 3 (M-H)_. (Step 3) 4-Fluoro-3-(2-methoxyethoxy)benzoic acid obtained in Step 2 (5. 0g, 23mmol) dissolved in toluene (0. 10L), next, add triethylamine (3. 3mL, 23mmol), diphenylphosphonium azide (5. 0 mL, 23 mmol), stirred at 100 ° C for 1 hour. Further, benzyl alcohol was added (2. 4 mL, 23 mmol), stirred at 100 ° C for 1 hour. After the reaction was completed, ethyl acetate (50 mL) and water (0. 10L), the organic layer was washed with saturated brine (30 mL) -210 - 200911240, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-fluoro_3_(2-methoxyethoxy)phenyl Benzyl carbamate (4. 8g, 64%). ESIMS m/z: 318 (M-H)-. (Step 4) According to Step 2 of Example 56, the benzyl 4-fluoro-3-(2-methoxyethoxy)phenylaminecarboxylate obtained in Step 3 (2. Lg, 6. 6mm〇l), ethanol (20mL), 10% pin-carbon (1. 6g), and hydrogen, to give 4-fluoro-3-(2-methoxyethoxy)aniline (1. 3g, 99%). ESIMS m/z: 184 (M-H)-. (Step 5) According to Step 1 of Example 1, 4-fluoro-3-(2-methoxyethoxy)aniline (l_lg, 5-9 mmol) obtained in Step 4, [bis(methylthio)) Methyl]malononitrile (l. Og, 5. 9 mmol) and ethanol (20 mL) gave 2-{[fluoro-3-(2-methoxyethoxy)phenyl]amino (methyl)-methylenesulfonyldicarbonitrile. Next, according to the step 2 of Example 1, the 2-{[4-fluoro-3-(2-methoxyethoxy)phenyl]amino(methylsulfonyl)methylene group obtained therefrom} Malononitrile and hydrazine monohydrate (0. 9 4 m L, 1 9 mm ο 1), 5-amino-4-cyano-3-[4-fluoro-3-(2-methoxyethoxy)phenyl]amino-1H- Shame (l. Lg, 6 4%) ° E S IM S m / z : 2 9 0 (Μ - Η)-. (Step 6) -211 - 200911240 According to the step 3 of Example 4, the 5-amino-4-cyano-3-[4-fluoro-3-(2-methoxyethoxy) obtained in the step 5 Phenyl]amino-1H-pyridinium (〇. 29g, 1. 0mmol) 2-chlorobenzothiazole (0. 13mL, l. Ommol), potassium carbonate (0. 55g, 4. 0mmol) and hydrazine, hydrazine-dimethylformamide (6. 0 mL) gave the compound 1 4 3 (0 · 1 2 g, 29.9%). ESIMS m/z: 423. (M-H) VH NMR (270MHz, DMSO-d6) 5 3. 35(s, 3H), 3. 75(m, 2H), 4. 20(m, 2H), 7. 09-7. 26(m, 2H), 7. 36(t, J = 7. 4Nz, 1H), 7. 54(t, J = 7. 4Hz, 1H), 7. 63(m, 1H), 7. 91 (d, J = 7. 4Hz, 1H), 8. 09(d, J = 7. 4Hz, 1H), 8. 39(br s, 2H), 9.  1 4 (br s, 1 H). Example 1 4 4 5-Amino-4-cyano-3-(3-methoxyphenyl)amino-l-[4-trifluoromethyl)benzothiazole-2-yl]-1 Η -pyrazole (Compound 14 4) 5-Amino-4-cyano-3-(3-methoxyphenyl) obtained in Step 2 of Example 91 according to Step 3 of Example 4. Amino-1Η-pyrazole (0. 1 4g, 0. 59 mmol), 2-bromo-4-trifluoromethylbenzothiazole (0. 20g, 0. 71 mmol), potassium carbonate (0. 33g, 2. 4 mmol) and hydrazine, hydrazine-dimethylformamide (5 mL) gave compound 1 44 (0. 22g, 87%). ESIMS m/z: 431 (M + H) + ; *H NMR (270 MHz, DMSO-d6) 8 3. 79(s, 3H), 6. 53 (dt, J = 7. 4, 2. 1Hz, 1H), 7. 16-7. 25(m, 3H), 7. 47(d, J = 2. 1 Hz, 1H), 7. 54(t, J = 7. 8Hz, 1H), 7. 86 (d, J: 7. 8Hz, 1H), 8. 28(s, 1H), 8. 43 (d, J = 7. 8Hz, 1H), 9. 19(s, 1 H). -212- 200911240 Example 145 5-Amino-1-(benzothiazol-2-yl)-4.cyano-3-(5-methylpyridin-3-yl)amino-1H-pyrazole ( Compound 145) (Step 1) According to Step 1 of Example 92, from [bis(methylthio)methylene]malononitrile (1. 4g, 8. 4 mmol), 3-amino-5-methylpyridine (1. 〇g, 9. 3mmol), hydrazine monohydrate (〇. 49 mL, 10 mmol) and ethanol (20 mL) gave 5-amino-4-amino-3-(5-methylindole ratio π-1,4-yl)amino-1H-H than hydrazine (〇. 37g, 2 1%). (Step 2) 5-Amino-4-cyano-3-(5-methylpyridin-3-yl)amino-1H-pyrazole obtained in Step 1 according to Step 3 of Example 4. 0. 20g, 0. 93 mmol), 2-chlorobenzothiazepine (〇_i5mL, l. Lmmol), cesium carbonate (〇. 52g, 3. 7 mmol) and N,N-dimethylformamide (5 m L) gave Compound 1 4 5 (0 · 1 4 g, 4 3%). ESIMS m/z: 3 4 8(M + H)VH N M R (2 7 0 Μ H z, D M S O · d 6) δ 2. 32(s, 3H), 7. 49(m, 1H), 7. 52(td, J = 7. 7, 1. 0Hz, 1H), 7. 89-7. 93 (m, 2H), 8. 01(s, 1H), 8. 10(d, J = 7. 7Hz, 1H), 8_34(s, 2H), 8. 72(d, J = 2. 5Hz, 1H), 9. 32(s, 1H). Example 146 5-Amino-4-amino-l-[5,6-dimethoxybenzoxanthene D-yl]-3-(3-methoxy-213- 2009-11240-phenyl)amine Base-1 Η-pyrazole (Compound 146) According to Step 3 of Example 4, 5-amino-4-cyano-3(3-methoxy) obtained in Step 2 of Example 9.1 Phenyl)amino-1 hydrazine-pyrazole (0.  1 5 g , 0. 65mmol), 2-bromo-5,6-dimethoxybenzothiazole (〇. 22§, 0. 78mmol), potassium carbonate (〇. 36g, 2. 6mmol) and N,N-dimethylformamide (5mL), obtained as [| compound 146 (0. 026g, 9%). ESIMS m/z: 42 3 (M + H)VH NMR (2 70 MHz, DMSO-d6) 5 3. 79(s, 3H), 3. 83(s, 3H), 3. 84(s, 3H), 6. 50 (m, 1H), 716-7. 18(m, 2H), 7. 50-7. 51(m, 2H), 7. 68(s, 1H), 8. 22(s, 2H), 9.  1 0 (s, 1 H). Example 147 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-phenylamino-1H-pyrazole (Compound 147) (Step 1) The procedure according to Example 1 1, from [bis(methylthio)methylene]malononitrile (1. 7g, 9. 8mmol), aniline (l. Og, llmmol) and ethanol (2 〇 mL) give 2-[methylsulfonyl (phenylamino)methylene]malononitrile (i. 8g, 8 7%" ESIMS m/z: 216(M + H)+ ; (Step 2) According to step 2 of Example 1, 2-[methylsulfonyl (phenylamine) obtained in step 2 Methyl]malononitrile (l_6g, 7. 3mmol) with hydrazine-214-200911240 hydrate (〇. 43mL, 8. 8 mmol) gave 5-amino-4-cyano-3-phenylamino-1 hydrazine-pyrazole (0.63 g, 36%). (Step 3) According to Step 3 of Example 4, 5-amino-4-cyano-3-phenylamino-1H-pyrazole obtained in Step 3 (0. 10g, oh. 5〇mmol), 2-chlorobenzothiazepine (0_068g, 0. 55mmol), cesium carbonate (0. 42g, 3. 0mmol), 1,8-diazabicyclo[5·4. 0]-7-undecene (〇. 15mL, l. Ommol) and hydrazine, hydrazine-dimethylformamide (5 · 0 m L) gave compound 1 4 7 (0.  1 0 g, 6 0 % ). ESIMS m/z: 3 3 3 (M + H)+. Example 1 4 8 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-ethoxyphenyl)amino group _ 1 Η -Shame (Compound 1 4 8) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]propanol (l_8g, 10_〇1), 3-ethoxyphenylene (1. 5g, llmm〇1) and ethanol (3〇mL) give 2_[(3_ethoxyphenyl)amino (methylsulfonyl)methylene]malononitrile (2 · 1 g, 7 9 %). (Step 2) 2 _[(3 ethoxyphenyl)amino (methylsulfonyl)methylene]malononitrile (16 g, obtained in Step 1 according to Step 2 of Example 1) 7 3 _01) with hydrazine monohydrate (0. 39mL, 8. 8mm〇1), and ethanol -215- 200911240 (30mL), 5-amino-4-cyano-3-(3-ethoxyphenyl)amino-1H-pyrazole (0. 6 7 g, 4 1 % ). ESIMS m/z: 244 (M + H) + ; (Step 3) According to Step 3 of Example 4, 5-amino-4-cyano-3-(3-ethoxyl) obtained in Step 2 Phenyl)amino-1H-pyrazole (0. 52g, 2. 1 mmol), 2-chlorobenzothiazole (0. 30mL, 2. 3mmol), potassium carbonate (1. 8 g, 13 mmol), and hydrazine, hydrazine-dimethylformamide (26 mL) gave compound 148 (0. 32 g, 40%) ° ESIMS m/z: 3 77 (M + H) +. Example 149 2-{3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]aminophenyl}ethinylmorpholine (Compound 149) According to Example 108, from Compound 96 (0. 10g, 0. 26 mmol), 1-benzotriazine monohydrate (0. 069 §, 0. 16111111〇1),]^-ethyl->4'-(3-dimethylaminopropyl)carbodiimide hydrochloride (〇. 〇98g,0. 51 mmol), morpholine (0. 034ml^ 0. 38 mmol) and N,N-dimethylformamide (20 mL) gave Compound 1 4 9 (0 · 1 1 g, 93%). ESIMS m/z: 460 (M + H)+. Example 1 5 胺 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-(2-hydroxyethyl)phenyl]amine-216- 200911240 BASE-1H -pyrazole (Compound 150) Compound 96 (0. 10g, oh. 25 mmol) of tetrahydrofuran solution (10 mL) was ice-cooled and borane was added. Tetrahydrofuran solution (1. 0 m ο 1 / L , 0. 5 2 m L,0. 5 2 mmol), warmed to room temperature while stirring for 1 hour. The reaction mixture was quenched with water and dried over anhydrous sodium sulfate. The residue obtained was purified by preparative thin layer chromatography (hexane / ethyl acetate = 1 / 1) to give compound 1 5 0 (0. 0 2 6 g, 2 7 %). ESIMS m/z: 3 77 (M + H)+. Example 1 5 1 5 -Amino-1 -(benzothiazol-2-yl)-4-cyano-3 -[ 3 -(4-hydroxypiperidin-1-yl)phenyl]amino-1H -pyrazole (Compound U1) (Step 1) to 3-fluoronitrobenzene (O. lOmL, 0. 94mm〇l) of N-methylpyrrolidinium (3_0mL) solution was added to potassium carbonate (0_65g, 4. 7mmol) with 4-hydroxypiperidine (0 · 4 8 g, 4. 7 m m ο 1), stir at 1 30 ° C for 1 〇 hours. Water was added to the reaction mixture, and ethyl acetate was evaporated. By refining the obtained residue by ruthenium dioxide colloid chromatography (chloroform/methanol = 90/10 - 80/20), 1-(3-nitrophenyl)piperidine-4-ol (〇) was quantitatively obtained. . 21g) 〇 ESIMS m/z: 223(M + H)+. (Step 2) -217- 200911240 1 - (3 · Nitrophenyl) piperidin-4-ol obtained in Step 1. (0. 2 1 g, 0_94 mmol) of ethanol (4. 2mL) solution added 10% pin-carbon (0. 021 g, 10 w/w%), stirred at room temperature overnight under a hydrogen atmosphere. The insoluble material was filtered off, and the obtained filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (chloroform / methanol = 95/5 - 80 / 20) to give 1-(3-aminophenyl)piperidin-4-ol (0. 13 g, 70%). ESIMS m/z: 1 93 (M + H)+. (Step 3) 1-(3-Aminophenyl)piperidin-4-ol obtained in Step 2 (0. 13g, 0. 16mmol) of ethanol (2. 5 mL) solution was added to [bis(methylthio)methylene]malononitrile (0.  1 2 g , 0 _ 7 2 m m ο 1), heated to reflux 5. 5 hours. Next, add hydrazine monohydrate (〇 · 0 4 8 m L , 0. 9 8 m m ο 1) 'Heating reflux 4 · 0 hours. Water was added to the reaction mixture, extracted with ethyl acetate, and the obtained organic layer was concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloidal chromatography (chloroform-chloroform/methanol = 80/20) to give 5-amino-4-cyano-3-[3-(4-hydroxypiperidin-1- Phenyl]amino-1H-pyrazole (0. 1 lg, 59%). ESIMS m/z: 299 (M + H)+. (Step 4) 5-Amino-4-cyano-3-[3-(4-hydroxypiperidin-1-yl)phenyl]amino-1H-pyrazole (O.) obtained in Step 3. Llg, 0. 38 mmol) of N,N-dimethylformamide (2. 7mL) solution was added to 2-chlorobenzothiazole (0. 05 7mL, 0. 46mmol) with potassium carbonate (〇. 21g, 1. 5mmol), stirred at 80 ° C 3. 5 hours. Water was added to the solution from the anti-218-200911240 solution and extracted with ethyl acetate. The obtained organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform-chloroform/methanol = 80/20), and methanol was added to the crude product. The precipitated solid was filtered to give Compound 1 5 1 (0 - 15 g, 89%). ESIMS m/z: 43 3 (M + H)VH NMR (3 00 MHz, DMSO-(16) δ 2H), 1. 85 (m, 2H), 2. 90(t, J = 9. 7Hz, 2H), 3 .  5 2 - 3. 7 3 (m, 3 H), 4. 6 6 (d, J = 4. 0 H z , 1 H ),6 _ 5 2 (m, 1 H), 7_08(s, 3H), 7. 09(d, J = 7_0Hz, 1H), 7. 38(t, J = 6_0Hz, 1H), 7. 41(s, 1H), 7. 51(t, J = 6. 0Hz, 1H), 7. 90 (d, J = 7. 7Hz, 1H), 8. 08(d, J = 7. 7Hz, 1H), 8. 27(s, 2H), 8. 91(s, 1H). Example 1 5 2 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3-(2,3-dimethoxyphenyl)amino-1 Η-pyrazole ( Compound 1 5 2 ) (Step 1) According to Step 1 of Example 1, from [bis(methylthio)methylene]malononitrile (1. Og, 5. 9mmol), 2,3-dimethoxyaniline (0. 90g, 5. 9 mm 〇 l) and ethanol (2 〇 mL) gave 2-[(2,3-dimethoxyphenyl)amino (methylsulfonyl)methylene]malononitrile. Next, according to the step 2 of Example 1, the obtained 2-[(4-fluorophenyl)amino (methylsulfonyl)methylene]malononitrile and hydrazine monohydrate (0-94 mL, 19 mmol) gave 5-amino-4-cyano-3-(2,3-dimethoxyphenyl)amino-1^1_pyrazole (0. 82 §, 54%). ESIMS m/z: 2 5 8 (M-H)-. -219- 200911240 (Step 2) According to Step 3 of Example 4, the 5-amino-4-cyano-3-(2,3-dimethoxyphenyl)amino group obtained in Step 1 - 111-pyrazole (0. 268,1. 0 mmol), 2-chlorobenzothiazole (〇_i3mL, l. Ommol), potassium carbonate (0. 55g, 4. 0mmol) and N,N-dimethylformamide (4. 0 m L), compound 152 (0. 25g, 65%). ESIMS m/z: 391 (M-H);]H NMR (270 MHz, DMSO-d6) 5 3. 77(s, 3H), 3. 84(s, 3H), 6. 74(d, J = 8. 1Hz, 1H), 7. 06(t, J = 8.  1 Hz, 1H), 7. 39(t, J = 7_3Hz, 1H), 7. 49(t, J = 7. 3Hz, 1H), 7. 61(br s, 1H), 7. 63(d, J = 8. 1Hz, 1H), 7. 93(d, J = 7. 3Hz, 1H), 8. 06(d, J = 7. 3Hz, 1 H), 8. 3 4 (b r s, 2 H). Example 1 5 3 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-methoxy-2-methylphenyl)amino-1 Η-pyridyl Azole (Compound 1 5 3 ) (Step 1) According to Step 1 of Example 56, from 3-methoxy-2-methylnitrobenzene (4. (^, 24111111〇1), methanol (80-claw 1 〇, 10% palladium-carbon (2,6 lv), and hydrogen' to give 3-methoxy-2-methylaniline (2. 7g, 82%) ° ESIMS m/z: 138 (M + H) + ° (Step 2) According to Step 1 of Example 1 'from 3-methoxy-2-methylaniline obtained in Step 1 ( 2. 4g, 18mmol), [bis(methylthio)methylene]propane-220- 200911240 nitrile (9. 9 g, 58 mmol) and ethanol (45 mL) gave 2-[(3-methoxy-2-methylphenyl)amino (methylsulfonyl)methylene]malononitrile (4. 5g, 98%). ESIMS m/z: 25 8 (M-H)-. (Step 3) According to Step 2 of Example 1, 2-[(3-methoxy-2-methylphenyl)amino (methylsulfonyl)methylene]propyl obtained in Step 2 Dinitrile (4. 5g, 17mmol) with hydrazine monohydrate (2. 8 mL, 57 mmol) gave 5-amino-4-cyano-3-(3-methoxy-2-methylphenyl)amino-1H-pyrazole (3. Lg, 74%). ESIMS m/z: 242 (M-H)·. (Step 4) According to Step 3 of Example 4, 5-amino-4-cyano-3-(3-methoxy-2-methylphenyl)amino-1H- obtained in Step 3. Pyrazole (0. 10g, 0. 41mmol), 2-chlorobenzothiazepine (0. 043mL, 0. 41mmol), potassium carbonate (0. 34g, 2. 5mmol) and N,N-dimethylformamide (2. 0 mL) gave compound 153 (0 _ 063 g, 4 1%). ESIMS m/z: 3 7 5 (M-H). . Example 154 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-trifluoro-3-(morpholin-4-yl)methyl)phenyl]amino- 1H-pyrazole (Compound 154) (Step 1) Same as in Step 1 of Example 1 'from [bis(methylthio)methylene]-221 - 200911240 malononitrile (l. Lg, 6. 6 mmol), 5-amino-2-fluorodecyl alcohol (0-98 g, 6. 9 mmol), and ethanol (20 mL) gave 2-[(4-fluoro-3-hydroxymethylbenzyl)amino (methylsulfonyl)methylene]malononitrile (i_4 g, 82%). (Step 2) According to Step 2 of Example 1, 2-[(4-fluoro-3-hydroxymethylphenyl)amino (methylsulfonyl)methylene]malononitrile obtained in Step 1. (丨·4^, 2. 8mmol), hydrazine monohydrate (0_31mL, 6. 5mm〇l), ethanol (30mL), to give 5-amino-4-cyano-3-(4-fluoro-3-hydroxymethylphenyl)amino-1 Η-pyrazole (1 _ 2 g, 8 8 % ). ESIMS m/z: 248 (M + H)+. (Step 3) According to Step 3 of Example 1, '5-Amino-4-cyano-3-(4-fluoro-3-methylphenyl)amine-based ιη·卩 obtained in Step 2 Than 4 3mmol), 2-chlorobenzothiazole (〇. 59g, 4. 8mmol), potassium carbonate (3. 9 Lu, 28 mmol), and hydrazine, hydrazine-dimethylformamide (3 〇 mL), to give 5-amino-b (benzothiazol-2-yl)-4-cyano-3-(4- Fluoro-3-hydroxymethylphenyl)amino- lH_pyrazole (0·14g, 8. 6%). ESIMS m/z: 3 8 1 (M + H)+. (Step 4) According to Example 8 7 'from 5 -amino group 2 -(benzothiazole-2-yl)-4-cyano-3-(4-fluoro-3-hydroxyl) obtained in step 3 Phenyl)amino-lH-pyrrole sitting-222 - 200911240 (0. 14g, 0. 37mmol) with a hospital sulfonate chlorine (〇_〇32mL, 0. 41mmol), morpholine (0. 071mL, 0. 81mmol) and N,N-dimethylacetamide (5. 0 mL) gave Compound 1 54 (72 mg, 43%). NMR (270 MHz, D M S Ο - d 6) δ 2 _ 4 4 (m, 4 Η ) , 3. 5 2 (s, 2H), 3. 61(m, 4H), 7. 11(d, J = 8. 1Hz, 1H), 7. 38 (m, J = 5. 4Hz 1H), 7. 52(t, J = 5. 4Hz, 1H), 7. 61 (m, 1 H), 7. 73(m, 1H), 7. 91(d, J = 8. 1Hz, 1H), 7. 92(d, J = 8. 1Hz, 1H), 8. 30(s, 2H), 9. 16(s, 1H). Example 1 5 5 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1H- Pyrazole-methanesulfonate (compound 155) according to Example 43, from compound 86 (0-55 g, 1. 3 mmol), methanesulfonic acid (0-091 mL, l_4 mmol) and methanol (ll mL) gave compound 1 5 5 (0. 6 1 g, 9 1 %). 'H NMR (270MHz, DMSO-d6) 5 2. 32(s, 3H), 3. 17- 3. 46(m, 4H), 3. 62-3. 71(m, 2H), 3. 97-4. 02(m, 2H), 4. 34(s, 2H), 7. 12(d, J = 7. 6Hz, 1H), 7. 3 8-7. 46(m, 2H), 7. 53(td, J = 7. 6, 1. 0Hz, 1H), 7. 67(s, 1H), 7. 78(d, J = 8. 2Hz, 1H), 7. 92(d, J = 8. 2Hz, 1H), 8. 07(d, J = 7. 9Hz, 1H). Example 1 5 6 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(1-ethylpiperidin-3-yl)-amino-1 Η-pyrazole (Compound 1 5 6) -223- 200911240 (Step 1) According to Step 1 of Example 92, from [bis(methylthio)methylene]malononitrile (0. 