HK40050961B - Imidazopyridinone compound - Google Patents

Description

imidazopyridone compounds

Technical Field

This invention relates to imidazopyridone compounds that can be used as pharmaceuticals. More specifically, this invention relates to imidazopyridone compounds or pharmaceutically acceptable salts thereof that have prolyl hydroxylase inhibitory activity and can be used as agents for treating inflammatory bowel diseases such as ulcerative colitis.

Background Technology

Inflammatory bowel disease (IBD) is a chronic disease in which inflammation and ulceration occur in the intestinal mucosa due to an excessive immune response. IBD includes, for example, ulcerative colitis and Crohn's disease.

Ulcerative colitis is a diffuse, nonspecific inflammatory disease of the large intestine that causes unexplained inflammation. The colonic mucosa is eroded, and erosions or ulcers may develop within the mucosa. Ulcerative colitis can be divided into an "active phase," in which bloody stools, erosions, and ulcers are observed, and a "remission phase," in which these observations disappear. Because relapses and remissions are frequent during treatment, long-term treatment is necessary.

For the treatment of ulcerative colitis, 5-aminosalicylic acid (5-ASA) preparations are initially used as standard agents. However, the efficacy of 5-ASA is approximately 50 to 65%, and only about 30 to 45% of patients experience remission after administration of 5-ASA. When no effect of 5-ASA is observed, steroids are used. In addition to these drugs, immunosuppressants, anti-TNF-α antibodies, etc., are sometimes used to treat ulcerative colitis. However, all of these drugs have problems, such as side effects and the need for careful administration. Therefore, there is a need for therapeutic agents for ulcerative colitis with novel modes of action.

It is known that in the pathological condition of IBD, the expression of genes related to the barrier function of the gastrointestinal epithelium is induced by hypoxia-inducible factor 1α (HIF-1α). HIF-1α is one of the subtypes of hypoxia-inducible factor α (HIF-α). HIF-α becomes stable in a hypoxic environment (hypoxia), and then it responds to hypoxia by activating the transcription of several genes. Conversely, in an aerobic environment (noroxic), the proline residues of HIF-α are hydroxylated by prolyl hydroxylase (PHD), and then HIF-α is degraded via the proteasome pathway.

PHD is known to have three subtypes: PHD1, PHD2, and PHD3. AKB-4924 is known to be a PHD2 inhibitor. AKB-4924 has been reported to stabilize HIF-1α in colonic tissue (Non-Patent Literature 1). Furthermore, AKB-4924 has a moderating effect in a trinitrobenzenesulfonic acid (TNBS)-induced colitis model.

In contrast, PHD inhibitors such as roxadustat and daprodustat have hematopoietic effects and have been developed as treatments for anemia (Non-Patent Literature 2). Therefore, when using PHD inhibitors as treatments for IBD, it is important to avoid systemic effects such as hematopoietic effects.

For example, spiro compounds as PHD inhibitors are described in Patent Documents 1 and 5 and Non-Patent Documents 3 and 4. Compounds comprising imidazopyridones are described or illustrated in Patent Documents 2 to 4. However, the aforementioned documents neither describe nor suggest the imidazopyridone compounds of the present invention.

Citation List

Patent documents

Patent Document 1: U.S. Patent Application Publication No. 2011/0152304

Patent Document 2: WO 2009/029609

Patent Document 3: WO 2003/037890

Patent Document 4: WO 2017/066014

Patent Document 5: U.S. Patent Application Publication No. 2010/0137297

Non-patent literature

Non-patent literature 1: Ellen Marks et al., "Inflamm.Bowel.Dis." 2015, Vol.21, No.2, pp.267-275

Non-patent literature 2: Mun Chiang Chan et al., "Molecular Aspects of Medicine", 2016, Vol. 47-48, pp. 54-75.

Non-patent literature 3: Guanghui Deng et al., "Bioorganic & Medicinal Chemistry", 2013, Vol.21, pp.6349-6358

Non-patent literature 4: Petr Vachal et al., "Journal of Medicinal Chemistry", 2012, Vol. 55, pp. 2945-2959

Summary of the Invention

The problem to be solved by this invention

The present invention aims to provide a novel compound with PHD2 inhibitory activity that can be used to treat inflammatory bowel disease.

means of solving the problem

This invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. That is, this invention relates to the following [1] to [16], etc.

[1] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

in

The ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _{3- or 8-} membered cycloalkyl or 3- to 8-membered heterocycloalkyl;

Ring Z is a group selected from (a) to (c) below:

[Chemical Formula 2]

and

[Chemical Formula 3]

in

^Ra , ^Rb , and ^Rc are each independently a hydrogen atom, a halogen atom, a _C1-6 alkyl group, a cyano group, a hydroxyl group, or a carboxyl group; and

R ^d is a hydrogen atom or a _C1-6 alkyl group;

^R1 is a hydrogen atom, a halogen atom, a _C1-6 alkyl group, a cyano group, a hydroxyl group, or a carboxyl group, wherein when m is 2 or 3, two or more ^R1s may be different from each other;

^R2 is a hydrogen atom, a halogen atom, a _C1-6 alkyl, a halo- _C1-6 alkyl, a _C1-6 alkoxy, a ^hydroxyl , _-CO2R4 or ^{-CONR5R5 '} , wherein when n is 2 or 3, two or more ^R2s may be different from each other;

^R4 is a hydrogen atom or a _C1-6 alkyl group; and

^R5 and R5 ^' are each independently a hydrogen atom, a _C1-6 alkyl group, a carboxyl _C1-6 alkyl group, a hydroxyl _C1-6 alkyl group, a halo- _C1-6 alkyl group, a _C3-8 cycloalkyl group, or a 3- to 8-membered heterocyclic alkyl group;

^R3 is a hydrogen atom, a halogen atom, a _C1-6 alkyl group, a halo _-C1-6 alkyl group, a _C1-6 alkoxy group, a halo _-C1-6 alkoxy group, a _C2-6 alkenyl group, a _C2-6 alkynyl group, a _C1-6 alkyl hydrogen sulfoyl group, a _C1-6 alkyl sulfinyl group, a _C1-6 alkyl sulfonyl group, a hydroxyl group, a cyano group, a nitro group ^{, -NR6R6 '} , _-CO2R7 , ^{-CONR8R8 '} , or the following group A, wherein when u is 2 or 3, two or more ^R3s may be different from each other;

^R6 and R6 ^' are each independently a hydrogen atom or a _C1-6 alkyl group;

R ⁷ is a hydrogen atom or a _C1-6 alkyl group;

^R8 and R8 ^' are each independently a hydrogen atom, a _C1-6 alkyl group, a carboxyl _C1-6 alkyl group, a hydroxyl _C1-6 alkyl group, a halo- _C1-6 alkyl group, a _C3-8 cycloalkyl group, or a 3- to 8-membered heterocyclic alkyl group;

Group A is selected from the following groups (a) to (h):

(a) Unsubstituted or substituted _C6-10 aryl groups, or substituted with 1 to 3 groups selected from substituent group B.

(b) Unsubstituted or substituted with 1 to 3 groups selected from substituent group B, 5- or 6-membered heteroaryl groups,

(c) Unsubstituted or substituted _C6-10 aryl- _C1-6 alkyl groups selected from substituent group B,

(d) Unsubstituted or substituted _C6-10 aryloxy groups, or those substituted with 1 to 3 groups selected from substituent group B.

(e) Unsubstituted or substituted with 1 to 3 groups selected from substituent group B, 5- or 6-membered heteroaryl _C1-6 alkyl.

(f) Unsubstituted or substituted with 1 to 3 groups selected from substituent group B, 5- or 6-membered heteroaryloxy groups,

(g) Unsubstituted _C3-8 cycloalkyl groups or those substituted with 1 to 3 groups selected from substituent group B, and

(h) Unsubstituted or substituted with 1 to 3 groups selected from substituent group B, 3- to 8-membered heterocyclic alkyl groups,

Substituent group B is composed of halogen atoms, _C1-6 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, ^hydroxyl , ^cyano , ^{-NR9R9 '} , _-NR9SO2R10 , _-CO2R10 ^{and -CONR11R11 '} .

^R9 and R9 ^' are each independently a hydrogen atom or a _C1-6 alkyl group;

R ¹⁰ is a hydrogen atom or a _C1-6 alkyl group; and

^R11 and R11 ^' are each independently a hydrogen atom, a _C1-6 alkyl group, a carboxyl _C1-6 alkyl group, a hydroxyl _C1-6 alkyl group, a halo- _C1-6 alkyl group, a _C3-8 cycloalkyl group, or a 3- to 8-membered heterocyclic alkyl group;

m, n, and u are each an independent integer from 1 to 3;

p and q are each independently 1 or 2; and

r is an integer from 0 to 6.

[2] The compound or its pharmaceutically acceptable salt according to [1] above, wherein ring Z is a group selected from (a) to (j) below:

[Chemical Formula 4]

and

[Chemical Formula 5]

[3] The compound or its pharmaceutically acceptable salt according to [1] or [2] above, wherein the ring W is phenyl or 5- or 6-heteroaryl.

[4] The compound or its pharmaceutically acceptable salt according to any one of [1] to [3] above, wherein r is 0.

[5] The compound or its pharmaceutically acceptable salt according to any one of [1] to [4] above, wherein p is 2 and q is 1.

[6] The compound or its pharmaceutically acceptable salt according to any one of [1] to [5] above, wherein ^R1 is a hydrogen atom or a halogen atom.

[7] The compound or its pharmaceutically acceptable salt according to any one of [1] to [6] above.

Where ^R2 is a hydrogen atom, a _C1-6 alkyl group, a halo _-C1-6 alkyl group, a _C1-6 alkoxy group, a carboxyl group, or ^{-CONR5R5 '} ;

^R5 and R5 ^' are each independently a hydrogen atom, a carboxyl _C1-6 alkyl group, or a 3- to 8-membered heterocyclic alkyl group.

[8] The compound or its pharmaceutically acceptable salt according to any one of [1] to [7] above.

Wherein ^R3 is a hydrogen atom, halogen atom, _C1-6 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, _C2-6 alkenyl, _C1-6 alkyl hydrogen sulfo, _C1-6 alkyl sulfonyl, _hydroxyl , ^cyano , -CO2R7, ^{-CONR8R8 '} or group A;

^R7 and u have the same meaning as described in [1] above;

^R8 and R8 ^' are each independently a hydrogen atom or a carboxyl _C1-6 alkyl group; and

Group A is an unsubstituted phenyl or an unsubstituted 5- or 6-membered heteroaryl group, substituted with 1 to 3 groups selected from substituent group B.

Substituent group B is a halogen atom, a _C1-6 alkyl group, a halo _-C1-6 alkyl group, a _C1-6 alkoxy group, a halo- _C1-6 alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group.

[9] The compound or pharmaceutically acceptable salt thereof according to any one of [3] to [8] above, wherein ring Z is a group selected from (a) to (e):

[Chemical Formula 6]

and

[Chemical Formula 7]

[10] A compound or a pharmaceutically acceptable salt thereof represented by the following formula:

[Chemical Formula 8]

in

X is CR ³ or N;

u is 1 or 2;

^R1 has the same meaning as described in [6] above;

^R2 has the same meaning as described above [7];

^R3 is a hydrogen atom, a _C1-6 alkyl group, or a hydroxyl group;

Group A has the same meaning as described above [8];

Ring Z has the same meaning as described above [9]; and

m and n have the same meaning as described in [1] above.

[11] Based on the compound or its pharmaceutically acceptable salt described in [1] above,

Where u is 2 or 3;

One R ³ is a group A; and

The other ^R3s are each independently a hydrogen atom, a halogen atom, a _C1-6 alkyl group, a halo- _C1-6 alkyl group, a _C1-6 alkoxy group, a halo _-C1-6 alkoxy group, a _C2-6 alkenyl group, a _C1-6 alkyl hydrogen sulfo group, ^a _C1-6 alkyl sulfonyl group, a hydroxyl group, a cyano group, a nitro group, ^{-NR6R6 '} , _-CO2R7 , or ^{-CONR8R8 '} ;

Groups A, ^R6 , ^R6' , ^R7 , ^R8 and R8 ^' have the same meaning as described above [1].

[12] The compound according to [1] above or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds:

[Chemical Formula 9]

and

[Chemical Formula 10]

[13] According to the compound described above [1] or its pharmaceutically acceptable salt, the compound is represented by the following formula:

[Chemical Formula 11]

[14] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof and a pharmaceutical additive according to any one of [1] to [13] above.

[15] The pharmaceutical composition described in [14] above is a pharmaceutical composition for treating inflammatory bowel disease.

[16] The pharmaceutical composition according to [15] above, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

In one embodiment, the present invention relates to a method for treating inflammatory bowel disease, the method comprising administering to a patient an essential amount of the pharmaceutical composition described above [14].

