TW200522964A - 5-aryl-pyrimidine derivatives - Google Patents

Abstract

The present invention relates to a pyrimidine derivative of the following formula (I) or the pharmaceutical acceptable salt thereof: , [wherein, R1 and R3: a lower alkyl group; R2 and R4: an aryl group etc.; R5: an aryl group etc.; R6: hydrogen; R7: an aryl group etc.], These compounds have the excellent MLR inhibiting activity.

Description

200522964 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a compound or a pharmacologically acceptable derivative that has an inhibitory effect on mixed lymphocyte culture response (Mix Lymphocyte R eacti ο η: hereinafter referred to as μ LR) Salt, and medicine containing it as an active ingredient. [Prior art]

The rejection of transplanted tissues, such as bone marrow transplantation and organ transplantation, is the reaction of transplant recipients' autolymphocytes with non-autologous cells in the transplanted tissue, resulting in the activation and proliferation of lymphoblasts and an aggressive rejection reaction.

This rejection reaction is a multi-stage reaction including: 1) non-autologous cell recognition, 2) increased expression of costimulatory molecules on the surface of lymphocytes to produce proliferating cytokines, 3) lymphocyte activation and proliferation, 4) proliferating lymph Spheroid cells • Multi-stage response to the attack on transplanted tissue. Lymphocytes pass Major Histocompatibility (MHC) to identify non-autologous cells. According to the difference of MHC, lymphocytes activated by non-autologous cells can be identified to produce cell kinetin called interleukin-2 (hereinafter referred to as IL-2). This IL-2 can proliferate and activate various immune cells. Co-stimulatory molecules found on the membrane surface by activated lymphocytes can proliferate and activate various immune cells. Proliferated activated T cells, B cells, and killer T cells will attack and exclude transplanted lymphocytes and histiocytes (IMMUNOBIOLOGY 3rd Edition, 67). MLR is a simple evaluation system for autologous lymphocytes that can reflect the activation and proliferation response to non-autologous lymphocytes in this rejection reaction. It is an evaluation system often used in the development of existing immunosuppressive agents. In recent years, it has been apparent that transplant rejection anti-200522964 should inhibit effective compounds; all of them also show significant inhibition in this system can be clearly expressed (Immunology 3rd edition, 505). Therefore, the compounds having an inhibitory effect in MLR can be expected to be used as a drug to suppress rejection of bone marrow transplantation, organ transplantation, etc., and to maintain long-term implantation of transplanted bone marrow and organs. Also evaluate the MLR test system as a liquid immune function test system that reflects cellular immunity such as lymphocyte proliferation and cytocidal activity, and antibody production. Therefore, agents with MLR inhibitory effects can participate in cellular immune functions and liquid immunity. The following diseases with excess function are effective. That is, the excess of cellular immune function and liquid immune function, chronic rheumatoid arthritis involved in inflammatory diseases, multiple sclerosis of organ specific autoimmune diseases, inflammatory bowel disease, diabetes, glomerulonephritis, protozoa Primary biliary cirrhosis, chronic hepatitis, malignant anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, dry addiction and Sjoegren's syndrome, organ non-specific autoimmune diseases, systemic lupus erythematosus , Diseases of allergic rhinitis, asthma, atopic dermatitis [Immunol. Today, Vol, 16, 34-38, (1 995); Science Vol. 260, 547-549, (1993); Immunity, Vol · 3, 171-174, (1995); J. Exp. Med., Vol. 190, 995-1003, (1999); Kidney Int., Vol. 52, 52-29, (1997); J. Exp. Med. Vol. 185, 65-70, (1 997), Nanshantang Medical Dictionary, 797], so MLR inhibitors have been shown to be effective in the treatment or prevention of the above diseases. Based on the above background, a compound with excellent inhibitory effect on MLR is to be developed 200522964 [Summary of the Invention] As a result of studying the derivative with MLR inhibitory effect, the present inventors found that the pyrimidine derivative of the present invention has excellent MLR inhibitory effect and low cell Toxicity can be used as an inhibitor of transplantation tissue rejection, such as bone marrow transplantation, organ transplantation, cancer cell inhibitors with selective cytocidal activity (such as inhibitors of cancerous lymphocytes), or chronic rheumatoid arthritis of inflammatory diseases , Organ-specific autoimmune diseases (such as multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, malignant anemia, Hashimoto's thyroiditis, atrophic gastritis , Myasthenia gravis, psoriasis, or Shecklen syndrome), organ non-specific autoimmune diseases (such as systemic lupus erythematosus) or allergic diseases (such as rhinitis, asthma or atopic dermatitis) preventives and / Or therapeutic agent (suppressing the rejection of transplanted tissues such as bone marrow transplantation and organ transplantation or chronic rheumatism The prophylactic and / or therapeutic agent for arthritis is effective, and the present invention has been completed. This invention relates to

(I) (1) A pyrimidine derivative or a pharmacologically acceptable salt thereof of the formula: [wherein R and R3 are the same or different, each is a low alkyl group, R and & 4 are the same or different, each is an aryl group, Heterocyclic group or aryl group having 1 to 5 substituents selected from any group of substituent group a, 200522964 R5 is an aryl group or aryl group 6 having 1 to 5 substituents selected from any group of substituent group b is hydrogen, Or, R 6 and R 5 combine with a nitrogen atom to form a saturated heterocyclic group. R 7 is a cycloalkyl group, an aryl group, a heterocyclic group, and has 1 to 5 substituted aryl groups selected from any group b of the substituent group b. 1 to 3 substituted heterocyclic groups selected from any group of the substituent group b, and the substituent group a is a low alkylsulfonyl group, a mono-low alkylamine sulfonyl group, a mono-cycloalkylamine sulfonyl group, a mono • Hydroxy oligoalkylamine sulfonyl, di-oligoalkylamine sulfonyl and nitrogen-containing saturated heterocyclic sulfonyl groups, the substituent group b is a halogen atom, lower alkyl, lower alkoxy, aryl, aryloxy » , Phenyl substituted with a halogen atom and phenoxy substituted with a halogen atom]. In the present invention, it is preferably (2) a pyrimidine derivative such as (1) or a pharmacologically acceptable salt thereof, wherein R 1 and R 3 are methyl groups, and (3) such as (1) or (2) a pyrimidine derivative or a pharmacologically acceptable salt thereof Pharmacologically tolerable salts, where R2 and R4 are the same or different, each is a heterocyclic group or an aryl group substituted with an arbitrary group selected from the substituent group a, (4) such as any one of (1) or (2) A pyrimidine derivative or a pharmacologically acceptable salt thereof, wherein R 2 and R 4 are the same or different, and each is pyridyl or oligoalkylsulfonyl, mono-oligoalkylaminesulfonyl, mono-cycloalkylaminesulfonyl, Mono-hydroxy oligoalkylamine sulfonyl or (1-azetidinyl) sulfonyl substituted phenyl at the 4-position, (5) a pyrimidine derivative such as any of (1) or (2) or Pharmacological capacity delta noon salt, in which R2 and R4 are the same or different, each is' pyridyl, carbomethyl 200522964 sulfonyl phenyl, acetomethyl phenyl, "methylamine sulfonyl phenyl, 4-ethylamine sulfonyl Benzene, 4-Cyclopyridine, Phenyl, Hydroxyethyl) Aminosulfonyl] phenyl. Or 4-[(Buazetidinyl) sulfonyl] phenyl, (6) such as (1) or (2) a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of Only: and 1 ^ are the same or different, each is 4-pyridyl, mesylsulfonyl phenyl or [methylamine phenyl] (7) such as pyrimidine of any of (1) or (2) Derivatives or pharmacologically acceptable salts thereof, wherein R2 and R4 are 'methylaminesulfonylphenyl, (8) A pyrimidine derivative such as any of (1) or (2) or a pharmacologically acceptable salt thereof, wherein R 2 and R 4 are the same or different, and each is a phenyl group substituted at the 4-position with a pyridyl group or a lower alkylsulfonyl group or a mono-lower alkylaminesulfonyl group, (9) such as any one of (1) or (2) Item of pyrimidine derivatives or pharmacologically acceptable salts thereof, in which R2 and r4 are the same or different, each of which is 4-pyridyl, carbamate phenyl, 4-ethylsulfonylphenyl, 4-methylaminesulfonylbenzene Or "ethylaminosulfonylphenyl,

(10 ^ The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (9), wherein R5 is aryl or there are, 1 or 2 aryl substituted with any H group selected from the substituent group b '(11) The pyrimidine derivative or pharmacologically acceptable salt thereof according to any one of (1) to (9), wherein R5 is a phenyl group or a phenyl group substituted with 1 or 2 fluorine atoms, chlorine atoms or methyl groups (12) The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of (1) to (9), wherein R5 is phenyl, fluorophenyl, fluorophenyl, or 5-fluoro-2-tolyl,- 10- 200522964 (13) A pyrimidine derivative or a pharmacologically-acceptable salt thereof according to any one of (1) to (9), wherein R5 is phenyl '. (14) As in any of (1) to (9) Item of pyrimidine derivatives or pharmacologically acceptable salts thereof, wherein R5 is phenyl or 5-fluoro-2-tolyl, (15) such as the pyrimidine derivative of any one of (1) to (14) or its pharmacologically acceptable salts Wherein R6 is a hydrogen atom '(16) The pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (1 5), wherein R7 is an aryl group, a heterocyclic group, and 1 or 2 members are selected from The aryl group substituted with any group in the substituent group b may have 1 to 3 substituents selected A pyrazolyl group substituted with any group φ of group b, (1 7) A pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (1 5), wherein R7 is phenyl; thienyl; 1 or 2 fluorine atom, chlorine atom, methyl group or methoxy-substituted phenyl group; or pyrazolyl group with 1 to 3 methyl groups, (18) such as any one of (1) to (15) Pyrimidine derivatives or their pharmacological glutamates, where R7 is phenyl, 3-thienyl, 2-fluorophenyl, 3-fluorophenyl, 2-aminobenzyl, 2-methylbenzyl, 3-tolyl , 4-tolyl, 3-fluoro-4 tolyl, or 1,3,5-trimethyl-4-pyrazolyl, (1 9) such as the pyrimidine of any of (1) to (1 5) A derivative or a pharmacologically acceptable salt thereof, wherein R7 is phenyl, 3-thienyl, 2-fluorophenyl, 3-fluorophenyl, 2-tolyl, 'tolyl or 3-fluoro-4-tolyl, 2) A pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (1 5), wherein R7 is a phenyl group or a 3-thienyl group, (2 1) such as (1) to (1 5) A pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of 11-200522964, wherein R7 is aryl, heterocyclic or 1 or 2 selected from An aryl group substituted with an arbitrary group of group b, (22) A pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (15), wherein R7 is phenyl, thienyl, or 1 or 2 fluorine atom, chlorine atom, methyl group or methoxy substituted phenyl group, (23) a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (15), wherein R7 is a phenyl group , 3-thienyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 2-tolyl, 3-tolyl, [tolyl or 3-fluoro_4-tolyl, Xin (24 ) A pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (1 5), wherein R7 is phenyl, 3-thienyl, 1-tolyl, or 3-fluoro-4-tolyl, (25 ) For example, the pyrimidine derivative or its pharmacologically acceptable salt of (1), wherein Ri and R3 are methyl, R2 & R4 are the same or different, and each is pyridyl or low-sulfonyl, mono-low-sulfonylamine Fluorenyl, mono-cycloamidinylsulfonyl, mono-hydroxy-loweramine sulfonyl or (1-azetidinyl) sulfonyl substituted phenyl at the 4-position, R5 is phenyl or has 1 or 2 fluorines Atom, chlorine atom or methyl substituted β radical 'R6 is hydrogen, R7 is phenyl; thienyl; 1 or 2 fluorine atoms, chlorine atoms, methyl or methoxy substituted phenyl groups; or pyrazolyl substituted with 1 to 3 methyl groups, (%) a pyrimidine derivative such as (1) or its pharmacological allowance Salt, wherein Ri and R · 3 are methyl groups, R2 and R4 are the same or different, and each is cardiopyridyl, 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 4-methylaminesulfonylphenyl , 'Ethylaminesulfonyl phenyl, 4-cyclopropylaminesulfonyl phenyl, 4-[(Ethyl) amine disulfide-12- 200522964 yl] phenyl or 4-((1-Dγbutylidene) denyl) Alkyl] Phenyl 'R5 is phenyl, 2-fluorophenyl, 4-fluorophenyl or 5-fluoro-2-tolyl, R6 is hydrogen, R7 is -phenyl, 3-thienyl, 2-fluoro Phenyl, 3-fluorophenyl, 2-chlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 3-fluoro-4-tolyl, or 1,3,5-trimethyl-4 -Pyrazolyl, (27) a pyrimidine derivative such as (1) or a pharmacologically acceptable salt thereof, wherein R1 and R3 are methyl, R2 and R4 are the same or different, and each is 4-pyridyl, 4-methanesulfonyl Phenyl or 4-methylaminesulfonylphenyl, R5 is phenyl, 2-fluorophenyl, 4-fluorophenyl or 5-fluoro-2-tolyl, R6 is hydrogen, R7 is phenyl, 3-Φ Thienyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 3-fluoro-4-tolyl, or 1,3,5-trimethyl 4-pyrazolyl, (28) a pyrimidine derivative such as (1) or a pharmacologically acceptable salt thereof, wherein

