JP2022053557A - Pyridone derivative - Google Patents

Abstract

To provide a therapeutic agent and a therapeutic method for cancer, non-cancerous proliferative disease, fibrotic disease, inflammatory disease, viral infection, and the like by inhibiting a function of BET (bromodomain and extra-terminal) protein.SOLUTION: The present invention relates to a compound represented by general formula (1) or a salt thereof, and a pharmaceutical composition containing the compound as an active ingredient. (In the formula, R1 is H, lower alkyl, or the like; R2 is H or lower alkyl; R3 is substituted/unsubstituted aryl or the like; R4 is H, substituted/unsubstituted lower alkyl, a substituted/unsubstituted heterocyclic group, or the like; X1, X2 and X3 are each C or N; and a double line consisting of a solid line and a dotted line is a single bond or a double bond.)SELECTED DRAWING: Figure 1

Description

The present invention relates to a compound represented by the following general formula (1) (definition of each reference numeral in the formula will be described later).

Further, the compound of the present invention inhibits the function of a BET (Bromodomain and extra-terminal) protein consisting of BET (Bromodomain and extra-terminal) proteins having a bromodomain: BRD2, BRD3, BRD4, BRDT and the like, for example. Since it is effective in treating diseases such as cancer, non-cancerous proliferative disease, fibrous disease, inflammatory disease, and viral infection, the present invention relates to a therapeutic agent and a treatment method for these diseases.

In eukaryotes, double-stranded DNA wraps around histone proteins in the cell nucleus to form nucleosomes, which are the building blocks of chromatin. Structural changes in chromatin play an important role in the regulation of gene transcription by controlling the access of transcriptional regulatory proteins to DNA. Remission and condensation of chromatin structures are regulated by various post-translational modifications of histone proteins. These reversible modifications include acetylation, methylation, phosphorylation, ubiquitination and SUMOylation. These epigenetic modifications or demodifications are made by specific enzymes.

Histone acetylation usually positively regulates gene transcription. Epigenetic acetylated lysine in histones is decoded by a particular protein. This decoding is done by binding highly conserved sequences called bromodomains to acetylated lysine residues. There are more than 60 bromodomain-containing proteins in the human genome.

The BET family of bromodomain-containing proteins includes four proteins (BRD2, BRD3, BRD4 and BRDT). BRDT is restricted to germ cells and BRD2, BRD3 and BRD4 are widely expressed. The BET protein uses two bromodomains (BD1, BD2) to recognize the N-acetylated lysine residue of the histone protein. These interactions regulate gene expression by recruiting transcription factors to specific genomic positions. For example, histone-bound BRD4 mobilizes the transcription factor P-TEFb as a promoter and initiates transcription by RNA polymerase II (Non-Patent Document 1). The BRD2 and BRD4 proteins have been shown to be required for transcriptional promotion of key genes including cyclin D and c-Myc that initiate the cell cycle (Non-Patent Document 2). BRD4-deficient cells arrest the cell cycle.

In addition to acetylated histones, the BET protein binds to acetylated transcription factors including the RelA subunit of NF-kB and GATA1 to regulate gene expression related to inflammation and hematopoietic cell differentiation (Non-Patent Document 3). 4).

In addition, some viruses bind the viral genome to the chromatin of the host cell to utilize the transcription and replication functions of the host cell, but use the BET protein to bind the viral genome to chromatin, or the viral gene. BET proteins are used to promote transcription and inhibition (Non-Patent Documents 5 and 6).

Based on the above, by inhibiting the binding between BET protein and acetylated lysine, cancer and cell proliferation diseases other than cancer (non-cancerous proliferation diseases), fibrous diseases, inflammatory diseases and viral infections can be detected. Treatment or prevention is expected to be achieved.

Several compounds are known that inhibit bromodomain proteins. For example, Patent Document 1 discloses that certain pyridinones (pyridones) can be BRD4 inhibitors. Patent Document 2 discloses that a certain substituted benzimidazole inhibits a bromodomain and can be a therapeutic agent for diseases such as cancer.

Special Table 2016-530259 Gazette Special Table 2018-522925

Yang et al. , Mol. Cell. Biol. 28: 967-976 (2008) Mochizuki et al. , J. Biol. Chem. 283: 9040-9048 (2008) Huang et al. , Mol. Cell Biol. , 29: 1375-1387 (2009) Lamonica et al. , Proc. Nat. Acad. Sci. USA.108: E159-168 (2011) You et al. , Cell. 117: 349-60 (2004) Zhu et al. , Cell Rep. 2: 807-816 (2012)

Inhibition of BET protein binding to acetylated lysine to achieve treatment of cancer and non-cancer cell proliferation, fibrotic, inflammatory and viral infections involving the BET protein. There is a need to.
The main object of the present invention is to provide a novel compound capable of inhibiting the binding between the BET protein and the acetylated lysine. Another object of the present invention is to provide a novel pharmaceutical composition containing the compound as an active ingredient.

As a result of diligent studies, the present inventors have found that the compound represented by the general formula (1) inhibits the binding between the BET protein and acetylated lysine, and have completed the present invention. ..

Examples of the present invention include the following.
[1] A compound represented by the following general formula (1) or a salt thereof.

(During the ceremony,
R ¹ represents H, lower alkyl, halogen, or cyano.
R ² represents H, or lower alkyl.
R ³ represents an aryl that may be substituted or an arylalkyl that may be substituted, or a heteroaryl that may be substituted or a heteroarylalkyl that may be substituted.
^R4 represents H, a lower alkyl which may be substituted, an oxo, an aryl which may be substituted, a heterocyclic group which may be substituted, and a cycloalkyl which may be substituted.
X ¹ is C or N,
If X ¹ is C, one of X ² and X ³ is N and the other is N-R ⁵ , O, or S, or one of X ² and X ³ is N-R ⁵ . The other is N-R ⁶ or C-R ⁷ .
When X ¹ is N, one of X ² and X ³ is N and the other is CH, or both X ² and X ³ are N.
R ⁵ and R ⁶ are the same or different and represent H, a lower alkyl which may be substituted, a heterocyclic group which may be substituted, cyano, or a cycloalkyl which may be substituted.
R ⁷ represents H, or a lower acyl.
The two solid and dotted lines represent single or double bonds, depending on X ¹ , X ² , X ³ and R ⁴ and adjacent carbon atoms. )

[2] X ¹ is C and one of X ² and X ³ is N and the other is N-R ⁵ , or X ¹ is N and one of X ² and X ³ is N. The compound according to the above [1], or a salt thereof, which is N and the other is CH.
[3] The compound according to the above [1] or [2], or a salt thereof, wherein R ¹ is H or a lower alkyl and R ² is a lower alkyl.
[4] The compound according to any one of the above [1] to [3], or a salt thereof, which is a lower alkyl in which ^R4 may be substituted, or a heterocyclic group in which R4 may be substituted.
[5] X ¹ is C, X ² is N, and X ³ is NH, or X ¹ is N, X ² is CH, and X ³ is N, and R ¹ is H or a lower alkyl. Yes, R ² is a lower alkyl, R ³ is an optionally substituted aryl, R ⁴ may be substituted lower alkyl, optionally substituted heterocycloalkyl, or substituted. The compound according to any one of the above [1] to [4], or a salt thereof, which is also a good heteroaryl.
[6] X ¹ is C, X ² is N, and X ³ is NH, or X ¹ is N, X ² is CH, and X ³ is N, and R ¹ is H or a lower alkyl. Yes, R ² is a lower alkyl, R ³ is a optionally substituted phenyl, and R ⁴ is a methyl, tetrahydropyranyl, or optionally substituted pyrazolyl, the above [1] to [5]. ], Or a salt thereof.

[7] The compound according to any of the following (1) to (155), or a salt thereof.
(1) 3-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (2) 3-Methyl-5- (2-) (1-Methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (3) 3-methyl-5- (4-) Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (4) 5- (2-methyl-4-phenoxy-) 1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (5) 5- (2- (1-methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [ d] Imidazole-5-yl) Pylidin-2 (1H) -on (6) 5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5- Ill) Pylidyl-2 (1H) -on (7) 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -on (8) ) 1-Methyl-5-(2- (1-Methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (9) ) 1-Methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (10) 1 , 3-Dimethyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (11) 1,3-dimethyl-5- (2-) (1-Methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (12) 1,3-dimethyl-5-( 4-Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (13) 5- (2-chloro Phenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (14) 5- (4- ( 3-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) -1-methylpyridine-2 (1H) -one (15) 5- (4- (4-chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d ] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one (16) 5- (4- (2-fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (17) 5- (4- (3-fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (18) 5- (4- (4-fluorophenoxy) -2- (tetrahydro-2H-pyran-4) -Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyran-2 (1H) -one (19) 5- (4- (2,6-difluorophenoxy) -2- (tetrahydro-) 2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (20) 5- (4- (3,5-difluorophenoxy)- 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (21) 5- (4- (3,4) -Difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (22) 5- (4) -(2,4-Difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (23) ) 5- (4- (2,3-Difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) )-On (24) 5- (4- (2,5-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methyl Ppyridine-2 (1H) -on (25) 5- (4- (2-methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl)- 1-Methylpyran-2 (1H) -on (26) 5- (4- (3-me) Toxiphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (27) 5- (4-yl) (4-methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (28) N- (2-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4 -Il) oxy) phenyl) acetamide (29) N-(3-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4) -Il) -1H-benzo [d] imidazole-4-yl) oxy) phenyl) acetamide (30) N-(4-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3-) Il) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) phenyl) acetamide (31) 1-methyl-5- (2- (tetrahydro-2H) -Pyran-4-yl) -4- (2- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -one (32) 1-methyl-5- (2- (Tetrahydro-2H-pyran-4-yl) -4-(3- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -one (33) ) 1-Methyl-5-(2- (Tetrahydro-2H-pyran-4-yl) -4- (4- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -on (34) 2-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazole-4-yl) oxy) benzonitrile (35) 2-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-) 2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (36) 3-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3) -Il) -2- (Tetrahydro-2) H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (37) 3-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine) -3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (38) 4-((5- (1-methyl-) 6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (39) 4- ((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) Il) Oxy) Benzonitrile (40) 5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl)- 1-Methylpyridine-2 (1H) -one (41) 5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) -1,3-dimethylpyranid-2 (1H) -one (42) 1-methyl-5-(4-((2-methylpyran-4-yl) oxy) -2- (tetrahydro-2H) -Pyran-4-yl) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -on (43) 5- (4-((5-chloropyridine-3-yl) oxy)- 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (44) 5- (4-((5-5-yl) Fluoropyridine-3-yl) Oxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (45) ) 5- (4-((5-Fluoropyridine-3-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1,3 -Dimethylpyran-2 (1H) -on (46) 5-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -1-methyl-2- (tetrahydro-) 2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) Nicotinonitrile (47) 1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((5- (trifluoromethyl) pyridin-3-yl) oxy) -1H -Benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (48) 1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((6) -(Trifluoromethyl) Pyridine-3-yl) Oxy) -1H-Benzo [d] Pyridine-5-yl) Pyridine-2 (1H) -On (49) 1,3-Dimethyl-5- (2-( Tetrahydro-2H-Pyran-4-yl) -4-((2- (Trifluoromethyl) Pyridine-4-yl) Oxy) -1H-Benzo [d] Pyridine-5-yl) Pyridine-2 (1H)- On (50) 1-methyl-5-(4-((1-oxo-1,3-dihydroisobenzofuran-5-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (51) 1-methyl-5-(4-((3-oxo-1,3-dihydroisobenzofuran-5-yl) oxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (52) 1-methyl-5- (4-((1) -Oxo-1,3-dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -On (53) 1-methyl-5-(4-((3-oxo-1,3-dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H -Benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (54) 5- (4- (benzo [c] [1,2,5] oxadiazole-4-yloxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (55) 5- (4- (benzo [c] [ 1,2,5] Oxaziazole-5-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) )-On (56) 1-methyl-5- (4- (naphthalen-1-yloxy) -2- (tetrahydro-) 2H-Pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (57) 1-methyl-5- (4- (naphthalen-2-yloxy) -2 -(Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (58) 1-methyl-5- (4- (quinolin-8-) Iloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (59) 1-methyl-5- (4- (4- ( Kinolin-7-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (60) 5- (4- ( 2-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (61) 5-( 4- (3-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (62) 1-Methyl-5-(4- (2- (1-Methyl-1H-pyrazole-4-yl) phenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-Il) Pyridine-2 (1H) -on (63) 5- (4- (2- (Fran-2-yl) phenoxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-5-yl) -1-methylpyridin-2 (1H) -one (64) 5- (4- (2- (fran-3-yl) phenoxy) -2- (tetrahydro-2H-pyran) -4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (65) 5- (4- (benzyloxy) -2- (tetrahydro-2H-) Piran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (66) 1-methyl-5- (4-phenetoxy-2- (tetrahydro-) 2H-Pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (67) 5- (4-((5-chloropyrimidine-4-yl) oxy) -2- (Tetrahydro-2H-pyridine-4-yl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridine-2 (1H) -one (68) 1-methyl-5- (4- (pyrimidine-4-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (69) 5- (4-((6-chloropyridazine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4) -Il) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on (70) 5- (4-((5-chloropyrimidine-2-yl) oxy)- 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (71) 5- (4- (2,6) -Dimethylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (72) 5- (4- (2,6-dimethylphenoxy)- 2-Methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridine-2 (1H) -one (73) 5- (4- (4- (1H-pyrazol-1-yl)) Phenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridine-2 (1H) -one (74) 1,3-dimethyl-5- (2-methyl-4) -(2- (Oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (75) 1,3-dimethyl-5- (2-methyl- 4- (3- (Oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (76) 1,3-dimethyl-5- (2-methyl) -4- (4- (Oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (77) 5- (4- (3-cyclopropylphenoxy) )-2-Methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridine-2 (1H) -one (78) 1,3-dimethyl-5- (2-methyl-4-yl) (3- (1-Methyl-1H-pyrazol-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (79) 1,3-dimethyl-5- (2-Methyl-4- (3- (1-Methyl-1H-pyrazol-5-yl) phenoxy) -1H-benzo [d] imidazole Lu-5-yl) pyridine-2 (1H) -one (80) 1,3-dimethyl-5- (2-methyl-4-(3- (1-methyl-1H-pyrazol-3-yl) phenoxy) ) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (81) 1,3-dimethyl-5- (2-methyl-4- (3- (tetrahydro-2H-pyran-)- 4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (82) 5- (4- (4-cyclopropylphenoxy) -2-methyl-1H-benzo [d] Imidazole-5-yl) -1,3-dimethylpyridine-2 (1H) -one (83) 1,3-dimethyl-5- (2-methyl-4- (4- (1-methyl-1H) -Pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (84) 1,3-dimethyl-5- (2-methyl-4- (4) -(1-Methyl-1H-pyrazol-5-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (85) 1,3-dimethyl-5- (2) -Methyl-4- (4- (1-methyl-1H-pyrazol-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (86) 1,3 -Dimethyl-5- (2-methyl-4- (4- (tetrahydro-2H-pyran-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one ( 87) 1,3-Dimethyl-5-(2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine- 2 (1H) -one (88) 1,3-dimethyl-5-(2-methyl-4-(2-(1-methyl-1H-pyrazol-3-yl) phenoxy) -1H-benzo [d] imidazole) -5-yl) pyridine-2 (1H) -on (89) 5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1,3-dihydro-2H- Benzo [d] imidazol-2-one (90) 1-methyl-5- (2- (oxetane-3-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) )-On (91) 1-methyl-5- (4-phenoxy-2- (tetratetra-3-yl) -1H-benzo [d] Imidazole-5-yl) Pylidin-2 (1H) -one (92) 1-methyl-5- (2- (oxepan-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pylin-2 (1H) -one (93) 5- (2- (2-methoxycyclopropyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -On (94) 5- (2- (3-Hydroxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on (95) 1 -Methyl-5-(2- (3-oxocyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (96) 5- (2- (3) -Methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (97) 1-methyl-5- (4-phenoxy-2-) (7-oxaspiro [3,5] nonan-2-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (98) 5- (2-cyclohexyl-4-phenoxy-) 1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (99) 5- (2- (4,4-difluorocyclohexyl) -4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one (100) 5- (2-cycloheptyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methyl Pyridine-2 (1H) -one (101) 1-methyl-5- (4-phenoxy-2-phenyl-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (102) 1 -Methyl-5-(4-phenoxy-2-((tetrahydro-2H-pyran-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (103) 1-Methyl-5-(2- (morpholinomethyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (104) 1-methyl-5- (4-) Phenoxy-2- (4-phenyltetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (105) 5- (2- (4-yl) Ethoxytetrahydro-2H- Pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (106) 5- (2- (4-hydroxytetrahydro-2H) -Pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (107) 5- (2- (4-fluorotetrahydro-) 2H-Pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (108) 1-methyl-5- (2- (2- ( 2-Methylpyridine-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (109) 1-methyl-5- (2- (1-methyl) Piperidine-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (110) 5,5'-(4-phenoxy-1H-benzo [d] Imidazole-2,5-diyl) bis (1-methylpyridine-2 (1H) -on)
(111) 1,3-dimethyl-5-(2- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one (112) 1,3-dimethyl-5- (5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [ d] Imidazole-2-yl) Pyridine-2 (1H) -on (113) 5,5'-(4-phenoxy-1H-benzo [d] imidazol-2,5-diyl) bis (1,3-dimethyl) Pyridine-2 (1H) -on)
(114) 5- (2- (1,1-Dioxidetetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 ( 1H) -on (115) 5- (2- (1,1-dioxidetetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1,3 -Dimethylpyridin-2 (1H) -one (116) 5- (1,2-dimethyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (117) 5- (1-Cyclopropyl-2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (118) t-butyl- 3- (5- (1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-1-yl) azetidine-1 -Carboxylate (119) 5- (1- (azetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1,3-dimethylpyridin-2 (1H) )-On (120) 5- (1- (1-Acetylazetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1,3-dimethylpyridine -2 (1H) -on (121) 5- (1-isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1- Methylpyridin-2 (1H) -on (122) 5- (1-ethyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl)- 1-Methylpyridin-2 (1H) -one (123) 5- (1-cyclopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridin-2 (1H) -one (124) 5- (1-cyclobutyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) -1-methylpyridin-2 (1H) -one (125) 5- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -4-phenoxy-2- (tetrahydro-) 2H-Pyridine N-4-yl) -1H-benzo [d] imidazol-1-carbonitrile (126) 1-methyl-5- (2-methyl-1- (1-methyl-1H-pyrazol-4-yl) -4 -Phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (127) 1-methyl-5- (1- (1-methyl-1H-pyrazol-4-yl) -4) -Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (128) 1-methyl-5- (2-methyl) -1- (1-Methyl-1H-imidazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (129) 5- (1- ( 2,4-dimethyloxazol-5-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (130) 1,3 -Dimethyl-5- (2-methyl-5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-1-yl) pyridine- 2 (1H) -on (131) 5- (1- (3,5-dimethylisooxazol-4-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1 -Methylpyridine-2 (1H) -one (132) 1-methyl-5- (2-methyl-1-((3-methylisooxazol-5-yl) methyl) -4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) pyridine-2 (1H) -one (133a) 2- (6- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -7-phenoxy-2- ( Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-1-yl) acetonitrile (133b) 2- (5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) ) -4-Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-1-yl) acetonitrile (134) 2- (2-methyl-5- (1-methyl-) 6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-1-yl) acetonitrile (135) 2- (5- (1,5-dimethyl-6-oxo) -1,6-dihydropyridine-3 -Il) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-1-yl) acetonitrile (136a) 5- (1- (2-methoxyethyl) -2-methyl-7-phenoxy-1H- Benzo [d] imidazole-6-yl) -1-methylpyridin-2 (1H) -one (136b) 5- (1- (2-methoxyethyl) -2-methyl-4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) -1-methylpyridin-2 (1H) -one (137) 5- (1-((2-methoxyethoxy) methyl) -2-methyl-4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) -1-methylpyridin-2 (1H) -one (138) 5- (1- (methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5- Il) -1-methylpyridin-2 (1H) -one (139) 5- (1- (methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1, 3-Dimethylpyridin-2 (1H) -one (140a) 1-methyl-5- (2-methyl-1- (2-morpholinoethyl) -7-phenoxy-1H-benzo [d] imidazole-6-yl) Pyridine-2 (1H) -one (140b) 1-methyl-5- (2-methyl-1- (2-morpholinoethyl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (141) 1-methyl-5- (2-methyl-1- (3-morpholinopropyl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -On (142) 1-methyl-5- (2-methyl-1-((1-methyl-1H-pyrazole-4-yl) methyl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) ) Pyridine-2 (1H) -one (143) 3-bromo-1-methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5 -Il) Pyridine-2 (1H) -on (144) 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -2-oxo-1,2- Dihydropyridin-3-carbonitrile (145) 1,3-dimethyl-5- (2-methyl-4-phenoxybenzo [d] oxazol-5-yl) Pyridine-2 (1H) -one (146) 1-methyl- 5- (2-me Chill-4-phenoxybenzo [d] thiazole-5-yl) Pyridine-2 (1H) -one (147) 1,3-dimethyl-5- (2-methyl-4-phenoxybenzo [d] thiazole-5- Pyridine-2 (1H) -one (148) 1-methyl-5- (2-methyl-7-phenoxybenzo [d] thiazole-6-yl) Pyridine-2 (1H) -one (149) 5- (3-Acetyl-7-Phenoxy-1H-Indol-6-yl) -1-Methylpyridin-2 (1H) -On (150) 5- (3-Acetyl-7-Phenoxy-1H-Indol-6-yl) ) -1,3-Dimethylpyridin-2 (1H) -one (151) 1,3-dimethyl-5- (5-phenoxy-2- (tetrahydro-2H-pyran-4-yl) imidazo [1,2- a] Pyridine-6-yl) Pyridine-2 (1H) -on (152) 1-methyl-5- (2-methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridine -6-yl) Pyridine-2 (1H) -one (153) 1,3-dimethyl-5- (2-methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridin- 6-Il) Pyridine-2 (1H) -On (154) 1-Methyl-5- (5-Phenoxy-2- (Tetrahydro-2H-Pyran-4-yl)-[1,2,4] Triazolo [1 , 5-a] Pyridine-6-yl) Pyridine-2 (1H) -one (155) 1,3-dimethyl-5- (5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-[ 1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 (1H) -On

[8] A pharmaceutical composition containing the compound according to any one of the above [1] to [7] or a salt thereof as an active ingredient.
[9] A pharmaceutical composition containing the compound according to any one of the above [1] to [7] or a salt thereof, and other drugs as active ingredients.
[10] A pharmaceutical composition containing the compound according to any one of the above [1] to [7] or a salt thereof as an active ingredient, which is used in combination with other drugs.
[11] The pharmaceutical composition according to any one of the above [8] to [10] for inhibiting a BET protein.
[12] The pharmaceutical composition according to the above [11], wherein the BET protein is selected from the group consisting of BRD2, BRD3, BRD4, and BRDT at least one.
[13] The pharmaceutical composition according to any one of the above [8] to [10] for treating a cancer, a non-cancerous proliferative disease, a fibrous disease, an inflammatory disease, or a viral infection.
[14] Cancer or non-cancerous, characterized by comprising means for administering the pharmaceutical composition according to any one of the above [8] to [10] in vivo and means for performing medical therapy. A treatment system for proliferative disorders.
[15] The treatment system according to the above [14], wherein the medical therapy is γ-ray irradiation, neutron beam irradiation therapy, electron beam irradiation therapy, proton beam therapy, proximity irradiation therapy, or radiation therapy.
[16] Cancer, non-cancerous proliferative disease, fibrous, which comprises a step of administering a therapeutically effective amount of the pharmaceutical composition according to any one of the above [8] to [10] in vivo. How to treat a disease, inflammatory disease, or viral infection.

Since the compound of the present invention represented by the general formula (1) or a salt thereof (hereinafter, also referred to as “the compound of the present invention”) can inhibit the binding between the BET protein and the acetylated lysine, the present invention. According to the above, it is useful for treating cancer and cell proliferative diseases other than cancer, fibrous diseases, inflammatory diseases, viral infections and the like in which the BET protein is involved.

It represents the inhibition result of lipopolysaccharide-induced IL-6 production. The vertical axis shows the IL-6 concentration (ng / mL) in plasma. The left black column shows the result of control (without induction by lipopolysaccharide), the second black column from the left shows the result when only the vehicle (Vehicle) was administered, and the three white columns on the right show the compound of the present invention (the compound of the present invention). The results when Examples 9, 139 and 151) are administered are shown respectively.

Hereinafter, the present invention will be described in detail.

1 Compound of the present invention The compound of the present invention is a compound represented by the following general formula (1) or a salt thereof.

(During the ceremony,
R ¹ represents H, lower alkyl, halogen, or cyano.
R ² represents H, or lower alkyl.
R ³ represents an aryl that may be substituted or an arylalkyl that may be substituted, or a heteroaryl that may be substituted or a heteroarylalkyl that may be substituted.
^R4 represents H, a lower alkyl which may be substituted, an oxo, an aryl which may be substituted, a heterocyclic group which may be substituted, and a cycloalkyl which may be substituted.
X ¹ is C or N,
If X ¹ is C, one of X ² and X ³ is N and the other is N-R ⁵ , O, or S, or one of X ² and X ³ is N-R ⁵ . The other is N-R ⁶ or C-R ⁷ .
When X ¹ is N, one of X ² and X ³ is N and the other is CH, or both X ² and X ³ are N.
R ⁵ and R ⁶ are the same or different and represent H, a lower alkyl which may be substituted, a heterocyclic group which may be substituted, cyano, or a cycloalkyl which may be substituted.
R ⁷ represents H, or a lower acyl.
The two solid and dotted lines represent single or double bonds, depending on X ¹ , X ² , X ³ and R ⁴ and adjacent carbon atoms. )

A compound in which R ¹ is H or a lower alkyl is preferable.
A compound in which R3 is an aryl that may be substituted ^, an arylalkyl that may be substituted, or a heteroaryl that may be substituted is preferable, and a compound that is an aryl that may be substituted is more preferable. Compounds that are optionally substituted phenyls are particularly preferred.
A compound in which ^R4 is a optionally substituted lower alkyl or a optionally substituted heterocyclic group is preferred, optionally substituted lower alkyl, optionally substituted heterocycloalkyl, or substituted. Compounds that are heteroaryls, which may be substituted, are more preferred, and compounds which are methyl, tetrahydropyranyl, or pyrazolyl, which may be substituted, are particularly preferred.
Compounds in which R ⁵ and R ⁶ are the same or different, H, a lower alkyl which may be substituted, or a heterocyclic group which may be substituted are preferable.

Of these, X ¹ is C and one of X ² and X ³ is N and the other is N-R ⁵ , or X ¹ is N and one of X ² and X ³ is N. The compound of the invention in which N and the other is CH, or the compound of the invention in which R ¹ is H or a lower alkyl and R ² is a lower alkyl, or a lower alkyl in which R ⁴ may be substituted, or substitutions. The compound of the present invention, which is a heterocyclic group which may be used, is preferable. More preferably, X ¹ is C, X ² is N, and X ³ is NH, or X ¹ is N, X ² is CH, and X ³ is N, and R ¹ is H or lower alkyl. R ² is a lower alkyl, R ³ is a optionally substituted aryl, R ⁴ may be substituted lower alkyl, optionally substituted heterocycloalkyl, or substituted. It is a compound of the present invention which is a heteroaryl which may be used. More preferably, X ¹ is C, X ² is N, and X ³ is NH, or X ¹ is N, X ² is CH, and X ³ is N, and R ¹ is H or lower alkyl. It is a compound of the present invention in which R ² is a lower alkyl, R ³ is a optionally substituted phenyl, and R ⁴ is a methyl, tetrahydropyranyl, or optionally substituted pyrazolyl.

The compound of the present invention also includes tautomers, geometric isomers and optical isomers of the compound represented by the general formula (1).

1.1 Significance of substituents according to the compound of the present invention The significance of the substituents according to the compound of the present invention is as follows.

Examples of the "alkyl" of the "lower alkyl" and the "arylalkyl" and the "heteroarylalkyl" include linear or branched alkyl having 1 to 4 carbon atoms. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Of these, methyl and ethyl are preferable.

Examples of the substituent in the "optionally substituted lower alkyl" according to ^R4 include halogen; cyano; lower alkoxy; heterocycloalkyl. The substituent can be substituted at any position of the lower alkyl.
Examples of the substituent in the "optionally substituted lower alkyl" according to R ⁵ and R ⁶ include halogen; cyano; lower alkoxy; lower alkoxy alkoxy; heterocycloalkyl; nitrogen atom, oxygen atom, or sulfur atom. A 5-membered ring aromatic heterocyclic group which may be substituted with a lower alkyl containing 1 to 4 ring-constituting atoms (for example, pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl). Can be mentioned. The substituent can be substituted at any position of the lower alkyl.

Examples of the "lower alkoxy" include linear or branched alkoxy having 1 to 4 carbon atoms. Specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy. Of these, methoxy and ethoxy are preferable.
Examples of the "lower alkoxyalkoxy" include linear or branched alkoxyalkoxy having 2 to 6 carbon atoms. Specific examples thereof include methoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxymethoxy, isopropoxymethoxy, propoxyethoxy, and isopropoxyethoxy.
Examples of the "lower acyl" include linear or branched saturated or unsaturated acyls having 1 to 4 carbon atoms. Specific examples thereof include formyl, acetyl, propionyl, butyroyl, and acryllyl. Of these, acetyl is preferable.
Examples of the "lower alkoxycarbonyl" include linear or branched alkoxycarbonyl having 2 to 6 carbon atoms. Specific examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and tert-butoxycarbonyl.

Examples of the "cycloalkyl" include those having a 3- to 8-membered ring. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Substituents in the "optionally substituted cycloalkyl" include, for example, halogen; cyano; lower alkyl; halogen-substituted lower alkyl; optionally protected hydroxy; oxo; lower alkoxy; spiro-bonded heterocycloalkylene. Can be mentioned.

Hydroxy protecting groups include all groups that can be used as conventional hydroxyl group protecting groups, such as "Greene's Protective Groups in Organic Synthesis" by P.G.M.Wuts and T.W.Greene (5th Edition). , 2014) ”. Specific examples thereof include, but are limited to, methyl, ethyl, t-butyl, methoxymethyl, benzyl, p-methoxybenzyl, 2- (trimethylsilyl) ethoxymethyl, trimethylsilyl, t-butyldimethylsilyl and the like. is not.

Examples of the "heterocycloalkyl" include those having a 4- to 8-membered ring containing 1 to 3 oxygen atoms, nitrogen atoms, or sulfur atoms as ring-constituting atoms. Specifically, for example, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, thietanyl, tetrahydrothienyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl can be mentioned.

Examples of the "halogen" include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the "aryl" of "aryl" and "arylalkyl" include monocyclic or condensed aromatic hydrocarbon groups having a total number of atoms in the ring of 6 or 10. Specifically, for example, phenyl and naphthyl can be mentioned. Of these, phenyl is preferred.
Substituents in the "optionally substituted aryl" and the "optionally substituted arylalkyl" include, for example, halogen; cyano; lower alkyl; halogen-substituted lower alkyl; lower alkoxy; acetylamino; cycloalkyl; hetero. Cycloalkyl; A 5-membered ring aromatic heterocyclic group (eg, pyrrolyl, furanyl, imidazolyl, pyrazolyl) which may be substituted with a lower alkyl containing 1 to 4 nitrogen, oxygen, or sulfur atoms as ring constituent atoms. , Oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl). The substituent can be substituted at any position of the aryl or arylalkyl. Further, the aryl may be condensed with a heterocycloalkane such as oxetane, tetrahydrofuran, tetrahydropyran, oxepane, azetidine, pyrrolidine, piperidine, azepan, thietan, tetrahydrothiophene, tetrahydrothiopyran, morpholine and piperazine. The condensation is included in the substitution.

The "heteroaryl" of "heteroaryl" and "heteroarylalkyl" includes, for example, a total of 5 to 10 atoms in a ring containing 1 to 3 nitrogen atoms, oxygen atoms, or sulfur atoms as ring-constituting atoms. Can be mentioned as a monocyclic or condensed ring aromatic heterocyclic group composed of. Specifically, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, indolyl, isoindrill, benzoimidazolyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolinyl, furanyl, benzofuranyl, Isobenzofuranyl, thienyl, benzothienyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, benzoxazolyl, isobenzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzoisothiazolyl Can be mentioned.
Examples of the substituent in the "optionally substituted heteroaryl" and the "optionally substituted heteroarylalkyl" include halogen; cyano; lower alkyl; halogen-substituted lower alkyl; lower alkoxy. The substituent may be substituted at any position of the heteroaryl or heteroarylalkyl.

The "heterocyclic group" contains, for example, heterocycloalkyl, heteroaryl, and 1 to 4 oxygen atoms, nitrogen atoms, or sulfur atoms as ring-constituting atoms, and has saturated and unsaturated bonds in the ring. Examples thereof include monocyclic or condensed heterocyclic groups having a total number of atoms in the ring of 4 to 10. Specific examples of such heterocyclic groups include, for example, dihydropyrrolyl, dihydropyridyl, tetrahydropyridyl, imidazolinyl, pyrazolinyl, dihydropyranyl, indolinyl, isoindolinyl, dihydroquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroquinoly. Examples thereof include xalinyl, tetrahydrocinnolinyl, dihydrobenzofuranyl, dihydroisobenzofuranyl, chromanyl and chromenyl. Further, in the "heterocyclic group" according to ^R4 , a heterocycloalkyl containing an oxygen atom and a sulfur atom as ring-constituting atoms; five members such as pyrrolyl, furanyl, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, and triazolyl. Ring aromatic heterocyclic groups; 6-membered ring aromatic heterocyclic groups of pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl; dihydropyridyl, tetrahydropyridyl are more preferred, and tetrahydropyranyl and pyrazolyl are particularly preferred. In the "heterocyclic group" according to R ⁵ and R ⁶ , a heterocycloalkyl containing a nitrogen atom and an oxygen atom as ring-constituting atoms; Membered ring aromatic heterocyclic groups; 6-membered ring aromatic heterocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl; dihydropyridyl, tetrahydropyridyl are more preferred.

Examples of the substituent in the "optionally substituted heterocyclic group" according to ^R4 include halogen; cyano; lower alkyl; halogen-substituted lower alkyl; optionally protected hydroxy; oxo; lower alkoxy; phenyl. Can be mentioned. The substituent can be substituted at any position of the heterocyclic group.
Examples of the substituent in the "optionally substituted heterocyclic group" according to R ⁵ and R ⁶ include halogen; cyano; lower alkyl; halogen-substituted lower alkyl; lower acyl; lower alkoxycarbonyl. The substituent can be substituted at any position of the heterocyclic group.

1.2 Salt of the compound of the present invention The salt of the compound of the present invention is a pharmaceutically acceptable salt, and examples thereof include a pharmaceutically acceptable acid addition salt, a base addition salt, an ammonium salt, and an amino acid addition salt. The salt may be used alone or in combination of two or more.
Further, the compound of the present invention (including a salt) may be in the form of a hydrate or a solvate.

Examples of the acid addition salt include a salt with an inorganic acid and a salt with an organic acid. Examples of the salt with the inorganic acid include inorganic acid salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Examples of the salt with the organic acid include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, and the like. Salts with ascorbic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid and the like can be mentioned.

Examples of the base addition salt include a salt with an inorganic base and a salt with an organic base. Examples of the salt with an inorganic base include salts with alkali metals such as sodium and potassium; and salts with alkaline earth metals such as calcium and magnesium.

Examples of the salt with the organic base include trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, 4-methylmorpholin, diethylamine, dicyclohexylamine, prokine, dibenzylamine and N-benzyl. Salts with nitrogen-containing organic bases such as -β-phenethylamine, 1-ephenamine and N, N'-dibenzylethylenediamine can be mentioned.

Examples of the ammonium salt include methylpyridinium salt and acetylpyridinium salt. Examples of amino acid addition salts include addition salts such as lysine, glycine, alanine, phenylalanine, glutamic acid, aspartic acid, and arginine.

2 Method for producing the compound of the present invention Next, a method for producing the compound of the present invention will be described. The production method shown below is an example of the production method of the compound of the present invention, and is not limited to the production method shown below.
The compound of the present invention can be produced by applying various known synthetic methods by utilizing its basic structure or characteristics based on the type of substituent. At that time, depending on the type of the functional group, it may be effective in terms of manufacturing technology to replace the functional group with an appropriate protecting group at the stage from the raw material to the intermediate. Examples of such protecting groups include the protecting groups described in "Greene's Protective Groups in Organic Synthesis (5th Edition, 2014)" by PGMWuts and TWGreene. It may be appropriately selected and used according to the reaction conditions of. In such a method, a desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group as necessary.

Further, in each step or reaction, the post-reaction treatment can be carried out by a method usually used. The compound obtained in each step or reaction can be used in the next reaction as a state of a reaction solution or a crude product. The product can also be isolated from the reaction mixture according to conventional methods. The isolation or purification of the product can be carried out by appropriately selecting and combining conventional methods such as crystallization, recrystallization, distillation, liquid separation and chromatography, if necessary.

2.1 First manufacturing method

(In the formula, X represents a halogen, boronic acid, or boronic acid pinacol ester, and Py is the following general formula (4).

Group represented by, or the following general formula (5)

Indicates a group represented by, Y indicates a halogen or a hydroxy that may be protected, and R ¹ , R ² , R ³ , R ⁴ , X ¹ , X ² and X ³ are the same as described above. Show the meaning. Here, examples of the "hydroxy protecting group" include methyl, ethyl, t-butyl, methoxymethyl, benzyl, p-methoxybenzyl, 2- (trimethylsilyl) ethoxymethyl, trimethylsilyl, t-butyldimethylsilyl and the like. However, it is not limited to these (hereinafter, synonymous). )

(1-1a)
When X is a halogen, the compound represented by the general formula (3) is a compound represented by the general formula (2) in a solvent inert to the reaction, in the presence of a base and a palladium catalyst, in the presence of a ligand or not. It can be obtained by reacting with an equal amount or an excess amount of boronic acid or boronic acid pinacol ester in the presence. This reaction may be stirred under cooling to heating, preferably at room temperature to 160 ° C. for 5 minutes to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not limited to tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, and the like. Examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water, toluene or a mixture thereof.

Examples of the base used in this reaction include inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate and potassium hydroxide, and organic bases such as triethylamine and diisopropylethylamine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound represented by the general formula (2).

The palladium catalyst used in this reaction is not particularly limited, but for example, an inorganic palladium salt such as palladium chloride; an organic palladium salt such as palladium (II) acetate; tetrakis (triphenylphosphine) palladium (0), bis ( Triphenylphosphine) palladium (II) dichloride, bis (acetoform) palladium (II) dichloride, bis (benzonitrile) palladium (II) dichloride, bis (2,4-pentandionato) palladium (II), bis (dibenzylidene) Acelatin) Palladium (0), Tris (dibenzylideneacetone) Dipalladium (0), (1,1'-bis (diphenylphosphino) ferrocene) Palladium (II) dichloride, dichlorobis (di-t-butyl (p-dimethyl) Aminophenyl) phosphino) palladium (II), and organic palladium complexes such as allylpalladium (II) chloride (dimer) and polymer-supported bis (acetate) triphenylphosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphenylphosphine palladium. Examples thereof include polymer-immobilized organic-palladium complexes such as (II), which may be used in combination. The amount of the palladium catalyst used may be 0.00001 to 1 times mol, preferably 0.01 to 0.2 times mol, with respect to the compound represented by the general formula (2).