In one embodiment, the present invention relates to the use of the compound or pharmaceutically acceptable salt thereof according to any one of [1] to [13] above for the manufacture of a pharmaceutical composition for use in the treatment of inflammatory bowel disease.

Effects of the present invention

The compounds of the present invention have excellent PHD2 inhibitory activity, and therefore the compounds of the present invention or their pharmaceutically acceptable salts can be used as remedies for the treatment of inflammatory bowel disease.

Invention Details

In the following text, embodiments of the present invention are described in more detail.

In this invention, unless otherwise specified, each term has the following meaning.

The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. Fluorine atoms are preferred as ^R1 , ^R2 , and ^R3 .

The term " _C1-6 alkyl" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.

The term "C _2-6 alkenyl" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms. Examples include vinyl, allyl, 1-propenyl, isopropenyl, etc.

The term "C _2-6 ynyl" means a straight-chain or branched ynyl group having 2 to 6 carbon atoms. Examples include ethynyl, 2-propynyl, etc.

The term "C _1-6 alkoxy" means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy, etc.

The term "carboxylated _C1-6 alkyl" means a _C1-6 alkyl group that has been substituted with a carboxyl group. For example, carboxymethyl, etc., can be cited as examples.

The term "hydroxy _C1-6 alkyl" means a _C1-6 alkyl group that has been replaced by a hydroxyl group. Examples of such alkyl groups include hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, etc.

The term "halogenated _C1-6 alkyl" means a _C1-6 alkyl group that is substituted with one to three identical or different halogen atoms. Examples of such alkyl groups include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, etc.

The term "halogenated _C1-6 alkoxy" means a _C1-6 alkoxy group that is substituted with one to three identical or different halogen atoms. Examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, etc.

The term " _C1-6 alkylhydrothioyl" means a group represented by ( _C1-6 alkyl)-S-.

The term " _C1-6 alkyl sulfinyl" means a group represented by ( _C1-6 alkyl)-S(=O)-.

The term " _C1-6 alkylsulfonyl" means a group represented by ( _C1-6 alkyl) _-SO2- . Examples include methanesulfonyl, ethanesulfonyl, etc.

The term "C _6-10 aryl" means phenyl or naphthyl. Phenyl is preferred as group A.

The term "5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include furanyl, pyrroleyl, thiopheneyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc. As ring W, thiopheneyl, pyridinyl, etc. are preferred, and pyridinyl is more preferred. As group A, pyridinyl, etc. are preferred.

The term "9- or 10-membered heteroaryl" means a bicyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include indolyl, isoyindolyl, benzofuranyl, benzobenzylthio, benzimidazolyl, purinyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, terpineyl, pteridinyl, chromenyl, isochromenyl, etc. As the ring W, quinolinyl, etc., are preferred.

The term "C _3-8 cycloalkyl" means a 3- to 8-membered saturated hydrocarbon group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term "3- to 8-membered heterocyclic alkyl" means a 3- to 8-membered heterocyclic alkyl group having one or two heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include azirropropyl, azirrobutyl, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidinyl, 4-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, etc. Tetrahydropyranyl, etc., are preferred as ^R5 and R5 ^' .

The term " _C6-10 aryl _C1-6 alkyl" means a _C1-6 alkyl group substituted with a _C6-10 aryl group. For example, benzyl can be cited as an example.

The term "C _6-10 aryloxy" means a group represented by (C _6-10 aryl)-O-. For example, phenoxy can be cited as an example.

The term "5- or 6-membered heteroaryl _C1-6 alkyl" means a _C1-6 alkyl group substituted with a 5- or 6-membered heteroaryl group.

The term "5- or 6-membered heteroaryloxy" means a group represented by (5- or 6-membered heteroaryl)-O-.

When a group is replaced by two or three groups selected from substituent group B, these groups may be the same as or different from each other.

The following abbreviations in the instructions and tables have the following meanings:

CDI: Carbonyldiimidazole

CPME: Cyclopentylmethyl ether

DEAD: Diethyl azodicarbonate

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-methylmorpholine hydrochloride

EDC-HCl: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

HOBt: 1-Hydroxybenzotriazole

HOBt-H ₂ O: 1-Hydroxybenzotriazole monohydrate

LAH: Lithium Aluminum Hydrogen

LDA: Lithium diisopropylamide

NaBH(OAc) ₃ : Sodium triacetoxyborohydride

NMP: 1-Methyl-2-pyrrolidone

Pd(amphos) _Cl₂ : bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II) dichloride

THF: Tetrahydrofuran

TsCl: p-Toluenesulfonyl chloride

T3P (registered trademark): Propylphosphonic anhydride (cyclic trimer)

9-BBN: 9-Boronbicyclo[3.3.1]nonane

Amino-silicone: Aminopropylated silicone

ODS column chromatography: Octadecyl-methylsilylated silica gel column chromatography

Process: Process

Reaction route: Reaction route

Ref. No.: Reference example number

Ex.No.: Example Number

Structure: Structural formula

Physical data: Physical data

_IC50 : The concentration required for 50% inhibition.

(The numbers marked with "*" in the table represent the inhibition rate at a compound concentration of 100 μM.)

FITC: Fluorescein isothiocyanate

^1H -NMR: Proton nuclear magnetic resonance spectrum

DMSO-d6: Dimethyl sulfoxide-d6

CDCl ₃ : Chloroform-d1

MS: Mass Spectrometry

ESI_APCI: Multiple ionization using electrospray ionization-atmospheric pressure chemical ionization

In one embodiment, the compound represented by formula (I) is, for example, a compound represented by the following formula. In this formula, R ^3' has the same meaning as R ³ in [1] above, provided that R ^3' is not group A. Other symbols have the same meaning as described in [1] above.

[Chemical Formula 12]

In one embodiment, the compound represented by formula (I) is a compound in which the group represented by the following formula is selected from the groups (a) to (d) below.

[Chemical Formula 13]

The symbols in the formula have the same meaning as those described in [1] above.

[Chemical Formula 14]

In one embodiment, the compound represented by formula (I) is preferably the compound according to [1] above, wherein the group is selected from [A] to [I] below or any combination thereof.

[A] Ring W is phenyl, naphthyl, thiophene, pyridyl, quinolinyl, or cyclohexyl.

[B] ^Ra , ^Rb , and ^Rc are each independently a hydrogen atom, a halogen atom, a methyl group, a cyano group, a hydroxyl group, or a carboxyl group.

[C]R ^d is a hydrogen atom or a methyl group.

[D]R ¹ is a hydrogen atom, a halogen atom, or a methyl group.

[E] ^R2 is a hydrogen atom, methyl, trifluoromethyl, methoxy, _-CO2H or ^{-CONR5R5 '} ; wherein ^R5 and R5 ^' are each independently a hydrogen atom, carboxymethyl or tetrahydropyranyl.

[F]R ³ is a hydrogen atom, a halogen atom, a methyl atom, a trifluoromethyl atom, a methoxy atom, a trifluoromethoxy atom, a vinyl atom, a methylthio atom, an ethanesulfonyl atom, a hydroxyl atom, a cyano atom, a nitro atom, a dimethylamino atom, a -CO ₂ R ⁷ atom, a -CONR ⁸ R ^8' atom, or a group A, wherein when u is 2, the two R ^3s can be different from each other;

Group A is selected from the following groups (a) to (f):

(a) An unsubstituted phenyl group or a phenyl group substituted with one or two groups selected from substituent group B,

(b) Pyridyl group,

(c) Benzyl,

(d) phenoxy group,

(e) Cyclopropyl, and

(f) Morpholinyl;

Substituent group B is composed of halogen atoms, methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxyl, cyano, -NHSO ₂ R ¹⁰ and -CO ₂ R ^10' .

^R10 and ^R10 ' are each independently a hydrogen atom or a methyl group;

R ⁷ is a hydrogen atom or a methyl group; and

^R8 and R8 ^' are each independently a hydrogen atom or a carboxymethyl atom.

[G]m, n, and u are each 1 or 2 independently.

[H]p and q are each independently 1 or 2.

[I]r is 0 or 1.

In cases where the compound represented by formula (I) contains one or more asymmetric carbon atoms, stereoisomers taking the R- or S- configuration at each of the asymmetric carbon atoms, and mixtures thereof, are included in the present invention. In such cases, racemic compounds, racemic mixtures, single enantiomers, and mixtures of diastereomers are also included within the scope of the present invention.

In the case where the compound represented by formula (I) has cis-trans isomers, all of the cis-trans isomers are included in this invention.

In the presence of tautomers of the compound represented by formula (I), the present invention includes all of the tautomers.

In this invention, stereochemical determination can also be performed according to methods known in the art.

If desired, compounds represented by formula (I) can also be converted into their pharmaceutically usable salts using conventional methods. Examples of such salts include acid addition salts and salts formed with bases.

Examples of acid addition salts include those using inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and those using 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.

Examples of salts formed with bases include those formed with inorganic bases such as lithium, sodium, potassium, calcium, and magnesium, and those formed with organic bases such as N-methyl-D-glucosamine, N,N'-diphenylmethylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline.

The present invention includes all crystalline forms where the compound represented by formula (I) or its pharmaceutically acceptable salt exists, for example, as a crystal. For example, pharmaceutically acceptable salts also include their solvates with pharmaceutically acceptable solvents such as water or ethanol, their eutectics with suitable eutectic forms (auxiliary forms), etc.

In the compounds represented by formula (I), some atoms may be replaced by corresponding isotopes. The present invention includes compounds in which atoms are replaced by these isotopes. Examples of such isotopes include isotopes of hydrogen, carbon, ^chlorine , fluorine, ^iodine , nitrogen ^, oxygen, phosphorus, and sulfur atoms, represented by ^2H , ^3H , ^11C , ^13C , ^{14C , 36Cl} , ^18F , ^123I , ^125I , ^13N , ^15N , 15O, 17O, 18O, 32P, and ^35S . In one embodiment, an example may be a compound represented by formula (I) in which some hydrogen atoms are replaced by ^2H (D: deuterium).

The compounds represented by formula (I) in which some atoms are replaced by isotopes can be prepared using commercially available components with introduced isotopes, in a manner similar to the manufacturing method described below. For example, compounds represented by formula (I) in which some hydrogen atoms are replaced by deuterium atoms can also be prepared by the methods described above and in the literature (see, for example, Yukigosei-kagaku kyokaishi, Vol. 65, No. 12, pp. 1179-1190, 2007). For example, compounds represented by formula (I) in which some carbon atoms are replaced by ^13C can also be prepared by the methods described above and in the literature (see, for example, RADIOISOTOPES 2007, Vol. 56, No. 11, pp. 35-44).

The compound represented by formula (I) can be prepared, for example, by the methods described in reaction routes 1 to 5, similar methods, methods described in the literature, or similar methods.

For each reaction in the process, commercially available products can be used when the starting materials and reagents are commercially available.

For each reaction in the process, unless otherwise specified, the reaction time is typically 30 minutes to 3 days, depending on the starting materials, solvents, reaction temperature, etc.

For each reaction in the process, unless otherwise specified, the reaction temperature is typically from -78°C to reflux temperature, depending on the starting materials, solvents, etc. used.

For each reaction in the process, unless otherwise specified, the pressure is typically between 1 atm and 20 atm, depending on the starting materials, solvents, reaction temperature, etc.

For each reaction in the process, a microwave reactor, such as Biotage's initiator, can also be used. When the reaction is carried out using a microwave reactor, the reaction can be carried out under the following conditions: pressure range: 1 to 30 bar, power range: 1 to 400 W, reaction temperature: room temperature to 300°C, and reaction time: 1 minute to 1 day, which varies depending on the starting materials, solvents, models, etc. used.

For each reaction in the process, unless otherwise stated, the reaction is carried out without any solvent or using a suitable solvent. Examples of suitable solvents include solvents that are inert to the reaction. Specific examples of such solvents include the solvents described in the reference examples or embodiments corresponding to each process, or the following solvents:

Alcohols: methanol, ethanol, tert-butanol, 2-propanol, etc.;

Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, 2-methyloxacyclopentane, 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: such as dimethyl sulfoxide;

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.; and

water.

The solvents described above can be used as a mixture of two or more of them in a suitable proportion.

When a base is used in a reaction in each process, the reaction is carried out using a base suitable for that reaction. Specific examples of such a base may be exemplified by the base described in the reference examples or embodiments corresponding to each process, or by 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-dimethylpyridine, piperidine, etc.;

Metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide, etc.

Alkali metal hydrides: sodium hydride, etc.;

Metal amide salts: sodium amino acid, LDA, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, etc.

Organic magnesium: methyl magnesium bromide, isopropyl magnesium chloride, allyl magnesium bromide, phenyl magnesium bromide, etc.; and

Organic lithium: n-butyllithium, sec-butyllithium, tert-butyllithium, etc.

