Method for producing imidazopyridinone compounds

Abstract

To provide a novel production method of an imidazopyridinone compound useful as a treatment agent for inflammatory bowel diseases (IBDs).SOLUTION: The present disclosure provides a method for the synthesis of, for example, an imidazopyridinone compound shown below. The method includes a process of introducing a desired substituent into the 1st-position of 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine, having an N-protected 3-pyrrolidino group at the 3rd-position; then deprotecting a 3rd-position substituent; and further introducing a desired substituent into N of the pyrrolidino group.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing an imidazopyridinone compound useful as a pharmaceutical. More specifically, the present invention relates to a method for producing an imidazopyridinone compound or a pharmacologically acceptable salt thereof that has an inhibitory effect on prolyl hydroxylase and is useful as a therapeutic agent for inflammatory bowel diseases such as ulcerative colitis. [Background technology]

[0002] Inflammatory bowel disease (IBD) is a chronic disease in which inflammation and ulcers occur in the intestinal mucosa due to an immune hyperresponse. IBD includes, for example, ulcerative colitis and Crohn's disease. Ulcerative colitis is a disease of the large intestine that causes diffuse nonspecific inflammation of unknown cause. The mucous membrane of the large intestine is invaded, and erosions or ulcers may form in the mucous membrane. Ulcerative colitis can be divided into an "active stage" in which bloody stools, erosions, ulcers, etc. are observed, and a "remission stage" in which the symptoms of the active stage disappear. Since relapses and remissions often occur repeatedly during the course of the disease, long-term treatment is required. 5-aminosalicylic acid preparations (5-ASA) are used as the standard drug for the treatment of ulcerative colitis. However, the efficacy of 5-ASA is about 50-65%, and only about 30-45% of patients achieve remission with the administration of 5-ASA. When 5-ASA is ineffective, steroids are used. In addition to these drugs, immunosuppressants, anti-TNFα antibodies, etc. may be used to treat ulcerative colitis. However, all of these drugs have issues such as side effects and the need for careful administration, and there is a demand for therapeutic agents for ulcerative colitis with new mechanisms of action.

[0003] In the pathology of IBD, it is known that hypoxia-inducible factor 1α (HIF-1α) induces the expression of genes related to the barrier function of the gastrointestinal epithelium. HIF-1α is one of the subtypes of hypoxia-inducible factor α (HIF-α). HIF-α is stabilized in a hypoxic environment (hypoxia) and activates the transcription of various genes in response to hypoxia. On the other hand, in an oxygen-rich environment (normoxia), the proline residues of HIF-α are hydroxylated by prolyl hydroxylases (PHDs), and the HIF-α is degraded by the proteasome.

[0004] PHDs are known to have three subtypes: PHD1, PHD2, and PHD3. AKB-4924 is known as a PHD2 inhibitor, and it has been reported that AKB-4924 stabilizes HIF-1α in colonic tissue (Non-Patent Document 1). Furthermore, AKB-4924 has been shown to have an improving effect in a trinitrobenzene sulfonic acid (TNBS)-induced colitis model. On the other hand, PHDs inhibitors such as Roxadustat and Daprodustat have hematopoietic effects and have been developed as therapeutic agents for anemia (Non-Patent Document 2). Therefore, when using PHDs inhibitors as therapeutic agents for IBD, it is important to distinguish them from systemic effects such as hematopoietic effects.

[0005] As PHDs inhibitors, for example, spiro compounds are described in Patent Documents 1 and 5, and Non-Patent Documents 3 and 4. In addition, compounds containing imidazopyridinone are described or exemplified in Patent Documents 2 to 4. However, the imidazopyridinone compound of the present invention is neither described nor suggested in the above documents. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. 2011 / 0152304 [Patent Document 2] International Publication No. 2009 / 029609 [Patent Document 3] International Publication No. 2003 / 037890 [Patent Document 4] International Publication No. 2017 / 066014 [Patent Document 5] US Patent Application Publication No. 2010 / 0137297 [Non-patent literature]

[0007] [Non-Patent Document 1] Ellen Marks et al., Inflamm. Bowel. Dis., 2015, Vol. 21, No. 2, pp. 267-275 [Non-Patent Document 2] Mun Chiang Chan et al., Molecular Aspects of Medicine, 2016, Vol. 47-48, pp. 54-75 [Non-Patent Document 3] Guanghui Deng et al., Bioorganic & Medicinal Chemistry, 2013, Vol. 21, pp. 6349-6358 [Non-Patent Document 4] Petr Vachal et al., Journal of Medicinal Chemistry, 2012, Vol. 55, pp. 2945-2959 Summary of the Invention [Problem to be solved by the invention]

[0008] An objective of the present invention is to provide a method for producing an imidazopyridinone compound which has a PHD2 inhibitory effect and is useful for treating inflammatory bowel disease. [Means for solving the problem]

[0009] The present invention relates to a method for producing a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof. That is, the present invention relates to the following [1] to

[17] , etc. [1] A compound represented by formula (I): [ka] [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; Ring Z is a group selected from the group consisting of the following (a) to (c): [ka] and [ka] (In the formula, R a , R b and R c are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy, or carboxy; R d is a hydrogen atom or C 1-6 is alkyl); R 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R 1 may be different from each other); R 2 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, -CO2R 4 , or -CONR 5 R 5’ (When n is 2 or 3, 2 or more R 2 may be different from each other); R 4 is a hydrogen atom or C 1-6 is alkyl; R 5 and R 5’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; R 3 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, hydroxy, cyano, nitro, -NR 6 R 6’ , -CO2R 7 , -CONR 8 R 8’ or a group A below (wherein when u is 2 or 3, there are two or more R 3 may be different from each other); R 6 and R 6’ are each independently a hydrogen atom or C 1-6 is alkyl; R 7 is a hydrogen atom or C 1-6 is alkyl; R 8 and R 8’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group A is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; The substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy, cyano, -NR 9 R 9’ , -NR 9 SO2R 10 , -CO2R 10 , and -CONR 11 R 11’ The group consisting of: R 9 and R 9’ are each independently a hydrogen atom or C 1-6 is alkyl; R 10 is a hydrogen atom or C 1-6 is alkyl; R 11 and R 11’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; m, n, and u are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof, Formula (II): [ka] wherein m, n, p and q are as defined above; R 1R is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group (when m is 2 or 3, two or more R 1R may be different from each other); R 2R is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy which may be protected by a protecting group, -COR 4R , or -CONR 5R R 5R’ (When n is 2 or 3, 2 or more R 2R may be different from each other); R 4R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; R X is a hydrogen atom or a group represented by formula (III): [ka] (Wherein, rings W, u and r are as defined above; R 3R is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, optionally protected hydroxy, cyano, nitro, -NR 6R R 6R’ , -CO2R 7R , -CONR 8R R 8R’ or the following group AA (wherein when u is 2 or 3, two or more R 3R may be different from each other); R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) unsubstituted or 3-8 membered heterocycloalkyl substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, optionally protected hydroxy, cyano, -NR 9R R 9R’ , -NR 9R SO2R 10R , -CO2R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; and R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxy C 1-6 Alkyl, haloC1-6 Alkyl, C 3-8 or a salt thereof, Formula (IV): [ka] [In the formula, ring ZZ is a group selected from the group consisting of the following (a) to (c): [ka] and [ka] (In the formula, R A , R B and R C are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group; R D is a protecting group, a hydrogen atom, or C 1-6 or a salt thereof, Formula (V): [ka] [In the formula, ring ZZ, R 1R , R 2R , R X , m, n, p and q are as defined above] or a salt thereof. [2] The manufacturing method according to [1] above, Formula (IIA): [ka] [In the formula, R 1R , R 2R , R 3R , ring W, m, n, p, q, r and u have the same meanings as in [1] above. or a salt thereof; Using the compound represented by formula (IV) or a salt thereof, Formula (VA): [ka] [In the formula, ring W, ring ZZ, R 1R , R 2R , R 3R , m, n, p, q, r and u have the same meanings as in the above-mentioned [1], or a salt thereof. [3] The manufacturing method according to [1], Formula (IIB): [ka] [In the formula, R 1R , R 2R , m, n, p and q have the same meanings as in [1] above. or a salt thereof; Using the compound represented by formula (IV) or a salt thereof, Formula (VB): [ka] [In the formula, ring ZZ, R 1R , R 2R , m, n, p and q are as defined above in [1], or a salt thereof. [4] Formula (I): [ka] [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; Ring Z is a group selected from the group consisting of the following (a) to (c): [ka] and [ka] (In the formula, R a , R b and R c are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy, or carboxy; R d is a hydrogen atom or C 1-6 is alkyl); R 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R 1 may be different from each other); R 2 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, -CO2R 4 , or -CONR 5 R 5’ (When n is 2 or 3, 2 or more R 2 may be different from each other); R 4 is a hydrogen atom or C 1-6 is alkyl; R 5 and R 5’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; R 3 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, hydroxy, cyano, nitro, -NR 6 R 6’ , -CO2R 7 , -CONR 8 R 8’ or a group A below (wherein when u is 2 or 3, there are two or more R 3 may be different from each other); R 6 and R 6’ are each independently a hydrogen atom or C 1-6 is alkyl; R 7 is a hydrogen atom or C 1-6 is alkyl; R 8 and R 8’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group A is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; The substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy, cyano, -NR 9 R 9’ , -NR 9 SO2R 10 , -CO2R 10 , and -CONR 11 R 11’ The group consisting of: R 9 and R 9’ are each independently a hydrogen atom or C 1-6 is alkyl; R 10 is a hydrogen atom or C 1-6 is alkyl; R 11 and R 11’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; m, n, and u are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof, Formula (IIC): [ka] [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; R 1R is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group (when m is 2 or 3, two or more R 1R may be different from each other); R 2R is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy which may be protected by a protecting group, -COR 4R , or -CONR 5R R 5R’ (When n is 2 or 3, 2 or more R 2R may be different from each other); R 4R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; R 3RA is a halogen atom or a group AA; R 3RB and R 3RC are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, optionally protected hydroxy, cyano, nitro, -NR 6R R 6R’ , -CO2R 7R , -CONR 8R R 8R’ or the group AA: R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, optionally protected hydroxy, cyano, -NR 9R R 9R’ , -NR 9R SO2R 10R , -CO2R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; and R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; m and n are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and r is an integer from 0 to 6. or a salt thereof. [5] Formula (I): [ka] [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; Ring Z is a group selected from the group consisting of the following (a) to (c): [ka] and [ka] (In the formula, R a , R b and R c are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy, or carboxy; R d is a hydrogen atom or C 1-6 is alkyl); R 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R 1 may be different from each other); R 2 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, Hydroxy, -CO2R 4 , or -CONR 5 R 5’ (When n is 2 or 3, 2 or more R 2 may be different from each other); R 4 is a hydrogen atom or C 1-6 is alkyl; R 5 and R 5’ are each independently a hydrogen atom, C 1-6Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; R 3 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, hydroxy, cyano, nitro, -NR 6 R 6’ , -CO2R 7 , -CONR 8 R 8’ or a group A below (wherein when u is 2 or 3, there are two or more R 3 may be different from each other); R 6 and R 6’ are each independently a hydrogen atom or C 1-6 is alkyl; R 7 is a hydrogen atom or C 1-6 is alkyl; R 8 and R 8’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group A is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; Substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy, cyano, -NR 9 R 9’ , -NR 9 SO2R 10 , -CO2R 10 , and -CONR 11 R 11’ The group consisting of: R 9 and R 9’ are each independently a hydrogen atom or C 1-6 is alkyl; R 10 is a hydrogen atom or C 1-6 is alkyl; R 11 and R 11’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; m, n, and u are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof, Formula (VC): [ka] [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; Ring ZZ is a group selected from the group consisting of the following (a) to (c): [ka] and [ka] (In the formula, R A , R B and R C are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group; R D is a protecting group, a hydrogen atom, or C 1-6 alkyl); R 1R is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group (when m is 2 or 3, two or more R 1R may be different from each other); R 2R is a hydrogen atom, a halogen atom, C 1-6Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy which may be protected by a protecting group, -COR 4R , or -CONR 5R R 5R’ (When n is 2 or 3, 2 or more R 2R may be different from each other); R 4R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; R 3RA is a halogen atom or a group AA; R 3RB and R 3RC are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, optionally protected hydroxy, cyano, nitro, -NR 6R R 6R’ , -CO2R 7R , -CONR 8R R 8R’ or the group AA: R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7Ris a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, optionally protected hydroxy, cyano, -NR9R R 9R’ , -NR 9R SO2R 10R , -CO2R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; and R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; m and n are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and r is an integer from 0 to 6. or a salt thereof. [6] The manufacturing method according to any one of [1] to [5], Ring Z is one of the following (a) to (j): [ka] and [ka] is a group selected from the group consisting of: Ring ZZ is a group selected from the group consisting of the following (aa) to (jj): [ka] and [ka] (wherein PG is a hydrogen atom or a protecting group). The method for producing the compound according to claim 1, wherein the compound is a group selected from the group consisting of [7] The method according to any one of [1] to [6] above, wherein ring W is phenyl, or a 5- or 6-membered heteroaryl. [8] The method for producing the compound according to any one of [1] to [7] above, wherein r is 0. [9] The method for producing any one of [1] to [8] above, wherein p is 2 and q is 1.

[10] R 1 and R 1R is a hydrogen atom or a halogen atom.

[11] The manufacturing method according to any one of [1] to

[10] , R 2 is a hydrogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, carboxy, or -CONR 5 R 5’ and; R 5 and R 5’ are each independently a hydrogen atom, a carboxy C 1-6 alkyl, or 3-8 membered heterocycloalkyl; R 2R is a hydrogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, carboxy which may be protected by a protecting group, or -CONR 5R R 5R’ and R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or a carboxy group C which may be protected by a protecting group 1-6 alkyl, or 3-8 membered heterocycloalkyl.

[12] The manufacturing method according to any one of [1] to

[11] , R3 is hydrogen atom, halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfonyl, hydroxy, cyano, -CO2R 7 , -CONR 8 R 8’ or a group A; R 8 and R 8’ are each independently a hydrogen atom or a carboxy C 1-6 is alkyl; Group A is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, or unsubstituted 5- or 6-membered heteroaryl; Substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 alkoxy, hydroxy, cyano, or carboxy; R 3R is hydrogen atom, halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfonyl, optionally protected hydroxy, cyano, -COR 7R , -CONR 8R R 8R’ or the group AA; R 7 , R 7R and u has the same meaning as in [1] above; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or a carboxy group C which may be protected by a protecting group; 1-6 is alkyl; The group AA is phenyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, or unsubstituted 5- or 6-membered heteroaryl; and The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 The compound is alkoxy, hydroxy which may be protected by a protecting group, cyano, or carboxy which may be protected by a protecting group.

[13] The manufacturing method according to any one of [1] to

[12] , Ring Z is one of the following (a) to (e): [ka] and [ka] is a group selected from the group consisting of: Ring ZZ is the following (aa) to (ee): [ka] and [ka] (wherein PG is a hydrogen atom or a protecting group). The method for producing the compound according to claim 1, wherein the compound is a group selected from the group consisting of

[14] The manufacturing method according to any one of [1] to

[11] , u is 2 or 3; One R 3 is group A; Other R 3 are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 1-6 Alkylsulfanyl, C 1-6Alkyl sulfonyl, hydroxy, cyano, nitro, -NR 6 R 6’ , -CO2R 7 , or -CONR 8 R 8’ and; One R 3R is the group AA; Other R 3R are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 1-6 Alkylsulfanyl, C 1-6 Alkyl sulfonyl, optionally protected hydroxy, cyano, nitro, -NR 6R R 6R’ , -CO2R 7R , or -CONR 8R R 8R’ and; Group A, R 6 , R 6’ , R 7 , R 8 , R 8’ , base AA, R 6R , R 6R’ , R 7R , R 8R and R 8R’ has the same meaning as in [1] above.