The ligands optionally used in this reaction include, for example, trialkylphosphines such as trimethylphosphine and tri-t-butylphosphine; tricycloalkylphosphines such as tricyclohexylphosphine; tria such as triphenylphosphine and tritrylphosphine. Lille phosphines; trialkyl phosphites such as trimethyl phosphine, triethyl phosphine and tributyl phosphine; tricycloalkyl phosphites such as tricyclohexylphosphine; triarylphosphite such as triphenylphosphine; 1, Imidazolium salts such as 3-bis (2,4,6-trimethylphenyl) imidazolium chloride; diketones such as acetylacetone and octafluoroacetylacetone; amines such as trimethylamine, triethylamine, tripropylamine and tributylamine; 1,1 '-Bis (diphenylphosphine) ferrocene; 2,2'-bis (diphenylphosphine) -1,1'-binaphthyl; 2-dicyclohexylphosphine-2', 6'-dimethoxybiphenyl; 2-dicyclohexylphosphine- 2', 4', 6'-triisopropylbiphenyl; 2- (di-t-butylphosphine) -2', 4', 6'-triisopropylbiphenyl; and 2- (di-t-butylphosphine) Biphenyl is mentioned, and these may be used in combination.

(1-1b)
When X is a boronic acid or a boronic acid pinacol ester, the compound represented by the general formula (3) is a compound represented by the general formula (2) in the presence of a base and a palladium catalyst in a solvent inert to the reaction. It can be obtained by reacting with an equal amount or an excess amount of a halogen compound in the presence or absence of a ligand. This reaction may be carried out according to (1-1a).

(1-2a)
When Py is a group represented by the general formula (4) and Y is a halogen, the compound represented by the general formula (1) is a compound represented by the general formula (3), which is not suitable for water or reaction. It can be obtained by hydrolysis in the presence or absence of an acid or base in a mixture of active solvent and water. This reaction may be stirred under cooling to heating, preferably at room temperature to 100 ° C. for 5 minutes to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not particularly limited, but tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, N, Examples thereof include N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene or a mixture thereof.

The acid optionally used in this reaction is not particularly limited, and examples thereof include hydrochloric acid and sulfuric acid.
The base optionally used in this reaction is not particularly limited, and examples thereof include sodium hydroxide and potassium hydroxide.
The amount of the acid or base used may be 0.1 to 100 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula (3).

(1-2b)
When Py is a group represented by the general formula (4) and Y is a halogen, the compound represented by the general formula (1) is a compound represented by the general formula (3) in an anhydrous alcohol solvent or a reaction. Y can be converted to a protected hydroxy group by stirring in the presence of a base in a mixed solvent of an unaffected solvent and an anhydrous alcohol solvent.

Examples of the anhydrous alcohol solvent include methanol, benzyl alcohol, allyl alcohol and the like, and examples of the solvent that does not affect the reaction include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N, N-dimethylformamide. , N, N-dimethylacetamide and the like. This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 100 ° C. for 5 minutes to 24 hours. The base used in this reaction is not particularly limited, but is, for example, alkali metals such as lithium, sodium and potassium, potassium carbonate, sodium hydrogen carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate, sodium hydroxide and hydroxide. Examples thereof include inorganic bases such as potassium, organic bases such as diisopropylethylamine, pyridine, N-methylmorpholin, 1-methylimidazole, N, N-dimethylbenzylamine and triethylamine.

(1-2c)
When Py is a group represented by the general formula (4) and Y is a protected hydroxy group, the compound represented by the general formula (1) is removed from the compound represented by the general formula (3). It can be obtained by protecting. Removal of the protecting group of compound (3) can be carried out, for example, by referring to the method described in "Greene's Protective Groups in Organic Synthesis" described above.
2.2 Second manufacturing method

(In the formula, Z represents a protecting group of R ³ or hydroxy, X ^2a represents a group represented by the general formula NR ⁵ , O, or S, and X ^3a represents a group represented by the general formula NR ⁵ . , O or S, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² , X ³ and Py have the same meanings as described above.)

(2-1a)
When X ¹ is C, the compound represented by the general formula (7) is a compound represented by the general formula (6) in a reaction-inert solvent in the presence or absence of an acid or an acid compound. It can be obtained by reacting with an equal amount or an excess amount of carboxylic acids, esters, or ortho acid esters. This reaction may be stirred under cooling to heating, preferably at 0 to 180 ° C. for 0.05 to 48 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not limited to tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, and the like. N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, or mixtures thereof can be mentioned. Acids optionally used in this reaction include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and polyphosphoric acid, p-toluene sulfonic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, 10-camper sulfonic acid and p. -Includes organic acids such as pyridinium toluene sulfonate and Lewis acids such as zirconium chloride (IV) and itterbium trifluoromethanesulfonate (III). Examples of the acid chloride used in this reaction as desired include thionyl chloride, phosphorus oxychloride, phosphorus trichloride and the like. The amount of the acid or acid chloride used may be 0.001 to 50 times mol, preferably 0.1 to 10 times mol, of the compound represented by the general formula (6).

(2-1b)
When X ¹ is C, the compound represented by the general formula (7) is a compound represented by the general formula (6) in a solvent inert to the reaction, in the presence or absence of an oxidizing agent, etc. It can also be obtained by reacting with an amount or excess of aldehydes. This reaction may be stirred under cooling to heating, preferably at 0 to 180 ° C. for 0.05 to 48 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not limited to tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, and the like. N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, or mixtures thereof can be mentioned. Examples of the oxidizing agent optionally used in this reaction include one or more selected from air, oxygen, iodine, silver (I) oxide, ammonium cerium (IV) nitrate, hydrogen peroxide, aldehydes and the like. .. The amount of the oxidizing agent used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound represented by the general formula (6).

(2-1c)
When X ¹ is C, the compound represented by the general formula (7) is a compound represented by the general formula (6) and a compound represented by the general formula (8a) or (8b) or a mixture thereof. After that, it can be obtained by subjecting it to a cyclization reaction.

(2-1c-1)
The compound represented by the general formula (8a) or (8b) or a mixture thereof is a compound represented by the general formula (6) in a solvent inert to the reaction, in the presence or absence of a base, etc. It can be obtained by reacting with an amount or excess of an acid halide or acid anhydride. This reaction may be stirred under cooling to heating, preferably at room temperature to 180 ° C. for 1 to 24 hours. The solvent used in this reaction is not particularly limited as long as it is inert to this reaction, but is not particularly limited, but isocyanate, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, N. , N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, or mixtures thereof. Bases optionally used in this reaction include, for example, inorganic bases such as potassium carbonate, sodium hydrogen carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate and potassium hydroxide, and diisopropylethylamine, pyridine, N-methylmorpholin, 1 -Includes organic bases such as methylimidazole, N, N-dimethylbenzylamine and triethylamine. The amount of the base used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound represented by the general formula (6).

(2-1c-2)
The compound represented by the general formula (8a) or (8b) or a mixture thereof is a compound represented by the general formula (6) in the presence of an additive in a solvent inert to the reaction in the presence of a condensing agent. It can be obtained by reacting with an equal amount or an excess amount of a carboxylic acid in the presence or absence of a base, in the presence or absence of a base. This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it is inert to this reaction, but is not particularly limited, but isocyanate, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, N. , N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, or mixtures thereof. Examples of the condensing agent used in this reaction include N, N'-dicyclocarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), N, N'-di- (t-butyl) carbodiimide and 1. Carbodiimides such as-(3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI); 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonyldi (1,2,4-triazole) ( CDT) and imidazoles such as 1,1'-oxalyldiimidazole; O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), O -(7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), N, N, N', N'-tetramethyl-O- (N-Succinimidyl) Uronium Tetrafluoroborate (TSTU), N, N, N', N'-Tetramethyl-O- (N-Succinimidyl) Uronium Hexafluorophosphate (HSTU), O- (3, 4-Dihydro-4-oxo-1,2,3-benzotriazine-3-yl) -N, N, N', N'-tetramethyluronium tetrafluoroborate (TDBTU), N, N, N' , N'-tetramethyl-S- (1-oxide-2-pyridyl) thiouronium tetrafluoroborate (TOTT), O- [2-oxo-1 (2H) -pyridyl] -N, N, N' , N'-Tetramethyluronium Tetrafluoroborate (TPTU) and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholinocarbodinium hexafluorophosphate (COMU) and other uroniums; 1H-benzotriazole-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1H-benzotriazole-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azaazabenzotriazole) -1-Iloxy) Tripyrolidinophosphonium hexafluorophosphate (PyAOP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), bromotris (dimethylamino) phosphonium hexafluorophosphart (Brop) and 3- (diethoxyphosphoryl) Phosphoniums such as oxy) -1,2,3-benzotriazine-4 (3H) -one (DEPBT) can be mentioned. The amount of the condensing agent used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound represented by the general formula (6).

Additives optionally used in this reaction include, for example, 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu) and dicarbonate (N-succinimidyl). ) (DSC) and the like. The amount of the additive used may be 0.01 to 10 times mol, preferably 0.1 to 5 times mol, with respect to the condensing agent.
Examples of the base optionally used in this reaction include organic bases such as triethylamine, diisopropylethylamine and N-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. The amount of the base used may be 0.1 to 10 times mol, preferably 1 to 5 times mol, with respect to the condensing agent.

(2-1c-3)
The compound represented by the general formula (7) is a compound represented by the general formula (8a) or (8b) or a mixture thereof in a solvent inert to the reaction, in the presence or absence of an acid or a base. It can be obtained by subjecting it to a cyclization reaction. This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not particularly limited, but isocyanate, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane and chloroform. , N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, and mixtures thereof. Examples of the acid optionally used in this reaction include hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, p-toluenesulfonic acid and acetic acid. Bases optionally used in this reaction include, for example, inorganic bases such as potassium carbonate, sodium hydrogen carbonate, sodium carbonate, cesium carbonate, tripotassium phosphate and potassium hydroxide, and diisopropylethylamine, pyridine, N-methylmorpholin, 1 -Includes organic bases such as methylimidazole, N, N-dimethylbenzylamine and triethylamine. The amount of the acid or base used may be 0.1 to 100 times mol, preferably 1 to 10 times mol, with respect to the compound represented by the general formula (8a) or (8b) or a mixture thereof. Further, if desired, a dehydrating reagent such as thionyl chloride, phosphorus oxychloride, or polyphosphoric acid may be added.
(2-1d)

(In the formula, ^R4 , Z and Py have the same meanings as described above.)

(2-1d-1)
Among the compounds represented by the general formula (7), the compound represented by the general formula (7a) is a compound represented by the general formula (9) in which an acid or a base is present in a solvent inert to the reaction. It can be obtained by reacting with an equal amount or an excess amount of the α-haloketone derivative in the presence or absence of the substance. This reaction may be stirred under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but water, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, etc. Included are chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, toluene, xylene, or mixtures thereof. Acids optionally used in this reaction include, for example, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphate, thionyl chloride, phosphorus oxychloride, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acetic acid, anhydrous acetic acid and trifluoro. Examples include acetic acid. Examples of the base optionally used in this reaction include organic bases such as triethylamine, diisopropylethylamine and N-methylmorpholine, and inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and sodium hydroxide. The amount of the acid or base used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound represented by the general formula (10).

(2-1d-2)
Among the compounds represented by the general formula (7), the compound represented by the general formula (7b) is obtained by converting the compound represented by the general formula (9) into a compound represented by the general formula (11) and then using the compound represented by the general formula (11). It can be obtained according to (2-1a to c).

The compound represented by the general formula (11) is prepared by substituting the compound represented by the general formula (9) with an equal amount or an excess amount of O-substitution in a solvent inert to the reaction in the presence or absence of a base. It can be obtained by reacting with hydroxylamine or a hydrochloride thereof. This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not limited to tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, and the like. Examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, and mixtures thereof. Examples of the base optionally used in this reaction include organic bases such as triethylamine, diisopropylethylamine and N-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. The amount of the base used may be 0.1 to 10 times mol, preferably 1 to 5 times mol, of the compound represented by the general formula (9). Examples of the O-substituted hydroxylamine used in this reaction include O-methythylene sulfonyl hydroxylamine, O- (2,4-dinitrophenyl) hydroxyamine and hydroxyamine-O-sulfonic acid.

(2-1d-3)
Among the compounds represented by the general formula (7), the compound represented by the general formula (7b) is obtained by converting the compound represented by the general formula (9) into a compound represented by the general formula (12) and then using the compound represented by the general formula (12). It can be obtained by subjecting it to a cyclization reaction.

(2-1d-3-1)
For the compound represented by the general formula (12), the compound represented by the general formula (9) is reacted with an equal amount or an excess amount of the N, N-dimethylformamide dialkylacetal derivative in a solvent inert to the reaction. After that, it can be obtained by reacting with an equal amount or an excess amount of hydroxylamine or a hydrochloride thereof. This reaction may be stirred under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not limited to tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, and the like. Examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, or a mixture thereof.

(2-1d-3-2)
The compound represented by the general formula (7b) can be obtained by subjecting the compound represented by the general formula (12) to a cyclization reaction in a solvent inert to the reaction in the presence of an acid. This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but water, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, etc. Chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, or mixtures thereof can be mentioned. Examples of the acid used in this reaction include hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphate, thionyl chloride, phosphorus oxychloride, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acetic acid, anhydrous acetic acid and trifluoroacetic acid. Can be mentioned. The amount of the acid used may be 0.1 to 100 times mol, preferably 1 to 50 times mol, of the compound represented by the general formula (12).
(2-2)

(In the formula, Z ^a has a hydroxy protecting group, L ¹ has a leaving group, and X ¹ , X ² , X ³ , R ³ , R ⁴ , and Py have the same meanings as described above. Examples of the "leaving group" include halogen, optionally substituted alkylsulfonyloxy having 1 to 6 carbon atoms, and optionally substituted arylsulfonyloxy. The alkylsulfonyloxy and arylsulfonyloxy may be mentioned. Examples of the substituent that can be substituted with the above include halogen, nitro, cyano, and lower alkyl (hereinafter, synonymous).

Among the compounds represented by the general formula (7), when the compound is represented by the general formula (7c), the compound represented by the general formula (10) is the compound represented by the general formula (10) with the protective group of the hydroxy group removed. It can be obtained by preparing the compound represented by (13) and then reacting with the compound represented by the general formula (14).

(2-2-1)
Removal of the protecting group of the compound represented by the general formula (7c) can be carried out, for example, with reference to the method described in the above-mentioned "Greene's Protective Groups in Organic Synthesis".
(2-2-2)
The compound represented by the general formula (10) is a compound represented by the general formula (13) in an equal amount or an excess amount in a solvent inert to the reaction, in the presence or absence of a base. It can be obtained by reacting with the compound represented by 14). This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not limited to tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, and the like. Examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, and / or a mixture thereof. Examples of the base optionally used in this reaction include organic bases such as triethylamine, diisopropylethylamine and N-methylmorpholine, and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. The amount of the base used may be 0.1 to 10 times mol, preferably 1 to 5 times mol, of the compound represented by the general formula (13).

(2-3)
When Py is a compound which is a group represented by the general formula (4), the compound represented by the general formula (1) is derived from the compound represented by the general formula (10) (1-2a to c). Can be obtained according to.

2.3 Raw material manufacturing method The raw materials in the first manufacturing method and the second manufacturing method can be obtained by, for example, the following manufacturing methods.
2.3.1 Manufacturing method A

(In the formula, L ² indicates a leaving group, and R ³ , R ⁴ , X and X ^3a have the same meanings as described above.)
Among the compounds represented by the general formula (2), the compounds represented by the general formula (2a) are the compounds represented by the general formulas (15) to the compounds represented by the general formulas (16) to (20). Can be obtained via.

(A-1-1)
The compound represented by the general formula (16) is obtained by reacting the compound represented by the general formula (15) with an equal amount or an excess amount of alcohols in a solvent inert to the reaction in the presence of a base. Obtainable. This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it is inert to this reaction, but is not particularly limited, but isocyanate, 1,2-dimethoxyethane, 1,4-dioxane, acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, N. , N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, toluene, xylene, or mixtures thereof. Examples of the base used in this reaction include potassium carbonate, cesium carbonate and sodium hydride. The amount of the base used may be 1 to 50 times mol, preferably 2 to 10 times mol, of the compound represented by the general formula (15).

(A-1-2) The compound represented by the general formula (17) can be obtained by subjecting the compound represented by the general formula (16) to a reduction reaction of a nitro group. In this reaction, the compound represented by the general formula (16) is mixed with the compound represented by the general formula (16) in a solvent inert to the reaction, using an excessive amount of metal powder in the presence of an acid, under cooling to heating, preferably at room temperature to 180 ° C. The mixture may be stirred for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, and examples thereof include methanol, ethanol, acetic acid, water, and a mixture thereof. Examples of the metal powder used in this reaction include iron, zinc and tin. Examples of the acid used in this reaction include hydrochloric acid, ammonium chloride and acetic acid. The amount of the acid used is not particularly limited, but is preferably 5 to 10 times mol with respect to the compound represented by the general formula (16), and acetic acid may be used as the solvent.

The compound represented by the general formula (17) can also be obtained by reducing the compound represented by the general formula (16) in a solvent inert to the reaction under a hydrogen atmosphere using a catalytic reduction catalyst. be able to. This reaction may be carried out by stirring under cooling to heating, preferably at room temperature to 180 ° C. for 0.05 to 24 hours. The solvent used in this reaction is not particularly limited as long as it does not inhibit this reaction, but is not particularly limited, such as tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, methanol, ethanol, acetic acid, water or a mixture thereof. Can be mentioned. Examples of the catalytic reduction catalyst used in this reaction include palladium-carbon, platinum, osmium and the like. The amount of the catalytic reduction catalyst used is 0.001 to 5 times (W / W), preferably 0.01 to 1 times (W / W) with respect to the compound represented by the general formula (16). All you need is.

(A-1-3)
The compound represented by the general formula (2a) can be obtained from the compound represented by the general formula (17). This reaction may be carried out according to (2-1a to c).

(A-2-1)
The compound represented by the general formula (18) can be obtained by acylating the compound represented by the general formula (15). This reaction may be carried out according to (2-1c-1) or (2-1c-2).

(A-2-2)
The compound represented by the general formula (19) can be obtained by reacting the compound represented by the general formula (18) with an equal amount or an excess amount of alcohols. This reaction may be carried out according to (A-1-1).

(A-2-3)
The compound represented by the general formula (20) can be obtained by subjecting the compound represented by the general formula (19) to a reduction reaction of a nitro group. This reaction may be carried out according to (A-1-2).

(A-2-4)
The compound represented by the general formula (2a) can be obtained by subjecting the compound represented by the general formula (20) to a cyclization reaction. This reaction may be carried out according to (2-1c-3).
2.3.2 Manufacturing method B

(In the formula, R ³ , R ⁴ , X and X ^2a have the same meanings as described above.)

Among the compounds represented by the general formula (2), the compound represented by the general formula (2b) can be obtained according to the production method A.
2.3.3 Manufacturing method C

(In the formula, X, ^X3a , Z and Py have the same meanings as described above.)
Among the compounds represented by the general formula (6), the compound represented by the general formula (6a) can be obtained from the compound represented by the general formula (21) via the compound represented by the general formula (22). can.

(C-1)
The compound represented by the general formula (22) can be obtained from the compound represented by the general formula (21). This reaction may be carried out according to (1-1a) or (1-1b).

(C-2)
The compound represented by the general formula (6a) can be obtained by subjecting the compound represented by the general formula (22) to a reduction reaction of a nitro group. This reaction may be carried out according to (A-1-2).
2.3.4 Manufacturing method D

(In the formula, X ^2a , Z and Py have the same meanings as described above.)
Among the compounds represented by the general formula (6), the compound represented by the general formula (6b) can be obtained according to the production method C.
2.3.5 Manufacturing method E

(In the formula, L ³ indicates a leaving group, and X, Z and Py have the same meanings as described above.)
The compound represented by the general formula (9) can be obtained from the compound represented by the general formula (23) via the compound represented by the general formula (24).

(E-1)
The compound represented by the general formula (24) can be obtained by reacting the compound represented by the general formula (23) with an equal amount or an excess amount of alcohols. This reaction may be carried out according to (A-1-1).

(E-2)
The compound represented by the general formula (9) can be obtained from the compound represented by the general formula (24). This reaction may be carried out according to (1-1a) or (1-1b).

2.4 Others The produced compound of the present invention can be isolated or purified as a free substance or by subjecting it to a salt forming treatment by a conventional method and as a salt thereof. The isolation or purification method is not particularly limited, and for example, commonly used methods such as crystallization, recrystallization, distillation, liquid separation, and chromatography can be appropriately selected and combined. The hydrate or solvate of the compound of the present invention can be obtained according to a method known per se.
The present invention also includes various crystals and co-crystals of the compound of the present invention (including salts).

3. Uses of the compound of the present invention The compound of the present invention can inhibit the binding of one or more of the BET proteins BRD2, BRD3, BRD4, and BRDT to acetylated lysine, for example. In addition, the compound of the present invention can selectively inhibit one or more BET proteins over bromodomain-containing proteins other than BET proteins. As used herein, "selective" means that a compound binds to or inhibits a BET protein, respectively, with greater affinity or intensity of action compared to criteria such as another BET protein.
Therefore, the compound of the present invention is useful, for example, when treating a disease involving a BET protein. A disease involving a BET protein refers to a disease in which one or more of BRD2, BRD3, BRD4, and BRDT, or a mutant thereof, contributes to the onset.

3.1 Diseases for which the compound of the present invention is effective Examples of diseases for which the compound of the present invention is effective for treatment include cancer. In addition, as diseases or conditions that can be treated with the compound of the present invention, for example, diseases or conditions related to cell proliferation diseases other than cancer, fibrous diseases, inflammatory diseases, viral infections, ischemia-reperfusion injury, etc. Can be mentioned.

Examples of the above cancers include, but are not limited to, neuroma, leukemia, lymphocytic leukemia, myeloid leukemia, T-cell leukemia, T-cell lymphoma, basal cell carcinoma, spinous cell carcinoma, malignant melanoma, bile duct cancer, etc. Bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, spinal cord tumor, chorionic villus cancer, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, colon cancer, colorectal cancer, cranial pharyngoma, cyst Adenocarcinoma, diffuse large B-cell lymphoma, abnormal growth dysfunction, embryonic cancer, uterine body cancer, epithelial sarcoma, coat cell tumor, epithelial cancer, erythrocytosis, esophageal cancer, estrogen receptor-positive breast cancer, essential platelets Hememia, Ewing tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glial blastoma, glioma, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, smooth Myoma, fatty sarcoma, lung cancer, lymphatic endothelial sarcoma, lymphangioma, lymphoblastic leukemia, lymphoma (hodgkin and non-hodgkin), colon cancer, ovarian cancer, pancreatic cancer, prostate cancer, meningeal tumor, mesopharyngeal tumor , Multiple myeloma, myeloma, mucoid sarcoma, neuroblastoma, NUT midline cancer (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, papillary adenocarcinoma, papillary cancer, Pine fruit tumor, true erythrocytosis, rectal cancer, renal cell cancer, retinal blastoma, rhabdomyomyoma, sarcoma, adipose adenocarcinoma, sperm epithelioma, small cell lung cancer, gastric cancer, squamous epithelial cancer, synovial tumor , Sweat adenocarcinoma, thyroid cancer, testicular tumor and the like.

Examples of cell proliferative disorders other than the above cancers are, but are not limited to, insulinoma, pituitary adenoma, brown cell tumor, ganglion, malformation, myoma, Cushing syndrome, aldosteronism, eosinophilia syndrome, perianal. Adenomas, osteochondroma, mixed tumors, lipomas, gastrointestinal stromal tumors, small intestinal tumors, nerve sheath tumors, polytemia, adenomas, salivary gland tumors, obesity cell tumors, squamous cysts, fibroblastomas, etc. Be done.

Examples of the above-mentioned fibrotic diseases include, but are not limited to, myelofibrosis, idiopathic pulmonary fibrosis, renal fibrosis, postoperative stenosis, hypertrophic scars, keloids, sclerosis, and myocardial fibrosis. ..
Examples of the above-mentioned inflammatory diseases are not limited to these, but are allergies, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary disease, degenerative joint disease, organ rejection, glomerular nephritis, hepatitis, pituitary inflammation, inflammation. Lupus erythematosus, Kawasaki disease, lupus nephritis, polysclerosis, myocarditis, myitis, nephritis, severe myasthenia, dermatitis, eczema, atopic dermatitis, psoriasis, psoriatic arthritis, septicemia, septic syndrome, septic These include shock, systemic lupus erythematosus, tissue transplant rejection, type I diabetes, white spots, and circular alopecia.

Examples of the above viral infections are not limited to these, but are caused by infections with adenovirus, Epstein-Bur virus, hepatitis B virus, hepatitis C virus, herpesvirus, human immunodeficiency virus, human papillomavirus, and poxvirus. Diseases to be mentioned.
Examples of diseases or conditions associated with the above-mentioned ischemia-reperfusion injury are, but are not limited to, myocardial infarction, cerebrovascular ischemia (stroke), acute coronary syndrome, renal reperfusion injury, organ transplantation, coronary artery bypass, cardiopulmonary. Bypass methods and conditions such as lung, kidney, liver, gastrointestinal tract, or peripheral limb embolism can be mentioned.

In addition, the compounds of the present invention are useful for treating disorders of lipid metabolism mediated by APO-A1 regulation such as hypercholesterolemia, atherosclerosis, and Alzheimer's disease. It is also useful in the treatment of ophthalmic signs such as dry eye.

3.2 Combination therapy The compounds of the present invention can be used in combination with other drugs. That is, one or more compounds of the present invention can be used in combination therapy with other drugs. The compounds of the present invention and other drugs can be administered simultaneously or sequentially in no particular order.

The compounds of the invention can also be used in conjunction with agents that target epigenetic regulators. Examples of epigenetic regulators include histone lysine methyltransferases, histone arginine methyltransferases, histone demethylases, histone deacetylases, histone acetylases, and DNA methyltransferases.

One or more compounds of the invention and one or more other drugs can be used in combination to treat cancer and cell proliferation disorders other than cancer. The compounds of the invention are also used in conjunction with surgery or medical therapies such as, for example, γ-ray irradiation, neutron beam irradiation therapy, electron beam irradiation therapy, proton beam therapy, proximity irradiation therapy, and radiation therapy such as systemic radioisotopes. be able to. Examples of the other drug include the following.

Avalerix, aldesroykin, alemtuzumab, alitretinoin, alloprinol, altretamine, anastrozole, arsenic, asparaginase, azacitidine, bevasizumab, bexarotene, bleomycin, voltezomib, busulfan, carsterone, capesitabin, carboplatin Cladribine, Clofarabine, Cyclophosphamide, Citarabin, Dacarbazine, Dactinomycin, Dartepalin sodium, Dasatinib, Daunorubicin, Decitabin, Deniroykin, Deniroykin diphthitox, Dexrazoxane, Dosetaxel, Doxorubicin, Propionate dromostanolone , Estramstin, Etoposide Phosphate, Etoposide, Exemestane, Philgrastim, Floxuridine, Fludarabin, Fluorouracil, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab Ozogamycin, Goselelin acetate, Histrelin acetate, Ibritumomabuchi Uxetane, Idalbicin, Iphosphamide, Imatinib mesylate, Interferon alpha 2a, Ilinotecan, Lapatinib tosylate, Lenalidemide, Retrozol, Leucovorin, Leuprolide acetate, Revamisol, Romustin, Mechloretamine, Megestrol acetate, Melfalan, Melcaptoposide Metoxalen, Mitomycin C, Mitotan, Mitoxanthron, Nandrolonephenpropionate, Nerarabin, Nofetumomab, Oxaliplatin, Paclitaxel, Pamidronic acid, Panitumumab, Pegaspargase, Pegfilgrastim, Pemethrexed disodium, Pentostatin, Pipobromanth, Mycin, procarbazine, quinacrine, lasbricase, rituximab, luxolitinib, sorafenib, streptozosine, sunitinib, snitinib apple acid, tamoxyphene, temozolomid, teniposide, testlactone, salidomidose, thioguanine, thiotepa, topotepa , Valrubicin, bin blastin, bin kristin, binorelbin, bolinostat, zoledronic acid, gilteritinib, bemurafenib, defacitinib, rapamycin, tramethinib, binimeti Nibs, Temsirolimus, etc.

Also in the treatment of fibrotic or inflammatory diseases, the compounds of the invention can be used, for example, in combination with one or more other drugs selected from:
Corticosteroids such as triamcinolone, dexamethasone, betamethasone, fluosinolone, cortisone, prednisolone, flumetholone, clobetazol; non-steroidal anti-inflammatory agents such as diclofenac, flurbiprofen, ketrolac, sprofene; chromolin, rhodoxamide, levocabastine, nafazoline Antiallergic agents such as pheniramine; heparin-like substances; sodium hyaluronate; cyclosporine; tachlorimus; active vitamin D3 derivative; pimechlorimus; rituximab; secquinumab; dehydroepiandrosterone; anakinla; efarizumab; sodium mycophenolate; etanelcept; hydroxychlorokin; Salidomide etc.

Also in the treatment of viral infections, the compounds of the invention can be used, for example, in combination with one or more other drugs selected from:
Acyclovir, Vidarabin, Baracyclovir, Famcyclovir, Amenamevir, Gancyclovir, Balgancyclovir, Hoscalnet as therapeutic agents for herpesvirus infections, Imikimod, Servirix, Gardacil as therapeutic agents for human papillomavirus infections, Paribizumab as a therapeutic agent for RS virus infection, amantadin, zanamivir, oseltavir, rimantadine, favipyrabir, baroxavir malvoxil as a therapeutic agent for influenza, azidothymidine (zidovudine) as a therapeutic agent for human immunodeficiency syndrome, zidovudine, zarcitabine, sanilbudin, ramibdin, abacavir, Tenofovir, Emtricitabin, Nevirapin, Efabilentz, Delabirdin, Etravirin, Lilpibilin, Inzinaville, Sakinaville, Ritonavir, Nerphinavir, Amprenaville, Atazanaville, Hosamprenaville, Darnaville, Lartegrabir, Elbitegrabir Nucleic acid analog drugs such as interferon (IFN), ramibdin, adefovir, entecavir, tenofovir, bemlidi, tervibdin, and klevdin as hepatitis treatments, and interferon (IFN), boceprevir, teraprevir, simeprevir, vaniprevir, asunaprevir, paritaprevir as hepatitis C treatments. , NS3 / 4A (protease) inhibitors such as ritonavir, glazoprevir, grecaprevir, NS5A inhibitors such as dacratasvir, regipasvir, ombitasvir, elvasvir, pibrentasvir, NS5B (polymer) inhibitors such as sophosbuvir, dasabvir, beclabvir, etc. medicine.

Examples of other drugs that can be used in combination with the compounds of the invention include:
Drugs for Alzheimer's disease such as donepezil and rivastigmin; Multiple sclerosis (MS) treatments such as Tron; Asthma treatments such as albuterol and Montercast; Seroquel, haloperidol and other schizophrenia treatments; Other immunosuppressive drugs; anti-rheumatic drugs such as sulfasalazine, interferon, TNF blockers, IL-1 inhibitors; neuronutrient factors; anti-convulsants; ion channel blockers; muscular atrophic lateral sclerosis (ALS) such as rilzole Therapeutic agents; β-blockers; ACE inhibitors; diuretics; nitrates; calcium channel inhibitors; HMG-CoA reductase inhibitors; ring disease therapeutic agents; blood disease therapeutic agents; anesthetics; Pim kinase inhibitors; PI3 kinase Inhibitors (including PI3K-δ selectivity and broad spectrum PI3K inhibitors); cyclin-dependent kinase inhibitors; proteasome inhibitors such as voltezomib, calfilzomib; amicacin, gentamycin, tobramycin, streptomycin, netylmycin, canamycin, cyprofloxacin , Norfloxacin, ofloxacin, trovafloxacin, romefloxacin, levofloxacin, enoxacin, naphthylidine, sulfonamide, polymyxin, chloramphenicol, neomycin, paramomycin, choristimetato, bacitrasin, bancomycin, tetracycline, rifampicin and its derivatives, cycloserine, cephalo Antibacterial drugs such as spolin, amphotelicin, azithromycin, faropenem, ozenoxacin; antifungal drugs such as fluconazole, flucitosine, natamicin, myconazole, ketoconazole, lanoconazole.

3.3 Formulation, dosage form, and administration The compound of the present invention can be used or administered in the form of a pharmaceutical composition. A pharmaceutical composition containing the compound of the present invention as an active ingredient (hereinafter, also referred to as “composition of the present invention”) can be prepared by a conventional method. In addition, the compositions of the present invention can be administered by various routes, depending on whether topical or systemic treatment is desired, and depending on the site to be treated. Administration includes topical administration (including transdermal, epithelial, ocular, and mucosal administration including intranasal, vaginal, and rectal delivery), pulmonary administration (including intratracheal or intranasal, eg, nebulizer). The powder or aerosol used may be inhaled), orally or parenterally, and may be appropriately selected as desired.

Examples of the composition (formulation) of the present invention for topical administration include percutaneous application, ointment, lotion, cream, gel, foam, drip, suppository, spray, liquid, and liquid. Examples include powders.
The compositions of the invention for topical administration may include one or more carriers. The ointment can include water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, and white petrolatum. The cream may include glycerin and water in combination with one or more other ingredients such as glycerin monostearate, PEG-glycerin monostearate, and cetostearyl alcohol. The gel agent can include isopropyl alcohol and water in an appropriate combination with other components such as, for example, glycerin, hydroxyethyl cellulose and the like. Foaming agents (foaming agents) include polyoxyethylene sorbitan monostearate, glyceryl stearate, polyoxyethylene hydrogenated castor oil, polyethylene glycol monostearate, sucrose lauric acid ester, polyoxyethylene stearyl ether, sodium laurate, Foaming agents such as arginine stearate or sodium lauryl sulfate can be included. In addition, the topical preparation can be appropriately encapsulated in a container such as a tube, an atomizer, or a bottle, which is suitable for treating the skin or eyes.

The compositions of the invention for inhalation administration include, for example, solutions, suspensions, or powder compositions. The liquid or solid composition may contain suitable and pharmaceutically acceptable excipients as described above. The composition is administered by the oral or nasal respiratory route for topical or systemic action. In addition, the composition can be sprayed using an inert gas. The spray solution may be aspirated directly from the sprayer, or the sprayer may be attached to the face mask cover or intermittent positive pressure respirator. The solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the formulation in a suitable manner.

In the compositions of the invention for oral administration, the compounds of the invention are usually mixed with excipients, diluted with excipients, or, for example, capsules, sachets, paper bags, or other forms. It is enclosed in a carrier that can be processed into. When the excipient acts as a diluent, the excipient may be a solid, semi-solid, or liquid substance that acts as a vehicle, carrier, or medium for the compounds of the invention. Accordingly, the compositions of the invention are, for example, tablets, pills, powders, lozenges, sachets, cashiers, elixirs, suspensions, emulsions, liquids, syrups, aerosols (as solids or in liquid media). It can be in the form.

Examples of the above excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginic acid, tragacant, gelatin, calcium silicate, crystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and Methyl cellulose can be mentioned. The compositions of the present invention further include lubricants and fluidizers (eg, talc, magnesium stearate, and mineral oils, etc.), wetting agents, emulsifiers and suspending agents, preservatives (eg, methyl and propylhydroxybenzoic acid). ), Sweeteners, flavors, etc. can be blended. After administration to a subject (patient) using means known in the art, the compositions of the invention may be formulated to provide rapid, sustained or delayed release of the compounds of the invention.

In order to prepare the composition of the present invention such as tablets, the compound of the present invention can be mixed with an excipient to prepare a uniform solid prescription composition. The prescription composition in which the compound of the present invention is uniformly dispersed can be easily subdivided into unit dosage forms such as tablets, pills, and capsules.

The tablets and pills according to the composition of the present invention may be coated, or may be blended separately to obtain a release-controlled preparation. For example, a tablet or pill may include an inner pharmaceutical component and an outer pharmaceutical component, the latter being a form that covers the former. The two components may be separated by an enteric layer. It acts to resist decomposition in the stomach, allowing the inner components to pass through the duodenum intact or delaying release. Various substances can be used for such enteric layers or coatings. Such substances include several polymeric acids, as well as mixtures of polymeric acids with such substances such as cellac, cetyl alcohol, and cellulose acetate.

Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal injection or infusion; or intracranial, eg, intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus administration or, for example, administration by a continuous infusion pump.
Liquid forms in which the compounds of the invention or compositions of the invention can be incorporated into oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and cottonseed oil, sesame oil, coconut oil. , Or flavored emulsions with edible oils such as peanut oil, as well as elixirs, as well as similar pharmaceutical vehicles.

In the preparation of the composition of the present invention, the compound of the present invention may be milled to obtain an appropriate particle size before being combined with other components. When the compound of the present invention is substantially insoluble, it can be milled to a particle size of less than 200 mesh. When the compound of the present invention is substantially water-soluble, the particle size can be adjusted by milling to obtain a substantially uniform distribution in the composition, for example, a particle size of about 40 mesh.
The compound of the present invention may be milled using a known grinding method such as wet grinding to obtain a particle size suitable for tablets and other formulation types. A pharmaceutical product obtained by micronizing (nanoparticles) the compound of the present invention can be prepared by a procedure known in the art.

The composition of the present invention can be formulated in a unit dosage form, and 1 g of the composition of the present invention can contain about 1 to 1,000 mg, more generally about 100 to about 500 mg of the compound of the present invention. The term "unit dosage form" refers to physically separate units suitable for doses of units to human subjects and other mammals, and for pharmaceuticals, each unit is calculated to provide the desired therapeutic effect. Contains the amount of the compound of the invention.

In some embodiments, the composition of the invention can contain from about 1 to about 50 mg of the compound of the invention in 1 g. In addition, about 1 to about 10 mg, about 10 to about 15 mg, about 15 to about 20 mg, about 20 to about 25 mg, about 25 to about 30 mg, about 30 to about 35 mg, about 35 to about 40 mg in 1 g of the composition of the present invention. , About 40 to about 45 mg, or about 45 to about 50 mg of the compound of the invention.

In some embodiments, the composition of the invention can contain from about 50 to about 500 mg of the compound of the invention in 1 g. In addition, about 50 to about 100 mg, about 100 to about 150 mg, about 150 to about 200 mg, about 200 to about 250 mg, about 250 to about 300 mg, about 350 to about 400 mg, about 400 to about 450 mg in 1 g of the composition of the present invention. , Or may contain from about 450 to about 500 mg of the compound of the invention.

In some embodiments, the composition of the invention can contain from about 500 to about 1,000 mg of the compound of the invention in 1 g. In addition, about 500 to about 550 mg, about 550 to about 600 mg, about 600 to about 650 mg, about 650 to about 700 mg, about 700 to about 750 mg, about 750 to about 800 mg, and about 800 to about 850 mg in 1 g of the composition of the present invention. , About 850 to about 900 mg, about 900 to about 950 mg, or about 950 to about 1,000 mg of the compound of the invention.

The compounds of the invention may be provided in a physiological buffer aqueous solution for parenteral administration, eg, at about 0.1 to about 10% by weight / volume. Some typical dose ranges are from about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. Effective doses can be estimated from dose-response curves derived from in vitro or animal model testing systems.