When an acid or acidic catalyst is used in the reaction of each process, the reaction is carried out using an acid or acidic catalyst suitable for the reaction. Specific examples of such acid or acidic catalysts may be exemplified by the acid or acidic catalyst described in the reference examples or embodiments corresponding to each process, or the following acid or acidic 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.; and

Lewis acids: boron trifluoride-diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride, etc.

When a condensing agent is used in the reaction of each process, the reaction is carried out using a condensing agent suitable for the reaction. Specific examples of such condensing agents may include the condensing agents described in the reference examples or embodiments corresponding to each process, or the following condensing agents:

Carbodiimides: EDC-HCl, N,N'-dicyclohexylcarbodiimide, etc.;

Carbonyl diimidazoles: CDI, etc.;

Ureunium and phosphonium salts: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylhexafluorophosphate ureunium, 1H-benzotriazol-1-yloxytris(dimethylamino)hexafluorophosphate phosphonium, etc.;

Triazine derivatives: DMTMM, etc.; and

Others: T3P, etc.

When a reducing agent is used in the reaction of each process, the reaction is carried out using a reducing agent suitable for the reaction. Specific examples of such reducing agents may include the reducing agents described in the reference examples or embodiments corresponding to each process, or the following reducing agents:

Metal hydrides: LAH, lithium borohydride, sodium borohydride, NaBH(OAc) ₃ , sodium cyanoborohydride, diisobutylaluminum hydride, etc.; and

Boranes: borane-tetrahydrofuran complex, 9-BBN, methylpyridineborane, etc.

In each process, when a protecting group is required based on the type of functional group, the introduction and removal operations can optionally be performed in combination according to general methods. Examples of the types of protecting groups, protection, and deprotection are included in the methods described in Theodora W. Greene & Peter G.M. Wuts, eds., *Greene's Protective Groups in Organic Synthesis*, 4th edition, Wiley-Interscience, 2006.

In each process, the reaction can be carried out by hydrolysis or the like when removing the protecting group.

In each process, the hydrolysis reaction can be carried out in the presence of an acid or a base. Examples of the acid and base mentioned above can be cited as examples.

In each process, the catalytic reduction reaction can be carried out in the presence of a catalyst under a hydrogen atmosphere. Examples of catalysts include carbon-supported palladium powder, carbon-supported platinum powder, Raney nickel, etc.

In each process, the reduction reaction can be carried out in the presence of a reducing agent. Examples of such reducing agents include those mentioned above.

In each process, the amidation reaction can be carried out in the presence of a condensing agent and a base, or in the presence of a condensing agent alone. Examples of the condensing agent and base mentioned above can be cited as examples. When using carbodiimide as the condensing agent, additives such as HOBt or DMAP can be added if desired. The amidation reaction can also be carried out using acyl halides or acid anhydrides.

In each process, during the reductive amination reaction, the reaction can be carried out in the presence of a reducing agent. Examples of such reducing agents include those mentioned above. Preferably, NaBH(OAc) ₃ is an example of such a reducing agent.

In each process, during the aromatic nucleophilic substitution reaction, the reaction can be carried out in the presence of a base. Examples of such a base include those mentioned above.

In each process, during the intramolecular carbonylation reaction, the reaction can be carried out in the presence of a condensing agent. Examples of such condensing agents include those mentioned above.

In each process, during the Ullmann condensation reaction, the reaction can be carried out in the presence of a copper catalyst, a ligand, and a base. Examples of the copper catalyst include copper iodide. Examples of the ligand include N,N'-dimethylethylenediamine. Examples of the base include those mentioned above.

In each process, during the Chan-Lam-Evans coupling reaction, the reaction can be carried out in the presence of a copper catalyst and a base. Examples of the copper catalyst include copper(II) acetate. Examples of the base include those mentioned above.

In each process, the Mitsunobu reaction can be carried out in the presence of an azodicarbonate and a phosphine. Examples of the azodicarbonate include DEAD, etc. Examples of the phosphine include triphenylphosphine, etc.

In each process, the Suzuki-Miyaura crosslinking 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.

In each process, unless otherwise specified, the symbols in the structural formula have the same meaning as described above [1]. Y is a bromine atom, an iodine atom, boric acid, or a hydroxyl group. Y' is a fluorine atom or a chlorine atom. Y” is boric acid or a borate ester. X is ^CR3 or N.

The compound represented by formula (I) can be prepared, for example, by the methods described in processes 1-1 to 1-3 in reaction route 1.

[Chemical Formula 15]

Reaction route 1

Process 1-1

Compounds (1-3) can also be prepared by the Ullmann condensation reaction, Chan-Lam-Evans coupling reaction or Mitsunobu reaction of compounds (1-1) and (1-2).

When Y is a bromine or iodine atom, r is 0, and W is aryl or heteroaryl, the Ullmann condensation reaction is preferred. When Y is boric acid, r is 0, and W is aryl or heteroaryl, the Chan-Lam-Evans coupling reaction is preferred. When Y is hydroxyl, r is 0, and W is cycloalkyl or heterocycloalkyl, the Mitsunobu reaction is preferred. When Y is hydroxyl and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Process 1-2

Compounds (1-4) can also be prepared by removing the protecting group of compounds (1-3).

Process 1-3

Compound (I) can also be prepared by reductive amination of compounds (1-4) and (1-5). The protecting group may also be removed if desired.

Compound (1-1) can be prepared, for example, by the methods described in processes 2-1 to 2-3 in reaction route 2.

[Chemical Formula 16]

Reaction route 2

Process 2-1

Compound (2-3) can also be prepared by the aromatic nucleophilic substitution reaction of compounds (2-1) and (2-2).

Process 2-2

Compounds (2-4) can also be prepared by the catalytic reduction reaction of compound (2-3).

Process 2-3

Compound (1-1) can also be prepared by the intramolecular carbonylation reaction of compound (2-4).

Compound (IA) can be prepared, for example, by the methods described in processes 3-1 to 3-4 in reaction route 3.

[Chemical Formula 17]

Reaction route 3

Process 3-1

Compound (3-2) can also be prepared by the Ullmann condensation reaction, Chan-Lam-Evans coupling reaction or Mitsunobu reaction of compounds (1-1) and (3-1).

When Y is a bromine or iodine atom and r is 0, the Ullmann condensation reaction is preferred. When Y is boric acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. When Y is a hydroxyl group and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Process 3-2

Compounds (3-4) can also be prepared by the Suzuki-Miyaura crosslinking reaction of compounds (3-2) and (3-3).

Process 3-3

Compounds (3-5) can also be prepared by removing the protecting group of compounds (3-4).

Process 3-4

Compound (IA) can also be prepared by reductive amination of compounds (3-5) and (1-5). The protecting group can also be removed if desired.

Compound (I) can be prepared, for example, by the methods described in processes 4-1 to 4-3 in reaction route 4.

[Chemical Formula 18]

Reaction route 4

Process 4-1

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

Process 4-2

Compound (4-2) can also be prepared by the reductive amination reaction of compounds (4-1) and (1-5).

Process 4-3

Compound (I) can also be prepared by the Ullmann condensation reaction, Chan-Lam-Evans coupling reaction, or Mitsunobu reaction of compounds (4-2) and (1-2). The protecting group can also be removed if desired.

When Y is a bromine or iodine atom, r is 0, and W is an aryl or heteroaryl group, the Ullmann condensation reaction is preferred. When Y is boric acid, r is 0, and W is an aryl or heteroaryl group, the Chan-Lam-Evans coupling reaction is preferred. When Y is hydroxyl, r is 0, and W is a cycloalkyl or heterocycloalkyl group, the Mitsunobu reaction is preferred. When Y is hydroxyl and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Compound (IA) can be prepared, for example, by the methods described in processes 5-1 to 5-2 in reaction route 5.

[Chemical Formula 19]

Reaction route 5

Process 5-1

Compound (5-1) can also be prepared by the Ullmann condensation reaction, Chan-Lam-Evans coupling reaction or Mitsunobu reaction of compounds (4-2) and (3-1).

When Y is a bromine or iodine atom and r is 0, the Ullmann condensation reaction is preferred. When Y is boric acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. When Y is a hydroxyl group and r is an integer from 1 to 6, the Mitsunobu reaction is preferred.

Process 5-2

Compound (IA) can also be prepared by the Suzuki-Miyaura crosslinking reaction of compounds (5-1) and (3-3). The protecting group can also be removed if desired.

The above reaction route is an exemplary method for preparing the compound represented by formula (I) or a synthetic intermediate thereof. The above reaction route can be modified or altered in a manner readily understood by one of ordinary skill in the art.

If necessary, the compound represented by formula (I) and its synthetic intermediates may also be separated and purified using separation and purification techniques known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography or preparative high-performance liquid chromatography.

Examples of column chromatography on silica gel and on amino-silica gel include rapid chromatography using columns such as SNAP Pultra and SNAP Isolute NH2 (Biotage), Hi-Flash columns (Yamazen), etc.

As an example of ODS column chromatography, preparative separation can be achieved using, for example, a preparative purification LC system (Gilson, flow rate: 30 mL/min, detection: UV at 225 nm) and a CAPCELL PAK C18 UG80 column (5 μm 20 x 50 mm).

The compounds of the present invention exhibit excellent PHD2 inhibition and are therefore suitable for use as therapeutic agents for IBD (see Nature Reviews Drug Discovery, 2014, 13, pp. 852-869). In this invention, the phrase “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 caused by collagenopathy. Preferably, the compounds of the present invention are suitable for use as therapeutic agents for ulcerative colitis or Crohn’s disease (see Inflamm. Bowel. Dis., 2015, 21(2), pp. 267-275).

In this invention, the phrase "treatment" includes the meaning of "prevention." Treatment of ulcerative colitis includes, for example, the meanings of "preventing recurrence" and "maintaining remission."

The therapeutic effect of the compounds of the present invention on colitis can be determined by the method described in Experimental Example 2 or by methods known in the art. For example, the method described in Biol. Pharm. Bull., 2004, 27(10), pp. 1599-1603 or similar methods can be exemplified.

In one embodiment, the compound of the present invention is a PHD2 inhibitor that specifically acts on colonic tissue to limit off-target effects of HIF-α stabilization. The term "specifically acts on colonic tissue" means, for example, that the concentration of the compound in the colonic tissue is higher than that in the blood, and that the compound exerts a therapeutic effect on the colonic tissue without systemic effects (e.g., hematopoiesis) (see Experimental Examples 2 and 3).

Depending on the usage, the pharmaceutical compositions of the present invention can be used in a variety of different dosage forms. Examples of such dosage forms include, for example, powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, plasters, and enemas.

The pharmaceutical compositions of the present invention comprise a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical compositions of the present invention can be prepared using a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutical additive. The pharmaceutical compositions can be formulated, according to a dosage form and following known formulation procedures, by suitable mixing, dilution, or dissolution with suitable pharmaceutical additives such as excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizers.

When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is determined according to each patient's age, sex, weight, degree of impairment, and suitability for treatment. The daily dose may be divided into 1, 2, 3, or 4 doses administered daily. Preferably, the pharmaceutical composition of the present invention is administered orally.

In the case of oral administration, the dosage for adults can be determined, for example, in the range of 0.1 to 1000 mg per day. In one embodiment, the oral administration dosage can be determined in the range of 1 to 500 mg per day, preferably 10 to 200 mg per day.

In the case of parenteral administration, the dosage for adults can be determined, for example, in the range of 0.1 to 1000 mg per day. In one embodiment, the parenteral administration dosage can be determined in the range of 0.5 to 200 mg per day, preferably 1 to 20 mg per day.

In one embodiment, the pharmaceutical composition of the present invention may also be used in combination with any other drug besides a PHD inhibitor. Examples of such other drugs that may be _used in combination for the treatment of inflammatory bowel disease include, for example, 5-ASA, steroids, immunosuppressants, anti-TNF-α antibodies, Janus kinase inhibitors, and _α4β7 integrin antibodies.

When compounds represented by formula (I) or their pharmaceutically acceptable salts are used in combination with the other drugs, they can be administered as formulations containing these active ingredients or as formulations separately formulated from each active ingredient. When formulated separately, these formulations can be administered separately or simultaneously. Furthermore, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt can be appropriately reduced based on the dosage of the other drugs used in the combination.

The compounds represented by formula (I) can each be suitably converted into prodrugs and used. For example, the prodrugs of the compounds represented by formula (I) can also be prepared by introducing the groups forming the prodrugs using appropriate reagents for prodrug preparation, such as halides, and then purifying them. Examples of the groups forming the prodrugs include, for instance, those described in *Development of Medicine*, 1990, Vol. 7, pp. 163-198, published by Hirokawa Shoten.