[15] Formula (IA): [ka] [During the ceremony, X is CR 3 or N; R 1 is a hydrogen atom or a halogen atom (when m is 2 or 3, two or more R 1 may be different from each other); R 2 is a hydrogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, carboxy, or -CONR5 R 5’ (When n is 2 or 3, 2 or more R 2 may be different from each other); R 5 and R 5’ are each independently a hydrogen atom, a carboxy C 1-6 alkyl, or 3-8 membered heterocycloalkyl; R 3 is a hydrogen atom, C 1-6 alkyl, or hydroxy (when u is 2, two R 3 may be different from each other); Group A is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B, or unsubstituted 5- or 6-membered heteroaryl; The substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 alkoxy, hydroxy, cyano, or carboxy; Ring Z is one of the following (a) to (e): [ka] and [ka] is a group selected from the group consisting of: m and n are each independently an integer from 1 to 3; and u is 1 or 2; or a pharmacologically acceptable salt thereof, Formula (IID): [ka] [In the formula, m and n are the same as defined in [1] above; R 1R is a hydrogen atom or a halogen atom (when m is 2 or 3, two or more R 1R may be different from each other); R 2Ris a hydrogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, carboxy which may be protected by a protecting group, or -CONR 5R R 5R’ (When n is 2 or 3, 2 or more R 2R may be different from each other); R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or a carboxy group C which may be protected by a protecting group 1-6 alkyl, or 3-8 membered heterocycloalkyl; and R Y is a hydrogen atom, formula (IIIA): [ka] Or, formula (IIIB): [ka] (Wherein, u is 1 or 2; X R CR 3R or N; R 3R is a hydrogen atom, C 1-6 alkyl, or hydroxyl optionally protected by a protecting group (when u is 2, two R 3R may be different from each other); L is a halogen atom; The group AA is phenyl, unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB, or unsubstituted 5- or 6-membered heteroaryl; and The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 or a salt thereof; Formula (IV): [ka] [In the formula, ring ZZ is a group selected from the group consisting of the following (aa) to (ee): [ka] and [ka] (wherein PG is a hydrogen atom or a protecting group). or a salt thereof, Formula (VD): [ka] [In the formula, ring ZZ, R 1R , R 2R , R Y , m and n are as defined above in

[15] ] or a salt thereof.

[16] Formula (IIC): [ka] [During the ceremony, R 3RA is a halogen atom or a group AA; R 3RB and R 3RC are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, optionally protected hydroxy, cyano, nitro, -NR 6R R 6R’ , -CO2R 7R , -CONR 8R R 8R’ or the group AA: R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) unsubstituted or 3-8 membered heterocycloalkyl substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, optionally protected hydroxy, cyano, -NR 9R R 9R’ , -NR 9R SO2R 10R , -CO2R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; and R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; Ring W, R 1R , R 2R , m, n, p, q and r are as defined above in [1], or a salt thereof.

[17] Formula (VC): [ka] [During the ceremony, R 3RA is a halogen atom or a group AA; R 3RB and R 3RC are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, optionally protected hydroxy, cyano, nitro, -NR 6R R 6R’ , -CO2R 7R , -CONR 8R R 8R’ or the group AA: R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) unsubstituted or 3-8 membered heterocycloalkyl substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, optionally protected hydroxy, cyano, -NR 9R R 9R’ , -NR 9R SO2R 10R , -CO2R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; and Ring W, Ring ZZ, R 1R , R 2R , m, n, p, q and r are as defined above in [1], or a salt thereof. Effect of the Invention

[0010] The present invention is useful as it provides a novel method for producing an imidazopyridinone compound represented by formula (I) or a pharmacologically acceptable salt thereof having excellent PHD2 inhibitory activity. Therefore, the imidazopyridinone compound or a pharmacologically acceptable salt thereof produced by the production method of the present invention is useful as a therapeutic agent for inflammatory bowel disease. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Hereinafter, the embodiments of the present invention will be described in more detail.

[0012] In the present invention, each term has the following meaning unless otherwise specified.

[0013] "Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. 1 , R 2 and R 3 As the group, a fluorine atom is preferable. "C 1-6 The term "alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. "C 2-6 The term "alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms. Examples include vinyl, allyl, 1-propenyl, and isopropenyl. "C 2-6 The term "alkynyl" refers to a straight or branched alkynyl group having 2 to 6 carbon atoms. Examples include ethynyl and 2-propynyl. "C 1-6 The term "alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, and isopropoxy.

[0014] "Carboxy C 1-6 "Alkyl" means a C substituted with one carboxy 1-6 It means alkyl, for example, carboxymethyl. "Hydroxy C 1-6 "Alkyl" means a C substituted with one hydroxyl group. 1-6 It means alkyl, for example, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, etc. "Haro C 1-6 "Alkyl" means a C alkyl group substituted with 1 to 3 identical or different halogen atoms. 1-6 Examples of the fluoroalkyl group include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl. "Haro C 1-6 "Alkoxy" means a C substituted with 1 to 3 identical or different halogen atoms. 1-6 Alkoxy means, for example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, etc.

[0015] "C 1-6 "Alkylsulfanyl" means (C 1-6 The term "alkyl" refers to a group represented by the formula: "C 1-6 "Alkylsulfinyl" means (C 1-6 The term "alkyl" refers to a group represented by the formula:-S(=O)-. "C 1-6 "Alkylsulfonyl" means (C 1-6 Sulfonyl is a group represented by the formula (alkyl)-SO2-. Examples thereof include methylsulfonyl and ethylsulfonyl.

[0016] "C 6-10 The term "aryl" means phenyl or naphthyl. As the group A and the group AA, phenyl is preferred. "5- or 6-membered heteroaryl" refers to a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms in the ring. For example, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. are mentioned. As ring W, thienyl, pyridyl, etc. are preferable, and pyridyl is more preferable. As group A and group AA, pyridyl, etc. are preferable. "9- or 10-membered heteroaryl" refers to a bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms in the ring. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, pryl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, pteridinyl, chromenyl, isochromenyl, etc. Ring W is preferably quinolyl, etc. "C 3-8 "Cycloalkyl" refers to a 3- to 8-membered saturated hydrocarbon group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "3- to 8-membered heterocycloalkyl" refers to a 3- to 8-membered heterocycloalkyl group containing one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples of the heterocycloalkyl group include aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, and tetrahydropyranyl. R 5 and R 5’ As the aryl group, tetrahydropyranyl and the like are preferable.

[0017] "C 6-10 Aryl C 1-6 "Alkyl" means one C 6-10 Aryl-substituted C 1-6 It means alkyl, for example benzyl. "C 6-10 "Aryloxy" means (C 6-10 aryl)-O-. For example, phenoxy is mentioned. "5- or 6-membered heteroaryl C 1-6 "Alkyl" refers to a C substituted with one 5- or 6-membered heteroaryl. 1-6 It means alkyl. The term "5- or 6-membered heteroaryloxy" refers to a group represented by (5- or 6-membered heteroaryl)-O-. When substituted with two or three groups selected from the substituent group B, each group may be the same or different. When substituted with two or three groups selected from the substituent group BB, each group may be the same or different.

[0018] "May be protected by a protecting group" means that hydroxy, amino, amide, or carboxy may be protected by a group commonly used as a protecting group, and any group may be used as long as it functions as a protecting group. Examples of the protecting group include the protecting groups described in "Greene's Protective Groups in Organic Synthesis", 4th Edition, edited by Theodra W. Greene & Peter GM Wuts, Wiley-Interscience, 2006, or "Greene's Protective Groups in Organic Synthesis", 5th Edition, Wiley-Interscience, 2014, edited by Peter GM Wuts.

[0019] The following abbreviations used in the text, figures and tables have the following meanings: CDI: Carbonyldiimidazole CPME: Cyclopentyl methyl ether DEAD: Diethyl azodicarboxylate DIPEA: N,N-diisopropylethylamine DMA: N,N-Dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride EDC·HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt: 1-hydroxybenzotriazole HOBt·H2O: 1-Hydroxybenzotriazole monohydrate LAH: Lithium aluminum hydride LDA: Lithium diisopropylamide NaBH(OAc)3: Sodium triacetoxyborohydride NMP: 1-methyl-2-pyrrolidinone Pd(amphos)Cl2: Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) THF: tetrahydrofuran TsCl: p-Toluenesulfonyl chloride T3P®: Propylphosphonic anhydride (cyclic trimer) 9-BBN: 9-Borabicyclo[3.3.1]nonane Aminosilicagel: Aminopropylated silica gel ODS column chromatography: Octadecylsilylated silica gel column chromatography Process: Process Scheme Ref.No.: Reference number Ex.No.: Example No. Structure: Physical data: Physical properties I C 50 :50% inhibitory concentration (The numbers with "*" in the table indicate the inhibition rate at a compound concentration of 100 μM.) FITC: Fluorescein isothiocyanate 1 H-NMR: Hydrogen nuclear magnetic resonance spectrum DMSO-d6: Dimethylsulfoxide-d6 CDCl3: Chloroform-d1 MS: Mass spectrometry ESI_APCI: Electrospray ionization - atmospheric pressure chemical ionization multi-ionization method

[0020] One embodiment of the compound represented by formula (I) is, for example, a compound represented by the following formula: 3’ is R in [1] above. 3 (However, R 3’ is not group A). ​​The other symbols have the same meaning as in (1) above. [ka]

[0021] One embodiment of the compound represented by formula (IIA) is, for example, a compound represented by the following formula: 3R’ is R in [1] above. 3R (However, R 3R’ is not the group AA). The other symbols have the same meaning as in (1) above. [ka]

[0022] One embodiment of the compound represented by formula (I) is a compound in which the group represented by the following formula is a group selected from the group consisting of the following (a) to (d): [ka] The symbols in the formula have the same meanings as in [1] above. [ka]

[0023] One embodiment of the compounds represented by formulae (II), (IIA), (IIB) and (IIC) includes compounds in which the group represented by the following formula is a group selected from the group consisting of the following (a) to (d): [ka] The symbols in the formula have the same meanings as in [1] above. [ka]

[0024] One embodiment of the compounds represented by formulae (V), (VA), (VB) and (VC) includes compounds in which the group represented by the following formula is a group selected from the group consisting of the following (a) to (d): [ka] The symbols in the formula have the same meanings as in [1] above. [ka]

[0025] In one embodiment of the compound of formula (I), a compound selected from the group consisting of: [ka] and [ka] or a pharmacologically acceptable salt thereof.

[0026] In one embodiment of the compound of formula (I), there is provided the compound: [ka] or a pharmacologically acceptable salt thereof.

[0027] As one embodiment of the compound represented by formula (I), the compound described in the above [1] is preferably a group selected from the group consisting of the following [A] to [I] or a combination thereof. [A] Ring W is phenyl, naphthyl, thienyl, pyridyl, quinolyl, or cyclohexyl. [B] R a , R b and R c are each independently a hydrogen atom, a halogen atom, methyl, cyano, hydroxy, or carboxy. [C]R d is a hydrogen atom or methyl. [D] R 1 is a hydrogen atom, a halogen atom, or methyl. [E]R 2 is a hydrogen atom, methyl, trifluoromethyl, methoxy, -COH, or -CONR 5 R 5’ and; R 5 and R 5’ are each independently a hydrogen atom, carboxymethyl, or tetrahydropyranyl. [F] R 3 is a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, vinyl, methylthio, ethylsulfonyl, hydroxy, cyano, nitro, dimethylamino, -COR 7 , -CONR 8 R 8’ or a group A (where u is 2, then two R 3 may be different from each other); The group A is a group selected from the group consisting of the following (a) to (f): (a) phenyl which is unsubstituted or substituted with 1 to 2 groups selected from the substituent group B; (b) pyridyl, (c) benzyl, (d) phenyloxy, (e) cyclopropyl, and (f) morpholino; Substituent group B is a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, cyano, -NHSO2R 10 and -CO2R 10’ The group consisting of; R 10 and R 10’ are each independently a hydrogen atom or methyl; R 7 is a hydrogen atom or methyl; R 8 and R 8’ are each independently a hydrogen atom or carboxymethyl. [G] m, n, and u are each independently 1 or 2. [H] p and q each independently represent 1 or 2. [I] r is 0 or 1.

[0028] As one embodiment of the compounds represented by formulae (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), the compounds described in the above [1] to [5] and

[15] to

[17] are preferably a group selected from the group consisting of the following [A] to [I] or a combination thereof. [A] Ring W is phenyl, naphthyl, thienyl, pyridyl, quinolyl, or cyclohexyl. [B] R A , R B and R C each independently represents a hydrogen atom, a halogen atom, methyl, cyano, hydroxy which may be protected with a protecting group, or carboxy which may be protected with a protecting group. [C]R D is a hydrogen atom or methyl. [D] R 1R is a hydrogen atom, a halogen atom, or methyl. [E]R 2R represents a hydrogen atom, methyl, trifluoromethyl, methoxy, a carboxy which may be protected by a protecting group, or -CONR 5R R 5R’ and; R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, carboxymethyl which may be protected by a protecting group, or tetrahydropyranyl. [F] R 3R represents a hydrogen atom, a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, vinyl, methylthio, ethylsulfonyl, a hydroxyl group which may be protected by a protecting group, a cyano group, a nitro group, a dimethylamino group, -COR 7R , -CONR 8R R 8R’ or a group AA (wherein when u is 2, two R 3R may be different from each other); The group AA is a group selected from the group consisting of the following (a) to (f): (a) phenyl which is unsubstituted or substituted with 1 to 2 groups selected from the substituent group BB; (b) pyridyl, (c) benzyl, (d) phenyloxy, (e) cyclopropyl, and (f) morpholino; The substituent group BB is a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, a hydroxyl group which may be protected by a protecting group, a cyano group, -NHSOR 10R and -CO2R 10R’ The group consisting of; R 10R and R 10R’ are each independently a protecting group, a hydrogen atom, or methyl; R 7R is a hydrogen atom or methyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or a carboxymethyl which may be protected by a protecting group. [G] m, n, and u are each independently 1 or 2. [H] p and q each independently represent 1 or 2. [I] r is 0 or 1.

[0029] In the compounds represented by formulae (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), when one or more asymmetric carbon atoms are present, the present invention also includes compounds in which each asymmetric carbon atom is in the R configuration, the S configuration and any combination thereof. In addition, their racemates, racemic mixtures, single enantiomers and diastereomeric mixtures are also included within the scope of the present invention.

[0030] In the compounds represented by formulas (I), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), when cis-trans isomers exist, the present invention includes all of the cis-trans isomers.

[0031] In the compounds represented by formulas (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), when tautomers exist, the present invention includes all of the tautomers.

[0032] In the present invention, the determination of stereochemistry can also be carried out by methods known in the art.

[0033] The compound represented by formula (I) can be converted into a pharmacologically acceptable salt thereof according to a conventional method, if necessary. Such salts include acid addition salts and salts with bases.

[0034] The compounds represented by formulae (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD) can be converted into salts thereof, if necessary, in a conventional manner. Such salts include acid addition salts and salts with bases.

[0035] Examples of the acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and acid addition salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, and aspartic acid.

[0036] Examples of salts with bases include salts with inorganic bases such as lithium, sodium, potassium, calcium, and magnesium, and salts with organic bases such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

[0037] When the compounds of formula (I) and (IA) or pharmacologically acceptable salts thereof exist, for example, as crystals, the present invention includes any crystalline form. For example, pharmacologically acceptable salts include solvates with pharma- ceutical acceptable solvents such as water or ethanol, co-crystals with suitable co-crystal formers, and the like.

[0038] When the compounds represented by formula (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD) or salts thereof exist as crystals, any crystalline form is included. For example, the salts include solvates with pharma- ceutical acceptable solvents such as water or ethanol, cocrystals with a suitable coformer, and the like.

[0039] In the compounds represented by formulas (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), a part of each atom may be replaced with the corresponding isotope. The present invention also includes compounds replaced with these isotopes. Examples of isotopes are 2 H, 3 H, 11 C.13 C. 14 C. 36 Cl, 18 F, 123 I, 125 I, 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, and 35 Examples of isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, phosphorus, and sulfur atoms represented by S include isotopes of hydrogen, carbon, chlorine, fluorine, iodine, nitrogen, oxygen, phosphorus, and sulfur atoms. In one embodiment, some of the hydrogen atoms of the compound represented by formula (I) are 2 H (D: deuterium atom) is substituted.

