FAP-targeted covalent radiotheranostics

Abstract

Disclosed are compounds that are covalent inhibitors of fibroblast activation protein (FAP). Also disclosed are methods of treating cancer using the compounds.

Description

[0001] TUV-19125

[0002] FAP-TARGETED COVALENT RADIODIAGNOSTICS RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U. S. Provisional Application No.: 63 / 725,710, filed November 27, 2024; the contents of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND

[0005] Fibroblast Activation Protein (FAP) is a type II transmembrane serine protease from the dipeptidyl peptidase 4 family, known for its dual enzymatic roles in tissue remodeling and disease progression. While FAP is typically absent in healthy adult tissues, its expression significantly increases in the stroma of over 90% of epithelial carcinomas, particularly within cancer-associated fibroblasts (CAFs) in the tumor microenvironment. This pattern of expression, linked to poor patient outcomes, underscores the therapeutic potential of FAP, with Fibroblast Activation Protein Inhibitors (FAPi) emerging as a crucial development in oncological therapies.

[0006] The tumor microenvironment, especially the stromal component which can constitute more than 90% of the tumor mass, provides a foundational role for cancer proliferation and metastasis. CAFs enhance tumor growth, cellular migration, and disease progression through their interactions with cancer cells and the extracellular matrix. The use of FAP targeting in diagnostic imaging and endoradiotherapeutic strategies aims to disrupt this supportive environment and inhibit tumor growth.

[0007] Advancements have led to the development of FAP inhibitors designed for high specificity. These agents facilitate the precise delivery of diagnostic and therapeutic radionuclides directly to the tumor site, improving imaging accuracy and the effectiveness of radioligand therapies (RLTs) while aiming to minimize the impact on healthy tissues. Despite the potential of FAP inhibitor based RLTs, challenges remain. Ongoing research efforts are focused on addressing these challenges, including the development of albumin binder-conjugated FAP inhibitors and multivalent FAP inhibitor derivatives to improve systemic circulation and tumor uptake. Exploring radionuclides with shorter half-lives is being considered to optimize therapeutic efficacy while reducing toxicity.

[0008] Recent advances in FAP-targeted radiopharmaceuticals have demonstrated significant clinical progress, particularly with the introduction of 18F-labeled FAP inhibitors that can

[0009] -1- Foley HoagUS 13184486.1 TUV-19125

[0010] potentially offer superior imaging capabilities compared to traditional tracers in various cancers. However, transitioning from diagnostic applications to effective RLTs requires further refinement in FAP inhibitor design. This involves addressing resistance mechanisms, optimizing inhibitors to support an integrated immune response without eliciting adverse reactions, and improving the pharmacokinetic profile for sustained tumor targeting and minimized exposure of healthy tissues.

[0011] The prevalent role of FAP in cancer-associated fibroblasts across many epithelial tumors, along with its association with poor prognoses, emphasizes the importance of targeting FAP. Such targeting not only enhances the specificity and efficacy of therapies, reducing the impact on healthy cells but also supports the accurate diagnosis of malignancies. Accordingly, there remains a vital need for therapeutic agents that can effectively disrupt FAP's role in tumor support and progression.

[0012] SUMMARY OF THE INVENTION

[0013] In certain aspects, the present disclosure provides compound of the formula:

[0014]

[0015] ^2b

[0016] wherein:

[0017] O W9

[0018] each W is independently

[0019]

[0020] O

[0021] O Wo O

[0022]

[0023] Wi is halogen or cyano;

[0024] each W2 is independently selected from the group consisting of -H, -C1-3 alkyl, aryl, and aralkyl;

[0025] W4 is selected from the group consisting of -H, -C1-3 alkyl, aryl, and aralkyl;

[0026] W3 is selected from the group consisting of cycloalkyl, aryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with one or more substituents independently

[0027] -2- Foley HoagUS 13184486.1 TUV-19125

[0028] selected from the group consisting of -Ci-6 alkyl, -Cnehaloalkyl, -Ci-6 alkoxy, halogen, nitro, cyano, hydroxyl, amino, sulfoxyl, sulfonyl, sulfonamide, acyl, - C(O)2Ri3, -C(O)NRi3Ri4, and

[0029] -N(RI3)C(O)ORI3;

[0030] or W3 is C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, amino, formyl, cycloalkyl, aryl, aralkyl, heterocyclyl, -C(O)2Ri3, -C(O)NRi3Ri4, and -N(Ri3)C(O)ORi3;

[0031] X is a chelator suitable for radiolabeling, or a chelator bound to a radioactive atom or complex;

[0032] Li is a bond, or a group of the formula:

[0033]

[0034] wherein each n is independently 0, 1, 2, 3, 4, or 5;

[0035] q is 0, 1, or 2;

[0036] each Z is independently =0 or =NR2C;

[0037] A is -H or -COOH;

[0038]

[0039] -3- Foley HoagUS 13184486.1 TUV-19125

[0040]

[0041] wherein

[0042] each R is independently -H, Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;

[0043] each Ri is independently -H or -C1-3 alkyl;

[0044] R2a, R2b, and R2c at each occurrence are each independently -H or -C1-3 alkyl;

[0045] R3a and Rsb at each occurrence are each independently -H, -OH, or halogen; and L2 is a group of the formula:

[0046]

[0047] wherein R4e and R4f are each independently -H or -C1-3 alkyl;

[0048] R a and Rsb are each independently -H or -C1-3 alkyl;

[0049] Reaand Reb are each independently -H or -C1-3 alkyl; and

[0050] R?ais -H or -C1-3 alkyl;

[0051] each Y is independently selected from the group consisting of:

[0052]

[0053] wherein each Rs is independently -H, -OH, halogen, -ORsa, -NRsbRsc, -COOH, or a 5- to 6-membered heteroaryl;

[0054] each R9 is independently -H, -OH, halogen, -ORga, -NRooRoc, or -COOH;

[0055] each Rio is independently -H, -OH, halogen, -ORioa, -NRiobRiOc, or -COOH; and each Rn is independently -H, -OH, halogen, -ORna, -NRiibRiic, or -COOH;

[0056] -4- Foley HoagUS 13184486.1 TUV-19125

[0057] wherein Rsa, Rsb, and Rscat each occurrence are each independently -H or -C1-3 alkyl; R a, R b, and Rgcat each occurrence are each independently -H or -C1-3 alkyl;

[0058] Rioa, Riob, and Rioc at each occurrence are each independently -H or -C1-3 alkyl;

[0059] Riia, Riib, and Riic at each occurrence are each independently -H or -C1-3 alkyl; each R12 is independently -H, -OH, halogen, -ORga, -NRgnRgc. or -COOH;

[0060] ni is 1, 2, 3, or 4;

[0061] ii2 is 1, 2, 3, or 4;

[0062] ns is 1, 2, 3, 4, or 5;

[0063] niis 1, 2, 3, 4, 5, 6, 7, or 8;

[0064] ns is 1, 2, 3, or 4; and

[0065] ne is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0066] each R13 is independently -H, -C1-3 alkyl, aryl, aralkyl, or heterocyclyl; and

[0067] each R14 is independently -H or -C1-6 alkyl; or R13 and R14, along with the nitrogen atom to which R13 and R14 are attached, combine to form a heterocyclyl;

[0068] a pharmaceutically acceptable salt thereof.

[0069] In further aspects, the present disclosure provides compositions comprising the compounds disclosed herein.

[0070] In yet further aspects, the present disclosure provides methods of treating cancer using the compounds disclosed herein.

[0071] DETAILED DESCRIPTION OF THE INVENTION

[0072] In certain aspects, the present disclosure provides compounds of the formula:

[0073] R1 O,, O w

[0074] NH

[0075]

[0076] ^2b

[0077] wherein:

[0078] -5- Foley HoagUS 13184486.1 TUV-19125

[0079] O W2O W2o

[0080] each W is independently

[0081]

[0082] , 0,0W4,

[0083] 0 W20 0 W20

[0084]

[0085] O, or0W4O.

