Novel treatments and prevention of sarcopenia-related diseases

Abstract

The present disclosure has solved problems associated with the TGF-β family or the like, which is called Myostatin / GDF-8 as a molecular mechanism and targeted by sarcopenia, by evaluating a pharmaceutical product in physiological aging models, and in particular, by evaluating an increase in muscle mass and an increase in muscle strength; and has overcome harmful effects by applying targets of diseases different from sarcopenia such as dystrophia. The present disclosure has unexpectedly found a use for an OK-1-related compound as a sarcopenia treatment method through a pathway different from that of Wnt signal (proliferation of muscle stem cells) associated with Wnt / β-catenin inhibition, and is thus provided due to the findings.

Description

[Technical Field]

[0001] This disclosure relates to novel treatments and preventions for sarcopenia-related diseases, disorders, or symptoms. This disclosure also provides compounds, compositions, pharmaceuticals, and therapeutic methods useful for novel treatments and preventions of sarcopenia-related diseases, disorders, or symptoms. [Background technology]

[0002] Currently, several companies are developing this technology, primarily targeting muscle differentiation and myocyte death by targeting a TGF-β family factor called Myostatin / GDF-8. Therefore, development is underway not only for sarcopenia but also for muscular dystrophy (Patent Documents 1-4, Non-Patent Document 1). In addition, a monoclonal antibody (bimagrumab) is being developed targeting Activin Receptor ACVR2B, and Phase 2 trials were completed in 2017. Bimagrumab inhibits signaling by myostatin and activin A, promoting muscle differentiation and increasing muscle mass. However, it failed to dramatically improve sarcopenia symptoms, including walking speed and grip strength, and development was discontinued in 2018.

[0003] In addition, development targeting androgen receptors (MK-2866) is underway, but the relationship between hormones and muscles is unclear, making its development uncertain. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2016 / 168613 [Patent Document 2] International Publication No. 2013 / 137832 [Patent Document 3] International Publication No. 2017 / 072515 [Patent Document 4] International Publication No. 2015 / 162590 [Non-patent literature]

[0005] [Non-Patent Document 1] Arounleut P, ​​Bialek P, Liang LF, Upadhyay S, Fulzele S, Johnson M, Elsalanty M, Isales CM, Hamrick MW. A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength. Exp Gerontol. 2013 Sep;48(9):898-904. [Overview of the project] [Means for solving the problem]

[0006] This disclosure addresses the challenges associated with targeting sarcopenia by evaluating drugs in a physiological aging model, particularly by assessing muscle mass and muscle strength increases. It also resolves the drawbacks of applying targets intended for diseases other than sarcopenia, such as dystrophy. Unexpectedly, this disclosure provides the finding that OK-1 related compounds have potential applications as a treatment for sarcopenia via a pathway different from the Wnt signal (muscle stem cell proliferation) associated with Wnt / β-catenin inhibition.

[0007] This disclosure provides, for example, the following: (Item A1) A composition comprising a compound selected from the OK-1 related compound group, a pharmaceutically acceptable salt thereof, or a solvate thereof, for modulating, delaying the progression of, preventing or treating sarcopenia-related diseases, disorders, or symptoms. (Item 1) A composition for modulating, delaying the progression, preventing or treating sarcopenia-related diseases, disorders or symptoms, comprising a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is Compound group [1] General formula (I)

Chemical formula

[0008] [Item B1] A composition comprising a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the regulation, delaying progression, prevention or treatment of sarcopenia-related diseases, disorders or symptoms, wherein the compound is of general formula (I) [ka] Compound represented by [wherein A is -CHR] 7 -(Here, R 7 OH, -OR 8 (Here, R 8 C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 alkyl, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 3-10 Cycloalkyl-C 1-10 Alkyl, C 6-14 Aryl, or C 3-10 It is a cycloalkyl, G is -NR 6 -, or -O-(where R 6 C 1-10 Alkyl and C 2-10 (They are chosen independently of Alkenil.) R 1 is -Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10(This is a condensed bicyclic heteroaryl which may be substituted with substituents selected from naphthyl or -NH2 and halogens.) R 2 Ha-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -O- or -NH-, and Rb is a bond or C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C 1-10 C may be substituted with alkyl or halogen compounds. 6-14 Aryl, heteroaryl, or C 3-10 It is a cycloalkyl and R 3 C 1-10 It is alkyl, A composition in which "heteroaryl" means a 5 to 14-membered monocyclic or polycyclic aromatic group in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon. [Term B2]R 7 However, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, or C 3-10 Cycloalkyl-C 1-10 A composition that is alkyl, as described in any of the preceding items. [Section B3]R 2 ga-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C may be substituted with a halogen.6-14 Aryl, heteroaryl, or C 3-10 A composition according to any one of the preceding items, wherein it is a cycloalkyl compound. [Section B4]R 3 C 1-4 A composition according to any one of the preceding items, wherein the composition is alkyl. [Section B5]R 6 C 1-6 Alkyl or C 2-6 A composition according to any one of the preceding items, wherein the composition is an alkenyl. [Item B6] Ra is C 1-6 It is alkylene and R 10 The composition according to any one of the preceding items, wherein the composition is naphthyl, quinolinyl, isoquinolinyl, quinozalinyl, benzothienyl, benzothiazolyl which may be substituted with -NH2, benzothiadiazolyl which may be substituted with halogen, or thienopyridinyl which may be substituted with halogen. [Item B7] Ra is C 1-6 It is alkylene and R 10 The composition according to any one of the preceding items, wherein the composition is naphthyl, quinolinyl, isoquinolinyl, quinozalinyl, benzothienyl, benzothiazolyl which may be substituted with -NH2, benzothiadiazolyl which may be substituted with halogen, or thienopyridinyl which may be substituted with halogen. [Section B8]R 3 C 1-4 A composition according to any one of the preceding items, wherein the composition is alkyl. [Section B9]R 2 ga-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-6 It is alkylene and R 20 C may be substituted with a halogen. 6-14 A composition according to any one of the preceding claims, which is aryl or heteroaryl. [Section B10]R 7However, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, or C 3-10 Cycloalkyl-C 1-10 It is alkyl, R 1 ga-Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10 These are naphthyl, quinolinyl, isoquinolinyl, quinozalinyl, benzothienyl, benzothiazolyl (which may be substituted with -NH2), benzothiadiazolyl (which may be substituted with halogen), R 3 C 1-4 It is alkyl, R 2 ga-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-6 It is alkylene, R 20 C may be substituted with a halogen. 6-14 A composition according to any one of the preceding claims, wherein the composition is aryl or heteroaryl. [Section B11]R 7 but, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 3-10 Cycloalkyl-C 1-10 It is alkyl; R 1 ga-Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10These are naphthyl, quinolinyl, isoquinolinyl, quinozalinyl, benzothienyl, benzothiazolyl (which may be substituted with -NH2), benzothiadiazolyl (which may be substituted with halogen), R 3 C 1-4 It is alkyl, R 2 ga-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-6 It is alkylene, R 20 C may be substituted with a halogen. 6-14 A composition according to any one of the preceding claims, wherein the composition is aryl or heteroaryl. [Item B12] The compound is, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalene-1-ylmethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxamide, (6S,9S)-8-((2-aminobenzo[d]thiazole-4-yl)methyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl phosphate sodium, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(naphthalene-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl phosphate sodium, (6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N-((R)-1-phenylethyl)-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N-((S)-1-phenylethyl)-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxy-2,6-dimethylbenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-8-(benzo[b]thiophen-3-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-8-(benzo[c][1,2,5]thiadiazole-4-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-8-(isoquinoline-5-ylmethyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-8-((5-chlorothieno[3,2-b]pyridine-3-yl)methyl)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinozalin-5-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-N-(thiophene-2-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide(C82), and 4-{[(6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl]methyl}phenoxy)phosphate (OK-1) A composition selected from any one of the preceding items. [Item B13] The composition according to any one of the preceding items, wherein the compound is (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide. [Item B14] The composition according to any one of the preceding items, wherein the compound is 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate. [Section B15]R 7 However, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 It is alkyl, G is -NR 6 -, or -O-(where R 6 C 1-6 Alkyl and C 2-6(They are chosen independently of Alkenil.) R 1 However, -Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10 (This is a condensed bicyclic heteroaryl which may be substituted with substituents selected from naphthyl or -NH2 and halogens.) R 2 ga-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C may be substituted with a halogen. 6-14 (It is an aryl or heteroaryl) and R 3 However, C 1-6 A composition according to any one of the preceding items, wherein the composition is alkyl. [Item BA1] Use in the manufacture of a pharmaceutical product for the regulation, delaying progression, prevention or treatment of sarcopenia-related diseases, disorders or symptoms, comprising a compound or pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is of general formula (I) [ka] Compound represented by [wherein A is -CHR] 7 -(Here, R 7 OH, -OR 8 (Here, R 8 C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 alkyl, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C3-10 Cycloalkyl-C 1-10 Alkyl, C 6-14 Aryl, or C 3-10 It is a cycloalkyl, G is -NR 6 -, or -O-(where R 6 C 1-10 Alkyl and C 2-10 (They are chosen independently of Alkenil.) R 1 is -Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10 (This is a condensed bicyclic heteroaryl which may be substituted with substituents selected from naphthyl or -NH2 and halogens.) R 2 Ha-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -O- or -NH-, and Rb is a bond or C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C 1-10 C may be substituted with alkyl or halogen compounds. 6-14 Aryl, heteroaryl, or C 3-10 It is a cycloalkyl and R 3 C 1-10 It is alkyl, The term "heteroaryl" means a 5- to 14-membered monocyclic or polycyclic aromatic group in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon. [Section BA2] Uses described in paragraph BA1, including one or more features described in any one or more preceding paragraphs. [Item BB1] A method for modulating, delaying the progression of, preventing or treating a sarcopenia-related disease, disorder, or symptom in a subject, comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is of general formula (I) [ka] Compound represented by [wherein A is -CHR] 7 -(Here, R 7 OH, -OR 8 (Here, R 8 C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 alkyl, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 3-10 Cycloalkyl-C 1-10 Alkyl, C 6-14 Aryl, or C 3-10 It is a cycloalkyl, G is -NR 6 -, or -O-(where R 6 C 1-10 Alkyl and C 2-10 (They are chosen independently of Alkenil.) R 1 is -Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10 is naphthyl or It is a condensed bicyclic heteroaryl (which may be substituted with substituents selected from -NH2 and halogens), R 2 Ha-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22is -O- or -NH-, and Rb is a bond or C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C 1-10 C may be substituted with alkyl or halogen compounds. 6-14 Aryl, heteroaryl, or C 3-10 It is a cycloalkyl and R 3 C 1-10 It is alkyl, A method in which "heteroaryl" means a 5 to 14-membered monocyclic or polycyclic aromatic group in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon. [Section BB2] The method according to item BB1, comprising one or more features described in any one or more preceding items. [Item BC1] Compounds or pharmaceutically acceptable salts thereof, or solvates thereof, for the regulation, delaying progression, prevention or treatment of sarcopenia-related diseases, disorders or symptoms, wherein the compound is of general formula (I) [ka] Compound represented by [wherein A is -CHR] 7 -(Here, R 7 OH, -OR 8 (Here, R 8 C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 alkyl, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 3-10 Cycloalkyl-C 1-10 Alkyl, C 6-14 Aryl, or C 3-10 It is a cycloalkyl, G is -NR 6 -, or -O-(where R 6 C 1-10 Alkyl and C 2-10 (They are chosen independently of Alkenil.) R 1 is -Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10 (This is a condensed bicyclic heteroaryl which may be substituted with substituents selected from naphthyl or -NH2 and halogens.) R 2 Ha-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -O- or -NH-, and Rb is a bond or C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C 1-10 C may be substituted with alkyl or halogen compounds. 6-14 Aryl, heteroaryl, or C 3-10 It is a cycloalkyl and R 3 C 1-10 It is alkyl, "Heteroaryl" means a compound or pharmaceutically acceptable salt thereof, or a solvate thereof, in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon, forming a 5 to 14-membered monocyclic or polycyclic aromatic group. [Section BC2] A compound described in item BC1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, comprising one or more characteristics described in any of the preceding items. [Term ZZ] The aforementioned compound, substance, or factor is OK1 [ka] Or C-82 [ka] Alternatively, any composition, method, use, medicine, compound, or pharmaceutically acceptable salt thereof or solvates thereof as described in any one of the above items, including a pharmaceutically acceptable salt thereof or a solvate thereof.

[0009] In this disclosure, the one or more of the above features are intended to be provided in combinations other than those explicitly stated. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary. [Effects of the Invention]

[0010] This disclosure provides a technology that can treat or prevent sarcopenia and related diseases, disorders, and symptoms for the first time. This disclosure also provides a technology that can treat or prevent age-related diseases, disorders, and symptoms for the first time. [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 shows the improvement of sarcopenia with OK-1 administration. A shows the endurance (muscle strength) of young mice (15 weeks old) and aged mice (79 weeks old) measured using a treadmill. The effects of administering PBS (control) or OK-1 for 3 months were also examined. B shows the muscle mass of aged mice administered PBS (control) or OK-1, after exercising on a treadmill for 3 weeks, quantified using MRI. [Figure 2-1] Figure 2 shows the gene regulation in the muscles of mice that were administered OK-1 but not subjected to exercise. (A) shows the genes whose expression was increased (206 genes) and decreased (445 genes) after OK-1 administration (p<0.05), and (B) shows the pathway analysis diagram of the genes whose expression was increased. [Figure 2-2]Figure 2 shows the gene regulation in the muscles of mice that were administered OK-1 but not subjected to exercise. (C) shows the pathway analysis of genes whose expression was reduced. [Figure 2-3] Figure 2 shows the gene regulation in the muscles of mice that were administered OK-1 but not subjected to exercise. D) shows the upstream transcription factor analysis of genes in which changes in gene expression were observed. [Figure 3] Figure 3 shows the results of GSEA analysis of gene expression changes in the muscles of mice that were administered OK-1 but not subjected to exercise. (A) shows the pathways in which gene expression increased in the muscles due to OK-1 administration, and (B) shows the pathways in which gene expression decreased in the muscles due to OK-1 administration. [Figure 4-1] Figure 4 shows the top 50 genes whose gene expression was altered in the muscles of mice that were administered OK-1 but did not exercise. [Figure 4-2] Figure 4 shows the top 50 genes whose gene expression was altered in the muscles of mice that were administered OK-1 but did not exercise. [Figure 5-1] Figure 5 shows the gene regulation in the muscles of mice administered OK-1 and subjected to exercise. (A) shows the genes whose expression was increased (145 genes) and decreased (631 genes) after OK-1 administration (p<0.05), and (B) shows the pathway analysis diagram of the genes whose expression was increased. [Figure 5-2] Figure 5 shows the gene regulation in the muscles of mice administered OK-1 and subjected to exercise. (C) shows the pathway analysis of genes with decreased expression, and (D) shows the upstream transcription factor analysis of genes that showed changes in gene expression. [Figure 6] Figure 6 shows the results of GSEA analysis of changes in gene expression in the muscles of ta mice administered OK-1 and then subjected to exercise. (A) shows the pathway in which gene expression increased in the muscles after OK-1 administration, and (B) shows the pathway in which gene expression decreased in the muscles after OK-1 administration. [Figure 7-1]Figure 7 shows the top 50 genes whose gene expression was altered in the muscles of mice that were administered OK-1 and then exercised. [Figure 7-2] Figure 7 shows the top 50 genes whose gene expression was altered in the muscles of mice that were administered OK-1 and then exercised. [Figure 8-1] Figure 8 shows a list of related diseases registered in MedlinePlus that correlate with gene expression changes due to OK-1 treatment. [Figure 8-2] Figure 8 shows a list of related diseases registered in MedlinePlus that correlate with gene expression changes due to OK-1 treatment. [Figure 9] Figure 7 shows the top 50 genes whose gene expression was altered in the muscles of mice that were administered OK-1 and then exercised. [Figure 10A] Figure 10A shows that 581 genes increased and 611 genes significantly decreased in myoblasts treated with C-82. [Figure 10B] Figure 10B shows the top 30 genes whose gene expression was altered by C-82 treatment. [Figure 10C] Figure 10C shows the categorization of biological functions (GOs) associated with genes whose gene expression increased due to C-82 treatment. [Figure 10D] Figure 10D shows the categorization of biological functions (GOs) associated with genes whose gene expression was reduced by C-82 treatment. [Figure 10E] Figure 10E shows a ranking of upstream transcription factors for genes whose gene expression was altered by C-82 treatment. [Figure 11] Figure 11 shows the changes in muscle strength (endurance) and grip strength in mice administered C-82. Compared to unadministered mice, C-82-administered mice showed a significant increase in muscle strength (endurance). While no statistically significant difference was observed in grip strength, a concentration-dependent increasing trend was seen. [Modes for carrying out the invention]

