USOO8835443B2

(12) United States Patent (10) Patent No.: US 8,835,443 B2 Kawasaki et al. (45) Date of Patent: *Sep. 16, 2014

(54) PYRIMIDINE COMPOUND AND MEDICAL (56) References Cited USE THEREOF U.S. PATENT DOCUMENTS (75) Inventors: Hisashi Kawasaki. Takatsuki (JP); 3,139,432 A 6/1964 Scarborough Hiroyuki Abe, Takatsuki (JP); Kazuhide 2004/O138285 A1 7, 2004 Okazaki Hayakawa, Takatsuki (JP); Tetsuya Iida, Takatsuki (JP); Shinichi Kikuchi, FOREIGN PATENT DOCUMENTS Takatsuki (JP); Takayuki Yamaguchi, Takatsuki (JP); Toyomichi Nanayama, A s A. 38: Takatsuki (JP); Hironori Kurachi, JP HO6-502152. A 3, 1994 Takatsuki (JP); Masahiro Tamaru, JP 2002-532414 T 10, 2002 Takatsuki (JP); Yoshikazu Hori, E. 5833. o I 1939: Takatsuki (JP); Mitsuru Takahashi, JP 2005ss4381 T 10, 2002 Takatsuki (JP); Takayuki Yoshida, JP 2002-332247 A 11, 2002 Yokohama (JP); Toshiyuki Sakai, Kyoto JP 2003-504401 T 2, 2003 (JP) JP 2004-504294 T 2, 2004 WO WOOO/35435 A1 6, 2000 WO WOOO/35436 A2 6, 2000 (73) Assignee: Japan Tobacco Inc., Tokyo (JP) WO WOOOf 40235 A2 7, 2000 WO WOOOf 40237 A1 T 2000 (*) Notice: Subject to any disclaimer, the term of this WO WOO1,05393 A2 1, 2001 patent is extended or adjusted under 35 W W 9:32, A. 38: U.S.C. 154(b) by 631 days. WO WOO2,06520 A1 1/2002 This patent is Subject to a terminal dis- (Continued) claimer. OTHER PUBLICATIONS (21) Appl. No.: 12/626,443 West, Anthony R., Solid State Chemistry and Its Applications, Wiley, New York, 1988, 358.* (22) Filed: Nov. 25, 2009 (Continued) (65) Prior Publication Data Primary Examiner — Erich A Leeser US 2010/O240613 A1 Sep. 23, 2010 (74) Attorney, Agent, or Firm — Leydig, Voit & Mayer, Ltd. (57) ABSTRACT Related U.S. Application Data The present invention relates to a pyrimidine- 0 compound or a (63) Continuation of application No. 12/053,133, filed on pharmaceutically acceptable salt thereof represented by the Mar. 21, 2008, now abandoned, which is a following formula II continuation of application No. 1 1/150,792, filed on Jun. 10, 2005, now Pat. No. 7,378,423. (60) Provisional application No. 60/630,596, filed on Nov. R R6 I 23, 2004. o NN1 (30) Foreign Application Priority Data RN ls l, 1 R4 N W X Jun. 11, 2004 (JP) ...... 2004-174770 1. 1s Nov. 10, 2004 (JP) ...... 2004-327111 O N1-x O (51) Int. Cl. R2 R3 A 6LX3/59 (2006.01) C07D 239/545 (2006.01) wherein each symbol is as defined in the specification and a CO7D 47L/04 (2006.01) method of therapeutically or prophylactically treating an CO7D 487/04 (2006.01) undesirable cell proliferation, comprising administering Such (52) U.S. Cl. a compound. The compound of the present invention has CPC ...... C07D 471/04 (2013.01); C07D 239/545 Superior activity in Suppressing undesirable cell proliferation, (2013.01); A61 K3 1/519 (2013.01); C07D particularly, an antitumor activity, and is useful as an antitu 48704 (2013.01) mor agent for the prophylaxis or treatment of cancer, rheu USPC ...... 514/262.1: 514/264.1 matism, and the like. In addition, the compound of the present (58) Field of Classification Search invention can be a more effective antitumor agent when used CPC ...... A61K31/519; C07D 239/545; C07D in combination with other antitumor agents such as an alky 471/04: CO7D 487/04 lating agent or metabolism antagonist. USPC ...... 514/262.1, 264.1 See application file for complete search history. 49 Claims, No Drawings US 8,835,443 B2 Page 2

(56) References Cited Burova et al., Chemistry of Heterocyclic Compounds, 5: 674-680 (1991) Translation pp. 538-544 (1991). FOREIGN PATENT DOCUMENTS Calvet, J. Am. Soc. Nephrol. 17: 1498-1500 (2006). Crees, Calif St. J. Med. V(II): 292-293 (1907). WO WO O2/O87620 A1 11, 2002 Guo et al., Leukemia, 20: 115-121 (2006). WO WO 02/094824 A1 11, 2002 Hannon et al., Nature, 371: 257-261 (Sep. 15, 1994). WO WO 03/062236 A1 T 2003 Hitomi et al., FEBS Letters, 554: 347-350 (2003). Hoshino et al., Journal of Biological Chemistry, 276(4): 2686-2692 OTHER PUBLICATIONS (Jan. 26, 2001). Khattab et al., Journal far Praktische Chemie, 338: 151-156 (1996). Khattab, et al., Ring Closure Reaction of 5-Hydroxy-pyrido2,3- Ogura et al., Chem. Pharm. Bull., 21 (9): 2014-2018 (1973). dipyrimidine-2,4,7-triones tO Benzo(bpyrimido-4,5-h1.6- Su et al., Journal of Medicinal Chemistry, 29(5): 709-715 (1986). naphthyridine-1,3,6-triones, Journal fur Praktische Chemie, vol.338, Tamir et al., Cel Growth and Differentiation, 11: 269-277 (May 151-156 (1996).* 2000). Eissa, et al., Deletion of p. 16 and p. 15 genes in Schistosomiasis Wang et al., J. Biol. Chem, 280(13): 12339-12343 (2005). associated bladder cancer (SABC), Clinica Chimica Acta 300, 159 Broom et al., J. Org. Chem., 41(7): 1095-1099 (1976). 169 (2000).* Hirota et al., J. Org. Chem., 46: 846-851 (1981). Thornber, C.W., Isosterism and Molecular Modification in Drug Khattab et al., J. prakt. Chem., 338: 151-156 (1996). Design, 563-580.* Khattab et al., Monatshefie fiur Chemie, 127: 917-925 (1996). Ogura, et al., Studies on Heterocyclic Compounds. XII. A Novel Ogura et al., Chemistry Letters, 657-658 (1972). Synthesis of 5-Oxo- and 7-Oxo-pyrido2,3-dipyrimidines, Chem. Scarborough, J. Org. Chem., 29(1): 219-221 (1964). Pharm. Bull, vol. 21, No. 7, 2014-2018 (1973).* Su et al., J. Med. Chem., 29: 709-715 (1986). Thornber, Chem. Soc. Rev., 8: 563-580 (1979).* Boultwood et al., Brit. J. of Haematol. 138:3-11 (2007). * cited by examiner US 8,835,443 B2 1. 2 PYRIMIDINE COMPOUND AND MEDICAL dence in p16 knock out mice has been demonstrated, and USE THEREOF therefore, clinical application of p 16 inducer has been tried. Under such situation, p15 protein (aka: INK4B, also sim CROSS-REFERENCE TO RELATED ply referred to as p15) has been found as a p16 family. In APPLICATIONS 1994, induction of p15 expression by TGF-B stimulation was confirmed in human keratinocyte cell (HaCaT), and p15 was This patent application is a continuation of U.S. patent considered to be one of the factors negatively regulating the application Ser. No. 12/053,133, filed Mar. 21, 2008, now cell cycle. It is known that induction of G1 phase cell cycle abandoned, which is a continuation of U.S. patent application arrest in HaCaT by TGF-B leads to the suppression of cell Ser. No. 11/150,792, filed Jun. 10, 2005, now U.S. Pat. No. 10 proliferation (Letters to Nature, Sep. 15, 1994, vol. 371, pp. 7,378,423, which claims the benefit of U.S. Provisional 257-261). Patent Application No. 60/630,596, filed Nov. 23, 2004, While the histondeacetylase (HDAC) inhibitor is known to which is incorporated by reference. arrest cell cycles at G1 phase or G2 phase in human cancer TECHNICAL FIELD 15 cell, it has been found recently that trichostatin A, which is an HDAC inhibitor, induces p15 gene in human colon cancer cell The present invention relates to a novel pyrimidine com (HCT116p21(-/-)), and the induction of p15 by trichostatin pound or a pharmaceutically acceptable salt thereofuseful as A is involved in the inhibition of the cell proliferation of the an agent for the prophylaxis or treatment of diseases caused cancer cells (FEBS Letters, 2003, vol. 554, pp. 347-350). by undesirable cell proliferation, particularly, an antitumor In this way, a compound that induces p15 and/or p27 is agent. Moreover, the present invention relates to novel use of expected to inhibit the cell proliferation of cancer cells and a certain kind of pyrimidine compound or a pharmaceutically the like. acceptable salt thereof as an agent for the prophylaxis or In the meantime, Mitogen-activated protein (MAP) treatment of a disease caused by undesirable cell prolifera Kinase/extracellular signal-regulated kinase (ERK) kinase tion, particularly, as an antitumor agent. More particularly, 25 (hereinafter to be referred to as MEK) is known to be involved the present invention relates to a pharmaceutical agent com in the regulation of cell proliferation as a kinase that mediates prising a pyrimidine compound showing a p15 protein induc Raf-MEK-ERK signal transduction pathway, and the Raf ing action and/or a p27 protein inducing action and/or an family (B-Raf, C-Rafetc.) activates the MEK family (MEK MEK inhibitory action, or a pharmaceutically acceptable salt 1. MEK-2 etc.) and the MEK family activates the ERK family thereof. 30 (ERK-1 and ERK-2). Activation of Raf-MEK-ERK signal transduction pathway BACKGROUND ART in cancer, particularly colorectal cancer, pancreatic cancer, lung cancer, breast cancer and the like, has been frequently A “cell cycle” means a cycle wherein the period for a cell observed. to divide and once again divide is one cycle, and this cycle is 35 In addition, since the signals produced by signal molecules also referred to as a “cell division cycle”. Such as growth factor, cytokine and the like converge to the A cell cycle includes four phases in a determined order. activation of MEK-ERK, inhibition of these functions is con They are DNA duplication preparation phase (G1 phase), sidered to more effectively suppress Raf-MEK-ERK signal DNA duplication phase (Sphase), division preparation phase transduction than the suppression of the function of RTK, (G2 phase) and division phase (M phase), and regulated by 40 Ras, Raf and the like in the upstream. many factors. Among them, the kinase activity of a cyclin/ Moreover, it is also known in recent years that a compound cyclindependent kinase (CDK) complex is essential for the having an MEK inhibitory activity extremely effectively regulation of the cell cycle. induces inhibition of ERK1/2 activity and suppression of cell As a protein to inhibit the kinase activity, a CDK inhibitory proliferation (The Journal of Biological Chemistry, vol. 276, protein is known. The CDK inhibitory proteins of mamma 45 No. 4, pp. 2686-2692, 2001), and the compound is expected lian cells are p21 family and p16 family, both of which are to show effects on the disease caused by undesirable cell considered to negatively regulate the progress of cell cycle proliferation, such as tumor and the like. In addition, an MEK and responsible for cell differentiation, apoptosis and repair inhibitor is expected to inhibit infiltration or metastaticity of of DNA damage due to irradiation of X ray and the like. At cells via promotion of expression of Matrix metalloprotein present, p21, p27 and p57 have been reported as a p21 family, 50 ase (MMP) and CD44, and angiogenesis via promotion of and p16, p15, p18 and p19 have been reported as a p16 family. expression of vascular endothelial growth factor (VEGF). When these CDK inhibitory proteins are highly expressed Furthermore, application to chronic pain (JP 2003-504401: in the cell, the cell proliferation is arrested at G1 phase. WO 01/005393), application to diseases or symptoms medi The p21 family shows an inhibitory activity on a relatively ated by neutrophile (JP2002-332247: CA-2385412), applica wide range and plural cyclin/CDK complexes. For example, 55 tion to graft rejection (JP 2002-532414: WO 00/35435), cyclin E/CDK2 which is an important cyclin/CDK complex application to arthritis (JP 2002-532415: WO 00/35436), from G1 phase to G1/S transition phase, cyclin B/Cdc2 which application to asthma (JP 2002-534380: WO 00/40235), is important for M phase and the like can be mentioned. The application to viral diseases (JP 2002-534381: WO p16 family is a specific inhibitory factor against cyclin 00/40237), application to diseases caused by deformation or D/CDK 4 and cyclin D/CDK 6, which are one of the cyclin/ 60 injury of cartilage (WO2002/087620; US 2004/138285), CDKs in the G1 phase, and is considered to dissociate the application to Peutz-Jeghers syndrome (WO02/006520) are cyclin/CDK complex by binding with CDK 4 and CDK 6, expected. respectively. However, Such pharmaceutical agent has not been marked From the examination of clinical materials of cancer of heretofore. esophangus, pancreatic cancer, non-Small cell lung cancer, 65 As an already commercially available antitumor agent, the skin cancer and the like, highly frequent incidence of genetic following compound (Gefitinib) and the like are known abnormality of P16 has been reported, and high cancer inci (Iressa tablet 250 package insert). US 8,835,443 B2 4

O OMe O Me NN N es O Me Me In these literatures, however, the compound of the present invention is not disclosed, nor is there found a description JP-A-2004-504294 (patent family: WO2002/006213) Suggestive thereof. describe the following compound and the like as compounds Furthermore, WO2002/094824 discloses the following having an antitumor activity. In addition, the MEK inhibitory 15 compound and the like (WO2002/094824, p. 55, Example 9) activity of such compounds is described (JP-A-2004-504294, as a therapeutic agent having a cytokine regulating action for pp. 123-124. Example 39, Example 241). immune, inflammatory or allergic disease.

2O OH O Me

F I 25

OH O HN In-N- NN F In the literatures issued in 1996, synthetic methods of the H 30 following compound and the like are disclosed (Journal fur Praktische Chemie, 1996, vol.338, pp. 151-156 (p. 154, Table F 1, compound 8f)).

35

O HN Known compounds relatively similar to the pharmaceuti cal agent of the present invention are described below. 40 N N In the literatures issued in 1991, the antitumor activity of pyrido 2,3-dipyrimidine derivative has been studied and it is es O described, for example, that Some of the following com pounds and the like have an inhibitory activity in sarcoma, as Me leukemia cells (Khimia geterotsiklicheskikh Soedinenii, 1991, No. 5, pp. 674-680 (English translation p. 542, lines 4-7; p. 538, compound IIIa)). In the literatures issued in 1986, synthetic methods of the 50 following compound and the like as a synthetic intermediate for aminopterin analog having an antitumor activity are dis closed (Journal of Medicinal Chemistry, 1986, vol. 29, No. 5, pp. 709-715 (p. 709 abstract; p. 712, Table 1, compound 9b)). es N O 55 H O Me Meo1N N CN 60 1s, N O In the literatures issued in 1973, novel synthetic methods of the following compound and the like are disclosed and the MeO J. " antitumor activity of pyrido 2,3-dipyrimidine derivative is 65 described (Chem. Pharm. Bull., 1973, No. 21, vol. 9, pp. However, this literature does not contain a description 2014-2018 (p. 2015, chart 2, compound VIII)). relating to the use of these compounds as antitumor agents, US 8,835,443 B2 5 6 the compound of the present invention is not disclosed and a R", R, and Rare the same or different and each is description Suggestive thereof is not found. a C alkyl group, a C2-alkenyl group, DISCLOSURE OF THE INVENTION wherein the Calkyl group and the Coalkenyl group are optionally substituted by 1 to 3 substituents selected An object of the present invention is to provide a pharma from the following group A, or ceutical agent containing a pyrimidine compound showing undesirable cell proliferation inhibitory action, particularly an antitumor action or a pharmaceutically acceptable salt thereof. 10 o chn-G) The present inventors have conducted intensive studies in an attempt to find a compound having Such action and com pleted the present invention. wherein m is 0 or an integer of 1 to 4, More particularly, the present invention provides the fol ring Cy is a C-carbon ring group or a heterocyclic group, lowing (1) to (37). 15 wherein the heterocyclic group is a saturated or unsat (1) Use of a compound represented by the following formula urated ring group having, besides carbon atom, 1 to 4 II or a pharmaceutically acceptable salt thereof as an hetero atoms selected from an oxygen atom, a nitro active ingredient for the production of a pharmaceutical gen atom and a Sulfur atom, the C-2 carbon ring agent for treating a tumor: group and the heterocyclic group are optionally Sub stituted by 1 to 5 substituents selected from the fol lowing group B, R. R. and Rare the same or different and each is a hydrogen atom, a hydroxyl group, 25 a C- alkyl group, a C2-alkenyl group, wherein the Calkyl group and the Coalkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, 30 a C-1 carbon ring group or a heterocyclic group, wherein wherein the heterocyclic group is a saturated or unsatur X' and X’ are the same or different and each is a carbonatom ated ring group having, besides carbon atom, 1 to 4 or a nitrogen atom, a hetero atoms selected from an oxygen atom, a nitrogen 35 atom and a sulfur atom, and the C. carbon ring group and the heterocyclic group are optionally Substituted by 1 to 5 substituents selected from the following group B, O RandR are optionally linked to form a C- alkylenegroup, 40 O RandR are optionally linked to forma Calkylenegroup, wherein group A is a group consisting of 1) a halogen atom, 2) a nitro group, 45 3) a cyano group, 4) a C- alkyl group, moiety is 5) —OR' wherein R' is a hydrogen atom or a C alkyl grOup, 6) - SR' wherein R' is a hydrogen atom or a C alkyl 50 grOup, 7)—NR'R'' wherein RandR'' are the same or different and each is a hydrogenatom or a C alkyl group, 8)—COOR wherein R' is a hydrogenatom or a C- alkyl grOup, 55 9) - NRCOR7 wherein R is a hydrogen atom or a Ca alkyl group, R is a C- alkyl group, a C-12 carbon ring group or a heterocyclic group, 10) - NRCOOR wherein R and R' are the same or different and each is a hydrogenatom or a Calkyl group, 60 11) a C-12 carbon ring group and 12) a heterocyclic group, wherein the heterocyclic group is a saturated or unsatur ated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen 65 atom and a Sulfur atom, each of the C alkyl groups of the above-mentioned 4), R11, R12, R-43, R14, R15, R16, R-17, R. and R' is US 8,835,443 B2 7 8 optionally substituted by the same or different 1 to 3 above-mentioned 23), R. R. R'' and R'7 is Substituents selected from the following group C, and optionally substituted by the same or different 1 to 5 each of the C-2 carbon ring groups of the above-men Substituents selected from the following group C, and tioned 11) and R', and the heterocyclic groups of 12) group C is a group consisting of and R7 is optionally substituted by the same or different 1) a halogen atom, 1 to 5 substituents selected from the following group C group B is a group consisting of 2) a cyano group, 1) a halogen atom, 3) a C alkyl group, 2) a nitro group, 4) —OR' wherein R is a hydrogen atom or a C alkyl 3) a cyano group, 10 grOup, 4) a C-s alkyl group, 5) - NR'R' wherein RandR are the same or different 5) a C2-alkenyl group, and each is a hydrogenatom or a C alkyl group, 6) a C2-alkynyl group, 6)—COOR." wherein R is a hydrogenatom or a C- alkyl 7) —OR' wherein R' is a hydrogen atom or a C alkyl group and grOup, 15 8) —SR' wherein R’ is a hydrogen atom or a C alkyl 7) an oxo group. grOup, (2) A compound represented by the following formula II" or 9)-NR'R'" wherein R’ is a hydrogen atom, a C alkyl a pharmaceutically acceptable salt thereof: group, a C-12 carbon ring group or a heterocyclic group, and R is a hydrogen atom or a C- alkyl group, 10) - NRCOR wherein R is a hydrogenatom or a Ca alkyl group, andR is a hydrogenatom, a C- alkyl group, O RS - R' a C-2 carbon ring group or a heterocyclic group, 11) - NR7COOR wherein R7 and Rare the same or l different and each is a hydrogenatom or a Calkyl group, 25 RN - -- 12) NR''CONR'R' wherein R, Rio and R'll are the same or different and each is a hydrogenatom or a Ca -----'s alkyl group, 13) NR2CONROR wherein R12, R1 and R' are the same or different and each is a hydrogen atom or a 30 C. alkyl group, wherein 14) NR'SOR' wherein R' is a hydrogenatom or a C. alkyl group, and R' is a C- alkyl group, a C-12 R. R° and Rare the same or different and each is carbon ring group or a heterocyclic group, a C- alkyl group, 15) -SO, R'7 wherein R'7 is a C alkyl group or a 35 a C2-alkenyl group, heterocyclic group, wherein the Calkyl group and the Coalkenyl group are 16). SONR'R' wherein RandR'' are the same or optionally substituted by 1 to 3 substituents selected different and each is a hydrogenatom or a Calkyl group, from group A of the above-mentioned (1), or 17) P(=O)(R')(R') wherein R’ and R'' are the same or different and each is a C alkyl group, 40 18) -COOR’ wherein R’ is a hydrogen atom or a Ca alkyl group, —CHym–G) 19). CONR'R' wherein RandR'' are the same or different and each is a hydrogenatom or a Calkyl group, 20) NR?.2.5SONR2R27 wherein R25, R26 and R27 45 m is an integer of 0 or 1 to 4. are the same or different and each is a hydrogen atom or a ring Cy is a C-12 carbon ring group or a heterocyclic group C. alkyl group, wherein the heterocyclic group is a saturated or unsat 21). NR?.28SONR?.2°CONR'R' wherein R2, R?.29, urated ring having, besides carbonatom, 1 to 4 hetero R'' and R'' are the same or different and each is a atoms selected from an oxygenatom, a nitrogenatom hydrogen atom or a C alkyl group, 50 and a sulfur atom, and the C. carbon ring group and 22) a C-12 carbon ring group and the heterocyclic group are optionally substituted by 1 23) a heterocyclic group to 5 substituents selected from group B of the above wherein each of the “Cs alkyl group' of the above-men mentioned (1), tioned 4), and the C alkyl groups for R' to R'' is provided that, when the optionally substituted by the same or different 1 to 3 55 Substituents selected from the above-mentioned group A, R each of the Calkenyl group of 5) and the C- alkynyl n1 group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above 60 mentioned group A, the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms Selected from an oxygen atom, a nitrogen atom and a Sulfur atom, and 65 each of the C-2 carbon ring group of the above-mentioned 22), R. RandR', and the heterocyclic group of the US 8,835,443 B2 10 moiety is (6) Use of the above-mentioned (1), wherein R' is a Calkyl group. (7) Use of the above-mentioned (1), wherein R' is R N1 R6 R4 N - (CH)m. –G) s

O 10 wherein m is 0, and ring Cy is a C-2 carbon ring group R3 wherein the C-2 carbon ring group is optionally Substi tuted by 1 to 5 substituents selected from group B of the above-mentioned (1). then R is not a methyl group, and (8) Use of the above-mentioned (1), wherein R' is a Cls when R is a phenyl group, then R' is notaphenyl group, and 15 cycloalkyl group. other symbols are as defined in the above-mentioned (1). (9) Use of the above-mentioned (8), wherein R' is a cyclo (3) Use of the above-mentioned (1), wherein the compound is propyl group. represented by the following formula I-1: (10) Use of the above-mentioned (1), wherein R is