40g, 2. 3 mmol), 1-ethylpiperidin-3-amine (0. 30g, 2. 3mmol), hydrazine monohydrate (0. 1 1 m L, 2. 3 m m ο 1) and ethanol (9. 0 m L), 5-amino-4-cyano-3-(1-ethylacridin-3-yl)amino-1H-pyrazole (0. 1 5g, 2 8%) ° 'H NMR (270MHz, D M S Ο - d6 ) δ 1 .  0 6 (t, J = 7 _ 2 H z, 3 Η), 1. 3 7- 1. 62(m, 2Η), 1. 79(m, 2H), 2. 16 (m, 1H), 2. 18(m, 1H), 2. 45 (q, J = 7. 2Hz, 2H), 2. 56(m, 2H), 2. 90(s, 1H), 3. 57 (m, 1H), 4. 35(s, 2H), 4_61(s, 1H), 4. 79 (s, 1H). (Step 2) According to Step 3 of Example 4, 5-amino-4-ylidene-3-(1-ethylindole-3-yl)amino-1H-D obtained in Step 1. Comparison (0. 20g, 0. 93mmol), 2-chlorobenzothiazepine (0_053mL, 0. 40mmol), potassium carbonate (0. 20g, 1. 5 mmol) and hydrazine, hydrazine-dimethylformamide (5 mL) gave compound 156 (0. 03g, 22%) ° ESIMS m/z: 3 6 8 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 1. 10(t, J = 7. 2Hz, 3H), 1. 66-1. 91(m, 4H), 2. 3 7-2. 5 3 (m, 5H), 2. 76(m, 1H), 3. 94(s, 1H), 4. 65(s, 1H), 6. 76(s, 2H), 7. 31 (dt, J-15. 9, 4. 4Hz, 9H), 7. 44(tt, J = 7. 7, 2. 2Hz, 1H), 7. 76-7. 81 (m, 2H). Example 1 5 7 -224- 200911240 5-Amino-4-cyano-l-[6-(2-hydroxyethyl)benzothiazol-2-yl]-3-(3-hydroxymethylphenyl Amino-1H-pyrazole (Compound 157) (Step 1) 5-Amino-4-cyano-3(3-) obtained in Step 1 of Example 70 according to Step 3 of Example 4. Hydroxymethylphenyl)amino-1 Η-pyrazole (1 · 1 g , 4. 8 mmol), 2-bromo-6-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzothiazole (2. 9g, 5. 8mmol), potassium carbonate (2. 7g, 19mmol) and N,N-dimethylformamide (20mL) give 5-amino-dibutyl-phenyl decyloxy)ethyl]benzothiazol-2-yl}-4-cyanide Base - 3-(3-hydroxymethylphenyl)amino-1H-pyrazole (0. 91g, 29%). ESIMS m/z: 645 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 〇. 94(s, 9H), 2. 95(t, J = 6. 2Hz, 2H), 3. 88(t, J = 6. 2Hz, 2H), 4. 50 (d, J = 5.  8Hz, 2H), 5.  18(t, J = 5. 8Hz, 1H), 6. 90 (d, J = 7. 4Hz, 1H), 7. 25(t, J = 7. 8Hz, 1H), 7. 32-7. 51(m, 11H), 7. 59(d, J = 8. 3Hz, 1H), 7. 63(s, 1H), 7. 50 (d, J = 8. 3Hz, 1H), 7. 88(d, J=1. 3Hz, 1H), 8. 26(s, 2H), 9. 12(s, 1H). (Step 2) 5-Amino-1-{6-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzothiazole obtained in Step 1 according to Step 4 of Example 91 -2-yl}-4-cyano-3-(3-methylphenyl)amino-1H-U 哩(O. Lg,0. 16mmol), 70% tetrabutylammonium fluoride (〇. 〇87mL, 0. 23 mmol) and tetrahydrofuran (1 mL) gave compound 1 57 (0. 040g, 63%). ESIMS m/z: 407 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 -225 - 200911240 2. 84(t, J = 6. 9Hz, 2H), 3. 63-3. 70 (m, 2H), 4. 50 (d, J = 5. 6Hz, 2H), 4. 7l(t, J = 5. 1Hz, 1H), 5. 18(t, J-5. 6Hz, 1H), 6. 90 (d, J = 7. 6Hz, 1H), 7. 25(t, J = 7. 6Hz, 2H), 7. 37 (dd, J = 8. twenty one. 6Hz, 7H), 7. 59(m, 1H), 7. 63(s, 1H), 7. 79(d, J = 8. 2Hz, 1H), 7. 91 (d, J=1. 6Hz, 1H), 8. 25(s, 2H), 9. 11 (s, 1H). Example 1 5 8 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(2-oxypropyl)phenyl]amino-1 - Η-pyridyl Azole (compound 1 5 8) to compound 149 (0. 062g, 0. 14 mmol) of tetrahydrofuran (l〇mL) solution was added methyl magnesium bromide at room temperature (〇. 96mol/L, 0_56mL, 0. 54 mmol), stirred at room temperature for 2 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. Purification by cerium oxide colloidal column chromatography (hexane/ethyl acetate = 2/1) gave compound 158 (0. 018g, 3 4%) 〇ESIMS m/z: 3 89(M + H)+ 〇Example 1 5 9 5-Amino-4-cyano-l-[6-(2-hydroxyethyl)benzo Thiazol-2-yl]-3-[3-(morpholin-4-yl)methyl)phenyl]amino-1H-pyrazole (Compound 159) (Step 1) According to Example VIII, 5-Amino-1-{6-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzothiazol-2-yl}-4-cyanide obtained in Step 1 of Example 1 3-(3-hydroxymethylphenyl)amino-1H-pyrazole (0. 050g, -226- 200911240 0. 078mmol), methane sulfonium chloride (〇. 〇〇 9mL, 0. 12mmol), morpholine (0. 034mL, 0. 39 mmol) and N,N-dimethylformamide (1 mL) gave 5-amino-l-(6-[2-(t-butyldiphenylphosphonyloxy)ethyl]benzothiazole- 2_yl}-4-cyano-3-(3-(morpholinomethyl)phenyl]amino-1H-pyrazole (〇. 〇49g, 8 8%) ° E SIM S m / z : 7 1 4 (M + Η) +. (Step 2) 5-Amino-1·{6-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzothiazole obtained in Step 1 according to Step 4 of Example 91 -2_基}_ 4-Cyano-3-[3-(morpholinylmethyl)phenyl]amino-1Η-卩 is more than Π(〇. L6g, 0. 23 111111〇1), 70% tetrabutyl fluorinated money (0. 13111[,0. 34111111〇1) and tetrahydrofuran (2 _ 0 m L), giving compound 1 5 9 (0. 0 4 6 g, 4 3 %). ESIMS m/z: 476 (M + H) + ; 1H NMR (270 MH, DMSO-d6) 5 2. 40(t, J = 4. 6Hz, 4H), 2. 85(t, J = 6. 9Hz, 2H), 3. 44(s, 2H), 3. 61-3. 67(m, 4H), 3. 66(d, J = 5. 2Hz, 2H), 4. 7 0 (t, J = 5. 2 Hz, 1H), 6. 87 (d, J = 7. 6Hz, 2H), 7. 24(t, J = 7. 6Hz, 1H), 7. 37(d, J = 8. 2Hz, 1H), 7. 60 (m, 1H), 7. 66(s, 1H), 7. 80 (d, J = 8. 2Hz, 1H), 7. 90(s, 1H), 8. 25(s, 2H), 9. 11 (s, 1H). Example 160 5-Amino-4-cyano-1_(4,6-difluorobenzothiazol-2-yl)-3-(3-hydroxymethylphenyl)amino-1H-pyrazole (Compound 160 According to Example 8 8, 5 - -227- 200911240 Amino-4-cyano-3-(3-hydroxymethylphenyl)amino-1H-pyrazole obtained in Step 1 of Example 70 (〇. 65g, 2. 8mmol), 2-bromo-4,6-difluorobenzothiazole (〇. 78g, oh. 21mmol), potassium carbonate (1. 6g, llmmol) and N,N-dimethylformamidine (12mL) gave compound 1 6 0 (0. 8 9 g, 8 0 %). ESIMS m/z: 3 97(Μ-Η)·;'Η NMR (27〇MHz, DMSO-d6)5 4. 49(s, 2H), 5. 20(s, aH), 6. 88(d, J = 7. 7H2, 1H), 7. 23(t, J = 8. 1Hz, 1H), 7. 45 (m, 1H), 7. 59(s, 2H), 7. 61(s, 1H), 7. 86 (d, J = 8_4Hz, 1H), 7. 95(s, 1H), 9. 01(s, 1H). Example 1 6 1 5-Amino-4-cyano-1-(4,6-difluorobenzothiazol-2-yl)-3-[3-(morpholin-4-ylmethyl)phenyl Amino-1H-pyrazole (Compound 161) According to Example 86, from Compound 160 (0. 75g, l_9mmol), methanesulfonate chloride (〇. 29mL, 3. 8 mmol), morpholine (l_6 mL, 19 mmol), triethylamine (0. 55mL, 3_9mmol) and hydrazine, hydrazine-dimethylformamide (8. 0 mL), compound 1 6 1 was obtained (0. 4 3 g, 4 9 %). ESIMS m/z: 468 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 5 2. 40(t, J = 4. 5Hz, 4H), 3. 45(s, 2H), 3. 60(t, J = 4. 5Hz, 4H), 6. 89 (d, J = 7, 3Hz, 1H), 7. 25(t, J = 7. 6Hz, 1H), 7. 50 (m, 1H), 7. 61(s, 1H), 7. 64(s, 1H), 7. 90 (m, 1H), 8. 20(s, 2H), 9. 19(s, 1 H). Example 162 5-Amino-l-[6-(2-chloroethyl)benzothiazol-2-yl]-4-cyano-3- [3-morpholine--228- 2009-11240 4- base Phenyl]amino-1H-pyrazole (Compound 162) (Step 1) According to Example 86, by compound 1 5 9 (0. 0 5 g, 0. 11 mmol) 'Methyl sulfonium chloride (〇. 〇16mL, 0. 21mmol), triethylamine (0_059mL, 0. 42mmol) and hydrazine, hydrazine-dimethylformamide (l. OmL) was heated at 100 ° C to give compound 1 62 (0. 027g, 52%). ESIMS m/z: 494 (M + H) VH NMR (270 MHz, DMSD-d6) S 2. 40(t, J = 4. 5Hz, 4H), 3. 16(t, J = 6. 9Hz, 2H), 3. 46(s, 2H), 3. 61 (t, J = 4. 5Hz, 4H), 3,92 (t, J = 6. 9Hz, 2H), 6. 88(d, J = 7. 7Hz, 1 H), 7. 25(t, J = 7. 7Hz, 1H), 7. 44 (dd, J = 8. 3, 1,7Hz, 1H), 7. 59(m, 1H), 7. 66(m, 1H), 7. 84(d, J = 8. 3Hz, 1H), 7_98 (d, J=1. 3Hz, 1H), 8_27(s, 2H), 9. 13(s, 1H). Example 163 5-Amino-4-cyano-1-[6-(2-methanesulfonyloxyethyl)benzothiazol-2-yl]-3-[3-(morphin-4-yl) Methyl)phenyl]amino-1H-pyrazole (Compound 163) According to Example 86, from Compound 1 59 (0. 025g, 0. 05 3mmol), methane sulfonium chloride (〇. 〇〇8mL, O. Lllmmol), triethylamine (0. 03mL, 0. 21 mmol) and hydrazine, hydrazine-dimethylformamide (l. OmL), to obtain compound 163 (0. 021g, 72%). ESIMS m/z: 5 54 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 2. 40(t, J = 4. 5Hz, 4H), 3. 13(s, 3H), 3. 33(t, J = 6. 6Hz, 2H), 3. 46(s, 2H), 3. 61(t, J = 4, 5Hz, 4H), 4. 48(t, J = 6. 6Hz, 2H), 6. 88(d, J = 7. 3Hz, 1 H), 7 · 2 5 (t, J = 7. 8 H z, 1H), 7. 45 (dd, -229- 200911240 J = 8. 6, 1. 7Hz, 1H), 7_59(m, 1H), 7. 66(s, 1H), 7. 85(d, J = 8. 6Hz, 1 H), 7. 99(d, J=1. 3Hz, 1H), 8. 27(s, 2H), 9. 13(s, 1 H). Example 164 5-Amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1-(6-ethylpyrylbenzothiazole-2-yl) -1 Η-pyrazole (compound 1 6 4) makes compound 162 (0. 014g, 0. 028mmol) dissolved in hydrazine, hydrazine-monomethylcarbamamine (l. OmL), add sodium iodide (0. 0042g, 0. 028mmol) and 1,8-diazabicyclo[5·4. 0]-7-undecene (〇_〇17mL, O. Llmmol), heated at 70 t for 2 hours. The obtained crystal was washed with water by adding water to the reaction liquid to obtain a compound 1 64 (0. 0083 g, 65%). ESIMS m/z: 45 8 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 6 2. 40(t, J = 4. 5Hz, 4H) 3. 46(s, 2H), 3. 61(t, J = 4. 5Hz, 4H), 5. 32(d, J=1 1. 2Hz, 1H), 5. 91 (d, J = 17. 5Hz, 1H), 6. 79- 6. 90 (m, 2H), 7. 25(t, J = 7. 8Hz, 1H), 7. 59-7. 66(m, 3H), 7. 86(d, J = 8. 4Hz, 1H), 8. 18(s, 1H), 8. 39(s, 2H), 9. 13(s, 1H). Example 165 5-Amino-4-chloro-1-(4,6-difluorobenzoin-2-yl)-3-[3-(indol-4-yl)phenyl]amino -1 Η-pyrazole (Compound 165) According to Example 8 8, 5-amino-4-cyano-3-[3-(morpholine-4) obtained in Step 5 of Example 15. -yl)phenyl]amino-1Η-pyrazole (〇. 〇50g, -230- 200911240 0. 18 mmol), 2-bromo-4,6-difluorobenzothiazole (〇. 〇53g, 〇. 21mmol), potassium carbonate (0_097g, 0. 70mmol) and hydrazine, hydrazine-dimethylformamide (2. 〇mL), to obtain compound 165 (0. 0 19g, 23%). ESIMS m/z: 454 (M + H) VH N M R (2 7 0 Μ Η z, D M S Ο - d 6) δ 3 .  1 4 (t, J = 4. 8Hz, 4H), 3. 7 9 ( f, J = 4. 8Hz, 4H), 6. 5 7(t, J = 5. 8Hz, 1H), 7. 13(s, 1 H), 7. 1 4 (s, 1 H), 7 3 8 (s, 1 H), 7. 5 0 (m, 1 H ), 7. 9 3 ( d d, J = 8 · 9,2. 0 H z, 1 H), 8 · 1 9 ( s , 2 H), 9. 04(s, 1H). Example 166 5-Amino-4-amino-1-[6-(2-methylaminoethyl)benzosin-2-yl]- 3-[3-(morpholin-4-yl) Methyl)phenyl]amino-11pyrazole (Compound 166) gives Compound 1 64 (0. 026g, 0. 047 mmol) dissolved in N,N-dimethylformamide (1. OmL), join 2. 0M dimethylamine tetrahydrofuran solution (0. 12mL, 0. 24mm〇l), heated to reflux for 6 hours. After the addition of water, the mixture was extracted with ethyl acetate. The residue obtained was purified by cerium oxide colloidal column chromatography (chloroform/methanol = 10/1), and further ethanol was added (1. OmL), and then slurryed to obtain the compound 166 (0. 012g, 50%). ESIMS m/z: 503 (Μ + Η) + ; *Η NMR (2 70MHz, DMSO-d6)8 2. 19(s, 6H), 2. 40(t, J4. 6Hz, 4H), 2. 83(t, J = 7. 4Hz, 2H), 3. 33(s, 2H), 3. 35(t, J = 7. 4Hz, 2H), 3. 62(t, J = 4. 6Hz, 4H), 6. 88(d, J = 7. 6Hz, 1H), 7. 24(t, J = 7. 6Hz, 1H), 7. 38(m, 1H), 7. 58 (d, J = 7. 9Hz, 1H), 7. 65(s, 1H), 7. 79(d, J=8. 6Hz, 1H), -231 - 200911240 7. 91(s, 1H), 8. 25(s, 2H), 9. 11 (s, 1H). Example 167 5-Amino-4-cyano-l-[6-(2-hydroxymethyl)benzothiazol-2-yl]-3-[3-(morpholin-4-yl)phenyl] Amino-1H-pyrazole (Compound 167) (Step 1) 5-Amino-4-cyano-3-[3_(#) obtained in Step 4 of Example 15 according to Step 3 of Example 4.琳琳-1-yl)phenyl]amino-1H-pyrazole (0. 74g, 2. 6 mmol), 2-bromo-6-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzothiazole (1. 6g, 3_lmmol), potassium carbonate (1. 4g, 10mmol) and N,N-dimethylformamide (10mL) give 5-amino-l-{6-[2-(t-butyldiphenylphosphonio)ethyl]benzene Thiazol-2-yl}-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1 hydrazine-pyrazole (0 _ 6 3 g, 34%). ESIMS m/z: 700 (M + H)+. (Step 2) 5-Amino-1-{6-[2-(t-butyldiphenylphosphoniumoxy)ethyl]benzothiazole obtained in Step 1 according to Step 4 of Example 91 -2-yl}-4-chloro-3-[3-(?咐-4-yl)phenyl]amino-anthracene- 挫. 67g, 0. 96mmol), 70% tetrabutyl fluorinated money (2. 0mL, 5. 3 mmol) and tetrahydrofurfuryl (1 OmL) gave Compound 1 6 7 (0 _ 4 1 g, 92 %). ESIMS m/z: 462 (M + H) + ; *H NMR (270 MHz, DMSO-d6) 5 2. 85(t, J = 6. 9Hz, 2H), 3. 15(1, J = 4. 6Hz, 4H), 3. 46(s, 2H), 3_80(t, J = 4. 6Hz, 4H), 4. 72(t, J = 5.  1 Hz, 1H), 6. 55(d, -232- 200911240 J = 7. 3Hz, 1H), 7. 11-7_17(m, 2H), 7. 37 (dd, J two 8. 4,1. 8Hz, 1H), 7. 45(s, 1H), 7. 79(d, J = 8. 6Hz, 1H), 7. 93(d, J=1. 3Hz, 1H), 8. 25(s, 2H), 8_97(s, 1H). Example 1 6 8 5-Amino-4-cyano-1-[6-(2-dimethylaminoethyl)benzothiazol-2-yl]-3-[3-(morpholine-4) _ yl)phenyl]amino-111-pyrazole (Compound 168) (Step 1) Compound 1 67 (0. 3 8g, 0. 82 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (5. 0mL), adding triethylamine (〇. 45mL, 3. 26mm〇l) with methane sulfonium chloride (0_13mL, 1. 6 mmol), stirred for 1 hour. After the reaction mixture was poured into water, ethyl acetate was evaporated, and the organic layer was dried over anhydrous sodium sulfate. By re-slurrying the obtained residue with chloroform to give 5-amino-4-yl-cyano-l-[6-(2-methanesulfonyloxyethyl)benzothiazol-2-yl]-3 -[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (0. 30g, 67%). ESIMS m/z: 5 3 9 (M + H)VH NMR (2 70 MHz, DMSO-d6) 5 3. 11-3. 15(m, 9H), 3. 80(t, J = 4. 8Hz, 4H), 4. 48(t, J = 6. 6Hz, 2 H ), 6 · 5 6 (d , J = 7 · 6 H z, 1 H ), 7 .  1 1 - 7 · 1 4 (m , 2 H ), 7 · 4 4 - 7. 4 6 (m, 2H), 7. 84, (d, J = 8_3Hz, 1H), 8. 02(s, 1H), 8. 26(s, 2H), 8. 99(s, 1H). (Step 2) 5-Amino-4-cyano-l-[6-(2-methanesulfonyloxyethyl)benzothiazol-2-yl] obtained in Step 1 according to Example 166 -3-[3-(morpholine- -233- 200911240 4-yl)phenyl]amino-1H-pyrazole (0. 03 5 g,0. 065mmol), 2. 0M dimethylamine tetrahydrofuran solution (l. OmL, 2. 0 mmol) and N,N-dimethylformamide (5 · 0 m L) gave compound 1 6 8 (0. 0 2 5 g, 8 6 %). ESIMS m/z: 48 9 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 19(s, 6H), 2. 84(t, J = 7. 4Hz, 2H), 3. 15(t, J = 4. 6Hz, 4H), 3_50(t, J = 7. 4Hz, 2H), 3. 80(t, J = 4. 6Hz, 4H), 6. 56(d, J = 7. 9Hz, 1H), 7. 07-7. 17(m, 2H), 7. 37(m, 1H), 7. 45(s, 1H), 7. 79(d, J = 8. 2Hz, 1H), 7. 94(s, 1H), 8. 24(s, 2H), 8. 97(s, 1H). Example 169 5-Amino-4-amino- l-(6-{2-[4-(3-carbyl-3-methylbutyl)oxime-1-yl]ethyl}benzothiazole 2-yl)-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (Compound 169) according to Example 1 66, obtained from Step 2 of Example 1 68 5-Amino-4-cyano-l-[6-(2-methanesulfonyloxyethyl)benzothiazol-2-yl]-3-[3-(indol-4-yl)benzene Amino-1H-pyrazole (0. 03g, 0. 056 mmol), 2-methyl-4-(piperazin-1-yl)butan-2-ol (0. 038g, 0. 22 mmol) and hydrazine, hydrazine-dimethylformamide (1 mL) gave compound 1 69 (0. 02 1 g, 62%) 〇 ESIMS m/z: 616 (M + H) VH NMR (2 70 MHz, DMSO-d6) 5 l_08 (s, 6H), 1 . 5 1 (m, 2H), 2. 40 (m, 4H), 2. 84(m, 2H), 3. 15(m, 4H), 3. 3 0- 3. 4 5 (m, 8H), 3. 80 (m, 4H), 4. 71(s, 1H), 6. 57(s, 1H), 7. 12(d, J = 1 0. 5Hz, 2H), 7. 37(d, J = 8. 0Hz, 1H), -234- 200911240 7. 46(s, 1H), 7. 79(d, J = 8. 0Hz, 1H), 7. 94(s, 1H), 8. 24(s, 2H), 8. 97 (s, 1H). Example 1 7 0 5-Amino-4-cyano-l-{6-[2-(morpholin-1-yl)ethyl]benzothiazol-2-yl}-3-[3-( Phenyl-4-yl)phenyl]amino-1^pyrazole (Compound 170) According to Example 1 66, 5-amino-4-cyano-l- obtained in Step 2 of Example 1 68 [6-(2-methanesulfonyloxyethyl)benzothiazol-2-yl]-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (〇_〇) 35g, 0. 065 mmol), morpholine (0. 023mL, 4. 26 mmol) and N,N-dimethylformamide (1 mL) gave Compound 1 70 (0-026 g, 76%). ESIMS m/z: 531 (M + H) +; 'H NMR (270 MHz, DMSO-d6) 5 2. 44(t, J = 4. 3Hz, 4H), 2. 58(t, J = 8.  1 Hz, 2H), 2. 87(t, J = 8. 1Hz, 2H), 3. 16(d, J = 4. 6Hz, 4H), 3. 59(t, J = 4. 3Hz, 4H), 3. 80(t, J = 4. 6Hz, 4H), 6. 56(d, J = 7. 2Hz, 1H), 7. 08-7. 14(m, 2H), 7. 38(d, J = 8. 2Hz, 1H), 7. 46(s, 1H), 7. 79(d, J = 8. 2Hz, 1H), 7. 95(s,1H), 8. 25(s, 2H), 8_98(s, 1H). Example 1 7 1 5-Amino-4-cyano-3-[3-(morpholin-1-yl)phenyl]amino-l-{6-[2-(thiomorpholin-4-yl) Ethyl]benzothiazol-2-yl}-111-pyrazole (Compound 171) According to Example 1 66, the 5-amino-4-cyano group obtained in Step 2 of Example 168 L-[6-(2-Methanesulfonyloxyethyl)benzothiazol-2-yl]_3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (0. 035g, 0. 065 -235- 200911240 mmol), thiomorpholine (〇. 〇67g,0. 65mmol) and N,N-dimethylformamide (1.  0 m L) gives compound 1 7 1 (0 _ 0 2 5 g, 70%). ESIMS m/z: 54 7 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 8 2. 6 1 - 2. 6 3 ( m , 6H), 2. 7 2 - 2. 