Detailed Implementation

Example

The present invention is further described in more detail through the following embodiments. However, the present invention is not limited thereto.

Apart from commercially available reagents, the compounds described in the following examples are named using ChemDraw Professional (Perkin Elmer), Marvin Sketch (ChemAxon), etc.

See Example A-1

(S)-3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

2-Fluoro-3-nitropyridine (10.00 g), (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (13.10 g), and potassium carbonate (11.67 g) were added to NMP (100 mL) under ice-cooling. The reaction mixture was stirred at 150 °C for 1 hour. The reaction mixture was allowed to cool to room temperature. Ethyl acetate and water were added to the reaction mixture, and the mixture was stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (21.70 g).

See Example A-2

(R)-3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of 2-fluoro-3-nitropyridine (2.00 g), (R)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester (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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth (registered trademark), and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 95/5-70/30) to give the title compound (3.61 g).

See Example A-3

4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.25 g).

See Example A-4

3-((3-nitropyridin-2-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example A-3, using tert-butyl 3-aminoazacyclobutane-1-carboxylate instead of tert-butyl 4-aminopiperidine-1-carboxylate.

See Example A-5

(3R,4R)-3-fluoro-4-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of 2-fluoro-3-nitropyridine (0.69 g), (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (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 the mixture was stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-20/80) to give the title compound (1.40 g).

See Example A-6

A mixture of tert-butyl (S)-3-((3-nitro-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate was stirred at 80°C for 1 hour under microwave irradiation. Ethyl acetate and water were added to the reaction mixture, and the mixture was stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-20/80) to give the title compound (1.66 g).

See Example A-7

4-Methyl-4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example A-5, using tert-butyl 4-amino-4-methylpiperidine-1-carboxylate instead of (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate.

See Example A-8

(S)-6-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)amino)-5-nitropyridinecarboxylate methyl ester

A mixture of methyl 6-chloro-5-nitropyridinecarboxylate (1.00 g), (S)-3-aminopyrrolidine-1-carboxylate tert-butyl ester (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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.47 g).

See Example A-9

(S)-3-((5-methyl-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example A-6, using 2-chloro-5-methyl-3-nitropyridine instead of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine.

See Example A-10

(S)-3-((5-methoxy-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example A-6, using 2-chloro-5-methoxy-3-nitropyridine instead of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine.

See Example B-1

(S)-3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

10% carbon-supported palladium (2.17 g, wet weight) 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 for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (19.74 g).

See Example B-2

(R)-3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-2 instead of Reference Example A-1.

See Example B-3

4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

10% carbon-supported palladium (0.22 g, wet weight) 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 diatomaceous earth, and the filtrate was concentrated under reduced pressure to give the title compound (2.06 g).

See Example B-4

3-((3-aminopyridin-2-yl)amino)azacyclobutane-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-4 instead of Reference Example A-1.

See Example B-5

(3R,4R)-3-((3-aminopyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-5 instead of Reference Example A-1.

See Example B-6

(S)-3-((3-amino-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-6 instead of Reference Example A-1.

See Example B-7

4-((3-aminopyridin-2-yl)amino)-4-methylpiperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-7 instead of Reference Example A-1.

See Example B-8

(S)-5-amino-6-((1-(tert-butoxycarbonyl)pyrrolidine-3-yl)amino)pyridinecarboxylic acid methyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-8 instead of Reference Example A-1.

See Example B-9

(S)-3-((3-amino-5-methylpyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-9 instead of Reference Example A-1.

See Example B-10

(S)-3-((3-amino-5-methoxypyridin-2-yl)amino)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example B-1, using Reference Example A-10 instead of Reference Example A-1.

See Example C-1

(S)-3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

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 min. Sodium hydroxide aqueous solution (5 mol/L, 30 mL) was added to the reaction mixture, and the resulting mixture was stirred for 10 min. Hydrochloric acid (2 mol/L, 75 mL) was added to the reaction mixture. After stirring, the mixture was 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 50/50-0/100) to give the title compound (17.61 g). MS (ESI_APCI, m/z): 303 (MH) ^-

See Example C-2

(R)-3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

CDI (4.28 g) was added to the compound from Reference Example B-2 (3.68 g) and THF (20 mL). The reaction mixture was stirred at room temperature for 30 minutes. Sodium hydroxide aqueous solution (5 mol/L, 4 mL) was added to the reaction mixture, and the resulting mixture was 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 50/50-0/100) to give the title compound (4.00 g). MS (ESI_APCI, m/z): 303 (MH) ^-

See Example C-3

4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

CDI (2.29 g) was added to the compound in 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (1.96 g). MS (ESI_APCI, m/z): 317 (MH) ^-

See Example C-4

3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example C-1, using Reference Example B-4 instead of Reference Example B-1. MS(ESI_APCI,m/z):289( ^MH )

See Example C-5

(3R,4R)-3-fluoro-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example C-2, using Reference Example B-5 instead of Reference Example B-2. MS(ESI_APCI,m/z):321( ^MH )

See Example C-6

(S)-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example C-2, using Reference Example B-6 instead of Reference Example B-2. MS(ESI_APCI,m/z):371( ^MH )

See Example C-7

4-Methyl-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example C-2, using Reference Example B-7 instead of Reference Example B-2. MS(ESI_APCI,m/z):331( ^MH )

See example C-8

(S)-3-(1-(tert-butoxycarbonyl)pyrrolidone-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

The title compound was prepared in a manner similar to that described in Reference Example C-3, using Reference Example B-8 instead of Reference Example B-3. MS(ESI_APCI,m/z):361( ^MH )

See example C-9

(S)-3-(6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example C-2, using Reference Example B-9 instead of Reference Example B-2. MS(ESI_APCI,m/z):317( ^MH )

See Example C-10

(S)-3-(6-methoxy-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example C-2, using Reference Example B-10 instead of Reference Example B-2. MS(ESI_APCI,m/z):333( ^MH )

See Example D-1

(S)-3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (168 mg), (4-chloro-2-methylphenyl)boric 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. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (114 mg).

See Example D-2

(S)-3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (500 mg), 1-chloro-4-iodobenzene (431 mg), N,N'-dimethylethylenediamine (0.212 mL), cuprous iodide (I) (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). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (583 mg).

See Example D-3

(R)-3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example D-1, using Reference Example C-2 instead of Reference Example C-1.

See Example D-4

(S)-3-(1-(4-chloro-2-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (100 mg), 5-chloro-2-iodophenol (125 mg), N,N'-dimethylethylenediamine (0.042 mL), cuprous iodide (I) (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). After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 35/65) to give the title compound (61 mg).

See Example D-5

(S)-3-(1-(4-chloro-3-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (100 mg), 2-chloro-5-iodophenol (100 mg), N,N'-dimethylethylenediamine (0.042 mL), cuprous iodide (I) (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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 35/65) to give the title compound (135 mg).

See Example D-6

(S)-3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (100 mg), 2-chloro-5-iodopyridine (94 mg), N,N'-dimethylethylenediamine (0.042 mL), cuprous iodide (I) (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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 35/65) to give the title compound (117 mg).

See example D-7

(R)-3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-2 (500 mg), 2-chloro-5-iodopyridine (433 mg), N,N'-dimethylethylenediamine (0.212 mL), cuprous iodide (I) (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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-45/55) to give the title compound (420 mg).

See Example E-1

(S)-3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (113 mg), 4-iodo-1,1'-biphenyl (125 mg), N,N'-dimethylethylenediamine (0.048 mL), cuprous 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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (138 mg).

See Example E-2

(R)-3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-1, using Reference Example C-2 instead of Reference Example C-1.

See Example E-3

(S)-3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-1, using iodobenzene instead of 4-iodo-1,1'-biphenyl.

See Example E-4

4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-1, using Reference Example C-3 instead of Reference Example C-1.

See Example E-5

3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl) tert-butyl 1-azacyclobutane carboxylate

A mixture of Reference Example C-4 (100 mg), 4-iodo-1,1'-biphenyl (96 mg), N,N'-dimethylethylenediamine (0.044 mL), cuprous iodide (I) (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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (105 mg).

See Example E-6

(S)-3-(1-(4-(methoxycarbonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (200 mg), methyl 4-iodobenzoate (172 mg), N,N'-dimethylethylenediamine (0.085 mL), cuprous iodide (I) (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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-45/55) to give the title compound (271 mg).

See Example E-7

(S)-3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (100 mg), 1-iodo-4-methoxybenzene (85 mg), N,N'-dimethylethylenediamine (0.042 mL), cuprous iodide (I) (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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (119 mg).

See Example E-8

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(tert-butoxycarbonyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

A mixture of Reference Example C-8 (100 mg), 4-iodo-1,1'-biphenyl (93 mg), N,N'-dimethylethylenediamine (0.036 mL), cuprous iodide (I) (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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-45/55) to give the title compound (120 mg).

See Example E-9

4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-4-methylpiperidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-7 (50 mg), 4-iodo-1,1'-biphenyl (51 mg), N,N'-dimethylethylenediamine (0.019 mL), cuprous iodide (I) (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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-40/60) to give the title compound (70 mg).

See Example E-10

(S)-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-carboxylic acid tert-butyl ester

A mixture of Reference Example C-10 (136 mg), methyl 4'-bromo-[1,1'-biphenyl]-4-carboxylate (131 mg), N,N'-dimethylethylenediamine (0.053 mL), cuprous iodide (I) (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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-25/75) to give the title compound (128 mg).

See 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-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-10, using Reference Example C-5 instead of Reference Example C-10.

See Example E-12

(S)-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-tert-butyl carboxylate

The title compound was prepared in a manner similar to that described in Reference Example E-10, using Reference Example C-6 instead of Reference Example C-10.

See Example E-13

(S)-3-(1-(3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (87 mg).

See Example E-14

(S)-3-(1-(2'-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (105 mg).

See Example E-15

(R)-3-(1-(3-methyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-13, using Reference Example D-3 instead of Reference Example D-1.

See Example E-16

(S)-3-(1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-14, using (4-fluorophenyl)boronic acid instead of o-tolylboronic acid.

See Example E-17

(S)-3-(1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-14, using (4-methoxyphenyl)boronic acid instead of o-tolylboronic acid.

See Example E-18

(S)-3-(2-oxo-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-14, using (2-(trifluoromethyl)phenyl)boronic acid instead of o-tolylboronic acid.

See Example E-19

(S)-3-(1-(4'-cyano-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-14, using (4-cyanophenyl)boronic acid instead of o-tolylboronic acid.

Reference Example E-20

(S)-3-(2-oxo-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-14, using (4-(trifluoromethoxy)phenyl)boronic acid instead of o-tolylboronic acid.

See Example E-21

(S)-3-(1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-1, using 4'-iodo-[1,1'-biphenyl]-4-ol instead of 4-iodo-1,1'-biphenyl.

See Example E-22

(S)-3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-14, using 4-pyridylboronic acid instead of o-tolylboronic acid.

See Example E-23

(S)-3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (212 mg).

See Example E-24

(R)-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-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-23, using Reference Example D-3 instead of Reference Example D-2.

See Example E-25

(S)-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-carboxylic acid tert-butyl ester

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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-35/65) to give the title compound (55 mg).

See Example E-26

(S)-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-carboxylic acid tert-butyl ester

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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-30/70) to give the title compound (122 mg).

See Example E-27

(S)-3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-30/70) to give the title compound (95 mg).

See example E-28

(S)-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-carboxylic acid tert-butyl ester

A mixture of Reference Example D-2 (121 mg), methyl 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-30/70) to give the title compound (71 mg).

See example E-29

(S)-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-carboxylic acid tert-butyl ester

A mixture of Reference Example D-2 (200 mg), methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-35/65) to give the title compound (165 mg).

Reference Example E-30

(S)-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-carboxylic acid tert-butyl ester

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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-35/65) to give the title compound (406 mg).

See example K-19

(S)-3-(1-(4-chloro-3-(methoxymethoxy)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

Add DIPEA (1.55 mL) and chloromethyl methyl ether (0.34 mL) to a mixture of Reference Example D-5 (1.29 g) and THF (15 mL). Stir the reaction mixture overnight at room temperature. Concentrate the reaction mixture under reduced pressure. Purify the residue by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (1.33 g).

See Example E-31

(S)-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-carboxylic acid tert-butyl ester

A mixture of Reference Example K-19 (500 mg), 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-40/60) to give the title compound (332 mg).

See Example E-32

(S)-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-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-31, using Reference Example D-6 instead of Reference Example K-19.

See example K-20

(S)-3-(1-(4-chloro-2-(methoxymethoxy)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example K-19, using Reference Example D-4 instead of Reference Example D-5.

See example E-33

(S)-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-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-31, using Reference Example K-20 instead of Reference Example K-19.

See Example K-2

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(tert-butoxycarbonyl)pyrrolidine-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. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (227 mg).

