WO2010150837A1 - Indoline derivative - Google Patents

Abstract

A therapeutic agent for hyperparathyroidism, secondary hyperparathyroidism, primary hyperparathyroidism, renal osteodystrophy, hypercalcemia or the like, which has a calcium sensing receptor activation activity and comprises a compound represented by general formula (I) [wherein R¹ and R² independently represent a hydrogen atom, a halogeno group, or the like; R³ and R⁴ independently represent a C1-C3 alkyl group; R⁵ represents a hydrogen atom, or the like; R⁶ represents a carboxyphenyl group, or the like; and R⁸, R⁹ and R¹⁰ independently represent a hydrogen atom, a halogeno group, a cyano group, or the like] or a pharmacologically acceptable salt thereof as an active ingredient.

Description

Indoline derivative

The present invention relates to a novel indoline derivative having an activating action of an excellent calcium sensing receptor (CaSR).

Parathyroid hormone (PTH) is a polypeptide hormone consisting of 84 amino acid residues secreted from the parathyroid gland and has the function of maintaining homeostasis of blood calcium concentration.

Increase in blood PTH increases the calcium concentration in blood by promoting calcium elution from bone to blood and promoting calcium reabsorption in renal tubules. There is a close relationship between blood PTH concentration and blood calcium concentration. Decreasing blood calcium concentration promotes secretion of PTH from the parathyroid gland, and increase of blood calcium concentration suppresses secretion of PTH from the parathyroid gland. To do. With such a feedback system, the calcium concentration in the blood is strictly controlled within a certain range. It is thought that this calcium calcium concentration change is detected mainly by a calcium sensing receptor (CaSR) present on the cell membrane of the parathyroid gland.

CaSR is one of the seven transmembrane G protein-coupled receptors, and when activated by extracellular calcium, CaSR in parathyroid cells increases intracellular calcium concentration and decreases PTH secretion. Are known.

Secondary hyperparathyroidism is known to occur frequently in patients with renal insufficiency, and PTH secretion increases continuously with a decrease in renal function. In secondary hyperparathyroidism, the balance between blood PTH and calcium concentration is disrupted, which is thought to cause renal osteodystrophy, arteriosclerosis associated with cardiovascular calcification, and myocardial infarction. Yes.

As a conventional therapeutic agent for secondary hyperparathyroidism, mainly the administration of vitamin D preparation has been mainly performed. Administration of the vitamin D preparation suppresses PTH secretion from the parathyroid gland, but promotes calcium absorption from the intestinal tract, and therefore the dosage is limited due to the concern of an increase in blood calcium concentration. Therefore, it has been a problem that a sufficient therapeutic effect cannot be exhibited.

On the other hand, CaSR activator (agonist) acts on CaSR in the parathyroid gland to increase the sensitivity of the receptor to blood calcium, thereby suppressing PTH secretion from the parathyroid gland and secondarily blood calcium concentration. Has an action mechanism that lowers Therefore, it can be expected that blood PTH is reduced without causing hypercalcemia. Therefore, a drug having a CaSR activating (acting) action is expected as a therapeutic drug for hyperparathyroidism, renal osteodystrophy, hypercalcemia and the like.

Recently, cinacalcet developed as a CaSR activator (see, for example, Patent Document 1) has been used in clinical settings as a novel therapeutic agent for hyperparathyroidism. However, since cinacalcet has problems in effectiveness and safety, creation of a powerful and highly safe CaSR activator is desired (see Non-Patent Document 1, Patent Document 1 and Patent Document 2). Moreover, although the compound which has a CaSR activation (operation | movement) effect | action is disclosed (patent document 3), a structure differs from the compound of this invention.

International Publication No. 1994/18959 Pamphlet International Publication No. 1996/12697 Pamphlet International Publication No. 1998/01417 Pamphlet

Currently known CaSR activators (agonists) are not satisfactory in terms of effectiveness or safety, and CaSR activators (activators) excellent in safety and effectiveness are eagerly desired.

The present inventors have an excellent CaSR activating (acting) action, exhibiting good metabolic stability, safety, etc., and various synthetic studies aiming at obtaining therapeutic agents for secondary hyperparathyroidism. Went. As a result, a novel indoline derivative having the general formula (I) has been found that has an excellent CaSR activation action and has good qualities such as oral absorption, metabolic stability, safety, water solubility, and pharmacokinetics. The present invention has been completed.

The present invention provides a novel indoline derivative exhibiting an excellent CaSR activating action or a pharmacologically acceptable salt thereof and a medicament containing these. Furthermore, the present invention provides a novel indoline derivative having a carboxy group introduced therein or a pharmacologically acceptable salt thereof and a medicament containing them, which exhibit an excellent CaSR activation action and excellent pharmacokinetics.

That is, the present invention
[1] General formula (I)

[Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogeno group, a C1-C6 alkyl group or a C1-C6 alkoxy group;
R ³ and R ⁴ each independently represent a C1-C3 alkyl group (wherein R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring) You may have)
R ⁵ , R ⁶ and R ⁷ represent the following (1) or (2), (1) R ⁵ represents a hydrogen atom, and R ⁶ is substituted with 1 to 3 C1-C3 alkyl groups. A carboxy C1-C6 alkyl group, a carboxyphenyl group, a carboxybenzyl group, a carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group, wherein R ⁷ is a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group; Group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group.
(2) R ⁵ and R ⁶ each independently represent a hydrogen atom or a C1-C3 alkyl group (wherein R ⁵ and R ⁶ together with the carbon atom to which they are attached, cyclopropane Or R ⁷ may be a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group. A group, a carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group; ;
R ⁸ , R ⁹ and R ¹⁰ each independently represent a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group. . ]
Or a pharmacologically acceptable salt thereof,
[2] The compound according to the above [1], wherein R ¹ is a halogeno group, and R ² is a C1-C6 alkoxy group, or a pharmaceutically acceptable salt thereof,
[3] The compound according to the above [1], wherein R ¹ is a hydrogen atom, and R ² is a halogeno group or a C1-C6 alkoxy group, or a pharmaceutically acceptable salt thereof,
[4] R ¹ and R ² are both hydrogen atoms, the compound or a pharmacologically acceptable salt thereof, according to [1],
[5] The compound according to any one of the above [1] to [4], wherein R ³ and R ⁴ are both methyl groups, or a pharmaceutically acceptable salt thereof,
[6] The compound according to any one of the above [1] to [4], wherein R ³ and R ⁴ together with the carbon atom to which they are bonded form a cyclopropane ring, or a compound thereof A pharmacologically acceptable salt,
[7] R ⁵ is a hydrogen atom, and R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group, a carboxyphenethyl group, A carboxymethylphenyl group or a carboxyethylphenyl group, and R ⁷ is a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group A compound according to any one of the above [1] to [6], or a pharmacologically acceptable salt thereof,
[8] R ⁵ is a hydrogen atom, R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, and R ⁷ is a hydrogen atom, a halogeno group, a cyano group Or a pharmacologically acceptable salt thereof, which is a group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group,
[9] R ⁵ is a hydrogen atom, R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, and R ⁷ is a hydrogen atom, a halogeno group, a cyano group The compound according to the above [7], which is a group, a C1-C6 alkyl group or a C1-C6 alkoxy group, or a pharmaceutically acceptable salt thereof,
[10] ^{R 5} is a hydrogen atom, ^{R 6} is 1 to 3 C1 ~ C3 alkyl optionally substituted carboxy C1 ~ C6 alkyl group with a group, ^{R 7} is a hydrogen atom, the [ 7], or a pharmacologically acceptable salt thereof,
[11] R ⁵ and R ⁶ are each independently a hydrogen atom or a C1-C3 alkyl group (wherein R ⁵ and R ⁶ together with the carbon atom to which they are attached, a cyclopropane ring Or it may form a cyclobutane ring.), R ⁷ is a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group , A carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group, the compound according to any one of the above [1] to [6], or a pharmacologically acceptable salt thereof,
[12] a ^{R 5} and ^{R 6} are both hydrogen atom, ^{R 7} is a carboxy group, 1-3 C1-C3 alkyl group substituted by - optionally carboxy C1 be the C6 alkyl group, carboxyphenyl group, carboxy The compound according to [11] above, which is a benzyl group, a carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group, or a pharmaceutically acceptable salt thereof,
[13] R ⁵ and R ⁶ are both hydrogen atoms, and R ⁷ is a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, or a carboxyphenyl group. , The compound according to the above [11], or a pharmacologically acceptable salt thereof,
[14] The compound according to the above [11], wherein R ⁵ and R ⁶ are both hydrogen atoms, and R ⁷ is a carboxyphenyl group, or a pharmacologically acceptable salt thereof,
[15] R ⁸ is a hydrogen atom, halogeno group, cyano group, C1-C6 alkyl group, halogeno C1-C6 alkyl group, C1-C6 alkoxy group or C1-C6 alkylsulfonyl group, and R ⁹ is a hydrogen atom or halogeno Or a pharmacologically acceptable salt thereof according to any one of the above [1] to [14], wherein R ¹⁰ is a hydrogen atom,
[16] The compound of the above-mentioned [15], wherein R ⁸ is a halogeno group or a halogeno C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof,
[17] The compound according to the above [15], wherein R ⁸ is a halogeno group or a halogeno C1-C6 alkyl group, or a pharmaceutically acceptable salt thereof,
[18] R ⁹ is a hydrogen atom, a compound or a pharmacologically acceptable salt thereof, according to [15],
[19] {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} acetic acid,
(1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl} acetic acid,
3- {5-chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid,
3- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid,
3- (1- {N- [1- (3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
3- (1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
3- (5-fluoro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -5-methyl-2,3-dihydro-1H-indol-3-yl) propionic acid,
3- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -5- (trifluoromethyl) -2,3-dihydro-1H-indol-3-yl} propionic acid,
4- {5-fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -1H-indol-3-yl} butanoic acid,
4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} butanoic acid,
3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} -2,2-dimethylpropionic acid ,
1- {N- [1- (3-methoxyphenyl) cyclopropyl] β-alanyl} indoline-4-carboxylic acid,
3- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid,
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propionic acid,
3- {5,6-difluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid,
4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid,
4- (1- {N- [1- (3,4-difluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) benzoic acid,
(4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} phenyl) acetic acid, and
Selected from the group consisting of 4-({1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} methyl) benzoic acid The compound according to the above [1], or a pharmacologically acceptable salt thereof,
[20] A medicament comprising as an active ingredient the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof,
[21] A calcium-sensing receptor agonist comprising as an active ingredient the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof,
[22] A therapeutic agent for hyperparathyroidism comprising the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof as an active ingredient,
[23] A therapeutic agent for secondary hyperparathyroidism comprising the compound according to any of [1] to [19] or a pharmacologically acceptable salt thereof as an active ingredient,
[24] A therapeutic agent for primary hyperparathyroidism comprising the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof as an active ingredient,
[25] A therapeutic agent for renal osteodystrophy containing the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof as an active ingredient,
[26] A therapeutic agent for hypercalcemia, comprising as an active ingredient the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof,
[27] A pharmaceutical composition comprising the compound according to any one of the above [1] to [19] or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier,
[28] For use in the method for treating hyperparathyroidism, secondary hyperparathyroidism, primary hyperparathyroidism, renal osteodystrophy or hypercalcemia [1] to [28] [19] The compound according to any one of the above or a pharmacologically acceptable salt thereof,
[29] A method for treating a disease by administering a pharmaceutical comprising the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof as an active ingredient, and
[30] Hyperparathyroidism, secondary parathyroid gland by administering a pharmaceutical comprising the compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof as an active ingredient The present invention provides a method for treating hyperfunction, primary hyperparathyroidism, renal osteodystrophy or hypercalcemia.

The novel indoline derivative having the general formula (I) of the present invention has an excellent calcium sensory receptor agonistic action, and exhibits high oral absorption, plasma concentration and retention in blood, and exhibits excellent pharmacological action. Indicated. Further, the compound of the general formula (I) of the present invention is excellent in pharmacokinetics such as distribution in the body and blood retention, and has high safety for organs such as kidney and liver.

Therefore, the novel indoline derivative having the general formula (I) of the present invention is useful as a medicine, and particularly useful as a therapeutic agent for hyperparathyroidism, renal osteodystrophy or hypercalcemia. .

Hereinafter, the substituents in this specification will be described.

“Halogeno group” means a fluoro group, a chloro group, a bromo group, or an iodo group.

“C1-C3 alkyl group” means a straight or branched saturated hydrocarbon group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

“C1-C4 alkyl group” means a straight-chain or branched saturated hydrocarbon group having 1 to 4 carbon atoms. For example, in addition to the examples of the C1-C3 alkyl group, an n-butyl group, sec- Examples thereof include a butyl group, a tert-butyl group, and an isobutyl group.

“C1-C6 alkyl group” means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. For example, in addition to the examples of the C1-C4 alkyl group, an n-pentyl group, n- Examples include hexyl group, 1-ethylpropyl group, 2,2-dimethylpropyl group and the like.

The “halogeno C1-C6 alkyl group” means the C1-C6 alkyl group having the halogeno group as a substituent, for example, a chloromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-fluoro-1 -Methylethyl group and the like can be mentioned.

“Carboxy C1-C6 alkyl group” means the C1-C6 alkyl group having one carboxy group as a substituent, and examples thereof include a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, and the like. It is done.

The term “carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups” refers to the above-mentioned optionally having 1 to 3 C1-C3 alkyl groups as a substituent. Means a carboxy C1-C6 alkyl group, for example, in addition to the examples of the carboxy C1-C6 alkyl group, 1,1-dimethyl-2-carboxyethyl group, 2,2-dimethyl-2-carboxyethyl group, 2, And 2-diethyl-2-carboxyethyl group.

“C1-C6 alkoxy group” means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as a methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group. And isobutyloxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, 1-ethylpropoxy group, 2,2-dimethylpropoxy group and the like.

“C1-C6 alkylsulfonyl group” means a sulfonyl group having the C1-C6 alkyl group, and examples thereof include a methylsulfonyl group and an ethylsulfonyl group.

The “C1-C5 alkylene group” means a divalent group formed from a linear or branched saturated hydrocarbon group having 1 to 5 carbon atoms, such as a methylene group, an ethylene group, propane-1, A 3-diyl group, a butane-1,4-diyl group, a pentane-1,5-diyl group and the like can be mentioned.

“Carboxyphenyl group” means a phenyl group having one carboxy group as a substituent, and examples thereof include a 2-carboxyphenyl group, a 3-carboxyphenyl group, and a 4-carboxyphenyl group.

“Carboxybenzyl group” means a benzyl group having one carboxy group as a substituent, and examples thereof include a 2-carboxybenzyl group, a 3-carboxybenzyl group, and a 4-carboxybenzyl group.

“Carboxyphenethyl group” means a phenethyl group having one carboxy group as a substituent on a phenyl group, and examples thereof include a 2-carboxy-1-phenethyl group, a 3-carboxy-1-phenethyl group, 4- Examples include carboxy-1-phenethyl group, 2-carboxy-2-phenethyl group, 3-carboxy-2-phenethyl group, 4-carboxy-2-phenethyl group, and the like.

“Carboxymethylphenyl group” means a phenyl group having one carboxymethyl group as a substituent, for example, 2-carboxymethylphenyl group, 3-carboxymethylphenyl group, 4-carboxymethylphenyl group and the like. Can be mentioned.

“Carboxyethylphenyl group” means a phenyl group having one carboxyethyl group as a substituent, for example, 2-carboxyethylphenyl group, 3-carboxyethylphenyl group, 4-carboxyethylphenyl group and the like. Can be mentioned.

Hereinafter, the compound of the general formula (I) will be described in detail.

R ¹ and R ² each independently represents a hydrogen atom, a halogeno group, a C1-C6 alkyl group or a C1-C6 alkoxy group. As the bonding position of R ¹ and R ^{2 to} the phenyl group, it is preferable that R ¹ is the 4-position of the phenyl group and R ² is the 3-position of the phenyl group. R ¹ and R ^{2 are} as follows: R ¹ is a halogeno group and R ² is a C1-C6 alkoxy group; R ¹ is a hydrogen atom and R ² is a halogeno group or a C1-C6 alkoxy group; ¹ that ^{R 2} is a halogeno group is a hydrogen atom, ^{R 1} and ^{R 2} are both hydrogen atoms, and, preferably ^{R 1} and ^{R 2} are both halogeno groups, among others, ^{R 1} is A halogeno group and R ² is a C1-C6 alkoxy group, R ¹ is a hydrogen atom, R ² is a halogeno group or a C1-C6 alkoxy group, and both R ¹ and R ² are hydrogen atoms. More preferably. Here, the halogeno group is preferably a fluoro group, and the C1-C6 alkoxy group is preferably a methoxy group.

R ³ and R ⁴ each independently represents a C1-C3 alkyl group. Here, R ³ and R ⁴ may be combined with the carbon atom to which they are bonded to form a cyclopropane ring or a cyclobutane ring. R ³ and R ⁴ are both methyl groups, and, R ³ and R ⁴ are preferably they form a cyclopropane ring together with the carbon atom bonded.

R ⁵ , R ⁶ and R ⁷ represent the following (1) or (2).
(1) R ⁵ represents a hydrogen atom, and R ⁶ represents a carboxy C1-C6 alkyl group, carboxyphenyl group, carboxybenzyl group, carboxyphenethyl group, which may be substituted with 1 to 3 C1-C3 alkyl groups. represents carboxymethyl phenyl group or carboxyethyl phenyl group, ^{R 7} is a hydrogen atom, a halogeno group, cyano group, C1 ~ C6 alkyl group, a halogeno C1 ~ C6 alkyl group, C1 ~ C6 alkoxy group or C1 ~ C6 alkylsulfonyl group Indicates.
(2) R ⁵ and R ⁶ each independently represent a hydrogen atom or a C1-C3 alkyl group (wherein R ⁵ and R ⁶ together with the carbon atom to which they are attached, cyclopropane Or R ⁷ may be a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group. A group, a carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group;

The above (1) will be described in detail below.

R ⁵ is a hydrogen atom, R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, R ⁷ is a hydrogen atom, a halogeno group, a cyano group, C1 Is preferably a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group, R ⁵ is a hydrogen atom, and R ⁶ is 1-3 C1-C3 alkyl More preferably, it is a carboxy C1-C6 alkyl group optionally substituted with a group, and R ⁷ is a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group or a C1-C6 alkoxy group, and R ⁵ is a hydrogen atom, R ⁶ is 1 to 3 C1 ~ C3 alkyl optionally substituted carboxy C1 ~ C6 alkyl group with a group, this R ⁷ is a hydrogen atom It is more preferable. Here, the carboxy C1-C6 alkyl group optionally substituted by 1 to 3 C1-C3 alkyl groups includes a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, and 2,2-dimethyl group. A -2-carboxyethyl group is preferred. The C1-C6 alkyl group is preferably a methyl group, the halogeno group is preferably a fluoro group or a chloro group, the halogeno C1-C6 alkyl group is preferably a trifluoromethyl group, and the C1-C6 alkoxy group is a methoxy group or ethoxy group. A group is preferred, and the C1-C6 alkylsulfonyl group is preferably a methylsulfonyl group.

Next, (2) will be described in detail below.

R ⁵ and R ⁶ are both hydrogen atoms, and R ⁷ is a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group, It is preferably a carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group, wherein R ⁵ and R ⁶ are both hydrogen atoms, R ⁷ is substituted with a carboxy group, and 1 to 3 C1-C3 alkyl groups. More preferably, it may be a carboxy C1-C6 alkyl group or a carboxyphenyl group, more preferably R ⁵ and R ⁶ are both hydrogen atoms, and R ⁷ is a carboxyphenyl group. Here, the carboxy C1-C6 alkyl group optionally substituted by 1 to 3 C1-C3 alkyl groups is preferably a 2-carboxyethyl group, and the carboxyphenyl group is a 3-carboxyphenyl group and a 4-carboxy group. A phenyl group is preferred, and the carboxybenzyl group is preferably a 3-carboxybenzyl group or a 4-carboxybenzyl group.

R ⁸ , R ⁹ and R ¹⁰ each independently represent a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group. . R ⁸ is a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group, and R ⁹ is a hydrogen atom or a halogeno group R ¹⁰ is preferably a hydrogen atom. Here, the halogeno group is preferably a fluoro group and a chloro group, the C1-C6 alkyl group is preferably a methyl group and an ethyl group, the halogeno C1-C6 alkyl group is preferably a trifluoromethyl group, and the C1-C6 alkoxy group Are preferably a methoxy group and an ethoxy group, and the C1-C6 alkylsulfonyl group is preferably a methylsulfonyl group. More preferably, R ⁸ is a halogeno group or a halogeno C1-C6 alkyl group, and R ⁸ is a hydrogen atom. R ⁹ is preferably a hydrogen atom or a halogeno group, more preferably a hydrogen atom. R ¹⁰ is preferably a hydrogen atom.

Preferred specific examples of the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof include the following. {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} acetic acid monohydrochloride, (1- {N -[1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl} acetic acid, 3- {5-chloro-1- [N- (1- Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid, 3- {1- [N- (1-methyl-1-phenylethyl) -β -Alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid monohydrochloride, 3- (1- {N- [1- (3-methoxyphenyl) -1-methylethyl] -β- Alanyl} -2,3-dihydro-1H-indole-3-i L) propionic acid monohydrochloride, 3- (1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indole -3-yl) propionic acid, 3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid , 3- (5-Fluoro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid monohydrochloride 3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -5-methyl-2,3-dihydro-1H-indol-3-yl) propionic acid, 3- {1- [N- (1-Meth -1-phenylethyl) -β-alanyl] -5- (trifluoromethyl) -2,3-dihydro-1H-indol-3-yl} propionic acid, 4- {5-fluoro-1- [N- ( 1-methyl-1-phenylethyl) -β-alanyl] -1H-indol-3-yl} butanoic acid, 4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl]- 2,3-dihydro-1H-indol-3-yl} butanoic acid 0.75 hydrochloride, 3- {5-chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl]- 2,3-dihydro-1H-indol-3-yl} -2,2-dimethylpropionic acid, 1- {N- [1- (3-methoxyphenyl) cyclopropyl] β-alanyl} indoline-4-carboxylic acid Monohydrochloride, 3- {1- [N (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid monohydrochloride, 3- (1- {N- [1- (3- Methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propionic acid monohydrochloride, 3- {5,6-difluoro-1- [N- (1-methyl -1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid monohydrochloride, 4- {1- [N- (1-methyl-1-phenylethyl) -Β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid monohydrochloride, 4- (1- {N- [1- (3,4-difluorophenyl) -1-methylethyl ] -Β-alanyl} -2,3-dihydride -1H-indol-4-yl) benzoic acid monohydrochloride, (4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indole- 4-yl} phenyl) acetic acid monohydrochloride and 4-({1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} Methyl) benzoic acid monohydrochloride.