R1 and R3 are methyl, R2 and R4 are the same or different, each is 4-pyridyl, 4-methanesulfonylphenyl or 4-methylaminosulfonylphenyl, R5 is phenyl, 2-fluorophenyl, 4-fluorophenyl or 5-fluoro-2-tolyl, R6 is hydrogen, R7 is phenyl, 3-thienyl, 2-fluorophenyl, 3-fluorophenyl, 2-tolyl, 4-tolyl Or 3-fluoro-4-tolyl, (29) A pyrimidine derivative or a pharmacologically acceptable salt thereof as described in (1), wherein R1 and R3 are methyl groups, R2 and R4 are 4-methylaminesulfonylphenyl groups, and R5 is Phenyl, R6 is hydrogen, R7 is phenyl or 3-thienyl, (30) A pyrimidine derivative such as (1) or a pharmacologically acceptable salt thereof, wherein R1 and R3 are methyl, R2 and R4 are the same or different, Each is a heterocyclyl group or an aryl group substituted with an arbitrary group selected from the substituent group a, R5 is an aryl group or -13-200522964 1 or 2 aryl groups substituted with any arbitrary group selected from the substituent group 13, R6 Is hydrogen, R'7 is an aryl group, a heterocyclic group or an aryl group having 1 or 2 substituted with any group selected from the substituent group b, (3 1) A pyrimidine derivative such as (1) or a pharmacologically acceptable salt thereof , Where R1 and R3 are methyl groups, R2 and R4 are the same or different, and each is 4-pyridyl, 4-methanesulfonylphenyl, 'ethanesulfonyl 4-methylaminosulfonylphenyl or 4-ethylaminosulfonylphenyl 'R5 is phenyl or 5-fluorotolyl, R6 is hydrogen, R7 is phenyl, 3-thienyl or 1 or 2 A halogen atom, a methyl group or a methoxy substituted phenyl group, Φ (32) such as the pyrimidine derivative of (1) or a pharmacologically acceptable salt thereof, wherein R1 and R3 are methyl groups, R2 and R4 are the same or different, each 4-methylpyridyl, 4-methanesulfonylphenyl or 4-methylaminosulfonylphenyl, R5 is phenyl, r6 is hydrogen, R7 is phenyl, 3-thienyl, 2-fluorophenyl, A 3-pyridine derivative of phenyl, 2-chlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl or 3-fluorotolyl, or a pharmacologically acceptable salt thereof, (33) as (1) Pyrimidine derivatives or pharmacologically acceptable salts thereof, in which R1 and R3 are methyl groups, R2 and R4 are 4-methylaminosulfophenyl, r5 is cinnamophenyl, R6 is hydrogen, R7 is phenyl, and 3-thienyl ^ Fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 2-tolyl, 3-methylbenzyl, 4-tolyl or 3-fluoro-4-tolyl, (34) such as (1 ) Pyrimidine derivatives or pharmacologically acceptable salts thereof, in which R1 and R3 are methyl groups, R2 and R4 are 4-methylaminosulfophenyl, R5 is phenyl, R6 is hydrogen, and R7 Phenyl, 3-thienyl, 4-tolyl or 4-tolyl, -14-200522964 (35) such as the pyrimidine derivative of (1) or a pharmacologically acceptable salt thereof, which is (4-methylaminesulfonylbenzene) ) -1-ethyl ketone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine} -5- (3-thienyl)- 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ) Ethylene] hydrazine, 5-phenyl-4-pyrimidinyl), hydrazine, and (4-methylaminesulfonylphenyl) -1-ethanone 1 ^ (2-aniline-5- (4- Tolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl)- 1-Ethyl ketone N- (2-aniline-5- (3-fluoro-4-tolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine} -4-pyrimidinyl) hydrazine, 1- (4-methylaminosulfonylphenyl) -bucetophenone N- (2-anilinyl-5- (2-fluorophenyl) -6- {2- [1 -(4-methylaminesulfonylphenyl) ethylene] hydrazino} -4-pyrimidinyl) hydrazine, (4-methylaminesulfonylphenyl) -buthionone N- (2-phenylamino- 5-o-tolyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (1,3,5-trimethyl-1H-pyrazol-4-yl) -6 -{2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N -(2- (5-fluoro-2-tolylamino) · 5-phenyl_6_ {2- [1- (4-methylaminesulfonylphenyl) ethylene] pyridyl 4-pyrimidinyl) Amidene 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-morpholin-1-yl-5-phenyl-6- {2- [1- (4-methylaminesulfonate醯 Phenyl) ethylene] hydrazinob 4-pyrimidinyl) sulfenyl, 1- (4-pyridyl) -1-ethyl ketone N- (2-anilino-5-phenyl-6- {2- [1- (4-pyridinyl) ethylene] hydrazinob4-pyrimidinyl) hydrazine, 1 · (4-methylsulfonylphenyl) -1-ethanone N- (2-anilino-5- Phenyl-6 — {2- [1- 200522964 (4-methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methanesulfonylphenyl) -1- Ethyl ketone N- (2-anilino-5- (3-fluorophenyl) -6M2- [l- (4-methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1 -(4-methanesulfonylphenyl) -1-ethanone N- (2-aniline-5- (2-chlorophenyl) -6- {2- [1- (4-methanesulfonylphenyl) Ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- ( 4-Ethylsulfonylphenyl) -1-ethanone 1 ^ (2-anilino-5-phenyl-6- {2- [1- (4 > Ethylsulfonylphenyl) ethylene] hydrazine 4-pyrimidinyl) hydrazine, bu (4-ethylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5-phenyl-6- {2- [bu (4-ethylaminesulfonyl)醯 Phenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, ^ (4-azetidin-1-yl-sulfonamidophenyl) -1-ethanone N- (2-aniline-5 -Phenyl-6- {2- [1- (4-azetidin-1-yl-sulfonamidophenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-cyclopropylamine Sulfophenyl) -1-ethanone N- (2-anilino-5-phenyl-6- 丨 2- [1- (4-cyclopropylaminesulfonylphenyl) ethylene] hydrazinopyrimidine Amidinyl) sulfenyl, 1- [4- (2-hydroxyethyl) -sulfamoylphenyl] -1-ethanone & [2-anilino-5-phenyl-6- (2- {1- [4- (2-Hydroxyethyl) -aminosulfonylphenyl] ethylene 丨 hydrazino) -4-pyrimidinyl] hydrazine, N-methyl_4_ {1-[(5-phenylaniline -6- {Ν '-[1-pyridin-4-yl-ethylidene] · hydrazinopyrimidin-4-yl) -hydrazino] -ethylbenzylsulfonium.amine, 4- {1- [(2- (4-fluoroaniline) -5-phenyl-6- {Hydroxy- [1-pyridin-4-yl-ethylidene] _hydrazinopyrimidin-4-yl) -hydrazinyl] -Ethyl N-toluenesulfonium Or 4- {1-[(2- (2-fluoroaniline) -5-phenyl-6- {N '-[1-pyridin-4-yl-ethylidene] _hydrazinopyrimidine-4- ) -Hydrazinyl] -ethylbenzene N-toluenesulfonamide, (36) a pyrimidine derivative such as (1) or a pharmacologically acceptable salt thereof, which is 200522964 1- (4-methylaminesulfonylphenyl) 1-Ethyl ketone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine) -5- (3-thienyl) -4- Pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl)) Ethyl] hydrazinob 5-phenyl-4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone 1 (2-anilino-5- (4-tolyl ) -6- {2- [1- (4-Methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) sulfenyl, 1- (4-methylaminesulfonylphenyl) -1- Ethyl ketone 1 ^ (2-anilino-5- (3-fluoro-4-tolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine 4- Pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -bucetone N- (2-aniline-5- (2-fluorophenyl) -6- {2- [1- (4 -Methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5- adjacent Phenyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylidene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-pyridyl) -buethylone N- (2-anilinyl-5-phenyl-6- {2- [1- (4-pyridyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylsulfonylphenyl ) -1-Ethyl ketone N- (2-anilino-5-phenyl-6 — {2- [Bu (4-methylsulfonylphenyl) ethylene] hydrazino} -4-pyrimidinyl) hydrazine , 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-phenylamino- 5- (3-fluorophenyl) -6- {2- [1- (4-methylsulfonylbenzene Alkyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, N-methyl-4- {l-[(5-phenyl-2-anilino-6- {N,-[1-pyridine- 4-yl-ethylidenehydrazinopyrimidin-4-yl) -hydrazinyl] -ethylbenzylsulfonamide, 4- {1-[(2- (4-fluoroaniline) -5-benzene Phenyl-6- {N, -Π-pyridin-4-yl-ethylene] -hydrazinopyrimidin-4-yl) -hydrazino] -ethylbenzyl-toluenesulfonamide or 4- {1 -[(2- (2-fluoroaniline) -5-phenyl-6- {乂-[1-pyridin-4-yl-ethylidene] -hydrazinopyrimidin-4-yl) -hydrazinyl ] -Ethyl N-toluenesulfonamide '200522964 (37) A pyrimidine derivative or a pharmacologically acceptable salt thereof as in (1), which is 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine plant 5- (3-thienyl) -4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine 5-phenyl-4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -bucetone N- (2-aniline-5- (4-tolyl) -6- {2 -[1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethyl ketone N- (2 -Anilino-5- (3-fluoro-4-tolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -acetylacetone N- (2-aniline-5- (2-fluorophenyl) -6- {2- [1- (4-methylaminesulfonylphenyl) Alkyl) ethylene] hydrazinob 4-pyrimidinyl) fluorene, 1- (4-methylaminesulfonylphenyl) -buethylone N- (2-anilino-5-o-tolyl-6- { 2- [1-([methylaminesulfonylphenyl) ethylidene] hydrazinob4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethylone N- (2 -(5-fluoro-2-tolylamino) -5-phenyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine , 1- (4-methylamine sulfonate Phenyl) -1-ethanone N- (2-morpholin-1-yl-5-phenyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylidene] hydrazine 4-pyrimidinyl) hydrazine, 1- (4-pyridyl) -1-ethanone N- (2-anilino-5 · phenyl-6- {2- [1- (4-pyridyl) ethylene Yl] hydrazino} -4-pyrimidinyl) hydrazine, 1- (4-methylsulfonylphenyl) -1-ethanone N- (2-aniline-5-phenyl-6 — {2- [1 -(4-Methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-aniline-5 -(3-fluorophenyl) -6- {2- [1- (4-methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, -18- 200522964 1-(4- Methanesulfonylphenyl) -1-ethanone N- (2-anilino-5- (2-chlorophenyl) -6- {2_ [1- (4-methylsulfonylphenyl) ethylene] hydrazine Benzyl 4-pyrimidinyl) hydrazine, 1- (4-ethanesulfonylphenyl) -1-ethanone N- (2-anilino-5-phenyl-6- {2- [1- (4- Ethylsulfonylphenyl) ethylene] hydrazino} -4-pyrimidinyl) hydrazine, or 1- (4-ethylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5- Phenyl-6- {2-[((4-ethylaminesulfonylphenyl) ethylene] hydrazino} -4_pyrimidinyl) hydrazine, (38) such as the pyrimidine derivative of (1) or its pharmacology Allow salt, which (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine}- 5- (3-thienyl) -4-pyrimidinyl) fluorene, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 5-phenyl-4-pyrimidinyl) fluorene, 1- (4-methylaminesulfonylphenyl) -buethylone 1 (2- Aniline-5- (cardiotolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methyl Aminosulfenylphenyl) -1-ethyl ketone N- (2-aniline-5- (3-fluoro-4-tolyl) -6- {2- [1- (cardiomethylaminesulfonylphenyl) Ethyl] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (2-fluorophenyl) -6 -{2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylsulfonylphenyl) -1-ethanone N- (2-Anilino-5-phenyl-6-{2- [1- (4-methylsulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine or 1- (4-methylsulfonate Fluorenyl) -1-ethyl ketone N- (2-aniline-5- (3-fluorophenyl) -6- {2- [1- (4-methylsulfonylphenyl) ethylene] hydrazine Bu 4-pyrimidinyl) hydrazine (39) A pharmaceutical composition containing a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (3 8) as an active ingredient, and (40) a pharmaceutical composition that inhibits a mixed lymphocyte culture reaction Substances, -19-19200522964 containing a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (3 8) as an active ingredient, (41) an inhibitory effect on rejection of transplanted tissues such as bone marrow transplantation and organ transplantation A pharmaceutical composition that responds to or prevents and / or treats an inflammatory disease, an organ-specific autoimmune disease, an organ non-specific autoimmune disease, or an allergic disease, and is contained in any of (1) to (38) The sulfonium derivative or its pharmacologically acceptable salt is the active ingredient, (42) — a kind of prevention and / or treatment of chronic rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary Biliary cirrhosis, chronic active hepatitis, malignant anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, dry addiction, Sjoegren's syndrome, systemic lupus erythematosus, rhinitis, wheezing or ectopic Dermatitis A pharmaceutical composition containing a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (38) as an active ingredient, (43) A pharmaceutical composition containing cancer cells, such as (1) to (3 8) The pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of the active ingredients, (44) A pharmaceutical composition that inhibits cancerous lymphocytes, and contains any one of (1) to (3 8) A pyrimidine derivative or a pharmacologically acceptable salt thereof is an active ingredient. (45) A medicinal composition that inhibits the rejection of transplanted tissues such as bone marrow transplantation and organ transplantation or prevents and / or treats chronic rheumatoid arthritis. (1) ~ (3 8) The pyrimidine derivative or its pharmacologically acceptable salt is an active ingredient, (46) A use for manufacturing a pharmaceutical composition, such as (1) ~ (-20- 200522964 3 8 ) The pyrimidine derivative or its pharmacological allowance: (47) The use as (46), wherein the pharmaceutical composition is a composition that can inhibit the mixed lymphocyte culture reaction, (48) As in (46) Use, in which the medicinal composition is capable of inhibiting bone marrow transplantation, organ transplantation, etc. Rejection of transplanted tissue or prevention and / or treatment of inflammatory diseases, organ-specific autoimmune diseases, organ non-specific autoimmune diseases or allergic diseases, (49) Uses such as (46), wherein the pharmaceutical composition For the prevention and / or treatment of chronic rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, sugar and urine, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, malignant anemia, Hashimoto Thyroiditis, atrophic gastritis, myasthenia gravis, psoriasis, Sjoegren's syndrome, systemic lupus erythematosus, rhinitis, wheezing or atopic dermatitis, (50) Uses as described in (46), of which the pharmaceutical composition The substance is a composition that can inhibit cancer cells, (51) such as (46), wherein the pharmaceutical composition is a composition that can inhibit cancerous lymphocytes, (52) such as (46), the pharmaceutical composition It can inhibit the rejection of transplanted tissues such as bone marrow transplantation and organ transplantation or prevent and / or treat chronic rheumatoid arthritis. (53) —Suppresses the rejection of transplanted tissues such as bone marrow transplantation and organ transplantation. The method of reaction is to administer a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of (1) to (38) to a warm-blooded animal, (54) a method for preventing and / or treating a disease Pharmacologically effective -21-200522964 An amount of pyrimidine derivative according to any one of (1) to (3 8) or its pharmacological allowance: administration of salt to warm-blooded animals,. (55) such as (54) Method, wherein the disease is an inflammatory disease, an organ-specific autoimmune disease, an organ non-specific autoimmune disease, or an allergic disease, (56) a method of (54), wherein the disease is chronic rheumatoid arthritis, Sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, malignant anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, dry addiction, Xie Kelian ( Lu Sjoegren's syndrome, systemic lupus erythematosus, rhinitis, wheezing or atopic dermatitis, (57) The method of (54), wherein the disease is chronic rheumatoid arthritis (58)-a method of suppressing cancer cells Pharmacologically effective amount For example, the pyrimidine derivative according to any one of (1) to (3 8) or a pharmacologically acceptable salt thereof can be administered to a warm-blooded animal, (59) the method according to (5 8), wherein the cancer cells are cancerous lymphocytes. (60) The method according to any one of (53) to (59), wherein the warm-blooded animal is a human. In the present invention, the "low alkyl" may be, for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl , 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl Base, 3 '3-dimethylbutyl, 2' 2-dimethylbutyl, 1,1-dimethylbutyl, 1 -22- 200522964, 2-dimethylbutyl, 1,3- Cl ~ 6 straight or branched alkyl groups such as dimethylbutyl, 2,3-dimethylbutyl, ιethylbutyl, or 2-ethylbutyl, preferably Crq alkyl, or Alkyl is more preferably methyl. In the present invention, "aryl" may be a C6 ~ 14 aromatic hydrocarbon group such as phenyl, indenyl, naphthyl, phenanthryl, anthracenyl, or manganyl, etc., preferably C6-C1G aryl, and% is preferably phenyl or Naphthyl is more preferably phenyl. In the present invention, a "heterocyclic group" is a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms, and / or nitrogen atoms, such as furyl, thienyl, pyrrolyl, azetidinyl, and pyrazolyl. , Imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, pyranyl, pyridine Aromatic heterocyclic groups such as methyl, daphyl, pyrimidinyl or pyridyl, tetrahydropyranyl, tetrahydrothienyl, morpholinyl, thiomorphyl, pyrrolidyl, pyrrolyl, imidazolyl , Pyrazoridinyl, piperidinyl, piperidinyl, stildiazolyl, isoxadiawyl, thiazolyl, stilbene, ππyl, Ershu Maoyuan or Ershu Yuan, etc. or Fully reduced saturated heterocyclic group, the above heterocyclic group may be fused with other rings such as benzene ring, such as benzothienyl, benzothiyl, benzoesinyl, isobenzofuranyl, quinolinyl, 1,3 -Benzodisorcinyl, benzobisindolyl, indolyl, isoindolyl, or indololinyl, R2 and R4 are preferably the same or different, and each is 6-membered aromatic Heterocyclic group, preferably 4-Laidinyl, R 7 is preferably 3-thienyl, 4-fluorenyl, 1 '3-benzodifluorenyl-5-yl or 1,4-benzodioxan-6-yl , Preferably 3-thienyl or 4-pyrazolyl, more preferably 3-thienyl. In the present invention, the saturated heterocyclic group portion of "R6 and R5 and the combined nitrogen atom to form a saturated heterocyclic group" is a 5 to 7-membered heterocyclic group containing 1 to 3 nitrogen atoms-23-200522964, such as morpholinyl , Thiomorpholinyl, aziridinyl, azetidinyl, pyrrolidinyl-, pyrrolyl, imidazolyl, pyrazidinyl, piperidinyl, piperidinyl, iso: oxazolyl, thiazolyl, or Pyrazolidinyl is preferably a 5- or 6-membered saturated heterocyclic group, and also 4-morpholinyl (that is, morpholinyl). In the present invention, "cycloalkyl" is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and preferably cyclopentyl. In the present invention, the "lower sulphydryl group" is the base of the above "lower sulphydryl group" in combination with the stilbene group, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, butanesulfonyl Fluorenyl, isobutylsulfonyl, second sulfonylfluorenyl, third sulfonyl® fluorenyl, pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, neopentylsulfonyl, 1-ethylpropanesulfonyl, hexylsulfonyl, 4-methylpentylsulfonyl, 3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl, 3,3-dimethylbutanesulfonyl, 2,2 "dimethylbutanesulfonyl, 1,1-dimethylbutanesulfonyl, 1,2-dimethylbutanesulfonyl, 1, Crq alkylsulfonyl groups such as 3-dimethylbutanesulfonyl, 2,3-dimethylbutanesulfonyl, or 2-ethylbutanesulfonyl, preferably alkylsulfonyl and alkylsulfonyl醯 Base, more preferably a base extension. · In the present invention, the "mono-lower alkylamine sulfonyl group" is one of the above-mentioned "low alkyl" combined with an amine group and a sulfonyl group, such as methylamine sulfonyl, ethylamine sulfonyl, and propylsulfonyl Methyl, isopropylamine sulfonyl, butylamine sulfonyl, isobutylamine sulfonyl, second butylamine sulfonyl, third butylamine sulfonyl, pentylamine sulfonyl, isoamylsulfonyl, 2-methylbutylaminesulfonyl, neopentylaminesulfonyl, 1-ethylpropylaminesulfonyl, hexylaminesulfonyl, isohexylaminesulfonyl, 4-methylpentylamine, 3- Methylpentylsulfonylsulfonyl, 2-methylpentylsulfonylsulfanyl, 1-methylpentylsulfuron yellow-24- 200522964 fluorenyl, 3,3-dimethylbutylaminesulfonyl, 2,2- Dimethylbutylaminesulfonyl, 1,1-dimethylbutylaminesulfonyl, 1,2-dimethylbutylaminesulfonyl, 1,3-dimethylbutylaminesulfonyl, 2, 3-dimethylbutylaminesulfonyl, or 2-ethylbutylaminesulfonyl, preferably mono-CrQ alkylaminesulfonyl, but also monoalkylaminesulfonyl, more preferably methylaminesulfonyl base. In the present invention, the "monocycloalkylaminesulfonyl group" is cyclopropylaminesulfonyl, cyclobutylaminesulfonyl, cyclopentylaminesulfonyl or cyclohexylaminesulfonyl, preferably mono-C3-C4 cycloalkane Aminosulfosulfanyl is also preferably sulfapropylsulfenyl. In the present invention, the "mono- (hydroxy-lower alkyl) aminosulfonyl" is a group in which one hydroxyl group is substituted with the "low-alkyl" moiety of the above-mentioned "mono-lower alkylaminesulfonyl", for example, hydroxymethylaminesulfonyl Fluorenyl, 2-hydroxyethylamine sulfonyl, 1-hydroxyethylamine sulfonyl, 3-hydroxypropylamine sulfonyl, 4-hydroxybutylamine sulfonyl, 5-hydroxypentylamine sulfonyl, or 6-hydroxyl Hexylaminesulfonyl is preferably hydroxyalkylaminesulfonyl, more preferably hydroxyalkylaminesulfonyl, and more preferably 2-hydroxyethylaminesulfonyl. In the present invention, the "di-lower alkylamine sulfonyl group" is the same or different two of the above-mentioned "lower radicals" combined with an amine group and a sulfonyl group, for example, dimethylamine sulfonyl and diethyl Aminesulfonyl, N-ethyl-N-methylaminesulfonyl, dipropylaminesulfonyl, dibutylaminesulfonyl, dipentylaminesulfonyl or dihexylaminesulfonyl, preferably the same or similar The two different C ^ C4 alkyl groups combined with one C ^ C4 alkylaminosulfonyl group, and preferably the same or different two < 3 ^ (: 2 alkyl groups combined with one C1 · C 2 alkylaminosulfonyl, more preferably dimethylaminesulfonyl. In the present invention, a "nitrogen-containing saturated heterocyclic sulfonyl" is a 3 to 7-membered saturated heterocyclic group containing 3 nitrogen atoms combined with sulfonyl. Radicals such as morpholin-^-sulfonyl, thiomorpholin-1-yl-sulfonyl, aziridin-1 -yl-sulfonyl, azetidine-25- 200522964 pyridin-1-yl -Sulfonyl, pyrrolidin-1-yl-sulfonyl, piperidin-l-yl-sulfonyl:, pyrrolin-1 -yl-sulfonyl, imidazolidine-1 -yl-sulfonyl, Pyrazolidine-.yl-sulfonyl, piperidin-1 -yl-sulfonyl, piperidin-1 -yl-sulfonyl, isoxazolidine-1-yl-sulfonyl, thiazolidine-1 -Base-Sulfur Or pyrazolidine-1-yl-fluorenyl, preferably azetidin-1 ... yl-sulfonyl. In the present invention, the "halogen atom" is fluorine, chlorine, bromine, or an atom, preferably fluorine. Atom or chlorine atom, and also preferably a fluorine atom. In the present invention, the "low alkoxy group" refers to the above-mentioned "low alkyl" group combined with an oxygen atom, such as a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. Group, butoxy group, isobutoxy group, second butoxy group, third butoxy group, n-pentyloxy group, isopentyloxy group, 2-methylbutoxy group, 1-ethylpropoxy group, 2 ... ethylpropoxy, neopentyloxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 3,3 · dimethylbutoxy Group, 2,2-dimethylbutoxy, ^ dimethylbutoxy, 1 '2 -monomethylbutoxy, 1' 3 -monomethylbutoxy or 2 '3- -methyl Butoxy is preferably Ci-CU, and is more preferably C1-C2, and more preferably methoxy. In the present invention, "aryloxy" is the above-mentioned "aryl" combined with an oxygen atom. ®, such as phenoxy, indenyloxy, naphthyloxy, phenanthryloxy, onionoxy or manganyloxy, preferably C6-C.1 () aryloxy In the present invention, a "phenyl group substituted with a halogen atom" is a benzene substituted with 1 to 5 of the same or different above-mentioned "halogen atoms". Group, such as fluorophenyl, chlorophenyl, bromophenyl, or difluorophenyl, is preferably fluorophenyl, and more preferably 4-fluorophenyl. In the present invention, the "phenoxy group substituted with a halogen atom" is There are 1 to 5 phenoxy groups, such as fluorophenoxy, chlorophenoxy, bromophenoxy, or difluorophenyloxy, which are substituted by the same "halogen atom" as described above, or 26-26200522964 or different, preferably Cardiofluorophenoxy. In the present invention, the "substituent group a" is preferably a lower alkylsulfonyl group, a mono-loweramine sulfonyl group, a mono-cycloalkylamine sulfonyl group, and a mono-hydroxyloweramine group. Fluorenyl or (1-azetidinyl) sulfonyl, preferably low alkylsulfonyl or mono-loweraminesulfonyl, more preferably methylsulfonyl, ethylsulfonyl, methylaminesulfonyl Or ethylaminesulfonyl. In the present invention, the "substituent group b" is preferably a halogen atom, a lower alkyl group or a lower alkoxy group, and also a fluorine atom, a chlorine atom, a methyl group or a methoxy group. In the present invention, "there is 5 to 5 aryl groups substituted with any group selected from the substituent group a" is 1 to 5 of the above "aryl groups" substituted with any group selected from the substituent group a 1 phenyl substituted with any group selected from the substituent group a, preferably 4-methylsulfonylphenyl, ethylsulfonylphenyl, 4-methylaminesulfonylphenyl, 4-ethylfe: sulfonylphenyl, 4-Cyclopropylaminesulfonylphenyl, 4-[(2-Ethyl) aminosulfonyl] phenyl or 4-[(1-azetidinyl) sulfonyl] phenyl, preferably 4-methylsulfonate Benzene, 'ethylsulfonylphenyl, 4-methylaminesulfonylphenyl or 4-ethylaminesulfonylphenyl' is more preferably 4methylsulfonylphenyl or 4-methylaminesulfonylphenyl, particularly preferably It is 4-methylamine diphenyl. · In the present invention, "there are 1 to 5 aryl groups substituted with any group selected from the substituent group b" is the above-mentioned "aryl group". 1 to 5 of these are selected from the arbitrary group substituted with the group b. Substituted groups 'For example, 1 or 2 phenyl substituted with any group selected from the substituent group b' is preferably a phenyl substituted with 1 or 2 halogen atoms, methyl or methoxy, and 2-fluorophenyl in R5 is preferred , 4-fluorophenyl or 5-fluoro-2-tolyl, more preferably 5-fluoro-2-tolyl, and r7 is preferably 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 2-Tolyl, tolyl, 4-tolyl or% fluoro-4-tolyl, more preferably -27-200522964 is 4-tolyl or 3-fluoro-4-tolyl. : In the present invention, "the heterocyclic group having 1 to 3 substituents selected from any of the substituent group b. The cyclic group" refers to the "heterocyclic group" which has 1 to 3 substituents selected from the arbitrary group of the substituent group b , Such as 1,3,5-trimethyl-4-pyrazolyl. In the present invention, R1 and R3 are preferably methyl. In the present invention, it is preferable that R2 and R4 are the same or different, each is a heterocyclic group or an aryl group substituted with an arbitrary group selected from the substituent group a, and it is also preferable that R2 and R4 are the same or different, and each is 4-pyridine. 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 4-methylaminesulfonylphenyl, 4-ethylaminesulfonylphenyl, 4-cyclopropylaminesulfonylphenyl φ, 4- [( 2-Hydroxyethyl) aminosulfonyl] phenyl or 4-[(1-azetidinyl) sulfonyl] phenyl, more preferably R2 and R4 are the same or different, each of which is 4-pyridyl , 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 4-methylsulfonylphenyl, or 4-ethylsulfonylphenyl, particularly preferably R2 and R4 are the same or different, and each is more specific , 4-methanesulfenylphenyl, or 4-methanesulfenylphenyl, most preferably R2 and R4 are 4-methanesulfenylphenyl. In the present invention, preferably R5 is an aryl group or an aryl group substituted with 1 or 2 arbitrary groups selected from the substituent group 1), and it is also preferable that R5 is a phenyl group, a fluorophenyl group, a 4-fluorophenyl group or a 5-fluoro group. 2-Tolyl, more preferably R5 is phenyl or 5-fluoro-2-tolyl, and particularly preferably RS is phenyl. In the present invention, R6 is preferably a hydrogen atom. In the present invention, it is preferred that R7 is an aryl group, a heterocyclic group, an aryl group substituted with 1 or 2 arbitrary groups selected from the substituent group b, or a pyrazolyl group substituted with 1 to 3 selected from a substituent group. R7 is phenyl; thienyl; fluorine atom, chlorine atom, phenyl substituted with 1 or 2 methyl or methoxy; or pyrazolyl substituted with 1 to 3 methyl-28-200522964, more preferably R 7 is phenyl, 3-thienyl or i or 2 halogen: atom, methyl or methoxy substituted phenyl, more preferably R7 is phenyl, 3-thienyl, 2-fluorophenyl, 3 -Fluorophenyl, 2-chlorophenyl, 2-tolyl, tolyl, 4-tolyl or 3-fluorotolyl, particularly preferably R 7 is phenyl, 3-thienyl, 4-tolyl or 3- Gas 4-tolyl 'is most preferably R7 is phenyl or 3-thienyl. "The pharmacologically acceptable salt" refers to a salt of the present invention having a formula (I), a chelated Ding derivative, which reacts with an acid when a basic group such as an amine group is present. The salt of the basic group is preferably a hydrofluoride, a hydrochloride, a hydrobromide, a hydroacid beta salt, and other inorganic acid salts such as a hydrohalide, a nitrate, a perchlorate, a sulfate, and an orthoacid. ; Low sulfonates such as mesylate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and other aromatic sulfonates, acetate, malate, fumaric acid Organic salts such as salts, succinates, citrates, ascorbates, tartrates, oxalates, and maleates; and glycine, lysine, spermine, ornithine Amino acid salts such as glutamate, aspartate, and the like are most preferably hydrohalide, inorganic acid salt, or organic acid salt. The pyrimidine derivative of formula (I) or its pharmacologically acceptable salt of the present invention can have various isomers due to the presence of asymmetric carbon atoms in the molecule ®. In the compounds of the present invention, the isomers and mixtures of the isomers are all represented by a single formula, that is, formula (I). Therefore, the present invention also includes isomers and mixtures of the isomers in any ratio. The pyrimidine derivative of formula (I) or a pharmacologically acceptable salt thereof of the present invention may have geometric isomers due to the presence of a double bond in the molecule. In the compounds of the present invention, the geometric isomers and geometric isomer mixtures thereof are both represented by a single formula, that is, formula (I). Therefore, the present invention also includes geometric isomers and mixtures of geometric isomers in any ratio. -29- 200522964 The pyrimidine derivative of formula (I) or a pharmacologically acceptable salt thereof according to the present invention may be placed in the atmosphere or recrystallized to absorb water, adsorb water, or form hydrates_ 'These hydrates also include The salt in the present invention. Specific examples of the compound of formula (I) of the present invention may be the compounds' described in Table 1 below, but the present invention is not limited thereto. In the following Table 1, the abbreviations are as follows: M e: methyl, E t: ethyl, P h: phenyl, $ P h (A) · 5-gas-2-tolyl, 4-M e NH S. 2C6H4: 4-methylaminosulfonylphenyl, 3-F-4-M e-C6H3: 3-fluoro-4-tolyl, 4-Py: 4-pyridyl, 3-Th: 3-thienyl, 3 '5-Me3_4-P yra: 1,3,5-trimethyl-4-pyrazolyl, c P ent: cyclopentyl, heart (^ A zt) -S 〇2C 6H 4: 4- [(1 -Azetidinyl) sulfonyl] phenyl, "4-cP r NH S〇2C6H4: Cyclopropylaminesulfonylphenyl, P h (B): 4- [(2-hydroxyethyl) sulfanyl ] Phenyl, 2 '4- (M e 〇) 2 · 〇6Η3: 2,4-dimethoxyphenyl, P h (C) ·· 3-(cardiofluorophenoxy) phenyl, P h (D ): 1,3-Benzodisuecene-5-yl, P h (E): 1,4-Benzodisuecene-6-yl. -30- 200522964

Compound Number R1 R2 R3 R4 R5 R6 R7 1 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 3-Th 2 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H Ph 3 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 4-Me- C6H4 4 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 3-F-4-Me-C6H3 5 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-F-C6H4 6 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 3- F-C6H4 7 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-Cl-C6H4 8 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-Me-C6H4 9 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H cPent

