Neurotensin receptor ligand

Abstract

This invention provides neurotensin receptor ligands, pharmaceutical compositions containing neurotensin receptor ligands, methods for using neurotensin receptor ligands for the treatment of diseases, and methods for producing neurotensin receptor ligands. [Solution] The present invention relates to a compound of the following formula: TIFF2026106435000709.tif54128 The present invention also provides pharmaceutical compositions comprising the compound, methods for using the compound for the treatment of diseases, and methods for preparing the compound.

Description

[Technical Field]

[0001] The present invention relates to neurotensin receptor ligands, pharmaceutical compositions containing neurotensin receptor ligands, methods for using neurotensin receptor ligands for the treatment of diseases, and methods for producing neurotensin receptor ligands. [Background technology]

[0002] Neurotensin receptors (NTSRs) are G protein-coupled receptors (GPCRs) involved in regulating the dopamine pathway and metabolism in the central nervous system. Neurotensin receptor 1 (NTSR1) is overexpressed in several cancers (e.g., breast cancer, endometrial cancer, gastric cancer, colorectal cancer, lung cancer, pancreatic cancer, and head and neck cancer). Small molecule agonists and antagonists targeting cancers associated with NTSR1 overexpression have been developed and adapted for radioligand therapies (RLTs). Nevertheless, there is a need for NTSR1-targeted RLTs with improved selectivity, efficacy, stability, biodistribution, or duration on tumors. [Overview of the Initiative] [Means for solving the problem]

[0003] In one embodiment, the present invention relates to a compound of formula (I),

[0004] [ka] During the ceremony, R 1 However, it is a C1-C6 alkyl or C3-C6 cycloalkyl, Z is -COOH, -C(=O)NH2, or -tetrazolyl. R 2 However, C6~C10 Cycloalkyl or C6-C 10 Cycloalkyl-C1-C6 alkyl-, and C6-C 10 Cycloalkyl and C6-C 10 Cycloalkyl-C1-C6 alkyl- is each optionally substituted with 1 to 3 halogens, R 3 is H, or R 2 and R 3 together with the carbon atom to which they are attached, form a C6-C cycloalkyl optionally substituted with 1 to 3 halogens, 10 forming a cycloalkyl, R 4 is

[0005]

Chemical formula

[0006] In another embodiment, a method for treating cancer using a compound of formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition thereof is provided herein. The method comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need.

[0007] In another embodiment, compounds of formula (I) and pharmaceutically acceptable salts thereof are provided herein for use in therapy. Additionally, compounds of formula (I) and pharmaceutically acceptable salts thereof are provided herein for use in the treatment of cancer. Furthermore, the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of cancer is provided herein. [Modes for carrying out the invention]

[0008] The present invention relates to a compound of formula (I),

[0009] [ka] In the formula, R 1 , R 2 , R3 , Z, R 4 , Q, X 1 , Cy 1 , X 2 , L 1 , Ch 1 , and M 1 provide a compound, or a pharmaceutically acceptable salt thereof, as defined above.

[0010] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is C1-C6 alkyl or C3-C6 cycloalkyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is isopropyl or tert-butyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is isopropyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is tert-butyl.

[0011] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 2 is C6-C 10 cycloalkyl or C6-C 10 cycloalkyl-C1-C6 alkyl-, and C6-C 10 cycloalkyl and C6-C 10 cycloalkyl-C1-C6 alkyl- are each optionally substituted with 1-3 halogens, and R 3 is H. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 2 and R 3 together with the carbon atom to which they are attached form a C6-C 10 cycloalkyl optionally substituted with 1-3 halogens. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 2 is adamantyl or adamantyl-CH2-, and R 3 is H. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 2is adamantyl, and R 3 is H. In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 is adamantyl-CH2-, and R 3 is H.

[0012] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 2 and R 3 together with the carbon atom to which they are attached form adamantyl.

[0013] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, Z is selected from -COOH, -C(=O)NH2, and -tetrazolyl.

[0014] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, Z is -COOH. In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, Z is -C(=O)NH2. In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, Z is -tetrazolyl.

[0015] In one embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 4 is

[0016]

Chemical formula

[0017] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, D is a 5-6 membered heteroaryl compound containing 1-3 heteroatoms independently selected from N, O, and S, and is optionally substituted with 1-3 groups independently selected from halo, hydroxy, amino, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, or C1-C6 dialkylamino.

[0018] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0019] [ka] And R 4a and R 4b Each of these is independently H or a halogen (preferably fluoro).

[0020] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0021] [ka] And R 4a , R 4b , R 4c , and R 4d Each of these is independently H or a halogen (preferably fluoro).

[0022] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0023] [ka] And R 4a and R 4b Each of these is independently H or a halogen (preferably fluoro).

[0024] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0025] [ka] That is the case.

[0026] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0027] [ka]

[0028] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0029] [ka] Selected from.

[0030] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0031] [ka] That is the case.

[0032] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0033] [ka] That is the case.

[0034] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0035] [ka] That is the case.

[0036] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 is 5-methoxybenzo[d][1,3]dioxol-4-yl, 2,2-difluoro-5-methoxybenzo[d][1,3]dioxol-4-yl, or benzo[1,2-d:4,5-d']bis([1,3]dioxol)-4-yl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 This is 5-methoxybenzo[d][1,3]dioxol-4-yl.

[0037] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0038] [ka] That is the case.

[0039] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0040] [ka] That is the case.

[0041] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0042] [ka] That is the case.

[0043] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4teeth,

[0044] [ka] That is the case.

[0045] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0046] [ka] That is the case.

[0047] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0048] [ka] That is the case.

[0049] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0050] [ka] That is the case.

[0051] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 These are 5-cyanobenzo[d][1,3]dioxol-4-yl, 5-(2-methoxyethoxybenzo[d][1,3]dioxol-4-yl, benzo[c]]1,2,5]thiadiazole-4-yl, 5-fluoro[d][1,3]dioxol-4-yl, or 5-trifluoromethoxy[d][1,3]dioxol-4-yl.

[0052] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Q is a six-membered aryl or heteroaryl ring containing 0 to 3 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon.

[0053] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Q is

[0054] [ka] That is the case.

[0055] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Q is

[0056] [ka] That is the case.

[0057] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Q is

[0058] [ka] That is the case.

[0059] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 4 teeth,

[0060] [ka] And, Q is,

[0061] [ka] That is the case.

[0062] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1-NR x1 - and R x1 is H or C1-C3 alkyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1 is a bond. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1 is -O-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1 It is -NH-.

[0063] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 This is a 4-12 member monocyclic or polycyclic system having 1-3 oxo substituents, optionally substituted with 1-3 substituents independently selected from halo, hydroxy, amino, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino, provided that Cy 1 If X is a join, 1 However, it is a combination.

[0064] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1This is a 5 or 6-membered heteroaryl, C4-C6 cycloalkyl, C4-C6 cycloalkenyl, 4-6-membered heterocycloalkyl, or 4-6-membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from the bonds, phenyl, N, O, and S, and wherein phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is a 4-6-membered heteroalkyl, containing 1-3 heteroatoms independently selected from the bonds, phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl. Optionally condensed to a ring selected from chloroalkyls and 4-6 membered heterocycloalkenyls; or a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is optionally spiro-connected to another ring selected from a C4-C6 cycloalkyl, C4-C6 cycloalkenyl, 4-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, and S, or a 4-6 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from N, O, and S; or a cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl optionally contains a bridging group having 1, 2, or 3 bridging atoms independently selected from N, O, and S, Cy 1 However, it is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, hydroxy, amino, cyano, nitro, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylamino, and C1-C6 dialkylamino, and optionally possesses 1 to 3 oxo substituents, provided that Cy 1 If X is a join, 1 However, it is a combination.

[0065] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1is a bond, phenyl, or triazolyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 This is a bond. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 is phenyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 It is triazolyl.

[0066] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 It is 1,3-difluorophenyl.

[0067] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 It is a monocyclic heteroaryl ring which is 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridine, or pyridazine.

[0068] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 It is a monocyclic heteroaryl ring that is 3-fluoropyridine.

[0069] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 It is a condensed bicyclic ring system consisting of isoindorin-1-one, isoquinoline-1-one, 3,4-dihydroisoquinoline-1-one, isoquinoline, 3,4-dihydroisoquinoline, quinoline, indazole, or naphthalene.

[0070] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 It is a condensed bicyclic ring system that is 1,5-naphthyridine, quinoxaline, or [1,2,3]triazolo[1,5-a]pyridine.

[0071] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1is a saturated or partially saturated heterocyclic ring (including the spiro ring portion) which is piperidine, piperazine, 3,6-dihydropyridine, 3-azaspiro[5.5]undecane, or 3,9-diazaspiro[5.5]undecane.

[0072] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 is a saturated or partially saturated heterocyclic ring (including the spiro ring portion) which is 2,5-diazabicyclo[2.2.1]heptane, 2,6-diazaspiro[3.3]heptane, 2,7-diazaspiro[3.5]nonane, or 3,9-diazaspiro[5.5]undecane-2-one.

[0073] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 This is an aromatic ring substituted with an electron-withdrawing group or an electron-donating group, namely a benzonitrile ring (cyanosubstituted phenyl ring), a nitrophenyl ring, or a methoxyphenyl ring.

[0074] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 teeth,

[0075] [ka] That is the case.

[0076] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Cy 1 teeth,

[0077] [ka] That is the case.

[0078] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Z is -COOH, and R 4 teeth,

[0079] [ka] And, R 4e It is methyl, and Cy 1 This is a 5 or 6-membered heteroaryl compound containing phenyl or 1 to 3 heteroatoms independently selected from N, O, and S (whereas Cy 1 If X is a join, 1 (However, it is a combination.)

[0080] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , Rx19 , and R x20 Each is independently selected from H and C1-C6 alkyl, where the C1-C6 alkyl is optionally substituted with amino, C1-C6 alkylamino, C1-C6 dialkylamino, or pyrrolidinyl in each instance, and the pyrrolidinyl is optionally substituted with C1-C6 alkyl, preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each of these is independently selected from H and methyl.

[0081] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 - and R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with a 5 or 6-membered heterocyclyl, preferably pyrrolidinyl, containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocyclyl is C1-C6 alkyl, preferably R x2 It is arbitrarily replaced in R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each of these is independently selected from H and methyl.

[0082] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NC H3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-.

[0083] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-.

[0084] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a bond. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NH-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NCH3-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -O-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NHC(O)-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NCH3C(O)-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -C(O)NCH3-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NHC(O)NH-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2is -NHC(O)NCH3-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NCH3C(O)NCH3-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NHC(O)O-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NCH3C(O)O-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is -NHC(O)S-. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 It is -NHS(O)2NCH3-.

[0085] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0086] [ka] It includes one or more elements independently selected from, During the ceremony, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , and X 23 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NRx24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkylene, C2~C 20 Alkenylenes, and C2~C 20 Alkinylene appears in C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C10 It is arbitrarily interrupted by one or more groups independently selected from the heteroarylene, C1~C 20 Alkylene, C1~C 20 Alkenylene, C1~C 20 Alkynylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, the heteroarylene is optionally substituted with one or more groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. The alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with one or more groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0087] Alkylene groups, for example, C1-C 20 When used herein with respect to alkylenes, "arbitrarily interrupted by 1 to 5 groups" means that the alkylene skeleton is separated by one or more alkylene segments, e.g., C3 to C5 interruption units, as explicitly enumerated for the relevant embodiments. 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, or C5~C 10 This means that it may contain heteroarylenes. Each interruption unit is L 1 These are divalent residues that form part of the skeleton and are inserted into the skeleton rather than becoming a pendant chain, and are bonded at two positions to adjacent alkylene carbon atoms. Unless otherwise specified, the number of carbon atoms in the alkylene group is as described, for example, "C1~C 20" refers to the total number of carbon atoms in the alkylene segment only, excluding atoms contained within any one or more interruption units. The interruption units may be the same or different, and may occur in any order.

[0088] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, linker L 1 teeth,

[0089] [ka] It includes 1 to 20 bases independently selected from, During the ceremony, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , and X 23 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NRx35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkylene, C2~C 20 Alkenylenes, and C2~C 20 Alkinylene appears in C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C2~C 20 Alkenylene, C2~C 20 Alkynylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10In each instance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. The alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0090] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, linker L 1 teeth,

[0091] [ka] It includes 1 to 5 bases independently selected from, During the ceremony, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , and X 23 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24-, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkylene, C2~C 20 Alkenylenes, and C2~C 20 Alkinylene appears in C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C2~C 20 Alkenylene, C2~C 20 Alkynylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. The alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0092] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0093] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from the above. During the ceremony, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. The alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0094] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0095] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from the above. During the ceremony, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35-, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1-C3 alkylenes, in their respective appearances, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10In each instance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. The alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0096] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0097] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from, where X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, H and C1-C6 alkyl groups are independently selected.

[0098] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0099] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from, where X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and Rx22 In each instance, H and C1-C6 alkyl groups are independently selected.

[0100] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0101] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from, where X 3 In each occurrence, -NH-, -NCH3-, -O-, and -NHC(O)- are independently selected.

[0102] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0103] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from, where X 3 In each occurrence, -NH-, -NCH3-, -O-, and -NHC(O)- are independently selected.

[0104] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0105] [ka] And v is 1, 2, 3, 4, or 5. (That is, L 1 teeth,

[0106] [ka] (Selected from), in the formula, X 3 In each occurrence, -NRx21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. The alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0107] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0108] [ka] And v is 1, 2, 3, 4, or 5. (That is, L 1 teeth,

[0109] [ka] (Selected from), in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NRx22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1-C3 alkylenes, in their respective appearances, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. The alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0110] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0111] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5.

[0112] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0113] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5.

[0114] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0115] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5.

[0116] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0117] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5.

[0118] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0119] [ka] Selected from.

[0120] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0121] [ka] That is the case.

[0122] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0123] [ka] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 14,7-triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic acid-N',N''-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic acid-N',N''-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic acid) (NOTP); 1,4,7,10-tetraazacyclododecane (

[12] aneN4) (cyclo 1,4,7,10-Tetraazacyclotridecane(

[13] aneN4); 1,4,7,11-Tetraazacyclotetradecane(iso-cyclum); 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetate(DOTA); 2-(1,4,7,10-Tetraazacyclododecane-1-yl)acetate(DO1A); 2,2'-(1,4,7,10-Tetraazacyclododecane-1,7-diyl)diacetate(DO2A); 2,2',2''-(1,4,7,10-Tetraazacyclododecane-1,4,7-triyl) )Triacetic acid (DO3A); 1,4,7,10-Tetraazacyclododecane-1,4,7,10-Tetra(methanephosphonic acid) (DOTP); 1,4,7,10-Tetraazacyclododecane-1,7-Di(methanephosphate) (DO2P); 1,4,7,10-Tetraazacyclododecane-1,4,7-Tri(methanephosphonic acid) (DO3P); 1,4,7,10-Tetraazacyclo-decane-1-Glutamic acid-4,7,10-Triacetic acid (DOTAGA); 1,4,7,10-Tetraazacyclodecane-1-Succinic acid-4,7,10-Triacetic acid (DOT ASA); 1,4,8,11-Tetraazacyclotetradecane(

[14] aneN4)(cyclum); 1,4,8,12-Tetraazacyclopentadecane(

[15] aneN4); 1,5,9,13-Tetraazacyclohexadecane(

[16] aneN4); 1,4-Ethanol-1,4,8,11-Tetraazacyclotetradecane(et-cyclum); 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); 2-(1,4,8,11-Tetraazacyclotetradecane-1-yl)acetic acid (TE1A);2,2'-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A); 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane (Sar); 2,2,2,2-(1,4,7,1 0-Tetraazacyclododecane-1,4,7,10-tetraacetamide (TCMC); 1,4,7,10-Tetraazacyclododecane-7-acetamide-1,4,10-triacetate (PSC); derived from N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine, or porphyrin.

[0124] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 DOTA, DOTATOC, DO3A, PEPA, EDTA, CHX-A”-DTPA, HEHA, DOTMP, tu-BU-calix, arene-tetracarboxylic acid, macropa, macropa-NCS, H4py4pa, H4octapa, H4noonpa, H5decapa, H4CHXoctapa, DOTP, DOTPH, DOTPOEt, DOTPI, NETA, diethylenetriaminepentaacetic acid (DTPA), TCMC, 2-(4-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M-DTPA), DTMP, HOPO, octapa me-3,2-HOPO, DOTANOC, DOTAMTATE, DATA 5m It originates from PA-DOTA, DO4S, DO3S, DO2A2S, DTPAm, EGTA, EGTAm, H2ampa, H2ampa, H2macropa, HEHA, py-macrodipa, DTCBP, or ATMS.

[0125] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1It is an acyclic chelating agent. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is Ch 1 It is a macrocyclic chelating agent.

[0126] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 It is an aminopolycarboxylate chelating agent. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is Ch 1 It is a macrocyclic aminopolycarboxylate chelating agent.

[0127] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 teeth,

[0128] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , R n , R l , R q , and R r Each of these is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2.

[0129] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 teeth,

[0130] [ka] Selected from, R a , R b , R c , R d , R e , and Rf However, each is independently selected from -OH and -NH2, and m, n, and p are independently 0, 1, or 2.

[0131] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 teeth,

[0132] [ka] And R a , R b , and R c Each is independently selected from -OH and -NH2. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R a , R b , and R c Each of these is -OH. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R a and R c Each of these is -OH, and R b is -NH2. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R a , R b , and R c These are all -NH2.

[0133] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 teeth,

[0134] [ka] Selected from.

[0135] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 teeth,

[0136] [ka] Selected from.

[0137] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 teeth,

[0138] [ka] Selected from.

[0139] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 teeth,

[0140] [ka] That is the case.

[0141] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 is a radionuclide. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 teeth, 188 Re, 186 Re, 153 Sm, 66 Ho, 68 Ga, 67 Ga, 89 Zr, 90 Y, 89 Sr, 111 In, 153 Gd, 225 Ac, 212 Bi, 213 Bi, 211 At, 60 Cu, 61 Cu, 67 Cu, 64 Cu, 62 Cu, 198 Au, 99 Au, 195m Pt, 193m Pt, 197 Pt, 117m Sn, 103 Pd, 105 Rh, 103m Rh, 177 Lu, 223 Ra, 224Ra, 227 Th, 229 Th, 149 Tb, 161 Tb, 32 P, 33 P, 125 I, 203 Pb, 212 Pb, 201 Tl, 119 Sb, 58m Co, 47 Sc, 149 Pm, or 161 Ho. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 teeth, 177 Lu, 212 Pb, or 225 Ac. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 teeth, 177 Lu. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 teeth, 212 It is Pb. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 teeth, 225 It is Ac.

[0142] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 It does not exist. In other embodiments, M 1 Ch 1 It is a radionuclide that forms a complex with [another substance]. Suitable radionuclides are not limited to [specific radionuclides], 177 Lu, 212 Pb, and 225 Ac is an example. In a particular embodiment, M 1 teeth, 177 It is Lu.

[0143] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, M 1 These are radionuclides suitable for diagnostic imaging (e.g., gamma emitters or positron emitters). Examples of diagnostic radionuclides include, but are not limited to, 68 Ga or 67Ga (for PET or SPECT imaging, respectively), 64 Cu (for PET imaging, possessing beta radiation that can provide therapeutic effects), 89 Zr (particularly useful for longer imaging windows, such as those used in PET imaging and antibody-based imaging), and 111 In (for SPECT imaging and dosimetry) is one example. By administering a compound of formula (I) labeled with such imaging radionuclides to a target, it may be possible to visualize or detect cells that overexpress NTSR1, thereby enabling the location of NTSR1-positive tumors or metastases.

[0144] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is used in a theranostic approach. For example, the compound of formula (I) 68 Ga or 111 By radiolabeling with diagnostic radionuclides such as In, tumor uptake and localization can be evaluated via imaging, and the corresponding compound, optionally the same compound of formula (I) or a structurally similar compound, can be used for therapeutic purposes. 225 Ac or 177 It can be radiolabeled with therapeutic radionuclides such as Lu. In an exemplary example, formula (I) 111 The In-labeled compound was administered to the target, and NTSR1-positive tumors were confirmed by imaging via SPECT, followed by formula (I). 225 Ac-labeled compounds can be administered to provide targeted alpha particle therapy to these tumors. Similarly, compounds of formula (I) 68 The Ga labeling method may be used for PET imaging, patient selection, or disease progression monitoring, and corresponding 177 Lu indicator configuration or 67 Cancer can be treated using Cu-labeled embodiments. These pairs of diagnostic / therapeutic radionuclides, for example, but not limited to, 111 In / 225 Ac, 68 Ga / 177 Lu, 64 Cu / 67Cu exemplifies a theranostic strategy that provides both imaging and therapy using compounds that target the same molecular receptor.

[0145] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 ) is

[0146]

Chemical formula

[0147] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 ) is

[0148]

Chemical formula

[0149] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 )teeth,

[0150] [ka] And in the formula, R a , R b , and R c Each is independently selected from -OH and -NH2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 Ac. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R a , R b , and R c Each of these is -OH. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R a and R c Each of these is -OH, and R b is -NH2. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R a , R b , and R c These are all -NH2.

[0151] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 )teeth,

[0152] [ka] Selected from, in the formula, M 1 However, it is a radionuclide, preferably M 1is 177 Lu, 212 Pb, or 225 Ac.

[0153] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 ) is

[0154] <00​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 )teeth,

[0160] [ka]

[0161] [ka] Selected from, in the formula, M 1 However, it is a radionuclide, preferably M 1 but, 177 Lu, 212 Pb, or 225 It is Ac.

[0162] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 )teeth,

[0163] [ka] Selected from.

[0164] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, Ch 1 (M 1 )teeth,

[0165] [ka] That is the case.

[0166] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, W is absent, Z is -COOH, and R 4 The following formula

[0167] [ka] It is the basis of, R 4e It is methyl, and Cy 1 This is a 5 or 6-membered heteroaryl compound containing phenyl or 1 to 3 heteroatoms independently selected from N, O, and S (whereas Cy 1 If X is a join, 1 (However, it is a combination.)

[0168] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is isopropyl or tert-butyl, and R 2 is adamantyl or adamantyl-CH2-, and R 3 is H. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is isopropyl, and R 2 is adamantyl or adamantyl-CH2-, and R 3 is H. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is tert-butyl, and R 2 is adamantyl or adamantyl l-CH2-, and R 3 H is H.