Hereinafter, the production method of the indoline derivative of the present invention will be described, but the present invention is not limited to this method.

The compound represented by the general formula (I) of the present invention can be produced according to the following method A to method C.

In the reaction of each step of the following methods A to C, when the compound serving as a reaction substrate has a group that inhibits the desired reaction such as an amino group, a hydroxyl group, or a carboxyl group, those compounds are appropriately selected as necessary. A protecting group may be introduced into the group, and a protecting group introduced as appropriate may be removed as necessary. Such a protecting group is not particularly limited as long as it is a protecting group that is usually used to cause the reaction to proceed. For example, T. W. Greene, P. G. Wuts, Protective Groups in Organic Synthesis. It may be a protecting group described in John Wiley & Sons, Inc. The introduction reaction of these protecting groups and the removal reaction of the protecting groups can be carried out according to conventional methods such as the methods described in the above-mentioned documents.

The solvent used in the reaction in each step of the following method A to method C is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting material, and is selected from the following solvent group. Solvent groups include aliphatic hydrocarbons such as hexane, pentane, petroleum ether, and cyclohexane; aromatic hydrocarbons such as benzene, toluene, and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, and dichlorobenzene. Halogenated hydrocarbons such as: ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; ethyl acetate, propyl acetate Esters such as butyl acetate; Nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; acetic acid, propionic acid, trifluoro Carboxylic acids such as acetic acid; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, 2-methyl-2-propanol; formamide, Amides such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; water; and mixtures thereof.

The acid used in the reaction of each step of the following method A or method C is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group. Acid groups include organic acids such as acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid, organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, and hydrochloric acid, bromide It consists of inorganic acids such as hydroacid, hydroiodic acid, phosphoric acid, sulfuric acid and nitric acid.

The base used in the reaction of each step of the following method A or method C is not particularly limited as long as it does not inhibit the reaction, and is selected from the following group of bases. Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide; lithium diisopropylamide Lithium alkylamides; silylamides such as lithium bistrimethylsilylamide and sodium bistrimethylsilylamide; alkyllithiums such as n-butyllithium, sec-butyllithium and tert-butyllithium; methylmagnesium chloride, methylmagnesium bromide, iodide Alkyl magnesium halides such as methyl magnesium, ethyl magnesium chloride, ethyl magnesium bromide, isopropyl magnesium chloride, isopropyl magnesium bromide, isobutyl magnesium chloride; and triethylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, N-methyl Morpholine, N-ethylmorpholine, pyridine, picoline, 4- (N, N-dimethylamino) pyridine, 4 Pyrrolidinopyridine, 2,6-di (tert-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4,3,0] nona From organic amines such as 5-ene (DBN), 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) Become.

In the reaction of each step of Method A to Method C below, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.

In the reaction of each step of Method A or Method C below, the target compound or intermediate in each step is isolated from the reaction mixture according to a conventional method after the reaction is completed. For example, (i) if necessary, insoluble matter such as a catalyst is removed by filtration, and (ii) water and a solvent immiscible with water (for example, methylene chloride, diethyl ether, ethyl acetate, etc.) are added to the reaction mixture. Compound III is extracted, (iii) the organic layer is washed with water, dried using a desiccant such as anhydrous magnesium sulfate, and (iv) the solvent is distilled off to obtain the target compound. The obtained target compound can be further purified by a conventional method such as recrystallization, reprecipitation, silica gel column chromatography or the like, if necessary. Further, the target compound の of each step can be used as it is in the next reaction without purification.

Method A is a method for producing compound (2), which is an intermediate for producing the compound represented by formula (I).
[Method A]

Here, R ¹ and R ² are the same as those in the general formula (I), and R ³ and R ⁴ are the same C1-C3 alkyl group. In the case where R ³ and R ⁴ together with the carbon atom to which they are bonded form a cyclopropane ring, for example, [J. Org. Chem. 2003, 68, 7133-7136].

Method B is a method for producing a compound in which R ⁵ , R ⁶ and R ⁷ represent the above (1) among the compounds represented by the general formula (I).

The method B will be described in detail according to the following [Method B-1] to [Method B-5] according to the structure of R ⁶ .
[Method B-1]

^{Wherein, R 1, R 2, R} 3, R 4, R 7, R 8, R 9 and ^{R 10} represents the general formula (I) and the ^{same, R 11} represents a C1 ~ C4 alkyl group.
[Method B-2]

Here, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same as in general formula (I), R ¹¹ is a C1-C4 alkyl group, R ¹² and ^{R 13} represents a hydrogen atom or a C1 ~ C3 alkyl group each independently.
[Method B-3]

^{Wherein, R 1, R 2, R} 3, R 4, R 7, R 8, R 9 and ^{R 10} represents the general formula (I) and the ^{same, R 11} represents a C1 ~ C4 alkyl group, A ¹ represents a single bond or a C1-C5 alkylene group which may be substituted with 1 to 3 C1-C3 alkyl groups.
[Method B-4]

Here, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same as in general formula (I), R ¹¹ is a C1-C4 alkyl group, R ¹² and R ¹³ each independently represents a hydrogen atom or a C1-C3 alkyl group.
[Method B-5]

Here, R ¹ , R ² , R ³ , R ⁴ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are the same as in general formula (I), R ¹¹ is a C1-C4 alkyl group, R ¹⁴ represents a protecting group, and A represents a single bond or a C1-C2 alkylene group.

Method C is a method for producing a compound in which R ⁵ , R ⁶ and R ⁷ represent the above (2) among the compounds represented by the general formula (I).

The C method, to no [C-1 Method] of the following, depending on the structure of ^{R 7} will be described separately in [C-3 method.
[C-1 method]

Here, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ and R ¹⁰ are the same as those in formula (I), and R ¹¹ represents a C1-C4 alkyl group. Show.
[Method C-2]

Here, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ and R ¹⁰ are the same as those in formula (I), and R ¹¹ represents a C1-C4 alkyl group. Show. In the case where R ⁷ is a carboxy C1 to C6 alkyl group optionally substituted with 1 to 3 C1 to C3 alkyl groups, it can be suitably produced by combining with known methods in the same manner.
[C-3 method]

^{Wherein, R 1, R 2, R} 3, R 4, R 5, R 6, R 8, R 9 and ^{R 10} represents the general formula (I) and the ^{same, R 11} is a C1 ~ C4 alkyl group A represents a single bond or a C1-C2 alkylene group.

The reaction in each step of Method A to Method C will be described below.
(Process a)
Step a is a step of producing amine (2) by allowing alkyllithium to act on compound (1). The reaction was carried out according to the method of Ciganek et al. Org. Chem. 1992, 57, 4521-4527, etc. can be cited as references.
(Process b)
Step b is a step of producing an ester by esterifying a carboxyl group. Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
(Process c)
Step c is a method for producing indoline compound (5) or (25) by reducing indole compound (4) or (24) with a reducing agent. Examples of the reducing agent used include borohydride metal salts such as sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride; and alkylsilanes such as triethylsilane and triphenylsilane. Sodium cyanoborohydride or triethylsilane. The solvent used is preferably a carboxylic acid as exemplified above, and more preferably acetic acid or trifluoroacetic acid. The reaction temperature is usually −20 to 60 ° C., preferably 0 to 25 ° C. The reaction time is usually 10 minutes to 6 hours, preferably 10 minutes to 4 hours.
(Process d)
Step d is a method for producing compound (7) by subjecting compound (5) and acryloyl chloride (6) to a basic conditioned reaction. The base used is preferably an organic amine as exemplified above, and more preferably triethylamine. The solvent used is preferably a halogenated hydrocarbon or ether as exemplified above, and more preferably methylene chloride or tetrahydrofuran. The reaction temperature is usually −78 to 25 ° C., preferably 0 to 25 ° C. The reaction time is usually 10 minutes to 24 hours, preferably 1 to 16 hours.
(Process e)
Step e is a method for producing compound (8) by coupling compound (7) and compound (2). The solvent used is preferably an alcohol as exemplified above, and more preferably ethanol. The reaction temperature is usually 25 to 80 ° C, preferably 60 to 80 ° C. The reaction time is usually 30 minutes to 12 hours, preferably 2 to 8 hours.
(Process f)
Step f is a step of producing carboxylic acid (I) by hydrolyzing the ester group of compound (8). Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
(Process g)
Step g is a step of producing compound (12) by reacting compound (9) with Meldrum's acid (10) and compound (11). The reaction was carried out according to the method J. Rajswaran et al. Org. Chem. 1999, 64, 1369-1371 etc. can be cited as references.
(Process h)
Step h is a step of producing compound (4-b) by decarboxylating the diester part of compound (12) in the presence of a copper catalyst. The reaction was carried out by the method of Yonemitsu et al. Chem. Pharm. Bull. 1982, 30, 3092-3096, etc. can be cited as references.
(Process i)
Step i is a step of producing compound (14) by reacting compound (9) with compound (13) in the presence of a Lewis acid. Examples of Lewis acids used include titanium tetrachloride, tin tetrachloride, aluminum chloride, zinc chloride, magnesium chloride, boron trifluoride diethyl ether complex, titanium tetraisopropoxide, and titanium triethoxide. Aluminum chloride. The solvent used is preferably an ether or halogenated hydrocarbon as exemplified above, and more preferably methylene chloride. The reaction temperature is usually 0 to 60 ° C., preferably 25 to 40 ° C. The reaction time is usually 30 minutes to 12 hours, preferably 1 to 4 hours.
(Process j)
Step j is a step of producing compound (4-c) by reducing the carbonyl group of compound (14) in the presence of an acid catalyst. Examples of the reducing agent used include borohydride metal salts such as sodium cyanoborohydride, sodium triacetoxyborohydride and sodium borohydride; and alkylsilanes such as triethylsilane and triphenylsilane. Sodium borohydride. The acid catalyst used is, for example, titanium tetrachloride, tin tetrachloride, aluminum chloride, zinc chloride, magnesium chloride or boron trifluoride diethyl ether complex, preferably boron trifluoride diethyl ether complex. The solvent used is preferably an ether or halogenated hydrocarbon as exemplified above, and more preferably tetrahydrofuran. The reaction temperature is usually 0 to 40 ° C., preferably 0 to 25 ° C. The reaction time is usually 1 to 12 hours, preferably 2 to 8 hours.
(Process k)
Step k is a step of producing compound (16) by reducing the carbonyl group of compound (15). Examples of the reducing agent used include lithium aluminum hydride, diisobutylaluminum hydride, lithium borohydride, sodium borohydride and the like, and preferably lithium aluminum hydride. The solvent used is preferably an aliphatic hydrocarbon, an aromatic hydrocarbon or an ether as exemplified above, and more preferably tetrahydrofuran. The reaction temperature is usually 0 to 100 ° C., preferably 0 to 40 ° C. The reaction time is usually 10 minutes to 6 hours, preferably 10 minutes to 1 hour.
(Process l)
Step 1 is a step for producing compound (4-d) by reacting compound (16) with compound (17) in the presence of a magnesium perchlorate catalyst. The reaction was carried out by the method of Grieco et al., Tetrahedron. Lett. 1997, 38, 2645-2648, etc. can be cited as references.
(Process m)
Step m is the method of Suzuki, Miyaura et al. Chem. Rev. This is a process for producing a biphenyl type compound by using a Suzuki coupling reaction which can be cited as a reference document such as 1995, 95, 2457-2483. The reaction can be carried out according to the above documents and the cited references in the documents.
(Process n)
Step n is a step of deprotecting the protecting group on the nitrogen of the indole. Examples of the reaction include T.W. W. Greene, P.M. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, 1999, John Wiley & Sons, Inc. You can refer to the documents listed in the review books.
(Process o)
Step o is a method of Maryoff et al., Chem. Rev. 1989, 89, 863-927 is a process for producing compound (23) from compound (22) using Horner-Emmons reaction, which can be cited as a reference. The base used is preferably a metal carbonate, metal hydride or alkali metal alkoxide as exemplified above, and more preferably potassium carbonate or sodium hydride. The solvent used is preferably an aromatic hydrocarbon or ether as exemplified above, and more preferably tetrahydrofuran. The reaction temperature is usually 0 to 80 ° C., preferably 25 to 80 ° C. The reaction time is usually 10 minutes to 12 hours, preferably 1 to 6 hours.
(Process p)
Step p is a step of producing compound (4-g) from compound (23) by catalytic hydrogenation reaction in the presence of a metal catalyst. The metal catalyst used is not particularly limited as long as it is used in a normal catalytic reduction reaction. For example, palladium carbon, palladium black, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine- Examples thereof include rhodium chloride (Wilkinson complex), palladium-barium sulfate, and Raney nickel, preferably palladium carbon. The reaction solvent used is preferably alcohols, ethers, aromatic hydrocarbons, aliphatic hydrocarbons or esters as exemplified above, more preferably alcohols, and even more preferably. Is ethanol. The hydrogen pressure is usually 1 to 10 atmospheres. The reaction temperature is usually 0 to 50 ° C., preferably 0 to 30 ° C. The reaction time is usually 10 minutes to 24 hours, preferably 10 minutes to 2 hours.

In addition, when the target compound or intermediate is a mixture of isomers such as stereoisomers, it can be appropriately separated and purified by medium pressure preparative chromatography using an optically active column or the like, HPLC or the like.

When the compound (I) of the present invention or its production intermediate has an asymmetric carbon, an optical isomer exists. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) recrystallizing with an appropriate salt and column chromatography. References for methods for resolving optical isomers from racemates include: “Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc.” by Jacques et al.

The indoline derivative of the present invention has an excellent calcium sensory receptor agonistic action, is excellent in pharmacokinetics such as high oral absorption, retention in blood and metabolic stability, and is also safe for organs such as kidney and liver. Since it is expensive, it is useful as a medicine. The indoline derivative of the present invention has an excellent calcium sensing receptor agonistic action, and acts on CaSR of the parathyroid gland to increase the sensitivity of the receptor to blood calcium, thereby suppressing PTH secretion from the parathyroid gland. It is useful as a therapeutic agent for hyperparathyroidism. More specific examples of hyperparathyroidism include secondary hyperparathyroidism, tertiary hyperparathyroidism, primary hyperparathyroidism, and the like. More specifically, secondary hyperparathyroidism includes secondary hyperparathyroidism under maintenance dialysis, secondary hyperparathyroidism in patients with chronic renal disease under dialysis, end stage of maintenance dialysis Secondary hyperparathyroidism in patients with kidney disease. Further, the indoline derivative of the present invention has an excellent calcium sensing receptor agonistic action and suppresses PTH secretion from the parathyroid gland by acting on CaSR of the parathyroid gland and increasing the sensitivity of the receptor to blood calcium. Since it has an action mechanism that secondarily lowers the blood calcium concentration, it is useful as a therapeutic agent for renal osteodystrophy or hypercalcemia. Specific examples of hypercalcemia include hypercalcemia associated with malignant tumors or hypercalcemia in patients with parathyroid cancer.

Since the compound represented by formula (I) of the present invention has a basic group such as an amino group, it can be converted to an acid addition salt with a pharmacologically acceptable acid. Such salts include, for example, hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; nitrates, perchlorates, sulfates, phosphates, etc. Inorganic acid salts; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetic acid, malic acid Organic acid salts such as fumarate, succinate, citrate, tartrate, succinate, maleate; and amino acid salts such as ornithate, glutamate, aspartate; Hydrohalide and organic acid salts are preferred.

In addition, since the indoline derivative represented by the general formula (I) has an acidic group such as a carboxy group, it is generally possible to form a base addition salt. Examples of pharmacologically acceptable salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt and morpholine. Salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N -Organic amine salts such as-(2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt; amino acid salts such as arginine salt; and the like.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may exist as a free form or a solvate, and these solvates are also included in the scope of the present invention. The solvate is not particularly limited as long as it is pharmacologically acceptable, and specifically, a hydrate, an ethanolate, and the like are preferable. Further, when a nitrogen atom is present in the compound of the present invention represented by the general formula (I), it may be an N-oxide, and these solvates and N-oxides are also within the scope of the present invention. included.

The compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof and a production intermediate of the compound of the present invention may be a geometric isomer such as a cis isomer, a trans isomer, etc. Alternatively, various isomers such as optical isomers such as d-form and l-form can exist, but the compound of the present invention is not limited to these isomers, stereoisomers and any ratio of these isomers. It also includes isomers and stereoisomer mixtures.

In addition, the compound of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound. The atomic isotopes such as deuterium ⁽² H), tritium ⁽³ H), carbon ^{-13 (13} C), carbon ^{-14 (14} C), nitrogen ^{-15 (15} N), chlorine -37 ⁽³⁷ Cl) or iodine-125 ( ¹²⁵ I). The compound may also be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

Furthermore, the present invention relates to a compound that is converted into compound (I) which is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, Also included in the present invention is a compound that undergoes hydrolysis or the like and is converted to compound (I), or a “pharmaceutically acceptable prodrug compound” that undergoes hydrolysis or the like by gastric acid or the like and is changed to compound (I). .

For the pharmaceutical composition containing the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, an appropriate preparation is selected according to the administration method, and methods for preparing various commonly used preparations Can be prepared.

When a pharmaceutical composition mainly comprising the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof is administered to a mammal (particularly a human), it can be administered systemically or locally, orally or It can be administered parenterally.

Examples of oral pharmaceutical forms include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive. Prepared as a mixed pharmaceutical composition. The preparation of the pharmaceutical composition comprises any suitable pharmaceutically acceptable binder, disintegrant, lubricant, swelling agent, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier. As needed from swelling aids, coating agents, plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffering agents, wetting agents, etc. Can be carried out in accordance with a conventional method using an appropriately selected one.

The parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, inhalants, etc. Is mentioned. These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive. Prepared as a mixed pharmaceutical composition. The preparation of the pharmaceutical composition may be performed as any suitable pharmaceutically acceptable stabilizer, preservative, solubilizer, humectant, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier. , Preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, solubilizing agents, buffering agents, isotonic agents, surfactants, coloring agents, buffering agents, thickeners, wetting agents, filling It can be carried out according to a conventional method using an agent, an absorption accelerator, a suspending agent, a binder and the like appropriately selected as necessary.

References regarding the above-mentioned pharmaceutically acceptable excipients include, for example, “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A. Wade and PJ Weller”.

In addition, as a reference for the pharmaceutically acceptable carrier or diluent, for example, “Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985)” can be cited.

The dose of the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof varies depending on symptoms, age, body weight, the kind and dose of drugs administered in combination, etc. When used as a pharmaceutical, the amount of Compound (I) in the range of 0.001 mg to 1000 mg, preferably in the range of 0.1 mg to 200 mg, more preferably in the range of 1 mg to 100 mg per adult. In terms of body weight, the compound (I) is contained in the range of 0.001 mg / kg to 20 mg / kg, preferably in the range of 0.005 mg / kg to 5 mg / kg, more preferably 0.01 mg / kg to 3 mg. / Kg range. This daily dose may be administered systemically or locally, once a few days to once to several times a day, orally or parenterally, or intravenously in the range of 1-24 hours per day Administer continuously. The daily dose may exceed the above amount if necessary.

Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to these methods.