-31-200522964 10 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 1,3,5-Me3 + Pyra 11 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-CH -Me-C6H3 12 Me 4-MeNHS02C6H4 Me 4- MeNHS02C6H4 Ph (A) H 3-Th 13 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H Ph 14 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 4-Me-C6H4. 15 Me 4 ~ MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 3 ~ F-4-Me-C6H3 16 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 2 + C6H4 17 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 3- F-C6H4 18 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 2-C Bu C6H4 19 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 2-Me-C6H4 20 Me 4-MeNHS02C6H4 Me 4-MeNHS02CH Ph (A) H cPent 21 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H l, 3,5-Me3-4-Pyra 22 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 2-C1 -4 -Me-C6H3 23 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 -CH2CH2OCH2CH2- 3-Th 24 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 -ch2ch2och2ch2- Ph 25 Me 4-MeNHS02C6H2 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 -CH2CH20CH2CH2- 3-F-4-Me-C6H3 27 Me 4-Py Me 4-Py Ph H 3-Th 28 Me 4-Py Me 4-Py Ph H Ph 29 Me 4-Py Me 4-Py Ph H 4-Me-C6H4 30 Me 4-Py Me 4-Py Ph H 3-F-4-Me-C6H3 31 Me 4-Py Me 4-Py Ph H 2-F-C6H4 32 Me 4-Py Me 4 -Py Ph H 3-F-C6H4 33 Me 4-Py Me 4-Py Ph H 2-C Bu C6H4 34 Me 4-Py Me 4-Py Ph H 2-Me-C6H4 35 Me 4-Py Me 4-Py Ph H cPent 36. Me 4-Py Me 4-Py Ph H 1, 3, 5-Me3-4-Pyra 37 Me 4-Py Me 4-Py Ph H 2 ~ C1-4 ~ M6 ~ C6H3 38 Me. 4 -Py Me 4-Py Ph (A) H 3-Th 39 Me 4-Py Me 4-Py Ph (A) H Ph -32 200522964 40 Me 4-Py Me 4-Py Ph (A) Ή 4-Me ~ C6H4 41 Me 4-Py Me 4-Py Ph (A) H 3-F-4-Me-C6H3 42 Me 4-Py Me 4-Py Ph (A) H 2-F-C6H4 43 Me 4-Py Me 4 -Py Ph (A) H 3-F-C6H4 44 Me .4-Py Me 4-Py Ph (A) H 2-C C6H4 45 Me 4-Py Me 4-Py .Ph (A) .H 2- Me-C6H4 46 Me 4-Py Me 4-Py-CH2CH20CH2CH 「3-Th 47 Me 4-Py Me 4-Py-ch2ch2och2ch「 Ph 48 Me 4-Py Me 4-Py -ch2ch2och2ch2 -4 -Me-C6H4 49 Me 4-Py Me 4-Py-ch2ch2och2ch 「3 -F + Me-C6H3 50 Me 4 ~ M6S02C6H4 Me. 4-MeS02C6H4 Ph H 3-Th 51 Me 4 ~ M6S02C6H4 Me 4-MeS02C6H4 Ph H Ph 52 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 4-Me-C6H4 53 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 3-F-4 ~ Me -C6H3 54 Me 4 ~ M6S02C6H4 Me 4-MeS02C6H4 Ph H 2 -F-C6H4 55 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph, H 3-F-C6H4 56 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 2-Cl- C6H4 57 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 2-Me-C6H4 58 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H cPent 59 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 1,3,5-Me3-Pyra 60 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 2-C1-4-M6-C6Hj 61 Me 4 ~ MeS02C6H4 Me 4-MeS02C6H4 Ph (A) H 3-Th 62 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph (A) H Ph 63 Me 4 ~ M6S02C6H4 Me 4-MeS02C6H4 Ph (A) H 4-Me-C6H4 64 Me 4-MeS02C6H4 Me 4-MeSO2C04 Ph (A) H 3-F + Me-C6H3 65 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph (A) H 2-F-C6H4. 66 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph (A) H 3-F-C6H4 67 Me 4 ~ M6S02G6H4 Me 4-MeS02C6H4 Ph (A) H · 2-Cl-C6H4 68 Me 4r-MeS02C6H4 Me 4-MeS02C6H4 Ph (A) H 2-Me-C6H4 69 Me 4-MeS02C6H4 Me 4-MeS02C 6H4 -CH2CH2OCH2CH2- 3-Th • 33- 200522964 70 Me 4-MeS02C6H4 Me 4-MeS02C6H4 -CH2CH20CH2CHr Ph 71 Me '4-MeS02C6H4 Me 4-MeS02C6H4-CH2CH2OCH2CHr 4-Me-C6H4 72 Me4-MeS -02 CH2CH2OCH2CHr 3-F-4-Me-C6H3 73 Me 4-EtS02C6H4 Me 4 ~ E t S02C6H4 Ph H .3-Th 74 Me 4-EtS02C6H4 Me 4-EtS02C6H4 Ph H Ph 75 Me 4 -EtS02C6H4 Ph H 4-Me-C6H4 76 Me 4 -EtS02C6H4 Me 4 -EtS02C6H4 Ph H 3 -F + Me-C6H3 77 Me 4-E t S02C6H4 Me 4-EtS02C6H4 Ph H 2-F-C6H4 78 Me 4-Et S02C6H4 Me 4- EtS02C6H4 Ph H 3-F-C6H4 79 Me 4 -EtS02C6H4 Me 4-EtS02C6H4 Ph H 2-C Bu C6H4 80 Me 4 -EtS02C6H4 Me 4-EtS02C6H4 Ph H 2-Me-C6H4 81 Me 4_EtS02C6H4 Me 4-Et ) H 3-Th 82 Me 4 -EtS02C6H4 Me 4_EtS02C6H4 Ph (A) H Ph 83. Me 4 -E tS02C6H4 Me 4-EtS02C6H4 Ph (A) H 4-Me-C6H4 84 Me 4-EtS02C6H4 Me (EtS02C6H4 Ph ( A) H 3-F-4 -Me-C6H3 85 Me 4-EtS02C6H4 Me 4-EtS02C6H4 Ph (A) H 2-F-C6H4 86 Me 4-EtS02C6H4 Me 4 -EtS02C6H4 Ph (A) H 3-F-C6H4 87 Me 4-EtS02C6H4 Me 4-EtS02C6H4 Ph (A) H 2-C BU C6H4 88 Me 4-EtS02C6H4 Me 4-EtS02C6H4 Ph (A) H 2-Me-C6H4 89 Me 4-EtS02C6H4 Me 4-EtS02C6H4 -CH2CH20CH2CHr 3-Th 90 Me 4-EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph H 3-Th 91 Me 4 -EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph H Ph 92 Me 4-EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph H 4-Me-C6H4 93 Me 4 -EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph H 3-F-4-Me-C6H3 94 Me .2C6H4 Me 4-EtNHS02C6H4 Ph H 2-F-C6H4 95 Me 4-EtNHS02C6H4 Me 4 -EtNHS02C6H4 Ph H 3-F-C6H4 96 Me 4 -EtNHS02C6H4 Me 4 ·-EtNHS02C6H4 Ph H 2-C Bu C6H4 97 Me 4- EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph H 2-Me-C6H4 98 Me 4-EtNHS02C6H4 Me 4 -EtNHS02C6H4 Ph (A) H 3-Th 99 Me 4-EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph (A) H Ph -34- 200522964 100 4 -EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph (A) H 4-Me-C6H4 101 Me 4-Et_2C6H4 Me 4-EtNHS02C6H4 Ph (A) H '3-F-4-Me-C6H3 102 Me 4-EtNHS02C6H4 Ph (A) H 2-F-C6H4 103 Me 4-EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph (A) H 3-F-C6H4 104 Me 4-EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph (A) H 2-CJ-C6H4 105 Me 4 ~ EtNHS02C6H4 Me 4-EtNHS02C6H4 Ph (A) H 2 -Me-C6H4 106 Me 4 ~ EtNHS02C6H4 Me '4 -EtNHS02C6H4-CH2CH2OCH2CH 2- 3 ~ Th 107 Me 4- (1-Azt) -S02C6H4 Me 4- (Bu Azt) -S02C6H4 Ph H 3-Th 108 Me 4 ~ (l ~ Az t) -S02C6H4 Me 4- (l ~ Azt) * ~ S02C6H4 Ph H Ph 109 Me 4-cPrNHS02C6H4 Me 4-cPrNHS02C6H4 Ph H 3-Th 110 Me 4-cPrNHS02C6H4 Me 4-cPrNHS02C6H4 Ph H Ph 111 Me Ph⑻ Me Ph (B) Ph H 3-Th 112 Me PMB) Me Ph⑻ Ph H Ph 113 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 4-Cl-C6H4 114 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 4-C C6H4 115 Me 4-PyMe 4-Py Ph H 4-Cl ~ C6H4 116 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-MeO-C6H4 117 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 2-Me0- C6H4 118 Me 4-Py Me 4-Py Ph H 2-MeO-C6H4 119 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 3-MeO-C6H4 120 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 3-MeO-C6H4 121 Me 4HPy Me 4-Py Ph H 3-MeO-C6H4 122 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 4-MeO-C6H4 123 Me 4-MeS02C6H4 Me 4-MeS0zC6H4 Ph H 4-MeO-C6H4 124 Me 4-Py Me 4-Py PhH 4-MeO-C6H4 125 Me 4-MeNHS02C6H 4 Me 4-MeNHS02C6H4 Ph H 2,4- (MeO) 2-C6H3 126 Me 4-MeS02C6H4 Me H -4- (MeO) rC6H3 127 Me 4-Py Me 4-Py Ph H. 2, 4- (MeO) rC6H; 128 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 3-Cl-C6H4 129 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 3- (M-C6H4 -35- 200522964 130 Me 4-Py Me 4-Py Ph H 3 普 C6H4 131 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H •, 4-F-C6H4 132 Me 4 ~ MeS02C6H4 Me 4-MeS02C6H4 Ph H 4 + C6H4 133 Me 4-Py Me 4-Py Ph H 4-F-C6H4 134 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 3-Me-C6H4 135 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H • 3-Me-C6H4 136 Me 4-Py Me 4-Py Ph H 3-Me-C6H4 137 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2, 3-Me2-C6H3 138 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 2, 3-Me2-C6H3 139 Me 4-Py. Me 4- Py Ph H 2, 3-Me2-C6H3 140 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2, 4-F2-C6H3 141 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 2, 4-F2-C6H3 142 Me 4- Py Me 4-Py Ph H 2, 4-F2-C6H3 143 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 3-C BU 2-F-C6H3 144 Me 4-MeS02C6 H4 Me 4-MeS02C6H4 Ph H 3-C Bu 2-F-C6H3 145 Me 4-Py Me 4-Py Ph H 3-C1-2 -F-C6H3 146 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 4-Π -2-F-C6H3 147 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 4-Cl-2-F-C6H3 148 Me 4-Py Me 4-Py Ph H 4-Π-2 + C6H3 149 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2, 3-Cl2-C6tt3 150 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H 2,3-Cl2-C6H3 151 Me 4-Py Me 4-Py Ph H • 2,3-Cl2_C6H3 152 Me 4 -MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-F ~ 5 ~ M6 ~ C6H3 153 Me 4 ″ MeS02C6H4 Me 4-MeS02C6H4 Ph H 2-F-5-Me-C6H3 154 Me 4-Py Me 4-Py Ph H 2- F + Me-C6H3 155 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-Π-4-Me-C6H3 156 Me 4-MeS02C6H4 Me 4 ~ M6S02C6H4 Ph H 2 * ~ C1-4 * ~ Me-C6H3 157 Me 4 -Py Me 4-Py Ph H 2-Cl " " 4 ~ M0-C6H3 158 • Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-MeO-5 ~ Ph-C6H3 159 Me 4 ~ M6S02C6H4 Me 4-MeS02C6H4 Ph H 2 ~ M6〇 ~ 5 * ~ Ph ~ C6H3 -36- 200522964 160 Me 4-Py Me 4-Py Ph H 2-MeO-5-Ph-C6H3 161 Me '4-MeNHS02C6H4 Me 4-MeNHS02C6H4 丨 Ph H Ph (C) 162 Me4-MeS0 2C6H4 Me 4-MeS02C6H4 Ph H Ph (C) 163 Me 4-Py Me 4-Py Ph H Ph (C) 164 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 Ph H Ph (D) 165 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H PMD) 166 Me 4-Py Me. 4-Py Ph H PHD) 167 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 .. Ph H PIKE) 168 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Ph H Ph (E) 169 Me 4HPy Me. 4-Py Ph H Ph (E) 170 Me 4-MeNHS02C6H4 Me 4-Py Ph H 3-Th 171 Me 4-MeNHS02C6H4 Me 4-Py Ph H Ph 172 Me 4-MeNHS02C6H4 Me 4-Py Ph H 4 -Me-C6H4 173 Me 4-MeNHS02C6H4 Me 4-Py Ph H 3-F-4-Me-C6H3 174 Me 4-MeNHS02C6H4 Me 4-Py Ph H 2 + C6H4 175 Me 4-MeNHS02C6H4 Me 4-Py Ph H 3 -F-C6H4 176 Me 4-MeNHS02C6H4 Me 4-Py .Ph H 2-Cl-C6H4 177 Me 4-MeNHS0? C6H4 Me 4-Py Ph H 2-Me ~ C6H4 178 Me 4-MeNHS02C6H4 Me 4-Py 4- F-C6H4 H 3-Th 179 Me 4-MeNHS02C6H4 Me 4-Py 4 -F-C6H4 H Ph 180 Me 4-MeNHS02C6H4 Me 4-Py 4-F-C6H4 H 4-Me-C6H4 181 Me 4-MeNHS02C6H4 Me 4 -Py 4-F-C6H4 H 3-F-4 ~ Me-C6H3 182 Me 4-MeNHS02C6H4 Me 4-Py 4-F-C6H4 H 2-F-C6H4 183 Me 4-MeNHS02C6H4 Me 4-Py 4-F- C6H4. H 3-F -C6H4 184 Me 4-MeNHS02C6H4 Me 4-Py 4-F-C6H4 H 2-CK6H4 185 Me 4-MeNHS02C6H4 Me 4-Py 4 + C6H4 H 2-M0 ~ C6H4 186 Me 4-MeNHS02C6H4 Me 4-Py 2 + C6H4 H 3-Th 187 Me 4-MeNHS02C6H4 Me 4-Py 2 + C6H4 H Ph 188 Me 4-MeNHS02C6H4 Me 4-Py 2-F-C6H4 H 4 ~ Me ~ C6H4 189 Me 4-MeNHS02C6H4 Me 4-Py 2-F -C6H4 H 3-F-4-Me-C6H3 -37 200522964 190 Me 4-MeNHS02C6H4 Me 4_Py 2-F-C6H4 H 2-F_C6H4 191 Me 4-MeNHS02C6H4 Me 4-Py 2-F-C6H4 H 3-F ~ C6H4 192 Me 4-MeNHS02C6H4 Me 4-Py 2-F-C6H4 H 2 C6H4 193 Me 4-MeNHS02C6H4 Me 4-Py 2 + C6H4 H 2-Me-C6H4 194 Me 4-MeNHS02C6H4 Me 4-Py Ph (A) H 3-Th 195 Me 4-MeNHS02C6H4 Me 4-Py Ph (A) H Ph 196 Me 4-MeNHS02C6H4 Me · 4-Py Ph (A) H 4-Me-C6H4 197 Me 4 ~ MeNHS02C6H4 Me 4-Py Ph ( A) H 3 -F + Me-C6H3 198 Me 4-MeNHS02C6H4 Me 4-Py Ph (A). H 2-F-C6H4, 199 Me 4-MeNHS02C6H4 Me 4-Py Ph (A) H 3 + C6H4 200 Me 4-MeNHS02C6H4 Me 4-Py Ph (A) H 2-Cl-C6H4 201 Me 4-MeNHS02C6H4 Me '4-Py Ph (A) H 2-Me-C6H4 202 Me 4-MeS02C6H4 Me 4-Py Ph H 3- Th 203 Me 4-MeS02C6H4 Me 4-Py Ph H Ph 204 Me 4-MeS02C6H4 Me 4-Py Ph H 4 ~ Me ~ C6H4 205 Me 4-M6S02C6H4 Me 4-Py Ph H 3 One F One 4-Me * ~ C6H3 206 Me 4-MeS02C6H4 Me 4-Py: .Ph H 2-F-C6H4 207 Me 4-MeS02C6H4 Me 4-Py Ph H 3-F-C6H4 208 Me 4-MeS02C6H4 Me 4-Py Ph H 2-C Bu C6H4 209 Me 4-MeS02C6H4 Me 4-Py Ph H 2-Me-C6H4 210 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H 3-Th 211 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H Ph 212 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H 4-Me-C6H4 213 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H 3_f_4-Me * ~ C6H3 214 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H 2 -F-C6H4 215 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H 3-F-C6H4 216 Me 4-MeS02C6H4 Me 4-Py 4 + C6H4 H 2 Pu C6H4 217 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H. 2-Me-C6H4 218 Me 4-MeS02C6H4 Me 4-Py 2-F-C6H4 H 3-Th 219 Me 4-MeS02C6H4 Me 4-Py 2 + C6H4 H Ph -38- 200522964 220 Me 4-MeS02C6H4 Me 4 ~ Py 2-F-C6H4 H 4-M6 ~ C6H4 221 Me 4-MeS02C6H4 Me 4-Py 2-F-C6H4 H 3-F-4-Me-C6H3 222 Me 4-MeS02C6H4 Me 4- Py 2 + C6H4 H 2-F-C6H4 223 Me 4-MeS02C6H4 Me 4-Py 2-F-C6H4 H 3-F-C6H4 224 Me 4-MeS02C6H4 Me 4-Py 2 + C6H4 H 2-C1-C6H4 225 Me 4-MeS02C6H4 Me 4-Py 2-F-C6H4 H 2- Me-C6H4 226 Me 4-MeS02C6H4 Me 4-Py Ph (A) H 3-Th 227 Me 4-MeS02C6H4 Me 4-Py Ph (A) H Ph 228 Me 4-MeS02C6H4 Me 4-Py Ph (A) H 4 -Me-C6H4 229 Me 4-MeS02C6H4 Me 4-Py Ph (A) H 3-F-4-Me-C6H3 230 Me 4-MeS02C6H4 Me 4-Py Ph (A) H 2-F-C6H4 231 Me 4- MeS02C6H4 Me 4-Py Ph (A) H 3 -F-C6H4 232 Me 4-MeS02C6H4 Me 4-Py Ph (A) H 2-C Bu C6H4 233 Me 4-MeS02C6H4 Me 4-Py Ph (A) H 2- Me-C6H4 234 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 4 + C6H4 H 3 ~ Th 235 Me 4-MeNHS02C6H4 Me 4-MeNHS02Q6H4 4-F-C6H4 H Ph 236 Me 4-MeNHS02C6H4 Me-MeNHS02C6H4 4-F-C 4-Me-C6H4 237 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 4-F-C6H4 H 3-F-4-Me-C6H3 238 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 4 + C6H4 H 2-F-C6H4 239 Me 4 -MeNHS02C6H4 Me 4-MeNHS02C6H4 4 + C6H4 H 3-F-C6H4 240 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 4-F-C6H4 H 2-C Bu C6H4 241 Me 4-MeNHS02C6H4 Me 4-MeNHS02C- 6H4 4- C6H4 H 2-Me-C6H4 242 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 2-F-C6H4 H 3-Th 243 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 2-F-C6H4 H Ph 244 Me 4-MeNHS02C6H4 Me 4-MeNHS 2-F-C6H4 H 4-Me-C6H4 245 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 2 -F-C6H4 H 3-F-4-Me-C6H3 246 • Me 4_MeNHS02C6H4 Me 4-MeNHS02C6H4 2-F-C6H4 H 2 + C6H4 247 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 2-F-C6H4 H 3-F-C6H4 248 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 2 -F-C6H4 H 2-C Bu C6H4 249 Me 4-MeNHS02C6H4 Me 4- MeNHS02C6H4 2-F-C6H4 H 2-Me-C6H4 -39- 200522964 250 Me 4-MeS02C6H4 Me 4-MeS02C6H4 4-F-C6H4 H 3-Th 251 Me 4-MeS02C6H4 Me 4-MeS02C6H4 4-F-C6H4 H Ph 252 Me 4-MeS02C6H4 Me 4-MeS02C6H4 4-f-c6h4 H 4-Me ~~ C6H4 253 Me 4-MeS02CpH4 Me 4-MeS02C6H4 4-F-C6H4 H 3 one p one 4 one Me-C6H3 254 Me 4-MeS02C6H4 Me 4-MeS02C6H4 4-F-C6H4 H 2 + C6H4 255 Me 4-MeS02C6H4 Me 4-MeS02C6H4 4 -F-C6H4 H 3 + C6H4 256 Me 4-MeS02C6H4 Me .4-MeS02C6H4 4-F-C6H, H 2- CK6H4 257 Me 4-MeS02C6H4 Me 4-MeS02C6H4 4-F-C6H4 H, 2-Me-C6H 4 258 Me 4-MeS02C6H4 Me 4-MeS02C6H4 2-F-C6H4 H 3-Th 259 Me 4-MeS02C6H4 Me 4-MeS02C6H4 2-F-C6H4 H Ph f 260 Me 4-MeS02C6H4 Me 4-MeS02C6H4 2-F-C6H4 H 4-Me-C6H4 261 Me 4-MeS〇2C6H4 Me 4-MeS02C6H4 2-F-C6H4 H 3 -F + Me-C6H3 262 Me 4-MeS02C6H4 Me 4-MeS02C6H4 2 + C6H4 H 2-F-C6H4 263 Me 4-MeS02C6H4 Me 4-MeS02C6H4 2 -F-C6H4 H 3-F-C6H4 264 Me 4-MeS02C6H4 Me 4-MeS02C6H4 .2-F-C6H4 H 2-C Bu C6H4 265 Me 4-MeS02C6H4 Me 4-MeS02C6H4 '2 -F-C6H4. H .2-Me-C6H4 266 Me 4-Py Me 4-Py 4-F-C6H4 H 3-Th 267 Me. 4-Py Me 4-Py 4 -F-C6H4 H Ph 268 Me 4 -Py Me 4-Py 4-F-C6H4 H 4-Me ~ C6H4 269 Me 4-Py Me 4-Py 4-F-C6H4 H 3_F-4-Me-C6H3 270 Me 4-Py Me 4-Py 4+ C6H4 H 2-F_C6H4 271 Me 4-Py Me 4-Py 4 -F-C6H4 H 3-F-C6H4 272 Me 4-Py Me 4-Py 4 + C6H4 H 2-Cl-C6H4 273 Me 4-Py Me 4 -Py 4-F-C6H4 H 2-Me-C6H4 274 Me 4-Py Me 4-Py 2-F-C6H4 H 3-Th 275 Me 4-Py Me 4-Py 2-F-C6H4 H Ph 276 Me 4 -Py Me 4-Py 2-F-C6H4 H 4-Me-C6H4 277 Me 4-Py Me 4-Py 2-F-C6H4 H 3-F-4-Me-C6H 3 278 Me 4-Py Me 4-Py 2 -F-C6H4 H 2-F-C6H4 279 Me 4-Py Me 4-Py Me 4-Py 2-F-C6H4 H 3-F-C6H4 -40- 200522964 280 Me 4-Py Me 4-Py 2 -F-C6H4 H 2-C Bu C6H4 281 Me 4-Py Me 4-Py 2-F-C6H4 H 2-Me-C6H4 282 Me 4-MeNHS02C6H4 Me 4-Py Ph (A) H 3 ~ M6 ~ C6H4 283 Me 4-MeS02C6H4 Me • 4-Py Ph H 3-Me-C6H4 284 Me 4-MeS02C6H4 Me 4-Py 4-F-C6H4 H 3-Me-C6H4 285 Me 4 ~ M6S02CgH4 Me 4-Py 2-F-C6H4 H 3-Me-C5H4 286 Me 4-MeS02C6H4 Me 4-Py Ph (A) H 3-Me-C6H4 287 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 4 -F-C6H4 H 3-Me- C6H4 288 Me 4-MeNHS02C6H4 Me 4-MeNHS02C6H4 2-F-C6H4 H 3-Me-C6H4 289 Me 4-MeS02C6H4 Me 4-MeS02C6H4 4 + C6H4 H 3-Me-C6H4 290 Me 4-M6S02C6H4 Me 4-MeS02C F-C6H4 H 3-Me-C6H4 291 Me 4-Py Me 4-Py 4-F-C6H4 H 3-Me-C6H4 292 Me 4-Py Me 4-Py 2-F-C6H4 H 3-Me-C6H4 293 Me 4-MeNHS02C6H4 Me 4-Py Ph H 3-Me-C6H4 294 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph H 3-Th 295 Me 4-MeS02C6H4 Me 4 -MeNHS02C6H4 Ph H Ph 296 Me 4-MeS02C6H4 Me 4-MeNHS02C6 Ph H 4-Me-C6H4 297 Me 4-MeS02C6H4 .Me 4-MeNHS02C6H4 Ph H 3-F-4-Me * ~ C6H3 298 Me 4-MeS02C6H4 Me 4 ~ MeNHS02C6H4 Ph H 2-F-C6H4 299 Me 4-MeS02C6H4 Ph H 3 -F-C6H4 300 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-C Bu C6H4 301 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph H 2-Me-C6H4 302 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph H 3- -C6H4 303 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 3-Th 304 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H Ph 305 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 4 ~ Me-C6H4 306 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 3 -F_4 -Me-C6H3 307 Me 4 ~ M6S02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 2-F-C6H4 Me 308 Me 4-MeS02C6H4 Me 4 -MeNHS02C6H4 Ph (A) H 3-F-C6H4 309 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 Ph (A) H 2 pu C6H4 -4 1-200522964 310 Me 311 Me 4-MeS02C6H4 Me 4-MeS02C6H4 Me 4-MeNHS02C6H4 4 -MeNHS02C6H4 Ph (A) Ph (A) Η Η 2- Me-C6H4 3- Me-C6H4 0 In Table 1, the preferred compounds are compound numbers 1, 2, 3, 4, 5, 8 X 10, 1, 3. 24, 28, 51, 55, 56, 74 , 91, 108, 110, 1 12 170, 171, 172, 173, 174, 175, 176, 177, 178 '179 180, 181, 182, 183, 184, 185 ^ 186, 187, 188, 189 190, 191 , 192, 193, 194, 195, 196, 197 > 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208 '209 2 11, 219' 227 '235, 243, 251, 251, Compound No. 259, 267, 275, 283 or 293, and preferably Compound No. 1, 2, 3, 4, 5 '8, 10, 13, 24, 28, 51, 55 > 56, 74, 91, 108, 110, 1 12, 170, 171, 172, 173, 174, 175, 176, 177 '179, 187, 202, 203, 204, 205, 206, 207, 208, 209 > 211, 219' 227, 235, Compounds No. 243, 251, 259, 267, 275, 283, or 293, more preferably compound numbers 1, 2, 2, 4, 5, > 8, 10, 13, 24, 28, 5 1, 55 '56, 74 , 91, 108, 1 10, 1 12, 170, 171, 172, 173, 174, 175 '176, 177, 179, 187' 203'211 219, 235, 243, 251 '259, 267: or compound No. 275, particularly preferably a chemical compound: 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-: anilino -6- {2- [1- (4-methylaminesulfonylphenyl) ethylidene] hydrazino) -5- (3 • thiophene: m) · 4-ι 废 pyrimidinyl) pentene: (compound number η 1 1- (4-Methylaminesulfonylphenyl) -acetophenone N- (2-anilino-6- {2-[l- (4-methylamine

-42-200522964 Sulfonylphenyl) ethylene] hydrazinob 5-phenyl-4-pyrimidinyl) sulfinyl (compound number: code 2), 1- (4-methylaminesulfonylphenyl)- 1-Ethyl ketone N- (2-anilino-5 "4-tolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) Hydrazine (Compound No. 3), 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (3-fluoro-4-tolyl) -6- {2 -[1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob4-pyrimidinyl) hydrazine (Compound No. 4), 1- (4-methylaminesulfonylphenyl) -acetylacetone N- (2-aniline-5- (2 · fluorophenyl) -6- # {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) Hydrazine (Compound No. 5), ^ (4-methylaminosulfonylphenyl) -acetylacetone & (2-anilino-5-o-tolyl-6- {2_ Π- (4-methylaminesulfonyl) Alkyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 8), 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- ( 1,3,5-trimethyl-1H-pyrazol-4-yl) -6- {2- [1- [4- (methylaminosulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) Hydrazine (compound number 10), ^ 1- (4-methylaminesulfonylbenzene) ) -Butanone (2- (5-fluoro-2-tolylamino) -5-phenyl_6_ {2_ [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine -Pyrimidinyl) arylene (Compound No. 1 3), 1- (4-methylaminosulfonylphenyl) -1_ethyl ketone 1 ^-(2-morpholin-1-yl-5-phenyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylidene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 24), 1- (4-pyridamidine) -1-ethyl N- (2 · anilino-5-phenyl · 6- {2- [1- [4- (bipyridine-43-200522964)) ethylene] hydrazinob 4-pyrimidinyl) hydrazine ( Compound No. 28), 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-anilino-5-phenyl-6- {2- [b (4-methylsulfonylphenyl) Ethylene] hydrazinob 4-pyrimidinyl) hydrazine (Compound No. 51), 1- (4-methylsulfonylphenyl) -1-ethanone N- (2.anilino-5- (3-fluoro Phenyl) -6- {2- [1- (4-methanesulfonylphenyl) ethylene] hydrazinobfpyrimidinyl) hydrazine (compound number 55), 1- (4-methanesulfonylphenyl) ) · Ethyl ketone N- (2-anilino-5- (2-chlorophenyl) -6- {2- [1- (4-methylsulfonylphenyl) ethylene] hydrazine ) Hydrazine (Compound No. 56), 1- (4-Ethylsulfonylphenyl) -Ethyl ethyl ketone 1 ^-(2-anilino-5-phenyl-6- {2- [1- (4-ethanesulfonylphenyl) ethylene] hydrazinobu 4-pyrimidinyl) hydrazine ( Compound No. 74) '1- (4-Ethylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5-phenyl-6- {2- [ (Alkylene) ethylidene] hydrazine 4-pyrimidinyl) sulfinyl (compound number 91), ^ (4-azetidin-1-yl-sulfofluorenyl) -1-ethyl ketone N- (2-aniline -5-phenyl-6- {2- [1- (4-azetidin-1-yl-sulfofluorenyl) ethyl] hydrazinob 4-pyrimidinyl) hydrazine (compound number 108) , 1- (4-Cyclopropylaminesulfonylphenyl) · bucetone N- (2-anilino-5-phenyl-6 · {2- [1- (4-Cyclopropylaminesulfonylphenyl) ethylene Yl] hydrazinyl 4-pyrimidinyl) hydrazine (compound number 1 1 〇), 1- [4- (2-hydroxyethyl) -sulfamoylphenyl] -1-ethyl ketone > ^ [2- Anilino-5-phenyl-6- (2- {1- [4- (2-hydroxyethyl) -sulfamophenyl] ethylidene} hydrazino) -4-pyrimidinyl 200522964] hydrazine ( Compound No. 112) ,; N-methyl-4- {l-[(5-phenyl-2-anilino-6- {N '-[1-pyrene-4-yl-ethylidene. ] -Hydrazinepyrimidin-4-yl) -Hydrazine l · ethylbenzafide (Compound No. 17 1), 4- {1-[(2- (4-fluoroaniline) -5-phenyl-6- {1 ^ '-[1-pyridin-4-yl-ethylidene] -hydrazine} -Pyrimidin-4-yl) -hydrazinyl] -ethyl N-tosylsulfonamide (compound number 179) or 4- {1-[(2- (2-fluoroaniline) -5 -phenyl- 6- {N '-[1-pyridine-4-yl-ethylidene] -hydrazinopyrimidin-4-yl) -hydrazinopyridineb-N-toluenesulfonamide (Compound No. · Code 1 8 7) Most preferably a compound: 1- (4-methylaminesulfonylphenyl) -1-ethanone 1 ^ (2-aniline-6- {2- [1- (4-methylaminesulfonylphenyl) ) Ethylene] hydrazino} -5- (3-thienyl) -4-pyrimidinyl) hydrazine (compound number 1), 1- (4-methylaminesulfonylphenyl) -1-ethyl ketone N- (2-aniline-6- {2- [l- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 5-phenyl-4-pyrimidinyl) hydrazine (compound number 2), 1 -(4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5- (4-tolyl) -6-U- [1- (4-methylaminesulfonylphenyl) Ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 3), 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (3- Fluoro-4 · tolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] fluorenyl} -4-pyrimidinyl) Hydrazine (Compound No. 4), -45- 200522964 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5- (2-fluorophenyl) -6-; { 2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob4-pyrimidinyl) hydrazine (chemical compound number 5), 1- (4-methylaminesulfonylphenyl) 1-Ethyl ketone 1 ^ (2-anilino-5-o-tolyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) Hydrazine (Compound No. 8), 1- (4-pyridyl) -acetophenone N- (2-anilino-5-phenyl-6- {2- [1- (4-pyridyl) ethylene] Hydrazine 4-pyrimidinyl) hydrazine (compound number 28), 1- (4-methanesulfonylphenyl) -1-ethanone N- (2-anilino-5-phenyl-6-{2- [1- Φ (4-Methanesulfonylphenyl) ethylene] hydrazinob4-pyrimidinyl) hydrazine (Compound No. 51), 1- (4-methylsulfonylphenyl) -1-ethanone N -(2-aniline- 5- (3-fluorophenyl) -6- {2- [1- (4-methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound No. 55), 1 ^ -methyl-4- {1-[(5-phenyl-2_anilino-6- {1 ^,-[1-pyridin-4-yl-ethylidene] -fluorenyl Pyrimidin-4-yl) -hydrazinyl] -ethylbenzamide (compound number 171), 4- {1-[(2- (4-fluoroaniline) -5_phenyl [pyridin-4-yl-ethylidene] -hydrazinopyridin-4-yl) _hydrazinylethyl N-toluenesulfonamide (compound number 179) or 4- {1-[(2 · (2-fluoroaniline) phenyl jqNH-pyridin-4-yl-ethylidene] -hydrazinopyridin-4 -Yl) -hydrazinyl] -ethyl N-tosylsulfonamide (compound number 187). The compound of formula (I) of the present invention can be produced as follows. -46- 200522964 Method A is a method for producing a compound of formula A

R5, / R6 N

N people N X

X (V) A1 project, h2n—nh2 N people N __ A2 project

R5 \ / R6 N

HIJT, IJH nh2 r7 nh2 (II) R2 human 1 (III) 〇 R4 human R3 (IV) rVr6 R4

HN I N

, N

NH N ^ .R1 (I) R2 In the present invention, R1, R2, R3, R4, R5, r6, and R7 are as defined above, and X is a halogen atom, an aromatic sulfonate group, or an alkanoate group. Project A 1 This project is a manufacturing process of a compound of formula (I I). The compound of formula (V) is reacted with hydrazine monohydrate or anhydrous tritium in the presence or absence of an inert solvent (preferably in the absence of). The solvent used in this project is not hindering the reaction, so long as it can dissolve the starting materials to a certain extent, such as formamide, N, N-dimethylformamide, Ν, Ν · dimethylacetamide Isoamines; ethers, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; dichloromethane, 1,2-dichloroethane, chlorobenzene And other halogenated hydrocarbons; aromatic hydrocarbons such as benzene, toluene, xylene; or methanol, ethanol, n-propanol, isopropanol, n-butanol, third butanol, isoamyl alcohol, diethylene glycol, glycerin, Alcohols such as octanol, cyclohexanol, and 2 · methoxyethanol are preferably alcohols (most preferably ethanol). -47- 200522964 The reaction temperature in this project may vary depending on the raw material compounds, inert solvents used, etc. It is usually room temperature to 120 ° C (preferably 50 ° C to 110 ° C). The reaction time in this project varies depending on the raw material compound, the inert solvent used, the reaction temperature, etc., and is usually 30 minutes to 24 hours (preferably 1 hour to 3 hours). Process A 2 This process is a process for producing a compound of formula (I). In the presence of an inert solvent, a compound of formula (I I) is reacted with a compound of formula (I I I) and a compound of formula (I V). When the compound of the formula (I I I) and the compound of the formula (IV) are the same compound, they can be reacted at the same time. When they are different compounds, they are reacted with the compound of the formula (I I I) and then reacted with the compound of the formula (IV). The inert solvent used in this project is non-obstructive to the reaction, and it is not limited to be able to dissolve the starting materials to a certain degree, such as formamidine, N, N-dimethylformamide, N, N-dimethylacetamide Isoamines; ethers, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and other ethers; dichloromethane, 1,2-dichloroethane, chlorobenzene And other halogenated hydrocarbons, aromatic hydrocarbons such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, n-propanol, isopropanol, diethylene glycol, and glycerol; and dysprosiums such as dimethylarsine and cyclobutane Nitriles such as acetonitrile; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; or a mixed solvent of the above solvents, preferably ethers or alcohols (most preferably two Pinane or ethanol). The reaction temperature in this project may vary depending on the raw material compound, the inert solvent used, etc., and is usually room temperature to 120 ° C (preferably 90 ° C to 100 ° C). 200522964 The reaction time in this project varies depending on the raw material compound, the inert solvent used, the reaction temperature, etc., and is usually 1 hour to 48 hours (preferably 15 hours to 24 hours). After the completion of the reaction in each process in the above method A, each purpose Compounds can be prepared from the reaction mixture by conventional methods. For example, the reaction mixture is appropriately neutralized, and when insoluble matter is filtered off, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated, washed with water, etc., and then dried with anhydrous magnesium sulfate, Anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc. are obtained by drying the solvent. If necessary, the obtained target compound is obtained by conventional methods, such as recrystallization, reprecipitation, and other conventional methods for separating and refining organic compounds, and combining them with appropriate methods, applying chromatography, and dissolving and purifying them with an appropriate eluent. Method B is a process for producing a compound of formula (V), which is a raw material compound of method A.

Method B R5

Process B 2 (VIII) (VI) In the present invention, R5, R6, R7, and X are as defined above, and R8 is a lower alkyl group. Project B 1 This project is a manufacturing process for compounds of formula (VI). It is in an inert solvent (preferably amidoamines, ethers, alcohols or halogenated hydrocarbons, most preferably alcohols), in the presence of a base (should Are alkali metal hydroxides, alkali metal carbonates or organic salts, most preferably alkali metal hydroxides), let the compound of formula (VII) and the compound of formula (v III) at room temperature to 120. (: (Preferably -49- 200522964 80 ° C ~ 100 ° C) for 1 hour to 48 hours (preferably 10 hours to 24 hours) to carry out. Section B 2 This project is the manufacture of compounds of formula (V) Engineering, (i) when X is halogen, in the presence or absence of an inert solvent (preferably in the presence of ethers, aromatic hydrocarbons or halogenated hydrocarbons), make the compound of formula (VI) and a halogenating agent (preferably Phosphorus oxyhalides such as phosphorus oxychloride, phosphorus oxybromide, and phosphorus iodide, most preferably phosphorus oxychloride), react at 20 ° C ~ 120 ° C (preferably 80 ° C ~ 100 ° C) 30 minutes to 24 hours (preferably 4 hours to 8 hours) 'Let the hydroxyl group in the compound of formula (VI) be changed with halogen, (ii) when X is an aromatic sulfonate or alkane sulfonate, in an inert solvent In the presence or absence (preferably in the presence of halogenated hydrocarbons), the compound of formula (VI) and a sulfonating agent (preferably tosylsulfonium chloride, 2,4,6-trimethylsulfonylsulfonium chloride, 2,4, 6-Tricumylsulfonyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride and other sulfonyl chloride, most preferably 2,4,6-tricumylsulfonyl chloride, at 0 ° C ~ 80 ° C (preferably room temperature ~ 4 (TC)) 30 minutes ~ 24 hours It is preferably 4 hours to 8 hours), and the hydroxyl group in the compound of the formula (VI) is converted by using an aromatic sulfonate group or an alkanesulfonate group. After the completion of each engineering reaction in the above method B, each target compound can be prepared according to a conventional method. The reaction mixture is prepared. For example, the reaction mixture is appropriately neutralized, and when there is insoluble matter, it is filtered off, and an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound, and after washing with water, It is obtained by drying anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., and then distilling off the solvent. The obtained target compound is obtained by ordinary methods such as recrystallization, reprecipitation, etc. A suitable combination is obtained by applying chromatography to dissociation and purification with an appropriate eluent. Method C is a method for producing a compound of formula (v II) in method B raw material compounds. Method C r5JH r5 ^ ΝΝΗ (IX) ΝΗ2 (VII) This In the invention, R5 and R6 are as defined above.

