KR101236188B1 - Novel Pyrrolopyridinone Derivatives and Therapeutic Uses for MCH Receptor-1 Related Diseases - Google Patents

Abstract

The present invention is for preventing or treating a novel pyrrolopyridinone derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof, a preparation method thereof and MCH receptor-1 (melanin enriched hormone) -related diseases containing the same as an active ingredient In a pharmaceutical composition, the derivative according to the present invention acts as an antagonist to MCH receptor-1 and thus MCH receptor-1 such as obesity, diabetes, metabolic disorders, anxiety and depression caused by MCH binding to MCH receptor-1. It can be usefully used to prevent or treat related diseases.
Formula 1

Description

Novel Pyrrolopyridinone Derivatives and Therapeutic Uses for MCH Receptor-1 Related Diseases}

The present invention relates to novel pyrrolopyridinone derivatives and their therapeutic use for MCH receptor-1 related diseases.

Recently, the obesity population is rapidly increasing due to changes in energy balance in the human body, lifestyle changes and industrialization due to genetic, environmental, and mental factors caused by modernization. Obesity and overweight are becoming serious social problems due to the high risk of complications such as heart disease, stroke, diabetes, respiratory disease and certain cancers.

Obesity treatments such as Xenical ™, which inhibits lipase secreted from the pancreas and digestive system, and Reductil ™, which inhibits serotonin reuptake, are currently on the market related to obesity, but have low anti-obesity effects and high side effects. There is a problem that the use is limited (Trisha Gura, Science 2003, 299, 849-852).

Obesity occurs through complex nervous system and energy metabolism, and various hormones and peptides are involved in controlling it. Recent development of anti-obesity drugs focuses on identifying new peptides related to weight control and developing new obesity drugs using these mechanisms of action. Among the major neuropeptide targets involved in appetite regulation, studies have been conducted on a promising target for obesity therapy, as the melanin concentrating hormone receptor-1 antagonist is known to play an important role in appetite and energy regulation functions .

 Melanin concentrating hormone (MCH) is a cyclic peptide consisting of 19 amino acids and is identical in all mammals. It is mainly expressed in the brain's lateral hypothalamus and zona incerta. MCH neurons are widely distributed in other regions of the brain, and are known to regulate food intake and energy balance. Two types of MCH receptors are known. One is the MCH receptor R1, one of the 7TM seven transmembrane G-protein-coupled receptors (GPCRs), which are present simultaneously in rodents and humans. The other is present only in humans as MCH receptor R2. MCH receptor R2 is not found in rodents, so MCH-R2's role in intake and energy balance is difficult to study because there are no animal models to study.

 Studies of the function of MCH in animal models have shown that MCH mRNA was increased three-fold in fasted rats compared to ob / ob mice, which are standard and leptin deficient. And, direct injection of MCH through the rat ventricle (icv) causes overeating and obesity. (See D. Qu., Et al., Nature, 380 (6571), 243-7, 1996). Transgenic mice overexpressing the MCH gene develop obesity and overeating and insulin resistance. Transgenic mice that do not produce the MCH-R1 gene are dry and have decreased appetite because their metabolic rate increases. Rats knocked out of the MCH-R1 receptor gene are not obese even on a high fat diet. (See A. L. Handlon and H. Zhou, J. Med. Chem. 49, 4017-22, 2006).

On the other hand, MCH receptor-1 antagonists may be useful not only to control food intake but also to treat depression or anxiety (B. Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002). ) And animals treated with MCH receptor-1 antagonists show significant weight loss and provide anxiety and antidepressant effects in addition to appetite loss (B. Borowsky et al., Nature Medicine, 8 (8), 825-30, 2002). In addition, MCH receptor-1 antagonists have been shown to be effective in treating diabetes and metabolic disorders in addition to treating obesity, depression and anxiety (DS Ludwig et al., J. Clin. Invest. 107, 379-386, 2001). Reference).

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

While we are studying therapeutic candidates with various skeletons that show oral administration, CNS infiltration, and in vivo weight loss in relation to MCH receptor-1 antagonists, due to various pharmacokinetics (PK) profile issues and hERG binding issues Full-scale clinical research has not been done. Therefore, the present inventors are studying to develop a compound that exhibits an excellent antagonistic effect on MCH receptor-1, and the novel pyrrolopyridinone derivative compounds act as an antagonist to MCH receptor-1, resulting in metabolic diseases (eg, obesity and diabetes). The present invention has been completed and found to be useful for preventing or treating MCH receptor-1 related diseases such as neurological diseases (eg, anxiety and depression).

Accordingly, it is an object of the present invention to provide novel pyrrolopyridinone derivatives or pharmaceutically acceptable salts thereof.

Another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of MCH receptor-1 related diseases.

Still another object of the present invention is to provide a food composition for preventing or ameliorating MCH receptor-1 related diseases.

Another object of the present invention is to provide a method for preparing the pyrrolopyridinone derivative compound.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides a pyrrolopyridinone derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:

Formula 1

In the above formula, R ¹ and R ² are each independently hydrogen, halogen, CN, C ₁ -C ₁₀ straight or branched alkyl, C ₁ -C ₄ alkenyl, OR ⁵ , COR ⁵ , CO ₂ R ⁵ , CX ₃ (X is F, Cl, Br or I), NHR ⁵ , an aryl group and a conjugated aryl group; R ³ and R ⁴ are each independently a C ₁ -C ₁₀ branched or straight chain alkyl group or R ³ and R ⁴ together form a five or six membered heterocycle containing a hetero element; R ⁵ is hydrogen, C ₁ -C ₅ straight or branched alkyl, aryl or arylalkyl; A is carbon or nitrogen.

While we are studying therapeutic candidates with various skeletons that show oral administration, CNS infiltration, and in vivo weight loss in relation to MCH receptor-1 antagonists, due to various pharmacokinetics (PK) profile issues and hERG binding issues Full-scale clinical research has not been done. Therefore, the present inventors are studying to develop a compound that exhibits an excellent antagonistic effect on MCH receptor-1, and the novel pyrrolopyridinone derivative compounds act as an antagonist to MCH receptor-1, resulting in metabolic diseases (eg, obesity and diabetes). The present invention has been completed and found to be useful for preventing or treating MCH receptor-1 related diseases such as neurological diseases (eg, anxiety and depression).

The pyrrolopyridinone derivative of the present invention is represented by the formula (1).

As used herein, the term “alkyl” refers to a straight or branched unsubstituted or substituted saturated hydrocarbon group, for example methyl, ethyl, propyl, isopropyl, isobutyl, sec butyl, tert butyl, pentyl, hexyl, heptyl , Octyl, nonyl and decyl. C ₁ -C ₁₀ alkyl means an alkyl group having an alkyl unit of 1 to 10 carbon atoms, C ₁ -C ₁₀ When alkyl is substituted, the carbon number of the substituent is not included. In Formula 1, R ¹ and R ² C ₁ -C ₁₀ of position Alkyl is preferably a C _{1 -8} alkyl, more preferably C _{1 -5} alkyl, and more preferably, C _{1 -4} alkyl, most preferably C _{2 -3} alkyl. In formula 1, R ³ and R ⁴ position or position C _1-10 alkyl is preferably C _{1 -5} alkyl, more preferably C _{1 -3} alkyl, more preferably C _{1 -2} alkyl more.

The term “alkenyl” refers to a straight or branched unsubstituted or substituted unsaturated hydrocarbon group having the specified carbon number, for example ethenyl, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, n -pentenyl and n -Hexenyl.

The term “aryl” refers to a substituted or unsubstituted monocyclic or polycyclic carbon ring which is wholly or partially unsaturated. C _{6 -30} aryl group is not included in the carbon number of the substituent when the aryl group means a group having a carbon ring atom of a carbon number of 6 to 30, C _{6 -30} aryl-substituted. Most preferably said aryl is substituted or unsubstituted phenyl. When monoaryl, such as phenyl, is substituted, substitutions may be made by various substituents at various positions, such as halo, hydroxy, nitro, cyano, C ₁ -C ₄ Substituted or unsubstituted straight or branched chain alkyl or C ₁ -C ₄ It may be substituted by straight chain or branched alkoxy.

The term "arylalkyl" refers to an alkyl group substituted with an aryl group. Alkyl is preferably C _{1 -3} alkyl, more preferably C ₁ alkyl. In arylalkyl, aryl may be substituted by various substituents at various positions, such as halo, hydroxy, nitro, cyano, C ₁ -C ₄ Substituted or unsubstituted straight or branched chain alkyl, C ₁ -C ₄ Or substituted by straight or branched alkoxy or alkylcarboxylnitro.

The term “fused aryl group” means a cyclic group consisting of fused multiple aryl rings, naphthalene, phenanthrene, anthracene, benzo [a] pyrene, benzo [b] pyrene, benzo [e] pyrene, ace Naphthalene, acenaphthene, benzo [b] fluoranthene, benzo [j] fluoranthene, chrysene, fluoranthene, fluorene, pyrene and the like, which are substituted or unsubstituted conjugated aryl groups. Substitutions may be made at various positions by various substituents, for example halo, hydroxy, nitro, cyano, C ₁ -C ₄ Substituted or unsubstituted straight or branched chain alkyl or C ₁ -C ₄ It may be substituted by straight chain or branched alkoxy.

,

,

,

또는

를 형성하고; A는 독립적으로 탄소 혹은 질소이다.According to a preferred embodiment of the invention, the R ¹ And R ² are each independently hydrogen, halogen, C ₁ -C ₅ Linear or branched alkyl, C ₁ -C ₂ alkenes, OR ⁵ , COR ⁵ , CO ₂ R ⁵ , CN, CF ₃ , NHR ⁵ , an aryl group or a conjugated aryl group; R ⁵ is independently hydrogen, C ₁ -C ₅ Linear or branched alkyl, or benzyl; R ³ And R ⁴ together

,

,

,

or

To form; A is independently carbon or nitrogen.

,

,

,

또는

를 형성하고; A는 독립적으로 탄소 혹은 질소이다.More preferably, the R ¹ And R ² are each independently hydrogen, F, Cl, methyl, ethyl, propyl, n-butyl, i -propyl, t -butyl, vinyl, OR ⁵ , COR ⁵ , CO ₂ R ⁵ , CN, CF ₃ , NH ₂ , phenyl, a conjugated aryl group; Then each R ⁵ is independently hydrogen, methyl or benzyl; Wherein the conjugated aryl group is 2-naphthalene, 1-naphthalene; R ³ and R ⁴ are methyl, ethyl, propyl or R ³ And R ⁴ together

,

,

,

or

To form; A is independently carbon or nitrogen.

Even more preferably, the R ¹ And R ² is hydrogen, C ₁ -C ₅ Linear or branched alkyl or conjugated aryl groups; R ³ And R ⁴ together form a five-membered heterocycle containing a hetero element; One of A is carbon and the other is nitrogen.