The symbols “IR”, “ ¹ H-NMR”, “MS”, and “Anal” in the examples are “infrared absorption spectrum”, “nuclear magnetic resonance spectrum”, “mass analysis”, and “elemental analysis”, respectively. Means. The ratio of the eluting solvent described in the section of separation and purification by chromatography indicates a volume ratio unless otherwise specified. The parentheses in “ ¹ H-NMR” indicate the measurement solvent, and TMS (tetramethylsilane) was used as an internal standard substance. Multiplicity in ¹ H-NMR means s = singlet, d = doublelet, t = triplet, q = quartet, m = multiplet, and br = broad. Moreover, the following abbreviations were used in this specification.
Boc: tert-butoxycarbonyl CDCl ₃ : deuterated chloroform DMSO-D ₆ : dimethyl sulfoxide D6
CD ₃ OD: Heavy methanol [Reference Example 1]
2- (4-Fluoro-3-methoxyphenyl) propan-2-amine

Anhydrous cerium chloride (4.9 g, 20 mmol) was dried by superheated stirring at 150 ° C. for 2 hours under high vacuum and cooled to room temperature. After adding 50 ml of tetrahydrofuran and heating to reflux for 30 minutes and cooling to −78 ° C., 20 ml (20 mmol) of methyl lithium (1.0 M ether solution) was added dropwise and stirred for 1 hour. 4-Fluoro-3-methoxybenzonitrile (1.0 g, 6.6 mmol) was added as a solid all at once, and the temperature was gradually raised to room temperature. Under ice-cooling, 40 ml of aqueous ammonia was added to the reaction solution, and the aqueous phase was extracted with ether. The obtained organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 0.81 g (61%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 1.61 (2H, br s), 3.92 (3H, s), 6.97-7.02 (2H, m), 7.19 (1H, br dd, J = (7.8, 2.0 Hz).
[Reference Example 2]
2- (3,4-Difluorophenyl) propan-2-amine

The reaction was conducted in the same manner as in Reference Example 1 using 3,4-difluorobenzonitrile to obtain the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.47 (6H, s), 7.09 (1H, dt, J = 10.2, 8.4 Hz), 7.18-7.23 (1H, m), 7.34 (1H, ddd, J = 12.3, (7.6, 2.3 Hz).
[Example 1]
{5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} acetic acid monohydrochloride

(Process 1)
(5-Chloro-1H-indol-3-yl) acetic acid methyl ester

1.00 g (4.8 mmol) of (5-chloro-1H-indol-3-yl) acetic acid is dissolved in 10 mL of N, N-dimethylformamide, and 0.99 g (7.2 mmol) of potassium carbonate and iodine are added under ice cooling. 0.36 mL (5.8 mmol) of methyl chloride was added and stirred overnight at room temperature. Water was added to the reaction solution, the aqueous phase was extracted with ethyl acetate, the obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane = 1/2) to obtain 0.96 g (90%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 3.72 (3H, s), 3.74 (2H, s), 7.16 (1H, dd, J = 8.6, 2.0 Hz), 7.21 (1H, d, J = 2.3 Hz), 7.28 (1H, d, J = 8.6 Hz), 7.58 (1H, d, J = 2.0 Hz), 8.11 (1H, s).
(Process 2)
(5-Chloro-2,3-dihydro-1H-indol-3-yl) acetic acid methyl ester

0.96 g (4.3 mmol) of (5-chloro-1H-indol-3-yl) acetic acid methyl ester obtained in Example 1 (Step 1) was dissolved in 5 mL of trifluoroacetic acid, and triethylsilane was cooled under ice cooling. 1.4 mL (8.7 mmol) was added dropwise and stirred for 1 hour. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / hexane = 1/2 to 1/1) to obtain 0.84 g (87%) of the target compound.
_{^{1 H-NMR (CDCl 3)}} δ: 2.58 (1H, dd, J = 16.3, 9.0 Hz), 2.74 (1H, dd, J = 16.3, 5.7 Hz), 3.29 (1H, dd, J = 9.0, 6.3 Hz ), 3.67-3.75 (1H, m), 3.73 (3H, s), 3.81 (1H, t, J = 9.0 Hz), 6.55 (1H, d, J = 8.2 Hz), 6.98-7.01 (1H, m) , 7.03-7.04 (1H, m).
(Process 3)
(1-acryloyl-5-chloro-2,3-dihydro-1H-indol-3-yl) acetic acid methyl ester

0.85 g (3.7 mmol) of (5-chloro-2,3-dihydro-1H-indol-3-yl) acetic acid methyl ester obtained in Example 1 (Step 2) was dissolved in 8.5 mL of tetrahydrofuran, Under ice-cooling, 1.0 mL (7.5 mmol) of triethylamine and 0.33 mL (4.1 mmol) of acrylic acid chloride were sequentially added and stirred at room temperature for 1 hour. Water and saturated brine were added to the reaction solution, the aqueous phase was extracted with ethyl acetate, the obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / methylene chloride = 1/15), and the obtained solid was washed with isopropyl ether to obtain 0.51 g (49%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 2.59 (1H, dd, J = 16.5, 9.6 Hz), 2.83 (1H, dd, J = 16.5, 3.9 Hz), 3.75 (3H, s), 3.84 (2H, s ), 3.90 (2H, dd, J = 10.1, 6.1 Hz), 4.46 (1H, t, J = 10.1 Hz), 5.83 (1H, dd, J = 7.8, 4.3 Hz), 6.49-6.57 (2H, m) , 7.14 (1H, s), 7.22 (1H, d, J = 8.2 Hz), 8.24 (1H, d, J = 7.0 Hz).
(Process 4)
{5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} acetic acid methyl ester

(1-acryloyl-5-chloro-2,3-dihydro-1H-indol-3-yl) acetic acid methyl ester 0.15 g (0.54 mmol) obtained in Example 1 (Step 3) and cumylamine 89 mg (0 .66 mmol) was dissolved in 5 mL of ethanol and heated to reflux for 10 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (methanol / ethyl acetate = 1/10) to obtain 0.15 g (68%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, br s), 2.50-2.57 (3H, m), 2.65-2.70 (2H, m), 2.79 (1H, dd, J = 17.0, 4.5 Hz), 3.70-3.73 (1H, m), 3.74 (3H, s), 3.75-3.82 (1H, m), 4.26 (1H, t, J = 9.8 Hz), 7.11 (1H, s), 7.17-7.23 (2H, m), 7.32 (2H, t, J = 7.4 Hz), 7.48 (2H, d, J = 7.4 Hz), 8.16 (1H, d, J = 9.0 Hz).
(Process 5)
{5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} acetic acid monohydrochloride

{5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl obtained in Example 1 (Step 4) } Acetic acid methyl ester 0.15g (0.36mmol) was melt | dissolved in ethanol 1.5mL, 1N sodium hydroxide aqueous solution 0.7mL was added, and it stirred at room temperature for 1 hour. A 1N aqueous hydrochloric acid solution was added to acidify the aqueous phase, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was suspended in isopropyl ether and collected by filtration to obtain 0.16 g (93%) of monohydrochloride of the target compound.
¹ H-NMR (DMSO-D ₆ ) δ: 1.73 (6H, br s), 2.53-2.61 (1H, m), 2.77-2.92 (5H, m), 3.71-3.80 (2H, m), 4.29 (1H , t, J = 8.8 Hz), 7.25 (1H, dd, J = 8.6, 2.3 Hz), 7.41 (1H, s), 7.43 (1H, t, J = 7.4 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.64 (2H, d, J = 7.4 Hz), 8.01 (1H, d, J = 8.6 Hz), 9.06-9.18 (2H, m), 12.48 (1H, br s);
IR (KBr) vmax 3421, 2975, 2745, 1703, 1662, 1588, 1479, 1407, 1165, 768, 702 cm ^-1 ;
MS (FAB) m / z: 401 (M + H) +.

Examples 2 to 5 were synthesized in the same manner as in Example 1 using appropriate indoleacetic acid and benzylamine.
[Example 2]
(5-Chloro-1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] β-alanyl} -2,3-dihydro-1H-indol-3-yl) acetic acid 1 Hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.73 (6H, s), 2.58 (1H, dd, J = 16.8, 9.4 Hz), 2.80-2.92 (5H, m), 3.71-3.80 (2H, m) , 3.92 (3H, s), 4.30 (1H, t, J = 9.2 Hz), 7.11-7.15 (1H, m), 7.25-7.32 (2H, m), 7.41 (1H, s), 7.55 (1H, d , J = 8.2 Hz), 8.01 (1H, d, J = 9.0 Hz), 9.26-9.38 (1H, m), 12.49 (1H, br s);
IR (KBr) vmax 3423, 2977, 1737, 1671, 1524, 1481, 1402, 1028, 820 cm ^-1 ;
MS (FAB) m / z: 449 (M + H) ⁺ .
[Example 3]
(1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl} acetic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.87 (2H, m), 0.92 (2H, m), 2.51 (2H, m), 2.70-2.81 (4H, m), 3.72 (2H, m), 3.74 (3H, s), 4.27 (1H, m), 6.73 (1H, m), 6.85 (1H, m), 6.96-7.01 (2H, m), 7.16 (1H, t, J = 7.4 Hz), 7.19 ( 1H, t, J = 7.8 Hz), 7.27 (1H, d, J = 7.4 Hz), 8.05 (1H, d, J = 7.8 Hz);
Anal. Calcd. For C ₂₃ H ₂₆ N ₂ O ₄ .0.75H ₂ O Found C, 67.41. H, 6.94. N, 6.93;
IR (KBr) vmax 3413, 3222 , 1633, 1483, 1431, 1228, 1050, 756, 701 cm -1;
MS (FAB) m / z: 395 (M + H) ⁺ .
[Example 4]
(5-Fluoro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl} acetic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.81-0.89 (4H, m), 1.05 (1H, t, J = 7.4 Hz), 2.55-2.46 (2H, m), 2.68 (2H, t, J = 7.4 Hz), 2.80 (1H, dd, J = 16.0, 4.0 Hz), 3.32-3.37 (1H, m), 3.70 (3H, s), 3.62-3.76 (1H, m), 4.26 (1H, t, J = 10.6 Hz), 6.69 (1H, dd, J = 8.2, 2.0 Hz), 6.81 (1H, d, J = 8.2 Hz), 6.92-6.98 (2H, m), 7.12-7.18 (2H, m), 7.99 -8.03 (1H, m);
IR (KCl) vmax 3409, 1651, 1349, 1120, 782, 537 cm ^-1 ;
MS (ESI) m / z: 413 (M + H) ⁺
[Example 5]
{1- [N- (1-Methyl-1-phenylethyl) β-alanyl} -5- (trifluoromethyl) -2,3-dihydro-1H-indol-3-yl} acetic acid monohydrochloride

^{1 H-NMR (DMSO-D} 6) δ: 1.76 (6H, s), 2.62 (1H, m), 2.85-3.00 (5H, m), 3.80-3.85 (2H, m), 4.34 (1H, t, J = 9.4 Hz), 7.42 (1H, t, J = 7.4 Hz), 7.47-7.51 (2H, m), 7.58 (1H, d, J = 8.6 Hz), 7.69 (2H, d, J = 7.4 Hz) , 8.15 (1H, d, J = 8.6 Hz), 9.46 (1H, br s), 9.55 (1H, br s), 12.43 (1H, br s);
Anal. Calcd. For C ₂₃ H ₂₅ N ₂ O ₃ F ₃ .HCl.H ₂ O Found C, 56.66. H, 5.90. N, 5.41. F, 11.48. Cl, 6.87;
IR (KBr) vmax 3413, 2959, 1772, 1728, 1668, 1450, 1322, 1161, 1116, 829, 701 cm ^-1 ;
MS (FAB) m / z: 435 (M + H) ⁺ .
[Example 6]
3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

(Process 1)
3- (5-Chloro-1H-indol-3-yl) propionic acid ethyl ester

1.52 g (10 mmol) of 5-chloroindole was dissolved in 10 mL of acetonitrile, and 1.73 g (12 mmol) of Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione) and 1 mL of formaldehyde (36%) Aqueous solution, 12 mmol) and 58 mg (0.5 mmol) of L-proline were added and stirred at room temperature for 18 hours. The reaction mixture was concentrated, and the resulting residue was dissolved in 6 mL of ethanol and 30 mL of pyridine, and then 635 mg (10 mmol) of copper powder was added and stirred at 105 ° C. for 4 hours. After filtration of the reaction solution, the filtrate was concentrated, ethyl acetate was added, the organic phase was washed with 1N aqueous hydrochloric acid solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-60% ethyl acetate / hexane) to obtain 1.62 g (64%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7.0 Hz), 2.65 (2H, t, J = 7.5 Hz), 3.02 (2H, t, J = 7.5 Hz), 4.10 (2H, q, J = 7.0 Hz), 7.00 (1H, d, J = 1.6 Hz), 7.10 (1H, dd, J = 8.0, 2.0 Hz), 7.23 (1H, d, J = 8.0 Hz), 7.53 (1H, d, J = 1.6 Hz), 7.97 (1H, br s).
(Process 2)
3- (5-Chloro-2,3-dihydro-1H-indol-3-yl) propionic acid ethyl ester

1.62 g (6.4 mmol) of 3- (5-chloro-1H-indol-3-yl) propionic acid ethyl ester obtained in Example 6 (Step 1) was dissolved in 15 mL of trifluoroacetic acid, and the mixture was cooled on ice. Triethylsilane 2.06mL (12.9mmol) was dripped and it stirred for 15 minutes. To the reaction solution was added 1N aqueous hydrochloric acid solution, neutralized with 1N aqueous sodium hydroxide solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-60% ethyl acetate / hexane) to obtain 714 mg (47%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.4 Hz), 1.79-1.89 (1H, m), 2.01-2.12 (1H, m), 2.32-2.37 (2H, m), 3.19 -3.29 (2H, m), 3.67 (2H, t, J = 7.5 Hz), 4.11 (2H, q, J = 7.4 Hz), 6.50 (1H, d, J = 8.3 Hz), 6.95 (1H, d, J = 8.3 Hz), 7.02 (1H, s).
(Process 3)
3- (1-acryloyl-5-chloro-2,3-dihydro-1H-indol-3-yl) propionic acid ethyl ester

3- (5-Chloro-2,3-dihydro-1H-indol-3-yl) propionic acid ethyl ester 714 mg (2.8 mmol) obtained in Example 6 (Step 2) was added to 6 mL of methylene chloride and 6 mL of triethylamine. After dissolution and cooling to −78 ° C., 0.34 mL (4.2 mmol) of acryloyl chloride was added dropwise, stirred for 30 minutes, warmed to room temperature, and further stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (0-18% ethyl acetate / methylene chloride) to obtain 699 mg (81%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.0 Hz), 1.83-1.93 (1H, m), 2.04-2.13 (1H, m), 2.34 (2H, t, J = 7.5 Hz ), 3.38-3.46 (1H, m), 3.79-3.84 (1H, m), 4.11 (2H, q, J = 7.0 Hz), 4.26 (1H, t, J = 10.0 Hz), 5.78-5.81 (1H, m), 6.48-6.53 (2H, m), 7.14-7.19 (2H, m), 8.20 (1H, d, J = 8.2 Hz).
(Process 4)
3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid ethyl ester

308 mg (1.0 mmol) of 3- (1-acryloyl-5-chloro-2,3-dihydro-1H-indol-3-yl) propionic acid ethyl ester obtained in Example 6 (Step 3) was added to 2 mL of ethanol. It melt | dissolved, cumylamine 135 mg (1.0 mmol) was added, and it stirred at 90 degreeC for 1 hour. After cooling to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (0-18% methanol / ethyl acetate) to obtain 413 mg (93%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.49 (6H, s), 1.81-1.89 (1H, m), 2.03-2.11 (1H, m), 2.33 (2H , t, J = 7.5 Hz), 2.50-2.54 (2H, m), 2.64-2.69 (2H, m), 3.36-3.42 (1H, m), 3.63-3.67 (1H, m), 4.08-4.16 (3H , m), 7.13-7.21 (3H, m), 7.30 (2H, t, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 8.13 (1H, d, J = 9.0 Hz).
(Process 5)
3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indole-3 obtained in Example 6 (Step 4) -Il} propionic acid ethyl ester 412 mg (0.93 mmol) was dissolved in ethanol 2 mL, 2N aqueous sodium hydroxide solution 0.5 mL was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, neutralized with 2N aqueous hydrochloric acid, and ether was further added. Insoluble matter was collected by filtration, and the obtained powder was washed with water and ether to obtain 337 mg (87%) of the desired compound.
¹ H-NMR (DMSO-D ₆ ) δ: 1.33 (6H, s), 1.63-1.72 (1H, m), 1.90-2.00 (1H, m), 2.18-2.30 (2H, m), 2.43-2.59 ( 4H, m), 3.32-3.40 (1H, m), 3.74-3.80 (1H, m), 4.14 (1H, t, J = 9.8 Hz), 7.12-7.20 (2H, m), 7.23-7.30 (3H, m), 7.44 (2H, d, J = 8.2 Hz), 7.99 (1H, d, J = 8.2 Hz);
IR (KCl) vmax 3400, 1664, 1400, 1253, 1040, 793 cm ^-1 ;
MS (ESI) m / z: 415 (M + H) ⁺ .

Examples 7 to 44 were synthesized in the same manner as Example 6 using the appropriate substituted indole and benzylamine.
[Example 7]
3- (5-Chloro-1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl ) Propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.73-1.79 (1H, m), 1.73 (6H, br s), 1.97-2.05 (1H, m), 2.20-2.35 (2H, m), 2.85 (4H , br s), 3.42-3.49 (1H, m), 3.76 (1H, dd, J = 10.4, 5.5 Hz), 3.92 (3H, s), 4.17 (1H, t, J = 10.4 Hz), 7.12-7.16 (1H, m), 7.24-7.32 (2H, m), 7.37 (1H, d, J = 1.8 Hz), 7.57 (1H, dd, J = 8.2, 1.8 Hz), 8.02 (1H, d, J = 8.6 Hz), 9.26-9.39 (2H, m);
IR (KBr) vmax 3412, 2973, 2755, 1730, 1660, 1525, 1480, 1409, 1160, 1028, 822 cm ^-1 ;
MS (FAB) m / z: 463 (M + H) ⁺ .
[Example 8]
3- (5-Chloro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.88-0.95 (2H, m), 1.71-1.78 (1H, m), 1.97-2.06 (1H, m), 2.23-2.36 (2H, m), 2.56- 2.64 (2H, m), 2.74-2.76 (2H, m), 3.40-3.45 (1H, m), 3.77 (3H, s), 3.77-3.82 (1H, m), 4.19 (1H, t, J = 10.2 Hz), 6.76 (1H, dd, J = 7.8, 2.0 Hz), 6.88 (1H, d, J = 7.8 Hz), 6.99 (1H, s), 7.20-7.25 (2H, m), 7.35 (1H, s ), 8.06 (1H, d, J = 8.6 Hz);
IR (KCl) vmax 3405, 2927, 1454, 1279, 1101, 974, 832, 647, 446 cm ^-1 ;
MS (ESI) m / z: 443 (M + H) ⁺ .
[Example 9]
3- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid monohydrochloride

^{1 H-NMR (DMSO-D} 6) δ: 1.75 (6H, s), 1.99 (1H, m), 2.20-2.36 (3H, m), 2.83 (4H, m), 3.42 (1H, m), 3.71 (1H, m), 4.14 (1H, m), 7.04 (1H, t, J = 7.0 Hz), 7.19 (1H, t, J = 7.0 Hz), 7.28 (1H, d, J = 7.4 Hz), 7.40 -7.51 (2H, m), 7.66-7.69 (2H, m), 8.04 (1H, d, J = 7.8 Hz), 9.27 (2H, br m), 12.18 (1H, br s);
Anal. Calcd. For C ₂₃ H ₂₈ N ₂ O ₃ .HCl.0.5H ₂ O Found C, 65.00. H, 7.20. N, 6.47. Cl, 8.58;
IR (KBr) vmax 3419, 3111, 2981, 2744, 1727, 1633, 1590, 1486, 1440, 1187, 773 cm ^-1 ;
MS (FAB) m / z: 381 (M + H) +.
[Example 10]
3- (1- {N- [1- (3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.73 (6H, s), 1.98 (1H, m), 2.20-2.36 (3H, m), 2.85 (4H, m), 3.43 (1H, m), 3.71 (1H, m), 3.81 (3H, s), 4.14 (1H, m), 6.99 (1H, m), 7.05 (1H, t, J = 7.0 Hz), 7.17-7.22 (2H, m), 7.25- 7.30 (2H, m), 7.40 (1H, t, J = 8.2 Hz), 8.04 (1H, d, J = 8.2 Hz), 9.18 (2H, br m), 12.18 (1H, br s);
Anal. Calcd. For C ₂₄ H ₃₀ N ₂ O ₄ .HCl.0.5H ₂ O Found C, 63.21. H, 7.18. N, 6.04. Cl, 8.28;
IR (KBr) vmax 3429, 3164, 2931, 2738, 1724, 1637, 1588, 1487, 1438, 1184, 770 cm ^-1 ;
MS (FAB) m / z: 411 (M + H) ⁺ .
[Example 11]
3- (1- {N- [1- (3-Fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid 0.75 hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.71 (6H, br s), 2.01 (1H, m), 2.20-2.38 (3H, m), 2.85 (2H, m), 3.33 (2H, m), 3.43 (1H, m), 3.73 (1H, m), 4.16 (1H, m), 7.04 (1H, m), 7.19 (1H, t, J = 7.8 Hz), 7.22-7.31 (2H, m), 7.47 -7.59 (3H, m), 8.04 (1H, d, J = 7.8 Hz), 9.18 (1.8H, br m);
..... Anal Calcd For C 23 H 27 N 2 O 3 .0.75HCl.0.5H 2 O Found C, 63.25 H, 6.46 N, 6.21 Cl, 6.06;
IR (KBr) vmax 2927, 2740, 2730, 1639, 1592, 1484, 1420, 1275, 1168, 772, 700 cm ^-1 ;
MS (FAB) m / z: 399 (M + H) ⁺ .
[Example 12]
3- (1- {N- [1- (4-Fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

_{^{1 H-NMR (CDCl 3)}} δ: 1.73 (1H, m), 1.76 (3H, s), 1.78 (3H, s), 2.10-2.24 (3H, m), 2.74 (1H, br d, J = 17.1 Hz), 2.87-3.06 (3H, m), 3.36 (1H, br s), 3.77 (1H, m), 3.95 (1H, m), 3.98 (3H, s), 7.00-7.08 (3H, m), 7.15 (2H, br d, J = 7.8 Hz), 7.45 (1H, d, J = 6.8 Hz), 8.08 (1H, d, J = 7.8 Hz), 8.24 (1H, br s);
MS (FAB) m / z: 429 (M + H) ⁺ .
[Example 13]
3- (1- {N- [1- (3,4-Difluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.72-1.75 (1H, m), 1.73 (6H, br s), 1.95-2.04 (1H, m), 2.21-2.38 (2H, m), 2.82-2.91 (4H, m), 3.39-3.47 (1H, m), 3.73 (1H, dd, J = 10.2, 5.7 Hz), 4.15 (1H, t, J = 10.2 Hz), 7.05 (1H, t, J = 7.5 Hz), 7.20 (1H, t, J = 7.5 Hz), 7.29 (1H, d, J = 7.5 Hz), 7.50-7.63 (2H, m), 7.80 (1H, t, J = 9.8 Hz), 8.05 ( 1H, d, J = 7.5 Hz), 9.20 (1H, s), 12.18 (1H, br s);
MS (FAB) m / z: 417 (M + H) ⁺ .
[Example 14]
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.88 (2H, m), 0.93 (2H, m), 1.70 (1H, m), 1.98 (1H, m), 2.25 (2H, m), 2.56 (2H , m), 2.73 (2H, m), 3.72 (2H, m), 3.75 (3H, s), 4.14 (1H, m), 6.74 (1H, m), 6.56 (1H, d, J = 7.8 Hz) , 6.97-7.03 (2H, m), 7.15-7.26 (3H, m), 7.19 (1H, d, J = 8.2 Hz);
Anal. Calcd. For C ₂₄ H ₂₈ N ₂ O ₄ .0.5H ₂ O Found C, 69.26. H, 7.26. N, 6.75;
IR (KBr) vmax 2933, 1649, 1596, 1482, 1415, 1236, 1038, 758, 701 cm ^-1 ;
MS (FAB) m / z: 409 (M + H) ⁺ .
[Example 15]
3- {5-Fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.42 (6H, s), 1.64-1.75 (1H, m), 1.93-2.02 (1H, m), 2.18-2.35 (2H, m), 2.50-2.61 ( 4H, m), 3.34-3.44 (1H, m), 3.72-3.81 (1H, m), 4.16 (1H, t, J = 9.8 Hz), 6.97 (1H, t, J = 9.8 Hz), 7.13 (1H , d, J = 7.0 Hz), 7.18-7.23 (1H, m), 7.31 (2H, t, J = 7.0 Hz), 7.49 (2H, d, J = 7.0 Hz), 7.99-8.03 (1H, m) ;
IR (KCl) vmax 3407, 1607, 1251, 943, 620 cm ^-1 ;
MS (ESI) m / z: 399 (M + H) ⁺ .
[Example 16]
3- (5-Fluoro-1- {N- [1- (3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.47 (6H, s), 1.63-1.77 (1H, m), 1.92-2.03 (1H, m), 2.18-2.35 (2H, m), 2.54-2.68 ( 4H, m), 3.35-3.44 (1H, m), 3.74 (3H, s), 3.75-3.79 (1H, m), 4.16 (1H, t, J = 9.4 Hz), 6.79-6.86 (1H, m) , 6.98 (1H, t, J = 9.8 Hz), 7.03-7.16 (3H, m), 7.23-7.30 (1H, m), 7.98-8.04 (1H, m);
IR (KCl) vmax 3400, 1734, 1413, 1119, 787 cm ^-1 ;
MS (ESI) m / z: 429 (M + H) ⁺ .
[Example 17]
3- (5-Fluoro-1- {N- [1- (3-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid 0 .9 Hydrochloride