[0012] The present disclosure is described below in best form. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (e.g., "a," "an," "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0013] The following provides definitions of terms used specifically in this specification and / or basic technical concepts as appropriate.

[0014] (Definition of terms) In this specification, "sarcopenia" refers to a condition diagnosed when, in addition to evidence of 1. low muscle mass, 2. low muscle strength or 3. low physical function is also present (European Working Group on Sarcopenia in Older People (EWGSOP)). Since the skeletal structures of Caucasians and Asians differ, the AWGS (ASIAN working group FOR SARCOPENIA) in 2014 created diagnostic criteria specific to Asians that can also be applied to the physique of Japanese people (Sportsmedicine 27(9), 2-11, 2015-11, Bookhouse HD). Sarcopenia is classified into "primary sarcopenia," which is caused by aging, and "secondary sarcopenia," which has causes other than aging. Besides aging, muscle weakness can also be caused by daily living activities, diseases, and nutritional status. This includes disuse due to being bedridden or having reduced activity, diseases such as cancer, ischemic heart failure, end-stage renal failure, and endocrine disorders, malabsorption of nutrients, loss of appetite due to gastrointestinal diseases or drug side effects, insufficient energy and protein intake, and other causes such as decreased or lost activity due to neurodegeneration (e.g., ALS). Muscle weakness refers to a decrease in muscle mass due to aging or disease, resulting in a decline in muscle strength throughout the body, including grip strength, lower limb muscles, and trunk muscles. As a result, physical function declines, such as walking speed slowing down and the need for canes or handrails.

[0015] Muscles possess not only the function of "muscle strength" but also the elements of "energy metabolism" and "secretory organs." When muscle mass or muscle function decreases, from the perspective of "muscle strength," the function of internal organs such as the heart and respiratory system declines, and in the joints, the burden on the bones increases, leading to arthritis. From the perspective of "energy metabolism," a decrease in muscle mass makes it impossible to use fats and sugars in the blood, leading to obesity. Furthermore, the inability to metabolize fat can lead to metabolic diseases such as myocardial infarction. NAMPT synthesizes NAD from NMN in muscles. If NAD decreases, brain function and metabolic function decline. From the perspective of "secretory organs," muscles secrete inflammatory substances such as IL-6 and growth factors such as insulin-like growth factor 1 (IGF-1) and BDNF, which affect cancer, bone, nerves, and blood cell proliferation. (See Hoffmann C, Weigert C. Skeletal Muscle as an Endocrine Organ: The Role of Myokines in Exercise Adaptations. Cold Spring Harb Perspect Med. 2017;7(11):a029793. Published 2017 Nov 1. doi:10.1101 / cshperspect.a029793) The importance of treating sarcopenia lies not only in the recovery of muscle strength, but also in the recovery of muscles as metabolic and secretory organs, and in addressing systemic aging. Therefore, it can be said that patients with sarcopenia are prone to a wide range of diseases.

[0016] Muscle mass is maintained by the repeated synthesis and breakdown of muscle protein. Muscle mass decreases when factors necessary for muscle protein synthesis decrease, or when muscle protein breakdown exceeds muscle protein synthesis. Sarcopenia develops as a result of a combination of factors: a decrease in sex hormones related to muscle growth, apoptosis (programmed cell death) of cells necessary for muscle function, and mitochondrial dysfunction due to aging, along with disuse, malnutrition, and muscle atrophy (cachexia) due to wasting diseases such as cancer and diabetes. Sarcopenia can also occur due to the loss of motor neurons that transmit signals from the brain to the muscles, and the influence of hormones related to muscle growth, such as corticosteroids, growth hormone (GH), insulin-like growth factor 1 (IGF-1), thyroid dysfunction, and insulin resistance. It is also thought that an increase in inflammatory cytokines due to various diseases, which leads to accelerated muscle protein breakdown, contributes to the development of sarcopenia.

[0017] In this specification, “sarcopenia-related disorders, conditions, or symptoms” means disorders, conditions, or symptoms associated with sarcopenia and one or more of the characteristic sarcopenic conditions of muscle weakness, impaired energy metabolism, and impaired endocrine organs. Sarcopenia-related disorders, conditions, or symptoms can be discussed separately as disorders, conditions, or symptoms resulting from muscle weakness; disorders, conditions, or symptoms resulting from impaired energy metabolism; and disorders, conditions, or symptoms resulting from impaired endocrine organs (however, there may be disorders, conditions, or symptoms that fall into more than one of these categories), and these are considered to be comprehensive. Sarcopenia-related disorders, conditions, or symptoms can also be discussed as primary sarcopenia, secondary sarcopenia, and the disorders, conditions, or symptoms associated therewith. Sarcopenia-related diseases, disorders, or symptoms include, but are not limited to, lifestyle-related diseases (non-wasting diseases), wasting diseases, tumor-related diseases (including cancer cachexia), musculoskeletal disorders, neurodegenerative diseases (including ALS), cognitive impairment, and other related disorders (defined as including malnutrition, frailty, spinal and lung injury, inactivity, decreased activity, disuse syndrome, and invasive injuries such as trauma and surgery).

[0018] In this specification, "aging-related diseases, disorders, or symptoms" or "age-related diseases, disorders, or symptoms" are interchangeable and refer to diseases, disorders, or symptoms that develop in connection with aging. Examples of aging-related diseases, disorders, or symptoms include sarcopenia, lifestyle-related diseases (non-debilitating diseases), debilitating diseases, musculoskeletal disorders, neurodegenerative diseases, cognitive impairment, and other related disorders. More specifically, examples include sarcopenia, dementia, metabolic diseases, rheumatoid arthritis, osteoporosis, and decreased muscle mass.

[0019] In this specification, "diseases, disorders, or symptoms resulting from muscle weakness" refers to any disease, disorder, or symptom related to a decrease in muscle mass or a decrease in muscle quality (muscle function). For example, this includes diseases, disorders, or symptoms such as a decrease in the function of internal organs such as the heart and respiratory system from the perspective of "muscle strength," and arthritis due to increased stress on the bones in the joints. Examples of diseases, disorders, or symptoms resulting from muscle weakness include neurogenic muscle atrophy, myogenic muscle atrophy (muscular dystrophy, congenital myopathy, mitochondrial encephalomyopathy, myopathy due to congenital metabolic disorders, etc.), dysphagia, chronic respiratory failure, excretory disorders (urinary incontinence, fecal incontinence, etc.), essential hypotension, hyperopia, ptosis, etc.

[0020] In this specification, "diseases, disorders, or symptoms resulting from impaired energy metabolism" refers to any disease, disorder, or symptom resulting from impaired energy metabolism. Muscle loss leads to an inability to utilize blood fats and sugars, resulting in obesity, or the inability to metabolize fat can lead to metabolic diseases such as myocardial infarction. NAMPT synthesizes NAD from NMN in muscles. A decrease in NAD leads to a decline in brain function, metabolic function, etc., and any disease resulting from such function can be listed as a disease, disorder, or symptom resulting from impaired energy metabolism in relation to sarcopenia. Examples of diseases, disorders, or symptoms resulting from impaired energy metabolism include diabetes, dyslipidemia, obesity, metabolic syndrome, osteoporosis, fatty liver, hyperuricemia, and hypertension.

[0021] In this specification, “disease, disorder, or symptom resulting from a disorder of an endocrine organ” means any disease, disorder, or symptom related to a disorder of the muscle as an endocrine organ that secretes or produces substances from the muscle. Muscles secrete inflammatory substances such as IL-6 and growth factors such as insulin-like growth factor 1 (IGF-1) and BDNF, which affect cancer, bone, nerves, and hematopoietic proliferation (Hoffmann C, Weigert C. Skeletal Muscle as an Endocrine Organ: The Role of Myokines in Exercise Adaptations. Cold Spring Harb Perspect Med. 2017;7(11):a029793. Published 2017 Nov 1. doi:10.1101 / cshperspect.a029793 = https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC5666622 / ). A disorder of this function as an endocrine organ results in a disease, disorder, or symptom. These are all related to diseases, disorders, or symptoms caused by dysfunction of the secretory organs. Examples of diseases, disorders, or symptoms caused by dysfunction of the secretory organs include diabetes, pancreatitis, ulcerative colitis, and diarrhea.

[0022] In this specification, "disease, disorder, or symptom resulting from a disorder of the nervous system" means any disease, disorder, or symptom related to a disorder of nerves associated with muscles. Muscles contract in response to signals from the nervous system, and there is a close relationship between muscles and nerves. When this function of the nervous system is impaired, diseases, disorders, or symptoms occur. Those related to these are included in diseases, disorders, or symptoms resulting from disorders of endocrine organs. Examples of diseases, disorders, or symptoms resulting from disorders of the nervous system include neurodegenerative diseases (including ALS) and cognitive impairments.

[0023] In this specification, "primary sarcopenia" refers to sarcopenia that has no obvious cause other than aging.

[0024] In this specification, "secondary sarcopenia" refers to sarcopenia caused by factors other than aging, and includes activity-related sarcopenia (which may be caused by being bedridden, having an inactive lifestyle, or being in a weightless state), disease-related sarcopenia (which may be associated with severe organ failure (heart, lungs, liver, kidneys, brain), inflammatory diseases, malignant tumors, or endocrine diseases), and nutrition-related sarcopenia (which may be caused by insufficient energy and / or protein intake due to malabsorption, gastrointestinal diseases, or the use of drugs that cause loss of appetite).

[0025] In this specification, "OK-1" means [ka] Its chemical name is 4-{[(6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl]methyl}phenoxy)phosphate, or also known as 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-2H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate.

[0026] In this specification, "C-82" means, [ka] Its chemical name is (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

[0027] In this specification, “OK-1 related compounds” means compounds related to compound group [1] to [9], pharmaceutically acceptable salts thereof, or solvates thereof, and is defined otherwise in this specification.

[0028] In this disclosure, when a compound is referred to, it is understood that this includes enantiomers of that compound.

[0029] In this specification, “medically acceptable salt” or “pharmaceutically acceptable salt” means an acid addition salt and a base addition salt that is permitted for pharmaceutically acceptable use. Specific examples of “pharmaceutically acceptable salts” include acetate, propionate, butyrate, formate, trifluoroacetate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethyl succinate, malonate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, benzenesulfonic acid, p-toluenesulfonate (tosylate), lauryl sulfate, malate, ascorbate, mandelate, saccharinate, xinafoate, pamoate, and ke Examples of acid addition salts include, but are not limited to, arsenate, adipine, cysteine, N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate, acrylic acid polymer salt, and carboxyvinyl polymer; inorganic base addition salts such as lithium salt, sodium salt, potassium salt, and calcium salt; organic base addition salts such as morpholine and piperidine; and addition salts with amino acids such as aspartic acid and glutamic acid.

[0030] In this specification, the term "solvate" means a compound further comprising a stoichiometric or nonstoichiometric amount of solvent bonded by non-covalent intermolecular forces. If the solvent is water, the solvate is a hydrate.

[0031] In this specification, the term “stereoisomer” encompasses all enantiomerically / stereoisomerically pure and enantiomerically concentrated compounds of the compounds provided herein. An enantiomer is a stereoisomer of a compound having one chiral center. It is understood that the compounds of this disclosure may include any corresponding stereoisomer.

[0032] The scope of this disclosure also includes prodrugs of the compounds disclosed herein. In this disclosure, a prodrug is a derivative that, in vivo, is degraded, for example, by acid hydrolysis or enzymatically, to yield the compounds described herein. For example, if the compounds described herein have a hydroxyl group, an amino group, or a carboxyl group, these groups can be modified according to conventional methods to produce prodrugs. The technology of prodrugs is described, for example, in CG Wermuth, “The Practice of Medicinal Chemistry”, 4th Ed., Academic Press, (2015), Chapter 28. Therefore, the compounds of this disclosure may also be provided as prodrugs, and the compositions of this disclosure may be in a form that includes prodrugs of the compounds of this disclosure.

[0033] The term “prodrug” is intended to encompass compounds that, under physiological conditions, are converted into therapeutic agents of the present disclosure (e.g., compounds of formula I). ​​A common method for preparing a prodrug is to include one or more selected moieties that expose a desired molecule by hydrolysis under physiological conditions. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present disclosure. In certain embodiments, a portion of the formulations described above or a compound of the present disclosure may be replaced with a corresponding suitable prodrug, for example, where the hydroxyl group in the parent compound is given as an ester or carbonate, or the carboxylic acid present in the parent compound is given as an ester.

[0034] In this specification, "exercise therapy" refers to therapy through exercise. Furthermore, non-pharmacological interventions for sarcopenia include exercise and dietary therapy such as vitamin D and omega-3 fatty acids.