[0040] In the compounds represented by formulae (I), (IA), (II), (IIA), (IIB), (IIC), (IID), (IV), (V), (VA), (VB), (VC) and (VD), compounds in which some atoms are replaced with isotopes can be produced by a method similar to the production method described below using a commercially available building block containing an isotope. For example, a compound in which some hydrogen atoms in a compound represented by formula (I) are replaced with deuterium atoms can also be produced by the above method and a method described in the literature (see, for example, Journal of Organic Synthesis, Vol. 65, No. 12, pp. 1179-1190, 2007). In addition, for example, a compound in which some carbon atoms in a compound represented by formula (I) are replaced with deuterium atoms can also be produced by the above method and a method described in the literature (see, for example, Journal of Organic Synthesis, Vol. 65, No. 12, pp. 1179-1190, 2007). 13 Compounds substituted at C can also be prepared using the methods described above and methods described in the literature (see, for example, RADIOISOTOPES, Vol. 56, No. 11, pp. 35-44, 2007).

[0041] The compound represented by formula (I) can be produced, for example, according to the methods shown in Schemes 1 to 5 or methods analogous thereto, or methods described in the literature or methods analogous thereto.

[0042] In the reactions of each step, when raw materials and reagents are commercially available, commercially available products can be used. In the reaction of each step, the reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days unless otherwise specified. In the reactions of each step, the reaction temperature varies depending on the starting materials and solvents used, but is usually from −78° C. to the reflux temperature, unless otherwise specified. In the reaction of each step, the pressure varies depending on the starting materials, the solvent, the reaction temperature, etc. used, but is usually 1 atm to 20 atm unless otherwise specified. In the reactions of each step, a microwave reaction apparatus such as Initiator manufactured by Biotage can also be used. When the reactions are carried out using a microwave reaction apparatus, the conditions vary depending on the raw materials, solvent, and model used, but can include a pressure range of 1 to 30 bar, a power range of 1 to 400 W, a reaction temperature of room temperature to 300° C., and a reaction time of 1 minute to 1 day.

[0043] In the reactions of each step, unless otherwise specified, these reactions are carried out without solvent or using a suitable solvent. Examples of suitable solvents include solvents that are inert to the reaction. Specific examples of the solvent include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents. Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.; Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, 2-methyloxolane, CPME, etc.; Aromatic hydrocarbons: chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.; Saturated hydrocarbons: cyclohexane, n-hexane, etc.; Amides: DMF, DMA, NMP, etc.; Halogenated hydrocarbons: dichloromethane, 1,2-dichloroethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used in combination of two or more kinds in an appropriate ratio.

[0044] When a base is used in the reaction of each step, the reaction is carried out using a base suitable for each reaction. Specific examples of the base include the bases described in the Reference Examples or Examples corresponding to each step, or the following bases. Inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc.; Organic bases: triethylamine, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, piperidine, etc.; Metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.; Alkali metal hydrides: sodium hydride, etc.; Metal amides: sodium amide, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.; Organomagnesiums: methylmagnesium bromide, isopropylmagnesium chloride, allylmagnesium bromide, phenylmagnesium bromide, etc.; Organolithium compounds: n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

[0045] When an acid or an acid catalyst is used in the reaction of each step, the reaction is carried out using an acid or an acid catalyst suitable for each reaction. Specific examples of the acid or acid catalyst include the acids or acid catalysts described in the Reference Examples or Examples corresponding to each step, or the following acids or acid catalysts. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc.; Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; Lewis acids: boron trifluoride-diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

[0046] When a condensing agent is used in the reaction of each step, the reaction is carried out using a condensing agent suitable for each reaction. Specific examples of the condensing agent include the condensing agents described in the Reference Examples or Examples corresponding to each step, or the following condensing agents. Carbodiimides: EDC·HCl, N,N'-dicyclohexylcarbodiimide, etc.; Carbodiimidazoles: CDI etc.; Uronium and phosphonium salts: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, etc.; Triazines: DMTMM etc.; Others: T3P, etc.

[0047] When a reducing agent is used in the reaction of each step, the reaction is carried out using a reducing agent suitable for each reaction. Specific examples of the reducing agent include those described in the Reference Examples or Examples corresponding to each step, or the following reducing agents. Metal hydrides: LAH, lithium borohydride, sodium borohydride, NaBH(OAc)3, sodium cyanoborohydride, diisobutylaluminum hydride, etc.; Boranes: borane-tetrahydrofuran complex, 9-BBN, picoline borane, etc.

[0048] In each step, when a protecting group is required depending on the type of functional group, the introduction and removal operations can be appropriately combined according to a conventional method. For the types of protecting groups, protection, and deprotection, for example, the methods described in "Greene's Protective Groups in Organic Synthesis", edited by Theodora W. Greene & Peter GM Wuts, fourth edition, Wiley-Interscience, 2006 can be mentioned.

[0049] When a protecting group is removed in each step, this reaction can be carried out using a hydrolysis reaction or the like.

[0050] In each step, when a hydrolysis reaction is carried out, the reaction can be carried out in the presence of an acid or a base. Examples of the acid and base include those mentioned above.

[0051] In each step, when a catalytic reduction reaction is carried out, the reaction can be carried out under a hydrogen atmosphere in the presence of a catalyst, such as palladium carbon powder, platinum carbon powder, Raney nickel, etc.

[0052] In the case where a reduction reaction is carried out in each step, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent include those mentioned above.

[0053] In each step, when an amidation reaction is carried out, the reaction can be carried out in the presence of a condensing agent and a base, or in the presence of a condensing agent. Examples of the condensing agent and the base include those mentioned above. When a carbodiimide is used as a condensing agent, an additive such as HOBt or DMAP may be added to the reaction as necessary. The amidation reaction can also be carried out using an acyl halide or an acid anhydride.

[0054] In each step, when a reductive amination reaction is carried out, the reaction can be carried out in the presence of a reducing agent. Examples of the reducing agent include those mentioned above. As the reducing agent, preferably, NaBH(OAc)3 and the like are included.

[0055] In each step, when an aromatic nucleophilic substitution reaction is carried out, the reaction can be carried out in the presence of a base. Examples of the base include those mentioned above.

[0056] In the case where an intramolecular carbonylation reaction is carried out in each step, the reaction can be carried out in the presence of a condensing agent. Examples of the condensing agent include those mentioned above.

[0057] When the Ullmann condensation reaction is carried out in each step, the reaction can be carried out in the presence of a copper catalyst, a ligand, and a base. The copper catalyst can be copper iodide or the like. The ligand can be N,N'-dimethylethylenediamine or the like. The base can be the above-mentioned examples.

[0058] In each step, when the Chan-Lam-Evans coupling reaction is performed, these reactions can be performed in the presence of a copper catalyst and a base. The copper catalyst can be copper(II) acetate or the like. The base can be any of the above-mentioned examples.

[0059] When the Mitsunobu reaction is carried out in each step, the reaction can be carried out in the presence of an azodicarboxylate and a phosphine. The azodicarboxylate can be DEAD or the like. The phosphine can be triphenylphosphine or the like.

[0060] When Suzuki-Miyaura cross-coupling reaction is carried out in each step, the reaction can be carried out in the presence of a palladium catalyst and a base. Examples of the palladium catalyst include Pd(amphos)Cl2. Examples of the base include those mentioned above.

[0061] In each step, unless otherwise specified, the symbols in the formulae have the same meanings as those in the above [1]. Y is a bromine atom, an iodine atom, a boronic acid, or a hydroxyl. Y' is a fluorine atom or a chlorine atom. Y'' is a boronic acid or a boronic acid ester. X is CR 3 Or N.

[0062] The compound represented by formula (I) can be produced, for example, according to the methods of steps 1-1 to 1-3 described in scheme 1. [ka]

[0063] Process 1-1 Compound (1-3) can also be produced by Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction of compound (1-1) and compound (1-2). When Y is bromine or iodine, r is 0, and W is aryl or heteroaryl, the Ullmann condensation reaction is preferred. When Y is boronic acid, r is 0, and W is aryl or heteroaryl, the Chan-Lam-Evans coupling reaction is preferred. When Y is hydroxy, r is 0, and W is cycloalkyl or heterocycloalkyl, the Mitsunobu reaction is preferred. When Y is hydroxy and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

[0064] Process 1-2 Compound (1-4) can also be prepared by removing the protecting group of compound (1-3).

[0065] Process 1-3 Compound (I) can also be produced by subjecting compound (1-4) to a reductive amination reaction with compound (1-5). If necessary, the protecting group may be removed.

[0066] Compound (1-1) can be produced, for example, according to the methods of steps 2-1 to 2-3 described in Scheme 2. [ka]

[0067] Process 2-1 Compound (2-3) can also be produced by subjecting compound (2-1) and compound (2-2) to an aromatic nucleophilic substitution reaction.

[0068] Process 2-2 The compound (2-4) can also be produced by catalytic reduction of the compound (2-3).

[0069] Process 2-3 The compound (1-1) can also be produced by an intramolecular carbonylation reaction of the compound (2-4).

[0070] Compound (IA) can be produced, for example, according to the methods of steps 3-1 to 3-4 described in Scheme 3. [ka]

[0071] Process 3-1 Compound (3-2) can also be produced by subjecting compound (1-1) and compound (3-1) to Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction. When Y is a bromine atom or an iodine atom and r is 0, the Ullmann condensation reaction is preferred. When Y is a boronic acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. When Y is a hydroxyl and r is an integer of 1 to 6, the Mitsunobu reaction is preferred.

[0072] Process 3-2 Compound (3-4) can also be produced by subjecting compound (3-2) and compound (3-3) to Suzuki-Miyaura cross-coupling reaction.

[0073] Process 3-3 Compound (3-5) can also be prepared by removing the protecting group of compound (3-4).

[0074] Process 3-4 Compound (IA) can also be produced by subjecting compound (3-5) to a reductive amination reaction with compound (1-5). If necessary, the protecting group may be removed.

[0075] Compound (I) can be produced, for example, according to the methods of steps 4-1 to 4-3 described in Scheme 4. [ka]

[0076] Process 4-1 Compound (4-1) can also be prepared by removing the protecting group of compound (1-1).

[0077] Process 4-2 Compound (4-2) can also be produced by subjecting compound (4-1) to a reductive amination reaction with compound (1-5).

[0078] Process 4-3 Compound (I) can also be produced by Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction of compound (4-2) and compound (1-2). If necessary, protective groups may be removed. When Y is bromine or iodine, r is 0, and W is aryl or heteroaryl, the Ullmann condensation reaction is preferred. When Y is boronic acid, r is 0, and W is aryl or heteroaryl, the Chan-Lam-Evans coupling reaction is preferred. When Y is hydroxy, r is 0, and W is cycloalkyl or heterocycloalkyl, the Mitsunobu reaction is preferred. When Y is hydroxy and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

[0079] Compound (IA) can be produced, for example, according to the methods of steps 5-1 and 5-2 described in Scheme 5. [ka]

[0080] Process 5-1 Compound (5-1) can also be produced by Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction of compound (4-2) and compound (3-1). When Y is a bromine atom or an iodine atom and r is 0, the Ullmann condensation reaction is preferred. When Y is a boronic acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. When Y is a hydroxyl and r is an integer of 1 to 6, the Mitsunobu reaction is preferred.

[0081] Process 5-2 Compound (IA) can also be produced by subjecting compound (5-1) to Suzuki-Miyaura cross-coupling reaction with compound (3-3). If necessary, protective groups may be removed.

[0082] The above-described scheme is an example of a method for producing a compound represented by formula (I) or a production intermediate thereof. The above scheme can be modified in various ways as would be easily understood by a person skilled in the art.

[0083] The compound represented by formula (I) and its production intermediates can also be isolated and purified, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, etc. Examples of silica gel column chromatography and amino silica gel column chromatography include flash chromatography using SNAP Ultra and SNAP Isolute NH2 (Biotage), and Hi-Flash columns (Yamazen). Examples of ODS column chromatography include separation using a preparative purification LC system (Gilson, flow rate: 30 mL / min, detection: UV at 225 nm) and a column: CAPCELL PAK C18 UG80 (5 μm 20×50 mm).

[0084] The compound represented by formula (I) or a pharmacologically acceptable salt thereof has an excellent PHD2 inhibitory effect and can be used as a therapeutic agent for IBD (see Nature Reviews Drug Discovery, 2014, 13, p.852-869). In the present invention, IBD includes, for example, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious enteritis, radiation enteritis, drug-induced enteritis, ischemic enteritis, mesenteric venous sclerosis (venous sclerosing colitis), obstructive colitis, and enteritis associated with collagen disease. Preferably, the compound of the present invention can be used as a therapeutic agent for ulcerative colitis or Crohn's disease (see Inflamm. Bowel. Dis., 2015, 21 (2), p.267-275).

[0085] In the present invention, "treatment" includes the meaning of "prevention." For example, the treatment of ulcerative colitis includes the meanings of "prevention of recurrence" and "maintenance of remission."

[0086] The therapeutic effect of the compound represented by formula (I) or a pharmacologically acceptable salt thereof against colitis can be confirmed by the method described in Test Example 2 or a method well known in the art, such as the method described in Biol. Pharm. Bull., 2004, 27 (10), p. 1599-1603, or a method similar thereto.

[0087] In one embodiment, in order to limit off-target effects due to stabilization of HIF-α, the compound represented by formula (I) or a pharmacologically acceptable salt thereof is a PHD2 inhibitor that acts specifically on colon tissue. "Acting specifically on colon tissue" means, for example, that the compound is concentrated at a higher level in colon tissue than in blood, and exerts a therapeutic effect in the colon without any systemic effect (e.g., hematopoietic effect) (see Test Examples 2 and 3).

[0088] Pharmaceutical compositions containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient are used in various dosage forms depending on the method of use. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, patches, and enemas.

[0089] A pharmaceutical composition containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient is prepared using the compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical additive. These pharmaceutical compositions can also be prepared by appropriately mixing, diluting or dissolving with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants, diluents, buffers, isotonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, etc., by a method known in pharmaceutical science according to the dosage form.

[0090] When a pharmaceutical composition containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient is used for treatment, the dosage of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is appropriately determined depending on the age, sex, weight, disease, and degree of treatment of the patient. The daily dosage may be administered once, twice, three times, or four times. Preferably, the pharmaceutical composition of the present invention is administered orally. In the case of oral administration, the dosage for an adult can be set within the range of, for example, 0.1 to 1000 mg / day. In one embodiment, the oral dosage can be set within the range of 1 to 500 mg / day, and is preferably within the range of 10 to 200 mg / day. In the case of parenteral administration, the dosage for an adult can be set, for example, in the range of 0.1 to 1000 mg / day. In one embodiment, the parenteral dosage can be set in the range of 0.5 to 200 mg / day, preferably in the range of 1 to 20 mg / day.

[0091] In one embodiment, the pharmaceutical composition containing the compound represented by formula (I) or a pharmacologically acceptable salt thereof as an active ingredient can be used in combination with other drugs other than PHDs inhibitors. Examples of other drugs that can be used in combination in the treatment of inflammatory bowel disease include 5-ASA, steroids, immunosuppressants, anti-TNFα antibodies, Janus kinase inhibitors, and α4β7 integrin antibodies.

[0092] When the compound represented by formula (I) or its pharmacologically acceptable salt is used in combination with other drugs, it can be administered as a preparation containing these active ingredients together, or as a preparation in which each of these active ingredients is separately formulated. When separately formulated, these preparations can be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or its pharmacologically acceptable salt may be appropriately reduced according to the dosage of the other drug used in combination.

[0093] The compound represented by formula (I) may be used after being appropriately converted into a prodrug. For example, the prodrug of the compound represented by formula (I) can be produced by introducing a group constituting a prodrug using a prodrug-forming reagent such as a corresponding halide, followed by purification. Examples of the group constituting a prodrug include the groups described in "Drug Development" (Hirokawa Shoten, 1990), Vol. 7, p. 163-198. EXAMPLES

[0094] The present invention will be described in more detail below based on examples, but the present invention is not limited to the contents thereof.

[0095] The names of compounds described in the following examples were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc., except for commercially available reagents.

[0096] Reference example A-1 (S)-tert-Butyl 3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate Under ice cooling, 2-fluoro-3-nitropyridine (10.00 g), (S)-3-aminopyrrolidine-1-carboxylate tert-butyl (13.10 g) and potassium carbonate (11.67 g) were added to NMP (100 mL). The reaction mixture was stirred at 150° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, and ethyl acetate and water were added and mixed. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (21.70 g).