See example E-34

(S)-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-carboxylic acid tert-butyl ester

Add EDC-HCl (77 mg), HOBt- _H₂O (61 mg), triethylamine (0.139 mL), and 4-aminotetrahydropyran (24 mg) to a mixture of Reference Example K-2 (100 mg) and DMF (1 mL). Stir the reaction mixture at room temperature for 4 hours. Add water and ethyl acetate to the reaction mixture. After stirring, extract the mixture with ethyl acetate. Wash the organic layer with brine, dry on anhydrous magnesium sulfate, and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-20/80) to give the title compound (19 mg).

Reference Example E-35

(S)-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-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-34, using glycine methyl ester hydrochloride instead of 4-aminotetrahydropyran.

See example E-36

(R)-3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

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 diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-40/60) to give the title compound (377 mg).

See example E-37

(S)-3-(1-(naphthyl-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (200 mg), 2-bromonaphthalene (136 mg), N,N'-dimethylethylenediamine (0.085 mL), cuprous 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 a mixture of ethyl acetate and water. After stirring, the mixture was filtered through Celite diatomaceous earth. The filtrate was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (250 mg).

Reference example E-38

(S)-3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

A mixture of Reference Example C-1 (200 mg), 3-bromo-1,1'-biphenyl (153 mg), N,N'-dimethylethylenediamine (0.085 mL), cuprous 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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (345 mg).

Reference example E-39

(S)-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-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example E-10, using Reference Example C-9 instead of Reference Example C-10.

See example F-1

(S)-1-([1,1'-biphenyl]-4-yl)-3-(pyrrolidone-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 (4 mol/L, 1,4-dioxane solution, 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) ⁺

See example F-2

(R)-1-([1,1'-biphenyl]-4-yl)-3-(pyrrolidone-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-2 instead of Reference Example E-1. MS(ESI_APCI,m/z):357(M+H) ⁺

Reference example F-3

(S)-1-Phenyl-3-(pyrrolid-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 (4 mol/L, 1,4-dioxane solution, 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) ⁺

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

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-4 instead of Reference Example E-3. MS(ESI_APCI,m/z):371(M+H) ⁺

Reference example F-5

1-([1,1'-biphenyl]-4-yl)-3-(azacyclobutane-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-5 instead of Reference Example E-3. MS(ESI_APCI,m/z):343(M+H) ⁺

Reference example F-6

(S)-4-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl benzoate hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-6 instead of Reference Example E-1. MS(ESI_APCI,m/z):339(M+H) ⁺

Reference example F-7

(S)-1-(4-methoxyphenyl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-7 instead of Reference Example E-3.

Reference example F-8

(S)-1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolid-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-8 instead of Reference Example E-3.

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 prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-9 instead of Reference Example E-3.

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-carboxylic acid methyl ester hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-10 instead of Reference Example E-3.

Reference example F-11

4'-(3-((3R,4R)-4-fluoropyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-11 instead of Reference Example E-3.

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-carboxylic acid methyl ester hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-12 instead of Reference Example E-3.

Reference example F-13

(S)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-13 instead of Reference Example E-1. MS(ESI_APCI, m/z): 371(M+H) ⁺

Reference example F-14

(S)-1-(2'-methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-14 instead of Reference Example E-1. MS(ESI_APCI,m/z):371(M+H) ⁺

Reference example: F-15

(R)-1-(3-methyl-[1,1'-biphenyl]-4-yl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-15 instead of Reference Example E-1. MS(ESI_APCI,m/z):371(M+H) ⁺

Reference example F-16

(S)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-16 instead of Reference Example E-1. MS(ESI_APCI, m/z): 375 (M+H) ⁺

Reference example F-17

(S)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-17 instead of Reference Example E-1. MS(ESI_APCI, m/z): 387(M+H) ⁺

Reference example F-18

(S)-3-(pyrrolidone-3-yl)-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-18 instead of Reference Example E-1. MS(ESI_APCI, m/z): 425 (M+H) ⁺

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-carboxylon hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-19 instead of Reference Example E-1. MS(ESI_APCI,m/z):382(M+H) ⁺

Reference example: F-20

(S)-3-(pyrrolidone-3-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-20 instead of Reference Example E-1. MS(ESI_APCI,m/z):441(M+H) ⁺

Reference example F-21

(S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-21 instead of Reference Example E-1. MS(ESI_APCI,m/z):373(M+H) ⁺

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

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-22 instead of Reference Example E-1. MS(ESI_APCI, m/z): 358 (M+H) ⁺

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-carboxylic acid methyl ester hydrochloride

A mixture of Reference Example E-23 (212 mg) and hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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) ⁺

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-carboxylic acid methyl ester hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-1, using Reference Example E-24 instead of Reference Example E-1. MS(ESI_APCI,m/z):429(M+H) ⁺

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-carboxylic acid methyl ester hydrochloride

A mixture of Reference Example E-25 (55 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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-carboxylic acid methyl ester hydrochloride

A mixture of Reference Example E-26 (122 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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)methyl benzoate hydrochloride

A mixture of Reference Example E-27 (95 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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-carboxylic acid methyl ester hydrochloride

A mixture of Reference Example E-28 (71 mg) and hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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-carboxylic acid methyl ester hydrochloride

A mixture of Reference Example E-29 (165 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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)methyl benzoate hydrochloride

A mixture of Reference Example E-30 (406 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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-carboxylon hydrochloride

A mixture of Reference Example E-31 (332 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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 (4 mol/L, 1,4-dioxane solution, 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).

Reference example F-33

(S)-3',4-Dihydroxy-4'-(2-oxo-3-(pyrrolid-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylon hydrochloride

A mixture of Reference Example E-33 (77 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

Reference example F-34

(S)-1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolid-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 (4 mol/L, 1,4-dioxane solution, 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).

Reference example: F-35

(S)-(1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidone-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carbonyl)glycine methyl ester hydrochloride

A mixture of Reference Example E-35 (91 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

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)methyl benzoate hydrochloride

A mixture of Reference Example E-36 (377 mg), hydrogen chloride (4 mol/L, 1,4-dioxane solution, 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).

Reference example: F-37

(S)-1-(naphth-2-yl)-3-(pyrrolid-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-37 instead of Reference Example E-3.

Reference example F-38

(S)-1-([1,1'-biphenyl]-3-yl)-3-(pyrrolidone-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-38 instead of Reference Example E-3.

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-carboxylic acid methyl ester hydrochloride

The title compound was prepared in a manner similar to that described in Reference Example F-3, using Reference Example E-39 instead of Reference Example E-3.

See 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)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

NaBH(OAc) _₃ (65 mg) was added to a mixture of Reference Example F-1 (30 mg), methyl 2-formyl isonicotinic acid (25 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-45/55) to give the title compound (26 mg). MS (ESI_APCI, m/z): 506 (M+H) ⁺

See 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)pyrrolidine-1-yl)methyl)nicotinic acid methyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-1, using methyl 6-formylnicotinic acid ester instead of methyl 2-formylisonicotinic acid ester. MS(ESI_APCI,m/z):506(M+H) ⁺

Reference example G-3

(S)-2-((3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

The title compound was prepared in a similar manner to that described in Reference Example G-1, using Reference Example F-7 instead of Reference Example F-1. MS(ESI_APCI, m/z): 460 (M+H) ⁺

See example G-4

(S)-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

The title compound was prepared in a similar manner to that described in Reference Example G-1, using Reference Example F-3 instead of Reference Example F-1. MS(ESI_APCI, m/z): 430 (M+H) ⁺

See Example J-1

1-Methyl-1H-imidazol-5-carboxylic acid tert-butyl ester

A mixture of 1-methyl-1H-imidazol-5-carboxylic acid (5.00 g), tert-butanol (37.7 mL), pyridine (16.0 mL), and TsCl (15.11 g) was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction mixture. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (6.24 g).

See example J-2

2-Formyl-1-methyl-1H-imidazol-5-carboxylic acid tert-butyl ester

In a dry ice/acetone bath at -70°C or lower, LDA (1.0 mol/L, THF/n-hexane solution, 48 mL) was slowly added dropwise to a mixture of Reference Example J-1 (5.82 g), DMF (7.43 mL), and THF (60 mL). The reaction mixture was stirred under ice-cooled conditions for 10 minutes. Again in a dry ice/acetone bath at -70°C or lower, LDA (1.0 mol/L, THF/n-hexane solution, 16 mL) and DMF (1 mL) were slowly added dropwise to the reaction mixture. The reaction mixture was stirred under ice-cooled conditions for 10 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. After stirring for 5 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (6.72 g).

See example G-6

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-imidazo-5-carboxylic acid tert-butyl ester

Reference Example J-2 (41 mg) and NaBH(OAc) ₃ (68 mg) were added to a mixture of Reference Example F-9 (67 mg), THF (1 mL), and triethylamine (0.112 mL). The reaction mixture was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (73 mg). MS (ESI_APCI, m/z): 579 (M+H) ⁺

See example G-7

(S)-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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-6, using Reference Example F-10 instead of Reference Example F-9. MS(ESI_APCI, m/z): 639(M+H) ⁺

See 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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-6, using Reference Example F-11 instead of Reference Example F-9. MS(ESI_APCI, m/z): 627(M+H) ⁺

See example G-9

(S)-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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-6, using Reference Example F-12 instead of Reference Example F-9. MS(ESI_APCI,m/z):677(M+H) ⁺

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)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

The title compound was prepared in a similar manner to that described in Reference Example G-1, using Reference Example F-23 instead of Reference Example F-1. MS(ESI_APCI,m/z):564(M+H) ⁺

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)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

NaBH(OAc) _₃ (363 mg) was added to a mixture of Reference Example F-26 (200 mg), methyl 2-formyl isonicotinic acid (141 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/80/200) to give the title compound (207 mg). MS (ESI_APCI, m/z): 580 (M+H) ⁺

See 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)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-16, using Reference Example F-27 instead of Reference Example F-26. MS(ESI_APCI, m/z): 565 (M+H) ⁺

Reference example G-18

(S)-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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

NaBH(OAc) _₃ (912 mg) was added to a mixture of Reference Example F-25 (502 mg), Reference Example J-2 (339 mg), and dichloromethane (3 mL). 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 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (450 mg). MS (ESI_APCI, m/z): 625 (M+H) ⁺

Reference example G-19

(S)-2-((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-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

NaBH(OAc) _₃ (561 mg) was added to a mixture of Reference Example F-30 (308 mg), Reference Example J-2 (221 mg), and dichloromethane (3 mL). 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 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (558 mg). MS (ESI_APCI, m/z): 624 (M+H) ⁺

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)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

NaBH(OAc) _₃ (283 mg) was added to a mixture of Reference Example F-31 (150 mg), methyl 2-formyl isonicotinic acid (110 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/50/50) to give the title compound (188 mg). MS (ESI_APCI, m/z): 563 (M+H) ⁺

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)pyrrolidine-1-yl)methyl)isonicotinate

NaBH(OAc) _₃ (390 mg) was added to a mixture of Reference Example F-32 (200 mg), methyl 2-formyl isonicotinic acid (152 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 the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/50/50) to give the title compound (495 mg). MS (ESI_APCI, m/z): 548 (M+H) ⁺

See 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)pyrrolidine-1-yl)methyl)isonicotinic acid methyl ester

NaBH(OAc) _₃ (119 mg) was added to a mixture of Reference Example F-33 (63 mg), methyl 2-formyl isonicotinic acid (46 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 the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/50/50) to give the title compound (77 mg). MS (ESI_APCI, m/z): 563 (M+H) ⁺

See example G-23

(S)-1-methyl-2-((3-(1-(naphth-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-6, using Reference Example F-37 instead of Reference Example F-9. MS(ESI_APCI, m/z): 525 (M+H) ⁺

Reference example G-24

(S)-2-((3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-6, using Reference Example F-38 instead of Reference Example F-9. MS(ESI_APCI,m/z):551(M+H) ⁺

Reference example H-1

(S)-3-(pyrrolidone-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 (4 mol/L, 1,4-dioxane solution, 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).

See Example I-1

(S)-1-methyl-2-((3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

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 the mixture was stirred at room temperature for 30 minutes. Methanol was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the residue. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 95/5/0-0/100/0-0/90/10) to give the title compound (3.52 g).