When the composition of the present invention is an aqueous solution, it can be sterilized by a conventional sterilization technique, and can also be sterilized and filtered. The aqueous solution can be encapsulated for use as is or lyophilized. The lyophilized preparation is reconstituted by adding a sterile aqueous solution before administration. The pH of the composition of the present invention is usually between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. The use of certain said excipients, carriers, or stabilizers can form pharmaceutically acceptable salts. The compounds of the invention can be effective over a wide range of doses and are generally administered in pharmaceutically effective amounts. In addition, the initial treatment may be performed at a relatively low dose, which is less than the optimal dose of the compound of the present invention, and then the dose may be increased little by little until the optimal effect is reached. Further, the total daily dose may be divided (for example, 2 to 4 times a day) and administered in small portions during the day.

The dosage of the compound of the invention is usually the condition to be treated, the relative biological efficiency of the compound of the invention selected, the route of administration selected, the dosage form, and the individual patient response, age, body weight, and patient. It is determined according to the situation including the severity of the symptoms of.

3.4 Others Examples of the administration target (patient, individual) of the compound of the present invention or the composition of the present invention include all animals including mammals. Specific examples include primates including mice, rats, hamsters, guinea pigs and other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, humans and monkeys. Above all, it is preferable to administer humans.

In the present invention, terms such as therapeutically effective amount, effective amount or effective dose refer to the amount of a compound or drug that induces a biological or pharmaceutical response, which is a tissue, system, animal, individual, or human. Can be determined by a researcher, veterinarian, doctor of medicine, or other clinician.

In the present invention, "treatment" means one or more of the following.
(1) Prevention of disease: Prevention of disease, condition, or disorder in, for example, an individual who may suffer from a disease, condition, or disorder but has not yet experienced or has not yet exhibited the pathophysiology or general symptoms of the disease. What to do (2) Suppression of disease: Suppressing a disease, condition, or disorder (ie, pathology and disorder), for example, in an individual who is experiencing or presenting a condition or general symptom of the disease, condition, or disorder. / Or to prevent further development of general symptoms)
(3) Disease remission: A disease, condition, or disorder in an individual who is experiencing or exhibiting, for example, the pathology or general symptoms of the disease, condition, or disorder, such as reducing the severity of the disease. Remission (ie, relieve pathology and / or general symptoms)

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited thereto.

In Reference Examples, Examples, and Test Examples, the temperature is in degrees Celsius (° C) unless otherwise specified. Reagents were purchased from reagent suppliers or manufactured by known methods.

Biotage Initiator + was used as the microwave reactor. Purification by silica gel column chromatography was performed using either Biotage Isolera or Isco Combi Flash Rf150. Preparative HPLC was performed under acidic mobile phase conditions using a Gilson automated purification device and a 30 × 150 mm Angela Durashell C18 column. NMR spectra were recorded using either a Bruker 400MHz spectrometer, a Varian 400MHz spectrometer, a JEOL 400MHz spectrometer, or a JEOL 500MHz spectrometer. The mass spectrum was measured using either Waters SQ Detector 2 or SHIMADZU LC MS-2010. As an ionization method, an electrospray ionization (ESI) was used for measurement.

The main abbreviations in Reference Examples and Examples are as follows.
Boc: t-butoxycarbonyl
CDI: 1,1'-Carbonyldiimidazole
DAST: (diethylamino) Sulfur Trifluoride
DMF: N, N-dimethylformamide
DMSO: Dimethyl sulfoxide
DMSO-d ₆ : Deuterated dimethyl sulfoxide
HATU: 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate
DIPEA: Diisopropylethylamine
HOBt: 1-Hydroxybenzotriazole
HPLC: High Performance Liquid Chromatography
¹ H NMR: Proton Nuclear Magnetic Resonance Spectrometry
LDA: Lithium diisopropylamide
2-MeTHF: 2-Methyltetrahydrofurfurte
n-: Normal
PdCl ₂ (dppf): [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride
Pd / C: Carbon-supported palladium (0)
SEM: 2- (trimethylsilyl) ethoxymethyl
t-: Tarshary
T3P: Propylphosphonic acid anhydride (cyclic trimmer)
TBAF: Tetrabutylammonium fluoride
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
TLC: Thin Layer Chromatography
p-: Para

Example 1
3-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole
Triethyl orthoacetate (189 mg) was added to a solution of 4-bromo-3-phenoxybenzene-1,2-diamine (400 mg) in THF (5 mL), and the mixture was heated and stirred at 70 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added to the residue, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole (140 mg).
ESI-MS m / z 303 [M + H] ⁺

b. 5- (6-Methoxy-5-methylpyridine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole
5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole (70 mg), 2-methoxy-3-methyl-5- (4,4,5,5-tetramethyl-1,3,2) -Sodium carbonate (74 mg) and PdCl ₂ (dppf) / dichloromethane adduct (3.4 mg) in a mixed solution of 1,4-dioxane (4 mL) of pyridine (63 mg) and water (1 mL). In addition, the mixture was heated and stirred at 90 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methanol = 10: 1) and 5- (6-methoxy-5-methylpyridine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d]. Imidazole (30 mg) was obtained.
ESI-MS m / z 346 [M + H] ⁺

c. 3-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one
5- (6-Methoxy-5-methylpyridine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole (30 mg) in a 1,4-dioxane (3 mL) solution at 6 mol / L Hydrochloric acid (0.5 mL) was added, and the mixture was heated and stirred at 90 ° C. for 5 hours. After cooling the reaction mixture to room temperature, water and then saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% aqueous ammonia solution) and then freeze-dried to 3-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) pyridine-. 2 (1H) -on (5.5 mg) was obtained.
ESI-MS m / z 332 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.65 (s, 1H), 7.47 (d, J = 8.0Hz, 1H), 7.38 (s, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.18 (dd, J = 8.4, 7.2Hz, 2H), 6.92 (t, J = 7.2Hz, 1H), 6.71 (d, J = 8.4Hz, 2H), 2.53 (s, 3H), 2.06 ( s, 3H).

Example 2
3-Methyl-5-(2- (1-Methyl-1H-Pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

5-bromo-2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazole
A 30% hydrogen peroxide solution (1.65) in a 1,4-dioxane (5 mL) solution of 4-bromo-3-phenoxybenzene-1,2-diamine (400 mg) and 1-methylpyrazole-4-carboxyaldehyde (189 mg). mL) and ammonium ammonium nitrate (IV) (79 mg) were added, and the mixture was heated and stirred at 50 ° C. for 3 hours. After cooling the reaction mixture to room temperature, water and then saturated aqueous sodium sulfite solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazole ( 150 mg) was obtained.
ESI-MS m / z 369 [M + H] ⁺

b. 5- (6-Methoxy-5-methylpyridine-3-yl) -2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazole
5-bromo-2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazole (100 mg), 2-methoxy-3-methyl-5- (4,4, Sodium carbonate (86 mg) and PdCl ₂ in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL) of 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl pyridine (81 mg). (Dppf) -dichloromethane adduct (4.0 mg) was added, and the mixture was heated and stirred at 90 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane / methanol = 10: 1) and 5- (6-methoxy-5-methylpyridine-3-yl) -2- (1-methyl-1H-pyrazole-4-yl). -4-Phenoxy-1H-benzo [d] imidazole (60 mg) was obtained.
ESI-MS m / z 412 [M + H] ⁺

c. 3-Methyl-5-(2- (1-Methyl-1H-Pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one
5- (6-Methoxy-5-methylpyridine-3-yl) -2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazole (60 mg) 1, 6 mol / L hydrochloric acid (0.5 mL) was added to the 4-dioxane (3 mL) solution, and the mixture was heated and stirred at 90 ° C. for 5 hours. After cooling the reaction mixture to room temperature, water and then saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 3-methyl-5- (2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-. 1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (8.8 mg) was obtained.
ESI-MS m / z 398 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.22 (s, 1H), 8.09 (s, 1H), 7.66 (s, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.39 ( s, 1H), 7.31 (d, J = 8.4Hz, 1H), 7.18 (dd, J = 8.4, 7.6Hz, 2H), 6.91 (t, J = 7.6Hz, 1H), 6.73 (d, J = 8.4) Hz, 2H), 3.97 (s, 3H), 2.07 (s, 3H).

Example 3
3-Methyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

N- (2-Amino-4-bromo-3-phenoxyphenyl) tetrahydro-2H-pyran-4-carboxamide and N- (6-amino-3-bromo-2-phenoxyphenyl) tetrahydro-2H-pyran- 4-Carboxamide
To a solution of 4-bromo-3-phenoxybenzene-1,2-diamine (400 mg) and pyridine (227 mg) in THF (4 mL) is added a solution of tetrahydropyran-4-carboxylic acid chloride (234 mg) in THF (1 mL). The mixture was heated and stirred at 50 ° C. for 3 hours. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to N- (2-amino-4-bromo-3-phenoxyphenyl) tetrahydro-2H-pyran-4-carboxamide and N- (6-amino-3-bromo-2-phenoxy). A mixture of phenyl) tetrahydro-2H-pyran-4-carboxamide (600 mg) was obtained.
ESI-MS m / z 391 [M + H] ⁺

b. 5-bromo-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
N- (2-Amino-4-bromo-3-phenoxyphenyl) tetrahydro-2H-pyran-4-carboxamide and N- (6-amino-3-bromo-2-phenoxyphenyl) tetrahydro-2H-pyran-4- A solution of a mixture of carboxamide (560 mg) in acetic acid (5.0 mL) was heated and stirred at 90 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water, saturated aqueous sodium hydrogen carbonate solution was added until the pH reached 8, and the mixture was extracted with dichloromethane. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 5-bromo-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (. 550 mg) was obtained.
ESI-MS m / z 373 [M + H] ⁺

c. 5- (6-Methoxy-5-Methylpyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
5-bromo-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (100 mg), 2-methoxy-3-methyl-5- (4,4,5,, Sodium carbonate (82 mg) and PdCl ₂ (dppf) in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL) of 5-tetramethyl-1,3,2-dioxaborolan-2-yl pyridine (77 mg). ) -Dichloromethane adduct (3.7 mg) was added, and the mixture was heated and stirred at 90 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 5- (6-methoxy-5-methylpyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole crude product (100 mg) was obtained.
ESI-MS m / z 416 [M + H] ⁺

d. 3-Methyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one
5- (6-Methoxy-5-methylpyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] 1 of crude imidazole product (100 mg) 6 mol / L hydrochloric acid (0.7 mL) was added to the 4-dioxane (4 mL) solution, and the mixture was heated and stirred at 90 ° C. for 5 hours. After cooling the reaction mixture to room temperature, water and then saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 3-methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-. Benzo [d] imidazole-5-yl) pyridin-2 (1H) -one (23.4 mg) was obtained.
ESI-MS m / z 402 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.64 (s, 1H), 7.52 (s, 1H), 7.37 (d, J = 2.0Hz, 1H), 7.29 (d, J = 8.0Hz, 1H), 7.17 (dd, J = 8.0, 6.4Hz, 2H), 6.91 (t, J = 6.4Hz, 1H), 6.70 (d, J = 8.0Hz, 2H), 4.04 (d, J = 11.2Hz, 2H), 3.61-3.51 (m, 2H), 3.22-3.12 (m, 1H), 2.06 (s, 3H), 2.02-1.89 (m, 4H).

Example 4
5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

Similar to the method of Example 1, 2-methoxy-3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine instead of 2- 5- (2-Methyl-4-phenoxy-1H-benzo [d] with methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine Imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 318 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.34 (brs, 1H), 11.19 (brs, 1H), 7.59 (dd, J = 9.2, 2.4Hz, 1H), 7.40 (d, J = 2.4Hz, 2H), 7.22 (dd, J = 8.0, 7.2Hz, 2H), 7.20 (d, J = 8.0Hz, 1H), 6.94 (t, J = 7.2Hz, 1H), 6.69 (d, J = 8.0Hz, 2H), 6.28 (d, J = 9.6Hz, 1H), 2.43 (s, 3H).

Example 5
5- (2- (1-Methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

Similar to the method of Example 2, 2-methoxy-3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine instead of 2- 5- (2- (1-Methyl-1H-pyrazole-4-yl) pyridine using methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine ) -4-Phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one was obtained.
ESI-MS m / z 384 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.68 (s, 1H), 8.38 (s, 1H), 7.72 (d, J = 8.4Hz, 1H), 7.67 (dd, J = 9.6, 2.8Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.54 (d, J = 2.8Hz, 1H), 7.24 (dd, J = 8.0, 7.6Hz, 2H), 6.99 (t, J = 7.6Hz, 1H), 6.78 (d, J = 8.0Hz, 2H), 6.34 (d, J = 9.3Hz, 1H), 3.98 (s, 3H).

Example 6
5- (4-Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

Similar to the method of Example 3, 2-methoxy-3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine instead of 2- Using methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, 5- (4-phenoxy-2- (tetrahydro-2H-pyran-4) -Il) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 388 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.58 (d, J = 7.2Hz, 1H), 7.54-7.40 (m, 1H), 7.39 (d, J = 1.6Hz, 1H), 7.27 -7.15 (m, 3H), 6.98-6.87 (m, 1H), 6.69 (d, J = 8.0Hz, 2H), 6.27 (d, J = 9.6Hz, 1H), 3.97-3.83 (m, 2H), 3.46-3.38 (m, 2H), 3.12-3.02 (m, 1H), 1.94-1.67 (m, 4H).

Example 7
1-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole (70 mg), 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxabolorane-2) -Il) Pyridine-2 (1H) -one (60 mg) in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL) with sodium carbonate (73.4 mg) and PdCl ₂ (dppf) -dichloromethane adduct ( 3.4 mg) was added, and the mixture was heated and stirred at 90 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) pyridine. -2 (1H) -on (28.7 mg) was obtained.
ESI-MS m / z 332 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.79-7.70 (m, 2H), 7.47 (s, 1H), 7.29 (d, J = 8.4Hz, 1H), 7.19 (dd, J = 8.0) , 7.2Hz, 2H), 6.96-6.89 (t, J = 7.2Hz, 1H), 6.72 (d, J = 8.0Hz, 2H), 6.48 (d, J = 9.2Hz, 1H), 3.53 (s, 3H) ), 2.53 (s, 3H).

Example 8
1-Methyl-5-(2- (1-Methyl-1H-Pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

In the same manner as in Example 7, 5-bromo-2- (1-methyl-1H-pyrazole-4-yl) instead of 5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole ) -4-Phenoxy-1H-benzo [d] With imidazole, 1-methyl-5- (2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] Imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 398 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.51 (s, 1H), 8.27 (s, 1H), 7.90 (d, J = 2.4Hz, 1H), 7.82-7.72 (m, 2H), 7.70-7.64 (m, 1H), 7.25 (dd, J = 8.0, 7.2Hz, 2H), 7.00 (t, J = 7.2Hz, 1H), 6.82 (d, J = 8.0Hz, 2H), 6.54 (d) , J = 9.2Hz, 1H), 4.06 (s, 3H), 3.56 (s, 3H).

Example 9
1-Methyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

5-bromo-4-phenoxy-2- (tetrahydro-2H-pyran-4) instead of 5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole in the same manner as in Example 7. -Il) -1H-benzo [d] imidazole with 1-methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5- Il) Pyridine-2 (1H) -on was obtained.
ESI-MS m / z 402 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.76-7.72 (m, 2H), 7.54 (d, J = 8.2Hz, 1H), 7.31 (d, J = 8.2Hz, 1H), 7.19 ( dd, J = 7.6,7.2Hz, 2H), 6.93 (t, 1H), 6.72 (d, J = 8.8Hz, 2H), 6.48 (d, J = 9.2Hz, 1H), 4.07-4.04 (m, 2H) ), 3.61-3.54 (m, 5H), 3.22-3.16 (m, 1H), 2.05-1.94 (m, 4H).

Example 10
1,3-Dimethyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

Substituting 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one in the same manner as in Example 7. 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one, 1,3-dimethyl -5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 346 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.76-7.64 (m, 3H), 7.59 (dd, J = 2.4, 1.2Hz, 1H), 7.30-7.21 (m, 2H), 7.07-6.96 ( m, 1H), 6.81 (dd, J = 8.8,1.0Hz, 2H), 3.54 (s, 3H), 2.85 (s, 3H), 2.08 (s, 3H).

Example 11
1,3-dimethyl-5-(2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

5-Bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole and 1-methyl-5- (4,4,5,5-tetramethyl-1,2) in the same manner as in Example 7. 3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -onstead of 5-bromo-2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d ] With imidazole and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one, 1,3 -Dimethyl-5- (2- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 412 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.61 (s, 1H), 8.33 (s, 1H), 7.76 (d, J = 2.4Hz, 1H), 7.68 (d, J = 8.4Hz) , 1H), 7.55-7.47 (m, 2H), 7.25 (dd, J = 8.0, 7.2Hz, 2H), 6.98 (t, J = 7.2Hz, 1H), 6.80 (d, J = 8.0Hz, 2H) , 3.99 (s, 3H), 1.95 (s, 3H), 1.23 (s, 3H).

Example 12
1,3-dimethyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

5-Bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole and 1-methyl-5- (4,4,5,5-tetramethyl-1,2) in the same manner as in Example 7. 3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -on instead of 5-bromo-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole And 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one with 1,3-dimethyl -5- (4-Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 416 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.79-7.72 (m, 1H), 7.70-7.66 (m, 2H), 7.58 (s, 1H), 7.25 (dd, J = 8.0, 7.4Hz) , 2H), 7.01 (t, J = 7.4Hz, 1H), 6.80 (d, J = 8.0Hz, 2H), 4.16-4.07 (m, 2H), 3.62 (dt, J = 11.5,3.0Hz, 2H) , 3.53 (s, 4H), 2.14-2.04 (m, 7H).

Example 13
5- (4- (2-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

N- (4-bromo-3-fluoro-2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide
In a solution of 4-bromo-3-fluoro-2-nitroaniline (6.81 g) in THF (76 mL), under ice-cooling, pyridine (7.73 mL) and tetrahydropyran-4-carboxylic acid chloride (4.26 g) in THF (29 mL) ) The solution was added and stirred at room temperature for 17 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give N- (4-bromo-3-fluoro-2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (1.45 g). rice field.
ESI-MS m / z 347 [M + H] ⁺

b. N- (4-bromo-3- (2-chlorophenoxy) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide
Cesium carbonate (282 mg) and 2-chlorophenol (0.088 mL) in a DMF (10 mL) solution of N- (4-bromo-3-fluoro-2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (300 mg). Was added, and the mixture was heated and stirred at 120 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to concentrate N- (4-bromo-3- (2-chlorophenoxy) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide. (457 mg) was obtained.
ESI-MS m / z 455 [M + H] ⁺

c. 5-bromo-4- (2-chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
To a solution of N- (4-bromo-3- (2-chlorophenoxy) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (394 mg) in acetic acid (10 mL), add iron powder (241 mg) to the microwave. The mixture was heated and stirred at 120 ° C. for 10 minutes in a wave reactor. The reaction mixture was cooled to room temperature, filtered through cerite, and the filtrate was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 5-bromo-4- (2-chlorophenoxy) -2- (tetrahydro-2H-pyran-4). -Il) -1H-benzo [d] imidazole (354 mg) was obtained.
ESI-MS m / z 407 [M + H] ⁺

d. 5- (4- (2-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on
5-bromo-4- (2-chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (353 mg), 1-methyl-5- (4,4,5) , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (305 mg) in a mixed solution of 1,4-dioxane (9.0 mL) and water (1.8 mL). Sodium carbonate (184 mg) and PdCl ₂ (dppf) / dichloromethane adduct (35.4 mg) were added, and the mixture was heated and stirred at 160 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 5- (4- (2-chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl). -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (52.6 mg) was obtained.
ESI-MS m / z 436 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.82 (d, J = 2.3Hz, 1H), 7.65 (d, J = 9.2Hz, 1H), 7.61-7.40 (brs, 1H), 7.35 ( d, J = 6.9Hz, 1H), 7.29 (d, J = 8.6Hz, 1H), 6.96 (brs, 1H), 6.89 (brs, 1H), 6.42 (d, J = 9.2Hz, 1H), 6.29 ( d, J = 8.0Hz, 1H), 4.13-3.95 (m, 2H), 3.59-3.50 (m, 5H), 3.22-3.11 (m, 1H), 2.07-1.86 (m, 4H).

Example 14
5- (4- (3-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (3-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 3-chlorophenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 436 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.76 (s, 1H), 7.69 (dd, J = 9.2,2.3Hz, 1H), 7.63-7.38 (m, 1H), 7.29 (d, J) = 8.0Hz, 1H), 7.12 (brs, 1H), 6.91 (brs, 1H), 6.78-6.65 (m, 1H), 6.62 (d, J = 8.0Hz, 1H), 6.47 (d, J = 9.7Hz) , 1H), 4.13-3.94 (m, 2H), 3.62-3.45 (m, 5H), 3.21-3.09 (m, 1H), 2.13-1.86 (m, 4H).

Example 15
5- (4- (4-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (4-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 4-chlorophenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 436 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.73 (s, 1H), 7.68 (d, J = 9.2Hz, 1H), 7.63-7.36 (m, 1H), 7.27 (d, J = 8.6) Hz, 1H), 7.13 (d, J = 8.0Hz, 2H), 6.66 (d, J = 8.0Hz, 2H), 6.46 (d, J = 9.2Hz, 1H), 4.14-3.93 (m, 2H), 3.57-3.49 (m, 5H), 3.13 (s, 1H), 2.03-1.86 (m, 4H).

Example 16
5- (4- (2-Fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (2-Fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 2-fluorophenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 420 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.83-7.72 (m, 1H), 7.65 (d, J = 9.2Hz, 1H), 7.61-7.34 (m, 1H), 7.27 (d, J) = 8.6Hz, 1H), 7.13-7.03 (m, 1H), 6.90-6.77 (m, 2H), 6.42 (d, J = 9.2Hz, 1H), 6.35 (dd, J = 9.2,7.4Hz, 1H) , 4.06-3.98 (m, 2H), 3.57-3.49 (m, 5H), 3.20-3.11 (m, 1H), 2.03-1.88 (m, 4H).

Example 17
5- (4- (3-Fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (3-Fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 3-fluorophenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 420 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.75 (s, 1H), 7.69 (d, J = 9.7Hz, 1H), 7.62-7.40 (m, 1H), 7.28 (d, J = 8.0) Hz, 1H), 7.18-7.08 (m, 1H), 6.69-6.58 (m, 1H), 6.49 (d, J = 8.0Hz, 1H), 6.46 (d, J = 9.2Hz, 1H), 6.44-6.36 (m, 1H), 4.00 (d, J = 11.5Hz, 2H), 3.62-3.49 (m, 5H), 3.18-3.09 (m, 1H), 2.06-1.92 (m, 4H).

Example 18
5- (4- (4-Fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (4-Fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 4-fluorophenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 420 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.73 (s, 1H), 7.69 (d, J = 9.2Hz, 1H), 7.60-7.38 (m, 1H), 7.27 (d, J = 8.6) Hz, 1H), 6.93-6.82 (m, 2H), 6.71-6.63 (m, 2H), 6.46 (d, J = 9.2Hz, 1H), 4.04-3.97 (m, 2H), 3.57-3.49 (m, 5H), 3.19-3.09 (m, 1H), 2.04-1.86 (m, 4H).

Example 19
5- (4- (2,6-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 2,6-difluorophenol instead of 2-chlorophenol, 5- (4- (2,6-difluorophenoxy) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.65 (s, 1H), 7.58-7.21 (m, 2H), 7.08 (d, J = 5.2Hz, 1H), 7.00-6.88 (m, 1H) ), 6.88-6.75 (m, 2H), 6.38 (s, 1H), 4.15-3.91 (m, 2H), 3.71-3.41 (m, 5H), 3.18 (s, 1H), 2.12-1.81 (m, 4H) ).

Example 20
5- (4- (3,5-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 3,5-difluorophenol instead of 2-chlorophenol, 5- (4- (3,5-difluorophenoxy) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.79 (s, 1H), 7.71 (dd, J = 9.5,2.0Hz, 1H), 7.66-7.40 (m, 1H), 7.31 (d, J) = 8.0Hz, 1H), 6.50 (d, J = 9.2Hz, 2H), 6.30 (brs, 2H), 4.06-3.97 (m, 2H), 3.62-3.45 (m, 5H), 3.22-3.12 (m, 1H), 2.05-1.89 (m, 4H).

Example 21
5- (4- (3,4-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 3,4-difluorophenol instead of 2-chlorophenol, 5- (4- (3,4-difluorophenoxy) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.75 (d, J = 2.3Hz, 1H), 7.69 (dd, J = 9.5,2.6Hz, 1H), 7.50 (brs, 1H), 7.28 ( d, J = 8.6Hz, 1H), 7.07-6.99 (m, 1H), 6.62 (brs, 1H), 6.47 (d, J = 9.2Hz, 1H), 6.46-6.42 (m, 1H), 4.00 (d) , J = 11.5Hz, 2H), 3.61-3.44 (m, 5H), 3.22-3.07 (m, 1H), 2.01-1.87 (m, 4H).

Example 22
5- (4- (2,4-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 2,4-difluorophenol instead of 2-chlorophenol, 5- (4- (2,4-difluorophenoxy) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.78 (d, J = 2.9Hz, 1H), 7.65 (dd, J = 9.5,2.6Hz, 1H), 7.61-7.39 (m, 1H), 7.27 (d, J = 8.0Hz, 1H), 7.03-6.93 (m, 1H), 6.67-6.57 (m, 1H), 6.46 (d, J = 9.2Hz, 1H), 6.38 (ddd, J = 9.5, 9.2,5.2Hz, 1H), 4.13-3.94 (m, 2H), 3.63-3.46 (m, 5H), 3.21-3.12 (m, 1H), 2.06-1.82 (m, 4H).

Example 23
5- (4- (2,3-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 2,3-difluorophenol instead of 2-chlorophenol, 5- (4- (2,3-difluorophenoxy) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.80 (d, J = 2.3Hz, 1H), 7.67 (dd, J = 9.2,2.3Hz, 1H), 7.64-7.38 (m, 1H), 7.29 (d, J = 8.6Hz, 1H), 6.80 (brs, 2H), 6.47 (d, J = 9.2Hz, 1H), 6.25-6.11 (m, 1H), 4.13-3.94 (m, 2H), 3.63 -3.46 (m, 5H), 3.21-3.08 (m, 1H), 2.04-1.88 (m, 4H).

Example 24
5- (4- (2,5-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 2,5-difluorophenol instead of 2-chlorophenol, 5- (4- (2,5-difluorophenoxy) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.82 (s, 1H), 7.68 (d, J = 9.7Hz, 1H), 7.64-7.38 (m, 1H), 7.30 (d, J = 8.0) Hz, 1H), 7.11 (brs, 1H), 6.62 (brs, 1H), 6.47 (d, J = 9.2Hz, 1H), 6.09 (s, 1H), 4.02 (d, J = 11.5Hz, 2H), 3.59-3.49 (m, 5H), 3.23-3.12 (m, 1H), 2.02-1.91 (m, 4H).

Example 25
5- (4- (2-Methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (2-Methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 2-methoxyphenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 454 [M + Na] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.84 (d, J = 2.4Hz, 1H), 7.69 (dd, J = 9.2, 2.4Hz, 1H), 7.52 (d, J = 8.4Hz, 1H), 7.30 (d, J = 8.4Hz, 1H), 6.99 (dd, J = 8.0, 1.2Hz, 1H), 6.93-6.85 (m, 1H), 6.69-6.60 (m, 1H), 6.44 (d) , J = 9.2Hz, 1H), 6.28 (dd, J = 8.0, 1.6Hz, 1H), 4.11-4.02 (m, 2H), 3.91 (s, 3H), 3.62-3.54 (m, 2H), 3.53 ( s, 3H), 3.29-3.11 (m, 1H), 2.11-1.91 (m, 4H).

Example 26
5- (4- (3-Methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (3-Methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 3-methoxyphenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 454 [M + Na] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.77-7.67 (m, 2H), 7.51 (d, J = 8.4Hz, 1H), 7.29 (d, J = 8.0Hz, 1H), 7.05 ( dd, J = 8.4,8.0Hz, 1H), 6.54-6.44 (m, 2H), 6.32-6.29 (m, 1H), 6.27-6.21 (m, 1H), 4.07-3.99 (m, 2H), 3.67 ( s, 3H), 3.59-3.51 (m, 5H), 3.23-3.11 (m, 1H), 2.05-1.98 (m, 4H).

Example 27
5- (4- (4-Methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (4-Methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl), using 4-methoxyphenol instead of 2-chlorophenol, in the same manner as in Example 13. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 432 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.77-7.69 (m, 2H), 7.51 (d, J = 8.4Hz, 1H), 7.29 (d, J = 8.4Hz, 1H), 6.74 ( dd, J = 6.8,2.4Hz, 2H), 6.65 (dd, J = 6.8, 2.4Hz, 2H), 6.49 (d, J = 9.2Hz, 1H), 4.09-4.02 (m, 2H), 3.69 (s) , 3H), 3.62-3.52 (m, 5H), 3.26-3.14 (m, 1H), 2.09-1.90 (m, 4H).

Example 28
N-(2-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole -4-yl) Oxy) Phenyl) Acetamide

N-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-)-(5- (1-methyl-6-oxo-1,6-dihydropyridine-), using 2'-hydroxyacetanilide instead of 2-chlorophenol, in the same manner as in Example 13. 3-Il) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-yl) oxy) phenyl) acetamide was obtained.
ESI-MS m / z 481 [M + Na] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.63-7.53 (m, 2H), 7.21-7.06 (m, 3H), 7.04-6.98 (m, 1H), 6.81-6.74 (m, 1H), 6.72-6.64 (m, 1H), 6.55-6.49 (m, 1H), 4.14-4.00 (m, 2H), 3.67 (s, 3H), 3.54-3.45 (m, 2H), 2.97-2.86 (m, 1H) ), 2.11 (s, 3H), 2.06-1.83 (m, 4H).

Example 29
N-(3-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole -4-yl) Oxy) Phenyl) Acetamide

Similar to the method of Example 13, 3'-hydroxyacetanilide was used instead of 2-chlorophenol to N-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3). -Il) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-yl) oxy) phenyl) acetamide was obtained.
ESI-MS m / z 459 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.73 (d, J = 2.3Hz, 1H), 7.67 (dd, J = 9.2,2.3Hz, 1H), 7.48 (d, J = 8.6Hz, 1H), 7.27 (d, J = 8.1Hz, 1H), 7.07 (dd, J = 8.1, 8.0Hz, 2H), 6.99 (d, J = 8.0Hz, 1H), 6.52-6.37 (m, 2H), 4.04-3.96 (m, 2H), 3.61-3.39 (m, 5H), 3.23-3.06 (m, 1H), 2.10-1.84 (m, 7H).

Example 30
N-(4-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole -4-yl) Oxy) Phenyl) Acetamide

Similar to the method of Example 13, N- (4- (1-methyl-6-oxo-1,) was used instead of 2-chlorophenol using N- (4-hydroxyphenyl) acetamide. 6-Dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) phenyl) acetamide was obtained.
ESI-MS m / z 459 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.58-12.28 (m, 1H), 9.83-9.72 (m, 1H), 7.85-7.77 (m, 1H), 7.60-7.50 (m, 1.5) H), 7.42-7.37 (m, 2H), 7.37-7.33 (m, 0.5H), 7.26-7.18 (m, 1H), 6.68-6.61 (m, 2H), 6.36-6.28 (m, 1H), 3.97 -3.87 (m, 2H), 3.45-3.89 (m, 5H), 3.13-3.04 (m, 1H), 1.97 (s, 3H), 1.91-1.70 (m, 4H).

Example 31
1-Methyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-(2- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

1-Methyl-5- (2- (tetrahydro-2H-pyran-4-yl) -4-) using 2-hydroxybenzotrifluoride instead of 2-chlorophenol in the same manner as in Example 13. (2- (Trifluoromethyl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 470 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 10.10 (brs, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.63-7.56 (m, 1H), 7.55-7.44 (m, 2H) , 7.27-7.15 (m, 2H), 6.98 (dd, J = 7.5, 7.4Hz, 1H), 6.51-6.35 (m, 2H), 4.07-3.95 (m, 2H), 3.54-3.38 (m, 5H) , 3.22-3.06 (m, 1H), 2.05-1.75 (m, 4H).

Example 32
1-Methyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-(3- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

1-Methyl-5- (2- (tetrahydro-2H-pyran-4-yl) -4-) using 3-hydroxybenzotrifluoride instead of 2-chlorophenol in the same manner as in Example 13. (3- (Trifluoromethyl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 470 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.74 (s, 1H), 7.70-7.58 (m, 1H), 7.58-7.41 (m, 1H), 7.40-7.23 (m, 2H), 7.19 (d, J = 8.0Hz, 1H), 6.97 (s, 1H), 6.89 (d, J = 8.0Hz, 1H), 6.51-6.35 (1H), 3.99 (d, J = 11.5Hz, 2H), 3.68 -3.39 (m, 5H), 3.19-3.09 (m, 1H), 2.05-1.80 (m, 4H).

Example 33
1-Methyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4- (4- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

1-Methyl-5- (2- (tetrahydro-2H-pyran-4-yl) -4-) using 4-hydroxybenzotrifluoride instead of 2-chlorophenol in the same manner as in Example 13. (4- (Trifluoromethyl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 470 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.92-7.74 (m, 1H), 7.62-7.69 (m, 1H), 7.52 (d, J = 8.6Hz, 1H), 7.47 (d, J) = 9.2Hz, 2H), 7.30 (d, J = 8.0Hz, 1H), 6.83 (d, J = 8.6Hz, 2H), 6.45 (d, J = 9.2Hz, 1H), 4.03-3.96 (m, 2H) ), 3.57-3.47 (m, 5H), 3.19-3.09 (m, 1H), 2.00-1.86 (m, 4H).

Example 34
2-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) Il) Oxy) Benzonitrile

2-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl)) using 2-cyanophenol instead of 2-chlorophenol in the same manner as in Example 13. -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-yl) oxy) benzonitrile was obtained.
ESI-MS m / z 427 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.83 (d, J = 2.3Hz, 1H), 7.73-7.40 (m, 3H), 7.30 (d, J = 8.6Hz, 2H), 7.02 ( s, 1H), 6.45 (d, J = 9.7Hz, 1H), 6.37 (d, J = 8.0Hz, 1H), 4.00 (d, J = 11.5Hz, 2H), 3.24-3.10 (m, 1H), 3.59-3.47 (m, 5H), 2.00-1.82 (m, 4H).

Example 35
2-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 4-yl) oxy) benzonitrile

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 (1H) in the same manner as in Example 13. )-Instead of on 2-cyanophenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H)- Using on, 2-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-4-yl) oxy) benzonitrile was obtained.
ESI-MS m / z 441 [M + H] ⁺

¹ H NMR (DMSO-d _6,500MHz ) δ (ppm): 7.79 (d, J = 8.0Hz, 1H), 7.68 (s, 1H), 7.62-7.36 (m, 3H), 7.28 (d, J = 8.0Hz, 1H), 7.10 (m, 1H), 6.43-6.32 (m, 1H), 3.91 (m, 2H), 3.48-3.40 (m, 2H), 3.43 (s, 3H), 3.15-3.06 (m) , 1H), 1.97 (s, 3H), 1.93-1.70 (m, 4H).

Example 36
3-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) Il) Oxy) Benzonitrile

Similar to the method of Example 13, 3-cyanophenol was used instead of 2-chlorophenol, and 3-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl)) was used. -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-yl) oxy) benzonitrile was obtained.
ESI-MS m / z 427 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.77 (d, J = 2.3Hz, 1H), 7.70 (dd, J = 9.6, 2.4Hz, 1H), 7.48 (brs, 1H), 7.41- 7.19 (m, 3H), 7.10-6.94 (m, 2H), 6.47 (d, J = 9.2Hz, 1H), 4.09-3.93 (m, 2H), 3.59-3.42 (m, 5H), 3.14 (d, J = 5.7Hz, 1H), 2.06-1.82 (m, 4H).

Example 37
3-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 4-yl) oxy) benzonitrile

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 (1H) in the same manner as in Example 13. )-Instead of on 3-cyanophenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 (1H)- Using on, 3-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-4-yl) oxy) benzonitrile was obtained.
ESI-MS m / z 441 [M + H] ⁺

¹ H NMR (DMSO-d _6,500MHz ) δ (ppm): 7.77-7.50 (m, 1H), 7.49-7.37 (m, 4H), 7.32-7.12 (m, 2H), 7.03 (m, 1H), 3.96-3.84 (m, 2H), 3.47-3.39 (m, 2H), 3.42 (s, 3H), 3.15-3.00 (m, 1H), 1.96 (s, 3H), 1.92-1.70 (m, 4H).

Example 38
4-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) Il) Oxy) Benzonitrile

4-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl)) using 4-cyanophenol instead of 2-chlorophenol in the same manner as in Example 13. -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-yl) oxy) benzonitrile was obtained.
ESI-MS m / z 427 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.76 (d, J = 2.3Hz, 1H), 7.68 (dd, J = 9.2,2.9Hz, 1H), 7.64-7.42 (m, 3H), 7.31 (d, J = 8.0Hz, 1H), 6.85 (d, J = 8.6Hz, 2H), 6.46 (d, J = 9.7Hz, 1H), 4.08-3.94 (m, 2H), 3.61-3.48 (m) , 5H), 3.21-3.07 (m, 1H), 2.04-1.88 (m, 4H).

Example 39
4-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 4-yl) oxy) benzonitrile

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 (1H) in the same manner as in Example 13. )-4-Cyanophenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H)-instead of on Using on, 4-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-4-yl) oxy) benzonitrile was obtained.
ESI-MS m / z 441 [M + H] ⁺

¹ H NMR (DMSO-d _6,500MHz ) δ (ppm): 12.54-12.45 (m, 1H), 7.79-7.52 (m, 3H), 7.60-7.42 (m, 2H), 7.27-7.23 (dd, J) = 8.3,6.0Hz, 1H), 6.87 (d, J = 8.6Hz, 2H), 3.94-3.87 (m, 2H), 3.70-3.38 (m, 2H), 3.42 (s, 3H), 3.17-3.01 ( m, 1H), 1.95 (s, 3H), 1.93-1.67 (m, 4H).

Example 40
5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 2,6-dimethylphenol instead of 2-chlorophenol, 5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 430 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.72 (d, J = 9.2Hz, 1H), 7.54 (s, 1H), 7.41 (d, J = 8.0Hz, 1H), 7.22-7.09 (m) , 4H), 6.63 (d, J = 9.7Hz, 1H), 4.05-3.90 (m, 2H), 3.62 (s, 3H), 3.47 (dd, J = 12.0, 9.7Hz, 2H), 2.99-2.91 ( m, 1H), 2.12 (s, 6H), 1.80 (d, J = 12.6Hz, 2H), 1.66-1.55 (m, 2H).

Example 41
5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 ( 1H)-On

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) in the same manner as in Example 13. )-Instead of on, 2,6-dimethylphenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) )-With on, 5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1, 3-Dimethylpyridin-2 (1H) -one was obtained.
ESI-MS m / z 444 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.62-7.59 (m, 1H), 7.47 (d, J = 1.7Hz, 1H), 7.40 (d, J = 8.6Hz, 1H), 7.24-7.11 (m, 4H), 4.05-3.91 (m, 2H), 3.64 (s, 3H), 3.57-3.39 (m, 2H), 3.50-3.43 (m, 1H), 2.22 (s, 3H), 2.15 (s) , 6H), 1.82-1.74 (m, 2H), 1.65-1.53 (m, 2H).

