Compounds targeting fibroblast activation protein and methods of use thereof - Patents.com

Abstract

Fibroblast activation protein (FAP) targeting compounds; methods for imaging cancer and fibrosis; and methods for treating fibrosis, inflammatory diseases / disorders and cancer.

Description

[Technical field]

[0001] Priority This patent application is related to and claims the benefit of priority to (a) U.S. Provisional Patent Application No. 63 / 200,593, filed March 16, 2021; (b) U.S. Provisional Patent Application No. 63 / 165,563, filed March 24, 2021; (c) U.S. Provisional Patent Application No. 63 / 200,592, filed March 16, 2021; (d) U.S. Provisional Patent Application No. 63 / 165,550, filed March 24, 2021; (e) U.S. Provisional Patent Application No. 63 / 161,835, filed March 16, 2021; and (f) U.S. Provisional Patent Application No. 63 / 165,583, filed March 24, 2021. The entire contents of each of the above applications are incorporated herein by reference. [Background technology]

[0002] Tumor survival and growth may depend on the tumor microenvironment (TME), including but not limited to the percentage of tumor stroma (TSP). High TSP may be associated with poorer long-term patient survival compared to low TSP (>50% vs. ≦50%, respectively). TSP may also be an important prognostic factor for tumor recurrence, growth, and metastasis.

[0003] Apart from cancer cells, tumors (and TSPs) contain infiltrating immune and inflammatory cells such as tumor-associated fibroblasts (TAFs) or cancer-associated fibroblasts (CAFs), extracellular matrix (ECM) proteins, T cells, tumor-associated macrophages (TAMs), myelosuppressor cells, blood and lymphatic vasculature, etc. These cells aid in tumor growth and development through growth factor secretion, immune suppression, metastasis, resistance, etc.

[0004] TAFs or CAFs are one of the major types of cells present in the tumor stroma and play several important roles in promoting tumor growth. These functions include ECM production, remodeling, and cytokine secretion. They result in angiogenesis that promotes tumor growth, secretion of signaling factors that increase chemoresistance, denser tumor stroma that provides physical barriers to immune cells, and increased cell motility that directs metastasis. In some cases, these processes resemble the behavior of pathogenic fibroblasts in fibrotic diseases.

[0005] In some cases, a frequent marker of CAF is fibroblast activation protein alpha (FAPα). FAPα is a serine protease found (mainly) on the cell surface of activated fibroblasts in diseased cells and tissues, such as fibrosis, inflammatory disease, and / or cancer (e.g., fibrosis, rheumatoid arthritis, wound healing, and cancer). More than 90% of epithelial cancers show FAPα expression in immunohistochemical (IHC) staining. Additional FAPα expression has been found in primary glioma cell cultures and a subset of TAMs. Recently, FAPα expression has been detected in at least 28 different types of human cancers. However, FAPα expression is very low or absent in the majority of adult tissues. Thus, since its expression is restricted to the surface of diseased cells, such as carcinomas, FAPα has been uniquely identified as a receptor for selectively delivering drug therapeutics to tumors by ligand targeting.

[0006] Radiotherapy and chemotherapy and other therapies can be considered for the treatment of various cancers, fibrotic disorders and inflammatory diseases to kill tumor cells.However, in many cases, such therapies are not used as first-line treatments due to the side effects (e.g., systemic) that may occur.As a result, there is a need for targeted therapy, such as therapies using targeted radiotherapy and / or chemotherapy, which can target affected cells and tissues and treat diseases (e.g., cancer, fibrotic disorders and / or inflammatory diseases) with minimal or reduced off-target or systemic effects. Summary of the Invention

[0007] A compound (e.g., a conjugate) of formula X: A mx -L-B' (X) (In the formula, A is a radical of a fibroblast activation protein alpha (FAPα) ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000); L is a (e.g., bi- or tri-functionalized) linker that links one or more A groups to B' (e.g., through a first covalent bond that links L to A and a second covalent bond that links L to B'); B' is a photodynamic therapy agent, a radioimaging agent, a radiotherapeutic agent, a chemotherapeutic agent, an antifibrotic agent, or an anticancer agent (e.g., an anticancer agent that is effective against cancer cells or cancer-associated fibroblasts, myofibroblasts, or other tumor microenvironment factors) (e.g., a radical thereof); mx is 1 to 6. is provided.

[0008] Similarly, a compound of Formula I (e.g., a conjugate): AL-B'(I) (In the formula, A comprises a FAPα ligand (i.e., a targeting moiety) (e.g., a radical thereof); L comprises a linker (e.g., bifunctionalized or trifunctionalized) that connects one or more A groups to B'; B' includes a photodynamic therapy agent, a radioimaging agent, a radiotherapeutic agent, a chemotherapeutic agent, an antifibrotic agent, or an anticancer agent (e.g., an anticancer agent effective against cancer cells or cancer-associated fibroblasts, myofibroblasts, or other tumor microenvironment factors) (e.g., radicals thereof). is provided.

[0009] Compounds (e.g., conjugates) of Formula I':

[0010] [ka] (In the formula, A is a radical of a FAPα ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000); L is a trivalent linker, B' is a radical of a phosphoinositide 3-kinase (PI3K) inhibitor, a chelating group optionally bound to an isotope, or a group covalently bound to an isotope, said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin-binding ligand, polyethylene glycol n (PEG) n (n is an integer from 0 to 32), a peptide, peptidoglycan, or sugar radical. is provided.

[0011] Similarly, a compound of formula (II) (e.g., a conjugate):

[0012] [ka] (In the formula, A comprises a radical of a FAPα ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000); L comprises a trivalent linker; B' comprises a radical of a PI3K inhibitor, a chelating group optionally bound to an isotope or a group covalently bound to an isotope, said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) n (n is an integer from 0 to 32, including a peptide, peptidoglycan, or sugar radical).

[0013] [ka] (In the formula, L is a linker containing at least one carbon atom, p is 0, 1, 2 or 3.

[0014] A compound represented by the structure of formula (X): A m -L-B' (X) (In the formula, A is a compound of the formula XB:

[0015] [ka] is the radical of the FAPα ligand, During the ceremony, T is a substituted or unsubstituted methylene (-CH-), substituted or unsubstituted amino (-NH-), -O-, or -S- (e.g., the substituents on T are C1-C3 alkyl, haloalkyl, or halo); J is C(R J ) 0~3 and R J are each independently H or alkyl, or two or more R J together to form oxo, R 1 and R 2are each independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, -SC 1~6 independently selected from the group consisting of alkyl, F, Cl, Br and I; L is a linker connecting A to B', B' is a radical of a therapeutic agent, a radioimaging agent, a radiotherapeutic agent, a magnetic resonance imaging agent, a chemotherapeutic agent, an antifibrotic agent, or an anticancer agent; m = 1 to 6) is also provided.

[0016] In certain embodiments, such compounds further comprise C', where L links C' to one or more A groups and B', and C' is an albumin binding ligand, (PEG) n (n is an integer from 0 to 32), a peptide, peptidoglycan, or a sugar radical.

[0017] In some embodiments, B' is a radical of a PI3K inhibitor, a chelating group optionally bound to an isotope, or a group covalently bound to an isotope, wherein said isotope (or metal) is suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0018] A compound represented by the structure of formula (I'):

[0019] [ka] (In the formula, A is a FAP ligand (i.e., a targeting moiety, such as and without limitation, a FAPα ligand) of formula XB:

[0020] [ka] is a radical of During the ceremony, T is a substituted or unsubstituted methylene (-CH-), substituted or unsubstituted amino (-NH-), -O-, or -S- (e.g., the substituents on T are C1-C3 alkyl, haloalkyl, or halo); J is C(R J ) 0~3 and R J are each independently H or alkyl, or two or more R J together to form oxo, R 1 and R 2 are each independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6alkyl, R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, alkyl, and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, -SC 1~6 each independently selected from the group consisting of alkyl, F, Cl, Br and I; L is a trivalent linker, B' is a radical of a chelating group optionally bound to an isotope, said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) n (n is an integer from 0 to 32), a peptide, peptidoglycan, or sugar radical. is also provided.

[0021] In certain embodiments of the compound, A is

[0022] [ka] may be also possible.

[0023] In certain embodiments of the compound, A is

[0024] [ka] may be also possible.

[0025] In at least one embodiment of the compound, A is

[0026] [ka] Includes.

[0027] Alternatively, A may be

[0028] [ka] where X is 1 to 20.

[0029] In certain embodiments, A is

[0030] [ka] Includes.

[0031] B' may also be the radical of a chelating group optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0032] B' is

[0033] [ka] each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0034] In certain embodiments, B' is

[0035] [ka] each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0036] B' may be, for example, the radical of a chelating group bound to an isotope suitable for PET imaging, SPECT imaging, other radioimaging techniques, magnetic resonance imaging, or radiotherapy. B' may, in certain embodiments, comprise a radical of DOTA. B' may comprise a radical of isotope-chelated (or metal-chelated) DOTA. B' may comprise a radical of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. B' may be the radical of a group covalently bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging. B' may be

[0037] [ka] The group may include a group selected from:

[0038] B' is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0039] [ka] B' can include a radical of a radioimaging, radiotherapeutic, or magnetic resonance isotope. In certain embodiments, B' includes a chelating group and a radioimaging, radiotherapeutic, or magnetic resonance isotope (or metal) bound to the chelating group.

[0040] In certain embodiments, B' comprises a radioimaging isotope, radiotherapeutic isotope, or magnetic resonance isotope, or a radical of a radioimaging isotope, radiotherapeutic isotope, or magnetic resonance isotope that is a chelating group and an isotope (e.g., a metal) bound to the chelating group, wherein the isotope is 18 F, 32 P, 44 Sc, 47 Sc, 52 Mn, 55 Co,64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 89 Sr, 89 Zr, 90 Y, 99m Tc, 111 In, 114m In, 117m Sn, 124 I, 125 I, 131 I, 149 Tb, 153 Sm, 152 Tb, 155 Tb, 161 Tb, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ab, 225 Ac or 227 The isotope of B' is selected from 111 The isotope of B' may be 177 In certain embodiments, the isotope may be: 11 C. 13 C. 13 N, 15 O. 60 Co and 123 I is selected from the group consisting of

[0041] Compound A can have a binding affinity to FAPα of about 1 nM to about 25 nM. In certain embodiments, A has a binding affinity to FAP of about 1 nM to about 25 nM.

[0042] L of the compound can include a non-releasable linker. L can include a releasable linker. In certain embodiments, L is PEG. nand n=0-36. L can comprise a peptide. L can comprise a peptidoglycan. In certain embodiments, L comprises

[0043] [ka] Includes.

[0044] L is

[0045] [ka] may include.

[0046] C' may be a radical of an albumin binding ligand, having the following structure:

[0047] [ka] has.

[0048] In certain embodiments, C' is a radical of an albumin binding ligand and has the following structure:

[0049] [ka] has.

[0050] C' can be, for example, the following:

[0051] [ka] It may also be one of the radicals:

[0052] C' may in some embodiments be the radical of an albumin binding small protein scaffold, including ABD035, ABDCon, DARPin, dsFv CA645, nanobody and VNAR(E06). C' may be PEG. nwhere n is an integer from 0 to 32. C' may be a peptide. C' may be a peptidoglycan. C' may be a sugar.

[0053] In certain embodiments, C' is

[0054] [ka] It is.

[0055] C' is

[0056] [ka] may be also possible.

[0057] In certain embodiments, the compound has the structure of formula (V):

[0058] [ka] It can be expressed by During the ceremony, L is a linker containing at least one carbon atom, p is 0, 1, 2 or 3.

[0059] However, in some embodiments, the compound is:

[0060] [ka] isn't it.

[0061] p may be 2. p may be 0.

[0062] Furthermore, L is

[0063] [ka] may include During the ceremony, m is an integer from 1 to 9; n is an integer from 1 to 32, q is an integer from 0 to 4, s is an integer from 0 to 4.

[0064] In certain embodiments, the compound is

[0065] [ka] and In the formula, t is 0 or 1, and u is an integer of 2 to 12.

[0066] In some embodiments, the compound is

[0067] [ka] and m is an integer from 1 to 4.

[0068] In some embodiments, the compound has the formula:

[0069] [ka] It is.

[0070] In some embodiments, the compound has the formula:

[0071] [ka] It is.

[0072] In some embodiments, the compound has the formula:

[0073] [ka] It is.

[0074] In some embodiments, the compound has the formula:

[0075] [ka] It is.

[0076] In some embodiments, the compound has the formula:

[0077] [ka] It is.

[0078] In some embodiments, the compound has the following structure:

[0079] [ka] each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0080] In some embodiments, the compound has the following structure:

[0081] [ka] each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0082] In some embodiments, the compound has the following structure:

[0083] [ka] each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0084] In some embodiments, the compound has the following structure:

[0085] [ka] each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0086] In certain embodiments, the compound has the following structure:

[0087] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging procedures.

[0088] In certain embodiments, the compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0089] [ka] It is.

[0090] The compound, in certain embodiments, has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0091] [ka] has.

[0092] In certain embodiments, the compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0093] [ka] may have the following structure:

[0094] In certain embodiments, the compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0095] [ka] may have the following structure:

[0096] The compounds herein have the following structure:

[0097] [ka] each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0098] In certain embodiments, the compounds herein have the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0099] [ka] may have the following structure:

[0100] The compounds herein have the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0101] [ka] may have the following structure:

[0102] The compounds herein have the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0103] [ka] may have the following structure:

[0104] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0105] [ka] may have the following structure:

[0106] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0107] [ka] may have the following structure:

[0108] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0109] [ka] may have the following structure:

[0110] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0111] [ka] may have the following structure:

[0112] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0113] [ka] may have the following structure:

[0114] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0115] [ka] may have the following structure:

[0116] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0117] [ka] may have the following structure:

[0118] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0119] [ka] may have the following structure:

[0120] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0121] [ka] may have the following structure:

[0122] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0123] [ka] may have the following structure:

[0124] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0125] [ka] may have the following structure:

[0126] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0127] [ka] may have the following structure:

[0128] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0129] [ka] may have the following structure:

[0130] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0131] [ka] may have the following structure:

[0132] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0133] [ka] may have the following structure:

[0134] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0135] [ka] may have the following structure:

[0136] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0137] [ka] may have the following structure:

[0138] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0139] [ka] may have the following structure:

[0140] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0141] [ka] may have the following structure:

[0142] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0143] [ka] may have the following structure:

[0144] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0145] [ka] may have the following structure:

[0146] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0147] [ka] may have the following structure:

[0148] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0149] [ka] may have the following structure:

[0150] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0151] [ka] may have the following structure:

[0152] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0153] [ka] may have the following structure:

[0154] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0155] [ka] may have the following structure:

[0156] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0157] [ka] may have the following structure:

[0158] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0159] [ka] may have the following structure:

[0160] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0161] [ka] may have the following structure:

[0162] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0163] [ka] may have the following structure:

[0164] The compound has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0165] [ka] may have the following structure:

[0166] Certain compounds herein have the structure of formula (X): A m -L-B' (X) is represented by During the ceremony, A is a structure of formula XX:

[0167] [ka] is represented by

[0168] [ka] teeth,

[0169] [ka] having a structure selected from the group consisting of: n=1 to 5, n'=1 to 5, Ring C is optional; X, Y and Z in ring B are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' in ring C are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N; P is the point of attachment of ring C (if present) to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl; L, if present, is a linker; B' is a radical of an imaging agent or a radical of a therapeutic agent; m=1~6.

[0170] The compound can further include C', where L links C' to one or more A groups and B', and C' is an albumin binding ligand, (PEG) n (n is an integer from 0 to 32), a peptide, peptidoglycan, or a sugar radical.

[0171] In certain embodiments, B' is a radical of a radioimaging agent, a radiotherapeutic agent, or a magnetic resonance imaging agent.

[0172] B' may be aromatic. In certain embodiments, n=2, n'=1, and A is of the formula (XZ):

[0173] [ka] It is represented by:

[0174] In certain embodiments, n=0-4 and A is a structure of formula XY:

[0175] [ka] It is represented by:

[0176] In certain embodiments, the compound has the structure:

[0177] [ka] has.

[0178] In certain embodiments, the compound has the structure:

[0179] [ka] has.

[0180] In certain embodiments, the compound has the structure:

[0181] [ka] has.

[0182] In certain embodiments, the compound has the structure:

[0183] [ka] has.

[0184] L of the compound can include one or more linker groups, each of which is independently selected from the group consisting of alkyl(alkylene), heteroalkyl(alkylene), heterocycloalkyl(alkylene), heteroaryl, aryl, alkoxy, thioether, disulfide, carboxylic acid, anhydride, carbonate, carbamate, thioether, sugar, peptide, and peptidoglycan. L may be a single linker. L may include two or more linker groups. In certain embodiments, each of the linker groups may be PEG.

[0185] In certain embodiments, L of the compound is 1 ) p -W-(L 2 ) q And L 1 is the first linker, L 2 is a second linker, W is a third linker, p=1 to 5 and q=1 to 5. 1 and each L 2 can independently comprise one or more linker groups, each of which is independently selected from the group consisting of alkyl(alkylene), heteroalkyl(alkylene), heterocycloalkyl(alkylene), heteroaryl, aryl, alkoxy, thioether, disulfide, carboxylic acid, anhydride, carbonate, carbamate, thioether, sugar, peptide, and peptidoglycan. In certain embodiments, each L 1 and each L 2 can independently comprise one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(ene), amide, phenyl, and triazole. In certain embodiments, W has an amine core, an aromatic core, or an alkylene core.

[0186] Compound L, L 1 , L 2 or L 1 and L 2can have a length of 5 angstroms to 200 angstroms. In some embodiments, L, L 1 , L 2 or L 1 and L 2 The structure:

[0187] [ka] wherein n is an integer from 0 to 10.

[0188] L, L 1 , L 2 or L 1 and L 2 The structure:

[0189] [ka] In other embodiments, L, L 1 , L 2 or L 1 and L 2 The structure:

[0190] [ka] where n=1-32.

[0191] In certain embodiments (e.g., including triazoles), B' is a radical of a dye. The dye may be, for example, fluorescent. B' may be a radical of an anti-cancer agent. B' may be a radical of an anti-fibrotic agent. B' may be a radical of a PI3K inhibitor. B' may be a radical of a radioimaging agent that includes a chelated radioisotope. In certain embodiments, the radioisotope is 99m Tc, 111 In, 18 F, 68 Ga, 124 I,125 I and 131 I. In certain embodiments, the radioisotope is selected from the group consisting of: 32 P, 89 Sr, 90 Y, 153 Sm, 169 Er, 177 Lu, 186 Re, 188 Re, 149 Tb, 211 At, 212 Bi, 213 Bi and 225 Ac. B' may be a radical of a dye. B' may be a radical of a fluorescent dye. B' may be a radical of an anticancer drug. B' may be a radical of an antifibrotic drug.

[0192] A ligand is also provided, in certain embodiments, the ligand is to a FAP and comprises an isoindoline scaffold into which a triazole moiety is incorporated, the ligand having a Schrodinger molecular docking score of at least about -8.0 kcal / mol.

[0193] In certain embodiments, A of the compound has the structure X-X′:

[0194] [ka] is represented by

[0195] [ka] has the formula XB, P is the point of attachment to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0196] In certain embodiments, A has the structure of formula XY:

[0197] [ka] is represented by

[0198] [ka] has the formula XB, n=0 to 4, X, Y and Z are each independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' are each independently selected from O, N and S, with the proviso that at least one of X' and Y' is N or Z is N; P is the point of attachment to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0199] A is a structure of formula XZ:

[0200] [ka] This can be further expressed by:

[0201] [ka] has the formula XB, X, Y and Z are each independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' are each independently selected from O, N and S, with the proviso that at least one of X' and Y' is N or Z is N; P is the point of attachment to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0202] Provided is a pharmaceutical composition comprising any of the compounds described herein.Such a pharmaceutical composition can, for example, comprise any one of the compounds described herein and a pharma-ceutically acceptable carrier.

[0203] Further provided is a method for imaging cancer or fibrosis (e.g., pulmonary fibrosis, renal fibrosis, or liver fibrosis) in a subject having cancer or fibrosis. The method comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition comprising the compound. The method can further comprise imaging the subject. In certain embodiments, the method further comprises generating an image of cancer or fibrosis in the subject.

[0204] Further provided is a method for treating fibrosis in a subject. The method comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition comprising the compound. The fibrosis can be selected, for example, from pulmonary fibrosis, renal fibrosis and hepatic fibrosis.

[0205] Further provided is a method of treating an inflammatory disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition comprising the compound (e.g., as described herein).

[0206] Also provided is a method for treating cancer.In certain embodiments, the method for treating cancer comprises administering a therapeutically effective amount of the compound herein or a pharmaceutical composition comprising the compound to a subject in need thereof.The cancer can be selected from the group consisting of lung cancer, breast cancer, colon cancer, cervical cancer and brain cancer (e.g., glioblastoma).In certain embodiments, the method further comprises administering chemotherapy or radiation therapy to the subject (or, for example, administering additional cancer treatment to the subject).

[0207] Further provided is a method for improving the affinity of a ligand comprising an isoindoline scaffold for a FAP, in certain embodiments, the method comprises introducing a triazole moiety into the isoindoline scaffold of the ligand by molecular modeling to achieve a higher Schrödinger molecular docking score. [Brief description of the drawings]