^{1 H-NMR (DMSO-D} 6) δ: 1.72 (1H, m), 1.74 (6H, s), 2.03 (1H, m), 2.20-2.37 (2H, m), 2.81-2.89 (4H, m) , 3.45 (1H, m), 3.76 (1H, m), 4.18 (1H, t, J = 10.3 Hz), 7.00 (1H, m), 7.18 (1H, m), 7.28 (1H, t, J = 7.8 Hz), 7.49-7.60 (3H, m), 8.02 (1H, m), 9.34 (1H, br s), 9.41 (0.9H, br s);
Anal.Calcd.For C ₂₃ H ₂₆ N ₂ O ₃ F.0.9HCl.0.5H ₂ O Found C, 63.06.H, 6.19.N, 5.93.F, 6.89.Cl, 6.83;
IR (KBr) vmax 3412, 2955, 2764, 1727, 1656, 1486, 1417, 1253, 1168, 793, 701 cm ^-1 ;
MS (FAB) m / z: 417 (M + H) ⁺ .
[Example 18]
3- (5-Fluoro-1- {N- [1- (4-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (CDCl ₃ ) δ: 1.68 (6H, s), 1.70-1.80 (1H, m), 2.03-2.28 (3H, m), 2.61-2.68 (1H, m), 2.75-2.91 (3H, m), 3.36 (1H, br s), 3.72 (1H, dd, J = 10.6, 5.1 Hz), 4.03 (1H, t, J = 10.0 Hz), 6.86 (2H, br s), 7.06-7.10 (2H , m), 7.52-7.56 (2H, m), 8.10 (1H, dd, J = 9.4, 4.7 Hz), 8.62 (1H, br s);
MS (FAB) m / z: 417 (M + H) ⁺ .
[Example 19]
3- (5-Fluoro-1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl ) Propionic acid

¹ H-NMR (CD ₃ OD) δ: 1.78-1.84 (1H, m), 1.82 (6H, s), 2.06-2.18 (2H, m), 2.28 (2H, t, J = 7.2 Hz), 2.72- 2.90 (2H, m), 3.06 (1H, dd, J = 11.1, 4.9 Hz), 3.47 (1H, m), 3.83 (1H, dd, J = 10.6, 5.5 Hz), 3.98 (3H, s), 4.16 (1H, t, J = 10.0 Hz), 6.92 (1H, t, J = 8.8 Hz), 7.05 (1H, d, J = 8.2 Hz), 7.12-7.21 (2H, m), 7.37 (1H, d, J = 7.8 Hz), 8.11 (1H, dd, J = 8.8, 4.9 Hz);
MS (FAB) m /: 447 (M + H) ⁺ .
[Example 20]
3- (5-Fluoro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.19 (2H, br s), 1.45 (2H, br s), 1.66-1.75 (1H, m), 1.94-2.02 (1H, m), 2.17-2.35 ( 2H, m), 2.80-2.86 (2H, m), 3.03-3.10 (2H, m), 3.38-3.44 (1H, m), 3.70-3.73 (1H, m), 3.77 (3H, s), 4.14 ( 1H, t, J = 10.0 Hz), 6.95-7.02 (1H, m), 7.13-7.16 (2H, m), 7.21 (1H, s), 7.32-7.36 (1H, m), 7.98-8.01 (1H, m), 9.41 (2H, br s);
IR (KBr) vmax 3181, 2767, 1735, 1420, 1162, 891, 598 cm ^-1 ;
MS (ESI) m / z: 427 (M + H) ⁺
[Example 21]
3- {5-Methyl-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.33 (6H, s), 1.59-1.68 (1H, m), 1.89-1.97 (1H, m), 2.17-2.30 (2H, m), 2.46 (3H, s), 2.42-2.55 (4H, m), 3.26-3.33 (1H, m), 3.68-3.72 (1H, m), 4.10 (1H, t, J = 9.8 Hz), 6.92 (1H, d, J = 7.8 Hz), 7.02 (1H, s), 7.14 (1H, t, J = 7.8 Hz), 7.26 (2H, t, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz), 7.88 (1H , d, J = 7.8 Hz);
IR (KCl) vmax 3523, 2657, 1490, 1282, 1071, 900, 768, 461 cm ^-1 ;
MS (ESI) m / z: 395 (M + H) ⁺ .
[Example 22]
3- (1- {N- [1- (3-Fluorophenyl) -1-methylethyl] -β-alanyl} -5-methyl-2,3-dihydro-1H-indol-3-yl) propionic acid 0 .9 Hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.70 (1H, m), 1.74 (6H, s), 2.00 (1H, m), 2.21-2.37 (5H, m), 2.77-2.89 (4H, m) , 3.38 (1H, m), 3.70 (1H, m), 4.13 (1H, t, J = 10.3 Hz), 6.99 (1H, d, J = 7.3 Hz), 7.09 (1H, s), 7.28 (1H, t, J = 7.3 Hz), 7.48-7.58 (3H, m), 7.92 (1H, d, J = 8.3 Hz), 9.19 (1H, br s), 9.26 (0.9H, br s);
Anal.Calcd.For C ₂₄ H ₂₉ N ₂ O ₃ F.0.9HCl.0.5H ₂ O Found C, 63.46.H, 7.13.N, 6.00.F, 3.60.Cl, 6.85;
IR (KBr) vmax 3421, 2953, 2760, 1728, 1655, 1591, 1491, 1441, 1163, 823, 701 cm ^-1 ;
MS (FAB) m / z: 413 (M + H) ⁺ .
[Example 23]
3- (1- {N- [1- (4-Fluorophenyl) -1-methylethyl] -β-alanyl} -5-methyl-2,3-dihydro-1H-indol-3-yl) propionic acid

_{^{1 H-NMR (CDCl 3)}} δ: 1.75 (1H, br t, J = 6.6 Hz), 1.87 (6H, s), 2.05-2.24 (3H, m), 2.28 (3H, s), 2.83 (1H, br d, J = 16.8 Hz), 2.93-3.01 (2H, m), 3.11-3.17 (1H, m), 3.31 (1H, br s), 3.79 (1H, br s), 3.93 (1H, t, J = 9.3 Hz), 6.97 (2H, m), 7.13 (2H, m), 7.70 (2H, br s), 7.93 (1H, br d, J = 7.8 Hz), 9.41 (1H, br s);
MS (FAB) m / z: 413 (M + H) ⁺ .
[Example 24]
3- (1- {N- [1- (4-Fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -5-methyl-2,3-dihydro-1H-indol-3-yl ) Propionic acid

¹ H-NMR (CDCl ₃ ) δ: 1.81 (1H, m), 1.87 (3H, s), 1.90 (3H, s), 2.03 (1H, m), 2.15-2.25 (2H, m), 2.30 (3H , s), 2.77 (1H, dt, J = 17.3, 5.0 Hz), 2.91-2.97 (1H, m), 3.01-3.09 (1H, m), 3.17-3.27 (1H, m), 3.36 (1H, br s), 3.87-3.95 (2H, m), 4.01 (3H, s), 6.96-7.12 (4H, m), 7.60 (1H, dd, J = 8.0, 1.8 Hz), 7.91 (1H, d, J = 8.2 Hz);
MS (FAB) m / z: 443 (M + H) ⁺ .
[Example 25]
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -5-methyl-2,3-dihydro-1H-indol-3-yl) propionic acid

^{1 H-NMR (DMSO-D} 6) δ: 0.88-0.97 (4H, m), 1.67-1.75 (1H, m), 1.97-2.03 (1H, m), 2.29 (3H, s), 2.25-2.38 ( 2H, m), 2.54-2.63 (2H, m), 2.73-2.76 (2H, m), 3.36-3.39 (1H, m), 3.77 (3H, s), 3.73-3.79 (1H, m), 4.16 ( 1H, t, J = 10.3 Hz), 6.76 (1H, dd, J = 8.3, 2.0 Hz), 6.89 (1H, d, J = 8.3 Hz), 7.00 (2H, s), 7.09 (1H, s), 7.23 (1H, t, J = 8.3 Hz), 7.96 (1H, d, J = 8.3 Hz);
IR (KCl) vmax 3404, 2924, 1644, 1361, 1165, 1017, 829, 569 cm ^-1 ;
MS (ESI) m / z: 423 (M + H) ⁺ .
[Example 26]
3- {5-Ethyl-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.11 (3H, t, J = 7.5 Hz), 1.33 (6H, s), 1.57-1.69 (1H, m), 1.89-1.99 (1H, m), 2.21 -2.29 (2H, m), 2.46-2.55 (6H, m), 3.29-3.33 (1H, m), 3.68-3.74 (1H, m), 4.10 (1H, t, J = 9.9 Hz), 6.95 (1H , d, J = 8.2 Hz), 7.05 (1H, s), 7.14 (1H, t, J = 7.8 Hz), 7.26 (2H, t, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz ), 7.90 (1H, d, J = 8.2 Hz);
IR (KCl) vmax 3407, 1612, 1337, 1073, 799, 461 cm ^-1 ;
MS (ESI) m / z: 409 (M + H) ⁺ .
[Example 27]
3- (5-Ethyl-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.81-0.89 (4H, m), 1.12 (3H, t, J = 7.8 Hz), 1.58-1.69 (1H, m), 1.89-1.99 (1H, m) , 2.20-2.30 (2H, m), 2.47-2.55 (4H, m), 2.64-2.70 (2H, m), 3.29-3.31 (1H, m), 3.66-3.70 (1H, m), 3.70 (3H, s), 4.09 (1H, t, J = 9.8 Hz), 6.69 (1H, dd, J = 8.2, 2.1 Hz), 6.82 (1H, d, J = 7.8 Hz), 6.92-6.97 (2H, m), 7.05 (1H, s), 7.16 (1H, t, J = 7.8 Hz), 7.91 (1H, d, J = 8.2 Hz);
IR (KCl) vmax 3228, 1709 , 1413, 1165, 1017, 822, 568 cm -1;
MS (ESI) m / z: 437 (M + H) ⁺ .
[Example 28]
3- (5-Methoxy-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

^{1 H-NMR (DMSO-D} 6) δ: 0.89-0.98 (4H, m), 1.69-1.77 (1H, m), 2.00-2.07 (1H, m), 2.25-2.39 (2H, m), 2.54- 2.62 (2H, m), 2.74-2.77 (2H, m), 3.37-3.41 (1H, m), 3.76 (3H, s), 3.78 (3H, s), 3.75-3.79 (1H, m), 4.17 ( 1H, t, J = 10.3 Hz), 6.75-6.78 (2H, m), 6.88-6.91 (2H, m), 7.01 (1H, s), 7.23 (1H, t, J = 7.8 Hz), 8.00 (1H , d, J = 8.8 Hz);
IR (KCl) vmax 3412, 2935, 1489, 1240, 975, 783, 530 cm ^-1 ;
MS (ESI) m / z: 439 (M + H) ⁺ .
[Example 29]
3- {5-Ethoxy-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.30 (3H, t, J = 7.4 Hz), 1.36 (6H, s), 1.62-1.75 (1H, m), 1.93-2.03 (1H, m), 2.18 -2.34 (2H, m), 2.45-2.59 (4H, m), 3.30-3.38 (1H, m), 3.71-3.77 (1H, m), 3.97 (2H, q, J = 7.4 Hz), 4.13 (1H , t, J = 9.8 Hz), 6.70 (1H, d, J = 8.8 Hz), 6.83 (1H, s), 7.18 (1H, t, J = 7.4 Hz), 7.29 (2H, t, J = 7.4 Hz ), 7.48 (2H, d, J = 7.4 Hz), 7.94 (1H, d, J = 8.8 Hz);
IR (KCl) vmax 3385, 1652, 1395, 1044, 903, 744, 525 cm ^-1 ;
MS (ESI) m / z: 425 (M + H) ⁺ .
[Example 30]
3- (5-Ethoxy-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.80-0.89 (4H, m), 1.26 (3H, t, J = 6.8 Hz), 1.26 (3H, t, J = 6.8 Hz), 1.59-1.68 (1H , m), 1.89-1.98 (1H, m), 2.13-2.30 (2H, m), 2.43-2.54 (2H, m), 2.64-2.71 (2H, m), 3.26-3.34 (1H, m), 3.65 -3.69 (1H, m), 3.70 (3H, s), 3.94 (2H, q, J = 6.8 Hz), 4.09 (1H, t, J = 11.0 Hz), 6.65-6.71 (2H, m), 6.78- 6.83 (2H, m), 6.93 (1H, s), 7.15 (1H, t, J = 7.4 Hz), 7.91 (1H, d, J = 8.6 Hz);
IR (KCl) vmax 3413, 2926, 1476, 1328, 1045, 812, 438 cm ^-1 ;
MS (ESI) m / z: 453 (M + H) ⁺ .
[Example 31]
3- (5-Cyano-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.90-1.12 (4H, m), 1.68-1.77 (1H, m), 1.94-2.03 (1H, m), 2.17-2.34 (2H, m), 2.62- 2.93 (2H, m), 3.40-3.46 (1H, m), 3.73 (3H, s), 3.76-3.82 (1H, m), 4.18 (1H, t, J = 10.0 Hz), 6.74-7.10 (3H, m), 7.14-7.32 (1H, m), 7.65 (1H, d, J = 7.8 Hz), 7.71 (1H, s), 8.11 (1H, d, J = 8.8 Hz);
IR (KBr) vmax 3410, 2223, 1437, 1192, 735, 484 cm ^-1 ;
MS (ESI) m / z: 434 (M + H) ⁺ .
[Example 32]
3- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -5- (trifluoromethyl) -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (CDCl ₃ ) δ: 1.88 (7H, br s), 2.02-2.28 (3H, m), 2.80-3.10 (3H, m), 3.20 (1H, br s), 3.41 (1H, br s ), 3.86-4.02 (2H, m), 7.33-7.50 (5H, m), 7.68 (2H, br s), 8.16 (1H, d, J = 8.2 Hz);
MS (FAB) m / z: 449 (M + H) ⁺ .
[Example 33]
3- [1- {N- [1- (4-Fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -5- (trifluoromethyl) 2,3-dihydro-1H-indole- 3-yl] propionic acid

¹ H-NMR (CD ₃ OD) δ: 1.79 (7H, br s), 2.10-2.25 (3H, m), 2.75-2.95 (2H, m), 3.02 (2H, m), 3.48 (1H, br s ), 3.85-4.00 (1H, m), 3.97 (3H, s), 4.18 (1H, t, J = 10.0 Hz), 7.10-7.20 (2H, m), 7.37 (1H, br d, J = 6.6 Hz) ), 7.49 (1H, d, J = 7.8 Hz), 7.56 (1H, s), 8.24 (1H, d, J = 8.2 Hz);
MS (FAB) m / z: 497 (M + H) ⁺ .
[Example 34]
3- {4-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.73-1.75 (1H, m), 1.74 (6H, s), 2.01-2.10 (1H, m), 2.14-2.22 (1H, m), 2.27-2.36 ( 1H, m), 2.74-2.97 (4H, m), 3.48-3.54 (1H, m), 3.89 (1H, dd, J = 10.5, 2.0 Hz), 4.09 (1H, t, J = 10.5 Hz), 7.10 (1H, d, J = 8.0 Hz), 7.25 (1H, t, J = 8.0 Hz), 7.43 (1H, t, J = 7.4 Hz), 7.50 (2H, t, J = 7.4 Hz), 7.66 (2H , d, J = 7.4 Hz), 8.02 (1H, d, J = 8.0 Hz), 9.11 (2H, br s), 12.17 (1H, br s);
IR (KBr) vmax 3355, 2978, 2789, 1713, 1704, 1666, 1455, 1408, 1349, 1281, 791, 698 cm ^-1 ;
MS (FAB) m / z: 415 (M + H) ⁺ .
[Example 35]
3- (4-Chloro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.22 (2H, br s), 1.47 (2H, br s), 1.67-1.78 (1H, m), 2.00-2.09 (1H, m), 2.12-2.21 ( 1H, m), 2.27-2.36 (1H, m), 2.75-2.84 (1H, m), 2.94-3.02 (1H, m), 3.10 (2H, br s), 3.47-3.54 (1H, m), 3.80 (3H, s), 3.89 (1H, dd, J = 10.2, 2.2 Hz), 4.08 (1H, t, J = 10.2 Hz), 6.99 (1H, d, J = 7.8 Hz), 7.10 (1H, d, J = 7.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 7.23-7.28 (2H, m), 7.38 (1H, t, J = 7.8 Hz), 8.01 (1H, d, J = 7.8 Hz) , 9.36-9.48 (2H, m), 12.18 (1H, br s);
IR (KBr) vmax 3356, 2941, 2755, 1713, 1667, 1585, 1427, 1407, 1338, 1257, 1040, 794, 702 cm ^-1 ;
MS (FAB) m / z: 443 (M + H) ⁺ .
[Example 36]
3- (4-Fluoro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.90-1.04 (4H, m), 1.67-1.77 (1H, m), 1.94-2.02 (1H, m), 2.15-2.34 (2H, m), 2.55- 2.86 (4H, m), 3.55-3.61 (1H, m), 3.74 (3H, s), 3.82-3.86 (1H, m), 4.12 (1H, t, J = 10.2 Hz), 6.80-7.07 (4H, m), 7.19-7.24 (2H, m), 7.86 (1H, d, J = 8.6 Hz);
IR (KCl) vmax 3362, 2838, 1612, 1324, 1110, 878, 569 cm ^-1 ;
MS (ESI) m / z: 427 (M + H) ⁺ .
[Example 37]
3- {4-Methyl-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.34 (6H, s), 1.47-1.56 (1H, m), 1.77-1.86 (1H, m), 2.23 (3H, s), 2.13-2.31 (2H, m), 2.40-2.48 (3H, m), 2.58-2.68 (1H, m), 3.28-3.34 (1H, m), 3.87-3.97 (2H, m), 6.78 (1H, d, J = 7.8 Hz) , 7.03 (1H, t, J = 8.2 Hz), 7.15 (1H, t, J = 7.8 Hz), 7.27 (2H, t, J = 7.8 Hz), 7.45 (2H, d, J = 7.8 Hz), 7.86 (1H, d, J = 8.2 Hz);
IR (KCl) vmax 3406, 1625, 1403, 1239, 963, 585 cm ^-1 ;
MS (ESI) m / z: 395 (M + H) ⁺ .
[Example 38]
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -4-methyl-2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.81-0.90 (4H, m), 1.46-1.55 (1H, m), 1.77-1.84 (1H, m), 2.23 (3H, s), 2.12-2.32 ( 2H, m), 2.41-2.46 (1H, m), 2.59-2.70 (3H, m), 3.28-3.34 (1H, m), 3.71 (3H, s), 3.85 (1H, d, J = 10.6 Hz) , 3.93 (1H, d, J = 10.6 Hz), 6.70 (1H, dd, J = 7.8, 2.0 Hz), 6.77-6.83 (2H, m), 6.94 (1H, s), 7.03 (1H, t, J = 7.8 Hz), 7.16 (1H, t, J = 7.8 Hz), 7.86 (1H, d, J = 8.2 Hz);
IR (KCl) vmax 3412, 1729, 1406, 1255, 997, 701, 465 cm ^-1 ;
MS (ESI) m / z: 423 (M + H) ⁺ .
[Example 39]
3- {4-Methoxy-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.33 (6H, s), 1.56-1.66 (1H, m), 1.92-2.02 (1H, m), 2.08-2.22 (2H, m), 2.42-2.48 ( 2H, m), 2.52-2.63 (2H, m), 3.31-3.40 (1H, m), 3.75 (3H, s), 3.82 (1H, dd, J = 11.0, 2.8 Hz), 4.01 (1H, t, J = 9.8 Hz), 6.64 (1H, d, J = 7.8 Hz), 7.09-7.16 (2H, m), 7.26 (2H, t, J = 7.8 Hz), 7.44 (2H, d, J = 7.8 Hz) , 7.65 (1H, d, J = 8.2 Hz);
IR (KCl) vmax 3526, 1665, 1369, 1161, 1038, 797, 599 cm ^-1 ;
MS (ESI) m / z: 41 (M + H) ⁺ .
[Example 40]
3- (4-Methoxy-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 0.79-0.90 (4H, m), 1.48-1.60 (1H, m), 1.93-2.09 (3H, m), 2.41-2.59 (2H, m), 2.64- 2.70 (2H, m), 3.28-3.37 (1H, m), 3.70 (3H, s), 3.74 (3H, s), 3.77-3.81 (1H, m), 3.98 (1H, t, J = 10.6 Hz) , 6.63 (1H, d, J = 7.8 Hz), 6.69 (1H, d, J = 7.8 Hz), 6.81 (1H, d, J = 7.4 Hz), 6.93 (1H, s), 7.09 (1H, t, J = 7.8 Hz), 7.16 (1H, t, J = 7.4 Hz), 7.65 (1H, d, J = 7.8 Hz);
IR (KCl) vmax 3343, 2961, 1464, 1290, 1067, 819, 570 cm ^-1 ;
MS (ESI) m / z: 439 (M + H) ⁺ .
[Example 41]
3- {4-Cyano-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, br s), 1.78-1.87 (1H, m), 2.08-2.24 (2H, m), 2.31-2.40 (1H, m), 2.81-2.88 (3H, m), 2.92-3.01 (1H, m), 3.67-3.73 (1H, m), 3.92 (1H, dd, J = 10.2, 3.7 Hz), 4.16 (1H, t, J = 10.2 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.46-7.51 (3H, m), 7.67 (2H, d, J = 7.6 Hz), 8.31 (1H, d, J = 8.2 Hz), 9.36 (2H, br s);
IR (KBr) vmax 3359, 2976, 2790, 2230, 1709, 1670, 1580, 1459, 1408, 1162, 700 cm ^-1 ;
MS (FAB) m / z: 406 (M + H) ⁺ .
[Example 42]
3- (4-Cyano-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.22 (2H, br s), 1.47 (2H, br s), 1.77-1.86 (1H, m), 2.07-2.23 (2H, m), 2.31-2.37 ( 1H, m), 2.79-2.88 (1H, m), 2.92-3.01 (1H, m), 3.10 (2H, br s), 3.66-3.73 (1H, m), 3.80 (3H, s), 3.91 (1H , dd, J = 10.4, 3.7 Hz), 4.15 (1H, t, J = 10.4 Hz), 6.99 (1H, d, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.23 (1H , s), 7.37 (1H, t, J = 8.0 Hz), 7.42 (1H, t, J = 8.0 Hz), 7.49 (1H, d, J = 8.0 Hz), 8.32 (1H, d, J = 8.0 Hz) ), 9.43 (2H, br s);
IR (KBr) vmax 3358, 2936, 2736, 2232, 1718, 1668, 1581, 1460, 1408, 1043, 791, 702 cm ^-1 ;
MS (FAB) m / z: 434 (M + H) ⁺ .
[Example 43]
3- {6-Fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid

¹ H-NMR (DMSO-D ₆ ) δ: 1.34 (6H, s), 1.61-1.70 (1H, m), 1.86-1.96 (1H, m), 2.17-2.30 (2H, m), 2.42-2.59 ( 4H, m), 3.30-3.34 (1H, m), 3.77-3.81 (1H, m), 4.17 (1H, t, J = 10.0 Hz), 6.78 (1H, t, J = 8.2 Hz), 7.14 (1H , t, J = 7.4 Hz), 7.20-7.28 (3H, m), 7.44 (2H, d, J = 8.2 Hz), 7.76 (1H, d, J = 11.3 Hz);
IR (KCl) vmax 3337, 1660, 1442, 1262, 1003, 769, 488 cm ^-1 ;
MS (ESI) m / z: 399 (M + H) ⁺ .
[Example 44]
3- {5,6-Difluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.72 (1H, m), 1.75 (6H, s), 2.01 (1H, m), 2.19-2.37 (2H, m), 2.84-2.93 (4H, m) , 3.44 (1H, m), 3.77 (1H, m), 4.17 (1H, t, J = 10.2 Hz), 7.39-7.51 (4H, m), 7.69 (2H, d, J = 7.8 Hz), 7.95 ( 1H, dd, J = 12.0, 7.4 Hz), 9.44 (1H, br s), 9.52 (1H br s), 12.13 (1H, br s);
Anal. Calcd. For C ₂₃ H ₂₆ N ₂ O ₃ F ₂ .HCl.H ₂ O Found C, 58.77. H, 6.17. N, 5.87. F, 7.75. Cl, 7.30;
IR (KBr) vmax 3415, 2956, 2769, 1728, 1660, 1497, 1437, 1162, 768, 701 cm ^-1 ;
MS (FAB) m / z: 417 (M + H) ⁺ .
[Example 45]
4- {5-Fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -1H-indol-3-yl} butanoic acid

(Step 1) 4- (5-Fluoro-1H-indol-3-yl) -4-oxobutanoic acid methyl ester

5.79 g (43.3 mmol) of aluminum chloride was suspended in 40 mL of methylene chloride and stirred at room temperature. 4-Chloro-4-oxobutanoic acid methyl ester was added little by little, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 2.00 g (14.8 mmol) of 5-fluoroindole was dissolved and added in 10 mL of methylene chloride, stirred at room temperature for 5 hours, and then stirred at 35 ° C for 2.5 hours. The reaction solution returned to room temperature was poured into 2N hydrochloric acid added with ice, extracted with methylene chloride, and insolubles were removed by filtration. The organic layer of the filtrate was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Biotage, elution solvent; hexane / The product was purified by ethyl acetate to obtain 1.58 g (43%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 2.81 (2H, t, J = 6.6 Hz), 3.19 (2H, t, J = 6.6 Hz), 3.72 (3H, s), 7.01 (1H, m), 7.30 ( 1H, m), 7.87 (1H, d, J = 2.3 Hz), 8.01 (1H, dd, J = 9.8, 2.7 Hz), 8.90 (1H, br s).
(Process 2)
4- (5-Fluoro-1H-indol-3-yl) -4-butanoic acid methyl ester

1.58 g (6.34 mmol) of 4- (5-fluoro-1H-indol-3-yl) -4-oxobutanoic acid methyl ester obtained in Example 45 (Step 1) was dissolved in 40 mL of tetrahydrofuran and hydrogenated. 481 mg (12.7 mmol) of sodium boron was added and stirred at room temperature. Thereto was added boron trifluoride diethyl ether complex (2.23 mL) little by little, and the mixture was stirred at room temperature for 6 hours. After adding 2 mL of acetone to the reaction solution, it was poured into a mixed solvent of ethyl acetate and 1N hydrochloric acid, the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to obtain 0.85 g (50%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 2.02 (2H, m), 2.38 (2H, t, J = 7.4 Hz), 2.76 (2H, t, J = 7.4 Hz), 3.66 (3H, s), 6.93 ( 1H, m), 7.04 (1H, d, J = 2.0 Hz), 7.21-7.28 (2H, m), 7.94 (1H, br s).
(Process 3)
3- (1-acryloyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) butanoic acid methyl ester

0.84 g (3.57 mmol) of 4- (5-fluoro-1H-indol-3-yl) -4-butanoic acid methyl ester obtained in Example 45 (Step 2) was dissolved in 20 mL of trifluoroacetic acid, The mixture was stirred under ice cooling. Triethylsilane 2.31mL (14.2mmol) was added there, and it stirred at 0 degreeC after addition for 4 hours. The reaction mixture was evaporated under reduced pressure, and the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give methyl 4- (5-fluoro-2,3-dihydro-1H-indol-3-yl) butanoate. Was obtained as a crude product. The total amount of the resulting crude product was dissolved in 10 mL of tetrahydrofuran, 0.99 mL of triethylamine was added, and the mixture was stirred under ice-cooling. Acrylic acid chloride 0.43mL was added there, and it stirred at room temperature after addition for 15 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solution under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to obtain 0.92 g (88%) of the target compound.
(Process 4)
4- {5-Fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -1H-indol-3-yl} butanoic acid methyl ester

510 mg (1.75 mmol) of 3- (1-acryloyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) butanoic acid methyl ester obtained in Example 45 (Step 3) was added to 10 mL of ethanol. After dissolution, 338 mg (2.50 mmol) of cumylamine was added and the mixture was heated to reflux for 4 hours. The reaction solution was brought to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Biotage, elution solvent: methanol / ethyl acetate) to obtain 331 mg (44%) of the target compound. .
¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 1.52-1.82 (4H, m), 2.36 (2H, m), 2.54 (2H, t, J = 6.3 Hz), 2.68 (2H, t , J = 6.3 Hz), 3.36 (1H, m), 3.67 (1H, m), 3.69 (3H, s), 4.13 (1H, m), 6.85-6.90 (2H, m), 7.20 (1H, t, J = 7.2 Hz), 7.32 (2H, t, J = 7.6 Hz), 7.49 (2H, t, J = 7.6 Hz), 8.17 (1H, m).
(Process 5)
4- {5-Fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} butanoic acid monohydrochloride

Methyl 4- {5-fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -1H-indol-3-yl} butanoate obtained in Example 45 (Step 4) 326 mg (0.76 mmol) of the ester was dissolved in 10 mL of ethanol, 4 mL of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was evaporated under reduced pressure, and the residue was acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. did. The obtained crude product was suspended in ethyl acetate, insoluble matter was collected by filtration and dried to obtain 305 mg (82%) of monohydrochloride of the target compound.
¹ H-NMR (DMSO-D ₆ ) δ: 1.47-1.58 (3H, m), 1.75 (6H, s), 1.76 (1H, m), 2.25 (2H, m), 2.86 (4H, br s), 3.43 (1H, m), 3.71 (1H, m), 4.20 (1H, t, J = 9.8 Hz), 7.03 (1H, m), 7.13 (1H, m), 7.42 (1H, t, J = 7.4 Hz ), 7.46-7.51 (2H, m), 7.68 (2H, d, J = 7.4 Hz), 8.01 (1H, m), 9.35 (2H, br s), 12.05 (1H, br s);
Anal. Calcd. For C ₂₄ H ₂₉ N ₂ O ₃ F.HCl Found C, 63.93. H, 6.79. N, 6.25. F, 4.35. Cl, 7.85;
IR (KBr) vmax 3024, 2757, 1735, 1661, 1483, 1413, 1254, 1173, 825, 697 cm ^-1 ;
MS (FAB) m / z: 413 (M + H) ⁺ .

Examples 46 to 49 were synthesized in the same manner as Example 45 using the appropriate substituted indole and benzylamine.
[Example 46]
4- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} butanoic acid 0.75 hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.48-1.77 (10H, m), 2.25 (2H, m), 2.77 (4H, br s), 3.40 (1H, m), 3.68 (1H, m), 4.03 (1H, m), 7.03 (1H, t, J = 7.4 Hz), 7.17 (1H, t, J = 8.2 Hz), 7.24 (1H, d, J = 7.4 Hz), 7.32-7.250 (3H, br m), 7.56-7.66 (2H, br m), 8.04 (1H, d, J = 8.2 Hz);
..... Anal Calcd For C 24 H 30 N 2 O 3 .0.75HCl Found C, 67.66 H, 7.38 N, 6.56 Cl, 6.60;
IR (KBr) vmax 2950, 2759, 1735, 1660, 1482, 1416, 1166, 756, 699 cm ^-1 ;
MS (FAB) m / z: 395 (M + H) ⁺ .
[Example 47]
4- (1- {N- [1- (3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) butanoic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.48-1.60 (4H, m), 1.73 (6H, s), 2.26 (2H, m), 2.87 (4H, br s), 3.42 (1H, m), 3.67 (1H, m), 3.81 (3H, s), 4.17 (1H, m), 6.96-7.06 (2H, m), 7.14-7.21 (2H, m), 7.23-7.29 (2H, m), 7.40 ( 1H, t, J = 7.4 Hz), 8.03 (1H, d, J = 7.8 Hz), 9.29 (2H, br m), 12.06 (1H, br s);
Anal. Calcd. For C ₂₅ H ₃₂ N ₂ O ₄ .HCl.0.5H ₂ O Found C, 63.92. H, 7.19. N, 5.94. Cl, 8.08;
IR (KBr) vmax 3158, 2936, 1730, 1634, 1593, 1486, 1441, 1244, 1163, 767, 705 cm ^-1 ;
MS (FAB) m / z: 425 (M + H) ⁺ .
[Example 48]
4- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) butanoic acid 0.8 hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.21 (2H, br s), 1.47-1.58 (5H, m), 1.76 (1H, m), 2.26 (2H, m), 2.86 (2H, br s) , 3.09 (2H, br s), 3.41 (1H, br s), 3.67 (1H, m), 3.80 (3H, s), 4.17 (1H, m), 6.99 (1H, m), 7.04 (1H, t , J = 7.3 Hz), 7 / 16-7.26 (4H, m), 7.37 (1H, m), 8.04 (1H, d, J = 8.3 Hz), 9.43 (1.8H, br m);
Anal.Calcd.For C ₂₅ H ₃₀ N ₂ O ₄ .0.8HCl.H ₂ O Found C, 63.55.H, 7.03.N, 5.96.Cl, 6.22;
IR (KBr) vmax 3404, 2948, 1723, 1643, 1597, 1487, 1432, 1345, 1237, 1033, 767 cm ^-1 ;
MS (FAB) m / z: 423 (M + H) ⁺ .
[Example 49]
4- {5-Methyl-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} butanoic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.46-1.58 (3H, m), 1.70-1.80 (7H, m), 2.2.5-2.31 (5H, m), 2.85 (4H, s), 3.38 ( 1H, m), 3.65 (1H, m), 4.15 (1H, t, J = 9.8 Hz), 6.97 (1H, d, J = 7.8 Hz), 7.05 (1H, s), 7.42 (1H, t, J = 7.3 Hz), 7.47-7.51 (2H, m), 7.58 (2H, d, J = 7.8 Hz), 7.90 (1H, d, J = 8.3 Hz), 9.34 (2H, br s), 12.06 (1H, br s);
Anal. Calcd. For C ₂₅ H ₃₂ N ₂ O ₃ .HCl.0.3H ₂ O Found C, 66.83. H, 7.49. N, 6.40. Cl, 7.66;
IR (KBr) vmax 2925, 1736, 1659, 1489, 1409, 1170, 823, 699 cm ^-1 ;
MS (FAB) m / z: 409 (M + H) ⁺ .
[Example 50]
3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} -2,2-dimethylpropionic acid

(Process 1)
3- (5-Chloro-1H-indol-3-yl) 2,2-dimethylpropionic acid methyl ester

1.37 g (7.63 mmol) of 5-chloroindole-3-carboxaldehyde was dissolved in 40 mL of tetrahydrofuran and stirred under ice cooling. Thereto was gradually added 0.29 g (7.63 mmol) of lithium aluminum hydride, and the mixture was stirred at room temperature for 1.5 hours after the addition. The reaction solution was stirred again under ice-cooling, and 0.29 mL of water, 0.72 mL of 2N aqueous sodium hydroxide solution and 0.72 mL of water were sequentially added. The precipitate was removed by filtration, and the filtrate was concentrated to give (5-chloro-1H-indol-3-yl) methanol as a crude product. The total amount of (5-chloro-1H-indol-3-yl) methanol obtained was dissolved in 20 mL of methylene chloride, and 2.66 g (15.3 mmol) of dimethyl ketenemethyltrimethylsilyl acetal and 0.17 g (0. 76 mmol) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to obtain 1.26 g (62%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, s), 2.96 (2H, s), 3.64 (3H, s), 6.99 (1H, d, J = 2.4 Hz), 7.11 (1H, dd, J = 8.3, 2.0 Hz), 7.24 (1H, d, J = 8.3 Hz), 7.53 (1H, d, J = 2.0 Hz), 8.05 (1H, s).
(Process 2)
3- (1-acryloyl-5-chloro-2,3-dihydro-1H-indol-3-yl) -2,2-dimethylpropionic acid methyl ester

Instead of 4- (5-fluoro-1H-indol-3-yl) -4-butanoic acid methyl ester obtained in Example 45 (Step 2), 3-methyl obtained in Example 50 (Step 1) was used. Using 1.26 g (4.74 mmol) of (5-chloro-1H-indol-3-yl) 2,2-dimethylpropionic acid methyl ester, the reaction and purification were carried out in the same manner as in Example 45 (Step 3). 0.84 g (55%) of the target compound was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, s), 1.31 (3H, s), 1.86 (1H, t, J = 12.1 Hz), 2.16 (1H, m), 3.38 (1H, m), 3.73 (3H, s), 3.75 (1H, m), 4.32 (1H, t, J = 10.0 Hz), 5.82 (1H, t, J = 6.1 Hz), 6.51 (2H, d, J = 6.1 Hz), 7.12-7.20 (2H, m), 8.20 (1H, d, J = 7.8 Hz).
(Process 3)
3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} -2,2-dimethylpropionic acid Methyl ester

Instead of the 3- (1-acryloyl-5-fluoro-2,3-dihydro-1H-indol-3-yl) butanoic acid methyl ester obtained in Example 45 (Step 3), Example 50 (Step 2) 3- (1-acryloyl-5-chloro-2,3-dihydro-1H-indol-3-yl) -2,2-dimethylpropionic acid methyl ester 0.32 g (1.00 mmol) The reaction and purification were conducted in the same manner as in Example 45 (Step 4) to obtain 0.37 g (87%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, s), 1.29 (3H, s), 1.49 (6H, s), 1.80 (1H, m), 2.15 (1H, m), 2.50 (2H, m ), 2.66 (2H, m), 3.31 (1H, m), 3.59 (1H, m), 3.73 (3H, s), 4.13 (1H, t, J = 10.0 Hz), 7.11-7.24 (3H, m) , 7.32 (2H, t, J = 7.6 Hz), 7.48 (2H, d, J = 7.6 Hz), 8.12 (1H, d, J = 8.6 Hz).
(Process 4)
3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} -2,2-dimethylpropionic acid 0.85 hydrochloride

3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indole-3 obtained in Example 50 (Step 3) -Il} -2,2-dimethylpropionic acid methyl ester (365 mg, 0.80 mmol) was dissolved in ethanol (6 mL) and tetrahydrofuran (4 mL), 2N aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at 50 ° C. for 8 hr. The reaction mixture was brought to room temperature, the solvent was evaporated under reduced pressure, the residue obtained was acidified with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated. The obtained residue was suspended in ethyl acetate, insoluble matter was collected by filtration and dried to obtain 324 mg (84%) of 0.85 hydrochloride of the target compound.
¹ H-NMR (DMSO-D ₆ ) δ: 1.20 (6H, s), 1.75 (6H, s), 1.78 (1H, m), 2.13 (1H, d, J = 12.5 Hz), 2.77-2.93 (4H , m), 3.38 (1H, m), 3.73 (1H, m), 4.26 (1H, t, J = 10.2 Hz), 7.23 (1H, m), 7.28 (1H, s), 7.40 (1H, m) , 7.42-7.51 (2H, m), 7.65-7.70 (2H, m), 7.99 (1H, d, J = 8.6 Hz), 9.40 (1.9H, br s);
Anal.Calcd.For C ₂₅ H ₃₁ ClN ₂ O ₃ F.0.85HCl.0.7H ₂ O Found C, 61.80.H, 6.59.N, 5.65.Cl, 13.8;
IR (KBr) vmax 3426, 2974, 2766, 1728, 1662, 1481, 1405, 1165, 826, 767, 700 cm ^-1 ;
MS (FAB) m / z: 443 (M + H) ⁺ .

Examples 51 to 55 were synthesized in the same manner as in Example 50 using the appropriate substituted indole-3-carbaldehyde and benzylamine.
[Example 51]
2,2-Dimethyl-3- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} -propionic acid 0.15 Hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.20 (6H, s), 1.38 (6H, s), 1.75 (1H, m), 2.10 (1H, d, J = 13.7 Hz), 2.49-2.57 (4H , m), 3.32 (1H, m), 3.71 (1H, dd, J = 10.1, 7.0 Hz), 4.26 (1H, t, J = 10.1 Hz), 7.01 (1H, t, J = 7.8 Hz), 7.12 -7.22 (3H, m), 7.26-7.32 (m, 2H), 7.45-7.50 (m, 2H), 8.02 (1H, d, J = 7.8 Hz);
Anal. Calcd. For C ₂₅ H ₃₂ N ₂ O ₃ .0.15HCl. Found C, 72.71. H, 7.91. N, 6.88. Cl, 1.12;
IR (KBr) vmax 2967, 1663, 1570, 1482, 1414, 1363, 1280, 754, 701 cm ^-1 ;
MS (FAB) m / z: 409 (M + H) ⁺ .
[Example 52]
3- (1- {N- [1- (3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) -2,2-dimethylpropion Acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.21 (6H, s), 1.71 (6H, s), 1.76 (1H, m), 2.15 (1H, d, J = 12.5 Hz), 2.83 (4H, br m), 3.35 (1H, m), 3.69 (1H, dd, J = 10.2, 7.3 Hz), 3.81 (3H, s), 4.25 (1H, t, J = 10.2 Hz), 6.98 (1H, m), 7.05 (1H, m), 7.14-7.20 (2H, m), 7.22-7.26 (2H, m), 7.39 (1H, t, J = 7.8 Hz), 8.01 (1H, d, J = 7.8 Hz), 9.31 (2H, br m);
Anal.Calcd.For C ₂₆ H ₃₄ N ₂ O ₄ .HCl.0.8H ₂ O Found C, 63.60.H, 7.44.N, 5.85.Cl, 7.12;
IR (KBr) vmax 3513, 2963, 1727, 1659, 1599, 1484, 1420, 1252, 1033, 958, 703 cm ^-1 ;
MS (FAB) m / z: 439 (M + H) ⁺ .
[Example 53]
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) -2,2-dimethylpropionic acid 1 hydrochloric acid salt

¹ H-NMR (DMSO-D ₆ ) δ: 1.20 (6H, s), 1.22 (2H, m), 1.51 (2H, m), 1.75 (1H, m), 2.13 (1H, d, J = 12.5 Hz ), 2.84 (2H, m), 3.08 (2H, br s), 3.35 (1H, m), 3.67 (1H, m), 3.80 (3H, s), 4.23 (1H, t, J = 10.2 Hz), 6.98 (1H, m), 7.05 (1H, m), 7.15-7.28 (4H, m), 7.37 (1H, t, J = 7.8 Hz), 8.01 (1H, d, J = 7.8 Hz), 9.61 (2H , m), 12.37 (1H, br s);
Anal.Calcd.For C ₂₆ H ₃₂ N ₂ O ₄ .HCl.0.5H ₂ O Found C, 64.64.H, 7.38.N, 5.88.Cl, 7.28;
IR (KBr) vmax 3423, 2971, 2744, 1729, 1656, 1597, 1484, 1419, 1035, 763, 701 cm ^-1 ;
MS (FAB) m / z: 437 (M + H) ⁺ .
[Example 54]
3- {5-Fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} -2,2-dimethylpropionic acid 0.9 Hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.20 (6H, s), 1.75 (6H, s), 1.78 (1H, m), 2.13 (1H, d, J = 12.1 Hz), 2.77-2.90 (4H , m), 3.38 (1H, m), 3.72 (1H, m), 4.27 (1H, t, J = 9.8 Hz), 7.00 (1H, m), 7.09 (1H, m), 7.41 (1H, m) , 7.42-7.51 (2H, m), 7.65-7.69 (2H, m), 7.99 (1H, m), 9.38 (1.9H, br s);
Anal.Calcd.For C ₂₅ H ₃₁ N ₂ O ₃ F.0.9HCl.0.5H ₂ O Found C, 64.37.H, 7.20.N, 5.83.F, 3.99.Cl, 7.09;
IR (KBr) vmax 3415, 2974, 2768, 1724, 1658, 1487, 1416, 1254, 1162, 768, 701 cm ^-1 ;
MS (FAB) m / z: 427 (M + H) ⁺ .
[Example 55]
2,2-Dimethyl-3- {5-methyl-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid 0.9 Hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.20 (6H, s), 1.70 (1H, m), 1.74 (6H, s), 2.13 (1H, d, J = 13.7 Hz), 2.26 (3H, s ), 2.76-2.90 (4H, m), 3.31 (1H, m), 3.66 (1H, m), 4.23 (1H, t, J = 10.2 Hz), 6.97 (1H, d, J = 7.8 Hz), 7.04 (1H, s), 7.40 (1H, m), 7.42-7.51 (2H, m), 7.65-7.70 (2H, m), 7.88 (1H, d, J = 8.2 Hz), 9.37 (1.9H, br s ), 12.43 (1H, br s);
Anal. Calcd. For C ₂₆ H ₃₄ N ₂ O ₃ .0.9HCl.H ₂ O Found C, 65.85. H, 7.54. N, 5.86. Cl, 7.11;
IR (KBr) vmax 3424, 2970, 2766, 1724, 1656, 1491, 1445, 1159, 822, 768, 701 cm ^-1 ;
MS (FAB) m / z: 423 (M + H) ⁺ .
[Example 56]
1- {N- [1- (3-methoxyphenyl) -1-methylethyl] β-alanyl} indoline-4-carboxylic acid monohydrochloride