Section C 1

This project is a manufacturing process of the compound of formula (VII), in an inert solvent (preferably amidoamines, ethers, alcohols, water or a mixed solvent of the above solvents, most preferably amidoamines or alcohols), let the formula ( IX) compounds and guanidine derivatives (e.g. cyanamide or 1H-pyrazole-1-carboxamidine hydrochloride, 3,5-dimethylpyrazole-1-carboxamidine nitrate and other pyrazole activated carboxamidine compounds , Preferably cyanamide or 1H-pyrazole-1-carboxamidine hydrochloride, and react at room temperature to 120 ° C (preferably 8 (TC to 100 ° C)) for 1 hour to 48 hours (preferably 1 (0 hours to 24 hours). After the completion of each engineering reaction in the above method C, each target compound can be prepared from the reaction mixture according to the usual method. For example, the reaction mixture is appropriately neutralized, and when insoluble matter is filtered off, Add an immiscible organic solvent such as water and ethyl acetate to separate the organic layer containing the target compound, wash it with water, etc., dry with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., and evaporate the solvent to obtain it. The obtained target compound is isolated and purified according to ordinary methods, such as recrystallization, reprecipitation, etc. The method is appropriately combined, and it is obtained by applying chromatography -51- 200522964 to dissolve and purify with an appropriate eluent. Method D is a method for producing the compound of formula (v I I I) as the raw material compound in method b. Method D R80

(X) 〇 〇 Project D1 R7-Y (XI)

In the present invention, R7 and R8 are as defined above, and Y is a halogen atom. Project D 1

This project is a manufacturing process for compounds of formula (VI I I).

Hennessy, E.J., Buchwald, S. L. Org. Lett. 4, 2, 2002, 269-272, in an inert solvent (preferably ethers, most preferably tetrahydrofuran or difane), copper (Preferably copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) triflate, or monovalent copper salt, most preferably copper (I) iodide In copper (I) fumarate, phenol (preferably 2-phenylphenol), and base (preferably carbonic acid), the halogenated aryl group of the formula (XI) and the compound of the formula (X) are prepared at room temperature ~ The reaction is performed at 100 ° C (preferably 60 ° C to 80 ° C) for 2 hours to 7 days (preferably 15 hours to 48 hours). After the reaction of each process in the above method D is completed, each target compound can be prepared from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and when insoluble matter is filtered off, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated, washed with water, etc., and then dried with anhydrous magnesium sulfate, Anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc. are obtained by drying the solvent. If necessary, the obtained target compound can be obtained by conventional methods, for example, recrystallization, reprecipitation, and other conventional methods for separating and refining organic compounds by appropriate combination, and applying chromatography-52-200522964 to dissolve and purify with an appropriate eluent. The E method is a method for producing the compound of the formula (I) in the aforementioned A method. E method

Article E 1-^ RVR 6 people

υΛλυ is called R7 (ΧΠ)

In the present invention, R1, R2, R3, R4, R5, R6, ruler 7 and ¥ are as defined above. Section E 1

This project is a manufacturing process of compounds of formula (XII), in the presence or absence of an inert solvent (preferably in the presence of ethers, aromatic hydrocarbons or halogenated hydrocarbons). VI) Compounds and halogenating agents (preferably phosphorus oxyhalides such as phosphorus oxychloride, phosphorus oxybromide, and phosphorus iodide, most preferably phosphorus oxychloride), at 20 ° C ~ 120 ° C (preferably 80 ° C ~ 100 ° C) for 30 minutes to 24 hours (preferably 4 hours to 8 hours), and the hydroxyl group and the halogen in the compound of the formula (VI) are changed. Project E 2 This project is a manufacturing process of a compound of formula (X I I I). In the presence of an inert solvent, the compound of formula (XII) and hydrazine monohydrate or anhydrous hydrazine trans-53- 200522964 should be carried out. The inert solvent used in this project is non-obstructive to the reaction, and it is not limited to be able to dissolve the starting materials to a certain degree, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl Ethers such as ethers; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chlorobenzene; aromatic hydrocarbons such as benzene, toluene, and xylene; methanol, ethanol, n-propanol, isopropanol, Alcohols such as diethylene glycol and glycerol; sub-classes such as dimethylarsine and cyclobutane; or mixed solvents of the above solvents, preferably alcohols (most preferably ethanol). The reaction temperature in this project may vary depending on the raw material compound, the inert solvent used, etc. 'It is usually 0 ° C ~ 100 ° C (preferably room temperature ~ 60. (:). The reaction time in this project may depend on the raw material compound and the inert material used. Solvent, reaction temperature, etc. are usually 1 hour to 48 hours (preferably 15 hours to 36 hours). Project E 3 This project is a manufacturing process for a compound of formula (XIV). In the presence of an inert solvent, let the formula ( XI II) compound, which is carried out by reacting with the compound of formula (III). The inert solvent used in this project is not restrictive to the reaction, and there is no particular limitation on the solubility of starting materials to a certain extent, such as formazan, N, N-dimethylformamide Methylamines such as methylformamide, N, N-dimethylacetamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; Halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chlorobenzene; aromatic hydrocarbons such as benzene, toluene, and xylene; methanol, ethanol, n-propanol, isopropanol, diethylene glycol, and glycerol And other alcohols; dimethyl arylene, cyclobutadiene, and other subarsenides; acetonitrile and other nitriles; -54-20 0522964 Ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate: and other esters; or a mixed solvent of the above solvents, preferably ethers or alcohols (most preferably · Ershuyuan or ethanol ). The reaction temperature in this project may vary depending on the raw material compound, the inert solvent used, etc., usually room temperature ~ 120 ° C (preferably 60 ° C ~ 100 ° C). The reaction time in this project may depend on the raw material compound, The inert solvent used, the reaction temperature, etc. vary, usually from 1 hour to 24 hours (preferably 3 hours to 15 hours). E4th project Luben process is a manufacturing process of the compound of formula (I) in an inert solvent In the presence of a palladium catalyst, a phosphorus compound, and a base, a compound of formula (XIV) is reacted with a compound of formula (XV) for execution. The solvent used in this project is not to interfere with the reaction, and the starting materials can be dissolved to a certain extent. Specific limitations, such as formazan, N, N-dimethylformamide, N, N-dimethylacetamide, and other amines, N-methyl-2-pyrrolidone, N-methylpyrrole Amines such as pyridone, hexamethylphosphonium triamine; ether, diisopropyl ether, tetrahydrofuran, 1 Ethers such as 4-dioxane, dimethoxyethane, and diethylene glycol dimethyl ether β: Dimethanine, cyclobutadiene, and other sublimines; methylene chloride, 1,2-dichloroethane, Halogenated hydrocarbons such as chlorobenzene; or aromatic hydrocarbons such as benzene, toluene, and xylene, preferably amines, ethers, or aromatic hydrocarbons, and also Ν, Ν-dimethylformamide, Ν , N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, toluene or xylene. The palladium catalyst used in this project is, for example, a divalent palladium catalyst or a zero-valent palladium catalyst, preferably palladium -Activated carbon, palladium (II) acetate, palladium (II) trifluoroacetate, palladium-55-200522964 rhenium, palladium (II) bromide, chlorinated pin (π), palladium iodide (II), palladium cyanide: (II), Palladium (II) nitrate, Palladium (II) oxide, Palladium (II) sulfate, Di-chlorobis (acetonitrile) 16 (11), Monochlorobis (dry nitrile) pin (11), Dichloro (1 , 5-cyclooctadienyl) palladium (Π), acetoacetonepalladium (II), palladium (II) sulfide, tris (dibenzylideneacetone) dipalladium (0), (acetonitrile) palladium (Π) Fluorate, chlorinated aryl dimer, and preferably palladium acetate (11) or tris (dibenzylideneacetone) dipalladium 0) ° The phosphorus compound used in this project is, for example, an alkylphosphine, an aromatic phosphine or an aromatic phosphine, preferably an aromatic phosphine or a second compound aromatic phosphine, and preferably a triphenylphosphine, tri-tertiary butyl Phenylphosphine, 2,2, -bis (diphenylphosphine) -1,1'-binapthyl, bis (2-diphenylphosphinephenyl) ether, 2- (di-tertiary butylphosphino) biphenyl, 2 -(Dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2 '(N, N-di-methylamino) biphenyl, 2- (dicyclohexylphosphino) -2'- Methyl-biphenyl, 9,9-dimethyl-4, 5-bis (diphenylphosphine) xanthine, 2- (diphenylphosphine) -2'- (N, N-dimethylamino) Phenyl or 1,2-bis (diphenylphosphine) ferrocene. The alkalis used in this project are alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate; alkali metals such as sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate are hydrogen carbonates; lithium hydride and sodium hydride Alkali metal hydrides such as sodium and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, palladium hydroxide, and lithium hydroxide; inorganic alkalis such as alkali fluorides such as sodium fluoride and potassium fluoride ; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium third butoxide, potassium methoxide, potassium ethoxide, potassium third butyl oxide, lithium methoxide, etc .; sodium methyl sulfide, sodium ethionate, etc. Alkyl thiohydrogens; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine-56- 200522964, pyridine, 4-pyrrole Pyridopyridine, picolin, 4- (N, N-dimethylamino) pyridine, 2,6-bis (third butyl) -4-methylpyridine, quinoline, N, N-dimethyl Aniline., 1 ^, ~ diethylaniline, 1,5-diazine bicyclo [4.3.0] non-5-ene (〇81 ^) bu 4-diazine bicyclo [2.2.2] octane (〇 八 3 (: 〇), 1,8-diazine bicyclic ring [5.4 .0] -7-undecene (DBU) and other organic bases; or organic metal bases such as butyllithium, lithium diisopropylamidamine, lithium bis (trimethylsilyl) amidamine, preferably alkali metal carbonates Type, alkali metal hydroxides, alkali metal alkoxides, or organometallic salts, and also preferably potassium carbonate, carbonic acid shavings, sodium hydroxide, potassium hydroxide, third butoxide, third butoxide, or double (Trimethylsilyl) lithium amidoamine. Φ The reaction temperature in this project may vary depending on the raw material compound and the inert solvent used, usually 50 ° C ~ 200 ° C, preferably 80 ° C ~ 150 ° C. This project The reaction time varies depending on the raw material compound, the inert solvent used, the reaction temperature, etc., and is usually from 0.5 to 48 hours, preferably from 3 to 24 hours. After the completion of the reaction in each process in the above E method, each purpose Compounds can be prepared from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and when insolubles are filtered off, an immiscible organic solvent such as water and ethyl acetate is added to separate the organic layer containing the target compound. 'After washing with water, etc., use anhydrous magnesium sulfate and anhydrous sulfur Sodium, anhydrous sodium bicarbonate, etc. are obtained by drying and evaporating the solvent. The obtained target compound may be appropriately combined with a conventional method such as recrystallization, reprecipitation and other organic compounds, if necessary, by appropriate methods, and chromatography may be used for proper dissolution. It is obtained by dissolving and refining the agent. Method F is a method for producing the compound of formula (χν) of the raw material compound in the aforementioned E method E4 process. -57- 200522964 F method 0χ R4 human R3 (IV) F1 project > h2n—nh2 ^ nh2 N ^ R4 Person 3 (XV) In the present invention, R3 and R4 are as defined above. F1 Project This project tS is a compound z manufacturing process of formula (X /). In the presence of an inert solvent, let formula (IV) Compounds are carried out by reaction with hydrazine monohydrate or anhydrous hydrazine. The inert solvent used in this project is non-obstructive to the reaction, and it is not limited to be able to dissolve the starting materials to a certain degree, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl Ethers such as ethers; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, and chlorobenzene; aromatic hydrocarbons such as benzene, toluene, and xylene; methanol, ethanol, n-propanol, isopropanol, Alcohols such as ethylene glycol and glycerin; sublimines such as dimethylarylene and cyclobutane; or mixed solvents of the above solvents, preferably alcohols (most preferably methanol or ethanol). The reaction temperature in this project may vary depending on the raw material compound, the inert solvent used, etc., and is usually 0 ° C to 100 ° C (preferably room temperature to 60 ° C). The reaction time in this project varies depending on the raw material compound, the inert solvent used, the reaction temperature, etc., and is usually 1 hour to 24 hours (preferably 2 hours to 8 hours). After the reaction of each process in the above F method is completed, each target compound can be prepared from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and when insoluble matter is filtered off, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated, washed with water, etc., and then dried with anhydrous magnesium sulfate, After anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc. are dried, the solvent is distilled off to obtain 58-200522964. The obtained target compound is obtained by conventional methods, such as recrystallization, reprecipitation, and other conventional methods for separating and purifying organic compounds, if necessary, by combining them appropriately, and applying chromatography 'to dissolve and purify them with a suitable eluent. The starting compounds (I I I), (ί V), (I X), (X), and (X I) are well-known compounds, or they can be easily manufactured by known methods or similar methods. When the pyrimidine derivative of the above formula (I) or a pharmacologically acceptable salt thereof of the present invention is used for medical purposes, it can be mixed alone or with appropriate pharmaceutical acceptable excipients, diluents, etc., as tablets, capsules, granules, Powders or syrups are administered orally or parenterally as injections or suppositories. This formulation can use excipients (such as lactose, sugar, glucose, mannose, sorbose and other sugar derivatives; corn starch, potato starch, alpha starch, dextrin and other starch derivatives; cellulose derivatives such as crystalline cellulose Acacia gum; Polydextrose; Polytriglucose and other organic excipients; Silicic acid derivatives such as light silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium aluminum silicate; phosphates such as calcium hydrogen phosphate; Carbonates such as calcium carbonate; and inorganic excipients such as sulfates such as calcium sulfate; lubricants (such as stearic acid metal salts such as stearic acid, calcium stearate, and magnesium stearate; talc; colloidal silicon Stone; propolis, cetyl wax, etc .; boric acid; adipic acid; sulfates such as sodium sulfate; ethylene glycol; fumaric acid; sodium benzoate; DL leucine; fatty acid sodium salt; Dodecyl sulfates such as dodecyl magnesium sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above starch derivatives), binding agents (such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene Pyrrolidone, polyethylene glycol and the aforementioned excipients, etc.) Disintegrating agents (for example, low-substituted hydroxypropyl cellulose, carboxymethyl-59-200522964 cellulose, cellulose calcium calcium, internal croscarmellose sodium and other fibers: vitamin derivatives; carboxymethyl starch , Sodium carboxymethyl starch, cross-linked polyvinyl β acetone, etc., chemically modified powdered cellulose, stabilizers (p-benzoic acid methyl ester, p-benzoic acid propyl ester, etc. Formates; alcohols such as chlorobutanol, methanol, phenethyl alcohol; benzane ammonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (such as conventional sweetness) Additives, sour flavors and fragrances, etc.), thinners and other additives are manufactured according to customary methods. The dosage varies according to symptoms, age, etc. For example, when taken orally, the lower limit is 0.0015mg / kg body weight (preferably 0.008nlg / kg body weight) and the upper limit 70mg / kg body weight (preferably 7mg / kg body weight), when administered intravenously to adults, the daily lower limit is 0.00015mg / kg body weight (preferably 0.0008mg / kg body weight), and the upper limit is 8.5mg / kg body weight (preferably 5mg / kg body weight), depending on symptoms Can be administered 1 to 6 times a day. [Embodiment] Examples, reference examples, and test examples are described in detail below, but the present invention is not limited thereto. · The measurement equipment for various analytical data and the measurement conditions for liquid chromatography are as follows. (Measurement conditions for liquid chromatography and mass analysis) The measurement equipment for liquid chromatography mass analysis (LCMS) is HP-1 100LC / MSD manufactured by HP. . The column was an inverse layer, and CD-C18 manufactured by Intact was used. The analytical conditions were a column temperature of 4 CTC, and acetonitrile and water (containing 0.01% trifluoroacetic acid) were used for the mobile layer. The flow rate was 1.5 ml / min, and acetonitrile made a 8% to -60-200522964 99% linear gradient of 10%. The mass spectrometer uses an atmospheric pressure chemical ionization method (hereinafter referred to as APCI). (Measuring device for nuclear magnetic resonance spectrum (hereinafter referred to as ^ -NMR)) W-NMR data was measured using a JEOLJNM-GX 270FT-NMR or Varian Mercury 400 or Varian Inova 500 measuring device. Tetramethylsilane is used as a reference substance, and chemical shifts are described as (5 ppm. The splitting pattern is described by the singlet line as s, the doublet line as d, the triplet line as t, and the quadruple line as q. Etc.) DMF is dimethylformamide. Example 1 (4-pyridyl) -1-ethanone N- (2-aniline-5-phenyl-6- {2- [1- (4_ Pyridyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 28) 4,6-diazino-5-phenyl-2-phenylamino-pyrimidine (0 · 1 mmol) was dissolved in ethanol (1 ml), 4-acetamidine B (0.66 ml, 0.3 mmol) was added, and stirred for 18 hours. The precipitated solid was pulverized, and the target substance (28 mg, 55 %). W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.24 (s, 1H), 8.55 (brs, 2H), 8.52 (d, 4H, J = 6.2 Hz), 8.17 (d, 2H, J = 8.4 Hz), 7.61-7.39 (m, 9H), 7.31 (t, 2H, J = 8.4 Hz), 6.95 (t, 1H, J = 7.3 Hz), 1.99 (s, 6H) .MS (APCI, m / z): 514 (M + 1) +. HPLC (reverse phase): Rt. (min) = 3.21. Example 2 1- (4-Methanesulfonylphenyl) -bucetone N- (2-aniline -5-phenyl-6- {2- [1- (4- 200522964 methanesulfonylphenyl) ethylene] hydrazine Pyrimidinyl) hydrazine (Compound No. 51) The 4,6-dihydrazino-5 -phenyl-2 -anilino-pyrimidine (0.1 mmol) produced in Reference Example 2 in ethanol (1 ml) Dissolve, add 4-methanesulfonylacetophenone (59 mg, 0.3 mmol), and stir for 18 hours. The precipitated solid is pulverized and filtered to obtain the target compound (41 mg, 61%).

W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.23 (s, 1H), 8.52 (brs, 2H), 8.18 (d, 2H, J = 8.4 Hz), 7.85 (d, 4H, J = 8.6 Hz ), 7.68 (d, 4H, J = 8.6 Hz), 7.61-7.46 (m, 5H), 732 (t, 2H, J = 8.4 Hz), 6.97 (t, 1H, J = 7.3 Hz), 3.24 (s , 6H), 2.04 (s, 6H). MS (APCI, m / z): 668 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.49. Example 3 1- (4-Methylaminesulfonylphenyl) -1-ethanone 1 ^ (2-aniline-5-phenyl-6- {2- [1- (4-methylaminesulfonylphenyl) ) Ethylene] hydrazino} -4-pyrimidinyl) hydrazine (Compound No. 2) The 4,6-diazino-5-phenyl-2-phenylamino-pyrimidine (0 · 1 mmol) was dissolved in ethanol (1 ml), 4-ethylamidine · N-toluenesulfonamide (64 mg, 0.3 mmol) was added, and the mixture was stirred for 18 hours. The precipitated solid was pulverized, and the target substance (49 mg, 70%) was collected by filtration. W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.21 (s, 1H), 8.49 (brs, 2H), 8.17 (d, 2H, J = 8.1 Hz), 7.72-7.46 (m, 15H), 7.27 (t, 2H, J = 8.1 Hz), 6.96 (t, 1H, J = 7.3 Hz), -62- 200522964 2 · 41 (d, 6H, J = 4.1 Hz), 1.90 (s, 6H) · MS (APCI, m / z): 698 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.09. Example 4 1- (4-methylaminesulfonylphenyl)- 1-Ethyl ketone (2-anilino-5-cyclopentyl-6- {2- [1- (cardiomethylaminesulfonylphenyl) ethylene] hydrazinob 4-fluorenyl) hydrazine (compound No. 9) Reaction and purification according to the method of Example 3 to obtain the target compound (21 mg, 30%) ° W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.03 (s, 1H), 8.47 ( brs, 2H), 8.02-7.90 (m, 6H), 7.84 (d, 4H, J = 8.4 Hz), 7.50 (brs, 2H), 7.38-7.20 (m, 2H), 7.10-6.90 (m, 1H), 3.78-3.40 (m, 1H), 2.45 (brs, 6H), 2.39 (s, 6H), 2.05- 1.60 (m, 8H). MS (APCI, m / z): 690 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.12. Example 5 Ethylaminosulfonylphenyl) -1-ethanone N- (2-anilino-5-phenyl-6- {2-Π · (4-Ethylaminesulfonylphenyl) ethylene] hydrazine 4- Pyridyl) hydrazine (Compound No. 9 1) The 4,6-diazino-5-phenyl-2 · anilino-pyrimidine (0.1 mmol) produced in Reference Example 2 was dissolved in ethanol (1 ml) and added 4-Ethyl-N-ethylbenzidine (68 mg, 0.3 mmol) was stirred for 18 hours. The precipitated solid was pulverized, and the target compound (53 mg, 72%) was collected by filtration. 200522964 1H-NMR Spectrum (270 MHz, DMSO-d6) δ ppm: 9.21 (s, 1H), 8.48 (brs, 2H), 8.17 (d, 2H, J = 7.8 Hz), 7.73-7.45 (m, 15H), 7.29 (t , 2H, J = 7.8 Hz), 6.95 (t, 1H, J = 7.3 Hz), 2.78 (q, 4H, J = 7.2 Hz), 2.02 (s, 6H), 0.97 (t, 6H, J = 7.2 Hz ). MS (APCI, m / z): 726 (M + 1) + HPLC (reverse phase): Rt. (Min) = 4.43. Example 6

1- (4-Ethylsulfonylphenyl) -1-ethanone N- (2-anilino-5-phenyl-6- {2- [1- (4-ethanesulfonylphenyl) ethylene] Hydrazine 4-pyrimidinyl) hydrazine (Compound No. 74) 4,6-Dihydrazino-5-phenyl-2-anilino-pyrimidine (0.1 mmol) produced in Reference Example 2 in ethanol (1 ml) Dissolve, add 4-ethanesulfonylacetophenone (59 mg, 0.3 mmol), and stir for 18 hours. The precipitated solid is pulverized and filtered to obtain the target compound (47 mg, 68%).

W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.20 (s, 1H), 8.52 (s, 2H), 8.16 (d, 2H, J = 8.6 Hz), 7.80 (d, 4H, J = 8.6 Hz), 7.68 (d, 4H, J = 8.1 Hz), 7.63-7.45 (m, 5H), 7.31 (t, 2H, J = 8.1 Hz), 6.96 (t, 1H, J = 7.4 Hz), 3.34- 3.27 (m, 4H), 2.04 (s, 6H), 1.11 (t, 6H, J = 7.3 Hz). MS (APCI, m / z): 696 (M + l) +. HPLC (reverse phase): Rt . (min) = 4.41 Example 7 (4-methylaminesulfonylphenyl) -1-ethanone N · (2-aniline-5- (4-chlorophenyl) -6- -64 -200522964 {2- [1- (4-Methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (Compound No. 113) According to the method of Example 3, the target substance can be obtained by purification. (34 mg, 53%) ° 1H-NMR spectrum (270 MHz, DMSO-d6) 5ppm ·· 9.18 (s, 1H), 8.56 (brs, 2H), 8.15 (d, 2H, J = 7.8 Hz) , 7.74-7.56 (m, 10H), 7.46 (d, 4H, J = 8.4 Hz) 7.29 (d, 2H, J = 7.8 Hz) 6.96 (t, 1H, J = 7.3 Hz), 2.42 (s, 6H) , 2.09 (s, 6H).

MS (APCI, m / z): 732 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.35. Example 8 1- (4-methylaminesulfonylphenyl) -1-ethyl Ketone N- (2-aniline-5- (3-fluorophenyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) Hydrazine (compound number 6) was reacted and purified according to the method of Example 3 to obtain the target compound (67 mg, 93%) °

iH-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.21 (s, 1H), 8.58 (brs, 2H), 8.16 (d, 2H, J = 7.8 Hz), 7.73-7.26 (m, 16H), 6.96 (t, 1H, J = 7.4 Hz), 2.41 (s, 6H), 2.08 (s, 6H). MS (APCI, m / z): 716 (M + l) +. HPLC (reverse phase): Rt. (min) = 4.33. Example 9 1- (4-Acetidine-1-yl-sulfophenyl) -1-ethanone N- (2-anilino-5-phenyl-6- {2- [1- (4-Acetidine-1-yl-sulfofluorenyl) ethyl] hydrazinob 4-pyrimidinyl) -65- 200522964 hydrazine (compound number 1 0 8) Manufactured in Reference Example 2 4,6-Dihydrazino-5-phenyl-2-anilino-pyrimidine (0.1 mmol) was dissolved in ethanol (1 ml), and 1- [4- (azetidin-1-sulfonyl) was added ) -Phenyl] -ethanone (72 mg, 0.3 mmol), and stirred for 18 hours. The precipitated solid is pulverized and collected by filtration to obtain a quantitative target.

W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.22 (s, 1H), 8.55 (brs, 2H), 8.16 (d, 2H, J = 8.1 Hz), 7.72-7.46 (m, 13H), 7.34-7.28 (m, 2H), 6.98-6.96 (m, 1H), 3.70-3.64 (m, 8H), 2.06 (s, 6H), 2.03- 1.96 (m, 4H). MS (APCI, m / z ): 750 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.74. Example 10 1- (4-Cyclopropylaminesulfonylphenyl) -acetophenone N- (2-aniline -5-phenyl-6- {2- [1- (4-cyclopropylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 110)

The 4,6-diazino-5-phenyl-2-anilino-pyrimidine (0.1 mmol) produced in Reference Example 2 was dissolved in ethanol (1 ml), and the 4-acetamyl-N-ring After probenesulfone (72 mg, 0.3 mmol), stir for 18 hours. The precipitated solid was pulverized, and the target substance was obtained by filtration (68 mg, 91%). W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.20 (s, 1H), 8.49 (brs, 2H), 8.16 (d, 2H, J = 7.8 Hz), 8.91 (brs, 2H), 7.74-7.46 (m, 13H), 7.29 (t, 2H, H = 7.3 Hz), 6.98-6.96 (m, 1H), 2.26-2.07 (m, 1H), 2.03 (s, 6H), 0.49-0.45 (m, 4H ), 0.39-0.33 (m, 4H) · -66- 200522964 MS (APCI, m / z): 750 (M + 1) + · HPLC (reverse phase): Rt. (Min) = 4.58. Example 1 1 l- [4- (2-Hydroxyethyl) -sulfamoylphenyl] -1-ethanone ^ [2-anilino-5-phenyl-6- (2- {b [4- ( 2-Hydroxyethyl) -sulfamophenyl] ethylidene 丨 hydrazino) -4-pyrimidinyl] hydrazine (Compound No. 112)

The 4,6-diazino-5-phenyl-2-anilino-pyrimidine (0.1 mmol) produced in Reference Example 2 was dissolved in ethanol (1 ml), and 4-acetamido-N- (2- After hydroxyethyl) -benzenesulfonamide (73 mg, 0.3 mmol), it was stirred for 18 hours. The precipitated solid was pulverized, and the target substance (74 mg, 97%) was obtained by filtration. 'H-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.21 (s, 1H), 8.47 (brs, 2H), 8.16 (d, 2H, J = 7.6 Hz), 7.73-7.45 (m, 15H ), 7.29 (t, 2H, H = 8.1 Hz), 6.93-6.97 (m, 1H), 4.68 (t, 2H, J = 5.7 Hz), 3.39-3.31 (m, 4H), 2.78 (q, 4H, J = 6.2 Hz), 2.02 (s, 6H) · MS (APCI, m / z): 758 (M + l) + ·

HPLC (reverse phase): Rt. (Min) = 3.69. Example 1 2 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (3- Fluorotolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (Compound No. 4) was reacted according to the method of Example 3 and Refined target substance (86 mg, 59%) ^ W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.18 (s, 1H), -67- 200522964 8.58 (brs, 2H), 8. 16 ( d, 2H, J = 7.6 Hz), 7.74-7.66 (m, 8H), 7.50-7.44 (m, 3H), 7.32-7.19 (m, 4H), 6.96 (t, 1H, J = 7.4 Hz), 2.42 (s, 6H), 2.33 (s, 3H), 2.09 (s, 6H) · MS (APCI, m / z): 730 (M + l) + · HPLC (reverse phase): Rt. (min) = 4.41 Example 13

1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-6- {2- [l- (4-methylaminesulfonylphenyl) ethylene] hydrazine) -5- (3-thienyl) -4-pyrimidinyl) hydrazine (compound number 1) was reacted and purified according to the method of Example 3 to obtain the target compound (135 mg, 96%) ° 1H-NMR spectrum (270 MHz , DMSO-d6) < 5 ppm ·· 9 · 2 3 (s, 1 Η), 8.61 (brs, 2H), 8.18 (d, 2H, J = 7.8 Hz), 7.86-7.74 (m, 11H), 7.47 (brs, 1H), 7.33-7.23 (m, 3H), 6.96 (t, 1H, J = 7.4 Hz), 2.43 (s, 6H), 2.11 (s, 6H). MS (APCI, m / z) : 704 (M + l) + ·

HPLC (reverse phase): Rt. (Min) = 4.29. Example 14 1- (4-methylaminesulfonylphenyl) -1-ethyl ketone 1 (2-aniline-5- (2-methoxyphenyl) ) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (Compound No. 1 1 6) was reacted and purified according to the method of Example 3. Available target (37 mg, 51%) ° W-NMR spectrum (270 MHz, DMSO-d6) 6ppm: 9.15 (s, 1H), -68- 200522964 8.47 (brs, 2H), 8.16 (d, 2H, J = 8.1 Hz), 7.72-7.13 (m, 16H), 6.98-6.92 (m, 1H), 3.73 (s, 3H), 2.41 (s, 6H), 2.03 (s, 6H ). MS (APCI, m / z): 728 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.17 · Example 15 1- (4-methylaminesulfonylphenyl) -1 -Ethyl ketone N- (2-anilino- 5- (2,4-dimethoxyphenyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine 4-pyrimidinyl) hydrazine (Compound No. 125) was reacted and purified according to the method of Example 3 to obtain the target compound (44 mg, 58%) ° W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.15 (s , 1H), 8.42 (s, 2H), 8.17 (d, 2H, J = 7.8 Hz), 7.77-7.70 (m, 9H), 7.48-7.41 (m, 2H), 7.31-7.21 (m, 3H), 7.02-6.92 (m, 1H), 6.77- 6.71 (m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.42 (d, 6H, J = 3.8 Hz), 2.05 (s, 6H). MS (APCI, m / z): 758 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.166. Example 16 1- (4-Methylaminesulfonylphenyl) -1-ethanone 1 ^ (2-anilino-5- (3-methoxyphenyl) -6- {2- [1- (4- Methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (Compound No. 1 1 9) According to the method of Example 3, the target compound (52 mg, 71% 200522964 W- NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.21 (s, 1H), 8.54 (s, 2H), 8.18 (d, 2H, J = 7.6 Hz), 7.91 (m9 8H), 7.55-7.49 (m , 3H), 7.32-7.26 (m, 2H), 7.09-6.93 (m, 4H), 3.78 (s, 3H)? 2.41 (s, 6H), 2.06 (s, 6H). MS (APCI, m / z ): 728 (M + 1) + · HPLC (reversed phase): Rt. (Min) = 4.21 · Example 17 Benzene (4-methylaminesulfonylphenyl) -1-ethanone 1 (2-anilino- 5- (4-methoxyphenyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (Compound No. 1 2 2) Reaction and purification according to the method of Example 3 to obtain the target compound (55 mg, 75%) ° W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.21 (s, 1H), 8.43 (s, 2H), 8.18 (d, 2H, J = 7.6 Hz), 7.77-7.70 (m, 8H), 7.46 (brs, 2H), 7.39 (d, 2H, J = 8.6 Hz), 7.29 (m, 2H), 7.15 (d, 2H, J = 8.9 Hz), 6.95 (t, 1 H, J = 7.3 Hz), 3.84 (s, 3H), 2.42 (s, 6H), 2.04 (s, 6H). MS (APCI, m / z): 728 (M + l) +. HPLC (reverse phase ): Rt. (Min) = 4.18. Example 18 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-anilino-5- (4-chlorophenyl) -6- { 2- [1- (4-Methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound No. 1 14) was reacted and purified according to the method of Example 2 to obtain the target compound (37 mg , 90% 200522964 h-NMR spectrum (270 MHz, DMSO-d6) δ ppm: 9.21 (s, 1H)? 8.61 (s, 2H), 8.16 (d, 2H, J = 8.6 Hz), 7.87 (d, 4H , J = 8.4 Hz), 7.71-7.59 (m, 6H), 7.47 (d, 2H, J = 8.1 Hz), 7.31 (t, 2H, J = 7.8 Hz), 6.97 (t, 1H, J = 7.0 Hz )? 3.24 (s, 6H), 2.10 (s, 6H) · MS (APCI, m / z): 702 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.33.