More specifically illustrating the pyrrolopyridinone derivative of the present invention represented by the formula (1) is as follows:

(1) 2-phenyl-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] Pyridin-7-one;

(2) 2- (2-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;

(3) 2- (3-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;

(4) 2- (2-ethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(5) 2- (4-ethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(6) 2- (4-propylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(7) 2- (4-butylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(8) 2- (4-isopropylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(9) 2- (4-t-butylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(10) 2- (4-vinylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(11) 2- [4- (methoxycarbonyl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro -Pyrrolo [3,4-b] pyridin-7-one;

(12) 2- [4- (trifluoromethyl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro -Pyrrolo [3,4-b] pyridin-7-one;

(13) 2- (4-formylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(14) 2- (4-acetylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(15) 2- (benzo [1,3] dioxol-5-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6 -Dihydro-pyrrolo [3,4-b] pyridin-7-one;

(16) 2- (4-hydroxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(17) 2- (4-aminophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(18) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;

(19) 2- (4-methoxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(20) 2- (4-benzyloxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(21) 2- (4-chlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(22) 2- (4-fluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(23) 2- (2-methoxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(24) 2- (3-methoxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(25) 2- (2-chlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(26) 2- (3-chlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;

(27) 2- (2-fluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(28) 2- (3-fluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(29) 2- (3-cyanophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(30) 2- (4-cyanophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(31) 2- (2,3-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(32) 2- (2,5-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(33) 2- (3,5-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(34) 2- (3,4-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(35) 2-[(3-fluoro-4-methyl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6- Dihydro-pyrrolo [3,4-b] pyridin-7-one;

(36) 2- (2,3-difluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro- Pyrrolo [3,4-b] pyridin-7-one;

(37) 2- (3,4-difluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro- Pyrrolo [3,4-b] pyridin-7-one;

(38) 2- (2,3-dichlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-py Rolo [3,4-b] pyridin-7-one;

(39) 2- (3,5-dichlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-py Rolo [3,4-b] pyridin-7-one;

(40) 2- (naphthalen-2-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(41) 2- (naphthalen-1-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;

(42) 2- (biphenyl-4-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(43) 2- (biphenyl-3-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(44) 2- [4- (naphthalen-1-yl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-di Hydro-pyrrolo [3,4-b] pyridin-7-one;

(45) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;

(46) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-morpholin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4 -b] pyridin-7-one;

(47) 2- (4-methylphenyl) -6- [3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;

(48) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-thiomorpholin-4-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;

(49) 2- (4-methylphenyl) -6- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b ] Pyridin-7-one;

(50) 2- (4-methylphenyl) -6- [3-methoxy-4-[(2-diethylamino) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b ] Pyridin-7-one;

(51) 2- (4-methylphenyl) -6- [3-methoxy-4-[(2-dipropylamino) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b ] Pyridin-7-one;

(52) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6-phenyl-2,3-dihydro-pyrrolo [3,4-c] Pyridin-1-one;

(53) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6- (4-methylphenyl) -2,3-dihydro-pyrrolo [3, 4-c] pyridin-1-one;

(54) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6- (4-ethylphenyl) -2,3-dihydro-pyrrolo [3 , 4-c] pyridin-1-one; And

(55) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6- (naphthalen-2-yl) -2,3-dihydro-pyrrolo [ 3,4-c] pyridin-1-one.

The specific compounds of the present invention are summarized in the table as follows:

compound rescue compound rescue compound rescue One

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

According to a most preferred embodiment of the invention, the pyrrolopyridinone derivatives of the invention are in 2- (4-ethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl- Methoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one; 2- (4-isopropylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4 -b] pyridin-7-one; 2- (4-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b ] Pyridin-7-one; And 2- (naphthalen-2-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one. As demonstrated in the examples below, the four pyrrolopyridinone derivatives exhibit IC ₅₀ values of 100 nM or less in MCH receptor-1 binding inhibition experiments, indicating an effective therapeutic effect against MCH receptor-1 related diseases.

The present invention includes not only the pyrrolopyridinone derivative compound represented by Formula 1, but also a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts of the derivatives of Formula 1 of the present invention include acid addition salts formed with pharmaceutically acceptable free acids. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. From non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, , Or may be prepared by drying, or after the solvent and excess acid are distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

In addition, the present invention includes not only the pyrrolopyridinone derivative represented by Formula 1 and a pharmaceutically acceptable salt thereof, but also possible solvates, hydrates, and stereoisomers that can be prepared therefrom.

According to another aspect of the present invention, the present invention provides a pyrrolo comprising the step of reacting a compound of formula 2 with a compound of formula 3 in a solvent according to Scheme 1 in the presence of a catalyst and a base to obtain a compound of formula 1 Provided are methods for preparing pyridinone derivatives:

Scheme 1

In the above formula, R ¹ And R ² are each independently hydrogen, halogen, CN, C ₁ -C ₁₀ Linear or branched alkyl, C ₁ -C ₄ alkenes, OR ⁵ , COR ⁵ , CO ₂ R ⁵ , CX ₃ (X is F, Cl, Br or I), NHR ⁵ , an aryl group and a conjugated aryl group; R ³ And R ⁴ are each independently C ₁ -C ₁₀ branched or straight chain alkyl group or R ³ And R ⁴ together form a 5- or 6-membered heterocycle containing a hetero element; R ⁵ is hydrogen, C ₁ -C ₅ Linear or branched alkyl, aryl or arylalkyl; A is carbon or nitrogen.

Method 1:

The pyrrolopyridinone derivative represented by Chemical Formula 1 according to the present invention reacts a boronic acid compound represented by Chemical Formula 2 with a boronic acid compound represented by the following Compound 3 in a solvent in the presence of a catalyst and a base: It can be prepared via Suzuki type coupling reaction. However, the present invention is not limited to Suzuki-type coupling reactions, but includes all coupling reactions capable of carbon-carbon bonds, including Stilli-type coupling, Hiyama-type coupling, and Negishi-type coupling. Coupling reactions and the like.

Scheme 1

In the above formula, R ¹ And R ² are each independently hydrogen, halogen, CN, C ₁ -C ₁₀ Linear or branched alkyl, C ₁ -C ₄ alkenes, OR ⁵ , COR ⁵ , CO ₂ R ⁵ , CX ₃ (X is F, Cl, Br or I), NHR ⁵ , an aryl group and a conjugated aryl group; R ³ And R ⁴ are each independently C ₁ -C ₁₀ branched or straight chain alkyl group or R ³ And R ⁴ together form a 5- or 6-membered heterocycle containing a hetero element; R ⁵ is hydrogen, C ₁ -C ₅ Linear or branched alkyl, aryl or arylalkyl; A is carbon or nitrogen.

Hereinafter, the preparation method 1 according to the present invention will be described in more detail step by step.

First, palladium, nickel, platinum derivatives may be used as the catalyst in the reaction, and it is preferable to use a palladium catalyst. Palladium catalysts include Pd (PPh ₃ ) ₄ , Pd-C, PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ , PdCl ₂ (dppf), [PdCl (allyl)] ₂ , Pd (OAc) ₂ or PdCl ₂ and the like can be used.

In order to promote the reaction and increase the yield, phosphine compounds such as PPh ₃ , P- ( O- tolyl) ₃ , PBu _3, etc. are used as adducts, or salts such as lithium chloride, lithium bromide, and lithium iodide are adducts. Can be used as

In the reaction, the boronic acid compound of formula 3 is used commercially available compounds, or prepared by using known methods from the corresponding halide compounds.

In addition, the reaction may be used as the base that can be used to react in the presence of a base, such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, etc., can be used equivalent or excess.

The reaction solvent is an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, aromatic hydrocarbon solvent such as benzene, toluene, xylene, alcohol solvent such as methanol, ethanol, dimethylformamide (DMF ), Dimethyl sulfoxide, acetonitrile, water and the like can be used alone or in combination. The reaction temperature is from 0 deg. C to the boiling point of the solvent.

In addition, the compound of Formula 2 used in Scheme 1 may be prepared and used as shown in Scheme 2 below.

Specifically, oxidizing the compound represented by Formula 4 to prepare a compound of Formula 5 (Step 1);

Preparing a compound of formula 6 by chlorolating the compound of formula 5 prepared in step 1 (step 2);

Preparing a compound of formula 7 by bromination of the compound of formula 6 prepared in step 2 (step 3); And

It can be prepared by a manufacturing method comprising the step (step 4) of preparing a compound of formula 2 by condensation reaction of the compound of formula 7 prepared in step 3 with a compound of formula (8).

Scheme 2

Wherein R ¹ , R ² , R ³ , R ⁴ And A is as defined in Formula 1).

Hereinafter, Scheme 2 will be described in more detail.

First, Step 1 according to the present invention is a step of preparing a compound of Chemical Formula 5 by oxidizing the compound of Chemical Formula 4.

Examples of the oxidizing agent that can be used in the reaction include m -chloroperbenzoic acid (MCPBA), perbenzoic acid, peracetic acid, trifluoro peracetic acid, hydrogen peroxide (H ₂ O ₂ ), dioxirane, and the like. Preference is given to using equivalents.

The reaction solvent may be used alone or mixed with an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dichloromethane, dichloroethane, chloroform, water and the like, and the reaction temperature is solvent at 0 ° C. Up to the boiling point of is preferred.

Next, step 2 is a step of preparing a compound of formula 6 by chlorolating the N -oxide compound of formula 5 obtained in step 1 in a solvent.

The chlorolation reagent used in the reaction may be phosphorus oxychloride (POCl ₃ ) or phosphorus trichloride (PCl ₃ ) and the reaction solvent may be ether such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc. Aromatic hydrocarbon solvents such as solvents, benzene, toluene and xylene, dichloromethane, dichloroethane, chloroform and the like can be used alone or in combination. The reaction temperature is preferably from room temperature to the boiling point of the solvent.

Next, step 3 is a step of preparing a compound of formula 7 by bromination of the compound of formula 6 obtained in step 2 in the presence of a radical initiator and a solvent.

Examples of radical initiators usable in the reaction include benzoyl peroxide or azobisisobutylnitrile (AIBN), and the reaction solvent is preferably carbon tetrachloride, and the reaction temperature is preferably from room temperature to the boiling point of the solvent.

Next, the step 4 is condensation of the compound of formula 7 obtained in step 3 with the compound of formula 8 in acetic acid solvent to prepare a compound of formula 2 or by reacting with the compound of formula 8 in a base and solvent compound of formula 4 Manufacturing step.

Acids usable in addition to acetic acid in the reaction include hydrochloric acid, sulfuric acid, p -toluenesulfonic acid, and the like.

The base usable in the reaction is preferably a tertiary amine organic base such as triethylamine or isopropylethylamine and inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate and barium hydroxide.

The reaction solvent may be used alone or in combination with an ether solvent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, water and the like. . At this time, the reaction temperature is preferably up to the boiling point of the solvent at room temperature.

Recipe 2:

The present invention also provides another method of preparing a derivative of formula (I). It can be prepared and used as shown in Scheme 3 below.

Specifically, preparing a compound represented by the formula (9) through a Suzuki-type coupling reaction of the compound represented by the formula (Stage 1);

Preparing a compound of formula 10 by bromination of the compound of formula 9 prepared in step 1 (step 2); And

The compound of Formula 10 prepared in step 2 may be prepared by a condensation reaction with a compound of Formula 8 to prepare a compound of Formula 1 (Step 3).

Scheme 3

In the above formula, R ¹ And R ² are each independently hydrogen, halogen, CN, C ₁ -C ₁₀ Linear or branched alkyl, C ₁ -C ₄ alkenes, OR ⁵ , COR ⁵ , CO ₂ R ⁵ , CX ₃ (X is F, Cl, Br or I), NHR ⁵ , an aryl group and a conjugated aryl group; R ³ And R ⁴ are each independently C ₁ -C ₁₀ branched or straight chain alkyl group or R ³ And R ⁴ together form a 5- or 6-membered heterocycle containing a hetero element; R ⁵ is hydrogen, C ₁ -C ₅ Linear or branched alkyl, aryl or arylalkyl; A is carbon or nitrogen.

According to another aspect of the present invention, the present invention is for the prevention or treatment of MCH receptor-1 related diseases containing pyrrolopyridinone derivative represented by the formula (1) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient It provides a pharmaceutical composition.

Since the pharmaceutical composition of the present invention includes the pyrrolopyridinone derivative represented by Chemical Formula 1 as an active ingredient, common content between the two is omitted in order to avoid excessive complexity of the present specification.