[0086] Wi is halogen or cyano;

[0087] each W2 is independently selected from the group consisting of -H, -C1-3 alkyl, aryl, and aralkyl;

[0088] W4 is selected from the group consisting of -H, -C1-3 alkyl, aryl, and aralkyl;

[0089] W3 is selected from the group consisting of cycloalkyl, aryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of -C1-6 alkyl, -Cnehaloalkyl, -C1-6 alkoxy, halogen, nitro, cyano, hydroxyl, amino, sulfoxyl, sulfonyl, sulfonamide, acyl, - C(O)2Ri3, -C(O)NRI3R14, and

[0090] -N(Ri3)C(O)ORi3;

[0091] or W3 is C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, amino, formyl, cycloalkyl, aryl, aralkyl, heterocyclyl, -C(O)2Ri3, -C(O)NRi3Ri4, and -N(Ri3)C(O)ORi3;

[0092] X is a chelator suitable for radiolabeling, or a chelator bound to a radioactive atom or complex;

[0093] Li is a bond, or a group of the formula:

[0094]

[0095] wherein each n is independently 0, 1, 2, 3, 4, or 5;

[0096] q is 0, 1, or 2;

[0097] each Z is independently =0 or =NR2C;

[0098] A is -H or -COOH;

[0099]

[0100] -6- Foley HoagUS 13184486.1 TUV-19125

[0101]

[0102] wherein

[0103] each R is independently -H, Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;

[0104] each Ri is independently -H or -C1-3 alkyl;

[0105] R2a, R2b, and R2c at each occurrence are each independently -H or -C1-3 alkyl; R3a and Rsb at each occurrence are each independently -H, -OH, or halogen; and L2 is a group of the formula:

[0106]

[0107] wherein R4e and R4f are each independently -H or -C1-3 alkyl;

[0108] R a and Rsb are each independently -H or -C1-3 alkyl;

[0109] Reaand Reb are each independently -H or -C1-3 alkyl; and

[0110] -7- Foley HoagUS 13184486.1 TUV-19125

[0111] R?ais -H or -Ci-3 alkyl;

[0112] each Y is independently selected from the group consisting of:

[0113] (Rg)n2

[0114]

[0115] wherein each Rs is independently -H, -OH, halogen, -ORsa, -NRsbRsc, -COOH, or a 5- to 6-membered heteroaryl;

[0116] each R9 is independently -H, -OH, halogen, -ORga, -NRgbR c, or -COOH;

[0117] each Rio is independently -H, -OH, halogen, -ORioa, -NRiobRiOc, or -COOH; and each Rn is independently -H, -OH, halogen, -ORna, -NRiibRiic, or -COOH; wherein Rsa, Rsb, and Rscat each occurrence are each independently -H or -C1-3 alkyl; R a, R9b, and Rgcat each occurrence are each independently -H or -C1-3 alkyl;

[0118] Rioa, Riob, and Rioc at each occurrence are each independently -H or -C1-3 alkyl;

[0119] Riia, Riib, and Riic at each occurrence are each independently -H or -C1-3 alkyl; each R12 is independently -H, -OH, halogen, -ORga, -NRgnFCc. or -COOH;

[0120] m is 1, 2, 3, or 4;

[0121] rn is 1, 2, 3, or 4;

[0122] is 1, 2, 3, 4, or 5;

[0123] is 1, 2, 3, 4, 5, 6, 7, or 8;

[0124] ns is 1, 2, 3, or 4; and

[0125] ne is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0126] each R13 is independently -H, -C1-3 alkyl, aryl, aralkyl, or heterocyclyl; and

[0127] each R14 is independently -H or -C1-6 alkyl; or R13 and R14, along with the nitrogen atom to which R13 and R14 are attached, combine to form a heterocyclyl;

[0128] a pharmaceutically acceptable salt thereof.

[0129] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0130] Ri o

[0131] L1 T

[0132] N Z

[0133]

[0134] -8- Foley HoagUS 13184486.1 TUV-19125

[0135] or a pharmaceutically acceptable salt thereof.

[0136] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0137]

[0138] ^2b

[0139] or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0141]

[0142] or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0144]

[0145] ^2b

[0146] or a pharmaceutically acceptable salt thereof.

[0147] -9- Foley HoagUS 13184486.1 TUV-19125

[0148] o

[0149] In certain embodiments, W is

[0150]

[0151] . In certain embodiments, Wi is chloro. In O W2o w2o

[0152]

[0153] certain embodiments, W is O. In certain embodiments, W is ®w4 O W2O

[0154] o

[0155]

[0156] r O

[0157] In certain embodiments, W2 is -H.

[0158] In certain embodiments, W4 is -H.

[0159] In certain embodiments, W3 is aralkyl. In certain embodiments, W3 is heteroaralkyl.

[0160] In certain embodiments, W3 is optionally substituted with one or more substituents selected from the group consisting of -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 alkoxy, halo, nitro, cyano, hydroxyl, amino, sulfoxyl, sulfonyl, sulfonamide, acyl, -C(O)2R13, -C(O)NRi3Rt4, and -N(0)0Ri3; further wherein each R13 is independently -H, -C1-3 alkyl, aryl, aralkyl or heterocyclyl; and each R14 is independently -H or alkyl. In certain embodiments, W3 is substituted with trifluoromethyl. In certain embodiments, W3 is substituted with -C1-6 alkyl, -C1-6 haloalkyl, -C1-6 alkoxy, halogen, nitro, cyano, hydroxyl, amino, sulfoxyl, sulfonyl, sulfonamide, acyl, -C(O)2Ri3, -C(O)NRi3Rt4, and -N(Ri3)C(O)ORi3; further wherein, each R13 is independently -H, -Cnsalkyl, aryl, aralkyl, or heterocyclyl; and each R14 is

[0161] independently -H or - Ci-6 alkyl. In certain embodiments, W3 is

[0162]

[0163]

[0164] . In certain

[0165] embodiments, W3 is

[0166]

[0167] . In certain embodiments, W3 is -C1-6 alkyl or

[0168] -10- Foley HoagUS 13184486.1 TUV-19125

[0169] cycloalkyl. In certain embodiments, W3 is

[0170]

[0171]

[0172] In certain embodiments, W3 is -C1-6 alkyl substituted with halogen, hydroxyl, amino, formyl, cycloalkyl, aryl, aralkyl, heterocyclyl, -C(O)2Ri3, -C(O)NRi3Ri4, or -N(Ri3)C(O)ORi3; further wherein, each R13 is independently -H, -C1-3 alkyl, aryl, aralkyl, or heterocyclyl; and R14 is independently -H or C1-6 alkyl. In certain embodiments, W3 is substituted with -C(O)NRi3Ri4; further wherein R13 and R14, along with the nitrogen atom to which R13 and R14 are attached, combine to form a

[0173]

[0174] In certain embodiments, W is

[0175]

[0176] . In certain embodiments, ne is 1, 2, or 3. In certain embodiments, Ruis -H or -C1-6 alkyl.

[0177] -11- Foley HoagUS 13184486.1 TUV-19125

[0178] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0179]

[0180] or a pharmaceutically acceptable salt thereof;

[0181] wherein each R is independently -H, -Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;

[0182] each W2 is independently H or (Ci-Ce)alkyl; and

[0183] Y 1 is aryl or heteroaryl.

[0184] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0185] W2N

[0186]

[0187] ^2b

[0188] or a pharmaceutically acceptable salt thereof.

[0189] wherein each R is independently -H, -Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;

[0190] each W2 is independently -H or -Ci-Cealkyl; and

[0191] Y 1 is aryl or heteroaryl.