7 4 ( m, 4H), 2. 82-2. 88(m, 2H), 3. 16(t, J = 4. 6Hz, 4H), 3. 79(t, J = 4. 6Hz, 4H) 6. 56(d, J = 7. 6Hz, 1H), 7. 07-7. 17(m, 2H), 7. 37(d, J = 8. 2Hz, 1H), 7. 46(s, 1H), 7. 79(d, J = 8. 2Hz, 1H), 7. 94(s, 1H), 8. 24(s, 2H), 8. 97(s, 1H). Example 1 7 2 5-Amino-4-cyano-l-(6-{2-[2-hydroxyethylmethyl]aminoethylbenzothiazol-2-yl}-3-[3- (morpholin-4-yl)phenyl]amino-1H-pyrazole (Compound 172) 5-Amino-4-cyano-l- obtained from Step 2 of Example 168 according to Example 166 [6-(2-Methanesulfonyloxyethyl)benzothiazol-2-yl]-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (0. 035g, 0. 065 mmol), 2-(methylamino)ethanol (〇. 〇52mL,0. 65mmol) and N,N-dimethylformamide (1. 0 m L) gave compound 1 7 2 (0 · 0 1 6 g, 48%). ESIMS m/z: 519(Μ + Η) + ;*Η NMR (2 70MHz, DMSO-d6)8 2. 27(s, 3H), 2. 46-2. 49(m, 2H), 2. 61-2. 67(m, 2H), 2. 81- 2. 90(m, 2H), 3 · 1 6 (t, J = 4 · 8 Η z, 4H), 3. 44-3. 51(m, 2H), 3_80(t, J = 4. 8Hz, 4H), 4. 32(t, J=5. 4Hz, 1H), 6. 56(t, J = 3. 6Hz, 1 H), 7. 08-7. 17(m, 2N), 7. 37 (dd, J = 8. 6, 1. 6Hz, 1H), 7. 47(s, 1H), 7. 79(d, J=8, 2Hz, 1H), 7. 95(d, J=l, 3Hz, -236- 200911240 1 H), 8. 25(s, 2H), 8. 98(s, 1 Η). Example 173 5-Amino-4-cyano-l-[6-(2-methylthiomethyl)benzothiazol-2-yl]-3-[3-(morpholin-4-yl)benzene Amino-1H-pyrazole (Compound 173) 5-Amino-4-cyano-1·[6-(2-methane) obtained in Step 2 of Example 1 68 according to Example 1 66 Sulfomethyloxyethyl)benzothiazol-2-yl]·3-[3-(morpholin-4-yl)phenyl]amino-1Η-pyrazole (0. 026g, 0. 048 mmol), 15% sodium methyl mercaptanate aqueous solution (0. 23mL, 0. 48mmol) and N,N-dimethylformamide (l. OmL), compound 173 (0. 0 19g, 79%). ESIMS m/z: 492 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 10(s, 3H), 2. 74-2. 82(m, 2H), 2. 95-3. 00(m, 2H), 3. 16(t, J = 4. 6Hz, 4H), 3. 80(t, J = 4. 6Hz, 4H), 6. 56(d, J = 7. 9Hz, 1H), 7. 08-7. 17(m, 2H), 7. 41 (dd, J = 5. 6, 1. 6Hz, 1H), 7. 47(m, 1H), 7. 81(d, J = 8. 2Hz, 1H), 7. 98(d, J=1. 6Hz, 1H), 8. 25(s, 2H), 8. 98(s, 1H). Example 174 5-Amino-4-cyano-l-[6-(hydroxymethyl)benzosoxazol-2-yl]-3-[3·(morpholin-4-yl)phenyl]amine Base-1-pyrazole (Compound 174) (Step 1) 5-Amino-4-cyano-3-[3-() obtained in Step 4 of Example 15 according to Step 3 of Example 4.琳琳-4-yl)phenyl]amino-1H-D is sitting at the mouth (0. 21g, 0_45mmol), 2-bromo-6-(t-butyldiphenylphosphonyloxymethyl)-237- 200911240 Benzothiazide (0. 83g, 1. 7mmol), potassium carbonate (0. 87g, 6. 28 mmol) and N,N-dimethylformamide (5 mL) gave 5-amino-1-[6-(t-butyldiphenylphosphonyloxy)benzothiazol-2-yl] -4 -Cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyrazole (0. 52g, 48%). (Step 2) 5-Amino-1-[6-(t-butyldibenzomethoxymethyl)benzothiazol-2-yl] obtained in Step 1 according to Step 2 of Example 91 4-cyano-3-[3-(morpholin-4-yl)phenyl]amino] 1 Η-pyrazole (0 _ 5 2 g , 0. 76 mmol), 70% tetrabutylammonium fluoride (2 mL, 5. 3 mmol) and tetrahydrofuran (10 m L) gave compound 1 7 4 (0 _ 2 8 g, 83%). ESIMS m/z: 44 8 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 6 3.  1 5 (t, J = 4. 6Hz, 4H), 3. 80 (1, J = 4. 6Hz, 4H), 4. 62 (d, J = 3. 3Hz, 2H), 5. 34(t, J = 3. 3Hz, 1H), 6. 56(m, 1H), 7. 12- 7. 18(m, 2H), 7. 44-7. 47(m, 2H), 7. 84(d, J-8. 2Hz, 1H), 8. 03(s,1H), 8. 26(s, 2H), 8. 98 (s, 1H). Example 1 7 5 5-Amino-4-cyano-1-6-(morpholin-4-yl)methyl)benzothiazol-2-yl]-3-[3-(morpholin-4- Phenylamino-1H-pyrazole (Compound 175) According to Example 86, from Compound 174 (0. 030g, 0_067mmol), methane sulfonium chloride (0. 013mL, 0. 17mmol), triethylamine (〇_〇47mL, 〇. 34mmol), morpholine (〇. 12mL, 1. 34 mmol) and N,N-dimethylformamide (1. 0 m L), compound 1 7 5 (Ο _ Ο Ο 9 g, 2 6 %) was obtained. -238- 200911240 ESIMS m/z: 517 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 2. 39(t, J = 4. 8Hz, 4H) 3. 15(t, J = 4. 6Hz, 4H), 3. 58(s, 2H), 3. 61 (t, J = 4. 8Hz, 4H), 3,80(t, J = 4. 5Hz, 4H), 6. 56(d, J = 7. 6Hz, 1 H), 7. 08-7. 1 7 (m, 2H), 7. 44-7. 47(m, 2H), 7. 84(d, J = 8. 2Hz, 1H), 8. 03(s, 1H), 8. 27(s, 2H), 8_98(s, 1H). Example 176 5-Amino-4-cyano-l-[6-(dimethylaminomethyl)benzothiazol-2-yl]-3-[3_(morphin-4-yl)phenyl Amino-1H-pyrazole (Compound 176) According to Example 86, from Compound 1 74 (0. 03g, 0. 067mmol), a hospital sulfonium chloride (〇. 〇26mL, 0. 34mmol), triethylamine (0. 093mL, 0. 67 mmol), 2. 0M dimethylamine tetrahydrofuran solution (l. OmL, 2. 0 mmol) and hydrazine, hydrazine-dimethylformamide (1 mL) gave compound 1 76 (0. 006g, 19%) ° ESIMS m/z: 47 5 (M + H) + ; *H N M R (2 7 Ο Μ Η z, D M S Ο - d 6) δ 2. L8(s, 6H), 2. 76(s, 2H), 3. 15(t, J = 4. 6Hz, 4H), 3. 80(t, J = 4. 6Hz, 4H), 6. 56(d, J = 7. 2Hz, 1H), 7. 08-7. 17(m, 2H), 7. 42-7. 46(m, 2H), 7. 8 3 ( d, J = 8. 6 H z, 1 H), 8. 02(s, 1H), 8. 27(s, 2H), 8. 98 (s, 1H). Example 1 7 7 5-Amino-4-cyano-methylthiomethyl)benzothiazol-2-yl]-3-[3-(morpholin-4-yl)phenyl]amino-1 Η-pyrazole (compound 177) According to Example 86, from compound 174 (0. 060g, 0_13mmol), -239- 200911240 A hospital expanded acid chloride (〇_〇52mL, 0. 67mmol), triethylamine (0. 19mL, 1. 34 111111〇丨), 15% sodium methyl mercaptan sodium solution (0. 63111[,1. 34111111〇1) and 1>1-dimethylformamide (l. OmL), compound 1 77 (0. 008g, 13%). ESIMS m/z: 478(M + H)VH N M R (2 7 Ο Μ Η z, D M S Ο - d 6) δ 1. 99(5, 3Η), 3. 17(t, J = 4. 8Hz, 4H), 3. 80(t, J = 4. 8Hz, 4H), 3. 83(s, 2H), 6. 56(d, J = 7. 2Hz, 1H), 7. 09-7. 17(m, 2H), 7. 45 -7. 47(m, 2H), 7. 84(d, J = 8. 6Hz, 1H), 8. 03(s, 1H), 8. 26(s, 2H), 8_98(s, 1 H). Example 1 7 8 5 -amino-1-(benzothiazol-2-yl)-4-cyano-3-(3,4-dimethoxybenzyl)amino-1 hydrazine-pyrazole ( Compound 1 7 8 ) (Step 1) [Bis(methylthio)methylene]malononitrile (6. 2g, 36mmol) was dissolved in ethanol (0. 10L), 3,4-dimethoxybenzylamine was added under ice-cooling conditions (5. 0 mL, 33 mmol), stirred at room temperature for 30 min. To the reaction mixture was added hydrazine monohydrate (2.  LmL, 50mmol), stirred at 80 °C. 0 hours. After cooling to room temperature, the organic solvent was distilled off under reduced pressure. The residue obtained was reslurryed with water to give 5-amino-4-cyano-3-(3,4-dimethoxybenzyl) Amino-1H-pyrazole (6. 3g, 70%). ESIMS m/z: 274 (M + H) + ; *H NMR (3 00 MHz, DMSO-d6) 5:3. 71(s, 3H), 3. 73(s, 3H), 4. 14(s, 2H), 5. 87(s, 1H), 6. 05(s, 2H), 6. 84-6. 8 5 (m, 2H), 6. 95 -6. 97(m, 1H), 10. 61 (s, 1H). -240- 200911240 (Step 2) 5-Amino-4-cyano-3-(3,4-dimethoxybenzyl)amino-1H-pyrazole (3. 0g, llmmol), 2-chlorobenzothiazole (1. 7mL, 13mmol), potassium carbonate (6. 1 g, 44 mmol) was dissolved in N,N-dimethylformamide (30 mL) and stirred at 80 °C. 5 hours. After cooling to room temperature, saturated brine was added, and the mixture was stirred for 1 hour, and the obtained crystal was filtered. Re-slurry with chloroform-ethyl acetate to give compound 178 (2. 6g, 58%). ESIMS m/z: 407 (M + H) + ; 1H NMR (3 OOMHz, DMSO- ά6) δ: 3. 72(s, 3H), 3. 74(5, 3H), 4. 76(d, J = 6. 2Hz, 2H), 6. 13(s, 2H), 6. 92-6. 98(m, 2H), 7. 05 -7. 06(m, 1H), 7. 33- 7. 3 8 (m, 1H), 7. 46-7. 51(m, 1H), 7. 80 (d, J = 8. 1Hz, 1H), 8. 02(d, J = 7. 3Hz, 1 H), 8 · 9 5 - 9 · 0 0 (m, 1H). Example 179 5-Amino-4-cyano-3-[3-(hydroxymethyl)phenyl]amino-1-(4,5,6,7-tetrahydrobenzothiazol-2-yl) -1 Η-pyrazole (Compound 179) (Step 1) 5-Amino-4-cyano-3(3-hydroxymethylphenyl)amine obtained in Step 1 of Example 70 Base-1Η-pyrazole (〇. 〇8〇8, 〇. 35111111〇1), 2-bromo-4,5,6,7-tetrahydrobenzothiazole (〇. 〇99§, 0_45mmol), copper iodide (1) (0. 〇12g, 0. 064mmol), potassium phosphate (〇. 15g, 〇. 68mmol), trans-cyclohexane-1,2-diamine (〇. 〇22mL, 〇. 24mmol) dissolved in methanol (1. In 6 mL), the mixture was stirred at 80 ° C for 7 hours under an argon atmosphere. The solvent was distilled off under reduced pressure -241 - 200911240, and the resulting residue was subjected to ethyl acetate and water. Compound 17 9 (25 mg, 19%) ° ESIMS m/z: 3 67 (M + H) + ; 1H NMR (3 OOMHz, DMSO-d6) 5:2 by recrystallization of the crystals with ethanol. . 62-2. 75 (m, 8H), 4. 46(s, 2H), 6. 85 (d, J = 6. 9Hz, 1H), 7. 20 (dd, J-7. 8, 6. 9Hz, 1H), 7. 52 (d, J = 7. 8Hz, 1H), 7. 58(s, 1H)’ 7. 95(s, 2H), 8. 99(s, 1H). Example 1 8 0 5-Amino-4-cyano-3-[3-(?咐-4-ylmethyl)phenyl]amino-1-(4,5,6,7-tetrahydrobenzene And thiazol-2-yl)-1 oxime-pyrazole (Compound 1 80) (Step 1) According to Step 1 of Example 92, from [bis(methylthio)methylene]malononitrile (4. 6g, 27mmol), 3-(morpholin-4-ylmethyl)aniline (5. 4g, 28 mmol), hydrazine monohydrate (1_6 mL, 32 mmol) and ethanol (80 mL) gave 5-amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl Amino-1H-pyrazole (4 · 2 g, 53 %). ESIMS m/z: 299 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 2. 33(t, J = 4. 4Hz, 4H), 3. 36(s, 2H), 3. 56(t, J = 4. 4Hz, 4H), 6. 24(s, 2H), 6. 70 (d, J = 7. 4Hz, 1H), 7. 10(t, J = 7. 7Hz, 1H), 7. 31 (d, J-7. 7Hz, 1H), 7. 39(s, 1H), 8. 31(s, 1H), 11. 19(s, 1 H). (Step 2) -242- 200911240 The 5-amino-4-cyano-3_[3 _(morpholin-4-ylmethyl)phenyl]amino-1H-D ratio obtained in the first step Azole (〇. L〇g, 〇. 34 mmol) was suspended in toluene (2 mL), and was added with tripotassium phosphate (4 g, 0-67 mmol), trans-N, N'-dimethylcyclohexane-1,2-diamine (〇. 〇21mL, 0. 13mmol), copper iodide (I) (0. 013g, 0. 067 mmol), 2-bromo-4,5,6,7-tetrahydrobenzothiazole (〇_〇95§, 0 4 4 mm ο 1), stirred at 100 Torr for 3 hours. After the addition of water, the mixture was extracted with ethyl acetate. The compound 1 8 0 (0 _ 0 1 1 g, 8%) was obtained by re-slurrying the obtained crude crystals with chloroform. ESIMS m/z: 43 6 (M + H) +; *H NMR (270 MHz, DMSO-d6) 6 1. 71-1. 80 (m, 4H), 2. 25 -2. 3 8 (m, 4H), 2. 70(t, J = 4. 1Hz, 4H), 3. 42(s, 2H), 3. 59(t, J = 4. 1Hz, 4H), 6. 83 (d, J = 6. 9Hz, 1H), 7. 20 (m, 1H), 7. 53 (d, J = 7. 9Hz, 1H), 7. 61(s, 1H), 7. 95(s, 2H), 8. 99 (s, 1H). Example 1 8 1 5-Amino-4-cyano- 3_[3-(morpholin-4-ylmethyl)phenyl]amino-l-[5-(t-butoxycarbonyl)-4, 5,6,7-Tetrathiathiazolo[5,4-c]pyridin-2-yl]-1H-pyrazole (Compound 8.1) According to Step 2 of Example 1 80, by the procedure of Example 180 1 obtained 5-amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1H-H than hydrazine (0. 19g, 0. 65mmol), tripotassium phosphate (0. 28g, 1. 30 mmol), trans-Ν, Ν'-dimethylcyclohexan-1,2-diamine (0. 082mL, 0_52mmol), copper iodide (I) (〇_〇49g, 0. 26 mmol), 2-bromo-5-(t-butoxycarbonyl)--243- 200911240 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0. 27g, 0. 84 mmol) and toluene (4 mL) gave Compound 181 (0-061 g, 18%). ESIMS m/z: 53 7 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 3 1. 43(s, 9H), 2. 38(t, J = 3. 9Hz, 4H), 2. 73(s, 2H), 3. 33- 3. 45 (m, 3H), 3. 59(t, J-3. 9Hz, 4H), 3. 67(m, 1H), 4. 56(s, 2H), 6. 85(d, J = 7. 6Hz, 1 H), 7. 2 0 (t, J = 7 · 7 Hz, 1 H), 7. 5 6 (t, J = 6. 7Hz, 2H), 7. 96(s, 2H), 9. 02(s, 1H). Example 182 5-Amino-4-cyano-3- [3-(morpholin-4-ylmethyl)phenyl]amino-1-(4,5,6,7-tetrahydrothiazolo[ 5,4-c]pyridin-2-yl)-1Η-pyrazole (Compound 182) According to Step 3 of Example 6 2, Compound 1 8 1 (0·0 6 1 g, 18%), concentrated hydrochloric acid ( 0. 05 0 mL) and methanol (1 mL) gave compound 182 (0. 031g, 78%). ESIMS m/z: 43 7(M + H) + ;1 Η N M R(2 7 0 Μ Η z, D M S Ο - d 6) δ 2. 37(1, J = 4. 1Hz, 4H) 2. 63 -2. 66(m, 2H), 3. 03(t, J = 5. 6Hz, 2H), 3. 3 8-3. 42 (m, 3H), 3. 59(t, J = 4. 1Hz, 4H), 3. 89(s, 2H), 6. 84 (d, J = 7. 6Hz, 1H), 7. 20(t, J = 7. 9Hz, 1H), 7. 53(m, 1H), 7. 59(s, 1H), 7. 96(s, 2H), 9_00(s, 1H). Example 1 8 3 5 -Amino-4-cyano-1-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-3-[3-( Morpholin-4-yl)methyl)phenyl]amino-1H-pyrazole (Compound 1 83) According to the procedure of Example 1 80, step 2 'from step 1 -244 to 200911240 of Example 180 5-Amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino] 1H-pyrazole (0. 097g, O_33mmol), tripotassium phosphate (0. 14g, 0. 65mmol), trans-Ν, Ν·-dimethylcyclohexan-1,2-diamine (0. 021mL, 0-13111111〇1), monumental copper (1) (0. 012§, 0_065111111〇1), 2-bromo-6,7-dihydro-4H-pyrano[4,3-d]thiazole (0. 086g, 0. 39 mmol) and toluene (2_0 mL) gave compound 1 8 3 (0. 028g, 20%). ESIMS m/z : 43 8(M + H) + ;1 Η N M R (2 7 0 Μ ζ ζ , D M S Ο - d 6) δ 2. 38(t, J = 4. 4Hz, 4Η), 2. 77(t, J = 5. 0Hz, 2H), 3. 44(s, 2H), 3. 58(t, J = 4. 4Hz, 4H), 3. 94(t, J = 5. 0Hz, 2H), 4. 73(s, 2H), 6. 84 (d, J = 7. 2Hz, 1H), 7. 20(t, J = 7. 7Hz, 1H), 7. 5 4 - 7. 5 7 (m ,.  2H), 7_97(s, 2H), 9_02(s, 1H). Example 1 8 4 5-Amino-4-cyano-1-(6,7-dihydro-4H-thiopyrano-[4. 3-d]thiazol-2-yl)-3-[3-(morpholin-4-yl)methylphenyl]amino-1H-pyrazole (Compound 84) According to Step 2 of Example 1 80, 5-Amino 4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1H-pyrazole obtained in Step 1 of Example 1 80 (〇. 14g, 0. 47 mmol), tripotassium phosphate (0-20 g, 0-94 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (0-030 mL, 0-19 mmol), copper iodide (1) (0. 018§,0. 0941^11〇1), 2-bromo-6,7-dihydro-411-thiopyrano[4,3-(1]thiazole (0. 16§, 0. 57111111〇1) and toluene (2. 51111〇, get the compound 1 84 (0. 04g, 19%) ° ESIMS m/z: 454 (M + H) + ; 'H NMR (270MHz, DMSD-d6) 5 2. 37(t, J = 4. 3Hz, 4H), 2. 9 5 - 2. 9 8 (m, 4H), 3. 42(s, 2H), -245- 200911240 3. 59(t, J = 4. 3Hz, 4H), 3. 87(s, 2H), 6. 84 (d, J = 7. 6Hz, 1H), 7_20(t, J = 7. 9Hz, 1H), 7. 5 2-7. 5 8 (m, 2H), 7. 97(s, 2H), 9. 02(s, 1H) Example 1 8 5 5-Amino-4-cyano-1-(5,7-dihydro-41^-spiro[benzothiazole-6,2|-[1,3] Dioxolane-2-yl)-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1 hydrazine-pyrazole (Compound 185) According to Step 2 of Example 1 80, 5-Amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1Η-pyrazole obtained in Step 1 of Example 1 80 (0. 15g, 0. 51mmol), tripotassium phosphate (〇_22g, l. Ommol), trans-Ν, Ν1-dimethylcyclohexane-1,2-diamine (0. 032mL, 0. 20mmol), copper iodide (I) (〇. 〇19g, O. lOmmol), 2-bromo-5,7-dihydro-4H-spiro[benzothiazole-6,2·-[1,3]dioxolane] (0. 17g, 0. 61 mmol) and toluene (2 mL) gave compound 1 85 (0. 065g, 26%). ESIMS m/z: 494 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) S 1. 94(t, J = 5. 8Hz, 2H), 2. 3 7-2. 3 8 (m, 4H), 2. 76-2. 81(m, 2H), 2. 91(s, 2H), 3. 42(s, 2H), 3. 59(t, J = 4. 5Hz, 4H), 3. 96(s, 4H), 6. 83(d, J = 7. 3Hz, 1H), 7. 20(t, J = 7. 8Hz, 1H), 7. 53 (m, 1H), 7. 59(s,1H), 7. 95(s, 2H), 9. 00 (s, 1H). Example 1 8 6 5-Amino-4-chloro-3-(3-(morphin-4-yl)methyl)phenyl]arm-1(5,6,7,8-tetrahydrol -411-cyclohepta[(1)thiazol-2-yl)-1^1-pyrazole (Compound 186) -246- 200911240 According to Step 2 of Example 180, obtained from Step 1 of Example 180 5-Amino-4-cyano-3-[3-(morpholine-4-ylmethyl)phenyl]amino-1H-B than hydrazine (〇. 30g, l. Ommol), tripotassium phosphate (〇. 43g, 2. 0mmol), trans-Ν, Ν,-dimethylcyclohexane-1,2-diamine (0. 063mL, l_2mmol), Yaohua Copper (1) (0. 038§, 0_20111111〇1), 2-bromo-5,6,7,8-tetraki-4}1-cyclohepta [d]thiazole (〇. 28g, 1. 21 mmol) and toluene (3 mL) gave compound 186 (〇. 〇42g, 9%) ° ESIMS m/z: 45 0(Μ + Η) + ;*Η NMR(270MHz, DMSO-d6)5 1. 65-1. 81(m, 6H), 2. 38(t, J = 4. 3Hz, 4H), 2. 77(t, J = 4. 9Hz, 2H), 2. 84(t, J = 4. 9Hz, 2H), 3. 42(s, 2H), 3. 59(t, J = 4. 3Hz, 4H), 6. 82 (d, J = 7. 6Hz, 1H), 7. 19(t, J = 7. 6Hz, 1H), 7. 51 (m, 1H), 7. 60(s,1H), 7. 92(s, 2H), 8. 96 (s, 1H). Example 1 8 7 5-Amino-4-cyano-1-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-(:]pyridine-2-yl)- 3-3-(morpholin-4-yl)methylphenylamino-1H-pyrazole (Compound 18 7) According to Step 2 of Example KF 1 800, from Step 1 in Example 180 5-Amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1H-pyrazole (0. 30g, l. Ommol), tripotassium phosphate (0. 43g, 2. 0mmol), trans-Ν, Ν'-dimethylcyclohexan-1,2-diamine (0. 063mL, 1. 2mmol), pickled copper (I) (0. 038g, 0. 20 mmol), 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0. 2 8g, 1. 21 mmol) and toluene (3 mL) gave compound 1 87 (0. 03 8g, 8%).