[0169] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is isopropyl or tert-butyl, and R 2 and R 3 These, together with the carbon atoms to which they are bonded, form adamantyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is isopropyl, and R 2 and R 3 These, together with the carbon atoms to which they are bonded, form adamantyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is tert-butyl, and R 2 and R 3 These, together with the carbon atoms to which they are bonded, form adamantyl.

[0170] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 2 is adamantyl or adamantyl-CH2-, and R 3 H is R 4 is 5-methoxybenzo[d][1,3]dioxol-4-yl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 2 and R 3 These, together with the carbon atoms to which they are bonded, form adamantyl, R 4 This is 5-methoxybenzo[d][1,3]dioxol-4-yl.

[0171] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is isopropyl or tert-butyl, and R 2 is adamantyl or adamantyl-CH2-, and R 3 H is R 4 is 5-methoxybenzo[d][1,3]dioxol-4-yl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is isopropyl, and R 2 This is adamantyl or adamantyl-CH 2 - and R 3 H is R 4 is 5-methoxybenzo[d][1,3]dioxol-4-yl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is tert-butyl, and R 2 This is adamantyl or adamantyl-CH 2 - and R 3 H is R 4 This is 5-methoxybenzo[d][1,3]dioxol-4-yl.

[0172] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 is isopropyl or tert-butyl, and R 2and R 3 These, together with the carbon atoms to which they are bonded, form adamantyl, R 4 is 5-methoxybenzo[d][1,3]dioxol-4-yl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is isopropyl, and R 2 and R 3 These, together with the carbon atoms to which they are bonded, form adamantyl, R 4 is 5-methoxybenzo[d][1,3]dioxol-4-yl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, R 1 It is tert-butyl, and R 2 and R 3 These, together with the carbon atoms to which they are bonded, form adamantyl, R 4 This is 5-methoxybenzo[d][1,3]dioxol-4-yl.

[0173] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1 This is a bond, and Cy 1 is a bond. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1 This is a bond, and Cy 1 is phenyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1 This is a bond, and Cy 1 This is a 5 or 6-membered heteroaryl compound containing 1 to 3 heteroatoms independently selected from N, O, and S, preferably Cy 1 is triazolyl. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is X 1 is -O- and Cy 1 is phenyl. In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 1 It is -NH- and Cy 1 It is phenyl.

[0174] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , Rx5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0175] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , Rx28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each appearance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl and -N(C1~C4 alkyl)(C1~C4 alkyl), and v is 1, 2, 3, 4, or 5.

[0176] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , Rx10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0177] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NRx34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1-C3 alkylenes, in their respective appearances, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10In each appearance, the heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl and -N(C1~C4 alkyl)(C1~C4 alkyl), and v is 1, 2, 3, 4, or 5.

[0178] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0179] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NRx22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5.

[0180] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , Rx10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0181] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5.

[0182] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2, R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , Rx16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0183] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5.

[0184] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , Rx4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0185] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5.

[0186] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2, R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , Rx16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0187] [ka] Selected from.

[0188] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 -L 1 teeth,

[0189] [ka]

[0190] [ka]

[0191] [ka] Selected from.

[0192] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 -L 1 teeth,

[0193] [ka] Selected from.

[0194] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0195] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0196] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R nEach is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0197] [ka] Selected from, more preferably, Ch 1 teeth,

[0198] [ka] That is the case.

[0199] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0200] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1-C3 alkylenes, in their respective appearances, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0201] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0202] [ka] Selected from, more preferably, Ch 1 teeth,

[0203] [ka] That is the case.

[0204] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0205] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0206] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0207] [ka] Selected from, more preferably, Ch 1 teeth,

[0208] [ka] That is the case.

[0209] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0210] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0211] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0212] [ka] Selected from, more preferably, Ch 1 teeth,

[0213] [ka] That is the case.

[0214] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0215] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0216] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0217] [ka] Selected from, more preferably, Ch 1 teeth,

[0218] [ka] That is the case.

[0219] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0220] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0221] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0222] [ka] Selected from, more preferably, Ch 1 teeth,

[0223] [ka] That is the case.

[0224] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0225] [ka] And, Ch 1 teeth,

[0226] [ka] And in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, more preferably Ch 1 teeth,

[0227] [ka] And, moreover, Ch 1 teeth,

[0228] [ka] That is the case.

[0229] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 -Ch 1 teeth,

[0230] [ka] That is the case.

[0231] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0232] [ka] And in the formula, X 3In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkilen, in each appearance, C3~C10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0233] [ka] And in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0234] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0235] [ka] That is the case.

[0236] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0237] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NRx37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1-C3 alkylenes, in their respective appearances, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0238] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0239] [ka] Selected from, more preferably, Ch 1 (M1 )teeth,

[0240] [ka] That is the case.

[0241] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0242] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0243] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0244] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0245] [ka] That is the case.

[0246] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0247] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0248] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0249] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0250] [ka] That is the case.

[0251] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0252] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0253] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R nEach is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0254] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0255] [ka] That is the case.

[0256] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0257] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0258] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , Rj , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0259] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0260] [ka] That is the case.

[0261] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 teeth,

[0262] [ka] Selected from, Ch 1 (M 1 )teeth,

[0263] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and Rn Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0264] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0265] [ka] That is the case.

[0266] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 -Ch 1 (M 1 )teeth,

[0267] [ka] Selected from, in the formula, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac.

[0268] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, L 1 -Ch 1 (M 1 )teeth,

[0269] [ka] Selected from.

[0270] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , Rx4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0271] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , Rx27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0272] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0273] [ka] Selected from, more preferably, Ch 1 teeth,

[0274] [ka] That is the case.

[0275] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , Rx5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0276] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , Rx28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1-C3 alkylenes, in their respective appearances, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0277] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0278] [ka] Selected from, more preferably, Ch 1 teeth,

[0279] [ka] That is the case.

[0280] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , Rx15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0281] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0282] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0283] [ka] Selected from, more preferably, Ch 1 teeth,

[0284] [ka] That is the case.

[0285] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14, R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0286] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0287] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0288] [ka] Selected from, more preferably, Ch 1 teeth,

[0289] [ka] That is the case.

[0290] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , Rx10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0291] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0292] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , Rk , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0293] [ka] Selected from, more preferably, Ch 1 teeth,

[0294] [ka] That is the case.

[0295] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8-, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , Rx3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0296] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 teeth,

[0297] [ka] Selected from, in the formula, R a , R b , R c , Rd , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0298] [ka] Selected from, more preferably, Ch 1 teeth,

[0299] [ka] That is the case.

[0300] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0301] [ka] Selected from, Ch 1 teeth,

[0302] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2, preferably Ch 1 teeth,

[0303] [ka] Selected from, more preferably, Ch 1 teeth,

[0304] [ka] That is the case.

[0305] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 -L 1 -Ch 1 teeth,

[0306] [ka]

[0307] [ka] Selected from.

[0308] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NRx2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , Rx5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0309] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , Rx28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1~C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1~C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0310] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0311] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0312] [ka] That is the case.

[0313] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5-, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , Rx4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17, R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0314] [ka] And in the formula, X 3 In each occurrence, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 -Selected independently of, R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39In each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl. C1-C3 alkylenes, in their respective appearances, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from the heteroarrene, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, heteroarylene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl). v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0315] [ka] Selected from, in the formula, R a , R b , Rc , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0316] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0317] [ka] That is the case.

[0318] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NRx15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17, R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0319] [ka] X3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0320] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0321] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0322] [ka] That is the case.

[0323] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , Rx5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0324] [ka] X 3 In each occurrence, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 In each instance, is independently selected from H and C1-C6 alkyl groups, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0325] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu,212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0326] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0327] [ka] That is the case.

[0328] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NRx11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , Rx3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0329] [ka] X 3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0330] [ka] Selected from, in the formula, R a , R b , Rc , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0331] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0332] [ka] That is the case.

[0333] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NRx15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2 is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17, R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0334] [ka] X3 In each occurrence, v is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5. Ch 1 (M 1 )teeth,

[0335] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0336] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0337] [ka] That is the case.

[0338] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 is a combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NRx3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NR x10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and preferably, X 2 is a combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -and more preferably, X 2 The bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NH-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NCH3S(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-, and more preferably X 2is a bond, -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)N CH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with pyrrolidinyl, preferably, the heterocyclyl is optionally substituted with C1-C6 alkyl, preferably, R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x4 , Rx5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 Each is independently selected from H and methyl, L 1 teeth,

[0339] [ka] Selected from, Ch 1 (M 1 )teeth,

[0340] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R n Each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac, preferably Ch 1 (M 1 )teeth,

[0341] [ka] Selected from, more preferably, Ch 1 (M 1 )teeth,

[0342] [ka] That is the case.

[0343] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 -L 1 -Ch 1 (M 1 )teeth,

[0344] [ka]

[0345] [ka] Selected from, in the formula, M 1 is a radionuclide, preferably M 1 teeth, 177 Lu, 212 Pb, or 225 It is Ac.

[0346] In one embodiment of the compound of formula (I), or a pharmaceutically acceptable salt thereof, X 2 -L 1 -Ch 1 (M 1 )teeth,

[0347] [ka]

[0348] [ka] Selected from.

[0349] The present invention also relates to compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), or (Io),

[0350] [ka]

[0351] [ka]

[0352] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 Cy 1 , X 2 , L 1 Ch 1 , and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above.

[0353] The present invention also relates to compounds of formula (Ip), (Iq), (Ir), (Is), or (It),

[0354] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , L 1 Ch 1 , and M 1As defined above, Het A is a 5 or 6-membered heteroaryl compound containing 1 to 3 heteroatoms independently selected from N, O, and S, or provides a pharmaceutically acceptable salt thereof.

[0355] The present invention also relates to compounds of formula (Ia-1), (Ib-1), (Ic-1), (Id-1), (Ie-1), (If-1), or (Ig-1),

[0356] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 2 , L 1 Ch 1 , and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above.

[0357] The present invention also relates to compounds of formula (Ia-2), (Ib-2), (Ic-2), (Id-2), (Ie-2), (If-2), or (Ig-2),

[0358] [ka]

[0359] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , L 1 Ch 1 , and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above.

[0360] The present invention also relates to compounds of formula (Ia-3), (Ib-3), (Ic-3), (Id-3), (Ie-3), (If-3), or (Ig-3),

[0361] [ka]

[0362] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , L 1 Ch 1 , and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above.

[0363] The present invention also relates to compounds of formula (Ia-4), (Ib-4), (Ic-4), (Id-4), (Ie-4), (If-4), or (Ig-4),

[0364] [ka]

[0365] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , L 1 Ch 1 , and M 1 As defined above, Het A is a 5 or 6-membered heteroaryl compound containing 1 to 3 heteroatoms independently selected from N, O, and S, or provides a pharmaceutically acceptable salt thereof.

[0366] The present invention also relates to compounds of formula (Ia-5), (Ib-5), (Ic-5), (Id-5), (Ie-5), (If-5), or (Ig-5),

[0367] [ka]

[0368] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , L 1 Ch 1 , and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above.

[0369] The present invention also relates to compounds of formula (Ig-1-a), (Ig-1-b), (Ig-1-c), (Ig-1-d), (Ig-1-e), (Ig-1-f), (Ig-1-g), (Ig-1-h), or (Ig-1-i),

[0370] [ka]

[0371] [ka] In the formula, R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , R x20 , L 1 Ch 1 , and M 1This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above, preferably R x2 , R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each of these is independently selected from H and methyl.

[0372] The present invention also relates to compounds of formula (Ig-2-a), (Ig-2-b), (Ig-2-c), (Ig-2-d), (Ig-2-e), (Ig-2-f), (Ig-2-g), (Ig-2-h), or (Ig-2-i),

[0373] [ka]

[0374] [ka]

[0375] [ka] In the formula, R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , R x20 , X 1 , L 1 Ch 1, and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above, preferably R x2 , R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each of these is independently selected from H and methyl.

[0376] The present invention also relates to compounds of formula (Ig-3-a), (Ig-3-b), (Ig-3-c), (Ig-3-d), (Ig-3-e), (Ig-3-f), (Ig-3-g), (Ig-3-h), or (Ig-3-i),

[0377] [ka]

[0378] [ka]

[0379] [ka] In the formula, R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , R x20 , X 1 , L 1Ch 1 , and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above, preferably R x2 , R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each of these is independently selected from H and methyl.

[0380] The present invention also relates to compounds of formula (Ig-4-a), (Ig-4-b), (Ig-4-c), (Ig-4-d), (Ig-4-e), (Ig-4-f), (Ig-4-g), (Ig-4-h), or (Ig-4-i),

[0381] [ka]

[0382] [ka]

[0383] [ka] In the formula, R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , R x20 , X1 , L 1 Ch 1 , and M 1 The compound or pharmaceutically acceptable salt thereof is provided, as defined above, where Het A is a 5 or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, preferably R x2 , R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each is independently selected from H and C1-C6 alkyl, more preferably R x2 , R x3 , R x5 , R x7 , R x8 , R x11 , R x13 , R x19 , and R x20 Each of these is independently selected from H and methyl.

[0384] The present invention also relates to a compound of formula (Ig--5-a),

[0385] [ka] In the formula, X 1 , L 1 Ch 1 , and M 1 This provides a compound, or a pharmaceutically acceptable salt thereof, as defined above.

[0386] The present invention also relates to formula (I-ChM A ), (I-ChM B ), (I-ChM A1 ), (I-ChM B1 ), (I-ChM A2 ), (I-ChM B2 ), (Ig-ChM A2 ), or (Ig-ChM B2 A compound of )

[0387] [ka]

[0388] [ka]

[0389] [ka]

[0390] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 Cy 1 , X 2 , L 1 M 1 , R a , R b , R c , R d , R e , R f The present invention provides a compound, or a pharmaceutically acceptable salt thereof, where m, n, and p are as defined above.

[0391] The present invention also,

[0392] [ka]

[0393] [ka]

[0394] [ka]

[0395] [ka]

[0396] [ka]

[0397] [ka] compounds selected from Or provide a pharmaceutically acceptable salt thereof.

[0398] The present invention also,

[0399] [ka]

[0400] [ka]

[0401] [ka]

[0402] [ka]

[0403] [ka]

[0404] [ka] The present invention provides compounds selected from, or pharmaceutically acceptable salts thereof.

[0405] The present invention also,

[0406] [ka]

[0407] [ka]

[0408] [ka]

[0409] [ka]

[0410] [ka]

[0411] [ka] The present invention provides compounds selected from, or pharmaceutically acceptable salts thereof.

[0412] The present invention also,

[0413] [ka]

[0414] [ka]

[0415] [ka]

[0416] [ka]

[0417] [ka]

[0418] [ka] The present invention provides compounds selected from, or pharmaceutically acceptable salts thereof.

[0419] The present invention also,

[0420] [ka]

[0421] [ka]

[0422] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0423] The present invention also,

[0424] [ka]

[0425] [ka]

[0426] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0427] The present invention also,

[0428] [ka]

[0429] [ka]

[0430] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0431] The present invention also,

[0432] [ka]

[0433] [ka]

[0434] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0435] The present invention also,

[0436] [ka]

[0437] [ka]

[0438] [ka]

[0439] [ka]

[0440] [ka]

[0441] [ka]

[0442] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0443] The present invention also,

[0444] [ka]

[0445] [ka]

[0446] [ka]

[0447] [ka]

[0448] [ka]

[0449] [ka]

[0450] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0451] [ka]

[0452] [ka]

[0453] [ka]

[0454] [ka]

[0455] [ka]

[0456] [ka]

[0457] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0458] The present invention also,

[0459] [ka]

[0460] [ka]

[0461] [ka]

[0462] [ka]

[0463] [ka]

[0464] [ka]

[0465] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0466] The present invention also relates to a compound of formula (II),

[0467] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 Cy 1 , and X 2 This is as defined herein, and each Y 1 These can be used independently, combined, or -NR. y1 - and Y 2 -NR y2 R y3 , or a 5 or 6-membered heterocycle selected from pyrrolidine, piperazine, or piperidine, wherein the 5 or 6-membered heterocycle is optionally substituted with a C1-C6 alkyl group, R y1 , R y2, and R y3 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, in which, in each appearance, H and C1-C6 alkyl are selected, and q is 0, 1, 2, 3, 4, 5, or 6.

[0468] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 3, and Y 1 In each appearance, it is a combination, Y 2 , NR y2 R y3 That is the case.

[0469] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 1, and Y 1 Y is a combination. 2 This is a 5- or 6-membered heterocycle selected from pyrrolidine, piperazine, or piperidine, wherein the 5- or 6-membered heterocycle is optionally substituted with a C1-C6 alkyl group.

[0470] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 6, and Y 1 The five occurrences of are a combination, Y 1 The single occurrence of -NR y1 - and Y 2 , NR y2 R y3 That is the case.

[0471] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, -X 2 -(CH2-Y 1 ) q -CH2-Y 2 teeth,

[0472] [ka] Selected from.

[0473] The present invention also relates to a compound of formula (II-a),

[0474] [ka] In the formula, X 1 Cy 1 , X 2 , Y 1 , Y 2 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, where q and q are as defined above.

[0475] The present invention also,

[0476] [ka]

[0477] [ka]

[0478] [ka] The present invention provides compounds selected from, or pharmaceutically acceptable salts thereof.

[0479] The present invention also relates to a compound of formula (III),

[0480] [ka] In the formula, R 1 , R 2 , R 3 , R 4 , X 1 Cy 1 , and X 2 This is as defined herein, and each Y 1 These can be used independently, combined, or -NR. y1 - and Y 2 -NR y2 R y3 , or a 5 or 6-membered heterocycle which is pyrrolidine, piperazine, or piperidine, and the 5 or 6-membered heterocycle is optionally substituted with a C1-C6 alkyl group, R y1 , R y2 , and Ry3 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, in which, in each appearance, H and C1-C6 alkyl are selected, and q is 0, 1, 2, 3, 4, 5, or 6.

[0481] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 3, and Y 1 In each appearance, it is a combination, Y 2 , NR y2 R y3 That is the case.

[0482] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 1, and Y 1 Y is a combination. 2 It is a 5- or 6-membered heterocycle that is pyrrolidine, piperazine, or piperidine, and the 5- or 6-membered heterocycle is optionally substituted with a C1-C6 alkyl group.

[0483] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 6, and Y 1 The five occurrences of are a combination, Y 1 The single occurrence of -NR y1 - and Y 2 , NR y2 R y3 That is the case.

[0484] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, -X 2 -(CH2-Y 1 ) q -CH2-Y 2 teeth,

[0485] [ka]

[0486] [ka] That is the case.

[0487] The present invention also relates to a compound of formula (III-a),

[0488] [ka] In the formula, Z, R 4 , Y, X 1 Cy 1 , 2 , Y 1 , 2 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, where q and q are as defined above.

[0489] The present invention also,

[0490] [ka]

[0491] [ka]

[0492] [ka] The present invention provides a compound that is, or a pharmaceutically acceptable salt thereof.

[0493] The present invention also relates to a compound of formula (IV),

[0494] [ka] In the formula, R 1 , R 2 , R 3 , Z, R 4 Q, X 1 Cy 1 , and X 2 This is as defined herein, and each Y 1 These can be used independently, combined, or -NR. y1 - and Y 2 -NR y2 R y3, or a 5 or 6-membered heterocycle which is pyrrolidine, piperazine, or piperidine, and the 5 or 6-membered heterocycle is optionally substituted with a C1-C6 alkyl group, R y1 , R y2 , and R y3 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, in which, in each appearance, H and C1-C6 alkyl are selected, and q is 0, 1, 2, 3, 4, 5, or 6.

[0495] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 3, and Y 1 In each appearance, it is a combination, Y 2 , NR y2 R y3 That is the case.

[0496] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 1, and Y 1 Y is a combination. 2 It is a 5- or 6-membered heterocycle that is pyrrolidine, piperazine, or piperidine, and the 5- or 6-membered heterocycle is optionally substituted with a C1-C6 alkyl group.

[0497] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, q is 6, and Y 1 The five occurrences of are a combination, Y 1 The single occurrence of -NR y1 - and Y 2 , NR y2 R y3 That is the case.

[0498] In one embodiment of the compound of formula (II), or a pharmaceutically acceptable salt thereof, -X 2 -(CH2-Y 1 ) q -CH2-Y 2 teeth,

[0499] [ka] This invention also states that

[0500] [ka] The present invention provides a compound that is [a compound].

[0501] The compound of formula (I) can react with several inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Examples of salt formation, reactions, and conditions are known to those skilled in the art. See, for example, P. Stahl, et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, (VCHA / Wiley-VCH, 2002); SMBerge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1, January 1977.

[0502] It will be understood that the compound of formula (I) can be represented as a single stereoisomer. As used herein, a reference to a single stereoisomer also means a mixture of stereoisomers containing the compound named or described of formula (I). In this specification, the Cahn-Ingold-Prelog designations (R)- and (S)- may be used to refer to specific stereoisomers. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or concentrated starting materials. Certain stereoisomers of any starting material, intermediate, or racemic mixture containing a compound of formula (I) can be resolved by techniques well known in the art, such as those found in Stereochemistry of Organic Compounds, E.I. Eliel and SH Wilen (Wiley 1994) and Enantiomers, Racemates, and Resolutions, J., Jacques, A. Collet, and SH Wilen (Wiley 1991), including chromatography on a chiral stationary phase, enzymatic resolution, or fractional crystallization or chromatography of diastereomers (e.g., diastereomer salts) formed for that purpose. With respect to a compound of formula (I) having a configuration with all the stereocenters shown, "substantially enantiomerically pure" means an enantiomer excess of more than 90% isomer purity.

[0503] In another embodiment, the isomer purity of the compound of formula (I) is enantiomeric excess of over 95%.

[0504] In yet another embodiment, the isomer purity of the compound of formula (I) is enantiomeric excess of over 98%.

[0505] In yet another embodiment, the isomer purity of the compound of formula (I) is enantiomeric excess of over 99%. All stereoisomers of the compound of formula (I) are intended to be within the scope of this application. The designations "isomer 1" and "isomer 2" refer to the compounds that elute first and second from chiral chromatography, respectively, and the same designations apply to subsequent intermediates and examples if chiral chromatography is initiated early in the synthesis.

[0506] Compounds of formula (I) or any of the illustrated formulas, or salts thereof, may be prepared by various procedures, some of which are illustrated in the following preparations and examples. The specific synthesis steps of each described pathway may be combined in different ways, or combined with steps from different pathways, to prepare the compounds or salts of the present invention. The products of each step in the following preparations can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, grinding, and crystallization.