[0097] Reference example A-2 (R)-tert-Butyl 3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate A mixture of 2-fluoro-3-nitropyridine (2.00 g), (R)-3-aminopyrrolidine-1-carboxylate tert-butyl (2.62 g), potassium carbonate (2.33 g) and NMP (15 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite (registered trademark), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 95 / 5 to 70 / 30) to obtain the title compound (3.61 g).

[0098] Reference example A-3 tert-Butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate A mixture of 2-fluoro-3-nitropyridine (1.00 g), tert-butyl 4-aminopiperidine-1-carboxylate (1.41 g), potassium carbonate (1.94 g) and DMF (10 mL) was stirred at 120° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (2.25 g).

[0099] Reference example A-4 3-((3-nitropyridin-2-yl)amino)azetidine-1-carboxylate tert-butyl ester The title compound was obtained in the same manner as in Reference Example A-3, except that tert-butyl 3-aminoazetidine-1-carboxylate was used instead of tert-butyl 4-aminopiperidine-1-carboxylate.

[0100] Reference example A-5 (3R,4R)-tert-butyl 3-fluoro-4-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate A mixture of 2-fluoro-3-nitropyridine (0.69 g), (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate tert-butyl (1.00 g), potassium carbonate (1.35 g) and DMF (10 mL) was stirred at 80° C. for 1 hour under microwave irradiation. Ethyl acetate and water were added to the reaction mixture and mixed. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (1.40 g).

[0101] Reference example A-6 (S)-tert-Butyl 3-((3-nitro-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate A mixture of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.00 g), (S)-3-aminopyrrolidine-1-carboxylate tert-butyl (0.82 g), potassium carbonate (1.22 g) and DMF (10 mL) was stirred at 80° C. for 1 hour under microwave irradiation. Ethyl acetate and water were added to the reaction mixture and mixed. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (1.66 g).

[0102] Reference example A-7 tert-Butyl 4-methyl-4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example A-5, except that tert-butyl 4-amino-4-methylpiperidine-1-carboxylate was used instead of tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate.

[0103] Reference example A-8 (S)-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-5-nitropicolinic acid methyl ester A mixture of methyl 6-chloro-5-nitropicolinate (1.00 g), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (0.86 g), potassium carbonate (1.27 g) and DMF (10 mL) was stirred at 120° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.47 g).

[0104] Reference example A-9 (S)-tert-Butyl 3-((5-methyl-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example A-6, except that 2-chloro-5-methyl-3-nitropyridine was used instead of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine.

[0105] Reference example A-10 (S)-tert-Butyl 3-((5-methoxy-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example A-6, except that 2-chloro-5-methoxy-3-nitropyridine was used instead of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine.

[0106] Reference example B-1 (S)-tert-Butyl 3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylate Palladium 10%-carbon (2.17 g, wet) was added to a mixture of Reference Example A-1 (21.70 g) and ethanol (300 mL) under an argon atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (19.74 g).

[0107] Reference example B-2 (R)-tert-Butyl 3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-2 was used instead of Reference Example A-1.

[0108] Reference example B-3 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate tert-Butyl Palladium 10%-carbon (0.22 g, wet) was added to a mixture of Reference Example A-3 (2.25 g), ethanol (20 mL) and THF (10 mL) under an argon atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.06 g).

[0109] Reference example B-4 3-((3-aminopyridin-2-yl)amino)azetidine-1-carboxylate tert-Butyl ester The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-4 was used instead of Reference Example A-1.

[0110] Reference example B-5 (3R,4R)-tert-butyl 3-((3-aminopyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-5 was used instead of Reference Example A-1.

[0111] Reference example B-6 (S)-tert-Butyl 3-((3-amino-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-6 was used instead of Reference Example A-1.

[0112] Reference example B-7 tert-Butyl 4-((3-aminopyridin-2-yl)amino)-4-methylpiperidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-7 was used instead of Reference Example A-1.

[0113] Reference example B-8 (S)-5-Amino-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)picolinic acid methyl ester The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-8 was used instead of Reference Example A-1.

[0114] Reference example B-9 (S)-tert-Butyl 3-((3-amino-5-methylpyridin-2-yl)amino)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-9 was used instead of Reference Example A-1.

[0115] Reference example B-10 (S)-tert-Butyl 3-((3-amino-5-methoxypyridin-2-yl)amino)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example B-1, except that Reference Example A-10 was used instead of Reference Example A-1.

[0116] Reference example C-1 (S)-tert-Butyl 3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate CDI (22.82 g) was added to a mixture of Reference Example B-1 (19.59 g) and THF (200 mL) under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydroxide solution (5 mol / L, 30 mL) was added to the reaction mixture and stirred for 10 minutes. Hydrochloric acid (2 mol / L, 75 mL) was added to the reaction mixture, stirred, and concentrated under reduced pressure. Water was added to the resulting mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain the title compound (17.61 g). MS (ESI_APCI, m / z): 303 (MH) -

[0117] Reference example C-2 (R)-tert-Butyl 3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate CDI (4.28 g) was added to a mixture of Reference Example B-2 (3.68 g) and THF (20 mL). The reaction mixture was stirred at room temperature for 30 minutes. Aqueous sodium hydroxide solution (5 mol / L, 4 mL) was added to the reaction mixture and stirred for 5 minutes. Hydrochloric acid (2 mol / L, 10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 50 / 50 to 0 / 100) to obtain the title compound (4.00 g). MS (ESI_APCI, m / z): 303 (MH) -

[0118] Reference example C-3 tert-Butyl 4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate CDI (2.29 g) was added to a mixture of Reference Example B-3 (2.06 g) and THF (30 mL). The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (1.96 g). MS (ESI_APCI, m / z): 317 (MH) -

[0119] Reference example C-4 tert-Butyl 3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-carboxylate Using Reference Example B-4 instead of Reference Example B-1, the title compound was obtained in the same manner as in Reference Example C-1. MS (ESI_APCI, m / z): 289 (MH) -

[0120] Reference example C-5 (3R,4R)-3-Fluoro-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl ester Using Reference Example B-5 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m / z): 321 (MH) -

[0121] Reference example C-6 (S)-tert-Butyl 3-(2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate Using Reference Example B-6 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m / z): 371 (MH) -

[0122] Reference example C-7 4-Methyl-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate tert-Butyl Using Reference Example B-7 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m / z): 331 (MH) -

[0123] Reference example C-8 (S)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester Using Reference Example B-8 instead of Reference Example B-3, the title compound was obtained in the same manner as in Reference Example C-3. MS (ESI_APCI, m / z): 361 (MH) -

[0124] Reference example C-9 (S)-tert-Butyl 3-(6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate Using Reference Example B-9 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m / z): 317 (MH) -

[0125] Reference example C-10 (S)-tert-Butyl 3-(6-methoxy-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate Using Reference Example B-10 instead of Reference Example B-2, the title compound was obtained in the same manner as in Reference Example C-2. MS (ESI_APCI, m / z): 333 (MH) -

[0126] Reference example D-1 (S)-tert-Butyl 3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (168 mg), (4-chloro-2-methylphenyl)boronic acid (282 mg), copper(II) acetate (201 mg), triethylamine (0.383 mL) and dichloromethane (3 mL) was stirred at room temperature for 3 hours. Water and hydrochloric acid (1 mol / L) were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (114 mg).

[0127] Reference example D-2 (S)-tert-Butyl 3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (500 mg), 1-chloro-4-iodobenzene (431 mg), N,N'-dimethylethylenediamine (0.212 mL), copper (I) iodide (375 mg), potassium carbonate (681 mg) and acetonitrile (10 mL) was stirred at 90°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L), and the mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (583 mg).

[0128] Reference example D-3 (R)-tert-Butyl 3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example D-1, except that Reference Example C-2 was used instead of Reference Example C-1.

[0129] Reference example D-4 (S)-tert-Butyl 3-(1-(4-chloro-2-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (100 mg), 5-chloro-2-iodophenol (125 mg), N,N'-dimethylethylenediamine (0.042 mL), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (3 mL) was stirred at 100°C for 2 hours under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L), and the mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 35 / 65) to obtain the title compound (61 mg).

[0130] Reference example D-5 (S)-tert-Butyl 3-(1-(4-chloro-3-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (100 mg), 2-chloro-5-iodophenol (100 mg), N,N'-dimethylethylenediamine (0.042 mL), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 35 / 65) to obtain the title compound (135 mg).

[0131] Reference example D-6 (S)-tert-Butyl 3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (100 mg), 2-chloro-5-iodopyridine (94 mg), N,N'-dimethylethylenediamine (0.042 mL), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 35 / 65) to obtain the title compound (117 mg).

[0132] Reference example D-7 (R)-tert-Butyl 3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-2 (500 mg), 2-chloro-5-iodopyridine (433 mg), N,N'-dimethylethylenediamine (0.212 mL), copper (I) iodide (375 mg), potassium carbonate (681 mg) and acetonitrile (10 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 45 / 55) to obtain the title compound (420 mg).

[0133] Reference example E-1 (S)-tert-Butyl 3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (113 mg), 4-iodo-1,1'-biphenyl (125 mg), N,N'-dimethylethylenediamine (0.048 mL), copper iodide (I) (85 mg), potassium carbonate (154 mg) and acetonitrile (4 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (138 mg).

[0134] Reference example E-2 (R)-tert-Butyl 3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-1, except that Reference Example C-2 was used instead of Reference Example C-1.

[0135] Reference example E-3 (S)-tert-Butyl 3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-1, except that iodobenzene was used instead of 4-iodo-1,1'-biphenyl.

[0136] Reference example E-4 tert-Butyl 4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-1, except that Reference Example C-3 was used instead of Reference Example C-1.

[0137] Reference example E-5 tert-Butyl 3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-carboxylate A mixture of Reference Example C-4 (100 mg), 4-iodo-1,1'-biphenyl (96 mg), N,N'-dimethylethylenediamine (0.044 mL), copper (I) iodide (79 mg), potassium carbonate (143 mg) and acetonitrile (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (105 mg).

[0138] Reference example E-6 (S)-tert-Butyl 3-(1-(4-(methoxycarbonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (200 mg), methyl 4-iodobenzoate (172 mg), N,N'-dimethylethylenediamine (0.085 mL), copper (I) iodide (150 mg), potassium carbonate (272 mg) and acetonitrile (1 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 45 / 55) to obtain the title compound (271 mg).

[0139] Reference example E-7 (S)-tert-Butyl 3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (100 mg), 1-iodo-4-methoxybenzene (85 mg), N,N'-dimethylethylenediamine (0.042 mL), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (1 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and hydrochloric acid (1 mol / L). After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (119 mg).

[0140] Reference example E-8 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester A mixture of Reference Example C-8 (100 mg), 4-iodo-1,1'-biphenyl (93 mg), N,N'-dimethylethylenediamine (0.036 mL), copper (I) iodide (63 mg), potassium carbonate (114 mg) and acetonitrile (1 mL) was stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 45 / 55) to obtain the title compound (120 mg).

[0141] Reference example E-9 tert-Butyl 4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpiperidine-1-carboxylate A mixture of Reference Example C-7 (50 mg), 4-iodo-1,1'-biphenyl (51 mg), N,N'-dimethylethylenediamine (0.019 mL), copper (I) iodide (34 mg), potassium carbonate (50 mg) and acetonitrile (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60) to obtain the title compound (70 mg).

[0142] Reference example E-10 (S)-tert-Butyl 3-(6-methoxy-1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-10 (136 mg), 4'-bromo-[1,1'-biphenyl]-4-methyl carboxylate (131 mg), N,N'-dimethylethylenediamine (0.053 mL), copper (I) iodide (94 mg), potassium carbonate (136 mg) and acetonitrile (1 mL) was stirred at 100 ° C. for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 25 / 75) to obtain the title compound (128 mg).

[0143] Reference example E-11 (3R,4R)-3-Fluoro-4-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate tert-butyl ester The title compound was obtained in the same manner as in Reference Example E-10, except that Reference Example C-5 was used instead of Reference Example C-10.

[0144] Reference example E-12 (S)-tert-Butyl 3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-10, except that Reference Example C-6 was used instead of Reference Example C-10.

[0145] Reference example E-13 (S)-tert-Butyl 3-(1-(3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-1 (114 mg), phenylboronic acid (39 mg), Pd(amphos)Cl2 (19 mg), sodium carbonate (68 mg), DMF (1 mL) and water (0.1 mL) was stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (87 mg).

[0146] Reference example E-14 (S)-tert-Butyl 3-(1-(2'-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-2 (100 mg), o-tolylboronic acid (39 mg), Pd(amphos)Cl2 (17 mg), sodium carbonate (61 mg), DMF (1 mL) and water (0.1 mL) was stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (105 mg).

[0147] Reference example E-15 (R)-tert-Butyl 3-(1-(3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-13, except that Reference Example D-3 was used instead of Reference Example D-1.

[0148] Reference example E-16 (S)-tert-Butyl 3-(1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-14, except that (4-fluorophenyl)boronic acid was used instead of o-tolylboronic acid.

[0149] Reference example E-17 (S)-tert-Butyl 3-(1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-14, except that (4-methoxyphenyl)boronic acid was used instead of o-tolylboronic acid.

[0150] Reference example E-18 (S)-tert-Butyl 3-(2-oxo-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-14, except that (2-(trifluoromethyl)phenyl)boronic acid was used instead of o-tolylboronic acid.

[0151] Reference example E-19 (S)-tert-Butyl 3-(1-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-14, except that (4-cyanophenyl)boronic acid was used instead of o-tolylboronic acid.

[0152] Reference example E-20 (S)-tert-Butyl 3-(2-oxo-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-14, except that (4-(trifluoromethoxy)phenyl)boronic acid was used instead of o-tolylboronic acid.

[0153] Reference example E-21 (S)-tert-Butyl 3-(1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-1, except that 4'-iodo-[1,1'-biphenyl]-4-ol was used instead of 4-iodo-1,1'-biphenyl.

[0154] Reference example E-22 (S)-tert-Butyl 3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-14, except that 4-pyridylboronic acid was used instead of o-tolylboronic acid.

[0155] Reference example E-23 (S)-tert-Butyl 3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-2 (200 mg), (4-(methoxycarbonyl)phenyl)boronic acid (104 mg), Pd(amphos)Cl2 (34 mg), sodium carbonate (123 mg), DMF (2 mL) and water (0.2 mL) was stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (212 mg).

[0156] Reference example E-24 (R)-tert-Butyl 3-(1-(4'-(methoxycarbonyl)-3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-23, except that Reference Example D-3 was used instead of Reference Example D-2.

[0157] Reference example E-25 (S)-tert-Butyl 3-(1-(3-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-4 (61 mg), (4-(methoxycarbonyl)phenyl)boronic acid (31 mg), Pd(amphos)Cl2 (10 mg), sodium carbonate (36 mg), DMF (1 mL) and water (0.1 mL) was stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 35 / 65) to obtain the title compound (55 mg).

[0158] Reference example E-26 (S)-tert-Butyl 3-(1-(2-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-5 (135 mg), (4-(methoxycarbonyl)phenyl)boronic acid (113 mg), Pd(amphos)Cl2 (22 mg), sodium carbonate (80 mg), NMP (3 mL) and water (0.3 mL) was stirred at 150°C for 5 hours under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 30 / 70) to obtain the title compound (122 mg).

[0159] Reference example E-27 (S)-tert-Butyl 3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-6 (117 mg), (4-(methoxycarbonyl)phenyl)boronic acid (61 mg), Pd(amphos)Cl2 (20 mg), sodium carbonate (72 mg), DMF (3 mL) and water (0.3 mL) was stirred at 150°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 30 / 70) to obtain the title compound (95 mg).

[0160] Reference example E-28 (S)-tert-Butyl 3-(1-(4'-hydroxy-3'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-2 (121 mg), 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (98 mg), Pd(amphos)Cl2 (21 mg), sodium carbonate (75 mg), DMF (1 mL) and water (0.1 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate=80 / 20-30 / 70) to obtain the title compound (71 mg).