ESIMS m/z: 451 (M + H) VH NMR (270MHz, DMSO-d6) S-247- 200911240 2.3 5 - 2.49 (m, 7 Η), 2 _ 7 3 (t, J = 4.6 Η z, 4 Η), 3.4 2 (s, 2 Η), 3.55(s, 2H), 3.59(t, J = 4.6Hz, 4H), 6.84(d, J = 7.6Hz, 1H), 7.20(t, J = 7.6 Hz, 1H), 7.53 (m, 1H), 7.60 (s, 1H), 7.95 (s, 2H), 9.00 (s, 1 H). Example 1 8 8 5 -Amino-4-cyano-1-(quinoxalin-2-yl)-3-[3-(morpholin-4-yl)methylphenyl]amino-1 -Pyrazole (Compound 1 8 8 ) 5-Amino-4-cyano-3-[3-(morpholin-4-yl) obtained in Step 1 of Example 180 according to Step 2 of Example 180 Methyl)phenyl]amino-1Η-pyrazole (0.14g, 0.47mmol), tripotassium phosphate (〇.20g, 0.94mmol), trans-Ν,Ν1·dimethylcyclohexane-1,2- Diamine (〇.〇30mL, O.I9mmol), copper iodide (I) (〇_〇18g, 0.094mmol), 2-bromoquinoxaline (0.12g, 0.57mmol) and toluene (2.5mL) Compound 188 (0.082 g, 4 1%). ESIMS m/z: 427 (M + H) +; 1H NMR (270MHz, DMSO-d6) 6 2.41 (t, J = 4.1 Hz, 4H) 3.47 (s, 2H), 3.64 (t, J = 4.1 Hz, 4H), 6.84 (d, J = 7.3 Hz, 1 H), 7.25 (t, J = 7.7 Hz, 1 H), 7.56 (t, J = 4.5 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.8 7-7.8 9(m, 2H), 8.10(d, J = 8.6Hz, 1H), 8.21(d, J = 8.6Hz, 1H), 8.40(s, 2H), 9_00(s, 1H ), 9.49(s, 1H). Example 189 5-Amino-4-cyano-3- [3-(morpholin-4-ylmethyl)phenyl]amino-1-(thiazol-248- 200911240 [5,4-b] Pyridin-2-yl)-1 oxime-pyrazole (Compound 189) 5-Amino-4-cyano-3 - [3-] obtained in Step 1 of Example 180 from Step 1 of Example 180 (morpholin-4-ylmethyl)phenyl]amino-1Η-pyrazole (0.17g, 0.57mmol), tripotassium phosphate (〇.24g, 1.15mmol), trans-N,N,-dimethyl Cyclohexane-1,2-diamine (〇.〇36mL, 0.23mmol), copper (I) iodide (〇.〇22g, 0.12mmol), 2-bromothiazino[5,4-b]pyridine (0.12 g, 0.57 mmol) and toluene (2.5 mL) gave Compound 189 (0.020 g, 8%). ESIMS m/z: 43 3 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 8 2.40 (t, J = 4.3 Hz, 4H), 3.45 (s, 2H), 3.62 (t, J = 4.3 Hz, 4H), 6.8 7 ( d , J = 8.6 H z, 1 H), 7 · 2 5 (t, J = 8 1 H z, 1 H ), 7.5 1 (m, 1 H), 7.58 ( m, 1H), 7.76 (s, 1H), 8.25 (t, J = 4.8 Hz, 1H), 8.33 (s, 2H), 8.51 (d, J = 4.6 Hz, 1H), 9.17 (s, 1H). Example 1 9 0 5-Amino-4-cyano-l-(5,6-dihydro-4H-cyclohept[d]thiazol-2-yl)-3-[3-(morpholin-4- Phenyl]amino-lH-pyrazole (Compound 190) 5-Amino-4-cyano-3 obtained in Step 1 of Example 180 according to Step 2 of Example 1 80 - [3-(Methyl-4-ylmethyl)phenyl]amino-1H-pyrazole (0.22 g, 0-72 mmol), tripotassium phosphate (〇_31 g, 1.44 mmol), trans-N, N'- Dimethylcyclohexane-1,2-diamine (〇.〇45mL, 0.29mmol), copper (I) (〇_〇27g, 0.14mmol), 2-bromo-5,6-dihydro- 4H-cyclohepta[d]thiazole (0.29 g, 1.4 mmol) and toluene (6_〇mL) gave compound 190 (0·0 4 5 g, 15%). -249- 200911240 ESIMS m/z: 422 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 2.3 7-2.46 (m, 6H), 2.76 (t, J = 6.9 Hz, 2H), 2.88 (t, J = 6.9Hz, 2H), 3.42(s, 2H), 3.58(t, J = 4.3Hz, 4H), 6 8 4 ( d, J = 7.2 H z, 1 H), 7.20(t, J = 7.8 Hz, 1H), 7, 51 (m, 1H), 7.62 (s, 1H), 7.92 (s, 2H), 9.00 (s, 1H). Example 1 9 1 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(6-methylpyridin-2-yl)amino-1 Η-pyrazole (compound) 1 9 1 ) (Step 1) Compound 178 (2.6 g, 6.4 mmol), trifluoromethyl acid (1.4 mL, 16 mmol), benzoic acid (2 1 mL, 19 mmol) was dissolved in trifluoroacetic acid (13 mL) at room temperature Stir for 6.0 hours. The solvent was concentrated under reduced pressure, and the residue was evaporated and evaporated. The crystallization obtained by filtration was re-slurryed with ethanol to obtain 3,5-diamino-1-(benzothiazol-2-yl)-4-cyano-1 Η-pyrazole (1 _ 5 g). , 8 9 %). *H NMR (3 00 MHz, DMSO-d6) 5 : 6.11 (s, 2H), 7.35 (dd, J = 8.1, 8.0 Hz, 1H), 7.48 (dd, J = 8.1, 8.0 Hz, 1H), 7.85 ( d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.1 Hz, 1H), 8.16 (s, 2H). (Step 2) To a solution of 2-bromo-6-methylpyridine (0.050 mL, 0.43 mmol) in N,N-dimethylformamide (2.5 mL) was added EtOAc ( EtOAc. 1,10-morpholine (〇_〇28mg, 〇_16mmol), copper iodide (1) (0. 〇15g, -250- 200911240 0.078mmol), and 3,5 obtained in step 1. Diamino-1 -(benzothiazol-2-yl)-4-cyano-1H-pyrazole (0.10 g, 〇_39 mmol) was stirred at 1 1 ° C for 1.5 hours under microwave irradiation. To the reaction mixture was added 28% aqueous ammonia, and ethyl acetate was evaporated. The residue obtained was purified by silica gel chromatography (chloroform-chloroform/methanol = 80/20) to afford compound 191 (0.010 g, 7%). ESIMS m/z: 348 (M + H)VH NMR (2 70MHz, CDC13) δ: 2.64 (s, 3H), 4.41 (s, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.89 (d , J = 7.2 Hz, 1H), 7.35 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 5.3 Hz, 1H), 7.78-7.88 (m , 2H), 11.27(s, 1H). Example 192 5-Amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1-(4,5,6,7-tetrahydrobenzothiazole 2-yl)-1 -pyrazole-methanesulfonate (Compound I92) According to Example 43, from compound 180 (0.026 g, 0.06 mmol), methanesulfonic acid (?? (1 mL) 'Compound 1 92 (0.02 8 g, 88%) 'H NMR (270MHz, DMSO-d6) 6 1.80 (s, 4H), 2.29 (5, 3H), 2.71-2.75 (m, 4H), 3.15 -3.24(m, 4H), 3.5 8-3.67(m, 2H), 3.97(d, J=12.8Hz, 2H), 4.30(s, 2H), 7.05(d, J = 7.2Hz, 1H), 7.39 (t, J = 7.9Hz, 1H), 7.61(s, 1H), 7.68(d, J = 7.9Hz, 1H), 8.01(s, 2H), 9_19(s, 1H), 9_76(s, 1H) Example 1 9 3 -251 - 200911240 5 -Amino-1-(benzothiazol-2-yl)-4-cyano-3-(6-methoxypyridine-2-yl)amino-1 Η-pyrazole (Compound 1 9 3 ) According to the step 2 of Example 1 9 1 'from 2-bromo-6-methoxy-deep (〇.〇77 mL, 〇.62 mmol), tripotassium phosphate (〇.25g) , l211111101), 1,1〇_morpholine (0_028g, 0.16mmol) 'copper iodide (Η0·015. 〇.〇75mmol), 3,5·diamine obtained in step 1 of Example 191 Base-1-(benzo Azole_2_yl)_4_cyano-1H-pyrazole (〇.10§, °·39 mmol), and hydrazine, hydrazine-dimethylformamide (2.5 mL)' gave compound 193 (〇_〇) 3 0g, 2 1%) ESIMS m/z: 3 64(M + H) + ; 'H NMR (27〇MHz, CDC13) δ :4.09(s, 3H), 4.38(s, 2H), 6.52( d, J = 7.6Hz, 1H), 6.66(d, J = 7.sHz, 1H), 7.36(t, J = 7.6Hz, 1H), 7.48(t, J-7.9Hz, 1H), 7.61(t , J = 7.9 Hz, 1H), 7.76-7.88 (m, 2H), 10.86 (s, 1H). Example 1 94 5-amino-1-(benzothiazol-2-yl)-3-(6 -Bromopyridin-2-yl)amino-4-cyano-1H-pyrazole (Compound 194) According to Step 2 of Example 191, from 2,6-dibromopyridine (0.044 g, 0.19 mmol), Potassium (〇.〇75g, 0.35mmol), 1,10-morpholine (0.0084g, 〇.〇47mmol), copper iodide (1) (0.004 5 g, 0.023 mmol), Step 1 of Example 191 3,5-Diamino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazole (30 g, 0.12 mmol), and N,N-dimethyl Formamidine (1 · 5 m L ) gave compound 1 9 4 (0 · 0 〇 3 mg, 6%). ESIMS m/z: 413 (M + H) + ; 1H NMR (270MHz, CDC13) - 252 - 200911240 δ : 4.43 (s, 2H), 7.01 (d, J = 7.9 Hz, 1H), 7.22 (m, 1H) ), 7.37(t, J = 9.6Hz, 1 H), 7.46-7.66(m, 2H), 7.84(d, J = 6.7Hz, 1H), 7_86(d, J = 6.7Hz, 1H), 11.29( s, 1H). Example 1 9 5 5 -Amino-4-cyano-1-(6,7-dihydro-4H-thiopyrano[4,3-d]thiazol-2-yl)-3-[3- (morpholin-4-yl)phenyl]amino-1H-pyrazole (Compound 195) 5-Amino-4-cyano group obtained in Step 4 of Example 15 according to Step 2 of Example 180 -3 - [ 3 -(morpholin-4-yl)phenyl]amino-1 Η-pyridinium (0.18 g, 0.64 mmol), tribasic acid (〇.27 g, 1.27 mmol), trans-Ν, Ν1-dimethylcyclohexane-1,2-diamine (〇.〇4〇mL, 0.25mmol), copper (I) iodide (0_024g, 0.13mmol), 2-bromo-6,7-anthracene -4H - thiopurin than methane [4,3-(1]thiazole (0.18 §, 0.76111 «1〇1) and toluene (2.〇1111〇, compound 195 (0.063 g, 23%) ° ESIMS m/ z: 440 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 5 2.89-3.01 (m, 4H), 3.10 (t, J = 4.6 Hz, 4H), 3.76 (t, J = 4.6 Hz , 4H), 3.87 (s, 2H), 6.51 (m, 1H), 7.04-7.13 (m, 2H), 7.37 (s, 1 H), 7.95 (s, 2H), 8.87 (s, 1H). Example 1 9 6 5-Amino-4-cyano-1-(isoquinolin-1-yl)-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1 Η - Pyrazole (compound 1 9 6) according to step 1 of Example 1 80 'from step 1 in Example 180 5-Amino-4-cyano-3-[3-(morpholinomethyl)phenyl]amino--253 - 200911240 1H-pyrazole (0.12 g, 0-40 mmol), tripotassium phosphate 0·17^, 0.80mmo1), trans-N, N'-dimethylcyclohexane-1,2-diamine (〇.〇25mL, 0,16mmol), copper iodide (I) (〇_〇) 15 g, 0.08 mmol), bromoisopropargyl (0-091 g, 〇 _ 44 mmol) and toluene (2 mL) afforded Compound 196 (0.050 g, 30%). MSIMS m/z: 426 (M + H) + ; H NMR (270MHz, DMSO-d6) 6 2.30 (t, J = 4.4 Hz, 4H) 3.36 (s, 2H), 3.46 (t, J = 4.4 Hz, 4H), 6.77 (d, J = 7.9 Hz, 1H) ), 7.14(t, J = 7.9Hz, 1H), 7.40(s, 2H), 7.45(dd, J = 7.9, 1.3Hz, 1H), 7.60(m, 1H), 7.71(m, 1H), 7.8 3 -7.8 9(m, 2H), 8.08(d, J = 7.9Hz, 1H), 8.39(d, J = 5.6Hz, 1H), 8.77(d, J = 8.6Hz, 1H), 8.81(s, 1H). Example 1 9 7 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(4-methylpyridin-2-yl)amino-1H-pyrazole (Compound 197 According to Step 2 of Example 191 'from 2-bromo-4-methylpyridine (0.028 g, 0-19 mmol), tripotassium phosphate (〇.25 g, l_2 mmol), 1,10-morpholine (0_028 g, 0.16 mmol) , copper iodide (I) (〇.〇15g, 0.078 mmol), 3,5-monoamino-1-(benzothiazol-2-yl)-4-cyanide obtained in the first step of Example 191 Base-1H-pyrazole (〇.l〇g, 39. 39 mmol), and N,N-dimethylformamide (2.5 mL) gave Compound 197 (0.33 Og, 22%). ESIMS m/z: 3 4 8 (Μ + Η) + ; *Η NMR (2 70 MHz, DMSO-d6) δ: 2.44 (s, 3H), 5.76 (s, 1H), 6.50 (s, 2H), 7.01 (d, J = 7.9Hz, 1H), 7.29-7.3 9(m, 2H), 7.47(t, J = 7.6Hz, 1H), 7.84(d, J:7.9Hz, 1H), 8.02(d, J = 7.9 Hz, 1H), 8.39 (s, 1H), 9.23 (d, -254- 200911240 J = 7.2 Hz, 1H). Example 1 9 8 5-Amino-1-(benzothiophen-2-yl)-4·cyano-3-[3-(morpholin-4-yl)methylphenyl]amino-1H-pyridyl Azole (Compound 198) To a solution of 2-bromobenzothiophene (〇.43 g, 2.0 mmol) in toluene (10 mL) was added tris-potassium phosphate (1. lg, 5.4 mmol), trans-N, N. Cyclohexyl-1,2-diamine (0.085 mL, 0-54 mmol), copper (I) iodide (19 g, 0.10 mmol), and the 5-amino group obtained in Step 1 of Example 180 4-Cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1H-pyrazole (0.40 g, 1.3 mmol). To the reaction mixture, 28% aqueous ammonia was added, and the mixture was extracted with ethyl acetate, and the obtained organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform-chloroform/methanol = 90/10), methanol was added, and the precipitated solid was filtered to give compound 1 9 8 (0.2 4 g, 41%) . ESIMS m/z: 43 1 (M + H) + ; ]H NMR (27 nMHz, DMSO-d6) 5:2.32-2.4 1 (m, 4H), 3.42 (s, 2H), 3.54-3.62 (m, 4H) ), 6.81(d, J-6.9Hz, 1H), 7.12-7.24(m, 3H), 7.31-7.43(m, 2H), 7.48-7.62(m, 3H), 7.77(d, J = 7.9Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H), 8.84 (s, 1H). Example 1 9 9 5-Amino-4-cyano-1-(4-methoxybenzothiazol-2-yl)-3-[3-(morpholin-4-ylmethyl)phenyl]amine Base-1H-pyrazole (Compound 199) -255- 200911240 According to Step 3 of Example 4, '5-Amino-4-cyano-3' [3 - obtained in Step 1 of Example 180] (morpholine-4-ylmethyl)phenyl]amino-1Η-Π 哩 (0_73g, 2.45mm〇l), 2-di-4-pyridinium oxime (〇.66g, 2.7mmol And N,N-dimethylformamide (1 〇m L) ' gave compound 1 99 (0.48 g, 43%). ESIMS m/z: 462 (M + H) + ; 'H NMR (270MHz, DMSO-d6) 8 2.40 (t, J = 4.3 Hz, 4H), 3.46 (s, 2H), 3.61 (t, J = 4.3 Hz, 4H), 3.97(s, 3H), 6.88(d, J = 6.9Hz, 1H), 7.11(d, J = 8.2Hz, 1H), 7.24(t, J = 7.7Hz, 1H), 7.35( t, J = 8.1 Hz, 1H), 7.59-7.64 (m, 3H), 8.26 (s, 2H), 9_ 