RU2776844C1 - Imidazopyridinone compound - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds represented by the formula (I) and to a pharmaceutical composition based thereon.

EFFECT: creation of new compounds exhibiting an inhibitory effect on PHD2, applicable in treating inflammatory bowel diseases, such as ulcerative colitis or Crohn's disease.

16 cl, 17 tbl, 91 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to imidazopyridinone compounds useful as medicines. More specifically, the present invention relates to imidazopyridinone compounds, or pharmaceutically acceptable salts thereof, having an inhibitory effect on prolyl hydroxylase and which are used as agents for the treatment of inflammatory bowel diseases such as ulcerative colitis.

BACKGROUND OF THE INVENTION

Inflammatory bowel disease (IBD) is a chronic disease in which inflammation and ulcers 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 disease of the colon that causes diffuse non-specific inflammation of unknown cause. The colonic mucosa is ulcerated, which can lead to erosion or ulceration of the mucosa. Ulcerative colitis can be divided into an "active phase" in which bloody stools, erosions, ulcers, and the like are observed, and a "remission phase" in which active phase observations disappear. Long-term treatment is required, since relapses and remissions are often repeated during the course.

For the treatment of ulcerative colitis, the formulation 5-aminosalicylic acid (5-ASA) is first used as a standard treatment. However, the effectiveness of 5-ASA is about 50 to 65%, and in patients in remission with the introduction of 5-ASA is about 30 to 45%. When the effect of 5-ASA is not observed, a steroid is used. In addition to these drugs, immunosuppressants, anti-TNF-α antibodies, and the like are sometimes used to treat ulcerative colitis. However, all drugs create problems such as side effects and use with caution. Therefore, a therapeutic agent having a novel mechanism of action in ulcerative colitis is desirable.

It is known that the expression of genes associated with the barrier function of the epithelium of the gastrointestinal tract is induced by hypoxia-induced factor 1α (HIF-1α) in the pathological condition of IBD. HIF-1α is one of the hypoxia-inducible factor α (HIF-α) subtypes. HIF-α is stabilized in a hypoxic environment (hypoxia) and then it activates the transcription of several genes in response to hypoxia. Conversely, the proline residues of HIF-α are hydroxylated by prolyl hydroxylases (PHD) in an oxygen-rich environment (normoxia), and then HIF-α is degraded by the proteasome pathway.

Three subtypes of PHD are known, namely PHD1, PHD2 and PHD3. AKB-4924 is known to be a PHD2 inhibitor. AKB-4924 is reported to stabilize HIF-1α in colon tissue (Non-Patent Literature 1). Moreover, AKB-4924 has an improved effect in a trinitrobenzenesulfonic acid (TNBS) induced colitis model.

Conversely, PHD inhibitors such as roxadustat and daprodustat have hematopoietic effects and have been developed as a therapeutic agent for anemia (Non-Patent Literature 2). Thus, it is important to avoid systemic effects such as hematopoietic effects when a PHD inhibitor is used as a therapeutic agent for IBD.

For example, spiro compounds are described in Patent Literature 1 and 5 and Non-Patent Literature 3 and 4 as PHD inhibitors. Compounds, including imidazopyridinone, are described or illustrated in Patent Literature 2-4. However, the imidazopyridinone compounds of the present invention are not described or proposed in the above literature.

List of opposed materials

Patent Literature

Patent Literature 1: U.S. Published Application No. 2011/0152304

Patent Literature 2: WO 2009/029609

Patent Literature 3: WO 2003/037890

Patent Literature 4: WO 2017/066014

Patent Literature 5: U.S. Published Application 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

Problems solved by the invention

The present invention is directed to a novel compound which has an inhibitory effect on PHD2 and which is useful in the treatment of inflammatory bowel diseases.

Troubleshooting Tools

The present invention relates to a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. That is, the present invention relates to the following [1]-[16] and the like.

[1] The compound represented by formula (I):

[Chem.1]

where

ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;

ring Z is a group selected from the group consisting of the following (a)-(c):

[Chem.2]

and

[Chem.3]

where

R ^a , R ^b and R ^c each independently is a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy or carboxy; and

R ^d is a hydrogen atom or C _1-6 alkyl;

R ¹ is a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy or carboxy, where if m is 2 or 3, two or more R ¹ may be different from each other;

R ² is hydrogen, halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ or -CONR ⁵ R ^5' where if n is 2 or 3, two or more R ² may be different from each other;

R ⁴ is a hydrogen atom or C _1-6 alkyl; and

R ⁵ and R ^5' are each independently hydrogen, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;

R ³ is hydrogen atom, halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _{1- 6} alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' or the following group A, where if u is 2 or 3, two or more R ³ may be different from each other;

R ⁶ and R ^6' are each independently hydrogen or C _1-6 alkyl;

R ⁷ is a hydrogen atom or C _1-6 alkyl;

R ⁸ and R ^8' are each independently hydrogen, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;

group A is a group selected from the group consisting of the following (a)-(h):

(a) C _6-10 aryl which is unsubstituted or substituted with 1-3 groups selected from substituent group B,

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

(c) C _6-10 aryl C _1-6 alkyl which is unsubstituted or substituted with 1-3 groups selected from substituent group B,

(d) C _6-10 aryloxy which is unsubstituted or substituted with 1-3 groups selected from substituent group B,

(e) 5- or 6-membered heteroaryl C _1-6 alkyl which is unsubstituted or substituted with 1-3 groups selected from substituent group B,

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

(g) C _3-8 cycloalkyl which is unsubstituted or substituted with 1-3 groups selected from substituent group B, and

(h) 3-8 membered heterocycloalkyl which is unsubstituted or substituted with 1-3 groups selected from substituent group B,

where substituent group B is a group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ R ^9' , - NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ and -CONR ¹¹ R ^11' ;

where R ⁹ and R ^9' each independently is a hydrogen atom or C _1-6 alkyl;

R ¹⁰ is a hydrogen atom or C _1-6 alkyl; and

R ¹¹ and R ^11' are each independently hydrogen, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;

m, n and u are each independently an integer 1-3;

p and q are each independently 1 or 2; and

r is an integer 0-6;

or a pharmaceutically acceptable salt thereof.

[2] The compound according to [1] above, wherein ring Z is a group selected from the group consisting of the following (a)-(j):

[Chem.4]

and

[Chem.5]

or a pharmaceutically acceptable salt thereof.

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

[4] A compound according to any of the above [1]-[3] or a pharmaceutically acceptable salt thereof, wherein r is 0.

[5] A compound according to any of the above [1]-[4] or a pharmaceutically acceptable salt thereof, wherein p is 2 and q is 1.

[6] The compound according to any of the above [1]-[5] or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a halogen atom.

[7] A compound according to any of the above [1]-[6]:

where R ² is hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, carboxy, or —CONR ⁵ R ^5' ;

where R ⁵ and R ^5' each independently is a hydrogen atom, carboxy C _1-6 alkyl or 3-8-membered heterocycloalkyl;

or a pharmaceutically acceptable salt thereof.

[8] A compound according to any of the above [1]-[7]:

where R ³ is hydrogen atom, halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkylsulfanyl, C _{1 -6} alkylsulfonyl, hydroxy, cyano, -CO ₂ R ⁷ , -CONR ⁸ R ^8' or group A;

where R ⁷ and u have the same meanings as described in [1] above;

R ⁸ and R ^8' are each independently hydrogen or carboxy C _1-6 alkyl; and

group A is phenyl which is unsubstituted or substituted by 1-3 groups selected from substituent group B or unsubstituted 5- or 6-membered heteroaryl;

where substituent group B is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano or carboxy;

or a pharmaceutically acceptable salt thereof.

[9] The compound according to any of the above [3]-[8], wherein the ring Z is a group selected from the group consisting of the following (a)-(e):

[Chem.6]

and

[Chem.7]

or a pharmaceutically acceptable salt thereof.

[10] A compound represented by the following formula:

[Chem.8]

where

X is CR ³ or N;

u is 1 or 2;

R ¹ has the same meanings as described in [6] above;

R ² has the same meanings as described in [7] above;

R ³ is a hydrogen atom, C _1-6 alkyl or hydroxy;

group A has the same meanings as described in [8] above;

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

m and n have the same meanings as described in [1] above;

or a pharmaceutically acceptable salt thereof.

[11] Connection as above [1]:

where u is 2 or 3;

one R ³ is group A; and

the other R ³ is each independently hydrogen, halogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ or -CONR ⁸ R ^8' ;

where the group A, R ⁶ , R ^6' , R ⁷ , R ⁸ and R ^8' have the same meanings as described in the above [1];

or a pharmaceutically acceptable salt thereof.

[12] The compound according to [1] above, which is selected from the group consisting of the following compounds:

[Chem.9]

and

[Chem.10]

or a pharmaceutically acceptable salt thereof.

[13] The compound according to the above [1], which is represented by the following formula:

[Chem.11]

or a pharmaceutically acceptable salt thereof.

[14] A pharmaceutical composition containing a compound according to any of the above [1]-[13] or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive.

[15] The pharmaceutical composition according to the above [14], which is a pharmaceutical composition for use in the treatment of inflammatory bowel diseases.

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

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

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

Invention Effect

The compounds of the present invention have excellent PHD2 inhibitory activity, and therefore the compounds of the present invention, or pharmaceutically acceptable salts thereof, are useful as agents for the treatment of inflammatory bowel diseases.

Method for implementing the invention

Next, embodiments of the present invention are described in more detail.

In the present invention, each term has the following meanings, unless otherwise indicated.

The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. As R ¹ , R ² and R ³ a fluorine atom is preferred.

The term "C _1-6 alkyl" means a straight or branched alkyl group having 1-6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert -butyl, and the like may be illustrative.

The term "C _2-6 alkenyl" means a straight or branched alkenyl group having 2-6 carbon atoms. For example, vinyl, allyl, 1-propenyl, isopropenyl, and the like may be illustrative.

The term "C _2-6 alkynyl" means a straight or branched alkynyl group having 2-6 carbon atoms. For example, ethynyl, 2-propynyl, and the like may be illustrative.

The term "C _1-6 alkoxy" means a straight or branched alkoxy group having 1-6 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy and the like may be illustrative.

The term "carboxy C _1-6 alkyl" means C _1-6 alkyl substituted with one carboxy. For example, carboxymethyl and the like may be illustrative.

The term "hydroxy C _1-6 alkyl" means C _1-6 alkyl substituted with one hydroxy. For example, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl and the like may be illustrative.

The term "halo C _1-6 alkyl" means C _1-6 alkyl substituted with 1-3 identical or different halogen atoms. For example, monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and the like may be illustrative.

The term "halo C _1-6 alkoxy" means C _1-6 alkoxy substituted with 1-3 identical or different halogen atoms. For example, monofluoromethoxy, difluoromethoxy, trifluoromethoxy and the like can be illustrative.

The term "C _1-6 alkylsulfanyl" means a group represented by (C _1-6 alkyl)-S-.

The term "C _1-6 alkylsulfinyl" means a group represented by (C _1-6 alkyl)-S(=O)-.

The term "C _1-6 alkylsulfonyl" means a group represented by (C _1-6 alkyl)-SO ₂ -. For example, methylsulfonyl, ethylsulfonyl and the like may be illustrative.

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

The term "5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group having any 1-4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring. For example, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl pyridyl, pyrimidyl, pyrazinyl, pyridazinyl and the like may be illustrations. As the W ring, thienyl, pyridyl and the like are preferred, and pyridyl is more preferred. As Group A, pyridyl and the like are preferred.

The term "9- or 10-membered heteroaryl" means a bicyclic aromatic heterocyclic group having any 1-4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring. For example, indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzoimidazolyl, purinyl, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, pteridinyl, chromenyl, isochromenyl and the like can be illustrative. As the W ring, quinolyl and the like are preferred.

The term "C _3-8 cycloalkyl" means a 3-8 membered saturated hydrocarbon group. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like may be illustrative.

The term "3-8 membered heterocycloalkyl" means a 3-8 membered heterocycloalkyl group having any 1 or 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring. For example, aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, and the like may be illustrative. As R ⁵ and R ^5' , tetrahydropyranyl and the like are preferred.

The term "C _6-10 aryl C _1-6 alkyl" means C _1-6 alkyl substituted with one C _6-10 aryl. For example, an illustration may be benzyl.

The term "C _6-10 aryloxy" means a group represented by (C _6-10 aryl)-O-. For example, the illustration could be phenoxy.

The term "5- or 6-membered heteroaryl C _1-6 alkyl" means C _1-6 alkyl substituted with one 5- or 6-membered heteroaryl.

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

If a group is substituted with 2 or 3 groups selected from substituent group B, these groups may be the same or different.

The following abbreviations in the description, drawings and tables have the following meanings, respectively.

CDI: carbonyldiimidazole

CPME: cyclopentyl methyl ether

DEAD: diethyl azodicarboxylate

DIPEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMSO: dimethyl sulfoxide

DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

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

HOBt: 1-hydroxybenzotriazole

HOBt-H ₂ O: 1-hydroxybenzotriazole monohydrate

AHL: lithium aluminum hydride

DAL: lithium diisopropylamide

NaBH(OAc) ₃ : sodium triacetoxyborohydride

NMP: 1-methyl-2-pyrrolidinone

Pd(amphos)Cl ₂ : bis[di-tert-butyl(4-dimethylaminophenyl)phosphine] dichloropalladium (II)

THF: tetrahydrofuran

TsCl: p-toluenesulfonyl chloride

T3P (registered trademark): propylphosphonic acid anhydride (cyclic trimer)

9-BBN: 9-borabicyclo[3.3.1]nonane

amino silica gel: aminopropyl silica gel

ODS column chromatography: octadecyl-silylated silica gel column chromatography

Process: process

Scheme: Scheme

Ref. no.: reference number of the example

Ex. No. Example number

Structure: structural formula

Physical data: physical data

IC ₅₀ : concentration required for 50% inhibition

(Numerical values with "*" in the table indicate the degree of inhibition at a compound concentration of 100 μM.)

FITC: fluorescein isothiocyanate

¹ H-NMR: nuclear magnetic resonance hydrogen spectrum

DMSO-d6: dimethylsulfoxide-d6

CDCl ₃ : chloroform-d1

MS: mass spectrometry

ESI_HIAD: multiionization using electrospray ionization - atmospheric pressure chemical ionization

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

[Chem.12]

In an embodiment, the compound represented by formula (I) is a compound wherein the group represented by the following formula is a group selected from the group consisting of the following (a)-(d).

[Chem.13]

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

[Chem.14]

In an embodiment, the compound represented by formula (I) is preferably the compound of [1] above, wherein the groups are groups selected from the groups constituting the following [A]-[I] or any combination thereof.

[A] ring W is phenyl, naphthyl, thienyl, pyridyl, quinolyl, or cyclohexyl.

[B] R ^a , R ^b and R ^c are each independently hydrogen, halogen, methyl, cyano, hydroxy or carboxy.

[C] R ^d is hydrogen or methyl.

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

[E] R ² is hydrogen, methyl, trifluoromethyl, methoxy, -CO ₂ H or -CONR ⁵ R ^5' ;

where R ⁵ and R ^5' each independently is a hydrogen atom, carboxymethyl or tetrahydropyranyl.

[F] R ³ is hydrogen, halogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, vinyl, methylthio, ethylsulfonyl, hydroxy, cyano, nitro, dimethylamino, -CO ₂ R ⁷ , -CONR ⁸ R ^8' or group A, where if u is 2, the two R ³ may be different from each other;

group A is a group selected from the group consisting of the following (a)-(f):

(a) phenyl which is unsubstituted or substituted with 1 or 2 groups selected from substituent group B,

(b) pyridyl,

(c) benzyl,

(d) phenyloxy,

(e) cyclopropyl and

(f) morpholino;

where substituent group B is a group consisting of a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, cyano, -NHSO ₂ R ¹⁰ and -CO ₂ R ^10' ;

where R ¹⁰ and R ^10' each independently is a hydrogen atom or methyl;

R ⁷ is a hydrogen atom or methyl; and

R ⁸ and R ^8' are each independently hydrogen or carboxymethyl.

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

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

[I]r is 0 or 1.

In the case where the compounds represented by formula (I) contain one or more asymmetric carbon atoms, stereoisomers in the R - or S -configuration on each of the asymmetric carbon atoms and mixtures of any combinations thereof are included in the present invention. In such cases, racemic compounds, racemic mixtures, individual enantiomers and mixtures of diastereomers are also included within the scope of the present invention.

In the case where the compounds represented by formula (I) have cis-trans isomers, all cis-trans isomers are included in the present invention.

In the case where tautomers of the compounds represented by formula (I) exist, the present invention includes all tautomers.

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

The compound represented by formula (I) can also be converted into a pharmaceutically acceptable salt thereof by a known method, if necessary. Examples of such salts are acid addition salt and base salt.

As an acid addition salt, an acid addition salt with a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, and an acid addition salt with an organic acid 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, carboxylic acid acid, benzoic acid, glutamic acid and aspartic acid, may be an illustration.

As a salt with a base, a salt formed with an inorganic base such as lithium, sodium, potassium, calcium and magnesium, and a salt formed with an organic base such as N-methyl-D-glucamine, N,N'-dibenzylethylenediamine, triethylamine, piperidine, morpholine, pyrrolidine, arginine, lysine, and choline may be illustrative.