The pyrrolopyridinone derivative represented by the formula (1) according to the present invention shows an excellent inhibitory effect on MCH receptor-1 by measuring the MCH receptor-1 binding inhibitory activity, showing an excellent IC ₅₀ value of 100 nM or less. It can be seen that (see Experimental Example and Table 2).

Therefore, the derivative of formula 1 according to the present invention can be used for the prevention or treatment of various diseases, diseases or conditions caused by MCH receptor-1 by acting as an antagonist to MCH receptor-1.

According to a preferred embodiment of the invention, the disease, disorder or condition which can be prevented or treated by the pharmaceutical composition of the present invention is obesity, diabetes, metabolic disorders, anxiety, depression, sleep disorders, social phobia, dizziness, obsessive compulsive disorder , Panic disorder, post-traumatic stress disorder, Parkinson's disease, schizophrenia, schizophrenic cognitive decline and deficit, elderly dementia, Alzheimer's disease, mental disorder, depressive disorder, substance abuse disorder, degenerative neurodementia, cognitive disorder and epilepsy It includes.

When the composition of the present invention is used as a medicine, the pharmaceutical composition containing the derivative represented by the formula (1) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient may be used for various oral or parenteral administrations during clinical administration. It may be formulated in a form and administered, but is not limited thereto.

Formulations for oral administration include, for example, tablets, pills, hard / soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols. Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

Pharmaceutical compositions comprising the derivative represented by Formula 1 as an active ingredient may be administered parenterally, and parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection, intrathoracic injection or intrathecal administration. All.

At this time, in order to formulate into a formulation for parenteral administration, the pyrrolopyridinone derivative of Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or a buffer to prepare a solution or suspension, and the ampoule or vial unit It may be prepared in a dosage form. The compositions may contain sterile and / or preservatives, stabilizers, hydrating or emulsifying accelerators, auxiliaries such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulating It may be formulated according to the formulation or coating method.

The dosage of the pharmaceutical composition containing the derivative of Formula 1 as an active ingredient to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and preferably 0.01 to 200 mg. / Kg / day may be administered by oral or parenteral route by dividing a predetermined time interval several times a day, preferably once to three times a day, depending on the judgment of the doctor or pharmacist.

According to another aspect of the present invention, the present invention is a food for the prevention or improvement of MCH receptor-1 related diseases containing pyrrolopyridinone derivative represented by the formula (1) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient To provide a composition.

The food composition of the present invention contains not only the pyrrolopyridinone derivative represented by the formula (1) as an active ingredient, but also components commonly added in the manufacture of food, and include, for example, proteins, carbohydrates, fats, nutrients, seasonings and Contains flavors. Examples of the above carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And sugars such as conventional sugars such as polysaccharides such as dextrin, cyclodextrin and the like and xylitol, sorbitol, erythritol. As flavoring agents, natural flavoring agents (tauumatin, stevia extract (for example rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.

The features and advantages of the present invention are summarized as follows:

(a) The present invention relates to a novel pyrrolopyridinone derivative of Formula 1 and a therapeutic agent for MCH receptor-1 related diseases comprising the same.

(b) the pyrrolopyridinone derivatives of formula (I) of the present invention exhibit excellent inhibitory activity against MCH receptor-1 and are characterized by obesity, diabetes, metabolic disorders, anxiety, depression, sleep disorders, Social phobia, dizziness, obsessive compulsive disorder, panic disorder, post traumatic stress disorder, Parkinson's disease, schizophrenia, schizophrenic cognitive decline and deficiency, dementia, dementia, Alzheimer's disease, mental disorder, depressive disorder, substance abuse disorder, degenerative nerve Diseases It can be usefully used to prevent or treat MCH receptor-1 related diseases such as dementia, cognitive impairment and epilepsy.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

< Example  1> 2- Phenyl -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - pyrrolo [ 3,4-b] pyridine -7-one

Step 1: Preparation of 3-methyl-1-oxy-pyridine-2-carboxylic acid methyl ester

After dissolving in 100 ml of 3-methylpyridine-2-carboxylic acid methyl ester (5.0 g, 33.1 mmol) in dichloromethane, metachlorobenzoic acid (mCPBA, 8.9 g, 39.7 mmol) was added thereto, followed by stirring at room temperature for 4 hours. Extracted with 100 ml of saturated sodium hydrogen carbonate. The water layer was extracted several more times with dichloromethane. The oil layer was dried over anhydrous MgSO _4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 20/1, v / v) to give 5.3 g of the target compound as a yellow oil (98%): Rf = 0.29 (dichloromethane and methanol, 20 / 1, v / v); ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, J = 6.3 Hz, 1H), 7.12 (m, 1H), 7.13 (d, J = 7.9 Hz, 1H), 4.03 (s, 3H), 2.30 (s, 3 H).

Step 2: Preparation of 6-chloro-3-methylpyridine-2-carboxylic acid methyl ester

3-methyl-1-oxy-pyridine-2-carboxylic acid methyl ester (500 mg, 2.99 mmol) prepared in step 1 was dissolved in 4 ml of dichloroethane (DCE), followed by phosphorus trichloride (POCl) at 0 ° C. ₃ ) (547 μl, 5.98 mmol) was added and the mixture was stirred under reflux for 4 hours. The reaction solution was poured into 10 g of ice water and extracted with 30 ml of dichloromethane. The organic layer was washed with 30 ml of saturated sodium hydrogen carbonate. The oil layer was dried over anhydrous MgSO _4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane and ethyl acetate, 10/1, v / v) to give 223 mg of the target compound as a colorless oil compound (40%). Rf = 0.32 (normal hexane and ethyl acetate, 10/1 v / v); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.59 (dd, J = 0.48, 8.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H), 2.57 (s, 3H) .

Step 3: Preparation of 3-bromomethyl-6-chloro-pyridine-2-carboxylic acid methyl ester

6-chloro-3-methylpyridine-2-carboxylic acid methyl ester (500 mg, 2.69 mmol) prepared in step 2 was dissolved in 8 ml of carbon tetrachloride, and then N-bromosuccinimide (NBS, 719 mg, 4.04 mmol) and benzoyl peroxide were added and the mixture was stirred under reflux for 3 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (normal hexane and ethyl acetate, 50/1, v / v) to obtain 422 mg of the target compound as a colorless crystal (59%): Rf = 0.15 (normal Hexanes and ethyl acetate, 10/1, v / v); ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.50 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H).

Step 4: 2-Chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] Preparation of Pyridin-7-one

To 3-bromomethyl-6-chloropyridine-2-carboxylic acid methyl ester (422 mg, 1.60 mmol) and 3-methoxy-4- [2- (pyrrolidin-1-yl) prepared in step 3 above. Toxy] phenylamine (343 mg, 1.45 mmol) was dissolved in 8 ml of acetic acid and stirred under reflux for 4 hours. The solvent was concentrated under reduced pressure and extracted with 30 ml of dichloromethane and 30 ml of saturated sodium bicarbonate. The water layer was extracted once more. The oil layer was dried over anhydrous MgSO _4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 10/1, v / v) to give 370 mg of the target compound as a yellow solid (60%): Rf = 0.37 (dichloromethane / methanol / ammonia water, 10/1/1%, v / v); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.85 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.04 (m , 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.83 (s, 2H), 4.2 (t, J = 4.3 Hz, 2H), 3.92 (s, 3H), 2.99 (t, J = 4.3 Hz , 2H), 2.69 (m, 4H), 1.84 (m, 4H).

Step 5: 2phenyl-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine -7-on

Toluene (4 ml) and methanol (1 ml) in 2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro- Pyrrolo [3,4-b] pyridin-7-one (70 mg, 0.18 mmol) with phenylboronic acid (44 mg, 0.36 mmol), tetrakis (triphenylphosphine) palladium (20 mg, 0.018 mmol), And 2M-sodium carbonate (0.18 ml, 0.54 mmol) is added sequentially, and then heated at 100 ℃ for 10 minutes using a microwave. After the reaction was completed, the reaction solution was extracted with 20ml of dichloromethane 20ml water. The organic layer was washed twice with 20 ml of brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated residue was separated and purified using column chromatography (dichloromethane: methanol = 1: 9) to give the title compound (52 mg, 0.12 mmol, 67%) as a yellow solid: Rf = 0.22 (dichloromethane: methanol = 1: 9); ¹ H-NMR (300 MHz, CDCl₃) δ = 8.20 (d, J = 8.1 Hz, 1H), 8.06 (dd, J = 8.1 Hz and 1.7 Hz, 2H), 7.87 (d, J = 5.6 Hz, 1H) , 7.85 (s, 1H), 7.48-7.57 (m, 3H), 7.05 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.93 (s, 2H) , 4.19 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.65-2.69 (m, 4H), 1.80-1.85 (m, 4H)

Example 2 2- (2-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (60 mg, 0.15 mmol) and 2-methylphenylboronic acid (24 mg, 0.18 mmol) were reacted in the same manner as in Step 5 of Example 1 (33 mg, dark green solid) to obtain 50% of the title compound. Got it.

Rf = 0.39 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ = 7.92 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.45 ( m, 1H), 7.30 (m, 3H), 7.08 (dd, J = 2.3, 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.88 (s, 2H), 4.17 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.96 (m, 4H), 1.82 (m, 4H).

< Example  3> 2- (3- Methylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -ON (80 mg, 0.21 mmol) and 3-methylphenylboronic acid (34 mg, 0.25 mmol) were reacted in the same manner as in Step 5 of Example 1, whereby 80% of the title compound was obtained (73 mg, brown solid). .

Rf = 0.39 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.04 (s, 1H), 7,89 (m, 4H), 7.36 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 8.7 Hz, 1H ), 7.03 (dd, J = 2.4, 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.81 (s, 2H), 4.16 (t, J = 6.4 Hz, 2H), 3.93 (s , 3H), 2.95 (t, J = 6.4 Hz, 2H), 2.64 (m, 4H), 2.44 (s, 3H), 1.82 (m, 4H).

< Example  4> 2- (2- Ethylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -On (80 mg, 0.21 mmol) and 2-ethylphenylboronic acid (40 mg, 0.27 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain a yellow title compound (45 mg, 47%).

Rf = 0.29 (dichloromethane / methanol, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 7.9 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.41-7.32 (m, 3H), 7.27 (m, 1H), 7.09 (dd, J = 2.4, 8.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.89 (s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.77 (q, J = 7.5, 15.0 Hz, 2H), 2.65 (m, 4H), 1.82 ( m, 4H), 1.13 (t, J = 7.5 Hz, 3H).

< Example  5 > 2- (4- Ethylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 4-ethylphenylboronic acid (40 mg, 0.27 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain the title compound (60 mg, 63%) as a brown solid. .

Rf = 0.39 (dichloromethane / methanol, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 2.4 Hz, 1H), 7.88 (s, 2H), 7.31 (d, J = 8.2 Hz , 1H), 7.04 (dd, J = 2.4, 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.81 (s, 2H), 4.16 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.71 (q, J = 7.5, 15.0 Hz, 2H), 2.65 (m, 4H), 1.82 (m, 4H), 1.28 (t, J = 7.5 Hz, 3H).

< Example  6> 2- (4- Propylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

Toluene (4 ml) and methanol (1 ml) in 2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one (80 mg, 0.2 mmol) and 4-propylphenyl boronic acid (100 mg, 0.6 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title of the yellow solid. Compound (40 mg, 0.08 mmol, 41%) was obtained.

