JP2016183151A - Treatment agent for diagnosis or treatment of disease associated with integrin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a treatment agent for diagnosis or treatment of disease associated with integrin.SOLUTION: A treatment agent comprises a complex of a compound represented by formula (1) or salt thereof and metal. In the formula (1), Ais a chelate group; Rand Rindependently represent H, alkyl, or an amino protective group; Z-Zindependently represent N or CR; Ris H or a substituted/unsubstituted Calkyl group or the like; Lis a group represented by formula (3); Land Lindependently represent a substituted/unsubstituted Calkylene group. In the formula (3), R-Rindependently represent H, alkyl or the like.SELECTED DRAWING: None

Description

  The present invention relates to a therapeutic agent for diagnosis or treatment of a disease involving integrin, which contains a complex of a novel nitrogen-containing compound or a salt thereof and a metal.

Integrins form a family of heterodimeric glycoprotein complexes formed by α and β subunits, and are a type of cell adhesion receptor that is mainly involved in cell adhesion to and transmission of information from the extracellular matrix. is there.
While integrin alpha _V beta ₃ and alpha _V beta ₅ is a vitronectin receptor among integrin expression on endothelial cells epithelial cells and maturation is kept low, it expressed in a variety of tumor cells and new blood vessels increased It is known to do. Increased expression of integrin α _V β ₃ and α _V β ₅ is involved in exacerbations such as cancer invasion and metastasis with tumor angiogenesis, and is said to be highly related to malignancy (for example, Non-Patent Document 1). ). Cancers in which the expression of these integrin is enhanced include, for example, head and neck cancer, colorectal cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, glioblastoma, malignant melanoma, pancreatic cancer, and prostate cancer ( For example, Non-Patent Document 2).
Integrin-related diseases have also been shown to increase integrin expression in vascular endothelial cells during angiogenesis after ischemia in ischemic diseases such as ischemic heart disease and peripheral vascular disease (for example, non-integrin) Patent Document 3).

  The relationship between these diseases and the expression of integrin is interesting as a pharmaceutical target. Treatment with low molecular weight compounds (Patent Documents 1 to 4) and compounds into which radioisotopes have been introduced (Patent Documents 5 to 7), disease sites Imaging has been reported.

For example, Non-Patent Documents 4 and 5 and the like, and Patent Document 5 and the like have been reported as an attempt of imaging using a peptide ligand having an Arg-Gly-Asp (RGD) sequence, and an attempt to use a non-peptide low molecule. . In addition, human tumors have been visualized with compounds introduced with ¹⁸ F of positron nuclide (Non-Patent Documents 6 and 7) (Non-Patent Documents 8 and 9).

US Pat. No. 6,0019,611 US Pat. No. 6,130,231 US Patent Application Publication No. 2002/169200 US Patent Application Publication No. 2001/53853 Special Table 2002-532440 gazette International Publication No. 2013/048996 Pamphlet International Publication No. 2011/149250 Pamphlet

Nature Reviews Cancer, Vol. 10, pp. 9-23, 2010 Clinical Cancer Research, Vol. 12, pp. 3942-3949, 2006 Circulation, 107, 1046-1052, 2003 Cancer Res., 61, pp. 1781-1785, 2001 Cardiovascular Research, Vol. 78, pp. 395-403, 2008 Clinical Cancer Research, Vol. 13, pp. 6610-6616, 2007 Journal of Nuclea Med., 49, 879-886, 2008 Cancer Res., 62, 6146-6151, 2002 International Journal of Cancer (Int. J. Cancer), 123, 709-715, 2008

  Since the peptide having a conventional RGD sequence has low tumor accumulation and persistence, the effect when applied to imaging and treatment has not been sufficient.

In addition, when blood clearance is slow, in terms of imaging, it may take from several days to a week until imaging in which the blood level that becomes the background decreases, and the half-life of a radioactive metal suitable for imaging is short. This is a serious drawback.
In terms of treatment with therapeutic nuclides, long-term blood circulation indicates that irradiation of the bone marrow is dominant and prone to severe myelotoxicity.

  Accordingly, an object of the present invention is to provide a diagnostic or therapeutic treatment agent comprising an integrin-binding compound as an active ingredient, which has high angiogenesis and tumor accumulation and persistence in which integrin is involved and high blood clearance. is there.

  Under such circumstances, the present inventors have conducted intensive studies, and as a result, the compound represented by the following general formula (1) or a salt thereof and a metal complex are diagnosed or treated for diseases in which integrin is involved. It was found to be useful as a treatment agent.

That is, the present invention provides the following [1] to [11].
[1]
General formula (1)

(Wherein A ¹ represents a chelate group; R ¹ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group; R ² represents a hydrogen atom, optionally substituted) A C _1-6 alkyl group or an amino protecting group; Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are the same or different and are each a nitrogen atom or CR ³ (wherein R ³ is a hydrogen atom, A halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkoxy group, or a general formula (2)

Wherein R ⁴ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group; n R ⁵ and n R ⁶ are the same or different and represent a hydrogen atom, A halogen atom, an optionally substituted C _1-6 alkyl group or an optionally protected carboxyl group; R ⁷ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group; R ⁸ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or a bond to L ⁵ : R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and represent a hydrogen atom, halogen atom, a protected or an amino group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkylamino group, optionally substituted di (C _1-6 alkyl) amino group or it indicates a bond to L ^5; or, R ⁸ and R ^9, taken together, is a substituted Shows a C _1-6 alkylene group; provided that any one of ^{R 8, R 9, R 10} , R 11 and R ^12, shows a bond to L ^5, the other four, L not exhibit a bond to ^5; L ⁴ is substituted aromatic hydrocarbon group or divalent, the substituted a divalent heterocyclic group or a bond may be; L ⁵ represents a substituted C _1-6 alkylene group which may be substituted, —O—C _1-6 alkylene group which may be substituted (wherein the bond on the left side is bonded to L ⁴ ) or —NH which may be substituted -C _1-6 alkylene group (wherein the left bond is bonded to L ⁴ ); m represents 0 or 1; n represents an integer of 1 to 3; Represents 0 or 1; provided that when R ⁸ is a bond to L ⁵ , L ⁴ represents a divalent aromatic hydrocarbon group which may be substituted. . Provided that at least one of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is CR ^3a (wherein R ^3a represents the general formula (2))

(Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , L ⁴ , L ⁵ , m, n and p have the same meanings as described above. A group represented by: L ² represents an optionally substituted C _1-6 alkylene group; L ³ represents an optionally substituted C _1-6 alkylene group; L ¹ represents a compound represented by the general formula (3)

Wherein r R ^{13 s} are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group; q × r R ¹⁴ and q × r R ¹⁵ is the same or different and represents a hydrogen atom or an optionally substituted C _1-6 alkyl group; r R ¹⁶ is the same or different and represents a hydrogen atom or an optionally substituted C _1-6. Alkyl group or general formula (4)

(Wherein s R ¹⁷ s are the same or different and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group; t R ^{18 s} are the same or different and represent a hydrogen atom or a substituted one. An optionally protecting C _1-6 alkyl group or an amino protecting group; t R ^{19 s} are the same or different and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group; 3 represents an integer of 3; t represents an integer of 0 to 3; R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , L ² and L ³ have the same meaning as described above. Q represents an integer of 0 to 3; and r represents an integer of 0 to 3. ) Is represented. A therapeutic agent for diagnosis or treatment of a disease involving integrin, comprising a complex of a compound represented by (1) or a salt thereof and a metal.
[2]
Z ¹ , Z ² , Z ⁴ and Z ⁵ are the same or different, and CR ^3b (wherein R ^3b is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group or a substituted group). be) shows a C _1-6 alkoxy group;. is Z ^3, CR ^3c (wherein, R ^3c has the general formula (2a)

(Wherein, n pieces of R ^5a and n-number of R ^6a are the same or different, a hydrogen atom, a optionally substituted C _1-6 alkyl group or a protected or a carboxyl group which; R ^8a is Represents a hydrogen atom or an optionally substituted C _1-6 alkyl group; R ^9a represents a hydrogen atom; or R ^8a and R ^9a together represent an optionally substituted C _1-6 alkylene. L ^5a represents an optionally substituted C _1-6 alkylene group; L ⁴ and n have the same meaning as described above.) The treatment agent according to [1].
[3]
R ^3c is the formula (2b)

(Wherein R ^5a , R ^6a , L ⁴ , L ^5a and n have the same meaning as described above), and the treatment agent according to [2].
[4]
The treatment agent according to any one of [1] to [3], wherein A ¹ is a group having a polyaza macrocyclic structure, a group having a polyaminopolycarboxylic acid structure, or a group having a polyaminopolyphosphonic acid structure. .
[5]
A ¹ is represented by the general formula (5), (6), (7), (8), (9), (10), (11) or (12).

(Wherein R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h and R ⁱ are the same or different and each represents a hydrogen atom or a carboxyl protecting group; X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ are the same or Differently, an optionally substituted C _1-6 alkylene group or an optionally substituted C _3-8 cycloalkylene group; X ¹⁰ represents an optionally substituted C _1-6 alkylene group; X ^4a And X ^8a are the same or different and each represents a C _1-6 alkanetriyl group which may be substituted; Q ¹ represents an oxygen atom or a sulfur atom. -The treatment agent as described in any one of [4].
[6]
A ¹ is represented by the formulas (5a), (6a), (7a), (8a), (8b), (8c), (9a), (10a), (10b), (11a), (11b), ( 11c) or (12a)

The treatment agent according to any one of [1] to [5], which is a group represented by:
[7]
The compound represented by the general formula (1) or a salt thereof is 2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxyl). -2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5 , 8,13-Tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl ) Triacetic acid, 2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2 -(4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamide) L) Sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraaza Cyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10-((4R, 7R, 10R) -19- (4- (N-((S) -1-) Carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2, 5,8,11,16-pentaoxo-4,7,10-tris (sulfomethyl) -3,6,9,12,15-pentaazanonadecyl) -1,4,7,10-tetraazacyclododecane- 1,4,7-trii ) Triacetic acid, (S) -2,2 ′, 2 ″-(10- (19- (4- (N- (1-carboxy-2- (4- (2- (5,6,7,8) -Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,11,16-trioxo-6,9-dioxa-3,12,15- Triazanonadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10-((S) -4- ( 4-Aminobutyl) -22- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridine-2- Yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,14 , 19-tetraoxo-9,12-dioxa-3,6,15,18-tetraazadocosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, S) -2,2 ′, 2 ″-(10- (28- (4- (N- (1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1, 8-Naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,11,20,25-tetraoxo-6,9,15,18-tetraoxa-3,12,21 , 24-tetraazaoctacosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10-((R) -22- (4- (N-((S) -1-carboxy-2- (4- (2 (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,14,19-tetraoxo-4- (Sulfomethyl) -9,12-dioxa-3,6,15,18-tetraazadocosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2, 2 ′, 2 ″-(10-((9R) -18- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro -1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -4-(((R) -1-((2- (4- (4- (N -((S) -1-carboxy-2- (4- (2- (5 , 7,8-Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropane-2 -Yl) carbamoyl) -2,7,10,15-tetraoxo-9- (sulfomethyl) -3,8,11,14-tetraazaoctadecyl) -1,4,7,10-tetraazacyclododecane-1, 4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10-((4R, 7R) -16-((5- (2-carboxy-1- (5- (2- (5 6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethoxy) -1H-indol-1-yl) ethyl) pyridin-3-yl) oxy) -2,5,8,13-tetraoxo- 4,7 -Bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,

2,2 ′, 2 ″-(10-((4R, 7R) -16-((5- (2-carboxy-1- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) -1H-indol-1-yl) ethyl) pyridin-3-yl) oxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl)- 3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10− (2-(((R) -1-((2- (4- (4- (N-((R) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) pentanamide) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamide) eth ) Amino) -1-oxo-3-sulfopropan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2 , 2 ′, 2 ″-(10-((4S, 9R) -18 (4- (N-((S) -2- (4- (2- (6-aminopyridin-2-yl) ethyl)) Benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) -4-(((R) -1-((2- (4- (4- (N-((S) -2- ( 4- (2- (6-Aminopyridin-2-yl) ethyl) benzamide) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropane -2-yl) carbamoyl) -2,7,10 15-tetraoxo-9- (sulfomethyl) -3,8,11,14-tetraazaoctadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ', 2' '-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -2- (4- (2- (6-amino Pyridin-2-yl) ethyl) benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino) -2 -Oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10-((4R, 7R) -16- ( 4- (N-((S) -2- (4- (2- (6-aminopyridine- 2-yl) ethyl) benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9, 12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) ) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10 -Tetraazacyclododecane-1 4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S)-) 1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino ) -1-oxo-3-sulfopropan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ', 2' '-(10-((4R, 7R) -16- (4-((S) -2-carboxy-1- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) benzamido) ethyl) -2-fluorophenoxy) -2, , 8,13-Tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl ) Triacetic acid, 2,2 ′-((1-(((S) -2- (bis (carboxymethyl) amino) -3- (4- (3-((R) -1-(((R)) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridine- 2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino) -1-oxo-3-sulfo Propan-2-yl) thioureido) phenyl) propyl) (carbo (Cymethyl) amino) propan-2-yl) azanediyl) diacetic acid, (S) -2,2 ′, 2 ″-(10- (2-((2- (4- (4- (N- (1- Carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl ) Amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″, 2 ′ ″-(2- (4- (3-((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro -1,8-naphthyridin-2-yl) pentanamide) ethyl) sulfamoyl) -3,5-dimethylphenoxy Cis) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) thioureido) benzyl) -1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) Tetraacetic acid, 2,2 ′-((1-(((S) -2- (bis (carboxymethyl) amino) -3- (4- (3-((R) -1-((2- (4 -(4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl)- 3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) thioureido) phenyl) propyl) (carboxymethyl) amino) propan-2-yl) azanediyl) diacetic acid, 2, 2 ' 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (5,6, 7,8-tetrahydro-1,8-naphthyridin-2-yl) butanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) Amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10- (2-(((( R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (6- (5,6,7,8-tetrahydro-1,8-naphthyridine-2 -Yl) hexaneamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) eth ) Amino) -1-oxo-3-sulfonyl-2-yl) amino) -2-oxoethyl) -1,4,7,10 tetraazacyclododecane-1,4,7-triyl) triacetic acid,

2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (5- (2- (5,6,7 , 8-Tetrahydro-1,8-naphthyridin-2-yl) ethyl) thiophene-2-carboxamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7- Bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ′ '-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1, 8-Naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) phenoxy) -2 5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7- Triyl) triacetic acid hexasodium salt, 2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- ( 3- (Pyridin-2-ylamino) propyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9 , 12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,

2,2 ′-(7-((R) -1-carboxy-4-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2 -(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo -3-Sulfopropan-2-yl) amino) -4-oxobutyl) -1,4,7-triazonan-1,4-diyl) diacetic acid and 5-(((R) -1-((2- ( 4- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1- Oxo-3-sulfopropan-2-yl) amino) -2- (11- (carboxymethyl) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) -5 -The treatment agent according to [1], which is a compound selected from the group consisting of oxopentanoic acid or a salt thereof.
[8]
The therapeutic treatment agent according to any one of [1] to [7], wherein the metal is a cytotoxic radioactive metal.
[9]
The therapeutic treatment agent according to [8], wherein the cytotoxic radioactive metal is a metal selected from the group consisting of ⁶⁴ Cu, ⁶⁷ Cu, ⁹⁰ Y, ¹⁶⁶ Ho, ¹⁵³ Sm, ¹⁷⁷ Lu, and ²²⁵ Ac.
[10]
The diagnostic treatment agent according to any one of [1] to [7], wherein the metal is a non-cytotoxic radioactive metal.
[11]
The diagnostic treatment agent according to [10], wherein the non-cytotoxic radioactive metal is a metal selected from the group consisting of ¹⁸ F aluminum complex, ¹¹¹ In, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ Ga and ⁸⁹ Zr.

  The treatment agent of the present invention has high accumulation and persistence in integrin-expressing cells such as cancer cells and rapid blood clearance, and is therefore useful for diagnosis or treatment of diseases involving integrin.

It is a figure which shows correlation with the amount of tumor accumulation, and the integrin (beta) 3 expression level in a tumor mass. The imaging result of the integrin expression tumor by PET using [ ⁶⁴ Cu]-(P2) is shown. The imaging result of the integrin expression tumor by PET using [ ⁶⁴ Cu]-(Aa7) is shown. The imaging result of the integrin expression tumor by PET using [ ⁶⁴ Cu]-(Ab9-a) is shown. The imaging result of the integrin expression tumor by PET using [ ⁶⁴ Cu]-(Ab9-b) is shown. The imaging result of the integrin expression tumor by a gamma camera is shown. The results of imaging integrin-expressing tumors in an intracranial tumor model are shown. The blood concentration transition in monkeys using [ ¹¹¹ In]-(P2) is shown. Fig. 5 shows the results of monkey planar imaging over time using [ ^111In ]-(P2).

Hereinafter, the present invention will be described in detail.
General formula used in the present invention

The group represented by x is a group in which x A's are bonded.

Means. The x A's may be the same or different.

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

  A halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

C _1-4 alkyl group means a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group.
C _1-6 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 2-pentyl, 3-pentyl and hexyl groups. A chain or branched C _1-6 alkyl group is meant.
An aryl group means C _6-10 aryl groups such as phenyl and naphthyl groups.
An al C _1-6 alkyl group means a C _6-10 al C _1-6 alkyl group such as benzyl, diphenylmethyl, trityl, phenethyl, 2-phenylpropyl, 3-phenylpropyl and naphthylmethyl groups.

The C _1-4 alkylene group means a linear or branched C _1-4 alkylene group such as methylene, ethylene, propylene and butylene groups.
The C _1-6 alkylene group means a linear or branched C _1-6 alkylene group such as methylene, ethylene, propylene, butylene, pentylene and hexylene groups.
The —O—C _1-6 alkylene group means a group in which a C _1-6 alkylene group is bonded to an oxygen atom such as oxyethylene, oxypropylene and oxybutylene groups.
The —NH—C _1-6 alkylene group means a group in which a C _1-6 alkylene group is bonded to an amino group such as aminoethylene, aminopropylene, and aminobutylene group.
The C _3-8 cycloalkylene group means a cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene or cyclooctylene group.

The C _1-4 alkanetriyl group means a linear or branched C _1-4 alkanetriyl group such as methanetriyl, ethanetriyl, propanetriyl and butanetriyl groups.
The C _1-6 alkanetriyl group means a linear or branched C _1-6 alkanetriyl group such as methanetriyl, ethanetriyl, propanetriyl, butanetriyl, pentanetriyl and hexanetriyl groups. To do.

C _1-6 alkoxy group means linear, cyclic or methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, cyclobutoxy, pentyloxy and hexyloxy groups It means a branched C _1-6 alkyloxy group.
The C _1-6 alkoxy C _1-6 alkyl group means a C _1-6 alkyloxy C _1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl group.

C _1-6 alkylamino group means methylamino, ethylamino, propylamino, isopropylamino, cyclopropylamino, butylamino, sec-butylamino, tert-butylamino, cyclobutylamino, pentylamino, cyclopentylamino, hexyl It means a linear, branched or cyclic C _1-6 alkylamino group such as amino and cyclohexylamino groups.
Di (C _1-6 alkyl) amino group means dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, di (tert-butyl) amino, dipentylamino, dihexylamino, (ethyl) (methyl) amino, Linear, branched or cyclic di (C ₁ ) such as (methyl) (propyl) amino, (cyclopropyl) (methyl) amino, (cyclobutyl) (methyl) amino, (cyclohexyl) (methyl) amino groups _-6 alkyl) amino group.

The C _2-6 alkanoyl group means a linear or branched C _2-6 alkanoyl group such as acetyl, propionyl, valeryl, isovaleryl and pivaloyl groups.
An aroyl group means a C _6-10 aroyl group such as benzoyl and naphthoyl groups.
Heterocyclic carbonyl groups are monocyclic or bicyclic heterocyclic groups such as furoyl, thenoyl, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl and pyridinylcarbonyl groups. Means a carbonyl group.
An acyl group means a formyl group, a succinyl group, a glutaryl group, a maleoyl group, a phthaloyl group, a C _2-6 alkanoyl group, an aroyl group or a heterocyclic carbonyl group.

The C _1-6 alkoxycarbonyl group is a linear or branched C _1-6 alkyloxy group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, and 1,1-dimethylpropoxycarbonyl group. Means a carbonyl group.
The al C _1-6 alkoxycarbonyl group means a C _6-10 al C _1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups.

The C _1-6 alkylthio group means a C _1-6 alkylthio group such as methylthio, ethylthio, propylthio and butylthio groups.
The C _1-6 alkylsulfonyl group means a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl and propylsulfonyl groups.
An arylsulfonyl group means a C _6-10 arylsulfonyl group such as benzenesulfonyl, p-toluenesulfonyl and naphthalenesulfonyl groups.
The C _1-6 alkylsulfonyloxy group means a C _1-6 alkylsulfonyloxy group such as methylsulfonyloxy and ethylsulfonyloxy groups.
An arylsulfonyloxy group means a C _6-10 arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy groups.

Monocyclic nitrogen-containing heterocyclic groups include aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, piperidyl, tetrahydropyridyl, dihydropyridyl, pyridyl, homopiperidinyl, octahydroazosinyl, imidazolidinyl, imidazolinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolinyl, pyrazolinyl , Piperazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, homopiperazinyl, triazolyl and tetrazolyl groups, and the like means a monocyclic heterocyclic group containing only a nitrogen atom as a hetero atom forming the ring.
The monocyclic oxygen-containing heterocyclic group is an oxygen atom as a hetero atom forming the ring such as oxetanyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, 1,3-dioxanyl and 1,4-dioxanyl groups. Means a monocyclic heterocyclic group containing only
The monocyclic sulfur-containing heterocyclic group means a monocyclic heterocyclic group containing only a sulfur atom as a hetero atom forming a ring such as a thienyl group.
The monocyclic nitrogen-containing / oxygen heterocyclic group is a monocyclic heterocyclic group containing only a nitrogen atom and an oxygen atom as hetero atoms forming the ring, such as oxazolyl, isoxazolyl, oxadiazolyl, morpholinyl and oxazepanyl groups. Means.
A monocyclic nitrogen-containing / sulfur heterocyclic group is a heterocycle that forms the ring such as thiazolyl, isothiazolyl, thiadiazolyl, thiomorpholinyl, 1-oxidethiomorpholinyl and 1,1-dioxidethiomorpholinyl groups. It means a monocyclic heterocyclic group containing only nitrogen and sulfur atoms as atoms.
Monocyclic heterocyclic group means monocyclic nitrogen-containing heterocyclic group, monocyclic oxygen-containing heterocyclic group, monocyclic sulfur-containing heterocyclic group, monocyclic nitrogen-containing / oxygen heterocyclic group It means a group or a monocyclic nitrogen-containing / sulfur heterocyclic group.

Bicyclic nitrogen-containing heterocyclic groups include indolinyl, indolyl, isoindolinyl, isoindolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrazolopyridinyl, quinolyl, tetrahydroquinolinyl, quinolyl, tetrahydroisoquinolyl Bicyclic heterocycles containing only a nitrogen atom as a hetero atom forming the ring such as nyl, isoquinolinyl, quinolidinyl, cinnolinyl, phthalazinyl, quinazolinyl, dihydroquinoxalinyl, quinoxalinyl, naphthyridinyl, purinyl, pteridinyl and quinuclidinyl groups Means a formula group.
Bicyclic oxygen-containing heterocyclic groups include 2,3-dihydrobenzofuranyl, benzofuranyl, isobenzofuranyl, chromanyl, chromenyl, isochromanyl, 1,3-benzodioxolyl, 1,3-benzodi It means a bicyclic heterocyclic group containing only an oxygen atom as a hetero atom forming the ring, such as oxanyl and 1,4-benzodioxanyl group.
The bicyclic sulfur-containing heterocyclic group means a bicyclic heterocyclic group containing only a sulfur atom as a hetero atom forming the ring, such as 2,3-dihydrobenzothienyl and benzothienyl groups. To do.
Bicyclic nitrogen-containing / oxygen heterocyclic groups include benzoxazolyl, benzisoxazolyl, benzooxadiazolyl, benzomorpholinyl, dihydropyranopyridyl, dioxoropyridyl, furopyridinyl, dihydrodio A bicyclic heterocyclic group containing only a nitrogen atom and an oxygen atom as the hetero atoms forming the ring, such as a xinopyridyl and dihydropyridoxazinyl group.
Bicyclic nitrogen-containing / sulfur heterocyclic groups are bicyclic heterocycles containing nitrogen and sulfur atoms as the hetero atoms forming the ring, such as benzothiazolyl, benzisothiazolyl, and benzothiadiazolyl groups. Means a cyclic group.
A bicyclic heterocyclic group is a bicyclic nitrogen-containing heterocyclic group, a bicyclic oxygen-containing heterocyclic group, a bicyclic sulfur-containing heterocyclic group, or a bicyclic nitrogen-containing group. -An oxygen heterocyclic group or a bicyclic nitrogen-containing / sulfur heterocyclic group.

  The heterocyclic group means a monocyclic heterocyclic group or a bicyclic heterocyclic group.

The divalent aromatic hydrocarbon group means a divalent aromatic hydrocarbon group that may be partially hydrogenated, such as phenylene, pentalenylene, indanylene, indenylene, and naphthylene groups.
Divalent heterocyclic groups include pyrrole diyl, imidazole diyl, triazole diyl, tetrazole diyl, pyrrolidine diyl, imidazolidine diyl, frangyl, thiophene diyl, oxazole diyl, thiazole diyl, pyridine diyl, pyrimidine diyl, indole diyl, quinoline diyl And a group formed by further removing one hydrogen atom from a heterocyclic group such as an isoquinolinediyl group.

Amino protecting groups include all groups that can be used as protecting groups for ordinary amino groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, an al C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, an acyl group, a C _1-6 alkoxycarbonyl group, an al C _1-6 alkoxycarbonyl group, a C _{1- 6} alkylsulfonyl group, and arylsulfonyl group, or a silyl group.

Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pages 16-366, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specifically, for example, C _1-6 alkyl group, al C _1-6 alkyl group, C _1-6 alkoxy C _1-6 alkyl group, acyl group, C _1-6 alkoxycarbonyl group, al C _1-6 Examples thereof include an alkoxycarbonyl group, a C _1-6 alkylsulfonyl group, an arylsulfonyl group, a silyl group, a tetrahydrofuranyl group, and a tetrahydropyranyl group.

The carboxyl protecting group includes all groups that can be used as protecting groups for ordinary carboxyl groups. W. Greene et al., Protective Groups in Organic Synthesis 4th Edition, pp. 533-646, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specific examples include a C _1-6 alkyl group, an aryl group, an ar C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, and a silyl group.

Examples of thiol protecting groups include all groups that can be used as protecting groups for ordinary thiol groups. W. Greene et al., Protective Groups in Organic Synthesis, 4th edition, pp. 647-695, 2007, John Wiley & Sons (John Wiley & Sons, INC.). Specific examples include a C _1-6 alkyl group, an al C _1-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, an acyl group, and a silyl group.

  The silyl group means trimethylsilyl, triethylsilyl, tributylsilyl group, tert-butyldimethylsilyl group or the like.

Examples of the leaving group include a halogen atom, a C _1-6 alkylsulfonyloxy group, and an arylsulfonyloxy group. The C _1-6 alkylsulfonyloxy group and arylsulfonyloxy group may be substituted.

A chelate group means an organic group to which a metal can chelate bond. Specifically, a group having an alkylene diamine structure, a bipyridine structure, an alkylene diamine tetraacetic acid structure, a phenanthroline structure, a porphyrin structure, a crown ether structure, a polyaza macrocyclic structure, a polyaminopolycarboxylic acid structure or a polyaminopolyphosphonic acid structure. Can be mentioned.
The polyaza macrocyclic structure means a structure having a cyclic basic skeleton in which 3 to 5 nitrogen atoms are connected by the same number of C _1-6 alkylene groups as the nitrogen atoms. For example, Cyclen, Cyclam, Bridged -Cyclam, ET-Cyclam or diasar.
The polyaminopolycarboxylic acid structure is a structure in which 3 to 5 nitrogen atoms are connected by the same number of C _1-6 alkylene groups as the nitrogen atoms to form a closure, and at least two of the nitrogen atoms have at least two nitrogen atoms. A structure having a basic skeleton to which each C _1-6 alkyl group substituted with one carboxyl group is bonded, or a C _1-6 alkylene group having 2 to 4 nitrogen atoms less than the number of nitrogen atoms And / or a C _3-8 cycloalkylene group connected to form an open chain, and at least two of the nitrogen atoms are each bonded with a C _1-6 alkyl group substituted with at least one carboxyl group. For example, DOTA, DO3A, DO2A, CB-DO2A, TETA, TE3A, TE2A, CB-TE2A, NOTA, NODASA, N DAGA, BCNOTA, EDTA, DTPA, include 1B4M-DTPA or CHX-DTPA.
The polyaminopolyphosphonic acid structure means a basic skeleton obtained by replacing at least one carboxyl group of the basic skeleton of the polyaminopolycarboxylic acid structure with a phosphono group, and examples thereof include DOTP, NOTP, EDTP, HDTP, and NTP.
A group having a polyaza macrocyclic structure, a polyaminopolycarboxylic acid structure or a polyaminophosphonic acid structure as a chelating group is coordinated to a metal with a plurality of nitrogen atoms, carboxyl groups and / or phosphono groups to form a complex. The metal and the N terminus of L ¹ are linked via a carboxyl group not involved in coordination, a phosphono group not involved in coordination, or a side chain introduced onto the basic skeleton thereof. Such a side chain is preferably one that can be easily bonded to L ^1, and is an active group such as an anhydride group, bromoacetamide group, iodoacetamide group, isothiocyanato group, N-hydroxysuccinimide group, or maleimide group. (Liu et al., Advanced Drug Delivery Reviews 60: 1347-1370 (2008)).