[0035] In this specification, "dietary therapy" refers to therapy through diet. Furthermore, non-pharmacological interventions for sarcopenia include exercise and dietary therapy such as vitamin D and omega-3 fatty acids.

[0036] In this specification, "other drug therapies" refers to drug therapies other than those using the "OK-1 related compounds" disclosed herein. When multiple OK-1 related compounds are used, it is not referred to as "other drug therapies," but rather as when multiple compounds, etc., of this disclosure are used.

[0037] In this specification, "prevention" means the act of administering the active ingredient of this disclosure to a healthy person who has not developed a disease, for example, with the aim of preventing the onset of a disease.

[0038] In this specification, “treatment” means the act of administering the active ingredient of this disclosure to a person (patient) who has been diagnosed by a physician with a disease.

[0039] In this specification, "modulation" means that the condition of a subject suffering from a disease (e.g., sarcopenia-related disease, disorder, or symptoms) is altered, preferably improved, when the compound is administered, compared to when the compound is not administered.

[0040] In this specification, "inhibition of progression" means that the degree of the disease, etc. (e.g., sarcopenia-related disease, disability, or symptoms) in a subject who has developed the disease does not worsen, and preferably improves.

[0041] In this specification, “kit” means a unit in which the components to be provided (e.g., compounds, pharmaceuticals, compositions, etc., and instructions, etc.) are provided, usually divided into two or more compartments. This kit form is preferred when the purpose is to provide a composition that should not be provided mixed for stability or other reasons, but is preferably mixed immediately before use. Alternatively, this kit is also preferred when provided as a companion drug in combination with a drug for pre-identifying the patient. Such a kit is preferably advantageous to include instructions or a manual describing how to use the provided components or how to dispose of the reagents or waste liquids after use. When a kit is used as a pharmaceutical kit in this specification, the kit usually includes instructions describing how to administer the pharmaceutical, etc.

[0042] In this specification, “Instructions” are instructions for the user on how to use the Disclosure. These instructions contain language that directs the use (e.g., administration) of the compounds etc. of the Disclosure. If necessary, these instructions will be prepared in accordance with the format prescribed by the supervisory authority of the country where the Disclosure is implemented (e.g., the Ministry of Health, Labour and Welfare or the Ministry of Agriculture, Forestry and Fisheries in Japan, or the Food and Drug Administration (FDA) or the Department of Agriculture (USDA) in the United States) and will be clearly indicated as having been approved by that supervisory authority. Instructions may, but are not limited to, be provided in paper form, and may also be provided in electronic form, for example (e.g., a homepage provided on the Internet, email).

[0043] (Description of the compound) The OK-1 related compounds used in this disclosure include the compound groups [1] to [9] described below. Although we do not wish to be bound by theory, the compound groups [2] to [9] were developed to have similar functions to the compound group [1], and those skilled in the art will understand that in this disclosure as well, they have similar functions to the compound group [1] represented by OK-1. Compound group [1] Compounds used in one aspect of this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, may be compound group [1], which is described in Japanese Patent 5530427, the contents of which are incorporated herein by reference, for example, the following general formula (I) [ka] Compound represented by [wherein A is -CHR] 7 -(Here, R 7 (is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl), G is -NH-, -NR 6 -, -O-, -CHR 6 -or -C(R 6 )2-(Here, R 6 (which is independently selected from optionally substituted alkyls, optionally substituted alkenyls, and optionally substituted alkynyls), R 1 This is an arylalkyl as needed, an arylalkyl as needed, an arylalkyl as needed, an cycloalkylalkyl as needed, or an hydroxylalkyl as needed. R 2 Ha-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- or -(SO2)-, W 22 These are bonded, -O-, -NH-, or optionally substituted lower alkylenes. Rb is a lower alkylene that is bound or optionally substituted, and R 20 (which is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl), and R 3 [This is an alkyl, alkenyl, or alkynyl that is substituted as needed.] Alternatively, it may be a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0044] In one embodiment, A is -CHR 7 -(Here, R 7 (is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl).

[0045] Examples of alkyl groups that may be substituted as needed include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0046] Examples of alkenyl groups include ethenyl, allyl, 1-propenyl, and 2-methylallyl.

[0047] Examples of alkynyl groups include 1-propynyl and ethynyl.

[0048] Examples of aryl and heteroaryl compounds include biphenyl, phenyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0049] Examples of cycloalkyls and optionally substituted heterocycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0050] In other embodiments, A is -CHR 7 -(Here, R 7 This is an optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl, each having the formula -Rc-R 70 (Here, Rc is a lower alkylene that is bonded or optionally substituted, and R 70It is represented by (which is an aryl, which is a heteroaryl, which is a heterocycloalkyl, which is a heterocycloalkyl, which is a heterocycloalkyl, which is a substituted aryl, which is a heteroaryl, which is a substituted aryl, which is a heteroaryl, which is a substituted aryl, which is a heterocycloalkyl, which is a substituted aryl

[0051] Examples of lower alkylene groups include methylene, ethylene, methylmethylene, 1,2-propylene, 1,3-propylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 1,2,3-propanetriyl, and 1,3,3-propanetriyl.

[0052] Examples of aryl and heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0053] Examples of cycloalkyl groups and optionally substituted heterocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0054] In a particular embodiment of formula (I), R in the above-described embodiment is 70 These are aryl and heteroaryl substituted as needed.

[0055] Examples of aryl and heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0056] Preferred examples of aryl and heteroaryl groups include phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, and benzothienyl.

[0057] The most preferred example of an allyl group is phenyl.

[0058] R 7 Examples of substituents for this include -R 8 -OH, -OR 8 ,-OC(O)R 8 -OC(O)OR 8 -COOH, -COOR 8 -CONH2, -CONHR 8 ,-CONR 8 R 4 -NH2, -NHR 8 , -NR 8 R 4 -SH, -SR 8 , -SO2R 8 -SO2NH2, -SO2NHR 8 -SO2NR 8 R 4 -SO3H, -SOR 8 、-NHC(NH2)(=NH), -NHC(NHR 8 )(=NR 4 ), -OP(=O)(OH)2, -OP(=O)(ONa)2, -OP(=O)(OR 8 )2, -OP(=O)(OR 8 )(OH), -OP(=O)(OH)-OP(=O)(OH)2, -OP(=O)(ONa)-O-OP(=O)(ONa) 2、 -CN, -NO2 and halogens (where R 8 and R 4 These can be independently selected from linear or branched chains, cyclic or acyclic structures, substituted or unsubstituted structures, alkyl chains, aryl and arylalkyl moieties.

[0059] Preferred examples of the substituent include -OH, -COOH, and -OC(O)R 8 -OC(O)OR 8 -NH2, -SH, -SO3H, -SOR 8 、 -OP(=O)(OH)2, -OP(=O)(OR 8 )2, -OP(=O)(OR 8 )(OH), -OP(=O)(ONa) 2、 Examples include -OP(=O)(OH)-OP(=O)(OH)2, -OP(=O)(ONa)-O-OP(=O)(ONa)2, and halogens.

[0060] The most preferred examples of such substituents include -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and halogens.

[0061] In one embodiment, G is -NH-, -NR 6 -, -O-, -CHR 6 -or -C(R 6 )2-(Here, R 6 (which is independently selected from optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl).

[0062] G is preferably -NH-, -NR6 - or -O-, more preferably -NR 6 - is

[0063] Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 Alkyl compounds are examples.

[0064] Examples of alkenyl groups include ethenyl, allyl, 1-propenyl, and 2-methylallyl.

[0065] Examples of alkynyl groups include 1-propynyl and ethynyl.

[0066] R 6 The element is preferably an optionally substituted alkyl or optionally substituted alkenyl, more preferably a lower alkyl (e.g., methyl) or lower alkenyl (e.g., allyl).

[0067] In one embodiment, R 1 is an optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl, each having the formula -Ra-R 10 (Here, Ra is a lower alkylene that is bonded or optionally substituted, and R 10 (wherein it is an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl that is substituted as needed.)

[0068] In other embodiments, R 1 is an optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl, each having the formula -Ra-R 10(Here, Ra is a lower alkylene that is bonded or optionally substituted, and R 10 (wherein it is a fused bicyclic aryl or a fused bicyclic heteroaryl, which is substituted as needed.)

[0069] Examples of lower alkylene groups include methylene, ethylene, methylmethylene, 1,2-propylene, 1,3-propylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 1,2,3-propanetriyl, and 1,3,3-propanetriyl.

[0070] Examples of aryl and heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0071] Examples of cycloalkyl and heterocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0072] In a particular embodiment of formula (I), Ra in the above embodiment is a lower alkylene which is substituted as needed, and R 10 These are aryl and heteroaryl substituted as needed.

[0073] Examples of lower alkylene groups include methylene, ethylene, methylmethylene, 1,2-propylene, 1,3-propylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 1,2,3-propanetriyl, and 1,3,3-propanetriyl.

[0074] Examples of aryl and heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0075] Preferred examples of lower alkylene groups include methylene or ethylene.

[0076] Preferred examples of aryl and heteroaryl groups include fused bicyclic aryl groups and fused bicyclic heteroaryl groups such as naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0077] R 1 Examples of substituents for this include -R 8 -OH, -OR8 -COOH, -COOR 8 -CONH2, -CONHR 8 ,-CONR 8 R 4 -NH2, -NHR 8 , -NR 8 R 4 -SH, -SR 8 , -SO2R 8 -SO2NH2, -SO2NHR 8 -SO2NR 8 R 4 -SO3H, -SOR 8 、 -NHC(NH2)(=NH), -NHC(NHR 8 )NR 4 -OP(=O)(OH)2, -OP(=O)(ONa)2, -CN, -NO2 and halogens (where R 8 and R 4 These can be independently selected from linear or branched chains, cyclic or acyclic structures, substituted or unsubstituted structures, alkyl chains, aryl and arylalkyl moieties.

[0078] Preferred examples of the substituent include -NH2, -OH, and -OR. 8 -COOH, -CONH2, -CONHR 8 ,-CONR 8 R 4 , -NHR 8 , -NR 8 R 4 Examples of substituents include -NH2, -OH, -COOH, -CONH2, or halogens.

[0079] In one embodiment, R 2 Ha-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- or -(SO2)-; W 22 R is a bonded, -O-, -NH- or optionally substituted lower alkylene; Rb is a bonded or optionally substituted lower alkylene; and R20 These include alkyl groups that are optionally substituted, alkenyl groups that are optionally substituted, alkynyl groups that are optionally substituted, aryl groups that are optionally substituted, heteroaryl groups that are optionally substituted, cycloalkyl groups that are optionally substituted, and heterocycloalkyl groups that are optionally substituted.

[0080] W 22 Examples of lower alkylene groups include methylene, ethylene, propylene, and butylene.

[0081] Examples of lower alkylene groups for Rb include methylene, ethylene, methylmethylene, 1,2-propylene, 1,3-propylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 1,2,3-propanetriyl, and 1,3,3-propanetriyl.

[0082] Examples of alkyl groups that may be substituted as needed include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, aminomethyl, aminoethyl, aminopropyl, aminobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carbamoylmethyl, carbamoylethyl, carbamoylpropyl, carbamoylbutyl, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methylthiomethyl, methylthioethyl, methylthiopropyl, methylthiobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl.

[0083] Examples of alkenyl groups include ethenyl, allyl, 1-propenyl, and 2-methylallyl.

[0084] Examples of alkynyl groups include 1-propynyl and ethynyl.

[0085] Examples of aryl and heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0086] Examples of cycloalkyl and heterocycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.

[0087] In a particular embodiment of formula (I), R in the above-described embodiment is 2 Ha-W 21 -W 22 -Rb-R 20 , W 21 ha-(CO)-;W 22 -NH-;Rb is a lower alkylene which is substituted as needed, R 20 These are aryl or heteroaryl compounds as needed.

[0088] Examples of lower alkylene groups for Rb include methylene, ethylene, methylmethylene, 1,2-propylene, 1,3-propylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 1,2,3-propanetriyl, and 1,3,3-propanetriyl.

[0089] Examples of aryl and heteroaryl groups include biphenyl, phenyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, imidazolyl, tetrahydronaphthyl, naphthyl, quinolinyl, isoquinolinyl, quinazolinyl, quinozalinyl, sinnolinyl, naphthilidinyl, benzotriazinyl, indenyl, pyridopyrimidinyl, pyridopyradinyl, pyridopyridazinyl, pyridotriazinyl, benzofuryl, benzothienyl, indolyl, indazolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, phlopyridinyl, thienopyridinyl, pyropyridinyl, oxazolopyridinyl, thiazolopyridinyl, and imidazopyridinyl.

[0090] Preferred examples of aryl and heteroaryl groups include monocyclic aryl groups or monocyclic heteroaryl groups such as phenyl, naphthyl, pyridyl, pyrimidyl, pyridadinyl, pyrazinyl, triazinyl, pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, and imidazolyl.

[0091] R 20 Examples of substituents for this include -R 8 -OH, -OR 8 -COOH, -COOR 8 -CONH2, -CONHR 8 ,-CONR 8 R 4 -NH2, -NHR 8 , -NR 8 R 4 -SH, -SR 8 , -SO2R 8 -SO2NH2, -SO2NHR 8 -SO2NR 8 R 4 -SO3H, -SOR 8 、 -NHC(NH2)(=NH), -NHC(NHR 8 )NR 4 -OP(=O)(OH)2, -OP(=O)(ONa)2, -CN, -NO2 and halogens (where R8 and R 4 These can be independently selected from linear or branched chains, cyclic or acyclic structures, substituted or unsubstituted structures, alkyl chains, aryl and arylalkyl moieties.

[0092] Preferred examples of the substituent include -NH2, -OH, and -OR. 8 -COOH, -CONH2, -CONHR 8 ,-CONR 8 R 4 , -NHR 8 , -NR 8 R 4 Examples include halogens.

[0093] In one embodiment, R 3 This is an alkyl group that is substituted as needed, an alkenyl group that is substituted as needed, or an alkynyl group that is substituted as needed.

[0094] Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. 1-4 Alkyl compounds are examples.

[0095] Preferred examples of alkyl groups include methyl and ethyl.

[0096] Examples of alkenyl groups include ethenyl, allyl, 1-propenyl, and 2-methylallyl.

[0097] Examples of alkynyl groups include 1-propynyl and ethynyl.

[0098] R 3 Preferably, C is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. 1-4 It is alkyl, and more preferably methyl or ethyl.