Rf = 0.36 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.07 (d, J = 8.1 Hz, 2H), 7.88-7.90 (m, 3H), 7.27-7.31 (m, 2H), 7.04 (dd, J = 8.7 Hz and 2.3 Hz, 1H), 6.93 (d , J = 8.7 Hz, 1H), 4.82 (s, 2H), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.3 Hz, 2H), 2.62-2.68 (m, 6H), 1.80-1.83 (m, 4H), 1.68 (q, J = 7.3 Hz, 2H), 0.97 (t, J = 7.3 Hz, 3H)

< Example  7> 2- (4- Butylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (75 mg, 0.2 mmol) and 4-butylphenylboronic acid (73 mg, 0.4 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a white solid (54 mg, 0.11 mmol, 58%). )

Rf = 0.35 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300 MHz, CDCl₃)

δ = 8.07 (d, J = 8.2 Hz, 2H), 7.89-7.90 (m, 3H), 7.30 (d, J = 8.2 Hz, 2H), 7.04 (dd, J = 8.7 Hz and 2. Hz, 1H) , 6.93 (d, J = 8.7 Hz, 1H), 4.83 (s, 2H), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 2.97 (t, J = 6.3 Hz, 2H) , 3.93 (s, 3H), 2.97 (t, J = 6.3 Hz, 2H), 1.81-1.85 (m, 6H), 1.61-1.67 (m, 2H), 1.34-1.42 (m, 2H), 0.94 (t , J = 7.3 Hz, 3H)

< Example  8> 2- (4- Isopropylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro -blood Rolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4-isopropylphenylboronic acid (60 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a yellow solid (60 mg, 0.13 mmol, 70 %) Was obtained.

Rf = 0.36 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.11 (d, J = 8.2 Hz, 2H), 7.91-7.93 (m, 3H), 7.36 (d, J = 8.2 Hz, 2H), 7.05 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 4.85 (s, 2H), 4.20 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.00 (t, J = 6.3 Hz, 2H), 2.90-2.98 (m, 1H), 2.70-2.72 (m, 4H), 1.82-1.88 (m, 4H), 1.31 (s, 3H), 1.28 (s, 3H)

< Example  9> 2- (4-t- Butylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4-tert-butylphenylboronic acid (67 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (45 mg, 0.09 mmol, 51.3%).

Rf = 0.31 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.11 (d, J = 8.4 Hz, 2H), 7.93 (d, J = 2.4 Hz, 1H), 7.91 (s, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.04 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.85 (s, 2H), 4.21 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.03 ( t, J = 6.1 Hz, 2H), 2.72-2.76 (m, 4H), 1.84-1.89 (m, 4H), 1.37 (s, 9H)

< Example  10> 2- (4- Vinylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (60 mg, 0.15 mmol) and 4-vinylphenylboronic acid (46 mg, 0.3 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (40 mg, 0.087 mmol, 57%) as a yellow solid. )

Rf = 0.34 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.15 (d, J = 8.3 Hz, 2H), 7.89-7.95 (m, 3H), 7.53 (d, J = 8.3 Hz, 2H), 7.05 (dd, J = 8.7 Hz and 2.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.77 (dd, J = 17.6 Hz and 10.9 Hz, 1H), 5.84 (d, J = 17.6 Hz, 1H), 5.33 (d, J = 10.9 Hz, 1H) , 4.84 (s, 2H), 4.18 (t, J = 6.2 Hz, 2H), 3.94 (s, 3H), 2.98 (t, J = 6.2 Hz, 2H), 2.67-2.69 (m, 4H), 1.81- 1.88 (m, 4H)

< Example  11> 2- [4- ( Methoxycarbonyl ) Phenyl ] -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4- (methoxycarbonyl) phenylboronic acid (65 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (35 mg, 0.07 mmol, 40%).

Rf = 0.22 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.22 (d, J = 8.1 Hz, 2H), 8.13 (d, J = 8.1 Hz, 2H), 7.88-7.95 (m, 3H), 7.03 (d, J = 8.7 Hz, 1H), 6.92 (d , J = 8.7 Hz, 1H), 4.83 (s, 2H), 4.16 (t, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.93 (s, 3H), 2.96 (t, J = 5.7 Hz , 2H), 2.64-2.68 (m, 4H), 1.80-1.84 (m, 4H)

< Example  12> 2- [4- ( Trifluoromethyl ) Phenyl ] -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4- (trifluoromethyl) phenylboronic acid (68 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (31 mg, 0.07 mmol, 39%).

Rf = 0.2 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.28 (d, J = 8.2 Hz, 2H), 7.93-7.99 (m, 2H), 7.90 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.05 (dd , J = 8.7 Hz and 2.4 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.87 (s, 2H), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 2.97 (t, J = 6.3 Hz, 2H), 2.65-2.69 (m, 4H), 1.81-1.85 (m, 4H)

< Example  13> 2- (4- Formylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4-formylphenylboronic acid (54 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (33 mg, 0.07 mmol, 40%) as a yellow solid. )

Rf = 0.2 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

delta = 10.10 (s, 1H). 8.22 (d, J = 8.2 Hz, 2H), 8.00-8.03 (m, 4H), 7.91 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.7 Hz and 2.3 Hz, 1H), 8.95 ( d, J = 8.7 Hz, 1H), 4.89 (s, 2H), 4.19 (t, J = 6.2 Hz, 2H), 3.94 (s, 3H), 2.98 (t, J = 6.2 Hz, 2H), 2.66- 2.70 (m, 4H), 1.81-1.86 (m, 4H)

< Example  14> 2- (4- Acetylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4-acetylphenylboronic acid (60 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a white solid (65 mg, 0.13 mmol, 76%). )

Rf = 0.25 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.27 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 7.98 (s, 2H), 7.90 (d, J = 2.5 Hz, 1H), 7.05 (dd, J = 8.7 Hz and 2.5 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.87 (s, 2H), 4.18 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 2.98 ( t, J = 6.3 Hz, 2H), 2.66-2.70 (m, 4H), 1.81-1.86 (m, 4H)

< Example  15> 2- ( Benzo [1,3] dioxoles -5-day) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 3,4- (methylenedioxyl) phenylboronic acid (60 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (70 mg) as a white solid. , 0.15 mmol, 82%) was obtained.

Rf = 0.2 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 7.91 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 8.2 Hz and 1.7 Hz, 1H), 7.04 (dd, J = 8.7 Hz and 2.5 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.2 Hz , 1H), 6.03 (s, 2H), 4.84 (s, 2H), 4.19 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 2.99 (t, J = 6.3 Hz, 2H), 2.68 -2.72 (m, 4H), 1.82-1.86 (m, 4H)

< Example  16> 2- (4- Hydroxyphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - pyrrolo [ 3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4-hydroxyphenylboronic acid (50 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a yellow solid (27 mg, 0.06 mmol, 34 %) Was obtained.

Rf = 0.06 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 9.83 (s, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.2 Hz, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 8.7 Hz and 2.5 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 4.99 (s, 2H), 4.07 (t, J = 5.9 Hz, 2H), 3.80 (s, 3H), 2.84 (t, J = 5.9 Hz, 2H), 2.54-2.62 (m, 4H), 1.66-1.72 (m, 4H )

< Example  17> 2- (4- Aminophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 4-aminophenylboronic acid pinacol ester (79 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (31 mg, 0.07 mmol) as a yellow solid. , 39%).

Rf = 0.07 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.03 (d, J = 8.5 Hz, 2H), 7.91 (d, J = 2.4 Hz, 1H), 7.84 (s, 2H), 7.05 (dd, J = 8.7 Hz and 2.5 Hz, 1H), 6.95 ( d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.5 Hz, 2H), 4.82 (s, 2H), 4.19 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 3.89 ( brs, 2H), 2.98 (t, J = 6.3 Hz, 2H), 2.64-2.70 (m, 4H), 1.81-1.85 (m, 4H)

< Example  18> 2- (4- Methylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 4-methylphenylboronic acid (44 mg, 0.32 mmol) were reacted in the same manner as in Step 5 of Example 1 to obtain the title compound (53 mg, 57%) as a white solid.

Rf = 0.44 (MC: MeOH = 9: 1 + 0.5% NH ₄ OH)

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.06 (d, 2H, J = 8.2 Hz), 7.97 (d, 1H, J = 2.3 Hz), 7.88 (s, 2H), 7.28 (d, 2H, J = 8.2 Hz), 7.00 (dd, 1H, J = 8.7, 2.3 Hz), 6.93 (d, 1H, J = 8.7 Hz), 4.81 (s, 2H), 4.30 (t, 2H, J = 5.7 Hz), 3.00 (s, 3H), 3.18 (t, 2H, J = 5.7 Hz), 2.98 (m, 4H), 2.41 (s, 3H), 1.96 (m, 4H)

< Example  19> 2- (4- Methoxyphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 4-methoxyphenylboronic acid (49 mg, 0.32 mmol) were reacted in the same manner as in Step 5 of Example 1 to obtain the title compound (63 mg, 65%) as a white solid. Got it.

Rf = 0.44 (MC: MeOH = 9: 1 + 0.5% NH ₄ OH)

¹ H NMR (300 MHz, CDCl 3): δ 8.12 (d, 2H, J = 8.9 Hz), 7.90 (d, 1H, J = 2.4 Hz), 7.84 (m, 2H), 7.03 (dd, 1H, J = 8.7 , 2.4 Hz), 6.99 (d, 2H, J = 8.9 Hz), 6.92 (d, 1H, J = 8.7 Hz), 4.79 (s, 2H), 4.16 (t, 2H, J = 6.5 Hz), 3.92 ( s, 3H), 3.86 (s, 3H), 2.96 (t, 2H, J = 6.5 Hz), 2.65 (m, 4H), 1.82 (m, 4H)

< Example  20> 2- (4- Benzyloxyphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol), 4- (benzyloxy) phenylboronic acid pinacol ester (99 mg, 0.32 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a white solid (45 mg). , 40%).

Rf = 0.44 (MC: MeOH = 9: 1 + 0.5% NH ₄ OH)

¹ H NMR (300 MHz, CDCl 3): δ 8.13 (d, 2H, J = 8.6 Hz), 7.96 (d, 1H, J = 2.3 Hz), 7.85 (m, 2H), 7.48-7.34 (m, 5H), 7.08 (d, 2H, J = 8.6 Hz), 7.01 (dd, 1H, J = 8.7, 2.4 Hz), 6.95 (d, 1H, J = 8.7 Hz), 5.13 (s, 2H), 4.81 (s, 2H ), 4.28 (t, 2H, J = 5.9 Hz), 3.92 (s, 3H), 3.13 (t, 2H, J = 5.9 Hz), 2.91 (m, 4H), 1.93 (m, 4H)

< Example  21> 2- (4- Chlorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (98 mg, 0.25 mmol) and 4-chlorophenylboronic acid (59 mg, 0.38 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain the title compound (50 mg, 43%) as a white solid. .

Rf = 0.43 (MC: MeOH = 9: 1 + 1% NH ₄ OH)

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.10 (d, 2H, J = 8.6 Hz), 7.88 (m, 3H), 7.45 (d, 2H, J = 8.6 Hz), 7.02 (dd, 1H, J = 8.7, 2.4 Hz, 6.93 (d, 1H, J = 8.7 Hz), 4.82 (s, 2H), 4.20 (t, 2H, J = 6.2 Hz), 3.92 (s, 3H), 3.02 (t, 2H, J = 6.2 Hz), 2.74 (m, 4H), 1,86 (m, 4H)

< Example  22> 2- (4- Fluorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol), 4-fluorophenylboronic acid (45 mg, 0.32 mmol) were reacted in the same manner as in Step 5 of Example 1 to obtain the title compound (44 mg, 47%) as a white solid. Got it.