[0507] Synthesis method The compounds of the present invention can be synthesized according to the steps outlined in general schemes 1, 2, and 3. The starting materials are either commercially available or prepared by known procedures in known literature in the art or as illustrated below.

[0508] The compound of intermediate (6) may be prepared from intermediate (1) as shown in scheme 1, where R 1 , R 2 , R 3 , R 4 , X 1 Cy 1 , X 2 , and L 1 As previously defined, Z 1 is a halogen, preferably bromine or iodine, Z 2 The compound is a C-C6 alkyl group, preferably ethyl.

[0509] Scheme 1

[0510] [ka]

[0511] In the pyrazole cyclization reaction, intermediate (1) can be obtained by reacting phenylhydrazine with a diketo-ester. Phenylhydrazine and diketo-esters are commercially available or can be prepared by methods well known to those skilled in the art.

[0512] The alkyl ester of intermediate (1) can be hydrolyzed using methods well known to those skilled in the art, such as LiOH in a solvent mixture of MeOH and H2O. The resulting carboxylic acid can be coupled with a suitable amino acid in a suitable solvent, in the presence of a coupling agent and a suitable base to obtain intermediate (2). A typical amino acid for this coupling is tert-butyl 2-aminoadamantane-2-carboxylate. Suitable coupling agents include TCFH and HATU. Suitable solvents include DMF and ACN. Suitable bases include DIEA and imidazole.

[0513] Intermediate (2) is prepared in a suitable solvent, in the presence of a suitable palladium catalyst, with a suitable phenyldioxaborolane and Z 1 The intermediate compound (3) can be obtained by Suzuki coupling at the 11 position. A typical phenyldioxaborolane useful for this coupling is 4-carboxyphenylboronic acid pinacol ester. The necessary phenyldioxaborane useful for this coupling can be commercially available or prepared by methods well known to those skilled in the art. Suitable palladium catalysts are commercially available and include PdCl2(PPh3)2, Pd2(dba)3, and Pd(dppf)Cl2. Suitable solvents include mixtures of dioxane and H2O.

[0514] Alternatively, intermediate (2) is Z 1The compound can undergo palladium-catalyzed hydroxylation at the 11 position to give the intermediate compound (3). A suitable hydroxide source is KOH. Suitable palladium catalysts are commercially available, such as t-BuBrettPhos Pd G3. Suitable solvents include a mixture of dioxane and H2O.

[0515] Alternatively, intermediate (2) is Z 1 Copper-mediated amination at the 11th position may yield the intermediate compound (3). A suitable amine source is NH3·H2O. A suitable copper source is CuI. Suitable solvents include dioxane.

[0516] Intermediate (3) is the linker portion L 1 The intermediate (6) can be synthesized via the linkage. The linker can be linked, for example, via an amide, amino, ether, carbamate, urea, carbamothioate, or sulfamide group formed by coupling methods well known to those skilled in the art. The necessary linkers are commercially available or can be prepared by methods well known to those skilled in the art.

[0517] Alternatively, intermediate (2) can undergo Sonogashira coupling to introduce an alkyne, thereby introducing a linker (L 1 During treatment with the functionalized azide, copper-mediated 1,3-dipolar cycloaddition is performed to yield the intermediate triazole compound (6). The necessary functionalized azides useful for this cycloaddition are commercially available or can be prepared by methods well known to those skilled in the art. A commercially available catalyst system suitable for Sonogashira coupling is PdCl2(PPh3)2 containing CuI. Toluene is a suitable solvent for Sonogashira coupling. CuSO4 is a suitable copper source for dipolar cycloaddition. A suitable solvent system for dipolar cycloaddition is a mixture of MeOH, DCM, and H2O.

[0518] Alternatively, the compound of intermediate (2) may be subjected to a suitable alkylamine linker (L) in a suitable solvent, in the presence of a suitable palladium catalyst and a suitable ligand. 1 ) and Z 1The intermediate compound (6) can be obtained by Buchwald coupling at the 11 position. The necessary alkylamine linkers useful for this coupling are commercially available or can be prepared by methods well known to those skilled in the art. Suitable palladium catalysts are commercially available and include PdCl2(PPh3)2, Pd2(dba)3, and Pd(dppf)Cl2. Suitable ligands are commercially available and include XPhos. Suitable solvents include dioxanes.

[0519] Alternatively, the compound of intermediate (6) may be prepared from intermediate (4) as shown in scheme 2, where R 1 , R 2 , R 3 , R 4 , X 1 Cy 1 , X 2 , and L 1 As previously defined, Z 2 The compound is a C1-C6 alkyl group, preferably ethyl.

[0520] Scheme 2

[0521] [ka]

[0522] The intermediate (4) containing a carboxylic acid (CO2H) is converted into a suitable alkylamine linker (L) in the presence of an amide coupling agent. 1 The intermediate compound (5) can be obtained by amide coupling with ). The necessary alkylamine linker useful for this coupling is commercially available or can be prepared by methods well known to those skilled in the art. A suitable amide coupling agent is T3P. Suitable solvents include DMF.

[0523] The alkyl ester of intermediate (5) can be hydrolyzed using methods well known to those skilled in the art, such as LiOH in a solvent mixture of MeOH and H2O. The resulting carboxylic acid can be coupled with a suitable amino acid in a suitable solvent, in the presence of a coupling agent and a suitable base, to obtain intermediate (6). A typical amino acid for this coupling is tert-butyl 2-aminoadamantane-2-carboxylate. Suitable coupling agents include TCFH and HATU. Suitable solvents include DMF and ACN. Suitable bases include DIEA and imidazole.

[0524] The compound of formula (I) may also be prepared from intermediate (6) as shown in scheme 3, where R 1 , R 2 , R 3 , R 4 , X 1 Cy 1 , X 2 , L 1 Ch 1 , and M 1 This is as previously defined, Ch 1 Pg has a suitable protecting group Ch 1 That is the case.

[0525] Scheme 3

[0526] [ka]

[0527] Intermediate (6) is coupled with a suitable chelating agent to obtain intermediate (7). For example, a suitable protecting group for the chelating agent may be a tert-butyl ester. A typical chelating agent useful for this coupling may be [4,7-bis-tert-butoxycarbonylmethyl-10-(2,5-dioxo-pyrrolidine-1-yloxycarbonylmethyl)-1,4,7,10-tetraaza-cyclododeca-1-yl]-tert-butyl acetate. Suitable solvents include DCM and DMF. Suitable bases include pyridine, DIPEA, and TEA.

[0528] Intermediate (8) can be obtained by the overall deprotection of intermediate (7) by a method known to those skilled in the art. For example, the tert-butyl ester protecting group can be cleaved by treatment with a suitable acid such as TFA in a suitable solvent such as DCM.

[0529] The compound of formula (I) can be obtained by metal chelation with intermediate (8). Metal chelation can occur by heating a solution of intermediate (8) in the presence of a suitable metal. For example, the suitable solution may be a sodium acetate-acetic acid buffer at pH 5, and the suitable metal may be lutetium(III) chloride.

[0530] Those skilled in the art will understand that the order of the steps described in the scheme above can be modified as needed or desired to provide useful synthetic intermediates and compounds of formula (I). For example, the linker or part of the linker can be coupled to a chelating agent before coupling with the intermediate.

[0531] Certain intermediates described in the following preparations may contain one or more nitrogen and oxygen protecting groups. It is understood that the protecting groups may vary depending on the specific reaction conditions and the specific transformations performed, as will be understood by those skilled in the art. The conditions for protection and deprotection are well known to those skilled in the art and are described in the literature (see, for example, "Greene's Protective Groups in Organic Synthesis," Fifth Edition, Peter GMWuts and Theodora W. Greene, John Wiley and Sons, Inc. 2014).

[0532] Examples of known synthetic procedures and methods include those described in general reference books such as Comprehensive Organic Transformations, VCH Publishers Inc, 1989; Compendium of Organic Synthetic Methods, Volumes 1-10, 1974-2002, Wiley Interscience; Advanced Organic Chemistry, Reactions Mechanisms, and Structure, 5th Edition, Michael B. Smith and Jerry March, Wiley Interscience, 2001; and Advanced Organic Chemistry, 4th Edition, Part B, Reactions and Synthesis, Francis A. Carey and Richard J. Sundberg, Kluwer Academic / Plenum Publishers, 2000, as well as the references cited therein.

[0533] Pharmaceutical composition Pharmaceutical compositions comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof are also provided herein. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained-release or sustained-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration using all forms well known to those skilled in the pharmaceutical art.

[0534] Compounds of formula (I), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof may be administered to subjects by any convenient route of administration, whether systemic / peripheral or topical (i.e., at the desired site of action).

[0535] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., including by patches, plasters, etc.); transmucosal (e.g., including by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., by use through the mouth or nose, e.g., by inhalation or inhalation therapy); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral administration by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, subarachnoid, intraspinal, intracapsular, intrasacral, intravesical, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intrasternal; and implantation of depots or reservoirs, e.g., subcutaneous or intramuscular.

[0536] In preferred embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered by injection.

[0537] Pharmaceutical compositions containing the compound of formula (I), or a pharmaceutically acceptable salt thereof, can be prepared using pharmaceutically acceptable carriers, diluents, or excipients that are compatible with other additives to the composition or preparation and are not harmful to the patient. Examples of processes for pharmaceutical compositions and their preparations can be found in "Remington: The Science and Practice of Pharmacy," Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include saline, water, starch, sugar, mannitol, and silica derivatives; binders such as carboxymethylcellulose, alginates, gelatin, and polyvinylpyrrolidone; kaolin and bentonite; and polyethyl glycol.

[0538] therapeutic use Furthermore, therapies comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disease, such as cancer, in a patient.

[0539] Furthermore, the Specified Method of Treating Cancer comprises administering to a patient in need a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Cancer may have one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1). In one embodiment, cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0540] Furthermore, the Specified Method provides for treating cancer associated with neurotensin receptor 1 (NTSR1) overexpression, comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need. The cancer status associated with neurotensin receptor 1 (NTSR1) overexpression can be determined by several assays known in the art. For example, NTSR1 overexpression can be detected by immunohistochemical (IHC) analysis of tumor biopsy specimens, by enzyme-linked immunosorbent assay (ELISA), or by other suitable protein or gene expression detection methods. If desired, such assays can be used to screen patients to confirm that their tumors overexpress NTSR1, thereby identifying patients who are likely to benefit from treatment with a compound of formula (I). In one embodiment, the cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0541] Also provided herein is a method for treating cancer, comprising administering to a patient in need a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, wherein the cancer has cells that overexpress neurotensin receptor 1 (NTSR1). The state of one or more cancer cells can be determined by several assays known in the art. In one embodiment, the cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0542] Also provided herein is a method for treating cancer, comprising administering to a patient in need a therapeutically effective amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, wherein the patient has cancer determined to overexpress neurotensin receptor 1 (NTSR1). In one embodiment, the cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0543] Compounds according to formula (I) or pharmaceutically acceptable salts thereof for therapeutic use are further provided herein. In one embodiment, the compound or pharmaceutically acceptable salt thereof is for use in the treatment of cancer. Cancer may have one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1). In one embodiment, cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0544] Compounds provided herein by formula (I), or pharmaceutically acceptable salts thereof, may also be used in the manufacture of pharmaceuticals for the treatment of cancer. Cancer may have one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1). In one embodiment, cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0545] Also provided herein is a method for diagnosing cancer associated with neurotensin receptor 1 (NTSR1) overexpression, comprising administering a diagnostically effective dose of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a patient in need.

[0546] Furthermore, the Specified herein provides a method for imaging cancers associated with neurotensin receptor 1 (NTSR1) overexpression, comprising administering to a patient in need an imaging-effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0547] Exemplary aspects Various aspects of the present invention are described in the following numbered clauses.

[0548] Article 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof,

[0549] [ka] In the formula, R 1 However, Z is C1-C6 alkyl or C3-C6 cycloalkyl, and Z is -COOH, -C(=O)NH2, or -tetrazolyl, and R 2 However, C6~C 10 Cycloalkyl or C6-C 10 It is cycloalkyl-C1~C6alkyl-, and C6~C 10 Cycloalkyl and C6-C 10 Each cycloalkyl-C1~C6 alkyl- is arbitrarily substituted with 1 to 3 halogens, R 3 However, it is either H or R 2 and R 3 However, together with the carbon atoms to which they are bonded, C6-C6 atoms are optionally substituted with 1-3 halogens. 10 Forming a cycloalkyl group, R 4 However, the following formula:

[0550] [ka] It is the basis of, R 4a , R 4b , R 4c , and R 4d However, each is independently either H or halogen, and R 4e However, R is hydrogen, methyl, trifluoromethyl, or methoxyethyl. 4f However, it is cyano or fluoro, R 4g is hydrogen, D is a 5-6 membered heteroaryl ring containing 1-3 heteroatoms independently selected from N, O, and S, and is optionally substituted with 1-3 groups independently selected from halo, trifluoromethyl, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 alkylamino, or C1-C4 dialkylamino, and Q is a 6-membered aryl or heteroaryl ring containing 0-3 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon, and X 1 However, it is bonded, -O-, or -NR x1 - and Cy 1 However, the compound is a 4 or 10-membered heterocycle containing a bond, phenyl, or 1 to 3 heteroatoms independently selected from N, O, and S, which may be monocyclic, fused polycyclic, crosslinked, or spirocyclic, and each phenyl or heterocycle is optionally substituted with 1 to 3 substituents independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C4 alkylamino, or C1-C4 dialkylamino, provided that Cy 1 If X is a join, 1 However, it is a combination, X 2 However, the combination, -NR x2 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x3 C(O)-, -NR x4 C(S)-, -C(O)NR x5 -, -C(S)NR x6 -, -NR x7 C(O)NR x8 -, -NR x9 C(S)NRx10 -, -NR x11 C(O)O-, -NR x12 C(S)O-, -NR x13 C(O)S-, -OC(O)NR x14 -, -OC(S)NR x15 -, -SC(O)NR x16 -, -S(O)2NR x17 -, -NR x18 S(O)2-, or -NR x19 S(O)2NR x20 - and R x1 However, it is H or C1-C3 alkyl, and R x2 , R x3 , R x4 , R x5 , R x6 , R x7 , R x8 , R x9 , R x10 , R x11 , R x12 , R x13 , R x14 , R x15 , R x16 , R x17 , R x18 , R x19 , and R x20 However, each is independently selected from H and C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocycline is optionally substituted with C1-C6 alkyl, L 1 However, it is a linker, Ch 1 However, it is a chelating agent, M 1 Either it does not exist, or Ch 1 A compound, or a pharmaceutically acceptable salt thereof, which is a radionuclide that forms a complex with a radioactive nuclide.

[0551] Clause 2.R 4 but,

[0552] [ka] And, Q is

[0553] [ka] The compounds described in Clause 1, or their pharmaceutically acceptable salts.

[0554] Clause 3.Z is -COOH, and R 4 but,

[0555] [ka] And R 4e However, it is methyl, Cy 1 However, it is a 5 or 6-membered heteroaryl compound containing phenyl or 1 to 3 heteroatoms independently selected from N, O, and S (whereas Cy 1 If X is a join, 1 A compound described in Clause 1 (but which is a bond), or a pharmaceutically acceptable salt thereof.

[0556] Clause 4.R 1 However, the compounds described in clauses 1 to 3, which are C1-C6 alkyl, or pharmaceutically acceptable salts thereof.

[0557] Clause 5.R 1 However, the compounds described in Clause 1 or 4, which are isopropyl, or pharmaceutically acceptable salts thereof.

[0558] Clause 6.R 1 However, the compounds described in Clause 1 or 4, which are tert-butyl, or pharmaceutically acceptable salts thereof.

[0559] Clause 7.R 1 However, the compounds described in Clause 1 or 4, which are C3-C6 cycloalkyl, or pharmaceutically acceptable salts thereof.

[0560] Clause 8.R 1However, the compound described in Clause 7, which is cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0561] Clause 9.R 1 However, the compound described in Clause 7, which is cyclopentyl, or a pharmaceutically acceptable salt thereof.

[0562] Clause 10.R 2 However, C6~C 10 Cycloalkyl or C6-C 10 A compound described in any one of clauses 1 to 9, which is cycloalkyl-C1-C6 alkyl-, or a pharmaceutically acceptable salt thereof.

[0563] Clause 11.R 2 However, C6~C 10 A cycloalkyl compound as described in Clause 10, or a pharmaceutically acceptable salt thereof.

[0564] Clause 12.R 2 However, adamantyl is a compound as described in Clause 11, or a pharmaceutically acceptable salt thereof.

[0565] Clause 13.R 2 However, C6~C 10 A compound described in Clause 10, which is cycloalkyl-C1~C6 alkyl-, or a pharmaceutically acceptable salt thereof.

[0566] Clause 14.R 2 However, the compound described in Clause 13, which is adamantyl-CH2-, or a pharmaceutically acceptable salt thereof.

[0567] Clause 15.R 2 and R 3 However, together with the carbon atoms to which they are bonded, they form C6-C atoms optionally substituted with 1-3 halogens. 10 A compound described in any one of clauses 1 to 9 that forms a cycloalkyl group, or a pharmaceutically acceptable salt thereof.

[0568] Clause 16.R 2 and R 3However, the compounds described in Clause 15, or pharmaceutically acceptable salts thereof, which, together with the carbon atoms to which they are bonded, form adamantyl.

[0569] Clause 17.R 4 but,

[0570] [ka] The compound described in any one of clauses 1 to 16, or a pharmaceutically acceptable salt thereof.

[0571] Clause 18.R 4 but,

[0572] [ka] The compound described in any one of clauses 1 to 17, or a pharmaceutically acceptable salt thereof.

[0573] Clause 19.R 4 but,

[0574] [ka] The compounds described in any one of clauses 1, 2, or 4-15, or their pharmaceutically acceptable salts.

[0575] Clause 20.R 4 However, the following compounds are included in Article 1 or any one of Articles 4-15, or their pharmaceutically acceptable salts.

[0576] [ka]

[0577] Clause 21.X 1 However, the compound is a compound described in any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, which is a bond.

[0578] Clause 22.X1 A compound described in any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, which is -O-.

[0579] Clause 23.X 1 A compound described in any one of clauses 1 to 19, which is -NH-, or a pharmaceutically acceptable salt thereof.

[0580] Clause 24.X 1 A compound described in any one of clauses 1 to 19, which is -NCH3-, or a pharmaceutically acceptable salt thereof.

[0581] Article 25.Cy 1 However, the compound is a compound described in any one of clauses 1 to 19, or a pharmaceutically acceptable salt thereof, which is a bond.

[0582] Article 26. 1 However, a compound described in any one of clauses 1 to 24, which is phenyl, or a pharmaceutically acceptable salt thereof.

[0583] Article 27. 1 The compound described in any one of Clauses 1 to 24, or a pharmaceutically acceptable salt thereof, is a 5 or 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S.

[0584] Article 28. 1 However, the compound described in Clause 27, which is triazolyl, or a pharmaceutically acceptable salt thereof.

[0585] Article 29. 1 but,

[0586] [ka] A compound described in any one of clauses 1 or 3 to 28, or a pharmaceutically acceptable salt thereof.

[0587] Article 30.Q is,

[0588] [ka] A compound that is the basis of any one of the clauses 1 or 4-28, or a pharmaceutically acceptable salt thereof.

[0589] Clause 31.X 2 However, the combination, -NR x2 -, -O-, -NR x3 C(O)-, -C(O)NR x5 -, -NR x7 C(O)NR x8 -, -NR x11 C(O)O-, -NR x13 C(O)S-, or -NR x19 S(O)2NR x20 -A compound described in any one of clauses 1 to 29, or a pharmaceutically acceptable salt thereof.

[0590] Clause 32.X 2 A compound described in any one of clauses 1 to 29, or a pharmaceutically acceptable salt thereof, wherein the bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, -NCH3C(O)S-, -NHS(O)2NH-, -NHS(O)2NCH3-, or -NCH3S(O)2NCH3-.

[0591] Clause 33.X 2 A compound described in any one of clauses 1 to 30, or a pharmaceutically acceptable salt thereof, wherein the bond is -NH-, -NCH3-, -O-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, -NHC(O)NH-, -NHC(O)NCH3-, -NCH3C(O)NCH3-, -NHC(O)O-, -NCH3C(O)O-, -NHC(O)S-, or -NHS(O)2NCH3-.

[0592] Clause 34.X 2However, the compound is a compound described in any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, which is a bond.

[0593] Clause 35.X 2 A compound described in any one of clauses 1 to 31, which is -NH-, or a pharmaceutically acceptable salt thereof.

[0594] Clause 36.X 2 A compound described in any one of clauses 1 to 31, which is -NCH3-, or a pharmaceutically acceptable salt thereof.

[0595] Clause 37.X 2 A compound described in any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof, which is -O.

[0596] Clause 38.X 2 A compound described in any one of clauses 1 to 31, which is -NHC(O)-, or a pharmaceutically acceptable salt thereof.

[0597] Clause 39.X 2 A compound described in any one of clauses 1 to 31, which is -NCH3C(O)-, or a pharmaceutically acceptable salt thereof.

[0598] Clause 40.X 2 A compound described in any one of clauses 1 to 31, which is -C(O)NCH3-, or a pharmaceutically acceptable salt thereof.

[0599] Clause 41.X 2 A compound described in any one of clauses 1 to 31, which is -NHC(O)NH-, or a pharmaceutically acceptable salt thereof.

[0600] Clause 42.X 2 A compound described in any one of clauses 1 to 31, which is -NHC(O)NCH3-, or a pharmaceutically acceptable salt thereof.

[0601] Clause 43.X 2A compound described in any one of clauses 1 to 31, wherein the compound is -NCH3C(O)NCH3-, or a pharmaceutically acceptable salt thereof.

[0602] Clause 44.X 2 A compound described in any one of clauses 1 to 31, which is -NHC(O)O-, or a pharmaceutically acceptable salt thereof.

[0603] Clause 45.X 2 A compound described in any one of clauses 1 to 31, which is -NCH3C(O)O-, or a pharmaceutically acceptable salt thereof.

[0604] Clause 46.X 2 A compound described in any one of clauses 1 to 31, which is -NHC(O)S-, or a pharmaceutically acceptable salt thereof.

[0605] Clause 47.X 2 A compound described in any one of clauses 1 to 31, which is -NHS(O)2NCH3-, or a pharmaceutically acceptable salt thereof.