[0099] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, are of the following general formula (I): [ka] This may be a compound represented by or a pharmaceutically acceptable salt thereof, or a solvate thereof, where, A is -CHR 7 -and, R 7 -OH, -OR 8 (Here, R 8 C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 alkyl, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 3-10 Cycloalkyl-C 1-10 Alkyl, C 6-14 Aryl, or C 3-10 It is a cycloalkyl, G is -NR 6 -, or -O- R 6 C 1-10 Alkyl and C 2-10 Chosen independently from Alkenil, R 1 is -Ra-R 10 And, Ra is C 1-6 It is alkylene and R 10 This is a condensed bicyclic heteroaryl which may be substituted with substituents selected from naphthyl or -NH2 and halogens. R 2 Ha-W 21 -W 22 -Rb-R 20 And, W 21 is -(CO)-, W 22 It is -O- or -NH-, Rb is a bond or C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C 1-10 C may be substituted with alkyl or halogen compounds. 6-14 Aryl, heteroaryl, or C 3-10 It is cycloalkyl, R 3 C 1-10 It is alkyl, Here, heteroaryl means a 5 to 14-membered monocyclic or polycyclic aromatic group in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon.

[0100] In one embodiment, A is -CHR 7 - and R 7 -OH, -OR 8 (Here, R 8 C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 alkyl, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 3-10 Cycloalkyl-C 1-10 Alkyl, C 6-14 Aryl, or C 3-10 It is a cycloalkyl group.

[0101] In one embodiment, R 7 However, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10Alkyl, or C 3-10 Cycloalkyl-C 1-10 It is alkyl.

[0102] In one embodiment, G is -NR 6 -, or -O-, R 6 C 1-10 Alkyl and C 2-10 They are chosen independently from Alkenil.

[0103] In one embodiment, R 1 is -Ra-R 10 And Ra is C 1-6 It is alkylene and R 10 This is a condensed bicyclic heteroaryl compound which may be substituted with substituents selected from naphthyl or -NH2 and halogens.

[0104] In one embodiment, Ra is C 1-6 It is alkylene and R 10 However, these are naphthyl, quinolinyl, isoquinolinyl, quinozalinyl, benzothienyl, benzothiazolyl (which may be substituted with -NH2), benzothiadiazolyl (which may be substituted with halogen), or thienopyridinyl (which may be substituted with halogen).

[0105] In one embodiment, R 2 Ha-W 21 -W 22 -Rb-R 20 And W 21 is -(CO)- and W 22 is -O- or -NH-, and Rb is a bond or C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C 1-10 C may be substituted with alkyl or halogen compounds. 6-14 Aryl, heteroaryl, or C 3-10 It is a cycloalkyl group.

[0106] In one embodiment, R 3 C 1-10 It is alkyl.

[0107] In one embodiment, R 2 ga-W 21 -W 22 -Rb-R 20 And W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-10 C may be substituted with alkyl. 1-6 It is alkylene; and R 20 C may be substituted with a halogen. 6-14 Aryl, heteroaryl, or C 3-10 It is a cycloalkyl group.

[0108] In one embodiment, R 2 ga-W 21 -W 22 -Rb-R 20 And W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-6 It is alkylene and R 20 C may be substituted with a halogen. 6-14 It is an aryl or heteroaryl compound.

[0109] In one embodiment, R 3 C 1-4 It is alkyl.

[0110] In one embodiment, R 6 C 1-6 Alkyl or C 2-6 It is Alkenil.

[0111] In one embodiment, R 7 However, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, or C 3-10 Cycloalkyl-C 1-10 It is alkyl; R 1 ga-Ra-R 10 And Ra is C 1-6 It is alkylene and R 10 R is naphthyl, quinolinyl, isoquinolinyl, quinozalinyl, benzothienyl, benzothiazolyl (which may be substituted with -NH2), benzothiadiazolyl (which may be substituted with halogen), and 3 C 1-4 It is alkyl, R 2 ga-W 21 -W 22 -Rb-R 20 And W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-6 It is alkylene, R 20 C may be substituted with a halogen. 6-14 It is either aryl or heteroaryl.

[0112] In one embodiment, the compound represented by formula (I) is (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalene-1-ylmethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxamide, (6S,9S)-8-((2-aminobenzo[d]thiazole-4-yl)methyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl phosphate sodium, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(naphthalene-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl phosphate sodium, (6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N-((R)-1-phenylethyl)-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N-((S)-1-phenylethyl)-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxy-2,6-dimethylbenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-8-(benzo[b]thiophen-3-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-8-(benzo[c][1,2,5]thiadiazole-4-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-8-(isoquinoline-5-ylmethyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-8-((5-chlorothieno[3,2-b]pyridine-3-yl)methyl)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinozalin-5-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-N-(thiophene-2-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide(C82), and 4-{[(6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl]methyl}phenoxy)phosphate (OK-1) They are selected from among them.

[0113] In one embodiment, the compound represented by general formula (I) is (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide. In one embodiment, the compound represented by general formula (I) is (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

[0114] In one embodiment, the compound represented by general formula (I) is 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate. In one embodiment, the compound represented by general formula (I) is 4-{[(6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl]methyl}phenoxy)phosphate.

[0115] In one embodiment, R 7 However, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 It is alkyl, and G is -NR 6 -, or -O-, R 6 C 1-6 Alkyl and C 2-6 Selected independently from Alkenil, R 1 However, -Ra-R 10 And Ra is C 1-6 It is alkylene and R 10 R is a condensed bicyclic heteroaryl which may be substituted with substituents selected from naphthyl or -NH2 and halogens, 2 ga-W 21 -W 22 -Rb-R 20 And W 21 is -(CO)- and W 22 is -NH-, and Rb is C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C may be substituted with a halogen. 6-14 It is an aryl or heteroaryl, and R 3 However, C 1-6 It is alkyl.

[0116] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, are exemplified in Japanese Patent No. 5530427, for example, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalene-1-ylmethyl)-4,7-dioxohexahydropyrazino[2,1-c][1,2,4]oxadiazine-1(6H)-carboxamide, (6S,9S)-8-((2-aminobenzo[d]thiazole-4-yl)methyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-N-benzyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-8-(naphthalene-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate, 4-(((6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl phosphate sodium, (6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N-((R)-1-phenylethyl)-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-2-allyl-6-(4-hydroxybenzyl)-9-methyl-4,7-dioxo-N-((S)-1-phenylethyl)-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxy-2,6-dimethylbenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-8-(benzo[b]thiophen-3-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-8-(benzo[c][1,2,5]thiadiazole-4-ylmethyl)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-8-(isoquinoline-5-ylmethyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-8-((5-chlorothieno[3,2-b]pyridine-3-yl)methyl)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxooctahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinozalin-5-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-N-(thiophene-2-ylmethyl)octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9S)-N-benzyl-6-(4-hydroxybenzyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide(C82), or 4-{[(6S,9S)-1-(benzylcarbamoyl)-2,9-dimethyl-4,7-dioxo-8-(quinoline-8-ylmethyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl]methyl}phenoxy)phosphate (OK-1) Alternatively, it may be a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0117] Compound group [2] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, may be from compound group [2], which is described in JP 2012-505153, the contents of which are incorporated herein by reference, for example, The following general formula: [ka] It may be a compound represented by or a pharmaceutically acceptable salt thereof, or a solvate thereof, in which, A J ha-(CHR 7J )- (Here, R 7J (is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl) B J and E J These are, either identical or different, independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl and optionally substituted alkynyl, or, as indicated by the dotted line, optionally substituted spiro rings, G J -NH-, -NR J6 -, -O-, -CH2-, -CHR 6J -or -C(R 6J )2- (Here, R 6J Each of these is independently selected from alkyls, alkenyls, and alkynyls, which are either identical or different and optionally substituted. R 1JThese are optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl. R 2J Ha-W 21J -W 22J -Rb J -R 20J (Here, W 21J is -(CO)- or -(SO2)-, W 22J These are bonded, -O-, -NH-, or optionally substituted lower alkylenes. Rb J is a lower alkylene that is bonded or optionally substituted, and R 20J (which is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl), and R 3J This is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl, however, 1) Rb J In the case of lower alkylenes which are substituted as needed, W 22J It must be -O- or -NH-, 2) E J and B J If R is hydrogen, 3J It must be hydrogen, 3) G J -NH-, -CH2-, -CHR 6J - or -NR 6J - In the case of B J and E J It must not be hydrogen, and, 4) GJ ga -O-, B J and E J is hydrogen, R 3J If R is hydrogen, 1J It must not be 8-quinolylmethyl. Here, the various substituents can take the same embodiments as in compound group 1.

[0118] Compound group [3] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, may be from compound group [3], which is described in JP 2012-505153, the contents of which are incorporated herein by reference, for example, General formula (III) [ka] It may be a compound represented by or a pharmaceutically acceptable salt thereof, or a solvate thereof, where A J2 is, -(CHR 7J2 )-(Here, R 7J2 OH, -OR 8J2 (Here, R 8J2 C 6-14 Aryl-C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 Alkyl, C 6-14 C may be substituted with aryl or OH groups. 6-14 Aryl-C 1-10 (It is alkyl) and; B J2 and E J2 is hydrogen; G J2 is -O-; R 1J2 These are OH, -COOH, and -COOR 8J2 '(Here, R 8J2 ' is C 1-10 C may be substituted with substituents selected from (representing alkyl). 1-10 Alkyl, C 6-14 Aryl-C 1-10heteroaryl-C optionally substituted with alkyl, -NH2 1-10 alkyl, or C 3-10 cycloalkyl-C 1-10 is alkyl; R 2J2 is -W 21J2 -W 22J2 -Rb J2 -R 20J2 (wherein, W 21J2 is -(CO)- or -(SO2)-; W 22J2 is a bond, -O-, or C 1-6 alkylene; Rb J2 is a bond or C 1-6 alkylene; and R 20J2 is C 1-10 alkyl, C optionally substituted with halogen 6-14 aryl, or heteroaryl); and R 3J2 is hydrogen; "heteroaryl" means a 5- to 1- member monocyclic or polycyclic aromatic group in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon, provided that however, 1) when Rb J2 is C 1-6 alkylene, W 22J2 must be -O-, and 2) R 1J2 must not be 8-quinolylmethyl.[[ID=6ģ]]

[0119] Compound group [4] The compounds or pharmaceutically acceptable salts thereof, or solvates thereof, used in the present disclosure may be compound group [4], which is described in International Publication No. 2012-526042, the content of which is incorporated herein by reference. For example, the following general formula (IV):

Chemical formula

[0120] Compound group [5] The compounds or pharmaceutically acceptable salts thereof, or solvates thereof, used in the present disclosure may be compound group [5], and compound group [5] is described in Patent 5768239, the content of which is incorporated herein by reference. For example, the following general formula (V):

Chemical formula

[0121] Compound group [6] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, may be from the group of compounds [6], which are described in Japanese Patent 6040344, the contents of which are incorporated herein by reference, for example, the following general formula (VI): [ka] It may be a compound represented by or a pharmaceutically acceptable salt thereof, or a solvate thereof, in which, [ka] It is either a single bond or a double bond. A 6 ha-CHR 67 - (Here, R 67(is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl) E 6 ha-CHR 65 -, -O-, or -NR 68 - (Here, R 65 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl, and R 68 (is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl), B 6 It does not exist, or G 6 and Y 6 It is a monocyclic ring formed together with, and substituted as needed, D 6 It does not exist, or Y 6 A spiro ring formed together with, and substituted as needed, however B 6 and D 6 Neither exists. B 6 If G 6 and Y 6 These are independently carbon atoms or nitrogen atoms, D 6 If Y exists, 6 is a carbon atom, and G 6 -NR 66 -, -O-, -CHR 66 -or -C(R66 )2-, B 6 and D 6 If neither exists, G 6 and Y 6 These are either the same or different, and each is -NR 66 -, -O-, -CHR 66 -or -C(R 66 )2- (Here, R 66 Each of these is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. R 61 This is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkylalkyl, or optionally substituted heterocycloalkylalkyl. R 62 Ha-W 621 -W 622 -Rb 6 -R 620 (Here, W 621 is -(CO)- or -(SO2)-, W 622 These are bonded, -O-, -NH-, or optionally substituted lower alkylenes. Rb 6 is an alkylene that is bonded or optionally substituted, and R 620(which is an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl), and R 63 This is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.

[0122] Compound group [7] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, may be from compound group [7], which is described in JP 2008-533155, the contents of which are incorporated herein by reference, for example, the following general formula (VII) [ka] It may be a compound represented by or a pharmaceutically acceptable salt thereof, or a solvate thereof, where A 7 is, -(CHR 73 )-(C=O)- and B 7 is, -(NR 74 )- and D 7 is, -(CHR 75 )- or -(C=O)- and E 7 is, -(ZR 76 )-, -(C=O)-, G 7 is, -(X 7 R 77 ) n7 -,-(CHR 77 )-(NR 78 )-,-(C=O)-(X 7 R 79 )-, or -(C=O)-, W 7 is, -Y 7 (C=O)-, -(C=O)NH-, -(SO2)-, or not present, Y 7 is oxygen or sulfur, X 7 and Z 7n7=0 or 1 is independently nitrogen or CH, and R 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , and R 79 The linker is independently selected from the same or different amino acid side chains, derivatives of amino acid side chains, linkers that facilitate linking to another part of the compound or to another compound, linkers that bind the compound to a solid support, and a solid support, and its stereoisomers.

[0123] R in equation (VII) 71 , R 72 , R 73 , R 74 , R 75 , R 76 , R 77 , R 78 , and R 79 is amino C 2-5 Alkyl, Guanidino C 2-5 Alkyl, C 1-4 Alkylguanidino C 2-5 Alkyl, diC 1-4 Alkylguanidino-C 2-5 Alkyl, Amidino C 2-5 Alkyl, C 1-4 Alkylamidino C 2-5 Alkyl, diC 1-4 Alkylamidino C 2-5 Alkyl, C 1-3 Alkoxyl, phenyl, substituted phenyl (substituents include amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 (Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), benzyl, substituted benzyl (substituted on benzyl may be amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 (Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), naphthyl, substituted naphthyl (substituents are amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 (Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), bis-phenylmethyl, substituted bis-phenylmethyl (substituents are amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 (Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), pyridyl, substituted pyridyl, (substituents are amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 (Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), pyridyl C 1-4 Alkyl, substituted pyridyl C 1-4 Alkyl (pyridine substituents include amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3(Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), pyrimidyl C 1-4 Alkyl, substituted pyrimidyl C 1-4 Alkyl (pyrimidine substituents include amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 Alkoxyl (or one or more independently selected from nitro, carboxy, cyano, sulfuryl, or hydroxyl), triazine-2-yl-C 1-4 Alkyl, substituted triazine-2-yl-C 1-4 Alkyl (triazine substituents include amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 (Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), imidazo C 1-4 Alkyl, substituted imidazole C 1-4 Alkyl (imidazole substituents include amino, amidino, guanidino, hydrazino, amidrazonyl, C) 1-4 Alkylamino, C 1-4 Dialkylamino, halogen, perfluoroC 1-4 Alkyl, C 1-4 Alkyl, C 1-3 (Independently selected from one or more of alkoxyl, nitro, carboxyl, cyano, sulfuryl, or hydroxyl), imidazolinyl C 1-4 Alkyl, N-amidinopiperazinyl-NC 0-4 Alkyl, hydroxy C 2-5 Alkyl, C 1-5 Alkylamino C 2-5 Alkyl, hydroxy C 2-5 Alkyl, C 1-5 Alkylamino C2-5 Alkyl, C 1-5 Dialkylamino C 2-5 Alkyl, N-amidinopiperidinyl C 1-4 Alkyl and 4-aminocyclohexyl C 0-2 It is independently selected from the group consisting of alkyl groups.