[0161] Reference example E-29 (S)-tert-Butyl 3-(1-(2'-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-2 (200 mg), 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (147 mg), Pd(amphos)Cl2 (34 mg), sodium carbonate (123 mg), DMF (1 mL) and water (0.1 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate=80 / 20-35 / 65) to obtain the title compound (165 mg).

[0162] Reference example E-30 (S)-tert-Butyl 3-(1-(6-(4-(methoxycarbonyl)-2-methylphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-6 (353 mg), (4-(methoxycarbonyl)-2-methylphenyl)boronic acid (198 mg), Pd(amphos)Cl2 (60 mg), sodium carbonate (216 mg), DMF (10 mL) and water (1 mL) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 35 / 65) to obtain the title compound (406 mg).

[0163] Reference example K-19 (S)-tert-Butyl 3-(1-(4-chloro-3-(methoxymethoxy)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate To a mixture of Reference Example D-5 (1.29 g) and THF (15 mL), DIPEA (1.55 mL) and chloromethyl methyl ether (0.34 mL) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (1.33 g).

[0164] Reference example E-31 (S)-tert-Butyl 3-(1-(3'-cyano-4'-hydroxy-2-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example K-19 (500 mg), 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (387 mg), Pd(amphos)Cl2 (75 mg), sodium carbonate (268 mg), DMF (10 mL) and water (1 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60) to obtain the title compound (332 mg).

[0165] Reference example E-32 (S)-tert-Butyl 3-(1-(6-(3-cyano-4-hydroxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-31, except that Reference Example D-6 was used instead of Reference Example K-19.

[0166] Reference example K-20 (S)-tert-Butyl 3-(1-(4-chloro-2-(methoxymethoxy)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example K-19, except that Reference Example D-4 was used instead of Reference Example D-5.

[0167] Reference example E-33 (S)-tert-Butyl 3-(1-(3'-cyano-4'-hydroxy-3-(methoxymethoxy)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-31, except that Reference Example K-20 was used instead of Reference Example K-19.

[0168] Reference example K-2 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid Lithium hydroxide monohydrate (103 mg) was added to a mixture of Reference Example E-8 (251 mg), methanol (0.5 mL), THF (0.5 mL) and water (1 mL). The reaction mixture was stirred at room temperature for 3 hours. Hydrochloric acid (2 mol / L, 1.2 mL) was added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (227 mg).

[0169] Reference example E-34 (S)-tert-Butyl 3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate To a mixture of Reference Example K-2 (100 mg) and DMF (1 mL), EDC·HCl (77 mg), HOBt·H2O (61 mg), triethylamine (0.139 mL) and 4-aminotetrahydropyran (24 mg) were added. The reaction mixture was stirred at room temperature for 4 hours. Water and ethyl acetate were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (19 mg).

[0170] Reference example E-35 (S)-tert-Butyl 3-(1-([1,1'-biphenyl]-4-yl)-5-((2-methoxy-2-oxoethyl)carbamoyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-34, except that glycine methyl ester hydrochloride was used instead of 4-aminotetrahydropyran.

[0171] Reference example E-36 (R)-tert-Butyl 3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example D-7 (420 mg), (4-(methoxycarbonyl)phenyl)boronic acid (236 mg), Pd(amphos)Cl2 (72 mg), sodium carbonate (257 mg), DMF (10 mL) and water (1 mL) was stirred at 120°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 40 / 60) to obtain the title compound (377 mg).

[0172] Reference example E-37 (S)-tert-Butyl 3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (200 mg), 2-bromonaphthalene (136 mg), N,N'-dimethylethylenediamine (0.085 mL), copper (I) iodide (150 mg), potassium carbonate (218 mg) and acetonitrile (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water. After stirring, the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (250 mg).

[0173] Reference example E-38 (S)-tert-Butyl 3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate A mixture of Reference Example C-1 (200 mg), 3-bromo-1,1'-biphenyl (153 mg), N,N'-dimethylethylenediamine (0.085 mL), copper iodide (I) (150 mg), potassium carbonate (218 mg) and acetonitrile (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (345 mg).

[0174] Reference example E-39 (S)-tert-Butyl 3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-10, except that Reference Example C-9 was used instead of Reference Example C-10.

[0175] Reference example F-1 (S)-1-([1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride A mixture of Reference Example E-1 (138 mg) and hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (110 mg). MS (ESI_APCI, m / z): 357 (M+H). +

[0176] Reference example F-2 (R)-1-([1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-2 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 357 (M+H) +

[0177] Reference example F-3 (S)-1-Phenyl-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride A mixture of Reference Example E-3 (360 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 2 mL) and methanol (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (400 mg). MS (ESI_APCI, m / z): 281 (M+H). +

[0178] Reference example F-4 1-([1,1'-biphenyl]-4-yl)-3-(piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-4 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3. MS (ESI_APCI, m / z): 371 (M+H) +

[0179] Reference example F-5 1-([1,1'-biphenyl]-4-yl)-3-(azetidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-5 instead of Reference Example E-3, the title compound was obtained in the same manner as in Reference Example F-3. MS (ESI_APCI, m / z): 343 (M+H) +

[0180] Reference example F-6 (S)-4-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoic acid methyl ester hydrochloride Using Reference Example E-6 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 339 (M+H) +

[0181] Reference example F-7 (S)-1-(4-Methoxyphenyl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-7 was used instead of Reference Example E-3.

[0182] Reference example F-8 (S)-1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-8 was used instead of Reference Example E-3.

[0183] Reference example F-9 1-([1,1'-biphenyl]-4-yl)-3-(4-methylpiperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-9 was used instead of Reference Example E-3.

[0184] Reference example F-10 (S)-4'-(6-Methoxy-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-10 was used instead of Reference Example E-3.

[0185] Reference example F-11 4'-(3-((3R,4R)-4-fluoropyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-11 was used instead of Reference Example E-3.

[0186] Reference example F-12 (S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-12 was used instead of Reference Example E-3.

[0187] Reference example F-13 (S)-1-(3-Methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-13 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 371 (M+H) +

[0188] Reference example F-14 (S)-1-(2'-Methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-14 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 371 (M+H) +

[0189] Reference example F-15 (R)-1-(3-Methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-15 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 371 (M+H) +

[0190] Reference example F-16 (S)-1-(4'-Fluoro-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-16 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 375 (M+H) +

[0191] Reference example F-17 (S)-1-(4'-Methoxy-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-17 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 387 (M+H) +

[0192] Reference example F-18 (S)-3-(pyrrolidin-3-yl)-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-18 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 425 (M+H) +

[0193] Reference example F-19 (S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carbonitrile hydrochloride Using Reference Example E-19 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 382 (M+H) +

[0194] Reference example F-20 (S)-3-(pyrrolidin-3-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-20 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 441 (M+H) +

[0195] Reference example F-21 (S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-21 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 373 (M+H) +

[0196] Reference example F-22 (S)-1-(4-(pyridin-4-yl)phenyl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride Using Reference Example E-22 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 358 (M+H) +

[0197] Reference example F-23 (S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride A mixture of Reference Example E-23 (212 mg) and hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (205 mg). MS (ESI_APCI, m / z): 415 (M+H). +

[0198] Reference example F-24 (R)-3'-Methyl-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride Using Reference Example E-24 instead of Reference Example E-1, the title compound was obtained in the same manner as in Reference Example F-1. MS (ESI_APCI, m / z): 429 (M+H) +

[0199] Reference example F-25 (S)-3'-Hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride A mixture of Reference Example E-25 (55 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (59 mg).

[0200] Reference example F-26 (S)-2'-Hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride A mixture of Reference Example E-26 (122 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (147 mg).

[0201] Reference example F-27 (S)-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester hydrochloride A mixture of Reference Example E-27 (95 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (126 mg).

[0202] Reference example F-28 (S)-4-Hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylate methyl ester hydrochloride A mixture of Reference Example E-28 (71 mg) and hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (67 mg).

[0203] Reference example F-29 (S)-2-Hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride A mixture of Reference Example E-29 (165 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (147 mg).

[0204] Reference example F-30 (S)-3-Methyl-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester hydrochloride A mixture of Reference Example E-30 (406 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 3 mL) and methanol (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (308 mg).

[0205] Reference example F-31 (S)-2',4-Dihydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carbonitrile hydrochloride A mixture of Reference Example E-31 (332 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 3 mL) and methanol (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (384 mg).

[0206] Reference example F-32 (S)-2-Hydroxy-5-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzonitrile hydrochloride A mixture of Reference Example E-32 (472 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 2 mL) and methanol (2 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (349 mg).

[0207] Reference example F-33 (S)-3',4-Dihydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carbonitrile hydrochloride A mixture of Reference Example E-33 (77 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (73 mg).

[0208] Reference example F-34 (S)-1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxamide hydrochloride A mixture of Reference Example E-34 (19 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (18 mg).

[0209] Reference example F-35 Methyl (S)-(1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonyl)glycinate hydrochloride A mixture of Reference Example E-35 (91 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 1 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (79 mg).

[0210] Reference example F-36 (R)-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester hydrochloride A mixture of Reference Example E-36 (377 mg), hydrogen chloride-1,4-dioxane solution (4 mol / L, 2 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give the title compound (418 mg).

[0211] Reference example F-37 (S)-1-(Naphthalen-2-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-37 was used instead of Reference Example E-3.

[0212] Reference example F-38 (S)-1-([1,1'-biphenyl]-3-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-38 was used instead of Reference Example E-3.

[0213] Reference example F-39 (S)-4'-(6-methyl-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl ester hydrochloride The title compound was obtained in the same manner as in Reference Example F-3, except that Reference Example E-39 was used instead of Reference Example E-3.

[0214] Reference example G-1 (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester To a mixture of Reference Example F-1 (30 mg), methyl 2-formyl isonicotinate (25 mg) and dichloromethane (1 mL), NaBH(OAc)3 (65 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 45 / 55) to obtain the title compound (26 mg). MS (ESI_APCI, m / z): 506 (M+H) +

[0215] Reference example G-2 (S)-6-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)nicotinic acid methyl ester The title compound was obtained by the same method as in Reference Example G-1, except that 6-formyl methyl nicotinate was used instead of 2-formyl isonicotinate methyl. MS (ESI_APCI, m / z): 506 (M+H) +

[0216] Reference example G-3 (S)-2-((3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester Using Reference Example F-7 instead of Reference Example F-1, the title compound was obtained in the same manner as in Reference Example G-1. MS (ESI_APCI, m / z): 460 (M+H) +

[0217] Reference example G-4 (S)-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester Using Reference Example F-3 instead of Reference Example F-1, the title compound was obtained in the same manner as in Reference Example G-1. MS (ESI_APCI, m / z): 430 (M+H)+

[0218] Reference example J-1 1-Methyl-1H-imidazole-5-carboxylate tert-Butyl A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (5.00 g), tert-butanol (37.7 mL), pyridine (16.0 mL) and TsCl (15.11 g) was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (6.24 g).

[0219] Reference example J-2 2-Formyl-1-methyl-1H-imidazole-5-carboxylate tert-Butyl To a mixture of Reference Example J-1 (5.82 g), DMF (7.43 mL) and THF (60 mL), LDA (1.0 mol / L, THF / n-hexane solution, 48 mL) was slowly added dropwise at -70°C or lower in a dry ice / acetone bath. The reaction mixture was stirred for 10 minutes under ice cooling. Again, LDA (1.0 mol / L, THF / n-hexane solution, 16 mL) and DMF (1 mL) were slowly added dropwise to the reaction mixture at -70°C or lower in a dry ice / acetone bath. The reaction mixture was further stirred for 10 minutes under ice cooling. A saturated aqueous ammonium chloride solution was added to the reaction mixture and stirred for 5 minutes, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (6.72 g).

[0220] Reference example G-6 tert-Butyl 2-((4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpiperidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate To a mixture of Reference Example F-9 (67 mg), THF (1 mL) and triethylamine (0.112 mL), Reference Example J-2 (41 mg) and NaBH(OAc)3 (68 mg) were added. The reaction mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (73 mg). MS (ESI_APCI, m / z): 579 (M+H) +

[0221] Reference example G-7 (S)-tert-butyl 2-((3-(6-methoxy-1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate Using Reference Example F-10 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m / z): 639 (M+H) +

[0222] Reference example G-8 2-(((3R,4R)-3-fluoro-4-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate tert-butyl ester Using Reference Example F-11 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m / z): 627 (M+H) +

[0223] Reference example G-9 (S)-tert-butyl 2-((3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate Using Reference Example F-12 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m / z): 677 (M+H) +

[0224] Reference example G-14 (S)-2-((3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester Using Reference Example F-23 instead of Reference Example F-1, the title compound was obtained in the same manner as in Reference Example G-1. MS (ESI_APCI, m / z): 564 (M+H) +

[0225] Reference example G-16 (S)-2-((3-(1-(2-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester To a mixture of Reference Example F-26 (200 mg), methyl 2-formyl isonicotinate (141 mg) and dichloromethane (2 mL), NaBH(OAc)3 (363 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (207 mg). MS (ESI_APCI, m / z): 580 (M+H) +

[0226] Reference example G-17 (S)-2-((3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester Using Reference Example F-27 instead of Reference Example F-26, the title compound was obtained in the same manner as in Reference Example G-16. MS (ESI_APCI, m / z): 565 (M+H) +

[0227] Reference example G-18 (S)-tert-butyl 2-((3-(1-(3-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate To a mixture of Reference Example F-25 (502 mg), Reference Example J-2 (339 mg) and dichloromethane (3 mL), NaBH(OAc)3 (912 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (450 mg). MS (ESI_APCI, m / z): 625 (M+H) +

[0228] Reference example G-19 (S)-tert-butyl 2-((3-(1-(6-(4-(methoxycarbonyl)-2-methylphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate To a mixture of Reference Example F-30 (308 mg), Reference Example J-2 (221 mg) and dichloromethane (3 mL), NaBH(OAc)3 (561 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (3 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (558 mg). MS (ESI_APCI, m / z): 624 (M+H) +

[0229] Reference example G-20 (S)-2-((3-(1-(3'-cyano-2,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester To a mixture of Reference Example F-31 (150 mg), methyl 2-formyl isonicotinate (110 mg) and dichloromethane (2 mL), NaBH(OAc)3 (283 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 50 / 50) to obtain the title compound (188 mg). MS (ESI_APCI, m / z): 563 (M+H) +

[0230] Reference example G-21 (S)-2-((3-(1-(6-(3-cyano-4-hydroxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester To a mixture of Reference Example F-32 (200 mg), methyl 2-formyl isonicotinate (152 mg) and dichloromethane (2 mL), NaBH(OAc)3 (390 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 50 / 50) to obtain the title compound (495 mg). MS (ESI_APCI, m / z): 548 (M+H) +

[0231] Reference example G-22 (S)-2-((3-(1-(3'-cyano-3,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid methyl ester To a mixture of Reference Example F-33 (63 mg), methyl 2-formyl isonicotinate (46 mg) and dichloromethane (2 mL), NaBH(OAc)3 (119 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 50 / 50) to obtain the title compound (77 mg). MS (ESI_APCI, m / z): 563 (M+H) +

[0232] Reference example G-23 (S)-tert-Butyl 1-methyl-2-((3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate Using Reference Example F-37 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m / z): 525 (M+H)+

[0233] Reference example G-24 (S)-tert-butyl 2-((3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate Using Reference Example F-38 instead of Reference Example F-9, the title compound was obtained in the same manner as in Reference Example G-6. MS (ESI_APCI, m / z): 551 (M+H) +

[0234] Reference example H-1 (S)-3-(Pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride A mixture of Reference Example C-1 (3.00 g), hydrogen chloride-1,4-dioxane solution (4 mol / L, 10 mL) and methanol (4 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to give the title compound (2.80 g).

[0235] Reference example I-1 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate A mixture of Reference Example H-1 (2.68 g), Reference Example J-2 (3.05 g), THF (30 mL) and triethylamine (4.67 mL) was stirred at room temperature for 10 minutes. NaBH(OAc)3 (3.55 g) was added to the reaction mixture and stirred at room temperature for 30 minutes. Methanol was added to the reaction mixture and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and then ethyl acetate and water were added to the residue. The mixture was stirred and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 95 / 5 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (3.52 g).