[0606] Clause 48.L 1 but,

[0607] [ka] It includes one or more elements independently selected from, In the formula, X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 , X 22 , and X23 However, in each instance, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 - Selected independently of R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 However, in each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocyclyl is optionally substituted with C1-C6 alkyl, and C1-C 20 Alkylene, C2~C 20 Alkenylenes, and C2~C20 Alkinylene, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10 Arrine is arbitrarily interrupted by one or more groups independently selected, C1~C 20 Alkylene, C1~C 20 Alkenylene, C1~C 20 Alkynylene, C3~C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10 A compound according to any one of Clauses 1 to 47, or a pharmaceutically acceptable salt thereof, wherein in each appearance, arirene is optionally substituted with one or more groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl are each optionally substituted with one or more groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0608] Clause 49.L 1 but,

[0609] [ka] A compound according to Clause 48, or a pharmaceutically acceptable salt thereof, comprising 1 to 20 groups independently selected from the above.

[0610] Clause 50.L 1 but,

[0611] [ka] A compound according to Clause 48, or a pharmaceutically acceptable salt thereof, comprising 1 to 5 groups independently selected from the above.

[0612] Clause 51.L 1 but,

[0613] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from the above. In the formula, X 3 However, in each instance, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 - Selected independently of R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38, and R x39 However, in each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocyclyl is optionally substituted with C1-C6 alkyl, and C1-C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10 It is arbitrarily interrupted by 1 to 5 groups independently selected from arrine, C1 to C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10 A compound described in any one of Clauses 1 to 47, or a pharmaceutically acceptable salt thereof, wherein in each instance, arirene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0614] Clause 52.L 1 but,

[0615] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from the above. In the formula, X 3However, in each instance, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 - Selected independently of R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 However, in each instance, independently selected from H and C1-C6 alkyl, the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1-3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, the heterocycline is optionally substituted with C1-C6 alkyl, and the C1-C3 alkylene is C3-C 10 Cycloalkylene, C4~C 10heterocycle, and C6~C 10 Arrine is arbitrarily interrupted by 1 to 5 groups independently selected, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10 A compound described in any one of Clauses 1 to 47, or a pharmaceutically acceptable salt thereof, wherein in each instance, arirene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl and -S-C1~C6 alkyl are each optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl and -N(C1~C4 alkyl)(C1~C4 alkyl).

[0616] Clause 53.L 1 but,

[0617] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from X 3 However, in each instance, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 This refers to a compound described in any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, which is independently selected from H and C1-C6 alkyl groups in each instance.

[0618] Clause 54.L 1 but,

[0619] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from X 3 However, in each instance, -NR x21 -, -O-, and -NR x22 Selected independently from C(O)-, R x21 and R x22 This refers to a compound described in any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, which is independently selected from H and C1-C6 alkyl groups in each instance.

[0620] Clause 55.L 1 but,

[0621] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from X 3 However, in each instance, a compound described in any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-.

[0622] Clause 56.L 1 but,

[0623] [ka] It comprises 1 to 20 groups, preferably 1 to 5 groups, independently selected from X 3 However, in each instance, a compound described in any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof, is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-.

[0624] Clause 57.L 1 but,

[0625] [ka] And in the formula, X 3 However, in each instance, -NRx21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33 -, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 - Selected independently of R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 However, in each instance, H and C1-C6 alkyl are independently selected, and the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, and the heterocyclyl is optionally substituted with C1-C6 alkyl, and C1-C 20 Alkilen, in each appearance, C3~C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C10 It is arbitrarily interrupted by 1 to 5 groups independently selected from arrine, C1 to C 20 Alkylene, C3~C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10 In each instance, arirene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. A compound according to any one of Clauses 1 to 47, or a pharmaceutically acceptable salt thereof, wherein each C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl alkyl group is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl), and v is 1, 2, 3, 4, or 5.

[0626] Clause 58.L 1 but,

[0627] [ka] And in the formula, X 3 However, in each instance, -NR x21 -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -NR x22 C(O)-, -NR x23 C(S)-, -C(O)NR x24 -, -C(S)NR x25 -, -NR x26 C(O)NR x27 -, -NR x28 C(S)NR x29 -, -NR x30 C(O)O-, -NR x31 C(S)O-, -NR x32 C(O)S-, -OC(O)NR x33-, -OC(S)NR x34 -, -SC(O)NR x35 -, -S(O)2NR x36 -, -NR x37 S(O)2-, or -NR x38 S(O)2NR x39 - Selected independently of R x21 , R x22 , R x23 , R x24 , R x25 , R x26 , R x27 , R x28 , R x29 , R x30 , R x31 , R x32 , R x33 , R x34 , R x35 , R x36 , R x37 , R x38 , and R x39 However, in each instance, independently selected from H and C1-C6 alkyl, the C1-C6 alkyl is optionally substituted in each instance with a 5 or 6-membered heterocycline containing 1-3 heteroatoms independently selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, or N, O, and S, the heterocycline is optionally substituted with C1-C6 alkyl, and the C1-C3 alkylene is C3-C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10 Arrine is arbitrarily interrupted by 1 to 5 groups independently selected, C1-C3 alkylenes, C3-C 10 Cycloalkylene, C4~C 10 heterocycle, and C6~C 10In each instance, arirene is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl. A compound according to any one of Clauses 1 to 47, or a pharmaceutically acceptable salt thereof, wherein each C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl alkyl group is optionally substituted with 1 to 3 groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl), and v is 1, 2, 3, 4, or 5.

[0628] Article 59.L 1 but,

[0629] [ka] X 3 However, in each appearance, the compound is independently selected from -NH-, -NCH3-, -O-, and -NHC(O)-, and v is 1, 2, 3, 4, or 5, as described in any one of Clauses 1 to 47, or a pharmaceutically acceptable salt thereof.

[0630] Clause 57.L 1 but,

[0631] [ka] A compound selected from any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof.

[0632] Clause 61.L 1 but,

[0633] [ka] The compound described in any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof.

[0634] Clause 62.L 1 but,

[0635] [ka] The compound described in any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof.

[0636] Clause 63.X 2 -L 1 but,

[0637] [ka]

[0638] [ka]

[0639] [ka] A compound selected from any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof.

[0640] Clause 64.X 2 -L 1 but,

[0641] [ka] A compound selected from any one of clauses 1 to 31, or a pharmaceutically acceptable salt thereof.

[0642] Article 65. 1However, 4,7-triazacyclononane (TACN); 1,4,7-triazacyclononane-triacetic acid (NOTA); 1,4,7-triazacyclononane-N-succinic acid-N',N''-diacetic acid (NOTASA); 1,4,7-triazacyclononane-N-glutamic acid-N',N''-diacetic acid (NODAGA); 1,4,7-triazacyclononane-N,N',N''-tris(methylenephosphonic acid) (NOTP); 1,4,7,10-tetraazacyclododecane (

[12] aneN4) (cyclene); 1,4,7,10-tetraazacyclotridecane ([ 13]aneN4); 1,4,7,11-Tetraazacyclotetradecane(iso-cyclum); 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 2-(1,4,7,10-Tetraazacyclododecane-1-yl)acetate (DO1A); 2,2'-(1,4,7,10-Tetraazacyclododecane-1,7-diyl)diacetic acid (DO2A); 2,2',2''-(1,4,7,10-Tetraazacyclododecane-1,4,7-triyl)triacetic acid (DO3A); 1,4,7,10-Tetraazacyclododecane-1, 4,7,10-Tetra(methanephosphonic acid) (DOTP); 1,4,7,10-Tetraazacyclododecane-1,7-di(methanephosphate) (DO2P); 1,4,7,10-Tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P); 1,4,7,10-Tetraazacyclo-decane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA); 1,4,7,10-Tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA); 1,4,8,11-Tetraazacyclotetradecane(

[14] aneN4) (Sy Crumb); 1,4,8,12-Tetraazacyclopentadecane(

[15] aneN4); 1,5,9,13-Tetraazacyclohexadecane(

[16] aneN4); 1,4-Ethanol-1,4,8,11-Tetraazacyclotetradecane(et-cyclomb); 1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-Tetratetraacetic acid (TETA); 2-(1,4,8,11-Tetraazacyclotetradecane-1-yl)acetic acid (TE1A); 2,2'-(1,4,8,11-Tetraazacyclotetradecane-1,8-diyl)diacetic acid (TE2A);4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A); 3,6,10,13,16,19-hexazabicyclo[6.6.6]icosane (Sar); 2,2,2,2-(1,4,7,10-tetraazabicyclododecane-1,4,7,10-tetraacetamide (TCMC); 1,4,7,10-tetraazabicyclododecane-7-acetamide-1,4,10-triacetic acid (PSC); N,N'-Bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanine, or porphyrin, as described in any one of clauses 1 to 31, or pharmaceutically acceptable salts thereof.

[0643] Article 66. 1 However, the compound described in any one of the clauses 1 to 64, which is an aminopolycarboxylate chelating agent, or a pharmaceutically acceptable salt thereof.

[0644] Article 67. 1 However, a compound described in any one of clauses 1 to 64, which is a macrocyclic aminopolycarboxylate chelating agent, or a pharmaceutically acceptable salt thereof.

[0645] Article 68. 1 (M 1 )but,

[0646] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , R f , R g , R h , R i , R j , R k , and R nA compound according to any one of clauses 1 to 64, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from -OH and -NH2, and m, n, o, and p are each independently 0, 1, or 2.

[0647] Article 69. 1 (M 1 )but,

[0648] [ka] Selected from, in the formula, R a , R b , R c , R d , R e , and R f A compound described in any one of clauses 1 to 64, or a pharmaceutically acceptable salt thereof, wherein each is independently selected from -OH and -NH2, and m, n, and p are each independently 0, 1, or 2.

[0649] Article 70. 1 (M 1 )but,

[0650] [ka] A compound selected from any one of clauses 1 to 64, or a pharmaceutically acceptable salt thereof.

[0651] Clause 71.M 1 However, no compound described in any one of clauses 1 to 70, or any pharmaceutically acceptable salt thereof, exists.

[0652] Clause 72.M 1 However, a compound that is a radionuclide, as described in any one of clauses 1 to 70, or a pharmaceutically acceptable salt thereof.

[0653] Clause 73.M 1 but, 177 Lu, 212 Pb, or 225Ac, the compound described in Clause 72, or a pharmaceutically acceptable salt thereof.

[0654] Clause 74.M 1 but, 177 A compound described in Article 72 or 73, or a pharmaceutically acceptable salt thereof, which is Lu.

[0655] Clause 75.L 1 -Ch 1 (M 1 )but,

[0656] [ka] Selected from, in the formula, M 1 However, it is a radionuclide, preferably M 1 but, 177 Lu, 212 Pb, or 225 Ac, a compound as described in any one of clauses 1 to 47, or a pharmaceutically acceptable salt thereof.

[0657] Clause 76.X 2 -L 1 -Ch 1 (M 1 )but,

[0658] [ka]

[0659] [ka] Selected from, in the formula, M 1 However, it is a radionuclide, preferably M 1 but, 177 Lu, 212 Pb, or 225 A compound described in any one of clauses 1 to 26, which is Ac, or a pharmaceutically acceptable salt thereof.

[0660] Article 77.

[0661] [ka]

[0662] [ka] A compound as described in Clause 1, or a pharmaceutically acceptable salt thereof, selected from or a pharmaceutically acceptable salt thereof.

[0663] Article 78.

[0664] [ka]

[0665] [ka]

[0666] [ka] The compounds described in Clause 1, or their pharmaceutically acceptable salts.

[0667] Article 79.

[0668] [ka]

[0669] [ka]

[0670] [ka]

[0671] [ka]

[0672] [ka]

[0673] [ka]

[0674] [ka] A compound selected from the compounds described in Clause 1.

[0675] Clause 80.M 1 but, 177 Lu, 212 Pb, or 225 A compound described in clauses 77-79, or a pharmaceutically acceptable salt thereof, which is Ac.

[0676] Clause 81.M 1 but, 177 A compound described in Clause 80, or a pharmaceutically acceptable salt thereof, which is Lu.

[0677] Article 82. A pharmaceutical composition comprising a compound described in any one of Articles 1 to 781, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0678] Article 83. A method for treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective dose of any one of Articles 1 to 81, or a pharmaceutically acceptable salt thereof.

[0679] Clause 84. The method according to Clause 83, wherein the cancer has one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1).

[0680] Clause 85. The method according to Clause 83 or 84, wherein the cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0681] Clause 86. A compound described in any one of Clauses 1 to 81, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0682] Clause 87. A compound described in any one of Clauses 1 to 81, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0683] Clause 88. The compound for use described in Clause 82 or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1).

[0684] Clause 89. The compound for use described in Clause 87 or 88 or a pharmaceutically acceptable salt thereof, for use in which cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0685] Clause 90. Use of any compound described in Clauses 1 to 81, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicine for the treatment of cancer.

[0686] Clause 91. Use as described in Clause 90, wherein the cancer has one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1).

[0687] Clause 92. Use as described in Clause 90 or 91, where the cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

[0688] Clause 93. Cancer is breast cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 85-87.

[0689] Clause 94. The cancer is colorectal cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0690] Clause 95. The cancer is endometrial cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0691] Clause 96. Cancer is gastric cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0692] Clause 97. Cancer is lung cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0693] Clause 98. The cancer is pancreatic cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0694] Clause 99. Cancer is prostate cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0695] Clause 9100. The cancer is head and neck cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0696] Clause 101. The method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92, wherein the cancer is non-small cell lung cancer (NSCLC).

[0697] Clause 102. If the cancer is pleural mesothelioma, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0698] Clause 103. The method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92, wherein the cancer is head and neck squamous cell carcinoma (HNSCC).

[0699] Clause 104. If the cancer is a glioma, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0700] Clause 105. The cancer is glioblastoma multiforme (GBM), the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0701] Clause 106. If the cancer is a meningioma, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0702] Clause 107. If the cancer is Ewing's sarcoma, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0703] Clause 108. If the cancer is a gastrointestinal stromal tumor, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0704] Clause 109. If the cancer is a uterine leiomyoma, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0705] Clause 110. If the cancer is cutaneous T-cell lymphoma, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0706] Clause 111. If the cancer is small cell lung cancer, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0707] Clause 112. If the cancer is pancreatic ductal adenocarcinoma, the method described in any one of Clauses 83-85, the compound for use described in any one of Clauses 87-89, or the use described in any one of Clauses 90-92.

[0708] definition The term "albumin-binding group" refers to a group that can bind to albumin by covalent or non-covalent bonds. Albumin-binding groups may include, or consist of, groups selected from fatty acids, phthalocyanines, coumarins, flavonoids, tetracyclines, naphthalenes, arylcarboxylic acids, heteroarylcarboxylic acids, lipids, alkylamines, cyclic or linear tetrapyrroles and their organometallic compounds, halo-substituted aromatic acid derivatives, organic dyes, and derivatives of tryptophan and thyroxine. Certain exemplary albumin-binding groups include:

[0709] [ka] These are some examples.

[0710] The term "alkenyl" refers to a monovalent hydrocarbon group, either straight-chain or branched, that contains at least one double bond in its chain. The double bond of an alkenyl group may or may not be conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl.

[0711] The term "alkenylene" refers to a straight-chain or branched-chain divalent hydrocarbon group that contains at least one double bond in its chain.

[0712] The term "alkyl" refers to a monovalent hydrocarbon group, preferably a linear or branched chain, comprising 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Examples of C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

[0713] The term "alkylene" refers to a saturated, straight-chain or branched-chain divalent hydrocarbon group.

[0714] The term "alkynyl" refers to a monovalent hydrocarbon group in a straight or branched chain that contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl.

[0715] The term "alkynylene" refers to a straight-chain or branched-chain divalent hydrocarbon group that contains at least one triple bond in its chain.

[0716] The term "amino" refers to -NH2.

[0717] The term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl, unless otherwise defined. If it contains two aromatic rings (such as two rings), the aromatic rings of the aryl group may be bonded at one point (e.g., biphenyl) or condensed (e.g., naphthyl). Furthermore, if it contains two condensed rings, the aryl group as defined herein may have one or more saturated or partially unsaturated rings condensed with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenantrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannerenyl.

[0718] The term "arylene" refers to a divalent aryl group.

[0719] As used herein, the terms “cancer” and “malignant” refer to or describe a physiological condition in a patient typically characterized by uncontrolled cell proliferation. This definition includes both benign and malignant cancers.

[0720] The term "chelating agent" refers to a group that can form a complex with a radionuclide. A chelating agent can form a complex with a radionuclide via one or more functional groups (e.g., carbonyl, carboxylic acid, amino, or amide groups) or atoms (e.g., nitrogen or oxygen atoms). It should be understood that, if present, one or more carboxylic acid groups of the chelating agent may exist as carboxylate anions, and one or more carboxylate anions may coordinate to the radionuclide. Chelating agents can be fully ionized, partially ionized, or non-ionized. A chelating agent complexed with a radionuclide may be illustrated in other ways, for example, 177 DOTA-based chelating agents that form complexes with Lu(3+) are as follows:

[0721] [ka] It may be shown as follows.

[0722] The term "cycloalkyl" refers to a monocyclic or polycyclic saturated carbon ring containing 3 to 18 carbon atoms, preferably 3 to 10 carbon atoms, unless otherwise defined. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, bicyclo[2.2.2]octanyl, and adamantyl.

[0723] The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0724] When used in relation to a compound, the term "diagnostic effective dose" refers to the amount or dose of the compound that produces the desired diagnostic effect through a single or multiple dose administration to a patient. The diagnostic effective dose can be determined by those skilled in the art using known techniques.

[0725] The terms "halogen" or "halo" refer to fluorine, chlorine, bromine, or iodine.

[0726] The term "heteroaryl" refers, unless otherwise defined, to a monovalent monocyclic or polycyclic aromatic group containing 5 to 24 ring atoms, preferably 5 to 10 ring atoms, which include one or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being carbon atoms. Examples of heteroaromatic groups include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, and imidazo[1,2-b]pyrazo Ryl, flo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuranyl, chromani Lu, Thiochromanil, Tetrahydroquinolinil, Dihydrobenzothiadinil, Quinolinil, Isoquinolinil, 1,6-Naphthilidinil, Benzo[de]isoquinolinil, Pyrido[4,3-b][1,6]naphthilidinil, Thieno[2,3-b]pyradinil, Quinazolinil, Tetrazolo[1,5-a]pyridinil, [1,2,4]triazolo[4,3-a]pyridinil, Isoindolyl, Pyrrolo[2,3-b]pyridinil, Pyrrolo[3,4-b]pyridinil, Pyrro Ro[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyridinyl, flo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzoisoxazolyl, flo[2,[3-b]pyridinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazo Examples include 1,3-dihydro-2H-benzo[d]imidazole-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrolyl, and 3H-indolyl. Furthermore, when containing two or more fused rings, the heteroaryl group as defined herein may have one or more saturated or partially unsaturated rings fused with one or more fully unsaturated aromatic rings. In heteroaryl ring systems containing three or more fused rings, the saturated or partially unsaturated rings may be further fused with the saturated or partially unsaturated rings described herein. Furthermore, when containing three or more fused rings, the heteroaryl group as defined herein may have one or more spirocondensed saturated or partially unsaturated rings. The saturated or partially unsaturated rings described herein may also be optionally substituted with one or more oxos. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, oxyindolyl, indolyl, and 1,6-dihydro-7H-pyrazolo[3,4-c]pyridine-7 -Onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, pyrazolo[1,5-a]pyrimidine-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indole-1(2H)-onyl, benzo[c][1,2]Oxabolol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine-9-onyl, and 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-9'-onyl are included.

[0727] The term "heteroarylene" refers to a divalent heteroaryl group.

[0728] The terms “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” refer to monocyclic or polycyclic rings containing 3 to 24 atoms, preferably 3 to 10 atoms, including carbon, and one or more heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, unless otherwise defined. As used herein, “heterocyclic” can be aromatic or non-aromatic. Thus, the term encompasses heteroaryl rings, which are aromatic heterocyclic rings and heteroaryl rings that are typically 5 to 10-membered monocyclic or fused bicyclic ring systems as defined for “heteroaryl,” as well as saturated or partially unsaturated heterocyclic rings (sometimes called heterocycloalkyl or heterocycloalkenyl, and generally including 4 to 10-membered rings). Any of these heterocyclic rings may be fused, bridged, or spirocyclic, as defined herein. Unless otherwise specified, heterocycles are optionally substituted with 1 to 3 substituents independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, cyano, nitro, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, C1-C6 haloalkoxy, or C1-C6 dialkylamino. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranil, tetrahydropyranil, pyrrolidinyl, oxazolidinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranil, tetrahydropyranil, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinyl, and homotropanyl. Unless otherwise specified, "heterocyclyl" includes a ring that is saturated or partially unsaturated and may have one or more ring "oxo" substituents. For example, a carbonyl group may be incorporated into the ring to form, for example, a lactam, lactone, imide, cyclic urea, cyclic carbamate, or cyclic carbonate functional group, provided that the ring system is non-aromatic.Examples include, but are not limited to, pyrrolidine-2-on-yl (2-oxopyrrolidineyl), piperidine-2-on-yl, morpholine-3-on-yl, 1,3-oxazinane-2-on-yl, imidazolidinone-yl, oxazolidinone-yl, thiazolidinone-yl, succinimidyl, and 1,3-dioxolan-2-on-yl.

[0729] The term "heterocycloalkenyl" refers to a non-aromatic monocyclic or polycyclic monovalent group containing 3 to 24 ring atoms (preferably 3 to 10), where one or more ring atoms are heteroatoms selected from N, O, S, P, or B (preferably N, O, or S), and the ring system contains at least one intra-ring carbon-carbon double bond. Unless otherwise specified, the heterocycloalkenyl group may be condensed, bridged, or spirocyclic as defined herein, and may be bonded via ring carbons or ring heteroatoms, and may contain oxidized heteroatoms (e.g., N-oxide, S-oxide, S,S-dioxide) and / or ring "oxo" substituents (e.g., lactam). Non-limiting examples include 2,3-dihydrofuranyl, 3,4-dihydropyranyl, 2,3-dihydro-1,4-dioxynyl, 1,2-dihydropyridinyl, 3,4-dihydropyradinyl, and 2,3-dihydro-1,3-oxazinyl.

[0730] The term "heterocycloalkylene" refers to a divalent non-aromatic heterocyclyl group. Unless otherwise specified, the bond may be formed via a ring carbon or ring heteroatom, and the ring may be condensed, bridged, or spirocyclic, and may contain an oxidized heteroatom or ring "oxo" substituent.