Rf = 0.44 (MC: MeOH = 9: 1 + 0.5% NH ₄ OH)

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.16 (m, 2H), 7.90 (m, 3H), 7.17 (m, 2H), 7.04 (dd, 1H, J = 8.7, 2.4 Hz), 6.93 (d, 1H, J = 8.7 Hz), 4.84 (s, 2H), 4.19 (t, 2H, J = 6.3 Hz), 3.93 (s, 3H), 2.99 (t, 2H, J = 6.3 Hz), 2.69 (m, 4H), 1.84 (m, 4H)

< Example  23> 2- (2- Methoxyphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

Step 1: 6- (2- Methoxyphenyl ) -3- methyl Pyridine-2- Carboxylic acid methyl  Preparation of esters

6-chloro-3-methyl-pyridine-2-carboxylic acid methyl ester (150 mg, 0.97 mmol) with 2-methoxyphenylboronic acid (147 mg, 0.97 mmol), 2M-sodium carbonate, catalytic amount of Pd (PPh _{3 4} ) was refluxed for 2 hours in 9 ml of toluene and methanol (1/1, v / v) solvent. After cooling to room temperature, the mixture was extracted twice with 30 ml of ethyl acetate and 30 ml of water. The organic layer was washed once with brine. The oil layer was dried over anhydrous MgSO _4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (normal hexane and ethyl acetate, 50/1, v / v) to give 170 mg of the target compound as a white solid (82%).

R _f = 0.26 (normal hexane and ethyl acetate, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (d, J = 8.1 Hz, 1H), 7.82 (dd, J = 1.8, 7.6 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.36 (m, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 3.97 (s, 3H), 3.84 (s, 3H), 2.59 (s, 3H) .

Step 2: 3- Bromomethyl -6- (2- Methoxyphenyl ) -Pyridine-2- Carboxylic acid methyl  Preparation of esters

6- (2-methoxyphenyl) -3-methylpyridine-2-carboxylic acid methyl ester (165 mg, 0.64 mmol) was dissolved in 5 ml of carbon tetrachloride and then N -bromosuccinimide (NBS, 171 mg). , 0.96 mmol) and benzoyl peroxide were added, and the mixture was stirred under reflux for 3 hours. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (normal hexane and ethyl acetate, 50/1, v / v) to give 125 mg of the target compound as a yellow solid (58%).

R _f = 0.26 (normal hexane and ethyl acetate, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (d, J = 8.3 Hz, 1H), 7.85 (dd, J = 8.3, 1.6 Hz, 2H), 7.39 (m, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 4.93 (s, 2H), 4.02 (s, 3H), 3.85 (s, 3H).

Step 3: 2- (2- Methoxyphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine Preparation of -7-one

3-bromomethyl-6- (2-methoxyphenyl) -pyridine-2-carboxylic acid methyl ester (125 mg, 0.37 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl -Ethoxy) phenylamine (80 mg, 0.34 mmol) was dissolved in 3 ml of acetic acid and stirred under reflux for 4 hours. The solvent was concentrated under reduced pressure and extracted with 30 ml of dichloromethane and 30 ml of saturated sodium hydrogen carbonate. The water layer was extracted once more. The oil layer was dried over anhydrous MgSO _4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane and methanol, 10/1, v / v) to give 48 mg of the target compound as a yellow foam compound (28%).

Rf = 0.17 (dichloromethane / methanol, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.90-7.82 (m, 2H), 7.39 (t, J = 7.5 Hz, 1H), 7.13-7.04 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.83 (s, 2H), 4.17 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 2.95 (t, J = 6.4 Hz, 2H), 2.64 (m, 4H), 1.82 (m, 4H).

< Example  24 > 2- (3- Methoxyphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-bromomethyl-6- (3-methoxyphenyl) -pyridine-2-carboxylic acid methyl ester (112 mg, 0.33 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl -Ethoxy) phenylamine (71 mg, 0.30 mmol) was reacted in the same manner as Step 3 of Example 23 to obtain the title compound (78 mg, 51%) as a pale yellow solid.

Rf = 0.26 (dichloromethane / methanol, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (m, 3H), 7.76 (m, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.04 (dd, J = 2.4, 8.7 Hz, 1H), 6.99 (dd, J = 2.4, 8.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.84 (s, 2H), 4.17 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 2.96 (s, 3H), 2.65 (m, 4H), 1.82 (m, 4H).

< Example  25> 2- (2- Chlorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-Bromomethyl-6- (2-chlorophenyl) -pyridine-2-carboxylic acid methyl ester (139 mg, 0.41 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl- Ethoxy) phenylamine (87 mg, 0.37 mmol) was reacted in the same manner as Step 3 of Example 23 to obtain the title compound (90 mg, 52%) as a yellow solid.

Rf = 0.47 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.23 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.62 (m , 2H), 7.51 (m, 2H), 7.39 (dd, J = 2.1, 8.8 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 5.09 (s, 2H), 4.28 (t, J = 4.6 Hz, 2H), 3.85 (s, 3H), 3.54 (t, J = 4.6 Hz, 2H), 3.33 (m, 4H), 1.94 (m, 4H).

< Example  26> 2- (3- Chlorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-Bromomethyl-6- (3-chlorophenyl) -pyridine-2-carboxylic acid methyl ester (100 mg, 0.29 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl- Ethoxy) phenylamine (68 mg, 0.26 mmol) was reacted in the same manner as Step 3 of Example 23 to obtain the title compound (53 mg, 44%) as a pale yellow solid.

Rf = 0.40 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 7.98 (m, 1H), 7.94-7.82 (m, 3H), 7.38 (d, J = 4.2 Hz, 2H), 7.01 (dd, J = 2.2, 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.80 (s, 2H), 4.17 (t, J = 6.3 Hz, 2H), 3.91 (s, 3H), 2.99 ( t, J = 6.3 Hz, 2H), 2.70 (m, 4H), 1.84 (m, 4H).

< Example  27> 2- (2- Fluorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-Bromomethyl-6- (2-fluorophenyl) -pyridine-2-carboxylic acid methyl ester (124 mg, 0.38 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl -Ethoxy) phenylamine (83 mg, 0.35 mmol) was reacted in the same manner as Step 3 of Example 23 to obtain the title compound (76 mg, 49%) as a pale yellow solid.

Rf = 0.43 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.24 (d, J = 8.1 Hz, 1H), 8.01 (dd, J = 1.5, 8.1 Hz, 1H), 7.96 (m, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.54 (m, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.38 (m, 1H), 7.15 (d, J = 8.8 Hz, 1H), 5.08 (s, 2H) , 4.27 (t, J = 4.7 Hz, 2H), 3.85 (s, 3H), 2.53 (t, J = 4.7 Hz, 2H), 3.33 (m, 4H), 2.49 (m, 4H).

< Example  28> 2- (3- Fluorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-bromomethyl-6- (3-fluorophenyl) -pyridine-2-carboxylic acid methyl ester (76 mg, 0.23 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl -Ethoxy) phenylamine (50 mg, 0.21 mmol) was reacted in the same manner as Step 3 of Example 23 to obtain the title compound (42 mg, 45%) as a pale yellow solid.

Rf = 0.4 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97-7.89 (m, 5H), 7.45 (m, 1H), 7.14 (m, 1H), 7.05 (dd, J = 2.4, 8.7 Hz, 1H), 6.95 ( d, J = 8.7 Hz, 1H), 4.87 (s, 2H), 4.19 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.98 (t, J = 6.4 Hz, 2H), 2.68 ( m, 4H), 1.83 (m, 4H).

< Example  29> 2- (3- Cyanophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-Bromomethyl-6- (3-cyanophenyl) -pyridine-2-carboxylic acid methyl ester (123 mg, 0.37 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl -Ethoxy) phenylamine (80 mg, 0.34 mmol) was reacted in the same manner as Step 3 of Example 23 to obtain the title compound (63 mg, 39%) as a yellow solid.

Rf = 0.3 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.42 (m, 2H), 8.00 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 2.4 Hz , 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.06 (dd, J = 2.4, 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz , 1H), 4.89 (s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.65 (m, 4H), 1.82 (m, 4 H).

< Example  30> 2- (4- Cyanophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-bromomethyl-6- (4-cyanophenyl) -pyridine-2-carboxylic acid methyl ester (64 mg, 0.19 mmol) and 3-methoxy-4- (2-pyrrolidin-1-yl -Ethoxy) phenylamine (41 mg, 0.17 mmol) was reacted in the same manner as Step 3 of Example 23 to obtain the title compound (31 mg, 38%) as a yellow solid.

Rf = 0.16 (dichloromethane / methanol / ammonia water, 20/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.28 (d, J = 8.4 Hz, 2H), 8.00 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.88 (d , J = 2.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.05 (dd, J = 2.4, 8.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.87 (s , 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.98 (t, J = 6.4 Hz, 2H), 2.68 (m, 4H), 1.83 (m, 4H).

< Example  31> 2- (2,3- Dimethylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - pyrrolo [ 3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (60 mg, 0.15 mmol) and 2,3-dimethylphenylboronic acid (27 mg, 0.18 mmol) were reacted in the same manner as in Step 5 of Example 1 to obtain the title compound (13 mg, 19%) as a dark green solid. Got it.

Rf = 0.40 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.27 (m) , 2H), 7.20 (m, 1H), 7.08 (dd, J = 2.4, 8.7 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 4.89 (s, 2H), 4.20 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.99 (t, J = 6.4 Hz, 2H), 2.69 (m, 4H), 2.35 (s, 3H), 2.25 (s, 3H), 1.84 (m, 4H).

< Example  32> 2- (2,5- Dimethylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - pyrrolo [ 3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 2,5-dimethylphenylboronic acid (41 mg, 0.27 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a brown solid (61 mg, 64%). Got.

Rf = 0.38 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.32 (s , 1H), 7.16 (m, 2H), 7.07 (dd, J = 2.3, 8.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.88 (s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.97 (t, J = 6.4 Hz, 2H), 2.66 (m, 4H), 2.36 (m, 4H), 1.82 (m, 4H).

< Example  33> 2- (3,5- Dimethylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - pyrrolo [ 3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 3,5-dimethylphenylboronic acid (41 mg, 0.27 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as an orange solid (49 mg, 51%). Got.

Rf = 0.39 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (d, J = 2.4 Hz, 1H), 7.89 (m, 2H), 7.78 (s, 2H), 7.08 (s, 1H), 7.04 (dd, J = 2.4, 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.81 (s, 2H), 4.16 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.95 (t, J = 6.4 Hz, 2H), 2.65 (m, 4H), 2.40 (s, 6H), 1.82 (m, 4H).

< Example  34> 2- (3,4- Dimethylphenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) - Phenyl ] -5,6- Dihydro -blood Rolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 3,4-dimethylphenylboronic acid (54 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (44 mg, 0.09 mmol, 54%).

Rf = 0.21 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.02 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 1.6 Hz, 2H), 7.85 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.03 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.82 (s, 2H), 4.20 (t, J = 6.3 Hz, 2H), 3.92 (s, 3H), 3.00 (t, J = 6.3 Hz, 2H), 2.70-2.74 (m, 4H), 2.35 (s, 3H), 2.32 (s, 3H), 1.82-1.86 (m , 4H)

< Example  35> 2-[(3- Fluoro -4- methyl ) Phenyl ] -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 3-fluoro-4-methylphenylboronic acid (42 mg, 0.27 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (35 mg, 36% as an ocher solid). )

Rf = 0.44 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92-7.81 (m, 5H), 7.28 (m, 1H), 7.04 (dd, J = 2.4, 8.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 4.83 (s, 2H), 4.17 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.65 (m, 4H), 2.33 ( s, 3H), 1.82 (m, 4H).