Example 42
1-Methyl-5-(4-((2-Methylpyridine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine -2 (1H)-On

1-Methyl-5-(4-((2-Methylpyridine-4-yl) oxy) oxy, using 4-hydroxy-2-methylpyridine instead of 2-chlorophenol, in the same manner as in Example 13. ) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one was obtained.
ESI-MS m / z 417 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.16 (d, J = 5.6Hz, 1H), 7.81 (d, J = 2.4Hz, 1H), 7.73 (dd, J = 9.2, 2.8Hz, 1H), 7.65-7.48 (m, 1H), 7.36 (d, J = 8.4Hz, 1H), 6.69 (d, J = 2.4Hz, 1H), 6.59 (dd, J = 6.0, 2.4Hz, 1H), 6.52 (d, J = 9.2Hz, 1H), 4.09-4.02 (m, 2H), 3.61-3.54 (m, 5H), 3.25-3.15 (m, 1H), 2.40 (s, 3H), 2.03-1.94 ( m, 4H).

Example 43
5- (4-((5-Chloropyridine-3-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine -2 (1H)-On

5-(4-((5-Chloropyridine-3-yl) oxy) -2-, using 3-chloro-5-hydroxypyridine instead of 2-chlorophenol, in the same manner as in Example 13. (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 437 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 8.17-8.10 (m, 1H), 8.06-7.88 (m, 1H), 7.81 (s, 1H), 7.72 (dd, J = 9.5,2.6Hz) , 1H), 7.50 (d, J = 8.6Hz, 1H), 7.40-7.23 (m, 1H), 7.21-7.06 (m, 1H), 6.51 (d, J = 8.6Hz, 1H), 4.05-3.97 ( m, 2H), 3.65-3.39 (m, 6H), 2.02-1.88 (m, 4H).

Example 44
5- (4-((5-Fluoropyridine-3-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine -2 (1H)-On

5-(4-((5-Fluoropyridine-3-yl) oxy) -2-, using 3-fluoro-5-hydroxypyridine instead of 2-chlorophenol, in the same manner as in Example 13. (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 421 [M + H] ⁺

¹ H NMR (DMSO-d _6,500MHz ) δ (ppm): 8.23 (dd, J = 7.4,2.3Hz, 1H), 8.05 (d, J = 8.0Hz, 1H), 7.88-7.80 (m, 1H) , 7.65-7.51 (m, 1H), 7.45 (d, J = 8.6Hz, 1H), 7.27-7.22 (m, 1H), 7.17-6.99 (m, 1H), 6.38-6.31 (m, 1H), 3.96 -3.84 (m, 2H), 3.52-3.38 (m, 5H), 3.17-3.01 (m, 1H), 1.94-1.62 (m, 4H).

Example 45
5- (4-((5-fluoropyridin-3-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1,3- Dimethylpyridin-2 (1H) -on

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) in the same manner as in Example 13. )-Instead of one 3-fluoro-5-hydroxypyridine and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 Using (1H) -one, 5- (4-((5-fluoropyridin-3-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) -1,3-dimethylpyridin-2 (1H) -one was obtained.
ESI-MS m / z 435 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 8.09-8.05 (m, 1H), 8.03 (s, 0.5H), 7.91-7.86 (m, 0.5H), 7.70 (d, J = 8.6Hz, 0.5H), 7.41 (d, J = 8.0Hz, 1H), 7.36 (d, J = 8.0Hz, 0.5H), 7.31 (d, J = 10.3, 2.3Hz, 1H), 7.25-7.16 (m, 1H) ), 6.79 (d, J = 9.7Hz, 0.5H), 6.61-6.56 (m, 0.5H), 4.10-4.02 (m, 2H), 3.57-3.47 (m, 5H), 3.24-3.14 (m, 1H) ), 2.14 (s, 1.5H), 2.12 (s, 1.5H), 2.10-1.87 (m, 4H).

Example 46
5-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -1-methyl-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [ d] Imidazole-4-yl) oxy) nicotinonitrile

In the same manner as in Example 13, 4-bromo-3-fluoro-2-nitroaniline, 2-chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one instead of 4-bromo-3-fluoro-N-methyl-2-nitroaniline, 3-cyano-5-hydroxypyridine and 1,3-dimethyl -5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -on with 5-((5- (1,5-) Dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -1-methyl-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) nicoti Nonitrile was obtained.
ESI-MS m / z 478 [M + Na] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.67 (d, J = 1.6Hz, 1H), 8.50 (d, J = 2.8Hz, 1H), 7.73-7.68 (m, 2H), 7.56 (d, J = 8.4Hz, 1H), 7.49-7.45 (m, 1H), 7.36-7.30 (m, 1H), 3.92-3.80 (m, 5H), 3.51-3.43 (m, 5H), 3.31-3.23 (m, 1H), 2.00 (s, 3H), 1.82-1.58 (m, 4H).

Example 47
1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((5- (trifluoromethyl) pyridin-3-yl) oxy) -1H-benzo [d] imidazole -5-yl) Pyridine-2 (1H) -on

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) in the same manner as in Example 13. )-On instead of 3-hydroxy-5- (trifluoromethyl) pyridine and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Pyridine-2 (1H) -one with 1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((5- (trifluoromethyl) pyridine-3) -Il) Oxy) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 485 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 9.75 (s, 0.35H), 9.65 (s, 0.65H), 8.47 (s, 1H), 8.39 (d, J = 2.3Hz, 0.65H), 8.30 (s, 0.35H), 7.72 (d, J = 8.6Hz, 0.35H), 7.41-7.34 (m, 1.65H), 7.31-7.29 (m, 0.65H), 7.27-7.20 (m, 1H), 7.09 (s, 0.35H), 4.12-4.02 (m, 2H), 3.62-3.44 (m, 5H), 3.28-3.11 (m, 1H), 2.19-1.83 (m, 7H).

Example 48
1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((6- (trifluoromethyl) pyridin-3-yl) oxy) -1H-benzo [d] imidazole -5-yl) Pyridine-2 (1H) -on

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) in the same manner as in Example 13. )-Instead of one, 5-hydroxy-2- (trifluoromethyl) pyridine and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Pyridine-2 (1H) -one with 1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((6- (trifluoromethyl) pyridine-3) -Il) Oxy) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 485 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 10.15-9.85 (m, 1H), 8.22 (s, 0.6H), 8.08 (s, 0.4H), 7.70 (d, J = 8.6Hz, 0.4H) ), 7.50 (d, J = 8.6Hz, 0.6H), 7.44 (s, 0.4H), 7.42 (s, 0.6H), 7.37 (s, 0.6H), 7.36 (s, 0.4H), 7.31 (s) , 0.4H), 7.22 (d, J = 8.0Hz, 0.6H), 7.17 (d, J = 8.0Hz, 0.6H), 6.99-6.89 (m, 0.4H), 4.10-4.02 (m, 2H), 3.57-3.44 (m, 5H), 3.24-3.13 (m, 1H), 2.16-1.83 (m, 7H).

Example 49
1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((2- (trifluoromethyl) pyridin-4-yl) oxy) -1H-benzo [d] imidazole -5-yl) Pyridine-2 (1H) -on

2-Chlorophenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) in the same manner as in Example 13. )-On behalf of 4-hydroxy-2- (trifluoromethyl) pyridine and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Pyridine-2 (1H) -one with 1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((2- (trifluoromethyl) pyridine-4) -Il) Oxy) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 485 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 8.45 (d, J = 5.2Hz, 0.65H), 8.39 (s, 0.35H), 7.73 (d, J = 8.6Hz, 0.35H), 7.46- 7.32 (m, 1.65H), 7.31-7.16 (m, 2H), 7.05 (d, J = 2.3Hz, 0.65H), 6.97 (d, J = 3.4Hz, 0.35H), 6.85 (d, J = 5.2) Hz, 0.65H), 6.67 (s, 0.35H), 4.11-4.02 (m, 2H), 3.60-3.43 (m, 5H), 3.29-3.10 (m, 1H), 2.14-1.85 (m, 7H).

Example 50
1-Methyl-5-(4-((1-oxo-1,3-dihydroisobenzofuran-5-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-5-yl) Pyridine-2 (1H) -on

In the same manner as in Example 13, 5-hydroxyisobenzofuran-1 (3H) -one was used instead of 2-chlorophenol, and 1-methyl-5-(4-((1-oxo-1,1)-. 3-Dihydroisobenzofuran-5-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained. ..
ESI-MS m / z 458 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.88-7.70 (m, 3H), 7.58 (d, J = 8.0Hz, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.04 ( d, J = 8.8Hz, 1H), 6.87 (d, J = 2.0Hz, 1H), 6.50 (d, J = 9.6Hz, 1H), 5.21 (s, 2H), 4.13-4.00 (m, 2H), 3.62-3.54 (m, 5H), 3.26-3.09 (m, 1H), 2.08-1.87 (m, 4H).

Example 51
1-Methyl-5-(4-((3-oxo-1,3-dihydroisobenzofuran-5-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-5-yl) Pyridine-2 (1H) -on

In the same manner as in Example 13, 1-methyl-5-(4-((3-oxo-1,1-)-on, 6-hydroxyisobenzofuran-1 (3H) -one, was used instead of 2-chlorophenol. 3-Dihydroisobenzofuran-5-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained. ..
ESI-MS m / z 458 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.84 (d, J = 2.4Hz, 1H), 7.77 (dd, J = 9.2,2.8Hz, 1H), 7.58 (d, J = 8.4Hz, 1H), 7.50 (dd, J = 8.4,0.8Hz, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.33 (dd, J = 8.4, 2.4Hz, 1H), 6.94 (d, J = 2.0) Hz, 1H), 6.49 (d, J = 9.2Hz, 1H), 5.29 (s, 2H), 4.08-4.02 (m, 2H), 3.62-3.52 (m, 5H), 3.24-3.14 (m, 1H) , 2.07-1.92 (m, 4H).

Example 52
1-Methyl-5-(4-((1-oxo-1,3-dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-5-yl) Pyridine-2 (1H) -on

In the same manner as in Example 13, 4-hydroxy-3H-isobenzofuran-1-one was used instead of 2-chlorophenol, and 1-methyl-5-(4-((1-oxo-1, 1-oxo-1,1)) was used. 3-Dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained. ..
ESI-MS m / z 458 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.92-7.82 (m, 1H), 7.67-7.24 (m, 5H), 6.85-6.61 (m, 1H), 6.38-6.30 (m, 1H) ), 5.43-5.17 (m, 2H), 3.98-3.81 (m, 2H), 3.50-3.39 (m, 5H), 3.15-3.02 (m, 1H), 1.97-1.69 (m, 4H).

Example 53
1-Methyl-5-(4-((3-oxo-1,3-dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-5-yl) Pyridine-2 (1H) -on

In the same manner as in Example 13, 1-methyl-5-(4-((3-oxo-1,1-)) was used instead of 2-chlorophenol using 7-hydroxy-1 (3H) -isobenzofuranone. 3-Dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained. ..
ESI-MS m / z 458 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.74-12.31 (brs, 1H), 7.98 (d, J = 2.0Hz, 1H), 7.75-7.42 (m, 3H), 7.38-7.26 ( m, 1H), 7.22-7.10 (m, 1H), 6.38-6.18 (m, 2H), 5.40 (s, 2H), 4.02-3.79 (m, 2H), 3.49-3.38 (m, 5H), 3.18- 3.01 (m, 1H), 2.00-1.65 (m, 4H).

Example 54
5- (4- (Benzodiazepine [c] [1,2,5] oxadiazole-4-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridine-2 (1H) -on

5- (4- (Benzo [c] [1,2,5] oxadiazole-4-) using 4-hydroxybenzoflazan instead of 2-chlorophenol in the same manner as in Example 13. Iloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 444 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.76-12.31 (m, 1H), 7.93-7.82 (m, 1H), 7.69-7.43 (m, 3H), 7.40-7.25 (m, 2H) ), 6.40-6.17 (m, 2H), 3.99-3.79 (m, 2H), 3.49-3.34 (m, 5H), 3.13-3.01 (m, 1H), 1.94-1.64 (m, 4H).

Example 55
5- (4- (Benzodiazepine [c] [1,2,5] oxadiazole-5-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridine-2 (1H) -on

Similar to the method of Example 13, using 2,1,3-benzoxadiazole-5-ol instead of 2-chlorophenol, 5- (4- (benzo [c] [1,2, 5] Oxadiazole-5-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one Obtained.
ESI-MS m / z 444 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.69-12.37 (m, 1H), 8.17-8.00 (m, 1H), 7.95-7.81 (m, 1H), 7.68-7.44 (m, 3H) ), 7.36-7.24 (m, 1H), 6.64-6.46 (m, 1H), 6.40-6.28 (m, 1H), 4.01-3.79 (m, 2H), 3.47-3.36 (m, 5H), 3.16-3.02 (m, 1H), 1.95-1.67 (m, 4H).

Example 56
1-Methyl-5-(4- (Naphthalene-1-yloxy) -2- (Tetrahydro-2H-Pyran-4-yl) -1H-Benzodiazepine [d] Imidazole-5-yl) Pyridine-2 (1H)- on

1-Methyl-5-(4- (naphthalen-1-yloxy) -2- (tetrahydro-2H-pyran-), using 1-naphthol instead of 2-chlorophenol, in the same manner as in Example 13. 4-yl) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 452 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 8.40 (d, J = 8.0Hz, 1H), 7.78 (d, J = 8.6Hz, 1H), 7.75 (d, J = 2.3Hz, 1H) , 7.61 (dd, J = 9.2,2.3Hz, 1H), 7.57-7.42 (m, 3H), 7.38 (d, J = 8.1Hz, 1H), 7.30 (d, J = 8.0Hz, 1H), 7.12- 7.04 (dd, J = 8.1, 8.0Hz, 1H), 6.24 (d, J = 8.6Hz, 2H), 4.07-3.89 (m, 2H), 3.55-3.42 (m, 2H), 3.22 (s, 3H) , 3.16-2.95 (m, 1H), 2.08-1.80 (m, 4H).

Example 57
1-Methyl-5-(4- (Naphthalene-2-yloxy) -2- (Tetrahydro-2H-Pyran-4-yl) -1H-Benzodiazepine [d] Imidazole-5-yl) Pyridine-2 (1H)- on

1-Methyl-5-(4- (naphthalen-2-yloxy) -2- (tetrahydro-2H-pyran-), using 2-naphthol instead of 2-chlorophenol, in the same manner as in Example 13. 4-Il) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 452 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.82-7.52 (m, 4H), 7.52 (d, J = 8.6Hz, 1H), 7.43 (d, J = 8.0Hz, 1H), 7.34 7.16 (m, 3H), 7.08 (dd, J = 8.6, 2.3Hz, 1H), 6.76 (d, J = 1.7Hz, 1H), 6.34 (d, J = 9.2Hz, 1H), 4.06-3.82 (m) , 2H), 3.52-3.20 (m, 5H), 3.15-2.97 (m, 1H), 2.08-1.74 (m, 4H).

Example 58
1-Methyl-5-(4- (quinoline-8-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H)- on

1-Methyl-5-(4- (quinoline-8-yloxy) -2- (tetrahydro-2H-pyran-), using 8-quinolinol instead of 2-chlorophenol, in the same manner as in Example 13. 4-Il) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 453 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 8.85 (d, J = 2.9Hz, 1H), 8.36-8.22 (m, 1H), 7.93 (d, J = 1.7Hz, 1H), 7.67 ( dd, J = 9.5,2.6Hz, 1H), 7.58-7.52 (m, 2H), 7.46 (d, J = 8.1Hz, 1H), 7.32 (d, J = 8.0Hz, 1H), 7.24 (dd, J = 8.1,8.0Hz, 1H), 6.54 (d, J = 7.4Hz, 1H), 6.24 (d, J = 9.7Hz, 1H), 4.05-3.89 (m, 2H), 3.53-3.36 (m, 2H) , 3.03 (s, 3H), 3.18-3.01 (m, 1H), 2.04-1.79 (m, 4H).

Example 59
1-Methyl-5-(4- (quinoline-7-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H)- on

1-Methyl-5-(4- (quinoline-7-yloxy) -2- (tetrahydro-2H-pyran), using 7-hydroxyquinoline instead of 2-chlorophenol, in the same manner as in Example 13. -4-yl) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 453 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 8.69-8.52 (m, 1H), 8.33-8.14 (m, 1H), 7.93-7.62 (m, 3H), 7.59-7.50 (m, 1H) , 7.45-7.23 (m, 3H), 6.91-6.83 (m, 1H), 6.44-6.35 (m, 1H), 4.02-3.90 (m, 2H), 3.66-3.35 (m, 5H), 3.21-3.01 ( m, 1H), 2.04-1.78 (m, 4H).

Example 60
5- (4- (2-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

N- (3- (2-bromophenoxy) -4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide
DMF (3-fluoro-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (0.30 g) To the 8.0 mL) solution, cesium carbonate (0.39 g) and 2-bromophenol (0.20 g) were added, and the mixture was heated and stirred at 80 ° C. for 2.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L aqueous sodium hydroxide solution and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform / methanol) to N- (3- (2-bromophenoxy) -4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2. -Nitrophenyl) Tetrahydro-2H-pyran-4-carboxamide (0.377 g) was obtained.
ESI-MS m / z 528 [M + H] ⁺

b. 5- (4- (2-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on
N- (3- (2-bromophenoxy) -4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (0.377) Acetic acid (0.82 mL) and iron powder (200 mg) were added to a solution of g) in ethanol (7.15 mL), and the mixture was heated and stirred at 140 ° C. for 15 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. After concentrating the filtrate under reduced pressure, the residue was purified by silica gel chromatography (chloroform / methanol) to 5- (4- (2-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-. Benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (263 mg) was obtained.
ESI-MS m / z 480 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.82 (d, J = 2.3Hz, 1H), 7.65 (d, J = 9.7Hz, 1H), 7.51 (d, J = 7.4Hz, 2H) , 7.29 (d, J = 8.0Hz, 1H), 7.01 (brs, 1H), 6.80 (brs, 1H), 6.43 (d, J = 9.2Hz, 1H), 6.26 (d, J = 8.0Hz, 1H) , 4.02 (dd, J = 8.3,2.6Hz, 2H), 3.62-3.46 (m, 5H), 3.22-3.08 (m, 1H), 2.07-1.86 (m, 4H).

Example 61
5- (4- (3-Bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (4- (3-Bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl)) using 3-bromophenol instead of 2-bromophenol in the same manner as in Example 60. -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 480 [M + H] ^+
1 H NMR (CDCl _3,500MHz ) δ (ppm): 10.25-10.08 (m, 1H), 7.66 (d, J = 8.0Hz, 0.65H), 7.51 (dd, J = 9.5,2.6Hz, 1H), 7.40 (dd, J = 6.9,1.7Hz, 1H), 7.34 (d, J = 8.0Hz, 0.35H), 7.20 (d, J = 8.6Hz, 0.65H), 7.18 (d, J = 8.6Hz, 0.35) H), 7.09-6.95 (m, 2H), 6.82 (s, 1H), 6.71 (d, J = 8.0Hz, 0.35H), 6.60 (d, J = 8.0Hz, 0.65H), 6.49 (d, J) = 9.2Hz, 1H), 4.09-4.01 (m, 2H), 3.55-3.46 (m, 5H), 3.24-3.09 (m, 1H), 2.06-1.88 (m, 4H).

Example 62
1-Methyl-5-(4- (2- (1-Methyl-1H-pyrazole-4-yl) phenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) Pyridine-2 (1H) -on

5- (4- (2-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridin-2 (1H) -one Sodium carbonate (93 mg) and PdCl ₂ (dppf) in a mixed solution of 1,4-dioxane (3.0 mL) and water (0.5 mL) of (140 mg), 1-methyl-1H-pyrazole-4-boronic acid (656 mg). ) -Dichloromethane adduct (23.8 mg) was added, and the mixture was heated and stirred at 160 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform / methanol) to 1-methyl-5-(4- (2- (1-methyl-1H-pyrazole-4-yl) phenoxy)-. 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (65.9 mg) was obtained.
ESI-MS m / z 482 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 9.76 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.6Hz, 1H), 7.53 (d) , J = 5.2Hz, 1H), 7.42 (dd, J = 9.5,2.6Hz, 1H), 7.35 (d, J = 2.3Hz, 1H), 7.22 (d, J = 8.0Hz, 1H), 7.09-6.95 (m, 2H), 6.50 (d, J = 8.0Hz, 1H), 6.41 (d, J = 9.7Hz, 1H), 4.09-4.01 (m, 2H), 3.81 (s, 3H), 3.59-3.43 ( m, 2H), 3.28 (s, 3H), 3.20-3.03 (m, 1H), 2.06-1.88 (m, 4H).

Example 63
5- (4- (2- (Fran-2-yl) phenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine- 2 (1H)-On

5- (4- (2- (Fran-2-yl) phenoxy) using 2-furylboronic acid instead of 1-methyl-1H-pyrazole-4-boronic acid in the same manner as in Example 62. -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 468 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.81 (dd, J = 7.2,2.0Hz, 1H), 7.70-7.55 (m, 1H), 7.52 (s, 1H), 7.46 (d, J = 5.7Hz, 1H), 7.42 (d, J = 8.6Hz, 1H), 7.22 (d, J = 8.6Hz, 1H), 7.08-6.92 (m, 3H), 6.51 (s, 1H), 6.48-6.42 ( m, 1H), 6.38 (d, J = 9.2Hz, 1H), 4.12-3.98 (m, 2H), 3.58-3.42 (m, 5H), 3.18-3.05 (m, 1H), 2.06-1.90 (m, 4H).

Example 64
5- (4- (2- (Fran-3-yl) phenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine- 2 (1H)-On

5- (4- (2- (Fran-3-yl) phenoxy) using 3-furylboronic acid instead of 1-methyl-1H-pyrazole-4-boronic acid in the same manner as in Example 62. -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 468 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 8.00 (s, 1H), 7.60 (d, J = 8.6Hz, 1H), 7.44-7.29 (m, 3H), 7.15 (d, J = 8.0Hz) , 1H), 7.10 (d, J = 6.9Hz, 1H), 6.92 (dd, J = 7.4, 7.3Hz, 1H), 6.70 (dd, J = 7.3, 7.2Hz, 1H), 6.49 (s, 1H) , 6.37 (d, J = 8.6Hz, 1H), 6.12 (d, J = 9.2Hz, 1H), 4.04-3.95 (m, 2H), 3.62-3.33 (m, 2H), 3.24-2.99 (m, 4H) ), 2.07-1.86 (m, 4H).

Example 65
5- (4- (benzyloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5-bromo-1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-ol
5-bromo-4-((4-Methoxybenzyl) oxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (4.40 g) acetonitrile Cerium (III) chloride heptahydrate (5.33 g) and sodium iodide (1.43 g) were added to the (70 mL) solution, and the mixture was heated and stirred at 80 ° C. for 3.5 hours. After cooling the reaction mixture to room temperature, 1 mol / L hydrochloric acid was added until the pH reached 4-5, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole. -4-All (2.50 g) was obtained.
ESI-MS m / z 341 [M + H] ⁺

b. 4- (Benzyloxy) -5-bromo-1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
Benzyl bromide (10 mL) in DMF (10 mL) solution of 5-bromo-1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-ol (500 mg) 376 mg) and potassium carbonate (304 mg) were added, and the mixture was heated and stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 4- (benzyloxy) -5-bromo-1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl)-. 1H-benzo [d] imidazole (500 mg) was obtained.
ESI-MS m / z 431 [M + H] ⁺

c. 5- (4- (benzyloxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine -2 (1H)-On
4- (Benzyloxy) -5-bromo-1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (450 mg), 1-methyl-5- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (319 mg) in a mixed solution of DMF (8 mL) and water (2 mL) with carbonate Sodium (221 mg) and PdCl ₂ (dppf) / dichloromethane adduct (38 mg) were added, and the mixture was heated and stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5- (4- (benzyloxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H. -Benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (250 mg) was obtained.
ESI-MS m / z 460 [M + H] ⁺

d. 5- (4- (benzyloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
5- (4- (benzyloxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 Pyridine hydrochloride (327 mg) was added to a solution of (1H) -on (130 mg) in DMF (2.5 mL), and the mixture was heated and stirred at 100 ° C. for 15 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.225% formic acid aqueous solution) and then freeze-dried to 5- (4- (benzyloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d]. Imidazole-5-yl) -1-methylpyridine-2 (1H) -one (55.1 mg) was obtained.
ESI-MS m / z 416 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.35 (brs, 1H), 7.66 (s, 1H), 7.55 (d, J = 9.2Hz, 1H), 7.39-7.25 (m, 5H) , 7.24-7.10 (m, 1H), 7.05 (d, J = 8.0Hz, 1H), 6.37 (d, J = 9.2Hz, 1H), 5.67 (brs, 2H), 4.02-3.91 (m, 2H), 3.56-3.45 (m, 2H), 3.42 (s, 3H), 3.22-3.12 (m, 1H), 2.02-1.83 (m, 4H).

Example 66
1-Methyl-5-(4-phenetoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

1-Methyl-5- (4-phenetoxy-2- (tetrahydro-2H-pyran-4-yl)-" using (2-bromoethyl) benzene instead of benzyl bromide in the same manner as in Example 65. 1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 430 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.29 (brs, 1H), 7.64 (m, 1H), 7.47 (m, 1H), 7.34-6.95 (m, 7H), 6.32 (d, J = 9.2Hz, 1H), 4.90 (brs, 2H), 4.02-3.88 (m, 2H), 3.53-3.44 (m, 2H), 3.42 (s, 3H), 3.20-3.09 (m, 1H), 2.96 (t, J = 6.8Hz, 2H), 2.00-1.79 (m, 4H).

Example 67
5- (4-((5-Chloropyrimidine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine -2 (1H)-On

5-bromo-4-((5-chloropyrimidine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
5-bromo-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-ol (240 mg) in N-methyl-2-pyrrolidone (9 mL) solution, 4,5- Dichloropyrimidine (240 mg) and potassium carbonate (167 mg) were added, and the mixture was heated and stirred at 50 ° C. for 18 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to 5-bromo-4-((5-chloropyrimidine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl). -1H-benzo [d] imidazole (152 mg) was obtained.
ESI-MS m / z 409 [M + H] ⁺

b. 5- (4-((5-Chloropyrimidine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1- Methylpyridine-2 (1H) -on
5-bromo-4-((5-chloropyrimidine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (152 mg), 1-methyl-5 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (174 mg) mixed solution of DMF (3 mL) and water (0.5 mL) Sodium carbonate (98.3 mg) and PdCl ₂ (dppf) / dichloromethane adduct (27.2 mg) were added to the mixture, and the mixture was heated and stirred at 95 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with methanol. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.225% formic acid aqueous solution) and then freeze-dried to perform 5- (4-((5-chloropyrimidine-4-yl) oxy) -2- (tetrahydro). -2H-Pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (50.9 mg) was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 8.70 (s, 1H), 8.41 (s, 1H), 7.84 (d, J = 2.0Hz, 1H), 7.69 (dd, J = 9.2, 2.4Hz) , 1H), 7.57 (d, J = 8.0Hz, 1H), 7.33 (d, J = 8.4Hz, 1H), 6.52 (d, J = 9.6Hz, 1H), 4.12-4.02 (m, 2H), 3.72 -3.54 (m, 5H), 3.24-3.12 (m, 1H), 2.10-1.92 (m, 4H).

Example 68
1-Methyl-5-(4- (Pyrimidine-4-yloxy) -2- (Tetrahydro-2H-Pyran-4-yl) -1H-Benzodiazepine [d] Imidazole-5-yl) Pyridine-2 (1H)- on

5- (4-((5-Chloropyridine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine To a solution of -2 (1H) -one (48.1 mg) in methanol (5 mL) was added 10% Pd / C (50 mg), and the mixture was stirred under a hydrogen atmosphere for 72 hours. The reaction mixture was filtered through Celite and the insoluble material was washed with methanol. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1-methyl-5- (4- (pyrimidine-4-yloxy) -2- (tetrahydro). -2H-Pyran-4-yl) -1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one (11.2 mg) was obtained.
ESI-MS m / z 404 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 9.27-9.15 (brs, 1H), 8.71-8.66 (s, 1H), 8.56 (dd, J = 6.8, 6.0Hz, 1H), 7.72 (d, J = 7.6Hz, 0.4H), 7.54-7.44 (m, 1H), 7.42-7.36 (m, 1.6H), 7.21 (dd, J = 8.4,3.6Hz, 1H), 6.99 (d, J = 5.2Hz) , 0.6H), 6.82 (d, J = 5.6Hz, 0.4H), 6.53 (d, J = 9.2Hz, 1H), 4.13-4.03 (m, 2H), 3.59-3.47 (m, 5H), 3.25- 3.11 (m, 1H), 2.09-1.85 (m, 4H).

Example 69
5- (4-((6-chloropyridazine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine -2 (1H)-On

5- (4-((6-chloropyridazine-4-yl) oxy) -2-, using 3,5-dichloropyridazine instead of 4,5-dichloropyrimidine, in the same manner as in Example 67. (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.97 (d, J = 2.4Hz, 1H), 7.87 (d, J = 2.4Hz, 1H), 7.73 (dd, J = 9.6, 2.4Hz, 1H), 7.67-7.58 (m, 1H), 7.39 (d, J = 8.4Hz, 1H), 6.95 (d, J = 2.4Hz, 1H), 6.57 (d, J = 9.2Hz, 1H), 4.10- 3.98 (m, 2H), 3.64-3.52 (m, 5H), 3.26-3.13 (m, 1H), 2.04-1.92 (m, 4H).

Example 70
5- (4-((5-Chloropyrimidine-2-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine -2 (1H)-On

5- (4-((5-Chloropyrimidine-2-yl) oxy) -2-, using 2,5-dichloropyrimidine instead of 4,5-dichloropyrimidine, in the same manner as in Example 67. (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 438 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.58-12.17 (m, 1H), 8.80-8.61 (m, 2H), 7.76 (d, J = 2.4Hz, 1H), 7.57-7.34 ( m, 2H), 7.24-7.14 (m, 1H), 6.34 (d, J = 9.2Hz, 1H), 4.00-3.82 (m, 2H), 3.49-3.38 (m, 5H), 3.12-3.00 (m, 1H), 1.95-1.65 (m, 4H).

Example 71
5- (4- (2,6-dimethylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

4-bromo-3- (2,6-dimethylphenoxy) -2-nitroaniline
To a DMSO (30 mL) solution of 4-bromo-3-fluoro-2-nitroaniline (3.00 g), add cesium carbonate (4.99 g) and 2,6-dimethylphenol (1.87 g), and stir at 35 ° C for 16 hours. bottom. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3- (2,6-dimethylphenoxy) -2-nitroaniline (1.83 g).
ESI-MS m / z 337 [M + H] ⁺

b. 4-bromo-3- (2,6-dimethylphenoxy) benzene-1,2-diamine
4-bromo-3- (2,6-dimethylphenoxy) -2-nitroaniline (1.80 g) in a mixed solution of methanol (18 mL) and water (9 mL), iron powder (2.09 g) and ammonium chloride (2.00 g) Was added, and the mixture was heated and stirred at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3- (2,6-dimethylphenoxy) benzene-1,2-diamine (1.45 g).
ESI-MS m / z 307 [M + H] ⁺

c. 5-bromo-4- (2,6-dimethylphenoxy) -2-methyl-1H-benzo [d] imidazole
Trimethyl orthoacetate (1.64 g) and p-toluenesulfonic acid monohydrate in a solution of 4-bromo-3- (2,6-dimethylphenoxy) benzene-1,2-diamine (1.40 g) in THF (15 mL). (86.7 mg) was added, and the mixture was heated and stirred at 50 ° C. for 16 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 5-bromo-4- (2,6-dimethylphenoxy) -2-methyl-1H-benzo [d] imidazole (1.06 g). rice field.
ESI-MS m / z 331 [M + H] ⁺

d. 5- (4- (2,6-dimethylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
5-bromo-4- (2,6-dimethylphenoxy) -2-methyl-1H-benzo [d] imidazole (200 mg), 1-methyl-5- (4,4,5,5-tetramethyl-1,) Add sodium carbonate (192 mg) and PdCl ₂ (dppf) / dichloromethane to a mixed solution of 3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one (170 mg) of DMF (4 mL) and water (1 mL). A substance (44.2 mg) was added, and the mixture was heated and stirred at 100 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 5- (4- (2,6-dimethylphenoxy) -2-methyl-1H-benzo [d] imidazole-5. -Il) -1-Methylpyridine-2 (1H) -one (116 mg) was obtained.
ESI-MS m / z 360 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.38-7.24 (m, 3H), 7.00-6.83 (m, 4H), 6.29 (t, J = 6.4Hz, 1H), 3.44 (s, 3H) , 2.57 (s, 3H), 2.00 (s, 6H).

Example 72
5- (4- (2,6-dimethylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one

Substituting 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one in the same manner as in Example 71. With 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one, 5- (4- (4- (2,6-Dimethylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one was obtained.
ESI-MS m / z 374 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.28 (d, J = 8.0Hz, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 6.98 (d, J = 8.4Hz, 1H), 6.85-6.81 (m, 3H), 3.44 (s, 3H), 2.62 (s, 3H), 1.99 (s, 6H), 1.96 (s, 3H).

Example 73
5- (4- (4- (1H-Pyrazole-1-yl) phenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one

2,6-dimethylphenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 in the same manner as in Example 71. (1H) -Instead of on, 4- (1H-pyrazole-1-yl) phenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il) Pyridine-2 (1H) -one with 5- (4- (4- (1H-pyrazole-1-yl) phenoxy) -2-methyl-1H-benzo [d] imidazole-5- Ill) -1,3-dimethylpyridin-2 (1H) -one was obtained.
ESI-MS m / z 412 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.49 (brs, 1H), 8.33 (s, 1H), 7.80-7.58 (m, 4H), 7.56-7.33 (m, 2H), 7.30- 7.15 (m, 1H), 6.91-6.73 (m, 2H), 6.48 (s, 1H), 3.43 (s, 3H), 2.45 (s, 3H), 1.96 (s, 3H).

Example 74
1,3-dimethyl-5-(2-methyl-4-(2- (oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

2,6-dimethylphenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 in the same manner as in Example 71. Instead of (1H) -one, 2- (oxetane-3-yl) phenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Il) Pyridine-2 (1H) -one with 1,3-dimethyl-5- (2-methyl-4- (2- (oxetane-3-yl) phenoxy) -1H-benzo [d] imidazole- 5-Il) Pyridine-2 (1H) -on was obtained.
ESI-MS m / z 402 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.60-7.40 (m, 4H), 7.28 (d, J = 8.0Hz, 1H), 7.08-6.95 (brs, 2H), 6.30-6.22 (m) , 1H), 5.14-5.06 (m, 2H), 4.66-4.93 (m, 2H), 4.86-4.74 (m, 1H), 3.54 (s, 3H), 2.54 (s, 3H), 2.07 (s, 3H) ).

Example 75
1,3-dimethyl-5-(2-methyl-4-(3- (oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

2,6-dimethylphenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 in the same manner as in Example 71. Instead of (1H) -one, 3- (oxetane-3-yl) phenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-) Il) Pyridine-2 (1H) -one with 1,3-dimethyl-5- (2-methyl-4- (3- (oxetane-3-yl) phenoxy) -1H-benzo [d] imidazole- 5-Il) Pyridine-2 (1H) -on was obtained.
ESI-MS m / z 402 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.75-7.61 (m, 1H), 7.51-7.33 (m, 2H), 7.25-7.12 (m, 2H), 7.02-6.91 (m, 1H) ), 6.88-6.78 (m, 1H), 6.50 (dd, J = 8.4,2.0Hz, 1H), 4.92-4.83 (m, 2H), 4.47 (t, J = 6.4Hz, 2H), 4.19-4.08 ( m, 1H), 3.41 (s, 3H), 2.45 (s, 3H), 1.94 (s, 3H).

Example 76
1,3-dimethyl-5-(2-methyl-4-(4- (oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

2,6-dimethylphenol and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 in the same manner as in Example 71. Instead of (1H) -one, 4- (oxetane-3-yl) phenol and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-) Il) Pyridine-2 (1H) -one with 1,3-dimethyl-5- (2-methyl-4- (4- (oxetane-3-yl) phenoxy) -1H-benzo [d] imidazole- 5-Il) Pyridine-2 (1H) -on was obtained.
ESI-MS m / z 402 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.49-12.30 (m, 1H), 7.76-7.67 (m, 1H), 7.54-7.35 (m, 2H), 7.31-7.18 (m, 3H) ), 6.73-6.66 (m, 2H), 4.91-4.82 (m, 2H), 4.57-4.50 (m, 2H), 4.20-4.09 (m, 1H), 3.44-3.39 (m, 3H), 2.46-2.41 (m, 3H), 1.95 (s, 3H).

Example 77
5- (4- (3-Cyclopropylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one

5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one
5-bromo-4- (3-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole (1.30 g), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1) , 3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one (1.15 g) in a mixed solution of DMF (13 mL) and water (4 mL) with sodium carbonate (816 mg) and PdCl ₂ (dppf). Dichloromethane adduct (141 mg) was added, and the mixture was heated and stirred at 100 ° C. for 36 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5- (4- (3-chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3. -Dimethylpyridin-2 (1H) -on (600 mg) was obtained.
ESI-MS m / z 380 [M + H] ⁺

b. 5- (4- (3-Cyclopropylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one
5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one (300 mg) and cyclopropylboronic acid Cesium fluoride (86.3 mg) and dichlorobis (di-t-butyl (p-dimethylaminophenyl) phosphino) palladium in a mixed solution of (88.2 mg) 1,4-dioxane (6.0 mL) and water (1.5 mL). (II) (55.9 mg) was added, and the mixture was heated and stirred at 120 ° C. for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 5- (4- (3-cyclopropylphenoxy) -2-methyl-1H-benzo [ d] Imidazole-5-yl) -1,3-dimethylpyridine-2 (1H) -one (24.0 mg) was obtained.
ESI-MS m / z 386 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.60-7.58 (m, 2H), 7.48 (s, 1H), 7.28 (d, J = 8.4Hz, 1H), 7.06-7.02 (m, 1H) , 6.66 (d, J = 7.6Hz, 1H), 6.49 (s, 1H), 6.45-6.42 (m, 1H), 3.54 (s, 3H), 2.55 (s, 3H), 2.08 (s, 3H), 1.82-1.75 (m, 1H), 0.92-0.88 (m, 2H), 0.56-0.52 (m, 2H).

Example 78
1,3-dimethyl-5-(2-methyl-4-(3- (1-methyl-1H-pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one (50 mg) and 1-methyl- 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole (32.87 mg) mixed solution of 1,4-dioxane (1.0 mL) and water (0.2 mL) Sodium carbonate (41.9 mg) and bis (tri-t-butylphosphine) palladium (0) (6.73 mg) were added to the mixture, and the mixture was heated and stirred at 120 ° C. for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1,3-dimethyl-5- (2-methyl-4- (3- (1- (1-) 1-). Methyl-1H-pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (11.8 mg) was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.43 (brs, 1H), 8.04 (s, 1H), 7.78-7.69 (m, 2H), 7.49 (s, 1H), 7.38-7.22 ( m, 2H), 7.15-7.06 (m, 3H), 6.36 (s, 1H), 3.84 (s, 3H), 3.40 (s, 3H), 2.44 (s, 3H), 1.94 (s, 3H).