In the case where the compound represented by formula (I) or a pharmaceutically acceptable salt thereof exists, for example, in the form of a crystal, the present invention includes all crystalline forms. For example, a pharmaceutically acceptable salt also includes a solvate thereof with a pharmaceutically acceptable solvent such as water or ethanol, a co-crystal thereof with a suitable co-crystal former (coformer), and the like.

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

Compounds represented by formula (I) in which some of the atoms are replaced by isotopes can be prepared in a manner similar to the production method described below using a commercial isotopically introduced building block. For example, the compound represented by formula (I) in which part of the hydrogen atoms is replaced by deuterium atoms can also be obtained by the above method and the method described in the literature (see, for example, Yukigosei-kagaku kyokaishi, Vol. 65, No. 12 , pp.1179-1190, 2007). For example, the compound represented by formula (I) in which part of the carbon atoms is replaced by ¹³ C can also be obtained by the above method and the method described in the literature (see, for example, RADIOISOTOPES 2007, Vol. 56, No. 11, pp. 35-44).

The compound represented by formula (I) can be obtained, for example, by the method described in Schemes 1 to 5, by the same method, by the method described in the literature, or by the same method.

Commercial products may be used for the reaction in each process if the starting materials and reagents are commercially available.

For the reaction in each process, the reaction time is usually 30 minutes to 3 days, depending on the starting material used, the solvent, the reaction temperature, and the like, unless otherwise indicated.

For the reaction in each process, the reaction temperature is usually -78° C. to reflux temperature, depending on the starting material, solvent or the like used, unless otherwise indicated.

For the reaction in each process, the pressure is usually between 1 atm. up to 20 atm., depending on the used starting material, solvent, reaction temperature and the like, unless otherwise indicated.

For the reaction in each 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 in a pressure range: 1 to 30 bar, in a power range: 1 to 400 W, at a reaction temperature: from room temperature to 300°C, and at a reaction time: from a minute to 1 day, depending on the used starting material, solvent, model and the like.

For the reaction in each process, the reactions are carried out without any solvent or using a suitable solvent, unless otherwise indicated. As an example of a suitable solvent, a solvent that is inert to the reaction may be illustrative. As specific examples of the solvent, illustrative solvents may be those described in the Reference Examples or the examples corresponding to each process, or the following solvents:

alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol and the like;

ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, 2-methyloxolane, CPME and the like;

aromatic hydrocarbons: chlorobenzene, 1,2-dichlorobenzene, toluene, xylene and the like;

saturated hydrocarbons: cyclohexane, n-hexane and the like;

amides: DMF, DMA, NMP and the like;

halogenated hydrocarbons: dichloromethane, 1,2-dichloroethane, carbon tetrachloride and the like;

nitriles: acetonitrile and the like;

sulfoxides: dimethyl sulfoxide and the like;

aromatic organic bases: pyridine and the like;

acid anhydrides: acetic anhydride and the like;

organic acids: formic acid, acetic acid, trifluoroacetic acid and the like;

esters: ethyl acetate, methyl acetate, isopropyl acetate and the like;

ketones: acetone, methyl ethyl ketone and the like; and

water.

The above solvents may be used as a mixture of two or more of them in a suitable ratio.

When a base is used for the reaction in each process, the reaction is carried out using a base suitable for the reaction. As specific examples of the base, the illustration may be the bases that are described in the reference examples or examples corresponding to each process, or the following bases:

inorganic bases: sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate and the like;

organic bases: triethylamine, DIPEA, diethylamine, pyridine, DMAP, 2,6-lutidine, piperidine and the like;

metal alkoxides: sodium ethoxide, sodium methoxide, potassium tert-butoxide and the like;

alkali metal hydrides: sodium hydride and the like;

metal amides: sodium amide, DAL, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide;

organic magnesium compounds: methylmagnesium bromide, isopropylmagnesium chloride, allylmagnesium bromide, phenylmagnesium bromide and the like; and

organic lithium compounds: n-butyllithium, sec-butyllithium, tert-butyllithium and the like.

When an acid or an acid catalyst is used for the reaction in each process, the reaction is carried out using an acid or an acid catalyst which is suitable for the reaction. As specific examples of the acid or acid catalyst, the acids or acid catalysts which are described in the Reference Examples or the examples corresponding to each process, or the following acids or acid catalysts, may be illustrative:

inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like;

organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; and

Lewis acid: boron trifluoride-diethyl ether complex, zinc iodide, aluminum chloride, zinc chloride, titanium(IV) chloride and the like.

When a condensing reagent is used for the reaction in each process, the reaction is carried out using a suitable condensing reagent for the reaction. As specific examples of the condensing agent, the condensing reagents that are described in the Reference Examples or the examples corresponding to each process, or the following condensing reagents, can be illustrated:

carbodiimides: EDC-HCl, N, ^N' -dicyclohexylcarbodiimide and the like;

carbonyldiimidazoles: CDI and the like;

uronium and phosphonium salts: O-(7-azabenzotriazol-1-yl)-N, N,N',N'-tetramethyluronium hexafluorophosphate, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate and the like;

triazines: DMTMM and the like; and

others: T3P and the like.

When a reducing reagent is used for the reaction in each process, the reaction is carried out using an appropriate reducing reagent for the reaction. As specific examples of the reducing agent, the reducing agents which are described in the Reference Examples or the examples corresponding to each process, or the following reducing agents, may be illustrative:

metal hydrides: AHL, lithium borohydride, sodium borohydride, NaBH(OAc) ₃ , sodium cyanoborohydride, diisobutylaluminum hydride and the like; and

boranes: borane-tetrahydrofuran complex, 9-BBN, picoline borane and the like.

In each process where a protecting group is needed depending on the type of functional group, the addition and removal operations can also be optionally carried out in combination according to the general method. Examples regarding types of protecting groups, protection and deprotection include the methods described in Theodora W. Greene & Peter G.M. Wuts Eds., "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley-Interscience, 2006.

In each process, when carrying out deprotection, the reaction may be carried out by a hydrolysis reaction or the like.

In each process, when carrying out the hydrolysis reaction, the reaction can be carried out in the presence of an acid or a base. An illustration of an acid and a base may be the above examples.

In each process, when carrying out the catalytic reduction reaction, the reaction can be carried out in a hydrogen atmosphere in the presence of a catalyst. As the catalyst, powdered palladium-on-charcoal, powdered platinum-on-charcoal, Raney nickel, and the like can be illustrated.

In each process, when carrying out a reduction reaction, the reaction may be carried out in the presence of a reducing agent. As a reducing agent, the above examples may be illustrative.

In each process, when carrying out an amidation reaction, the reaction can be carried out in the presence of a condensing reagent and a base, or in the presence of a condensing reagent. As the condensing agent and the base, the above examples may be illustrative. When carbodiimide is used as a condensing agent, an additive such as HOBt or DMAP may be added if necessary. The amidation reaction can also be carried out using an acyl halide or an acid anhydride.

In each process, when carrying out a reductive amination reaction, the reaction can be carried out in the presence of a reducing agent. As a reducing agent, the above examples may be illustrative. As the reducing agent, NaBH(OAc) ₃ and the like can preferably be used.

In each process, when carrying out an aromatic nucleophilic substitution reaction, the reaction can be carried out in the presence of a base. As a basis, the above examples may be illustrative.

In each process, when carrying out an intramolecular carbonylation reaction, the reaction can be carried out in the presence of a condensing reagent. As a condensing agent, the above examples may be illustrative.

In each process, when carrying out the Ullmann condensation reaction, the reaction can be carried out in the presence of a copper catalyst, a ligand and a base. As the copper catalyst, copper iodide and the like can be illustrated. As a ligand, N, ^N' -dimethylethylenediamine and the like can be illustrated. As a basis, the above examples may be illustrative.

In each process, when carrying out the reaction of the Chan-Lam-Evans coupling, the reaction can be carried out in the presence of a copper catalyst and a base. As the copper catalyst, copper(II) acetate and the like can be illustrated. As a basis, the above examples may be illustrative.

In each process, when carrying out the Mitsunobu reaction, the reaction can be carried out in the presence of an azodicarboxylic acid ester and a phosphine. As the azodicarboxylic acid ester, DEAD and the like can be illustrated. As the phosphine, triphenylphosphine and the like can be illustrated.

In each process, in the behavior of the Suzuki-Miyaura coupling reaction, the reaction can be carried out in the presence of a palladium catalyst and a base. As the palladium catalyst, Pd(amphos)Cl ₂ and the like can be illustrated. As a basis, the above examples may be illustrative.

In each process, the symbols in the formulas have the same meanings as described in [1] above, unless otherwise noted. Y is a bromine atom, an iodine atom, boronic acid or hydroxy. Y ^' is a fluorine atom or a chlorine atom. Y ^'' is boronic acid or an ester of boronic acid. X is CR ³ or N.

The compound represented by formula (I) can be obtained, for example, by the method described in processes 1-1-1-3 in Scheme 1.

[Chem.15]

Scheme 1

Process 1-1

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

If Y is a bromine atom or an iodine atom, r is 0, and W is aryl or heteroaryl, the Ullmann condensation reaction is preferred. If Y is boronic acid, r is 0, and W is aryl or heteroaryl, the Chan-Lam-Evans coupling reaction is preferred. If Y is hydroxy, r is 0, and W is cycloalkyl or heterocycloalkyl, the Mitsunobu reaction is preferred. If Y is hydroxy and r is an integer of 1-6, the Mitsunobu reaction is preferred.

Process 1-2

Compound (1-4) can also be obtained by removing the protective group of compound (1-3).

Process 1-3

Compound (I) can also be obtained by reductive amination reaction of compound (1-4) and compound (1-5). Deprotection can also be carried out, if necessary.

Compound (1-1) can be prepared, for example, by the method described in processes 2-1-2-3 in Scheme 2.

[Chem.16]

Scheme 2

Process 2-1

Compound (2-3) can also be obtained by aromatic nucleophilic substitution reaction of compound (2-1) and compound (2-2).

Process 2-2

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

Process 2-3

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

Compound (IA) can be prepared, for example, by the method described in processes 3-1-3-4 in Scheme 3.

[Chem.17]

Scheme 3

Process 3-1

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

If Y is a bromine atom or an iodine atom and r is 0, the Ullmann condensation reaction is preferred. If Y is boronic acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. If Y is hydroxy and r is an integer of 1-6, the Mitsunobu reaction is preferred.

Process 3-2

Compound (3-4) can also be obtained by a Suzuki-Miyaura cross-linking reaction of compound (3-2) and compound (3-3).

Process 3-3

Compound (3-5) can also be obtained by removing the protective group of compound (3-4).

Process 3-4

Compound (IA) can also be obtained by a reductive amination reaction of compound (3-5) and compound (1-5). Deprotection can also be carried out, if necessary.

Compound (I) can be prepared, for example, by the method described in processes 4-1-4-3 in Scheme 4.

[Chem.18]

Scheme 4

Process 4-1

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

Process 4-2

Compound (4-2) can also be obtained by a reductive amination reaction of compound (4-1) and compound (1-5).

Process 4-3

Compound (I) can also be produced by Ullmann condensation reaction, Chan-Lam-Evans coupling reaction or Mitsunobu reaction of compound (4-2) and compound (1-2). Deprotection can also be carried out, if necessary.

If Y is a bromine atom or an iodine atom, r is 0, and W is aryl or heteroaryl, the Ullmann condensation reaction is preferred. If Y is boronic acid, r is 0, and W is aryl or heteroaryl, the Chan-Lam-Evans coupling reaction is preferred. If Y is hydroxy, r is 0, and W is cycloalkyl or heterocycloalkyl, the Mitsunobu reaction is preferred. If Y is hydroxy and r is an integer of 1-6, the Mitsunobu reaction is preferred.

Compound (IA) can be prepared, for example, by the method described in processes 5-1-5-2 in Scheme 5.

[Chem.19]

Scheme 5

Process 5-1

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

If Y is a bromine atom or an iodine atom and r is 0, the Ullmann condensation reaction is preferred. If Y is boronic acid and r is 0, the Chan-Lam-Evans coupling reaction is preferred. If Y is hydroxy and r is an integer of 1-6, the Mitsunobu reaction is preferred.

Process 5-2

Compound (IA) can also be produced by a Suzuki-Miyaura coupling reaction of compound (5-1) and compound (3-3). Deprotection can also be carried out, if necessary.

The above schemes are exemplary methods for the preparation of compounds represented by formula (I) or synthetic intermediates thereof. The above diagrams can be changed or modified into diagrams that can be easily understood by a person skilled in the art.

The compounds represented by formula (I) and their synthetic intermediates may also be isolated and purified, if desired, according to isolation and purification methods well known to the person skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, or preparative high performance liquid chromatography.

Illustrations of silica gel column chromatography and amino silica gel column chromatography can be flash chromatography using, for example, SNAP Ultra and SNAP Isolute NH2 (Biotage), Hi-Flash columns (Yamazen) and the like.

An illustration of ODS column chromatography can be preparative isolation using, for example, a preparative purification LC system (Gilson, flow rate: 30 ml/min, detection: UV at 225 nm) and column: CAPCELL PAK C18 UG80 (5 µm 20×50 mm ).

The compounds of the present invention have an excellent inhibitory effect on PHD2 and therefore can be used as therapeutic agents for IBD (see Nature Reviews Drug Discovery, 2014, 13, pp. 852-869). In the present invention, the phrase "IBD" includes, for example, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, infectious enteritis, radiation enteritis, drug enteritis, ischemic enteritis, mesenteric phlebosclerosis (phlebosclerotic colitis), obstructive colitis, and collagen disease enteritis. Preferably, the compounds of the present invention can be used as therapeutic agents for ulcerative colitis or Crohn's disease (see Inflamm. Bowel. Dis., 2015, 21 (2), pp. 267-275).

In the present invention, the phrase "treatment" includes the meaning of "prophylaxis". Treatment of ulcerative colitis includes, for example, the meanings of "prevention of relapse" and "maintenance of remission".

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

In an embodiment, the compounds of the present invention are a PHD2 inhibitor that specifically acts on colonic tissue to limit off-target stabilization effects of HIF-α. The term "specifically acts on colonic tissue" means, for example, that the concentration of the compound in colonic tissue is high compared to the concentration in the blood, and that the compound has a therapeutic effect on the colon without systemic effects (for example, a hematopoietic effect) (see. experimental examples 2 and 3).

The pharmaceutical composition of the present invention is used in various dosage forms depending on the application. As such dosage forms, for example, powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, suppositories, poultices, and enema agents are illustrative.

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

The pharmaceutical composition 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 composition may be formulated by appropriate mixing, diluting or dissolving with appropriate pharmaceutical additives such as excipients, disintegrants, binding agents, lubricants, diluents, buffers, tonicity regulators, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents and solubilizing agents. agents, according to a well known formulating technique depending on the dosage form.

When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is appropriately selected depending on the age, sex, body weight, degree of disorder and treatment of each patient, and the like. The daily dose may be divided into one, two, three or four doses per day. Preferably, the pharmaceutical composition of the present invention is administered orally.

The dosage for an adult can be determined in the range, for example, from 0.1 to 1000 mg per day in the case of oral administration. In an embodiment, the dosage for oral administration may be selected in the range of 1 to 500 mg per day, preferably 10 to 200 mg per day.

The dosage for an adult can be determined, for example, from 0.1 to 1000 mg per day in the case of parenteral administration. In an embodiment, the dosage for parenteral administration may be selected in the range of 0.5 to 200 mg per day, preferably 1 to 20 mg per day.

In an embodiment, the pharmaceutical composition of the present invention may also be used in combination with any drug other than PHD inhibitors. Illustrative of such other drugs used in combination for the treatment of inflammatory bowel disease, for example, can be 5-ASA, steroids, immunosuppressants, anti-TNF-α antibodies, Janus kinase inhibitors, and anti-α4β7 integrin antibodies.

When a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used in combination with another drug, they may be administered as a formulation containing these active ingredients or as formulations each separately formulated with each active ingredient. When formulated separately, these formulations may be administered separately or simultaneously. In addition, the dosage of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be appropriately reduced depending on the dosage of the other drug used in combination.

Each of the compounds represented by formula (I) can be suitably converted into a prodrug and used. For example, a prodrug of the compound represented by formula (I) can also be obtained by introducing a prodrug-forming group using an appropriate prodrug-producing reagent such as a halide compound and purifying. As a group forming a prodrug, for example, an illustration may be the group described in "Development of Medicine" 1990, Vol. 7, pp. 163-198 published by Hirokawa Shoten.

EXAMPLES

The present invention is further illustrated in more detail with the help of the following examples. However, the present invention is not limited to them.

The names of the compounds described in the following examples were created using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), or similar, except for commercially available reagents.

Reference Example A-1

tert-Butyl (S)-3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate

To NMP (100 ml) are added 2-fluoro-3-nitropyridine (10.00 g), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (13.10 g) and potassium carbonate (11.67 g) when chilled on ice. The reaction mixture was stirred at 150°C for 1 hour. The reaction mixture is cooled to room temperature. Ethyl acetate and water are added to the reaction mixture, and the mixture is stirred. The mixture is 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).

Reference Example A-2

tert-Butyl (R)-3-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate

Mixture of 2-fluoro-3-nitropyridine (2.00 g), tert-butyl (R)-3-aminopyrrolidine-1-carboxylate (2.62 g), potassium carbonate (2.33 g) and NMP (15 ml) stirred at 150°C under microwave for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and water, and the resulting mixture was stirred. The mixture is filtered through Celite (registered trademark) and the filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5-70/30) to obtain the title compound (3.61 g).