[0731] The term "condensation" (or "condensed ring system") refers to two rings that share two adjacent atoms and a bond between them (a common end). A condensed ring may be carbocyclic or heterocyclic, and may be aromatic, partially unsaturated, or saturated. Descriptors may be modified with aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl groups.

[0732] The term “bridged” (or “bridged bicyclic / tricyclic ring system”) refers to a polycyclic system having two bridgehead atoms connected by one or more bridges, such that the rings share a bridgehead but do not share a single common edge. Such systems are generally described by von Baeyer notation (e.g., bicyclo[abc]). Non-restrictive examples include norbornyl (bicyclo[2.2.1]heptanyl), bicyclo[2.2.2]octanyl, quinuclidinyl, and adamantyl (including heteroatom-containing analogs). Descriptors may be modified by aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl groups.

[0733] The term “spiro ring” (or “spiro”) refers to a polycyclic system in which two rings share exactly one common atom (a spiro atom), which may be carbon or a heteroatom. The rings do not share any other atoms or edges. The descriptor may be modified by an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or heterocycloalkenyl group.

[0734] Ring size conventions for condensed / bridging / spiro systems. Unless otherwise specified, when ring size is given for condensed, bridging, spiro, or other polycyclic systems, the descriptor refers to the ring containing the bond to the rest of the molecule. In spiro systems, the spiro-bonded atoms are counted in each ring size. In bridging systems, ring size is assigned using the smallest set of intrinsic rings, following standard nomenclature conventions (including von Baeyer notation).

[0735] When used in relation to compounds, the term "imaging effective dose" refers to the amount or dose of a compound that produces the desired imaging effect through a single or multiple dose administration to a patient. The imaging effective dose can be determined by those skilled in the art using known techniques. Known imaging techniques include positron emission tomography (POST), single-photon emission computed tomography (SMTR), and radioisotope tomography.

[0736] The term "isomer" refers to compounds that have the same molecular formula but differ in the nature or order of the bonding of their atoms, or in the spatial arrangement of their atoms. Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if the compound is bonded to four different groups, then pairs of enantiomers are possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by the Cahn and Prelog R and S sequence rules, or by the rotation of the plane of polarization of the molecule, and by designation as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist either as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0737] The term "linker" refers to a molecular structure that connects two or more other molecular structures together. In exemplary embodiments, the linker is one or more groups independently selected from amines, ethers, thioethers, carbonyls, thiocarbonyls, sulfones, sulfoxides, ureas, thioureas, and amides (e.g., 1 to 20 groups, 1 to 10 groups, 1 to 5 groups, or 1 to 3 groups); and C1 to C 20 Alkylene, C2~C 20 Alkenylenes, and C2~C 20 It comprises one or more groups independently selected from alkynylene (e.g., 1 to 20 groups, 1 to 10 groups, 1 to 5 groups, or 1 to 3 groups), any of which are amines, ethers, thioethers, carbonyls, thiocarbonyls, sulfones, sulfoxides, ureas, thioureas, amides, C3-C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10It is arbitrarily interrupted by one or more groups independently selected from the heteroarylene (e.g., 1 to 20 groups, 1 to 10 groups, 1 to 5 groups, or 1 to 3 groups), and one or more C1-C 20 Alkylene, C2~C 20 Alkenylene, C2~C 20 Alkynylene, C3~C 10 Cycloalkylene, C4~C 10 Heterocycloalkylene, C6~C 10 Arylene, and C5~C 10 In each instance, the heteroarylene is optionally substituted with one or more groups independently selected from halo, -CO2H, -OH, -SH, -NH2, -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl, and the alkyl groups of -NHC1~C4 alkyl, -N(C1~C4 alkyl)(C1~C4 alkyl), C1~C6 alkyl, -O-C1~C6 alkyl, and -S-C1~C6 alkyl are optionally substituted with one or more groups independently selected from halo, -CO2H, -OH, -NH2, -NHC1~C4 alkyl, and -N(C1~C4 alkyl)(C1~C4 alkyl) in each instance. In certain embodiments, the linker includes one or more albumin-binding groups. In certain embodiments, the linker contains one albumin-binding group. In certain embodiments, the linker contains zero albumin-binding groups.

[0738] The term "5-membered heteroaryl" means, unless otherwise defined, a monovalent monocyclic aromatic group of five ring atoms comprising one or more ring heteroatoms selected from N, O, S, P, or B, preferably 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being carbon atoms. Examples of 5-membered heteroaryl groups include, but are not limited to, furyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazole, triazolyl, and tetrazolyl.

[0739] The term "6-membered heteroaryl", unless otherwise defined, means a monovalent monocyclic aromatic group of 6 ring atoms containing one or more ring heteroatoms selected from N, O, S, P or B, preferably 1, 2, 3 or 4 ring heteroatoms selected from N, O or S, with the remaining ring atoms being carbon atoms. Exemplary 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

[0740] The term "optionally substituted" refers to a group that is unsubstituted or substituted with one or more of the referenced substituents.

[0741] The term "patient" or "subject" refers to a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or macaque. Preferably, the mammal is a human.

[0742] The term "therapeutically effective amount" when used in connection with a compound refers to the amount or dosage of the compound that, upon single or multiple dosing to a patient, produces the desired effect in the patient being treated. A therapeutically effective amount can be determined by one of ordinary skill in the art using known techniques. In determining the therapeutically effective amount for a patient, several factors can be considered, including, but not limited to, the species of the patient; its size, age, and general health; the particular disease or disorder involved; the degree or involvement or severity of the disease or disorder; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dosage regimen selected; the use of concomitant medications; and other related circumstances.

[0743] The term "treating" with respect to a subject includes suppressing, slowing down, halting, or reversing the progression or severity of an existing symptom or disorder.

Examples

[0744] Certain abbreviations are defined as follows: "AcOH" refers to acetic acid, "ACN" refers to acetonitrile, "aq." refers to aqueous, "B2pin2" refers to bis(pinacolate)diborone, "Boc2O" refers to di-tert-butyldecarbonate, "Burgess reagent" refers to methyl N-[(triethylazaniumyl)sulfonyl]carbamate oxidani, "BuLi" refers to butyllithium, and "CDMT" refers to 2-chloro "L-4,6-dimethoxy-1,3,5-triazine" refers to carbon monoxide, "CO" refers to carbon monoxide, "Cs2CO3" refers to cesium carbonate, "CuI" refers to copper iodide, "CuSO4" refers to copper sulfate, "DBU" refers to 1,8-diazabicyclo[5.4.0]undeca-7-ene, "DCC" refers to N,N'-dicyclohexylcarbodiimide, "DCM" refers to dichloromethane, and "DIAD" refers to diisopropyl azodicarboxylate. "Azodicarboxylate" refers to 1,N-diisopropylethylamine, "DMAP" refers to 4-dimethylaminopyridine, "DMF" refers to dimethylformamide, "DMP" refers to des-martin periodinane, "DMSO" refers to dimethyl sulfoxide, "EA" refers to ethyl acetate, "EDCI" refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, "Et3N" refers to triethylamine, "Et2O" refers to diethyl ether, "EtOH" refers to ethyl alcohol, "siRNA" refers to ethyl acetate, "FA" refers to formic acid, "h" refers to time, and "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] refers to pyridinium 3-oxide hexafluorophosphate, where "HCl" refers to hydrochloric acid, "H2O" refers to water, "Hep" refers to heptane, "Hex" refers to hexane, "HOAc" refers to acetic acid, "HOBT" refers to hydroxybenzotriazole, "HOSu" refers to N-hydroxysuccinimide, "iPrOH" refers to isopropyl alcohol, "KOAc" refers to potassium acetate, "K2CO3" refers to potassium carbonate, and "KOH" refers to potassium hydroxide. "Lawson's Reagent" " is 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane, "LiOH" is lithium hydroxide, "Me" is methyl, "MeCN" is acetonitrile, "MeOH" is methanol, "MeI" is methyl iodide, "min" is minute, "N2H4" is hydrazine, "NaI" is sodium iodide, "NMM" is N-methylmorpholine, and "NaOAc" is sodium acetate. "NaBH(OAc)3" refers to sodium triacetoxyborohydride, "N2" refers to nitrogen, "NaNO2" refers to sodium nitrite, "Na2SO4" refers to sodium sulfate, "NH3" refers to ammonia, "NH4OAc" refers to ammonium acetate, "ON" refers to overnight, "PCl3" refers to phosphorus trichloride, "PyBOP" refers to benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, and "Pd / C" refers to palladium on carbon "Pd(OAc)2" refers to palladium(II) acetate, "PdCl2(PPh3)2" refers to bis(triphenylphosphine)palladium(II) dichloride, "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium(O), "Pd(dppf)Cl2" refers to (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride, and "Pd(dppf)Cl2·DCM" refers to the (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride complex with dichloromethane. "Pd(OH)2 / C" refers to palladium hydroxide on carbon, "PE" refers to petroleum ether, "PPh3" refers to triphenylphosphine, "PtO2" refers to platinum(IV) oxide, "sat" refers to saturation, "RT" refers to room temperature, "pTsOH" refers to p-toluenesulfonic acid, "STAB" refers to sodium triacetoxyborohydride, "SnCl2" refers to tin(II) chloride, "soln" refers to solution, "t-BuBrettPhos Pd G3" refers to [(2-di-tert-butylphosphino-3,6-dimethoxy-2’,4’,6’-triisopropyl-1,1’-biphenyl)-2-(2’-amino-1,1’-biphenyl)]palladium(II) methanesulfonate Generation 3, "TBTU" refers to O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate, "TCFH" refers to chloro-N,N,N’,N’-tetramethylformamidinium hexafluorophosphate, "TEA" refers to triethylamine, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "TMS" refers to chlorotrimethylsilane, "T3P" refers to propylphosphonic anhydride, "TIPS" refers to triisopropylsilane, "tol" refers to toluene, "XPhos" refers to 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl, and "wt" refers to weight.

[0745] Preparation 1 tert-butyl (3-((3-azidopropyl)(methyl)amino)propyl)(methyl)carbamate

[0746] [Chemical Structure] A solution of 3-azido-N-methylpropan-1-amine (200 mg, 1.75 mmol) and methyl-(3-oxo-propyl)-carbamate tert-butyl ester (361 mg, 1.93 mmol) in DCM (10 mL) was treated with STAB (557 mg, 2.63 mmol) and acetic acid (121 μL, 2.10 mmol). After stirring at room temperature for 1 hour, the mixture was diluted with DCM (10 mL), washed with saturated NaHCO3 (10 mL), extracted with DCM (3 × 15 ml), dried over Na2SO4, filtered, and concentrated to obtain the title compound (432 mg, 86%). MS ES+ m / z 286[M+H] + .

[0747] The following compounds were prepared in a manner essentially similar to that of tert-butyl(3-((3-azidopropyl)(methyl)amino)propyl)(methyl)carbamate, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0748] [Table 1]

[0749] Preparation 81 2-(3-(3-azidopropoxy)propyl)isoindorin-1,3-dione

[0750] [ka] A solution of 3-azido-1-propanol (0.183 mL, 1.98 mmol) in THF (8 mL) was treated with NaH (119 mg, 60 wt%, 2.97 mmol) at 0°C. After 20 minutes, the mixture was treated with 1-phthalimide-3-bromopropane (530 mg, 1.98 mmol) at 0°C. After stirring for 1 hour while warming to room temperature, the mixture was cooled to 0°C and treated with NH4Cl aqueous solution (5 mL). The mixture was basicized to pH 8-9 using a saturated aqueous solution of Na2CO3. The mixture was extracted with Â(Triple) (3 times). The combined organic layers were dried over Na2SO4, concentrated, and purified by silica gel column chromatography Â(Triple) (0-100%) to obtain the title compound (434 mg, 76.1%) as a white solid. MS ES+ m / z 311[M+Na] + .

[0751] The following compounds were prepared in a manner essentially similar to that of the preparation of 2-(3-(3-azidopropoxy)propyl)isoindoline-1,3-dione, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0752] [Table 2]

[0753] Preparation 2 Ethyl 4-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)(methyl)amino)butanoate

[0754] [ka] A solution of ethyl 4-(methylamino)butanoate hydrochloride (3.96 g, 21.812 mmol) and DIEA (15.38 mg, 0.120 mmol) in MeCN (100 mL) was treated with tert-butyl N-(3-bromopropyl)-N-methylcarbamate (5 g, 19.829 mmol) added portionwise at room temperature. After stirring at 80 °C for 16 h, the mixture was concentrated and purified by reverse phase flash chromatography (column, C18; mobile phase, 10 - 40% ACN in H2O (10 mmol / L NH4HCO3)) under the following conditions to give the title compound (1.7 g, 47.81%) as a white liquid. MS ES+ m / z 317 [M+H] + .

[0755] The following compounds were prepared in an essentially similar manner to the preparation method of ethyl 4-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)(methyl)amino)butanoate using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and adjusting the purification system as necessary.

[0756]

Table 3

[0757] Preparation 4 4-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)(methyl)amino)butanoic acid

[0758]

Chemical formula

[0759] Preparation 82 tert-butyl(3-((3-(dimethylamino)propyl)amino)propyl)(methyl)carbamate

[0760] [ka] A solution of N1,N1-dimethylpropane-1,3-diamine (10.0 g, 97.7 mmol) and tert-butyl N-methyl-N-(3-oxopropyl)carbamate (13.5 g, 72.1 mmol) in EtOH (100 mL) was treated by adding NaBH4 (7.4 g, 195.7 mmol) in several portions over 2 minutes at 0°C under N2. After stirring at room temperature for 16 hours, the mixture was cooled to 0°C, treated with ice water, concentrated, and purified by silica gel column chromatography DCM / MeOH (1:99) to obtain the title compound (10 g, 37.4%) as a yellow solid. MS ES+ m / z 274[M+H] + .

[0761] The following compounds were prepared in a manner essentially similar to that of tert-butyl(3-((3-(dimethylaminopropyl)amino)propyl)(methyl)carbamate, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0762] [Table 4]

[0763] Preparation 84 Benzyl 4-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)butanoate

[0764] [ka] A solution of benzyl 4-oxobutanoate (9 g, 46.8 mmol) in DCE (100 mL) was treated with tert-butyl N-[3-(methylamino)propyl]carbamate (9.70 g, 51.5 mmol). After stirring at room temperature under N2 for 1 hour, the resulting mixture was treated with STAB (19.85 g, 93.65 mmol). After stirring at room temperature under N2 for 1 hour, the resulting mixture was treated with ice water (10 mL) at 0°C. The resulting mixture was diluted with water (500 mL) and extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (2 × 200 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography DCM / MeOH (10:1) to obtain the title compound (8 g, 46.8%) as a white solid. MS ES+ m / z 365[M+H] + .

[0765] The following compounds were prepared in a manner essentially similar to the method for preparing benzyl 4-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)butanoate, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0766] [Table 5]

[0767] Preparation 88 N 1 ,N 1 -dimethyl-N 3 -(pyridine-2-ylmethyl)propane-1,3-diamine

[0768] [ka] A solution of (3-aminopropyl)dimethylamine (307 μL, 2.45 mmol) and pyridine-2-carboaldehyde (279 μL, 2.94 mmol) in DCM (10 mL) was treated with STAB (778 mg, 3.67 mmol) and AcOH (154 μL, 2.69 mmol). After stirring at room temperature for 6 hours, the reaction mixture was concentrated and purified by reverse-phase flash chromatography (column, C18; mobile phase, 0-50% DCM in MeOH) under the following conditions to obtain the title compound (218 mg, 46.1%) as a yellow solid. MS ES+ m / z 194[M+H] + .

[0769] Preparation 5 4-(methyl(3-(methylamino)propyl)amino)butanoic acid

[0770] [ka] A solution (20 mL) of 4-({3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(methyl)amino)butanoic acid (4 g, 13.870 mmol) and HCl in 1,4-dioxane (4.0 M) was stirred at room temperature for 6 hours, then concentrated to obtain the crude title compound (6 g, >100%). MS ES+ m / z 189[M+H] + .

[0771] The following compounds were prepared in a manner essentially similar to that of the preparation of 4-(methyl(3-(methylamino)propyl)amino)butanoic acid, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0772] [Table 6]

[0773] Preparation 90 Benzyl (3-((3-aminopropyl)(methyl)amino)propyl)carbamate

[0774] [ka] A solution of benzyl N-[3-({3-[(tert-butoxycarbonyl)amino]propyl}(methyl)amino)propyl]carbamate (12 g, 31.62 mmol) in DCM (120 mL) was treated with the addition of TFA (30 mL) dropwise. After stirring overnight under N2 at room temperature, the mixture was concentrated to obtain the crude compound (12 g) indicated in the title. MS ES+ m / z 280[M+H] + .

[0775] The following compounds were prepared in a manner essentially similar to that of the preparation of benzyl(3-((3-aminopropyl)(methyl)amino)propyl)carbamate, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0776] [Table 7]

[0777] Preparation 93 (5r,7r)-2-(1-benzyl-1H-tetrazole-5-yl)adamantan-2-amine

[0778] [ka] A solution of adamantanone (300 mg, 1.997 mmol) and NH4Cl (160 mg, 2.996 mmol) in MeOH (3 mL) and H2O (1 mL) was treated with (isocyanomethyl)benzene (234 mg, 1.997 mmol) and NaN3 (195 mg, 2.996 mmol) at room temperature under N2. After stirring overnight, the mixture was filtered, and the filter cake was washed with H2O (3 × 5 mL). The combined filtrate was concentrated under reduced pressure to obtain the crude title compound 2-(1-benzyl-1,2,3,4-tetrazole-5-yl)adamantan-2-amine (590 mg, 95.4%) as a white solid. MS ES+ m / z 310[M+H]+ .

[0779] Preparation 94 3-(3-iodo-1H-indazole-1-yl)-N,N-dimethylpropane-1-amine

[0780] [ka] A solution of 3-iodo-1H-indazole (200 mg, 0.820 mmol) in DMF (4 mL) was treated with potassium tert-butoxide (138 mg, 1.23 mmol). After stirring at room temperature for 30 minutes, the mixture was treated with a solution of 3-chloro-N,N-dimethylpropan-1-amine (120 mg, 0.983 mmol) in DMF (1 mL). After stirring at room temperature for 23 hours, the reaction product was filtered and directly purified by reverse-phase flash chromatography (column, C18; mobile phase, 30%-50% ACN in MeOH (5% 10 mM NH4HCO3)) under the following conditions to obtain the title compound (98 mg, 36%) as a white solid. MS ES+ m / z 330[M+H] + .

[0781] Preparation 95 2-(2-((2-hydroxyethyl)(methyl)amino)ethyl)isoindoline-1,3-dione

[0782] [ka] A solution of 2-[(2-aminoethyl)methylamino]ethanol (400.0 mg, 3.385 mmol) in 2-methyltetrahydrofuran (3 mL) was treated at room temperature with phthalic anhydride (360 μL, 3.723 mmol) and TEA (1.41 mL, 10.15 mmol). After stirring at 85°C for 3 hours, the mixture was concentrated. The residue was diluted with saturated Na2CO3 aqueous solution (5 mL), extracted with RINKAN (2 × 10 mL), dried over anhydrous Na2SO4, and concentrated to obtain the crude title compound (570 mg, 67.8%) as a pale yellow solid. MS ES+ m / z 249[M+H] + .

[0783] Preparation 96 3-Bromo-N-(3-(dimethylamino)propyl)-N-methylquinoline-7-carboxamide

[0784] [ka] A solution of 3-bromoquinoline-7-carboxylic acid (100 mg, 0.397 mmol) in DCM (2 mL) was treated with DIPEA (0.276 mL, 1.59 mmol) and HATU (151 mg, 0.397 mmol). After stirring at room temperature for 3 hours, the mixture was treated with N,N,N'-trimethyl-1,3-propanediamine (0.116 mL, 0.793 mmol). After stirring at room temperature for 1 hour, the reaction mixture was dried under N2 and dissolved in DMSO (2 mL). The mixture was purified by reverse-phase flash chromatography (column, C18; mobile phase, 10-100% ACN in MeOH (10 mM NH4HCO3)) under the following conditions to obtain the title compound (113 mg, 81.3%) as a colorless oil. MS ES+ m / z 350 / 352[M+H] + ( 79 Br / 81 Br).

[0785] The following compounds were prepared in a manner essentially similar to that of the preparation of 3-bromo-N-(3-(dimethylamino)propyl)-N-methylquinoline-7-carboxamide, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0786] [Table 8]

[0787] Preparation 102 N-(4-(benzyloxy)phenyl)-4-(dimethylamino)butanamide

[0788] [ka] A solution of 4-(dimethylamino)butanoate (3 g, 17.897 mmol) in ACN (50 mL) was treated with TCFH (7.53 g, 26.845 mmol) and 1-methyl-1H-imidazole (2.94 g, 35.794 mmol). After stirring at room temperature under N2 for 30 minutes, the mixture was treated with 4-(benzyloxy)aniline (4.28 g, 21.476 mmol). After stirring at room temperature for 2 hours, the mixture was diluted with H2O (100 mL) and extracted with SiO2 (3 × 150 mL). The combined organic layers were washed with brine (3 × 200 mL), dried over Na₂SO₄, filtered, concentrated, and purified by reverse-phase flash chromatography (column: C18; mobile phase: 50–70% ACN in H₂O (0.1% FA)) under the following conditions to obtain the title compound (3.5 g, 62.6%) as a yellow solid: MS ES+ m / z 313[M+H] + .

[0789] The following compounds were prepared in a manner essentially similar to that of the preparation of N-(4-(benzyloxy)phenyl)-4-(dimethylamino)butanamide, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0790] [Table 9]

[0791] Preparation 104 4-((4-(4-iodophenyl)butanamide)methyl)benzoic acid

[0792] [ka] A solution of tert-butyl 4-{[4-(4-iodophenyl)butanamide]methyl}benzoate (33 g, 68.842 mmol) in DCM (300 mL) was treated with HCl (4.0 M) (86 mL, 344.210 mmol) in 1,4-dioxane in several portions under N2 conditions at room temperature. After stirring at 50°C for 4 hours, the mixture was concentrated to obtain the crude title compound (30 g) as a white solid. MS ES+ m / z 424[M+H] + .