< Example  36> 2- (2,3- Difluorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 2,3-difluorophenyl-boronic acid (43 mg, 0.27 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a brown solid (48 mg, 49 %) Was obtained.

Rf = 0.15 (dichloromethane / methanol, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.01 (m, 3H), 7.88 (s, 1H), 7.30-7.20 (m, 2H), 7.07 (dd, J = 2.4, 8.7 Hz, 1H), 6.95 ( d, J = 8.7 Hz, 1H), 4.90 (s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.97 (t, J = 6.4 Hz, 2H), 2.65 ( m, 4H), 1.82 (m, 4H).

< Example  37> 2- (3,4- Difluorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (190 mg, 0.49 mmol) and 3,4-difluorophenylboronic acid (117 mg, 0.74 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (52 mg, 23%) as a white solid. )

Rf = 0.44 (MC: MeOH = 9: 1 + 0.5% NH ₄ OH)

¹ H NMR (300 MHz, CDCl ₃ ): δ 8.05 (m, 1H), 7.96-7.85 (m, 4H), 7.26 (m, 1H), 7.04 (dd, 1H, J = 8.7, 2.4 Hz), 6.94 ( d, 1H, J = 8.7 Hz), 4.86 (s, 2H), 4.20 (t, 2H, J = 6.3 Hz), 3.93 (s, 3H), 3.01 (t, 2H, J = 6.3 Hz), 2.72 ( m, 4H), 1.86 (m, 4H)

< Example  38> 2- (2,3- Dichlorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -On (65 mg, 0.17 mmol) and 2,3-dichlorophenylboronic acid (42 mg, 0.22 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as an ivory solid (20 mg, 24%). Got.

Rf = 0.15 (dichloromethane / methanol, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (d, J = 8.0 Hz, 1H), 7.85-7.80 (m, 2H), 7.60 (dd, J = 1.7, 7.8 Hz, 1H), 7.55 (dd, J = 1.7, 8.0 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.09 (dd, J = 2.6, 8.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.91 ( s, 2H), 4.18 (t, J = 6.4 Hz, 2H), 3.93 (s, 3H), 2.97 (t, J = 6.4 Hz, 2H), 2.66 (m, 4H), 1.83 (m, 4H).

< Example  39> 2- (3,5- Dichlorophenyl ) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (80 mg, 0.21 mmol) and 3,5-dichlorophenylboronic acid (52 mg, 0.27 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a yellow solid (36 mg, 34% )

Rf = 0.18 (dichloromethane / methanol, 10/1, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (d, J = 1.2 Hz, 2H), 7.97 (d, J = 8.1 Hz, 1H), 7.88 (m, 2H), 7.43 (m, 1H), 7.04 (dd, J = 1.8, 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.87 (s, 2H), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H) , 2.97 (t, J = 6.3 Hz, 2H), 2.65 (m, 4H), 1.82 (m, 4H).

< Example  40> 2- (naphthalen-2-yl) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

3-Bromomethyl-6-naphthalen-2-yl-pyridine-2-carboxylic acid methyl ester (6-9) (108 mg, 0.30 mmol) and 3-methoxy-4- (2-pyrrolidine- 1-yl-ethoxy) phenylamine (64 mg, 0.27 mmol) was reacted in the same manner as in Step 3 of Example 23, to obtain the title compound (58 mg, 40%) as a yellow solid.

Rf = 0.31 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.67 (s, 1H), 8.28 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 8.00-7.90 (m, 4H) , 7.87 (m, 1H), 7.53 (m, 2H), 7.05 (dd, J = 1.9, 8.6 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 4.82 (s, 2H), 4.17 ( t, J = 6.4 Hz, 2H), 3.94 (s, 3H), 2.96 (t, J = 6.4 Hz, 2H), 2.65 (m, 4H), 1.82 (m, 4H).

< Example  41> 2- (naphthalen-1-yl) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (70 mg, 0.18 mmol) and 1-naphthaleneboronic acid (62 mg, 0.36 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a red solid (45 mg, 0.09 mmol, 52%). Got.

Rf = 0.35 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.09 (d, J = 7.5 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.89-7.95 (m, 3H), 7.77 (d, J = 7.9 Hz, 1H), 7.69 (d , J = 6.5 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.45-7.54 (m, 2H), 7.09 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.92 (s, 2H), 4.21 (t, J = 6.2 Hz, 2H), 3.93 (s, 3H), 3.02 (t, J = 6.2 Hz, 2H), 2.72-2.74 (m , 4H), 1.84-1.86 (m, 4H)

< Example  42> 2- ( Biphenyl -4-yl) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (60 mg, 0.15 mmol) and 4-ylphenylboronic acid (60 mg, 0.3 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound as a white solid (50 mg, 0.098 mmol, 64%). )

Rf = 0.34 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.24 (d, J = 8.3 Hz, 2H), 7.91-7.97 (m, 3H), 7.72 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 7.4 Hz, 2H), 7.47 (d , J = 7.2 Hz, 2H), 7.35-7.40 (m, 1H), 7.05 (dd, J = 8.7 Hz and 2.3 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.83 (s, 2H ), 4.17 (t, J = 6.3 Hz, 2H), 3.93 (s, 3H), 2.97 (t, J = 6.3 Hz, 2H), 2.65-2.69 (m, 4H), 1.81-1.85 (m, 4H)

< Example  43> 2- ( Biphenyl -3-yl) -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) - Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (60 mg, 0.15 mmol) and 3-ylphenylboronic acid (61 mg, 0.3 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (50 mg, 0.1 mmol, 64%) as a yellow solid. )

Rf = 0.33 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.39 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.98 (d, J = 6.7 Hz, 2H), 7.94-7.96 (m, 1H), 7.69 (d, J = 7.7 Hz , 3H), 7.59 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.3 Hz, 2H), 7.39 (d, J = 7.3 Hz, 1H), 7.05 (dd, J = 8.7 Hz and 2.4 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.88 (s, 2H), 4.19 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 2.98 (t, J = 6.3 Hz, 2H), 2.66-2.70 (m, 4H), 1.82-1.84 (m, 4H)

< Example  44> 2- [4- (naphthalen-1-yl) Phenyl ] -6- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -One (60 mg, 0.15 mmol) and 4- (1-naphthyl) phenylboronic acid (76 mg, 0.3 mmol) were reacted in the same manner as in Step 5 of Example 1 to give the title compound (50 mg, 0.09 mmol, 58%).

Rf = 0.37 (dichloromethane: methanol = 1: 9)

¹ H-NMR (300MHz, CDCl₃)

δ = 8.30 (d, J = 8.2 Hz, 2H), 7.87-8.04 (m, 6H), 7.64 (d, J = 8.2 Hz, 2H), 7.43-7.57 (m, 4H), 7.08 (dd, J = 8.7 Hz and 2.3 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 4.89 (s, 2H), 4.18 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 2.98 (t , J = 6.3 Hz, 2H), 2.65-2.69 (m, 4H), 1.82-1.85 (m, 4H)

< Example  45> 2- (4- Methylphenyl ) -6- [3- Methoxy -4- (2-piperidin-1-yl- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -On (125 mg, 0.32 mmol) and 4-methylphenylboronic acid (65 mg, 0.48 mmol) were reacted in the same manner as in Example 5, to obtain the title compound (110 mg, 75%) as a brown solid.

Rf = 0.27 (dichloromethane / methanol _/ ammonia water, 10/1/1%, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.1 Hz, 2H), 7.89 (m, 3H), 7.29 (d, J = 8.1 Hz, 2H), 7.04 (dd, J = 2.5, 8.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.82 (s, 2H), 4.17 (t, J = 6.5 Hz, 2H), 3.93 (s, 3H), 2.83 (t, J = 6.5 Hz, 2H), 2.54 (m, 4H), 2.42 (s, 3H), 1.63 (m, 4H), 1.46 (m, 2H).

< Example  46> 2- (4- Methylphenyl ) -6- [3- Methoxy -4- (2- Morpholine -1 day- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-morpholin-4-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7- On (140 mg, 0.35 mmol) and 4-methylphenylboronic acid (72 mg, 0.53 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain the title compound (150 mg, 93%) as a brown solid.

Rf = 0.16 (dichloromethane / methanol, 20/1 /, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.0 Hz, 2H), 7.91 (s, 3H), 7.30 (d, J = 8.0 H, 2H), 7.08 (dd, J = 2.2, 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.82 (s, 2H), 4.18 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 3.75 (t, J = 4.5 Hz, 4H), 2.85 (t, J = 6.1 Hz, 2H), 2.61 (m, 4H), 2.42 (s, 3H ).

< Example  47> 2- (4- Methylphenyl ) -6- [3- Methoxy -4- [2- (4- Methylpiperazine -1 day) Ethoxy ] Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b] Reaction of pyridin-7-one (85 mg, 0.21 mmol) with 4-methylphenylboronic acid (44 mg, 0.53 mmol) in the same manner as in step 5 of Example 1 to give the title compound as a yellow solid (65 mg, 66%). Got.

Rf = 0.13 (dichloromethane / methanol, 10/1 /, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.08 (d, J = 8.0 Hz, 2H), 7.90 (s, 3H), 7.30 (d, J = 8.0 H, 2H), 7.06 (dd, J = 2.4, 8.7 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 4.84 (s, 2H), 4.17 (t, J = 6.2 Hz, 2H), 3.93 (s, 3H), 2.87 (t, J = 6.2 Hz, 2H), 2.65 (m, 4H), 2.50 (m, 4H), 2.42 (s, 3H), 2.30 (s , 3H).

< Example  48> 2- (4- Methylphenyl ) -6- [3- Methoxy -4- (2- Thiomorpholine Yl- Ethoxy ) Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-thiomorpholin-4-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridine-7 -On (160 mg, 0.39 mmol) and 4-methylphenylboronic acid (80 mg, 0.53 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain the title compound (159 mg, 86%) as a yellow solid.

Rf = 0.16 (dichloromethane / methanol, 10/1 /, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.05 (d, J = 8.0 Hz, 2H), 7.87 (s, 3H), 7.27 (d, J = 8.0 H, 2H), 7.04 (dd, J = 2.2, 8.7 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 4.79 (s, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 2.87 (m, 6H) , 2.07 (m, 4 H), 2.41 (s, 3 H).

< Example  49> 2- (4- Methylphenyl ) -6- [3- Methoxy -4-[(2- Dimethylamino ) Ethoxy ] Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-Chloro-6- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one (100 mg, 0.28 mmol) and 4-methylphenylboronic acid (57 mg, 0.42 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain the title compound (94 mg, 55%) as a yellow solid.

Rf = 0.34 (dichloromethane / methanol, 10/1 /, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, J = 8.0 Hz, 2H), 7.92 (s, 3H), 7.30 (d, J = 8.0 H, 2H), 7.06 (dd, J = 2.4, 8.7 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 4.86 (s, 2H), 4.15 (t, J = 6.1 Hz, 2H), 3.93 (s, 3H), 2.80 (t, J = 6.1 Hz, 4H), 2.42 (s, 3H), 2.36 (s, 6H).

< Example  50> 2- (4- Methylphenyl ) -6- [3- Methoxy -4-[(2- Diethylamino ) Ethoxy ] Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-Chloro-6- [3-methoxy-4- (2-dimethylamino-ethoxy) -phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one (95 mg, 0.25 mmol) and 4-methylphenylboronic acid (52 mg, 0.38 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain the title compound (95 mg, 86%) as a brown solid.