[0124] Compound group [8] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, may be from the group of compounds [8], which are described in U.S. Patent No. 5929237, which is incorporated herein by reference, for example, the following general formula (VIII) [ka] This may be a compound represented by or a pharmaceutically acceptable salt thereof, or a solvate thereof, where A 8 is, -(CHR 8 ') n8 - and B 8 is, -(CHR 8 ") m8 - where n8 = 0, 1 or 2, and m8 = 1, 2 or 3, where R 8 ', R 8 ", R 81 , R 82 , R 83 , R 84 and R 85 This is the same as defined below. In the above equation (VIII), R 82 , R 83 and R 85 The solid lines indicating the bonding mean that these R groups can be either above or below the plane of this page. If the compound of formula (VIII) is intended to resemble the reverse turn of a naturally occurring amino acid (i.e., "L-amino acid"), then these R groups are generally below the plane of this page in formula (VIII). [ka] ). However, if the compound of formula (VIII) is intended to resemble a reverse turn containing one or more D-amino acids, then the corresponding R group is located above the plane of this page in formula (VIII). [ka] ). In one embodiment, R 81 and R 84 These are either identical or different, representing the remainder of this compound, and R 8 ', R 8 ", R 82 , R 83 and R 85 These are either identical or different, and are independently selected from amino acid side chain moieties or their derivatives. 8 'and R 8 Regarding "R 8 'and R 8 It should be understood that each of the following is independently selected from the amino acid side chain portion or its derivatives. For example, when m8=2, B 8 -CHR 8 "CHR 8 "- is a part. In this case, both R 8 The existence of “ is independently selected, and can be identical or different. Therefore, the first R 8 " is hydrogen, and the second R 8 If " is methyl, then B 8 It has a -CH2CH(CH3)- structure. As used herein, the term “residue of the compound” is used with respect to R 81 and / or R 84 This term refers to any part, reagent, compound, support, molecule, linker, amino acid, peptide, or protein that is covalently bonded to the basic skeletal structure of the compound of formula (VIII) at any of its positions. The term also includes amino acid side chain portions and their derivatives. As used herein, the term “amino acid side chain moiety” refers to any amino acid side chain moiety found in naturally occurring proteins (including, but not limited to, the naturally occurring amino acid side chain moieties identified in Table 1). Other naturally occurring amino acid side chain moieties of this disclosure include, but are not limited to, 3,5-dibromotyrosine, 3,5-diiodotyrosine, hydroxylysine, γ-carboxyglutamate, phosphotyrosine, and phosphoserine. Furthermore, glycosylated amino acid side chains may also be used in the implementation of this disclosure, including, but are not limited to, glycosylated threonine, serine, and asparagine. [Table 1] In addition to naturally occurring amino acid side chain moieties, the amino acid side chain moieties of this disclosure also include various derivatives thereof. As used herein, “derivatives” of amino acid side chain moieties include modifications and / or alterations of naturally occurring amino acid side chain moieties. For example, the amino acid side chain moieties of alanine, valine, leucine, isoleucine, and phenylalanine can generally be classified as lower-chain alkyl, aryl, or aralkyl moieties. Derivatives of amino acid side chain moieties include other linear or branched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated, lower-chain alkyl, aryl, or aralkyl moieties. The term "lower chain alkyl moiety" contains 1 to 12 carbon atoms, the "lower chain aryl moiety" contains 6 to 12 carbon atoms, and the "lower chain aralkyl moiety" contains 7 to 12 carbon atoms. Therefore, in one embodiment, the amino acid side chain derivative is C 1-12 Alkyl, C 6-12 Aryl, and C 7-12 Selected from Aralquil, and in a more preferred embodiment, C 1-7 Alkyl, C 6-10 Aryl, and C 7-11 Selected from Aralquil. The amino acid side-chain derivatives of this disclosure further include derivatives substituted with lower-chain alkyl, aryl, and aralkyl moieties, where the substituent is selected from (but not limited to) one or more of the following chemical moieties: -OH, -OR 88 -COOH, -COOR 88 -CONH2, -NH2, -NHR 88 , -NR 88 R 88 -SH, -SR 88 , -SO2R 88 -SO2H, -SOR 88 , and halogens (including F, Cl, Br, and I), where R 88 Each of these entities is independently selected from the lower-chain alkyl, aryl, or aralkyl moiety. Furthermore, the cyclic lower-chain alkyl, aryl, and aralkyl moieties of this disclosure include naphthalenes and heterocyclic compounds (e.g., thiophenes, pyrroles, furans, imidazoles, oxazoles, thiazoles, pyrazoles, 3-pyrrolines, pyrrolidines, pyridines, pyrimidines, purines, quinolines, isoquinolines, and carbazoles). The amino acid side-chain derivatives further include heteroalkyl derivatives of the alkyl moieties of the lower-chain alkyl and aralkyl moieties, and include (but are not limited to) alkyl and aralkyl phosphonates and silanes. In yet another embodiment, R 81 , R 82 , R 83 , R 84 or R 85 is either an amino acid side chain moiety or a derivative thereof, or R 81 and R 84 In addition to being the remainder of this compound, it may also be a linker that facilitates binding to other parts of this compound or to other compounds. For example, the compounds of this disclosure can be bound to one or more known compounds (e.g., biotin) for use in diagnostic assays or screening assays. Furthermore, R 81 , R 82 , R 83 , R 84 or R 85This R is either a linker that binds the compound to a solid support (e.g., a support used in solid-phase peptide synthesis), or it may be the support itself. In this embodiment, binding to other parts or compounds or binding to the solid support is this R 81 or R 84 Preferably at position R 84 In terms of position, it is even more preferable. In a preferred embodiment, R 85 It is hydrogen. In one embodiment of this disclosure, n8=0, and R 8 " is hydrogen, and R 85 is hydrogen, and the compound of formula (VIII) is the following formula (VIIIa): [ka] It is expressed as, where m8 = 1, 2, or 3, and R 81 , R 82 , R 83 and R 84 This is the same as defined above. In a preferred embodiment, m8 = 1 or 2, and R 81 and R 84 This is the remainder of this compound, and R 82 and R 83 These are individually selected from the amino acid side chain portions. In other embodiments, n8=0, m8=1, and R 8 " is hydrogen, and R 85 is hydrogen, and the compound of formula (VIII) is the following formula (VIIIb): [ka] It is expressed as, where R 81 , R 82 , R 83 and R 84 This is the same as defined above. In a preferred embodiment, R 81 and R 84 This is the remainder of this compound, and R 82 and R 83These are independently selected from the amino acid side chain portions.

[0125] The compounds used in this disclosure are of the following general formula (VIII) [ka] It can be a compound represented by, where A 8 is, -(CHR 8 ') n8 - and B 8 is, -(CHR 8 ") m8 - and n8 is 0, 1 or 2, m8 is 1, 2 or 3, R 8 ', R 8 ", R 82 , R 83 , and R 85 are the same or different, and exist R 8 ', R 8 ", R 82 , R 83 , and R 85 Each of these is independently selected from the group consisting of an amino acid side chain moiety, an amino acid side chain derivative, a linker, and a solid support. R 81 and R 84 R represents the remainder of this compound, where R 81 and R 84 These are either the same or different, and are independently selected from the group consisting of a part, an active substance, a compound, a support, a molecule, a linker, an amino acid, a peptide, and a protein. In one embodiment, R 8 ', R 8 ", R 81 , R 82 , R 83 , R 84 , or R 85 One or fewer of these are solid supports. In one embodiment, R 8 ' is hydrogen. In one embodiment, R 8 " is hydrogen. In one embodiment, n8 = 0. In one embodiment, m8 = 1 or 2. In one embodiment, R 85 It is hydrogen. In a preferred embodiment, n8=0, and R 8 "and R 85 is hydrogen, and the compound has the following structural formula (VIIIa) [ka] It is represented by this formula. In a preferred embodiment, R 82 and R 83 They are the same or different, and are independently selected from the amino acid moiety or its derivatives. In a preferred embodiment, R 84 It is connected to a solid support. In a more preferred embodiment, n8=0, R 8 ", and R 85 is hydrogen, m8=1, and the compound has the following structural formula (VIIIb) [ka] It is represented as follows: In embodiments of the compound of this formula, R 82 and R 83 They are identical or different, independently selected from the amino acid moiety or its derivatives, R 84 It is connected to a solid support.

[0126] The compounds of formula (VIII) used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, are represented by the following formula ICG-001 [ka] This includes derivatives thereof, pharmaceutically acceptable salts thereof, or solvates thereof.

[0127] Compound group [9] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, may be from the group of compounds [9], which are described in Japanese Patent 6085040 (WO2015 / 098853), the contents of which are incorporated herein by reference, for example, the following general formula (IX) [ka] It may be a compound represented by or a pharmaceutically acceptable salt thereof, or a solvate thereof, where R V1 is C 1-6 R means alkyl group. V2 and R V3 These are either identical or distinct, and are either hydrogen atoms or C 1-6 It means alkyl group, X V2 , X V3 and X V4 These represent, respectively, the same or different hydrogen atom or halogen atom, and X V5 This represents a hydrogen atom, -P(=O)(OH)2.

[0128] The compounds used in this disclosure, or pharmaceutically acceptable salts thereof, or solvates thereof, are: (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((3S)-3,4-dimethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((3R)-3,4-dimethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazine-1-yl)azetidine-1-yl)-5-fluoropyridine-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((5-fluoro-6-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-8-((6-(3-(4-(propan-2-yl)piperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-8-((5-fluoro-6-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-8-((6-(3-(4-(propan-2-yl)piperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-8-((6-(3-(4-(propan-2-yl)piperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-ethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-(4-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((2S)-2,4-dimethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3S)-3,4-dimethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((2S)-2,4-dimethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((3S)-4-ethyl-3-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-3-((3R)-4-ethyl-3-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((3S)-4-ethyl-3-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((3R)-4-ethyl-3-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3S)-4-ethyl-3-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-6-((2,6-difluoro-4-hydroxyphenyl)methyl)-8-((6-(3-((3R)-4-ethyl-3-methylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, (6S,9aS)-N-benzyl-8-((6-(3-((3R)-3,4-dimethylpiperazine-1-yl)azetidine-1-yl)-5-fluoropyridine-2-yl)methyl)-6-((4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide, 4-(((6S,9aS)-1-(benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)-3-fluorophenyl dihydrogen phosphate, or, 4-(((6S,9aS)-1-(benzylcarbamoyl)-8-((6-(3-(4-ethylpiperazine-1-yl)azetidine-1-yl)pyridine-2-yl)methyl-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-6-yl)methyl)phenyl dihydrogen phosphate, Alternatively, it may be a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0129] (Method of compound preparation) The methods for producing the compounds disclosed herein are described below, but the methods for producing the compounds disclosed herein are not limited to these. For example, the compounds of this disclosure can be manufactured using the manufacturing methods, conditions, materials, etc. described in Japanese Patent No. 5530427, Japanese Patent Publication No. 2012-505153, Japanese Patent No. 5545573, Japanese Patent Publication No. 2012-526042, Japanese Patent No. 5768239, Japanese Patent No. 6040344, Japanese Patent No. 6085040 (WO2015 / 098853), U.S. Patent No. 5929237, Japanese Patent Publication No. 2008-533155, etc., the descriptions of which are incorporated herein by reference in their entirety.

[0130] The compounds disclosed herein, but are not limited to those described below, can be produced by the following manufacturing methods. These manufacturing methods can be appropriately modified based on the knowledge of a person proficient in organic synthesis chemistry. In the manufacturing methods described below, salts of the compounds may be used as raw materials, provided that they do not interfere with the reaction.

[0131] In the manufacturing method of this disclosure, even if the use of protecting groups is not explicitly stated, if any functional group other than the reaction site changes under the reaction conditions, or if it is unsuitable for post-reaction processing, the target compound can be obtained by protecting the non-reaction site as necessary and deprotecting it after the reaction is complete or after the series of reactions have been carried out. Protecting groups used in these processes are described in the reference (TW Greene and PGM Wuts, “Protective Group in Organic Synthesis”, 3 rd Conventional protecting groups as described in Ed., John Wiley and Sons, Inc., New York (1999) can be used. Furthermore, the introduction and removal of protecting groups can be carried out by methods commonly used in organic synthesis chemistry (e.g., the methods described in the above-mentioned literature) or similar methods.

[0132] The starting materials and intermediates in the manufacturing method of this disclosure are commercially available or can be obtained by methods described in the public literature or by synthesis from known compounds in accordance with known methods. Furthermore, salts of these starting materials and intermediates may be used, provided they do not interfere with the reaction.

[0133] The intermediates and target compounds in the manufacturing method of this disclosure can also be converted into other compounds included in this disclosure by appropriately changing their functional groups. The conversion of functional groups in this case can be done using methods commonly used in organic synthesis chemistry (e.g., RC Larock, “Comprehensive Organic Transformations”, 2 nd This can be done by the method described in Ed., John Wiley and Sons, Inc., New York (1999), or by a similar method.

[0134] The compounds used in this disclosure can generally be synthesized by the techniques described in synthesis schemes 1, 2, and 3 below. Synthesis Scheme 1 [ka] Synthesis Scheme 2 [ka] Synthesis scheme 3 [ka]

[0135] For example, referring to schemes 1, 2, and 3, compound LIX has the shown structure (wherein R 1 and R 3 As defined above, R 91 and R 92 The protecting group is suitable for use in synthesis and may have a protecting group that is bonded to a solid polymer support or linker to enable solid-phase synthesis. 91 Base and R 92 Examples of the base include optionally substituted alkyl groups, and in preferred embodiments, R 91 and R 92 Both are methyl or ethyl groups. Such compound IX is H2N-R 1CH(OR 91 )(OR 92 )-C(=O)R 3 Through reduction and amination, R 1a -CHO(in the formula, R 1 CH2-R 1a CH(OR) equal to 91 )(OR 92 )-CHR 3 Reductive amination with NH2 results in H2N-R 1 and CH(OR 91 )(OR 92 )-CHR 3 By substitution reaction with -LG (wherein LG refers to a leaving group, e.g., a halogen (Hal) group), or LG-R 1 and CH(OR 91 )(OR 92 )-CHR 3 It can be readily synthesized by substitution reaction with -NH2 (wherein LG refers to a leaving group, e.g., a halogen (Hal) group).