Halogenated hydrocarbons mean methylene chloride, chloroform or dichloroethane.
Ethers mean diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
Alcohol means methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
Ketones mean acetone, 2-butanone, 4-methyl-2-pentanone or methyl isobutyl ketone.
Esters mean methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
Amides mean N, N-dimethylformamide, N, N-dimethylacetamide or N-methylpyrrolidone.
Nitriles mean acetonitrile or propionitrile.
The sulfoxide means dimethyl sulfoxide or sulfolane.
Aromatic hydrocarbons mean benzene, toluene or xylene.

Inorganic base means sodium hydroxide, potassium hydroxide, tert-butoxy sodium, tert-butoxy potassium, sodium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate.
Organic base means triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo (5.4.0) undec-7-ene (DBU), 4-dimethylaminopyridine or N-methylmorpholine.

As the salt of the compound represented by the general formula (1) and the compound represented by the general formula (S1a), generally known salts in basic groups such as amino groups, acidic groups such as hydroxyl groups and carboxyl groups Can be mentioned.
Examples of salts in basic groups include salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, Salts with organic carboxylic acids such as tartaric acid, aspartic acid, trichloroacetic acid and trifluoroacetic acid; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Can be mentioned.
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, pyridine, N, N— Nitrogen-containing organic bases such as dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine And a salt thereof.
Among the above-described salts, preferred salts include pharmaceutically acceptable salts.

Treatment means diagnosis, prevention or treatment of various diseases.
Diagnosis means judgment of a disease to be treated or a state of a disease to be treated.
Prevention means inhibition of onset, reduction of onset risk or delay of onset.
Treatment means improvement of a target disease or condition or suppression of progression.
The treatment agent means a substance provided for the purpose of treatment.

  The compound contained in the treatment agent of the present invention has the general formula (1)

(Wherein R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , L ¹ , L ² , L ³ and A ¹ have the same meaning as described above). The

A ¹ is a chelate group.
The chelate group for A ¹ is preferably a group having a polyaza macrocyclic structure, a group having a polyaminopolycarboxylic acid structure or a group having a polyaminopolyphosphonic acid structure, more preferably a group having a polyaminopolycarboxylic acid structure, General formula (5), (6), (7), (8), (9), (10), (11) or (12)

(In the formula, R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ⁱ , X ¹ , X ² , X ³ , X ⁴ , X ^4a , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ^8a , X ⁹ , X ¹⁰ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ and Q ¹ have the same meaning as described above. And a group represented by formulas (5a), (6a), (7a), (8a), (8b), (8c), (9a), (10a), (10b), (11a), (11b), (11c) or (12a)

The group represented by formula (5a), (8c) or (12a) is particularly preferred.

The group represented by is most preferable.

R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h and R ⁱ are a hydrogen atom or a carboxyl protecting group.
R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h and R ⁱ are preferably a hydrogen atom or a C _1-6 alkyl group, more preferably a hydrogen atom.

^{X 1, X 2, X 3} , X 4, X 5, X 6, X 7, X 8, X 9, Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7 and Y ⁸ Is an optionally substituted C _1-6 alkylene group or an optionally substituted C _3-8 cycloalkylene group.
^{X 1, X 2, X 3} , X 4, X 5, X 6, X 7, X 8, X 9, Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7 and Y ⁸ as is preferably a good C _1-4 alkylene group which may be substituted, more preferably C _1-4 alkylene group, a methylene group, an ethylene group or a propylene group are more preferable.
^{X 1, X 2, X 3} , X 4, X 5, X 6, X 7, X 8, X 9, Y 1, Y 2, Y 3, Y 4, Y 5, Y 6, Y 7 and Y ⁸ _{Examples of the} substituent of the C _1-6 alkylene group or C _3-8 cycloalkylene group include one or more groups selected from the substituent group α.

Substituent group α: halogen atom, cyano group, carbamoyl group, sulfo group, amino group which may be protected, hydroxyl group which may be protected, carboxyl group which may be protected, C _1-6 alkyl group , C _1-6 alkoxy group, aryl group, heterocyclic group and oxo group.

X ¹⁰ is an optionally substituted C _1-6 alkylene group.
The X ^10, preferably has good C _1-4 alkylene group which may be substituted, more preferably C _1-4 alkylene group, an ethylene group is more preferred.
Examples of the substituent for the C _1-6 alkylene group represented by X ¹⁰ include one or more groups selected from the substituent group α.

X ^4a and X ^8a are ^optionally substituted C _1-6 alkanetriyl groups.
As X ^4a and X ^{8a, an optionally} substituted C _1-4 alkanetriyl group is preferable, and a C _1-4 alkanetriyl group is more preferable.
^Examples of the substituent of the C _1-6 alkanetriyl group of X ^4a and X ^8a include one or more groups selected from the substituent group α.

R ¹ is a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group.
R ¹ is preferably a hydrogen atom or an optionally substituted C _1-6 alkyl group, more preferably a hydrogen atom.
_Examples of the substituent for the C _1-6 alkyl group represented by R ¹ include one or more groups selected from the substituent group α.

R ² is a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group.
R ² is preferably a hydrogen atom or an optionally substituted C _1-6 alkyl group, and more preferably a hydrogen atom.
_Examples of the substituent for the C _1-6 alkyl group represented by R ² include one or more groups selected from the substituent group α.

Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are each a nitrogen atom or CR ³ (wherein R ³ has the same meaning as described above). However, at least one of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is CR ^3a (wherein R ^3a has the same meaning as described above).

The Z ¹ and Z ^5, the same or different, CR ³ (wherein, R ³ is. Which are of the same meaning) is preferred, in CR ^3b (wherein, R ^3b is the same meaning as defined above Is more preferable, and CR ^3d (wherein R ^3d represents a hydrogen atom or an optionally substituted C _1-6 alkyl group) is more preferable.

Z ² is preferably a nitrogen atom or CR ³ (wherein R ³ has the same meaning as described above), and a nitrogen atom or CR ^3b (wherein R ^3b has the same meaning as described above). ) Is more preferable, and CR ^3b (wherein R ^3b has the same meaning as described above) is further preferable, and CR ^3d (wherein R ^3d has the same meaning as described above) is particularly preferable. preferable.

Z ³ is preferably CR ³ (wherein R ³ has the same meaning as described above).
When Z ² is a nitrogen atom, Z ³ is preferably CR ^3b (wherein R ^3b has the same meaning as described above).
When Z ² is CR ³ (wherein R ³ has the same meaning as described above), Z ³ is CR ^3a (wherein R ^3a has the same meaning as described above). ) Is preferred.
Z ³ is more preferably CR ^3c (wherein R ^3c has the same meaning as described above), and CR ^3e (wherein R ^3e represents the general formula (2c)).

(In the formula, n ¹ R ^5b and n ¹ R ^6b are the same or different and each represents a hydrogen atom or an optionally protected carboxyl group; L ^4a represents an optionally substituted divalent fragrance. A hydrocarbon group or a bond; n ¹ represents 1 or 2, and L ^5a has the same meaning as described above.)
The group represented by these is shown. Is particularly preferred.

Z ⁴ is preferably CR ³ (wherein R ³ has the same meaning as described above).
When Z ² is a nitrogen atom, Z ⁴ is more preferably CR ^3a (wherein R ^3a has the same meaning as described above).
When Z ² is CR ³ (wherein R ³ has the same meaning as described above), Z ⁴ is CR ^3b (wherein R ^3b has the same meaning as described above). ) Is more preferable.
Z ⁴ is more preferably CR ^3b (wherein R ^3b has the same meaning as described above), and CR ^3d (wherein R ^3d has the same meaning as described above) is particularly preferable. .

Preferred structures of the 6-membered ring having Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ include the following structures.

(Wherein R ³ has the same meaning as described above.)

More preferable structures of the 6-membered ring having Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ include the following structures.

(Wherein R ^3b and R ^3c have the same meaning as described above.)

More preferable structures of the 6-membered ring having Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ include the following structures.

(Wherein R ^3b and R ^3c have the same meaning as described above.)

R ³ represents a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkoxy group, or general formula (2)

(Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , L ⁴ , L ⁵ , m, n and p have the same meanings as described above. It is a group represented by.

Examples of the substituent for the C _1-6 alkyl group and the C _1-6 alkoxy group represented by R ³ include one or more groups selected from the substituent group α.

R ^3b is a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group or an optionally substituted C _1-6 alkoxylated groups.
R ^3b is preferably a hydrogen atom or an optionally substituted C _1-6 alkyl group.
^Examples of the substituent for the C _1-6 alkyl group and the C _1-6 alkoxy group of R ^3b include one or more groups selected from the substituent group α.

R ^3c represents the general formula (2a)

(Wherein R ^5a , R ^6a , R ^8a , R ^9a , L ⁴ , L ^5a and n have the same meaning as described above.
).
As R ^3c , general formula (2b)

(Wherein R ^5a , R ^6a , L ⁴ , L ^5a and n have the same meaning as described above) are preferred, and the general formula (2c)

(Wherein, R ^5b , R ^6b , L ^4a , L ^5a and n ¹ have the same meaning as described above) are more preferable.

R ⁴ is a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group.
R ⁴ is preferably a hydrogen atom.
_Examples of the substituent for the C _1-6 alkyl group represented by R ⁴ include one or more groups selected from the substituent group α.

n R ⁵ and n R ⁶ are the same or different and each represents a hydrogen atom, a halogen atom, an optionally substituted C _1-6 alkyl group or an optionally protected carboxyl group.
R ⁵ and R ⁶ are the same or different and are preferably a hydrogen atom, an optionally substituted C _1-6 alkyl group or an optionally protected carboxyl group.
_Examples of the substituent for the C _1-6 alkyl group represented by R ⁵ and R ⁶ include one or more groups selected from the substituent group α.

n R ^5a and n R ^6a are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an optionally protected carboxyl group.
R ^5a is preferably a hydrogen atom or an optionally protected carboxyl group.
R ^6a is preferably a hydrogen atom or an optionally protected carboxyl group.
^Examples of the substituent for the C _1-6 alkyl group represented by R ^5a and R ^6a include one or more groups selected from the substituent group α.

n ¹ R ^5b and n ¹ R ^6b are the same or different and each represents a hydrogen atom or an optionally protected carboxyl group.
R ^5b is preferably a hydrogen atom.
R ^6b is preferably a hydrogen atom.

R ⁷ is a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group.
R ⁷ is preferably a hydrogen atom.
_Examples of the substituent for the C _1-6 alkyl group represented by R ⁷ include one or more groups selected from the substituent group α.

R ⁸ is a hydrogen atom, an optionally substituted C _1-6 alkyl group, a bond to L ⁵ or an optionally substituted C _1-6 alkylene group together with R ⁹ .
As R ^8, a hydrogen atom, a C _1-6 alkylene group is preferable may be substituted together with a C _1-6 alkyl group or R ⁹ may be substituted, it is substituted together with R ⁹ An optional C _1-6 alkylene group is more preferable.
_Examples of the substituent for the C _1-6 alkyl group represented by R ⁸ include one or more groups selected from the substituent group α.
Examples of the substituent of the C _1-6 alkylene group formed together with R ⁹ include one or more groups selected from the substituent group β.

Substituent group β: halogen atom, cyano group, carbamoyl group, sulfo group, amino group which may be protected, hydroxyl group which may be protected, carboxyl group which may be protected, C _1-6 alkyl group A C _1-6 alkoxy group, an aryl group, a C _1-6 alkylamino group, a di (C _1-6 alkyl) amino group, a heterocyclic group, and an oxo group.

R ^8a is a hydrogen atom or an optionally substituted C _1-6 alkyl group; R ^9a is a hydrogen atom; or R ^8a and R ^9a together are optionally substituted C _{1 -6} alkylene group.
R ^8a and R ^9a are preferably a C _1-6 alkylene group which may be substituted together.
^Examples of the substituent for the C _1-6 alkyl group represented by R ^8a include one or more groups selected from the substituent group α.
^Examples of the substituent of the C _1-6 alkylene group formed together with R ^9a include one or more groups selected from the substituent group β.

R ⁹ is a hydrogen atom, a halogen atom, a protected or an amino group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkylamino group, optionally substituted di ( C _1-6 alkyl) amino group, a bond to L ⁵ or a C _1-6 alkylene group which may be substituted together with R ⁸ .
The R ^9, preferably a hydrogen atom or a C _1-6 alkylene group which may be substituted together with R ^8, and more preferably a C _1-6 alkylene group which may be substituted together with R ⁸ .
_Examples of the substituent for the C _1-6 alkyl group represented by R ⁹ include one or more groups selected from the substituent group α.
Examples of the substituent of the C _1-6 alkylene group formed together with R ⁸ include one or more groups selected from the substituent group β.

R ¹⁰ and R ¹¹ are the same or different, a hydrogen atom, a halogen atom, a protected or an amino group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkylamino group , A bond with an optionally substituted di (C _1-6 alkyl) amino group or L ⁵ .
R ¹⁰ and R ¹¹ are the same or different and are preferably a hydrogen atom, a halogen atom or an optionally substituted C _1-6 alkyl group, more preferably a hydrogen atom.
The substituent for the C _1-6 alkyl group, the C _1-6 alkylamino group and the di (C _1-6 alkyl) amino group of R ¹⁰ and R ¹¹ is one or more groups selected from the substituent group α. Can be mentioned.

R ¹² is a hydrogen atom, a halogen atom, a protected or an amino group, an optionally substituted C _1-6 alkyl group, an optionally substituted C _1-6 alkylamino group, optionally substituted di ( C _1-6 alkyl) amino group or a bond to L ⁵ .
R ¹² is preferably a bond with L ⁵ .
_Examples of the substituent of the C _1-6 alkyl group, the C _1-6 alkylamino group and the di (C _1-6 alkyl) amino group of R ¹² include one or more groups selected from the substituent group α.

Preferred structures of the 6-membered ring having R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² include the following structures.

(Wherein R ^8a and R ^9a have the same meaning as described above.)

More preferable structures of the 6-membered ring having R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² include the following structures.

More preferred structures of the 6-membered ring having R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² include the following structures.

L ⁴ is a divalent aromatic hydrocarbon group that may be substituted, a divalent heterocyclic group that may be substituted, or a bond.
L ⁴ is preferably a divalent aromatic hydrocarbon group, a divalent heterocyclic group or a bond, more preferably an optionally substituted divalent aromatic hydrocarbon group or a bond, a phenylene group, Indole diyl groups or bonds are more preferred.
Examples of the substituent of the divalent aromatic hydrocarbon group and divalent heterocyclic group of L ⁴ include one or more groups selected from the substituent group α.

L ⁵ represents a substituted C _1-6 alkylene group which may, optionally substituted -O-C _1-6 alkylene group or an optionally substituted -NH-C _1-6 alkylene group.
L ⁵ is preferably a C _1-6 alkylene group which may be substituted.
_{Examples of the} substituent of the C _1-6 alkylene group, —O—C _1-6 alkylene group and —NH—C _1-6 alkylene group of L ⁵ include one or more groups selected from the substituent group α. .

L ^5a is an optionally substituted C _1-6 alkylene group.
^Examples of the substituent for the C _1-6 alkylene group of L ^5a include one or more groups selected from the substituent group α.

m is 0 or 1.
As m, 1 is preferable.

n is an integer of 1 to 3.
n is preferably 1 or 2.

p is 0 or 1.
As p, 1 is preferable.

L ² is an optionally substituted C _1-6 alkylene group.
L ² is preferably a C _1-6 alkylene group, and more preferably a C _1-4 alkylene group.
Examples of the substituent for the C _1-6 alkylene group represented by L ² include one or more groups selected from the substituent group α.

L ³ is an optionally substituted C _1-6 alkylene group.
L ³ is preferably a C _1-6 alkylene group, and more preferably a C _1-4 alkylene group.
Examples of the substituent for the C _1-6 alkylene group of L ³ include one or more groups selected from the substituent group α.

L ¹ represents the general formula (3)

(Wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , q and r have the same meaning as described above).
As L ¹ , the general formula (3a)

(Wherein r ¹ R ^16a are the same or different and each represents a C _1-4 alkyl group which may be substituted with a sulfo group; r ¹ represents 1 or 2) Is preferred.

r R ^{13 s} are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group.
As r R < ¹³ >, a hydrogen atom or an amino protecting group is preferable, and a hydrogen atom is more preferable.
Examples of the substituent for the r R ¹³ C _1-6 alkyl groups include one or more groups selected from the substituent group α.

q × r R ¹⁴ and q × r R ¹⁵ are the same or different and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group.
As q × r R ¹⁴ and q × r R ¹⁵ , a hydrogen atom or a C _1-6 alkyl group is preferable, and a hydrogen atom is more preferable.
Examples of the substituent of the C _1-6 alkyl group of q × r R ¹⁴ and q × r R ¹⁵ include one or more groups selected from the substituent group α.

r R ^{16 s} are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, or a group represented by the general formula (4)

(Wherein R ¹ , R ² , R ¹⁷ , R ¹⁸ , R ¹⁹ , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , L ² , L ³ , s and t have the same meanings as described above. It is group represented by this.

The R ^16, a hydrogen atom, preferably a group represented by which may C _1-4 alkyl group or a group represented by formula is substituted (4), a hydrogen atom, may be substituted with a sulfo group C _1-4 alkyl group Or the group represented by General formula (4) is more preferable, and the _C1-4 alkyl group which may be substituted by a sulfo group is still more preferable.
_Examples of the substituent for the C _1-6 alkyl group represented by R ¹⁶ include one or more groups selected from substituent group γ.

Substituent group γ: halogen atom, cyano group, carbamoyl group, sulfo group, guadinino group, amino group which may be protected, hydroxyl group which may be protected, carboxyl group which may be protected, protected Mercapto group, C _1-6 alkyl group, C _1-6 alkoxy group, aryl group, C _1-6 alkylamino group, di (C _1-6 alkyl) amino group, C _1-6 alkylthio group, complex Cyclic and oxo groups.

s R ¹⁷ s are the same or different and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group.
R ¹⁷ is preferably a hydrogen atom or a C _1-6 alkyl group.
_Examples of the substituent for the C _1-6 alkyl group represented by R ¹⁷ include one or more groups selected from substituent group γ.

t R ^{18 s} are the same or different and each represents a hydrogen atom, an optionally substituted C _1-6 alkyl group or an amino protecting group.
R ¹⁸ is preferably a hydrogen atom or an amino protecting group.
_Examples of the substituent for the C _1-6 alkyl group represented by R ¹⁸ include one or more groups selected from the substituent group α.

t R ^{19 s} are the same or different and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group.
R ¹⁹ is preferably a hydrogen atom or a C _1-6 alkyl group.
_Examples of the substituent for the C _1-6 alkyl group represented by R ¹⁹ include one or more groups selected from the substituent group γ.

s is an integer of 1 to 3.
As s, 1 or 2 is preferable.

t is an integer of 0-3.
t is preferably 1 or 2.

q is an integer of 0-3.
r is an integer of 0-3.
As r, an integer of 1 to 3 is preferable.

In the compound represented by the general formula (1) or a salt thereof, A ¹ is a group having a polyaminopolycarboxylic acid structure; R ¹ is a hydrogen atom or an optionally substituted C _1-6 alkyl group R ² is a hydrogen atom or an optionally substituted C _1-6 alkyl group; Z ¹ , Z ² , Z ⁴ and Z ⁵ are the same or different and CR ^3b (wherein R ^3b is Z ³ is CR ^3c (wherein R ^3c has the same meaning as described above); and L ² may be substituted C _{1. -6} alkylene group; L ³ is an optionally substituted C _1-6 alkylene group; L ¹ is a group represented by the general formula (3)

(Wherein R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , q and r have the same meanings as described above); wherein the substituents of each group are the same as described above Or a salt thereof is preferred.

As the compound represented by the general formula (1) or a salt thereof, A ¹ is represented by the general formula (5), (6), (7), (8), (9), (10), (11) or (12)

(In the formula, R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h , R ⁱ , X ¹ , X ² , X ³ , X ⁴ , X ^4a , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ^8a , X ⁹ , X ¹⁰ , Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ , Y ⁷ , Y ⁸ and Q ¹ have the same meaning as described above. R ¹ is a hydrogen atom; R ² is a hydrogen atom; Z ¹ , Z ² , Z ⁴ and Z ⁵ are the same or different, and CR ^3d (Wherein R ^3d has the same meaning as described above); Z ³ is CR ^3e (wherein R ^3e has the same meaning as described above); and L ² is An optionally substituted C _1-6 alkylene group; L ³ is an optionally substituted C _1-6 alkylene group; and L ¹ is a group represented by the general formula (3a)

(Wherein R ^16a and r ¹ have the same meaning as described above); wherein the substituents of each group are the same as described above, and a compound or a salt thereof is more preferable .

As the compound represented by the general formula (1) or a salt thereof, the following compounds or salts thereof described in Examples are more preferable.
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7 , 8-Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 3, Compound No .: A8)
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo -3-Sulfopropan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 4, Compound No. B2) )
2,2 ′, 2 ″-(10-((4R, 7R, 10R) -19- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6 , 7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,11,16-pentaoxo-4,7, 10-tris (sulfomethyl) -3,6,9,12,15-pentaazanonadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 5) Compound No .: C3)
(S) -2,2 ′, 2 ″-(10- (19- (4- (N- (1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,11,16-trioxo-6,9-dioxa-3,12,15-triazanonadecyl ) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 6, compound number: D3)
2,2 ′, 2 ″-(10-((S) -4- (4-aminobutyl) -22- (4- (N-((S) -1-carboxy-2- (4- (2 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,14,19-tetraoxo-9 , 12-Dioxa-3,6,15,18-tetraazadocosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 7, Compound No .: E3)
(S) -2,2 ′, 2 ″-(10- (28- (4- (N- (1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,11,20,25-tetraoxo-6,9,15,18-tetraoxa-3,12 21,24-tetraazaoctacosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 8, compound number: F3)
2,2 ′, 2 ″-(10-((R) -22- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8 -Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,14,19-tetraoxo-4- (sulfomethyl) -9,12- Dioxa-3,6,15,18-tetraazadocosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 9, compound number: G3)
2,2 ′, 2 ″-(10-((9R) -18- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8 -Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -4-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl)- 3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) carbamoyl) -2,7,10,15-tetraoxo-9- (sulfomethyl) -3,8, 11,14-tetraazaoctadecyl) -1,4,7 10 tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 10, Compound No.: H9)

2,2 ′, 2 ″-(10-((4R, 7R) -16-((5- (2-carboxy-1- (5- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethoxy) -1H-indol-1-yl) ethyl) pyridin-3-yl) oxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl)- 3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 11, compound number: I21)
2,2 ′, 2 ″-(10-((4R, 7R) -16-((5- (2-carboxy-1- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) -1H-indol-1-yl) ethyl) pyridin-3-yl) oxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl)- 3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 12, compound number: J9)
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((R) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 13, Compound No .: K8)
2,2 ′, 2 ″-(10-((4S, 9R) -18 (4- (N-((S) -2- (4- (2- (6-aminopyridin-2-yl) ethyl ) Benzamide) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) -4-(((R) -1-((2- (4- (4- (N-((S) -2-)) (4- (2- (6-Aminopyridin-2-yl) ethyl) benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) carbamoyl) -2,7,10,15-tetraoxo-9- (sulfomethyl) -3,8,11,14-tetraazaoctadecyl) -1,4,7,10-tetraazacyclododecane -1,4,7-triyl) trivinegar (Reference Example 14, Compound No.: L10)
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -2- (4- (2- ( 6-aminopyridin-2-yl) ethyl) benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino ) -2-Oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 15, Compound No .: M2)
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -2- (4- (2- (6-aminopyridin-2-yl)) Ethyl) benzamide) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraaza Hexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 16, compound number: N3)
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8- Tetrahydro-1,8-naphthyridin-2-yl) pentanamide) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6 , 9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 17, Compound No .: O10)
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 18, Compound No .: P2)
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4-((S) -2-carboxy-1- (4- (2- (5,6,7,8- Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) -2-fluorophenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9, 12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 19, Compound No .: Q12)
2,2 ′-((1-(((S) -2- (bis (carboxymethyl) amino) -3- (4- (3-((R) -1-(((R) -1- ( (2- (4- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino) -1-oxo-3-sulfopropane-2- Yl) thioureido) phenyl) propyl) (carboxymethyl) amino) propan-2-yl) azanediyl) diacetic acid (Reference Example 20, Compound No .: R3)
(S) -2,2 ′, 2 ″-(10- (2-((2- (4- (4- (N- (1-carboxy-2- (4- (2- (5,6,6 7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -2-oxoethyl) -1,4,7, 10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 21, compound number: S2)

2,2 ′, 2 ″, 2 ′ ″-(2- (4- (3-((R) -1-((2- (4- (4- (N-((S) -1- Carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino)- 1-oxo-3-sulfopropan-2-yl) thioureido) benzyl) -1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid (Reference Example 22, Compound No. : T2)
2,2 ′-((1-(((S) -2- (bis (carboxymethyl) amino) -3- (4- (3-((R) -1-((2- (4- (4 -(N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5 -Dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) thioureido) phenyl) propyl) (carboxymethyl) amino) propan-2-yl) azanediyl) diacetic acid (Reference Example 23) , Compound No .: U1)
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropane -2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 24, Compound No .: V8)
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (6- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) hexanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 25, Compound No .: W10)
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (5- (2- (5,6,7 , 8-Tetrahydro-1,8-naphthyridin-2-yl) ethyl) thiophene-2-carboxamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7- Bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 26, Compound No .: X9)
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7 , 8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) phenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9 , 12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid hexasodium salt (Reference Example 27, compound number: Y13)
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- (3- (pyridin-2-ylamino) ) Propyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (Reference Example 28, Compound No .: Z8)
2,2 ′-(7-((R) -1-carboxy-4-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2 -(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo -3-Sulfopropan-2-yl) amino) -4-oxobutyl) -1,4,7-triazonan-1,4-diyl) diacetic acid (Reference Example 29, Compound No .: Aa7)
5-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1, 8-Naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino) -2- (11 -(Carboxymethyl) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) -5-oxopentanoic acid (Reference Example 30, compound numbers: Ab9-a and Ab9- b (Ab9-a and Ab9-b are stereoisomers))

Next, the manufacturing method of the compound represented by General formula (1) is demonstrated.
The compound represented by the general formula (1) is produced by combining methods known per se, and can be produced, for example, according to the production method shown below.

Manufacturing method 1

Wherein R ^A represents an amino protecting group; R ¹ , R ² , R ^B , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , A ¹ , L ¹ , L ² and L ³ are And have the same meaning as above.)

(1)
The compound represented by the general formula (S1a) can be produced by deprotecting the compound represented by the general formula (S1).
This reaction is described, for example, in T.W. W. TWGreene et al., Protective Groups in Organic Synthesis, 4th edition, pages 696-926, 2007, John Wiley & Sons, INC.).

(2)
The compound represented by the general formula (S2) is a compound known as a bifunctional chelate.
Examples of the compound represented by the general formula (S2) include DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), TETA (1,4,8,11). -Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid, DTPA (diethylenetriaminepentaacetic acid) and carboxyl-protected DOTA (1,4,7,10-tetraazacyclododecane-1,4,7 , 10-tetraacetic acid tri-tert-butyl ester and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tribenzyl ester).

(2-1)
If R ^B of the general formula (S2) is a hydroxyl group, the general formula (1) compound represented by the presence of a condensing agent, the presence or absence of a base, represented by the general formula (S1a) It can manufacture by making the compound represented by general formula (S2) react with this compound.
This reaction is described, for example, in the method described in Bioconjugate Chem., Vol. 3, Section 2, 1992 or Chemical Reviews, Vol. 97, p. 2243, 1997, etc. Can be performed.

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include ethers, esters, halogenated hydrocarbons, nitriles, amides, alcohols and water. These solvents may be used as a mixture. Preferable solvents include amides, and N, N-dimethylformamide and N, N-dimethylacetamide are more preferable.
Although the usage-amount of a solvent is not specifically limited, What is necessary is just 1-1000 times amount (v / w) with respect to the compound represented by general formula (S1a).

Bases optionally used in this reaction include inorganic bases or organic bases.
The amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula (S1a).

Examples of the condensing agent used in this reaction include carbodiimides such as N, N′-dicyclohexylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide; carbonyls such as carbonyldiimidazole; diphenylphosphoryl Acid azides such as azide; acid cyanides such as diethyl phosphoryl cyanide; 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; O-benzotriazol-1-yl-1,1,3,3- Ureas such as tetramethyluronium = hexafluorophosphate and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium = hexafluorophosphate; benzotriazol-1-yloxy -Trisdimethylaminophospho Ium hexafluorophosphate, and the like phosphonium salts such as (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate.
The condensation method may be performed by mixing the compound represented by the general formula (S1a) and the compound represented by the general formula (S2) and then adding a condensing agent. Alternatively, the compound represented by the general formula (S2) may be activated with a condensing agent in advance and then reacted with the compound represented by the general formula (S1a). Furthermore, active esters such as N-hydroxysuccinimide or pentafluorophenol can also be used.