Reference Example A-3

tert-Butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

A mixture of 2-fluoro-3-nitropyridine (1.00 g), tert-butyl 4-aminopiperidine-1-carboxylate (1.41 g), potassium carbonate (1.94 g) and DMF (10 ml) was stirred at 120° C under microwaves for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and water, and the resulting mixture was stirred. The mixture is filtered through Celite and the filtrate is 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).

Reference Example A-4

tert-Butyl 3-((3-nitropyridin-2-yl)amino)azetidine-1-carboxylate

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

Reference Example A-5

tert-Butyl (3R,4R)-3-fluoro-4-((3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate

Mixture of 2-fluoro-3-nitropyridine (0.69 g), tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1.00 g), potassium carbonate (1.35 g) and DMF (10 ml) stirred at 80°C under microwave for 1 hour. Ethyl acetate and water are added to the reaction mixture, and the mixture is stirred. The mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-20/80) to obtain the title compound (1.40 g).

Reference Example A-6

tert-Butyl (S)-3-((3-nitro-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate

A mixture of 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (1.00 g), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (0.82 g), potassium carbonate (1.22 g) and DMF (10 ml) was stirred at 80°C under microwave for 1 hour. Ethyl acetate and water are added to the reaction mixture, and the mixture is stirred. The mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-20/80) to obtain the title compound (1.66 g).

Reference Example A-7

tert-Butyl 4-methyl-4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

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

Reference Example A-8

Methyl (S)-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-5-nitropicolinate

A mixture of methyl 6-chloro-5-nitropicolinate (1.00 g), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (0.86 g), potassium carbonate (1.27 g) and DMF (10 ml ) stirred at 120°C under microwave for 1 hour. The reaction mixture was poured into a mixture of ethyl acetate and water, and the resulting mixture was stirred. The mixture is filtered through Celite and the filtrate is 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).

Reference Example A-9

tert-Butyl (S)-3-((5-methyl-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate

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.

Reference Example A-10

tert-Butyl (S)-3-((5-methoxy-3-nitropyridin-2-yl)amino)pyrrolidine-1-carboxylate

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.

Reference Example B-1

tert-Butyl (S)-3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylate

To a mixture of Reference Example A-1 (21.70 g) and ethanol (300 ml) was added 10% palladium-carbon (2.17 g, wet) under argon. The mixture is stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound (19.74 g).

Reference Example B-2

tert-Butyl (R)-3-((3-aminopyridin-2-yl)amino)pyrrolidine-1-carboxylate

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.

Reference Example B-3

tert-Butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate

To a mixture of Reference Example A-3 (2.25 g), ethanol (20 ml) and THF (10 ml) was added 10% palladium-carbon (0.22 g, wet) under argon. The mixture is stirred under a hydrogen atmosphere at room temperature for 7 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (2.06 g).

Reference Example B-4

tert-Butyl 3-((3-aminopyridin-2-yl)amino)azetidine-1-carboxylate

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.

Reference Example B-5

tert-Butyl (3R,4R)-3-((3-aminopyridin-2-yl)amino)-4-fluoropyrrolidine-1-carboxylate

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.

Reference Example B-6

tert-Butyl (S)-3-((3-amino-5-(trifluoromethyl)pyridin-2-yl)amino)pyrrolidine-1-carboxylate

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.

Reference Example B-7

tert-Butyl 4-((3-aminopyridin-2-yl)amino)-4-methylpiperidine-1-carboxylate

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.

Reference Example B-8

Methyl (S)-5-amino-6-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)picolinate

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.

Reference Example B-9

tert-Butyl (S)-3-((3-amino-5-methylpyridin-2-yl)amino)pyrrolidine-1-carboxylate

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.

Reference Example B-10

tert-Butyl (S)-3-((3-amino-5-methoxypyridin-2-yl)amino)pyrrolidine-1-carboxylate

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.

Reference Example C-1

tert-Butyl (S)-3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

To a mixture of Reference Example B-1 (19.59 g) and THF (200 ml) was added CDI (22.82 g) under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 30 minutes. An aqueous sodium hydroxide solution (5 mol/l, 30 ml) was added to the reaction mixture, and the resulting mixture was stirred for 10 minutes. Hydrochloric acid (2 mol/l, 75 ml) was added to the reaction mixture. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/50-0/100) to obtain the title compound (17.61 g). MS (ER_HIAD, m/z): 303 (MH) ^-

Reference Example C-2

tert-Butyl (R)-3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

To a mixture of Reference Example B-2 (3.68 g) and THF (20 ml) was added CDI (4.28 g). The reaction mixture was stirred at room temperature for 30 minutes. An aqueous sodium hydroxide 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=50/50-0/100) to obtain the title compound (4.00 g). MS (ER_HIAD, m/z): 303 (MH) ^-

Reference Example C-3

tert-Butyl 4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate

To a mixture of Reference Example B-3 (2.06 g) and THF (30 ml) was added CDI (2.29 g). 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to obtain the title compound (1.96 g). MS (ER_HIAD, m/z): 317 (MH) ^-

Reference Example C-4

tert-Butyl 3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)azetidine-1-carboxylate

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 (ER_HIAD, m/z): 289 (MH) ^-

Reference Example C-5

tert-Butyl (3R,4R)-3-fluoro-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

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 (ER_HIAD, m/z): 321 (MH) ^-

Reference Example C-6

tert-Butyl (S)-3-(2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-carboxylate

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 (ER_HIAD, m/z): 371 (MH) ^-

Reference Example C-7

tert-Butyl 4-methyl-4-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)piperidine-1-carboxylate

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 (ER_HIAD, m/z): 331 (MH) ^-

Reference Example C-8

Methyl (S)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate

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 (ER_HIAD, m/z): 361 (MH) ^-

Reference Example C-9

tert-Butyl (S)-3-(6-methyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-carboxylate

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 (ER_HIAD, m/z): 317 (MH) ^-

Reference Example C-10

tert-Butyl (S)-3-(6-methoxy-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

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 (ER_HIAD, m/z): 333 (MH) ^-

Reference Example D-1

tert-Butyl (S)-3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-carboxylate

A mixture of Reference Example C-1 (168 mg), (4-chloro-2-methylphenyl)boronic acid (282 mg), copper (II) acetate (201 mg), triethylamine (0.383 ml) and dichloromethane (3 ml) was stirred at room temperature for 3 hours. Water and hydrochloric acid (1 mol/l) are added to the reaction mixture. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (114 mg).

Reference Example D-2

tert-Butyl (S)-3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-carboxylate

A mixture of Reference Example C-1 (500 mg), 1-chloro-4-iodobenzene (431 mg), N, ^N' -dimethylethylenediamine (0.212 ml), copper (I) iodide (375 mg), potassium carbonate (681 mg) and acetonitrile (10 ml) stirred at 90°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and hydrochloric acid (1 mol/l). After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (583 mg).

Reference Example D-3

tert-Butyl (R)-3-(1-(4-chloro-2-methylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-carboxylate

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.

Reference Example D-4

tert-Butyl (S)-3-(1-(4-chloro-2-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-carboxylate

A mixture of Reference Example C-1 (100 mg), 5-chloro-2-iodophenol (125 mg), N, ^N' -dimethylethylenediamine (0.042 ml), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (3 ml) stirred at 100°C under microwave for 2 hours. The reaction mixture is poured into a mixture of water and hydrochloric acid (1 mol/l). After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=35/65) to obtain the title compound (61 mg).

Reference Example D-5

tert-Butyl (S)-3-(1-(4-chloro-3-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-carboxylate

A mixture of Reference Example C-1 (100 mg), 2-chloro-5-iodophenol (100 mg), N, ^N' -dimethylethylenediamine (0.042 ml), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (3 ml) stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and hydrochloric acid (1 mol/l). After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=35/65) to obtain the title compound (135 mg).

Reference Example D-6

tert-Butyl (S)-3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-carboxylate

A mixture of Reference Example C-1 (100 mg), 2-chloro-5-iodopyridine (94 mg), N, ^N' -dimethylethylenediamine (0.042 ml), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (3 ml) stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and hydrochloric acid (1 mol/l). After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=35/65) to obtain the title compound (117 mg).

Reference Example D-7

tert-Butyl (R)-3-(1-(6-chloropyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-carboxylate

A mixture of Reference Example C-2 (500 mg), 2-chloro-5-iodopyridine (433 mg), N, ^N' -dimethylethylenediamine (0.212 ml), copper (I) iodide (375 mg), potassium carbonate (681 mg) and acetonitrile (10 ml) stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-45/55) to obtain the title compound (420 mg).

Reference Example E-1

tert-Butyl (S)-3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3 -yl)pyrrolidine-1-carboxylate

A mixture of Reference Example C-1 (113 mg), 4-iodo-1,1'-biphenyl (125 mg), N, ^N' -dimethylethylenediamine (0.048 ml), copper (I) iodide (85 mg), potassium carbonate ( 154 mg) and acetonitrile (4 ml) were stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and hydrochloric acid (1 mol/l). After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (138 mg).

Reference Example E-2

tert-Butyl (R)-3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3 -yl)pyrrolidine-1-carboxylate

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.

Reference Example E-3

tert-Butyl (S)-3-(2-oxo-1-phenyl-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-carboxylate

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.

Reference Example E-4

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

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

Reference Example E-5

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

A mixture of Reference Example C-4 (100 mg), 4-iodo-1,1'-biphenyl (96 mg), N, ^N' -dimethylethylenediamine (0.044 ml), copper (I) iodide (79 mg), potassium carbonate ( 143 mg) and acetonitrile (3 ml) were stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (105 mg).

Reference Example E-6

tert-Butyl (S)-3-(1-(4-(methoxycarbonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1 -carboxylate

A mixture of Reference Example C-1 (200 mg), methyl 4-iodobenzoate (172 mg), N, ^N' -dimethylethylenediamine (0.085 ml), copper (I) iodide (150 mg), potassium carbonate (272 mg) and acetonitrile ( 1 ml) stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-45/55) to obtain the title compound (271 mg).

Reference Example E-7

tert-Butyl (S)-3-(1-(4-methoxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

A mixture of Reference Example C-1 (100 mg), 1-iodo-4-methoxybenzene (85 mg), N, ^N' -dimethylethylenediamine (0.042 ml), copper (I) iodide (75 mg), potassium carbonate (136 mg) and acetonitrile (1 ml) stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and hydrochloric acid (1 mol/l). After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (119 mg).

Reference Example E-8

Methyl (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-(tert-butoxycarbonyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H -imidazo[4,5-b]pyridine-5-carboxylate

A mixture of Reference Example C-8 (100 mg), 4-iodo-1,1'-biphenyl (93 mg), N, ^N' -dimethylethylenediamine (0.036 ml), copper (I) iodide (63 mg), potassium carbonate ( 114 mg) and acetonitrile (1 ml) were stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-45/55) to obtain the title compound (120 mg).

Reference Example E-9

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

A mixture of Reference Example C-7 (50 mg), 4-iodo-1,1'-biphenyl (51 mg), N, ^N' -dimethylethylenediamine (0.019 ml), copper (I) iodide (34 mg), potassium carbonate ( 50 mg) and acetonitrile (3 ml) was stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into ethyl acetate and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-40/60) to obtain the title compound (70 mg).

Reference Example E-10

tert-Butyl (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-carboxylate

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), copper (I) iodide (94 mg), potassium carbonate (136 mg) and acetonitrile (1 ml) are stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into ethyl acetate and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-25/75) to obtain the title compound (128 mg).

Reference Example E-11

tert-Butyl (3R,4R)-3-fluoro-4-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro- 3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine-1-carboxylate

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.

Reference Example E-12

tert-Butyl (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-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.

Reference Example E-13

tert-Butyl (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-carboxylate

A mixture of Reference Example D-1 (114 mg), phenylboronic acid (39 mg), Pd(amphos)Cl ₂ (19 mg), sodium carbonate (68 mg), DMF (1 ml) and water (0.1 ml) was stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (87 mg).

Reference Example E-14

tert-Butyl (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-carboxylate

A mixture of Reference Example D-2 (100 mg), o-tolylboronic acid (39 mg), Pd(amphos)Cl ₂ (17 mg), sodium carbonate (61 mg), DMF (1 ml) and water (0.1 ml ) stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (105 mg).

Reference Example E-15

tert-Butyl (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-carboxylate

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.

Reference Example E-16

tert-Butyl (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-carboxylate

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.

Reference Example E-17

tert-Butyl (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-carboxylate

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.

Reference Example E-18

tert-Butyl (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-carboxylate

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.

Reference Example E-19

tert-Butyl (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-carboxylate

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

tert-Butyl (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-carboxylate

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.

Reference Example E-21

tert-Butyl (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-carboxylate

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 in place of 4-iodo-1,1'-biphenyl.

Reference Example E-22

tert-Butyl (S)-3-(2-oxo-1-(4-(pyridin-4-yl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl )pyrrolidine-1-carboxylate

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

Reference Example E-23

tert-Butyl (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-carboxylate

A mixture of Reference Example D-2 (200 mg), (4-(methoxycarbonyl)phenyl)boronic acid (104 mg), Pd(amphos)Cl ₂ (34 mg), sodium carbonate (123 mg), DMF (2 ml) and water (0.2 ml) stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (212 mg).

Reference Example E-24

tert-Butyl (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-carboxylate

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.

Reference Example E-25

tert-Butyl (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-carboxylate

A mixture of Reference Example D-4 (61 mg), (4-(methoxycarbonyl)phenyl)boronic acid (31 mg), Pd(amphos)Cl ₂ (10 mg), sodium carbonate (36 mg), DMF (1 ml) and water (0.1 ml) stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-35/65) to obtain the title compound (55 mg).

Reference Example E-26

tert-Butyl (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-carboxylate

A mixture of Reference Example D-5 (135 mg), (4-(methoxycarbonyl)phenyl)boronic acid (113 mg), Pd(amphos)Cl ₂ (22 mg), sodium carbonate (80 mg), NMP (3 ml) and water (0.3 ml) stirred at 150°C under microwave for 5 hours. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-30/70) to obtain the title compound (122 mg).

Reference Example E-27

tert-Butyl (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-carboxylate

A mixture of Reference Example D-6 (117 mg), (4-(methoxycarbonyl)phenyl)boronic acid (61 mg), Pd(amphos)Cl ₂ (20 mg), sodium carbonate (72 mg), DMF (3 ml) and water (0.3 ml) stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-30/70) to obtain the title compound (95 mg).

Reference Example E-28

tert-Butyl (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-carboxylate

A mixture of Reference Example D-2 (121 mg), methyl 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (98 mg), Pd(amphos )Cl ₂ (21 mg), sodium carbonate (75 mg), DMF (1 ml) and water (0.1 ml) were stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-30/70) to obtain the title compound (71 mg).

Reference Example E-29

tert-Butyl (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-carboxylate

A mixture of Reference Example D-2 (200 mg), methyl 3-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (147 mg), Pd(amphos )Cl ₂ (34 mg), sodium carbonate (123 mg), DMF (1 ml) and water (0.1 ml) were stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-35/65) to obtain the title compound (165 mg).

Reference Example E-30

tert-Butyl (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-carboxylate

A mixture of Reference Example D-6 (353 mg), (4-(methoxycarbonyl)-2-methylphenyl)boronic acid (198 mg), Pd(amphos)Cl ₂ (60 mg), sodium carbonate (216 mg), DMF (10 ml) and water (1 ml) stirred at 120°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-35/65) to obtain the title compound (406 mg).

Reference Example K-19

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

To a mixture of Reference Example D-5 (1.29 g) and THF (15 ml) was added DIPEA (1.55 ml) and chloromethyl methyl ether (0.34 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (1.33 g).

Reference Example E-31

tert-Butyl (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-carboxylate

A mixture of Reference Example K-19 (500 mg), 2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (387 mg), Pd(amphos) Cl ₂ (75 mg), sodium carbonate (268 mg), DMF (10 ml) and water (1 ml) was stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-40/60) to obtain the title compound (332 mg).

Reference Example E-32

tert-Butyl (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-carboxylate

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.

Reference Example K-20

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

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

Reference Example E-33

tert-Butyl (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-carboxylate

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.

Reference Example K-2

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

To a mixture of Reference Example E-8 (251 mg), methanol (0.5 ml), THF (0.5 ml) and water (1 ml) was added lithium hydroxide monohydrate (103 mg). 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 is 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).

Reference Example E-34

tert-Butyl (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-carboxylate

To a mixture of Reference Example K-2 (100 mg) and DMF (1 ml) was added EDC-HCl (77 mg), HOBt-H ₂ O (61 mg), triethylamine (0.139 ml) and 4-aminotetrahydropyran (24 mg). The reaction mixture was stirred at room temperature for 4 hours. Water and ethyl acetate are added to the reaction mixture. After stirring, the mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-20/80) to obtain the title compound (19 mg).

Reference Example E-35

tert-Butyl (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-carboxylate

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

Reference Example E-36

tert-Butyl (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-carboxylate

A mixture of Reference Example D-7 (420 mg), (4-(methoxycarbonyl)phenyl)boronic acid (236 mg), Pd(amphos)Cl ₂ (72 mg), sodium carbonate (257 mg), DMF (10 ml) and water (1 ml) stirred at 120°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-40/60) to obtain the title compound (377 mg).

Reference Example E-37

tert-Butyl (S)-3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1- carboxylate

A mixture of Reference Example C-1 (200 mg), 2-bromonaphthalene (136 mg), N, ^N' -dimethylethylenediamine (0.085 ml), copper (I) iodide (150 mg), potassium carbonate (218 mg) and acetonitrile (3 ml) stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into a mixture of ethyl acetate and water. After stirring, the mixture is filtered through Celite. The filtrate is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (250 mg).

Reference Example E-38

tert-Butyl (S)-3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3 -yl)pyrrolidine-1-carboxylate

A mixture of Reference Example C-1 (200 mg), 3-bromo-1,1'-biphenyl (153 mg), N, ^N' -dimethylethylenediamine (0.085 ml), copper (I) iodide (150 mg), potassium carbonate ( 218 mg) and acetonitrile (3 ml) were stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into ethyl acetate and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (345 mg).

Reference Example E-39

tert-Butyl (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-carboxylate

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.

Reference Example F-1

(S)-1-([1,1'-Biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-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 (ER_HIAD, m/z): 357 (M+H) ⁺

Reference Example F-2

(R)-1-([1,1'-Biphenyl]-4-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-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 (ER_HIAD, m/z): 357 (M+H) ⁺

Reference Example F-3

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

A mixture of Reference Example E-3 (360 mg), hydrogen chloride (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 (ER_HIAD, 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 (ER_HIAD, m/z): 371 (M+H) ⁺

Reference Example F-5

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

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 (ER_HIAD, m/z): 343 (M+H) ⁺

Reference Example F-6

Methyl (S)-4-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)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 (ER_HIAD, m/z): 339 (M+H) ⁺

Reference Example F-7

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

The title compound was 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

Methyl (S)-1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5- b]pyridine-5-carboxylate 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

Methyl (S)-4'-(6-methoxy-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)- [1,1'-biphenyl]-4-carboxylate 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

Methyl 4'-(3-((3R,4R)-4-fluoropyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)- [1,1'-biphenyl]-4-carboxylate 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

Methyl (S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-6-(trifluoromethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl )-[1,1'-biphenyl]-4-carboxylate 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-(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-13 instead of Reference Example E-1. MS (ER_HIAD, m/z): 371 (M+H) ⁺

Reference Example F-14

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

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 (ER_HIAD, m/z): 371 (M+H) ⁺

Reference Example F-15

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

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 (ER_HIAD, m/z): 371 (M+H) ⁺

Reference Example F-16

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

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 (ER_HIAD, m/z): 375 (M+H) ⁺

Reference Example F-17

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

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 (ER_HIAD, m/z): 387 (M+H) ⁺

Reference Example F-18

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

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 (ER_HIAD, 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-carbonitrile 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 (ER_HIAD, m/z): 382 (M+H) ⁺

Reference Example F-20

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

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 (ER_HIAD, m/z): 441 (M+H) ⁺

Reference Example F-21

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

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 (ER_HIAD, 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 (ER_HIAD, m/z): 358 (M+H) ⁺

Reference Example F-23

Methyl (S)-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1 '-biphenyl]-4-carboxylate 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 (ER_HIAD, m/z): 415 (M+H) ⁺

Reference Example F-24

Methyl (R)-3'-methyl-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl) -[1,1'-biphenyl]-4-carboxylate 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 (ER_HIAD, m/z): 429 (M+H) ⁺

Reference Example F-25

Methyl (S)-3'-hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl) -[1,1'-biphenyl]-4-carboxylate 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

Methyl (S)-2'-hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl) -[1,1'-biphenyl]-4-carboxylate 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

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

Methyl (S)-4-hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)- [1,1'-biphenyl]-3-carboxylate 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

Methyl (S)-2-hydroxy-4'-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)- [1,1'-biphenyl]-4-carboxylate 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

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

A mixture of Reference Example E-33 (77 mg), hydrogen chloride (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-(pyrrolidin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-2 ,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxamide hydrochloride

A mixture of Reference Example E-34 (19 mg), hydrogen chloride (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

Methyl (S)-(1-([1,1'-biphenyl]-4-yl)-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5 -b]pyridine-5-carbonyl)glycinate hydrochloride

A mixture of Reference Example E-35 (91 mg), hydrogen chloride (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

Methyl (R)-4-(5-(2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyridin-2 -yl)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-(Naphthalene-2-yl)-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-3 using Reference Example E-37 instead of Reference Example E-3.

Reference Example F-38

(S)-1-([1,1'-Biphenyl]-3-yl)-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridine-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

Methyl (S)-4'-(6-methyl-2-oxo-3-(pyrrolidin-3-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)- [1,1'-biphenyl]-4-carboxylate 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.

Reference Example G-1

Methyl (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine -3-yl)pyrrolidin-1-yl)methyl)isonicotinate

To a mixture of Reference Example F-1 (30 mg), methyl 2-formylisonicotinate (25 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (65 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-45/55) to obtain the title compound (26 mg). MS (ER_HIAD, m/z): 506 (M+H) ⁺

Reference Example G-2

Methyl (S)-6-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine -3-yl)pyrrolidin-1-yl)methyl)nicotinate

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

Reference Example G-3

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

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

Reference Example G-4

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

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

Reference Example J-1

tert-Butyl 1-methyl-1H-imidazole-5-carboxylate

A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (5.00 g), tert-butanol (37.7 ml), pyridine (16.0 ml) and TsCl (15.11 g) was stirred at room temperature in during the night. Water and ethyl acetate are added to the reaction mixture. After stirring, the mixture is 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).

Reference Example J-2

tert-Butyl 2-formyl-1-methyl-1H-imidazole-5-carboxylate

To a mixture of Reference Example J-1 (5.82 g), DMF (7.43 ml) and THF (60 ml) was added slowly dropwise DAL (1.0 mol/l, solution in THF/n-hexane, 48 ml ) at -70°C or less in a dry ice/acetone bath. The reaction mixture was stirred under ice-cooling for 10 minutes. DAL (1.0 mol/l, solution in THF/n-hexane, 16 ml) and DMF (1 ml) were again slowly added dropwise to the reaction mixture at −70° C. or less in a dry ice/acetone bath. The reaction mixture was stirred under ice-cooling for 10 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture. After stirring for 5 minutes, the mixture is 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).

Reference Example G-6

tert-Butyl 2-((4-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3 -yl)-4-methylpiperidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

To a mixture of Reference Example F-9 (67 mg), THF (1 ml) and triethylamine (0.112 ml) was added Reference Example J-2 (41 mg) and NaBH(OAc) ₃ (68 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to obtain the title compound (73 mg). MS (ER_HIAD, m/z): 579 (M+H) ⁺

Reference Example G-7

tert-Butyl (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 639 (M+H) ⁺

Reference Example G-8

tert-Butyl 2-(((3R,4R)-3-fluoro-4-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1, 2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 627 (M+H) ⁺

Reference Example G-9

tert-Butyl (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 677 (M+H) ⁺

Reference Example G-14

Methyl (S)-2-((3-(1-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[ 4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinate

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

Reference Example G-16

Methyl (S)-2-((3-(1-(2-hydroxy-4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro- 3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinate

To a mixture of Reference Example F-26 (200 mg), methyl 2-formylisonicotinate (141 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (363 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/80/200) to give the title compound (207 mg). MS (ER_HIAD, m/z): 580 (M+H) ⁺

Reference Example G-17

Methyl (S)-2-((3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5- b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinate

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 (ER_HIAD, m/z): 565 (M+H) ⁺

Reference Example G-18

tert-Butyl (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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

Reference Example G-19

tert-Butyl (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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

Reference Example G-20

Methyl (S)-2-((3-(1-(3'-cyano-2,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro -3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinate

To a mixture of Reference Example F-31 (150 mg), methyl 2-formylisonicotinate (110 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (283 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/50/50) to give the title compound (188 mg). MS (ER_HIAD, m/z): 563 (M+H) ⁺

Reference Example G-21

Methyl (S)-2-((3-(1-(6-(3-cyano-4-hydroxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5 -b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinate

To a mixture of Reference Example F-32 (200 mg), methyl 2-formylisonicotinate (152 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (390 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/50/50) to obtain the title compound (495 mg). MS (ER_HIAD, m/z): 548 (M+H) ⁺

Reference Example G-22

Methyl (S)-2-((3-(1-(3'-cyano-3,4'-dihydroxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro -3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinate

To a mixture of Reference Example F-33 (63 mg), methyl 2-formylisonicotinate (46 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (119 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/50/50) to give the title compound (77 mg). MS (ER_HIAD, m/z): 563 (M+H) ⁺

Reference Example G-23

tert-Butyl (S)-1-methyl-2-((3-(1-(naphthalen-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 525 (M+H) ⁺

Reference Example G-24

tert-Butyl (S)-2-((3-(1-([1,1'-biphenyl]-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b ]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 551 (M+H) ⁺

Reference Example H-1

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

A mixture of Reference Example C-1 (3.00 g), hydrogen chloride (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).

Reference Example I-1

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl) methyl)-1H-imidazole-5-carboxylate

A mixture of Reference Example H-1 (2.68 g), Reference Example J-2 (3.05 g), THF (30 ml) and triethylamine (4.67 ml) was stirred at room temperature for 10 minutes. NaBH(OAc) ₃ (3.55 g) was added to the reaction mixture, and 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 is concentrated under reduced pressure. Ethyl acetate and water are added to the residue. After stirring, the mixture is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=95/5/0-0/100/0-0/90/10) to obtain the title compound (3.52 g).

Reference Example G-25

tert-Butyl (S)-2-((3-(1-(4-(dimethylamino)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl )pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

A mixture of Reference Example I-1 (100 mg), 4-bromo-N, N-dimethylaniline (55 mg), N, ^N' -dimethylethylenediamine (0.032 ml), copper (I) iodide (57 mg), potassium carbonate (83 mg) and acetonitrile (3 ml) was stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into ethyl acetate and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-20/80) to give the title compound (77 mg). MS (ER_HIAD, m/z): 518 (M+H) ⁺

Reference Example G-26

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(4-phenoxyphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

The title compound was prepared in a manner similar to that described in Reference Example G-25 using 1-iodo-4-phenoxybenzene in place of 4-bromo-N,N-dimethylaniline. MS (ER_HIAD, m/z): 567 (M+H) ⁺

Reference Example G-27

tert-Butyl (S)-2-((3-(1-(4-benzylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 565 (M+H) ⁺

Reference Example G-28

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(p-tolyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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

Reference Example G-29

tert-Butyl (S)-2-((3-(1-(4-chlorophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 509 (M+H) ⁺

Reference Example G-30

tert-Butyl (S)-1-methyl-2-((3-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine -3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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

Reference Example G-31

tert-Butyl (S)-2-((3-(1-(4-(ethylsulfonyl)phenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl )pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 567 (M+H) ⁺

Reference Example G-32

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethoxy)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine -3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 559 (M+H) ⁺

Reference Example G-33

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(4-(trifluoromethyl)phenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine -3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 543 (M+H) ⁺

Reference Example G-34

tert-Butyl (S)-2-((3-(1-(4-cyanophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (IER_HIAD, m/z): 500 (M+H) ⁺

Reference Example G-35

tert-Butyl (S)-1-methyl-2-((3-(1-(4-nitrophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 520 (M+H) ⁺

Reference Example G-36

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(quinolin-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 526 (M+H) ⁺

Reference Example G-37

tert-Butyl (S)-1-methyl-2-((3-(1-(4-morpholinophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(4-phenylcyclohexyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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

Reference Example G-39

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(4-vinylphenyl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 501 (M+H) ⁺

Reference Example G-40

tert-Butyl (S)-1-methyl-2-((3-(2-oxo-1-(thiophen-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 481 (M+H) ⁺

Reference Example G-41

tert-Butyl (S)-2-((3-(1-benzyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl) methyl)-1-methyl-1H-imidazole-5-carboxylate

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

Reference Example G-42

tert-Butyl (S)-2-((3-(1-(4-cyclopropylphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 515 (M+H) ⁺

Reference Example G-43

tert-Butyl (S)-2-((3-(1-(4-hydroxyphenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin- 1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

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 (ER_HIAD, m/z): 491 (M+H) ⁺

Reference Example G-44

tert-Butyl (S)-1-methyl-2-((3-(1-(4'-(methylsulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2- dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylate

A mixture of Reference Example G-29 (50 mg), 4-(methylsulfonylamino)phenylboronic acid (25 mg), Pd(amphos)Cl ₂ (6.8 mg), sodium carbonate (25 mg), DMF (1 ml) and water (0.1 ml) stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of water and ethyl acetate. After stirring, the mixture is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/90/10) to give the title compound (37 mg). MS (ER_HIAD, m/z): 644 (M+H) ⁺

Reference Example G-45

tert-Butyl (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

To a mixture of Reference Example F-39 (72 mg) and THF (3 ml) was added triethylamine (0.065 ml) and Reference Example J-2 (36 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-30/70) to obtain the title compound (65 mg). MS (ER_HIAD, m/z): 623 (M+H) ⁺

Reference Example G-46

tert-Butyl (S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-5-((tetrahydro-2H-pyran-4-yl)carbamoyl )-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

To a mixture of Reference Example F-34 (18 mg), triethylamine (0.024 ml) and THF (1.0 ml) was added Reference Example J-2 (8.7 mg) and NaBH(OAc) ₃ (15 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to give the title compound (20 mg). MS (ER_HIAD, m/z): 678 (M+H) ⁺

Reference Example G-47

tert-Butyl (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

To a mixture of Reference Example F-35 (79 mg), triethylamine (0.11 ml) and THF (1.0 ml) was added Reference Example J-2 (40 mg) and NaBH(OAc) ₃ (67 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-20/80) to obtain the title compound (92 mg).

Reference Example K-1

Methyl (S)-(4-(3-(1-((3-methylpyridin-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4.5 -b]pyridin-1-yl)benzoyl)glycinate

A mixture of Example 21 (50 mg), methyl glycinate hydrochloride (15 mg), EDC-HCl (31 mg), HOBt-H ₂ O (22 mg), triethylamine (0.119 ml) and DMF (1 ml) was stirred at room temperature for night. Water, ethyl acetate and saturated sodium bicarbonate aqueous solution were added to the reaction mixture. After stirring, the mixture is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/90/10) to give the title compound (7 mg). MS (ER_HIAD, m/z): 501 (M+H) ⁺

Reference Example K-3

Methyl (5-bromopyridine-2-carbonyl) glycinate

A mixture of 5-bromopicolinic acid (300 mg), methyl glycinate hydrochloride (224 mg), EDC-HCl (427 mg), HOBt-H ₂ O (341 mg), triethylamine (1.03 ml) and THF (3 ml) was stirred at room temperature overnight. Water and ethyl acetate are added to the reaction mixture, and the mixture is stirred. The mixture is 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 silica gel column chromatography (eluent: n-hexane/ethyl acetate=90/10-50/50) to obtain the title compound (247 mg).

Reference Example K-4

tert-Butyl (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate

A mixture of Reference Example I-1 (100 mg), Reference Example K-3 (75 mg), N, ^N' -dimethylethylenediamine (0.032 ml), copper (I) iodide (57 mg), potassium carbonate (83 mg) and acetonitrile (1 ml) stirred at 100°C under microwave for 1 hour. The reaction mixture is poured into ethyl acetate and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to obtain the title compound (25 mg). MS (ER_HIAD, m/z): 591 (M+H) ⁺

The chemical structures of some Reference Examples are shown in the following table.

[Table 1]

Example G-5

Methyl (S)-1-([1,1'-biphenyl]-4-yl)-3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)- 2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylate

To a mixture of Reference Example F-8 (105 mg), 1-methyl-1H-imidazole-2-carbaldehyde (51 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (197 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to obtain the title compound (128 mg). MS (ER_HIAD, m/z): 509 (M+H) ⁺

Example G-10

Methyl (S)-3'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate

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

Example G-11

Methyl (S)-2'-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate

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

Example G-12

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

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

Example G-13

Methyl (S)-4-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylate

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

Example G-15

Methyl (S)-2-hydroxy-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate

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

Example G-48

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

To a mixture of Reference Example F-23 (100 mg), 3-methyl-2-pyridine carboxyaldehyde (54 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (282 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to give the title compound (80 mg). MS (ER_HIAD, m/z): 520 (M+H) ⁺

Example K-5

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

To a mixture of Reference Example F-21 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (139 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (415 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to give the title compound (286 mg). MS (ER_HIAD, 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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carbonitrile

A mixture of Example K-5 (286 mg), tetrakis(triphenylphosphine)palladium (0) (61 mg), zinc cyanide (123 mg) and NMP (3 ml) was stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of ethyl acetate and water, and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/90/10) to give the title compound (185 mg). MS (ER_HIAD, m/z): 492 (M+H) ⁺

Example K-7

Methyl (S)-4'-(3-(1-((5-bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate

To a mixture of Reference Example F-23 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (168 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (376 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to obtain the title compound (218 mg). MS (ER_HIAD, m/z): 587 (M+H) ⁺

Example K-8

Methyl (S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate

A mixture of Example K-7 (218 mg), tetrakis(triphenylphosphine)palladium (0) (43 mg), zinc cyanide (87 mg) and NMP (3 ml) was stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of ethyl acetate and water, and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to obtain the title compound (319 mg). MS (ER_HIAD, m/z): 534 (M+H) ⁺

Example K-9

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

To a mixture of Reference Example F-26 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (162 mg) and dichloromethane (3 ml) was added NaBH(OAc) ₃ (363 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/80/20) to give the title compound (297 mg). MS (ER_HIAD, m/z): 603 (M+H) ⁺

Example K-10

Methyl (S)-4'-(3-(1-((5-cyano-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-b]pyridin-1-yl)-2'-hydroxy-[1,1'-biphenyl]-4-carboxylate

A mixture of Example K-9 (297 mg), tetrakis(triphenylphosphine)palladium (0) (57 mg), zinc cyanide (116 mg) and NMP (3 ml) was stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of ethyl acetate and water. After stirring, the mixture is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/80/20) to give the title compound (178 mg). MS (ER_HIAD, m/z): 550 (M+H) ⁺

Example K-11

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

To a mixture of Reference Example F-27 (200 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (167 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (375 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to give the title compound (214 mg). MS (ER_HIAD, m/z): 588 (M+H) ⁺

Example K-12

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

A mixture of Example K-11 (214 mg), tetrakis(triphenylphosphine)palladium (0) (42 mg), zinc cyanide (86 mg) and NMP (3 ml) was stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of ethyl acetate and water. After stirring, the mixture is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to obtain the title compound (244 mg). MS (ER_HIAD, 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)pyrrolidin-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 K-11 using Reference Example F-1 instead of Reference Example F-27. MS (ER_HIAD, 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]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carbonitrile

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

Example K-15

(S)-3-(1-((5-Bromo-1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-1-phenyl-1,3-dihydro-2H-imidazo[ 4,5-b]pyridine-2-one

The title compound was prepared in a manner similar to that described in Example K-11 using Reference Example F-3 instead of Reference Example F-27. MS (ER_HIAD, 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)pyrrolidin-1-yl )methyl)-1H-imidazole-5-carbonitrile

A mixture of Example K-15 (103 mg), tetrakis(triphenylphosphine)palladium (0) (26 mg), zinc cyanide (53 mg) and DMF (1 ml) was stirred at 150°C under microwave for 1 hour. The reaction mixture is poured into a mixture of ethyl acetate and water, and the resulting mixture is stirred. The mixture is filtered through Celite and the filtrate is 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 amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100) to give the title compound (75 mg). MS (IER_HIAD, m/z): 400 (M+H) ⁺

Example K-17

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

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

Example K-18

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

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

Example 1

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

To a mixture of Reference Example F-1 (20 mg), 3-methyl-2-pyridine carboxyaldehyde (8.0 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (65 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-50/50) to obtain the title compound (16 mg).

Example 2

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

To a mixture of Reference Example F-1 (20 mg), 1-methyl-1H-imidazole-2-carbaldehyde (7.2 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (65 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100), and then purified by ODS column chromatography (eluent: water/acetonitrile=80/20-30/70) to obtain the indicated in the title compound (11 mg).

Example 3

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

To a mixture of Reference Example F-2 (20 mg), 1-methyl-1H-imidazole-2-carbaldehyde (11 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (65 mg). 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 is 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)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[ 4,5-b]pyridine-2-one

The title compound was prepared in a manner analogous to that described in Example 2 using 2-pyridine carboxyaldehyde instead of 1-methyl-1H-imidazole-2-carbaldehyde.

Example 5

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

The title compound was prepared in a manner analogous to that described in Example 1 using 1H-imidazole-4-carbaldehyde instead of 3-methyl-2-pyridine carboxyaldehyde.

Example 6

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

To a mixture of Reference Example F-1 (30 mg), 1-methyl-1H-imidazole-4-carbaldehyde (17 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (81 mg). The mixture is 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate/methanol=80/20/0-0/100/0-0/90/10). Hydrogen chloride (1 mol/l, ethanol solution, 0.2 ml) was added to the resulting product, and the mixture was stirred. The mixture was concentrated under reduced pressure to give the title compound (37 mg).

Example 7

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

The title compound was prepared in a manner analogous to that described in Example 1 using 1H-imidazole-2-carbaldehyde instead of 3-methyl-2-pyridinecarboxyaldehyde.

Example 8

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

The title compound was prepared in a manner analogous to that described in Example 1 using 3-hydroxypyridine-2-carboxyaldehyde instead of 3-methyl-2-pyridinecarboxyaldehyde.

Example 9

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

The title compound was prepared in a manner analogous to that described in Example 1 using 5-hydroxypyridine-2-carboxyaldehyde instead of 3-methyl-2-pyridinecarboxyaldehyde.

Example 10

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

To a mixture of Reference Example F-1 (30 mg), 4-hydroxypyridine-2-carboxyaldehyde (19 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (65 mg). 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 is 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)pyrrolidin-3-yl)-1-phenyl-1,3-dihydro-2H-imidazo[4,5- b]pyridin-2-one hydrochloride

To a mixture of Reference Example F-3 (100 mg), 1-methyl-1H-imidazole-2-carbaldehyde (70 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (268 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-0/100), and then purified 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

To a mixture of Reference Example F-4 (237 mg), 1-methyl-1H-imidazole-2-carbaldehyde a (128 mg) and dichloromethane (3 ml) was added NaBH(OAc) ₃ (495 mg). 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 is added to the reaction mixture, and the mixture is stirred. The mixture is extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (eluent: n-hexane/ethyl acetate=80/20-20/80), and then purified by ODS column chromatography (eluent: water/acetonitrile=80/20-30/70) to obtain the indicated in the title compound (144 mg).

Example 13

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

To a mixture of Reference Example F-5 (105 mg), 1-methyl-1H-imidazole-2-carbaldehyde (61 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (354 mg). 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 is 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 is concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile=80/20-30/70) to obtain 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)pyrrolidin-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)pyrrolidin-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]pyridine- 3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid

To a mixture of Reference Example G-1 (26 mg), methanol (0.5 ml) and THF (0.5 ml) was added an aqueous solution of sodium hydroxide (5 mol/l, 1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with hydrochloric acid (2 mol/l). The mixture was purified by ODS column chromatography (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]pyridine- 3-yl)pyrrolidin-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)pyrrolidin-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)pyrrolidin-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)pyrrolidin-3-yl)-2 -oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid

To a mixture of Example G-5 (118 mg), methanol (0.5 ml) and THF (0.5 ml) was added aqueous sodium hydroxide solution (5 mol/l, 1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized with hydrochloric acid (2 mol/l) 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b ]pyridin-1-yl)benzoic acid hydrochloride

To a mixture of Example 15 (257 mg), methanol (1 ml) and THF (1 ml) was added aqueous sodium hydroxide solution (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 is concentrated under reduced pressure. Dichloromethane and anhydrous magnesium sulfate were added to the residue. The mixture is stirred at room temperature for 10 minutes. The mixture is filtered through Celite and the filtrate is 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-(naphthalene-2-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl )pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid

To a mixture of Reference Example G-23 (154 mg), ethyl acetate (1 ml) and methanol (0.5 ml) was added hydrogen chloride (4 mol/l, ethyl acetate solution, 2 ml). The reaction mixture is refluxed for 2 hours. The reaction mixture is cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water with 0.1% formic acid/acetonitrile=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-imidazole-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 is cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water with 0.1% formic acid/acetonitrile=90/10-30/70) to give the title compound (39 mg).

Example 24

(S)-2-((3-(1-(4'-Carboxy-[1,1'-biphenyl]-4-yl)-6-methoxy-2-oxo-1,2-dihydro-3H-imidazo [4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Reference Example G-7 (145 mg), water (0.5 ml) and concentrated sulfuric acid (0.024 ml) was stirred at 90° C. for 3 hours. The reaction mixture is cooled to room temperature. Methanol (0.5 ml) and lithium hydroxide monohydrate (95 mg) were added to the mixture. The reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (eluent: water with 0.1% formic acid/acetonitrile=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-fluoropyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-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'-Carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-6-(trifluoromethyl)-1,2-dihydro-3H -imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

The title compound was 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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Reference Example G-45 (65 mg), methanol (0.2 ml), water (1 ml) and concentrated sulfuric acid (0.04 ml) was stirred at 110°C under microwave for 1 hour. 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 with 0.1% formic acid/acetonitrile=90/10-30/70) to give the title compound (27 mg).

Example 28

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

The title compound was 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)pyrrolidin-3-yl)-1-(2'-methyl-[1,1'-biphenyl]-4 -yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was 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)pyrrolidin-3-yl)-1-(3-methyl-[1,1'-biphenyl]-4- yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was 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)pyrrolidin-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)pyrrolidin-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)pyrrolidin-3-yl)-1-(2'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl )-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)-[1,1'-biphenyl]-4-carbonitrile

The title compound was 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)pyrrolidin-3-yl)-1-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl )-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

The title compound was 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)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3 -dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride

To a mixture of Reference Example F-22 (43 mg), 1-methyl-1H-imidazole-2-carbaldehyde (22 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (127 mg). 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 is 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

Methyl (S)-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate

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

Methyl (R)-3'-methyl-4'-(3-(1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-2-oxo-2,3- dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylate

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

A mixture of Example G-10 (20 mg), methanol (0.5 ml), THF (0.5 ml) and aqueous sodium hydroxide solution (5 mol/l, 1 ml) was stirred at room temperature overnight. Hydrochloric acid (2 mol/l, 2.5 ml) was added to the reaction mixture, and the mixture was stirred. The mixture is concentrated under reduced pressure. Methanol is added to the residue and the mixture is stirred. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure. The residue was purified by ODS column chromatography (eluent: water/acetonitrile=90/10-30/70) to obtain the title compound (6.3 mg).

Example 40

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

The title compound was 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyridin-1-yl)pyridin-2-yl)benzoic acid

The title compound was 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-3-carboxylic acid

The title compound was 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'-Carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5 -b]pyridin-3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid

The title compound was 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid

The title compound was 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)pyrrolidin-1-yl)methyl)isonicotinic acid

To a mixture of Reference Example G-16 (207 mg), methanol (0.5 ml) and THF (0.5 ml) was added an aqueous sodium hydroxide solution (5 mol/l, 1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is 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]pyridine- 3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid

To a mixture of Reference Example G-17 (455 mg), methanol (0.5 ml) and THF (0.5 ml) was added an aqueous solution of sodium hydroxide (5 mol/l, 1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized by adding hydrochloric acid (2 mol/l) and the precipitate was collected by filtration. The 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[ 4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid

To a mixture of Example 37 (48 mg), methanol (0.5 ml) and THF (0.5 ml) was added aqueous sodium hydroxide solution (5 mol/l, 1 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 is concentrated under reduced pressure. Methanol is added to the residue and the mixture is stirred. The insoluble product is removed through Celite and the filtrate is 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro -1H-imidazo[4,5-b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid

The title compound was 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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Reference Example G-18 (450 mg) and concentrated hydrochloric acid (2 ml) was stirred at 110° C. under microwaves for 1 hour. The reaction mixture was kept at room temperature and the precipitate was collected by filtration. The resulting solid is washed with cold water and dried. A portion of the resulting product (26 mg, out of 222 mg) was purified by ODS column chromatography (eluent: water with 0.1% formic acid/acetonitrile=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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Reference Example G-19 (413 mg) and concentrated hydrochloric acid (2 ml) was stirred at 110°C under microwave for 1 hour. The reaction mixture was neutralized by adding an aqueous solution of sodium hydroxide (5 mol/l). The insoluble product is removed by filtration. The filtrate was purified by ODS column chromatography (eluent: water with 0.1% formic acid/acetonitrile=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)pyrrolidin-1-yl)methyl)isonicotinic acid

A mixture of Reference Example G-20 (188 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. To the reaction mixture was added concentrated sulfuric acid (0.2 ml) under ice-cooling with stirring. The reaction mixture is refluxed for 4 days. The reaction mixture is cooled to room temperature, and then the mixture is neutralized by adding an aqueous solution of sodium hydroxide (5 mol/l). The precipitate is 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)pyrrolidin-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)pyrrolidin-1-yl)methyl)isonicotinic acid

A mixture of Reference Example G-22 (77 mg), water (0.5 ml) and concentrated sulfuric acid (0.5 ml) was refluxed for 7 hours. The reaction mixture is cooled to room temperature. An aqueous sodium hydroxide solution (5 mol/l, 4 ml) was added to the mixture under ice-cooling. The mixture is stirred at room temperature overnight. 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]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-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)pyrrolidin- 1-yl)methyl)-1-methyl-1H-imidazole-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-imidazole-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)pyrrolidin-1-yl )methyl)-1-methyl-1H-imidazole-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-imidazole-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)pyrrolidin-1-yl )methyl)-1-methyl-1H-imidazole-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]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid

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

Example 61

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

The title compound was 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]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-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]pyridine-3- yl)pyrrolidin-1-yl)methyl)-1H-imidazole-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)pyrrolidin-1-yl )methyl)-1-methyl-1H-imidazole-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-imidazole-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 )pyrrolidin-1-yl)methyl)-1H-imidazole-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-morpholinophenyl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidine -1-yl)methyl)-1H-imidazole-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-imidazole-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-imidazole-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-(thiophen-3-yl)-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl )pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid

The title compound was 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-Benzyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)- 1-methyl-1H-imidazole-5-carboxylic acid

The title compound was 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)pyrrolidin-1-yl )methyl)-1-methyl-1H-imidazole-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)pyrrolidin-1-yl )methyl)-1-methyl-1H-imidazole-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'-(methylsulfonamido)-[1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H -imidazo[4,5-b]pyridin-3-yl)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid

The title compound was 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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)benzoyl)glycine

To a mixture of Reference Example K-1 (7.7 mg), methanol (0.5 ml) and THF (0.5 ml) was added an aqueous sodium hydroxide solution (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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Reference Example G-47 (92 mg), methanol (0.5 ml), water (0.5 ml) and concentrated sulfuric acid (0.022 ml) was refluxed for 1 hour. The reaction mixture is cooled to room temperature. Lithium hydroxide monohydrate (70 mg) was added to the mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was purified by ODS column chromatography (eluent: water with 0.1% formic acid/acetonitrile=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]pyridine -3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-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)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl) -1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of Reference Example F-22 (285 mg), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (250 mg) and dichloromethane (2 ml) was added NaBH(OAc) ₃ (561 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (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)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carbonitrile

A mixture of Example 79 (351 mg), tetrakis(triphenylphosphine)palladium (0) (77 mg), zinc cyanide (155 mg) and NMP (3 ml) was stirred at 120°C under microwave for 90 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water, and the resulting mixture was stirred. The mixture is filtered through Celite and the filtrate is 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 amino silica gel column chromatography (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)pyrrolidin-1-yl)methyl)-1H-imidazole-5-carboxylic acid

A mixture of Example 80 (190 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. An aqueous solution of sodium hydroxide (5 mol/l) was added to the reaction mixture under ice-cooling until a precipitate formed. The precipitate is 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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Example K-6 (150 mg) and concentrated hydrochloric acid (2 ml) was stirred at 110°C under microwave for 1 hour. The reaction mixture was neutralized by adding an aqueous solution of sodium hydroxide (5 mol/l). The mixture was diluted with DMSO, and then purified by ODS column chromatography (eluent: water/acetonitrile=98/2-30/70) to obtain the title compound (83 mg).

Example 83

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

A mixture of Example K-8 (199 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. The reaction mixture was neutralized by adding an aqueous solution of sodium hydroxide (5 mol/l). The mixture was diluted with DMSO, and then purified by ODS column chromatography (eluent: water/acetonitrile=98/2-30/70) to obtain 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)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Example K-10 (178 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. 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 resulting product (16 mg out of 107 mg) was then purified by ODS column chromatography (eluent: water with 0.1% formic acid/acetonitrile=98/2-30/70) to obtain 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]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Example K-12 (195 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. The reaction mixture was neutralized by adding an aqueous solution of sodium hydroxide (5 mol/l). The mixture is diluted with DMSO. The insoluble product is removed through Celite. The filtrate was purified by ODS column chromatography (eluent: water/acetonitrile=98/2-30/70) to obtain 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]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Example K-14 (58 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. The reaction mixture was neutralized by adding an aqueous solution of sodium hydroxide (5 mol/l), and then concentrated under reduced pressure. DMSO is added to the residue. The insoluble product is removed through Celite. The filtrate was purified by ODS column chromatography (eluent: water/acetonitrile=90/10-30/70) to obtain 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)pyrrolidin-1-yl )methyl)-1H-imidazole-5-carboxylic acid

A mixture of Example K-16 (75 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. The reaction mixture was neutralized by adding an aqueous solution of sodium hydroxide (5 mol/l). The mixture was diluted with DMSO, and then purified by ODS column chromatography (eluent: water/acetonitrile=98/2-30/70) to obtain 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]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid

A mixture of Example K-18 (207 mg) and concentrated hydrochloric acid (1 ml) was stirred at 110°C under microwave for 1 hour. The reaction mixture was neutralized by adding an aqueous solution of sodium hydroxide (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)pyrrolidin-3-yl)- 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

To a mixture of Reference Example F-21 (35 mg), 3-methyl-2-pyridinecarboxyaldehyde (18 mg) and dichloromethane (1 ml) was added NaBH(OAc) ₃ (94 mg). 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 is concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (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)pyrrolidin-3-yl)-1-(4-(pyridin-4-yl)phenyl)-1,3-dihydro-2H -imidazo[4,5-b]pyridine-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)pyrrolidin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- b]pyridin-1-yl)-[1,1'-biphenyl]-4-carboxylic acid

To a mixture of Example G-48 (72 mg), methanol (1 ml) and THF (1 ml) was added aqueous sodium hydroxide solution (5 mol/l, 2 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 tables show the chemical structure, physical properties and inhibitory effect on PHD2 (see Experimental Example 1) of the Examples.

[Table 2] Etc. No. Structure Physical Data IC _fifty (µM) one

^one H-NMR (CDCl ₃ ) δ ppm: 2.30-2.48(4H, m), 2.50-2.60(1H, m), 3.10-3.13(3H, m), 3.17-3 .25 (1H, m), 3.83-3.99 (2H, m), 5.25-5.38 (1H, m), 6.99 (1H, dd, J=5.2, 7, 8 Hz), 7.09 (1H, dd, J=4.8, 7.6 Hz), 7.33 (1H, dd, J=1.4, 7.8 Hz), 7.38-7, 54 (4H, m), 7.56-7.66 (4H, m), 7.71-7.78 (2H, m), 8.10 (1H, dd, J=1.4, 5.2 Hz), 8.37-8.42 (1H, m) 8.43 2

^one H NMR (CDCl ₃ ) δ ppm: 2.25-2.41(1H, m), 2.52-2.64(1H, m), 2.89-3.12(4H, m), 3.76(3H , s), 3.80-3.90 (2H, m), 5.21-5.33 (1H, m), 6.84 (1H, d, J=1.2 Hz), 6.91 ( 1H, d, J=1.2 Hz), 7.00 (1H, dd, J=5.2, 7.8 Hz), 7.33 (1H, dd, J=1.4, 7.8 Hz ), 7.36-7.52 (3H, m), 7.55-7.65 (4H, m), 7.72-7.77 (2H, m), 8.09 (1H, dd, J =1.4, 5.2 Hz) 0.79 3

^one H NMR (CDCl ₃ ) δ ppm: 2.23-2.40(1H, m), 2.53-2.64(1H, m), 2.89-3.09(4H, m), 3.76(3H , s), 3.81-3.89 (2H, m), 5.23-5.32 (1H, m), 6.84 (1H, d, J=1.2 Hz), 6.91 ( 1H, d, J=1.2 Hz), 7.00 (1H, dd, J=5.2, 7.8 Hz), 7.33 (1H, dd, J=1.4, 7.8 Hz ), 7.38-7.52 (3H, m), 7.56-7.64 (4H, m), 7.71-7.76 (2H, m), 8.09 (1H, dd, J =1.4, 5.2 Hz) 3.90 four

MS (YER_HIAD, m/z): 448 (M+H) ⁺ 3.45 5

MS (IES_HIAD, m/z): 437 (M+H) ⁺ 2.98 6

MS (YER_HIAD, m/z): 451 (M+H) ⁺ *34% 7

MS (IES_HIAD, m/z): 437 (M+H) ⁺ 15.64

[Table 3] Etc. No. Structure Physical Data IC _fifty (µM) eight

^one H NMR (DMSO) δ ppm: 2.25-2.36 (1H, m), 2.42-2.55 (1H, m), 2.72-2.80 (1H, m), 2 .99-3.10 (2N, m), 3.15-3.22 (1N, m), 3.86-4.10 (2N, m), 5.15-5.26 (1N, m) , 7.09-7.18(3H, m), 7.38-7.55(4H, m), 7.65-7.70(2H, m), 7.73-7.77(2H, m), 7.84-7.90 (2H, m), 7.95 (1H, dd, J=1.8, 4.3 Hz), 8.10 (1H, dd, J=1.4, 5.2Hz) *29% 9

^one H NMR (DMSO-d6) δ ppm: 2.14-2.27 (1H, m), 2.39-2.53 (1H, m), 2.80-3.05 (4H, m) , 3.69(2H, s), 5.04-5.15(1H, m), 7.07-7.16(2H, m), 7.25-7.32(1H, m), 7 .38-7.55 (4N, m), 7.64-7.69 (2N, m), 7.71-7.78 (2N, m), 7.83-7.89 (2N, m) , 8.01-8.04 (1H, m), 8.10 (1H, dd, J=1.4, 5.2 Hz), 9.77 (1H, brs) 8.03 ten

^one H NMR (DMSO-d6) δ ppm: 2.20-2.31 (1H, m), 2.43-2.54 (1H, m), 2.83-3.09 (4H, m) , 3.51-3.70 (2H, m), 5.08-5.23 (1H, m), 5.90-6.14 (2H, m), 7.12 (1H, dd, J= 5.2, 7.8 Hz), 7.38-7.59(5H, m), 7.64-7.70(2H, m), 7.72-7.78(2H, m), 7 .84-7.90 (2H, m), 8.11 (1H, dd, J=1.4, 5.2 Hz), 11.23 (1H, brs) 5.49 eleven

MS (YER_HIAD, m/z): 375 (M+H) ⁺ 85.38 12

^one H NMR (CDCl ₃ ) δ ppm: 1.80-1.88(2H, m), 2.24-2.33(2H, m), 2.74-2.87(2H, m), 2.93-3 .02 (2H, m), 3.67 (2H, s), 4.50-4.61 (1H, m), 6.87 (1H, d, J=1.2 Hz), 6.93 ( 1H, d, J=1.2 Hz), 6.99 (1H, dd, J=5.2, 7.8 Hz), 7.31-7.42 (2H, m), 7.45-7 .51 (2H, m), 7.57-7.65 (4H, m), 7.71-7.77 (2H, m), 8.09 (1H, dd, J=1.4, 5, 2 Hz) 4.95 13

^one H NMR (CDCl ₃ ) δ ppm: 3.98(3H, s), 4.46-4.56(2H, m), 4.61-4.70(2H, m), 4.98-5.07(2H , m), 5.57-5.70 (1H, m), 6.98 (1H, d, J=1.2 Hz), 7.07-7.12 (2H, m), 7.38- 7.43(2H, m), 7.46-7.53(2H, m), 7.56-7.65(4H, m), 7.74-7.79(2H, m), 8, 19 (1Н, dd, J=1.4, 5.2 Hz) 0.12 fourteen

^one H NMR (CDCl ₃ ) δ ppm: 2.24-2.39(1H, m), 2.47-2.61(1H, m), 2.93-3.11(4H, m), 3.78(3H , s), 3.80-3.97 (2H, m), 5.14-5.26 (1H, m), 6.81-6.89 (3H, m), 6.92-7.00 (2H, m), 7.19-7.24 (1H, m), 7.29-7.42 (4H, m), 7.54-7.59 (2H, m), 8.05 (1H , dd, J=1.4, 5.2 Hz) 0.36

[Table 4] Etc. No. Structure Physical Data IC _fifty (µM) fifteen

^one H NMR (CDCl ₃ ) δ ppm: 2.28-2.40(1H, m), 2.43(3H, s), 2.47-2.57(1H, m), 2.98-3.10(3H , m), 3.15-3.23 (1H, m), 3.82-3.98 (5H, m), 5.24-5.35 (1H, m), 7.00 (1H, dd , J=5.2, 7.8 Hz), 7.06-7.11 (1H, m, J=4.8, 7.6 Hz), 7.34 (1H, dd, J=1.4 , 7.8 Hz), 7.41-7.46 (1H, m), 7.62-7.67 (2H, m), 8.11 (1H, dd, J=1.4, 5.2 Hz), 8.17-8.23 (2H, m), 8.37-8.40 (1H, m) 64.50 16

MS (YER_HIAD, m/z): 492 (M+H) ⁺ 0.14 17

MS (YER_HIAD, m/z): 492 (M+H) ⁺ 0.52 eighteen

MS (YER_HIAD, m/z): 446 (M+H) ⁺ 1.95 19

MS (YER_HIAD, m/z): 416 (M+H) ⁺ 6.34 twenty

MS (YER_HIAD, m/z): 495 (M+H) ⁺ 6.71 21

MS (YER_HIAD, m/z): 430 (M+H) ⁺ *39%

[Table 5] Etc. No. Structure Physical Data IC _fifty (µM) 22

^one H NMR (DMSO-d6) δ ppm: 2.16-2.29 (1H, m), 2.41-2.54 (1H, m), 2.85-3.05 (4H, m) , 3.83 (2H, s), 3.91 (3H, s), 5.06-5.19 (1H, m), 7.11 (1H, dd, J=5.2, 7.8 Hz ), 7.46 (1H, dd, J=1.4, 7.8 Hz), 7.50 (1H, s), 7.58-7.64 (2H, m), 7.70 (1H, dd, J=2.0, 8.8 Hz), 7.99-8.06 (2H, m), 8.08-8.16 (3H, m), 12.79 (1H, brs) 0.30 23

^one H NMR (DMSO-d6) δ ppm: 1.56 (3H, s), 1.79-1.92 (2H, m), 2.22-2.34 (2H, m), 2.57 -2.65(2H, m), 3.39-3.50(2H, m), 3.55(2H, s), 3.88(3H, s), 7.09(1H, dd, J \u003d 5.2, 7.8 Hz), 7.37-7.55 (5H, m), 7.63-7.68 (2H, m), 7.72-7.78 (2H, m), 7.83-7.89 (2H, m), 8.05 (1H, dd, J=1.4, 5.2 Hz), 12.72 (1H, br) 5.50 24

^one H NMR (DMSO-d6) δ ppm: 2.16-2.27 (1H, m), 2.37-2.48 (1H, m), 2.82-3.01 (4H, m) , 3.77-3.83 (5H, m), 3.90 (3H, s), 4.99-5.09 (1H, m), 7.12 (1H, d, J=2.5 Hz ), 7.48 (1H, s), 7.69-7.74 (2H, m), 7.83 (1H, d, J=2.5 Hz), 7.86-7.96 (4H, m), 8.03-8.08 (2H, m), 12.34-13.27 (2H, m) 0.11 25

^one H NMR (DMSO-d6) δ ppm: 2.82-2.90 (1H, m), 2.94-3.26 (3H, m), 3.85 (2H, s), 3.91 (3H, s), 4.99-5.15 (1H, m), 5.67-5.86 (1H, m), 7.14 (1H, dd, J=5.2, 7.8 Hz ), 7.47-7.53(2H, m), 7.70-7.75(2H, m), 7.86-7.91(2H, m), 7.92-7.97(2H , m), 8.04-8.11 (3N, m), 12.50-13.28 (2N, m) 0.11 26

^one H NMR (DMSO-d6) δ ppm: 2.14-2.32 (1H, m), 2.40-2.56 (1H, m), 2.81-3.04 (4H, m) , 3.82(2H, s), 3.91(3H, s), 5.06-5.18(1H, m), 7.42-7.49(1H, m), 7.63(1H , d, J=1.8 Hz), 7.70-7.77 (2H, m), 7.86-7.91 (2H, m), 7.93-7.99 (2H, m), 8.04-8.09 (2H, m), 8.48-8.52 (1H, m), 12.41-13.27 (2H, m) 0.13 27

^one H NMR (DMSO-d6) δ ppm: 2.13-2.27 (1H, m), 2.30 (3H, s), 2.38-2.50 (1H, m), 2.82 -3.02 (4H, m), 3.81 (2H, s), 3.91 (3H, s), 5.01-5.11 (1H, m), 7.31-7.35 (1H , m), 7.48 (1H, s), 7.67-7.73 (2H, m), 7.85-7.97 (5H, m), 8.03-8.09 (2H, m ), 12.91 (2H, shs) 0.11 28

^one H NMR (CDCl ₃ ) δ ppm: 2.22 (3H, d, J=5.3 Hz), 2.29-2.41 (1H, m), 2.52-2.67 (1H, m), 2, 90-3.11 (4H, m), 3.76 (3H, s), 3.79-3.90 (2H, m), 5.20-5.34 (1H, m), 6.84 ( 1Н, d, J=1.2 Hz), 6.91 (1Н d, J=1.2 Hz), 6.95-6.97 (2Н, m), 7.31-7.42 (2Н, m), 7.44-7.50 (2H, m), 7.51-7.56 (1H, m), 7.58-7.64 (3H, m), 8.06-8.09 ( 1N, m) 28.2

[Table 6] Etc. No. Structure Physical Data IC _fifty (µM) 29

^one H NMR (CDCl3) δ ppm: 2.26-2.39 (4H, m), 2.53-2.64 (1H, m), 2.91-3.12 (4H, m), 3 .76 (3H, s), 3.80-3.89 (2H, m), 5.21-5.34 (1H, m), 6.84 (1H, d, J=1.2 Hz), 6.91 (1H, d, J=1.2 Hz), 7.00 (1H, dd, J=5.2, 7.8 Hz), 7.24-7.32 (4H, m), 7 .35 (1Н, dd, J=1.4, 7.8 Hz), 7.46-7.58 (4Н, m), 8.09 (1Н, dd, J=1.4, 5.2 Hz ) 2.09 thirty

^one H NMR(CDCl3) δ ppm: 2.21(3H, d, J=5.3Hz), 2.27-2.40(1H, m), 2.51-2.65(1H, m ), 2.89-2.99 (1H, m), 3.01-3.12 (3H, m), 3.76 (3H, s), 3.80-3.90 (2H, m), 5.18-5.33 (1H, m), 6.84 (1H, d, J=1.2 Hz), 6.91 (1H, d, J=1.2 Hz), 6.94-6 .97 (2N, m), 7.29-7.64 (8N, m), 8.07-8.09 (1N, m) 3.48 31

^one H NMR (CDCl3) δ ppm: 2.28-2.41 (1H, m), 2.43 (3H, s), 2.48-2.60 (1H, m), 2.99-3 .10 (3H, m), 3.16-3.24 (1H, m), 3.82-3.99 (2H, m), 5.25-5.37 (1H, m), 6.99 (1Н, dd, J=5.2, 7.8 Hz), 7.09 (1Н, dd, J=4.8, 7.6 Hz), 7.12-7.20 (2Н, m), 7.32 (1H, dd, J=1.4, 7.8 Hz), 7.41-7.46 (1H, m), 7.49-7.61 (4H, m), 7.65- 7.71 (2H, m), 8.09 (1H, dd, J=1.4, 5.2 Hz), 8.37-8.41 (1H, m) 12.45 32

^one H NMR (CDCl3) δ ppm: 2.28-2.41 (1H, m), 2.43 (3H, s), 2.47-2.60 (1H, m), 2.99-3 .10 (3H, m), 3.16-3.24 (1H, m), 3.83-3.98 (5H, m), 5.23-5.37 (1H, m), 6.95 -7.03 (3H, m), 7.09 (1H, dd, J=4.8, 7.6 Hz), 7.29-7.33 (1H, m), 7.41-7.46 (1H, m), 7.50-7.58 (4H, m), 7.66-7.71 (2H, m), 8.09 (1H, dd, J=1.4, 5.2 Hz ), 8.37-8.41 (1H, m) 42.10 33

^one H NMR (CDCl3) δ ppm: 2.28-2.41 (1H, m), 2.43 (3H, s), 2.48-2.60 (1H, m), 2.98-3 .12 (3H, m), 3.14-3.25 (1H, m), 3.82-4.00 (2H, m), 5.24-5.40 (1H, m), 6.95 -7.03(1H, m), 7.05-7.13(1H, m), 7.28-7.63(9H, m), 7.75-7.80(1H, m), 8 .10 (1H, dd, J=1.4, 5.2 Hz), 8.36-8.42 (1H, m) *41% 34

^one H NMR (CDCl3) δ ppm: 2.27-2.60 (5H, m), 2.99-3.11 (3H, m), 3.17-3.23 (1H, m), 3 .82-3.99 (2H, m), 5.25-5.39 (1H, m), 7.00 (1H, dd, J=4.8, 7.6 Hz), 7.34 (1H , dd, J=1.4, 7.8 Hz), 7.41-7.47 (1H, m), 7.62-7.80 (8H, m), 8.11 (1H, dd, J \u003d 1.4, 5.2 Hz), 8.36-8.42 (1H, m) 5.70 35

^one H NMR (CDCl3) δ ppm: 2.28-2.40 (1H, m), 2.43 (3H, s), 2.47-2.60 (1H, m), 2.99-3 .10 (3H, m), 3.16-3.24 (1H, m), 3.82-3.99 (2H, m), 5.23-5.36 (1H, m), 7.00 (1H, d, J=5.2, 7.8 Hz), 7.06-7.11 (1H, m), 7.28-7.35 (3H, m), 7.40-7.54 (2H, m), 7.57-7.73 (5H, m), 8.10 (1H, dd, J=1.4, 5.2 Hz), 8.36-8.42 (1H, m ) 80.5

[Table 7] Etc. No. Structure Physical Data IC _fifty (µM) 36

MS (YER_HIAD, m/z): 452 (M+H) ⁺ 1.51 37

^one H NMR (CDCl3) δ ppm: 2.26-2.39 (1H, m), 2.52-2.64 (1H, m), 2.90-2.98 (1H, m), 3 .00-3.10 (3H, m), 3.76 (3H, s), 3.80-3.89 (2H, m), 3.96 (3H, s), 5.22-5.33 (1H, m), 6.83 (1H, d, J=1.2 Hz), 6.91 (1H, d, J=1.2 Hz), 7.01 (1H, dd, J=5, 2, 7.8 Hz), 7.33 (1H, dd, J=1.4, 7.8 Hz), 7.60-7.65 (2H, m), 7.67-7.72 (2H , m), 7.75-7.81 (2Н, m), 8.09 (1Н, dd, J=1.4, 5.2 Hz), 8.12-8.17 (2Н, m) 6.82 38

^one H NMR(CDCl3) δ ppm: 2.23 (3H, d, J=5.3 Hz), 2.28-2.40 (1H, m), 2.54-2.64 (1H, m), 2.90- 2.99(1H, m), 3.00-3.11(3H, m), 3.76(3H, s), 3.79-3.90(2H, m), 3.96(3H, s), 5.20-5.34 (1H, m), 6.84 (1H, d, J=1.2 Hz), 6.91 (1H, d, J=1.2 Hz), 6, 94-6.97 (2H, m), 7.35-7.40 (1H, m), 7.55-7.60 (1H, m), 7.62-7.65 (1H, m), 7.66-7.71 (2H, m), 8.07-8.10 (1H, m), 8.11-8.17 (2H, m) 4.63 39

MS (YER_HIAD, m/z): 511 (M+H) ⁺ 0.34 40

MS (YER_HIAD, m/z): 511 (M+H) ⁺ 0.76 41

^one H NMR (DMSO-d6) δ ppm: 2.15-2.27 (1H, m), 2.41-2.49 (1H, m), 2.82-3.00 (4H, m) , 3.69 (3H, s), 3.74 (2H, s), 5.03-5.16 (1H, m), 6.74 (1H, d, J=1.2 Hz), 7, 07 (1Н, d, J=1.2 Hz), 7.13 (1Н, dd, J=5.2 7.8 Hz), 7.54 (1Н, dd, J=1.4, 7.8 Hz), 8.06-8.14 (3H, m), 8.17 (1H, dd, J=2.6, 8.5 Hz), 8.25-8.30 (3H, m), 8 .93-8.96 (1H, m), 13.11 (1H, ws) 1.46

[Table 8] Etc. No. Structure Physical Data IC _fifty (µM) 42

MS (YER_HIAD, m/z): 511 (M+H) ⁺ 0.32 43

MS (YER_HIAD, m/z): 536 (M+H) ⁺ 0.20 44

MS (YER_HIAD, m/z): 511 (M+H) ⁺ 0.97 45

MS (YER_HIAD, m/z): 552 (M+H) ⁺ 0.27 46

MS (YER_HIAD, m/z): 537 (M+H) ⁺ 0.15 47

^one H NMR (DMSO-d6) δ ppm: 2.14-2.26 (1H, m), 2.39-2.56 (1H, m), 2.81-3.00 (4H, m) , 3.69 (3H, s), 3.73 (2H, s), 5.03-5.16 (1H, m), 6.74 (1H, d, J=1.1 Hz), 7, 07 (1Н, d, J=1.1 Hz), 7.11 (1Н, dd, J=5.2 7.8 Hz), 7.46 (1Н, dd, J=1.3, 7.8 Hz), 7.68-7.74 (2H, m), 7.85-7.91 (2H, m), 7.91-7.97 (2H, m), 8.03-8.08 ( 2H, m), 8.09 (1H, dd, J=1.3, 5.2 Hz), 13.06 (1H, brs) 0.41 48

MS (YER_HIAD, m/z): 509 (M+H) ⁺ 0.35

[Table 9] Etc. No. Structure Physical Data IC _fifty (µM) 49

MS (YER_HIAD, m/z): 555 (M+H) ^+
one H NMR (DMSO-d6) δ ppm: 2.14-2.30 (1H, m), 2.38-2.56 (1H, m), 2.82-3.03 (4H, m) , 3.81(2H, s), 3.91(3H, s), 5.00-5.14(1H, m), 7.01-7.09(2H, m), 7.31(1H , dd, J=2.0, 8.2 Hz), 7.36 (1H, d, J=2.0 Hz), 7.44-7.52 (2H, m), 7.77-7, 83 (2H, m), 8.02-8.08 (3H, m), 10.21 (1H, shs), 12.90 (2H, shs) 0.12 fifty

^one H NMR (DMSO-d6) δ ppm: 2.17-2.29 (1H, m), 2.38-2.55 (4H, m), 2.84-3.03 (4H, m) , 3.82 (2H, s), 3.91 (3H, s), 5.04-5.18 (1H, m), 7.13 (1H, dd, J=5.2, 7.8 Hz ), 7.49 (1H, s), 7.55 (1H, dd, J=1.3, 7.8 Hz), 7.59 (1H, d, J=8.0 Hz), 7.81 (1Н, dd, J=0.7, 8.4 Hz), 7.86-7.95 (2Н, m), 8.12 (1Н, dd, J=1.3, 5.2 Hz), 8.16 (1H, dd, J=2.6, 8.4 Hz), 8.93 (1H, dd, J=0.7, 2.6 Hz), 12.90 (2H, brs) 0.14 51

MS (YER_HIAD, m/z): 568 (M+H) ⁺ 0.14 52

MS (YER_HIAD, m/z): 553 (M+H) ⁺ 0.28 53

MS (YER_HIAD, m/z): 568 (M+H) ⁺ 0.14 54

^one H NMR (DMSO-d6) δ ppm: 2.15-2.28 (1H, m), 2.40-2.55 (1H, m), 2.80-3.03 (4H, m) , 3.82 (2H, s), 3.91 (3H, s), 5.03-5.17 (1H, m), 7.10 (1H, dd, J=5.2, 7.8 Hz ), 7.37-7.53(5H, m), 7.54-7.59(1H, m), 7.63-7.70(1H, m), 7.71-7.79(3H , m), 7.84-7.87 (1H, m), 8.08 (1H, dd, J=1.4, 5.2 Hz), 12.80 (1H, brs) 0.77 55

^one H NMR (DMSO-d6) δ ppm: 2.11-2.26 (1H, m), 2.38-2.57 (1H, m), 2.81-3.02 (10H, m) , 3.80(2H, s), 3.90(3H, s), 4.98-5.12(1H, m), 6.79-6.88(2H, m), 7.05(1H , dd, J=5.2, 7.8 Hz), 7.19 (1Н, dd, J=1.4, 7.8 Hz), 7.27-7.33 (2Н, m), 7, 48 (1H, s), 8.03 (1H, dd, J=1.4, 5.2 Hz), 12.82 (1H, brs) 0.49

[Table 10] Etc. No. Structure Physical Data IC _fifty (µM) 56

^one H NMR (DMSO-d6) δ ppm: 2.10-2.27 (1H, m), 2.38-2.54 (1H, m), 2.81-3.01 (4H, m) , 3.80(2H, s), 3.90(3H, s), 5.01-5.14(1H, m), 7.05-7.24(6H, m), 7.35(1H , dd, J=1.4, 7.8 Hz), 7.41-7.49 (3H, m), 7.53-7.60 (2H, m), 8.07 (1H, dd, J =1.4, 5.2 Hz), 12.79 (1H, brs) 0.41 57

^one H NMR (DMSO-d6) δ ppm: 2.13-2.27 (1H, m), 2.37-2.54 (1H, m), 2.81-3.00 (4H, m) , 3.80 (2H, s), 3.89 (3H, s), 4.03 (2H, s), 5.00-5.12 (1H, m), 7.06 (1H, dd, J \u003d 5.2, 7.8 Hz), 7.18-7.24 (1H, m), 7.27-7.36 (5H, m), 7.39-7.50 (5H, m), 8.06 (1H, dd, J=1.4, 5.2 Hz), 12.80 (1H, brs) 0.71 58

^one H NMR (DMSO-d6) δ ppm: 2.14-2.26 (1H, m), 2.36-2.46 (4H, m), 2.82-3.01 (4H, m) , 3.81 (2H, s), 3.90 (3H, s), 5.02-5.13 (1H, m), 7.07 (1H, dd, J=5.2, 7.8 Hz ), 7.32 (1Н, dd, J=1.3, 7.8 Hz), 7.35-7.46 (4Н, m), 7.49 (4Н, m), 8.06 (1Н, dd, J=1.3, 5.2 Hz), 12.73 (1Н, brs) 1.02 59

^one H NMR (DMSO-d6) δ ppm: 2.13-2.27 (1H, m), 2.37-2.48 (1H, m), 2.81-3.02 (4H, m) , 3.81 (2H, s), 3.90 (3H, s), 5.01-5.13 (1H, m), 7.09 (1H, dd, J=5.2, 7.8 Hz ), 7.40 (1H, dd, J=1.3, 7.8 Hz), 7.49 (1H, s), 7.58-7.67 (4H, m), 8.08 (1H, dd, J=1.3, 5.2 Hz), 12.75 (1Н, br) 0.18 60

^one H NMR (DMSO-d6) δ ppm: 2.14-2.27 (1H, m), 2.38-2.49 (1H, m), 2.54 (3H, s), 2.83 -3.00 (4H, m), 3.81 (2H, s), 3.90 (3H, s), 5.01-5.13 (1H, m), 7.08 (1H, dd, J =5.2, 7.8 Hz), 7.34 (1H, dd, J=1.3, 7.8 Hz), 7.41-7.54 (5H, m), 8.07 (1H, dd, J=1.3, 5.2 Hz), 12.76 (1Н, br) 0.59 61

^one H NMR (DMSO-d6) δ ppm: 1.15 (3H, t, J=7.4 Hz), 2.15-2.28 (1H, m), 2.38-2.50 (1H , m), 2.82-3.01 (4H, m), 3.38 (2H, q, J=7.4 Hz), 3.81 (2H, s), 3.90 (3H, s) , 5.04-5.16 (1H, m), 7.13 (1H, dd, J=5.2, 7.8 Hz), 7.48 (1H, s), 7.58 (1H, dd , J=1.3, 7.8 Hz), 7.88-7.93 (2H, m), 8.04-8.09 (2H, m), 8.12 (1H, dd, J=1 .3, 5.2 Hz), 12.82 (1H, brs) 7.07 62

^one H NMR (DMSO-d6) δ ppm: 2.14-2.28 (1H, m), 2.38-2.49 (1H, m), 2.82-3.02 (4H, m) , 3.81 (2H, s), 3.90 (3H, s), 5.03-5.14 (1H, m), 7.09 (1H, dd, J=5.2, 7.8 Hz ), 7.44 (1H, dd, J=1.3, 7.8 Hz), 7.49 (1H, s), 7.54-7.61 (2H, m), 7.69-7, 77 (2H, m), 8.09 (1H, dd, J=1.3, 5.2 Hz), 12.77 (1H, br) 1.85

[Table 11] Etc. No. Structure Physical Data IC _fifty (µM) 63

^one H NMR (DMSO-d6) δ ppm: 2.15-2.28 (1H, m), 2.38-2.49 (1H, m), 2.81-3.02 (4H, m) , 3.82 (2H, s), 3.90 (3H, s), 5.03-5.16 (1H, m), 7.12 (1H, dd, J=5.2, 7.8 Hz ), 7.49 (1H, s), 7.53 (1H, dd, J=1.3, 7.8 Hz), 7.82-7.88 (2H, m), 7.92-7, 98 (2H, m), 8.11 (1H, dd, J=1.3, 5.2 Hz), 12.80 (1H, br) 1.92 64

^one H NMR (DMSO-d6) δ ppm: 2.13-2.27 (1H, m), 2.37-2.49 (1H, m), 2.82-3.01 (4H, m) , 3.81 (2H, s), 3.90 (3H, s), 5.03-5.14 (1H, m), 7.12 (1H, dd, J=5.2, 7.8 Hz ), 7.48 (1H, s), 7.54 (1H, dd, J=1.3, 7.8 Hz), 7.80-7.86 (2H, m), 8.02-8, 08 (2H, m), 8.11 (1H, dd, J=1.3, 5.2 Hz), 12.79 (1H, br) 7.89 65

^one H NMR (DMSO-d6) δ ppm: 2.14-2.28 (1H, m), 2.37-2.49 (1H, m), 2.82-3.01 (4H, m) , 3.81 (2H, s), 3.90 (3H, s), 5.04-5.16 (1H, m), 7.14 (1H, dd, J=5.2, 7.8 Hz ), 7.47 (1H, s), 7.60 (1H, dd, J=1.3, 7.9 Hz), 7.88-7.95 (2H, m), 8.13 (1H, dd, J=1.3, 5.2 Hz), 8.39-8.45 (2H, m), 12.82 (1H, br) 2.40 66

^one H NMR (DMSO-d6) δ ppm: 2.17-2.30 (1H, m), 2.42-2.54 (1H, m), 2.83-3.04 (4H, m) , 3.82 (2H, s), 3.91 (3H, s), 5.06-5.09 (1H, m), 7.13 (1H, dd, J=5.2, 7.8 Hz ), 7.48 (1H, s), 7.58 (1H, dd, J=1.3, 7.8 Hz), 7.69-7.75 (1H, m), 7.83-7, 89 (1H, m), 8.08-8.15 (3H, m), 8.65 (1H, d, J=2.5 Hz), 9.12 (1H, d, J=2.5 Hz ), 12.82 (1H, shs) 1.17 67

^one H NMR (DMSO-d6) δ ppm: 2.12-2.27 (1H, m), 2.37-2.49 (1H, m), 2.81-3.01 (4H, m) , 3.14-3.22(4H, m), 3.72-3.79(4H, m), 3.80(2H, s), 3.90(3H, s), 5.00-5 .13 (1H, m), 7.02-7.13 (3H, m), 7.25 (1H, dd, J=1.4, 7.8 Hz), 7.34-7.40 (2H , m), 7.48 (1H, s), 8.04 (1H, dd, J=1.4, 5.2 Hz), 12.77 (1H, brs) 0.52 68

^one H NMR (DMSO-d6) δ ppm: 1.58-1.69 (2H, m), 1.88-2.57 (9H, m), 2.74-3.12 (4H, m) , 3.74(2H, s), 3.87(3H, s), 4.27-4.39(1H, m), 4.89-5.01(1H, m), 6.93-7 .00 (1H, m), 7.12 (1H, dd, J=1.2, 8.0 Hz), 7.21-7.27 (1H, m), 7.33-7.49 (5H , m), 7.94 (1Н, dd, J=1.2, 5.3 Hz), 12.79 (1Н, brs) 8.15 69

^one H NMR (DMSO-d6) δ ppm: 2.14-2.27 (1H, m), 2.36-2.56 (1H, m), 2.83-3.02 (4H, m) , 3.82 (2H, s), 3.90 (3H, s), 5.02-5.13 (1H, m), 5.35 (1H, d, J=11.0 Hz), 5, 93 (1H, d, J=17.7 Hz), 6.82 (1H, dd, J=11.0, 17.7 Hz), 7.09 (1H, dd, J=5.2, 7, 8 Hz), 7.40 (1H, dd, J=1.3, 7.8 Hz), 7.49 (1H, s), 7.53-7.58 (2H, m), 7.64- 7.71 (2H, m), 8.08 (1H, dd, J=1.3, 5.2 Hz), 12.77 (1H, br) 0.50

[Table 12] Etc. No. Structure Physical Data IC _fifty (µM) 70

^one H NMR (DMSO-d6) δ ppm: 2.14-2.26 (1H, m), 2.37-2.48 (1H, m), 2.82-3.01 (4H, m) , 3.81 (2H, s), 3.90 (3H, s), 5.01-5.13 (1H, m), 7.12 (1H, dd, J=5.2, 7.8 Hz ), 7.43 (1H, dd, J=1.4, 5.2 Hz), 7.48 (1H, s), 7.50 (1H, dd, J=1.4, 7.8 Hz) , 7.75 (1H, dd, J=3.2, 5.2 Hz), 7.81 (1H, dd, J=1.4, 3.2 Hz), 8.08 (1H, dd, J =1.4, 5.2 Hz), 12.76 (1H, brs) 1.45 71

^one H NMR (DMSO-d6) δ ppm: 2.12-2.25 (1H, m), 2.31-2.44 (1H, m), 2.80-3.00 (4H, m) , 3.81 (2H, s), 3.89 (3H, s), 4.98-5.10 (3H, m), 7.03 (1H, dd, J=5.2, 7.8 Hz ), 7.23-7.37 (5H, m), 7.44 (1H, dd, J=1.4, 7.8 Hz), 7.49 (1H, s), 7.99 (1H, dd, J=1.4, 5.2 Hz), 12.77 (1Н, br) 13.9 72

^one H NMR (DMSO-d6) δ ppm: 0.69-0.78 (2H, m), 0.96-1.06 (2H, m), 1.96-2.06 (1H, m) , 2.14-2.27(1H, m), 2.36-2.49(1H, m), 2.81-3.01(4H, m), 3.81(2H, s), 3 .90 (3H, s), 5.01-5.14 (1H, m), 7.06 (1H, dd, J=5.2, 7.8 Hz), 7.23-7.28 (2H , m), 7.31 (1Н, dd, J=1.3, 7.8 Hz), 7.39-7.43 (2Н, m), 7.49 (1Н, s), 8.06 ( 1Н, dd, J=1.3, 5.2 Hz), 12.77 (1Н, br) 0.10 73

^one H NMR (DMSO-d6) δ ppm: 2.13-2.26 (1H, m), 2.37-2.48 (1H, m), 2.81-2.99 (4H, m) , 3.80(2H, s), 3.90(3H, s), 5.00-5.11(1H, m), 6.87-6.93(2H, m), 7.05(1H , dd, J=5.2, 7.8 Hz), 7.23 (1Н, dd, J=1.4, 7.8 Hz), 7.28-7.35 (2Н, m), 7, 47 (1H, s), 8.04 (1H, dd, J=1.4, 5.2 Hz), 9.82 (1H, brs), 12.77 (1H, brs) 3.00 74

^one H NMR (DMSO-d6) δ ppm: 2.15-2.29 (1H, m), 2.39-2.48 (1H, m), 2.83-2.03 (4H, m) , 3.05(3H, s), 3.82(2H, s), 3.91(3H, s), 5.03-5.15(1H, m), 7.10(1H, dd, J =5.2, 7.8 Hz), 7.30-7.36 (2H, m), 7.44 (1H, dd, J=1.3, 7.8 Hz), 7.49 (1H, s), 7.61-7.67 (2H, m), 7.70-7.76 (2H, m), 7.80-7.86 (2H, m), 8.09 (1H, dd, J=1.3, 5.2 Hz), 9.93 (1H, s), 12.78 (1H, br) 1.85 75

MS (YER_HIAD, m/z): 487 (M+H) ⁺ 99.90 76

^one H NMR (DMSO-d6) δ ppm: 1.61-1.85 (4H, m), 2.22-2.52 (2H, m), 2.84-2.99 (3H, m) , 3.04-3.12 (1H, m), 3.38-3.48 (2H, m), 3.77-3.95 (7H, m), 3.98-4.12 (1H, m), 5.30-5.43 (1H, m), 7.38-7.45 (1H, m), 7.47-7.57 (4H, m), 7.65-7.71 ( 2H, m), 7.72-7.82 (3H, m), 7.85-7.92 (2H, m), 8.28 (1H, d, J=8.3 Hz), 12.79 (1Н, shs) 9.74

[Table 13] Etc. No. Structure Physical Data IC _fifty (µM) 77

^one H NMR (DMSO-d6) δ ppm: 2.19-2.34 (1H, m), 2.38-2.51 (1H, m), 2.85-3.08 (4H, m) , 3.80-3.91 (5H, m), 4.01 (2H, d, J=5.9 Hz), 5.26-5.39 (1H, m), 7.38-7.45 (1H, m), 7.47-7.58 (4H, m), 7.66-7.72 (2H, m), 7.73-7.82 (3H, m), 7.85-7 .92 (2H, m), 8.84 (1H, t, J=5.9 Hz) 0.61 78

^one H NMR (DMSO-d6) δ ppm: 2.15-2.29 (1H, m), 2.39-2.50 (1H, m), 2.83-3.02 (4H, m) , 3.82 (2H, s), 3.91 (3H, s), 3.98 (2H, d, J=6.0 Hz), 5.03-5.16 (1H, m), 7, 13 (1H, dd, J=5.2, 7.8 Hz), 7.48 (1H, s), 7.59 (1H, dd, J=1.3, 7.8 Hz), 8.12 (1Н, dd, J=1.3, 5.2 Hz), 8.20-8.29 (2Н, m), 8.93 (1Н, dd, J=0.8, 2.3 Hz), 9.06 (1H, t, J=6.0 Hz), 12.80 (2H, br) 11.0 79

^one H NMR (CDCl3) δ ppm: 2.25-2.40 (1H, m), 2.52-2.65 (1H, m), 2.89-2.98 (1H, m), 3 .00-3.10 (3H, m), 3.71 (3H, s), 3.80-3.91 (2H, m), 5.22-5.34 (1H, m), 6.90 (1H, s), 7.01 (1H, dd, J=5.2, 7.8 Hz), 7.34 (1H, dd, J=1.4, 7.8 Hz), 7.51- 7.56(2H, m), 7.64-7.68(2H, m), 7.78-7.82(2H, m), 8.10(1H, dd, J=1.4.5 .2 Hz), 8.69-8.72 (2H, m) 32.85 80

^one H NMR (CDCl3) δ ppm: 2.29-2.41 (1H, m), 2.54-2.64 (1H, m), 2.86-2.95 (1H, m), 3 .02-3.15 (3H, m), 3.89-3.91 (5H, m), 5.23-5.37 (1H, m), 7.03 (1H, dd, J=5, 2, 7.8 Hz), 7.35 (1H, dd, J=1.4, 7.8 Hz), 7.51-7.56 (3H, m), 7.63-7.69 (2H , m), 7.78-7.83 (2Н, m), 8.10 (1Н, dd, J=1.4, 5.2 Hz), 8.68-8.74 (2Н, m) 65.88 81

^one H NMR (DMSO-d6) δ ppm: 2.16-2.28 (1H, m), 2.39-2.48 (1H, m), 2.84-3.03 (4H, m) , 3.82 (2H, s), 3.91 (3H, s), 5.04-5.15 (1H, m), 7.11 (1H, dd, J=5.2, 7.8 Hz ), 7.44-7.51(2H, m), 7.71-7.77(2H, m), 7.77-7.82(2H, m), 7.98-8.04(2H , m), 8.10 (1Н, dd, J=1.3, 5.2 Hz), 8.65-8.72 (2Н, m), 12.74 (1Н, br 0.50 82

^one H NMR (DMSO-d6) δ ppm: 2.14-2.28 (1H, m), 2.39-2.49 (1H, m), 2.81-3.00 (4H, m) , 3.73(2H, s), 3.93(3H, s), 5.03-5.15(1H, m), 6.86-6.94(2H, m), 7.09(1H , dd, J=5.2, 7.8 Hz), 7.13 (1H, s), 7.41 (1H, dd, J=1.2, 7.8 Hz), 7.53-7, 63 (4H, m), 7.72-7.79 (2H, m), 8.08 (1H, dd, J=1.2, 5.2 Hz) 0.13 83

MS (YER_HIAD, m/z): 539 (M+H) ⁺ 0.14

[Table 14] Etc. No. Structure Physical Data IC _fifty (µM) 84

MS (YER_HIAD, m/z): 555 (M+H) ^+
one H NMR (DMSO-d6) δ ppm: 2.14-2.28 (1H, m), 2.38-2.53 (1H, m), 2.82-3.03 (4H, m) , 3.81(2H, s), 3.91(3H, s), 5.04-5.16(1H, m), 7.08-7.14(2H, m), 7.21(1H , d, J=2.1 Hz), 7.46 (1H, s), 7.47-7.52 (2H, m), 7.72-7.76 (2H, m), 7.97- 8.02 (2H, m), 8.09 (1H, dd, J=1.3, 5.2 Hz), 10.30 (1H, brs), 12.90 (2H, brs) 0.15 85

^one H NMR (DMSO-d6) δ ppm: 2.15-2.30 (1H, m), 2.40-2.56 (1H, m), 2.82-3.04 (4H, m) , 3.82 (2H, s), 3.91 (3H, s), 5.05-5.17 (1H, m), 7.13 (1H, dd, J=5.2, 7.8 Hz ), 7.49 (1H, s), 7.56 (1H, dd, J=1.3, 7.8 Hz), 8.06-8.11 (2H, m), 8.12 (1H, dd, J=1.3, 5.2 Hz), 8.18 (1H, dd, J=2.6, 8.6 Hz), 8.25-8.32 (3H, m), 8.95 (1Н, dd, J=0.5, 2.6 Hz), 12.95 (2Н, br) 0.18 86

MS (YER_HIAD, m/z): 495 (M+H) ⁺ 0.27 87

MS (YER_HIAD, m/z): 419 (M+H) ⁺ 3.99 88

MS (YER_HIAD, m/z): 540 (M+H) ⁺ 0.27 89

MS (YER_HIAD, m/z): 478 (M+H) ⁺ 3.17

[Table 15] 90

MS (YER_HIAD, m/z): 463 (M+H) ⁺ 7.46 91

MS (YER_HIAD, m/z): 506 (M+H) ⁺ 0.96

Experimental Example 1 PHD2 Inhibition Test

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

Human PHD2 _184-418 containing amino acid residues 184-418 of the protein represented by CAC42509 (GenBank Access ID) was expressed and prepared by the following method.

The human PHD2 _184-418 expression construct containing an N-terminal histidine tag is introduced into the pET-30a(+) vector and the sequence verified. This vector is introduced into strain BL21 (DE3) and cultured at 37°C in LB medium containing antibiotics. After culturing, the cells are ruptured with ultrasound. The broken suspension is centrifuged and the supernatant is purified by a Ni column to give human PHD2 _184-418 .

(2) Ways

Enzyme (human PHD2 _184-418 ) and substrate are diluted with assay buffer (pH 7.4) containing 10 mM HEPES, 150 mM NaCl, 10 μM MnCl ₂ -4H ₂ O, 2 μM 2-oxoglutarate and 0.05% Tween -twenty. Test compounds are diluted with DMSO. Test compounds and human PHD2 _184-418 are added to a 384-well plate (Corning, black, opaque bottom) in advance. The reaction is started by adding FITC-labeled HIF-1α _556-574 . After incubation at 37° C. for 60 minutes, fluorescent polarization (excitation wavelength: 470 nm, fluorescence wavelength: 530 nm) was measured on a PHERAstar FSX (BMG Labtech). The fluorescent polarization of each well is measured, and the inhibition of human PHD2 binding by the test compounds is measured based on the value for the group without the test compound.

As shown in the above tables, the compounds of the present invention inhibit the binding between PHD2 and HIF-1α, and thus it is shown that the compounds of the present invention can be used as a PHD2 inhibitor.

Experimental Example 2 Therapeutic Effect in Ulcerative Colitis Model

(1) Rat model of TNBS-induced colitis

Inflammation is known to locally occur in the colon when TNBS is administered to the colon, and then the intestinal permeability increases due to impaired barrier function in the intestine, and therefore, the suppressive effect on intestinal permeability by oral administration of the test compounds is evaluated as an indicator of drug efficacy. funds.

(2) Ways

SD Rats: 8 week old male SLC rats (Japan SLC) were used. Under anesthesia with phenobarbital, 300 μl of TNBS (28 mg/ml) prepared in 50% ethanol is injected at a point 8 cm from the anus into the colon to induce inflammation. The vehicle-treated group is injected with 300 μl of 50% ethanol. Animals are fasted for 48 hours prior to administration of TNBS. Test compounds (3 mg/kg) formulated in 0.05% methylcellulose solution were administered orally once a day starting the next day and administered for a total of 3 days. After administration for 3 days, 50 mg/kg FITC is administered orally 4 hours after administration. Blood samples are taken from the jugular vein under isoflurane anesthesia after 4 hours. The serum is centrifuged and the fluorescence intensity is determined on a PHERAstar FSX (BMG Labtech) to measure the concentration of FITC that has entered the bloodstream through the mesentery. The degree of intestinal permeability suppression by the test compounds is calculated based on the value for the no test compound group of 0 and the value of the TNBS untreated group of 100.

(3) Results

The degree of inhibition (%, mean) of intestinal permeability of each tested compound (inhibition) is shown below.

[Table 16] Etc. No. Inhibition (%) Etc. No. 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

Intestinal permeability of FITC, which was increased due to administration of TNBS, is suppressed by administration of the compound of the present invention, and thus the compounds of the present invention are shown to be useful as agents for the treatment of inflammatory bowel diseases.

Experimental Example 3 Concentration of Compounds in Colonic Tissue

(1) PK study in rats

Test compounds (3 mg/kg/5 ml) formulated in 0.05% methylcellulose were orally administered to non-starved rats (SD, 8 week old male, Japan SLC). Blood samples are collected from the jugular vein at 0.25, 0.5, 1, 2, 4, 6 and 8 hours after administration. Laparotomy is performed under isoflurane anesthesia and the colon is removed. The collected distal colon (about 5 cm) is cut, and then the colon is washed with saline on a dish. After washing, the large intestine is crushed with small scissors. About 150 mg of this substance is transferred into a test tube. 100 µl of saline is added to the tube, the mixture is homogenized using a Shake Master (1000 rpm x 30 minutes). Samples are prepared by adding four times the volume of saline as the final volume. Colon tissue and plasma concentrations of test compound are determined by quantitative analysis using liquid chromatography-mass spectrometry (LC/MS).

[Table 17] Etc. No. Cmax PPK Plasma Colon C/R 39 7 2090 3 214 71 40 <1 HP <1 209 >209 43 eight 2111 2 84 42 45 2 401 <1 87 >87 46 3 314 <1 174 >174 47 60 20011 eighteen 317 eighteen 49 four 898 <1 201 >201 83 5 1292 <1 54 >54 84 one 76 <1 99 >99 85 one 117 <1 164 >164

The symbols in the table have the following meanings.

Cmax: maximum plasma concentration of tested compounds when administered orally (ng/ml)

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

Plasma: Plasma test compound concentration at 8 hours (ng/mL)

Colon: test compound concentration in colon tissue at 8 hours (ng/g)

C/P: ratio of the above colon/plasma

PR: not calculated (below the lower calculation limit)

INDUSTRIAL APPLICABILITY

The compounds of the present invention, or pharmaceutically acceptable salts thereof, are useful as agents for the treatment of inflammatory bowel diseases.

Claims (100)

1. The compound represented by formula (I): [Chem.1]

where ring W is C _6-10 aryl, 5- or 6-membered heteroaryl containing 1-4 heteroatoms selected from nitrogen and sulfur, 10-membered heteroaryl containing 1-4 nitrogen atoms, or cyclohexyl; ring Z is a group selected from the group consisting of the following (a)-(c): [Chem.2]

and [Chem.3]

where R ^a , R ^b and R ^c are each independently hydrogen, halogen, C _1-6 alkyl, cyano, hydroxy or carboxy; and R ^d is a hydrogen atom or C _1-6 alkyl; R ¹ is a hydrogen atom, a halogen atom, C _1-6 alkyl; R ² is hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ or -CONR ⁵ R ^5' ; R ⁴ is a hydrogen atom; and R ⁵ and R ^5' are each independently hydrogen, C _1-6 alkyl, carboxy C _1-6 alkyl, or 6-membered heterocycloalkyl containing 1 or 2 oxygen atoms; R ³ is hydrogen atom, halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, C _2-6 alkenyl, C _1-6 alkylsulfanyl, C _{1- 6} alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' or the following group A, where if u is 2, two R ³ can to differ from each other; R ⁶ and R ^6' are each independently C _1-6 alkyl; R ⁷ is a hydrogen atom or C _1-6 alkyl; R ⁸ and R ^8' are each independently hydrogen, carboxy C _1-6 alkyl; group A is a group selected from the group consisting of the following (a)-(f): (a) phenyl which is unsubstituted or substituted with 1 or 2 groups selected from substituent group B, (b) a 6-membered heteroaryl containing 1-4 nitrogen atoms, which is unsubstituted or substituted with 1 or 2 groups selected from substituent group B, (c) C _6-10 aryl C _1-6 alkyl which is unsubstituted or substituted with 1 or 2 groups selected from substituent group B, (d) phenoxy which is unsubstituted or substituted with 1 or 2 groups selected from substituent group B, (e) cyclopropyl which is unsubstituted or substituted with 1 or 2 groups selected from substituent group B, and (f) a 6-membered heterocycloalkyl containing 1-2 heteroatoms selected from an oxygen atom, a nitrogen atom, which is unsubstituted or substituted by 1 or 2 groups selected from substituent group B, where substituent group B is a group consisting of a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano, -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ and -CONR ¹¹ R ^11' ; where R ⁹ represents a hydrogen atom; R ¹⁰ is a hydrogen atom or C _1-6 alkyl; and R ¹¹ and R ^11' are each independently hydrogen, C _1-6 alkyl; m and u are each independently 1 or 2; n is 1; p and q are each independently 1 or 2; and r is 0 or 1; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, where the ring Z is a group selected from the group consisting of the following (a)-(j): [Chem.4]

and [Chem.5]

or a pharmaceutically acceptable salt thereof. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein ring W is phenyl or a 5- or 6-membered heteroaryl containing 1-4 heteroatoms, selected nitrogen atoms and sulfur atoms. 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. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a halogen atom. 7. Connection according to claim 6, where R ² is hydrogen, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, carboxy, or —CONR ⁵ R ^5' ; where R ⁵ and R ^5' each independently is a hydrogen atom, carboxy C _1-6 alkyl or 6-membered heterocycloalkyl containing 1 or 2 oxygen atoms; or a pharmaceutically acceptable salt thereof. 8. Connection according to claim 7, where R ³ is hydrogen atom, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, cyano, -CO ₂ R ⁷ , -CONR ⁸ R ^{8 '} or group A; where R ⁷ and u have the same meanings as described in paragraph 1; R ⁸ and R ^8' are each independently hydrogen or carboxy C _1-6 alkyl; and group A is phenyl which is unsubstituted or substituted by 1 or 2 groups selected from substituent group B or unsubstituted 5- or 6-membered heteroaryl containing 1-4 nitrogen atoms; where substituent group B is a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, cyano or carboxy; or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 8, where the ring Z is a group selected from the group consisting of the following (a)-(e): [Chem.6]

and [Chem.7]

or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9, represented by the following formula: [Chem.8]

where X is CR ³ or N; u is 1 or 2; R ¹ has the same meanings as described in clause 6; R ² has the same meanings as described in paragraph 7; R ³ is a hydrogen atom, C _1-6 alkyl or hydroxy; group A has the same meanings as described in clause 8; ring Z has the same meaning as described in clause 9; and m and n have the same meanings as described in clause 1; or a pharmaceutically acceptable salt thereof. 11. Connection according to claim 1, where u is 2; one R ³ is group A; and the other R ³ is hydrogen, halogen, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ or -CONR ⁸ R ^8' ; where the group A, R ⁶ , R ^6' , R ⁷ , R ⁸ and R ^8' has the same meanings as described in paragraph 1; or a pharmaceutically acceptable salt thereof. 12. A compound selected from the group consisting of the following compounds: [Chem.9]

and [Chem.10]

or a pharmaceutically acceptable salt thereof. 13. A compound represented by the following formula: [Chem.11]

or a pharmaceutically acceptable salt thereof. 14. Pharmaceutical composition having an inhibitory effect on PHD2, containing a compound according to any one of paragraphs. 1-13 in an amount providing a daily dose, or a pharmaceutically acceptable salt thereof and a pharmaceutical additive. 15. The pharmaceutical composition of claim 14, which is a pharmaceutical composition for use in the treatment of inflammatory bowel disease. 16. The pharmaceutical composition according to claim 15, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.