Example 19 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-aniline-5- (2-methoxyphenyl) -6- {2- [1- (4-methyl Sulfophenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound No. 1 17) The reaction was carried out according to the method of Example 2 and purified to obtain the target compound (50 mg, 71%) ° W-NMR Spectrum (270 MHz, DMSO-d6) (5ppm: 9.18 (s, 1H), 8.52 (s, 2H)? 8.18-6.93 (m, 17H), 3.73 (s, 3H), 3.24 (s,

6H), 2.04 (s, 6H). MS (APCI, m / z): 698 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.08. Example 20 1- (4- 甲Sulfophenyl) -1-ethanone N- (2-aniline-5 (3-methoxyphenyl) -6- {2- [1- (4-methylsulfonylphenyl) ethylene] Hydrazine 4-pyrimidinyl) hydrazine (Compound No. 120) According to the method of Example 2 and purified to obtain the target compound (65 mg, 93% -71-200522964 iH-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.23 (s, 1H), 8.57 (s, 2H), 8.18 (d, 2H, J = 7.8 Hz), 7.87 (d, 4H, J = 8.6 Hz), 7.75 (d, 4H, J = 8.4 Hz), 7.52 (t, 1H, J = 7.8 Hz), 7.3 5-7.29 (m, 2H), 7.11-6.94 (m, 4H), 3.78 (s, 3H), 3.24 (s, 6H), 2.07 ( s, 6H). MS (APCI, m / z): 698 (M + 1) +. HPLC (reverse phase): Rt. (min) = 4.18.

Example 2 1 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-anilino-5- (4-methoxyphenyl) -6- {2- [1- (4- Methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 1 2 3) was reacted and purified according to the method of Example 2 to obtain the target compound (60 mg, 86%) ° NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.23 (s, 1H),

8.45 (s, 2H), 8.19 (d, 2H, J = 7.8 Hz), 7.89-7.78 (m, 8H), 7.41-7.29 (m, 4H), 7.17-7.14 (m, 2H), 6.99-6.94 ( m, 1H), 3.85 (s, 3H), 3.24 (s, 6H), 2.05 (s, 6H). MS (APCI, m / z): 698 (M + l) +. HPLC (reverse phase): Rt . (min) = 4.15. Example 22 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-anilino-5- (2,4-dimethoxyphenyl) -6- {2- [1- (4-Methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound No. 1 2 6) -72- 200522964 The target compound (63 mg '86%) ° W-NMR spectrum (270 MHz, DMS〇, d6): 9.18 (S, 1H), 8.46 (s, 2H), 8.18 (d, 2H, J = 8 · 1 Ηζ), 7.90-7.77 (m, 8H), 7.34-7.25 (m, 3H), 6.98-6.93 (m, 1H), 6.77-6.72 (m, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.24 (s, 6H), 2.06 (s, 6H) · MS (APCI, m / z): 728 (M + 1) + · HPLC (reverse phase): Rt. (Min) = 4.12. Example 23 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-anilino-5- (3-fluorophenyl) -6- {2- [1- (4-Methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 55) The method according to Example 2 Reaction and purification to obtain the target substance (59 mg, 86%) ° iH-NMR spectrum (270 MHz, DMSO-d6) accounted for PPm: 9.23 (s, 1H), 8.61 (s, 2H), 8.16 (d, 2H, J = 7.B Hz), 7.88-7.85 (m, 4H), 7.72-7.59 (m, 5H), 7.37-7.29 (m, 5H), 6.97 (t, 1H, J = 7.2 Hz), 3.24 (s , 6H), 2.09 (s, 6H). MS (APCI, m / z): 686 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.24. Example 24 1- (4- Methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5- (2-chlorophenyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene Group] hydrazinob 4-pyrimidinyl) hydrazine (compound number 7) -73- 200522964 According to the method of Example 3 and purified, the target compound (44 mg, 60%) was obtained. 0 W-NMR spectrum (270 MHz, DMSO-d6) ·· 9 · 16 (s, 1H), 8.57 (brs, 1H), 8.13 (d, 2H, J 2 7.8 Hz), 7.74-7.20 (m, 17H), 6.96 (t, 1H, J = 7.3Hz), 2.41 (s, 6H), 2.06 (s, 6H). MS (APCI, m / z): 732 (M + l) + · HPLC (reverse phase): Rt. (Min) = 4 · 31. Example 25

1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilinechlorophenyl) -6_ {2- [1- (4-methylaminesulfonylphenyl) ethylene] Hydrazine 4-pyrimidino) hydrazine (compound number 1 2 8) According to the method of Example 3 and purified to obtain the target compound (60 mS, 82%) ° W-NMR spectrum (270 MHz, DMSO-d6 ): 9.19 (s, 1H), 8.60 (s, 2H), 8.15 (d, 2H, J = 7.6 Hz), 7.73-7.26 (m, 16H), 6.96 (t, 1H, J = 7.3Hz) , 2.42 (s, 6H), 2.09 (s, 6H) ·

MS (APCI, m / z): 732 (M + 1) 'HPLC (reversed phase): Rt. (Min) = 4.36. Example 26 1- (4-Methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5 · (4-fluorophenylbenzene 6 · {2- [1- (4-methylamine Sulfonylphenyl) ethylene] hydrazinob 4 * ^ d Ddenyl) hydrazine (compound No. 131) was reacted and purified according to the method of Example 3 to obtain the target product <62 mS, 86% -74- 200522964 iH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 9.19 (s, 1H), 8.48 (brs, 2H), 8.16 (d, 2H, J = 7.8 Hz), 7.74-7.71 (m , 8H), 7.53-7.26 (m, 8H), 6.96 (t, 1H, J = 7.2 Hz), 2.42 (s, 6H), 2.07 (s, 6H). MS (APCI, m / z): 716 ( M + l) 'HPLC (reverse phase): Rt. (Min) = 4.20. Example 27

l- (4-methanesulfonylphenyl) -1-ethanone N- (2-anilinyl-5- (2-chlorophenyl) -6- {2- [1- (4-methanesulfonylphenyl) ) Ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 5 6) According to the method of Example 2 and purified to obtain the target compound (59 mg, 84%) ° W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.18 (s, 1H), 8.61 (brs, 2H), 8.13 (d, 2H, J = 8.1 Hz), 7.82 (d, 4H, J = 8.6 Hz), 7.66-7.53 (m, 8H), 7.32 (t, 2H, J = 7.8 Hz), 6.97 (t, 1H, J = 7.2 Hz), 3.23 (s, 6H), 2.08 (s, 6H).

MS (APCI, m / z): 702 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.36. Example 28 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-aniline- 5- (3-chlorophenyl) -6- {2- [1- (4-methanesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) fluorene ( Compound No. 1 2 9) According to the method of Example 2 and reacted to obtain the target compound (60 mg, 86% -75- 200522964 W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 9.22 (s, 1H) , Two 8.63 (s, 2H), 8.15 (d, 2H, J = 7.8 Hz), 7.86 (d, 4H, J = 8.6

Hz), 7.69 (d, 4H, J = 8.4 Hz), 7.61-7.55 (m, 3H), 7.44-7.41 (m, 1H)? 7.31 (t? 2H, J = 7.8 Hz), 6.9 7 (t, 1H, J = 7.3

Hz), 3.24 (s, 6H), 2.10 (s, 6H) · MS (APCI, m / z): 702 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.40. Examples 2 9 1- (4-Methanesulfonylphenyl) -1-ethanone N- (2-anilino-5- (4-fluorophenyl) -6- {2- · [1- (4-methylsulfonyl醯 Phenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound No. 13 2) was reacted and purified according to the method of Example 2 to obtain the target compound (59 mg, 86% W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9 · 22 (s, 1H),

8.51 (s, 2Η), 8.17 (d, 2H, J = 8.1 Hz), 7.88 (d, 4H, J = 8.6 Hz), 7.74 (d, 4H, J = 8.6 Hz), 7.53-7.29 (m, 6H ), 6.97 (t, 1H, J = 7.3 Hz), 3.24 (s, 6H), 2.08 (s, 6H). MS (APCI, m / z): 686 (M + l) +. HPLC (reverse phase) : Rt. (Min) = 4.22. Example 30 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2 · anilino-5- (2-fluorophenyl) -6- { 2- [l- (4-Methylaminesulfonylphenyl) ethylene] fluorenyl 4-pyrimidinyl) fluorene (Compound No. 5) was reacted and purified according to the method of Example 3 to obtain the target compound (1〇 9 mg, 76%-76-200522964 h-NMR spectrum (270 MHz, DMSO-d6) 5ρρπι: 9.18 (s, 1H), 8.65 (brs, 2H), 8.13 (d, 2H, J = 7.6 Hz), 7.68 (d, 4H, J = 8.6 Hz), 7.60-7.27 (m, 12H), 6.96 (t, 1H, J = 7.3 Hz), 2.41 (s, 6H), 2.08 (s, 6H) · MS (APCI, m / z): 716 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.35. Example 31

1- (4-methylaminesulfonylphenyl) -butanone 1 (2-aniline-5-o-tolyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene ] Hydrazino} -4-pyrimidinyl) hydrazine (compound number 8) The reaction was performed according to the method of Example 3 and purified to obtain the target compound (75 mg, 53%). 0 j-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.15 (s, 1H), 8.42 (brs, 2H), 8.15 (d, 2H, J = 7.6 Hz), 7.67 (d, 4H, J =

8.6 Hz), 7.55 (d, 4H, J = 8.6 Hz), 7.48-7.23 (m, 8H), 6.96 (t, 1H, J = 7.2 Hz), 2.41 (d, 6H, J = 5.1 Hz), 2.12 (s, 3H), 2.00 (s, 6H). MS (APCI, m / z): 712 (M + 1) +. HPLC (reverse phase): Rt. (min) = 4.32. Example 32 l- ( 4-methylaminesulfonylphenyl) -1-ethanone N- (2.aniline-5-m-tolyl-6- {2-Π- (4-methylaminesulfonylphenyl) ethylene] hydrazine Glycidyl 4-pyrimidinyl) hydrazine (compound number 134) -77- 200522964 According to the method of Example 3 and purified, the target compound (27 mg, 19% ') ° _ W-NMR spectrum (270 MHz, DMSO -d6) (5ppm: 9.19 (s, 1H), 8.49 (brs, 2H), 8.17 (d, 2H, J = 7.6 Hz), 7.7 3 -7.65 (m, 8H), 7.50-7.45 (m, 3H) , 7.37-7.23 (m, 5H), 6.96 (t, 1H, J = 7.3 Hz), 2.42 (d, 6H, J = 4.6 Hz), 2.38 (s, 3H), 2.03 (s, 6H). MS ( APCI, m / z): 712 (M + 1) +. HPLC (reversed phase): Rt. (Min) = 4.39. Example 3 3 Φ (4-methylaminesulfonylphenyl) -butanone 1 ^ (2-aniline-5-p-tolyl-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 3) Reaction and purification according to the method of Example 3 To give the desired product (39 mg ,. 27%) 0

W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.19 (s, 1H), 8.47 (brs, 2H), 8.18 (d, 2H, J = 8.1 Hz), 7.70 (brs, 8H), 7.48-7.26 (m, 8H), 6.96 (t, 1H, J = 7.2 Hz), 2.44-2.41 (m, 9H), 2.04 (s, 6H). MS (APCI, m / z): 712 (M + l) + HPLC (reverse phase): Rt. (Min) = 4.45. Example 34 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- [3- (4 -Fluorophenoxy) phenyl] -6- {2- [l- (4-methylaminesulfonylphenyl) ethylene] fluorenyl} -4-pyrimidinyl) hydrazine (compound number 1 6 1) -78- 200522964 Reaction and purification according to the method of Example 3 to obtain the target compound (54 mg, 67% W-NMR spectrum (270 MHz, DMSO-d6) accounted for PPm: 9.18 (s, 1H), 8.63 (brs, 2H), 8.15 (d, 2H, J = 7.8 Hz), 7.76-7.59 (m, 9H), 7.49 (brs, 2H), 7.33-7.26 (m, 3H), 7.16-7.06 (m , 3H), 6.98- 6.86 (m, 4H), 2.41 (s, 6H), 2.10 (s, 6H). MS (APCI, m / z): 808 (M + l) +. HPLC (reverse phase) · · Rt. (Min) = 4.69 · Example 3 5 1- (4-Methylaminesulfonylphenyl) -bucetone N- (2-anilino-5- (4-methoxybiphenyl-3) -Yl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) (Compound Number 158) The reaction according to the method of Example 3 to give the desired product may be purified and (42 mg, 52%

W-NMR spectrum (270 MHz, DMSO-d6) δρριη: 9.17 (s, 1H), 8.59 (brs, 2H), 8.17 (d, 2H, J = 7.8 Hz), 7.83-7.23 (m, 20H), 6.95 (t, 1H, J = 7.4 Hz), 3.77 (s, 3H), 2.39 (s, 6H), 2.04 (s, 6H). MS (APCI, m / z): 804 (M + l) +. HPLC (Inverted): Rt. (Min) = 4.61. Example 3 6 l- (4-Methylaminesulfonylphenyl) -1-ethanone 1 (2-anilino-5-benzo [1,3] oxazol-5-yl-6- {2- [ 1- (4-Methylaminesulfonylphenyl) ethylene] fluorenyl 4-pyrimidinyl) hydrazine (compound number 164) -79- 200522964 The reaction was performed according to the method of Example 3 and purified to obtain the target compound (25 mg, 34%) ° H-NMR spectrum (270 MHz, DMS0-d6) 5 ppm: 9 · 19 (s, 1 ，), 8.50 (brs, 2 ，), 8.18 (d, 2 ，, J = 7 · 8 Ηζ), 7.77 (dd, 8Η, J = 8.6 Hz, 14.6 Hz), 7.52-7.46 (m, 2H), 7.29 (t, 2H, J = 7.8 Hz), 7.14 (d, 1H, J = 7.8 Hz), 7.00-6.92 (m, 3H), 6.06 (s, 2H), 2.43 (d, 6H, J = 5.1 Hz), 2.09 (s, 6H). MS (APCI, m / z): 742 (M + l) +.

HPLC (reversed phase): Rt. (Min) = 4.25 [1,4] Ethyl-6-yl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 167 ) According to the method of Example 3 and reacted to obtain the target substance (39 mg, 52%) °

1H-NMR spectrum (270 MHz, DMSO-d6) &lt; 5 ppm: 9 · 18 (s, 1 Η), 8.52 (brs, 2Η), 8.17 (d, 2Η, J = 7 · 8 Ηζ) , 7.79-7.71 (m, 8Η), 7.49 (brs, 2H), 7.29 (t, 2H, J = 7.8 Hz), 7.08 (d, 1H, J = 8.6 Hz), 6.98-6.92 (m, 3H), 4.30-4.20 (m, 4H), 2.43 (s, 6H), 2.08 (s, 6H) · MS (APCI, m / z): 756 (M + 1) +. HPLC (reverse phase): Rt. (Min ) = 4.27 · Example 3 8 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2- (5-fluoro-2-tolylamino) -5-benzene-80- 200522964 group -6- {2- [l- (4-Methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine · (Compound No. 1 3) The reaction and purification according to the method of Example 3 may be The target compound (45 mg, 61%) ° W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 8.82-8.62 (m, 3H), 7.65-7.45 (m, 16H), 7.24 (t, 1H, J = 7 · 7 Ηζ), 6.83 (t, 1H, J = 8.4 Hz), 2.40 (d, 6H, J = 4.9 Hz), 2.34 (s, 3H), 2.04 (s, 6H) · MS ( APCI, m / z): 730 (M + 1) '· HPLC (reversed phase): Rt. (Min): = 4.50 · Example 3 9 1- (4-methylaminesulfonylphenyl) -1 -Ethyl ketone N- (2-anilino-5 "2,3-xylyl) -6- {2- [1- (4-Methylaminesulfonylphenyl) ethylidene] fluorenyl 44 pyridine &lt; Compound No. 137) According to the method of Example 3, the target compound (26 mg ' 36%

, r _ _ · 9.14 (s, 1H), h-NMR spectrum (270 MHz, DMSO-d6) (5ppm ·, 7 67 (d, 4H, J = 8.41 (brs, 2H), 8.14 (d, 2H, J = 7.8 Hz), f? H, J = 5.0 Hz), 8.5 Hz), 7.56 (d, 4H, J = 8.5 Hz), 7.47 (q, z 卩,

2.41 (d, 6H, J 7.36-7.15 (m, 5H), 6.95 (t, 1H, J = 7.3 Hz), / Γ TT \ = 4.9 Hz), 2.29 (s, 3H), 2.04 (s, 3H) , 2.〇〇 (s, · MS (APCI, m / z): 726 (M + 1) +. HPLC (reverse phase): Rt. (Min) = 4.50 · Example 40 -81-200522964 1 -(4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5- (2,4-difluorophenyl) -6- {2- [1- (4-methylamine Sulfonylphenyl) ethylene] hydrazino} -4-pyrimidinyl) hydrazine (Compound No. 14 0) was reacted according to the method of Example 3 and purified to obtain the target compound. W-NMR spectrum (270 MHz, DMSO -d6) 5ppm: 9.17 (s, 1H), 8.72 (brs, 2H), 8.12 (d, 2H, J = 7.8 Ηζ), 7.71 (d, 4H, J = 8.6 Hz), 7.64 Learn 7.55 (m, 5H), 7.50-7.40 (m, 1H), 7.35-7.23

(m, 5H), 6.96 (t, 1H, J = 7.3 Hz), 2.42 (d, 6H, J = 4.9 Hz), 2.13 (s, 6H). MS (APCI, m / z): 734 (M + 1) + · HPLC (reverse phase): Rt. (Min) = 4.24. Example 4 1 1- (4-Methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (3-chloro-2-fluorophenyl) -6- {2- [1 -(4-Methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) sulfinium (Compound No. 143) was reacted and purified according to the method of Example 3 to obtain the target compound.

1H-NMR spectrum (270 MHz, DMSO, d6) 5 ppm: 9 · 16 (s, 1 Η), 8.84 (brs, 2 Η), 8.10 (d, 2H, J = 7.8 Hz), 7.69 (d, 4H, J = 8.9 Hz), 7.61-7.26 (m, 11H), 6.96 (t, 1H, J = 7.4 Hz), 2.42 (d, 6H, J = 4.9Hz), 2.14 (s, 6H) · MS (APCI, m / z): 750 (M + 1) +. HPLC (reverse phase): Rt. (min) = 4.39. Example 42 1- (4-methylaminesulfonylphenyl) -1-ethyl ketone N- ( 2-aniline- 5- (4-chloro-2-fluorophenyl-82-200522964) -6- (2- [1- (4-methylaminesulfonylphenyl) ethylidene] hydrazine 4- Pyrimidinyl) hydrazine (; compound number 1 4 6). The target compound was obtained by reaction and purification according to the method of Example 3. i-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 9.16 (s, 1H), 8.80 (brs, 2H), 8.11 (d, 2H, J = 8.4 Hz), 7.71 (d, 4H, J = 8.4 Hz), 7.59-7.26 (m, 11H), 6.96 (t, 1H, J = 7.3 Hz) , 2.43 (d, 6H, J = 4.6 Hz), 2,15 (s, 6H). MS (APCI, m / z): 750 (M + l) +. HPLC (reverse phase): Rt. ( min) = 4.39. φ Example 4 3 1- (4-Methylaminesulfonylphenyl) -1-ethanone N- (2-morpholin-1-yl-5-phenyl-6- {2-Π -(4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound Code 24) the reaction by the method of Example 3 and purified target compound can be obtained.

W-NMR spectrum (270 MHz, DMSO-d6) δ ppm: 8.53 (brs, 2H), 7.63 (d, 4H, J = 8.6 Hz), 7.58-7.30 (m, 11H), 3.85-3.78 (m, 4H ), 3.76-3.65 (m, 4H), 2.39 (d, 6H, J = 4.9 Hz), 1.99 (s, 6H). MS (APCI, m / z): 692 (M + l) +. HPLC (reverse Phase): Rt. (Min) = 4.12. Example 44 1 · (4-Methylaminesulfonylphenyl) -bucetone N- (2-aniline-5 · (2,3-dichlorophenyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (Compound No. 149) -83- 200522964 reacted according to the method of Example 3 and Refined target substance (41 mg, 53%) ° W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.13 (s, 1H), 8.74 (brs, 2H), 8.09 (d, 2H, J = 7.8 Hz), 7.69-7.25 (m, 15H), 6.98-6.92 (m, 1H), 2.42 (s, 6H), 2.12 (s, 6H). MS (APCI, m / z): 766 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.47. Example 45

(4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (1,3,5-trimethyl-1 fluorene-pyrazol-4-yl) -6- {2- [1- (4-Methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine (compound number 10) was reacted and purified according to the method of Example 3 to obtain the target compound (37 mg, 50%)

W-NMR spectrum (270 MHz, DMSO-d6) (5ppm · 9.20 (s, 1H), 8.33 (brs, 2H), 8.18 (d, 2H, J = 7.3 Hz), 7.89 (d, 4H, J = 8.1 Hz), 7.78 (d, 4H, J = 8.1 Hz), 7.47 (brs, 2H), 7.30-7.23 (m, 2H), 6.94 (t, 1H, J = 7.3 Hz), 3.76 (s, 3H) , 2.43 (brs, 6H), 2.10 (brs, 9H), 2.00 (s, 3H). MS (APCI, m / z): 730 (M + l) +. HPLC (reverse phase): Rt. (Min) = 3.86. Example 4 6 (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (2-fluoro-5-tolyl) -6- 丨 2- [ 1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) sulfinyl (Compound No. 15 2) -84- 200522964 According to the method of Example 3, the product can be obtained by reaction and purification. (10 mg, 9%) 〇W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9.18 (s, 1H), 8.68 (brs, 2H), 8.13 (d, 2H, J = 7.6 Hz) , 7.72-7.65 (m, 5H), 7.59 (d, 4H, J = 8.6 Hz), 7.49-7 · 15 (m, 6H), 6.96 (t, 1H, J = 7.3 Hz), 2.42 (d, 6H, J = 5.1 Hz), 2.39 (s, 3H), 2.09 (s, 6H), MS (APCI, m / z): 730 (M + l) + · HPLC (reverse phase): Rt. (Min) = 4.49 · Example 47 1- (4-methylaminesulfonylphenyl) 1-Ethyl ketone N- (2-aniline- 5- (2-chloro-4-tolyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazine } -4-pyrimidinyl) hydrazine (compound number 155) was reacted and purified according to the method of Example 3 to obtain the target compound (33 mg, 79%) ° W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 9.14 (s, 1H), 8.58 (s, 2H), 8.13 (d, 2H, J = 7.8 Hz), 7.70-7.26 (m, 15H), 6.96 (t, 1H, J = 7.2 Hz), 2.42 (d, 9H, J = 4.9 Hz), 2.07 (s, 6H). MS (APCI, m / z): 746 (M + l) +. HPLC (reverse phase): Rt. (Min) = 4.44. Example 4 8 Cardiomethyl-4- 丨 1 _ [(5-phenyl-2-aniline-6- {乂-[1-pyridin-4-yl-ethylenepyrazinopyrimidin-4-yl) -hydrazino] -Ethyllbenzamide (Compound No. 200522964 17 1)

4- {1-[(6-Chloro-5-phenyl-2-anilino-pyrimidine-cardiyl) -hydrazino] -ethylbenzene N-toluenesulfonamide (1.14 g, 2.0 mm) ), [1-pyridin-4-yl-ethylidene] -hydrazine (406 mg, 3.0 mmol) was dissolved in i, 4-dioxane (35 ml), and tris (dibenzylideneacetone) dipalladium (92 mg, 0.1 mmol), 2-dicyclohexylphosphine-2 '-(N, N-dimethylamino) biphenyl (157 mg, 0.4 mmol), sodium tert-butoxide (577 mg, 6.0 mmol), Stir under nitrogen at 100 ° C for 14 hours. After concentration, purification by silica gel column chromatography gave the target compound (1.67 g, 35%). 1H-NMR spectrum (500 MHz, DMSO-d6) 5ppm: 9.22 (s, 1H), 8.52 (d, 3H, J = 5.86 Hz), 8.17 (d, 2H, J = 8.8 Hz), 7.70- 7.28 (m , 14H), 6.95 (t, 1H, J = 7.3 Hz), 2.40 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H) · MS (APCI, m / z): 606 (M + l) +. HPLC (reverse phase) · Rt. (min) = 3.74. Example 49 4- {l-[(2- (4-fluoroaniline) -5-phenyl-6- {N'- [l-pyridin-4-yl-ethylidene] -hydrazinopyrimidin-4-yl) -hydrazino] -ethylpyridine N-tosylsulfonamide (Compound No. 1 7 9) 4- (1 -{[6-Chloro-2- (4-fluoroaniline) -5-phenyl-pyrimidin-4-yl] -hydrazinylethyl) tosylsulfonamide (2.00 g, 3.81 mmol), [1-pyridine 4-Alkyl-ethylidene] -hydrazine (0.772 g, 5.71 mmol) was dissolved in N, N-dimethylformamide (20 ml), and tris (dibenzylideneacetone) dipalladium (175 mg , 0.191 mmol), 2-dicyclohexylphosphine-2 '-(N, N-dimethylamino) biphenyl 300 mg, 0.762 mmol), tertiary butoxide (1 · ιg, ιι · 4 mmol ), And then stirred under nitrogen-86-200522964 gas and 100 t for 4 hours. After concentration, purification by silica gel column chromatography gave the target compound (1.17 g, 49%). W-NMR spectrum (500 MHz, DMSO-d6) 5 ppm: 9.28 (brs, 1H), 8.49 (d, 4H, J = 6.3 Hz), 8 · 15 (dd, 2H, J = 5.1, 9 · 4 Hz), 7.67 (d, 2H, J = 8.6 Hz), 7.60_7.43 (m, 8H), 7.36 (d, 2H, J = 6.3 Hz), 7.09 (t, 2H, J = 9.0 Hz ), 2.41 (d, 3H, J = 5.1 Hz), 2.02 (s, 3H), 1.97 (s, 3H). MS (APCI, m / z): 624 (M + l) +. HPLC (reverse phase) : Rt. (Min) = 3.66. Example 50 4- {l-[(2- (2-fluoroaniline) -5-phenyl-6- {N '-[l-pyridin-4-yl-ylidene Ethyl hydrazinopyrimidin-4-yl) -hydrazino phenyl ethyl pyrimidine N-toluenesulfonamide (Compound No. 1 8 7) 4- (1-{[6-chloro-2- (2-fluoroaniline) -5-phenyl-pyrimidin-4-yl] -hydrazinylethyl) -N-toluenesulfonamide (2.63 g, 5.01 mmol), [1-pyridine-