[0192] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0193] -12- Foley HoagUS 13184486.1 TUV-19125

[0194]

[0195] or a pharmaceutically acceptable salt thereof.

[0196] wherein each R is independently -H, Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;

[0197] each W2 is independently -H or Ci-Cealkyl.

[0198] In certain embodiments, the compounds disclosed herein have a structure represented by the formula:

[0199]

[0200] or a pharmaceutically acceptable salt thereof.

[0201] wherein each R is independently -H, Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;

[0202] each W2 is independently -H or Ci-Cealkyl.

[0203] In certain preferred embodiments, each R is -CH3.

[0204] In certain embodiments, Li is selected from the group consisting of: a bond, and a group of the formula:

[0205]

[0206] -13- Foley HoagUS 13184486.1 TUV-19125

[0207] wherein A is -H or -COOH.

[0208] In certain embodiments, Li is selected from the group consisting of: a bond, and a group of the formula:

[0209]

[0210] In certain embodiments, R?; Iis -OH. In certain embodiments, R?; Iis -F. In certain embodiments, Rja is -H.

[0211] In certain embodiments, Rab is -OH. In certain embodiments, Rsb is -F. In certain embodiments, Rab is -H.

[0212] In certain embodiments, E is selected from the group consisting of:

[0213]

[0214] -14- Foley HoagUS 13184486.1 TUV-19125

[0215] , and

[0216]

[0217] In certain embodiments, L2is selected from the group consisting of:

[0218]

[0219] or

[0220] -N(CH3)2; and Rio is -H, -Cl, -OH, or -N(CH3)2.

[0221] In certain embodiments, Y is selected from the group consisting of:

[0222]

[0223]

[0224] , and

[0225] -15- Foley HoagUS 13184486.1 TUV-19125

[0226] In certain embodiments, X is a chelator suitable for radiolabeling selected from the group consisting of:

[0227]

[0228] m is 0, 1, or 2;

[0229] R4ais independently -H, -COOH, or -CONH2;

[0230] R4bis independently -H, -COOH, or -CONH2; and

[0231] R4Cis independently -H, -COOH, or -CONH2.

[0232] In certain embodiments, X is a chelator suitable for radiolabeling selected from the group consisting of:

[0233]

[0234] -16- Foley HoagUS 13184486.1 TUV-19125

[0235] o

[0236]

[0237] In certain embodiments, X is a chelator suitable for radiolabeling of the formula: O,

[0238] HO

[0239] / 0

[0240] , N^ OH

[0241] o^ OH O

[0242] In certain embodiments, X is a chelator suitable for radiolabeling of the formula:

[0243]

[0244] In certain embodiments, X is a chelator suitable for radiolabeling of the formula: o,

[0245] HO

[0246] o

[0247] OH

[0248]

[0249] o

[0250] In certain embodiments, X is a chelator bound to a radioactive atom selected from the group consisting of:

[0251] -17- Foley HoagUS 13184486.1 TUV-19125

[0252]

[0253] wherein M is the radioactive atom,

[0254] m is 0, 1, or 2;

[0255] R4ais independently -H, -COOH, or -CONH2;

[0256] R4bis independently -H, -COOH, or -CONH2;

[0257] R4cis independently -H, -COOH, or -CONH2; and

[0258] R4dis independently -H, -COOH, or -CONH2.

[0259] In certain embodiments, X is a chelator bound to a radioactive atom and the radioactive atom is selected from the group consisting of:223Ra,94mTc,99mTc,186Re,188Re,203Pb,212Pb,67Ga,68Ga,47Sc,111In,97Ru,62Cu,64Cu,86Y,88Y,89Zr,90Y,121Sn,161Tb,153Sm,166Ho,105Rh,177LU,123I,124I,125I,131I,18F,211At,225Ac,89Sr,117mSn,169Er, and [18F]A1F. In certain embodiments, X is a chelator bound to a radioactive atom and the radioactive atom is selected from the group consisting of:225Ac,211At,64Cu,67Cu,18F, [18F]A1F,67Ga,68Ga,111In,177Lu,203Pb,212Pb,161Tb,86Y,90Y, and89Zr. In certain embodiments, the radioactive atom is177Lu. In certain embodiments, the radioactive atom is212Pb. In certain embodiments, the radioactive atom is [18F]A1F. In certain embodiments, the radioactive atom is225Ac. In certain embodiments, the radioactive atom is161Tb.

[0260] In certain embodiments, X is a chelator bound to a radioactive atom selected from the group consisting of:

[0261]

[0262] -18- Foley HoagUS 13184486.1 TUV-19125

[0263] In certain embodiments, X is a chelator bound to a radioactive atom selected from the group consisting of:

[0264]

[0265] In certain embodiments, X is a chelator bound to a radioactive atom selected from the group consisting of:

[0266]

[0267] In certain embodiments, the compound is selected from the group consisting of:

[0268] -19- Foley HoagUS 13184486.1 TUV-19125

[0269]

[0270] -20- Foley HoagUS 13184486.1 TUV-19125

[0271]

[0272] , and

[0273] -21- Foley HoagUS 13184486.1 TUV-19125

[0274]

[0275] ; or a pharmaceutically acceptable salt thereof.

[0276] In certain embodiments, X is a chelator bound to a radioactive atom and the radioactive atom is selected from the group consisting of:225Ac,211At,64Cu,67Cu,18F, [18F]A1F,67Ga,68Ga,111In,177LU,203Pb,212Pb,161Tb,86Y,90Y, and89Zr. In certain embodiments, the radioactive atom is212Pb. In certain embodiments, the radioactive atom is177Lu. In certain embodiments, the radioactive atom is [18F]A1F. In certain embodiments, the radioactive atom is225Ac.

[0277] In another aspect, the present disclosure provides compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, diluent or excipient.

[0278] In yet another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, cancer is characterized by the expression of Fibroblast Activation Protein (FAP) on a tumor, fibroblast, or pericyte within the subject.

[0279] In yet another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer, bone cancer, adenocarcinoma, non-melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic

[0280] -22- Foley HoagUS 13184486.1 TUV-19125

[0281] lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

[0282] In yet another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

[0283] In yet another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma, cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, or fallopian tube carcinoma.

[0284] In yet another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

[0285] In yet another aspect, the present disclosure provides method for diagnosing cancer in a subject, comprising:

[0286] administering to the subject a diagnostically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, that binds to Fibroblast Activation Protein, wherein the Fibroblast Activation Protein is expressed on a tumor, fibroblast, or pericyte associated with the cancer;

[0287] detecting the binding of the compound to the Fibroblast Activation Protein; and correlating the presence of bound compound to the expression of Fibroblast Activation Protein, thereby diagnosing the cancer in the subject.

[0288] In certain embodiments, the subject is also administered in simultaneous, separate, or sequential combination an effective amount of one or more of a PD-1 inhibitor, a PD-L1

[0289] -23- Foley HoagUS 13184486.1 TUV-19125

[0290] inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salts thereof.

[0291] In yet another aspect, the present disclosure provides method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition disclosed herein. In certain embodiments, the cancer is characterized by the expression of Fibroblast Activation Protein (FAP) on a tumor, fibroblast, or pericyte within the subject.