Reference example G-25

(S)-2-((3-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

A mixture of Reference Example I-1 (100 mg), 4-bromo-N,N-dimethylaniline (55 mg), N,N'-dimethylethylenediamine (0.032 mL), cuprous iodide (I) (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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-20/80) to give the title compound (77 mg). MS (ESI_APCI, m/z): 518 (M+H) ⁺

Reference example G-26

(S)-1-methyl-2-((3-(2-oxo-1-(4-phenoxyphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described 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) ⁺

Reference example G-27

(S)-2-((3-(1-(4-benzylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 1-benzyl-4-iodobenzene instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 565 (M+H) ⁺

Reference example G-28

(S)-1-methyl-2-((3-(2-oxo-1-(p-tolyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 1-iodo-4-methylbenzene instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI,m/z):489(M+H) ⁺

Reference example G-29

(S)-2-((3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 1-chloro-4-iodobenzene instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 509(M+H) ⁺

Reference example G-30

(S)-1-methyl-2-((3-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 4-iodobenzyl sulfide instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 521(M+H) ⁺

Reference example G-31

(S)-2-((3-(1-(4-(ethylsulfonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described 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) ⁺

Reference example G-32

(S)-1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described 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) ⁺

Reference example G-33

(S)-1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described 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) ⁺

Reference example G-34

(S)-2-((3-(1-(4-cyanophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 4-bromobenzonitrile instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 500 (M+H) ⁺

Reference example G-35

(S)-1-methyl-2-((3-(1-(4-nitrophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 1-bromo-4-nitrobenzene instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 520(M+H) ⁺

Reference example G-36

(S)-1-methyl-2-((3-(2-oxo-1-(quinolin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 3-bromoquinoline instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 526 (M+H) ⁺ Reference Example G-37

(S)-1-methyl-2-((3-(1-(4-morpholinylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 4-(4-iodophenyl)morpholine instead of 4-bromo-N,N-dimethylaniline.

Reference example G-38

(S)-1-methyl-2-((3-(2-oxo-1-(4-phenylcyclohexyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

DEAD (40%, in toluene, 0.171 mL) was slowly added to a mixture of Reference Example I-1 (100 mg), 4-phenylcyclohexane-1-ol (44 mg), triphenylphosphine (99 mg), and THF (3 mL) under ice cooling and stirring. The reaction mixture was stirred at the same temperature for 10 minutes, then at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (59 mg). MS (ESI_APCI, m/z): 557 (M+H) ⁺

Reference example G-39

(S)-1-methyl-2-((3-(2-oxo-1-(4-vinylphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 1-bromo-4-vinylbenzene instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 501(M+H) ⁺

Reference example G-40

(S)-1-methyl-2-((3-(2-oxo-1-(thien-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 3-bromothiophene instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 481(M+H) ⁺

Reference example G-41

(S)-2-((3-(1-phenylmethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-38, using benzyl alcohol instead of 4-phenylcyclohexyl-1-ol. MS(ESI_APCI,m/z):489(M+H) ⁺

Reference example G-42

(S)-2-((3-(1-(4-cyclopropylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 1-bromo-4-cyclopropylbenzene instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 515(M+H) ⁺

Reference example G-43

(S)-2-((3-(1-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidone-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

The title compound was prepared in a manner similar to that described in Reference Example G-25, using 4-bromophenol instead of 4-bromo-N,N-dimethylaniline. MS(ESI_APCI, m/z): 491(M+H) ⁺

Reference example G-44

(S)-1-methyl-2-((3-(1-(4'-(methanesulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid tert-butyl ester

A mixture of Reference Example G-29 (50 mg), 4-(methanesulfonylamino)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 brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (37 mg). MS (ESI_APCI, m/z): 644 (M+H) ⁺

Reference example G-45

(S)-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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

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 residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-30/70) to give the title compound (65 mg). MS (ESI_APCI, m/z): 623(M+H) ⁺

Reference example G-46

(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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

Reference Example J-2 (8.7 mg) and NaBH(OAc) ₃ (15 mg) were added to a mixture of Reference Example F-34 (18 mg), triethylamine (0.024 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 the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (20 mg). MS (ESI_APCI, m/z): 678 (M+H) ⁺

Reference example G-47

(S)-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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

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 the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-20/80) to give the title compound (92 mg).

See Example K-1

(S)-(4-(3-(1-(((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzyl)glycine methyl ester

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 overnight at room temperature. Water, ethyl acetate, and a saturated aqueous solution of sodium bicarbonate were added to the reaction mixture. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (7 mg). MS (ESI_APCI, m/z): 501 (M+H) ⁺

See example K-3

(5-bromopyridine-2-carbonyl)glycine methyl ester

A mixture of 5-bromopyridinecarboxylic 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 overnight at room temperature. Water and ethyl acetate were added to the reaction mixture, and the mixture was stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate = 90/10-50/50) to give the title compound (247 mg).

See Example K-4

(S)-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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid tert-butyl ester

A mixture of Reference Example I-1 (100 mg), Reference Example K-3 (75 mg), N,N'-dimethylethylenediamine (0.032 mL), cuprous iodide (I) (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 decanted into ethyl acetate, and the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (25 mg). MS (ESI_APCI, m/z): 591 (M+H) ⁺

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

[Table 1]

Example G-5

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

NaBH(OAc) _₃ (197 mg) was added to a mixture of Reference Example F-8 (105 mg), 1-methyl-1H-imidazol-2-carboxaldehyde (51 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 the mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (128 mg). MS (ESI_APCI, m/z): 509 (M+H) ⁺

Example G-10

(S)-3'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner to that described in Example G-5, using Reference Example F-25 instead of Reference Example F-8. MS(ESI_APCI, m/z): 525(M+H) ⁺

Example G-11

(S)-2'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner to that described in Example G-5, using Reference Example F-26 instead of Reference Example F-8. MS(ESI_APCI, m/z): 525(M+H)+

Example G-12

(S)-4-(5-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)methyl benzoate

The title compound was prepared in a similar manner to that described in Example G-5, using Reference Example F-27 instead of Reference Example F-8. MS(ESI_APCI, m/z): 510(M+H) ⁺

Example G-13

(S)-4-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylic acid methyl ester

The title compound was prepared in a similar manner to that described in Example G-5, using Reference Example F-28 instead of Reference Example F-8. MS(ESI_APCI, m/z): 525 (M+H) ⁺

Example G-15

(S)-2-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

The title compound was prepared in a similar manner to that described in Example G-5, using Reference Example F-29 instead of Reference Example F-8. MS(ESI_APCI, m/z): 525 (M+H) ⁺

Example G-48

(S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

NaBH(OAc) _₃ (282 mg) was added to a mixture of Reference Example F-23 (100 mg), 3-methyl-2-pyridinecarboxaldehyde (54 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (80 mg). MS (ESI_APCI, m/z): 520 (M+H) ⁺

Example K-5

(S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) _₃ (415 mg) was added to a mixture of Reference Example F-21 (200 mg), 5-bromo-1-methyl-1H-imidazol-2-carboxaldehyde (139 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (286 mg). MS (ESI_APCI, m/z): 545 (M+H) ⁺

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)pyrrolidone-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxynitrile

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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (185 mg). MS (ESI_APCI, m/z): 492 (M+H) ⁺

Example K-7

(S)-4'-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

NaBH(OAc) _₃ (376 mg) was added to a mixture of Reference Example F-23 (200 mg), 5-bromo-1-methyl-1H-imidazol-2-carboxaldehyde (168 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (218 mg). MS (ESI_APCI, m/z): 587 (M+H) ⁺

Example K-8

(S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

A mixture of 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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (319 mg). MS (ESI_APCI, m/z): 534 (M+H) ⁺

Example K-9

(S)-4'-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid methyl ester

NaBH(OAc) _₃ (363 mg) was added to a mixture of Reference Example F-26 (200 mg), 5-bromo-1-methyl-1H-imidazol-2-carboxaldehyde (162 mg), and dichloromethane (3 mL). 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 residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/80/20) to give the title compound (297 mg). MS (ESI_APCI, m/z): 603(M+H) ⁺

Example K-10

(S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-carboxylic acid methyl ester

A mixture of 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. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/80/20) to give the title compound (178 mg). MS (ESI_APCI, m/z): 550 (M+H) ⁺

Example K-11

(S)-4-(5-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)methyl benzoate

NaBH(OAc) _₃ (375 mg) was added to a mixture of Reference Example F-27 (200 mg), 5-bromo-1-methyl-1H-imidazol-2-carboxaldehyde (167 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (214 mg). MS (ESI_APCI, m/z): 588 (M+H) ⁺

Example K-12

(S)-4-(5-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)methyl benzoate

A mixture of 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. After stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (244 mg). MS (ESI_APCI, m/z): 535 (M+H) ⁺

Example K-13

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a similar manner to that described in Example K-11, using Reference Example F-1 instead of Reference Example F-27. MS(ESI_APCI, m/z): 529 (M+H) ⁺

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxynitrile

The title compound was prepared in a similar manner to that described in Example K-12, using Example K-13 instead of Example K-11. MS(ESI_APCI, m/z): 476 (M+H) ⁺

Example K-15

(S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a similar manner to that described in Example K-11, using Reference Example F-3 instead of Reference Example F-27. MS(ESI_APCI, m/z): 453 (M+H) ⁺

Example K-16

(S)-1-Methyl-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidone-1-yl)methyl)-1H-imidazo-5-carboxynitrile

A mixture of 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 the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (75 mg). MS (ESI_APCI, m/z): 400 (M+H) ⁺

Example K-17

(R)-4-(5-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)methyl benzoate

The title compound was prepared in a similar manner to that described in Example K-11, using Reference Example F-36 instead of Reference Example F-27. MS(ESI_APCI, m/z): 588 (M+H) ⁺

Example K-18

(R)-4-(5-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)methyl benzoate

The title compound was prepared in a similar manner to that described in Example K-16, using Example K-17 instead of Example K-15. MS(ESI_APCI, m/z): 535 (M+H) ⁺

Example 1

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) _₃ (65 mg) was added to a mixture of Reference Example F-1 (20 mg), 3-methyl-2-pyridinecarboxaldehyde (8.0 mg), and dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-50/50) to give the title compound (16 mg).

Example 2

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) ₃ (65 mg) was added to a mixture of Reference Example F-1 (20 mg), 1-methyl-1H-imidazol-2-carboxaldehyde (7.2 mg), and dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100), followed by purification by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70) to give the title compound (11 mg).

Example 3

(R)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) _₃ (65 mg) was added to a mixture of Reference Example F-2 (20 mg), 1-methyl-1H-imidazol-2-carboxaldehyde (11 mg), and dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 20 minutes. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70) to give the title compound (10 mg).

Example 4

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(pyridin-2-ylmethyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 2, using 2-pyridinecarboxaldehyde instead of 1-methyl-1H-imidazol-2-carboxaldehyde.

Example 5

(S)-3-(1-((1H-imidazol-4-yl)methyl)pyrrolidine-3-yl)-1-([1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 1, using 1H-imidazol-4-carboxaldehyde instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 6

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-4-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

Add NaBH(OAc) _₃ (81 mg) to a mixture of Reference Example F-1 (30 mg), 1-methyl-1H-imidazol-4-carboxaldehyde (17 mg), and dichloromethane (1 mL). Stir the mixture at room temperature for 30 minutes. Add methanol (1 mL) to the reaction mixture and stir for 30 minutes. Concentrate the reaction mixture under reduced pressure. Purify the residue by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10). Add hydrogen chloride (1 mol/L, ethanol solution, 0.2 mL) to the resulting product and stir the mixture. Concentrate the mixture under reduced pressure to give the title compound (37 mg).

Example 7

(S)-3-(1-((1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1-([1,1'-biphenyl]-4-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 1, using 1H-imidazol-2-carboxaldehyde instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 8

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((3-hydroxypyridin-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 1, using 3-hydroxypyridine-2-carboxaldehyde instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 9

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((5-hydroxypyridin-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 1, using 5-hydroxypyridine-2-carboxaldehyde instead of 3-methyl-2-pyridinecarboxaldehyde.

Example 10

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((4-hydroxypyridin-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) _₃ (65 mg) was added to a mixture of Reference Example F-1 (30 mg), 4-hydroxypyridine-2-carboxaldehyde (19 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70) to give the title compound (14 mg).

Example 11

(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidone-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-imidazol-2-carboxaldehyde (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 the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100), followed by purification by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70). Hydrogen chloride (4 mol/L, ethyl acetate solution, 2 mL) was added to the resulting product, and the mixture was stirred. The mixture was concentrated under reduced pressure to give the title compound (59 mg).

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-imidazol-2-carboxaldehyde (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 the mixture was stirred for 10 minutes. Water was added to the reaction mixture, and the mixture was stirred. The mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-20/80) and then by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70) to give the title compound (144 mg).

Example 13

1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)azacyclobutane-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) _₃ (354 mg) was added to a mixture of Reference Example F-5 (105 mg), 1-methyl-1H-imidazol-2-carboxaldehyde (61 mg), and dichloromethane (2 mL). The reaction mixture was stirred at room temperature for 30 minutes. Methanol (1 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70). Hydrogen chloride (4 mol/L, ethyl acetate solution) and methanol were added to the resulting product, and the mixture was stirred. The mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70) to give the title compound (2.8 mg).