[0136] Compound LIII may have the structure shown, where PG is an amino protecting group suitable for use in peptide synthesis, and A is as defined above. Preferred protecting groups include 9H-fluorenylmethyloxycarbonyl (FMOC), t-butyldimethylsilyl (TBDMS), t-butyloxycarbonyl (BOC), methyloxycarbonyl (MOC), and allyloxycarbonyl (Alloc). N-protected amino acids are commercially available. For example, when FMOC amino acids are provided as compound LIII, azide derivatives of amino acids available from various sources can be produced from the corresponding amino acids by the reaction disclosed in Zaloom et al. (J.Org.Chem.46:5173-76, 1981).

[0137] Compound LVI in this disclosure has the shown structure (wherein PG and R 2 (as defined above) may have the following properties. Other suitable compounds LVI are commercially available from various sources or can be prepared by methods well known in organic chemistry.

[0138] Compounds LX, LXI, LXIII, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, and LXXI are commercially available from various sources or can be prepared by methods well known in organic chemistry.

[0139] As illustrated in Figures 1, 2, and 3, the compound of formula (I) (compound I) can be synthesized by reacting compound LIX with compound LX to obtain the conjugated compound LIII, and then treating the conjugated compound LIII with piperidine to obtain compound LIV. Compound LIV then sequentially reacts with compound LVI to obtain the conjugated compound LII, and then this intermediate is cyclized to obtain the compound of formula (I). Alternatively, as illustrated in synthesis schemes 1, 2, and 3, the compound of formula (I) can be synthesized by reacting compound LVI with compound LXV to obtain the conjugated compound LVII, and then treating the conjugated compound LVII with lithium hydroxide, sodium hydroxide, or potassium hydroxide to obtain compound LVIII. Compound LVIII then sequentially reacts with compound LIX to obtain the conjugated compound LII, and then this intermediate is cyclized to obtain the compound of formula (I).

[0140] Methods for preparing the compounds of formula (I) are not limited to those described herein. For example, the compounds of this disclosure may be prepared by modifying or transforming substituents of compounds that serve as precursors to the compounds, according to methods or combinations of methods described in general publications in the field of chemistry.

[0141] As recrystallization solvents, for example, alcohol-based solvents such as methanol, ethanol, or 2-propanol; ether-based solvents such as diethyl ether; ester-based solvents such as ethyl acetate; aromatic hydrocarbon-based solvents such as benzene or toluene; ketone-based solvents such as acetone; halogen-based solvents such as dichloromethane or chloroform; hydrocarbon-based solvents such as hexane; aprotic solvents such as dimethylformamide or acetonitrile; water; or mixtures thereof can be used. Other purification methods include those described in Volume 1 of "Experimental Chemistry Series" (edited by the Chemical Society of Japan, Maruzen). Furthermore, the molecular structure of the compounds disclosed herein can be easily determined by referring to the structures derived from each starting compound and using spectroscopic techniques such as nuclear magnetic resonance spectroscopy, infrared absorption spectroscopy, and circular dichroism spectroscopy, as well as mass spectrometry.

[0142] Furthermore, the intermediates or final products in the above manufacturing method can be converted to other compounds included in this disclosure by appropriately changing their functional groups, particularly by extending various side chains from amino, hydroxyl, carbonyl, halogen, etc., and by performing the protection and deprotection described below as necessary. The conversion of functional groups and the extension of side chains can be carried out by commonly used methods (see, for example, Comprehensive Organic Transformations, RC Larock, John Wiley & Sons Inc. (1999), etc.).

[0143] Examples of amino protecting groups include alkylcarbonyl (e.g., acetyl, propionyl), formyl, phenylcarbonyl, alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), phenyloxycarbonyl, arylalkyloxycarbonyl (e.g., benzyloxycarbonyl), trityl, phthaloyl, tosyl, and benzyl.

[0144] Examples of protecting groups for carboxyls include alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, benzyl, trityl, and silyl groups (e.g., trimethylsilyl, tert-butyldimethylsilyl).

[0145] Examples of hydroxyl protecting groups include methyl, tert-butyl, allyl, substituted methyl (e.g., methoxymethyl, methoxyethoxymethyl), ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trityl, arylalkyl (e.g., benzyl), alkylcarbonyl (e.g., acetyl, propionyl), formyl, benzoyl, arylalkyloxycarbonyl (e.g., benzyloxycarbonyl), and silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl).

[0146] Carbonyl protection can be achieved by converting the carbonyl to an acyclic ketal (such as dimethyl ketal or diethyl ketal) or a cyclic ketal (such as 1,3-dioxolane or 1,3-dioxane).

[0147] Equation (I) [ka] The compounds of the present disclosure, represented by , or pharmaceutically acceptable salts thereof, may exhibit chirality or have substituents with chiral carbons, and in such compounds, optical isomers exist. The compounds of the present disclosure also include mixtures of these isomers and isolated compounds, which can be prepared by conventional methods.

[0148] Manufacturing methods include, for example, using raw materials with chiral centers, or introducing chirality at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage in the manufacturing process. An example of an optical resolution method is formula (I) [ka] If the compound represented by or its intermediate has a basic functional group, a diastereomer method is used to form a salt using an optically active acid (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, and lactic acid, dicarboxylic acids such as tartaric acid, o-diisopropylidenatartaric acid, and malic acid, and sulfonic acids such as camphor sulfonic acid and bromocamphor sulfonic acid) in an inert solvent (e.g., alcoholic solvents such as methanol, ethanol, and 2-propanol, etheric solvents such as diethyl ether, esteric acid, hydrocarbon solvents such as toluene, aprotic solvents such as acetonitrile, or a mixture of two or more solvents selected from the above).

[0149] Equation (I) [ka] If the compound of the present disclosure represented by or an intermediate thereof has an acidic functional group such as a carboxyl group, optical resolution can also be performed by forming a salt using an optically active amine (for example, an organic amine such as 1-phenylethylamine, quinine, quinidine, cinconidine, cinconine, or strychnine).

[0150] The temperature for salt formation is selected from a range of -50°C to the boiling point of the solvent, preferably from 0°C to the boiling point, and more preferably from room temperature to the boiling point of the solvent. To improve optical purity, it is desirable to raise the temperature to near the boiling point of the solvent. When filtering the precipitated salt, cooling can be performed as needed to improve the yield. The amount of optically active acid or amine used is suitable in the range of about 0.5 to about 2.0 equivalents relative to the substrate, preferably around 1 equivalent. If necessary, the crystals can be recrystallized in an inert solvent (for example, alcoholic solvents such as methanol, ethanol, 2-propanol; etheric solvents such as diethyl ether; esteric solvents such as ethyl acetate; hydrocarbon solvents such as toluene; aprotic solvents such as acetonitrile; or a mixed solvent of two or more solvents selected from the above) to obtain a high-purity optically active salt. Alternatively, if necessary, the optically resolved salt can be treated with an acid or base in a conventional manner to obtain a free form.

[0151] Of the raw materials and intermediates used in each of the manufacturing methods described above, those whose manufacturing methods are not specifically mentioned can be commercially available compounds or synthesized from commercially available compounds by methods known to those skilled in the art, or by similar methods.

[0152] (Method of a preferred embodiment) Preferred embodiments of the Disclosure are described below. The embodiments provided below are provided for a better understanding of the Disclosure, and it will be understood that the scope of the Disclosure should not be limited to the descriptions below. Accordingly, it will be obvious that those skilled in the art can make appropriate modifications within the scope of the Disclosure, taking into consideration the descriptions herein. It will also be understood that the embodiments of the Disclosure below can be used individually or in combination.

[0153] (Treatment, prevention, progression control, and regulation of sarcopenia-related diseases, disorders, or symptoms) In one aspect, the Disclosure provides compositions, pharmaceuticals, methods, compounds, uses, etc., for modulating, slowing the progression, preventing or treating sarcopenia-related diseases, disorders, or symptoms, comprising or utilizing at least one selected from the OK-1 related compound group [1] to [9]. The Disclosure is completed and provided by the discovery that the OK-1 related compound group can unexpectedly modulate, slow the progression, prevent or treat sarcopenia-related diseases, disorders, or symptoms.

[0154] The OK-1 related compounds used in this disclosure may be any compound included in compound group [1] to [9], pharmaceutically acceptable salts thereof, or solvates (e.g., hydrates) thereof. Compound group [1] to [9] may also be referred to as OK-1 related compounds group [1] to [9]. Therefore, in a preferred embodiment, the group of compounds of the present disclosure is the group of compounds [1], The group of compounds [1] is described in Patent No. 5530427, the contents of which are incorporated herein by reference, for example, The following general formula (I): [ka] [In the formula, A is -CHR 7 -(Here, R 7 teeth, OH, -OR 8 (Here, R 8 C 1-10 C may be substituted with substituents selected from alkyl, -NH2, -COOH, and -CONH2. 1-10 alkyl, -OH, -OP(=O)(OH)2, -OP(=O)(ONa)2, and C 1-10 C may be substituted with substituents selected from alkyl groups. 6-14 Aryl-C 1-10 Alkyl, heteroaryl-C 1-10 Alkyl, C 3-10 Cycloalkyl-C 1-10 Alkyl, C 6-14 Aryl, or C 3-10 It is a cycloalkyl, G is -NR 6 -, or -O-(where R 6 C 1-10 Alkyl and C 2-10 (They are chosen independently of Alkenil.) R 1 is -Ra-R 10 (Here, Ra is C 1-6 It is alkylene and R 10 (This is a condensed bicyclic heteroaryl which may be substituted with substituents selected from naphthyl or -NH2 and halogens.) R 2 Ha-W 21 -W 22 -Rb-R 20 (Here, W 21 is -(CO)- and W 22 is -O- or -NH-, and Rb is a bond or C 1-10 C may be substituted with alkyl. 1-6 It is alkylene and R 20 C 1-10 C may be substituted with alkyl or halogen compounds. 6-14 Aryl, heteroaryl, or C 3-10 It is a cycloalkyl and R 3 C 1-10 It is alkyl, Examples include compounds represented by "heteroaryl" (meaning a 5- to 14-membered monocyclic or polycyclic aromatic group in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, and the remaining ring atoms are carbon), or pharmaceutically acceptable salts thereof, or solvates thereof. Various embodiments of the compounds used in this disclosure include any embodiments described in the (Description of Compounds) section of this specification or elsewhere, or in reference to cited documents. Thus, this disclosure can be used to modulate, slow the progression of, prevent or treat not only sarcopenia but also sarcopenia-related diseases, disorders, or symptoms.

[0155] In one embodiment, sarcopenia-related diseases, disorders, or symptoms that can be regulated, slowed, prevented, or treated in this disclosure include at least one selected from the group consisting of diseases, disorders, or symptoms resulting from muscle weakness; diseases, disorders, or symptoms resulting from energy metabolism disorders; and diseases, disorders, or symptoms resulting from endocrine disorders.

[0156] In specific embodiments, sarcopenia-related diseases, disorders, or symptoms may include lifestyle-related diseases (non-wasting diseases), wasting diseases, tumor-related diseases (including cancer cachexia), musculoskeletal disorders, neurodegenerative diseases (including ALS), cognitive impairment, and other related disorders (defined as including malnutrition, frailty, spinal and lung injury, inactivity, decreased activity, disuse syndrome, trauma, surgery, and other invasive conditions). These include, but are not limited to, respiratory diseases (such as respiratory failure), visceral diseases (or urinary tract diseases) (such as chronic kidney disease (CKD)), bone-related diseases (such as osteoporosis), and muscle-related diseases (such as dystrophy, myofibrilary myopathy, and ALS).

[0157] The diseases, disorders, or symptoms covered by this disclosure include, but are not limited to, diseases, disorders, or symptoms related to the digestive system (gastrointestinal tract), circulatory system, respiratory system (including vocal organs), urinary system, reproductive system, endocrine system, sensory system, nervous system, musculoskeletal system (bones, joints, ligaments, muscles, etc.), and neoplasms (cancer, tumors, etc.), which may be directly or indirectly related to sarcopenia, for example, through muscle strength, energy metabolism, or the endocrine system.

[0158] In another aspect, the present disclosure provides compositions, methods, compounds, or uses for modulating, delaying the progression of, preventing or treating age-related diseases, disorders, or symptoms comprising at least one of the OK-1 related compound group.

[0159] In one embodiment, the age-related disease, disorder, or symptom is selected from sarcopenia, lifestyle-related diseases (non-debilitating diseases), debilitating diseases, musculoskeletal disorders, neurodegenerative diseases, cognitive impairment, and other related disorders (as above). In yet another embodiment, the age-related disease, disorder, or symptom is selected from sarcopenia, dementia, metabolic diseases, rheumatoid arthritis, osteoporosis, and muscle loss.

[0160] In one embodiment, the OK-1 related compound group used in this disclosure is compound group [1].

[0161] In another embodiment, the OK-1 related compounds used in this disclosure are orally administered.