(Process 1)
Indoline-4-carboxylic acid methyl ester

3.00 g (17 mmol) of methyl indole-4-carboxylate was dissolved in acetic acid (15 mL), 3.23 g (51 mmol) of sodium cyanotrihydroborate was slowly added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane = 1/2), and the obtained solid was washed with a mixed solvent of hexane / isopropyl ether to obtain 1.88 g (62%) of the target compound. It was.
¹ H-NMR (CDCl ₃ ) δ: 3.40 (2H, t, J = 8.4 Hz), 3.60 (2H, t, J = 8.4 Hz), 3.88 (3H, s), 6.78 (1H, dd, J = 7.7 , 0.8 Hz), 7.07 (1H, t, J = 7.7 Hz), 7.34 (1H, dd, J = 7.7, 0.8 Hz).
(Process 2)
1-acryloylindoline-4-carboxylic acid methyl ester

400 mg (2.3 mmol) of indoline-4-carboxylic acid methyl ester obtained in Example 56 (Step 1) was dissolved in 5 mL of tetrahydrofuran, and 0.63 mL (4.5 mmol) of triethylamine and acrylic acid chloride 0 were dissolved under ice cooling. 20 mL (2.5 mmol) was sequentially added and stirred at room temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the aqueous phase was extracted with ethyl acetate, the obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was washed with a mixed solvent of ethyl acetate / isopropyl ether to obtain 310 mg (59%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 3.58 (2H, t, J = 8.5 Hz), 3.91 (3H, s), 4.22 (2H, t, J = 8.5 Hz), 5.83 (1H, dd, J = 9.6 , 2.5 Hz), 6.50-6.65 (2H, m), 7.30 (1H, t, J = 7.9 Hz), 7.70 (1H, dd, J = 7.9, 1.2 Hz), 8.54 (1H, d, J = 5.9 Hz ).
(Process 3)
1- {N- [1- (3-methoxyphenyl) -1-methylethyl] β-alanyl} indoline-4-carboxylic acid methyl ester

200 mg (0.87 mmol) of 1-acryloylindoline-4-carboxylic acid methyl ester obtained in Example 56 (Step 2) and 190 mg (1.2 mmol) of 2- (3-methoxyphenyl) propan-2-amine were mixed with ethanol. Dissolved in 4 mL and heated to reflux for 5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (methanol / methylene chloride = 1/15) to obtain 181 mg (53%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 2.58 (2H, t, J = 5.9 Hz), 2.71 (2H, t, J = 5.9 Hz), 3.53 (2H, t, J = 8.5 Hz), 3.82 (3H, s), 3.90 (3H, s), 4.03 (2H, t, J = 8.5 Hz), 6.74-6.78 (1H, m), 7.06-7.10 (2H, m), 7.23-7.30 (2H, m), 7.67 (1H, d, J = 7.8 Hz), 8.46 (1H, d, J = 8.2 Hz).
(Process 4)
1- {N- [1- (3-methoxyphenyl) -1-methylethyl] β-alanyl} indoline-4-carboxylic acid monohydrochloride

1- {N- [1- (3-Methoxyphenyl) -1-methylethyl] β-alanyl} indoline-4-carboxylic acid methyl ester 181 mg (0.46 mmol) obtained in Example 56 (Step 3) was used. It melt | dissolved in ethanol 2mL, 1N sodium hydroxide aqueous solution 0.9mL was added, and it stirred at room temperature all night. The solvent was distilled off under reduced pressure, and 1N hydrochloric acid aqueous solution was added to make it acidic. Isopropyl ether was added and sonicated, and the resulting powder was collected by filtration and washed with isopropyl ether and hexane to obtain 165 mg (87%) of the target compound monohydrochloride.
¹ H-NMR (DMSO-D ₆ ) δ: 1.72 (6H, s), 2.86 (4H, s), 3.46 (2H, t, J = 8.5 Hz), 3.81 (3H, s), 4.06 (2H, t , J = 8.5 Hz), 6.99 (1H, d, J = 8.0 Hz), 7.19 (1H, d, J = 8.0 Hz), 7.26 (1H, s), 7.30 (1H, t, J = 8.0 Hz), 7.40 (1H, t, J = 8.0 Hz), 7.58 (1H, d, J = 8.0 Hz), 8.29 (1H, d, J = 8.0 Hz), 9.21-9.34 (2H, m), 13.05 (1H, br s);
IR (KBr) vmax 3411, 2968, 2767, 1706, 1658, 1585, 1463, 1249, 702 cm ^-1 ;
MS (FAB) m / z: 383 (M + H) ⁺ .

Examples 57 and 58 were synthesized in the same manner as Example 56 using the appropriate benzylamine.
[Example 57]
1- {N- [1- (4-Fluoro-3-methoxyphenyl) -1-methylethyl] β-alanyl} indoline-4-carboxylic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.73 (6H, s), 2.86 (4H, br s), 3.46 (2H, t, J = 8.5 Hz), 3.93 (3H, s), 4.07 (2H, t, J = 8.5 Hz), 7.12-7.16 (1H, m), 7.28-7.33 (2H, m), 7.53-7.59 (2H, m), 8.30 (1H, d, J = 8.2 Hz), 9.25 (2H , br s), 13.03 (1H, br s);
IR (KBr) vmax 3397, 2967, 2766, 1710, 1658, 1525, 1464, 1415, 1264, 1224, 1131, 1028, 783, 759 cm ^-1 ;
MS (FAB) m / z: 401 (M + H) +.
[Example 58]
1- {N- [1- (3-methoxyphenyl) cyclopropyl] β-alanyl} indoline-4-carboxylic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 0.88-0.97 (4H, m), 2.57 (2H, t, J = 6.1 Hz), 2.76 (2H, t, J = 6.1 Hz), 3.42 (2H, t , J = 8.5 Hz), 3.74 (3H, s), 4.06 (2H, t, J = 8.5 Hz), 6.75 (1H, d, J = 7.8 Hz), 6.88 (1H, d, J = 7.8 Hz), 6.98 (1H, s), 7.21 (1H, t, J = 7.8 Hz), 7.27 (1H, t, J = 7.8 Hz), 7.54 (1H, d, J = 7.8 Hz), 8.31 (1H, d, J = 7.8 Hz).
[Example 59]
3- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid monohydrochloride

(Process 1)
3- (1H-Indol-4-yl) acrylic acid ethyl ester

Dissolve 4.90 g (34 mmol) of 1H-indole-4-carbaldehyde and 8.1 mL (41 mmol) of ethyl diethylphosphonoacetate in 50 mL of tetrahydrofuran, add 11.7 g (84 mmol) of potassium carbonate under heating to reflux, and heat for 4 hours. Refluxed. The reaction solution was cooled to room temperature, water was added, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane = 1/2) to obtain 7.21 g (99%) of the objective compound.
¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.1 Hz), 4.30 (2H, q, J = 7.1 Hz), 6.62 (1H, d, J = 16.0 Hz), 6.86 (1H, s), 7.22 (1H, t, J = 7.7 Hz), 7.33 (1H, t, J = 2.7 Hz), 7.38 (1H, d, J = 7.7 Hz), 7.45 (1H, d, J = 7.7 Hz) , 8.10 (1H, d, J = 16.0 Hz), 8.35 (1H, br s).
(Process 2)
3- (1H-Indol-4-yl) propionic acid ethyl ester

Under nitrogen flow, 3- (1H-indol-4-yl) acrylic acid ethyl ester (7.16 g, 33 mmol) obtained in Example 59 (Step 1) was dissolved in ethanol (70 mL), and 10% palladium / After carbon (1.41 g) was added, it was replaced with hydrogen and stirred at room temperature for 30 minutes. After substituting with nitrogen, the catalyst was filtered off, and the solvent of the filtrate was distilled off under reduced pressure to obtain 6.93 g (96%) of the desired compound.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.1 Hz), 2.75 (2H, t, J = 8.0 Hz), 3.25 (2H, t, J = 8.0 Hz), 4.15 (2H, q, J = 7.1 Hz), 6.60-6.62 (1H, m), 6.95 (1H, d, J = 7.6 Hz), 7.13 (1H, t, J = 7.6 Hz), 7.22 (1H, t, J = 2.7 Hz), 7.28 (3H, d, J = 7.6 Hz), 8.19 (1H, br s).
(Process 3)
3- (2,3-Dihydro-1H-indol-4-yl) propionic acid ethyl ester

2.20 g (10 mmol) of 3- (1H-indol-4-yl) propionic acid ethyl ester obtained in Example 59 (Step 2) was dissolved in acetic acid (10 mL) to obtain 1.92 g of sodium cyanotrihydroborate. (31 mmol) was slowly added and stirred at room temperature for 1 hour. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / hexane = 1/2 to 1/1) to obtain 1.70 g (77%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.2 Hz), 2.58 (2H, t, J = 8.1 Hz), 2.86 (2H, t, J = 8.1 Hz), 3.01 (2H, t, J = 8.4 Hz), 3.57 (2H, t, J = 8.4 Hz), 4.14 (2H, q, J = 7.2 Hz), 6.52 (1H, d, J = 7.6 Hz), 6.54 (1H, d, J = 7.6 Hz), 6.97 (1H, t, J = 7.6 Hz).
(Process 4)
3- (1-acryloyl-2,3-dihydro-1H-indol-4-yl) propionic acid ethyl ester

1.70 g (7.8 mmol) of 3- (2,3-dihydro-1H-indol-4-yl) propionic acid ethyl ester obtained in Example 59 (Step 3) was dissolved in 15 mL of tetrahydrofuran, and the mixture was cooled with ice. Then, triethylamine (2.2 mL, 15 mmol) and acrylic acid chloride (0.69 mL, 8.5 mmol) were sequentially added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the aqueous phase was extracted with ethyl acetate, the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate / hexane = 1/1) to obtain 1.85 g (87%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.2 Hz), 2.61 (2H, t, J = 7.9 Hz), 2.88 (2H, t, J = 7.9 Hz), 3.16-3.23 ( 2H, m), 4.13 (2H, q, J = 7.2 Hz), 4.20 (2H, t, J = 8.4 Hz), 5.80 (1H, dd, J = 9.8, 2.7 Hz), 6.47-6.63 (2H, m ), 6.88 (1H, d, J = 7.8 Hz), 7.18 (1H, t, J = 7.8 Hz), 8.18 (1H, d, J = 7.8 Hz).
(Process 5)
3- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid ethyl ester

130 mg (0.48 mmol) of 3- (1-acryloyl-2,3-dihydro-1H-indol-4-yl) propionic acid ethyl ester obtained in Example 59 (Step 4) and 77 mg (0.57 mmol) of cumylamine Was dissolved in 5 mL of ethanol and heated to reflux for 8 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (methanol / methylene chloride = 1/15) to obtain 128 mg (66%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.2 Hz), 2.61 (2H, t, J = 7.8 Hz), 2.88 (2H, t, J = 7.8 Hz), 3.17-3.22 ( 2H, m), 4.13 (2H, q, J = 7.2 Hz), 4.20 (2H, t, J = 8.4 Hz), 5.80 (1H, dd, J = 9.8, 2.3 Hz), 6.48-6.63 (2H, m ), 6.89 (1H, d, J = 7.6 Hz), 7.18 (1H, t, J = 7.6 Hz), 8.19 (1H, d, J = 7.6 Hz).
(Step 6)
3- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid monohydrochloride

3- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propion obtained in Example 59 (Step 5) 128 mg (0.31 mmol) of acid ethyl ester was dissolved in 1.3 mL of ethanol, 0.6 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and 1N hydrochloric acid aqueous solution was added to make it acidic. Ethyl acetate was added and sonicated, and the resulting powder was collected by filtration and washed with isopropyl ether and hexane to obtain 93 mg (71%) of the desired compound monohydrochloride.
¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, br s), 2.49-2.53 (2H, m), 2.75 (2H, t, J = 7.4 Hz), 2.84 (4H, br s), 3.14 (2H, t, J = 8.4 Hz), 4.04 (2H, t, J = 8.4 Hz), 6.88 (1H, d, J = 8.0 Hz), 7.10 (1H, t, J = 8.0 Hz), 7.39-7.46 (1H, m), 7.49 (2H, t, J = 7.5 Hz), 7.66 (2H, d, J = 7.5 Hz), 7.90 (1H, d, J = 8.0 Hz), 9.22 (2H, br s);
MS (FAB) m / z: 381 (M + H) +.

Examples 60 to 69 were synthesized in the same manner as Example 59 using the appropriate substituted indole-4-carbaldehyde and benzylamine.
[Example 60]
3- (1- {N- [1- (3-Fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, br s), 2.49-2.54 (2H, m), 2.75 (2H, t, J = 7.6 Hz), 2.82-2.92 (4H, m), 3.14 (2H, t, J = 8.3 Hz), 4.05 (2H, t, J = 8.3 Hz), 6.88 (1H, d, J = 7.8 Hz), 7.11 (1H, t, J = 7.8 Hz), 7.29 ( 1H, t, J = 7.8 Hz), 7.49-7.59 (3H, m), 7.91 (1H, d, J = 7.8 Hz), 9.28 (2H, br s);
Anal. Calcd. For C ₂₃ H ₂₇ FN ₂ O ₃ .HCl Found C, 63.26. H, 6.46. N, 6.45. F, 4.61. Cl, 8.03;
MS (FAB) m / z: 399 (M + H) ⁺ .
[Example 61]
3- (1- {N- [1- (4-Fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propionic acid 1 Hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.73 (6H, br s), 2.50-2.54 (2H, m), 2.75 (2H, t, J = 7.8 Hz), 2.77-2.90 (4H, m), 3.14 (2H, t, J = 8.4 Hz), 3.92 (3H, s), 4.05 (2H, t, J = 8.4 Hz), 6.88 (1H, d, J = 7.9 Hz), 7.08-7.17 (3H, m ), 7.11 (2H, t, J = 7.9 Hz), 7.27-7.35 (1H, m), 7.51 (1H, d, J = 7.0 Hz), 7.92 (1H, d, J = 7.9 Hz), 9.12 (2H , br s).
IR (KBr) vmax 3352, 2960, 1734, 1705, 1659, 1629, 1586, 1525, 1465, 1028, 791 cm ^-1 ;
Anal. Calcd. For C ₂₃ H ₂₈ N ₂ O ₃ .HCl Found C, 66.47. H, 7.01. N, 6.87. Cl, 8.78;
MS (FAB) m / z: 429 (M + H) ⁺ .
[Example 62]
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.22 (2H, br s), 1.47 (2H, br s), 2.50-2.54 (2H, m), 2.75 (2H, t, J = 7.6 Hz), 2.85 (2H, t, J = 6.5 Hz), 3.07-3.16 (4H, m), 3.80 (3H, s), 4.03 (2H, t, J = 8.4 Hz), 6.88 (1H, d, J = 7.4 Hz) , 6.99 (1H, d, J = 7.8 Hz), 7.10 (1H, t, J = 7.4 Hz), 7.17 (1H, d, J = 7.4 Hz), 7.24 (1H, s), 7.37 (1H, t, J = 7.8 Hz), 7.90 (1H, d, J = 7.8 Hz), 9.39 (2H, br s);
IR (KBr) vmax 3358, 2921, 2747, 1706, 1655, 1585, 1465, 1417, 1342, 1257, 1039, 796, 700 cm ^-1 ;
MS (FAB) m / z: 429 (M + H) ⁺ .
[Example 63]
3- {5-Fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, s), 2.46 (2H, t, J = 7.8 Hz), 2.78 (2H, t, J = 7.8 Hz), 2.85 (4H, br s) , 3.20 (2H, t, J = 8.2 Hz), 4.06 (2H, t, J = 8.2 Hz), 6.96 (1H, t, J = 9.4 Hz), 7.40-7.51 (3H, m), 7.65-7.68 ( 2H, m), 7.89 (1H, m), 7.98 (1.9H, br m), 12.25 (1H, br s);
Anal. Calcd. For C ₂₃ H ₂₇ N ₂ O ₃ F.HCl.0.9H ₂ O Found C, 61.40. H, 6.49. N, 6.06. F, 4.28.Cl, 7.65;
IR (KBr) vmax 3423, 2979, 1732, 1655, 1472, 1415, 1231, 1161, 820, 769, 702 cm ^-1 ;
MS (FAB) m / z: 399 (M + H) ⁺ .
[Example 64]
3- (5-Fluoro-1- {N- [1- (3-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propionic acid 1 Hydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, s), 2.45 (2H, t, J = 7.8 Hz), 2.77 (2H, t, J = 7.8 Hz), 2.86 (4H, s), 3.20 (2H, t, J = 8.3 Hz), 4.07 (2H, t, J = 8.3 Hz), 6.97 (1H, t, J = 9.3 Hz), 7.27 (1H, m), 7.50-7.58 (2H, m ), 7.89 (1H, m), 9.40 (2H, br m), 12.18 (1H, br s);
Anal. Calcd. For C ₂₃ H ₂₆ N ₂ O ₃ F ₂ .HCl.1.2H ₂ O Found C, 58.31.H, 6.13.N, 5.90.F, 7.87.Cl, 7.47;
IR (KBr) vmax 3401, 2260, 1713, 1632, 1478, 1207, 799, 700 cm ^-1 ;
MS (FAB) m / z: 417 (M + H) ⁺ .
[Example 65]
3- (5-Fluoro-1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl ) Propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, s), 2.46 (2H, t, J = 7.8 Hz), 2.78 (2H, t, J = 7.8 Hz), 2.86 (4H, s), 3.20 (2H, t, J = 8.3 Hz), 3.92 (3H, s), 4.07 (2H, t, J = 8.3 Hz), 6.97 (1H, t, J = 9.3 Hz), 7.14 (1H, m), 7.29 (1H, m), 7.59 (1H, d, J = 8.3 Hz), 7.89 (1H, m), 9.39 (2H, br m), 12.23 (1H, br s);
Anal. Calcd. For C ₂₄ H ₂₈ N ₂ O ₄ F ₂ .HCl.0.7H ₂ O Found C, 58.11. H, 6.13. N, 5.68. F, 7.39. Cl, 7.10;
IR (KBr) vmax 2975, 2754, 1616, 1525, 1472, 1164, 1028, 819 cm ^-1 ;
MS (FAB) m / z: 447 (M + H) ⁺ .
[Example 66]
3- {5,6-Difluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.75 (6H, s), 2.48 (2H, m), 2.80-2.90 (6H, m), 3.18 (2H, t, J = 8.6 Hz), 4.08 (2H , t, J = 8.6 Hz), 7.42 (1H, m), 7.46-7.51 (2H, m), 7.69 (2H, d, J = 8.2 Hz), 7.84 (1H, m), 9.47 (1H, br s ), 9.56 (1H, br s), 12.28 (1H, br s);
Anal. Calcd. For C ₂₃ H ₂₆ N ₂ O ₃ F ₂ .HCl.0.5H ₂ O Found C, 59.54. H, 5.82. N, 6.08. F, 8.14. Cl, 7.49;
IR (KBr) vmax 3417, 2928, 1730, 1649, 1486, 1442, 1179, 852, 770, 701 cm ^-1 ;
MS (FAB) m / z: 417 (M + H) ⁺ .
[Example 67]
3- (5,6-Difluoro-1- {N- [1- (3-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propion Acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, s), 2.49 (2H, m), 2.80-2.90 (6H, m), 3.18 (2H, t, J = 8.3 Hz), 4.09 (2H , t, J = 8.3 Hz), 7.27 (1H, m), 7.52-7.59 (3H, m), 7.85 (1H, m), 9.52 (2H, br m), 12.32 (1H, br s);
Anal. Calcd. For C ₂₃ H ₂₅ N ₂ O ₃ F ₃ .HCl.0.8H ₂ O Found C, 57.04. H, 5.44. N, 5.82. F, 11.35. Cl, 7.26;
IR (KBr) vmax 2926, 1715, 1646, 1486, 1436, 1165, 850, 696, 613 cm ^-1 ;
MS (FAB) m / z: 435 (M + H) ⁺ .
[Example 68]
3- (5,6-Difluoro-1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indole-4 -Yl) propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, s), 2.49 (2H, m), 2.80-2.90 (6H, m), 3.17 (2H, d, J = 8.3 Hz), 3.92 (3H , s), 4.09 (2H, t, J = 7.8 Hz), 7.13 (1H, m), 7.29 (1H, m), 7.62 (1H, d, J = 8.3 Hz), 7.84 (1H, m), 9.48 (2H, br m), 12.25 (1H, br s);
Anal. Calcd. For C ₂₄ H ₂₇ N ₂ O ₄ F ₃ .HCl Found C, 58.17. H, 5.84. N, 5.78. F, 10.86. Cl, 6.88;
IR (KBr) vmax 2944, 1708, 1654, 1483, 1437, 1182, 1027, 851, 817 cm ^-1 ;
MS (FAB) m / z: 465 (M + H) ⁺ .
[Example 69]
3- {5-Methyl-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.75 (6H, s), 2.24 (3H, s), 2.37 (2H, t, J = 8.0 Hz), 2.76 (2H, t, J = 8.0 Hz), 2.84 (4H, s), 3.09 (2H, t, J = 8.4 Hz), 4.02 (2H, t, J = 8.4 Hz), 6.96 (1H, d, J = 8.2 Hz), 7.42 (1H, t, J = 7.2 Hz), 7.46-7.53 (2H, m), 7.67 (2H, d, J = 7.4 Hz), 7.79 (1H, d, J = 8.2 Hz), 9.27 (1H, br s), 9.34 (1H, br s);
Anal. Calcd. For C ₂₄ H ₃₀ N ₂ O ₃ .HCl.0.7H ₂ O Found C, 64.07. H, 7.26. N, 6.32. Cl, 9.21;
IR (KBr) vmax 3398, 2955, 2768, 1723, 1653, 1626, 1480, 1159, 769, 701 cm ^-1 ;
MS (FAB) m / z: 395 (M + H) ⁺ .
[Example 70]
4- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid monohydrochloride