[0793] Preparation 105 tert-butyl N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-(4-((4-(4-iodophenyl)butanamide)methyl)benzoyl)-L-lysinate

[0794] [ka] A solution of 4-{[4-(4-iodophenyl)butanamide]methyl}benzoic acid (30 g, 70.880 mol) and NMM (21.51 g, 212.640 mmol) in DMF (300 mL) was treated by adding CDMT (14.93 g, 85.056 mmol) in several batches at room temperature under N2 conditions. After stirring for 30 minutes, the mixture was treated with tert-butyl(2S)-2-amino-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}hexanoate (36.11 g, 85.056 mmol). After stirring for 4 hours, the mixture was diluted with ELISA (500 mL). The combined organic layers were washed with brine (3 × 300 mL), dried over Na₂SO₄, filtered, concentrated, and purified by reverse-phase flash chromatography (column: C₁₄; mobile phase: 50–70% ACN in H₂O (0.1% FA)) under the following conditions to obtain the title compound (60 g) as a pale yellow solid: MS ES+ m / z 830[M+H] + .

[0795] Preparation 106 N6-(((9H-fluoren-9-yl)methoxy)carbonyl)-N2-(4-((4-(4-iodophenyl)butanamide)methyl)benzoyl)-L-lysine

[0796] [ka] A solution of tert-butyl(2S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2-[(4-{[4-(4-iodophenyl)butanamide]methyl}phenyl)formamide]hexanoate (20 g, 24.103 mmol) in DCM (200 mL) was treated with HCl (4.0 M) (12 mL, 48.206 mmol) in 1,4-dioxane at room temperature under N2 conditions. After stirring overnight, the mixture was concentrated to obtain the crude title compound (18 g, 96.0%) as a yellow solid. MS ES+ m / z 774[M+H] + .

[0797] Preparation 107 tert-butylrac-4-(6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)hexanoate)

[0798] [ka] A solution of (2S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2-[(4-{[4-(4-iodophenyl)butanamide]methyl}phenyl)formamide]hexanoic acid (16 g, 20.681 mmol) in ACN (200 mL) was treated with 1-methyl-1H-imidazole (5.09 g, 62.043 mmol) and TCFH (8.70 g, 31.022 mmol) at room temperature under N2. After stirring for 30 minutes, the mixture was treated with tert-butyl 4-aminobutanoate (4.94 g, 31.022 mmol). After stirring at 50°C for 16 hours, the mixture was diluted with H2O (500 mL) and extracted with siRNA (3 × 300 mL). The combined organic layers were washed with brine (1 × 100 mL), dried over Na₂SO₄, filtered, concentrated, and purified by reverse-phase flash chromatography (column: C₁₄; mobile phase: 50–70% ACN in H₂O (0.1% FA)) under the following conditions to obtain the title compound (9.6 g, 50.7%) as a white solid: MS ES+ m / z 915[M+H] + .

[0799] Preparation 108 rac-4-(6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)hexanamide)butanoic acid

[0800] [ka] A solution of tert-butylrac-4-(6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)hexanoamide)butanoate (9.6 g, 8.744 mmol) in DCM (50 mL) was treated with HCl (4.0 M) (10 mL, 0.002 mmol) in 1,4-dioxane. After stirring overnight at room temperature, the mixture was concentrated to obtain the crude title compound (8 g, 83.3%) as a yellow solid. MS ES+ m / z 859[M+H] + .

[0801] Preparation 109 (S)-4-(6-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)hexanamide)butanoic acid

[0802] [ka] Rac-4-(6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)hexanamide)butanoic acid (8g) was processed under the following conditions: Prep-SFC (column, CHIRALPAK IE OBD 3 * The sample was purified by 40% DCM / THF (1:1) in EtOH / THF (1:1) mobile phase at 25 cm, 5 μm. The second elution peak fraction was concentrated and purified by reverse-phase flash chromatography (column: C18; mobile phase: 50-70% ACN (0.1% FA) in H2O) under the following conditions to obtain the title compound (2.008 g, 26.6%) as a yellow solid. MS ES+ m / z 859[M+H] + .

[0803] Preparation 110 3-((3-(dimethylamino)propyl)amino)propanenitrile

[0804] [ka] A solution of N1,N1-dimethylpropane-1,3-diamine (6.3 g, 44.039 mmol) in MeOH (40 mL) was treated with acrylonitrile (3.20 mL, 48.443 mmol) at 0°C. After stirring at 0°C for 2 hours, the mixture was concentrated to obtain the crude title compound (7 g, 73.11%) as a colorless liquid. MS ES+ m / z 156[M+H] + .

[0805] Preparation 111 tert-butyl(2-cyanoethyl)(3-(dimethylamino)propyl)carbamate

[0806] [ka] A solution of 3-{[3-(dimethylamino)propyl]amino}propanenitrile (7 g, 45.090 mmol) in MeOH (100 mL) was treated with Boc2O (14.76 g, 67.635 mmol). After stirring overnight at room temperature under N2, the mixture was concentrated and purified by reverse-phase flash chromatography (column, C18; mobile phase, 10-50% ACN in H2O (0.1% NH4OH)) under the following conditions to obtain the title compound (6.3 g, 54.71%) as a pale yellow liquid. MS ES+ m / z 256[M+H] + .

[0807] Preparation 112 tert-butyl(3-aminopropyl)(3-(dimethylamino)propyl)carbamate

[0808] [ka] A solution of Raney nickel (2 g, 34.075 mmol) and NH4OH (1 mL) in MeOH (50 mL) was treated with tert-butyl N-(2-cyanoethyl)-N-[3-(dimethylamino)propyl]carbamate (6.3 g, 24.671 mmol). After stirring overnight at room temperature under N2, the mixture was filtered, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated and purified by reverse-phase flash chromatography (column, C18; mobile phase, 10-50% ACN in H2O (10 mmol / L NH4HCO3)) under the following conditions to obtain the title compound (6.3 g, 98.45%) as a pale yellow liquid. MS ES+ m / z 260[M+H] + .

[0809] Preparation 113 tert-butyl(3-(6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)hexanamide)propyl)(3-(dimethylamino)propyl)carbamate

[0810] [ka] A solution of (2S)-6-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-2-[(4-{[4-(4-iodophenyl)butanamide]methyl}phenyl)formamide]hexanoic acid (14 g, 18.096 mmol) in DCM (200 mL) was treated at room temperature with (3-[[(ethylimino)methylidene]amino]propyl)dimethylamine hydrochloride (5.20 g, 27.144 mmol) and HOBT (4.89 g, 36.192 mmol). After stirring for 5 minutes, the mixture was treated with tert-butyl N-(3-aminopropyl)-N-[3-(dimethylamino)propyl]carbamate (5.63 g, 21.715 mmol). After stirring for 2 hours, the mixture was diluted with H2O (500 mL) and extracted with SiO (2 × 500 mL). The combined organic layers were dried over Na2SO4, acidified to pH 1 with concentrated HCl, filtered, concentrated, and purified by reverse-phase flash chromatography under the following conditions (column: C18; mobile phase: 10-50% ACN in H2O (0.1% HCl)) to obtain the title compound (16 g, 67.65%) as a pale yellow liquid: MS ES+ m / z 1015[M+H] + .

[0811] Preparation 114 (9H-Fluoren-9-yl)methylRac-(6-((3-((3-(dimethylaminopropyl)amino)propyl)amino)-5-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)-6-oxohexyl)carbamate

[0812] [ka] A solution of tert-butylrac-(3-(6-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)hexanamide)propyl)(3-(dimethylamino)propyl)carbamate (16 g, 11.034 mmol) in DCM (200 mL) was treated at room temperature with HCl (4.0 M) (50 mL, 200 mmol) in 1,4-dioxane. After stirring at room temperature for 16 hours, the mixture was concentrated to obtain the crude title compound (16 g). MS ES+ m / z 916[M+H] + .

[0813] Preparation 115 (9H-Fluoren-9-yl)methyl(S)-(6-((3-((3-(dimethylaminopropyl)amino)propyl)amino)-5-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)-6-oxohexyl)carbamate

[0814] [ka] (9H-fluoren-9-yl)methylRac-(6-((3-((3-(dimethylamino)propyl)amino)propyl)amino)-5-(4-((4-(4-iodophenyl)butanamide)methyl)benzamide)-6-oxohexyl)carbamate (16g) was subjected to chiral HPLC under the following conditions (column: B_ASA CHIRALPAK IE OBD 5) * The compound was purified by 25 cm, 10 μm; mobile phase: 35% MtBE (0.1% DEA) in EtOH (1:1). The second elution peak fraction was acidified to pH 1 with concentrated HCl, concentrated, and purified by reverse-phase flash chromatography (column: C18; mobile phase: 10-50% ACN (0.1% FA) in H2O) under the following conditions to obtain the title compound (3.2 g, 21.3%) as a pale yellow solid. MS ES+ m / z 916[M+H] + .

[0815] Preparation 116 4-(dimethylamino)-N-(4-nitrophenyl)butanamide

[0816] [ka] A solution of p-nitroaniline (1.65 g, 11.93 mmol) in pyridine (20 mL) was treated with PCl3 (0.82 g, 5.966 mmol) at room temperature under N2 conditions. After stirring for 1 hour, the mixture was treated with 4-(dimethylamino)butanoate (1 g, 5.96 mmol). After stirring for a further 3 hours at 50°C, the mixture was diluted with DCM (400 mL) and washed with 1 M HCl (3 × 200 mL). The combined acidic layers were basicized with 1 M NaOH and extracted with CH2Cl2 (3 × 400 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over Na₂SO₄, filtered, concentrated, and purified by reverse-phase flash chromatography under the following conditions (column: C₁₄; mobile phase: 30%–50% ACN in H₂O (10 mmol / L NH₄HCO₃)) to obtain the title compound (620 mg, 41.3%) as a yellow solid. MS ES+ m / z 252[M+H] + .

[0817] Preparation 117 N-(4-aminophenyl)-4-(dimethylamino)butanamide

[0818] [ka] A solution of 4-(dimethylamino)-N-(4-nitrophenyl)butanamide (500 mg, 1.990 mmol) in siRNA (6 mL) was treated with 10 wt% Pd / C (424 mg) at room temperature under N2. After stirring under H2 for 4 hours, the mixture was filtered, the filter cake was washed with siRNA (6 mL) (3 × 5 mL), and the filtrate was concentrated to obtain the crude title compound (400 mg, 90.8%) as a pale yellow oil. MS ES+ m / z 222[M+H] + .

[0819] Preparation 118 4-(dimethylamino)-N-(4-hydroxyphenyl)butanamide

[0820] [ka] A solution of N-[4-(benzyloxy)phenyl]-4-(dimethylamino)butanamide (3 g, 9.603 mmol) in ethyl acetate (30 mL) was treated with 10 wt% Pd / C (1.02 g). After stirring overnight at room temperature under H2, the mixture was filtered, and the filter cake was washed with SiO2 (3 × 30 mL). The combined organic layer was washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude title compound (1.8 g, 84.3%) as a brown oil. ES+ m / z 223[M+H] + .

[0821] Preparation 7 4-(N-methyl-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamide)butanoic acid

[0822] [ka] A solution of tert-butyl 2-{4,7-bis[2-(tert-butoxy)-2-oxoethyl]-10-{2-[(2,5-dioxopyrrolidine-1-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1-yl}acetate (4.00 g, 5.97 mmol) and 4-(methylamino)butyrate (1.38 g, 8.95 mmol) in DCM (70 mL) was treated with DIEA (3.09 g, 23.88 mmol). After stirring at room temperature under N2 for 2 hours, the mixture was concentrated under reduced pressure and purified by reverse-phase flash chromatography (column, C18; mobile phase, 30%-50% ACN (0.1% FA) in H2O) under the following conditions to obtain the title compound (2.211 g, 51.5%) as a white solid. MS ES+ m / z 672[M+H] + .

[0823] The following compounds were prepared in a manner essentially similar to that of the preparation of 4-(N-methyl-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamide)butanoic acid, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing a purification system as necessary.

[0824] [Table 10]

[0825] Preparation 9 Tri-tert-butyl 2,2',2''-(10-(2-(methyl(3-(methylamino)propyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

[0826] [ka] A solution of N1,N3-dimethylpropane-1,3-diamine (1 g, 0.01 mol), 2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid (3 g, 5 mmol), and N-ethyl-N-isopropylpropane-2-amine (3 g, 0.02 mol) in DMF (8 mL) was treated with T3P (7 g, 50 wt%, 0.01 mol) at 25 °C. After stirring at room temperature for 16 hours, the mixture was concentrated under high pressure and purified by reverse-phase flash chromatography (column, C18; mobile phase, 0%-30% ACN in H2O (0.1% FA)) under the following conditions to obtain the title compound (1.2 g, 30%) as a pale yellow oil. MS ES+ m / z 658[M+H] + .

[0827] Preparation 10 Tri-tert-butyl 2,2',2''-(10-(2-((3-((3-hydroxypropyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

[0828] [ka] A solution of tert-butyl 2-(4-{[(3-{[3-(benzyloxy)propyl](methyl)amino}propyl)(methyl)carbamoyl]methyl}-7,10-bis[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1-yl) acetate (2 g, 2.484 mmol) in EtOH (100 mL) was treated with 20 wt% Pd(OH)2 / C (50% H2O) (700 mg) under nitrogen at room temperature. After stirring at 80°C for 13 hours under H2 (1.0 MPa), the mixture was filtered and the filter cake was washed with EtOH (3 × 20 mL). The filtrate was concentrated and subjected to Prep-HPLC under the following conditions (column: Xtimate C18 OBD 50). * The compound was purified using a mobile phase of 10-40% MeOH (0.1% FA) in H2O at 250 mm and 10 μm to obtain the title compound (298 mg, 16%) as a white solid. MS ES+ m / z 716[M+H] + .

[0829] The following compounds were prepared in a manner essentially similar to the method for preparing tri-tert-butyl 2,2',2''-(10-(2-((3-((3-hydroxypropyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, using appropriate reagents (the aryl halide of the starting material is preferably bromo or iodine), adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing a purification system as necessary.

[0830] [Table 11]

[0831] Preparation 123 4-(methyl(3-(N-methyl-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamidopropyl)amino)butanoic acid

[0832] [ka] A solution of benzyl 4-{methyl[3-(2-{4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1-yl}acetamidopropyl]amino}butanoate (5.3 g, 6.471 mmol) in MeOH (50 mL) was treated with 20 wt% Pd(OH)2 / C (2.73 g). After stirring overnight under H2 at room temperature, the mixture was filtered, and the filter cake was washed with MeOH (3 × 21 mL). The filtrate was concentrated to obtain the crude title compound (3.05 g, 64.6%) as a yellow solid. MS ES+ m / z 730[M+H] + .

[0833] Preparation 124 4-((3-(dimethylamino)propyl)(3-(N-methyl-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamide)propyl)amino)butanoic acid

[0834] [ka] A solution of 10 wt% Pd / C (0.82 g) in siRNA (100 mL) was treated at room temperature by adding benzyl 4-{[3-(dimethylamino)propyl][3-(N-methyl-2-{4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1-yl}acetamidopropyl]amino}butanoate (7 g, 7.741 mmol) in several portions. After stirring overnight under H2, the mixture was filtered, the filter cake was washed with ACN (3 × 50 mL), and concentrated to obtain the crude title compound (4.5 g, 65.19%) as a white solid. MS ES+ m / z 815[M+H] + .

[0835] The following compounds were prepared in a manner essentially similar to the method for preparing 4-((3-(dimethylamino)propyl)(3-(N-methyl-2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetamidopropyl)amino)butanoic acid, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing a purification system as necessary.

[0836] [Table 12]

[0837] Preparation 126 Tri-tert-butyl 2,2',2''-(10-(2-((3-((3-aminopropyl)(methyl)amino)propyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate

[0838] [ka] A solution of tert-butyl 2-{4-[({3-[(3-{[(benzyloxy)carbonyl]amino}propyl)(methyl)amino]propyl}carbamoyl)methyl]-7,10-bis[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1-yl}acetate (7.1 g, 8.512 mmol) in SiO2 (70 mL) was treated with 10 wt% Pd / C (2.5 g). After stirring overnight at room temperature under H2, the mixture was filtered, and the filter cake was washed with ACN (3 × 100 mL). The filtrate was concentrated to obtain the crude title compound (5.486 g, 92%) as an off-white solid. MS ES+ m / z 701[M+H] + .

[0839] Preparation 388 1-(tert-butyl)5-(2,5-dioxopyrrolidine-1-yl)2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)pentanedioate

[0840] [ka] A solution of rac-(4R)-5-(tert-butoxy)-5-oxo-4-{4,7,10-tris[2-(tert-butoxy)-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid (2 g, 2.85 mmol) and HOSu (656 mg, 5.7 mmol) in DCC (15 mL) was treated with DCC (1.18 g, 5.7 mmol) at room temperature under N2. The mixture was stirred overnight and concentrated under reduced pressure to obtain the title compound (2.2 g, 100%). MS ES+ m / z 799[M+H] + .

[0841] Preparation 11 4-Iodo-2-isopropylaniline

[0842] [ka] A solution of 2-isopropylaniline (50 g, 369.795 mmol) and iodine (122.01 g, 480.734 mmol) in HOAc (500 mL) was treated with NaOAc (30.34 g, 369.795 mmol). After stirring under N2 at room temperature for 2 hours, the resulting mixture was concentrated. The concentrate was diluted with H2O (500 mL). The resulting mixture was extracted with EA (3 × 500 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography PE / EA (10:1) to obtain the title compound (84 g, 87.0%) as a brown oil. MS ES+ m / z 262[M+H] + .

[0843] Preparation 127 6-Bromo-4-isopropylpyridine-3-amine

[0844] [ka] A solution of 4-isopropylpyridine-3-amine (1.03 g, 7.562 mmol) in DMF (50 mL) was cooled in an ice bath, and NBS (1.481 g, 8.319 mmol) was added in three separate additions. After stirring for 1 hour, the reaction mixture was treated with H2O (10 mL) and diluted with  (10 mL). The organic layer was separated, washed with brine, concentrated, and purified by reverse-phase flash chromatography (column, C18; mobile phase, 5-35% ACN in H2O (10 mmol / L NH4HCO3)) under the following conditions to obtain the title compound (150 mg, 9.2%). MS ES+ m / z 217[M+H] + .

[0845] Preparation 12 (4-iodo-2-isopropylphenyl)hydrazine

[0846] [ka] A solution of 4-iodo-2-isopropylaniline (40 g, 153.19 mmol) in HCl (80 mL) was treated with NaNO2 (21.14 g, 306.38 mmol) in H2O (40 mL) at -10°C under N2. After stirring at 0°C for 1 hour under N2, SnCl2·2H2O (114.07 g, 505.540 mmol) in HCl (40 mL) was added at -10°C. After stirring at 0°C for 1 hour under N2, the mixture was stirred at room temperature for a further 3 hours. The precipitated solid was collected by filtration and washed with Et2O. The residue was ground with PE / EA (5:1) (200 mL). The resulting mixture was filtered. The filter cake was washed with PE / EA (5:1) (2 × 50 mL). The filtrate was concentrated to obtain the title compound (35 g, crude) as a yellow solid. MS ES+ m / z 277[M+H] + .

[0847] The following compounds were prepared in a manner essentially similar to that of (4-iodo-2-isopropylphenyl)hydrazine, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0848] [Table 13]

[0849] Preparation 131 4-(2-(tert-butoxycarbonyl)hydrazinyl)-3-isopropylbenzoic acid

[0850] [ka] A solution of 4-hydrazinyl-3-isopropylbenzoate (4 g, 20.594 mmol) in THF (40 mL) and H2O (10 mL) was treated with Boc2O (8.99 g, 41.188 mmol) and NaHCO3 (3.46 g, 41.188 mmol). After stirring at room temperature under N2 for 1 hour, the mixture was concentrated and purified by silica gel column chromatography PE / EA (5:1) to obtain the title compound (4 g, 65.9%) as a white solid. MS ES+ m / z 295[M+H] + .

[0851] Preparation 132 tert-butyl 2-(4-((3-(dimethylamino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)hydrazine-1-carboxylate

[0852] [ka] A solution of 4-{[(tert-butoxycarbonyl)amino]amino}-3-isopropylbenzoic acid (4 g, 13.589 mmol) in MeCN (50 mL) was treated with [3-(dimethylamino)propyl](methyl)amine (4.74 g, 40.767 mmol), 1-methyl-1H-imidazole (3.35 g, 40.767 mmol), and TCFH (11.44 g, 40.767 mmol). After stirring overnight under N2 at room temperature, the solution was concentrated and purified by reverse-phase flash chromatography (column, C18; mobile phase, 10-50% ACN (0.1% FA) in H2O) under the following conditions to obtain the title compound (4.6 g, 86.2%) as a white solid. MS ES+ m / z 393[M+H] + .

[0853] Preparation 133 N-(3-(dimethylamino)propyl)-4-hydrazinyl-3-isopropyl-N-methylbenzamide

[0854] [ka] A solution of 4-{[(tert-butoxycarbonyl)amino]amino}-N-[3-(dimethylamino)propyl]-3-isopropyl-N-methylbenzamide (4.6 g, 11.718 mmol) in DCM (30 mL) was treated with HCl (4.0 M) (20 mL) in 1,4-dioxane. After stirring under N2 at room temperature for 1 hour, the mixture was concentrated to obtain the crude title compound (4.3 g) as a white solid. MS ES+ m / z 293[M+H] + .

[0855] Preparation 16 5-Methoxybenzo[d][1,3]dioxol

[0856] [ka] A solution of benzo[d][1,3]dioxol-5-ol (70 g, 506.79 mmol) and K2CO3 (210 g, 1520.39 mmol) in acetone (1000 mL) was treated with MeI (143 g, 1013.59 mmol) at room temperature under N2. After stirring at 50°C for 6 hours under N2, the mixture was cooled to room temperature and filtered. The filter cake was washed with EA (3 × 100 mL). The filtrate was concentrated under reduced pressure, diluted with H2O (1 L), and extracted with EA (3 × 700 mL). The combined organic layers were washed with brine (1 × 1000 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography PE / EA (20:1) to obtain the title compound (72 g, 93.5%) as a pale yellow oil. MS ES+ m / z 153[M+H] + .