Although the usage-amount of the compound represented by general formula (S2) is not specifically limited, What is necessary is just 0.5-10 times amount (w / w) with respect to the compound represented by general formula (S1a).
The reaction temperature may be -30 to 100 ° C, preferably 0 to 50 ° C, for 1 minute to 72 hours.

(2-2)
In the case where R ^{B in the} general formula (S2) is a leaving group, the compound represented by the general formula (1) is represented by the general formula (S2) in the presence of a base in the compound represented by the general formula (S1a). It can manufacture by making the compound represented react.

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include ethers, esters, halogenated hydrocarbons, nitriles and amides. You may mix and use a solvent.
Although the usage-amount of a solvent is not specifically limited, What is necessary is just 1-1000 times amount (v / w) with respect to the compound represented by general formula (S1a).

Examples of the base used in this reaction include an inorganic base and an organic base.
The amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula (S1a).

Although the usage-amount of the compound represented by general formula (S2) is not specifically limited, What is necessary is just 0.5-10 times amount (w / w) with respect to the compound represented by general formula (S1a).
The reaction temperature may be -30 to 100 ° C, preferably 0 to 50 ° C, for 1 minute to 72 hours.

Manufacturing method 2

(In the formula, B ¹ , R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , L ¹ , L ² , L ³ and Q ¹ have the same meaning as described above.)

As a compound represented by the general formula (S3), for example, NCS-DOTA (2- (p-isothiocyanatobenzyl) -1,4,7,10-tetraazacyclododecane-1,4,7,10- Tetraacetic acid) and MXDTPA (2- (p-isothiocyanatobenzyl) -5 (6) -methyl-diethylenetriaminepentaacetic acid) and the like are known.
The compound represented by the general formula (1a) can be produced by reacting the compound represented by the general formula (S1a) with the compound represented by the general formula (S3).

The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include ethers, esters, halogenated hydrocarbons, nitriles, amides, alcohols and water. These solvents may be used as a mixture. Preferable solvents include amides, and N, N-dimethylformamide and N, N-dimethylacetamide are more preferable.
Although the usage-amount of a solvent is not specifically limited, What is necessary is just 1-1000 times amount (v / w) with respect to the compound represented by general formula (S1a).

Examples of the base used in this reaction include an inorganic base and an organic base.
The amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula (S1a).

Although the usage-amount of the compound represented by general formula (S3) is not specifically limited, What is necessary is just 0.5-10 times amount (w / w) with respect to the compound represented by general formula (S1a).
The reaction temperature may be -30 to 100 ° C, preferably 0 to 50 ° C, for 1 minute to 72 hours.

Production method 3

(In the formula, R ¹ , R ^A , R ^B , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , L ¹ , L ² , L ³ and A ¹ have the same meaning as described above.)

(1)
The compound represented by the general formula (S4a) can be produced by deprotecting the compound represented by the general formula (S4).
This reaction may be performed according to production method 1 (1).

(2)
The compound represented by the general formula (1b) can be produced by reacting the compound represented by the general formula (S4a) with the compound represented by the general formula (S5).
This reaction may be performed according to production method 1 (2).

Next, the manufacturing method of a manufacturing raw material is demonstrated.
Manufacturing method A

(Wherein R ^C represents a leaving group; R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^A , R ^B , Z ¹ , Z ² , Z ⁴ , Z ⁵ , L ³ , L ⁴ , L ⁵ and n have the same meaning as described above.)

(1)
As the compound represented by the general formula (S6), for example, 4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzoic acid is known. .
As a compound represented by the general formula (S8), for example, benzyl (2-aminoethyl) carbamate is known.
The compound represented by the general formula (S7) can be produced by reacting the compound represented by the general formula (S8) with the compound represented by the general formula (S6).
This reaction may be performed according to production method 1 (2).

(2)
The compound represented by the general formula (S7a) can be produced by deprotecting the compound represented by the general formula (S7).
This reaction may be performed according to production method 1 (1).

(3)
The compound represented by the general formula (S5a) can be produced by reacting the compound represented by the general formula (S7a) with the compound represented by the general formula (S9) in the presence of a base.
The solvent used in this reaction is not particularly limited as long as it does not affect the reaction, and examples thereof include ethers, esters, halogenated hydrocarbons, nitriles and amides. You may mix and use a solvent. Preferable solvents include halogenated hydrocarbons, and methylene chloride is more preferable.
Although the usage-amount of a solvent is not specifically limited, What is necessary is just 1-1000 times amount (v / w) with respect to the compound represented by general formula (S7a).

Bases optionally used in this reaction include inorganic bases or organic bases.
The amount of the base used may be 1 to 50 times mol, preferably 1 to 10 times mol, of the compound represented by the general formula (S7a).
Although the usage-amount of the compound represented by general formula (S9) is not specifically limited, It is 1-50 times mole with respect to the compound represented by general formula (S7a), Preferably, it may be 1-10 times mole. That's fine.

  The reaction temperature may be -30 to 100 ° C, preferably 0 to 50 ° C, for 1 minute to 72 hours.

In this manufacturing method, the conversion of Z ³ has been described. Similarly to this method, Z ¹ , Z ² , Z ⁴ or Z ⁵ can also be converted.

Manufacturing method B

(Wherein R ² , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^A , R ^B , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , L ² , L ³ and q are the same as above. Has meaning.)

(1)
As a compound represented by the general formula (S11), for example, benzyl (2-aminoethyl) carbamate is known.
The compound represented by the general formula (S10) can be produced by reacting the compound represented by the general formula (S11) with the compound represented by the general formula (S5).
This reaction may be performed according to production method 1 (2).

(2)
The compound represented by the general formula (S10a) can be produced by deprotecting the compound represented by the general formula (S10).
This reaction may be performed according to production method 1 (1).

(3)
As the compound represented by the general formula (S12), for example, Fmoc-cysteic acid and Fmoc-8-amino-3,6-dioxaoctanoic acid are known.
The compound represented by the general formula (S1b) can be produced by reacting the compound represented by the general formula (S10a) with the compound represented by the general formula (S12).
This reaction may be performed according to production method 1 (2).

Manufacturing method C

(In the formula, R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^B , Z ¹ , Z ² , Z ⁴ , Z ⁵ , L ² , L ³ , L ⁴ , L ⁵ , m and n have the same meaning as described above.)

As the compound represented by the general formula (S6), for example, 4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzoic acid is known. .
Examples of the compound represented by the general formula (S13) include (S) -methyl 3-amino-2- (4- (4-((2-(((benzyloxy) carbonyl) amino) ethyl) amino)- 4-oxobutoxy) -2,6-dimethylphenylsulfonamido) propanoate The compound represented by the general formula (S10b) is the same as the compound represented by the general formula (S13). It can be produced by reacting.
This reaction may be performed according to production method 1 (2).

In this manufacturing method, the conversion of Z ³ has been described. Similarly to this method, Z ¹ , Z ² , Z ⁴ or Z ⁵ can also be converted.

Manufacturing method D

(Wherein R ^D represents a carboxyl protecting group; R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^B , Z ¹ , Z ² , Z ⁴ , Z ⁵ , L ³ , L ⁴ , L ⁵ , m and n have the same meaning as described above.)

The compound represented by the general formula (S5b) can be produced by reacting the compound represented by the general formula (S6) with the compound represented by the general formula (S14).
This reaction may be performed according to production method 1 (2).

In this manufacturing method, the conversion of Z ³ has been described. Similarly to this method, Z ¹ , Z ² , Z ⁴ or Z ⁵ can also be converted.

Manufacturing method E

(Wherein R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^A , R ^B , A ¹ , L ² and q have the same meaning as described above.)

(1)
The compound represented by the general formula (S15) can be produced by reacting the compound represented by the general formula (S11) with the compound represented by the general formula (S12).
This reaction may be performed according to production method 1 (2).

(2)
The compound represented by the general formula (S15a) can be produced by deprotecting the compound represented by the general formula (S15).
This reaction may be performed according to production method 1 (1).

(3)
The compound represented by the general formula (S4b) can be produced by reacting the compound represented by the general formula (S2a) with the compound represented by the general formula (S15a).
This reaction may be performed according to production method 1 (2).

Manufacturing method F

(Wherein R ¹⁴ , R ¹⁵ , R ¹⁶ , R ^A , B ¹ , L ² , Q ¹ and q have the same meaning as described above.)

The compound represented by the general formula (S4c) can be produced by reacting the compound represented by the general formula (S15a) with the compound represented by the general formula (S3a).
This reaction may be carried out according to production method 2.

  The compound obtained by the above production method is subjected to a reaction known per se such as condensation, addition, oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or a combination of these reactions as appropriate. Can be derived into other compounds.

  The compound obtained by the above production method can be isolated and purified by a usual method such as extraction, crystallization, distillation or column chromatography. The compound obtained by the above production method may be used in the next reaction as it is without being isolated.

  In the compound obtained by the above production method and an intermediate thereof, when an amino, hydroxyl or carboxyl group is present, the reaction can be carried out by appropriately combining those protecting groups. Moreover, when there are two or more protecting groups, they can be selectively deprotected by subjecting them to a reaction known per se.

  Among the compounds used in the above production method, compounds that can take the form of salts can also be used as salts. Examples of the salts include the same salts as the salts of the compound represented by the general formula (1) described above.

  In the compound used in the above production method, when isomers (for example, optical isomers, geometric isomers, tautomers and the like) exist, these isomers can also be used. Also, when solvates, hydrates and crystals of various shapes are present, these solvates, hydrates and crystals of various shapes can also be used.

The complex of the compound represented by the general formula (1) or a salt thereof and a metal can be produced, for example, as follows.
A complex can be produced by mixing the compound represented by the general formula (1) or a salt thereof and a metal ion in the presence of a buffer solution.
The buffer used in this reaction is not particularly limited as long as it does not affect the reaction. For example, sodium acetate buffer, ammonium acetate buffer, sodium citrate buffer or ammonium citrate buffer may be used. Can be mentioned.
The pH range of the buffer is preferably 3-6.
The reaction temperature and reaction time differ depending on the combination of the compound represented by the general formula (1) or a salt thereof and the radioactive metal, but may be 0 to 150 ° C. and 5 to 60 minutes.
The complex obtained by the above production method can be isolated and purified by a usual method such as extraction, crystallization, distillation or column chromatography.
Even when the metal is a radioactive metal, a complex can be produced according to the above production method, but the following points are taken into consideration in consideration of the radioactive metal emitting radiation and the radioactive metal in a trace amount. There is a need to.
Unnecessary extension of reaction time is not preferable because it may cause decomposition of the compound by radiation. Usually, the labeled compound can be obtained with a radiochemical yield of over 80%, but if higher purity is required, preparative liquid chromatography, preparative TLC, dialysis, solid phase extraction and / or limiting. It can be purified by methods such as external filtration.
Further, a metal fluoride complex that is a conjugate of fluoride and metal is regarded as a metal, and the complex can be produced by reacting with a compound represented by the general formula (1) or a salt thereof. This reaction can be performed, for example, by the method described in Japanese Patent No. 5388355.
In order to suppress degradation by radiation, it is preferable to add an additive such as gentisic acid, ascorbic acid, benzyl alcohol, tocopherol, gallic acid, gallic acid ester or α-thioglycerol.

  Examples of the complex used in the treatment agent of the present invention include the following for each application.

  Complexes useful for treatment agents such as nuclear magnetic resonance diagnosis include, for example, metal ions exhibiting paramagnetism (for example, Co, Mn, Cu, Cr, Ni, V, Au, Fe, Eu, Gd, Dy, Tb, And a complex having a metal component as a metal paramagnetic ion selected from the group consisting of Ho and Er.

  Complexes useful for therapeutic agents such as X-ray diagnosis include, for example, metal ions that absorb X-rays (for example, Re, Sm, Ho, Lu, Pm, Y, Bi, Pb, Os, Pd, Gd, La, And a complex having a metal component of a metal ion selected from the group consisting of Au, Yb, Dy, Cu, Rh, Ag, and Ir.

Complexes useful for therapeutic agents such as radioactive diagnosis or therapy include, for example, metal ions of radioactive metals (for example, ¹⁸ F aluminum complex, ¹⁸ F gallium complex, ¹⁸ F indium complex, ¹⁸ F lutetium complex, ¹⁸ F thallium complex, ⁴⁴ Sc, ⁴⁷ Sc, ⁵¹ Cr, ^{52 m} Mn, ⁵⁵ Co, ⁵⁷ Co, ⁵⁸ Co, ⁵² Fe, ⁵⁹ Fe, ⁶⁰ Co, ⁶² Cu, ⁶⁴ Cu, ⁶⁷ Cu, ⁶⁷ Ga, ⁶⁸ Ga, ⁷² As, ⁷² Se ⁷³ Se, ⁷⁵ Se, ⁷⁶ As, ⁸² Rb, ⁸² Sr, ⁸⁵ Sr, ⁸⁹ Sr, ⁸⁹ Zr, ⁸⁶ Y, ⁸⁷ Y, ⁹⁰ Y, ⁹⁵ Tc, ^{99 m} Tc, ¹⁰³ Ru, ¹⁰³ Pd, ¹⁰⁵ Rh, ¹⁰⁹ Pd, ¹¹¹ In, ^{114 m} In, ^{117 m} Sn, ¹¹¹ Ag, ^{113 m} In, ¹⁴⁰ La, ¹⁴⁹ Pm, ¹⁴⁹ Tb, ¹⁵² Tb, ¹⁵⁵ Tb, ¹⁶¹ Tb, ¹⁵³ Sm, ¹⁵⁹ Gd, ¹⁶⁵ Dy, ¹⁶⁶ Dy, ¹⁶⁶ Ho, ¹⁶⁵ Er, ¹⁶⁹ Yb, ^{175 b, 177 Lu, 186 Re,} 188 Re, 192 Ir, 197 Hg, 198 Au, 199 Au, 201 Tl, 203 Hg, 211 At, 212 Bi, 212 Pb, 213 Bi, 217 Bi, 223 Ra, 225 Ac and And a complex having a metal component of a metal ion of a radioactive metal selected from the group consisting of ²²⁷ Th and the like.

  The radioactive metal is preferably a cytotoxic radioactive metal when used as a therapeutic treatment agent, and is preferably a non-cytotoxic radioactive metal when used as a diagnostic treatment agent.

Non-cytotoxic radiometals used for diagnostic treatment agents include, for example, gamma-ray emitting nuclides or positron emitting nuclides (for example, ¹⁸ F aluminum complex, ¹⁸ F gallium complex, ¹⁸ F indium complex, ¹⁸ F lutetium complex, ¹⁸ F thallium). Complex, ^99m Tc, ¹¹¹ In, ^{113 m} In, ^{114 m} In, ⁶⁷ Ga, ⁶⁸ Ga, ⁸² Rb, ⁸⁶ Y, ⁸⁷ Y, ¹⁵² Tb, ¹⁵⁵ Tb, ²⁰¹ Tl, ⁵¹ Cr, ⁵² Fe, ⁵⁷ Co, ⁵⁸ Co, ⁶⁰ Co, ⁸² Sr, ⁸⁵ Sr, ¹⁹⁷ Hg, ⁴⁴ Sc, ⁶² Cu, ⁶⁴ Cu or ⁸⁹ Zr).
¹⁸ F aluminum complex, ¹¹¹ In, ⁶⁷ Ga, ⁶⁸ Ga, ⁶⁴ Cu, or ⁸⁹ Zr is preferable from the viewpoints of half-life, radiation energy, and ease of labeling reaction.

Examples of the cytotoxic radioactive metal used for the therapeutic treatment agent include alpha-emitting nuclides and beta-emitting nuclides.
Specifically, ⁹⁰ Y, ^{114 m} In, ^{117 m} Sn, ¹⁸⁶ Re, ¹⁸⁸ Re, ⁶⁴ Cu, ⁶⁷ Cu, ⁵⁹ Fe, ⁸⁹ Sr, ¹⁹⁸ Au, ²⁰³ Hg, ²¹² Pb, ¹⁶⁵ Dy, ¹⁰³ Ru, ¹⁴⁹ Tb, ¹⁶¹ Tb, ²¹² Bi, ¹⁶⁶ Ho, ¹⁶⁵ Er, ¹⁵³ Sm, ¹⁷⁷ Lu, ²¹³ Bi, ²²³ Ra, ²²⁵ Ac, or ²²⁷ Th.
Among these radioactive metals, ⁶⁴ Cu, ⁶⁷ Cu, ⁹⁰ Y, ¹⁵³ Sm, ¹⁶⁶ Ho, ¹⁷⁷ Lu or ²²⁵ Ac are preferable from the viewpoint of half-life, radiation energy, ease of labeling reaction, and stability of the complex. .

The treatment agent of the present invention includes a method of providing a pre-labeled preparation containing a complex of a compound represented by the general formula (1) or a salt thereof and a metal, a compound represented by the general formula (1) or a salt thereof However, any method may be used.
When provided as a pre-labeled preparation, a diagnostic or therapeutic treatment agent containing the labeled complex can be used for administration as it is.
When provided as a kit preparation, it can be used for administration after being labeled with a desired radioactive metal in the clinical field.
Kit formulations are provided as aqueous solutions or lyophilized formulations. When using a kit preparation, it is necessary to undergo a special purification process simply by adding and reacting with a radioactive metal obtained from a generator that is routinely used in the clinical setting or a radioactive metal provided by a pharmaceutical manufacturer separately or in combination with the kit preparation. The reaction solution can be prepared as it is as an administration solution.

The therapeutic treatment agent of the present invention may be used in combination with other anticancer agents. Examples of such other anticancer agents include alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum preparations, molecular targeted drugs, hormonal agents or biologics.
Examples of the alkylating agent include nitrogen mustard anticancer agents such as cyclophosphamide, nitrosourea anticancer agents such as ranimustine, and dacarbazine.
Examples of the antimetabolite include 5-FU, UFT, carmofur, capecitabine, tegafur, TS-1, gemcitabine and cytarabine.
Examples of the microtubule inhibitor include alkaloid anticancer agents such as vincristine and taxane anticancer agents such as docetaxel and paclitaxel.
Antibiotic anticancer agents include mitomycin C, doxorubicin, epirubicin, daunorubicin and bleomycin.
Examples of the topoisomerase inhibitor include irinotecan and nogitecan having a topoisomerase I inhibitory action and etoposide having a topoisomerase II inhibitory action.
Examples of platinum preparations include cisplatin, paraplatin, nedaplatin, and oxaliplatin.
Molecular targeted drugs include trastuzumab, rituximab, imatinib, gefitinib, erlotinib, bevacizumab, cetuximab, panitumumab, bortezomib, sunitinib, sorafenib, crizotinib and regorafenib.
Hormonal agents include dexamethasone, finasteride, tamoxifen and the like.
Biologics include interferons α, β and γ, interleukin 2, and the like.

  The therapeutic agent of the present invention may be used in combination with a cancer therapy, and in addition to surgery, radiation therapy (gamma knife therapy, cyber knife therapy, boron neutron capture therapy, proton beam therapy / heavy particle beam therapy) ), MR-guided focused ultrasound surgery, cryotherapy, radiofrequency coagulation therapy, ethanol infusion therapy, arterial embolization therapy, and the like.

Examples of the target disease of the treatment agent of the present invention include diseases involving mammalian integrins including humans.
Diseases involving integrin include, for example, cancer, ischemic disease, thrombosis, myocardial infarction, arteriosclerosis, angina, inflammation, osteolysis, osteoporosis, diabetic retinopathy, macular degeneration, myopia Ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeautic glaucoma, ulcerative colitis, Crohn's disease, multiple sclerosis, psoriasis and recurrent stenosis.
The type of cancer is not particularly limited. For example, rectal cancer, colon cancer, colon cancer, familial colorectal polyposis cancer and hereditary non-polyposis colorectal cancer, esophageal cancer, oral cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma Medullary thyroid cancer, papillary thyroid cancer, renal cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, endometrial cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, breast cancer, ureteral cancer , Skin cancer, melanoma, brain tumor, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumor, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acute lymphoblastic leukemia ( ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia bone (AML), chronic myelogenous leukemia (CML), adult T cell leukemia, hepatocellular carcinoma, gallbladder cancer, bile duct cancer, biliary tract cancer, bronchial cancer, lung cancer (Small cell lung cancer, non-small cell lung cancer, etc.), many Myeloma, basal cell tumor, teratoma, retinoblastoma, neuroblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myoma, fat Examples include sarcoma, fibrosarcoma, Ewing sarcoma, and plasmacytoma.
The treatment agent of the present invention may be used for solid cancer, preferably head and neck cancer, colorectal cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, glioblastoma, malignant melanoma, pancreatic cancer or prostate cancer. preferable.

  The therapeutic treatment agent of the present invention can be used to suppress cancer by administering an effective amount thereof to mammals including humans. When used as an anticancer agent, for example, preventive action of preventing cancer development, metastasis / implantation, recurrence, and inhibiting cancer cell growth or reducing cancer to prevent cancer progression Has the broadest meaning, including both therapeutic effects of improving symptoms and is not to be construed as limiting in any way.

Usually, a pharmacologically acceptable additive may be appropriately mixed with the treatment agent of the present invention.
Examples of the additive include an excipient, a disintegrant, a binder, a lubricant, a corrigent, a coloring agent, a flavoring agent, a surfactant, a coating agent, a stabilizer, and a plasticizer.
Excipients include sugar alcohols such as erythritol, mannitol, xylitol and sorbitol; sugars such as sucrose, powdered sugar, lactose and glucose; α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl β- Cyclodextrins such as cyclodextrin and sulfobutyl ether β-cyclodextrin sodium; celluloses such as crystalline cellulose and microcrystalline cellulose; and starches such as corn starch, potato starch and pregelatinized starch.
Examples of the disintegrant include carmellose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, crospovidone, low-substituted hydroxypropylcellulose, and partially pregelatinized starch.
Examples of the binder include hydroxypropylcellulose, carmellose sodium and methylcellulose.
Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid, and sucrose fatty acid ester.
Examples of the corrigent include aspartame, saccharin, stevia, thaumatin and acesulfame potassium.
Examples of the colorant include titanium dioxide, iron sesquioxide, yellow iron sesquioxide, black iron oxide, food red No. 102, food yellow No. 4, and food yellow No. 5.
Examples of flavoring agents include essential oils such as orange oil, lemon oil, peppermint oil and pine oil; essences such as orange essence and peppermint essence; flavors such as cherry flavor, vanilla flavor and fruit flavor; apple micron, banana micron, Powder fragrances such as peach micron, strawberry micron and orange micron; vanillin; and ethyl vanillin.
Examples of the surfactant include sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polysorbate and polyoxyethylene hydrogenated castor oil. Examples of the coating agent include hydroxypropyl methylcellulose, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, and methacrylic acid copolymer S. Can be mentioned.
Examples of the stabilizer include gentisic acid, ascorbic acid, benzyl alcohol, tocopherol, gallic acid, gallic acid ester, and α-thioglycerol.
Examples of the plasticizer include triethyl citrate, macrogol, triacetin, and propylene glycol.
These additives may be used alone or in combination of two or more.
The blending amount is not particularly limited, and may be blended appropriately so that the effect is sufficiently exhibited according to each purpose.
These are tablets, capsules, powders, syrups, granules, pills, suspensions, emulsions, solutions, powder formulations, suppositories, eye drops, nasal drops, ear drops, patches in accordance with conventional methods. It can be administered orally or parenterally in the form of an agent, ointment or injection. In addition, the administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. In general, for adults, it can be administered orally or parenterally (eg, injection, infusion, administration to the rectal site, etc.).

  When a radioactive metal is used, examples of the type include alpha-emitting nuclides, beta-emitting nuclides, gamma-emitting nuclides, positron-emitting nuclides, and the like. , A nuclide that emits β-rays).

The diagnostic treatment of the present invention can be used for integrin expression imaging. When a tumor or neovascular vessel that expresses integrin protein exists in the body, the compound represented by the general formula (1) or a complex thereof with a metal salt is accumulated in the tumor, etc., and a single photon tomography (SPECT), A tumor can be imaged by detecting radiation using a device such as a positron tomograph (PET) or a scintillation camera. A diagnostic agent is administered before treatment, and the integrin expression is confirmed or the presence or absence of abnormal accumulation in normal tissues is determined to judge the application of the therapeutic agent. The effect of the drug can be predicted to be high.
It can also be used for determination of therapeutic effect. By administering not only the therapeutic agent of the present invention but also any one of the treatments, the diagnostic agent of the present invention is administered, the tumor is imaged, and the change in accumulation over time is observed. It can be ascertained whether the tumor is shrinking over time and whether it is growing.

  The dose of the therapeutic treatment agent of the present invention varies depending on the age, sex, symptom, route of administration, number of doses, and dosage form of the patient. In general, the dose of the pharmaceutical composition is, for example, about a single dose. The range of 0.0000001 mg to 100 mg per kg of body weight can be selected, but is not limited to these ranges. For a single administration to an adult, the dose can be administered in such an amount that the radioactivity is 18.5 MBq to 7400 MBq.

  The dose of the diagnostic treatment agent of the present invention also varies depending on the age, sex, symptom, route of administration, number of doses, and dosage form of the patient. The range of 0.0000001 mg to 100 mg per kg of body weight can be selected, but is not limited to these ranges. For a single administration to an adult, it can be administered in an amount such that the radioactivity is 111 MBq to 740 MBq.

  Next, although a reference example, an Example, and a test example are given and this invention is demonstrated further in detail, this invention is not limited to these.

Unless otherwise specified, silica gel 60N (spherical / neutral) 63 to 210 μm (Kanto Chemical Co., Inc.) was used as a carrier in silica gel column chromatography.
The mixing ratio in the eluent is a volume ratio.
For example, “hexane / ethyl acetate = 90/10 to 50/50” changed the eluent of “hexane: ethyl acetate = 90: 10” to the eluent of “hexane: ethyl acetate = 50: 50”. Means.

^{The 1} H-NMR spectrum was measured using Bruker AV300 (Bruker) or JEOL JNM-AL400 (JEOL) using tetramethylsilane as an internal standard, and the δ value was expressed in ppm.

Unless otherwise specified, HPLC analysis is performed by Nexera HPLC System (Shimadzu Corporation) (column: TSKgel ODS-100Z (Tosoh Corp.), solvent: A solution = 0.1% formic acid / water, B solution = 0.1% formic acid / methanol / acetonitrile. (4: 1), gradient cycle: 0.0 min (A liquid / B liquid = 90/10), 30 min (A liquid / B liquid = 0/100), 40 min (A liquid / B liquid = 0/100), flow rate : 1.0 mL / min) or Waters 600E system (Waters) (column: SunFire C18OBD 4.6 x 150 mm (Waters) and CAPCELL PAK C18MG 4.6 x 150 mm (Shiseido)), gradient cycle: 0.0 min (A / B = 80/20), 10 min (A solution / B solution = 0/100), 15 min (A solution / B solution = 0/100), flow rate: 1.0 mL / min). When analysis conditions such as separation of optical isomers were different, the conditions were described in the examples.
Unless otherwise noted, preparative HPLC was performed on a Waters 600E system (Waters) (column: SunFirePrepC18OBD 30 x 150 mm (Waters) or SunFire PrepC18OBD 19 x 150 mm (Waters)), solvent: Solution A = 0.1% formic acid / water , Solution B = 0.1% formic acid / methanol: acetonitrile (4: 1) or solvent: solution A = 10 mmol / L ammonium acetate aqueous solution, solution B = 10 mmol / L ammonium acetate / methanol: acetonitrile (4: 1)) I went.
Unless otherwise specified, silica gel 60F ₂₅₄ (MERCK) or RP-18F ₂₅₄ (MERCK) was used for TLC analysis.

MS and LC / MS analysis was performed using LCMS-2010EV (Shimadzu Corporation) (column: SunFire C18 4.6x150 mm (Waters), solvent: A solution = 0.1% formic acid / water, B solution = 0.1% formic acid / methanol: acetonitrile ( 4: 1), gradient cycle: 0.0 min (A liquid / B liquid = 80/20), 10.0 min (A liquid / B liquid = 0/100), 15.0 min (A liquid / B liquid = 0/100), Flow rate 1mL / min) or ACQUITY SQD LC / MS System (Waters) (column: BEHC18 2.1 x 30mm (Waters), A solution = 0.1% formic acid / water, B solution = 0.1% formic acid / acetonitrile, gradient cycle: 0.0 min (A liquid / B liquid = 95/5), 2.0 min (A liquid / B liquid = 5/95), 3.0 min (A liquid / B liquid = 5/95), flow rate 0.5 mL / min) It was measured.
Retention time (min) was expressed as rt (min), and ESI positive and negative ion peaks were detected.
MS spectra of some high molecular weight compounds were measured using Q-TOF Premier (Waters).

Each abbreviation has the following meaning.
Bn: benzyl
Boc: tert-butoxycarbonyl
^t Bu: tert-butyl
DIEA: N, N-diisopropylethylamine
DMAc: N, N-dimethylacetamide
DMAP: 4-dimethylaminopyridine
DMF: N, N-dimethylformamide
DMFDA: N, N-dimethylformamide dimethyl acetal
DMSO: Dimethyl sulfoxide
Et: ethyl
Fmoc: 9-fluorenylmethyloxycarbonyl
HATU: O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
HBTU: O-benzotriazol-1-yl 1,1,3,3-tetramethyluronium hexafluorophosphate
NMP: N-methylpyrrolidone
TBS: tert-butyldimethylsilyl
TFA: trifluoroacetic acid
THF: tetrahydrofuran
Z: benzyloxycarbonyl

Reference example 1

  (A1) was obtained according to the method described in Journal of Medicinal Chemistry, 2000, Vol. 43, pages 3736-3745.