1 5 (s, 1 H). Example 200 5-Amino-1-(benzofuran-2-yl)-4-chloro-3-(3-(morphin-4-yl)methylphenyl]amino-1H-pyridyl Azole (Compound 2〇〇) According to Example 198, from 2-bromo-1-benzofuran (0.15 g, 0.76 mmol), tri-potassium phosphate (〇.43 g, 2.0 mmol), trans-Ν, Ν' - Methylcyclohexane-1,2-diamine (32 mL, 0.20 mmol), copper (I) iodide (0.019 g, 0.1 mmol), 5-amine obtained in Step 1 of Example 180 4--4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1 hydrazine-pyrazole (0.15 g, 0.50 mmol), and toluene (3.8 mL) 200 (0.096g, 46%) ° ESIMS m/z: 41 5(M + H) + ; 1H NMR (3 00MHz, CDC13) δ: 2.40-2.56 (m, 4H), 3.52 (s, 2H), 3.68 -3, 79(m, 4H), 5.44(s, 2H), 6.18(s, 1H), 6.69(s, 1H), 6.97(d, J = 7.3Hz, -256- 200911240 1H), 7.23-7.3 5(m, 3H), 7.41-7.54(m, 3H), 7.59(m, lH) 〇 Example 201 (S)-5-Amino-1-(benzothiazol-2-yl)-4-cyanide 3-[3-(3-Hydroxypyrrolidin-1-yl)phenyl]amino-1H-pyrazole (Compound 201) (Step 1) According to Step 1 of Example 151, 3-fluoronitro Benzene (0.1 mL, 〇.94 mmol), carbon Acid bismuth (〇.65g, 4.7mmol), (S)-(-)-3-妣 酉 酉 (酉.23mL, 2.8mmol), and N-methylpyrrolidone (3.0mL) 'obtained (S) 1-(3-Nitrophenyl)pyrrolidin-3-ol (0.19 g, 94%). ESIMS m/z: 209 (M + H)+. (Step 2) According to Step 2 of Example 151, (S)-1-(3-nitrophenyl)pyrrolidin-3-ol (0-19 g, 0-89 mmol) obtained in Step 1, 10% palladium-carbon (0.02 1 g, 10 w/w%), hydrogen, and ethanol (3.7 mL) gave (S)-l-(3-aminophenyl)pyrrolidin-3-ol (0.12 g, 75%). ESIMS m/z: 1 79 (M + H)+. (Step 3) According to Step 3 of Example 1 5 1 , (s)-1-(3-nitrophenyl)pyrrolidin-3-ol (0-12 g, 0.66 mmol) obtained in Step 2, [double (Methylthio)methylene]propane dinitrile (〇_12g, 〇_73mmol), hydrazine monohydrate (0.048mL, 0.98mmol), and ethanol (2_4mL), giving (S)-5-amino group - -257- 200911240 4-Cyano-3-[3-(3-hydroxypyrrolidin-1-yl)phenyl]amino-1H-pyrazole (〇.18g, 94%) ° ESIMS m/z: 285 (M + H)+. (Step 4) According to the step 4 of Example 1 5 1 , the (S)- 5-amino-4-amino-3-[3·(3- via 啦 Π疋-1-) obtained in the step 3 Phenyl]amino-1H-indole ratio π (0.18g, 〇.62mmol), 2-chlorobenzothiazole (0.092mL, 0.74mmol), potassium carbonate (0.34g, 2.5mmol), and N, N-dimethylformamide (4.4 mL) gave Compound 2 ( Η (0 · 1 7 g, 6 6 %). ESIMS m/z: 418 (M + H) + ; 'H NMR (270 MHz, DMSO -d6)5 : 1.84-2.1 6(m, 2H), 3.06-3.24(m, 2H), 3.2 5 - 3.5 3 (m, 2H), 4.44(s, 1H), 4.96(d, J = 3.6 Hz, 1H), 6.12 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1 H), 7 · 0 0 - 7.1 1 (m, 2 H), 7 · 3 8 ( t, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 8.08 (d, J = 7.6 Hz, 1H), 8.26 (s, 2H), 8.90 (d, J = 8.6HZ, 1H). Example 202 5-Amino-1-(benzo-phen-2-yl)-4-cyano-3-(3-methoxybenzene Amino-1 hydrazine-pyrazole (Compound 2 0 2 ) According to Example 198, from 2-bromobenzothiophene (〇.21g, 0.98 mmol), tripotassium phosphate (〇.56§, 2.6mmo1), trans-N,N'-dimethylcyclohexanin_1,2_diamine (0.041L,0 .26 mmol), copper (I) iodide (〇.〇25g, 0.13mmol), 5-amino-4-cyano-258-200911240 3-(3-A obtained in step 2 of Example 8. Oxyphenyl)amino-1H-pyrazole (0.15 g, 〇. 65 mmol), and toluene (3.8 m) afforded compound 2 2 2 (0.0 5 8 g, 25 %). z: 3 62(M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 : 3.75 (s, 3H), 6.45 (m, 1H), 7.09-7.25 (m, 4H), 7.29- 7.45 (m) , 3H), 7.52 (s, 1H), 7.77 (d, J = 6.9 Hz, 1H), 7.95 (d, J-7.6 Hz, 1 H), 8.86 (s, 1 H). Example 203 5-Amino-1-(benzo[b]thiophen-2-yl)-4-cyano-3-[3-(morpholin-4-yl)phenyl]amino-1H-pyridyl Azole (Compound 203) According to Example 198, from 2-bromobenzothiophene (〇.39g, 1.9mmol), tribasic potassium (1.Og, 4-9mmol), trans-N,N'-dimethylcyclohexane -1 -Diamine (0.078 mL, 0.49 mmol), copper (I) iodide (〇.〇 47 g, 0.25 mmol), 5-amino-4-cyanide obtained in Step 4 of Example 15. 3-[3-(morpholin-4-yl)phenyl]amino-1Η-pyrazole (0.35 g, 1.2 mmol), and toluene (8.8 m L) afforded compound 2 0 3 (0 · 0 6 2 g, 1 2 %). ESIMS m/z: 418 (M + H) VH NMR (270 MHz, DMSO-ά6) δ: 3.08-3. 1 7 (m, 4H), 3.7 2 - 3 . 8 0 (m, 4H), 6.49 (m , 1H), 7.09(d, J = 5.0Hz, 2H), 7.19(s, 2H), 7.29-7.45(m, 3H), 7.51.(s, 1H), 7.74(d, J = 7.3Hz, 1H ), 7.95 (d, J = 7.3 Hz, 1H), 8.72 (s, 1 H). Example 204 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-{[methyl(tetrahydro-2H-pyridin-259- 2009-11240)-4-yl Amino]methyl}phenyl)amino-1H-pyrazole (Compound 204) (Step 1) in 3-Nitrobenzamide (〇.5〇g, 3.3mmol) of tetrahydrofuran (l 〇mL) solution was charged with N-methyltetrahydro-2-indole-pyran-4-amine hydrochloride (〇. 60 g, 4.0 mmol) and triethylamine (0. 〇 46 mL, 0.33 mmol). Stir at room temperature for 1.5 hours. Next, sodium triethyloxyborohydride (0.84 g, 4.0 mmol) was added and the mixture was further stirred for 2.5 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated, and the obtained organic layer was concentrated under reduced pressure. The residue was purified by ruthenium dioxide colloid chromatography (hexane/ethyl acetate = 8 0/20-20/80) to obtain N.methyl-N-(3-nitrobenzyl)tetrahydro-2. Η-pyran 4-amine (〇_ 4 3 g, 52%). ESIMS m/z: 25 1 (M + H) + ° (Step 2) According to Step 2 of Example 1 5 1 , n-methyl-N-(3-nitrobenzyl) obtained in Step 1 Tetrahydro-2H-pyran-4-amine (〇.43g, 1.7mmol), 1 Ο % - carbon (〇_ 〇6 4 g, 15 w / w %), hydrogen 'and ethanol (8,5 m L ) gave N-(3-aminobenzyl)-N-methyltetrahydro-2N-pyran-4-amine (0.030 g, 8%). ESIMS m/z: 22 1 (M + H)+. (Step 3) According to Step 3 of Example 1 5, N-(3-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine obtained in Step 2 ((K030g) , 0.14 mmol), [bis(methylthio)methylene]malononitrile (〇.026g, 〇·15 mm〇i), -260- 200911240 hydrazine monohydrate (O.OlOmL, 0.20 mmol), And ethanol (〇_60 mL) to give 5-amino-4-cyano-3-(3-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl) Amino-1 Η-pyrazole (Ο · 0 1 7 g, 3 8 %) ESIMS m/z: 3 27 (M + H) + (Step 4) According to step 4 of Example 1 5 1 5-Amino-4-cyano-3_(3-{[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)amino-1H obtained in Step 3 -pyrazole (〇.〇〇8mg, 0.02 5mmol), 2-chlorobenzothiazole (0.003 6mL, 0.029mmol), potassium carbonate (〇.〇14g, 0_098mmol), and N,N-dimethylformamidine Amine (0.40 mL), mp mp (m. 1.77 (m, 2H), 2.00 (m, 1H), 2.15 (s, 3H), 3.37 (m, 2H), 3.55 (s, 2H), 3.92 (m, 2H), 6.86 (d, J = 6.6 Hz , 1H), 7.22(t, J = 7.9Hz, lH), 7.39(t, J = 7.0Hz, lH), 7.49- 7.58(m, 2H), 7.70(s, 1H), 7.90(d, J = 7.9 Hz, 1H), 8.06 (d, J-7.0 Hz, 1 H), 8 _27 (s, 2H), 9. 1 0 (s, 1 H). Example 205 5-Amino-1-(Benzene) Thiazol-2-yl)-4-cyano-3- [3·(tetrahydro-2H-pyran-4-ylamino)phenyl]amino-1 Η-pyrazole (Compound 2 0 5 ) ( Step 1) Adding tetrahydro-4H-pyran-4-one to a solution of tert-butyl 3-aminophenylamine formate (〇.30 gl. 4 mmol) in tetra-261 - 200911240 hydrogen furan (6.0 mL) (0.16 mL, 1.7 mm 〇l) and acetic acid (0.13 mL, 2.3 mmol). Next, sodium triethoxy hydride hydride (0.37 g, 711.711111101) was added and stirred at room temperature for 1.5 hours to further reflux for 7.0 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate was evaporated. The third butyl 3-(tetrahydro-2H-pyran-4-ylamino group) was obtained by purifying the residue with ruthenium dioxide colloidal chromatography (hexane/ethyl acetate = 80/20-20/80). Phenylcarbamate (〇.28g, 6 7%) ° ESIMS m/z: 293(M + H)+. (Step 2) The dibutyl 3-(tetrahydro-2H-pyran-4-ylamino)phenylamine formate (0.28 g, 0.9 6111111〇1) obtained in the step 1 Methane (5.61111 〇 solution was added to trifluoroacetic acid (1.4 mL, 5.0 v/w), and the mixture was stirred at room temperature for 7.0 hours. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. Concentration. The residue was purified by silica gel chromatography (chloroform-chloroform/methanol = 90/10) to give 1-amino-3-(tetrahydro-2H-pyran-4-yl)aminobenzene. (0.12 g, 65%) ESIMS m/z: 193 (M + H) + (Step 3) According to Step 3 of Example 1 51, from the 1-amino 3-(() obtained in Step 2 Tetrahydro-2H-indolepy-4-yl)aminobenzene (0-12 g, 0-62 mmol), [bis-262-200911240 (methylthio)methylene]malononitrile (〇.12g, 〇.68mmol), Diamine monohydrate (0.045 mL, 0.93 mmol), and ethanol (2.4 mL) afforded 5-amino-4-cyano-3-[3-(tetrahydro-2H-pyran-4-ylamino) Phenyl]amino-1 H-pyrazole (0.17 g, 90%) ° ESIMS m/z: 299 (M + H) + (Step 4) According to step 4 of Example 1 5 1 In step 3 5-Amino-4-cyano-3-[3-(tetrahydro-2H-pyran-4-ylamino)phenyl]amino-1H-pyrazole (0.17 g, 0-56 mmol), 2 -Chlorobenzothiazole (0.083 mL, 0.67 mmol), potassium carbonate (0.31 g, 2.2 mmol), and N,N-dimethylformamide (4-2 mL) afforded Compound 205 (0.1 lg, 45%). m/z: 43 3 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 = 1.42 (m, 2H), 1.96 (d, J = 10.9 Hz, 2H), 3.3 7-3.54 (m, 3H), 3.91 (d, J = 11.5 Hz, 2H), 5.45 (d, J = 7.9 Hz, 1H), 6.23 (d, J = 7.6 Hz, 1H), 6.82-7.01 (m, 3H), 7.39 ( t, J = 7.6Hz, 7H), 7.52(t, J = 7.6Hz, 1H), 7_90(d, J = 7.9Hz, 1H), 8.06(d, J = 8,2Hz, 1H), 8_26(s , 2H), 8.78(s, 1H). Example 206 5-Amino-1-(benzoisothiazol-3-yl)-4-cyano-3-[3-(morpholin-4-yl)methyl)phenyl]amino-1 oxime -Pyrazole (Compound 2 0 6) 5-Amino-4-cyano-3-[3-(morpholine) obtained in Step 1 of Example 180 according to Step 2 of Example 1 80 -4-ylmethyl)phenyl]amino--263- 200911240 1H-pyrazole (0.20 g, 0.67 mmol), tripotassium phosphate (〇_57g, 2_68mmol), N,N'-dimethylethylene Amine (〇.16 mL, 1.47 mmol), iodine: copper (1) (0.14 g, 0.74 mmol), 3-bromobenzoisothiazepine (0.16 g, 〇.74 mmol) and toluene (2 m L) Compound 2 0 6 (0 · 0 2 5 g, 9 %). ESIMS m/z: 43 2 (M + H) + ; 'Η NMR (2 7 0 Μ H z, DMSO - d 6) δ 2.37 (t, J = 4.4 Hz, 4H), 3.46 (s, 2H), 3.53 (t, J = 4.4 Hz, 4H), 6.88 (d, J = 7.6 Hz, 1H), 7 _ 2 5 (t, J 7.6 H z , 1 H), 7.48 (d, J = 7.6 Hz, 1H), 7.57(t, J = 7.6Hz, 1H), 7.69-7.75(m, 2H), 7.99(s, 2H), 8.28(d, J = 7.6Hz, 1H), 8.94(s, 1H), 9.03 (d, J = 8.6 Hz, 1H). Example 2 0 7 5 -Amino-4-cyano-1-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-pyridin-2-yl)-3 [3-(morpholine-4-ylmethyl)phenyl]amino-1 hydrazine-pyrazole (Compound 207) was obtained according to Step 2 of Example 1 80, obtained from Step 4 of Example 15. 5-amino-4-cyano-3 -[ 3 -(morpholin-4-ylmethyl)phenyl]amino-1Η-pyrazole (0.20 g, 0.71 mmol), tripotassium phosphate (〇_61g) , 2.9 mmol), hydrazine, hydrazine-dimethyl dimethyldiamine (0.17 mL, 1.6 mmol), copper (I) iodide (〇_15g, 0.79111111〇1), 2-bromo-5-methyl-4 ,5,6,7-Tetrahydrothiazolo[5,4-(:]pyridine (0.18, 0.79 mmol) and toluene (2 mL) afforded Compound 207 (0.025 g, 8%) ESIMS m/z: 43 7 (M + H) + ; 'H NMR (2 70MHz, DMSO-d6) 5 2.38 (s, 3H), 2.68-2.75 (m, 4H), 3.11 (t, J = 4.5Hz, 4H), -264- 200911240 3.56(s, 2H), 3.76(t, J = 4.5Hz, 4H), 6.52(m, 1H), 7.05- 7.13(m, 2H), 7.38Cs, 1H), 7.96(s, 2H),8.88 (s, 1H" Example 208 3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]amino-N-methylbenzene Formamide (Compound 208) (Step 1) According to Example 92 Step 1, from [bis(methylthio)methylene]malononitrile (l.lg, 6.7 mmol), 3-amino-N-methylbenzamide (1. g, 9.3 mmol), Hydrazine monohydrate (〇.65mL, 13mmol) and ethanol (2〇mL) ' to give 3-(5-amino-4-cyano-1 Η-pyrazol-3-yl)amino-N- Benzobenzamide (0 · 15 g, 9%).