[0162] (Sarcopenia-related genes, screening, and companion diagnostics / treatment) In some embodiments, regulation, progression delay, prevention or treatment of the subject's Ppara, Pou2f2, Foxo1, Pparg, Pou2f1, Trp63, Sp1, Tcf3, Zeb1, Srebf1, Sp3, Ebf1, Mycn, Pbx1, IRF1, NFE2L2, PPARG, FOXO1, CEBPB, PPARA, CEBPA, STAT1, STAT5A, MYOD1, REL, NFKB1, SPI1, IRF8, SP1, FOXM1, Krt27, Krt71, Dsp, Krt72, Krt17, Krtap15, Krtap7-1, Comp, Krt31, Krt33b, Pkp1, Prr9, Krt34, Trim29, Krt86, Krt26, Krtap1-5, Krt81, Krtap22-2, Tchhl1, Krtap6-5, Gprc5d, Krt73, Krt35, Krt83, Pof1b , Krtap6-1, Krtap14, 1110025L11Rik, Krtap8-1, Gm10229, Krt33a, Crct1, Igkv5-39, Tgtp1, Dsc1, Dsg1a, Serpinb5, Krt14, Krtap21-1, Abca12, Gm102 28, Krt77, S100a14, Gm49425, Krtap19-3, Ighg1, Krt25, Tchh, Krtap1-3, Jun, Ets1, Sp1, Ep300, Usf2, Fosl1, Nfkb1, Smad3, Srf, Junb, Runx2, Ets2, E tv4, Tgfb1, Tgfb1i1, ETS2, ETS1, EP300, RUNX2, SMAD3, SMAD4, E2F1, NOTCH1, TRP53, PAX6, SMAD1, SP1, SPI1, NFKB1, Thbs2, Igkv12-41, Cpxm2, Cd248, I gsf10, Igkv4-69, Igkv10-96, Lox, Col1a1, Col14a1, C3ar1, Lepr, P3h3, Fn1, Ogn, Igkv4-70, Il33, Nbl1, Gm26910, Pzp, 4933406L23Rik, Fbln1, Mfap5 , Cnn1, Nnat, Cd109, Igfbp6, Ppil3, Nmrk2, Plxnb2, Qpct, Gm22771, Rin2, Col1a2, Gm23935, Gm43154, Marcks, Dntt, Gpnmb, Pcolce, Gm45481, Colec12,Igkv3-4, Gm47381, Gm24270, Dpysl3, Lpar1, Loxl2, Pitpnm2os2, Emilin1, Dsp, Krt17, Comp, Krt86, Krt8 1, Krt83, Krt14, Abca12, Tchh, Krt5, Dsg4, Lpl, Myh6, Tfap2a, Col1a1, Lepr, Fn1, Col1a2, Col6a1, Col3a This may be confirmed by the regulation of at least one gene selected from the group consisting of 1, Mmp2, Acta2, F13a1, Col6a2, Cx3cr1, Nfkb1, Srebf2, Sp1, Trp53, Xbp1, Myod1, Srebf1, Jun, Stat3, Sp3, Myf6, Nr3c1, Foxo3, Nfe2l2, Myf5, Ahr, Ep300, Myog, and Usf2.

[0163] In one aspect, the present disclosure provides compositions for modulating, delaying the progression of, preventing or treating age-related diseases, disorders, or symptoms comprising at least one of the OK-1-related compound group. In one embodiment, the age-related diseases, disorders, or symptoms are selected from sarcopenia, lifestyle-related diseases (non-wasting diseases), wasting diseases, musculoskeletal disorders, neurodegenerative diseases, cognitive impairment, and other related disorders (any disorder defined as including malnutrition, frailty, spinal and lung injury, inactivity, decreased activity, disuse syndrome, trauma, surgery, and other invasive events). In a particular embodiment, the age-related diseases, disorders, or symptoms are selected from sarcopenia, dementia, metabolic diseases, rheumatoid arthritis, osteoporosis, and decreased muscle mass.

[0164] In one aspect, the present disclosure provides a composition for use in the diagnosis or examination of a sarcopenia-related disease, disorder, or symptom in a subject, the composition comprising means or reagents for identifying the presence or level of expression of at least one gene selected from a group consisting of therapeutic genes. In some embodiments, the therapeutic genes include Ppara, Pou2f2, Foxo1, Pparg, Pou2f1, Trp63, Sp1, Tcf3, Zeb1, Srebf1, Sp3, Ebf1, Mycn, Pbx1, IRF1, NFE2L2, PPARG, FOXO1, CEBPB, PPARA, CEBPA, STAT1, STAT5A, MYOD1, REL, NFKB1, SPI1, IRF8, SP1, FOXM1, Krt27, Krt71, Dsp, Krt72, Krt17 , Krtap15, Krtap7-1, Comp, Krt31, Krt33b, Pkp1, Prr9, Krt34, Trim29, Krt86, Krt26, Krtap1-5, Krt81, Krtap22-2, Tchhl1, Krtap 6-5, Gprc5d, Krt73, Krt35, Krt83, Pof1b, Krtap6-1, Krtap14, 1110025L11Rik, Krtap8-1, Gm10229, Krt33a, Crct1, Igkv5-39, Tgtp 1, Dsc1, Dsg1a, Serpinb5, Krt14, Krtap21-1, Abca12, Gm10228, Krt77, S100a14, Gm49425, Krtap19-3, Ighg1, Krt25, Tchh, Krtap1 -3, Jun, Ets1, Sp1, Ep300, Usf2, Fosl1, Nfkb1, Smad3, Srf, Junb, Runx2, Ets2, Etv4, Tgfb1, Tgfb1i1, ETS2, ETS1, EP300, RUNX2, SMA D3, SMAD4, E2F1, NOTCH1, TRP53, PAX6, SMAD1, SP1, SPI1, NFKB1, Thbs2, Igkv12-41, Cpxm2, Cd248, Igsf10, Igkv4-69, Igkv10-96, L ox, Col1a1, Col14a1, C3ar1, Lepr, P3h3, Fn1, Ogn, Igkv4-70, Il33, Nbl1, Gm26910, Pzp, 4933406L23Rik, Fbln1, Mfap5, Cnn1, Nnat,Cd109, Igfbp6, Ppil3, Nmrk2, Plxnb2, Qpct, Gm22771, Rin2, Col1a2, Gm23935, Gm43154, Marcks, Dntt, Gpnmb, Pcolce, Gm45481, C olec12, Igkv3-4, Gm47381, Gm24270, Dpysl3, Lpar1, Loxl2, Pitpnm2os2, Emilin1, Dsp, Krt17, Comp, Krt86, Krt81, Krt83, Krt14 , Abca12, Tchh, Krt5, Dsg4, Lpl, Myh6, Tfap2a, Col1a1, Lepr, Fn1, Col1a2, Col6a1, Col3a1, Mmp2, Acta2, F13a1, Col6a2, Cx3cr1, Contains Nfkb1, Srebf2, Sp1, Trp53, Xbp1, Myod1, Srebf1, Jun, Stat3, Sp3, Myf6, Nr3c1, Foxo3, Nfe2l2, Myf5, Ahr, Ep300, Myog, and Usf2. ,

[0165] In one embodiment, the therapeutic gene group can be classified as follows. Immune response-related gene group Lax1, Prg4, Ifi213, Rasgrp1, Thbs1, B2m, Sla2, Nfatc2, Tnfsf10, Cd5l, S100a8, S100a9, Gbp7, Gbp3, Gbp2, Lck, Cd36, Jchain, Cxcl9, Sh2b2, Lep, Trbc1, Trbc2, Igkv14-111, Igkv4-53, Igkv5-39, Igkv8-28, Igkv8-27, Igkv3-7, Cd8b1, Cd8a, Pparg, Clec4d, Ercc1, Cd79a, Ffar2, Cd22, Cd19, Ifitm1, Nlrc5, Cd3d, Cadm1, Eomes, Raet1e, H60b, Vsir, Cfd, Itk, Irf1, Irgm2, Ccl5, Skap1, Ccr7, Cd79b, Rsad2, Ighg3, Ighd, Ighm, Ighv5-4, Ighv2-3, Ighv11-1, Ighv9-3, Ighv10-3, Ighv1-76, H2bc12, Cxcl14, Ptk2b, Il7r, Tnfrsf13c, Mx2, Fpr2, H2-K1, Tap2, H2-Eb2, Ltb, H2-D1, H2-Q6, H2-Q7, H2-T23, Cnpy3, Aqp4, Gpr17, Iigp1, Ms4a1, Cd274, Ifit3 Genes related to the outer side of the plasma membrane Sell, Thbs1, B2m, Cd2, Lepr, Cd36, Cxcl9, Trbc1, Trbc2, Cd8b1, Cd8a, Cd79a, Cd19, Itgax, Cd3d, Raet1e, H60b, Vsir, Atp1b2, Ccr7, Cd79b, Ighg3, Ighd, Ighv5-4, Ighv2-3, Ighv{11}-1, Ighv9-3, Ighv10-3, Ighv1-76, Ctsb, Il7r, Tnfrsf13c, Abcg1, H2-K1, H2-D1, H2-Q6, H2-Q{7}, H2-T23, Aqp4, Ms4a1, Cd274 Genes related to the response to external biological stimuli Note: I'm not sure if the "Ighv{11}-1" and "H2-Q{7}" in the original text are supposed to be like this. If they are incorrect, please adjust according to the correct content in the original. Also, the "H2bc12" in the original might be a misspelling, it's translated as is for now.Fmo1, Ifi213, Rasgrp1, B2m, Pck1, Fabp4, S100a8, S100a9, Gbp7, Gbp3, Gbp2, Cd36, Jchain, Cxcl9, Lep, Trbc1, Trbc2, Cd8a, Pp arg,Clec4d,Mgst1,Ffar2,Thrsp,Itgax,Cyp2e1,Ifitm1,Lpl,Nlrc5,Acp5,Cadm1,Raet1e,H60b,Gja1,Cfd,Irf1,Irgm2,Ccl5 ,Ccr7,Cd79b,Rsad2,Dgkb,Tmem229b,Ifi27l2a,Ighg3,Ighd,Ighm,Ighv5-4,Ighv2-3,Ighv11-1,Ighv9-3,Ighv10-3,Ighv1- 76,H2bc12,Cxcl14,Clu,Adipoq,Mx2,Fpr2,H2-K1,Tap2,H2-Q7,H2-T23,Cnpy3,Lrg1,Aqp4,Iigp1,Ms4a1,Cd274,Ifit3,Car5b Genes related to the positive regulation of intracellular regulation Hdac4,En1,Rgs2,Glul,Sell,Lpgat1,G0s2,Ccdc3,Tnfaip6,Creb3l1,Fmn1,Rasgrp1,Thbs1,B2m,Tpx2,Sla2,Nnat,Fam83d,Chd6,Nfatc2,Pck1,Cdh 4,Fabp4,Car2,Tnfsf10,Sh3d19,Cd5l,S100a8,S100a9,Cd2,Casq2,Lhx8,Pax5,Klf4,Epb41l4b,Lepr,Rab3b,Lck,Sfn,Slc30a2,Pla2g5,Pax7,Cd36 ,Cytl1,Klb,Rhoh,Cxcl9,Tbx3,Kdm2b,Sh2b2,Asns,Lep,Ptn,Trbc1,Trbc2,Epha1,Cd8a,Ghrl,Pparg,Clec4d,Ercc1,Ffar2,Cebpa,Ccne1,Atf5,Tenm4,Dgat2,Stard10,Mical2,Spon1,Cd19,Itgax,Ifitm1,Pnpla2,Retn,Adrb3,Lpl,Comp,Slc27a1,Nlrc5,Nqo1,Zfp821,Mmp3,Panx1,Dnmt1,Nrgn,C d3d,Cadm1,Pou2af1,Slc51b,Zic1,Eomes,Cited2,Raet1e,Tpd52l1,Vgll2,Gja1,Vsir,Aifm2,Lrrtm3,Shc2,Spic,Socs2,Wif1,Cdk2,Il9r,Irf1,Irgm2,Atp1b2,Inpp5k,Cryba1,Ccl5,Hoxb3,Skap1,Ccr7,Aoc3,Rsad2,Egln3,Wars,Ighg3,Ighd,Ighv5-4,Ighv2-3,Ighv11-1,Ighv9-3,Ighv10-3,Ig hv1-76,Rnf144b,Cxcl14,Thbs4,Pik3r1,Tspan14,Clu,Ptk2b,Htr2a,Slc1a3,Il7r,Ptp4a3,Gpt,Mrtfa,Tnfrsf13c,Fbln1,Glis2,Adipoq,Trp63,R obo1,Tiam1,Smoc2,Fpr2,Abcg1,H2-K1,Tap2,Ltb,H2-D1,H2-Q6,H2-Q7,H2-T23,Lrg1,Mib1,Gpr17,Cd274,Fgfbp3,Pitx3,Gsto1,Nutf2-ps1,Hdac8,Gpr174, Leukocyte activation-related gene group Lax1,Cr2,Rasgrp1,Thbs1,B2m,Sla2,Nfatc2,Cd2,Lepr,Lck,Rhoh,Lep,Trbc1,Trbc2,Cd8a,Clec4d,Ercc1,Cd79a,Cd22,Cebpa,Cd19,Cd3d,Eomes,Gja1,Vsir,Itk,Irf 1,Ccl5,Ccr7,Cd79b,Rsad2,Ighg3,Ighd,Ighv5-4,Ighv2-3,Ighv11-1,Ighv9-3,Ig hv10-3, Ighv1-76, Pik3r1, Clu, Ptk2b, Il7r, Tnfrsf13c, Fpr2, H2-T23, Ms4a1, Cd274 Keratinization-related gene group Pkp1,Sprr1a,Lce1a1,Lce1b,Lce1a2,Lce1c,Lce1m,Rptn,Tchh,Klk5,Pkp3,Gm45618,Gm45337,Gm4553, Gm7579,Krtap5-5,Gm40460,Perp,Gm19402,Krtap12-1,Gm18596,Krt25,Krt26,Krt27,Krt28,Krt23,Krt 39,Krt40,Krtap3-3,Krtap3-1,Krtap1-5,Krtap1-4,Krtap1-3,Krtap9-3,Gm11562,Krtap4-1,Krtap4- 2,Krtap4-7,Gm11555,Gm11563,Krtap4-8,Krtap4-9,Gm11596,Krtap4-16,Gm11568,Gm11559,Krtap9-1, Gm11567,Krtap16-1,Krt33a,Krt33b,Krt34,Krt31,Krt35,Krt36,Krt14,Krt17,Evpl,Dsp,Krt80,Krt8 7,Krt81,Krt86,Krt83,Krt84,Krt82,Krt75,Krt6a,Krt5,Krt71,Krt72,Krt73,Krt1,Krt77,Krt79,Krta p13-1, Krtap15, Krtap19-2, Krtap19-3, Krtap19-4, Krtap16-3, Gm10229, Krtap6-1, Gm10228, Krtap6-5 ,Krtap6-3,Gm10061,1110057P08Rik,Krtap8-1,Krtap11-1,Dsc3,Dsc2,Dsc1,Dsg1a,Dsg4,Spink5,Lipm Genes related to developmental biology Pkp1,Sprr1a,Lce1a1,Lce1b,Lce1a2,Lce1c,Lce1m,Rptn,Tchh,Klk5,Pkp3,Gm45618,Gm45337,Gm4553,G m7579,Krtap5-5,Gm40460,Perp,Gm19402,Krtap12-1,Gm18596,Krt25,Krt26,Krt27,Krt28,Krt23,Krt3 9,Krt40,Krtap3-3,Krtap3-1,Krtap1-5,Krtap1-4,Krtap1-3,Krtap9-3,Gm11562,Krtap4-1,Krtap4-2, Krtap4-7,Gm11555,Gm11563,Krtap4-8,Krtap4-9,Gm11596,Krtap4-16,Gm11568,Gm11559,Krtap9-1,Gm1 1567,Krtap16-1,Krt33a,Krt33b,Krt34,Krt31,Krt35,Krt36,Krt14,Krt17,Cacng4,Evpl,Dsp,Krt80,K rt87,Krt81,Krt86,Krt83,Krt84,Krt82,Krt75,Krt6a,Krt5,Krt71,Krt72,Krt73,Krt1,Krt77,Krt79,Kr tap13-1,Krtap15,Krtap19-2,Krtap19-3,Krtap19-4,Krtap16-3,Gm10229,Krtap6-1,Gm10228,Krtap6- 5,Krtap6-3,Gm10061,1110057P08Rik,Krtap8-1,Krtap11-1,Dsc3,Dsc2,Dsc1,Dsg1a,Dsg4,Spink5,Lipm Estrogen signaling pathway-related genes Krt25,Krt26,Krt27,Krt28,Krt10,Krt23,Krt39,Krt40,Krt33a,Krt33b,Krt34,Krt31,Krt32,Krt35,Krt36,Krt15,Krt14,Krt17,Calml3,Calm4,Calm5 Desmosome-related gene group Pkp1,Pkp3,Perp,Evpl,Dsp,Dsc3,Dsc2,Dsc1,Dsg1a,Dsg1b,Dsg4,Pof1b Extracellular structure and tissue-related gene group Col3a1,Col5a2,Fn1,Fmod,Ddr2,Olfml2b,Dpp4,Postn,Ctss,Col11a1,Col16a1,Angptl7,Mmp23,Emilin1,Pdgfra,Col1a2,Loxl3,Antxr1,Fbln2,Tgfb1,Gas2,Serpinh1,Co mp,Mmp2,Mmp12,Mmp11,Lum,Aebp1,Adamts2,Col1a1,Itgb3,Lamb1,Nid1,Ecm2,Mmp14,Scara3,Loxl2,Col14a1,Col22a1,Scx,Fbln1,Myh11,Abi3bp,Col8a1,Smoc2,Tnxb,Lox Collagen-binding related genes Ddr2,Dpp4,Thbs1,Ctsk,Ctss,Pcolce,Antxr1,Serpinh1,Comp,Mmp12,Pcolce2,Col6a2,Col6a1,Dcn,Lum,Aebp1,Sparc,C1qtnf1,Nid1,Ecm2,Aspn,Thbs4,Abi3bp,Tnxb,Lox Genes related to vascular development Col3a1,Fn1,Cfh,Cd34,Thbs1,Rin2,Ptgis,Svep1,Lepr,Angptl7,Emilin1,Pdgfra,Pf4,Col1a2,A ntxr1,C3ar1,Gpr4,Tgfb1,Nr2f2,Anpep,Itgax,Comp,Hmox1,Mmp2,Dnmt1,Loxl1,Aldh1a2,Tgfbr2 ,Cx3cr1,Dcn,Sparc,Pik3r6,Arhgef15,Serpinf1,Ccl2,Col1a1,Grn,Itgb3,Ace,Apob,Meox2,Thb s4,Plau,Stab1,Mmp14,Loxl2,Klf5,Spry2,Itga5,Col8a1,Smoc2,Thbs2,Angptl4,Lox,Acta2,Tnmd Fibronectin-binding related genes Myoc,Thbs1,Ctsk,Ctss,Tnc,Loxl3,Ssc5d,Comp,Mmp2,Itgb3,Thbs4,Fbln1,Igfbp6 Genes related to vascular development Col3a1,Fn1,Cfh,Cd34,Thbs1,Rin2,Ptgis,Lepr,Emilin1,Pdgfra,Pf4,Col1a2,Antxr1,C 3ar1,Gpr4,Tgfb1,Nr2f2,Anpep,Itgax,Comp,Hmox1,Mmp2,Loxl1,Aldh1a2,Tgfbr2,Cx3cr 1,Dcn,Sparc,Pik3r6,Serpinf1,Ccl2,Col1a1,Grn,Itgb3,Ace,Apob,Meox2,Thbs4,Plau,Stab1,Mmp14,Loxl2,Klf5,Spry2,Itga5,Col8a1,Smoc2,Thbs2,Angptl4,Lox,Acta2,Tnmd Extracellular region-related gene group Adamts13,Cel,Cela2a,Cxcl9,Lep,Try4,Igkv1-122,Igkv15-103,Igkv10-96,Igkv4-70,Igkv6-20,Igkv3-5,Dmbt1 ,Ctrb1,Ighv5-6,Ighv5-9,Ighv5-15,Ighv1-19,Ighv1-34,Ighv1-80,Tnfsf11,Slurp1,Apol7e,Cdsn,Dsc3,Crtac1 Genes related to heme removal from plasma Igkv1-122, Igkv10-96, Ighv5-6, Ighv5-9, Ighv5-15, Apol7e