[0857] Preparation 134 5-(trifluoromethoxy)benzo[d][1,3]dioxol

[0858] [ka] A solution of 4-(trifluoromethoxy)benzene-1,2-diol (1000 mg, 5.152 mmol) in DMF (10 mL) was treated with Cs2CO3 (2.35 g, 7.212 mmol) and methylene bromide (1.254 g, 7.212 mmol). After heating at 110°C for 3 hours, the solution was cooled, diluted with H2O (20 mL), and extracted with siRNA (3 × 20 mL). The organic layer was separated, washed with brine (20 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography hep / siRNA (0-100%) to obtain the title compound (480 mg, 45.2%) as an oil. 1 H NMR (500MHz, DMSO) δ 7.05 (dt, J = 1.7, 0.9 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.87-6.80 (m, 1H), 6.11 (s, 2H).

[0859] The following compounds were prepared in a manner essentially similar to that of the preparation of 5-(trifluoromethoxy)benzo[d][1,3]dioxole, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0860] [Table 14]

[0861] Preparation 17 4-iodo-5-methoxybenzo[d][1,3]dioxol

[0862] [ka] A solution of 5-methoxybenzo[d][1,3]dioxol (70 g, 460.07 mmol) in THF (1000 mL) was treated with n-BuLi (220 mL, 552.09 mmol) under N2 at -20°C, stirred for 1 hour, and then treated with iodine (163.48 g, 644.105 mmol). After stirring under N2 at room temperature for 30 minutes, the mixture was treated with saturated Na2S2O3 (500 mL) at 0°C. The resulting mixture was diluted with H2O (1000 mL) and extracted with Et2O diethyl ether (3 × 800 mL). The combined organic layers were washed with brine (1 × 1000 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography PE / EA (30:1) to obtain the title compound (71 g, 55.5%) as a pale yellow solid. MS ES+ m / z 279[M+H] + .

[0863] The following compounds were prepared in a manner essentially similar to that of the preparation of 4-iodo-5-methoxybenzo[d][1,3]dioxol, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0864] [Table 15]

[0865] Preparation 18 1-(5-methoxybenzo[d][1,3]dioxol-4-yl)ethane-1-one

[0866] [ka] A solution of 4-iodo-5-methoxybenzo[d][1,3]dioxol (70 g, 251.75 mmol) and tributyl(1-ethoxyethenyl)stannane (136.39 g, 377.637 mmol) in dioxane (800 mL) was treated with Pd(dppf)Cl2 (18.42 g, 25.17 mmol) at room temperature under N2. After stirring at 80°C for 3 hours under N2, the mixture was treated with HCl (4.0 M) (95 mL, 377.63 mmol) in 1,4-dioxane at 0°C. After stirring at room temperature for 1 hour, the mixture was treated with saturated KF (1000 mL) at 0°C and filtered. The filter cake was washed with EA (3 × 100 mL), the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography PE / EA (4:1) to obtain the title compound (35 g, 71.5%) as a yellow oil. MS ES+ m / z 195[M+H] + .

[0867] Preparation 19 Ethyl(Z)-4-hydroxy-4-(5-methoxybenzo[d][1,3]dioxol-4-yl)-2-oxobuta-3-enoate

[0868] [ka] A solution of 1-(5-methoxybenzo[d][1,3]dioxol-4-yl)ethane-1-one (32 g, 164.79 mmol) in EtOH (400 mL) was treated with sodium ethanolate (112.14 g, 329.58 mmol, 20% in ethanol). After stirring under N2 at room temperature for 30 minutes, the mixture was treated with ethyl oxalate (36 g, 247.18 mmol). After stirring overnight at 80°C, the mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with H2O (3 × 50 mL) to obtain the title compound (42 g, 86.6%) as a yellow solid. MS ES-m / z 293[MH] - .

[0869] The following compounds were prepared in a manner essentially similar to that of the preparation of ethyl(Z)-4-hydroxy-4-(5-methoxybenzo[d][1,3]dioxol-4-yl)-2-oxobuta-3-enoate, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0870] [Table 16]

[0871] Preparation 20 Ethyl 1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0872] [ka] A solution of ethyl(Z)-4-hydroxy-4-(5-methoxybenzo[d][1,3]dioxol-4-yl)-2-oxobuta-3-enoate (8.12 g, 28.97 mmol) in EtOH (80 mL) was treated with (4-iodo-2-isopropylphenyl)hydrazine (8 g, 28.97 mmol) at room temperature under N2. After stirring at 50°C for 4 hours under N2, the mixture was concentrated under reduced pressure and purified by silica gel column chromatography PE / EA (2:1) to obtain the title compound (12 g, 79.6%) as a yellow solid. MS ES+ m / z 535[M+H] + .

[0873] The following compounds were prepared in a manner essentially similar to that of the preparation of ethyl 1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0874]

Table 17

[0875] Preparation 21 Ethyl 1-(4-bromo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0876]

Chemical formula

[0877] The following compounds were prepared in an essentially similar manner to the preparation method of ethyl 1-(4-bromo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate by using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and adjusting the purification system as necessary.

[0878]

Table 18

[0879] Preparation 23 4-(3-(Ethoxycarbonyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazol-1-yl)-3-isopropylbenzoic acid

[0880] [ka] A solution of 4-hydrazinyl-3-isopropylbenzoic acid (350 mg, 1.80 mmol) and ethyl(Z)-4-hydroxy-4-(5-methoxybenzo[d][1,3]dioxol-4-yl)-2-oxobuta-3-enoate (530 mg, 1.80 mmol) in AcOH (6 mL) was stirred under reflux. After 12 hours, the suspension was poured into an ice bath (15 mL), filtered, and the isolated solid was washed with H2O. Purification by silica gel column chromatography (MeOH / DCM, 0-30%) yielded the title compound (390 mg, 48%) as a yellow solid. MS ES+ m / z 453[M+H] + .

[0881] Preparation 146 3-Bromo-4-(5-(2,6-dimethoxyphenyl)-3-(ethoxycarbonyl)-1H-pyrazole-1-yl)benzoic acid

[0882] [ka] A solution of 3-bromo-4-hydrazinylbenzoic acid (30 g, 90.890 mmol) in EtOH (200 mL) was treated with ethyl(3Z)-4-(2,6-dimethoxyphenyl)-4-hydroxy-2-oxobuta-3-enoate (30.57 g, 109.068 mmol). After stirring at room temperature for 1 hour, the precipitated solid was collected by filtration, washed with EtOH (200 mL) (3 × 50 mL), and dried to obtain the crude title compound (37 g, 100%) as a pale yellow solid. MS ES+ m / z 475 / 477[M+H] + ( 79 Br / 81 Br).

[0883] Preparation 147 Ethyl 1-(4-amino-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0884] [ka] A solution of ethyl 1-(4-iodo-2-isopropylphenyl)-5-(5-methoxy-2H-1,3-benzodioxol-4-yl)pyrazole-3-carboxylate (2.5 g, 4.679 mmol) and (2S)-pyrrolidine-2-(13C)carboxylic acid (0.81 g, 7.019 mmol) in DMSO (20 mL) was treated with 38% NH4OH (21.57 g, 233.950 mmol) and CuI (1.78 g, 9.358 mmol) at room temperature under N2. After stirring at 100°C for 6 hours under N2, the mixture was cooled to room temperature, diluted with siRNA (150 mL), and washed with brine (5 × 150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel column chromatography PE / siRNA (1:1) to obtain the title compound (980 mg, 49.4%) as a yellow solid. MS ES+ m / z 424[M+H] + .

[0885] Preparation 24 Ethyl 1-(4-((3-(dimethylamino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0886] [ka] A solution of 4-(3-(ethoxycarbonyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-1-yl)-3-isopropylbenzoic acid (194 mg, 429 μmol), N,N,N-trimethyl-1,3-propanediamine (144 μL, 1.07 mmol), DIEA (554 mg, 738 μL, 10 Eq, 4.29 mmol), and T3P (657 μL, 50 wt%, 1.07 mmol) in degassed DMF (15 mL). After stirring under N2 at 22°C for 1.5 hours, the mixture was concentrated to obtain the crude title compound (236 mg, 100%) as a yellow liquid. MS ES+ m / z 551[M+H] + .

[0887] The following compounds were prepared in a manner essentially similar to the method for preparing ethyl 1-(4-((3-(dimethylamino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate, using appropriate reagents (the aryl halide of the starting material is preferably bromo or iodine), adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing a purification system as necessary.

[0888] [Table 19]

[0889] Preparation 152 Ethyl 1-(4-((3-(dimethylamino)propyl)(pyridine-2-ylmethyl)carbamoyl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0890] [ka] N in DMF (4 mL) 1 ,N 1 -dimethyl-N 3A solution of 4-(3-(ethoxycarbonyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-1-yl)-3-isopropylbenzoic acid (120 mg, 0.265 mmol) in -(pyridine-2-ylmethyl)propan-1,3-diamine (76.9 mg, 0.398 mmol) was cooled to 0°C and treated with DIEA (0.137 mL, 0.796 mmol) and T3P (0.468 mL, 50% by weight, 0.796 mmol). After stirring at room temperature for 1 hour, the mixture was diluted with H2O (10 mL) and extracted with Âr (3 × 10 mL). The combined organic phases were washed with saturated NaHCO3 solution (10 mL), then with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude title compound (103 mg, 61.9%) as a white solid. MS ES+ m / z 628[M+H] + .

[0891] Preparation 153 Ethyl 1-(2-bromo-4-((3-(dimethylamino)propyl)(methyl)carbamoyl)phenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxylate

[0892] [ka] A solution of 3-bromo-4-[5-(2,6-dimethoxyphenyl)-3-(ethoxycarbonyl)pyrazole-1-yl]benzoic acid (37 g, 77.846 mmol) and [3-(dimethylamino)propyl](methyl)amine (10.86 g, 93.415 mmol) in ACN (500 mL) was treated at 0°C with 1-methyl-1H-imidazole (19.17 g, 233.538 mmol) and TCFH (26.21 g, 93.415 mmol). After stirring at room temperature for 1 hour, the mixture was diluted with H2O (800 mL) and extracted with SiO (2 × 800 mL). The combined organic layers were washed with brine (2 × 500 mL), dried over Na₂SO₄, filtered, and purified by reverse-phase flash chromatography (column: C₁₄; mobile phase: 10–50% ACN in H₂O (0.1% FA)) under the following conditions to obtain the title compound (27 g, 36.21%) as a pale yellow solid: MS ES+ m / z 573 / 575[M+H] + ( 79 Br / 81 Br).

[0893] Preparation 154 Ethyl 1-(4-(5-(3-((tert-butoxycarbonyl)amino)propyl)-1,3,4-thiadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0894] [ka] A solution of ethyl 1-(4-(2-(4-((tert-butoxycarbonyl)amino)butanoyl)hydrazine-1-carbonyl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate (400 mg, 0.614 mmol) in anhydrous THF (8 mL) was treated with Lawson's reagent (496 mg, 1.23 mmol). After microwave heating at 120 °C for 1 hour, the mixture was cooled to room temperature, treated with saturated NaHCO3 solution (10 mL), and extracted with  (3 × 25 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, concentrated until dry, and purified by silica gel column chromatography Hep /  (0-100%) to obtain the title compound (210 mg, 52.7%) as a white solid. MS ES+ m / z 650[M+H] + .

[0895] Preparation 155 Ethyl 1-(4-(5-(3-((tert-butoxycarbonyl)amino)propyl)-1,3,4-oxadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0896] [ka] A solution of ethyl 1-(4-(2-(4-((tert-butoxycarbonyl)amino)butanoyl)hydrazine-1-carbonyl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate (260 mg, 0.399 mmol) in anhydrous THF (8 mL) was treated with Burgess reagent (285 mg, 1.20 mmol). After microwave heating at 100°C for 1 hour, the mixture was concentrated and purified by silica gel column chromatography Hep / Â (0-100%) to obtain the title compound (219 mg, 86.6%) as a yellow gum. MS ES+ m / z 634[M+H] + .

[0897] Preparation 156 Ethyl 1-(4-(5-(3-aminopropyl)-1,3,4-thiadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0898] [ka] A solution of ethyl 1-(4-(5-(3-((tert-butoxycarbonyl)amino)propyl)-1,3,4-thiadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate (210 mg, 0.323 mmol) in DCM (2 mL) was treated with TFA (2 mL). After stirring at room temperature for 1 hour, the mixture was concentrated, dissolved in DCM (1 mL) and heptane (3 mL), and concentrated again to obtain the crude title compound (191 mg, 89%) as a pale green solid. MS ES+ m / z 550[M+H] + .

[0899] The following compounds were prepared in a manner essentially similar to that of the preparation of ethyl 1-(4-(5-(3-aminopropyl)-1,3,4-thiadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0900] [Table 20]

[0901] Preparation 160 1-(4-(5-(3-(4-(dimethylamino)butanamide)propyl)-1,3,4-thiadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-N-methyl-1H-pyrazole-3-carboxamide

[0902] [ka] A solution of ethyl 1-(4-(5-(3-aminopropyl)-1,3,4-thiadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate (120 mg, 0.218 mmol) in DMF (4 mL) was treated with 4-(N,N-dimethylamino)butanoic acid (28.6 mg, 0.218 mmol). The mixture was cooled to 0°C and treated with DIEA (0.113 mL, 0.655 mmol) and T3P 50 wt% (0.257 mL, 0.437 mol). After stirring at room temperature for 1 hour, the mixture was diluted with H2O (15 mL) and extracted with  (3 × 10 mL). The combined organic phases were washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude title compound (128 mg, 88.5%) as a beige solid. MS ES+ m / z 663[M+H] + .

[0903] The following compounds were prepared in a manner essentially similar to the method for preparing 1-(4-(5-(3-(4-(dimethylamino)butanamide)propyl)-1,3,4-thiadiazole-2-yl)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-N-methyl-1H-pyrazole-3-carboxamide, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0904] [Table 21]

[0905] Preparation 164 Ethyl 1-(4-(4-(dimethylamino)butanamide)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate

[0906] [ka] A solution of ethyl 1-(4-amino-2-isopropylphenyl)-5-(5-methoxy-2H-1,3-benzodioxol-4-yl)pyrazole-3-carboxylate (200 mg, 0.472 mmol) and 4-(dimethylamino)butanoate (119 mg, 0.708 mmol) in DCM (5 mL) was treated with DIEA (305 mg, 2.360 mmol) and T3P (50% in Â) (451 mg, 1.416 mmol) at room temperature under N2. After stirring for 4 hours, the mixture was concentrated and purified by reverse-phase flash chromatography (column, C18; mobile phase, 30-50% ACN (0.1% FA) in H2O) under the following conditions to obtain the title compound (200 mg, 78.9%) as a white solid. MS ES+ m / z 537[M+H] + .

[0907] Preparation 25 1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylic acid

[0908] [ka] A solution of ethyl 1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylate (6 g, 11.22 mmol) in MeOH (60 mL) and H2O (12 mL) was treated by adding LiOH·H2O (0.94 g, 22.45 mmol) in several portions at room temperature under N2. After stirring at 50°C for 4 hours under N2, the mixture was diluted with H2O (100 mL) and extracted with EA (2 × 200 mL). The combined organic layer was washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography PE / siRNA (2:1) to obtain the title compound (5.4 g, 94.9%) as a pale yellow solid. MS ES+ m / z 507[M+H] + .

[0909] The following compounds were prepared in a manner essentially similar to that of the preparation of 1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylic acid, using appropriate reagents, controlling the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0910] [Table 22-1]

[0911] [Table 22-2]

[0912] [Table 22-3]

[0913] Preparation 173 Ethyl 5-bromo-1-(4-(ethoxycarbonyl)-2-isopropylphenyl)-1H-pyrazole-3-carboxylate

[0914] [ka] 4-[3-(ethoxycarbonyl)-5-hydroxypyrazole-1-yl]-3-isopropylbenzoic acid (1 g, 3.14 mmol, 1.00 equivalent) was treated with phosphoroyl tribromide (20 g) at room temperature under N2. After stirring overnight at 150°C under N2, the mixture was cooled to room temperature, diluted with siRNA (800 mL), and then treated with EtOH (1.6 L) at 0°C. The resulting mixture was filtered, the filter cake was washed with siRNA (3 × 100 mL), the filtrate was concentrated, and purified by silica gel column chromatography PE / siRNA (7:1) to obtain the title compound (24 g, 30%) as a yellow oil. MS ES+ m / z 409 / 411[M+H] + ( 79 Br / 81 Br).

[0915] Preparation 174 5-Bromo-1-(4-(ethoxycarbonyl)-2-isopropylphenyl)-1H-pyrazole-3-carboxylic acid

[0916] [ka] A solution of ethyl 5-bromo-1-[4-(ethoxycarbonyl)-2-isopropylphenyl]pyrazole-3-carboxylate (23 g, 56.19 mmol) in DCE (400 mL) was treated with trimethylstannanol (20.32 g, 112.39 mmol). After stirring at 80°C for 2 hours under N2, the mixture was cooled to room temperature, diluted with H2O (1000 mL), extracted with siRNA (3 × 600 mL), washed with brine (1 × 800 mL), dried over anhydrous Na2SO4, filtered, and purified by silica gel column chromatography PE / siRNA (1:1) to obtain the title compound (9.5 g, 44.3%) as a yellow solid. MS ES+ m / z 381 / 383[M+H] + ( 79 Br / 81 Br).

[0917] Preparation 29 tert-butyl(5r,7r)-2-(1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantan-2-carboxylate

[0918] [ka] A solution of 1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylic acid (5 g, 9.876 mmol) and tert-butyl 2-aminoadamantane-2-carboxylate (3.72 g, 14.81 mmol) in ACN (50 mL) was treated with 1-methyl-1H-imidazole (2.43 g, 29.628 mmol) and TCFH (4.16 g, 14.81 mmol). After stirring under N2 at room temperature for 2 hours, the mixture was diluted with water (200 mL) and extracted with EA (2 × 300 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure and lyophilized under high reduced pressure to obtain the title compound (5.2 g, 71.1%) as a yellow solid. MS ES-m / z 738[MH] - .

[0919] The following compounds were prepared in a manner essentially similar to that of the preparation of tert-butyl(5r,7r)-2-(1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0920] [Table 23]

[0921] Preparation 389 tert-butyl(5r,7r)-2-(5-(5-bromobenzo[d][1,3]dioxol-4-yl)-1-(4-hydroxy-2-isopropylphenyl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0922] [ka] A solution of tert-butyl 2-aminoadamantane-2-carboxylate (677 mg, 2.7 mmol) in THF (10 mL) was treated at room temperature under N2 with 5-(5-bromo-2H-1,3-benzodioxol-4-yl)-1-(4-hydroxy-2-isopropylphenyl)pyrazole-3-carboxylic acid (1.2 g, 2.7 mmol), EDCI·HCl (619 mg, 3.2 mmol), HOBT (437 mg, 3.2 mmol), and DIEA (696 mg, 5.4 mmol). The mixture was stirred overnight, concentrated under reduced pressure, and purified by reverse-phase flash chromatography (column, C18; mobile phase, 10%-50% ACN (0.1% FA) in H2O) under the following conditions to obtain the title compound (1 g, 55%) as a white solid. MS ES+ m / z 678 / 680[M+H] + ( 79 Br / 81 Br).

[0923] Preparation 178 tert-butyl(5r,7r)-2-(5-(5-cyanobenzo[d][1,3]dioxol-4-yl)-1-(4-((3-(dimethylamino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0924] [ka] A solution of tert-butyl 2-[5-(5-bromo-2H-1,3-benzodioxol-4-yl)-1-(4-{[3-(dimethylamino)propyl](methyl)carbamoyl}-2-isopropylphenyl)pyrazole-3-amide]adamantane-2-carboxylate (300 mg, 0.373 mmol) and Zn(CN)2 (88 mg, 0.746 mmol) in DMF (2 mL) was treated with XantPhos Pd G3 (71 mg, 0.075 mmol) at room temperature under N2. After stirring at 80°C for 2 hours under N2, the mixture was concentrated and purified by reverse-phase flash chromatography (column, C18; mobile phase, 30%-70% ACN (0.1% FA) in H2O) under the following conditions to obtain the title compound (240 mg, 85.74%) as a pale yellow solid. MS ES+ m / z 752[M+H] + .

[0925] The following compounds were prepared in a manner essentially similar to the preparation method for tert-butyl(5r,7r)-2-(5-(5-cyanobenzo[d][1,3]dioxol-4-yl)-1-(4-((3-(dimethylamino)propyl)(methyl)carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0926] [Table 24]

[0927] Preparation 179 tert-butyl(5r,7r)-2-(1-(2-bromo-4-((3-(dimethylamino)propyl)(methyl)carbamoyl)phenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0928] [ka] A solution of 1-(2-bromo-4-{[3-(dimethylamino)propyl](methyl)carbamoyl}phenyl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carboxylic acid (16 g, 29.334 mmol) in DMF (150 mL) was treated with PyBOP (22.90 g, 44.001 mmol) and DIEA (11.37 g, 88.002 mmol). After stirring at room temperature for 10 minutes, the mixture was treated with tert-butyl 2-aminoadamantane-2-carboxylate (14.75 g, 58.668 mmol). After stirring at room temperature for 2 hours, the mixture was diluted with H2O (800 mL) and extracted with siRNA (2 × 500 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by reverse-phase flash chromatography (column: C18; mobile phase: 10-50% ACN in H2O (0.1% FA)) under the following conditions to obtain the title compound (7.5 g, 32.83%) as a pale yellow solid. MS ES+ m / z 778 / 780[M+H] + ( 79 Br / 81 Br).

[0929] Preparation 180 4-(5-bromo-3-(((5r,7r)-2-(tert-butoxycarbonyl)adamantan-2-yl)carbamoyl)-1H-pyrazole-1-yl)-3-isopropylbenzoic acid

[0930] [ka] A solution of tert-butyl 2-{5-bromo-1-[4-(ethoxycarbonyl)-2-isopropylphenyl]pyrazole-3-amide}adamantane-2-carboxylate (3.60 g, 5.85 mmol) in THF (50 mL) and H2O (10 mL) was treated with LiOH·H2O (368.68 mg, 8.78 mmol) at room temperature under N2. After stirring at 50°C for 4 hours under N2, the mixture was cooled to room temperature, concentrated, diluted with H2O (800 mL), and extracted with siRNA (2 × 400 mL). The combined organic layers were washed with brine (1 × 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18; mobile phase: 70-90% ACN (0.1% FA) in H2O) to obtain the title compound (2.85 g, 82.9%) as a white solid. MS ES+ m / z 586 / 588[M+H] + ( 79 Br / 81 Br).