[0292] In another aspect, the present disclosure provides methods of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition disclosed herein, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer, bone cancer, adenocarcinoma, non-melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

[0293] In yet another aspect, the present disclosure provides methods of treating a subject for cancer, comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition disclosed herein, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

[0294] In yet another aspect, the present disclosure provides methods of treating a subject for cancer, comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition disclosed herein, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer,

[0295] -24- Foley HoagUS 13184486.1 TUV-19125

[0296] small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma, cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

[0297] In yet another aspect, the present disclosure provides methods of treating a subject for cancer, comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition disclosed herein, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

[0298] In yet another aspect, the present disclosure provides method for diagnosing cancer in a subject, comprising:

[0299] administering to the subject a diagnostically effective amount of a pharmaceutical composition according disclosed herein that selectively binds to Fibroblast Activation Protein, wherein the Fibroblast Activation Protein is expressed on a tumor, fibroblast, or pericyte associated with the cancer;

[0300] detecting the binding of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to the Fibroblast Activation Protein; and

[0301] correlating the presence of bound compound or salt to the expression of Fibroblast Activation Protein, thereby diagnosing the cancer in the subject.

[0302] In certain embodiments, the subject is also administered in simultaneous, separate, or sequential combination with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salts thereof.

[0303] In yet another aspect, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, disclosed herein, for use in therapy.

[0304] In yet another aspect, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, disclosed herein, for use in the treatment of cancer. In certain embodiments, the cancer is selected from the group consisting of is breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer,

[0305] -25- Foley HoagUS 13184486.1 TUV-19125

[0306] bone cancer, adenocarcinoma, non-melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, nonHodgkin’s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma. In certain embodiments, the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. In certain embodiments, the cancer is selected from the group consisting of selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma, cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, or fallopian tube carcinoma. In certain embodiments, the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

[0307] In yet another aspect, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, disclosed herein for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof in the treatment of cancer.

[0308] In yet another aspect, the present disclosure provides a pharmaceutical composition disclosed herein for use in therapy.

[0309] In yet another aspect, the present disclosure provides a pharmaceutical composition disclosed herein for use in the treatment of cancer. In certain embodiments, the cancer is selected from the group consisting of is breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer, bone cancer, adenocarcinoma, non- -26- FoleyHoagUS 13184486.1 TUV-19125

[0310] melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma. In certain embodiments, the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer. In certain embodiments, the cancer is selected from the group consisting of selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma, cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma. In certain embodiments, the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

[0311] In yet another aspect, the present disclosure provides a pharmaceutical composition disclosed herein for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof in the treatment of cancer.

[0312] Pharmaceutical Compositions

[0313] The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In

[0314] -27- Foley HoagUS 13184486.1 TUV-19125

[0315] preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0316] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0317] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0318] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and -28- Foley HoagUS 13184486.1 TUV-19125

[0319] potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0320] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U. S. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

[0321] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0322] Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with

[0323] -29- Foley HoagUS 13184486.1 TUV-19125

[0324] liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0325] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0326] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0327] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0328] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0329] -30- Foley HoagUS 13184486.1 TUV-19125

[0330] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

[0331] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0332] Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

[0333] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0334] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0335] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0336] In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective

[0337] -31- Foley HoagUS 13184486.1 TUV-19125

[0338] to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0339] If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

[0340] The patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.

[0341] In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.

[0342] The present disclosure includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, IH-imidazole, lithium, L-lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2-hydroxyethyljpyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4- acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, 1-ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, d-glucoheptonic acid, d-gluconic acid, d-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, 1-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene- 1,5 -disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic -32- Foley HoagUS 13184486.1 TUV-19125

[0343] acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, 1-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, 1-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylenic acid acid salts.

[0344] The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

[0345] Definitions

[0346] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings that are commonly understood by those of ordinary skill in the art. Generally, nomenclature used in connection with, and techniques of, chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics and protein and nucleic acid chemistry, described herein, are those well known and commonly used in the art.

[0347] The methods and techniques of the present disclosure are generally performed, unless otherwise indicated, according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, e.g. “Principles of Neural Science”, McGraw-Hill Medical, New York, N. Y. (2000); Motulsky, “Intuitive Biostatistics”, Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.”, W. H. Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.”, W. H. Freeman & Co., N. Y. (1999); and Gilbert et al., “Developmental Biology, 6th ed.”, Sinauer Associates, Inc., Sunderland, MA (2000).

[0348] Chemistry terms used herein, unless otherwise defined herein, are used according to conventional usage in the art, as exemplified by “The McGraw-Hill Dictionary of Chemical Terms”, Parker S., Ed., McGraw-Hill, San Francisco, C. A. (1985).

[0349] All of the above, and any other publications, patents and published patent applications referred to in this application are specifically incorporated by reference herein. In case of conflict, the present specification, including its specific definitions, will control.

[0350] The term “agent” is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a

[0351] -33- Foley HoagUS 13184486.1 TUV-19125

[0352] carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues. Agents include, for example, agents whose structure is known, and those whose structure is not known.

[0353] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).

[0354] “Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0355] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount.

[0356] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0357] -34- Foley HoagUS 13184486.1 TUV-19125

[0358] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0359] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0360] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0361] As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.

[0362] It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a

[0363] -35- Foley HoagUS 13184486.1 TUV-19125

[0364] substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.

[0365] As used herein, the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with the radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O-alkyl, -OP(O)(O-alkyl)2 or -CH2-OP(O)(O-alkyl)2. Preferably, “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.

[0366] As used herein, the term “alkyl” refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or C1-C10 branched-chain alkyl groups. Preferably, the “alkyl” group refers to C1-C6 straight-chain alkyl groups or C1-C6 branched-chain alkyl groups. Most preferably, the “alkyl” group refers to C1-C4 straight-chain alkyl groups or C1-C4 branched-chain alkyl groups. Examples of “alkyl” include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1 -heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alkyl” group may be optionally substituted. Moreover, the term “alkyl” as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.

[0367] The term “acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

[0368] The term “acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(O)NH-.

[0369] The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0370] The term “alkoxy” refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

[0371] The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

[0372] The term “Cx.y” or “Cx-Cy”, when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x -36- Foley HoagUS 13184486.1 TUV-19125

[0373] to y carbons in the chain. Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. A Cnealkyl group, for example, contains from one to six carbon atoms in the chain.

[0374] The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

[0375] The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

[0376] The term “amido”, as used herein, refers to a group

[0377] O

[0378]

[0379] R10

[0380] wherein R9and R10each independently represent a hydrogen or hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0381] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

[0382] R9R9

[0383] N or N-Ri°

[0384]

[0385] R10R10'

[0386] wherein R9, R10, and R10’ each independently represent a hydrogen or a hydrocarbyl group, or R9and R10taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

[0387] The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

[0388] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

[0389] The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7-membered ring, more preferably a 6-membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

[0390] The term “carbamate” is art-recognized and refers to a group

[0391] -37- FoleyHoagUS 13184486.1 TUV-19125

[0392] o o

[0393] A IL R10y IL RI°

[0394]

[0395] R9R9

[0396] wherein R9and R10independently represent hydrogen or a hydrocarbyl group.

[0397] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0398] The term “carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH-indene and bicyclo[4.1.0]hept-3-ene. “Carbocycles” may be substituted at any one or more positions capable of bearing a hydrogen atom.

[0399] The term “carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

[0400] The term “carbonate” is art-recognized and refers to a group -OCO2-.

[0401] The term “carboxy”, as used herein, refers to a group represented by the formula -CO2H.

[0402] The term “cycloalkyl” includes substituted or unsubstituted non-aromatic single ring structures, preferably 4- to 8-membered rings, more preferably 4- to 6-membered rings. The term “cycloalkyl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is cycloalkyl and the substituent (e.g., R100) is attached to the cycloalkyl ring, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole,

[0403] -38- Foley HoagUS 13184486.1 TUV-19125

[0404] oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, denzodioxane, tetrahydroquinoline, and the like.

[0405] The term “ester”, as used herein, refers to a group -C(O)OR9wherein R9represents a hydrocarbyl group.