4-yl-Ethylene dihydrazide (1.24 g, 7.51 mmol) was dissolved in N, N-dimethylformamidine (20 ml), and the force | 0.251 mmol), 2-dicyclohexylphosphine-2 '-(N, N-dimethylamino) biphenyl (394 mg, 1.00 mmol), sodium tert-butoxide (1.44 g, 15.0 mmol), 100 ° C. stirred for 3.5 hours. After concentration, purification by silica gel column chromatography gave the target compound (2.06 g, 66%). 1H-NMR spectrum (500 MHz, DMSO-de) (5 ppm: 9.68 (td, 1H, J = 8.2, 1.5 Hz), 8.61 (brd, 2H, J = 5.8 Hz), 8.47 (d, 2H, J = 6.3 Hz), 8.18 (brd, 1H, J = 2.2 Hz), 7.64 (d, 2H, J = 8.6 -87- 200522964

Hz), 7.57-7.41 (m? GH), 7.30 (d, 2H, J = 5.8 Hz), 7.26-7.18; (m, 2H), 7.09-7.03 (m, 1H), 2.40 (d, 3H , J = 2.2 Hz), 2.01 · (s, 3H), 1.96 (s, 3H). MS (APCI, m / z): 624 (M + l) +. HPLC (reverse phase): Rt. (Min) = 3.80. Reference Example 1 4.6-Dihydroxy-5-phenyl j-anilino-pyrimidine. Aniline (0.456 ml, 5 mmol) was dissolved in ethanol (2 ml), and 1H-pyrazole hydrochloride small residual formazan (733 mg, 5 mmol), heated under reflux for 15 # hours. After the reaction, ethanol (18 ml), sodium ethoxide (21 wt%, 9.3 ml, 25 mmol) and diethyl phenylmalonate (3.2 ml, 15 mmol) were added. After heating under reflux for 15 hours, acetic acid was added. The reaction was stopped, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with water. After concentrating the organic layer, diethyl ether was added to the residue. The precipitated solid was pulverized, collected, and washed with diethyl ether to obtain the target substance (558 mg, 40%). W-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: ι67 · 67 (brs, 2H), 8.80 (s, 1H), 7.69 (d, 2H, J = 7.3 Hz), 7.46 (d, 2H, J = 7.6 Φ H z), 7 · 3 4 (t, 2 H, J = 7 · 6 H z), 7 · 2 8 (t, 2 H, J = 7 · 3 H z) , 7 · 1 4 (t, 1H, J = 7.6 Hz), 7.06 (t, 1H, J = 7.3 Hz). HPLC (reverse phase): Rt. (Min) = 3.42. MS (APCI, m / z): 280 (M + 1) +. Reference Example 2 4.6- Dihydrazino-5-phenyl-2-anilino-pyrimidine 4,6-dihydroxy-5-phenyl-2 produced in Reference Example 1 -Anilino-pyrimidine (-88-200522964 279 mg, 1 mmol), phosphorus oxychloride (1 ml) was added, and the mixture was stirred at 100 ° C for 6 hours. After the reaction was completed, it was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with a phosphate buffer solution (PH7.0). After concentration, it was purified by silica gel column chromatography. Hydrazine monohydrate-ethanol (2: 1, v / v, 3 ml) was added at 95 ° C was stirred for 2 hours. The reaction solution was cooled at room temperature and water was added. The precipitated solid was pulverized and collected by filtration. The obtained solid was washed with water and ethyl acetate and dried under reduced pressure to obtain the target substance (154 mg, 50%) H-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 9 · 03 ( s, 1H),

7.87 (d, 2H, J = 7.3 Hz), 7.79-7.18 (m, 7H), 6.88 (t, 1H, J = 7.3 Hz), 6.23 (s, 2H), 4.45 (brs, 4H). HPLC (reverse phase): Rt. (Min) = 2.82. MS (APCI, m / z): 308 (M + l) +. Reference Example 3 5-Cyclopentyl-4,6-dihydroxyanilino-pyrimidine was prepared from diethyl 2-cyclopentanopropionate (3.2 mmol) according to the method of Reference Example 1. 25%). HPLC (reverse phase): Rt. (Min) = 3.81. MS (APCI, m / z): 272 (M + 1) +. Reference Example 4 5-Cyclopentyl-4,6-dihydrazinoanilino-pyrimidine The 5-cyclopentyl-4,6-dihydroxy-2 -anilino group 1 produced in Reference Example 3 (271 mg , 1 mmol), according to the method of Reference Example 2 to obtain the target compound (60 mg, 20%). HPLC (reversed phase): Rt. (Min) = 2.79 · 200522964 MS (APCI, m / z): 300 (M + 1) +. Reference Example 5 Diethyl 2- (4-chlorophenyl) -malonate was prepared from copper iodide (95 mg · 0.5 mmol), 2-phenylphenol (170 mg, 1 mmol), and carbonic acid (4 · 89 g, 15 mmol) dissolved in a tetrahydrofuran solution (10 ml) 'Add 1-Amo-4-stele (2.38 g, 10 mmol), propionic acid-ethyl acetate (3.04 ml, 20 mmol), at 70 ° C with heating and stirring for 24 hours. After the reaction, the solution was filtered through celite, concentrated, and purified by column chromatography to obtain the target compound (0.85 g, 31%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.48-7.26 (m, 4Η), 4.57 (s, 1Η), 4.26-4.17 (m, 4Η), 1.26 (t, 6Η, J = 7.0 Hz). MS (APCI, m / z): 271 (M + l) +. Reference Example 6 5- (4-chlorophenyl) -4,6-dihydroxy-2-anilino-pyrimidine The 2- (4-chlorophenyl) -malonic acid diethyl ester (3.2 mmol), and the reaction was carried out according to the method of Reference Example 1 to obtain the target compound (170 mg, 27%). HPLC (reverse phase): Rt. (Min) = 3.86 · MS (APCI, m / z): 314 (M + 1) + 〇 Reference Example 7 5- (4-chlorophenyl) -4,6- Dihydrazino-2-anilino-pyrimidine 5- (4-chlorophenyl) -4,6-dihydroxy-2-anilino-pyrimidine (170 mg, 0.54 mmol) produced in Reference Example 6, according to the reference example The reaction of method 2 can obtain the target compound (76 mg, 51%) in 200522964. W-NMR spectrum (270 MHz, DMSO-d6) δ ppm: 8.92 (s, 1H), 7.86 (d, 2H, J = 7 · 8Ηζ), 7.47-7.44 (m, 2H), 7.25- 7.17 (m, 4H), 6.86 (t, 1H, 7.3Hz), 6.35 (s, 2H), 4.09 (brs, 4H), HPLC (reverse phase): Rt. (Min) = 2.91. MS (APCI , M / z): 342 (M + 1) +. Reference Example 8 Diethyl 2- (3-fluorophenyl) -malonate

The target compound (1.39 g, 56%) was obtained by reacting 1-fluoro-3- Yaobenzene (1.2 ml, 10 mmol) according to the method of Reference Example 5. W-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 7.48-6.97 (m, 4H), 4.60 (s, 1H), 4.28-4.14 (m, 4H), 1.27 (t, 6H, J = 7.2 Hz). MS (APCI, m / z): 255 (M + 1) +. Reference Example 9 4.6- Dihydroxy-5- (3-fluorophenyl) -2-anilino-pyrimidine Diethyl 2- (3-fluorophenyl) -malonate (5.47 ® mmol) was reacted according to the method of Reference Example 1 to obtain the target compound (0.65 mg, 60%) ° HPLC (reverse phase): Rt . (min) = 3.49. MS (APCI, m / z): 298 (M + 1) +. Reference Example 1 〇4.6- Dihydrazino- 5- (3-fluorophenyl) -2-anilino-pyrimidine The 4,6-dihydroxy-5- (3-fluorophenyl) -2-anilino-pyrimidine-91 · 200522964 pyridine (0.5 g, 1.68 mmol) produced in Reference Example 9 was reacted according to the method of Reference Example 2 The target compound was obtained (0.15 g, 27%). HPLC (reverse phase): Rt. (Min) = 2.88. MS (APCI, m / z): 3 26 (M + 1) +. Reference Example 1 1 2- (3-fluoro-4-tolyl) -diethyl malonate

The 2-fluoro-4-iodo-1-toluene (3.78 g, 16 mmol) was reacted according to the method of Reference Example 5 to obtain the target compound (3.90 g, 91%). iH-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 7.19-7.03 (m, 3H), 4.56 (s, 1H), 4.30-4.13 (m? 4H), 2.26 (d, 3H, J = 1.9 Hz), 1.25 (t5 6H, J = 7.0 Hz). HPLC (reversed phase): Rt. (Min) = 5.39. MS (APCI, m / z): 269 (M + 1) +. Reference example 1 2 4 , 6-dihydroxy-5- (3-fluoro-4-tolyl) -2-aniline-pyrimidine

The 2- (3-fluoro-4-tolyl) -malonic acid diethyl ester (8.5 mmol) produced in Reference Example 11 was reacted according to the method of Reference Example 1 to obtain the target compound (1.31 g, 84%). iH-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 11.45 (brs, 2H), 8.55 (brs, 1H), 7.66 (dd, 2H, J = 1.1 Hz, 8.4 Hz), 7.34-7.26 (m , 4H), 7.09-6.98 (m, 2H), 2.20 (s, 3H). HPLC (reverse phase): Rt. (Min) = 3.81. MS (APCI, m / z): 312 (M + 1) + Reference Example 1 3 -92-200522964 4.6-Dihydrazino-5- (3-fluoro-4-tolyl) -2-anilino-pyrimidine The 4,6-dihydroxy-5- ( 3-Fluoro-4-tolyl) -2-anilino-pyrimidine (6M mg, 2 mmol), which can be obtained by performing the reaction according to the method of Reference Example 2. W-NMR spectrum (270 MHz, DMSO-d6) ( 5ppm: 8.91 (s, 1H), 7.86 (dd, 2H, J = 1.1 Hz, 8.6 Hz), 7.33 (t, 1H, J = 7.8 Hz), 7.25-7.19 (m, 2H), 6.93-6.82 (m , 3H), 6.30 (s, 2H), 4.15 (s, 4H), 2.26 (d, 3H, J = 1.6 Hz). HPLC (reverse phase): Rt. (Min) = 3.03. MS (APCI, m / z): 340 (M + 1) +. Reference Example 14 2-Thien-3-yl-malonate diethyl 3-iodothiophene (2.1 ml, 16 mmol) was carried out according to the method of Reference Example 5. The target compound was obtained by the reaction (3.77 g, 94%). IH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.37-7.26 (m, 2H), 7.18-7.15 (m, 1H), 4.75 (s, 1H), 4.3 1-4.11 (m, 4H), 1.27 (t, 6H, J = 7.3 Hz). HPLC (reverse phase): Rt. (Min) = 4.74. MS (APCI, m / z): 243 (M + 1) Reference Example 15 4.6-Dihydroxy-2-anilino-5-thien-3-yl-pyrimidine The 2-thien-3-yl-malonate diethyl ester (5.6 mmol) produced in Reference Example 14 was used according to The target compound (929 mg, 6 5%) was obtained by performing the reaction in Reference Example 1. 200522964 kNMR spectrum (270 MHz, DMSO-d6) 5 ppm: 111 () (brs, 2H), 8.81 (brs, 1H), 7.83 (dd, 1H, J = i] Hz, 30 Hz), 7 74 7 65 (m, 3H), 7.39-7.30 (m, 3H), 7.06 (t, 1H, j = 7.3 Hz). HPLC (Reverse phase): Rt. (Min) = 3.51. MS (APCI, m / z): 286 (M + 1) +. Reference Example 1 6,4,6-Dihydrazino-2-anilino-5-thien-3-yl-methyl i;

The 4,6-dihydroxy-2-anilino-5-thien-3-yl-pyrimidine (57 1 mg, 2 mmol) produced in Reference Example 15 was reacted according to the method of Reference Example 2 to obtain the target compound (5 11 mg, 79%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 8.92 (s, 1H), 7.86 (d, 2H, J = 7.8 Hz), 7.67 (dd, 1H, J = 3.0 Hz, 5.1 Hz), 7.40 (dd, 1H, J = 1.1 Hz, 3.0 Hz), 7.23 (t, 2H, J = 7.8 Hz), 6.99 (dd, 1H, J = 1.4 Hz, 5.1 Hz), 6.86 (t, 1H, J = 7.3 Hz), 6.22 (s, 2H), 4.18 (s, 4H). HPLC (reverse phase): Rt. (Min) = 2.62 ·

MS (APCI, m / z): 314 (M + 1) +. Reference Example 17 2- (2-methoxyphenyl) -malonate Diethyl iodine-2-methoxybenzene (2.0 ml, 15 mmol) was reacted according to the method of Reference Example 5 to obtain Target (I35 S, 34%) ° 1 Η-NMR spectrum (2 7 OM Hz, DMS 0-d 6) accounts for PP m: 7 · 3 5-7 · 2 6 (m, 2H), 7.00- 6.88 (m, 2H), 5.11 (s, 1H), 4.27-4.17 (m, 4H), 3.82 (s, 3H), 1.27 (t, 6H, J = 7.0 Hz). -94- 200522964 MS (APCI, m / z): 267 (M + 1) +. '' Reference Example 18. 4,6-Dihydroxy-5- (2-methoxyphenyl) -2-anilino-pyrimidine The 2- (2-methoxyphenyl) -malonate produced in Reference Example 17 Ethyl ester (2.97 mmol) was reacted according to the method of Reference Example 1 to obtain the target compound (0.48 mg, 79%). HPLC (reverse phase): Rt. (Min) = 3.16. MS (APCI, m / z): 310 (M + 1) +. Reference Example 1 9 # 4,6-Dihydrazino-5- (2-methoxyphenyl) -2-anilino-pyrimidine The 4,6-dihydroxy-5- (2-methoxy group) produced in Reference Example 18 Phenyl) -2-anilino-pyrimidine (0.4 g, 1.29 mmol) was reacted in the same manner as in Reference Example 2 to obtain the desired compound (0 · 17 g, 39%). HPLC (reverse phase): Rt. (Min) = 2.77. MS (APCI, m / z): 338 (M + 1) +. Reference Example 20 2- (2,4-Dimethoxyphenyl) -diethylmalonate Φ 1-iodo-2,4-dimethoxybenzene (4.0 g, 15 mmol), as described in Reference Example 5 The target compound was obtained by the method (4.12 g, 93%) ° j-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 7.29-7.24 (m, 1H), 6.52-6.46 (m, 2H), 5.02 (s, 1H), 4.26-4.17 (m, 4H), 3.80 (d, 6H, J = 1.6Hz), 1.26 (t, 6H, J = 6.5 Hz). MS (APCI, m / z): 297 ( M + l) +0 Reference Example 21 -95- 200522964 4,6-Dimethynyl 5- (2,4-dimethoxyphenyl) -2-anilino-pyrimidine 2,4-Dimethoxyphenyl) -diethyl malonate (13.8 mmol), which was reacted according to the method of Reference Example 1 to obtain the target compound (2.66 g, 86%). HPLC (reverse phase): Rt. (min) = 3.25 MS (APCI, m / z): 340 (M + 1) + 〇 Reference Example 22 4.6-Dihydrazino-5- (2,4-dimethoxyphenyl) -2_ Anilino-pyrimidine

The 4,6-dihydroxy-5- (2,4-dimethoxyphenyl) -2-anilino-pyrimidine (1 g, 2.95 mmol) produced in Reference Example 21 may be reacted according to the method of Reference Example 2 The target product was obtained (0.41 g, 38%). HPLC (reverse phase): Rt. (Min) = 2.89 · MS (APCI, m / z): 368 (Μ + 1), Reference Example 23 2- (3-methoxyphenyl) -malonate Ethyl ester

The target compound (1.81 g, 45%) was obtained by reacting -methoxybenzene (1.8 ml, 15 mmol) according to the method of Reference Example 5. i-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 7.30-7 · 24 (m, 1H), 6.98-6.90 (m, 2H), 6.89-6.86 (m, 1H), 4.58 (s, 1H), 4.28-4.13 (m, 4H), 3.81 (s, 3H), 1.27 (t, 6H, J = 7.0 Hz). MS (APCI, m / z): 267 (M + 1) + Reference Example 24 4.6-Dihydroxy-5- (3-methoxyphenyl) -2-anilino-pyrimidine The 2- (3-methoxyphenyl) -malonate diethyl ester produced in Reference Example 23 ( 3.76 -96- 200522964 mmol), and the target compound (0.64 g, 5 5%) was obtained according to the method of Reference Example 1. HPLC (reverse phase): Rt. (Min) = 3.37. MS (APCI, m / z ): 310 (M + 1) + 〇 Reference Example 25 4.6-monohydrazino-5-(3-methoxyphenyl) -2-aniline-pentin

The 4,6 · dihydroxy-5- (3-methoxyphenyl) -2-anilino-pyrimidine (0.5 5 g, 1.78 mmol) produced in Reference Example 24 was reacted according to the method of Reference Example 2 to obtain the objective. (0 · 1 4 g, 2 3%). HPLC (reverse phase): Rt. (Min) = 2.72. MS (APCI, m / z): 338 (M + 1) +. Reference example 2 6 2- (4-methoxyphenyl) · diethyl malonate The reaction was carried out by reacting 1-fluorene-4 · methoxybenzene (3.5 g, 15 mmol) according to the method of Reference Example 5 (1.88 g, 47%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.35-7.28 (m,

2H), 6.92-6.85 (m, 2H), 4.55 (s, 1H), 4.31-4.13 (m, 4H), 3.80 (s, 3H), 1.26 (t, 6H, J = 7.2 Hz) .MS (APCI , M / z): 267 (M + 1) +. Reference Example 27 4.6-Dihydroxy-5- (4-methoxyphenyl) -2-anilino-pyrimidine The 2- (4-methoxyphenyl) -malonate (3.76) produced in Reference Example 26 mmol), and the reaction was performed according to the method of Reference Example 1 to obtain the target compound (0.75 g, -97-65%). 200522964 HPLC (reversed phase): Rt. (Min) = 3.37 MS (APCI, m / z): 310 (M + 1) +. Reference Example 28 4,6-Dihydrazino-5- (4-methoxyphenyl) -2-anilino-pyrimidine The 4,6-dihydroxy-5- (4-methoxyphenyl) produced in Reference Example 27 ) -2-anilino-pyrimidine (0.65 g, 2.1 mmol). The target compound (0.26 g, 37%) can be obtained by performing the reaction according to the method of Reference Example 2. HPLC (reverse phase): Rt. (Min) = 2.77.

MS (APCI, m / z): 3 3 8 (M + 1) +. Reference Example 29 2- (2-Chlorophenyl) -malonate Dichloro-2-iodobenzene (1.8 m 1,15 mmol) was reacted according to the method of Reference Example 5 to obtain the target compound (1.1 g, 27%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm ·· 7.50-7.46 (π, 1H), 7.42-7.38 (m, 1H), 7.31-7 · 24 (m, 2H), 5.21 (s , 1H), 4.3 and 4.19 (m, 4H), 1.28 (t, 6H, J = 7.0 Hz).

MS (APCI, m / z): 271 (M + 1) +. Reference Example 3 0 5- (2-Chlorophenyl) -4,6-dihydroxy-2-anilino-pyrimidine The 2- (2-chlorophenyl) -malonate diethyl ester produced in Reference Example 29 ( (3.9 mmol), and the reaction was carried out according to the method of Reference Example 1 to obtain the target compound (0.34 g, 36%). HPLC (reverse phase): Rt. (Min) = 3.39 MS (APCI, m / z): 3 14 (M + 1) +. -98-200522964 Reference Example 3 1 5- (2-chlorophenyl) -4,6-diazino-2-anilino-pyrimidine 5- (2-chlorophenyl) -4 produced in Reference Example 30, 6-Dihydroxy-2-anilino-pyrimidine (0.34 g, 1.0 8 mmol) was reacted according to the method of Reference Example 2 to obtain the target compound (0.13 g, 35%). HPLC (reverse phase): Rt. (Min) = 2.81. MS (APCI, m / z): 342 (M + 1) +. Reference Example 32 Diethyl 2- (3-chlorophenyl) -malonate The target compound was obtained by reacting 1-chloro-3-stilbene (1.86 ml, 15 mmol) according to the method of Reference Example 5. (1.62g, 40%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.42 (s, 1H), 7.31-7.30 (m, 3H), 4.57 (s, 1H), 4.28-4.17 (m, 4H), 1.27 (t , 6H, J = 7.2 Hz). MS (APCI, m / z): 271 (M + 1) + 〇 Reference Example 3 3 5- (3-chlorophenyl) -4,6-dihydroxy-2-aniline -Pyrimidine The 2- (3-chlorophenyl) -malonic acid diethyl ester (3.9 mmol) produced in Reference Example 32 was reacted according to the method of Reference Example 1 to obtain the target compound (0.4 g, 4 3%). HPLC (reverse phase): Rt. (Min) = 3.80 · MS (APCI, m / z): 314 (M + 1) +. Reference Example 3 4 5- (3-chlorophenyl) -4,6-diazino-2-anilino-pyrimidine 200522964 5- (3-chlorophenyl) -4,6-di manufactured from Reference Example 33 Hydroxy-2-anilino-pyrimidine (04 g, 1.27 mm01) 'The reaction was carried out according to the method of Reference Example 2 to obtain the target compound (0.18 g, 42%). HPLC (reverse phase): Rt. (Min) = 2.99. MS (APCI, m / z): 342 (M + 1) +. Reference Example 35 Diethyl 2- (4-fluorophenyl) -malonate

The target compound (1.45 g, 38%) was obtained by reacting 1-fluoro-4-iodobenzene (1.8 ml, 15 mmol) according to the method of Reference Example 5. ! H-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.4 BU 7.36 (m '2H), 7.08-7.02 (m, 2H), 4.59 (s, 1H), 4.28-4.16 (m, 4H ), 1.26 (t, 6H, J = 7.3 Hz). MS (APCI, m / z): 255 (M + 1) +. Reference example 3 6 4,6-Dihydroxy-5- (4-fluorophenyl) -2-aniline-pyrimidine

The target product (^ 3g '34%) was obtained by reacting 2- (4-fluorophenyl) -malonate diethyl alcohol (1 · mmol) produced in Reference Example 35 according to the method of Reference Example 1. HPLC (reverse phase): Rt. (Min) = 3.47. MS (APCI, m / z): 298 (M + 1) + 0 Reference example 3 7 4,6-Dihydrazino- 5- (4-fluorobenzene Phenyl) -2-anilino-pyrimidine 4,6-dihydroxy-5 · (4-fluorophenyl) -2-limb produced in Reference Example 36

^ (¾ &quot; 5J pyrimidine (0.3 g, 1.0 mmol), according to the method of reference example 2 into the lamp sigh ... -100- 200522964 to obtain the target (0.14 g, 42%). HPLC (reverse phase): Rt. (Min) = 2.73. MS (APCI, m / z): 326 (M + 1) +. Reference Example 3 8 2- (2-fluorophenyl) -diethylmalonate The target compound (2.5 ml, 61%) can be obtained by reacting 1-fluoro-2-carboxene (1.8 ml, 16 mmol) according to the method of Reference Example 5. iH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.50-7.44 (m,

1H), 7.36-7.26 (m, 1 H), 7 · 19-7.0 5 (m, 2 H), 4 · 9 8 (s, 1H), 4.33-4.16 (m, 4H), 1.27 (t, 6H, J = 7.3 Hz). HPLC (reverse phase): Rt. (Min) = 4.90. MS (APCI, m / z): 255 (M + 1) +. Reference Example 3 9 4.6-Dihydroxy- 5- (2-fluorophenyl) -2-anilino-pyrimidine The 2- (2-fluorophenyl) -malonic acid diethyl ester (7.9 mmol) produced in Reference Example 38 ), According to the method of Reference Example 1, the target compound (805 mg,

54%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 112〇 (brs, 2H), 8 · 4 7 (brs, 1 Η), 7 · 6 7 (dd, 2 Η, J = 〇8 η z, 7.6 Η z), 7 · 3 4-7.2 2 (m, 4H), 7.14-7.01 (m, 3H). HPLC (reverse phase): Rt. (Min) = 3.25. MS (APCI, m / z): 298 (M + 1) +. Reference Example 40 4.6-Dihydrazino-5- (2-fluorophenyl) -2-aniline group 4 dense-101-200522964 4,6-dihydroxy-5- (2-fluorobenzene) produced in Reference Example 39 Group) -2-anilino-pyridine D (595 mg, 2 mmol), and the reaction was carried out according to the method of Reference Example 2 to obtain the target compound (526 mg, 79%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 8.92 (s, 1H), 7.87 (dd, 2H, J = 1.1 Hz, 8.4 Hz), 7.44-7.36 (m, 1H), 7.28-7.16 ( m, 5H), 6.86 (t, 1H, J = 7.3 Hz), 6.31 (s, 2H), 4.17 (brs, 4H) · HPLC (reversed phase): (11111〇 = 2.84 ·)

MS (APCI, m / z): 326 (M + 1) +. Reference Example 41 2-O-toluene-diethyl propionate 1-Pro-2-toluene (2.0 ml, 16 mmol) was reacted according to the method of Reference Example 5 to obtain the target compound (3.72 g, 93%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.42-7.36 (m, 1H), 7.26-7.16 (m, 3H), 4.87 (s, 1H), 4.31-4.15 (m, 4H), 2.34 (s, 3H), 1.27 (t, 6H, J = 7.0 Hz).

HPLC (reverse phase): Rt. (Min) = 5.14. MS (APCI, m / z): 251 (M + 1) +. Reference Example 4 2 4,6-Dihydroxy-2-anilino-5-o-tolyl-pyrimidine Diethyl 2-o-toluopropionate (8.3 mmol) produced in Reference Example 41 was carried out according to the method of Reference Example 1. The target substance was obtained by the reaction (1.03 g, 70%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 11.15 (brs, 2H), 8.86 (brs, 1H), 7.68 (dd, 2H, J = 1.4 Hz, 7.6 Hz), 7.32 (t, -102 -200522964 2H, J = 7.3 Hz), 7.18-7.01 (m, 5H), 2.11 (s, 3H) · HPLC (reverse phase): Rt. (Min) = 3.47. MS (APCI, m / z): 294 (M + 1) +. Reference Example 43 4,6-Dihydrazino-2-anilino-5-o-tolyl-pyrimidine The 4,6-dihydroxy-2-anilino-5-o-tolyl-pyrimidine (5 87 mg, 2 mmol), and the reaction was carried out according to the method of Reference Example 2 to obtain the target compound (447 mg, 68%).

iH-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 8.90 (s, 1H), 7.89 (dd, 2H, J = 1.1 Hz, 7.6 Hz), 7.34-7.19 (m, 6H), 6.85 (t , 1H, J = 7.6 Hz), 5.80 (s, 2H), 4.16 (brs, 4H), 2.07 (s, 3H). HPLC (reverse phase): Rt. (Min) = 2.76. MS (APCI, m / z): 322 (M + 1) +. Reference Example 44 Diethyl 2-toluenepropionate

1-Bei-3-toluene (2.1 ml, 16 mmol) was reacted according to the method of Reference Example 5 to obtain the target compound (3.77 g, 94%). 1H-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 7.28-7.13 (m, 3H), 4.57 (s, 1H), 4.30-4.13 (m, 4H), 2.36 (s, 3H), 1.31- 1.24 (m, 6H). HPLC (reverse phase): Rt. (Min) = 5.19. MS (APCI, m / z): 251 (M + 1) +. Reference Example 45 -103- 200522964 4,6-II Hydroxy-2-anilino-5-m-tolyl-pyrimidine Diethyl 2-m-toluenepropionate (5.6 mmol) produced in Reference Example 44 was reacted according to the method of Reference Example 1 to obtain the target compound. 1H-NMR Spectrum (270 MHz, DMSO-d6) 5ppm: 10.64 (brs, 2H), 8.81 (brs, 1H)? 7.68 (dd, 2H, J = 1.1 Hz, 8.6 Hz), 7.37-7.30 (m, 2H) , 7.25-7.13 (m, 3H), 7.09-7.02 (m, 1H), 6.96 (d, 1H, J = 7.3 Hz), 2.28 (s, 3H). HPLC (reverse phase): Rt. (Min) = 3.73.