Example 79
1,3-dimethyl-5-(2-methyl-4-(3- (1-methyl-1H-pyrazole-5-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

1-Methyl-5- instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole in the same manner as in Example 78. Using (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole, 1,3-dimethyl-5- (2-methyl-4- (3- (1- (1- (1-) Methyl-1H-pyrazole-5-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.48 (brs, 1H), 8.18 (s, 1H), 7.73-7.31 (m, 5H), 7.08 (d, J = 6.8Hz, 1H) , 6.84 (s, 1H), 6.74 (d, J = 7.2Hz, 1H), 6.28 (d, J = 2.0Hz, 1H), 3.71 (s, 3H), 3.42 (s, 3H), 2.45 (s, 3H), 1.96 (s, 3H).

Example 80
1,3-dimethyl-5-(2-methyl-4-(3- (1-methyl-1H-pyrazole-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

1-Methyl-3- instead of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole in the same manner as in Example 78. Using (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole, 1,3-dimethyl-5- (2-methyl-4- (3- (1- (1- (1-) Methyl-1H-pyrazole-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.62-7.60 (m, 2H), 7.56 (s, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.34-7.29 (m, 2H) ), 7.23-7.18 (m, 2H), 6.67 (d, J = 8.0Hz, 1H), 6.49 (s, 1H), 3.88 (s, 3H), 3.51 (s, 3H), 2.56 (s, 3H) , 2.05 (s, 3H).

Example 81
1,3-dimethyl-5-(2-methyl-4-(3- (tetrahydro-2H-pyran-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -on

5- (4- (3- (3,6-dihydro-2H-pyran-4-yl) phenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethyl Pyridine-2 (1H) -on
5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one (120 mg) and 2- (3) , 6-dihydro-2H-pyran-4-yl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79.6 mg) 1,4-dioxane (3.0 mL) and water (1.0) Sodium carbonate (100 mg) and bis (tri-t-butylphosphine) palladium (0) (16.3 mg) were added to the mixed solution of mL), and the mixture was heated and stirred at 120 ° C. for 1 hour in a microwave reactor. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) and 5- (4- (3- (3,6-dihydro-2H-pyran-4-yl) phenoxy) -2-methyl-1H-benzo [ d] Imidazole-5-yl) -1,3-dimethylpyridine-2 (1H) -one (120 mg) was obtained.
ESI-MS m / z 450 [M + Na] ⁺

b. 1,3-Dimethyl-5-(2-Methyl-4-(3- (tetrahydro-2H-pyran-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On
5- (4- (3- (3,6-dihydro-2H-pyran-4-yl) phenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin- To a solution of 2 (1H) -on (120 mg) in methanol (10 mL) was added 20% palladium hydroxide / carbon (770 mg) and 10% Pd / C (714 mg), and the mixture was stirred under a hydrogen (15 psi) atmosphere for 16 hours. .. The reaction mixture was filtered through Celite and the insoluble material was washed with ethyl acetate. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.225% formic acid aqueous solution) and then freeze-dried to 1,3-dimethyl-5- (2-methyl-4- (3- (tetrahydro-2H-)). Pyran-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (17.0 mg) was obtained.
ESI-MS m / z 430 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.61 (s, 1H), 7.60 (s, 1H), 7.48 (d, J = 8.0Hz, 1H), 7.29 (d, J = 8.0Hz, 1H), 7.12 (dd, J = 8.0, 7.6Hz, 1H), 6.83 (d, J = 7.6Hz, 1H), 6.66 (s, 1H), 6.53 (dd, J = 7.6, 1.6Hz, 1H), 3.99 (d, J = 8.4Hz, 2H), 3.53 (s, 3H), 3.51-3.47 (m, 2H), 2.72-2.66 (m, 1H), 2.56 (s, 3H), 2.07 (s, 3H) , 1.67-1.61 (m, 4H).

Example 82
5- (4- (4-Cyclopropylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one

In the same manner as in Example 77, 5-bromo-4- (3-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole instead of 5-bromo-4- (4-chlorophenoxy)-. 5-(4- (4-Cyclopropylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethyl with 2-methyl-1H-benzo [d] imidazole Pyridine-2 (1H) -on was obtained.
ESI-MS m / z 386 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.61 (s, 1H), 7.59 (s, 1H), 7.46 (d, J = 8.2Hz, 1H), 7.28 (d, J = 8.2Hz, 1H), 6.91 (d, J = 8.4Hz, 2H), 6.60 (d, J = 8.4Hz, 2H), 3.55 (s, 3H), 2.54 (s, 3H), 2.09 (s, 3H), 1.86- 1.76 (m, 1H), 0.94-0.82 (m, 2H), 0.60-0.50 (m, 2H).

Example 83
1,3-dimethyl-5-(2-methyl-4-(4- (1-methyl-1H-pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

5- (4- (4-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one
5-bromo-4- (4-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole (800 mg), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,) Add sodium carbonate (753 mg) and PdCl ₂ (dppf) / dichloromethane to a mixed solution of 3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one (590 mg) of DMF (8 mL) and water (2 mL). A substance (173 mg) was added, and the mixture was heated and stirred at 95 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5- (4- (4-chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3. -Dimethylpyridin-2 (1H) -one (473 mg) was obtained.
ESI-MS m / z 380 [M + H] ⁺

b. 1,3-Dimethyl-5-(2-methyl-4-(4- (1-methyl-1H-pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin- 2 (1H)-On
5- (4- (4-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one (150 mg) and 1-methyl- 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole (107 mg) in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL) with carbonate Sodium (126 mg) and bis (tri-t-butylphosphine) palladium (0) (20.2 mg) were added, and the mixture was heated and stirred at 95 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1,3-dimethyl-5- (2-methyl-4- (4- (1-methyl-1H-pyrazole-)-). 4-Il) Phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (6.18 mg) was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.98 (s, 1H), 7.78-7.68 (m, 2H), 7.61-7.35 (m, 4H), 7.21 (d, J = 8.0Hz, 1H), 6.75-6.63 (m, 2H), 3.83 (s, 3H), 3.42 (s, 3H), 2.44 (s, 3H), 1.96 (s, 3H).

Example 84
1,3-dimethyl-5-(2-methyl-4-(4- (1-methyl-1H-pyrazole-5-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) in the same manner as in Example 78. -On and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) instead of pyrazole 5- (4- (4-chlorophenoxy) -2 -Methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one and 1-methyl-5- (4,4,5,5-tetramethyl-1,1) Using 3,2-dioxaborolan-2-yl) pyrazole, 1,3-dimethyl-5-(2-methyl-4-(4- (1-methyl-1H-pyrazole-5-yl) phenoxy) -1H -Benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.52-12.43 (brs, 1H), 7.71-7.80 (m, 1H), 7.53-7.34 (m, 5H), 7.24 (d, J = 8.4) Hz, 1H), 6.86-6.78 (m, 2H), 6.30 (d, J = 2.0Hz, 1H), 3.84-3.73 (m, 3H), 3.52-3.40 (m, 3H), 2.49-2.41 (m, 3H), 1.97 (s, 3H).

Example 85
1,3-dimethyl-5-(2-methyl-4-(4- (1-methyl-1H-pyrazole-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) in the same manner as in Example 78. -On and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) instead of pyrazole 5- (4- (4-chlorophenoxy) -2 -Methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one and 1-methyl-3- (4,4,5,5-tetramethyl-1,1) Using 3,2-dioxaborolan-2-yl) pyrazole, 1,3-dimethyl-5-(2-methyl-4-(4- (1-methyl-1H-pyrazole-3-yl) phenoxy) -1H -Benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 448 [M + Na] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.44 (brs, 1H), 7.77-7.58 (m, 4H), 7.52-7.33 (m, 2H), 7.38 (d, J = 8.4Hz, 1H), 6.79-6.69 (m, 2H), 6.54 (d, J = 3.6Hz, 1H), 3.83 (s, 3H), 3.42 (s, 3H), 2.44 (s, 3H), 1.95 (s, 3H) ).

Example 86
1,3-dimethyl-5-(2-methyl-4-(4- (tetrahydro-2H-pyran-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -on

5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) in the same manner as in Example 81. -Use 5- (4- (4-chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one instead of on , 1,3-Dimethyl-5-(2-Methyl-4- (4- (tetrahydro-2H-pyran-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) )-Get on.
ESI-MS m / z 430 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.68-7.27 (m, 4H), 7.15-7.02 (m, 2H), 6.87 (d, J = 9.2Hz, 2H), 4.05-3.96 (m) , 2H), 3.59-3.47 (m, 5H), 2.78-2.65 (m, 1H), 2.55 (s, 3H), 2.08 (s, 3H), 1.78-1.66 (m, 4H).

Example 87
1,3-dimethyl-5-(2-methyl-4-(2- (1-methyl-1H-pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

N- (4-bromo-3-fluoro-2-nitrophenyl) acetamide
DIPEA (4.82 mL) and acetyl chloride (1.97 mL) were added to a solution of 4-bromo-3-fluoro-2-nitroaniline (5.01 g) in dichloromethane (50 mL), and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give N- (4-bromo-3-fluoro-2-nitrophenyl) acetamide (3.2 g).
ESI-MS m / z 277 [M + H] ⁺

b. N- (4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -3-fluoro-2-nitrophenyl) acetamide
N- (4-bromo-3-fluoro-2-nitrophenyl) acetamide (7.0 g), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-Il) Pyridine-2 (1H) -one (7.55 g) in a mixed solution of DMF (70 mL) and water (15 mL) with sodium carbonate (8.0 g) and PdCl ₂ (dppf) / dichloromethane adduct (1.1 g) ) Was added, and the mixture was heated and stirred at 100 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and N- (4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -3-fluoro-2. -Nitrophenyl) Acetamide (3.2 g) was obtained.
ESI-MS m / z 320 [M + H] ⁺

c. N- (3- (2-bromophenoxy) -4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitrophenyl) acetamide
Phenol in a DMSO (30 mL) solution of N- (4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -3-fluoro-2-nitrophenyl) acetamide (3.2 g) Cesium (3.92 g) and 2-bromophenol (2.08 g) were added, and the mixture was stirred at 35 ° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and N- (3- (2-bromophenoxy) -4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3). -Il) -2-nitrophenyl) acetamide (3.4 g) was obtained.
ESI-MS m / z 472 [M + H] ⁺

d. N- (2-Amino-3- (2-bromophenoxy) -4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) phenyl) acetamide
Methanol (30 mL) of N- (3- (2-bromophenoxy) -4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitrophenyl) acetamide (3.4 g) ) And water (15 mL), iron powder (2.81 g) and ammonium chloride (2.70 g) were added, and the mixture was heated and stirred at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to N- (2-amino-3- (2-bromophenoxy) -4- (1,5-dimethyl-6-oxo-). A crude product of 1,6-dihydropyridine-3-yl) phenyl) acetamide (4.3 g) was obtained.
ESI-MS m / z 442 [M + H] ⁺

e. 5- (4- (2-Bromophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one
N- (2-amino-3- (2-bromophenoxy) -4- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) phenyl) acetamide crude product (4.3 g) To a solution of 1,4-dioxane (40 mL) was added p-toluenesulfonic acid monohydrate (185 mg), and the mixture was heated and stirred at 100 ° C. for 18 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to 5- (4- (2-bromophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethyl. Pyridine-2 (1H) -on (1.3 g) was obtained.
ESI-MS m / z 424 [M + H] ⁺

f. 1,3-Dimethyl-5-(2-methyl-4-(2- (1-methyl-1H-pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin- 2 (1H)-On
5- (4- (2-bromophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one (180 mg) and 1-methyl- 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole (177 mg) in a mixed solution of 1,4-dioxane (3.0 mL) and water (0.8 mL) , Tripotassium phosphate (270 mg) and bis (tri-t-butylphosphine) palladium (0) (21.7 mg) were added, and the mixture was heated and stirred at 130 ° C. for 1.5 hours in a microwave reactor. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.225% formic acid aqueous solution) and then freeze-dried to 1,3-dimethyl-5- (2-methyl-4- (2- (1-methyl-). 1H-pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (36 mg) was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.21 (s, 1H), 8.03 (s, 1H), 7.59-7.56 (m, 1H), 7.49 (d, J = 8.4Hz, 1H), 7.43 (s, 1H), 7.38 (m, 1H), 7.27 (d, J = 8.4Hz, 1H), 6.96-6.94 (m, 2H), 6.37-6.34 (m, 1H), 3.98 (s, 3H) , 3.29 (s, 3H), 2.59 (m, 3H), 1.86 (s, 3H).

Example 88
1,3-dimethyl-5-(2-methyl-4-(2- (1-methyl-1H-pyrazole-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridin-2 ( 1H)-On

5- (4- (3-Chlorophenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) in the same manner as in Example 78. -On and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) instead of pyrazole 5- (4- (2-bromophenoxy) -2 -Methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one and 1-methyl-3- (4,4,5,5-tetramethyl-1,1) Using 3,2-dioxaborolan-2-yl) pyrazole, 1,3-dimethyl-5-(2-methyl-4-(2-(1-methyl-1H-pyrazole-3-yl) phenoxy) -1H -Benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.84-7.82 (m, 1H), 7.69 (m, 1H), 7.52-7.49 (m, 2H), 7.44 (s, 1H), 7.30 (d) , J = 8.4Hz, 1H), 7.04-6.98 (m, 3H), 6.36 (d, J = 9.2Hz, 1H), 4.00 (s, 3H), 3.29 (s, 3H), 2.60 (s, 3H) , 1.89 (s, 3H).

Example 89
5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1,3-dihydro-2H-benzo [d] imidazol-2-one

5- (4-Amino-3-nitro-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one
4-bromo-2-nitro-3-phenoxyaniline (477 mg), 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 ( To a mixed solution of 1H) -one (435 mg) 1,4-dioxane (12.9 mL) and water (2.6 mL), add sodium carbonate (409 mg) and PdCl ₂ (dppf) / dichloromethane adduct (56 mg), and add micro. The mixture was heated and stirred at 160 ° C. for 10 minutes in a wave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 5- (4-amino-3-nitro-2-phenoxyphenyl) -1-methylpyridine-2 (1H). )-On (432 mg) was obtained.
ESI-MS m / z 338 [M + H] ⁺

b. 5- (3,4-diamino-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one
Ammonium chloride in a mixed solution of 5- (4-amino-3-nitro-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (430 mg) in ethanol (8.5 mL) and water (4.3 mL). (682 mg) and iron powder (356 mg) were added, and the mixture was heated and stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give 5- (3,4-diamino-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (396 mg).
ESI-MS m / z 308 [M + H] ⁺

c. 5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1,3-dihydro-2H-benzo [d] imidazol-2-one
CDI (1.0 g) was added to a solution of 5- (3,4-diamino-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (396 mg) in THF (13 mL) in a microwave reactor. , Heated and stirred at 150 ° C. for 10 minutes. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol) and 5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1,3-dihydro-2H- Benzo [d] imidazol-2-one (202 mg) was obtained.
ESI-MS m / z 334 [M + H] ⁺

¹ H NMR (DMSO-d _6,500MHz ) δ (ppm): 10.95 (brs, 1H), 10.87 (brs, 1H), 7.77 (d, J = 2.9Hz, 1H), 7.50 (dd, J = 9.5, 2.6Hz, 1H), 7.28-7.15 (m, 2H), 7.02 (d, J = 8.0Hz, 1H), 6.97-6.86 (m, 2H), 6.69 (dd, J = 6.3, 1.7Hz, 2H), 6.28 (d, J = 9.2Hz, 1H), 3.37 (s, 3H).

Example 90
1-Methyl-5-(2- (oxetane-3-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one

5-bromo-2- (oxetane-3-yl) -4-phenoxy-1H-benzo [d] imidazole
Oxetane-3-carbaldehyde (463 mg) is added to a mixed solution of DMF (9.0 mL) and water (1.0 mL) of 4-bromo-3-phenoxybenzene-1,2-diamine (1.00 g) at 80 ° C. The mixture was heated and stirred for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 5-bromo-2- (oxetane-3-yl) -4-phenoxy-1H-benzo [d] imidazole (517 mg).
ESI-MS m / z 345 [M + H] ⁺

b. 1-Methyl-5-(2- (oxetane-3-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one
5-bromo-2- (oxetane-3-yl) -4-phenoxy-1H-benzo [d] imidazole (200 mg), 1-methyl-5- (4,4,5,5-tetramethyl-1,3) , 2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one (204 mg) in a mixed solution of DMF (4 mL) and water (0.5 mL), potassium carbonate (160 mg) and tetrakis (triphenylphosphine) palladium ( 0) (134 mg) was added, and the mixture was heated and stirred at 90 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1-methyl-5- (2- (oxetane-3-yl) -4-phenoxy-. 1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one (93.3 mg) was obtained.
ESI-MS m / z 374 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.79 (d, J = 2.0Hz, 1H), 7.74 (dd, J = 9.2, 2.4Hz, 1H), 7.59 (s, 1H), 7.36 ( d, J = 8.4Hz, 1H), 7.20 (dd, J = 8.0, 7.2Hz, 2H), 6.94 (t, J = 7.2Hz, 1H), 6.74 (d, J = 8.0Hz, 2H), 6.49 ( d, J = 9.6Hz, 1H), 5.18-4.96 (m, 4H), 4.61-4.50 (m, 1H), 3.54 (s, 3H).

Example 91
1-Methyl-5-(4-Phenoxy-2- (tetrahydrofuran-3-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one

N- (2-amino-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -3-phenoxyphenyl) tetrahydrofuran-3-carboxamide and N- (6-amino-3) -(1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-phenoxyphenyl) Tetrahydrofuran-3-carboxamide
In a solution of 5- (3,4-diamino-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (560 mg) in THF (5 mL) with tetrahydrofuran-3-carbonyl chloride (245 mg) and pyridine (0.445). mL) was added, and the mixture was heated and stirred at 50 ° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to N- (2-amino-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-. 3-Phenyloxyphenyl) tetrahydrofuran-3-carboxamide and N- (6-amino-3- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-phenoxyphenyl) tetrahydrofuran-3-carboxamide A mixture (530 mg) was obtained.
ESI-MS m / z 406 [M + H] ⁺

b. 1-Methyl-5- (4-phenoxy-2- (tetrahydrofuran-3-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one
N- (2-amino-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -3-phenoxyphenyl) tetrahydrofuran-3-carboxamide and N- (6-amino-3- (6-amino-3- ( A solution of 1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-phenoxyphenyl) tetrahydrofuran-3-carboxamide mixture (530 mg) in acetic acid (5 mL) was heated and stirred at 100 ° C. for 16 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, and the residue is purified by preparative HPLC (acetonitrile / 0.05% hydrochloric acid) and then freeze-dried to 1-methyl-5- (4-phenoxy-2- (tetrahydrofuran-3). -Il) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one (217.4 mg) was obtained.
ESI-MS m / z 388 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.15 (d, J = 2.4Hz, 1H), 8.01 (dd, J = 9.2, 2.4Hz, 1H), 7.88-7.69 (m, 2H), 7.27 (dd, J = 8.0, 7.6Hz, 2H), 7.10-6.96 (t, J = 7.6Hz, 1H), 6.83 (d, J = 8.0Hz, 2H), 6.79 (d, J = 9.6Hz, 1H) ), 4.25-4.10 (m, 3H), 4.09-3.97 (m, 1H), 3.92 (q, J = 8.0Hz, 1H), 3.72 (s, 3H), 2.70-2.60 (m, 1H), 2.4- 2.27 (m, 1H).

Example 92
1-Methyl-5-(2- (oxepane-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one

N- (2-amino-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -3-phenoxyphenyl) oxepane-4-carboxamide and N- (6-amino-3) -(1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-phenoxyphenyl) Oxepane-4-carboxamide
Oxepane-4-carboxylic acid (120 mg) in a solution of 5- (3,4-diamino-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (214 mg) in DMF (5 mL) under ice-cooling. , Triethylamine (78 mg) and 50% T3P (DMF solution, 487 mg) were added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and N- (2-amino-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -3-phenoxy). Phenyl) Oxepan-4-carboxamide and N- (6-amino-3- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-phenoxyphenyl) oxepan-4-carboxamide mixture (126 mg) ) Was obtained.
ESI-MS m / z 434 [M + H] ⁺

b. 1-Methyl-5-(2- (oxepane-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one
N- (2-amino-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -3-phenoxyphenyl) oxepan-4-carboxamide and N- (6-amino-3- ( 1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-phenoxyphenyl) Oxepan-4-carboxamide mixture (126 mg) in a 1,4-dioxane (10 mL) solution with p-toluenesulfonic acid Monohydrate (6.0 mg) was added, and the mixture was heated and stirred at 100 ° C. for 8 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1-methyl-5- (2- (oxepane-4-yl) -4-phenoxy-1H-benzo [d]. Imidazole-5-yl) pyridin-2 (1H) -one (29 mg) was obtained.
ESI-MS m / z 416 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.41-12.32 (brs, 1H), 7.83-7.76 (m, 1H), 7.59-7.49 (m, 1.5H), 7.37 (d, J = 8.4Hz, 0.5H), 7.15-7.25 (m, 3H), 6.96-6.87 (m, 1H), 6.69 (d, J = 8.4Hz, 2H), 6.33-6.27 (m, 1H), 3.80-3.67 ( m, 2H), 3.66-3.52 (m, 2H), 3.39 (s, 3H), 3.16-3.04 (m, 1H), 2.11-1.94 (m, 3H), 1.93-1.62 (m, 3H).

Example 93
5- (2- (2-Methoxycyclopropyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5-bromo-4-phenoxy-1H-benzo [d] imidazole
To a solution of 4-bromo-3-phenoxybenzene-1,2-diamine (10.1 g) in THF (100 mL), methyl orthoformate (11.4 g) and p-toluenesulfonic acid monohydrate (617 mg) were added. The mixture was heated and stirred at 50 ° C. for 7 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 5-bromo-4-phenoxy-1H-benzo [d] imidazole (12.3 g).
ESI-MS m / z 289 [M + H] ⁺

b. 5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole
To a solution of 5-bromo-4-phenoxy-1H-benzo [d] imidazole (12.3 g) in DMF (160 mL) was added 60% sodium hydride (1.94 g) under ice-cooling, and the mixture was stirred at 15 ° C. for 1 hour. .. 2- (Chloromethoxy) ethyltrimethylsilane (8.10 g) was added to the reaction mixture, and the mixture was stirred at 15 ° C. for 15 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (7.00 g). ) Was obtained.
ESI-MS m / z 419 [M + H] ⁺

c. 5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-carbaldehyde
5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (7.00 g) in 2-MeTHF (110 mL) solution at -70 ° C, 2 mol / L LDA (THF / heptane / ethylbenzene solution, 10.0 mL) was added, and the mixture was stirred at −70 ° C. for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2- Carbaldehyde (6.00 g) was obtained.
ESI-MS m / z 447 [M + H] ⁺

d. (Z) -5-bromo-2- (2-methoxyvinyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole
Add 2.5 mol / L n-butyllithium (n-hexane solution, 4.67 mL) to a solution of (methoxymethyl) triphenylphosphonium chloride (4.21 g) in THF (50 mL) under ice-cooling, and stir at 15 ° C for 1 hour. bottom. In the reaction mixture, under ice-cooling, 5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-carbaldehyde (6.00 g) in THF ( 20 mL) solution was added and stirred at 15 ° C. for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to (Z) -5-bromo-2- (2-methoxyvinyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy). Methyl) -1H-benzo [d] imidazole (2.25 g) was obtained.
ESI-MS m / z 475 [M + H] ⁺

e. 5-bromo-2- (2-methoxycyclopropyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole diiodomethane (4.51 g) dichloromethane (20 mL) ) To the solution, 1 mol / L diethylzinc (toluene solution, 16.8 mL) was added at -10 ° C, and the mixture was stirred at -10 ° C for 30 minutes. In the reaction mixture at -10 ° C (Z) -5-bromo-2- (2-methoxyvinyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole ( 1.60 g) of a solution of dichloromethane (20 mL) was added, and the mixture was stirred at 25 ° C. for 16 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, the mixture was filtered, and the insoluble material was washed with dichloromethane. The filtrate was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-2- (2-methoxycyclopropyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl)-. 1H-benzo [d] imidazole (270 mg) was obtained.
ESI-MS m / z 489 [M + H] ⁺

f. 5- (2- (2-Methoxycyclopropyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine -2 (1H)-On
5-bromo-2- (2-methoxycyclopropyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (270 mg), 1-methyl-5- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (169 mg) in a mixed solution of DMF (4 mL) and water (0.8 mL) Sodium carbonate (117 mg) and PdCl ₂ (dppf) / dichloromethane adduct (20.2 mg) were added, and the mixture was heated and stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5- (2- (2-methoxycyclopropyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H. -Benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (230 mg) was obtained.
ESI-MS m / z 518 [M + H] ⁺

g. 5- (2- (2-Methoxycyclopropyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
5- (2- (2-Methoxycyclopropyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 1 mol / L TBAF (THF solution, 2.30 mL) was added to a (1H) -one (230 mg) THF (2.3 mL) solution, and the mixture was heated and stirred at 60 ° C. for 100 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (methanol / ethyl acetate) and then freeze-dried to 5- (2- (2-methoxycyclopropyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1. -Methylpyridine-2 (1H) -on (10.0 mg) was obtained.
ESI-MS m / z 388 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.50 (brs, 1H), 7.94-7.70 (m, 1H), 7.52-7.49 (m, 1H), 7.48-7.31 (m, 1H), 7.30-7.11 (m, 3H), 7.06-6.83 (m, 1H), 6.82-6.57 (m, 2H), 6.40-6.22 (m, 1H), 3.70-3.49 (m, 1H), 3.39 (s, 3H) ), 3.31 (s, 3H), 2.28-2.21 (m, 1H), 1.46-1.14 (m, 2H).

Example 94
5- (2- (3-Hydroxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

3- (5-bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol (140 mg), 1-methyl-5- (4,4,5,5-tetramethyl-) 1,3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one (110 mg) in a mixed solution of DMF (4 mL) and water (1.2 mL) with sodium carbonate (82.6 mg) and PdCl ₂ (dppf) ) -Dichloromethane adduct (17.1 mg) was added, and the mixture was heated and stirred at 100 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.225% ammonium formate aqueous solution) and then freeze-dried to 5- (2- (3-hydroxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl). -1-Methylpyridine-2 (1H) -one (58.0 mg) was obtained.
ESI-MS m / z 388 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.80-7.69 (m, 2H), 7.58-7.50 (m, 1H), 7.31 (d, J = 8.4Hz, 1H), 7.20 (dd, J) = 8.4,7.2Hz, 2H), 6.93 (t, J = 7.2Hz, 1H), 6.72 (d, J = 8.4Hz, 2H), 6.48 (d, J = 9.2Hz, 1H), 4.60-4.55 (m) , 0.2H), 4.35-4.16 (m, 0.8H), 3.77-3.68 (m, 0.2H), 3.33 (s, 3H), 3.26-3.13 (m, 0.8H), 2.82-2.67 (m, 2H) , 2.50-2.26 (m, 2H).

Example 95
1-Methyl-5-(2- (3-oxocyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

Similar to the method of Example 94, instead of 3- (5-bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol, 3- (5-bromo-4-) Phenoxy-1H-benzo [d] imidazol-2-yl) with cyclobutane-1-one, 1-methyl-5- (2- (3-oxocyclobutyl) -4-phenoxy-1H-benzo [d] Imidazole-5-yl) pyridine-2 (1H) -one was obtained.
ESI-MS m / z 386 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.81-7.70 (m, 2H), 7.56 (d, J = 8.0Hz, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.25- 7.16 (m, 2H), 7.00-6.90 (m, 1H), 6.78-6.7 (m, 2H), 6.49 (d, J = 9.2Hz, 1H), 3.98-3.84 (m, 1H), 3.63-3.47 ( m, 7H).

Example 96
5- (2- (3-Methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

3- (5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol
3- (5-Bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol (500 mg) in DMF (5 mL) solution in 60% sodium hydride (61.2) under ice-cooling. mg) was added, and the mixture was stirred at 15 ° C. for 30 minutes. Under ice-cooling, 2- (chloromethoxy) ethyltrimethylsilane (232 mg) was added to the reaction mixture, and the mixture was stirred at 15 ° C. for 3 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 3- (5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole. -2-yl) Cyclobutane-1-ol (140 mg) was obtained.
ESI-MS m / z 489 [M + H] ⁺

b. 5-bromo-2- (3-methoxycyclobutyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole
3- (5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol (140 mg) DMF (3 mL) To the solution, 60% sodium hydride (12.6 mg) was added under ice-cooling, and the mixture was stirred at 15 ° C. for 30 minutes. Iodomethane (44.7 mg) was added to the reaction mixture, and the mixture was stirred at 15 ° C. for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 5-bromo-2- (3-methoxycyclobutyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl. ) -1H-Benzo [d] imidazole (150 mg) was obtained.
ESI-MS m / z 503 [M + H] ⁺

c. 5-bromo-2- (3-methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazole
In a solution of 5-bromo-2- (3-methoxycyclobutyl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (150 mg) in methanol (1 mL), 3 mol / L hydrochloric acid (2 mL) was added, and the mixture was stirred at 40 ° C. for 20 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 5-bromo-2- (3-methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazole (81.0 mg). Got
ESI-MS m / z 373 [M + H] ⁺

d. 5- (2- (3-Methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
5-bromo-2- (3-methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazole (81.0 mg), 1-methyl-5- (4,4,5,5-tetramethyl-1,) 3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one (56.1 mg) in a mixed solution of DMF (2 mL) and water (0.4 mL) with sodium carbonate (46.0 mg) and PdCl ₂ (dppf) -A dichloromethane adduct (9.5 mg) was added, and the mixture was heated and stirred at 100 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.225% ammonium formate aqueous solution) and then freeze-dried to 5- (2- (3-methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl). -1-Methylpyridine-2 (1H) -one (15.0 mg) was obtained.
ESI-MS m / z 402 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.8-12.2 (m, 1H), 7.92-7.72 (m, 1H), 7.64-7.33 (m, 2H), 7.29-7.11 (m, 3H) ), 7.00-6.84 (m, 1H), 6.77-6.61 (m, 2H), 6.38-6.24 (m, 1H), 4.26-3.75 (m, 1H), 3.62-3.56 (m, 0.2H), 3.40 ( s, 3H), 3.21-3.05 (m, 3.8H), 2.68-2.56 (m, 2H), 2.36-2.11 (m, 2H).

Example 97
1-Methyl-5-(4-phenoxy-2- (7-oxaspiro [3,5] nonane-2-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

5-bromo-4-phenoxy-2- (7-oxaspiro [3.5] nonane-2-yl) -1H-benzo [d] imidazole
Potassium iodide (431 mg) and 7-oxaspiro [3.5] nonane-2-carbaldehyde (724 mg) were added to a solution of 4-bromo-3-phenoxybenzene-1,2-diamine (400 mg) in DMF (20 mL). The mixture was heated and stirred at 80 ° C. for 15 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-4-phenoxy-2 (7-oxaspiro [3.5] nonane-2-yl) -1H-benzo [d] imidazole (950 mg). ) Was obtained.
ESI-MS m / z 413 [M + H] ⁺

b. 1-Methyl-5-(4-phenoxy-2- (7-oxaspiro [3,5] nonane-2-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H)- on
5-bromo-4-phenoxy-2 (7-oxaspiro [3.5] nonan-2-yl) -1H-benzo [d] imidazole (300 mg), 1-methyl-5- (4,4,5,5-tetra) Methyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (205 mg) in a mixed solution of DMF (5 mL) and water (1 mL) with sodium carbonate (154 mg) and PdCl ₂ (dppf) ) -Dichloromethane adduct (26.6 mg) was added, and the mixture was heated and stirred at 100 ° C. for 15 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.225% ammonium formate aqueous solution) and then freeze-dried to 1-methyl-5- (4-phenoxy-2- (7-oxaspiro [3,5] nonane-2-yl)-. 1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one (128 mg) was obtained.
ESI-MS m / z 442 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.54-12.28 (m, 1H), 7.87-7.75 (m, 1H), 7.62-7.34 (m, 2H), 7.27-7.14 (m, 3H) ), 6.99-6.87 (m, 1H), 6.76-6.64 (m, 2H), 6.31 (dd, J = 9.6, 9.2Hz, 1H), 3.71-3.58 (m, 1H), 3.58-3.49 (m, 2H) ), 3.493.36 (m, 5H), 2.28-2.03 (m, 4H), 1.70-1.45 (m, 4H).

Example 98
5- (2-Cyclohexyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (2-Cyclohexyl-4-phenoxy-1H-benzo [d] imidazol-5-yl)-using cyclohexanecarboxyaldehyde instead of oxetane-3-carbaldehyde in the same manner as in Example 90. 1-Methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 400 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.38-12.29 (m, 1H), 7.86-7.75 (m, 1H), 7.64-7.53 (m, 1H), 7.52-7.35 (m, 1H) ), 7.27-7.14 (m, 3H), 6.97-6.87 (m, 1H), 6.70 (d, J = 8.0Hz, 2H), 6.31 (dd, J = 9.2, 6.0Hz, 1H), 3.41 (s, 3H), 2.86-2.75 (m, 1H), 2.01-1.89 (m, 2H), 1.83-1.71 (m, 2H), 1.71-1.63 (m, 1H), 1.63-1.47 (m, 2H).

Example 99
5- (2- (4,4-difluorocyclohexyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (2- (4,4-Difluorocyclohexyl) -4-phenoxy-1H, using 4,4-difluorocyclohexanecarboxylic acid instead of oxepane-4-carboxylic acid, similar to the method of Example 92. -Benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 436 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.86 (s, 1H), 7.78-7.69 (m, 3H), 7.26 (dd, J = 8.4, 7.2Hz, 2H), 7.02 (t, J) = 7.2Hz, 1H), 6.81 (d, J = 8.4Hz, 2H), 6.50 (d, J = 9.6Hz, 1H), 3.55 (s, 3H), 3.42-3.36 (m, 1H), 2.32-2.27 (m, 4H), 2.14-1.97 (m, 4H).

Example 100
5- (2-Cycloheptyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

Similar to the method of Example 91, using cycloheptane carboxylic acid chloride instead of tetrahydrofuran-3-carbonyl chloride, 5- (2-cycloheptane-4-phenoxy-1H-benzo [d] imidazole-5- Ill) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 414 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.78 (d, J = 2.3Hz, 1H), 7.72-7.64 (m, 2H), 7.60 (d, J = 8.6Hz, 1H), 7.24- 7.18 (m, 2H), 7.00-6.94 (m, 1H), 6.76 (d, J = 8.0Hz, 2H), 6.45 (d, J = 9.2Hz, 1H), 3.49 (s, 3H), 3.34-3.28 (m, 1H), 2.18-2.10 (m, 2H), 1.951.84 (m, 4H), 1.79-1.57 (m, 6H).

Example 101
1-Methyl-5- (4-Phenyl-2-phenyl-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

1-Methyl-5- (4-phenoxy-2-phenyl-1H-benzo [d], using benzaldehyde instead of 7-oxaspiro [3.5] nonane-2-carbaldehyde, in the same manner as in Example 97. ] Imidazole-5-yl) Pyridine-2 (1H) -one was obtained.
ESI-MS m / z 394 [M + H] ⁺

¹ H NMR (DMSO-d _6,500MHz ) δ (ppm): 8.27-8.16 (m, 2H), 7.91 (d, J = 2.8Hz, 1H), 7.70 (d, J = 8.8Hz, 1H), 7.64 (d, J = 2.0Hz, 2H), 7.61 (d, J = 4.8Hz, 2H), 7.52 (d, J = 8.4Hz, 1H), 7.23 (dd, J = 8.0, 7.6Hz, 2H), 6.96 (t, J = 7.6Hz, 1H), 6.79 (d, J = 8.0Hz, 2H), 6.34 (d, J = 9.6Hz, 1H), 3.41 (s, 3H).

Example 102
1-Methyl-5-(4-phenoxy-2-((tetrahydro-2H-pyran-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

1-Methyl-5- (4-phenoxy-2) using 2- (tetrahydro-2H-pyran-4-yl) acetylchloride instead of tetrahydrofuran-3-carbonylchloride in the same manner as in Example 91. -((Tetrahydro-2H-pyran-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 416 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.72 (d, J = 1.7Hz, 1H), 7.68 (d, J = 9.2Hz, 1H), 7.47 (d, J = 8.0Hz, 1H) , 7.26 (d, J = 8.0Hz, 1H), 7.15 (dd, J = 8.6, 7.5Hz, 2H), 6.89 (t, J = 7.5Hz, 1H), 6.68 (d, J = 8.6Hz, 2H) , 6.44 (d, J = 9.2Hz, 1H), 3.89-3.83 (m, 2H), 3.49 (s, 3H), 3.39-3.31 (m, 2H), 2.76 (d, J = 7.4Hz, 2H), 2.20-1.95 (m, 1H), 1.53 (d, J = 12.0Hz, 2H), 1.38-1.23 (m, 2H).

Example 103
1-Methyl-5-(2- (morpholinomethyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

1-Methyl-5- (2- (morpholinomethyl) -4-phenoxy-1H-benzo [ d] Imidazole-5-yl) Pyridine-2 (1H) -on was obtained.
ESI-MS m / z 417 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.82-7.66 (m, 2H), 7.54 (s, 1H), 7.33 (d, J = 8.0Hz, 1H), 7.21-7.14 (m, 2H) ), 6.95-6.89 (m, 1H), 6.72 (d, J = 8.0Hz, 2H), 6.48 (d, J = 9.2Hz, 1H), 3.76 (s, 2H), 3.73-3.67 (m, 4H) , 3.53 (s, 3H), 2.54-2.49 (m, 4H).

Example 104
1-Methyl-5-(4-Phenyltetrahydro-2H-Pyran-4-yl) -1H-Benzodiazepine [d] Imidazole-5-yl) Pyridine-2 (1H) -On

1-Methyl-5- (4-phenoxy-2) using 4,4-phenyltetrahydro-2H-pyran-4-carboxylic acid instead of oxepane-4-carboxylic acid in the same manner as in Example 92. -(4-Phenyltetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -one was obtained.
ESI-MS m / z 478 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.76-7.67 (m, 2H), 7.66-7.36 (m, 1H), 7.35-7.24 (m, 5H), 7.23-7.07 (m, 3H) , 6.96-6.83 (m, 1H), 6.73 (d, J = 7.6Hz, 1H), 6.63 (d, J = 8.0Hz, 1H), 6.52-6.38 (m, 1H), 3.97-3.79 (m, 2H) ), 3.67-3.53 (m, 2H), 3.51 (s, 3H), 2.85-2.66 (m, 2H), 2.35-2.18 (m, 2H).

Example 105
5- (2- (4-ethoxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

In the same manner as in Example 92, 4-ethoxytetrahydro-2H-pyran-4-carboxylic acid was used instead of oxepane-4-carboxylic acid to use 5- (2- (4-ethoxytetrahydro-2H-pyran). -4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridin-2 (1H) -one was obtained.
ESI-MS m / z 446 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.85-7.75 (m, 2H), 7.70-7.50 (brs, 1H), 7.35 (d, J = 8.0Hz, 1H), 7.19 (dd, J) = 8.0, 7.6Hz, 2H), 6.93 (t, J = 7.6Hz, 1H), 6.73 (d, J = 8.0Hz, 2H), 6.50 (d, J = 8.8Hz, 1H), 3.95-3.83 (m) , 2H), 3.82-3.68 (m, 2H), 3.54 (s, 3H), 3.29-3.10 (m, 2H), 2.39-2.20 (m, 2H), 2.20-2.08 (m, 2H), 1.22-1.05 (m, 3H).