I-1 o R YN1 R6 - (CH)m. –G) s RI R4 NN N 25 wherein m is 0, and ring Cy is a C-2 carbon ring group or a heterocyclic group wherein the C. carbon ring group and the heterocyclic es O group are optionally substituted by 1 to 5 substituents R2 R3 selected from group B of the above-mentioned (1). 30 (11) Use of the above-mentioned (1), wherein R is a C alkyl group. wherein each symbol in the formula is as defined in the (12) Use of the above-mentioned (1), wherein R is a hydro above-mentioned (1). gen atom. (4) Use of the above-mentioned (1), wherein the compound is 35 (13) Use of the above-mentioned (1), wherein R is a hydro represented by the following formula I-2: gen atom. (14) Use of the above-mentioned (1), wherein R is I-2 R R6 o NN1 40 - (CH)m. –G) s RN N NN wherein m is 0, and ring Cy is a C-2 carbon ring group or a heterocyclic group es 1s. 45 wherein the C. carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of the above-mentioned (1). wherein each symbol in the formula is as defined in the (15) Use of a compound of the formula II of the above above-mentioned (1). 50 mentioned (1) or a pharmaceutically acceptable salt (5) Use of the above-mentioned (1), wherein the compound is thereof as an active ingredient for the production of an represented by the following formula I-3: antitumor agent. (16) Use of a compound of the formula II of the above mentioned (1) or a pharmaceutically acceptable salt 55 thereof as an active ingredient for the production of a 5 6 I-3 R R pharmaceutical agent capable of inhibiting MEK. o NN1 (17) Use of a compound of the formula II of the above RI R4 mentioned (1) or a pharmaceutically acceptable salt NN 2N1 thereof as an active ingredient for the production of a 60 pharmaceutical agent capable of inducing p15 protein. (18) Use of a compound of the formula II of the above es N O mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agents for treating a disease caused by an 65 undesirable cell proliferation. wherein each symbol in the formula is as defined in the (19) Use of the above-mentioned (18), wherein the disease above-mentioned (1). causing by an undesirable cell proliferation is rheumatism. US 8,835,443 B2 11 12 (20) Use of a compound of the formula II of the above (1) or a pharmaceutically acceptable salt thereof, which is mentioned (1) or a pharmaceutically acceptable salt used in combination with (b) at least one other antitumor thereof as an active ingredient for the production of a compound. pharmaceutical agent capable of inhibiting undesirable cell (35) An antitumor agent comprising, as an active ingredient, proliferation. 5 (a) a compound of the formula II of the above-mentioned (21) Use of a compound of the formula II of the above (1) or a pharmaceutically acceptable salt thereof, and (b) at mentioned (1) or a pharmaceutically acceptable salt least one other antitumor compound, in combination. thereof as an active ingredient for the production of a pharmaceutical agent capable of regulating cell cycle. (36) The agent of the above-mentioned (34), wherein (a) a (22) A pharmaceutical composition which comprises a com 10 compound of the formula III of the above-mentioned (1) or pound of the formula II of the above-mentioned (2) or a a pharmaceutically acceptable salt thereof and (b) at least pharmaceutically acceptable salt thereof, and a pharma one other antitumor compound are administered to a mam ceutically acceptable carrier. mal simultaneously or sequentially. (23) A pharmaceutical composition for the treatment of a 15 (37) The agent of the above-mentioned (35), wherein (a) a tumor, which comprises a compound of the formula II of compound of the formula III of the above-mentioned (1) or the above-mentioned (1) or a pharmaceutically acceptable a pharmaceutically acceptable salt thereof and (b) at least salt thereof, and a pharmaceutically acceptable carrier. one other antitumor compound are administered to a mam (24) A pharmaceutical composition for treating a disease mal simultaneously or sequentially. causing by an undesirable cell proliferation, which com prises a compound of the formula II of the above-men BEST MODE FOR EMBODYING THE tioned (1) or a pharmaceutically acceptable salt thereof, INVENTION and a pharmaceutically acceptable carrier. (25) A commercial package comprising a pharmaceutical composition of the above-mentioned (23) and a written 25 The definitions of each substituent and each moiety used in matter associated therewith, the written matter stating that the present specification are as follows. the pharmaceutical composition can or should be used for X' and X’ are the same or different, and each is a carbon treating tumor. atom or a nitrogen atom, a (26) A commercial package comprising a pharmaceutical composition of the above-mentioned (24) and a written 30 matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for treating disease causing by an undesirable cell prolifera tion. 35 (27) Use of (a) a compound of the formula II of the above mentioned (1) or a pharmaceutically acceptable salt thereofas an active ingredient, which is used in combina tion with (b) at least one other antitumor compound, for the production of an antitumor agent. 40 (28) Use of (a) compound of the formula III of the above mentioned (1) or a pharmaceutically acceptable salt moiety is thereof as an active ingredient and (b) at least one other antitumor compound, incombination, for the production of an antitumor agent. 45 (29) A pharmaceutical composition comprising, as an active ingredient, (a) a compound of the formula II of the above mentioned (1) or a pharmaceutically acceptable salt thereof and (b) at least one otherantitumor compound, and a pharmaceutical acceptable carrier, in combination. 50 (30) A kit for treating a tumor comprising (a) a pharmaceuti cal composition comprising, as an active ingredient, a com pound of the formula II of the above-mentioned (1) or a pharmaceutically acceptable salt thereof and (b) a pharma ceutical composition comprising, as an active ingredient, at 55 least one other antitumor agent, in combination. (31) An antitumor agent comprising a compound of the for mula II of the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient. (32) A MEK inhibitor comprising a compound of the formula 60 II of the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient. (33) A p15 protein inducer comprising a compound of the formula II of the above-mentioned (1) or a pharmaceuti cally acceptable salt thereofas an active ingredient. 65 (34) An antitumor agent comprising, as an active ingredient, (a) a compound of the formula II of the above-mentioned US 8,835,443 B2 13 14 preferably, butyl group, pentyl group, isopentyl group, hexyl group, hep tyl group, octyl group and the like can be mentioned. AS2) of group B, methyl group, ethyl group, propyl group, R R6 R R6 isopentyl group, 1-ethyl-1-propyl group, 3-methylbutyl n N 1. n N1 group and 1-propyl-1-butyl group are preferable and methyl R or R*, group and ethyl group are more preferable. N 2n-1 The “C. alkenyl group' is a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, and specifi O N O cally, vinyl group, 1-propenyl group, 2-propenyl group, iso 10 propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl R3 R3 group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,2-dimethyl-1-propenyl group, 1,2-dim 15 ethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2- propenyl group, 1-methyl-1-butenyl group, 1-methyl-2-bute nyl group, 2-methyl-1-butenyl group, 1-isopropylvinyl group, 2.4-pentadienyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2.4-hexadienyl group, 1-methyl-1-pentenyl group and the like can be mentioned. As R', R. R. R. R. R. Rand R. vinyl group, 1-pro penyl group and 2-propenyl group are preferable and 2-pro penyl group is more preferable. 25 The “C. alkenyl group' is a straight chain or branched chain alkenyl group having 2 to 4 carbon atoms, and specifi The "halogen atom' is a fluorine atom, a chlorine atom, a cally, vinyl group, 1-propenyl group, 2-propenyl group, iso bromine atom or an iodine atom, which is preferably a fluo propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl rine atom, a chlorine atom or a bromine atom for 1) of group group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl A and 1) of group C, more preferably a fluorine atom for 1) of group, 2-methyl-2-propenyl group, 1-ethylvinyl group and group A, more preferably a fluorine atom or a bromine atom the like can be mentioned. for 1) of group C, and preferably a fluorine atom or an iodine As 5) of group B. vinyl group and 1-propenyl group are atom for 1) of group B. preferable, and vinyl group is more preferable. The “C. alkyl group' is a straight chain or branched chain The “C. alkynyl group' is a straight chain or branched alkyl group having 1 to 6 carbon atoms, and specifically, 35 chain alkynyl group having 2 to 4 carbon atoms, and specifi methyl group, ethyl group, propyl group, isopropyl group, cally, ethynyl group, 1-propynyl group, 2-propynyl group, 2,2-dimethylpropyl group, butyl group, isobutyl group, sec isopropynyl group, 1-butynyl group, 2-butynyl group, 3-bu butyl group, tert-butyl group, pentyl group, hexyl group and tynyl group, 1-methyl-1-propynyl group, 1-methyl-2-propy the like can be mentioned. nyl group, 2-methyl-2-propynyl group, 1-ethylethynyl group As R. R. R. R. and R, methyl group, ethyl group, 40 and the like can be mentioned. propyl group, isopropyl group, 2,2-dimethylpropyl group, AS 6) of group B, ethynyl group, 1-propynyl group and butyl group and isobutyl group are preferable, methyl group 1-butynyl group are preferable, and ethynyl group is more and ethyl group are more preferable, and methyl group is preferable. particularly preferable. As R. RandR, methyl group, ethyl The “C, alkylene group” optionally formed by R’ in group, propyl group and isobutyl group are preferable, and 45 junction with R and the “C. alkylene group' optionally methyl group is more preferable. formed by R' in junction with R is a straight chain or The "Calkyl group' is a straight chain or branched chain branched chain alkylene group having 1 to 4 carbon atoms, alkyl group having 1 to 4 carbon atoms, and specifically, and specifically, methylene group, ethylene group, trimeth methyl group, ethyl group, propyl group, isopropyl group, ylene group, 2-methyltrimethylene group, tetramethylene 50 group and the like can be mentioned. butyl group, isobutyl group, sec-butyl group, tert-butyl group The “C, alkylene group” optionally formed by R’ in and the like can be mentioned. junction with R is preferably methylene group, ethylene AS4) of group A and 3) of group C, methyl group and ethyl group or trimethylene group, more preferably trimethylene group are preferable and methyl group is more preferable. As group. R1, R1, R1, R1, R1, R1, R-7, R and R, methyl group, 55 The "Calkylenegroup” optionally formed by Rinjunc ethyl group and butyl group are preferable and methyl group tion with R is preferably methylene group, ethylene group or is more preferable. As R' to R', methyl group, ethyl group, trimethylene group, more preferably ethylene group. propyl group, isopropyl group and butyl group are preferable As m, preferred is 0 or an integer of 1 or 2, more preferably and methyl group, ethyl group and propyl group are more O. preferable. As R. R. R. RandR, methyl group and 60 The “C. carbon ring group' is a Saturated or unsaturated ethyl group are preferable and methyl group is more prefer cyclic hydrocarbon group having 3 to 12 carbonatoms, which able. means a phenyl group, naphthyl group, Cascycloalkyl group, The “Cs alkyl group' is a straight chain or branched chain or a fused ring group of Cs cycloalkyl and benzene. alkyl group having 1 to 8 carbon atoms, and specifically, The "Cs cycloalkyl group' is a saturated cyclic hydrocar methyl group, ethyl group, propyl group, isopropyl group, 65 bon group having 3 to 8 carbonatoms, and specifically, cyclo 1-ethyl-1-propyl group, butyl group, isobutyl group, sec-bu propyl group, cyclobutyl group, cyclopentyl group, cyclo tyl group, tert-butyl group, 3-methylbutyl group, 1-propyl-1- hexyl group, cycloheptyl group, cyclooctyl group, US 8,835,443 B2 15 16 norbornanyl group and the like can be mentioned, and pref 5-indolyl group, 6-indolyl group. 7-indolyl group etc.), isoin erably cyclopropyl group, cyclobutyl group, cyclopentyl dolyl group, 1,3-dihydro-1,3-dioxoisoindolyl group and ben group or cyclohexyl group. Zofuranyl groups (e.g., 4-benzofuranyl group. 7-benzofura As the “fused ring group of C-scycloalkyl group and ben nyl group etc.), indazolyl group, isobenzofuranyl group and Zene', indanyl group, 1,2,3,4-tetrahydronaphthyl group (1.2, 5 benzothiophenyl groups (e.g., 4-benzothiophenyl group, 3,4-tetrahydro-2-naphthyl group, 5,6,7,8-tetrahydro-2-naph 5-benzothiophenyl group. 7-benzothiophenyl group etc.), thyl group etc.) and the like can be specifically mentioned, benzoxazolyl groups (e.g., 4-benzoxazolyl group. 7-benzox which is preferably indanyl group, 1,2,3,4-tetrahydronaph azolyl group etc.), benzimidazolyl groups (e.g., 4-benzimi thyl group and the like, and more preferably indanyl group. As R', R. R. R. Rand R, phenyl group, cyclopropyl 10 dazolyl group, 5-benzimidazolyl group. 7-benzimidazolyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group etc.), benzothiazolyl groups (e.g., 4-benzothiazolyl group are preferable, and phenyl group and cyclopropyl group, 7-benzothiazolyl group etc.), quinolyl group, iso group are more preferable. As R', cyclopropyl group is par quinolyl group, 1,2-dihydro-2-oxoquinolyl group, quinazoli ticularly preferable, and as R and R, phenyl group is par nyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl ticularly preferable. As 11) of group A, R'', 22) of group B, 15 group, 2,3-dihydroindolyl group, isoindolinyl group, 1,2,3,4- R. R. and R', phenyl group, cyclopropyl group, tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl cyclobutyl group, cyclopentyl group and cyclohexyl group group, benzo 1.3dioxolyl group, chromanyl group, isochro are preferable, and phenyl group and cyclopropyl group are manyl group, more preferable. The "heterocyclic group' is a saturated monocyclic ring or 20 an unsaturated monocyclic ring having 5 or 6 ring-constitut ing atoms, which contains, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a Sulfur atom, as a ring-constituting atom, a fused ring of the monocycle and a benzene ring or a spiro ring of these mono- 25 cycles or fused rings and the above-mentioned C-2 carbon NH, NH, NH, ring, each of which may have 1 to 4, preferably 1 or 2, oxo N groups. H As the "heterocyclic group', which is a monocycle of a O b-(O - O saturated ring, pyrrolidinyl group, tetrahydrofuryl group, tet- 30 rahydrothienyl group, imidazolidinyl group, 2-oxoimidazo lidinyl group, 2,4-dioxoimidazolidinyl group, pyrazolidinyl group, 1,3-dioxolanyl group, 1.3-oxathiolanyl group, oxazo lidinyl group, 2-oxooxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, 2-oxopiperazinyl 35 group, tetrahydropyranyl group, tetrahydrothiopyranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl NH NH NH group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group, SS NSS NS 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group, thiadia M O, H M O, s Zolidinyl group (e.g., 1,1-dioxo-1,2,5-thiadiazolidin-2-yl 40 O O group etc.) and the like can be mentioned. Preferably, pyrro lidinyl group, piperidinyl group, piperazinyl group and mor pholinyl group can be mentioned. As the "heterocyclic group', which is a monocycle of unsaturated ring, pyrrolyl group (e.g., 2-pyrrolyl group etc.), 45 furyl group, thienyl group, imidazolyl group (e.g., 4-imida Zolyl group etc.), 1,2-dihydro-2-oxoimidazolyl group, pyra Zolyl group (e.g., 5-pyrazolyl group etc.), diazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiaz NH, NH NH olyl group, 1,2,4-triazolyl group, 1,2,3-triazolyl group, tetra- 50 2. Ns. Zolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl O group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group (e.g., 3-pyridyl group etc.), pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, pyrazinyl group, 1,3,5-triazinyl group, 55 imidazolinyl group (e.g., 2-imidazolinyl group etc.), pyra Zolinyl group, oxazolinyl group (2-oxazolinyl group, 3-ox NH NH t aZolinyl group, 4-oxazolinyl group), isoxazolinyl group, 'Sulls O SEO thiophenyl group, thiazolinyl group, isothiazolinyl group, S s O, N pyranyl group, 2-oxopyranyl group, 2-oxo-2,5-dihydrofura- 60 nyl group, 1,1-dioxo-1H-isothiazolyl group and the like can be mentioned. Preferably, pyrrolyl group, thienyl group, imi dazolyl group, pyrazolyl group, oxazolyl group, isooxazolyl and the like can be mentioned. group, thiophenyl group, thiazolyl group, isothiazolyl group As the Spiro ring of the above-mentioned monocycle or and pyridyl group can be mentioned. 65 fused ring and the above-mentioned C. carbon ring, for As the "heterocyclic group' which is a fused ring of mono example, groups represented by the following formulas can cycle and benzene ring, indolyl groups (e.g., 4-indolyl group, be mentioned. US 8,835,443 B2 17 18 alkyl group', the above-defined “C. carbon ring group' or the above-defined "heterocyclic group'. As the " OR'', hydroxyl group, methoxy group, ethoxy group, propoxy group, isopropyloxy group, tert-butoxy group and the like can be specifically mentioned. As the “ SR', mercapto group, methylsulfanyl group, NH, ethylsulfanyl group, propylsulfanyl group, isopropylsulfanyl group, tert-butylsulfanyl group and the like can be specifi cally mentioned. 10 As the “ SR'R'', amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, tert-butylamino group, dimethylamino group, diethy lamino group, N-ethyl-N-methylamino group, N-methyl-N- propylamino group, N-isopropyl-N-methylamino group and 15 the like can be specifically mentioned. NH As the “ COOR'', carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, iso propoxycarbonyl group, tert-butoxycarbonyl group and the like can be specifically mentioned. As the " NR'COR', acetylamino group, propiony lamino group, butyrylamino group, isobutyrylamino group, Preferably, it is a fused ring group of monocyclic 5- or pivaloylamino group, N-acetyl-N-methylamino group, butyl 6-membered heterocycle and a benzene ring, which is spe cifically, indolyl group, indazolyl group, benzothiophenyl carbonylamino group and the like can be specifically men group, benzimidazolyl group, 2,3-dihydroindolyl group, 1.2, tioned. 25 As the “ NRCOOR'', carboxyamino group, car 3,4-tetrahydroquinolyl group, benzo 1.3dioxolyl group and boxymethylamino group, carboxyethylamino group, meth the like. oxycarbonylamino group, methoxycarbonylmethylamino As R', R. R. R. RandR, pyrrolidinyl group, piperidi group and the like can be specifically mentioned. nyl group, piperazinyl group, morpholinyl group, pyridinyl As the “group A', preferably, fluorine atom, chlorine atom, group, thiophenyl group, thiazolyl group, indolyl group, 30 bromine atom, methyl group, ethyl group, propyl group, indazolyl group, benzothiophenyl group, benzimidazolyl hydroxyl group, methoxy group, ethoxy group, propoxy group, 2,3-dihydroindolyl group, 1,2,3,4-tetrahydroquinolyl group, amino group, methylamino group, ethylamino group, group and benzo 1.3dioxolyl group are preferable, and pip dimethylamino group, diethylamino group, carboxyamino eridinyl group, pyridinyl group, thiophenyl group, thiazolyl group, butylcarbonylamino group, carboxy group, phenyl group, indolyl group, indazolyl group, benzothiophenyl 35 group, 4-morpholinyl group, 1-pyrrolidinyl group, 1-pip group, benzimidazolyl group, 2,3-dihydroindolyl group, 1.2, eridinyl group and 1-piperazinyl group can be mentioned. 3,4-tetrahydroquinolyl group, benzo 1.3dioxolyl group are As the “group A”, particularly preferably, fluorine atom, more preferable. As 12) of group A, R'' and 23) of group B, chlorine atom, methyl group, hydroxyl group, methoxy R. R. R'' and R'', pyrrolidinyl group, piperidinyl group, amino group, dimethylamino group, diethylamino group, piperazinyl group, morpholinyl group, pyridyl group 40 group, carboxyamino group, butylcarbonylamino group, car and oxazolinyl group are preferable, and pyrrolidinyl group, boxy group, phenyl group, 4-morpholinyl group, 1-pyrrolidi piperidinyl group, piperazinyl group and morpholinyl group nyl group, 1-piperidinyl group and 1-piperazinyl group can are more preferable. be mentioned. The "Ce alkyl group” and “Coalkenyl group” for R', R The preferable number of the substituent is 1, and the and R, and R. Rand Rare optionally substituted by 1 to 3 45 Substituent may be used at any Substitutable position. substituents selected from group A. That is, the above-defined The "C-2 carbon ring group' and "heterocyclic group' “C. alkyl group” and "Calkenyl group” may be substi for ring Cy, and “C. carbon ring group' and "heterocyclic tuted by 1 to 3 substituents selected from group A, and include group” for R, R or R are optionally substituted by 1 to 5 unsubstituted "C. alkyl group' and unsubstituted "Calk substituents selected from group B. That is, the above-defined enyl group'. 50 "C. carbon ring group' and "heterocyclic group” may be Each of the above-defined “Cs alkyl group' for the substituted by 1 to 5 substituents selected from group B, and below-defined 4) of group B, and the above-defined “Ca includes unsubstituted "C-2 carbon ring group' and unsub alkyl group” for R' to R'' is optionally substituted by the stituted "heterocyclic group'. same or different 1 to 3 substituents selected from group A. The “group B is a group consisting of 1) the above-defined Each of the above-defined “C. alkenyl group' for the 55 "halogen atom. 2) a nitro group, 3) a cyano group. 4) the below-defined 5) of group B and the above-defined “C. above-defined "Cs alkyl group”, 5) the above-defined “C. alkynyl group' for 6) is optionally substituted by the same or alkenyl group'. 6) the above-defined "Calkynyl group'. 7) different 1 to 3 substituents selected from group A. The 'group A is a group consisting of 1) the above-defined "halogenatom', 2) nitro group, 3) cyano group. 4) the above 60 defined “C, alkyl group”, 5) “ OR'', 6) “ SR'', 7) * NR-R-14, 8) * COOR-15, 9) : NR COR 17, 10) “ NRCOOR'', 11) the above-defined “C, carbon ring group' and 12) the above-defined "heterocyclic group'. wherein R, R., R., R., R. R. R. and Rare the 65 * NRSONR''CONR'R'', 22) the above-defined same or different and each is a hydrogen atom, or, the above “C. carbon ring group' and 23) the above-defined "hetero defined “C, alkyl group”, R' is the above-defined “Ca cyclic group”, wherein R', R, R, R, R-7, R, R, US 8,835,443 B2 1. 20 R?.10, R'll, R? 12, R? 13, R? 14, Ps, RBIs, R519, R22, R723, ylphosphinoyl group, diethylphosphinoyl group and the like R?.24, R?.25, RP26, R?.27, R-28, R?.29, R?.30 and R?.31 are the can be specifically mentioned. same or different and each is a hydrogen atom or the above As the “ COOR', carboxyl group, methoxycarbonyl defined “C, alkyl group', RandR'' are each a hydrogen group, ethoxycarbonyl group, propoxycarbonyl group, iso atom, the above-defined "C. alkyl group”, the above-de 5 propoxycarbonyl group, tert-butoxycarbonyl group and the fined “C. carbon ring group' or the above-defined "hetero like can be specifically mentioned. cyclic group', R' is the above-defined “C, alkyl group", As the “ CONR'R'', carbamoyl, methylcarbamoyl, the above-defined “C. carbon ring group' or the above dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, pro defined "heterocyclic group', R'' is the above-defined"Ca pylcarbamoyl, butylcarbamoyl and the like can be specifi 10 cally mentioned. alkyl group' or the above-defined "heterocyclic group', and As the “ NR’SONR'R'', sulfamoylamino group, R'' and R'' are the same or different and each is the above dimethylsulfamoylamino group and the like can be specifi defined "C. alkyl group'. cally mentioned. As the “ OR'', hydroxyl group, methoxy group, ethoxy As the “ NR?.28SONR?.2°CONR'R'', (2-hy group, propoxy group, isopropyloxy group, tert-butoxy 15 droxyethyl)carbamoyl (2-hydroxyethyl)sulfamoylamino group and the like can be specifically mentioned. group and the like can be specifically mentioned. As the “ SR', mercapto group, methylsulfanyl group, As the “group B, preferably, fluorine atom, chlorine atom, ethylsulfanyl group, propylsulfanyl group, isopropylsulfanyl bromine atom, iodine atom, nitro group, cyano group, methyl group, tert-butylsulfanyl group and the like can be specifi group, ethyl group, propyl group, isopropyl group, butyl cally mentioned. group, isobutyl group, pentyl group, isopentyl group, hexyl As the “ NR'R'', amino group, methylamino group, group, 1-ethylpropyl group, 1-propylbutyl group, vinyl ethylamino group, 2-aminoethylamino group, propylamino group, l-propenyl group, ethynyl group, l-propynyl group. group, isopropylamino group, tert-butylamino group, dim 1-butynyl group, hydroxyl group, methoxy group, ethoxy ethylamino group, diethylamino group, N-ethyl-N-methy group, propoxy group, isopropoxy group, methylthio group. lamino group, N-methyl-N-propylamino group, N-isopro 25 ethylthio group, amino group, methylamino group, ethy pyl-N-methylamino group, N-(imidazolin-2-yl)amino group lamino group, dimethylamino group, diethylamino group, and the like can be specifically mentioned. ethylmethylamino group, methylcarbonylamino group, eth As the “ NRCOR', amino group, formylamino ylcarbonylamino group, propylcarbonylamino group, isopro group, acetylamino group, hydroxyacetylamino group, pro pylcarbonylamino group, (methylcarbonyl)(methyl)amino pionylamino group, butyrylamino group, isobutyrylamino 30 group, ethoxycarbonylamino group, methylaminocarbony group, pivaloylamino group, N-acetyl-N-methylamino lamino group, dimethylaminocarbonylamino group, meth group, 3-aminopropionylamino group, 3-(pentanoylamino) oxyaminocarbonylamino group, methylsulfonylamino propionylamino group, 4-imidazolylcarbonylamino group, group, ethylsulfonylamino group, propylsulfonylamino (1-methylpyrrol-2-yl)carbonylamino group, 4-pyrazolylcar group, isopropylsulfonylamino group, phenylsulfonylamino bonylamino group and the like can be specifically mentioned. 