[0208] [Figure 1-1] We show both exemplified and predicted structure extraction examples of various fibroblast activation proteins (FAPs). Structures FAP-3000-3017 are synthetic examples, while FAP-3018-FAP-3029 are predicted. [Figure 1-2] Same as above. [Figure 1-3] Same as above. [Figure 1-4] Same as above. [Figure 1-5] Same as above. [Figure 1-6] Same as above. [Figure 1-7] Same as above. [Figure 1-8] Same as above. [Figure 1-9] Same as above. [Figure 1-10] Same as above. [Diagram 2]FIG. 2A illustrates the replacement of FAP ligand conjugated to rhodamine fluorescent dye from HEK-FAP cells with FAP ligand conjugated to DOTA without albumin binder (FAP-3000) at a range of concentrations. FIG. 2B illustrates the same displacement assay with FAP ligand conjugated to DOTA with iodobenzene albumin binder (FAP-3001). FIG. 2C illustrates the same displacement assay with FAP ligand conjugated to NOTA with fluorobenzene albumin-binder (FAP-3002). FIG. 2D illustrates the same displacement assay with FAP ligand conjugated to NOTA with chlorobenzene albumin-binder (FAP-3003). FIG. 2E illustrates the same displacement assay with FAP ligand conjugated to DOTA with a shorter PEG(4) spacer (FAP-3015). Figure 2F illustrates the same displacement assay with a FAP ligand conjugated to a longer PEG(12) spacer (FAP-3016), and Figure 2G illustrates the same displacement assay with a monofluoro analog of the FAP ligand (FAP-3017). [Figure 3-1] FIG. 3A shows indium-111 radiolabeling data for FAP-3000. [Figure 3-2] FIG. 3B shows lutetium-177 radiolabeling data for FAP-3000. [Figure 3-3] FIG. 3C shows indium-111 radiolabeling data for FAP-3001. [Diagram 3-4] FIG. 3D shows lutetium-177 radiolabeling data for FAP-3001. [Figure 4] Figure 4A illustrates the binding curve of In-FAP-3000 to the cancer-associated fibroblast cell line Hs894 over a range of concentrations in the absence or presence of 100x excess FAP ligand as competitive blockade. Figure 4B illustrates the same binding curve assay with In-FAP-3001. [Diagram 5]Figure 5A illustrates a study of In-FAP-3000 administration using the same amount of radioactivity but different molecular numbers in nude mice bearing HT29 tumors, using single photon emission computed tomography / computed tomography (SPECT / CT). Figure 5B illustrates a study of In-FAP-3001 administration using the same amount of radioactivity but different molecular numbers in nude mice bearing HT29 tumors, using SPECT / CT. [Figure 6] Figure 6A illustrates a study of 111In-FAP-3000 administration using the same amount of radioactivity but different molecular numbers in nude mice bearing 4T1 tumors, using single photon emission computed tomography / computed tomography (SPECT / CT). Figure 6B illustrates a study of 111In-FAP-3001 administration using the same amount of radioactivity but different molecular numbers in nude mice bearing 4T1 tumors, using SPECT / CT. The highest intensity of radioactivity is identified by an open circle in each image. [Figure 7] Figure 7A illustrates the retention study of 111In-FAP-3001 in BALB / c mice bearing 4T1 tumors using SPECT / CT. Figure 7B illustrates the retention study of 111In-FAP-3001 in mice bearing KB tumors using SPECT / CT. The highest intensity of radioactivity is identified by an open circle in each image. [Figure 8] Figure 8A illustrates the biodistribution study of 177Lu-FAP-3000 at various time points in BALB / c mice bearing 4T1 tumors. Figure 8B illustrates the biodistribution study of 111In-FAP-3001 at various time points in BALB / c mice bearing 4T1 tumors. Standard error bars are shown in both Figures 8A and 8B. [Figure 9]Figure 9A illustrates a radiotherapy study using two different doses of Lu-177-radiolabeled 177In-FAP-3001 (0.25 mCi vs. 0.5 mCi) using a 4T1 tumor growth chart in BALB / c mice injected on day 0. Figure 9B tracks the relative weight of the mice. Figure 9C shows a SPECT / CT scan of one of the treated mice 24 hours after injection, with the highest intensity of radioactivity identified by an open circle in each image. Standard error bars are shown in both Figures 9A and 9B. [Figure 10] Figure 10A illustrates a radiotherapy study with 177In-FAP-3000 radiolabeled at 0.5 mCi using the KB tumor growth chart in nude mice injected on day 0. Figure 10B illustrates the survival curve of the same study. Figure 10C tracks the relative weight of mice in the same study. Standard error bars are shown in both Figures 10A and 10C. [Figure 11] Figure 11A illustrates a radiotherapy study with 0.5 mCi radiolabeled 177In-FAP-3001 using the KB tumor growth chart in nude mice injected on day 0. Figure 11B illustrates the survival curve of the same study. Figure 11C tracks the relative body weight of mice in the same study. Standard error bars are shown in both Figures 11A and 11C. [Figure 12-1] Figure 12A illustrates a radiotherapy study using 0.25 mCi radiolabeled 177In-FAP-3001 using a HT29 tumor growth chart in nude mice injected on day 0. Figure 12B illustrates the survival curve of the same study. Figure 12C tracks the relative body weight of mice in the same study. [Figure 12-2] Figure 12D shows a photograph of the tumors dissected after euthanasia. Standard error bars are shown in both Figures 12A and 12C. [Figure 13]Figure 13A illustrates a radiotherapy study using two different doses of Lu-177 radiolabeled 177In-FAP-3001 (0.25mCi vs. 0.5mCi) injected on day 0 using a U87MG tumor growth chart in nude mice. Figure 13B illustrates the survival curve of the same study. Figure 13C tracks the relative weight of mice in the same study. Standard error bars are shown in both Figures 13A and 13C. [Figure 14] Shown are images of tissue sections taken from various organs of interest in the control and treatment (0.5 mCi) groups that were H&E stained for evaluation. [Figure 15-1] Figure 15A illustrates a radiotherapy study with 177In-FAP-3001 (1.5mCi injected on day 0 or two different doses, 1.5mCi+0.60mCi injected on days 0 and 3, respectively). Figure 15B illustrates the survival curve of the same study. Figure 15C tracks the relative body weight of mice in the same study. [Figure 15-2] Figure 15D shows SPECT / CT scans of one of the treated mice at various time points after injection. Standard error bars are shown in both Figures 15A and 15C. [Figure 16] Figure 16A illustrates a radiotherapy study with 1.5 mCi of radiolabeled 177In-FAP-3001 injected on day 0 and then measured by two investigators in a blinded fashion. Figure 16B illustrates the survival curve of the same study. Figure 16C tracks the relative body weight of mice in the same study. Standard error bars are shown in both Figures 16A and 16C. [Figure 17] Figure 17A illustrates a radiotherapy study with 1.5 mCi radiolabeled 177In-FAP-3001 versus 177In-FAP-3005 injected on day 0. Figure 17B illustrates the survival curves of the same study. Figure 17C tracks the relative weights of mice in the same study. Standard error bars are shown in both Figures 17A and 17C. [Figure 18]Figure 18A shows a summary of the histopathology of autopsy tissues from radiotherapy treatment with 177Lu-FAP-3001 at different doses and various time points after injection. Figure 18B shows images of tissue sections taken from various organs of interest in the control and treatment (1.5 mCi) groups at various time points after injection, stained with H&E for evaluation. [Figure 19] 1 illustrates a SPECT / CT scan of 111In-FAP-3001 in a pulmonary fibrosis model 24 hours after injection. The upper arrow indicates the lung. The lower arrow indicates the kidney. [Figure 20-1] 20A and 20B illustrate the structures of various fibroblast activation protein (FAP)-phosphoinositide 3-kinase (PI3K) (FAP5-PI3K) inhibitors. [Figure 20-2] Same as above. [Figure 21] Results of FAP5-PI3K inhibitor after 24 hours are shown. [Figure 22] Results of FAP5-PI3K inhibitor after 48 hours are shown. [Diagram 23] Figures 23A and 23B show graphical data relating to inhibition of Akt phosphorylation by FAP5-PI3K inhibitors after 24 hours of incubation (Figure 5A) and after 48 hours of incubation (Figure 5B). [Figure 24] Mass spectrometry data is shown, respectively, confirming that the desired compounds of interest were produced. [Diagram 25] Mass spectrometry data is shown, respectively, confirming that the desired compounds of interest were produced. [Figure 26] A molecular model of a known FAP inhibitor (FAP inhibitor 1) and a molecular model of FAP-4001 are depicted, illustrating that when docked, the interaction between FAP and FAP-4001 is increased. [Figure 27-1] Molecular models of various compounds and their interactions with the FAP when docked are illustrated. [Figure 27-2] Same as above. [Figure 27-3] Same as above. [Figure 27-4] Same as above. [Figure 27-5] Same as above. [Figure 28-1] 1 shows exemplary structures of various FAP triazole scaffolds. [Figure 28-2] Same as above. [Figure 29] 1 shows exemplary structures of various compounds without a linker. [Diagram 30] 1 shows exemplary structures of various compounds that include a PEG linker. [Diagram 31] 1 shows exemplary structures of various compounds that include alkyl linkers. [Diagram 32] Figures 32A and 32B illustrate fluorescent images (panels I and iv) and white light images (panels ii and v), merged in panels ii and vi, taken from studies of internalizing FAP-4004 (Figure 32A) and FAP-4003 (Figure 32B) in HT1080-FAP cells. Figures 32C and 32D show graphical data regarding the binding affinity and specificity of FAP-4004 (Figure 32C) and FAP-4002 (Figure 32D) herein. [Diagram 33] Figures 33A-33C depict graphical data regarding an analysis of the ability of the FAP targeting ligand FAP-4002 to inhibit the closely related dipeptidyl peptidases FAP (Figure 33A), PREP (Figure 33B), and DPP-IV (Figure 33C). [Figure 34-1] Figures 34A-34C illustrate data relating to confirmation of production of certain compounds herein, with Figures 34A and 34B showing H nuclear magnetic resonance spectroscopy (H NMR) data for compound 16 and Figure 34C showing H NMR (DO) spectral data for FAP-4003. [Figure 34-2] Same as above. [Figure 34-3] Same as above. [Diagram 35] 1 shows the excitation (Ex) and emission (Em) spectra of a 1 μM solution of FAP-4003 in PBS, pH 7.4. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0209] The present disclosure relates to the preparation and use of compounds and compositions that reduce the tendency of off-target toxicity following administration of therapeutic and / or imaging agents (e.g., radioimaging, radiotherapeutic, chemotherapeutic, antifibrotic or anticancer agents). The term "off-target toxicity" refers to organ or tissue damage, or loss of a subject's body weight that is undesirable to the physician treating the subject, or any other effect on the subject that is a potentially adverse indicator to the treating physician (e.g., B-cell aplasia, fever, decreased blood pressure or pulmonary edema). The terms "treat", "treating", "treated" or "treatment" (related to a disease or condition) are used in reference to an approach to obtain a beneficial or desired result, such as a clinical result. Such results include, but are not limited to, one or more of the following: amelioration of a condition related to a disease, cure of a disease, reduction in the severity of a disease, delay in progression of a disease, relief of one or more symptoms related to a disease, improvement in the quality of life of those suffering from a disease, prolonged survival, and / or prophylactic (e.g., preventative) treatment. In particular, with reference to cancer, the terms "treat," "treating," "treated," or "treatment" can further mean reduction in tumor size, complete or partial removal of a tumor (e.g., complete or partial response), stabilization of the disease, prevention of cancer progression (e.g., progression-free survival), or any other effect on cancer that a physician considers to be a therapeutic or prophylactic treatment of the cancer.

[0210] The compounds herein may include a fibroblast activation protein (FAP) targeting ligand (or a radical thereof) that is attached to a linker that includes one or more linker groups (e.g., three linker groups), and the linker is further attached to a therapeutic or imaging agent. FAP is a type II membrane-bound serine protease that cleaves proline-amino acid peptide bonds and can be expressed in cancer-associated fibroblasts (CAFs) and myofibroblasts that produce collagen. In certain embodiments, the compounds can target therapeutic compounds to FAPs that express cancer, or fibrotic disease, or inflammatory disease. In certain embodiments, such improved FAP targeting ligand scaffolds can be further used with albumin-binding moieties to achieve targeted delivery of radiolabeled and other functional groups. In certain embodiments, the FAP targeting ligand refers to a high affinity FAP ligand that includes a triazole moiety (or a derivative thereof) that is introduced into the ligand scaffold. In certain embodiments, the FAP targeting ligand refers to a high affinity FAP ligand that includes a triazole moiety (or a derivative thereof) and a phenyl ring incorporated into the ligand scaffold (e.g., an isoindoline ring scaffold). Unless otherwise specified, "high affinity" or "higher affinity" in reference to the affinity of a ligand for a target refers to a ligand that has a Schrodinger molecular docking score of at least about -8.0 kcal / mol. In certain embodiments, the high affinity FAP ligand has improved affinity for the FAP compared to a ligand that does not include a triazole moiety incorporated therein.

[0211] The compounds, compositions and methods will now be described in detail.In order to facilitate understanding of the principles presented herein, reference will be made to the embodiments illustrated in the drawings, and specific phrases will be used to describe them.Nevertheless, it will be understood that the description of these embodiments is not intended to limit the scope.On the contrary, the present disclosure is intended to encompass alternatives, modifications and equivalents that may be included within the spirit and scope of the present application as defined by the appended claims.As previously stated, the present technology may be illustrated and described in one or more preferred embodiments, but the compositions, compounds and methods herein may include many different configurations, forms, materials and auxiliary materials.

[0212] compound A compound of formula X (i.e., a conjugate): A mx -L-B' (X) (In the formula, A is a radical of a fibroblast activation protein alpha (FAPα) ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000); L is a (e.g., bi- or tri-functionalized) linker that links one or more A groups to B' (e.g., through a first covalent bond that links L to A and a second covalent bond that links L to B'); B' is a photodynamic therapy agent, a radioimaging agent, a radiotherapeutic agent, a chemotherapeutic agent, an antifibrotic agent, or an anticancer agent (e.g., an anticancer agent that is effective against cancer cells or cancer-associated fibroblasts, myofibroblasts, or other tumor microenvironment factors) (e.g., a radical thereof); mx is 1 to 6. is provided.

[0213] In certain embodiments, mx is 1. In certain embodiments, mx is 2. In certain embodiments, mx is 3. In certain embodiments, mx is 4. In certain embodiments, mx is 5. In certain embodiments, mx is 6. mx may be 1 to 3, 2 to 4, or 1 to 5.

[0214] The present disclosure also relates to compounds of formula I (i.e., conjugates): AL-B'(I) (In the formula, A comprises a FAPα ligand (i.e., a targeting moiety) (e.g., a radical thereof); L comprises a linker (e.g., bifunctionalized or trifunctionalized) that connects one or more A groups to B'; B' includes a photodynamic therapy agent, a radioimaging agent, a radiotherapeutic agent, a chemotherapeutic agent, an antifibrotic agent, or an anticancer agent (e.g., an anticancer agent effective against cancer cells or cancer-associated fibroblasts, myofibroblasts, or other tumor microenvironment factors) (e.g., radicals thereof). Regarding.

[0215] Similarly, a compound of Formula I (e.g., a conjugate): AL-B' (I) (In the formula, A comprises a FAPα ligand (i.e., a targeting moiety) (e.g., a radical thereof); L comprises a linker (e.g., bifunctionalized or trifunctionalized) that connects one or more A groups to B'; B' comprises a radiolabeled functional group (e.g., a radical thereof) suitable for PET imaging, SPECT imaging, other radioimaging techniques, or radiotherapy. is provided.

[0216] Similarly, a compound represented by the structure of formula (X): AL-B'(X) (In the formula, A is a compound of the formula XB:

[0217] [ka] is the radical of the FAPα ligand, During the ceremony, T is a substituted or unsubstituted methylene (-CH-), substituted or unsubstituted amino (-NH-), -O-, or -S- (e.g., the substituents on T are C1-C3 alkyl, haloalkyl, or halo); J is C(R J ) 0~3 and R J are each independently H or alkyl, or two or more R J together to form oxo, R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, alkyl, and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, -SC 1~6 independently selected from the group consisting of alkyl, F, Cl, Br and I; L is a linker connecting A to B', B' is a therapeutic agent, a radioimaging agent, a radiotherapeutic agent, a chemotherapeutic agent, an antifibrotic agent, or an anticancer agent. is provided.

[0218] In some embodiments, A of formula X has the structure of formula X-X':

[0219] [ka] is represented by

[0220] [ka] has the formula XB, P is the point of attachment to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0221] In some embodiments, A of formula X has the structure of formula XX:

[0222] [ka] is represented by

[0223] [ka] has the formula XB, n=1 to 5, n'=1 to 5, Ring C is optional; X, Y and Z in ring B are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' in ring C are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N; P is the point of attachment of ring C (if present) to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0224] In some embodiments,

[0225] [ka] teeth,

[0226] [ka] The compound has a structure selected from the group consisting of:

[0227] In some embodiments, the compound further comprises C′, L links C' to one or more A groups and to B'; C' is an albumin-binding ligand, polyethylene glycol n (PEG) n (n is an integer from 0 to 32), a peptide, peptidoglycan, or a sugar radical.

[0228] Similarly, a compound represented by the structure of formula (I'):

[0229] [ka] (In the formula, A is a compound of the formula XB:

[0230] [ka] is a radical of a FAPα ligand (targeting moiety) of During the ceremony, T is a substituted or unsubstituted methylene (-CH-), substituted or unsubstituted amino (-NH-), -O-, or -S- (e.g., the substituents on T are C1-C3 alkyl, haloalkyl, or halo); J is C(R J ) 0~3 and R J are each independently H or alkyl, or two or more R J together to form oxo, R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, -SC 1~6 each independently selected from the group consisting of alkyl, F, Cl, Br and I; L is a trivalent linker, B' is a radical of a chelating group optionally bound to an isotope, said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) n(n is an integer from 0 to 32), a peptide, peptidoglycan, or sugar radical. is provided.

[0231] In some embodiments, B' is a radical of a therapeutic or imaging agent, such as, for example, a phosphoinositide 3-kinase (PI3K) inhibitor, a chelating group optionally bound to an isotope (or metal), or a group covalently bound to an isotope (or metal), wherein the isotope (or metal) is suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0232] In some embodiments, B' is a radical of a chelating group optionally bound to a metal, or a group covalently bound to an isotope, said metal or isotope being suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0233] Compounds (e.g., conjugates) of Formula I':

[0234] [ka] (In the formula, A is a radical of a FAPα ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000); L is a trivalent linker, B' is a radical of a therapeutic or imaging agent, such as, for example, a PI3K inhibitor, a chelating group optionally bound to an isotope (or metal), or a group covalently bound to an isotope (or metal), said metal or isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) n (n is an integer from 0 to 32), a peptide, peptidoglycan, or a sugar radical). is also provided.

[0235] The present disclosure also relates to compounds (e.g., conjugates) of formula (II):

[0236] [ka] (In the formula, A comprises a radical of a FAPα ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000); L comprises a trivalent linker; B' comprises a radical of a PI3K inhibitor, a chelating group optionally bound to a metal or a group covalently bound to an isotope, said metal or isotope being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) n (n is an integer from 0 to 32), including radicals of peptides, peptidoglycans, or sugars). Regarding.

[0237] The present disclosure also relates to a compound of formula (II) (i.e., a conjugate):

[0238] [ka] (In the formula, A comprises a radical of a FAPα ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000); L comprises a trivalent linker; B' comprises a radical of a PI3K inhibitor, a chelating group optionally bound to an isotope (or metal) or a group covalently bound to an isotope (or metal), said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' contains the radical of an albumin-binding ligand. Regarding.

[0239] In some embodiments, the compound has the structure of Formula (I'):

[0240] [ka] (In the formula, A is a radical of a FAPα ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000);

[0241] [ka] Including, L is a trivalent linker, B' is a radical of a PI3K inhibitor, a chelating group optionally bound to an isotope (or metal) or a group covalently bound to an isotope (or metal), said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) n (n is an integer from 0 to 32), a peptide, peptidoglycan, or sugar radical. It is represented by:

[0242] In some embodiments, the compound has the structure of Formula (I'):

[0243] [ka] (In the formula, A is a radical of a FAPα ligand (i.e., a targeting moiety) (e.g., having a molecular weight of less than 10,000);

[0244] [ka] Including, L is a trivalent linker, B' is a radical of a chelating group optionally bound to an isotope (or metal), said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is the radical of an albumin-binding ligand. It is represented by:

[0245] In some embodiments, the compound has the structure of Formula (X): A m -L-B' (X) (In the formula, A is a structure of formula XX:

[0246] [ka] is represented by

[0247] [ka] teeth,

[0248] [ka] and any other FAP ligand structure described herein, n=1 to 5, n'=1 to 5, Ring C is optional; X, Y and Z in ring B are each independently selected from O, N and S, provided that at least one of X and Y is N or Z is N; X' and Y' in ring C are each independently selected from O, N and S, with the proviso that at least one of X' and Y' is N; P is the point of attachment of ring C (if present) to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl; L, if present, is a linker; B' is a radical of an imaging agent or a radical of a therapeutic agent; m = 1 to 6) It is represented by:

[0249] The compounds contain one or more asymmetric centers and can therefore give rise to enantiomers, diastereomers and other stereoisomers defined in terms of absolute stereochemistry as (R)- or (S)-. Unless otherwise specified, all stereoisomers of the compounds are intended to be contemplated. When the compounds contain an alkene double bond, and unless otherwise specified, this is intended to include both E and Z geometric isomers (e.g., cis or trans). Similarly, all possible isomers, as well as their racemic and optically pure forms, and all tautomers are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho-, meta- and para-isomers around a benzene ring. Those skilled in the art will further recognize that the compounds can be "deuterated", meaning that one or more hydrogen atoms can be replaced by deuterium.

[0250] The compound may be a monovalent conjugate (e.g., a compound that includes one binding ligand (described elsewhere herein, e.g., one FAP binding ligand). The compound may be a bivalent conjugate (e.g., a compound that includes one or more binding ligands (described elsewhere herein, e.g., one or more FAP binding ligands) conjugated (e.g., via a linker) to a therapeutic or imaging agent (described elsewhere herein). The compound may be a multivalent conjugate (e.g., a compound that includes two or more binding ligands (described elsewhere herein, e.g., two or more FAP binding ligands) conjugated to a multipoint linker).

[0251] Binding Ligand / Targeting Moiety (A) In certain embodiments, A in formula (X), (I), (I') or (II) is a targeting moiety / binding ligand. A binding ligand (also referred to herein as a targeting ligand or a targeting moiety) may be a compound (or a radical thereof) that binds to a biomolecule (e.g., a polypeptide (e.g., an enzyme)) that is localized to a specific cell, tissue, organ, etc. A binding ligand may be a FAP ligand (or a radical thereof). A binding ligand may be a fibroblast activation protein alpha (FAPα) ligand (or a radical thereof). As used herein, a "ligand" refers to a molecule, ion, or atom that is bound to a central atom or ion (e.g., a drug) of a compound. A "ligand" also encompasses a binding agent that is neither an agonist nor an antagonist, and does not have agonistic or antagonistic properties.

[0252] In certain embodiments, the targeting moiety binds to activated fibroblasts that express FAPα, such activated fibroblasts being involved in cancer or inflammatory disease.

[0253] The targeting moiety may be a radical of a FAPα ligand having a molecular weight of, for example, less than about 10,000, less than 7,500, less than 5,000, less than 2,500, less than 1,000, less than 760, less than 500; about 500 to about 10,000 g / mol, about 1,000 to about 7,500 g / mol, about 750 g / mol to about 1,500 g / mol, about 1,000 to about 5,000 g / mol, or about 500 to about 2,500 g / mol.

[0254] The targeting moiety is capable of binding to activated fibroblasts that express FAPα, such activated fibroblasts being involved in cancer or inflammatory diseases.

[0255] In certain embodiments, A has a structure represented by formula (I-A1) or (I-A2):

[0256] [ka] having During the ceremony,

[0257] [ka] is a functionalized 5-10 membered N-containing aromatic or non-aromatic, monocyclic or bicyclic heterocycle, said heterocycle optionally further comprising 1-3 heteroatoms selected from oxygen, nitrogen and sulfur; In formula (I-A1), Z is a bond, a substituted or unsubstituted alkylene (e.g., -CH2-), a substituted or unsubstituted amino (e.g., -NH-), -O- or -S-; T is a substituted or unsubstituted methylene (-CH-), a substituted or unsubstituted amino (-NH-), -O- or -S-; R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; Q in formula (I-A2) 1 is selected from the group consisting of -H, -CH3, -CH2OH, and -CH(CH3)2;

[0258] [ka] is the point of attachment of the FAPα-binding ligand (e.g., via a linker, L, or to the imaging / therapeutic moiety, B′), which may be at any carbon atom of a 5-10 membered N-containing aromatic or non-aromatic, monocyclic or bicyclic heterocycle, o Or 2 o This can be via either an amine, or a functionalized alkyl or cycloalkyl motif, as well as the stereoisomers and pharma- ceutically acceptable salts thereof.

[0259] A is a compound having a structure represented by formula IB:

[0260] [ka] and During the ceremony, T is a substituted or unsubstituted methylene (-CH-), a substituted or unsubstituted amino (-NH-), -O- or -S-; R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6independently selected from the group consisting of alkyl, F, Cl, Br and I.

[0261] In certain embodiments, A has the structure represented by formula IC:

[0262] [ka] having During the ceremony, T is a substituted or unsubstituted methylene (-CH-), a substituted or unsubstituted amino (-NH-), -O- or -S-; R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 independently selected from the group consisting of alkyl, F, Cl, Br and I.

[0263] A is a structure represented by the following formula:

[0264] [ka] and In the formula, T is a substituted or unsubstituted methylene (-CH-), a substituted or unsubstituted amino (-NH-), -O-, or -S-; R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 each independently selected from the group consisting of alkyl, F, Cl, Br and I.

[0265] In certain embodiments, A has the structure represented by formula XA:

[0266] [ka] having During the ceremony, Q is aryl, heteroaryl, or heterocyclyl (e.g., including aryl and non-aryl ring structures) (e.g., a 5-10 membered N-containing aromatic or non-aromatic monocyclic or bicyclic heterocycle, said heterocycle optionally further containing 1-3 heteroatoms selected from O, N, and S); Z is a bond, a substituted or unsubstituted C1-C3 alkylene (e.g., -CH2-), a substituted or unsubstituted heteroalkyl (e.g., 1-3 atoms in length), amino (e.g., NH), -O-, or -S-; T is a substituted or unsubstituted methylene (-CH-), substituted or unsubstituted amino (-NH-), -O-, or -S- (e.g., the substituents on T are C1-C3 alkyl, haloalkyl, or halo); R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo.

[0267] In certain embodiments of formula (XA), Q is bonded to L (e.g., L or L1 (see linker section below)). Q may be aryl, heteroaryl, or heterocyclyl. Heterocyclyl may include aryl and non-aryl ring structures. Q may be bonded to L at the heteroalkyl, alkyl, or aryl position of Q. Q may be bonded to L at the aryl position of Q. Q may be bonded to L through a nitrogen atom (e.g., of L). Q may be bonded to L through a triazolyl or amide (e.g., of L). Heteroaryl may include aryl and non-aryl ring structures. Heteroaryl or heterocyclyl may include 1-3 heteroatoms selected from O, N, and S. Heterocyclyl may include 1-3 heteroatoms selected from O, N, and S. Q may be a 5-10 membered N-containing aromatic or non-aromatic monocyclic or bicyclic heterocycle (e.g., optionally including aryl and non-aryl ring structures). Q may be an N-linked heterocyclyl (e.g., optionally including aryl and non-aryl ring structures). Q may be a C6-C9-N-linked heterocyclyl (e.g., optionally including aryl and non-aryl ring structures). The N-linked heterocyclyl is bonded to Z via an N-heterocycloalkyl. Q may be (e.g., N-linked) isoindolinyl (e.g., N is bonded to Z of formula (XA)).

[0268] As specified above, in certain embodiments of formula (XA), Z is a bond, substituted or unsubstituted C1-C3 alkylene, substituted or unsubstituted heteroalkylene (e.g., 1-3 atoms in length), amino (e.g., NH), -O-, or -S-. Z may be a bond. Z may be a substituted methylene. Z may be -CH2-. Z may be a substituted ethylene. Z may be ethylene substituted with oxo. Z may be -C(CO)CH2-. Z may be -CH2CH2-. Z may be a C1-C3 heteroalkylene.

[0269] In certain embodiments, A has the structure represented by formula XB:

[0270] [ka] is or contains During the ceremony, T is a substituted or unsubstituted methylene (-CH-), substituted or unsubstituted amino (-NH-), -O-, or -S- (e.g., the substituents on T are C1-C3 alkyl, haloalkyl, or halo); J is C(R J ) 0~3 and R J are each independently H or alkyl, or two or more R J together to form oxo, R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, -SC 1~6independently selected from the group consisting of alkyl, F, Cl, Br and I.

[0271] In certain embodiments, A has the structure represented by formula XC:

[0272] [ka] is or contains During the ceremony, T is a substituted or unsubstituted methylene (-CH-), substituted or unsubstituted amino (-NH-), -O-, or -S- (e.g., the substituents on T are C1-C3 alkyl, haloalkyl, or halo); J is C(R J ) 0~3 and R J are independently H or alkyl, or two or more R J together to form oxo, R 1 and R 2 is independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl; R 3 and R 4 are -H, -OH, F, Cl, Br, I, -C 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 independently selected from the group consisting of alkyl, R 5 , R 6 , R 7 and R 8 is independently selected from the group consisting of H, alkyl and halo; R 9 , R 10 and R 11 -H, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -OC1~6 Alkyl, -SC 1~6 independently selected from the group consisting of alkyl, F, Cl, Br and I.

[0273] In some embodiments, J is C(R J ) 1~3 It is.

[0274] J in formula (XB), (XC) or (XD) can be attached to L of the compound (e.g., L or L1 (see Linker section below)). J can be attached to L through a nitrogen atom. J can be attached to L through a triazolyl or amide (e.g., of L). J can be attached to C(R J )2, R J are each independently H or alkyl, or R J together form oxo. J may be a C1-C3 alkyl. J may be -CH2-. J may be -CH2CH2-. J may be C=O. J may be a bond.

[0275] T in formula (XB) or (XC) may be substituted or unsubstituted methylene (e.g., -CH2-), substituted or unsubstituted amino (e.g., -NH-), -O- or -S-. The substituent of T may be C1-C3 alkyl, C1-C3 haloalkyl or (in the case of methylene) halo. T may be (-CH2-). The substituent of T may be C1-C3 alkyl, haloalkyl or halo. T may be unsubstituted.

[0276] In certain embodiments of formula (XB) or (XC), R 1 and R 2 are each independently selected from the group consisting of -H, -CN, -CHO, -B(OH)2, -C(O)alkyl, -C(O)aryl-, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SON2NH2, -PO3H2, -SO2F, -CONH2, and 5-tetrazolyl. R 1 and R2 Each R can be independently selected from the group consisting of H, -CN, -CHO, and -B(OH). 1 and R 2 Each R can be independently selected from the group consisting of H, -CN, -CHO, and -CONH2. 1 may be H. 2 R may be -CN, -CHO, -B(OH)2 or -CONH2. 1 may be H, R 2 R may be -CN, -CHO, -B(OH)2 or -CONH2. 1 may be H, R 2 R may be -CN. 1 may be H, R 2 R may be -CHO. 1 may be H, R 2 may be -B(OH). 1 may be H, R 2 may be -CONH2.

[0277] R in formula (XB) or (XC) 3 and R 4 are -H, -OH, F, Cl, Br, I, and -C, respectively. 1~6 Alkyl, -OC 1~6 Alkyl and -SC 1~6 R can be independently selected from the group consisting of alkyl. 3 and R 4 Each of R may independently be -H or -F. 3 may be H, R 4 may be -F. 3 may be F, R 4 may be -F.

[0278] In certain embodiments, R 1 is H and R 2 is -CN and R 3 is H and R 4is -F. In certain embodiments, R 1 is H and R 2 is -CN and R 3 is F and R 4 is -F. Furthermore, R 1 may be H, R 2 may be -CHO, R 3 may be H, R 4 may be -F. R 1 may be H, R 2 may be -CHO, R 3 may be F, R 4 may be -F. R 1 may be H, R 2 may be -B(OH)2, R 3 may be H, R 4 may be -F. R 1 may be H, R 2 may be -B(OH)2, R 3 may be F, R 4 may be -F. R 1 may be H, R 2 may be -CONH2, R may be H, R 4 may be -F. R 1 may be H, R 2 may be -CONH2, R 3 may be F, R 4 may be -F.

[0279] R 5 , R 6 , R 7 and R 8 Each R can be independently selected from the group consisting of H, alkyl, and halo. 5 , R 6 , R 7 and R 8 may each be H.

[0280] R 9 , R 10 and R11 are H and -C, respectively. 1~6 Alkyl, -C 1~6 Haloalkyl, -OC 1~6 Alkyl, -SC 1~6 R can be independently selected from the group consisting of alkyl, F, Cl, Br and I. 9 , R 10 and R 11 are H and -C, respectively. 1~6 R can be independently selected from the group consisting of haloalkyl, F and Cl. 9 and R 11 may be H, R 10 -H, -C 1~6 R may be haloalkyl, F or Cl. 9 and R 11 may be H, R 10 R may be H, -CF3, F or Cl. 9 and R 11 may be H, R 10 R may be -CF3. 9 and R 11 may be H, R 10 may be F. 9 and R 11 may be H, R 10 R may be Cl. 9 , R 10 and R 11 may be H.

[0281] In certain embodiments, A has the structure represented by formula (XD):

[0282] [ka] is or contains During the ceremony, J is C(R J 2) 0~3 and R J Each of 2 is H or two or more R J 2 together to form oxo, R 1 is selected from the group consisting of -CN, -CHO and -B(OH)2; R 3 and R 4 are each independently selected from the group consisting of -H and F; R 10 is selected from the group consisting of H, -CF3, F, Cl, Br and I.

[0283] A may be attached to L of the compounds herein through a nitrogen atom (e.g., of L). A may be attached to L through a triazolyl or amide (e.g., of L).

[0284] In certain embodiments, A is

[0285] [ka] It is.

[0286] A is,

[0287] [ka] The compound may be selected from the group consisting of:

[0288] The compound A also has

[0289] [ka] The compound may be selected from the group consisting of:

[0290] A is,

[0291] [ka] may be also possible.

[0292] A is,

[0293] [ka] may be also possible.

[0294] In some embodiments, A is

[0295] [ka] is or contains

[0296] In some embodiments, A is

[0297] [ka] is or contains

[0298] In some embodiments, A is

[0299] [ka] is or contains X is between 1 and 20.

[0300] In some embodiments, A is

[0301] [ka] is or contains

[0302] In certain embodiments, A of the compounds herein (e.g., a FAPα-binding ligand) can have a binding affinity to a FAP (e.g., FAPα) in the range of between about 1 nM and about 25 nM, such as 1 nM to about 25 nM or about 1 nM to 25 nM.

[0303] In certain embodiments, A of the compound comprises a high affinity FAP binding ligand. Such high affinity FAP ligands can, in certain embodiments, comprise a triazole moiety or one or more of its derivatives. In certain embodiments, A is a FAP ligand comprising a triazole moiety within an isoindoline scaffold. In certain embodiments, A is a FAP ligand comprising a triazole moiety and a phenyl ring. In certain embodiments, A is a FAP ligand comprising an ethyldiaminoaryltriazole moiety. In certain embodiments, A is a FAP ligand comprising an ethyldiaminoaryltriazole moiety and a phenyl ring. In certain embodiments, the triazole moiety can further comprise a primary or secondary amine, or a functionalized alkyl or cycloalkyl motif.

[0304] When a FAP ligand contains a triazole moiety (or a derivative thereof) (e.g., incorporated into an isoindoline scaffold), additional interactions with the FAP target can result in higher docking scores in Schrödinger molecular docking calculations (see, e.g., FIG. 26) (compared to FAP ligands that do not have a triazole moiety and / or a phenyl ring attached to the FAP ligand).

[0305] In certain embodiments, ligands to FAPs are provided that include an isoindoline scaffold incorporating a triazole moiety, the ligand having a Schrödinger molecular docking score of at least about -8.2 kcal / mol.

[0306] In certain embodiments, A is

[0307] [ka] and n=1 to 5, n'=1 to 5, Ring C is optional; X, Y and Z in ring B are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' in ring C are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N; P is the point of attachment of ring C (if present) to linker (L) or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0308] [ka] may be any FAP ligand structure provided herein. In certain embodiments,

[0309] [ka] teeth,

[0310] [ka] The structure is selected from the group consisting of:

[0311] In certain embodiments, the B and C rings may each be a functionalized 5-10 membered N-containing aromatic or non-aromatic monocyclic or bicyclic heterocycle, which may optionally further comprise 1-3 heteroatoms selected from O, N, and S. In certain embodiments, when ring C is absent, the point of attachment to L or B' of formula (X) may be through any of the carbon atoms of the 5-10 membered N-containing B ring. Additionally, the point of attachment to L or B' of formula (X) (e.g., P) may be between a functionalized alkyl or cycloalkyl motif of the B or C ring, or a primary or secondary amine.

[0312] In certain embodiments, the high affinity FAP binding ligand further comprises C'. C' can be linked to one or more of the A groups and to B' by L. C' can be, for example, an albumin binding ligand, (PEG) n (n is an integer from 0 to 32), and may be a radical of a peptide, peptidoglycan, or a sugar.

[0313] In certain embodiments, Ring B is non-aromatic. In certain embodiments, Ring B is aromatic.

[0314] In certain embodiments, A is of formula (XZ):

[0315] [ka] wherein: Ring C is optional; X, Y and Z in ring B are each independently selected from O, N and S, provided that at least one of X and Y is N or Z is N; X' and Y' in ring C are each independently selected from O, N and S, with the proviso that at least one of X' and Y' is N; P is the point of attachment of ring C (if present) to linker (L) or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0316] In certain embodiments, A is of formula XY:

[0317] [ka] wherein: Ring C is optional; n=0 to 4, X, Y and Z in ring B are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' in ring C are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N; P is the point of attachment of ring C (if present) to linker (L) or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0318] In some embodiments, A has the structure of formula XZ:

[0319] [ka] is represented by

[0320] [ka] has the formula XB (or any other FAP ligand structure described herein), X, Y and Z are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N or Z is N; P is the point of attachment to L or B' of formula (X) and is selected from the group consisting of -H, -OH, -NH2, -COOH, -CONH2, -CHO, -N3, -CN, -B(OH)2, -C(O)alkyl, -C(O)aryl, -C=CC(O)aryl and -C=CS(O)aryl.

[0321] In some embodiments, A of the compounds herein (e.g., high affinity FAP ligands) can have a Schrödinger molecular docking score of at least about -8.2 kcal / mol. In certain embodiments, A of the compounds herein can have a Schrödinger molecular docking score of at least about -11.5 kcal / mol.

[0322] Therapeutic and / or Imaging Agents (B') As specified above, the compounds herein further comprise a group B'. In some embodiments, B' is or comprises a therapeutic agent or imaging agent (or any of the radicals described above). In some embodiments, B' is or comprises a radical of an anti-cancer agent. In some embodiments, B' is or comprises a radical of a dye (e.g., a fluorescent dye). In some embodiments, B' is or comprises a radical of an anti-fibrotic agent. In some embodiments, B' is or comprises a radical of a PI3K inhibitor. In some embodiments, B' is or comprises a radical of a chelated radioisotope (e.g., 99m Tc, 111 In, 18 F, 68 Ga, 124 I, 125 I, 131 I, 32 P, 89 Sr, 90 Y, 153 Sm, 169 Er, 177 Lu, 186 Re, 188 Re, 149 Tb, 211 At, 212 Bi, 213 Bi or 225 B' is or comprises a radical of a radioimaging agent comprising 99m Tc, 111 In, 18 F, 68 Ga, 124 I, 125 I and 131I. In certain embodiments, B′ can be or include a radical of a radioisotope selected from the group consisting of: 32 P, 89 Sr, 90 Y, 153 Sm, 169 Er, 177 Lu, 186 Re, 188 Re, 149 Tb, 211 At, 212 Bi, 213 Bi and 225 Ac is or comprises a radical of a radioisotope selected from the group consisting of:

[0323] In certain embodiments, B' is or includes a radical of a PI3K inhibitor, a chelating group optionally bound to an isotope (or metal), or a group covalently bound to an isotope (or metal), wherein the isotope or metal is suitable for radioimaging, radiotherapy or magnetic resonance imaging; an anti-cancer agent; an anti-fibrotic agent; and / or a dye (e.g., a fluorescent dye).

[0324] In some embodiments, B' is a radical of a chelating group optionally bound to an isotope (or metal) or a group covalently bound to an isotope (or metal), wherein said isotope (or metal) is suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0325] In some embodiments, B' is or comprises a radical of a radioimaging agent, a radiotherapeutic isotope, or a magnetic resonance isotope, or a chelating group and a radical of a radioimaging agent, a radiotherapeutic isotope, or a magnetic resonance isotope bound to a chelating group, wherein the isotope is 32 P, 89 Sr, 90 Y, 153 Sm, 169 Er, 177 Lu, 186 Re, 188 Re, 149 Tb, 211 At,212 Bi, 213 Bi and 225 In some embodiments, B' is or comprises a radical of a radioimaging agent, a radiotherapeutic isotope or a magnetic resonance isotope, or a chelating group, and a radical of a radioimaging agent, a radiotherapeutic isotope or a magnetic resonance isotope bound to a chelating group, wherein the isotope is selected from the group consisting of: 18 F, 32 P, 44 Sc, 47 Sc, 52 Mn, 55 Co, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 89 Sr, 89 Zr, 90 Y, 99m Tc, 111 In, 114m In, 117m Sn, 124 I, 125 I, 131 I, 149 Tb, 153 Sm, 152 Tb, 155 Tb, 161 Tb, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ab, 225 Ac or 227 In some embodiments, the isotope is selected from 111 In some embodiments, the isotope is 177 In some embodiments, the isotope is 11 C. 13 C. 13 N, 15 O. 60 Co and 123I is selected from the group consisting of

[0326] The therapeutic agent (or radical thereof) may be any entity capable of producing a desired physiological response. The therapeutic agent (or radical thereof) may be an anti-fibrotic agent, an anti-cancer agent, a chemotherapeutic agent, a photodynamic therapeutic agent, a radiotherapeutic agent, etc. The therapeutic agent may be a compound (e.g., or a radical thereof) that is effective against (e.g., effective in eliminating, destroying, reducing (e.g., reducing the amount of) or reducing the effect of) cancer cells or pro-fibrotic cells (e.g., cancer-associated fibroblasts, myofibroblasts, etc. (e.g., other tumor microenvironment factors)). Examples of therapeutic agents (or radicals thereof) include, but are not limited to, photodynamic therapeutic agents, radiotherapeutic agents, chemotherapeutic agents, anti-fibrotic agents, and anti-cancer agents. The therapeutic agent provided herein may be a PI3K inhibitor (or a radical thereof). Figure 20A shows the structures of various exemplary FAP5-PI3K inhibitors.

[0327] The therapeutic agent may be an anti-cancer agent (or a radical thereof). The therapeutic agent may be an anti-fibrotic agent (or a radical thereof). The therapeutic agent may be a compound (or a radical thereof) selected from a transforming growth factor (TGF) beta / Smad inhibitor, a Wnt / beta-catenin inhibitor, a kinase inhibitor (e.g., a kinase inhibitor for vascular endothelial growth factor receptor (VEGFR), a kinase inhibitor for fibroblast growth factor receptor (FGFR), a kinase inhibitor for platelet-derived growth factor receptor (PDGFR), a kinase inhibitor for focal adhesion kinase (FAK) or a kinase inhibitor for Rho-associated protein kinase (ROCK)), a Toll-like receptor agonist (TLR), a nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor (NF-κB), an inhibitor of collagen synthesis, and a PI3K inhibitor. In certain embodiments, B' is a phosphoinositide-3-kinase (PI3K) inhibitor (or a radical thereof).

[0328] In certain embodiments, B' is

[0329] [ka] is selected from the group consisting of:

[0330] In certain embodiments, B' is an imaging agent. The imaging agent may be any compound (or a radical thereof) that emits a detectable signal (e.g., an electromagnetic signal (e.g., a radio signal, a fluorescent signal, a gamma ray) or a mass). Examples of imaging agents include, but are not limited to, radio imaging agents (e.g., a PET imaging agent or a SPECT imaging agent), fluorescent imaging agents (e.g., a fluorescent dye), and the like. The imaging agent may be a magnetic resonance (MR) agent. In some embodiments, B' comprises a radiolabeled functional group (e.g., a radical thereof) suitable for PET imaging, SPECT imaging, other radio imaging techniques, magnetic resonance imaging, or radiotherapy. B' may comprise a radical of a radioimaging isotope, a radiotherapeutic isotope, or a magnetic resonance isotope.

[0331] B' can include an imaging agent, a radioimaging agent, a photodynamic therapy agent, a chemotherapeutic agent, an antifibrotic agent and / or a radiotherapeutic agent (e.g., radicals thereof), where B' is an anticancer agent that is effective against cancer cells or cancer-associated fibroblasts, myofibroblasts or other tumor microenvironment factors.

[0332] B' may be a radical of a PI3K inhibitor. B' may be a radical of a chelating group optionally bound to an isotope (or metal). B' may be a chelating group covalently bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0333] B' may be a chelating group (e.g., a chelating agent (or radical thereof)). Representative chelating groups include, but are not limited to, the free base form, such as COH (COOH) with one or more protons (H+) removed to form COO-).

[0334] [ka] Including, Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0335] B' can include a chelating group, including but not limited to: DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or a derivative thereof; TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid) or a derivative thereof; SarAr (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]-eicosane-1,8-diamine or a derivative thereof; NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid) or its derivatives; NETA (4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl)acetic acid or its derivatives; TRAP (1,4,7-triazacyclononane-1,4,7-tris[methyl(2-carboxyethyl)phosphinic acid) or its derivatives; HBED (N,N0-bis(2-hydroxybenzyl)-ethylenediamine-N ,N0-diacetic acid) or its derivatives;2,3-HOPO(3-hydroxypyridin-2-one) or its derivatives;PCTA(3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9-triacetic acid) or its derivatives;DFO(desferrioxamine) or its derivatives;DTPA(diethylenetriaminepentaacetic acid) or its derivatives;OCTAPA(N,N0-bis(6-carboxy-2-pyridylmethyl)- ethylenediamine-N,N0-diacetic acid) or a derivative thereof; or H2-MACROPA (N,N'-bis[(6-carboxy-2-pyridipmethyl)]-4,13-diaza-18-crown-6) or a derivative thereof; H2dedpa (1,2-[[carboxy)-pyridin-2-yl]-methylamino]ethane or a derivative thereof; and an EC20 head containing β-1-diaminopropionic acid, aspartic acid and cysteine.

[0336] B' can include a radical of DOTA. In certain embodiments, B' is isotope- (or metal-) chelated DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid).

[0337] B' may be or include a radical of a group covalently bonded to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0338] B' may be or may include a chelating group bound to an isotope (or metal) suitable for PET imaging, SPECT imaging, other radioimaging techniques or radiotherapy.

[0339] B' is

[0340] [ka] may be also possible.

[0341] B' is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0342] [ka] may be also possible.

[0343] B' is the following chelating group:

[0344] [ka] , each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

[0345] B' can comprise a magnetic resonance, radioimaging or radiotherapy isotope. In some embodiments, B' comprises a chelating group and a radioimaging isotope, radiotherapy isotope or magnetic resonance isotope that is a metal (e.g., a metal suitable for radioimaging, radiotherapy or magnetic resonance imaging) bound to the chelating group. In some embodiments, the isotope is a metal atom bound to the chelating group of B'. In some embodiments, the radioimaging isotope, radiotherapy isotope or magnetic resonance isotope (or a metal suitable for radioimaging, radiotherapy or magnetic resonance imaging) is 18 F, 32 P, 44 Sc, 47 Sc, 52 Mn, 55 Co, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 89 Sr, 89 Zr, 90 Y, 99m Tc, 111 In, 114m In, 117m Sn, 124 I, 125 I, 131 I, 149 Tb, 153 Sm, 152 Tb, 155 Tb, 161 Tb, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ab, 225 Ac or 227 In some embodiments, the radioimaging isotope, radiotherapeutic isotope, or magnetic resonance isotope is 11 C. 13 C. 13 N, 15 O.60 Co or 123 In some embodiments, the radioimaging isotope, radiotherapeutic isotope, or magnetic resonance isotope is 225 Ac, 32 P, 89 Sr, 117m Sn, 153 Sm, 169 Er, 186 Re, 188 Re, 149 Tb, 212 Bi or 213 In some embodiments, the isotope is Bi. 111 In some embodiments, the isotope is In. 177 This is Lu.

[0346] B' may comprise a radioimaging nuclide. The radioimaging nuclide may be any suitable radioimaging nuclide. The radioimaging nuclide may be: 99m Tc, 111 In, 18 F, 68 Ga, 124 I, 125 I and 131 It can be selected from the group consisting of I.

[0347] B' can include a radiotherapeutic nuclide, which is 177 Lu, 90 Y and 211 At may be selected from the group consisting of:

[0348] B' can include a radiolabeled prosthetic group (or a radical thereof). The radiolabeled prosthetic group is 18 F, 124 I, 125 I, 131 I and 211 The radioisotope may include a radioisotope selected from the group consisting of At.

[0349] In certain embodiments, B′ (e.g., a radiolabeled prosthetic group (or radical thereof)) has the following structure:

[0350] [ka] having During the ceremony, Each X is independently 18 F, 124 I, 125 I, 131 I and 2ll is a radioisotope selected from the group consisting of At, R or R 1 each is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; Each n is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0351] Representative radiolabeled prosthetic groups (e.g., B') include, but are not limited to,

[0352] [ka] Includes.

[0353] In the case of radiotherapeutic nuclides, when B' is a chelating agent, in certain embodiments B' is capable of forming a chelate with the nuclide.

[0354] B' may be a PI3K inhibitor or a radical thereof.

[0355] A PI3K inhibitor (or a radical thereof) (e.g., a compound or a conjugate that includes a PI3K inhibitor (or a radical thereof)) has the structure of Formula III:

[0356] [ka] and During the ceremony, X is

[0357] [ka] is selected from the group consisting of:

[0358] X in formula (III) may be a radical of B' (e.g., a radical is present on a heteroatom (e.g., S, N, or O of X)). B' may be attached to L of the compound through X (e.g., a hydroxyl radical of X).

[0359] The B′ PI3K inhibitor (or radical thereof) of the compound (e.g., a compound or a conjugate that includes a PI-3 kinase inhibitor (or radical thereof)) has the structure:

[0360] [ka] may have the following structure:

[0361] L is

[0362] [ka] where n is an integer from 1 to 32. L may be

[0363] [ka] where m is an integer from 1 to 9. L may be

[0364] [ka] wherein m is an integer from 1 to 9, n is an integer from 1 to 32, q is an integer from 0 to 4, and s is an integer from 0 to 4.

[0365] m may be 1. m may be 2. m may be 3. m may be 4. m may be 5. m may be 6. m may be 7. m may be 8. m may be 9.

[0366] n may be 1 to 12. n may be 1. n may be 2. n may be 3. n may be 4. n may be 5. n may be 6. n may be 7. n may be 8. n may be 9. n may be 10. n may be 11. n may be 12. n may be 13. n may be 14. n may be 15. n may be 16. n may be 17. n may be 18. n may be 19. n may be 20. n may be 21. n may be 22. n may be 23. n may be 24. n may be 25. n may be 26. n may be 27. n may be 28. n may be 29. n may be 30. n may be 31. n may be 32.

[0367] q may be 0. q may be 1. q may be 2. q may be 3. q may be 4.

[0368] s may be 0. s may be 1. s may be 2. s may be 3. s may be 4.

[0369] Linker (L) L of the compound is a linker, such as any suitable linker. As used herein, the term "linker" generally refers to a portion of a compound that forms a chemical bond with A (e.g., a binding ligand) and / or B' (e.g., a therapeutic or imaging agent) and / or C' (e.g., an albumin-binding ligand, PEG, peptide, peptidoglycan, or sugar). In particular, a "linker" can link two or more functional portions of a molecule to form a compound provided herein. By way of example, a linker may include atoms selected from C, N, O, S, Si, and P; C, N, O, S, and P; or C, N, O, and S. A linker can link different functional capabilities of a compound, such as a group of a FAP ligand and a DOTA chelator. A linker can include several linker groups, such as, for example, in a contiguous backbone, ranging from about 2 to about 100 atoms.

[0370] The linker can be a releasable linker. The linker may be a non-releasable linker. L may be a trivalent linker. L may be a biofunctionalized linker. For example, at least in formulas (X) and (I), the (e.g., bifunctionalized) linker can form a chemical bond between A and B'. L may be a (e.g., bifunctionalized) linker that links one or more A groups to B' (e.g., by a first covalent bond that links L to A and a second covalent bond that links L to B').

[0371] L can include one or more linker groups, each of which is independently selected from the group consisting of alkyl(alkylene), heteroalkyl(alkylene), heterocycloalkyl(alkylene), heteroaryl, aryl, alkoxy, thioether, disulfide, carboxylic acid, anhydride, carbonate, carbamate, thioether, sugar, peptide, and peptidoglycan. L can include one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, anhydride, carbonate, ester, carbamate, thioether, triazole, sugar, and peptide. L can include one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, carbonate, ester, phenyl, triazole, and carbamate. L can include one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, phenyl, triazole, ester, and carbonate. L can include one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, ester, and carbonate. L can include one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, and amide. L can include one or more linker groups, each of which is independently selected from the group consisting of alkyl(alkylene), disulfide, and amide. L can include one or more linker groups, each of which is independently selected from the group consisting of amide, alkyl(alkylene), PEG, phenyl, and triazole. L can include one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(ene) and amide.L can include one or more linker groups, each of which is independently selected from the group consisting of alkyl(alkylene) and amide. L can include one or more linker groups, each of which is independently selected from the group consisting of PEG and amide. The linker can include one or more triazole linker groups. The linker can include one or more disulfide linker groups. The linker can include one or more amide linker groups. The linker can include one or more PEG linker groups.

[0372] L may be a non-releasable linker (e.g., divalently (e.g., covalently) linked to B' and A). L may be a releasable linker (e.g., divalently (e.g., covalently) linked to B' and A).

[0373] In certain embodiments, for example and without limitation, in formulas (I') and (II), L comprises three linker groups, each of which is independently selected from the group consisting of alkyl(alkylene), heteroalkyl(alkylene), heterocycloalkyl(alkylene), heteroaryl, aryl, alkoxy, thioether, disulfide, carboxylic acid, anhydride, carbonate, carbamate, thioether, sugar, and peptide. In certain embodiments, L comprises three linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, anhydride, carbonate, ester, carbamate, thioether, triazole, sugar, and peptide. L can also comprise three linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, carbonate, ester, phenyl, triazole, and carbamate. In certain embodiments, L comprises three linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, phenyl, triazole, ester, and carbonate. L can comprise three linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, amide, carboxylic acid, ester, and carbonate. L can comprise three linker groups, each of which is independently selected from the group consisting of PEG, alkyl(alkylene), disulfide, and amide. L can comprise three linker groups, each of which is independently selected from the group consisting of alkyl(alkylene), disulfide, and amide. L can comprise three linker groups, each of which is independently selected from the group consisting of amide, alkyl(alkylene), PEG, phenyl, and triazole. L can include three linker groups, each of which is independently selected from the group consisting of PEG, alkyl(ene) and amide.L can include three linker groups, each of which is independently selected from the group consisting of alkyl(ene) and amide. L can include three linker groups, each of which is independently selected from the group consisting of PEG and amide.

[0374] L may contain one or more releasable groups.

[0375] L can be attached (e.g., covalently) to A through an amide linker group. L can be attached (e.g., covalently) to B' through an amide linker group. L can be attached (e.g., covalently) to C' through an amide linker group. L can be attached (e.g., covalently) independently to A, B', and (in formulas (I') and (II)) C' through an amide linker group (such as by a covalent bond).

[0376] L can be attached (e.g., covalently) to A through a triazole linker group. L can be attached (e.g., covalently) to B' through a triazole linker group. L can be attached (e.g., covalently) to A and B', independently, through triazole linker groups (e.g., covalently).

[0377] L can be attached (e.g., covalently) to A through a triazole linker group. L can be attached to A through a triazole linker group and to B' through an amide linker group.

[0378] L can be attached (e.g., covalently) to B' through a carbamate linker group. L can be attached to A through an amide linker group and to B' through a carbamate linker group.

[0379] The linker can be a releasable linker. The linker can be a non-releasable linker.

[0380] The linker may be a reductively cleavable linker (e.g., a disulfide). The linker may be an oxidatively cleavable linker (e.g., an amino-aromatic group). The linker may be or include an oxime ester. The linker may be or include a hydrazone. The linker may be a PEG. n (n=0 to 36). The linker may be or may include a peptide. The linker may be or may include a peptidoglycan.

[0381] L is (L 1 )-(L 2 ) or (L 1 )-(L 2 )-(L 3 ), wherein L 1 is the first linker, L 2 is a second linker, (if necessary), L 3 is the third linker.

[0382] L 1 , L 2 and L 3 may be the same. 1 , L 2 and L 3 Two of the L's may be the same. 1 , L 2 and L 3 can be different. 1 is the A group (and L 2 L 2 is the B' group (as well as L 2 and L 3 It can be bonded to the L 3 is the C' group (and L 2 The aryl group can be bonded to the aryl group.

[0383] L 1 , L2 and L 3 may each independently be 15 to 200 angstroms (Å) in length.

[0384] L is (L 1 ) p -W-(L 2 ) q wherein L 1 is the first linker, L 2 is a second linker, p=1 to 5; q=1~5.

[0385] In certain embodiments, each L 1 and each L 2 independently comprises one or more linker groups, each of which is independently selected from the group consisting of PEG, alkyl(ene), amide, phenyl, and triazole.

[0386] W, when present, may be an amine core, an aromatic core or an alkylene core.

[0387] L 1 and L 2 may each independently be 5 to 200 Å in length.

[0388] L has the following structure:

[0389] [ka] may have the following structure:

[0390] L is

[0391] [ka] may be also possible.

[0392] L is

[0393] [ka] may be also possible.

[0394] L can include at least one linker group, each of which is selected from the group consisting of PEG, alkyl, sugar, and peptide. The linker can be a dual linker based on PEG (e.g., pegylated), alkyl, sugar, and peptide.

[0395] L may be a non-releasable linker (e.g., divalently (e.g., covalently) linked to B' and A). L may be a releasable linker (e.g., divalently (e.g., covalently) linked to B' and A).

[0396] L has the following structure:

[0397] [ka] and In the formula, n is 0 to 10.

[0398] L has the following structure:

[0399] [ka] and one or more linker groups (e.g., L 1 , L 2 and / or L 3 (where applicable) In the formula, n is 0 to 10.

[0400] L has the following structure:

[0401] [ka] and In the formula, n is 1 to 32.

[0402] L has the following structure:

[0403] [ka] and In the formula, n is 1 to 32.

[0404] L has the following structure:

[0405] [ka] and During the ceremony, R 12 and R 13 may each independently be H or C1-C6 alkyl; and z is an integer from 1 to 8.

[0406] L has the following structure:

[0407] [ka] and During the ceremony, R 12 and R 13 may each independently be H or C1-C6 alkyl; and z is an integer from 1 to 8.

[0408] L has the following structure:

[0409] [ka] and one or more linker groups (e.g., L 1and each L 2 ).

[0410] L has the following structure:

[0411] [ka] The linker group may include one or more linker groups having the following structure:

[0412] L has the following structure:

[0413] [ka] and During the ceremony, R 16 is H or C1-C6 alkyl, R 14a , R 14b , R 15a and R 15b may each independently be H or C1-C6 alkyl.

[0414] L has the following structure:

[0415] [ka] may include.

[0416] L has the following structure:

[0417] [ka] and In the formula, n is 0 to 15.

[0418] L can include a reductively cleavable linker. L can include an oxidatively cleavable linker. L can include an oxime ester. L can include a hydrazone. L can include PEGn, where n=0-36. L can include a peptide. L can include a peptidoglycan.

[0419] L is

[0420] [ka] may be also possible.

[0421] L is

[0422] [ka] may be also possible.

[0423] C’ In certain embodiments of the compounds herein (eg, compounds having the structure of Formula (I') or (II)), the compound further comprises a C' connected to the linker of the compound.

[0424] C' may be any pharmacokinetic extender. In certain embodiments, C' is an albumin binding ligand. C' may be an albumin binding small protein scaffold containing albumin binding domain 035 (ABD035), albumin binding domain Con (ABDCon), a peptide of 45 three-helix bundle amino acids in length, a designed ankyrin repeat protein (DARPin), a disulfide-stabilized Fv fragment (dsFv) CA645 (anti-albumin antibody), any nanobody that forms a complex with human serum albumin (nanobody) and a variable new antigen receptor E06 (VNAR(E06)).

[0425] In certain embodiments, C' is

[0426] [ka] is or contains

[0427] In certain embodiments, C' is

[0428] [ka] is or contains Where applicable, R 12~19 are each (as appropriate) independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, -CN, -CHO, -B(OH)2, -C(O) alkyl, -C(O) aryl-, -C=CC(O) aryl, -C=CS(O)2 aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2 or -SO2F; R 20 and R 21 are each independently -H, -C1-C6 alkyl, -F, -Cl, -Br, -I, or -OC 1~6 It is alkyl, -CN, -CHO, -B(OH)2, -C=CC(O)aryl, -C=CS(O)2aryl, -CO2H, -SO3H, -SO2NH2, -PO3H2, -SO2F or CF3.

[0429] In some embodiments, C' is

[0430] [ka] is or contains

[0431] In some embodiments, C' is

[0432] [ka] is or contains

[0433] In some embodiments, C' is

[0434] [ka] is or contains

[0435] In certain embodiments, C' of the compound is (PEG) n (n is an integer from 0 to 32), a peptide, a peptidoglycan, or a sugar (eg, radicals thereof).

[0436] C' is (PEG) n where n is an integer from 0 to 32. C' may be a peptide. C' may be a peptidoglycan. C' may be a sugar.

[0437] In some embodiments, C' is

[0438] [ka] is or contains

[0439] In some embodiments, C' is

[0440] [ka] is or contains

[0441] Similarly, a compound of formula (V) (e.g., a conjugate):

[0442] [ka] is provided, During the ceremony, L is a linker containing at least one carbon atom, p is 0, 1, 2 or 3.

[0443] For compounds of formula (V), L may be or may include a group as set forth in one of the embodiments set forth above for the linker L. In certain embodiments of compounds of formula (V), p may be 0. In certain embodiments of compounds of formula (V), p may be 1. In certain embodiments of compounds of formula (V), p may be 2. In certain embodiments of compounds of formula (V), p may be 3.

[0444] Compounds / Conjugates In some embodiments, the compound is selected from the group consisting of:

[0445] [ka] isn't it.

[0446] AL-B' has the following structure:

[0447] [ka] and During the ceremony, n is an integer from 1 to 5.

[0448] AL-B' has the following structure:

[0449] [ka]

[0450] [ka] and During the ceremony, n is an integer from 1 to 5.

[0451] The compound has the formula:

[0452] [ka] and t is 0 or 1, and u is an integer from 2 to 12.

[0453] The compound has the formula

[0454] [ka] where n is an integer from 1 to 12.

[0455] The compound has the formula

[0456] [ka] where m is an integer from 1 to 4.

[0457] The compound has the formula

[0458] [ka] may have the following structure:

[0459] The compound has the formula

[0460] [ka] may have the following structure:

[0461] The compound has the formula

[0462] [ka] may have the following structure:

[0463] The compound has the formula

[0464] [ka] may have the following structure:

[0465] The compound has the formula

[0466] [ka] may have the following structure:

[0467] In certain embodiments, AL-B' of the compounds herein has the following structure:

[0468] [ka] may have the following structure:

[0469] AL-B' has the following structure:

[0470] [ka] may have the following structure:

[0471] AL-B' has the following structure:

[0472] [ka] may have the following structure:

[0473] AL-B' has the following structure:

[0474] [ka] may have the following structure:

[0475] AL-B' has the following structure:

[0476] [ka]

[0477] [ka] may have the following structure:

[0478] AL-B' has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging:

[0479] [ka] may have the following structure:

[0480] AL-B' has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging:

[0481] [ka] may have the following structure:

[0482] AL-B' has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging:

[0483] [ka] may have the following structure:

[0484] AL-B' has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging:

[0485] [ka] may have the following structure:

[0486] AL-B' has the following structure, optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging:

[0487] [ka] may have the following structure:

[0488] The compound (e.g., conjugate) may have the following structure:

[0489] [ka]

[0490] [ka] may have the following structure:

[0491] The compound (e.g., conjugate) may have the following structure:

[0492] [ka]

[0493] [ka] may have the following structure:

[0494] The compound (e.g., conjugate) may have the following structure:

[0495] [ka]

[0496] [ka] may have the following structure:

[0497] The compound (e.g., conjugate) may have the following structure:

[0498] [ka]

[0499] [ka] may have the following structure:

[0500] The compound (e.g., conjugate) may have the following structure:

[0501] [ka] may have the following structure:

[0502] The compound (e.g., conjugate) may have the following structure:

[0503] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0504] The compound (e.g., conjugate) may have the following structure:

[0505] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0506] The compound (e.g., conjugate) may have the following structure:

[0507] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0508] The compound (e.g., conjugate) may have the following structure:

[0509] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0510] The compound (e.g., conjugate) may have the following structure:

[0511] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0512] The compounds (e.g., conjugates) have the following structure, optionally linked to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging:

[0513] [ka] may have the following structure:

[0514] The compound (e.g., conjugate) may have the following structure:

[0515] [ka]

[0516] [ka]

[0517] [ka] may have the following structure:

[0518] The compound (e.g., conjugate) may have the following structure:

[0519] [ka]

[0520] [ka]

[0521] [ka] may have the following structure:

[0522] The compound (e.g., conjugate) may have the following structure:

[0523] [ka]

[0524] [ka]

[0525] [ka] may have the following structure:

[0526] The compound (e.g., conjugate) may have the following structure:

[0527] [ka]

[0528] [ka]

[0529] [ka] may have the following structure:

[0530] The compound (e.g., conjugate) may have the following structure:

[0531] [ka]

[0532] [ka]

[0533] [ka] may have the following structure:

[0534] The compound (e.g., conjugate) may have the following structure:

[0535] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0536] The compound (e.g., conjugate) may have the following structure:

[0537] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0538] The compound (e.g., conjugate) may have the following structure:

[0539] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0540] The compound (e.g., conjugate) may have the following structure:

[0541] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0542] The compound (e.g., conjugate) may have the following structure:

[0543] [ka] and Each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0544] The compound can have the structure of any of the compounds depicted in FIG. 1, each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

[0545] The compound has the formula:

[0546] [ka] and t is 0 or 1, and u is an integer from 2 to 12.

[0547] The compound has the formula

[0548] [ka] where n is an integer from 1 to 12.

[0549] The compound has the formula

[0550] [ka] where m is an integer from 1 to 4.

[0551] The compound has the formula

[0552] [ka] may have the following structure:

[0553] The compound has the formula

[0554] [ka] may have the following structure:

[0555] The compound has the formula

[0556] [ka] may have the following structure:

[0557] The compound has the formula

[0558] [ka] may have the following structure:

[0559] The compound has the formula

[0560] [ka] may have the following structure:

[0561] The compound can have any of the formulas illustrated in Figure 20A.

[0562] In certain embodiments, the compound (i.e., the conjugate) has the following structure:

[0563] [ka] may have the following structure:

[0564] In certain embodiments, the compound (i.e., the conjugate) has the following structure:

[0565] [ka] may have the following structure:

[0566] In certain embodiments, the compound (i.e., the conjugate) has the following structure:

[0567] [ka] may have the following structure:

[0568] In certain embodiments, the compound (i.e., the conjugate) has the following structure:

[0569] [ka] may have the following structure:

[0570] In certain embodiments, the compound (ie, the conjugate) can have any of the structures in Figures 28-31.

[0571] In certain embodiments, the compound has the following structure:

[0572] [ka] The present invention can have either

[0573] Pharmaceutical Compositions, Routes of Administration and Dosing In certain embodiments, a pharmaceutical composition is provided that includes a compound and a pharma- ceutically acceptable carrier. In certain embodiments, the pharmaceutical composition includes a plurality of compounds and a pharma- ceutically acceptable carrier.

[0574] In certain embodiments, the pharmaceutical composition further comprises at least one additional pharma- ceutical active agent. The at least one additional pharma- ceutical active agent may be an agent useful in the treatment of ischemia-reperfusion injury.

[0575] Pharmaceutical compositions can be prepared by combining one or more compounds with a pharma- ceutically acceptable carrier and, optionally, one or more additional pharma- ceutical active agents.

[0576] As used herein, "effective amount" refers to any amount sufficient to achieve a desired biological effect. By selecting among various active compounds and weighting factors such as potency, relative bioavailability, patient weight, severity of adverse side effects, and mode of administration, in combination with the teachings presented herein, an effective prophylactic or therapeutic treatment regimen can be designed that does not cause serious undesirable toxicity, but is still effective in treating a particular subject. The effective amount for any particular application may vary depending on factors such as the disease or condition being treated, the particular compound being administered, the size of the subject, or the severity of the disease or condition. Those skilled in the art can empirically determine the effective amount of a particular compound and / or other therapeutic agent without undue experimentation. Depending on some medical judgment, a maximum dose, i.e., the highest safe dose, can be used. Repeated doses per day can be used to achieve an appropriate systemic level of the compound. The appropriate systemic level can be determined, for example, by the patient's peak measurements or sustained plasma levels of the drug. "Dose" and "administration" are used interchangeably herein.

[0577] In general, the daily oral dose of the compound is about 0.01 milligrams / kg per day to 1,000 milligrams / kg per day for human subjects. Oral doses ranging from 0.5 to 50 milligrams / kg per day, in one or multiple administrations per day, can produce therapeutic results. The dosage can be appropriately adjusted to achieve the desired local or systemic drug levels, depending on the mode of administration. For example, intravenous administration can vary from one order of magnitude to several orders of magnitude lower doses per day. If the response in the subject is inadequate at such doses, even higher doses (or higher doses with higher efficacy by different, more localized delivery routes) can be used to the extent that patient tolerance allows. Repeated doses per day are contemplated to achieve adequate systemic levels of the compound.

[0578] A "therapeutically effective amount" (or "effective amount") of a compound for use in treatment refers to the amount of compound in a preparation that, when administered (to a mammal, such as a human) as part of a desired dosing regimen, alleviates the symptoms, ameliorates the condition, or delays the onset of a disease state, according to clinically accepted criteria for the disorder or condition being treated or for cosmetic purposes, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment.

[0579] For any compound, the therapeutically effective amount can be initially determined from animal models. The therapeutically effective dose can also be determined from human data for compounds tested in humans and compounds known to exhibit similar pharmacological activity, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Based on the above methods and other methods known in the art, adjusting the dose to achieve maximum efficacy is well within the capabilities of a person of ordinary skill in the art.

[0580] For clinical use, any compound may be administered in an amount equal to or equivalent to 0.2 to 2,000 milligrams (mg) of compound per kilogram (kg) of subject's body weight per day. The compound may be administered in a dose equal to or equivalent to 2 to 2,000 mg of compound per kg of subject's body weight per day. The compound may be administered in a dose equal to or equivalent to 20 to 2,000 mg of compound per kg of subject's body weight per day. The compound may be administered in a dose equal to or equivalent to 50 to 2,000 mg of compound per kg of subject's body weight per day. The compound may be administered in a dose equal to or equivalent to 100 to 2,000 mg of compound per kg of subject's body weight per day. The compound may be administered in a dose equal to or equivalent to 200 to 2,000 mg of compound per kg of subject's body weight per day. If a precursor or prodrug of the compound is to be administered, it is administered in an amount equivalent, ie, sufficient, to deliver the above-mentioned amounts of the compound.

[0581] The formulation of the compound may be administered to a human subject in a therapeutically effective amount. Typical dosage ranges are about 0.01 micrograms to about 2 mg per kg of body weight per day. The dosage of the drug administered will likely depend on variables such as the type and extent of the disorder, the overall health of the particular subject, the specific compound administered, the excipients used to formulate the compound, and its route of administration. Routine experimentation can be used to optimize the dosage and frequency of administration for any particular compound.

[0582] The compounds may be administered at concentrations ranging from about 0.001 micrograms / kg to greater than about 500 mg / kg. For example, concentrations may range from 0.001 micrograms / kg, 0.01 micrograms / kg, 0.05 micrograms / kg, 0.1 micrograms / kg, 0.5 micrograms / kg, 1.0 micrograms / kg, 10.0 micrograms / kg, 50.0 micrograms / kg, 100.0 micrograms / kg, 500 micrograms / kg, 1.0 mg / kg, 5.0 mg / kg, 10.0 mg / kg, 15.0 mg / kg, 20.0 mg / kg, 25.0 mg / kg, 300 mg / kg, 5 ... The range may be 0.0 mg / kg, 35.0 mg / kg, 40.0 mg / kg, 45.0 mg / kg, 50.0 mg / kg, 60.0 mg / kg, 70.0 mg / kg, 80.0 mg / kg, 90.0 mg / kg, 100.0 mg / kg, 150.0 mg / kg, 200.0 mg / kg, 250.0 mg / kg, 300.0 mg / kg, 350.0 mg / kg, 400.0 mg / kg, 450.0 mg / kg, up to about 500.0 mg / kg or any increment therein. It should be understood that all values ​​and ranges between these values ​​and ranges are intended to be encompassed.

[0583] The compounds can be administered at dosages ranging from about 0.2 milligrams / kg / day to greater than about 100 mg / kg / day. For example, dosages can range from 0.2 mg / kg / day to 100 mg / kg / day, 0.2 mg / kg / day to 50 mg / kg / day, 0.2 mg / kg / day to 25 mg / kg / day, 0.2 mg / kg / day to 10 mg / kg / day, 0.2 mg / kg / day to 7.5 mg / kg / day, 0.2 mg / kg / day to 5 mg / kg / day, 0.25 mg / kg / day to 100 mg / kg / day, 0.25 mg / kg / day to 50 mg / kg / day, 0.25 mg / kg / day to 25 mg / kg / day, 0.25 mg / kg / day to 10mg / kg / day, 0.25mg / kg / day~7.5mg / kg / day, 0.25mg / kg / day~5mg / kg / day, 0.5mg / kg / day~50mg / kg / day, 0.5mg / kg / day~25mg / kg / day, 0.5mg / kg / day~ 20mg / kg / day, 0.5mg / kg / day ~ 15mg / kg / day, 0.5mg / kg / day ~ 10mg / kg / day, 0.5mg / kg / day ~ 7.5mg / kg / day, 0.5mg / kg / day ~ 5mg / kg / day, 0.75mg / kg / day ~ 50 mg / kg / day, 0.75mg / kg / day ~ 25mg / kg / day, 0.75mg / kg / day ~ 20mg / kg / day, 0.75mg / kg / day ~ 15mg / kg / day, 0.75mg / kg / day ~ 10mg / kg / day, 0.75mg / kg / day ~7.5mg / kg / day, 0.75mg / kg / day ~5mg / kg / day, 1.0mg / kg / day ~50mg / kg / day, 1.0mg / kg / day ~25mg / kg / day, 1.0mg / kg / day ~20mg / kg / day, 1.0mg / kg / day ~1 It may be 5 mg / kg / day, 1.0 mg / kg / day to 10 mg / kg / day, 1.0 mg / kg / day to 7.5 mg / kg / day, 1.0 mg / kg / day to 5 mg / kg / day, 2 mg / kg / day to 50 mg / kg / day, 2 mg / kg / day to 25 mg / kg / day, 2 mg / kg / day to 20 mg / kg / day, 2 mg / kg / day to 15 mg / kg / day, 2 mg / kg / day to 10 mg / kg / day, 2 mg / kg / day to 7.5 mg / kg / day, or 2 mg / kg / day to 5 mg / kg / day.

[0584] The compounds can be administered at dosages ranging from about 0.25 milligrams / kg / day to about 25 mg / kg / day. For example, dosages can be 0.25 mg / kg / day, 0.5 mg / kg / day, 0.75 mg / kg / day, 1.0 mg / kg / day, 1.25 mg / kg / day, 1.5 mg / kg / day, 1.75 mg / kg / day, 2.0 mg / kg / day, 2.25 mg / kg / day, 2.5 mg / kg / day, 2.75 mg / kg / day, 3.0 mg / kg / day, 3.25 mg / kg / day, 3.5 mg / kg / day, 3.75 mg / kg / day, 4.0 mg / kg / day, 5.0 mg / kg / day, 6.0 mg / kg / day, 7.0 mg / kg / day, 8.0 mg / kg / day, 9.0 mg / kg / day, 10.0 mg / kg / day, 11.0 mg / kg / day, 12.0 mg / kg / day, 13.0 mg / kg / day, 14.0 mg / kg / day, 15.0 mg / kg / day, 16.0 mg / kg / day, 17.0 mg / kg / day, 18.0 mg / kg / day, 19.0 mg / kg / day, 20.0 mg / kg / day, 21.0 mg / kg / day, 22.0 mg / kg / day, 23.0 mg / kg / day, 24.0 mg / kg / day, 25.0 mg / kg / day, 26.0 mg / kg / day, 27.0 mg / kg / day, 28.0 mg / kg / day, 29.0 mg / kg / day, 30.0 mg / kg / day, 31.0 mg / kg / day, 32.0 mg / kg / day g / day, 4.25mg / kg / day, 4.5mg / kg / day, 4.75mg / kg / day, 5mg / kg / day, 5.5mg / kg / day, 6.0mg / kg / day, 6.5mg / kg / day, 7.0mg / kg / day, 7. 5mg / kg / day, 8.0mg / kg / day, 8.5mg / kg / day, 9.0mg / kg / day, 9.5mg / kg / day, 10mg / kg / day, 11mg / kg / day, 12mg / kg / day, 13mg / kg / day, 14 mg / kg / day, 15mg / kg / day, 16mg / kg / day, 17mg / kg / day, 18mg / kg / day, 19mg / kg / day, 20mg / kg / day, 21mg / kg / day, 22mg / kg / day, 23mg / k g / day, 24mg / kg / day, 25mg / kg / day, 26mg / kg / day, 27mg / kg / day, 28mg / kg / day, 29mg / kg / day, 30mg / kg / day, 31mg / kg / day, 32mg / kg / day, 3 It may be 3 mg / kg / day, 34 mg / kg / day, 35 mg / kg / day, 36 mg / kg / day, 37 mg / kg / day, 38 mg / kg / day, 39 mg / kg / day, 40 mg / kg / day, 41 mg / kg / day, 42 mg / kg / day, 43 mg / kg / day, 44 mg / kg / day, 45 mg / kg / day, 46 mg / kg / day, 47 mg / kg / day, 48 mg / kg / day, 49 mg / kg / day, or 50 mg / kg / day.

[0585] The compounds or precursors thereof can be administered at concentrations ranging from 0.01 micromolar to 500 micromolar or more. For example, doses can be 0.01 micromolar, 0.02 micromolar, 0.05 micromolar, 0.1 micromolar, 0.15 micromolar, 0.2 micromolar, 0.5 micromolar, 0.7 micromolar, 1.0 micromolar, 3.0 micromolar, 5.0 micromolar, 7.0 micromolar, 10.0 micromolar, 15.0 micromolar, 20.0 micromolar, 25.0 micromolar, 30.0 micromolar, 35.0 micromolar, 40.0 micromolar, 50.0 micromolar, 60.0 micromolar, 70.0 micromolar, 80.0 micromolar, 90.0 micromolar, 100.0 micromolar, 110.0 micromolar, 120.0 micromolar, 130.0 micromolar, 140.0 micromolar, 150.0 micromolar, 160.0 micromolar, 170.0 micromolar, 180.0 micromolar, 190.0 micromolar, 210.0 micromolar, 220.0 micromolar, 230.0 micromolar, 240.0 micromolar, 250.0 micromolar, 260.0 micromolar, 270.0 micromolar, 280.0 micromolar, 290.0 micromolar, 300.0 micromolar, 350.0 micromolar, 360.0 micromolar, 370.0 micromolar, 380.0 micromolar, 390.0 micromolar, 400.0 micromolar, 410 The range may be 100.0 micromolar, 45.0 micromolar, 50.0 micromolar, 60.0 micromolar, 70.0 micromolar, 80.0 micromolar, 90.0 micromolar, 100.0 micromolar, 150.0 micromolar, 200.0 micromolar, 250.0 micromolar, 300.0 micromolar, 350.0 micromolar, 400.0 micromolar, 450.0 micromolar, up to about 500.0 micromolar or any increment therein. It should be understood that all values ​​and ranges between these values ​​and ranges are intended to be encompassed.

[0586] The compound or its precursor can be administered at a concentration ranging from 0.10 micrograms / mL to 500.0 micrograms / mL. For example, concentrations can be 0.10 micrograms / mL, 0.50 micrograms / mL, 1 micrograms / mL, 2.0 micrograms / mL, 5.0 micrograms / mL, 10.0 micrograms / mL, 20 micrograms / mL, 25 micrograms / mL, 30 micrograms / mL, 35 micrograms / mL, 40 micrograms / mL, 45 micrograms / mL, 50 micrograms / mL, 60.0 micrograms / mL, 70.0 micrograms / mL, 80.0 micrograms / mL, 90.0 micrograms / mL, 100.0 micrograms / mL, 110.0 micrograms / mL, 120.0 micrograms / mL, 130.0 micrograms / mL, 140.0 micrograms / mL, 150.0 micrograms / mL, 160.0 micrograms / mL, 170.0 micrograms / mL, 180.0 micrograms / mL, 190.0 micrograms / mL, 200.0 micrograms / mL, 210.0 micrograms / mL, 220.0 micrograms / mL, 230.0 micrograms / mL, 240.0 micrograms / mL, 250.0 micrograms / mL, 260.0 micrograms / mL, 270.0 micrograms / mL, 280.0 micrograms / mL, 290.0 micrograms / mL, 300.0 micrograms / mL, 350.0 micrograms / mL, 400.0 micrograms / mL, 400.0 micrograms / mL, 400.0 micrograms / mL, L, 80.0 micrograms / mL, 90.0 micrograms / mL, 100.0 micrograms / mL, 150.0 micrograms / mL, 200.0 micrograms / mL, 250.0 micrograms / mL, 250.0 micrograms / mL, 300.0 micrograms / mL, 350.0 micrograms / mL, 400.0 micrograms / mL, 450.0 micrograms / mL, up to about greater than 500.0 micrograms / mL, or any increment therein. It should be understood that all values ​​and ranges between these values ​​and ranges are intended to be encompassed.

[0587] The formulation can be administered in a pharmaceutically acceptable solution, which can routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. The administration of pharmaceutical compositions can be carried out by any means known to those skilled in the art. Routes of administration include, but are not limited to, intravenous, intramuscular, intraperitoneal, intravesical (bladder), oral, subcutaneous, direct injection (e.g., in tumor or abscess), mucosa (e.g., topically to the eye), inhalation, and topical.

[0588] For intravenous and other parenteral routes of administration, the compounds can be formulated as lyophilized preparations, as lyophilized preparations of the active compound intercalated or encapsulated in liposomes, as lipid complexes in aqueous suspension, or as salt complexes.Lyophilized preparations are generally reconstituted in a suitable aqueous solution, for example, sterile water or saline, immediately prior to administration.

[0589] For oral administration, the compound can be easily formulated by combining the active compound with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the compound to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Pharmaceutical preparations for oral use can be obtained by processing the mixture of granules, optionally after grinding the mixture obtained and adding suitable auxiliary agents if necessary, as solid excipients to obtain the core of tablets or dragees. Suitable excipients are sugars, including lactose, sucrose, mannitol or sorbitol, among others; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or fillers, such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents such as cross-linked PVP, agar, or alginic acid or a salt thereof such as sodium alginate can be added. Optionally, oral preparations can be formulated in saline or a buffer for neutralizing internal acidic conditions, such as EDTA, or can be administered without any carrier.

[0590] Similarly, oral dosage forms of the compound are contemplated. The compound may be chemically modified so that oral delivery of the derivative is effective. In general, the contemplated chemical modification is the attachment of at least one moiety to the compound itself, where the moiety (a) inhibits acid hydrolysis, and (b) allows uptake into the bloodstream from the stomach or intestine. Similarly, it is desirable to increase the overall stability of the compound and increase circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, PVP, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts," In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al., J Appl Biochem 4:185-189 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane.For pharmaceutical uses, as indicated above, polyethylene glycol moieties are preferred.

[0591] The release location of the compound herein may be the stomach, small intestine (e.g., duodenum, jejunum or ileum) or large intestine.Those skilled in the art have available formulations that do not dissolve in the stomach but release material in the duodenum or anywhere in the intestine.This release can avoid the adverse effects of the stomach environment by either protecting the compound or releasing the compound beyond the stomach environment, such as in the intestine.

[0592] To ensure complete gastric resistance, a coating that is impermeable to at least pH 5.0 is essential. Examples of the more common inactive ingredients used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP), HPMCP50, HPMCP55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S and shellac. These coatings can be used as mixed films.

[0593] A coating, or a mixture of coatings, may also be used on the tablet surface, which is not intended to protect against the stomach. This may include sugar coatings, or coatings that make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutics (e.g., powder), and for liquid forms, a soft gelatin shell may be used. The shell material of cachets may be thick starch paper or other edible paper. For pills, lozenges, molded tablets, or powder tablets, moist mashing techniques may be used.

[0594] The therapeutic agent may be included in the formulation as fine multiparticles in the form of granules, or as pellets with a particle size of about 1 mm. The formulation of the material for capsule administration may also be as lightly compressed plugs of powder, or even as tablets. The therapeutic agent may be prepared by compression.

[0595] All flavoring and coloring agents may be included. For example, the compounds may be formulated (such as by liposome or microsphere encapsulation) and then further included in an edible product, such as a cooling beverage, that contains coloring and flavoring agents.

[0596] Inert substances may be used to dilute or increase the volume of therapeutic agents.These diluents may include carbohydrates, particularly mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextran and starch.Certain inorganic salts may also be used as fillers, including calcium triphosphate, magnesium carbonate and sodium chloride.Some commercially available diluents are Fast-Flo, Emdex, STA-Rx1500, Emcompress and Avicell.

[0597] Disintegrants can be included in solid dosage forms in the formulation of therapeutic agents. Substances used as disintegrants include, but are not limited to, starch, including Explotab, a commercial disintegrant based on starch. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, sea sponge and bentonite can all be used. Another form of disintegrant is the insoluble cation exchange resin. Powdered gums can be used as disintegrants and binders, and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0598] Binders can be used to hold the therapeutic agent together to form a hard tablet and include materials derived from natural products such as acacia, tragacanth, starch and gelatin. Others include methylcellulose (MC), ethylcellulose (EC) and carboxymethylcellulose (CMC). Both PVP and hydroxypropylmethylcellulose (HPMC) can be used in alcoholic solutions to granulate the therapeutic agent.

[0599] Antifriction agents can be included in the formulation of therapeutic agent to prevent adhesion during the formulation process.Lubricants can be used as a layer between the therapeutic agent and the die wall, and can include, but are not limited to, stearic acid, including magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes.Soluble lubricants can also be used, such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycols of various molecular weights, Carbowax 4000 and 6000.

[0600] Glidants can be added which can improve the flow properties of the drug during formulation and aid in rearrangement during compression. Glidants can include starch, talc, pyrogenic silica and hydrated silicoaluminate.

[0601] Surfactants can be added as wetting agents to aid in the dissolution of therapeutic agents into the aqueous environment. Surfactants can include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents that can be used include benzalkonium chloride and benzethonium chloride. Potentially non-ionic detergents that can be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid esters, methylcellulose and carboxymethylcellulose. These surfactants can be present in the formulation of the compound or its derivatives either alone or as a mixture of different ratios.

[0602] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain active ingredients in a mixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. Microspheres formulated for oral administration can also be used. Such microspheres are well defined in the art. All formulations for oral administration should be in a dosage suitable for such administration.

[0603] For buccal administration, the compositions may take the form of conventionally formulated tablets or lozenges.

[0604] For local administration, the compounds can be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art. Systemic formulations include those designed to be administered by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, and those designed for transdermal, transmucosal, oral or pulmonary administration.

[0605] For administration by inhalation, the compound can be conveniently delivered in the form of aerosol spray supply from pressurized pack or nebulizer with the use of suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.For pressurized aerosol, dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, for example, gelatin, can be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch, for use in inhaler or insufflator.

[0606] Similarly, pulmonary delivery of the compound (or salt thereof) is contemplated. The compound is delivered to the lungs of a mammal during inhalation and passes through the epithelial lining of the lungs into the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) (a1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins," Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony-stimulating factor; incorporated herein by reference). Methods and compositions for pulmonary delivery of drugs for systemic effect are described in Wong et al., U.S. Patent No. 5,451,569, issued September 19, 1995 (specifically incorporated herein by reference for its disclosure in this regard).

[0607] A wide range of mechanical devices designed for pulmonary delivery of therapeutic products are contemplated for use, including, but not limited to, nebulizers, metered dose inhalers and dry powder inhalers, all of which are well known to those skilled in the art.

[0608] Nasal delivery of pharmaceutical compositions is also contemplated.Nasal delivery allows pharmaceutical compositions to enter the bloodstream directly after administering the product to the nose, without the need for deposition of therapeutic products in the lungs.Formulations for nasal delivery include those that contain dextran or cyclodextran.

[0609] Compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion, when it is desired to deliver them systemically.Injection preparations can be provided in unit dosage form, for example, in ampoules or in multi-dose containers with added preservative.Compositions can take the form of suspension, solution or emulsion in oily or aqueous vehicle, and can contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents.

[0610] Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compound in water-soluble form.Furthermore, suspensions of the active compound can be prepared as suitable oily injection suspensions.Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran.Optionally, the suspension can also contain suitable stabilizers or agents that improve the solubility of the compound, allowing the preparation of highly concentrated solutions.

[0611] Alternatively, the active compounds can be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0612] The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0613] In addition to the above formulations, the compound can also be formulated as a depot preparation.Such long-acting preparations can be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil), or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0614] The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0615] Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated with fine gold particles, contained in liposomes, nebulized, aerosolized, pelleted for skin implantation, or dried on sharp objects for skin rubbing. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations with sustained release of active compounds, in which excipients and additives and / or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweeteners or solubilizers are conventionally used as described above. This pharmaceutical composition is suitable for use in various drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-1533 (1990).

[0616] The compound and optionally one or more other therapeutic agents can be administered as it is (undiluted) or in the form of a pharmaceutically acceptable salt.When used in medicine, the salt should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may be conveniently used to prepare pharmaceutically acceptable salts thereof.Such salts include, but are not limited to, those prepared from the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid.Similarly, such salts can be prepared as alkali metal salts or alkaline earth salts, such as sodium, potassium or calcium salts of carboxylic acid group.

[0617] Suitable buffering agents include acetic acid and salts (1-2% w / v), citric acid and salts (1-3% w / v), boric acid and salts (0.5-2.5% w / v), and phosphoric acid and salts (0.8-2% w / v).Suitable preservatives include benzalkonium chloride (0.003-0.03% w / v), chlorobutanol (0.3-0.9% w / v), parabens (0.01-0.25% w / v), and thimerosal (0.004-0.02% w / v).

[0618] The pharmaceutical composition contains an effective amount of the compound described herein and one or more other therapeutic agents, which may be included in a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers, diluents or encapsulating substances suitable for administration to humans or other vertebrates. The term "carrier" refers to a natural or synthetic organic or inorganic component that brings active ingredients together to facilitate application. The components of the pharmaceutical composition can also be mixed with the compound and with each other such that there is no interaction that would substantially impair the desired pharmaceutical effectiveness.

[0619] Specifically, therapeutic agents, including but not limited to compounds, can be provided in particles. "Particles" as used herein means nanoparticles or microparticles (or in some examples, larger particles) that can consist of all or part of the compounds described herein or other therapeutic agents. Particles can contain a therapeutic agent in a core surrounded by a coating agent, including but not limited to an enteric coating. The therapeutic agent can also be dispersed throughout the particle. The therapeutic agent can also be adsorbed to the particle. The particle can be of any order of release rate, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic agent, the particle can include any of the materials commonly used in the pharmaceutical and pharmaceutical fields, including but not limited to edible materials, non-edible materials, biodegradable or non-biodegradable materials, or combinations thereof. The particle can be a microcapsule containing a compound in solution or in a semi-solid state. The particle can be of virtually any shape.

[0620] Both non-biodegradable and biodegradable polymeric materials can be used to manufacture particles for delivering therapeutic agents. Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include biodegradable hydrogels, as described in Sawhney et al., Macromolecules 26:581-587 (1993), the teachings of which are specifically incorporated herein by reference. These include polyhyaluronic acid, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) and poly(octadecyl acrylate).

[0621] The therapeutic agent may be contained in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. It refers to immediate release formulations and non-immediate release formulations, which include, but are not limited to, sustained release formulations and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a drug formulation that provides a gradual release of drug over an extended period of time, and can provide substantially constant blood levels of the drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a delay between administration of the drug formulation and the release of the drug therefrom. "Delayed release" may or may not include a gradual release of drug over an extended period of time, and therefore may or may not be a "sustained release".

[0622] For the treatment of chronic conditions, the use of long-term sustained release implants may be particularly suitable. "Long-term" release, as used herein, means that the implant is configured and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and up to 30-60 days. Long-term sustained release implants are well known to those skilled in the art and include some of the release systems described above.

[0623] Treatment Also provided is a method for treating inflammatory disease or disorder. The method for treating inflammatory disease or disorder can be by modulating the activity of activated fibroblasts. As used herein, the term "modulate" and its variants refer to changing or inducing modification of a specific biological activity. Modulation includes, but is not limited to, stimulating or inhibiting activity, for example, by activating a receptor to inhibit the receptor from transmitting a signal transduction pathway, by activating an endogenous inhibitor that attenuates biological activity, or by inhibiting the activity of a protein that inhibits a specific biological function, to initiate a signal transduction cascade.

[0624] The method can include administering a compound (e.g., a conjugate) of any of the formulas presented herein. The method can include administering any of the pharmaceutical compositions described herein. The method can include administering a therapeutically effective amount of a compound (e.g., a conjugate) of any of the formulas provided herein (whether as part of a pharmaceutical composition or otherwise).

[0625] In some embodiments, the inflammatory disease or disorder is selected from the group consisting of Crohn's disease, lupus, inflammatory bowel disease (IBS), Addison's disease, Graves' disease, Sjogren's syndrome, celiac disease, Hashimoto's thyroiditis, myasthenia gravis, autoimmune vasculitis, reactive arthritis, psoriatic arthritis, pernicious anemia, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis or fibrotic disease, graft versus host disease (GVHD), transplant rejection, fatty liver disease, asthma, osteoporosis, sarcoidosis, ischemia-reperfusion injury, hip prosthesis lysis, glomerulonephritis, scleroderma, psoriasis with autoimmune myocarditis, spinal cord injury, central nervous system, viral infection, influenza, coronavirus infection, cytokine storm syndrome, bone injury, inflammatory brain disease, and atherosclerosis.

[0626] Methods of treating cancer are provided. The methods of treating cancer can be by modulating the activity of activated fibroblasts. The methods can include administering a compound (e.g., a conjugate) of any formula provided herein and / or any pharmaceutical composition provided herein. The methods can include contacting CAFs (e.g., CAFs of a cancer patient) with a compound (e.g., a conjugate) of any formula provided herein. In some embodiments, the cancer is lung cancer, bone cancer, pancreatic cancer, skin cancer, head cancer, neck cancer, cutaneous melanoma, intraocular melanoma, uterine cancer, ovarian cancer, endometrial cancer, leiomyosarcoma, rectal cancer, stomach cancer, colon cancer, breast cancer, triple-negative breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, non-small cell lung cancer, small cell lung cancer. , adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic leukemia, acute leukemia, lymphocytic lymphoma, pleural mesothelioma, bladder cancer, Burkitt's lymphoma, ureteral cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, cholangiocarcinoma, Hurthle cell thyroid cancer, and gastroesophageal junction adenocarcinoma. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, colon cancer, cervical cancer, and brain cancer (e.g., glioblastoma).

[0627] Also provided is a method for treating fibrosis. The method for treating fibrosis can be by modulating the activity of activated fibroblasts. The method can include administering (e.g., a therapeutically effective amount of) a compound (e.g., a conjugate) of any formula provided herein (e.g., as part of a pharmaceutical composition provided herein or otherwise). In some embodiments, the fibrosis is selected from the group consisting of pulmonary fibrosis, renal fibrosis and hepatic fibrosis. In some embodiments, the fibrosis is idiopathic pulmonary fibrosis.

[0628] The method of treating fibrosis or cancer can further include administering chemotherapy or radiation therapy to the subject.In certain embodiments, the method of treating fibrosis or cancer includes administering (e.g., a therapeutically effective amount) of a compound (e.g., a conjugate) of any formula provided herein (e.g., as part of a pharmaceutical composition provided herein, or otherwise) alone.In certain embodiments, the method of treating fibrosis or cancer includes administering (e.g., a therapeutically effective amount) of a compound (e.g., a conjugate) of any formula provided herein (e.g., as part of a pharmaceutical composition provided herein, or otherwise) to the subject in combination with one or more additional therapies.Such additional therapies can include, but are not limited to, immunotherapy, DNA damage response pathway inhibitors, chemotherapy, and / or surgery.

[0629] Provided is a method for imaging cancer or fibrosis in a subject having cancer or fibrosis.In certain embodiments, the method comprises administering to the subject an effective amount (e.g., a therapeutically effective amount) of any compound provided herein (e.g., a conjugate) (e.g., as part of a pharmaceutical composition provided herein, or otherwise).In certain embodiments, the method further comprises imaging the subject.In certain embodiments, the method further comprises (e.g., after or simultaneously with administration of the compound) generating an image of cancer or fibrosis in the subject.

[0630] Also provided are compositions and methods for optical imaging. The compositions and methods may be for fluorescence-guided surgery. The compositions and methods may be for radiological imaging.

[0631] The present disclosure also relates to compositions and methods for magnetic resonance imaging (MRI).

[0632] The above method includes providing to a patient in need thereof an effective amount of a conjugated ALB, wherein A comprises a FAPα targeting moiety, such as a moiety having a molecular weight of less than 10,000, L comprises one or more linkers capable of forming chemical bonds with at least A and B', and B' comprises an optical dye (e.g., a fluorescent dye), a photodynamic therapy agent, a radioimaging agent, a radiotherapeutic agent, a chemotherapeutic agent, an antifibrotic agent, or an anti-cancer agent effective against cancer cells, cancer-associated fibroblasts, myofibroblasts, and / or other tumor microenvironment factors.

[0633] The radiological imaging agent may be a magnetic resonance (MR) contrast agent. The MR contrast agent may include iron oxide particles. The iron oxide particles may be nanoparticles. The iron oxide particles may be paramagnetic particles, superparamagnetic particles (SPIO) or ultrasmall superparamagnetic particles (USPIO).

[0634] Methods for improving the affinity of FAP ligands Methods for improving the affinity of a ligand of a FAP are also provided. In certain embodiments, the method for improving the affinity of a ligand of a FAP (such ligand comprises an isoindoline scaffold) comprises introducing a triazole moiety into the isoindoline or another scaffold of the ligand by molecular modeling to achieve a higher Schrodinger molecular docking score, thus improving the affinity of the ligand of the FAP. In certain embodiments, the method can comprise introducing an ethyldiaminoaryltriazole moiety into the FAP ligand. In certain embodiments, the method can comprise introducing a triazole moiety and a phenyl ring into the FAP ligand by molecular modeling to achieve a higher Schrodinger molecular docking score.

[0635] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in the chemical and biological fields.Furthermore, when used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.Thus, for example, if a compound / composition is substituted with "one" alkyl or aryl, the compound / composition is optionally substituted with at least one alkyl and / or at least one aryl.

[0636] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to a patient of one or more compounds of the present disclosure. The treatment is prophylactic (i.e., the treatment protects the host from the onset of the undesirable condition) when it is administered prior to clinical symptoms of an undesirable condition (e.g., a disease or other undesirable condition in a host animal), whereas the treatment is therapeutic (i.e., the treatment is intended to reduce, ameliorate, or stabilize an existing undesirable condition or its side effects) when it is administered after the manifestation of the undesirable condition.

[0637] The term "patient," "individual," or "subject" refers to a mammal in need of a particular treatment. The patient or subject may be a primate, canine, feline, or equine. The patient or subject may be an avian. The avian may be a domesticated avian, such as a chicken. The avian may be a poultry. The patient or subject may be a human.

[0638] "Oxo" refers to the =O radical.

[0639] "Alkyl" means an alkyl group having 1 to 15 carbon atoms (e.g., C1 to C 15"Alkyl" generally refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, such as having 1 to 13 carbon atoms (e.g., C1 to C6). The disclosure of "alkyl" provided herein is intended to include the independent recitation of saturated "alkyl" unless otherwise specified. Alkyl refers to any group having 1 to 13 carbon atoms (e.g., C1 to C6). 13 The alkyl can contain 1 to 8 carbon atoms (e.g., C1 to C8 alkyl). The alkyl can contain 1 to 5 carbon atoms (e.g., C1 to C5 alkyl). The alkyl can contain 1 to 4 carbon atoms (e.g., C1 to C4 alkyl). The alkyl can contain 1 to 3 carbon atoms (e.g., C1 to C3 alkyl). The alkyl can contain 1 to 2 carbon atoms (e.g., C1 to C2 alkyl). The alkyl can contain 1 carbon atom (e.g., C1 alkyl). The alkyl can contain 5 to 15 carbon atoms (e.g., C5 to C6 alkyl). 15 The alkyl group may include from 5 to 8 carbon atoms (e.g., C5 to C8 alkyl). The alkyl group may include from 2 to 5 carbon atoms (e.g., C2 to C5 alkyl). The alkyl group may include from 3 to 5 carbon atoms (e.g., C3 to C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond.

[0640] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0641] "Alkylene" or "alkylene chain" generally refers to a straight or branched divalent alkyl group, such as having 1 to 12 carbon atoms, that links the remainder of the molecule to a radical group, e.g., methylene, ethylene, propylene, i-propylene, n-butylene, etc.

[0642] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon from 5 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) pi-electron system according to Huckel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0643] An “aralkyl” or “aryl-alkyl” is a group of the formula —R c -aryl radical, R c is an alkylene chain as defined above, e.g., methylene, ethylene, etc. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.

[0644] "Carbocyclyl" or "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems having 3 to 15 carbon atoms. A carbocyclyl can contain 3 to 10 carbon atoms. A carbocyclyl can contain 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl or cycloalkyl is saturated (i.e., contains only a single C-C bond) or unsaturated (i.e., contains one or more double or triple bonds). Examples of saturated cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls." Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (ie, bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0645] "Carbocyclylalkyl" means a group of the formula -R c - a carbocyclyl radical, R c is an alkylene chain as defined above.

[0646] "Chelating group" or "chelating group", as used herein, refers to a multidentate chemical group that can bind to a central metal atom with multiple binding interactions by using two or more binding sites on the chelating group. The combination of a chelating group and a metal atom is a chelate. The binding of the chelating group to the metal atom can be by non-covalent interactions or bonds. In some embodiments, the binding of the chelating group to the metal atom is by multiple coordinate bonds. Chelating groups include, but are not limited to, DOTA, NOTA, and EDTA.

[0647] "Metal suitable for radioimaging, radiotherapy or magnetic resonance imaging" or "isotope suitable for radioimaging, radiotherapy or magnetic resonance imaging" includes, but is not limited to, 18 F, 32 P, 44 Sc, 47 Sc, 52 Mn, 55 Co, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 86 Y, 89 Sr, 89 Zr, 90 Y, 99m Tc, 111 In, 114m In, 117m Sn, 124 I, 125 I, 131 I, 149 Tb, 153 Sm, 152 Tb, 155 Tb, 161 Tb, 169 Er, 177 Lu, 186 Re, 188 Re, 211 At, 212 Pb, 212 Bi, 213 Bi, 223 Ra, 224 Ra, 225 Ab, 225 Ac and 227 In some embodiments, metals (or isotopes) suitable for radioimaging, radiotherapy or magnetic resonance imaging include: 177 In some embodiments, a metal (or isotope) suitable for radioimaging, radiotherapy or magnetic resonance imaging is: 111 In.

[0648] "Halo" or "halogen" refers to a bromo, chloro, fluoro or iodo substituent.

[0649] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0650] The term "heteroalkyl" refers to an alkyl group, as defined above, in which one or more skeletal carbon atoms of the alkyl are replaced by a heteroatom (with the appropriate number of substituents or valences, e.g., -CH2- can be replaced by -NH- or -O-). For example, each substituted carbon atom is independently replaced by a heteroatom, such as a carbon being replaced by nitrogen, oxygen, selenium or other suitable heteroatom. In some examples, each substituted carbon atom is independently replaced by oxygen, nitrogen (e.g., -NH-, -N(alkyl)- or -N(aryl)-, or another substituent contemplated herein), or sulfur (e.g., -S-, -S(=O)-, or -S(=O)2-). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. The heteroalkyl is attached to the remainder of the molecule at a heteroatom of the heteroalkyl. Heteroalkyl is a C1-C6 alkyl group. 18 Heteroalkyl is a C1-C 12 Heteroalkyl is a C1-C6 heteroalkyl. Heteroalkyl is a C1-C4 heteroalkyl. Heteroalkyl can include alkoxy, alkoxyalkyl, alkylamino, alkylaminoalkyl, aminoalkyl, heterocycloalkyl, heterocycloalkyl, and heterocycloalkylalkyl, as defined herein.

[0651] "Heteroalkylene" refers to a divalent heteroalkyl group, as defined above, that links one portion of the molecule to another portion of the molecule.

[0652] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that can contain 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically stated herein, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which optionally includes aromatic, fused, and / or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. The heterocyclyl radical is partially or fully saturated. The disclosure of "heterocyclyl" provided herein is intended to include an independent enumeration of heterocyclyl, including aromatic and non-aromatic ring structures, unless otherwise stated. The heterocyclyl is attached to the remainder of the molecule through any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, indolinyl, , isoindolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.

[0653] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0654] "Heteroaryl" refers to a radical derived from a 3-18 membered aromatic ring radical, which may contain 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, in which at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic delocalized (4n+2) pi-electron system according to the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the rest of the molecule through any atom of the ring. Examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzoindolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, ... 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-Methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyri These include pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl).

[0655] The term "radical" as used herein refers to a fragment of a molecule, which fragment has a free valence for bond formation. A monovalent radical has one free valence so that it can form one bond with another chemical group. Unless otherwise specified, a radical of a molecule (e.g., a radical of a FAP ligand) is generated by removing one hydrogen atom from the molecule to generate a monovalent radical with one free valence at the position where the hydrogen atom was removed. Where appropriate, the radical may be divalent, trivalent, etc., where two, three or more hydrogen atoms or other groups are removed to generate a radical that can bond to two, three or more chemical groups. Where appropriate, the free valence of the radical may be generated by removing a non-hydrogen atom (e.g., a halogen) or by removing two or more atoms (e.g., a hydroxyl group), so long as the removed atoms represent a small percentage of the total atoms in the molecule that form the radical (20% or less of the number of atoms). In some embodiments, the radical is formed by removing a hydroxyl group from a folate ester, antifolate, or folic acid analog.

[0656] The term "releasable linker" as used herein refers to a linker that contains at least one cleavable bond that can be cleaved under extracellular physiological conditions (e.g., a pH-labile bond, an acid-labile bond, an oxidatively labile bond, or an enzyme-labile bond). Releasable groups also include photochemically cleavable groups. Examples of photochemically cleavable groups include linkers containing 2-(2-nitrophenyl)-ethan-2-ol groups, and o-nitrobenzyl, decyl, trans-o-cinnamoyl, m-nitrophenyl, or benzylsulfonyl groups (see, for example, Dorman and Prestwich, Trends Biotech. 18:64-77 (2000); and Greene and Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, New York (1991)). The cleavable bond(s) can be present within the cleavable linker and / or at one or both ends of the cleavable linker. It should be recognized that such physiological conditions that result in bond cleavage include, for example, standard chemical hydrolysis reactions that occur at physiological pH or as a result of compartmentalization in organelles such as endosomes that have a pH lower than that of the cytoplasm. By way of example, the bivalent linkers described herein may undergo cleavage under other physiological or metabolic conditions, such as by the action of glutathione-mediated mechanisms. It is understood that the lability of the cleavable bond can be adjusted by including functional groups or fragments within the bivalent linker L that can assist or promote such bond cleavage, also referred to as adjacent assistance. The lability of the cleavable bond can also be adjusted by varying substitutions at or near the cleavable bond, such as, for example, by including an alpha branch adjacent to a cleavable disulfide bond, by increasing the hydrophobicity of the substituent on the silicon of a moiety having a hydrolyzable silicon-oxygen bond, or by homologating an alkoxy group that forms a hydrolyzable ketal or acetal moiety.It is further recognized that additional functional groups or fragments may be included within the bivalent linker, L, that can assist or facilitate further fragmentation of the compound following bond cleavage of the releasable linker, if present.

[0657] It will be appreciated by those of ordinary skill in the art that other suitable modifications and adaptations to the compositions and methods described herein will be readily apparent from the description contained herein, in light of the information known to those of ordinary skill in the art, and may be made without departing from the scope of the disclosure or any of its embodiments.

[0658] All patents, patent application publications, journal articles, textbooks, and other publications mentioned in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains. All such publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

[0659] In the above description, numerous specific details are set forth to provide a thorough understanding of the present disclosure. It should be understood that certain examples can be practiced without some or all of these specific details, and that the present disclosure is not limited to a particular biological system, a particular cancer, or a particular organ or tissue, which of course may vary, but remain applicable in light of the data presented herein.

[0660] Furthermore, various techniques and mechanisms of the present disclosure sometimes describe a relationship or association between two components. Words such as coupled, related, connected, associated, and similar terms with their inflected morphemes are used interchangeably unless a distinction is specified or otherwise made clear from the context. These words and expressions do not necessarily indicate a direct association, but include an association through an intermediate component. An association between two components does not necessarily mean a direct, unobstructed association, since various other components may exist between the two components of interest. Thus, an association does not necessarily mean a direct, unobstructed association, unless otherwise specified.

[0661] Moreover, the present disclosure has been presented in this manner for illustrative purposes only, and it is understood that the principles and embodiments described herein may be applied to compounds and / or compositional components having configurations other than those specifically described herein.Indeed, it is expressly contemplated that the components of the compositions and compounds of the present disclosure may be adjusted to facilitate their desired use.

[0662] When ranges relating to physical properties, such as molecular weight, or chemical properties, such as chemical formula, are used herein, it is intended that all combinations and subcombinations of the ranges and specific embodiments herein are included.

[0663] Additionally, the term "about," when referring to a number or numerical value or range (including, for example, integers, fractions, and percentages), means that the number or numerical range referred to is an approximation within laboratory variation (or within statistical experimental error), and thus the numerical value or range may vary between 1%-15% (e.g., + / - 5%-15% of the recited value) from the stated number or numerical range, provided that one of ordinary skill in the art would consider equivalent to the recited value (e.g., have the same function or result). The term "comprise" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that, in certain other embodiments, for example, any compound, composition of matter, composition, method, or process described herein, can "consist of" or "consist essentially of" the described features. The term "substantially" can allow for a degree of variation in a value or range, for example, within 90%, within 95%, or within 99% of a stated value or a stated boundary of a range.

[0664] When a method of treatment involves administering more than one treatment, compound or composition to a subject, it will be understood that the order, timing, number, concentrations and amounts of administration are limited only by the medical requirements and limitations of the treatments (i.e., two treatments may be administered to a subject, for example, simultaneously, sequentially, sequentially, alternatively, or according to any other regimen).

[0665] Furthermore, in describing representative embodiments, the disclosure may present the method and / or process as a particular order of steps. To the extent that the method or process does not rely on the particular order of steps described herein, the method or process should not be limited to the particular order of steps described. As one skilled in the art will recognize, other orders of steps may be possible. Thus, the particular order of steps disclosed herein should not be interpreted as a limitation on the claims. Furthermore, claims directed to the method and / or process should not be limited to performing those steps in the order described, as one skilled in the art can readily recognize that the order may vary and still remain within the spirit and scope of the disclosure. EXAMPLES

[0666] The following examples illustrate certain specific embodiments of the present disclosure and are not intended to limit the scope of the claimed invention in any way.

[0667] [Example 1A] Synthesis of FAP5-carbamate-PI3K inhibitors (PI3Ki)

[0668] [ka]

[0669] 4-Nitrophenyl chloroformate (20 mg, 0.1 mmol, 1.0 equiv) was dissolved in dimethylsulfoxide (DMSO) (1 mL) under N2 atmosphere. Then diisopropylethylamine (DIPEA) (15.48 mg, 0.12 mmol, 1.2 equiv) was added followed by compound 1 (58.85 mg, 0.11 mmol, 1.1 equiv). The mixture was maintained for 30 min. The reaction was monitored by liquid chromatography-mass spectrometry (LC-MS) until the starting material was completely consumed, then washed with ethyl acetate (EA) (2 mL) and three times with water (3 x 2 mL). The product was dried over sodium sulfate, concentrated under reduced pressure and purified by passing through a combi using Hex / EA as eluent. Compound 2 was obtained as a yellow oil in 42 mg.

[0670] Compound 2 (6.99 mg, 0.01 mmol, 1.0 equiv) was dissolved in DMSO (1 mL) under N2 atmosphere, then FAP5 free amine (5.16 mg, 0.01 mmol, 1.0 equiv) was added, followed by DIPEA (1.93 mg, 0.015 mmol, 1.5 equiv). The mixture was maintained for 2 h. After purification, the final compound was obtained as a white powder in 1.4 mg. Purification conditions: reversed phase C-18 column, ACN / NH4HCO3, pH=7, flow rate 8 mL / min.

[0671] [Example 1B] Comparison of various FAP5-PI3K inhibitors Primary HLFs at passage number 8 were seeded (approximately 100,000 cells / well) in 12-well plates in Dulbecco's modified Eagle medium (DMEM) containing 10% fetal bovine serum (FBS) to achieve approximately 80% confluence. Cells were then starved for 24 hours in DMEM containing 0.4% FBS and then stimulated with 10 ng / mL transforming growth factor-beta 1 (TGF-β1) for 24 hours.

[0672] After stimulation, cells were incubated with FAP5-PI3K inhibitor for 2 hours, then replaced with culture medium containing 2ng / mL TGF-β1 and incubated for 24 hours (see FIG. 21) and 48 hours (see FIG. 22). 0.1% DMSO was added as vehicle to all wells.

[0673] Cells were detached using trypsin and lysed in lysis buffer, and proteins from the cells were extracted for Western blot analysis.

[0674] Figures 23A and 23B show a comparison of inhibition of Akt phosphorylation by FAP5-PI3K inhibitors at 24 hours (Figure 23A) and 48 hours (Figure 23B) of incubation. pAkt was normalized to tAkt, positive controls were treated with TGF-β1 alone or no treatment, and negative controls were treated without TGF-β1 and no treatment. Among compounds with non-releasable linkers, FAP5-carbamate-PI3ki consistently performed better than FAP5-ester-PI3Ki and FAP5-PI3Ki-NR.

[0675] [Example 1C] Synthesis of FAP-3000

[0676] [ka]

[0677] Isoindoline-4-carboxylate 4-methyl hydrochloride was purchased from PharmaBlock (Hatfield, PA). Boc-L-pyroglutamic acid benzyl ester was purchased from Accela ChemBio (San Diego, CA). 4-(p-iodophenyl)butyric acid was purchased from AstaTech, Inc (Bristol, PA). NHS-ester-PEG6-NHFmoc and propargyl-PEG6-amine were purchased from BroadPharm. DOTA-NHS ester was purchased from Macrocyclics. Fmoc-Lys-OH was purchased from AAPPTec (Louisville, KY). 4,4-Difluoro-L-prolinamide hydrochloride and HATU were purchased from Chem-Impex International (Chicago, IL). 4-Ethynylbenzoic acid and mono-Fmoc ethylenediamine hydrochloride were purchased from AA Blocks LLC (San Diego, CA). Di-tert-butyl dicarbonate was purchased from Oakwood Chemical (Estill, SC). 10% palladium on carbon was purchased from Alfa Aesar (Haverhill, MA). Sodium borohydride, N-bromosuccinimide, triphenylphosphine, sodium azide, lithium bis(trimethylsilyl)amide, tert-butyl-bromoacetate, 1,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, imidazole, phosphoryl chloride, diethyl ether, DIPEA, trifluoroacetic acid (TFA), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DCM), methanol (MeOH), DMSO and all other reagents were purchased from Sigma-Aldrich (St. Louis, MO). All synthesized molecules were purified using either flash chromatography (CombiFlash RF, Teledyne) or RP-HPLC (Agilent 1200 Instrument) using XBridge OBD preparative columns (19 × 150 mm, 5 μm) purchased from Waters (Milford, MA).Low resolution mass spectrometry-liquid chromatography / mass spectrometry (LRMS-LC / MS) was performed using an Agilent 1220 Infinity LC equipped with a reversed-phase XBridge Shield RP18 column (3.0 × 50 mm, 3.5 μm).

[0678] The syntheses of the key intermediates fragment 1 and fragment 2 have been reported elsewhere in the literature.

[0679] Briefly, 4-ethynylbenzoic acid was dissolved in anhydrous DMF containing HATU (1 eq.) and anhydrous DIPEA (3 eq.) for 10 min. Mono-Fmoc ethylenediamine was dissolved in anhydrous DMF and DIPEA (1.5 eq.) and then added to the reaction mixture. The resulting solution was stirred under inert atmosphere for 2 h. The desired intermediate 1 was precipitated with ice-cold water, then filtered and dried under vacuum. Intermediate 1 was dissolved in anhydrous DMF, then CuI (0.5 eq.) and DIPEA (2.0 eq.) were added. The reaction mixture was heated to 55° C. and stirred for 5 h. The crude product was extracted with ethyl acetate (EtOAc), washed with ice-cold brine, and then purified by flash chromatography [A=Hex, B=EtOAc, solvent gradient from 0% B to 100% B in 20 min] to give the product intermediate 2. LC / MS (m / z): [M+H]+C 40 H 40 Calculated value of N6O5: 684.8; measured mass: 685.

[0680] Intermediate 2 was dissolved in DCM and diethylamine (20 eq.) and then stirred for 1 h. LC / MS (m / z): [M+H]+C 25 H 30Calculated for N6O3 462.6; found mass 463. Upon completion of deprotection, the product was isolated by rotary evaporation, washed several times with ice-cold diethyl ether, then placed on high vacuum for several hours, after which it was used without further purification. NHS ester-PEG6-NHFmoc (1.1 eq.) and DIPEA (3 eq.) were added and stirred for several hours. The crude product was washed and then purified by flash chromatography [A=DCM, B=MeOH, solvent gradient from 0% B to 30% B in 25 min] to give intermediate 3. LC / MS (m / z): [M+H]+C 55 H 69 NO 12 Calculated mass 1020.2; measured mass 1021.

[0681] Intermediate 3 was dissolved in ACN and cooled to 0° C. An equal volume of TFA was added and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by LC / MS. LC / MS (m / z): [M+H] + C 50 H 61 N7O 10 Calculated for 920.1; Found mass 921. Upon completion of deprotection, TFA was removed by rotary evaporation and the deprotected product was used without further purification. Fragment 2 was dissolved in anhydrous DMF and DIPEA (3 eq.) for 10 min. The previous deprotected product was dissolved in anhydrous DMF containing excess DIPEA and then added to the reaction mixture and stirred under inert atmosphere for 2 h. The crude product was extracted with EtOAc, washed with ice-cold brine and then purified by flash chromatography [A=DCM, B=MeOH, solvent gradient from 0% B to 30% B in 25 min] to give intermediate 4. [M+H] + C 62 H 72 F2N 10 O 13 Calculated mass 1203.3; measured mass 1204.

[0682] Intermediate 4 was dissolved in DCM and diethylamine (20 eq.) and then stirred for 1 h. LC / MS (m / z): [M+H]+C47H62F2N10O11 calcd 981.1; observed mass 982. Upon completion of deprotection, the product was isolated by rotary evaporation, washed several times with ice-cold diethyl ether, and then placed on high vacuum for several hours, after which it was used without further purification. The deprotected product was dissolved in anhydrous DMF containing DOTA-NHS ester (1.2 eq.) and DIPEA (3 eq.) and stirred under inert atmosphere for 12 h. The product was purified by RP-HPLC [A=20 mM ammonium acetate buffer (pH 5.0) and B=CH3CN, solvent gradient from 5% B to 55% B in 45 min] to give the final desired product FAP-3000 (see FIG. 24). [M+H]+C 63 H 88 F2N 14 O 18 Calculated mass 1367.47; measured mass 1368.

[0683] [Example 1D] Synthesis of FAP-3001

[0684] [ka]

[0685] 4-(p-Iodophenyl)butyric acid was dissolved in anhydrous DMF containing HATU (1 eq.) and anhydrous DIPEA (3 eq.) for 1 h. Fmoc-Lys-OtBu HCl (1 eq.) was dissolved in anhydrous DMF and DIPEA (1.5 eq.) and then added to the reaction mixture. The resulting solution was stirred under inert atmosphere for 2 h. The product was extracted with EtOAc, washed with ice-cold brine, and then purified by flash chromatography [A=DCM, B=MeOH, solvent gradient from 0% B to 20% B in 25 min] to give intermediate 5. LC / MS (m / z): [M+H] + C 31 H 33 Calculated IN2O5: 696.6; measured mass: 697.

[0686] Intermediate 5 was dissolved in anhydrous DMF containing HATU (1 eq.) and anhydrous DIPEA (3 eq.) for 10 min. Propargyl-PEG6-amine was dissolved in anhydrous DMF and DIEPA (1.5 eq.) and then added to the reaction mixture. The resulting solution was stirred under inert atmosphere for 3 h. The product was extracted with EtOAc, washed with ice-cold brine, and then purified by flash chromatography [A=DCM, B=MeOH, solvent gradient from 0% B to 20% B in 25 min] to give intermediate 6. LC / MS (m / z): [M+H] + C 46 H 60 IN3O 10 Calculated for 941.9; observed mass 943. The progress of the reaction was monitored by LC / MS.

[0687] Fragment 1 (1.2 equiv.) was dissolved in anhydrous DMF containing intermediate 6, then CuI (0.5 equiv.) and DIPEA (2.0 equiv.) were added. The reaction mixture was heated to 55° C. and stirred for 5 h. The product was extracted with EtOAc, washed with ice-cold brine, and then purified by flash chromatography [A=DCM, B=MeOH, solvent gradient from 0% B to 20% B in 25 min] to give intermediate 7. LC / MS (m / z): [M+H] + C 60 H 78 IN7O 12 Calculated mass 1216.2; measured mass 1217.

[0688] Intermediate 7 was dissolved in ACN and cooled to 0° C. An equal volume of TFA was added and the reaction mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by LC / MS. LC / MS (m / z): [M+H] + C 55 H 70 IN7O 10Calculated for 1116.11; Found mass 1117. Upon completion of deprotection, TFA was removed by rotary evaporation and the product with the deprotected amine was used without further purification. Fragment 2 was dissolved in anhydrous DMF and DIPEA (3 eq.) for 10 min. The previously deprotected product was dissolved in anhydrous DMF and excess DIPEA and then added to the reaction mixture and stirred under inert atmosphere for 2 h. The crude product was extracted with EtOAc, washed with ice-cold brine and then purified by flash chromatography [A=DCM, B=MeOH, solvent gradient from 0% B to 30% B in 25 min] to give intermediate 8. LC / MS (m / z): [M+H] + C 67 H 81 IN 10 O 13 Calculated value 1399.3; measured mass 1400.

[0689] Intermediate 8 was dissolved in DCM and diethylamine (20 eq.) and then stirred overnight. The reaction progress was monitored by LC / MS. LC / MS (m / z): [M+H] + C 52 H 71 F2IN 10 O 10 Calculated for 1177.11; observed mass 1178. Upon completion of deprotection, the amine-bearing product was isolated by rotary evaporation, washed several times with ice-cold ethyl acetate, washed once with ice-cold ether, and then placed under high vacuum for several hours, after which it was used without further purification. The deprotected product was dissolved in anhydrous DMF containing DOTA-NHS ester (1.2 eq.) and DIPEA (3 eq.) and stirred under inert atmosphere for 12 hours. The final desired product FAP-3001 was purified by RP-HPLC [A=20 mM ammonium acetate buffer (pH 5.0) and B=CH3CN, solvent gradient from 5% B to 55% B in 45 min] to give FAP-3001 (see Figure 25). LC / MS (m / z): [M+H] + C 68 H 97 F2IN 14 O 18 Calculated mass 1563.6; measured mass 1564.

[0690] Other structures presented herein were synthesized similarly to the two presented.

[0691] [Example 2] FAP conjugate binding affinity 250,000 HEK-FAP cells were seeded in amine-coated 24-well plates and allowed to reach confluence. HEK-FAP cells were used to replace 10 nM FAP-rhodamine with increasing concentrations of FAP-targeting conjugates for 1 h at 4°C. Cells were then washed three times with phosphate-buffered saline (PBS), dissolved in 1% sodium lauryl sulfate (SDS), transferred to 96-well clear-bottom black-wall plates, and analyzed on a Synergy Neo2 microplate reader. All samples were performed in triplicate, and bars indicate the standard error of the mean (SEM) (see Figures 6A and 6B). K of 2.67 nM d was used to calculate the inhibition constants.

[0692] [Example 3] Radiolabeled FAP conjugate binding affinity Radiolabeling of the conjugate with DOTA was performed as follows: The conjugate was diluted in ammonium acetate (0.5 M, pH 8.0) to reach a final DOTA concentration of 0.5 mM. 111 To produce an In radioimaging agent, 111 In ( 111 Addition of InCl3) resulted in specific activities up to 4.0 MBq / nmol, as shown, whereas the production of the corresponding radiotherapeutic agent was 177 Lu( 177LuCl3) was added to obtain a specific activity of up to 11.0 MBq / nmol. The resulting solution was then heated to 90 °C for 10-20 min, and the radiochemical purity of the labeled product was analyzed by radio-HPLC (20 mM ammonium acetate buffer (pH 7) (A) and acetonitrile (B)) with a linear gradient (5% B to 95% B in 15 min). Radiochemical purity was found to be greater than 95% in all studies. After confirming that the radiolabeling was successful, sodium diethylenetriaminepentaacetate solution (5 mM, pH 7.0) was added to a final concentration of approximately 0.2 mM to complex any unreacted traces of radioactive isotope.

[0693] In the absence or presence of 100x excess of FAP competing ligand, 111 In-FAP-3000 or 111 Cancer-associated fibroblasts (Hs894 cell line) were incubated with increasing concentrations of In-FAP-3001 for 1 hour at room temperature, washed three times with PBS, then dissolved in 1.0 M NaOH and analyzed by gamma counter (see Figures 4A and 4B). All samples were run in triplicate on the SEM bar.

[0694] [Example 4] Treatment study of HT29 tumors Nu / nu mouse shoulder, 5×10 6 Nude mice bearing HT29 tumors were inoculated with 1000 x 1000 cells of HT29 human colon cancer. Treatment studies were performed with increasing doses of either In-111 radiolabeled FAP-3000 or FAP-3001, and MILabs Vector 4+ Imaging was performed using the following equipment: Animals were anesthetized with isoflurane and scanned at various time points after injection. Luminescence scans were performed for 20-60 minutes using a MILabs VECTor / CT system. CT scans were acquired using an X-ray source set at 60 kV and 615 μA. U-SPECT II software and 171 111SPECT images were reconstructed with In γ-energy width and 241 keV. The POS-EM algorithm was used with 16 subsets and 4 iterations on a 0.8 mm voxel grid. CT images were reconstructed using NRecon software. Data sets were fused and filtered using PMOD software (version 3.2).

[0695] Nude mice bearing HT29 tumors were administered 0.3 mCi of In-111 chelated with either 20 nmol, 10 nmol, or 5 nmol of FAP-3000 via intravenous injection into the tail vein. Figure 5A illustrates mice receiving FAP-3000 using single photon emission computed tomography / computed tomography (SPECT / CT), with images taken 2 and 4 hours after injection.

[0696] Nude mice bearing HT29 tumors were administered 0.3 mCi of In-111 chelated with either 5 nmol or 1 nmol of FAP-3001 via intravenous injection into the tail vein. Figure 5B illustrates images of such mice using SPECT / CT taken at various times (6, 24, 48, 72, and 96 hours) after injection.

[0697] [Example 5] Treatment study of 4T1 tumors 1 x 10 in sterile PBS onto the shoulder of a Balb / cJ mouse 5 4T1 cells were inoculated into 4T1 tumor-bearing BALB / c mice. Treatment studies were performed by administering 0.3 mCi of In-111 chelated with either 30 nmol, 20 nmol, and 10 nmol FAP-3000 or 6 nmol, 4 nmol, and 2 nmol FAP-3001 via intravenous injection into the tail vein, and SPECT / CT images were taken at various intervals after injection. Figure 6A shows 111 Figure 6B shows images from mice administered In-FAP-3000. 111Images from mice administered In-FAP-3001 are shown.

[0698] [Example 6] Retention Consideration Retention studies were performed using FAP-3001 in both 4T1 tumor-bearing BALB / c mice and KB tumor-bearing mice. Both sets of mice were injected with 5 nmol of FAP-3001 radiolabeled with 0.3 mCi of Indium-111 via intravenous injection in the tail vein, and SPECT / CT images were taken at various intervals after injection. Figure 7A shows images from 4T1 tumor-bearing BALB / c mice, and Figure 7B shows images from KB tumor-bearing mice.

[0699] [Example 7] Effect of albumin binders on FAP biodistribution. Biodistribution studies were performed on 4T1 tumors with a volume of approximately 200 mm 3 Mice were treated with 100 μCi of FAP-3000 ( 177 Lu-FAP-3000), or 10 μCi of indium-111 ( 111 A single dose of 5 nmol of FAP-3001 radiolabeled with In-FAP-3001 was injected via intravenous injection into the tail vein (see Figures 8A and 8B, respectively) and measured in a Packard Cobra gamma counter. Each desired time point included 4-5 mice per conjugate that were asphyxiated by CO2. Organs of interest were immediately harvested and washed in cold PBS prior to gamma counter measurements. Results were normalized per gram of tissue as a percentage of the injected dose.

[0700] [Example 8] In 4T1 tumors 177 Lu-FAP-3001 radiotherapy study Treatment was performed on 4T1 tumors with a volume of approximately 50 mm 3Control mice were injected with 5% ethanol (EtOH) in sterile PBS, whereas treated mice received 0.25 mCi or 0.50 mCi of FAP-3001 radiolabeled with either lutetium-177 ( 177 A dose of 5 nmol of Lu-FAP-3001 was injected. The body weight of the mice was monitored as a measure of overall toxicity. Figure 9A shows the tumor growth data from this study, Figure 9B shows the relative body weight data from this study, and Figure 9C shows the SPECT / CT scan of one of the treated mice 24 hours after injection.

[0701] [Example 9] In KB tumors 177 Lu-FAP-3000 radiation therapy study Treatment was performed on KB tumors with a volume of approximately 50 mm 3 Control mice were injected with 5% EtOH in sterile PBS, whereas treated mice received 0.50 mCi of FAP-3000 radiolabeled with lutetium-177 ( 177 Lu-FAP-3000) was injected at one dose of 5 nmol. Mouse body weight was monitored as a measure of overall toxicity. Figure 10A shows the tumor growth data from this study (KB tumor growth chart used in nude mice for comparison), Figure 10B illustrates the survival curve of this study, and Figure 10C shows the relative mouse body weight data from this study.

[0702] [Example 10] In KB tumors 177 Lu-FAP-3001 radiotherapy study Treatment was performed on KB tumors with a volume of approximately 50 mm 3 Control mice were injected with 5% EtOH in sterile PBS, whereas treated mice received 0.50 mCi of FAP-3001 radiolabeled with lutetium-177 ( 177Lu-FAP-3001) was injected at a dose of 5 nmol. Mouse body weight was monitored as a measure of overall toxicity. Figure 11A shows the tumor growth data from this study (KB tumor growth chart used in nude mice for comparison), Figure 11B illustrates the survival curve of this study, and Figure 11C shows the relative mouse body weight data from this study.

[0703] [Example 11] In HT29 tumors 177 Lu-FAP-3001 radiotherapy study Treatment was performed on HT29 tumors with a volume of approximately 150 mm 3 Control mice were injected with 5% EtOH in sterile PBS, whereas treated mice received 0.25 mCi of FAP-3001 radiolabeled with lutetium-177 ( 177 Lu-FAP-3001) was injected at one dose of 5 nmol. Mice were monitored for body weight as a measure of overall toxicity. Figure 12A shows tumor growth data from this study (KB tumor growth chart used in nude mice for comparison), Figure 12B illustrates the survival curve of this study, and Figure 12C shows the relative body weight data of mice from this study. Figure 12D shows photographic images of tumors dissected after euthanasia.

[0704] [Example 12] In U87MG tumors 177 Lu-FAP-3001 radiotherapy study Treatment was performed on U87MG tumors with a volume of approximately 190 mm 3 Control mice were injected with 5% EtOH in sterile PBS, whereas treated mice received 0.50 mCi of FAP-3001 radiolabeled with lutetium-177 ( 177Lu-FAP-3001) was injected at a dose of 5 nmol. Mouse body weight was monitored as a measure of overall toxicity. Figure 13A shows the tumor growth data from this study (KB tumor growth chart used in nude mice for comparison), Figure 13B illustrates the survival curve of this study, and Figure 13C shows the relative mouse body weight data from this study.

[0705] [Example 13] 177 Lu-FAP-3001 Radiotherapy Toxicology Staining Mice were randomly selected from the control and treatment groups (0.5 mCi dose) for further toxicology evaluation. Organs of interest were harvested immediately after euthanasia, washed, and fixed in a buffered solution of 10% formalin for 48-72 hours. Organs were then maintained in a 70% ethanol solution until complete decay of radioactivity, after which the organs were submitted to the Purdue University Histology Laboratory for embedding in paraffin, sectioning, and staining with hematoxylin and eosin (H&E) (see Figure 14). Histological sections (n=4-8 per organ per mouse) were examined for lesions in a blinded fashion by a board-certified pathologist at the Purdue University Department of Comparative Pathobiology.

[0706] Table 1 summarizes the data observed from such studies (see also FIG. 14).

[0707] [Table 1]

[0708] [Example 14] 4T1-High dose 177 Lu-FAP-3001 radiotherapy study Treatment was performed on 4T1 tumors with a volume of approximately 200 mm 3Control mice were injected with 5% EtOH in sterile PBS via intravenous injection into the tail vein, whereas treated mice received 1.50 mCi of FAP-3001 radiolabeled with lutetium-177 ( 177 Lu-FAP-3001) 5 nmol per dose, or 1.50 + 0.6 mCi of lutetium-177 radiolabeled FAP-3001 ( 177 Two doses of 5 nmol of Lu-FAP-3001 were injected. Mice body weight was monitored as a measure of overall toxicity. Figure 15A shows tumor growth data from this study, Figure 15B illustrates the survival curves of this study, Figure 15C shows the relative body weight data of mice from this study, and Figure 15D shows the relative body weight data of mice from this study. 177 A SPECT / CT scan of one of the mice that received a single dose of Lu-FAP-3001 is shown.

[0709] [Example 15] 4T1-Blinded measurements 177 Lu-FAP-3001 radiotherapy study Treatment was performed on 4T1 tumors with a volume of approximately 100 mm 3 On day 0, control mice were injected with 5% EtOH in sterile PBS, whereas treated mice received 1.50 mCi of FAP-3001 radiolabeled with lutetium-177 ( 177 Lu-FAP-3001) was injected at a dose of 5 nmol. Tumors were measured with calipers every other day by two assistants in a blinded fashion (i.e., not knowing which mice were treated and which were controls). Mouse weights were monitored as a measure of overall toxicity. Figure 16A shows tumor growth data from this study 7, Figure 16B illustrates the survival curves of this study, and Figure 16C shows the relative mouse weight data from this study.

[0710] [Example 16] 4T1-Blinded measurements 177 Lu-FAP-3001 vs. 177 Radiation therapy study of Lu-FAP-3005 Treatment was performed on 4T1 tumors with a volume of approximately 100 mm 3 On day 0, control mice were injected with 5% EtOH in sterile PBS, whereas treated mice received 1.50 mCi of FAP-3001 or FAP-3005 radiolabeled with lutetium-177 (respectively) via intravenous injection into the tail vein. 177 Lu-FAP-3001 or 177 Lu-FAP-3005) was injected at a dose of 5 nmol. Tumors were measured with calipers every other day by two assistants in a blinded fashion (i.e., not knowing which mice were treated and which were controls). Mouse weights were monitored as a measure of overall toxicity. Figure 17A shows tumor growth data from this study 7, Figure 17B illustrates the survival curves of this study, and Figure 17C shows the relative mouse weight data from this study.

[0711] [Example 17] 177 Toxicological staining of Lu-FAP-3001 high dose radiation therapy Mice were randomly selected from control and treated mice (1.5 mCi dose) at various time points after injection for further toxicological evaluation. Organs of interest were harvested immediately after euthanasia, washed, and fixed in a buffered solution of 10% formalin for 48-72 hours. Organs were then maintained in a 70% ethanol solution until complete decay of radioactivity, after which the organs were submitted to the Purdue University histology laboratory for embedding in paraffin, sectioning, and staining with H&E (see Figure 14). Histological sections (n=1-4 per organ per mouse) were examined for lesions in a blinded fashion by board-certified pathologists at the Purdue University Department of Comparative Pathobiology. Tables summarize the results, and representative tissue sections are presented in Figures 18A and 18B, respectively.

[0712] [Example 18] In C57 / BL6 mice, disease was induced by intratracheal injection of bleomycin, and 14 days later,111 SPECT / CT scans were taken 24 hours after intravenous injection of In-FAP-3001 (5 nmol radiolabeled with 0.3 mCi). See Figure 19.

[0713] [Example 19] High affinity FAP ligands and molecular docking The design of drug conjugates requires specific selection of linker attachment points, so that the binding affinity of the modified drug remains similar to that of the parent drug. Molecular docking experiments were used to identify suitable linker attachment points in known FAP inhibitors 1.

[0714] [ka]

[0715] The crystal structure of human FAP [PDB ID: 1Z68] was retrieved from the Protein Data Bank (a global open access digital data source) and further prepared for docking using the Protein Preparation Toolbox included in the Schrodinger software package (Schrodinger, LLC, New York, NY). The protein structure was preprocessed using Schrodinger's default protocol and a pH value of 7.4 + / - 0.5 was used to generate heteroatom states using the Epik module. The protein structure was further refined to optimize intramolecular hydrogen bonds and a restrained energy minimization was performed using the OPLS4 force field.

[0716] The structures of the three FAP ligands (FAP inhibitor 1, intermediate 2' and FAP-4000 (see structures of intermediate 2' and FAP-4000 below)) were uploaded into Maestro (Schrodinger, LLC, New York, NY) and prepared for grid docking using the LigPrep program (Schrodinger, LLC, New York, NY). The three-dimensional geometries of the ligands were optimized using the OPLS4 force field and used for docking.

[0717] Ligands of interest were docked into the binding pocket of FAPs using standard induced fit docking (IFD) protocol in the Schrodinger software package. First, a receptor grid box was generated by identifying amino acid residues in the FAPs that have been reported to be involved in binding interactions. The IFD protocol utilized a grid docking protocol to generate up to 20 poses for each ligand, which were further refined using the Prime Refinement module. Residues within 5 Å of the ligand pose were refined and the side chains of the residues were optimized. Upon refining the binding site after the initial docking, the ligands were redocked to a structure that was within 30.0 kcal / mol of the best structure and within the top 20 structures overall. Standard refinement models were used for the grid redocking step.

[0718] Referring to Figure 27, in the docking pose of FAP inhibitor 1 with FAP, Glu204 and Tyr541 residues were found to be involved in non-covalent interactions, with Glu204 forming a hydrogen bond with the NH group of the pyrrolidine ring and Tyr541 forming a pi-pi interaction with the 2,3-dihydroisoindole ring of inhibitor 1. The shaded regions of the 2,3-dihydroisoindole ring mark the solvent exposed atoms (Figure 27).

[0719] Next, FAP inhibitor 1 was further functionalized at the C-4 position of the 2,3-dihydroisoindole ring. A methyleneamine (-CH2NH2) was attached at the C-4 position of the 2,3-dihydroisoindole ring of FAP inhibitor 1, resulting in intermediate 2'. When intermediate 2' was docked against the FAP protein, its interaction with the FAP protein was similar to that of the parent FAP inhibitor 1 with an additional cation-pi interaction between the 2,3-dihydroisoindole ring and Arg550. The methyleneamine (-CH2NH2) in intermediate 2' remained exposed to the solvent.

[0720] Since the presence of nearby aromatic amino acid residues was observed in the deep binding pocket of FAP, we sought a hydrophobic spacer that would promote the formation of new stable interactions with these aromatic amino acid residues. Thus, the methylene amine group in intermediate 2' was replaced by a triazole ring containing a solvent-exposed methylene amine (-CH2NH2) group (FAP-4000), resulting in a pi-pi interaction between the triazole ring and Phe350. In addition, the NH of the methylamine formed a hydrogen bond with Cys545, and Arg123 formed a hydrogen bond with the amide oxygen adjacent to the 2,3-dihydroisoindole ring (see Figure 27). The increased number of intermolecular interactions improved the docking score from -8.0 kcal / mol (FAP inhibitor 1) to -9.4 kcal / mol (FAP-4000).

[0721] Since the C-1 position (-CH2NH2 unit) of the triazole ring of FAP-4000 was found to be solvent exposed in the docking pose, the methylene amine in FAP-4000 was then replaced with aminoethylbenzamide to give FAP-4001. When FAP-4001 was docked against the FAP protein, the docking score was further improved to -11.5 kcal / mol. Specifically, the phenyl ring in FAP4001 formed a pi-pi interaction with Trp623, and the 2,3-dihydroisoindole ring formed an additional cation-pi interaction with Arg550.

[0722] Next, the modified structure was docked again into the same binding pocket (FAP4002) by utilizing the -NH2 moiety in FAP-4001 for the attachment of a PEG4-amine linker and setting a larger grid box to accommodate the ligand-PEG4-amine drug conjugate. The interactions of the ligand with Glu204 and Tyr541 residues were conserved in the docking pose of FAP4002 with FAP, resulting in a docking score of -9.5 kcal / mol. The triazole ring was involved in a pi-pi interaction with Phe350, as shown in Figure 27.

[0723] Thus, these data support that the addition of spacers and linkers to the parent (free) drug helps the drug maintain its binding affinity even after conjugation, without interfering with the parent drug's important non-covalent interactions.

[0724] [Example 20] Synthesis of FAP-targeting dye compounds The free amine functionality in FAP-4002 was utilized for the synthesis of a FAP-targeting dye conjugate (FAP-4003) according to Scheme 1 below:

[0725] [ka]

[0726] The synthesis of FAP-targeted fluorescent compounds then began from intermediates 5′, 6′, and 7′, as shown in Scheme 2.

[0727] [ka] Option 1

[0728] [ka] Alternatively option 2:

[0729] [ka]

[0730] Briefly, intermediate 5' was synthesized from commercially available Boc-L-pyroglutamic acid benzyl ester 8. Intermediate 6' was prepared from methyl 2,3-dihydro-1H-isoindole-4-carboxylate hydrochloride 9 by tert-butyloxycarbonyl (Boc) protection in dichloromethane to give compound 10 in quantitative yield. The methyl ester in compound 10 was then reduced with NaBH4 by heating in methanol and tetrahydrofuran to give the corresponding alcohol 11 in 90% yield. Bromination of 11 with NBS / PPh3 in DMF at room temperature, followed by nucleophilic displacement of the corresponding bromide 12 with NaN3 in DMF at 70 °C for 12 h afforded the key azide intermediate 6' in 95% yield. Coupling of mono-Fmoc ethylenediamine hydrochloride with 4-ethynylbenzoic acid 13 in the presence of HATU / DIPEA in dry DMF gave the alkyne intermediate 7'. Then, classical Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction of intermediate 6' with intermediate 7' in DMF at 55° C. for 5 h gave click product 14 with a phenyltriazole appendage, which was treated with trifluoroacetic acid (TFA) in DCM, followed by addition of activated acid 5, followed by Fmoc deprotection using diethylamine in DCM to give FAP-4001 (see Scheme 2, option 1).

[0731] Treatment of the same compound 14 with diethylamine in dichloromethane for 30 min, followed by coupling of the resulting amine with Fmoc-PEG4-NHS ester in the presence of DIPEA in CHCl gave intermediate 15 in 90% yield (see Scheme 2, option 2). Treatment of intermediate 15' with TFA in CHCl, followed by coupling of the resulting amine with key acid intermediate 5' in the presence of HATU / DIPEA in DMF afforded the FAP targeting ligand (intermediate 16) in 65% yield.

[0732] Referring now to Scheme 3, to generate the final FAP-targeted fluorescent dye used below, the Fmoc protecting group in compound 16 was deprotected with diethylamine in dichloromethane to generate the free amine 17 (compound 17). Coupling of the free amine 17 (compound 17) with 3-(4-hydroxyphenyl)propionic acid afforded FAP-4002. Subsequent displacement of the chloride from the near-infrared dye (ClS0456) under basic conditions afforded the FAP-targeted near-infrared dye FAP-4003 in 65% yield.

[0733] [ka]

[0734] [Example 21] Compound binding-induced internalization The following compounds were analyzed for their affinity for binding to FAP: FAP inhibitor 1; FAP targeting ligand with a linker (FTL-PEG-NH) (compound 17); a conjugate of compound 17 with 4-hydroxyphenylpropionic acid (FAP-4002); a conjugate of compound 17 with tetramethyl-rhodamine (FAP-4004); and a conjugate of FAP-4002 with ClS0456 (FAP-4003).

[0735] [ka]

[0736] HT1080-FAP cells were incubated with 25 nM FAP-4004 (see FIG. 32A) or FAP-4003 (see FIG. 32B) for 1 hour at 37° C. and examined by confocal and wide-field Nikon microscopy, respectively. The binding affinity and specificity of each compound was also quantified by measuring the fluorescence of either HT1080-FAP or HT1080 cells after 1 hour incubation at 4° C. in the presence or absence of 100-fold excess unlabeled FAP-4002, and increasing concentrations of FAP-4004 (see FIG. 32C) or FAP-4003 (see FIG. 32D).

[0737] The ability of FAP-targeted FAP-4002 to inhibit the closely related dipeptidyl peptidases FAP, PREP and DPP-IV was also evaluated. FAP, PREP and DPP-IV were incubated with FAP-targeted FAP-4002 at room temperature for 10 minutes, after which a fluorescent substrate was added. The reaction was allowed to proceed for 30 minutes before being stopped and the change in fluorescence was quantified as a measure of catalytic activity. All assays were performed in triplicate and SEM bars are shown (see Figures 33A-33C).

[0738] Synthesis example: The following examples further describe in detail the materials and methods used to synthesize the intermediates and compounds described in Examples 21-23 and Schemes 1-3. After synthesis, all intermediates and compounds / products were characterized by LC-MS and nuclear magnetic resonance spectroscopy (NMR).

[0739] [Example 22] Synthesis of 2-(tert-butyl) 4-methylisoindoline-2,4-dicarboxylate (compound 10) To a stirred solution of methyl 2,3-dihydro-1H-isoindole-4-carboxylate hydrochloride 9 (1.00 g, 5.64 mmol) at room temperature was added 20 mL of DCM. To this mixture was then added (Boc)2O (4.9 mL, 22.59 mmol) in one portion followed by triethylamine (2.9 mL, 22.59 mmol) dropwise. Stirring was continued for 12 h, and then the reaction mixture was diluted with water (30 mL) and extracted into DCM (2 x 25 mL).

[0740] The organic layer was dried over anhydrous MgSO4, filtered and the filtrate was evaporated under reduced pressure. The crude residue was purified by CombiFlash using hexane+ethyl acetate as the mobile phase to give compound 10 (1.4 g, 92%) as a white solid. 1 H-NMR (CDCl3, 500 MHZ) δ = 7.92 (dd, J1= 15.0 Hz, J2= 10.0 Hz, 1H); 7.44-7.32 (m, 1H); 7.33 (m, 1H); 4.94 (d, J = 12.6 Hz, 2H); 4.67 (d, J = 17.0 Hz, 2H); 3.90 (s, 3H); 1.51 (s, 9H) ppm. 13 C-NMR (CDCl3, 125 MHZ) δ = 166.41, 154.50, 154.33, 139.93, 138.96, 138.83, 138.56, 129.37, 128.96, 127.61, 127.17, 126.89, LCMS of 4: LC / MS (m / z): C 15 H 21 Calculated NO4[M+H]: 278.14, found 278.13g / mol.

[0741] [Example 23] Synthesis of tert-butyl 4-(hydroxymethyl)isoindoline-2-carboxylate (alcohol 11) To a stirred solution of compound 10 (1.0 g, 3.61 mmol) in THF (10.0 mL) under N2 atmosphere was added sodium bromide (1.37 g, 36.101 mmol) at room temperature. After this, methanol (10 mL) was added slowly to the reaction mixture over a period of 5 minutes. The reaction was warmed to 55° C. and stirred continuously for 5 hours.

[0742] The reaction mixture was then cooled to 0° C., slowly quenched with saturated aqueous ammonium chloride, and extracted into EtOAc (60 mL). The organic phase was collected, dried over sodium sulfate, and the solvent was evaporated to give a crude residue that was purified by CombiFlash to give alcohol 11 (700 mg, 70%) as a sticky white solid. 1 H-NMR (CDCl3, 500 MHZ) δ = 7.28-7.25 (m, 2H); 7.19-7.13 (m, 1H); 4.68-4.62 (m, 6H); 1.51 (s, 9H) ppm. 13 C-NMR (CDCl3, 125 MHZ) δ = 154.64, 137.60, 137.39, 135.62, 135.32, 143.92, 127.81, 125.90, 125.67, 122.05, 121.60, 79.87, LC-MS of 11. LC-MS (m / z): C 14 H 20 Calculated NO3[M+H]: 250.14, found 250.14g / mol.

[0743] [Example 24] Synthesis of tert-butyl 4-(bromomethyl)isoindoline-2-carboxylate (bromide 12) To a stirred solution of compound 11 (500 mg, 2.00 mmol) in DMF (10 mL) was added PPh3 (790 mg, 3.01 mmol) followed by freshly recrystallized N-bromosuccinimide (NBS) (532 mg, 3.01 mmol). The reaction mixture was stirred at room temperature under N2 atmosphere for 4-5 h, then diluted with water (40 mL) and extracted into ethyl acetate (2 x 25 mL). The organic layer was washed with water and brine, then dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give the crude residue, which was purified by CombiFlash to give bromide 12 (450 mg, 90%) as a white solid. 1 H-NMR (CDCl3, 500 MHZ) δ = 7.28-7.17 (m, 3H); 4.71 (m, 4H); 4.42 (d, J = 8.5 Hz, 2H); 1.52 (s, 9H) ppm. 13 C-NMR (CDCl3, 125 MHZ) δ = 154.46, 138.38, 138.03, 136.78, 136.48, 132.44, 132.17, 128.20, 128.13, 127.8, 123.18, 122.90, LC-MS of 12: LC-MS: (m / z): C 14 H 19 Calculated BrNO2[M+H]: 312.05, found 312.05 g / mol.

[0744] [Example 25] Synthesis of tert-butyl 4-(azidomethyl)isoindoline-2-carboxylate (intermediate 6') To a stirred solution of bromide compound 12 (400 mg, 1.286 mmol) in DMF, NaN3 (420 mg, 6.430 mmol) was added and the mixture was continuously stirred at 75 °C for 6 h. The reaction mixture was then diluted with water and extracted into ethyl acetate, the organic layer was washed with water, treated with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and purified by CombiFlash to afford the azide intermediate 6' (300 mg, 95%) as a white solid. 1 H-NMR (CDCl3, 500 MHZ) δ = 7.32-7.25 (m, 2H); 7.22-7.20 (m, 1H); 4.72-4.66 (m, 4H); 4.31 (s, 2H); 1.53 (s, 9H) ppm. 13 C-NMR (CDCl3, 125 MHZ) δ = 154.42, 138.28, 137.95, 136.34, 135.95, 130.18, 129.92, 128.08, 127.40, 127.30, 122.96, 122.65, LC-MS of 79.96, 52.59, 52.48, 52.39, 52.15, 51.05, 50.89, 28.56 ppm. 7: LC-MS (m / z): C 14 H 19 Calculated N4O2[M+H]: 275.14, found 275.14 g / mol.

[0745] [Example 26] Synthesis of (9H-fluoren-9-yl)methyl (2-(4-ethynylbenzamido)ethyl)carbamate (intermediate 7') To a stirred solution of 4-ethynylbenzoic acid compound 13 (500 mg, 3.424 mmol) in dry DMF (10 mL) under N2 atmosphere was added HATU (1.4 gm, 3.76 mmol) followed by DIPEA (1.7 mL, 10.27 mmol) at room temperature. The mixture was continuously stirred for 10 minutes to activate the acid.

[0746] N-Fmoc-ethylenediamine (1.0 g, 3.76 mmol) was then added to the reaction mixture and the mixture was continuously stirred for an additional 3 hours. After this, the reaction mixture was diluted with water (50 mL) and the resulting precipitate was filtered through a Buchner funnel to give a white solid. The white solid was again washed with water (2×50 mL) and dried under vacuum for 1 hour to give intermediate 7′ (1.2 gm, 85%). 1 7.25 (m, 2H); 4.44 (bs, 2H); 4.33 (d, J = 7.0 Hz, 1H); 4.16 (t, J = 7.0 Hz, 1H); 3.50 (s, 1H); 3.48 (t, J = 6.1Hz, 2H); 3.34(t, J = 6.0 Hz, 2H) ppm. 13 C-NMR (CD3OD +CDCl3, 125 MHZ) δ = 168.27, 158.16, 143.81, 141.20, 134.02, 131.83, 127.49, 127.06, 126.85, 125.62, 124.83, 119.65, 83.34, 79.69, 77.92, 66.61, 47.06,40.04 ppm. and LC-MS of 7: LC-MS (m / z): C 26 H 23 Calculated N2O3[M+H]: 411.16, Found 411.16 g / mol. HRMS-ESI: C 26 H 23 Calculated value for N2O3[M + H]+: 411.1708, found 411.1710.

[0747] [Example 27] Synthesis of tert-butyl 4-((4-(4-((2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethyl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)isoindoline-2-carboxylate (Compound 14) To a mixture of azide intermediate 6 (1.0 equiv.) and alkyne intermediate 7 (1.2 equiv.) in dry DMF (5.0 mL) was added CuI (0.5 equiv.) followed by DIPEA (2.0 equiv.). The reaction mixture was stirred at 55° C. for 1 h under nitrogen atmosphere, transferred to room temperature, diluted with saturated aqueous ammonium chloride (20 mL) and stirred vigorously for 15 min. The solid residue formed in the reaction mixture was filtered, washed with water (2×20 mL) and dried under vacuum for 1 h to give compound 14 as a brown solid.

[0748] Compound 14 was used in some cases for studies without purification. A quantity of compound 14 was also purified using an EtOAC / Hexane mixture as the mobile phase to give compound 14 (97%) as a white solid. 1 H-NMR (CDCl3, 500 MHZ) δ = 7.79 (bs, 3H); 7.78-7.70 (m, 2H); 7.68 (d, J = 7.9 Hz, 2H); 7.52 (d, J = 7.3 Hz, 2H); 7.73-7.720 (m, 7H); 7.15-7.13 (m, 1H); 5.50 (s, 2H); 4.67-4.57 (m, 4H); 4.34 (d, J = 6.7 Hz, 2H); 4.12 (t, J = 6.7 Hz, 1H); 3.48 (t, J = 5.7 Hz, 1H); 3.35-3.33 (m, 2H); 2.77 (s, 2H); 2.71 (bs, 1H); 1.46 (s, 9H) ppm. 13C-NMR (CDCl3, 125 MHZ) δ = 173.47, 167.26, 156.65, 154.33, 144.98, 141.27, 138.65, 138.46, 136.59, 135.92, 129.26, 129.03, 128.58, 127.82, 127.67, 127.44, 127.06, 125.61, 125.12, 123.58, 123.26, 119.95, 80.18, 80.08, 70.49, 70.13, 67.14, 66.58, 50.98, LC-MS of 14: LC-MS (m / z): C 40 H 41 Calculated value of N6O5[M+H]: 685.31, Found value: 685.31g / mol. HRMS-ESI: C 40 H 41 Calculated for N6O5[M + H]+: 685.3138, found 685.3139.

[0749] [Example 28] Synthesis of tert-butyl 4-((4-(4-((1-(9H-fluoren-9-yl)-3,19-dioxo-2,7,10,13,16-pentaoxa-4,20-diazasodocosane-22-yl)carbamoyl)phenyl)-1H-1,2,3-triazol-1-yl)methyl)isoindoline-2-carboxylate (Intermediate 15') To a stirred solution of compound 14 (400 mg, 0.584 mmol) in DCM+MeOH mixture (1+0.5 mL), (Et)2NH (1.0 mL) was added and stirred continuously for 2 h. The reaction mixture was evaporated under reduced pressure and the crude residue obtained was purified by CombiFlash using MeOH+CH2Cl2 as the mobile phase to give the free amine of compound 14, which was retained and used in the studies described herein.

[0750] A portion of the amine compound was dissolved in DCM (1 mL for 1 mmol) and to this was added Fmoc-NH(PEG)4NHS ester (1.2 eq.) and DIPEA (2.0 eq.) with stirring at room temperature under nitrogen for 1 h. The reaction mixture was evaporated under reduced pressure and the crude residue was purified by CombiFlash using DCM+MeOH as mobile phase to give intermediate 15' as a white solid in 80%. 1 H-NMR (CDCl3, 500 MHZ) δ = 7.86 (m, 4H); 7.74 (d, J = 7.5 Hz, 2H); 7.68 (d, J = 3.7 Hz, 1H); 7.57 (m, 3H); 7.37 (t, J = 7.5 Hz, 2H); 7.28 (m, 4H); 7.16 (m, 2H); 5.67 (bs, 1H); 5.51 (d, J=6.7 Hz, 2H); 4.71 (s, 2H); 4.65 (m, 2H); 4.37 (d, J=7.2Hz, 1H); Hz, 1H); 3.72-3.34 (m, 22H); 2.44 (s, 2H); 1.51 (s, 9H) ppm. 13 C-NMR (CDCl3, 125 MHZ) δ = 173.47, 167.26, 156.65, 154.33, 143.98, 141.27, 138.65, 138.46, 136.59, 135.92, 133.77, 133.19, 129.26, 129.03, 128.58, 127.82, 127.67, 127.44, 127.06, 125.61, 125.12, 123.58, 123.26, 119.95, 80.18, 80.08, 70.49, 70.42, 70.13, 70.06, 67.14, 66.58, 52.11, 51.92, 51.73, 50.90, 50.81, 47.25, 41.59, 40.90, 39.06, 36.85, 28.52 ppm. 15のLC-MS:LC-MS (m / z): C 51 H 62 N7O 10 [M+H] calculated value: 932.45, measured value 932.45g / mol. HRMS-ESI: C 51 H 61 N7O 10 Calculated value of Na [M + Na]+: 954.4377, measured value 954.4433.

[0751] [Example 29] Synthesis of (9H-fluoren-9-yl)methyl (1-(4-(1-((2-(2-((3S)-5-((S)-2-cyano-4,4-difluoropyrrolidine-1-carbonyl)-2-oxopyrrolidin-3-yl)acetyl)isoindolin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-1,6-dioxo-9,12,15,18-tetraoxa-2,5-diazaeicosan-20-yl)carbamate (compound 16) To a stirred solution of intermediate 15 (250 mg, 0.268 mmol) in DCM (1.0 mL) was added TFA (0.5 ml) at room temperature. The mixture was continuously stirred for 30 min, after which the solvent was evaporated and dried under vacuum. In a separate round-bottom flask, acid intermediate 5 (100 mg, 0.333 mmol) was dissolved in DMF (0.5 mL), followed by HATU (151 mg, 0.399 mmol) and DIPEA (0.170 mL, 0.999 mmol). To activate the acid functional group, the reaction mixture was stirred at room temperature under nitrogen atmosphere for 10 min.

[0752] The amine generated in situ from intermediate 15 (220 mg, 0.268 mmol) was dissolved in DMF (1 mL) and added to the above reaction mixture and stirred continuously for 2 h. The reaction mixture was then diluted with water (15 mL) and stirred at room temperature for 15 min. The black turbidity formed in the reaction mixture was filtered and redissolved in a mixture of methanol and dichloromethane. The organic layer was evaporated and the crude residue was purified by reverse-phase preparative high performance liquid chromatography (HPLC) (A=20 mm ammonium acetate buffer (pH=7), B=acetonitrile, solvent gradient from 5% to 95% B) in 60 min to give compound 16 as a white solid (175 mg, 65%). Figures 34A-34B show data supporting the formation of compound 16, and Figure 34C shows H NMR spectroscopy (Hz) confirming the formation of FAP-4003. 1 NMR (D2O) data is shown. 1H-NMR (CD3OD + CDCl3, 500 MHZ) δ = 8.32 (d, J= 15.0 Hz, 1H), 7.89-7.85 (m, 4H), 7.73 (d, J = 10.0 Hz, 2H); 7.58 (d, J = 5.0 Hz, 2H); 7.35-7.24 (m, 8H); 5.61-5.59 (m, 2H); 5.05 (dd, J1 = 9.1 Hz, J2 = 3.9 Hz, 1H); 4.85 (m, 2H); 4.72 (d, J = 17.2Hz, 2H); 4.45-4.37 (m, 1H); 4.31 (d, J = 6.8 Hz, 2H); 4.15-4.02 (m, 3H); 3.67 (t, J = 6.0 Hz, 2H); 3.55-3.48 (m, 20H); 3.31-3.25 (m, 6H); 3.0-2.74 (m, 5H); 2.60-2.54 (m, 1H); 2.43-2.30 (m, 4H) ppm. 13 C-NMR (CD3OD + CDCl3, 125 MHZ) δ = 173.28, 168.36, 156.66, 143.88, 141.19, 127.76, 127.45, 126.83, 125.34, 124.82, 121.72, 119.62, 70.72, 70.19, 69.99, 69.91, 69.62, 66.85, 66.30, 52.80, 52.06, 44.58, 40.44, 39.86, 38.69, 37.60 36.38 ppm. 16のLC-MS: LC-MS (m / z): C 58 H 65 F2N 10 O 11 [M+H] calculated value: 1115.47, measured value 1115.47 g / mol. HRMS-ESI: C 58 H 65 F2N 10 O 11 Calculated value of [M+H]: 1115.4802, measured value 1115.4817.

[0753] [Example 30] Sodium 2-((E)-2-((E)-2-(4-(1-(4-(1-((2-(2-((3S,5S)-5-((S)-2-cyano-4,4-difluoropyrrolidine-1-carbonyl)-2-oxopyrrolidin-3-yl)acetyl)isoindolin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)-1,6,22-trioxo-9,12,15,18-tetraoxo-9,12,15,18-tetraoxo-1,6,22-tri ... Synthesis of oxa-2,5,21-triazatetracosan-24-yl)phenoxy)-3-(2-((E)-3,3-dimethyl-5-sulfonate-1-(4-sulfonatebutyl)indolin-2-ylidene)ethylidene)cyclohex-1-en-1-yl)vinyl)-3,3-dimethyl-1-(4-sulfonatebutyl)-3H-indol-1-ium-5-sulfonate (FAP-4003) To a stirred solution of compound 16 (250.0 mg, 0.2244 mmol) in DCM+MeOH (1+1 mL), diethylamine (Et)2NH (2.0 mL) was added and stirred continuously at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure and the crude residue obtained was redissolved in EtOAc (10 mL). The resulting precipitate was filtered through a Buchner funnel to give the free amine (Intermediate 2) as a brown solid. LC-MS of 2: LC-MS (m / z): C 43 H 55 F2N 10 Calculated value for O9 [M+H]: 893.40, Found value: 893.40 g / mol. HRMS-ESI: C 43 H 55 F2N 10 Calculated value of O9 [M+H] + : 893.4121, found 893.4160. This material was used in the synthesis of FAP-targeting dye compound 4 described below.

[0754] Next, 4-(1-((2-((3S,5S)-5-((S)-2-cyano-4,4 -difluoropyrrolidine-1-carbonyl)-2-oxopyrrolidin-3-yl)acetyl)isoindolin-4-yl)methyl)-1H-1,2,3-triazol-4-yl)-N-(22-(4-hydroxyphenyl)-4,20-dioxo-7,10,13,16-tetraoxa-3,19-diazadocosyl)benzamide (intermediate 3) was prepared and the mixture was subjected to continuous stirring at room temperature for 30 min. The reaction mixture was then quenched with water (5 mL) and the crude residue obtained was purified by using UHPLC (A=20 Mm ammonium acetate buffer (pH=7), B=acetonitrile, solvent gradient from 5% to 95% B in 60 min) to give intermediate 3 as a white solid (34 mg, 60%). LC / MS of 3: LC-MS (m / z): C52 H 63 F2N 10 O 11 Calculated value [M+H]+: 1041.46, Found value: 1041.46. HRMS-ESI: C 52 H 63 F2N 10 O 11 Calculated value [M+H]+: 1041.4645, measured value 1041.4650.

[0755] To a stirred solution of intermediate 3 (5.0 mg, 0.00480 mmol) in anhydrous DMSO (500 μl) was added ClS0456 dye (4.6 mg, 0.0048 mmol) followed by Cs2CO3 (15.0 mg, 0.0480 mmol) at room temperature under argon atmosphere. The mixture was continuously stirred at room temperature for an additional 3-4 h and the progress of the reaction was monitored by LCMS.

[0756] The reaction mixture was then diluted with water and purified by UHPLC (A=20 mM ammonium acetate buffer (pH=7), B=acetonitrile 0, solvent gradient from 5% to 35% B in 60 min) to give intermediate 5 as a fluffy green solid (6.0 mg, 66%). LC-MS of 4: LC / MS (m / z): [M+H] C 90 H 110 F2N 12 O 23 S4 Calculated [M+H]: 1892.66, Found: 1892.60, [M+H] / 2: 946.0, and [M+H] / 3: 630.0 g / mol. 1H-NMR (D2O, 500 MHZ) δ = 8.27 (m, 1H); 7.62 (m, 10H); 7.12 (d, J = 6.2Hz, 5H); 6.97 (dd, J = 14.7 Hz, 7.9 Hz, 2H); 6.64 (dd, J = 14.1 Hz, 8.1 Hz, 2H); 5.86 (dd, J = 14.3 Hz, 3H); 5.40 (d, J = 9.8 Hz, 3H);4.97 (m, 3H); 4.54 (d, J = 7.5 Hz, 3H); 4.46 (s, 1H); 4.35 (s, 1H); 3.97 (m, 1H); 3.85 (s, 6H); 3.50 (s, 6H); 3.26 (m, 20H); 3.09 (m, 3H); 2.77(s, 10H); 2.62 (m, 4H); 2.33 (m,9H); 2.15 (m, 2H); 1.90 (d, J = 0.9 Hz, 7H); 1.68 (s, 10 H); 0.95 (s, 10 H) ppm.

[0757] FIG. 35 shows the excitation and emission spectra of a 1 μM solution of FAP-4003 in PBS at pH 7.4 after synthesis.

Claims

1. Structure of formula (X): A ｍ -L-B’ (X) (In the formula, A is of formula X-B: 【Chemistry 1】 is a radical of the fibroblast activation protein alpha (FAPα) ligand of During the ceremony, T is a substituted or unsubstituted methylene (-CH ２ -), substituted or unsubstituted amino (-NH-), -O- or -S- (e.g., the substitution of T is １ ~C ３ alkyl, haloalkyl or halo; J is C(R Ｊ ) ０～３ and R Ｊ are each independently H or alkyl, or two or more R Ｊ together to form oxo, R １ and R ２ is -H, -CN, -CHO, -B(OH) ２ , -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O) ２ Aryl, —CO ２ H, -SO ３ H, -SO ２ N.H. ２ , -PO ３ H ２ , -SO ２ F, -CONH ２ and 5-tetrazolyl; R ３ and R ４ is -H, -OH, F, Cl, Br, I, -C １～６ Alkyl, —O—C １～６ Alkyl and -S-C １～６ independently selected from the group consisting of alkyl, R ５ , R ６ , R ７ and R ８ is independently selected from the group consisting of H, alkyl and halo; R ９ , R １０ and R １１ is H, -C １～６ Alkyl, -C １～６ Haloalkyl, —O—C １～６ Alkyl, -S-C １～６ independently selected from the group consisting of alkyl, F, Cl, Br and I; L is a linker connecting A to B'; B' is a radical of a phosphoinositide 3-kinase (PI3K) inhibitor, a chelating group optionally bound to an isotope (or metal), or a group covalently bound to an isotope (or metal), said isotope or metal being suitable for radioimaging, radiotherapy or magnetic resonance imaging; m = 1 to 6) A compound represented by the formula: The compound further comprises C′, L links C' to one or more A groups and to B'; The compound, wherein C' is a radical of an albumin binding ligand, polyethylene glycol n (PEG) n (n is an integer from 0 to 32), a peptide, a peptidoglycan, or a sugar.

2. A compound represented by the structure of formula (I'): 【Chemistry 2】 (In the formula, A is of formula X-B: 【Chemistry 3】 is a radical of a FAPα ligand (targeting moiety) of During the ceremony, T is a substituted or unsubstituted methylene (-CH ２ -), substituted or unsubstituted amino (-NH-), -O- or -S- (e.g., the substitution of T is １ ~C ３ alkyl, haloalkyl or halo; J is C(R Ｊ ) ０～３ and R Ｊ are independently H or alkyl, or two or more R Ｊ together to form oxo, R １ and R ２ is -H, -CN, -CHO, -B(OH) ２ , -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O) ２ Aryl, —CO ２ H, -SO ３ H, -SO ２ N.H. ２ , -PO ３ H ２ , -SO ２ F, -CONH ２ and 5-tetrazolyl; R ３ and R ４ is -H, -OH, F, Cl, Br, I, -C １～６ Alkyl, —O—C １～６ Alkyl and -S-C １～６ independently selected from the group consisting of alkyl, R ５ , R ６ , R ７ and R ８ is independently selected from the group consisting of H, alkyl and halo; R ９ , R １０ and R １１ is H, -C １～６ Alkyl, -C １～６ Haloalkyl, —O—C １～６ Alkyl, -S-C １～６ independently selected from the group consisting of alkyl, F, Cl, Br and I; L is a trivalent linker; B' is a radical of a chelating group optionally bound to an isotope (or metal), said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) ｎ (n is an integer from 0 to 32) is a radical of a peptide, peptidoglycan, or sugar).

3. A compound represented by the structure of formula (X): A ｍ -L-B’ (X) (In the formula, A has the structure of formula X-X: 【Chemistry 4】 is represented by 【Chemistry 5】 teeth, 【Chemistry 6】 having a structure selected from the group consisting of: n=1 to 5; n′=1 to 5; Ring C is optional, X, Y and Z in ring B are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' in Ring C are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N; P is the point of attachment of ring C (if present) to L or B' of formula (X) and is -H, -OH, -NH ２ , -COOH, -CONH ２ , -CHO, -N ３ , -CN, -B(OH) ２ , —C(O)alkyl, —C(O)aryl, —C═C—C(O)aryl and —C═C—S(O) ２ aryl; L, when present, is a linker; B' is a radical of an imaging agent or a radical of a therapeutic agent; m=1 to 6, The compound further comprises C′, L links C' to one or more A groups and to B'; The compound, wherein C' is a radical of an albumin binding ligand, polyethylene glycol n (PEG) n (n is an integer from 0 to 32), a peptide, a peptidoglycan, or a sugar.

4. A has the structure of formula X-X': 【Chemistry 7】 is represented by 【Chemistry 8】 has the formula X-B, P is the point of attachment to L or B' in formula (X), -H, -OH, -NH ２ , -COOH, -CONH ２ , -CHO, -N ３ , -CN, -B(OH) ２ , —C(O)alkyl, —C(O)aryl, —C═C—C(O)aryl and —C═C—S(O) ２ 2. The compound of claim 1, wherein the compound is selected from the group consisting of aryl.

5. A is a compound having the structure of formula X-Y: 【Chemistry 9】 is represented by 【Chemistry 10】 has the formula X-B, n=0 to 4; X, Y and Z are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N or Z is N; P is the point of attachment to L or B' in formula (X), -H, -OH, -NH ２ , -COOH, -CONH ２ , -CHO, -N ３ , -CN, -B(OH) ２ , —C(O)alkyl, —C(O)aryl, —C═C—C(O)aryl and —C═C—S(O) ２ 2. The compound of claim 1, wherein the compound is selected from the group consisting of aryl.

6. A has the structure of formula X-Z: 【Chemistry 11】 is represented by 【Chemistry 12】 has the formula X-B, X, Y and Z are independently selected from O, N and S, with the proviso that at least one of X and Y is N or Z is N; X' and Y' are independently selected from O, N and S, with the proviso that at least one of X' and Y' is N or Z is N; P is the point of attachment to L or B' in formula (X), -H, -OH, -NH ２ , -COOH, -CONH ２ , -CHO, -N ３ , -CN, -B(OH) ２ , —C(O)alkyl, —C(O)aryl, —C═C—C(O)aryl and —C═C—S(O) ２ 2. The compound of claim 1, wherein the compound is selected from the group consisting of aryl.

7. B' is the following: phosphoinositide 3-kinase (PI3K) inhibitors, a chelating group optionally bound to an isotope (or metal) or a group covalently bound to an isotope (or metal), said isotope or metal being suitable for radioimaging, radiotherapy or magnetic resonance imaging, Anticancer drugs, antifibrotic agents, or Dyes (e.g., fluorescent dyes), The compound according to any one of claims 1 to 6, which is a radical of

8. A compound represented by the structure of formula (I'): 【Chemistry 13】 (In the formula, A is of formula X-B: 【Chemistry 14】 is a radical of a FAPα ligand (targeting moiety) of During the ceremony, T is a substituted or unsubstituted methylene (-CH ２ -), substituted or unsubstituted amino (-NH-), -O- or -S- (e.g., the substitution of T is １ ~C ３ alkyl, haloalkyl or halo; J is C(R Ｊ ) ０～３ and R Ｊ are independently H or alkyl, or two or more R Ｊ together to form oxo, R １ and R ２ is -H, -CN, -CHO, -B(OH) ２ , -C(O)alkyl, -C(O)aryl-, -C=C-C(O)aryl, -C=C-S(O) ２ Aryl, —CO ２ H, -SO ３ H, -SO ２ N.H. ２ , -PO ３ H ２ , -SO ２ F, -CONH ２ and 5-tetrazolyl; R ３ and R ４ is -H, -OH, F, Cl, Br, I, -C １～６ Alkyl, —O—C １～６ Alkyl and -S-C １～６ independently selected from the group consisting of alkyl, R ５ , R ６ , R ７ and R ８ is independently selected from the group consisting of H, alkyl and halo; R ９ , R １０ and R １１ is H, -C １～６ Alkyl, -C １～６ Haloalkyl, —O—C １～６ Alkyl, -S-C １～６ independently selected from the group consisting of alkyl, F, Cl, Br and I; L is a trivalent linker; B' is a radical of a chelating group optionally bound to an isotope (or metal), said isotope (or metal) being suitable for radioimaging, radiotherapy or magnetic resonance imaging; C' is an albumin binding ligand, (PEG) ｎ (n is an integer from 0 to 32) is a radical of a peptide, peptidoglycan, or sugar).

9. A, 【Chemistry 15】 The compound according to any one of claims 1, 2, 4 to 6, and 8,

10. A, 【Chemistry 16】 The compound according to any one of claims 1, 2, 4 to 6, and 8,

11. A, 【Chemistry 17】 The compound according to any one of claims 1, 2, 4-6, and 8, comprising:

12. A, 【Chemistry 18】 Including, X is 1 to 20; The compound according to any one of claims 1, 2, 4 to 6, and 8.

13. A, 【Chemistry 19】 The compound according to any one of claims 1, 2, 4-6, and 8, comprising:

14. A compound according to any one of claims 1 to 6 and 8, wherein B' is the radical of a chelating group optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

15. B' is as follows: 【Chemistry 20】 and B' is selected from the above, A compound according to any one of claims 1 to 6 and 8, each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

16. B' is as follows: 【Chemistry 21】 and B' is selected from the above, A compound according to any one of claims 1 to 6 and 8, each optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

17. The compound of any one of claims 1 to 6 and 8, wherein B' is a radical of a radioimaging agent, a radiotherapeutic agent or a magnetic resonance imaging agent.

18. 9. The compound of any one of claims 1 to 6 and 8, wherein B' comprises a radical of DOTA, an isotope (or metal) chelated DOTA radical, or a radical of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid.

19. B' is a radical of a group covalently bonded to an isotope suitable for radioimaging, radiotherapy or magnetic resonance imaging, said group being 【Chemical 22】 2. The compound of claim 1 , selected from:

20. B' is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging. 【Chemistry 23】 The compound according to any one of claims 1 to 6 and 8, comprising:

21. 9. The compound of any one of claims 1 to 6 and 8, wherein B' is a radioimaging, radiotherapeutic or magnetic resonance isotope or a chelating group and a radical of a radioimaging, radiotherapeutic or magnetic resonance isotope bound to said chelating group.

22. The compound of claim 3 , wherein Ring B is aromatic.

23. n=2, n′=1, and A is a group represented by the formula (X-Z): 【Chemistry 24】 The compound of claim 3, represented by:

24. where n=0-4 and A is a structure of formula X-Y: 【Chemistry 25】 The compound of claim 3, represented by:

25. 25. The compound of any one of claims 1 to 6, 8, 19, and 22 to 24, wherein A has a binding affinity for FAPα of about 1 nM to about 25 nM.

26. The compound of any one of claims 1 to 6, 8, 19, and 22 to 24, wherein L comprises a non-releasable linker.

27. The compound of any one of claims 1 to 6, 8, 19, and 22 to 24, wherein L comprises a releasable linker.

28. L is PEG ｎ (n=0-36), a peptide or peptidoglycan, and a compound according to any one of claims 1-6, 8, 19, and 22-24.

29. L, 【Chemistry 26】 The compound according to any one of claims 1 to 6, 8, 19, and 22 to 24, comprising:

30. L, 【Chemical 27】 The compound according to any one of claims 1 to 6, 8, 19, and 22 to 24, comprising:

31. 4. The compound of claim 3, wherein L comprises one or more linker groups, each linker group independently selected from the group consisting of alkyl(alkylene), heteroalkyl(alkylene), heterocycloalkyl(alkylene), heteroaryl, aryl, alkoxy, thioether, disulfide, carboxylic acid, anhydride, carbonate, carbamate, thioether, sugar, peptide, and peptidoglycan.

32. L is (L １ ) ｐ -W-(L ２ ) ｑ And L １ is the first linker, L ２ 32. The compound of claim 31 , wherein: R is a second linker, W is a third linker, p=1-5 and q=1-5.

33. Each L １ and each L ２ independently comprise one or more linker groups, each linker group being independently selected from the group consisting of alkyl(alkylene), heteroalkyl(alkylene), heterocycloalkyl(alkylene), heteroaryl, aryl, alkoxy, thioether, disulfide, carboxylic acid, anhydride, carbonate, carbamate, thioether, sugar, peptide, and peptidoglycan.

34. Each L １ and each L ２ 33. The compound of claim 32, wherein: independently comprises one or more linker groups, each linker group being independently selected from the group consisting of PEG, alkyl(ene), amide, phenyl, and triazole.

35. 35. The compound of claim 32, 33 or 34, wherein W has an amine core, an aromatic core or an alkylene core.

36. L, L １ , L ２ Or L １ and L ２ The compound of claim 32, wherein has a length of 5 angstroms to 200 angstroms.

37. L, L １ , L ２ Or L １ and L ２ But the structure: 【Chemistry 28】 and at least one linker group having the formula:

33. The compound of claim 32, wherein n is 0 to 10.

38. L, L １ , L ２ Or L １ and L ２ But the structure: ​ 33. The compound of claim 32, comprising at least one linker group having the formula:

39. L, L １ , L ２ Or L １ and L ２ But the structure: 【Chemistry 30】 and at least one linker group having the formula: The compound according to claim 32, wherein n=1 to 32.

40. C' is a radical of an albumin binding ligand having the following structure: 【Chemistry 31】 9. The compound of claim 2 or 8, having the formula:

41. C' is a radical of an albumin binding ligand having the following structure: 【Chemistry 32】 9. The compound of claim 2 or 8, having the formula:

42. C' is 【Chemical 33】 9. The compound according to claim 2 or 8, which is a radical of

43. 9. The compound of claim 2 or 8, wherein C' is a radical of an albumin binding small protein scaffold including ABD035, ABDCon, DARPin, dsFv CA645, nanobody and VNAR(E06).

44. C' is PEG ｎ 9. The compound according to claim 2 or 8, which is a peptide, peptidoglycan or a sugar, wherein n is an integer from 0 to 32.

45. C' is 【Chemical 34】 9. The compound according to claim 2 or 8,

46. C' is 【Chemistry 35】 9. The compound according to claim 2 or 8,

47. Structure of formula (V): 【Chemical 36】 (In the formula, L is a linker containing at least one carbon atom; p is 0, 1, 2 or 3.

2. The compound of claim 1 , represented by: 【Request 48】 【Chemical 37】 48. The compound of claim 47, which is not:

49. L, 【Chemical 38】 Including, During the ceremony, m is an integer from 1 to 9; n is an integer from 1 to 32; q is an integer from 0 to 4; 49. The compound of claim 47 or 48, wherein s is an integer from 0 to 4.

50. 【Catalog 39】 (In the formula, t is 0 or 1, and u is an integer from 2 to 12.) 49. The compound of claim 47 or 48, wherein

51. 【Catalogue 40】 (m is an integer from 1 to 4) 48. The compound of claim 47, wherein:

52. 【Chemical 41】 48. The compound of claim 47, wherein:

53. 【Catalogue 42】 48. The compound of claim 47, wherein: 【Request 54】 【Chemical 43】 48. The compound of claim 47, wherein:

55. 【Catalogue 44】 48. The compound of claim 47, wherein:

56. 【Catalogue 45】 48. The compound of claim 47, wherein:

57. A compound of the following structure: 【Chemistry 46】 And, Each compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

58. A compound of the following structure: 【Chemistry 47】 And, Each compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

59. A compound of the following structure: 【Chemistry 48】 And, Each compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

60. A compound of the following structure: 【Chemistry 49】 And, Each compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

61. A compound of the following structure: 【Chemistry 50】 And, Each compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

62. The structure: 【Chemistry 51】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

63. The structure: 【Chemistry 52】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

64. The structure: 【Chemistry 53】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

65. The structure: 【Chemical 54】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

66. The structure: 【Chemistry 55】 2. The compound of claim 1, wherein each is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy, or magnetic resonance imaging.

67. The structure: 【Chemistry 56】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

68. The structure: 【Chemistry 57】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

69. The structure: 【Chemistry 58】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

70. The structure: 【Chemistry 59】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

71. The structure: 【Chemistry 60】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

72. The structure: 【Chemistry 61】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

73. The structure: 【Chemistry 62】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

74. The structure: 【Chemistry 63】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

75. The structure: 【Chemistry 64】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

76. The structure: 【Chemistry 65】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

77. The structure: 【Chemistry 66】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

78. The structure: 【Chemistry 67】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

79. The structure: 【Chemistry 68】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

80. The structure: 【Chemistry 69】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

81. The structure: 【Chemistry 70】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

82. The structure: 【Chemistry 71】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

83. The structure: 【Chemical 72】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

84. The structure: 【Chemical 73】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

85. The structure: 【Chemical 74】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

86. The structure: 【Chemistry 75】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

87. The structure: 【Chemical Formula 76】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

88. The structure: 【Chemical Formula 77】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

89. The structure: 【Chemical 78】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

90. The structure: 【Chemical Formula 79】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

91. The structure: 【Chemistry 80】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

92. The structure: 【Chemistry 81】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

93. The structure: 【Chemistry 82】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

94. The structure: 【Chemistry 83】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

95. The structure: 【Chemistry 84】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

96. The structure: 【Chemistry 85】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

97. The structure: 【Chemistry 86】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

98. The structure: 【Chemistry 87】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

99. The structure: 【Chemistry 88】 2. The compound of claim 1, wherein the compound is optionally bound to an isotope (or metal) suitable for radioimaging, radiotherapy or magnetic resonance imaging.

100. The structure: 【Chemistry 89】 and optionally bound to a metal suitable for radioimaging, radiotherapy or magnetic resonance imaging.

101. structure: 【Chemistry 90】 4. The compound of claim 1 or 3, having the formula:

102. structure: 【Chemistry 91】 4. The compound of claim 1 or 3, having the formula:

103. structure: 【Chemistry 92】 4. The compound of claim 1 or 3, having the formula:

104. structure: 【Chemistry 93】 4. The compound of claim 1 or 3, having the formula:

105. A pharmaceutical composition comprising a compound according to any one of claims 1 to 104 and a pharma- ceutically acceptable carrier.

106. A compound described in any one of claims 1 to 104 or a pharmaceutical composition described in claim 105 for use in imaging cancer or fibrosis in a subject.

107. The compound or pharmaceutical composition described in claim 106, wherein the imaging includes generating an image of the cancer or the fibrosis in the subject.

108. 107. The compound or pharmaceutical composition of claim 106, wherein the fibrosis is selected from pulmonary fibrosis, renal fibrosis and hepatic fibrosis.

109. A compound according to any one of claims 1 to 104 or a pharmaceutical composition according to claim 105 for use in treating fibrosis in a subject.

110. 110. The compound or pharmaceutical composition of claim 109, wherein the fibrosis is selected from pulmonary fibrosis, renal fibrosis and hepatic fibrosis.

111. A compound according to any one of claims 1 to 104 or a pharmaceutical composition according to claim 105 for use in treating an inflammatory disease or disorder in a subject in need thereof.

112. A compound according to any one of claims 1 to 104 or a pharmaceutical composition according to claim 105 for use in treating cancer in a subject in need thereof.

113. 113. The compound or pharmaceutical composition of claim 112, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, colon cancer, cervical cancer and brain cancer (e.g., glioblastoma).

114. 114. The compound or pharmaceutical composition of claim 112 or 113 for further use in combination with administering chemotherapy or radiation therapy to said subject.

115. A method for improving the affinity of a ligand for FAP, wherein such ligand comprises an isoindoline scaffold, The method includes the step of introducing a triazole moiety into the isoindoline scaffold of the ligand through molecular modeling to achieve a higher Schrodinger molecular docking score, thereby improving the affinity of the ligand for FAP.

116. A ligand of FAP, comprising an isoindoline scaffold having a triazole moiety incorporated therein, and having a Schrodinger molecular docking score of at least about -8.0 kcal / mol.

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