Example 106
5- (2- (4-Hydroxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

4- (5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) tetrahydro-2H-pyran-4-ol
5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole (1.30 g) in 2-MeTHF (17 mL) solution at -70 ° C, 2 mol / L LDA (THF / Heptane / Ethylbenzene solution, 2.32 mL) was added, and the mixture was stirred at −70 ° C. for 30 minutes. A solution of tetrahydro-4H-pyran-4-one (466 mg) in 2-MeTHF (4 mL) was added to the reaction mixture at -70 ° C, and the mixture was stirred at -70 ° C for 1 hour. Methanol was added to the reaction mixture at −70 ° C., the temperature was raised to room temperature, an aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 4- (5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole. -2-yl) Tetrahydro-2H-pyran-4-ol (1.16 g) was obtained.
ESI-MS m / z 519 [M + H] ⁺

b. 5- (2- (4-Hydroxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridine-2 (1H) -on
4- (5-bromo-4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazol-2-yl) tetrahydro-2H-pyran-4-ol (1.3 g) , 1-Methyl-5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (765 mg) DMF (15 mL) and water (15 mL) Sodium carbonate (398 mg) and PdCl ₂ (dppf) / dichloromethane adduct (92 mg) were added to a mixed solution of 1.5 mL), and the mixture was heated and stirred at 100 ° C. for 20 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5- (2- (4-hydroxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1-((2- (trimethylsilyl)). ) Ethoxy) Methyl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (1.3 g) was obtained.
ESI-MS m / z 548 [M + H] ⁺

c. 5- (2- (4-Hydroxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
5- (2- (4-Hydroxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole-5-yl) To a solution of -1-methylpyridine-2 (1H) -one (300 mg) in methanol (6 mL) was added 36% hydrochloric acid (1.20 mL), and the mixture was stirred at room temperature for 48 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture until the pH reached 6, and the mixture was concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 5- (2- (4-hydroxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1H-benzo. [d] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one (134 mg) was obtained.
ESI-MS m / z 418 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.70-12.35 (brs, 1H), 7.89-7.75 (m, 1H), 7.65-7.35 (m, 2H), 7.30-7.14 (m, 3H) ), 6.92 (t, J = 7.2Hz, 1H), 6.71 (d, J = 8.0Hz, 2H), 6.31 (d, J = 9.2Hz, 1H), 5.77-5.51 (brs, 1H), 3.80-3.56 (m, 4H), 3.40 (s, 3H), 2.25-1.97 (m, 2H), 1.87-1.63 (m, 2H).

Example 107
5- (2- (4-Fluorotetrahydro-2H-pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (2- (4-Fluorotetrahydro-2H-pyran-4-yl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridine-2 (1H) -on
5- (2- (4-Hydroxytetrahydro-2H-pyran-4-yl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole-5-yl) DAST (354 mg) was added to a solution of -1-methylpyridine-2 (1H) -one (400 mg) in dichloromethane (20 mL) under ice-cooling, and the mixture was stirred at room temperature for 48 hours. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) and 5- (2- (4-fluorotetrahydro-2H-pyran-4-yl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy). ) Methyl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (380 mg) was obtained.
ESI-MS m / z 550 [M + H] ⁺

b. 5- (2- (4-Fluorotetrahydro-2H-pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
5- (2- (4-Fluorotetrahydro-2H-pyran-4-yl) -4-phenoxy-1-((2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] imidazole-5-yl) To a solution of -1-methylpyridine-2 (1H) -one (330 mg) in methanol (5.4 mL) was added 36% hydrochloric acid (1.07 mL), and the mixture was stirred at room temperature for 15 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture until the pH reached 6, and the mixture was concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.225% ammonium formate aqueous solution) and then freeze-dried to 5- (2- (4-fluorotetrahydro-2H-pyran-4-yl) -4-phenoxy-1H-benzo [ d] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one (135 mg) was obtained.
ESI-MS m / z 420 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 13.17-12.88 (brs, 1H), 7.89-7.79 (m, 1H), 7.69-7.43 (m, 2H), 7.36-7.28 (m, 1H) ), 7.20 (dd, J = 7.6, 7.2Hz, 2H), 6.93 (t, J = 7.6Hz, 1H), 6.77-6.64 (m, 2H), 6.38-6.24 (m, 1H), 3.83-3.65 ( m, 4H), 3.44-3.37 (m, 3H), 2.43-2.00 (m, 4H).

Example 108
1-Methyl-5-(2- (2-Methylpyridine-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

In the same manner as in Example 97, 1-methyl-5- (2- (2- (2- (2- (2-)], using 2-methylpyridine-4-carbaldehyde instead of 7-oxaspiro [3.5] nonane-2-carbaldehyde. Methylpyridine-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one was obtained.
ESI-MS m / z 409 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.57 (d, J = 5.2Hz, 1H), 8.00 (s, 1H), 7.91 (d, J = 4.8Hz, 1H), 7.82 (d, J = 2.4Hz, 1H), 7.78 (dd, J = 9.2, 2.4Hz, 1H), 7.64-7.73 (m, 1H), 7.45 (d, J = 8.8Hz, 1H), 7.24-7.20 (m, 2H) ), 6.95 (t, J = 7.2Hz, 1H), 6.78 (d, J = 7.6Hz, 2H), 6.51 (d, J = 9.6Hz, 1H), 3.56 (s, 3H), 2.64 (s, 3H) )

Example 109
1-Methyl-5-(2- (1-Methylpiperidin-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

1-Methyl-5- (2- (1-methylpiperidin-4-yl)-is using 1-methylpiperidine-4-carboxylic acid instead of oxepane-4-carboxylic acid in the same manner as in Example 92. ) -4-Phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one was obtained.
ESI-MS m / z 415 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 8.46 (s, 1H), 7.74 (d, J = 2.8Hz, 1H), 7.70 (dd, J = 8.8, 2.4Hz, 1H), 7.52 ( d, J = 8.4Hz, 1H), 7.31 (d, J = 8.4Hz, 1H), 7.24-7.11 (m, 2H), 6.91 (t, J = 7.2Hz, 1H), 6.70 (d, J = 8.0) Hz, 2H), 6.45 (d, J = 9.2Hz, 1H), 3.56-3.45 (m, 5H), 3.25-3.14 (m, 1H), 3.10-2.98 (m, 2H), 2.81 (s, 3H) , 2.39-2.10 (m, 4H).

Example 110
5,5'-(4-Phenoxy-1H-benzo [d] imidazole-2,5-diyl) bis (1-methylpyridine-2 (1H) -on)

5,5'-(4-phenoxy) using 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid instead of oxepan-4-carboxylic acid in the same manner as in Example 92. -1H-benzo [d] imidazole-2,5-diyl) bis (1-methylpyridine-2 (1H) -one) was obtained.
ESI-MS m / z 425 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.61 (brs, 1H), 8.69-8.32 (m, 1H), 8.28-7.98 (m, 1H), 7.84 (s, 1H), 7.69- 7.42 (m, 2H), 7.28 (d, J = 8.0Hz, 1H), 7.26-7.17 (m, 2H), 6.94 (t, J = 7.2Hz, 1H), 6.78-6.69 (m, 2H), 6.53 (d, J = 9.6Hz, 1H), 6.32 (d, J = 9.2Hz, 1H), 3.52 (s, 3H), 3.41 (s, 3H).

Example 111
1,3-dimethyl-5-(2- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H)-On

Oxepan-4-carboxylic acid and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 in the same manner as in Example 92. 1-Methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid instead of (1H) -one and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3) , 2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one with 1,3-dimethyl-5-(2- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) ) -4-Phenoxy-1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one was obtained.
ESI-MS m / z 439 [M + H] ⁺

¹ H NMR (CD ₃ CN, 400MHz) δ (ppm): 10.93 (brs, 1H), 8.38-8.17 (m, 1H), 8.13-7.83 (m, 1H), 7.62-7.43 (m, 3H), 7.29 (d, J = 8.4Hz, 1H), 7.26-7.18 (m, 2H), 6.97 (t, J = 7.2Hz, 1H), 6.82-6.69 (m, 2H), 6.52 (d, J = 9.2Hz, 1H), 3.55 (s, 3H), 3.44 (s, 3H), 2.02 (s, 3H).

Example 112
1,3-dimethyl-5-(5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-2-yl) pyridin-2 (1H)-On

Similar to the method of Example 92, 1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid was used instead of oxepan-4-carboxylic acid to use 1,3-dimethyl-5. -(5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-2-yl) pyridine-2 (1H) -on rice field.
ESI-MS m / z 439 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 13.29-12.40 (brs, 1H), 8.63-7.76 (m, 3H), 7.66-7.41 (m, 2H), 7.32-7.14 (m, 3H) ), 6.93 (t, J = 7.2Hz, 1H), 6.72 (d, J = 8.0Hz, 2H), 6.31 (d, J = 9.2Hz, 1H), 3.53 (s, 3H), 3.41 (s, 3H) ), 2.08 (s, 3H).

Example 113
5,5'-(4-Phenoxy-1H-benzo [d] imidazole-2,5-diyl) bis (1,3-dimethylpyridin-2 (1H) -on)

Oxepan-4-carboxylic acid and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 in the same manner as in Example 92. Instead of (1H) -one, 1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1) , 3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one with 5,5'-(4-phenoxy-1H-benzo [d] imidazole-2,5-diyl) bis (1) , 3-Dimethylpyridin-2 (1H) -on) was obtained.
ESI-MS m / z 453 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.05-10.45 (brs, 1H), 8.44 (s, 1H), 8.02 (s, 1H), 7.74-7.65 (m, 1H), 7.55- 7.44 (m, 2H), 7.30-7.15 (m, 3H), 6.93 (t, J = 7.2Hz, 1H), 6.72 (d, J = 8.0Hz, 2H), 3.53 (s, 3H), 3.41 (s) , 3H), 2.08 (s, 3H), 1.95 (s, 3H).

Example 114
5- (2- (1,1-Dioxide tetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H)- on

Similar to the method of Example 91, tetrahydro-2H-thiopyran-4-carbonyl chloride 1,1-dioxide was used in place of tetrahydrofuran-3-carbonyl chloride, and 5- (2- (1,1-dioxide) was used. Tetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 450 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.75 (s, 1H), 7.71 (dd, J = 9.2,2.3Hz, 1H), 7.65-7.40 (m, 1H), 7.31 (d, J) = 8.0Hz, 1H), 7.23-7.13 (m, 2H), 6.96-6.87 (m, 1H), 6.70 (d, J = 8.0Hz, 2H), 6.54-6.40 (m, 1H), 3.51 (d, J = 4.6Hz, 3H), 3.29-3.13 (m, 5H), 2.57-2.33 (m, 4H).

Example 115
5- (2- (1,1-Dioxide tetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) )-on

Tetrahydrofuran-3-carbonylchloride and 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 in the same manner as in Example 91. (1H)-Tetrahydrothiophene 1,1-dioxide and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin instead of on- 2- (1H) -on, 5- (2- (1,1-dioxide tetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl)- 1,3-Dimethylpyridin-2 (1H) -one was obtained.
ESI-MS m / z 464 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.58 (s, 1H), 7.55 (s, 1H), 7.48-7.36 (m, 1H), 7.29 (d, J = 8.6Hz, 1H), 7.15 (brs, 2H), 6.89 (brs, 1H), 6.68 (d, J = 8.0Hz, 2H), 3.49 (s, 3H), 3.26-3.21 (m, 2H), 3.21-3.10 (m, 2H) , 2.97-2.57 (m, 1H), 2.56-2.32 (m, 4H), 2.03 (s, 3H).

Example 116
5- (1,2-dimethyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

3-Fluoro-N-Methyl-2-nitroaniline
To a solution of 1,3-difluoro-2-nitrobenzene (3.0 g) in THF (50 mL) was added 2.0 mol / L methylamine (THF solution, 9.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. Methanol (30 mL) and 2.0 mol / L methylamine (THF solution, 4.0 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-fluoro-N-methyl-2-nitroaniline (3.06 g).
ESI-MS m / z 171 [M + H] ⁺

b. 4-Bromo-3-fluoro-N-methyl-2-nitroaniline
To a solution of 3-fluoro-N-methyl-2-nitroaniline (3.06 g) in DMF (50 mL) is added a solution of N-bromosuccinimide (2.56 g) in DMF (30 mL) at 20 ° C for 2 hours. Stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-bromo-3-fluoro-N-methyl-2-nitroaniline (3.30 g).
ESI-MS m / z 249 [M + H] ⁺

c. 4-bromo-N-methyl-2-nitro-3-phenoxyaniline
Cesium carbonate (5.18 g) and phenol (1.50 g) were added to a DMSO (30 mL) solution of 4-bromo-3-fluoro-N-methyl-2-nitroaniline (3.30 g), and the mixture was stirred at 20 ° C. for 2 hours. .. The reaction mixture was poured into ice water, and the precipitated solid was collected by filtration to obtain 4-bromo-N-methyl-2-nitro-3-phenoxyaniline (4.20 g).
ESI-MS m / z 323 [M + H] ⁺

d. 1-Methyl-5-(4- (Methylamino) -3-nitro-2-phenoxyphenyl) Pyridine-2 (1H) -on
4-bromo-N-methyl-2-nitro-3-phenoxyaniline (1.10 g), 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ) Pyridine-2 (1H) -one (800 mg) in a mixed solution of 1,4-dioxane (10 mL) and water (3 mL) with sodium carbonate (1.80 g) and PdCl ₂ (dppf) / dichloromethane adduct (125 mg) Was added, and the mixture was heated and stirred at 100 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 1-methyl-5- (4- (methylamino) -3-nitro-2-phenoxyphenyl) pyridin-2 (1H) -one ( 900 mg) was obtained.
ESI-MS m / z 352 [M + H] ⁺

e. 5- (3-Amino-4- (methylamino) -2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one
1-Methyl-5-(4- (Methylamino) -3-nitro-2-phenoxyphenyl) Pyridine-2 (1H) -one (900 mg) in a mixed solution of isopropanol (12 mL) and water (3 mL) with iron Powder (715 mg) and ammonium chloride (1.37 g) were added, and the mixture was heated and stirred at 55 ° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. The filtrate is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 5- (3-amino-4- (methylamino) -2-phenoxyphenyl) -1-methylpyridine-2 (1H)-. On (700 mg) was obtained.
ESI-MS m / z 322 [M + H] ⁺

f. 5- (1,2-Dimethyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
In a solution of 5- (3-amino-4- (methylamino) -2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (200 mg) in THF (5 mL) with trimethyl orthoacetate (90 mg) and p. -Toluenesulfonic acid monohydrate (24 mg) was added, and the mixture was heated and stirred at 70 ° C. for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), 1 mol / L hydrochloric acid (3 mL) was added, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% hydrochloric acid) and then freeze-dried to perform 5- (1,2-dimethyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine. -2 (1H) -one hydrochloride (125.6 mg) was obtained.
ESI-MS m / z 346 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.99 (d, J = 2.4Hz, 1H), 7.91-7.81 (m, 2H), 7.77-7.71 (m, 1H), 7.28-7.21 (m) , 2H), 7.05-6.98 (m, 1H), 6.80 (d, J = 8.4Hz, 2H), 6.62 (d, J = 9.2Hz, 1H), 4.06 (s, 3H), 3.69-3.56 (m, 3H), 2.85 (s, 3H).

Example 117
5- (1-Cyclopropyl-2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (1-Cyclopropyl-2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl)-using cyclopropaneamine instead of methylamine in the same manner as in Example 116. 1-Methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 372 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.71-7.60 (m, 2H), 7.59-7.46 (m, 2H), 7.20-7.13 (m, 2H), 6.98-6.92 (m, 1H), 6.98-6.93 (m, 2H), 6.65 (d, J = 9.7Hz, 1H), 3.53-3.45 (m, 4H), 2.99 (s, 3H), 1.48-1.41 (m, 2H), 1.31-1.25 ( m, 2H).

Example 118
t-Butyl-3- (5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl ) Azetidine-1-carboxylate

t-butyl-3- (5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl) azetidine-1-carboxylate (200 mg), 1,3-dimethyl-5- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (141 mg) 1,4-dioxane (3.5 mL) and water (0.7 mL) Sodium carbonate (115 mg) and PdCl ₂ (dppf) / dichloromethane adduct (36 mg) were added to the mixed solution of the above, and the mixture was heated and stirred at 160 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to t-butyl-3- (5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine). -3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-1-yl) azetidine-1-carboxylate (120 mg) was obtained.
ESI-MS m / z 501 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.58 (d, J = 8.6Hz, 1H), 7.42-7.38 (m, 1H), 7.33-7.30 (m, 1H), 7.24 (d, J = 8.6Hz, 1H), 7.19-7.13 (m, 2H), 6.91 (t, J = 7.4Hz, 1H), 6.82-6.69 (m, 2H), 5.27-5.13 (m, 1H), 4.66-4.47 (m) , 4H), 3.48 (s, 3H), 2.56 (s, 3H), 2.11 (s, 3H), 1.53 (s, 9H).

Example 119
5- (1- (azetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one

1- (azetidine-3-yl) -5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole
In a solution of t-butyl-3- (5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl) azetidine-1-carboxylate (0.87 g) in chloroform (9.5 mL), TFA (2.2 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, 1 mol / L sodium hydroxide was added to neutralize the mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to concentrate 1- (azetidine-3-yl) -5-bromo-2-methyl-4-phenoxy-1H-benzo [d]. Imidazole (564 mg) was obtained.
ESI-MS m / z 358 [M + H] ⁺

b. 5- (1- (Azetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one
1- (Azetidine-3-yl) -5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole (214 mg), 1,3-dimethyl-5- (4,4,5,5-) Sodium carbonate (158 mg) in a mixed solution of 1,4-dioxane (5 mL) and water (1 mL) of tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one (193 mg). And PdCl ₂ (dppf) -dichloromethane adduct (49 mg) were added, and the mixture was heated and stirred at 160 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 5- (1- (azetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [ d] Imidazole-5-yl) -1,3-dimethylpyridine-2 (1H) -one (8.5 mg) was obtained.
ESI-MS m / z 401 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.25-8.12 (m, 1H), 7.83-7.69 (m, 1H), 7.53-7.45 (m, 2H), 7.26-7.19 (m, 2H) ), 6.95 (t, J = 7.4Hz, 1H), 6.73-6.69 (m, 2H), 5.71-5.60 (m, 1H), 4.77-4.66 (m, 2H), 4.47-4.37 (m, 2H), 3.43 (s, 3H), 2.60 (s, 3H), 1.96 (s, 3H).

Example 120
5- (1- (1-Acetyl azetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H)- on

1-(3- (5-Bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl) azetidine-1-yl) ethane-1-one
1- (Azetidine-3-yl) -5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole (315 mg) in chloroform (10 mL) solution with DIPEA (0.34 mL) and acetyl chloride (0.10) mL) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to 1-(3- (5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl) azetidine. -1-yl) ethane-1-one (159 mg) was obtained.
ESI-MS m / z 400 [M + H] ⁺

b. 5- (1- (1-Acetyl azetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridine-2 (1H) )-on
1-(3- (5-Bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl) azetidine-1-yl) ethane-1-one (159 mg), 1,3-dimethyl -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one (129 mg) 1,4-dioxane (3.3 mL) and water Sodium carbonate (105 mg) and PdCl ₂ (dppf) -dichloromethane adduct (32 mg) were added to the mixed solution of (0.66 mL), and the mixture was heated and stirred at 160 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 5- (1- (1-acetylazetidine-3-yl) -2-methyl-4-phenoxy-. 1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one (85.8 mg) was obtained.
ESI-MS m / z 443 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.47 (d, J = 8.2Hz, 1H), 7.41-7.37 (m, 1H), 7.31 (d, J = 2.3Hz, 1H), 7.25 (d) , J = 8.7Hz, 1H), 7.16 (dd, J = 7.8, 7.3Hz, 2H), 6.91 (t, J = 7.3Hz, 1H), 6.75 (d, J = 7.8Hz, 2H), 5.34-5.18 (m, 1H), 4.85-4.54 (m, 4H), 3.48 (s, 3H), 2.58 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H).

Example 121
5- (1-Isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

3-Fluoro-N-isopropyl-2-nitroaniline
Isopropylamine (2.5 mL) was added to a solution of 1,3-difluoro-2-nitrobenzene (2.0 g) in DMF (25 mL), and the mixture was stirred at room temperature for 22 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-fluoro-N-isopropyl-2-nitroaniline (2.49 g).
ESI-MS m / z 199 [M + H] ⁺

b. 4-Bromo-3-fluoro-N-isopropyl-2-nitroaniline
To a solution of 3-fluoro-N-isopropyl-2-nitroaniline (2.49 g) in DMF (25 mL) is added a solution of N-bromosuccinimide (2.4 g) in DMF (25 mL) under ice-cooling, and the mixture is stirred at room temperature for 18 hours. bottom. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of 4-bromo-3-fluoro-N-isopropyl-2-nitroaniline (5.51 g).
ESI-MS m / z 277 [M + H] ⁺

c. 4-bromo-N-isopropyl-2-nitro-3-phenoxyaniline
Cesium carbonate (4.9 g) and phenol (1.3 mL) were added to a DMF (25 mL) solution of 4-bromo-3-fluoro-N-isopropyl-2-nitroaniline (3.48 g) at room temperature for 8 hours at 80 ° C. It was heated and stirred. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.5 mol / L aqueous sodium hydroxide solution and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 4-bromo-N-isopropyl-2-nitro-3-phenoxyaniline (5.09 g). ) Was obtained.
ESI-MS m / z 351 [M + H] ⁺

d. 4-bromo-N ¹ -isopropyl-3-phenoxybenzene-1,2-diamine
Add iron powder (3.5 g) and ammonium chloride (6.7 g) to a mixed solution of 4-bromo-N-isopropyl-2-nitro-3-phenoxyaniline (4.41 g) in ethanol (33 mL) and water (17 mL). , Heated and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain 4-bromo-N ¹ -isopropyl-3-phenoxybenzene-1,2-diamine (3.52 g). rice field.
ESI-MS m / z 321 [M + H] ⁺

e. 5-bromo-1-isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
To a solution of 4-bromo-N ¹ -isopropyl-3-phenoxybenzene-1,2-diamine (0.50 g) in chloroform (10 mL), add a solution of tetrahydropyran-4-carboxylic acid chloride (556 mg) in THF (1 mL). , Heated and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to 5-bromo-1-isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d. ] Imidazole (424 mg) was obtained.
ESI-MS m / z 415 [M + H] ⁺

f. 5- (1-Isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H)- on
5-bromo-1-isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (150 mg), 1-methyl-5- (4,4,5,, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (93 mg) in a mixed solution of 1,4-dioxane (3.0 mL) and water (0.6 mL) with carbonate Sodium (95 mg) and PdCl ₂ (dppf) / dichloromethane adduct (29 mg) were added, and the mixture was heated and stirred at 160 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (methanol / helyoform) to 5- (1-isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-. Benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (81.9 mg) was obtained.
ESI-MS m / z 444 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.53 (dd, J = 9.2,2.3Hz, 1H), 7.47-7.35 (m, 2H), 7.20-7.08 (m, 3H), 6.94-6.89 ( m, 1H), 6.85-6.72 (m, 2H), 6.52 (d, J = 9.7Hz, 1H), 4.81-4.65 (m, 1H), 4.12-3.97 (m, 2H), 3.53 (dd, J = 11.5,9.7Hz, 2H), 3.48 (s, 3H), 3.15-3.00 (m, 1H), 2.21-2.03 (m, 2H), 1.80 (d, J = 13.2Hz, 2H), 1.70 (d, J) = 7.4Hz, 6H).

Example 122
5- (1-Ethyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5- (1-Ethyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] using ethylamine instead of isopropylamine in the same manner as in Example 121. ] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 430 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.53 (dd, J = 9.5,2.6Hz, 1H), 7.41 (d, J = 2.6Hz, 1H), 7.32-7.09 (m, 4H), 6.92 (dd, J = 7.5,6.9Hz, 1H), 6.85-6.72 (m, 2H), 6.52 (d, J = 9.7Hz, 1H), 4.23 (q, J = 7.3Hz, 2H), 4.13-3.99 ( m, 2H), 3.67-3.43 (m, 5H), 3.14-2.99 (m, 1H), 2.24-2.06 (m, 2H), 1.80 (d, J = 13.2Hz, 2H), 1.49 (t, J = 6.9Hz, 3H).

Example 123
5- (1-Cyclopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

Similar to the method of Example 121, using cyclopropylamine instead of isopropylamine, 5- (1-cyclopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 442 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.52 (dd, J = 9.2,2.9Hz, 1H), 7.43-7.39 (m, 2H), 7.20-7.12 (m, 3H), 6.94-6.89 ( m, 1H), 6.77 (d, J = 7.4Hz, 2H), 6.52 (d, J = 9.2Hz, 1H), 4.09-4.03 (m, 2H), 3.58-3.50 (m, 2H), 3.49 (s) , 3H), 3.39-3.31 (m, 1H), 3.28-3.20 (m, 1H), 2.19-2.01 (m, 2H), 1.85 (d, J = 13.2Hz, 2H), 1.38-1.24 (2H), 1.20-1.06 (m, 2H).

Example 124
5- (1-Cyclobutyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

Similar to the method of Example 121, using cyclobutylamine instead of isopropylamine, 5- (1-cyclobutyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [ d] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 456 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.58 (d, J = 8.6Hz, 1H), 7.54 (dd, J = 9.5,2.6Hz, 1H), 7.43 (d, J = 2.3Hz, 1H) ), 7.22-7.08 (m, 3H), 6.98-6.85 (m, 1H), 6.84-6.71 (m, 2H), 6.53 (d, J = 9.7Hz, 1H), 5.02-4.91 (m, 1H), 4.06-4.01 (m, 2H), 3.61-3.43 (m, 5H), 3.17-2.94 (m, 3H), 2.64-2.47 (m, 2H), 2.19-1.93 (m, 4H), 1.86-1.71 (m) , 2H)

Example 125
5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-1- Carbonitrile

1-Methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (100 mg) DMF To the (0.5 mL) solution was added 60% sodium hydride (14.9 mg) and stirred for 30 minutes. Cyanogen bromide (31.7 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 21 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and 5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H). -Pyran-4-yl) -1H-benzo [d] imidazole-1-carbonitrile (7 mg) was obtained.
ESI-MS m / z 427 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.59-7.39 (m, 4H), 7.27-7.16 (m, 2H), 7.06-6.98 (m, 1H), 6.84-6.75 (m, 2H), 6.58 (d, J = 8.0Hz, 1H), 4.10-3.98 (m, 2H), 3.62-3.46 (m, 5H), 3.35-3.24 (m, 1H), 2.14-1.95 (m, 4H).

Example 126
1-Methyl-5-(2-Methyl-1- (1-Methyl-1H-Pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H)- on

1-Methyl-5-(4-((1-Methyl-1H-pyrazole-4-yl) amino) -3-nitro-2-phenoxyphenyl) Pyridine-2 (1H) -one
4-Iodo-1-methylpyrazole (4-iodo-1-methylpyrazole) in a DMF (12.5 mL) solution of 5- (4-amino-3-nitro-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (1.41 g). 895.5 mg), copper powder (255 mg) and potassium carbonate (1.13 g) were added, and the mixture was heated and stirred at 144 ° C. for 9 hours. The reaction mixture was cooled to room temperature and then filtered. The insoluble material was washed with water and ethyl acetate, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 1-methyl-5-(4-((1-methyl-1H-pyrazole-4-yl) amino) -3-nitro-2-. Phenoxyphenyl) pyridine-2 (1H) -one (354 mg) was obtained.
ESI-MSm / z 418 [M + H] ⁺

b. 5- (3-Amino-4-((1-Methyl-1H-pyrazole-4-yl) amino) -2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one
1-Methyl-5-(4-((1-Methyl-1H-pyrazole-4-yl) amino) -3-nitro-2-phenoxyphenyl) Pyridine-2 (1H) -one (465 mg) isopropanol (10 mL) ) And water (5 mL), iron powder (455 mg) and ammonium chloride (820 mg) were added, and the mixture was heated and stirred at 60 ° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered, and then washed with ethyl acetate and water. The filtrate is extracted with ethyl acetate, the organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to 5- (3-amino-4-((1-methyl-1H-pyrazole-4-). Il) amino) -2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (370 mg) was obtained.
ESI-MS m / z 388 [M + H] ⁺

c. 1-Methyl-5-(2-Methyl-1- (1-Methyl-1H-Pyrazole-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) )-on
5- (3-Amino-4-((1-Methyl-1H-pyrazole-4-yl) amino) -2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (169 mg) THF (5 mL) ) To the solution, trimethyl orthoacetate (60.5 mg) and p-toluenesulfonic acid monohydrate (5.4 mg) were added, and the mixture was heated and stirred at 70 ° C. for 4.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL), 0.2 mol / L hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture until the pH reached 8, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% hydrochloric acid) and then freeze-dried to 1-methyl-5- (2-methyl-1- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy). -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one hydrochloride (72.2 mg) was obtained.
ESI-MS m / z 412 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.36 (s, 1H), 7.95-7.90 (m, 2H), 7.60 (dd, J = 9.2, 2.4Hz, 1H), 7.56 (d, J = 8.4Hz, 1H), 7.43 (d, J = 8.4Hz, 1H), 7.30-7.23 (m, 2H), 7.00 (t, J = 7.6Hz, 1H), 6.80 (dd, J = 8.8,0.8) Hz, 2H), 6.35 (d, J = 9.2Hz, 1H), 4.00 (s, 3H), 3.41 (s, 3H), 2.60 (s, 3H).

Example 127
1-Methyl-5-(1- (1-Methyl-1H-pyrazole-4-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5 -Il) Pyridine-2 (1H) -On

5- (3-Amino-4-((1-Methyl-1H-pyrazole-4-yl) amino) -2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (60 mg) at 140 ° C. It was dissolved in tetrahydropyran-4-carboxylic acid (3.00 g) and heated and stirred at 140 ° C. for 12 hours. The reaction mixture was cooled to room temperature, water was added, potassium carbonate was added until the pH reached 8, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1-methyl-5- (1- (1-methyl-1H-pyrazole-4-yl) -4-phenoxy-. 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (9.8 mg) was obtained.
ESI-MS m / z 482 [M + H] ⁺

¹ H NMR (CD ₃ CN, 400MHz) δ (ppm): 7.85 (s, 1H), 7.65 (s, 1H), 7.63-7.55 (m, 2H), 7.27 (d, J = 8.4Hz, 1H), 7.25-7.19 (m, 2H), 7.14 (d, J = 8.4Hz, 1H), 7.01-6.93 (m, 1H), 6.79 (dd, J = 8.8, 1.2Hz, 2H), 6.32 (d, J = 8.8Hz, 1H), 4.19-4.04 (m, 2H), 3.96 (s, 3H), 3.42 (s, 3H), 3.14 (dd, J = 16.0, 4.8Hz, 1H), 3.10-3.00 (m, 1H) ), 2.87 (dd, J = 16.0, 8.4Hz, 1H), 2.36-2.26 (m, 1H), 2.14-2.08 (m, 1H), 2.06-1.96 (m, 1H), 1.91-1.74 (m, 1H) ).

Example 128
1-Methyl-5-(2-Methyl-1- (1-Methyl-1H-imidazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H)- on

1-Methyl-5- (2-methyl-1- (1-methyl), using 4-iodo-1-methylimidazole instead of 4-iodo-1-methylpyrazole in the same manner as in Example 126. -1H-imidazole-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 412 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.84 (d, J = 2.4Hz, 1H), 7.80 (s, 1H), 7.60 (d, J = 1.6Hz, 1H), 7.57 (d) , J = 9.2Hz, 1H), 7.31 (d, J = 1.2Hz, 2H), 7.23 (dd, J = 8.0, 7.6Hz, 2H), 6.94 (t, J = 7.6Hz, 1H), 6.75 (d , J = 8.0Hz, 2H), 6.33 (d, J = 9.6Hz, 1H), 3.79 (s, 3H), 3.42 (s, 3H), 2.43 (s, 3H).

Example 129
5- (1- (2,4-Dimethyloxazol-5-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

5-(1- (2,4-Dimethyloxazole-5-) using 5-iodo-2,4-dimethyloxazole instead of 4-iodo-1-methylpyrazole in the same manner as in Example 126. Il) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 427 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.78 (d, J = 2.4Hz, 1H), 7.72 (dd, J = 9.2, 2.4Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.24-7.22 (m, 1H), 7.22-7.18 (m, 2H), 6.94 (t, J = 7.2Hz, 1H), 6.76 (d, J = 7.6Hz, 2H), 6.49 (d, J) = 9.2Hz, 1H), 3.53 (s, 3H), 2.53 (s, 3H), 2.45 (s, 3H), 2.11 (s, 3H).

Example 130
1,3-Dimethyl-5- (2-Methyl-5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazole-1-yl) ) Pyridine-2 (1H) -on

1,3-Dimethyl-5-one using 5-iodo-1,3-dimethylpyridine-2 (1H) -one instead of 4-iodo-1-methylpyrazole in the same manner as in Example 126. (2-Methyl-5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-1-yl) Pyridine-2 (1H)- Got on.
ESI-MS m / z 453 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.09 (d, J = 2.8Hz, 1H), 7.82 (d, J = 2.8Hz, 1H), 7.52-7.59 (m, 2H), 7.30 (d, J = 8.4Hz, 1H), 7.19-7.27 (m, 3H), 6.95 (t, J = 7.6Hz, 1H), 6.74 (dd, J = 8.8, 1.2Hz, 2H), 6.33 (d, J = 9.6Hz, 1H), 3.52 (s, 3H), 3.42 (s, 3H), 2.38 (s, 3H), 2.09 (s, 3H).

Example 131
5- (1- (3,5-dimethylisoxazole-4-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H)- on

5- (1- (3,5-dimethylisoxazole-) using 4-iodo-3,5-dimethylisoxazole instead of 4-iodo-1-methylpyrazole in the same manner as in Example 126. 4-Il) -2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one was obtained.
ESI-MS m / z 427 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.78 (d, J = 2.4Hz, 1H), 7.72 (dd, J = 9.2, 2.4Hz, 1H), 7.38 (d, J = 8.4Hz, 1H), 7.23-7.15 (m, 3H), 6.96-6.89 (m, 1H), 6.75 (d, J = 7.6Hz, 2H), 6.49 (d, J = 9.2Hz, 1H), 3.53 (s, 3H) ), 2.53 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H).

Example 132
1-Methyl-5-(2-Methyl-1-((3-Methylisoxazole-5-yl) Methyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -on

1-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -2 (1H) -one (1.00 g) in DMF (12 mL) solution, 4-iodo- Add 3,5 dimethylisoxazole (1.35 g), cesium carbonate (2.95 g), copper iodide (I) (120 mg) and trans-N, N'-dimethylcyclohexane-1,2-diamine (180 mg), and nitrogen. The mixture was heated and stirred at 140 ° C. for 5 hours in a microwave reactor under an atmosphere. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added until the pH reached 8, filtered, and then concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate / methanol) and preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution), and then freeze-dried to 1-methyl-5- (2-methyl-1-((3). -Methylisoxazole-5-yl) Methyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one (40.5 mg) was obtained.
ESI-MS m / z 427 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.75 (d, J = 2.8Hz, 1H), 7.70 (dd, J = 9.2, 2.4Hz, 1H), 7.53 (d, J = 8.4Hz, 1H), 7.37 (d, J = 8.4Hz, 1H), 7.20-7.14 (m, 2H), 6.91 (t, J = 7.2Hz, 1H), 6.71 (d, J = 8.0Hz, 2H), 6.48 ( d, J = 9.2Hz, 1H), 6.30 (s, 1H), 5.65 (s, 2H), 3.52 (s, 3H), 2.63 (s, 3H), 2.26 (s, 3H).

Example 133a
2- (6- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -7-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole -1-yl) acetonitrile

Example 133b
2- (5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole -1-yl) acetonitrile

1-Methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one (150 mg) DMF Potassium carbonate (77.5 mg) and 2-bromoacetonitrile (67.2 mg) were added to the (1.5 mL) solution, and the mixture was heated and stirred at 80 ° C. for 16 hours. After cooling the reaction mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (acetonitrile / 0.05% aqueous ammonium hydroxide solution). The first fraction is 2- (6- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -7-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo. [d] Imidazole-1-yl) acetonitrile (87.0 mg) was obtained. The second fraction is 2- (5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazol-1-yl) acetonitrile (35 mg) was obtained.

2- (6- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -7-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole -1-yl) acetonitrile
ESI-MS m / z 441 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.70 (d, J = 8.0Hz, 1H), 7.51 (d, J = 9.6Hz, 1H), 7.40 (d, J = 2.4Hz, 1H), 7.29-7.23 (s, 1H), 7.25-7.19 (m, 2H), 7.06-6.93 (m, 1H), 6.76-6.67 (m, 2H), 6.49 (d, J = 8.0Hz, 1H), 5.07 ( s, 2H), 4.22-4.06 (m, 2H), 3.63-3.54 (m, 2H), 3.48 (s, 3H), 3.24-2.96 (m, 1H), 2.29-2.15 (m, 2H), 1.98- 1.90 (m, 2H).

2- (5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole -1-yl) acetonitrile
ESI-MS m / z 441 [M + H] ⁺

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.53 (d, J = 9.6Hz, 1H), 7.44 (s, 1H), 7.36-7.21 (m, 2H), 7.25-7.19 (m, 2H) , 6.99-6.91 (m, 1H), 6.79 (d, J = 8.0Hz, 2H), 6.54 (d, J = 8.0Hz, 1H), 5.08 (s, 2H), 4.15-4.01 (m, 2H), 3.63-3.54 (m, 2H), 3.48 (s, 3H), 3.15-3.01 (m, 1H), 2.20-2.03 (m, 2H), 1.99-1.79 (m, 2H).

Example 134
2- (2-Methyl-5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazole-1-yl) acetonitrile

1-Methyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 in the same manner as in Example 133. Using (1H) -one instead of 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -2 (1H) -one, 2- (2) -Methyl-5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-1-yl) acetonitrile was obtained.
ESI-MS m / z 371 [M + H] ⁺

¹ H NMR (DMSO-d _6,500MHz ) δ (ppm): 7.84 (d, J = 2.9Hz, 1H), 7.64-7.51 (m, 2H), 7.32 (d, J = 8.0Hz, 1H), 7.26 -7.21 (m, 2H), 7.00-6.94 (m, 1H), 6.73 (d, J = 8.0Hz, 2H), 6.29 (d, J = 9.7Hz, 1H), 5.30 (s, 2H), 3.38 ( s, 3H), 2.58 (s, 3H).

Example 135
2- (5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-1-yl) acetonitrile

1-Methyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 in the same manner as in Example 133. Using 1,3-dimethyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one instead of (1H) -one, 2 -(5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl) acetonitrile was obtained. ..
ESI-MS m / z 385 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.37-7.33 (m, 1H), 7.24 (d, J = 2.3Hz, 1H), 7.22-7.16 (m, 2H), 7.07 (d, J = 8.0Hz, 1H), 6.94 (dd, J = 7.5, 6.9Hz, 1H), 6.71-6.65 (m, 3H), 4.16 (d, J = 6.9Hz, 2H), 3.47 (d, J = 6.3Hz, 3H), 3.39-3.29 (m, 3H), 1.87 (s, 3H).