ESIMS m/z: 2 5 7(1^1 + 11)+/11 NMR (270MHz, DMSO-d6)S 2. 75(d, J = 4. 4Hz, 3H), 6. 30(s, 2H), 7. 15-7. 26(m, 2H), 7. 55 (d, J = 7. 6Hz, 1H), 7. 93(s, 1H), 8. 24(d, J = 4. 4Hz, 1H), 8. 52(s, 1H), 1 1. 21(s, 1H). (Step 2) According to Step 3 of Example 4, 3-( 5-amino-4-cyano-1H-pyrazol-3-yl)amino-N-methylbenzate obtained in Step 1. Guanamine (〇. 12g, 〇. 45 mmol), 2-chlorobenzothiazepine (0_07 mL, 0-54 mmol), potassium carbonate (0. 25g, 1. 8 mmol) and N,N-dimethylformamide (10 mL) to give compound 208 (0. 07g, 40%). ESIMS m/z: 3 90 (M + H) VH NMR (270 MHz, DMSO-d6) 5 -265- 200911240 2. 80 (d, J = 4. 3Hz, 3H), 7. 3 6-7. 42(m, 3H), 7. 52(td, J = 7. 7, 1 · 1 Hz, 1 H), 7. 8 5 -7. 95 (m, 3H), 8 _ 1 0 ( d, J = 6 · 9 H z, 2 H), 8. 34(d, J = 9. 5Hz, 2H), 9. 32 (s, 1H). Example 209 3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1H-pyrazol-3-yl]amino-N,N-dimethylbenzhydrazide Amine (Compound 209) (Step 1) According to Step 1 of Example 92, from [bis(methylthio)methylene]malononitrile (1. 9g, 11 mmol), 3-amino-N,N-dimethylbenzamide (1. 9g, 11 mmol), hydrazine monohydrate (l. LmL, 23 mmol) and ethanol (20 mL) give 3-(5-amino-4-cyano-1 Η-pyrazol-3-ylamino)-N,N-dimethylbenzamide ( 1. 1 g, 3 5%). !H NMR (270MHz, DMSO-d6) 5 2. 90(s, 3H), 2. 96(s, 3H), 6. 32(s, 2H), 6. 75 (d, J = 7. 6Hz, 1H), 7. 22(t, J = 7. 6Hz, 1H), 7. 46 (m, 1H), 7. 58(s, 1H), 8. 53(s,1H), 11. 18(s, 1H). (Step 2) According to Step 3 of Example 4, 3-( 5-amino-4-cyano-1H-pyrazol-3-yl)amino-N,N-dimethyl obtained in Step 1. Benzobenzamide (〇. 41g, 1 _5mmol), 2-chlorobenzothiazole (0. 24mL, 1. 8mm〇l), potassium carbonate (0. 83g, 6. 0 mmol) and N,N-dimethylformamide (10 mL) were obtained as compound 2 (0-40 g, 65%). ESIMS m/z: 404 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 -266- 200911240 3. 00(s, 6H), 6. 93(d, J = 7. 6Hz, 1 H), 7. 3 1 - 7 3 7 (m, 4 H), 7. 48(t, J = 7. 7Hz, 1H), 7. 71(m, 1H), 7. 76(m, 1H), 7. 85 (dd, J = 7. 6,3. 1Hz, 1H), 8. 05(m,ih), 8. 99(s, 1H). Example 2 1 0 5 -amino-1-(benzothiazol-2-yl)-4-yl-cyano- 3_[3-(morpholine-4-carbonyl)phenyl]amino-1 hydrazine-pyrazole ( Compound 2 1 〇) (Step 1) According to Step 1 of Example 92, from [bis(methylthio)methylene]malononitrile (1. 7g, lOmmol), (3-aminobenzimidyl)morpholine (2. 1g, 10 mmol), hydrazine monohydrate (〇. 98 mL, 20 mmol) and ethanol (20 mL) gave 5-amino-4-cyano-3-[3-(morpholin-4-carbonyl)phenyl]amino-1 hydrazine-pyrazole (0. 4 5 g, 1 4 % ). ESIMS m/z: 313 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 6 3. 35(s, 4H), 3. 59(s, 4H), 6. 33(s, 2H), 6. 78(d, J = 7. 2Hz, 1H), 7. 24(t, J = 7. 9Hz, 1 H), 7. 48 (m, 1 H), 7. 60(s, 1H), 8. 56(s, 1 H), 1 1 . 2 1 (s, 1 H). (Step 2) According to Step 3 of Example 4, 5-amino-4-cyano-3-[3-(morpholine-4-carbonyl)phenyl]amino-1H- obtained in Step 1. Pyrazole (0. 41g, 1. 5 mmol), 2-chlorobenzothiazole (〇. 24mL, 1. 8mmol), potassium carbonate (0. 83g, 6. 0 mmol) and N,N-dimethylformamide (10 m L) gave compound 210 (0. 40g, 6 5%) ° -267- 200911240 ESIMS m/z: 446(M + H) + ;1H NMR (2 70MHz, DMSO-d6)5 3. 40 (m, 4H), 3. 63, (m, 4H), 6. 96(d, J = 7. 6Hz, 1H), 7. 34-7. 40 (m, 4H), 7. 50(t, J = 7. 6Hz, 1H), 7. 73 (d, J=1. 3Hz, 1H), 7. 78(d, J = 7. 9Hz, 1 H), 7 · 8 8 ( d, J = 7. 9 H z, 1 H), 8. 07(d, J = 7. 9Hz, 1H), 8. 69 (s, 1H). Example 2 1 1 5-Amino-cyano-3-3-(morpholin-4-ylmethyl)phenylamino-1-thiazol-2-yl)-1H-pyrazole (Compound 21 1) According to Example 198, from 2-bromothiazole (45 μί, 0. 50 mmol), tripotassium phosphate (0. 28g, 1. 3 mmol), trans-Ν, Ν1-dimethylcyclohexane-1,2-diamine (0. 021mL, 0. 13mmol), copper iodide (1) (0. 013g, 0. 067 mmol), 5-amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1H-pyrazole obtained in Step 1 of Example 181 (0 . 10 g, 0-34 mmol), and toluene (2 · 5 m L) gave compound 2 1 1 (0 · 0 4 0 g, 31%). ESIMS m/z: 3 82 (M + H) + ; 1H NMR (2 70 MHz, CDC13) δ: 2. 41-2. 56(m, 4H), 3. 52(s, 2H), 3. 6 8 -3. 79(m, 4H), 6. 22(s, 1H), 6. 66(s, 2H), 6. 98 (d, J = 7. 6Hz, 1H), 7. 05(d, J = 3. 6 Hz, 1 H), 7_ 1 9-7_54 (m, 4H). Example 2 1 2 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(4-carbamimidylpiperazin-1-yl)phenyl]amino group -1H-pyrazole (Compound 212) (Step 1) -268- 200911240 According to Step 1 of Example 151, from 3-fluoronitrobenzene (o. l OmL, 0_94mmol), potassium carbonate (〇. 65g, 4. 7mmol), N-methylmercaptopiperazine (〇. 13g, l. Lmmol), and N-methylpyrrolidone (3. 0 mL) to give 4-(3-nitrophenyl)piperazine-1-carbaldehyde (0. 05 lg, 23%). ESIMS m/z: 23 6 (M + H)+. (Step 2) According to Step 2 of Example 1 51, 4-(3-nitrophenyl)piperazine-1-carbaldehyde obtained in Step 1 (〇. 〇51§, 0_22111111〇1), 10% palladium-carbon (0_0077g, 1 5w/w%), hydrogen, and ethanol (1. OmL), quantitatively obtained 4-(3-aminophenyl)piperazine-1-carbaldehyde (0. 045 g). ESIMS m/z: 206 (M + H)+. (Step 3) 4 - (3-Aminophenyl)piperazine-1-carbaldehyde obtained in Step 2 according to Step 3 of Example 1 51 (47 mg, 0. 23mmol), [bis(methylthio)methylene]malononitrile (0_043g, 0. 25mmol), hydrazine monohydrate (0. 017mL, 0_34mmol), and ethanol (〇. 94 mL) gave 5-amino-4-cyano-3(3-(4-carbamimidazine-indolyl)phenyl]amino-1H-pyrazole (0-031 g, 43%). ESIMS m/z: 3 1 2 (M + H) 1. (Step 4) 5-Amino-4-cyano-3-[3-(4-carbamimidazine-1-yl)benzene obtained in Step 3 according to Step 4 of Example 1 51 Amino-1H-pyrazole-269- 200911240 (0. 03 lg, O. lOmmol), 2-chlorobenzothiazole (0_015mL, 0. 1 2 mmol), carbonic acid #P (〇_〇55g, 0. 40 mmol), and N,N-dimethylformamide (1_6 mL) gave compound 212 (0. 17g, 66%). ESIMS m/z: 445 (M + H) + ; 1H NMR (3 00 MHz, 2 DMSO-d6) 5 : 3 · 1 1-3 · 2 4 (m , 4 H), 3 · 3 2 ( s, 2H ) , 3 · 4 5 - 3 · 5 4 (m , 4H ), 6. 08(d, J = 7. 3Hz, 1H), 6. 19(d, J = 7. 0Hz, 1H), 6. 20(s, 1H), 6. 88(t, J = 8.  1 Hz, 1 H), 7. 3 8(t, J = 6. 0Hz, 1 H), 7. 5 1 (t, J = 6. 0Hz, 1 H), 7. 89 (d, J = 7. 7Hz, 1H), 8. 22(s, 2H), 8. 77(s, 1 H). Example 2 1 3 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(tetrahydro-2H-thiopyran-4-ylamino)phenyl Amino-1 Η-pyrazole (Compound 213) (Step 1) According to Step 1 of Example 205, from butyl 3-aminophenylamine carboxate (0-22 g, l. Lmmol), 4-oxophene (4-oxothiane) (0. 15mL, 1. 3mmol), acetic acid (0. 096mL, l_7mmol), sodium triethyloxyborohydride (0. 27g, l_3mmol), and tetrahydrofuran (4. 4 mL) to give the third butyl 3-(tetrahydro-2H-thiopyran-4-ylamino)phenylamine formate (0. 2 1 g, 6 5 %). ESIMS m/z: 3 09 (M + H)+. (Step 2) According to Step 2 of Example 2 0, the third-270-200911240 butyl 3-(tetrahydro-2H-thiopyran-4-ylamino)phenylamine obtained in Step 1 Formate (〇_21g, 〇. 68mmol), trifluoroacetic acid (l. lmL, 5_0v/w), and dichlorocarbyl (4. 2 mL) to give 1-amino-3-(tetrahydro-2H-thiopyran-4-yl)aminobenzene (0. 1 1 g, 8 0 %). ESIMS m/z: 209 (M + H)+. (Step 3) According to Step 3 of Example 2, 5, 1-amino-3-(tetrahydro-2H-thiopyran-4-yl)aminobenzene (O.) obtained in Step 2. Llg, 0_54mmol), [bis(methylthio)methylene]malononitrile (0. 10g, 60mmol), hydrazine monohydrate (0. 039mL, 0. 81mmol), and ethanol (2. 3 mL), quantitatively obtained 5-amino-4-cyano-3-[3-(tetrahydro-2H-thiopyran-4-ylamino)phenyl]amino] 1 Η-pyrazole (0 .  1 7 g). ESIMS m/z: 315 (M + H)+. (Step 4) 5-Amino-4-cyano-3-[3-(tetrahydro-2H-thiopyran-4-ylamine) obtained in Step 3 according to Step 4 of Example 1 51 Phenyl]amino-indole-pyrazole (0. 17g, 0. 55mmol), 2-chlorobenzothiazole (4. 481mL, 0. 66 mmol), potassium carbonate (0. 30g, 2. 2mmol), and N,N-dimethylformamide (4. 3mL), compound 2 1 3 (0. 1 6g, 65%). ESIMS ra/z: 449 (M + H) +; *H NMR (270 MHz, DMSO-d6) 8 :1. 54(m, 2H), 2. 24(m, 2H), 2. 66-2. 77(m, 5H), 5. 46(d, J = 8. 3Hz, 1H), 6. 22 (d, J = 7. 9Hz, 1H), 6. 82-7. 04(m, 3H), -271 - 200911240 7. 38(t, J = 8.  1 Hz, 1H), 7. 52(t, J = 8. 1Hz, 1H), 7. 90 (d, J = 7. 6Hz, 1H), 8. 05(d, J = 7. 3Hz, 1H), 8. 25(s, 2H), 8. 77(s, 1 H). Example 2 1 4 5 -Amino-4-cyano-1-(5-methylthien-2-yl)-3-[3-(morpholin-4-ylmethyl)phenyl]amino- 1 Η-pyrazole (Compound 2 1 4) According to Example 198, from 2-bromo-5-methylthiophene (0. 089g, 0. 50 mmol), tripotassium phosphate (〇. 28g, 1. 3mmol), trans-Ν, Ν'-dimethylcyclohexan-1,2-diamine (〇. 〇21mL, 0. 13mmol), copper iodide (I) (〇. 〇13g, 0. 0 6 7 mmol), 5-amino-4-cyano-3-[3-(morpholin-4-ylmethyl)phenyl]amino-1H- obtained in Step 1 of Example 1 8 1 Pyrazole (0. 10g, 0. 34 mmol), and toluene (2. 5 mL) to give compound 214 (0. 031g, 23%). ESIMS m/z: 395 (M + N) VH NMR (270MHz, CDC13) δ: 2. 40-2. 5 0 (m, 4H), 2. 50(s, 3H), 3. 48(s, 2H), 3. 67-3. 76(m, 4H), 4_64(s, 2H), 6. 09(s, 1H), 6. 67(m, 1H), 6. 87(d, J = 4. 0Hz, 1 H), 6. 91 (d, J = 7. 9Hz, 1H), 7. 22(m, 1H), 7. 36(s, 1H), 7. 45 (d, J = 8. 6Hz, 1H). Example 2 1 5 3-[5-Amino-1-(benzothiazol-2-yl)-4-cyano-1 H-pyrazol-3-yl]amino-indole-(2-hydroxyethyl) ))-Ν-methylbenzamide (Compound 215) (Step 1) According to Step 1 of Example 92, from [bis(methylthio)methylene]propane-272- 200911240 nitrile (0. 64g, 3. 8 mmol), 3-amino-N-(2-hydroxyethyl)-N-methylbenzimidamide (0. 73g, 3_8mmol), hydrazine monohydrate (0. 36mL, 7. 5mmol) and ethanol (15mL) give 3-(5-amino-4-cyano-1H-pyrazol-3-yl)amino-N-(2-hydroxyethyl)-N-methylbenzate Guanamine (0. 30g, 26%). ESIMS m/z: 301 (m + H) + ; 1H NMR (270 MHz, DMSD-d6) 5 2. 96(s, 3H), 3. 25-3. 3 3 m, 2H), 3. 44-3. 5 9 (m, 2H), 4. 74(t, J=1, 5Hz, 1H), 6. 31(s, 2H), 6. 75 (d, J = 7. 3Hz, 1H), 7. 20(t, J = 7. 3Hz)lH), 7. 45 (m, 1 H), 7. 56(s, 1 H), 8. 5 1 (s, 1 H), 1 1 · 1 7 (s, 1 H). (Step 2) According to Step 3 of Example 4, 3-(5-amino-4-cyano-1H-pyrazol-3-yl)amino-N-(2-hydroxyl) obtained in Step 1. Ethyl)-N-methylbenzamide (0. 29g, 0. 95 mmol), 2-chlorobenzothiazole (0-15 mL, 1_1 mmol), potassium carbonate (0-53 g, 3. 8 mmol) and hydrazine, hydrazine-dimethylformamide (10 mL) gave compound 215 (0. 23g, 54%). ESIMS m/z: 43 4 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 3,02 (s, 3H), 3. 22-3. 66(m, 5H), 6. 91 (d, J = 7. 3 H z , 1H), 7. 30-7.  3 5 (m, 4H), 7_47 (t, J = 7. 6Hz, 1 H), 7. 63m, 1H), 7 · 7 6 (m , 1H), 7. 83(d, J = 7. 9Hz, 1H), 8. 02(d, J = 7, 6Hz, 1H), 8. 97(s, 1 H). Example 2 1 6 5 ·Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(lH-pyrazol-1-yl)benzene-273- 200911240 base]amine Base-1H-pyrazole (Compound 216) (Step 1) Dissolve 3-indolylamine (2_0 mL, 17 mmol) in toluene (15 mL) and dilute potassium carbonate (4. 0g, 29mmol), torn copper (I) (0. 13g, 0. 69mmol), pyrazole (0. 94g, 14mmol) and N,N'-dimethylethylenediamine (〇. 35mL, 3. 3 mmol), stirred at 10 ° for 10 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol=95/5) to give 3-(1?-pyrazol-1-yl)aniline (? . 65g, 29%). ESIMS m/z: Ιόί^Μ + Η^^Η NMR (270MHz, DMSO-d6)S 5. 34(s, 2H), 6. 48(m, 2H), 6. 89 (dd, J = 7. 7, 2. 1Hz, 1H), 7. 04-7. 12 (m, 2H), 7. 60 (s, 1H), 8. 29(d, J = 2. 6Hz, 1H). (Step 2) According to Step 1 of Example 92, the 3-(1H-pyrazol-1-yl)aniline obtained in Step 1 (0. 65g, 4. 1mm〇l), [bis(methylthio)methylene]malononitrile (〇. 55g, 3_3mmol), hydrazine monohydrate (0. 32mL, 6. 5 mmol) and ethanol (10 mL) give 5-amino-4-cyano-3-(3-(1Η-pyrazol-1-yl)phenyl]amino-1H-pyrazole (0-33 g, 3 1% ). ESIMS m/z: 266 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 6. 31(s, 2H), 6. 51(m, 1H), 7. 17(m, 1H), 7. 27(t, J = 7. 9Hz, 1H), 7. 34(d, J = 8. 2Hz, 1H), 7. 71 (d, J=1. 6Hz, 1H), 8. 07(s, 1H), 8. 32(d, J = 2. 6Hz, 1H), 8. 63(s, 1H), 11. 27(s, 1H). (Step 3) -274- 200911240 According to Step 3 of Example 4, 5-amino-4-cyano-3 -[3 -(1 Η-pyrazol-1-yl)benzene obtained in Step 2 Amino-1 Η-pyrazole (0 _ 3 3 g,1 .  2 mmol), 2-chlorobenzothiazole (1. 5mL, 〇. 19mmol), potassium carbonate (0. 69g, 5. 0 mmol) and N,N-dimethylformamide (1 〇 m L) ' to give compound 2 1 6 (0. 26g, 5 1%) ° ESIMS m/z: 3 99 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 6. 57(m, 1H), 7. 3 7-7. 44(m, 3H), 7. 52(td, J = 7. 6, 1. 1Hz, 1H), 7. 66(dt, J = 7. 1,1. 9Hz, 1H), 7. 77(d, J=1. 6Hz, 1H), 7. 92(t, J = 7. 9Hz, 1H), 8. 10(d, J = 7. 9Hz, 1H), 8. 22 (m, 1H), 8. 33(s, 2H), 8. 39(d, J = 2. 6Hz, 1H), 9. 41 (s, 1H). Example 2 1 7 5 -Amino-1-(benzothiazolyl-2-yl)_4-cyano-3-[3-(4-phenylpiperidinyl-phenylphenylamino-1H-pyrazole) (Compound 2 17) (Step 1) According to Step 151 of Example 151 from 3-fluoronitrobenzene (O. lOmL, 0. 94mmol), potassium carbonate (〇. 65g, 4. 7mmol), 4-phenylpiperidine (0. 45 g, 2_8 mmol), and N-methylpyrrolidone (3-3 mL) gave 丨-(3.nitrophenyl)-4-phenylpiperidine (〇.  1 7 g, 6 5 %). ESIMS m/z: 283 (M + H)+. (Step 2) According to the step 2 of Example 1 5 1 ', 1 _(3 _ nitrophenyl)-4-phenylpiperidine obtained in the step 1 (〇. 17g, 〇. 61mmol), 10% palladium-carbon -275- 200911240 (0. 026g, 15w/w%), hydrogen, and ethanol (4. 3 mL)' gave 3-(4-phenylpiperidin-1 -yl)phenylamine (0 · 0 5 7 g, 37%). ESIMS m/z: 253 (M + H)+. (Step 3) According to Step 3 of Example 1 5 1 , 3-(4-phenylpiperidin-1-yl)aniline obtained in Step 2 (0. 057g, 0_23mmol), [bis(methylthio)methylene]malononitrile (0. 042g, 0_25mmol), hydrazine monohydrate (17pL, 0. 34 mmol), and ethanol (l. LmL), 5-amino-4-cyano-3-[3-(4-phenylpiperidin-1-yl)phenyl]amino-1 Η-pyrazole (0 _ 0 3 2 g, 40%). ESIMS m/z: 359 (M + H)+. (Step 4) 5-Amino-4-cyano-3 -[3-(4-phenylpiperidin-1-yl)phenyl group obtained in Step 3 according to Step 4 of Example 1 51 Amino-1 Η-pyrazole (0. 032g, 〇_〇89mmol), 2-chlorobenzothiazole (0. 013mL, 0. 11 mmol), potassium carbonate (〇. 〇49g,0. 36 mmol), and hydrazine, hydrazine-dimethylformamide (1 · 6 m L ) gave compound 2 1 7 (0 · 0 2 5 g, 5 7 %). ESIMS m/z: 493 (M + H) + ; 1H NMR (270 MHz, DMSO-d6) 6 : 1 . 73 - 1 , 99 (m, 4H), 2. 25 (m, 1H), 2. 66-2. 94(m, 4H), 6. 5 8 (m , 1 H), 7 0 6. 7 .  1 4 (m, 2 H), 7 · 2 1 (m , 1 H), 7 · 2 7 - 7 · 4 1 (m, 3H), 7. 46-7. 54(m, 2H), 7. 89(d, J = 8. 3Hz, 1H), 8. 06(d, J = 7. 3Hz, 1 H), 8. 26- 8. 3 2 (m, 2H), 8. 3 3 ( s , 2 H ), 8 · 9 5 ( s , 1H). -276- 200911240 Example 2 1 8 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(1-methoxyethyl)phenyl]amino group -1 Η-pyrazole (compound 2 1 8 ) (step 1) in 1-(3-nitrophenyl)ethanol (0. 10g, 0. 61 mmol) of tetrahydrofuran / hydrazine, hydrazine-dimethylformamide (5/1, 3. LmL) solution, sodium hydride (60%, 0_029 g, 〇_73 mmol) was added under ice-cooling, and stirred. 0 hours. Next, add methyl iodide in the cold state (0. 0 57m L, 0. 9 2m mol) ' further stirring 1.  0 hours. Water was added to the reaction mixture, and ethyl acetate was evaporated. The residue was purified by ruthenium dioxide colloidal chromatography (hexane/ethyl acetate = 95/5 - 60/40) to give 1-(p-methoxyethyl)-3-nitrobenzene (0. 082g, 74%). ESIMS m/z: 1 82 (M + H)+. (Step 2) According to Step 2 of Example 1 5 1 , 1-(b-methoxyethyl)-3-nitrobenzene (0-082 g, 0. 45 mmol), 10% palladium-carbon (0. 012g, 15w/w%), hydrogen, and ethanol (2. 1 mL) gave 3-(1-methoxyethyl)aniline (〇_〇 42 g, 61%). ESIMS m/z: 1 52 (M + H)+. (Step 3) -277- 200911240 According to the step 3 of Example 1 5 1 , the 3 - (1 · methoxyethyl) I obtained in step 2 (0. 042g, 0. 28 mmol), [bis(methylthio)methylene]malononitrile (0. 05 2g, 〇. 31mmoi), hydrazine monohydrate (〇 2〇mL, 〇 42 mmol) and ethanol (〇. 84 mL) gave 5-amino-4-cyano-3(-[3 _(j-methoxyethyl)phenyl]amino-1 hydrazine-pyrazole (〇.  〇 4 8 g , 6 7 %). ESIMS m/z: 25 8 (M + H)+. (Step 4) 5-Amino-4-cyano-3-[3-(1-methoxyethyl)phenyl]amino group obtained in Step 3 according to Step 4 of Example 1 51 -1H-pyrazole (〇. 〇48g, 0. 19 mmol), 2-chlorobenzothiazole (0_028 mL, 0. 22mmol), potassium carbonate (0. 10g, 0. 75 mmol), and N,N-dimethylformamide (2. 4 mL) gave compound 2 1 8 (0 · 0 0 8 m g, 1 1 %). ESIMS m/z: 391 (M + H) + ; 'H N M R (D M S Ο - d 6) δ : 1. 37 (d, J = 6. 3Hz, 3H), 2. 59(s, 1H), 3. 16(s, 3H), 6. 87 (d, J = 7. 3Hz, 1H), 7. 27(t, J = 7. 8Hz, 1H), 7. 38(t, J = 7. 8Hz, 1H), 7. 52(t, J = 7. 3 Hz, 1H), 7. 60 (d, J = 7. 6Hz, 1H), 7. 67(s, 1H), 7. 90 (d, J = 7. 6Hz, 1H), 8. 09(d, J = 7. 8Hz, 1H), 8. 30(s, 2H), 9. 16(s, 1H). Example 2 1 9 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-3-(2. 3-Dihydrospiro[茚-1 1,1-piperidine]-plant-yl)phenyl]amino-1 H-pyrazole (Compound 2 1 9) (Step 1) -278- 200911240 According to Example ι51 Step 1 'by 3_fluoronitrobenzene (0. 