(Process 1)
4-bromoindoline

4-Bromo-1H-indole (3.00 g, 15 mmol) was dissolved in acetic acid (20 mL), sodium cyanotrihydroborate (2.88 g, 46 mmol) was slowly added, and the mixture was stirred for 2 hours. The reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / hexane = 1/5) to obtain 2.51 g (83%) of the desired compound.
¹ H-NMR (CDCl ₃ ) δ: 3.05 (2H, t, J = 8.6 Hz), 3.60 (2H, t, J = 8.6 Hz), 6.52 (1H, d, J = 7.6 Hz), 6.81 (1H, dd, J = 7.6, 1.2 Hz), 6.86 (1H, t, J = 7.6 Hz).
(Process 2)
4- (2,3-Dihydro-1H-indol-4-yl) benzoic acid methyl ester

300 mg (1.5 mmol) of 4-bromoindoline obtained in Example 70 (Step 1) was dissolved in 5 mL of 1,2-dimethoxyethane, and 320 mg (1.5 mmol) of [4- (methoxycarbonyl) phenyl] boric acid was dissolved. 3N aqueous sodium carbonate solution (2.0 mL, 6.0 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (120 mg, 0.15 mmol) were sequentially added and heated under reflux for 2 hours. did. The reaction solution was cooled to room temperature, water and ethyl acetate were added, insoluble matters were filtered off, and the aqueous phase was extracted with ethyl acetate. The obtained organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / methylene chloride = 1/15), and the obtained solid was washed with hexane to obtain 190 mg (50%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 3.10 (2H, t, J = 8.2 Hz), 3.56 (2H, t, J = 8.2 Hz), 3.89 (1H, br s), 3.94 (3H, s), 6.69 (1H, d, J = 7.8 Hz), 6.79 (1H, dd, J = 7.8, 0.8 Hz), 7.13 (1H, t, J = 7.8 Hz), 7.53 (2H, d, J = 8.6 Hz), 8.09 (2H, d, J = 8.6 Hz).
(Process 3)
4- (1-acryloyl-2,3-dihydro-1H-indol-4-yl) benzoic acid methyl ester

190 mg (0.75 mmol) of 4- (2,3-dihydro-1H-indol-4-yl) benzoic acid methyl ester obtained in Example 70 (Step 2) was dissolved in 2 mL of tetrahydrofuran, and triethylamine was cooled with ice. 0.21 mL (1.5 mmol) and acrylic acid chloride 0.07 mL (0.86 mmol) were sequentially added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the aqueous phase was extracted with ethyl acetate, the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate / methylene chloride = 1/20), and the obtained solid was washed with isopropyl ether to obtain 138 mg (60%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 3.20-3.27 (2H, m), 3.95 (3H, s), 4.19 (2H, t, J = 8.4 Hz), 5.83 (1H, dd, J = 9.2, 2.9 Hz ), 6.51-6.61 (2H, m), 7.10 (1H, d, J = 7.9 Hz), 7.33 (1H, t, J = 7.9 Hz), 7.48 (2H, d, J = 8.6 Hz), 8.11 (2H , d, J = 8.6 Hz), 8.35-8.40 (1H, m).
(Process 4)
4- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid methyl ester

120 mg (0.39 mmol) 4- (1-acryloyl-2,3-dihydro-1H-indol-4-yl) benzoic acid methyl ester obtained in Example 70 (Step 3) and 65 mg (0.48 mmol) cumylamine Was dissolved in 5 mL of ethanol and heated to reflux for 8 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (methanol / ethyl acetate = 1/10) to obtain 140 mg (81%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.51 (6H, s), 2.58 (2H, t, J = 6.1 Hz), 2.71 (2H, t, J = 6.1 Hz), 3.19 (2H, t, J = 8.2 Hz), 3.95 (3H, s), 4.00 (2H, t, J = 8.2 Hz), 7.07 (1H, d, J = 7.5 Hz), 7.21 (1H, t, J = 7.5 Hz), 7.29-7.35 ( 3H, m), 7.48 (2H, d, J = 8.2 Hz), 7.50 (2H, d, J = 7.8 Hz), 8.10 (2H, d, J = 8.2 Hz), 8.30 (1H, d, J = 7.5 Hz).
(Process 5)
4- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid monohydrochloride

4- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid obtained in Example 70 (Step 4) 140 mg (0.32 mmol) of acid methyl ester was dissolved in 1.4 mL of ethanol and 1.4 mL of tetrahydrofuran, 0.95 mL of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure, 1N aqueous hydrochloric acid was added to make the solution acidic, and the powder produced by sonication was collected by filtration, washed with isopropyl ether and hexane, and 141 mg (96 mg of the target compound monohydrochloride). %)Obtained.
¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, br s), 2.85 (4H, br s), 3.24 (2H, t, J = 8.3 Hz), 4.04 (2H, t, J = 8.3 Hz ), 7.12 (1H, d, J = 7.8 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.42 (1H, t, J = 7.4 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.61 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 7.4 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.14 (1H, d, J = 7.8 Hz), 9.17 ( 1H, br s);
IR (KBr) vmax 3384, 2981, 2768, 1715, 1646, 1459, 1417, 1254, 770, 701 cm ^-1 ;
MS (FAB) m / z: 395 (M + H) ⁺ .

Examples 71 to 77 were synthesized in the same manner as Example 70 using the appropriate phenylboronic acid and benzylamine.
[Example 71]
4- (1- {N- [1- (3-Fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) benzoic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.75 (6H, br s), 2.90 (4H, br s), 3.24 (3H, t, J = 8.2 Hz), 4.05 (2H, t, J = 8.2 Hz ), 7.12 (1H, d, J = 7.6 Hz), 7.26-7.34 (2H, m), 7.51-7.59 (3H, m), 7.62 (2H, d, J = 8.6 Hz), 8.02 (2H, d, J = 8.6 Hz), 8.14 (1H, d, J = 7.6 Hz), 9.36 (2H, br s), 13.01 (1H, br s);
IR (KBr) vmax 3420, 2960, 1738, 1659, 1610, 1589, 1457, 1229, 1177, 770, 701 cm ^-1 ;
MS (FAB) m / z: 447 (M + H) ⁺ .
[Example 72]
4- (1- {N- [1- (4-Fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) benzoic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.74 (6H, s) 2.79-2.94 (4H, m) 3.24 (2H, t, J = 8.3 Hz) 4.04 (2H, t, J = 8.3 Hz) 7.13 (1H , d, J = 7.8 Hz) 7.30-7.37 (3H, m) 7.62 (2H, d, J = 8.3 Hz) 7.67-7.75 (2H, m) 8.02 (2H, d, J = 8.3 Hz) 8.15 (1H, d, J = 7.8 Hz) 9.09 (1H, br s);
HRMS (ESI ⁺ ) calcd for C ₂₇ H ₂₈ FN ₂ O ₃ [M + H] ⁺ , required m / z ： 447.2084, found 447.2070.
[Example 73]
4- (1- {N- [1- (3,4-Difluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) benzoic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.74 (6H, br s) 2.89 (4H, br s) 3.24 (2H, t, J = 8.3 Hz) 4.05 (2H, t, J = 8.3 Hz) 7.12 (1H , d, J = 7.3 Hz) 7.32 (1H, t, J = 7.8 Hz) 7.47-7.65 (4H, m) 7.82 (1H, br m) 8.02 (2H, d, J = 8.8 Hz) 8.14 (1H, d , J = 8.3 Hz) 9.37 (1H, br s);
HRMS (ESI ⁺ ) calcd for C ₂₇ H ₂₇ F ₂ N ₂ O ₃ [M + H] ⁺ , required m / z: 465.1990, found 465.1997.
[Example 74]
4- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) benzoic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.22 (2H, br s), 1.49 (2H, br s), 2.90 (2H, br s), 3.10 (2H, br s), 3.23 (2H, t, J = 8.2 Hz), 3.81 (3H, s), 4.04 (2H, t, J = 8.2 Hz), 7.00 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 7.8 Hz), 7.18 (1H, d, J = 7.8 Hz), 7.26 (1H, s), 7.32 (1H, t, J = 7.8 Hz), 7.38 (1H, t, J = 7.8 Hz), 7.62 (2H, d, J = 8.2 Hz), 8.02 (2H, d, J = 8.2 Hz), 8.14 (1H, d, J = 7.8 Hz), 9.49-9.63 (2H, m);
IR (KBr) vmax 3415, 2959, 1713, 1656, 1608, 1583, 1458, 1416, 1254, 1233, 1036, 770, 702 cm ^-1 ;
MS (FAB) m / z: 457 (M + H) ⁺ .
[Example 75]
3- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.75 (6H, br s), 2.87 (4H, br s), 3.22 (2H, t, J = 8.3 Hz), 4.05 (2H, t, J = 8.3 Hz ), 7.11 (1H, d, J = 7.8 Hz), 7.31 (1H, t, J = 7.8 Hz), 7.42 (1H, t, J = 7.4 Hz), 7.49 (2H, t, J = 7.4 Hz), 7.61 (1H, t, J = 7.8 Hz), 7.68 (2H, d, J = 7.4 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.96 (1H, d, J = 7.8 Hz), 7.99 ( 1H, s), 8.12 (1H, d, J = 7.8 Hz), 9.32 (1H, br s);
IR (KBr) vmax 3457, 3300, 2929, 2765, 1718, 1645, 1463, 1432, 1188, 1169, 758 cm ^-1 ;
MS (FAB) m / z: 429 (M + H) ⁺ .
[Example 76]
3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) benzoic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.23 (2H, br s), 1.48 (2H, br s), 2.88 (2H, br s), 3.11 (2H, br s), 3.21 (2H, t, J = 8.4 Hz), 3.81 (3H, s), 4.04 (2H, t, J = 8.4 Hz), 7.00 (1H, d, J = 7.7 Hz), 7.11 (1H, d, J = 7.7 Hz), 7.18 (1H, d, J = 7.7 Hz), 7.25 (1H, s), 7.32 (1H, t, J = 7.7 Hz), 7.38 (1H, t, J = 7.7 Hz), 7.61 (1H, t, J = 7.8 Hz), 7.75 (1H, d, J = 7.8 Hz), 7.94-8.00 (2H, m), 8.13 (1H, d, J = 7.8 Hz), 9.42 (2H, br s), 13.08 (1H, br s);
IR (KBr) vmax 3420, 2960, 1714, 1656, 1584, 1459, 1253, 1230, 1036, 793, 757, 699 cm ^-1 ;
MS (FAB) m / z: 457 (M + H) ⁺ .
[Example 77]
(4- {1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} phenyl) acetic acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.75 (6H, s), 2.88 (4H, s), 3.21 (2H, t, J = 8.3 Hz), 3.63 (2H, s), 4.03 (2H, m ), 7.06 (1H, d, J = 7.3 Hz), 7.27 (1H, t, J = 7.8 Hz), 7.35 (2H, d, J = 7.8 Hz), 7.41-7.44 (3H, m), 7.47-7.51 (2H, m), 7.68 (2H, d, J = 7.8 Hz), 8.08 (1H, d, J = 7.8 Hz), 9.33 (2H, br s), 12.32 (1H, br s);
Anal.Calcd.For C ₂₈ H ₃₀ N ₂ O ₃ .HCl.1.2H ₂ O Found C, 67.05.H, 6.82.N, 6.65.Cl, 7.03;
IR (KBr) vmax 3368, 2779, 1732, 1646, 1459, 1420, 788, 697 cm ^-1 ;
MS (FAB) m / z: 443 (M + H) ⁺ .
[Example 78]
4- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) benzoic acid

(Process 1)
4- [1- (Phenylsulfonyl) -1H-indol-3-yl] benzoic acid ethyl ester

2.00 g (6.64 mmol) of 1- (phenylsulfonyl) -3-indoleboronic acid and 1.08 mL (6.64 mmol) of 4-bromobenzoic acid ethyl ester were dissolved in 1,2-dimethoxyethane, and 3M sodium carbonate 10 mL of an aqueous solution and 0.54 g (0.66 mmol) of dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) methylene chloride complex were added, and the mixture was stirred at 90 ° C. for 6 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The crude product obtained by concentrating the solvent was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate) to obtain 1.29 g (48%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 7.32 (1H, m), 7.40 (1H, m), 7.46- 7.49 (2H, m), 7.57 (1H, m), 7.68 (2H, d, J = 8.5 Hz), 7.78-7.79 (2H, m), 7.94-7.96 (2H, m), 8.07 (1H, d, J = 7.5 Hz), 8.14 (2H, d, J = 8.5 Hz).
(Process 2)
4- (1H-Indol-3-yl) benzoic acid methyl ester

1.29 g (3.18 mmol) of 4- [1- (phenylsulfonyl) -1H-indol-3-yl] benzoic acid ethyl ester obtained in Example 78 (Step 1) was dissolved in 5 mL of methanol and 10 mL of tetrahydrofuran. Then, 3.11 g (9.54 mmol) of cesium carbonate was added, and the mixture was stirred at room temperature for 3 hours. The reaction solvent was distilled off under reduced pressure, water was added to the resulting residue, and the mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration. Washing with water and drying gave 0.67 g (84%) of the desired compound.
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 7.22-7.30 (2H, m), 7.46-7.48 (2H, m), 7.76 (2H, d, J = 8.5 Hz), 7.97 (1H , d, J = 8.2 Hz), 8.11 (2H, d, J = 8.5 Hz), 8.36 (1H, br s).
(Process 3)
4- (1-acryloyl-2,3-dihydro-1H-indol-3-yl) benzoic acid methyl ester

670 mg (2.67 mmol) of 4- (1H-indol-3-yl) benzoic acid methyl ester obtained in Example 78 (Step 2) was dissolved in 15 mL of trifluoroacetic acid and stirred under ice cooling. Triethylsilane 0.86mL (5.34mmol) was added there, and it stirred under ice-cooling for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to give 4- (2,3-dihydro-1H-indole- There was obtained 604 mg (89%) of 3-yl) benzoic acid methyl ester. The obtained 4- (2,3-dihydro-1H-indol-3-yl) benzoic acid methyl ester (600 mg, 2.37 mmol) was dissolved in tetrahydrofuran (10 mL), triethylamine (0.66 mL, 4.74 mmol) was added, and iced Stir in the cold. Thereto was added 0.29 mL (3.55 mmol) of acryloyl chloride. Stir at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction solution, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to obtain 324 mg (44%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 3.91 (3H, s), 4.10 (1H, m), 4.64 (2H, m), 5.81 (1H, m), 6.54 (2H, m), 6.98 (1H, d , J = 7.4 Hz), 7.05 (1H, t, J = 7.4 Hz), 7.26-7.30 (3H, m), 8.00 (2H, d, J = 8.2 Hz), 8.39 (1H, s).
(Process 4)
4- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) benzoic acid methyl ester

320 mg (1.04 mmol) of 4- (1-acryloyl-2,3-dihydro-1H-indol-3-yl) benzoic acid methyl ester obtained in Example 78 (Step 3) was dissolved in 10 mL of ethanol. -(3-Methoxyphenyl) cyclopropanamine (180 mg, 1.10 mmol) was added, and the mixture was heated to reflux for 4.5 hours. The reaction solution was returned to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to give 281 mg (57%) of the desired compound. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 0.94-0.99 (4H, m), 2.49-2.56 (2H, m), 2.93 (2H, t, J = 6.1 Hz), 3.81 (3H, s), 3.86-3.88 (1H, m), 3.91 (3H, s), 4.39 (1H, t, J = 10.2 Hz), 4.64 (1H, dd, J = 10.2, 6.6 Hz), 6.74 (1H, dd, J = 8.0, 2.5 Hz), 6.94-7.01 (4H, m), 7.21-7.26 (4H, m), 7.99 (2H, d, J = 8.2 Hz), 8.28 (1H, d, J = 7.8 Hz).
(Process 5)
4- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) benzoic acid

4- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl obtained in Example 78 (Step 4) ) 277 mg (0.59 mmol) of benzoic acid methyl ester was dissolved in 6 mL of ethanol, 3 mL of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. After the solvent was distilled off under reduced pressure, the residue was neutralized with 2N hydrochloric acid, and the precipitate was collected by filtration. The filtered product was washed with water / ethyl acetate and dried to obtain 249 mg (91%) of the target compound, 0.25 hydrochloride.
¹ H-NMR (DMSO-D ₆ ) δ: 1.99 (6H, s), 2.62 (2H, m), 2.80 (2H, m), 3.74 (1H, m), 4.01 (1H, m), 4.53 (1H , t, J = 10.2 Hz), 4.76 (1H, m), 6.77 (1H, br m), 6.90 (1H, br s), 6.94-7.01 (3H, m), 7.20-7.24 (2H, m), 7.35 (2H, d, J = 8.6 Hz), 7.90 (2H, d, J = 8.6 Hz), 8.14 (1H, d, J = 8.2 Hz);
Anal.Calcd.For C ₂₈ H ₂₈ N ₂ O ₄ .0.25HCl.0.25H ₂ O Found C, 71.66.H, 6.24.N, 5.99.Cl, 1.83;
IR (KBr) vmax 3424, 3225, 1647, 1593, 1480, 763, 702 cm ^-1 ;
MS (FAB) m / z: 457 (M + H) ⁺ .
[Example 79]
4-({1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} methyl) benzoic acid monohydrochloride

(Process 1)
4-Bromoindoline-1-carboxylic acid-tert-butyl ester

4-bromoindole (5.00 g, 25.5 mmol) was dissolved in acetic acid (50 mL), sodium cyanotrihydroborate (6.41 g, 102 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The residue obtained by evaporating the solvent under reduced pressure was neutralized by adding saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4-bromoindoline as a crude product. The total amount of 4-bromoindoline thus obtained was dissolved in 20 mL of tetrahydrofuran, 7.07 mL of triethylamine and 6.12 g (28.1 mmol) of di-tert-butyl dicarbonate were added, and the mixture was stirred at room temperature for 15 hours, and then stirred at 50 ° C. for 3 hours. Stir for hours. The reaction mixture was allowed to cool to room temperature, water was added, the mixture was extracted with methylene chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to obtain 5.81 g (76%) of the target compound.
(Process 2)
4- {Hydroxy [4- (methoxycarbonyl) phenyl] methyl} indoline-1-carboxylic acid-tert-butyl ester

2.98 g (10.0 mmol) of 4-bromoindoline-1-carboxylic acid-tert-butyl ester obtained in Example 79 (Step 1) was dissolved in 20 mL of tetrahydrofuran and stirred at −78 ° C. Thereto was added 6.62 mL of n-butyllithium (1.66 M hexane solution), and the mixture was stirred at −78 ° C. for 1 hour. To the reaction solution was added 1.81 g (11.0 mmol) of 4-formyl-benzoic acid methyl ester, and the mixture was further stirred at −78 ° C. for 1 hour. The reaction solution was returned to room temperature, added with water and extracted with ethyl acetate. The layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated. The resulting crude product was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to obtain 0.53 g (14%) of the target compound.
¹ H-NMR (CDCl ₃ ) δ: 1.57 (9H, s), 2.89 (2H, m), 3.90 (2H, m), 3.91 (3H, s), 5.87 (1H, d, J = 3.4 Hz), 7.02 (1H, d, J = 7.8 Hz), 7.16-7.22 (2H, m), 7.42 (2H, d, J = 8.3 Hz), 7.99 (2H, d, J = 8.3 Hz).
(Process 3)
4-[(1-Acrylyl-2,3-dihydro-1H-indol-4-yl) methyl] benzoic acid methyl ester

4- {Hydroxy [4- (methoxycarbonyl) phenyl] methyl} indoline-1-carboxylic acid-tert-butyl ester 525 mg (1.37 mmol) obtained in Example 79 (Step 2) was dissolved in 10 mL of trifluoroacetic acid. And stirred under ice cooling. Triethylsilane 0.88mL (5.48mmol) was added there, and it stirred under ice-cooling for 1.5 hours after addition. The mixture was then stirred at room temperature for 2 hours and at 50 ° C. for 4 hours. The reaction mixture was brought to room temperature, poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was dissolved in 10 mL of tetrahydrofuran, 0.38 mL (2.74 mmol) of triethylamine was added, and the mixture was stirred under ice cooling. Acryloyl chloride 0.17mL (2.06mmol) was added there, and it stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with methylene chloride, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (Biotage, elution solvent; hexane / acetic acid). The target compound was obtained in an amount of 96 mg (22%).
¹ H-NMR (CDCl ₃ ) δ: 3.06 (2H, m), 3.90 (2H, s), 3.92 (3H, s), 4.14 (2H, m), 5.81 (1H, m), 6.51 (2H, m ), 6.88 (1H, d, J = 7.8 Hz), 7.30 (1H, t, J = 7.8 Hz), 7.38 (2H, d, J = 8.3 Hz), 8.00 (1H, d, J = 7.8 Hz), 8.04 (2H, t, J = 8.3 Hz).
(Process 4)
4-({1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} methyl) benzoic acid methyl ester

90 mg (0.28 mmol) of 4-[(1-acryloyl-2,3-dihydro-1H-indol-4-yl) methyl] benzoic acid methyl ester obtained in Example 79 (Step 3) was dissolved in 3 mL of ethanol. Then, 45 mg (0.34 mmol) of cumylamine was added, and the mixture was heated to reflux for 4 hours. The reaction solution is returned to room temperature, and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate) to obtain 29 mg (22%) of the target compound. It was.
¹ H-NMR (CDCl ₃ ) δ: 1.49 (6H, s), 2.53 (2H, t, J = 6.1 Hz), 2.68 (2H, t, J = 6.1 Hz), 2.94 (2H, t, J = 8.5 Hz), 3.90 (3H, s), 3.92-3.98 (4H, m), 6.84 (1H, d, J = 7.8 Hz), 7.16-7.21 (4H, m), 7.29-7.35 (2H, m), 7.48 (2H, d, J = 8.3 Hz), 7.94 (2H, d, J = 8.3 Hz), 8.14 (1H, d, J = 7.8 Hz).
(Process 5)
4-({1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} methyl) benzoic acid monohydrochloride

Methyl 4- {5-fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -1H-indol-3-yl} butanoate obtained in Example 45 (Step 4) 4-({1- [N- (1-Methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indole- obtained in Example 79 (Step 4) instead of ester 4-yl} methyl) benzoic acid methyl ester (26 mg, 0.057 mmol) was used for reaction and purification in the same manner as in Example 45 (Step 5) to obtain 23 mg (83%) of the target compound monohydrochloride.
¹ H-NMR (DMSO-D ₆ ) δ: 1.74 (6H, s), 2.81-2.83 (4H, m), 3.02 (2H, t, J = 8.3 Hz), 3.98-4.03 (4H, m), 6.90 (1H, d, J = 7.3 Hz), 7.14 (1H, t, J = 7.8 Hz), 7.28 (2H, d, J = 8.3 Hz), 7.42 (1H, t, J = 7.3 Hz), 7.46-7.51 (2H, m), 7.66 (2H, d, J = 7.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 7.93 (2H, d, J = 8.3 Hz), 9.24 (2H, br m), 12.83 (1H, br s);
Anal.Calcd.For C ₂₈ H ₃₀ N ₂ O ₃ .HCl.H ₂ O Found C, 67.23.H, 6.53.N, 5.62.Cl, 7.54;
MS (FAB) m / z: 443 (M + H) ⁺ .