35 group, (methylsulfonyl)(methyl)amino group, methylsulfo As the “ NR7COOR, carboxyamino group, car nyl group, piperazin-1-ylsulfonyl group, morpholin-4-ylsul boxymethylamino group, carboxyethylamino group, meth fonyl group, piperidin-4-ylsulfonyl group, pyrrolidin-4-yl oxycarbonylamino group, methoxycarbonylmethylamino Sulfonyl group, aminosulfonyl group, methylaminosulfonyl group and the like can be specifically mentioned. group, ethylaminosulfonyl group, dimethylaminosulfonyl As the “ NR'CONR'R'', aminocarbonylamino 40 group, dimethylphosphinoyl group, carboxy group, meth group, methylaminocarbonylamino group, dimethylami oxycarbonyl group, carbamoyl group, methylaminocarbonyl nocarbonylamino group, (methylaminocarbonyl)(methyl) group, ethylaminocarbonylamino group, dimethylaminosul amino group, (dimethylaminocarbonyl)(methyl)amino fonylamino group, cyclopropyl group, cyclohexyl group, group, (2-hydroxyethyl)carbamoylamino and the like can phenyl group, piperidinyl group, pyrrolidinyl group, piperidi be specifically mentioned. 45 nyl group, piperazinyl group and morpholinyl group can be As the “ NR''CONR'OR'', methoxyaminocarbo mentioned. nylamino group, (methylmethoxyaminocarbonyl)(methyl) As the “group B, particularly preferably, fluorine atom, amino group, (methylmethoxyaminocarbonyl)amino group chlorine atom, bromine atom, iodine atom, nitro group, cyano and the like can be specifically mentioned. group, methyl group, ethyl group, propyl group, isopropyl As the “ NR'SOR', sulfonylamino group, meth 50 group, butyl group, 1-ethylpropyl group, 1-propylbutyl ylsulfonylamino group, ethylsulfonylamino group, propyl group, butyl group, isobutyl group, isopentyl group, vinyl Sulfonylamino group, N-methyl-N-Sulfonylamino group, group, ethynyl group, 1-propynyl group, 1-butynyl group, N-methyl-N-methylsulfonylamino group, N-ethyl-N-sulfo hydroxyl group, methoxy group, propoxy group, isopropoxy nylamino group, N-ethyl-N-methylsulfonylamino group, group, methylthio group, amino group, methylamino group, 3-pyridylsulfonylamino group, morpholinosulfonylamino 55 ethylamino group, dimethylamino group, diethylamino group, piperidinomorpholinosulfonylamino group, 2-mor group, ethylmethylamino group, methylcarbonylamino pholinoethylsulfonylamino group and the like can be specifi group, ethylcarbonylamino group, propylcarbonylamino cally mentioned. group, isopropylcarbonylamino group, (methylcarbonyl)(m- As the “ SO R'', sulfonyl group, methylsulfonyl ethyl)amino group, ethoxycarbonylamino group, methylami group, ethylsulfonyl group, propylsulfonyl group, butylsul 60 nocarbonylamino group, dimethylaminocarbonylamino fonyl group and the like can be specifically mentioned. group, methoxyaminocarbonylamino group, methylsulfony As the “ SONR'R'', aminosulfonyl group, methy lamino group, ethylsulfonylamino group, propylsulfony laminosulfonyl group, dimethylaminosulfonyl group, ethyl lamino group, isopropylsulfonylamino group, phenylsulfo methylaminosulfonyl group and the like can specifically be nylamino group, (methylsulfonyl)(methyl)amino group, mentioned. 65 methylsulfonyl group, piperazin-1-ylsulfonyl group, mor As the “ P(=O)(R')(R')', phosphinoyl group, pholin-4-ylsulfonyl group, piperidin-4-ylsulfonyl group, pyr methylphosphinoyl group, dimethylphosphinoyl group, eth rolidin-4-ylsulfonyl group, aminosulfonyl group, methy US 8,835,443 B2 21 22 laminosulfonyl group, ethylaminosulfonyl group, As the "R", preferably, a C- alkyl group (wherein the dimethylaminosulfonyl group, dimethylphosphinoyl group, C. alkyl group is optionally substituted by 1 to 3 substitu carboxy group, methoxycarbonyl group, carbamoyl group, ents selected from group A) or methylaminocarbonyl group, ethylaminocarbonylamino group, dimethylaminosulfonylamino group, cyclopropyl group, phenyl group, piperidinyl group, pyrrolidinyl group, piperidinyl group, piperidinyl group and morpholinyl group —CHym–G) can be mentioned. The preferable number of substituent is 1 or 2, and when the “C. carbon ring group' is a phenyl group, ring Cy is 10 wherein each symbol is as defined above, can be mentioned. preferably mono-Substituted at the 2-position, mono-Substi Here, m is preferably 0, the “ring Cy” is preferably C. tuted at the 3-position, mono-Substituted at the 4-position, carbon ring group, and the "carbon ring group' is preferably di-substituted at the 2.3-position, di-substituted at the 2,4- cycloalkyl group (wherein the “C. carbon ring group' and position, di-substituted at the 2.5-position or di-substituted at “cycloalkyl group' are optionally substituted by 1 to 5 sub 15 stituents selected from group B). the 2.6-position, and particularly preferably mono-Substi Specifically, as the "R", methyl group, ethyl group, 2.2, tuted at the 4-position ordi-substituted at the 2,4-position, R 2-trifluoroethyl group, propyl group, isopropyl group, butyl is more preferably mono-substituted at the 3-position, and R' group, 2-propenyl group, cyclopropyl group, 2-methylcyclo is more preferably di-substituted at the 2.4-position. propyl group, cyclobutyl group, cyclopentyl group, cyclo Each of the above-defined “C. alkyl group” for 4) of the hexyl group, phenyl group, 4-chlorophenyl group, 4-fluo above-defined group A, and the above-defined “C. alkyl rophenyl group, o-tolyl group, m-tolyl group, p-tolyl group, group for R1, R12, R1, R1, R1, R1, R-7, R-18 or R1 is 4-methoxyphenyl group, thiophen-3-yl group, cyclopropyl optionally substituted by the same or different 1 to 3 substitu methyl group, 2-methoxyethyl, carboxymethyl, 2-hydroxy ents selected from the below-defined “group C. ethyl, 2-(dimethylamino)ethyl and benzyl group are prefer Each of the above-defined "C-2 carbon ring group' for 25 able. 11) of group A and R7, and the above-defined "heterocyclic More preferably, methyl group, ethyl group, 2.2.2-trifluo group” for 12) and R7 is optionally substituted by the same roethyl group, propyl group, isopropyl group, butyl group, or different 1 to 5 substituents selected from the below-de cyclopropyl group, 2-methylcyclopropyl group, cyclobutyl fined “group C. group, cyclopentyl group, cyclohexyl group, phenyl group. Each of the above-defined "C-2 carbon ring group' for 30 4-chlorophenyl group, 4-fluorophenyl group, o-tolyl group, the above-mentioned 22) of group B. R. RandR', and m-tolyl group, p-tolyl group, 4-methoxyphenyl group, the above-defined "heterocyclic group' for the above-men thiophen-3-yl group, 2-methoxyethyl, carboxymethyl, 2-hy tioned 23), R. R. R'' and R'7 is optionally substituted droxyethyl and 2-(dimethylamino)ethyl, particularly prefer by the same or different 1 to 5 substituents selected from the ably, methyl group or cyclopropyl group can be mentioned. below-defined “group C. 35 As the “R”, The “group C' is a group consisting of 1) the above-defined "halogenatom', 2) a cyano group, 3) the above-defined “Ca alkyl group”, 4) “ ORC'”, 5) “ NRCRC, 6) “ CO —CHym–G) OR and 7) an oxo group, wherein R', R, R and R' 40 are the same or different and each is a hydrogen atom or the above-defined “C. alkyl group'. wherein each symbol is as defined above, is preferable. Here, As the -OR.", hydroxyl group, methoxy group, ethoxy m is preferably 0, the “ring Cy” is preferably C. carbon group, propoxy group, isopropoxy group, tert-butoxy group ring group, and the "carbon ring group' is preferably phenyl and the like can be specifically mentioned. 45 group (wherein the “C. carbon ring group' and “phenyl As the “ NR'R'', amino group, methylamino group, group' are optionally substituted by 1 to 5 substituents ethylamino group, propylamino group, isopropylamino selected from group B, and as the “group B, “ NR'R'', group, tert-butylamino group, dimethylamino group, diethy lamino group, N-ethyl-N-methylamino group, N-methyl-N- propylamino group, N-isopropyl-N-methylamino group and 50 the like can be specifically mentioned. * NRSONR''CONR'R'' are preferable). As the “ COOR, carboxyl group, methoxycarbonyl Specifically, as the “R”, a hydrogen atom, methyl group, group, ethoxycarbonyl group, propoxycarbonyl group, iso ethyl group, 2.2.2-trifluoroethyl group, isopropyl group, propyloxycarbonyl group, tert-butoxycarbonyl group and the butyl group, isobutyl group, 2-propenyl group, cyclopropyl like can be specifically mentioned. 55 group, cyclobutyl group, cyclopentyl group, phenyl group. As the 'group C, the group consisting of 1) the above 4-chlorophenyl group, 2-fluorophenyl group, 4-fluorophenyl defined "halogen atom, 2) a cyano group, 3) the above group, 4-bromophenyl group, 2,6-difluorophenyl group, defined “C. alkyl group', 4) “ OR'', 5) “ NR'R'' o-tolyl group, m-tolyl group, p-tolyl group, 2,6-dimethylphe and 6)“. COOR are preferable, and specifically, fluorine nyl group, 2-ethylphenyl group, 3-(3-hydroxypropyl)phenyl atom, chlorine atom, bromine atom, cyano group, methyl 60 group, 3-(2-carboxyethyl)phenyl group, 3-(3-morpholin-4- group, ethyl group, propyl group, hydroxyl group, methoxy ylpropyl)phenyl group, 3-dimethylaminopropylphenyl group, ethoxy group, amino group, dimethylamino group. group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, diethylamino group, carboxyl group and methoxycarbonyl 2-methoxyphenyl group, 3-methoxyphenyl group, 4-meth group can be mentioned. oxyphenyl group, 3-dimethylaminoethoxyphenyl group, As the “group C. methyl group is particularly preferable. 65 3-carboxymethoxyphenyl group, 3-(3-dimethylaminopro The preferable number of the substituent is 1, and the poxy)phenyl group, 3-(2-morpholin-4-ylethoxy)phenyl Substituent may be used at any Substitutable position. group, 3-(2-pyrrolidin-1-ylethoxy)phenyl group, 3-(2-piperi US 8,835,443 B2 23 24 din-1-ylethoxy)phenyl group, 3-(2-diethylaminoethoxy)phe -continued nyl group, 3-3-(4-methylpiperazin-1-yl)propoxyphenyl group, 3-aminophenyl group, 3-methylaminophenyl group, 3-dimethylaminophenyl group, 3-(methanesulfonyl)methy laminophenyl group, 3-methylcarbonylaminophenyl group, 3-methanesulfonylaminophenyl group, 4-chloro-3-methane Sulfonylaminophenyl group, 3-ethanesulfonylaminophenyl NH, NH NH, group, 3-(propane-1-sulfonylamino)phenyl group, 3-(pro ls. pane-2-sulfonylamino)phenyl group, 3-chloromethanesulfo O b O nylaminophenyl group, 3-trifluoromethanesulfonylami 10 nophenyl group, 3-(2.2.2-trifluoroethanesulfonylamino) phenyl group, 3-(2-methoxyethyl)methylaminophenyl group, 3-methylcarbonylaminophenyl group, 3-ethylcarbo nylaminophenyl group, 3-propylcarbonylaminophenyl group, 3-isopropylcarbonylaminophenyl group, 3-ethoxycar 15 NH, NH bonylaminophenyl group, 3-(hydroxymethylcarbonyl)ami nophenyl group, 3-(2-hydroxyethylcarbonylamino)phenyl group, 3-ethylaminocarbonylaminophenyl group, 3-(2-dim O O ethylaminoethylcarbonylamino)phenyl group, 3-(3-dimethy laminopropylcarbonylamino)phenyl group, 3-(methoxym are preferable. ethylcarbonylamino)phenyl grOup, More preferably, phenyl group, 4-chlorophenyl group, 3-(butylcarbonylaminomethylcarbonylamino)phenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl 3-(2-butylcarbonylaminoethylcarbonylamino)phenyl group, group, 2,6-difluorophenyl group, o-tolyl group, m-tolyl 3-methylaminocarbonylaminophenyl group, 3-methoxyami group, p-tolyl group, 2,6-dimethylphenyl group, 2-ethylphe nocarbonylaminophenyl group, 3-dimethylaminocarbony 25 laminophenyl group, 3-(dimethylaminomethylcarbony nyl group, 3-(3-hydroxypropyl)phenyl group, 3-(2-carboxy lamino)phenyl group, 3-(2-morpholin-4-ylethylamino) ethyl)phenyl group, 3-(3-morpholin-4-ylpropyl)phenyl phenyl grOup, 3-(2-benzyloxycarbonylaminoethyl) group, 3-dimethylaminopropylphenyl group, 3-hydroxyphe Sulfonylaminophenyl grOup, 3-(2-aminoethyl) nyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, Sulfonylaminophenyl group, 3-(2-butylcarbonylaminoethyl) 30 3-methoxyphenyl group, 4-methoxyphenyl group, 3-dim Sulfonylaminophenyl grOup, ethylaminoethoxyphenyl group, 3-carboxymethoxyphenyl 3-dimethylaminosulfonylaminophenyl group, 3-carbox group, 3-(3-dimethylaminopropoxy)phenyl group, 3-(2-mor yphenyl group, 3-carbamoylphenyl group, 3-methanesulfo pholin-4-ylethoxy)phenyl grOup, 3-(2-pyrrolidin-1- nylphenyl group, 4-methanesulfonylphenyl group, 3-ethane ylethoxy)phenyl group, 3-(2-piperidin-1-ylethoxy)phenyl Sulfonylphenyl group, 3-methylaminosulfonylphenyl group, 35 group, 3-(2-diethylaminoethoxy)phenyl group, 3-3-(4-me 3-ethylaminosulfonylphenyl group, 3-benzenesulfonylami thylpiperazin-1-yl)propoxyphenyl group, 3-aminophenyl nophenyl group, 3-aminosulfonylphenyl group, 3-dimethy group, 3-methylaminophenyl group, 3-dimethylaminophe laminosulfonylphenyl group, 4-dimethylaminosulfonylphe nyl group, 3-(methanesulfonyl)methylaminophenyl group, nyl group, 3-(4-methylpiperazine-1-sulfonyl)phenyl group, 3-methylcarbonylaminophenyl group, 3-methanesulfony 3-(morpholine-4-Sulfonyl)phenyl group, 3-(piperidine-1- 40 laminophenyl group, 4-chloro-3-methanesulfonylaminophe Sulfonyl)phenyl group, 3-(pyrrolidine-1-sulfonyl)phenyl nyl group, 3-ethanesulfonylaminophenyl group, 3-(propane group, 3-methylaminocarbonylphenyl group, 3-morpholin 1-sulfonylamino)phenyl grOup, 3-(propane-2- 4-ylphenyl group, 3-pyrrolidin-1-ylphenyl group, 3-piperi Sulfonylamino)phenyl grOup, din-1-ylphenyl group, 3-(4-methylpiperazin-1-yl)phenyl 3-chloromethanesulfonylaminophenyl group, 3-trifluo group, 3-(2-oxopyrrolidin-1-yl)phenyl group, 3-(3-oxomor 45 romethanesulfonylaminophenyl group, 3-(2.2.2-trifluoroet pholin-4-yl)phenyl group, thiophen-3-yl group, pyridin-3-yl hanesulfonylamino)phenyl group, 3-(2-methoxyethyl)me group, benzyl group and the following groups: thylaminophenyl group, 3-methylcarbonylaminophenyl group, 3-ethylcarbonylaminophenyl group, 3-propylcarbo nylaminophenyl group, 3-isopropylcarbonylaminophenyl 50 group, 3-ethoxycarbonylaminophenyl group, 3-(hydroxym ethylcarbonyl)aminophenyl group, 3-(2-hydroxyethylcarbo nylamino)phenyl group, 3-ethylaminocarbonylaminophenyl grOup, 3-(2-dimethylaminoethylcarbonylamino)phenyl grOup, 3-(3-dimethylaminopropylcarbonylamino)phenyl NH, NH, NH, 55 group, 3-(methoxymethylcarbonylamino)phenyl group, 3-(butylcarbonylaminomethylcarbonylamino)phenyl group, H-( NS 3-(2-butylcarbonylaminoethylcarbonylamino)phenyl group, O O 3-methylaminocarbonylaminophenyl group, 3-methoxyami nocarbonylaminophenyl group, 3-dimethylaminocarbony 60 laminophenyl group, 3-(dimethylaminomethylcarbony lamino)phenyl group, 3-(2-morpholin-4-ylethylamino) phenyl grOup, 3-(2-benzyloxycarbonylaminoethyl) Sulfonylaminophenyl grOup, 3-(2-aminoethyl) y NH NH Sulfonylaminophenyl group, 3-(2-butylcarbonylaminoethyl) / N-N SN susO 65 Sulfonylaminophenyl grOup, HC s s s 3-dimethylaminosulfonylaminophenyl group, 3-carbox yphenyl group, 3-carbamoylphenyl group, 3-methanesulfo US 8,835,443 B2 25 26 nylphenyl group, 4-methanesulfonylphenyl group, 3-ethane nyl group, 4-bromo-2-methoxyphenyl group, 2-bromo-4- Sulfonylphenyl group, 3-methylaminosulfonylphenyl group, methoxyphenyl group, 4-methylthiophenyl group, 4-trifluo 3-ethylaminosulfonylphenyl group, 3-benzenesulfonylami romethylthiophenyl group, 2-fluoro-4-methylthiophenyl nophenyl group, 3-aminosulfonylphenyl group, 3-dimethy group, 4-aminophenyl group, 4-methylaminophenyl group, laminosulfonylphenyl group, 4-dimethylaminosulfonylphe 2-dimethylaminophenyl group, 3-dimethylaminophenyl nyl group, 3-(4-methylpiperazine-1-sulfonyl)phenyl group, group, 4-dimethylaminophenyl group, 4-ethylaminophenyl 3-(morpholine-4-Sulfonyl)phenyl group, 3-(piperidine-1- group, 4-diethylaminophenyl group, 4-ethylmethylamino-2- Sulfonyl)phenyl group, 3-(pyrrolidine-1-sulfonyl)phenyl fluorophenyl group, 4-nitrophenyl group, 4-cyanophenyl group, 3-methylaminocarbonylphenyl group, 3-morpholin group, 6-aminopyridin-3-yl group, 6-dimethylaminopyridin 4-ylphenyl group, 3-pyrrolidin-1-ylphenyl group, 3-piperi 10 3-yl group, 6-chloropyridin-2-yl group, 4-chloropyridin-3-yl din-1-ylphenyl group, 3-(4-methylpiperazin-1-yl)phenyl group, 4-carboxyphenyl group, 4-methoxycarbonylphenyl group, 3-(2-oxopyrrolidin-1-yl)phenyl group and 3-(3-oxo group, 4-ethylaminophenyl group, 4-(methylcarbonyl)me morpholin-4-yl)phenyl group can be mentioned. thylaminophenyl group, 4-methanesulfonylphenyl group, As the “R, 4-trifluoromethanesulfonylphenyl group, 4-dimethylamino 15 2-methylphenyl group, 4-dimethylamino-3-methylphenyl group, 4-dimethylamino-3-trifluoromethylphenyl group, 4-dimethylamino-2-propylphenyl group, 4-dimethylamino o chn-G) 2-fluorophenyl group, 4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphinoyl phenyl group, benzo 1.3di oXol-5-yl group, 1,1'-biphenyl-4-yl group, 4-(piperidin-1-yl) wherein each symbol is as defined above, is preferable. Here, phenyl group, 4-benzylphenyl group, 4-(morpholin-4-yl) m is preferably 0, the “ring Cy” is preferably C. carbon phenyl grOup, 1-methylpiperidin-4-yl grOup, ring group and the "carbon ring group' is preferably phenyl 1-isopropylpiperidin-4-yl group, thiazol-2-yl group, 2-dim group (wherein the “C. carbon ring group' and “phenyl ethylaminothiazol-4-yl group, 1-methyl-1,2,3,4-tetrahydro group' are optionally substituted by 1 to 5 substituents 25 quinolin-6-yl group, 1H-indol-5-yl group, 1-methyl-1H-in selected from group B, where the “group B preferably dol-5-yl group, 1-ethyl-1H-indol-5-yl group, 1-methyl-1H includes the above-defined “halogen atom', the above-de indol-6-yl group, 1-methyl-1H-indol-7-yl group, 1,2- fined "Cs alkyl group' and the above-defined “Calkynyl dimethyl-1H-indol-5-yl group, 1,2,3-trimethyl-1H-indol-5- group'). yl group, 6-fluoro-1H-indol-5-yl group, 1-methyl-1H Specifically, as the “R'', 2-methoxyethyl group, 2,2-dim 30 benzimidazol-5-yl group, 1-methyl-1H-indazol-5-yl group, ethylpropyl group, 3-dimethylaminopropyl group, cyclopro 1-methyl-2,3-dihydro-1H-indol-5-yl group, benzob. pyl group, cyclohexyl group, phenyl group, 2-chlorophenyl thiophen-5-yl group, 4-chlorobenzyl group, 2-bromobenzyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,4- group, 3-bromobenzyl group, 4-bromobenzyl group, dichlorophenyl group, 3,4-dichlorophenyl group, 4-bro 5-bromo-2-fluorobenzyl group, 2-morpholin-4-ylethyl group mophenyl group, 2-fluorophenyl group, 4-fluorophenyl 35 and pyridin-3-ylmethyl group are preferable. group, 4-iodophenyl group, o-tolyl group, p-tolyl group, More preferably, phenyl group, 2-chlorophenyl group, 2-ethylphenyl group, 4-ethylphenyl group, 2-propylphenyl 3-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlo group, 2-isopropylphenyl group, 4-isopropylphenyl group, rophenyl group, 3,4-dichlorophenyl group, 4-bromophenyl 2-butylphenyl group, 4-butylphenyl group, 2-isobutylphenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 4-io group, 4-tert-butylphenyl group, 2-(3-methylbutyl)phenyl 40 dophenyl group, o-tolyl group, p-tolyl group, 2-ethylphenyl group, 4-trifluoromethylphenyl group, 4-(2-fluoroethyl)phe group, 4-ethylphenyl group, 2-propylphenyl group, 2-isopro nyl group, 4-(2,2-difluoroethyl)phenyl group, 4-(2.2.2-trif pylphenyl group, 4-isopropylphenyl group, 2-butylphenyl luoroethyl)phenyl group, 4-(1-ethylpropyl)phenyl group, group, 4-butylphenyl group, 2-isobutylphenyl group, 4-tert 4-(1-propylbutyl)phenyl group, 4-ethynylphenyl group, 2,4- butylphenyl group, 2-(3-methylbutyl)phenyl group, 4-trif difluorophenyl group, 2,6-difluorophenyl group, 2,4-dichlo 45 luoromethylphenyl group, 4-(2-fluoroethyl)phenyl group, rophenyl group, 4-bromo-2-fluorophenyl group, 4-bromo-3- 4-(2,2-difluoroethyl)phenyl group, 4-(2.2.2-trifluoroethyl) fluorophenyl group, 4-bromo-2-chlorophenyl group, phenyl group, 4-(1-ethylpropyl)phenyl group, 4-(1-propyl 4-chloro-2-fluorophenyl group, 2-fluoro-4-iodophenyl butyl)phenyl group, 4-ethynylphenyl group, 2,4-difluorophe group, 2-chloro-4-methylphenyl group, 4-chloro-2-meth nyl group, 2,6-difluorophenyl group, 2,4-dichlorophenyl ylphenyl group, 4-bromo-2-methylphenyl group, 4-bromo-3- 50 group, 4-bromo-2-fluorophenyl group, 4-bromo-3-fluo methylphenyl group, 2-fluoro-4-methylphenyl group, rophenyl group, 4-bromo-2-chlorophenyl group, 4-chloro-2- 2-fluoro-4-trifluoromethylphenyl group, 4-bromo-2-eth fluorophenyl group, 2-fluoro-4-iodophenyl group, 2-chloro ylphenyl group, 4-ethyl-2-fluorophenyl group, 4-(2-carboxy 4-methylphenyl group, 4-chloro-2-methylphenyl group, ethyl)-2-fluorophenyl group, 2-fluoro-4-propylphenyl group, 4-bromo-2-methylphenyl group, 4-bromo-3-methylphenyl 2-fluoro-4-vinylphenyl group, 4-(2-carboxyvinyl)-2-fluo 55 group, 2-fluoro-4-methylphenyl group, 2-fluoro-4-trifluo rophenyl group, 4-ethynyl-2-fluorophenyl group, 2-fluoro-4- romethylphenyl group, 4-bromo-2-ethylphenyl group, (prop-1-ynyl)phenyl group, 2-fluoro-4-(3-hydroxyprop-1- 4-ethyl-2-fluorophenyl group, 4-(2-carboxyethyl)-2-fluo ynyl)phenyl group, 2-fluoro-4-(3-methoxyprop-1-ynyl) rophenyl group, 2-fluoro-4-propylphenyl group, 2-fluoro-4- phenyl group, 4-cyclopropyl-2-fluorophenyl group, 2-fluoro vinylphenyl group, 4-(2-carboxyvinyl)-2-fluorophenyl 4-(3-hydroxy-3-methylbut-1-ynyl)phenyl group, 4-(3- 60 group, 4-ethynyl-2-fluorophenyl group, 2-fluoro-4-(prop-1- dimethylaminoprop-1-ynyl)-2-fluorophenyl grOup, ynyl)phenyl group, 2-fluoro-4-(3-hydroxyprop-1-ynyl)phe 4-chloro-2-dimethylaminomethylphenyl group, 4-dimethy nyl group, 2-fluoro-4-(3-methoxyprop-1-ynyl)phenyl group, lamino-2-methylphenyl group, 4-hydroxyphenyl group, 4-cyclopropyl-2-fluorophenyl group, 2-fluoro-4-(3-hydroxy 2-methoxyphenyl group, 4-methoxyphenyl group, 4-trifluo 3-methylbut-1-ynyl)phenyl group, 4-(3-dimethylaminoprop romethoxyphenyl group, 4-isopropoxyphenyl group, 2,4- 65 1-ynyl)-2-fluorophenyl group, 4-chloro-2-dimethylaminom dimethoxyphenyl group, 4-methoxy-2-methylphenyl group, ethylphenyl group, 4-dimethylamino-2-methylphenyl group, 2-fluoro-4-methoxyphenyl group, 4-bromo-2-hydroxyphe 4-hydroxyphenyl group, 2-methoxyphenyl group, 4-methox US 8,835,443 B2 27 28 yphenyl group, 4-trifluoromethoxyphenyl group, 4-isopro The prodrug is utilized for, for example, improving absorp poxyphenyl group, 2,4-dimethoxyphenyl group, 4-methoxy tion by oral administration or targeting of a target site. 2-methylphenyl group, 2-fluoro-4-methoxyphenyl group, As the site to be modified, highly reactive functional 4-bromo-2-hydroxyphenyl group, 4-bromo-2-methoxyphe groups in the compound of the present invention, Such as nyl group, 2-bromo-4-methoxyphenyl group, 4-methylth- 5 hydroxyl group, carboxyl group, amino group, thiol group iophenyl group, 4-trifluoromethylthiophenyl group, and the like, are mentioned. 2-fluoro-4-methylthiophenyl group, 4-aminophenyl group, For example, a compound wherein a hydroxyl group is 4-methylaminophenyl group, 2-dimethylaminophenyl substituted by —CO-alkyl, —CO-alkyl, —CONH-alkyl, group, 3-dimethylaminophenyl group, 4-dimethylaminophe —CO-alkenyl, -CO-alkenyl, —CONH-alkenyl, -CO nyl group, 4-ethylaminophenyl group, 4-diethylaminophenyl 10 aryl, —CO-aryl, —CONH-aryl, —CO-heterocycle.—CO group, 4-ethylmethylamino-2-fluorophenyl group, 4-nitro heterocycle, —CONH-heterocycle (wherein alkyl, alkenyl, phenyl group, 4-cyanophenyl group, 6-aminopyridin-3-yl aryl and heterocycle are optionally substituted by halogen group, 6-dimethylaminopyridin-3-yl group, 6-chloropyridin atom, alkyl group, hydroxyl group, alkoxy group, carboxy 2-yl group, 4-chloropyridin-3-yl group, 4-carboxyphenyl group, amino group, amino acid residue, —POH, -SOH, group, 4-methoxycarbonylphenyl group, 4-ethylaminophe- 15 —OPOH, OSOH and the like) or —POH and the like, nyl group, 4-(methylcarbonyl)methylaminophenyl group, a compound wherein an amino group is Substituted by 4-methanesulfonylphenyl group, 4-trifluoromethanesulfo —CO— alkyl, -CO-alkyl, -CO-alkenyl, -CO-alkenyl, nylphenyl group, 4-dimethylamino-2-methylphenyl group, —CO-aryl, -CO— aryl, -CO-heterocycle, —CO-het 4-dimethylamino-3-methylphenyl group, 4-dimethylamino erocycle (wherein alkyl, alkenyl, aryl and heterocycle are 3-trifluoromethylphenyl group, 4-dimethylamino-2-propy- 20 optionally Substituted by halogen atom, alkyl group, lphenyl group, 4-dimethylamino-2-fluorophenyl group, hydroxyl group, alkoxy group, carboxy group, amino group, 4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphi amino acid residue, —POH, -SOH, - OPOH, noylphenyl group, 1,1'-biphenyl-4-yl group, 4-(piperidin-1- —OSOH and the like) or - POH and the like and the like yl)phenyl group, 4-benzylphenyl group and 4-(morpholin-4- can be mentioned. yl)phenyl group can be mentioned. 