Rf = 0.27 (dichloromethane / methanol, 10/1 /, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.1 Hz, 2H), 7.90 (d, J = 2.3 Hz, 1H), 7.89 (s, 2H), 7.29 (d, J = 8.1 Hz , 2H), 7.04 (dd, J = 2.3, 8.7 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 4.82 (s, 2H), 4.11 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 2.94 (t, J = 6.8 Hz, 2H), 2.65 (q, J = 7.1, 14.3 Hz, 4H), 2.41 (s, 3H), 1.08 (t, J = 7.1 Hz, 6H) .

< Example  51> 2- (4- Methylphenyl ) -6- [3- Methoxy -4-[(2- Dipropylamino ) Ethoxy ] Phenyl ] -5,6- Dihydro - Pyrrolo [3,4-b] pyridine -7-one

2-chloro-6- [3-methoxy-4- (2-dipropylamino-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one (110 mg, 0.27 mmol) and 4-methylphenylboronic acid (56 mg, 0.41 mmol) were reacted in the same manner as in Step 5 of Example 1, to obtain the title compound (81 mg, 64%) as a yellow solid.

Rf = 0.34 (dichloromethane / methanol, 10/1 /, v / v)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 8.0 Hz, 2H), 7.90 (m, 3H), 7.29 (d, J = 8.0 H, 2H), 7.06dd, J = 2.4, 8.8 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.83 (s, 2H), 4.10 (t, J = 6.8 Hz, 2H), 3.93 (s, 3H), 2.93 (t, J = 6.8 Hz, 2H), 2.50 (t, J = 7.3 Hz, 4H), 2.42 (s, 3H), 1.49 (m, 4H), 0.90 (t, J = 7.3 Hz, 6H).

< Example  52> 2- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -6- Phenyl -2,3- Dihydro - Pyrrolo [3,4-c] pyridine -1-one

6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -2-chloro-5,6-dihydro-pyrrolo [3,4-b] pyridine-7 90 mg (0.21 mmol, 81%) of the title compound was reacted in the same manner as in Example 5, using -one (80 mg, 0.21 mmol) and 63 mg (0.52 mmol) of phenylboronic acid. .

Rf = 0.13 (10% methanol / dichloromethane)

¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.94 (s, 1H), 8.21 (s, 1H), 8.09 (d, J = 6.7 Hz, 2H), 7.79 (s, 1H), 7.55-7.45 (m, 3H), 7.08 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 8.7 Hz, 1H), 4.96 (s, 2H), 4.18 (t, 2H), 3.93 (s, 3H), 2.97 ( t, 2H), 2.66 (m, 4H), 1.83 (m, 4H)

< Example  53> 2- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -6- (4- Methylphenyl ) -2,3- All Ehydro- Pyrrolo [3,4-c] pyridine -1-one

6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -2-chloro-5,6-dihydro-pyrrolo [3,4-b] pyridine-7 83 mg (0.18 mmol, 72%) of the brown solid title compound was reacted in the same manner as in Example 5, using -one (80 mg, 0.21 mmol) and 71 mg (0.52 mmol) of 4-methylphenylboronic acid. Got.

Rf = 0.13 (10% methanol / dichloromethane)

¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.92 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 7.6 Hz, 2H), 7.79 (s, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 8.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 4.97 (s, 2H), 4.21 (t, 2H), 3.94 (s, 3H) , 2.97 (t, 2H), 2.66 (m, 4H), 2.43 (s, 3H), 1.82 (m, 4H)

< Example  54> 2- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -6- (4- Ethylphenyl ) -2,3- Dihydro - Pyrrolo [3,4-c] pyridine -1-one

6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -2-chloro-5,6-dihydro-pyrrolo [3,4-b] pyridine-7 100 mg (0.22 mmol, 81%) of a yellow solid titled by reaction in the same manner as in Step 5 of Example 1 using -one (80 mg, 0.21 mmol) and 78 mg (0.52 mmol) of 4-ethylphenylboronic acid The compound was obtained.

Rf = 0.12 (10% methanol / dichloromethane)

¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.92 (s, 1H), 8.19 (s, 1H), 8.00 (d, J = 7.4 Hz, 2H), 7.79 (s, 1H), 7.33 (d, J = 7.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 4.97 (s, 2H), 4.21 (t, 2H), 3.91 (s, 3H) , 2.95 (t, 2H), 2.74 (q, 3H), 2.63 (m, 4H), 1.80 (m, 4H), 1.25 (t, 3H)

< Example  55> 2- [3- Methoxy -4- (2- Pyrrolidine -1 day- Ethoxy ) Phenyl ] -6- (naphthalen-2-yl) -2,3- Dihydro - pyrrolo [ 3,4-c] pyridine -1-one

6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -2-chloro-5,6-dihydro-pyrrolo [3,4-b] pyridine-7 120 mg (0.25 mmol, 96%) of the title compound was reacted in the same manner as in Step 5 of Example 1 using -one (80 mg, 0.21 mmol) and 89 mg (0.52 mmol) of 2-naphthaleneboronic acid. Got.

Rf = 0.4 (10% methanol / dichloromethane / 1% ammonia water)

¹ H NMR (300 MHz, CDCl ₃ ) δ = 8.99 (s, 1H), 8.59 (s, 1H), 8.36 (s, 1H), 8.23 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.89 (m, 1H), 7.79 (s, 1H), 7.55 (m, 2H), 7.08 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H) , 4.99 (s, 2H), 4.17 (t, 2H), 3.92 (s, 3H), 2.95 (t, 2H), 2.66 (m, 4H), 1.81 (m, 4H)

< Experimental Example  1> MCH  Receptor-1 receptor-1 binding inhibitory activity measurement

In order to investigate the MCH receptor-1 binding inhibitory activity against the pyrrolopyridinone derivatives according to the present invention, the following experiment was performed.

The buffer solution is prepared by two kinds of washing solution (25 mM HEPES pH 7.4, 5 mM MgCl ₂ , 1 mM CaCl ₂ ) and experimental solution (adding 0.5% BSA to the washing solution), and MCH receptor-1 (melanin). Enriched hormone receptor subtype-1; Euroscreen, Gosselies, Belgium) and 1 μM europium-labeled melanin enriched hormone (Europium-labeled MCH receptor-1, Eu-MCH receptor-1), PerkinElmer, Turku, Finland) and 1 mM melanin enriched hormone (MCH receptor-1, # 070-47, Phoenix, Belmont CA, USA) was prepared at 4 ° C. 1 μM europium-labeled melanin enriched hormone (Eu-MCH receptor-1) and 1 mM melanin enriched hormone were 8 nM (final reaction concentration: 2 nM) and 2 μM (final reaction concentration: 0.5 μM), respectively. Diluted. The buffer solution used in all dilutions and preparations was the experimental solution, and the wash solution was used only to wash the plate at the end.

After diluting and homogenizing MCH receptor-1 (200 assays / vial) in 1 ml of experimental solution, the 8-channel pie was placed on a filter paper-attached microplate (Multiwell 96 well filter plates PN5020, Pall Co. Ann Arbor MI, USA). The reaction was dispensed using a pet (multi 8-channel, Eppendorf, Hamburg, Germany) to 100 μl total volume per well. In this case, 25 μl of melanin enriched hormone (Eu-MCH receptor-1), 50 μl of receptor and 25 μl of melanin enriched hormone were used as a non-specific binding control, and total binding. As a control, 25 μl of 10% DMSO experimental solution, 25 μl of melanin-enriched hormone (Eu-MCH receptor-1) labeled with europium, and 50 μl of receptor were used. As the experimental group, 25 μl of the compounds of Examples 1 to 55, 25 μl of melanin-enriched hormone (Eu-MCH receptor-1) labeled with europium and 50 μl of the receptor were used. Since each test compound, europium-labeled melanin enriched hormone (Eu-MCH receptor-1) and melanin enriched hormone occupy 25% of the total volume during the reaction, it was prepared at a concentration of 4 times immediately before addition. Then, shake gently for 15 seconds and reacted at room temperature for 90 minutes. After the reaction, the plate was washed by applying pressure to a partially prepared washer (microplate washer, EMBLA, Molecular Devices). 300 μl per well was washed three times with the washing solution to remove the remaining melanin enriched hormone (Eu-MCH receptor-1) labeled with europium. Wipe off the water on the bottom and 150 μl per well was added to the dissociation solution (DELFIA Enhancement solution, PerkinElmer, Turku, Finland). After standing at room temperature for 2 to 4 hours, time-resolved fluorescence (TRF) values were measured using a multi-function fluorometer (multilabel counter, Victor2, PerkinElmer, Turku, Finland) (emission wavelength: 615 nm). , Excitation wavelength: 340 nm), and the differential fluorescence inhibition rate was calculated by the following equation.

Equation  One

After measuring the differential fluorescence inhibition rate, IC ₅₀ values were calculated for test substances inhibited by 50% or more, and the results are shown in Table 2 below.

compound IC ₅₀ (nM) Example 1 > 10,000 Example 2 1,040 Example 3 1,600 Example 4 2,000 Example 5 50 Example 6 210 Example 7 2,780 Example 8 90 Example 9 320 Example 10 130 Example 11 > 10,000 Example 12 540 Example 13 14,000 Example 14 7,180 Example 15 6,280 Example 16 > 10,000 Example 17 > 10,000 Example 18 80 Example 19 340 Example 20 18,000 Example 21 440 Example 22 3,100 Example 23 7,110 Example 24 2,010 Example 25 510 Example 26 5,650 Example 27 4,130 Example 28 > 10,000 compound IC ₅₀ (nM) Example 29 > 10,000 Example 30 > 10,000 Example 31 190 Example 32 300 Example 44 7,030 Example 34 180 Example 35 1,190 Example 36 16,200 Example 37 4300 Example 38 270 Example 39 > 10,000 Example 40 70 Example 41 300 Example 42 4,950 Example 43 1,240 Example 44 > 10,000 Example 45 570 Example 46 1,990 Example 47 1,130 Example 48 2,320 Example 49 360 Example 50 260 Example 51 320 Example 52 8,680 Example 53 900 Example 54 690 Example 55 360

As shown in Table 2, Examples 5, 8, 18, 40 in the case of excellent IC ₅₀ value of 100 nM or less, it can be seen that the inhibitory activity against the MCH receptor-1 receptor. Through this, the compound according to the present invention can be useful for preventing or treating MCH receptor-1 related diseases by acting as an antagonist for MCH receptor-1 with an excellent inhibitory effect on MCH receptor-1.

Therefore, the derivative according to the present invention acts as an antagonist to MCH receptor-1, thereby preventing or treating MCH receptor-1 related diseases such as obesity, diabetes, metabolic disorders, anxiety and depression caused by MCH binding to MCH receptor-1. This can be useful.

On the other hand, the pyrrolopyridinone derivative represented by the formula (1) according to the present invention can be formulated in various forms according to the purpose. The following are some examples of formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1> Sanje  Produce

2 g of pyrrolopyridinone of formula 1

1 g lactose

The above components were mixed and packed in airtight bags to prepare powders.

< Formulation example  2> Preparation of tablets

100 mg of pyrrolopyridinone derivative of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

< Formulation example  3> Preparation of capsules

100 mg of pyrrolopyridinone derivative of formula 1

Corn starch 100 mg

Lactose 100 mg

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

< Formulation example  4> Preparation of injection

100 mg of pyrrolopyridinone derivative of formula 1

180 mg mannitol

Na2HPO4 · 2H2O 26 mg

2974 mg of distilled water

According to a conventional method for preparing an injection, an injection was prepared by containing the above components in the contents shown.