Examples 80 to 88 were synthesized in the same manner as Example 50 using the appropriate substituted indole-3-carbaldehyde and substituted benzylamine.

[Example 80]
3- (5-Chloro-1- {N- [1- (3,5-difluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl)- 2,2-Dimethylpropionic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.20 (6H, s), 1.73 (6H, s), 1.75-1.81 (1H, m), 2.14 (1H, d, J = 12.7 Hz), 2.77-2.95 ( 4H, m), 3.36-3.43 (1H, m), 3.73 (1H, dd, J = 10.3, 7.3 Hz), 4.28 (1H, t, J = 9.8 Hz), 7.25 (1H, d, J = 8.8 Hz ), 7.29 (1H, s), 7.35 (1H, t, J = 9.0 Hz), 7.45 (2H, d, J = 7.3 Hz), 8.00 (1H, d, J = 8.3 Hz), 9.37 (2H, br s), 12.37 (1H, br s);
HRMS (ESI ⁺ ) calcd for C ₂₅ H ₃₀ ClF ₂ N ₂ O ₃ [M + H] ⁺ , required m / z: 479.1913, found 479.1915.
[Example 81]
3- (5-Fluoro-1- {N- [1- (3,5-difluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl)- 2,2-Dimethylpropionic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.21 (6H, s), 1.74 (6H, s), 1.75-1.81 (1H, m), 2.13 (1H, d, J = 12.7 Hz), 2.78-2.96 ( 4H, m), 3.36-3.43 (1H, m), 3.73 (1H, dd, J = 10.3, 7.3 Hz), 4.29 (1H, t, J = 9.8 Hz), 6.99-7.05 (1H, m), 7.10 (1H, dd, J = 8.5, 2.2 Hz), 7.35 (1H, t, J = 8.8 Hz), 7.46 (2H, d, J = 7.3 Hz), 8.01 (1H, dd, J = 8.8, 4.9 Hz) , 9.41 (2H, br s), 12.37 (1H, br s);
HRMS (ESI ⁺ ) calcd for C ₂₅ H ₃₀ F ₃ N ₂ O ₃ [M + H] ⁺ , required m / z: 463.2209, found 463.2212.

[Example 82]
3- (5-chloro-1- {N- [1- (4-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) -2, 2-Dimethylpropionic acid

¹ H NMR (DMSO-D ₆ ) d: 1.20 (6H, s), 1.60 (6H, br s), 1.77 (1H, dd, J = 13.9, 10.0 Hz), 2.12 (1H, d, J = 13.7 Hz ), 2.61-2.82 (4H, m), 3.34-3.42 (1H, m), 3.72 (1H, dd, J = 10.3, 7.3 Hz), 4.27 (1H, t, J = 10.0 Hz), 7.19-7.33 ( 4H, m), 7.63 (2H, br s), 8.00 (1H, d, J = 8.3 Hz);
HRMS (ESI ⁺ ) calcd for C ₂₅ H ₃₁ Cl ₁ F ₁ N ₂ O ₃ [M + H] ⁺ , required m / z: 461.2007, found 461.1998.
[Example 83]
3- (5-Chloro-1- {N- [1- (3,4-difluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl)- 2,2-Dimethylpropionic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.20 (6H, s), 1.74 (6H, s), 1.76-1.81 (1H, m), 2.14 (1H, dd, J = 14.3, 1.8 Hz), 2.77- 2.92 (4H, m), 3.37-3.44 (1H, m), 3.72 (1H, dd, J = 9.8, 7.4 Hz), 4.28 (1H, t, J = 10.0 Hz), 7.25 (1H, dd, J = 8.6, 2.0 Hz), 7.29 (1H, s), 7.49-7.63 (2H, m), 7.76-7.86 (1H, m), 8.00 (1H, d, J = 8.6 Hz), 9.29 (2H, br s) , 12.41 (1H, br s);
HRMS (ESI ⁺ ) calcd for C ₂₅ H ₃₀ ClF ₂ N ₂ O ₃ [M + H] ⁺ , required m / z: 479.1913, found 479.1923.
[Example 84]
2,2-dimethyl-3- (5-methyl-1- {N- [1- (4-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indole-3 -Yl) propionic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.21 (6H, s), 1.69-1.77 (7H, m), 2.15 (1H, d, J = 12.7 Hz), 2.27 (3H, s), 2.74-2.93 ( 4H, m), 3.33-3.37 (1H, m), 3.67 (1H, dd, J = 10.5, 7.1 Hz), 4.24 (1H, t, J = 10.3 Hz), 6.98 (1H, d, J = 7.8 Hz ), 7.05 (1H, s), 7.25-7.31 (1H, m), 7.47-7.58 (3H, m), 7.90 (1H, d, J = 7.8 Hz), 9.16 (2H, br s), 12.36 (1H , br s);
HRMS (ESI ⁺ ) calcd for C ₂₆ H ₃₄ FN ₂ O ₃ [M + H] ⁺ , required m / z: 441.2554, found 441.2553.
[Example 85]
3- (5-chloro-1- {N- [1- (3-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) -2, 2-Dimethylpropionic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.20 (6H, s), 1.74 (6H, s), 1.76-1.81 (1H, m), 2.14 (1H, d, J = 12.7 Hz), 2.75-2.92 ( 4H, m), 3.73 (1H, dd, J = 10.0, 7.1 Hz), 4.27 (1H, t, J = 9.8 Hz), 7.22-7.31 (3H, m), 7.48-7.58 (3H, m), 8.00 (1H, d, J = 8.8 Hz), 9.29 (2H, br s), 12.39 (1H, br s);
HRMS (ESI ⁺ ) calcd for C ₂₅ H ₃₁ ClFN ₂ O ₃ [M + H] ⁺ , required m / z: 461.2007, found 461.2008.
[Example 86]
3- (5-Chloro-1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl ) -2,2-Dimethylpropionic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.20 (6H, s), 1.73 (6H, s), 1.76-1.81 (1H, m), 2.14 (1H, d, J = 12.2 Hz), 2.75-2.90 ( 4H, m), 3.35-3.42 (1H, m), 3.72 (1H, dd, J = 10.0, 7.1 Hz), 3.92 (3H, s), 4.27 (1H, t, J = 10.0 Hz), 7.11-7.16 (1H, m), 7.23-7.33 (3H, m), 7.55 (1H, br s), 8.00 (1H, d, J = 8.3 Hz), 9.24 (2H, br s), 12.38 (1H, br s) ;
HRMS (ESI ⁺ ) calcd for C ₂₆ H ₃₃ Cl ₁ F ₁ N ₂ O ₄ [M + H] ⁺ , required m / z: 491.2113, found 491.2106.
[Example 87]
3- (5-fluoro-1- {N- [1- (3-fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) -2, 2-Dimethylpropionic acid monohydrochloride

¹ H NMR (DMSO-D ₆ ) d: 1.20 (6H, s), 1.74 (6H, s), 1.77-1.81 (1H, m), 2.13 (1H, d, J = 13.2 Hz), 2.73-2.92 ( 4H, m), 3.35-3.43 (1H, m), 3.72 (1H, dd, J = 10.0, 7.1 Hz), 4.27 (1H, t, J = 9.8 Hz), 6.98-7.12 (2H, m), 7.28 (1H, t, J = 7.8 Hz), 7.48-7.58 (3H, m), 8.01 (1H, dd, J = 8.8, 4.9 Hz), 9.29 (2H, br s), 12.39 (1H, br s);
HRMS (ESI ⁺ ) calcd for C ₂₅ H ₃₁ F ₂ N ₂ O ₃ [M + H] ⁺ , required m / z: 445.2303, found 445.2307.
[Example 88]
3- (1- {N- [1- (3-Fluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) -2,2-dimethylpropion Acid monohydrochloride

¹ H-NMR (DMSO-D ₆ ) δ: 1.10 (6H, s), 2.77 (2H, s), 2.87 (4H, br s), 3.13 (2H, t, J = 8.4 Hz), 4.02 (2H, t, J = 8.4 Hz), 6.83 (1H, d, J = 7.4 Hz), 7.09 (1H, t, J = 7.8 Hz), 7.25-7.31 (1H, m), 7.50-7.58 (3H, m), 7.94 (1H, d, J = 7.8 Hz), 9.36 (2H, br s), 12.31 (1H, br s).

[Test Example 1] Human CaSR activity measurement test Human medullary thyroid cancer cell line TT cell is a cell line expressing human CaSR, and when CaSR is activated by extracellular calcium ions, the intracellular calcium ion concentration is increased. It has been reported to increase (Endocrinology 137: 3842-3848, 1996). Therefore, the activation effect of the test compound on human CaSR was evaluated using the change in intracellular calcium concentration of TT cells as an index.
Black well / clear bottom 96-well plate (poly-D-lysine coat: manufactured by BD Bioscience) seeded with TT cells, F-12 Nutrient Mixture (Kaighn modified) containing 10% calf serum and 0.5% antibiotic antimyotic Cultured in the medium for about 24 hours. After that, the culture supernatant is removed by aspiration, and the labeling buffer (20 mM HEPES, Hanks' Balanced Salt Solutions containing 2.5 mM probenecid) containing FLIPR Calcium 3 assay kit (manufactured by Molecular Devices) that fluorescently labels intracellular calcium ions ( HBSS (Ca, Mg, free), 2 mM CaCl ₂ ) was added at 50 μL per well and allowed to stand for 1 hour at 37 ° C. Subsequently, the above plate was mounted on FlexStation (Molecular Devices) or FlexStation 3 (Molecular Devices). The fluorescence intensity before and after treatment with the test compound dissolved in the buffer for measurement (126 mM NaCl, 4 mM KCl, 1 mM MgCl ₂ , 20 mM HEPES (pH 7.4), 5.6 mM glucose, 2 mM CaCl ₂ ) was measured. A test compound dissolved in a dimethyl sulfoxide / methanol mixed solution (mixing ratio 7: 3) at a predetermined concentration was used, and a solution diluted with a measuring buffer solution was added to a final concentration of 0.1%.
Concentration response curves are calculated by calculating the rate of increase in fluorescence intensity at the time of test compound treatment at each concentration, assuming that the increase in fluorescence intensity at the time of treatment with a measurement buffer solution containing no test compound is 0% and the increase in fluorescence intensity due to 8 mM calcium is 100%. By drawing and calculating the concentration (EC ₅₀ value) of the test compound exhibiting a 50% increase in the fluorescence intensity, the human CaSR activation action by each test compound was evaluated. Further, as a control compound, the compound A (N. Nagano, Pharmacol. Ther., 2006, Mar, 109 (3), 339-365. And the compound described in WO 1996/12697 pamphlet: ((R) -1 -Naphthalen-1-yl-ethyl)-[3- (3-trifluoromethyl-phenyl) -propyl] -amine monohydrochloride) was evaluated in the same manner as described above, and an EC ₅₀ value was calculated. The human CaSR activity by each test compound was calculated as the relative activity to compound A.
The relative activity of the compound A = [EC ₅₀ of the test compound] / [EC ₅₀ of the compound A]
The test results are shown in Table 1.

In this test, each test compound showed an excellent human CaSR activation effect.

[Test Example 2] Rat blood parathyroid hormone and ionized calcium concentration measurement test The test compound was orally administered to 3 male SD rats (Japan SLC), blood parathyroid hormone (PTH) concentration and blood The effect on medium ionized calcium concentration was examined.

The test compound was administered dissolved or suspended in 0.5% methylcellulose 400 (MC) solution or 0.5% MC solution containing 10% ethanol. (Compound A used in Test Example 1 was administered as an MC suspension at a dose of 30 mg / kg as a comparative control.)
Before administration of each test compound and at 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration, blood was collected from the jugular vein under halothane or isoflurane anesthesia, and cartridge EG7 + (manufactured by Fuso Pharmaceutical Co., Ltd.) and i-STAT 300F The blood ionized calcium concentration was measured using Fuso Pharmaceutical Co., Ltd. In addition, plasma intact PTH concentration was measured using Rat intact PTH ELISA kit (manufactured by Immutopics).

Each test compound decreased blood PTH concentration and calcium concentration in this study.
(Results) Compound A decreased the calcium concentration by 25 to 30% at 6 or 8 hours after administration at a dose of 30 mg / kg. On the other hand, the compounds of Examples 5, 6, 7, 22, 24, 25, 32, 33, 37, 50, 60, 66, 70, 71, 72, and 75 which are compounds of the present invention have a dose of 10 mg / kg. In 6 or 8 hours after administration, the calcium concentration was reduced by 30% or more.

[Formulation Example 1]
Using the compound of Example (10 mg), colloidal silicon dioxide (0.2 mg), magnesium stearate (5 mg), microcrystalline cellulose (175 mg), starch (10 mg), and lactose (99.8 mg), Tablets are produced according to the method. The obtained tablets can be coated as necessary.

The compound of the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent calcium sensory receptor action, and has hyperparathyroidism, secondary hyperparathyroidism, primary accessory parathyroidism. It is useful as a therapeutic agent for hyperthyroidism, renal osteodystrophy or hypercalcemia.

Claims (30)

1. Formula (I)
   

   

   
   [Wherein, R ¹ and R ² each independently represent a hydrogen atom, a halogeno group, a C1-C6 alkyl group or a C1-C6 alkoxy group;
   R ³ and R ⁴ each independently represent a C1-C3 alkyl group (wherein R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclopropane ring or a cyclobutane ring) You may have)
   R ⁵ , R ⁶ and R ⁷ represent the following (1) or (2):
   (1) R ⁵ represents a hydrogen atom, and R ⁶ represents a carboxy C1-C6 alkyl group, carboxyphenyl group, carboxybenzyl group, carboxyphenethyl group, which may be substituted with 1 to 3 C1-C3 alkyl groups. represents carboxymethyl phenyl group or carboxyethyl phenyl group, ^{R 7} is a hydrogen atom, a halogeno group, cyano group, C1 ~ C6 alkyl group, a halogeno C1 ~ C6 alkyl group, C1 ~ C6 alkoxy group or C1 ~ C6 alkylsulfonyl group Indicates.
   (2) R ⁵ and R ⁶ each independently represent a hydrogen atom or a C1-C3 alkyl group (wherein R ⁵ and R ⁶ together with the carbon atom to which they are attached, cyclopropane Or R ⁷ may be a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group. A group, a carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group; ;
   R ⁸ , R ⁹ and R ¹⁰ each independently represent a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group. . ]
   Or a pharmacologically acceptable salt thereof.
2. The compound according to claim 1, or a pharmacologically acceptable salt thereof, wherein R ¹ is a halogeno group and R ² is a C1-C6 alkoxy group.
3. The compound according to claim 1, or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom and R ² is a halogeno group or a C1-C6 alkoxy group.
4. The compound according to claim 1, wherein R ¹ and R ² are both hydrogen atoms, or a pharmacologically acceptable salt thereof.
5. The compound according to any one of claims 1 to 4, wherein R ³ and R ⁴ are both methyl groups, or a pharmacologically acceptable salt thereof.
6. The compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, wherein R ³ and R ⁴ together with the carbon atom to which they are attached form a cyclopropane ring. Salt.
7. R ⁵ is a hydrogen atom, and R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group, a carboxyphenethyl group, a carboxymethylphenyl group Or a carboxyethylphenyl group, and R ⁷ is a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group. Item 7. The compound according to any one of Items 1 to 6, or a pharmacologically acceptable salt thereof.
8. R ⁵ is a hydrogen atom, R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, R ⁷ is a hydrogen atom, a halogeno group, a cyano group, C1 The compound according to claim 7, or a pharmacologically acceptable salt thereof, which is a -C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group.
9. R ⁵ is a hydrogen atom, R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, R ⁷ is a hydrogen atom, a halogeno group, a cyano group, C1 The compound according to claim 7, which is a -C6 alkyl group or a C1-C6 alkoxy group, or a pharmaceutically acceptable salt thereof.
10. The R ⁵ is a hydrogen atom, the R ⁶ is a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, and the R ⁷ is a hydrogen atom. Or a pharmacologically acceptable salt thereof.
11. R ⁵ and R ⁶ are each independently a hydrogen atom or a C1-C3 alkyl group (wherein R ⁵ and R ⁶ together with the carbon atom to which they are attached, a cyclopropane ring or a cyclobutane ring) R ⁷ is a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group, carboxyphenethyl The compound according to any one of claims 1 to 6, which is a group, a carboxymethylphenyl group or a carboxyethylphenyl group, or a pharmacologically acceptable salt thereof.
12. R ⁵ and R ⁶ are both hydrogen atoms, and R ⁷ is a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, a carboxyphenyl group, a carboxybenzyl group, The compound according to claim 11, which is a carboxyphenethyl group, a carboxymethylphenyl group or a carboxyethylphenyl group, or a pharmacologically acceptable salt thereof.
13. R ⁵ and R ⁶ are both hydrogen atoms, and R ⁷ is a carboxy group, a carboxy C1-C6 alkyl group optionally substituted with 1 to 3 C1-C3 alkyl groups, or a carboxyphenyl group. 11. The compound according to 11, or a pharmacologically acceptable salt thereof.
14. The compound according to claim 11, or a pharmacologically acceptable salt thereof, wherein R ⁵ and R ⁶ are both hydrogen atoms and R ⁷ is a carboxyphenyl group.
15. R ⁸ is a hydrogen atom, a halogeno group, a cyano group, a C1-C6 alkyl group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group or a C1-C6 alkylsulfonyl group, and R ⁹ is a hydrogen atom or a halogeno group The compound according to any one of claims 1 to 14, or a pharmacologically acceptable salt thereof, wherein R ¹⁰ is a hydrogen atom.
16. The compound according to claim 15, or a pharmacologically acceptable salt thereof, wherein R ⁸ is a halogeno group or a halogeno C1-C6 alkyl group.
17. The compound according to claim 15, wherein R ⁸ is a chloro group or a trifluoromethyl group, or a pharmacologically acceptable salt thereof.
18. The compound according to claim 15, wherein R ⁹ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
19. {5-chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} acetic acid,
    (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl} acetic acid,
    3- {5-chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid,
    3- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} propionic acid,
    3- (1- {N- [1- (3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
    3- (1- {N- [1- (4-fluoro-3-methoxyphenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
    3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
    3- (5-fluoro-1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-3-yl) propionic acid,
    3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -5-methyl-2,3-dihydro-1H-indol-3-yl) propionic acid,
    3- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -5- (trifluoromethyl) -2,3-dihydro-1H-indol-3-yl} propionic acid,
    4- {5-fluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -1H-indol-3-yl} butanoic acid,
    4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} butanoic acid,
    3- {5-Chloro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-3-yl} -2,2-dimethylpropionic acid ,
    1- {N- [1- (3-methoxyphenyl) cyclopropyl] β-alanyl} indoline-4-carboxylic acid,
    3- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid,
    3- (1- {N- [1- (3-methoxyphenyl) cyclopropyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) propionic acid,
    3- {5,6-difluoro-1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} propionic acid,
    4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} benzoic acid,
    4- (1- {N- [1- (3,4-difluorophenyl) -1-methylethyl] -β-alanyl} -2,3-dihydro-1H-indol-4-yl) benzoic acid,
    (4- {1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} phenyl) acetic acid, and
    Selected from the group consisting of 4-({1- [N- (1-methyl-1-phenylethyl) -β-alanyl] -2,3-dihydro-1H-indol-4-yl} methyl) benzoic acid The compound according to claim 1, or a pharmacologically acceptable salt thereof.
20. A pharmaceutical comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
21. A calcium-sensing receptor agonist comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
22. A therapeutic agent for hyperparathyroidism comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
23. A therapeutic agent for secondary hyperparathyroidism comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
24. A therapeutic agent for primary hyperparathyroidism comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
25. A therapeutic agent for renal osteodystrophy comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
26. A therapeutic agent for hypercalcemia, comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
27. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier.
28. 20. Any one of claims 1 to 19 for use in a method for treating hyperparathyroidism, secondary hyperparathyroidism, primary hyperparathyroidism, renal osteodystrophy or hypercalcemia. 2. The compound according to 1 or a pharmacologically acceptable salt thereof.
29. A method for treating a disease by administering a pharmaceutical comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient.
30. 20. Hyperparathyroidism, secondary hyperparathyroidism by administering a pharmaceutical comprising the compound according to any one of claims 1 to 19 or a pharmacologically acceptable salt thereof as an active ingredient, A method for treating primary hyperparathyroidism, renal osteodystrophy or hypercalcemia.