25 Specifically, as the modifying group of hydroxyl group, As the “R”, preferably, Calkyl group (wherein the C. acetyl group, propionyl group, isobutyryl group, pivaloyl alkyl group is optionally substituted by 1 to 3 substituents group, palmitoyl group, benzoyl group, 4-methylbenzoyl selected from group A) can be mentioned. group, dimethylcarbamoyl group, dimethylaminomethylcar Specifically, a hydrogen atom, methyl group, ethyl group, bonyl group, Sulfo group, alanyl group, fumaryl group and the propyl group, isobutyl group, 2-methoxyethyl group, cyclo- 30 like can be mentioned. The sodium salt of 3-carboxybenzoyl propyl group, 2-dimethylaminoethyl group and 2-propenyl group or 2-carboxyethylcarbonyl group and the like can be group are preferable, and methyl group is particularly pref also mentioned. erable. Specifically, as the modifying group of carboxyl group, As the “R”, preferably, a C- alkyl group (wherein the methyl group, ethyl group, propyl group, isopropyl group, C. alkyl group is optionally substituted by 1 to 3 substitu- 35 butyl group, isobutyl group, tert-butyl group, pivaloyloxym ents selected from group A) can be mentioned. ethyl group, carboxymethyl group, dimethylaminomethyl Specifically, a hydrogenatom, methyl group, propyl group group, 1-(acetyloxy)ethyl group, 1-(ethoxycarbonyloxy) and hydroxy group are preferable, and methyl group is par ethyl group, 1-(isopropyloxycarbonyloxy)ethyl group, 1-(cy ticularly preferable. clohexyloxycarbonyloxy)ethyl group, carboxylmethyl As the “R”, a hydrogen atom and methyl group are pref- 40 group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, ben erable, and a hydrogen atom is particularly preferable. Zyl group, phenyl group, o-tolyl group, morpholinoethyl The “pharmaceutically acceptable salt thereof may be any group, N,N-diethylcarbamoylmethyl group, phthalidyl group salt as long as it forms a non-toxic salt with the compounds of and the like can be mentioned. the above-mentioned formula I, II and I-1-I-3 and can Specifically, as the modifying group of amino group, tert be obtained by a reaction with an inorganic acid such as 45 butyl group, docosanoyl group, pivaloylmethyloxy group, hydrochloric acid, Sulfuric acid, phosphoric acid, hydrobro alanyl group, hexylcarbamoyl group, pentylcarbamoyl mic acid and the like; an organic acid Such as oxalic acid, group, 3-methylthio-1-(acetylamino)propylcarbonyl group, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, (5-me Succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, thyl-2-oxo-1,3-dioxol-4-yl)methyl group, (5-methyl-2-oxo gluconic acid, ascorbic acid, methanesulfonic acid, benzene- 50 1,3-dioxol-4-yl)methoxycarbonyl group, tetrahydrofuranyl Sulfonic acid and the like; an inorganic base Such as sodium group, pyrrolidylmethyl group and the like can be mentioned. hydroxide, potassium hydroxide, calcium hydroxide, magne The “tumor used in the present specification includes sium hydroxide, ammonium hydroxide and the like; an malignant tumor, and the “antitumor agent contains an anti organic base Such as methylamine, diethylamine, triethy cancer agent and is a compound having an antitumor activity. lamine, triethanolamine, ethylenediamine, tris(hydroxym- 55 The compound of the present invention can be adminis ethyl)methylamine, guanidine, choline, cinchonine and the tered to a mammal (human, mouse, rat, hamster, rabbit, cat, like; oranamino acid such as lysine, arginine, alanine and the dog, bovine, sheep, monkey etc.) and the like as an antitumor like. The present invention also encompasses hydrate and agent and the like. Solvate of each compound. When the compound of the present invention is used as a The present invention also encompasses prodrugs and 60 pharmaceutical preparation, it is generally admixed with metabolites of each compound. pharmaceutically acceptable carriers, excipients, diluents, By the “prodrug is meant a derivative of the compound of extending agents, disintegrants, stabilizers, preservatives, the present invention, which has a chemically or metaboli buffers, emulsifiers, flavoring agents, coloring agents, Sweet cally decomposable group and which, after administration to ening agents, thickeners, corrigents, dissolution aids, and a body, restores to the original compound to show its inherent 65 other additives, that are known per se, such as water, Veg efficacy, including a complex and a salt, not involving a etable oil, alcohol (e.g., ethanol, benzyl alcohol etc.), poly covalent bond. ethylene glycol, glycerol triacetate, gelatin, carbohydrate US 8,835,443 B2 29 30 (e.g., lactose, starch etc.), magnesium Stearate, talc, lanolin, In addition, treatment of chronic pain, specifically, neuro petrolatum and the like, formed into tablet, pill, powder, pathic pain, catapletic pain, pain associated with chronic granule, Suppository, injection, eye drop, liquid, capsule, tro alcoholism, vitamin deficiency, uremia and hypothyroidism che, aerosol, elixir, Suspension, emulsion, syrup and the like can be mentioned. Furthermore, neutrophile-mediated dis by a conventional method, and administered systemically or 5 ease or symptoms, specifically, ischemia reperfusion injury, topically, and orally or parenterally. chronic obstructive pulmonary disease, acute respiratory dis While the dose varies depending on age, body weight, ease syndrome, cystic fibrosis, catapletic pulmonary fibrosis, symptom, treatment effect, administration method and the sepsis, endotoxemia, lung emphysema and pulmonary asbes like, it is generally 0.01 mg to 1 g once for an adult, which is tosis can be mentioned. Furthermore, graft rejection can be 10 mentioned. Moreover, arthritis, specifically, rheumatoid given once to several times a day orally or in a dosage form of arthritis and osteoarthritis can be mentioned. In addition, an injection such as intravenous injection and the like. asthma can be mentioned. Moreover, viral diseases, specifi An antitumor agent is generally required to Sustain its cally, herpes virus (HSV-1) infection, human cytomegalovi effect for a long time, so that can be effective not only for rus (HCMV) infection, human immunodeficiency virus temporal Suppression of the proliferation of cancer cells but 15 (HIV) infection can be mentioned. Furthermore, disease also for the prohibition of the re-prohibition of cancer cells. caused by denaturation or injury of cartilage, specifically, This means that a prolonged administration is necessary and osteoarthrosis, rheumatoid arthritis, osteochondrosis disse that a high single dose may be frequently inevitable to Sustain cans and disease requiring chondrogenesis can be mentioned. effect for a longer period through the night. Such prolonged Besides the above, application to restenosis, psoriasis, ath and high dose administration increases the risk of causing erosclerosis, cardiac failure, apoplexies and the like can be side effects. mentioned. In view of this, one of the preferable embodiments of the As the “diseases caused by undesirable cell proliferation', pyrimidine compound of the present invention is such com tumor and rheumatism are preferable. pound as permitting high absorption by oral administration, As other'antitumor agent used for multiple drug therapy, and Such compound capable of maintaining blood concentra 25 alkylating agent, platinum complex, metabolism antagonist, tion of the administered compound for an extended period of antibiotics, plant alkaloid, interferon, cyclooxygenase-2 time. (COX-2) inhibitor, hormonal anticancer agent, cancer cell A compound capable of showing p15 protein induction vaccine, bacterial preparation, mushroom extract polysac and/or p27 protein induction and/or MEK inhibition in com charides, cytokine agonist, interleukin preparation, antibody bination is preferable. 30 drug, immunomodulator, angiogenesis inhibitor, intracellular This compound is useful for the treatment of diseases tube formation inhibitor, cell proliferation inhibitor, cell cycle caused by undesirable cell proliferation. regulator, apoptosis inducer, cancer gene therapy agent and As the “diseases caused by undesirable cell proliferation'. the like can be mentioned. for example, tumor, specifically cerebral tumor (neuroglioma As the alkylating agent, cyclophosphamide, ifosfamide, having a component of malignant astroglioma and oligoden 35 melpharan, buslfan, nimustine, ranimustine (MCNU), nitro droglioma and the like), cancer of esophangus, stomach can gen mustard-N-oxide hydrochloride, thiotepa, procarbazine cer, liver cancer, pancreatic cancer, colorectal cancer (colon hydrochloride, carboquone, mitobronitol, improSulfan tosy cancer, rectal cancer etc.), lung cancer (non-small cell lung late, estramustine phosphate sodium, dacarbazine, temozolo cancer, Small cell lung cancer, primary and metastatic squa mide, dacarbazine (DTIC), mustine hydrochride, treosulfan, mous cancer etc.), renal cancer, breast cancer, ovarian cancer, 40 temozolomide, MS-247, (-)-(S)-bromofosfamide and the prostate cancer, skin cancer, neuroblastoma, sarcoma, osteo like can be mentioned. chondroma, osteoma, osteosarcoma, seminoma, extrago As the platinum complex, cisplatin, carboplatin, nedapl nadal tumor, testicle tumor, uterine cancer (cervical cancer, atin, paraplatin, etoposide, Oxaliplatin, eptaplatin, miripla endometrial cancer and the like), head and neck tumor (max tion, lobaplatin, picoplatin, oxaliplatin, satraplatin, SLIT-cis illary cancer, larynx cancer, pharyngeal cancer, lingual can 45 platin and the like can be mentioned. cer, intraoral cancer and the like), multiple myeloma, malig As the metabolism antagonist, methotrexate, 6-mercap nant lymphoma (reticulosarcoma, lymphosarcoma, topurine, cytosine-arabinoside, enocitabine (BHAC), 5-fluo Hodgkin’s disease etc.), polycythemia Vera, leukemia (acute rouracil, tegafur, tegafur-uracil (UFT), carmofur (HCFU), myeloid leukemia, chronic myeloid leukemia, acute lympho doxifluridine, gemcitabine hydrochloride, hydroxyl carbam cytic leukemia, chronic lymphocytic leukemia etc.), goiter, 50 ide, procarbazine hydrochloride, pemetrexed disodium, renal pelvic cancer, ureteral tumor, bladder tumor, gallblad L-MDAM, mercaptopurine riboside, fludarabine phosphate, der cancer, bile duct cancer, chorioma, malignant melanoma, tegafur-gimestat-otastat, levofolinate-fluorouracil, folinate pediatric tumor (sarcoma of the ewing's family, Wilms calcium levofolinate, bemcitabine, calcium levolecuco Vorin, tumor, rhabdomyosarcoma, Vascular sarcoma, embryonal capecitabine, cytarabine, cytarabine ocfosfate, CS-682, testicle cancer, neuroblastoma, retinoblastoma, hepatoblas 55 3'-ethynylcytidine, TAS-102, capecitabine, fulvestrant, toma, nephroblastoma etc.) and the like can be mentioned. idoxuridine, hydroxyurea, pemetrexeddisodium, 3-AP. Application to cerebral tumor (neuroglioma having a com benspn, lometrexol, troxacitabine, ABT-510, AP-2/09, ponent of malignant astroglioma and oligodendroglioma AR-726, AVI-4126, belimumab, CA4P, colorectal cancer etc.), cancer of esophangus, stomach cancer, liver cancer, vaccine, COU-1, degarelix, DJ-927, DPC-974, EKB-569, pancreatic cancer, colorectal cancer (colon cancer, rectal can 60 enzastaurin hydrochloride, fentanyl citrate, fulvestrant, gal cer etc.), lung cancer (non-Small cell lung cancer, Small cell lium maltolate, HuMax-EGFR, IDD-1, LE-AON, MDX-070, lung cancer etc.), renal cancer, breast cancer, ovarian cancer, MT-201, NK-911, NV-07. Oncomyc-NG, pertuzumab, prostate cancer, skin cancer, neuroblastoma, sarcoma and the PX-103.1, renal cancer vaccine, SN-4071, TL-139, topix like can be mentioned. more preferably, colon cancer, pan antrone dihydrochloride, ZYC-101a and the like can be men creas cancer, renal cancer, lung cancer, and breast cancer is 65 tioned. preferable, and application to colon cancer and pancreas can As the antibiotics, actinomycin D, daunomycin, doxorubi cer is particularly preferable. cin (adriamycin), epirubicin, aclacinomycin A, mitomycin C, US 8,835,443 B2 31 32 bleomycin, pirarubicin hydrochloride, idarubicin hydrochlo body, KM2760, TRAIL receptor-2 monoclonal antibody, ride, aclarubicin hydrochloride, amrubicin hydrochloride, anti-TRAIL receptor DR5 antibody, TRAIL-R1mAb, peplomycin Sulfate, neocarzinostatine, Zinostatin Sti humanized anti-HM1.24 antibody, humanized FasL anti malamer, valrubicin, liposormal doxorubicin, NK911, BMS body, humanized anti-CD26 monoclonal antibody, C.-galac 247550 (epothilone derivative), KRN5500, KW-2170, anna tosylceramide, diphtheria toxin modified transferrin bond, mycin, becatecarin, PK1, Sabarubicin hydrochloride, CVS CD47 monoclonal antibody, anti-human melanoma mono 10290 and the like can be mentioned. clonal antibody, HoAKS-1 (anti-lung cancer monoclonal As the plant alkaloid, Vincristine, vinblastine, Vindesine, antibody) and the like can be mentioned. etoposide, docetaxel, paclitaxel, irinotecan hydrochloride, As the angiogenesis inhibitor, gefitinib (Iressa), thalido Vinorelbine tartrate, mitoxantrone hydrochloride, noscapine, 10 mide, cetuximab, semaxanib, TSU-68, KRN633, KRN951, Vinflunine, docetaxel, E-7010, polyglutamated paclitaxel, marimastat, S-3304, erlotinib hydrochloride, ZD6474, soblidotin, Bay59-8862, E-7389, DJ-927, HTI-286, GW572016, S-3304, E7820, SU6668, E7080, NK4, TAS AC-7700, T-3782, ABI-007, batabulin sodium, DHA-pacli 101, lapatinib, priomastat, RPI-4610, thalidomide, taxel, deoxyepothilone B, ixabepilone, MBT-0206, ortataxel, WX-UK1, 2-methoxyestradiol, SG-292, FYK-1388 and the SB-715992, AI-850, synthadotin, lxabepilone, rubitecan, 15 like can be mentioned. nogitecan hydrochloride, topotecan hydrochloride, SobuzOX As the intracellular tube formation inhibitor, TAC-01, ane, etoposide phosphate disodium salt, dexraZOxane hydro E-7820 and the like can be mentioned. chloride, rubitecan IST-622, exatecan mesylate, TOP-53, As the cell proliferation inhibitor, imatinib mesylate, tras edotecarin, karenitecan, AG-7352, TAS-103, T-0128, tuzumab, rituximab, gemtuzumab, AHIM, mulbritinib/TAK NK-314, CKD-602, BNP-1350, lurtotecan, pegamotecan, 165, KW-2871, KM8969, CP-724714 and the like can be rubitecan, LE-SN38, CPT-11 and the like can be mentioned. mentioned. As interferon, interferon C, interferon C-2a, interferon As the cell cycle regulator, Boltezomib (NF-Kf8 Activation C-2b, interferon B and interferony, interferon Y-1a, interferon inhibitor), histone deacetylase HDAC inhibitor (FK-228, Y-1b, interferon Y-n1 and the like can be mentioned. SAHA, CI-994, LAQ-824, pyroxamide, AN-9, PBA, MS-275 As the cyclooxygenase-2 inhibitor, rofecoxib, celecoxib, 25 and the like), E-7070, flavopiritol, UCN-01, CGP41251, lumiracoxib, tiracoxib (tilmacozib), CS-502, CS-706, Valde CCI-779, KT5555, HMN-214, Y-27632, vatalanib/PTK coxib, parecoxib, R-109339, deguelin, ajulemic acid, p-54, 787A, MGCD0130, temsirolirnus, (R)-roscovitine, indisu E-6087, LM-4108, R-109339, CBX-AC, CBX-PR, CBX lam and the like can be mentioned. BU, L-748706, DMNQ-S64, ON-09250, ON-09300 and the As the apoptosis inducer, bortezomib, arglabin, R-115777, like can be mentioned. 30 KW-2401, BMS-214662, tipifarnib, lonafarnib, arglabin, As the hormonal anticancer agent, leuprorelin acetate, gos bexarotene, exisulind, glufosfamide, irofulven, MX-126374, erelin acetate, aminoglutethimide, triptorelin, goserelin, MX-2167, GRN163, GM95, MST-312, (-)-EGCG (Teavigo) formestane, fabrozole monohydrochloride, letrozole, and the like can be mentioned. exemestane, deslorelin, buserelin acetate, cetrorelix acetate, As the cancer gene therapy agent, A-007, Ad/Q5-H-sDd, histrelin acetate, abarelix, atrigel-leuprolide, estramustine 35 apaziquone, AVE-8062. MS-214662, combretastatin A-4, phosphate Sodium, chlormadinone acetate, fosfetrol, fluta didox, dolastatin-10, ganglioside vaccine, GivaRex, ILX-23 mide, bicartamide, cyproterone acetate, medroxyprogester 7553, interleukins, itriglumide, KW-2401, MCC-465, miri one acetate, tamoxifen citrate, toremifene citrate, mepithios platin, MUC-1 vaccine, OSI-7904L, platelet factor 4. tane, epithiostanol, medroxyprogesterone acetate, SR-271425, ZK-230211 and the like can be mentioned. fluvestrant, ormeloxifene, raloxifene hydrochloride, miprox 40 As other antitumor agents, anticancer agents, L-asparagi ifene phosphate, TAS-108; FMPA, fadrozole, anastrozole, nase, tretinoin, levoleucoVorin calcium, celmoleukin, 1111n exemestan, letrozole, formestane, bosentan, atrasentan, pentetreotide, ibandronate Sodium hydrate, aminolevulinic dutasteride, ESI, KT5555, KAT-682 and the like can be men acid hydrochloride, ukrain, Stem cell factor, denileukin dif tioned. ftitox, menatetrenone, methoXSalen, trimetrexate glucur As the cancer cell vaccine, cancer vaccine, activated lym 45 onate, IOR R3, everolimus, cytokeratin 19, doxercalciferol, phocyte, UL56 deficient HSV, vaccine for colorectal cancer alitretionoin, bexarotene, Verteporfin, morphine Sulfate Sus treatment, cancer peptide vaccine and the like can be men tained-release, Bacillus Calmette Guerin, megestrol acetate, tioned. menadione, floXuridine, thyrotropin alfa, inositol hexaphos As the bacterial preparation, BCG, anti-malignant tumor phate, augmerosen, Thio TEPA, chorionic gonadotropin, his streptococcal preparation, LC9018, tubercle bacillus hot 50 tamine dihydrochloride, lycopene, talaporfin sidium, tason water an extract and the like can be mentioned. ermin, arsenic trioxide, levamisole hydrochroride, folic acid, As the mushroom extract polysaccharides, lentinan, Corio teniposide, mebendazole, morphine hydrochloride, ALA Me lus versicolor polysaccharides (krestin), sizofiran, CM6271 ester, anethole dithiolethion, testosterone propionate, cina and the like can be mentioned. calcet hydrochloride, anethole dithiolethione, testosterone, As the cytokine agonist, ubenimex and the like can be 55 mitotane, sodium thiosulfate, Zevalin, beXXar, salmon calci mentioned. tonin, novobiocin, aminoglutethimide, eflornithine hydro As the interleukin preparation, interleukin-2, teceleukin, chloride, lonidamine, amoXnox, pirarubicin, Vesnarinone, interleukin-12 and the like can be mentioned. pamidronate Sodium, clodronate disodium, Zoledronic acid As the antibody pharmaceutical agent, immunomodulator, monohydrate, ambamustine hydrochloride, ubestatin, ami trastuzumab, rituximab, gemtuzumab ozogamicin, iburitu 60 fostine hydrate, deoxyspergualin hydrochloride, pentostatin, momab tiuxetan, cetuximab, bevacizumab, caprpmab pen bisantrene, peplomycin, iobenguane, amsacrine, triloStane, detide, capromab pendetide indium, pemetrexed disodium, tramadol hydrochloride, elliptinium acetate, ladakamycin, yttrium 90 ibritumab tiuxetan, votumumab, humanized IL-6 bromebrate sodium, nitracrin dihydrochloride hydrate, altre receptor antibody, anti-TA226 human monoclonal antibody, tamine, OROS-oxyodone, fentanyl citrate, aspirin, AERX F(ab') human antibody GAH, EMD72000, partuzumab, ale 65 Morphine Sulfate, carmustine, metoclopramide hydrochlo mtuzumab, VEGF receptor FLt-1 antibody, KW-2871, ride, loperamide hydrochloride, nilutamide, polysaccharide humanized anti-GM2 antibody, humanized anti-GD2 anti K, ranimustine, atVogen, pipobroman, imiquimod (interferon US 8,835,443 B2 33 34 inducers), cladribine, tibolone, Suramin Sodium, leflunomide, shown in the following. However, the Production Methods of fentanyl, octreotide acetate, inositol, ursodiol, feverfew, len the compound of the present invention are not limited to these tinan, tetranabinex, (cannabinoid receptor agonists), pegas examples. pargase, triclosan, carbohydrate antigen 19-9., angiopeptin Even in the absence of description in the Production Meth acetate, fotemustine, gallium nitrate, trabectebin, raltitrexed, 5 ods, efficient production can be afforded by designs such as Zinostatin stimalamer, hexadecylphosphocholine, tazarotene, introducing, where necessary, a protecting group into a func finasteride, clofarabine, temoporfin, SY-801, human angio tional group followed by deprotection in a Subsequent step; tensin II, efaproxiral Sodium, amonafide (DNA-Intercalating Subjecting a functional group to each step as a precursor and Drug), SP-1053C (DNA-Intercalating Drug), antineoplaston 10 converting the group to a desired functional group in a Suit AS2-1, fenretinide (retinoids), trabectebin, mammastatin, able step; exchanging the order of respective Production DOS-47, ECO-04601, thymectacin, rhIGFBP-3, carboxya Methods and steps; and the like. midotriazole, CoFactor, davanat-1, tariquidar, ONT-093, The work-up treatment in each step can be applied by a minobronic acid, minodronic acid, dolfequidar fumarate typical method, wherein isolation and purification is per (MDR-1 inhibitors), tariquidar (MDR-1 Inhibitors), 15 Davanat-1, ranpirinase, atrasentan, meclinertant, tacedinline, formed as necessary by selecting or combining conventional troxacitabine, DN-101, EB-1627, ACO-04601, MX-116407, methods, such as crystallization, recrystallization, distilla STA-4783, Davanat-1, moverastin, mitoxantrone hydrochlo tion, partitioning, silica gel chromatography, preparative ride, procarbazine hydrochloride, octreotide acetate, por HPLC and the like. fimer Sodium, pentostatin, cladribine, Sobuzoxane, tretinoin, aceglatone, mitotane, porfimer sodium, elliptinium Acetate, AZD6126, tirapazamine, Bay43-9006, tipifarnib/R115777, Production Method 1 midostaurin, BMS-214662, EKB-569, E7107, CBP501, RI HMN-214, FK-866, WF-536, SU-11248, MKT-077, phe YNH noxodiol, NSC-330507, G-CSF, Edrecolomab (Monoclonal 25 R-NH + O=C=N-R2 - -- Antibodies), satumomab, sargramostin (GM-CSF), ep O NH tamibarotene (retinoid derivative), arsenic trioxide, dutast eride, menatetrenone, ZD4054, NIK-333, NS-9, ABT-510, R2 S-2678, methioninase, TAS-105, metastin, TOP-008, NCO 1. 2 3) 700, BCA and the like can be mentioned. 30 O As “other antitumor agents’ used for the multiple drug O RI therapy with the compound of the present invention, platinum cl NN complex, alkylating agent and metabolism antagonist are RCIO -- --- preferable. It is possible to use 2 or 3 or more pharmaceutical Step 2 1. Step 3 agents can be used in combination, wherein a combination of 35 O N O pharmaceutical agents having different action mechanism is RC2O O one of the preferable embodiments. Moreover, selection of R2 pharmaceutical agents having non-overlapping side effects is 4) 5) preferable. O Hal For a combined use of the compound of the present inven 40 3' tion with "other antitumor agents', these two or more kinds of RI RI HN-R NN NN N (7)7 compounds may be contained in the same composition. In -- He addition, a composition containing the compound of the 1. 1. Step 4 present invention and a composition containing “other anti O Hal O O tumor agents' may be simultaneously or sequentially admin 45 R2 R2 istered. When two agents are simultaneously administered, 6 'simultaneous' includes administration of 2 agents, with O R4 administration of one agent and then the other agent in several Re3O minutes after the first administration. By “sequentially” is 50 R3 O HN Y meant a lapse of a given time. For example, administration of RCO O the other agent several minutes to several dozen minutes after R a. RI the administration of the first agent, and administration of the N nN.1n 9 other agent several hours to several days after the administra 1. -- 1. Step 5 tion of the first agent are included, wherein the lapse of time 55 or N NH O1 N. O. is not limited. For example, one agent may be administered R2 R3. k once a day, and the other agent may be administered 2 or 3 8 times a day, or one agent may be administered once a week, O OH and the other agent may be administered once a day and the like. 60 RI R4 When the compound of the present invention is used as an NN N antitumor agent, and when the compound of the present HeStep 6 invention is used in combination with "other antitumor O O agents’, radiotherapy, activation lymphocyte therapy and the R2 R3 like may be further added. 65 Some examples of the Production Methods of the com 10 pound used for embodiment of the present invention are US 8,835,443 B2 36 As the solvent, acetic anhydride, acetyl chloride, phospho continued 5 6 O R RN-R rus oxychloride and the like can be mentioned. R R4 N Step 3 n N N 12 Her Here, Hal is preferably bromine atom or chlorine atom. The 1. Step 7 compound 6 can be obtained by reacting compound 5 with O O a halogenating agent such as phosphorus oxychloride, N-bro R2 R3' mosuccinimide, N-iodosuccinimide and the like, in a solvent 11 10 Such as trifluoromethanesulfonic acid, acetic acid, concen trated sulfuric acid, N,N-dimethylformamide (DMF), water and the like, at room temperature to under heating. Step 4 15 The compound 8 can be obtained by reacting compound 6 with compound 7 in a solvent under heating. R R6 As the solvent, alcohol solvents such as water-containing o NN1 or nonaqueous methanol, ethanol and the like; ether solvents RI R4 such as 1,4-dioxane, tetrahydrofuran (THF) and the like, and NN N the like can be mentioned. Step 5 es O The compound 10 can be obtained by reacting compound R2 R3 8 with compound 9 in a solvent under heating. 25 As the solvent, ether solvents such as diphenylether and the like; acetic anhydride, acetyl chloride and the like can be mentioned. wherein Hal is a halogenatom such as chlorine atom, bromine Step 6 atom and the like, R, R, R and R are the same or 30 different and each is a hydrogen atom or the above-defined The compound 11 can be obtained by introducing a leav “C, alkyl group', R is Rother than a hydrogenatom, R ing group into compound 10 by a conventional method. is a leaving group Such as a halogenatom, p-toluenesulfony For example, compound 11 can be obtained by reacting loxy, methanesulfonyloxy, trifluoromethanesulfonyloxy and compound 10 with methanesulfonyl chloride, p-toluene the like, and other symbols areas defined above. 35 sulfonyl chloride, trifluoromethanesulfonic anhydride and Step 1 the like, in the presence of base Such as trimethylamine hydro The compound 3 can be obtained by reacting compound chloride, triethylamine, pyridine and the like as necessary in 1 with compound 2 in a solvent preferably under a nitro a solvent. gen atmosphere from cooling to room temperature. 40 As the solvent, acetonitrile; ether solvents such as tetrahy As the solvent, ether solvents such as 1,4-dioxane, diethyl drofuran and the like; halogen solvents such as dichlo ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the romethane and the like, and the like can be mentioned. like; hydrocarbon Solvents such as benzene, toluene, Xylene, Step 7 hexane and the like; and the like can be mentioned. 45 The compound I-1-1 can be obtained by reacting com Step 2 pound 11 with compound 12 underheating as necessary in a solvent. The compound 5 can be obtained by reacting compound As the solvent, N,N-dimethylacetamide, chloroform and 3 with compound 4 in a solvent preferably under a nitro the like can be mentioned. gen atmosphere under heating. To improve reaction efficiency, 2.6-lutidine may be added.