[0236] Reference example G-25 (S)-tert-butyl 2-((3-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate A mixture of Reference Example I-1 (100 mg), 4-bromo-N,N-dimethylaniline (55 mg), N,N'-dimethylethylenediamine (0.032 mL), copper (I) iodide (57 mg), potassium carbonate (83 mg) and acetonitrile (3 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (77 mg). MS (ESI_APCI, m / z): 518 (M+H) +

[0237] Reference example G-26 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(4-phenoxyphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, using 1-iodo-4-phenoxybenzene instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 567 (M+H) +

[0238] Reference example G-27 (S)-tert-butyl 2-((3-(1-(4-benzylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 1-benzyl-4-iodobenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 565 (M+H) +

[0239] Reference example G-28 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(p-tolyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 1-iodo-4-methylbenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 489 (M+H) +

[0240] Reference example G-29 (S)-tert-butyl 2-((3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 1-chloro-4-iodobenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 509 (M+H) +

[0241] Reference example G-30 (S)-tert-Butyl 1-methyl-2-((3-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 4-iodothioanisole was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 521 (M+H) +

[0242] Reference example G-31 (S)-tert-Butyl 2-((3-(1-(4-(ethylsulfonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, using 1-bromo-4-(ethylsulfonyl)benzene instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 567 (M+H) +

[0243] Reference example G-32 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, using 1-bromo-4-(trifluoromethoxy)benzene instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 559 (M+H) +

[0244] Reference example G-33 (S)-tert-butyl 1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, using 1-bromo-4-(trifluoromethyl)benzene instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 543 (M+H) +

[0245] Reference example G-34 (S)-tert-butyl 2-((3-(1-(4-cyanophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 4-bromobenzonitrile was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 500 (M+H) +

[0246] Reference example G-35 (S)-tert-Butyl 1-methyl-2-((3-(1-(4-nitrophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-nitrobenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 520 (M+H) +

[0247] Reference example G-36 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(quinolin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, using 3-bromoquinoline instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 526 (M+H) +

[0248] Reference example G-37 (S)-tert-Butyl 1-methyl-2-((3-(1-(4-morpholinophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained in the same manner as in Reference Example G-25, except that 4-(4-iodophenyl)morpholine was used instead of 4-bromo-N,N-dimethylaniline.

[0249] Reference example G-38 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(4-phenylcyclohexyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate To a mixture of Reference Example I-1 (100 mg), 4-phenylcyclohexan-1-ol (44 mg), triphenylphosphine (99 mg) and THF (3 mL) was slowly added DEAD (40% toluene solution, 0.171 mL) under ice-cooling and stirring. The reaction mixture was stirred at the same temperature for 10 minutes and further stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (59 mg). MS (ESI_APCI, m / z): 557 (M+H) +

[0250] Reference example G-39 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(4-vinylphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-vinylbenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 501 (M+H) +

[0251] Reference example G-40 (S)-tert-Butyl 1-methyl-2-((3-(2-oxo-1-(thiophen-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 3-bromothiophene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 481 (M+H) +

[0252] Reference example G-41 (S)-tert-Butyl 2-((3-(1-benzyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-38, except that benzyl alcohol was used instead of 4-phenylcyclohexan-1-ol. MS (ESI_APCI, m / z): 489 (M+H) +

[0253] Reference example G-42 (S)-tert-Butyl 2-((3-(1-(4-cyclopropylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 1-bromo-4-cyclopropylbenzene was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 515 (M+H) +

[0254] Reference example G-43 (S)-tert-Butyl 2-((3-(1-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate The title compound was obtained by the same method as in Reference Example G-25, except that 4-bromophenol was used instead of 4-bromo-N,N-dimethylaniline. MS (ESI_APCI, m / z): 491 (M+H) +

[0255] Reference example G-44 (S)-1-Methyl-2-((3-(1-(4'-(methylsulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate tert-butyl ester A mixture of Reference Example G-29 (50 mg), 4-(methylsulfonylamino)phenylboronic acid (25 mg), Pd(amphos)Cl2 (6.8 mg), sodium carbonate (25 mg), DMF (1 mL) and water (0.1 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (37 mg). MS (ESI_APCI, m / z): 644 (M+H) +

[0256] Reference example G-45 (S)-tert-butyl 2-((3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate Triethylamine (0.065 mL) and Reference Example J-2 (36 mg) were added to a mixture of Reference Example F-39 (72 mg) and THF (3 mL). The reaction mixture was stirred at room temperature for 5 minutes. NaBH(OAc)3 (98 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. Methanol was added to the reaction mixture, and the mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 30 / 70) to obtain the title compound (65 mg). MS (ESI_APCI, m / z): 623 (M+H) +

[0257] Reference example G-46 (S)-tert-butyl 2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate To a mixture of Reference Example F-34 (18 mg), triethylamine (0.024 mL) and THF (1.0 mL), Reference Example J-2 (8.7 mg) and NaBH(OAc)3 (15 mg) were added. The reaction mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (20 mg). MS (ESI_APCI, m / z): 678 (M+H) +

[0258] Reference example G-47 (S)-tert-butyl 2-((3-(1-([1,1'-biphenyl]-4-yl)-5-((2-methoxy-2-oxoethyl)carbamoyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate Reference Example J-2 (40 mg) and NaBH(OAc)3 (67 mg) were added to a mixture of Reference Example F-35 (79 mg), triethylamine (0.11 mL) and THF (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) to obtain the title compound (92 mg).

[0259] Reference example K-1 Methyl (S)-(4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoyl)glycinate A mixture of Example 21 (50 mg), glycine methyl ester hydrochloride (15 mg), EDC·HCl (31 mg), HOBt·H2O (22 mg), triethylamine (0.119 mL) and DMF (1 mL) was stirred at room temperature overnight. Water, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture and stirred, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (7 mg). MS (ESI_APCI, m / z): 501 (M+H) +

[0260] Reference example K-3 Methyl (5-bromopyridine-2-carbonyl)glycinate A mixture of 5-bromopicolinic acid (300 mg), glycine methyl ester hydrochloride (224 mg), EDC·HCl (427 mg), HOBt·H2O (341 mg), triethylamine (1.03 mL) and THF (3 mL) was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture and stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 90 / 10 to 50 / 50) to obtain the title compound (247 mg).

[0261] Reference example K-4 (S)-tert-butyl 2-((3-(1-(6-((2-methoxy-2-oxoethyl)carbamoyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate A mixture of Reference Example I-1 (100 mg), Reference Example K-3 (75 mg), N,N'-dimethylethylenediamine (0.032 mL), copper (I) iodide (57 mg), potassium carbonate (83 mg) and acetonitrile (1 mL) was stirred at 100°C for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (25 mg). MS (ESI_APCI, m / z): 591 (M+H) +

[0262] The chemical structures of some reference examples are shown in the table below.

[0263] [Table 1]

[0264] Example G-5 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate methyl ester To a mixture of Reference Example F-8 (105 mg), 1-methyl-1H-imidazole-2-carbaldehyde (51 mg) and dichloromethane (2 mL), NaBH(OAc)3 (197 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (128 mg). MS (ESI_APCI, m / z): 509 (M+H) +

[0265] Example G-10 (S)-3'-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl Using Reference Example F-25 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m / z): 525 (M+H) +

[0266] Example G-11 (S)-2'-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl Using Reference Example F-26 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m / z): 525 (M+H) +

[0267] Example G-12 (S)-4-(5-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester Using Reference Example F-27 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m / z): 510 (M+H) +

[0268] Example G-13 (S)-4-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylate methyl Using Reference Example F-28 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m / z): 525 (M+H) +

[0269] Example G-15 (S)-2-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl Using Reference Example F-29 instead of Reference Example F-8, the title compound was obtained in the same manner as in Example G-5. MS (ESI_APCI, m / z): 525 (M+H) +

[0270] Example G-48 (S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl To a mixture of Reference Example F-23 (100 mg), 3-methyl-2-pyridinecarboxaldehyde (54 mg) and dichloromethane (2 mL), NaBH(OAc)3 (282 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (80 mg). MS (ESI_APCI, m / z): 520 (M+H) +

[0271] Example K-5 (S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-21 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (139 mg) and dichloromethane (2 mL), NaBH(OAc)3 (415 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (286 mg). MS (ESI_APCI, m / z): 545 (M+H) +

[0272] Example K-6 (S)-2-((3-(1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carbonitrile A mixture of Example K-5 (286 mg), tetrakis(triphenylphosphine)palladium(0) (61 mg), zinc cyanide (123 mg) and NMP (3 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (185 mg). MS (ESI_APCI, m / z): 492 (M+H) +

[0273] Example K-7 (S)-4'-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl To a mixture of Reference Example F-23 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (168 mg) and dichloromethane (2 mL), NaBH(OAc)3 (376 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (218 mg). MS (ESI_APCI, m / z): 587 (M+H) +

[0274] Example K-8 (S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl A mixture of Example K-7 (218 mg), tetrakis(triphenylphosphine)palladium(0) (43 mg), zinc cyanide (87 mg) and NMP (3 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (319 mg). MS (ESI_APCI, m / z): 534 (M+H) +

[0275] Example K-9 (S)-4'-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-carboxylate methyl To a mixture of Reference Example F-26 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (162 mg) and dichloromethane (3 mL), NaBH(OAc)3 (363 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (3 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (297 mg). MS (ESI_APCI, m / z): 603 (M+H) +

[0276] Example K-10 (S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-carboxylate methyl A mixture of Example K-9 (297 mg), tetrakis(triphenylphosphine)palladium(0) (57 mg), zinc cyanide (116 mg) and NMP (3 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water. The mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 80 / 20) to obtain the title compound (178 mg). MS (ESI_APCI, m / z): 550 (M+H) +

[0277] Example K-11 (S)-4-(5-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester To a mixture of Reference Example F-27 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (167 mg) and dichloromethane (2 mL), NaBH(OAc)3 (375 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (214 mg). MS (ESI_APCI, m / z): 588 (M+H) +

[0278] Example K-12 (S)-4-(5-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester A mixture of Example K-11 (214 mg), tetrakis(triphenylphosphine)palladium(0) (42 mg), zinc cyanide (86 mg) and NMP (3 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water. The mixture was stirred and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (244 mg). MS (ESI_APCI, m / z): 535 (M+H) +

[0279] Example K-13 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-1 instead of Reference Example F-27, the title compound was obtained in the same manner as in Example K-11. MS (ESI_APCI, m / z): 529 (M+H) +

[0280] Example K-14 (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carbonitrile Using Example K-13 instead of Example K-11, the title compound was obtained in the same manner as in Example K-12. MS (ESI_APCI, m / z): 476 (M+H) +

[0281] Example K-15 (S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Using Reference Example F-3 instead of Reference Example F-27, the title compound was obtained in the same manner as in Example K-11. MS (ESI_APCI, m / z): 453 (M+H) +

[0282] Example K-16 (S)-1-Methyl-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carbonitrile A mixture of Example K-15 (103 mg), tetrakis(triphenylphosphine)palladium(0) (26 mg), zinc cyanide (53 mg) and DMF (1 mL) was stirred at 150° C. for 1 hour under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (75 mg). MS (ESI_APCI, m / z): 400 (M+H) +

[0283] Example K-17 (R)-4-(5-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester Using Reference Example F-36 instead of Reference Example F-27, the title compound was obtained in the same manner as in Example K-11. MS (ESI_APCI, m / z): 588 (M+H) +

[0284] Example K-18 (R)-4-(5-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid methyl ester Using Example K-17 instead of Example K-15, the title compound was obtained in the same manner as in Example K-16. MS (ESI_APCI, m / z): 535 (M+H) +

[0285] Example 1 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-1 (20 mg), 3-methyl-2-pyridinecarboxaldehyde (8.0 mg) and dichloromethane (1 mL), NaBH(OAc)3 (65 mg) was added. The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 50 / 50) to obtain the title compound (16 mg).

[0286] Example 2 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-1 (20 mg), 1-methyl-1H-imidazole-2-carbaldehyde (7.2 mg) and dichloromethane (1 mL), NaBH(OAc)3 (65 mg) was added. The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) and then ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70) to obtain the title compound (11 mg).

[0287] Example 3 (R)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-2 (20 mg), 1-methyl-1H-imidazole-2-carbaldehyde (11 mg) and dichloromethane (1 mL), NaBH(OAc)3 (65 mg) was added. The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70) to obtain the title compound (10 mg).

[0288] Example 4 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(pyridin-2-ylmethyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 2, except that 2-pyridinecarboxaldehyde was used instead of 1-methyl-1H-imidazole-2-carbaldehyde.

[0289] Example 5 (S)-3-(1-((1H-imidazol-4-yl)methyl)pyrrolidin-3-yl)-1-([1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that 1H-imidazole-4-carbaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

[0290] Example 6 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-4-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride NaBH(OAc)3 (81 mg) was added to a mixture of Reference Example F-1 (30 mg), 1-methyl-1H-imidazole-4-carbaldehyde (17 mg) and dichloromethane (1 mL), and the mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 90 / 10). Hydrogen chloride (1 mol / L, ethanol solution, 0.2 mL) was added to the resulting product, and the mixture was stirred. The mixture was concentrated under reduced pressure to obtain the title compound (37 mg).

[0291] Example 7 (S)-3-(1-((1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-([1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that 1H-imidazole-2-carbaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

[0292] Example 8 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((3-hydroxypyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that 3-hydroxypyridine-2-carboxaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

[0293] Example 9 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((5-hydroxypyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that 5-hydroxypyridine-2-carboxaldehyde was used instead of 3-methyl-2-pyridinecarboxaldehyde.

[0294] Example 10 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((4-hydroxypyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-1 (30 mg), 4-hydroxypyridine-2-carboxaldehyde (19 mg) and dichloromethane (1 mL), NaBH(OAc)3 (65 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70) to obtain the title compound (14 mg).

[0295] Example 11 (S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride NaBH(OAc)3 (268 mg) was added to a mixture of Reference Example F-3 (100 mg), 1-methyl-1H-imidazole-2-carbaldehyde (70 mg) and dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) and then ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70). Hydrogen chloride (4 mol / L, ethyl acetate solution, 2 mL) was added to the resulting product and stirred. The mixture was concentrated under reduced pressure to obtain the title compound (59 mg).

[0296] Example 12 1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)piperidin-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one NaBH(OAc)3 (495 mg) was added to a mixture of Reference Example F-4 (237 mg), 1-methyl-1H-imidazole-2-carbaldehyde (128 mg) and dichloromethane (3 mL). The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. Water was added to the reaction mixture and stirred, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 20 / 80) and then ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70) to obtain the title compound (144 mg).

[0297] Example 13 1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)azetidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-5 (105 mg), 1-methyl-1H-imidazole-2-carbaldehyde (61 mg) and dichloromethane (2 mL), NaBH(OAc)3 (354 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70). Hydrogen chloride (4 mol / L, ethyl acetate solution) and methanol were added to the resulting product and stirred. The mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70) to obtain the title compound (2.8 mg).

[0298] Example 14 (S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 3, except that Reference Example F-21 was used instead of Reference Example F-2.

[0299] Example 15 (S)-4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoic acid methyl ester The title compound was obtained in the same manner as in Example 1, except that Reference Example F-6 was used instead of Reference Example F-1.

[0300] Example 16 (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid A mixture of Reference Example G-1 (26 mg), methanol (0.5 mL) and THF (0.5 mL) was added with aqueous sodium hydroxide solution (5 mol / L, 1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with hydrochloric acid (2 mol / L). The mixture was purified by ODS column chromatography (elution solvent: water / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (9.5 mg).

[0301] Example 17 (S)-6-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)nicotinic acid The title compound was obtained in the same manner as in Example 16, except that Reference Example G-2 was used instead of Reference Example G-1.

[0302] Example 18 (S)-2-((3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid The title compound was obtained in the same manner as in Example 16, except that Reference Example G-3 was used instead of Reference Example G-1.

[0303] Example 19 (S)-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid The title compound was obtained in the same manner as in Example 16, except that Reference Example G-4 was used instead of Reference Example G-1.