MS (APCI, m / z): 294 (M + 1) +. Reference Example 4 6,4,6-Dihydrazino-2-anilino-5-m-tolyl-pyrimidine The 4,6-dihydroxy-2-anilyl-5-m-tolyl-pyrimidine (referred to in Example 45) 5 87 mg, 2 mmol), and the reaction was carried out according to the method of Reference Example 2 to obtain the target compound (457 mg, 69%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 8.92 (s, 1H),

7.87 (d, 2H, J = 7.6 Hz), 7.39-7.17 (m, 4H), 7.10-6.97 (m, 2H), 6.86 (t, 1H, J = 7.3 Hz), 6.06 (s, 2H), 4.22 (brs, 4H), 2.33 (s, 3H). HPLC (reverse phase): Rt. (min) = 2.93 · MS (APCI, m / z): 322 (M + 1) + 〇 Reference Example 4 7 2-Ethyl p-toluene propionate 1-iodo-4-toluene (3.49 g, 16 mmol) was reacted according to the method of Reference Example 5 to obtain the target compound (3.70 g, 93%). -104- 200522964] H-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 7.29 (d, 2H, J = 7.8 Hz), 7.17 (d, 2H, J = 7.8 Hz), 4.57 (s, ih) , 4.27-4.15 (m, 4H), 2.34 (s, 3H), 1.26 (t, 6H, j = 70 Hz). HPLC (reverse phase): Rt. (Min) = 5.24. MS (APCI, m / z): 251 (M + 1) +. Reference Example 48 4,6-Diethyl p-toluene propionate (4-ethyltoluene propionate) manufactured by Reference Example 47 8 · 6 mmol), and the target compound (1.3 6 g, 93%) was obtained according to the method of Reference Example 1. iH-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 10.90 (brs, 2H) , 8.83 (brs, 1H), 7.67 (d, 2H, J = 7.6 Hz), 7.34-7.29 (m, 4H), 7.08-7.01 (m, 3H), 2.27 (s, 3H) HPLC (reverse phase): Rt. (Min) = 3.66 · MS (APCI, m / z): 294 (M + 1) + 〇 Reference Example 49 4,6-Difluorenyl-2-aniline-5- P-Tolyl-pyrimidine The 4,6-dihydroxyanilino-5-p-tolyl-pyrimidine (587 mg, 2 mmol) produced in Reference Example 48 was reacted according to the method of Reference Example 2 to obtain the target compound (495 mg , 75%). H-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 8.91 (s, 1H), 7.87 (d, 2H, J = 7 .8 Hz), 7.28-7.19 (m, 4H), 7.09 (d, 2H, J = 8.1 Hz), 6.86 (t, 1H, J = 7.3 Hz), 6.03 (s, 2H), 4.23 (brs, 4H ), 2.34 (s, 3H). HPLC (reverse phase): Rt. (Min) = 2.95. 200522964 MS (APCI, m / z): 322 (M + 1) +. Reference Example 5 0 2- [3- (4-fluorophenoxy) phenyl] -malonic acid diethyl ester 1- (4-fluorophenoxy) -3-iodobenzene (4.0 g, 13 mmol) was reacted according to the method of Reference Example 5. The target compound can be obtained (3.21 g, 72%). IH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.33-7.24 (m, 1H), 7.13-6.85 (m, 6H), 4.57 (s, 1 H), 4 · 2 7-4 · 0 8 (m, 4 H), 1.25 (t, 6H, J = 7.0 Hz).

HPLC (reverse phase): Rt. (Min) = 5.93. MS (APCI, m / z): 347 (M + 1) +. Reference Example 5 1 4,6-Dihydroxy-5- [3- (4-fluorophenoxy) -phenyl] -2-anilino-pyrimidine The 2- [3- (4-fluoro Phenoxy) -phenyl) -diethyl acetate malonate (5.5 mm ο 1) was reacted according to the method of Reference Example 1 to obtain the target compound (603 mg, 31%).

1H-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 1 〇. 9 3 (brs, 2 Η), 8.84 (brs, 1H), 7.67 (dd, 2H, J = 1.1 Hz, 7.8 Hz), 7.36 -7.16 (m, 7H), 7.10-7.02 (m, 3H), 6.77 (dt, 2H, J = 2.2 Hz, 7.0 Hz). HPLC (reverse phase): Rt. (Min) = 4.37. MS (APCI, m / z): 390 (M + 1) +. Reference Example 52 4,6-diazino-5- [3- (4-fluorophenoxy) -phenyl] -2-anilino-pyrimidine 4,6-dihydroxy-5- produced in Reference Example 51 [3- (4-Fluorophenoxy) -phenyl-106- 200522964] -2-anilino-pyrimidine (3 86 mg, 1 mmol) was obtained by performing the reaction according to the method of Reference Example 2 (329 mg, 80%). . iH-NMR spectrum (270 MHz, DMSO-d6) δ ppm: 8.9 1 (s, 1H), 7.86 (dd, 2H, J = 1.1 Hz, 8.6 Hz), 7.43 (t, 1H, J = 7.8 Hz) , 7.25-7.16 (m, 6H), 6.99-6.77 (m, 4H), 6.35 (s, 2H), 4.17 (brs, 4H). HPLC (reversed phase): Rt. (Min) = 3.63 · MS (APCI, m / z): 418 (M + 1) +. Reference Example 53 φ 2- (4-methoxybiphenyl-3-yl) -malonate Diethyl 3-iodo-4-methoxybiphenyl (4.96 g, 16 mmol) was prepared according to the method of Reference Example 5. The target substance was obtained by reaction (2.30 g, 42%). 1H-NMR spectrum (270 MHz, DMSO-d6) δ ppm: 7.59-7.49 (m, 4H), 7.43-7.37 (m, 2H), 7.32-7.25 (m, 1H), 6.96 (d, 1H, J = 8.4 Hz), 5.15 (s, 1H), 4.33-4.16 (m, 4H), 3.86 (s, 3H), 1.28 (t, 6H, J = 7.0 Hz). HPLC (reverse phase): Rt. (Min) = 5.95. Φ MS (APCI, m / z): 343 (M + 1) +. Reference Example 54 4,6-Dihydroxy-5- (4-methoxybiphenyl-3-yl) -2-anilino-pyrimidine 2- (4-methoxybiphenyl-3-yl) produced in Reference Example 53 ) -Diethyl malonate (5.5 mmol). The target compound (1.21 g, 63%) can be obtained by reacting according to the method of Reference Example 1. HPLC (reverse phase): Rt. (Min) = 4.13. -107- 200522964 MS (APCI, m / z): 386 (M + 1) +. Reference Example 55 4,6-Dihydrazino-5- (4-methoxybiphenyl-3-yl) -2-anilino-pyrimidine The 4,6-dihydroxy-5- (4- Methoxybiphenyl-3-yl) -2-anilino-pyrimidine (391 mg, 1 mmol) was reacted according to the method of Reference Example 2 to obtain the target compound (150 mg, 36%). W-NMR spectrum. (270 MHz, DMSO-d6) (5 ρρπκ 8.89 (s, 1H),

7.88 (d, 2H, J = 7.8 Hz), 7.68-7.62 (m, 3H), 7.43 (t, 2H, J = 7.3 Hz), 7.34-7.15 (m, 5H), 6.85 (t, 1H, J = 7.3 Hz), 6.11 (s, 2H), 4.16 (brs, 4H), 3.77 (s, 3H). HPLC (reverse phase): Rt. (Min) = 3.57. MS (APCI, m / z): 414 ( M + 1) +. Reference Example 5 6 2-Benzo [1,3] oxazol-5-yl-malonate diethyl 5-benzo-benzo [1,3] difluorene D (2.1 ml, 16 mmol), The reaction was performed according to the method of Reference Example 5 to obtain the target substance (2.63 g, 59%).

W-NMR spectrum (270 MHz, DMSO-d6) 5ppm: 6.95 (d, 1H, J = 1.5 Hz), 6.82 (dd, 1H, J = 1.5 Hz, 7.9 Hz), 6.77 (dd, 1H, J = 0.5 Hz, 7.9 Hz), 5.96 (s, 2H), 4.52 (s, 1H), 4.30-4.08 (m, 4H), 1.27 (t, 6H, J = 7.1 Hz). HPLC (reverse phase): Rt. ( min) = 4.73 · MS (APCI, m / z): 281 (M + 1) +. Reference Example 57 5-Benzo [1,3] nazol-5-yl-4,6-dihydroxy-2_anilino-pyrimidine-108- 200522964 2-benzo [1,3] produced in Reference Example 56 ] Oxazol-5-yl-malonic acid diethyl ester (4.3 mmol), the reaction was performed according to the method of Reference Example 1 to obtain the target compound (231 mg, 14%). HPLC (reverse phase): Rt. ( min) = 3.29 · MS (APCI, m / z): 324 (M + 1) +. Reference Example 5 8 5-Benz [1,3] oxazol-5-yl-4,6-diazino-2-anilino-pyrimidine 5-Benz [1,3] pyrene produced in Reference Example 57 Isoxazol-5-yl-4,6-dihydroxy-2-anilino-rannidine (230 mg, 0.71 mmol) was reacted according to the method of Reference Example 2 to obtain the target compound (66 mg, 26%). W-NMR spectrum (270 MHz, DMSO-d6) ppm: 8.89 (s, 1H), 7.86 (d, 2H, J = 7.8 Hz), 7.22 (t, 2H, J = 7.6 Hz), 6.97 (d, 1H, J = 7.8 Hz), 6.85 (t, 1H, J = 7.3 Hz), 6.68-6.61 (m, 2H), 6.21 (s, 2H), 6.04 (s, 2H), 4.23 (brs, 4H) · HPLC (reverse phase): Rt. (Min) = 2.9. MS (APCI, m / z): 352 (M + 1) +. Reference Example 5 9 2- (2,3-dihydrobenzo [i, 4] difluoren-6-yl) -malonate diethyl 6-iodo-2,3-dihydrobenzo [1 , 4] Ershuying (4.19 g, 16 mmol). The target compound (3.90 g, 83%) can be obtained by performing the reaction according to the method of Reference Example 5. W-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 6.94-6.93 (m, 1H), 6.84 (d, 2H, J: 1.5 Hz), 4.49 (s, 1H), 4.32 · 4 · 12 (m, 8H), 1.34-1.21 (m, 6H). HPLC (reversed phase): Rt. (Min) = 4.74. -109- 200522964 MS (APCI, m / z): 295 (M + 1) + Reference Example 6 0 5- (2,3-dihydrobenzo [1,4] difluoren-6-yl) -4,6-dihydroxy-2-anilino-pyrimidine was produced in Reference Example 59. The 2- (2,3-dihydrobenzo [1,4] dioxin-6-yl) -diethyl malonate (5.5 mm ο 1) can be reacted according to the method of Reference Example 1 to obtain the purpose HPLC (reverse phase): Rt. (Min) = 3.32. MS (APCI, m / z): 3 3 8 (M + 1) +. Reference Example 6 1 4.6- Dihydrazino- 5- (2, 3-Dihydrobenzo [1,4] disuoying-6-yl) -2-anilino-pyrimidine 5- (2,3-dihydrobenzo [1,4] manufactured in Reference Example 60 Dioxin-6-yl) -4,6-Once reacted with 2-anilino-IP-metidine (332 mg, 1 mmol), the reaction was carried out according to the method of Reference Example 2 to obtain the target compound (130 mg, 36 %). 1 Η-NMR spectrum (270 MHz, DMS 0-de) 5 ppm: 8.88 (s, 1H), 7.86 (d, 2H, J = 7.6 Hz), 7.22 (t, 2H, J = 7.6 Hz ), 6.93-6.82 (m, 2H), 6.65- 6.60 (m, 2H), 6.09 (s, 2H), 4.26 (s, 4H), 4.19 (brs, 4 H) · HPLC (reverse phase): ruler 1:. (111 ^ 11) = 2.99 · MS (APCI , M / z): 3 66 (M + 1) + 〇 Reference Example 62 4.6-Dihydroxy-2- (5-fluoro-2-tolylamino) -5-phenyl-pyrimidine Toluidine (1.25 g, 10 mmol) was dissolved in ethanol (4 ml)-110- 200522964, and 1H-pyrazole-carboxamidine hydrochloride (ι · 47 g, mm〇1) was added, and the mixture was heated under reflux for 15 hours After the reaction, ethanol (36 ml), sodium ethoxide (21 wt%, 18.6 ml, 50 mmol) and diethyl phenylmalonate (64 ml, 30 mmol) were added, and the mixture was heated under reflux for 15 hours. Acetic acid was added to stop the reaction, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with water. The organic layer was concentrated, and the residue was added with diethyl ether. The precipitated solid was pulverized and collected by filtration, and then washed with diethyl ether to obtain the target substance (2.10 g, 34%). 4-NMR spectrum (270 MHz, DMS〇-d6) (5ppm: 10.95 (brs, 2H), 8.15-8.10 (m, 2H), 7.45 (d, 2H, j = 8 4 HZ), 7.30- 7.21 (m, φ 3H), 7.17-7.11 (m, 1H), 6.84 (dt, ih, J = 2.4 Hz, 8.4 Hz), 2.24 (s, 3H). HPLC (reverse phase) : Rt. (Min) = 3.83. MS (APCI, m / z): 312 (M + 1) + 〇 Reference Example 6 3 ^^-monohydrazinyl ^-"-oxo-tolylamine ^^- Phenyl-chewidine will be 4,6-dihydroxy_2_ (5-fluoro-2-tolylamino) _5-phenyl-pyrimidine (360 mg, 1.2 mmol) produced in Reference Example 62, as described in Reference Example 2 The target was obtained by the method of φ reaction (1 85 mg, 47%). W-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 8〇5 (dd, 2H, j = 2.7 Hz, 12.2 Hz), 7.81 (s, 1H), 7.48-7.31 (m, 3H), 7.21-7.13 (m, 3H), 6.71 (dt, 1H, J = 2.7 Hz, 8.4 Hz), 6.11 (s, 2H), 4.15 (brs , 4H), 2.27 (s, 3H). HPLC (reverse phase): Rt. (Min): 3.01. MS (APCI, m / z): 340 (M + 1) +. -Ill-200522964 Reference example 64 2 -(2,3-xylyl) -diethyl malonate The 1-iodine-2,3-xylene (2.3 ml, 16 mmol) was reacted according to the method of Reference Example 5 to obtain the target compound (2 · 6 3 g, 6 2% ). W-NMR spectrum (270 MHz, DMSO-d6) ppm: 7.21-7.07 (m, 3H), 4.92 (s, 1H), 4.31-4.15 (m, 4H), 2.30 (s9 3H), 2.22 ( s, 3H), 1.27 (t, 6H, J = 7.0 Hz). HPLC (reverse phase): 1 ^. (11 ^ 11) = 5.39 · MS (APCI, m / z): 265 (M + 1) + Reference Example 65 4,6-Dihydroxy-5- (2,3-xylyl) -2-anilino-pyrimidine The 2- (2,3-xylyl) -malonic acid produced in Reference Example 64 Diethyl ester (5.8 mmol) was reacted according to the method of Reference Example 1 to obtain the target compound (1.24 g, 81%).

W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 11 · 40 (brs, 2H), 8.79 (brs, 1Η), 7.69 (d, 2Η, J = 7.6 Ηζ), 7.36-7.30 (m, 2Η), 7.07-6.97 (m, 3H), 6.93-6.90 (m, 1H), 2.18 (s, 3H), 2.00 (s, 3H). HPLC (reverse phase): Rt. (min ) = 3.70. MS (APCI, m / z): 308 (M + 1) +. Reference Example 6 6 4,6-Dihydrazino-5- (2,3-xylyl) -2-anilino- Pyrimidine The 4,6-dihydroxy-5- (2,3-xylyl) -2-anilino-pyrimidine (615 mg, 2 mmol) produced in Reference Example 65 was reacted according to the method of Reference Example -112 -200522964 The target substance was obtained (143 mg, 21%). IH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 8.90 (s, 1H), 7.89 (dd, 2H, J = 1.1 Hz, 8.6 Hz) , 7.31-6.83 (m, 6H), 5.76 (s? 2H), 4.20 (brs, 4H), 2.28 (s, 3H), 1.92 (s, 3H). HPLC (reverse phase): Rt. (Min) = 3.12. MS (APCI, m / z): 3 36 (M + 1) +. Reference Example 6 7 2- (2,4-difluorophenyl) -diethyl malonate

1,3-difluoro-4-_benzene (1.9 ml, 16 mmol) was reacted in the same manner as in Reference Example 5 to obtain the target compound (1.47 g, 34%). iH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.53-7 · 44 (m, 1Η), 6.96-6.80 (m, 2Η), 4.92 (s, 1Η), 4.32-4.16 (m, 4Η), 1.28 (t, 6H, J = 7.0 Hz). MS (APCI, m / z): 273 (M + 1) + 〇 Reference Example 6 8 5- (2,4-difluorophenyl) -4,6-dihydroxy-2-anilinopyrimidine

The 2- (2,4-difluorophenyl) -malonate (5.4 mmol) produced in Reference Example 67 was reacted according to the method of Reference Example 1 to obtain the target compound (799 mg, 51%). j-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 12.18 (brs, 2H), 8.91 (brs, 1H), 7.67 (dd, 2H, J = 1.1 Hz, 8.6 Hz), 7.37-7.27 (m, 3H), 7.18-6.98 (m, 3H). HPLC (reverse phase): Rt. (Min) = 3.42. MS (AP CI, m / z): 3 1 6 (M + 1) +. -113- 200522964 Reference Example 6 9 5- (2,4-difluorophenyl) -4,6-diazino-2-anilino-pyrimidine 5- (2, [difluorobenzene) produced in Reference Example 68 Group) -4,6-dihydroxy-2-anilino-pyrimidine (799 mg, 2.5 mmol), and the target compound (250 mg, 29%) was obtained by performing the reaction according to the method of Reference Example 2. iH-NMR spectrum (270 MHz, DMSO-d6) 5ppni: 8.91 (s, 1H), 7.86 (d, 2H, J = 8.6 Hz), 7.25-7.17 (m, 4H), 7.12-7.04 (m, 1H) , 6.89-6.82 (m, 1H), 6.55 (s, 2H), 4.15 (brs, 4H).

HPLC (reverse phase): Rt. (Min) = 2.94. MS (APCI, m / z): 344 (M + 1) +. Reference Example 7 0 2- (3-Chloro-2-fluorophenyl) -malonic acid diethyl ester. Chlorochloride-2-stilbene (4.10 g, 16 mmol) can be reacted according to the method of Reference Example 5. The target substance (2.87 g, 62%) was obtained. j-NMR spectrum (270 MHz, DMSO-d6) 6 ppm: 7.42-7.35 (m,

2H), 7.11 (dt, 1H, J = 1.0Hz, 7.8Hz), 4.98 (s, 1H), 4.33 · 4.17 (m, 4H), 1.28 (t, 6H, J = 7.0 Hz). HPLC (reverse phase ): Rt. (Min) = 5.44. MS (APCI, m / z): 289 (M + 1) +. Reference Example 7 1 5- (3-chloro-2-fluorophenyl) -4,6-dihydroxy-2-anilino-pyrimidine 2- (3-chloro-2-fluorophenyl) produced in Reference Example 70 -Diethyl malonate (5.5 mmol). The reaction was carried out according to the method of Reference Example 1 to obtain the target compound (6.88 mg, 41%). -114- 200522964 iH-NMR spectrum (270 MHz, DMS〇-d6) 0 ppm: 12.64 (brs, 2H), 7.94 (brs, 1H), 7.66 (d, 2H, J = 7.8 Hz), 7.50-7.04 ( m, 6H). HPLC (reverse phase): Rt. (min) = 3.66. MS (APCI, m / z): 33 2 (M + 1) +. Reference Example 7 2 5- (3-chloro-2-fluorophenyl) -4,6-diazino-2-anilino-pyrimidine 5- (3-chloro-2-fluorophenyl) produced in Reference Example 71 ) -4,6-dihydroxy-2-anilino-pyrimidine (68 8 mg, 2.1 mmol). The target compound (65 mg, 9%) can be obtained by performing the reaction according to the method of Reference Example 2. iH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 8.94 (s, 1H), 7.87 (d, 2H, J = 8.4 Hz), 7.53-7.47 (m, 1H), 7.26-7.16 (m, 3H ), 7.14-7.08 (m, 1H), 6.86 (t, 1H, J = 7.4 Hz), 6.69 (s, 2H), 4.22 (brs, 4H). HPLC (reverse phase): Rt. (Min) = 3.18 . MS (APCI, m / z): 360 (M + 1) +. Reference Example 7 3 2- (4-Chloro-2-fluorophenyl) -malonic acid diethyl ester 1-Chloro-3-fluoro-4-oxobenzene (2.1 ml, 16 mmol), as described in Reference Example 5 The reaction was carried out to obtain the target substance (1.95 g, 42%). 1H-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.49-7.3 8 (m, 1H), 7.19-7.10 (m, 2H), 4.92 (s, 1H), 4.32-4.18 (m, 4H), 1.27 (t, 6H, J = 7.0 Hz) · HPLC (reverse phase): Rt. (Min) = 5.55. MS (APCI, m / z): 289 (M + 1) +. 200522964 Reference Example 74 5- (4 -Gas 2- 2- ¾phenyl) -4,6-Mono-Chrysyl-2-benzyl | Ethyl-Nine, Π 疋 Manufactured from Reference Example 73 2- (4-chloro 2-Fluorophenyl) -diethyl malonate (5.8 mmol) was reacted according to the method of Reference Example 1 to obtain the target compound (728 mg, 44%). iH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 12.21 (brs, 2H), 8.90 (brs, 1H), 7.67 (d, 2H, J = 7.6 Hz), 7.38-7.18 (m, 5H ), 7.07 (t, 1H, J = 7.6 Hz).

HPLC (reverse phase): Rt. (Min) = 3.70. MS (APCI, m / z): 3 3 2 (M + 1) + 〇 Reference Example 75 5- (4-chloro-2-fluorophenyl)- 4,6-Dihydrazino-2-anilino-pyrimidine 5- (4-chloro-2-fluorophenyl) -4,6-dihydroxy-2-anilino-pyrimidine (728 mg, 2.2 mmol), and reacted according to the method of Reference Example 2 to obtain the target compound (145 mg, 18%). iH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 8.92 (s, 1H),

7.86 (dd, 2H, J = 1.1 Hz, 8.6 Hz), 7.40 (dd, 1H, J = 2.2 Hz, 9.5 Hz), 7.30-7.14 (m, 4H), 6.86 (t, 1H, J = 7.4 Hz) , 6.64 (s, 2H), 4.17 (brs, 4H) · HPLC (reverse phase): Rt. (Min) = 3.1. MS (APCI, m / z): 3 60 (M + 1) + 〇 Reference Example 7 6 4,6-Dihydroxy-2-morpholin-1-yl-5-phenyl-pyrimidine Dissolve morphine (436ml, 5mmol) in ethanol (2ml), add salt -116- 200522964 acid 1H-pyrazole- 1-Carboxamidine (73 3 mg, 5 mmol), and heat-reflux for 5 hours. After the reaction, ethanol (18 ml), sodium ethoxide (21 wt%, 9.3 ml, 25 mmol) and diethyl phenylmalonate (3.2 ml, 15 mmol) were added. After heating under reflux for 15 hours, acetic acid was added. The reaction was stopped, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with water. The organic layer was concentrated, and the residue was added with ether. The precipitated solid was pulverized and collected by filtration, and then washed with ether to obtain the target substance (928 mg, 68%).

'H-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 10.84 (brs, 2H), 7.45-7.39 (m, 2H), 7.29-7.20 (m, 2H), 7.14-7.07 (m, lH), 3.66-3.56 (m, 8H). HPLC (reverse phase): Rt. (Min) = 2.71. MS (APCI, m / z): 274 (M + 1) +. Reference Example 77 4,6-Dihydroxy-2 -morphinyl-5 -phenyl-methylidene 4,6-dihydroxy-2-morpholinyl-5-phenyl- manufactured in Reference Example 76 Pyrimidine (273 mg, 1 mmol) 'The reaction was performed according to the method of Reference Example 2 to obtain the target compound (90.3 mg, 30%). _ W-NMR spectrum (270 MHz, DMSO-d6) (5ppm: 7.46_7 · 38 (m, 2H), 7.35-7.27 (m, 1H), 7.18-7.12 (m, 2H), 5 91 (brs, 2H), 4.10 (brs, 4H), 3.75-3.70 (m, 4H), 3.68-3.62 (m, 4H). HPLC (reversed phase): Rt. (Min) = 1.73. MS (APCI, m / z) : 302 (M + 1) +. Reference Example 7 8 2- (2,3-dichlorophenyl) · diethyl malonate-117- 200522964 1,2-dichloro-3-iodobenzene (4.1 g, 15 mmol), and reacted according to the method of Reference Example 5 to obtain the target compound (1.81 g, 40%). j-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.47-7.38 (m, 2H), 7.28-7.20 (m, 1H), 5.24 (s, 1H), 4.30-4.21 (m, 4H), 1.28 (t, 6H, J = 7.2 Hz). MS (APCI, m / z): 305 (M + 1) +. Reference Example 79 5- (2,3-dichlorophenyl) -4,6-dihydroxy-2-anilino-pyrimidine

The 2- (2,3-dichlorophenyl) -malonate (5.9 mmol) produced in Reference Example 78 was reacted according to the method of Reference Example 1 to obtain the target compound (1.0 8 g, 68%). ). HPLC (reverse phase): Rt. (Min) = 3.75. MS (APCI, m / z): 348 (M + 1) +. Reference example 80 5- (2,3-dichlorophenyl) -4,6-dihydrazino-2-anilino-pyrimidine

The 5- (2,3-dichlorophenyl) -4,6-dihydroxy-2-anilino-pyrimidine (1.08 g, 4.54 mmol) produced in Reference Example 79 was reacted according to the method of Reference Example 2 to obtain Target (83 mg, 5%). HPLC (reverse phase) Rt. (Min) = 3.27. MS (APCI, m / z): 376 (Μ + 1) + 〇 Reference Example 8 1 2- (1,3,5-trimethyl-1H -Pyrazol-4-yl) -diethyl malonate The reaction of 4-iodo-1,3,5-trimethyl-1H-pyrazole (3.78 g, 16 mmol) was carried out according to the method of Reference Example 5. The target was obtained (1.69 g, 39%). -118- 200522964 iH-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 4.29-4.13 (m, 4H), 3.79 (s, 3H), 3.71 (s, 3H), 2.26 (s, 3H), 1.33 -1.21 (m, 6H). HPLC (reversed phase): Rt. (Min) = 3.7 6. MS (APCI, m / z): 269 (M + 1) +. Reference example 82

4,6-Dihydroxy-2-anilino-5- (1,3,5-trimethyl-1H-pyrazol-4-yl) -pyrimidine 2- (1,3,5) produced in Reference Example 81 -Trimethyl-1H-pyrazole_4-yl) -diethyl malonate (6.3 mmol), the reaction was performed according to the method of Reference Example 1 to obtain the target compound (321 mg, 21%). h-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 10.49 (brs, 2H), 8.90 (brs, 1H), 7.68 (d, 2H, J = 7.6 Hz), 7.32 (t, 2H, J = 7.6 Hz), 7.03 (t, 1H, J = 7.6 Hz), 3.63 (s, 3H), 1.98 (s, 3H), 1.92 (s, 3H) · HPLC (reverse phase): Rt. (Min) = 2.27 .

MS (APCI, m / z): 312 (M + 1) + 〇 Reference Example 83 4,6-Dihydrazino-2-anilino- 5- (1,3,5-trimethyl-1H-pyrazole 4-yl) -pyrimidine The 4,6-dihydroxy-2-anilino-5- (l, 3,5-trimethyl-1H-pyrazol-4-yl) -pyrimidine ( 321 mg, 1 mmol), and the reaction was performed according to the method of Reference Example 2 to obtain the target compound (45 mg, 13%). HPLC (reverse phase): Rt. (Min) = 2.51. MS (APCI, m / z): 340 (M + 1) + 〇 Reference Example 84 -119- 200522964 2- (2-fluoro-5-tolyl) -Diethyl malonate The 1-fluoro-2-bowl-4 -toluene (2.1 ml, 16 mmol) was reacted according to the method of Reference Example 5 to obtain the target compound (2.69 g, 63%). W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.26-7 · 22 (m, 1H), 7.12-7.06 (m, 1H), 6.99-6 · 92 (m, 1H), 4 · 93 (s, 1H), 4.33-4.16 (m, 4H), 2.32 (s, 3H), 1.30-1.24 (m, 6H). HPLC (reversed phase): Rt. (Min) = 5.44 · MS (APCI, m / z): 269 (M + 1) +. Reference Example 8 5 4,6-Dihydroxy-5- (2-fluoro-5-tolyl) -2-anilino-pyrimidine 2- (2-fluoro-5-tolyl) -propyl produced from Reference Example 84 Diethyl diacid (5.5 mmol) was reacted according to the method of Reference Example 1 to obtain the target compound (8 13 mg, 5 2%). 〇W-NMR spectrum (270 MHz, DMSO-d6) (5 ppm: 12.00 ( brs, 2H), 8.85 (brs, 1H)? 7.67 (d, 2H, J = 8.6 Hz), 7.37-7.31 (m, 2H), 7.09-6.96 (m, 4H), 2.27 (s, 3H). HPLC (Reverse phase): Rt. (Min) = 3.72. MS (APCI, m / z): 312 (M + 1) +. Reference example 86 4,6-dihydrazino-5- (2 · fluoro-5- Tolyl) -2-anilino · pyrimidine 4,6-dihydroxy-5- (2-fluoro-5-tolyl) -2-anilino-pyrimidine (6 1 5 mg, 2 mmo1) produced in Reference Example 85 ), The reaction can be obtained according to the method of Reference Example 2. W-NMR spectrum (270 MHz, DMSO-d6) δ ppm: 8.92 (s, 1H), -120- 200522964 7.87 (dd, 2H, J II 1.1 Hz, 8.6 Hz), 7.3 2-6.83 (m, 6H), 6.30 (s, 2H), 4.25 (brs, 4H), 2.30 (s, 3H). HPLC (reverse phase): Rt. (Min) = 3.06 MS (APCI, m / z): 340 (M + 1) +. Reference Example 87 2- (2-Chloro-4-tolyl) -malonate diethyl 2-chloro-1-iodo-4 -Toluene (3.79 g, 15 mmol), and the reaction was performed according to the method of Reference Example 5 to obtain the target compound (1.52 g, 36%).