Production Method 1-1 RI n NH

OFCFN es NH O R-NH + He + RCIO 2 Step 1 Step 2 NO

NO2 13 14 US 8,835,443 B2 38 -continued

O O O RI RI R NN NN 3' NN HN-R RCO O

O1. N O -- O1. N Hal (7) O1. N NH 9 Step 3 Step 4 Step 5

NO NO NO 15) 16 17 O OH O Rc5 RI R4 RI R4 NN N NN N

O N N O es N O Step 6 R3 R3

NO NO 18 19

Step

O Rc5 RN R4 R R6 N N NN1

O1. N. N. O - I12H - Step 8 R3'

NH2 NH2 20 I-1-2) Step "

O Rc5 RI R4 R NN N NN1

O1. N N O 12H Step 10 R3 4.O N1 INCH, H I-1-3) wherein each symbol is as defined above. US 8,835,443 B2 39 40 Step 1 Step 9 The compound 14 can be obtained by reacting compound The compound 21 can be obtained by reacting compound 1 with compound 13 in the same manner as in Production 20 with methanesulfonyl chloride in a solvent in the pres Method 1, Step 1. ence of base Such as triethylamine, pyridine and the like under Step 2 cooling. The compound 15 can be obtained by reacting compound As the solvent, acetonitrile; ether solvents such as tetrahy 14 with compound 4 in the same manner as in Production drofuran and the like; halogen solvents such as dichlo Method 1, Step 2. romethane and the like, and the like can be mentioned. Step 3 10 Step 10 The compound 16) can be obtained by reacting compound The compound I-1-3 can be obtained by reacting com 15 in the same manner as in Production Method 1, Step 3. pound 21 with compound 12 in the same manner as in Step 4 Production Method 1, Step 7.

Production Method 2 O R3 O HN1 ls O S O RI RI SECEN OR ls NN in 1s 23 NN N ORC6 1. 1. Step 1 1. H Step 2 O N NH O N O O N NH

22 24 R R6 O SH O SRC7 RS-R o NN1 H RINN SN RIYN SN (12 - RI SN NN

O1. N N 1sO Step 3 O1. N N 1sO Step 4 O1. N N 1sO

25 26 I-2

The compound 17 can be obtained by reacting compound 40 wherein R is a hydrogen atom oran C. alkyl group, SR 16 with compound 7 in the same manner as in Production (R’ is lower alkyl such as methyl, ethyl and the like or Method 1, Step 4. benzyl) is a leaving group, and other symbols are as defined Step 5 above. The compound 18 can be obtained by reacting compound Step 1 17 with compound 9 in the same manner as in Production 45 The compound 24 can be obtained by reacting compound Method 1, Step 5. 22 obtained in the same manner as in Production Method 1. Step 6 Step 1 to Step 4 with compound 23. The compound 19 can be obtained by reacting compound Step 2 18 in the same manner as in Production Method 1, Step 6. The compound 25 can be obtained by cyclizing com Step 7 50 pound 24 by a conventional method. For example, com The compound 20 can be obtained by reducing com- pound 25 can be obtained by stirring compound 24 in a pound 19 by a conventional method such as reduction with solvent such as N,N-dimethylformamide and the like in the Zinc or iron in a neutral or alkaline condition; iron and acid; presence of triethylamine at room temperature. tin or tin (II) chloride and concentrated hydrochloric acid; Step 3 alkali sulfide: alkaline hydrosulfite and the like, or hydroge- 55 The compound 26 can be obtained by reacting compound nation under hydrogen atmosphere and the like. 25 with lower alkyl halide or benzyl halide in the presence For example, compound 20 can be obtained by adding of base. acetic acid and Zinc powder to compound 19 under cooling As the base, potassium carbonate, sodium carbonate, to allow to react at room temperature. Alternatively, com- lithium hydride, sodium hydride, potassium hydride and the pound 20 can be obtained by adding palladium-carbon to a 60 like can be mentioned, potassium carbonate is preferable. solution of compound 19 in a mixed solvent of THF and As the lower alkyl halide, methyl iodide, ethyl iodide, methanol under hydrogen atmosphere to allow to react at benzyl iodide and the like can be mentioned, methyl iodide is room temperature. preferable. Step 8 Step 4 The compound I-1-2 can be obtained by reacting com- 65 The compound I-2 can be obtained by reacting com pound 20 with compound 12 in the same manner as in pound 26 with compound 12 in the same manner as in Production Method 1, Step 7. Production Method 1, Step 7. US 8,835,443 B2 42 -continued Production Method 3 R6 O HN1 R's NH n N 21 N1 R-NH + O=C=N-R6 Step 1 - -- ep O NH es N O R2 R3 1. 27 28 10 O O RI NN cl s s wherein R' is R' other than a hydrogen atom, and other RCIO Step 2 1. Step 3 15 symbols are as defined above. O N O Rc2O O Step 1 R6 The compound 28 can be obtained by reacting compound 4) 29 1 with compound 27 in the same manner as in Production O Hal Method 1, Step 1. R! RI HN - RD3 NN nN.1n 31 Step 2 -- 31 The compound 29 can be obtained by reacting compound O1. Hal O1. O Step 4 28 with compound 4 in the same manner as in Production 25 R6 R6 Method 1, Step 2. (30) Step 3 O The compound 30 can be obtained by reacting compound 3 R4 RCO 30 29 in the same manner as in Production Method 1, Step 3. O HN1 R4 Step 4 R R'S RCO O NN N1N (33) The compound 32 can be obtained by reacting compound 1. -- 1. ---Step 5 30 with compound 31 in the same manner as in Production O N NH O N O 35 Method 1, Step 4. R6 k R6 Step 5 32 The compound 34 can be obtained by reacting compound O OH 40 32 with compound 33 in the same manner as in Production RI R3 NN N Method 1, Step 5. 1. HeStep 6 Step 6 O N O The compound 35 can be obtained by reacting compound 45 R6 34 in the same manner as in Production Method 1, Step 6. 34 Step 7 O Rc5 The compound 37 can be obtained by reacting compound - D2 35 with compound 36 in the same manner as in Production R! R3 HN R 50 n N N 36 Method 1, Step 7. 1. HerStep 7 Step 8 O N O The compound I-3-1 can be obtained by stirring com R6 pound 37 in a solvent, in the presence of base at room 55 temperature to under reflux. (35) As the base, potassium carbonate, sodium carbonate, R2 O HN1 lithium hydride, sodium hydride, potassium hydride, Sodium methoxide and the like can be mentioned, potassium carbon RI R3 ate and sodium methoxide are preferable. NN N 60 He As the solvent, alcohol solvents such as methanol, ethanol, 1. Step 8 n-propanol, isopropanol and the like; mixed solvents of these O N N O solvent and amide solvents such as N,N-dimethylformamide, k . N,N-dimethylacetamide and the like, halogen solvents such 65 as dichloromethane, chloroform, carbon tetrachloride, 1,2- 37 dichloroethane and the like or ether solvents such as tetrahy drofuran (THF) and the like, and the like can be mentioned. US 8,835,443 B2 44 -continued Production Method 4-1 o R YN1 R6 O RI R4 5 n N N R!-NH RIYNH RCIO -sults HN-R2 1. 1. — - 2 Step 1 O NH Step 2 1. O R2 Me k 10 36 3 O O wherein each symbol is as defined above. R's Step 1 R YN 1sults N Step 4 15 The compound 3 can be obtained by reacting compound He-Step 3 1. He 36 with carbonyldiimidazole in a solvent in the presence of 1. NH O NH2 tertiary amine Such as triethylamine and the like under nitro gen or argon atmosphere from cooling to room temperature, R2 R2 and then reacting with compound 1. 39 40 As the solvent, N,N-dimethylformamide, chloroform, O dichloromethane, tetrahydrofuran and the like can be men tioned. R's Step 2 N Step 5 25 The compound 39 can be obtained by acylating com 2 pound 3 with compound 38 preferably under a nitrogen O1. N N1 atmosphere by a conventional method. R2 for example, when R is hydrogen, compound 38 can be condensed with compound 3 using acetic anhydride, acetyl 41 30 chloride, pivaloyl chloride, methanesulfonyl chloride and the like, particularly methanesulfonyl chloride in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide and the O like. R4 Step 3 Rc3O 35 The compound 40 can be obtained by reacting compound O 39 in a solvent in the presence of base at room temperature to under heating. R'S RCO O As the solvent, water, ethanol-water, tetrahydrofuran-wa N 9 ter and the like can be mentioned, water is preferable. 1. Step 6 40 As the base, potassium carbonate, sodium carbonate, O t potassium hydroxide, Sodium hydroxide, lithium hydride, Sodium hydride, potassium hydride and the like can be men R2 Me tioned, sodium hydroxide is preferable. 42 Step 4 45 The compound 41 can be obtained by reacting compound 40 with N,N-dimethylformamide dimethylacetal in a N.N- O OH dimethylformamide solvent preferably under a nitrogen atmosphere. RI R4 NN N Step 5 Hess 50 The compound 42 can be obtained by reducing com 1. Step 7 pound 41 by a conventional method. O O For example, compound 42 can be obtained by treating with a reducing agent such as Sodium borohydride, Sodium R2 Me cyanoborohydride and the like in an alcohol solvent such as 43 55 methanol, ethanol, isopropanol, tert-butanol and the like or a mixed solvent thereof under a nitrogen atmosphere. Step 6 c5 5 6 O R R N1 R The compound 43 can be obtained by reacting compound R R4 H 42 with compound 9 in the same manner as in Production n N N 12 60 Method 1, Step 5. Ho Step 7 1. Step 8 The compound 44 can be obtained by reacting compound O O 43 in the same manner as in Production Method 1, Step 6. R2 Me Step 8 65 The compound I-1-4 can be obtained by reacting com 44 pound 44 with compound 12 in the same manner as in Production Method 1, Step 7. US 8,835,443 B2

-continued R2 Production Method 4-2 O HN1 O RI R3 5 NN N RI -sults -- R!-NH YNH RCIO 1. Step 9 O O HN-R2 Step1. 1 1. —Step 2 - O NH R6 Me 10 52) 45 28 O O

n n R N 1sults RI N Step 4 15 1. He-Step 3 1. He O h O NH2 R6 R6 R6 O HN1 46 (47) RI Me O NN an 1 R's N Step 5 es S O 25 2 R2 R3 O1. N N1 I-3-2 R6

48 30 wherein each symbol is as defined above. Step 1 The compound 28 can be obtained by reacting compound O 45 with compound 1 in the same manner as in Production R3 Method 4-1; Step 1. Rc3O 35 Step 2 O The compound 46 can be obtained by reacting compound RN RCO O 28 with compound 38 in the same manner as in Production N (33) --- Method 4-1, Step 2. 1. Step 6 40 Step 3 O t The compound 47 can be obtained by reacting compound R6 Me 46 in the same manner as in Production Method 4-1, Step 3. 49 Step 4 45 The compound 48 can be obtained by reacting compound 47 in the same manner as in Production Method 4-1, Step 4. O OH Step 5 RI R3 The compound 49 can be obtained by reacting compound NN N 50 48 in the same manner as in Production Method 4-1, Step 5. 1. HessStep 7 Step 6 O O The compound 50 can be obtained by reacting compound R6 Me 49 with compound 33 in the same manner as in Production Method 1, Step 5. 50 55 Step 7 The compound 51 can be obtained by reacting compound O Rc5 50 in the same manner as in Production Method 1, Step 6. RI R3 HN-R22 Step 8 n N N 36 60 The compound 52 can be obtained by reacting compound 1. HeStep 8 51 with compound 36 in the same manner as in Production O O Method 1, Step 7. Step 9 R6 Me 65 The compound I-3-2 can be obtained by reacting com 51 pound 52 in the same manner as in Production Method 3. Step 8. US 8,835,443 B2

-continued Production Method 4-3 R2 O HN1 O RCSNN N R3 NH2 RCIO lus He 1. Step 10 HN-R --- (38) 2 Step 1 O h Step 2 O O R6 R6 Me 10 45 53) 61 R6 O O O HN 1 RCS Me HN lus HN Step 4 n Y Hess He 15 N 21 NN 1. Step 3 1. 1. Step 11 O h O NH2 O N O R6 R6 R2 R3 54 55 O 62 R6 O HN1 HN Step 5 RI-RC7 Me Y 2 HN 21 NN 64 O1. N N1 25 1. Step 12 R6 O S O 56) R2 R3 O 63 30 R6 R6 N Step 6 O HN1 2 RI Me O1. N N1 NN 21 NN1 R6 35 57 es S. O O R2 R3 R3 I-3-3 Re3O 40 O wherein R is a halogenatom such as bromine atom, chlorine R& RCO O atom and the like or a hydroxyl group and the other symbols N (33) are as defined above. Her 1. Step 7 45 Step 1 The compound 53 can be obtained by reacting compound O t 45 with carbonyldiimidazole in a solvent in the presence of R6 Me tertiary amine Such as triethylamine and the like under a 58) nitrogen or argon atmosphere from cooling to room tempera O OH 50 ture, and then reacting with ammonia. RCS R3 As the solvent, N,N-dimethylformamide, chloroform, NN N dichloromethane, tetrahydrofuran and the like can be men tioned. O1. O Steptep 8 Step 2 55 The compound 54 can be obtained by reacting compound R6 Me 53 with compound 38 in the same manner as in Production 59 Method 4-1, Step 2. O Rc5 Step 3 HN-R2 The compound 55 can be obtained by reacting compound RCS R3 2 60 n N N 36 54 in the same manner as in Production Method 4-1, Step 3. 1. HerStep 9 Step 4 O O The compound 56 can be obtained by reacting compound 55 in the same manner as in Production Method 4-1, Step 4. R6 Me 65 Step 5 60 The compound 57 can be obtained by introducing a pro tecting group into compound 56 by a conventional method. US 8,835,443 B2 49 50 Step 6 was filtered by suction, washed with ethyl acetate, and dried The compound 58 can be obtained by reacting compound to give 1-cyclopropyl-3-(nitrophenyl)urea 3 (33 g, 99%) as a 57 in the same manner as in Production Method 4-1, Step 5. yellow solid. Step 7 The compound 59 can be obtained by reacting compound Step 2 Synthesis of 1-cyclopropyl-3-(3-nitrophenyl) 58 with compound 33 in the same manner as in Production pyrimidine-2,4,6-trione Method 1, Step 5. Step 8 The compound 60 can be obtained by reacting compound 59 in the same manner as in Production Method 1, Step 6. Step 9 NH The compound 61 can be obtained by reacting compound 1. O 60 with compound 36 in the same manner as in Production O NH Ac2O Method 1, Step 7. 15 -- HO He Step 10 The compound 62 can be obtained by reacting compound 61 in the same manner as in Production Method 3, Step 8. HO O Step 11 The compound 63 can be obtained by deprotecting com O pound 62 by a conventional method. Step 12 3 4 The compound I-3-3 can be obtained by reacting com pound 63 with compound 64 by a conventional method. 25 As O For example, when R is a hydroxyl group, compound 63 is reacted with a condensing agent Such as diethylazodi carboxylate, diisopropyl azodicarboxylate and the like and triphenylphosphine in a solvent such as N,N-dimethylforma mide, acetonitrile, tetrahydrofuran and the like under a nitro 30 gen or argon atmosphere according to Mitsunobu reaction. Examples 35 Example 1-1 Synthesis of N-3-5-(4-bromo-2-fluoro-pheny To 1-cyclopropyl-3-(nitrophenyl)urea 3 (33 g) obtained in lamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7, Step 1 were added acetic anhydride (99 ml) and malonic acid 8-tetrahydro-2H-pyrido2,3-dipyrimidin-1-ylphe 40 4 (17g), and the mixture was stirred under heating at 110°C. nyl)-methanesulfonamide for 4 hrs. The reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue, and Step 1 Synthesis of the mixture was stirred at room temperature for 10 min. 1-cyclopropyl-3-(nitrophenyl)urea Chloroform insoluble material was filtered by suction and 45 dried to give 1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2, 4,6-trione 5 (28 g. 65%) as a brown solid. Step 3 Synthesis of 6-chloro-3-cyclopropyl-1-(3- nitrophenyl)-1H-pyrimidine-2,4-dione THF 50

O 55 A 1. No. 1. O N O POCl. --- O HO 60 3

To a solution of cyclopropylamine 1 (9 g) in tetrahydrofu ran (250 ml) was added 3-nitrophenylisocyanate 2 (25 g) by 65 Small portions, and the mixture was stirred at room tempera ture for 1 hr. The solid precipitated from the reaction mixture US 8,835,443 B2 51 52 -continued -continued O HN1

N es NH es O () -H ) ( )

O N.1O -- C. 2 O O O O O 6 7 15 8

To 1-cyclopropyl-3-(3-nitrophenyl)pyrimidine-2,4,6-tri To the mixture (30 g) of 6-chloro-3-cyclopropyl-1-(3-ni one 5 (28 g) obtained in Step 2 was added water (3 ml). trophenyl)-1H-pyrimidine-2,4-dione 6 and 4-chloro-3-cyclo phosphorus oxychloride (72 ml) was added dropwise by propyl-1-(3-nitrophenyl)-1H-pyrimidine-2,6-dione 7 small portions with stirring, and the mixture was stirred with obtained in Step 3 were added ethanol (300 ml) and a 40% heating at 110° C. for 1 hr. The reaction mixture was poured solution (150 ml) of methylamine in methanol, and the mix into ice water by small portions, and the precipitated solid was ture was stirred with heating at 80° C. for 4.5 hrs, ice-cooled filtered by suction. The filtrate was dissolved in chloroform and the precipitated solid was filtered by suction. The residue (300 ml), washed with water (30 ml) and brine (30 ml), and 25 was washed with water (1 liter) and dried to give 3-cyclopro the organic layer was dried over anhydrous magnesium Sul pyl-6-methylamino-1-(3-nitrophenyl)-1H-pyrimidine-2,4- fate, and concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:ac dione 8 (16 g. 55%) as a white solid. etone=9:1) to give a 2:1 mixture (10g, 34%) of 6-chloro-3- cyclopropyl-1-(3-nitrophenyl)-1H-pyrimidine-2,4-dione 6 Step 5 Synthesis of 3-cyclopropyl-5-hydroxy-8-me and 4-chloro-3-cyclopropyl-1-(3-nitrophenyl)-1H-pyrimi thyl-1-(3-nitrophenyl)-1H,8H-pyrido2,3-dipyrimi dine-2,6-dione 7 as a white solid. dine-2,4,7-trione

Step 4 Synthesis of 3-cyclopropyl-6-methylamino-1- 35 (3-nitrophenyl)-1H-pyrimidine-2,4-dione

40 ls NH --

45 2 O

1 O 8 50 O 6 C nN.1N 55 es O MeNH O Ho MeOHAEtOH 60 1\o Ph2O -- 1. O O O

O 65 US 8,835,443 B2 53 54 -continued -continued O OH O\/ O O o1 5 1. N O

10 O

O

10 15

To 3-cyclopropyl-6-methylamino-1-(3-nitrophenyl)-1H pyrimidine-2,4-dione 8 (16 g) obtained in Step 4 were added diphenyl ether (160 ml) and diethyl malonate 9 (40 ml), and To 3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)- the mixture was stirred under heating at 230° C. for 11 hrs 1H.8H-pyrido2,3-dipyrimidine-2,4,7-trione 10 (18 g) while evaporating the resulting ethanol. The reaction mixture obtained in Step 5 were added acetonitrile (180 ml), tosyl WaS purified by column chromatography chloride 11 (11 g) and triethylamine (8 ml), and the mixture (chloroform->chloroform:acetone=9:1) to give 3-cyclopro pyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H.8H-pyrido 25 was stirred with heating under reflux at 110° C. for 1 hr. The 2,3-dipyrimidine-2,4,7-trione 10 (10 g, 51%) as a brown reaction mixture was concentrated under reduced pressure. foamy oil. Water (100 ml) was added to the residue and the mixture was extracted with chloroform (800 ml). The organic layer was washed with brine (50 ml), dried over anhydrous magnesium Step 6 Synthesis of toluene-4-sulfonic acid 3-cyclo 30 propyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2, Sulfate, and concentrated under reduced pressure. The residue 3,4,7,8-hexahydropyrido2,3-dipyrimidin-5-yl ester was recrystallized from chloroform:diethyl ether-1:5 to give toluene-4-sulfonic acid 3-cyclopropyl-8-methyl-1-(3-nitro phenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido2,3-d 35 pyrimidin-5-yl ester 12 (21 g, 82%) as a white solid. O OH

40 Step 7 Synthesis of toluene-4-sulfonic acid 1-(3- aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo 1,2,3,4,7,8-hexahydro-pyrido2,3-dipyrimidin-5-yl ester 45

10 50

55 SnCl2-2H2O He THF

60 -S TEA CHCN

65 11 US 8,835,443 B2 55 56 -continued -continued V A” 1. S

O N O 10

O

NH2 N1 \N 15 H. O. 13 15

To a suspension of toluene-4-Sulfonic acid 3-cyclopropyl To toluene-4-Sulfonic acid 1-(3-aminophenyl)-3-cyclopro 8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8- pyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido2. hexahydro-pyrido 2,3-dipyrimidin-5-yl ester 12 (21 g) 3-dipyrimidin-5-yl ester 13 (5 g) obtained in Step 7 was obtained in Step 6 in tetrahydrofuran was added stannous added pyridine (40 ml), a solution of methanesulfonyl chlo chloride dihydrate (45 g), and the mixture was stirred at room ride 14 (0.9 ml) in chloroform (10 ml) was added dropwise temperature for 4 hrs. The reaction mixture was alkalified with stirring under ice-cooling, and the mixture was stirred with Saturated aqueous Sodium hydrogen carbonate, an 25 for 3 hrs in an ice bath. The reaction mixture was concentrated insoluble inorganic product was filtered off by Suction using under reduced pressure, 2N hydrochloric acid was added and celite as a filtration aides, and the filtrate was extracted with the mixture was extracted with chloroform. The organic layer ethyl acetate. The organic layer was washed with brine, dried was washed with brine, dried over anhydrous magnesium over anhydrous magnesium sulfate and concentrated under sulfate and concentrated under reduced pressure. The result reduced pressure. The residue was purified by column chro 30 ant solid was suspended in diethyl ether:hexane=1:1, and matography (chloroform:acetone-9:1) to give toluene-4-Sul filtered by suction to give toluene-4-sulfonic acid 3-cyclopro fonic acid 1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4, pyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-tri 7-trioxo-1,2,3,4,7,8-hexahydro-pyrido2,3-dipyrimidin-5-yl oxo-1,2,3,4,7,8-hexahydro-pyrido2,3-dipyrimidin-5-yl ester 13 (15g, 74%) as a white solid. 35 ester (5.5 g, 95%) as a white solid. Step 8 Synthesis of toluene-4-sulfonic acid 3-cyclo propyl-1-(3-methanesulfonylaminophenyl)-8-me Step 9 Synthesis of N-3-5-(4-bromo-2-fluoro-phe thyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido 2,3- nylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4, dpyrimidin-5-yl ester 7,8-tetrahydro-2H-pyrido2,3-dipyrimidin-1-ylphe 40 nyl)-methanesulfonamide

45

50

55 NH2 1 in 13 15 Br 60

O Ho Pyridine HN S CHCI c11 WN 3 F O 65 16 14 US 8,835,443 B2 57 58 -continued TABLE 1-1-continued Br Ex. No. structural formula