05 0mL, 0. 47mmol), potassium carbonate (〇. 33g, 2. 4mmol), 2,3-dihydrospiro[茚piperidine] (〇. 26g, 1. 4mm〇l), and N-methyl lalo hospital (l. OmL)' yields 1, _(3_nitrophenyl)-2,3-dihydrospiro[Ind., 4'-pipe steep] (〇_〇43g, 30%) ° ESIMS m/z: 3 09(M + H)+ ° (Step 2) 1 ,-(3-nitrophenyl)_2,3_dihydrospiro[茚_ 1,4'-pipe steep] obtained in step 1. 0. 054g, 〇. 18mmol) of ethanol (2. 7mL) solution added lead (IV) oxide (0. 0078g, 0. 03 50 mmol), stirred at room temperature under a hydrogen atmosphere. 0 hours. The reaction solution was filtered, and the filtrate was evaporated evaporated. The residue obtained was purified by ruthenium dioxide colloid chromatography (chloroform-chloroform/methanol = 90/10) to give 3-(2,3-dihydrospiro[茚-1,4'-piperidine]- 1'-yl)aniline (0 _ 0 4 3 g, 8 8 %). ESIMS m/z: 279 (M + H)+. (Step 3) According to Step 3 of Example 1 5, 3-(2,3-dihydrospiro[茚-1,4|-piperidine]-1,-yl)aniline obtained in Step 2 ( 0_061§,0. 22 mmol), [bis(methylthio)methylene]malononitrile (0. 041g, 〇_24mmol), hydrazine monohydrate (0_016mL, 0. 33mmol), and ethanol (1. 5 mL) to give 5-amino-4-cyano-3 -[ 3 -(2,3 -dihydrospiro[茚-1 , 4 '-piperidinyl]-indolyl)phenyl]amino- 1 Η-pyrazole (〇.  〇 1 4 g, 1 7 %). -279- 200911240 ESIMS m/z: 3 8 5 (M + H)+. (Step 4) According to the step 4 of Example 1 5 1 'from the 5-amino-4-amino-3-[3-(2,3 - snail) obtained in the step 3 ] 1 '-yl)phenyl]amino-1H-pyrazole (0. 014g, 〇. 〇36mmol), 2-chlorobenzothiazole (〇. 〇〇54mL, 0. 044mmol), potassium carbonate (〇. 〇20mg,0. 15mmol), and N,N-dimethylformamide (〇. 7〇mL), to obtain the compound 2 1 9 (0. 002mg, 1 1%). ESIMS m/z: 41 8 (M + H) + ; 1H NMR (270MHz, CDC13) δ: l_26 (m, 2H), 1. 72 (d, J = 10. 9Hz, 2H), 2. 12(m, 2H), 2_18, (s, 2H), 2. 91-3. 12(m, 4H), 3. 82 (d, J = 10. 9Hz, 2H), 6. 23(s, 1H), 6. 69 (d, J = 8. 9Hz, 1H), 6. 8 0-6. 89(m, 2H), 7. 16-7. 37(m, 5H), 7. 42-7. 5 2(m, 2H), 7. 7 8 (d, J = 10. 8Hz, 1H), 7. 82(d, J=1 0. 8Hz, 1H). Example 220 5-Amino-4-aryl-1-(5-ylbenzobenzophen-2-yl)-3-[3-(morphine-4-ylmethyl)phenyl]amino -1H-pyrazole (Compound 220) According to Example 198, from 2-bromo-5-methyl-1-benzothiophene (〇. I7g, 0. 76mmol), tripotassium phosphate (〇. 43g, 2. 0 mmol), trans-N, N'-dimethylcyclohexane-1,2-diamine (〇. 〇32mL, 0 · 2 0 mm ο 1), copper iodide (j) (0_019g, O. lOmmol), 5-amino-4-cyano-3- [3-(morpholin-4-ylmethyl)phenyl]amino-1H-pyrazole (0-15 g, 0. 50 mmol)' and toluene (3_8 mL) gave compound 220 (0. 023g, 10%). -280- 200911240 ESIMS m/z: 445 (M + H) + ; 'H N M R( D M S O - d 6) δ : 2. 32-2. 41 (m, 4H), 2. 42(s, 3H), 3. 42(s, 2H), 3. 5 3 -3. 64 (m, 4H), 4. 1 1 (s, 2H), 6. 80 (d, J = 7. 2Hz, 1H), 7. 12-7. 23m, 4H), 7. 44(s, 1H), 7. 45-7. 61(m, 3H), 7. 80 (d, J = 8. 2 Hz, 1 H), 8_85 (s, 1H). Example 221 5-Amino-1-(5-chloro-3-methylbenzothiophenyl)-4-cyano-3- [3-(is clear; 4-ylmethyl)phenyl]amine Benzyl-1H-pyrazole (Compound 221) According to Example 198' from 2-bromo-5-gas-3-methylbenzothiophene (0. 20g, 0. 76mmol), tripotassium phosphate (0. 43g, 2_0mmol), trans-Ν, Ν'-dimethylcyclohexane-1,2-diamine (0. 032L, 0_20mmol), copper iodide (I) (0. 019g, 0. 1 0 mm ο 1 ), 5-amino-4-cyano-3 -[ 3 -(morpholin-4-ylmethyl)phenyl]amino group obtained in the first step of Example 180 1 Η-pyrazole (0 _ 1 5 g, 0 _ 5 0 mmol), and toluene (3_8 mL) gave compound 221 (0. 014g, 6%). ESIMS m/z: 48 0 (M + H) + ; 1H NMR (270MHz, DMSO-de) 6:2. 26(s, 3H), 2. 2 9 - 2. 3 9 (m, 4H), 3. 37(s, 3H), 3. 48- 3. 58(m, 4H), 6. 75(d, J = 8. 1Hz, 1H), 6. 93(s, 1H), 7. 13(t, J = 8. 1 Hz, 1H), 7. 46-7. 53 (m, 3H), 7. 94 (d, J = 2. 0Hz, 1H), 8. 03(d, J = 8. 6Hz, 1H), 8. 71 (s, 1H). Example 222 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(lH-l,2,4-triazole·1·yl)phenyl]amine Base-1 Η-pyrazole (Compound 222) -281 - 200911240 (Step 1) According to Step 1 of Example 216, from 3-iodoaniline (2. 0mL, 1 7 «1111〇1), 1,2,4-triazole (0. 96§, 14«1111〇1), tripotassium phosphate (6. 2 Lu, 29 mmol), copper iodide (i) (〇. I3g, 〇. 69 mmol), and N,N-dimethylethylenediamine (0. 35 mL, 3_3 mmol) and toluene (15 mL) gave 3-(1Η-1,2,4-triazol-1-yl)aniline (1. 9g, 86%). ESIMS m/z: 161 (M + H) + ; 'H NMR (270 MHz, DMS 〇-d6) 8 5 · 4 8 ( s , 2 Η ) , 6 · 5 8 (m, 1 Η), 6. 9 3 (d t, J = 8 .  Oh, 1. 0 Η z , 1 Η), 7. 01(t, J = 2. 〇Hz, 1H), 7. 15(t, J = 8. 0Hz, 1H), 8. 17(s, 1H), 9. 13(s, 1H). (Step 2) According to Step 1 of Example 92, 3 · (1H-1,2,4-triazol-1-yl)aniline obtained in Step 1 (0. 76g, 4_7mmol), [bis(methylthio)methylene]malononitrile (〇. 81g, 4. 7mmol), hydrazine monohydrate (〇. 46mL, 9. 5 mmol) and ethanol (10 mL) give 5-amino-4-cyano-3-[3-(111-1,2,4-triazol-1-yl)phenyl]amino-1 Η-pyridyl Azole (0 · 4 5 g, 36 %). ESIMS m/z: 26 7 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 6. 33(s, 2H), 7. 22(m, 1H), 7. 33(t, J = 7. 9Hz, 1H), 7. 44 (m, 1H), 8. 09(s, 1H), 8. 20(s, 1H), 8. 76(s, 1H), 9. 16(s, 1H), 1 1. 23 (s, 1 H). (Step 3) According to Step 3 of Example 4, 5-amino--282-200911240 4-cyano-3-[3-(1Η-1,2,4-triazole-) obtained in Step 2 Phenyl)amino]-1H-pyrazole (0. 30g, l. Lmmol), 2-chlorobenzopyrene (〇. 18mL, 1. 4mmol), bismuth carbonate (0_62g, 4. 5mmol) and N,N-monomethyl-branched female (15mL)' gave compound 222 (0. 20g, 44%). ESIMS m/z: 400 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 8 7. 3 6 - 7 · 5 5 (m, 4 H), 7 _ 7 5 (m, 1 H), 7 _ 9 1 (d, J = 8 · 0 H z, 1 H), 8. 10(d, J = 8. 0Hz, 1H), 8. 24(t, J = 2. 0Hz, 1H), 8. 27(s, 1H), 8_35(s, 2H), 9. 23(s, 1H), 9. 51 (s, 1H). Example 223 2-{5-Amino-4-cyano-3- [3-(dimethylamino)phenyl]amino-1H-pyridin-j-yl b 6-bromobenzothiazole- Methyl 4-carboxylate (Compound 223) 5-Amino-4-cyano-3-(3-dimethylaminophenyl) obtained in Step 2 of Example 7 according to Step 3 of Example 2. Amino-1H-pyrazole (0. 19 Lu, 0. 78111111〇1), 2,6-dibromobenzothiazole-4-carboxylic acid methyl ester (0. 30 Lu, 〇. 86mmol), potassium carbonate (〇. 43g, 3. 1mmol) and hydrazine, hydrazine-dimethylformamide (8. 0 mL) gave Compound 223 (0·1 〇g, 25%). ESIMS m/z: 512 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 8 2. 94(s, 6H), 3. 92(s, 3H), 6. 34(m, 1H), 6. 99(d, J = 7. 2Hz, 1H), 7. 08(t, J = 8. 6Hz, 1H), 7. 23(s, 1H), 8. 11(d, J = 2. 2Hz, 1H), 8. 50(s, 2H), 8. 64 (d, J = 2. 2Hz, 1H), 9. 00 (s, 1H). Example 224 2-{5-Amino-4-cyano-3-[3-(dimethylamino)phenyl]amino-1H-pyrazole--283- 200911240 1-yl}-6- Bromobenzothiazole-4-carboxylic acid (compound 224) will be compound 223 (0. 03 5 g,0. 068 mmol) was dissolved in tetrahydrofuran (2 mL), and a 15% aqueous sodium hydroxide solution was added (0. 3 mL), stirred for 62 hours. The obtained crude crystals were washed with isopropyl ether to give a compound 224 (0. 03 g, 97%). ESIMS m/z: 49 8 (M + H) + ; *H NMR (270MHz, DMSO-d6) 5 2. 83(s, 6H), 6. 58(m, 1H), 7. 10-7. 29(m, 3H), 7. 35(s, 1H), 7. 88(d, J = 2. 0Hz, 1H), 8. 34(s, 2H), 8. 41 (d, J = 2. 3Hz, 1H), 9. 08 (s, 1H). Example 225 5-Amino- l-[6-chloro-4_(ylmethyl)benzoindole-2-yl]-4-mercapto-3-3-(dimethylamino)phenyl Amino-1H-pyrazole (Compound 225) (Step 1) According to Step 3 of Example 2, 5-amino-4-cyano-3_[(3) obtained in Step 2 of Example 7. -Dimethylamino)phenyl]amino-1 Η-pyrazole (0. 39g, 1. 6 mmol), 2-bromo-4-[(t-butyldiphenylphosphonyloxy)methyl]-6-chlorobenzothiazole (1. Og, 1. 9mmol), potassium carbonate (〇. 89g, 6. 4 mmol) and N,N-dimethylformamide (5 mL) gave 5-amino-Bu [4-(t-butyldiphenylphosphonyloxy)methyl-6-chlorobenzothiazole-2 - 4-cyano-3-(3-dimethylaminophenyl)amino-1 Η-pyrazole (0. 7 1 g , 6 5 %). *H NMR (270MHz, DMSO-d6) 5 l. 〇7(s, 9H), 2. 91(s, 6H), 5. 16(5, 2H), 6. 31 (d, J = 7. 9Hz, 1H), 6. 95(m, 1H), 7. 05(t, J = 8. 2Hz, 1H), 7. 23(s, 1 H), 7 4 4 - 7 · 4 6 (m, 7 H), 7. 5 7 ( d, -284- 200911240 J=1. 3Hz, 1H), 7. 66-7. 67(m, 5H), 8_10(s, 1H), 8. 78(s, 1H). (Step 2) 5-Amino-1_[4-(t-butyldiphenylfluorenyloxy)methyl-6-chlorobenzothiazole-2 obtained in Step 1 according to Step 2 of Example 91 -yl] 4-cyano-3-(3-dimethylaminophenyl)amino-1H-pyrazole (0. 70g, 1 · 0 mmol), l. Omol/L tetrabutyl fluorinated money (1. 6mL, 1. 6 mmol) and tetrahydrofuran (15 mL) gave compound 225 (0. 30g, 66%). ESIMS m/z: 440 (M + H) + ;, H NMR (270 MHz, DMSO-d6) 5 2. 93(s, 6H), 4. 90(s, 2H), 6. 30 (dd, J = 8.  1,2. 0Hz, 1 H), 6. 96(d, J = 8. 1Hz, 1H), 7. 05(t, J = 8. 1Hz, 1H), 7. 27(s, 2H), 7. 3 9-7. 48 (m, 2H), 8. 03(d, J = 2. 0Hz, 1H), 8. 66(s, 1H). Example 226 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(2-methylpyridin-4-yl)amino-1 hydrazine-pyrazole (Compound 2 2 6) According to Example 191, from 4-bromo-2-methylpyridine (0. 1 lg, 0. 62 mmol), tripotassium phosphate (〇. 25g, 1. 2mmol), 1,10-morpholine (0. 02 8g, 0. 16mmol), copper iodide (I) (〇_〇15g, 0. 07 8mmol), 3,5-diamino-1-(benzothiazin-2-yl)-4-cyano-1H-indole Π 〇 (〇. I〇g, 〇. 39 mmol), and N,N-dimethylformamide (2. 5 mL) to give compound 226 (0. 04 1 g, 3 0%) ° ESIMS m/z: 3 4 8 (M + H) + ; !H NMR (2 70 MHz, DMSO--285-200911240 ά6) δ : 2. 89(s, 3Η), 3. 37(s, 2H), 6. 11(s, 1H), 6. 38(m, 1H), 6. 60 (d, J = 7. 2Hz, 1H), 7. 1〇(d, J = 8. 1Hz, 1H), 7. 2 8-7. 5 7 (m, 2H), 8. 22(s, 1H), 8_32(m, 1H). Example 2 2 7 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-{ 3-[isobutyl(methyl)amino]phenyl}amino-1 Η-Petazole (Compound 2 2 7) (Step 1) According to Step 1 of Example 1 5 1 , from 3-fluoronitrobenzene (〇·10 m L, 0. 94mmol), potassium carbonate (0. 65 g, 4_7 mmol), N-methylisobutylamine (0. 34mL, 2. 8mmol), and N-methylpyrrolidone (2. 0 mL) to give N-isobutyl-N-methyl-3-nitroaniline (0. 082g, 42%). ESIMS m/z: 209 (M + H)+. (Step 2) According to Step 2 of Example 1 5 1 , N-isobutyl-heart methyl-3-nitroaniline obtained in Step 1 (0. 082§,0. 45111111〇1), 10% palladium-carbon (0_012g, 15w/w%), hydrogen, and ethanol (2. 1 mL), N1-isobutyl _ N1-methylbenzene-1,3-diamine (0. 042g, 60%). E SIM S m / z : 1 7 9 (M + Η) +. (Step 3) According to Step 3 of Example 1 51, the N1 _isobutyl-N1-methylbenzene-1,3-diamine obtained in Step 2 (0. 042g, 0. 24mmol), [bis(methylthio-286-200911240)methylene]malononitrile (〇. 〇44g, 0_26mmol), hydrazine monohydrate (0. 017mL, 0. 35mmol), and ethanol (l. lmL) ' to give 5-amino-4-yl-3-{3-[isobutyl(methyl)amino]phenyl}amino-1H-pyrazole (0. 006g, 9%). ESIMS m/z: 28 5 (M + H)+. (Step 4) According to the step 4 of Example 1 5 1 'from 5-amino-4-cyano-3-{3-[isobutyl(methyl)amino]phenyl} obtained in step 3. Amino-1H-pyrazole (0. 006mg, 〇. 〇21mmol), 2-chlorobenzo _ 哩 (0_0031mL, 0. 025 mmol), potassium carbonate (〇_〇12g, 0. 084 mmol), and N,N-dimethylformamide (0. 50 mL), compound 227 (0. 008g, 91%). ESIMS m/z: 418 (M + H) VH NMR (3 OOMHz, DMSO-ά6) δ :1. 10(d, J = 5. 6Hz, 6H), 1. 73 (m, 1H), 2. 90(s, 3H), 3. 45 (m, 2H), 6. 31 (d, J = 7. 7Hz, 1H), 6. 93(d, J = 7. 7Hz, 1H), 7. 06(t', J = 8. 1Hz, 1H), 7. 24(s, 1H), 7. 39(t, J = 7. 5Hz, 1H), 7. 5 1 (t, J-7. 5HZ, 1 H), 7. 90 (d, J = 8. 1Hz, 1 H), 8. 08(d, J = 8. 1Hz, 1H), 8. 27(s, 2H), 8. 87 (s, 1H). Example 228 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-indole-3-[methyl(propyl)amino]phenyl}amino-1H-pyrazole (Compound 228) (Step 1) According to Step 1 of Example 151, from 3-fluoronitrobenzene (O. lOmL, -287- 200911240 0. 94mmol), potassium carbonate (〇. 65g, 4. 7mmol), N-methyl-1-propylamine (0. 96mL, 9. 4mmol)' and N-methylpyrrolidone (i. 〇mL), to obtain N-methyl-3-nitro-N-propyl aniline (〇. 〇97g, 53%). ESIMS m/z: 195 (M + H)+. (Step 2) According to Step 2 of Example 1 5 1 , N-methyl-3-nitro-N-propylaniline obtained in Step 1 (〇. 〇97g, 0. 50mmol), 10% put-carbon (0. 015g, 15w/w%), hydrogen, and ethanol (2. 4 mL), N1-methyl-N1-propylbenzene-1,3-diamine (0. 064g, 78%). ESIMS m/z: 1 65 (M + H)+. (Step 3) According to Step 3 of Example 1 51, the N1-methyl-N1-propylbenzene-1,3-diamine obtained in Step 2 (0. 064g, 0. 39mmol), [bis(methylthio)methylene]malononitrile (〇_〇73g, 0. 43mmol), hydrazine monohydrate (0. 028mL, 0_59mmol), and ethanol (1. 6 mL) gave 5-amino-4-cyano-3-{3{methyl(propyl)amino]phenyl}amino-1H-pyrazole (0. 065g, 6 2%) 〇 ESIMS m/z: 27 1 (M + H)+. (Step 4) 5-Amino-4-cyano-3-{3-[methyl(propyl)amino]phenyl}amine obtained in Step 3 according to Step 4 of Example 1 51 KI-1H-pyrazole-288- 200911240 (0. 065 g, 〇. 24mmol), 2-chlorobenzothiazole (0_036mL, 0. 29 mmol), potassium carbonate (0. 13g, 0. 96mmol), and N,N-dimethylformamide (1. 6 mL) gave Compound 228 (0_065 g, 67%). ES IMS m/z: 404 (M + H) +; 1H NMR (300 MHz, DMSO-d6) 5:1. 09(t, J = 6. 9Hz, 3H), 1. 44 (m, 2H), 2. 90(s, 3H), 3. 50 (m, 2H), 6. 31 (d, J = 7. 7Hz, 1H), 6. 93(d, J = 7. 7Hz, 1H), 7. 06(t, J = 8. 1Hz, 1H), 7. 24(s, 1H), 7. 38(t, J = 7. 1Hz, 1H), 7. 49(t, J = 7. 1 Hz, 1 H), 7. 90 (d, J = 8. 1Hz, 1 H), 8. 08(d, J = 8. 1 Hz, 1 H), 8. 24(s, 2H), 8. 86(s, 1 H). Example 229 5-Amino-1-(benzothiazol-2-yl)-4-yl-cyano-3-[3-(furan-2-yl)phenyl]amino-1 hydrazine-pyrazole (Compound 2 2 9 ) (Step 1) Under a nitrogen atmosphere, in 3-iodoaniline (0. 50g, 2. 3mmol) added 2-(tributyltin) furan (〇. 86mL, 2. 7 mmol), [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride (〇. 〇93g, O. Llmmol) and tetrahydrofuran (8 mL) were heated to reflux for 3 h. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate = 82/18) to give 3-(furan-2-yl)aniline ( 0. 28 g,0. 76%). ESIMS m/z: 160 (M + H) + ; 'H NMR (270 MHz, DMSO-d6) 5 5. 16(s, 2H), 6. 49(m, 1H), 6. 54 (dd, J = 3. 3, 1. 8Hz, 1H), 6. 73 (d, J = 3. 3Hz, 1H), 6. 84 (d, J = 7. 7Hz, 1H), 6. 90 (1, J=1. 8Hz, 1H), 7. 05(t, J = 7. 7Hz, 1H), 7. 68 (d, J=1. 8Hz, -289- 200911240 1 Η). (Step 2) According to Step 1 of Example 9.2, 3-(furan-2-yl)aniline obtained in Step 1 (〇. 27g, 1. 7 mmol), [bis(methylthio)methylene]malononitrile (0. 29g, 1. 7mmol), hydrazine monohydrate (0. 16 mL, 3_4 mmol) and ethanol (10 mL) gave 5-amino-4-cyano-3-[3-(furan-2-yl)phenyl]amino-1 Η-pyrazole (0 _ 1 1 g ,twenty four %). ESIMS m/z: 266 (M + H) + ; 'H NMR (2 70 MHz, DMSO-d6) 5 6. 32(s, 2H), 6. 57(t, J = 2. 1Hz, 1H), 6. 78(d, J = 3. 3Hz, 1H), 7. 11(d, J = 7. 2Hz, 1H), 7. 21(t, J = 7, 9Hz, 1H), 7. 37 (d, J = 7. 9Hz, 1H), 7. 73(s, 1H), 7. 90(s, 1H), 8. 48(s, 1 H), 1 1. 23 (s, 1 H) (Step 3) According to Step 3 of Example 4, 5-amino-4-cyano-3-[3-(furan-2-yl)phenyl obtained in Step 2 Amino-1H-pyrazole (O. Llg, 0. 41 mmol), 2-chlorobenzothiazepine (〇. 〇 8mL, 0. 61mmol), potassium carbonate (0. 23g, 1. 6 mmol) and N,N-dimethylformamide (5 mL) gave compound 229 (0. 072g, 44%) ° ESIMS m/z: 3 99 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 8 6. 63 (dd, J = 3. 3, 1. 6Hz 1H), 6. 88(d, J = 3. 3Hz, 1H), 7. 25- 7. 39Ctd, J=1 5. 5,7. 7Hz, 5H), 7. 59(t, J = 7. 9Hz, 1H), 7. 61 (d, J = 7. 9Hz, 1H), 7. 80 (d, J=1. 6Hz, 1H), 7. 88(d, J = 7. 9Hz, 1H), -290- 200911240 8. 09(d, J = 7. 9Hz, 1H), 8. 15(s, 1H), 9. 16 (s, 1H). Example 230 5-Amino-1-(benzoindole-2-yl)-4-amino-3-[3-(indol-2-yl)benyl]amino-1H-pyrazole (compound) 23 0) (Step 1) According to the step 1 of Example 23 0, from 3-iodoaniline (〇. 27mL, 2. 3mmol), 2-(tributyltin)thiazole (0. 86mL, 2. 7 mmol), [1,2-bis(diphenylphosphino)ethane]palladium(II) dichloride (0. 056g, 0. 068 mm〇l) and tetrahydrofuran (2 mL) give 3-(thiazol-2-yl)aniline (0. 30g, 74%). 'H NMR (2 70MHz, DMSO-d6) S 5. 35(s, 2H), 6. 65 (dd, J = 7. 6, 1. 6Hz, 1H), 7. 05-7. 15(m, 2H), 7. 19(d, J=1. 6Hz, 1H), 7. 71 (d, J = 3. 3Hz, 1 H), 7 · 8 6 ( d, J = 3 · 3 Η z, 1H). (Step 2) According to Step 1 of Example 9.2, 3-(thiazol-2-yl)aniline obtained in Step 1 (0. 30g, 1. 7 mmol), [bis(methylthio)methylene]malononitrile (0. 29g, l_7mmol), hydrazine monohydrate (0. 16mL, 3. 4 mmol) and ethanol (10 mL) give 5-amino-4-cyano-3-[3-(thiazol-2-yl)phenyl]amino-1H-pyrazole (0. 1 lg, 23%). ESIMS m/z: 2 8 3 (Μ + Η) + ; *Η NMR (270 MHz, DMSO-d6) 5 6. 33(s, 2H), 7. 26-7. 3 7(m, 2H), 7. 55(d, J-7. 9Hz, 1 H), 7. 75(m, 1 H), 7. 90 (m, 1H), 8. 19(s, 1H), 8. 65(s, 1H), 1 1 _06(s, 1 H). -291 - 200911240 (Step 3) According to Step 3 of Example 4, the 5-amino- 4-cyano-3-[3-(thiazol-2-yl)phenyl]amine group obtained in Step 2 -1H-pyrazole (0_1 lg, 0. 38 mmol), 2-chlorobenzothiazole (0. 073mL0_56mmol), potassium carbonate (〇. 21g, 1. 5 mmol) and N,N-dimethylformamide (5 m L) gave compound 230 (0_0 8 3 g, 5 3%).