[0166] In a preferred embodiment, keratinization-related gene groups and extracellular structure-related gene groups can be used as therapeutic gene groups.

[0167] In one aspect, the present disclosure relates to Ppara, Pou2f2, Foxo1, Pparg, Pou2f1, Trp63, Sp1, Tcf3, Zeb1, Srebf1, Sp3, Ebf1, Mycn, Pbx1, IRF1, NFE2L2, PPARG, FOXO1, CEBPB, PPARA, CEBPA, STAT1, STAT5A, MYOD1, REL, NFKB1, SPI1, IRF8, SP1, FOXM1, Krt27, Krt71, Dsp, Krt72, Krt17, Krtap15, Krtap7-1, Comp, Krt31, Krt33b, Pkp1, Prr9, Krt34, Trim29, Krt86, Krt26, Krtap1-5, Krt81, Krtap22-2, Tchhl1, Krtap6-5, Gprc5d, Krt73, Krt35, Krt83, Pof1b, Krtap6-1, Krtap14, 1110Dpysl3, Lpar1, Loxl2, Pitpnm2os2, Emilin1, Dsp, Krt17, Comp, Krt86, Krt81, Krt83, Krt14, Abca12, Tchh, Krt5 , Dsg4, Lpl, Myh6, Tfap2a, Col1a1, Lepr, Fn1, Col1a2, Col6a1, Col3a1, Mmp2, Acta2, F13a1, Col6a2, Cx3cr1, Nfkb The present invention provides a composition for regulating, delaying the progression of, preventing, or treating sarcopenia-related diseases, disorders, or symptoms, comprising a substance or factor that modulates at least one gene selected from the group consisting of 1, Srebf2, Sp1, Trp53, Xbp1, Myod1, Srebf1, Jun, Stat3, Sp3, Myf6, Nr3c1, Foxo3, Nfe2l2, Myf5, Ahr, Ep300, Myog, and Usf2.

[0168] In another context, the present disclosure relates to a method for screening for substances or factors to modulate, delay the progression of, prevent or treat sarcopenia-related diseases, disorders or symptoms, the method being: A) A step of administering a candidate substance or factor to a subject, B) Conjugates include Ppara, Pou2f2, Foxo1, Pparg, Pou2f1, Trp63, Sp1, Tcf3, and Zeb1 Srebf1, Sp3, Ebf1, Mycn, Pbx1, IRF1, NFE2L2, PPARG, FOXO1, CEBPB, PPARA CEBPA STAT1 STAT5A MYOD1 REL NFKB1 SPI1 IRF8 SP1 FOXM1 Krt27 Krt71, Dsp, Krt72, Krt17, Krtap15, Krtap7-1, Comp, Krt31, Krt33b, Pkp1, P rr9, Krt34, Trim29, Krt86, Krt26, Krtap1-5, Krt81, Krtap22-2, Tchhl1, K rtap6-5, Gprc5d, Krt73, Krt35, Krt83, Pof1b, Krtap6-1, Krtap14, 111002 5L11Rik, Krtap8-1, Gm10229, Krt33a, Crct1, Igkv5-39, Tgtp1, Dsc1, Dsg1 a, Serpinb5, Krt14, Krtap21-1, Abca12, Gm10228, Krt77, S100a14, Gm49425 Krtap19-3, Ighg1, Krt25, Tchh, Krtap1-3, Jun, Ets1, Sp1, Ep300, Usf2, F osl1, Nfkb1, Smad3, Srf, Junb, Runx2, Ets2, Etv4, Tgfb1, Tgfb1i1, ETS2 TS1, EP300, RUNX2, SMAD3, SMAD4, E2F1, NOTCH1, TRP53, PAX6, SMAD1, SP1,S PI1, NFKB1, Thbs2, Igkv12-41, Cpxm2, Cd248, Igsf10, Igkv4-69, Igkv10-96 Lox, Col1a1, Col14a1, C3ar1, Lepr, P3h3, Fn1, Ogn, Igkv4-70, Il33, Nbl1 Gm26910, Pzp, 4933406L23Rik, Fbln1, Mfap5, Cnn1, Nnat, Cd109, Igfbp6. Ppil3, Nmrk2, Plxnb2, Qpct, Gm22771, Rin2, Col1a2, Gm23935, Gm43154, Ma rcks, Dntt, Gpnmb, Pcolce, Gm45481, Colec12, Igkv3-4, Gm47381, Gm24270.A step to confirm the regulation of at least one gene selected from the group consisting of Dpysl3, Lpar1, Loxl2, Pitpnm2os2, Emiliin1, Dsp, Krt17, Comp, Krt86, Krt81, Krt83, Krt14, Abca12, Tchh, Krt5, Dsg4, Lpl, Myh6, Tfap2a, Col1a1, Lepr, Fn1, Col1a2, Col6a1, Col3a1, Mmp2, Acta2, F13a1, Col6a2, Cx3cr1, Nfkb1, Srebf2, Sp1, Trp53, Xbp1, Myod1, Srebf1, Jun, Stat3, Sp3, Myf6, Nr3c1, Foxo3, Nfe2l2, Myf5, Ahr, Ep300, Myog, and Usf2. C)B) Based on the results, the process involves identifying the candidate substance or factor as having the ability to modulate, delay the progression of, prevent or treat sarcopenia-related diseases, disorders, or symptoms. Provides a method for including this.

[0169] (General explanation of medicines, treatment methods, etc.) The compounds, pharmaceuticals, compositions, etc. of this disclosure may be administered in any dosage form, preferably orally.

[0170] The “subjects” or “subjects” to which administration may be considered include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals, e.g., mammals (e.g., primates (e.g., crab-eating macaques, rhesus macaques), commercially relevant mammals (e.g., cattle, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds (e.g., chickens, ducks, geese, and / or turkeys)), reptiles, amphibians, and fish. In some embodiments, the non-human animal is a mammal. The non-human animal may be male or female at any stage of development. The non-human animal may be a transgenic animal.

[0171] As used herein, unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” mean actions taken while the subject is suffering from a disease, disorder, or condition. “Progression delay” means actions that reduce the severity of a disease, disorder, or condition or slow or reduce its progression, and “prevention” means actions that occur before the subject begins to suffer from a disease, disorder, or condition and that inhibit or reduce the severity of the disease, disorder, or condition.

[0172] Generally, the “effective dose” of a compound refers to the amount sufficient to elicit the desired biological response, i.e., to treat the disorder. As is obvious to those skilled in the art, the effective dose of the compounds in this disclosure may vary depending on the desired biological endpoint, the pharmacokinetics of the compound, the disorder to be treated, the mode of administration, and factors such as age, health, and subject. Effective doses encompass both therapeutic and prophylactic treatments.

[0173] As used herein, unless otherwise specified, the term “therapeutically effective amount” of a compound means an amount of the compound sufficient to prevent or reduce to some extent the manifestation of one or more symptoms of the disease being treated when administered. The term also refers to an amount of the compound sufficient to induce a biological or medical response in a biological molecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, as sought by researchers, veterinarians, physicians, or clinicians. Furthermore, a therapeutically effective amount of a compound means an amount of the drug alone or in combination with other therapies that provides a therapeutic benefit in the treatment or management of a disease. The term includes amounts that improve the overall therapy, amounts that reduce or avoid the symptoms or causes of a disease, or amounts that enhance the therapeutic effectiveness of another therapeutic agent.

[0174] As used herein, and unless otherwise specified, “a prophylactically effective amount” of a compound means an amount sufficient to inhibit or reduce the symptoms of a disease or to prevent the recurrence of the disease. A prophylactically effective amount of a compound means an amount of the therapeutic agent alone or in combination with other agents that provides a prophylactic benefit in inhibiting or reducing the symptoms or recurrence of the disease. The term “prophylactically effective amount” may include an amount that improves overall prevention or enhances the prophylactic effectiveness of another prophylactic agent.

[0175] As used herein, unless otherwise specified, “therapeutic dose” of a compound means an amount sufficient to provide a therapeutic effect in treating a disorder, or to delay or minimize one or more symptoms associated with the disorder. The therapeutic dose of a compound means the amount of the therapeutic agent, alone or in combination with other therapies, that provides a therapeutic effect in treating a disorder. The term “therapeutic dose” may include amounts that improve overall therapy, reduce or prevent symptoms or causes of a disorder, or enhance the therapeutic effect of another therapeutic agent.

[0176] As used herein, unless otherwise specified, the “preventive dose” of a compound is an amount sufficient to prevent or prevent the recurrence of one or more symptoms associated with a disor...

Claims

1. OK-1 【Chemistry 52】 Or C-82 【Chemistry 53】 A composition for improving, delaying the progression of, preventing or treating sarcopenia-related diseases, disorders or symptoms, comprising a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the sarcopenia-related disease, disorder or symptom is a disease, disorder or symptom resulting from muscle weakness.

2. The composition according to claim 1, wherein the sarcopenia-related disease, disorder, or symptom is at least one selected from the group consisting of primary sarcopenia, secondary sarcopenia, and diseases, disorders, or symptoms associated therewith.

3. The composition according to claim 1 or 2, wherein the sarcopenia-related disease, disorder, or symptom is selected from the group consisting of diseases resulting from muscle weakness, lifestyle-related diseases accompanied by disorders or symptoms, wasting diseases, tumors, musculoskeletal disorders, neurodegenerative diseases, cognitive impairments, and other disorders.

4. The composition according to any one of claims 1 to 3, wherein the sarcopenia-related disease, disorder, or symptom is a disease, disorder, or symptom resulting from a muscle weakness in a system selected from the group consisting of the digestive system, circulatory system, respiratory system, urinary system, reproductive system, endocrine system, sensory system, cranial nervous system, and musculoskeletal system.

5. The composition according to any one of claims 1 to 4, characterized in that the composition is formulated for oral administration.

6. The composition according to any one of claims 1 to 5, characterized in that it is administered in combination with at least one of exercise therapy, diet therapy, and other drug therapy.

7. The composition according to any one of claims 1 to 6, characterized in that it is administered in combination with exercise therapy.

8. The composition according to any one of claims 1 to 7, wherein the regulation, progression delay, prevention, or treatment is improvement, progression delay, prevention, or treatment of at least one of muscle loss and (muscle) endurance loss.

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