Example 14

(S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 3, using Reference Example F-21 instead of Reference Example F-2.

Example 15

Methyl (S)-4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoate

The title compound was prepared in a manner similar to that described in Example 1, using Reference Example F-6 instead of Reference Example F-1.

Example 16

(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)isonicotinic acid

Add an aqueous solution of sodium hydroxide (5 mol/L, 1 mL) to a mixture of Reference Example G-1 (26 mg), methanol (0.5 mL), and THF (0.5 mL). Stir the reaction mixture overnight at room temperature. Neutralize the reaction mixture with hydrochloric acid (2 mol/L). Purify the mixture by ODS column chromatography (eluent: water/acetonitrile = 90/10-30/70) to give the title compound (9.5 mg).

Example 17

(S)-6-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)nicotinic acid

The title compound was prepared in a manner similar to that described in Example 16, using Reference Example G-2 instead of Reference Example G-1.

Example 18

(S)-2-((3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)isonicotinic acid

The title compound was prepared in a manner similar to that described in Example 16, using Reference Example G-3 instead of Reference Example G-1.

Example 19

(S)-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)isonicotinic acid

The title compound was prepared in a manner similar to that described in Example 16, using Reference Example G-4 instead of Reference Example G-1.

Example 20

(S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid

An aqueous solution of sodium hydroxide (5 mol/L, 1 mL) was added to a mixture of Example G-5 (118 mg), methanol (0.5 mL), and THF (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with hydrochloric acid (2 mol/L), and the mixture was stirred for 20 minutes. The precipitate was collected by filtration, and the resulting solid was dried to give the title compound (44 mg).

Example 21

(S)-4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzoate

A mixture of Example 15 (257 mg), methanol (1 mL), and THF (1 mL) was added to an aqueous solution of sodium hydroxide (5 mol/L, 2 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized by adding hydrochloric acid (2 mol/L, 5 mL). The mixture was concentrated under reduced pressure. Dichloromethane and anhydrous magnesium sulfate were added to the residue. The mixture was stirred at room temperature for 10 minutes. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. Dichloromethane and hydrogen chloride (4 mol/L, ethyl acetate solution, 1 mL) were added to the residue, and the mixture was stirred. The mixture was concentrated under reduced pressure to give the title compound (120 mg).

Example 22

(S)-1-Methyl-2-((3-(1-(naphth-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-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 refluxed for 2 hours. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 90/10-30/70) to give the title compound (107 mg).

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-imidazo-5-carboxylic acid

A mixture of Reference Example G-6 (73 mg), dichloromethane (0.5 mL), and trifluoroacetic acid (0.5 mL) was refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 90/10-30/70) to give the title compound (39 mg).

Example 24

(S)-2-((3-(1-(4'-carboxyl-[1,1'-biphenyl]-4-yl)-6-methoxy-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-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. Methanol (0.5 mL) and lithium hydroxide monohydrate (95 mg) were added to the mixture. The reaction mixture was stirred overnight at room temperature. The reaction mixture was purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 90/10-30/70) to give the title compound (85 mg).

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-fluoropyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 24, using Reference Example G-8 instead of Reference Example G-7.

Example 26

(S)-2-((3-(1-(4'-carboxyl-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 24, using Reference Example G-9 instead of Reference Example G-7.

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-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 the mixture was stirred at 50 °C for 1 hour. The reaction mixture was purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 90/10-30/70) to give the title compound (27 mg).

Example 28

(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 3, using Reference Example F-13 instead of Reference Example F-2.

Example 29

(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 3, using Reference Example F-14 instead of Reference Example F-2.

Example 30

(R)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 3, using Reference Example F-15 instead of Reference Example F-2.

Example 31

(S)-1-(4'-fluoro-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 1, using Reference Example F-16 instead of Reference Example F-1.

Example 32

(S)-1-(4'-methoxy-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 1, using Reference Example F-17 instead of Reference Example F-1.

Example 33

(S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 1, using Reference Example F-18 instead of Reference Example F-1.

Example 34

(S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxynitrile

The title compound was prepared in a manner similar to that described in Example 1, using Reference Example F-19 instead of Reference Example F-1.

Example 35

(S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 1, using Reference Example F-20 instead of Reference Example F-1.

Example 36

(S)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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-imidazol-2-carboxaldehyde (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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile = 80/20-30/70). Hydrogen chloride (4 mol/L, ethyl acetate solution) and methanol were added to the resulting product, and the mixture was stirred. The mixture was concentrated under reduced pressure to give the title compound (25 mg).

Example 37

(S)-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

The title compound was prepared in a manner similar to that described in Example 3, using Reference Example F-23 instead of Reference Example F-2.

Example 38

(R)-3'-methyl-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid methyl ester

The title compound was prepared in a manner similar to that described in Example 3, using Reference Example F-24 instead of Reference Example F-2.

Example 39

(S)-3'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 an aqueous solution of sodium hydroxide (5 mol/L, 1 mL) was stirred overnight at room temperature. Hydrochloric acid (2 mol/L, 2.5 mL) was added to the reaction mixture, and the mixture was stirred. The mixture was concentrated under reduced pressure. Methanol was added to the residue, and the mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile = 90/10-30/70) to give the title compound (6.3 mg).

Example 40

(S)-2'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 39, using Example G-11 instead of Example G-10.

Example 41

(S)-4-(5-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid

The title compound was prepared in a manner similar to that described in Example 39, using Example G-12 instead of Example G-10.

Example 42

(S)-4-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 16, using Example G-13 instead of Reference Example G-1.

Example 43

(S)-2-((3-(1-(4'-carboxyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)isonicotinic acid

The title compound was prepared in a manner similar to that described in Example 16, using Reference Example G-14 instead of Reference Example G-1.

Example 44

(S)-2-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 16, using Example G-15 instead of Reference Example G-1.

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)pyrrolidine-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 to an aqueous solution of sodium hydroxide (5 mol/L, 1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized with hydrochloric acid. The mixture was purified by ODS column chromatography (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (109 mg).

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)pyrrolidine-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 to an aqueous solution of sodium hydroxide (5 mol/L, 1 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralized by adding hydrochloric acid (2 mol/L), and the precipitate was collected by filtration. The resulting solid was purified by ODS column chromatography (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (280 mg).

Example 47

(S)-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid

A 5 mol/L aqueous solution of sodium hydroxide (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 the mixture was stirred. The mixture was concentrated under reduced pressure. Methanol was added to the residue, and the mixture was stirred. Insoluble material was removed by passing through Celite diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile = 90/10-30/70) to give the title compound (17 mg).

Example 48

(R)-3'-methyl-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-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 prepared in a manner similar to that described in Example 47, using Example 38 instead of Example 37.

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-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 allowed to stand at room temperature, and the precipitate was collected by filtration. The resulting solid was washed with cold water and dried. A portion of the product obtained (26 mg out of 222 mg) was purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 98/2-30/70) to give the title compound (15 mg).

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-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). Insoluble material was removed by filtration. The filtrate was purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 90/10-70/30-10/90) to give the title compound (224 mg).

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)pyrrolidine-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 while ice-cooled and stirred. The reaction mixture was refluxed for 4 days. The reaction mixture was allowed to cool to room temperature and then neutralized by adding an aqueous sodium hydroxide solution (5 mol/L). The precipitate was collected by filtration. The resulting solid was purified by ODS column chromatography (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (16 mg).

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)pyrrolidine-1-yl)methyl)isonicotinic acid

The title compound was prepared in a manner similar to that described in Example 51, using Reference Example G-21 instead of Reference Example G-20.

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)pyrrolidine-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 refluxed for 7 hours. The reaction mixture was allowed to cool to room temperature. An aqueous solution of sodium hydroxide (5 mol/L, 4 mL) was added to the mixture under ice-cooling. The mixture was stirred overnight at room temperature. The reaction mixture was purified by ODS column chromatography (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (3 mg).

Example 54

(S)-2-((3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-24 instead of Reference Example G-6.

Example 55

(S)-2-((3-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-25 instead of Reference Example G-6.

Example 56

(S)-1-Methyl-2-((3-(2-oxo-1-(4-phenoxyphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-26 instead of Reference Example G-6.

Example 57

(S)-2-((3-(1-(4-benzylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-27 instead of Reference Example G-6.

Example 58

(S)-1-Methyl-2-((3-(2-oxo-1-(p-tolyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-28 instead of Reference Example G-6.

Example 59

(S)-2-((3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-29 instead of Reference Example G-6.

Example 60

(S)-1-Methyl-2-((3-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-30 instead of Reference Example G-6.

Example 61

(S)-2-((3-(1-(4-(ethylsulfonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-31 instead of Reference Example G-6.

Example 62

(S)-1-Methyl-2-((3-(2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-32 instead of Reference Example G-6.

Example 63

(S)-1-Methyl-2-((3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-33 instead of Reference Example G-6.

Example 64

(S)-2-((3-(1-(4-cyanophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-34 instead of Reference Example G-6.

Example 65

(S)-1-Methyl-2-((3-(1-(4-nitrophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-35 instead of Reference Example G-6.

Example 66

(S)-1-methyl-2-((3-(2-oxo-1-(quinolin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-36 instead of Reference Example G-6.

Example 67

(S)-1-Methyl-2-((3-(1-(4-morpholinylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-37 instead of Reference Example G-6.

Example 68

(S)-1-Methyl-2-((3-(2-oxo-1-(4-phenylcyclohexyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-38 instead of Reference Example G-6.

Example 69

(S)-1-Methyl-2-((3-(2-oxo-1-(4-vinylphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-39 instead of Reference Example G-6.

Example 70

(S)-1-methyl-2-((3-(2-oxo-1-(thien-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-40 instead of Reference Example G-6.

Example 71

(S)-2-((3-(1-phenylmethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-41 instead of Reference Example G-6.

Example 72

(S)-2-((3-(1-(4-cyclopropylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-42 instead of Reference Example G-6.

Example 73

(S)-2-((3-(1-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-43 instead of Reference Example G-6.

Example 74

(S)-1-Methyl-2-((3-(1-(4'-(methanesulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-44 instead of Reference Example G-6.

Example 75

(S)-(4-(3-(1-(((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzyl)glycine

A mixture of Reference Example K-1 (7.7 mg), methanol (0.5 mL), and THF (0.5 mL) was added to an aqueous solution of 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 (eluent: water/acetonitrile = 90/10-30/70) to give the title compound (2.5 mg).

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 23, using Reference Example G-46 instead of Reference Example G-6.

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-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 refluxed for 1 hour. The reaction mixture was allowed to cool to room temperature. Lithium hydroxide monohydrate (70 mg) was added to the mixture, and the mixture was stirred overnight at room temperature. The reaction mixture was purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 98/2-30/70) to give the title compound (33 mg).

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The title compound was prepared in a manner similar to that described in Example 77, using Reference Example K-4 instead of Reference Example G-47.

Example 79

(S)-3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) _₃ (561 mg) was added to a mixture of Reference Example F-22 (285 mg), 5-bromo-1-methyl-1H-imidazol-2-carboxaldehyde (250 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate = 80/20-0/100) to give the title compound (363 mg).

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)pyrrolidone-1-yl)methyl)-1H-imidazo-5-carboxynitrile

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 min under microwave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water, and the resulting mixture was stirred. The mixture was filtered through Celite diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (68 mg).

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)pyrrolidine-1-yl)methyl)-1H-imidazo-5-carboxylic acid

The mixture of Example 80 (190 mg) and concentrated hydrochloric acid (1 mL) was stirred at 110 °C for 1 hour under microwave irradiation. An aqueous solution of sodium hydroxide (5 mol/L) was added to the reaction mixture under ice cooling until a precipitate formed. The precipitate was collected by filtration. The resulting solid was purified by ODS column chromatography (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (25 mg).

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The 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 (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (83 mg).

Example 83

(S)-2-((3-(1-(4'-carboxyl-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The 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 (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (101 mg).

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The 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 (eluent: water/acetonitrile = 98/2-30/70). A portion of the product obtained (16 mg out of 107 mg) was further purified by ODS column chromatography (eluent: water/acetonitrile containing 0.1% formic acid = 98/2-30/70) to give the title compound (8 mg).

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The 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. Insoluble material was removed by diatomaceous earth. The filtrate was purified by ODS column chromatography (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (60 mg).

Example 86

(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The 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 residue. Insoluble material was removed by passing it through Celite diatomaceous earth. The filtrate was purified by ODS column chromatography (eluent: water/acetonitrile = 90/10-30/70) to give the title compound (2.2 mg).

Example 87

(S)-1-Methyl-2-((3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-yl)methyl)-1H-imidazo-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 (eluent: water/acetonitrile = 98/2-30/70) to give the title compound (48 mg).