[0304] Example 20 (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid To a mixture of Example G-5 (118 mg), methanol (0.5 mL) and THF (0.5 mL), an aqueous sodium hydroxide solution (5 mol / L, 1 mL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with hydrochloric acid (2 mol / L) and stirred for 20 minutes. The precipitate was collected by filtration, and the obtained solid was dried to obtain the title compound (44 mg).

[0305] Example 21 (S)-4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoic acid hydrochloride Aqueous sodium hydroxide solution (5 mol / L, 2 mL) was added to a mixture of Example 15 (257 mg), methanol (1 mL), and THF (1 mL). The reaction mixture was stirred at room temperature for 3 hours. Hydrochloric acid (2 mol / L, 5 mL) was added to the reaction mixture to neutralize it. The mixture was concentrated under reduced pressure. Dichloromethane and anhydrous magnesium sulfate were added to the obtained residue. The mixture was stirred for 10 minutes. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Dichloromethane and hydrogen chloride (4 mol / L, ethyl acetate solution, 1 mL) were added to the obtained residue, and the mixture was stirred. The mixture was concentrated under reduced pressure to give the title compound (120 mg).

[0306] Example 22 (S)-1-Methyl-2-((3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid Hydrogen chloride (4 mol / L, ethyl acetate solution, 2 mL) was added to a mixture of Reference Example G-23 (154 mg), ethyl acetate (1 mL) and methanol (0.5 mL). The reaction mixture was heated under reflux for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%) / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (107 mg).

[0307] Example 23 2-((4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpiperidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-6 (73 mg), dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was heated under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%) / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (39 mg).

[0308] Example 24 (S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-6-methoxy-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-7 (145 mg), water (0.5 mL), and concentrated sulfuric acid (0.024 mL) was stirred at 90°C for 3 hours. The reaction mixture was allowed to cool to room temperature, and then methanol (0.5 mL) and lithium hydroxide monohydrate (95 mg) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%) / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (85 mg).

[0309] Example 25 2-(((3R,4R)-3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-fluoropyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 24, except that Reference Example G-8 was used instead of Reference Example G-7.

[0310] Example 26 (S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 24, except that Reference Example G-9 was used instead of Reference Example G-7.

[0311] Example 27 (S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-45 (65 mg), methanol (0.2 mL), water (1 mL) and concentrated sulfuric acid (0.04 mL) was stirred at 110° C. for 1 hour under microwave irradiation. Lithium hydroxide monohydrate (100 mg) was added to the reaction mixture and stirred at 50° C. for 1 hour. The reaction mixture was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%) / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (27 mg).

[0312] Example 28 (S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 3, except that Reference Example F-13 was used instead of Reference Example F-2.

[0313] Example 29 (S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(2'-methyl-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 3, except that Reference Example F-14 was used instead of Reference Example F-2.

[0314] Example 30 (R)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 3, except that Reference Example F-15 was used instead of Reference Example F-2.

[0315] Example 31 (S)-1-(4'-Fluoro-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that Reference Example F-16 was used instead of Reference Example F-1.

[0316] Example 32 (S)-1-(4'-Methoxy-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that Reference Example F-17 was used instead of Reference Example F-1.

[0317] Example 33 (S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that Reference Example F-18 was used instead of Reference Example F-1.

[0318] Example 34 (S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carbonitrile The title compound was obtained in the same manner as in Example 1, except that Reference Example F-19 was used instead of Reference Example F-1.

[0319] Example 35 (S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 1, except that Reference Example F-20 was used instead of Reference Example F-1.

[0320] Example 36 (S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride NaBH(OAc)3 (127 mg) was added to a mixture of Reference Example F-22 (43 mg), 1-methyl-1H-imidazole-2-carbaldehyde (22 mg) and dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by ODS column chromatography (elution solvent: water / acetonitrile = 80 / 20 to 30 / 70). Hydrogen chloride (4 mol / L, ethyl acetate solution) and methanol were added to the resulting product and stirred. The mixture was concentrated under reduced pressure to obtain the title compound (25 mg).

[0321] Example 37 (S)-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl The title compound was obtained in the same manner as in Example 3, except that Reference Example F-23 was used instead of Reference Example F-2.

[0322] Example 38 (R)-3'-Methyl-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate methyl The title compound was obtained in the same manner as in Example 3, except that Reference Example F-24 was used instead of Reference Example F-2.

[0323] Example 39 (S)-3'-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid A mixture of Example G-10 (20 mg), methanol (0.5 mL), THF (0.5 mL) and aqueous sodium hydroxide solution (5 mol / L, 1 mL) was stirred at room temperature overnight. Hydrochloric acid (2 mol / L, 2.5 mL) was added to the reaction mixture and stirred. The mixture was concentrated under reduced pressure. Methanol was added to the obtained residue and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography (elution solvent: water / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (6.3 mg).

[0324] Example 40 (S)-2'-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid The title compound was obtained in the same manner as in Example 39, except that Example G-11 was used instead of Example G-10.

[0325] Example 41 (S)-4-(5-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid The title compound was obtained in the same manner as in Example 39, except that Example G-12 was used instead of Example G-10.

[0326] Example 42 (S)-4-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylic acid The title compound was obtained in the same manner as in Example 16, except that Example G-13 was used instead of Reference Example G-1.

[0327] Example 43 (S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid The title compound was obtained in the same manner as in Example 16, except that Reference Example G-14 was used instead of Reference Example G-1.

[0328] Example 44 (S)-2-Hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid The title compound was obtained in the same manner as in Example 16, except that Example G-15 was used instead of Reference Example G-1.

[0329] Example 45 (S)-2-((3-(1-(4'-carboxy-2-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid A mixture of Reference Example G-16 (207 mg), methanol (0.5 mL) and THF (0.5 mL) was added with aqueous sodium hydroxide solution (5 mol / L, 1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with hydrochloric acid. The mixture was purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2 to 30 / 70) to obtain the title compound (109 mg).

[0330] Example 46 (S)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid A mixture of Reference Example G-17 (455 mg), methanol (0.5 mL) and THF (0.5 mL) was added with an aqueous sodium hydroxide solution (5 mol / L, 1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized by adding hydrochloric acid (2 mol / L), and the precipitate was collected by filtration. The obtained solid was purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2 to 30 / 70) to obtain the title compound (280 mg).

[0331] Example 47 (S)-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid Aqueous sodium hydroxide solution (5 mol / L, 1 mL) was added to a mixture of Example 37 (48 mg), methanol (0.5 mL) and THF (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. Hydrochloric acid (2 mol / L, 2.5 mL) was added to the reaction mixture and mixed. The mixture was concentrated under reduced pressure. Methanol was added to the obtained residue and mixed. Insoluble matter was removed through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography (elution solvent: water / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (17 mg).

[0332] Example 48 (R)-3'-Methyl-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid The title compound was obtained in the same manner as in Example 47, except that Example 38 was used instead of Example 37.

[0333] Example 49 (S)-2-((3-(1-(4'-carboxy-3-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-18 (450 mg) and concentrated hydrochloric acid (2 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was left to stand at room temperature, and the precipitate was collected by filtration. The obtained solid was washed with cold water and dried. A part of the obtained product (26 mg out of 222 mg) was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%) / acetonitrile = 98 / 2 to 30 / 70) to obtain the title compound (15 mg).

[0334] Example 50 (S)-2-((3-(1-(6-(4-carboxy-2-methylphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-19 (413 mg) and concentrated hydrochloric acid (2 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L), and insoluble matter was removed by filtration. The filtrate was purified by ODS column chromatography (elution solvent: aqueous formic acid solution (0.1%) / acetonitrile=90 / 10-70 / 30-10 / 90) to obtain the title compound (224 mg).

[0335] Example 51 (S)-2-((3-(1-(3'-carboxy-2,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid A mixture of Reference Example G-20 (188 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. Concentrated sulfuric acid (0.2 mL) was added to the reaction mixture under stirring and ice cooling. The reaction mixture was heated under reflux for 4 days. After the reaction mixture was allowed to cool to room temperature, an aqueous sodium hydroxide solution (5 mol / L) was added to neutralize it. The precipitate was collected by filtration. The obtained solid was purified by ODS column chromatography (elution solvent: water / acetonitrile=98 / 2-30 / 70) to obtain the title compound (16 mg).

[0336] Example 52 (S)-2-((3-(1-(6-(3-carboxy-4-hydroxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid The title compound was obtained in the same manner as in Example 51, except that Reference Example G-21 was used instead of Reference Example G-20.

[0337] Example 53 (S)-2-((3-(1-(3'-carboxy-3,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid A mixture of Reference Example G-22 (77 mg), water (0.5 mL) and concentrated sulfuric acid (0.5 mL) was heated under reflux for 7 hours. The reaction mixture was allowed to cool to room temperature, and then an aqueous sodium hydroxide solution (5 mol / L, 4 mL) was added under ice cooling. The mixture was stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2 to 30 / 70) to obtain the title compound (3 mg).

[0338] Example 54 (S)-2-((3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-24 was used instead of Reference Example G-6.

[0339] Example 55 (S)-2-((3-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-25 was used instead of Reference Example G-6.

[0340] Example 56 (S)-1-Methyl-2-((3-(2-oxo-1-(4-phenoxyphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-26 was used instead of Reference Example G-6.

[0341] Example 57 (S)-2-((3-(1-(4-benzylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-27 was used instead of Reference Example G-6.

[0342] Example 58 (S)-1-Methyl-2-((3-(2-oxo-1-(p-tolyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-28 was used instead of Reference Example G-6.

[0343] Example 59 (S)-2-((3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-29 was used instead of Reference Example G-6.

[0344] Example 60 (S)-1-Methyl-2-((3-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-30 was used instead of Reference Example G-6.

[0345] Example 61 (S)-2-((3-(1-(4-(ethylsulfonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-31 was used instead of Reference Example G-6.

[0346] Example 62 (S)-1-Methyl-2-((3-(2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-32 was used instead of Reference Example G-6.

[0347] Example 63 (S)-1-Methyl-2-((3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-33 was used instead of Reference Example G-6.

[0348] Example 64 (S)-2-((3-(1-(4-cyanophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-34 was used instead of Reference Example G-6.

[0349] Example 65 (S)-1-Methyl-2-((3-(1-(4-nitrophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-35 was used instead of Reference Example G-6.

[0350] Example 66 (S)-1-Methyl-2-((3-(2-oxo-1-(quinolin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-36 was used instead of Reference Example G-6.

[0351] Example 67 (S)-1-Methyl-2-((3-(1-(4-morpholinophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-37 was used instead of Reference Example G-6.

[0352] Example 68 (S)-1-Methyl-2-((3-(2-oxo-1-(4-phenylcyclohexyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-38 was used instead of Reference Example G-6.

[0353] Example 69 (S)-1-Methyl-2-((3-(2-oxo-1-(4-vinylphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-39 was used instead of Reference Example G-6.

[0354] Example 70 (S)-1-Methyl-2-((3-(2-oxo-1-(thiophen-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-40 was used instead of Reference Example G-6.

[0355] Example 71 (S)-2-((3-(1-benzyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-41 was used instead of Reference Example G-6.

[0356] Example 72 (S)-2-((3-(1-(4-cyclopropylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-42 was used instead of Reference Example G-6.

[0357] Example 73 (S)-2-((3-(1-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-43 was used instead of Reference Example G-6.

[0358] Example 74 (S)-1-Methyl-2-((3-(1-(4'-(methylsulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-44 was used instead of Reference Example G-6.

[0359] Example 75 (S)-(4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoyl)glycine A mixture of Reference Example K-1 (7.7 mg), methanol (0.5 mL) and THF (0.5 mL) was added with aqueous sodium hydroxide (5 mol / L, 1 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was purified by ODS column chromatography (elution solvent: water / acetonitrile = 90 / 10 to 30 / 70) to obtain the title compound (2.5 mg).

[0360] Example 76 (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-5-((tetrahydro-2H-pyran-4-yl)carbamoyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 23, except that Reference Example G-46 was used instead of Reference Example G-6.

[0361] Example 77 (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-5-((carboxymethyl)carbamoyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-47 (92 mg), methanol (0.5 mL), water (0.5 mL) and concentrated sulfuric acid (0.022 mL) was heated under reflux for 1 hour. The reaction mixture was allowed to cool to room temperature, and then lithium hydroxide monohydrate (70 mg) was added and stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (elution solvent: aqueous formic acid (0.1%) / acetonitrile = 98 / 2 to 30 / 70) to obtain the title compound (33 mg).

[0362] Example 78 (S)-2-((3-(1-(6-((carboxymethyl)carbamoyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 77, except that Reference Example K-4 was used instead of Reference Example G-47.

[0363] Example 79 (S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-22 (285 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (250 mg) and dichloromethane (2 mL), NaBH(OAc)3 (561 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (2 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 80 / 20 to 0 / 100) to obtain the title compound (363 mg).

[0364] Example 80 (S)-1-Methyl-2-((3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carbonitrile A mixture of Example 79 (351 mg), tetrakis(triphenylphosphine)palladium(0) (77 mg), zinc cyanide (155 mg) and NMP (3 mL) was stirred at 120° C. for 90 minutes under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated saline, then dried by adding anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (68 mg).

[0365] Example 81 (S)-1-Methyl-2-((3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid A mixture of Example 80 (190 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. Aqueous sodium hydroxide solution (5 mol / L) was added to the reaction mixture under ice cooling until a precipitate was formed. The precipitate was collected by filtration. The obtained solid was purified by ODS column chromatography (elution solvent: water / acetonitrile=98 / 2 to 30 / 70) to obtain the title compound (25 mg).

[0366] Example 82 (S)-2-((3-(1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-6 (150 mg) and concentrated hydrochloric acid (2 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and then purified by ODS column chromatography (elution solvent: water / acetonitrile=98 / 2-30 / 70) to obtain the title compound (83 mg).

[0367] Example 83 (S)-2-((3-(1-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-8 (199 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and then purified by ODS column chromatography (elution solvent: water / acetonitrile=98 / 2-30 / 70) to obtain the title compound (101 mg).

[0368] Example 84 (S)-2-((3-(1-(4'-carboxy-2-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-10 (178 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized with an aqueous sodium hydroxide solution (5 mol / L) and then purified by ODS column chromatography (elution solvent: water / acetonitrile = 98 / 2 to 30 / 70). A portion of the obtained product (16 mg out of 107 mg) was purified by ODS column chromatography (elution solvent: aqueous formic acid solution (0.1%) / acetonitrile = 98 / 2 to 30 / 70) to obtain the title compound (8 mg).

[0369] Example 85 (S)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-12 (195 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and insoluble matter was removed through Celite. The filtrate was purified by ODS column chromatography (elution solvent: water / acetonitrile=98 / 2-30 / 70) to obtain the title compound (60 mg).

[0370] Example 86 (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-14 (58 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L), and then concentrated under reduced pressure. DMSO was added to the resulting residue, and the insoluble matter was removed through Celite. The filtrate was purified by ODS column chromatography (elution solvent: water / acetonitrile=90 / 10-30 / 70) to obtain the title compound (2.2 mg).

[0371] Example 87 (S)-1-Methyl-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid A mixture of Example K-16 (75 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L). The mixture was diluted with DMSO, and then purified by ODS column chromatography (elution solvent: water / acetonitrile=98 / 2-30 / 70) to obtain the title compound (48 mg).

[0372] Example 88 (R)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Example K-18 (207 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110° C. for 1 hour under microwave irradiation. The reaction mixture was neutralized by adding an aqueous sodium hydroxide solution (5 mol / L). The precipitate was collected by filtration, and the obtained solid was dried to obtain the title compound (40 mg).

[0373] Example 89 (S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one To a mixture of Reference Example F-21 (35 mg), 3-methyl-2-pyridinecarboxaldehyde (18 mg) and dichloromethane (1 mL), NaBH(OAc)3 (94 mg) was added. The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane / ethyl acetate / methanol = 80 / 20 / 0-0 / 100 / 0-0 / 90 / 10) to obtain the title compound (32 mg).

[0374] Example 90 (S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The title compound was obtained in the same manner as in Example 89, except that Reference Example F-22 was used instead of Reference Example F-21.