[0931] The following compounds were prepared in a manner essentially similar to that of the preparation of 4-(5-bromo-3-(((5r,7r)-2-(tert-butoxycarbonyl)adamantan-2-yl)carbamoyl)-1H-pyrazole-1-yl)-3-isopropylbenzoic acid, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0932] [Table 25]

[0933] Preparation 181 tert-butyl(5r,7r)-2-(1-(4-amino-2-isopropylphenyl)-5-bromo-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0934] [ka] A solution of 4-(5-bromo-3-{[2-(tert-butoxycarbonyl)adamantan-2-yl]carbamoyl}pyrazole-1-yl)-3-isopropylbenzoic acid (4.00 g, 6.82 mmol) and azidotrimethylsilane (3.14 g, 27.28 mmol) in dioxane (60 mL) was treated with T3P (50% in siRNA) (8.68 g, 13.64 mmol) and Et3N (2.76 g, 27.28 mmol) at room temperature under N2 conditions. After stirring at 100°C for 2 hours, the mixture was treated with H2O (1.23 g, 68.2 mmol) at room temperature. After stirring at 100°C for 2 hours, the mixture was cooled to room temperature, diluted with H2O (500 mL), and extracted with siRNA (3 × 300 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18; mobile phase: 70–90% ACN in H₂O (10 mmol / L NH₄HCO₃)) to obtain the title compound (1.9 g, 50%) as a pale yellow solid. MS ES+ m / z 557 / 559[M+H] + ( 79 Br / 81 Br).

[0935] Preparation 30 tert-butyl(5r,7r)-2-(1-(4-bromo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0936] [ka] A solution of 1-(4-bromo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylic acid (3000 mg, 6.532 mmol) in DMF (12 mL) was treated at 0°C with T3P (5.768 mL, 19.60 mmol), DIEA (3.37 mL, 19.60 mmol), and tert-butyl(5r,7r)-2-aminoadamantane-2-carboxylate (3.284 g, 13.06 mmol). After stirring at room temperature for 24 hours, the mixture was treated with another batch of tert-butyl(5r,7r)-2-aminoadamantane-2-carboxylate (3.284 g, 13.06 mmol), T3P (5.768 mL, 19.60 mmol), and DIEA (3.37 mL, 19.60 mmol), and stirred for 24 hours. The mixture was cooled to 0°C and treated with ice H2O. The resulting mixture was filtered, the isolated solid was washed with H2O (5 mL), and then dried overnight in a heated oven to obtain the title compound (4.0 g, 5.8 mmol, 88%) as a beige solid. MS ES+ m / z 692[M+H] + .

[0937] The following compounds were prepared in a manner essentially similar to that of tert-butyl(5r,7r)-2-(1-(4-bromo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate, using appropriate reagents, adjusting the temperature, adjusting the reaction time to determine the completion of the reaction, and preparing the purification system as necessary.

[0938] [Table 26-1]

[0939] [Table 26-2]

[0940] Preparation 187 tert-butyl(5r,7r)-2-(1-(6-chloro-4-isopropylpyridine-3-yl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0941] [ka] A solution of 1-(6-chloro-4-isopropylpyridine-3-yl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxylic acid (170 mg, 0.409 mmol) in DMF (4 mL) was treated with tert-butyl(5r,7r)-2-aminoadamantane-2-carboxylate (154 mg, 0.613 mmol), DIEA (0.356 mL, 2.04 mmol), and HATU (466 mg, 1.23 mmol). After stirring overnight, the mixture was treated with water (3 mL) and extracted with iPrOH / CHCl3 (1:3) (4 × 5 mL). The combined organic layers were washed with brine and concentrated to obtain the crude title compound (170 mg, 79.9%) as a brown solid. MS ES+ m / z 649[M+H] + .

[0942] Preparation 32 tert-butyl(5r,7r)-2-(1-(4-amino-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0943] [ka] A solution of tert-butyl(5r,7r)-2-(1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate (250 mg, 0.338 mmol) and (2S)-pyrrolidine-2-carboxylic acid (59 mg, 0.507 mmol) in DMSO (3 mL) was treated with NH3·H2O (0.1 mL) and CuI (129 mg, 0.676 mmol) at room temperature under N2 conditions. After stirring at 100°C for 2 hours under N2, the mixture was cooled to room temperature, concentrated, and purified by reverse-phase flash chromatography (column: C18; mobile phase: 90%-95% ACN in H2O (0.1% NH3·H2O)) under the following conditions to obtain the title compound (170 mg, 79.9%) as a white solid: MS ES+ m / z 629[M+H] + .

[0944] Preparation 33 tert-butyl(5r,7r)-2-(1-(4-((5-(dimethylamino)pentyl)amino)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate

[0945] [ka] A solution of N1,N1-dimethylpentane-1,5-diamine (46 μL, 0.30 mmol), tert-butyl(5r,7r)-2-(1-(4-iodo-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate (30 mg, 41 μmol), Cs2CO3 (40 mg, 0.12 mmol), XPhos (1.9 mg, 4.1 μmol), and Pd2(dba)3 (3.7 mg, 4.1 μmol) in 1,4-dioxane (1 mL) was degassed with argon for 2 minutes, stirred at 120°C for 17 hours, and then concentrated to obtain the title compound (30 mg, 100%). MS ES+ m / z 743[M+H] + .

[0946] The following compounds were prepared in a manner essentially similar to the method for preparing tert-butyl(5r,7r)-2-(1-(4-((5-(dimethylamino)pentyl)amino)-2-isopropylphenyl)-5-(5-methoxybenzo[d][1,3]dioxol-4-yl)-1H-pyrazole-3-carboxamide)adamantane-2-carboxylate, using appropriate reagents (the aryl halide of the starting material is preferably bromo or iodine), adjusting the temperature, adjusting the reaction time to determine the completion of the r...

Claims

1. Compounds of the following formula or their pharmaceutically acceptable salts: 【Chemistry 1】 [In the formula, R １ C １ ~C ６ Alkyl or C ３ ~C ６ It is a cycloalkyl, Z is -COOH, -C(=O)NH ２ , or -tetrazolyl, R ２ is C ６ to C １０ cycloalkyl or C ６ to C １０ cycloalkyl-C １ to C ６ alkyl-, and the C ６ to C １０ cycloalkyl and C ６ to C １０ cycloalkyl-C １ to C ６ alkyl- are each optionally substituted with 1 to 3 halogen atoms, R ３ is H, or R ２ and R ３ These, together with the carbon atoms to which they are bonded, are C, which is optionally substituted with 1 to 3 halogens. ６ ~C １０ Forming a cycloalkyl group, R ４ The formula is as follows: 【Chemistry 2】 It is the basis of, R ４ａ , R ４ｂ , R ４ｃ , and R ４ｄ Each of these is independently either H or halogen, R ４ｅ is H, methyl, trifluoromethyl, or methoxyethyl. R ４ｆ It is cyano or fluoro, R ４ｇ It is hydrogen, D is a 5-6 member heteroaryl compound containing 1-3 heteroatoms independently selected from N, O, and S, and is a halo, hydroxy, amino, cyano, nitro, or C compound. １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkylamino, and C １ ~C ６ It is optionally substituted with 1 to 3 groups independently selected from the dialkylamino, Q is a six-membered aryl or heteroaryl ring containing 0 to 3 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. X １ is a bond, -O-, or -NR ｘ１ - and Cy １ is a bond, or halo, hydroxy, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkylamino, and C １ ~C ６ A 4-12 member monocyclic or polycyclic system having 1-3 oxo substituents, optionally substituted with 1-3 substituents independently selected from dialkylamino, provided that Cy １ If X is a combination, １ It is a combination, X ２ is bonded, -NR ｘ２ -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O) ２ -, -NR ｘ３ C(O)-, -NR ｘ４ C(S)-, -C(O)NR ｘ５ -, -C(S)NR ｘ６ -, -NR ｘ７ C(O)NR ｘ８ -, -NR ｘ９ C(S)NR ｘ１０ -, -NR ｘ１１ C(O)O-, -NR ｘ１２ C(S)O-, -NR ｘ１３ C(O)S-, -OC(O)NR ｘ１４ -, -OC(S)NR ｘ１５ -, -SC(O)NR ｘ１６ -, -S(O) ２ NR ｘ１７ -, -NR ｘ１８ S(O) ２ -, or -NR ｘ１９ S(O) ２ NR ｘ２０ - and R ｘ１ is H or C １ ~C ３ It is alkyl, R ｘ２ 、R ｘ３ 、R ｘ４ 、R ｘ５ 、R ｘ６ 、R ｘ７ 、R ｘ８ 、R ｘ９ 、R ｘ１０ 、R ｘ１１ 、R ｘ１２ 、R ｘ１３ 、R ｘ１４ 、R ｘ１５ 、R ｘ１６ 、R ｘ１７ 、R ｘ１８ 、R ｘ１９ 、and R ｘ２０ are each independently selected from H and C １ ~C ６ alkyl, and said C １ ~C ６ alkyl is, in each occurrence, optionally substituted with amino, C １ ~C ６ alkylamino, C １ ~C ６ dialkylamino, or a 5- or 6-membered heterocyclyl containing 1 to 3 heteroatoms independently selected from N, O, and S, and said heterocyclyl is optionally substituted with C １ ~C ６ alkyl, L １ It is a linker, Ch １ It is a chelating agent, M １ It does not exist, or Ch １ It is a radioactive nuclide that forms a complex with [a certain substance].

2. R ４ However, the following formula: 【Transformation 3】 It is the basis of, Q is, 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. Z is -COOH, R ４ However, the following formula: 【Transformation 5】 It is the basis of, R ４ｅ However, it is methyl, Cy １ However, it is a 5 or 6-membered heteroaryl compound containing phenyl or 1 to 3 heteroatoms independently selected from N, O, and S (whereas Cy １ If X is a combination, １ (This is a combination.) A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. R １ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is isopropyl.

5. R １ The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the compound is cyclopropyl.

6. R ２ However, adamantyl or adamantyl-CH ２ - The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. R ２ and R ３ A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein these atoms, together with the carbon atoms to which they are bonded, form adamantyl.

8. R ４ but, 【Transformation 6】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R ４ but, 【Transformation 7】 The compound according to any one of claims 1, 2, or 4 to 7, or a pharmaceutically acceptable salt thereof.

10. R ４ but, 【Transformation 8】 The compound according to any one of claims 1 or 4 to 7, or a pharmaceutically acceptable salt thereof.

11. Q is, 【Chemistry 9】 The compound according to any one of claims 1 or 4 to 10, or a pharmaceutically acceptable salt thereof.

12. X １ A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein the compound is bonded.

13. X １ A compound according to any one of claims 1 to 11, wherein the compound is -O-, or a pharmaceutically acceptable salt thereof.

14. X １ A compound according to any one of claims 1 to 11, wherein the compound is -NH-, or a pharmaceutically acceptable salt thereof.

15. Cy １ However, a 5 or 6-membered heteroaryl compound containing 1 to 3 heteroatoms independently selected from the bond, phenyl, N, O, and S, C ４ ~C ６ Cycloalkyl, C ４ ~C ６ A cycloalkenyl, a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, and S, or a 4-6 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from N, O, and S; the phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl is phenyl, a 5 or 6 membered heteroaryl, C ４ ~C ６ Cycloalkyl, C ４ ~C ６ A cycloalkenyl, a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, and S, and a ring selected from a 4-6 membered heterocycloalkenyl, either condensed or otherwise fused to a ring selected from a cycloalkenyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, C ４ ~C ６ Cycloalkyl, C ４ ~C ６ A cycloalkenyl, a 4-6 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, and S, or a 4-6 membered heterocycloalkenyl containing 1-3 heteroatoms independently selected from N, O, and S, optionally spiro-connected to another ring selected from the cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl; or the cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl optionally contains a bridging group having 1, 2, or 3 bridging atoms independently selected from N, O, and S; Cy １ However, halo, hydroxy, amino, cyano, nitro, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkylamino, and C １ ~C ６ It is optionally substituted with 1 to 3 substituents independently selected from the group consisting of dialkylaminos, and optionally possesses 1 to 3 oxo substituents; however, Cy １ If X is a combination, １ The compound according to any one of claims 1 to 11, wherein the compound is a bond.

16. Cy １ A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the compound is bonded.

17. Cy １ The compound according to any one of claims 1 to 15, wherein the compound is phenyl, or a pharmaceutically acceptable salt thereof.

18. Cy １ The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the compound is triazolyl.

19. Cy １ but, 【Chemistry 10】 The compound according to any one of claims 1, 2, or 4 to 14, or a pharmaceutically acceptable salt thereof.

20. Cy １ but, 【Chemistry 11】 The compound according to any one of claims 1 or 4 to 10, or a pharmaceutically acceptable salt thereof.

21. X ２ However, the bond is -NH-, -NCH ３ -, -O-, -NHC(O)-, -NCH ３ C(O)-, -C(O)NH-, -C(O)NCH ３ -, -NHC(O)NH-, -NHC(O)NCH ３ -, -NCH ３ C(O)NCH ３ -, -NHC(O)O-, -NCH ３ C(O)O-, -NHC(O)S-, -NCH ３ C(O)S-, -NHS(O) ２ NH-, -NHS(O) ２ NCH ３ -, or -NCH ３ S(O) ２ NCH ３ - The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.

22. L １ but, 【Chemistry 12】 And, X ３ However, in each appearance, -NR ｘ２１ -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O) ２ -, -NR ｘ２２ C(O)-, -NR ｘ２３ C(S)-, -C(O)NR ｘ２４ -, -C(S)NR ｘ２５ -, -NR ｘ２６ C(O)NR ｘ２７ -, -NR ｘ２８ C(S)NR ｘ２９ -, -NR ｘ３０ C(O)O-, -NR ｘ３１ C(S)O-, -NR ｘ３２ C(O)S-, -OC(O)NR ｘ３３ -, -OC(S)NR ｘ３４ -, -SC(O)NR ｘ３５ -, -S(O) ２ NR ｘ３６ -, -NR ｘ３７ S(O) ２ -, or -NR ｘ３８ S(O) ２ NR ｘ３９ - Selected independently of, R ｘ２１ , R ｘ２２ , R ｘ２３ , R ｘ２４ , R ｘ２５ , R ｘ２６ , R ｘ２７ , R ｘ２８ , R ｘ２９ , R ｘ３０ , R ｘ３１ , R ｘ３２ , R ｘ３３ , R ｘ３４ , R ｘ３５ , R ｘ３６ , R ｘ３７ , R ｘ３８ , and R ｘ３９ However, in each appearance, H and C are independent of each other. １ ~C ６ Selected from alkyl, the C １ ~C ６ Alkyl, in each appearance, amino, C １ ~C ６ Alkylamino, C １ ~C ６ It is optionally substituted with a dialkylamino or a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heterocycline is C １ ~C ６ It is optionally substituted with alkyl, C １ ~C ２０ Alkylene, in each appearance, C ３ ~C １０ Cycloalkylene, C ４ ~C １０ Heterogeneous rings, and C ６ ~C １０ It is arbitrarily interrupted by 1 to 5 groups independently selected from arrine. C １ ~C ２０ Alkylene, C ３ ~C １０ Cycloalkylene, C ４ ~C １０ Heterogeneous rings, and C ６ ~C １０ Arirenes, in each appearance, produce a halo, -CO ２ H, -OH, -SH, -NH ２ , - NHC １ ~C ４ Alkyl, -N(C) １ ~C ４ (Alkyl) (C １ ~C ４ Alkyl), C １ ~C ６ Alkyl, -O-C １ ~C ６ Alkyl and -S-C １ ~C ６ It is optionally substituted with 1 to 3 groups independently selected from alkyl groups, and -NHC １ ~C ４ Alkyl, -N(C) １ ~C ４ (Alkyl) (C １ ~C ４ Alkyl), C １ ~C ６ Alkyl, -O-C １ ~C ６ Alkyl and -S-C １ ~C ６ The alkyl groups of the alkyl group are, respectively, halo and -CO. ２ H, -OH, -NH ２ , - NHC １ ~C ４ Alkyl and -N(C) １ ~C ４ (Alkyl) (C １ ~C ４ It is optionally substituted with 1 to 3 groups independently selected from alkyl groups. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein v is 1, 2, 3, 4, or 5.

23. L １ but, 【Chemistry 13】 And, X ３ However, in each appearance, -NR ｘ２１ -, -O-, -S-, -C(O)-, -C(S)-, -S(O)-, -S(O) ２ -, -NR ｘ２２ C(O)-, -NR ｘ２３ C(S)-, -C(O)NR ｘ２４ -, -C(S)NR ｘ２５ -, -NR ｘ２６ C(O)NR ｘ２７ -, -NR ｘ２８ C(S)NR ｘ２９ -, -NR ｘ３０ C(O)O-, -NR ｘ３１ C(S)O-, -NR ｘ３２ C(O)S-, -OC(O)NR ｘ３３ -, -OC(S)NR ｘ３４ -, -SC(O)NR ｘ３５ -, -S(O) ２ NR ｘ３６ -, -NR ｘ３７ S(O) ２ -, or -NR ｘ３８ S(O) ２ NR ｘ３９ - Selected independently of, R ｘ２１ , R ｘ２２ , R ｘ２３ , R ｘ２４ , R ｘ２５ , R ｘ２６ , R ｘ２７ , R ｘ２８ , R ｘ２９ , R ｘ３０ , R ｘ３１ , R ｘ３２ , R ｘ３３ , R ｘ３４ , R ｘ３５ , R ｘ３６ , R ｘ３７ , R ｘ３８ , and R ｘ３９ However, in each appearance, H and C are independent of each other. １ ~C ６ Selected from alkyl, the C １ ~C ６ Alkyl, in each appearance, amino, C １ ~C ６ Alkylamino, C １ ~C ６ It is optionally substituted with a dialkylamino or a 5 or 6-membered heterocycline containing 1 to 3 heteroatoms independently selected from N, O, and S, wherein the heterocycline is C １ ~C ６ It is optionally substituted with alkyl, C １ ~C ３ Alkylene, in each appearance, C ３ ~C １０ Cycloalkylene, C ４ ~C １０ Heterogeneous rings, and C ６ ~C １０ It is arbitrarily interrupted by 1 to 5 groups independently selected from arrine. C １ ~C ３ Alkylene, C ３ ~C １０ Cycloalkylene, C ４ ~C １０ Heterogeneous rings, and C ６ ~C １０ Arirenes, in each appearance, produce a halo, -CO ２ H, -OH, -SH, -NH ２ , - NHC １ ~C ４ Alkyl, -N(C) １ ~C ４ (Alkyl) (C １ ~C ４ Alkyl), C １ ~C ６ Alkyl, -O-C １ ~C ６ Alkyl and -S-C １ ~C ６ It is optionally substituted with 1 to 3 groups independently selected from alkyl groups, and -NHC １ ~C ４ Alkyl, -N(C) １ ~C ４ (Alkyl) (C １ ~C ４ Alkyl), C １ ~C ６ Alkyl, -O-C １ ~C ６ Alkyl and -S-C １ ~C ６ The alkyl groups of the alkyl group are, respectively, halo and -CO. ２ H, -OH, -NH ２ , - NHC １ ~C ４ Alkyl and -N(C) １ ~C ４ (Alkyl) (C １ ~C ４ It is optionally substituted with 1 to 3 groups independently selected from alkyl groups. v is 1, 2, 3, 4, or 5. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

24. L １ but, 【Chemistry 14】 And, X ３ However, in each instance, -NH- and -NCH ３ Selected independently from -, -O-, and -NHC(O)-, v is 1, 2, 3, 4, or 5. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof.

25. L １ but, 【Chemistry 15】 The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

26. L １ but, 【Chemistry 16】 A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof.

27. L １ but, 【Chemistry 17】 The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof.

28. Ch １ However, the compound according to any one of claims 1 to 27, which is an aminopolycarboxylate chelating agent, or a pharmaceutically acceptable salt thereof.

29. Ch １ However, the compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, is a macrocyclic aminopolycarboxylate chelating agent.

30. Ch １ (M １ )but, [Chemistry 18] And in the formula, R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , R ｈ , R ｉ , R ｊ , R ｋ , and R ｎ However, each independently, -OH and -NH ２ A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, selected from, wherein m, n, o, and p are each independently 0, 1, or 2.

31. Ch １ (M １ )but, 【Chemistry 19】 And in the formula, R ａ , R ｂ , R ｃ , R ｄ , R ｅ , and R ｆ However, each independently, -OH and -NH ２ A compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, selected from the above, wherein m, n, and p are each independently 0, 1, or 2.

32. Ch １ (M １ )but, 【Chemistry 20】 The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.

33. M １ However, a compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, does not exist.

34. M １ However, the compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, is a radionuclide.

35. M １ but, １７７ Lu, ２１２ Pb, or ２２５ A compound according to any one of claims 1 to 31, which is Ac, or a pharmaceutically acceptable salt thereof.

36. M １ but, １７７ A compound according to any one of claims 1 to 31, wherein the compound is Lu, or a pharmaceutically acceptable salt thereof.

37. M １ but, ６８ Ga, ６４ Cd, ８９ Zr, １１１ In, or １８ A compound according to any one of claims 1 to 31, which is an aluminum fluoride complex of F, or a pharmaceutically acceptable salt thereof. 【Request Item 38】 【Chemistry 21】 【Chemistry 22】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof. 【Request Item 39】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 The compound according to claim 1. 【Request Item 40】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】 【Transformation 30】 【Chemistry 31】 【Chemistry 32】 The compound according to claim 1.

41. M １ but, １７７ Lu, ２１２ Pb, or ２２５ A compound according to claim 39 or 40, which is Ac, or a pharmaceutically acceptable salt thereof.

42. M １ but, １７７ A compound according to claim 39 or 40, which is Lu, or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

44. A method for treating cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof.

45. The method according to claim 44, wherein the cancer has one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1).

46. The method according to claim 44 or 45, wherein the cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

47. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for use in therapy.

48. A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

49. The compound for use according to claim 47 or a pharmaceutically acceptable salt thereof, wherein the cancer has one or more cancer cells that overexpress neurotensin receptor 1 (NTSR1).

50. The compound for use according to claim 47 or 48 or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer, colorectal cancer, endometrial cancer, gastric cancer, lung cancer, pancreatic cancer, prostate cancer, head and neck cancer, non-small cell lung cancer (NSCLC), pleural mesothelioma, head and neck squamous cell carcinoma (HNSCC), glioma, glioblastoma multiforme (GBM), meningioma, Ewing's sarcoma, gastrointestinal stromal tumor, uterine leiomyoma, cutaneous T-cell lymphoma, small cell lung cancer, or pancreatic ductal adenocarcinoma.

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