[0406] The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

[0407] The terms “halo” and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

[0408] The terms “hetaralkyl” and “hetero aralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

[0409] The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0410] The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

[0411] The terms “heterocyclyl”, “heterocycle”, and “heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls,

[0412] -39- Foley HoagUS 13184486.1 TUV-19125

[0413] cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

[0414] The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or =S substituent, and typically has at least one carbonhydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.

[0415] The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0416] The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

[0417] The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

[0418] The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

[0419] The term “sulfonamide” is art-recognized and refers to the group represented by the general formulae

[0420] O R10OR10

[0421] S-N or s / ^o

[0422] o R9<-NR9

[0423]

[0424] wherein R9and R10independently represents hydrogen or hydrocarbyl.

[0425] -40- Foley HoagUS 13184486.1 TUV-19125

[0426] The term “sulfoxide” is art-recognized and refers to the group-S(O)-.

[0427] The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

[0428] The term “sulfone” is art-recognized and refers to the group -S(O)2-.

[0429] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

[0430] The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

[0431] The term “thioester”, as used herein, refers to a group -C(O)SR9or -SC(O)R9wherein R9represents a hydrocarbyl.

[0432] The term “thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

[0433] The term “urea” is art-recognized and may be represented by the general formula O

[0434]

[0435] R9R9

[0436] -41- Foley HoagUS 13184486.1 TUV-19125

[0437] wherein R9and R10independently represent hydrogen or a hydrocarbyl.

[0438] The term “modulate” as used herein includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.

[0439] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers and other materials and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0440] “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.

[0441] The term “pharmaceutically acceptable acid addition salt” as used herein means any non-toxic organic or inorganic salt of any base compounds disclosed herein. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids. Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection of the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts, e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0442] The term “pharmaceutically acceptable basic addition salt” as used herein means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.

[0443] Many of the compounds useful in the methods and compositions of this disclosure have at least one stereogenic center in their structure. This stereogenic center may be present in a R -42- Foley HoagUS 13184486.1 TUV-19125

[0444] or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 11-30. The disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01 / 062726.

[0445] Furthermore, certain compounds which contain alkenyl groups may exist as Z (zusammen) or E (entgegen) isomers. In each instance, the disclosure includes both mixture and separate individual isomers.

[0446] The term “Log of solubility”, “LogS” or “logS” as used herein is used in the art to quantify the aqueous solubility of a compound. The aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption. LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol / liter.

[0447] EXAMPLES

[0448] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

[0449] Example 1: Synthesis of Exemplary Compounds of the Disclosure

[0450] Synthesis of 7824-KA

[0451]

[0452] -43- Foley HoagUS 13184486.1 TUV-19125

[0453] Synthetic Scheme: i. a): DCM, rt; b). DCM, TFA, rt; c) DCM, Et3N, 0°C to rt., 80% yield; ii. H2, Pd(OH)2 / C, MeOH, rt., 92% yield; iii. 6, HATU, DIEA, DMF, 85% yield; iv. Dess-Martin periodinane, DCM, H2O, rt; v. 20% piperidine in DMF, 45% yield over two steps; vi. DOTA-NHS ester, TEA, DMF; vii. TFA-TIPS (95:5); Preparative HPLC purification: 25% over two steps.

[0454] General procedure for HPLC / MS Analyses: HPLC / MS was performed on a Thermo LTQXL LC / MS system or Agilent 1290 HPLC / 6460 Triple Quad LC / MS system with UV detector (monitoring at 215 nm or 254 nm), using an Agilent 300SB-C8 RP-HPLC column (4.6 x 100 mm, 3.5 μm) with solvent A (water containing 0.1% TFA) and solvent B (ACN) with a flow rate of 0.5 mL / min at rt. Unless otherwise noted, all HPLC retention times are given for an eluent gradient 2% B for the first 3 min, then from 2% to 98% B over 6 min, which was maintained for the next 6 min.

[0455] General procedure for Preparative HPLC purification. Preparative HPLC separations were run on a Varian semi-preparative system with a reversed phase Discovery C18569226-U RP-HPLC column (250 x 21.2 mm; 5pm particle size, 180 Å). Solvent A (water containing 0.1% TFA) and solvent B (ACN) were mixed in linear binary gradients. The gradients are described as: "10 to 40% B in 30 min", which means a linear gradient from 10% B (and correspondingly 90% A) to 40% B (and correspondingly 60% A) was run over 30 min. Flow-rate was 20 mL / min. A typical gradient for the purification of the compounds was started at 5-25% B and ended after 20 min at 35-50% B.

[0456] General procedures for Automated / Semi -automated Solid-Phase Synthesis.

[0457] Automated solid phase synthesis of peptides and polyamides was performed on a PurePep Chorus Peptide Synthesizer on 100 pmol scales. Manual steps were performed in plastic syringes equipped with frits. The amounts of reagents in the protocols described correspond to the 100 pmol scale, unless stated otherwise.

[0458] Synthesis protocols (SP)

[0459] SP-1: 2-CTC-resin loading

[0460] 2-CTC-resin (Chem-Impex, initial loading 1.43 mmol / g) was swollen in DCM (5 mL) for 30 min and washed with DCM (3 mL, 1 min). The resin was treated with a mixture of N-Fmoc-AMB-OH (1.5 eq) in anhydrous DCM with DIPEA (4.5 eq) at rt for 1 h and then drained. The remaining trityl chloride was capped by treating the resin with MeOH (2 mL / g) for 30 min. The resin was thoroughly washed sequentially with DCM (2x), DMF (2x), and MeOH (2x), and stored under vacuum overnight. The loading was determined using the weight difference.

[0461] -44- Foley HoagUS 13184486.1 TUV-19125

[0462] SP-2: Peptide synthesis via HATU coupling on SPPS

[0463] A solution of Fmoc-AA-OH (3.0 eq), HATU (3.0 eq), and DIPEA (6.0 eq) in DMF (10 mL / g resin) was added to the resin-bound free amine compound and reacted for 1 h at rt and then drained. If any coupling reaction was not completed (checked by Kaiser Test), the coupling reaction would be repeated. When complete, the resin was washed with DMF (6x).

[0464] SP-3: On-resin Fmoc-deprotection

[0465] The resin-bound Fmoc-protected compound was treated with 20% piperidine in DMF (v / v, 10 mL / g) for 15 min and then drained. The resin was again treated with 20% piperidine in DMF (v / v, 10 mL / g) for 15 min and then drained. After deprotection, the resin was washed with DMF (6x).

[0466] SP-4: Cleavage Method from Resin:

[0467] After the compound had been synthesized, the resin was washed with DCM (5 mL, 4 x 1 min), treated with 1% TFA in DCM, and agitated for 15 min. This process was repeated two more times. The filtrates were combined, treated with water (4 mL), and the solvent removed under reduced pressure. The residue was purified using the Preparative HPLC purification method written above.

[0468] SP-5: General procedure for the peptide coupling reaction:

[0469] A stirred solution of the protected peptidyl acid (1 mmol) in DMF (4.0 mL) was sequentially treated with DIPEA (400 pL, 2.2 mmol), HATU (400 mg, 1.1 mmol), and an amine (sometime as a hydrochloride, 1.1 mmol) at 0 °C. The reaction was stirred at rt for 1 h, concentrated under reduced pressure, purified using the Preparative HPLC purification method written above (a typical gradient was 20% B for the first 3 min, then from 20% to 98% B over 12 min, which was maintained for the next 5 min). The desired fractions were combined, concentrated under reduced pressure, and lyophilized.

[0470] SP-6: General procedure for the removal of the -Pbf protecting group on the last step:

[0471] The protected compound (0.05 mmol) was treated with TFA: TIPS (95:5, 5 mL). The resulting mixture was stirred at rt until the reaction was complete (typically 2 - 4 h). The mixture was concentrated under reduced pressure, purified using the Preparative HPLC purification method written above (a typical gradient was 5% B for the first 3 min and then from 5% to 35% B over 17 min) and lyophilized to give the target.