< Formulation example  5> Manufacture of health food

1000 mg of pyrrolopyridinone derivative of formula (1)

70 [mu] g of vitamin A acetate

Vitamin E 1.0 mg

0.13 mg of vitamin

0.15 mg of vitamin B2

0.5 mg vitamin B6

0.2 [mu] g vitamin B12

10 mg vitamin C

Biotin 10 μg

Nicotinic acid amide 1.7 mg

Folic acid 50 mg

Calcium pantothenate 0.5 mg

Mineral mixture quantity

1.75 mg of ferrous sulfate

0.82 mg of zinc oxide

Magnesium carbonate 25.3 mg

15 mg of potassium phosphate monobasic

Secondary calcium phosphate 55 mg

Potassium citrate 90 mg

100 mg of calcium carbonate

24.8 mg of magnesium chloride

Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.

< Formulation example  6> Manufacture of health drinks

1000 mg of pyrrolopyridinone derivative of formula (1)

Citric acid 1000 mg

100 g oligosaccharides

Plum concentrate 2 g

1 g of taurine

Purified water was added to a total of 900 ml

The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 for about 1 hour. The resulting solution was filtered and sterilized in a sterilized 2 liter container, And used for manufacturing.

Although the composition ratio is a composition that is relatively suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.

< Formulation example  7> Manufacture of Other Health Foods

7-1. Manufacturing of beverages

522 mg of honey

Chioctosanamide 5 mg

Nicotinamide 10 mg

Riboflavin Sodium Hydrochloride 3 mg

Pyridoxine hydrochloride 2 mg

Inositol 30 mg

Orthoic acid 50 mg

Pyrrolopyridinone Derivatives of Formula 1 0.48-1.28 mg

200 ml of water

A beverage was prepared using the above-mentioned composition and content by a conventional method.

7-2. Of chewing gum  Produce

Gum base 20%

Sugar 76.36-76.76%

0.24-0.64% pyrrolopyridinone derivative of formula (1)

1% fruit flavor

Water 2%

Chewing gum was prepared using the above-mentioned composition and content by a conventional method.

7-3. Manufacture of candy

50-60% sugar

Starch syrup 39.26-49.66%

0.24-0.64% of 5-pyrrolopyridinone derivative of Formula 1

Orange flavor 0.1%

The composition and the content of the candy were prepared using a conventional method.

7-4. Manufacture of flour food products

0.5 to 5 parts by weight of the pyrrolopyridinone derivative of Formula 1 was added to 100 parts by weight of wheat flour, and the mixture was used to prepare bread, cake, cookies, crackers, and noodles to prepare foods for health promotion.

7-5. dairy product( dairy products Manufacturing

5 to 10 parts by weight of the pyrrolopyridinone derivative of Formula 1 was added to 100 parts by weight of milk, and the milk was used to prepare various dairy products such as butter and ice cream.

7-6. Solar  Produce

Brown rice, barley, glutinous rice, and yulmu were alphanated by a known method to distribute the dried ones, and then prepared into a powder having a particle size of 60 mesh. Black soybeans, black sesame seeds, and perilla were also steamed and dried in a known manner to prepare a powder having a particle size of 60 mesh using a grinder. The grains and seeds prepared above and the pyrrolopyridinone derivative of the general formula (1) of the present invention were formulated in the following ratio.

Brown Rice 30%

15% rate

Barley 20%

Perilla 7%

Black Bean 7%

Black sesame 7%

3% pyrrolopyridinone derivative of formula 1

Ganoderma 0.5%

Foxglove 0.5%

Claims (15)

Pyrrolopyridinone derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
Formula 1

In the above formula, Y is a naphthyl group or

(R ¹ and R ² are each independently hydrogen, halogen, CN, C ₁ -C ₁₀ straight or branched alkyl, C ₂ -C ₄ alkenes, OR ⁵ , COR ⁶ , CX ₃ (X is F, Cl, Br or I), NHR ⁷ , or phenyl; R ³ and R ⁴ are each independently a C ₁ -C ₁₀ branched or straight chain alkyl group or R ³ and R ⁴ together are a 5-membered group comprising one or two hetero elements Or a six-membered heterocycle, wherein the hetero element is selected from the group consisting of nitrogen, oxygen and sulfur, wherein R ⁵ is hydrogen, C ₁ -C ₅ straight or branched chain alkyl or phenylC ₁ -C ₃ alkyl R ⁶ is hydrogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy, R ⁷ is hydrogen or C ₁ -C ₅ alkyl, A and B are each independently carbon or nitrogen, A And B are not carbon at the same time.
delete According to claim 1, wherein R ¹ and R ² are each independently hydrogen, F, Cl, methyl, ethyl, propyl, n-butyl, i -propyl, t -butyl, vinyl, OR ⁵ , COR ⁶ , CN, CF ₃ , NH ₂ or phenyl; R ³ and R ⁴ are each independently methyl, ethyl, or propyl or R ³ and R ⁴ together

,

,

,

or

To form; R ⁵ is hydrogen, methyl or benzyl; R ⁶ is hydrogen, methyl or methoxy; Wherein A and B are each independently carbon or nitrogen, and A and B are not carbon at the same time, or pyrrolopyridinone derivatives or pharmaceutically acceptable salts thereof.
4. The compound of claim 3, wherein R ³ and R ⁴ are each independently methyl, ethyl or propyl or R ³ and R ⁴ together

,

or

To form; Any one of A and B is carbon and the other is nitrogen, pyrrolopyridinone derivative or a pharmaceutically acceptable salt thereof.
The method of claim 1, wherein the derivative of Formula 1
(1) 2-phenyl-6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] Pyridin-7-one;
(2) 2- (2-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;
(3) 2- (3-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;
(4) 2- (2-ethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(5) 2- (4-ethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(6) 2- (4-propylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(7) 2- (4-butylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(8) 2- (4-isopropylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(9) 2- (4-t-butylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(10) 2- (4-vinylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(11) 2- [4- (methoxycarbonyl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro -Pyrrolo [3,4-b] pyridin-7-one;
(12) 2- [4- (trifluoromethyl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro -Pyrrolo [3,4-b] pyridin-7-one;
(13) 2- (4-formylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(14) 2- (4-acetylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(15) 2- (benzo [1,3] dioxol-5-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6 -Dihydro-pyrrolo [3,4-b] pyridin-7-one;
(16) 2- (4-hydroxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(17) 2- (4-aminophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(18) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;
(19) 2- (4-methoxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(20) 2- (4-benzyloxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(21) 2- (4-chlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(22) 2- (4-fluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(23) 2- (2-methoxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(24) 2- (3-methoxyphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(25) 2- (2-chlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(26) 2- (3-chlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3 , 4-b] pyridin-7-one;
(27) 2- (2-fluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(28) 2- (3-fluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(29) 2- (3-cyanophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(30) 2- (4-cyanophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(31) 2- (2,3-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(32) 2- (2,5-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(33) 2- (3,5-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(34) 2- (3,4-dimethylphenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(35) 2-[(3-fluoro-4-methyl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6- Dihydro-pyrrolo [3,4-b] pyridin-7-one;
(36) 2- (2,3-difluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro- Pyrrolo [3,4-b] pyridin-7-one;
(37) 2- (3,4-difluorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro- Pyrrolo [3,4-b] pyridin-7-one;
(38) 2- (2,3-dichlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-py Rolo [3,4-b] pyridin-7-one;
(39) 2- (3,5-dichlorophenyl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-py Rolo [3,4-b] pyridin-7-one;
(40) 2- (naphthalen-2-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(41) 2- (naphthalen-1-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [ 3,4-b] pyridin-7-one;
(42) 2- (biphenyl-4-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(43) 2- (biphenyl-3-yl) -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(44) 2- [4- (naphthalen-1-yl) phenyl] -6- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -5,6-di Hydro-pyrrolo [3,4-b] pyridin-7-one;
(45) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-piperidin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;
(46) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-morpholin-1-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3,4 -b] pyridin-7-one;
(47) 2- (4-methylphenyl) -6- [3-methoxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b] pyridin-7-one;
(48) 2- (4-methylphenyl) -6- [3-methoxy-4- (2-thiomorpholin-4-yl-ethoxy) phenyl] -5,6-dihydro-pyrrolo [3, 4-b] pyridin-7-one;
(49) 2- (4-methylphenyl) -6- [3-methoxy-4-[(2-dimethylamino) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b ] Pyridin-7-one;
(50) 2- (4-methylphenyl) -6- [3-methoxy-4-[(2-diethylamino) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b ] Pyridin-7-one;
(51) 2- (4-methylphenyl) -6- [3-methoxy-4-[(2-dipropylamino) ethoxy] phenyl] -5,6-dihydro-pyrrolo [3,4-b ] Pyridin-7-one;
(52) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6-phenyl-2,3-dihydro-pyrrolo [3,4-c] Pyridin-1-one;
(53) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6- (4-methylphenyl) -2,3-dihydro-pyrrolo [3, 4-c] pyridin-1-one;
(54) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6- (4-ethylphenyl) -2,3-dihydro-pyrrolo [3 , 4-c] pyridin-1-one; And
(55) 2- [3-methoxy-4- (2-pyrrolidin-1-yl-ethoxy) phenyl] -6- (naphthalen-2-yl) -2,3-dihydro-pyrrolo [ 3,4-c] pyridin-1-one, a pyrrolopyridinone derivative, or a pharmaceutically acceptable salt thereof, characterized in that any one selected from the group consisting of.
MCH receptor selected from the group consisting of obesity, diabetes, anxiety and depression comprising the pyrrolopyridinone derivative of any one of claims 1 and 3 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. -1 Pharmaceutical composition for the prevention and treatment of related diseases.
delete MCH receptor selected from the group consisting of obesity, diabetes, anxiety and depression comprising the pyrrolopyridinone derivative of any one of claims 1 and 3 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. -1 food composition for preventing or ameliorating related diseases.
delete A process comprising the step of reacting a compound of formula 2 with a compound of formula 3 in a solvent according to Scheme 1 in the presence of a catalyst and a base selected from the group consisting of palladium, nickel and platinum derivatives to obtain a compound of formula 1 Process for preparing rolopyridinone derivatives:
Scheme 1

In the above formula, R ¹ and R ² are each independently hydrogen, halogen, CN, C ₁ -C ₁₀ straight or branched alkyl, C ₂ -C ₄ alkene, OR ⁵ , COR ⁶ , CX ₃ (X is F, Cl , Br or I), NHR ⁷ or phenyl; R ³ and R ⁴ are each independently a C ₁ -C ₁₀ branched or straight chain alkyl group or R ³ and R ⁴ together form a five or six membered heterocycle containing one or two hetero elements, The hetero element is selected from the group consisting of nitrogen, oxygen and sulfur; R ⁵ is hydrogen, C ₁ -C ₅ straight or branched alkyl or phenylC ₁ -C ₃ alkyl; R ⁶ is hydrogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy; R ⁷ is hydrogen or C ₁ -C ₅ alkyl; A and B are each independently carbon or nitrogen, and A and B are not carbon at the same time.
delete The method of claim 10, wherein the palladium catalyst derivative is Pd (PPh ₃ ) ₄ , Pd-C, PdCl ₂ (PPh ₃ ) ₂ , Pd ₂ (dba) ₃ , PdCl ₂ (dppf), [PdCl (allyl)] ₂ , Pd (OAc) ₂ or PdCl ₂ , characterized in that any one or more selected from the group consisting of.
The method according to claim 10, wherein the base is any one or more inorganic bases selected from the group consisting of sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate and barium hydroxide.
11. The method of claim 10, wherein the solvent is any one selected from the group consisting of ether solvents, aromatic hydrocarbon solvents, alcohol solvents, dimethylformamide (DMF), dimethyl sulfoxide, acetonitrile, water Method for producing a mixed solvent.
The process according to claim 10, wherein the reaction is carried out at a temperature in the boiling point of the solvent from 0 ° C.