Reference example 2

  (A2) was obtained according to the method described in Bioconjugate chemistry, 2006, Vol. 17, pp. 1294-1313.

Reference example 3

(1)
A solution of HBTU (85.5 mg) in DMF (0.5 mL) was added to a solution of (A2) (130 mg), (A1) (57.0 mg) and DIEA (250 μL) in DMF (2 mL), and the mixture was stirred at room temperature for 1 hour. Water (500 μL) and acetonitrile (2 mL) were added and purified by preparative HPLC to give (A3) (152 mg).
LC / MS (SunFire)
rt (min): 9.43
MS (ESI, m / z): 829.10 [M + H] ⁺ , 827.15 [MH] ^-

(2)
(A3) (27.8 mg), methanol (10 mL) and 10% Pd / C (10 mg) were placed in a shield tube and stirred for 3 hours under a 0.5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (A4) (20.8 mg).
LC / MS (SunFire)
rt (min): 6.09
MS (ESI, m / z): 695.10 [M + H] ⁺ , 693.10 [MH] ^-

(3)
To a solution of (A4) (58.5 mg), Fmoc-cysteic acid (65.9 mg) and DIEA (100 μL) in DMF (0.8 mL), add HBTU (63.7 mg) in DMF (0.3 mL) and stir at room temperature for 1 hour. did. Water (100 μL) was added and purified by preparative HPLC to give (A5) (43.4 mg).
LC / MS (ACQUITY)
rt (min): 1.32
MS (ESI, m / z): 1068.6 [M + H] ⁺ , 1066.6 [MH] ⁻

(4)
To a solution of (A5) (26.5 mg) in DMF (0.5 mL) was added diethylamine (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and Fmoc-cysteic acid (19.4 mg), DMF (0.6 mL) and DIEA (100 μL) were added to the obtained oil, and then HBTU (18.8 mg) in DMF (150 μL) solution And stirred at room temperature for 70 minutes. Water (100 μL) was added, the solvent was distilled off under reduced pressure, DMF (0.5 mL) and diethylamine (0.5 mL) were added, and the mixture was stirred at room temperature for 1 hr. After evaporating the solvent under reduced pressure, the insoluble material was filtered off, 50% acetonitrile aqueous solution (300 μL) was added, and the mixture was purified by preparative HPLC to obtain (A6) (15.6 mg).
LC / MS (SunFire)
rt (min): 9.56
MS (ESI, m / z): 997.15 [M + H] ⁺ , 995.20 [MH] ^-

(5)
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (14.0 mg) and DIEA (50 μL) in DMF (200 μL) solution to HBTU (9.0 mg) Was added to a solution of (A6) (15.6 mg) and DIEA (10 μL) in DMF (200 μL), and the mixture was stirred at room temperature for 1 hour. Water (100 μL) and acetonitrile (100 μL) were added and purified by preparative HPLC to give (A7) (10.5 mg).
LC / MS (SunFire)
rt (min): 10.74
MS (ESI, m / z): 685.15 [M + 2H] ²⁺

(6)
A mixture of (A7) (5.4 mg), THF (450 μL), water (100 μL) and 3 mol / L aqueous lithium hydroxide solution (100 μL) was stirred at room temperature for 75 minutes. TFA was added and the solvent was distilled off under reduced pressure. To the obtained residue, TFA / triethylsilane (95/5) (1 mL) was added and stirred for 1.5 hours, and then the solvent was distilled off under reduced pressure. To the obtained residue, 50% acetonitrile aqueous solution (200 μL) and TFA (10 μL) were added, and the residue was purified by preparative HPLC to obtain (A8) (4.2 mg).
LC / MS (SunFire)
rt (min): 10.74
MS (ESI, m / z): 685.15 [M + 2H] ²⁺

Reference example 4

(1)
Diethylamine (0.5 mL) was added to a solution of (A5) (8.8 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 150 minutes. The solvent was distilled off under reduced pressure, DMF (0.2 mL) and DIEA (10 μL) were added, and then 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert -A solution of butyl (7.1 mg), DMF (0.1 mL), DIEA (20 μL) and HBTU (4.5 mg) in DMF (45 μL) was added, and the mixture was stirred at room temperature for 3 hours. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (7.0 mg), DMF (50 μL), DIEA (20 μL), HBTU (4.5 mg) and DMF (50 μL) was added and stirred for 30 minutes. Water (100 μL) and 50% acetonitrile aqueous solution (400 μL) were added and purified by preparative HPLC to obtain (B1) (10.0 mg).
LC / MS (SunFire)
rt (min): 8.89
MS (ESI, m / z): 701.25 [M + 2H] ²⁺ , 1399.20 [MH] ^-

(2)
To (B1) (2.4 mg) were added THF (0.7 mL), water (0.1 mL) and a 3 mol / L lithium hydroxide aqueous solution (100 μL), and the mixture was stirred at room temperature for 1.5 hours. TFA was added, the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. TFA was distilled off under reduced pressure, 20% acetonitrile aqueous solution (1.2 mL) was added, and purification was performed by preparative HPLC to obtain (B2) (1.8 mg).
LC / MS (SunFire)
rt (min): 8.14
MS (ESI, m / z): 609.90 [M + 2H] ²⁺ , 1217.05 [MH] ^-

Reference Example 5

(1)
After adding Fmoc-cysteic acid (21.1 mg), DMF (0.8 mL) and DIEA (30 μL) to (A6) (21.5 mg), add a solution of HBTU (19.7 mg) in DMF (200 μL) for 70 minutes at room temperature. Stir. Water (200 μL) and diethylamine (0.5 mL) were added, and the mixture was stirred at room temperature for 1 hour. After distilling off the solvent under reduced pressure, 50% acetonitrile aqueous solution (0.6 mL) was added, insoluble matter was removed by filtration, and purified by preparative HPLC to obtain (C1) (15.0 mg).
LC / MS (ACQUITY)
rt (min): 0.91
MS (ESI, m / z): 1148.4 [M + H] ⁺ , 1146.4 [MH] ^-

(2)
To (C1) (7.2 mg), a 50% aqueous methanol solution (300 μL) and a 4 mol / L hydrogen chloride / dioxane solution (20 μL) were added, and the solvent was distilled off under reduced pressure. To the resulting residue was added 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (12.6 mg), DMF (400 μL) and DIEA (20 μL). After the addition, a solution of HBTU (7.2 mg) in DMF (200 μL) was added and stirred at room temperature for 1 hour. After adding HBTU (10.0 mg) and stirring for 1 hour, water (300 μL) was added. Purification by preparative HPLC gave (C2) (4.1 mg).
LC / MS (ACQUITY)
rt (min): 1.16
MS (ESI, m / z): 852.3 [M + 2H] ²⁺ , 850.3 [M-2H] ^2-

(3)
A mixture of (C2) (4.1 mg), THF (1.3 mL), water (150 μL) and 3 mol / L aqueous lithium hydroxide solution (150 μL) was stirred at room temperature for 140 minutes. TFA was added and the solvent was distilled off under reduced pressure. TFA / triethylsilane (95/5) (1 mL) was added to the obtained residue, and the mixture was stirred for 2 hours, and then TFA was distilled off under reduced pressure. After adding 10 mmol / L aqueous ammonium acetate solution (800 μL), purification by preparative HPLC gave (C3) (2.3 mg).
LC / MS (ACQUITY)
rt (min): 0.93
MS (ESI, m / z): 759.7 [M-2H] ^2-

Reference Example 6

(1)
Fmoc-8-amino-3,6-dioxaoctanoic acid (31.0mg), (A4) (20.8mg) and DIEA (50μL) in DMF (400μL) solution with HBTU (22.7mg) in DMF (100μL) The mixture was further stirred at room temperature for 1 hour. Water (100 μL) and acetonitrile (100 μL) were added and purified by preparative HPLC to give (D1) (22.8 mg).
LC / MS (SunFire)
rt (min): 9.81
MS (ESI, m / z): 531.95 [M + 2H] ²⁺

(2)
Diethylamine (0.5 mL) was added to a solution of (D1) (7.5 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. To the obtained residue, 1,4,7,10-tetraazacyclododecane-1,4,7,10-triacetic acid tri-tert-butyl (8.1 mg), DMF (200 μL) and DIEA (40 μL) were added. After the addition, a solution of HBTU (5.3 mg) in DMF (100 μL) was added and stirred at room temperature for 1 hour. Water (100 μL) and acetonitrile (200 μL) were added and purified by preparative HPLC to obtain a fraction containing (D2).
LC / MS (SunFire)
rt (min): 8.36
MS (ESI, m / z): 698.10 [M + 2H] ²⁺ , 1392.50 [MH] ^-

(3)
After the solvent containing the fraction (D2) obtained in (2) was distilled off under reduced pressure, THF (350 μL), water (50 μL), 3 mol / L lithium hydroxide aqueous solution (50 μL) were added, and at room temperature. Stir for 1.5 hours. TFA was added and the solvent was distilled off under reduced pressure. To the obtained residue, TFA / triethylsilane (95/5) (1 mL) was added, stirred for 1.5 hours, and the solvent was distilled off under reduced pressure. A 50% acetonitrile aqueous solution (600 μL) was added, and purification was performed by preparative HPLC to obtain (D3) (1.8 mg).
LC / MS (SunFire)
rt (min): 7.66
MS (ESI, m / z): 606.85 [M + 2H] ²⁺ , 404.95 [M + 3H] ³⁺

Reference Example 7

(1)
Diethylamine (0.5 mL) was added to a solution of (D1) (29.8 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 2.5 hours, and then the solvent was distilled off under reduced pressure. After adding DMF (0.4 mL) and DIEA (10 μL) to the obtained residue, Fmoc-Lys (BOC) -OH (39.4 mg), DMF (150 μL), DIEA (20 μL) and HBTU (26.5 mg) were added. DMF (150 μL) solution was added and stirred at room temperature for 1 hour. Water (100 μL) was added and purified by preparative HPLC to give (E1) (4.4 mg).
LC / MS (SunFire)
rt (min): 10.56
MS (ESI, m / z): 645.85 [M + 2H] ²⁺ , 430.35 [M + 3H] ³⁺ , 1288.45 [MH] ^-

(2)
Diethylamine (0.5 mL) was added to a solution of (E1) (4.4 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 8 hours. After the solvent was distilled off under reduced pressure, DMF (0.4 mL) and DIEA (10 μL) were added and stirred, and then 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri- A solution of tert-butyl (7.8 mg), DMF (0.1 mL), DIEA (10 μL) and HBTU (5.2 mg) in DMF (100 μL) was added, and the mixture was stirred at room temperature for 1 hour. After adding water (100 μL), purification by preparative HPLC gave (E2) (4.4 mg).
LC / MS (SunFire)
rt (min): 8.21
MS (ESI, m / z): 812.35 [M + 2H] ²⁺

(3)
To (E2) (4.4 mg) were added THF (0.7 mL), water (0.1 mL) and a 3 mol / L lithium hydroxide aqueous solution (0.1 mL), and the mixture was stirred at room temperature for 1.5 hours. TFA was added, the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, 20% acetonitrile aqueous solution (1 mL) and methanol (0.6 mL) were added, and purification was performed by preparative HPLC to obtain (E3) (2.5 mg).
LC / MS (SunFire)
rt (min): 6.19
MS (ESI, m / z): 670.75 [M + 2H] ²⁺ , 447.60 [M + 3H] ³⁺

Reference Example 8

(1)
To a solution of (D1) (30.9 mg) in DMF (0.5 mL) was added diethylamine (0.5 mL), and the mixture was stirred at room temperature for 50 minutes. The solvent was distilled off under reduced pressure and DMF (0.3 mL) and DIEA (15 μL) were added, followed by Fmoc-8-amino-3,6-dioxaoctanoic acid (23.0 mg), DMF (150 μL), DIEA ( 15 μL) and HBTU (22.0 mg) in DMF (150 μL) were added, and the mixture was stirred at room temperature for 50 minutes. After adding water (100 μL), purification by preparative HPLC gave (F1) (10.9 mg).
LC / MS (ACQUITY)
rt (min): 1.29
MS (ESI, m / z): 1207.7 [M + H] ⁺ , 604.7 [M + 2H] ²⁺ , 1205.7 [MH] ⁻

(2)
To a solution of (F1) (10.9 mg) in DMF (0.5 mL) was added diethylamine (0.5 mL), and the mixture was stirred at room temperature for 1 hour. Evaporate the solvent under reduced pressure, add DMF (0.4 mL) and DIEA (15 μL), then add 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert -A solution of butyl (15.5 mg), DMF (100 μL), DIEA (15 μL) and HBTU (9.6 mg) in DMF (100 μL) was added and stirred at room temperature for 30 minutes. Water (100 μL) was added and the mixture was purified by preparative HPLC, and the solvent was distilled off under reduced pressure to obtain a fraction (12.4 mg) containing (F2).
LC / MS (SunFire)
rt (min): 7.80
MS (ESI, m / z): 514.10 [M + 3H] ³⁺ , 1537.80 [MH] ^-

(3)
To (F2) (10.4 mg), THF (0.7 mL), water (0.1 mL) and 3 mol / L lithium hydroxide aqueous solution (0.1 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. TFA was added, the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 80 minutes. TFA was distilled off under reduced pressure, 20% acetonitrile aqueous solution (2.1 mL) was added, and purification was performed by preparative HPLC to obtain (F3) (4.0 mg).
LC / MS (SunFire)
rt (min): 7.17
MS (ESI, m / z): 679.45 [M + 2H] ²⁺ , 453.35 [M + 3H] ³⁺

Reference Example 9

(1)
Diethylamine (0.5 mL) was added to a solution of (D1) (27.3 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 1 hour, and then the solvent was distilled off under reduced pressure. After adding Fmoc-cysteic acid (20.1 mg), DMF (0.7 mL) and DIEA (20 μL) to the obtained residue, a DMF (200 μL) solution of HBTU (19.5 mg) was added and stirred at room temperature for 10 minutes. . Water (0.5 mL) and ethyl acetate (2 mL) were added to the reaction mixture. The aqueous layer was separated and purified by preparative HPLC to obtain (G1) (11.2 mg).
LC / MS (SunFire)
rt (min): 11.78
MS (ESI, m / z): 1235.35 [M + Na] ⁺ , 629.40 [M + 2Na] ²⁺ , 1212.40 [MH] ⁻

(2)
To a solution of (G1) (11.2 mg) in DMF (0.5 mL) was added diethylamine (0.5 mL), and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, and DMF (0.2 mL) and DIEA (10 μL) were added to the resulting residue and stirred. To the reaction mixture was added 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (15.5 mg), DMF (200 μL), DIEA (10 μL) and HBTU (10.5 mg ) In DMF (100 μL) was added and stirred at room temperature for 30 minutes. Water (100 μL) was added, 50% aqueous acetonitrile (1.2 mL) was added, and the mixture was purified by preparative HPLC to give (G2) (7.6 mg).
LC / MS (SunFire)
rt (min): 8.26
MS (ESI, m / z): 1545.80 [M + H] ⁺ , 773.90 [M + 2H] ²⁺ , 1543.85 [MH] ^-

(3)
To (G2) (7.6 mg) were added THF (1 mL), water (140 μL) and a 3 mol / L lithium hydroxide aqueous solution (140 μL), and the mixture was stirred at room temperature for 1.5 hours. TFA was added, the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 100 minutes. TFA was distilled off under reduced pressure, 50% acetonitrile aqueous solution (1.2 mL) and water (500 μL) were added, and purification was performed by preparative HPLC to obtain (G3) (5.1 mg).
LC / MS (SunFire)
rt (min): 8.30
MS (ESI, m / z): 682.50 [M + 2H] ²⁺

Reference Example 10

(1)
L-glutamic acid dibenzyl ester hydrochloride (86.9 mg), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (114 mg), DMF (2 mL) and HBTU (83 mg) was added to a mixture of DIEA (100 μL) and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and ethyl acetate (5 mL) and saturated aqueous sodium chloride solution (3 mL) were added to the residue. The organic layer was separated, and the aqueous layer was extracted 5 times with ethyl acetate (5 mL). The combined organic layers were dried over anhydrous magnesium sulfate and purified by silica gel column chromatography (ethyl acetate) to obtain (H1) (96 mg).
TLC Rf: 0.58 (ethyl acetate / methanol = 5/1)
MS (ESI, m / z): 904.8 [M + Na] ⁺

(2)
(H1) (90.0 mg), methanol (10 mL) and 10% Pd / C (50 mg) were placed in a shield tube, and the mixture was stirred under a 0.4 MPa hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (H2) (80 mg).
LC / MS (SunFire)
rt (min): 9.50
MS (ESI, m / z): 702.20 [M + H] ⁺ , 700.35 [MH] ^-

(3)
4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) ethyl benzoate (2.76 g), THF (70 mL), DIEA (4.7 mL) and dicarbonate A mixture of -tert-butyl (4.1 mL) was refluxed for 19 hours. Di-tert-butyl dicarbonate (4 mL) and DIEA (5 mL) were added and refluxed for 6 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate (200 mL) and washed with water and saturated aqueous sodium chloride solution. Purification by silica gel column chromatography (hexane / ethyl acetate = 5/1 to 2/1) gave (H3) (1.47 g).
MS (ESI, m / z): 411.43 [M + H] ⁺

(4)
A 2 mol / L aqueous lithium hydroxide solution (3 mL) was added to a solution of (H3) (213 mg) in THF (15 mL) and methanol (5 mL), and the mixture was stirred at room temperature for 1 hour and then left overnight. Water (10 mL) was added, sodium hydrogen sulfate was added to adjust to pH 4, and the mixture was extracted 3 times with ethyl acetate (20 mL). The extract was washed 3 times with a saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (H4) (202 mg).
MS (ESI, m / z): 383.3 [M + H] ⁺ , 381.4 [MH] ⁻

(5)
HBTU (178 mg) was added to a solution of (A2) (266 mg) and (H4) (150 mg) in DMF (5 mL) and DIEA (0.6 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added, and the mixture was extracted twice with ethyl acetate (20 mL). The combined organic layer was washed twice with a saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate / methanol = 40/1), (H5) (187 mg) Got.
LC / MS (SunFire)
rt (min): 12.25
MS (ESI, m / z): 929.25 [M + H] ⁺ , 927.25 [MH] ^-

(6)
(H5) (180 mg), methanol (10 mL) and 10% Pd / C (50 mg) were placed in a shield tube and stirred for 5 hours under a 0.5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (H6) (131 mg).
MS (ESI, m / z): 795.7 [M + H] ⁺ , 695.5 [M-BOC] ⁺ , 793.2 [MH] ⁻

(7)
HBTU (68.4 mg) was added to a solution of (H6) (130 mg) and Fmoc-cysteic acid (77.0 mg) in DMF (4 mL) and DIEA (200 μL), and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium chloride solution (5 mL), ethyl acetate (5 mL) and water (5 mL) were added, the organic layer was separated, and the aqueous layer was extracted six times with ethyl acetate (10 mL). The organic layers were combined, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 5/1) to obtain (H7) (66.6 mg).
LC / MS (SunFire) Gradient cycle: 0.0 min (A liquid / B liquid = 30/70), 10.0 min (A liquid / B liquid = 0/100), 15.0 min (A liquid / B liquid = 0/100)
rt (min): 11.55
MS (ESI, m / z): 1166.40 [MH] ^-

(8)
To a solution of (H7) (55 mg) in DMF (4 mL) was added diethylamine (2 mL), and the mixture was stirred at room temperature for 150 minutes. The solvent was distilled off under reduced pressure. (H2) (11.0 mg), DMF (0.5 mL) and DIEA (50 μL) were added to the resulting residue, HBTU (15.1 mg) was added, and the mixture was stirred at room temperature for 20 minutes. DIEA (20 μL) was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC to give (H8) (3.2 mg).
LC / MS (SunFire)
Gradient cycle: 0.0 min (A liquid / B liquid = 60/40), 30.0 min (A liquid / B liquid = 0/100)
rt (min): 17.12
MS (ESI, m / z): 853.45 [M + 3H] ³⁺ , 819.85 [M + 3H-BOC] ³⁺ , 786.70 [M + 3H-2BOC] ³⁺

(9)
A mixture of (H8) (3.2 mg), THF (350 μL), water (50 μL) and 3 mol / L aqueous lithium hydroxide (35 μL) was stirred at room temperature for 90 minutes. TFA was added and the solvent was distilled off under reduced pressure. TFA / triethylsilane (95/5) (1 mL) was added to the obtained residue, and the mixture was stirred for 90 minutes, and then TFA was distilled off under reduced pressure.
A 50% aqueous acetonitrile solution (800 μL) was added to the resulting residue, and purification was performed by preparative HPLC to obtain (H9) (2.7 mg).
LC / MS (SunFire)
rt (min): 10.25
MS (ESI, m / z): 721.30 [M + 3H] ³⁺ , 1078.80 [M-2H] ^2-

Reference Example 11

(1)
A suspension of 1,4,7,10-tetraazacyclododecane (5.0 g), sodium acetate trihydrate (13.0 g) and DMAc (40 mL) in a solution of benzyl bromoacetate (22 g) in DMAc (20 mL) Was added dropwise at 20 ° C. or lower over 20 minutes, followed by stirring at room temperature for 20 hours. Ethyl acetate (500 mL) was added to the reaction mixture, washed with water (300 mL) three times, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate / methanol = 5/1 to 1/1). (I1) (2.0 g) was obtained.
TLC Rf: 0.07 (ethyl acetate / methanol = 5/1)

(2)
To a mixture of (I1) (0.650 g), acetonitrile (8 mL) and potassium carbonate (160 mg) was added tert-butyl bromoacetate (156 μL), and the mixture was stirred at room temperature for 24 hours. Ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (50 mL) were added, the organic layer was separated, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 3/1) to obtain (I2) (319 mg).
TLC Rf: 0.48 (acetonitrile / water = 9/1)
MS (ESI, m / z): 753.5 [M + Na] ⁺

(3)
A 4 mol / L hydrogen chloride / dioxane solution (4 mL) was added to (I2) (130 mg), and the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, 50% acetonitrile aqueous solution (2 mL) was added to the obtained residue, and purification was performed by preparative HPLC to obtain (I3) (39.2 mg).
LC / MS (SunFire)
rt (min): 9.44
MS (ESI, m / z): 675.10 [M + H] ⁺ , 673.25 [MH] ^-

(4)
Ethyl 4-bromobutanoate (3.9 mL) was added to a mixture of 5-bromo-3-hydroxypyridine (2.98 g), potassium carbonate (3.75 g) and DMF (35 mL), and the mixture was stirred at 40 ° C. for 2 hours. To the reaction mixture were added saturated aqueous ammonium chloride solution (30 mL) and ethyl acetate (100 mL). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1 to 7/1) to obtain (I4) (4.13 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.28 (1H, brs), 8.22 (1H, brs), 7.35 (1H, dd, J = 2.16, 2.24 Hz), 4.17 (2H, q, J = 7.16 Hz) ), 4.06 (2H, t, J = 6.12Hz), 2.52 (2H, t, J = 7.24Hz), 2.13 (2H, tt, J = 6.12,7.24Hz), 1.27 (3H, t, J = 7.12Hz) )

(5)
To a solution of (I4) (1.89 g) in methanol (20 mL) and THF (20 mL) was added 5 mol / L aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 2 hr. Concentrated hydrochloric acid (2 mL) was added, the solvent was distilled off under reduced pressure, water (50 mL) was added, and the mixture was extracted 4 times with ethyl acetate (50 mL). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (I5) (1.76 g).
TLC Rf: 0.19 (hexane / ethyl acetate = 1/1)
HPLC (SunFire)
rt (min): 11.97
MS (ESI, m / z): 259.9 [M + H] ⁺

(6)
HBTU (2.64 g) was added to a mixture of (I5) (1.76 g), Z-ethylenediamine hydrochloride (1.87 g), DMF (40 mL) and DIEA (2.8 mL), and the mixture was stirred at room temperature for 2.5 hours. Ethyl acetate (250 mL) and water (100 mL) were added, the organic layer was separated, washed twice with water (300 mL) and once with saturated aqueous sodium chloride solution (300 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from ethyl acetate to obtain (I6) (1.73 g).
TLC Rf: 0.58 (ethyl acetate)
HPLC (SunFire)
rt (min): 13.60

(7)
(I6) (1.70 g), 3,3,3-triethoxy-1-propyne (1.1 g), acetonitrile (20 mL), triethylamine (25 mL) and DMF (20 mL) were added to dichlorobis (triphenylphosphine) palladium ( II) (250 mg) and copper (I) iodide (38 mg) were added, and the mixture was stirred at 70 ° C. for 3 hours under a nitrogen atmosphere, and then left overnight at room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 mL), washed three times with water (100 mL), once with a saturated aqueous sodium chloride solution (100 mL), and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 0/10 to 2/8) to obtain (I7) ((1.7 g).
TLC Rf 0.26 (hexane / ethyl acetate = 1/2)
HPLC (SunFire)
rt (min): 14.65
MS (ESI, m / z): 550.3 [M + Na] ⁺

(8)
To a solution of (I7) (1.70 g) in acetonitrile (25 mL) was added 2 mol / L hydrochloric acid (2 mL), and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (100 mL) was added, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate / methanol = 0/10 to 2/8). , (I8) (1.3 g) was obtained.
TLC Rf: 0.26 (hexane / ethyl acetate = 1/2)
HPLC (SunFire)
rt (min): 13.74
MS (ESI, m / z): 454.1 [M + H] ⁺

(9)
A mixture of 4-((tert-butyldimethylsilyl) oxy) butan-2-one (22.0 g), 2-aminonicotinaldehyde (9.62 g), proline (4.6 g) and ethanol (120 mL) was refluxed for 10 hours. 4-((tert-Butyldimethylsilyl) oxy) butan-2-one (10 g) was added and refluxed for 10 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-3 / 1) to obtain (I9) (2.57 g).
LC / MS (SunFire)
rt (min): 13.94
MS (ESI, m / z): 289.40 [M + H] ⁺

(10)
(I9) (2.50 g), methanol (75 mL), ethanol (75 mL) and 10% Pd / C (450 mg) were placed in an autoclave, and the mixture was stirred for 4 hours under a 4 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (I10) (2.5 g).
HPLC (SunFire)
rt (min): 10.19

(11)
A mixture of (I10) (2.5 g), THF (25 mL), DIEA (7.5 mL) and di-tert-butyl dicarbonate (6 mL) was stirred at 70 ° C. for 11 hours. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain (I11) (1.85 g).
TLC Rf: 0.85 (hexane / ethyl acetate = 1/2)

(12)
To a solution of (I11) (1.85 g) in THF (25 mL), 1 mol / L tetrabutylammonium fluoride / THF solution (8 mL) was added and stirred at room temperature for 3 hours, and then ethyl acetate (50 mL) and saturated aqueous ammonium chloride solution (50 mL) was added. The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (100 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 80 / 20-30 / 70) to obtain (I12) (1.17 g).
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 279.4 [M + H] ⁺

(13)
To a solution of (I12) (1.17 g), triphenylphosphine (1.32 g) and 3-methyl-4-nitrophenol (837 mg) in THF (15 mL) was added dropwise diisopropyl azodicarboxylate (1.5 mL) over 5 minutes. And stirred at room temperature for 3.5 hours. Ethyl acetate (100 mL) and saturated aqueous sodium hydrogen carbonate solution (100 mL) were added, and the organic layer was separated and washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 85 / 15-60 / 40) to obtain a fraction containing (I13). Got. The solvent was distilled off under reduced pressure, DMF (30 mL), benzyl bromide (3 mL) and cesium carbonate (7.6 g) were added to the resulting residue, and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate (300 mL) and water (100 mL) were added, the organic layer was separated, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane / ethyl acetate). = 80/20 to 60/40) to obtain (I13) (1.53 g).
LC / MS (ACQUITY)
rt (min): 1.27
MS (ESI, m / z): 414.5 [M + H] ⁺

(14)
DMFDA (2.5 mL) and pyrrolidine (1.4 mL) were added to a solution of (I13) (1.53 g) in DMF (15 mL), and the mixture was stirred at 80 ° C. for 5 hours. Water (50 mL) and ethyl acetate (150 mL) were added, the organic layer was separated, washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 70 / 30-40 / 60) to obtain (I14) (0.93 g).
MS (ESI, m / z): 495.3 [M + H] ⁺

(15)
(I14) (930 mg), methanol (20 mL) and 10% Pd / C (200 mg) were placed in a shield tube, and the mixture was stirred for 3 hours under a 0.5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 75/25 to 70/30) to obtain (I15) (571 mg).
TLC Rf: 0.36 (hexane / ethyl acetate = 1/1)
LC / MS (SunFire)
rt (min): 9.15
MS (ESI, m / z): 394.10 [M + H] ⁺

(16)
DMF (2.5 mL) was added to (I15) (152.4 mg), (I8) (240 mg) and cesium fluoride (53 mg), and the mixture was stirred at 70 ° C. for 5 hours. Ethyl acetate (30 mL) was added, washed with water and saturated aqueous sodium chloride solution, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 90/10) to obtain (I16) (159 mg).
LC / MS (SunFire)
rt (min): 10.85, 11.17
MS (ESI, m / z): 847.20 [M + H] ⁺