O HN 5 1-2 A. F C N N 1s. O 10 O HN N N O es O N1 \n 15 H O CH3 17

To toluene-4-sulfonic acid 3-cyclopropyl-1-(3-methane sulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8- 1-3 hexahydropyrido2,3-dipyrimidin-5-yl ester 15 (3.5 g) obtained in Step 8 was added 2-fluoro-4-bromoaniline 16 (23 g), and the mixture was stirred under heating at 135° C. for 3 hrs. The reaction mixture was purified by column chromatog- 25 raphy (chloroform:acetone=9:1) to give N-3-5-(4-bromo O HN 2-fluoro-phenylamino)-3-cyclopropyl-8-methyl-2,4,7-tri oxo-3,4,7,8-tetrahydro-2H-pyrido2,3-dipyrimidin-1-yl) N N phenyl-methanesulfonamide 17 (3.0 g, 83%) as a white solid. 30 es O MS ESI m/e: 590,592 (M+H), 588, 590 (M-H). 'H-NMR (DMSO-d 300 MHz) & 0.71-0.79 (m, 2H), CH3 0.99-1.08 (m, 2H), 2.66 (s, 1H), 3.02 (s, 1H), 5.36 (s, 1H), 7.13 (d. J=9.0 Hz, 1H), 7.24-7.30 (m, 2H), 743-7.54 (m,3H), 35 7.74 (d. J=9.0 Hz, 1H), 10.00 (brs, 1H), 10.53 (brs, 1H). 1-4

Examples 1-2 to 1-343 40 O HN

In the same manner as in Example 1-1, the compounds of C Examples 1-2 to 1-343 were obtained. The structural formu N N las thereofare shown in Tables 1-1 to 1-58 with Example 1-1. 45 es O TABLE 1-1 CH3

Ex. No. structural formula 50 1-1 Br 1-5

O HN O HN C F As N N 55 N N es N O 60 CH es O O | -CH3 CH 1SS

65 US 8,835,443 B2 59 60 TABLE 1-1-continued TABLE 1-2-continued

Ex. No. structural formula Ex. No. structural formula 1-6 CH3

1-10 O HN

N N 10 N N C 1s, O CH3 15

1-11 Br TABLE 1-2

Ex. No. structural formula 1-7 CH N YCH, 25

O HN

30 N N es O 1-12 CH3 35

1-8 F 40

O HN

N N 45 es O CH 50 TABLE 1-3

Ex. No. structural formula 1-9 O NCH, 55 1-13 C O HN

O HN N N es O 60 NN N CH3 es N O

65 CH3 CH3 US 8,835,443 B2 61 62 TABLE 1-3-continued TABLE 1-3-continued

Ex. No. structural formula Ex. No. structural formula 1-18 C 1-14

10

15

CH3

1-15 TABLE 1-4

Ex. No. structural formula

1-19 C 25

O HN

30 N N es N N

35 1-16 CH

1-2O C

40

O HN

N N 45

50

1-17 C 1-21 CH 55 C

60

65 US 8,835,443 B2 64 TABLE 1-4-continued TABLE 1-5

Ex. No. structural formula Ex. No. structural formula 1-2S CH3 5 1-22 CH3

O HN O HN 10 CH3 N N N N es O es O CH3 15 CH3

20 1-26 C C

O HN

1-23 25 N N es O 30 CH O HN

N N

O1. N O 35 1-27 CH N

40 O HN

N N

45 1s. O CH

1-24 CH 50 O 1-28 r CH3 N CH O HN 55 O n-1 "3 N N O HN es O CH3 60

65 US 8,835,443 B2 65 66 TABLE 1-5-continued TABLE 1-6-continued

Ex. No. structural formula Ex. No. structural formula 1-29 1-33 F

O HN

N N 10 O HN

es N N N hi, 15 es O CH3

1-30

1-34 CH3

O HN 25 O HN

N N C N N

30 es O CH

35

C TABLE 1-6

structural formula 40 O HN CH3 HC NN N

O HN 45 es O N N CH es N O 50 hi, 1-36 CH3 H3C CH3

55 1-32 O HN

N N O HN

N N 1s, O CH3

65 US 8,835,443 B2 68 TABLE 1-7 TABLE 1-7-continued

Ex. Ex. No. structural formula 5 No. structural formula 1-37 O 1-40 CH OH 10 O HN CH N N O HN O1. N O 15 N N CH3 es N O 2O hi,

25

1-38 CH

30 1-41 C

O HN O HN N N 35 N N es O CH 40

45

1-39 CH3 50 1-42 C

CH3

55 O HN

N N es O 60 CH3

C 65 US 8,835,443 B2 69 70 TABLE 1-8 TABLE 1-8-continued

Ex. No. structural formula Ex. No. structural formula 1-47 C 1-43 C

O HN

CH 10 N N 1s. O

CH 15 1-48

1-44 C

O HN

N N 25 1s, O CH 30

TABLE 1-9

Ex. No. structural formula 35 1-49 CH 1-45 C

40 HCI O HN

N N es O 45 CH3

50 1-SO

1-46 NH2

55 O HN

N N HCI

es O 60 CH3

65 US 8,835,443 B2 71 72 TABLE 1-9-continued TABLE 1-10

Ex. No. structural formula Ex. No. structural formula

1-55 1-51 CH3

CH3

10

N CH 15 hi, O

1-52 C

HN 25 HN N N

30 N

35 1-53 C 1-57 NN

40

45

50 1-54 C

1-58 C

55

60

65 CH3 US 8,835,443 B2 73 74 TABLE 1-10-continued TABLE 1-11-continued

Ex. No. structural formula Ex. No. structural formula 1-62 CH3 1-59 O) CH3 O HN 10 N N N N 1s, N O 1. N O CH3 15

CH

1-63 21 C

N O HN N 25 N N es O 30 CH3 1-60 C

O HN 35 1-64 H3C N n V -(N es NH S 40 S. O HN

N N 45 es O TABLE 1-11 CH

Ex. No. structural formula 50 1-61 CH CH CH

55 HCI O HN

N N

60

65 US 8,835,443 B2 75 76 TABLE 1-11-continued TABLE 1-12-continued

Ex. No. structural formula Ex. No. structural formula 1-69 1-66 CH3

10

15

1-70 C

TABLE 1-12 25 Ex. No. structural formula

1-67 C

30

O HN

N N CH 35 ---, 1-71 CH

NCH 40

45

50

1-68 C 1-72 C

55 O HN CH3 N N

1s, O CH3 60 CH3

65 US 8,835,443 B2

TABLE 1-13 TABLE 1-13-continued

Ex. No. structural formula Ex. No. structural formula 1-73 HC CH 5 1-76 C N YCH, CH3 O HN O HN 10 N N

1. O N N O O N N O 15 CH3 CH

CH3 2O

25

1-74

N 1-77 C YCH, 30

s O HN O HN S le N N N N 35 1. 1. O N N O O N O CH CH 3 40 2 f S

45

1-75 Cl 50 CH3 1-78 C

O O HN O HN N N 55

O11 N N O - 1.rs O N N O CH 60 CH

O US 8,835,443 B2 79 80 TABLE 1-14 TABLE 1-14-continued

Ex. No. structural formula Ex. No. structural formula 1-83 C 1-79 C

O HN O HN 10 H3 1)N-1N N N N 1. N O es O CH CH 15

1-84 C F

O HN 1-80 C N N 25 es N O N N CH3 es O 30 CH

35 TABLE 1-15

Ex. No. structural formula 1-81 C 1-85 C

40 CH, O HN O HN --> N HC NN N es O 45 1. N O CH HC CH

50

1-82 C 1-86 C

55 O HN O HN H3CN-1a N H3C NN N

es O 60 1. N O CH3 CH3

65 US 8,835,443 B2 81 82 TABLE 1-15-continued TABLE 1-16

Ex. No. structural formula Ex. No. structural formula

1-87 C 1-91 C

O HN

HC 10 CH es O

CH 15

CH 1-92 Br

1-88 CH N YCH, 25 O HN

N N es O 30 CH 1-93 35

1-89 Br

40 O HN

N N es O 45 CH3

50 1-94 C

1-90 C

55 O HN

60

65 C US 8,835,443 B2 83 84 TABLE 1-16-continued TABLE 1-17-continued

Ex. No. structural formula Ex. No. structural formula 1-95 Br 1-99 CH

O HN CH

HC 10 3 NN N O HN es O NN N H3C CH3 15 es N H3C CH3

1-96 Br

O HN 1-1OO C

25 He1N N HN es O Au N N CH3 30 N CH

35 TABLE 1-17

Ex. No. structural formula 1-101 C 1-97 CH 40 CH

O HN

45 HC 1N N N es N N O l, 50

1-102 C

1-98 C 55

O HN

N N 60

65 US 8,835,443 B2 85 86 TABLE 1-18 TABLE 1-18-continued

Ex. No. structural formula Ex. No. structural formula 1-107 5 1-103 C

As 10 N N N 1s,

O N N O CH3 15 CH3 H3C

1-108

2O 1-104 C O HN F F O HN N N 25 N N F O N

O1. N O HC CH -O CH3 30 HC

35 TABLE 1-19 1-105 Ex. No. structural formula

1-109 O HN HC 40

Dr. CH3 1N O HN O N N O H3C N N

HC CH 45 O1. N HC CH

1-106 CH3 50 N 1-110 CH3 YCH, CH3 O HN 55

As N N O HN 1. He1N N O N O 60 1. HC CH O N N

65 US 8,835,443 B2 87 TABLE 1-19-continued TABLE 1-2O

Ex. No. structural formula Ex. No. structural formula

1-115 C 1-111 Br

O HN O HN 10 He1N N H3 1n N es O es O 15 F CH HC CH

1-116 Br 1-112 CH

N YCH, O HN

O HN 25 c.1N N N A. CH3 N N es O F CH es O 30 CH3

1-117 CH 35 1-113 Br N YCH,

O HN O HN 40 N N H3 1N N es N O es O 45 F CH F CH3

50 1-114 CH 1-118 CH3 N N YCH, YCH, 55

60

65 US 8,835,443 B2 89 90 TABLE 1-20-continued TABLE 1-21-continued

Ex. No. structural formula Ex. No. structural formula

1-119 CH3 1-122 CH N YCH, N YCH, 10 O HN O HN

N N HC 1. N 1. N O 15 es N O F CH3 CH F H3C

1-123 Br

25 O HN c.1N N N

30 O N O 1-120 Br CH H3C

O HN 35

N N 1-124 CI

1. N O 40 O HN F CH F re-1N N N

45 O N O CH3 TABLE 1-21 HC

Ex. No. structural formula 50

1-121 Cl 1-125 C

55 O HN

N N

O N O 60 es N N O F CH3 F

65 US 8,835,443 B2

TABLE 1-21-continued TABLE 1-22-continued

Ex. No. structural formula Ex. No. structural formula

5 1-129 O 1-126 CH NCH, N YCH, O HN

O HN 10 As N N N N es O

O1. N O 15 CH3 CH3

2O 1-130 CH

N CH3 YCH,

O HN 25 TABLE 1-22 As N N Ex. No. structural formula 1. O N N O 1-127 CH3 30 CH3 N YCH, 1-131 Br O HN 35

N N CH, O HN 1. N O 40 ls N N

CH O1. N O CH3 H3C 45 21 N N

1-132 CH 1-128 r CH 50 N NCH, N CH N1 3 O HN

O HN 55 As

es N O 60 CH3

65 F US 8,835,443 B2 93 94 TABLE 1-23 TABLE 1-23-continued

Ex. No. structural formula Ex. No. structural formula

1-133 CH3 1-137 CH

CH O n-1 "3 O HN HCI 10 N N es O 15 CH

1-134

25

30 1-138 CH3 /

35 O HN 1-135 NH N N 1. O O HN HCI 40 CH N N

es N O 45

TABLE 1-24

Ex. No. structural formula 50 1-139 CH 1-136 N CH YCH, 55 HCI

60

65 US 8,835,443 B2 95 96 TABLE 1-24-continued TABLE 1-24-continued

Ex. No. structural formula Ex. No. structural formula 1-140 CH 5 N YCH, 1-144

O HN HCI 10 O HN HC2 N1\ N As 1. N N O N N O 1. 15 O N N O CH3 CH3

1-141 CH 2O M N TABLE 1-25

O HN 25 Ex. No. structural formula A. N 1-145

30

1-142 CH3 35 Oall N N O

N CH YCH, 3

40 O HN A. CH3 N N

O1. N N O 45

50

1-143 CH3 1-146

55

N N 60 O N N O

65 US 8,835,443 B2 97 98 TABLE 1-25-continued TABLE 1-26

Ex. No. structural formula Ex. No. structural formula 1-147 CH3 1-151 Br CH3

CH3 As 10 All all all 15

1-148 CH3 1-152 N YCH,

F 25 O HN C As N F F f N 30 N O CH CH

35 1-153 Br 1-149 CH3 O HN 40 N N es O 45 CH3

CH

50 1-154 OYCH, 1-1SO

55 O HN v- N es N 60

65 US 8,835,443 B2 99 100 TABLE 1-26-continued TABLE 1-27-continued

Ex. No. structural formula Ex. No. structural formula 1-15S CH3

1-159 Br

O HN HCI 10 N N es O 15 HC1 O CH3

1-156 1-160 CH3 X/ 25 O HN N

SN N

30 es O CH3

35 TABLE 1-27 1-161 CH M Ex. No. structural formula N N 1-157 Br 40 7. O HN

O HN CH3

YN N 45 es CH 50

1-162 1-158 55

N N 1 1. HC 60 O N N O

65 US 8,835,443 B2 101 102 TABLE 1-28 TABLE 1-28-continued

Ex. No. structural formula Ex. No. structural formula

1-163 C 1-167

O HN A. C 10 N N es O 15 CH

1-164 Br

O HN 25 He1N N F es O 30 CH3

1-168 CH3

35 1-165 H N

O HN 40

45

TABLE 1 29 50 1-166 Ex. No. structural formula

1-169

55 1N1 N

60 N O

65 US 8,835,443 B2 103 104 TABLE 1-29-conti nued TABLE 1-29-continued

Ex. No. structural formula Ex. No. structural formula 5 1-174 F 1-170

P WNCH, O HN CH 10 As N N F es N O

15 CH

TABLE 1-30 1-171 C Ex. No. structural formula

1-175 25 YCH,

O HN A. F 30 N N

CH3 es O CH 35

1-172 OH 1-176 Br

40 O HN O HN N N A. C N N 45 1s, 1s, O CH CH3

50

1-173 1-177 Br

55 O HN O HN

YN N N N CH es 60 CH3

65 US 8,835,443 B2 105 106 TABLE 1-30-continued TABLE 31-continued

Ex. No. structural formula Ex. No. structural formula

5 1-178 O 1-182 CH CH3 o1 CH

O HN 10

es N O 15 CH3 CH3

20 1-179 o HN1 N1 O NCH, 1-183 Br

NN N 25 O HN

1s. O N N CH3 30 es CH

1-18O CH N1 35 O O HN HC1

YN N 40 1-184 es O CH 45

CH3

50 TABLE 31

Ex. No. structural formula 1-185 Br

1-181 55 O HN O HN

YN N N N 1. 60 es O N N O CH CH

65 US 8,835,443 B2 107 108 TABLE 31-continued TABLE 1-32-continued

Ex. No. structural formula Ex. No. structural formula - 1-186 Br 1-189 Br

O HN O HN

As F 10 O n N N 1. N CH

O1. N O O N O CH 15 O CH

O 2O 1-190 Br H3C 1

O HN TABLE 1-32 25 As N N Ex. No. structural formula 1. O N N O 1-187 O CH N 30 CH CH As O HN o1 CH N N 35 1. 1-191 Br O N O

CH O HN 40 As F 1. O 45 CH

o1 CH

50 1-188 Br 1-192 CH N YCH, O HN As F 55 O HN N N As 1. N N F O N O 1. CH3 60 O N O CH3

OH 65 US 8,835,443 B2 109 110 TABLE 1-33 TABLE 1-33-continued

Ex. No. structural formula Ex. No. structural formula

1-193 Br 1-197

O HN N N 10 es N O

15 O CH 1-194 Br

N UCON 25 es N O

CH3 30 1-198 Br

O HN 35 N N 1-195 es 40 CH Br

45

TABLE 1-34

Ex. No. structural formula 50 1-199 Br

1-196 Br

55

60

65 US 8,835,443 B2 111 112 TABLE 1-34-continued TABLE 1-34-continued

Ex. No. structural formula Ex. No. structural formula

1-200 Br 1-204 CH3

CH3 O HN 10 H3C NN N C es O CH3 15

Br

O HN TABLE 1-35

A. F 25 N N Ex. No. structural formula

es O 1-2OS CH

CH3 30 CH

O HN O A. F 35 N N 1-2O2 Br 1s. O

O HN 40 CH3 A. C N N es N O H 45

Br 50 1-2O3 CH3 O HN \ CH

55 YN N As CH 1s, N N CH 60

65 US 8,835,443 B2 113 114 TABLE 1-35-continued TABLE 1-36

Ex. No. structural formula Ex. No. structural formula 1-211 5

O HN O -C 10 As N Br es N O f l, 15 CH3

1-212 Br 2 H O HN

O HN 25 N N N F es N O hi, fO N N O 30 O C H3

35 1-213 Br

1-209 O HN O HN 40 N o4.

O N O f N N O 45 CH3 CH

OH

50 1-214 Br

1-210 55 f 60

65 US 8,835,443 B2 115 116 TABLE 1-36-continued TABLE 1-37-continued

Ex. No. structural formula Ex. No. structural formula 1-218 Br 1-215 Br

O HN O HN A. F A. F 10 N N N N es O 1. N O CH3 15 CH t 1N1,No.N C 1-219

O HN A. F 25 N N

1-216 Br es O CH3 30 O O HN A. F N N N

1. N O 35 su 1-22O Br CH

O HN 40 N A. F N N es O 45 TABLE 1-37 CH

Ex. No. structural formula O 50 re 1-217 CH3 N 1-221 CH3 55 O HN A. F N N

es N O 60 CH3

65 US 8,835,443 B2 117 118 TABLE 1-37-continued TABLE 1-38-continued

Ex. No. structural formula Ex. No. structural formula 1-222 2CH 5 1-225 Br

O HN 10 As N F

15 CH CH3

2O OSEO CH3 TABLE 1-38

Ex. No. structural formula 25

1-226 Br 1-223 Br C O HN As F N N F

1. 35 OJC N N O O N N O CH3 CH

O \, 40 1. HC1 \O OFSFO HC1 NYCH, 45

1-224 Br 50 1-227 Br

O HN O HN F N N 55 F 1. N N O N N O 1. O N N O CH3 60 CH3 O HC \, CH 3 N1 \ O N1 3 CH 65 CH3 US 8,835,443 B2 119 120 TABLE 1-38-continued TABLE 1-39-continued

Ex. No. structural formula Ex. No. structural formula

1-228 Br 1-231

O HN A. F 10 N N es N O 15 CH

N11 inWYCH, | 6 CH 1-232 Br

TABLE 1.-39 25 Ex. No. structural formula

1-229 CH3

CH3 30

O HN

YN N 35 es O 1-233 CH 40

45

50

1-234 1-230 CH

55 O HN

60

65 US 8,835,443 B2 121 122 TABLE 1-40 TABLE 1-40-continued

Ex. No. structural formula Ex. No. structural formula 1-235 1-239 CH3

OH A. S. 10 es N O O HN CH As N N F rt 15 O 1N1 NS-CH 1. N O CH 1-236

25

CH3 30 O 1--1a 1-240

35 1-237 O HN A. F N N 40 1. N O CH

45

TABLE 1-41 50 Ex. No. structural formula 1-238 OH 1-241

55 O HN A. F N N es O 60 CH

65 US 8,835,443 B2 123 124 TABLE 1-41-continued TABLE 1-41-continued

Ex. No. structural formula Ex. No. structural formula

1-242 1-246 CH

O HN 10

15

1-243 Br

TABLE 1-42 O HN 25 Ex. No. structural formula

1-247

30 OH

O HN OH F 35 1-244 rs f O CH3 40

45

50 1-245 Br 1-248

OH O HN 55 O

60 fO N O CH

65 US 8,835,443 B2 125 126 TABLE 1-42-continued TABLE 1-43

Ex. No. structural formula Ex. No. structural formula Br 1-249

O HN A. F 10 N N es O CH 15

O H3C 1 n-r CH

1-2SO 1-254 CH3 2^

25 O HN A. F N N 30 es O CH

35

1-255 Br

40 O HN A. F N N

45 es O CH3 rsu 50 O 1-2S2 \ F S F O y 55 F O HN A. OH N N 60 es O CH3

65 US 8,835,443 B2 127 128 TABLE 1-43-continued TABLE 1-44-continued

Ex. No. structural formula Ex. No. structural formula

5 1-260 1-257 I 2

O HN O HN As 10 As

O N N O N 15 CH CH O O O \/ HC1 NN N1 WYCH, H O 2O 1-261 Br

25 O HN F

1-2S8 CH3 30 t O N O CH3

O HN NN N 35 1. 1-262 Br O N O CH O HN 40 As

45 TABLE 1-44 CH o

Ex. No. structural formula 1 S CH3

1-259 2CH 50 O 2 1-263 Br

O HN

As F 55 O HN N N As F 1. N N O N O 1. O N N O CH 60 CH3 O O

O 65 US 8,835,443 B2 129 130 TABLE 1-44-continued TABLE 1-45-continued

Ex. No. structural formula Ex. No. structural formula 1-267 1-264 Br

10

15

1-268

TABLE 1-45

Ex. No. structural formula 25

1-265

30

1-269 35

40

45

50 1-270 1-266 Br

55

N 60

1 N 65 US 8,835,443 B2 131 132 TABLE 1-46

Ex. No. structural formula

1-271 Br

O HN

es O CH3 O

N1,N1)-ch,H )

1-272 Br

O HN A. F es O CH3 O

Y CH 3

irrCH3

1-273 F

O HN

SN N es O CH

1-274 I

O HN A. F N N 1s, O CH3 O\.1 N11S \ CH3 US 8,835,443 B2 133 134 TABLE 1-46-continued

Ex. No. structural formula

1-275 CH

N N es O CH3 \-CH N11. \,

1-276 C Br fes N CH3 O NRul -n-r NH O

45 TABLE 1-47 TABLE 1-47-continued

Ex. No. structural formula Ex. No. structural formula 50 1-277 Br 1-278 Br

O HN

F As N N 55 As N N F

O N O es O 60 CH CH Nullsth O O O HC1 NH 65 US 8,835,443 B2 135 136 TABLE 1-47-continued TABLE 1-48

Ex. No. structural formula Ex. No. structural formula

1-279 Br 1-283

10

15

1-284 1-28O Br

O HN N N 25 es N O hi, 30 O\/ O N1)x1 F F 35

1-281 1-285

40

45

50 1-282 Br 1-286

55

60

65 US 8,835,443 B2 137 138 TABLE 1-48-continued TABLE 1-49-continued

Ex. No. structural formula Ex. No. structural formula 5 1-287 1-290

O HN O B 10 N F

N O 15 CH O

N H CH

25

1-291

1-288 r

30 O O B As HN F N 35 es N O CH3

40 NH2 o? s1 O

45 TABLE 1-49

Ex. No. structural formula 50 1-292 Br 1-289 CH

O HN 55

es O 60 CH3 O \, 1Nchi, 1. \,O 65 US 8,835,443 B2 139 140 TABLE 1-49-continued TABLE 1-49-continued

Ex. No. structural formula Ex. No. structural formula 1-294 Br 5 1-293 F

O HN A. F 10 es O CH3 15 i? YCH,

TABLE 1-50

Ex. No. structural formula

1-295 Br

O HN As F

O CH

CH s1 N1 3 o?2 O

1-296 CH

O HN

es O CH3 O

H-- US 8,835,443 B2 141 142 TABLE 1-50-continued

Ex. No. structural formula

1-297 I

O

H s 1-298 a CH

O HN

N N es O CH3 1N1C3 N1H W)

1-299 Br

O HN A. F N N es O CH O O

les-- N ~us N H H

1-3OO CH3 CH CH US 8,835,443 B2 143 144 TABLE 1-51 TABLE 1-51-continued

Ex. No. structural formula Ex. No. structural formula 1-301 F 5 F

F 1-304

O HN 10 O HN F N N 1. N N O N N O 1. 15 O N N CH O O CH \/ HC1 NN 1. H 2O N1 || H

25

1-3O2 I 1-30S 30

N N

O1. N O 35 O11 N CH o CH 1NS N | CH, 40 N --> OH

45

1-306 50

1-303 Br O HN As F / \ O C 55 1. N

CH CH3 O 60 N --> N1

N --- 65 US 8,835,443 B2 145 146 TABLE 1-52

Ex. No. structural formula

1-307 Br

A. N F

D.C.N N O CHl NH N1H Nchi,

Br

O HN A. F N N es O CH3 O

NH ls,1Ne,

1-309 Br

O HN A. F N N es O CH O O \/ CH N1,N1 3 H CH 1-310 e

O HN A. F N N es O CH US 8,835,443 B2 147 148 TABLE 1-52-continued

Ex. No. structural formula

1-311 I

O HN A. F N N 1s N O CH O

N1 WN1)-chi,O

1-312 Br

O HN

N CH3 O O o11-ins- - -

TABLE 1-53

Ex. No. structural formula

fO N N O CH3 HCI S HN1)-1NH US 8,835,443 B2 149 150 TABLE 1-53-continued

Ex. No. structural formula

1-314 Br

O HN

As N N -s-s

1-315 Br

1-316

1-317 US 8,835,443 B2 151 152 TABLE 1-53-continued

Ex. No. structural formula 1-318 C Br

f N CH

Ol s1 O MV O O

TABLE 1-54 TABLE 1-54-continued

Ex. No. structural formula 25 Ex. No. structural formula 1-319 I 1-321 e

O HN 30 O HN A. F N N 35 1s N O CH O

40 S CH

45

50 1-320 CH 1-322 I

O HN 55 Au or C

N N O 60 fr C H3 O O N11 ||in YCH, 65 H US 8,835,443 B2 153 154 TABLE 1-55 TABLE 1-55-continued

Ex. No. structural formula Ex. No. structural formula 1-323 1-327 Br

O HN C 10

f O es N O CH3 15 O CH CH O N --- n H CH HC1 O NN ls N H H 1-324 Br 1-328

O HN O HN r F 25 All O CH3 30 es N O O CH3 N ls N1-ch 3 H CH3 35

1-32S Br TABLE 1-56

structural formula O HN 40 Ex. No. 1-329 F

f O 45 3 O ls CH3 N1 50 C H 1-326

1-330 C

60

65 CH3 CH3 US 8,835,443 B2 155 156 TABLE 1-56-continued TABLE 1-57-continued

Ex. No. structural formula Ex. No. structural formula 5 1-331 CH 1-334 N YCH, 10 O HN v- N N

O1. N O 15

CH

2O

25

1-335 Br

1-332 O 30 O HN A. F O N N CH O HN 35 1s. O CH3 N N O | 1. N O 40 N11. W N H O CH 2

45

TABLE 1-57

Ex. No. structural formula 50 1-336 1-333 F Br

O HN 55

60

O 65 US 8,835,443 B2 157 158 TABLE 1-57-continued TABLE 1-58-continued

Ex. No. structural formula Ex. No. structural formula

5 1-340 I 1-337 a CH

O HN O HN 10 As CH3 C N N N N 1. 1. O N O O N O 15 CH3 CH3 O O ! N1 WNCH, ls -CH O N1 \\ 2O O 1-341 SCH

O HN 25 A. F N N

1-338 F 1s, N O 30 CH3 O O HN ul A. F HC N N N 35 H

O1. N O 1-342 F F CH O. O 40 O HN

N 1\/ n CH3 As N N 45 1. O TABLE 1-58 CH O Ex. No. structural formula ls 1-339 Br 50 N CH3

1-343 S O HN

As N N F 55 O HN /

O1. N O Ya N N F CH 1.