Example 136a
5- (1- (2-Methoxyethyl) -2-methyl-7-phenoxy-1H-benzo [d] imidazol-6-yl) -1-methylpyridine-2 (1H) -one

Example 136b
5- (1- (2-Methoxyethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

1-Methyl-5-(4-Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) pyridine-2 in the same manner as in Example 133. (1H) -one and 2-bromo instead of acetonitrile 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -2 (1H) -one and 2- 5-(1- (2-Methoxyethyl) -2-methyl-7-phenoxy-1H-benzo [d] imidazole-6-yl) -1-methylpyridine-2 (1H) with chloroethylmethyl ether -On and 5- (1- (2-methoxyethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine were obtained.

5- (1- (2-Methoxyethyl) -2-methyl-7-phenoxy-1H-benzo [d] imidazol-6-yl) -1-methylpyridine-2 (1H) -one
ESI-MS m / z 390 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.61 (d, J = 8.0Hz, 1H), 7.52 (d, J = 9.7Hz, 1H), 7.35 (s, 1H), 7.20-7.13 (m) , 3H), 6.96-6.90 (m, 1H), 6.61 (d, J = 8.6Hz, 2H), 6.48 (d, J = 9.2Hz, 1H), 4.18 (t, J = 5.4Hz, 2H), 3.55 (t, J = 5.4Hz, 2H), 3.46 (s, 3H), 3.17 (s, 3H), 2.60 (s, 3H).

5- (1- (2-Methoxyethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one
ESI-MS m / z 390 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.61 (d, J = 8.6Hz, 1H), 7.52 (d, J = 9.2Hz, 1H), 7.35 (s, 1H), 7.20-7.13 (m) , 3H), 6.93 (t, J = 7.2Hz, 1H), 6.61 (d, J = 8.6Hz, 2H), 6.48 (d, J = 9.7Hz, 1H), 4.18 (t, J = 5.2Hz, 2H) ), 3.55 (t, J = 5.2Hz, 2H), 3.46 (s, 3H), 3.17 (s, 3H), 2.61 (s, 3H).

Example 137
5- (1-((2-Methoxyethoxy) methyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

1-Methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) pyridin-2 in the same manner as in Example 133. (1H) -one and 2-bromo instead of acetonitrile 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -2 (1H) -one and 2- 5-(1-((2-Methoxyethoxy) methyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 with methoxyethoxymethyl chloride (1H)-Get on.
ESI-MS m / z 420 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.60 (d, J = 8.0Hz, 1H), 7.54-7.44 (m, 1H), 7.34 (d, J = 2.9Hz, 1H), 7.21-7.09 (m, 3H), 6.93 (s, 1H), 6.63 (d, J = 8.0Hz, 2H), 6.47 (d, J = 9.2Hz, 1H), 5.54 (s, 2H), 3.48-3.38 (m, 5H), 3.28 (s, 3H), 3.32-3.28 (m, 2H), 2.65 (s, 3H).

Example 138
5- (1- (Methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one

1-Methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 in the same manner as in Example 133. (1H) -one and 2-bromoacetinate instead of 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -2 (1H) -one and chloromethyl Methyl ether is used to obtain 5- (1- (methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one. rice field.
ESI-MS m / z 376 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.62 (d, J = 8.0Hz, 1H), 7.51 (dd, J = 9.5,2.6Hz, 1H), 7.39-7.32 (m, 1H), 7.23 -7.10 (m, 3H), 7.00-6.87 (m, 1H), 6.71-6.58 (m, 2H), 6.47 (d, J = 9.2Hz, 1H), 5.60-5.36 (m, 2H), 3.46 (s) , 3H), 3.16 (d, J = 4.0Hz, 3H), 2.64 (s, 3H).

Example 139
5- (1- (Methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridin-2 (1H) -one

1-Methyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 in the same manner as in Example 133. (1H) -one and 1,3-dimethyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyrididine-2 (1H) -one instead of acetonitrile And 5- (1- (methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H)-with chloromethylmethyl ether. Got on.
ESI-MS m / z 390 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 7.60 (d, J = 8.0Hz, 1H), 7.38 (d, J = 1.1Hz, 1H), 7.25 (d, J = 2.2Hz, 1H), 7.20 (d, J = 8.6Hz, 1H) 7.18-7.13 (m, 2H), 6.92 (t, J = 7.4Hz, 1H), 6.70-6.58 (m, 2H), 5.42 (s, 2H), 3.45 ( s, 3H), 3.16 (s, 3H), 2.63 (s, 3H), 2.09 (s, 3H).

Example 140a
1-Methyl-5-(2-Methyl-1- (2-morpholinoethyl) -7-Phenoxy-1H-Benzodiazepine [d] Imidazole-6-yl) Pyridine-2 (1H) -On

Example 140b
1-Methyl-5-(2-Methyl-1- (2-morpholinoethyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

1-Methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 in the same manner as in Example 133. (1H) -one and 2-bromo instead of acetonitrile 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -2 (1H) -one and 4- Using (2-chloroethyl) morpholine hydrochloride, 1-methyl-5- (2-methyl-1- (2-morpholinoethyl) -7-phenoxy-1H-benzo [d] imidazol-6-yl) pyridin- 2 (1H) -one and 1-methyl-5- (2-methyl-1- (2-morpholinoethyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridin-2 (1H)- Got on.

1-Methyl-5-(2-Methyl-1- (2-morpholinoethyl) -7-Phenoxy-1H-Benzodiazepine [d] Imidazole-6-yl) Pyridine-2 (1H) -On
ESI-MS m / z 445 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.80-7.68 (m, 2H), 7.58-7.54 (s, 1H), 7.30 (d, J = 8.0Hz, 1H), 7.21 (dd, J = 8.0,7.6Hz, 2H), 6.94 (t, J = 7.6Hz, 1H), 6.69 (d, J = 8.0Hz, 2H), 6.44 (d, J = 9.2Hz, 1H), 4.37-4.25 ( m, 2H), 3.62-3.57 (m, 4H), 3.50 (s, 3H), 2.64 (s, 3H), 2.64 (t, J = 6.8Hz, 2H), 2.35 (t, J = 4.4Hz, 4H) ).

1-Methyl-5-(2-Methyl-1- (2-morpholinoethyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one
ESI-MS m / z 445 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.79-7.68 (m, 2H), 7.50 (d, J = 8.4Hz, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.16 (dd, J = 8.0,7.6Hz, 2H), 6.90 (t, J = 8.0Hz, 1H), 6.70 (d, J = 7.6Hz, 2H), 6.48 (d, J = 9.2Hz, 1H), 4.39 (t, J = 6.4Hz, 2H), 3.66 (t, J = 4.8Hz, 4H), 3.53 (s, 3H), 2.78 (t, J = 6.4Hz, 2H), 2.61 (s, 3H), 2.53 (t, J = 4.4Hz, 4H).

Example 141
1-Methyl-5-(2-Methyl-1- (3-morpholinopropyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one

1-Methyl-5-(4-((3-morpholinopropyl) amino) -3-nitro-2-phenoxyphenyl) Pyridine-2 (1H) -one
4- (3-Chloropropyl) morpholine (3- (3-chloropropyl) morpholine (2-chloropropyl) morpholine in a DMF (2.0 mL) solution of 5- (4-amino-3-nitro-2-phenoxyphenyl) -1-methylpyridine-2 (1H) -one (200 mg) 116 mg), potassium carbonate (164 mg) and sodium iodide (8.9 mg) were added, and the mixture was heated and stirred at 130 ° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then filtered. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / methanol) to 1-methyl-5-(4-((3-morpholinopropyl) amino) -3-nitro-2-phenoxyphenyl. ) Pyridine-2 (1H) -on (130 mg) was obtained.
ESI-MS m / z 465 [M + H] ⁺

b. 1-Methyl-5-(2-Methyl-1- (3-morpholinopropyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one
1-Methyl-5-(4-((3-morpholinopropyl) amino) -3-nitro-2-phenoxyphenyl) Pyridine-2 (1H) -one (130 mg) in acetic acid (3.0 mL) solution with iron powder (94 mg) was added, and the mixture was heated and stirred at 100 ° C. for 5 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in dichloromethane (2 mL), saturated aqueous sodium hydrogen carbonate solution was added until pH 8 and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.05% ammonium hydroxide aqueous solution) and then freeze-dried to 1-methyl-5- (2-methyl-1- (3-morpholinopropyl) -4-phenoxy-1H-benzo. [d] Imidazole-5-yl) Pyridine-2 (1H) -one (12.4 mg) was obtained.
ESI-MS m / z 459 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.81-7.71 (m, 2H), 7.57-7.54 (d, J = 8.4Hz, 1H), 7.38-7.36 (d, J = 8.0Hz, 1H) ), 7.18 (dd, J = 8.4,7.2Hz, 2H), 6.92 (t, J = 7.2Hz, 1H), 6.73-6.70 (d, J = 8.4Hz, 2H), 6.51-6.49 (d, J = 8.4Hz, 1H), 4.39-4.36 (m, J = 13.6,2H), 3.70-3.68 (t, J = 4.8Hz, 4H), 3.55 (s, 3H), 2.62 (s, 3H), 2.43-2.39 (m, 6H), 2.40-2.13 (m, 2H).

Example 142
1-Methyl-5-(2-Methyl-1-((1-Methyl-1H-Pyrazole-4-yl) Methyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 ( 1H)-On

1-Methyl-5- (2-Methyl-) using 4- (chloromethyl) -1-methylpyrazole hydrochloride instead of 4- (3-chloropropyl) morpholine in the same manner as in Example 141. 1-((1-Methyl-1H-pyrazole-4-yl) methyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one was obtained.
ESI-MS m / z 426 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.77-7.68 (m, 2H), 7.64 (s, 1H), 7.54 (d, J = 8.4Hz, 1H), 7.49 (s, 1H), 7.35 (d, J = 8.4Hz, 1H), 7.19-7.12 (m, 2H), 6.93-6.87 (m, 1H), 6.72-6.67 (m, 2H), 6.48 (d, J = 9.2Hz, 1H) , 5.37 (s, 2H), 3.84 (s, 3H), 3.52 (s, 3H), 2.61 (s, 3H).

Example 143
3-Bromo-1-methyl-5-(4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H) -one

N- (4- (5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -3-fluoro-2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide
DMF (3-fluoro-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (0.30 g) N-Bromosuccinimide (0.185 g) was added to the 16 mL) solution under ice-cooling, and the mixture was stirred at room temperature for 15.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to N- (4- (5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-yl)-. 3-Fluoro-2-nitrophenyl) Tetrahydro-2H-pyran-4-carboxamide crude product (694 mg) was obtained.
ESI-MS m / z 454 [M + H] ⁺

b. N- (4- (5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitro-3-phenoxyphenyl) tetrahydro-2H-pyran-4-carboxamide
N- (4- (5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -3-fluoro-2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide crude product A solution of cesium carbonate (0.52 g) and phenol (0.14 mL) was added to a solution of (694 mg) DMF (5 mL), and the mixture was heated and stirred at 80 ° C. for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol / L aqueous sodium hydroxide solution and then saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) and N- (4- (5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-yl) -2-. Nitro-3-phenoxyphenyl) tetrahydro-2H-pyran-4-carboxamide (497 mg) was obtained.
ESI-MS m / z 528 [M + H] ⁺

c. 3-bromo-1-methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridin-2 (1H)- on
N- (4- (5-bromo-1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitro-3-phenoxyphenyl) tetrahydro-2H-pyran-4-carboxamide (497 mg) Iron powder (263 mg) and acetic acid (1.0 mL) were added to the ethanol (10 mL) solution of the above, and the mixture was heated and stirred at 140 ° C. for 15 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to purify 3-bromo-1-methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4). -Il) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -one (0.381 g) was obtained.
ESI-MS m / z 480 [M + H] ⁺

¹ H NMR (CDCl _3,500MHz ) δ (ppm): 9.72 (brs, 1H), 7.95 (d, J = 2.3Hz, 1H), 7.64 (d, J = 8.0Hz, 1H), 7.39 (s, 1H) ), 7.21-7.14 (m, 3H), 7.00-6.92 (m, 1H), 6.72 (d, J = 8.0Hz, 2H), 4.10-3.99 (m, 2H), 3.60-3.42 (m, 5H), 3.20-3.08 (m, 1H), 2.05-1.92 (m, 4H).

Example 144
1-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -2-oxo-1,2-dihydropyridine-3-carbonitrile

1-Methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridine-3-carbonitrile
Potassium acetate (346 mg) and PdCl ₂ (dppf) in a 1,4-dioxane (7.0 mL) solution of 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (346 mg). Dichloromethane adduct (115 mg) was added, and the mixture was heated and stirred at 160 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was solidified with n-hexane and collected by filtration to 1-methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2). -Il) -1,2-dihydropyridine-3-carbonitrile (235 mg) was obtained.
ESI-MS m / z 261 [M + H] ⁺

b. 1-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -2-oxo-1,2-dihydropyridine-3-carbonitrile
5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazole (200 mg), 1-methyl-2-oxo-5- (4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl) -1,2-dihydropyridine-3-carbonitrile (257 mg) in a mixed solution of 1,4-dioxane (4.4 mL) and water (0.88 mL), sodium carbonate (175 mg) and PdCl ₂ (Dppf) -dichloromethane adduct (54 mg) was added, and the mixture was heated and stirred at 160 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-. Ill) -2-oxo-1,2-dihydropyridine-3-carbonitrile (19.6 mg) was obtained.
ESI-MS m / z 357 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 8.16 (d, J = 2.3Hz, 1H), 8.08 (d, J = 2.3Hz, 1H), 7.46 (brs, 1H), 7.36-7.24 ( m, 1H), 7.22-7.05 (m, 2H), 7.02-6.80 (m, 1H), 6.70 (d, J = 8.6Hz, 2H), 3.53 (s, 3H), 2.51 (s, 3H).

Example 145
1,3-Dimethyl-5- (2-Methyl-4-phenoxybenzo [d] Oxazole-5-yl) Pyridine-2 (1H) -one

5- (4-Hydroxy-3-nitro-2-phenoxyphenyl) -1,3-dimethylpyridin-2 (1H) -one
4-bromo-2-nitro-3-phenoxyphenol (600 mg), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine- Sodium carbonate (1.02 g) and PdCl ₂ (dppf) / dichloromethane adduct (28.2 mg) are added to a mixed solution of 2 (1H) -one (962 mg) 1,4-dioxane (30 mL) and water (6 mL). , Heated and stirred at 95 ° C. for 12 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, 1 mol / L hydrochloric acid was added until the pH reached 1, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5- (4-hydroxy-3-nitro-2-phenoxyphenyl) -1,3-dimethylpyridin-2 (1H) -one (180 mg). ) Was obtained.
ESI-MS m / z 353 [M + H] ⁺

b. 5- (3-Amino-4-hydroxy-2-phenoxyphenyl) -1,3-dimethylpyridin-2 (1H) -one
Add 10% Pd / C (12 mg) to a solution of 5- (4-hydroxy-3-nitro-2-phenoxyphenyl) -1,3-dimethylpyridin-2 (1H) -one (120 mg) in methanol (5 mL). In addition, the mixture was stirred under a hydrogen atmosphere for 8 hours. The reaction mixture was filtered through Celite and the insoluble material was washed with methanol. The filtrate was concentrated under reduced pressure to give 5- (3-amino-4-hydroxy-2-phenoxyphenyl) -1,3-dimethylpyridin-2 (1H) -one (120 mg).
ESI-MS m / z 323 [M + H] ⁺

c. 1,3-Dimethyl-5- (2-Methyl-4-phenoxybenzo [d] Oxazole-5-yl) Pyridine-2 (1H) -one
In a solution of 5- (3-amino-4-hydroxy-2-phenoxyphenyl) -1,3-dimethylpyridin-2 (1H) -one (120 mg) in THF (20 mL), trimethyl orthoacetate (89 mg) and p- Toluenesulfonic acid monohydrate (7.1 mg) was added, and the mixture was heated and stirred at 60 ° C. for 60 hours. The reaction mixture was cooled to room temperature, filtered, and then concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.1% TFA aqueous solution) and then freeze-dried to 1,3-dimethyl-5- (2-methyl-4-phenoxybenzo [d] oxazole-5-yl) pyridin-2. (1H)-on (3.5 mg) was obtained.
ESI-MS m / z 347 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.65 (d, J = 2.4Hz, 1H), 7.61-7.55 (m, 2H), 7.47 (d, J = 8.8Hz, 1H), 7.22 ( dd, J = 8.8,7.6Hz, 2H), 7.01-6.94 (m, 1H), 6.76 (d, J = 7.6Hz, 2H), 3.55 (s, 3H), 2.62 (s, 3H), 2.08 (s) , 3H).

Example 146
1-Methyl-5- (2-Methyl-4-phenoxybenzo [d] thiazole-5-yl) Pyridine-2 (1H) -on

1-bromo-3-nitro-2-phenoxybenzene
Potassium carbonate (5.92 g) and phenol (898 mg) were added to a solution of 1-bromo-2-fluoro-3-nitrobenzene (2.0 g) in acetonitrile (20 mL), and the mixture was heated and stirred at 80 ° C. for 16 hours. After cooling the reaction mixture to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-bromo-3-nitro-2-phenoxybenzene (3.14 g).
¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.98-7.88 (m, 1H), 7.36-7.23 (m, 3H), 6.98-6.83 (m, 4H).

b. 3-Bromo-2-phenoxyaniline
Add iron powder (4.2 g) and ammonium chloride (4.0 g) to a mixed solution of 1-bromo-3-nitro-2-phenoxybenzene (3.14 g) in methanol (20 mL), DMF (2 mL) and water (10 mL). In addition, the mixture was heated and stirred at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature and then filtered through Celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 3-bromo-2-phenoxyaniline (1.99 g).
ESI-MS m / z 264 [M + H] ⁺

c. N- (3-bromo-2-phenoxyphenyl) acetamide
Acetyl chloride (1.07 g) was added to a solution of 3-bromo-2-phenoxyaniline (1.80 g) in 1,2-dichloroethane (20 mL), and the mixture was heated and stirred at 80 ° C. for 30 minutes. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give N- (3-bromo-2-phenoxyphenyl) acetamide (1.96 g).
ESI-MS m / z 306 [M + H] ⁺

d. N- (3-bromo-2-phenoxyphenyl) ethanethioamide
Lawesson's reagent (2.38 g) was added to a solution of N- (3-bromo-2-phenoxyphenyl) acetamide (1.80 g) in 1,4-dioxane (15 mL), and the mixture was heated and stirred at 100 ° C. for 1.5 hours. The reaction mixture is cooled to room temperature, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give N- (3-bromo-2-phenoxyphenyl) ethanethioamide (1.57 g). Obtained.
ESI-MS m / z 322 [M + H] ⁺

e. 5-bromo-2-methyl-4-phenoxybenzo [d] thiazole
Disodium peroxodisulfate (1.47 g), pyridine (490 mg) and iron (III) chloride (100 mg) in a DMSO (17 mL) solution of N- (3-bromo-2-phenoxyphenyl) ethanethioamide (1.0 g). In addition, the mixture was heated and stirred at 60 ° C. for 16 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate / petroleum ether) and preparative HPLC (acetonitrile / 0.225% formic acid aqueous solution), and then freeze-dried to perform 5-bromo-2-methyl-4-phenoxybenzo [d] thiazole ( 140 mg) was obtained.
ESI-MS m / z 320 [M + H] ⁺

f. 1-Methyl-5- (2-Methyl-4-phenoxybenzo [d] thiazole-5-yl) Pyridine-2 (1H) -one
5-bromo-2-methyl-4-phenoxybenzo [d] thiazole (120 mg), 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Sodium carbonate (59.6 mg) and PdCl ₂ (dppf) / dichloromethane adduct (27.4 mg) were added to a mixed solution of pyridine-2 (1H) -one (106 mg) of DMF (7 mL) and water (0.7 mL). The mixture was heated and stirred at 120 ° C. for 5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.225% formic acid aqueous solution) and then freeze-dried to 1-methyl-5- (2-methyl-4-phenoxybenzo [d] thiazole-5-yl) pyridine-2 (1H). -On (90 mg) was obtained.
ESI-MS m / z 349 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.02 (d, J = 8.4Hz, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.62 (dd, J = 9.2, 2.4Hz) , 1H), 7.54 (d, J = 8.4Hz, 1H), 7.22 (dd, J = 8.0, 7.6Hz, 2H), 6.95 (t, J = 7.6Hz, 1H), 6.70 (d, J = 8.0Hz) , 2H), 6.35 (d, J = 9.2Hz, 1H), 3.43 (s, 3H), 2.73 (s, 3H).

Example 147
1,3-Dimethyl-5- (2-Methyl-4-phenoxybenzo [d] thiazole-5-yl) Pyridine-2 (1H) -one

Substituting 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one in the same manner as in Example 146. 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one, 1,3-dimethyl -5- (2-Methyl-4-phenoxybenzo [d] thiazole-5-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 363 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.90 (d, J = 8.4Hz, 1H), 7.69 (d, J = 2.4Hz, 1H), 7.61 (d, J = 1.6Hz, 1H) , 7.51 (d, J = 8.0Hz, 1H), 7.21-7.15 (m, 2H), 6.95-6.89 (m, 1H), 6.73-6.67 (m, 2H), 3.54 (s, 3H), 2.79 (s) , 3H), 2.08 (s, 3H).

Example 148
1-Methyl-5- (2-Methyl-7-Phenoxybenzo [d] Thiazole-6-yl) Pyridine-2 (1H) -On

1-Methyl-5- (2-methyl-7-phenoxybenzo [d], using 4-bromo-3-phenoxyaniline instead of 3-bromo-2-phenoxyaniline in the same manner as in Example 146. ] Thiazole-6-yl) Pyridine-2 (1H) -on was obtained.
ESI-MS m / z 349 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.98 (d, J = 2.4Hz, 1H), 7.89 (d, J = 8.4Hz, 1H), 7.67-7.59 (m, 2H), 7.34 -7.25 (m, 2H), 7.06 (t, J = 7.6Hz, 1H), 6.85 (d, J = 8.4Hz, 2H), 6.37 (d, J = 9.2Hz, 1H), 3.45 (s, 3H) , 2.75 (s, 3H).

Example 149
5- (3-Acetyl-7-Phenoxy-1H-Indole-6-yl) -1-Methylpyridine-2 (1H) -On

1-bromo-3-nitro-2-phenoxybenzene
Potassium carbonate (6.28 g) and phenol (2.35 g) were added to a solution of 1-bromo-2-fluoro-3-nitrobenzene (5.00 g) in acetonitrile (50 mL), and the mixture was heated and stirred at 80 ° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered. A 1 mol / L aqueous sodium hydroxide solution was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-bromo-3-nitro-2-phenoxybenzene (6.50 g).
¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 8.20-8.11 (m, 2H), 7.52 (t, J = 8.0Hz, 1H), 7.41-7.30 (m, 2H), 7.13-7.06 ( m, 1H), 6.89-6.81 (m, 2H).

b. 6-bromo-7-phenoxy-1H-indole
To a solution of 1-bromo-3-nitro-2-phenoxybenzene (3.00 g) in THF (75 mL), add 1 mol / L vinyl magnesium bromide (THF solution, 30.6 mL) under ice-cooling, and stir at 15 ° C for 20 hours. bottom. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 6-bromo-7-phenoxy-1H-indole (1.16 g).
ESI-MS m / z 288 [M + H] ⁺

c. 1- (6-bromo-7-phenoxy-1H-indole-3-yl) ethane-1-one
Tin (IV) chloride (217 mg) was added to a solution of 6-bromo-7-phenoxy-1H-indole (200 mg) in dichloromethane (8 mL) under ice-cooling, and the mixture was stirred at 15 ° C. for 30 minutes. Acetic anhydride (70.9 mg) and nitromethane (2.26 g) were added to the reaction mixture, and the mixture was stirred at 15 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 1- (6-bromo-7-phenoxy-1H-indole-3-yl) ethane-1-one ( 150 mg) was obtained.
ESI-MS m / z 330 [M + H] ⁺

d. 5- (3-Acetyl-7-phenoxy-1H-indole-6-yl) -1-methylpyridine-2 (1H) -one
1- (6-bromo-7-phenoxy-1H-indol-3-yl) ethane-1-one (150 mg), 1-methyl-5- (4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one (117 mg) in a mixed solution of DMF (3 mL) and water (1 mL) with sodium carbonate (96.3 mg) and PdCl ₂ (dppf) / dichloromethane adduct (20.0 mg) was added, and the mixture was heated and stirred at 100 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by preparative HPLC (acetonitrile / 0.225% formic acid aqueous solution) and then freeze-dried to 5- (3-acetyl-7-phenoxy-1H-indole-6-yl) -1-methylpyridine-2 (1H)-. On (35 mg) was obtained.
ESI-MS m / z 359 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.13 (brs, 1H), 8.29 (s, 1H), 8.11 (d, J = 8.0Hz, 1H), 7.90 (d, J = 2.4Hz) , 1H), 7.63 (dd, J = 9.2,2.4Hz, 1H), 7.30 (d, J = 8.4Hz, 1H), 7.23 (dd, J = 8.0, 7.2Hz, 2H), 6.95 (t, J = 7.2Hz, 1H), 6.70 (d, J = 8.0Hz, 2H), 6.32 (d, J = 9.2Hz, 1H), 3.41 (s, 3H), 2.49 (s, 3H).

Example 150
5- (3-Acetyl-7-phenoxy-1H-indole-6-yl) -1,3-dimethylpyridin-2 (1H) -one

Substituting 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one in the same manner as in Example 149. With 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one, 5- (3- (3-) Acetyl-7-phenoxy-1H-indole-6-yl) -1,3-dimethylpyridin-2 (1H) -one was obtained.
ESI-MS m / z 373 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.13 (brs, 1H), 8.28 (s, 1H), 8.10 (d, J = 8.4Hz, 1H), 7.76 (d, J = 2.4Hz) , 1H), 7.54 (s, 1H), 7.29 (d, J = 8.0Hz, 1H), 7.22 (dd, J = 8.0, 7.2Hz, 2H), 6.95 (t, J = 7.2Hz, 1H), 6.70 (d, J = 8.0Hz, 2H), 3.41 (s, 3H), 2.48 (s, 3H), 1.96 (s, 3H).

Example 151
1,3-dimethyl-5-(5-phenoxy-2- (tetrahydro-2H-pyran-4-yl) imidazole [1,2-a] pyridin-6-yl) pyridin-2 (1H) -one

6'-amino-1,5-dimethyl-2'-phenoxy- [3,3'-bipyridine] -6 (1H) -one
5-bromo-6-phenoxypyridine-2-amine (301 mg), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine- Sodium carbonate (306 mg) and PdCl ₂ (dppf) / dichloromethane adduct (70 mg) are added to a mixed solution of 2 (1H) -one (370 mg) of 1,4-dioxane (3.0 mL) and water (0.6 mL). , In a microwave reactor, heated and stirred at 160 ° C. for 10 minutes. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 6'-amino-1,5-dimethyl-2'-phenoxy- [3,3'-bipyridine]-. 6 (1H) -on (146 mg) was obtained.
ESI-MS m / z 308 [M + H] ⁺

b. 1,3-Dimethyl-5- (5-phenoxy-2- (tetrahydro-2H-pyran-4-yl) imidazole [1,2-a] pyridin-6-yl) Pyridine-2 (1H) -one
6'-Amino-1,5-dimethyl-2'-phenoxy- [3,3'-bipyridine] -6 (1H) -one (146 mg) in N, N-dimethylacetamide (1.5 mL) solution, 2- Bromo-1- (tetrahydro-2H-pyran-4-yl) etanone (149 mg) was added, and the mixture was heated and stirred at 170 ° C. for 30 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) and preparative HPLC (0.1% formic acid acetonitrile / 0.1% formic acid) to 1,3-dimethyl-5- (5-phenoxy-2- (tetrahydro). -2H-Pyran-4-yl) Imidazo [1,2-a] Pyridine-6-yl) Pyridine-2 (1H) -one (39 mg) was obtained.
ESI-MS m / z 416 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.74 (d, J = 2.1Hz, 1H), 7.61 (d, J = 1.0Hz, 1H), 7.55 (d, J = 9.2Hz, 1H) , 7.51 (d, J = 9.2Hz, 1H), 7.48 (s, 1H), 7.31 (dd, J = 8.6, 7.5Hz, 2H), 7.11 (t, J = 7.5Hz, 1H), 6.87 (dd, dd, J = 8.6,1.1Hz, 2H), 4.03 (dd, J = 11.7, 2.6Hz, 2H), 3.63-3.54 (m, 5H), 3.07-2.99 (m, 1H), 2.09 (s, 3H), 2.01 -1.93 (m, 2H), 1.88-1.77 (m, 2H).

Example 152
1-Methyl-5-(2-Methyl-5-Phenoxy- [1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 (1H) -On

N- (5-bromo-6-phenoxypyridin-2-yl) -N'-hydroxyacetimideamide
To a solution of 5-bromo-6-phenoxypyridin-2-amine (100 mg) in isopropanol (0.7 mL), add N, N-dimethylacetamide dimethyl acetal (0.12 mL) and in a microwave reactor at 110 ° C. for 30 minutes. It was heated and stirred. After cooling the reaction mixture to room temperature, hydroxylamine hydrochloride (50 mg) was added, and the mixture was heated and stirred at 50 ° C. for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give N- (5-bromo-6-phenoxypyridin-2-yl) -N'-hydroxyacetimideamide (98 mg).
ESI-MS m / z 322 [M + H] ⁺

b. 6-bromo-2-methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridine
To a solution of N- (5-bromo-6-phenoxypyridin-2-yl) -N'-hydroxyacetimideamide (97 mg) in THF (2 mL), add TFA anhydride (0.42 mL) under ice-cooling, and add micro. The mixture was heated and stirred at 160 ° C. for 1 hour in a wave reactor. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) and 6-bromo-2-methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridine (34 mg). Got
ESI-MS m / z 304 [M + H] ⁺

c. 1-Methyl-5-(2-Methyl-5-phenoxy- [1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 (1H) -on
6-bromo-2-methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridin (32 mg), 1-methyl-5- (4,4,5,5-tetramethyl-) 1,3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one (62 mg) in a mixed solution of 1,4-dioxane (1.6 mL) and water (0.4 mL) with sodium carbonate (33.5 mg) And PdCl ₂ (dppf) -dichloromethane adduct (30 mg) were added, and the mixture was heated and stirred at 180 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 1-methyl-5- (2-methyl-5-phenoxy- [1,2,4] triazolo [1]. , 5-a] Pyridine-6-yl) Pyridine-2 (1H) -one (12 mg) was obtained.
ESI-MS m / z 333 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.80 (s, 1H), 7.74 (d, J = 9.2Hz, 1H), 7.63 (d, J = 9.2Hz, 1H), 7.58 (d, J = 8.6Hz, 1H), 7.20-7.14 (m, 2H), 7.00-6.95 (m, 1H), 6.73 (d, J = 8.6Hz, 2H), 6.41 (d, J = 9.2Hz, 1H), 3.44 (s, 3H), 2.40 (s, 3H).

Example 153
1,3-Dimethyl-5- (2-Methyl-5-Phenoxy- [1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 (1H) -On

Substituting 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one in the same manner as in Example 152. 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one, 1,3-dimethyl -5- (2-Methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridin-6-yl) pyridin-2 (1H) -one was obtained.
ESI-MS m / z 347 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.81 (d, J = 9.2Hz, 1H), 7.74-7.72 (m, 1H), 7.65 (d, J = 9.2Hz, 1H), 7.58- 7.55 (m, 1H), 7.27-7.22 (m, 2H), 7.08-7.02 (m, 1H), 6.80 (d, J = 8.6Hz, 2H), 3.52 (s, 3H), 2.49 (s, 3H) , 2.05 (s, 3H).

Example 154
1-Methyl-5-(5-Phenoxy-2- (Tetrahydro-2H-Pyran-4-yl)-[1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 ( 1H)-On

1,6-diamino-3-bromo-2-phenoxypyridinium 2,4,6-trimethylbenzenesulfonate
O-Mesitylene sulfonyl hydroxylamine (600 mg) was added to a solution of 5-bromo-6-phenoxypyridine-2-amine (300 mg) in chloroform (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was collected by filtration and washed with ethyl acetate to give 1,6-diamino-3-bromo-2-phenoxypyridinium 2,4,6-trimethylbenzenesulfonate (263 mg).
ESI-MS m / z 280 [M] ⁺

b. 6-Bromo-5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-[1,2,4] triazolo [1,5-a] pyridine tetrahydropyran-4-carboxylic acid chloride (309 mg) ), A solution of 1,6-diamino-3-bromo-2-phenoxypyridinium 2,4,6-trimethylbenzenesulfonate (100 mg) in pyridine (3 mL) was added, and the mixture was heated and stirred at 85 ° C. for 15 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to 6-bromo-5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-[1,2,4] triazolo [ 1,5-a] Pyridine (33 mg) was obtained.
ESI-MS m / z 374 [M + H] ⁺

c. 1-Methyl-5-(5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-[1,2,4] triazolo [1,5-a] pyridin-6-yl) pyridin- 2 (1H)-On
6-bromo-5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-[1,2,4] triazolo [1,5-a] pyridine (32 mg), 1-methyl-5- (4) , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) Pyridine-2 (1H) -one (36 mg) of 1,4-dioxane (1.4 mL) and water (0.34 mL) Sodium carbonate (45.3 mg) and PdCl ₂ (dppf) / dichloromethane adduct (13.9 mg) were added to the mixed solution, and the mixture was heated and stirred at 180 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then filtered through Celite. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (n-hexane / ethyl acetate) to 1-methyl-5- (5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-. [1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 (1H) -one (3.5 mg) was obtained.
ESI-MS m / z 403 [M + H] ⁺

¹ H NMR (CD ₃ OD, 500MHz) δ (ppm): 7.92 (d, J = 2.3Hz, 1H), 7.85 (d, J = 9.2Hz, 1H), 7.75 (dd, J = 9.5,2.6Hz, 1H), 7.71 (d, J = 9.2Hz, 1H), 7.31-7.25 (m, 2H), 7.12-7.06 (m, 1H), 6.91-6.79 (m, 2H), 6.53 (d, J = 9.7Hz) , 1H), 4.00-3.94 (m, 2H), 3.59-3.52 (m, 5H), 3.21-3.15 (m, 1H), 1.97-1.89 (m, 4H).

Example 155
1,3-dimethyl-5-(5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-[1,2,4] triazolo [1,5-a] pyridin-6-yl) pyridin- 2 (1H)-On

Substituting 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one in the same manner as in Example 154. 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 (1H) -one, 1,3-dimethyl -5- (5-Phenoxy-2- (Tetrahydro-2H-Pyran-4-yl)-[1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 (1H)- Got on.
ESI-MS m / z 417 [M + H] ⁺

¹ H NMR (CD ₃ OD, 400MHz) δ (ppm): 7.81 (d, J = 9.2Hz, 1H), 7.75-7.72 (m, 1H), 7.66 (d, J = 9.2Hz, 1H), 7.59- 7.56 (m, 1H), 7.27-7.21 (m, 2H), 7.07-7.02 (m, 1H), 6.81 (d, J = 8.0Hz, 2H), 4.01-3.87 (m, 2H), 3.60-3.48 ( m, 5H), 3.18-3.10 (m, 1H), 2.05 (s, 3H), 1.98-1.81 (m, 4H).

Reference example 1
4-bromo-3-phenoxybenzene-1,2-diamine

4-bromo-2-nitro-3-phenoxyaniline
Cesium carbonate (4.99 g) and phenol (1.44 g) were added to a DMSO (50 mL) solution of 4-bromo-3-fluoro-2-nitroaniline (3.00 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / petroleum ether) to give 4-bromo-2-nitro-3-phenoxyaniline (2.88 g).
ESI-MS m / z 309 [M + H] ^+
1 H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.56 (d, J = 9.2Hz, 1H), 7.36-7.26 (m, 2H), 7.08-7.00 (m, 1H), 6.87-6.74 ( m, 3H), 6.63 (s, 2H).

b. 4-Bromo-3-phenoxybenzene-1,2-diamine
Ammonium chloride (2.80 g) and iron powder (2.93 g) are added to a mixed solution of 4-bromo-2-nitro-3-phenoxyaniline (4.50 g) in methanol (40.0 mL) and water (13.5 mL), and 60 The mixture was heated and stirred at ° C for 3 hours. The reaction mixture was cooled to room temperature, the reaction mixture was filtered, the filtrate was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3-phenoxybenzene-1,2-diamine (0.95 g).
ESI-MS m / z 279 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 7.31-7.18 (m, 2H), 7.02-6.91 (m, 1H), 6.76 (dd, J = 8.7, 1.0Hz, 2H), 6.64 ( d, J = 8.6Hz, 1H), 6.45-6.38 (m, 1H), 4.86 (s, 2H), 4.43 (s, 2H).

Reference example 2
N- (3-Fluoro-4- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2-nitrophenyl) Tetrahydro-2H-pyran-4-carboxamide

N- (4-bromo-3-fluoro-2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (1.00 g), 1-methyl-5- (4,4,5,5-tetramethyl-1,) 3,2-Dioxaborolan-2-yl) Pyridine-2 (1H) -one (1.01 g) in a mixed solution of 1,4-dioxane (25 mL) and water (5 mL), sodium carbonate (0.92 g) and PdCl ₂ (Dppf) -Dichloromethane adduct (118 mg) was added, and the mixture was heated and stirred at 100 ° C. for 17 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through Celite and the insoluble material washed with chloroform. The filtrate is concentrated under reduced pressure, the residue is purified by silica gel column chromatography (chloroform / methanol), and then freeze-dried to N- (3-fluoro-4- (1-methyl-6-oxo-1,6-dihydropyridine-3-). Il) -2-nitrophenyl) tetrahydro-2H-pyran-4-carboxamide (1.08 g) was obtained.
ESI-MS m / z 376 [M + H] ⁺

Reference example 3
5-bromo-4-((4-Methoxybenzyl) oxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole

4-bromo-3-((4-Methoxybenzyl) oxy) -2-nitroaniline
To a solution of 4-methoxybenzyl alcohol (16.81 g) in DMF (200 mL) was added 60% sodium hydride (4.87 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Under ice-cooling, 4-bromo-3-fluoro-2-nitroaniline (14.3 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3- ((4-methoxybenzyl) oxy) -2-nitroaniline (17.5 g).

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.46 (d, J = 8.8Hz, 2H), 7.41 (d, J = 8.8Hz, 1H), 6.94-6.87 (m, 2H), 6.48 (d , J = 8.8Hz, 1H), 5.10 (s, 2H), 4.97 (brs, 2H), 3.82 (s, 3H).

b. 4-Bromo-3-((4-Methoxybenzyl) oxy) benzene-1,2-diamine
4-Bromo-3-((4-Methoxybenzyl) oxy) -2-nitroaniline (16.0 g) in a mixed solution of methanol (160 mL) and water (80 mL) with iron powder (17.7 g) and ammonium chloride (17.7 g) 17.0 g) was added, and the mixture was heated and stirred at 60 ° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3- ((4-methoxybenzyl) oxy) benzene-1,2-diamine (10.0 g).