(17)
(I16) (159 mg), methanol (15 mL) and 10% Pd / C (80 mg) were placed in a shield tube and stirred for 6 hours under a 0.5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain (I17) (44.6 mg).
LC / MS (SunFire)
rt (min): 5.92
MS (ESI, m / z): 615.15 [M + H] ⁺

(18)
To a solution of (I17) (27.4 mg) and Fmoc-cysteic acid (39.3 mg) in DMF (0.8 mL) and DIEA (30 μL), add HBTU (37.4 mg) in DMF (0.2 mL) and stir at room temperature for 1 hour. did. Water (0.1 mL) was added and purified by preparative HPLC to give (I18) (12.0 mg).
LC / MS (SunFire)
rt (min): 11.97
MS (ESI, m / z): 494.90 [M + 2H] ²⁺ , 986.15 [MH] ^-

(19)
Diethylamine (0.5 mL) was added to a solution of (I18) (6.7 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 11 hours. The solvent was distilled off under reduced pressure, and Fmoc-cysteic acid (10.6 m), DMF (0.4 mL) and DIEA (20 μL) were added to the resulting residue, and then a solution of HBTU (9.5 mg) in DMF (0.1 mL) was added. And stirred at room temperature for 1 hour. Water (0.2 mL) was added and after stirring for 20 minutes, pyrrolidine (0.3 mL) was added and stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC to give (I19) (4.5 mg).
LC / MS (SunFire)
rt (min): 8.90
MS (ESI, m / z): 917.20 [M + H] ⁺ , 459.30 [M + 2H] ²⁺ , 915.10 [MH] ⁻

(20)
To a solution of (I3) (11.4 mg) in DMF (200 μL) and DIEA (10 μL), HBTU (6.4 mg) in DMF (100 μL) was added, and then (I19) (4.5 mg) in DMF (200 μL) and DIEA (10 μL) added to the solution and stirred at room temperature for 45 minutes. Water (100 μL) was added and purified by preparative HPLC to give (I20) (5.2 mg).
LC / MS (SunFire)
rt (min): 10.43
MS (ESI, m / z): 787.60 [M + 2H] ²⁺

(21)
A mixture of (I20) (5.2 mg), THF (1 mL), water (140 μL) and 3 mol / L aqueous lithium hydroxide solution (100 μL) was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, 50% acetonitrile aqueous solution (400 μL) and formic acid (14 μL) were added and purified by preparative HPLC to give (I21) (1.5 mg).
LC / MS (SunFire)
rt (min): 8.01
MS (ESI, m / z): 638.45 [M + 2H] ²⁺ , 425.65 [M + 3H] ³⁺

Reference Example 12

(1)
DMSO (40 mL) was added to sodium hydride (60% mineral oil suspension, 1.65 g), heated to 80 ° C., and then cooled to room temperature. Methyltriphenylphosphonium bromide (14.7 g) was added, and after stirring for 10 minutes, a solution of 5,6,7,8-tetrahydro-1,8-naphthyridine-2-carbaldehyde (2.46 g) in DMSO (25 mL) was added, Stir at room temperature for 30 minutes. After adding water (600 mL) and ethyl acetate (300 mL), the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (300 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain (J1) (1.13 g).
TLC Rf: 0.19 (hexane / ethyl acetate = 2/1)

(2)
To (J1) (1.37 g) was added di-tert-butyl dicarbonate (3.9 mL), DIEA (3.3 mL) and THF (15 mL), and the mixture was refluxed for 3 days. The solvent was removed under reduced pressure, and ethyl acetate (50 mL) and saturated aqueous sodium chloride solution (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8 / 1-7 / 1) to obtain (J2) (1.71 g).
TLC Rf: 0.51 (hexane / ethyl acetate = 2/1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.34 (1H, d, J = 10.2 Hz), 6.96 (1 H, d, J = 10.2 Hz), 6.73 (1 H, dd, 14.2, 23.1 Hz), 6.22 ( 1H, dd, 2.2,23.1Hz), 5.39 (1H, dd, 2.2,14.2Hz), 3.77 (2H, t, J = 8.6Hz), 2.75 (2H, t, J = 8.8Hz), 1.93 (2H, tt, J = 8.6,8.8Hz), 1.47 (9H, s)

(3)
(J2) (1.71 g), 4-bromoindole (824 μL), DMF (25 mL) and triethylamine (4 mL) were mixed with palladium (II) acetate (147 mg) and (2-biphenyl) di-tert-butylphosphine ( 392 mg) was added and the mixture was stirred at 110 ° C. for 20 hours. Ethyl acetate (300 mL) and water (100 mL) were added. The organic layer was separated, washed twice with a saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-5 / 1) to obtain (J3) (1.18 g).
TLC Rf: 0.31 (hexane / ethyl acetate = 2/1)
MS (ESI, m / z): 376.2 [M + H] ⁺

(4)
DMF (1.5 mL) was added to (J3) (150 mg), (I8) (180 mg) and cesium fluoride (60 mg), and the mixture was stirred at 60 ° C. for 20 hours. Ethyl acetate (10 mL) was added, washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10 / 0-9 / 1), and (J4) (130 mg)
Got.
TLC Rf: 0.2 (ethyl acetate)
LC / MS (SunFire)
rt (min): 12.15, 12.68
MS (ESI, m / z): 415.25 [M + 2H] ²⁺

(5)
(J4) (130 mg), methanol (20 mL) and 10% Pd / C (100 mg) were placed in a shield tube, and the mixture was stirred for 9 hours under a 0.5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by preparative HPLC to obtain (J5) (29.0 mg).
HPLC (SunFire)
rt (min): 7.42
LC / MS (SunFire)
rt (min): 6.66
MS (ESI, m / z): 599.35 [M + H] ⁺

(6)
To a solution of (J5) (29.0 mg) and Fmoc-cysteic acid (48.0 mg) in DMF (1 mL) and DIEA (60 μL) was added a solution of HBTU (45.9 mg) in DMF (0.4 mL), and the mixture was stirred at room temperature for 1 hour. . Water (1 mL) was added, the solvent was distilled off under reduced pressure, DMF (1 mL) and diethylamine (1 mL) were added to the resulting residue, and the mixture was allowed to stand at room temperature for 13 hours. The solvent was distilled off under reduced pressure, 50% acetonitrile aqueous solution was added to the obtained residue, and the residue was purified by preparative HPLC to obtain (J6).
HPLC (SunFire)
rt (min): 9.80

(7)
A solution of Fmoc-cysteic acid (48.0 mg), DMF (0.6 mL), DIEA (60 μL), and HBTU (45.9 mg) in DMF (0.4 mL) was added to (J6) obtained in (6), and 1.5 mL at room temperature was added. Stir for hours. Water (0.5 mL) was added and stirred for 5 minutes, pyrrolidine (0.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC to obtain (J7) (8.0 mg).
HPLC (SunFire)
rt (min): 9.17
LC / MS (SunFire)
rt (min): 9.23
MS (ESI, m / z): 901.10 [M + H] ⁺ , 451.35 [M + 2H] ²⁺ , 899.00 [MH] ^-

(8)
To a solution of (I3) (16.9 mg) in DMF (200 μL) and DIEA (20 μL), HBTU (9.5 mg) in DMF (60 μL) was added, and then (J7) (8.0 mg) in DMF (200 μL) and It was added to DIEA (10 μL) solution and stirred at room temperature for 2 hours. After adding water (100 μL), purification by preparative HPLC gave (J8) (6.9 mg).
LC / MS (SunFire)
rt (min): 10.46
MS (ESI, m / z): 779.65 [M + 2H] ²⁺

(9)
A mixture of (J8) (4.2 mg), THF (0.7 mL), water (0.1 mL) and 3 mol / L aqueous lithium hydroxide solution (70 μL) was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, 50% acetonitrile aqueous solution (400 μL) and formic acid (10 μL) were added to the obtained residue, and the residue was purified by preparative HPLC to obtain (J9) (1.2 mg).
LC / MS (SunFire)
rt (min): 8.62
MS (ESI, m / z): 630.45 [M + 2H] ²⁺ , 628.05 [M-2H] ^2-

Reference Example 13

(1)
4- (4- (Chlorosulfonyl) was added to a mixture of (R) -methyl 2-amino-3-((tert-butoxycarbonyl) amino) propanoate hydrochloride (3.92 g), acetonitrile (39 mL) and potassium carbonate (6.4 g). ) -3,5-Dimethylphenyloxy) butanoic acid (4.32 g) was added in 4 portions every 30 minutes, and then stirred at room temperature for 9 hours. Water (150 mL) and ethyl acetate (50 mL) were added, the aqueous layer was separated, and sodium chloride (20 g) and ethyl acetate (50 mL) were added. The organic layer was neutralized with concentrated hydrochloric acid, and the separated organic layer was washed twice with a saturated aqueous sodium chloride solution (100 mL), then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. (K1) (3.13 g) Got.
HPLC (CAPCELL PAK MG)
rt (min): 14.28
LC / MS (ACQUITY)
rt (min): 1.31
MS (ESI, m / z): 487.4 [MH] ^-

(2)
HBTU (2.55 g) was added to a mixture of (K1) (3.13 g), DMF (13 mL), Z-ethylenediamine hydrochloride (1.48 g) and DIEA (2.3 mL), and the mixture was stirred at room temperature for 1 hour. Water (16 mL) was added dropwise, and the mixture was stirred for 2 hr. Water (16 mL) was added, and the solid was collected by filtration to obtain (K2) (3.40 g).
HPLC (CAPCELL PAK MG)
rt (min): 14.98
LC / MS (ACQUITY)
rt (min): 1.46
MS (ESI, m / z): 665.5 [M + H] ⁺ , 663.6 [MH] ^-

(3)
TFA (10 mL) was added to a solution of (K2) (3.04 g) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure, a 4 mol / L hydrogen chloride / dioxane solution (10 mL) was added, and the solvent was distilled off under reduced pressure. (O4) (1.04 g), DMF (16 mL), DIEA (2.4 mL) and HBTU (1.91 g) were added to the resulting residue, and the mixture was stirred at room temperature for 1.5 hours. 5% Aqueous sodium hydrogen carbonate solution (80 mL) and ethyl acetate (80 mL) were added, and the mixture was stirred at room temperature for 10 min. The organic layer was separated, washed twice with a saturated aqueous sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate (16 mL) was added, and the solid was collected by filtration to give (K3) (2.52 g).
LC / MS (ACQUITY)
rt (min): 1.16
MS (ESI, m / z): 781.7 [M + H] ⁺

(4)
A mixture of 10% Pd / C (0.40 g), methanol (25 mL) and (K3) (1.90 g) was stirred at room temperature for 17 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (K4) (1.72 g).
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 647.6 [M + H] ⁺ , 645.6 [MH] ^-

(5)

To a mixture of (K4) (183 mg), Z-cysteic acid (85.8 mg), DMF (2 mL) and DIEA (172 μL), HBTU (113 mg) was added and stirred at room temperature for 1 hour. Water (10 mL) and acetic acid (0.5 mL) were added, the organic layer was separated, washed with water (10 mL), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5 to 65/35) to obtain (K5) (110 mg).
LC / MS (ACQUITY)
rt (min): 1.05
MS (ESI, m / z): 932.8 [M + H] ⁺ , 930.9 [MH] ^-

(6)
A mixture of (K5) (110 mg), 10% Pd / C (50 mg) and methanol / water (9/1) (14 mL) was stirred at room temperature for 2.5 hours under hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (K6) (84.3 mg).
LC / MS (ACQUITY)
rt (min): 0.80
MS (ESI, m / z): 798.7 [M + H] ⁺ , 796.8 [MH] ^-

(7)
(K6) (84.3 mg), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (60.7 mg), DMF (1 mL) and DIEA (50 μL) HBTU (40.2 mg) was added to the mixture and stirred at room temperature for 30 minutes. Water (1 mL), methanol (0.5 mL) and formic acid (200 μL) were added and purified by preparative HPLC to give (K7) (61.9 mg).
LC / MS (ACQUITY)
rt (min): 1.12
MS (ESI, m / z): 677.4 [M + 2H] ²⁺ , 1351.3 [MH] ^-

(8)
Concentrated hydrochloric acid (2 mL) was added to (K7) (29 mg), and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, 50% acetonitrile aqueous solution (2 mL) was added, and purification was performed by preparative HPLC to obtain (K8) (11.0 mg).
LC / MS (ACQUITY)
rt (min): 0.75
MS (ESI, m / z): 586.1 [M + 2H] ²⁺ , 584.0 [M-2H] ^2-

Reference Example 14

(1)
To a mixture of 2-amino-6-bromopyridine (1.73 g), THF (20 mL), DMAP (120 mg) and DIEA (7 mL), add di-tert-butyl dicarbonate (4.6 mL) and stir at room temperature for 3 hours. did. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain (L1) (3.09 g).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.55-7.59 (1H, m), 7.37-7.39 (1H, m), 7.27 (1H, m), 1.46 (18H, s)

(2)
To a mixture of ethyl 4-ethynylbenzoate (0.97 g), (L1) (1.44 g), acetonitrile (20 mL) and triethylamine (10 mL) was added dichlorobis (triphenylphosphine) palladium (II) (78.2 mg) and copper iodide. (I) (32 mg) was added and heated at 70 ° C. for 200 minutes. After cooling to room temperature, ethyl acetate (30 mL) and water (30 mL) were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (30 mL). The organic layers were combined, washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (hexane / acetone = 20 / 1-10). / 1) to obtain (L2) (1.22 g).
TLC Rf: 0.63 (hexane / ethyl acetate = 2/1)
LC / MS (SunFire)
rt (min): 14.63
MS (ESI, m / z): 467.10 [M + H] ⁺

(3)
(L2) (1.10 g), methanol (150 mL) and 10% Pd / C (300 mg) were placed in an autoclave and stirred for 8 hours under a 3 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (L3) (1.17 g).
TLC Rf: 0.59 (hexane / ethyl acetate = 2/1)
LC / MS (SunFire)
rt (min): 14.53
MS (ESI, m / z): 493.10 [M + Na] ⁺

(4)
To a solution of (L3) (610 mg) in methanol (15 mL) was added a solution of sodium hydroxide (0.29 g) in water (1 mL), and the mixture was stirred at room temperature for 1 hour. Sodium hydroxide (0.40 g), water (5 mL) and THF (5 mL) were added and stirred for 4 hours. About half of the solvent was distilled off under reduced pressure, water (20 mL) was added, and sodium hydrogen sulfate was added to adjust the pH to 4. Ethyl acetate (30 mL) and water (30 mL) were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (L4) (0.51 g).
TLC Rf: 0.24 (hexane / ethyl acetate = 2/1)
MS (ESI, m / z): 343.1 [M + H] ⁺ , 341.2 [MH] ^-

(5)
A solution of HBTU (235 mg) in DMF (2 mL) was added to a mixture of (A2) (390 mg), (L4) (208 mg), DMF (5 mL) and DIEA (0.6 mL), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 mL) and water (30 mL) were added, the organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 40/60 to 0/100) to obtain (L5) (599 mg).
LC / MS (SunFire)
rt (min): 13.67
MS (ESI, m / z): 889.40 [M + H] ⁺ , 887.35 [MH] ^-

(6)
(L5) (599 mg), methanol (30 mL) and 10% Pd / C (100 mg) were placed in a shield tube, and the mixture was stirred for 6 hours under a 0.5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (L6) (476 mg).
LC / MS (SunFire)
rt (min): 9.64
MS (ESI, m / z): 755.35 [M + H] ⁺ , 753.40 [MH] ^-

(7)
A solution of HBTU (138 mg) in DMF (1 mL) was added to a solution of (L6) (129 mg), Fmoc-cysteic acid (145 mg) in DMF (1 mL) and DIEA (70 μL), and the mixture was stirred at room temperature for 30 minutes. DIEA (0.1 mL) was added and stirred for 2 hours. Water (0.1 mL) was added and the solvent was removed under reduced pressure. DMF (0.8 mL) and diethylamine (0.8 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 15 minutes, then the solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC (L7 ) (77.8 mg) was obtained.
LC / MS (SunFire)
rt (min): 11.59
MS (ESI, m / z): 906.25 [M + H] ⁺ , 904.20 [MH] ⁻

(8)
A mixture of (L7) (51.6 mg) and (S) -bis (2,5-dioxopyrrolidin-1-yl) 2-((tert-butoxycarbonyl) amino) pentanedioate (12.5 mg) was added to DMF ( 0.4 mL) and DIEA (30 μL) were added and stirred at room temperature for 24 hours. After adding water (0.1 mL), the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. TFA was distilled off under reduced pressure, 50% acetonitrile aqueous solution (1.5 mL) was added, and purification was performed by preparative HPLC to obtain (L8) (24.8 mg). LC / MS (SunFire)
rt (min): 7.86
MS (ESI, m / z): 862.05 [M + 2H] ²⁺ , 859.95 [M-2H] ^2-

(9)
To a solution of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (5.2 mg) in DMF (0.1 mL) and DIEA (10 μL), add HBTU (4.4 mg ) In DMF (100 μL) (75 μL), (L8) (9.6 mg) in DMF (200 μL) and DIEA (20 μL) were added, and the mixture was stirred at room temperature for 50 minutes. Water (200 μL) was added and purified by preparative HPLC to give (L9) (7.2 mg).
LC / MS (SunFire)
rt (min): 8.98
MS (ESI, m / z): 1139.70 [M + 2H] ²⁺ , 760.15 [M + 3H] ³⁺ , 1137.35 [M-2H] ^2-

(10)
To (L9) (7.6 mg), THF (0.3 mL), water (0.1 mL) and a 3 mol / L lithium hydroxide aqueous solution (70 μL) were added, and the mixture was stirred at room temperature for 1.5 hours. After adding TFA, the solvent was distilled off under reduced pressure. TFA / triethylsilane (95/5) (1 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 1.5 hours. TFA was distilled off under reduced pressure, 50% acetonitrile aqueous solution (0.2 mL) was added, and purification was performed by preparative HPLC to obtain (L10) (2.3 mg). LC / MS (SunFire)
rt (min): 8.61
MS (ESI, m / z): 1041.55 [M + 2H] ²⁺ , 694.55 [M + 3H] ³⁺ , 1039.35 [M-2H] ^2-

Reference Example 15

(1)
To a solution of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (24.8 mg), DMF (0.2 mL) and DIEA (17 μL), add HBTU (17.0 mg) of DMF (100 μL) was added, and then added to a solution of (L7) (13.1 mg) in DMF (200 μL) and DIEA (10 μL), followed by stirring at room temperature for 1 hour. Water (200 μL) was added and purified by preparative HPLC to give (M1) (12.3 mg).
LC / MS (SunFire)
rt (min): 11.05
MS (ESI, m / z): 730.95 [M + 2H] ²⁺ , 1459.05 [MH] ^-

(2)
To (M1) (7.8 mg), THF (0.7 mL), water (0.1 mL) and a 3 mol / L lithium hydroxide aqueous solution (70 μL) were added, and the mixture was stirred at room temperature for 1.5 hours. TFA was added, the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TFA was distilled off under reduced pressure, 50% acetonitrile aqueous solution (0.8 mL) was added, and purification was performed by preparative HPLC to obtain (M2) (1.9 mg).
LC / MS (SunFire)
rt (min): 7.34
MS (ESI, m / z): 590.10 [M + 2H] ²⁺ , 588.25 [M-2H] ^2-

Reference Example 16

(1)
To a solution of Fmoc-cysteic acid (22.0 mg) in DMF (0.2 mL) and DIEA (20 μL) was added HBTU (21.0 mg) in DMF (100 μL), and then (L7) (16.3 mg) in DMF (0.4 mL) and DIEA (20 μL) solution and stirred at room temperature for 1 hour. Water (0.1 mL) was added, the solvent was distilled off under reduced pressure, DMF (0.5 mL) and diethylamine (0.5 mL) were added, and the mixture was allowed to stand at room temperature for 15 hours. The solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 20 minutes to remove TFA. The resulting residue was purified by preparative HPLC to give (N1) (9.6 mg).
LC / MS (SunFire)
rt (min): 8.93
MS (ESI, m / z): 957.10 [M + H] ⁺ , 955.15 [MH] ^-

(2)
To a solution of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (8.3 mg) in DMF (0.1 mL) and DIEA (10 μL), add HBTU (5.5 mg) in DMF (100 μL) was added, and then (N1) (4.6 mg) in DMF (200 μL) and DIEA (20 μL) were added and stirred at room temperature for 1.5 hours. Water (100 μL) was added and purified by preparative HPLC to give (N2) (3.5 mg).
LC / MS (SunFire)
rt (min): 9.69
MS (ESI, m / z): 756.70 [M + 2H] ²⁺ , 1509.45 [MH] ^-

(3)
To (N2) (3.5 mg), THF (0.7 mL), water (0.1 mL) and a 3 mol / L lithium hydroxide aqueous solution (70 μL) were added, and the mixture was stirred at room temperature for 2 hours. TFA was added, the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. TFA was distilled off under reduced pressure, 50% acetonitrile aqueous solution (0.4 mL) was added, and purification was performed by preparative HPLC to obtain (N3) (0.9 mg).
LC / MS (SunFire)
rt (min): 10.28
MS (ESI, m / z): 665.15 [M + 2H] ²⁺

Reference Example 17

(1)
Concentrated sulfuric acid (20 mL) was added to a methanol (1 L) solution of 6-oxoheptanoic acid (99.2 g), and the mixture was heated to reflux for 4 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure, and water (1 L) and ethyl acetate (600 mL) were added. The organic layer was separated, washed with 5% aqueous sodium hydrogen carbonate solution (600 mL) and saturated aqueous sodium chloride solution (600 mL), and the solvent was distilled off under reduced pressure to obtain (O1) (95.2 g).
TLC Rf: 0.45 (hexane / ethyl acetate = 2/1)

(2)
(O1) (189 g) and methanol (600 mL) were added to a mixture of 2-aminonicotinaldehyde (133 g) and methanol (500 mL), pyrrolidine (100 mL) was added, and the mixture was heated to reflux for 8 hours. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, toluene (100 mL) was added, and the solvent was distilled off under reduced pressure. Toluene (150 mL) was added to the resulting residue, and the mixture was stirred at 50 ° C. for 2 hours and then at room temperature for 3 hours, and the solid was collected by filtration to obtain (O2) (149 g).
TLC Rf: 0.56 (ethyl acetate / methanol = 5/1)
LC / MS (ACQUITY)
rt (min): 0.73
MS (ESI, m / z): 245.2 [M + H] ⁺

(3)
10% Pd / C (10.0 g), (O2) (97.5 g) and methanol (250 mL) were placed in an autoclave, and the mixture was stirred for 8 hours under a 5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Acetonitrile (100 mL) was added to the obtained residue, and the solid was collected by filtration to obtain (O3) (71.5 g).
HPLC (CAPCEL PAK MG)
rt (min): 8.06
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.05 (1 H, d, J = 7.5 Hz), 6.34 (1 H, d, 7.5 Hz), 4.74 (1 H, brs), 3.66 (3 H, s), 3.37- 3.42 (2H, m), 2.68 (2H, t, J = 6.0Hz), 2.52-2.57 (2H, m), 2.30-2.37 (2H, m), 1.90 (2H, tt, J = 5.7,6.0Hz) 1.63-1.70 (4H, m)

(4)
Methanol (210 mL) was added to (O3) (70,0 g) and heated and dissolved at 40 ° C., then a mixture of sodium hydroxide (16.9 g) and water (105 mL) was added dropwise over 15 minutes, and 1 ° C. at 40 ° C. Stir for hours. The solvent was distilled off under reduced pressure, water (210 mL) was added, the mixture was heated to 40 ° C., and concentrated hydrochloric acid was added dropwise so as to keep the temperature at 50 ° C. or lower until pH 5 was reached. Water (50 mL) was added, cooled to room temperature, and left overnight. The solid was collected by filtration to give (O4) (62.2 g).
HPLC (CAPCEL PAK MG)
rt (min): 7.03
LC / MS (ACQUITY)
rt (min): 0.62
MS (ESI, m / z): 235.2 [M + H] ⁺

(5)
To a mixture of (A2) (7.40 g), (O4) (3.37 g), DMF (50 mL) and DIEA (3.86 mL), HBTU (4.98 g) was added little by little and stirred at room temperature for 2 hours. 5% Aqueous sodium hydrogen carbonate solution (200 mL) and ethyl acetate (200 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. The organic layer was separated, washed 3 times with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Ethyl acetate (50 mL) was added to the obtained residue, and the solid was collected by filtration to obtain (O5) (9.20 g).
LC / MS (ACQUITY)
rt (min): 1.12
MS (ESI, m / z): 781.5 [M + H] ⁺ , 779.6 [MH] ⁻

(6)
Methanol (40 mL) was added to (O5) (7.20 g) and 10% Pd / C (300 mg), and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. Toluene (50 mL) was added to the obtained residue, and the solvent was distilled off under reduced pressure to obtain (O6) (5.45 g).
LC / MS (ACQUITY)
rt (min): 0.73
MS (ESI, m / z): 647.4 [M + H] ⁺

(7)
A solution of HBTU (141 mg) in DMF (1.5 mL) was added to a solution of (O6) (120 mg), Fmoc-cysteic acid (145 mg), DMF (2 mL) and DIEA (140 μL), and the mixture was stirred at room temperature for 20 minutes. Water (2 mL) was added and purified by preparative HPLC to give (O7) (87.7 mg).
LC / MS (SunFire)
rt (min): 11.83
MS (ESI, m / z): 1020.25 [M + H] ⁺ , 1018.50 [MH] ^-

(8)
Diethylamine (0.5 mL) was added to a solution of (O7) (29.8 mg) in DMF (0.5 mL), and the mixture was stirred at room temperature for 80 minutes. The solvent was distilled off under reduced pressure, and Fmoc-cysteic acid (22.8 mg), DMF (0.7 mL) and DIEA (22 μL) were added to the resulting residue, and then a solution of HBTU (22.2 mg) in DMF (200 μL) was added. The mixture was further stirred at room temperature for 30 minutes. Water (0.5 mL) was added, the solvent was distilled off under reduced pressure, DMF (0.5 mL) and diethylamine (0.5 mL) were added, and the mixture was stirred at room temperature for 70 min. After evaporating the solvent under reduced pressure, water (2 mL) was added, washed with hexane / ethyl acetate (1/1) (2 mL) three times, and purified by preparative HPLC to obtain (O8) (13.2 mg). Obtained.
LC / MS (SunFire)
rt (min): 8.47
MS (ESI, m / z): 949.15 [M + H] ⁺ , 947.20 [MH] ^-

(9)
To a solution of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (23.9 mg) in DMF (200 μL) and DIEA (20 μL), HBTU (15.8 mg) Was added to a solution of (O8) (13.2 mg) in DMF (300 μL) and DIEA (20 μL), and the mixture was stirred at room temperature for 1 hour. Water (200 μL) was added and purified by preparative HPLC to give (O9) (9.5 mg).
LC / MS (SunFire)
rt (min): 9.19
MS (ESI, m / z): 752.70 [M + 2H] ²⁺ , 1501.45 [MH] ^-

(10)
A mixture of (O9) (6.2 mg), THF (700 μL), water (100 μL) and 3 mol / L aqueous lithium hydroxide solution (100 μL) was stirred at room temperature for 2 hours. TFA was added to the reaction mixture, and the solvent was distilled off under reduced pressure. TFA / triethylsilane (95/5) (0.5 mL) was added and stirred for 1.5 hours, and then the solvent was distilled off under reduced pressure. A 20% acetonitrile aqueous solution (600 μL) and methanol (300 μL) were added to the obtained residue, and the residue was purified by preparative HPLC to obtain (O10) (1.6 mg).
LC / MS (SunFire)
rt (min): 11.49
MS (ESI, m / z): 661.35 [M + 2H] ²⁺ , 1319.35 [MH] ^- , 659.45 [M-2H] ^2-

Reference Example 18

(1)
To a solution of (O7) (28.1 mg) in DMF (0.5 mL) was added diethylamine (0.5 mL), and the mixture was stirred at room temperature for 1.5 hours. After distilling off the solvent under reduced pressure, DMF (400 μL) and DIEA (20 μL) were added, and then 1,4,7,10-tetraazacyclododecane-1,4,7,10-tri-tert-butyl tetraacetate (31.6 mg), DMF (150 μL), DIEA (20 μL) and HBTU (20.9 mg) in DMF (150 μL) were added, and the mixture was stirred at room temperature for 45 minutes. Water (500 μL) was added, and the mixture was extracted 3 times with hexane / ethyl acetate (1/1) (0.5 mL), and then purified by preparative HPLC to obtain (P1) (19.6 mg).
HPLC (SunFire)
rt (min): 9.71
LC / MS (ACQUITY)
rt (min): 1.12
MS (ESI, m / z): 1352.5 [M + H] ⁺ , 1350.6 [MH] ^-