ESIMS m/z: 416 (M + H) VH NMR (270 MHz, DMS 〇-d6) S 7.42 (dd, J = 16.5, 7.9 Hz, 2H), 7.54 (dd, J = 1 6.5, 7.9 Η z , 2H ), 7.77-7.81(m, 3H), 7.93(dd, J = 10.9, 5.6Hz, 1H), 8.11(d, J = 7.9Hz, 1H), 8.36(s, 1H), 8.43(s, 2H) , 9.42(s, 1H). Example 231 5-Amino-l-[6-chloro-4-(morpholinylmethyl)benzothiazol-2-yl]-4-cyano-3-[3-(dimethylamino)benzene Amino-1H-pyrazole (Compound 231) According to Example 86, Compound 225 (0.050 g, O.llmmol), sulphonyl chloride (〇.〇22 mL, 0.28 mmol), morpholine (0-060 mL) , 0.68 mmol) and hydrazine, hydrazine-dimethylformamide (5.0 mL) gave compound 231 (0.022 g, 3 8%) ESIMS m/z: 5 09 (M + H) VH NMR (2 70 MHz, DMSO -d6)5 2.93(s, 6H), 3.32(t, J = 4.1Hz, 4H), 3.59(t, J = 4.1Hz, 4H), 3.93(s, 2H), 6.34(m, 1H), 6.98 (m, 1H), 7.08(m, 1H), 7.22(s, 1H), 7.51(d, J = 2.0Hz, 1H), 8.13(d, J = 2.0Hz, 1H), 8_23(s, 2H) , 8.94(s, 1 H). -292- 200911240 Example 2 3 2 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-(3-[ethyl (A) Amino]phenyl]amino-1H-pyrazole (Compound 23 2) (Step 1) According to Step 1 of Example 15, from 3-fluoronitrobenzene (〇.i〇mL, 0.94 mmol) , cesium carbonate (〇.65g, 4.7mmol), N-ethylmethylamine (0.81mL, 9.4mmol) and N-methylpyrrolidone (2.0mL) gave N-ethyl-N-methyl-3- Nitroaniline (〇.l3 g, 76%) ESIMS m/z: 181 (M + H) + 〇 (Step 2) According to the step 2 of Example 1 5 1 , the N-ethyl-N-methyl group obtained in the step 1 3-Nitroaniline (〇13g, 0.71mmol), 1% by weight-carbon (0.019g, 15w/w%), hydrogen, and ethanol (3.2mL) give N1-ethyl-N1-methylbenzene -1,3-diamine (0_049g, 46%). ESIMS m/z: 1 5 1 (M + H) + (Step 3) According to Step 3 of Example 1 5 1 , obtained in Step 2 N1-ethyl-N1-methylbenzene-1,3-diamine (0.049 g, 0.33 mmol), [bis(methylthio)methylene]malononitrile (〇.〇61g, 0.36mmol), linked Amine monohydrate (0.024 mL, 0.49 mmol) ' and ethanol (1 - 2 mL) gave quantitatively 5-amino-4-cyano-3-{3-[ethyl(methyl)amino]phenyl}amine -1H_pyrazole-293- 200911240 (0.084 g) ° ESIMS m/z: 271 (M + H)+. (Step 4) 5-Amino-4-cyano-3-{3-[ethyl(methyl)amino]phenyl}amine obtained in Step 3 according to Step 4 of Example 1 51 -1H-pyrazole (0.084 g, 〇_33 mmol), 2-chlorobenzothiazole (0-055 mL, 0.45 mmol), potassium carbonate (0-21 g, 1.5 mmol), and N,N-dimethylformamide (2 · 4 m L) gives compound 2 3 2 (0 _ 0 1 0 mg, 8%). ESIMS m/z: 3 90 (M + H) + ; 1H NMR (3 00 MHz, DMSO-d6) 5 : 1.09 (t, J = 7.0 Hz, 3H), 2.90 (s, 3H), 3.42 (q, J = 7.〇Hz, 2H), 6.31(d, J-7.7Hz, 1H), 6.93(d, J = 7.7Hz, 1H), 7.06(1, J = 8.1Hz, 1H), 7.24(s, 1H ), 7.38(t, J = 7.3Hz, 1H), 7.51(t, J = 7.3Hz, 1H), 7.90(d, J = 8.1Hz, 1H), 8.08(d, J = 8.1Hz, 1H), 8.27 (s, 2H), 8.87 (s, 1 H). Example 2 3 3 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3- [3-(cis-2,6-dimethylmorpholine)phenyl]amino group -1H-pyrazole (Compound 23 3 ) (Step 1) According to Step 1 of Example 1 5 1 'from 3-fluoronitrobenzene (0.1 〇m L, 0.94 mmol), potassium carbonate (〇.65 g, 4.7 mmol) ), cis-2,6-dimethylmorpholine (1.2 mL, 9.4 mmol), and N-methylpyrrolidone (1-OmL) to give cis-2,6-dimethyl-4-(3-nitrate Phenyl phenyl) morpholine (0.074 g, 33%). -294- 200911240 ESIMS m/z: 237 (M + H)+. (Step 2) According to the step 2 of Example 1 5 1 , the c丨s _ 2,6-monomethyl-4-(3-nitrophenyl) morphine obtained in the step 1 (〇.〇74) §, 0.31111111〇1), 1〇% palladium-carbon (O.Ollg, 15w/w%), hydrogen, and ethanol (i_9mL) to give 3-(cis - 2,6 - _methylmorphinyl) aniline (0.050g, 77%). ESIMS m/z: 207 (M + H)+. (Step 3) 3 - (cis-2,6-dimethylmorpholinyl)aniline (0.050 g, 0.24 mmol) obtained in Step 2 according to Step 3 of Example 1 51, [Double (A) Thio)methylene]malononitrile (〇.〇45g, 0.27mmol), hydrazine monohydrate (0_018mL, 0_36mmol), and ethanol (1.3mL) give 5-amino-4-cyano-3 - [3-(cis-2,6-Dimethylmorpholinyl)phenyl]amino-1H-pyrazole (〇.〇65g, 8 6%). ESIMS m/z: 3 1 3 (M + H)+. (Step 4) According to the step 4 of Example 1 5 1 'from 5-amino-4-cyano-3 -[ 3 -( cis - 2,6-dimethylmorpholinyl) obtained in the step 3 Phenyl]amino-1 Η-pyrazole (0.065 g, 0.21 mmol), 2-chlorobenzothiazole (0.031 mL, 0.25 mmol), potassium carbonate (〇_12 g, 0.83 mmol) ' and Ν, Ν-二Methylformamide (1.6 mL) gave Compound 233 (0-029 g, 31%). -295- 200911240 ESIMS m/z: 447 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 : 1.19 (d, J = 6.6 Hz, 6H), 2.30 (t, J = 9.1 Hz, 2H ), 3.61(d, J = 9.1 Hz, 2H), 3.75(m, 2H), 6.57(d, J = 7.3Hz, 1H), 7.06- 7.15(m, 2H), 7.39(t, J = 8.1Hz , 1 H), 7.4 7 - 7 · 5 7 (m, 2 H), 7.90 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 8.28(s, 2H), 9.02 (s, 1 H). Example 2 3 4 5-Amino-1-(benzothiazol-2-yl)-4-cyano-3-[3-(3,5-dimethylpiperidin-1-yl)phenyl] Amino-1H-pyrazole (Compound 234) (Step 1) According to Step 1 of Example 151, from 3-fluoronitrobenzene (〇 〇 mL, 0.94111111 〇 1), cesium carbonate (0.658, 4.7111111 〇 1) , 3,5-dimethylindole (1.3 mL, 9.4 mmol), and N-methyl sylvestre (l_〇mL) to give 3,5-dimethyl-1-(3-nitrate Phenyl) piperidine (0.16 §, 75%). ESIMS m/z: 23 5 (M + N) + (Step 2) 3,5-Dimethyl-1-(3-nitrobenzene) obtained in Step 1 according to Step 2 of Example 1 5 1 Piperidine (0-16 g, 0.68 mmol), 10% palladium-carbon (0.024 g, 15 w/w%), hydrogen, and ethanol (4.0 mL) afforded 3-(3,5-dimethylpiperidine-1 -yl)aniline (0 · 0 7 8 g, 5 6 %). ESIMS m/z: 205 (M + H)+. -296- 200911240 (Step 3) According to Step 3 of Example 1 5 1 , 3 _(3,5-monomethyl-n-i-yl)aniline obtained in Step 2 (78 mg, 〇.38 mmol) , [Bis(methylthio)methylene]malononitrile (0.072 g, 0.42 mmol), hydrazine monohydrate (0.028 mL, 0-57 mmol), and ethanol (2.0 mL) afforded 5-amino-4 -Cyano-3-[3-(3,5-dimethylpiperidin-1-yl)phenyl]amino-2H-pyrazole (〇.〇 51g, 42% ESIMS m/z: 3 1 1 (M + H) + (Step 4) According to the step 4 of Example 1 5 1 , the 5-amino-4-cyano-3-[3-(3,5-di) obtained in the step 3 Methylpiperidin-1-yl)phenyl]amino-1H-pyrazole (0.05 1 g, 〇.16 mmol), 2-chlorobenzothiazole (0.024 mL, 0.20 mmol), potassium carbonate (0.091 g, 0.66) Methyl), and N,N-dimethylformamide (1 · 3 mL), obtained from IJ compound 2 3 4 (0 _ 0 2 9 g, 40%). ESIMS m/z: 44 5 (M + H) + ; 1H NMR (270MHz, DMSO-d6) 5 : 0.92 (d, J = 6.4Hz, 6H), 1.64- 1.84(m, 4H), 2.20(t, J=1 1 .5Hz, 2H) , 3.70(d, J=U.5Hz, 2H), 6.54(d, J = 7.9Hz, 1H), 7.02-7.12(m, 2H), 7.39(t, J = 7.7Hz, 1H), 7.46-7.5 6(m, 2H), 7.90(d, J = 7.9Hz , 1H), 8.00 (d, J = 7.9 Hz, 1H), 8.27 (s, 2H), 8.94 (d, J = 1 〇.9 Hz, 1H). Example 235 5-Amino-1-(Benzene) Thiazol-2-yl)-4-cyano-3-[3-(4-hydroxy-4-phenylpipe-297- 200911240 pyridine-1-yl)phenyl]amino-1 η-pyrazole (compound) 2 3 5 ) (Step 1) 隹 (0·1 OmL, -phenylpiperidine gives 1-(3- according to Example 1 5 1 Step 1 'from 3-fluoronitro: 0.94 mmol), potassium carbonate ( 65.65g, 4.7mmol), 4-hydroxyl (1.7g, 9.4mmol), and N-methyl D ratio succinimide (l_5mL) 'nitrophenyl)-4-phenylpiperidin-4-ol (0.2 6 g, 9 1 %). ESIMS m/z: 23 5 (M + H) + ° (Step 2) Step 2 in accordance with Example 1 5 1 'from nitrophenyl)-4-phenylpiperidin-4-ol (in step 1) 0.26 g, 0.86 mm 〇l) ' (0,03 8 g, 15 w/w%), hydrogen, and ethanol (6_4 mL) gave phenyl)-4-phenylpiperidin-4-ol (0-21 g, 90%) ). ESIMS m/z: 269 (M + H)+. (Step 3) 3 - [bis(methylthiomonohydrate amine-4-cyano-1 Η-pyrazole according to step 3 of Example 1 5 1 , by step 2 (3,5-dimethyl Isopiperidin-1-yl)aniline (0.21 §, 0_77111111〇1) yl)methylene]malononitrile (〇.14g, 0.84mmol), hydrazine (0.056mL, 1.2mmol), and ethanol (5.2mL) ), 5·yl-3-[3-(4-carbyl-4-phenylindoledin-1-yl)phenyl]amino group (0.28 g, 99%) = ESIMS m/z: 3 75 (M + H)+. -298- 200911240 (Step 4) According to the step 4 of Example 1 5 1 '5-Amino-4-cyano-3-[3-(4-hydroxy-4-phenylperidine) obtained in Step 3 Aridin-1-yl)phenyl]amino-1H-salt (〇_28g, 〇.76mmol), 2-chlorobenzothiazepine (O.llmL, 0_91 mmol), potassium carbonate (〇.42g, 3.0 mmo 丨)' and N,N-dimethylformamide (7.1 m L) gave compound 2 3 5 (0 · 1 4 g, 3 6 %). ESIMS m/z: 5 09 (M + H) VH NMR (2 70 MHz, DMSO-d6) 5 : 1.74 (d, J = 12.5 Hz, 2H), 2.00-2.19 (m, 2H), 3.15- 3.31 (m) , 2, H), 3. 7.28-7.41(m, 3H), 7.44-7.5 8(m, 4H), 7.90(d, J = 8.2Hz, 1H), 8.04(d, J = 8,2Hz, 1H), 8.29(s, 2H) , 8_95(s, 1H). [Industrial Applicability] According to the present invention, an antitumor agent or the like containing a pyrazole derivative or a lead drug thereof or a pharmaceutically acceptable salt thereof as an active ingredient can be provided. -299-

Claims (1)

200911240 X. Patent application scope 1 · An antitumor agent containing a pyrazole derivative represented by formula (1) or a lead drug thereof or a pharmaceutically acceptable salt thereof as an active ingredient, (In the formula, R1 represents a cycloalkyl group which may have a substituent, an aromatic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aliphatic heterocyclic group which may have a substituent, R2 It is a cyano group, a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, and an aromatic heterocyclic group COR6 which may have a substituent (wherein R6 represents a hydroxyl group, and may have a substituent. An alkyl group, a lower storage group which may have a substituent, a lower alkoxy group which may have a substituent, an aromatic group which may have a substituent or an aryloxy group which may have a substituent) or C〇NR7R8 (wherein R7 and R8) The same or different, representing a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, may have a substitution An aromatic group or an aliphatic heterocyclic group which may have a substituent, or R7 and R8 may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom, and R3 represents a hydrogen atom, -300- 200911240 R4 represents a hydrogen atom and may have a substituent a lower alkyl alkoxide group, a lower alkoxycarbonyl group which may have a substituent, an aromatic group which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aryl group which may have a substituent 'R5' An aromatic group of a substituent or an aromatic heterocyclic group which may have a substituent, and X represents -NR9- (wherein R9 represents a hydrogen atom, a lower alkyl group which may have a substituent or a lower alkoxy group which may have a substituent Alkylcarbonyl) or -S(0)n- (wherein η represents an integer of 〇 to 2)]. An antitumor agent characterized by containing the pyridoxine derivative of the first aspect of the patent application or a pharmaceutically acceptable salt thereof as an active ingredient. The antitumor agent according to any one of claims 1 to 2, wherein X-R9a- (wherein R9a represents a hydrogen atom or a lower-grade hospital group which may have a substituent). 4. The antitumor agent according to any one of claims 1 to 2, wherein X system-S(0)n- (wherein the η system is synonymous with the foregoing). 5. The antitumor agent according to any one of claims 1 to 4, wherein R2 is a cyano group. 6. The antitumor agent according to any one of claims 1 to 4, wherein R2 is CONR7R8 (wherein R7 and R8 are each synonymous with the foregoing) 7. In the scope of claims 1 to 6, Any one of the antitumor agents, wherein R4 is a hydrogen atom. 8. The antitumor agent according to any one of claims 1 to 7, wherein R5 is an aromatic heterocyclic group which may have a substituent. 9. The antitumor agent according to any one of claims 1 to 8, wherein -w - 200911240 wherein 'w is an aromatic group which may have a substituent. A pyrazole derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof is characterized by being represented by the formula (IA), [Chemical 10] [In the formula, R1A represents a cycloalkyl group which may have a substituent, a aryl group which may have a substituent, an aromatic heterocyclic group which may have a substituent or an aliphatic heterocyclic group which may have a substituent, and an R system which is not cyanide a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, an aromatic heterocyclic group which may have a substituent, COR6A (wherein R6A represents a hydroxyl group, a lower alkyl group which may have a substituent) a lower alkenyl group which may have a substituent, a lower alkoxy group which may have a substituent or an aryloxy group which may have a substituent) or C〇NR7ar8a (wherein, r?a and r8A are the same or different' represent hydrogen a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a lower alkoxy group which may have a substituent, a lower alkenyl group which may have a substituent, an aromatic group which may have a substituent or may have a substitution The aliphatic heterocyclic group, or the R7A and the aryl group may form a nitrogen-containing heterocyclic group which may have a substituent, the ruthenium 3& represents a gas atom, the R4A represents a hydrogen atom, may have a substituent Lower alkyl alkane group, which may have a substitution Lower alkoxycarbonyl group, aryl group which may have a substituent, 200911240 an aromatic heterocyclic group which may have a substituent or an aryl group which may have a substituent, and r5A means an aromatic group which may have a substituent or may have a substitution The aromatic heterocyclic group and the lanthanide group represent -NR9A- (wherein r9a represents a hydrogen atom, a lower alkyl group which may have a substituent or a lower alkoxycarbonyl group which may have a substituent) or _S(0) nA-(wherein nA represents an integer from 2 to 2), however, (i) XA is -NH-, and R2A is ethoxycarbonyl, and when RW is phenyl, R1A is not phenyl, 2- Ethoxyphenyl or 4-(diethylaminesulfonyl)phenyl, and when 1154 is 6-(4-methylphenyl)pyridazinyl, R1A is not phenyl, (iii) XA is - NH-, and R2A is an amine-mercapto group, and when R5A is a phenyl group, R1A is not 2-ethoxyphenyl or 4-(diethylaminesulfonyl)phenyl, (b) octa-series- >^-, and when R2A is an ethoxycarbonyl group, R5A is not a pyrazolyl group which may have a substituent, (v) XA is -NH-, and R2A is a cyano group or a methoxycarbonyl group, and R1A is 1 ,2,3,4-tetrahydro-2,4-dioxo-5-pyrimidine When R5A is not a phenyl group or a 4-nitrophenyl group, (乂丨)乂4 is a sulfur atom, and R2A is a cyano group, and R5A is a phenyl group, R1A is not a 3-methylphenyl group, and 4- Chlorophenyl or phenyl, (vii) XA is a sulfur atom, and R2A is a cyano group, and when R5A is a 2-benzothiazolyl group, -303-200911240 R1A is not a 3-methylphenyl group. 11. The pyrazole derivative or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, wherein xa is -S(0)nA_ (wherein nA is synonymous with the above). The pyrazole derivative of the first aspect of the invention, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein the lanthanide _nr9ai_ (wherein r9AI represents a hydrogen atom or may have a substituent Lower alkyl). The pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R2A is a cyano group. The pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 2, wherein R2A is a CONR7AR8A (wherein r7A& r8a are each Synonymous with the foregoing). The pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein r4A is a hydrogen atom. The pyrazole derivative or a prodrug thereof, or a pharmaceutically acceptable salt thereof, according to any one of the above-mentioned claims, wherein r5a is an aromatic heterocyclic group which may have a substituent . And a pharmaceutically acceptable salt thereof, wherein the rIA is a aryl group which may have a substituent, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 6 . 18_—a kind of medicine' characterized by containing a pyrazole derivative or a lead thereof as claimed in any one of claims 1 to 17 or a salt permissible as pharmaceutically-304-200911240 as an active ingredient . An antitumor agent comprising the pyrazole derivative of any one of claims 10 to 17 or a lead drug thereof or a pharmaceutically acceptable salt thereof as an active ingredient. A method for treating a tumor, which comprises the step of administering an effective amount of a pyrazole derivative or a lead drug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 of the patent application. . The use of a pyridazine derivative or a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 is used for the manufacture of an antitumor agent. A therapeutic method for a tumor, which comprises an effective amount of a pyrazole derivative or a lead drug thereof or a pharmaceutically acceptable salt thereof, which is any one of the claims 1 to 17 Steps 23 - The use of a specific ratio of 11 or 1 of the patent application No. 10 to 17 or its pharmaceutically acceptable salt or its pharmaceutically acceptable salt Manufacture of the agent. A pyrazole derivative according to any one of claims 10 to 17 or a pharmaceutically acceptable salt thereof. A pharmaceutical preparation comprising a pyrazole derivative according to any one of claims 10 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient. An antitumor agent characterized by containing the pyrazole derivative of any one of the claims 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient. -305- 200911240 2 7. A method for treating a tumor, which comprises an effective amount of a pyrazole derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 The steps. A pyrazole derivative according to any one of claims 10 to 17 or a pharmaceutically acceptable salt thereof, which is used for the production of an antitumor agent. -306- 200911240 VII. Designated representative map: (1) The representative representative of the case is: No (2), the representative symbol of the representative figure is a simple description: No. 8. If there is a chemical formula in this case, please reveal the best display invention. Chemical formula of the formula: formula (I)