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)pyrrolidine-1-yl)methyl)-1-methyl-1H-imidazo-5-carboxylic acid

The 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 resulting solid was dried to give the title compound (40 mg).

Example 89

(S)-1-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

NaBH(OAc) _₃ (94 mg) was added to a mixture of Reference Example F-21 (35 mg), 3-methyl-2-pyridinecarboxaldehyde (18 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 the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on amino-silica gel (eluent: n-hexane/ethyl acetate/methanol = 80/20/0-0/100/0-0/90/10) to give the title compound (32 mg).

Example 90

(S)-3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was prepared in a manner similar to that described in Example 89, using Reference Example F-22 instead of Reference Example F-21.

Example 91

(S)-4'-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidine-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid

A 5 mol/L aqueous solution of sodium hydroxide (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 under ice-cooling for 30 minutes. The precipitate was collected by filtration, and the resulting solid was dried to give the title compound (37 mg).

The following shows the chemical structure, physical properties, and PHD2 inhibitory activity of the examples (see Experimental Example 1).

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

Experimental Example 1: PHD2 Suppression Test

(1) Expression and preparation of human PHD2 _184-418

Human PHD2 _184-418 , containing amino acid residues 184 to 418 of the protein represented by CAC42509 (GenBank accession number), was expressed and prepared using the following method.

An expression construct containing an N-terminal histidine tag for human PHD2 _184-418 was introduced into the pET-30a(+) vector, and the sequence was confirmed. This vector was introduced into the BL21(DE3) strain and cultured in LB medium containing antibiotics at 37°C. After culturing, cell lysis buffer was added to the cells, and the cells were then disrupted by sonication. The disrupted suspension was centrifuged, and the supernatant was purified by Ni column chromatography to yield human PHD2 _184-418 .

(2) Method

Human HIF-1α _556-574 (FITC-labeled HIF-1α _556-574 ) containing N-terminal FITC-Ahx and amino acid residues (partial peptide) at positions 556 to 574 of HIF-1α was used as a substrate. Using FITC-labeled HIF-1α _556-574 , the competitive inhibition between 2-ketoglutarate and the test compound (PHD inhibitor) was evaluated based on fluorescence polarization changes using the following method.

The enzyme (human PHD2 _184-418 ) and the substrate were diluted with assay buffer (pH 7.4) containing 10 mM HEPES, 150 mM NaCl, ₁₀ μM MnCl₂ - _4H₂O , 2 μM 2-ketoglutaric acid, and 0.05% Tween-20. The test compound was diluted with DMSO. The test compound and human PHD2 _184-418 were pre-added to 384-well plates (Corning, black, opaque bottom). The reaction was initiated by adding FITC-labeled HIF-1α _556-574 . After incubation at 37 °C for 60 min, fluorescence polarization (excitation wavelength: 470 nm, fluorescence 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 values in the group without the test compound.

(3) Results

As shown in the table above, the compounds of the present invention inhibit the binding between PHD2 and HIF-1α, thus confirming that the compounds of the present invention can be used as PHD2 inhibitors.

Treatment efficacy in a colitis model (Example 2)

(1) TNBS-induced colitis model rats

It is known that when TNBS is administered into the large intestine, local inflammation occurs in the large intestine, and intestinal permeability is subsequently increased due to the disruption of the intestinal barrier function. Therefore, the inhibitory effect on intestinal permeability based on oral administration of the test compound was evaluated as an indicator of drug efficacy.

(2) Method

SD rats: Eight-week-old male SLCs (Japan SLCs) were used. Under pentobarbital anesthesia, 300 μL of TNBS (28 mg/mL) prepared with 50% ethanol was administered into the large intestine at a point 8 cm from the anus to induce inflammation. The solvent treatment group received 300 μL of 50% ethanol. Animals were fasted for 48 hours prior to TNBS administration. Starting the next day, the test compound (3 mg/kg) prepared with 0.05% methylcellulose solution was administered orally once daily for a total of 3 days. Four hours after day 3, 50 mg/kg FITC was administered orally. Four hours later, blood samples were collected from the jugular vein under isoflurane anesthesia. Serum was centrifuged and fluorescence intensity was detected using a PHERAstar FSX (BMG Labtech) to measure the concentration of FITC permeating through the mesentery into the circulating blood. The inhibition rate of intestinal permeability by the test compound was calculated based on the value as 0 for the no-test-compound group and the value as 100 for the untreated TNBS group.

(3) Results

The inhibition rate (%, average) of each tested compound on intestinal permeability (inhibition) is shown below.

[Table 16]

Example number inhibition(%) Example number inhibition(%) 39 95 47 85 40 84 49 82 41 74 82 96 43 59 83 85 45 51 84 117 46 63 85 101

The increased intestinal permeability of FITC due to TNBS administration was inhibited by administration of the compound of the present invention, thus confirming that the compound of the present invention can be used as a medicament for treating inflammatory bowel disease.

Compound concentration in colon tissue in Experimental Example 3

(1) Rat PK study

The test compound (3 mg/kg/5 mL) prepared with 0.05% methylcellulose was orally administered to fasting rats (SD, 8 weeks old, male, Japan SLC). Blood samples were collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6, and 8 hours post-administration. Laparotomy was performed under isoflurane anesthesia, and the large intestine was dissected. The collected distal large intestine (approximately 5 cm) was cut open and then washed with saline in a petri dish. After washing, the large intestine was minced with small scissors. Approximately 150 mg was transferred to a test tube. 100 μL of saline was added to the test tube, and the mixture was homogenized using a sample shaker (1000 rpm x 30 min). The sample was prepared by adding four times the volume of saline as the final volume. The concentration of the test compound in the large intestine tissue and plasma was measured by quantitative analysis using liquid chromatography-mass spectrometry (LC/MS).

(2) Concentration of compounds in colon tissue and plasma

As shown in the table below, the compounds of the present invention have been confirmed to have higher concentrations in colon tissue than in plasma. Therefore, the preferred compounds of the present invention are PHD2 inhibitors that specifically act on colon tissue.

[Table 17]

Example number Cmax AUC plasma colon C/P 39 7 2090 3 214 71 40 <1 NC <1 209 >209 43 8 2111 2 84 42 45 2 401 <1 87 >87 46 3 314 <1 174 >174 47 60 20011 18 317 18 49 4 898 <1 201 >201 83 5 1292 <1 54 >54 84 1 76 <1 99 >99 85 1 117 <1 164 >164

The symbols in the table have the following meanings:

Cmax: The highest plasma concentration (ng/mL) of the compound tested under oral administration conditions.

AUC: Area under the plasma test compound concentration-time curve (ng*min/mL)

Plasma: The concentration of the compound in the plasma was tested after 8 hours (ng/mL).

Colon: Concentration of the tested compound in colon tissue after 8 hours (ng/g)

C/P: The ratio of the colon to plasma mentioned above.

NC: Not calculated (below the lower limit of calculation)

Industrial applicability

The compounds of the present invention or their pharmaceutically acceptable salts can be used as remedies for treating inflammatory bowel disease.

Claims (19)

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: in Ring W is _C6-10 aryl, 5- or 6-heteroaryl, 9- or 10-heteroaryl, or _C3-8 cycloalkyl; Ring Z is a group selected from (a) to (c) below: in ^Ra , ^Rb , and ^Rc are each independently a hydrogen atom, a halogen atom, a _C1-6 alkyl group, a cyano group, a hydroxyl group, or a carboxyl group; and R ^d is a hydrogen atom or a _C1-6 alkyl group; ^R1 is a hydrogen atom, a halogen atom, or a _C1-6 alkyl group; ^R2 is a hydrogen atom, a _C1-6 alkyl group, a halo ^- _C1-6 alkyl group, a _C1-6 alkoxy group, _-CO2R4 , or ^{-CONR5R5 '} ; ^R4 is a hydrogen atom or a _C1-6 alkyl group; and ^R5 and R5 ^' are each independently a hydrogen atom, a carboxyl _C1-6 alkyl group, or a 3- to 8-membered heterocyclic alkyl group; ^R3 is a hydrogen atom, a halogen atom, a _C1-6 alkyl group, a halo- _C1-6 alkyl group, a _C1-6 alkoxy group, a halo- _C1-6 alkoxy group, a _C2-6 alkenyl group, a _C1-6 alkyl hydrogen sulfoyl group, a _C1-6 alkyl sulfinyl group, a _C1-6 alkyl sulfonyl group, a hydroxyl group, a cyano group, a nitro ^group , ^{-NR6R6 '} , _-CO2R7 , ^{-CONR8R8 '} , or the following group A, wherein when u is 2, the two ^R3s are the same or different from each other; ^R6 and R6 ^' are _C1-6 alkyl groups; R ⁷ is a hydrogen atom or a _C1-6 alkyl group; ^R8 and R8 ^' are each independently a hydrogen atom or a carboxyl _C1-6 alkyl group; Group A is selected from the following groups (a) to (f): (a) Unsubstituted or substituted _C6-10 aryl groups, or substituted with 1 to 3 groups selected from substituent group B. (b) Unsubstituted or substituted with 1 to 3 groups selected from substituent group B, 5- or 6-membered heteroaryl groups, (c) Unsubstituted or substituted _C6-10 aryl- _C1-6 alkyl groups selected from substituent group B, (d) Unsubstituted or substituted _C6-10 aryloxy groups, or those substituted with 1 to 3 groups selected from substituent group B. (e) Unsubstituted or substituted _C3-8 cycloalkyl groups, and (f) Unsubstituted or substituted with 1 to 3 groups selected from substituent group B, 3- to 8-membered heterocyclic alkyl groups, Substituent group B is composed of halogen atoms, _C1-6 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo _{- C1-6} alkoxy, hydroxyl, cyano, ^{-NR9SO2R10 and} _-CO2R10 ^{; R9} is a hydrogen atom; R ¹⁰ is a hydrogen atom or a _C1-6 alkyl group; and m is 1; n is 1; u is 1 or 2; p and q are each independently 1 or 2; and r is 0 or 1. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring Z is a group selected from (a) to (j) below: 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein ring W is phenyl or 5- or 6-membered heteroaryl. 4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein r is 0. 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein p is 2 and q is 1. 6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein ^R1 is a hydrogen atom or a halogen atom. 7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof. Where ^R2 is a hydrogen atom, a _C1-6 alkyl group, a halo _-C1-6 alkyl group, a _C1-6 alkoxy group, a carboxyl group, or ^{-CONR5R5 '} ; ^R5 and R5 ^' are as defined in claim 1. 8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, Wherein ^R3 is a hydrogen atom, halogen atom, _C1-6 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, _C2-6 alkenyl, _C1-6 alkyl hydrogen sulfo, _C1-6 alkyl sulfonyl, _hydroxyl , ^cyano , -CO2R7, ^{-CONR8R8 '} or group A; Wherein ^R7 , ^R8 , R8 ^' and u have the same meaning as described in claim 1; Group A is an unsubstituted phenyl or an unsubstituted 5- or 6-membered heteroaryl group, substituted with 1 to 3 groups selected from substituent group B. Substituent group B is a halogen atom, a _C1-6 alkyl group, a halo _-C1-6 alkyl group, a _C1-6 alkoxy group, a halo- _C1-6 alkoxy group, a hydroxyl group, a cyano group, or a carboxyl group. 9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein ring Z is a group selected from (a), (c), (d), (i), and (j) below: 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula: in X is CH or N; u is 1; R ¹ has the same meaning as described in claim 6; ^R2 has the same meaning as described in claim 7; ^R3 is a hydrogen atom, a _C1-6 alkyl group, or a hydroxyl group; Group A has the same meaning as described in claim 8; Ring Z has the same meaning as described in claim 9; and m and n have the same meaning as described in claim 1. 11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, Where u is 2; One R ³ is a group A; and Other ^R3s are hydrogen atoms, halogen atoms, _C1-6 alkyl, halo- _C1-6 alkyl, _C1-6 alkoxy, halo- _C1-6 alkoxy, _C2-6 alkenyl, _C1-6 ^alkyl hydrogen sulfo, _C1-6 alkyl sulfonyl, hydroxyl, cyano, nitro, ^{-NR6R6 '} , _-CO2R7 , or ^{-CONR8R8 '} ; The groups A, ^R6 , ^R6' , ^R7 , ^R8 and R8 ^' have the same meaning as described in claim 1. 12. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from the following compounds: 13. A compound or a pharmaceutically acceptable salt thereof, said compound being represented by the following formula: 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive thereof. 15. Use of the pharmaceutical composition according to claim 14 in the preparation of a medicament for treating inflammatory bowel disease. 16. The use according to claim 15, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. 17. Compounds represented by the following formula: Or its medicinal salt. 18. Compounds represented by the following formula: Or its medicinal salt. 19. Compounds represented by the following formula: Or its medicinal salt.