(2)
To (P1) (11.8 mg), THF (1.4 mL), water (200 μL) and a 3 mol / L lithium hydroxide aqueous solution (200 μL) were added, and the mixture was stirred at room temperature for 1.5 hours. TFA was added and the solvent was distilled off under reduced pressure. TFA / triethylsilane (95/5) (1 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 100 minutes. The solvent was distilled off under reduced pressure, water / acetonitrile (2/1) (1.8 mL) and formic acid (1.8 μL) were added, and purification was performed by preparative HPLC to obtain (P2) (8.9 mg).
HPLC (SunFire)
rt (min): 8.75
LC / MS (ACQUITY)
rt (min): 0.75
MS (ESI, m / z): 1170.4 [M + H] ⁺ , 585.9 [M + 2H] ²⁺ , 1168.4 [MH] ⁻

Reference Example 19

(1)
To a mixture of 4-bromo-2-fluorophenol (4.71 g), NMP (25 mL) and potassium carbonate (5.1 g) at 90 ° C. was added ethyl 4-bromobutanoate (4.2 mL) and stirred at the same temperature for 5.5 hours. did. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, washed with 4% hydrochloric acid, and dried over anhydrous magnesium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-7 / 3) to obtain (Q1) (7.3 g).
TLC Rf: 0.48 (hexane / ethyl acetate = 4/1)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.15-7.25 (2H, m), 6.83 (1H, t, J = 9.0 Hz), 4.15 (2H, q, J = 7.2 Hz), 4.06 (2H, t , J = 6.0Hz), 2.52 (2H, t, J = 7.5Hz), 2.15 (2H, tt, J = 7.5,6.0Hz), 1.27 (3H, t, J = 7.2Hz)

(2)
(Q1) (7.0 g), tert-butyl acrylate (15 mL), NMP (20 mL) and triethylamine (20 mL) in a nitrogen atmosphere, palladium (II) acetate (224 mg) and tri (o-tolyl) phosphine ( 609 mg) was added and the mixture was stirred at 110 ° C. for 8 hours. The reaction mixture was cooled to room temperature, the insoluble material was removed by filtration, and the filter cake was washed with ethyl acetate (200 mL). The organic layers were combined, washed twice with water (300 mL), washed with a saturated aqueous sodium chloride solution (300 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1 to 4/1) to obtain (Q2) (5.38 g).
TLC Rf: 0.40 (hexane / ethyl acetate = 4/1)
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.48 (1H, d, J = 15.6Hz), 7.17-7.26 (2H, m), 6.91 (1H, t, J = 5.1Hz), 6.22 (1H, d , J = 15.6Hz), 4.16 (2H, q, J = 7.2Hz), 4.11 (2H, t, J = 6.0Hz), 2.54 (2H, t, J = 7.2Hz), 2.15 (2H, tt, J = 6.0, 7.2Hz), 1.55 (9H, s), 1.26 (3H, t, J = 7.2Hz)
LC / MS (ACQUITY)
rt (min): 1.94
MS (ESI, m / z): 297.1 [M-tBu] ⁺

(3)
A solution of (R)-(+)-N-benzyl-1-phenylethylamine (5.13 g) in THF (50 mL) was cooled to -70 ° C., and butyl lithium (1.62 mol / L hexane solution, 13 mL) was added over 15 minutes. The solution was added dropwise so as to keep the temperature below -65 ° C. After raising the temperature to −30 ° C. over 50 minutes, the mixture was cooled to −70 ° C., and a solution of (Q2) (4.21 g) in THF (20 mL) was added dropwise over 15 minutes. The mixture was stirred at the same temperature for 2 hours, and a saturated aqueous ammonium chloride solution (100 mL) was added. Ethyl acetate (300 mL) and water (200 mL) were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (200 mL). The organic layer and the extract were combined, washed once with 10% aqueous acetic acid (300 mL), twice with saturated aqueous sodium chloride (300 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was recrystallized from IPA / hexane to obtain (Q3) (3.03 g). The recrystallized filtrate was purified by silica gel column chromatography (hexane / ethyl acetate = 10/0 to 9/1) to obtain (Q3) (2.75 g).
TLC Rf: 0.52 xane / ethyl acetate = 4/1)
LC / MS (ACQUITY)
rt (min): 2.32
MS (ESI, m / z): 564.3 [M + H] ⁺

(4)
(Q3) (434 mg), ethanol (5 mL), acetic acid (0.4 mL), water (40 μL) and 10% Pd / C (100 mg) were placed in a shield tube, and the mixture was stirred under a 0.5 MPa hydrogen atmosphere for 5 hours. The insoluble material was removed by filtration, neutralized with a saturated aqueous sodium hydrogen carbonate solution (50 mL), and extracted twice with ethyl acetate (100 mL). The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate to obtain (Q4) (290 m). TLC Rf: 0.15 (hexane / ethyl acetate = 5/1)
LC / MS (ACQUITY)
rt (min): 1.15
MS (ESI, m / z): 370.2 [M + H] ⁺

(5)
HBTU (228 mg) was added to a solution of (Q4) (220 mg) and (A1) (140 mg) in DMF (7 mL) and DIEA (420 μL), and the mixture was stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/0 to 9/1) to obtain (Q5) (310 mg).
TLC Rf: 0.74 (ethyl acetate / methanol = 5/1)
LC / MS (ACQUITY)
rt (min): 1.39
MS (ESI, m / z): 634.4 [M + H] ⁺

(6)
To a mixture of (Q5) (289 mg), THF (2.8 mL), methanol (2 mL) and water (0.4 mL) was added 2 mol / L lithium hydroxide aqueous solution (460 μL), and the mixture was stirred at room temperature for 2.5 hours. Water (10 mL) was added, citric acid (300 mg) was added, and the mixture was extracted 4 times with chloroform (15 mL). The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (Q6) (181 mg).
LC / MS (ACQUITY)
rt (min): 1.20
MS (ESI, m / z): 606.3 [M + H] ⁺ , 604.3 [MH] ^-

(7)
HBTU (147 mg) was added to a mixture of (Q6) (181 mg), Z-ethylenediamine hydrochloride (89.6 mg), DMF (2 mL) and DIEA (200 μL), and the mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added ethyl acetate (60 mL) and water (10 mL). The organic layer was separated and washed twice with water (30 mL), then with a saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/0 to 9/1) to obtain (Q7) (135 mg).
LC / MS (ACQUITY)
rt (min): 1.32
MS (ESI, m / z): 782.4 [M + H] ⁺

(8)
1,4-Cyclohexadiene (0.4 mL) was added to a mixture of (Q7) (130 mg), ethanol (10 mL) and 10% Pd / C (50 mg) at 60 ° C., and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled to room temperature, insolubles were filtered off, and the solvent was distilled off under reduced pressure to obtain (Q8) (108 mg).
LC / MS (ACQUITY)
rt (min): 1.02
MS (ESI, m / z): 648.3 [M + H] ⁺ , 324.7 [M + 2H] ²⁺

(9)
To a solution of (Q8) (108 mg) and Fmoc-cysteic acid (78.2 mg) in DMF (3 mL) and DIEA (70 μL), HBTU (75.9 mg) was added and stirred at room temperature for 25 minutes. Water (0.1 mL) was added to the reaction mixture, diethylamine (2 mL) was added, and the mixture was stirred at room temperature for 1.5 hr. Diethylamine was distilled off, water (1 mL) was added, the mixture was washed 3 times with ethyl acetate (2 mL), and purified by preparative HPLC to obtain (Q9) (63.2 mg).
HPLC (SunFire)
Solvent: Liquid A = 10 mmol / L ammonium acetate aqueous solution, Liquid B = 10 mmol / L ammonium acetate / methanol: acetonitrile (4: 1))
Gradient cycle: 0.0 min (A liquid / B liquid = 80/20), 10 min (A liquid / B liquid = 0/100), 15 min (A liquid / B liquid = 0/100)
(Flow rate: 1.0mL / min)
rt (min): 12.92
LC / MS (ACQUITY)
rt (min): 1.08
MS (ESI, m / z): 799.3 [M + H] ⁺ , 797.3 [MH] ⁻

(10)
To a solution of (Q9) (34.2 mg) and Fmoc-cysteic acid (33.5 mg) in DMF (0.6 mL) and DIEA (30 μL), a solution of HBTU (32.5 mg) in DMF (400 μL) was added and stirred at room temperature for 1 hour. . Water (0.5 mL) was added, diethylamine (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. Diethylamine was distilled off, water (1 mL) was added, the mixture was washed 3 times with ethyl acetate (2 mL), and purified by preparative HPLC to obtain (Q10) (13.9 mg).
HPLC (SunFire)
Solvent: Liquid A = 10 mmol / L ammonium acetate aqueous solution, Liquid B = 10 mmol / L ammonium acetate / methanol: acetonitrile (4: 1))
Gradient cycle: 0.0 min (A liquid / B liquid = 80/20), 10 min (A liquid / B liquid = 0/100), 15 min (A liquid / B liquid = 0/100)
(Flow rate: 1.0mL / min)
rt (min): 12.16
LC / MS (ACQUITY)
rt (min): 1.07
MS (ESI, m / z): 950.4 [M + H] ⁺

(11)
To a solution of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (25.1 mg) in DMF (150 μL) and DIEA (30 μL), HBTU (16.7 mg) Was added to a solution of (Q10) (13.9 mg) in DMF (400 μL) and DIEA (20 μL), and the mixture was stirred at room temperature for 45 minutes. Water (300 μL) was added and purified by preparative HPLC to give (Q11) (11.1 mg).
HPLC (SunFire)
rt (min): 10.80
LC / MS (ACQUITY)
rt (min): 1.24
MS (ESI, m / z): 1504.6 [M + H] ⁺ , 1502.6 [MH] ^-

(12)
TFA / triethylsilane (95/5) (1 mL) was added to (Q11) (5.2 mg), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water (1 mL) and 50% aqueous acetonitrile (0.2 mL) were added to the obtained residue, and the residue was purified by preparative HPLC to obtain (Q12) (3.7 mg).
HPLC (SunFire)
rt (min): 19.61
LC / MS (ACQUITY)
rt (min): 0.80
MS (ESI, m / z): 1280.2 [M + H] ⁺ , 1278.4 [MH] ^-

Reference Example 20

(1)
(R1) was obtained according to the methods described in Bioconjugate Chemistry, 1991, Volume 2, 187-194 and Bioconjugate Chemistry, 1991, Volume 2, 180-186.

(2)
A mixture of (A6) (12.4 mg), THF (1.4 mL), water (400 μL) and 3 mol / L aqueous lithium hydroxide solution (200 μL) was stirred at room temperature for 2 hours. Formic acid (50 μL) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Water (1 mL) was added and purified by preparative HPLC to give (R2) (6.9 mg).
HPLC (SunFire)
rt (min): 9.85
LC / MS (ACQUITY)
rt (min): 0.83
MS (ESI, m / z): 983.4 [M + H] ⁺ , 981.3 [MH] ^- , 490.1 [M-2H] ^2-

(3)
Water (300 μL) was added to a mixture of (R2) (6.9 mg), (R1) (10.1 mg), DMF (800 μL) and DIEA (10 μL), and the mixture was stirred at room temperature for 2 days. Water (400 μL) was added and purified by preparative HPLC to give (R3) (7.5 mg).
HPLC (SunFire)
Solvent: Liquid A = 10 mmol / L ammonium acetate aqueous solution, Liquid B = 10 mmol / L ammonium acetate / methanol: acetonitrile (4: 1))
Gradient cycle: 0.0 min (A liquid / B liquid = 80/20), 10 min (A liquid / B liquid = 0/100), 15 min (A liquid / B liquid = 0/100)
(Flow rate: 1.0mL / min)
rt (min): 7.26
LC / MS (ACQUITY)
rt (min): 0.83
MS (ESI, m / z): 769.4 [M + 2H] ²⁺ , 513.4 [M + 3H] ³⁺ , 767.4 [M-2H] ^2-

Reference Example 21

(1)
To a mixture of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (24.7 mg), DMF (150 μL) and DIEA (30 μL), add HBTU (16.4 mg ) In DMF (150 μL), (A4) (14.7 mg) in DMF (400 μL) and DIEA (20 μL) were added, and the mixture was stirred at room temperature for 50 minutes. Water (200 μL) was added and purified by preparative HPLC to give (S1) (15.7 mg).
HPLC (SunFire)
rt (min): 8.87
LC / MS (ACQUITY)
rt (min): 1.44
MS (ESI, m / z): 1249.6 [M + H] ⁺ , 1247.6 [MH] ⁻

(2)
To (S1) (12.8 mg), THF (1 mL), water (200 μL) and a 3 mol / L lithium hydroxide aqueous solution (200 μL) were added, and the mixture was stirred at room temperature for 1.5 hours. After adding TFA, the solvent was distilled off under reduced pressure, TFA / triethylsilane (95/5) (1 mL) was added, and the mixture was stirred at room temperature for 2 hours. TFA was distilled off, water / acetonitrile (2/1) (1.8 mL) and formic acid (1.8 μL) were added and purified by preparative HPLC to give (S2) (9.2 mg).
HPLC (SunFire)
rt (min): 7.76
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 534.4 [M + 2H] ²⁺ , 1065.4 [MH] ^-

Reference Example 22

(1)
To a solution of (O7) (120 mg) in DMF (1 mL) was added diethylamine (1 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water (1 mL) and 3 mol / L aqueous lithium hydroxide solution (100 μL) were added, and the mixture was stirred at room temperature for 14 hours. A 50% acetonitrile aqueous solution (1 mL) and water (1 mL) were added, washed with ethyl acetate (3 mL), and purified by preparative HPLC to obtain (T1) (69.8 mg).
HPLC (SunFire)
rt (min): 8.10
LC / MS (ACQUITY)
rt (min): 0.76
MS (ESI, m / z): 784.4 [M + H] ⁺ , 782.4 [MH] ⁻

(2)
To a mixture of (T1) (19.2 mg), DMF (200 μL) and DIEA (10 μL), add 2,2 ′, 2``, 2 '''-(2- (4-isothiocyanatobenzyl) -1,4 , 7,10-Tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid (13.5 mg) was added and stirred. DMF (600 μL), water (300 μL) and DIEA (30 μL) were added and stirred at room temperature for 2 days. Water (1.1 mL) and formic acid (100 μL) were added and purified by preparative HPLC to give (T2).
HPLC (CAPCEL PAK MG)
rt (min): 9.90
LC / MS (ACQUITY)
rt (min): 0.80
MS (ESI, m / z): 1335.7 [M + H] ⁺ , 668.5 [M + 2H] ²⁺ , 1333.7 [MH] ⁻

Reference Example 23

(1)
(R1) (22.4 mg) was added to a mixture of (T1) (17.5 mg), DMF (200 μL) and DIEA (10 μL) and stirred. DMF (600 μL), water (300 μL) and DIEA (30 μL) were added and stirred at room temperature for 2 days. Purification by preparative HPLC gave (U1).
HPLC (SunFire)
Solvent: Liquid A = 10 mmol / L ammonium acetate aqueous solution, liquid B = 10 mmol / L ammonium acetate / methanol: acetonitrile (4: 1)), liquid A / liquid B = 70/30
Flow rate: 1.0mL / min
rt (min): 6.65
LC / MS (ACQUITY)
rt (min): 0.93
MS (ESI, m / z): 669.7 [M + 2H] ²⁺

Reference Example 24

(1)
A mixture of ethyl 4- (1,8-naphthyridin-2-yl) butanoate (1.24 g), methanol (30 mL) and 10% Pd / C (205 mg) was stirred at room temperature for 16 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain (V1) (961 mg).
TLC Rf: 0.43 (dichloromethane / methanol = 95/5)
MS (ESI, m / z): 249.3 [M + H] ⁺

(2)
To a mixture of (V1) (961 mg), THF (10 mL) and DIEA (1.8 mL) was added di-tert-butyl dicarbonate (1.8 mL), and the mixture was heated to reflux for 19 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane to hexane / ethyl acetate = 4/1) to obtain (V2) (1.09 g).
TLC Rf: 0.50 (dichloromethane / methanol = 100/1)
MS (ESI, m / z): 349.3 [M + H] ⁺

(3)
To a solution of (V2) (1.1 g) in THF (8 mL) and methanol (8 mL) was added 1 mol / L aqueous lithium hydroxide solution (5.3 mL), and the mixture was stirred at room temperature for 14 hours. The mixture was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (V3) (982 mg).
TLC Rf: 0.52 (dichloromethane / methanol = 9/1)
MS (ESI, m / z): 321.3 [M + H] ⁺

(4)
To a solution of (V3) (130 mg) and (A2) (245 mg) in dichloromethane (7 mL) and DIEA (91 μL) were added HOBt (126 mg) and EDC · HCl (203 mg), and the mixture was stirred at room temperature for 2 hours. Dichloromethane and water were added, the organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane / methanol = 95/5) to obtain (V4) (255 mg).
TLC Rf: 0.22 (dichloromethane / methanol = 95/5)
MS (ESI, m / z): 867.5 [M + H] ⁺

(5)
A mixture of (V4) (255 mg), methanol (8 mL) and 10% Pd / C (121 mg) was stirred at room temperature for 14 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (V5) (163 mg).
TLC Rf: 0.05 (dichloromethane / methanol = 10/1)
MS (ESI, m / z): 733.5 [M + H] ⁺

(6)
Methanesulfonic acid (22 μL) was added to a mixture of disodium Fmoc-cysteic acid (100 mg) and DMF (3 mL), and the mixture was stirred for 5 minutes. DMF (5 mL), DIEA (200 μL) and (V5) (163 mg) were added and stirred for 5 minutes, then HBTU (187 mg) was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (V6) (172 mg).
TLC Rf: 0.25 (chloroform / ethanol / ammonia water = 7/3 / 0.5)
MS (ESI, m / z): 1104.2 [MH] ^-

(7)
TFA (1 mL) was added to (V6) (108 mg), and the mixture was stirred at room temperature for 45 minutes, and then the solvent was distilled off under reduced pressure. Acetonitrile / methanol (9/1) (3 mL) and diethylamine (0.5 mL) were added to the resulting residue and stirred for 1 hour. The solvent was distilled off under reduced pressure, and 50% acetonitrile aqueous solution (3 mL), toluene (3 mL) and hexane (3 mL) were added. The aqueous layer was separated, the solvent was distilled off under reduced pressure, and DMF (1 mL) and DIEA (60 μL) were added to the resulting residue, and then 1,4,7,10-tetraazacyclododecane-1, A solution of 4,7,10-tetraacetic acid tri-tert-butyl (89.2 mg), DMF (300 μL), DIEA (20 μL) and HBTU (59.1 mg) in DMF (300 μL) was added and stirred at room temperature for 80 minutes. After adding water (2 mL), purification by preparative HPLC gave (V7) (25.9 mg).
HPLC (SunFire)
rt (min): 8.76
LC / MS (ACQUITY)
rt (min): 1.28
MS (ESI, m / z): 670.2 [M + 2H] ²⁺ , 1337.0 [MH] ^-

(8)
TFA (1 mL) was added to (V7) (20.9 mg), and the mixture was stirred at room temperature for 5 hours, and then the solvent was distilled off under reduced pressure. Acetonitrile (1 mL) and TBME (1 mL) were added to the obtained residue, and the solvent was distilled off under reduced pressure. Water (0.6 mL) and a 3 mol / L lithium hydroxide aqueous solution (100 μL) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, formic acid (20 μL) was added, and purified by preparative HPLC, (V8) ( 9.6 mg) was obtained.
HPLC (SunFire)
rt (min): 8.36
LC / MS (ACQUITY)
rt (min): 0.71
MS (ESI, m / z): 1156.7 [M + H] ⁺

Reference Example 25

(1)
A mixture of 7-oxooctanoic acid (158 mg), ethanol (35 mL) and concentrated sulfuric acid (500 μL) was refluxed for 17 hours. After the solvent was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added. The organic layer was separated and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (W1) (180 mg).
MS (ESI, m / z): 187.2 [M + H] ⁺

(2)
A mixture of 2-aminonicotinaldehyde (118 mg), (W1) (180 mg), proline (56 mg) and methanol (10 mL) was refluxed for 18 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain (W2) (90 mg).
MS (ESI, m / z): 273.2 [M + H] ⁺

(3)
A mixture of (W2) (946 mg), methanol (20 mL) and 10% Pd / C (140 mg) was stirred at room temperature for 16 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (W3) (904 mg).
MS (ESI, m / z): 277.3 [M + H] ⁺

(4)
To a solution of (W3) (900 mg) in THF (10 mL) and DIEA (1.5 mL) was added di-tert-butyl dicarbonate (1.5 mL) and refluxed for 25 hours. Ethyl acetate and water were added, the organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane / methanol = 100/3) to obtain (W4) (904 mg).
TLC Rf: 0.33 (dichloromethane / methanol = 100/1)
MS (ESI, m / z): 377.2 [M + H] ⁺

(5)
To a solution of (W4) (1.05 g) in THF (18 mL) and methanol (9 mL) was added 1 mol / L lithium hydroxide aqueous solution (5 mL), and the mixture was stirred at room temperature for 3 hours. The mixture was neutralized with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (W5) (970 mg).
TLC Rf: 0.47 (dichloromethane / methanol = 9/1)
MS (ESI, m / z): 349.3 [M + H] ⁺

(6)
HOBt (122 mg) and EDC · HCl (233 mg) were added to a solution of (W5) (209 mg) and (A2) (265 mg) in dichloromethane (4 mL) and DIEA (120 μL), and the mixture was stirred at room temperature for 3 hours. Dichloromethane and water were added. The organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane / methanol = 95/5) to obtain (W6) (300 mg).
TLC Rf: 0.12 (dichloromethane / methanol = 95/5)
MS (ESI, m / z): 895.7 [M + H] ⁺

(7)
A mixture of (W6) (300 mg), methanol (8 mL) and 10% Pd / C (126 mg) was stirred under a hydrogen atmosphere at room temperature for 16 hours. Insoluble matter was removed by filtration, and the residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (W7) (194 mg).
TLC Rf: 0.05 (dichloromethane / methanol = 10/1)
MS (ESI, m / z): 761.5 [M + H] ⁺

(8)
Methanesulfonic acid (40 μL) was added to a mixture of Fmoc-disodium cysteate (120 mg) and DMF (3 mL), and the mixture was stirred for 5 minutes. DMF (7 mL), DIEA (250 μL) and (W7) (194 mg) were added and stirred for 5 minutes, then HBTU (201 mg) was added and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (W8) (216 mg).
TLC Rf: 0.31 (chloroform / ethanol / ammonia water = 7/3 / 0.5)
MS (ESI, m / z): 1132.2 [MH] ^-

(9)
TFA (1 mL) was added to (W8) (103 mg), and the mixture was stirred at room temperature for 45 minutes, and then the solvent was distilled off under reduced pressure. Acetonitrile / methanol (9/1) (3 mL) and diethylamine (0.5 mL) were added to the resulting residue and stirred for 1 hour. The solvent was distilled off under reduced pressure, and 50% acetonitrile aqueous solution (3 mL), toluene (3 mL) and hexane (3 mL) were added. The aqueous layer was separated and the solvent was distilled off under reduced pressure. After adding DMF (1 mL) and DIEA (60 μL) to the obtained residue, 1,4,7,10-tetraazacyclododecane-1,4,7,10-triacetic acid tri-tert-butyl (90.1 mg) ), DMF (300 μL), DIEA (60 μL) and HBTU (59.5 mg) in DMF (300 μL) were added, and the mixture was stirred at room temperature for 25 minutes. Water (2 mL) was added and purified by preparative HPLC to give (W9) (57.7 mg).
HPLC (SunFire)
rt (min): 8.93
LC / MS (ACQUITY)
rt (min): 1.26
MS (ESI, m / z): 1367.0 [M + H] ⁺ , 1365.0 [MH] ^-

(10)
TFA (1 mL) was added to (W9) (21.6 mg), and the mixture was stirred at room temperature for 4 hours, and then the solvent was distilled off under reduced pressure. Acetonitrile (1 mL) and TBME (1 mL) were added to the obtained residue, and the solvent was distilled off under reduced pressure. Water (0.6 mL) and a 3 mol / L lithium hydroxide aqueous solution (100 μL) were added to the resulting residue, and the mixture was stirred at room temperature for 1 hour, formic acid (20 μL) was added, and purified by preparative HPLC, (W10) ( 11.0 mg) was obtained.
HPLC (SunFire)
rt (min): 8.94
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 1184.8 [M + H] ⁺

Reference Example 26

(1)
To a mixture of (J2) (1.5 g), ethyl 5-bromothiophene-2-carboxylate (1.42 g), triethylamine (3.5 mL) and DMF (22 mL), palladium (II) acetate (133 mg) and (2- ( Di-tert-butylphosphino) biphenyl (352 mg) was added and stirred for 17 hours at 110 ° C. The reaction mixture was cooled to room temperature, ethyl acetate and water were added, the organic layer was separated, and anhydrous sodium sulfate was added. After drying, the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 9 / 1-5 / 1) to obtain (X1) (564 mg).
TLC Rf: 0.55 (hexane / ethyl acetate = 2/1)
MS (ESI, m / z): 415.3 [M + H] ⁺

(2)
(X1) (564 mg), methanol (20 mL) and 10% Pd / C (198 mg) were placed in a shield tube, and the mixture was stirred at room temperature for 17 hours in a hydrogen atmosphere. The insoluble material was removed by filtration, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/2) to obtain (X2) (498 mg).
TLC Rf: 0.47 (hexane / ethyl acetate = 2/1)
MS (ESI, m / z): 417.3 [M + H] ⁺

(3)
To a solution of (X2) (498 mg) in THF (8 mL) and methanol (4 mL) was added 1 mol / L aqueous lithium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 24 hours. After adding water (10 mL), acetic acid was added until cloudy.
The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane / ethanol = 9/1) to obtain (X3) (394 mg).
TLC Rf: 0.49 (dichloromethane / methanol = 9/1)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.64 (1 H, d, J = 4.0 Hz), 7.31 (1 H, d, J = 8.8 Hz), 6.79 (1 H, d, 4.0 Hz), 6.78 (1 H, d, J = 8.0Hz), 3.78 (2H, t, J = 6.4Hz), 3.29 (2H, t, J = 7.2Hz), 3.10 (2H, t, J = 7.2Hz), 2.73 (2H, t, J = 6.8Hz), 1.93 (2H, tt, J = 6.8,6.4Hz), 1.52 (9H, s)
MS (ESI, m / z): 389.3 [M + H] ⁺

(4)
HBTU (290 mg) was added to a mixture of (A2) (415 mg), (X3) (238 mg), DMF (5 mL) and DIEA (540 μL), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane / methanol = 95/5) to obtain (X4) (570 mg). .
TLC Rf: 0.41 (ethyl acetate)
MS (ESI, m / z): 935.5 [M + H] ⁺

(5)
(X4) (187 mg), methanol (15 mL) and 10% Pd / C (61 mg) were placed in a shield tube and stirred for 18 hours under a hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95/5 to chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (X5) (87 mg).
TLC Rf: 0.27 (chloroform / ethanol / ammonia water = 8/2 / 0.3)
MS (ESI, m / z): 801.4 [M + H] ⁺

(6)
A mixture of disodium Fmoc-cysteic acid (48 mg), DMF (1 mL) and methanesulfonic acid (8.5 μL) was stirred at room temperature for 30 minutes. DIEA (91 μL), DMF (2 mL), (X5) (87 mg) and HBTU (85 mg) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (X6) (106 mg).
TLC Rf: 0.26 (chloroform / ethanol / ammonia water = 7/3 / 0.5)
MS (ESI, m / z): 1172.1 [MH] ^-

(7)
To a solution of (X6) (80 mg) in DMF (0.5 mL) was added diethylamine (0.5 mL), and the mixture was stirred at room temperature for 80 minutes. The solvent was distilled off under reduced pressure, and DMF (1 mL), DIEA (60 μL), Fmoc-cysteic acid (65.4 mg) and HBTU (63.3 mg) were added to the obtained oil, and the mixture was stirred at room temperature for 20 minutes. Water (1 mL) was added, diethylamine (2 mL) was added, and the mixture was stirred at room temperature for 30 min. Water (2 mL) was added, washed twice with ethyl acetate (2 mL), and purified by preparative HPLC to give (X7) (66.8 mg).
HPLC (SunFire)
rt (min): 9.36
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 989.5 [M + H] ⁺ , 987.4 [MH] ⁻

(8)
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (39.0 mg) in DMF (150 μL) and DIEA (25 μL) in HBTU (24.8 mg) Was added to a solution of (X7) (27.3 mg) in DMF (0.3 mL) and DIEA (10 μL), and the mixture was stirred at room temperature for 30 minutes. Water (0.5 mL) and acetonitrile (0.2 mL) were added and purified by preparative HPLC to give (X8) (19.0 mg).
HPLC (SunFire)
rt (min): 9.89
LC / MS (ACQUITY)
rt (min): 1.03
MS (ESI, m / z): 1543.7 [M + H] ⁺ , 1541.7 [MH] ^-

(9)
TFA / triethylsilane (95/5) (1 mL) was added to (X8) (9.6 mg), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, 50% acetonitrile aqueous solution (1.2 mL) was added, and purification was performed by preparative HPLC to obtain (X9) (3.6 mg).
HPLC (SunFire)
rt (min): 10.08
LC / MS (ACQUITY)
rt (min): 0.78
MS (ESI, m / z): 688.4 [M + 2H] ²⁺ , 1373.5 [MH] ^- , 686.5 [M-2H] ^2-