O oS 60 O N CH3 O N1 O ---> Nul 65 US 8,835,443 B2 159 160 Example 2-1 To 1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g) obtained in Step 1 was added water (16 ml). Phosphorus Synthesis of 5-(4-chloro-phenylamino)-8-methyl-1, oxychloride (422 ml) was added dropwise under stirring at 3-diphenyl-1H.8H-pyrimido4,5-dipyrimidine-2,4,7- room temperature over 50 min. After the completion of the trione dropwise addition, the mixture was stirred under heating at 110° C. for 3 hrs. After allowing to cool to room temperature, Step 1 Synthesis of the reaction mixture was added to ice water by Small portions 1,3-diphenyl-pyrimidine-2,4,6-trione and the mixture was stirred at room temperature and extracted with ethyl acetate. The organic layer was washed with brine 10 and Saturated aqueous Sodium hydrogen carbonate, and dried over anhydrous sodium sulfate. Anhydrous sodium Sulfate was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chro matography (hexane:ethyl acetate=2:1->3:2) to give NH O 15 6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 20 (61.5 g. yield 74%) as pale-yellow crystals. O1. NH -- HO HeAc2O Step 3 Synthesis of HO O 6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-dione

18 4 O O 25

N N

1. HeMeNH2 O N CI MeOHIEtOH es O 30

35 19

Acetic anhydride (290 ml) was added to 1,3-diphenylurea 18 (148 g), malonic acid 4 (81.6 g) was added under a nitro gen atmosphere, and the mixture was stirred at 90° C. for 3 40 hrs. The mixture was stirred at 100° C. for 1.5 hrs and allowed to cool to room temperature. The reaction mixture was con centrated under reduced pressure. Ethanol (500 ml) was added to the residue, and the mixture was stirred at 90° C. When the mixture was cooled to 40° C., the crystals were 45 collected by filtration, washed with ethanol and dried to give 1,3-diphenyl-pyrimidine-2,4,6-trione 19 (78.0 g, yield 40%). Step 2 Synthesis of 6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 50

55 1s. NH POCl3 --- H2O C 60

21

65 In the same manner as in Step 4 of Example 1-1 and using 19 2O 6-chloro-1,3-diphenyl-1H-pyrimidine-2,4-dione 20 (5.0 g) obtained in Step 2, ethanol (25 ml), a 40% solution (21.7 ml) US 8,835,443 B2 161 162 of methylamine in methanol, 6-methylamino-1,3-diphenyl -continued 1H-pyrimidine-2,4-dione 21 (4.42 g, yield 90%) was obtained as colorless crystals. Step 4 Synthesis of ethyl(6-methylamino-2,4-dioxo 1,3-diphenyl-1,2,3,4-tetrahydro-pyrimidine-5-thio carbonyl)-carbamate

10

O 24 N S O N 15 To crude ethyl (6-methylamino-2,4-dioxo-1,3-diphenyl-1, O1. N -- Scs N ls O --DMF 2,3,4-tetrahydro-pyrimidine-5-thiocarbonyl)-carbamate 23 (1.58 g) obtained in Step 4 was added N,N-dimethylforma N mide (8.4 ml), triethylamine (0.63 ml) was added under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 min. Water (25 ml) was added, the mixture was stirred, 1N hydrochloric acid (5.0 ml) was added, and the 21 22 mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration, washed with water and dried to O S O give crude 5-mercapto-8-methyl-1,3-diphenyl-1H,8H-py 25 rimidoA,5-dipyrimidine-2,4,7-trione 24 (1.53 g, over N 1s, weight) as yellow crystals, which were used for the next step H N without purification. O N Step 6 Synthesis of 8-methyl-5-methylsulfanyl-1,3- diphenyl-1H.8H-pyrimidoA,5-dipyrimidine-2,4,7- trione

23 O SH To 6-methylamino-1,3-diphenyl-1H-pyrimidine-2,4-di one 21 (1.18 g) obtained in Step 3 was added N,N-dimethyl N NN formamide (5.9 ml), ethyl isothiocyanate formate 22 (0.52 40 ml) was added under a nitrogen atmosphere, and the mixture O1. N -NO 1 K2CODMF was stirred at room temperature for 1 hr. Water (30 ml) was added to the reaction mixture, and the crystals were collected by filtration and washed with water to give crude ethyl (6-me thylamino-2,4-dioxo-1,3-diphenyl-1,2,3,4-tetrahydro-pyri midine-5-thiocarbonyl)-carbamate 23 (1.68 g) as pale-yellow 45 crystals, which were used for the next step without purifica 24 25 tion. O s1

Step 5 Synthesis of 5-mercapto-8-methyl-1,3-diphe 50 nyl-1H.8H-pyrimido-4,5-dipyrimidine-2,4,7-trione N NN

O S O N 1s, H 26 NEt3 -- O N 60 DMF To crude 5-mercapto-8-methyl-1,3-diphenyl-1H.8H-py rimidoA,5-dipyrimidine-2,4,7-trione 24 (100 mg) obtained in Step 5 was added N,N-dimethylformamide (0.5 ml). Under a nitrogen atmosphere, potassium carbonate (44 mg) and 65 methyl iodide 25 (20 ul) were successively added, and the 23 mixture was stirred at room temperature for 3 hrs. Water was added, and the mixture was extracted with chloroform. The US 8,835,443 B2 163 164 organic layer was washed with water and brine, and dried over TABLE 2-1 anhydrous sodium Sulfate. Anhydrous sodium Sulfate was filtered off, and the filtrate was concentrated under reduced Ex. No. structural formula pressure. The residue was purified by column chromatogra phy (hexane:ethyl acetate-4:1->3:1) to give 8-methyl-5-me 2-1 C thylsulfanyl-1,3-diphenyl-1H,8H-pyrimido-4,5-dipyrimi dine-2,4,7-trione 26 (91 mg, yield 89%) as brown crystals. O HN Step 7 Synthesis of 5-(4-chloro-phenylamino)-8- methyl-1,3-diphenyl-1H,8H-pyrimido4,5-dipyrimi 10 N NN dine-2,4,7-trione es s CH3 15

es 2-2 F Br O HN

N n N 25 26 C es s Toluene --- CH O HN 30 27 N11 inWCH, C H

O HN 35 Example 3-1 N NN Synthesis of 5-(4-bromo-phenylamino)-3-cyclopro pyl-6,8-dimethyl-1-phenylamino-1H,6H-pyrido4.3- 40 dpyrimidine-2,4,7-trione Step 1 Synthesis of 1-(4-bromo-phenyl)-3-cyclopropyl-urea

45 28 To 8-methyl-5-methylsulfanyl-1,3-diphenyl-1H,8H-py rimidoA,5-dipyrimidine-2,4,7-trione 26 (149 mg) obtained On NH in Step 6 was added toluene (2 ml), 4-chloroaniline 27 (97 50 s mg) was added, and the mixture was stirred under reflux for 3.5 hrs. After allowing to cool to room temperature, diethyl As -- HerTHF O NH ether was added. The crystals were collected by filtration, NH2 washed with diethyl ether and dried to give 5-(4-chloro-phe nylamino)-8-methyl-1,3-diphenyl-1H.8H-pyrimido-4,5-d 55 pyrimidine-2,4,7-trione 28 (94 mg, yield 53%) as colorless crystals. Br Br MS ESI m/e: 472 (M+H), 470 (M-H). 'H-NMR (DMSO-de, 400 MHz) & 2.68 (s.3H), 7.34-7.39 1 30 31 (m. 2H), 7.41-7.61 (m, 10H), 7.80-7.87 (n, 2H), 11.34 (s, 60 1H). Under a nitrogen atmosphere, tetrahydrofuran (80 ml) was added to 4-bromophenyl isocyanate 30 (10.0 g), and a solu Example 2-2 tion of cyclopropylamine 1 (3.17 g) in tetrahydrofuran (20 ml) was added dropwise with stirring under ice-cooling. After In the same manner as in Example 2-1, the compounds of 65 the completion of the dropwise addition, the mixture was Example 2-2 were obtained. The structural formulas thereof stirred at room temperature for 3 hrs, and the reaction mixture are shown in Table 2-1 with Example 2-1. was concentrated under reduced pressure. Diethyl ether-hex US 8,835,443 B2 165 166 ane 1:1 (volume ratio), 100 ml was added to the residue and, dried to give 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine after stirring, the crystals were collected by filtration and 2,4,6-trione 32 (11.9 g, yield 73%) as pale-yellow crystals. dried to give 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g, over weight) as colorless crystals, which were used Step 3 Synthesis of 1-(4-bromo-phenyl)-6-chloro-3- for the next step without purification. 5 cyclopropyl-1H-pyrimidine-2,4-dione

Step 2 Synthesis of 1-(4-bromo-phenyl)-3-cyclopro pyl-pyrimidine-2,4,6-trione 10 Au Au N N es O POCl. es C 15 He- -- NH HO 1. O O NH Ac2O -- HO He

Br Br HO O 32 33

Br 25 31 4

30

35

40

As O 45 N Br es O 34 50 F To 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6- trione 32 (11.8 g) obtained in Step 2 was added water (1.31 ml) and phosphorus oxychloride (17.0 ml) was added drop 55 wise with stirring at room temperature. After the completion Br of the dropwise addition, the mixture was stirred at 110° C. 32 for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added to ice water by Small portions and the mixture was stirred. The mixture was stirred at room To 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g) 60 temperature and extracted with chloroform. The organic layer obtained in Step 1 was added acetic anhydride (25.8 ml), was washed with brine, and dried over anhydrous magnesium malonic acid 4 (5.79 g) was added under a nitrogen atmo Sulfate. Anhydrous magnesium sulfate was filtered off, and sphere, and the mixture was stirred at 100° C. for 3 hrs. After the filtrate was concentrated under reduced pressure. The allowing to cool to room temperature, the reaction mixture residue was purified by column chromatography (hexane: was concentrated under reduced pressure. Diethyl ether-etha 65 ethyl acetate=2:1->chloroform:acetone=30:1) to give a 1:1.4 nol 4:1 (volume ratio), 100 ml was added to the residue and, mixture (11.6 g., yield 93%) of 1-(4-bromo-phenyl)-6-chloro after stirring, the crystals were collected by filtration and 3-cyclopropyl-1H-pyrimidine-2,4-dione 33 and 3-(4-bromo US 8,835,443 B2 167 168 phenyl)-6-chloro-1-cyclopropyl-1H-pyrimidine-2,4-dione 1H-pyrimidine-2,4-dione 34 obtained in Step 3, ethanol 34 as a pale-yellow foamy oil. (20.9 ml) and a 40% solution (10.5 ml) of methylamine in Step 4 Synthesis of 1-(4-bromo-phenyl)-3-cyclopro methanol. pyl-6-methylamino-1H-pyrimidine-2,4-dione 5 Step 5 Synthesis of 1-(4-bromo-phenyl)-3-cyclopro pyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido 2,3-d pyrimidine-2,4,7-trione

10 As O AllNH 15 O N. NH es -- --

Br 2O 33

Br Br 35 36 25 O

C O PhO He 1. N 30 U O O N O MeNH2 He MeOHFEtOH 37 O OH 35 YN N

Br 1s, N O 34 40

O YNH 45 Br 38

1. N N O N NH es O 50 -- es O 55

Br Br 35 36

A 1: 1.3 mixture (5.34g, yield 78%) of 1-(4-bromo-phe 60 nyl)-3-cyclopropyl-6-methylamino-1H-pyrimidine-2,4-di O one 35 and 3-(4-bromo-phenyl)-1-cyclopropyl-6-methy lamino-1H-pyrimidine-2,4-dione 36 was obtained as 1-(4-Bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dim colorless crystals in the same manner as the synthesis of ethyl-1H.8H-pyrido2,3-dipyrimidine-2,4,7-trione 38 (0.40 compound 8 and using a 1:1.4 mixture (7.00 g) of 1-(4- 65 g, yield 32%) was obtained as pale-yellow crystals in the bromo-phenyl)-6-chloro-3-cyclopropyl-1H-pyrimidine-2,4- same manner as in Step 5 of Example 1-1 and using a 1:1.3 dione 33 and 3-(4-bromo-phenyl)-6-chloro-1-cyclopropyl mixture (1.00 g) of 1-(4-bromo-phenyl)-3-cyclopropyl-6- US 8,835,443 B2 169 170 methylamino-1H-pyrimidine-2,4-dione 35 and 3-(4-bromo 2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido2,3-dipyrimidin phenyl)-1-cyclopropyl-6-methylamino-1H-pyrimidine-2,4- 5-yl ester 39 (407 mg, yield 74%) as ocher crystals. dione 36 obtained in Step 4, 2-methyl-diethyl malonate 37 (2.56 ml) and diphenyl ether (1.49 g). Step 7 Synthesis of 1-(4-bromo-phenyl)-3-cyclopro 5 pyl-6,8-dimethyl-5-phenylamino-1H,8H-pyrido2,3- Step 6 Synthesis of toluene-4-sulfonic acid 1-(4- dpyrimidine-2,4,7-trione bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7- trioxo-1,2,3,4,7,8-hexahydro-pyrido2,3-dipyrimi din-5-yl ester 10 All 15

O N O --

Br Br 39 38 25

30

Her 1. TEA C MeCN HN 40 35 11

40 O\/ O O 1.

45

50

Br Br 55 39 41

To 1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6.8- To toluene-4-sulfonic acid 1-(4-bromo-phenyl)-3-cyclo dimethyl-1H,8H-pyrido2,3-dipyrimidine-2,4,7-trione 38 propyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-py (400 mg) obtained in Step 5 was added acetonitrile (8.0 ml), 60 rido 2,3-dipyrimidin-5-yl ester 39 (100 mg) obtained in Step tosyl chloride 11 (458 mg) and triethylamine (0.34 ml) were 6 was added aniline 40 (0.64 ml), and the mixture was stirred added under a nitrogen atmosphere, and the mixture was at 150° C. for 2.5 hrs. After allowing to cool to room tem stirred under reflux for 30 hrs. After allowing to cool to room perature, diethyl ether-hexane 1:1 (volume ratio), 30 ml was temperature, the mixture was concentrated under reduced added to the reaction mixture, and the crystals were collected pressure. The residue was purified by column chromatogra 65 by filtration. The obtained crystals were purified by column phy (chloroform:acetone=25:1->20:1) to give toluene-4-sul chromatography (chloroform:acetone 15:1) to give 1-(4- fonic acid 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5-pheny US 8,835,443 B2 171 172 lamino-1H,8H-pyrido 2,3-dipyrimidine-2,4,7-trione 41 (81 'H-NMR (CDC1, 400 MHz) & 0.77-0.82 (m, 2H), 1.09 mg, yield 93%) as pale-yellow crystals. 1.15 (m, 2H), 1.36 (s, 3H), 2.72-2.74 (m. 1H), 3.20 (s, 3H), 6.86 (d. 2H), 7.28-7.32 (m, 2H), 7.34-7.51 (m, 5H), 11.36 (s, Step 8 Synthesis of 5-(4-bromo-phenylamino)-3- 1H). cyclopropyl-6,8-dimethyl-1-phenylamino-1H,6H pyrido4.3-dipyrimidine-2,4,7-triune Example 3-7 Synthesis of N-3-3-cyclopropyl-5-(2-fluoro-4- iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- 10 tetrahydro-2H-pyrido4.3-dpyrimidin-1-yl) phenyl)methanesulfonamide Step 1 Synthesis of N-3-3-cyclopropyl-1-(2- fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2, 15 3,4,7,8-hexahydro-pyrido 2,3-dipyrimidin-5- ylaminolphenyl)methanesulfonamide

1. ---K2CO3 O N N O MeOH/CHCI O\/ O O o1 Ner, A. CH Br 25 N N 41 es O -- F CH 30

I 35 43 O 2,6-lutidine Br S-CH DMA HN N1 H. O. 40 44 O HN

S CH O HN N1 \ 45 A. CH3 H O N N 1s. O 50 F CH3 42

To 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-5- phenylamino-1H.8H-pyrido2,3-dipyrimidine-2,4,7-trione 55 I 41 (78 mg) obtained in Step 7 was added chloroform-metha 45 nol 1:1 (Volume ratio), 2.0 ml, potassium carbonate (22 mg) was added, and the mixture was stirred at room temperature for 10 hrs. The mixture was further stirred under reflux for 3 To trifluoromethanesulfonic acid 3-cyclopropyl-1-(2- hrs, and allowed to cool to room temperature. The mixture 60 fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8- was concentrated under reduced pressure and purified by hexahydro-pyrido2,3-dipyrimidin-5-yl ester 43 (30.0 g) column chromatography (chloroform:acetone 50:1) to give obtained in the same manner in Example 4-2, Step 6 to be 5-(4-bromo-phenylamino)-3-cyclopropyl-6,8-dimethyl-1- mentioned later and N-(3-aminophenyl)methanesulfonamide phenylamino-1H,6H-pyrido4.3-dpyrimidine-2,4,7-trione 44 (10.9 g) were added N,N-dimethylacetamide (60.0 ml) and 65 2.6-lutidine (6.82 ml), and the mixture was stirred at 130°C. 42 (23 mg, yield 26%) as colorless crystals. for 3.5 hrs. After allowing to cool to room temperature, MS ESI m/e: 493, 495 (M+H), 491,493 (M-H). methanol (60 ml) was added with stirring and the mixture was US 8,835,443 B2 173 174 stirred for 2 hrs. The crystals were collected by filtration and lamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H dried is to give N-3-3-cyclopropyl-1-(2-fluoro-4-iodophe pyrido4.3-dipyrimidin-1-yl)phenyl)methanesulfonamide nyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-py 46 (26.35 g, yield 93%) as white crystals. rido 2,3-dipyrimidin-5-ylamino MS ESI m/e: 652 (M+H), 650 (M-H). phenyl)methanesulfonamide 45 (30.5 g, yield 96%) as 'H-NMR (DMSO-de, 300 MHz) & 0.62-0.72 (m, 2H), colorless crystals. 0.91-1.01 (m, 2H), 1.25 (s.3H), 2.57-2.67 (m, 1H), 3.01 (s, Step 2 Synthesis of N-3-3-cyclopropyl-5-(2- 3H), 3.08 (s.3H), 6.92 (t, J=9.0 Hz, 1H), 7.09-7.14 (m. 1H), fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri 7.20-7.26 (m, 2H), 7.37-7.45 (m, 1H), 7.52-7.58 (m, 1H), oxo-3,4,6,7-tetrahydro-2H-pyrido4.3-dpyrimidin 10 7.79 (dd, J=1.8, 9.0 Hz, 1H), 9.89 (s, 1H), 11.08 (s, 1H). 1-yl)phenyl)methanesulfonamide Example 3-2 to 3-6, 3-8 and 3-9 In the same manner as in Examples 3-1 and 3-7, the com 15 pounds of Examples 3-2 to 3-6, 3-8 and 3-9 were obtained. The structural formulas thereof are shown in Table 3-1 to 3-2 S CH O HN N1\ with Examples 3-1 and 3-7. H. O. A. CH TABLE 3-1 N N 3 NaOMe, Ex. No. structural formula 1. HeMeOH O N O THF 3-1 Br

F CH 25

I 45 30 F I

O HN A. CH 35 N 4N1 3-2

O1. N Sa 1sO 40 CH

N1\S CH H. O. 45 46

Under a nitrogen atmosphere, to a solution (18.5 g) of 28% sodium methoxide in methanol was added tetrahydrofuran (284 ml), N-3-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6, 50 8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido 2,3- Br dipyrimidin-5-ylaminolphenyl)methanesulfonamide 45 (28.4 g) obtained in Step 1 was added, and the mixture was 3-3 Br stirred at room temperature for 1 hr. Acetic acid (12.5 ml) was added, and the mixture was stirred at room temperature for 1 55 hr and concentrated under reduced pressure. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added to the obtained solid, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight, and the crystals were col 60 lected by filtration and dried. A 9:1 mixed solvent (426 mL) of 1-butanol and water was added again to the obtained crystals, and the mixture was stirred with heating under reflux for 3 hrs. The mixture was allowed to return to room temperature and stirred overnight. The crystals were collected by filtration and 65 washed with a 9:1 mixed solvent of methanol and water and dried to give N-3-3-cyclopropyl-5-(2-fluoro-4-iodopheny US 8,835,443 B2 175 176 TABLE 3-1-continued TABLE 3-2

Ex. No. structural formula Ex. No. structural formula 3-7 F I 3-4 F Br 5 DO O HN CH As -CH3 10 N 2N1 1s-sN 21 NN 1.4N1S-1s O N O CH CH 15 O 1 in N 1 |in CH, N1 WCH, O H 3-8 CH 2O F a

25 As CH3 N 2N1

3-5 F Br O N O 30 CH O HN

21

35 O1. N N O 3-9 F O Br

CH3 O HN S CH N 1 WN1 3 40 As CH H O N 2N1 es S O 45 CH O | N11 in|| YCH, H 50 C

3-6 F Br DO Example 3-10 O HN 55

1. CH By treating N-3-3-cyclopropyl-5-(2-fluoro-4-iodophe 1.N 21 NN 2H-pyrido4.3-dpyrimidin-1-yl)nylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro O N N O phenyl)methanesulfonamide 46 according to conventional " methods, sodium salt and potassium salt thereof were CH O obtained. ls 8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido4.3-N-3-3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6, N CH3 as dipyrimidin-1-yl)phenyl)methanesulfonamide sodium salt: H-NMR (DMSO-de, 300 MHz) & 0.47 (brs, 2H), 0.70 0.90 (m, 2H), 1.23 (s.3H), 2.35 (brs, 1H), 2.82 (s.3H), 3.22 US 8,835,443 B2 177 178 (s.3H), 6.69 (t, J=8.8 Hz, 1H), 6.81 (d. J=8.1 Hz, 1H), 6.98 (s, -continued 1H), 7.02 (d. J=8.8 Hz, 1H), 7.10-7.30 (m, 2H), 7.38 (d. J=9.2 HZ, 1H), 10.22 (brs, 1H). As O MS (EST) m/z 652 MH". N N-3-3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6, 5 8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido4.3- dipyrimidin-1-yl)phenyl)methanesulfonamide potassium es N O salt: F Example 4-1 10 N-3-3-cyclopropyl-5-(2-fluoro-4-iodopheny lamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahy I dro-2H-pyrido4.3-dipyrimidin-1-yl-phenyl)-aceta 49 mide 15 To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)urea 48 (61.0 Step 1 Synthesis of g) obtained in Step 1 and malonic acid 4 (19.9 g) were added 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)urea acetic anhydride (300 ml) and acetyl chloride (27.2 ml), and the mixture was stirred under a nitrogen atmosphere at 60° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added dropwise to water-toluene 2:1 (volume ratio), 900 ml with stirring. The precipitated crys F 1) CDI tals were collected by filtration and dried to give 1-cyclopro EtN 25 pyl-3-(2-fluoro-4-iodophenyl)pyrimidine-2,4,6-trione 49 NH2 DMF --- (60.9 g, yield 82%) as pale-yellow crystals. 2) cPr-NH2 N NH Step 3 Synthesis of 6-chloro-3-cyclopropyl-1-(2- fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 30

47 48

Under a nitrogen atmosphere, to N,N-carbonyldiimidazole 35 All Au (39.9 g) were added N,N-dimethylformamide (200 ml) and N N triethylamine (34.3 ml) and a solution of 2-fluoro-4-iodoa niline 47 (48.5 g) in N,N-dimethylformamide (50 ml) was added dropwise with stirring under ice-cooling. After the es O POCl. es C completion of the dropwise addition, the mixture was stirred PhNMe2 at room temperature for 18 hrs. The reaction mixture was 40 HO ice-cooled, and cyclopropylamine (21.3 ml) was added drop wise. The reaction mixture was stirred at room temperature for 1 hr and added dropwise to water-toluene 2:1 (volume ratio), 750 ml with stirring. The precipitated crystals were collected by filtration and dried to give 1-cyclopropyl-3-(2- 45 49 fluoro-4-iodophenyl)urea 48 (61.3 g, yield 93.4%) as color less crystals. Step 2 Synthesis of 1-cyclopropyl-3-(2-fluoro-4- iodophenyl)pyrimidine-2,4,6-trione 50

55 NH 1. O I O NH 51

F -- HO HerAcCl 60 Ac2O To 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-pyrimidine 2,4,6-trione 49 (59.0 g) obtained in Step 2 were added phos HO O phorus oxychloride (85.0 ml) and dimethylaniline (29.0 ml), and water (8.3 ml) was added dropwise to the mixture at room I 65 temperature with stirring. After the completion of the drop 48 4 wise addition, the mixture was stirred with heating at 110°C. for 1 hr. After allowing to cool to room temperature, the US 8,835,443 B2 179 180 reaction mixture was added dropwise to ice water-toluene dophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 53 as 2:1 (volume ratio), 900 ml with stirring. The mixture was yellow crystals, which were used for the next step without stirred at room temperature for 1 hr. The organic layer was purification. separated, and washed successively with water (300 ml) and brine (300 ml). Anhydrous magnesium sulfate and activated 5 Step 5 Synthesis of 3-cyclopropyl-1-(2-fluoro-4- carbon were added and the mixture was stirred. Anhydrous iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido magnesium sulfate and activated carbon were filtered off, and 2,3-dipyrimidine-2,4,7-trione the filtrate was concentrated under reduced pressure to give a 1:2 mixture (62.9 g) of 6-chloro-3-cyclopropyl-1-(2-fluoro 4-iodophenyl)-1H-pyrimidine-2,4-dione 50 and 6-chloro-1- 10 cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4- dione 51 as a yellow foamy oil, which was used for the next step without purification. 15 Step 4 Synthesis of 3-cyclopropyl-1-(2-fluoro-4- iodophenyl)-6-methylamino-1H-pyrimidine-2,4- dione

O C 52 53 N SN1 N 25 O CH Ac2O es C es O MeNH2 HO ------F F MeOH 30 HO O 54 O OH A. CH N N I I 35 50 51 H3C O YNH F CH N N1S 40

I 55 45 O H3C NN CH3

52 50 n1s OH To a 1:2 mixture (62.9 g) of 6-chloro-3-cyclopropyl-1-(2- es O fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 50 and 6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyri F midine-2,4-dione 51 obtained in Step 3 were added methanol 55 (189 ml) and a solution (126 ml) of 40% methylamine in methanol, and the mixture was stirred at room temperature for 2hrs. The precipitated crystals were filtered off and the filtrate was concentrated under reduced pressure. The residue was 60 extracted with chloroform (200 ml) and water (200 ml), and To a 2:1 mixture (34.6 g) of 3-cyclopropyl-1-(2-fluoro-4- the organic layer was washed with brine (200 ml) and dried iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 over anhydrous magnesium sulfate. Anhydrous magnesium and 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)6-methy sulfate was filtered off and the filtrate was concentrated under lamino-1H-pyrimidine-2,4-dione 53 obtained in Step 4, and reduced pressure to give a 2:1 mixture (34.55 g) of 3-cyclo 65 2-methylmalonic acid 54 (10.2 g) was added acetic anhydride propyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyri (173 ml), and the mixture was stirred at 100° C. for 2 hrs. midine-2,4-dione 52 and 1-cyclopropyl-3-(2-fluoro-4-io After allowing to cool to room temperature, the reaction US 8,835,443 B2 181 182 mixture was concentrated under reduced pressure. Acetone pressure. 2-Propanol (198 ml) was added to the residue, and (104 ml) was added to the residue, and the mixture was stirred the mixture was stirred with heating under reflux, and allowed with heating under reflux for 30 min. After allowing to cool to to return to room temperature. The crystals were collected by room temperature, the precipitated crystals were collected by filtration and dried to give trifluoromethanesulfonic acid filtration and dried to give 3-cyclopropyl-1-(2-fluoro-4-io 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4, dophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido 2,3-d 7-trioxo-1,2,3,4,7,8-hexahydro-pyrido 2,3-dipyrimidin-5-yl pyrimidine-2,4,7-trione 55 (15.1 g, yield from 48, 21%) as ester 43 (31.9 g, yield 93%) as colorless crystals. colorless crystals.