W-NMR spectrum (270 MHz, DMSO-d6) 5 ppm: 7.35 (d, 1H, J = 8.1 Hz), 7.22 (s, 1H), 7.09 (d, 1H, J = 8.1 Hz), 5.16 (s, 1H), 4.29-4.18 (m, 4H), 2.32 (s, 3H), 1.27 (t, 6H, J = 7.2 Hz). MS (APCI, m / z): 285 (M + 1) +. Reference example 8 8 5- (2-Chloro-4-tolyl) -4,6-dihydroxy-2-anilino-pyrimidine

The 2- (2-chloro-4-tolyl) -malonic acid diethyl ester (5.27 mmol) produced in Reference Example 87 was reacted according to the method of Reference Example 1 to obtain the target compound (250 mg, 19%). HPLC (reverse phase): Rt. (Min) = 3.71. MS (APCI, m / z): 328 (M + 1) +. Reference Example 89 5- (2-chloro-4-tolyl) -4,6-diazino-2-anilino-pyrimidine 5- (2-chloro-4-tolyl) -4 produced in Reference Example 88 , 6-Dihydroxy-2-anilino-pyrimidine (250 mg, 0.76 mmol), according to the method of Reference Example 2 -121-200522964 reaction to obtain the target. HPLC (reverse phase): Rt. (Min) = 3.16. MS (APCI, m / z): 3 5 6 (M + 1) +. Reference Example 9 4-Ethyl-N-tosylsulfonamide

Dissolve 4-ethylammonium benzylsulfonium chloride (0.2 mol, 43.7 g) in Nihonin (200 ml), and add triethylamine (0.3 mol, 41.8 ml), 40% methylamine-methanol solution (0.3 mmol, 23.3 ml) and stirred at room temperature for 2 hours. The reaction solvent was distilled off under reduced pressure, and then extracted with ethyl acetate-water, and the organic layer was concentrated. The obtained residue was purified by recrystallization from ether to obtain the target substance (25.6 g, 6Q% HPLC (reverse phase): Rt. (Min) = 3.14. MS (APCI, m / z): 214 (M + 1) +. Example 91 4-Ethylfluorenyl-N-ethylbenzenesulfonamide

The target product can be obtained by reaction purification according to the method of Reference Example 87. HPLC (reverse phase): Rt. (Min) = 3.58 MS (APCI, m / z): 228 (M + 1) +. Reference Example 92 [4- (Acetidine-1-yl-sulfofluorenyl) phenylbuthionone] The target product was obtained by reaction purification according to the method of Reference Example 87. HPLC (reverse phase Rt. (Min) = 3.76. MS (APCI, m / z): 240 (M + 1) + 〇 Reference Example 93 -122- 200522964 4-Ethyl-N-cyclopropyl-benzenesulfonate The amidine was purified by the method of Reference Example 87. HPLC (reverse phase): Rt. (Min) = 3.69. MS (APCI, m / z): 240 (M + 1) +. Reference Example 94 4 -Acetyl-N- (2-hydroxyethyl) -benzenesulfonamide is reacted and purified according to the method of Reference Example 87 to obtain the target product °

HPLC (reverse phase): Rt. (Min) = 2.79. MS (APCI, m / z): 244 (M + 1) +. Reference example 95 (1-pyridin-4-yl-ethylene) -hydrazine 4-Ethylpyridine (5.53 ml, 50 mmol) was dissolved in methanol (50 ml), and hydrazine monohydrate (3.64 ml, 75 mmol) was added. ), And stirred for 5 hours. Concentrated, and the precipitated solid was filtered through isopropyl ether to obtain a quantitative target (7.02 g

W-NMR spectrum (500 MHz, DMSO-d6) 5 ppm: 8.48 (d, 2H, J = 4.6 Hz), 7.56 (d, 2H, J = 4.6 Hz), 6.94 (brs, 2H), 2.01 (s, 3H). HPLC (reverse phase): Rt. (Min): = 0.80. MS (APCI, m / z): 136 (M + l) + · Reference Example 9 6 4,6-Dichloro- 5-phenyl-2-aniline pyrimidine To 4,6-dihydroxy-5-phenyl-2 · aniline pyridine (279 mg, 1 mmol) was added phosphorus oxychloride (1 ml), and the mixture was stirred at 100 ° C. 6 hours. After the reaction was completed -123- 200522964, it was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with water. After concentration and purification by silica gel column chromatography, the target compound (167 mg, 53%) was obtained. 1H-NMR spectrum (270 MHz, DMSO-d6) accounts for PPm: 10 · 44 (brs, 1H).

7.70 (d, 2H, J = 7.6 Ηζ), 7.53-7.30 (m, 7H), 7.06 (t, 1H, J = 7.6 Hz). HPLC (reverse phase): Rt. (min) = 6.32. MS (APCI, m / z): 316 (M + l) +. Reference example 97

(4-Ga-6-Cryl-5-phenyl-II.Did-2-yl) -aniline 4,6-dichloro-5-phenyl-2-aniline pyrimidine (4.74 g, 15 mmol ) Ethanol (50 ml), hydrazine monohydrate (1.6 ml, 33 mmol) was added, and the mixture was stirred at room temperature for 72 hours. Water was added to the reaction solution, and the precipitated solid was pulverized and collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain the target substance (4.56 g, 98% "

^ -NMR spectrum (500 MHz, DMSO-d6) 5ppm: 9.58 (brs, 1H), 7.82 (d, 2H, J = 7.5 Hz), 7.48-7.25 (m, 7H), 6.96-6.63 (m, 1H) , 4.44 (brs, 2H). HPLC (reverse phase): Rt. (Min) = 4.24. MS (APCI, m / z): 312 (M + l) +. Reference Example 9 8 4- {l-[( 6-chloro-5-phenyl-2-anilino-pyrimidin 4-yl) _hydrazinyl μethylbenzene N_tosylsulfonamide will be (4-air-6-fluorenyl-5-phenylphenyl) Amine-2-yl) -aniline (4.05 g, 13 mmol) was dissolved in ethanol (80 ml). After adding 4-ethylamidine π-toluenesulfonium-124- 200522964 amine (3.05 g, 14.3 mmol), stir 5 hour. The precipitated solid was pulverized, and the target substance was obtained by filtration with ethanol (6.45 g, 98%). j-NMR spectrum (500 MHz, DMSO-d6) (5ppm: 9.89 (brs, 1H), 8.84 (brs, 1H), 8.04 (d, 2H, J = 7.1 Hz), 7.77-7.7.44 (m, 10H ), 7.33 (t, 1H, J = 7.7 Hz), 7.02 (t, 1H, J = 8.4 Hz), 2.44 (d, 3H, J = 5.1 Hz), 2.10 (s, 3H). HPLC (reverse phase) : Rt. (Min) = 6.00. MS (APCI, m / z): 507 (M + l) + · Reference Example 9 9 2_ (4-fluoroaniline) -5-phenyl-pyrimidine-4,6- The diol was dissolved in 4-fluoroaniline (10.4 ml, 1 10 mmol) in ethanol (50 ml), and 1H-D hydrochloric acid was added to the mixture to form a residual hydrazone (16.1 g, 110 mmol), and the mixture was heated under reflux for 15 hours. After the reaction, ethanol (200 ml), sodium ethoxide (21 wt%, 170 ml, 455 mmol) and diethyl phenylmalonate (50 ml, 232 mmol) were added, and the mixture was heated under reflux for 15 hours. The solvent was distilled off under pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with water. After the organic layer was concentrated, diethyl ether was added to the residue, the precipitated solid was pulverized and collected by filtration, and washed with ether to obtain the target substance (15.7 g, 48%). 1 Η-NMR spectrum (5 Ο Ο Μ H z, DMS 〇-d 6) (5 ppm: 8 · 8 3 (brs, 1 Η), 7.69 (dd, 2H, J = 5.0, 7.0 Hz) , 7.44 (d, 2H, J = 8.0 Hz), 7.27 (dd, J = 7.0, 7.0 Hz), 7.19-7.12 (m, 1H)? 7.16 (d, 2H, J = 8.0 Hz). HPLC (reverse phase ): Rt. (Min) = 3.46. MS (APCI, m / z): 298 (M + 1) +. 200522964 Reference example 1 0 0 4,6-dichloro-5-phenyl-2- (4- Fluorophenyl) -aminopyrimidine Add 2- (4-fluoroaniline) -5-phenyl-pyrimidine-4,6-diol (15.7 g, 52.9 mmol) to phosphorus oxychloride (15 ml) at 1 It was stirred for 6 hours at 〇 ° C. After the reaction was completed, the residue was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and the organic layer was washed with water. After concentration, purification by silica gel column chromatography gave the target compound (12.9 g, 73%). ). W-NMR spectrum (500 MHz, DMSO-d6) 5 ppm: 10.48 (s, 1H), 7.70-7.68 (m, 2H), 7.50-7.45 (m, 3H), 7.38 (d, 2H, J = 5.0 Hz), 7.21 (t, 2H, J = 7.5 Hz). HPLC (reverse phase): Rt. (Min) = 6.47 · MS (APCI, m / z): 334 (M + l) + 〇Reference Example 1 0 1 (4-Chloro-6-hydrazino-5-phenyl-pyrimidin-2-yl)-(4-fluorophenyl) -amine will contain 4,6-dichloro-5-phenyl 2- (4-fluorophenyl) -aminopyrimidine (4.68§, 14.0 mmol) in ethanol (70 ml), hydrazine monohydrate (2.17 ml) was added, and the mixture was stirred at room temperature for 68 hours. Water was added to the reaction solution, and the precipitated solid was pulverized and collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain the target substance (4.24 g, 92%). V HPLC (reverse phase): Rt. (Min) = 4.25. MS (APCI, m / z): 330 (M + 1) +. Reference Example 102 4- (l- {[6-Chloro-2- (4-fluoroaniline) -5-phenyl-pyrimidin-4-yl] -hydrazinyl} -ethyl) toluenesulfonate Amido-126- 200522964 (4-chloro-6-hydrazino-5-phenyl-pyrimidin-2-yl)-(4-fluorophenyl) -amine (4.24 g, 12.9 mmol) in ethanol (80 ml ) Dissolve, add 4-ethylfluorenyl-N-toluenesulfonamide (4.11 g, 19.3 mmol), and heat to reflux for 3.5 hours. After cooling at room temperature, the precipitated solid was pulverized, and the target substance was obtained by filtering with ethanol (6.66 g, 97%). HPLC (reverse phase): Rt. (Min) = 6.07 · MS (APCI, m / z): 525 (Μ + 1) + · Reference Example 103

2- (2-fluoroaniline) -5-phenyl-pyrimidine-4,6-diol

Dissolve 2-fluoroaniline (14.0 mL, 0.145 mol) in ethanol (67 ml), add 1H · pyrazole-1-carboxamidine hydrochloride (21.5 g, 0.147 mmol), and heat to reflux for 12 hours. After the reaction, ethanol (290 ml), sodium ethoxide (21 wt%, 250 ml, 3.19 mol), diethyl phenylmalonate (67 · 4 ml, 0.319 mol) were added, and the reaction mixture was heated under reflux for 15 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with water. The organic layer was concentrated and purified by silica gel column chromatography to obtain the target compound (5.87 g, 14%). W-NMR spectrum (500 MHz, DMSO-d6) 5 ppm: 8.71 (brs, 1H), 8.45 (t, 1H, 8.5 Hz), 7.45 (d, 2H, 8.0 Hz), 7.32-7.26 (m, 3H) , 7.20 (t, 1H, J = 8.0 Hz), 7.17-7.10 (m, 2H) · HPLC (reverse phase): Rt. (Min) = 3.53 · MS (APCI, m / z): 298 (M + 1 ) +. Reference Example 104 4,6 · Dichloro-5-phenyl-2- (2-fluorophenyl) -aminopyrimidine-127- 200522964 2- (2-fluoroaniline) -5-phenyl- Pyrimidine-4,6-diol (500 g, 227 mmol) was added with phosphorus oxychloride (23 ml), and the mixture was stirred at 1000 t for 3 hours. After completion of the reaction, it was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate ', and the organic layer was washed with water. After concentration, purification by silica gel column chromatography gave the target compound (2.74 g, 49%).

h-NMR spectrum (500 MHz, DMSO-d6) (5 ppm: ι〇 · 09 (brs, 1H), 7.59 (t, 1H, J = 7.5 Hz), 7.52-7.42 (m, 2H), 7. · 47 (d, 2H, j = 7.0 Hz), 7.36 (d, 2H, J = 7.0 Hz), 7.33-7.21 (m, 2H). HPLC (reverse phase): Rt. (Min) = 6.45. MS (APCI , M / z): 334 (M + 1) + · Reference Example 105 (4-Ga-6-Ceto-5-phenyl-rano-D-2--2-yl)-(2 · Gaphenyl) _amine Dissolve 4,6-dichloro-5-phenyl-2- (2-fluorophenyl) -amine videmidine (2.74 g, 8.20 mmol) in ethanol (40 ml), and add hydrazine monohydrate (1.27 ml), and stirred at room temperature for 91 hours. Water was added to the reaction solution, and the precipitated solid was pulverized and collected by filtration. The obtained solid was washed with water and dried under reduced pressure to obtain the target product (2.08 g, 77%). W-NMR spectrum (500 MHz, DMSO-d6) 5 ppm: 8.97 (brs, 1H), 7.97-7 · 93 (m, 1H), 7.48-7.08 (m, 9H), 4.38 (brs, 2H) · HPLC (reverse phase): Rt. (Min) = 4.44 · MS (APCI, m / z): 330 (M + 1) + 0 Reference Example 106 4- (l- {[6-chloro-2- (2- Fluoroanilide) -5-phenyl-pyrimidin-4-ylpyrazinoblylethyl) -N-toluenesulfonamide-128- 200522964 (4-chloro-6-hydrazino-5-phenyl-pyrimidine- 2-based) -(2-fluorophenyl) -amine (2.00 g, 6.07 mmol) was dissolved in ethanol (40 ml), 4-ethylammonyl-N-toluenesulfonamide (1.94 g, 9.10 mmol) was added, and the mixture was heated to reflux. 5 hours. After cooling at room temperature, the precipitated solid was pulverized, and the target substance (2.92 g, 92%) was obtained by filtration with ethanol. 〇j-NMR spectrum (500 MHz, DMS0.d6) 5 ppm: 9 26 (brs , IH), 8.90 (brs, 1H), 8.14 (brs, 1H), 7.71-7.16 (m, 13H), 2.42 (d, 3H, J = 4.9 Hz), 2.07 (s, 3H). HPLC (reverse phase ): Rt. (Min) = 5.97. MS (APCI, m / z): 525 (M + 1) +. Test Example 1: Measurement of MLR Inhibition The test compound was dissolved in dimethylarsine to 10 mg / Ml, diluted with culture medium to the desired concentration. Human peripheral hemolymph was derived from peripheral blood provided by two healthy blood donors using Ficoll-Paque PLUS (manufactured by Pharmacia) and Ficoll density gradient centrifugation. One of the two peripheral blood lymphocytes obtained was irradiated with 6000 rad of X-rays so that it could not colonize and was used as a stimulating cell. Human peripheral blood lymphocytes and stimulating cells, each of which had not been irradiated with X-rays, 130,000 cells each, in a phase-diluted test compound, 10% calf serum, 5mM 2-hydrothiothioethanol in RPMI culture solution (manufactured by Life Technologies) ) Were mixed in 0.2 ml, and cultured in a 96-well round bottom plate (manufactured by Corning). 120 hours later, [3H] thymidine (manufactured by Amersham) was added at 25 // 1 / points to achieve a final radioactivity of 82 kBq / ml, and cultured for another 16 hours, and intracellular absorption was measured on a / 3-plate (manufactured by WALLAC) Of radioactivity. The 50% inhibitory concentration of each compound is the concentration of the compound and the absence of test compounds for MLR reaction. The calculation was performed on a semi-logarithmic scale, and the results are shown in Table 2. Table 2 Test compound MLR inhibitory activity IC 50 (ng / m 1) Example 3 0 · 53 Example 13 0 · 25 Example 33 0 · 29 Example 48 0 · 50 According to the above results, the compound of the present invention obviously has Excellent MLR inhibition. Formulation Example 1: Capsule Example 2 or 30. Compound 50m g lactose 12 8m g corn starch 70m g magnesium stearate 2m g 250m g The above prescription powder was mixed, sieved with 60 mesh, 250mg powder was poured into No. 3 Gelatin capsules, capsules are available. Formulation Example 2: Lozenge Example 2 or 30 Compound 50m g lactose 126m g corn starch 23m g -130- 200522964 magnesium stearate 1 mg 200m g The above prescription powder was mixed, and corn starch paste was used for wet granulation. After drying, the tablets were shot with a tableting machine to obtain 1 200 mg tablets. Lozenges may be administered with sugar coating if necessary. Industrial Applicability The pyrimidine derivative of the formula (I) or a pharmacologically acceptable salt thereof according to the present invention has excellent MLR inhibitory effect and low cytotoxicity, and can be used as an inhibitor of rejection of transplanted tissues such as bone marrow transplantation and organ transplantation. Cancer cell inhibitors with selective cytocidal activity (such as inhibitors of cancerous lymphocytes), or chronic rheumatoid arthritis as an inflammatory disease, organ-specific autoimmune diseases (such as multiple sclerosis, inflammation Bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, malignant anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, dry addiction or Sj0egren's syndrome ), Non-specific autoimmune diseases of the stomach (such as systemic lupus erythematosus), preventive and / or therapeutic agents for allergic diseases (such as rhinitis, asthma or atopic dermatitis) (preferably bone marrow @ bottom Inhibitors of rejection of transplanted tissues such as organ transplantation or preventive and / or therapeutic agents for chronic M wet arthritis). -131-

Claims (1)

200522964 10. Scope of patent application: 1. A pyrimidine derivative or a pharmacologically acceptable salt thereof of the formula: [wherein R1 and R3 are the same or different, each is a lower alkyl group, R2 and R4 are the same or different, each is an aryl group, a heterocyclic group or There are 1 to 5 substituted aryl groups selected from any group of the substituent group a, R5 is an aryl group or 5 substituted aryl groups selected from any group of the substituent group b is R 6 is hydrogen, or R 6 and R 5 and Combining nitrogen atoms to form a saturated heterocyclic group, R7 is a cycloalkyl group, an aryl group, a heterocyclic group, 1 to 5 substituted aryl groups selected from the substituent group b, or an arbitrary group selected from the substituent group b 1 to 3 substituted heterocyclic groups, the substituent group a is a oligoalkylsulfonyl group, a mono-oligoalkylaminesulfonyl group, a mono-cycloalkylaminesulfonyl group, a mono-hydroxy oligoalkylaminesulfonyl group, Di-lower alkylamine sulfonyl and nitrogen-containing saturated heterocyclic sulfonyl, the substituent group b is a halogen atom, a lower alkyl group, a lower alkoxy group, an aryl group, an aryloxy group, and a halogen-substituted phenyl group And a phenoxy group substituted with a halogen atom] 2. For example, the pyrimidine derivative or its pharmacologically acceptable salt 20051964 in the scope of patent application, wherein R1 and R3 are methyl. 3. The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 or 2, wherein R2 and R4 are the same or different, each is a heterocyclic group or has one selected from the group of substituents a Aryl substituted with any radical. 4. The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of the items 1 or 2 of the scope of the patent application, wherein R2 and R4 are the same or different, and each is 0 or less than a U-based group or a lower alkylsulfonyl group, and mono-low Alkylaminesulfonyl, mono-cycloalkylamine fluorenyl, mono-hydroxy oligoalkylaminesulfonyl or (1-azetidinyl) sulfonyl substituted phenyl at the 4-position. 5. The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 or 2, wherein R 2 and R 4 are the same or different and each is 4-pyridyl, 4-methanesulfonylphenyl , 4-ethanesulfonyl phenyl, 4-methylaminesulfonyl phenyl, 4-ethylaminesulfonyl phenyl, 4-cyclopropylaminesulfonyl phenyl, '[(2-hydroxyethyl) aminesulfonyl] Phenyl or 4-[(1-azetidinyl) sulfonyl] phenyl. 6. The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 or 2, wherein R2 and R4 are the same or different, and each is 4-pyridyl, 4-methanesulfonylphenyl, or 4 -Methanesulfenyl phenyl. 7. The pyrimidine derivative or the burial allowable salt thereof according to any one of claims 1 or 2, wherein R2 and R4 are 4-methylaminesulfonylphenyl. 8. A pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein R5 is an aryl group or an aryl group substituted with 1 or 2 arbitrary groups selected from the substituent group b. 9 · The pyrimidine derivative or the 200522964 pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein R5 is a phenyl group or a phenyl group substituted with 1 or 2 fluorine atoms, chlorine atoms or methyl groups. 10. The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 7, wherein R5 is phenyl, 2-fluorophenyl, 4-fluorophenyl, or 5-fluoro-2-toluene base. 1 1. The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 7 in the scope of the patent application, wherein R5 is phenyl. 1 2 · The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 11 in the scope of patent application, wherein R6 is a hydrogen atom. 1 3 · The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 12 in the scope of the patent application, wherein R7 is an aryl group, a heterocyclic group, and has 1 or 2 arbitrary groups selected from the substituent group b The substituted aryl group may have 1 to 3 pyrazolyl groups substituted with any group selected from the substituent group b. 1 4 · The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of items 1 to 12 of the scope of patent application, wherein R7 is phenyl; thienyl; has 1 or 2 fluorine atoms, chlorine atoms, methyl groups or Methoxy substituted phenyl; or pyrazolyl substituted with 1 to 3 methyl groups. 1 5 · The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 12 in the scope of application for a patent, wherein R7 is phenyl, 3-thienyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 2-tolyl, 3-tolyl, 4-tolyl, 3-fluoro-4-tolyl or 1,3,5-trimethyl-4-pyrazolyl. 16 · The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of items 1 to 12 in the scope of the application for a patent, wherein R7 is phenyl, 3-thienyl, 2-fluorophenyl, 3-fluorophenyl, 2-tolyl, 4-tolyl or 3-fluoro-4-tolyl. -134- 200522964 1 7 · A pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 12 in the scope of patent application, wherein R7 is phenyl or 3-thienyl. 18. The pyrimidine derivative or pharmacologically acceptable salt thereof according to item 1 of the scope of patent application, which is 1- (4-methylaminesulfonylphenyl) -buethylone-1 ^-(2-phenylamino-6- { 2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazino) -5- (3-thienyl) -4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylbenzene ) -1-ethyl ketone 1 ^-(2-anilino-6- {2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazino} -5-phenyl_4_pyrimidine Hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone &amp; (2-aniline-5- (4-tolyl) -6- (242- (4-methylaminesulfonyl)醯 phenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-anilino-5- (3-fluoro -4-Tolyl) -6- (2- [1- (4-methylaminesulfonylphenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylbenzene ) -Buethylone N- (2-anilino-5- (2-fluorophenyl) -6- {2- [1- (4-methylaminesulfonylphenyl) ethylidene] hydrazine 4 -Pyrimidinyl) hydrazine, 1- (4-methylaminesulfonylphenyl) -1-ethanone N- (2-aniline-5-o-tolyl-6_ {2- [1- (4-methylamine Sulfophenyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1 · (4-pyridyl) -1-ethyl ketone N- (2-benzene Methyl-5-phenyl-6- {2- [1- (4-pyridyl) ethylene] hydrazinob 4-pyrimidinyl) hydrazine, 1- (4-methylsulfonylphenyl) -1- Ethyl ketone N- (2-anilino-5-phenyl-6-{2- 200522964 [1- (4-methylsulfonylphenyl) ethylidene] hydrazino} -4-pyrimidinyl) hydrazine, 1 -(4-Methenyl-phenyl) -1-Ethyl N- (2-aniline- 5- (3-Gaphenyl) -6- {2- [1- (4-Methanesulfonylphenyl) Ethylene] hydrazinob 4-pyrimidinyl) hydrazine, N-methyl-4- {1-[(5-phenyl-2-aniline-6- {N '-[1-pyridine-4- -Ethylidene] -hydrazinopyrimidin-4-yl) -hydrazinyl] -ethylbenzylsulfonamide, 4- {1-[(2- (4-fluoroaniline) -5-benzene -6- {1 ^ '-[1-pyridin-4-yl-ethylidene] -hydrazinopyrimidin-4-yl) -hydrazino] -ethylpyridine N-toluenesulfonamide or 4_ { 1-[(2_ (2-fluoroaniline) _5_phenyl-6- {N '-[1-pyridin-4-yl-ethylidene] -hydrazinopyrimidin-4-yl) -hydrazinyl ] -Ethylbenzene N-tolusulfamide. 1 9 · A pharmaceutical composition containing a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 12 in the scope of patent application as an active ingredient. 20 · —Medical composition for inhibiting mixed lymphosphere culture response The contents of the range of application for Patent i~i 8 The pyrimidine derivative or a pharmacologically allowable salt thereof according to any one of the active ingredient. 2 1. —Medicine that inhibits the rejection of transplanted tissues such as bone marrow transplantation and organ transplantation or prevents and / or treats inflammatory diseases, organ-specific autoimmune diseases, organ non-specific autoimmune diseases, or allergic diseases The composition 'contains a chewidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 18 in the scope of the patent application as an active ingredient. 2 2 · — Prevention and / or treatment of chronic rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis, malignant anemia, Hashimoto Thyroiditis, atrophic gastritis, myasthenia gravis, dry addiction, Sjogren's syndrome, systemic lupus erythematosus, rhinitis, asthma or atopic dermatitis 200522964, a pharmaceutical composition containing a patent application such as The pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of the items 1 to 18 is an active ingredient. 2 3-A pharmaceutical composition for inhibiting cancer cells, containing the pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims i to i in the scope of the patent application as an active ingredient. 24. A medicinal composition for inhibiting cancerous lymphocytes, containing the pyrimidine derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 18 in the patent application scope as an active ingredient. 25. A medicinal composition that inhibits the rejection of transplanted tissues such as bone marrow transplantation and organ transplantation, or prevents and / or treats chronic rheumatoid arthritis, and contains any of the items in the scope of patent applications 1 to 18 A pyrimidine derivative or a pharmacologically acceptable salt thereof is an active ingredient. 2 6. —Use in the manufacture of a pharmaceutical composition, which uses a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 18 in the scope of patent application. 27. The use of item 26 in the scope of the patent application, wherein the pharmaceutical composition is a composition that can inhibit the mixed lymphocyte culture reaction. 2 8 · If the application in the scope of patent application No. 26, the pharmaceutical composition is used to inhibit rejection of transplanted tissues such as bone marrow transplantation and organ transplantation or prevent and / or treat inflammatory diseases, organ-specific autoimmune diseases, Organ non-specific autoimmune disease or allergic disease. 2 9 · If the application in the scope of patent application No. 26, wherein the pharmaceutical composition can prevent and / or treat chronic rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease 'diabetes, glomerulonephritis, primary bile Cirrhosis, chronic active hepatitis, malignant anemia, Hashimoto's thyroiditis, atrophic stomach-137- 200522964 inflammation, myasthenia gravis, dryness, Sjoegren's syndrome &lt;, systemic lupus erythematosus, rhinitis , Asthma or atopic dermatitis. 30. The use of item 26 in the scope of patent application, wherein the medicinal composition is a composition that can inhibit cancer cells. 3 1 · If the application in the scope of patent application No. 26, the pharmaceutical composition is a composition that can inhibit cancerous lymphocytes. 32. The use according to item 26 of the patent application, wherein the medicinal composition is capable of inhibiting the rejection of transplanted tissues such as bone marrow transplantation and organ transplantation, or preventing and / or treating chronic rheumatoid arthritis. φ 33. —A method for inhibiting the rejection of transplanted tissues, such as bone marrow transplantation and organ transplantation, is based on a pharmacologically effective amount of a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 18 Administration to warm-blooded animals 03-A method for preventing and / or treating diseases, using a pharmacologically effective amount of a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 18 in the scope of patent application Administration to warm-blooded animals. 35. The method of claim 34, wherein the disease is an inflammatory disease, an organ-specific autoimmune disease, an organ non-specific autoimmune disease, or an allergic disease. 36. The method of claim 34, wherein the disease is chronic rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, diabetes, glomerulonephritis, primary biliary cirrhosis, chronic active hepatitis , Pernicious anemia, Hashimoto's thyroiditis, atrophic gastritis, myasthenia gravis, psoriasis, Sjoegren's syndrome, systemic lupus erythematosus, nasal-138-200522964 inflammation, asthma or atopic dermatitis ° 3 7 · For example, the method of claim 34, wherein the disease is chronic rheumatism &gt; &gt;, and arthritis. V 3 8 · A method for inhibiting cancer cells, which is administered to a warm-blooded animal with a pharmacologically effective amount of a pyrimidine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 18 in the scope of patent application. 39. The method of claim 38, wherein the cancer cells are cancerous lymphocytes. 40. The method according to any one of claims 33 to 39, wherein the warm-blooded animal is human. -139- 200522964 VII. Designated Representative Map: (1) The designated representative map in this case is: None. (2) Brief description of the representative symbols of the components in this representative picture 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: