JP7414550B2 - (Hetero)arylimidazolone compounds - Google Patents

Description

The present invention relates to (hetero)arylimidazolone compounds useful as pharmaceuticals. More specifically, the present invention relates to a (hetero)arylimidazolone compound having a prolyl hydroxylase inhibitory effect and useful as a therapeutic agent for inflammatory bowel diseases such as ulcerative colitis, or a pharmacologically acceptable compound thereof. Regarding salt.

Inflammatory bowel disease (IBD) is a chronic disease in which inflammation and ulceration occur in the intestinal mucosa due to immune overresponse. IBD includes, for example, ulcerative colitis and Crohn's disease.
Ulcerative colitis is a disease of the large intestine that causes diffuse nonspecific inflammation of unknown origin. The mucous membrane of the large intestine may be affected, resulting in the formation of mucosal erosions or ulcers. Ulcerative colitis can be divided into an ``active phase'' in which bloody stool, erosion, ulcers, etc. are observed, and a ``remission phase'' in which the findings of the active phase disappear. Since relapse and remission often occur repeatedly during the course of the disease, long-term treatment is required.
5-aminosalicylic acid (5-ASA) is the standard drug used to treat ulcerative colitis. However, the efficacy of 5-ASA is about 50-65%, and only about 30-45% of patients achieve remission after administration of 5-ASA. If 5-ASA is not effective, steroids are used. In addition to these drugs, immunosuppressants, anti-TNFα antibodies, etc. are sometimes used to treat ulcerative colitis. However, all drugs have problems such as side effects and the need for careful administration, and there is a need for therapeutic agents for ulcerative colitis that have a new mechanism of action.

In the pathology of IBD, hypoxia-inducible factor 1α (HIF-1α) is known to induce the expression of genes related to the barrier function of the gastrointestinal epithelium. HIF-1α is a subtype of hypoxia-inducible factor α (HIF-α). HIF-α is stabilized in hypoxic environments (Hypoxia) and activates transcription of various genes in response to hypoxia. On the other hand, in an oxygen-rich environment (Normoxia), the proline residue of HIF-α is hydroxylated by prolyl hydroxylases (PHDs), and HIF-α undergoes proteasomal degradation.

Three subtypes of PHDs are known: PHD1, PHD2, and PHD3. AKB-4924 is known as a PHD2 inhibitor, and it has been reported that AKB-4924 stabilizes HIF-1α in colon tissue (Non-Patent Document 1). Furthermore, AKB-4924 has been shown to have an ameliorating effect in a trinitrobenzenesulfonic acid (TNBS)-induced colitis model.

On the other hand, PHDs inhibitors, such as Roxadustat and Daprodustat, have hematopoietic effects and have also been developed as anemia therapeutics (Non-Patent Document 2).

As PHDs inhibitors, for example, spiro compounds are described in Patent Documents 1 and 2 and Non-Patent Documents 3 and 4. Furthermore, compounds containing heteroarylimidazolones are described or exemplified in Patent Document 3, and compounds containing arylimidazolones are described or exemplified in Patent Document 4, respectively. However, the above literature does not describe the (hetero)arylimidazolone compound of the present invention.

US Patent Application Publication No. 2011/0152304 US Patent Application Publication No. 2010/0137297 US Patent Application Publication No. 2019/0202830 International Publication No. 2005/035498

Ellen Marks et al., "Inflamm. Bowel. Dis.", 2015, Volume 21, No. 2, p. 267-275 Mun Chiang Chan et al., “Molecular Aspects of Medicine”, 2016, vol. 47-48, p.54-75 Guanghui Deng et al., “Bioorganic & Medicinal Chemistry”, 2013, Volume 21, p.6349-6358 Petr Vachal et al., Journal of Medicinal Chemistry, 2012, Volume 55, p.2945-2959

An object of the present invention is to provide a novel compound that has a PHD2 inhibitory effect and is useful for treating inflammatory bowel diseases.

〔式中、
m及びuは、それぞれ独立して、0から3の整数であり；
p及びqは、それぞれ独立して、1又は2であり；
rは、0から6の整数であり；
R¹は、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり（mが2又は3である場合、2以上のR¹は互いに異なっていてもよい）;
E、G、Q及びTは、以下の(1)～(7)からなる群から選択される基：
(1) EはCR^2e、QはCR^2q、TはCR^2t、GはN、
(2) EはCR^2e、GはCR^2g、TはCR^2t、QはN、
(3) EはCR^2e、GはCR^2g、QはCR^2q、TはN、
(4) EはCR^2e、QはCR^2q、G及びTはN、
(5) GはCR^2g、TはCR^2t、E及びQはN、
(6) GはCR^2g、QはCR^2q、E及びTはN、及び、
(7) EはCR^2e、GはCR^2g、QはCR^2q、TはCR^2t;
R^2e、R^2g、R^2q及びR^2tは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、－CO₂R⁴、又は－CONR⁵R^5’であり；
R⁴は、水素原子、又はC_1-6アルキルであり；
R⁵及びR^5’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
環Wは、C_6-10アリール、5又は6員環ヘテロアリール、9又は10員環ヘテロアリール、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
環Zは、以下の(a)～(c)からなる群から選択される基：

及び

(式中、
R^a、R^b及びR^cは、それぞれ独立して、水素原子、ハロゲン原子、C_1-6アルキル、シアノ、ヒドロキシ、又はカルボキシであり；
R^dは、水素原子、又はC_1-6アルキルである）；
R³は、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、ヒドロキシ、シアノ、ニトロ、－NR⁶R^6’、－CO₂R⁷、－CONR⁸R^8’、又は基Aであり（uが2又は3である場合、2以上のR³は互いに異なっていてもよい）；
R⁶及びR^6’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R⁷は、水素原子、又はC_1-6アルキルであり；
R⁸及びR^8’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルであり；
基Aは、以下の(a)～(h)からなる群から選択される基：
(a)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリール、
(b)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリール、
(c)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールC_1-6アルキル、
(d)非置換又は置換基群Bから選択される1から3個の基で置換されたC_6-10アリールオキシ、
(e)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールC_1-6アルキル、
(f)非置換又は置換基群Bから選択される1から3個の基で置換された5又は6員環ヘテロアリールオキシ、
(g)非置換又は置換基群Bから選択される1から3個の基で置換されたC_3-8シクロアルキル、及び
(h)非置換又は置換基群Bから選択される1から3個の基で置換された3～8員環ヘテロシクロアルキル；
置換基群Bは、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、シアノ、－NR⁹R^9’、－NR⁹SO₂R¹⁰、－CO₂R¹⁰、及び－CONR¹¹R^11’からなる群であり；
R⁹及びR^9’は、それぞれ独立して、水素原子、又はC_1-6アルキルであり；
R¹⁰は、水素原子、又はC_1-6アルキルであり；及び
R¹¹及びR^11’は、それぞれ独立して、水素原子、C_1-6アルキル、カルボキシC_1-6アルキル、ヒドロキシC_1-6アルキル、ハロC_1-6アルキル、C_3-8シクロアルキル、又は3～8員環ヘテロシクロアルキルである〕
で表される化合物又はその薬理学的に許容される塩。
〔2〕前記〔1〕に記載の化合物であって、以下の式：

〔式中、
uは、0から2の整数であり；
R^3’は、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、C_2-6アルケニル、C_2-6アルキニル、C_1-6アルキルスルファニル、C_1-6アルキルスルフィニル、C_1-6アルキルスルホニル、ヒドロキシ、シアノ、ニトロ、－NR⁶R^6’、－CO₂R⁷、又は－CONR⁸R^8’であり；
m、p、q、R¹、E、G、Q、T、環W、環Z、R⁶、R^6’、R⁷、R⁸、R^8’及び基Aは前記〔1〕と同じ意味である〕
で表される化合物又はその薬理学的に許容される塩。
〔3〕環Zが、以下の(A)～(J)からなる群から選択される基：

及び

である前記〔1〕又は〔2〕に記載の化合物又はその薬理学的に許容される塩。
〔4〕環Wが、フェニル、又は5又は6員環ヘテロアリールである前記〔1〕～〔3〕の何れかに記載の化合物又はその薬理学的に許容される塩。
〔5〕pが2であって、かつqが1である前記〔1〕～〔4〕の何れかに記載の化合物又はその薬理学的に許容される塩。
〔6〕mが0である前記〔1〕～〔5〕の何れかに記載の化合物又はその薬理学的に許容される塩。
〔7〕R^2e、R^2g、R^2q及びR^2tが、それぞれ独立して、水素原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、カルボキシ、又は－CONR⁵R^5’であり；
R⁵及びR^5’が、それぞれ独立して、水素原子、カルボキシC_1-6アルキル、又は3～8員環ヘテロシクロアルキルである前記〔1〕～〔6〕の何れかに記載の化合物又はその薬理学的に許容される塩。
〔8〕基Aが、非置換若しくは置換基群Bから選択される1から3個の基で置換されたフェニルであり；
置換基群Bが、ハロゲン原子、C_1-6アルキル、ハロC_1-6アルキル、C_1-6アルコキシ、ハロC_1-6アルコキシ、ヒドロキシ、シアノ、又はカルボキシである前記〔1〕～〔7〕の何れかに記載の化合物又はその薬理学的に許容される塩。
〔9〕環Zが、以下の(A)、(C)、(D)、(I)及び(J)からなる群から選択される基：

及び

である前記〔1〕～〔8〕の何れかに記載の化合物又はその薬理学的に許容される塩。
〔10〕前記〔1〕～〔9〕の何れかに記載の化合物であって、以下の式：

〔式中、
E、G、Q及びTは、以下の(1)～(7)からなる群から選択される基：
(1) E、Q、TはCH、GはN、
(2) E、G、TはCH、QはN、
(3) E、G、QはCH、TはN、
(4) E、QはCH、G、TはN、
(5) G、TはCH、E、QはN、
(6) G、QはCH、E、TはN、及び、
(7) E、G、T、QはCH;
Xは、CH、CR³、又はNであり；
R³は、C_1-6アルキル、又はヒドロキシであり；
基Aは、前記〔8〕と同じ意味であり；
環Zは、前記〔9〕と同じ意味である〕
で表される化合物又はその薬理学的に許容される塩。
〔11〕以下の化合物からなる群：

及び

から選択される化合物又はその薬理学的に許容される塩。
〔12〕前記〔1〕～〔11〕の何れかに記載の化合物又はその薬理学的に許容される塩、及び医薬品添加物を含む医薬組成物。
〔13〕炎症性腸疾患の治療用医薬組成物である、前記〔12〕に記載の医薬組成物。
〔14〕前記〔13〕に記載の医薬組成物であって、炎症性腸疾患が潰瘍性大腸炎又はクローン病である医薬組成物。 The present invention relates to a compound represented by the following formula (I) or a pharmacologically acceptable salt thereof. That is, the present invention relates to the following [1] to [14].
[1] Formula (I):

[During the ceremony,
m and u are each independently an integer from 0 to 3;
p and q are each independently 1 or 2;
r is an integer from 0 to 6;
R ¹ is a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
E, G, Q and T are groups selected from the group consisting of the following (1) to (7):
(1) E is CR ^2e , Q is CR ^2q , T is CR ^2t , G is N,
(2) E is CR ^2e , G is CR ^2g , T is CR ^2t , Q is N,
(3) E is CR ^2e , G is CR ^2g , Q is CR ^2q , T is N,
(4) E is CR ^2e , Q is CR ^2q , G and T are N,
(5) G is CR ^2g , T is CR ^2t , E and Q are N,
(6) G is CR ^2g , Q is CR ^2q , E and T are N, and
(7) E is CR ^2e , G is CR ^2g , Q is CR ^2q , T is CR ^2t ;
R ^2e , R ^2g , R ^2q and R ^2t are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' ;
R ⁴ is a hydrogen atom or C _1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

as well as

(In the formula,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or C _1-6 alkyl);
R ³ is a 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 alkyl sulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or group A (where u is 2 or 3, 2 or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
Group A is a group selected from the group consisting of (a) to (h) below:
(a) C _6-10 aryl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(b) 5- or 6-membered heteroaryl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(c) C _6-10 arylC _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(f) 5- or 6-membered heteroaryloxy unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(g) C _3-8 cycloalkyl, unsubstituted or substituted with 1 to 3 groups selected from substituent group B, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
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, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9' are each independently 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 a hydrogen atom, 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- to 8-membered heterocycloalkyl]
A compound represented by or a pharmacologically acceptable salt thereof.
[2] The compound described in [1] above, which has the following formula:

[During the ceremony,
u is an integer from 0 to 2;
R ^3' is 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 , or -CONR ⁸ R ^8' ;
m, p, q, R ¹ , E, G, Q, T, ring W, ring Z, R ⁶ , R ^6' , R ⁷ , R ⁸ , R ^8' and group A have the same meanings as in [1] above. ]
A compound represented by or a pharmacologically acceptable salt thereof.
[3] A group in which ring Z is selected from the group consisting of the following (A) to (J):

as well as

The compound according to [1] or [2] above, or a pharmacologically acceptable salt thereof.
[4] The compound according to any one of [1] to [3] above, or a pharmacologically acceptable salt thereof, wherein ring W is phenyl or a 5- or 6-membered heteroaryl.
[5] The compound according to any one of [1] to [4] above, wherein p is 2 and q is 1, or a pharmacologically acceptable salt thereof.
[6] The compound according to any one of [1] to [5] above, where m is 0, or a pharmacologically acceptable salt thereof.
[7] R ^2e , R ^2g , R ^2q and R ^2t are each independently a hydrogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, carboxy, or -CONR ⁵ R ^5' ;
The compound according to any one of [1] to [6] above, wherein R ⁵ and R ^5' are each independently a hydrogen atom, carboxyC _1-6 alkyl, or 3- to 8-membered heterocycloalkyl; or its pharmacologically acceptable salts;
[8] Group A is phenyl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
[1] to [7] above, wherein 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 pharmacologically acceptable salt thereof.
[9] A group in which ring Z is selected from the group consisting of the following (A), (C), (D), (I) and (J):

as well as

The compound according to any one of [1] to [8] above, or a pharmacologically acceptable salt thereof.
[10] A compound according to any one of [1] to [9] above, which has the following formula:

[During the ceremony,
E, G, Q and T are groups selected from the group consisting of the following (1) to (7):
(1) E, Q, T are CH, G is N,
(2) E, G, T are CH, Q is N,
(3) E, G, Q are CH, T is N,
(4) E, Q are CH, G, T are N,
(5) G, T are CH, E, Q are N,
(6) G, Q are CH, E, T are N, and
(7) E, G, T, Q are CH;
X is CH, CR ³ or N;
R ³ is C _1-6 alkyl or hydroxy;
Group A has the same meaning as in [8] above;
Ring Z has the same meaning as [9] above]
A compound represented by or a pharmacologically acceptable salt thereof.
[11] Group consisting of the following compounds:

as well as

or a pharmacologically acceptable salt thereof.
[12] A pharmaceutical composition comprising the compound according to any one of [1] to [11] above or a pharmacologically acceptable salt thereof, and a pharmaceutical additive.
[13] The pharmaceutical composition according to [12] above, which is a pharmaceutical composition for treating inflammatory bowel disease.
[14] The pharmaceutical composition according to [13] above, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.

The compound of the present invention has an excellent PHD2 inhibitory effect. Therefore, the compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for inflammatory bowel disease.

Embodiments of the present invention will be described in more detail below.

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

"Halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom. The halogen atoms for R ¹ , R ^2e , R ^2g , R ^2q , R ^2t and R ³ are preferably fluorine atoms.
"C _1-6 alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the like.
"C _2-6 alkenyl" means a straight or branched alkenyl group having 2 to 6 carbon atoms. Examples include vinyl, allyl, 1-propenyl, isopropenyl, and the like.
"C _2-6 alkynyl" means a linear or branched alkynyl group having 2 to 6 carbon atoms. Examples include ethynyl, 2-propynyl, and the like.
"C _1-6 alkoxy" means a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy, ethoxy, propoxy, isopropoxy and the like.

"CarboxyC _1-6 alkyl" means C _1-6 alkyl substituted with one carboxy. For example, carboxymethyl and the like can be mentioned.
"Hydroxy C _1-6 alkyl" means C _1-6 alkyl substituted with one hydroxyl group. Examples include hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1,1-dimethylmethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, and the like.
"HaloC _1-6 alkyl" means C _1-6 alkyl substituted with 1 to 3 of the same or different halogen atoms. Examples include monofluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, etc. It will be done.
"Halo C _1-6 alkoxy" means C _1-6 alkoxy substituted with 1 to 3 of the same or different halogen atoms. Examples include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, and the like.

"C _1-6 alkylsulfanyl" means a group represented by (C _1-6 alkyl)-S-.
"C _1-6 alkylsulfinyl" means a group represented by (C _1-6 alkyl)-S(=O)-.
"C _1-6 alkylsulfonyl" means a group represented by (C _1-6 alkyl)-SO ₂ -. Examples include methylsulfonyl, ethylsulfonyl, and the like.

"C _6-10 aryl" means phenyl or naphthyl. As group A, phenyl is preferred.
"5- or 6-membered heteroaryl" means a 5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. . For example, furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, Examples include pyridazinyl. As ring W, thienyl, pyridyl, etc. are preferable, and pyridyl is more preferable. As the group A, pyridyl and the like are preferred.
"9- or 10-membered heteroaryl" means a bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. Examples include indolyl, isoindolyl, benzofuryl, benzothiophenyl, benzimidazolyl, prill, benzotriazolyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, cinnolyl, pteridinyl, chromenyl, isochromenyl, and the like. As ring W, quinolyl and the like are preferable.
"C _3-8 cycloalkyl" means a 3- to 8-membered saturated hydrocarbon group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
"3- to 8-membered heterocycloalkyl" means a 3- to 8-membered heterocycloalkyl group containing 1 or 2 heteroatoms selected from oxygen, nitrogen, and sulfur atoms in the ring. . Examples include aziridino, azetidino, morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. As R ⁵ and R ⁵ ', tetrahydropyranyl and the like are preferred.

"C _6-10 arylC _1-6 alkyl" means C _1-6 alkyl substituted with one C _6-10 aryl. An example is benzyl.
"C _6-10 aryloxy" means a group represented by (C _6-10 aryl)-O-. For example, phenoxy can be mentioned.
"5- or 6-membered heteroaryl C _1-6 alkyl" means C _1-6 alkyl substituted with one 5- or 6-membered heteroaryl.
"5- or 6-membered heteroaryloxy" means a group represented by (5- or 6-membered heteroaryl)-O-.

C _6-10 aryl, 5- or 6-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is substituted with 2 or 3 groups selected from substituent group B. In this case, each group may be the same or different.

When a group containing C _6-10 aryl, 5- or 6-membered heteroaryl, C _3-8 cycloalkyl, or 3- to 8-membered heterocycloalkyl is substituted with a group selected from substituent group B. , its C _6-10 aryl moiety, 5- or 6-membered heteroaryl moiety, C _3-8 cycloalkyl moiety, or 3-8 membered heterocycloalkyl moiety is substituted.

The following abbreviations in the text, figures, and tables have the following meanings.
CDI: Carbonyldiimidazole
CPME: Cyclopentyl methyl ether
DEAD: Diethyl azodicarboxylate
DIPEA: N,N-diisopropylethylamine
DMA: N,N-dimethylacetamide
DMAP: 4-dimethylaminopyridine
DMF: N,N-dimethylformamide
DMSO: dimethyl sulfoxide
DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride
EDC・HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HOBt: 1-hydroxybenzotriazole
LAH: Lithium aluminum hydride
LDA: 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)
Pd(PPh ₃ ) ₄ : Tetrakis(triphenylphosphine)palladium(0)
Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium(0)
THF: Tetrahydrofuran
TsCl: p-toluenesulfonyl chloride
T3P (registered trademark): Propylphosphonic anhydride (cyclic trimer)
Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
9-BBN: 9-borabicyclo[3.3.1]nonamino silica gel: Aminopropylated silica gel
ODS column chromatography: octadecylsilylated silica gel column chromatography
Process：Process
Scheme: Scheme
Ref.No.：Reference example number
Ex.No.: Example number
Structure: Structural formula
Physical data：Physical property value
IC ₅₀ : 50% inhibitory concentration
FITC: Fluorosein isothiocyanate
¹ H-NMR: Hydrogen nuclear magnetic resonance spectrum
DMSO-d6: dimethyl sulfoxide-d6
CDCl ₃ : Chloroform-d1
MS: Mass spectrometry
ESI_APCI: Electrospray ionization method - atmospheric pressure chemical ionization method multi-ionization method

One embodiment of the compound represented by formula (I) includes, for example, a compound represented by the following formula. In the formula, u and R ^3' have the same meanings as in [2] above. Other symbols have the same meaning as [1] above.

式中の記号は、上記〔1〕と同じ意味である。

及び

One embodiment of the compound represented by formula (I) includes a compound in which the group represented by the following formula is a group selected from the group consisting of (a) to (d) below.

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

as well as

及び

式中、R^a、R^b及びR^cは、それぞれ独立して、水素原子、ハロゲン原子、メチル、シアノ、ヒドロキシ、又はカルボキシであり、R^dは、水素原子、又はメチルである。
〔H〕R³は、ハロゲン原子、メチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、ビニル、メチルチオ、エチルスルホニル、ヒドロキシ、シアノ、ニトロ、ジメチルアミノ、－CO₂R⁷、－CONR⁸R^8’、又は基Aであり（uが2である場合、2つのR³は互いに異なっていてもよい）；
R⁷は、水素原子、又はメチルであり；
R⁸及びR^8’は、それぞれ独立して、水素原子、又はカルボキシメチルであり；
基Aは、以下の(a)～(f)からなる群から選択される基：
(a)非置換又は置換基群Bから選択される1から2個の基で置換されたフェニル、
(b)ピリジル、
(c)ベンジル、
(d)フェニルオキシ、
(e)シクロプロピル、及び
(f)モルホリノ；
置換基群Bは、ハロゲン原子、メチル、トリフルオロメチル、メトキシ、トリフルオロメトキシ、ヒドロキシ、シアノ、－NHSO₂R¹⁰及び－CO₂R^10’からなる群：
R¹⁰及びR^10’は、それぞれ独立して、水素原子、又はメチルである。 One embodiment of the compound represented by formula (I) is the compound described in [1] above, in which a group selected from the group consisting of [A] to [H] below or a combination thereof preferable.
[A]m and u are each independently an integer from 0 to 3.
[B] p and q are each independently 1 or 2.
[C]r is 0 or 1.
[D]R ¹ is a halogen atom or methyl.
[E] E, G, Q and T are atoms selected from the group consisting of the following (1) to (7):
(1) E is CR ^2e , Q is CR ^2q , T is CR ^2t , G is N,
(2) E is CR ^2e , G is CR ^2g , T is CR ^2t , Q is N,
(3) E is CR ^2e , G is CR ^2g , Q is CR ^2q , T is N,
(4) E is CR ^2e , Q is CR ^2q , G and T are N,
(5) G is CR ^2g , T is CR ^2t , E and Q are N,
(6) G is CR ^2g , Q is CR ^2q , E and T are N, and
(7) E is CR ^2e , G is CR ^2g , Q is CR ^2q , T is CR ^2t ;
R ^2e , R ^2g , R ^2q and R ^2t are hydrogen atoms, methyl, trifluoromethyl, methoxy, trifluoromethoxy, -CO ₂ H, or -CONR ⁵ R ^5' ;
R ⁵ and R ^5' are each independently a hydrogen atom, carboxymethyl, or tetrahydropyranyl.
[F] Ring W is phenyl, naphthyl, thienyl, pyridyl, quinolyl, or cyclohexyl.
[G] Ring Z is a group selected from the group consisting of the following (a) to (c):

as well as

In the formula, R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, methyl, cyano, hydroxy, or carboxy, and R ^d is a hydrogen atom or methyl.
[H]R ³ is a halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, vinyl, methylthio, ethylsulfonyl, hydroxy, cyano, nitro, dimethylamino, -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or a group A (when u is 2, the two R ³ may be different from each other);
R ⁷ is a hydrogen atom or methyl;
R ⁸ and R ^8' are each independently a hydrogen atom or carboxymethyl;
Group A is a group selected from the group consisting of (a) to (f) below:
(a) phenyl unsubstituted or substituted with 1 to 2 groups selected from substituent group B;
(b) pyridyl,
(c) benzyl,
(d) phenyloxy,
(e) cyclopropyl, and
(f) Morpholino;
Substituent group B is a group consisting of halogen atom, methyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, cyano, -NHSO ₂ R ¹⁰ and -CO ₂ R ^10' :
R ¹⁰ and R ^10' are each independently a hydrogen atom or methyl.

式中、環Vは以下の(a)～(d)からなる群から選択される基であり、u及びR^3'は、上記〔2〕と同じ意味である。それ以外の記号は、上記〔1〕と同じ意味である。

及び

One embodiment includes, for example, a compound represented by the following formula (II).

In the formula, ring V is a group selected from the group consisting of (a) to (d) below, and u and R ^3' have the same meanings as in [2] above. Other symbols have the same meaning as [1] above.

as well as

及び

One embodiment of the compound represented by formula (II) includes the following compound.

as well as

When one or more asymmetric carbon atoms are present in the compound represented by formula (I), the present invention provides compounds in which each asymmetric carbon atom has the R configuration, S configuration, and any of them. Also includes compounds in combination. Racemic compounds, racemic mixtures, single enantiomers, and diastereomeric mixtures thereof are also included within the scope of the present invention.

When a cis-trans isomer exists in the compound represented by formula (I), the present invention includes any of the cis-trans isomers.

When a tautomer exists in the compound represented by formula (I), the present invention includes any of the tautomers.

In the present invention, stereochemistry can also be determined by methods well known in the art.

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

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

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

When the compound represented by formula (I) or a pharmacologically acceptable salt thereof exists, for example, as a crystal, the present invention includes any crystal form. For example, pharmacologically acceptable salts include solvates with pharmaceutically acceptable solvents such as water or ethanol, cocrystals with appropriate co-crystal formers, and the like.

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

A compound represented by formula (I) in which some atoms are replaced with an isotope can be produced by a method similar to the production method described below using a commercially available building block into which an isotope has been introduced. Can be done. For example, a compound in which some of the hydrogen atoms of the compound represented by formula (I) are replaced with deuterium atoms can be prepared by the above method and the method described in the literature (for example, Journal of the Society of Organic Synthetic Chemistry, Vol. 65, No. 12). , pp. 1179-1190, 2007). For example, a compound in which some of the carbon atoms of the compound represented by formula (I) are replaced with ^13C can be prepared by the above method and the method described in literature (for example, RADIOISOTOPES, Vol. 56, No. 11, 35- (see page 44, 2007).

The compound represented by formula (I) can be produced, for example, according to the method shown in Scheme 1 or a method analogous thereto, or a method described in a literature or a method analogous thereto.

In the reaction of each step, if raw materials and reagents are commercially available, commercially available products can be used. In the reaction of each step, the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but unless otherwise specified, it is usually 30 minutes to 3 days.
In the reaction of each step, the reaction temperature varies depending on the raw material and solvent used, but unless otherwise specified, it is usually from -78°C to the reflux temperature.
In the reaction of each step, the pressure varies depending on the raw material used, the solvent, the reaction temperature, etc., but unless otherwise specified, it is usually 1 atm to 20 atm.
In each step of the reaction, a microwave reaction device such as Initiator manufactured by Biotage can also be used. When performing a reaction using a microwave reactor, pressure range: 1 to 30 bar, output range: 1 to 400 W, reaction temperature: room temperature to 300°C, reaction time, although it varies depending on the raw materials, solvent, and model used. :The reaction can be carried out for 1 minute to 1 day.

In the reactions of each step, unless otherwise specified, these reactions are carried out without a solvent or using an appropriate solvent. Examples of suitable solvents include solvents that are inert to the reaction. Specific examples of the solvent include the solvents described in the Reference Examples or Examples corresponding to each step, or the following solvents.

Alcohols: methanol, ethanol, tert-butyl alcohol, 2-propanol, etc.;
Ethers: diethyl ether, THF, 1,2-dimethoxyethane, 1,4-dioxane, 2-methyloxolane, CPME, etc.;
Aromatic hydrocarbons: chlorobenzene, 1,2-dichlorobenzene, toluene, xylene, etc.;
Saturated hydrocarbons: cyclohexane, n-hexane, etc.;
Amides: DMF, DMA, NMP, etc.;
Halogenated hydrocarbons: dichloromethane, 1,2-dichloroethane, carbon tetrachloride, etc.;
Nitriles: acetonitrile, etc.;
Sulfoxides: DMSO, etc.;
Aromatic organic bases: pyridine, etc.;
Acid anhydrides: acetic anhydride, etc.;
Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.;
Esters: ethyl acetate, methyl acetate, isopropyl acetate, etc.;
Ketones: acetone, methyl ethyl ketone, etc.;
water.
Two or more of the above solvents may be used as a mixture in an appropriate ratio.

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

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

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

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

In each step, if a protective group is required depending on the type of functional group, introduction and removal operations can be appropriately combined in accordance with conventional methods. Regarding the types of protecting groups, protection, and deprotection, for example, the method described in "Greene's Protective Groups in Organic Synthesis", edited by Theodora W. Greene & Peter G. M. Wuts, fourth edition, Wiley-Interscience, 2006. can be mentioned.

When removing a protecting group in each step, these reactions can be performed using a hydrolysis reaction or the like.

When performing a hydrolysis reaction in each step, these reactions can be performed in the presence of an acid or a base. The acids and bases include the above-mentioned examples.

When performing a catalytic reduction reaction in each step, these reactions can be performed in a hydrogen atmosphere and in the presence of a catalyst. Examples of the catalyst include palladium carbon powder, platinum carbon powder, and Raney nickel.

In each step, when a reduction reaction is performed, these reactions can be performed in the presence of a reducing agent. Examples of the reducing agent include those mentioned above.

When performing an amidation reaction in each step, these reactions can be performed in the presence of a condensing agent and a base, or in the presence of a condensing agent. Examples of the condensing agent and base include those mentioned above. When using carbodiimides as a condensing agent, additives such as HOBt and DMAP may be added to the reaction as necessary. Moreover, the amidation reaction can also be carried out using an acyl halide or an acid anhydride.

When performing reductive amination reactions in each step, these reactions can be performed in the presence of a reducing agent. Examples of the reducing agent include those mentioned above. Preferred examples of the reducing agent include NaBH(OAc) ₃ and the like.

When aromatic nucleophilic substitution reactions are performed in each step, these reactions can be performed in the presence of a base. Examples of the base include those mentioned above.

In each step, when performing an intramolecular carbonylation reaction, these reactions can be performed in the presence of a condensing agent. Examples of the condensing agent include those mentioned above.

When performing Ullmann condensation reactions in each step, these reactions can be performed in the presence of a copper catalyst, a ligand, and a base. Examples of the copper catalyst include copper iodide. Examples of the ligand include N,N'-dimethylethylenediamine. Examples of the base include those mentioned above.

When carrying out the Chang-Lam-Evans coupling reaction in each step, these reactions can be carried out in the presence of a copper catalyst and a base. Examples of the copper catalyst include copper(II) acetate. Examples of the base include those mentioned above.

When carrying out the Mitsunobu reaction in each step, these reactions can be carried out in the presence of an azodicarboxylic acid ester and a phosphine. Examples of azodicarboxylic acid esters include DEAD and the like. Examples of phosphine include triphenylphosphine.

When carrying out the Suzuki-Miyaura cross-coupling reaction in each step, these reactions can be carried out in the presence of a palladium catalyst and a base. Examples of the palladium catalyst include Pd(amphos)Cl ₂ and the like. Examples of the base include those mentioned above.

In each step, unless otherwise specified, the symbols in the formula have the same meanings as in [1] above. Y is a bromine atom, an iodine atom, a boronic acid, or a hydroxyl. Y' is a fluorine atom or a chlorine atom.

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

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

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

Process 1-3
Compound (I) can also be produced by a reductive amination reaction of compound (1-4) and compound (1-5). The protective group may be removed if necessary.

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

Process 2-1
Compound (2-3) can also be produced by aromatic nucleophilic substitution reaction between compound (2-1) and compound (2-2).

Process 2-2
Compound (2-4) can also be produced by catalytic reduction reaction of compound (2-3).

Process 2-3
Compound (1-1) can also be produced by intramolecular carbonylation reaction of compound (2-4).

The scheme shown above is an illustration of a method for producing a compound represented by formula (I) or a production intermediate thereof. The above scheme can be modified in various ways as can be easily understood by those skilled in the art.

The compound represented by formula (I) and intermediates for its production may be prepared, if necessary, by isolation and purification means well known to those skilled in the art, such as solvent extraction, crystallization, recrystallization, chromatography, It can also be isolated and purified by preparative high performance liquid chromatography or the like.

Examples of silica gel column chromatography and amino silica gel column chromatography include flash chromatography using SNAP Ultra and SNAP Isolute NH2 (Biotage), Hi-Flash columns (Yamazen), and the like.

For ODS column chromatography, for example, a preparative purification LC system (Gilson, flow rate: 30 mL/min, detection: UV at 225 nm) and columns: CAPCELL PAK C18 UG80 (5 μm 20x50 mm) and SunFire C18 Prep OBD ( 5 μm 19x50 mm).

Since the compound of the present invention has an excellent PHD2 inhibitory effect, it can be used as a therapeutic agent for IBD (see Nature Reviews Drug Discovery, 2014, 13, p.852-869). In the present invention, IBD includes, for example, ulcerative colitis, Crohn's disease, enteric Behcet's, infectious enteritis, radiation-induced enteritis, drug-induced enteritis, ischemic enteritis, and mesenteric venous sclerosis (venosclerosing colitis). ), obstructive colitis, and enteritis associated with collagen disease. Preferably, the compound of the present invention can be used as a therapeutic agent for ulcerative colitis or Crohn's disease (see Inflamm. Bowel. Dis., 2015, 21 (2), p.267-275).

In the present invention, "treatment" includes the meaning of "prevention." For example, treatment of ulcerative colitis includes "relapse prevention" and "remission maintenance".

The therapeutic effect of the compound of the present invention on colitis can be confirmed according to the method described in Test Example 2 or a method well known in the art. For example, the method described in Biol. Pharm. Bull 2004, 27 (10), p.1599-1603, etc. or a method analogous thereto can be mentioned.

The pharmaceutical composition of the present invention can be used in various dosage forms depending on the usage. Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, and enemas. .

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

The pharmaceutical composition of the present invention is prepared using a compound represented by formula (I) or a pharmacologically acceptable salt thereof and at least one pharmaceutical excipient. These pharmaceutical compositions can be prepared by adding appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, tonicity agents, preservatives, It can also be prepared by appropriately mixing, diluting, or dissolving with pharmaceutical additives such as wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents.

When the pharmaceutical composition of the present invention is used for treatment, the dosage of the compound represented by formula (I) or a pharmacologically acceptable salt thereof is determined based on the patient's age, sex, body weight, disease, and degree of treatment. To be determined as appropriate. The daily dose may be administered in one, two, three or four divided doses. Preferably, the pharmaceutical compositions of the invention are administered orally.
In the case of oral administration, the dosage for adults can be determined, for example, in the range of 0.1 to 1000 mg/day. In one embodiment, the oral dosage may range from 1 to 500 mg/day, preferably from 10 to 200 mg/day.
In the case of parenteral administration, the dosage for adults can be determined, for example, from 0.1 to 1000 mg/day. In one embodiment, the parenteral dosage may range from 0.5 to 200 mg/day, preferably from 1 to 20 mg/day.

In one embodiment, the pharmaceutical composition of the present invention can also be used in combination with other drugs other than PHDs inhibitors. Other drugs that can be used in combination in the treatment of inflammatory _bowel disease include, for example, 5-ASA, steroids, immunosuppressants, anti-TNFα antibodies, Janus kinase inhibitors, and _α4β7 integrin antibodies. Can be mentioned.

When the compound represented by formula (I) or a pharmacologically acceptable salt thereof is used in combination with other drugs, preparations containing these active ingredients together or these active ingredients individually may be used. They can be administered as separately formulated preparations. When formulated separately, the formulations can be administered separately or simultaneously. Furthermore, the dose of the compound represented by formula (I) or a pharmacologically acceptable salt thereof may be reduced as appropriate depending on the dose of other drugs used in combination.

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

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

The compound names described in the following Examples, excluding commercially available reagents, were named using ChemDraw Professional (PerkinElmer), MarvinSketch (ChemAxon), etc.

Reference example A-1
tert-butyl (S)-3-((4-nitropyridin-3-yl)amino)pyrrolidine-1-carboxylate
A mixture of 3-fluoro-4-nitropyridine (1.11 g), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (1.46 g), potassium carbonate (2.16 g) and toluene (10 mL) was dissolved in a microcentrifuge. The mixture was stirred at 100°C for 1 hour under wave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 90/10 to 10/90) to obtain the title compound (1.87 g).

Reference example A-2
tert-butyl (S)-3-((3-nitropyridin-4-yl)amino)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example A-1, using 4-chloro-3-nitropyridine instead of 3-fluoro-4-nitropyridine.

Reference example A-3
tert-butyl (S)-3-((2-nitropyridin-3-yl)amino)pyrrolidine-1-carboxylate
A mixture of 3-fluoro-2-nitropyridine (1.00 g), tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (1.31 g), potassium carbonate (1.95 g) and DMF (10 mL) was heated in a microcentrifuge. The mixture was stirred at 80°C for 1 hour under wave irradiation. The reaction mixture was poured into a mixture of ethyl acetate and water and stirred. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 20/80) to obtain the title compound (1.73 g).

Reference example A-4
tert-butyl (S)-3-((2-nitrophenyl)amino)pyrrolidine-1-carboxylate
The title compound was obtained in the same manner as in Reference Example A-3 using 1-fluoro-2-nitrobenzene instead of 3-fluoro-2-nitropyridine.

Reference example B-1
tert-butyl (S)-3-((4-aminopyridin-3-yl)amino)pyrrolidine-1-carboxylate In a mixture of Reference Example A-1 (1.87 g) and ethanol (30 mL), under an argon atmosphere, Palladium 10%-carbon (0.19g, wet) was added. The mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite (registered trademark), and the filtrate was concentrated under reduced pressure to obtain the title compound (1.68 g).

Reference example B-2
tert-butyl (S)-3-((3-aminopyridin-4-yl)amino)pyrrolidine-1-carboxylate Use Reference Example A-2 instead of Reference Example A-1, and use Reference Example B-1 and The title compound was obtained in a similar manner.

Reference example B-3
tert-butyl (S)-3-((2-aminopyridin-3-yl)amino)pyrrolidine-1-carboxylate Use Reference Example A-3 instead of Reference Example A-1, and use Reference Example B-1 and The title compound was obtained in a similar manner.

Reference example B-4
tert-butyl (S)-3-((2-aminophenyl)amino)pyrrolidine-1-carboxylate Using the same method as Reference Example B-1, using Reference Example A-4 instead of Reference Example A-1. The title compound was obtained.

Reference example C-1
(S)-3-(2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)pyrrolidine-1-carboxylic acid tert-butyl Reference Example B-1 (1.68g ) and THF (15 mL) was added CDI (1.96 g). The mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution (5 mol/L, 3 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Hydrochloric acid (2 mol/L, 7.5 mL) and water were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0 ~ 0/100/0 ~ 0/90/10) to obtain the title compound (1.86 g ) was obtained. MS(ESI_APCI, m/z): 303(MH) ^-

Reference example C-2
(S)-3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl Instead of Reference Example B-1 The title compound was obtained using Reference Example B-2 in the same manner as Reference Example C-1. MS(ESI_APCI, m/z): 303(MH) ^-

Reference example C-3
(S)-3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)pyrrolidine-1-carboxylic acid tert-butyl Instead of Reference Example B-1 Using Reference Example B-3, the title compound was obtained in the same manner as in Reference Example C-1. MS(ESI_APCI, m/z): 303(MH) ^-

Reference example C-4
(S)-3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl Reference Example B- in place of Reference Example B-1 4, the title compound was obtained in the same manner as in Reference Example C-1. MS(ESI_APCI, m/z): 302(MH) ^-

Reference example M-1
Methyl 4-(5-bromopyridin-2-yl)benzoate Under argon atmosphere, 2,5-dibromopyridine (10.0g), (4-(methoxycarbonyl)phenyl)boronic acid (9.12g), Pd(PPh ₃ ) ₄ (1.46 g), potassium carbonate (11.7 g), 1,4-dioxane (56 mL) and methanol (24 mL) was stirred at 80° C. for 2 hours. After cooling to room temperature, dichloromethane and water were added to the reaction mixture and stirred. The mixture was filtered through Celite, and the filtrate was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Methanol (50 mL) was added to the obtained residue, and the mixture was heated under reflux for 30 minutes. The mixture was stirred for 30 minutes under ice cooling, and the resulting insoluble matter was filtered off. The obtained solid was washed with ice-cooled methanol and then dried under reduced pressure to obtain the title compound (8.78 g).

Reference example E-1
(S)-3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine- tert-butyl 3-yl)pyrrolidine-1-carboxylate Reference example C-1 (500mg), Reference example M-1 (480mg), N,N'-dimethylethylenediamine (0.21mL), Copper(I) iodide ( 375 mg), potassium carbonate (454 mg) and acetonitrile (5 mL) was stirred at 100° C. for 1 hour under microwave irradiation. The reaction mixture was poured into ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 80/20/0 to 0/100/0 to 0/90/10) to obtain the title compound (366 mg). I got it.

Reference example E-2
(S)-3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl) tert-Butyl pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-1, using 4-iodo-1,1'-biphenyl in place of Reference Example M-1.

Reference example E-3
(S)-3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine- tert-Butyl 1-yl)pyrrolidine-1-carboxylate The title compound was obtained in the same manner as Reference Example E-1, using Reference Example C-2 instead of Reference Example C-1.

Reference example E-4
(S)-3-(3-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl) tert-butyl pyrrolidine-1-carboxylate Instead of Reference Example C-1 and Reference Example M-1, Reference Example C-2 and 4'-bromo-[1,1'- The title compound was obtained in the same manner as in Reference Example E-1 using methyl biphenyl]-4-carboxylate.

Reference example E-5
(S)-3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine- 1-yl)pyrrolidine-1-carboxylic acid tert-butyl Reference example C-3 (239 mg), Reference example M-1 (252 mg), N,N'-dimethylethylenediamine (0.10 mL), Copper (I) iodide ( A mixture of potassium carbonate (217 mg) and acetonitrile (4 mL) was stirred at 100° C. for 2 hours under microwave irradiation. The reaction mixture was poured into a mixture of water and ethyl acetate and stirred. The mixture was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a 28% ammonia aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 20/80) to obtain the title compound (131 mg).

Reference example E-6
(S)-3-(3-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- b] pyridin-1-yl) tert-butyl pyrrolidine-1-carboxylate Instead of Reference Example C-1 and Reference Example M-1, Reference Example C-3 and 4'-bromo-[1,1'- The title compound was obtained in the same manner as in Reference Example E-1 using methyl biphenyl]-4-carboxylate.

Reference example E-7
(S)-3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Tert-butyl pyrrolidine-1-carboxylate The title compound was obtained in the same manner as in Reference Example E-5, using Reference Example C-4 instead of Reference Example C-3.

Reference example E-8
(S)-3-(3-([1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)pyrrolidine-1- tert-butyl carboxylate In place of Reference Example C-1 and Reference Example M-1, Reference Example C-4 and 4-iodo-1,1'-biphenyl were used, respectively, and in the same manner as Reference Example E-1. The title compound was obtained.

Reference example E-9
tert-butyl 2-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate
tert-butyl 1-oxo-2,9-diazaspiro[5.5]undecane-9-carboxylate (322 mg), Reference Example M-1 (292 mg), Xantphos (52 mg), Pd ₂ (dba) ₃ (27 mg), carbonic acid A mixture of cesium (461 mg) and 1,4-dioxane (1 mL) was stirred at 120° C. for 10 hours under microwave irradiation. Dichloromethane was added to the reaction mixture and stirred. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 70/30 to 0/100) to obtain the title compound (95 mg).

Reference example G-1
(S)-2-((3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5- c]Pyridin-3-yl)pyrrolidin-1-yl)methyl)methyl isonicotinate A mixture of Reference Example E-1 (338mg) and hydrogen chloride-1,4-dioxane solution (4mol/L, 3mL) was heated at room temperature. The mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure.
NaBH(OAc) ₃ (556 mg) was added to a mixture of the obtained compound (320 mg), methyl 2-formylisonicotinate (108 mg), triethylamine (0.46 mL) and dichloromethane (3 mL). The mixture was stirred at room temperature for 30 minutes. Methanol (3 mL) was added to the reaction mixture and stirred for 30 minutes. The mixture was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 80/20 to 0/100) to obtain the title compound (218 mg).

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 overnight. After adding water and ethyl acetate to the reaction mixture and stirring, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (6.24 g).

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

Reference example G-2
(S)-2-((3-(1-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5- c]tert-butylpyridin-3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained in the same manner as Reference Example G-1 using Reference Example J-2 instead of methyl 2-formylisonicotinate.

Reference example G-3
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine- tert-butyl (3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate In place of Reference Example E-1 and methyl 2-formylisonicotinate, Reference Example E- The title compound was obtained in the same manner as in Reference Example G-1 using Reference Example G-2 and Reference Example J-2.

Reference example G-4
(S)-2-((3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c]pyridin-1-yl)pyrrolidin-1-yl)methyl)methyl isonicotinate The title compound was obtained in the same manner as in Reference Example G-1, using Reference Example E-3 instead of Reference Example E-1. Ta.

Reference example G-5
(S)-2-((3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c] tert-butyl pyridin-1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate In place of Reference Example E-1 and methyl 2-formylisonicotinate, respectively Using Reference Example E-3 and Reference Example J-2, the title compound was obtained in the same manner as in Reference Example G-1.

Reference example G-6
(S)-2-((3-(3-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[ tert-butyl 4,5-c]pyridin-1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate Reference example E-1 and methyl 2-formylisonicotinate Instead, the title compound was obtained in the same manner as Reference Example G-1 using Reference Example E-4 and Reference Example J-2, respectively.

Reference example G-7
(S)-2-((3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- b] Methyl pyridin-1-yl)pyrrolidin-1-yl)methyl)isonicotinate A mixture of Reference Example E-5 (315 mg) and hydrogen chloride-1,4-dioxane solution (4 mol/L, 2 mL) was heated at room temperature. The mixture was stirred for 8 hours. The reaction mixture was concentrated under reduced pressure.
Methyl 2-formylisonicotinate (57 mg) and NaBH(OAc) ₃ (84 mg) were added to a mixture of the obtained compound (120 mg), triethylamine (0.056 mL) and THF (2 mL). The mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate/methanol = 20/80/0 to 0/100/0 to 0/90/10) to obtain the title compound (129 mg). I got it.

Reference example G-8
(S)-2-((3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- b]tert-butylpyridin-1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained in the same manner as Reference Example G-7 using Reference Example J-2 instead of methyl 2-formylisonicotinate.

Reference example G-9
(S)-2-((3-(3-(4'-(methoxycarbonyl)-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[ tert-butyl 4,5-b]pyridin-1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate Reference example E-1 and methyl 2-formylisonicotinate Instead, the title compound was obtained in the same manner as Reference Example G-1 using Reference Example E-6 and Reference Example J-2, respectively.

Reference example G-10
(S)-2-((3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- Methyl 1-yl)pyrrolidin-1-yl)methyl)isonicotinate Reference Example E-7 (718 mg), methanol (3 mL) and a mixture of hydrogen chloride-1,4-dioxane solution (4 mol/L, 2 mL), Stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure.
Methyl 2-formylisonicotinate (95 mg) and NaBH(OAc) ₃ (141 mg) were added to a mixture of the obtained compound (200 mg), triethylamine (0.093 mL) and THF (2 mL). The mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A mixed solvent of n-hexane/ethyl acetate (1/9) was added to the obtained residue. The mixture was stirred for 30 minutes under ice cooling, and insoluble matter was filtered off. The obtained solid was dried to obtain the title compound (188 mg).

Reference example G-11
(S)-2-((3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- tert-butyl (1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylate
The title compound was obtained in the same manner as Reference Example G-10 using Reference Example J-2 instead of methyl 2-formylisonicotinate.

Reference example G-12
(S)-2-((3-(3-([1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) tert-butyl pyrrolidin-1-yl)methyl-1-methyl-1H-imidazole-5-carboxylate Instead of Reference Example E-1 and methyl 2-formylisonicotinate, Reference Example E-8 and Reference Example The title compound was obtained using J-2 in the same manner as in Reference Example G-1.

Reference example G-13
2-((2-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-1-oxo-2,9-diazaspiro[5.5]undecane-9-yl)methyl)-1-methyl- Tert-butyl 1H-imidazole-5-carboxylate Same as Reference Example G-1, using Reference Example E-9 and Reference Example J-2 instead of Reference Example E-1 and methyl 2-formylisonicotinate, respectively. The title compound was obtained by the method.

Reference example N-1
2-((2-(6-(4-carboxyphenyl)pyridin-3-yl)-1-oxo-2,9-diazaspiro[5.5]undecane-9-yl)methyl)-1-methyl-1H-imidazole -5-Carboxylic acid A mixture of Reference Example G-13 (81 mg), water (0.6 mL) and concentrated sulfuric acid (0.03 mL) was stirred at 120°C for 1 hour. After cooling to room temperature, lithium hydroxide (4 mol/L, 0.49 mL) was added to the reaction mixture and stirred for 1 hour. Hydrochloric acid (1 mol/L, 0.85 mL) was added to the mixture, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and insoluble matter was filtered off. The obtained solid was dried to obtain the title compound (42 mg). MS(ESI_APCI, m/z): 504(M+H) ⁺

The chemical structural formulas and PHD2 inhibitory activities (see Test Example 1) of some reference examples are shown in the table below.

Example L-1
(S)-2-((3-(3-(6-(4-(methoxycarbonyl)phenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Reference example G-11 (220 mg), methanol (1.2 mL), water (1.2 mL) and concentrated sulfuric acid (0.039 mL) mixture was stirred at 100°C for 3 hours. After cooling to room temperature, the precipitate was collected by filtration. The obtained solid was dried to obtain the title compound (187 mg).

Example 1
(S)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine -3-yl)pyrrolidin-1-yl)methyl)isonicotinic acid Reference Example G-1 (217mg), methanol (1.5mL) and water (0.5mL) were added to a mixture of lithium hydroxide (4mol/L, 0.38mL). ) was added. The mixture was stirred at 65°C for 1 hour. After cooling to room temperature, hydrochloric acid (6 mol/L, 0.26 mL) was added to the reaction mixture, and the mixture was stirred at 50°C for 30 minutes. After filtering the precipitate, the obtained solid was dried to obtain the title compound (143 mg).

Example 2
(S)-2-((3-(1-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine -3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Reference example G-2 (274 mg), ethanol (2.5 mL), water (2.5 mL) and concentrated sulfuric acid ( 0.048 mL) was stirred at 90°C for 2 hours. After cooling to room temperature, lithium hydroxide monohydrate (189 mg) was added to the reaction mixture. After stirring the mixture at room temperature for 30 minutes, insoluble matter was filtered off. The filtrate was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%)/acetonitrile = 98/2 to 10/90) to obtain the title compound (36 mg).

Example 3
(S)-2-((3-(1-([1,1'-biphenyl]-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridine- 3-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid A mixture of Reference Example G-3 (70 mg), dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) , and heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The obtained residue was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%)/acetonitrile = 90/10 to 30/70) to obtain the title compound (42 mg).

Example 4
(S)-2-((3-(3-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine -1-yl)pyrrolidin-1-yl)methyl)isonicotinic acid The title compound was obtained in the same manner as in Example 1, using Reference Example G-4 instead of Reference Example G-1.

Example 5
(S)-2-((3-(3-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine -1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid By the same method as Example 2, using Reference Example G-5 instead of Reference Example G-2. The title compound was obtained.

Example 6
(S)-2-((3-(3-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5 -c]pyridin-1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Reference example G-6 (62 mg), methanol (0.5 mL), water (0.5 mL) and concentrated sulfuric acid (0.022 mL) was stirred at 90°C for 1 hour. After cooling to room temperature, lithium hydroxide monohydrate (85 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%)/acetonitrile = 90/10 to 30/70) to obtain the title compound (22 mg).

Example 7
(S)-2-((3-(3-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine -1-yl)pyrrolidin-1-yl)methyl)isonicotinic acid The title compound was obtained in the same manner as in Example 1, using Reference Example G-7 instead of Reference Example G-1.

Example 8
(S)-2-((3-(3-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine -1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid By the same method as Example 6, using Reference Example G-8 instead of Reference Example G-6. The title compound was obtained.

Example 9
(S)-2-((3-(3-(4'-carboxy-[1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5 -b]pyridin-1-yl)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Reference example G-9 (54 mg), methanol (0.2 mL), water (1.0 mL) and concentrated sulfuric acid (0.04 mL) was stirred at 110° C. for 1 hour under microwave irradiation. Lithium hydroxide monohydrate (100 mg) was added to the reaction mixture, and the mixture was stirred at 50°C for 1 hour. The reaction mixture was purified by ODS column chromatography (elution solvent: formic acid aqueous solution (0.1%)/acetonitrile = 90/10 to 30/70) to obtain the title compound (24 mg).

Example 10
(S)-2-((3-(3-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl )pyrrolidin-1-yl)methyl)isonicotinic acid The title compound was obtained in the same manner as in Example 1, using Reference Example G-10 in place of Reference Example G-1.

Example 11
(S)-2-((3-(3-(6-(4-carboxyphenyl)pyridin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl )pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid Example L-1 (187 mg), methanol (2.2 mL) and water (0.7 mL) were added to a mixture of lithium hydroxide aqueous solution. (4mol/L, 0.34mL) was added. The mixture was stirred at 65°C for 1 hour. After cooling to room temperature, methanol (1.1 mL) and hydrochloric acid (6 mol/L, 0.23 mL) were added to the reaction mixture, and the mixture was stirred at 50°C for 30 minutes. Insoluble materials were removed by filtration, and the filtrate was stirred for 30 minutes under ice cooling. After filtering the precipitate, the obtained solid was dried to obtain the title compound (68 mg).

Example 12
(S)-2-((3-(3-([1,1'-biphenyl]-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl) Pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazole-5-carboxylic acid The title compound was obtained in the same manner as in Example 3, using Reference Example G-12 instead of Reference Example G-3. .

The chemical structural formula, physical property values, and PHD2 inhibitory activity (see Test Example 1) of Examples are shown in the table below.

Test Example 1 PHD2 inhibition test (1) Expression and preparation of human PHD2 _184-418
Human PHD2 _184-418 , which contains amino acid residues 184 to 418 of the protein represented by GenBank accession ID: CAC42509, was expressed and prepared using the following method.
An expression construct for human PHD2 _184-418 incorporating an N-terminal histidine tag was introduced into pET-30a(+) vector, and the sequence was confirmed. This vector was introduced into BL21(DE3) strain and cultured at 37°C in LB medium containing antibiotics. After culturing, a cell lysis solution was added to the cells, and the cells were disrupted and suspended by ultrasonic disruption. The disrupted suspension was centrifuged, and the supernatant was purified using a Ni column to obtain human PHD2 _184-418 .
(2) Test method Human HIF-1α 556-574 containing FITC-Ahx at the N-terminus of HIF-1α _556-574 containing amino acid residues 556 to 574 (partial peptide) of human HIF- _1α ( FITC-labeled HIF-1α _556-574 ) was used as a substrate. Using FITC-labeled HIF-1α _556-574 , competitive inhibition between 2-oxoglutarate and the test compound (PHD inhibitor) was evaluated by the change in fluorescence polarization of FITC-labeled HIF-1α _556-574 using the following method. did.
Enzyme (human PHD2 _184-418 ) and substrate were diluted in assay buffer (pH 7.4) containing 10 mM HEPES, 150 mM NaCl, ₁₀ μM MnCl2.4H2O, 2 μM ₂ -oxoglutarate and 0.05% Tween-20. . Test compounds were diluted with DMSO. The test compound, human PHD2 _184-418 , was pre-added to a 384-well plate (Corning, black, opaque bottom) and the reaction was initiated by addition of FITC-labeled HIF-1α _556-574 . After incubation at 37°C for 60 minutes, fluorescence polarization (excitation wavelength 470 nm, fluorescence wavelength 530 nm) was measured using PHERAstar FSX (BMG Labtech). The fluorescence polarization of each well was measured, and the human PHD2 binding inhibitory activity of the test compound was calculated based on the value of the test substance-free group.
(3) Results As shown in the table above, the compound of the present invention inhibited the binding between PHD2 and HIF-1α. Therefore, it has been revealed that the compounds of the present invention are useful as PHD2 inhibitors.

TNBSの投与により亢進したFITCの腸管膜透過性は、本発明の化合物の投与により抑制された。したがって、本発明の化合物は、炎症性腸疾患の治療剤として有用であることが明らかとなった。 Test Example 2 Therapeutic effect in colitis model (1) TNBS-induced colitis model rat
It is known that administering TNBS into the large intestine of rats causes local inflammation in the large intestine, disrupts the intestinal barrier function, and increases the permeability of the intestinal membrane. Therefore, the effect of suppressing intestinal membrane permeability by oral administration of the test compound was evaluated as an indicator of drug efficacy.
(2) Test method
Eight-week-old SLC:SD male rats (Japan SLC) were used. Under pentobarbital anesthesia, 300 μL of 28 mg/mL TNBS prepared with 50% ethanol was administered to a site 8 cm from the anus in the large intestine to induce inflammation. 300 μL of 50% ethanol was administered to the vehicle treatment group. A 48-hour fast was performed before administering TNBS. Starting from the next day, the test compound prepared in a 0.05% methylcellulose solution was orally administered once a day for a total of 3 days. Three days after administration, 50 mg/kg FITC was orally administered 4 hours after administration of the test compound, and 4 hours later, blood was collected from the jugular vein under isoflurane anesthesia. The concentration of FITC permeated into the circulating blood through the intestinal membrane was measured by centrifuging the serum and detecting the fluorescence intensity using PHERAstar FSX (BMG Labtech). The intestinal membrane permeability inhibition rate of the test compound was calculated by setting the value of the test substance-free group as 0 and the value of the TNBS-untreated group as 100.
(3) Results The intestinal membrane permeability inhibition rate (%, average value) (Inhibition) of each test compound is shown below.

FITC intestinal membrane permeability, which was increased by administration of TNBS, was suppressed by administration of the compound of the present invention. Therefore, it has been revealed that the compound of the present invention is useful as a therapeutic agent for inflammatory bowel disease.

The compound of the present invention or a pharmacologically acceptable salt thereof is useful as a therapeutic agent for inflammatory bowel disease.

Claims (14)

Formula (I):

[During the ceremony,
m and u are each independently an integer from 0 to 3;
p and q are each independently 1 or 2;
r is an integer from 0 to 6;
R ¹ is a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy (when m is 2 or 3, two or more R ¹ may be different from each other);
E, G, Q and T are groups selected from the group consisting of the following (1) to (7):
(1) E is CR ^2e , Q is CR ^2q , T is CR ^2t , G is N,
(2) E is CR ^2e , G is CR ^2g , T is CR ^2t , Q is N,
(3) E is CR ^2e , G is CR ^2g , Q is CR ^2q , T is N,
(4) E is CR ^2e , Q is CR ^2q , G and T are N,
(5) G is CR ^2g , T is CR ^2t , E and Q are N,
(6) G is CR ^2g , Q is CR ^2q , E and T are N, and
(7) E is CR ^2e , G is CR ^2g , Q is CR ^2q , T is CR ^2t ;
R ^2e , R ^2g , R ^2q and R ^2t are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, halo C _1-6 alkyl, C _1-6 alkoxy, halo C _1-6 alkoxy, hydroxy, -CO ₂ R ⁴ , or -CONR ⁵ R ^5' ;
R ⁴ is a hydrogen atom or C _1-6 alkyl;
R ⁵ and R ^5' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
Ring W is C _6-10 aryl, 5- or 6-membered heteroaryl, 9- or 10-membered heteroaryl, C _3-8 cycloalkyl, or 3-8 membered heterocycloalkyl;
Ring Z is a group selected from the group consisting of the following (a) to (c):

as well as

(In the formula,
R ^a , R ^b and R ^c are each independently a hydrogen atom, a halogen atom, C _1-6 alkyl, cyano, hydroxy, or carboxy;
R ^d is a hydrogen atom or C _1-6 alkyl);
R ³ is a 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 alkyl sulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, hydroxy, cyano, nitro, -NR ⁶ R ^6' , -CO ₂ R ⁷ , -CONR ⁸ R ^8' , or group A (where u is 2 or 3, 2 or more R ³ may be different from each other);
R ⁶ and R ^6' are each independently a hydrogen atom or C _1-6 alkyl;
R ⁷ is a hydrogen atom or C _1-6 alkyl;
R ⁸ and R ^8' are each independently a hydrogen atom, C _1-6 alkyl, carboxy C _1-6 alkyl, hydroxy C _1-6 alkyl, halo C _1-6 alkyl, C _3-8 cycloalkyl, or a 3- to 8-membered heterocycloalkyl;
Group A is a group selected from the group consisting of (a) to (h) below:
(a) C _6-10 aryl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(b) 5- or 6-membered heteroaryl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(c) C _6-10 arylC _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(d) C _6-10 aryloxy unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(e) 5- or 6-membered heteroaryl C _1-6 alkyl, unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(f) 5- or 6-membered heteroaryloxy unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
(g) C _3-8 cycloalkyl, unsubstituted or substituted with 1 to 3 groups selected from substituent group B, and
(h) 3- to 8-membered heterocycloalkyl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
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, -NR ⁹ R ^9' , -NR ⁹ SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , and -CONR ¹¹ R ^11' ;
R ⁹ and R ^9' are each independently 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 a hydrogen atom, 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- to 8-membered heterocycloalkyl]
A compound represented by or a pharmacologically acceptable salt thereof. 2. A compound according to claim 1, having the following formula:

[During the ceremony,
u is an integer from 0 to 2;
R ^3' is 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 , or -CONR ⁸ R ^8' ;
m, p, q, R ¹ , E, G, Q, T, ring W, ring Z, R ⁶ , R ^6' , R ⁷ , R ⁸ , R ^8' and group A have the same meaning as in claim 1. be〕
A compound represented by or a pharmacologically acceptable salt thereof. A group in which ring Z is selected from the group consisting of the following (A) to (J):

as well as

The compound according to claim 2 or a pharmacologically acceptable salt thereof. 4. The compound or a pharmacologically acceptable salt thereof according to claim 3, wherein ring W is phenyl or a 5- or 6-membered heteroaryl. 5. The compound or a pharmacologically acceptable salt thereof according to claim 4, wherein p is 2 and q is 1. 6. The compound or a pharmacologically acceptable salt thereof according to claim 5, wherein m is 0. R ^2e , R ^2g , R ^2q and R ^2t are each independently a hydrogen atom, C _1-6 alkyl, haloC _1-6 alkyl, C _1-6 alkoxy, carboxy, or -CONR ⁵ R ^5' can be;
The compound or its pharmacologically acceptable compound according to claim 6, wherein R ⁵ and R ^5' are each independently a hydrogen atom, carboxyC _1-6 alkyl, or 3- to 8-membered heterocycloalkyl salt. group A is phenyl unsubstituted or substituted with 1 to 3 groups selected from substituent group B;
The compound according to claim 7, wherein 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 pharmacologically acceptable salt thereof. A group in which ring Z is selected from the group consisting of the following (A), (C), (D), (I) and (J):

as well as

The compound according to claim 8 or a pharmacologically acceptable salt thereof. 10. A compound according to claim 9, having the following formula:

[During the ceremony,
E, G, Q and T are groups selected from the group consisting of the following (1) to (7):
(1) E, Q, T are CH, G is N,
(2) E, G, T are CH, Q is N,
(3) E, G, Q are CH, T is N,
(4) E, Q are CH, G, T are N,
(5) G, T are CH, E, Q are N,
(6) G, Q are CH, E, T are N, and
(7) E, G, T, Q are CH;
X is CH, CR ³ or N;
R ³ is C _1-6 alkyl or hydroxy;
The group A has the same meaning as in claim 8;
Ring Z has the same meaning as in claim 9]
A compound represented by or a pharmacologically acceptable salt thereof. A group consisting of the following compounds:

as well as

or a pharmacologically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmacologically acceptable salt thereof, and a pharmaceutical excipient. The pharmaceutical composition according to claim 12, which is a pharmaceutical composition for treating inflammatory bowel disease. 14. The pharmaceutical composition according to claim 13, wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.