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.47 (dd, J = 6.8,2.0Hz, 2H), 6.95 (dd, J = 6.8,2.0Hz, 2H), 6.89 (d, J = 8.8Hz) , 1H), 6.43 (d, J = 8.4Hz, 1H), 4.94 (s, 2H), 3.85 (s, 3H), 3.44 (brs, 4H).

c. N- (2-amino-4-bromo-3-((4-methoxybenzyl) oxy) phenyl) tetrahydro-2H-pyran-4-carboxamide and N- (6-amino-3-bromo-2-( (4-Methenylbenzyl) Oxy) Phenyl) Tetrahydro-2H-Pyran-4-Carboxamide
Tetrahydropyran-4-carboxylic acid (4.25 g) in a solution of 4-bromo-3- ((4-methoxybenzyl) oxy) benzene-1,2-diamine (9.44 g) in dichloromethane (135 mL) under ice-cooling. Triethylamine (3.44 g) and 50% T3P (DMF solution, 21.7 g) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to N- (2-amino-4-bromo-3-((4-methoxybenzyl) oxy) phenyl) tetrahydro-2H-pyran-4-carboxamide and A crude mixture of N- (6-amino-3-bromo-2-((4-methoxybenzyl) oxy) phenyl) tetrahydro-2H-pyran-4-carboxamide (14.7 g) was obtained.
ESI-MS m / z 435 [M + H] ⁺

d. 5-bromo-4-((4-Methoxybenzyl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
N- (2-Amino-4-bromo-3-((4-Methoxybenzyl) oxy) phenyl) tetrahydro-2H-pyran-4-carboxamide and N- (6-amino-3-bromo-2-((4) -Methoxybenzyl) Oxy) Phenyl) Tetrahydro-2H-Pyran-4-Carboxamide To a solution of crude mixture (14.7 g) in 1,4-dioxane (250 mL), silica gel (58.8 g) is added, and the mixture is heated and stirred at 100 ° C for 6 hours. bottom. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-4-((4-methoxybenzyl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-. Benzo [d] imidazole (6.30 g) was obtained.
ESI-MS m / z 417 [M + H] ⁺

e. 5-bromo-4-((4-Methoxybenzyl) oxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole
5-bromo-4-((4-methoxybenzyl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (6.10 g) in DMF (70 mL) solution with ice. 60% sodium hydride (0.70 g) was added under cooling, and the mixture was stirred at room temperature for 30 minutes. Chloromethyl methyl ether (1.41 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to 5-bromo-4-((4-methoxybenzyl) oxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-). 4-Il) -1H-benzo [d] imidazole (5.40 g) was obtained.
ESI-MS m / z 461 [M + H] ⁺

Reference example 4
5-bromo-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-ol

5-bromo-4-((4-methoxybenzyl) oxy) -1- (methoxymethyl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole (800 mg) TFA ( To the 8 mL) solution was added 1,3-dimethoxybenzene (958 mg), and the mixture was heated and stirred at 70 ° C. for 20 hours. After cooling the reaction mixture to room temperature, water was added, the mixture was neutralized with sodium carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (8 mL), pyridine hydrochloride (2.01 g) was added, and the mixture was heated and stirred at 100 ° C. for 21 hours. The reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. In addition, the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to 5-bromo-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-4-ol (371 mg). ) Was obtained.
ESI-MS m / z 297 [M + H] ⁺

Reference example 5
5-bromo-4- (3-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole

4-bromo-3- (3-chlorophenoxy) -2-nitroaniline
Cesium carbonate (8.32 g) and 3-chlorophenol (3.28 g) were added to a DMSO (50 mL) solution of 4-bromo-3-fluoro-2-nitroaniline (5.10 g), and the mixture was heated and stirred at 40 ° C. for 5 hours. .. After cooling the reaction mixture to room temperature, water (500 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3- (3-chlorophenoxy) -2-nitroaniline (7.2 g).

¹ H NMR (CDCl _3,400MHz ) δ (ppm): 7.49 (d, J = 9.2Hz, 1H), 7.27-7.21 (m, 1H), 7.06-7.05 (m, 1H), 6.86 (dd, J = 2.2,2.0Hz, 1H), 6.78-6.75 (m, 1H), 6.66 (d, J = 9.2Hz, 1H), 5.26 (brs, 2H).

b. 4-bromo-3- (3-chlorophenoxy) benzene-1,2-diamine
4-Bromo-3- (3-chlorophenoxy) -2-Nitroaniline (7.20 g) in a mixed solution of methanol (90 mL) and water (45 mL) with iron powder (8.19 g) and ammonium chloride (7.85 g) In addition, the mixture was heated and stirred at 60 ° C. for 5 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3- (3-chlorophenoxy) benzene-1,2-diamine (6.5 g).
ESI-MS m / z 313 [M + H] ⁺

c. 5-bromo-4- (3-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole
Trimethyl orthoacetate (7.47 g) and p-toluenesulfonic acid monohydrate (394 mg) in a solution of 4-bromo-3- (3-chlorophenoxy) benzene-1,2-diamine (6.5 g) in THF (60 mL). ) Was added, and the mixture was heated and stirred at 50 ° C. for 5 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogen carbonate solution and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 5-bromo-4- (3-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole (6.4 g).
ESI-MS m / z 337 [M + H] ⁺

¹ HNMR (DMSO-d _6,400MHz ) δ (ppm): 12.66 (brs, 1H), 7.43 (d, J = 7.6Hz, 1H), 7.35-7.31 (m, 2H), 7.09-7.08 (m, 1H) ), 6.92-6.82 (m, 1H), 6.75 (d, J = 8.0Hz, 1H), 2.45 (s, 3H).

Reference example 6
5-bromo-4- (4-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole

4-bromo-3- (4-chlorophenoxy) -2-nitroaniline
Cesium carbonate (8.32 g) and 4-chlorophenol (3.28 g) were added to a DMSO (45 mL) solution of 4-bromo-3-fluoro-2-nitroaniline (5.00 g), and the mixture was heated and stirred at 45 ° C for 16 hours. .. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain 4-bromo-3- (4-chlorophenoxy) -2-nitroaniline (5.66 g).
ESI-MS m / z 343 [M + H] ⁺

b. 4-Bromo-3- (4-chlorophenoxy) benzene-1,2-diamine
4-Bromo-3- (4-chlorophenoxy) -2-Nitroaniline (5.66 g) in a mixed solution of methanol (40 mL) and water (12 mL) with iron powder (6.44 g) and ammonium chloride (6.17 g). In addition, the mixture was heated and stirred at 65 ° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the insoluble material was washed with ethyl acetate. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 4-bromo-3- (4-chlorophenoxy) benzene-1,2-diamine (2.92 g).
ESI-MS m / z 313 [M + H] ⁺

c. 5-bromo-4- (4-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole
Trimethyl orthoacetate (3.13 g) and p-toluenesulfonic acid monohydrate (149 mg) in a solution of 4-bromo-3- (4-chlorophenoxy) benzene-1,2-diamine (2.72 g) in THF (28 mL). ) Was added, and the mixture was heated and stirred at 55 ° C. for 16 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 5-bromo-4- (4-chlorophenoxy) -2-methyl-1H-benzo [d] imidazole (1.93 g).
ESI-MS m / z 337 [M + H] ⁺

¹ HNMR (DMSO-d _6,400MHz ) δ (ppm): 12.63 (brs, 1H), 7.45-7.31 (m, 4H), 6.92-6.75 (m, 2H), 2.44 (s, 3H).

Reference example 7
3- (5-Bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol

N- (2-Amino-4-bromo-3-phenoxyphenyl) -3-oxocyclobutane-1-carboxamide and N- (6-amino-3-bromo-2-phenoxyphenyl) -3-oxocyclobutane- 1-Carboxamide
HATU (4.09 g) and DIPEA (2.24 g) were added to a solution of 3-oxocyclobutanecarboxylic acid (818 mg) in DMF (40 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of 4-bromo-3-phenoxybenzene-1,2-diamine (2.0 g) in DMF (8 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 19 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to N- (2-amino-4-bromo-3-phenoxyphenyl) -3-oxocyclobutane-1-carboxamide and N- (6-amino). A mixture of -3-bromo-2-phenoxyphenyl) -3-oxocyclobutane-1-carboxamide (2.80 g) was obtained.
ESI-MS m / z 375 [M + H] ⁺

b. 3- (5-Bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-one
N- (2-amino-4-bromo-3-phenoxyphenyl) -3-oxocyclobutane-1-carboxamide and N- (6-amino-3-bromo-2-phenoxyphenyl) -3-oxocyclobutane-1- Acetic acid (704 mg) and molecular sieve (5.00 g) were added to a solution of carboxamide mixture (1.10 g) in DMF (100 mL), and the mixture was heated and stirred at 110 ° C. for 16 hours. After cooling the reaction mixture to room temperature, saturated sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 3- (5-bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-one (480 mg). Obtained.
ESI-MS m / z 357 [M + H] ⁺

c. 3- (5-Bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol
Sodium borohydride (29.1 mg) in a solution of 3- (5-bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-one (250 mg) in methanol (4 mL) under ice-cooling. ) Was added, and the mixture was stirred at 0 ° C. for 3 hours. 1 mol / L hydrochloric acid and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give 3- (5-bromo-4-phenoxy-1H-benzo [d] imidazol-2-yl) cyclobutane-1-ol (170 mg). Obtained.
ESI-MS m / z 359 [M + H] ⁺

¹ H NMR (DMSO-d _6,400MHz ) δ (ppm): 12.6-12.5 (m, 1H), 7.53-7.23 (m, 4H), 7.11-7.95 (m, 1H), 6.85-6.71 (m, 2H) ), 5.32-5.10 (m, 1H), 4.18-3.96 (m, 1H), 3.59-3.48 (m, 0.2H), 3.13-2.97 (m, 0.8H), 2.63-2.54 (m, 2H), 2.32 -2.08 (m, 2H).

Reference example 8

a. t-Butyl-3-((3-fluoro-2-nitrophenyl) amino) azetidine-1-carboxylate
To a solution of 1,3-difluoro-2-nitrobenzene (3.0 g) in DMF (38 mL) was added t-butyl-3-aminoazetidine-1-carboxylate (3.90 g), and the mixture was stirred at room temperature for 92.5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to produce a crude product of t-butyl-3-((3-fluoro-2-nitrophenyl) amino) azetidine-1-carboxylate. 8.03g) was obtained.
ESI-MS m / z 310 [MH] ^-

b. t-Butyl-3-((4-bromo-3-fluoro-2-nitrophenyl) amino) azetidine-1-carboxylate
N-Bromosuccinimide (3.70) in a solution of t-butyl-3-((3-fluoro-2-nitrophenyl) amino) azetidine-1-carboxylate crude product (8.03 g) in DMF (47 mL) under ice-cooling. A solution of g) in DMF (49 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to t-butyl-3-((4-bromo-3-fluoro-2-nitrophenyl) amino) azetidine-1-carboxylate. A crude product (8.43 g) was obtained.
ESI-MS m / z 388 [MH] ^-

c. t-Butyl-3-((4-bromo-2-nitro-3-phenoxyphenyl) amino) azetidine-1-carboxylate
Cesium carbonate (2.67 g) in a solution of t-butyl-3-((4-bromo-3-fluoro-2-nitrophenyl) amino) azetidine-1-carboxylate crude product (2.45 g) in DMF (22 mL). And phenol (565 mg) were added, and the mixture was heated and stirred at 80 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to t-butyl-3-((4-bromo-2-nitro-3-phenoxyphenyl) amino) azetidine-1-carboxylate. A crude product (2.56 g) was obtained.
ESI-MS m / z 462 [MH] ^-

d. t-Butyl-3-((2-amino-4-bromo-3-phenoxyphenyl) amino) azetidine-1-carboxylate
Mixing ethanol (10.8 mL) and water (5.4 mL) of t-butyl-3-((4-bromo-2-nitro-3-phenoxyphenyl) amino) azetidine-1-carboxylate crude product (2.5 g) Iron powder (1.5 g) and ammonium chloride (2.8 g) were added to the solution, and the mixture was heated and stirred at 140 ° C. for 20 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, filtered, and then the insoluble material was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give t-butyl-3-((2-amino-4-bromo-3-phenoxyphenyl) amino) azetidine-1-carboxylate (4.05 g).
ESI-MS m / z 432 [MH] ^-

e. t-Butyl-3- (5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl) azetidine-1-carboxylate
In a solution of t-butyl-3-((2-amino-4-bromo-3-phenoxyphenyl) amino) azetidine-1-carboxylate (1.85 g) in THF (15 mL), trimethyl orthoacetate (1.0 mL) and acetic acid (0.11 mL) was added, and the mixture was heated and stirred at 140 ° C. for 10 minutes in a microwave reactor. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to t-butyl-3- (5-bromo-2-methyl-4-phenoxy-1H-benzo [d] imidazol-1-yl). Azetidine-1-carboxylate (0.87 g) was obtained.
ESI-MS m / z 458 [M + H] ⁺

Test Example 1: Evaluation of bromodomain binding inhibitory activity (protein)
In the following test examples, BRD4 represents bromodomain protein 4, BD1 represents the first bromodomain, and BD2 represents the second bromodomain.

The compounds of the examples were evaluated for their inhibitory activity on the binding of each bromodomain (BD1 or BD2) of human BRD4 to histone H4 using a time-divided fluorescence resonance energy transfer (TR-FRET) assay.
In this evaluation, as a medium, 50 mM hydroxyethyl piperazine ethanesulfonic acid (HEPES) pH 7.5, 1 mM Tris (2-carboxyethyl) phosphine (TCEP), 0.069 mM polyoxyethylene 23 lauryl ether (Brij-35), 50. A buffer containing mM NaCl and 0.1 mg / mL bovine serum albumin (BSA) was used to give a final volume of 20 μL. In the evaluation of binding inhibitory activity to BD1, BRD4 (BD1) (49-170AA) (BPS Bioscience) with 6His tag added to the N-terminal of 4 nM as a reagent, 25 nM biotin-labeled tetraacetylated histone H4 peptide (H4Ac4) In addition, 0.2 nM lanthanide (Eu) chelate-labeled anti-6His antibody (Perkin Elmer) and 100 nM allophycocyanin-streptavidin (APC-SA) that bind to each were used. In the evaluation of binding inhibitory activity against BD2, BRD4 (BD2) (342-460AA) (BPS Bioscience) with a 6His tag added to the N-terminal of 15 nM as a reagent, 12.5 nM biotin-labeled tetraacetylated histone H4 peptide (H4Ac4) In addition, 0.2 nM lanthanide (Eu) chelate-labeled anti-6His antibody (Perkin Elmer) and 100 nM allophycocyanin-streptavidin (APC-SA) that bind to each were used.

After adding the above reagents to a white 384-well polystyrene plate, the compound was serially diluted to a final concentration of DMSO of 0.2% or less and added to the plate. The plate was sealed, incubated in the dark for 40 minutes at room temperature, and then detected with a plate reader (PerkinElmer EnVision, Ex340, Em615 / 665). IC ₅₀ calculations were performed using XLIFT software (LDBS) by fitting a curve of percent control activity to the log of inhibitor concentration.
The _IC50 for BD1 or BD2 of all the Examples compounds according to the present invention was 100 nM or less.

Test Example 2: Evaluation of intracellular bromodomain binding inhibitory activity For the compound of the example, NanoLuc (registered trademark) luciferase was labeled with an energy transfer donor, HaloTag (registered trademark) NanoBRET (registered trademark) 618 fluorescent Ligand (registered trademark). ) A bioluminescent resonance energy transfer (BRET) -based assay utilizing the protein (Promega) as an energy transfer acceptor was used to evaluate the inhibitory activity of human BRD4 and histon H4 on protein binding in living cells.

First, HEK293 cells (human fetal kidney cells) were seeded on a 10 cm dish. One day later, NanoLuc®-BRD4 (Full Length), HaloTag®-Histone H4 were added to Opti-MEM I reduced serum (Thermo Fisher Scientific) at a ratio of 1: 100, and FuGENE (Thermo Fisher Scientific) was added. The registered trademark) HD Transfection Reagent (Promega) was added and incubated for 10 minutes, which was then added to the cells. After another day, cells were stripped with trypsin-EDTA and seeded (16000 cells / well) on white 384-well polystyrene plates. After serially diluting the compound so that the final concentration of DMSO is 0.1% or less, adding to the same plate, and culturing in a 5% CO ₂ incubator for 20 to 24 hours, NanoBRET (trade name) Nano-Glo (registered trademark) Substrate ( (Promega) was added and read with a plate reader (PerkinElmer EnVision, Donor Em460, Acceptor Em618). The ratio of Em 618 nm / Em 460 nm was taken as the binding activity. IC ₅₀ calculations were performed using XLIFT software (LDBS) by fitting a curve of percent control activity to the log of inhibitor concentration.

Examples 9, 13, 15, 16, 17, 18, 20, 22, 35, 37, 39, 40, 41, 45, 47, 48, 56, 57, 60, 61, 63, 64, 72, 74, 77, 80, 82, 83, 85, 87, 88, 93, 95, 96, 97, 99, 102, 104, 118, 122, 123, 125, 133b, 135, 139, 143, 149, 150, 151, The _IC50 of the compounds of the present invention of 153 and 155 was 1000 nM or less.

Test Example 3: Evaluation of inhibition of mouse LPS (lipopolysaccharide) -induced IL-6 production
The compounds of the present invention of Examples 9, 139 and 151 were evaluated for inhibition of LPS (lipopolysaccharide) -induced IL-6 production in mice.
BALB / cAnNCrlCrlj mice (male, Nippon Charles River, 6 animals per group) were orally administered with the compound suspended in a medium (0.5% methylcellulose aqueous solution) or only the medium, and 1 hour later, the mice were treated with the same mice. Intraperitoneal loading of lipopolysaccharide (LPS) was performed (1.25 mg / kg, E. coli 0111: B4). Two hours after LPS loading, partial blood sampling was performed from the orbital venous plexus under anesthesia, and the collected blood was centrifuged to collect plasma. The recovered plasma was frozen at -80 ° C.

Next, the IL-6 concentration in plasma was measured by ELISA. Plasma samples were returned to room temperature and then measured according to the manufacturer's protocol for the ELISA kit (DuoSet Mouse IL-6 / R & D systems). Absorbance values were read with a Spectra Max 250 (Molecular Device) device. Statistical analysis uses Dunnett's Comparison Multiple Test to compare the IL-6 mean and standard deviation of the vehicle-treated group with the IL-6 mean and standard deviation of the compound-treated group using EXSUS (CAC). gone. A p-value <0.001 means that the probability of accidental differences between groups is less than 0.1%.
The results are shown in FIG. In the vehicle group, IL-6 production was significantly increased as compared with the control group (LPS unloaded group). The compound-administered group significantly suppressed IL-6 production as compared with the vehicle group.

The compound of the present invention is useful, for example, for treating a disease involving a BET protein (eg, cancer, non-cancerous proliferative disease, fibrous disease, inflammatory disease, or viral infection). ..

Claims (16)

A compound represented by the following general formula (1) or a salt thereof.

(During the ceremony,
R ¹ represents H, lower alkyl, halogen, or cyano.
R ² represents H, or lower alkyl.
R ³ represents an aryl that may be substituted or an arylalkyl that may be substituted, or a heteroaryl that may be substituted or a heteroarylalkyl that may be substituted.
^R4 represents H, a lower alkyl which may be substituted, an oxo, an aryl which may be substituted, a heterocyclic group which may be substituted, and a cycloalkyl which may be substituted.
X ¹ is C or N,
If X ¹ is C, one of X ² and X ³ is N and the other is N-R ⁵ , O, or S, or one of X ² and X ³ is N-R ⁵ . The other is N-R ⁶ or C-R ⁷ .
When X ¹ is N, one of X ² and X ³ is N and the other is CH, or both X ² and X ³ are N.
R ⁵ and R ⁶ are the same or different and represent H, a lower alkyl which may be substituted, a heterocyclic group which may be substituted, cyano, or a cycloalkyl which may be substituted.
R ⁷ represents H, or a lower acyl.
The two solid and dotted lines represent single or double bonds, depending on X ¹ , X ² , X ³ and R ⁴ and adjacent carbon atoms. ) X ¹ is C and one of X ² and X ³ is N and the other is N-R ⁵ , or X ¹ is N and one of X ² and X ³ is N. The compound according to claim 1, or a salt thereof, wherein the other is CH. The compound according to claim 1 or 2, or a salt thereof, wherein R ¹ is H or a lower alkyl and R ² is a lower alkyl. The compound according to any one of claims 1 to 3, or a salt thereof, wherein R ⁴ is a lower alkyl which may be substituted, or a heterocyclic group which may be substituted. X ¹ is C, X ² is N, and X ³ is NH, or X ¹ is N, X ² is CH, and X ³ is N, R ¹ is H or a lower alkyl, R. ² is a lower alkyl, R ³ is an optionally substituted aryl, R ⁴ may be substituted lower alkyl, optionally substituted heterocycloalkyl, or optionally substituted hetero. The compound according to any one of claims 1 to 4, which is aryl, or a salt thereof. X ¹ is C, X ² is N, and X ³ is NH, or X ¹ is N, X ² is CH, and X ³ is N, R ¹ is H or a lower alkyl, R. One of claims 1 to 5, wherein ² is a lower alkyl, R ³ is optionally substituted phenyl, and R ⁴ is methyl, tetrahydropyranyl, or optionally substituted pyrazolyl. The compound described in the above, or a salt thereof. The compound according to any of the following (1) to (155), or a salt thereof.
(1) 3-Methyl-5- (2-Methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (2) 3-Methyl-5- (2-) (1-Methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (3) 3-methyl-5- (4-) Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (4) 5- (2-methyl-4-phenoxy-) 1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (5) 5- (2- (1-methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [ d] Imidazole-5-yl) Pylidin-2 (1H) -on (6) 5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5- Ill) Pylidyl-2 (1H) -on (7) 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -on (8) ) 1-Methyl-5-(2- (1-Methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (9) ) 1-Methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (10) 1 , 3-Dimethyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (11) 1,3-dimethyl-5- (2-) (1-Methyl-1H-pyrazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (12) 1,3-dimethyl-5-( 4-Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (13) 5- (2-chloro Phenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (14) 5- (4- ( 3-Chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) -1-methylpyridine-2 (1H) -one (15) 5- (4- (4-chlorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d ] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one (16) 5- (4- (2-fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (17) 5- (4- (3-fluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (18) 5- (4- (4-fluorophenoxy) -2- (tetrahydro-2H-pyran-4) -Il) -1H-benzo [d] imidazole-5-yl) -1-methylpyran-2 (1H) -one (19) 5- (4- (2,6-difluorophenoxy) -2- (tetrahydro-) 2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (20) 5- (4- (3,5-difluorophenoxy)- 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (21) 5- (4- (3,4) -Difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (22) 5- (4) -(2,4-Difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (23) ) 5- (4- (2,3-Difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) )-On (24) 5- (4- (2,5-difluorophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methyl Ppyridine-2 (1H) -on (25) 5- (4- (2-methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl)- 1-Methylpyran-2 (1H) -on (26) 5- (4- (3-me) Toxiphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (27) 5- (4-yl) (4-methoxyphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (28) N- (2-((5- (1-Methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4 -Il) oxy) phenyl) acetamide (29) N-(3-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4) -Il) -1H-benzo [d] imidazole-4-yl) oxy) phenyl) acetamide (30) N-(4-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3-) Il) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) phenyl) acetamide (31) 1-methyl-5- (2- (tetrahydro-2H) -Pyran-4-yl) -4- (2- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -one (32) 1-methyl-5- (2- (Tetrahydro-2H-pyran-4-yl) -4-(3- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -one (33) ) 1-Methyl-5-(2- (Tetrahydro-2H-pyran-4-yl) -4- (4- (trifluoromethyl) phenoxy) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -on (34) 2-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazole-4-yl) oxy) benzonitrile (35) 2-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-) 2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (36) 3-((5- (1-methyl-6-oxo-1,6-dihydropyridine-3) -Il) -2- (Tetrahydro-2) H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (37) 3-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine) -3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (38) 4-((5- (1-methyl-) 6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) benzonitrile (39) 4- ((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) Il) Oxy) Benzonitrile (40) 5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl)- 1-Methylpyridine-2 (1H) -one (41) 5- (4- (2,6-dimethylphenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) -1,3-dimethylpyranid-2 (1H) -one (42) 1-methyl-5-(4-((2-methylpyran-4-yl) oxy) -2- (tetrahydro-2H) -Pyran-4-yl) -1H-benzo [d] imidazole-5-yl) pyridine-2 (1H) -on (43) 5- (4-((5-chloropyridine-3-yl) oxy)- 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (44) 5- (4-((5-5-yl) Fluoropyridine-3-yl) Oxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (45) ) 5- (4-((5-Fluoropyridine-3-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1,3 -Dimethylpyran-2 (1H) -on (46) 5-((5- (1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-yl) -1-methyl-2- (tetrahydro-) 2H-pyran-4-yl) -1H-benzo [d] imidazole-4-yl) oxy) Nicotinonitrile (47) 1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((5- (trifluoromethyl) pyridin-3-yl) oxy) -1H -Benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (48) 1,3-dimethyl-5-(2- (tetrahydro-2H-pyran-4-yl) -4-((6) -(Trifluoromethyl) Pyridine-3-yl) Oxy) -1H-Benzo [d] Pyridine-5-yl) Pyridine-2 (1H) -On (49) 1,3-Dimethyl-5- (2-( Tetrahydro-2H-Pyran-4-yl) -4-((2- (Trifluoromethyl) Pyridine-4-yl) Oxy) -1H-Benzo [d] Pyridine-5-yl) Pyridine-2 (1H)- On (50) 1-methyl-5-(4-((1-oxo-1,3-dihydroisobenzofuran-5-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (51) 1-methyl-5-(4-((3-oxo-1,3-dihydroisobenzofuran-5-yl) oxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (52) 1-methyl-5- (4-((1) -Oxo-1,3-dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -On (53) 1-methyl-5-(4-((3-oxo-1,3-dihydroisobenzofuran-4-yl) oxy) -2- (tetrahydro-2H-pyran-4-yl) -1H -Benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (54) 5- (4- (benzo [c] [1,2,5] oxadiazole-4-yloxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (55) 5- (4- (benzo [c] [ 1,2,5] Oxaziazole-5-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) )-On (56) 1-methyl-5- (4- (naphthalen-1-yloxy) -2- (tetrahydro-) 2H-Pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (57) 1-methyl-5- (4- (naphthalen-2-yloxy) -2 -(Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (58) 1-methyl-5- (4- (quinolin-8-) Iloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (59) 1-methyl-5- (4- (4- ( Kinolin-7-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (60) 5- (4- ( 2-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (61) 5-( 4- (3-bromophenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (62) 1-Methyl-5-(4- (2- (1-Methyl-1H-pyrazole-4-yl) phenoxy) -2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-Il) Pyridine-2 (1H) -on (63) 5- (4- (2- (Fran-2-yl) phenoxy) -2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] Imidazole-5-yl) -1-methylpyridin-2 (1H) -one (64) 5- (4- (2- (fran-3-yl) phenoxy) -2- (tetrahydro-2H-pyran) -4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (65) 5- (4- (benzyloxy) -2- (tetrahydro-2H-) Piran-4-yl) -1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (66) 1-methyl-5- (4-phenetoxy-2- (tetrahydro-) 2H-Pyran-4-yl) -1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (67) 5- (4-((5-chloropyrimidine-4-yl) oxy) -2- (Tetrahydro-2H-pyridine-4-yl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridine-2 (1H) -one (68) 1-methyl-5- (4- (pyrimidine-4-yloxy) -2- (tetrahydro-2H-pyran-4-yl) -1H- Benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (69) 5- (4-((6-chloropyridazine-4-yl) oxy) -2- (tetrahydro-2H-pyran-4) -Il) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on (70) 5- (4-((5-chloropyrimidine-2-yl) oxy)- 2- (Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (71) 5- (4- (2,6) -Dimethylphenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (72) 5- (4- (2,6-dimethylphenoxy)- 2-Methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridine-2 (1H) -one (73) 5- (4- (4- (1H-pyrazol-1-yl)) Phenoxy) -2-methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridine-2 (1H) -one (74) 1,3-dimethyl-5- (2-methyl-4) -(2- (Oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (75) 1,3-dimethyl-5- (2-methyl- 4- (3- (Oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (76) 1,3-dimethyl-5- (2-methyl) -4- (4- (Oxetane-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (77) 5- (4- (3-cyclopropylphenoxy) )-2-Methyl-1H-benzo [d] imidazol-5-yl) -1,3-dimethylpyridine-2 (1H) -one (78) 1,3-dimethyl-5- (2-methyl-4-yl) (3- (1-Methyl-1H-pyrazol-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (79) 1,3-dimethyl-5- (2-Methyl-4- (3- (1-Methyl-1H-pyrazol-5-yl) phenoxy) -1H-benzo [d] imidazole Lu-5-yl) pyridine-2 (1H) -one (80) 1,3-dimethyl-5- (2-methyl-4-(3- (1-methyl-1H-pyrazol-3-yl) phenoxy) ) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (81) 1,3-dimethyl-5- (2-methyl-4- (3- (tetrahydro-2H-pyran-)- 4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (82) 5- (4- (4-cyclopropylphenoxy) -2-methyl-1H-benzo [d] Imidazole-5-yl) -1,3-dimethylpyridine-2 (1H) -one (83) 1,3-dimethyl-5- (2-methyl-4- (4- (1-methyl-1H) -Pyrazole-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (84) 1,3-dimethyl-5- (2-methyl-4- (4) -(1-Methyl-1H-pyrazol-5-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (85) 1,3-dimethyl-5- (2) -Methyl-4- (4- (1-methyl-1H-pyrazol-3-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (86) 1,3 -Dimethyl-5- (2-methyl-4- (4- (tetrahydro-2H-pyran-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one ( 87) 1,3-Dimethyl-5-(2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl) phenoxy) -1H-benzo [d] imidazol-5-yl) pyridine- 2 (1H) -one (88) 1,3-dimethyl-5-(2-methyl-4-(2-(1-methyl-1H-pyrazol-3-yl) phenoxy) -1H-benzo [d] imidazole) -5-yl) pyridine-2 (1H) -on (89) 5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1,3-dihydro-2H- Benzo [d] imidazol-2-one (90) 1-methyl-5- (2- (oxetane-3-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) )-On (91) 1-methyl-5- (4-phenoxy-2- (tetratetra-3-yl) -1H-benzo [d] Imidazole-5-yl) Pylidin-2 (1H) -one (92) 1-methyl-5- (2- (oxepan-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pylin-2 (1H) -one (93) 5- (2- (2-methoxycyclopropyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -On (94) 5- (2- (3-Hydroxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -on (95) 1 -Methyl-5-(2- (3-oxocyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (96) 5- (2- (3) -Methoxycyclobutyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (97) 1-methyl-5- (4-phenoxy-2-) (7-oxaspiro [3,5] nonan-2-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (98) 5- (2-cyclohexyl-4-phenoxy-) 1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (99) 5- (2- (4,4-difluorocyclohexyl) -4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) -1-methylpyridine-2 (1H) -one (100) 5- (2-cycloheptyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methyl Pyridine-2 (1H) -one (101) 1-methyl-5- (4-phenoxy-2-phenyl-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (102) 1 -Methyl-5-(4-phenoxy-2-((tetrahydro-2H-pyran-4-yl) methyl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (103) 1-Methyl-5-(2- (morpholinomethyl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (104) 1-methyl-5- (4-) Phenoxy-2- (4-phenyltetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (105) 5- (2- (4-yl) Ethoxytetrahydro-2H- Pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (106) 5- (2- (4-hydroxytetrahydro-2H) -Pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (107) 5- (2- (4-fluorotetrahydro-) 2H-Pyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridine-2 (1H) -one (108) 1-methyl-5- (2- (2- ( 2-Methylpyridine-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (109) 1-methyl-5- (2- (1-methyl) Piperidine-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -on (110) 5,5'-(4-phenoxy-1H-benzo [d] Imidazole-2,5-diyl) bis (1-methylpyridine-2 (1H) -on)
(111) 1,3-dimethyl-5-(2- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) Pyridine-2 (1H) -one (112) 1,3-dimethyl-5- (5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [ d] Imidazole-2-yl) Pyridine-2 (1H) -on (113) 5,5'-(4-phenoxy-1H-benzo [d] imidazol-2,5-diyl) bis (1,3-dimethyl) Pyridine-2 (1H) -on)
(114) 5- (2- (1,1-Dioxidetetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 ( 1H) -on (115) 5- (2- (1,1-dioxidetetrahydro-2H-thiopyran-4-yl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) -1,3 -Dimethylpyridin-2 (1H) -one (116) 5- (1,2-dimethyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (117) 5- (1-Cyclopropyl-2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1-methylpyridin-2 (1H) -one (118) t-butyl- 3- (5- (1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-1-yl) azetidine-1 -Carboxylate (119) 5- (1- (azetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1,3-dimethylpyridin-2 (1H) )-On (120) 5- (1- (1-Acetylazetidine-3-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1,3-dimethylpyridine -2 (1H) -on (121) 5- (1-isopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl) -1- Methylpyridin-2 (1H) -on (122) 5- (1-ethyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5-yl)- 1-Methylpyridin-2 (1H) -one (123) 5- (1-cyclopropyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5- Il) -1-methylpyridin-2 (1H) -one (124) 5- (1-cyclobutyl-4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole- 5-yl) -1-methylpyridin-2 (1H) -one (125) 5- (1-methyl-6-oxo-1,6-dihydropyridin-3-yl) -4-phenoxy-2- (tetrahydro-) 2H-Pyridine N-4-yl) -1H-benzo [d] imidazol-1-carbonitrile (126) 1-methyl-5- (2-methyl-1- (1-methyl-1H-pyrazol-4-yl) -4 -Phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (127) 1-methyl-5- (1- (1-methyl-1H-pyrazol-4-yl) -4) -Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (128) 1-methyl-5- (2-methyl) -1- (1-Methyl-1H-imidazol-4-yl) -4-phenoxy-1H-benzo [d] imidazol-5-yl) pyridine-2 (1H) -one (129) 5- (1- ( 2,4-dimethyloxazol-5-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1-methylpyridine-2 (1H) -one (130) 1,3 -Dimethyl-5- (2-methyl-5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-1-yl) pyridine- 2 (1H) -on (131) 5- (1- (3,5-dimethylisooxazol-4-yl) -2-methyl-4-phenoxy-1H-benzo [d] imidazol-5-yl) -1 -Methylpyridine-2 (1H) -one (132) 1-methyl-5- (2-methyl-1-((3-methylisooxazol-5-yl) methyl) -4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) pyridine-2 (1H) -one (133a) 2- (6- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) -7-phenoxy-2- ( Tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-1-yl) acetonitrile (133b) 2- (5- (1-methyl-6-oxo-1,6-dihydropyridine-3-yl) ) -4-Phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazol-1-yl) acetonitrile (134) 2- (2-methyl-5- (1-methyl-) 6-oxo-1,6-dihydropyridine-3-yl) -4-phenoxy-1H-benzo [d] imidazol-1-yl) acetonitrile (135) 2- (5- (1,5-dimethyl-6-oxo) -1,6-dihydropyridine-3 -Il) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-1-yl) acetonitrile (136a) 5- (1- (2-methoxyethyl) -2-methyl-7-phenoxy-1H- Benzo [d] imidazole-6-yl) -1-methylpyridin-2 (1H) -one (136b) 5- (1- (2-methoxyethyl) -2-methyl-4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) -1-methylpyridin-2 (1H) -one (137) 5- (1-((2-methoxyethoxy) methyl) -2-methyl-4-phenoxy-1H-benzo [d] ] Imidazole-5-yl) -1-methylpyridin-2 (1H) -one (138) 5- (1- (methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5- Il) -1-methylpyridin-2 (1H) -one (139) 5- (1- (methoxymethyl) -2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -1, 3-Dimethylpyridin-2 (1H) -one (140a) 1-methyl-5- (2-methyl-1- (2-morpholinoethyl) -7-phenoxy-1H-benzo [d] imidazole-6-yl) Pyridine-2 (1H) -one (140b) 1-methyl-5- (2-methyl-1- (2-morpholinoethyl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) Pyridine-2 (1H) -one (141) 1-methyl-5- (2-methyl-1- (3-morpholinopropyl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) pyridin-2 (1H) -On (142) 1-methyl-5- (2-methyl-1-((1-methyl-1H-pyrazole-4-yl) methyl) -4-phenoxy-1H-benzo [d] imidazole-5-yl) ) Pyridine-2 (1H) -one (143) 3-bromo-1-methyl-5- (4-phenoxy-2- (tetrahydro-2H-pyran-4-yl) -1H-benzo [d] imidazole-5 -Il) Pyridine-2 (1H) -on (144) 1-methyl-5- (2-methyl-4-phenoxy-1H-benzo [d] imidazole-5-yl) -2-oxo-1,2- Dihydropyridin-3-carbonitrile (145) 1,3-dimethyl-5- (2-methyl-4-phenoxybenzo [d] oxazol-5-yl) Pyridine-2 (1H) -one (146) 1-methyl- 5- (2-me Chill-4-phenoxybenzo [d] thiazole-5-yl) Pyridine-2 (1H) -one (147) 1,3-dimethyl-5- (2-methyl-4-phenoxybenzo [d] thiazole-5- Pyridine-2 (1H) -one (148) 1-methyl-5- (2-methyl-7-phenoxybenzo [d] thiazole-6-yl) Pyridine-2 (1H) -one (149) 5- (3-Acetyl-7-Phenoxy-1H-Indol-6-yl) -1-Methylpyridin-2 (1H) -On (150) 5- (3-Acetyl-7-Phenoxy-1H-Indol-6-yl) ) -1,3-Dimethylpyridin-2 (1H) -one (151) 1,3-dimethyl-5- (5-phenoxy-2- (tetrahydro-2H-pyran-4-yl) imidazo [1,2- a] Pyridine-6-yl) Pyridine-2 (1H) -on (152) 1-methyl-5- (2-methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridine -6-yl) Pyridine-2 (1H) -one (153) 1,3-dimethyl-5- (2-methyl-5-phenoxy- [1,2,4] triazolo [1,5-a] pyridin- 6-Il) Pyridine-2 (1H) -On (154) 1-Methyl-5- (5-Phenoxy-2- (Tetrahydro-2H-Pyran-4-yl)-[1,2,4] Triazolo [1 , 5-a] Pyridine-6-yl) Pyridine-2 (1H) -one (155) 1,3-dimethyl-5- (5-phenoxy-2- (tetrahydro-2H-pyran-4-yl)-[ 1,2,4] Triazolo [1,5-a] Pyridine-6-yl) Pyridine-2 (1H) -On A pharmaceutical composition containing the compound according to any one of claims 1 to 7 or a salt thereof as an active ingredient. A pharmaceutical composition containing the compound according to any one of claims 1 to 7 or a salt thereof, and other drugs as active ingredients. A pharmaceutical composition used in combination with another drug, which comprises the compound according to any one of claims 1 to 7 or a salt thereof as an active ingredient. The pharmaceutical composition according to any one of claims 8 to 10, for inhibiting the BET protein. The pharmaceutical composition according to claim 11, wherein the BET protein is selected from the group consisting of BRD2, BRD3, BRD4, and BRDT at least one. The pharmaceutical composition according to any one of claims 8 to 10, for treating a cancer, a non-cancerous proliferative disease, a fibrous disease, an inflammatory disease, or a viral infection. A cancer or non-cancerous proliferative disease comprising a means for administering the pharmaceutical composition according to any one of claims 8 to 10 in vivo and a means capable of performing medical therapy. Treatment system. The treatment system according to claim 14, wherein the medical therapy is γ-ray irradiation, neutron beam irradiation therapy, electron beam irradiation therapy, proton beam therapy, proximity irradiation therapy, or radiation therapy. A cancer, a non-cancerous proliferative disease, a fibrous disease, or an inflammatory disease, which comprises a step of administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 8 to 10 in vivo. How to treat a disease or viral infection.

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