[0472] SP-7: General procedure for non-radioactive Lu labelling

[0473] -45- Foley HoagUS 13184486.1 TUV-19125

[0474] The precursor (5.4 pmol) was added to a LuCl3 (8.2 mg, 29 pmol) solution in sodium acetate buffer (0.23 M, pH 5.2, 9 mL). The pH of the solution was checked to make sure it was >5. The resulting mixture was stirred at 90 °C for 20 min and then was purified using a PLRP- o

[0475] S for Prep to Process column (25 x 300 mm, 8 pm, 300A) with UV detector (monitoring at 215 nm) eluted with a gradient of ACN in water (with 0.05% TFA). The combined fractions were lyophilized to give the non-radioactive Lu-labelled product.

[0476] Synthesis of Intermediate 4

[0477]

[0478] Molecular Weight: 499.56

[0479] N-Boc-L-prolinal (0.6 g, 3 mmol), Z-D-Ala-OH (0.67 g, 3 mmol) and 4-(isocyanomethyl)-l,2-dimethoxybenzene (0.54 g, 3 mmol) were dissolved in anhydrous DCM (40 mL) and stirred for 3.5 hours at room temperature. Trifluoroacetic acid (10 mL) was added, and the resulting mixture was stirred for 1 hour at room temperature. The mixture was then condensed in vacuo to remove all the volatiles. The oily residue was redissolved in anhydrous DCM (40 mL) and cooled down to 0° C with ice bath. Triethylamine (9 mL) was added dropwise, and resulting mixture was stirred at room temperature overnight. The mixture was again condensed in vacuo to remove all the volatiles and was then redissolved in DCM (50 mL), washed by water (3 x 10 mL), aq. NaCl (10 mL), and was then dried over NaSCU, filtered, concentrated in vacuo to give the crude intermediate product 4 [1.2 g, 80% yield; ESI / MS m / z: 500 (M+H)] which was then used in the next step without further purification.

[0480] Synthesis of Intermediate 5

[0481]

[0482] Molecular Weight: 365.43

[0483] The crude intermediate product 4 obtained above (0.4 g, 0.8 mmol) was dissolved in MeOH (20 mL). Pd(OH)2 on carbon (0.2 g) was added and the suspension was furnished with hydrogen atmosphere 3 times and was then stirred under hydrogen atmosphere for 3 hours.

[0484] -46- Foley HoagUS 13184486.1 TUV-19125

[0485] The mixture was filtered, and the liquid part was concentrated in vacuo to give the crude intermediate product 5 [0.27 g, 92% yield; ESI / MS m / z: 366 (M+H)]) which was then used in the next step without further purification.

[0486] Synthesis of Intermediate 6

[0487] FmocHN

[0488]

[0489] Molecular Weight: 881.06

[0490] The initial resin loading with 4-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)methyl)benzoic acid was performed as described in SP-1 (working on a 0.5 mmol scale). The Fmoc group was removed according to SP-3 and then coupled with 5-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)pentanoic acid according to SP-2. The Fmoc group was removed according to SP-3 and then coupled with N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-Nw-((2, 2,4,6, 7-pentamethyl-2,3-dihydrobenzofuran-5-yl)sulfonyl)-L-arginine according to SP-2. The compound was cleaved from the resin according to SP-4 to give the title compound (0.16 g, 40%). ESPMS m / z: 882 (M+H).

[0491] Synthesis of Intermediate 7

[0492] NHPbf

[0493] FmocHN

[0494]

[0495] Molecular Weight: 1228.47

[0496] The crude intermediate product 5 obtained above (80 mg, 0.21 mmol) was coupled with the compound 6 to give the coupling product which was purified by semi-preparative HPLC purification according to the General procedure for Preparative HPLC purification to give the intermediate product 7 (0.22 g, 85% yield). ESI / MS m / z: 1229 (M+H).

[0497] -47- Foley HoagUS 13184486.1 TUV-19125

[0498] Synthesis of Intermediate 8

[0499]

[0500] Molecular Weight: 1004.21

[0501] To a stirred solution of the intermediate product 7 (0.12 g, 0.1 mmol) in DCM (4 mL) was added Dess-Martin periodinane (0.17 g, 0.3 mmol), water (20 pL). The resulting mixture was stirred at room temperature overnight and more Dess-Martin periodinane (0.2 g), water (150 pL) and DMSO (1 mL) were added. The reaction mixture was again stirred at room temperature for 5 hours and was then concentrated in vacuo. 20% Piperidine in DMF (3 mL) was added to the residue. The reaction mixture was stirred at room temperature for 20 minutes and was then concentrated in vacuo, purified by semi-preparative HPLC purification according to the General procedure for Preparative HPLC purification to give the intermediate product 8 (0.05 g, 45% yield). ESI / MS m / z: 1005 (M+H).

[0502] Synthesis of Compound 7824-KA

[0503]

[0504] Molecular Weight: 1138.29

[0505] The intermediate product 8 (34 mg, 0.03 mmol) was conjugated with DOTA-NHS ester (2.0 eq.) in anhydrous DMF with 10 eq. of TEA. At the last, the Pbf protective group was removed according to SP-6 (TFA-TIPS only, no water was added) to afford a mixture of two diastereomers which were separated by preparative HPLC to give the target 7824-KA as a white powder (18.5 mg, 42% 25% yield over 2 steps). ESI / MS m / z: 1139 (M + H).

[0506] Synthesis of Compound 7824-KA-Lu was performed according to the example 6 SP-7.

[0507] ESI / MS m / z: 1311 (M+H).

[0508] -48- Foley HoagUS 13184486.1 TUV-19125

[0509]

[0510] Molecular Weight: 1310.23

[0511] INCORPORATION BY REFERENCE

[0512] All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0513] EQUIVALENTS

[0514] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0515] -49- Foley HoagUS 13184486.1

Claims

TUV-19125We claim:

1. A compound of the formula:^2bwherein:O W2O W2O X w, A -Xeach W is independently, O,0 w4Wi is halogen or cyano;each W2 is independently selected from the group consisting of -H, -C1-3 alkyl, aryl, and aralkyl;W4 is selected from the group consisting of -H, -C1-3 alkyl, aryl, and aralkyl;W3 is selected from the group consisting of cycloalkyl, aryl, aralkyl, and heteroaralkyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of -C1-6 alkyl, -Cnehaloalkyl, -C1-6 alkoxy, halogen, nitro, cyano, hydroxyl, amino, sulfoxyl, sulfonyl, sulfonamide, acyl, - C(O)2Ri3, -C(O)NRI3R14, and-N(Ri3)C(O)ORi3;or W3 is C1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, amino, formyl, cycloalkyl, aryl, aralkyl, heterocyclyl, -C(O)2Ri3, -C(O)NRi3Ri4, and -N(Ri3)C(O)ORi3;X is a chelator suitable for radiolabeling, or a chelator bound to a radioactive atom or complex;Li is a bond, or a group of the formula:-50- Foley HoagUS 13184486.1TUV-19125wherein each n is independently 0, 1, 2, 3, 4, or 5;q is 0, 1, or 2;each Z is independently =0 or =NR2C;A is -H or -COOH;whereineach R is independently -H, Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;each Ri is independently -H or -C1-3 alkyl;R2a, R2b, and R2c at each occurrence are each independently -H or -C1-3 alkyl; R3a and Rsb at each occurrence are each independently -H, -OH, or halogen; and L2 is a group of the formula:-51- Foley HoagUS 13184486.1TUV-19125wherein R4e and R4f are each independently -H or -C1-3 alkyl;R a and Rsb are each independently -H or -C1-3 alkyl;Reaand Reb are each independently -H or -C1-3 alkyl; andR?ais -H or -C1-3 alkyl;each Y is independently selected from the group consisting of:wherein each Rs is independently -H, -OH, halogen, -ORsa, -NRsbRsc, -COOH, or a 5- to 6-membered heteroaryl;each R9 is independently -H, -OH, halogen, -ORga, -NRgbR c, or -COOH;each Rio is independently -H, -OH, halogen, -ORioa, -NRiobRiOc, or -COOH; and each Rn is independently -H, -OH, halogen, -ORna, -NRiibRiic, or -COOH; wherein Rsa, Rsb, and Rscat each occurrence are each independently -H or -C1-3 alkyl; R a, R9b, and Rgcat each occurrence are each independently -H or -C1-3 alkyl;Rioa, Riob, and Rioc at each occurrence are each independently -H or -C1-3 alkyl;Riia, Riib, and Riic at each occurrence are each independently -H or -C1-3 alkyl; each R12 is independently -H, -OH, halogen, -ORga, -NRgnRgc, or -COOH;m is 1, 2, 3, or 4;rn is 1, 2, 3, or 4;is 1, 2, 3, 4, or 5;r is 1, 2, 3, 4, 5, 6, 7, or 8;ns is 1, 2, 3, or 4; andne is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;each R13 is independently -H, -C1-3 alkyl, aryl, aralkyl, or heterocyclyl; and-52- Foley HoagUS 13184486.1TUV-19125each R14 is independently -H or -Ci-6 alkyl; or R13 and R14, along with the nitrogen atom to which R13 and R14 are attached, combine to form a heterocyclyl;a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:R2b3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:-53- Foley HoagUS 13184486.1TUV-191255. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:

6. The compound according to any one of claims 1 to 5, or a pharmaceuticallyOWjacceptable salt thereof, wherein W is7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein Wi is chloro.

8. The compound according to any one of claims 1 to 5, or a pharmaceuticallyO W2WN'W3acceptable salt thereof, wherein W is O9. The compound according to any one of claims 1 to 5, or a pharmaceuticallyo w2o o w2o YV'A'W3acceptable salt thereof, wherein W is0 w4 or O10. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein W2 is -H; or W4 is -H; or W2 and W4 are -H.

11. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein W3 is aralkyl.

12. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein W3 is heteroaralkyl.-54- Foley HoagUS 13184486.1TUV-1912513. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein W3 is optionally substituted with one or more substituents selected from the group consisting of -C1-6 alkyl, -Cnehaloalkyl, -C1-6 alkoxy, halo, nitro, cyano, hydroxyl, amino, sulfoxyl, sulfonyl, sulfonamide, acyl, -C(O)2R13, -C(O)NRi3Ri4, and -N(Ri3)C(O)ORi3; further wherein each R13 is independently -H, -C1-3 alkyl, aryl, aralkyl or heterocyclyl; and each R14 is independently -H or C1-6 alkyl.

14. The compound according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein W3 is substituted with trifluoromethyl.

15. The compound according to claim 11 or 12, or a pharmaceutically acceptable salt thereof, wherein W3 is substituted with -C1-6 alkyl, -Cnehaloalkyl, -C1-6 alkoxy, halogen, nitro, cyano, hydroxyl, amino, sulfoxyl, sulfonyl, sulfonamide, acyl, -C(O)2R13, -C(O)NRI3R14, and -N(Ri3)C(O)ORi3; further wherein, each R13 is independently -H, -Cisalkyl, aryl, aralkyl, or heterocyclyl; and each R14 is independently -H or - C1-6 alkyl.

16. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt17. The compound according to claim 8 or 9, or a pharmaceutically acceptable saltthereof, wherein W3 is-55- Foley HoagUS 13184486.1TUV-1912518. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein W3 is -C1-6 alkyl or cycloalkyl.

19. The compound according to claim 8 or 9, or a pharmaceutically acceptable saltthereof, wherein W3 is20. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein W3 is -C1-6 alkyl substituted with halogen, hydroxyl, amino, formyl, cycloalkyl, aryl, aralkyl, heterocyclyl, -C(O)2R13, -C(O)NRi3Ri4, or -N(Ri3)C(O)ORi3; further wherein, each R13 is independently -H, -C1-3 alkyl, aryl, aralkyl, or heterocyclyl; and R14 is independently -H or C1-6 alkyl.

21. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt thereof, wherein W3 is substituted with -C(O)NRi3Ri4; further wherein R13 and R14, along with the nitrogen atom to which R13 and R14 are attached, combine to form a heterocyclyl.

22. The compound according to claim 8 or 9, or a pharmaceutically acceptable salt-56- Foley HoagUS 13184486.1TUV-1912523. The compound according to any one of claims 1 to 5, or a pharmaceuticallyO W2Oacceptable salt thereof, wherein W isW4024. The compound of claim 23, wherein ne is 1, 2, or 3.

25. The compound of claim 23 or 24, wherein R14 is -H or -Ci-6 alkyl.

26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:w2x^2bor a pharmaceutically acceptable salt thereof;wherein each R is independently -H, -Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;each W2 is independently H or (Ci-Ce)alkyl; andY 1 is aryl or heteroaryl.-57- Foley HoagUS 13184486.1TUV-1912527. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:or a pharmaceutically acceptable salt thereof.wherein each R is independently -H, -Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;each W2 is independently -H or -Ci-Cealkyl; andY 1 is aryl or heteroaryl.

28. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:or a pharmaceutically acceptable salt thereof.wherein each R is independently -H, -Ci-6 alkyl, or hydroxyl(Ci-C6)alkyl-;each W2 is independently -H or Ci-Cealkyl.

29. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, of the formula:-58- Foley HoagUS 13184486.1TUV-19125or a pharmaceutically acceptable salt thereof.wherein each R is independently -H, Ci-Cealkyl, or hydroxyl(Ci-C6)alkyl-;each W2 is independently -H or Ci-Cealkyl.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein each R is -CH3.

31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Li is selected from the group consisting of: a bond, or a group of the formula:wherein A is -H or -COOH.

32. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein Li is selected from the group consisting of: a bond, or a group of the formula:-59- Foley HoagUS 13184486.1TUV-1912533. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R?; Iis -OH.

34. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R?; Iis -F.

35. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R?; Iis -H.

36. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R?b is -OH.

37. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R?b is -F.

38. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R?b is -H.

39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein E is selected from the group consisting of:H H N NH N N H-60- Foley HoagUS 13184486.1TUV-19125, and40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein L21S selected from the group consisting of:

41. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein-61- Foley HoagUS 13184486.1TUV-19125N'NHRs is -H, -F, -OCH3, -COOH, orR9is -H, -OCH3, or -N(CH3)2; andRio is -H, -Cl, -OH, or -N(CH3)2.

42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein Y is selected from the group consisting of:

43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein X is a chelator suitable for radiolabeling selected from the group consisting of:m is 0, 1, or 2;R4ais independently -H, -COOH, or -CONH2;R4bis independently -H, -COOH, or -CONH2; andR4cis independently -H, -COOH, or -CONH2.

44. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein X is a chelator suitable for radiolabeling selected from the group consisting of:-62- Foley HoagUS 13184486.1TUV-19125o45. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein X is a chelator suitable for radiolabeling of the formula:o46. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein X is a chelator suitable for radiolabeling of the formula:-63- Foley HoagUS 13184486.1TUV-1912547. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein X is a chelator suitable for radiolabeling of the formula: o48. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein X is a chelator bound to a radioactive atom selected from the group consisting of:wherein M is the radioactive atom,m is 0, 1, or 2;R4ais independently -H, -COOH, or -CONH2;R4bis independently -H, -COOH, or -CONH2;R4cis independently -H, -COOH, or -CONH2; andR4dis independently -H, -COOH, or -CONH2.-64- Foley HoagUS 13184486.1TUV-1912549. The compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein X is a chelator bound to a radioactive atom and the radioactive atom is selected from the group consisting of:223Ra,94mTc,99mTc,186Re,188Re,2°3pb, 212pb, 67Ga, 68Ga, 47^ lllj^ 97Ru, 62^ 64^ 86y, 88y, 89^, 90y, 121^ 161^ 153Sm,166HO,105Rh,177LU,123I,1241,125I,1311,18F,211At,225Ac,89Sr,117mSn,169Er, and [18F]A1F.

50. The compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein X is a chelator bound to a radioactive atom and the radioactive atom is selected from the group consisting of:225Ac,211At,64Cu,67Cu,18F, [18F]A1F,67Ga,68Ga,111In,177Lu,203Pb,212Pb,161Tb,86Y,90Y, and89Zr.

51. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is177Lu.

52. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is212Pb.

53. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is [18F]A1F.

54. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is225Ac.

55. The compound according to claim 49, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is161Tb.

56. The compound according to claim 48, or a pharmaceutically acceptable salt thereof, wherein X is a chelator bound to a radioactive atom selected from the group consisting of:-65- Foley HoagUS 13184486.1TUV-1912557. The compound according to claim 48, or a pharmaceutically acceptable salt thereof, wherein X is a chelator bound to a radioactive atom selected from the group consisting of:

58. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein X is a chelator bound to a radioactive atom selected from the group consisting of:

59. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:-66- Foley HoagUS 13184486.1TUV-19125-67- Foley HoagUS 13184486.1TUV-19125, and-68- Foley HoagUS 13184486.1TUV-19125; or a pharmaceutically acceptable salt thereof.

60. The compound according to any one of claims 1 to 47 or 59, or a pharmaceutically acceptable salt thereof, wherein X is a chelator bound to a radioactive atom and the radioactive atom is selected from the group consisting of:225Ac,211At,64Cu,67Cu,18F,[18F]A1F,67Ga,68Ga,111In,177Lu,203Pb,212Pb,161Tb,86Y,90Y, and89Zr.

61. The compound according to claim 60, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is212Pb.

62. The compound according to claim 60, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is177Lu.

63. The compound according to claim 60, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is [18F]A1F.

64. The compound according to claim 60, or a pharmaceutically acceptable salt thereof, wherein the radioactive atom is225Ac.

65. A pharmaceutical composition comprising a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, diluent or excipient.

66. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claim 1 to 64, or a pharmaceutically acceptable salt thereof.-69- Foley HoagUS 13184486.1TUV-1912567. The method of claim 66, wherein the cancer is characterized by the expression of Fibroblast Activation Protein (FAP) on a tumor, fibroblast, or pericyte within the subject.

68. A method of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, nonsmall cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer, bone cancer, adenocarcinoma, non-melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’ s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

69. A method of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claim 1 to 64, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

70. A method of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, nonsmall cell lung cancer, small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma,-70- Foley HoagUS 13184486.1TUV-19125cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, or fallopian tube carcinoma.

71. A method of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

72. A method for diagnosing cancer in a subject, comprising:administering to the subject a diagnostically effective amount of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, that binds to Fibroblast Activation Protein, wherein the Fibroblast Activation Protein is expressed on a tumor, fibroblast, or pericyte associated with the cancer;detecting the binding of the compound to the Fibroblast Activation Protein; and correlating the presence of bound compound to the expression of Fibroblast Activation Protein, thereby diagnosing the cancer in the subject.

73. The method according to any one of claims 66 to 72, wherein the subject is also administered in simultaneous, separate, or sequential combination an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salts thereof.

74. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to claim 65.

75. The method of claim 74, wherein the cancer is characterized by the expression of Fibroblast Activation Protein (FAP) on a tumor, fibroblast, or pericyte within the subject.-71- Foley HoagUS 13184486.1TUV-1912576. A method of treating cancer in a subject in need thereof, the method comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition according to claim 65, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer, bone cancer, adenocarcinoma, non-melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

77. A method of treating a subject for cancer, comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition according to claim 65, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

78. A method of treating a subject for cancer, comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition according to claim 61, wherein the cancer is selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma, cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

79. A method of treating a subject for cancer, comprising administering to a subject in need thereof, an effective amount of a pharmaceutical composition according to claim 65, wherein the cancer is selected from the group consisting of breast cancer, lung cancer,-72- Foley HoagUS 13184486.1TUV-19125pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

80. A method for diagnosing cancer in a subject, comprising:administering to the subject a diagnostically effective amount of a pharmaceutical composition according to claim 65 that selectively binds to Fibroblast Activation Protein, wherein the Fibroblast Activation Protein is expressed on a tumor, fibroblast, or pericyte associated with the cancer;detecting the binding of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, to the Fibroblast Activation Protein; and correlating the presence of bound compound or salt to the expression of Fibroblast Activation Protein, thereby diagnosing the cancer in the subject.

81. The method according to any one of claims 74-80, wherein the subject is also administered in simultaneous, separate, or sequential combination with an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or a pharmaceutically acceptable salts thereof.

82. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 64, for use in therapy.

83. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 64, for use in the treatment of cancer.

84. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 83 wherein the cancer is selected from the group consisting of is breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer, bone cancer, adenocarcinoma, non-melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell-73- FoleyHoagUS 13184486.1TUV-19125carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

85. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 83 wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

86. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 83 wherein the cancer is selected from the group consisting of selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma, cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, or fallopian tube carcinoma.

87. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 83 wherein the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

88. A compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 64 for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof in the treatment of cancer.

89. A pharmaceutical composition according to claim 65 for use in therapy.-74- Foley HoagUS 13184486.1TUV-1912590. A pharmaceutical composition according to claim 65 for use in the treatment of cancer.

91. The pharmaceutical composition for use according to claim 90, wherein the cancer is selected from the group consisting of is breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, prostate cancer, ovarian cancer, melanoma, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, renal cell carcinoma, glioblastoma, thyroid carcinoma, sarcoma, endometrial cancer, cervical cancer, testicular cancer, mesothelioma, neuroendocrine cancer, bone cancer, adenocarcinoma, non-melanoma skin cancer, leukemia, lymphoma, multiple myeloma, adrenal cancer, cholangiocarcinoma, squamous cell carcinoma, diffuse large B cell lymphoma, squamous cell carcinoma, basal cell carcinoma, transitional cell carcinoma, salivary gland tumors, thymoma, pituitary adenoma, Merkel cell carcinoma, peritoneal carcinoma, nasopharyngeal carcinoma, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’ s lymphoma, uveal melanoma, cutaneous melanoma, mucosal melanoma, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

92. The pharmaceutical composition for use according to claim 90, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.

93. The pharmaceutical composition for use according to claim 90, wherein the cancer is selected from the group consisting of selected from the group consisting of breast cancer, colorectal cancer, pancreatic cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, liver cancer, gastric cancer, esophageal cancer, head and neck cancer, bladder cancer, thyroid carcinoma, sarcoma, cervical cancer, bone cancer, cholangiocarcinoma, salivary gland, gastrointestinal stromal cancer, vulvar cancer, and fallopian tube carcinoma.

94. The pharmaceutical composition for use according to claim 90, wherein the cancer is selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.-75- Foley HoagUS 13184486.1TUV-1912595. A pharmaceutical composition according to claim 65 for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4 / CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a mitotic inhibitor, a poly-ADP ribose polymerase (PARP) inhibitor, a SHP2 inhibitor, an antimetabolite, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof in the treatment of cancer.-76- Foley HoagUS 13184486.1

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