10 Step 6 Synthesis of trifluoromethanesulfonic acid Step 7 Synthesis of N-3-3-cyclopropyl-1-(2- 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dim fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2, ethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido2,3- 3,4,7,8-hexahydro-pyrido 2,3-dipyrimidin-5- dpyrimidin-5-yl ester ylaminolphenyl)acetamide 15

O OH CH N N VS / O o1 NCF, es N O CH3 -- N N F CH 25 es N O -- F CH3

I

55 30 O. O \/ I o1 NCF, 2,6-lutidine 43 CHCI SE 35 2,6-lutidine CF1 \ Hess O Y C a O DMA 56 HN2 H-- 3 O O \/ 57 O o1 NCF, 40 1 c N O O HN H s CH 45 All

Ols N N O F CH 50

43

Under a nitrogen atmosphere, to 3-cyclopropyl-1-(2- 58 fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethyl-1H,8H-py 55 rido 2,3-dipyrimidine-2,4,7-trione 55 (33.0 g) obtained in Step 5 were added chloroform (165 ml) and 2.6-lutidine (10.4 To trifluoromethanesulfonic acid 3-cyclopropyl-1-(2- ml), and trifluoromethanesulfonic anhydride 56 (14.4 ml) fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8- was added dropwise under ice-cooling with stirring. After the 60 hexahydro-pyrido2,3-dipyrimidin-5-yl ester 43 (25.0 g) completion of the dropwise addition, the mixture was stirred obtained in Step 6 and 3'-aminoacetanilide 57 (7.33 g) were at same temperature for 30 min and at room temperature for 2 added N,N-dimethylacetamide (50.0 ml) and 2.6-lutidine hrs. The reaction mixture was washed successively with (5.68 ml), and the mixture was stirred at 130° C. for 5 hrs. aqueous sodium hydrogen carbonate (165 ml), IN hydrochlo After allowing to cool to room temperature, methanol-water ric acid (165 ml) and brine (165 ml) and dried over anhydrous 65 1:2 (volume ratio), 150 ml was added with stirring. The magnesium Sulfate. Anhydrous magnesium sulfate was fil crystals were collected by filtration and dried to give N-3- tered off and the filtrate was concentrated under reduced 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4, US 8,835,443 B2 183 184 7-trioxo-1,2,3,4,7,8-hexahydro-pyrido2,3-dipyrimidin-5- 7.36 (t, J=8.2 Hz, 1H), 7.52-7.63 (m, 3H), 7.79 (dd, J=2.0, ylaminolphenyl)acetamide 58 (24.8 g., yield 99%) as 10.4 Hz, 1H), 10.10 (s, 1H), 11.08 (s, 1H). colorless crystals. Step 8 Synthesis of N-3-3-cyclopropyl-5-(2- Example 4-1 fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-tri oxo-3,4,6,7-tetrahydro-2H-pyrido4.3-dpyrimidin 1-yl)phenyl)acetamide Alternative Method

10 N-3-3-cyclopropyl-5-(2-fluoro-4-iodopheny lamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahy O dro-2H-pyrido4.3-dipyrimidin-1-yl)-phenyl)-aceta mide O HN --> H 15 A. CH3 Step 1 Synthesis of N N NaOMe, 1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 1. --MeOH O N O THF

F CH3 F 1) CDI V EtN O NH

25 NH2 --DMF F N I 2)) CPir-NHcPr 2 NH 58 I

I 30 47 48

F I Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (82.1 g) were added N,N-dimethylformamide (400 ml) and 35 triethylamine (70.5 ml), and a solution of 2-fluoro-4-iodoa O C niline 47 (100 g) in N,N-dimethylformamide (100 ml) was added dropwise under ice-cooling. After the completion of As 21 -CH the dropwise addition, the mixture was stirred at room tem perature for 5 hrs. The reaction mixture was ice-cooled, and 40 cyclopropylamine (44.0 ml) was added dropwise. The mix 1s. S O ture was stirred at room temperature for 1 hr., and the reaction CH3 mixture was added dropwise to water-toluene 2:1 (volume O ratio), 1500 ml with stirring. The precipitated crystals were collected by filtration and dried to give 1-cyclopropyl-3-(2- 45 fluoro-4-iodo-phenyl)-urea 48 (129 g, yield 95.5%) as color s less crystals. 59 Step 2 Synthesis of 1-(2-cyano-acetyl)-1-cyclopro Under a nitrogen atmosphere, to a solution (1.57 g) of 28% 50 pyl-3-(2-fluoro-4-iodo-phenyl)-urea sodium methoxide in methanol was added tetrahydrofuran (40 ml), N-3-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6, 8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido 2,3- dpyrimidin-5-ylaminolphenyl)acetamide 58 (5.00 g) obtained in Step 7 was added, and the mixture was stirred at 55 room temperature for 4 hrs. Acetic acid (0.56 ml) was added, As NH and the mixture was stirred at room temperature for 30 min. Water (40 ml) was added and the mixture was further stirred O for 1 hr. The crystals were collected by filtration and dried to O 1s + HO CN MsCI give N-3-3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)- 60 F He 6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido4. DMF 3-dipyrimidin-1-yl)phenyl)acetamide 59 (4.75 g, yield 95%) as colorless crystals. MS ESI m/e: 616 (M+H), 614 (M-H). 'H-NMR (DMSO-d 400 MHz) & 0.63-0.70 (m, 2H), 65 I 0.91-1.00 (m, 2H), 1.25 (s.3H), 2.04 (s, 3H), 2.58-2.66 (m, 48 73 1H), 3.07 (s.3H), 6.92 (t, J=8.8 Hz, 1H), 7.00-7.05 (m, 1H), US 8,835,443 B2 185 186 -continued fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione 75 (178 g. O yield from 48.88%) as pale-yellow crystals. Aulus Step 4 Synthesis of N'-(1-cyclopropyl-3-(2-fluoro-4- 5 iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimi es din-4-yl-N,N-dimethyl-formamidine F

10

I 74 15 es NH2 DMF-DMA --- Under a nitrogen atmosphere, to 1-cyclopropyl-3-(2- F DMF fluoro-4-iodo-phenyl)-urea 48 (167 g) and cyanoacetic acid 73 (80.0 g), was added N,N-dimethylformamide (83.6 ml), and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 4 hrs. The reaction mixture was cooled with water, and water-isopropanol 2:1 (volume ratio), 1670 75 ml was added dropwise. The mixture was stirred under water-cooling for 1 hr., and the precipitated crystals were 25 collected by filtration and dried to give 1-(2-cyano-acetyl)-1- cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-urea 74 (192 g). Step 3 Synthesis of 6-amino-3-cyclopropyl-1-(2- fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione 30

O As 1sults 35 1. O NH 2N NaOHaq. -- F HO 40

As O 45 74 es an 1 F 50

I 55 76

Under a nitrogen atmosphere, to 6-amino-3-cyclopropyl I 1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione 75 75 60 (178 g) were added N,N-dimethylformamide (356 ml) and N,N-dimethylformamide dimethylacetal (178 ml), and the To 1-(2-cyano-acetyl)-1-cyclopropyl-3-(2-fluoro-4-iodo mixture was stirred at room temperature for 2 hrs. Isopro phenyl)-urea 74 (192 g) were added water (962 ml) and 2N panol (178 ml) was added with stirring at room temperature, aqueous sodium hydroxide Solution (24.9 ml), and the mix and water (1068 ml) was added dropwise. The mixture was ture was stirred with heating at 80°C. for 1 hr. After allowing 65 stirred at room temperature for 2 hrs, and the precipitated to cool to room temperature, the crystals were collected by crystals were collected by filtration and dried to give N-1- filtration and dried to give 6-amino-3-cyclopropyl-1-(2- cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6- US 8,835,443 B2 187 188 tetrahydro-pyrimidin-4-yl-N,N-dimethyl-formamidine 76 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino (188 g, yield 92%) as yellow crystals. 1H-pyrimidine-2,4-dione 52, which were used for the next reaction without purification. Step 5 Synthesis of 3-cyclopropyl-1-(2-fluoro-4- 5 Step 6 Synthesis of 3-cyclopropyl-1-(2-fluoro-4- iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4- iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido dione 2,3-dipyrimidine-2,4,7-trione

O 10 O

N N 1. O O N NH es 4\1 NaBaBH4 15 + HO ---Ac2O F t-BOHFEtOH F

HO O

I 76 52 54

25

30

35

40 11 O O N N O

As N F

O1suls." N NH F I 55 50 Under a nitrogen atmosphere, to 3-cyclopropyl-1-(2- fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4- I dione 52 (34.4 g) and 2-methyl-malonic acid 54 (15.2 g) was 52 added acetic anhydride (34.4 ml), and the mixture was stirred 55 with heating at 100° C. for 3 hrs. After allowing to cool to 50° C., acetone (68.8 ml) was added dropwise, and the mixture Under a nitrogen atmosphere, to t-butanol-ethanol 2:1 was stirred as it was for 30 min. Water (172 ml) was further (volume ratio), 250 ml was added sodium borohydride (6.41 added dropwise, and the mixture was stirred for 1 hr. After g), and the mixture WaS stirred at room temperature for 1 hr. allowing to cool to room temperature with stirring, the pre Under water-cooling, N'-1 -cyclopropyl-3-(2-fluoro-4-iodo- 60 cipitated crystals were collected by filtration and dried to give phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl-N,N- crude crystals (37.7 g, LC purity 91%) of 3-cyclopropyl-1- dimethyl-formamidine 76 (50.0 g) was added, and the mix- (2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H ture was stirred for 2.5 hrs. Under water-cooling, water (225 pyrido 2,3-dipyrimidine-2,4,7-trione 55. Isopropanol (92.0 ml) and 10% aqueous citric acid solution (175 ml) were ml) was added to the obtained crude crystals (30.7g), and the successively added dropwise, and the mixture was stirred for 65 mixture was stirred at room temperature for 4 hrs. The crys 3 hrs. The precipitated crystals were collected by filtration tals were collected by filtration and dried to give 3-cyclopro and dried to give crude crystals (34.5 g, LC purity 91%) of pyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl US 8,835,443 B2 189 190 1H.8H-pyrido2,3-dipyrimidine-2,4,7-trione 55 (25.9 g, 8-hexahydro-pyrido 2,3-dipyrimidin-5-yl ester 77 (28.7 g. yield from 76, 58%) as pale-yellow crystals. yield 91%) as colorless crystals. Step 7 Synthesis of p-toluenesulfonic acid 3-cyclo Step 8 Synthesis of N-3-3-cyclopropyl-1-(2- propyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4, 5 fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2, 7-trioxo-1,2,3,4,7,8-hexahydro-pyrido2,3-dipyrimi 3,4,7,8-hexahydro-pyrido 2,3-dipyrimidin-5- din-5-yl ester ylaminol-phenyl)-acetamide

10 O OH As rs es N O 15 -- F O N N O

F

I 55

25 I 77

O. O VW NEt -S MeN-HCI C He 30 MeCN O 2,6-lutidine He DMA 11 HN N H 35 57 O\/ O O 1. 40

45

50

77

Under a nitrogen atmosphere, to 3-cyclopropyl-1-(2- 55 58 fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H.8H-py rido 2,3-dipyrimidine-2,4,7-trione 55 (23.9 g) was added To p-toluenesulfonic acid 3-cyclopropyl-1-(2-fluoro-4- acetonitrile (167 ml), and the mixture was stirred under ice cooling. Triethylamine (11.0 ml) and trimethylamine hydro iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahy chloride (2.37 g) were added, and a solution of p-toluene 60 dro-pyrido2,3-dipyrimidin-5-yl ester 77 (28.0 g) and 3'-ami sulfonyl chloride 11 (12.3 g) in acetonitrile (72.0 ml) was noacetanilide 57 (13.2 g) were added N,N- added dropwise. The mixture was stirred under ice-cooling dimethylacetamide (84.0 ml) and 2.6-lutidine (15.3 ml), and for 1 hr., and stirred at room temperature for 3 hrs. Methanol the mixture was stirred at 130°C. for 4 hrs. After allowing to (239 ml) was added, and the mixture was stirred at room cool with stirring, methanol (196 ml) was added dropwise, temperature for 1 hr. The crystals were collected by filtration 65 and the mixture was stirred at room temperature. The crystals and dried to give p-toluenesulfonic acid 3-cyclopropyl-1-(2- were collected by filtration and dried to give N-3-3-cyclo fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7, propyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-tri US 8,835,443 B2 191 192 oxo-1,2,3,4,7,8-hexahydro-pyrido 2,3-dipyrimidin-5- was stirred for 30 min allowed to cool with stirring. The ylaminol-phenyl-acetamide 58 (25.2 g, yield 93%) as crystals were collected by filtration and dried to give crystal 2 colorless crystals. (41.7 g) of N-3-3-cyclopropyl-5-(2-fluoro-4-iodo-pheny lamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H Step 9 Synthesis of N-3-3-cyclopropyl-5-(2- pyrido4,3-dipyrimidin-1-yl)-phenyl)-acetamide 59 as col fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4,7- orless crystals. trioxo-3,4,6,7-tetrahydro-2H-pyrido4,3-dipyrimi To crystal 2 (41.5 g) was added 1-butanol-water 19:1 din-1-yl)-phenyl)-acetamide (volume ratio), 415 ml, and the mixture was stirred at 130°C. for 18 hrs. After allowing to cool with stirring, the crystals 10 were collected by filtration and dried to give N-3-3-cyclo propyl-5-(2-fluoro-4-iodo-phenylamino)-6,8-dimethyl-2,4, 7-trioxo-3,4,6,7-tetrahydro-2H-pyrido4.3-dpyrimidin-1- yl-phenyl)-acetamide 59 (40.7 g, yield 89%) as colorless crystals. Cl-, 15 Example 4-3 Al-N- NaOMe, N-3-3-cyclopropyl-5-(4-ethynyl-2-fluoropheny MeOH lamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahy -----, THF dro-2H-pyrido4,3-dipyrimidin-1-yl) phenyl)acetamide Step 1 Synthesis of N-3-3-cyclopropyl-5-(2- fluoro-4-trimethylsilanylethynylphenylamino)-6,8- 25 dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido 4.3-dipyrimidin-1-yl)phenyl)acetamide 58 I

30 F I O HN O C All A. CH 35 N 4N1 1. -- D.C. O 1s O CH Cl 40 O 59 H s

Under a nitrogen atmosphere, to N-3-3-cyclopropyl-1- 45 (2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4, SiMe3 He 7,8-hexahydro-pyrido 2,3-dipyrimidin-5-ylamino-phe EtN nyl-acetamide 58 (45.7g) was added tetrahydrofuran (366 60 CHCl ml), and a solution (15.7 g) of 28% sodium methoxide in SiMe3 methanol was added dropwise with stirring at room tempera 50 ture and the mixture was stirred at room temperature for 4 hrs. Acetic acid (5.61 ml) was added, and the mixture was stirred at room temperature for 30 min. With stirring at 70° C. in an oil bath, water (366 ml) was added dropwise, and the mixture O HN was stirred for 1 hr. After allowing to cool with stirring, the 55 A. CH crystals were collected by filtration and dried to give crystal 1 N 2n 1 (46.0 g) of N-3-3-cyclopropyl-5-(2-fluoro-4-iodo-pheny lamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H pyrido4.3-dipyrimidin-1-yl)-phenyl)-acetamide 59. 1s, N O N,N-Dimethylacetamide (184 ml) was added to crystal 1 60 CH (46.0 g), and the mixture was stirred with heating at 130°C. O After complete dissolution, the solution was filtered by suc tion using with paper (5B), and washed with N,N-dimethy N lsCH3 lacetamide (92.0 ml). The filtrate was stirred under heating at H 130°C., 1-butanol (138 ml) and water (96.0 ml) were succes 65 61 sively added dropwise, and the mixture was stirred for 30 min. Water (46.0 ml) was further added dropwise, and the mixture US 8,835,443 B2 193 194 Under a nitrogen atmosphere, to N-3-3-cyclopropyl-5- To N-3-3-cyclopropyl-5-(2-fluoro-4-trimethylsilanyl (2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3, ethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tet 4,6,7-tetrahydro-2H-pyrido4.3-dpyrimidin-1-yl) rahydro-2H-pyrido4,3-dipyrimidin-1-yl)phenyl)acetamide phenyl)acetamide 59 (14.5 g) obtained in Example 4-1 were 61 (1.00 g) obtained in Step 2 and potassium carbonate (236 added chloroform (145 ml), trimethylsilylacetylene 60 (4.99 mg) was added methanol/N,N-dimethylformamide 1:1 (vol ml) and triethylamine (13.1 ml). Copper(I) iodide (22 mg) ume ratio), 10.0 ml, and the mixture was stirred at room and bis(triphenylphosphine)palladium(II) chloride (83 mg) temperature for 20 hrs. The mixture was neutralized with 2N were added, and the mixture was stirred at room temperature hydrochloric acid, water (10.0 ml) was added, and the mix for 20 hrs. The mixture was concentrated under reduced pres ture was stirred at room temperature for 1 hr. The crystals sure, activated carbon (435 mg) and methanol (435 ml) were 10 were collected by filtration and dried to give N-3-3-cyclo added to the residue, and the mixture was stirred with heating propyl-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethyl-2, at reflux for 2 hrs. Activated carbon was filtered off while it 4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido4.3-dpyrimidin-1- was hot, and the filtrate was concentrated under reduced ylphenyl)acetamide 62 (815 mg, yield 93%) as pale-yellow pressure. The residue was purified by column chromatogra 15 crystals. phy (chloroform:acetone=10: 1->4:1) and toluene-acetone MS ESI m/e: 514 (M+H), 512 (M-H). 5:1 (volume ratio), 87 ml] was added to the obtained crystals. The mixture was stirred at 80° C. for 1 hr. After allowing to 'H-NMR (DMSO-de, 400 MHz) & 0.63-0.70 (m, 2H), cool to room temperature, the crystals were collected by 0.91-0.99 (m, 2H), 1.26 (s.3H), 2.04 (s, 3H), 2.58-2.66 (m, filtration and dried to give N-3-3-cyclopropyl-5-(2-fluoro 1H), 3.10 (s, 3H), 4.30 (s, 3H), 701-7.06 (m. 1H), 7.09 (t, 4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7- J=8.4 Hz, 1H), 7.31 (dd, J=1.6, 8.4 Hz, 1H), 7.36 (t, J=7.8 Hz, trioxo-3,4,6,7-tetrahydro-2H-pyrido4,3-dipyrimidin-1-yl) 1H), 7.52 (dd, J=1.6, 11.6 Hz, 1H), 7.57-7.63 (m, 2H), 10.10 phenyl)acetamide 61 (12.9 g, yield 93%) as pale-yellow (s, 1H), 11.10 (s, 1H). crystals. 25 Example 4-16 Step 2 Synthesis of N-3-3-cyclopropyl-5-(4-ethy nyl-2-fluorophenylamino)-6,8-dimethyl-2,4,7-trioxo 3,4,6,7-tetrahydro-2H-pyrido4.3-dpyrimidin-1-yl) N-3-5-(2-fluoro-4-iodophenylamino)-3,6,8-trim phenyl)acetamide ethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido4.3- 30 dipyrimidin-1-yl)phenyl)methanesulfonamide

Step 1 Synthesis of SiMe3 1-(2-fluoro-4-iodophenyl)-3-methylurea F 2^ 35

O HN F 1) CDI EtN NH2 DMF A. 1 CH3 KCO N 21 NN S 40 He MeOH 2) 40% MeNH/MeOH DMF I 47 45 O NHt F N NH 21 50

63 O HN cr1 As CH3 55 Under a nitrogen atmosphere, to N,N-carbonyldiimidazole N 4N1 (61.4 g) were added N,N-dimethylformamide (300 ml) and triethylamine (52.8 ml) and a solution of 2-fluoro-4-iodoa 1. N O niline 47 (74.8 g) in N,N-dimethylformamide (75 ml) was added dropwise with stirring under ice-cooling. After the CH3 60 O completion of the dropwise addition, the mixture was stirred at room temperature for 5 hrs. The reaction mixture was ice-cooled, and a solution (60 ml) of 40% methylamine in H 1. methanol was added dropwise. The mixture was stirred at 62 65 room temperature for 1 hr., and the reaction mixture was added dropwise to water-toluene 2:1 (volume ratio), 1125 ml under stirring. The precipitated crystals were collected by US 8,835,443 B2 195 196 filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-me -continued thylurea 63 (87.9 g, yield 94.8%) as colorless crystals. C

HC Step 2 Synthesis of 1-(2-fluoro-4-iodophenyl)-3- 3 NN N methylpyrimidine-2,4,6-trione es O F YNH 10

O1. NH O I F + HO HeAcCl Ac2O 15 66

HO O Under a nitrogen atmosphere, to 1-(2-fluoro-4-iodophe nyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g) were added I phosphorus oxychloride (116.3 ml) and dimethylaniline 63 4 (39.5 ml) and water (11.6 ml) was added dropwise with O stirring under room temperature. After the completion of the H3C dropwise addition, the mixture was stirred at 125°C. for 1 hr. NN After allowing to cool to room temperature, the reaction 25 mixture was added dropwise with stirring to ice water (500 es O ml)/chloroform (150 ml). The mixture was stirred at room temperature for 1 hr., and chloroform (150 ml) was added. The F organic layer was separated, washed Successively with water (300 ml) and brine (300 ml), and dried over anhydrous 30 Sodium sulfate.

I 64 Anhydrous sodium sulfate was filtered off, and the filtrate 35 was concentrated under reduced pressure. To a solution of the Under a nitrogen atmosphere, to 1-(2-fluoro-4-iodophe residue in chloroform (250 ml), silica gel (200 ml) was added nyl)-3-methylurea 63 (87.9 g) obtained in Step 1 and malonic and the mixture was stirred. Silica gel was filtered off and acid 4 (31.1 g) were added acetic anhydride (264 ml) and washed with chloroform/ethyl acetate 10:1 (volume ratio), acetylchloride (42.5 ml), and the mixture was stirred at 65° C. 11. The filtrate was concentrated under reduced pressure to for 3 hrs. After allowing to cool to room temperature, the 40 give a 6:5 mixture (75.7g, yield 95.6%) of 6-chloro-1-(2- reaction mixture was added dropwise to water-toluene 2:1 fluoro-4-iodophenyl)-3-methyl-1H-pyrimidine-2,4-dione 65 (volume ratio), 800 ml with stirring, and hexane (132 ml) and 6-chloro-3-(2-fluoro-4-iodophenyl)-1-methyl-1H-pyri was successively added. The precipitated crystals were col midine-2,4-dione 66 as pale-yellow crystals. lected by filtration and dried to give 1-(2-fluoro-4-iodophe nyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g, yield 45 69.5%) as pale-yellow crystals. Step 4 Synthesis of 1-(2-fluoro-4-iodophenyl)-3- Step 3 Synthesis of 6-chloro-1-(2-fluoro-4-iodophe methyl-6-methylamino-1H-pyrimidine-2,4-dione nyl)-3-methyl-1H-pyrimidine-2,4-dione 50

55

60

65 65 64