Reference Example 27

(1)
Ethyl 4-bromobutanoate (4.8 mL) was added to a mixture of phenol (2.84 g), DMF (40 mL) and potassium carbonate (7.9 g), and the mixture was stirred at room temperature for 22 hours. Ethyl acetate and water were added. The organic layer was separated and the solvent was distilled off under reduced pressure. Ethanol (80 mL), water (20 mL) and sodium hydroxide (4.7 g) were added to the resulting residue, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane, dissolved in water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain (Y1) (5.08 g).
TLC Rf: 0.38 (ethyl acetate)

(2)
To a chloroform (30 mL) solution of (Y1) (5.08 g), chlorosulfonic acid (10 mL) was added dropwise at 0 ° C. or lower over 30 minutes, and the mixture was stirred at 0 ° C. for 15 minutes. The reaction mixture was added to ice water, and the solid substance was collected by filtration to obtain (Y2) (4.25 g).
TLC Rf: 0.38 (dichloromethane / methanol = 95/5)

(3)
(S) -2-Amino-3-((tert-butoxycarbonyl) amino) propanoic acid methyl hydrochloride (1.0 g), dichloromethane (10 mL) and DIEA (1.4 mL) in a mixture of (Y2) (1.25 g) Dichloromethane (35 mL) solution was added and stirred at room temperature for 70 hours. Water was added, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95/5) to obtain (Y3) (938 mg).
TLC Rf: 0.16 (dichloromethane / methanol = 95/5)

(4)
HATU (877 mg) was added to a mixture of (Y3) (938 mg), Z-ethylenediamine hydrochloride (517 mg), DMF (14 mL) and DIEA (1.4 mL), and the mixture was stirred at room temperature for 1 hour. Dichloromethane and water were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate) to obtain (Y4) (1.11 g).
TLC Rf: 0.25 (dichloromethane / methanol = 95/5)

(5)
TFA (10 mL) was added to a solution of (Y4) (1.11 g) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added. The organic layer was separated and dried over anhydrous sodium sulfate to obtain (Y5) (894 mg).
TLC Rf: 0.20 (dichloromethane / methanol = 9/1)

(6)
HATU (673 mg) was added to a solution of (Y5) (894 mgl) and (H4) (640 mg) in DMF (15 mL) and DIEA (1.46 mL), and the mixture was stirred at room temperature for 2 hours. Ethyl acetate and water were added. The organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (ethyl acetate / methanol = 100/5) to obtain (Y6) (1.47 g).
TLC Rf: 0.51 (dichloromethane / methanol = 9/1)

(7)
(Y6) (225 mg), methanol (10 mL) and 10% Pd / C (62 mg) were placed in a shield tube, and the mixture was stirred for 17 hours under a hydrogen atmosphere. Insoluble matter was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7: 3: 0.5) to obtain (Y7) (126 mg).
TLC Rf: 0.69 (chloroform / ethanol / ammonia water = 7/3 / 0.5)

(8)
A mixture of Fmoc-disodium cysteate (40 mg), DMF (0.5 mL) and methanesulfonic acid (7.2 μL) was stirred at room temperature for 30 minutes before DIEA (77 μL), DMF (1.5 mL) and (Y7) (69 mg ) Was added. HBTU (48 mg) was added, stirred at room temperature for 2.5 hours, and chloroform and water were added. The organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (Y8) (76 mg).
TLC Rf: 0.35 (chloroform / ethanol / ammonia water = 7/3 / 0.5)

(9)
A mixture of (Y8) (140 mg), DMF (2 mL) and diethylamine (200 μL) was stirred at room temperature for 80 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (Y9) (100 mg).
TLC Rf: 0.10 (chloroform / ethanol / ammonia water = 7/3 / 0.5)

(10)
A mixture of Fmoc-disodium cysteate (46 mg), DMF (1 mL) and methanesulfonic acid (8.3 μL) was stirred at room temperature for 30 minutes, then DIEA (89 μL), DMF (1.5 mL), (Y9) (100 mg) And HBTU (58 mg) were added and stirred at room temperature for 1.5 hours. Chloroform and water were added to the reaction mixture. The organic layer was separated, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 6/4/1) to obtain (Y10) (155 mg).
TLC Rf: 0.19 (chloroform / ethanol / ammonia water = 6/4/1)

(11)
A mixture of (Y10) (142 mg), DMF (2 mL) and diethylamine (200 μL) was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 5/5 / 1.5) to obtain (Y11) (89 mg).
TLC Rf: 0.21 (chloroform / ethanol / ammonia water = 5/5 / 1.5)
MS (ESI, m / z): 1013.3 [M-BOC + 2Na] ⁺ , 1067.3 [MH] ⁻ , 533.2 [M-2H] ²⁻

(12)
(Y11) (26 mg), 1,4,7,10-tetraazacyclododecane-1,4,7,10-triacetic acid tri-tert-butyl (16 mg), DMF (500 μL) and DIEA (21 μL) mixture Was added with HATU (23 mg) and stirred at room temperature for 5 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / ethanol / aqueous ammonia = 7/3 / 0.5) to obtain (Y12) (25 mg).
TLC Rf: 0.22 (chloroform / ethanol / ammonia water = 7/3 / 0.5)

(13)
TFA (2 mL) was added to (Y12) (45 mg), and the mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, DMF (2 mL) and sodium hydroxide (17 mg) were added to the resulting residue, and the mixture was stirred at room temperature for 47 hours. The solvent was distilled off under reduced pressure, and the residue was purified by reverse phase silica gel (Sep-Pak C18, water / methanol = 5/95 to 10/90) to obtain (Y13) (40 mg).
Reversed phase TLC Rf: 0.68 (water / acetonitrile = 95/5)

Reference Example 28

(1)
A solution of 2- (tert-butoxycarbonylamino) pyridine (1.07 g) in DMF (6 mL) is ice-cooled, sodium hydride (60% mineral oil dispersion, 221 mg) is added over 10 minutes, and the mixture is stirred at the same temperature for 15 minutes. Then, ethyl 4- (3-bromopropyl) benzoate (1.5 g) was added to a DMF (6 mL) solution, and the mixture was stirred at room temperature for 3 hours. The mixture was added to 2% hydrochloric acid, extracted with ethyl acetate, and washed successively with a saturated aqueous sodium carbonate solution and a saturated aqueous sodium chloride solution. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain (Z1) (1.8 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.37 (1H, dd, J = 2.1, 4.2 Hz), 7.94 (2H, d, J = 7.2 Hz), 7.54-7.65 (2H, m), 7.22 (2H , d, J = 7.2Hz), 6.99-7.03 (1H, m), 4.36 (2H, q, J = 7.2Hz), 3.98 (2H, t, J = 7.2Hz), 2.69 (2H, t, J = 7.2Hz), 1.93-2.03 (2H, m), 1.48 (9H, s), 1.38 (3H, t, J = 7.2Hz)

(2)
Concentrated hydrochloric acid (5 mL) was added to (Z1) (1.5 g), and the mixture was stirred at 70 ° C. for 3 hours, concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate solution was added until pH 4 and extracted with ethyl acetate. The solvent was distilled off under reduced pressure to obtain (Z2) (300 mg).
LC / MS (ACQUITY)
rt (min): 0.66
MS (ESI, m / z): 257.1 [M + H] ⁺

(3)
HBTU (296 mg) was added to a mixture of (A2) (750 mg), (Z2) (200 mg), DMF (3 mL) and DIEA (0.68 mL), and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and water were added. The organic layer was separated and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol) to obtain (Z3) (480 mg). It was.
LC / MS (ACQUITY)
rt (min): 1.16
MS (ESI, m / z): 803.5 [M + H] ⁺

(4)
(Z3) (480 mg), methanol (30 mL) and 10% Pd / C (100 mg) were placed in a shield tube, and the mixture was stirred for 5 hours under a hydrogen atmosphere. The insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain (Z4) (510 mg).

(5)
A mixture of disodium Fmoc-cysteic acid (73.4 mg), THF (1 mL) and methanesulfonic acid (11 μL) was stirred at room temperature for 30 minutes. DIEA (29 μL), NMP (1 mL) and (Z4) (94 mg) were added, then HBTU (64 mg) was added, and the mixture was stirred at room temperature for 2.5 hours. Methanol was added, insoluble matter was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was washed twice with water. THF (2 mL), NMP (0.3 mL) and diethylamine (2 mL) were added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure and washed with toluene to obtain (Z5) (74 mg).
LC / MS (ACQUITY)
rt (min): 0.78
MS (ESI, m / z): 820.4 [M + H] ⁺

(6)
A mixture of disodium Fmoc-cysteic acid (45.9 mg), THF (2 mL) and methanesulfonic acid (6.8 μL) was stirred at room temperature for 1 hour, then (Z5) (74 mg), NMP (0.7 mL), DIEA (18 μL) ) And HBTU (40.0 mg) were added, and the mixture was stirred at room temperature for 2.5 hours. Methanol was added, the solvent was distilled off under reduced pressure, and the mixture was washed with ethyl acetate. NMP (1 mL) and diethylamine (1 mL) were added to the residue, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative HPLC to give (Z6) (6.7 mg).
LC / MS (ACQUITY)
rt (min): 0.83
MS (ESI, m / z): 971.5 [M + H] ⁺ , 486.4 [M + 2H] ²⁺ , 969.5 [MH] ⁻

(7)
1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid tri-tert-butyl (5.9 mg), (Z6) (6.7 mg), NMP (200 μL) and DIEA (20 μL) To the solution, HBTU (5.2 mg) was added and stirred at room temperature for 50 minutes. After adding methanol (100 μL), purification by preparative HPLC gave (Z7) (3.9 mg).
LC / MS (ACQUITY)
rt (min): 1.08
MS (ESI, m / z): 763.9 [M + 2H] ²⁺

(8)
A mixture of (Z7) (3.9 mg), THF (200 μL), water (20 μL), 2-propanol (20 μL) and 4 mol / L lithium hydroxide aqueous solution (27 μL) was stirred at room temperature for 4 hours. TFA was added and the solvent was distilled off under reduced pressure. TFA / triethylsilane (95/5) (100 μL) was added and stirred for 2 hours, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC to give (Z8) (1.8 mg).
LC / MS (ACQUITY)
rt (min): 0.76
MS (ESI, m / z): 672.6 [M + 2H] ²⁺ , 670.6 [M-2H] ^2-

Reference Example 29

(1)
To a mixture of L-glutamic acid γ-benzyl ester (5.0 g), water (10 mL), sodium bromide (7.6 g) and hydrobromic acid (6 mL), sodium nitrite (2.6 g) was added at 5 ° C. or lower over 10 minutes. And stirred at 5 ° C. for 2 hours. Diisopropyl ether and concentrated sulfuric acid (2 mL) were added to the reaction mixture, and the organic layer was separated, washed successively with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain (Aa1) (3.1 g).
LC / MS (ACQUITY)
rt (min): 1.32
MS (ESI, m / z): 301.1 [M + H] ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ:
7.31-7.38 (5H, m), 5.1 (2H, s), 4.41 (1H, dd, J = 6.0,7.8Hz), 2.58-2.63 (2H, m), 2.25-2.50 (2H, m)

(2)
To a solution of (Aa1) (3.1 g) in chloroform (15 mL), a mixture of tert-butyl 2,2,2-trichloroacetimidate (4.3 mL) and hexane (12 mL) was added at room temperature over 20 minutes. After adding DMAc (1.5 mL) and BF ₃ · OEt ₂ (220 μL) and stirring at room temperature for 40 hours, the solvent was distilled off under reduced pressure, and silica gel column chromatography (hexane / ethyl acetate = 95/5 to 85 / The product was purified by 15) to obtain (Aa2) (2.84 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ:
7.31-7.38 (5H, m), 5.14 (2H, s), 4.24 (1H, dd, J = 6.0,8.7Hz), 2.53-2.59 (2H, m), 2.19-2.43 (2H, m), 1.47 ( 9H, s)

(3)
To a chloroform (60 mL) solution of 1,4,8,11-tetraazacyclotetradecane (1.84 g), a solution of (Aa2) (1.70 g) in chloroform (50 mL) was added over 90 minutes, and the mixture was stirred at room temperature for 3 days. did. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50 / 50-0 / 100, then ethyl acetate / methanol = 80/20) to obtain (Aa3) (0.76 g). Obtained.
LC / MS (ACQUITY)
rt (min): 0.91
MS (ESI, m / z): 406.5 [M + H] ⁺

(4)
To a mixture of (Aa3) (0.76 g), DMAc (7 mL) and potassium carbonate (607 mg), tert-butyl bromoacetate (580 μL) was added and stirred at room temperature for 2 hours. Ethyl acetate (30 mL) and water (30 mL) were added, the organic layer was separated, washed successively with water (30 mL) twice, saturated aqueous sodium chloride solution (30 mL) once, and dried over anhydrous sodium sulfate. . The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5-60 / 40) to obtain (Aa4) (1.04 g).
LC / MS (ACQUITY)
rt (min): 1.63
MS (ESI, m / z): 634.7 [M + H] ⁺

(5)
(Aa4) (0.28 g), isopropyl alcohol (20 mL), water (0.5 mL) and 10% Pd / C (0.10 g) were placed in a shield tube, and the mixture was stirred for 7 hours under a 0.5 MPa hydrogen atmosphere. The insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain (Aa5) (0.24 g).
LC / MS (ACQUITY)
rt (min): 1.34
MS (ESI, m / z): 544.7 [M + H] ⁺

(6)
(Aa5) (94.9 mg), (R) -2-amino-3-((2- (4- (4- (N-((S) -1-methoxy-1-oxo-3- (5- ( 5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) propan-2-yl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -3-oxopropane HBTU (64.5 mg) was added to a mixture of -1-sulfonic acid (104 mg), DMF (0.8 mL) and N, N-diisopropylethylamine (61 μL), and the mixture was stirred at room temperature for 35 minutes. Water (1.1 mL) and acetonitrile (0.8 mL) were added and stirred, and then purified by preparative HPLC to give (Aa6) (151 mg).
HPLC (CAPCELL PAK MG)
rt (min): 11.82
LC / MS (ACQUITY)
rt (min): 1.28
MS (ESI, m / z): 1324.2 [M + H] ⁺ , 1322.2 [MH] ⁻

(7)
Concentrated hydrochloric acid (2.5 mL) was added to (Aa6) (73 mg), stirred at room temperature for 2 days, and concentrated under reduced pressure. After dilution with 50% aqueous acetonitrile (2 mL), purification by preparative HPLC gave (Aa7) (33.3 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.37
LC / MS (ACQUITY)
rt (min): 0.77
MS (ESI, m / z): 1141.8 [M + H] ⁺ , 1139.8 [MH] ^-

Reference Example 30

(1)
39% glyoxal (4.5 mL) was added to a solution of 1,4,8,11-tetraazacyclotetradecane (5.35 g) in acetonitrile (450 mL), and the mixture was stirred at room temperature for 1.5 hours and then stirred at 50 ° C. for 2 hours. The solvent was evaporated under reduced pressure, diisopropyl ether (100 mL) was added, and the mixture was stirred at room temperature for 1 hr. The obtained solid was collected by filtration to obtain (Ab1) (2.46 g).
¹ H-NMR (300 MHz, CDCl ₃ ) δ:
3.49-3.57 (2H, m), 3.08 (2H, s), 2.93-2.97 (6H, m), 2.74 (2H, d, J = 11.1Hz), 2.01-2.35 (8H, m), 1.19-1.26 ( 2H, m)

(2)
Benzyl bromide (18 mL) was added to a solution of (Ab1) (2.40 g) in acetonitrile (40 mL), and the mixture was stirred at room temperature for 15 days. The precipitated solid was collected by filtration and washed with acetonitrile and dichloromethane to obtain (Ab2) (4.0 g).
LCMS (ACQUITY)
rt (min): 0.46
MS (ESI, m / z): 313.4 [M-Bn] ⁺

(3)
To a mixture of (Ab2) (4.0 g), ethanol (180 mL), and water (9 mL), sodium borohydride (4 g) was added in four 15-minute portions and stirred at room temperature for 3 days. Under cooling, 3M hydrochloric acid (80 mL) and water (100 mL) were sequentially added, neutralized with sodium hydroxide, and extracted twice with toluene (200 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain (Ab3) (1.9 g).
LC / MS (ACQUITY)
rt (min): 0.73
MS (ESI, m / z): 407.6 [M + H] ⁺

(4)
(Ab3) (0.90 g), acetic acid (25 mL) and 10% Pd / C (230 mg) were placed in a shield tube, and the mixture was stirred under a hydrogen atmosphere for 11 hours. Insoluble material was filtered off, the solvent was distilled off under reduced pressure, water (30 mL), sodium hydroxide (2 g) and saturated aqueous sodium chloride solution (10 mL) were added, and the mixture was extracted 3 times with toluene (50 mL). The solvent was distilled off under reduced pressure to obtain (Ab4) (509 mg).
LC / MS (ACQUITY)
rt (min): 0.20
MS (ESI, m / z): 227.4 [M + H] ^+
1 H-NMR (300 MHz, CDCl ₃ ) δ:
3.73 (1H, brs), 3.11 (2H, ddd, J = 2.7,9.9,13.2Hz), 2.59-2.94 (14H, m), 2.34-2.46 (4H, m), 2.26 (1H, brs), 1.85- 1.99 (2H, m), 1.25-1.36 (2H, m)

(5)
A solution of (Aa2) (880 mg) in acetonitrile (3 mL) was added to a mixture of (Ab4) (509 mg), acetonitrile (8 mL) and potassium carbonate (930 mg), and the mixture was stirred at room temperature for 1 day. Insoluble matters were filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / isopropylamine = 100/5 to 100/10) to obtain (Ab5) (467 mg).
LC / MS (ACQUITY)
rt (min): 0.92
MS (ESI, m / z): 503.6 [M + H] ⁺

(6)
To a mixture of (Ab5) (383 mg), DMAc (3 mL) and potassium carbonate (250 mg), tert-butyl bromoacetate (123 μL) was added and stirred at room temperature for 2 hours. Ethyl acetate (20 mL), water (10 mL) and saturated aqueous sodium chloride solution (20 mL) were added, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was sequentially purified by silica gel column chromatography (chloroform / methanol = 9/1, ethyl acetate / isopropylamine = 10/1) and preparative HPLC, and (Ab6-a) (76 mg) and (Ab6-b) (50 mg ) ((Ab6-a) and (Ab6-b) are stereoisomers).
(Ab6-a)
LC / MS (ACQUITY)
rt (min): 1.19
MS (ESI, m / z): 617.7 [M + H] ⁺
(Ab6-b)
LC / MS (ACQUITY)
rt (min): 1.64
MS (ESI, m / z): 617.7 [M + H] ⁺

(7-a)
(Ab6-a) (76 g), THF (2 mL), water (2 mL) and 10% Pd / C (10 mg) were placed in a shield tube, and the mixture was stirred under a hydrogen atmosphere for 6 hours. Insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain (Ab7-a) (64 mg).
LC / MS (ACQUITY)
rt (min): 0.82
MS (ESI, m / z): 527.5 [M + H] ⁺

(7-b)
(Ab6-b) (50 g), THF (2 mL), water (2 mL) and 10% Pd / C (10 mg) were placed in a shielded tube, and the mixture was stirred under a hydrogen atmosphere for 6 hours. Insoluble material was filtered off, and the solvent was distilled off under reduced pressure to obtain (Ab7-b) (45 mg).
LC / MS (ACQUITY)
rt (min): 1.30
MS (ESI, m / z): 527.5 [M + H] ⁺

(8-a)
(Ab7-a) (60.9 mg), (R) -2-amino-3-((2- (4- (4- (N-((S) -1-methoxy-1-oxo-3- (5 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) propan-2-yl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -3- HBTU (48.4 mg) was added to a mixture of oxopropane-1-sulfonic acid (92.6 mg), DMF (0.8 mL) and N, N-diisopropylethylamine (50 μL), and the mixture was stirred at room temperature for 15 minutes. Water (0.5 mL) and 50% aqueous acetonitrile (0.6 mL) were added and stirred, and then purified by preparative HPLC to give (Ab8-a) (74 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.74
LC / MS (ACQUITY)
rt (min): 0.91
MS (ESI, m / z): 1307.0 [M + H] ⁺ , 654.3 [M + 2H] ²⁺ , 1305.0 [MH] ⁻

(8-b)
(Ab7-b) (40.2 mg), (R) -2-amino-3-((2- (4- (4- (N-((S) -1-methoxy-1-oxo-3- (5 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) propan-2-yl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -3- HBTU (31.7 mg) was added to a mixture of oxopropane-1-sulfonic acid (60.6 mg), DMF (0.8 mL) and N, N-diisopropylethylamine (35 μL), and the mixture was stirred at room temperature for 15 minutes. Water (0.5 mL) and 50% aqueous acetonitrile (0.6 mL) were added and stirred, and then purified by preparative HPLC to give (Ab8-b) (69 mg).
HPLC (CAPCELL PAK MG)
rt (min): 11.88
LC / MS (ACQUITY)
rt (min): 1.22
MS (ESI, m / z): 1307.0 [M + H] ⁺ , 654.3 [M + 2H] ²⁺ , 1305.1 [MH] ⁻

(9-a)
Concentrated hydrochloric acid (2.5 mL) was added to (Ab8-a) (69.5 mg), and the mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. After dilution with 50% aqueous acetonitrile (2.4 mL), purification by preparative HPLC gave (Ab9-a) (44.1 mg). HPLC (CAPCELL PAK MG)
rt (min): 8.95
LC / MS (ACQUITY)
rt (min): 0.75
MS (ESI, m / z): 1180.8 [M + H] ⁺ , 590.9 [M + 2H] ²⁺ , 1178.8 [MH] ⁻

(9-b)
Concentrated hydrochloric acid (2.5 mL) was added to (Ab8-b) (64.4 mg), and the mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. After dilution with 50% aqueous acetonitrile (2.4 mL), purification by preparative HPLC gave (Ab9-b) (33.1 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.19
LC / MS (ACQUITY)
rt (min): 0.75
MS (ESI, m / z): 1180.8 [M + H] ⁺ , 591.0 [M + 2H] ²⁺ , 1178.7 [MH] ⁻

Example 1
(1)

To a mixture of (P2) (112 mg), water (1 mL), 1 mol / L aqueous ammonium acetate (1 mL) and acetic acid (300 μL), a solution of indium chloride tetrahydrate (129 mg) in water (0.5 mL) was added, and 110 Stir at 0 ° C. for 10 minutes. A 50% acetonitrile aqueous solution (3 mL) was added, and purification was performed by preparative HPLC to obtain (AA) (118 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.35
LC / MS (ACQUITY)
rt (min): 0.75
MS (ESI, m / z): 1280.9 [MH] ^-

(2)

(D3) (2.4 mg), water (80 μL), 0.5 mol / L aqueous ammonium acetate solution (100 μL), acetic acid (10 μL) and gentisic acid (0.4 mg) in a mixture of indium chloride tetrahydrate (15.6 mg) and A mixture (50 μL) of water (156 μL) was added and heated at 100 ° C. for 10 minutes. A 50% acetonitrile aqueous solution (500 μL) was added, and purification was performed by preparative HPLC to obtain (BB) (1.6 mg).
HPLC (SunFire)
rt (min): 7.89
LC / MS (SunFire)
rt (min): 7.76
MS (ESI, m / z): 662.75 [M + 2H] ²⁺ , 442.15 [M + 3H] ³⁺

(3)

(CC) (1.2 mg) was obtained in the same manner as in Example 1 (1) using (J9) (1.3 mg).
HPLC (SunFire)
rt (min): 10.93
LC / MS (SunFire)
rt (min): 10.25
MS (ESI, m / z): 686.30 [M + 2H] ²⁺ , 684.15 [M-2H] ^2-

Example 2

To a mixture of (P2) (140 mg), water (1 mL), 1 mol / L aqueous ammonium acetate solution (1 mL) and acetic acid (300 μL), a solution of yttrium chloride hexahydrate (143 mg) in water (0.5 mL) was added. Stir at 0 ° C. for 10 minutes. A 50% acetonitrile aqueous solution (3 mL) was added, and purification was performed by preparative HPLC to obtain (DD) (111 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.71
LC / MS (ACQUITY)
rt (min): 0.75
MS (ESI, m / z): 1256.6 [M + H] ⁺ , 1254.6 [MH] ^-

Example 3

A mixture of (P2) (36.8 mg), 0.5 mol / L sodium acetate aqueous solution / water / acetic acid (10/10/1) (1.2 mL) and copper (II) chloride (4.4 mg) was stirred at 110 ° C. for 10 minutes. . Purification with SepPak C18 (water / methanol = 1/1) gave (EE) (39.1 mg).
HPLC (MG)
rt (min): 9.23
LC / MS (ACQUITY)
rt (min): 0.75
MS (ESI, m / z): 1231.6 [M + H] ⁺ , 1229.6 [MH] ^-

Example 4

A mixture of (Aa7) (16.9 mg), 0.5 mol / L sodium acetate aqueous solution / water / acetic acid (10/10/1) (0.4 mL) and copper (II) chloride (3.2 mg) was stirred at 110 ° C. for 5 minutes. Thereafter, purification with SepPak C18 (water / methanol = 1/1) yielded (FF) (14.4 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.80
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 1202.5 [M + H] ⁺ , 601.9 [M + 2H] ²⁺ , 1200.5 [MH] ⁻

Example 5

A mixture of (Ab9-a) (16.2 mg), 0.5 mol / L aqueous sodium acetate / water / acetic acid (80/80/1) (0.4 mL) and copper (II) chloride (3.1 mg) at 110 ° C. for 10 minutes After stirring, purification by preparative HPLC gave (GG) (16.0 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.52
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 1241.7 [M + H] ⁺ , 621.5 [M + 2H] ²⁺ , 1239.7 [MH] ^-

A mixture of (Ab9-b) (13.6 mg), 0.5 mol / L aqueous sodium acetate solution / water / acetic acid (80/80/1) (0.4 mL) and copper (II) chloride (3.1 mg) at 110 ° C. for 10 minutes After stirring, purification by preparative HPLC gave (HH) (13.3 mg).
HPLC (CAPCELL PAK MG)
rt (min): 9.59
LC / MS (ACQUITY)
rt (min): 0.79
MS (ESI, m / z): 1241.7 [M + H] ⁺ , 621.5 [M + 2H] ²⁺ , 1239.7 [MH] ^-

Example 6
(1) Labeling method A
[ ¹¹¹ In] Indium chloride solution (80 MBq, 100 μL) was added to a mixture of (P2) (8.5 μg) and 0.2 mol / L sodium acetate buffer solution (pH 4.0) (1.5 mL). After heating at 100 ° C. for 15 minutes, the mixture was allowed to stand at room temperature for 5 minutes to obtain [ ¹¹¹ In]-(P2). As a result of analysis by reverse phase TLC (Whatman, KC18F, developing solvent: methanol / 0.5 mol / L aqueous ammonium acetate solution (50/50)), the Rf value of the radiolabeled compound was 0.4. The radiochemical purity immediately after preparation and after 24 hours at room temperature was 95% or more.

(2) Labeling method B
[ ⁹⁰ Y] (P2) (79 μg), gentisic acid (1.8 mg), 0.6 mol / L sodium acetate buffer solution (pH 4.0, 120 μL) and 0.4 mol / L sodium hydroxide aqueous solution (24 μL) Yttrium chloride solution (700 MBq, 240 μL) was added. After heating at 100 ° C. for 20 minutes, the mixture was allowed to stand at room temperature for 5 minutes to obtain [ ⁹⁰ Y]-(P2). As a result of analysis by reversed-phase TLC (Whatman, KC18F, developing solvent: methanol / 0.5 mol / L aqueous ammonium acetate solution (50/50)), the Rf value of the radiolabeled compound was 0.4. The radiochemical purity immediately after preparation and after 24 hours at room temperature was 95% or more.

(3) Labeling method C
[ ⁶⁴ Cu] copper chloride solution (pH 5, 35 MBq, 55 μL) was added to a mixture of (P2) (5.8 μg) and 0.2 mol / L sodium acetate buffer solution (pH 4.0, 219 μL). After heating at 100 ° C. for 15 minutes, the mixture was allowed to stand at room temperature for 5 minutes to obtain [ ⁶⁴ Cu]-(P2). As a result of analysis by reversed-phase TLC (Whatman, KC18F, developing solvent: methanol / 0.5 mol / L aqueous ammonium acetate solution (50/50)), the Rf value of the radiolabeled compound was 0.4. The radiochemical purity immediately after preparation and after 22 hours at room temperature were both 90% or higher.

(4)-(27)
Radiolabeled compounds were synthesized by the same method as (1) to (2).

(28) Labeling method D
[ ⁶⁴ Cu] copper chloride 0.2 mol / L sodium acetate buffer solution (Aa7) (4.2 μg), gentisic acid (1 mg) and 0.2 mol / L sodium acetate buffer solution (pH 4.0) (5.0 μL) pH 4.0) (40 MBq, 155 μL) was added. After heating at 100 ° C. for 15 minutes, the mixture was allowed to stand at room temperature for 5 minutes to obtain [ ⁶⁴ Cu]-(Aa7). As a result of analysis by reversed phase TLC (Merck, RP-8 F _254S , developing solvent: methanol / 0.5 mol / L aqueous ammonium acetate solution (50/50)), the Rf value of the radiolabeled compound was 0.4. The radiochemical purity immediately after preparation and after 24 hours at room temperature was 90% or more.

(29) and (30)
A radiolabeled compound was synthesized in the same manner as in (28).

  The results of (4) to (30) are shown below.