[0375] Example 91 (S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid Aqueous sodium hydroxide solution (5 mol / L, 2 mL) was added to a mixture of Example G-48 (72 mg), methanol (1 mL) and THF (1 mL). The reaction mixture was stirred at room temperature for 4 hours. Hydrochloric acid (2 mol / L, 5 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes under ice cooling. The precipitate was collected by filtration, and the obtained solid was dried to obtain the title compound (37 mg).

[0376] The chemical structures, physical properties, and PHD2 inhibitory activity (see Test Example 1) of the examples are shown in the table below.

[0377] [Table 2]

[0378] [Table 3]

[0379] [Table 4]

[0380] [Table 5]

[0381] [Table 6]

[0382] [Table 7]

[0383] [Table 8]

[0384] [Table 9]

[0385] [Table 10]

[0386] [Table 11]

[0387] [Table 12]

[0388] [Table 13]

[0389] [Table 14]

[0390] [Table 15]

[0391] Test Example 1 PHD2 Inhibition Test (1) Human PHD2 184-418 Expression and preparation Human PHD2 containing amino acid residues 184 to 418 of the protein represented by GenBank accession ID: CAC42509 184-418 was expressed and prepared as follows. Human PHD2 184-418 The expression construct of human PHD2 was introduced into the pET-30a(+) vector and the sequence was confirmed. This vector was introduced into the BL21(DE3) strain and cultured at 37°C in LB medium containing antibiotics. After culture, a cell lysis solution was added to the cells, and the cells were disrupted and suspended by ultrasonication. The disrupted suspension was centrifuged, and the supernatant was purified using a Ni column to identify human PHD2. 184-418 obtained. (2) Test method HIF-1α containing amino acid residues 556-574 (partial peptide) of human HIF-1α 556-574 Human HIF-1α with FITC-Ahx incorporated at the N-terminus 556-574 (FITC-labeled HIF-1α 556-574 ) was used as the substrate. FITC-labeled HIF-1α 556-574 Using FITC-labeled HIF-1α, competitive inhibition between 2-oxoglutarate and a test compound (PHD inhibitor) was examined. 556-574 The change in fluorescence polarization was evaluated in the following manner. Enzyme (human PHD2 184-418 ) and substrate were diluted in assay buffer (pH 7.4) containing 10 mM HEPES, 150 mM NaCl, 10 μM MnCl2·4H2O, 2 μM 2-oxoglutarate, and 0.05% Tween-20. Test compounds were diluted in DMSO. Test compound, human PHD2 184-418 was added to a 384-well plate (Corning, black, opaque bottom) in advance, and FITC-labeled HIF-1α 556-574 The reaction was started by adding 100 mM NaCl. After incubation at 37°C for 60 minutes, the fluorescence polarization (excitation wavelength 470 nm, emission wavelength 530 nm) was measured using a PHERAstar FSX (BMG Labtech). The fluorescence polarization of each well was measured, and the human PHD2 binding inhibitory activity of the test compound was calculated based on the value of the group without the addition of the test substance. (3) Results As shown in the above table, the compounds of the present invention inhibited the binding of PHD2 to HIF-1α. Therefore, it was revealed that the compounds of the present invention are useful as PHD2 inhibitors.

[0392] Test Example 2 Therapeutic effect in a colitis model (1) TNBS-induced colitis model rats It is known that administration of TNBS into the rat large intestine induces local inflammation in the large intestine, disrupts the intestinal barrier function, and increases mesenteric permeability. Therefore, the inhibitory effect of oral administration of test compounds on mesenteric permeability was evaluated as an index of drug efficacy. (2) Test method Eight-week-old SLC:SD male rats (Japan SLC) were used. Under pentobarbital anesthesia, 300 μL of 28 mg / mL TNBS prepared with 50% ethanol was administered to the site 8 cm from the anus in the large intestine to induce inflammation. 300 μL of 50% ethanol was administered to the solvent treatment group. The rats were fasted for 48 hours before administration of TNBS. From the next day, the test compound (3 mg / kg) prepared in 0.05% methylcellulose solution was orally administered once a day for a total of three days. Three days after administration, 50 mg / kg FITC was orally administered 4 hours after administration of the test compound, and blood was collected from the jugular vein under isoflurane anesthesia 4 hours later. The serum was centrifuged, and the concentration of FITC that had permeated into the circulating blood via the mesentery was measured by detecting the fluorescence intensity with a PHERAstar FSX (BMG Labtech). The mesenteric permeability inhibition rate of the test compound was calculated based on the value of the group without test substance added being 0 and the value of the TNBS untreated group being 100. (3) Results The mesenteric permeability inhibition rate (%, average value) of each test compound is shown below. [Table 16] The intestinal membrane permeability of FITC, which was enhanced by administration of TNBS, was suppressed by administration of the compound of the present invention, demonstrating that the compound of the present invention is useful as a therapeutic agent for inflammatory bowel disease.

[0393] Test Example 3 Compound concentration in colon tissue (1) PK study in rats The test compound (3 mg / kg / 5 mL) prepared with 0.05% methylcellulose was orally administered to non-fasted rats (SD, 8 weeks old, male, Japan SLC). Blood was collected from the cervical vein 0.25, 0.5, 1, 2, 4, 6, and 8 hours after administration, and the rat was opened under isoflurane anesthesia to remove the large intestine. Approximately 5 cm of the distal large intestine was collected and cut open, and the removed large intestine was washed with physiological saline on a dish. After washing, the large intestine was minced with small scissors, and approximately 150 mg of it was transferred to a tube. 100 μL of physiological saline was added to the tube, and the mixture was homogenized with a shake master (1000 rpm x 30 minutes). 4 times the final volume of physiological saline was added to prepare the sample. The test compound concentrations in the colon tissue and plasma were measured by quantitative analysis using liquid chromatography mass spectrometry (LC / MS). (2) Compound concentrations in colon tissue and plasma As shown in the table below, it was revealed that the concentration of the compound of the present invention in the colon tissue was higher than the plasma concentration. Therefore, the preferred compound of the present invention is a PHD2 inhibitor that acts specifically on the colon tissue. [Table 17] The symbols in the table have the following meanings. Cmax: Maximum plasma concentration of the test compound after oral administration (ng / mL) AUC: Area under the plasma test compound concentration-time curve (ng*min / mL) Plasma: Plasma concentration of test compound after 8 hours (ng / mL) Colon: Concentration of the test compound in colon tissue after 8 hours (ng / g) C / P: Ratio of Colon to Plasma NC: Not Calculated (below calculation limit) [Industrial Applicability]

[0394] The production method of the present invention is useful as a method for producing a compound represented by formula (I) or a pharmacologically acceptable salt thereof.

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; Ring Z is a group selected from the group consisting of the following (a) to (c): 【Chemistry 2】 and 【Chemistry 3】 (In the formula, R a , R b and R c are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy, or carboxy; R d is a hydrogen atom or C 1-6 alkyl); R 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R 1 may be different from each other); R 2 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, -CO 2 R 4 , or -CONR 5 R 5’ (When n is 2 or 3, there are two or more R 2 may be different from each other); R 4 is a hydrogen atom or C 1-6 is alkyl; R 5 and R 5’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; R 3 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, hydroxy, cyano, nitro, -NR 6 R 6’ , -CO 2 R 7 , -CONR 8 R 8’ or a group A below (wherein when u is 2 or 3, there are two or more R 3 teeth may be different from each other); R 6 and R 6’ are each independently a hydrogen atom or C 1-6 is alkyl; R 7 is a hydrogen atom or C 1-6 is alkyl; R 8 and R 8’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; The group A is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; Substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy, cyano, -NR 9 R 9’ , -NR 9 SO 2 R 10 , -CO 2 R 10 , and -CONR 11 R 11’ The group consisting of: R 9 and R 9’ are each independently a hydrogen atom or C 1-6 is alkyl; R 10 is a hydrogen atom or C 1-6 is alkyl; R 11 and R 11’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; m, n, and u are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof, Formula (II): 【Chemistry 4】 wherein m, n, p and q are as defined above; R 1R is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group (when m is 2 or 3, two or more R 1R may be different from each other); R 2R is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy which may be protected by a protecting group, -CO 2 R 4R , or -CONR 5R R 5R’ (When n is 2 or 3, there are two or more R 2R may be different from each other); R 4R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; R X is a hydrogen atom or a group represented by formula (III): 【Chemistry 5】 (Wherein, rings W, u and r are as defined above; R 3R is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, hydroxyl which may be protected by a protecting group, cyano, nitro, -NR 6R R 6R’ , -CO 2 R 7R , -CONR 8R R 8R’ or the following group AA (wherein when u is 2 or 3, two or more R 3R may be different from each other); R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR 9R R 9R’ , -NR 9R SO 2 R 10R , -CO 2 R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; and R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 or a salt thereof; Formula (IV): 【Chemistry 6】 [During the ceremony, Ring ZZ is a group selected from the group consisting of the following (a) to (c): 【Chemistry 7】 and 【Chemistry 8】 (In the formula, R A , R B and R C are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group; R D is a protecting group, a hydrogen atom, or C 1-6 or a salt thereof, Formula (V): 【Chemistry 9】 [In the formula, ring ZZ, R 1R , R 2R , R X , m, n, p and q are as defined above] or a salt thereof.

2. The method according to claim 1, Formula (IIA): 【Chemistry 10】 [In the formula, R 1R , R 2R , R 3R , ring W, m, n, p, q, r and u have the same meanings as in claim 1. or a salt thereof; Using the compound represented by formula (IV) or a salt thereof, Formula (VA): 【Chemistry 11】 [In the formula, ring W, ring ZZ, R 1R , R 2R , R 3R , m, n, p, q, r and u have the same meanings as defined in claim 1] or a salt thereof.

3. The method according to claim 1, Formula (IIB): 【Chemistry 12】 [In the formula, R 1R , R 2R , m, n, p and q have the same meanings as in claim 1. or a salt thereof; Using the compound represented by formula (IV) or a salt thereof, Formula (VB): 【Chemistry 13】 [In the formula, ring ZZ, R 1R , R 2R , m, n, p and q have the same meanings as in claim 1. or a salt thereof.

4. Formula (I): 【Chemistry 14】 [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; Ring Z is a group selected from the group consisting of the following (a) to (c): 【Chemistry 15】 and 【Chemistry 16】 (In the formula, R a , R b and R c are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy, or carboxy; R d is a hydrogen atom or C 1-6 alkyl); R 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R 1 may be different from each other); R 2 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, -CO 2 R 4 , or -CONR 5 R 5’ (When n is 2 or 3, there are two or more R 2 may be different from each other); R 4 is a hydrogen atom or C 1-6 is alkyl; R 5 and R 5’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; R 3 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, hydroxy, cyano, nitro, -NR 6 R 6’ , -CO 2 R 7 , -CONR 8 R 8’ or a group A below (wherein when u is 2 or 3, there are two or more R 3 may be different from each other); R 6 and R 6’ are each independently a hydrogen atom or C 1-6 is alkyl; R 7 is a hydrogen atom or C 1-6 is alkyl; R 8 and R 8’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; The group A is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; Substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy, cyano, -NR 9 R 9’ , -NR 9 SO 2 R 10 , -CO 2 R 10 , and -CONR 11 R 11’ The group consisting of: R 9 and R 9’ are each independently a hydrogen atom or C 1-6 is alkyl; R 10 is a hydrogen atom or C 1-6 is alkyl; R 11 and R 11’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; m, n, and u are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof, Formula (IIC): 【Chemistry 17】 [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; R 1R is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group (when m is 2 or 3, two or more R 1R may be different from each other); R 2R is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy which may be protected by a protecting group, -CO 2 R 4R , or -CONR 5R R 5R’ (When n is 2 or 3, there are two or more R 2R may be different from each other); R 4R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; R 3RA is a halogen atom or a group AA; R 3RB and R 3RC are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, hydroxyl which may be protected by a protecting group, cyano, nitro, -NR 6R R 6R’ , -CO 2 R 7R , -CONR 8R R 8R’ or the group AA: R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR 9R R 9R’ , -NR 9R SO 2 R 10R , -CO 2 R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; and R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; m and n are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and r is an integer from 0 to 6. or a salt thereof.

5. Formula (I): 【Chemistry 18】 [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; Ring Z is a group selected from the group consisting of the following (a) to (c): 【Chemistry 19】 and 【Chemistry 20】 (In the formula, R a , R b and R c are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy, or carboxy; R d is a hydrogen atom or C 1-6 alkyl); R 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R 1 may be different from each other); R 2 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy, -CO 2 R 4 , or -CONR 5 R 5’ (When n is 2 or 3, there are two or more R 2 may be different from each other); R 4 is a hydrogen atom or C 1-6 is alkyl; R 5 and R 5’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; R 3 is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkyl sulfonyl, hydroxy, cyano, nitro, -NR 6 R 6’ , -CO 2 R 7 , -CONR 8 R 8’ or a group A below (wherein when u is 2 or 3, there are two or more R 3 may be different from each other); R 6 and R 6’ are each independently a hydrogen atom or C 1-6 is alkyl; R 7 is a hydrogen atom or C 1-6 is alkyl; R 8 and R 8’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; The group A is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group B 3-8 Cycloalkyl, and (h) a 3- to 8-membered heterocycloalkyl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group B; Substituent group B is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy, cyano, -NR 9 R 9’ , -NR 9 SO 2 R 10 , -CO 2 R 10 , and -CONR 11 R 11’ The group consisting of: R 9 and R 9’ are each independently a hydrogen atom or C 1-6 is alkyl; R 10 is a hydrogen atom or C 1-6 is alkyl; R 11 and R 11’ are each independently a hydrogen atom, C 1-6 Alkyl, Carboxy C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; m, n, and u are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and and r is an integer of 0 to 6; or a pharmacologically acceptable salt thereof, Formula (VC): 【Chemistry 21】 [During the ceremony, Ring W is C 6-10 Aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; Ring ZZ is a group selected from the group consisting of the following (a) to (c): 【Chemical 22】 and 【Chemistry 23】 (In the formula, R A , R B and R C are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group; R D is a protecting group, a hydrogen atom, or C 1-6 alkyl); R 1R is a hydrogen atom, a halogen atom, C 1-6 alkyl, cyano, hydroxy which may be protected by a protecting group, or carboxy which may be protected by a protecting group (when m is 2 or 3, two or more R 1R may be different from each other); R 2R is a hydrogen atom, a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, hydroxy which may be protected by a protecting group, -CO 2 R 4R , or -CONR 5R R 5R’ (When n is 2 or 3, there are two or more R 2R may be different from each other); R 4R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 5R and R 5R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; R 3RA is a halogen atom or a group AA; R 3RB and R 3RC are each independently a hydrogen atom, a halogen atom, or C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkylsulfanyl, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, hydroxyl which may be protected by a protecting group, cyano, nitro, -NR 6R R 6R’ , -CO 2 R 7R , -CONR 8R R 8R’ or the group AA: R 6R and R 6R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 7R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 8R and R 8R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; The group AA is a group selected from the group consisting of the following (a) to (h): (a) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl, (b) a 5- or 6-membered heteroaryl which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (c) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryl C 1-6 Alkyl, (d) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 6-10 Aryloxy, (e) a 5- or 6-membered heteroaryl C which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 1-6 Alkyl, (f) a 5- or 6-membered heteroaryloxy which is unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; (g) C unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB 3-8 Cycloalkyl, and (h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from the substituent group BB; The substituent group BB is a halogen atom, C 1-6 Alkyl, haloC 1-6 Alkyl, C 1-6 Alkoxy, HaloC 1-6 Alkoxy, hydroxy which may be protected by a protecting group, cyano, -NR 9R R 9R’ , -NR 9R SO 2 R 10R , -CO 2 R 10R , and -CONR 11R R 11R’ The group consisting of: R 9R and R 9R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 is alkyl; R 10R is a protecting group, a hydrogen atom, or C 1-6 is alkyl; and R 11R and R 11R’ each independently represents a protecting group, a hydrogen atom, or C 1-6 Alkyl, optionally protected carboxy C 1-6 Alkyl, optionally protected hydroxyl C 1-6 Alkyl, haloC 1-6 Alkyl, C 3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl; m and n are each independently an integer from 1 to 3; p and q are each independently 1 or 2; and r is an integer from 0 to 6. or a salt thereof.

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