Test Example 1 integrinα _V β ₃ binding affinity test
0.2 μg / mL α _V β ₃ (Chemicon) was immobilized on a 96-well plate (Corning), blocked with 1% Block Ace (DS Pharma Biomedical) solution, and then T-PBS (0.05% Tween20 was added). Washed with PBS). Compound solution of 2 times concentration (10 concentrations from 0.3 μmol / L to 3.16 times dilution, buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 1 mM MnCl ₂ )) and 4 μg / mL 50 μL of each of the biotinylated vitronectin solutions (Vitronectin (Upstate Biotechnology) labeled with EZ-Link SμLfo-NHS-Biotinylation Kit (Pierce) and adjusted in concentration) was added and shaken at room temperature for 2 hours. After washing with T-PBS, 0.2 μg / mL avidin peroxidase (Pierce) solution was added and shaken at room temperature for 1 hour. After washing with T-PBS, color was developed with an o-phenylenediamine (Sigma) solution (stopped with 4 mol / L sulfuric acid), and the absorbance (490 nm, Reference: 595 nm) was measured. IC ₅₀ values were calculated using XLfit 3.0 (ID Business Solutions Ltd.). RGDfV (Bachem AG) was measured as a QC sample for each plate using duplicate.

Test Example 2 integrinα _V β ₅ binding affinity test
After immobilizing 0.2 μg / mL α _V β ₅ (Chemicon) on a 96-well plate (Corning), blocking with 1% Block Ace (DS Pharma Biomedical) solution, PBST (10 mM Na ₂ HPO ₄ pH 7 .5, 150 mM NaCl, 0.01% Tween20). Compound solution of 2 times concentration (10 concentrations from 0.3 μmol / L to 3.16 times dilution, buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 1 mM MnCl ₂ )) and 4 μg / mL 50 μL of each of the biotinylated vitronectin solutions (Vitronectin (Upstate Biotechnology) labeled with EZ-Link SμLfo-NHS-Biotinylation Kit (Pierce) and adjusted in concentration) was added and shaken at room temperature for 2 hours. After washing with PBST, 0.2 μg / mL avidin peroxidase (Pierce) solution was added and shaken at room temperature for 1 hour. After washing with PBST, color was developed with an o-phenylenediamine (Sigma) solution (stopped with 4 mol / L sulfuric acid), and the absorbance (490 nm, Reference: 595 nm) was measured. IC ₅₀ values were calculated using XLfit 3.0 (ID Business Solutions Ltd.). RGDfV (Bachem AG) was measured as a QC sample for each plate using duplicate.

  The results of Test Example 1 and Test Example 2 are shown below.

  The compounds in Table 3 showed excellent integrin binding affinity.

Test Example 3 Accumulation in integrin-expressing tumor Integrin-specific accumulation of ¹¹¹ In-labeled compound in the tumor of mice transplanted subcutaneously with integrin-expressing cells was confirmed by tissue extraction radioactivity measurement.

1. Confirmation of integrin expression in tumor cells used in experiments
Integrin expression in tumor mass transplanted subcutaneously with A375 (human melanoma), A498 (human renal cell carcinoma), HCT116 (human colorectal cancer), U87MG (human glioblastoma) or T98G (human glioblastoma) cell lines The amount was confirmed by Western blotting.
Each cultured cell was transplanted to 1 × 10 ⁷ cells / mouse subcutaneously on the right flank of Balb / c AJcl-nu / nu (Claire Japan, male, 6-8 weeks old). Tumors were removed 2-12 weeks after transplantation.
The excised tumor was finely cut with scissors, and then a homogenate was prepared with a homogenizer.
Prepare protein amount of 1mg / mL (1xTris / Glycine / SDS + 100mM DTT Buffer) and use integrin α _V β ₃ (RD, 3050-AV) and α _V β ₅ (Chemicon, CC1024) as standards. 4 concentrations (1, 2, 5, 10 ng / well) and simultaneously separated by SDS-PAGE (10% gel: manufactured by Biocraft). After separation, it was transferred to a PVDF membrane, and the transfer membrane was blocked with a blocking solution (5% skim milk / PBS-T) for 1 hour and then washed twice with PBS-T. Anti-integrin β ₃ antibody (Cell Signaling Technology, # 4702), anti-integrin β ₅ antibody (Santa Cruz, SC-5402), anti-β-actin antibody (SIGMA, A5441) were reacted as primary antibodies. And then washed 3 times with PBS-T. ECL Anti-Rabbit IgG horseradish Peroxidase (GE Healthcare, NA934V) or ECL Anti-mouse IgG horseradish Peroxidase (GE Healthcare, NA931V), Donkey Anti-goat antibody HRP conjugate (BETHYL, A50-101P) And reacted 3 times with PBS-T. Luminescence was performed with a chemiluminescence reagent (Super Signal West Femto Maximum Sensitivity Substrate; Thermo, 34096), and measurement was performed with LAS3000 (GE Healthcare). The expression level of integrin per 1 μg of tumor mass was calculated from the standard.
The results are shown below.

2. Confirmation of integrin-specific accumulation of [ ^111In ]-(A8) by tissue excision radioactivity measurement
SK-MEL-28 (human melanoma), A375 (human melanoma), A498 (human renal cell carcinoma), Caki-2 (human renal cell carcinoma), HCT116, U87MG, and T98G cells were examined as follows.
The cells were cultured and transplanted to 1 × 10 ⁷ cells / mouse subcutaneously on the right flank of Balb / c AJcl-nu / nu (Claire Japan, male, 6-8 weeks old). After rearing until the tumor volume reaches 85-1075 mm ³ , assign ³ animals at the time of dissection so that the tumor volume does not become disequilibrium, and then add [ ¹¹¹ In]-(A8) (740 kBq) to the tail vein The animals were sacrificed at the time of dissection and the tumors were removed. After measuring the weight of the tumor, the radioactivity was measured with a gamma counter, and the tumor radioactivity concentration (% ID / g:% Injected Dose / g) was calculated.
The results are shown below.

By cells, differences in expression level of integrin tumor mass was observed, with β _3, 1.54~8.28ng / μg, in beta _5, was 1.99~13.51ng / μg.
^[111 In] - accumulation to administration 4 hours after and 24 hours after tumor (A8) is modified according to cells, in 4 hours, in from 3.1 to 13.1% ID / g, 24 hours after, 2.9 to 9.3% ID / g.
Furthermore, a strong correlation (R = 0.727) was confirmed between the expression level of integrin β _{3 in} the tumor mass and tumor radioactivity accumulation 24 hours after administration (FIG. 1).

Test Example 4 Evaluation of ¹¹¹ In Labeled Compound, ⁶⁴ Cu Labeled Compound, and ⁹⁰ Y Labeled Compound by Tumor Radioactivity Concentration
⁷ U87MG cells 1x10 ⁷ were transplanted subcutaneously into the right flank of Balb / c AJcl-nu / nu (Japan Claire or Japan SLC, 6-9 weeks old), after 2 to 3 weeks, the tumor was 200-500 mm ³ At that time, they were divided into groups of 3 animals per time point. ¹¹¹ In-labeled compound (740 kBq) was administered into the tail vein, and after a certain period of time, the animals were sacrificed and the tumors were removed. The weight of the tumor was measured, the radioactivity was measured with a gamma counter, and the tumor radioactivity concentration (% ID / g) was calculated. The tumor radioactivity concentration (% ID / g) was calculated for ⁶⁴ Cu-labeled compound (500 kBq) and ⁹⁰ Y-labeled compound (500 kBq) in the same manner.
The results are shown below.

  The tumor radioactivity concentrations of the compounds in Table 5 were 6.95-12.80% ID / g at 4 hours after administration, and 3.34-15.29% ID / g at 24 hours after administration.

Test Example 5 Positron emission tomography using [ ⁶⁴ Cu]-(P2), [ ⁶⁴ Cu]-(Aa7), [ ⁶⁴ Cu]-(Ab9-a) and [ ⁶⁴ Cu]-(Ab9-b) PET) Imaging of integrin-expressing tumors 1x10 ⁷ U87MG cells were transplanted subcutaneously into the right flank of Balb / c AJcl-nu / nu (Japan Claire or Japan SLC, male, 6-9 weeks old) for 2 weeks Later, [ ⁶⁴ Cu]-(P2) was administered to mice with tumors ranging from 250 to 650 mm ³ in the tail vein of 4.8 MBq per mouse, and microPET / CT under isoflurane anesthesia after 1, 4, 24 and 48 hours Images were taken at (Inveon, Siemens). After 48 hours of imaging, whole blood was collected from the posterior vena cava under deep anesthesia with isoflurane, euthanized, and the tumor was removed. Tumor weight was measured, radioactivity was measured with a gamma counter, and tumor radioactivity concentration (% ID / g) was calculated. Imaging of [ ⁶⁴ Cu]-(Aa7), [ ⁶⁴ Cu]-(Ab9-a) and [ ⁶⁴ Cu]-(Ab9-b) was performed in the same manner. However, the tumor radioactivity concentration was not calculated.
2 to 5 show PET images of each compound at each time point.
From 1 hour after administration, accumulation of any compound was confirmed in the tumor, and the tumor was visualized until 48 hours later. In addition, [ ⁶⁴ Cu]-(P2) showed a low accumulation in the center of the tumor on the image, so when the tumor removed after 48 hours of imaging was observed, it was found in the center that matched the image. A hematoma was confirmed. The tumor radioactivity concentration at the time of dissection (48 hours after administration) was 5.6% ID / g.

Test Example 6 ^[111 In] - imaging of integrin-expressing tumors by gamma camera using a (P2) U87MG cells 1x10 ⁷ pieces of Balb / c AJcl-nu / nu ( CLEA Japan, Inc., male, 6 weeks old) right flank Two weeks later, mice with tumors of 300-600 mm ³ were administered [ ¹¹¹ In]-(P2) at 1 MBq per mouse into the tail vein and administered 24, 48, 72 After an hour, planar imaging with a gamma camera (Symbia, Siemens) was performed under isoflurane anesthesia. Tumor radioactivity (% ID) was calculated by image analysis.
FIG. 6 shows images and tumor radioactivity at each time point. From 24 to 72 hours after administration, the radioactivity of the tumor was higher than that of other organs, and the tumor was clearly confirmed.

Test Example 7 Imaging of integrin-expressing tumors using [ ^111In ]-(P2) (intracranial tumor model)
^Seven U87MG cells 1x10 ⁷ were transplanted into the skull of Balb / c AJcl-nu / nu (Claire Japan, male, 6 weeks old) with a two-stage needle, and after 2-4 weeks, [ ¹¹¹ In]-( P2) The administration solution was administered into the 1 MBq tail vein per animal. Planar imaging with a gamma camera (Symbia, Siemens) was performed under isoflurane anesthesia 24, 48, and 72 hours after administration (FIG. 7). After final time point imaging, the brain was removed and frozen sections were prepared. Several pieces of tumor sections were contacted with an IP plate and integrated images were obtained by autoradiography (ARG). Sequential sections were stained with hematoxylin and eosin to confirm the tumor. Planar imaging and ARG confirmed the accumulation of [ ^111In ]-(P2) consistent with the tumor in an intracranial tumor model.

Test Example 8 Treatment experiment of U87MG subcutaneous transplantation model using [ ⁹⁰ Y]-(P2)
⁷ U87MG cells 1x10 ⁷ were transplanted subcutaneously into the right flank of Balb / c Slc-nu / nu (Japan SLC, male, 6 weeks old). After 2 weeks, the tumors were grouped by mice with tumors of 100-500 mm ³ Went. Phosphate buffered saline (PBS) or [ ⁹⁰ Y]-(P2) was administered into the tail vein and tumor volume was measured. Anti-tumor activity was assessed when the tumor volume of mice in the PBS group exceeded the humane endpoint of 2000 mm ³ . Evaluation value is tumor growth inhibition rate ((1- (average tumor volume of compound administration group−average tumor volume before administration of compound administration group) / (average tumor volume of PBS group−average tumor volume before administration of PBS group) Volume)) x100 (however, when it exceeded 100%, it was set as 100%)) and the number of individuals below the tumor volume at the start (regression number).
The results are shown below.

  The compounds in Table 6 showed excellent antitumor activity.

Test Example 9 Treatment experiment of U87MG subcutaneous transplantation model using [ ⁹⁰ Y]-(A8)
⁷ U87MG cells 1x10 ⁷ were transplanted subcutaneously into the right flank of Balb / c AJcl-nu / nu (Claire Japan, male, 6 weeks old), and grouped by mice with tumors 100-500 mm ³ after 2 weeks Went. Phosphate buffered saline (PBS) or [ ⁹⁰ Y]-(A8) was administered into the tail vein and tumor volume was measured. Evaluation values were calculated in the same manner as in Test Example 8 to evaluate antitumor activity.
The results are shown below.

  The compounds in Table 7 showed excellent antitumor activity.

Test Example 10 Treatment experiment of T98G subcutaneous transplantation model using [ ⁹⁰ Y]-(P2)
Equal volume mixture of T98G cell suspension (human glioblastoma, 1x10 ⁷ cells) and Matrigel (Japan BD) was subcutaneously applied to the right flank of Balb / cSlc-nu / nu (Japan SLC, male, 6 weeks old) After transplantation, 77 days later, when the tumor reached 300-1200 mm ³ , grouping was performed. Phosphate buffered saline (PBS) or [ ⁹⁰ Y]-(P2) was administered into the tail vein and tumor volume was measured. Evaluation values were calculated in the same manner as in Test Example 8 to evaluate antitumor activity.
The results are shown below.

  The compounds in Table 8 showed excellent antitumor activity.

Test Example 11 Treatment experiment of T98G subcutaneous transplantation model using [ ⁹⁰ Y]-(A8)
Equal volume mixture of T98G cell suspension (human glioblastoma, 1x10 ⁷ cells) and Matrigel (Japan BD) was subcutaneously applied to the right flank of Balb / c AJcl-nu / nu (Claire Japan, female, 6 weeks old) After 90 days, when the tumor reached 100 to 400 mm ³ , grouping was performed. Phosphate buffered saline (PBS) or [ ⁹⁰ Y]-(A8) was administered into the tail vein and tumor volume was measured. Evaluation values were calculated in the same manner as in Test Example 8 to evaluate antitumor activity.
The results are shown below.

  The compounds in Table 9 showed excellent antitumor activity.

Test Example 12 Monkey imaging using [ ^111In ]-(P2)
Using [ ¹¹¹ In]-(P2), blood kinetic parameters were calculated by OLINDA / EXM1.0 from the blood concentration of radioactivity by blood sampling over time in cynomolgus monkeys. ^{Also, [111 In] - (P2} ) was used to calculated the OLINDA / EXM1.0 the absorbed dose of organs when administered to a human from an organ distribution by imaging.
[ ¹¹¹ In]-(P2) (98 MBq / 9.3 μg) was administered to cynomolgus monkeys (Hamley, male, 3 years old, 3.4 kg) under anesthesia, and blood sampling and imaging with a gamma camera were performed over time after administration. Blood collection was performed at 10, 30, 60 minutes, 2, 4, 5, 6, 24, 48, 72 and 144 hours after administration. Imaging was performed by planar imaging with a gamma camera (Symbia, Siemens) after 1, 2, 4, 6, 24, 48, 72 and 144 hours. Anesthesia was anesthetized with ketamine 20 mg / kg before [ ¹¹¹ In]-(P2) administration, and maintained by inhalation anesthesia (isoflurane 2-3%, 5-8 L / min) until the end of imaging 6 hours after administration. After 24 hours, ketamine 20 mg / kg and xylazine 2 mg / kg were introduced, and blood collection and imaging were performed.
FIG. 8 shows changes in blood concentration of radioactivity in monkeys using [ ¹¹¹ In]-(P2). The blood kinetic parameters are shown below.

AUC is 0.22 (% ID · h / mL), T _1/2 α is 0.46 (h), T _1/2 β is 19.3 (h), Cmax is 0.018 (% ID / mL), CL is 130.2 (mL / mL) h / kg) and Vss was 3.52 (L / kg).

FIG. 9 shows the planar imaging results of monkeys over time using [ ¹¹¹ In]-(P2). In the imaging, accumulation in the bladder and gallbladder increased over time from 6 hours after administration. Moreover, the absorbed dose in each labeled body in human is shown below.

  The treatment agent of the present invention has high accumulation and persistence in integrin-expressing cells such as cancer cells, and has high blood clearance, so that it is useful for diagnosis or treatment of diseases involving integrin expression. .

Claims (11)

General formula (1)
(Where
A ¹ represents a chelating group;
R ¹ is
Hydrogen atom,
_Represents an optionally substituted C _1-6 alkyl group or an amino protecting group;
R ² is
Hydrogen atom,
_Represents an optionally substituted C _1-6 alkyl group or an amino protecting group;
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are the same or different and
Nitrogen atom or CR ³
(Where
R ³ is
Hydrogen atom,
Halogen atoms,
An optionally substituted C _1-6 alkyl group,
C _1-6 alkoxy group which may be substituted or general formula (2)
(Where
R ⁴ is
Hydrogen atom,
_Represents an optionally substituted C _1-6 alkyl group or an amino protecting group;
n R ⁵ and n R ⁶ may be the same or different;
Hydrogen atom,
Halogen atoms,
A C _1-6 alkyl group which may be substituted or a carboxyl group which may be protected;
R ⁷ is
Hydrogen atom,
_Represents an optionally substituted C _1-6 alkyl group or an amino protecting group;
R ⁸ is
Hydrogen atom,
A C _1-6 alkyl group which may be substituted or a bond with L ⁵ is shown:
R ⁹ , R ¹⁰ , R ¹¹ and R ¹² are the same or different and
Hydrogen atom,
Halogen atoms,
An amino group which may be protected,
An optionally substituted C _1-6 alkyl group,
An optionally substituted C _1-6 alkylamino group,
A di (C _1-6 alkyl) amino group which may be substituted or a bond to L ⁵ ;
R ⁸ and R ⁹ together are
Represents an _optionally substituted C _1-6 alkylene group;
Provided that any one of R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ and R ¹² represents a bond with L ^5, and the other 4 did not exhibit a bond with L ⁵ ;
L ⁴ is
A divalent aromatic hydrocarbon group which may be substituted,
A divalent heterocyclic group or a bond which may be substituted;
L ⁵ is
An optionally substituted C _1-6 alkylene group,
An optionally substituted —O—C _1-6 alkylene group (wherein the left bond is bonded to L ⁴ ) or an optionally substituted —NH—C _1-6 alkylene group (wherein The left hand bond binds to L ⁴ );
m is
Represents 0 or 1;
n is
Represents an integer from 1 to 3;
p is
Represents 0 or 1;
However, when R ⁸ is a bond with L ⁵ , L ⁴ represents a divalent aromatic hydrocarbon group which may be substituted. ) Is represented. );
Provided that at least one of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ is
CR ^3a
(Wherein R ^3a represents the general formula (2)
(Wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , L ⁴ , L ⁵ , m, n and p have the same meanings as described above. A group represented by: );
L ² represents an optionally substituted C _1-6 alkylene group;
L ³ represents an optionally substituted C _1-6 alkylene group;
L ¹ is
General formula (3)
(Where
r R ^{13 s} are the same or different,
Hydrogen atom,
_Represents an optionally substituted C _1-6 alkyl group or an amino protecting group;
q × r R ¹⁴ and q × r R ¹⁵ are the same or different,
Represents a hydrogen atom or an optionally substituted C _1-6 alkyl group;
r R ^{16 s} are the same or different,
Hydrogen atom,
An optionally substituted C _1-6 alkyl group or a general formula (4)
(Where
s R ¹⁷ 's are the same or different;
Represents a hydrogen atom or an optionally substituted C _1-6 alkyl group;
t R ¹⁸ may be the same or different;
Hydrogen atom,
_Represents an optionally substituted C _1-6 alkyl group or an amino protecting group;
t R ^{19 s} are the same or different;
Represents a hydrogen atom or an optionally substituted C _1-6 alkyl group;
s is
Represents an integer from 1 to 3;
t is
Represents an integer from 0 to 3;
R ¹ , R ² , Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ , L ² and L ³ have the same meaning as described above. ) Represents a group represented by
q represents an integer of 0 to 3;
r represents an integer of 0 to 3. ) Is represented. A therapeutic agent for diagnosis or treatment of a disease involving integrin, comprising a complex of a compound represented by (1) or a salt thereof and a metal. Z ¹ , Z ² , Z ⁴ and Z ⁵ are the same or different,
CR ^3b
(Where
R ^3b is
Hydrogen atom,
Halogen atoms,
An optionally substituted C _1-6 alkyl group or an optionally substituted C _1-6 alkoxy group is shown. );
Z ³ is
CR ^3c
(Where
R ^3c is
General formula (2a)
(Where
n R ^5a and n R ^6a are the same or different,
Hydrogen atom,
A C _1-6 alkyl group which may be substituted or a carboxyl group which may be protected;
R ^8a is
Represents a hydrogen atom or an optionally substituted C _1-6 alkyl group;
R ^9a is
Represents a hydrogen atom; or R ^8a and R ^9a together
Represents an _optionally substituted C _1-6 alkylene group;
L ⁴ is
A divalent aromatic hydrocarbon group which may be substituted,
A divalent heterocyclic group or a bond which may be substituted;
L ^5a is
Represents an _optionally substituted C _1-6 alkylene group;
n is
An integer of 1 to 3 is shown. ) Is represented. The treatment agent according to claim 1, wherein R ^3c is the formula (2b)
(Where
n R ^5a and n R ^6a are the same or different,
Hydrogen atom,
A C _1-6 alkyl group which may be substituted or a carboxyl group which may be protected;
L ⁴ is
A divalent aromatic hydrocarbon group which may be substituted,
A divalent heterocyclic group or a bond which may be substituted;
L ^5a is
Represents an _optionally substituted C _1-6 alkylene group;
n is
An integer of 1 to 3 is shown. The treatment agent of Claim 2 which is group represented by this. A ¹ is
A group having a polyaza macrocyclic structure,
The treatment agent according to any one of claims 1 to 3, which is a group having a polyaminopolycarboxylic acid structure or a group having a polyaminopolyphosphonic acid structure. A ¹ is represented by the general formula (5), (6), (7), (8), (9), (10), (11) or (12).
(Where
R ^a , R ^b , R ^c , R ^d , R ^e , R ^f , R ^g , R ^h and R ⁱ are the same or different,
Represents a hydrogen atom or a carboxyl protecting group;
X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ , X ⁹ , Y ¹ , Y ² , Y ³ , Y ⁴ ,
Y ⁵ , Y ⁶ , Y ⁷ and Y ⁸ are the same or different,
An optionally substituted C _1-6 alkylene group or an optionally substituted C _3-8 cycloalkylene group;
X ¹⁰ is
Represents an _optionally substituted C _1-6 alkylene group;
X ^4a and X ^8a are the same or different,
_{Shows an} optionally substituted C _1-6 alkanetriyl group:
Q ¹ is
An oxygen atom or a sulfur atom is shown. )
The treatment agent as described in any one of Claims 1-4 which is group represented by these. A ¹ is represented by the formulas (5a), (6a), (7a), (8a), (8b), (8c), (9a), (10a), (10b), (11a), (11b), ( 11c) or (12a)
The treatment agent as described in any one of Claims 1-5 which is group represented by these. The compound represented by the general formula (1) or a salt thereof is
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7 , 8-Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo -3-sulfopropan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4R, 7R, 10R) -19- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6 , 7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,11,16-pentaoxo-4,7, 10-tris (sulfomethyl) -3,6,9,12,15-pentaazanononadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
(S) -2,2 ′, 2 ″-(10- (19- (4- (N- (1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,11,16-trioxo-6,9-dioxa-3,12,15-triazanonadecyl ) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((S) -4- (4-aminobutyl) -22- (4- (N-((S) -1-carboxy-2- (4- (2 -(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,14,19-tetraoxo-9 , 12-dioxa-3,6,15,18-tetraazadocosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
(S) -2,2 ′, 2 ″-(10- (28- (4- (N- (1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,11,20,25-tetraoxo-6,9,15,18-tetraoxa-3,12 21,24-tetraazaoctacosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((R) -22- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8 -Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,14,19-tetraoxo-4- (sulfomethyl) -9,12- Dioxa-3,6,15,18-tetraazadocosyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((9R) -18- (4- (N-((S) -1-carboxy-
2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -4-(( (R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8 Naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) carbamoyl) -2,7, 10,15-tetraoxo-9- (sulfomethyl) -3,8,11,14-tetraazaoctadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4R, 7R) -16-((5- (2-carboxy-1- (5- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethoxy) -1H-indol-1-yl) ethyl) pyridin-3-yl) oxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl)- 3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4R, 7R) -16-((5- (2-carboxy-1- (4- (2- (5,6,7,8-tetrahydro-1 , 8-naphthyridin-2-yl) ethyl) -1H-indol-1-yl) ethyl) pyridin-3-yl) oxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl)- 3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((R) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4S, 9R) -18 (4- (N-((S) -2- (4- (2- (6-aminopyridin-2-yl) ethyl ) Benzamide) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) -4-(((R) -1-((2- (4- (4- (N-((S) -2-)) (4- (2- (6-Aminopyridin-2-yl) ethyl) benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) carbamoyl) -2,7,10,15-tetraoxo-9- (sulfomethyl) -3,8,11,14-tetraazaoctadecyl) -1,4,7,10-tetraazacyclododecane -1,4,7-triyl) trivinegar ,
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -2- (4- (2- ( 6-aminopyridin-2-yl) ethyl) benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino ) -2-Oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid, 2,2 ′, 2 ″-(10-((4R, 7R) — 16- (4- (N-((S) -2- (4- (2- (6-aminopyridin-2-yl) ethyl) benzamido) -1-carboxyethyl) sulfamoyl) -3,5-dimethylphenoxy ) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) 3,6,9,12-tetraazacyclododecane-hexadecyl) -1,4,7,10 tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8- Tetrahydro-1,8-naphthyridin-2-yl) pentanamide) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6 , 9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4-((S) -2-carboxy-1- (4- (2- (5,6,7,8- Tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) -2-fluorophenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9, 12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′-((1-(((S) -2- (bis (carboxymethyl) amino) -3- (4- (3-((R) -1-(((R) -1- ( (2- (4- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) Ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) amino) -1-oxo-3-sulfopropane-2- Yl) thioureido) phenyl) propyl) (carboxymethyl) amino) propan-2-yl) azanediyl) diacetic acid,
(S) -2,2 ′, 2 ″-(10- (2-((2- (4- (4- (N- (1-carboxy-2- (4- (2- (5,6,6 7,8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -2-oxoethyl) -1,4,7, 10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″, 2 ′ ″-(2- (4- (3-((R) -1-((2- (4- (4- (N-((S) -1- Carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino)- 1-oxo-3-sulfopropan-2-yl) thioureido) benzyl) -1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl) tetraacetic acid,
2,2 ′-((1-(((S) -2- (bis (carboxymethyl) amino) -3- (4- (3-((R) -1-((2- (4- (4 -(N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5 -Dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropan-2-yl) thioureido) phenyl) propyl) (carboxymethyl) amino) propan-2-yl) azanediyl) diacetic acid,
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfopropane -2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10- (2-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2- (6- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) hexanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo-3-sulfo Propan-2-yl) amino) -2-oxoethyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (5- (2- (5,6,7 , 8-Tetrahydro-1,8-naphthyridin-2-yl) ethyl) thiophene-2-carboxamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7- Bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- (2- (5,6,7 , 8-tetrahydro-1,8-naphthyridin-2-yl) ethyl) benzamido) ethyl) sulfamoyl) phenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9 , 12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid hexasodium salt,
2,2 ′, 2 ″-(10-((4R, 7R) -16- (4- (N-((S) -1-carboxy-2- (4- (3- (pyridin-2-ylamino) ) Propyl) benzamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) -2,5,8,13-tetraoxo-4,7-bis (sulfomethyl) -3,6,9,12-tetraazahexadecyl) -1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid,
2,2 ′-(7-((R) -1-carboxy-4-(((R) -1-((2- (4- (4- (N-((S) -1-carboxy-2 -(5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1-oxo -3-Sulfopropan-2-yl) amino) -4-oxobutyl) -1,4,7-triazonan-1,4-diyl) diacetic acid and 5-(((R) -1-((2- ( 4- (4- (N-((S) -1-carboxy-2- (5- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) pentanamido) ethyl) sulfamoyl) -3,5-dimethylphenoxy) butanamido) ethyl) amino) -1- Oxo-3-sulfopropan-2-yl) amino) -2- (11- (carboxymethyl) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) -5 The treatment agent according to claim 1, which is a compound selected from the group consisting of -oxopentanoic acid or a salt thereof.   The therapeutic treatment agent according to any one of claims 1 to 7, wherein the metal is a cytotoxic radioactive metal. The therapeutic therapeutic agent according to claim 8, wherein the cytotoxic radioactive metal is a metal selected from the group consisting of ⁶⁴ Cu, ⁶⁷ Cu, ⁹⁰ Y, ¹⁶⁶ Ho, ¹⁵³ Sm, ¹⁷⁷ Lu and ²²⁵ Ac.   The diagnostic agent according to any one of claims 1 to 7, wherein the metal is a non-cytotoxic radioactive metal. Non-cytotoxic radioactive metal is ¹⁸ F aluminum complex, ¹¹¹ In, ⁶⁴ Cu, ⁶⁷ Ga, ⁶⁸ G
The diagnostic treatment agent according to claim 10, which is a metal selected from the group consisting of a and ⁸⁹ Zr.